Crystal and Molecular Structure of N,N'-Diethyl-N,N'-Diphenylurea

Proceedings of the National Academy of SciencesVol. 67, No. 1, pp. 426-433, September 1970

Crystal and Molecular Structure ofNN'-Diethyl-NN'-Diphenylurea

P. Ganis,* G. Avitabile,t E. Benedetti,t C. Pedone,4 and M. Goodman

DEPARTMENT OF CHEMISTRY, POLYTECHNIC INSTITUTE OF BROOKLYN,BROOKLYN, NEW YORK 11201

Communicated by H. Mark, July 1, 1970

Abstract. N,N'-diphenyl-N,N'-diethylurea (C,7H20N20) crystallizes in thespace group P21/c. The unit cell constants are: a = 10.42 4 0.01 A, b = 16.864 0.02A, c = 10.66 0.01 A,I = 125016' 4 5'; Z = 4, D_, = 1.16 g cm-3,Dmeas = 1.16 i 0.01 g cm-3. Data for 1392 reflections were collected at roomtemperature on a Picker automated diffractometer. The crystal structure wassolved by direct methods and refined by bloc-diagonalized matrix least-squarescalculations. The molecule is characterized by a pseudo C2 symmetry; bothphenyl groups are trans with respect to the oxygen atom. The hybridizationof the two nitrogen atoms is intermediate between trigonal and tetrahedral; thenonplanar distortion of the amide groups is about 300. The amide C-N bondlengths are 1.37 A.

Nonplanar distortion of the peptide units has been observed in several poly-peptides.1 2 This distortion is quite small in acyclic polypeptide structures(less than 50).1 However, in cyclic polypeptide structures larger deviationsfrom planarity (up to 15') have been found because of the necessity for ringclosure.2 It has been suggested that in cyclic di-, tri-, and tetrapeptides thedeviation from the planarity could be even larger than 25°.3These distortions have been always explained in terms of a torsion about the

peptide bond.4 However, in most cases that have been studied crystallographi-cally, the nitrogen atom of the peptide group is bonded to a hydrogen atom, theposition of which cannot be localized with accuracy by x-ray analysis. It is,therefore, impossible to exclude the idea that other mechanisms can be simul-taneously involved in this kind of distortion. This idea has already been sup-ported by the structural analysis of4-diethylcarbamoyl-1-cyclohexane-5carboxylicacid.5 In this structure the nonplanar distortion of the peptide group is about200. In order to obtain further information about this point, we studied thecrystal structure of N,N'-diphenyl-N,N'-diethylurea. We expected that itsmolecular structure could be described in terms of three resonance structures:

oe oe o

N N - N N@E N N

426

VOL. 67, 1970 CRYSTAL STRUCTURE OF SUBSTITUTED UREA 427

instead of only two as in the case of the compound quoted in ref. 5. As a con-sequence, a decrease of the double-bond character of the peptide bond and anincrease of the pyramidal hybridization of the nitrogen atoms is expected.Methods. Crystals of N,N'-diethyl-N,N'-diphenyl urea were prepared by a

modified Michler synthesist Instead of allowing N-ethylanilinine to react with phosgenein chloroform we employed Schotten-Baumann conditions. The crystals were crystal-lized in the form of needles from aqueous solution. Weisenberg photographs indicate thespace group P21/c, with 4 units of C17H2oN2O per unit cell. A single crystal was mountedon a Picker four-circle automated diffractometer. The unit cell constants were calculatedfrom the accurately determined setting angles of twelve reflections by a least-squaresprocedure. They are given in Table 1. The intensities of 1392 non-zero independentreflections were measured using MoKa radiation.

TABLE 1. Crystal data of N,N'-diethyl-N,.N'-diphenylurea.a = 10.42 i 0.01 A Space group P21/cb = 16.86 i 0.02 X D. = 1.16 g-cm 3C = 10.66 i 0.01 X Dmoas = 1.16 i 0.01 g-cm-3= 125°16' i 5' Z = 4

V = 1529.3 A3

Structure determination: A preliminary packing model was determined by directmethods. The signs of 27 reflections were obtained by the procedure of Allegra andValle;7,8 the signs of further 202 reflections were derived by means of a program perform-ing a symbolic addition. The structure factor calculation for this model yielded a dis-crepancy factor:

R -I I ~c 0.48E IFoI -The model was refined first by the Fourier method and then by the bloc-diagonalizedmatrix least-square program of Immirzi.9 Unit weights were assigned to all the reflec-tions. The R value dropped to 0.134 with isotropic thermal factors. At this stage aniso-tropic thermal factors were introduced and the hydrogen atoms were included with iso-tropic thermal factors. The final R value of 0.067 is thus obtained.The ultimate position parameters are given in Table 2 and the thermal parameters in

Table 3 (see footnote§).Results and Discussion. The relevant internal coordinates of the molecule

are reported in Fig. 1 and in Table 4. The molecule is characterized by apseudo C2 symmetry.Both phenyl groups are trans with respect to the oxygen atom; for this con-

formation the nonbonded interactions between phenyl groups can be relaxedboth through a rotation of the phenyl group around the bonds Cl-N and Cl'-N'and through a displacement of the bonds Cl-N and Cl'-N' out of the plane ofthe amide group in opposite directions. In fact, the dihedral angles between theplanes C2-Cl-N and Cl-N-C, and C2'-Cl'-N and Cl'N-C are -48° and+ 48°, respectively. The shortest intramolecular distance between atoms ofthe phenyl group is 2.88 A. On the other hand the bonds C7-N and C7'-N'lie almost in the plane N-C-N' (the torsion angles C7-N-C-N' and N-C-N'-C7' are + 1750 and - 1750, respectively). The nonplanar distortion of thesystems

428 CHEMISTRY: GANIS ET AL. PROC. N. A. S.

C7 0 0 C7'

N-C and C-N'/ \ / \

C1 N' N C1'

TABLE 2. Positional parameters.(x) X (y) X ¢(z)X

x/a y/b 2/c 104 104 104 x/a y/b 2/cC1 0.5694 0.0736 0.2886 5 3 6 H2 0.472 0.070 0.419C2 0.4709 0.0966 0.3288 6 3 6 H3 0.289 0.179 0.273C3 0.3778 0.1630 0.2608 6 4 7 H4 0.304 0.252 0.096C4 0.3800 0.2055 0.1506 6 4 8 H5 0.484 0.209 0.033C5 0.4784 0.1801 0.1092 7 4 7 H6 0.663 0.095 0.167C6 0.5730 0.1149 0.1781 6 3 6 H2' 0.971 0.078 0.487C1' 0.8547 0.1224 0.5738 5 3 5 H3' 0.048 0.190 0.456C2' 0.9394 0.1252 0.5120 6 3 6 H4' 0.987 0.316 0.515C3' 0.9845 0.1999 0.4886 6 4 6 H5' 0.847 0.309 0.633C4' 0.9504 0.2670 0.5322 8 4 8 H6' 0.734 0.190 0.653C5' 0.8687 0.2641 0.5955 8 4 7 H7A 0.703 -0.106 0.295C6' 0.8181 0.1918 0.6183 6 3 6 H7B 0.596 -0.047 0.156C7 0.6080 -0.0663 0.2481 6 3 6 H8A 0.415 -0.145 0.136C8 0.4570 -0.1011 0.2116 7 4 7 H8B 0.370 -0.063 0.172C7' 0.9009 0.0284 0.7738 7 4 6 H8C 0.462 -0.113 0.303C8' 0.0724 0.0132 0.8459 8 5 7 H7A' 0.842 -0.023 0.782C 0.7516 -0.0152 0.5058 6 3 6 H7B' 0.871 0.071 0.822N1 0.6623 0.0023 0.3317 4 2 4 H8A' 0.129 0.007 0.947N1' 0.8155 0.0476 0.6087 4 2 4 H8B' 0.118 0.064 0.8270 0.7769 -0.0830 0.5532 4 2 4 H8C' 0.080 -0.032 0.792

appear to be accomplished not only through a rotation around the amide bondsC-N and C-N', but also through a displacement of C1 and Cl' out of the planesC7-N-C and C-N'-C7'. As a consequence the coordination of the nitrogenatoms is pyramidal, with a hybridization intermediate between trigonal andtetrahedral. The bond length N-C (1.37 4 0.02 A) is greater than the usualvalue for an amide bond in a planar system (1.32 A).10 However, substantialdouble-bond character both for N-C and N'-C appears to be retained (the nor-mal length for a C-N single bond adjacent to a double bond is 1.45 A)." In4-diethylcarbamoyl-1-cyclohexane-5-carboxylic acid,5 the length of the peptidebond is 1.34 A. This result is in agreement with the resonance picture presentedin our introduction.As noted above, similar nonplanar distortions have been observed in several

cyclo-oligopeptides.2 They were justified because of the cyclic nature of thecompounds and explained only in terms of rotations about the amide bonds.In our structure, intramolecular nonbonded interactions are responsible fordeviation from amide planarity. Because of the presence of two carbon sub-stituents on the nitrogen atoms, it is possible to emphasize that the torsion aroundthe amide bond is not the only manner to achieve nonplanar distortion of theamide group.The methyl groups C8 and C8' are as far as possible from the phenyl groups and

from the oxygen atom (CH3. ..0 = 3.23-3.28 A; CH3....CH = 3.56-3.57 ).This fact is accomplished through dihedral angles between the planes C8-C7-Nand C7-N-C, C-N'-C7' and N'-C7'-C8' of +86 and -890, respectively.

H O

eq cq- CO N. M vC. f. N V

cq cq CID c cq cq cq cq cq c4 cN cN c VD cN cm ----P.55 5d 05555,ooooooo

mS 0:: : OO:::O;c

b

"N~lflC~ ff ffl> N ~l C CtC;l C; C C;N I 1

b

cqi c cq cq cm cN cqi cqi~cq m cmcmeq m~ c c iN N 4

SIe~~~ c~~1 c~~ c~ c ~ C C.1c; c C;i C .)b

O C) O O C) C) C' OC; OOO0° 0000 0 0C0 0 000l 0r- 00co 00 00 0N X0 mes m

en . . 4. . . . . . . . . . . .cqC.1cq 1 eq eqcq cq e eq c e eecq eNem

00m >00 q00eq00000c_ -00004co00 _ q000q

Ca 0 f 0 Co 4 4co cc CO t_. 0 q ClI I I I I I

0m eN N _ M_ -I N N N N N N N CO M Ct 00

. .. .4 . . . . . .6 . . . .6 . . .

mmm C6 M, M, M, 11

Co C55oo O otov4 _1Cq r_4

IOIIS**I

SI

W -NC N _ O -l OOC CvX e OC

-eqeq** * * * * . . . . . . . . . .OOOOOOOQQQOOOOO0 £+ < C OOZtCDo

H

430 CHEMISTRY: GANIS ET AL. Pnoc. N. A. S.

0

u8C 8'

ite 117~~~~121115.5"~~~~~~~~~~~~~~~I.

122.2 1 07'2'.2

il302-l--1 8 C2! C' -fC48

C81 7N-8060'C7Ni .690

C55

FIG1.MoecuargeoetyC oNN'C-dehNN'-d31 pheNylurea Th2ot8 motatcn

A similar conformation of the ethyl groups was found inT4-diethylcarbamoyl-1-cyclohexane-5-carboxylic acid; however, it deviates from the conformationalminima around the N-C bond as proposed by Brant and Flory.12 The otherinternal parameters are quite normal.


TABLE 4. Conformational parameters of the structural unit.Bond lengths A a(A) Bond angles 0 a(°)C-O 1.217 0.006 N1-C-N1' 117.8 0.2C-N1 1.374 0.008 N1-C-O 122.2 0.3C-N1' 1.385 0.007 N1'-C-O 120.0 0.3Ni-Cl 1.443 0.007 C-Ni-Cl 123.0 0.2Cl-C2 1.377 0.009 C-N1-C7 115.5 (1.2C2-C3 1.381 0.009 C1-N1-C7 116.2 0.2C3-C4 1.388 0.010 C-N1'-C1' 122.9 0.2C4-C5 1.398 0.011 C-N1'-C7' 117.3 0.2C5-C6 1.371 0.010 C1'-N1'-C7' 115.7 0.2C6-Cl 1.387 0.009 N1-C1-C2 120.7 0.3N1-C7 1.469 0.007 Nl-Cl-C6 118.3 0.3C7-C8 1.505 0.011 C6-C1-C2 120.8 0.3Nl'-C1' 1.440 0.007 Cl-C2-C3 119.3 0.3C1'-C2' 1.375 0.009 C2-C3-C4 120.9 0.3C2'-C3' 1.414 0.008 C3-C4-C5 118.9 0.3C3'-C4' 1.347 0.009 C4-C5-C6 120.5 0.3C4'-C5' 1.359 0.012 C5-C6-Cl 119.6 0.3C5'-C6' 1.404 0.009 N1-C7-C8 113.2 0.3C6'-Cl' 1.395 0.008 Nl'-C1'-C2' 120.7 0.3N1'-C7' 1.479 0.009 N1'-C1'-C6' 118.2 0.2C7'-C8' 1.506 0.013 C6'-Cl'-C2' 120.8 0.3

Cl'-C2'-C3' 119.1 0.3Dihedral angles 0 C2'-C3'-C4' 120.4 0.3

Nl'-C-N1 A C-Ni-Cl 31 C3'-C4'-C5' 120.5 0.4C-Ni-Cl A N1-Cl-C2 49 C4'-C5'-C6' 121.5 0.3Ni-C-Ni' A C-N1'-C1' 28 C5'-C6'-C1' 117.7 0.3C-N1'-Cl' A N1'-C1'-C2' 48 Nl'-C7'-C8' 111.5 0.3Nl'-C-N1 A C-N1-C7 175C-N1-C7 l" N1-C7-C8 86Ni-C-N1' A C-N1'-C7' 175C-N1'-C7' A N1'-C7'-C8' 90

0

FIo. 2. Projection of the packing on 010. The shortest intermolecular contactdistances are reported.

432 CHEMISTRY: GANIS ET AL. PROC. N. A. S.

b~~~~'tam

a + C

FIG. 3. Packing of molecules of NN'-diethyl-NN'-diphenylurea in the planes 101.

In Fig. 2 the projection of the structure on 010 is reported. The moleculeslie almost in the planes 101. The shortest intermolecular distances betweenthese planes are reported in Fig. 2. The packing in the planes 101 is shown inFig. 3. We are at present extending our work in this area by examining thespectroscopic characteristics (nmr, ir, and uv) of the substituted urea andrelated compounds.The authors wish warmly to thank Dr. Giuseppe Allegra for his guidance and comments

with respect to this research. We want also to acknowledge the financial support of theNational Institutes of Health through grant GM08974.

* Visiting professor at Polytechnic Institute of Brooklyn, 1969-1970.t Postdoctoral fellow on leave from Universita di Napoli, Istituto Chimico, Via Mezzocan-

none 4, 80134 Napoli (Italy).X Universita di Napoli, Istituto Chimico, Via Mezzocannone 4, 80134 Napoli (Italy).§ A list of the observed and calculated structure factors has been deposited as Document No.

NAPS 01086 with the ASIS National Auxiliary Publication Service, c/o CCM InformationCorporation, 22 West 34th St., New York, N.Y. 10001. A copy may be secured by citing thedocument number and remitting $2.00 for microfiche or $5.00 for photocopies to ASIS-NAPSby check or money order.

1 Lakshminarayarian, A. V., Conformation of Biological Macromolecules, Vol. I, Conforma-tion of Amino Acids, ed. G. N. Ramachandran (Plenum Press: New York) 1970.


2 Zalkin, A., J. D. Forrester, and D. H. Templeton, J. Amer. Chem. Soc., 88, 1810 (1966).3Ramachandran, G. N., Biopolymers, 6 (10), 1494 (1968).4Ramachandran, G. N., and V. Sasisekharan, Advan. Protein Chem., 23, 283 (1968).6 Pedone, C., E. Benedetti, A. Immirzi, and G. Allegra, J. Amer. Chem. Soc., in press.6Michler, W., Chem. Ber., 9, 399 (1870); and Chem. Ber., 9, 712 (1876).7Allegra, G., Ada Crystallog., 19, 949 (1965).8 Allegra, G., and S. Valle, Ada Cryst., B25, 107 (1969).9 Immirzi, A., Ric. Sci., 37, 743, 846, 850 (1967).10 Pauling, L., The Nature of the Chenical Bond, 3rd ed. (Cornell University Press: Ithaca,

New York, 1960), p. 281.11lnteratomic Distances and Configuration in Molecules and lons, Special Publ. 77, London:

The Chemical Soc. (1958).12 Brant, D. E., and P. J. Flory, J. Amer. Chem. Soc., 87, 2791 (1965).

772 Biochemistry: Schlessinger and Steinberg

of chromophores, both intrinsic and extrinsic, in a varietyof systems of biological interest.

1. Edelman, G. M. & McClure, W. 0. (1969) Accounts Chem.Res. 1, 65-70.

2. Stryer, L. (1968) Science 162, 526-533.3. Weber, G. (1953) Advan. Protein Chem., 8, 415-459.4. Yguerabide, J., Epstein, H. F. & Stryer, L. (1970) J. Mol.

Biol. 51, 573-590.5. Weller, A. (1961) Progr. React. Kinet. 1, 187-214.6. van Duuren, B. L. (1963) Chem. Rev., 63, 325-354.7. Condon, E. U., Alter, W. & Eyring, H. (1937) J. Chem. Phys.

5,753-775.

Correction: In the article "Crystal and Molecular Struc-ture of N,N'-Diethyl-N,N'-Diphenylurea", by Ganis, P.,Avitabile, G., Benedetti, E., Pedone, C. & Goodman, M.,which appeared in the September 1970 issue of Proc. Nat.Acad. Sci. USA 67, 426-433, the following correctionshould be made in Table 2, p. 428: The z coordinate ofatom N1 is 0.3517, not 0.3317.

8. Emies, C. A. & Oosterhoff, L. J. (1971) J. Chem. Phys. 54,4809-4819.

9. Haugland, R. P. & Stryer, L. (1967) Conformation of Bio-polymers, ed. Ramachandran, G. N. (Academic Press,New York), Vol. 1, pp. 321-335.

10. McClure, W. 0. & Edelman, G. M. (1967) Biochemistry 6,559-566.

11. Steinberg, I. Z., Patent Application no. 36297, Israel.12. Steinberg, I. Z. & Gafni, A., Rev. Sci. Instrum., in press.13. Kuhn, W. (1930) Trans. Faraday Soc. 26, 293-308.14. Gafni, A. & Steinberg, I. Z. (1972) Photochem. Photobiol. 15,

93-96.15. McClure, W. 0. & Edelman, G. M. (1966) Biochemistry 5,

1908-1919.

made. The last line of the legend to Table 4, p. 2347,should read: "the nuclear fraction of 6.3 X 107 infectedcells was used for each hybridization." In Table 6, p. 2349,the right-center column head should read" "% Total cellu-lar radioactivity."

Correction. In the article "DNA and Gene Therapy: Trans-fer of Mouse DNA to Human and Mouse Embryonic Cellsby Polyoma Pseudovirions," by Qasba, P. K. & Aposhian,H. V., which appeared in the October 1971 issue of Proc.Nat. Acad. Sci. USA 68, 2345-2349, several correctionsshould be made. On p. 2345, column 2, line 10 (from thetop) should read: "10-40% sucrose gradient, contain-ing. . .," not "10-20%....." Due to editorial errors made inthe PROCEEDINGS office, the following corrections should be

Correction. In the article "Regulation of the NucleolarDNA-Dependent RNA Polymerase by Amino Acids inEhrlich Ascites Tumor Cells", by Franze-FernAndez,M. T. & Pogo, A. O., which appeared in the December 1971issue of Proc. Nat. Acad. Sci. USA 68, 3040-3044, thefollowing corrections should be made. In the legend toTable 1, p. 3042, reference "(18)" should read "(13)". Onp. 3043, eleven lines from the bottom, right-hand column,the sentence beginning "Assumptions b and c suggest"should read "Assumptions a and b suggest".

Proc. Nat. Acad. Sci. USA 68 (1972)

Crystal and Molecular Structure of N,N'-Diethyl-N,N'-Diphenylurea

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