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BO O K O F ORGANIC CHEMISTRY

THE MACM ILLAN CO MPANY

NEW YORK BO STO N 0 CHICAG O DALLAS

ATLANTA SAN F RANCISCO

MACM ILLAN 8: CC . ,Lmrrm)

LO NDO N BO MBAY CALCU’

I’

I‘

A

MELBO URNE

THE MACMILLAN CO . OF CANADA,

TORONTO

A TEXT-BO O K

O RGANIC CHEMISTRY

FOR STUDENTS OF MEDICINE AND BIOLOGY

E 1 W'

McC O LLUM , PH .D .

PROFE SSOR O F BIOC HEM ISTRY, SCHOOL O F HYG IENE , J OHNS HOPK INSMEDICAL SCHOOL ; FORMERLY PROFE SSOR O F AG RICULTURAL

CHE MISTRY . UNIVE RSITY O F WI SCONSIN

Namgoth

THE MACMILLAN COMPANY

1 9 1 7

All righta roam ed

Co rm xen'r, 1 91 6,

Br THE MACM ILLAN COMPANY.

Set up ande lectrotyped. PublishedOctober, ReprintedJ uly, October, 1 9 1 7.

Nortnoou 1 5mmJ . S. Cushing Co .

— Berwick Smith Co .

Norwood, M a ss. , U.S .A.

PREF ACE

IN preparing thi s text-book the aim ha s been to re

strict its contents to a degree which should make itsuitable for a course continuing through

‘a ha l f o f anacademic year . The book embodies the substance ofthe discussion of orga nic chemistry presented with theauthor’s course in the chemistry of nutrition duringthe la st eight years, and empha sizes the biologicalrather than the synthetic a nd technica l viewpoint . Itis hoped , therefore , that it should serve a s a sa ti sfactorytext for students of medicine and others who can givebut a semester to this subject, a nd whose interest is insome field of biology .

The text-books ordina ri ly placed in the hands of students contain more matter than ca n be assim ilated inan academic year, and make necessary some omi ssions .They reflect the special interests o f thei r writers i nex tending the subject matter rela ting to methods o f

synthesis, with an undesira ble multipl i ca tion o f indi

v idual compounds described, o r in restricting these andextending the description o f technical proces ses . Ithas not infrequently been the case that in text-booksdesigned for medical students the other extreme h a s

been reached , a nd wholly inadequate evidence ha s

been ofiered in support of the structura l formul a s presented . The book then consists o f a description o f

vi Prefa ce

the biological ly important compounds, burdened withformidable formulas in which the student sees no

mea ning.

It is the bel ief o f the author that, i f properly presented, the theory of organic chemistry never fai ls toarouse the interest of a bright-minded student . To beappreciated by the beginner i t must be shorn a s far

a s possible of detai l s which burden the memory. Theaim ha s been to present a complete l ine of reasoning,based upon the properties o f the substances considered ,i n support of the va l idity o f every formula employed .

This end ha s been attained except in the case of theterpenes a nd a few alkaloids . In al l cases the effort

h a s been made to select fo r purposes of i l lustrationthose compounds which have biological importancerather than technical . The course here offered wil l ,i t is hoped , serve to fit the student for intel l igent workin physiological chemistry by giving him an a pprecia

tion of the spi rit of organic chemistry a nd an understanding o f the relationships a nd transformations which

go on in the plant and animal world .

Since the book is not intended to serve a s a guideto manipulation the usual introductory chapter on

methods o f laboratory work is omitted . Such infor

mation is now readily available in a number of laboratory manual s .

E. V. MCCO LLUM.

TABLE O F CONTENTS

/CHAPTER 1

THE SArUnA'rEn F Ar'

rr Hrnno cu mo x s ( 1 -1 1 )Metha ne, 1 . Deriva tives of meth a ne , 3 . Structure

o f methane , 6 . Chlo r deriva tives, 7 . Methy l iodide,1 0. E th a ne , 1 0. Nomencl a ture o f the hydroca rbons,1 4. Petro leum,

1 5. Isomerism of the hydroca rbons, 1 7.

AHAPTER II

THE ALco no ns ( 1 2—27)Nomenc l a ture of the a lcoho ls, 23. E thy l a lcoho l , 24.

Alcoh ola tes, 26 . A lcoho lic bevera ges,27. Homo logues

(if ethy l a lcoho l , 28 . T’ropy l , buty l , a nd amy l a lcohols,

28 . Isomerism o f the amy l a lcoho ls, 3 1 . Higher a lcoho ls, 36 . Dia tomic a lcoh o ls, 37. Tria tomic a lcoho ls, 39.

Tetra tomic a lcohols, 42 . Merca pta ns, 42.

‘/CHAPTER III

ETHE RS AND Esrsns (28—29)E thy l sulphuric a cid, 44 . Esters o f sulphurous a c id ,

46 . Ethers of sulphurous a c id,47. E thy l nitra te a nd

ethy l n itrite, 48. Amy l ni trite, 48 . Structure o f the

ethers, 5 1 . Methy l a ndethy l ether, 50. Mix ed ethers, 52.

CHAPTER IV

ALDEHrDEs AND KE TONE S (30—39)Constitution of a ldehydes a nd a cids, ‘56 .

o f the a ldehydes, 57. Fo rma ldehyde, 6 3 .

VII

44-55

56-76

Tab le of Contents

hyde,65 . Chlora l , 66 . Glyco l a ldehyde, 67. Glycer

a ldehyde, 68. Ketones,68 . Methods of forma tion a nd

structure, 69 . Properties, 70. Acetone, 73 . Dihydrox ya cetone, 75.

CHAPTER V

THE NITRILE S AND THE IR REDUCTION PRODUCTS . THE

AM INE S (40—49)Structure o f the ni tri les a nd isonitri les a s shown by

their mo des o f fo rma tion and chemica l beha vior,77.

Cya namide, 83 . Prima ry , seconda ry , a nd tertia ryamines

,84 . Methods o f prepa ra tion o f amines, 86 .

Isomerism o f the amines,89. Methy l amine , 90.

E thy l amine,9 1 . Cho l ine

,92 . Physio logica l proper

ties of the amines,94 .

CHAPTER VITHE FATTY Ac s (50—77)

Formic a cid , 96 . Acetic a cid , 99. Acid ch lorides,1 03 . Acid amides, 1 04. Ch lor a cetic a cids, 1 07. Hydro x y a cids, 1 08 . Amino a cids, 1 09 . Urea

, 1 1 1 . Thiourea , 1 1 5 . Esters of ca rbamic a cids, 1 1 6 . Uretha nes

,

1 1 7. Gua nidine,1 1 7. Arginine

,1 1 8 . G lyco co l l , 1 20.

Crea tine and crea tinine, 1 23 . Sa rcosine, 1 24 . Beta ines,

1 25 . Acid a nhydrides,1 26. Propion ic a cid

,a nd its

deriva tives, l a ctic a nd pyruvic a cids, cystine a nd a la

n ine, 1 27. Stereochemistry of the l a ctic a cids, 1 31 .

Butyric a cids, 1 40. Va leria n ic a c id a nd va l ine , 1 42 .

The ca pro ic a cids a nd their deriva tives, lysine, leucine,and iso leucine

,1 46 . The h igher fa tty a cids, 1 49.

CHAPTER VIITHE OLE FINE S AND ACETYLENE S (78-88)

Methy lene, 1 53 . Ethy lene, 1 54 . Propy lene, 1 59 .

Propy l idene, 1 60. D iolefines, 1 6 1 . Acety lene, 1 62.

Substitution products of the unsa tura ted hydroca rbons,

PAGES

77 95

96—1 52

1 53-1 74

Ta b le of Contents

1 67. A l ly l a lcoho l , 1 67. Acro lein, 1 68 . Acids of the

o leic a cid series, a cry l ic, a nd cro tonic , 1 69. O leic a cid ,1 72. Acids w ith two a nd three doub le bonds, 1 73.

CHAPTER VIII

THE FATS AND WAx E S AND RE LATED COMPOUNDS (89-99)The anima l fa ts, 1 75. The vegeta b le fa ts, 1 76 . So a ps

,

1 79. The c lea nsing a ction o f so a ps, 1 8 1 . Methods of

cha ra cteriza tion of the fa ts, 1 83 . Wa x es, 1 90. Lecithins and phosph a tides

,1 93 . Neurine, 1 95 . Cerebro

sides, 1 97. Stero ls, 1 97.

CHAPTER IXTHE D IBASIC AC IDS ( 1 00-1 08)

Ox a l ic a cid,1 99 . M a lonic a cid

,202 . Succinic a cid,

205 . Aspa rtic a cid a nd a spa ra gine,206 . G luta ric a c id

a nd its deriva tives,g lutamic a cid a nd g l utamine, 207.

Adip ic , pime lic, a nd suberic a c ids, 208 .

CHAPTER X

CYCLO PARAFFINS AND PYRROLE DE RIVAT IVE S ( 1 09-1 20)Trimethy lene, tetramethy lene, pentamethy lene, hex a

methy lene, a nd heptamethy lene, 2 1 0. Anhydrides of

the diba sic a x ids,21 5 . Succinimide a nd gluta rimide,

21 6 . Pyrro le a nd pyrro l id ine, 2 1 6 . Pro l ine, 223. O x y

pro l ine, 224 . Pyrro l idone ca rbo x y l ic a cid , 224.

CHAPTER XIHa o x r AND KE TONE AC IDS ( 1 21 -1 32)

Ta rtronic, ma l ic , a nd ta rta ric a c ids , 225 . Ox ybutyrica cid , 235 . 7

—hydrox y a cids,236 . y

-amino a c ids, 237.

Aceto a cetic a cid , 237. Meso x a l ic a c id,242 . Levul in ic

a cid , 243 . O x a la cetic a c id , 243. Acetone dica rbo x y l ica cid , 244 . C itric a c id , 245.

PAGES

1 75—1 98

1 99—209

2 1 0—224

225—246

x Ta b le of Contents

CHAPTER XIIMALE IC AND FUMAR IC AC IDS AND THE IR ISOMER ISM ( 1 33)

The isomerism due to the doub le bond , 247. Tra nsfo rma tion oi the ma lenoid into the fuma ro id fo rm a nd

the reverse tra nsfo rma tion ,25 1 . The bio logica l proper

ties oi the cis a nd tra ns isomers, 252.

CHAPTER XIIITHE URE IDE S ( 1 34-1 40) 253—263

Acety l urea , 253. Dia cety l urea,253 . G lyco luric

a cid , 254 . Hyd a nto in ,255 . A l l a nto in, 256 . Histidine

a nd urocanic a cid , 257 . Pyra zo le, 259. Ox a luric a nd

pa ra ba nic a cids, 259 . A l lox a n,262 .

CHAPTER XIVTHE PYR IM IDINE S , PYBAZ INES, AND PURINE S ( 1 41 —1 49) 264—282

Pyrimidines,264 . Thymine

,265 . Cytosine, 265 .

Ura ci l , 266 . Pyra zines, 266 . Pipera zine,269 . Dik eto

pipera zines, 270. The purines, 270. Uric a cid , 271 .

Purine,275. Hypo x a nthine a nd x a nthine, 277. Ade

nine a nd gua nine, 278 . Th e nuc leic a cids, 280. Methy lpurines — theobromine a nd ca ffeine, 28 1 .

CHAPTER XVTHE CARBOHYDRATE S ( 1 50-1 63) 283—337

Composi tion, 283 . Determina tion of structure,285.

Synthesis of ca rbohydra tes,288 . Determina tion o f con

figura tion ,297. Pentoses, 301 . Methy l pento ses, 308 .

Structure of the hex oses,303. Keto ses, 307. Specia l

properties of the hex oses,3 1 1 . Action of a lk a l ies on

g lucose, 3 1 4 . Disa ccha rides,3 1 8. Impo rta nce of stereo

chemistry in rela tion to the bio logica l va l ues o f the

suga rs, 321 . Rafiinose, 323. ,G lucosides, 323 . Polysa c

cha rides, 329. Chitin a ndg lucosamine, 334. Inul in, 336.

Ta ble Of Contents

CHAPTER XVIPAGES

THE CHEM ICAL CHANGE S INVOLVED IN THE FE RMENTAT IONo r THE SUGARS ( 1 64— 1 65) 338—346

A lcoholic fermenta tion,338 . La ctic a cid fermenta

tion, 342. Butyric a cid fermenta tion, 342 . The re lation o f the intermedia ry products Of fermenta tion to thefo rma tion of fa ts in the a nima l body, 343 .

CHAPTER XVIIBENZENE AND ITS DER IVAT IVE S ( 1 66-2 1 4) 347—383

Structure of benzene, 347. Determina tion of the

position o f substituting gro ups, 350. Physio logica lproperties of benzene

,353 . Homo logues, 353 . To lu

ene, 353. Structure o f the ch lor deriva tives of to l uene,355. The x y lenes

, 356 . Mesi ty lene,356 . Ha logen de

riva tives of benzene, 358 . Nitrobenzene, 359. Ani l ine,359 . Aceta ni l ide, 36 1 . A lk y l a ni l ines, 36 1 . Dipheny lamine, 36 1 . Dia zo benzene, 362. Benzene sulph onica cid , 364 . Pheno l , 365 . Pheno l sulphuric a cid , 366 .

Pheno l sulphonic a cid, 366 . Pheno l ethers, 367. Cre

80 1 8 , 367 . Picric a cid , 368 . Tyrosine, 368 . Tyramine,370. Dihydrox y benzenes, 371 . Guia col a nd vera tro l ,37 1 . Quinone , 372 . Trihydro x y benzenes

,373 . Inc

site, 373 . Thymo l a nd ca rva cro l , 374 . Pro toc a techu ic

a cid , 374 . Vera tric a cid, va ni l l in , a nd con ifery l a lcoho l ,374 . Homogentisic a cid

,375 . Adren in , 376 . Benzo ic

a cid , 377 . Sa ccha rin, 378 . Hippuric a c id , 378. Benzy la lcoh o l , 379. Benza ldehyde, 379. Pheny l a cetic a c idand pheny l a l a n ine, 380. Cinnamic a cid , 38 1 . Sa l icy l ica ldehyde a nd sa l icy l ic a c id , 38 1 . Asp irin, 38 1 . Sa lo l ,382. Ga llic and ta nnic a cids

,382 . Ta nnins, 382.

CHAPTER XVIIICONDEN SED BENZENE R ING S (2 1 5—21 6)

Na phtha lene, 384 . Anthra cene, 385 .

Ta ble of Contents

CHAPTER XIX

THE DYE S (2 1 7—2 1 9)Alizerin, 387. Tripheny l meth a ne dyes, 388. The

a zo dyes, 390.

0

CHAPTER XXHETEROCYCL IC COMPOUNDS (220—227) 391 399

Pyridine,39 1 . Pico l ines, 393 . Nico tinic a cid , 393 .

Quino l inic a cid , 394 . Quino l ine , 394 . Indo le a nd its

deriva tives,indo le

,sca to le , indo x yl, a nd indigo , 395.

Tryptoph a ne, 398. Tra nsfo rma tion products of tryptopha ne, 399.

CHAPTER XXITHE TERPENE S (228-229) 400-405

Addition products of the terpenes w i th nitrosy l chloride a nd o zone, 400. C itronel lo l , gera n io l , l ina lool , a ndmyrcene, 402 . Cymene, menthene, a ndmentha ne

,403.

Pinene, borneo l , a ndcampho r, 403. The cho lestero ls, 404.

CHAPTER XXIITHE ALKALOIDS (230-239) 406—4 1 0

Piperine,406 . Coniine

,406 . Nico tine, 407. Hygrine,

408 . A tropine a nd hyoscyamine, 408. Co ca ine , 409.

Cinchon ine, 4 1 0. Strychn ine, 4 1 0. Mo rph ine, 4 1 0. Pa

pa verine, 4 1 0. Na rcotine, na rceine, a nd l a uda nosine, 4 1 0.

CHAPTER XXIIIORGANIC ARSENIC COMPOUNDS (240—242) 4 1 1 -4 1 3

Ca cody l ic a cid a nd ca cody l o x ide , 4 1 1 . Arrhena l , 4 1 2.

Ato x y l , 4 1 2. Sa lva rsa n ,4 1 3. Arsenobenzene, 4 1 4 .

Ta ble of Contents x i i i

CHAPTER XXIVPROTE INS (243)The physica l properties O f the pro te ins, 4 1 4 . Na ture

of the “peptide ” union ,4 1 5 . Di tri tetra etc. ,

peptides,'

4 1 5 . Yields of individua l amino a cids byva rious pro teins, 4 1 6 . The conjuga ted pro te ins, 4 1 6 .

ORGANIC CHEMISTRY FOR STUDENTS

OF MEDICINE

THE FATTY COMPOUNDS

CHAPTER I

THE SATURATED HYDRO CARBO NS

1 . The simplest of the compounds composed of carbon

and hydrogen is metha ne, CH4 . The compounds con

taining only these two elements are called hydrocarbons .

It occurs widely distributed in nature , in the ga ses evolved

from volcanoes , and in those which escape from coal

mines , where it is called fire da mp , and as the principal

constituent o f na tura l ga s. Coal gas contains consider

able amounts of this compo und (30— 40 since it results

from the destructive distillation Of many kinds o f o r

ganie matter . Methane also results from the degradation

of vegetable matter, especially cellulose , by certain kinds

o f micro Orga nisms. In this way it is produced by the

fermentation Of vegeta ble tissues under water in marshes ,and derived its older name O f ma rsh ga s in this way . It

is an ever present constituent Of the gases in the intestines

and is normally found in small amounts in the respired

air, some of the methane produced by fermentation in

the intestines being absorbed into the circulation and

eliminated through the lungs.

B 1

2 Orga nic Chemistry for Students of Medicine

Preparation

(a )When a mixture of carbon monoxide and hydrogenis passed through a tube containing reduced nickel

,heated

to 200°

C . , there is produced methane and water

CO + 3 H2= CIL+ H20

(b) At somewhat higher temperatures (230°—300

° C .)carbon dioxide is likewise reduced by hydrogen in the

presence of finely divided nickel , the latter undergoing

no changeC02 + 4 H2 CH, 2 1 1 20

(e) Hydrogen sulphide and carbon disulphide , when

passed through a tube containing heated copper, react to

form copper sulphide and methane :

Other methods will be described for the formation of

methane from certain of its deriva tives later .

Properties : Methane is a colorless and odorless gas .

Its specific gravity is air being taken as 1 . Whensubjected to a pressure O f 1 40 atmospheres it liquefies at

0° C . Its boiling point is — 1 62

° C . and it'

solidifies at— 1 86

° C . The electric sparks from an induction coil de

compose methane into carbon,which is deposited as a

black soot, and hydrogen gas . The strongest oxidiz ing

agents , such as nitric and chromic acids, scarcely attack

it, and concentrated sulphuric acid and alkalies have no

action upon it . It is therefore one of the most stable

and inert O f chemical compounds . On being led through

a red-hot tube it is split up in part into its elements,

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4 Organ ic Chemistry for Students of Medicine

Water in contact with pipes in which the expansion is

allowed to take place is frozen .

Methyl chloride is a.

good solvent for the etherea l oils

and is employed for extracting the Odors from flowers .

Its extraordinary volatility makes it possible to separate

the solvent from the extracted odorous substances, which

are themselves very volatile .

Methyl chloride may also be called chlormetha ne.

Either of these names gives an idea o f the nature of the

substance and from what mother substance it is derived .

The chlorine atom in methyl chloride behaves very dif

ferently from that in the ha lides of the metals . The latter

give with silver nitrate a precipitate of silver halide .

Methyl chloride gives a precipitate Of silver chloride only

very slowly when left long in conta ct with silver nitrate in

solution .

This difference in behavior is due to the fact that in

solutions of the metallic halides the chlorine is dissocia ted

from the metal to a considerable extent as chlorine ion :

Na Cl2 Na+ C l

“

In the dissociated condition the chlorine ion carries a

charge of negative electricity,and when a current of elec

tricity is passed through a solution of sodium chloride the

Na+ ion migratesto the negative pole and the C 1

“ion to the

positive pole , thus transporting the charges which they

carry . They are therefore conductors of electricity.

Methyl chloride is not appreciably ionized when in solu

tion , and does not therefore conduct the electric current .

Its low rate of reactivity with AgNO B is also the result of

The F a tty Compounds 5

its nearly undissociated condition . In general molecules

do not react with each other, but chemical change is usually

the result of the property of compounds which causes them

to dissociate into simpler parts which are in a much more

active state chemically than the molecule from which they

were formed . Since 'methyl chloride does react very slowly

with AgN03 it is believed by many chemists to be in a

very slight degree dissociated .

A compound such as CIL, in which all the valences of

each of the a toms it contains are saturated , should theo

retica lly show no tendency to react with other chemical

substances . The reason why, e.g. , chlorine does react

with methane is best explained by the theory elaborated

by Nef, which postulates a very slight dissociation of

methane into methylene and hydrogen :

HCH4 2 CH2 + |

H

These components are In dynamic equilibrium with each

other . This means that any agent which removes one of

the dissociation products w ill induce the further dissociar

tion of a part O f the CH, molecules to maintain certain

relationships with respect to the three components Of the

system . Only the dissociation products are active chemi

cally so that the speed of reaction will be determined by

the degree of dissociation of the methane . This is greater

at higher temperatures than at lower,so that reactions of

this sort are greatly accelerated by heat . According to

this theory the reaction of methane with chlorine takes

place in thefollowing way

6 O rganic Chemistry for Students of Medicine

H ’ H CI H HCH4 2 CH2 + I ;

H H C 1 C 1 C1M ethylene

H C 1

CH2 l CHaCl ; CHz I CH2C 1 2C l C l

M ethyl M ethylenech loride ch loride

(chlormetha ne) (dichlo rmeth a ne)

Simultaneously some of the active methylene groups should

theoretically react with each other forming molecules with

two carbon atoms, etc . This theory is in accord with

the Observed facts , viz . that the reaction of methane with

chlorine does not lead to the formation of a single prod

uct, but O f several products simultaneously . In repre

senting the reactions between organic compounds among

themselves and with inorganic substances, the equation

written represents the principal reaction only . Further

evidence in support of this belief will be presented later.

3 . The Geometrical Structure of Methane . The ex

perience of many chemists has shown

that the relationship which exists be

tween the very numerous organic com

pounds can be expressed in a very useful

way by assuming that the atoms which

make up the molecules occupy definite

relations to each other in space . The

carbon atom is conceived to have its

four affinities directed toward the angles

of a regular four-sided figure (tetrahedron), the C atom it

self occupying the center (Fig .

F IG . 1


M ethane is expressed by the spatial formula shown in

F igure 2, the hydrogen atoms forming a system of satellites

F IG . 2 F IG . 3

about the C atom which may be likened to the sun and the

planets Of the solar system . Chlormethane o r methyl

chloride is represented by the structure in Figure 3 .

This formula is, however, so cumbersome to write that

in ordinary practice it is not employed . Figure 4 shows

the various types of simplified figures employed to describe

the carbon atom and its many derivatives produced by the


substitution of its hydrogen atoms by other elements or

complexes .

Of these symbols CH4 is employed in all ordinary cases

in writing formulae . It is known as the emfirica lformula ,the geometrical arrangement being employed only for

special demonstration . The student should accustom

himself to visualize the spatial formulae .

Now in Figure 2 each of the four hydrogen atoms occu

pies the same relative position with respect to the C atom

and it should make no difference whether, in making

Chlormethane, we substitute one hydrogen atom , or a n

other, by the chlorine . The methyl chloride should have

the same configura tion in each case, which is equivalent to

saying that only one methyl chloride is possible . This

is in accord with experience . NO matter how methyl

chloride be prepared , and there are several methods

for its preparation , the product always has the same

specific gravity, boiling point, and other physical

properties .

In assigning four valences to carbon , it should be borne

in mind that there is one very common compound , carbon

monoxide , CO , in which carbon must exist in the divalent

state, or with two of its valences polarized or latent . In a

number of its compounds carbon shows a marked tendency

to pass from the tetravalent into the divalent state,or

vice versa . This is seen in the relation between carbon

dioxide and carbon monoxide (also called carbonic oxide).

At ordinary temperatures C02 is a stable gas, but under

the influence O f the silent electrical discharge it tends to

change into C0 0 . Carbon monoxide on the other

The Fa tty Compounds 9

hand can readily add on certain elements,chlorine

,

pass back into the tetravalent state .

C0 O CO.C0 C 1 2 CO C 1 2

C a rbo nylch lo ride

The latter reaction takes place very slowly in the dark,

but is greatly accelerated by sunlight . Most organic

substances exhibit this tendency to pass in some degree into

labile active forms .

4 . If in a mixture Of methane and chlorine the latter is

present in excess two , three , or four hydrogen atoms are

substituted by chlorine . These are called dichlor, trichlor,and tetra chlor methane , respectivel Since the group

l:GH2 IS termed methylene d1 ch orfiieth a ne 1 8 sometimes

called methylene chloride. Trichlormethane is chloroform,

”C

a familiar substance employed as an anesthetic . Tetra

chlormethane is familiarly known as ca rbon tetra chloride.

It is much employed as a solvent for fats and Oils , and is

used in the dry cleaning of clothes . Its action is to dis

solve the grease from spots and when the latter is removed

from the fabric the dirt which adhered to the grease

readily separates . Both chloroform and carbon tetra

chloride are non-inflamma ble .

There are bromine and iodine substitution products of

methane , entirely analogous to the chlorine compounds .

Some of these are Of great interest and value in synthetic

work . While chlorine reacts with methane at ordina rytemperatures, forming substitution products and hydro

chloric acid , bromine must be heated in a sealed tube before

CCJ

1 0 Organic Chemistry for Students Of Medicine

any reaction will take place, and iodine will not react with

methane,even under pressure and at high temperatures,

to form substitution products .

5 . Methyl Iodide . For the preparation of the iodine

derivatives advantage is taken of the greater affinity of

the mono and divalent metals for chlorine than has the

methyl radical , thus

CH3C 1 KI CHsl KClMethylIodide

Methyl iodide is a heavy liquid with a pleasant ethereal

odor, boiling at 43°

C . Its specific gravity is It is so

unstable that on keeping it decomposes, setting free iodine .

6 . Etha ne , C sCH3\ZIIIC methylCH3/

Zn 1 s a derivative of methane

which is formed when methyl iodide is warmed with a

mixture of z inc and copper in a powdered form . The

reaction may be represented as follows :

CH3 1 ZII CH3— Zn— ‘ I

2 CH, — zn— I a 2CH3>

Zinc methyl is a colorless liquid boiling at 46° C . , which

is so unstable that it explodes when exposed to the oxygen

of the air . It is therefore a highly reactive substance and

can be used to build up synthetically other hydrocarbons

from methane . Zinc methyl reacts readily with methyliodide to form etha ne

CH. CHACH3 01 1 3 1

ZIIIz 2 Cé-

{ia neCI—

L

1 2 Organ ic Chemistry for Students of Medicine

i s assumed to be that shown in Figure 5 (a ) and (b), but

for simplicity the formulae (d), or (e) are employed .

’

Ethane may be regarded as methyl methane and is

occasionally spoken o f as dimethyl . It is a colorless and

odorless gas which is liquefied at 4° by 46 atmospheres

pressure . It is slightly more soluble than methane in

water and alcohol . It occurs with methane in natural gas

and is present in petroleum .

The property of the carbon atom Of combining with other

carbon atoms in a very firm union to form ca rbon cha ins

F IG . 5 .

is unique among the elements . Ethane and its homologuesare very stable substances and very resistant to reagents . ’

Ethyl chloride , CHs— CHzCl, can be prepared by the

action of chlorine on ethane :

CIL— CHa 2C l CHs— ‘ CH2C1 HCl

The ethane molecule less one hydrogen atom is called

the ethyl radica lor group . Methyl,ethyl

,and their higher

homologues are frequently called alkyl radicals or groups,and their halogen derivatives a lkyl ha lides.

H- C —H CH,

The F a tty Compounds 1 3

Ethyl chloride i s a sweet-smelling liquid boiling at

In a manner entirely ana logous to the forma

tion o f methyl iodide, ethyl iodide can be produced

from the chloride

CHa— CHzCl KI= CI~L— CH2 1 KC ]Ethyl iodide

Ethyl iodide boils at It can react with methyl

iodide to produce a hydrocarbo n containing three carbon

atoms, called propa ne

CHs— CHgI CHa I 2Na CHs—'

CH2-CH:1

Pro pa ne

This synthesis can also be effected by the action of z inc

methyl on ethyl iodide

CH, ICHz— CHz CHa— GHz— CHs

ZIlIz

CH, ICH, -~CH8 CIL— GHz— OH3

If metallic sodium be allowed to act on ethyl iodide , two

ethyl radicals are combined to form butane :

GIL— “CHzl ICHg— CI‘Is CH3_CH2_CH2— CH3

Buta ne

Since it will be necessary later to Speak of the dihalogenderivatives of ethane in illustrating the structure of certain

compounds (aldehydes), mention should here be made o f

the nomenclature of these .

When two of the hydrogen atoms of ethane are replacedby halogen, two compounds are possible according to

whether the halogen atoms are attached to the same or to

different carbon atoms .

1 4 Organic Chemistry for Students of Medicine

CHzCl CHE

CHzCl CHC 1 2Ethylene Ethyhdenech loride ch loride

The symmetrica l isomer is distinguished by the ending ene

and the unsymmetrical isomer by the ending idene pre

ceded by the prefix denoting the hydrocarbon from which

it was derived . Compounds Of this class will be c on

sidered later

7. Startingwithmethane, therefore, it is possible to build

up a series O fhydrocarbons each differing from the next lower

one by a CH2 group . Their formulae, CHA, C2H6, C3H8,

C4Hl o, C 5H1 2, CAHM , etc . , all correspond to the general ex

pression C a l—1 21 1 44 . They have the general name Of sa tura ted

hydroca rbons, because all the valences o f the carbon atoms

not holding other carbon atoms are saturated with hydro

gen, so that they cannot take up any more of the latter .

Nomencla ture.

— The saturated hydrocarbons are de

signa tedby the termination ane .

” Methane , ethane, pro

pane, and butane , have special names . The higher ones

are denoted by the Greek o r Latin numeral signifying

the number Of carbon atoms they contain . Thus, C 5H1 4 is

called hexane ; C 1 0H22, decane ; C 1 6H34 , hexadecane ; etc .

The groups Of atoms which are derived from the hydro

carbons by the removal of a hydrogen atom are termed

a lkyl groups ; they are denoted by changing the ending

ane to yl. Thus CH3 ismethyl ; C2H5 ethyl ;C3HT propyl ; C4Hg butyl etc .

Properties of the pa rafiins. The compounds of this

series containing from 1 to 4 carbon atoms are gases ; those

Th e Fa tty Compounds 1 5

with 5 to 1 6 carbon atoms, l iquids at ordinary temperatures

and pressures ; while those having more than 1 6 carbon

atoms in the molecule are sol ids . Members containing

from 1 to 60 carbon atoms are actually known .

8 . Crude Petroleum , which occurs in nature in enor

mous quantities, consists of a mixture of all the members

o f the series from the lowest to the highest . When distilled

the lower members volatilize first , the temperature in the

still rising as the distillation proceeds . The lightest

fraction which is collected distills at 0° and consists of

gases, chiefly butane, which are liquefied under pressure

and employed for the production of cold by evaporation .

As a rule the distillate is collected until the product coming

over has a specific gravity of .729. This is reached at a

temperature o f about at which point chiefly nonane

and decane distill . All the product so Obtained is known

as crude na phtha . This is redistilled and separated into

rhigolene B. P. petroleum ether or na phtha B. P. 50—60,

containing chiefly C 5H1 2 and C GHM ; benzine B. P. 70

chiefly C GHM and C 7H1 6 ; l igroin B. P. 90 and

petroleum benzine B. P. 1 20 chiefly mixtures of

C 7H1 6 and Cn g. From 1 50— 300° there is collected the

burning O il distillate ,” which is redistilled into several

grades of kerosene. The safety of these Oils depends on

their volatility, for their vapors mixed with air form

explosive mixtures . Their use is attended with consider

able danger . The quality of the product is determined by

the fla sh point and burning point .” These are deter

mined by heating a sample in a dish and at intervals bring

ing a small flame near the surface . When vapors are

1 6 Orga nic Chemistry for Students of Medicine

given Off rapidly enough to form a combustible mixture ,there is a flash , which is at once extinguished . At a higher

temperature va pors are given O ff rapidly enough to support

a flame . This is known as the burning point . Most

states require a flash point of at least 1 1 0° F . and a burning

point of 1 1 0 to 1 50° F .

Above 300° F. there are distilled various grades o f

lubricating oils . From the residues vaseline and paraffin

are separated , the latter by chilling .

The physical constants of a number of the normal

hydrocarbons are given below

TABLE I

BOILING POINT

CH, Methane .4 1 5 a t 1 6 4°

C s EthaneC3H3 PropaneC41 1“) Buta neC 5H1 2 Pentang

GeHM Hex ane

C 7H1 3 HeptaneC gHm O ctane

C 1 6H34 HexadecaneC I7H36 Hep ta decaneC 1 3H33 O ctadeca ne

C 27H55 Hep ta co sane 270 M PC31H64 Hen tria contane 302 At .78 1

C 32H56 Do tria conta ne 3 1 0 1 5 mm. .78 1

C 35H72 Penta tria con pressureta ne


9 . Isomerism . J ust as in the case of methane , there

is but one substance known having the formula CH4 , so

there is but one compound having the formula C2H5

(ethane), and one having the formula CaHg (propane).Buta ne , C4H1 0, however, exists in two forms . They have

the same percentage composition with respect to carbon

and hydrogen , and the sa me molecular weight, but differ

in their boiling points and specific gravities . Both are

gases , but one is liquefied at 1° while the other remains a

gas until cooled to 4 The existence of two o r more

compounds having the same chemical formula but different

physical properties is explained by the structural formulas .

Thus while all the hydrogen atoms in metha ne and ethane

are alike with respect to the remainder of the molecule ; in

propane and butane and the higher homologues this is

not the case , a s is illustrated in Figure 6 .

If in (b) a chlorine atom should be substituted for a

hydrogen atom , the same chlor propane or propyl chloride

should result whichever one of the hydrogen atoms

attached to either end carbon atom might be replaced,0

1 8 O rganic Chemistry for Students of Medicine

but a different compound should result provided the

chlorine should be substituted for a hydrogen attached to

the middle carbon atom . This C atom differs from the

two end ones in that two of its valences are in union with

No rma l but a ne Isobuta ne

o rm a l buta neethy l-ethy lmeth a ne)

F IG . 7 .

methyl groups, while the others are each linked to carbon

by only one bond . Theory calls therefore for only one

propane, and only one is known , while it calls for two

mono-chlor propanes and both of these are known . Nor

ma l propyl chloride, CHa— GHz— CH2C 1 , abbreviated

H

‘E

‘ H

H— C— CH,

H— C —H

H

20 Organic Chemistry for Students Of Medicine

from simpler ones o f known structure . Thus , by the

Wurtz reaction one molecule of normal propyl iodide andone of ethyl iodide can yield one molecule Of normal

pentane (1 ) one molecule of isopropyl iodide and one of

ethyl iodide can yield dimethyl-ethyl-methane and

from one Of the isobutyl iodides a nd methyl iodide are

Obtained tetramethyl methane (3)

cm— CHg— CHzr — CHz— CI’L 2Na I

CHI ICHz— CHa 2 Na

CH— CHr — CH, 2Na I

CH3 CH3

+ ICI1 3 + 2 Na\ C/

CH3 CH3 CH3 CH3

The number o f possible isomers increases very rapidly

with increasing carbon atoms. The following table shows

the number theoretically possible for some of them

NUMBER O E ISOMERS

Hexane C 5H1 4 5

Heptane C 7H1 6 9

Octane Cn 3 1 8

Nonane C 9H2 o 35

Decane C 1 0H22 75

Undecane C 1 1H24 1 59

Dodecane C 1 2s 354

Tridecane C 1 3H23 802

Th e Fa tty Compounds 2 1

Most Of these compounds have never been prepared

because they are not of sufficient importance to induce

chemists to give the necessa ry effort . The methods of

forming them are well understood and it is quite possible

to produce large numbers of them synthetically.

1 0. A carbon atom which is only linked to one other

carbon atom is called prima ry ; one which is linked to two

carbon atoms is seconda ry ; one linked to three is tertia ry ;a nd to four, qua terna ry. When situated at the end o f a

chain a carbon atom is called termina l. The carbon atoms

Of a chain are designated by numbers, the terminal one

being denoted by 1 , the next by 2, etc . , for example

2

F requently the longer chains are written

CPL— (CHz)n— CHg.

The terminal carbon atom is frequently denoted by w,

the Greek letter omega , the next by a (a lpha ) and the

succeeding ones byB, 7 , etc . Methane and its homo

lognes are collectively spoken Of as the metha ne series, or

the pa rafiin hydroca rbons .

1 1 . The assumption that the four valences of the ca rbon

atom are directed toward the angles of a regular tetra he

dron does not necessitate regarding their positions with

respect to each other as fixed . There is good reason to

believe that they may revolve around a position of equi

l ibrium without changing the order of succession .

CHAPTER II

THE ALCOHO LS

1 2. TheMona tomic Alcohols — When methyl chloride,bromide, or Iodide is warmed with water, halogen acid and

a new substance, methyl alcohol , are formed . It may be

looked upon as water in which one H atom is replaced by

the CH3 radical .

CHsCl HOH CHsOH HClM ethyla lcoho l

Its synthetic formation has only a scientific interest, for

in practice it is always obtained as a by-product o f‘

wood

distillation .

The alcohols and the corresponding alkyl halides are in

general mutually transformable into each other . Thus

on treatment with phosphorus pentachloride the alcohols

are converted into alkyl chlorides, the OH group being

replaced by C 1

OH.- CH,OH PC1 , CH3— GE2G1 PO C 1 3 HCIPho sphoruso xych loride

It is customary in illustrating reactions which , like this

one,are characteristic Of a series by employing the symbol

R in place of the alkyl group attached to carbinol , as :

R_CH20H PC 1 5 R— CH2C 1 PO C 1 3+HC 1

22

The Alcoho ls 23

Methyl alcohol is known as wood alcohol because it is

produced .when wood is heated out O f contact with the oxy

gen O i the air to a temperature sufficient to decompose it .

Properties. The methyl alcohol of commerce is Obtained

in this way . It is a colorless liquid which is neutral in

reaction ; that is , it does not dissociate H1“or OH

“ions, a

fact which is Shown by its’ failure to act on indicators suchas litmus, or to conduct the electric current . It is soluble

in water in all proportions, has a burning taste, and boils

at

Methyl alcohol is the lowest member of a homologous

series of alcohols derived from the hydrocarbons of the

methane series, the second member being ethyl a lcohol

CHa— CHo .

1 3 . Nomencla ture of the Alcohols. Certain of the

more common alcohols have received special names which

they retain as the result of long usage . In the systematic

nomenclature usually employed they are regarded as

derivatives of ca rbinol or methyl alcohol . This system

is Of especial utility in indicating the structures Of

the isomeric alcohols . Thus ethyl alcohol is methyl

ca rbino l, CHsCHzOH, and the two primary butyl a l

cohols are propyl ca rbinol and isopropyl ca rbinol.

Further examples are given in connection with the

amyl alcohols

Another system of nomenclature which is frequently

employed is that Of using the name of the hydrocarbon

with the same number of carbon atoms and employing the

suffix -0 1 to indicate the alcohol . Thus methyl alcohol is

methanol ; ethyl alcohol , ethanol ; etc.

24 Organic Chemistry for Students of Medicine

The relationship of the first five alcohols to the cor

responding hydrocarbons is illustrated by the following

formulae

Methyl a lcoho l CH30H Metha no l, carbinol .Ethyl alcohol CHa— CHzO H Etha no l

,methy l c ar

binol.

Propyl a lcoho l CH3_CH2— CH20H Propa no l, ethy l car

binol.

n-Butyl a lcoho l CH3— (CH2)2CH20H Butano l, n-Propyl carC binol.

Isobutyl alcoho l/CH— CH20H Isobuta ne ] , Isopropyl

CH3 ca rbinol.n-Pentyl a lcoho l CHa— (CH2)3— CHZOH n-Pent ano l, n-Butyl(Amyl a lcoho l) ca rbinol.

1 4 . Ethyl Alcohol, etha nol, methyl ca rbinol This is

the ordinary alcohol obtained by fermentation of sugar by

yeasts . It occurs in all fermented liquids such as wine

and beer . It is made chiefly from . potatoes, grains,and molasses . The starch is converted into sugar and

the latter into alcohol and carbon dioxide . The chemical

reactions involved in this process will be described in con

nection with the fermentation of sugars

Ethyl'

a lcohol i s prepared technically by distilling fer

mented solutions . It is a liquid Of agreeable odor,which boils at and although the fermented liquids

never contain more than 1 8% of alcohol, by carrying

out the distillation in a fractionating column alcohol of

84 to 90% strength may be obtained . The fractionating

column is an apparatus in which a relatively large cooling

surface is offered and a considerable time is allowed for

the condensation of the less volatile liquid . There are

Th e Alcohols 25

ordinarily placed in the vapors ascending from the still ,Obstructions such as glass beads o r platinum gauze, to

retard their escape , thus giving greater Opportunity for

the condensation Of the higher boiling liquid of themixture,which then runs back into the still . The lower boiling

constituent esca pes condensation and passes over into the

receiver.

On redistilling the alcohol thus Obtained in an efficient

rectifying apparatus a product containing but 4% of

water is obtained . This strength Of alcohol is much used

in the arts as a solvent .

Absolute a lcohol is Obtained bytiea ting96 alcohol with

quicklime , which removes the water, forming calcium

hydrate , C a (O H)2 . The alcohol is then rectified again .

The product so Obtained contains about .5 of water .

This is the commercial absolute alcohol . Pure absolute

alcohol is Obtained by treating the latter with a small

amount of metallic sodium o r calcium and distilling a gain .

Traces of water in alcohol can be readily detected by

placing in it a small amount of copper sulphate from which

the water of crystallization has been driven Off by heating .

This is a white powder . The a nhydrous CuSO 4 takes

up even very slight traces of water from the alcohol and

forms the deep blue hydrated salt .

Among inorganic substances alcohol dissolves the halo

gens, sulphur and phosphorus to some extent, boracic acid ,the hydrates o f potassium and sodium

,the chlorides of

calcium and strontium,ferric chloride and mercuric

chloride . It is also a solvent for many organic acids, bases,and neutral substances

,the resins, soaps, and fats . Alco

26 O rganic Chemistry for Students Of Medicine

holic solutions of substances employed in medicine are

called essences, spirits, and tinctures . Certain proteins Of

the cereal grains readily dissolve in 70 alcohol , but most

proteins are precipitated from their solutions by alcohol .

For use in the arts alcohol is now sold without the pay

ment Of the internal revenue ta x which is levied on all

alcoholic beverages . Such alcohol to be tax free must be

dena tured o r rendered unfit for drinking by the addition

of poisonous and distasteful substances . The regulations

o f the United States Commissioner of Internal Revenue

prescribe the addition of 1 0 parts Of methyl alcohol and 1

part of benzine to each 1 00 parts Of alcohol . Another

formula which may be used requires the addition of2 parts

of wood alcohol and l or 2 parts of pyridine .

Ethyl alcohol is widely distributed in nature . Small

amounts of it are found in the distillate from leaves,

flowers , in the ethereal oils, and in humus-rich soil . Traces

occur in bread made with yeast . Very small amounts

are regularly found in the blood and tissues of animals .

Indeed there are strong reasons for believing that in the

destruction Of sugar through the normal physiological

processes, ethyl alcohol is an intermediate product .

1 5 . The Alcohola tes.

— Metallic sodium reacts w ith

great energy on alcohol, forming sodium ethylate and

hydrogenC2H5O H Na Cs oNa H

Sodium ethylate is readily soluble in alcohol and forms

a crystalline compound C2H50Na 2C2H 5OH . This

loses its alcohol at leaving the sodium ethylate as

a white powder . It is very useful in synthetic work.


Rum i s made from fermented molasses . It not infre

quently contains enough o f the higher alcohols, butyl and

amyl alcohols and their esters, to render it more toxic than

ordinary whiskey prepared from grains .

1 7 . High er Homologues of Ethyl Alcohol.

CH4 CHz— CHa CHs— CHz— ‘CHsMetha ne Etha ne Propa ne

CIR— OH CHa— CH20H CHa— CHz— ‘

CHgOHM ethyl a lco ho l Ethyl a lco ho l Propyl a lco ho l

CHs— (CHzlr — CHS CHS_(CH2)3— CHsButa ne Penta ne

Butyl a lco ho l Amyl a lcoho l

Being derived from the hydrocarbons of the

series by the replacement of H by OH these alcohols have

the general formula CnH23 + 1 OH. Those derived from the

hydrocarbons are normal ls. Mgrou is attached to anend ga rbon a tgrn it i s known a s a-0“fl ""

prima ry ; I ton necandarx ca rhona toma secondary ;_a ndM

if to a tertiary carbon atom, a tertiagy alcohol . Those

derived from branched cha in hydrqgfl ns a re alco

hols , andma ybefi ma ry

GIL— CHz— CHo CHs— CH(OH)— CH3

Prima ry pro pyl a lcoho l (norma l) Seconda ry propyl a lco ho l (iso propyl a lcoho l)

1 8 . The Butyl Alcohols. C4H90H.

BO ILINGPOINT

1 . CHs— GHz— CHz— CH2OH 1 1 7°

Normal butyl alcohol (primary)

(Propyl carbinol)

The Alcohols 29

2. C

C

Isobutyl alcohol (primary)

(Isopro pyl carbinol)

3 . CHa— CH2\

o

CIE/CH H

Normal secondary butyl alcohol

(Methyl ethyl carbinol)

CHs

CHs OH

CHs

Tertiary butyl alcohol

(Trimethyl carbinol)

H,— CH20H

m>CH

Normal primary butyl alcohol occurs in fusel oil to a

small extent , but has little biological importance . It is

produced , together with a number of other products, by

Ba cillus butylicus, growing on glycerin and various sugars

and related substances (see butyric acid fermentation,1 64)The most important butyl alcohol is isopropyl cagbiglql.It is produced by yeasts during fermentation of sugar

into ethyl alcohol and carbon dioxide. It has its origin

not from sugar , but from one of the protein digestion

products, valin . It is formed in relatively large amounts

when po tatoes are malted and fermented by yeasts, be

cause the mother substance valin (73) is present in

greater amount than in the malted grains .


The remaining two butyl alcohols have been prepared

synthetically, but do not occur in nature .

Physiologica l properties.

— The butyl alcohols are all

distinctly poisonous both to plants and animals. The

toxic action of monatomic alcohols increases with higher

carbon content and with increasing molecular weight .

This is the Rule of Richa rdson . The normal primary a l

cohol is more toxic than isopropyl ca rbinol , and the latter

is more toxic than secondary and tertiary butyl alcohols .

1 9. The Amyl Alcohols.

1 . No rma l primary CHa CH2 CH, CHz CHzO H(butyl ca rbmol)

2. Isobutyl ca rbmolCHs\

(prima ry)(Active amyl a lcohol)

CH°/CH— CH2 —CHgO H

3. Seconda ry butyl C/Hs

ca rbino l (prima ry) CHs— CHzH CH2()H

4 . Tertiary butyl gH3

— CH20Hca rbinol (pri

ma ry) CH3

5. Methyl propylca rbinol (seconda ry)

6 . Methyl isopropyl 1 1 2°

8 1 9

ca rbinol (secondary)

7. Diethyl ca rbino l

CHs CHz

CH3

CH3

\C/c

CHa/H

CHa — C

CHa — C

The Alcohols 3 1

8 . Dimethyl ethyl ggik cca rbinol (tertia ry)

CHa — GHz/

The only two amyl alcohols which are of any great im

portance in biological processes are prima ryisobutylca rbinol

and seconda ry butyl ca rbinol. These both occur in fusel oil

through the life processes of yeasts , and , l ike isobutyl alco

hol , are derived from the cleavage products o fproteins

Physiologica lProperties. All have disagreeable smells

and produce headache . Normal amyl alcohol is about

four times as toxic as ethyl alcohol . A .5 solution

quickly destroys infusoria , and a 1 solution kills algae

within a day . In dilutions as great as . 1 certain bac

teria can use it a s a source of carbon .

A saturated solution of isoamyl alcohol exerts a

powerful bactericidal action . The toxi city of the amyl alco

hols is distinctly greater than that of the lower members of

the series . fa n solution is as destructive to B. pyogenes

as afi n solution o f butyl , a fi n solution of propyl , a lfi n

solution o f ethyl , and a 2l n solution of methyl alcohol .

20. Isomeri sm of the AmylAlcohols. One of the amyl

alcohols, secondary butyl carbinol , also called active or

fermentation amyl alcohol , presents a very interesting case

of i somerism . Three isomers o f this one alcohol are known,but they have all the same chemical and , with a single

exception , the same physical properties . This exception

is found in their action on polarized light . The ray of

polarized light may be likened to a ribbon of light, as con

tra sted with a ray of ordinary light the waves of which

are vibrating in every direction at right angles to the path


of the ray . In the polarized ray the vibrations all lie in

the same plane . When such a ray is passed into either

of two of these amyl alcohols the ray is rotated by one of

them to the right and by the other to the left . One is said

to be dextrorotatory, the other levorotatory. The third pro

duces no rotation at all . Two are said to be optica lly a ctive

the other, ina ctive. The effect is as if the ray had received

a twist in passing through the optically active substance .

Now these two active isomers when treated with gaseous

HI are transformed into two optically active amyl iodides,and the inactive one into an amyl iodide which is not

optically active .

CHa

H1

CHa— C CHzI

The amyl iodides, l ike the alcohols from which they were

derived , have identical chemical and , except in their be

havior toward polarized light, the same physical properties .

Suppose we consider the iodide which is derived from levo

rota tory amyl a lcohol, which is the important one from the

biological standpoint . If it be converted into penta ne

by the action of nascent hydrogen, which removes the

iodine , replacing it by H , there results a pentane which is

optica lly ina ctive

CHa- C CHs— CActive

The Alcoho ls 33

O n the other hand , if this iodide is caused to react with

ethyl iodide in the presence of sodium, there is produced a

hepta newhich is optically active :

GIL— C H2I 2Na ICHz— CHx

GHz— CHsM ethyl-ethyl;

-pr0p l-methaneActiv i

If the above reaction is carried out with methyl iodide

instead of ethyl iodide there is formed a hex a ne which is

optically inactive

Hzl 2Na ICHa

M ethyl-diethyl-methane(Ina ctive)

An inspection of these formulas shows that those com

pounds are optically active in which each of the bonds of

affinity of one carbon atom is linked to different groups or

atoms . Whenever two bonds of this carbon atom are

linked to the same kind of group (as two methyl or two

ethyl groups) the optical activity is lost .

Van’t Hoff first discovered that Optically active com

pggn ve in enera l at least one carbon atom which isD


name ‘‘

a sw ric”

Van’t Hoff further showed that the existence ofthreeisomers must necessarily result from the structure of a n

asymmetric carbon atom , if the assumption be correct tha t

the four valences o f the carbon atom are directed as to

ward the four solid angles of a regular tetrahedron , the

carbon atom itself occupying the center of the figure .

F IG . 8 . F IG . 9 .

With such an arrangement there must result two kinds ofmolecules which resemble each other in the same way as

the right hand resembles the left, or as an object resembles

its reflection in a mirror . If such molecules be represented

as mirror images (Fig . 8 and Fig . 9) it will be seen that on

turning one so that the a and b in both figures coincide ,the c and d of one will not coincide with c and d of the

other . If now Figure 8 rotates the plane of polarized

light to the right, Figure 9 will rotate it to the left be

cause of its opposite handed structure . This isomerism in

space is termed stereochemica lisomerism or stereoisomerism.


This type of isomerism is of great significance in biology,since with but few exceptions the organic compoundswhich

play important rdles in the life processes of plants and

animals possess this type of asymmetry.

2 1 . The Higher Alcohols. One of the higher homo

lognes of methyl alcohol which should be mentioned, is

normal hex yl alcohol , CIL —(CH2)4 —CH20H (B. P.

which occurs in the oil of the seeds of Hera cleum giga n

teum, in the o il of the fruit o f several plants, and in slight

amount in fusel oil . The following are also biologically

important

Norma l hep tyl a lcoho l CHa— (CHg)5— CH20H B . P. 1 76

°

No rma l o ctyl a lcohol CH3 —(CH2)6

— CH20H B . P. 1 96°

Nony l a lcoho l CHg—(CH2)7— CH20H B . P. 21 3

°

Dodecyl a lcoho l CHg— (Ct o— CHQO H M . P. 24— 26

°

Cetyl a lcoho l CHg—(Ct r

— CHzO H M . P. 49°

O ct adecy l a lcoho l CHa— (CH2)1 6

— CH20H M . P. 59°

Ca rna ubyl a lcoho l CHa— (CH2)22— CH20H M. P. 68

°

Cery l alcohol C25H530H

Myricyl alcoho l Cso O H

The higher alcohols, O 8 to C 1 8, are found in various plant

oils in small amounts usually combined with organic acids,

as esters Cetyl alcohol occurs as a constituent o f

spermaceti, an animal wax derived from the sperm whale,and in the O il secreted by water birds for lubricating their

feathers .

Ceryl alcohol is an important constitutent of many

waxes, as Chinese wax, beeswax, etc .

Myricyl alcohol is likewise a very common constituent

of waxes . (See waxes,

The Alcoho ls 37

22 . The Dia tomic Alcohols.

— It has been found im

possible to prepare in the isolated state compounds o f the

typeR

>C such as HzC for the reason that

R

they are unsta ble and as soon a s formed they sepa rate a

molecule of water with the formation of a new cla ss o f

compounds , the aldehydes . These wil l be treated more

fully later

There are, however, many examples of compounds which

conta in more than one alcohol radical . The simplest

CHzO Ho f these is ethylene glycol or glycol I It is formed

CH20H

in a manner analogous to monatomic alcohols, viz . , by the

action of water or metallic hydroxides on ethylene ha logen

deriva tives Ethylene chloride is too stable to react

with water directly even under pressure , but ethylene

bromide will react when heated in a sealed tube with

water, forming glycol and hydrobromic acid :

CHzBr HOH CHzO H2 HBr.

CHgBI’ HOH CH20H

Glycol is a colorless liquid , readily soluble in water,and has a sweet taste . It boils without decomposition

at 1 97° and solidifies in a freezing mixture . Its melting

point is and its specific gravity at 0° is water

being It is therefore heavier, volume fo r volume,than any of the monatomic alcohols, which are a ll lighter

than water .


Glycol does not occur in nature in the free state, but is

a constituent of a very important class of compounds of

complex structure, the lecithiris Moreover it is of

great theoretical interest, since it probably occurs as an

intermediary product in the degradation of certain food

stuffs in the processes of metabolism

Glycol reacts with alkali metals, as do the monatomic

alcohols, forming e.g. sodium , or potassium glycollate, and

hydrogenCH20H CHgO Na

+ 2Na = |CHzOH CH20Na

With fuming nitric acid it reacts to form glycol dinitrateCH20H HNO 3 CH2N03

2H20

CH20H HNo 3 CH2N03

Glycol chlorhydrin , CH20H_CH2C 1 , i s obtained by

passing hydrochloric acid gas into warm glycol

It is a liquid , soluble in water, and boiling at

23 . Ethylene O xide . G lycol does not

0

form an a nhydride on treating it with reagents which

abstract water . From glycol chlorhydrin, by abstracting

a molecule of Hc l by treatment with alkalies, there results

ethylene ox ide . This compound is a gas, since it boil s at

It readily takes up water, forming glycol

H CHzOH

OH CHzOH.

The Alcoho ls 39

It also readily adds hydrochloric acid , forming glycol

H CH20Hchlorhydrin

Cl CHzCl.

24 . From propane two glycols are derived : Alpha or

a -propylene glycol CH3 CHOH — CH20H, in which one

hydroxyl group is attached to the middle carbon atom and

therefore in the alpha position to the end carbon atoms,and Beta o rB-propylene glycol , in which each hydroxyl is

bound to an end carbon atom and is therefore in the 3position to the other .

25 . Tria tomic Alcohols. Glycerol , commonly called

glycerine, a name which it received before the modern

system of chemical nomenclature was developed , i s a

derivative of propane , from which it is formed by the sub

stitution of three hydroxyl groups for three hydrogen atoms .

It is a never-failing constituent of all fats, where it occurs

in combination with the fatty acids . It has been prepared

synthetically from triiodo-propane by the action of water

CHzI CHzOH

ICHI 3HOH CHOH 3HI

CHzI CHzOH

Glycerol reacts with phosphorus truodide, PI3, to form

the triiodo propane,this being also called triiodo-hydrin .

Glycerol is a colorless, odorless, oily liquid of sweet

taste . It has a strong affinity for water, and takes up

moisture from the air . It is soluble in water and in alcohol

in all proportions,but very nearly insoluble in ether . On


long standing at low temperatures it solid ifies,and the crys

tals thus formed do not melt below It boils at 290°

but undergoes some decomposition . Under reduced pres

sure it can be distilled without decomposition . At 1 2mm .

it distills at It is slowly volatile with water vapor .

Its specific gravity at 1 5° is Its chemical behavior

is in accord with the theory that it is a triatomic alcohol .

Thus when glycerol is slowly dropped into a mixture of

concentrated sulphuric acid and fuming nitric acid trinitro

glycerol , usually called nitroglycerine, is formed. The sul

phuric acid facilitates the reaction by its a flinity for water,which it withdraws from the system as soo n as formed

CHzO H CHzNO B

CHOH 3 HN03 CHNO a 3H20

CHzOH CHzNO ,Nitroglycerine

Nitroglycerine is a heavy colorless O il when pure, but

usually has a yellow color . It is sweet to the taste and is

extremely poisonous , acting chiefly on the central nervous

system . It is employed in medicine for its action on the

heart and is directly injected into the blood as a remedy

in case of carbon monoxide poisoning . When heated to1 80

° it explodes . Its explosion can be induced by a sharp

blow . The principal use o f nitroglycerine is as an ex plo

sive . When absorbed by certain porous substances, assawdust , clay, wood pulp , etc . ,

it forms dynamite . Mixed

with nitrocellulose, vaseline, and acetone, it forms the

smokeless powder ca lled cordite.

The Alcohols 4 1

Glycerol , l ike other compounds containing several

hydroxyl groups , dissolves alkalies and oxides o f the heavy

metals, forming compo unds analogous to the a lcoho la tes.

The hydrogen atoms o f the OH groups are in these replaced

by the meta l . The structure of such compounds may be

illustrated by the following formula

CHzO H

Cu

CHOH Cu(OH)2 CHO 2H20

CHZOH CH20H

With basic lead acetate and ammonia glycerol forms aninsoluble lead glycerate .

When heated with hydrochloric acid , glycerol reacts

with the formation o fwater and the replacement of one o r

two hydroxyl groups by chlorine :

CHZOH CH2C 1

CHOH HCl CHOH H20

CH20H CH20HM ono chlo rhydrin

CHzCl CHzCl

CHOH Hcl CHOH H20

CH20H CHgClDich lorhydrin

This reaction cannot be effected by the use of hydriodic

acid,since the latter acts as a strong reducing agent, owing


to the great tendency it shows to separate free iodine , thus

mak ing available nascent hydrogen for the abstraction of

oxygen . Thus on heating glycerol with five molecular

equivalents of hydriodic a cid , isopropyl iodide is produced

CH20H CHa

CHOH + 5 HI = CHI + 3 H20 + 4 I

CHZOH CH3

ISO pro py liOdide

Under carefully regulated conditions this reaction is

nearly quantitative, and on the measurement of the iodine

in the isopropyl iodide produced from a sample depends the

quantitative estimation of glycerol proposed by Zeisel and

Panto .

Glycerol is readily oxidized , i.e. it exerts a reducing a c

tion (abstraction of oxygen)on Fehling’s solution even in

the cold , owing to its conversion into glyceraldehyde

26 . Erythritol or Erythrite ,

CHo — (CHO H)2 —CH20H,

exists in nature in certain algae .

27. The Sulphur Alcohols. Mercapta ns. J ust as the

alcohols are derivatives of water , formed by replacing one

o f the hydrogen atoms by an alkyl group, so also there

exists a class of compounds of analogous constitution

derived from hydrogen sulphide . These are known as

thio-a lcohols, merca pta ns, or alkyl sulph-hydrates

H— O — H R— O — H H— S— H R— S— HWa ter A lcoho l Hydrogen M erca pta n

sulphide

CHAPTER III

ESTERS AND ETHERS

28 . Esters.

— When alcohols are treated with acids

which have a strong affinity for water , a reaction may take

place in which a molecule of water and a new compound

called an ester are produced . Thus the action of hydri

odic acid on alcohol with the production o f an alky l

halide (20) i s representative of a general type of rea c

tion . Thus

(a )Cm— CHQH

A lcoho l Ethyl sulphuric a cid

Compounds of the type of ethyl sulphuric acid are

known as etherea l a cids.

(b) 2 C2H50H CH3 — C

2+ 2H20

CHs— CDiethyl su lpha te

D iethyl sulphate is a neutral ester .

These compounds can also be formed by the action of the

silver salts o f the acids on the alkyl iodides

/O Ag ICH3 CH3

802 502 + 2 AgI\O Ag ICH3 0Silver sulpha te M ethyl D imethyl

iodide sulpha te

Esters a nd Ethers 45

D iethyl sulphate is a colorless oily liquid possessing a

peppermint Odor . It is insoluble in water. It boils at

It is readily hydrolysed , i.e. broken up with the

entrance of water into the compound , but the original

substances, alcohol and sulphuric acid , from which it was

formed , are not regenerated . Instead diethyl ether is

produced

(0)CHa— CHif

02+HOH C2H5— O — C2H5+H2804

CHa— C Ethyl ether

The structure of diethyl sulphate is also shown by its

formation from alcohol and sulphuryl chloride, SO zClz.

C l HOC2H52Hcl

Cl HOC2H5 H5

(d) Ethyl Sulphuric Acid is a strongly acid liquid of

an oily character and possesses no odor . It is soluble in

water in all proportions . It is obtained by mixing alcohol'

with strong sulphuric acid . The calcium and ba rium salts

are soluble while barium sulphate is insoluble . The

solution containing ethyl sulphuric acid , alcohol, and sul

phuric acid is neutralized with Ba CO s and the BasO 4filtered off. On adding just enough sulphuric acid to

combine with the barium in the filtrate the barium is

removed and free ethyl sulphuric acid is left in solution .

It is not very stable, decomposing slowly into alcohol

and sulphuric acid in the presence of water at ordinary

temperatures and quickly on boiling. Potassium ethyl


sulphate is very stable and can be recrystallized from boil

ing alcohol .

When ethyl sulphuric acid is heated it forms the neutralester diethyl sulphate and free sulphuric acid

H5 C2H5

H CgH

(e) Esters of Sulphurous Acid. When alkyl iodidesreact with sodium sulphite there is formed the sodium salt

of ethyl sulphonic acid :

C2H51 Naasog C2H5S03Na Na I

The free acid C2H5SO 3H i s a very stable strong mono

ba sic acid ea sily soluble in water . It is not sa ponifled

even by boiling with water or alkalies . Even boiling

concentrated nitric acid does not act upon it, nor does free

chlorine, but fused potassium hydroxide decomposes it,regenerating alcohol and forming potassium sulphite .

The same compound is formed by the oxidation of

mercaptan with nitric acid or potassium permanganate

C2H5SH 3 O

That this acid contains a hydroxyl group is shown by its

yielding with PC 1 5 an acid chloride which decomposes

with water, regenerating the acid . The method of forma

tion also shows that the sulphur is linked directly to carbon .

By the action of alkyl iodide on silver sulphite sulphonic

ethers are formed .

Esters and Ethers 47

2 CHa— CHzl Agzso, zAgIEthyl sulphonicethy l other

This is so stable that it isdiflicultly sa ponifia ble. B.P.

(f) Ethers of Sulphurous Acid. When alcohol reacts

with sulphuryl chloride there is formed a compound

which is isomeric with ethyl sulphonic ethyl ether, but

has entirely different properties :

1 HOC2H5

2Hcll HOC2H5

Diethy l sulphite

D iethyl sulphite is rapidly sa ponified by water . On

careful partial sa ponifica tion the unstable potassium salt

C2H

o f ethyl sulphurous acid 0 3 is formed . The free

acid which is isomeric with ethyl sulphonic acid is inca pable o f existence , decomposing at once into its components .

The sta ble ethyl sulphonic acid,being known to have its

sulphur directly linked to carbon and to contain one

hydroxyl group, is assigned the structure

C2H5

and the isomeric ethyl GiH5— 0\

= osulphurous acid theHO/

fOHOWing 2 Ethyl sulphurous a cid

(9) Ethyl alcohol reacts with nitric-acid HO N02 to

produce ethyl nitrate

CHs— CH20H HO N02 C2H50N02 H20


It is a liquid which boils at It has a pleasant Odor .

It is soluble in water .

Ethyl nitra te, CHs— CH2O — NO 2 , is produced directly

from its components and resembles methyl nitrate . It

boils at has a sweet taste, but a bitter after taste .

It is soluble in alcohol and ether .

Both of these substances are explosive when hea ted

quickly .

Amyl nitra te, C 5HuO N02, is prepared in a n analogous

manner . It is a colorless l iquid which boils at

(h) Two esters o f nitrous acid are importa nt because

of their pharmacological properties . They are ethylnitrite,which is frequently called nitrous ether . It is a gas which

boils at

C2H 5OH HONO C2H5ONONitrous a cid Ethyl nitrite

It is employed in solution in ethyl alcohol (1 5

Amyl nitrite boils at Its physiologica l action is

distinct from that of amyl nitrate .

29 . Eth ers . J ust a s a molecule of a lcohol and one

of an acid can be condensed with the formation o f one of

an ester and one of water, so twomolecules of alcohol can

be condensed with the loss o f water to form an ether :

(a ) Alcohol Acid Ester Water

(b) CH3 |OH HlO CHs CHy — O — CIL,r

M ethyl ether

The formation of ethyl ether,which is the most common

one a nd is usua lly referred to as ether, has been described

in connection with the hydrolysis of the ester diethyl sul

Esters a nd Ethers 49

phate (28 In practice it is prepared by dropping alco

hol continuously into a solution o f ethyl sulphuric acid

heated to 1 40— 1 45°C .

CQH

502 H20 C2H5— O — C2H5 H2504

2 C2H5OH 02 Hzo

Ho/ czH,o

D iethyl sulphate is alternately formed and decomposed

and the ether distills over, together with some alcohol and

802 . From this it would appear that since the sulphuric

acid is constantly being regenerated it should act over and

over again so that a small amount should induce the forma

tion of ether indefinitely . This is not the case, for the

following reason : With the formation of , each molecule

o f ether there is likewise produced a molecule of water .

Now ethyl sulphuric acid is readily hydrolyzed to alcohol

and sulphuric acid in the presence of water, and in any

solution containing these three substances there will be

established a state of equil ibrium in which there will exist

a definite rela tionship between the amount of alcohol ,ethyl sulphuric acid , sulphuric acid , and water . Increa s

ing the concentration of alcohol will cause the formation

o f more ethyl sulphuric acid, while adding water'

causes

the sa poniflca tion of some of the ethyl sulphuric acid intoits components . The water which is produced in the for

mation of ether distills over to some extent, but a partE


remains behind in the still . This tends therefore to cause

a progressive decrease in the amount of ethyl sulphuric

acid in the flask, so that a fter a time little or no ether is

formed . Instead the alcohol distills over as fast as added .

The latter is removed from the distillate by neutraliz ing

the H2803 with milk of lime . The alcohol passes princi

pally into the water layer, and the ether, which is separ

rated from the water la yer ' in a separatory funnel , is again

distilled .

The last traces of water and alcohol are removed from

ether by placing in it granulated calcium chloride , which

has a strong a flinity for both these substances .

Ethyl ether boils at It has an agreeable odor .

Prolonged breathing of it causes loss of consciousness.

It is much employed in surgery as an anaesthetic . One

volume dissolves in volumes of water at and

ether dissolves water to the extent of about a 2%solution by volume at It is much less soluble in a

saturated salt solution . With air ether vapors produce

highly explosive mixtures . Great care should be ex er

cised therefore in handling ether wherever there is a

possibil ity of ignition , as during distillation . It is best

to place the distillation flask in hot water and to dis

pense with a flame . A small flask should be employed

and fresh portions of ether added from time to time,as the distillation proceeds . Small receivers frequently

emptied are preferable to one large one .

Ether dissolves a great variety of chemical substances

and is indispensable a s a solvent in chemica l work . In

many instances substances can be separated from complex


The formation o f ethers in this way proves that in these

the two alkyl groups are linked together through oxygen .

This is calledWill iamson’s reaction, after the name Of itsdiscoverer.

If to the mixture of alcohol and sulphuric acid (contain

ing ethyl sulphuric acid) there is added , beginning just

before distillation commences, an alcohol other than ethyl

alcohol , a mix ed ether will result . In this way numerous

ethers containing different alkyl radicals can be produced .

02+HO C 5H1 1 O ‘s — O — ‘ CsHu +H2504Amyl a lco ho l Ethyl amyl ether

This furnishes further evidence that the steps in the

formation of ether are as described above .

CHAPTER IV

THE ALDEHYDES AND KETO NES

30. O x idation Products of the Alcohols. It has long

been known that alcohol-containing solutions , as fer

mented cider, wine, or beer, soon become sour when

exposed to the air in open vessels at room temperature .

Vinega r is formed through the change of alcohol into

a cetic a cid. In the absence of oxygen this change does

not take place, and it is greatly accelerated by thorough

a era tion of the solution , as by causing it to pass through

porous ma terial . The oxidation is not spontaneous , but

results from the growth in the solutions of amicroOrga nism

Mycoderma a ceti, or mother of vinegar.” If the vessel

containing the alcoholic solution which is undergoing this

change admits but an inadequate supply of air (oxygen)there accumulates an intermediary product known as

a ldehyde or, from its relation to acetic acid , a ceta ldehyde.

The change which takes place in these processes is

shown by the following equations

CHa— CHzOH O CHa— CHO HzO

Aceta ldehyde

CHa— CHO O CHa— GOOHAcetic a cid

Oxygen of the air (molecular oxygen) cannot effect this

oxidation,except through the agency of an oxygen

carrier,

”or catalyzer, which activates it .

’

This action53


i s brought about by the presence in the acetic acid organ

ism O f ox yda ses.

Numerous examples are known of the activation of

molecular oxygen through the agency of inorganic cata

lyzers. Thus a mixture of hydrogen and a ir is stable at

ordinary temperatures and can be left for a long period

without the hydrogen and oxygen combining to form

water . If a platinum spiral be introduced into such a

mixture, the volume of the gas mixture will decrease

noticeably and the platinum grow warm . The hydrogen

and oxygen will now rapidly combine . If instead of a

platinum spiral very finely divided metal , platinum sponge,be employed , the two elements may combine with ex plo

sive violence .

Another example of the effect of an inorganic catalyzer

is seen in the technical process of converting methyl alcohol

into formaldehyde . Air and methyl alcohol in the proper

proportions to supply oxygen for the oxidation of the alco

hol form a relatively stable mix ture . It can be heated to

a relatively high temperature without any oxidation taking

place . If however a copper gauze which has been o x i

dized on its surface be warmed gently and the air-alcohol

mixture passed slowly over it, the oxidation o f the alcohol

is rapidly effected , water and formaldehyde being formed .

The heat generated by the oxidation serves to keep the

copper in a glowing condition :

GILOH O HO HO H20Forma ldehyde

The exact nature of the process by which these accelera

tions of reactions is brought about is not known with cer

The Aldehydes a nd Ketones 55

tainty. The amount of acceleration depends upon the

amount of surface of metal or oxide exposed to the react

ing mixture, and it is known that platinum can absorb

relatively large amounts of certain gases , and the more the

greater the degree of fineness of its division . Since the

more finely divided the metal the greater the surface ex

posed , the reason for the higher efficiency of the metal in

a fine state O f division becomes apparent . The catalytic

action is most simply explained by assuming that the gases

dissolve in the surface layer of the metal and therefore exist

in much more concentrated state by which more molecules

are brought together for interaction in a given time .

For the preparation of acetaldehyde , which is for brev

ity ordinarily referred to as aldehyde, in the laboratory

the oxidation of alcohol is effected by chromic acid

3 C2H50H 2K2CI’O 4 5H2804

3 C I'L3 — CHO C l‘2(SO 4)3 2K2804 8H20.

A ldehyde

In this reaction the sulphuric acid first reacts with the

pota ssium chromate, forming chromic acid :

OH

K2C I‘O 4 H2804 K2SO 4 C l‘

OH

The chromium in the chromic acid gives up its oxygen

to the alcohol, passing from the hexavalent to the trivalent

state .

The green color of the chromous sulphate and the fruity

odor of the aldehyde are so characteristic that this reaction


is employed reversa bly as a qualitative test for both

chromic acid and for alcohol .

When chlorine is passed into a primary or secondaryalcohol , hydrogen is replaced by chlorine, in a manner

analogous to the behavior of hydrocarbons . The chlorine

atom always replaces a hydrogen attached to the carbon

atom which holds the hydroxyl group , i.e. to the ca rbon

atom already linked to a negative group . The two nega

tive groups cannot remain attached in this way, so the

chlorinated alcohol has but a transitory existence . There

results at once a separation of HCl and the formation of

an aldehyde :

CHa -CH20H C 1 2 CHa— CHCI— OH HCl

CHs— CHCl— O H CIL— CHO HCl

3 1 . Constitution Of the Aldehydes and Acids.

- The

relationship between the primary alcohols and their

oxidation products the aldehydes and acids:is shown bythe following consrdera tion : The primary alcohols cor

respond to the general formula CnH27H QO ; the aldehydes

to the formula Ca nO , due to the loss of two hydrogen

atoms through the first stage of Oxidation ; while the acids

which result from the oxidation of the aldehydes cor

respond to the general formula Ca nO z.

The constitutional formulae assigned to these three

classes of compounds are as follows :

R R R

I/H Ic or CHO c— OH or co OH\O \OA ldehyde


The primary alcohols, the aldehydes and corresponding

acids are derived from the hydroca rbons by the substitution o f a hydrogen atom linked to a primary carbon atom

by the following groups :0

C

OHCarbo xyl oup

or Keto ne) (Acid? r

The behavior of these groups when acted upon by PC 1 5throws further light upon their structure . Thus the alco

hols yield, as already pointed out, alkyl halides, the OH

acting as a unit and being replaced by C 1 , a monovalent

element . When Pcl5 acts upon aldehydes, the oxygenis replaced by two C l atoms forming dichlor hydrocarbons .

With the organic acids PC 1 5 replaces the OH group as inthe alcohols and leads to the formation of a cidchlorides .

PC1 5 CHs— CHzCl PO Cla HClEthy l ch loride

CHa— CHO PC1 5 CHs— CHClz PO CleEthylidene ch lo ride

CHs— GOOH PCls CHa— CO Cl PoCls +HClAcetyl ch loride

32. Properties O f the Aldehydes. (1 )The aldehydes

are characterized by exceptional chemical activity . They

are easily oxidized , slowly by contact with the air and

quickly by oxidizing agents such as chromic acid . They

possess thereforemarked reducing properties, and abstract

oxygen from the oxides of the noble metals . Theyreducean ammoniacal solution of silver oxide or silver salts, caus


ing the deposition ofmetallic silver . Someof the aldehydes

will likewise reduce alkaline copper solutions, especially

in the presence of sodium hydroxide . This property is

sufficiently characteristic and delicate to be of use as a

reagent for detecting and estimating aldehydes (Fehling’s

solution).

(2) The aldehydes are easily reduced by nascent

hydrogen to the same primary alcohols from which they

are derived by oxidation

CHs— CHO 2 H CHaCHzOH

(3) Conversion into dichlor derivatives of the type

R— CHXz (X Halogen)

(4) Addition reactions (a )Aldehydes react with

ammonia and hydrocyanic acid to form addition products .

With ammonia there is formed OH

CHs— CHO HNH2 CHa — OH

NH2A ldehyde ammonia

The addition reaction of aldehyde and HCN is Of

especial importance because it forms a method of building

up synthetically compounds which are at the same time

alcohols and acids OH

CHr CHO HCN CH3 -O H

CNEthylidene cya nhydrin

Ethylidene cyanhydrin is readily transformed into

lactic acid

60 Organic Ch emistry for Students of Medicine

From such considerations the conclusion may be drawn

that two hydroxyl groups cannot as a rule exist bound to

the same carbon atom . A molecule of water is separated

and an oxygen atom becomes bound to the carbon atom

by both its affinities instead . When several negativeatoms in the radical are introduced in place of hydrogen

such ‘ hydrates can exist . Thus trichlor acetaldehyde,commonly called chlora l, combines with water to form

chloral hydrate :

CCls— CHO HOH CC 13‘ — C

Ch lora l Ch lora l hydra te

This compound does not behave lik e a diatomic alcohol,however

,but like the aldehyde from which it was derived,

owing to the ease with which water is separated .

(5) The aldehydes polymerize readily. By polymeriza

tion is meant the transformation of a compound into a n

other having the same percentage composition with respect

to the elements, but with a molecular weight which is a.

multiple of that represented by the simplest formula .

In the case of formic aldehyde this change is spontaneous

at the ordinary temperatures . Acetaldehyde does not

polymerize so readily, but the changeis brought about by

the presence of traces of hydrochloric, sulphuric, or sul

phurous acid, z inc chloride, etc . The reason for their

cata lytic effect is unknown .

Alkalies induce a different kind of polymerization of

aldehydes, leading to the formation Of a ldehyde resins.

For acetaldehyde this is reddish brown in color , insoluble

The Aldehydes a nd Ketones 6 1

in water, but soluble in alcohol, and gives off a peculiar

odor which is characteristic .

Formic aldehyde, on the other hand, in the presence

of alkali shows the phenomenon known as the Ca nniza rro

rea ction , in which through the action of water one molecule

of aldehyde is oxidized to acid , and another is reduced

to an alcohol , thus

2 HCHO HzO CH30H HCO O HFormic a cid

(6) The aldehydes show a tendency to form condenser

tion products in which two molecules combine with a

rearrangement of the bonds o f the carbon atoms, a hydro

gen atom of one molecule changing its l inkage from carbon

to oxygen with the formation of a hydroxyl group . Thus

when aldehyde stands in contact with acids or alkalies it

undergoe s what is known as the a ldol condensa tion .

There is formed B-oxybutyric aldehyde

CHsCHO —l CH2H— CHO CHa— CH(OH)— CH2— CHOB-o xybutyric a ldehyde (A ldo l)

This property of the aldehydes is of fundamental im

portance in biology, for the formation of carbohydrates ,fats, proteins , etc . , which occur in the animal and vege

table kingdoms .

Formic aldehyde does not condense through the influ

ence of acids, but does so readily through the influence

Of very weak alkalies , even calcium carbonate greatly

accelerating the action . The condensation products o f

formaldehyde will be considered in detail in connection

with the synthesis of the sugars


(7)With hydroxylamine, NHzOH, aldehydes condense

to form a ldox imes, water being formed in the reaction :

CfLCHO NHzOH CHg— CHZ N— ‘ O H HzO

(8)With hydrazine, NHz— NHQ, or its substitution

products, aldehydes condense to form hydra zones, com

pounds containing two nitrogen atoms

CH3CHO NHz— NHE CHs

— CHr—“N— NHE HzO

(9) The aldehydes react with sodium bisulphite to

form crystalline compounds which are readily soluble in

water, but sparingly so in alcohol . These are looked upon

as sulphonic acid esters of the hypothetical ethylidene

glycol

CH3— CHO HOH Cit— CH

OH

O

CHr -CH S Cm- CH<OH>A ldehyde sodium bisulphite

OH Na O 0

Such compounds are easily broken up on warming with

a solution of sodium carbonate , with the re-formation of

aldehydes . These compounds are o f great importance,

therefore , in the isolation of aldehydes .Nomencla ture.

— The aldehydes are named from the

hydrocarbons from which they are derived with the ter

mination -a l. Several of the more important ones ‘have

The Aldehydes and Ketones 63

long had names which do not correspond to this sys

tem of nomenclature .

/O

33 . F ormaldehyde . H— C<

(Methanal). ResultsH

from the regulated oxidation ofmethyl alcohol , employing

a glowing platinum or copper spira l as a catalyzer

Other oxidiz ing agents acting on methyl alcohol do not

yield the aldehyde . Instead the oxidation goes farther ,formic acid being produced It is a ga s which when

cooled strongly condenses to a liquid which boils at

Formaldehyde is formed by the direct union of hydrogen

and carbon monoxide under the influence of the silent

electrical discharge . At 600° C . it is again dissociated

into hydrogen and carbon monoxide

H

o : c< H2

H

This is an example of the change o f carbon from the

divalent into the tetrava lent state and v ice versa . This

typ e of change in the nature of carbonwill be further treated

under the isonitriles Formaldehyde IS supplied commercia lly as a 40 solution known as formalin .

Formaldehyde is a powerful poison by reason Of its

power to react_with the proteins of the tissues, destroying their special properties a s components of the living

protoplasm . It is employed in disinfection and in thepreservation and hardening of anatomic specimens .

With ammonia it forms hexamethylenetetramine, or

urotropin,a feebly basic crystalline solid , soluble in


parts of water and 1 0 parts of alcohol . (Sometimes also

called aminoform and cystamin.)

6 CH20 4 NH, (CH2)6N4 6H20

It is employed internally in medicine as an antiseptic .It is absorbed without decomposition and passes through

the kidneys in great measure unchanged , but the urine

after its administration frequently contains traces of

formaldehyde .

Polymeriza tion of forma ldehyde — According to the

conditions formaldehyde polymerizes in different ways .

Pa raforma ldehyde is formed when formalin is eva po

rated on a water bath . It is a white solid which melts

at about 1 53° and on strongly heating evolves forma lde

hyde . It is looked upon as (CH20)2 .

Triox ymethylene (CH20)3 is a white crystalline com

pound which separates from solutions o f formaldehyde on

standing. This substance differs from paraldehyde in

that it does not dissolve in water, alcohol , o r ether . It

is formed spontaneously when formaldehyde solution is

allowed to evaporate a'

t ordinary temperatures . It passes

into formaldehyde again on heating .

F ormose (CH20)5 i s a condensation product resulting

from the action of milk of lime on formaldehyde . It con

sists of a mixture of sugars Of the glucose group

Methylal, CH2(O CH3)2, may be looked upon as derived

from one molecule of formaldehyde and two o f methyl

alcohol

CH2(O CHa)2 . H20}

The Aldehydes and Ketones

It is therefore an ether of the hypothetical glycol

OH

<O HIt is employed as a soporific and anesthetic, B. P.

It is soluble in water, in alcohol , and in oils .

Acetaldehyde (a cetic a ldehyde, etha na l, a ldehyde),CHgCHO . The preparation of this aldehyde by the

oxidation Of alcohol has already been described It

is purified by conversion into aldehyde ammonia, which is

filtered and washed with ether. The aldehyde ammonia

is afterward distilled with dilute sulphuric acid .

It is Obtained in large quantities as a by-product in the

distillation of fermented solutions in the manufacture of

Spirits. It is a colorless l iquid , B. P. specific gravity

about .8 . It has a characteristic suffocating Odor . It isi

a

solvent for sulphur, phosphorus and iodine . Aldehyde

dissolves readily in water , alcohol , and ether. PC1 5 con

verts it into ethylidene chloride

Pa ra ldehyde (C2H4O )3 i s formed when a little HCl,CO Clz, 802 , or ZnClz i s added to aldehyde . It is formed

with a violent reaction on adding concentrated sulphuric

acid to aldehyde .

It is a colorless l iquid which crystall izes below

B. P. It possesses a peculiar, aromatic, suffocating

Odor and a warm taste ; is soluble in alcohol, ether, oils

and chloroform , and in ten parts of water . Specific

gravity, .995 at 1 5°

Paraldehyde is a hypnotic and antispasmodic, and is used

in medicine to a considerable extent .F


Paraldehyde has the constitution

O

CH3~ -CH<0

It reacts in the same way as a ldehyde with Pcl5, but

does not react with hydroxylamine, ammonia , or sodium

bisulphite . The ease with which paraldehyde is recon

verted into aldehyde by distillation with dilute sulphuric

acid is taken as evidence that the ca rbon atoms are linked

through oxygen and not carbon directly to carbon . The

bond.between two carbon atoms is much too stable to be

broken in this manner .

Meta ldehyde (C2H4O )3 is formed by the action o f gaseous

HCl or 802 in aldehyde cooled to the temperature of a

freez ing mixture . It is a white crystalline substance,insoluble in water, soluble in chloroform , benz ine, slightly

soluble in alcohol and in ether . It sublimes at 1 1 2— 1 1 5°

with pa rtial conversion into aldehyde . It is employed

as a hypnotic and sedative .

Aldehyde ammonia , CHs— C i s prepared by2

passing dry ammonia gas into a solution of aldehyde in

ether. It forms white crystals which are readily soluble

in water,but slightly soluble in ether ; M . P. 70— 80

°

It distills undecomposed at 1 00°

34 . Ch loral , Trichlora ceta ldehyde, CCls— CHO , a

liquid with a sharp and chara cteristic, disa greeable odor,B. P. is formed as the end product o f the action of


CHOG lyoxa l , I results from the oxidation of glycol or

CHO

may be prepared by oxidiz ing acetaldehyde with nitric

acid at ordinary temperatures . It is not crystallizable,but

is a solid when free from water . It forms a bisulphite

compound which is useful in its isolation .

CH20H

36. G lyceraldehyde , CHO H, results from the oxidation

CHO

of glycerol by sodium hypobromite or by hydrogen per

oxide in the presence of ferrous sulphate . There is

CHzOH

always formed with it the isomeric compound, CO

CHzOHDihydro xya ce to ne

the latter representing the principal product of the oxida

tion . Glyceraldehyde can also be prepared from acrylic

aldehyde which confirms its structure .

37. Ketones . — When secondary alcohols are oxidizedthey lose two hydrogen atoms and yield ketones, com

pounds containing the carbonyl group in a secondary

position

(1 ) CH3 —CHOH —CH3 +0 CHy— CO — CHa H20Seconda ry rop yl D imethylk etone

a lco ho lp

(Aceto ne)

They contain the carbonyl group linked to two carbon

atoms,and may be looked upon as aldehydes in which the


H of the CHO group has been replaced by an alkyl group ,or as organic acids whose hydroxyl is exchanged for alkyl .

The existence of ketones having less than three carbon

atoms is theoretically not possible.

CHs c/H

CPL

Aldehyde\0

Ketone

(2) Acetone, CHs— CO — CH3 , is also formed by the

dry distillation of the calcium o r barium salt of acetic acid

CH3

CO C a Cos

ICHs

(3)By employing acids having longer carbon cha ins

ketones with higher alkyl groups are formed . Thus a

mixture of equal molecules of ca lcium acetate and cal

cium propionate, CfL— GHz— CO O ca (ca a Ca), yields a

mixed ketone :

CHa

CHP COco C a Cos

CHr -CHr

(4) Alkyl dichlorides of the type CC 1 2 react with

R

water to form ketones


CHa CHs

CClz HZO CC 2HCl

CHs CH3

(5) Zinc alkyl reacts with the acid chlorides, forming

ketones

CIL— COCI CHazn CHa — CO — CHs i: ZHG1 2Acetyl ch loride

(zn -5Zn)

Nomencla ture. The name of the alkyl radical followed

by the ending ketone indicates the structure of these com

pounds, as dimethyl , diethyl , methyl-ethyl ketone , etc .

This also indicates the isomerism among the ketones, which

may be due to (a )The a lkyl groups having the normal or

branched structure, or (b)to the position o f the CO group

in similar carbon chains . Thus a ketone containing six

carbon atoms may be methyl-butyl ketone , or ethyl

propyl ketone, Clix— CO — ‘ C4Hg, or C2H5— CO — C3H7 .

Chemica l Beha vior (1 ) The ketones, l ike the alde

hydes , are reducible to the alcohols from which they are

formed on oxidation, thus

CHa CHz

C0 2H CHO H

Iso propyl a lcoho l

Ketones yield on reduction therefore secondary alcohols .

(2) Ketones differ markedly from aldehydes in their be

havior toward oxidiz ing agents. They yield acids having

Th e Aldehydes and Ketones 7 1

a lesser number of carbon atoms than the ketones them

selves, whereas the aldehydes yield acids of the same num

ber o f carbon atoms, thus

CHs

C0 3 O CHa— GOOH HCO O HAcetic a cid Formic a c id

Methyl-ethyl ketone may be oxidized in two ways , thus

OH3— CO; CH2— OH., yielding 2 CHeCO O H

CHe i— CO — CHe— CHn, yielding

CHa— CH2_CO O H HCO O HPropionic a cid Formic a cid

Under the influence of oxidizing agents, as chromic acid ,as well as in the animal body, the cleavage of the carbon

chain in such compounds never follows one l ine to the

exclusion of all others . There results a certain amount of

each o f the possible oxidation products . In .the case o f

methyl-ethyl ketone, formic, acetic, a nd propionic acids

would be formed , but not necessarily in equivalent amounts .

(3) The ketones are converted by PC 1 5 into dichlorides

of the type R22 CCl2 . It has been pointed out above

that these can react with water with the re formation of

ketones .

The carbonyl group o f the ketones shows less tendency

to unite with water a ndwith alcohol than in the case of


the aldehydes . With hydrocyanic acid , however, there

are formed addition products called nitriles . These

compounds are of the greatest importance in synthetic

chemistry. They will be dealt with in detail later (40,

(4) The ketones differ from the aldehydes in that they

do not polymerize . They do form condensation products,however, analogous to the behavior of aldehydes . Ace

tone, when acted upon by Hcl , H2804, KOH, C a O , and

other reagents, condenses with the separation of water .

Two molecules unite to form mesityl oxide , C sHl oO ;

three molecules condense to form mesitylene

(5) Like the aldehydes, the ketones condense with

hydroxylamine to form ketoximes

CH3\O HN— O H C — N— O H H O2

CH3/2

Acetone Aceto xime

Acetoxime on heating with concentrated Hc l decom

poses into acetone and hydroxylamine .

In a similar manner,ketones react with the amino

group of the hydrazines, forming hydra zones

CH

3

Those ketones which contain the radical CHa— CO

and a few others,form addition products with sodium

bisulphite in a manner similar to the aldehydes

/OH(CHn)2: CO HNaSO e

The Aldehydes and Ketones 73

These when heated with sodium carbonate solution

regenera te ketones. These compounds are of great

value in separating ketones from mix tures and in purify

ing them .

38 . Acetone , CHa— CO — CHn, is the simplest and

most common ketone . It is a liquid with a characteristic

etherea l odor, B. P. 56°

Its specific gravity at 0° is It is soluble in water,but much less so in solutions o f inorganic salts . Th is

property is made use of in separating it from water solu

tions . It likewise dissolves in all proportions in alcohol

and in ether.

It is a very stable substance toward oxidiz ing agents ,not being attacked by cold KM a ,

solutions , but it is

oxidized to acetic and formic acids by chromic acid . It is

very inflammable and should be handled with caution

against the ignition of its va pors . Acetone occurs in

normal urine in very small amounts, but is present in

la rge quantities in the urine of diabetic patients . Its

formation in the body will be explained later (see aceto

acetic acid,Lieben’s iodoform test fo r acetone depends upon the

fact that alkaline iodine solutions oxidize acetone and

form triiodo methane or iodoform . A solution of iodine

and KI is added to the solution to be tested and then

dilute sodium hydroxide added drop by drop . The iodine

color is discharged at once and there sepa rates at once a

crystalline deposit of iodoform . The reactions involved

are


CHn— CO — CHs 3 KIO =CfL— CO — C 1 3 + 3 KOHPo ta ssium Triodo a ceto nehypo-iodite

Po ta ssium a ce ta te Iodoform

The iodoform can be extracted with ether, and on eva

pora tion of the latter is left a s yellow hexagonal plates

having a characteristic odor . On the formation of iodo

form under these conditions depends the qualitative detec

tion of acetone devised by Vourna so s. This test is not

characteristic for acetone but is given by alcohol and alde

hyde as well .

Acetone in the presence of alka l i dissolves mercuric oxide,and this property is made use of in testing for its presence

in solution . A mercuric salt, as the chloride or nitrate, is

added to the solution to be tested, and then sodium hydro x ide to strong alkalinity, and then an equal volume

of alcohol . The solution is then filtered and the filtrate

acidified with HCl and a layer of (NHmS solution pouredcarefully upon it . If mercury is precipitated as the black

sulphide, it indicates a positive test . Aldehydes also give

this reaction .

Acetone forms with mercuric oxide the compound

2 CHn— CO — CHa 3HgO , insoluble in dilute acetic acid ;also a white crysta lline compound ,

The latter compound is very insoluble in dilute acetic

acid,and its formation is the basis o f the test for acetone

designed by Deniges.

Acetone does not reduce Fehling’s solution . With


CH— GOOH

CHaIso butyric a cid

D ihydroxyacetone chemically related to sugars

CHzCl

C 1

PO Cle

CHnCl

6H

CHAPTER V

THE NITRILES AND THEIR REDUCTIO N PRO DUCTS,THE AMINES

40. The Nitriles a nd Isonitriles. It has been pointed

out (28) that alkyl halides react with certain salts Of

acids, yielding esters , and that these on hydrolysis are

resolved into alcohols and acids . The behavior of the

salts of hydrocyanic a cid is different from others in that it

yields two classes of derivatives which do not go back into

alcohol and hydrocyanic acid , but yield a new type of

compound on hydrolysis

CHaI KCN = CI‘Is“— CN KIPo ta ssium M eth lcya nide cy a ni e

Methyl cya nide is a colorless l iquid boiling at

Its specific gravity is .805 at It is soluble in water and

is combustible .

On being warmed with either acids o r alkalies nitriles

add water (sa ponifica tion) and are converted into acid

and ammonia :

Acetic a cid

This behavior is analogous to that of hydrocyanic acid ,which when heated with dilute acids is converted into

formic acid and NH",HCN 2H20 HCO OH NH3

Formic a cid77


Aside from the importance of the nitriles for the forma

tion of acids they are of the greatest importance for build

ing up carbon chains . Thus any alcohol can be converted

by PCl5 into its alkyl halide derivative, and this on being

converted into a nitrile gains a new carbon atom

PCI5 KCNCHn— OH CH3C 1 CHa

— CN

2H20CHn— CO O H

Two practices prevail regarding the nomenclature of the

alkyl cyanides . They are called methyl cyanide , ethyl

cyanide,propyl cyanide, etc . , but are more frequently

called nitriles,and are then named after the acid which

they yield on hydrolysis . CHa— CN is called aceto

nitrile ; CH3_ CH2— 'CN, propionitrile , etc .

Nascent hydrogen reduces the nitriles to compounds

called amines . The process is one of addition of hydrogen

CH3CN 4 H CH3— CH2— NH2

Ethyl a mine

The amines may be looked upon as ammonia in which

one hydrogen atom is replaced by an alkyl group (see

amines,The formation of carboxyl and ammonia on hydrolysisand of amines o n reduction shows that in the nitrile the

nitrogen cannot be directly linked to the alkyl radical .

The CN group is linked to the alkyl group by its carbon .

Isonitriles. If instead of KCN we cause alkyl ha lide

to react with silver cyanide, there is obtained a colorless

l iquid slightly soluble in water which has an intolerable

The Nitriles a nd Amines 79

odor and poisonous properties. It ha s the same percent

age composition with respect to the elements as ethyl

nitrile , and is isomeric with it

CHé— ‘CHzl AgNC CH3— GH2 — NCEthyl iso cya nide

This substa nce behaves on heating with water or with

acids in a manner entirely different from ethyl cyanide

CH3*— CH2— N i C 2H20

CH3— CH2— NH2 HCO OHEthyl amine Fo rmic a cid

In this compound the carbon atom of the isocyanide is

split off, which indicates tha t the nitrogen is l inked directly

to the ethyl group . Unlike the nitriles they are very

stable toward alkalies .

From the above considerations it appears that the silver

sa lt of hydrocyanic acid has a structure different from that

o f potassium cyanide .

A great interest atta ches to the isonitriles or alkyl

isocyanides beca use they a ppa rently form an exception

to the general rule tha t ca rbon in orga nic compounds is

always tetravalent . Several possible assumptions may

be made regarding the structure of these compounds.

The carbon atom ma y be in a divalent state (I) o r two

o f its valences may be free, or polarized ~(II) o r the

nitrogen may exi st in the pentavalent state (III) as it is

known to be, e.g., in ammonium hydrox ide, a ll four

valences of the carbon atom being in union with nitrogen .

R— N = C R— N = C<o r R— N = C: 1 R— Ng cI I I II I


The extensive studies of Neff have afforded the -most

satisfactory exp lanation of the structure of the isonitriles,and the principles which they disclosed are of great im

portance in elucidating the nature of reactions generally

among organic compounds . A discussion of some reaotions which throw light on the behavior of these compounds

will be of value .

The isonitriles are assumed by Neff to possess the struc

ture represented by R— N C , but there exists a small

number of the molecules dissociated into the active

form R— N = C<, these being in dynamic equilibrium

with the form R— N = C which , either because its car

bon is divalent, or because two of its bonds of affinity

are polarized o r latent, i s incapable of any chemical

activity whatever . The percentage of active mole

cules varies with the nature and mass of R , a fact shown

by the variation in the chemical activity of compounds o f

this typ e .

1 . Halogens (chlorine, bromine , iodine), speed of reao

tion in the order named, are absorbed by the alkyl iso

cyanides with great evolution of heat, forming dihalogen

derivatives

R— N C<+X = X -> R— N c

/X

R— N C (X Halogen)\x

2. Ox ygen and sulphur convert the isocyanides into

isocyanates and isothiocyanates respectively

The Nitriles and Amines 8 1

R— N = C< O —> R— N = C = O

R —> R — N = C = S

3 . Alcohols in the presence of alkali”

are absorbed , giving

compounds known as imido ethers :

HR —> R— N = O

O — R O — R

4 . Hydrogen sulphide and mercaptans give the addition

products :

R— N c< s R— NH— C

R— N = C< HS— R — > R —N = C

SR

A striking property of these addition products of the

isonitriles is their low point of dissociation, i.e. the car

bon atom which has absorbed the X Y, thus becoming

tetravalent , is unable to hold X— Y above certain tem

pera ture limits . There is therefore a certain temperature,varying with the nature of all the groups in the compound ,at which the carbon atom becomes spontaneously divalent,the X— Y becoming dissociated , thus

/X

R— N =C (“ R— N =C X— Y.

\ y_>

The dissociation is very slight at low and moderate tem

pera tures and increases as the temperature is raised .

G

82 Orga nic Chemistry for Students Of Medicine

There is an equilibrium between divalent and tetravalent

carbon .

Dynamic equilibrium implies a set of conditions in

which if one o f the components of a system is withdrawn ,it is replaced by the further dissociation of a part of the

undissociated component, so that a definite relationship

always exists among the components of the system . Thus

the dihalogen addition products of the alkyl isocyanides

are converted back into the alkyl isocyanides if kept in

contact with z inc dust, the latter serving simply to tie

up progressively and remove from the system the small

amount of halogen which is dissociated . The dissociation

becomes progressive under these conditions and the rea c

tion goes to completion

/Cl

R— N = C Zn — > R— N = C + ZnC 1 2

The isonitriles ha ve a marked tendency to polymerize

and form resinous products. This is without doubt due

to the combination of the active dissociation products

with each other, the reaction in this case being non

reversible .

4 1 . Fulminic Acid.— When KCN is oxidized there is

produced potassium cyanate, KCNO . There appears to

exist an acid isomeric with cyanic acid in fulminic acid .

The free acid is not known in a state of purity, but its

salts, especially the mercuric and the silver fulminates, are

well known . The formulae for these compounds corre

spond to Hg(O NC)2 and AgO NC .

84 Organic Chemistry for Students of Medic ine

It is now made on a large scale and is used as a fertilizer .Calcium cyanamide is slowly decomposed bywater

,form

ing calcium carbonate and ammonia :

N E C -N = C a 3H20 2NH3 C a CO s

As an intermediate product cyanic acid is formed

N E C— N Ca 3 H20 CN— O H NH3 C a (O H)2Cya nic a cid

Cyanic acid readily reacts with water to form ammonia

and carbon dioxide

N s C— OH Hzo NH3 4 co2

Cyanamide is a crystalline compound readily soluble in

water,alcohol , and ether . It melts at 40

°

43 . Th e Amines. The hydrogen atoms of ammonia

may be replaced by alkyl groups, forming a class of com

pounds called amines, which have a great biological im

portance . Many o f them occur in nature, especially as

products of the action o f putrefactive bacteria on proteins .

The amines containing the lower alcohol radicals closely

resemble ammonia in odor and are even more strongly

ba sic than the latter . Like ammonia , they form white

clouds of finely divided salts when brought into contact

with volatile acids . The union with acids is attended

with the evolution of heat . They behave like ammonia

in forming double salts with salts of the heavy metals

such as platinic or gold chloride .

They difl'

er from ammonia in being combustible . The

lower members are readily soluble in water . The solubil

ity in water dimin i shes with increasing length of the carbo n

The Nitriles a nd Amines 85

chains . The volatility likewise diminishes with increasing

molecular weight, the highest members being solids insoluble in water and without odor. These are, however,still soluble in alcohol and ether and are basic in character

,

readily combining with acids to form salts . The specific

gravity of all the amines is considerably less than that of

water .

Cla ssifica tion . The amines are termed primary,secon

dary, or tertiary, depending on whether one, two, o r three

hydrogen atoms of ammonia are replaced by alkyl groups,6 .g.

CH3— NH2 (CH3)2 =NH (CH3)3 E N

M ethyl amine Dimethyl amine D imethyl amine(prima ry) (seconda ry) (tertia ry)

The characteristic group o f the primary amines is there

fore — NH2, of the secondary amines =NH, and of the

tertiary amines E N.

The rela tion of the amines to the hydrocarbons is shown

by their synthesis from the alkyl halides and ammonia

CHaI NHa CH3_NH2 HIM ethyl ammonium iodide

Methyl ammonium iodide is a salt entirely analogous

to ammonium iodide . O n the treating this salt with an

alkali, methyl amine“bermCHn— N HI NaQLL= CHa— NHZ Na I Hzo .

The amines show their cha racter a s substituted ammo

nias in uniting with water to form hydroxides

CHy — CHn— NHe H20 C2H5NH30HEthylamine Ethyl a mmo nium hydro xide

(CH3)2 =NH H20 (CH3)2 =NH20HDimethylamine Dimethyl ammonium hydro xide


The secondary amines are formed from the primary by

the further action o f alkyl halide :

CH3— NH2 CHa I (CH3)2 =NH HI

(CH3)2 NH HI Na O H (CH3)2 NH20H Na I

(CHs)2— NH + C2H5 1Cs /

N HI

Dimethy l ethyl ammonium iodide

(CHa)2\N HI N OH NHOHaC2H5/

D imethyl-ethyl ammonium hydro xide

Trimethylamine is formed by the action of alkyl halide

upon dimethylamine

(CH3)2=NH CHal (CH3)3=N HITrimethyl ammonium iodide

Trimethyl ammonium iodide on treatment with an

alkali yields trimethylamine in a manner analogous to the

primary a nd secondary compounds . Trimethylamine

can likewise take up a molecule of methyl halide (or other

alkyl halide)and form tetramethyl ammonium iodide

(CILh E N CHsI ENITetra methyl ammonium io dide

These compounds are known as quaternary bases.

They are not capable of reacting with hydroxides of the

alkali metals . They are so stable that they can be boiled

with sodium hydrox ide without decomposition . The

liquid and gaseous amines are volatile with steam , as is

ammonia , but the ammonium bases or quaternary bases

are not volatile .

88 Organ ic Chemistry for Students Of Medicine

M ethyl-methylene amineB . P . 1 66°

(CH3)2 NH (cm)2 N\HCHO CHn H2()

(ca n. NH (CH3)2 N/Methylene deriva tive o fdimethylamineB . P. 80—85

°

The wide difference in the boiling points of these two

compounds makes possible their separation . The bases

can be regenerated from the methylene compounds by

hydrolysis .

45 . Methods of Prepa ra tion . (1 ) The nitro derivatives

o f the hydrocarbons are reduced by nascent hydrogen, yield

ing primary amines

CHn— NO n 6H CI'I3 — NH2 2 H20

(2) The nitriles , including hydrocyanic acid, can take

up four atoms o f hydrogen , passing into primary amines

CHa— CN 4 H CHa— CHgNHz

HCN 4 H CHn— NHe

(3) Hydrolysis of alkyl isocyanides yields primary

amines and formic acid

(4) The action of alkyl halides on ammonia has already

been referred to

(5) The oximes (32)are reduced by nascent hydrogenwith the formation of primary amines

CPL— CH NOH 4 H CHn— CHn— NHe H20Aceta ldo x ime

(6) From acid amides by the action of bromine and

sodium hydroxide

Th e N itriles a nd Amines 89

46 . Isomerism of the‘

Amines.

— Two types of isomers of

the amines should be mentioned . One is like the isomer

ism O i the ethers , viz . metamerism . Thus

/cHeCHn— CHn— NHz and NH

\CHa

CHs\ CH3\CHn— CHn— CHg— NHg with NH and with CPL— N

Propylamine CH3— CH2/ CH3/

M ethyl-ethyl amine Trimethyla mine

The other depends upon the presence of normal or

branched carbon chains as in the alcohols

Chemica lBeha vior. (1 )The amines are not decom

posed by saponifying agents , as acids and alkalies, and

are oxidized only with great difficulty.

(2) A reaction which distinguishes the primary from

the secondary and tertiary amines is their behavior w ith

chloroform . The primary amines react with CHC 1 3 and

alcoholic potassium hydroxide, with the formation of

isonitriles . The characteristic odor of the isonitriles (40)serves as a delicate qualita tive test :

CHa— NH2+CHCL3+3KOH

CH3-N =C +3KCl+3H20

M ethyl iso cya nide

This is known as Hoffman’s carbylamine reaction .

(3)Nitrous acid reacts with primary amines , replacing

the -NH2 group by hydroxyl , — O H. Elementary

nitrogen is l iberated from the amino group

CHa— NHn HONO CHaOH N2 HnO

90 Organic Chemistry for Students Of Medicine

This reaction is of great importance in synthetic chemis

try, since it makes possible the conversion of amines into

the corresponding alcohols .

Recently it has assumed great importance in the eyes of

physiological chemists as the result of the discovery by

Van Slyke of the conditions necessary for making this

reaction the basis Of‘

a simple and highly accurate quanti

ta tive estimation of amino groups .

With the secondary amines no elementary nitrogen isformed from the imino group =NH. Instead there are

formed nitrosamines

C CH.3\HO NO

CH/Dimethyl nitrosamine

N — NO

D imethyl nitrosamine is an oil with a yellowish color

which is readily volatile with steam and can be separated

from its mixtures in this way .

Tertiary amines are not acted upon by nitrous acid .

47 . Methyla mine , CHa— NHg, occurs in Mercuria lis

perennis and in the distillate from bones and wood

and in herring brine and putrefaction mixtures . It also

appears to be a normal constituent of urine , but in very

small amounts . It is a gas which greatly resembles am

monia , but its Odor is also distinctly fish-like . It is even

more strongly basic than ammonia . Its mixtures with air

are explosive , and it burns with a yellow flame, in which

it differs from ammonia , which is not combustible . One

volume ofwater dissolves at 1 25 °

1 1 50volumes of the gas .

It precipitates as double salts the salts of platinum and

92 Organic Chemistry for Students'

Of Medicine

anaerobic bacteria on the same, but its origin through the

latter agency has not been demonstrated . It has little

biological importance .

O x yethylamine, CH20H_CH2—_NH2, has been found

among the products Of hydrolysis of lecithin

Aside from those mentioned the most important ali

phatic amines are the following

CHa\

Isobutylamine, CH— CHg— NHz, is a liquidCH3/

which boils at It mixes with water in all proportions .

It is formed by putrefactive bacteria acting on amino

isovalerianic acid , one of the digestion products Of the

proteins . Its formation will be described later It

differs from the primary amines having lower alkyl groups

in that it causes a rise of blood pressure in animals .

CH.1\

CH/It results from the putrefaction O f proteins, being

derived from the amino acid leucine (75) also on sterile

self-digestion (autolysis) of the mushroom , Boletus edu

lus, doubtless formed from leucine . When intravenously

injected it raises the blood pressure . With hydrochloric

acid it forms a salt , isoamylamine hydrochloride , which

is employed to some extent as an antipyretic . Both the

free base and its hydrochloride are soluble in water .

48 . Choline is a base of great physiological interest,since it occurs in all cells of both animals and plants and

is especially abundant in : nervous tissue . It does not occur

CH— CHn— CHn— NHg, boils atIsoamylamine,

The Nitriles and Amines 93

free in appreciable amount under normal conditions in the

animal body, but may a ccumulate in the cerebrospinal

fluid under certain pathological conditions,in which

degeneration of nervous tissue is tak ing place . Choline is

always a constituent of certain compounds related to the

fats, called lecithins which are present in large

amounts in brain tissue and in egg yolk . R om its mode

of synthesis it is shown to be a derivative of glycol

and trimethylamine . It is formed by the condensation of

trimethyl ammonium hydroxide with ethylene oxide

CH;CHs

— N +0 lCHn/ \OH \OH2 CH2

O HCHa

C ho lme

The group — CH2 —CHQO H may be called ox yethyl.

The name of choline , considering it as a substituted am

monium hydroxide , is trimethyl-oxyethyl-ammonium

hydroxide .

Choline is a strong ba se . In the free sta te it absorbs

moisture and C02 readily from the air . Its solutions may

be concentrated by boiling to 4 when it decomposes into

trimethylamine and glycol . Choline is precipitated by a

number.

of reagents, the most efficient being potassium

periodide , which precipitates 1 part in of water.

Choline possesses no marked physiological action , but

by the action of bacteria and of chemical reagents which

abstract water, a base neurine is formed , which is 1 0—20

times more toxic than is choline itself


Other amines of physiological importance can best be

described in their relations to the amino acids .

49. Physiologica l Action of the Amine s . — Whereas

ammonia, intravenously injected , produces tetanic con

vulsions, with quickening o f the heart and respiration,

the amines resulting from the replacement of the hydro

gen O f ammonia by the aliphatic hydrocarbons have but

a slight physiological action , although they irritate the

mucous membranes . The convulsant effect of ammonia

diminishes progressively as the hydrogen atoms are suc

cessively substituted , dimethylamine being less toxic than

methylamine, etc .

When the tertiary amines pass over to ammonium

compounds , i.e. the nitrogen changes from the trivalent

to the pentavalent state, a great increase in toxicity occurs .

These substances resemble many of the alkaloids in their

properties .


0 oR— CH20H R — CHO i "R— GOOHA lcoho l Aldehyde Acid

The acids derived from the aliphatic hydrocarbons are

called fatty acids beca use most o f them are found as esters

in the fa ts of animals and plants . The lower members

of the series are liquids of pungent odor and corrosive

action . They boil without decomposition and are readily

soluble in water and behave like strong acids .

F ormic acid, HCO O H, is the lowest member of the

series . It occurs free in ants and in the stings of some

insects, as bees and caterpillars, and also in certain

nettles , in the fruit of the soap tree (Sa pindus sa po

na ria ), and in tamarinds and fir cones . It is always

found in traces in perspiration and in urine . It is a

colorless liquid w ith a pungent odor . At 20° its spe

cific gravity is It solidifies in a freez ing mixture,melts at 8 3

° and boils at Formic acid is

readily soluble in wa ter and in many organic solvents .

Its vapors are combustible .

It is the strongest acid of the series , being dissociated

into H+ ions to about twelve times the extent of acetic .

acid . It produces intense irritation of the skin and forms

blisters .

Formic acid does not behave like its homologues in cer

tain respects . It is easily oxidized, with the formation of

carbon dioxide and water, and therefore possesses strong

reducing power,depositing mercury and silver from solutions of their oxides . In this respect it has the properties

of an aldehyde, a nd its ready decomposition through oxidar

The F a tty Acids

tion probably finds its explanation in the acid possessing

/O

the formula HO — C<

or hydroxy formaldehyde .H

On taking up oxygen the compound , hydro'

xy formic

/0

acid containing two hydroxyls, HO — C<

is formed .

OHTwo hydroxyls cannot remain atta ched to a single carbon

atom , however, except in a few circumstances (see chloral),and water is immediately separated with the liberation of

carbon dioxide :/0HO — C<OH C02 H20

F orma tion . (1 )Formic acid is obtained by the oxida

tion of methyl alcohol :

CHr —OH 2 O HCO O H H20

(2) Hydrocyanic acid , HCN, behaves a s a nitrile in

that it can take up two molecules of water , forming the

ammonium sa lt of formic acid

HCN 2H20 HCO O NH4

From the ammonium sa lt free formic acid can be ob

ta inedby treatment with a nonvola tile acid and distilling

2HCO O NH4 H2804 2HCO O H (NH4)280¢

(3) Carbon monox ide gas , CO, reacts with the caustic

alkalies :

C0 KO H HCO O KPo ta ssmm forma te


Chemica l beha vior. (1 ) The above reaction serves as

another example of the passage of carbon from the divalent

to the tetravalent state At 1 69° formic acid is again

dissociated into water and carbon monoxide

Fo rmic a cid

indicating that at high temperatures the carbon in certain

complexes tends to become spontaneously divalent .

(2) On strongly heating the alkali formates with alkali

hydroxide they are decomposed into alkali carbonate and

hydrogem HCO O K KOH m o 3 H2

(3) The alkali formates when heated to about 400°

decompose into oxalic acid a nd hydrogen :

COOK2HCO O K I H2

COOK

(4) Formic acid can be transformed back into its nitrile,HCN, by heating its ammonium salt above its melting

point . As an intermediary product, formamide is

produced .

— H20 —H20HCO O NH4 HCO NHz HCNAmmonium fo rm a ts Formamide

(5) Concentrated sulphuric acid withdraws the ele

ments of water from formic acid, l iberating carbon mon

0><ide= HCO O H HZO co

Of the salts of formic acid most are readily soluble .

Mercury formate, (HCO O )2Hg, and silver formates,

1 00 Orga n ic Chemistry for Students of Medicine

into alcohol and the subsequent oxidation of the alcohol

through aldehyde to acid :

O O

CPL— CHnOH CHs— CHO CHaCO OH

Its formation is the cause o f the souring of beer, wine,and cider . C ider vinegar contains small amounts of

alcohol and o f acids other than acetic (tartaric, succinic,etc .) and also ethyl esters of these acids, and to these

it owes its flavor . It contains usually but 3 to 5

of acid . The acid volatilizes readily, and in order to

Obtain it in a pure form from its dilute solutions it is con

verted into a salt which, being non-volatile, can be heated

to evaporate the water . The salt is finally treated with

hydrochloric acid , avoiding an excess, and the mixture

distilled , when strong acetic acid pa sses over

(CHy — CO O hC a 2HCl 2 CHn— CO O H C a Cln

Pyroligneous Acid.

— When hardwoods are heated in a

distilling apparatus, a ta rry product containing carbolic

acid and related substances is formed, a nd there distill s

over a gaseous mixture containing hydrogen , methane,carbon monoxide, and ca rbon dioxide , a moderate amount

of higher hydrocarbons (7 and a mixture of water,methyl alcohol , acetone, and acetic acid , together with

numerous other compounds in small quantities as im

purities . This mixture is known as pyroligneous a cid.

Methyl alcohol and acetone are so rea dily volatile tha t

they can be distilled from the dilute acetic acid, thus efl’ect

The F a tty Acids 01

ing a partial separation . The acetic acid is then neutral

izedwith lime , forming calcium acetate, C a (O O C— Cf1 3)2,and the latter is then heated to 200° in contact with air

to oxidize the tarry matters . From this crude calcium

acetate the acetic acid is obta ined .

In marked contrast to formic acid , acetic acid is extra or

dina rily resistant to oxidation . It is not oxidized by

chromic acid under any ordinary conditions and can be

passed through a glowing tube without decomposition .

It is not oxidized by dilute solutions o f potassium per

manganate, which quickly decompose formic acid . Silver

acetate in water solution can be heated without reduc

tion (blackening)taking place .

It is this great stability which explains why acetic acid

occurs in such large quantities in the pyroligneous acid .

During the decomposition of the various complex com

pounds (cellulose , lignin , pentosans, etc .) numerous de

composition products are formed which, being unstable at

high temperatures, are further decomposed, and in the

end only the most stable products remain . Numerous

compounds on oxidation yield acetic acid , and owing to its

great stability the reaction stops at this pomt.

Even the animal body possesses but a very limited

capa city to oxidize acetic acid . Normal human urine

contains from 60 to 280mgm . o f acetic acid per day .

Acetic acid , despite its stability, is readily fermented

in the form o f its calcium salt by certain organisms into

methane and carbon dioxide :

CHs— GOOH= CH4 C02


Calcium acetate when heated in the dry condition to the

point o f decomposition yields acetone and calcium car

bonate :

This type of decomposition is common to the higher

fatty acids and is therefore a general method of preparing

ketones . When the salts of two different acids are employed, mixed ketones result

t — CO O ca CHg— CH2

_CO O C38,Ca lcium pro piona te

CHg— CO — CHn— CHg (ca 1} Ca)

M ethyl e thyl-keto ne

Gla cia lAceticAcid.

— When nearly free from water aceticacid solidifies when cooled below 1 6 7

° to a crystalline

mass, from which it derived its name , gla cia l a cetic a cid.

It boils at 1 1 8° and has a specific gravity of at

When mixed with wa ter, contra ction and increase in density ensue, the ma ximum cha nge taking place when equal

molecules of water and acetic acid are combined . This

solution contains 76 per cent acid and at 1 5° has a specific

gravity of On further dilution the specific gravitydecreases until a 50 per cent solution has nearly the same

density as has the glacial acid . It is therefore impossible

to employ the specific gravity as an index to the strength

of this acid . This is obtained by titration with a standard

solution of an alkali employing an indicator.

1 04 Orga nic Chemistry for Students Of Medicine

with a known volume of standardized alcoholic potassium

hydroxide and heated until the ester is completely hydrolysed, i.e. reconverted into acetic acid and alcohol .

From the amount of alkali used up in neutralizing the

acetic acid which was formed in the hydrolysis the number

of hydroxyl groups can be estimated .

53 . The AcidAmides.

— The amides may be regarded

a s organic acids in which the hydroxyl of the carboxyl

group is replac ed by the amino group, — NH2 :

0

R— C R— C< R— C

ClAcid Acid ch loride Acid amide

The amides are formed in several ways which illustrate

their relationship to other classes of compounds

(1 ) Acid chlorides react with ammonia, forming hydro

chloric acid and amide :

CHn— COCI 2NHa CHs— CO NHn NILCI.Acetamide

If substituted ammonias (amines) are employed for

ammonia,alkylated amides result

CHn— CO Cl 2 NHg— CHa CHn— CO — NHCHaM ethyla mine M ethyl a cetamide

CHs— NHsClM ethyl-ammonium ch loride

(2) The a'

lkyl nitriles react with one molecule of water,forming acid amides

CILCN HnO CHg— C O — NH2

This reaction is the first step in the formation O f acid

from nitrile . The amides take on a second molecule of

The Fa tty Acids 1 05

water, passing into the ammonium salts of the correspo nd

ing acids

Strong dehydrating reagents, such as phosphorus pen

to x ide, can abstract from the acid amides a molecule ofwater with the regeneration of nitriles :

3 CHn.

— CO — NH2 +P205 3 CHg— CN 2HaPO 4

In order to effect the a ddition of one molecule o f water

only, the nitriles are treated with some reagent which con

tains water, but which has a strong affinity for the latter

(e.g. strong sulphuric o r hydrochloric acid).

(3)By the dry distillation of the ammonium salts of the

fatty acids, or by heating them in a closed tube to

water is separated with the formation of the amide :

CH;,— CO O NH., CHa— CO — NHZ HnO

(4) Esters can react with ammonia with the production

of amides and alcohols :

CHn— COOC2H5 NH, CHr —CO — NHn Ca OH

The amides, being derivatives of ammonia , which is

strongly basic, formed by the exchange of one hydrogen

for an acid radical , possess very feeble basic properties .

Thus acetamide forms a salt with hydrochloric acid,which

is however very easily decomposed by water . Acetamide

hydrochloride is formedwhen dry hydrochloric acid gas IS

passed into an ethereal solution of acetamide .

On the other hand the hydrogen of the NHg group in the

acid amides behaves like acid hydrogen . An aqueous

solution of acetamide dissolves mercuric oxide, forming a

compo und analogous to the salts :


CHs— CO — NH

2 CHn— CO — NHn HgO >Hg HnO

CHe— CO — NH

The relationships and mutual transformations among

the compounds o f the types thus far considered , excluding

the ethers a nd esters , a re shown by the following scheme .

The series includes some compounds which will be con

sidered immediately

CH CH C + o C

I3

+ C 1 |3

AgO H IH° Ha

GIL CH2C 1 CH,OH H

O O H O OOH

lAgOHCHnO H

CHO

H I

CO O H

CHnOH

0CHnOH

CH, CH;,

I‘

H o |H2 -

2-> CH2

GOOH

1 08 Organ ic Ch emistry for Students of Medicine

The successive carbon atoms of the fatty acids are

designated by the letters of the Greek alphabet , in order

o f their position , with respect to the carboxyl group .

Thus0 CH2_CH2 -GH2 —CH2

—CO OHa 7 B a

55 . The Hydroxy Acids . With water on prolonged

boiling the alpha-halogen acids react with the repla cement

of halogen by hydroxyl . The exchange is greatly facili

ta ted by the presence of silver oxide .

CHzCl CH20HHOH Hcl

GOOH GOOHCh lora cetic a cid Glyco lic a cid

Glycolic acid is o f interest from the biological standpoint.

It may be regarded as an oxyacetic acid . It is found in

unripe gra pes , in sugar cane , and in many other pla nts,especially in the green parts . It is taken interna lly there

fore with the food to a slight extent . It is somewha t toxic

in large doses . It is a crystalline compound , M . P.

easily soluble in water, alcohol , and ether, but difficultlyin acetone . It does not appear in the urine after a dminis

tra tion,but has been found a fter the ingestion of glycol .

It is a possible intermediary product o f the oxida tion of

certa in complex foodstuffs in the course of metabolism .

Its relation to alcohol a nd glycol , from which it is formed

by oxidation, is seen from the following formulae

CH3 CHzOH

CH20H CHO CO O HEthyl a lco ho l Aceta ldehyde Ace tic a cid

The F a tty Acids 1 09

CHzOH

CHzOH CHzO HGlyco l G lyco l a ldehyde Glyo xy l ic a cid

On further oxidation it yields a compound called gly

ox ylic acid , which is at the same time both an acid and

an aldehyde .

Glyoxylic acid is in turn in conformity with its aldehyde

nature oxidized to ox a lic a cid (1 00) which contains two

carboxyl groups

Oxa lic a cid

56 . The Amino Acids. Not only can a hydrogen atom

o f the methyl group of acetic acid be replaced by halogen,

hydroxyl , or alkyl group , but also by the amino group— NH2, with the formation o f amino a cids . In respect to

halogen , hydroxyl , and amino derivatives , formic acid

behaves very differently from its homologues, acetic,propionic

,etc . , acids . Thus chlor formic a cid ClCO O H is

incapable of existence in the free state , but its esters are

known . Thus CO C lg, which is to be regarded a s the acid

chloride o f chlor formic acid , reacts with a lcohols to form

chlor fqrmic esters :

Cl— CO — Cl HOC2H5 Cl— COOC2H5 HClCh lo r fo rmic esters

The chlor formic esters behave like acid chlorides, hOWever

,in that they are decomposed by water .

1 1 0 Orga n ic Chemistry for Students Of Medicine

Ca rbamic Acid. The ammonium salt of amino-formic

acid , or ca rbamic a cid, is formed when ammonia gas

reacts with carbon dioxide

2NH3 C02 NH2— CO O NH4

Ammo nium ca rbama te

Ammonium carbamate is present a s an impurity in

commercial ammonium carbonate . On treatment of

NH2—CO O NH4 with a mineral acid it is at once decom

posed with evolution of carbon dioxide

NHg— CO O NH4 HCl NH4Cl NHg

— CO O H

NHn— CO O H C02 NH;

The metallic salts of carbamic acid are more sta ble , but

decompose at ordinary temperatures in solution into car

bona tes

NHg— COOK H20 NH3 KHC03

Carbamic acid is distinguished from carbonic aCid in the

solubility of certain o f its sa lts. Solutions of sodium or

potassium carbamate give no precipitate with calcium

chloride , as do the corresponding carbonates .

The alkali salts o f carbamic acid lose water on heating

to redness andpass into the cyanates :

NHz— COOK KCNO H20

Ammonium carbamate is an intermediary compound in

the formation o f urea in the living tissues . Ammonium

carbamate on the abstraction o f a molecule of water forms

the amide of carbamic acid , or ca rbamide, the popular name

for the latter being urea , a name which was given to the

1 1 2 Organic Chemistry for Students of Medicine

/NH

ture C ~ OH . Thus methyl alcohol condenses with\NH2

cyanamid C to form methyl isourea

O CH3

C HOCH 3 C= 'NH.

\NH2 \NH2

The structure i s proven by the fact that on heating this

compound with hydrochloric acid (hydrolysis) methyl

chloride is formed . From methylurea , which is formed

when the salt of cyanic acid with methylamine (methyl

ammonium cyanate) is heated alone, there results, on

hydrolysis with hydrochloric acid , methylamine :

Rea rra n ement NHCH3gCO/

\NH2

M ethyl urea

CH3NH2 HO CN

HnO NH3

In isomethyl urea the methyl group cannot be linked to

nitrogen .

When heated , urea melts and at a higher temperaturebegins to evolve ga s, consisting of ammonia a nd carbon

dioxide . The melt finally solid ifies . There are several

typ es o f decomposition which take place, the principal

ones being the formation o f biuret and cyanuric acid .

(1 ) NHn— CO NH2 H HN— CO — NHz

NHn— CO — NH— CO — NHZ NH,

B ruret

The Fa tty Acids 1 1 3

(2) HN— CO — NH

/CO — NH

\NH C0 2NH..

\CO — NH/Cya nuric a cid

The reactive form of cyanuric acid is probably not that

indicated by the above formula . It is a tribasic acid , and

forms salts, indicating the presence o f three acid hydrogens .

It is best represented by the following structural formula

/OH

C

\O H

57. Urea is one of the longest known of organic com

pounds. It constitutes 85— 90 of the nitrogen o f normal

human urine . The average amount of urea eliminated

daily by a man on an ordina ry diet is about 30grams . The

amount ma y vary grea tly with the character of the diet,being high when much protein 1 8 eaten a nd low when the

protein inta ke is low . It is a neutra l substance, forming

crystals which melt a t 1 30 very soluble in water

( 1 1 )a nd in a lcohol (1 5 of cold alcohol), but insoluble in

ether and chloroform .

Urea is a neutra l substa nce with respect to indicators,but acts as a feeble base in tha t it forms sa lts with acids .

Urea nitrate, CO (NH2)2 HNO 3, is a crysta ll ine compound

soluble in water,but slightly soluble in nitric acid . It is

— OH

1 1 4 Organic Chemistry for Students of Medicine

slightly soluble in alcohol , but easily in acetone . It is

employed for the isolation of urea from urine . The salt

is decomposed by barium carbonate

2 CO (NH2)2 ° HN03 Ba c03 Ba (N03)2 "i" C02

NH2

H20 CO<

The urea is separated from Ba (N03)2 by solution in

alcohol . Urea forms salts with other acids, the most

important being that with oxalic acid ,This is a crystalline compound soluble in water, but nea rly

insoluble in oxalic acid solutions, slightly soluble in alcohol .

It is also employed for the isolation of urea from urine .

Urea also forms a compound with mercuric nitrate and

mercuric oxide o f the formula

2 CO (NH2)2 Hg(N03)2 3HgO

It likewise forms a compound with mercuric oxide,CO (NH2)2HgO .

Urea in moderate concentration possesses no appre

cia ble toxi city for the higher animals, but is much more

toxic to birds. The latter do not excrete their waste

nitrogen as urea , but principally as ammonium urate

Even in so great dilution as in solutions, urea is

noticeably toxic to certain plants . Certain bacteria can

employ urea as a source of energy, although it yields very

little energy on decomposition . The change which takes

place in urea fermentation is as follows :

CO (NH2)2 H20 C02 2NH; 1 02 Calories

1 1 6 Orga nic Chemistry for Students Of Medicine

Thiourea crystallizes readily in very large crystals .

It is readily soluble in water but insoluble in alcohol . It

melts at It exhibits the behavior of existing in the

tautomeric form in part , for on treatment with alkyl

iodide it forms alkyl thioureas which possess the pseudo

form , the alkyl group being linked to sulphur instead of

nitrogen

/NH2 /NH2

C— SH IC a C— S— C a HI\NH

Pseudo-ethyl—thiourea

That the alkyl group is linked to sulphur is shown by its

decomposition into ethyl mercaptan instea d of ethyl

amine, as it would were the ethyl group linked to nitrogen

When treated with mercuric oxide thiourea loseshydrogen sulphide and forms cyanamide :

NH2

C C + H,s

\N

59. Esters of Carbamic Acid. Carbon oxychloride,CO Clg, which is formed by the direct union of carbon

monoxide and chlorine in sunlight, can react with alcohol

to form the ethyl ester of chlor formic acid

C 1 -CO — C 1 HOQ E , C l — O Q H6 HClCh lor formic ester

Chlor formic ethyl ester is a volatile liquid of very pun

gent odor which boils at It reacts like an acid chloride,being decomposed by water .

The F a tty Acids 1 1 7

60. Urethanes.

— Chlor formic ester reacts with am

monia to form amino ethylforma te, the ethyl ester of amino

formic acid . This compound is called uretha ne

C0 NHe C0 HC 1

\O Q H5\O C2H5

Urethane is a colorless crystalline substance possessing a

faint peculiar odor and a taste somewhat like that of

potassium nitrate . It is soluble in parts of alcohol ,1 part o f water, 1 part of ether, and in 3 parts Of glycerol .

It melts at 48—50° and boils at It is employed as

a sedative and hypnotic . A number o f derivatives of

urethane have been introduced as hypnotics and sedatives

in the quest fo r those which possess the most advantageous

properties . Among these may be mentioned

Hedona l is an ester of carbamic acid with the amyl

alcohol, methyl propyl carbinol

CO/CH;,

\O CH— CH,— OH2— CH,

It has a greater hypnotic effect than has urethane . The

urethanes are diuretics , as well as hypnotics . In the body

they are oxidized to carbon dioxide and urea .

6 1 . Guanidine is formed when cyanamide reacts with

ammonium chloride

NH2+ NILC 1 = C = NH HC1

\NH2

Gua nidine hydro ch lo ride

1 1 8 Organic Chemistry for Students Of Medicine

It may be regarded as urea in which the oxygen is re

placed by the divalent =NH group (imino group). It

also results from heating thiourea through the loss of

hydrogen sulphide

HnN— Cu NHn— CN

/NH2NH2

'_C E N NHs HCNS C Z NH +HCNSCya na mide Ammonium thio cya na te \NH2

Guanidine is a colorless crystalline compound of a

strongly basic character which absorbs moisture and

carbon dioxide readily, forming a solution o f guanidine

carbonate, [NH = C

It is hydrolyzed by alkalies to urea and ammonia

/NH2 NH2

\NH2 \NH2

Guanidine reacts with strong nitric acid to form a nitro

compound , nitro gua nidine, which on

i

reduction yieldsamino gua nidine

/NH— No2 /NH

— NH2

C z NH + 6H = C= NH\NH2 \NH2

The latter is hydrolyzed by boiling with dilute acids o r

alka l ies, forming hydraz ine carbon dioxide, and am

monia .

62 . Arginine is an amino acid obtained by the hydrolysis of proteins by mineral acids . On hydrolysis by

alkalies it is split up into urea and ornithine, an acid con


/NH2CHg

— CO O H,

is found in the free state in the adductor muscle of the

scallop and in plant juices . It is a constituent of many

proteins and is formed from these on hydrolysis by a cids.

It is the only amino acid derived from proteins which

is certainly dispensable from the diet during growth .

It plays an important mile in the body as a protective

substance, being condensed with severa l types of organic

acids which are toxic, forming, with the separation of

water, combinations which are of very much lower

toxicity. An example of such a union is hippuric acid

(see Hippuric Acid). Glycocoll is also a constituent of

bile, where it exists combined with cholic acid as glyco

cholic acid .

Glycocoll is both an acid and base by reason of its car

bo xyl and amino groups, but these neutralize each other’s

effects so that its solutions react neutral to litmus , phenol

phthalein, and certain other indicators . It forms salts

with bases, the most important because of its tendency to

crystall ize being that with c0pper :

NHn— CHn— COO\

NHn— CHz— COO/

This salt forms a deep blue solution . It likewise forms

salts with acids, e.g

CH2— NH2 HC 1

63 . Aminoacetic Acid, glycine , glycocoll,

GOOHGlyco co l l ch lorhydra te

The Fa tty Acids 1 2 1

These salts are crystalline , but are extremely soluble in

water and are acid in rea ction .

Of great importance in the isolation of glycocoll , as

well as other amino acids, is the ethyl ester . It is formed

by passing dry HC 1 gas into a suspension of the amino acid

in absolute alcohol . As the hydrochloride is formed,it

goes into solution and is then esterified. When the alcoholis evaporated the hydrochloride of the ester is obtained .

From this, on treatment with strong sodium hydroxide , the

ester is set free from the HC1 and can be extracted with

ether . All the esters of the amino acids are soluble in

ether.

Glycocoll ester chlorhydrate iS '

very sparingly soluble in

CHn— TNHz HC 1

COOC2H5

absolute alcohol,which contains all the HCl gas which it

can dissolve and crystall izes from such a solution to a n

extent approximating a.

quantitative separation . This

principle has been utilized for its estimation and prepara

tion .

Glycocoll ester distills with some decomposition at

ordinary pressures at Under diminished pressure it

distills without decomposition .

With HNO z glycocoll , l ike other amino acids, decom

poses with the formation of a hydrOx y acid and elementary

nitrogen .

GHQ— GOOH HONO CHzOH— O OOH+N2+H20


With formaldehyde its amino group condenses to forma methylene derivative which has no basic properties and

can be sharply titrated with alkali and an indicator :

CHn— GOOH HCHO CHe— GOOHno

NH2 N CH2

Amino acids, when treated with acid chlorides, yield

a cetyl derivatives of the following type :

CHgNHg CHg— NH— CO — CH3

CHe— COCI HC 1GOOH GOOH

Acetyl glyco co l l

Acetyl derivatives of the a mines and amino acids are

readily hydrolyzed into acetic acid and free amino group

by boiling with dilute alka l ies . Derivatives o f this class

can be formed by employing chlorides of other organic

acids, as propionyl or butyryl chlorides . The groups

are collectively known as a cyl radicals , and the process of

forming esters from alcohols and acid chlorides or amides

from amines a nd acid chlorides is known a s acylation .

Acyl derivatives can frequently be purified much more

satisfactorily , because o f grea ter insolubility or greater

tendency toward crystalliza tion , than the alcohols or

amines themselves, a nd are useful for the isola tion and

purification of many compounds, these being afterward

regenerated by hydrolysis

CHz— NH— CO — CHa+HOH l +CH.CO O H

CO O H GOOH


It is soluble in parts of water at 1 00 cc . of 85

per cent alcohol at 1 7° dissolve .008 grams . On heating

with alkalies it is hydrolyzed into urea and sarcosine or

methyl glycocoll.

NI‘IzCH.

HN_— _C +HOH C0

/CHe NH— CHn— GOOHN Sa rco sine\CH2— GOO H

Creatinine is the inner a nhydride of creatine . It is

formed from creatine by boiling with mineral acids, which

causes the abstraction of the elements of water

/NHHHNz C Hzo HN

—C

/CHsN\CH2__CO OH Crea tinine

This compound is a never failing constituent o f the ur ines

of mammals . The da ily excretion for man is .75 to

gram, and on diets free from creatine or creatinine the

output is surprisingly constant and is independent of the

intake of protein . Its precursor in the body is unkno

Creatinine is soluble in parts of cold water and more

readily in hot. It dissolves in 625 parts of cold absolute

alcohol . It is a strongerbase than ammonia and displaces

the latter from its salts . The most important salts are the

potassium creatinine picrate,

C4H70N3 C 6H307N3 C 6H207N2K


and the z inc chloride double salt, The

most important color reaction o f creatinine is that with

picric acid and sodium hydrate . The color closely resem

bles the deep orange of a solution of potassium dichromate .

The Betaine s . — These form a group of natural

bases . The simplest member of the group is beta ine or

trimethyl glycocoll anhydride .

CH2 — N(CHa)3 CHz

IH.oC O 0

Trimethyl ammo nium Be ta ineAcetic a c id (hypo thetica l)

Its relation to the following bases is of interest

CH. CH— NH\

C — N/ CH2 CH— Co

CH2 N — o

CH CH. CH.Sta chydrine or

CPro lme—be ta ine

Trimethyl histidine

CHn— CH20H CH. CH2

N (CHa)3 NE (CHs)3

Cho line

CHz— CC

Beta ine

1 26 Orga nic Ch emistry for Students of Medicine

The beta ines are found in numerous plant extracts .

Those from mushrooms and spores have been most

investigated .

fy-n-butyro beta ine has been isolated from putrid meat ;

trimethyl histidine and musca rine from mushroom extract ;sta chydrine from various plants ; and choline and neurine

from the brain , the latter only after decomposition .

64 . Acid Anhydride s . — There exists an important class

o f compounds which may be regarded as derived from two

molecules of acid by the abstraction of a molecule of

water . These are known as acid anhydrides

CH.— GOOH CH.— C0

\0 noCH.

— CO O H CH.— CO>O

Acetic a nhydride

Corresponding anhydrides of the other fatty acids are

known . The lower members are liquids ; those of higher

molecular weight, solids of neutral reaction . The lower

members react readily with water, regenerating the acids

from which they were formed :

CHs— CO

H20 2 CH.CO O HCHs

— CO

The higher members are much more stable toward

water . Acid anhydrides react with alcohol to form esters

in the sense of the following equation :

R— CO HO R’

>o 2 R— COOR'

no

Ester


strong calcium chloride solutions . On adding this salt

to its solutions it separates as an oil. Propionic acid

is diflicult to test fo r with certainty, since its properties

are so closely similar to those of its immediate homologues,acetic and butyric acids . The silver salt contains

o f silver, and the barium salt of barium . The

analysis o f these salts, both of which are sparingly

soluble in water, is the most convincing qua lita titive test .

a -chlor propionic acid , CHa— CHCl— CO O H, is

formed by the direct action of chlorine upon propionic

acid in the sunlight . The isomeric fl-chlor derivative,CHzCl— CHz— GOOH, is likewise formed to some extent .

The structure of these acids is made clear by other methods

o f formation ; thus acetaldehyde adds hydrocyanic acid,forming hydroxy propionitrile

CH. CH.

2moHCN CHOH + NH.

O H GOOHCN

a -hydroxy propionic acid , or lactic acid , yields when

treated with PCI5 a product in which both the hydroxyl

group of the carbo xyl and that on the a —carbon atom are

replaced by chlorine , viz . : a -chlor propionyl chloride,CHa — CHCl— COCI. This, l ike acid chlorides in general,is decomposed by water, forming a -chlor propionic acid

CHs— CH2Cl— COC 1 HOH CHa— CHCl— GOOH

HC1


a —chlor propionic acid is of interest because it can beemployed either fo r conversion into lactic acid or intoa -amino—propionic acid , or alanine, one of the amino acids

derived from proteins on hydrolysis

CH.— CHC1 — C OOR AgOH

CH.— CHOH -COOR AgClLa ctic a cid ester

CHa— CHCl— COOR NHs

CHa— CH— COOR HC1

66 . Lactic Acid, CHa— CHOH— CO O H, is the acid of

sour milk . It is formed from milk sugar by the action

of the lactic acid bacteria . Other sugars, as cane

sugar, can likewise be used by this organism with the

production of this acid . If a liter of 1 0% cane sugar

solution be treated with 40 grams of calcium carbonate

and 20—30 cc . of sour milk to supply the bacteria and the

proteins , salts , etc . , necessary for their multiplication , and

the mixture kept at 37° fo r six to eight days, with occa

siona l agitation , it will contain a considerable amount of

calcium lactate . The solution is then boiled and eva po

rated to a small volume and cooled , when calcium lactate

will crystallize out . On treating the crystals with sulphu

ric acid , calcium sulphate and free lactic acid are formed .

The lactic acid can be extracted from the mixture by ether,in which it is readily soluble . On distilling off the ether

lacticacid remains .Lactic acid occurs in other fermented substances, such a s


sauerkraut and ensilage , in both cases arising through the

agency of micro Orga nisms. The conditions essential to

the preservation of succulent vegetables and -green fodders

in these forms are close packing in an air-tight container

from which the gases produced can escape . Rapid fer

mentation and respiration quickly remove the small

amount of oxygen from the container, and through the

catalytic action of enzymes in the plant cells a part of the

sugars are converted into lactic acid . The acidity, to

gether with the very considerable rise in temperature,causes the death o f most of the micro Orga nisms, and

the material is preserved from putrefaction or further

fermentation .

Lactic acid is a sirupy liquid which decomposes on dis

tilla tion at ordinary atmospheric pressure , but can be

distilled at about 85° if the pressure be reduced to .5 mm .

o f mercury . D istilled in this way, it crystallizes . The

crystals are hygroscopic . It is readily soluble in water,alcohol , and ether, but insoluble in chloroform , carbon

disulphide, o r petroleum ether . It does not distill with

steam . Lactic acid is decomposed when heated with

dilute sulphuric acid into acetaldehyde and formic acid :

CHs— CHOH— CO O H CHa— CHO HCO O H

According to certain investigators this reaction is

catalyzed in the production of alcohol by fermentation,the formic acid being further decomposed into hydrogen

and carbon dioxide , and the hydrogen serving to re

duce the aldehyde to alcohol . (See Fermentation .) The

most characteristic salt o f lactic acid is the z inc salt,


an a symmetric ca rbon a tom, i.e. one whose four valences are

bound each to a different radical or group . Lactic acid

possesses a structure which conforms with the require

ments of asymmetry, and we should“therefore expect to

find two kinds of lactic acid , having the same chemical

properties and the same physical properties (specific

gravity, boiling point , melting point , etc .) except in their

behavior toward pola rized light . This is actually the case .

There are two classes of substances which show optical

activity. Some , l ike quartz and sodium chlorate, produce

rotation only in the crystallized state . When they are

dissolved or fused the optical property disappears . Others,l ike active amyl a lcohol , lactic acid , oil O f turpentine,camphor, and sugar, are optically active whether in the

crystalline or in the liquid state , or in solution . In the

former case the molecules themselves do not have an a sym

metric structure , but they unite to form crystals which do .

We may liken this to the construction of a spiral staircase ,an asymmetrical structure from symmetrical bricks . When

the staircase is again resolved into its component bricks,the asymmetry disappears . The optical activity of these

substances depends therefore upon a peculiar arrangement

of the molecules to form a n asymmetric structure . In the

case of compounds which are Optically active in the liquid

state , the asymmetry resides in the molecules themselves .

Ordinary lactic acid, obtained either by fermentation of

milk or by synthesis, i s optically inactive . There is in the

normal muscle tissue of all higher anima ls, especially after

activity , an appreciable amount of dextrorotatory lactic

acid . The typhus bacillus and various vibrios ferment


cane sugar with the formation of levorotatory lactic acid,

and when these are mixed in equimolecular proportions

there results the inactive acid identical with that obtained

by synthesis or from fermented milk . Dextrolactic acid ,from its presence in muscle, is called sa rcola ctic a cid. It is

present in muscle to the extent of .3 parts per thousand .

For brevity the two forms are written d and l-lactic acids .

The reason for the difference in optical properties is best’

explained by the theory of Van’t Hoff and Le Bel, who

arrived at the same conclusions simultaneously and inde

pendently in 1 874 . The reasoning is briefly as follows

The four affinities of the carbon atom are not to be con

ceived o f as lying in the same plane, otherwise isomers

should exist in compounds of the general type Ca a bb,where a and b represent atoms or radicals N0 such

isomerism ha s ever been observed . The simplest a ssumption that we can make with regard to the distribution in

space o f the four atoms o r groups attached to the carbon

atom is that the direction of each makes equal angles with

the directions of the three others . This is equivalent to

saying that the four a toms or groups are situated at the

solid angles of a tetrahedron in the center of which the

carbon atom itself is situated .

‘ If the groups or atoms are all alike, they will be equally

attracted by the carbon atom and the tetrahedron will be

regular . If they are all different, the force with which each

will be attracted will probably be different and they will

arrange themselves at different distances from the carbon

atom ; the tetrahedron will then be irregular, i.e. it will

have no plane of symmetry . Any compounds of the for


mula CHa bc can ex ist in two forms called ena ntiomorphs,

which are alike in the sense that an object is like its mirror

image, but they will not be superposable .

F ro . 1 1 .

A consideration of Fig . 1 1 will help to make clear

If we consider any group of three of the atoms or groups,

(HI HO ‘

CO O HGO O H

F IG . 1 2 .

as Hbc, looking toward the face about which they are

arranged , any order as Hbc which is clockwise in one

figure will be counterclockwise in the other . If they are


chance of affecting the other . In the synthesis of hydroxy

propionitrile the same reasoning holds good . Whenhydrocyanic acid condenses with acetaldehyde , Fig . 1 4,

the addition will take place as frequently according to one

scheme as the other, and the acid resulting from the hydrol

ysis of the nitrile must be inactive .

The formation of inactive lactic acid in fermentation in

volves without doubt an addition of H and OH to an inter

HCN

- O —H

F IG . 1 4 .

mediary product of bacterial action in ‘

which the law of

chance determines the positions which each radical takes .

This will be further discussed in connection with fermenta

tion

The production of l-lactic acid by certain organisms or

the d-acid in the muscle tissues results from the cleavage of

lactic acid from more complex compounds (sugars)which

are themselves optically active and on which the positions

of the H and OH groups are already determined in the

molecule of the mother substance .

Lactic acid is decomposed by heating,with sulphuric

acid into acetaldehyde and formic acid

CHa— CHOH— GOOH CHa— CHO HCO OH


This decomposition is of interest because it shows the

ea siest line of cleavage of lactic acid . Acetaldehyde is

without doubt formed from lactic acid in its decomposi

tion by living tissues .

69. d-Ala nine , a -aminopropionic acid ,

CHa— CH— CO O His a constituent of the protein

NH2

molecule and is formed on hydrolysis of the proteins by

boiling with strong mineral acids . It is present in silk to

the extent o f over 20 It is formed , as a re all the other

amino acids found in proteins, by complete digestion of the

latter with the enzymes , trypsin from the pancreas and

erepsin from the mucous lining of the intestine . It is

formed from a -chlor propionic acid on treatment with

ammonia

CHn— CHCl— CO O H+NHs CHs— CH— CO OH+HC 1

NH2

Al so by the interaction of acetaldehyde with ammonium

cyanideHNH2 /

NH2CI‘Ia— CHO CHa— CH H20

\CN

CHt— CH 2H20

CHg— CHNHz

— GOOH+NH3

The reactions of alanine with chemical reagents are

analogous to those of glycocoll With nitrous acid it


is converted into lactic acid . Since it contains an a sym

metric carbon atom (68)it possesses optical activity and

occurs in the d and l forms and in the d, 1 form . Its

isomerism is that of enantiomorphs and is analogous to

that of the lactic acids .

Of the two optical isomers only the d form is of biological importance . When yeast is allowed to act on a sugar

solution containing d , l-alanine , the d form is used up as a

source of energy, leaving the 1 form unchanged . This

method is employed generally in preparing the form of

amino acids not found in nature . It is a remarkable fact

that in the life processes of animals and plants, with but

few exceptions, the compounds which play an important

rOle are optically active, and but a single optical form occurs

in na ture . In no case can the Optical antipode when

synthesized in the laboratory be substituted for the nat

ura lly occurr ing form in biological processes .

A remarkable transformation of one optical form of

alanine into the other occurs when d-ala nine is treated with

nitrosyl bromide, and the resulting l-a —brom propionic

acid is again converted into alanine by treatment with

ammonia .

‘With each repetition of these two transform

a tions the alanine is changed from one optical form

into the other . The following scheme will make this

clear :

d-alanine NH3 d-a -brom propionic

1‘

NGBr

fl-a -brom propionic acid NH3 l-alanine


CHZOH

Serine , a -aminO-B-hydroxy propionic acid'

, CH_NH2

GO O H

is another amino acid found among the products of the

hydrolysis of the proteins. It is especially plentiful in

silk . It is closely related to cystine , on the one hand, and

to alanine, on the other .

70. Butyric Acid.

— Two acids having the for

mula C3H7CO O H are known . Normal butryic acid,CHs

— CHa— CHz— GOOH , is formed from primary

propyl iodide by the action of KCN and subsequent

hydrolysis of the resulting nitrile

CH. — CH2— CH21 +KCN CHs— CHz— CHz— CN+KI

CHa— CHn— CHz— CN+2HzO

CHa— CHe— CHz

— CO O H+NH.

Isobutyric acid is formed in a simila r manner from sec

onda ry propyl iodide and KCN. It is therefore dimethyl

acetic acid

CHe CHa+2H.o

CHI +KCN CH — CN CH— GOOH

Normal butyric acid is found in butter, as the glycerin

ester, to the extent of 2— 4 Several kinds o f micro

organisms have been described (e.g. B. butylicus)which


ferment sugars with the formation of butyric acid .

Al l Of these produce the normal acid . It is not produced

in putrefaction . B. hollobutyricus can produce butyric

acid from calcium lactate . The mechanism of this trans

formation can be discussed more satisfactorily after the

properties o f the unsaturated compounds have been

treated Normal butyric acid is a colorless, viscous

liquid with a pungent, disagreeable, rancid odor . It is

readily soluble in water, but is salted out by calcium

chloride and other salts . It boils at

The calcium salt (C4H702)2C a HZO is more soluble in

cold than in hot water . This peculiar behavior is prob

ably to be explained by the formation at low temperatures

of a compound between the Ca salt and water whereby a

hydra te is produced which is soluble . This is unstable

at higher temperatures , so that on heating the higher

hydra te disappears and the sa lt with the lower water

content, being insoluble, separates out.

There is no a -amino butyric acid corresponding to glyco

coll and alanine found in nature . In very dilute solutions

a nd in the presence of suitable salts and a source

o f nitrogen, various molds, yeasts, and bacteria can

employ butyric acid as a source of carbon . It is toxic,however, and possesses the property ofparalyzing the motor

nerve endings without interfering with the power of the

muscle to contract .

71 . Isobutyric Acid,\CH— CO O H, is a product

CH./

of the putrefaction of proteins, where it results from the


decomposition of valin or a -amino isovalerianic acid

This isomer of normal butyric acid is not formed in

fermentation of the sugars . Its odor is similar to that of

n-butyric acid, but is not so offensive . It boils at 1 54°

and, unlike its isomer, its calcium salt, is more soluble in

hot water than in cold . No amino derivatives of iso

butyric acid occur in nature . Its physiological and phar

ma cologica l properties closely resemble those of n—butyric

acid .

72 . Valerianic Acid, CHa— (CH2)3 —GOOH . Four

isomers are possible . There are but two of these which

are of biological importance , the most common one being

isova leria nic or isova leric, which is isopropylacetic acid

CHa

>CH— CH. -GOOH

‘ 0

CH3( ”W i n - C

lix” 5-0“

a t?"It occurs in valerian root and in other plant juices, and

among the putrefaction products of proteins, where it is

derived from the amino acid leucine It results from

the oxidation of fermentation amyl alcohol . B. P.

It has an Odor like tha t of Old cheese .

Bromine acts on isovaleric acid, forming a -brom iso

valeric acid . M . P. B. P. 1 50° and 44 mm . pressure .

O rnithine , a -O-diamino va leria nic a cid, does not occur in

nature as such but is a cleavage product of arginine

resulting from the hydrolysis of the guanidine radical .

Ornithine is the mother substance of tetramethylene

diamine, or putrescine, a base found in putrefying protein

mixtures .


and its mirror image, and have therefore the same physical

properties (density , solubility, etc .)except as respects their

influence upon polarized light There are in many

plants organic bases of complex constitution which contain

in their molecules one o r more asymmetric carbon atoms

and are therefore capable of existing in optically active

forms . As in the case of alanine and valin and other

amino acids to be described later, there is found in nature

only one Optical variety, the other being incapable of play:

ing any r61 e in biological processes. Examples of such

natural plant bases are quinine, strychnine, nicotine, etc .

When now an inactive mixture of d and l acids istreated in solution with an optically active (i.e. a symmetri

cal)base , as strychnine, there are formed salts of the acid,e.g. d

,l-valin , and base in the following combinations :

l-strychnine l-valin

l-strychnine d-va l in

The salt molecules thus produced are no longer of the

same structure and accordingly show different physical

properties,as solubility, etc The form having the greater

insolubil ity tends therefore to crystallize out first when the

solution is concentrated by evaporation of a part of the

solvent . After recrystallization of the salt it is decomposed

by the addition of a stronger alkali to it in solution, when

the very sparingly soluble strychnine crystallizes out,

leaving the optically active acid in solution as a metallic

salt . The mother liquor contains the more soluble isomer.

Mention has already been ma de of a second method of

preparing one Optical isomer from the inactive mixture


which is based upon the ability of a living organism to use

as food but one Of the two forms This method

applies only to the preparation o f that form which has no

biological value .

Valin is the mother substa nce of isobutyl alcohol, as it is

formed through the agency of yeast during fermentation .

Yeast possesses the power to catalyze the following teac

tions

(1 ) CH3\CH— CH— CO O H

CHeNH2

tH20 >CH— CH— C O OH NH.

CH3

iv o ry-iso va leric a cid

>CH— CH.OH CO .

Iso butyl a lcoho l

It is this type of decomposition of various amino acids

which leads to the formation of fusel oil. Amyl alcohol

has its origin in a similar manner from the amino acid

leucine

Under the influence of putrefactive bacteria (anaerobic

conditions) the amino acids are deaminated, i.e. lose the

1 46 Organic Ch emistry for Students of Medicine

amino group without losing the carboxyl group (deca r

bo x yla tion).

CH.

>CH— CH— CO O H 2 H

H —CH2— GOOH NH3

Iso va leric a cid

It is by this type of reaction that the valeric acid in

feces and other putrefying mixtures is formed . The

anaerobic organisms have the power of obtaining oxygen

from certain organic compounds, and in so doing hydrogen

becomes available in the nascent state, when it effects such

reactions as that just described .

74 . Caproic Acid, CH3(CH2)4 — GOOH .

-The normal

acid has been found in several pla nts, but it is of little

biological importance . One of the isocaproic acids, iso

butyl acetic,

(CH3)2 CH— CHz— CHz— CO O H

is contained in butter in the form of its glycerol ester.

This isomer is of interest because one o f its derivatives,viz . ,

a -amino-isobutyl acetic acid , called for brevity

leucine, is a regular constituent of the proteins, from which

it results on hydrolysis .

Lysine,a -e-diamino caproic acid , is one of the amino

acids derived from the hydrolysis of proteins . It together

with arginine (62)and histidine were formerly, and still to

some extent are, designated as the“hexone bases because


ammonia with the replacement of the hydroxyl by an

animo group . On hydrolysis of the nitrile to the corre

sponding acid inactive leucine results

CH— CHz— CHo 0

CH— CHg— CHO HCN NH3

CH— CHg— CH— CN 2H2O — NH3

NH.

a -amino-iso va leronitrile

OH— CHz— CH —CO OH

Leucine is the mother substance of the inactive isoamyl

alcohol of fermentation . The reactions by which it is

probably formed were described under valin ' It is

not definitely established however whether or not the

steps in the reaction involve the formation of isova lera lde

hyde and formic acid

CH. 5

>OH— CH. — CHO:H — CO O HCH. 5

subsequent reduction Of the aldehyde to isoamyl

Such a course is in harmonywith the well-known

Th e Fa tty Acids 1 49

tendency of lactic acid to separate into acetaldehyde and

formic acid

76 . Isoleucine , CH— CH— CO O H,

CH. CH.NH.

a -amino-methyl-ethyl propionic acid , has been isolated from

beet molasses and from germ inated peas , and occurs

among the hydrolysi s products of many proteins . Since

so far as is known all o f the amino acids found in proteins,with the single exception of glycocoll , are indispensable

in the diet, all amino acids so derived are of the greatest

interest and importance .

Isoleucine is , like leucine , used by yeasts as a source

of nitrogen and energy . It undergoes cleavage into a n

optically active amyl alcohol , secondary butyl carbinol ,by the loss o f carbon dioxide and ammonia :

CH.

>CH— CH— GOOH H.OCH.

— CH.

NH2

CH.

>CH— CH.OH CO 2 NH.CH. CH.

Putrefa ctive organisms change isoleucine into isocaproic

acid, which is found in feces

77 . High er F atty Acids . From C. upward only those

members of the fatty acid series, have any

portance which"

contain an even number of carbon atoms .

Those with an uneven number o f C atoms either do not


occur or are found but seldom and in traces. This remark

able fact has led to much speculation as to the mode of

formation of the fatty acids in the plant and animal

world , since any proposed series of chemical changes which

lead to the building up of these acids in nature must, to

constitute a tenable hyp othesis, produce the even members

only . Recently Miss Smedley ofEngland has carried out

synthetic work which throws much light on the mecha

nism of this synthesis . Its description must be deferred

until certain other compounds are described

The interest in the fatty acids from C 6 to C 1 3 depends

upon their great biological value a s constituents of the fats .

None of the fatty acids conta ining more than six C atoms

are found in nature in the form of their amino derivatives .

By definition fa ts a re the esters of the tria tomic a lcohol

glycerolwith thefa tty a cids. Accordingly the ester of acetic

o r propionic acids would be classed chemically with the

fats, although they do not have the characteristic physical

properties o f the fats,viz . a smooth, greasy feel , insol

ubility in water, and oh character when melted . The

term fat usually signifies only those members of the series

which possess the physica l properties of fats . The names

of the fats are derived from the name of the fatty acid

with the ending -in substituted for -ic . Thus the tri

ester of glycerol with formic acid is triformin ; with acetic

and butyric acid, tria cetin, tributyrin, etc .

Since three esters are possible according a s one, two, or

three acid radicals are joined in ester formation with one

molecule of glycerol , we distinguish mono di and tri

butyrin, caproin, etc .


(37) the higher fatty acids are convertible into the lower

members of the series .

Thus when barium stearate and barium acetate are

subjected to dry distillation in a vacuum , barium car

bonate and ma rga ryl-methyl-ketone are produced :

C 1 7H35 CO O ba +ba O O CCH3 C 1 7H35— “CO — CH3

On oxidation of the ketones the carbon chain is broken

(37)and a fatty acid containing 1 7 carbon atoms, ma rga ric

acid , C 1 7H3502 , and acetic acids are formed . By repeating

the ketone formation and ox idation as described the carbon

chain has been shortened by CH. in successive steps with

the formation successively of palmitic,myristic, lauric,

and capric acids on each occasion when the product had

an even number of carbon atoms . The acids up to capric

have been synthesized by building up the carbon chain,

e.g. by the formation of the nitrile from the primary halide

of nonane, and hydrolysis of the nitrile to the correspond

ing acid .

CHAPTER VII

THE UNSATURATED HYDRO CARBONS

78 . Alkylenes or O lefines, — When halogens

react with the hydrocarbons of the paraffin series to form

derivatives there is always formed one molecule of halogen

acid , HC 1 or HBr, for each atom which enters the hydro

carbon in pla ce of hydrogen . This is characteristic of

substitution rea ctions . There is, however, another class of

hydrocarbons which behave very differently toward

chemical agents . When halogen comes into contact with

the members of this series it is quickly absorbed or added

to the molecule without the simultaneous formation of

halogen hydride . Nascent hydrogen and the halogen

acids are likewise absorbed by these hydrocarbons, the

resulting compounds derived by hydrogen addition being

identical with the hydrocarbons of the series , and

those formed by the absorption of halogen or halogen

acids are identical with derivatives of the saturated hydro

carbons of the same composition , produced by substitu

tion . Numerous efforts in the past to prepa re a com

pound containing but one carbon atom and possessing the

properties of the olefines have been unsuccessful . It has

been already pointed out (2, 40) tha t the occurrence of

many reactions of compounds containing carbon can best

be explained on the assumption that very small amounts of1 53

1 54 Organic Ch emistry for Students of Medicine

the radical methylene CH. exist in dynamic equilibrium

with molecules of different types . Thus the reactivity o f

methane, methyl alcohol , and methyl chloride depends

upon the fact that each contains a relatively small per

cent of activemethylene p a rticles at ordinary temperatures

H.=C\H H

=C<O H

2 H.C/+H.o

\H

79. Ethylene, CH. CH..

— When ethyl alcohol is actedupon by concentrated sulphuric acid or z inc chloride ,powerful dehydrating agents, water is abstracted from the

molecule and the simplest of the o lefines, ethylene, i s

formed . The same change is effected by heating ethyl a l

cohol alone to It separates into ethylene and water;

GHz— CHz 30 CH2

_ CH2CH.

=CH.

Intermedia ry Ethyleneproduct

F urther instances o f the formation of ethylene by dis

sociation are the following

/H at 800°

\H

CH.— CH— H

Ethyl ether >OCH.— CH— H

Ethane CHs— CH

at 550°


The double bond does not bind the C atoms in a morestable union than the single bond . On the contrary, as has

been stated,there is a pronounced tendency for the double

bond to absorb with avidity atoms or groups and to pass

into a saturated condition . Compounds containing

the double bond , are , because of this property, spoken of as

unsaturated compounds . The unsaturated compounds

are given the ending ene preceded by the name of the alkyl

radical from which they are derived . This high reactivity

of the olefines is doubtless due to the existence of a con

sidera ble amount of dissociated particles R— CH— CH— R

along with the form represented by Figure 1 6 , for the

double bond . These are in dynamic equilibrium with

the undissociated form, and when compounds capable of

absorption become a vailable, the dissociated particles are

rapidly removed a nd more double bonds dissociate until

the reaction is complete ‘

2RCHz CH2 S CH2_CH2 1 -9 ' CHgR— CHgR

Another method of preparing ethylene and its homo

logues confirms the hypothesis advanced concerning its

structure . Thus ethyl iodide , when treated with aqueous

KO H, yields ethyl alcohol . With alcoholic KO H solutionit yields ethylene

CI’Ia— CH21 +KOH CHs— ‘GHz

— OH+KIAqueous

A lcoho lic

The Unsa tura ted Hydrocarbons 1 57

When ethylene is mixed with hydrogen and passed overfinely divided nickel heated to addition of hydrogen

atoms takes place a nd ethane is formed :

GH2 GHz Hzé CHs— { jHa (CwN")In a similar manner halogen acids are a bsorbed by the

olefines with the formation o f halogen derivatives of the

pa ra ffins :

CH2 CH? HI-bCH3— CHQI

This reaction takes place with moderate speed at about

the boiling point of water, but HBr reacts much more

slowly than hydriodic acid and HC 1 does not react at all .

This finds its explanation in the fact that the acid as a

molecule is not added by the o lefine, but its constituent

atoms ; HI is an easily dissocia ted a cid , readily liberating

iodine, in the presence of even feeble oxidizing agents ;while HC 1 is a very stable acid . HBr is intermediate in

its stability . Since the bond between H and C l must be

broken before a ddition can take place , the firm union in

HC 1 prevents its reaction .

The olefines are much more easily oxidized than are the

saturated compounds . While ethane is not oxidized by

potassium permanganate or chromic acid , the o lefines are

readily attacked . D ilute permanganate oxidizes ethylene

to ethylene glycol

GH2 GH2 HOH O CHzO H— CHzOH

The decolorization of dilute permanganate solution

serves to detect unsa turated compounds in a mixture of

hydrocarbons .


Halogens combine with olefines to form di-halogen

compounds : CHgX— CHQX (X halogen). The order of

reactivity is C l> Br> I . The interaction between the

halogens and o lefines is greatly accelerated by light . As

we have seen before in other relations, the most active

halogen forms the least active halogen acid with respect to

o lefines. In an atmosphere of chlorine , even in diffused

light, ethylene burns with the deposition of much carbon .

The principal reaction is represented by the following

equation :

Sulphuric acid absorbs the olefines with the formation of

alkyl acid sulphate

GHz GH2+H CH3— CH2

This serves as a method of separating unsaturated from

saturated hydrocarbons .

Hyp ochlorous acid , HO Cl, is a bsorbed by olefines.

Ethylene forms ethylene chlorhydrin

CH2 CH2 HO Cl CHo — CH2C1

The olefineswith 2, 3 and 4 atoms of carbon are gases .

The higher members are liquids and solids . They are but

slightly soluble in water, but dissolve in alcohol , ether,and in other organic solvents . Al l are combustible

with a smoky flame, and mixed with air or oxygen

they form dangerously explosive mixtures . Ethylene a b

sorbs two atoms of bromine, forming ethylene bromide,

CHzBr— CHzBr. Analogous compounds also result from


81 . Propylidene Compounds.

— It has already been

pointed out (36) that the chlorides of phosphorus react

with aldehydes and ketones with the replacement of

the oxygen of the carbonyl group CO by two chlorine

atoms C C 1 2 . Thus propyl aldehyde yields propylidene

chloride

CHa— CHz— CHClz

and acetone yields dichlora cetone :

CHs— CClz— CHs

On removing one molecule of ha loid acid from compounds

of these types there result two isomeric chlor propylenes,having chlorine link ed to a doubly linked carbon atom .

— HClCH3_ CH2

_ CHC 1 2 CHa— CHr—CHCI

Propyl idene ch loride a -ch lor propylene

— HClOH3

— CClz— CH3 CHs— CCl CH2Chlo ra ceto ne B-ch lor pro pylene

This type of halogen compound differs markedly from

the alkyl halides in which the halogen is linked to a carbon

atom having only single bonds . While in the alkyl halidesthe halogen is readily repla ceable by hydroxyl , alkyl ,amino groups , etc . , this property is almost wholly wanting

in compounds whose halogen is l inked to carbon with a

double bond . They do not react with alkalies to produce

alcohols nor with sodium ethylate to produce ethers .

Instead there are formed compounds which are substitu

The Unsa tura ted Hydroca rbons 1 6 1

tion products of the triple bond hydrocarbons, the a cetylenes From CH3— CC1 2— CH3 by the abstraction

o f two HCl there never results a diolefine CH2 = C = CHg,

as might be expected .

An isomer of a and Bchlor propylene is known asallyl chloride , CH2

= CH— CHzCl. This reacts just as

do alkyl halides, notwithstanding the presence of the

double bond in the molecule . Thus with KO H it yields

allyl alcohol

GHZ= CH— CH2C 1 +KOH= GH2= CH CH20H+ KC 1

This alcohol will be described later

82. TheDio lefines. Compounds containing two double

bonds are known which have considerable importance .

Allene, CH2= C = CH2, IS a gaseous hydrocarbon which

can be prepa red from tribrom propane by the abstrae

tion of one molecule o f HBr by mea ns o f a lcoholic KO H,

and the subsequent remova l of the remaining two bro

mine atoms by zinc dust

HBCH2Br— CHBr — CH2Br — £ CH2

= CBr— CHgBrD ibrom propylene

It is a colorle

H

ss gas .

Isoprene ,H3

> C— OH= CH2 , 1 s a liqu 1d, B. P.

CHz/

It is formed by the destructive distillation of India

rubber,and also by passing turpentine through a tubeM


heated to redness . On treatment with acids it poly

merizes, forming rubber aga in .

It is also formed from isobutyl carbinol , one of the amyl

alcohols , by the following series of transformations

CH— CHg— CHgO H CH— CHg— CHzClCH3/ CH/

+2 C1 CH3CCl — CH2

-CH2C 1

In the presence of metallic sodium it polymerizes to a

product having the physical properties of rubber,but not

identical with it chemically .

Butylene s . Three butylenes are known,and this

number only is theoretica lly possible .

CHs\

CH/

CH3— ‘CH OH— CH3

CH3— GH2— CH CH2 C CH2

They are prepared by methods analogous to propylene .

They differ from ethylene in their tendency to polymerize

when treated with HgSO 4, or ZIIClg. Numerous higher

homologues of this series are known .

83 . Acetylene s . On treatment of dibrom ‘ethane with

alcoholic KOH two molecules of HBr are abstracted with


HEAT o r HEAT o nCOMBUSTION FORMATION

Whereas ethane is formed from its elements with theliberation of Cal . of heat for each gram molecule,energy must be supplied to induce the formation of the

double bond and still more to form the triple bond . We

may liken the formation of these unsaturated compounds

to the bending o f a bow into a position of tension . Whileunder a strain and possessing stored up energy it has a

strong tendency to change to a body of a new conforma

tion .

When placed under pressure greater than two atmos

pheres, acetylene is readily exploded by a shock . The

change which takes place is one of polymeriza tion , three

molecules uniting to form one molecule o f benzene. The

nature of this change will be treated later

Prep a ra tion— Acetylene is formed from ethylene bro

mide by the abstraction of two molecules o fHBr. This is

readily effected by heating with alcoholic KOH :

CH+2KOH I“+2KBr+2HZO

CH

Metallic zinc abstracts bromine from tetra brom ethane

in alcoholic solution, with the formation of acetylene :

The Unsa tura ted Hydro ca rbons 1 65

CHBI‘z CH

+2 Zn ”I +2 ZnBr2CHBI'z CH

A characteristic property of hydrocarbons containing the

group HC E is the formation o f insoluble metallic com

pounds oi the composition C2Ag2 and C2CU2, silver and

cuprous acetylides respectively, when acetylene or its

mono a lkyl deriva tives are passed into an ammoniacal solu

tion of silver nitrate o r of cuprous chloride . This prop

erty is utilized in analytical work to determine the a cetylene content of a mixture . The quantita tive capacity to

absorb bromine serves as an estimation of the total un

saturated group (olefines and acetylenes), and the amount

of meta llic derivative forms a basis for the calculation of

the content of doubly a nd triply unsaturated hydroca r

bons in the mixture . These compounds are highly ex plo

sive when dry. They a re decomposed by hydrochloric

acid with the regeneration of acetylene

Q Agz 2HC1 CH E CH 2AgCl

Derivatives of acetylene in which both hydrogen atoms

are substituted by alkyl groups do not form these metallic

compounds . Acetylene is most conveniently prepared

by treating calcium carbide with water. When lime and

carbon (coal)are heated together in a n electric furnace, the

calcium oxide is reduced and calcium and carbon combine

to form calcium acetylide , commonly called ca lcium

ca rbide, CzC a . This compound reacts with water some

what violently with the evolution of considerable heat

and the formation of acetylene :

CzC a +2H20 CH s CH+C a (O H)2


When liberated through a suitable burner, acetyleneburns with an intensely luminous flame . Its mixtures

with air are much more dangerously explosive than are

mixtures of air and coal gas, due to the reactive properties

of the acetylene as compared with the paraffin hydro

carbons, and also to the wide limits of composition of air

and acetylene which form explosive mixtures . Mixtures

containing 3 to 82 per cent of acetylene are explosive ,while the limits for coa l gas are only 5 to 28 per cent . In

addition the velocity o f propagation of the reaction be

tween oxygen (of the a ir)and acetylene is much greater

in the case of the acetylene mixture, which intensifies the

force of explosion .

The carbides of certain other metals yield hydrocarbons

other than acetylene . Aluminum carbide yields methane

on decomposition by water . Uranium carbide yields mix

tures of methane and of liquid and solid hydrocarbons .

Acetylene , CH E CH, i s a gas of unpleasant odor . One

volume of water dissolves about 1 volume of the gas ;benzene and alcohol dissolve 4 and 6 volumes respec

tively, at ordinary temperatures ; while acetone, which is

the best solvent, dissolves 25 volumes, and much greater

quantities under pressure .

It can be synthesized from its elements by pa ssing an

electric spark between carbon poles in an atmosphere of

hydrogen,a small amount of methane and ethane be ing

simultaneously produced . It is produced in small amount

when many organic substances are subjected to incom

plete combustion .

Acetylene is more poisonous than ethane or ethylene . A

1 68 O rganic Chemistry for Students of Medicine

The structure of this compound is made clear by the

following beha vior ”i

(1 ) It behaves like an alcohol in reacting with sodium

with the evolution o f hydrogen .

(2) It yields an a cetylderiva tive when treated with acetyl

chloride .

(3)With nascent hydrogen (Zn HgSO 4)it is converted

into normal propyl alcohol . This shows that the alcohol

radical is attached to an end carbon atom and is therefore

a primary alcohol .

(4) The evidence that it is a primary alcohol is sup

ported by the fact that it yields an aldehyde and an acid

containing the same number of carbon atoms as the alcohol

itself.

Acrylic Aldehyde, Acrolein, GH2 = CH— CHO, is best

prepared by the abstraction of twomolecules of water from

glycerol . This is best effected by heating with potassium

bisulphate . The reaction which takes place is probably

the following

CHgOH

CHOH

This behavior is in agreement with experience which, as

pointed out above, leads to rearrangement of the atoms

with the formation of an aldehyde whenever we should

expect the formation of an alcohol group in union with a

doubly linked carbon atom

CH2

CH

CHOAcro lein

The Unsa tura ted Hydroca rbons 1 69

Allyl alcohol is found as an ester in the form of allyl

iso-thio-cyanate , C3H5NCS, in the seeds of mustard . It

is not free but combined with glucose as a glucoside

Allyl Sulphide , (C3H5)2S, i s the principal constituent of

oil of ga rl ic.

Acrylic aldehyde , o r a crolein, can in turn be oxidized tothe corresponding acid, acrylic acid

CH2=CH— CHO+O GHz

= CH— GOOHAcrylic a cid

B-Amino Acids, R— CH— GHz— GOOH , are unstable

NHz

and readily split off ammonia with the formation of un

saturated compounds. Thus B—iodopropionic acid yieldswith ammonia B-aminopropionic acid which splits off

ammonia, forming acrylic acid .

86 . Acids of the O le ic Series, CJ lgn-202 .

— The first

member of this series of acids, which differ from the

saturated fatty acids by having one double bond , is acrylic

acid . The second member , methyl a crylic a cid, is known as

crotonic acid . It is formed by the action of dehydrating

agents upon B-oxy—butyric acid . The latter compound

is formed directly by the condensation of two molecules of

acetaldehyde by the aldol condensation (32, 1 24)

CHa— CHOH4—CHz— GOOH

_H20CHa— OH =CH— CO OH.

This acid occurs in croton oil. It is a crystalline sub

stance which melts a t 72° and boils at At 1 9° it is

soluble in parts of water .

1 70 Orga n ic Chemistry for-Students of Medicine

There is however an isocrotonic acid which is an oil

which boils at 1 72° and when maintained for a time at a

temperature of 1 70— 1 80 goes over into crotonic acid .

Both of these acids yield normal butyric acid on treatment

with nascent hydrogen and have, therefore, the normal

carbon chain . They exh ibit a kind of isomerism which

cannot be explained by the ordinary constitutional for

mulac . This type of isomerism , which is peculiar to the

CH3

O O O H H CO O H

F IG. 1 8 .

ethylene compounds, is the necessary result of the restric

tion of motion of two ca rbon atoms linked by a double

bond . Thus butyric acid may be represented as in Figure

1 8 .

The system of the carbon atom at the center of the upper

tetrahedron and its three combined atoms or groups should

have no restriction as to the relative positions which they

may assume with respect to the carbon atom at the center

of the lower tetrahedron and its system of atoms and

groups. Each should be free to rotate freely about

their common axis,and all the possible arrangements

probably occur ; and because all are constantly shifting,


one differing from crotonic acid in the position of the

double bond, the other having a branched structure :

CH2

>C— CO OH

CE

87. O le ic Acid, C 1 8H3402 , is widely distributed in both the

animal and vegetable fats in the form of its glycerol ester,triolein . It differs from stearic acid in having two less hydro

gen atoms and in containing a double bond . Its carbon

chain has the normal structure, as is shown by its conver

sion into stearic acid by the absorption of two hydrogen

atoms in the presence of catalyzers. Oleic acid differs

widely from the saturated stearic acid . It melts at 1 4°

and is therefore an o il at ordina ry tempera tures . In the

hydrocarbons a nd acids of the fa tty series the properties

of the homologues change progressively with increasingcarbon content . The longer the carbon chain, the higher

the boiling point o r melting point . In the unsaturated

compounds the properties tend to run counterwise to thi s

rule , e.g. butyric a cid melts at crotonic acid melts at

stearic acid melts a t while oleic acid melts at

It is colorless when pure a nd ha s no odor . It undergoes

transformation into its isomer, ela idic a cid, when treated

with nitrous oxide .

Ela idic a cid has the same percentage composition with

respect to its elements, the same molecula r weight , a nd

absorbs the same amount of iodine as does oleic acid (2

atoms), showing that it still conta ins the double bond .

While oleic melts at elaidic acid melts at 45 This

change involves the transformation of the same type as

GHz CH — GHz-CO OH

Th e Unsa tura ted Hydroca rbons 1 73

that represented by crotonic and isocrotonic acid . Oleic

acid represents the cis and elaidic acid the tra ns form .

The position of the double bond in oleic acid is establishedby the fact that when compounds containing this linkage

are oxidized, the oxidation takes place at the point of

unsaturation ; thus

CHa— OH ECH— CO O HCrownic a cid

4 OCHa— GOOH+HOOG GOOHAcetic a cid Oxa lic a cid

4 OCH? CH— GOOH HCO OH+HO O C— CO O H

Acrylic a cid Form ic a cid

the ox idation in all such cases leads first to the forma

tion of two secondary alcohol groups

CHa — CH- CH— GOOH

O H OH

then a separation of the carbon chain . Thus oleic acid

when oxidized with a dilute solution of potassium per

manganate yields , first dihydroxy stearic acid , then

pela rgonic a cid, CHs— (CH2)7— CO O H, and a zelia c acid,CO O H— (CH2)7 —GOOH . From this evidence it is con

cluded that the double bond in oleic acid is at the middle

o f the chain, i.e. between the ninth and tenth carbon atoms .

88 . Acids with two Double Bonds,

Linolic

Acid, C 1 3H3202 .

— In many plant oils there occur fatty

acids which tend to take up oxygen and harden to a resin

like state . Such acids show a chemical behavior which

indicates that they possess two double bonds. These are

1 74 Orga nic Ch emistry for Students of Medic ine

called linolic acid , because of ' their prevalence in linseed

oil . Fats containing this class of acids are found espe

cia lly in cottonseed , walnut, cedar, and hemp oils a nd to

some extent in corn oil and in many other oils, but not in

so high a per cent of the whole as in linseed oil . On this

property depends the peculiar value of the latter oil for

the manufacture of paints .

Linolic acid still remains an oil at It absorbs 4

atoms of bromine, or two molecules of hydriodic acid . On

oxidation it yields a tetrahydroxy derivative . On vigor

ous reduction with hydriodic acid and phosphorus, it

yields stearic acid . Like oleic a nd stearic acids, l inolic

acid has the normal and not a branched structure . The

tetrabromideof linolic acid is soluble in all the ordinary fat

solvents except petroleum ether . This last solvent dis

solves readily dibrom stearic acid , and can be employed

as a useful mea ns of distinguishing between the two .

Acids with th ree Double Bonds, Ca n— sog ; Linoleic

Acid, C 1 8H3002 . This acid Occurs especially in linseed

oil and shows in still higher degree the drying property.

It forms a hexabromid, and when ox idized with dilute

perma nganate solution a hexahydroxy stearic acid . The

oils from many fishes contain fatty acids containing two

and three double bonds .

It is interesting to note that the solubility of the hydro x y stea ric acids in water ra pidly increases with increa s

ing number of hydroxy groups . D ihydroxy stearic acid

is nearly insoluble ; tetrahydroxy stearic acid , difficultly

soluble ; while the solubility of the hexahydroxy acid is

quite marked .


relative proportions of the different fats in the mixture

determine the melting point .

Butter fat occupies a peculiar place among the animal

fats . It consists mainly of a mixture o f pa lmitin , stearin,and olein , but contains from 6 to 8 per cent of fatty acids

volatile with steam , as glycerides , i.e. , butyric, caproic,caprylic, and capric, and also some lauric and myristic

acids . No other fats from either animal or vegetable oils

yield on sa ponifica tion so high a proportion of volatile

fatty acids .

90. Vegetable F ats. Even greater diversity of char

acter is found among the vegetable fats than among those

from animals . Pa lm oil consists mainly of p a lmitin and

olein, but contains small amounts of other glycerides .

Cocoa butter contains about 40 of stearin , 20 of

pa lma tin, 30% of olein, and 6 % of l inolein , together

with some other fats .

There is a class of fats which are liquids and are there

fore called oils, which are known as the non-drying oils to

differentiate them from certain others which have different

properties . The non—drying oils include olive oil , the oil

o f wheat , date, hazelnut , and rice . They consist mainly

o f triolein .

The drying oils are easily oxidized in the air and light,especially after being heated for a time with manganese di

oxide , or lead oxide, which act as catalyzers of the oxida

tion process . This class includes linseed , cedar-nut; hemp ,walnut

,and sunflower oils , and a few others . They consist

principally of triglycerides of linolic and linoleic acids‘

.

The semi-drying oils consist principally of glycerides o f

The Fa ts, Wa x es, a nd Rela ted Compounds 1 77

oleic and linolic acids . In this group are corn and cotton

seed oil and sesame o il. These on exposure to oxygen

(air)are only very slowly and incompletely converted into

resinous products .

Croton oildeserves special mention because of its marked

pharmacological action . It is pressed from the seeds of

Croton tiglium, and is a sherry-colored viscid liquid with an

acrid taste and somewhat rancid smell , and a fluorescent

appearance . It is a violent purgative , in most cases a

single drop being sufficient to effect intestinal activity .

When rubbed upon the skin it produces rubefaction and

pustular eruption .

Croton oil when sa ponified and subsequently acidified

and distilled with steam yields about half as great a per

centage of volatile fa tty acids a s does butter fat . Among

these are formic, acetic, a ndvalerianic acids, which are not

found in butter fat .

Ca stor oil is derived from the castor bean . It consists

mainly of the glyceride of ricinoleic a cid. The latter

conta ins eighteen carbon atoms and one double bond , but

in addition it shows the reactions o f a secondary alcohol ,e.g. it forms an acetyl derivative with acetic a nhydride ,and yields an ester, ricinoleic sulphonic a cid, when treated

with concentrated sulphuric acid . The latter compound

is used in the Turkey-red industry . The structural

formula o f ricinoleic acid is represented as follows

CH, - CHOH- CH CH —(CH2)7 — GOOH

A distinguishing prope rty of castor o il is its insolubility

in petroleum ether . It is l ikewise the heaviest of the fats,N


Sp . gr . .960 Other fats range in specific gravity

from .850 to .950.

91 . Propertie s of the F ats . Since the natural fats do

not represent individual chemical compounds, but mixtures

of several kinds, their physical properties depend upon the

proportions in which they are mixed , and especially on the

content of olein . They are insoluble in water, but slightly

soluble in cold alcohol . They are readily soluble in ether,petroleum ether, benzene , chloroform , and in other solvents .

The fats can be heated to 200—250° without undergoing

any essential change , but above this temperature they

evolve the irritating vapors of acrolein (CH2 CH— CHO),which causes profuse secretion of tears . This ha s its

origin from glycerol, from which it is formed by the

loss of two molecules of water This test is best

carried out by heating the fat with potassium bisulphate

(KHSO 4). This acrolein test serves to distinguish the

fats from the mineral oils, oily esters, and other substances

having the physical properties of fats or oils .

The commercial fats on keeping become rancid . This is

due to the action o f the oxygen of the air, especially in the

presence of light, which greatly accelerates their oxidation .

In the process of becoming rancid the neutral fats become

acid in reaction . Fats, especially from plant sources, are

liable to become acid in reaction owing to their containing

the enzyme lip a se, which accelerates the hydrolysis of

esters into alcohol and acid . In part the rancidity of im

pure fats is brought about by the action of bacteria on

the proteins, carbohydrates, etc . , with which they areco ntaminated .


Many antiseptic substances, such as carbolic acid ,salicylic acid , or cresol , thymol, tar, sulphur , naphthalene,camphor, mercury, etc . , are added to soap . The finer

grades are usually perfumed and frequently colored .

White Castile soap is made of olive oil and sodium hy

dro x ide . It is strongly alkal ine . Green soap is made

from linseed oil and po sta ssium hydroxide, and is therefore

principally potassium linolate and linoleate . Lead soa p

or leadpla ster is prepared by saponifying olive oilwith lead

oxide . It is yellowish white , pliable and tenacious . It is

insoluble in water, but soluble in chloroform and in ben

zene .

Ordinary soaps are crystalline, and the cheaper grades

frequently conta in rosin, sodium silicate , etc . The trans

parent soaps are made by dissolving crystalline soap in

alcohol and then evaporating most of the solvent . They

are in the colloidal state and owe their transparency to this

cause .

Physiology of the F ats a nd Soaps — The body fat of

animals is in part derived directly from the food , since

peculiar fatty acids not found in the body fat unless con

ta ined in the food are deposited in the fat of the tissues .

Carefully conducted experiments ha ve shown that pigs and

geese may accumulate much more fat in their bodies during

the experimental period than was contained in the food .

The animal body is therefore able to form fats from sugars

and from proteins . This necessarily means that both

fatty acids and glycerol are formed from other compounds.

Free fatty acids are never found in the blood , and when

an animal is fed free fatty acids instead of neutra l'

fa ts, it

The Fa ts, Wa x es,and Rela ted Compounds 1 81

forms glycerol to combine with them to form neutral fats

before they enter the circulation .

Since the fa ts are not soluble in water, and there are no

fat solvents in the digestive tract , fats are not capable of

being absorbed directly, but must be converted into water

soluble products before absorption . The digestion of fats

consists in their hydrolysis to fatty acids a nd glycerol .

This takes place in the intestine under the influence of an

enzyme , l ipase, in a faintly alkaline solution . The free

fatty acids at once combine with bases to form soaps .

Both the soaps and glycerol are water soluble and absorb

able . In the cells lining the intestine the fatty acids

and glycerol are recombined to form neutral fats before

entering the circulation .

93 . The C leansing Actionof Soap . The sodium and

potassium soaps are soluble in water, and being the salts

of very weak acids they undergo hydrolytic dissociation,that is

,they react with water to some extent , with the

formation of free fatty acid and sodium hydroxide

(I) CH3_(CH2)1 6— "COON3So dium ste a ra te

CHa — CO O +Na +

Steera te ion

(2) CH3 +Na++HOH

Ste a ra te ion Wa ter

2 CH3_(CH2)1 5— GOOH+N30HSte a ric a cid

This reaction is due to the fact that sa lts of wea k a cids

are strongly dissocia tedwhile the weak acids themselves are

but slightly dissociated into fatty acid ions and hydrogen


ions . The acid ions combine with the hydrogen ions of

the water to form undissociated fatty acid molecules .

The acids thus liberated combine with a molecule o f soap

and form insoluble stubsta rices which give the milkyappearance to water solutions of soap . The amount of

free alkali produced depends on the degree 'of dilution of

the soap solutions . Strong soap solution scarcely causes

the pink color cha ra cterisitc of alkalies with phenol

phthalein, and the depth of pink steadily increases as the

solution is diluted with water .

When fats come into contact with soap solutions, they

tend when agitated to form an emulsion, i.e. the droplets

of fat break up into very fine particles, each surrounded

by a film o f soap solution which separates each drop from

its fellows and prevents their union into larger drops and

consequent separation . The action of soap in removing

grease is therefore twofold : the free alkali will saponify a

pa rt of the fats and thus part will pass into solution as

soap ; the remainder is emulsified and remains permanently

suspended in the soap solution .

As the free alkali is used up by the sa ponifica tion of fats,more soap dissociates to replace thatwhich has disappeared .

Soap therefore serves as a reserve supply o f alkali, and

in washing there is automatically maintained a constant

content of hydroxyl ions in solution without at any time an

undesirably high content . Soap is for this reason superior

to a free alkali solution for washing . A dilute solution of

the latter would show a progressive decrease in hydroxyl

ions as its use progressed .

Soap does not readily remove the higher hydrocarbons,


of potassium hydroxide in alcohol , a nd heating until

sa ponifica tion is complete . Water is then added and the

free a lkali in the solution is titrated by the a ddition of

standard acid to the neutral point, using phenolphthalein

as indicator . The difference between the KOH content o f

the solution employed to saponify the fat a nd the alkali

remaining unneutralized after the sa ponifica tion shows

how much alkali has been neutralized by the fatty acids

formed . Essentially this method is a determination of the

molecular weight of the fat, as the following table shows

SAPO NIF ICA ’I‘IO N

M O L. WE IGHT

Unsa ponifia bleResidue . It is obvious that the saponi

fica tion number can give reliable data concerning the

molecular weights of the fatty acids contained in the fats,only when glycerol is the only alcohol present in the fats .

Now it not infrequently happens that there occur with the

fats certa in other alcohols, a s cetyl and octa decyl alcohols

and cholesterol (C27II430H), an alcohol of high molecular

weight which is structurally very different from the higher

alcohols derived from the aliphatic hydrocarbons

These occur free o r in ester linka ge with fatty acids .

Cholesterol possesses physical properties very similar to

Th e Fa ts, Wa x es, a nd Re la ted Compounds 1 85

the fats and fa tty acids , and occurs free a nd a s esters

almost universally distributed in animal and plant tissues .

Since these alcohols have molecular weights of 242, 270

and 384 respectively, whereas that of glycerol is but 92,the sa ponifica tion number can be properly interpreted

only when the content of these higher alcohols is known .

These alcohols are collectively estimated by repeatedly

shak ing with petroleum ether the solution of the soaps,glycerol, and higher alcohols obtained in the determina

tion o f the sa ponifica tion number a fter again making it

alkaline after the titration . Petroleum ether does not

dissolve soaps, glycerol, or potassium hydroxide, but

rea dily dissolves the higher alcohols in question . After

separa ting the petroleumether, filtering, and evaporatingit, and again taking up the residue of higher alcohols in a

fat solvent such as ether, the solution is filtered , and the

solvent evaporated in a weighed dish . The residue is

weighed after keeping the dish in a desiccator until its

weight is consta nt . This weight represents the higher

alcohols which were present in the sample o f fat .

A few typical values of the higher a lcohols in some com

mon fats will illustrate the importance of this determina

t Il UNSAPONIF IABLE MATTER

Orga nic Chemistry Students of Medicine

Shark liver oil

Sperm oil

Beeswax 52 0—56 0

The Iodine Number. The relative content of saturated

and unsaturated fatty a cids in fats is determined by the

capacity of the fa ts to a bsorb iodine . As an example

of the determination of this value , the Hubl method will

be described :

(1 ) A standard solution of iodine containing 25 grams of

iodine and 30 grams of mercuric chloride dissolved in

500 c .c . of alcohol , free from fusel oil.

(2) A solution of sodium thiosulphate containing 24

grams of the salt per liter . This solution is standardized

by determining the number of milligrams of iodine which

is reduced by a cubic centimeter of the solution .

The sample of fat, .3 to .4 gram of Olein-rich fats or .8

to 1 gram of solid fats , is weighed into a glass stoppered

bottle and dissolved in 1 5— 25 c . c . of chloroform . It is then

heated with 25 c .c . of the iodine solution: After 6 to 1 0hours 20 c .c . of a 1 0 potassium iodide solution is

added , the whole diluted with water, and the unabsorbed

iodine is titrated by mea ns of the sodium thiosulphate

solution . The KI is added to prevent the separation of

iodine in the solid sta te on dilution with water .

The following values illustrate the iodine values for

several kinds o f fa ts

Olein

Linolein

Linolen in

IODINE NUMBERS PURE FATS


This method of examination is of great service for the

examination of butter for adulteration . No other fat

approximates the high value of butter fat in volatile fatty

acids, and the lowering of this value by the addition of

vegetable fats or the body fats of animals is readily de

tected.

Acetyl Number.

— Very few of the natural fats contain

hydroxylated fatty acids . Chief among these is castor

oil, which in ricinoleic acid contains a secondary alcohol

group The amount of hydroxy fatty acids is arrived

at through treatment o f the fat with acetic anhydride

(64) and heat, whereby the hydroxyl group o f the fat

forms an acetic ester '

HOH HC— O O C— CHs

CO — 'CH3 RI/

Acetic a nhydride CHa— GOOH

Such esters are stable to boiling water, and the excess of

acetic anhydride can be converted into a cetic a cid by

boiling

(CH3— CO O )20 H20 2CH3

— GOOH

The acetylated fats are then separated mechanically,since they are insoluble in water and form a layer . After

washing these free from‘ acid reaction and collecting on a

filter paper they are dried at 1 00° to constant weight . A

carefully weighed sample (2— 5 grams) is then sa ponified

with an excess o f ca refully measured standa rd solution

of alcoholic potassium hydroxide N/1 0. When saponi

fica tion i s complete, the same volume of N 1 0 acid is

The Fa ts, Wa x es, and Re la ted Compounds 1 89

added as was added of N/1 0 alkali in the sa ponifica tion

and the solution warmed . The aqueous layer is then

siphoned off through filter paper and the remaining oil

is washed until all soluble acids are washed out . The

filtrate and washings are titrated with N/1 0 alkali, using

phenolphthalein as an indicator . Soluble fatty acids

must be determined separately and their amount deducted

from the value found .

The following table shows the values for the acetyl

number of some common fats

Linseed oil Beeswax

Ol ive oil Cod liver oil

Palm oil Shark liver oil

Lard Seal fat

Tallow (beef) Spermaceti

Wool wax

The ela idin testdepends upon the fact that oleic acid

changes from the cis to the tra ns form (86)with a marked

rise in melting point when treated with nitrous oxide .

The test is carried out by placing the oil (1 0 c .c .)in a test

tube with nitric acid c .c .) underneath it, and placing

in the acid a piece of copper If much oleic acid

is present, the fat will have become solid at the temper

ature of 25° by the following day . Fats having two or

three double bonds do not give this test .

The Hex a bromide Test. — D ibrom and tetra brom stearic

acids result from the absorption of bromine by oleic and

linolic acids or their fats . Both of these are soluble in

ether . Linolenic acid having three double bonds , yields a


hex a brom derivative , which is insoluble in ether. The

test is of value therefore in detecting linolenic acid and its

fats . One to two c . c . of fat are treated with 40c .c . of ether

and cooled to Bromine is then added until the brown

color is permanent . Linolenic acid-containing fa ts yield

a precipitate within three hours . It can be filtered and

washedwith acetic acid , alcohol , and ether , and weighed

after keeping in a desiccator to constant weight .

Sep a ra tion of oleic a cid a s the leadsoa p . The lead soap

of oleic acid is soluble in ether and in benzene, while the

corresponding soaps of stearic and palmitic acids are

practically insoluble in these solvents . This property is

made use of in effecting their separation .

95 . The Waxe s . The surfa ces of all organisms,both

animals and plants, are covered with a layer of wax, which

also permeates the external layers of cells . There are

several kinds of waxes ; all , however, are esters derived

from one of the higher fatty acids and a mona tomic alcohol

of high molecular weight . They have the common property of being more or less solid at ordinary temperatures,but on warming they soften and can be kneaded . They

melt at 60 to The waxes are wholly insoluble in

water, but soluble in boiling alcohol , and less soluble in

ether . They also dissolve in chloroform and turpentine .Like fats they produce a transparent spot when melted on

paper, and confer a shiny a ppearance on objects coated

with them . Water does not penetra te even a thin wax

layer . They are not altered by light or air, or by bac

teria or molds, and are proof against changes similar to

rancidity . Furthermore waxes are among the poorest heat


produced by a leaf louse in Finland , is the ester formed of

psylla alcohol,C33H67OH, a ndpsylla acid, C33H6602 . Bees

wa x consists principally of myricyl a lcohol and cerotic

and melissic acids in ester combination . It is employed

by the honeybees for protecting their eggs and larvae

against cold and also for honeycomb . It also contains

impurities gathered from plants .

The gland at the base of the tail in birds secretes a

liquid wax which the birds spread over their feathers

to render them waterproof and soft . This wax consists

of palmitic,stearic, and oleic acid esters of octadecyl

alcohol, C 1 3H330 .

Sperma ceti is a wax, principally cetyl palmitate, which is

obtained from a cavity in the head o f the sperm whale .

From this cavity a canal runs to the tail and branches

communicate with pockets in the panniculus . The wax

is thus conveyed to a ll parts of the skin, which it permeates

and protects from the action of the sea water . Similar

esters are found in whale oil and in the oil from dolphins .

The production of Sperma ceti is closely analogous to thesecretion o f wax by the ta il glands of birds and to the uni

versal distribution of the sebaceous glands in the skin of

the higher anima ls which produce an oily secretion of

liquid wax which protects the skin and hair.

Wool wax (lanolin), the natural covering of sheep’s

wool,contains much cholesterol and oxycholesterol in the

free state, and also as esters of several fatty acids, espe

cia lly myristic, cerotic, and la no ceric . Wool wax also contains other higher alcohols, as carnaubyl , CuHsoO , and

lanolin alcohol, Cmn O .

The Fa ts, Wa xe s, a nd Rela ted Compounds 1 93

96. Lecithins a nd oth er Phosphatides.— As co nstitu

ents of every living cell , both animal and plant , there

occur compounds closely related to the fats , called lecithins .

These on hydrolysis yield one molecule of glycerol , two

o f fatty acid , one of orthophosphoric acid (H3PO 4), and one

o f choline

Glycerol forms with phosphoric acid an ester, glycero

phospho ric acid :

CH20H CH20H

CHOH CHOH

CH2IO H+HIO — PO (OH)2 CHz— O — PO(OH)2Glycerophosphor ic a cid

Lecithins are regarded as complexes of the following

structure

CHz— O O C— R

Fatty acid radicalsCH —O O G —R

Phosphoric acid radical

Nz Choline group

OH

Little is known with certainty of the chemistry of the

various lecithins . It is evident that different fatty acids0

1 94 O rga n ic Chemistry for Students of Medic ine

In the molecule would lead to lecithins of different proper

ties . Furthermore there is the possibility that two differ

ent fatty acids may be linked in the same molecule, forming

mixed lecithins . Isomerism is likewise possible due to the

different linking Of the phosphoric acid-choline group

CHgO — fatty acid A CHgO — fatty acid A

CHO — fatty acid A or CHO — phosphoricacid-choline

CHgO — phosphoric acid-choline CHzO — fatty acid A

The investigation of this class of compounds presents

almost insurmountable difficulties . They are of a wa xy

nature , and do not form compounds with other substances

which can be crystallized , for purposes of purification , and

they cannot be distilled without decomposition, and have

no definite melting point . There is therefore no criterion

by which to judge when one is in possession of an indi

vidual chemical compound or is dealing with a mixture,except constancy of composition of the material after

repeated solution and precipitation of the lecithin . This

is ca rried out in most insta nces by dissolving the lecithin

in ether and pouring the solution into a large volume of

acetone in which lecithin is insoluble . The precipitates

are always amorphous . When on repeating this method ofpurification the precipitate is found to contain the same

percentages o f nitrogen and phosphorus, these being the

easiest elements to determine quantitatively, the a ssumption is often made that the precipitated material represents

’

a chemical individual . Instances are known however in

which two substances precipitate in fairly constant pro


choline is the only nitrogen base contained in the natural

compounds of the lecithin type . Thudicum, a worker of

distinction in this field , states that from certain pho spha

tides of the brain (cephalin) he obtained neurine. It is

highly probable that bases other than choline exist in

lecithins . Neurine is derived from choline by the loss of

a molecule o f water

CHoH20

CHz— N E (CH:1)3 CH— N E (CHa)3

Neurine is much more toxi c than choline .

Choline, being an alcohol as well as a base , can

aldehyde on oxidation

CHzOH

l

M usca rine

As an alcohol , choline yields esters with various acids.

These in general possess pronounced pharmacological prop

erties, being much more toxic than choline itself .

97 . Muscarine , a highly toxi c substance, occurs in

some of the poisonous mushrooms, but appears not to be

toxic enough to account for all of their poisonous prop

erties.

The Fa ts, Wa x es, and Rela ted Compounds 1 97

Other phosphatides (compounds yielding fatty acids,glycerol , some nitrogen-containing base, and phosphoric

acid) have been described , among them cephalin , the

acids of which are more unsaturated than those of ordinary

lecithins . The base is apparently not choline . It is not

as yet satisfactorily studied .

98 . The Cerebroside s . There is found in the nervous

tissue a group of substances which contain no phosphorus,but yield on hydrolysis a nitrogen-containing base o f

unknown chemica l nature , a sugar (galactose), and a fatty

acid . They are not found in embryonic nervo'

us tissues,but develop during medullation . Two such compounds

are phrenosin and kera sin . They still need further study

to reveal their chemical structure .

99. Sterols. The brain at different ages contains

varying amounts o f cho lesterol (4— 9 and possibly several

more or less closely related compounds of this nature . Its

content increases with age . As sta ted under waxes (95)cholesterol is an alcohol o f high molecular weight . Its

formula is represented by C27H4GO . Several of its esters

are known . Its structure has been in part elucida ted .

Its alcohol group is a secondary one , since it oxidizes to a

ketone . It also contains a double bond , as shown by its

forming an addition product with bromine or iodine . The

structure of the rest of the molecule is not yet esta blished .

Compounds closely related to cholesterol are found in the

fats of plants . These are called phytosterols.

Cholesterol is a crystalline solid , insoluble in water,sparingly soluble in cold , but readily in hot , alcohol , ether,acetone, chloroform , and other organic solvents . Choles


terol melts at 1 47 It forms an acetyl derivative (ester)when heated with acetic anhydride , which melts at 1 1 4

°

and is useful in identifying cholesterol .

Cholesterol forms with a natural glycoside , digitonin,a compound sparingly soluble in 95 % alcohol . It is

frequently precipitated in this form and weighed in its

quantitative estimation .

An isocholesterol has been described as occurring in

lanolin , and a derivative called coprosterol has been iso

lated from feces . It has no double bond and results from

the reduction of cholesterol , due to bacterial action .


of many plants , from which it is obtained in a crystalline

form on evaporation . The calcium salt is so slightly

soluble in water and in dilute acetic acid that it is em

ployed for the quantita tive estimation of calcium .

The salt of urea with oxalic acid is soluble in 23 parts

of water and in 60 parts of alcohol . This compound has

been employed for the isolation of urea from urine .

With great care and with proper conditions oxalic acidcan be decomposed by heat into formic acid and carbon

dioxideGOOH

HCO O H C02GOOH

On heating strongly the formic acid decomposes into

water and carbon monoxide . The calcium salt on being

heated forms calcium carbonate (calcium oxide carbon

dioxide)a ndcarbon monoxide°

CO O\Ca = C a O + CO z + CO .

coo/

Oxalic acid can also be formed by quickly raising sodium

formate to a high temperature .

2 HCO O Na H". (CO O Na )2

Dehydrating agents such as concentrated sulphuric acid

decompose oxalic acid, forming carbon monoxide, carbon

dioxide, and water . This is a convenient way of preparing

carbon monoxide . Characteristic of oxalic acid is its

conversion into volatile products without charring when

heated on platinum , and also the absence o f charring when

it is heated with concentrated sulphuric acid . In dilute

The D iba sic Acids 201

sulphuric acid it is easily oxidized by potassium perman

ga na te solution . This decolorization of dilute permanga

nate solutions is caused by many other compounds . It

is also formed by the oxidation o f many orga nic substances

such as starch,wood

,etc. It results from the oxida tion of

alcohol by pota ssium permanganate . The various stages

through which the oxidation may pass are illustrated by

the following scheme

CH CH. CH. CH20H CHO

+ o + 0 + 0 1 9CHzO H

‘ — > CHO— "

GOOH GOOH

CHo CHO CHOO O I

CHzO H CH20H CHO CO OH

This series of compounds illustrates what not infre

quently happens in rea ctions involving the oxida tion of

orga nic compounds. The rea ction does not proceed with

the formation of the end products indicated by the simple

equations usually written , but stepwise , and with the

formation of a number o f oxidation products . Only be

cause the oxalic acid is highly resistant to further oxida

tion under certain conditions does the reaction stop at

this point instead o f going on to carbon dioxide and water .

In many synthetic reactions the same type o f change

occurs , viz . there is a principal reaction accompanied by

a number of side reactions which form by-products a nd

diminish the yield of the desired substance . By allowing


the reaction to proceed for but a short time or conducting

it at low temperatures, etc . , the intermediary compounds

can frequently be accumulated in greater amounts .

Properties of O xalic Acid. It crystallizes from water

in colorless prisms containing two molecules of water of

crystallization . In this form it melts at On

being heated for a time at 1 00° it loses its water and forms

a white powder of a nhydrous acid which melts at It

dissolves readily in alcohol but very slightly in ether, and

is insoluble in chloroform, petroleum ether, and benzene .

Oxa l ic acid is a strong acid . On evaporating a solution

of sodium chloride with oxalic acid, sodium oxalate crys

ta llizes out, and on heating a mixture of sodium chloride

and oxalic acid , hydrochloric ac id gas is evolved . It is

a corrosive poison which acts very quickly . In general

it cannot serve a s a source of carbon for molds or bacteria,but

.there are some observations tending to show that cer

tain organisms can so use it . Oxalic acid is produced from

sugars by certain molds .

In the higher animals oxalic acid is burned to but very

slight extent .

The dibasic acids form esters, amides, etc . , as do the

monobasic acids . There is in each case, however, a deriva

tive possible in which but one carboxyl is substituted , as

well as one derived by the reaction of both acid radicles .

GOOH

1 01 . MalonicAcid, GH2 -This acid results from the

GOOH


This property of the hydrogen atoms of methylene

groups being replaceable by metals is found only in com

pounds in which the methylene group is linked on both

sides to strongly negative groups . Other instances of this

character will appear later (see aceto-acetic acid,This compound reacts with alkyl iodide just as do the

sodium a lcohola tes the sodium being replaced by the

alkyl groups :

COOC2H5 COOC2H5

CHNa ICHa OH— CH3 Na I

COOC2H5 (3000 sM a lo nic ester

The resulting alkyl derivative on sa ponifica tion yields

methylma lonic a cid, which on heating above its melting

point decomposes into propionic a cid.

GO O C s GOOH CHs

+ 2H20 | — Coz ICH— CHs CH— CH3 CH2

COOC2H5 GOOH GOOH

By treating methylmalonic ester with sodium the second

hydrogen is replaced by metal and this in turn can be

substituted by methyl , ethyl , etc . groups, which on loss

o f C02 yield dimethyl, methyl-ethyl , etc . , derivatives of

acetic acid , viz . isobutyric and isova leric acids . The

malonic ester synthesis is therefore a general method for

prepa ring any o f the isomeric monoba sic fa tty a cids as well

as a great number of homologues of malonic acid .


Succinic acid and urea condense to barbituric acid

1 03 . Succinic Acid.

GOOH This acid occurs in the urine after ingestion of

I asparagus . It is found in amber , fossilized wood,CH? and many plants . It is crystalline and melts

CH2at That this acid is a homo logue o f

malonic acid is shown by its synthesis from ethy

GOOH lene bromide, through ethylene cyanide , which

on hydrolysis yields succinic acid .

CH2Br KCN CH2—CN CH2_CO O H

Ethylene cya nide

The dibasic acids can likewise be synthesized by the

malonic ester synthesis . Not only does sodioma lonic

ester rea ct with alkyl halides but with halogen de

riva tives such as the ester o f chloracetic acid :

GO O C s COOC2H5

CHNa +Cl— ' CH2_CO O C2H5 CH_CH2 COOC2H5

I ch lor ethy la ceta te

CO O CzH

GOOH

GOOH

GOOH

GOOH

CH2

CH2

COOC2H 5

ICH— CH2


By the same reaction substituted succinic acids can be

obtained . Thus by employing a -brom propionic acid

methyl succinic acid is obtained .

COOR CHa

(

IJHNa Br —OH

COOR COOC2H5

COORCHs

O H— OH/

\Cooc,H,

COOR

GHz— CO O HM ethyl succinic

a c 1 d

1 04 . Aspartic Acid, GOOH— CHg— CHNHz— GOOH .

The a -amino derivative of succinic acid is one of the prod

ucts of the hydrolysis of all proteins except the protamines

The carbon atom to which the amino group is

attached is a symmetric (30) and it exists therefore in .two

Optical forms . From the proteins the levo form is always

obtained . Since it contains both carboxyl and amino

groups it forms salts with both acids and bases, with the

latter two series according to whether one o r both of the

carboxyl groups enter into salt formation . The acid salts,i.e. those having One free carboxyl group and the amino

group , react neutral ; those in which the ca rboxyl groups

-H

H3NaBr CH — CH

/G

\CO 0HCO OH

C02

CHs— CH— GOOH

208 Organic Ch emistry for Students of Medicine

boil at It is easily soluble in water, alcohol and

ether.

1 06 . Glutamic Acid, CO O H— CHz— GH2* — CHNH2

CO OH, a -amino gluta ric acid, is present in many proteins,forming about 40 of the total nitrogen content of the

wheat proteins, gliadin and glutenin . The naturally

occurring form is dextroro tatory, but its salts rotate the

plane of polarized light to the left . Its diethyl ester boils

under 1 0mm . pressure at 1 39 Glutamic acid is sol

uble at 1 6° in 1 00parts of water. It forms salts with both

acids and bases as does aspartic acid Of special

importance for its isolation is the hydrochloride, which

is very sparingly soluble in concentrated hydrochloric

acid. On saturating its solutions with hydrochloric acid

gas the hydrochloric acid salt separates on cooling nearly

quantitatively . This property differentiates it from as

pa rtic acid .

1 07. G l u t a m i n e,’

CO NH2_CH2 — CH2— CHNH2“

CO O H, is found widely distributed in the sap of plants .

After everything which is precipitable by lead has been

removed from plant extracts, glutamine is precipitated by

mercuric nitrate . Certain other a mino acids are likewise

precipitated with it, so that its purification is not simple .

It is much more soluble in water than is asparagine . It

seems highly probable that glutamic acid occurs within the

protein molecule as glutamine . On hydrolysis with acids

the amide group is converted into ammonia

1 08 . Adipic Acid, CO O H— (CH2)4 —C O O H, is said to

occur in beet juice . It is formed by the action of s ilver

on fl-iodio propionic acid .


HOOG— CHz— CH2 1 1 CHg— CHz CO O HAg+Ag

HO O C— (CHz)4— CO O H

It melts at It is of interest mainly because it is

convertible into a ring structure . This will be described

later

Pimelic Acid, CO O H— (CH2)5 — GOOH, has not been

found in nature . It melts at and is soluble in 25

parts of water at

Suberic Acid, GOOH— (CH2)6 — CO O H, melts at

At one part of the acid is soluble in 600 parts of

water.

CHAPTER X

THE PO LYMETHYLENE COMPO UNDS

CH21 09 . Trimethylene , >CH2, is obtained by the a cI

CH2

tion of metallic sodium on trimethylene bromide

CHzBl' This compound is also

formed by the interactionGH2 2Na

of ethylene bromide on

CHzBI'sodiomalonic ester

CO O CzHa COOC2H5

CHzBI’

Na zCHzBI‘

COOC2H5

CH2

I >COH; H C

Trimethylene is isomeric with propylene, CH2

CH— CHs, but differs from it in its properties . Both are

gases, but whereas propylene is easily oxidized by pota s

sium permanganate , trimethylene is not attacked by this

reagent . It unites with bromine only very slowly to form

trimethylene bromide, and more readily with hydriodic2 1 0

2 1 2 O rganic Chemistry for Students of M edicine

tions which are of interest , starting with the calcium salt

of adipic acid

CHz— CH2

>GHQ

— CHgCa lcium a d ipa te KetO penta methylene

The structure of the ketone derivative o f pentamethyl

ene i s further shown by the fact that it oxidizes to glutaric

acidCHg

— CHg— CO O H

CHz— GO O H

Pentamethylene itself is o btained by reducing its ketone

derivative to a secondary alcohol , then replacing the

hydroxy l of the alcoho l by iodine by treatment with hydri

odic acid , followed by the replacement o f the iodine by

hydrogen

CHg— GHz

>co2 1 1

>CHO HCHg— C Hg CHg— GHz

CH2—GH2

+HI >CHI +2H

GHz— GHz

Pentamethylene is a liquid boiling at It will be

recalled that normal pentane boils at Wh ile the

tetramethylene ring shows a tendency to open a nd add

two halogen atoms, it does not undergo this change as

readily as does trimethylene . Pentamethylene , however,i s so stable that it does not react with bromine . It is

exceedingly stable toward oxidizing agents, as nitric acid,

The Po lymethylene Compounds

a ndshows none o f the tendency of unsaturated compounds

to condense with sulphuric acid

CHz— CHz

1 1 2. Hexamethylene, CH2<CH2_CH2

formed from the calcium salt of normal pimelic acid in a

manner entirely analo gous to that described for the fo r

mation of pentamethylene .

Hexamethylene is stable toward oxidizing agents such

as potassium permanganate, a nd does not form a n addition

product with bromine . It has a n odor like petroleum, a nd

boils at 69°

1 1 3 . Heptamethylene ,

CHg— CHz

CH2— CH/

The ketone derivative of this hydrocarbon ca n likewise

be prepa red in the manner just described by dry distilla

tion of the calcium salt o f suberic acid , GOOH— (CHg)6GOOH . And a n eight-membered ring results from the

calcium sa lt o f a zelia c acid , GOOH— (GH2)7 —GOOH .

The stability o f the polymethylene compounds in

creases up to pentamethylene . There is little difference

in stability between this“a nd hexamethylene, but ring

structures having seven a nd eight carbon atoms show

progressive decrease in stability . The reason for this

was suggested by Baeyer, a nd was formulated in the

following way

2 1 4 Orga nic Chemistry for Students of M edicine

The four valences of a carbon atom a ct parallel to

lines forming the corners of a tetrahedron with its cen

ter, making angles o f 1 09°28

’ with one another . The

direction of the valences ca n be altered, but a ny such

alteration produces a strain whose amount is propor

tiona l to the angle through which the valences are

diverted .

”

The following figures show the angle of deviation neces

sary for the formation of the ring structure in the several

polymethylenes

Trimethylene

Tetramethylene

Pentamethylene


these anhydrides in water converts them back into the

acids from which they were derived .

The failure of the two a nd three carbon dibasic acids to

form anhydrides is in harmony with the strain theory

1 1 5 . Succinimide .

-When the ammonium salt of suc

cimic acid is heated strongly to the distillation point, a mole

cule of ammonia a nd one of water are split off a nd a ring

structure co ntaining the imide group =NH is formed

GHz— CO O NH4 CH2

NH3 a ndH20 NHCHg

— CO O NH4 cnz— co/

Succinimide is a crystalline compound which melts at

1 25°

a nd bo ils at O n warming with barium hy

dro x ide solution it takes on one molecule of water, forming

the half amide of succinic acid

CHz— CO

\CH2

— GOOHNH +mO = |

CH2— co/ GHz— CO — NHz

Gluta rimide is produced in a similar manner from the

ammonium salt of glutaric ac id . These are examples of

compounds in which nitrogen takes part with carbon in

the formation of cyclic compounds.

1 1 6 . Pyrrol,

CHZ CH\

is formed from succinimide by distilling

NH the latter with z inc dust, which a h

CHZ CH stra cts oxygen :

NHonz

— co/ GHz-

CH

The Po lymethylene Compounds 2 1 7

Pyrrol does not take up ha logens directly, as would be

exp ected from its possessing two double bonds . This

peculiarity o f certa in cyclic compounds differentiates them

sharply from the o lefines. Pyrrol ca n, however, take up

two atoms of hydro gen when reduced with acetic acid a nd

z inc dust (nascent hydro gen), a ndthe resulting Pyrroline,or dihydropyrro l, absorbs two atoms of bromine as do the

olefines. This peculiar behavior has led to the assumption

that instead o f the double bond between the two pairs of

carbon atoms one bond from each of the four is directed

toward the center of the ring . This fo rm should be very

sta ble '

a s compared with the double bond . The fact that

nascent hydrogen is ta ken up by pyrro l proba bly finds a n

explanation in the existence of a small amount o f the

fo rmula containing the do uble bond in dynamic equilib

rium with the centric formula

CH— OHHC -CH

CH CHHC CH

NHNH

Ac tive modifica tio n Hni

i

pc

a

t

llv

fg

When two atoms of hydrogen are absorbed the centric

formula is changed to one containing a double bond, as inpyrroline

+ 2 H

Pyrro lidme


Pyrrol is a constituent of coal tar a nd is a product of the

distillation of bones . The latter is called bone oil a nd

contains pyridine (230) a nd various cyclic hydrocarbons,benzene, etc . pyrrol a nd its homologues , together

with large amounts of the n itriles of fatty acids . When

agitated with dilute acid the basic compo unds form salts

which are soluble in water a nd are removed . The nitriles

are sa ponified by boiling with alkali a nd the oil which

remains is distilled . The fraction which distills between

1 1 5°a nd 1 30

°

contains the pyrrol . The hydrogen of the

imino group is replaceable by metals , alkyl , acetyl , etc . ,

a nd when warmed with potassium hydroxide the solid

compound potassium pyrrol , C4H4NK, is formed . This is

filtered off a nd decomposed by water, which regenerates

pyrrol :

NK HOHCH==CH/ CHr —C

Pyrrol is a colorless liquid with a n odor similar to

that of chloroform . It boils at a nd is but

slightly soluble in water . It disso lves readily in a l

cohol a nd ether . Potassium dissolves in pyrrol with

the evolution of hydrogen, forming potassium pyrrol ,yet pyrrol has a feebly basic character Pyrrol gives

a bright red color with a pine shaving moistened with

hydrochloric acid .

Derivatives of Pyrrol . — While pyrrol itself is a poison

ous substance a nddoes not have a biological role, several

o f its derivatives are of great importance as constituents

o f the protein molecule , of chlorophyll , the green pigment

of plants, of haemin a nd haema toporphyrin, both o f which

220 Orga nic Chemistry for Students of M edicine

Haemin, C33H3204N4F eCl, crysta llizes out when defibrin

ated blood is dropped into a large volume of glacial

acetic acid containing some sodium chloride, the solution

being heated to This treatment separates the

ha ema tin from the haemoglobin, a nd the compound haemin

which crystall izes out i s the hydrochloride o f haematin.

It forms minute bluish bla ck crystals with a metallic

luster . It is insoluble in water , alcohol , or ether, but

dissolves in chlo roform containing quinine o r pyridine .

From such a solution it crystallizes out when alcohol con

taining sufficient hydrochloric o r acetic acid to neutralize

the base (quinine o r pyridine) is added .

Haemin contains two carboxyl groups . It combines

with twomolecules of hydrobromic acid . The iron becomes

loosened in this reaction, a ndsome further unknown change

takes place . The dibrom compound when hydrolyzed

loses its bromine, the latter being replaced by two hydroxyls .

The resulting compound , known as haema tO porphyrin, is a

dihydroxy-dibasic acid

HC31H34N4<8O O H

This when heated with methyl alcoholic potassium

hydroxide in pyridine solution undergoes reduction a nd

loses two molecules of water

CssHsso sN4 H2 C33H36O4N4 2H20

The product thus obtained is called haemoporphyrin.

It is a diba sic acid . O n heating haemoporphyrin with sodalime (a mixture of C a O a ndNa 20)the two carboxyl groups

The Po lymethylene Compounds 221

are destroyed , C02 being split off, a nd a new compound,aetiopo rphyrin, is formed . The following formul ae for the

last-named derivatives have been proposed byWillstatter

HCz CH

CHs— C— CH C — C

C2H — C — C/C —CH

o,H,— c: c

C<C : C — C2H5

C>NH HN

CHa— C : <c_ C— cm

CHsE t io po rphyrin, C a Hac

HC Z CH

ens— c— cn

C2H5— C H

HO O C— GHz— CHz

— C : C- GH2— GHz— CO O H

CH3— o z o/ \

q: — cx,

in, CH3

Ha mO po rphyrin , C uHmO c .

ZEtioporphyrin is, according to the researches of W ill

statter a nd his pupils, the mother substance from which

both chlorophyll a nd haematin are derived . In both

therefore the molecules consist o f four substituted pyrrol

groups . They assume that the iron in haematin is united

with nitrogen.

In chlorophyll the condensed pyrrol nucleus possesses


two carboxyl groups which are united with two alco

hols, methyl alcohol a nd phytol, a secondary alcohol with

the formula C20H390H, to form a n ester . Instead of

iron, chlorophyll contains magnesium linked to nitrogen .

A number of decomposition products of both haematin

a nd chlorophyll have been described a nd carefully

studied with a view to elucidating their chemical na

ture , but their description would be beyond the scope

of this book . The essential fact to be borne in mind is

the close chemical relationship between these plant a nd

animal pigments .

It should be pointed out as a n interesting biological fact

that carefully conducted feeding experiments with labora

tory animals have shown that neither chlorophyll nor

haematin is a n essential constituent of the diet . The a ni

mal body is able to construct the red respiratory pig

ment from certain o f the amino acids yielded by the

proteins of the food . Probably those containing the

pyrrol ring are of particular M porta nce for this purpose .

The bile acids, bilirubin a nd biliverdin, are derived from

disintegrated red corpuscles a nd are derivatives of con

densed pyrrol nuclei which have their origin in the haema

tin complex of the haemoglobin .

1 1 7 . Pyrrolidine is of great biological interest since

CH2_ C its derivatives, proline (a -pyrrolidine

H carboxylic acid) a nd ox yproline

GHz— C (a -o x ypyrrolidine carboxylic acid),occur among the amino acids which result from the hydrolysis of proteins .

In addition to the method described for preparing


wise soluble in alcohol , a nd this salt is made use of in the

purification. Racemic proline , the mixture of equal parts

o f the two optical forms, forms a copper salt which is

violet when dry but absorbs moisture from the air a nd

becomes blue again . Proline forms a salt with picric acid

(1 84)which is useful in its identification . Among the

proteins gelatin yields the largest amount of this amino

acid .

1 1 9. O xy-Proline , a —ox y-pyrrolidine ca rbox ylic a cid,

HO — CH— CHz

GHz CH— GOOH

occurs in gelatin . It decomposes at 270° with foaming.

The vapors evolved give the reactions o f pyrrol

1 20. Pyrrolidone Carboxylic Acid — O i theoretical in

terest is the property of glutamic acid (1 06)of separating

a molecule of water when heated to 1 85— 1 90° with the

formation o f a ketone derivative of proline

GH2 OH— CO O H CH2 — CH — GOOH

/N

a —pyrro l idone ca rbo xyl ic a c id

CHAPTER XI

HYDROXY AND KETONE ACIDS

Hydrox y Diba sic Acids

1 21 . Tartronic Acid.

— The simplest member

series of dibasic hydroxy acids is tartronic acid ,

CO O H

This acid does not occur in nature . It is formed from

malonic acid by the following reactions

CO O H CO O H GOOH

2 1 3 I H ICHz CHBr CHOH + AgBr

CO O H

acid melts at carbon

CHOH

CO O H

The glycolic acid formed at this temperature at once

reacts with a second molecule to form a n ester called

glycolide.

Q

GOOH

with the loss

CHzOH

IGOOH


CHzO IH HO iO C CHz— O O G

CO OHzC CG lyco ligz

c

1 22. M a lic Acid, hydrox y/succinic a cid, is present inGOOH various unripe fruits, as apples, pears , etc .

It is best prepared from unripe mountain

a sh berries or from rhubarb stalks . Its

structure is indicated by its conversion into

chiorsuccinic acid by treatment with phos

CO O H phorus pentachloride, a nd by the fact that

the alcohol group in succinic ester reacts with acetyl

chloride, forming a n acetyl derivative

COOC2H5 COOC2H5

CHOH

CHOH ClO C— CH3 CHO O C,

— CH;;

CHz

COOC2H5 COOC2H5

On boiling the juice of rhubarb or of mountain ash

berries with milk of lime, calcium malate is precipitated,since it is relatively insoluble . The salt is washed , dried,a nd weighed, a nd is then treated with the calculated

amount of sulphuric acid . Insoluble calcium sulpha te

separates out . The solution containing the malic acid is

evaporated to the point of crystallization .

M alic acid is readily soluble in water, alcohol, a nd

ether . The calcium salt is precipitated from dilute water

solutions by the addition of alcohol . Like normal ca l


Their differences are the result of the presence of two

asymmetric carbon atoms in their molecules which makes

possible enantiomorphous isomerism . (See lactic acids .)With the presence of two asymmetric carbon atoms in a

molecule four modifications of the compound must exist,viz a right-rotating a nd a left-rotating form , a n inactive

form composed like inactive amyl alcohol or inactive lactic

acid of equal molecules of the d a ndl forms, a nd a fourth

modification, mesotartaric acid , lik ewise inactive, in which

the configuration of one a symemtric carbon atom is the

mirror image of the other one in the same molecule, i.e.

the rotatory power is internally compensated . It is

impossible to establish in the case of a ny two configura

tion formulae, e.g. the lactic acids, which mode of arrange

ment actually represents the d o r the 1 form , but if we

make a n arbitrary assumption in the case o f one configu

ration, as for example that a ny one grouping represents

levorotation, its mirror image must represent the oppo

site or dextrorotation

IH— C— O H HO — C— H

GOOH CO O Hle vo ro ta to ry Dextro ro ta to rya rra ngemen t a rrra ngement

When one of these groupings is inverted so as to be united

with the other to form one molecule, the entire complex

must be levorotatory as I , a nd its image II will be dextro

rotatory . In III the two halves o f the molecule will

mutually neutralize the effect of each on the plane of

Hydroxy and Ketone Acids 229

po larized light, a nd a n inactive compo und results . This

form is called mesota rta ric a cid to differentiate it from the

racemic form, which consists of both the d a nd l acids

in equal amounts . M esotarta ric acid cannot be separated

into d a nd l-ta rtaric acids as can the racemic ta rtaric

a cid .

GOOH GOOH

HO — C —H

H— C— OH

COI

O H

GOOH

Ho t | H

H | 1‘O H

COI

O H

Ra cemic a cid is actually a compound of one molecule

of d-‘

a nd one o f l-tarta ric acids a ndnot simply a mix ture

of the two k inds of molecules . It has a different crys

ta lline form from the two active acids, a nd the crystals

carry water'

of crysta llization. The racemic acid crys

tals are much less soluble in water than are the active

acids , a nd have a higher melting point . The union is

however a feeble one, a ndin solution it exi sts a s separate

molecules of the optically active acids . This is indicated

by the fact that the molecular weight a s shown by the

CO O H

H— C— OH HO — C— H

HO — C— H HO — C— H

CO O HI I I


freezing point a nd boiling point methods corresponds

to the formula C4H606 . The esters of tartaric acids

are volatile, a nd their vapor densities correspond to the

single instead of to double molecules . Crystals of ra

cemic acid have the composition 2 C4H606 2 H20.

d a nd l—tartaric acids cry stallize without water of crys

ta lliza tion.

Dex tro a nd levo-ta rta ric a cids melt at 1 00 parts

of water at 20° C . dissolve parts , a nd at 1 00°

parts of either the d or 1 acids . They are much

less soluble in alcohol a nd insoluble in ether . Tartaric

acid when strongly heated with a dehydrating agent such

as potassium bisulphate loses water a nd carbon dioxide

a nd there distills over a ketone acid , pyruvic a cid. This

acid is l ikewise known as pyrora cemic a cid a nd as methyl

glyox ylic a cid

HCH;

CHOH — c02 a ndH20— > CO

CHOHCO O H

CO OH M etmxggliga c idPyruvic acid ha s great biological interest . It will be

further considered in connection with carbohydrate

metabolism a nd the synthesis of fats . It is probable that

the first step in the decomposition is the loss of carbon

dioxide a nd the formation of glyceric a cid which then

loses a molecule ofwater . Glyceric acid itself when heated

is converted into pyruvic acid .


oxide, SbO , to form potassium antimonyl tartrate or

tartar emetic COOK

(CHOH)2

CO O SbO

Racemic acid a nd mesotartaric acid are both formed

from d-tartaric acid by bo iling with sodium hydroxide .

This is explained by the assumption that water is alter

mately separated a nd added .

CO OH O OOH

HO —i—C— j—H

GOOH GOOHGOOH

H HO — C— H OHor or

HO H— C— O H H

GOOH

HO — (

ll— H

HO — C— H

CO OHMeso ta rta ric a cid

GOOH

H— C— O H HO — C — H

IHO — C— H H— C— O H

CO O Hd-ta rta ric a cid

Hydroxy a nd Ketone Acids 233

According to the law of chance, if water is split off from

a compound a nd added on again in the way described ,a n OH group will take the place o f H , just as frequently

as it will replace the separated OH . Thus on repeating

the separation a nd addition o f water a sufficient number

of times a state of equilibrium will be established in which

all possible arrangements of H a nd OH groups will exist

in the solution . Such a conception helps to make clear

the process of racemization a nd likewise the transforma

tion of certain sugars into others .

SEPARATION OF RACEM IC SUBSTANCES INTO THEIROPTICALLY ACTIVE CONSTITUENTS

Optically active isomers show no differences in their

solubility , melting point , boiling po int, or amount of

water of crystallization . They differ only with respect

to their effect in twisting the ray o f polarized light . Ordi

nary methods oi separating mix tures depend on differ

emees of physica l or chemical properties , so that for the

separation of optical isomers special pro cedures had to

be devised . Three general methods for accomplishing

such separations are known, a nd all o f these were dis

covered by the brilliant French chemist, Pasteur .

The first o f these depends upon the property possessed

by sodium ammonium racema te, when allowed to crys

ta llize at temperatures below o f depositing side by

side the sodium ammonium salt o f dextro a nd of levo

tartaric acids . These crystals possess hemihedral faces,a nd are , like mirror images, not superimpo sable . They

234 Orga n ic Chemistry for Students of M edicine

ca n be recognized by their appearance a nd separated by

picking out the two kinds of crystals by hand . O n pre

paring the free acids from these two kinds of crystals a nddissolving each kind separately they are found to have

opposite optical properties . O n mixing the two solutions

racemic acid is re-formed .

The second method depends upon combining the d

a nd 1 forms of acids with a n optically active base . The

resulting salt molecules are no longer alike in their con

figuration a nd therefore show different physical proper

ties . Such salts ca n be separated by fractional crystal

liza tion . The natural bases quinine, cinchonine, brucine,a nd others are optically active a nd are useful in such

separations of racemic mixtures of acids . When the

racemic mixture to be separated is a ba se a n optically

active acid must be selected

The third method devised by Pasteur for obtaining

a n active compound from a racemic mixture depends

upon the fact that but one of the two forms of the

enantiomorphous isomers has a n appreciable biological

value . The proteins of which the animal a nd plant

tissues are made up are composed of o ptically active

amino acids, a nd only o ne optical form o f each occurs in

nature . The sugars are likewise optica lly_a ctive substa nces . When a l iving orga nism is present in a racemic

mixture of some compound which it is able to use as a

source of energy, it ca n in general use one optical form

much better than the other, a nd not infrequently one of

such isomers is without value as a nutrient . Pasteur

found that the mold Penicillium gla ucum could make


volatile with steam ,a nd ca n be obtained in the crystal

line form, but the crystals are unstable . It is readily

soluble in water , alcohol , ether, a nd acetic ether, but

insoluble in benzene a nd petroleum ether . Its salts are

all soluble in water, a nddifiicultly soluble in alcohol , a nd

are precipitated from alcoho l by the addition of ether.

The silver salt is of use in its detection . It consists of

fine white needles .

O n heating with water o r dilute sulphuric acid

butyric acid is converted into crotonic acid

CHa CHa

CHOH CHHzo

CH2 CH

CO OH GOOHB—o x

a

ycqg

tyric nt

ioinic

O n oxidation with chromic acid it yields the ketone acid ,aceto-acetic acid , which readily breaks down into acetone

a nd carbon dioxide .

CH3

CHOH -co,

CHz

GOOH CO O H

1 25 . y-HydroxyAcids,R— CHOH_CH2

— CH2— GOOH,

show a peculiar tendency to lose water with the formation

Hydroxy a nd Ketone Acids 237

of internal esters called lactones . This tendency is so

pronounced that many acids of this type are not known in

the free state, but only as salts , esters , etc . O n being set

free they at once pass into the cyclic structure . Alkalies

convert lactones back into the salts of the y-hydroxy

acids . The same conversion is in part effected by boiling

with water .

R— O H— CHg— CHg— CO OHH 0

O H-2-> R — CH— CH2— CH2— CO

La cto ne

1 26 . y-Amino Acids show the same tendency to lose

water a nd form cyclic compounds . These are known as

lacta ms

R— CH— GHz— CHz— CO O HH O

NH, R— OH— CHg— GHz— CO

L_ NH_ _JLa cta m

1 27. Aceto-a cetic Acid, Cm— CO — CHg— GOOH,

possesses great physiological interest since it occurs in

the blood a nd urine in diabetes , where it results from the

oxidation of. fi-oxybutyric acid . It is a very unstable,

strongly acid sirup which absorbs moisture readily from

the air . O n warming it decomposes into acetone a nd

carbon dioxide as illustrated above . In the tissues 6oxybutyric acid results from the oxidation of fat a nd in

small amount from protein decomposition . This acid is

particularly difficult for the diabetic to oxidize, although


the normal organism is able to accomplish it . B—o x ybutyric acid is partly oxidized to aceto-acetic acid in the

blood a nd the decomposition of the latter acid into acetone

a nd carbon dioxide takes place spontaneously, so that in

the severe diabetic blood there a re always found the three

compounds, fl-oxybutyric a nd aceto-acetic acids a nd

acetone, together .

A certain peculiarity in the isomerism displayed by

aceto—acetic acid , together with the great importance o f

its ester in synthesis, make it desirable to describe the

behavior of the latter in some detail .

Aceto-acetic Ester is formed by the reaction of ethyl

acetate with sodium ethylate . There are three stages to

the reaction : the formation of a n addition product be

tween ethyl acetate a nd sodium ethylate

/O Na

(1 ) CH,3— C O — C2H5 Na O C2H5

= CHs —C_OC2H5

\0Q H5

This then reacts with a second molecule of ethyl

acetate to form the sodium compound of aceto-acetic

ester

/O Na

(2) CHs— C— O C2H5 C— COOC2H5\oczH,

/O Na

CH3_C : CH—_COOC2H5 2 C2H50H

The ethyl aceto-acetate is fo rmed on treating the sodium

compound with a n acid . This is known as Cla isen’

s

synthesis


Thus when sodio-aceto-acetic ester rea cts with n—octyl

iodide , the octyl group replaces the sodium. O n a cid

decomposition this compound yields capric acid,(3ro e02 .

CHa— CO — CHNa

COOC2H5

Na I

01 1 i Hco— icH—

fc l,

icooia H,

HEOH

cm— co0H+CH,— (CH2)8Ace tic a c id C a pn c a cid A lco ho l

The same compound when subjected to the ketone

decomposition yields methyl-nonyl-ketone

CHg— CO — CH— C SHH

CHa— CO _C QH1 9+C02+C2H50H

Me thyl-nony l-ke to neNumerous higher acids a nd ketones have been readily

prepared by this reaction .

ICHg— (CHz)s— CHsn-o c tyl io dide

CH3— CO — CH— C 8H1 7

COOC2H5

Hydroxy and Ketone Acids 24 1

As was stated above, sodio-aceto-acetic ester may have

either of two structures

CH3—C: CH —COOC2H5

IO Na or CHa— CO — CHNa —COOC2H5

Eno l fo rm Ke to fo rm

When a n acid chloride reacts with sodio—aceto-acetic

ester,it is possible to obtain at will a compound in

which the acetyl group is linked directly to carbon or

through oxygen to carbon .

CHa— C r —CH— COOC2H5 CHg— CO - CH— CO O C s

O — CO CHs CO — CH3O —deriva t ive C-deriva tive

(Inso luble in a lka l i) (So lub le in a lka li)When the sodio-aceto-acetic ester is treated directly with

acetyl chlo ride, the C-derivative only is fo rmed . This

compo und is soluble in alkali since the hydrogen in the

CH gro up is link ed to three negative radicals , two acetyl

a nd one carbethoxyl groups . (Compare malonic ester .)When, however, the aceto-acetic ester is mix ed with

pyridine a nd the acetyl chloride added to the mix ture,the O -derivative only is formed .

As a general rule the solubil ity in alka l i of such deriva

tives as result from the condensation of halogen com

pounds with metallic compounds o i substances which

show tautomerism is accepted as evidence of the fo rmation

of the C type of derivative, since solubility in alkal i should

be expectedwhere there is a n active hydrogen atom which

would permit the fo rmation in alkali of a sodium or

potassium derivative .R


The study of a large number of such compounds has

revealed some in which the change from the keto into the

enol form or vice versa takes place slowly even in solution,a nd a few where one form is a solid a nd is stable except

in solution. It has been found that the enol form gives

a n intense color reaction with ferric chloride a nd that

the keto form does not. This serves as a n easy test for

identifying a tautomer .

1 28 . M esoxalic acid,GOOH

is formed when dibrom malonic ester is boiled

CO with barium hydro xide solution, the two bromine

atoms bein re laced by hydroxyl rou sCOOH

g P g P

GO O C s COOC2H5 COOC2H5

HB3 (OH)2 C

\C0 H20

OH

COOC2H5 COOC2H5 COOC2H5

We have here another instance o f the ability of one ca r

bon atom to hold two hydroxyl groups when it is in close

proximity to strongly negative radicals (compare glyoxylic

acid a nd chloral hydrate). M esoxalic acid is consider

ably more unstable than malonic acid , for on boiling with

water it separates carbon dioxide a nd forms glyoxylic

acid :

. H— c4 302

IGOOH

244 Orga nic Chemistry-

for Students of M edicine

C s O O C— C C— COOC2H5

CH— CO O Q H5

B

(32H5000— CO —

g— CHzT coocz

H,

Like aceto—acetic ester oxalacetic ester ca n hydrolyze

in two ways (1 27) at the points indicated by A a nd B.

The first is accomplished by treatment with alkalies a nd

yields oxalic a nd acetic acids ; the second is effected by

the action of dilute sulphuric acid a nd leads to the forma

tion of pyruvic ester carbon dioxide a nd alcohol .

1 3 1 . Acetone D icarboxylic Acid, GOOH~— CH2— CO

CHz— GOOH, results from the nitrile formed by the action

of potassium cyanide upon symmetrical dichlora cetone :

CHzCl+KCN GHz—“CN (HIT —GOOH

-> co +4H20 co +2NIL

CH2C 1 +KCN CHz— CN CHg— GOOH

£33213;

Ace tone dicya nide Aceto ne dica rbo xy lic a cid

It is also formed by the action of strong dehydrating

agents upon citric a cid, a fact which gives a clue to the

structure of the latter acid . C itric acid is fo rmed from

acetone dicarboxylic acid by the addition of hydrocyanic

acid a nd subsequent hydrolysis of the o x ynitrile.

Hydroxy and Ketone Acids 245

1 32. C itric Acid — As stated above, the nitrile of citric

acid is formed by the cyanhydrin formation from acetone

dicarboxylic acid :

CHz— CO OHCHz— GOOH

CO +HON

CHz— COCH

GOOH+NH3

CHz— GOOH

The reverse reaction by which citric acid is converted

into acetone dicarboxylic acid by dehydrating agents is

as follows :

GHz— CO OH CHz— ‘ GOOH

CHz— GOOH CHz

— GOOH

C itric acid occurs in the juice of many plants, espe

cia lly in lemon juice, from which five per cent or more may

be obtained , a nd in gooseberries, which contain about one

per cent . It is also a normal constituent of the milk of

CN

CH2_CO O HCya nhydrin o f ci tric a cid

CHz— GOOH

OH


animals, but it is not certain whether it comes from the

food or is the product of the milk glands . It has also

been detected in certain grains, a nd is therefore one of the

most widely distributed compounds in nature . It crys

ta llizes with one molecule of water in large colorless

prisms . When it loses its water of crystall ization through

heating, it forms a fine white powder .

It is formed by the fermentative action of certainbacteria a ndmolds, but the nature of the chemical pro

cess by which it is produced from sugars is not clear , since

the sugars all contain the normal carbon chain whereas

citric acid contains a branched carbon chain. It ha s

been suggested that citric acid may result in fermentation

by the condensation with loss of water from three mole

cules of glycolic acid :

HzC— CO OH

HO — C —CO O H

GOOHThree mo lecules of glyco lic a cid

CHz- CO OH

OH

GOOH

CHg— “GOOHC i tric a cid


o f rotation . In fact we should exp ect that some one

arrangement of the atoms would be more stable than a ny

other, a nd that if the atoms were arranged in a ny way

whatever they would return to the stable position a nd

a ny movement within the molecule would constitute a n

oscillation about the sta ble position

Such freedom of motion of one carbon atom with re

spect to another is in part lost when the double bond is

CO OH CO OHEthylene fo rm H Tra ns fo rm

F ro . 2 1 . M a leic a ndFuma ric Acids .

established, as was pointed out in discussing the isomerism

o f the crotonic acids Assuming that in the case of

the double bond the tetrahedra which represent the

carbon atoms are in the position which is illustrated by

their having one edge in contact, ethylene would be

represented by Figure 21 . In such a molecule we should

expect two modifications of ethylene dicarboxylic acid :

CH— CO OH CH— CO O H

CH— GOOH HOOG— CH

The carboxyl groups may be arranged on the same or on

opposite sides of the molecule . Since in compounds of

Unsa tura ted D iba sic Acids 249

this type there is no asymmetric carbon atom, optical

activity is not to be anticipated . Theory agrees with

experience, which shows that fumaric a nd maleic as well

as the crotonic acids (86)do not rotate the plane of polar

ized light . I

Ethylene dicarboxylic acid results from malic acid

(1 22)by the withdrawal of a molecule of water . Its rela

tion to succinic a ndtartaric acids is shown by the follow

ing reactions :

GOOH CO O H

CHOH CH4 1 20 I I

GHz CH

The decision as to which of the configurations in Figure

21 is to be assigned to maleic a nd which to fumaric acid

is determined by the following data : Both are produced

from malic acid by splitting off water , but the conditions

under which the reaction is effected determines the nature

of the product . When the temperature of malic acid is

raised to 1 40— 1 50° a ndmaintained there during 40 hours,fumaric acid is the principal product . When, however,the malic acid is contained in a distillation flask connected

with a condenser a nd the temperature is quickly raised

to there distills over the anhydride of maleic acid

together with water .

Fumaric acid does not melt when heated , but sublimes .

CO O H GOOH

CHBr CHOH+2Br I 2AgO H I

CHBr CHOH


It is but slightly soluble in water, 1 part dissolving in

parts at It does not form an anhydride

which on tak ing up water regenerates fumaric acid, but

when heated to the point of decomposition forms, along

with considerable charring, maleic acid a nd its anhydride .

M aleic acid is soluble in 2 parts of water, at It

readily forms a n anhydride which takes up water, regenera ting maleic acid . When maleic acid is heated in a

sealed tube in aqueous solution to 2 1 0° it is converted

partially into fumaric acid . Since both acids contain the

same percentages of carbon, hydrogen, a nd oxygen, both

absorb the same amount o f halogen (2 atoms)a nd yieldhalogen-substituted succinic acids a nd both result from

malic acid by the loss of one molecule of water, it is evi

dent that their difference is a stereochemical one .

The d ibrom succinic acids are not identical . That

derived from fumaric acid is called dibrom succinic acid ,a nd is but slightly soluble in water . That derived from

maleic is called isodibrom succinic ac id , a nd i s much more

soluble in water .

Since fumaric acid does not form an anhydride, it would

appear that of the two possible positions which the CO O H

groups may occupy in Figure 21 , the most probable one i s

that wh ich separates them most . Th is separation should

interfere with the abstraction o f water from the two

groups,a nd therefore to fumaric ac id the tra ns structure

has been assigned . M aleic is therefore the cis form .

HOOG -C— H H— C— CO O H H— C— CO

H— C— CO O H H— C— GOOH H— C— COFuma ric a cid Ma le ic a cid Ma leic a nhydride


result . If now in Figure 24 hydrobromic acid is sepa

rated from the isodibrom succinic acid , a nda double bond

again established, it must involve the rotation of the

carbon atom represented by one tetrahedron through 1 20°

in order to bring H a ndBr together . This, together with

the folding of the two tetrahedra together, brings the two

carboxyl groups into the tra ns position, a nd there results,from maleic acid , bromfuma ric acid . In a perfectly

analogous manner there should result from fumaric acid ,by the addition of two bromine atoms, followed by the

abstraction of hydrobromic acid , brom maleic acid .

Experiment has demonstrated that by this process the cis

a ndtra ns forms are transformed into the opposite isomer.

Fuma ric acid occurs in nature in various plants . M aleic

acid does not occur in nature . Fumaric acid serves as a

source of energy for Penicilliuin gla ucum a nd Asper

gillus niger, while maleic acid is not utilized by these

molds . Here we see another example o f the fact which

has been several times emphasized , that living organisms,being themselves constructed of complexes which exhibit

the peculiarities of stereochemical configuration, show a

decided preference for one isomer a s contrasted with

another as a source of nutriment .

CHAPTER XIII

THE UREIDES

Ureides of the Monoba sic Acids

1 34 . Acetyl Urea .

~ Urea , which was treated as the

amide of carbamic acid (57) (amino formic acid) may

also be regarded as a substituted ammonia in which a

hydrogen atom of ammonia is replaced by NHz— CO .

Urea does in fact form a series of compounds in which it

acts as does ammonia ; thus it reacts with acid chlorides

forming'

a cetyl, propionyl, etc ., ureas :

ICHa— COi—C l HIHN —,cc— NH2

(3H.— C0— NH — cc -NH2 HC 1Ace tyl urea

The same derivatives are formed by the action of urea

on acid anhydrides :

CHa— CO HN— CO — NHz

CHa— C HN— CO — NHz

2 CHa— CO — NH— CO — NHz +H20

These compounds are solids . Acetyl urea forms silky

needles melting at It is easily soluble in water a nd

alcohol .

Dia cetyl Urea, CHa— CO — NH— CO — NH- CO — CHg,

is formed by the action of carbonyl chloride on acetamide

254 O rga nic Chemistry for Students of M edicine

C lCHa— CO — NHH

(30

C l

CHs— CO — NH— CO — NH CO — CH3 2 HC 1

It is slightly soluble in cold water a nd in alcohol . M . P.

O n heating with acids it is hydrolized to acetic

acid, carbon dioxide, a nd ammonia .

cm- cc NH-

‘

CO — iNHi— CO — CH.

OH’

H H?o ZHH'

OH

2 CHa— GOOH co, +2NHa

1 35 . G lycoluric Acid or hyda ntoic a cid is formed by the

condensation of glycolic acid with urea :

CH20H HHN— CO — NHz CHz— NH— CO — NHz

Urea

GOOH GOOHG lyco lic a cid G lyco luric a c id

This compound ca n further condense the M 1 2 a ndCO OH

groups with the separation of water a nd the formation of

a cyclic ureide , hyda ntoin .

(

ll — NH— CO CHz— NH— CO

GOOH NH CO — NHHyda nto in

Nearly all of the amino acids , when introduced into the

animal body, are either eliminated unchanged , as is the


HN— OH

BC

This ring structure is likewise referred to as imida zole.

Hydantoin is a white crystalline compound which melts

at The formation of substituted hydantoins re

sults from the employment of amino acids other than gly

co coll. These derivatives of the amino acids are in some

cases compounds with much more favorable properties

than the amino acids themselves, a nd serve a useful pur

pose in chemical work with these substances .

1 37. Alla ntoin is a urea derivative of hydantoin. It

results from the condensation of two molecules of urea

with one of glyoxylic acid . Glyoxylic acid although

it has the properties of both a n acid a nd a n aldehyde,always contains a molecule of water a nd appears to act

as if it contained two hydroxyl groups linked to one ca r

bon atom . The formation of allantoin i s one of the

reactions in which it displays this property .

NH —CH OH H HN NH —CH— NH

CC CO C0

NH NH2 CO — NHG lyoxylic a cid Al la nto in

Allantoin i s a constituent of various tissues of animals,occurring in small amounts . It is a constant constitu

ent of the urine of various animals, much more in other

The Ureides 257

animals than in ma n . Allantoin is a crystalline com

pound having neither taste nor odor . Its solutions are

neutral to litmus . It dissolves in 1 60 parts of cold

water,but much more rea dily in hot water or hot alcohol .

It melts with decomposition at It is precipitated

by silver in ammoniacal solutions , but the precipitate is

soluble in excess of ammonia . Lead , copper, a ndmercury

likewise form insoluble compounds with it . It reduces

Fehling’s solution a nd is a disturbing factor in the em

ployment of this reagent as a test for sugars in the

urine .

O n hydrolysis with acids or alkalies allantoin yields

a mmonia, carbon dioxide (from the urea complexes), a nd

acetic a nd oxalic acids . Its identification i s effected by

its iso lation as the silver compound , which contains

o f silver a nd by a positive qualitative test for

oxalic acid after hydrolysis o f a sample.1 38 . Histidine .

— The glyoxaline or imidazol ring

structure is present in one of the amino acids derived

from the hydrolysis of many proteins, viz . histidine :

CH— NH\CH

C N/

CHNH2

CO O H

w—aminoTB-imida zo lepropionic a cid8

CH— NH\

C N/

CH

CH

CO O HUroca nic a cid

(misfits)


Histidine crystallizes in platelets which melt at 253°

with decomposition. It dissolves readily in water, very

slightly in alcohol, a nd not at all in ether. Its solution

is alkaline to litmusf It forms salts with acids , the mono

a nddihydrochlorides being of special importance in its iso

lation . It is precipitated from its solutions alkaline with

sodium carbonate by mercuric chloride ; by silver nitrate

a ndammonia or barium hydroxide ; by mercuric sulphate

in sulphuric acid solution ; a nd by phosphotungstic acid .

Only l-histidine occurs in nature . It has a sweet

taste . Putrefactive bacteria cause the elimination of

carbon dioxide from it with the formation of histamine,

or B—imidazole-ethylamine . While histidine itself is

one of the essential amino acids which must be present

in the food proteins, a nd ca n be introduced into the body

without disturbance , histamine is a base which possesses

most marked physiological action . Its action is pri

marily a stimulant effect on plain muscle . O ne part in

25 millions of Ringer’s solution induces distinct contrae

tions in a non-pregnant uterus . Larger doses induce

tonic contraction .

H istamine dihydrochloride, C 5HgN3 . 2 HC1 , is rea d

ily soluble in water, but sparingly in ethyl alcohol . It

crystallizes in prisms which melt at The base

forms a double salt with hydro chloro platinic acid which

is soluble in hot water but very slightly soluble in alcohol .

O n boiling with bromine water histamine gives a claret

color . It is precipitated by phosphotungstic acid , by

ammoniacal silver solutions, a nd in alkaline solutions bymercuric chloride.


This type of compound is known as a cidureide.

It is not found practicable to stop the condensa

tion of oxalic acid a nd urea at this stage . Oxaluric

acid may be prepared by the careful hydrolysis of

parabanic acid .

A second molecule o f water may be separated with the

formation of a cyclic compound :

CO — NH CO — NH

I HzoCO

CO IO H HINHO x a lun c a c id(Ac id ure ide)

Parabanic acid is the simplest of the ureides.

Oxaluric acid occurs in the urine in traces . It is a

white crystalline compound soluble with difficulty in

wa ter . O n warming with alkalies it is hydrolyzed to

oxalic acid a nd urea .

Parabanic acid is likewise crystalline a nd is much more

soluble than oxaluric acid . Parabanic acid is obtained

by the oxidation of uric acid . Since its structure was

understood from its synthesis from, a nd hydro lysis to,oxalic acid a nd urea it served to give a clue to the strue

ture'

of the more complex uric acid mo lecule .

Ureides are also yielded bymalonic , tartronic a ndmeso x

alic acids . They are hydrolyzed to urea a nd the acids

from which they were derived on boiling with acids or

alkalies , the urea breaking down into ammonia a ndcarbon

dioxide . Their structures are illustrated by the following

fo rmulae

The Ure ides 26 1

CO — NH CO — NH CO — NH

H2C CO HCOH CO

CO — NHB a rbituric a c id(Ma lony l urea )

M alonyl urea is of special interest because of the na r

cotic effect of certain of its derivatives . The compound

itself is without noticeable physiological action. Numer

ous derivatives have been prepared by substituting one

or both hydrogen atoms of the malonyl group by alkyl

a nd other groups . The fo llowing selected list will illus

trate the remarkable influence which is exerted by cer

tain groups as compared with others on the pharmaco

logical action . Especially marked is the effect oi accumula ting alkyl groups , a nd the position occupied .

CO — NH CO -NH

C CO

CO — NH

Cs I

a s)?CO NHD ie thy l

ma lonyl urea(Vero na l)(3)

(

I30 N— CHs

(ma

y : COC s /

CO — NHD ieth l-N-methylma o nyl urea

(5)


When the derivatives (1 )a nd (2)above were given to dogs

weighing 6— 8 kilograms , in doses of 3 to 4 grams, there

was no noticeable effect . The diethyl derivative (3) in

doses of 1 — 1 5 gm . induced deep sleep in about thirty minutes

,lasting 24 hours . Of the dipropyl derivative (4) a

l-gram dose produced sleep after 30 minutes, lasting 48

hours, a nd 2 grams induced sleep within 1 5 minutes, a nd

death . The toxic influence of introducing into diethyl

barbituric acid (3) a methyl gro up linked to nitrogen as

in (5) is very marked . A l-gram dose induced sleep in

1 0 minutes which lasted two days a nd ended in death .

Veronal a nd a few other simil ar compounds ha ve found

use as hypnotics .

1 40. Alloxa n, or mesox a lyl a rea , is formed from the o x i

dation of uric acid . O n treatment with alkali it is hydro

lyzed to mesoxalic acid a nd urea .

CO — NH CO O H NH2

CO CO + 2 H20 = CO + CO

CO — NH CO O H NH2

O n boiling alloxan with dilute nitric acid it is oxidized

to parabanic acid a ndcarbon dioxide . This is a n example

of the transformation o f a six-membered ring to one con

taining but five

The formation of alloxan by the oxidation of uric acid

served as further evidence a s to the structure of a part of

the molecule of that substance .

O n reduction alloxan yields a derivative, a llo x a ntine,containing two alcohol groups, which has double the mc lee

CHAPTER XIV

THE PYRIM IDINES, PYRAZINES AND PURINES

1 4 1 . The Pyrimidines. In the nuclei of anima l a nd

plant cells occur the nucleic acids , complex compounds

which on hydrolysis yield phosphoric acid , purines

pyrimidinesp a nda carbohydrate group There have

been found in nucleic acids three representatives of the

pyrimidines

1 NH— 6CO

2CO 5C— CH, CO CH

3NH— 4CH NH— CH NH— CH2. 6-dio xy—5-methyl 2-o x y-6-amino 2 , 6-dio xy

p vrlmidine pyrimid ine p im1d1 ne

(Thymine) (Cyto sine) {Cra cib

In the o x y pyrimidines there appears to be in the dis

solved state a dynamic equilibrium between the mole

cules in which the oxygen is linked doubly to carbon, the

keto form, with the enol form in which oxygen is singly

linked to carbon a nd is in union with hydrogen forming

a hydroxyl group

NH— CO N C -OH

CO CH 2 HO C CH

NH— CH N— CH

The Pyrimidines, Pyra zines a nd Purines 265

tWhen, e.g. , uracil is acted upon by phosphorus o x ychloride, the oxygen atoms are not replaced by two chlorine

atoms, but chlorine replaces hydroxyl , a nd 2, 6—dichlor

pyrimidine results . This ca n be reduced to pyrimidine

itself.N : C— C l N : CH

C l— C CH + 4 H = HC CH

N— CH2 , 6—dichlo r pyrimidlne

Thymlne a nd cytosine are obtained from animal nu

cleic acids , a nd uracil a nd cytosine from plant nucleic

acids .

1 42. Thymine , C 5H602N2, is diflicultly soluble in cold,but rea dily in hot, water, a nd slightly soluble in alcohol .

It is precipitated by silver nitrate in the presence of a slight

excess of ammonium or barium hydrox ide, the precipi

tate being soluble in a n excess of the alkalies . It is

likewise precipitated by mercuric chloride a nd nitrate

in the presence of sodium hydroxide . Phosphotungstic

acid does not precipitate it, but it is readily carried down

where other substances are precipitated by this reagent .

Thymine sinters when heated quickly, at a ndmelts

with the evolution of gas at

1 43 . Cytosine , C4H50N3H20, is soluble in 1 29 parts of

water at It crystallizes from hot water in prisms

which decompose .with gas evolution at 320° The

salts formed with sulphuric or hydrochloric acids are

readily soluble, those with picric acid a nd hydrochloro

platinic acid difficultly soluble in water .


Cytosine is precipitated by phosphotungstic acid

a nd by potassium bismuth iodide . It gives the Weidel

reaction .

O n treatment with nitrous acid it is converted into

ura cil . The mechanism o f this tra nsformation is the

same as in the conversion o f methyl amine into methyl

alcohol Here however there exists a n equilibrium

between the keto form usually written for ura cil,'

a nd a

small amount only of the enol form . The apparent re

placement o f the amino group by o xygen instead o f by

hydro xyl as in the primary amines is ea sily understoodin the light o f the beha vior of urea a nd thiourea in the

pseudo or iso form (56, 58) a nd of aceto acetic acid inthe enol a nd keto forms

1 44 . Uracil , C4H402N2, is a white crystalline powder

easily soluble in hot, difficultly soluble in cold, water . It

disso lves readily in ammonia but scarcely at all in alcohol

or ether . It is precipitated by mercuric nitrate, but not by

phosphotungstic acid . It is precipitated under the same

conditions as thymine by silver nitrate a ndammonium or

ba rium hydroxide . Uracil melts with decomposition at

335— 338° It likewise gives the Weidel reaction .

Numerous experiments in feeding animals with rations,all the constituents of which were known, have demon

stra ted that, although the nuclei of all cells yield at least

two of the three pyrimidines just described , the diet need

not contain a ny of these complexes . They ca n be syn

thesizedin the animal body from certain of the amino acids

yielded by the proteins of the food . The mode of forma

tion of these compounds in the body is not understood .


/NH2

C4H904— ‘ CH CHO

CHO CH— C4HgO 4

Fructosamine

N

C4HgO 4— C CH

HC C— C4H9

'

O 4

NFructo sa zine

HOOG C CH6 C02 8 H20

HC C— CO O H

2 , 5-pyra zine dica rbo xyl ic a cid

Fructosa zine is oxidized outside the body by hydrogen

peroxide with the formation o f the same 2, 5-pyrazine

dicarboxylic acid . The latter compo und gives in neutral

or faintly acid solution with ferrous sulpha te a fine vio

let color which is easily seen in dilutions of 1 to

parts o f water . By means o f this reaction it has been

shown that this pyra zme derivative when introduced

into rabbits, even in small amounts, passes into the

urine .

The Pyrimidines, Pyra zines and Purines 269

The above condensation is of interest because it po ints

to the possibility of the rea ction of carbohydrates in the

body with certain intermediary decomposition products

of the amino acids with the formation of heterocyclic

compounds, i.e. cyclic compounds conta ining more than

one kind o f element in the ring .

1 46 . Pipera zine differs from pyraz ine in that the doublelinkages are eliminated by the addition of hydrogen or

substituting groups,i.e. it is a reducedpyrazine .

HC CH c CH2

HC CH H2C CH2

NHPyra z ine Pipera zine

Piperaz ine IS fo rmed by heating the hydrochloricsalt of ethylene diamine .

NH2 HHN

CH22 NH3

NH2 HHNE thylene diamine

Esters of the amino acids change on standing, with the

separation of alcohol, into their cyclic anhydrides , substituted ketone derivatives of piperaz ine . The change is

accelerated by heating .

CH2

H2C GHZ


-co

CH3— CH HC— CHs

CO IO C2H5 HINHAla n ine ester

These cyclic anhydrides have in many cases much more

favorable properties for manipulation, as sparing solu

bility, etc . , than have the amino acids themselves . O n

heating with acids they are hydrolyzed to the free amino

acids .

NH2co CH2

l I 2H20CHz CO

NHD iketo p ipera z ine

THE PURINES1 47. The researches of Emil Fischer on uric acid made

clear the constitution of the group of compounds known asthe

’

purines. The constitution of uric acid w a s arrived at

through the observation that on oxidation it yields

CHa— OH co

co CH- CH,

NH2 , 5—dimethyl-diketo

p ipera zme


Uric acid was synthesized in 1 895 by Emil Fischer by

the following series of reactions

NH— CO NH— CO

CO CH— NH2+HCNO CO CH— NHsCNO

NH— CO NH— COUramll Cya nic a cid sa l t o f uramil

Urea NH— COrearrangement I

CO Cfl—N

NH— COPseudo uric a cid

t — moNH— Cc

CO C -NH\I I

NH— C — NHUric a cid

The second product in this series of reactions may be

looked upon as a substituted ammonium cyanate . It

should be expected therefore to rearrange on heating, into

a substituted urea (urea in which one hydrogen atom is

replaced by barbituric acid), a nd this is what happens .

O n heating this last product with oxalic acid it loses a

molecule of water, passing into uric acid .

Uric acid is present in the urine of all animals . Among

birds a nd reptiles the greater portion of the total nitrogen

excreted is in the form of ammonium urate . M ammals

excrete the greater part o f their waste nitrogen as urea,only 1 per cent being eliminated as purines a nd this

The Pyrimidines, Pyra zines a nd Purines 273

mostly as uric acid a nd allantoin . Among mammals

ma n occupies a peculiar position with respect to the exore

tion of uric acid . Studies of a considerable number of

animals of diverse types have shown that the greater part

of the purine nitrogen is eliminated in the form of allan

toin . In ma n there is but a trace of allantoin excreted ,practically all of the purine nitrogen appearing in the

urine as uric acid . This finds its explanation in the fact

that the reaction by which uric acid is transformed into

allantoin, oxidation a nd hydrolysis , is catalyzed by a

specific enzyme . This enzyme, which ca n be recognized

in a tissue by its ability, under suitably regulated condi

tions , to destroy uric acid , is present in the tissues of all

animals except ma n . In the absence of this catalytic

agent the conversion of uric acid to allantoin goes on with

extreme slowness .

Uric acid has been synthesized by a considerable number

of methods starting from widely different material s . The

early synthesis (1 888)byBehrend a ndRoosen, which is par

ticula rly instructive, is illustrated by the following reactions

NH— CO NH— CO

+HN03 ICO CH CO — C— Noz

NH— C— CHs NH— C— CO O H4-methyl ura ci l 5-n itro ura ci l

4—ca rbo nic a cid

Potassium salt NH— CO

heated to 1 30° ICO C


Reduction with NH —~CO NH— CO

Sn —I—Hcl N20 3 l lCO C— NHz CO C— OH

NH— CH NH— CH5-amino ura c i l 5-o x y-ura c i l

NH — CO HN— CO

+AgO HCO C— OH CO C — OH

NH— C— Br NH— C — O H4-bro

ua-

0

51

-

oy 4 , 5-dioxy ura c il

NH CO

l

|

\lH

CO C OH H HNfi lj gCO C_N

/CO Dchydrz

;t1 ng

I HNH— C-HN

g“Urea Uric a c 1 d

Uric acid is ordinarily prepared from ur 1 ne . It exists

in the urine in the form of the sodium a ndpotassium salts,which are fairly soluble . O ne gram of dipotassium

urate disso lves in 44 c .c . of water at room temperature,a nd 1 gram of disodium urate in 77 c .c . The free uric

acid is soluble in about 4000 parts of water at room tem

pera ture . O n adding hydrochloric acid to urine , to a

distinctly acid reaction, uric acid crystallizes out usually

arranged in sheaves , a nd greatly pigmented . By dissolv

ing in strong sulphuric acid (35 a nd diluting with

water the acid crystallizes out a ndmay thus be purified .

Uric acid acts like a dibasic acid, forming two series of

salts , acid a nd neutral urates . The ammonium, calcium,

a ndbarium salts are more difficulty soluble than a rethose


Purine is formed from trichlor purine, which results

directly from the action of phosphorus oxychloride on

uric acid .

N C— O H

HO — C C— NH\

N — C N/Uric a cid (ta utomeric fo rm)

C— OH

N C— C l

+ PoCla ClC C— NH\C C l

+H3PO 4

N CH

HC C— NH\

+ 4 H 1 0 C — NH\

N— C N/ N— C N/Purine 2 , 6-d 1 iodo purine

The urea complexes behave in these reactions as if they

had the iso structure (57,Purine is a crystalline substance which melts at 2 1 1

It is a basic compound a ndforms salts with various

acids .

Hypoxanthine , C 5H4N4O .

— There are besides uric acid

two other o x ypurines which are o f great biological interest,viz . xanthine a nd hypoxanthine . Their relation to uric

acid is shown by their formul ae :

The Pyrimidines, Pyra zines and Purines 277

NH— CO

CHN C N/6-o x y purine (Hypoxa n thine)

NH— CO

0C C— NH\CO

2 , 6. 8-trio x y purine (Ur1 c a c id)

Hypoxanthine is a crystalline compound soluble in

parts of boiling water a nd in 1 400 parts at It dis

solves readily inmineral acids a ndalkalies . It is inso luble

in alcohol . The hydrochloride, C 5H4N4O . HC 1 + H20,

i s decomposed on crystallization from water, but ca n

be crystallized from concentrated hydro chloric acid .

The sulphate a nd nitrate are likewise decomposed by

water . Hypoxanthine picrate is a characteristic salt .

Hypoxanthine is precipitated from its solutions by

ammoniaca l silver nitrate .

Hypoxanthine is found in the muscles a nd organs of

the animal body a nd is accumulated in beef extract .

It is l ikewise widely distributed in plants .

Xanthine, C 5I‘I4N4O-z, is likewise found in animal tissues

a nd widely distributed in plants . It 1 s very slightly sol

uble in water , about 1 to parts at a nd in 1 400

parts of bo ilingi

w a ter. It dissolves more readily in

alkalies . Xanthine, like hypoxanthine, forms salts with

acids . However, it also forms crystalline compounds

with alkalies .

NH— CO

O C C— NH\CH

NH— C N/2 , 6-dioxy purine (Xa nth ine)


O n evaporation with concentrated nitric acid , there

remains a yellow residue, which on treatment with sodium

hydroxide becomes reddish yellow a nd on heating purple

red . This is a modification of Weidel’s reaction.

AM INO PURINES

1 48 . Adenine, C 5H5N5 .

— There is but one amino

purine found in na ture , viz . 6—amino purine or adenine .

It is a product of the hydrolysis of nucleic acids of both

plant a nd animal origin . It is crystalline a nddecomposes

at 360 It is soluble in 1 55 parts of water at

It forms salts with mineral acids which in contrast to those

o f hypoxanthine a nd xanthine ca n be crystallized from

water . Its oxalate a nd picrate are characteristic salts .

The latter serves to separate adenine from hypoxanthine .

Adenine does not give the xanthine or murexide tests .

It is best prepared from extracts of tea leaves .

Adenine is usually associated with the closely related

purine base guanine, or 2-amino—6-oxy purine .

N C— NHz NH— CO

HC C— NH\

HzN— C C— NH\I I H

/CH CH

N— C— N6-amino purine 2-amino-6-o x y purine(Adenine) (Gua nine)

Gua nine is found widely distributed in both animal a nd

plant tissues, a nd is present in nucleic acids . It is the

principal constituent of the excrement o f spiders , a nd is

occasionally found deposited as crystals in the joints of

swine in the so—called guanine gout .” Guanine is


inize adenine to hypoxanthine, a nd a gua na se which cata

lyzes the transformation of guanine into xanthine as de

scribed above . Not all tissues contain all the enzymes

necessary to the transformation of the amino purines

into o x ypurines. Thus adenase is not found in the tissues

o f the rat . Guanase is absent from the spleen a nd liver

of the pig a nd from the human spleen, but is present in

most other tissues . The enzyme which accelerates the

oxidation of hypoxanthine into xanthine is called hypo

x a nthine-ox ida se ; that which oxidizes xanthine to uric

acid is called xanthine-oxidase . The enzyme which

accelerates the oxidation of uric acid to allanto ini scalled urica se. The ending a se i s employed to designate

enzymes or organic catalysers .

The nucleic acids o f both animal a nd plant origin con

tain but two purines, adenine a nd guanine . The hypo

xanthine, xanthine, a nd uric acid found in the tissues are

formed by the deamination a nd oxidation of these .

Within recent years feeding experiments with young

animals have shown that with diets entirely free from

a ny of the purines , growth a nd hence the synthesis of

nucleic acids ca n take place at the normal rate . Such

animals regularly excrete uric acid . There is no doubt

that in such experimental animals adenine a nd guanine

are produced synthetically. The substances from which

purines are formed in mammals are not known with cer

tainty, but experiments with birds make it highly prob

able that they are urea, ammonia, a nd lactic acid . In

birds the seat of synthesis of uric acid is the liver. When

the liver of a bird is excised the bird has been found to

The Pyrimidines, Pyra zines and Purines 28 1

excrete, during the few hours it ca n live , ammonia a nd

lactic acid instead of uric acid .

THE METHYL PURINES

1 49. Aside from the purines ingested as adenine a nd

guanine o r their degradation products there occur inplant foods two important methylated purines, theobromine a nd caffeine .

Theobromine is -diox y -dimethyl purine

NH— CO

CO C— N

H CH

CIL— N— C— N/

Occurs in the cocoa bean, a nd is found in chocolate to

the extent of 1 to 2 per cent . It is a dimethyl xanthine .

It is a white crystalline powder, soluble in ether, in

soluble in alcohol a nd water, but somewhat soluble

in hot chloroform . It forms crystalline salts with

strong acids, but these are decomposed into the base

a nd acid by water . It sublimes unchanged at

It is a powerful diuretic a nd nerve stimulant . It has a

bitter taste . The hydrochloride a nd salicylate are also

much employed .

Ca fl eine is —di0x y -trimethyl purine

CHa— N —CO

CHsCO C

l

— N

CHCHa— N - C

l— N

/


It occurs in tea a nd coffee, guarana, a nd in kola nuts .

Coffee contains about one per cent. It is soluble in 80

parts of water ; 55 parts of alcohol , 7 parts of chloroform,

a nd 555 parts of ether at Caffeine crystallizes from

water in white fleecy masses of silky needles , having a

bitter taste . It sublimes at

Caffeine is a diuretic a nd cerebral stimulant a nd has a

pronounced stimulating action on the heart .

In passing through the body caffeine a nd theobromine

are partially demethyla ted, a nd they appear in the urine

to some extent as monomethyl a nd dimethyl purines .

In part the methyl groups are completely removed, the

nucleus being excreted as uric acid .


the greater part of the diet . In ma n there frequently

occurs a patholo gical state (diabetes) in which the bo dy

is incapable of oxidizing carbohydrates , the absorbed

sugars,wholly or in part , being eliminated unchanged in

the urine . The exact nature O f this diso rder is not under 7

stood, a nd it is therefore o f the first importance that we

should have a full understanding of the chemical nature

of the carbohydrates a ndo f the changes which they under

go in the course O f no rmal metabo lism .

The cla ssification of the carbohydrates is based upon the

fact that there a re found widely disseminated in nature

certain aldoses a ndketo ses which contain six carbon atoms ,called hexoses (glucose, fructose , a nd others called

polysaccharides (starches, dextrine, cellulose , etc .)which

are polymers of the hexoses a ndyield the latter on hydrolysis. Widely prevalent also are the pentosans, polysa c

cha rides which on hydrolysis yield aldopentoses, or sugars

containing five carbon atoms . The four aldohexo ses a nd

five aldopento ses are all aldehydes a ndin addition contain

alcohol groups Between these pentoses a nd hexoses,which are termed monoses , a nd their complex polymers ,are the disaccharides , trisaccha rides , etc . , yielding on

hydrolysis two , three , etc . , molecules of monoses . The

term sugar is usually applied only to mono di a nd

trisaccharides .

Before discussing the chemistry of the carbohydrates it

is necessa ry to describe in further detail the behavior of

phenylhydra z ine with several typ es of compounds . The

reaction o f hydrazine, NH2_NH2, a nd its derivatives with

aldehydes a nd ketones has already been pointed out

The Ca rbohydra tes 285

(32, With compounds o f the type O f acetaldehyde o r

acetone , mono derivatives , hydra zones, are formed . With

glyoxal , phenylhydrazine reacts to form a dihydrazone,or osa zone.

CHO HgN— NH— C 6H5 CH =N— NH— C 6H5

CHO HaN— NH— C 6H5 CH =N— NH— C 6Ha

G lyo xa l Pheny lhydra zine G lyo xa l o sa zo ne

The same osazone is obtained by the action of phenyl

hydraz ine upon glyco laldehyde, the simplest of the

carbohydrates.

The reaction with glycolaldehyde takes place in three

stages , in one of which a hydra zone is fo rmed , in the second

the adjacent carbinol group is converted by the with

dra wa l Of two hydrogen atoms into carbonyl , with the

destruction of a molecule Of phenylhydrazine . In the

third step another molecule o f phenylhydrazine is con

densed with the newly formed carbonyl group producing

the osazone .

CHzO H

CHO 2 HzN— NH— C 6H5

CH N— NH— C 6H5

CHO CH N— NH— C GHs

"

I +H2N— NH— C 6H5

CH N— NH— Cn CH N NH— C 6H5

G lyo xa l hydra zone


This conversion of the group

C =N NH— C 6H5

into IC N— NH— C 6H5

i s characteristic of the action of phenylhydrazine on the

simple carbohydrates, a nd indicates that a secondary

alcohol group is attached to the carbon atom adjacent to

the aldehyde group .

The Observation of the formation of o sa zones by the

sugars ma de possible the ready separation a nd purification

o f sugars . The difliculties attending the crystall ization of

sugars from their solutions, owing to their great solubility

a nd .tendency to form sirups, had previously prevented

rapid advance in the study of the chemistry of the carbo

hydrates . The o sa zones are difficultly soluble in water,crystallize well, a nd have definite melting points . The

latter property makes it easy to identify the individual

sugars .

The aldohexoses all have the formula C 6H1 206. They

all react with phenylhydraz ine in the manner described

above, showing that they contain the aldehyde group and

a hydroxyl in the alpha position to it . Their aldehyde

property is further shown by the fact that they exert a

reducing action on certain salts of the heavy metals, as

alkaline copper a nd bismuth solutions a nd ammoniacal

silver solutions . They are reduced by nascent hydro

gen to hexahydric alcohols , a nd are oxidized to penta

hydroxy acids containing six carbon atoms .


more than one hydroxyl is untenable . Each one except

the end ones must be linked on two sides to carbon a nd

on one to hydroxyl . The remaining bond must be occu

pied by hydro gen . By such reasoning we arrive a t the

conclusion that the structure of the aldohexoses is the

following

CHzO H— CHOHw CHOH- CHOH— CHOH— CHO

1 5 1 . M eth ods Of Synthesis of the M onoses. 1 . By

the carefully regulated o xidation Of the po lyatomic alco

hols . As a n example may serve the oxidation o f glycerol .

It has previously been described (36) how by cautious

oxidation o f this triatomic alcoho l there results glycera lde

hyde , which in the terminology of the carbohydrates is

glycerose . The chief product of this reaction is always

the isomer dihydroxy acetone

CHZOH CH20H CHzOH

I2 CHOH i i ? C0 CHOH 2H20

ICH,OH CHO

D ihydro xy a ce to ne G lycera ldehyde

Glyceraldehyde ca n be prepared free from dihydroxy

acetone by the oxidation of acrolein the aldehyde

group of the latter being protected during the process by

first converting it into the acetal As in the case of

the fatty acids, oxidation of compounds containing doubly

linked carbon leads first to the formation of hydroxy

groups at this point .


ocs n

CH<5Q H5

Acryl ic a ldehyde a ce ta l

CHOH ”1 20 2 C2H50H

CH(O C2H5)2 CHOG lycera ldehyde a ce ta l G lycera ldehyde Alco ho l

2 . By hydrolysis of brom aldehydes with barium

hydroxide . M ention ha s a leady been made O f the forma

tion of glycol aldehyde from brom acetaldehyde by this

method By this method glyceraldehyde may also

be prepared . Sta rting with acrylic aldehyde , two bromine

atoms are added . The dibrom propyl aldehyde reacts

with water when heated with barium hydroxide, the

bromine atoms being replaced by hydroxyl .

CH +2 3 ?C O H CHOH

CHO CHO CHO

3 . When formaldehyde is treated with weak alkali

(limewa ter) it condenses to a mixture of compounds of

the formula C eHmO e. The mixture is sirup-l ike a ndsweet .

It has received the name formose. In its fo rmation s ix

molecules o f formaldehyde condense to form a mixture o f

aldohexose s

290 Orga nic Chemistry for Students O f M edicine

CHZO HHCO HHCO HHCO HHCO HHCOS 1 r mo lecules o f fo rma ldehyde

CHzO H— CHOH— CHOH — CHOH— CHOH— CHOAldohexose

4 . D ilute alkalies cause two mo lecules of glyceraldehyde

to condense, forming a n aldohexose . It is called a crose.

Like synthetic compounds in general the hexoses formed

by the methods just described are optically inactive,whereas all the sugars found in nature exhibit optical

activity .

5 . A most important method discovered by Kiliani

makes possible the building up of tetro ses from trioses,hexoses from pentoses, etc . It consists in the addition of

hydrocyanic acid to the aldehyde group of the pentose,forming a n o x ynitrile, in a ma nner analogous to the for

mation of lactic acid from acetaldehyde The nitrile

radical is hydrolyzed to a carboxyl group . This in solution

forms a lactone with the hydroxyl in the 7-position

a nd the lactone ca n be reduced by means of nascent

hydrogen (sod ium amalgam)to a n aldehyde .

CHOH CHOH CHOH CHOH

ICHO CH £ 522 CHOH iiE CHOH

GOOH

Kilia ni’s rea ct ion

6 . Wohl discovered a method which makes possible the

reversal of the preceding operation (Kilia ni’

s reaction)a nd the formation of a stiga r molecule having one less


7. It has also been found that when a simple sugar, as a n

aldohexose,i s oxidized carefully, the first product of the

reaction is a n acid having the same number of carbon

atoms . O n further oxidation of the calcium salt of this

with hydrogen peroxide in the presence ofi

a little ferric

acetate which acts as a catalytic agent, carbon dioxide is

separated a nd the alcohol group which in the sugar o ccu

pied the a -position to the aldehyde group is oxidized to

aldehyde . There results the aldo sugar having one less

carbon atom than that employed in the o xidation.

CH20H CH20H CHzO H

(CHOH), (CHOH)3 (CHOH)3

Hex omc a c 1d

The pento ses are readily distinguishable from the

hexo ses by their tendency to lose three mo lecules of water

a nd pass into furfural , a cyclic aldehyde containing four

carbon atoms a nd one oxygen atom in its ring.

CHzOH

CHOHCH= C CH= CH

I /0 O I > O

CHI CGOOH

Furfura l Pyromuc1 c a c id


The structure of furfura l is evident from (1 )itsmode of

formation, (2) its conversion into a n acid, pyromucic acid,C4H30CO O H, on oxidation , (3)the formation of furfura ne

by the loss of carbon dioxide

CH ==CH\O

_co , CH :=

O

CH\

OH = C/0

CH : CH/O

F urfura ne

on heating in a sealed tube to That furfura ne has its

oxygen in the r ing a nd not in the form o f a carbinol or

carbonyl group is shown by the fa ct that with metallic

sodium no hydrogen is evolved , as is the case with the alco

hols a ndit does not rea ct with hydroxylamine or other

reagents with which aldehydes or ketones condense . Fur

fura l is a n oily liquid with a n agreeable odor which boils

at With paper moistened with aniline acetate it

gives a n intense red co lor .

Those carbohydrates which contain a n aldehyde group

are called a ldoses, a nd those which contain a ketone group

ketoses. The names of the sugars end in ose a nd those of

the alcohols which result from the reduction o f the ca r

bonyl group end in ite. Glyco l aldehyde a nd glycerose,while chemically sugars, do not o ccur in nature except

possibly as unstable , transitory, intermedia ry products of

the ox idation of the carbohydrates . They are not named

in accordance with the systematic nomenclature O f the

sugars . Since every representative of this group Of sub

stances contains in addition to the ca rbonyl group C = O


(aldehyde or ketone group) at least one ca rbinol group

HCOH, it must follow that for each of the aldoses, there

are two acids which ca n be derived by oxidation a nd a n

alcohol which ca n be Obtained by reduction. The fo llow

ing ré sumé of the simple aldoses, together with the co r

responding alcohols a ndacids, will serve to illustrate their

relationships

D iose, CZIL02

CHzOH CH20H CO O H

Triose (glycerose), C3H503

CHzOH CHzOH CO OH

CHOH CHOH CHOH

Tetrose (erythrose), C4H804

CHzOH CH20H CO O H

CHOH CHOH CHOH

CHOH CHOH CHOH

CO OHErythronic

a c id(Trio x y butyric a c id)


CHzOH CHzOH CHQOH

IHO — C— H H— C— O H H— C— O H

HO — C— H H— C — O H HO — C— H

IH— C— O H H— C— O H

CHO CHO(l) l-ribose (2) d-ribo se

CH20H CHgOH CHzOH CHzOH

IHO — C— H H— C — O H HO — C— H H— C— O H

IH— C— O H HO — C— H HO — C — H H— C— O H

H —C— OH HO — C — H H— C— OH HO — C— H

ICHO CHO CHO

(5) l-Iyx o se (7) l-a ra binose (8) d-a ra b inose

From these are obtained on reducing the aldehyde

groups to primary alcohol radicals , the following alcohols,the pentites.

CH20H CH20H CHgO H CHzOH

H— C— OH H— C— O H H— C- OH HO — C— H

IH— C— O H HO — C— H HO — C— H H— C— O H

H— C— O H H— C — O H HO — C— H H— C— O H

ICH20H CH20Hl-a ra bite d-a ra bi te

(From l-lyxo se (From d-b'x osea nd l-a ra binose) a ndd—a ra bmose)

CHzOH

HO — C— H

H~ C— OH

HO — C — H


Adonite a ndxylite are optically inactive although each con

tains two asymmetric carbon atoms . The central carbon

atom in the pentose loses its asymmetry when the carbonyl

group is changed to carbinol , for in the case of adonite the

two groupsmarked off by the dotted lines are alike a nd

there exists accord ingly the same type of interna lcom

pensa tion with respect to influence on light, as was seen

in mesotartaric acid

CHgOH CHZO H

H— C — O H H— C— O H

H— C — OH H —C— O H H— C— OH

IH— C— OH R H— C— OH

CH20H

When the symmetry of the molecule is destroyed by

oxidation of one primary alcohol ra dical , the central ca r

bon atom again becomes asymmetric a nd Optical activity

is restored . A simple test as to whether a compound is

inactive because of intramo lecular compensation , is to

determine whether by rotating the projection formula

1 80°

in the pla ne of the p a per it ca n be made to coincide

with the projection fo rmula of its mirror image . When

ever the two formul ae ca n be made to c0 1 nc1de, the mo le

cules which they represent are identical a nd therefore ca n

not be Optica lly different . l-a ra binose a nd l-xylose a nd

possibly d-ribose occur in nature, while lyx ose does no t.

1 52 . Determina tion of Structure .

— We may now in


quire in what way it is possible to decide which Of the sev

eral formulae (1 — 8) of the aldopentoses is to be assigned

to each Of the naturally occurring sugars . If the pro

jection formula for each one of the four pentoses having

different configuration ca n be determined , the other four,being their mirror images , ca n at once be properly named .

If the four forms in question (page 296) be oxidized at

both the aldehyde group a ndat the primary alcohol group

there will result for each pentose form a trihydroxy

glutaric acid of similar configuration .

CH20H CHzOH CHzOH CH20H

HO — C— H HO — C— H H —C— O H H— C— OH

HO — C— H HO — C— H HO —C —H HO — C— H

HO — C— H H— C — O H H— C— OH HO — C— H

HO — C— H HO — C— H H— C— OH

HO — C— H HO — C— H HO— C— H

HO — C —H H— C— OH H- C— OH HO — C -H

GOOH GOOH CO O H COOR( 1 ) Ina c t ive (2) Active (3) Ina ct ive (4) Act ive

Two of these will be active a nd two inactive because onconverting both endcarbon atoms into similar groups (car


CHzOH CHzOH

H— C— OH

HO — C— H

H— C— OH

CHzOH CH20H

HO — C — H HO — C— H H— C— OH

HO — C— H HO — C— H HO — C— H

H- C— O H H— C— OH HO — C— H

HO — C— H H —~C— OH HO — C— H

CO OH

HO — C— H HO — C— H H— C— O H


H— C— O H H— C— OH HO — C— H

HO— C— H H— C— O H HO — C— H

CO O H(2) Ac tive a cid

GOOH(4) Ina c tive a cid

H —C— OH

HO — C— H

HO — C— H

H— C— OH

H— C— OH

HO — C— H

HO — C— H

H— C— OH


It follows,therefore, that the fo rmula of arabinose must

be a nd ribose which yields the same osazone must be

a nd lyx ose , being the only pentose from which hexoses

are derived yielding a n active a nd a n inactive dica rbo x ylic acid , must be Xylo se mustt hen be represented

by the only one remaining .

THE PENTOSES

1 53 . The structural formul ae fo r the three bio lo gically

impo rtant pentoses are the fo llowing

CHzO H CHgOH CH20H

HO — C— H HO — C— H H— C— O H

HO — C — H HO — C — H HO — C— H

HO — C— H H— C — O H H— C— OH

CHO CHO CHOd-ribose l-a ra bino se l-xylo se

d-ribose ha s been found only in the nucleic ac ids. J udg

ing from the amount of furfural Obta ined from various

tissues when these a re distilled with acids , the human body

contains about grams of pentose . l-ara bino se a nd

l-xylose are apparently not found in na ture in the free

state , but o nly in the form o f their polysaccharides, a raban

a ndxylan (1 62)in the gums a ndwoody tissues Of plants .

The pentoses a re water-so luble a nd show the general

properties of alcohols a nd aldehydes . l-arabinose is

O bta ined from the hydro lysis of gum arabic, pea ch gum,

cherry gum, etc . It crystallizes in prisms a ndhas a sweet


ta ste . It is dextrorotatory, its designation l-arabinose

being due to its stereochemical relationship to glucose

It melts at

l-xylose is formed by hydrolysis of xylan, which is

found to the ex tent,of 1 7— 25 in the straw of wheat,

rye, a nd other cereal gra ins . It crystallizes in doubly

refractive prisms which melt at 1 44

In marked contrast to the more common hexoses , the

pentoses are incapable of oxidation in the animal body

except to a very slight extent . After the administration

Of even small doses by mouth they appear in the urine .

In the case of certain individuals , there is excreted regu

la rly in the urine, regardless o f the character of the diet, a

considerable amount Of a pentose which has not been iden

tifiedwith certainty, but is probably arabinose o r ribose .

As much as 36 grams per day has been reported in the

urines of such persons . This chronic pentosuria appears

to be without ill effects, a nd is apparently hereditary.

Temporary pentosuria frequently follows the ingestion

of fruits a nd berries , many of which contain pentoses or

soluble pentosans .

Rea ctions of Pentoses. The reaction for the estima

tion of the pentoses or their polysaccharides depends upon

the ready formation of furfural on treatment with mineral

acids . The furfural produced is distilled Off with steam

a nd is precipitated with phloroglucinol The latter

is a cycl ic tria lcohol compound with which furfural forms

a very insoluble compound on condensation . From the

weight of furfural phloroglucide the pentose content of the

sample is estimated . Barbituric acid (1 39)by virtue of its


CHzO H— (CHOH)4— CHO. These represent eight formsa nd their mirror images . Of the eight pairs of sugars

possible, two pairs are unknown , so that but six need be

considered . Their structural formul ae are arrived at

through their relation to the pentoses a ndthe Optical prop

erties of the dibasic acids which they yield on oxidation .

When Kilia ni’s reaction (1 5 1 ) is applied to arabinose ,there are obtained on reducing the resulting lactone two

aldohexo ses which are very common in nature, viz . ,

glucose a ndmanno se . It has been pointed out in describ

ing the synthesis o f hexoses from pentoses that the only

difference possiblemust be due to the difference in positionof the hydroxyl group on the carbon atom adjoining the

aldehyde group . Glucose a nd mannose must be repre

sented by the following two structures, A a ndB

CH20H CHZO H CH20H



H— C— OH H —C —OH H— C— O H

H— C— OH HO — C— H

Ara b inose

When glucose is oxidized, it yields a dibasic acid called

sa ccha ric a cid(p . O ne of the hexoses not found in

nature , but Obtained by Fischer by synthesis, viz . gulose ,also yields on oxidation saccharic acid . This being the


case , the arrangement of the H a ndOH groups on all the

four central carbon atoms must be alike in glucose a nd

gulose, for these carbon atoms a nd their H a nd OH

groups are not affected in a ny way by transfo rming the

sugar into saccharic acid . It follows that the difference

between glucose a nd gulose must be explainable as the re

sult Of the asymmetry due to the difference in position of

the aldehyde a nd primary alcohol groups with respect to

the peculiar arrangement of the rest of the molecule . It

also follows that a ny fo rmula which is the same when

the CHO a nd CHo groups are transposed cannot

represent gluco se a ndgulose, for such a fo rmula could not

represent two different sugars . In the following formul ae

C fulfills the last condition, while D , on transposing the

end groups, leads to a different sugar .

CH,OH CHO CH,OH‘

HO — C— H HO — C — H HO — C— H HO — C— H

HO — C— H HO — C— H HO — C— H'

HO — C— H

H— C— O H H— C— O H H— C— O H H— C— O H

H— C— O H H— C— O H HO — C— H HO — C — H

I

CHO CHgOH CHO CHzOHC :D

Sa me suga r a fter tra nspo sing D ifferent suga r a fter tra nspo singtermina l gro ups termina l groups

Glucose is therefo re represented by the formula D a nd

mannose is C . The formula F must accordingly represent

gulose .


CHzOH CH20H

H- C— O H H— C— O H

HO — C -H HO — C — H

H— C— OH H— C— O H

H— C— O H HO — C— H

CHOF

Idose,another sugar not found in nature but O h

ta ined synthetically, yields the same osazone as gulose,a nd their difference in structure rests therefore in the

positions of the H a nd OH adjacent to the aldehyde

group, since only these two are a fl'

ected in osazone

formation . This i s further supported by the fact that

xy lose when subjected to Kilia ni’

s reaction yields a

mixture of gulose a nd idose . It has been already shown

that gulose is represented by F, so idose must have the

structure G .

d-galactose is a naturally occurring sugar . O n redue

tion it'

yields a n inactive hexahydric alcohol a nd on oxida

tion a n inactive dibasic acid . When converted byKilia ni’

s

reaction into two heptonic acids a nd on further ox idation

of the latter into pentahydroxy pimelic acids, both prod

ucts a re optically active . From considerations anal

ogous to those described in arriving at the structures

of other hexoses, the formula ascribed to galactose is the

following:


It is distinctly sweeter than a ny other sugar, a nd is more

unstable than the aldohexoses . The constitution a s

signed to it is :CHzOH

HO — C— H

O n oxidation it yields formic, glycolic, tartaric,hydroxy glutaric acids .

CHzOH

HO — C— H

HO - C— H4 O

CH20H

Since the cleavage may take place on one side of the

carbonyl group as well as on the other, this group Of o x i

dation products shows that the carbonyl group is but one

removed from the terminal carbon atom .

GO OH

HO — C— H

HO — C— H

(EconHCO O H

Trihydro xy gluta ricfo rmic a c1ds

The Ca rbohydra tes

CHgOH

HO — C— H

HO — C — H

H— C— O H

C O

CHo

309

CO O H

HO — C — H

HO — C -H

CO O H

CO O H

Whereas the aldopentoses a nd aldohexoses yield no rmal

carbon chain derivatives when subjected to the cya nhy

drin synthesis (page fructose yields an acid with

the following structure

CHzOH CHéO H



H— C — O H H— C— OH

C = O +HO N (I/OH\CN

CH,OH CH,OHCya nhydrin

CH20H

HO — C -H

This harmonizes with the assumption that the structureassigned to fructose is co rrect, for the ketone structure o f

fructose must necessarily lead to the formation Of a

branched carbon chain .

HO —‘

C— H

H—

c— OH

H+2H20 CL CO OH

CH20HHepto nic a c id


This heptonic acid when reduced by heating with hydri

odic acid (1 49)is changed into methyl-n-butyl acetic acid

Clix —CHz —CHz— C

CH— GOOH

which has been synthesized by the Claisen reaction

The same osazone is Obtained from d-fructose as from

d-glucose . It is therefore evident that the configuration

of the molecules of these hexo ses differ only in the ketone

group a nd its adjacent terminal carbon atom . The

identity of the o sa zones serves to confirm the idea that in

glucose the a -carbon atom a nd in fructose the terminal

carbon atom react with a second molecule of phenyl

hydrazine after hydrazone forma tion has taken place . In

other words , it is definite evidence that in the o sa zones the

two phenylhydraz ine groups are united to adjacent carbon

atoms . The osazone from these two sugars, which may

properly be called glucosazone or fructosazone, has the fol

lowing constitution

(CHOH),

C N— NH— Cdis

CH N— NH— C 6H5

Glucose may be converted into fructose by warming the

osazone with hydrochloric acid . The two phenylhydra

zine groups are separated by hydrolysis a nd there results

3 1 2 Orga nic Chemistry for Students O f M edicine

CHzOH CH20H CH20H CH20H

HO — C— H HO — C —H HO — C— H HO — C— H

HO — C— H HO — C— H HO — C— H H— C— OH

H— C— O H H— C— O H H— C— OH H— C— O H

H— C— OH HO — C— H C O HO — C— H

CHzOH CHOd-ma nnose d-fruc'to se d-ga la ctoseM anno se is seldom found in nature as such a nd only

in small amounts . It forms in plants a cellulose-like sub

stance, ma nno cellulo se (mannan), in the cell walls, a nd in

this form occurs in large quantities, a n especially good

source being the ivory nut. M annose is obtained as a

hard , solid amorphous mass which is deliquescent a nd

dissolves easily in water, slightly in alcohol a nd is insoluble

in ether . It is identified as the phenylhydrazone which

melts at 1 95

O n reduction with nascent hydrogen mannose is con

verted into the hexahydric alcohol, ma nnite. The latter

is found in considerable amounts in manna, that from the

ash containing 30—60 M annose is easily fermentable

by yeast . It is crystalline a ndmelts at

d-gluco se (dextrose, grape sugar) is found widely distributed with fructose in ripe fruits a nd other parts of

plants, including the nectar Of flowers . It is formed

from the hydrolysis o f cane sugar, malt sugar, a ndmilk

sugar, starch , etc . It is the sugar which is a normal con

stituent of the blood a nd lymph, being present to 1 part

The Ca rbohydra tes 3 1 3

in 1 000. In diabetes , a disease of the pancreas , it occurs

in the urine sometimes in large amounts .O n reduction of gluco se the hexahydric alcohol d-sorbite

is formed, a nd on oxidation gluconic acid , analogous to

mannonic acid, a nd on further oxidation the dibasic

saccharic acid , analogous to manno-saccharic acid .

d—glucose crystallizes from alcohol in water-free form,

a nd from water as a hydrate, C en O a HgO . Waterfree glucose melts at 1 46° a nd at 1 70° loses water from its

H a ndOH groups, several molecules o f glucose condensing

to a polysaccharide glucosa n . By treating glucose with

dehydrating agents , such as strong acids , several molecules

are condensed to'

form polysaccharides , complexes having

a high molecular weight .

O n oxidation of d-glucose the aldehyde group is first

attacked a nd is converted into gluconic acid , a ndon further

oxidation the primary alcohol group is converted succes

sively into a n aldehyde a nd then into a carboxyl group

CH20H CH20H GOOH

(CHOH), +0 (CHOH). +0 (CHOH)4 +0 (CHOH),

CHO . CO O H CO O H CO O Hd-glumse d-gluconic a cid d-glycuro n ic a c id Sa ccha ric a cid

Although this is the course of the oxidation of glucose

in the laboratory,a nd although animals regularly oxidize

large amounts of glucose, these acids do not represent the

course of the first steps in the destruction of sugar by the

l iving organism . Instead the glucose molecule is disso

cia ted into simpler compounds containing but three a nd

3 1 4 Orga nic Chemistry for Students O f M edicine

two ca rbon atoms , a nd it is these which are oxidized . The

first step in the biological degradation of the sugars is

therefore not oxidative but hydrolytic

d-glucose is the most easily utilized of the hexoses . In

healthy persons the capacity to utilize this sugar is as

great as the capacity of the digestive tract to absorb it .

Healthy young men have been known to absorb more than

a pound of glucose within twenty-four hours without the

appearance of sugar in the urine . It is likewise easily

fermented by yeasts, in which process it is converted into

alcohol a nd carbon dioxide (see fermentation).

ACTION OF ALKALIES ON GLUCOSE

When allowed to stand for several months with dilute

alkali glucose is converted to the extent of 50—6 0% into

inactive lactic acid , .5— 2 into formic acid, a nd 30—50%into several hydroxy acids . Among other cleavage prod

ucts formed by alkalies is methyl glyox a l, the aldehyde of

pyruvic acid .

A reaction of biological interest is the'

forma tion of

methyl imida zole by the action of ammonia a nd z inc

hydroxide on glucose . This illustrates in a suggestive

way the possibility of the formation of certa in cyclic

compounds within the animal body through the participa

tion of carbohydrate . It will be recalled that one of the

amino acids, histidine derived from proteins, contains

the imidazole ring . The formation of methyl imidazole

from gluco se a nd ammonia is best explained as the result

of the interaction of ammonia with the dissociation pro

ducts of glucose , methyl glyoxal, a nd formaldehyde


The change is believed to take place through the labilityof one hydrogen atom marked X in the intermediate formswhereby it ca n wander from one to the o ther of the two

neighboring ca rbon atoms . By the shifting o f a hydrogen

from the endcarbon atom to the second a n aldose would be

regenerated , but by the la w Of chance the hydroxyl group

would ta ke its pla ce on one side o f the chain as frequently

as the other, a ndd-gluco se would be regenerated o rd-ma n

nose would be formed a ccordingly . By a shifting of the

hydrogen atom from the second to the end carbon atom

a ketone suga r d-fructose would result . When therefore

a ny one Of the three sugars d-gluco se , d-manno se, o r d

fructose is in solution in the presence of a low concentra

tion of hydroxyl ions, it will pass in part into the o ther

two , until a certain proportion exists among the three

kinds of molecules , i.e. each form is in dynamic equilib

rium with the other two . If by some means the glucose

is removed from the system, more will be formed .

This observation is of the greatest importance in that

it enables us to understand how a n anima l may absorb

from the digestive tract mannose o r fructose a ndyet these

never be present in the blo od . They are alwa ys trans

formed into d-glucose if the a bsorption is not too ra pid , in

which case the fructo se a nd manno se are said to exceed

the assimila tion limit since they escape into the urine .

d-glucose yields a phenylhydrazone which melts at

1 44 a nd a n osazone which melts at O n redue

tion it yields the hexa hydroxy alcoho l d-so rbite .

d-fructose is actually levorotatory, but is called thedextro form because o f its structural relationship to d

The Ca rbohydra tes 3 1 7

glucose . Although d-fructo se yields the same osazone as

do d-glucose a nd d-mannose, it is easily distinguishable

from these by its peculiar behavior with methyl phenyl

hydra zin e

°

C GH5— N— NH2

CHo

With this methyl-substituted phenylhydrazine d-fruo

tose a ndother ketoses yield o sa zones. The aldoses , on the

other hand , do not react with this reagent beyond the

hydrazone stage under ordinary conditions . The methyl

phenylo sa zone of fructose melts at 1 58

The capacity of the animal organism to utilize fructose

is much less than for d-glucose . d-fructose is easily fer

menta ble by yeast .

An extremely interesting Observation is the formation

of d-fructo se from d-ma nnite by a kind of fermentation

induced by Ba cterium x ylinum Brown,through which

the alcohol is oxidized to a ketone .

d-gala ctose is present in milk sugar in union with

d-glucose . It also occurs in certain polysaccharides, as

agar-agar, a ndin certain glucosides . It exists in the brain

in considerable amount in union with a fatty acid a nd a

base o f unknown chemical nature . The hexose itself has

never been found in the free state in either plants or

animals . Ga lactose is easily distinguishable from the

other hexoses by the insolubility in dilute nitric acid Of

the dica rbo x y acid , mucic a cid, which results on oxidation

of the sugar with nitric acid . M ucic acid is so insoluble

a nd is formed so nearly quantitatively that its formation


serves as the best availa ble method of estimating galactose

o r galactose-yielding polysaccharides .

d-galactose is much less readily utilized in the animal

body than is either glucose or fructose, a nd on the inges

tion of even moderate amounts is eliminated in part

unchanged in the urine .

1 58 . The D isaccharides.

— There are three sugars O f

great biological interest which yield on hydro lysis two

molecules of hexose . The molecular weights Of all of

them correspond to the formula C lgHggO n. They are

sucrose, or cane sugar, which yields on hydrolysis onemole

cule of d—glucose a nd one of d-fructo se ; ma ltose, or malt

sugar, which yields two molecules of d-glucose ; a ndla ctose,or milk sugar, which yields one molecule of d-galactose

a nd one Of d-glucose .

Sucrose , C 1 2H2201 1 , occurs in the juices o f many plants,especially sugar cane a ndsugar beet . As much as 1 6— 20

Of the dry substance of the plant is sucrose . It crystallizes

readily . The sugar is extracted from the finely rasped

beets with warm water a nd the solution treated with lime,which causes the neutralization O f acids in the juice, a nd

is then boiled to coagulate the proteins . The solution is

then treated with carbon dioxide to precipitate most of the

calcium, a ndafter thiswith sulphur dioxide whose reducing

action discharges the color . It is again bo iled a ndfiltered ,a nd the filtra te eva po rated under diminished pressure to

crystall ization. The mother liquo r from the crystals is

molasses . The molasses yields another po rtion of sucrose

on treatment with lime or strontium hydroxide , a n insol

uble calcium or strontium sa ccha ra te being formed . The


(e.g. Fehling’s solution) as do glucose, fructose , mannose,a nd the other aldoses a nd ketoses

,nor does it form com

po unds with hydraz ines . It does not therefore contain a

carbonyl (aldehyde or ketone)group , but on hydrolysis to

glucose a nd fructose a n aldehyde a nd a ketone group are

formed . It contains , however, eight hydroxyl groups,since it yields a n octa-acetyl derivative .

Sucrose is regarded as a glucoside ofd-fructose It

cannot be util ized directly by a n animal , being excreted

in the urine when introduced directly into the blood . In

the digestive tract it is hydrolyzed into glucose a nd fruo

tose before abso rption.

M altose , C 1 2H220u HgO , is found in small amounts

in many plants . It is the end product.

O i the action on

starch of the enzyme amyla se of the saliva of the omniv

orous animals, includingma n. It has been found in human

urine in disease o f the pancrea s , but in the normal organ

ism maltose is readily utilized either when introduced

into the alimenta ry tract or directly into the blood . The

blood contains a n enzyme ma lta se which converts maltose

into two molecules of d-gluco se . This change is likewise

effected by heating with dilute acids . There is no cor

responding enzyme in the blood or tissues for the hydrolysis O i sucrose or lactose .

M altose reduces solutions of the oxides of the heavy

metals, which indicates that it contains a carbonyl group .

M a lto sa zone melts at

Isomaltose is a disaccharide which is formed by the

dehydrating action of strong hydrochloric acid on a con

centra ted solution of glucose . Its osazone melts at 200°

The Ca rbohydra tes 32 1

a nd is more so luble in water than is ma lto sa zone . Its

stereochemical configuration is sufficiently diflerent from

maltose to make it non-fermentable with yeast . The

enzymes o f yea st do not hydrolyze it to hexoses , but the

enzyme emulsin found in the almond converts it into two

molecules of glucose .

Lactose orM ilk Sugar, Cq oO n HoO , is found nowhere

but in the milk Of animals . It contains a carbonyl group,since it reduces certain oxides Of the heavy metals . Its

osazone melts at

In the animal organism lacto se behaves as does cane

sugar . When taken into the alimentary tract, it is hydro

lyzed by the enzyme la cta se into d-glucose a ndd-galactose

before being absorbed ; a nd if introduced directly into the

blood, is principally excreted unchanged in the urine . The

lactose o f the milk is derived from d-glucose a ndnot from

the food .

M elibio se is isomeric with lactose a nd yields the same

hexoses on hydrolysis . It results together with d-fructose

from the action of dilute a cids or Of inverta se upon the

trisaccharide ra ffino se . Like lactose , it is a reducing sugar .It resembles la ctose in being hydrolyzed by emulsin ,

but

differs from it in not being cleaved by lactase .1 59. The Stereochemica l Configura tion of the Suga rs

Determine s theirBiologica lValue . Of the sixteen isomers

o f the aldohexoses only three are readily utilized by the

higher animals, a nd of these three , d-glucose , d-fructose,a nd d-mannose, only the former has a high assimilation

limit . Galacto se is util ized with more difliculty than thethree first named .


A similar relationship holds in the case Of the disa ccha

rides . Before these ca n be utilized biologically they must

be converted into the C 6 sugars , a nd there is a marked

difference in the extent to which various organisms are

prepared with the specific enzymes necessary for their

cleavage . Thus the invertase Of yeast , but not the malt

ase a nd lactase , a ct on cane sugar . Invertase a nd la c

tase do not cleave maltose . Emulsin does not hydrolyze

a ny of these disaccharides . Certain of the molds are

provided with all of these enzymes.

The limitations of the digestive tract are similar to

those of yeasts . The mucous membrane of the intestine

in all animals contains invertase a ndmaltase a nd usually

lactase . The blood contains maltase, but no invertase

o r lactase .

Yeasts show among the races great variation in their

capacity to effect the hydrolysis of the disaccharides .

Thus , the yeast which induces alcoholic fermentation of

milk, forming kephir, contains lactase , while beer yeast

does not. The latter, however, ca n cleave cane sugar a nd

ferment the resulting sugars . M any yeasts contain both

invertase a ndmaltase , a nd ca n ferment both these sugars,but Sa ccha romyces M a rx ia nus contains only invertase

a nd ca n ferment therefore sucrose, but not maltose .

Sa ccha romyces octosporus, on the other hand, ca n ferment

maltose but not sucrose, a nd Sa ccha romyces a picula tus ,

which is capable of fermenting d-glucose, d-mannose,a nd d-fructose, contains no enzyme for the hydrolysis

of a ny of the disaccharides, a nd cannot ferment the

latter.

324 Orga nic Chemistry for Students of M edic ine

for biochemical studies . The roots of Spiraea contain

ga ultherin, mustard seeds yield myrosin, etc .

O ne of the best known of the glucosides is amygda lin,from the bitter almond . Solutions of amygdalin do not

reduce solutions of the heavy metals, a fact which is

taken to indicate that there is no free aldehyde group .

After hydrolysis with dilute acids the presence of glucose

ca n be detected by the reduction of Fehl ing’s so lution,a nd by the formation of a n insoluble osazone (p . 286)which melts at Benzaldehyde ca n be detected by its

odor, a ndHCN by its precip itate with silver nitrate . It

is soluble in alcohol a nd ca n be crystallized from this

solvent . Emulsin, a n enzyme contained in the almond ,hydrolyses amygdalin into benzaldehyde hydro

cyanic acid, a nd two glucose molecules . Water extract of

beer yeast contains a n enzyme which splits off hydro

lytically but one molecule Of glucose a nd leaves the com

bination benzaldehyde, hydrocyanic acid, a nd glucose,the glucoside of mandel ic acid nitrile

CONSTITUTION OF THE GLUCOSIDES

The best-known synthetical glucosides are those from

glucose a nd methyl alcohol . When a concentrated solu

tion of d-gluco se in methyl alcoho l is treated with gaseous

hydrochloric acid, there result two compounds known as

a -methyl glucoside a ndfi-methyl glucoside . The a -form

is dextrorotato ry a nd is soluble in 200 parts of alcohol ;while the fi-form is levorotatory a nd is soluble in

parts of alcohol at They ca n therefore be separated

by their different solubilities . M altase hydro lyzes the


a -glucoside but not the B—form, while emulsin hydro lyzes

the B-form but not the a -form . The natural gluco sides

are in general hydro lyzed only by emulsin, a nd for this

reason they.

are termed fl-glucosides . The structural

formul ae assigned to a nd fl-methyl glucosides are asfollows :

CHZO H

H— C— OH

H —C H— C

HO m— C

H— C

H —C CHsO — Ca -Methyl gluco side B—Me thyl glucos ide

The reasons fo r assigning these constitutional formul ae

are the following

1 . Only a single molecule Of alcohol reacts with one of

glucose , with the elimination of a molecule o f water .

O ne of the secondary alcohol radicals must therefore enter

into the reaction. This is in all probability the fy—hy

dro x yl group , since this is the onewhich reacts in the forma

tion o f lactones a nd since no compounds other than

those containing 7=hydroxyl gro ups form glucosides . The

ease with which the glucosides are decomposed by hydrolysis argues strongly aga inst the union O f the alcohol

radical directly to carbon, a nd for the assumption of link

age through oxygen as in the ethers . The mechanism

of glucoside forma tion may therefore be represented thus :


H— C— O H

H— C— O

HO — C— H

H— C— OH

G lucoside

Muta rota tion . Freshly prepared solutions of gluco se

rotate the plane of polarized light nearly twice as much

as they do after standing for a time . If the water is

evaporated a nd the sugar crystallized it will, on again

dissolving it, show the high rotation value . There must

H— C— OH

H— C

HO — C


Sucrose, which contains no carbonyl group, is represented

CH,OH

— C— O H

H C— 0 H— C— O H

HO — C— H HO — (IJ— O H

H— C— O H

Sucrose

Emil Fischer has suggested the comparison of the spe

cific action o f enzymic action in the hydrolysis o f sugars

a nd other compounds, with the relationship between lock

a nd key . The stereochemical structures of both the

enzyme a nd the molecules of the substrate determine

whether they ca n interact . This specificity of ferment

The Carbohydra tes 329

action is of the greatest significance for the life of the

animal o r plant cell .

The union of galactose in the ga la ctolipins of the braina nd o f ribose in nucleic acids is pro ba bly o f the nature of

glucosides .THE POLYSACCHARIDES

1 62. Sta rch (amylum) is a non-crystalline

carbohydrate produced by plants as a reserve material . It

is closely related to cellulo se on the one hand , a compound

whose peculiar properties fit it to be the skeletal tissue

o f plants , a nd to the simple hexo ses a nd disaccharides on

the other, into which it is readily converted by hydrolysis .

Starch is insoluble in water a nd exists in grains, tubers ,fruits

, etc . , in the form of grains . These consist O f at

least two kinds Of carbohydrates : gra nulose, which is

colored blue by iodine, a nd starch cellulo se, which is not.

The blue color produced by iodine is discharged on heating

but reappears on coo ling . Starch has a very high molco

ular weight a nd when bo iled with water under

goes incipient hydrolysis a ndis changed into soluble sta rch.

The latter fo rms a n opalescent colloidal solution .

The amylase of the saliva o f certain animals rapidly

causes hydro lysis o f starch into a series of simpler car

bohydra tes, the dextrines, the final product being maltose .

Acid hydrolysis converts starch into d-glucose .

The’

form a nd appearance of the starch grains vary

with their origin . It is a simple matter fo r one familiar

with the forms to identify by microscopical methods the

source o f the starch .

Starch is not the first product Of the synthetic activity


of the plant.

The latter absorbs carbon dioxide from the

air a ndwater a nd inorganic salts , including nitrates, from

the soil. It is generally assumed , since formaldehyde ispresent in minute amounts in functioning leaves , a nd,

as po inted out earlier is polymerized to a mixture

o f hexoses, that it is the first product formed :

C0; H20 HCHO 02

6 HCHO C 6H1 206glucose

The formation of starch is not dependent on the forma

tion of glucose . Leaves which have been kept in the dark

until they are starch-free a nd then in the dark are floated

on sugar solutions quickly form starch . d-glucose a nd

d-fructose are most readily utilized for this purpo se, but

certain plants ca n use mannose a nd even galactose for

starch synthesis . Stereochemical transformation is,of

course , necessary in these cases .

Starch is easily hydrolyzed by acids, but only with great

difficulty by alkalies .

D extrines correspond to the same empirical formula as

starch, but their molecular weight is much smaller. It is

assumed that there are a large number of dextrines of

diflerent molecular complexities, but only two ca n be

readily distinguished . 1 4W , which gives a red

color with iodine, is first fo rmed by the action of amylase

on starch ; a nd am , which gives no color with

iodine, is fo rmed somewhat la ter/

Cellulose is much more resistant tha n is starch . It is

not acted upon by enzymes formed by the higher animals


acetyl cellulose in acetone . When a solution of cellulose

acetate in glacial acetic acid is poured into alcohol, a

precipitate is formed which contains much alcohol a nd

burns without melting o r leaving a n ash a nd is sold as

solid alcohol .”

Cellulose is indigestible in the alimentary tract of a ni

mals , but certain bacteria present there ferment it with

the formation of carbon dioxide, methane , hydrogen, a nd

formic, acetic , butyric, valeria nic, a nd other acids . Cer

tain molds a nd saprophytic plants secrete a n enzyme,cyta se, which dissolves cellulose . The products formed are

not known.

Cellulose is insoluble in all ordinary solvents, but

dissolves in a n ammoniacal solution of copper oxide

(Schweitzer’s reagent), a nd in a solution of z inc chloride

in hydrochloric acid .

Hemicelluloses are important constituents of nut shells

a nd stony seeds of fruits, coconut rind , etc . , a nd are

present in considerable amounts in the seeds Of legumes

(pea, bean, O n hydrolysis with acids they yield

mannose, a nd those o f the legumes especially galactose .

A certain amount of arabinose a nd xylose is also usually

fo rmed . They are not well-cha racterized compounds

therefo re, a nd appear to be either mixtures of mannans,xylan, araban, galacta n, or complex carbohydrates com

posed of complexes representing several kinds of sugars .

Pentosa ns are polysaccharides which correspond to the

celluloses, but they yield on hydrolysis a pentose sugar .

Thus x yla n, which is present in the straws to the extent of

1 8— 28 yields xylose ; a nda ra ba n, which occurs in cherry,


peach, a nd other gums a nd is the principal constituent of

gum arabic, yields arabino se on hydro lysis. They are

soluble in alkalies a nd are precipitated by alkaline copper

solutions, a s copper xylan, etc . Like the pentoses, they

yield furfural on distillation.

Pectins are the constituents of fruit juices which cause

the setting of jellies . Carrots , beets , a nd rhubarb are

especially rich in these constituents . Their chemistry

is not well understood . Preparations of pectins made by

precipitation with alcohol yield both pento ses a ndhexoses,a nd in addition acids which seem to be o f the type o f

gluconic acid .

Plant M ucilages are substances which swell in water a ndform mucilaginous solutions . As examples may be cited

fla x seed mucila ge , a nd those of the roots of salep a nd

althea . They yield both pento ses a nd hexoses on hydro l

ysis, but their chemistry has not been thoroughly studied .

Gums contain the salts of as yet unidentified organic

acids, a ndyield these acids a nd certain reducing sugars on

hydrolysis . Arabinose, xylose, fuco se , a nd galactose

have been identified .

Glycogen is a polysaccharide contained in animal a nd

in certain plant tissues which resembles soluble starch in

certain respects, but gives a reddish colo r with iod ine .

It is soluble in coldwater, forming a n Opalescent solution.

It is formed by the condensation o f a number ofmolecules

Of glucose, water being separated in the union of each two

molecules . It is acted upon by amyla se, which converts

it into maltose as in the case Of starch .

The glycogen content is higher in the liver than a ny


other tissue , usually from 1 to 4 but the livers of highly

fed animals have shown contents as high as 1 5 It is

found in other tissues , especially muscles .

Among plants yeast is richest in glycogen. When

animals o r yeasts are starved the glycogen content de

creases markedly, being slowly converted into glucose

which passes into the blo od to keep up the no rmal content

of one part to one thousand o f the latter . Glycogen i s

formed in the animal body from certain sugars other than

glucose,as manno se , levulose , etc . , but only as these are

converted into glucose

1 63 . Ch itin is a peculiar polysaccharide which forms the

matrix of the shells of the crustacea (lobsters, the

external covering a nd the l ining of parts of the alimentary

canal of insects , a nd the covering of certain worms (Hiru

dinea ). When freed from incrusting calcium salts in the

case of lobster shells chitin fo rms a leathery substance

which on hydrolysis with mineral acids yields a n amino

derivative of glucose , glucosamine , the only nitrogen-con

taining carbohydrate .

O n heating chitin with strong alkali, a treatment which

does not change cellulose o r tunicin, it is decomposed by

hydrolysis into acetic acid a nd Chitosa n, which is soluble

in acetic acid but is precipitated by alkalies . Chitosan is

a base a nd forms sa lts with acids . O n boiling it with acids

it is hydrolyzed to glucosamine a nd a further amount of

acetic acid .

G lucosamine , C GHHO QNHo, is a n amino sugar derived

from many proteins on hydrolysis . It contains a n alde

hyde group , as is shown by its formation of a n oxime with


It is not certain whether the amino group is on one or

the other side o f the carbon chain,a nd the compound may

be either glucosamine or mannosamine . That the amino

group is united to the carbon atom neighboring the alde

hyde is made highly probably by the decomposition de

scribed by II

euberg, of glucosamine into erythronic acid

(1 50)by boiling with barium hydroxide .

H OH OH

HO G— CH C— C— CHoOH G lucosamine

OH H H

OH OH

HOOG— C— ‘C— ‘CH20H Erythromc a c id

H H

O n treatment Of glucosamine with nitrous acid the amino

group is replaced by hydroxyl . The resulting hexose is

however not glucose or mannose . It is known as chitose.

It does not ferment, a nddoes not yield a diflicultly so luble

osazone . By comparison with the synthetically prepared

compo und , Fischer assigned to chitose the following cyclic

structure HO HC — CHOH

HO H2C HC CH— CHO

YChitose

Inulin (C 6H1 005)n is a polysaccharide entirely analogousto starch, which is found a s a reserve ca rbohydrate in


dahlia roots a nd other tubers Of the Compositae. O n

hydrolysis it yields only d-fructose . In the plant tissues

where inulin occurs there is formed a n enzyme, inula se,which effects its hydrolysis whenever growth begins .

There is no inulase in the digestive secretions of animals

a nd therefore no provision for the utilization of this

carbohydrate .

CHAPTER XVI

THE CHEMICAL CHANGES IN THE FERMENTATIONOF THE SUGARS

1 64 . The nature Of the chemical changes involved in

the fermentation of sugars has been very carefully investi

gated , a nd the mechanism of the change of hexose into

alcohol is fairly definitely understood . O n the one hand

the method of investigation consisted of the careful study

of the compounds which result from the decomposition of

glucose by chemica l agents, especially alkalies, since they

induce decompositions o f a profound character resembling

a certain type Of fermentation (lactic acid). There is a

certain degree Of proba bility that the cleavage Of the

glucose molecule by alkalies will follow the same lines as

those on which sugar normally tends to dissociate, a nd it is

along these l ines that the enzymes of the yeast accelerate

change .

O n the other hand the inquiry may be directed toward

testing under carefully regulated conditions the ability of

yeast to take a ny suppo sed intermediary product in the

process of cleavage in fermentation a nd to complete the

process of conversion of this into alcohol . Any compound

which ca n be so converted is regarded as a possible inter

mediary product, a nd a ny one which cannot be converted

into alcoho l must be excluded .

Another procedure possible of application in certain

instances is to conduct the trial with the yeast in the pres338


C02

£ 139 CHOH L953: CH,OH

The central idea is the alternate dissociation a nd re

addition of the elements Of water . When alkali acts on

glucose, lactic acid is formed to the extent of 54 per

cent of the theoretical amount, formic acid to .5— 2 per cent,a nd 40per cent of a mixture of hydroxy acids containing

four a nd six carbon atoms . About 1 per cent o f alcohol

a nd C02 are also formed . There is no glycolic or oxalic

acid , nor glycol o r glycerol formed . If lactic acid were

formed by a separation of the carbon chain into two three

carbon aldehydes a nd subsequent oxidation a nd reduction,

the resulting lactic acid should be Optica lly active, which

is not the case in lactic acid fermentation, a nd this lends

support to the view that some three-carbon aldehyde

other than glyceraldehyde is first formed .

Pyruvic acid, CH3~ — CO —GOOH

M ethyl glyoxal, CHa— CO — CHO

Glyceric aldehyde, CILO H— CHOH— CHO

D ihydroxyacetone, CHooH— CO — CHzO H

have all been proposed as the most probable intermediary

cleavage product .

M ethyl glyoxal is not fermentable by yeasts, while the

results are positive for glyceraldehyde a nd dihydroxy

Fermenta tion 34 1

acetone . The most satisfactory explanation is probably

the following

C eHmO s 2 CH3— CO —CO O H 4 HPyruv ic a cid

2 CHg— CO — CO O H 2 CHs— CHO 2 C02

2 CHg— CHO 4 H 2 CHr —CHoOH

This scheme receives strong support from the now well

substantiated Observation that yeast juice free from living

cells contains the enzyme, ca rbox yla se, which accelerates

the decomposition of pyruvic acid into acetaldehyde a nd

carbon diox ide . Acetaldehyde is rea dily reduced to alcohol .

Another theory o f alcoholic fermentation deserves to be

mentioned . Schade showed that lactic acid treated with

dilute sulphuric acid formed acetaldehyde a ndformic acid :

OH, -CHO"H -CO O H CH,— CHO+H— CO O H

showing a tendency for this line of clea vage which might be

accelerated by a yeast enzyme . Formic acid is ra pidly

decompo sed catalytica lly by means of metallic rhodium

into hydrogen a nd carbon dioxide . Schade held that

the latter reaction might also be ca ta lyzed by a ferment,thus producing through lactic acid a s a first product from

hexo se, acetaldehyde, a nd hydrogen in a nascent state to

reduce it, together with one mo lecule of carbon dioxide

for each molecule of alcohol produced . This is the pro

portion actually Observed in yea st fermenta tion . Yeasts

do not however ferment a mixture of acetaldehyde a nd

sodium formate .

342 O rga nic Chemistry for Students of‘

M edicine

La ctic AcidFermenta tion is equally in harmony with the

assumption that pyruvic acid is first formed from hexose .

Lactic acid ca n be oxidized to pyruvic acid or the latter

reduced to lactic acid :

CHs CHs CHs

ICHOH if), CO 1 231 CHOH

CO O H GOOH CO O HLa c t ic a cid Pyruvic a cid La ct ic a cid

Butyric Acid Fermentation .

— Ba cillus holobutyricus

has been shown capable of converting lactic acid into

butyric acid in considerable amounts . The products

are n-butyric acid , carbon dioxide, a nd hydrogen. The

destruction oflactic acid by bacteria leads to the a ccumu

lation of appreciable amounts of the follow ing products

36332 of”;CHOH CH, CO O H CO OH

Ace t ic Fo rmica c id a cid

CO OH GOOHLa c t ic Propionica c1d a cid

The most plausible explanation of butyric acid fer

mentation from lactic acid is that based on the condensa

tion of acetaldehyde with acetic acid , analogous to the

condensation o f benzaldehyde with acetic acid to form

cinnamic acid in Perkin’s synthesis (207)

CHs— CH-HC— GOOH

CHa— CHZ ZCH— CO O H

The resulting crotonic acid would be reduced to butyric

acid .

344 Orga nic Ch emistry for Students O f M edicine

This cannot therefore be considered a very probable

explanation o f what ta kes pla ce in the anima l body .

The most plausible hypothesis yet advanced concerning

the biological method o f forming fats is that of Smedley,

who condensed croton aldehyde with pyruvic acid , a nd

by oxidizing the resulting ketonic acid with hydrogen

peroxide , C02 w a s split O ff a nd the doubly unsaturated

sorbic a cidwas formed

1 . CIL— CH CH— CHO CH 3— C O — CO O H

Cro to n a ldehyde Pyruv ic a cidCHg

— CH CH— CH CH— CO — CO OH

2 . CHa— CH CH— CH CH— CO —CO O H O

CHa— CH CH— CH CH— GOOH CO,So rbic a cid

It is easy to understand how the double bonds could be

removed from such a n acid by reduction .

Smedley suggests pyruvic acid a nd acetaldehyde as the

starting point for fat synthesis in the body . The following

rea ctions will illustrate the process

3 . CHa— CO — GOOH CH3—_CHO

Pyruv ic a c id Ace ta ldehydeCH3

— CHl'iil— CHEl

— CO — CO OH

4 . CH, — CH CH— CG —CO O H OPenty lenic a -keto a c id

CHs— CH CH- CO O H CO 2Cro to n ic a c id

5 . CHa— CH CH— CO O H 2 H

CHa— CHz— CHz

— GOOHButyric a cid

Fermenta tion 345

o. CH,— CH CH— CO — ICO OEH — C O ,Penty lenic a -ke to a cid

CHo— O H CH— CHOCroto n ic a ldehyde

By reactions 1 a nd2 sorbic acid is formed .

CHa— CH CH— ~CH CH— GOOH 4 HSo rbic a c id

CHa— CHo— CHz— CHg— CHz— CO O H

Ca pro ic a c id

By a n extension of this synthesis the higher fatty acids

would result.

CHAPTER XVII

THE AROMATIC COMPOUNDS

1 66 . The hydrocarbons Of the aliphatic series , or the

fatty compounds , are not products of animal o r plant

metabolism , with the exception of methane, which

results from the bacterial fermentation Of cellulose . None

of them have highly agreeable Odors . There are in cer

tain products of vegetable origin compounds which con

tain only carbon a nd hydrogen, a nd are very poor in

hydrogen, suggesting compounds of a highly unsaturated

character, as isoprene These differ in every re

spect in their properties from the unsaturated o r the sat

ura ted hydrocarbons o f the aliphatic series . Thus toluene,C 7H3, from Tolu balsam , a nd cymene, C 1 0H1 4, from O il of

eucalyp tus , Oil of thyme , oil O f caraway, a nd other essen

tia l O ils, are hydrocarbons of pronounced a nd charac

teristic aromatic odors . They do not form addition

products with the halogens as do the unsaturated hydro

carbons . Benzoic a cid, which is found in gum benzoin,

in cranberries , a nd elsewhere in plants , yields when its

calcium salt is subjected to dry distillation, a hydro

carbon, C 6H6, benzene.

Toluene is oxidized to benzoic acid a nd is therefore

closely related to benzene . Cymene yields o n oxidation a

dibasic acid, tera phtha lic a cid, which on distillation of its

calcium salt likewise yields benzene .


CH

HC CH

H 6HHC CH

CH,Benzene Hexa methylene

Kekule also emphas ized the fact that a ll of the six

hydrogen a toms of benzene a re equa l, since each is attached

to a carbon which is alternately singly a nd doubly

bound , i.e. to carbon atoms which are a like . If this is

true there should be but one mono-substitution product

of benzene as chlo r, brom, nitro, amino, etc . ,benzene,

all of which derivatives are known . Actually but a

single compo und o f these types is known . O n the nor

ma l aliphatic hydro ca rbon containing six carbon atoms,three isomeric mono-substitution products exist, depend

ing on whether the substituting group is at 1 , 2, o r 3,G -C— C— C z

— C r— C i

O n the other hand , theory calls for three disubstitu

tion products o f such a hexa gonal mug, a nd three dichlor,dinitro , dihydroxy , etc . , benzenes , but no more than

three, a re known . These are called ortho meta a nd

pa ra derivatives (designated as o m a nd p according

Ortho Meta

The Aroma tic Compounds 349

to whether the substituting groups occupy positions on

neighbo ring carbon atoms (1 2) o r on atoms separated

by one (1 3)o r by two carbon atoms (1 4) respectively .

The po sition 1 5 is the same as 1 3 a nd 1 6 is the same

as The number o f isomers should be the same for

disubstitution products whether these a re similar or dis

similar .

There should be , according to theory, three isomers of

a trisubstitution product o f benzene provided all substi

tuting groups are similar, but more if two are similar a nd

o ne dissimilar .

Adja cen t or v icina l Symmetrica l unsymme trica l

Of the vast number o f derivatives Of benzene which

ha ve been prepa red a nd studied , theo ry has in all cases

acco rded with Observation .

It is essential, if we accept this structure fo r benzene,to assume that the double bonds are alternating between

the a nd the positions , otherwise there should

be observed different properties for a disubstitution prod

uct in which the groups were separa ted by a single a nd

double bond respectively . Such a vibra tion was assumed

by Kekule. To obviate this difficulty, since but one

ortho disubstitution product has been observed , the

centric formula was proposed by Armstrong . According


to his assumption the fourth bond of each carbon atom in

the ring is directed toward the center

Such a structure accounts for the extreme stability of

benzene , which is much greater than that of the aliphatic

hydrocarbons , a nd also accounts for the peculiar isom

erism of its derivatives a nd for its aromatic char

acter . The six-membered ring is referred to as the

benzene nucleus , a nd since many derivatives Of benzene

are known in which one or more aliphatic groups replace

the hydrogen atoms Of the nucleus, these are called side

chains .” Substitution ca n be efl’ected either in the

nucleus or in the side cha1 n.

DETERM INATION OF POSITION OF SUBSTITUTINGGROUPS IN THE NUCLEUS

1 67. This has been determined by very extensive a nd

elaborate study for a few substitution products of benzene

by a method , the principle of which was enunciated by

KOrner. It depends upon the fact that when a third

substituent y is introduced into a n ortho compound , in

which both substituting groups are similar, but two

isomers ca n be formed. This is true whether y is like or

unl ike a::


which have the same composition, but different physical

properties ; i.e. , isomers . The fact that patient search

has revealed the existence of all the isomers demanded

by theory, a nd in no insta nce more tha n these, is convino

ing evidence of the validity of the theory .

Benzene , C sHs, is a colo rless liquid with a character

istic Odor, which boils at When strongly cooled it

crystallizes, the crystals melting when warmed to

Its specific gravity at 20° i s .874 . It burns with a

smoky flame a nd its vapors are inflammable . It dis

solves in all proportions in alcoho l or ether, but is in

soluble ih water . It dissolves fats , resins , etc . , a nd i s

a good solvent for sulphur , phosphorus, iodine, a nd

many other substances .

The benzene o f commerce, also called benzole, was for

merly Obtained from co al tar, which on distillation yields

in the fraction obtained up to from 3— 5 per cent of

a mixture of benzene a nd its homo logues, toluene a nd

x ylene. Recently Rittmann has perfected a process by

means of which the aliphatic hydrocarbons of petro

leum ca n be made to yield 1 0— 1 5 per cent of these cyclic

hydrocarbons . This process consists in heating the petro

leum under pressure for a time, a nd then distilling the

product . The principle involved depends upon the

dissocia tion of the aliphatic hydrocarbons under these

conditions into various unsatura ted hydrocarbons , among

which are a small content of a cetylene a nd Of its alkyl

derivatives (see p . At high temperatures a nd pres

sures acetylene condenses to benzene, a n irreversible

reaction .

Th e Aroma tic Compounds 353

PHYSIOLOGICAL PROPERTIES OF BENZENE

1 68 . The aliphatic a nd aromatic hydrocarbons show

considerable differences in their physiological properties .

The lower members of the methane series produce sleep

if inh aled , and death by asphyxia . The toxicity in

creases as the carbon atoms become more numerous .

Hexane is actively intoxicant, producing a long stage of

excitement followed by deep anaesthesia . It acts on the

senso ry side . Benzene a nd other aromatic hydrocarbons

act principa lly o n the motor centers , producing convul

sions a ndparalysis. Benzene has furthermore a selective

toxic effect for the white blood co rpuscles, producing

leucopenia, a nd is employed in medicine in cases of

leucaemia.

HOMOLOGUES OF BENZENE

1 69. Friedel and Crafts Reaction: When benzene is

treated with a n aliphatic halogen compo und in the pres

ence of aluminum chloride a rea ction takes pla ce in which

hydrochloric acid gas is evolved a nd the aliphatic group

is linked to the benzene nucleus

+CH,C 1“10 3

—CH,

For the sake of simplicity the hexagonal ring is employed

to represent benzene .

By the employment of the homologues of methyl chlo

ride , ethyl , propyl , etc . , gro ups ca n be substituted for a

hydrogen atom in the benzene ring . The benzene nucleus2 A


less one hydrogen is called the phenyl group . Several of

these compounds are Of great importance, a nd their

chemical behavio r is Of considerable interest .

Toluene, C6H5CH3, is formed by the dry distillation of

tolu balsam a nd of many resins . It occurs in coal tara nd i s separated from it by distillation along with benzene .

It boils at 1 1 0° a nd by fractional distillation ca n be sep

a ra ted from benzene a nd other homologues . It is much

employed as a n antiseptic in biochemical work .

When oxidized by chromyl chloride , Cr02C1 2, it isconverted by the oxidation of the side chain, the

methyl group , into a n aldehyde, C 5H5CHO , called benza l

dehyde, which may be regarded as phenyl formaldehyde .

M ore vigorous oxidiz ing agents convert toluene directly

into benzoic acid , C 6H5CO O H, which is the acid corre

sponding to benza ldehyde . It may be regarded as phenyl

formic acid . It has been noted that on hea ting the ca l

o ium salt of benzoic acid carbon dioxide is removed from

the carboxyl group a nd benzene is formed . The following transformations for toluene illustrate the general

behavior of the compounds containing both a n aromatic

a nd a n aliphatic group :

To luene Benza ldehyde Benzo ic Ac id

Longer side chains as in ethyl propyl isopropyl etc . ,

benzene oxidize,no matter how many carbon atoms con

356 Orga nic Chemistry for Students”

of M edicine

The group C eHs— CHQ is called the benzyl-radical

C 6H 5CH benzal a nd C 6H5CHE benzo radical . The

behavior o f these will be further described later .

1 71 . Xylenes. D imethyl , benzenes, are

formed by the F ittig reaction, employing brom toluenes

a ndmethyl bromide

CHgBI' 2 Na2 NaBr

The same result is Obtained by means of the Friedel

a nd Crafts reaction by means of which all of the

hydrogens of the benzene nucleus have been successively

replaced by methyl groups .

Ortho meta a nd para-xylenes ca n yield by oxidation

either monobasic o m a nd p-toluic acids, or the three

corresponding dibasic acids :

GOOH

CO O H GOOH

Phth a hc a c id Iso phtha l ic a c id Tera phth a lic a c id

Phthalic acid when heated loses a molecule o f water,forming a n anhydride . This is employed extensively in

the preparation of dyes .

1 72 . M esitylene , symmetrical trimethyl benzene,C 5H3(CH3)3, is formed by methods analogous to the for


mation of xylene a nd a lso by the polymerization of

acetone in the presence of strong sulphuric acid

C

H— C H— C C— H

CH,— C C— CHs 3 H,O

CHs— C

Another class of hydrocarbons is known in which two

or three phenyl groups replace as many hydrogen atoms

in the methane group :

CeH5— CH4 C 6H5\ C 6H5\

Tegena CH, C ,H,

— CHphenyl metha ne

C 6H5/ C 6H5/D iphenyl metha ne Triphenyl me tha ne

D iphenyl methane is formed by the interaction of

benzyl chloride with benzene by the Friedel a nd Crafts

reaction .

Triphenyl methane is prepared in large quantities in

the dye industry from chloroform,

’

CHC1 3 , a nd benzene,likewise by the Friedel a nd Crafts reaction

1 73 . Cymene, or methyl-p-isopropyl benzene, occurs


CH , CH3

in numerous essential oils . It yields successively on cx i

dation p—toluic acid a nd tera phtha lic acids

Ha logen Derivatives of Benzene . Chlorine acts upon

benzene, substituting its hydrogen atoms in a manner

analogous to the aliphatic hydrocarbons .

+ 2 C l +HCl

Benzene Ch lo r benzeneThe action is greatly accelerated by the presence o f

iodine . This action is in part due to the fact that in the

formation of iodine chlorides, ICl a nd ICl3, the molecule

of chlorine C 1 2 is broken up with the formation Of na scent

chlorine ; a nd in part to the instability of the chlorides

of iodine which causes them to dissociate into active,na scent, chlorine . There will be in the system containing

chlorine a nd iodine , some of the chlorides of iodine to

gether with their dissociation products .

Bromine l ikewise acts directly on benzene with the

evolution Of hydrobromic acid gas . The action is grea tly

accelerated by the presence of metallic aluminum .


Anil ine may be regarded as a substituted ammonia .

The benzene nucleus with one hydrogen atom re

moved is termed the phenyl group a nd is commonly a b

brevia ted to C 6H5 except where the illustration of

structure is desired . Aniline may therefore be called

phenyl amine. It is a weak base, but forms salts with

acids . From these the free base is liberated by treat

ment with alkalies . It is appreciably soluble in water,

a nd readily so in alcohol a nd ether . It has a character

istic Odor a nd is highly toxic , producing muscular spasms

of central origin a nd causing destruction of the red blood

corpuscles .

The presence of a n amino group on the benzene nucleus

greatly increases the ease with which the other hydrogen

atoms ca n be substituted . Thus bromine acts but slowly

on benzene a ndby direct action the principal end-product

is monobrom benzene, while it reacts readily with anil ine,forming symmetrical tribrom aniline

+ 6Br + 3HBr

The favorable influence of the amino group on either

halogenation o r nitration is so great that in order to pre

pare the monobrom or mononitro aniline the amino

group must be acetylated . This is effected by boiling

aniline with glacial acetic acid . The acetyl group serves

to protect the benzene nucleus


+HO O C— CHa +H20

NH— CO — CHaAnihne Ace tic a c id Ace ta n i l ide

Aceta nilide is a co lo rless crystalline substance , which

melts at 1 1 6° a nd boils at It is a n impo rtant

a ntipyretic . It is hydrolyzed into anil ine a nd acetic

acid .

1 76 . Alkyl Anilines. Aniline will react with one o r

two molecules of alkyl halide to form alkyl anilines :

C eH5— NH2 CHoI CeHs

— NH— CHa HI

CHs

cmThe dimethyl anilines are rea dily prepared by boiling

aniline with methyl alcohol a nd hydro chloric acid .

Methyl chlo ride is formed progressively as the reaction

proceeds a nd uses it up . Other alkyl groups ca n be in

troduced into anil ine by employing the corresponding

alcoho ls .

The alkyl anilines a re stronger bases than aniline .

The methyl deriva tives o f aniline in which the alkyl

groups occupy a position on the benzene nucleus are

known respectively a s O m a nd p-toluidines .

C GH

D iphenyl Amine , NH, is a crystalline compoundC 6H

which melts at 54° a nd boils at It is prepared by

C cHo— NHfi cHs CHsI C cH


heating aniline hydrochloride with aniline under pressure

at 240°

C aHs— NHQ HCl“l"C 6H5NH2 (CcHa)2 NH NmCl

Owing to the influence of the negative character of the

phenyl groups the remaining hydrogen attached to the

nitrogen in diphenyl amine behaves like acid hydrogen

a nd is replaceable by metals . By heating the potassium

compound of diphenyl amine with brom benzene, there is

formed triphenyl amine :

C oHNK+C 5H5BI' (C 6H5)3 E N KBI‘

C 6H Triphenyl amine

1 77. D ia zobenzene , C 6H5— N N— OH . There is a

very marked difference in the behavior O f aniline , a pri

mary amine of the aromatic series , a nd Of the aliphatic

primary amines . The former are converted into the

corresponding alcohols while the latter form dia zo

compounds

HN02 N N -OH+HzOAni l ine D ia zobenzene

D iazobenzene results from aniline . It behaves like a

strong base a nd is unknown in the free state, since it is so

unstable that it decomposes with a n explosion . Its salts

are crystalline a nd are safe only in a moist state, since

they decompose violently when struck o r heated . The


meyer reaction. It Offersa ready means O f synthesis for

compounds which canno t be formed directly. Thus

chlorine does not enter the meta position to the methyl

group in toluene , but does in the chlorination o f p-tolui

dine . The amino group ca n thereafter be removed by the

dia zo reaction, yielding meta-chlor-to luene .

1 78 . Benzene Sulphonic Acid, C 6H5— SO 3H, is fo rmed

by the action Of concentrated sulphuric acid on benzene .

It is a hygroscopic substance which melts at Its

aqueous solutions a re strongly acid a nd it fo rms salts

which crystallize well .

O n heating with acids it is hydrolyzed into sulphuric

acid a nd benzene .

/0S

—

O H20Benzene

\O HBenzene su lpho n ic

a cid

Benzene sulphonic a cid reactswith alcohols to fo rm esters

C 6H5- SO o— OH HOR C 6H5

“— SO<

2_O R HQO

When subjected to the action of vigorous reducing agents

it is reduced to phenyl mercaptan

C sHs— SO 3H+ 6 H = C eH5SH 3 H20

The hydroxyl o f benzene sulphonic acid is replaced

by chlorine when acted upon by phosphorus pentachloride,forming benzene sulphonyl chloride

C 6H5S02— OH PC ] , C 6H5— SO Q— C l PO C 1 3 HC 1


The salts o f benzene sulphonic acid when fused with

sodium hydroxide are decomposed into the metallic de

riva tive of phenyl alcohol or pheno l :

C 6H5— SO 3H 2Na OH C 6H50Na Na zSO g H20

1 79. Phenol, or ca rbolic a cid, is Obtained by the

action of acids on the sodium phenolate produced by

the decomposition Of benzene sulphonic acid by fu

sion with alkalies .

HC 1 Na Cl

ONaSodium phena te Pheno l

Phenol is present in coal tar a nd is Obtained in the dis

tilla tion of the latter . It is separated from hydrocarbons

a nd basic compounds by the solubility of its sodium com

pound ih water . Sodium pheno late or phenate is readily

formed in aqueous solutions of sodium hydroxide . In

this respect phenol shows properties markedly different

from the alcohols o f the aliphatic series . These are

neutral in reaction a nd form metallic derivatives , the

a lcoho la tes, only in non-aqueous solutions a nd with the

alkali metals .'

Phenol , while chemically a tertiary alco

hol , has distinctly acid properties . It is not a sufficiently

strong acid to reactwith carbonates, however, a nd while,e.g. , sodium phenolate is stable to water, it is decomposed

by carbon dioxide .

As a n alcohol pheno l fo rms esters , but these are not

readily formed by the direct heating Of phenol with a n

366 O rga nic Chemistry for Students of M edicine

acid . They are easily formed by the action of acid

chlorides upon phenol or its salts

CHs— CO — C lAce tyl ch lo ride

— CHoPheno l a ceta te

1 80. Ph enol Sulphuric Acid, also called phenyl sul

phuric a cid, is formed in the animal body by the union

Of phenol with sulphur1 c acid . Since phenol is a product

of the putrefaction O f proteins by bacteria in the intes

tine, it is regularly absorbed to some extent . Phenyl

sulphuric acid is therefore a regular constituent of the

urine , a nd its amount depends upon the extent to which

putrefaction goes on in the alimentary canal :

+H20

o r Cfi sM Q H

1 8 1 . Phenol Sulphonic Acids. O n disso lving phenol

in concentrated sulphuric acid the sulphonic acid group

is readily introduced into the benzene nucleus a nd phenol

sulphonic a cids are formed . The O a nd p derivatives

are thus Obtained . When two sulphonyl groups are

introduced into benzene they take the meta position a nd

on fusion with potassium hydroxide one i s replaced by

hydroxyl, forming m-phenol sulphonic acid .

368 O rgamc Chemistry for Students of M edicine

They all occur in the distillate from coal tar . They

po ssess a ntiseptic'

properties a nd are much employed in

disinfection . When pure they are crystalline solids .

o-cresol melts at the m a nd p-cresols at 5°

a nd

36° respectively . Like phenol they give a coloration

with ferric chloride a nd are readily brominated a nd

nitrated .

1 84 . Picric Acid. Nitric acid acts energetically on

phenol , forming symmetrical trinitro phenol, or picric

a cid. The latter compound is also formed by the a o

tion o f nitric acid upon various substances containing

proteins, since the phenyl a nd phenol gro ups are con

ta ined in two Of the amino acids found in nature, viz .

phenyl alanine a nd tyrosine . Picric acid is a bright

yellow crystalline substance of strongly acid character.

The introduction of negative groups , as halogens , o r

nitro groups , into pheno l increases its acid character,while the intro duction of basic groups, as NH2, de

presses the acid character .

Picric acid forms readily crystallizing salts Of slight

solubility with many natural bases a nd i s of great impor

tance in the isolation a nd purification of these . It melts

at 1 22° a nd ca n be sublimed without decomposition,

but is explosive, owing to the large amount of oxygen

contained within its molecule , which makes possible its

complete a nd sudden self-oxidation . The salts of picric

acid are much more explosive, decomposing with violence

when heated or struck .

1 85 . Tyrosine , a -amino, B—Oxyphenyl propionic acid ,or pa ra

-ox yphenyl a la nine :


CHz— CH— GOOH

NH,

is a constituent of many proteins , a ndwas first isolated by

Liebig in 1 846 . It is set free from its union with other

amino acids during the digestion of the proteins, a nd is

also formed by boiling proteins with mineral acids . It is

not present in gelatin, a nd the best yield is obtained from

the hydrolysis of silk. With the other amino acids it is

always present in the blo o d in minute amounts . Tyro sme

is a colorless compound forming long silky needles which

a re but slightly so luble in co ld water , but more easily in

hot . D ilute acids or a lkalies disso lve it, a nd on neutra liz

ing the solutions , it crystallizes o ut. It gives a red color

with a solution Of mercuric nitrate in nitric acid , containing

some nitro us acid . This is the Miltons reaction, which

has long served as a qualitative test for proteins . Gela

tin when pure do es not respond to this test . This color

reaction is also given by pheno l a nd other phenyl deriva

tives containing a hydroxyl group attached to the benzene

nucleus .

Tyrosine is apparently one of the amino acids which is

indispensable from the diet . O n being acted upon by

anaerobic ba cteria the alanine complex is removed a nd

phenol formed . Tyrosine is the source of the phenol2 B

370 Orga nic Ch emistry for Students of M edicine

formed by putrefactive action in the intestine . The

transformations involved are illustrated by the following

CHz— CHo— CO O H CHg— CH— GOOH CH2_CH2NH2p-o xyphenyl; Ty ramineprop ionic a c 1d p—o xypheny l

NH2 e thylamineTyro sine

a -am ino-B-o xy pheny lprop iomc a cid

Pheno lCHo

— GOOHp—o xyphenyl-a ce t ic p

-creso la c1 d

These changes are the result of the power of bacteria

to remove CO, from the carboxy l group in a manner

analogous to that of the enzyme carboxylase on pyruvic

acid ; to remove the amino group from amino acids as

ammonia ; a nd to oxidize aliphatic side chains .

OH1 86 . Tyra mine , C 6 or p

-0xyphe

H2_CH2

— NH2

nyl-ethylamine, i s a substance o f mild toxicity occurring

in putrefaction mixtures . Doses o f 1 —2 mg . injected intra


The former is found in beech wood tar a nd the latter in

the seeds of Sa badilla ofiicina lis .

1 90. Resorcinol, m-dihydrox y benzene, C 6H4(OH)2, is

obtained from benzene m-disulphonic acid by fusion

with potassium hydro xide at high temperatures . It is a

colorless crystalline compound which melts at 1 1 9° a nd

is somewhat volatile with steam . It has not been found

in nature, but results from the fusion of various plant

tissues with alkali . Its homologue, methyl resorcinol

orcin (m-dihydroxy toluene), occurs in certain mosses .

Resorcinol is largely used for the preparation Of the dye

eosin .

1 91 . Hydroquinone , p-dihydrox y benzene, C 6H4 (OH)2occurs as a glucoside a rbutin which is widely distributed in

plants of the family Ericaceae . It is crystalline a ndmelts

at It is diflicultly soluble in the ordinary solvents .

1 92 . Quinone is formed by the oxidation Of aniline

CO

HC CH

with chromic acid . It is a n evil-smelling substance,easily volatile with steam . Easily soluble in hot water

a nd in organic solvents . It is converted into hydro

quinone on reduction . Quinone forms golden yellow

crystals which melt at


TRIHYDROXY BENZENES

1 93 . Pyrogallol : 1 , 2, 3 trihydrox y benzene, C 6H3(OH)3,is formed by the distillation of gall ic acid

Co (OH)3— GOOH C oHe(OH)a CO ,

Its alkali salts absorb oxygen readily, a nd its solution

in sodium hydroxide is employed in gas analysis fo r this

purpose . The compound is oxidized a ndcarbon monoxide

is liberated as one of the decomposition products . It is

employed as a developer in photography .

1 94 . Phloroglucin , 1 , 3, 5 trihydrox y benzene, C 6H3(OH)3,is prepared by the oxidation of resorcinol . It crys

ta llizes from water , a nd melts at It gives a

blue violet color with ferric chloride .

1 95 . Inosite , C eHq , occurs innature in several isomeric

forms . It is a derivative of the reduced benzene ring,hexamethylene, a nd is hexahydroxy benzene :

CHOH

HOHC CHOH

HOHC CHOH

CHOH

Inosite is found in heart muscle , in the brain, a nd is

widely distributed in plants , especially in beans a nd peas

in the unripe state . Its hex a phosphoric acid ester is

called phytic acid , a nd is present in considerable amount

in wheat bran a nd is a common constituent Of plants .


1 96 . Thymol a nd Ca rvacrol are naturally occurring

methyl-isopropylphenols. They are derivatives of cymene .

Thymol a nd carvacrol are found in many plants .

They have a very pleasant mint-like odor a nd possess

mild antiseptic action .

1 97. Protocatechuic Acid, ca techol ca rbox ylic a cid, re

sults from the fusion of many resins with alkali . It is

readily soluble in water a ndmelts at

1 98 . Vera tric Acid, Va nillin,‘

a nd ConiferylAlcohol.

OCH;,

O CHs

CH CH— CHzOHVera tric a cid Va nil l in Conifery l a lco ho l

Vera tric acid, the dimethyl ester O f protocatechuic acid,occurs in the seeds of Vera trum Sabadilla .

Va nillin is the substance giving the pleasant odor to


Hz— NH— CH";is the active principle of the adrenal glands , a nd one of

the endogenous hormones , i.e. chemical regulators of

metabolism . It has been produced synthetically by the

following reactions :

O C— CHoCl CH2C1 HNHCH,

C a techo l+Chlo ra cetic a c id C hlora ceto-c a techo l+M ethyl amine

CHo— NH— CH3 CHg— NH— CH3Methyl-amino-a ceto-ca techo l Adrenin

lTh e Aroma tic Compounds 377

The synthetic product is Optically inactive , but has

been resolved into its Optical components . The natural

product is levorotato ry a nd greatly surpasses the dextro

form in physiological activity . Adrenin produces a

marked rise o f blood pressure through a constriction o f

the blood vessels .

201 . Benzoic Acid, C eHsCO O H, is formed by the o x i

dation of toluol a nd its homologues containing longer

side chains . It is found in gum benzoin, a nd other resins .In gum benzoin it is

'

present chiefly as its ester, with

benzyl alcoho l as benzoate . It occurs also in cranberries .

Benzoic acid is formed from benzotrichloride by boil

ingwith water . The behavio r o f the three chlor toluenes

in which the chlorine is in the side chain, when boiled with

water, is of synthetic interest

C 6H5— CH2C 1 HOH C 6H5

— CH20H +HClBenzyl ch lo ride Benzyl a lco ho l

C 6H57 CHC1 2 2 HOH C eHs— CHO 2 HC1

Benza l ch lo ride Benza ldehyde

C 6H5_CC1 3 +

03 HOH C eH5

— CO O H 3 HC1Benzo trich lo ride Benzo ic a c id

Benzoic acid results from the oxidation of either benza l

dehyde or of benzyl a lcohol with benzaldehyde as a n inter

mediate product . .The a cid ca n also be formed by the

hydro lysis of phenyl nitrile

Benzoic acid has all the ordinary properties of a n acid ,forming salts , esters , etc . It is a colo rless crystalline

compound which is fairly readily soluble in hot water,but very slightly soluble in cold (1 part in


Physiologica l Properties. Benzoic acid has very little

toxicity, large doses not being followed by a ny appreciable

effects . Within the tissues it undergoes conjugation with

glycocoll to form hippuric a cid:

CO-HN— CHz— GOOH

CO — NH— CHo— CO OH HoO

H ippuric a cid (benzoyl-g lyco co l l)Sa ccha rin is a derivative of o-sulphobenzoic acid , which

is Of particular interest because of its extreme sweetness .

It is about 500 times sweeter than cane sugar, a nd has

been employed to a considerable extent as a n adulterant

of foodstuffs in place of sugar, which is more expensive .

The following reactions show the method of synthesis

H HC 5H5CH3 —9 ' C 6H4<S

C

0 1 1 C 6/

CO:CI30

202 . Hippuric Acid (201 )is normally found in very small

amount in the urine especially of the herbivora . It is

not, however, a product of metabolism , but is present

there because the foodstuffs o f the herbivorous animal,


O n shaking a n a lcholic solution Of benzaldehyde with

potassium cyanide two molecules condense to form the

ketone alcohol benzoin . Benzaldehyde yields nitro

derivatives, sulphonic acids , etc . o-nitrobenza ldehyde

condenses with acetone to form indigo blue .

PHENYL FATTY ACIDS

205 . Ph enyl Acetic Acid is formed in small amounts inputrefaction of proteins . It is clo sely related to mandelic

acid , the nitrile of which occurs in amygdalin

C 6H5CH,— CO O H C 6H5CHOH— GOOHPheny la ce tic a cid M a ndehc a c id

Its nitrile is formed from benzyl chloride by the action

of potassium cyanide :

C 6H5CH,C 1 +KCN =C oH5CH2CN+KC 1

206 . Phenyl Amino Propionic Acid, C 6H5— CH,

CH— CO O H, or phenyl a la nine, is a constant constituent

NH,of proteins . O n putrefaction it gives rise to phenylpropionic acid

C sHa— CHz

— CH— CO O H 2 H

C 6H5— CH,

— CH,— GOOH+NH3

Phenyl alanine is not readily isolated from among the

products of hydrolysis of proteins . The form which

occurs in nature is levorotatory . It is crystalline a nd

melts at 275

The Aroma tic Compounds 38 1

207. Cinnamic Acid, C 6H5— CH =CH— CO O H, phe

nyl acrylic acid , is found in the resin storax. It is the

most important phenyl derivative conta ining a n un

saturated side chain . A synthesis described by Per

kin is O f unusual interest . Benzaldehyde condenses with

sodium acetate when the two are heated together in the

presence of a dehydrating agent (acetic anhydride).

C eHn— CH CH— CO O Na

Benza ldehyde Sod ium a ce ta te

C 6H5— CH CH— COONa

Alcohol , aldehyde a ndacid derivatives of phenol are alsofound in nature . The first Of these is represented by sa ligenin, which occurs in the glucoside sa licin in willow bark .

It is a crysta lline solid easily soluble in water a ndmelting

at The phenol group is in the ortho position .

H208 . Sa licylic Aldehyde, C 6H4

\The ortho

CHO

compound is found in certain volatile Oils .H

209 . Sa licylic Acids. The ortho com

CO O H

pound is of greatest importance . It occurs as the methyl

ester in oil of Wintergreen, a nd the acid is likewise found inthe flowers of Spiraea .

2 1 0. Aspirin is acetyl salicylic acid

OH O C— CH,C , CH3

— COC 1 O GH/0

GO O H Ace ty l ch lo ride 4

\CO O I_ISa l icylic a cid Ace tyl sa licylic a cid

382 Orga nic Chemistry for Students M edicine

2 1 1 . Sa lol is phenyl salicylate

H

21 2. Ga llic Acid, is found in manyHO CO O H

plants , as gall nuts , tea , etc . It is formed when tannin is

hydrolyzed . It is a crystalline compound melting at

It gives the same reaction with ferric chloride as does

pyrogallol .

2 1 3. TannicAcid, or diga llic a cid,

OH HO O C

Ta nnic a cid

is a n ester formed between two molecules of gallic acid .

It occurs in gall nuts , sumach , a nd other barks .

2 1 4 . Tannins are of several varieties, distinguished by

the color reactions which they give with various reagents .

There are distinguished two general classes , the pyrogallol

a nd the catechol varieties . The former give a dark blue

color with ferric salts (ink)a nd the latter a greenish black .

The latter forms a dark red ring at the juncture of the

liquids when its solutions are treated with concentrated

sulphuric acid .

CHAPTER XVIII

CONDENSED BENZENE RINGS

2 1 5 . Naphth alene , C ln , i s present in considerable

amount in coal ta r. Its structure is made clear by the

behavior of its nitro a nd amino derivatives on oxidation .

Naphthalene on oxidation yields phthalic acid

which shows that it contains a benzene nucleus a nd two

substituting groups in the ortho position. O n oxidizing

the nitro compound , nitrophtha lic acid is formed . When

the nitro group is reduced to a n amino group a nd the

na phthyl amine oxidized , phthalic acid is formed . The

molecule must therefore consist Of two benzene rings hav

ing two carbon atoms in common :

GOOH

CO O H

Na phtha lene Phtha lic a cid Ni trona phtha lene

CO O H

CO O H

Nitrophtha lic a cid Amino na phtha lene Phtha l ic a c id

Condensed Benzene Rings 385

Naphthalene derivatives are extensively employed in

the manufacture of dyes .

Naphthalene yields two mono substitution products

a a nd6

2 1 6 . Anthra cene , CMHI O, is formed by the F ittig synthe

sis from a -brom benzyl bromide , with subsequent oxida

tion

— 2 H

Anthra cene

The structure of a n anthracene derivative is arrived at

through a study of the structure Of its simpler oxidation

products .

Anthracene is a constituent o f coal tar, a nd is the mother

substance o f the red dye derived from the madder root .

It is a co lo rless crystalline solid with a blue fluorescence,which melts at 2 1 3° a ndboils a t It is easily so luble

in benzene but difficultly in water , alcoho l , a nd ether .2 c

386 Organic Chemistry for Students of M edicine

Nitric acid oxidizes anthracene to a nthra quinone, a pale

An thra quinone

yellow crystalline substance with the nature of a ketone .It is used in making the dye a lizerin.


F la vopurpurin

Only those phenol derivatives of anthracene containing

two hydroxyls in the ortho position to each other are dyes .

THE TRIPHENYL METHANE DYES

21 8 . M alachite Green is formed by heating benza lde

hyde with dimethyl aniline a nd a dehydrating agent

(ZIlClz).

N(CHa)z

Nazis),

/C ,H.

\O ,H.Ma la ch i te green

Benza ldehyde

C 6H5— CH

It is a n excellent dye for silk a nd wool , but for dyeing

cotton a mordant is required .

Brilliant G reen is prepared in the same way as is mala

chite green, but diethyl aniline is employed .

Acid Green is also analo gous to malachite green except

that ethylbenzyla niline is employed .

Pararosa niline is prepared from p-toluidine a nd anil ine

by the action of a n oxidizing agent

Alizerin Dyes 389

p-to luidine-NH,

Aniline

/C 6H4— NH,

H,N —C 6H4—CH\CeHi— NHz

p-rosa ni l ine

Rosa niline , fuchsine, orma genta , is prepared from a mixture o f p-toluidine , O -toluidine, a nd aniline in a n analogous

manner .

Ro sa niline a nd pararosaniline are reddish-blue dyes a ndca n be converted into dyes having a bluer tint by methyla

tion with methyl iodide

Ethylation of the amino groups forms deeper blue dyes,while phenylation forms a pure blue dye known as a nilineblue .

Ph enolphthalein is another triphenyl methane derivativeformed from phenol a nd phthalic anhydride :

Phtha l ic a nhydride

/C6H4OH

C“ H OHO ,H/ \ O

6 4

Pheno lphtha le in


Fluorescein, eosin, erythrosin, a nd many other dyes

are derivatives Of triphenyl methane .

THE AZO DYES

2 1 9. By substituting the hydroxyl of diazo-benzene

(1 77)by amines , phenols , etc . , a great number of dyes of

both basic (from amines)a nd acid (from phenols)charac

ter have been produced :

C sHs— N N— OH NH,

C 6H5— N N — NH,

O 6H5 N N— OH+ H

C sHs— N N— C 6H4— OH

Congo red , bismarck brown, chrysoidin,helianthin,

resorcin yellow, belong to this class .


OH, —C H C CH2

Pen tame thylene-diam ine hydro ch lo ride

Piperidine

Pyridine a nd certain of its homologues are present in coal

tar, a ndin D ippel’s Oil,

” the foul-smelling product o f the

dry distillation of bones .

Pyridine is a colorless liquid with the odor of tobacco

smoke . It is a strongly a lkaline“

substance which mix es

with water in all propo rtions . It boils at It is

one Of the most stable of organic substances, being

unattacked by boiling nitric or chromic acid . With

sulphuric acid it reacts, fo rming a sulphonic acid .

Halogens scarcely attack it . O n heating pyridine with

hydriodic acid at 300° it is destroyed,yielding normal

pentane a nd ammonia .

Pyridine fo rms salts with acids . It does not form a

nitroso derivative with nitrous acid .

As a tertiary amine pyridine combines w ith alkyl halides .

These show a n interesting rearrangement when heated ,

Heterocycl ic Compounds 393

the alkyl group changing its position from the nitrogen to

the a —carbon atom .

CHaI

a -me thyl pyrid ineCH, I

Pyridine methiodide

A delicate test fo r pyridine consists in heating the sub

stance to be tested with a few drops o fmethyl iodide , then

a dding a sma ll quantity of solid potassium hydroxide a nd

heating aga in. M ethyl pyridine hydroxide , ha ving a n

extremely disagreeable odor, i s formed when pyridine is

present .

Piperidine, C 5H1 0NH, is formed by heating the hydro

chloride O f pentamethylene diamine (74)or by the redue

tion o f pyridine with sodium a nd alcohol . It behaves like

a seconda ry amine in forming a nitroso derivative when

treated with nitrous a cid .

Piperidine occurs a s a constituent O f the alkaloid piperine

found in pepper . It is a strong base , which boils at

HOMOLOGUES OF PYRIDINE

The methyl pyridines are known as picolines ; the di

methyl pyridines , a s lutidines ; a ndthe trimethyl pyridines,a s collidines. Their properties are closely similar to tho se

of pyridine .

221 . Nicotinic Acid is the B—pyridine carboxylic acid :


GOOH

CO O H

Pico l in ic a cid N ico t in ic a cid Ison ico t in ic a c id

Nicotinic acid is derived from the alkaloid nicotine by

oxidation .

Picolinic acid is distinguished from the other isomeric

acids by its property of giving a red color with ferrous

sulphate .

Quinolinic Acid is a n (LB-dica rbo xy pyridine . At 1 90°

Quino l inic a c id

it loses carbon dioxide a nd is converted into nicotinic acid .

222. Quinoline is a compound containing a benzene ring

condensed with a pyridine ring

Iso quin‘

o l ine

Both isomers occur in coal tar,but quinoline is usually

prepared by synthesis . Its structure is made clear by itssynthesis from allyl aniline by oxidation

396 Orga nic Ch emistry for Students Of M edicine

in proteins . o—a mino mandelic acid is converted by the

elimination Of water into dioxindole, from which by vigor

ous reduction indole is formed

— CHOH —CO

o-amino ma nde l ic a c id

— CHOH2 O

D io xindo le Indo leIndole is crystalline a nd

.melts at It has a fecal-like

odor, a nd is volatile with steam . It is soluble in various

organ ic solvents .

It is the complex which gives the red colo r with sul

phuric acid a nd glyoxylic acid (Hopk ins a nd Cole’s re

agent)which is characteristic O f many proteins .

224 . M ethyl Indole , or Scatole , is fo und in putrefa ction

mixtures a nd in feces, where it results from tryptophane,one of the amino acids :

Sca to le

225 . Indox yl occurs in Isatis tinctoria as a glucoside,indica n .

Hetero cyc lic Compounds 397

This is hydrolyzed by a n enzyme in the plant a nd

the free indoxyl undergo es o xidation to the blue dye

indigo . Indoxyl is a product of the putrefaction of tryptO

phane a nd is formed in the intestine from proteins a nd

being absorbed is eliminated in the urine , principally as

indoxyl sulphuric acid , which is analogo us to phenol sul

phuric acid (1 80) in its constitution . The formation of

indigo is the basis of the indica n reaction of urine.

226. Indigo

C — c

Ien d

2 Indo xy l

Indigo b lueIndigo white is a reduction product of indigo blue

OH HO C

Indigo white


227. Tryptopha ne , ora —amino ,B—indole propionic acid, is

H, — CH— CO OH

a constituent of many proteins . It is the complex which

gives Adamkiewic’

s reaction for proteins (Hopkins-Cole

reaction).

It is a colorless crystalline compound readily soluble in

hot water,but difficultly soluble in cold . Insoluble in

absolute alcohol a ndin ether . It is soluble in hot pyridine .

It melts at 252° after becoming brown at It is a

weak base a nd forms salts with acids . Some of its acyl

derivatives formed by the action of acid chlorides are of

experimental value because of their properties . Trypto

phane is destroyed in the hydrolysis of proteins by mineral

acids , but is stable to barium hydrate .

Tryptophane gives a red colo r when a trace of bromine

is added to its solutions acid with acetic acid . With con

centra ted sulphuric acid a nd glyoxylic acid it gives areddish violet color .

Persons suffering from melanotic tumor excrete a pigmented substance called melanin in the urine . It has

been rendered highly probable that the tryptophane

complex in the pro tein molecule is the chief precursor of

melanin in such subjects .

The more important products resulting from trypto

phane in biolo gical processes are represented by the following transformations

CHAPTER XXI

THE TERPENES

228 . M any of the volatile oil s o f plants are esters , but

others which are contained especially in the flowers a nd

stems ofvarious coniferae consist ofhydrocarbonsof several

types a nd their derivatives . These are grouped together

a s terpenes . Turpentine consists of a mixture Of these,some liquid a nd holding in solution the solid forms . O n

distilling with steam the lighter members pass over, a nd

the solid residue remaining behind is colophony .

M ost o f the terpenes correspond to the formula C, oHls.

They are with few exceptions unsaturated , a nd are color

less , highly refractive liquids , boiling between 1 55 a nd 1 80°

Camphene is, however, a solid . They ca n be distilled with

steam a ndhave pleasant odors . They are soluble in many

o rgamc solvents, but not in water . The terpenes dissolve

sulphur, phosphorus, iodine, rubber, a nd resins, a nd are

much employed as solvents in varnishes , paints a ndin the

arts . In most cases they contain one ormore asymmetric

carbon atoms a nd are therefore optically active, since,generally speaking, but one form occurs in nature . There

a re a few instances in which both Optical forms occur

naturally . They are easily decomposed by acids .

The terpenes yield addition products with nitrosyl

chloride . From this on heating with alcoholic potassium

The Terpenes 401

hydroxide HC 1 is split off, leaving a nitroso compound .

They add on ozone at the points of double linkage, form

ing ozonides Of the general type

R R

\CH\C

II 03CH

R/

The ozonides on treatment with water are decomposed

into aldehydes

R— CHOH20 H202

R— CHO

The terpenes by virtue O f their unsaturated character

form addition products with halogens . O n reduction they

are converted into hydroterpenes. O n exposure to air

they are oxidized to resins . They polymerize also to form

resins . O n ox idation with pota ssium permanganate

they are in many cases oxidized to benzene derivatives .

The terpenes may be considered as derived from hydro

carbons O i the composition C 5H8, Of which isoprene (82)is a n example . Two o r more molecules of this substance

ca n polymerize to form in the first instance a hydrocarbon,

C lo , or to a polyterpene ; (C 5H3)n , of unknown mole

cula r weight . The compounds Of this series found innature warrant the classification

2 D

402 . Orga nic Chemistry for Students of M edicine

1 . Hemiterpenes C 5H3 3. Sesquiterpenes C 1 5H,4

2 . Terpenes C lo 4 . D iterpenes Go sz

5 . Polyterpenes (C 5Hg)n

The structure of many natural terpenes has been deter

mined a ndmany have been prepared synthetically. The

formulae assigned to a few of those possessing Open a nd

closed chains are shown, but it would be beyond the scope

of this book to give in detail the methods employed in

proving their structures :

\C — CHr— OH,— CHz— CH

CH3 \OH,— CH,OHCi tronel lo l (Lemon o il)

/CHa

C= CH— OH, —~CH,—C\OH— CH,OH

Gera nio l (Oi l o f gera nium)

/CHs

C= OH— CH,— CH,— C — CH= CH,\OH

Lina lool (O il o f la vender)

= CH— CH,— CH, — C

Myrcene

Another class of terpenes are derivatives Of hydro ben

zene . Thus menthane is closely related to cymene, which

is a constituent of many volatile O ils of plants :


Hs— C— C IL

CHOH

Assuming the skeleton illustrated a nd a union between

carbon atoms 2 a nd 8 , pinene consists Of a six-membered

a nd a four-membered ring . Borneol is believed to have a

union between 8 a nd 1 , giving the formula shown above .

d-pinene is the chief constituent of turpentine from

America, Algeria, a ndGreece , while tha t from France a nd

Spain is l-pinene . d—borneol is fo und in the product from

Borneo a nd Suma tra .

Camphor is a sesqu iterpene from the camphor tree . It

is now made from pinene by oxidation. It differs from

pinene in containing a ketone group .

229. The Cholesterols are closely related to the ter

penes. While they resemble the hard fats in their phys

ical properties, they differ from these in their remarkable

stability toward ox idation . M icro-o rga n isms do not

attack them a nd they appear to be fo rmed in every cell

for protective purpo ses, a nd they pla y a n important rOIein the liv ing protoplasm by reaso n o f their peculiar physi

The Terpenes 405

cal properties . The structure O f cholesterol is not entirely

known, but Winda us assigns to the following partial

provisional constitution

H— CH,— O H,

CH CH

H,C CH CH— CH,

I I IH,C CH, CH

CHOH CH,

The nature of the complex Ca is entirely unk nown .

The properties of cholesterol have already been described

(99)

CHAPTER XXII

THE ALKALOIDS

The term alkaloid now includes those basic substances

occurring in plants which are derived from pyridine,quinoline , isoquinoline , tropa ine, o r pyrrolidine .

230. Piperine , C 1 7H1 9NO 3, is a derivative Of pyridine .

O n hydrolysis it yields piperidine a nd a n acid , piperic a cid,which may be regarded as the methylene ester Of cinna

menyla crylic acid

H OH— CH CH— C O

Methylene cinna menyl gro up Acryl ic a c id group

Piperidine

Piperine is a white solid substance melting at It

does not dissolve in water, but is soluble in alcohol a nd

ether . Black pepper contains about 8 per cent of thisalkaloid .

231 . Comme, C 8H 1 7N, is the poisonous principle of

the hemlock . It is dextrorotatory a -n-propylpiperidine.

It is a strong base which distill s with steam when the seeds406


boils at 247° a nd has a n unpleasant smell a nd a n ex

tremely burning taste . Naturally o ccurring nicotine is

levorotatory. The synthetic product is inactive, a nd

d-nicotine has been prepared from it a nd from the natural

product after racemization . The physiological effects o f

the natural fo rm are twice as pronounced as are those of

the Optical isomer d-nicotine . It is extremely poisonous .

The alkaloids are not found generally distributed in

plants, but certain ones are produced only by particular

plant groups . The fo rmation o f pyrrolidine from tetra

methylene diamine (1 1 7)a ndpiperidine from pentamethyl

ene diamine (320)give a clue to their mode of formation

in the metabolism of the plant . These are formed from

o rnithine a nd lysine respectively, both Of which amino

acids occur in the course o f protein decomposition . The

formation of alkaloids is do ubtless closely associated with

the protein metabolism o f the plant .

233 . Hygrine , a n alkaloid found in coca leaves, is

B—acetyl-N-methyl pyrrolidine

H,C— CH— CO -CH,

H,C CH,

N

ICH,

234 . Atropine a ndHyoscyamine differ chemically onlyin respect to their Optical properties

,the former being

the d, l a nd the latter the l-hyoscyamine . Atropine is

found in the deadly nightshade a nd in henbane, a nd

The Alk alo ids 409

hyoscyamine in the J amestown weed, Da tura stramonium.

It is a white crystall ine substance melting at

rea dily so luble in alcohol , ether, a nd chloroform , but

sparingly soluble inwater . It is one o f the most poisonous

substances known .

O n hydrolysis atropine yields tropic acid a nd tropine .

Tropic acid has been shown to be a —phenyl-B—hydroxypropionic acid CH,OH

CH- C sH,

CO O H

Tropine is made up of two condensed rings , one with

five members, the other with six, a nitrogen atom serving as

a bridge .

”

H,C —CH

N— CH, CHOH

CH,

CHTro pine

CH,

Ecgo nine

Atropine is the ester of tropic acid with the secondary

alcohol tropine .

235 . Cocaine , C 1 7H, 1NO 4, i s a n alkalo id in coca leaves .

It is crystalline a ndmelts at O n hydrolysis it yields

methyl alcohol , benzoic acid, a ndecgonine . Its formula is


H,C CH HC— COOCH,

N— CH, CH— O O C— C eHs

H,C CH — CH,

236 . Cinchonine , C 1 9H22N20, present with quinine in

cinchona bark , yields Cinchonic acid or quinoline ca r

bo x ylic acid a nd a piperidine derivative .

The structure of quinine is similar but is not known with

certainty. It yields both quinoline a nd pyridine deriva

tives on hydrolysis .

237. Strychnine, C2 1H22N202 ; Brucine , 023H25N204 , a nd

Curarine are all present in the seeds of Strychnos nux

vomica a nd other plants o f that family . They are all

extremely poisonous . Strychnine yields both quinoline

a nd indol on fusion with alkalies . The constitution of

these alkaloids is not known .

238 . M orphine , C 1 7H 1 9N03 , occurs in the juice of the

poppy. There are a number of other alkaloids in the plant .

Opium is the dried juice of the seed capsule Of Pa pa ver

somniferum, a variety Of poppy . It contains other alka

loids as well as a large number of substances such as fats ,resins , proteins, sugars , inorganic salts , etc .

239. Papaverine , Narcotine , Narceine , La udanosine,a re all found in opium along with morphine . They are

derivatives of isoquinoline .

4 1 2 Orga nic Ch emistry for Students of M edicine

This salt is a white crystalline powder which dissolves

readily in water . It is much less poisonous than are the

salts of arsenious acid .

241 . Arrhena l, sodium methyl arsenate,

CHg

is fo rmed by the action Of methyl iodide on sodium arsenate

in alkaline solution

/O Na /CH:5O =As —O Na CHaI O As— O Na Na IO

\O Na . \O Na

The great stabil ity Of these arsenic derivatives containing

aliphatic radicals, a nd the correspondingly slight arsenical

effect which follows their administration, has led to the

substitution in great measure of aromatic arsenic com

pounds in medicine .

242. Atoxyl, sodium p-amino-phenyl-a rsena te, is formed

when aniline a nd arsenic acid are heated together . As an

intermediate product, aniline arsenate, is formed

C 5H5NH2 AS(OH)3 C 3H5NH3— O AAni lin a rsena te

NHz— C GH4A

p-amino-phenyl-a rsenic a cid

ONaAcetyla tox yl, CHs

— CO — NH— C eiL— ASZ O is also

\OHAcetyl a to xyl

employed as a compound for the slow admin istrationof arsenic in medicine .

Orga nic Arsenic Compounds 4 1 3

Sa lvarsan, a n arsenic compound having a peculiar

specific toxic effect upon the protozoa causing syphilis,is

one of the most va luble remedies yet discovered . It is

p-dihydroxy—m-diamino—arseno—benzene . The following

reactions illustrate its preparation :

As = As

p-dihydroxy-m-diamino-a rseno-benzene

On heating pheno l with arsenic acid , condensation takes

place at the para positionOH

HO — As O

\OH

/O H

HO As_—: O +H,O

\OHp-pheno l a rsenic a cid

On nitration this yields a nitro derivative having the— NO, group in the 0 position to the — O H. O n

complete reduction of this compound the nitro group is

converted into a n amino group a nd the oxygen is removed

from the arsenic acid group , the two residues are condensed :

H

Asz o + 2O H

i ~\O H

H+ 1 0H,O '


Salvarsan is a derivative of arseno-benzene,

C eH5— AS AS— C 6H5

which is analogous to a zo benzene : C 6H5— N=N -C 5H5 .

THE PROTEINS

243 . The proteins form a very important group of sub

stances which constitute the greater part of the solids of

animal tissues a ndare present in all tissues of both animal

a nd plant origin. Typ ical proteins are the white of egg,casein of milk, which is the part separated in the curdling

of milk, hair, nails , silk, etc .

Chemically the proteins are made up O f amino acids ;seventeen of these, glycocoll, alanine, valine , leucine a nd

isoleucine, phenylalanine, tyrosine, serine, cystine, pro

line , oxyproline , aspartic acid , glutaminic acid , arginine,lysine , histidine, a nd tryptophane have been isolated a nd

identified . These have all been described in this book .

It is possible that there are o thers as yet un identified .

The proteins differ most widely in their physical

properties , some being soluble in water (albumins), others

insoluble in water, but soluble in dilute salt solutions

(globulins), others insoluble in both these solvents, but

soluble in dilute acids or alkalies (glutelins). There is aclass called prolamines , which are especially abundant in

wheat, rye , barley, a nd maize, which are insoluble in

water or salt solutions, but dissolve readily in 70—80 percent alcohol .

Nearly all proteins contain sulphur , a nda few also contain

phosphorus ; the latter occur only in milk a nd in eggs .


Proteins are known which consist of the three diamino

acids arginine, lysine, a nd histidine, a nd arginine in one

instance constitutes about 85 per cent of the total nitro

gen content . These are termed protamines a nd occur

only in the heads of the spermatozoa Of animals .

Proteins differ greatly in the proportions of the different

amino acids which they yield . Glutamic acid occurs to

the extent of 40per cent in certain of the wheat proteins

(gliadin) a nd as little as 2 per cent in the globulin globin

of the blood . Silk is more than half made up of peptide

combinations of glycocoll a nd alanine . Tryptophane,tyrosine

,a nd cystine are all lacking from gelatin, derived

by the incipient hydrolysis of connective tissue,the

organic matrix of bones, etc . A few yield no glycocoll .

In digestion by enzymes such as pepsin or trypsin the

peptide linkages are broken, the elements o f water being

taken up to fo rm a n amino a nd a carboxyl group, i.e.

digestion i s the reverse o f the process described in the for

mation of the peptides .

THE CONJ UGATED PROTEINSThe proteins also exist in nature in certain instances

in union with other substances as phosphoric acid (phos

phoproteins), glucosamine (glycoproteins), nucleic acids

(nucleoproteins), etc .

The chemistry of the proteins is so extensive a ndinvolves

a consideration of their physical properties as colloids, as

well as their chemical constitution, that it properly belongs

in the special bra nch of physiological chemistry a nd will

not be further dealt with here .

Abso lute a lco ho l , 25 .

Aceta l , 59 .

Ace t a ldehyde , 53 , 65 .

Aceta ldo x ime , 63 , 72 , 88 .

Ace t amide , 1 04 .

Aceta nil ide , 36 1 .

Aceta te , ethyl , 1 03 .

Acetic a cid , 53 , 7 1 , 77 , 99 , 1 01 .

a nhydride , 1 26 .

ester , 1 03 .

Aceto -a ce t ic a cid , 236 , 237 .

ester , 238—24 1 .

Aceto ne , 68 , 69 , 73 , 1 02 , 236 .

dica rbo xyl ic a c id , 244 .

Aceto nitrile , 78 .

Ace to xime , 72 .

Acetyla t io n , 1 03 , 1 88 .

Ace tyl chlo ride , 95 .

number , 1 88 .

urea , 253 .

Acety lene , 1 63 , 1 66 , 347.

Acetylenes, 1 6 1 , 1 62 .

Achro odex trine , 330.

Ac id am ides, 1 04 .

a nhydrides, 1 26 .

chlo rides, 95 , 1 03 .

number , 1 83 .

ure ides, 260.

Ac ids, amino , 1 20, 1 37 , 1 39 ,

206 , 208 , 368 , 398 .

d iba sic , 1 99 .

fa tty , 95— 1 5 1 .

mo noba sic , 95 .

Acro lein , 1 6 8 , 289 .

Acro se , 290.

Acryl ic a c id , 1 73 , 407 .

Acyla t io n , 1 22 , 1 27 .

Additio n compo unds, 58 .

Adena se , 279 .

Adenine , 278 .

2 15:

INDEX

Ad ipic a cid , 208 , 2 1 2.

Ado nite , 296 .

Adrenin , 376 .

E tio po rphyrin , 22 1 .

Al a nine , 1 37 , 4 1 5 .

Ala ny l-glycine , 4 1 5 .

Ala nyl-glycyl-phenyla la nine ,bumins, 4 1 4 .

Alco ho l , 24 , 1 06 , 201 , 340.

Alcoho la tes, 26 .

’6

Alco ho l ic fermenta tion , 338 .

Alco ho ls, 22 .

Aldehyde , 53 .

ammo ni a , 58 , 66 .

Aldehydes, 53 , 56 .

a rom a t ic , 354 , 379 .

Aldo l , 6 1 .

co ndensa t io n , 6 1 .

Aldo se , 284 .

Aldo ximes, 63 , 72 .

Alipha t ic series, 1 — 2 1 .

Alizerin , 386 , 387 .

Alka lo ids, 406 .

Al ka pto nu ri a , 376 .

Alky l ammonia s, 85 , 90.

a nilines, 36 1 .

cya na tes, 1 1 2 .

cya nides, 77 , 78 .

ha l ides, 1 2 .

iso cya na tes, 80, 8 1 .

iso cya nides, 79 , 80.

thio cya na tes, 80, 8 1 .

Alla nto ine , 256 .

Allene , 1 6 1 .

Allo xa n , 26 1 , 262 .

Allo x a ntine , 263 .

Al lyl a lco ho l , 1 67 .

iso thio cya na te , 1 69 .

pyri d ine , 407 .

sulphide , 1 69 .

4 1 8

Aluminum ca rbide , 1 66 .

Amides, 98 , 1 04 .

Amines, 84 , 87 , 94 .

Amino a ce t ic a cid , 1 20.

a -Amino a cids, 1 09 .

fi-Amino a cids, 1 69 .

“pl-Amino a c ids, 237 .

Amino benzene , 359 .

gluco se , 334 .

gluta ric a cid , 208 .

iso ca pro ic a c id , 1 47.

iso va leria nic a cid , 1 43 .

na phtha lene , 384 .

nitro gen , 1 2 1 .

o xypu rine , 278 .

pro pionic a c id , 1 37 4 1 5 .

purine , 278 .

Ammo nium ca rbama te , 1 1 0.

fo rma te , 77 .

iso cya na te , 1 1 1 .

thio cya na te , 1 1 5 .

ura te , 272 .

Amygda l in , 324 .

Amyl a lcoho ls, 30.

nitra te , 48 .

n itrite , 48 .

Amyla se , 329 .

Amylum , 329 .

Anhydrides, a cid , 1 26 .

Anil ine , 359 , 36 1 .

Anthra cene , 385 .

Anthra quino ne , 386 .

An t ipyrine , 259.

Ara ba n , 332 .

Ara bino se , 296 .

Ara bite , 296 .

Ara chic a c id , 1 5 1 .

Arginine , 1 1 8 .

Argo l , 23 1 .

Aroma tic compounds,Arrhena l , 4 1 2 .

Index

Azo benzene , 4 1 4 .

dyes, 390.

Arsenic , compounds, o rga nic, 4 1 1 .

Aspa ra gine , 207 .

Aspa rt ic a cid , 206 .

Aspirin , 38 1 .

Asymmetric ca rbo n a tom, 34 , 206 .

Ato xyl , 4 1 2 .

Atro p ine , 408 .

Azelia c a cid , 1 73 , 2 1 3 .

Ba rbituric a cid , 26 1 .

Beesw a x , 1 92 .

Behenic a cid , 1 5 1 .

Benza l chlo ride , 355 , 377.

Benza ldehyde , 354 , 379 .

Benzene , 347 , 352 , 363 .

sulphonic a cid , 364 .

sulpho nyl chlo ride , 364 .

Benzo ic a cid , 354 , 377.

Benzo in , 380.

Benzo ni trile 363 .

trichlo ri de 355 , 377.

Benzo yl glycine , 378 .

Benzyl a lco ho l , 377 , 379.

chlo ride , 355 , 377.

Beta ine , 1 25 .

Beta ines, 1 25 .

Bevera ges, a lcoho lic , 27.

B iuret , 1 1 2 .

Bo ne O il, 392 .

Bo rneo l , 403 .

B ril l ia nt green , 388 .

Brom benzene , 363 .

Brucine , 4 1 0.

Burning po int , 1 5 .

Buta ne , 1 3 , 1 8 .

But ter fa t, 1 76 .

Butyl a lco ho ls, 28 .

Butylenes, 1 62 .

Butyric a c i ds, 1 40.

fermenta t io n , 342 .

Butyro beta ine , 1 25 .

C a co dyl compounds, 4 1 1 .

C a da verine , 1 47 .

C a ffeine , 28 1 .

C a lcium c a rbide , 1 65 .

C ampho r , 403 .

C a ne suga r , 3 1 8 , 328 .

C a nniza rro rea ction , 6 1 .

C a pric a c id , 1 5 1 , 240.

Ca pro ic a c i d , 1 46 , 1 5 1 , 345 .

Ca pryl ic a cid , 1 5 1 .

Ca ramel , 3 1 9 .

C a rbamic a c id , 1 1 0, 255 .

esters, 1 1 6 .

420

D ia sta se (see amyla se).D ia tomic a lco ho ls, 37 .

D ia zo benzene , 362 .

rea ctio n , 362 .

D ia zo nium sa lts, 363 .

D iba sic a c ids, 1 99 .

a ci d ure ides, 259 .

D ichlo r a cetic a cid , 1 07.

hydrin , 4 1 .

D iethyl a niline , 36 1 .

a rsine , 1 1 .

sulphi te , 47

D iga llic a cid , 382 .

D igita lin , 323 .

D i hydro xy a cetic a c id , 256 .

a ceto ne , 75 , 340.

benzenes, 37 1 .

succ inic a c id , 227 , 249.

D ime thyl am ine , 85 , 9 1 .

a niline , 36 1 .

benzenes, 352 , 356 .

selenide , 1 1 .

sulpha te ,44 .

tel luride , 1 1 .

x a nthine , 28 1 .

D io lefines, 1 6 1 .

D io se , 294 .

D io x ypurine , 277 .

D ipeptides, 4 1 5 .

D iphenyl am ine , 36 1 .

meth a ne , 357 .

D isa cch a rides, 3 1 8 .

hydro lysis by enzymes, 3 1 9 ,

D iterpenes, 402 .

Do decyl a lco ho l , 36 .

Double bo nd , 1 54 , 1 69 ,1 72 .

Dry d ist illa tio n o f wo o d , 1 00.

D rying o ils, 1 76 .

Dulci te , 303 .

Dyes, 387— 390.

Ecgonine , 409 .

Egg a lbumen ,4 1 4 .

Ela id ic a c id , 1 72 .

Ela idin test , 1 89 .

Empirical fo rmula , 8 .

Emulsin , 324 .

Emu lsio ns, 1 82 .

Ena n tiomo rphs, 1 34 .

Eno l fo rm , 24 1 .

Enzymes, 338 , 34 1 .

Eo sin , 390.

Erythrite ,42 294 .

Erythrodex tr me , 330.

Erythro se , 294 .

Esters, 44 .

E tha na l , 65 .

Etha ne , 1 0.

Etha no l , 24 .

Ethers, 44 , 48 .

Ethyl a ceta te , 1 03 .

a lco ho l , 24 .

amine , 78 , 79 , 85 , 9 1 .

ca rbino l , 24 .

chlo ride , 1 2 , 1 3 .

ether , 48 .

merca pt a n , 43 .

nitra te , 48 .

nitrite ,47 .

ra dica l , 1 2 .

sulpha tes, 44 , 49 .

sulphuric a c id , 44 , 45 .

sulphurous a c id , 47 .

Ethyla te , so d ium ,26 .

Ethylene , 1 54 .

chlo ride , 1 4 , 247 .

cya nide ,205 .

d ibrom ide , 1 58 , 1 63 .

glyco l , 37 .

o xide , 38 .

Ethyl idene chlo ride , 1 4 .

cya nhydrin , 58 .

glyco l , 59 .

Fa ts, 1 75 , 1 78 .

emulsifica t io n o f, 1 82 .

sa po nifica tio n o f, 1 79 .

Fa tty a c i ds, 955— 1 5 1 , 343 .

Fehl ing’s so lut io n , 58 .

Fermen t a t io n ,

F ittig’

s rea ction , 1 1 .

F l a sh po int , 1 5 .

F luo rescene , 390.

Fo rma ldehyde , 54 , 63 .

Fo rm a lin , 63 .

Fo rmam i de , 98 .

Fo rmic a cid , 6 1 , 7 1 , 77 , 96 .

nitrile, 77.

Index 42 1

Fo rmo l t itra tio n , 88 .

Fo rmo se , 64 , 289 .

Fo rmula , empirica l , 8 .

genera l , 1 4 .

gr a ph ic , 6 , 8 .

F rieda l a nd Cra fts rea ctio n ,

F ructo sa zine , 268 .

Fructo se , 307 .

Fruit suga r , 307 .

Fuco se , 303 .

Fulminic a cid , 82 .

Fuma ric a cid , 247— 252 .

Furfura l , 292 .

Fu rfura ns , 293 .

Fusel o il, 29 , 3 1 , 1 45 .

Ga la cta n , 3 1 7 , 332 .

G ala cto se , 306 , 3 1 7 .

Ga ll ic a cid , 382 .

Gela tin , 4 1 6 .

Gera nio l , 402 .

G la cia l a cetic a cid , 1 02 .

Gl ia din , 4 1 6 .

Globulins, 4 1 4 .

Gluco nic a cid , 3 1 3 .

Gluco samine , 334 , 4 1 6 .

Gluco sa n , 3 1 3 .

Gluco se , 304 , 3 1 2 .

Gluco sides, 323 , 324 .

Glutamic a c id , 208 .

Gluta mine , 208 .

Gluta ric a cid , 207 .

a nhydride , 2 1 5 .

Gluta rimide , 2 1 6 .

Glycera ldehyde , 68 , 288 , 340.

Glyceric a c i d , 230.

Glycerides, 1 75 .

V Glycero l , 39 , 288 .

Glycero-pho spho ric a cid , 1 93 .

Glycero se , 294 .

G lyceryl esters, 1 75 .

G lycine , 1 20.

Glyco co ll , 1 20.

Glyco gen , 333 .

G lyco l , 37 , 1 06 , 1 09 , 201 .

a ldehyde , 67 , 1 06 , 1 09 .

chlo rhydrin , 39 .

G lyco lic a c id , 1 08 , 225 , 254 .

ureides, 254 .

Glyco lide , 225 .

Glyco luric a cid , 254 .

Glycuro nic a cid , 3 1 3 .

Glyo xa l , 68 , 285 .

Glyo xa line deriv a tives,Glyo xylic a cid , 1 09 .

Gra nulo se , 329 .

Gra pe suga r , 3 1 2 .

Gu a ltherin , 324 .

Gua na se , 280.

Gua nidine , 1 1 7 .

Gu a nine , 278 .

Guia cho l, 37 1 .

Gums, 333 .

Gunco tto n , 33 1 .

Ha ama tin , 2 1 9 .

Haem in , 220.

Ha amoglobin , 220.

Haemo po rphyrin , 22 1 .

H a lo gen deriva t ives o f fa tty a cids,1 07 .

deriva tives o f hydro ca rbo ns, 3 ,

1 2 , 1 3 , 358 .

Hedo na l, 1 1 7.

He lia n thin , 390.

Hemicellulo se , 332 .

Hemite rpenes, 402 .

Hepta deca ne , 1 6 .

Heptamethylene , 2 1 3 .

Hepta nes, 1 6 .

Heptyl a lco ho l , 36 .

Hete ro cycl ic compo unds, 39 1 .

Hexa brom ide test , 1 89 .

Hex a hydric a lcoho ls, 295 .

Hex a hydro benzene , 347 .

Hexamethylene , 2 1 3 , 347.

tetramene , 63 .

Hexa ne , 1 6 .

Hexo ses, 295 , 296 , 303 , 3 1 1 .

Hexyl a lco ho l , 36 .

io dide , 287 .

Hippuric a c id , 378 .

H istamine , 257 .

Hist idine , 1 25 , 257 .

Homo gent isic a cid , 375 .

Homo lo gous series, 1 2 .

Ho rmo nes, 376 .

Hyd a nto ic a cid , 255 .

422 Index

Hyda nto in , 254 , 255 .

Hydra z ine , 62 .

Hydra zo nes, 72 , 285 .

Hydro a roma tic compo unds, 347 .

Hydro ca rbo ns, 1 , 1 54 , 1 63 , 347 .

sa tura ted , 1 — 2 1 .

unsa tura ted , 1 54 , 1 63 .

Hydro cya nic a cid , 77 , 1 99.

Hydro quino ne, 372 .

Hydro xy a cids, 1 08 .

a ldehydes, 67 , 1 09 .

benzo ic a c id , 38 1 .

butyric a cid , 1 69 , 235 .

Hydro xyl group , 220, 383 .

Hydro x ypheny l a cetic a cid , 370.

a la nine , 368 .

ethyl amine , 370.

pro pio nic a c i d , 370.

Hydro xypro line , 224 .

Hydro xypro pio nic a cid , 1 29 .

Hygrine , 408 .

Hyo scyam ine , 408 .

Hypo xa nthine, 277.

Ido se , 306 .

Imida zo les, 257.

a crylic a c id , 257.

amino-pro pio nic a cid , 1 25 , 257.

ethyl amine , 257 .

Imides, 2 1 6 .

Imino gro up , 2 1 6 .

Ina ctive ta rta ric a cid , 229, 232 .

India rubber , 1 6 1 .

Indica n , 397 , 399 .

Indigo , 397 .

wh ite , 397 .

Indo le , 395 , 399 .

a cet ic a c id , 399 .

amino-pro pionic a cid , 399 .

ethyl am ine , 399 .

pro pio nic a cid , 399.

Indo xyl , 396 , 399.

Ink , 382 .

Ino site , 373 .

Interna l compensa tion , 229 , 297

Inul in , 336 .

Inversio n, 3 1 9 .

Inverta sq , 3 1 9 .

Invert suga r , 3 1 9.

J a pa n w a x , 1 9 1 .

.Iodine'

number, 1 86 .

Io do benzene , 359 , 363 .

Io do fo rm, 74 .

Iso amylamine , 92 .

Iso buta ne , 1 8 .

Iso butyl alco ho l , 29, 1 45 .

amine , 92 .

Iso butyric a cid , 75 , 1 4 1 .

Iso cya na tes, a lkyl , 80. l

Iso cya nides, a lkyl , 78 , 80.

Iso haamo pyrro l, 2 1 9 .

Iso leucine , 1 49 .

Isoma lto se , 320.

Isomers, 1 9 , 34 .

Iso nico tinic a cid , 394 .

Iso nitrile rea ctio n , 89 .

Iso nitriles. 77, 78 , 80.

Iso pho no pyrro l ca rbo xy lic2 1 9 .

Iso phtha lic a cid , 356 .

Iso prene , 1 6 1 .

Iso pro pyl a lco ho l , 28 , 70.

io d ide , 42 .

Iso quino l ine , 394 .

Iso thio cya na tes, alkyl , 80, 8 1 .Iso urea , 1 1 2 .

Iso va leria n ic a cid , 1 43 .

Kera tins, 4 1 4 .

Kero sene , 1 5 .

Keto a cids, 236 , 237, 242.

fo rm , 24 1 .

Keto nes, 53 , 68 .

Keto ses, 307 .

Kilia ni’

s rea ctio n , 290.

Kryp to pyrro l, 2 1 9 .

La ctam , 237.

La cta se , 32 1 .

La ct ic a c id , 1 29 , 340.

fermenta t io n , 342 .

La cto nes, 237.

La cto se , 3 1 8 , 32 1 .La no lin , 1 92 .

La urie a cid , 1 5 1 .

La vender o il, 402 .

Lecithins, 93 , 1 93 .

Index

Oleic a cid , 1 69, 1 72 .

Olein , 1 75 .

Optica l a ctivity , 32 .

Orcin , 372 .

Ornithine , 1 1 9, 1 42 .

O rtho deriv a t ives, 348 .

O sa zo nes, 285 , 3 1 1 .

O so nes, 3 1 1 .

Oxa la cetic a cid , 243 .

Oxa l ic a c id , 1 06 , 1 09 ,1 99 ,

201 ,

ni t rile , 1 99 .

Oxa luric a c id , 259 .

Oxa lyl urea , 260.

Ox imes, 63 , 72 .

Oxy a cids, 1 29 , 237 .

B—Oxybutyric a cid , 1 69 , 235 .

Oxyd a ses, 54 .

O x yethylamine , 92 .

O x yphenylpro pionic a cid , 370.

Oxypro l ine , 224 .

O x y purines, 274 ,277.

Ozo n ides, 401 .

Pa lmitic a cid , 1 5 1 .

Pa lmitin , 1 76 .

Pa pa verine , 4 1 0.

Pa ra ba nic a cid , 259 .

P a ra deriva tives, 348 .

Pa ra ffin , 1 6 .

Pa ra ldehyde , 65 .

Pa ra ro sa n iline , 388 .

Pectins, 333 .

Pela rgon ic a cid , 1 73 .

Pen tamethylene , 2 1 1 .

d iamine , 1 47 , 408 .

Penta nes, 1 9 , 32 .

Pento sa ns, 332 .

Pento se in nucle ic a c ids, 301 .

Pento ses, 295 , 301 .

Peptides, 4 1 5 .

Petro leum , 1 5 .

benz ine , 1 5 .

ether , 1 5 . o

na phtha , 1 5 .

Phena tes, 365 .

Pheno l , 363 , 365 .

ethers, 367 .

sulphon ic a cid , 366 .

Pheno lphtha lein , 389 .

Phenyl a cetic a cid , 380.

a l a n ine , 380.

amine , 360.

cya n i de , 363 .

hydra z ine , 285 .

metha ne , 352 , 354 .

pro pio nic a cid , 380.

ra d ica l , 360.

sulphuric a cid , 366 .

Phlo riz in , 323 .

Phlo ro gluc ino l , 373 .

Pho spha t ides, 1 93 .

Pho spho-pro te ins, 4 1 6 .

Phtha lic a cid , 356 , 384 .

a nhydride , 356 .

Phyllo pyrro l, 2 1 9 .

Phytic a cid , 372 .

Phyto stero ls, 1 97.

Pico l ines, 393 .

Pico l inic a c id , 394 .

Picric a c id , 368 .

Pimel ic a cid , 209 , 2 1 3 .

Pinene , 403 .

Pipera zine , 269 , 270.

Piperic a cid , 406 .

Piperidine , 39 1 , 392 , 393 .

Piperine , 406 .

Po lymeriza t ion , 64 , 65 , 1 64 .

Po lysa ccha rides, 329 .

Po lyterp enes, 402 .

Prima ry alcoho ls, 28 .

am ines, 85 .

Pro line , 223 .

beta ine , 1 25 .

Pro pa ne , 1 3 , 1 7 .

Pro pio nic a cid , 7 1 , 1 27 , 204 .

Pro pio nitrile , 78 .

Pro pyl a lco ho l , 28 .

chlo ride, 1 7 .

Pro pylene , 1 59 .

glyco l , 39.

Pro pylidene chlo rides, 1 60.

Pro tamine , 4 1 6 .

Pro teins, 4 1 4 .

conjuga ted , 4 1 6 .

Co nst itu tio n , 4 1 5 .

hydro lysis, 4 1 6 .

putrefa c t ion , 369 .

Pro to ca techu ic a cid , 374 .

Index

Pseudo urea , 1 1 2 , 1 1 6 .

uric a c id , 272 .

Psy l la w a x , 1 9 1 .

Purine , 275 , 276 .

Purines, 270—282 .

Pu trefa ctio n , 369 .

Putrescine , 1 43 .

Pyra zines , 266 .

Pyra zo le , 259 .

Pyridine , 392 , 407.

Pyrimidines, 264 , 39 1 .

Pyro ca techin , 37 1 .

Pyro ga llo l , 373 .

Pyro ligneo us a cid , 1 00.

Pyromuc ic a cid , 292 .

Pyro ra cemic a cid , 230.

Pyrro l , 2 1 6 , 389 .

Pyrro lidine , 2 1 6 , 222 .

ca rbo xy lic a cid , 223 .

Pyrro lido ne ca rbo xylic a c id , 224 .

Pyrro line , 2 1 6 .

Pyruvic a cid , 1 3 1 , 230, 340, 344 .

Qua te rna ry amines, 86 .

Quinine , 4 1 0.

Quino l ine , 394 .

Quino linic a cid , 394 .

Q uino ne , 372 .

Ra cemic a cid , 229 , 232 .

R a fiino se , 307 , 323 .

Re ichert-Me issl number , 1 87.

Reso rc in , 390.

Reso rcino l , 372 .

Rhamno se , 303 .

Rhigo line , 1 5 .

Ribo se , 296 .

Ricino le ic a cid , 1 77 .

Ro chelle sa lt , 23 1 .

Ro sa niline , 389 .

Ruberythric a c id , 387.

Sa ccha ric a cid , 235 , 304 , 3 1 3 .

Sa ccha rin , 378 .

Sa licin , 323 , 38 1 .

Sa l icy lic a c id , 38 1 .

a ldehyde , 38 1 .

Sa lo l , 382 .

Sa lva rsa n , 4 1 3 .

425

Sa ndmeyer rea ction , 364 .

Sa p o nifica tio n , 1 79, 1 80.

number , 1 83 .

Sa rco la ctic a cid , 1 33 .

Sa rco sine , 1 24 , 255 .

Sca to le , 396 , 399 .

Seco nda ry a lco ho ls, 28 .

Se rine , 1 40.

Sesqu ite rpenes, 402.

S ide cha ins, 350, 354 .

Silk , 4 1 6 .

So a ps, 1 79 , 1 90.

So rbic a c id , 344 .

So rensen titra tion , 88 , 1 22 .

Spe rma ceti , 1 92 .

Sta chydrine , 1 25 .

Sta rch , 329 .

Stea ric a c id , 1 5 1 .

Ste a rin , 1 75 .

Stereo isomerism , 34 .

Stero ls, 1 97.

S t rychnine , 4 1 0.

Suberic a cid , 209 , 2 1 3 .

Succinic a cid , 205 .

a nh ydride , 2 1 5 .

Succ inimide , 2 1 6 .

Sucro se , 3 1 8 , 328 .

Suga rs ,

Sul pho na l , 74 .

Su lphur a lco ho ls, 42 , 8 1 .

Ta nnic a cid , 382 .

Ta nnins, 382 .

Ta rta r emet ic , 232 .

Ta rta ric a cid , 227 , 249 , 294 .

Ta rtro nic a cid , 225 , 294 .

Ta rtro nyl u re a , 26 1 .

Ta utomerism , 276 .

Tera phth a lic a c id , 356 .

Terpenes , 400.

Terpentine , 400.

Tertia ry a lco ho ls, 28 , 3 1 .

am ines, 2 1 0.

Tetra hydro xy d iba sic a cids,Tetramethy lene , 2 1 1 .

d iam ine , 1 43 .

Tetramethy l metha ne, 1 9 .

Tetro ses, 294 .

Theo bromine , 28 1 .

426

Thio a lco ho ls, 42 , 8 1 .

Thio cya na tes, a lkyl , 80, 8 1 .

Thio urea , 1 1 5 .

Thymine , 264 , 265 .

Thymo l , 374 .

To luene , 352 , 354 .

To lu idines, 36 1 , 389 .

Tra ns fo rm , 1 7 1 .

Tribrom a niline , 360.

pheno l , 367 .

Trichlo r a cetic a cid , 1 07.

metha ne , 9 .

Trihydric a lco ho ls, 39 .

pheno ls, 373 .

Trihydro x ybenzenes, 373 .

Trihydro xy gluta ric a cid , 235 .

Triiodo pro pa ne , 39 .

Trimethyl amine , 85 .

Trimethylene , 2 1 0.

Trio lein , 1 72 .

Trio ses, 294 .

Trio x ygluta ric a cid , 295 .

Trio xymethylene , 64 .

Trio x y purine , 27 1 , 274 .

Tripep tides, 4 1 5 .

Triphenylam ine , 362 .

Triphenyl meth a ne , 357 , 388 .

Triple bo nd , 1 63 .

Trisa ccha rides, 307 , 323 .

Tro pic a cid , 409 .

Tro pine , 409 .

Trypto pha ne , 398 .

Tun icin , 33 1 .

Turpent ine , 400.

Ty ramine , 370.

Tyro sine , 368 , 375 .

Unsa p onifia ble residue , 1 84 .

Unsa tura ted a cids, 1 69, 1 72 ,a ldehydes, 1 68 .

hydro ca rbons, 1 53 , 1 6 1 .

Index

Va leria nic a cid , 1 42 .

Va l ine , 29 , 1 43 .

Va nillin , 374 .

Va n Slyke rea ction , 90.

Va ra tric a c id , 374 .

Va se line , 1 6 .

Vera tro l , 37 1 .

Vero na ] , 26 1 .

Vinega r , 53 .

V inyl a lco ho l , 1 67.

bromide , 1 59 .

Vo la t ile fa tty a cids, 1 76

Wa lden’

s tra nsfo rm a tio n , 1 38 .

Wa xes, 1 90.

Wohl ’s rea c tion , 290.

Woo d a lco ho l , 22 .

dist illa tion , 1 00.

Wo o l w a x , 1 92 .

X a nthine , 277 .

o xida se , 280.

Xyla n , 332 .

Xylenes. 352 , 356 .

Xyli te , 296 .

Xylo se , 296 .

Yea st, 24 , 340.

Zinc methyl , 1 0.

Ura cil , 264 , 266 .

Uramil , 263 , 272 .

Urea , 1 1 1 , 1 1 3 .

Urea se , 1 1 5 .

Ureides, 253—263 .

Uretha ne , 1 1 7.

Uric a c id , 27 1 , 274 .

Uro ca nic a cid , 257.

Uro tro pin , 63 .

The Trea tment o f Acute Infectious Disea ses

BY FRANK SHERMAN MEARA, MD .

Pro fesso r o fThera peutics, Co rne l l Med ica l Scho o l

Clot/z, 8720,

A widely known tea cher ha s written this book a long

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ea c/z c/zapter, where the mo st impo rta nt points of thecha pter a re ta bu la ted fo r the use o f the student’s review

a nd for the busy pra ctitioner . In this way proceduresthat necessa rily must be referred to a ga in a nd a ga in willhave sep a ra te considera tion a nd will be referred to inthe individual instances . A ll ma terial is thus imme

dia tely at ha nd without consta nt reference to o thersources or otherp a rts o f the bo ok . The work is un iquein its conception a nd the ma teria l is authorita tive in

every w a y.

THE M ACM ILLAN C O M PANY

Publish ers 64—66 F ifth Avenue New Yo rk

Medica l a ndVeterina ry Entomo logy

BY WILLIAM B . HERMSAsso cia te Pro fesso r o f Pa ra sito logy in the Universi ty o f Ca lifo rnia

Consu l ting Pa ra sito lo g ist fo r the Cal ifo rn ia Sta teBo a rd o f H ea lth , etc.

Clot/z, 871 0, illustra ted,

A work o f interest to physicians , veterina ria ns , hea lthofficers , a nd sa nita rians a s wel l a s to students. Herein i sconta ined a discussion o f a ll the more important insectsa nd arachnids rela ting to disea se a nd irrita tions o f ma n

a nd bea st. The a uthor h a s pla ced specia l empha sis on

control a nd prevention . He ha s aimed to familia rizethe student with the specific p a rasite treated in a cha pter,its identity

,life history

,ha bits

,rela tion to disea se trans

mission o r c a usation ,a nd to indicate methods fo r its

contro l a ndprevention . There a re 2 2 8 i llustrations in thetext, largelymade from o riginal photogra phs o rdrawings .

Ma nua l o fBa cterio logyBY ROBERT MUIR, M .A. , M .D . , (En )

Pro fesso r o f Pa tho lo gy, Un iversity o f G la sgowAND

JAMES RITCHIE, M .A. , M .D . , (En )Superintendent o f the Roya l Co llege o fPhysic ia ns' La bo ra to ry, Edinburgh

Fo rmerly Pro fesso r o f Pa tho logy in the Univers ity o f Oxfo rd

Szx t/z edition . Wif}; one Imndred a nd seventy

four illustra tions in the tex t a nd rzx coloredpla tes.

Clot/z, 736 pp” bz'

blzog. , index , col. l a ma ,

A new edition o f this va lua ble work embodying importa nt recent additions in nearly every department o fbacteriolo gical resea rch . Several new i l lustra tions a nda series o f co lored p lates ha ve a lso been added .

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Publishers 64—66 F ifth Avenue New York

Disea ses o fNutrition a ndInfa nt FeedingBY JO HN LOVETT MORSE , A.M . , M .D .

Pro fesso r o f Pedia trics,H a rva rd Med ica l Scho o l , V isiting Physic ia n

a t the Ch i ldren’

s H ospita l , etc .

FRITZ B. TALBOT, A.B. , M .D .

Instructo r in Ped ia trics, H a rva rd Medica l Scho o l , Chief o f Chi ldren ’

s

Med ica l Depa rtment , M a ssa chusetts Genera l H o spi ta l,etc.

Clot/i, Crown 8720, 340pp, index ,

This impo rta nt new wo rk is based o n the un ique me tho ds o f th e Ped ia tricDepa rtment o f the Ha rva rd Med ica l Scho o l. By these metho ds the food 2:

fittedto Memay a nd not t/ze ba by to til efood, wh i le a ll pro cedures a re presentedfor a definite rea son a nd o n a scientific ba sis. There h a s, up to th e present ,been no bo o k in English presenting in deta il the physio logy o f d igestio n a nd

meta bo l ism in infa ncy — wh ich must fo rm th e ba Sis o f a ll scientific a nd ra tiona linfa nt feed ing a nd no ne describing in deta i l how to feed ba bies a cco rding tothe indica tio ns in the ind ividua l ca se . The a utho rs firs t present the scientificfa cts on which ea ch cond ition is ba sed , a nd then a pply them pra ctica l ly a nd in

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on th is subject.

Lectures on the Nervous a ndChemica lRegula to rs o fMeta bo lism

BY D . NOEL PATON, M .D . , B . Sc .

Pro fesso r o f Physio logy in the Un iversity o f G la sgowClot/z, 2 1 7pp , ozblzog.

, 800,

The ma jo rity o f bo oks thus fa r publ ished on the a cti on o f the ductless glandsa re so technica l , ela bo ra te a nd la rge , th a t they a re o bso lete befo re they ca n betho ro ugh ly studied by th e a vera ge pra ctitio ner. Pa rticula rly time ly

,therefo re ,

is th is monogra ph , wh ich presents the subject in a brief a nd comprehensivema nner , well summa rized a nd no t to o technical . Three fa cto rs a re ch iefly considered: (I) H ered ita ry Inertia o f Inherited Developmental Tendencies2) The Nervo us System ; (3) Th e Chemica l Pro ducts o f Va rio us Orga ns, theso-ca lled Internal Secretio ns.

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