Hydrogen Bonding in Crystal Structures of - American Chemical Society

Hydrogen Bonding in Crystal Structures of N,N′-Bis(3-pyridyl)urea. Why Is the N-H‚‚‚O Tape Synthon Absent in Diaryl Ureas with Electron-Withdrawing Groups? L. Sreenivas Reddy, Srinivas Basavoju, Venu R. Vangala, and Ashwini Nangia*

CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 1 161-173

School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India ReceiVed June 8, 2005

ABSTRACT: The urea tape R-network of bifurcated N-H‚‚‚O hydrogen bonds is a common motif in diaryl ureas and their molecular complexes. We analyzed the X-ray crystal structures of N,N′-bis(3-pyridyl)urea 3 and some of its derivatives: hydrates of stoichiometry 3‚(4/3)H2O and 3‚2H2O, cocrystals 3‚SA and 3‚FA‚H2O with succinic acid and fumaric acid, bis pyridine N-oxide 8, and bis N-methylpyridinium iodide 9. Crystal packing in pyridyl urea structures is directed by N-H‚‚‚Npyridyl, N-H‚‚‚Owater, N-H‚‚‚Oacid, and N-H‚‚‚I- hydrogen bonds instead of the common one-dimensional N-H‚‚‚Ourea tape. We postulated that the urea tape is absent in these structures because the CdO acceptor is weakened by two intramolecular C-H‚‚‚Ourea interactions (synthon III) in a planar molecular conformation. Electrostatic surface potential (ESP) charges (DFT-B3LYP/6-31G*) showed that the C-H‚‚‚O interactions sufficiently reduce the electron density at the urea O, and so other electronegative atoms, such as pyridyl N, H2O, COOH, and I-, become viable hydrogen-bond acceptors for the strong NH donors. 1H NMR difference nOe confirmed that the planar conformation of dipyridyl urea 3 in the solid-state persists in solution. Interestingly, even though the strong hydrogen-bond motifs changed in structures of 3, the C-H‚‚‚O interactions of synthon III (energy 4.6-5.0 kcal/mol) occurred throughout the family. In addition to dipyridyl urea, other electron-withdrawing diaryl ureas, e.g., those with phenylpyridyl and phenyl-nitrophenyl groups, also deviated from the prototype N-H‚‚‚O tape because of the interference from weak C-H‚‚‚O hydrogen bonds. Therefore, when one or both aryl rings have hydrogen-bond acceptor groups (e.g., pyridine, PhNO2), the NH donor(s) preferentially bond to pyridyl N, nitro O, or solvent O atom instead of the urea CdO acceptor. We classify supramolecular organization in diaryl ureas into those with the R-network (twisted molecular conformation) or non-urea tape structures (stable, planar conformation) depending on the substituent group. Our results suggest a model to steer urea crystal structures toward the tape synthon (Ph and electrondonating groups) or with non-urea hydrogen-bond motifs and a high probability for urea‚‚‚solvent hydrogen bonding (electronwithdrawing groups) by appropriate selection of functional aryl and heterocyclic groups. Introduction Crystal structures of mono- and diaryl ureas are well-known in the crystal engineering literature.1 The dominant recognition motif in N,N′-diaryl ureas is the R-network, a chain of bifurcated N-H‚‚‚O hydrogen bonds between NH donors and the CdO acceptor (Scheme 1). The urea N-H‚‚‚O tape synthon is so strong that it can persist even in the presence of other strong hydrogen-bonding functional groups, such as COOH and CONH2.2 In contrast to the well-documented predominance of the N-H‚‚‚O urea synthon, we noted recently that crystal structures of 4-nitrophenyl-4-X-phenyl urea 1 behave differently.3 The common hydrogen-bond pattern in 1 is bonding of NH donors to the NO2 group or to a solvent of crystallization (synthons I and II). The urea N-H‚‚‚O tape could be engineered in 2 out of 12 crystal structures (X ) I, CtCH) by engaging the interfering NO2 group in I‚‚‚O2N or C-H‚‚‚O2N interactions. This result showed that specific and directional interactions, even if they are weak (energy 1-4 kcal/mol), are able to direct the strong hydrogen-bond network (energy 5-15 kcal/mol) in crystal structures. Etter4 showed that the NH donors of bis(3nitrophenyl)urea 2 interact either with a solvent of crystallization (THF, DMSO) or with an acceptor molecule (Ph3PdO), but the urea tape synthon is generally absent, except in a metastable polymorph.5 The purpose of this study is to understand the factors that divert hydrogen bonding in diaryl ureas with electron-withdrawing groups, e.g., as in 1 and 2, toward nonurea tape motifs. The urea functional group is important in * To whom correspondence should be addressed. Fax: +91 40 23011338; e-mail: [email protected].

Scheme 1.

Supramolecular Synthons of Diaryl Ureas Discussed in This Paper

crystal engineering and supramolecular chemistry.6 Onedimensional urea tape is the target network in channel inclusion compounds, nonlinear optical materials, and modular assembly of hydrogen-bonded complexes. Non-urea tape hydrogen-bond motifs are found in pyridyl urea-based plant-growth inhibitors, organo-gelators, anion receptors, and as models for DNA complexes. We address the following related issues in this study. What functional groups in diaryl ureas lead to the tape synthon and which groups result in other hydrogen-bonding motifs? Is

10.1021/cg0580152 CCC: $33.50 © 2006 American Chemical Society Published on Web 10/29/2005

162 Crystal Growth & Design, Vol. 6, No. 1, 2006 Scheme 2.

Diaryl Ureas in This Studya

a Pyridyl rings are drawn in the conformation (see Scheme 3) present in the crystal structure.

there a common synthon when the urea tape is not adopted? What are the factors that favor one or the other crystal packing motif? Even as several research groups continue to examine the connection between molecular perturbation and crystal packing in the solid-state,7 our understanding of how a functional group or alkyl chain modification will alter the supramolecular structure is still evolving. According to Miller,8 the reality lies somewhere between crystal engineering and crystal mysticism. Results and Discussion We studied N,N′-bis(3-pyridyl)urea 3 (Scheme 2) for the following reasons. (1) The intramolecular C-H‚‚‚O motif III observed in structures of nitrophenyl ureas 1 and 2 will be favored in 3 because the proximal CH donors are activated in the 3-pyridyl ring, similar to the hydrogens of 3-nitrophenyl group in 2. Electron-withdrawing groups increase the acidity of donor hydrogen and consequently their hydrogen-bond strength.9 (2) One can compare hydrogen bonding in 3 with the persistent urea tape synthons in cocrystals of homologues pyridyl ureas 4 and 5.2a The reason for the nonformation of urea tape in 3-pyridyl ureas is different from 2-pyridyl ureas in which an intramolecular N-H‚‚‚N interaction changes the conformation, e.g., as in o-pyridyl urea 6,10 but this motif is not possible in m/p-pyridyl ureas. (3) Dipyridyl urea 3 is a symmetrical molecule that is isosteric with N,N′-diphenyl urea. Hence, steric effects are minimal and differences in hydrogen bonding may be understood through the pyridyl functional group. For example, the crystal structure of N-3-pyridylurea11 is very different from N-phenyl urea. A cursory examination of

Reddy et al. Scheme 3.

Conformation of Dipyridyl Urea in Crystal Structures

the Cambridge Structural Database (CSD)12 for phenylpyridyl ureas (search fragment 7) showed that the N-H‚‚‚Ourea tape is frequently replaced by N-H‚‚‚Npyridyl hydrogen bonding. These observations prompted the present systematic study of hydrogen bonding in bis(3-pyridyl)urea 3, its hydrates 3‚(4/3)H2O and 3‚2H2O, cocrystals 3‚SA and 3‚FA‚H2O, and derivatives 8 and 9. Dipyridylurea 3 was prepared by the solid-phase transamidation of urea with 3-aminopyridine.13 Diffraction-quality single crystals of 3 were obtained from hot EtOAc. Crystallization from MeOH and EtOH afforded hydrates of different stoichiometry, 3‚(4/3)H2O and 3‚2H2O, respectively. Cocrystallization of the pyridine moiety in 3 with succinic acid and fumaric acid (SA and FA) afforded equimolar complexes, 3‚SA and 3‚FA‚H2O. Smooth oxidation of the pyridine ring with m-CPBA gave bis N-oxide as a crystalline monohydrate, 8‚H2O. N-Methylation of the pyridyl ring (CH3I) gave pyridinium salt 9. All new compounds were characterized by NMR and IR spectra, and their crystal structures were determined by X-ray diffraction. Crystallographic data are summarized in Table 1, ORTEP diagrams are shown in Supporting Information (Figure S1), and hydrogen-bond interactions are listed in Table 2. Dipyridyl Urea 3, Its Hydrates, and N-Oxide 8. Dipyridyl urea 3 crystallizes in the orthorhombic space group Aba2 (No. 41). The molecule resides on the 2-fold axis such that the pyridyl N atoms are syn to the urea carbonyl. The activated CH donors (ortho to pyridyl N) form short intramolecular C-H‚‚‚O interactions (2.18 Å) of motif III via the syn-syn molecular conformation (Scheme 3), with the pyridyl moiety being coplanar with the urea carbonyl group (torsion angle C-CpyridylN-Ccarbonyl 4.5°). The NH donors hydrogen bond to different pyridine N acceptors through short and linear interactions (Figure 1). N-H‚‚‚Npyridyl hydrogen bonding disrupts the robust R-network of urea in 3, while the urea carbonyl accepts intraand intermolecular C-H‚‚‚O interactions. To complete the crystal packing, glide-related molecules produce layers mediated via N-H‚‚‚N and C-H‚‚‚O interactions, and such layers are connected through N-H‚‚‚N hydrogen bonds (Table 2). Even though the inclusion of water in organic crystals is a common phenomenon for structural chemists and crystal engineers,14 it is not properly understood when and why water is included in crystal structures. Hydration is favored in small molecules with an excess of acceptor groups.15 Crystallization of 3 from MeOH afforded single crystals of a hydrate, 3‚(4/3)H2O, having 1.5 molecules of 3 and two water molecules in the asymmetric unit (space group C2/c). The pyridyl moiety and urea carbonyl are roughly coplanar (C-Cpyridyl-N-Ccarbonyl ∼ 10°) with pyridine N atoms being anti to the urea carbonyl (Figure 2). Intramolecular C-H‚‚‚O interactions (2.22, 2.33 Å) stabilize the planar conformation III. The characteristic R-network is disrupted because the urea NH donors hydrogen bond with one of the water molecules in a bifurcated motif. Hydrogen atoms of water bond to different pyridyl moieties. In the crystallographically independent pair of 3 and water, one of the urea NHs and the adjacent phenyl CH form a bifurcated motif

Hydrogen Bonding in N,N′-Bis(3-pyridyl)urea

Crystal Growth & Design, Vol. 6, No. 1, 2006 163

Table 1. Crystallographic Data and Structure Refinement Parameters (CCDC Nos. 270959-270967)

chemical formula formula weight crystal system space group T/K a/Å b/Å c/Å R/° β/° γ/° Z V/Å3 Dcalc/g cm-3 µ/mm-1 reflns collected unique reflns observed reflns R1[I > 2σ(I)] wR2 [all] goodness-of-fit diffractometer

3

3‚(4/3)H2O

C11H10N4O 214.23 orthorhombic Aba2 293(2) 13.707(3) 7.014(1) 10.006(2) 90 90 90 4 962.0(3) 1.479 0.101 575 575 518 0.0431 0.0999 1.13 Enraf-Nonius FAST area detector

C33H38N12O7 714.75 monoclinic C2/c 120(2) 12.941(3) 11.789(2) 22.401(5) 90 101.37(3) 90 4 3350.5(13) 1.417 0.103 3834 3834 3171 0.0449 0.1307 1.10 Enraf-Nonius FAST area detector

3‚2H2O (293 K) C11H14N4O3 250.26 monoclinic P21/c 293(2) 6.8138(5) 19.586(11) 9.292(4) 90 101.24(3) 90 4 1216.3(9) 1.367 0.102 2402 2402 1675 0.0522 0.1409 1.04 Enraf-Nonius FAST area detector

3‚2H2O (100 K) C11H14N4O3 250.26 monoclinic P21/c 100(2) 6.7982(8) 19.560(2) 9.2746(11) 90 101.26(2) 90 4 1208.7(2) 1.375 0.103 5789 2386 1651 0.0499 0.1097 1.03 SMART-APEX CCD

3‚SA

3‚FA‚H2O

8‚H2O

9

10

C15H16N4O5 332.32 monoclinic C2/c 298(2) 38.093(8) 5.282(1) 16.428(3) 90 109.35(3) 90 8 3118.7(11) 1.416 0.109 3606 3565 2369 0.0676 0.1546 1.12 Enraf-Nonius-MACH-3

C15H16N4O6 348.32 triclinic P1h 298(2) 7.404(2) 8.068(4) 13.562(3) 104.55(3) 98.02(2) 95.52(3) 2 769.2(5) 1.504 0.119 3799 3522 1743 0.0651 0.1682 1.12 Enraf-NoniusMACH-3

C11 H12 N4 O4 264.25 monoclinic C2/c 298(2) 7.9686(7) 12.224(1) 24.538(2) 90.0 90.650(2) 90.0 8 2390.1(4) 1.469 0.115 17207 2349 1994 0.0462 0.1097 1.12 SMART-APEX CCD

C13H16I2N4O 498.10 triclinic P1h 100(2) 7.7439(15) 10.464(2) 10.683(2) 101.42(3) 100.55(3) 99.28(3) 2 816.5(3) 2.026 0.101 10526 3216 3119 0.0194 0.0490 1.104 SMART-APEX CCD

C12 H11 N3 O 213.24 orthorhombic Pbca 100(2) 11.779(1) 9.461(1) 18.262(2) 90 90 90 8 2035.0(4) 1.392 0.093 11545 2014 1897 0.0425 0.1038 1.12 SMART-APEX CCD

with the water O and H atoms donate to pyridyl N and urea O acceptors. All hydrogen bonds are in the usual distance-angle range (Table 2). Water is bonded to pyridyl urea, but there are no water‚‚‚water hydrogen bonds. A dihydrate, 3‚2H2O, was crystallized from EtOH in space group P21/c with one molecule of dipyridyl urea and two water molecules in the asymmetric unit. The O atom of one of the water molecules is disordered over two orientations with about equal occupancy (0.52, 0.48). The pyridyl moiety and urea carbonyl are in the same plane (C-H‚‚‚O interactions of III 2.19, 2.24 Å). Figure 3 shows the role of water molecule in disrupting the urea R-network. The ordered water forms a bifurcated N-H‚‚‚O and also connects the remaining structure via O-H‚‚‚Npyridyl and O-H‚‚‚Odisordered water hydrogen bonds. The disordered water molecule accepts N-H‚‚‚O from urea NHs and connects to pyridine and urea carbonyl moieties. When X-ray reflections were collected at 100 K to minimize water disorder, no improvement in the ordered nature of the atoms was observed. Having obtained three non-urea tape structures with the common synthon III, we decided to activate the pyridyl CH

donors of 3 by oxidation to bis N-oxide 8. Pyridine N-oxide, N+-O-, is a very strong hydrogen-bond acceptor group.16 The hydrate structure, 8‚H2O, contains one molecule of 8 and two 0.5 water molecules in the asymmetric unit (space group C2/c). Both pyridine N-oxide rings and urea carbonyl groups are roughly in the same plane. The activated CH donors participate in synthon III (2.16, 2.19 Å) with both N-oxide groups being syn to the urea carbonyl. One of the N-oxides forms a bifurcated N-H‚‚‚O- bond, whereas the other N-oxide is engaged in hydrogen bonding with a water molecule (Figure 4). Translation-related molecules are arranged in offset tapes via N-H‚‚‚O- H bonds and C-H‚‚‚O-, C-H‚‚‚Owater interactions (Table 2) connect such glide-related tapes. Complexes of 3 with Succinic and Fumaric Acids. A crystal engineering approach to favor the formation of the R-network in dipyridyl urea would be to engage the interfering pyridyl group in strong and robust COOH‚‚‚pyridine hydrogen bonding.17 For example, molecular complexes of homologous dipyridyl ureas 4 and 5 with dicarboxylic acids have the urea N-H‚‚‚O tape and acid‚‚‚pyridine O-H‚‚‚N synthons in roughly orthogonal directions.2 Cocrystallization of 3 with

164 Crystal Growth & Design, Vol. 6, No. 1, 2006

Reddy et al.

Table 2. Geometrical Parameters of Hydrogen Bonds pyridyl urea (τ/°)a 3 (4.5) 3‚(4/3)H2O (9.0, 9.9, 10.8)

3‚2H2O (1.7, 5.1)

3‚SA (0.9, 0.9)

3‚FA • H2O (0.7, 4.5)

8‚H2O (7.7, 16.1)

9 (2.1, 6.0) 10 (1.7, 15.6)

interactionb

D /Å

d /Å

q /°

N1-H1‚‚‚N2 C3-H3‚‚‚O1 C6-H6‚‚‚O1c N1-H1‚‚‚O3 N2-H2‚‚‚O3 N5-H5A‚‚‚O4 O4-H4A‚‚‚O1 O3-H3B‚‚‚N6 O3-H3A‚‚‚N4 O4-H4B‚‚‚N3 C5-H5‚‚‚O2 C16-H16‚‚‚O1 C6-H6‚‚‚O1c C11-H11‚‚‚O1c C17-H17‚‚‚O2c N1-H1‚‚‚O2 N2-H2‚‚‚O2 O2-H2B‚‚‚N4 O2-H2A‚‚‚O3 O3-H3A‚‚‚N3 O3-H3B‚‚‚O1 C9-H9A‚‚‚O1 C3-H3‚‚‚O1c C8-H8‚‚‚O1c O5-H5A‚‚‚N1 N3-H3A‚‚‚O2 N4-H4A‚‚‚O2 N4-H4A‚‚‚O3 N2-H2A‚‚‚O3 C5-H5‚‚‚O4 C1-H1‚‚‚O5 C10-H10‚‚‚O3 C9-H9A‚‚‚O3 C8-H8‚‚‚O1c C5-H5‚‚‚O1c O5-H5A‚‚‚N1 N3-H3A‚‚‚O2 N4-H4A‚‚‚O3 N2-H2A‚‚‚O6 O6-H6B‚‚‚O4 O6-H6A‚‚‚O3 C10-H10‚‚‚O3 C2-H2‚‚‚O2 C3-H3‚‚‚O2 C6-H6‚‚‚O5 C7-H7‚‚‚O1 C5-H5‚‚‚O1c C8-H8‚‚‚O1c N2-H2‚‚‚O2 N3-H3‚‚‚O2 O4-H4A‚‚‚O3 O5-H5A‚‚‚O3 C5-H5‚‚‚O5 C4-H4‚‚‚O3 C10-H10‚‚‚O4 C6-H6‚‚‚O1c C11-H11‚‚‚O1c N1-H1‚‚‚I1 N2-H2‚‚‚I1 C6-H6‚‚‚O1c C9-H9‚‚‚O1c N2-H2‚‚‚N1 N3-H3‚‚‚N1 C2-H2A‚‚‚O1 C4-H4‚‚‚O1c C8-H8‚‚‚O1c

3.064(4) 3.190(4) 2.807(4) 3.057(2) 2.819(2) 2.832(2) 2.831(2) 2.831(2) 2.861(2) 2.828(2) 3.479(2) 3.376(2) 2.875(2) 2.863(2) 2.902(2) 3.162(3) 2.767(3) 2.814(3) 2.613(8) 2.810(5) 2.761(9) 3.407(3) 2.853(3) 2.885(3) 2.637(3) 2.772(3) 3.024(3) 3.151(3) 2.563(3) 3.207(3) 3.415(4) 3.471(3) 3.314(3) 2.821(3) 2.848(3) 2.556(4) 2.742(4) 2.817(4) 2.639(4) 2.796(5) 2.683(4) 3.346(5) 3.398(6) 3.350(5) 3.463(5) 3.170(5) 2.785(5) 2.780(5) 2.735(2) 2.767(2) 2.781(2) 2.769(3) 3.202(3) 3.319(3) 3.183(3) 2.839(2) 2.870(2) 3.664(3) 3.477(3) 2.815(4) 2.843(4) 3.343(2) 2.922(2) 3.138(2) 2.882(2) 2.903(2)

2.08 2.48 2.18 2.16 1.84 1.90 1.86 1.88 1.90 1.85 2.55 2.45 2.22 2.22 2.33 2.30 1.78 1.83 1.71 1.89 1.94 2.51 2.19 2.24 1.66 1.78 2.14 2.55 1.56 2.44 2.37 2.47 2.32 2.16 2.16 1.58 1.74 1.82 1.64 1.85 1.72 2.50 2.32 2.54 2.39 2.17 2.08 2.11 1.81 1.80 1.80 1.79 2.20 2.38 2.36 2.16 2.19 2.70 2.47 2.12 2.18 2.46 1.92 2.20 2.25 2.24

163.7 122.3 123.7 147.5 162.2 152.1 167.6 162.3 165.3 175.4 143.4 143.4 116.2 115.7 119.2 141.8 164.9 175.9 159.9 154.6 138.9 138.9 116.8 116.2 169.3 166.1 145.1 159.9 173.4 126.7 162.5 153.8 151.8 117.2 118.7 168.7 171.9 170.3 167.6 160.7 164.4 134.5 173.2 130.8 169.1 152.3 119.6 117.0 150.4 157.3 171.4 172.2 151.9 144.0 131.0 118.3 118.4 159.5 176.7 119.5 117.4 145.4 170.2 143.0 115.0 117.3

a τ ) C-C b pyridyl-N-Ccarbonyl torsion angle. All C-H, N-H, and O-H distances are neutron normalized to 1.083, 1.009, and 0.983 Å. c Intramolecular C-H‚‚‚O interactions of synthon III.

succinic and fumaric acids from EtOH afforded complexes, 3‚ SA and 3‚FA‚H2O. In 3‚SA (space group C2/c), the pyridyl urea molecule resides in a perfectly planar conformation (C-Cpyridyl-N-Ccarbonyl < 1°) with one pyridyl N syn to the urea CdO and the other anti.

The carboxylic acid groups of succinic acid adopt a rare conformation in which one of the COOH groups is syn and the other is anti; furthermore, the ethylene chain is in a gauche conformation. As anticipated, both COOH donors hydrogen bond with the pyridyl residues of 3, but there are important differences: one of the acid-pyridine synthons (syn COOH) has neutral O-H‚‚‚N interaction, whereas partial proton transfer occurs in anti COOH to give N+-H‚‚‚O- H bond (1.56 Å, 173.4°).18 NH donors preferentially bond to the anti COOH carbonyl acceptor instead of the urea CdO because the former is a like a strong carboxylate acceptor (Figure 5). The supramolecular architecture of this molecular complex is a helical assembly of acid‚‚‚pyridine hydrogen bonds along the b-axis, and such helices are interwoven to form a triple helix19 via urea‚‚‚COO- H bonds (Figure 6). In 3‚FA‚H2O (space group P1h), the urea molecule resides in a planar syn-anti conformation, as in the previous cocrystal. In comparison to partial proton transfer in 3‚succinic acid the stronger fumaric acid (1st pKa: succinic acid 4.16, fumaric acid 3.03) completely transfers one of its acidic protons to the pyridine base.18 In addition to urea‚‚‚carboxylate20 hydrogen bonding, the pyrNH+ donor is connected to a water molecule. The network of COOH‚‚‚pyridine, water hydrogen bonds with COOH and COO- groups, and urea hydrogen bonds is shown in Figure 7. Even though there are significant differences in the strong hydrogen-bond networks of 3‚COOH complexes, the C-H‚‚‚O synthon III is present in both structures. The urea tape, however, is absent because of N-H‚‚‚Oacid hydrogen bonding. N-Methyl Dipyridinium Urea 9. To block the pyridine N from behaving as a hydrogen-bond acceptor for the urea NHs, dipyridyl urea 3 was N-methylated, which will lead to new structural changes. Since the pyridyl N is now quaternized as pyr-N+-Me it cannot accept hydrogen bonds. The CH donors, however, are strengthened in the electropositive pyridyl ring, and so C-H‚‚‚O synthon III will be favored. Does compound 9 form the N-H‚‚‚O urea tape, or a hydrate/solvate, or does it adopt a different crystal packing? The crystal structure of 9 shows bifurcated N-H‚‚‚I- hydrogen bonds with the soft counterion along with C-H‚‚‚I- interactions to the second iodide (Figure 8). The more activated CH (ortho to pyrN+Me) makes a shorter contact with the urea CdO compared to the anti pyridyl ring (synthon III: 2.12, 2.18 Å) in a syn-anti conformation. The structure of 9 shows that the strong NH donors seek out the best available acceptor even as the urea CdO consistently participates in intramolecular C-H‚‚‚O interactions with pyridyl CH donors. To summarize, the C-H‚‚‚O interactions of synthon III are shorter than the van der Waals sum of H and O (2.7 Å) in all structures. Even though the pyridyl ring could have twisted out of the urea plane, it is always present in the planar conformation, stabilized by short, intramolecular C-H‚‚‚O interactions. The persistence of C-H‚‚‚O synthon III in a variety of crystal structures of dipyridyl urea means that it is a structure-directing synthon even though it is a weak interaction in this family of strongly hydrogen-bonded pyridyl ureas. The remaining strong donors and acceptors then form N-H‚‚‚O/ N-H‚‚‚N hydrogen bonds to complete the crystal packing. Contrary to the hydrogenbond hierarchy rule,21 the urea CdO which is believed to be the strongest acceptor group in the molecule is not involved in hydrogen bonding with strong NH donors. Our results show that CdO accepts intramolecular C-H‚‚‚O interactions from activated C-H donors in electron-withdrawing dipyridyl ureas.



Figure 1. N-H‚‚‚Npyridyl hydrogen bonds and C-H‚‚‚Ourea interactions in the crystal structure of dipyridyl urea 3. Note the absence of urea tape synthon. C-H‚‚‚O interactions of synthon III are highlighted with an arrow in this and subsequent figures.

Figure 2. N-H‚‚‚Owater, O-H‚‚‚Ourea, and O-H‚‚‚Npyridyl hydrogen bonds and auxiliary C-H‚‚‚O interactions in hydrate 3‚(4/3)H2O.

The deviation in the R-network because of interference from C-H‚‚‚O synthon III is referred to as non-urea tape structures. We examined the crystal packing for possible stabilization from π-π stacking interactions between the planar pyridyl urea molecules. Whereas there is some degree of overlap between neighboring pyridyl rings (distance 3.5-4.0 Å), the stabilization that may accrue from aromatic stacking is small because the rings are offset and tilted. The molecules form infinite tapes in some cases, but there are no extended layer motifs (except Figure 7) that would result in significant π-π stacking energy. Stacking is generally favored in crystal structures of heteroaromatic compounds, but hydrogen bonding appears to direct the assembly in pyridyl ureas. Phenylpyridyl Ureas. The pyridyl group in N-(3-pyridyl)N′-phenyl urea 10 (space group Pbca)22 accepts a bifurcated N-H‚‚‚N interaction that disrupts the characteristic urea R-network (Figure 9). The molecule adopts a quasi-planar conformation through synthon III (τ ∼ 2, 15°; C-H‚‚‚O 2.24, 2.25 Å). We noted the lack of urea tape in several phenylm/p-pyridyl ureas 7 in the Cambridge Structural Database12 (see

Table 3; full list of CSD refcodes is available in Table S1, Supporting Information). These molecules have m-pyridyl or p-pyridyl rings and share common structural features with dipyridyl urea 3: (1) a planar molecular conformation stabilized by C-H‚‚‚O synthon III; (2) absence of one-dimensional urea tape; and (3) NH donors hydrogen bond with other electronegative acceptor atoms instead of the urea CdO. Why is the Urea R-Network Absent in Pyridyl Ureas? Why is the CdO group a strong hydrogen-bond acceptor for NH donors in some ureas and not others? We hypothesize that the two intramolecular C-H‚‚‚O interactions of synthon III, a persistent motif in these structures, weaken the urea oxygen acceptor23 because the electropositive hydrogen atoms share the electron density of oxygen lone-pairs. An electron-deficient aryl ring with potential hydrogen-bond acceptor groups, e.g., as in pyridyl or PhNO2, simultaneously activates the proximal CH donors that stabilize synthon III via two C-H‚‚‚O interactions. As the urea O gets weakened, pyridyl N and O atoms of solvent/ water molecules (or NO2 group) become stronger acceptors for urea NHs. This leads to the observed non-urea tape motifs in electron-withdrawing aryl ureas.


Reddy et al.

Figure 3. (a) N-H‚‚‚Owater, O-H‚‚‚Ourea, and O-H‚‚‚Npyridyl hydrogen bonds in hydrate 3‚2H2O. Note that one water molecule is ordered and the other is disordered. (b) Stereoview of the overall crystal packing.

The strength of urea CdO and pyridyl N acceptors was computed by the negative electrostatic surface potential (ESP) using Spartan (DFT-B3LYP/6-31G*).24 ESP charges were calculated on the molecular conformation extracted from the crystal structure (single-point energy) and also in the energyminimized conformation. The single-point and energy-minimized conformations are nearly the same in all structures except N,N′-diphenyl urea (Table 4). The energy of diphenyl urea and atomic charge on N/O atoms were calculated as a function of the aryl-N-CdO torsion angle (Figure 10). Analysis of data

in Table 4 and Figure 10 leads to the following points. (1) The charge on urea O is sensitive to the aryl-N-CdO torsion angle, it being more electron rich (better HB acceptor) when the aryl group is twisted and less negative (poorer HB acceptor) when it is planar. The electron density on urea O in the experimental twisted conformation of diphenyl urea is much greater than the charge in the minimized planar conformation (-50.8 vs -38.6 kcal/mol). A weakening of the CdO acceptor strength causes a change in hydrogen bonding from the urea R-network to other motifs. The distant pyridyl N is largely unaffected in various



Figure 4. (a) N-H‚‚‚Ooxide hydrogen bonding disrupts the urea R-network in pyridyl N-oxide hydrate 8‚H2O. (b) The N-oxide accepts hydrogen bonds from different water molecules.

Figure 5. Syn and anti conformations of COOH groups hydrogen bonded to different pyridyl acceptors in the succinic acid complex, 3‚SA. Note the partial transfer of proton from the anti COOH donor and its role as a hydrogen-bond acceptor for the urea NHs in a bifurcated motif.

conformations, as would be expected if the C-H‚‚‚O interactions are attenuating the electron density at the CdO acceptor

(see Figure S2, Supporting Information). (2) ESP charges (Table 4) nicely parallel the observed hydrogen-bond acceptor order


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Figure 6. (a) Helical assembly of in 3‚SA along the b-axis mediated by COOH‚‚‚pyridyl synthons. (b) Triple helix architecture with atoms shown as spheres. Urea‚‚‚acid hydrogen bonds are not shown for clarity. Table 3. Hydrogen Bonds in Some Phenylpyridyl Ureas 7a

a

The R-network is absent except in TAPRAD.

for urea NH donors in complexes of 3: COO- > N-oxide > H2O > pyridyl N > urea O (in planar conformation). Second, pyridyl N has greater negative charge than urea O (planar conformation). This suggested that the urea R-network would be observed if the pyridine N is sufficiently deactivated. The N-H‚‚‚O tape is present in phenyl-tetrafluoropyridyl urea 11

(ESP charge on urea O is more negative than pyridyl N in 11, Table 4).25 All this means that the intramolecular C-H‚‚‚O interactions of synthon III sufficiently reduce the electron density at the urea O so that it is not available for strong NH donors in the competitive environment of pyridyl N or water/ solvent O (or nitro O) acceptors. Remarkably, it is the weak



Figure 7. (a) Layered structure of fumaric acid hydrate, 3‚FA‚H2O, stabilized by urea‚‚‚COO- and water O-H‚‚‚O hydrogen bonds. (b) The layers are connected via water O-H‚‚‚O H bonds to the carboxylate anion of the next layer.

C-H‚‚‚O interactions of the electron-withdrawing phenyl rings that direct the strong hydrogen-bond networks in diaryl urea structures. The energy profile in Figure 10 shows that the planar conformation of diphenyl urea (ι ) 0, 180°) is more stable than the twisted conformation (ι ) 90°) by 9.0 kcal/mol, an energy difference that is in agreement with a recent calculation on torsional parameters about the urea amide bond.26 The planar conformation of diaryl urea is more stable in the gas phase because of two additive effects: conjugation of urea N with electron-withdrawing phenyl ring and intramolecular C-H‚‚‚O interactions. To estimate the stabilization from conjugation only, the energy profile of the methylene analogue of diphenyl urea, 12, was calculated (Scheme 4). The energy difference between the stable, near planar (ι ) 30°) and the high energy, twisted (ι ) 90°) conformation is 4.4 kcal/mol in 12. This value gives an estimate for the stabilization due to resonance effects only. Conjugation of urea N with the electronwithdrawing aryl groups is less effective because the nitrogen lone pair is nicely conjugated to the CdO group. There is little alternation in C-C bond lengths of the aryl ring in X-ray crystal structures, an observation that is consistent with the absence of extended conjugation. The energy difference of 9.0-4.4 ) 4.6 kcal/mol is an estimate for the stabilization from two short

C-H‚‚‚O interactions (H‚‚‚O ∼ 2.2 Å) of synthon III. We estimate that out of the 9.0 kcal/mol stability to the planar conformer of diphenyl urea, 4.0 kcal/mol is due to resonance and 5.0 kcal/mol accrues from the two C-H‚‚‚O interactions. Energy of 2.5 kcal/mol per interaction is in the normal range for activated, weak C-H‚‚‚O hydrogen bonds.9 The intramolecular C-H‚‚‚O interaction is stronger (4-8 kcal/mol) in the highly activated carboranyl group27 compared to the phenyl ring (pKa: carborane 27, benzene 43). DFT calculations on dipyridyl urea 3 parallel the trend in diphenyl urea: the planar conformation is more stable than the metastable twisted conformer (see Figure S2 for plots, Supporting Information). Intramolecular carboranyl C-H‚‚‚O interactions have been characterized in solution by NMR spectroscopy.27 To find out the conformation of diaryl ureas in solution, difference nOe 1H NMR experiments were performed in DMSO-d6. Irradiation of the NH proton of dipyridyl urea 3 at δ 9.01 shows enhancement of the ortho-H signal at δ 7.98 (28%), implying that the planar syn-syn conformation of 3 in the crystal is present in solution. Similarly, irradiation of the diphenyl urea NH proton at 8.71 (DMSO-d6) showed nOe to the ortho-H signal at δ 7.48 (22%) in a planar conformation (Figure 11). The more activated CH donor proximal to pyridyl N makes C-H‚‚‚O interactions with urea O in the observed syn-syn conformation. The persistence


Reddy et al.

Figure 8. N-H‚‚‚I- hydrogen bonds with the counterion along with C-H‚‚‚I- interactions to the second iodide in the crystal structure of pyridinium salt 9. Table 4. Electrostatic Surface Potential (ESP) Charge Calculated in Spartan24 (DFT-B3LYP/6-31G*, kcal/mol) on Urea O and Pyridyl N Acceptor Atoms

a The molecular conformation is defined as planar when the aryl ring and urea N-C(O)-N group are roughly coplanar (C-C-N-C torsion angle ι ) 0-15°) and twisted for ι ) 30-45°. The orthogonal conformation (ι ) 90°) is the least stable and has the highest ESP charge on urea O.

of a bifurcated synthon III and planar molecular conformation in solution is consistent with its strength of ca. 5 kcal/mol. C-H‚‚‚O hydrogen bonds in peptides (energy 2.0-2.5 kcal/ mol) have been characterized by NMR spectroscopy.28 Variabletemperature NMR of dipyridyl urea 3 in MeOH-d4 (300-200 K) shows no change in peak positions, which means that the conformation remains the same upon cooling to 200 K, a result that is in agreement with the higher stability of the planar conformation in the gas phase (DFT calculations). When NMR spectra were recorded at varying concentrations (0.005-0.5 M in MeOH-d4), there was no change in peak profile, which could

mean that the urea molecules perhaps aggregate with the solvent, but there is no evidence for dimeric/oligomeric urea species at higher concentrations. NMR spectra in MeOH-d4 and DMSOd6 are virtually identical in δ and J values. Difference nOe experiments were carried out in DMSO-d6 because the NH protons exchange rapidly in MeOH-d4. On the other hand, variable temperature and concentration-dependent NMR studies had to be done in MeOH-d4 for solubility reasons. These data suggest that 3‚MeOH and 3‚DMSO aggregates in NMR solvents resemble the related complexes of diaryl ureas with water and DMSO/DMF.3,4



Figure 11. 1H NMR nOe (DMSO-d6) on dipyridyl urea 3 and diphenyl urea. Enhancement of the δ 7.98 signal means that 3 resides in the syn-syn conformation in solution.

Scheme 5. Correlation between Molecular Functional Group and Hydrogen-Bond Synthon in Diaryl Urea Structures

Figure 9. Bifurcated N-H‚‚‚Npyridyl hydrogen bonds interfere with the urea R-network in phenylpyridyl urea 10. Note that the urea CdO accepts a C-H‚‚‚O interaction. Several phenylpyridyl ureas listed in Table 3 have similar hydrogen-bond motifs.

Figure 10. Spartan computations (DFT-B3LYP/6-31G*) on diphenyl urea as a function of the aryl-N-CdO torsion angle. Relative energy is plotted such that the highest energy conformer is arbitrarily fixed at 0. The planar molecular conformation is the most stable. Note that the ESP charge on the urea O atom is higher (better hydrogen-bond acceptor) in the twisted conformation.

Scheme 4. Contribution from Resonance but No C-H‚‚‚O Interaction in Model Compound 12 (Spartan, DFT-B3LYP/ 6-31G*)24

conformation that is present in solution. Therefore, stronger acceptors such as pyridyl N, solvent O, or nitro O form aggregates with urea NH donors. On the other hand, when urea O is the only acceptor group, e.g., as in diphenyl urea or electron-donating ureas, the molecule twists to the metastable conformation. This twisting not only enables the molecules to form stronger hydrogen bonds but also to achieve better close packing of aryl rings along the 4.7 Å urea tape. A spot-check and manual analysis of about 35 diaryl urea crystal structures in the CSD (see Table S1 for refcodes, Supporting Information), as well as our results on a dozen crystal structures of 1,3 follow the hydrogen-bonding model of Scheme 5. We plan to carry out low-temperature X-ray diffraction studies of some model crystals to get experimental urea O charge densities as a function of phenyl ring twist to compare with calculated values. In summary, diaryl ureas may be classified into two broad categories: (1) Urea tape structures have a twisted conformation. (2) The planar conformation leads to non-urea tape motifs. The observation that molecules belonging to category (2) generally have an electron-withdrawing group that activates the phenyl CH donors testifies to the significance of weak C-H‚‚‚O synthon III. We argue that the C-H‚‚‚O is not just a bystander interaction in the strong N-H‚‚‚O/ N-H‚‚‚N hydrogen-bonded structure but is in fact an important structure-directing perturbation in diaryl ureas. In the absence of this crucial C-H‚‚‚Ourea interaction, e.g., as in homologous pyridyl ureas 4 and 5 with an adjacent CH2 group instead of the pyridyl ring,2 the expected urea tape structure is always observed. These results underscore the point that the intrusive role of weak C-H‚‚‚O interactions in strongly hydrogen-bonded structures must be carefully examined by analyzing individual crystal structures. It is very difficult to predict whether a particular interaction will be passive, supportive, or structure-directing by a casual inspection of the molecular structure. The significance of weak C-H‚‚‚O hydrogen bonds is being increasingly characterized and quantified in small molecule and protein structures.29 Conclusions

Why is hydrogen bonding in dipyridyl urea different from diphenyl urea? Our structural, NMR, and computational results are consistent with the following model. The diaryl urea CdO is a marginal hydrogen-bond acceptor in the stable, planar

Hydrogen bonding in dipyridyl ureas, and in general in diaryl ureas with electron-withdrawing groups, is different from diaryl ureas having neutral or electron-donating groups. Difference nOe NMR experiments confirm that the planar syn-syn conformation of dipyridyl urea 3 in its crystal structure is also present in


solution. The acceptor strength of urea CdO depends on the molecular conformation and the presence of intramolecular C-H‚‚‚O interactions: it is a better hydrogen-bond acceptor in the twisted conformation than in the planar one. Because of reduced acceptor strength in C-H‚‚‚O-bonded CdO of dipyridyl urea 3, strong NH donors approach other potential acceptors such as pyridyl N, solvent O, or nitro O atoms. The notion that urea N-H‚‚‚O tape is the result of strongest-donor to strongest-acceptor hierarchy breaks down in pyridyl and nitrophenyl ureas because of interference from weak C-H‚‚‚O interactions. Surprisingly, the urea CdO is hardly involved in strong hydrogen bonding among the non-urea tape structures. The role of alkyl groups and steric control over hydrogen bonding in thio-urea structures was analyzed recently.30 We show in this paper that the robust one-dimensional urea tape synthon can be perturbed in a systematic way by electronwithdrawing groups on the phenyl ring. It is generally believed that alkyl group changes are the most easily predicted structures in crystal engineering.8 The molecular complexes of dipyridyl urea 3 with succinic acid and fumaric acid are a case in contrast because they are very different from the structures of homologous ureas 4, 5 with dicarboxylic acids.2 These observations add yet another dimension to the design of target supramolecular structures, namely, the effect of pendant alkyl group8 and methylene chain length16 modifications on crystal packing. In terms of prognostication, the above trends on hydrogenbond donor-acceptor preferences should be transferable to metal-ligand bonding modes in coordination polymers and hybrid materials, e.g., metal-pyridine vs metal-carbonyl bonding for isonicotinamide and dipyridyl urea ligand.31 Drug molecules typically contain several hydrogen-bonding groups of the acid, amide, urea, and pyridine type (e.g., piroxicam). The multifunctional dipyridyl urea system should serve as a guide for understanding drug polymorphism and to design new pharmaceutical cocrystals.32 Experimental Section Synthesis. All compounds were characterized by IR and NMR. 1H NMR spectra (δ scale, J coupling in Hz) were recorded on a Bruker Avance spectrometer at 400 MHz and FT-IR spectra (ν in cm-1) were recorded on a Jasco 5300 spectrophotometer. Melting points were recorded on a Fisher-Johns apparatus. N,N′-Bis(3-pyridyl)urea 3.13 A 2:1 molar solid mixture of 3-aminopyridine and urea (10 mmol, 940 mg; 5 mmol, 300 mg) was heated at 160 °C for 5 h. The reaction mixture was cooled and poured into water. The light-violet colored precipitated was filtered and washed with EtOAc and recrystallized from the same solvent (60%). IR (KBr): 3526, 3256, 1714, 1631, 1485, 1026, 802; 1H NMR (DMSO-d6): 7.35 (dd, 8,5, 2H,), 7.98 (d, 8, 2H), 8.20 (d, 5, 2H), 8.62 (s, 2H), 9.01 (s, NH, 2H). m.p. 224 °C. Hydrates of 3. Crystallization of 3 from MeOH at room temperature afforded needle-shaped single crystals of the hydrate, 3‚(4/3)H2O, and crystallization from EtOH at room temperature afforded trigonal-shaped crystals of the dihydrate, 3‚2H2O. We did not observe both hydrates in the same crystallization batch. The release of water from hydrate crystals was confirmed by DSC and TGA (see Table S2 and Figure S3, Supporting Information). 3‚Succinic Acid. A 1:1 molar mixture of ground dipyridyl urea 3 and succinic acid (0.2 mmol, 40 mg; 0.2 mmol, 24 mg) was dissolved in ethanol. Slow evaporation at room temperature afforded single crystals of the molecular complex 3‚SA. 1H NMR (MeOH-d4): 2.45 (s, 4H), 7.34 (dd, 8,5, 2H), 8.00 (d, 8, 2H), 8.17 (d, 5, 2H), 8.59 (br s, 2H). m.p. 179-181 °C. 3‚Fumaric Acid‚H2O. A 1:1 molar mixture of manually ground dipyridyl urea 3 and fumaric acid (0.2 mmol, 40 mg; 0.2 mmol, 23 mg) was dissolved in ethanol. Slow evaporation at room temperature afforded single crystals of the hydrate, 3‚FA‚H2O. 1H NMR (DMSO-

Reddy et al. d6): 6.70 (s, 2H), 7.49 (dd, 8,5, 2H), 8.02 (d, 8, 2H), 8.28 (br s, 2H), 8.38 (s, 1H), 8.70 (br s, 2H), 9.11 (s, NH, 2H). m.p. 134 °C. N,N′-Bis(3-pyridyl-N-oxide)urea 8. Oxidation of dipyridyl urea 3 (1 mmol, 214 mg) with m-CPBA (2 mmol, 340 mg) in EtOAc afforded the product (78%), which was crystallized from methanol to obtain 8‚H2O. Water content in the hydrate crystal was confirmed by DSC and TGA (see Table S2 and Figure S3, Supporting Information). IR (KBr): 3290, 1716, 1589, 1423, 1153, 790; 1H NMR (DMSO-d6): 7.17 (m, 2H), 7.36 (d, 8, 2H), 7.80 (d, 6, 2H), 8.59 (s, 2H), 9.04 (s, NH, 2H). m.p. 280 °C (dec). N,N′-Bis(N-methyl-3-pyridinium)urea Iodide 9. To a solution of dipyridyl urea 3 (0.7 mmol, 160 mg) in 5 mL of DMSO was added MeI (3.7 mmol, 0.23 mL) at room temperature. The reaction mixture was stirred for 8 h. A yellow-colored precipitate was formed on adding EtOAc (10 mL). The precipitate was filtered and dried under vacuum (65%). Diffraction-quality single crystals were obtained from EtOH. IR (KBr): 3217, 2978, 1716, 1635, 1597, 1556, 1504, 1469, 1309, 1199, 1037, 951. 1H NMR (DMSO-d6): 3.85 (s, 3H), 4.38 (s, 3H), 8.09 (br s, 2H), 8.46 (br s, 2H), 8.69 (br s, 2H), 9.15 (br s, 2H), 10.20 (br s, 2H). m.p. 256 °C. N-Phenyl-N′-(3-pyridyl)urea 10. Prepared by the reaction of phenylisocyanate (10 mmol, 0.5 mL) with 3-aminopyridine (10 mmol, 470 mg) in benzene (83%). IR (KBr): 3364, 3271, 3200, 1711, 1628, 1489,1024, 802; 1H NMR (DMSO-d6): 7.00 (t, 7, 1H), 7.30-7.32 (m, 3H), 7.47 (d, 8, 2H), 7.95 (d, 8, 1H), 8.19 (d, 4, 1H), 8.60 (s, 1H), 8.80 (s, NH, 1H), 8.84 (s, NH, 1H). m.p. 165 °C. X-ray Crystallography. X-ray reflections on dipyridyl urea 3, 3‚ (4/3)H2O, and 3‚2H2O were collected on an Enraf-Nonius FAST area detector with rotating anode source, 3‚SA and 3‚FA‚H2O were collected on an Enraf-Nonius MACH-3 diffactometer, and 3‚2H2O (100 K), 8‚ H2O, 9, and 10 were collected on a SMART APEX CCD diffractometer. All data were collected using Mo KR radiation (λ ) 0.71073 Å), and crystal structures were solved by direct methods using SHELXS-97 and refined by full matrix least-squares refinement on F2 with anisotropic displacement parameters for non-H atoms using SHELXL97.33,34 N-H and O-H hydrogens were refined from difference Fourier maps; aromatic and aliphatic C-H hydrogens were generated by the Riding model in idealized geometries. Table 1 gives the pertinent crystallographic data, and Table 2 gives the hydrogen-bond distances. DSC/TGA. DSC was recorded on Mettler Toledo DSC 822e module and TG was recorded on a Mettler Toledo TGA/SDTA 851e module, managed by the integrated STAR software. The stoichiometry of 3‚ (4/3)H2O, 3‚2H2O, and 8‚H2O determined by X-ray diffraction is consistent with DSC and TGA measurements. 1 H-1H NMR Difference nOe. The appropriate diaryl urea (8-10 mg) was dissolved in 0.5 mL of DMSO-d6, and the sample was 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. Irradiation of the urea NH signal at δ 9.01 showed positive enhancement of the signal at 7.98 in dipyridyl urea 3. No enhancement was observed at 8.62. Similarly irradiation of the 8.71 peak in diphenyl urea enhanced the peak at 7.48. The percentage enhancement was calculated as the ratio of the enhanced signal to the irradiated peak. Proton nOe enhancements of 20-30% are normal for proximal hydrogen atoms in constrained systems.35

Acknowledgment. A.N. thanks the DST for funding (SR/S5/OC-02/2002). L.S.R., S.B., and V.R.V. thank the CSIR for a fellowship. Funds for the CCD diffractometer are provided by DST (IRPHA) and the UPE program is supported by UGC. Crystal data for dipyridyl urea 3 and its hydrates were collected by Dr. H. L. Carrell (Fox Chase Cancer Center, Philadelphia, USA). We thank a referee for critical comments and suggestions. Supporting Information Available: Crystallographic data (.cif) for crystal structures, Figures S1-S3, and Tables S1-S2 are available via the Internet at http://pubs.acs.org.

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Hydrogen Bonding in Crystal Structures of - American Chemical Society

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