Crystal Structures of N-Aryl-Nâ²-4-Nitrophenyl Ureas: Molecular

Crystal Structures of N-Aryl-N′-4-Nitrophenyl Ureas: Molecular Conformation and Weak Interactions Direct the Strong Hydrogen Bond Synthon L. Sreenivas Reddy, Sreekanth K. Chandran, Sumod George, N. Jagadeesh Babu, and Ashwini Nangia*

CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 12 2675–2690

School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India ReceiVed February 13, 2007; ReVised Manuscript ReceiVed August 28, 2007

ABSTRACT: Hydrogen bond competition was studied in 21 X-ray crystal structures of N-X-phenyl-N′-p-nitrophenyl urea compounds (X ) H, F, Cl, Br, I, CN, C≡CH, CONH2, COCH3, OH, Me). These structures are classified into two families depending on the hydrogen bond pattern: urea tape structures contain the well-known R-network assembled via N-H · · · O hydrogen bonds; however, in nonurea tape structures the N–H donors hydrogen bond with NO2 groups or solvent O acceptor atoms. Surprisingly, the urea CdO hardly accepts strong H bonds in nonurea type structures sustained by urea · · · nitro and urea · · · solvent synthons. The carbonyl group accepts intra- and intermolecular C-H · · · O interactions. The molecular conformation and H bonding motifs are different in the two categories of structures: the phenyl rings are twisted out of the urea plane in the tape motif, but they are coplanar in the nonurea category. Even though hydrogen bond synthon energy and urea carbonyl acceptor strength favor the N-H · · · O tape structure, the dominant pattern in electron-withdrawing aryl urea crystal structures is the urea · · · nitro/urea · · · solvent synthon and persistence of intramolecular C-H · · · O interactions. Remarkably, the presence of functional groups that can promote specific C-I · · · O or C-H · · · O interactions with the interfering NO2 group, for example, when X ) I, C≡CH, NMe2, and Me, steers crystallization toward the N-H · · · O urea tape structure, and now the diaryl urea molecule adopts the metastable, twisted conformation. Molecular conformer energy calculations and difference nuclear Overhauser enhancement NMR experiments show that the planar, trans-transN,N′-diphenyl urea conformation is more stable than the N-Ph twisted rotamer. However, the urea CdO is a better hydrogen bond acceptor in the twisted conformer compared to the planar one, based on electrostatic surface potential (ESP) charges. These diaryl ureas together with previously reported crystal structures provide a global structural model to understand how functional groups, molecular conformation, hydrogen bonding, and crystal packing are closely related and influence each other in subtle yet definitive ways. Our strategy simultaneously exploits weak, soft intermolecular interactions and strong, hard hydrogen bonds [supramolecular hard and soft acid-base (HSAB) principle] in the crystal engineering of multifunctional molecules. Introduction The design of new structures and materials of small to large molecular mass and with tailored physical and chemical properties is of current interest in chemistry, biology, and materials science.1 A reliable method for the design of supramolecular assemblies is to use intermolecular interactions, notably, hydrogen bonding,2 halogen bonding,3 metal–ligand bonding,4 and π-stacking,5 to guide the molecules into ordered mesoscale aggregates. Since intermolecular interactions arise from molecular functionalities, it is important to identify common hydrogen bond patterns, or supramolecular synthons,6 in crystal structures for predictable design and synthetic planning. With an enhanced knowledge of hydrogen bond synthons in crystals, rational strategies may be planned for the construction of target supramolecular architectures. A major challenge that still remains to be tackled in the crystal engineering of multifunctional molecules is to know a priori how the individual functional groups will interact when several of them are simultaneously competing with each other.7 It is therefore important to understand self-assembly in the “real” competitive milieu to understand hydrogen bonding preferences in complex chemical systems. Not only the nature of the functional groups but also their placement in the molecule, for example, regioisomeric compounds, change the intermolecular interactions or synthons in crystal structures.8 Etter9 published hydrogen bonding rules that were expected to apply in the organic crystal chemistry of molecules containing * Fax: +91 40 2301 1338. E-mail: [email protected].

N-H donors and CdO acceptors. (1) All good proton donors and acceptors are used in hydrogen bonding. (2) Six-memberring intramolecular hydrogen bonds form in preference to intermolecular hydrogen bonds. (3) The best proton donors and acceptors remaining after intramolecular hydrogen-bond formation form intermolecular hydrogen bonds to one another. The third rule deals with ranking hydrogen-bond donors and acceptors based on strength: the strongest donor interacts with the strongest acceptor, the second best donor bonds to the second best acceptor, and so on. This paper deals with understanding hydrogen-bond capability of urea NH donors and CdO acceptors in substituted N,N′-diphenyl ureas. Is the change in donor/ acceptor strength inherent to the functional group, or is it due to a remote substitution group, or a particular conformation? What is the role of weak C-H · · · O interactions in attenuating the strength of strong CdO acceptor? Is crystal packing in electron-withdrawing diaryl ureas different from those substituted with electron-donating or neutral groups? The hierarchic model of hydrogen bonding has been exploited to generate multicomponent assemblies containing acid, pyridine, and amide functional groups. Thus, strong acid · · · pyridine, moderate acid · · · amide, and amide · · · amide synthons are persistent hydrogen-bond motifs in cocrystal structures.10 However, a limitation with several recently reported systems is that they highlight tailored molecules in which synthon recognition is optimized2,3,10 instead of analyzing crystal structures that will challenge competition between hydrogen bond donors/acceptors of similar strength.7,8 The latter situation is important because in reality there may be shades of differences among similar

10.1021/cg070155j CCC: $37.00  2007 American Chemical Society Published on Web 12/05/2007

2676 Crystal Growth & Design, Vol. 7, No. 12, 2007 Scheme 1. Chemical Structures of Symmetrical Diaryl Ureas Reported Previously (1–4) and Unsymmetrical Diaryl Urea Derivatives 5 Discussed in This Papera

Reddy et al.

structures of N,N′-bis(m-pyridyl)urea 4 because of the C-H · · · O stabilized planar conformation in the electron-deficient metapyridyl ring (Scheme 2).18 Soon thereafter, Steed pointed out the persistence of intramolecular C-H · · · O interactions in pyridyl ureas.19 Results

a

C-H · · · O interactions stabilize the planar conformation of 1 and 4.

acceptors even in relatively simple molecules, leading to the occurrence of polymorphism.11 We examine hydrogen bond competition between urea, nitro, and X groups (halogen, ethynyl, alkyl, cyano, OH, CONH2) together with the solvent component (DMF, DMSO) in some substituted N,N′-diphenyl ureas. Our objective was to analyze the result of competition between different functional groups and solvents during crystallization. Surprisingly, we find that even though urea · · · urea hydrogen bonding is traditionally the strongest and dominant motif of the urea functional group,12 urea · · · NO2 and urea · · · solvent hydrogen bonding frequently win over the N-H · · · O tape structures in nitro-Ph-urea-Ph-X compounds 5 (Scheme 1). The urea tape synthon could be engineered only by engaging the interfering NO2 group in weak C-H · · · Onitro or C-I · · · Onitro interactions.13 Molecular and synthon energy calculations show that the stable, planar trans-trans-N,N′-diphenyl urea conformation is present in the metastable nonurea synthon, whereas a metastable, twisted rotamer is required to assemble the stable urea tape synthon. Diaryl ureas 5 and their solvates are classified into two broad categories of crystal structures depending on the molecular conformation, hydrogen bonding, and crystal packing, namely, nonurea tape and urea tape structures. The organic urea structural chemistry literature is surveyed as background. N,N′-Bis(m-nitrophenyl)urea (1) exists in three concomitant polymorphic forms (R, β, and δ) of different colors.14 It readily forms solvates and cocrystals with compounds having strong to moderate hydrogen bond acceptors.15 The characteristic urea R-network is absent except in the β-polymorph of 1. meta-Dicyano derivative 2 and its hydrate are devoid of the R-network.16 In the oxoanions of para-dinitro compound 3 the strong carboxylate acceptor disrupts the R-network because of urea · · · COO- hydrogen bonding.17 We recently noted the absence of urea tape synthon in crystal

All compounds were prepared by the reaction of paranitrophenyl isocyanate with the corresponding meta/para-Xaniline in dry benzene. Meta-substituted compounds were studied to understand the effect of functional group position on the crystal structure. Some of the compounds crystallized with included solvent of crystallization. Diaryl ureas were characterized by their satisfactory NMR and IR spectra and single crystal X-ray structures. Crystallographic data (Table 1), hydrogen bond parameters (Table 2), torsion angles, and intramolecular C-H · · · O interactions are tabulated (Table 3). Nonurea Tape Structures. Compounds 5.1-5.16 come under this category. Crystal structures 5.1-5.7 are unsolvated and have similar packing in para- or meta-substituted compounds, 5.8-5.15 are solvates of DMF or DMSO, and 5.16 is a monohydrate. These structures are referred to as nonurea tape structures because they do not contain the characteristic tape synthon I. Unsolvated para-Substituted Compounds. The molecular arrangement and hydrogen bonding in the fluoro derivative 5.1 is representative of crystal packing in structures 5.1-5.4. It crystallizes in the centrosymmetric space group P21/n with one molecule in the asymmetric unit. The molecule adopts a flat planar conformation stabilized by intramolecular C-H · · · O hydrogen bonds (2.24, 2.25 Å; 118.2, 117.5°), further assisted by resonance in the extended aromatic molecule. The characteristic urea R-network of N-H · · · O hydrogen bonds, shown as synthon I in Scheme 2, is absent. Glide related urea molecules interact via synthon II such that one of the oxygen atoms of the nitro group acts as a bifurcated acceptor to form onedimensional (1D) zigzag tapes, and these tapes are further connected by C-H · · · O (2.45 Å, 170.0°) interactions in a layered structure (Figure 1). Adjacent π-stacked layers are held together by van der Waals interactions. The nitro O competes successfully to replace the stronger urea carbonyl O and hydrogen bonds with the strongest N-H donors (Table 2). The urea CdO does not accept strong hydrogen bonds but only weak C-H · · · O interactions. There are no significant interfluorine contacts. Crystal structures 5.1-5.4 are isomorphous and isostructural.20 Hydrogen bonding and crystal packing in these four structures is very similar, showing only slight differences in distances, angles, and orientation of the substituent groups (Figure S1, Supporting Information). The four molecules in crystal structures 5.1-5.4 have similar conformation (Figure 2). Unsolvated meta-Substituted Compounds. The metasubstituted derivatives, iodo 5.5, bromo 5.6, and methyl 5.7, have similar hydrogen bonding synthon and molecular packing. Crystal structures of 5.5 and 5.6 are isostructural and in the monoclinic space group P21/n with one molecule in the asymmetric unit, whereas 5.7 crystallized in the triclinic space group P1j with two molecules in the asymmetric unit. The molecules are hydrogen bonded via planar synthon III and pack in a herringbone fashion in structure 5.5 (Figure 3). The phenyl hydrogen meta to the iodo group forms a weak C-H · · · O with a glide related molecule to make a flat layer in the (101) plane. There is a weak C-H · · · I (2.92 Å, 134.4°) interaction from the phenyl hydrogen ortho to the nitro group. Adjacent π-stacked

Crystal Structures of N-Aryl-N′-4-Nitrophenyl Ureas

Crystal Growth & Design, Vol. 7, No. 12, 2007 2677

Scheme 2. Synthons Observed in Crystal Structures of 5a

a

“A” refers to any hydrogen bond acceptor group. Intramolecular C-H · · · O interactions are present in synthons II-IV but absent in I.

layers are held together by van der Waals interactions. Similar to previous crystal structures, the urea molecule adopts a planar conformation stabilized by intramolecular C-H · · · O (2.19, 2.23 Å; 118.7, 116.6°) and the carbonyl acceptor participates in intermolecular C-H · · · O interaction. In 5.7, two symmetry independent molecules interact Via synthon III in a layered structure (Figure S2, Supporting Information) and van der Waals interactions interlayer packing. Both molecules adopt the planar conformation together with intramolecular C-H · · · O hydrogen bonds (Table 3). The four molecules in 5.5-5.7 have similar conformation (Figure 4). There is a minor difference between structures 5.1-5.4 and 5.5-5.7 in the mode of urea NH hydrogen bonding to the nitro group: the O acceptor is bifurcated in 5.1–5.4 (synthon II), whereas bonding occurs to different O atoms in 5.5–5.7 (synthon III). What is common in these seven crystal structures is that the nitro group is the acceptor for the strongest NH donors not the urea carbonyl. Solvent Inclusion Urea Structures. Why are solvent molecules included in the crystal lattice during crystallization? Nangia and Desiraju21 showed that when the solvent is attached to the solute via multipoint synthon of strong and weak hydrogen bonds, for example, O-H · · · O, N-H · · · O, C-H · · · O, the extrusion of the solvent molecule from the solvated aggregate is disfavored for enthalpy reasons, and so the solvent is retained in the nucleating crystal. Accordingly, solvents such as DMF and DMSO, which have excellent acceptor and donor groups, show a high probability of inclusion. The OH/NH donors on the solute molecule hydrogen bond to the solvent O and the solvent CH donors complete the cyclic synthon by bonding back to the solute molecule. A few ureas in the present study failed to crystallize in pure form but readily crystallized as solvates. Others crystallized in pure form as well as solvates. Solvents with stronger hydrogen bond acceptors than nitro O and urea CdO, such as DMF, DMSO, were included in the crystal lattice. DMF Solvates. DMF is included in the crystalline solvates of diaryl ureas 5.8-5.10. Although they belong to different j 5.10, P1, j crystal systems and space groups (5.8, P21/c; 5.9, P1; the hydrogen bond pattern in these three structures is similar. The urea molecule adopts a near planar conformation stabilized by intramolecular C-H · · · O hydrogen bonds and maximization of resonance (see Table 3 for torsion angle and C-H · · · O

interaction parameters). In structure 5.8, the DMF O interrupts the urea tape through bifurcated synthon IV (Figure 5) by successfully replacing the urea carbonyl or nitro acceptor groups (Table 2). Surprisingly, the hitherto “hydrogen bond active” nitro acceptor of synthon II or III is not involved in strong hydrogen bonding. DMF solvent disrupts the urea R-network through N-H · · · ODMF hydrogen bonds in 5.9 and 5.10 (Figure S3, Supporting Information). The second amide NH of the dimer synthon (1.93 Å, 173.1°) hydrogen bonds with the urea CdO in 5.10 (2.31 Å, 161.2°). DMSO Solvates. Similar to the DMF solvent replacing the urea CdO or nitro O acceptor in structures 5.8-5.10, DMSO too behaves as the strongest acceptor in 5.11-5.15. There are two molecules of the nitro urea and two DMSO in the asymmetric unit of 5.11. The sulfoxide oxygen of DMSO is a bifurcated acceptor to the urea NH donors in synthon IV (Figure 6a). One of the DMSO methyl groups is bonded to the nitro O via C-H · · · O hydrogen bond (2.44, 2.48 Å; 160.5, 168.8°). In effect, DMSO acts as a spacer between two urea molecules, and there are no intersolvent hydrogen bonds. In 5.12, DMSO acts as spacer between urea molecules and amide dimers hydrogen bond to make the two-dimensional (2D) layer structure. Adjacent layers are connected through the amide N-Hanti · · · ODMSO hydrogen bond (2.05 Å, 156.2°). In crystal structures 5.13–5.15, the DMSO solvent disrupts the characteristic urea R-network (Figure S4, Supporting Information). The urea molecules have a near planar conformation in solvates 5.11–5.15, with the urea carbonyl involved in intra- and intermolecular C-H · · · O hydrogen bonds (Table 3). The 1D urea tape synthon is absent. Both the urea CdO and nitro O are now left over to accept weak C-H · · · O hydrogen bonds. Hydrate. The anhydrous form of meta-hydroxy urea 5.16 could not be obtained, but single crystals of a monohydrate were crystallized from methanol at room temperature (space group j Now the water O accepts hydrogen bonds from urea NH P1). donors in bifurcated motif IV. The OH group donates hydrogen bond to the nitro O (2.07, 2.43 Å; 127.5, 175.1°) in the layered structure (Figure 6b). These layers are connected via water OH donor and the urea CdO acceptor in the O-H · · · O bond (1.76 Å, 172.5°). The urea carbonyl participates in strong hydrogen bonding with the available crystalline water. This structure

5.3

5.14 C17H19N3O5S 377.41 triclinic P1j 6.0509(6) 12.4575(12) 12.5937(11) 78.120(2) 82.89(2) 80.105(2) 2 911.3(2) 1.375 5415 4087 2105 246 0.0531 0.1559 0.89

C13H10BrN3O3 336.14 monoclinic P21/n 7.9974(8) 13.4826(13) 12.0227(12) 90.00 94.671(2) 90.00 4 1292.1(2) 1.728 8669 3120 1919 181 0.0491 0.1489 0.96 5.16 C13H13N3O5 291.26 triclinic P1j 6.7307(10) 10.2019(15) 10.2840(15) 77.995(3) 84.110(10) 75.686(3) 2 668.3(2) 1.447 6219 2644 1708 210 0.0502 0.1280 1.00

5.15a C15H15F2N3O4S 371.36 triclinic P1j 9.1958(10) 9.5491(10) 10.5716(11) 69.9990(10) 79.3480(10) 69.5910(10) 2 815.30(2) 1.513 7443 3201 2940 236 0.0365 0.0979 1.05

5.5 C13H10IN3O3 383.14 monoclinic P21/n 8.4419(17) 12.987(3) 12.399(3) 90.00 96.59(3) 90.00 4 1350.4(5) 1.885 5931 3075 1825 189 0.0647 0.1775 0.91

5.4 C14H10N4O3 282.26 monoclinic P21/n 7.919(4) 13.692(6) 11.777(6) 90.00 94.517(10) 90.00 4 1272.9(10) 1.473 5981 3037 1606 199 0.0501 0.1527 0.97

Reflections collected at 100 K. All other data were measured at 293–298 K.

emp formula formula wt crystal system space group a /Å b /Å c /Å R /deg β /deg γ /deg Z volume /Å3 Dcalc /g cm-3 N-total N-independent N-observed N-parameters R1 [I > 2σ(I)] wR2 GOF

a

5.13 C16H19N3O4S 349.40 monoclinic P21/n 16.0665(10) 5.7448(4) 39.100(3) 90 100.115(2) 90 8 3552.8(4) 1.306 23182 8599 3157 464 0.0649 0.2356 0.87

5.12 C16H18N4O5S 378.40 triclinic P1j 8.4835(13) 9.5690(14) 11.8457(18) 105.069(3) 103.506(3) 98.203(3) 2 881.4(2) 1.426 6195 3482 1893 253 0.0626 0.1368 0.97

5.2

C13H10ClN3O3 291.69 monoclinic P21/n 8.0360(5) 13.3397(8) 11.8513(7) 90 94.882(2) 90 4 1265.82(13) 1.531 8434 3067 2200 181 0.0468 0.1515 1.06

5.1

C13H10FN3O3 275.24 monoclinic P21/n 8.1241(8) 12.9932(12) 11.6524(11) 90 94.967(2) 90 4 1225.4(2) 1.492 8210 2958 1740 189 0.0521 0.1731 1.10

emp formula formula wt crystal system space group a /Å b /Å c /Å R /deg β /deg γ /deg Z volume /Å3 Dcalc /g cm-3 N-total N-independent N-observed N-parameters R1 [I > 2σ(I)] wR2 GOF 5.17 C13H10IN3O3 383.14 monoclinic Cc 13.552(3) 4.6722(9) 21.377(6) 90 90.40(3) 90 4 1353.5(5) 1.880 4355 2212 2036 201 0.0288 0.0739 1.00

C13H10BrN3O3 336.15 monoclinic P21/n 8.4078(9) 12.7289(13) 12.3376(13) 90 97.552(2) 90 4 1308.9(2) 1.706 6248 2580 1444 189 0.0481 0.1137 0.97

5.6

5.18 C15H11N3O3 281.00 monoclinic Cc 13.422(3) 4.6511(9) 21.261(4) 90 94.97(3) 90 4 1322.3(5) 1.413 3017 3017 1912 180 0.0475 0.1232 1.07

C14H13N3O3 271.27 triclinic P1j 6.8807(5) 12.7415(10) 15.2876(11) 84.972(1) 81.159(1) 80.654(1) 4 1304.1(2) 1.382 12566 4565 3644 379 0.0433 0.1245 1.04

5.7

Table 1. Crystallographic Data and Structure Refinement Parameters 5.8

5.19 C15H16N4O3 300.32 triclinic P1j 6.0710(12) 7.5613(15) 31.715(6) 89.95(3) 87.01(3) 85.23(5) 4 1448.8(5) 1.377 5543 5055 2331 417 0.0749 0.2719 1.02

C16H17N4O4 330.34 monoclinic P21/c 9.4442(19) 7.3883(15) 23.863(5) 90 97.73(3) 90 4 1650.0(6) 1.294 4014 3789 1467 237 0.0783 0.2408 1.09

5.9

5.20 C19H14IN3O3 459.23 monoclinic P21/c 14.3837(15) 9.3167(10) 13.3889(14) 90 104.847(2) 90 4 1734.3(3) 1.759 11780 3445 1977 243 0.0518 0.1143 0.96


5.10

5.22 C14H13N3O3 271.27 orthorhombic Fdd2 9.851(3) 56.994(18) 9.211(3) 90 90 90 16 5171(3) 1.394 11913 1204 1173 190 0.0404 0.1096 1.12


5.11 C30H32I2N6O8S2 922.54 triclinic P1j 10.184(2) 13.346(3) 15.502(3) 66.82(3) 88.22(3) 68.75(3) 2 1790.0(6) 1.712 8625 8168 3868 437 0.0768 0.2286 1.01

2678 Crystal Growth & Design, Vol. 7, No. 12, 2007 Reddy et al.



Table 2. Hydrogen Bond Geometry in Diaryl Urea Crystal Structures compound

interactiona

d /Å

D /Å

θ/°

5.1

N1-H1 · · · O2 (nitro) N2-H2 · · · O2 (nitro) C10-H10 · · · O1 (urea) N2-H9 · · · O1 (nitro) N3-H10 · · · O1 (nitro) C8-H5 · · · O3 (urea) N2-H9 · · · O1 (nitro) N3-H10 · · · O1 (nitro) C8-H5 · · · O3 (urea) N1-H1 · · · O2 (nitro) N2-H2 · · · O2 (nitro) C12-H12 · · · O1 (urea) N1-H1 · · · O3 (nitro) N2-H2 · · · O2 (nitro) C12-H12 · · · O1 (urea) N1-H1 · · · O3 (nitro) N2-H2 · · · O2 (nitro) C12-H12 · · · O1 (urea) N4-H1 · · · O3 (nitro) N5-H2 · · · O2 (nitro) N2-H3 · · · O5 (nitro) N1-H4 · · · O6 (nitro) C21-H21 · · · O1 (urea) C25-H25 · · · O4 (urea) N1-H1A · · · O4 (DMF) N2-H2A · · · O4 (DMF) C10-H10 · · · O1 (urea) N1-H1 · · · O4 (DMF) N2-H2 · · · O4 (DMF) C10-H10 · · · O1 (urea) N1-H1 · · · O5 (DMF) N2-H2 · · · O5 (DMF) N3-H3B · · · O4 (amide) N3-H3Aanti · · · O1 (urea) N1-H1 · · · O4 (DMSO) N2-H2 · · · O4 (DMSO) N4-H4 · · · O8 (DMSO) N5-H5 · · · O8 (DMSO) C10-H10 · · · O5 (urea) C25-H25 · · · O1 (urea) N1-H1 · · · O5 (DMSO) N2-H2 · · · O5 (DMSO) N4-H4A · · · O4 (amide) N4-H4B · · · O5 (DMSO) C15-H15A · · · O1 (urea) N1-H1 · · · O8 (DMSO) N2-H2 · · · O8 (DMSO) N4-H4A · · · O4 (DMSO) N5-H5A · · · O4 (DMSO) C31-H31B · · · O5 (urea) C32-H32B · · · O5 (urea) N1-H1 · · · O5 (DMSO) N2-H2 · · · O5 (DMSO) C6-H6 · · · O1 (urea) N1-H1 · · · O4 (DMSO) N2-H2 · · · O4 (DMSO) C14-H14B · · · O1 (urea) C15-H15B · · · O1 (urea) N1-H1 · · · O5 (H2O) N2-H2 · · · O5 (H2O) O2-H2A · · · O3 (nitro) O2-H2A · · · O4 (nitro) O5-H5A · · · O1 (urea) O5-H5B · · · O2 (H2O) N1-H1 · · · O1 (urea) N2-H2 · · · O1 (urea) C7-I1 · · · O3 (nitro) C7-I1 · · · O2 (nitro) N1-H1 · · · O1 (urea) N2-H4 · · · O1 (urea) C15-H15 · · · O3 (nitro) C15-H15 · · · O2 (nitro) N1-H1 · · · O4 (urea) N2-H2 · · · O4 (urea)

2.22 1.90 2.45 1.94 2.13 2.68 1.97 2.12 2.83 2.14 1.94 2.99 2.01 2.07 2.61 2.04 2.02 2.52 2.13 1.92 1.96 2.11 2.67 2.45 1.88 1.90 2.44 1.90 1.89 2.25 1.98 1.91 1.93 2.31 1.94 1.95 1.95 2.08 2.61 2.48 1.88 2.14 1.98 2.05 2.38 1.87 1.82 1.94 1.83 2.26 2.57 1.96 1.85 2.36 1.81 1.92 2.51 2.45 1.93 1.92 2.07 2.43 1.76 1.89 1.99 1.99

3.135(3) 2.871(3) 3.520(3) 2.913(2) 3.069(2) 3.745(2) 2.936(5) 3.064(4) 3.878(5) 3.033(3) 2.908(3) 3.885(3) 3.021(7) 3.110(7) 3.583(8) 3.032(4) 2.992(4) 3.532(4) 3.127(2) 2.910(2) 2.957(2) 3.112(2) 3.729(3) 3.458(3) 2.844(4) 2.853(4) 3.425(5) 2.865(4) 2.846(3) 3.295(4) 2.918(3) 2.856(3) 2.936(3) 3.286(3) 2.892(11) 2.901(11) 2.907(11) 3.019(11) 3.497(12) 3.430(13) 2.876(4) 3.097(4) 2.984(4) 3.002(4) 3.430(5) 2.859(4) 2.812(4) 2.903(4) 2.811(4) 3.238(4) 3.463(4) 2.877(3) 2.796(3) 3.361(3) 2.777(2) 2.858(2) 3.429(2) 3.385(2) 2.888(3) 2.880(3) 2.778(3) 3.416(3) 2.743(3) 2.850(3) 2.925(7) 2.930(6) 3.286 3.618 2.914(4) 2.919(4) 3.325(7) 3.833(7) 3.058(6) 3.189(6)

149.3 160.3 170.0 160.8 154.1 166.0 159.9 155.4 163.2 146.9 160.0 161.8 175.0 154.3 149.6 168.5 160.0 154.7 170.8 166.2 167.4 169.9 165.1 154.8 159.4 157.0 149.8 159.6 157.6 160.3 153.9 154.9 173.1 161.2 157.1 156.8 157.2 153.2 138.4 145.9 168.4 158.2 173.3 156.2 163.4 164.4 167.5 159.0 161.9 148.4 139.1 148.8 155.0 152.1 159.6 153.7 141.6 143.1 158.2 158.3 127.5 175.1 172.5 163.9 152.8 153.8 169.0 154.3 154.1 153.3 166.8 142.0 141.6 152.6

5.2

5.3

5.4

5.5

5.6

5.7

5.8

5.9

5.10

5.11

5.12

5.13

5.14

5.15

5.16

5.17

5.18

5.19

1.97 1.98 2.26 2.92 2.20 2.26

Table 2. Continued compound

interactiona

d /Å

D /Å

θ/°

5.20

N5-H5 · · · O1 (urea) N6-H6 · · · O1 (urea) C14-H14B · · · O6 (nitro) C15-H15C · · · O5 (nitro) C29-H29B · · · O2 (nitro) C30-H30C · · · O3 (nitro) N1-H1 · · · O1 (urea) N2-H2 · · · O1 (urea) C17-I1 · · · O2 (nitro) C17-I1 · · · O3 (nitro) N1-H1 · · · O1 (urea) N2-H2 · · · O1 (urea) C6-H6 · · · O3 (nitro)

2.16 2.16 2.85 2.39 2.95 2.53 1.98 2.09

3.103(6) 3.098(6) 3.868(9) 3.564(8) 3.689(8) 3.573(9) 2.890(6) 3.011(7) 3.978 3.432 2.906(4) 2.986(4) 3.504(4)

153.8 154.4 156.3 167.0 125.6 160.6 148.8 150.8 160.6 157.8 155.9 145.6 153.2

5.22

1.95 2.00 2.50

a N-H, C-H, and O-H distances were neutron normalized to 1.009, 1.083, and 0.983 Å.

Table 3. Molecular Conformation and C-H · · · O Interactions in Diaryl Urea Structuresa torsion angle hydrogen intramolecular compound C-H · · · Ourea (d/ Å) (C-Caryl-N-Ccarbonyl /°) bond synthon 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.22

2.24, 2.25, 2.24, 2.25, 2.19, 2.23, 2.20, 2.25, 2.13, 2.35, 2.29, 2.18, 2.28, 2.25, 2.22, 2.25, 2.58, 2.59, 2.26, 2.37, 2.45,

2.25 2.25 2.24 2.26 2.23 2.20 2.22, 2.29 2.14 2.40 2.24, 2.18 2.40, 2.23 2.19 2.30 2.63 2.61 2.72, 2.94 2.86

2.20, 2.22

2.27, 2.22 2.21, 2.29

2.10, 2.26

5.1, 4.6 7.0, 5.9 7.2, 5.9 6.6, 5.9 12.9, 3.8 14.7, 3.0 3.4, 15.9, 4.2, 13.3 9.4, 12.8 2.7, 6.8 4.2, 8.1 4.6, 5.7, 14.0, 14.6 0.1, 11.0 14.8, 20.0, 21.5, 31.7 5.2, 2.4 9.3, 15.2 0.7, 9.3 46.0, 49.0 48.5, 49.0 27.3, 51.5, 20.6, 88.0 24.8, 63.0 38.7, 59.4

II II II II III III III IV IV IV IV IV IV IV IV IV I and I and I and I and I

V VI VII V

a Ureas 5.1–5.16 have shorter C-H · · · O contacts and lower τ angles, whereas 5.17–5.22 have longer contacts and higher τ values.

closely resembles monohydrate form of 1 (γ-form).14b Structural features for the formation of organic crystal hydrates were summarized recently.22 The overlay of molecular conformations of diaryl urea molecules 5.8–5.16 is very good in the p-NO2-Ph-NH-CO-NH portion, but the atoms are scattered in the N-Ph-X moiety (Figure 7), reinforcing the idea that when the phenyl CH donor is activated by an adjacent electron-withdrawing group the C-H · · · Ourea interaction locks the flexible molecule in a planar conformation.18,19 Urea Tape Structures. The p-iodo, p-ethynyl, p-N,Ndimethylamino, p-iodophenyl, p-ethynylphenyl, and p-methyl compounds 5.17-5.22 belong to this category. Compound 5.17 crystallized in the polar space group Cc with one molecule in the asymmetric unit. Self-assembly in 5.17 occurs via the urea N-H · · · O synthon I to produce the 1D R-network along the b-axis (Figure 8). The iodine atom is in close contact with the nitro group because of the bifurcated I · · · O synthon V (3.29, 3.62 Å; 169.0, 154.3°).23 The urea groups are aligned along the short b-axis (4.67 Å), and the aryl groups are twisted out of the urea plane (45.4, 49.2°) to accommodate the hydrogen bonded R-network. The p-ethynyl derivative 5.18 also crystallized in polar space group Cc and is isostructural to 5.17 (Figure S5, Supporting Information), consistent with recent observations on iodo-ethynyl exchange (synthon V f VI) without disturbing

2680 Crystal Growth & Design, Vol. 7, No. 12, 2007

Figure 1. Crystal structure p-fluoro compound 5.1 showing the N-H · · · Onitro and intramolecular C-H · · · Ocarbonyl interactions in the nonurea tape synthon II. Note the additional C-H · · · Onitro interaction stabilizing synthon II. Crystal structures of the chloro, bromo, and cyano derivatives 5.2–5.4 are similar (see Figure S1, Supporting Information).

Figure 2. Overlay diagram of molecules in structures 5.1-5.4 to show their similar conformation (red ) fluoro 5.1, green ) chloro 5.2, brown ) bromo 5.3, and purple ) cyano 5.4).

the crystal packing.24 The aryl groups are twisted out of the urea plane in these tape structures (Figure 9). The noncentrosymmetric solid 5.17 showed a strong quadratic nonlinear efficiency upon irradiation using Nd3+-YAG laser at 1064 nm with an intense green signal at 532 nm equal to that of the organic NLO benchmark compound 3-methyl-4-nitropyridineN-oxide (POM). The SHG activity of iodo compound 5.17 is 13 times that of urea and ethynyl derivative 5.18 has an efficiency of 1.2 × U.13 Upon observing the N-H · · · O urea tape in two structures, crystal structure of 5.19 was determined to confirm the synthondirecting role of the weak C-H · · · O interaction with the nitro group. N,N-Dimethylamino compound 5.19 crystallized in the triclinic space group P1j with two molecules in the asymmetric unit. Remarkably, the N-H · · · O urea tape (Table 2) is reproduced faithfully. Weak C-H · · · O (2.39, 2.85, 2.53, 2.95 Å; 167.0, 156.3, 160.6, 125.6°) interactions between the NMe2 group and the O atom of the nitro group (synthon VII)25 provide auxiliary support to the R-network in the orthogonal direction (Figure 10). However, in contrast to the polar alignment of I · · · O2N and C-H · · · O2N synthons in 5.17 and 5.18, the NMe2 · · · O2N synthons are arranged antiparallel along the c-axis in the centrosymmetric packing of molecules. The phenyl rings

Reddy et al.

are twisted out of the urea group plane (torsion angle of 27.3, 51.5, 20.6, 88.0°) to accommodate the urea tape motif. The centrosymmetric space group of crystal 5.19 ruled out SHG measurements. To test the robustness of weak interactions in the orthogonal direction in directing the urea tape synthon and also to take advantage of the biphenyl twist for noncentrosymmetric packing, extended biphenyl urea compounds 5.20 and 5.21 were synthesized. Disappointingly, compound 5.20 crystallized in the centrosymmetric space group P21/c with one molecule in the asymmetric unit. Yet, our crystal design objective was successful because the characteristic urea R-network of N-H · · · O hydrogen bonds I and I · · · NO2 synthon V are present (Figure 11). Adjacent inversion-related layers are connected by van der Waals interactions. The Ph-N-urea moiety is twisted (24.8, 63.0°) in the 1D tape structure. The ethynyl biphenyl compound 5.21 failed to give diffraction quality single crystals. A comparison of the powder X-ray diffraction (PXRD) pattern of 5.21 and 5.20 (Figure 12) suggested that 5.21 should have a urea R-network structure. Moreover, PXRD lines of 5.20 and 5.21 are different from the heteroaromatic layered prototype in p-chloro 5.2 and p-bromo 5.3 (Figure S6, Supporting Information) with characteristic peaks at 2θ ) ∼25, 28° corresponding to π-stacking d spacing of 3.5, 3.2 Å (Figure S6, Supporting Information).13b Whereas iodo and ethynyl derivatives 5.17 and 5.18 crystallized in the noncentrosymmetric and polar space group Cc, N,N-Me2 and iodobiphenyl compounds 5.19 and 5.20 adopt centrosymmetric packing. From a synthon or hydrogen bond network design objective, these crystal structures validate a recurring design element because they contain the target urea tape motif and auxiliary interactions with the nitro group in the orthogonal direction. Crystal engineering of 1D chains and 2D layers is now relatively common, but control of the complete three-dimensional (3D) molecular organization including the space group symmetry is still a distant goal, in a general sense, for organic molecular solids.26 Noting the importance of weak interactions in the orthogonal direction to “enable” the urea tape in structures 5.17–5.21, X-ray crystal structure of p-methyl derivative 5.22 was determined. It crystallized in the noncentrosymmetric space group Fdd2 with one molecule in the asymmetric unit. The diaryl urea molecule adopts a twisted conformation (38.7, 59.4°) in the 1D tape of N-H · · · O hydrogen bonds (synthon I) along the c-axis (Figure 13). These 1D tapes are connected through phenyl C-H · · · Onitro interaction to form a 2D layer structure. Whereas we expected the tolyl CH3 group to be the CH donor, the meta-phenyl CH is actually involved in the weak lateral interaction (2.50 Å, 153.2°). There is additional contribution from a longer (Me)C-H · · · Onitro interaction (2.73 Å, 155.2°) in a two-point motif like VII. Once again, the NO2 group is engaged in C-H · · · O interactions and the urea R-network is present in 5.22. Energy Calculations. In conformationally flexible molecules, such as diaryl ureas, it is important to consider both the molecular conformation and the hydrogen bond synthon energy. Since there are several low-lying conformers about C-C single bonds in equilibrium at 25–100 °C, the typical temperature range for crystallization of organic molecules, it is possible that a metastable conformer crystallizes in the solid-state because of energy compensation through stronger hydrogen bonds and better overall crystal packing.27 Synthon Energy. Calculations were performed on model systems,N,N′-dimethylureahomodimer,andnitromethane · · · N,N′dimethylurea and DMF · · · N,N′-dimethylurea heterodimers (Scheme 3), by full geometry optimization in Spartan at the



Figure 3. N-H · · · Onitro and intramolecular C-H · · · Ocarbonyl interactions in the nonurea tape synthon III in the crystal structure of m-iodo derivative 5.5. See Figure S2, Supporting Information for similar packing in structures 5.6 and 5.7.

Figure 4. An overlay of molecules in crystal structures 5.5-5.7 showing their similar conformation (red ) iodo 5.5, brown ) bromo 5.6, blue and green ) symmetry-independent molecules in the methyl compound 5.7).

RHF/6-31G** level.28 Synthon energy was computed as the difference between the N-H · · · O hydrogen-bonded dimer and the sum of the isolated monomers. The urea dimer has synthon energy of -10.8 kcal mol-1, which increases to -11.2 kcal mol-1 for the trimer (per synthon) indicating that there is cooperative stabilization in the 1D tape. In comparison, urea · · · NO2 synthon ) -7.4 kcal mol-1, and urea · · · DMF heterosynthon ) -9.0 kcal mol-1. The above energies take into account strong N-H · · · O hydrogen bonds but do not explicitly include stabilization from weak C-H · · · O interactions. These computations had to be carried out on dimethyl urea instead of diphenyl urea for faster number-crunching. Among solute · · · solute synthons, although the urea tape provides greater stabilization than the urea · · · nitro synthon, the latter motif is preferred in structures 5.1-5.7 perhaps due to the stable, planar diphenyl urea conformation. Conformation Energy. The energy of unsubstituted diphenyl urea molecule as a function of the aryl-N-CdO torsion angle (Figure 14) was calculated. The energy profile shows that the planar trans-trans-diphenyl urea (ι ) 0, 180°) is more stable than twisted trans-trans-rotamer (ι ) 90°) by 9.0 kcal mol-1.29 This is due to two additive effects: conjugation of urea N with the electron-withdrawing phenyl ring as well as two intramo-

lecular C-H · · · O interactions. We have estimated that stabilization due extended conjugation is worth ∼4 kcal mol-1 and the two C-H · · · O interactions add up to ∼5 kcal mol-1.18 The aryl-N-CdO torsion angle, conformer energy, and CdO charge in diphenyl urea are interrelated. The urea O acceptor is more electron-rich (better hydrogen bond acceptor) when the aryl groups are twisted and less negative (poorer hydrogen bond acceptor) when the molecule is planar. The electron density on urea O in the experimental twisted, metastable conformation of diphenyl urea (τ ≈ 45°) is -45.7 kcal mol-1 compared to -38.6 kcal mol-1 in the planar, stable conformation. The two C-H · · · O interactions attenuate the charge and hydrogen bond acceptor strength of urea O as the molecular conformers at equilibrium change during crystallization. Finally, weakening of the CdO acceptor strength in the planar conformation changes the crystal structure from urea R-network to urea · · · nitro synthon. The situation in urea · · · solvent aggregates 5.8-5.16 is analogous to nonurea structures 5.1-5.7. Nuclear Overhauser Enhancement (NOE). To find out the major 1conformation of diphenyl ureas in solution, difference NOE H NMR experiments were carried out in DMSO-d6. Irradiation of the NH proton of diphenyl urea (reference molecule) at δ 8.71 showed NOE to the ortho-H signal at δ 7.48 (22%), implying that it is in the planar conformation (Figure 15a). Similarly, p-iodo and p-methyl derivatives also showed NOE to the ortho-proton, indicating that both 5.17 and 5.22 adopt the planar trans-trans-conformation in solution even as they have different conformations and crystal structures in the solid-state. Variable-temperature NMR of diphenyl urea in MeOH-d4 (300–200 K) showed no change in peak positions, which means that there is no change in the conformation upon cooling to 200 K, consistent with the stability of the planar conformation in the gas phase (DFT calculations, Figure 14). The cis-trans-diphenyl urea conformer is unlikely (or in very minor amount) in NMR solution experiments because the transNH proton will be highly shielded relative to the cis-NH because the former lies in the shielding cone of the cis-N-oriented phenyl ring (Figure 15b).30 We did not observe upfield shift of 2–3 δ


Reddy et al.

Figure 5. Urea N-H · · · ODMF and intramolecular C-H · · · Ocarbonyl interactions of synthon IV in the DMF solvate of the phenyl compound 5.8. The interrupted urea tape due to the solvent molecule is a common pattern in these structures (see Figure S3, Supporting Information).

for one of the urea NHs. When NMR spectra were recorded at varying concentrations (0.005–0.5 M in MeOH-d4) there is no change in peak positions, implying that the urea molecule aggregates with the solvent, but there is no evidence of dimeric species at higher concentration because otherwise the NMR lines would have changed. NMR spectra in MeOH-d4 and DMSOd6 are near-identical in terms of δ and J values. NOE experiments were carried out in DMSO-d6 due to NH proton exchange in MeOH-d4. On the other hand, the variable temperature and concentration-dependent NMR studies were performed in MeOH-d4 at 200 K. These NMR data suggest that diphenyl urea aggregation in NMR solvents resembles the solvated X-ray crystal structures of diaryl ureas discussed above. Discussion In unsolvated diaryl urea crystal structures 5.1-5.7, the dominant hydrogen bonding is synthon II or synthon III. The urea molecule adopts a planar conformation with good intramolecular C-H · · · O hydrogen bonds in a six-member ring. The hydrogen bond acceptor strength of an electronegative atom/ group may be estimated by one of three methods: (1) pKa of the conjugate acid, (2) calculated charge on the atom, (3) pKHB scale. We have argued31 that the pKHB scale is a better indicator of the hydrogen bond acceptor strength because it measures the ability of proton-sharing as compared to the pKa scale which ranks proton-transfer ability of various acids. The urea carbonyl (pKHB of tetramethylurea ) 2.44, tertraphenylurea ) 1.74)32 is a better hydrogen bond acceptor than nitro O (pKHB of nitrobenzene ) 0.30, N,N-dimethyl-p-nitroaniline ) 0.83). However, due to the planar conformation and intramolecular C-H · · · O hydrogen bonds, the electron density on the carbonyl O is considerably reduced and hence it becomes a weaker acceptor than nitro O in molecule 5. In effect, the molecular conformation influences the relative hydrogen bond acceptor strength leading to a reranking of urea O and nitro O strengths, and rationalizing the frequent synthons in these crystal structures. The strongest acceptor in planar diaryl urea molecule 5 is the nitro group, which interacts with the strongest urea NH donors via synthons II and III. Crystal structures of solvates 5.8-5.15 are now easily explained as arising from the better hydrogen bond acceptor strength of DMF or DMSO oxygen compared to

urea and nitro O. The urea molecule behaves as a hydrogenbond donor substrate to acceptor-rich molecules15,18 in the C-H · · · O stabilized planar conformation (synthons II, III, and IV). Both DMF and DMSO (pKHB 2.10, 2.58) are stronger hydrogen bond acceptors. A similar hydrogen bond strength to synthon analysis based on atomic charges or pKa values gave inconsistent reasoning. Why is the urea tape synthon observed in crystal structures 5.17-5.22? Whereas the urea tape is the expected synthon in diaryl urea crystal structures with neutral and electron-donating groups, this is not the case when an electron-withdrawing group is present on one or both of the phenyl rings.15–18 Out of 57 diaryl urea crystal structures extracted from the Cambridge Structural Database33 (Table S1, Supporting Information), 20 structures adopt the urea R-network whereas 37 hits have nonurea hydrogen bonding. The experimentally accessible region in diaryl urea crystal structures (marked with dash lines in the left-hand corner of Figure 14) is between τ ) 0–60° or -6 to -9 kcal mol-1, giving an energy window of 2.5–3.0 kcal mol-1 for the observed conformers. We do not consider the cis-transdiphenyl urea conformer in this discussion because it is not observed in reported diaryl urea crystal structures (see Table S1, Supporting Information for CSD refcodes). The cis-transrotamer is very close in energy to the trans-trans-conformer, the latter being different by hardly 0.5 kcal mol-1 depending on the computation level and method used.29 In any case, both cis-trans and trans-trans diphenyl urea rotamers should be accessible under ambient thermal conditions (RT ∼ 0.6 kcal mol-1). Molecules in the nonurea synthon category, both unsolvated and solvated structures, have at least one phenyl ring substituted with electron-withdrawing group(s). The planar synthon is favored in electron-deficient aryl urea 5, which makes nitro O as the strongest acceptor in the molecule. Therefore the “interfering” NO2 group must be trapped via specific interactions, such as nitro · · · iodo (synthon V), nitro · · · ethynyl (synthon VI), or nitro · · · N,N-dimethylamino (synthon VII), and only then is the CdO acceptor “available” to make the urea tape synthon I. However, rotation of the N-Ph moiety in the molecule, from the stable, planar to the metastable, twisted conformation, is a necessary requirement for the urea tape synthon I self-assembly.



Figure 6. DMSO solvates of (a) p-iodo compound 5.11, and (b) monohydrate of meta-hydroxy compound 5.16. Solvent molecules interrupt the urea R-network (see Figure S4, Supporting Information). The two symmetry independent molecules of 5.11 are shown as ball-stick and cylinder models in (a).

Similar observations were made by us18 in the context of electron-withdrawing dipyridyl ureas 4. On the basis of the discussion so far, the nonurea structure of N,N′-bis(4-hydroxyphenylethyl)urea (4-HPEU) is due to interference from the phenol OH acceptor. However, in N,N′-bis(3,4-dihydroxyphenylethyl)urea dihydrate (3,4-DHPEU, Scheme 4),34 the phenol OH hydrogen bonds to the water molecule and the selfcomplementary urea homosynthon is now present. Crystal structures of 5 may be classified into two broad categories: the nonurea tape structures 5.1–5.16, which are subdivided into nonsolvated (5.1–5.7) and solvated (5.8–5.16) structures, and the urea tape R-network structures 5.17–5.22. Related to the R-network and nonurea hydrogen bond synthon structures is the molecular conformation change (Figure 16). There is a one-to-one relationship between molecular conforma-

tion, hydrogen bonding, and crystal packing. Among the nonsolvated diaryl urea structures, the stable, planar conformer is present in the less stable urea · · · O2N synthon, whereas the metastable, twisted rotamer is present in the stable urea · · · urea tape motif. From the available data, it is difficult to say whether the urea tape or the nonurea crystal structures are more stable when both these opposing effects are accounted for. Since intramolecular (conformer) and intermolecular (synthon) energy compensation is of comparable magnitude, and both categories of urea structures are observed depending on the other functional groups present in the molecule, we surmise that the observed crystal structures should have similar energies in the competitive milieu. Our conclusion is consistent with hydrogen bonding in concomitant polymorphs of bis(m-nitrophenyl)urea 1: one NH bonds to nitro O, while the other bonds to urea O in both R-form


Reddy et al.

Figure 7. An overlay of molecules in (a) DMF solvates 5.8-5.10 (green ) phenyl 5.8, magenta ) cyano 5.9, yellow ) amide 5.10), and (b) DMSO solvates 5.11–5.15 (brown ) iodo 5.11, red ) amide 5.12, orange and purple ) symmetry-independent molecule of methyl compound 5.13, black ) acetyl 5.14, blue ) difluoro 5.15). Note the planarity of the nitrophenyl ring with the urea moiety on the left compared to the scatter of X-phenyl portion atoms on the right in these solvates.

Figure 8. (a) N-H · · · O urea tape synthon I along the b-axis and I · · · O2N halogen bonding synthon V in the crystal structure of p-iodo compound 5.17. (b) View down the b-axis to show the parallel alignment of polar chains.

and δ-form (synthon III), whereas in the β-form both NH donors bond to urea O (synthon I).14b The difference between R- and δ-forms is in their molecular conformation and the orientation of nitro groups. Concomitant polymorphs crystallize under the

same crystal growth conditions and typically have very small energy differences (250 °C) and were found to decompose prior to melting. Second, these diaryl ureas were not soluble in MeOH-d4 at sufficiently high concentration to record 13C NMR in a routine way. The structure was secured by 1H NMR, IR and confirmed by single crystal X-ray diffraction. General Procedure. A mixture of 4-nitrophenylisocyanate and the appropriate aniline in 1:1 molar ratio in 10 mL of benzene was heated at reflux for 60–90 min. The product was isolated after column chromatography or crystallization in ∼90% yield.15 N-4-Fluorophenyl-N′-4′-nitrophenylurea, 5.1. Crystallized from THF/EtOH. 1H NMR (DMSO-d6): δ 9.42 (s, 1H), 8.93 (s, 1H), 8.16 (d, J ) 8, 2H), 7.66 (d, J ) 8, 2H), 7.45 (d, J ) 8, 2H), 7.10 (d, J ) 8, 2H). IR (KBr): 3406, 1724, 1618, 1408 cm-1. Mp > 250 °C. N-4-Chlorophenyl-N′-4′-nitrophenylurea, 5.2. Crystallized from THF/EtOH. 1H NMR (DMSO-d6): δ 9.46 (s, 1H), 9.05 (s, 1H), 8.17 (d, J ) 8, 2H), 7.66 (d, J ) 8, 2H), 7.48 (d, J ) 8, 2H), 7.33 (d, J ) 8, 2H). IR (KBr): 3369, 1724, 1595, 1415 cm-1. Mp > 250 °C. N-4-Bromophenyl-N′-4′-nitrophenylurea, 5.3. Crystallized from THF/EtOH/benzene. 1H NMR (DMSO-d6): δ 9.47 (s, 1H), 9.06 (s, 1H), 8.31 (d, J ) 8, 2H), 7.70 (d, J ) 8, 2H), 7.47 (s, 4H). IR (KBr): 3368, 1726, 1614, 1417 cm-1. Mp > 250 °C.


Reddy et al.

Figure 10. Urea R-network (synthon I) in the crystal structure of N,N-dimethylamino compound 5.19 and lateral C-H · · · O interactions of synthon VII. Symmetry-independent molecules alternate within a urea tape.

Figure 11. (a) Packing diagram to show the urea R-network synthon I along the b-axis and synthon V in iodo-biphenylyl 5.20. (b) View down the b-axis to show the interlayer space filling of aromatic groups.

Figure 12. Experimental powder X-ray diffraction pattern of (a) p-iodophenyl 5.20 and (b) p-ethynylphenyl 5.21. Peaks 2θ ) ∼13, 22° match nicely. The peak at ∼5° is due to sample holder. N-4-Cyanophenyl-N′-4′-nitrophenylurea, 5.4. Compound was crystallized from THF and ethanol mixture. 1H NMR (DMSO-d6): δ 9.62 (s, 1H), 9.42 (s, 1H), 8.2 (d, J ) 8, 2H), 7.6 (m, 6H). IR (KBr): 3412, 2220, 1728, 1597, 1531, 1413 cm-1. Mp > 250 °C.

N-3-Iodophenyl-N′-4′-nitrophenylurea, 5.5. Crystallized from DMSO. 1H NMR (DMSO-d6): δ 9.49 (s, 1H), 9.04 (s, 1H), 8.17 (d, J ) 8, 2H), 8.01 (s, 1H), 7.67 (d, J ) 8, 2H), 7.35 (d, J ) 8, 2H), 7.10 (t, J ) 6, 1H). IR (KBr): 3380, 1640, 1410 cm-1. Mp > 250 °C.



Figure 13. N-H · · · O urea tape synthon I along the c-axis in p-methyl compound 5.22. The nitro group is involved in C-H · · · Onitro interaction along the b-axis with a phenyl CH donor.

Scheme 3. Synthon Energy Calculations in Spartan on the Urea · · · Urea Homodimer and Urea · · · Nitro and Urea · · · DMF Heterodimers

N-3-bromophenyl-N′-4′-nitrophenylurea, 5.6. Crystallized from THF. 1H NMR (DMSO-d6): δ 9.52 (s, 1H), 9.04 (s, 1H), 8.31 (d, J ) 8, 2H), 8.10 (s, 1H), 7.70 (d, J ) 8, 2H), 7.30 (d, J ) 8, 2H), 7.00 (t, J ) 6, 1H). IR (KBr): 3410, 3368, 1614, 1417 cm-1. Mp > 250 °C. N-3-Tolyl-N′-4′-nitrophenylurea, 5.7. Crystallized from MeOH. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.92 (s, 1H), 7.57 (d, J ) 8, 2H), 7.10 (d, J ) 8, 2H), 6.74 (s, 1H), 6.64 (d, J ) 6, 1H), 6.59 (t, J ) 6, 1H), 6.27 (d, J ) 6, 1H), 2.69 (s, 3H). IR (KBr): 3362, 1712, 1597, 1477, 1325 cm-1. Mp 224–227 °C. N-Phenyl-N′-4′-nitrophenylurea, 5.8. Crystallized from DMF. 1H NMR (DMSO-d6): δ 9.42 (s, 1H), 8.91 (s, 1H), 8.17 (d, J ) 8, 2H), 7.66 (d, J ) 8, 2H), 7.45 (d, J ) 8, 2H), 7.27 (t, J ) 8, 2H), 7.02 (t, J ) 6, 1H). IR (KBr): 3298, 1649, 1698, 1562, 1446 cm-1. Mp 226–229 °C. N-4-Carboxamidophenyl-N′-4′-nitrophenylurea. 5.10. Crystallized from DMSO/DMF. 1H NMR (DMSO-d6): δ 9.52 (s, 1H), 9.17 (s, 1H),

Figure 14. Spartan computations (DFT-B3LYP/6-31G*) on trans-transdiphenyl urea as a function of the aryl C-C-N-CdO torsion angle. Relative energy is plotted such that the highest energy conformer is fixed at 0. The planar molecular conformation is the most stable rotamer. The ESP charge on the urea O atom is higher (better hydrogen bond acceptor) in the twisted conformation. Rotation of a m-NO2 group with respect to the phenyl ring imposes an insignificant energy penalty of 250 °C. N-4-Acetylphenyl-N′-4′-nitrophenylurea, 5.14. Crystallized from DMSO. 1H NMR (DMSO-d6): δ 9.54 (s, 1H), 9.32 (s, 1H), 8.19 (d, J ) 8, 2H), 7.91 (d, J ) 8, 2H), 7.69 (d, J ) 8, 2H), 7.59 (d, J ) 8, 2H). IR (KBr): 3317, 1649, 1520, 1403 cm-1. Mp > 250 °C. N-3,5-Diflorophenyl-N′-4′-nitrophenylurea, 5.15. Crystallized from DMSO. 1H NMR (DMSO-d6): δ 9.60 (s, 1H), 9.30 (s, 1H), 8.22 (d, J ) 8, 2H), 7.78 (d, J ) 8, 2H), 7.21 (d, J ) 8, 2H), 6.91 (t, J ) 5, 1H). IR (KBr): 3364, 1616, 1572, 1437 cm-1. Mp > 250 °C. N-3-Hydroxyphenyl-N′-4′-nitrophenylurea, 5.16. Crystallized from MeOH. 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 9.35 (s, 1H), 8.81 (s, 1H), 8.22 (d, J ) 8, 2H), 7.70 (d, J ) 8, 2H), 7.07 (m, 1H), 6.84 (d, J ) 6, 1H), 6.44 (d, J ) 6, 1H). IR (KBr): 3369, 1707, 1618, 1412 cm-1. Mp 210–212 °C. N-4-Iodophenyl-N′-4′-nitrophenylurea, 5.17. Crystallized from THF. 1H NMR (DMSO-d6): δ 9.45 (s, 1H), 9.03 (s, 1H), 8.23 (d, J ) 8, 2H), 7.71 (d, J ) 8, 2H), 7.63 (d, J ) 8, 2H), 7.31 (d, J ) 8, 2H). IR (KBr): 3308, 1647, 1388 cm-1. Mp > 250 °C. N-4-Ethynylphenyl-N′-4′-nitrophenylurea, 5.18. 4-Iodoaniline was coupled with trimethylsilylacetylene via a Sonogashira coupling39 and the product condensed with the 4-nitrophenylisocyanate followed by deprotection of the TMS group to obtain the product. 4-(2-Trimethylsilyl-1-ethynyl)aniline. Trimethylsilylacetylene (3.42 mmol, 335 mg, 0.48 mL) was added to 4-iodoaniline (500 mg, 2.28 mmol) in 7 mL of Et3N at 0 °C under inert N2 atmosphere. Cuprous iodide (15 mg) and palladium catalyst [(PdCl2(PPh3)] (40 mg) were added, and the reaction mixture was allowed to stir at room temperature for 12 h. Et3N was removed, and the product was purified by column chromatography on neutral silica gel using hexane eluent. 1H NMR (DMSO-d6): δ 0.24 (s, 9H), 5.51 (s, 2H), 6.54 (d, J ) 8, 2H), 7.11 (d, J ) 8, 2H). IR (KBr): 3464, 2146, 1622, 1510 cm-1. Mp 99–101 °C. N-4-(2-Trimethylsilyl-1-ethynyl)phenyl-N′-4′-nitrophenylurea. A mixture of 4-(2-trimethylsilyl-1-ethynyl)aniline (294 mg, 1.55 mmol) and 4-nitrophenyl isocyanate (306 mg, 1.87 mmol) in 12 mL benzene was heated to reflux until there was no starting material (TLC). The product was purified on silica gel column. 1H NMR (DMSO-d6): δ 0.25 (s, 9H), 7.22 (d, J ) 8, 2H), 7.41 (d, J ) 8, 2H), 7.73 (d, J ) 8, 2H), 8.33 (d, J ) 8, 2H), 9.21 (s, 1H), 9.55 (s, 1H). IR (KBr): 3364, 2156, 1680, 1595, 1408 cm-1. Mp > 250 °C. N-4-Ethynylphenyl-N′-4′-nitrophenylurea, 5.18. To the TMSprotected urea derivative prepared above (344 mg, 1 mmol) in 15 mL of MeOH was added 180 mg of K2CO3 in MeOH (10 mL). The reaction mixture was stirred for 1 h and the product was purified by silica gel chromatography after usual workup. 1H NMR (DMSO-d6): δ 9.61 (s, 1H), 8.90 (s, 1H), 8.20 (d, J ) 8, 2H), 7.75 (d, J ) 8, 2H), 7.54 (d, J ) 8, 2H), 7.45 (d, J ) 8, 2H), 4.1 (s, 1H). IR (KBr): 3260, 1647, 1585, 1502, 1408 cm-1. Mp > 250 °C. N-4-(N,N-Dimethylamino)phenyl-N′-4′-nitrophenylurea. 5.19: Crystallized from EtOAc/hexane. 1H NMR (DMSO-d6): δ 9.32 (s, 1H), 8.55 (s, 1H), 8.19 (d, J ) 8, 2H), 7.64 (d, J ) 8, 2H), 7.25 (d, J ) 8, 2H), 6.68 (d, J ) 8, 2H), 2.84 (s, 6H). IR (KBr): 3310, 1643, 1612, 1406 cm-1. Mp 246 °C (sublimes). 4-Iodo-4′-nitrobiphenyl. To a powdered mixture of biphenyl (900 mg, 6.0 mmol) and iodine (450 mg, 3.5 mmol) in acetic acid (10 mL) was slowly added conc. HNO3 over 30 min, and the resulting mixture was refluxed for 2 h. The cooled reaction mixture was then poured into water (100 mL), and the yellow solid was filtered, washed with


Reddy et al.

Figure 15. (a) 1H NMR NOE in diphenyl urea, p-iodo and p-methyl compounds 5.17 and 5.22, recorded in DMSO-d6. The ortho-H peak enhancement indicates that the dominant conformation of diaryl urea in solution is the planar species. This is the stable conformation in the gas phase. (b) trans-trans (planar), trans-trans (twisted), trans-cis and cis-cis conformers of diphenyl urea. The trans-Ph-NH proton resides in the shielding cone of cis-Ph-NH and will be shifted upfield in the trans-cis conformer. This was not observed in NMR spectra. The cis-trans and cis-cis conformations are not present in acyclic diaryl urea crystal structures discussed herein (Table S1, Supporting Information).

Scheme 4. Effect of Hydration on Nonurea Vs Urea Tape Structuresa

a

The phenol OH disrupts the urea tape in 4-HPEU, whereas 3,4-DHPEU dihydrate adopts the R-network.

Figure 16. A qualitative energy vs crystallization plot to show the interplay of molecular conformation and hydrogen bonding in nitrophenyl urea 5 crystal structures. The metastable rotamer leads to the stable synthon, and vice versa. Compensation of conformer and synthon energy gives urea tape and nonurea tape crystal structures of similar crystal energies. water, extracted with boiling EtOH (2 × 50 mL), and purified by column chromatography. 1H NMR (CDCl3): δ 8.32 (d, J ) 9, 2H), 7.86 (d, J ) 9, 2H), 7.72 (d, J ) 9, 2H), 7.38 (d, J ) 9, 2H). Mp 202–203 °C.40 4-Iodo-4′-aminobiphenyl. 4-iodo-4′-nitrobiphenyl (1.0 g, 3.0 mmol) was dissolved in acetic acid (15 mL) and Fe powder (450 mg, excess) was added slowly over 10 min to the refluxing solution.

After heating for 15 min, the solution was cooled to room temperature and poured into crushed ice. A pale yellow compound precipitated form the solution. 1H NMR (CDCl3): δ 7.71 (d, J ) 9, 2H), 7.37 (d, J ) 9, 2H), 7.28 (d, J ) 9, 2H), 7.73 (d, J ) 9, 2H). IR (KBr): 3408, 3290, 1602, 1477 cm-1. N-4-Iodobipheny-N′-4′-nitrophenylurea, 5.20. Prepared by the condensation of 4-nitrophenylisocyanate and 4-iodo-4′-aminobiphenyl

Crystal Structures of N-Aryl-N′-4-Nitrophenyl Ureas in dry benzene, and crystallized from THF. 1H NMR (DMSO-d6): δ 9.47 (s, NH), 9.05 (s, NH), 8.20 (d, J ) 9, 2H), 7.78 (d, J ) 9, 2H), 7.70 (d, J ) 9, 2H), 7.63 (d, J ) 9, 2H), 7.57 (d, J ) 9, 2H), 7.46 (d, J ) 9, 2H). IR (KBr): 3314, 3265, 1649, 1113 cm-1. Mp > 250 °C. N-4-Ethynylbipheny-N′-4′-nitrophenylurea, 5.21. It was prepared by the ethynylation of 20 with TMS-acetylene followed by deprotection with K2CO3 in MeOH. 1H NMR (DMSO-d6): δ 9.53 (s, NH), 9.10 (s, NH), 8.20 (d, J ) 9, 2H), 7.64–7.70 (m, 6H), 7.58 (d, J ) 9, 2H), 7.53 (d, J ) 9, 2H), 4.21 (s, 1H). IR (KBr): 3344, 3296, 3018, 1640, 1204 cm-1. Mp > 250 °C. N-4-Tolyl-N′-4′-nitrophenylurea, 5.22. Crystallized from DMSO. 1 H NMR (DMSO-d6): δ 9.38 (s, 1H), 8.80 (s, 1H), 8.16 (d, J ) 8, 2H), 7.69 (d, J ) 8, 2H), 7.33 (d, J ) 8, 2H), 7.13 (d, J ) 8, 2H), 2.25 (s, 3H). IR (KBr): 3302, 1647, 1512, 1408 cm-1. Mp 238 °C. X-ray Crystal Structure. The unit cell parameters, space group, and crystal structures were determined from single crystal X-ray diffraction reflections collected on Enraf-Nonius CAD-4 or Bruker Smart Apex CCD diffractometer at the University of Hyderabad and The Chinese University of Hong Kong using Mo KR incident X-radiation (λ ) 0.71073 Å). Data reduction was performed using the Xtal 3.541 and SAINT softwares. Structures were solved using the direct methods in SHELX-97.42 Structural analysis was carried out in PLATON43 on Silicon Graphics and PC computers. Semi empirical and multiscan absorption correction SADABS44 were applied. Reflections were collected at ambient temperature (293–298 K) except for crystal 5.15 at 100 K. Crystal structures solved satisfactorily (Table 1) and all atoms are fully ordered except in 5.11 O atoms of one symmetry independent NO2 (O2 and O3) group have larger thermal ellipsoids, 5.13 S atom of one symmetry-independent DMSO (S1, S1”) has sof 0.60 and 0.40, and 5.17 I and NO2 groups occupy different orientations with sof 0.91 and 0.09.13 PXRD was collected on Philips X-ray diffractometer (Cu KR, λ ) 1.5405 Å) under ambient conditions at the University of Hyderabad. 1 H-1H NMR Difference NOE:30 Diphenyl urea and substituted diphenyl ureas (8–10 mg) were dissolved in 0.5 mL of DMSO-d6, and the samples were degassed with dry N2 under vacuum. The built-in program for difference NOE spectroscopy in Bruker Avance 400 was used: power 50 db, relaxation delay 6 s, 128 scans. The percentage enhancement was calculated as the ratio of the enhanced peak to the irradiated signal.

Acknowledgment. A.N. thanks the DST for funding (SR/ S5/OC-02/2002 and SR/S1/RFOC-01/2006). L.S.R. and S.K.C. thank the CSIR, and N.J.B. is recipient of UGC fellowship. Funds for the CCD X-ray diffractometer were provided by DST (IRPHA) and the UPE program is supported by UGC. We thank Prof. Thomas Mak and Dr. Chi-Keung Lam (The Chinese University of Hong Kong) for X-ray data collection on a few single crystals. Supporting Information Available: Packing diagrams, list of CSD refcodes and crystallographic data (.cif) are available free of charge via the Internet at http://pubs.acs.org.


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