Amina
Senyawa Organik Basa
Kelompok Amin
Berdasarkan jumlah alkil/aril yang terikat dengan atom N :
1º ( amina primer ) RNH2
2º (amina sekunder ) R2NH
3º (amina tersier ) R3N
4º (Garam amina kuartener ) R4N+
Penamaan amina sederhana
Amina primer sederhanan “alkilamina” Contoh :
metillamina CH3NH2
etilamin CH3CH2NH2
butilamin CH3CH2CH2CH2NH2
Amina 2º atau 3º simetris “dialkilamina” atau “trialkiamina” Contoh:
dietilamina (CH3CH2)2NH; trimetilamina (CH3)3N
Penamaan amina lebih lanjut Amina dengan lebih dari satu jenis gugus alkil
dinamai N-subtituen amina primer . Rantai alkil terpanjang menentukan nama dasar .
Contoh N-methylpropylamine CH3NHCH2CH2CH3
N,N-dimethylethylamine (CH3)2NCH2CH3
Penamaan lebih lanjut
Amina yang mempunyai lebih dari satu gugus fungsi menggunakan namanya “amino” sebagai substituen pada molekul induknya
Prioritas N paling rendah dibandingkan dengan gugus fungsi lainnya : amina < etanol, maka N-amino----
Examples: 2-aminoethanol H2NCH2CH2OH
4-aminobutanoic acid H2NCH2CH2CH2CO2H
Amina Heterosiklik
Amina yang unsur N merupakan bagian dari penyusun cincin . Penamaannya tidak sistemantik (non-systematic),
NH2
N N
N
N
H
N
N
H
N
H
N
N
HN
aniline pyridine pyrimidine pyrrole
quinoline indole imidazole benzimidazole
Struktur amines
Amina mempunyai sp3 hybridized nitrogen In principle, tertiary amines with three different R
groups should be chiral (i.e., have a stereocenter). However, rapid pyramidal inversion of the amine
nitrogen prevents isolation of the enantiomers except where the nitrogen is part of a ring or has other geometrical constraint.
N
YZ
X
N
YZ
Xfast
Properties of amines
Amines are moderately polar and are capable of hydrogen bonding.
Low MW amines (up to about C5) are soluble in water; higher MW amines will dissolve in acidic solution (as their conjugate acid).
Many amines have foul odors. Amines are weak bases.
Contoh amina biologically active
H2NCH2CH2CH2CH2NH2 putrescine H2NCH2CH2CH2CH2CH2NH2 cadaverine
H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2 s permidineH
H2N(CH2)N(CH2)4N(CH2)3NH2 s permineH H
NHCH3
OHH
HO
HO
epinephrine(adrenaline)
NH2
OHH
HO
HO
norepinephrine(noradrenaline)
NH2HO
HO
dopamine
Lanjut …
NH2
CH3H
amphetamine(benzadrine)
N
CH2CH2NH2
HO
H
NHCH3
CH3H
methamphetamine (speed)
serotonin
mescaline
NH2CH3O
CH3O
OCH3
N
CO2H
nicotinic acid(niacin)
NN
CH2CH2NH2
H
histamine
Lanjut-----
H2N C OCH2CH3
O
benzocaine(a topical anesthetic)
Cl
N
N
H
O
O
diazepam (Valium)
N
N
O
NN
CH3
CH2CH2CH3
H
SOO
N
NCH3
CH3CH2O
Sildenafil (Viagra)
Lanjut-----
R'O
O
RO
NCH3
codeine (R = CH3, R' = H)morphine (R and R' = H)heroin (R and R' = COCH3)
mepiridine(Demerol)
N
N
N
N
O
O
CH3
H3CCH3
caffeine
N
N
CH3
H
nicotine
NH3C
C
O
HO
C
O
H
OCH3
cocaine
NCH3C
O
CH3CH2O
Methadone
C6H5 NCH3C
O
CH3CH2
CH3
CH3
Lanjut -----
N
HO
H N
H
H
quinineN
O
N
O
H
H
strychnine
N
NH
C
O
(CH3CH2)2NCH3
lysergic acid diethylamide (LSD)
N
H
CH2CH2CH3
H
coniin (the poison from hemlock used to kill Socrates)
Kebassan amina
Amin sedikit basa, karena mempunyai pasangan elektron bebas dapat mendonorkan ke proton, bersifat nucleophiles.
Amina mempunyai nilai Kb = 10-3 to 10-4
RNH2 + H OH RNH3 + O H
Kb = [RNH3 ] [OH ]
[RNH2]
Kebasaan amina -------
Biasa digunakan nilai Ka asam konjugat amina Asam konjugat lebih lemah, lebih basa (amina) Amina sejenis mempunyai Ka values (conjugate
acids) dari 10-10sampai 10-11 (nilai pKa 10 sampai 11.)
RNH3 RNH2 + H Ka = [RNH3 ]
[RNH2] [H ]
Nilai pKa asam konjugat amina
CH3NH2 10.7
CH3CH2NH2 10.8
(CH3)2NH 10.7
(CH3CH2)2NH 10.5
(CH3)3N 9.8
(CH3CH2)3N 11.0
pKa = 14 – pKb atau pKb = 14 - pKa
Semua nya mempunyai nilai yang sama .
Efek substituen sama menstabilkan karbokation, maka .
Gugus pelepas elektron (alkil) , pada nitrogen menaikkan kebasaan
N nya lebih banyak mengikat substituen gugs alkil nilai pKa lebih rendah (kurang asam atau lebih basa)
Kebasaan amina
1. Jika amina bebas terstabilkan terhadap kationnya, maka amina merupakan basa yang lebih lemah
2. Jika kation itu relatf terstabilkan terhadap amina bebasnya , maka aminanya basa lebih kuat
Amina basanya lemah
(conj. acid)
Anilin basa lemah karena adanya delokalisasi elektron melalui resonansi
Pyridine is weaker because it is an imine (C=N). Pyrrole is much weaker because the lp of electrons is
delocalized with the other electrons to make 6 e-. Therefore, the lp is unavailable to act as a base.
aniline pyridine pyrrole pKa = 4.6 5.2 0.4
NH2
NN
H
Efek Substituent pada kebasaan anilin
Resonance stabilizes free base, destabilizes its protonated form (see next slide)
2 Penjelasan mengenai kebasaan :
NH2 NH2
OCH3
NH2
NO2pKa of conj. acid: 5.3 1.04.6
(much weaker base)
NH2
NO2
NH2
NOO
NH2
NOO
NH2
NOO
NH3
NO2
Pengaruh Substituent pada kebassan Anilin
NH3
NH3CH3O
NH3O2N
Reaction progress (protonation)
Energy
Amina yang tingkat kebasan lebih kuat Hanya satu jenis amine : basanya lebih kuat
Basa guanidin Guanidine basa kuat karena asam konjugatnya terstabilkan melalui resonansi
guanidine pKa = 13.6(conj. acid)
A guanidine group is part of the structure of the amino acid arginine.
NH
CH2N NH2
NH2
CH2N NH2
NH2
CH2N NH2
NH2
CH2N NH2
NH2
CH2N NH2
Amina terprotonasi pada pH Physiological
Persamaan Henderson-Hasselbalch :
Consider the neurotransmitter dopamine, a typical amine (having a pKa of its conjugate acid = 10.6) in a living cell (buffered at pH = 7.3):
That is, the concentration of the protonated amine is 2000x that of the neutral amine! Typical amines are >99.9% protonated at physiological pH.
pH = pKa + log [RNH2]
[RNH3+]
7.3 = 10.6 + log [RNH2]
[RNH3+]
log [RNH2]
[RNH3+]
-3.3 =
[RNH2]
[RNH3+]
2 x 103 =
;
;[RNH2]
[RNH3+]
5 x 10- 4 =
Sintesis Amina
Sintesis amina, melalui :
reaksi Substitusi, reaksi reduksi dan penataan ulang
a. Substitusi Nu :
SN2 OH-
a. RX + NH3 RNH3+ X- RNH2
b. Reduksi
c. Penataan ulang amida :
Chapter 19 24
Electrophilic Substitution of Aniline
-NH2 is strong activator, o-,p-directing. May trisubstitute with excess reagent. H+ changes -NH2 to -NH3
+, a meta-directing deactivator.
Attempt to nitrate aniline may explode.
=>
Chapter 19 25
Aniline Substitution
=>
Chapter 19 26
Electrophilic Substitution of Pyridine
Strongly deactivated by electronegative N. Substitutes in the 3-position. Electrons on N react with electrophile.
N
fuming H2SO4
HgSO4, 230oC
N
SO3H
=>
Chapter 19 27
Nucleophilic Substitutionof Pyridine
Deactivated toward electrophilic attack. Activated toward nucleophilic attack. Nucleophile will replace a good leaving
group in the 2- or 4-position.
N Cl
OCH3
_
N OCH3
+ Cl_
=>
Chapter 19 28
Alkylation of Amines Amines react with 1 alkyl halides via the SN2
mechanism. Mixtures of the mono-, di-, and tri-alkylated
products are obtained.
=>
Chapter 19 29
Useful Alkylations Exhaustive alkylation to form the
tetraalkylammonium salt.
CH3CH2CHCH2CH2CH3
N(CH3)3
CH3CH2CHCH2CH2CH3
NH23 CH3I
NaHCO3
+ _I
• Reaction with large excess of NH3 to form the primary amine.
CH3CH2CH2BrNH3 (xs)
CH3CH2CH2NH2 + NH4Br
=>
Chapter 19 30
Acylation of Aminesby Acid Chlorides
Amine attacks C=O, chloride ion leaves. Product is amide, neutral, not basic. Useful for decreasing activity of aniline toward
electrophilic aromatic substitution.
NH2
CH3 C
O
Cl
NH
C
O
CH3
N
to remove HCl
=>
Chapter 19 31
Formation of Sulfonamides Primary or secondary amines react with
sulfonyl chloride.
R NH2 S
O
O
R' Cl S
O
O
R' NH R
H
+Cl
_base S
O
O
R' NH R
• Sulfa drugs are sulfonamides that are antibacterial agents.
NH2
S OO
NH2
=>
Chapter 19 32
Oxidation of Amines Amines are easily oxidized, even in air. Common oxidizing agents: H2O2 , MCPBA. 2 Amines oxidize to hydroxylamine (-NOH) 3 Amines oxidize to amine oxide (-N+-O-)
=>
Chapter 19 33
Nitrous Acid Reagent
Nitrous acid is produced in situ by mixing sodium nitrite with HCl.
The nitrous acid is protonated, loses water to form the nitrosonium ion.
H O N OH
+
H O N O
H
+H2O + N O
+N O
+
=>
Chapter 19 34
Reaction with Nitrous Acid
1 Amines form diazonium salts, R-N+N. Alkyldiazonium salts are unstable, but
arenediazonium salts are widely used for synthesis.
2 Amines form N-nitrosoamines, R2N-N=O, found to cause cancer in laboratory animals.
=>
Chapter 19 35
Arenediazonium Salts Stable in solution at 0°–10°C. The -+NN group is easily replaced by
many different groups. Nitrogen gas, N2, is a by-product.
HBF4 (KI)
H3O+
CuCl (Br)
CuCN
H3PO2
H Ar'
Ar N N+
Ar OH
Ar Cl
Ar C N
Ar F
Ar H
Ar N N Ar'
(Br)
(I)
phenolsaryl halides
benzonitriles
aryl halides
benzene
azo dyes =>
Chapter 19 36
Synthesis by Reductive Amination To produce a 1 amine, react an aldehyde
or ketone with hydroxylamine, then reduce the oxime.
To produce a 2 amine, react an aldehyde or ketone with a 1 amine, then reduce the imine.
To produce a 3 amine, react an aldehyde or ketone with a 2 amine, then reduce the imine salt. =>
Chapter 19 37
Examples
primary amine
CH3CH2CH2 CH
NH2
CH3NiH2CH3CH2CH2 C
N
CH3
OH
H+
NH2 OHCH3CH2CH2 C
O
CH3
secondary amine
CH3 CH
NHCH3
CH32)
1)
H2O
LiAlH4CH3 C
NCH3
CH3H+
CH3NH2CH3 C
O
CH3
tertiary amine=>
C
N
H
CH3H3C
HNa(CH3COO)3BHC
N
H
CH3H3C+
H+
HN(CH3)2C
O
HCH3COOH
Chapter 19 38
Acylation-Reduction
An acid chloride reacts with ammonia or a 1 amine or a 2 amine to form an amide.
The C=O of the amide is reduced to CH2 with lithium aluminum hydride.
Ammonia yields a 1 amine. A 1 amine yields a 2 amine. A 2 amine yields a 3 amine.
=>
Chapter 19 39
Examples
CH3 C
O
ClNH3
CH3 C
O
NH2
LiAlH4
H2O
1)
2)CH3 CH2 NH2
primary amine
LiAlH4
H2O
1)
2)C
O
ClHN(CH3)2
C
O
N(CH3)2CH2 N(CH3)2
tertiary amine =>
Chapter 19 40
Direct Alkylation (1)
Use a large excess (10:1) of ammonia with a primary alkyl halide or tosylate.
Reaction mechanism is SN2.
CH3CH2CH2 BrNH3
+CH3CH2CH2 NH2 NH4Br
=>
Chapter 19 41
Azide Reduction (1)
Azide ion, N3-, is a good nucleophile.
React azide with unhindered 1 or 2 halide or tosylate (SN2).
Alkyl azides are explosive! Do not isolate.
Br
NaN3
N3LiAlH4
H2O
1)
2)
NH2
=>
Chapter 19 42
Nitrile Reduction (1)
Nitrile, -CN, is a good SN2 nucleophile.
Reduction with H2 or LiAlH4 adds -CH2NH2.
Br
NaCN
CNLiAlH4
H2O
1)
2)
CH2NH2
=>
Chapter 19 43
Reduction of Nitro Compounds (1) -NO2 is reduced to -NH2 by catalytic
hydrogenation, or active metal with acid. Commonly used to synthesize anilines.
CH3
NO2
Zn, HCl
CH3CH2OH
CH3
NH2
=>
Chapter 19 44
Hofmann Rearrangement of Amides (1)
In the presence of a strong base, primary amides react with chlorine or bromine to form amines with one less C.
C
O
NH2H2O
Br2, OH_
NH2
=>
Chapter 19 45
Gabriel Synthesis (1) Use the phthalimide anion as a form of
ammonia that can only alkylate once. React the anion with a good SN2
substrate, then heat with hydrazine.
+N
O
O_
R XN
O
O
R H2N NH2heat
NH
NH
O
O
R NH2
=>
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