Tautomeric Preference and Conformation Locking in Fenobam

Jul 11, 2014 - Department of Chemistry, Mangalore University, Mangalore, 574199, Karnataka, India. ∥. School of Chemistry and Biochemistry, The ...
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Tautomeric Preference and Conformation Locking in Fenobam, Thiofenobam, and Their Analogues: The Decisive Role of Hydrogen Bond Hierarchy Sajesh P. Thomas,†,∥ K. Shashiprabha,‡,§ K. R. Vinutha,† Suresh P. Nayak,§ K. Nagarajan,‡ and T. N. Guru Row*,† †

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, 560012, Karnataka, India Alkem Laboratories Ltd., Bangalore, 560023, Karnataka, India § Department of Chemistry, Mangalore University, Mangalore, 574199, Karnataka, India ∥ School of Chemistry and Biochemistry, The University of Western Australia, 6009, Crawley, Western Australia, Australia ‡

S Supporting Information *

ABSTRACT: The crystal and molecular structures of the potential antidepressant drug fenobam and its derivatives are examined in terms of the preferred form among the two possible tautomeric structures. In this study, chemical derivatization has been utilized as a means to “experimentally simulate” the tautomeric preference and conformational variability in fenobam. Eight new derivatives of fenobam have been synthesized, and structural features have been characterized by single-crystal X-ray diffraction and NMR spectroscopy. The specific tautomeric preference found in all of these compounds and their known crystal forms have been construed in terms of the stabilizing intramolecular N−H···O and N−H···S hydrogen bonding. The hierarchy of intramolecular hydrogen bonds evidenced as the preference of the C−H···O hydrogen bond over C−H···N and that of the C−H···N hydrogen bond over C−H···S explains the two distinct conformations adopted by fenobam and thiofenobam derivatives. The relative energy values of different molecular conformations have been calculated and compared.

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antidepressant known for more than 36 years.4 Recent studies have shown that fenobam is a selective and potent mGluR5 antagonist with positive effects against the fragile X syndrome in animal models and with no significant adverse effects.5−9 In a recent communication,10 we have shown that the tautomeric form exhibited by fenobam in its polymorphs and hydrates is different from the commonly conceived form (Figure 1) and that reported

INTRODUCTION

The phenomenon of tautomerism, in a sense, is the molecular counterpart of what polymorphism is in the supramolecular context. While in polymorphs,1the same molecule gets arranged in different packing and/or conformational motifs, the tautomeric forms are generated when the proton positions are swapped among the atoms of the same molecule, resulting in possible isomeric structures. Though, in the solution state, the different tautomeric forms usually exist in equilibrium with each other,2 in the solid state, the molecule often resorts to the energetically favorable form. In the case of nearly equi-energy tautomeric forms, these can lead to positional disorder and even tautomeric polymorphism, as observed in the intriguing case of omeprazole.3 Since the phenomenon is pertaining to the molecular structure itself, it is essential to know the true preference of the molecules over the possible tautomeric forms. A wrongly assessed tautomeric form can result in an interchange of hydrogen bond donor and acceptor sites. Hence, the knowledge of correct tautomeric form is indispensable in many areas of structural chemistry, including crystal structure prediction, ab initio structure solution from powder diffraction, etc. In this paper, we discuss the tautomeric preference exhibited by the potential drug fenobam, and its eight analogues. Fenobam, is an anxiolytic and © 2014 American Chemical Society

Figure 1. Molecular structures of the possible tautomers of fenobam.

Received: January 9, 2014 Revised: July 2, 2014 Published: July 11, 2014 3758

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(mp 136−142 °C). Similarly, (5) 1-o-fluorophenyl-3-(1-methyl-4oxo-2-imidazolidinylidene)thiourea, (6) 1-m-fluorophenyl-3-(1-methyl4-oxo-2-imidazolidinylidene)thiourea, (7) 1-p-fluorophenyl-3-(1-methyl4-oxo-2-imidazolidinylidene)thiourea, and (8) 1-o,p-difluorophenyl-3(1-methyl-4-oxo-2-imidazolidinylidene)thiourea were prepared. (see the Supporting Information for the synthetic schemes). 1: 1H NMR (400 MHz, CDCl3): δ 10.71 (s, 1H), 7.43−7.46 (m, 1H), 7.21−7.25 (m, 1H), 7.09−7.11 (bd, 1H), 6.73−6.77 (m, 1H), 3.92 (s, 2H), 3.12 (s, 3H). 2: 1H NMR (400 MHz, CDCl3): δ 10.71 (s, 1H), 8.20−8.24 (t, 1H), 7.52 (bs, 1H), 7.10−7.14 (m, 1H), 7.05−7.07 (m, 1H), 6.96− 7.02 (m, 1H), 3.91 (s, 2H), 3.14 (s, 3H). 3: 1H NMR (400 MHz, CDCl3): δ 10.74 (s, 1H), 7.41−7.45 (m, 2H), 7.16 (bs, 1H), 6.97−7.02 (t, 2H), 3.89 (s, 2H), 3.09 (s, 3H). 4: 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 10.56 (s, 1H), 7.80 (bs, 1H), 7.49 (bs, 1H), 7.28−7.32 (t, 1H), 7.09−7.11 (d, 1H), 4.13 (s, 2H), 3.00 (s, 3H). 5: 1H NMR (400 MHz, CDCl3): δ 12.35, 12.44 (2bs, total 1H), 8.30 (bs, 1H), 8.21, 7.90 (2bs, total 1H), 7.17 (m, 3H), 3.94 (s, 2H), 3.03, 3.11 (2s, total 3H). 6: 1H NMR (400 MHz CDCl3,): δ 12.41, 12.30 (2bs, total 1H), 8.36 (bs, 1H), 7.46−7.48, 7.62 (bd, bs, total 1H), 7.22−7.35, 6.987.04 (2bs, 2H), 3.92, 3.96 (two overlapping singlets total 2H), 3.10 (s, 3H). 7: 1H NMR (400 MHz, CDCl3): δ 12.53, 12.32 (2s, total 1H), 8.80, 8.25 (2bs, total 1H), 7.37−7.53 (m, 2H), 7.00−7.11 (m, 2H), 3.93 (s, 2H), 3.00, 3.18 (2s, total 3H). 8: 1H NMR (400 MHz, CDCl3): δ 12.32, 12.40 (2bs, total 1H), 8.14 (bs, 1H), 7.72−7.74, 8.05 (d, bs, total 1H), 6.85−6.87 (d, 2H), 3.93 (s, 2H), 3.11, 2.98 (2s, total 3H). Crystallization. The compounds 1−8 have been crystallized by a slow evaporation method using methanol, acetone, and acetonitrile as solvents at room temperature (25 °C). X-ray Crystallography. The crystals were cooled to 100 K with a liquid nitrogen stream using an Oxford Instruments Cryojet-HT nitrogen gas-stream cooling device. X-ray diffraction data were collected on an Oxford Xcalibur (Mova) diffractometer equipped with an Eos CCD detector using Mo Kα radiation of wavelength 0.71073 Å. The scan width (ω) was chosen to be 1° per frame, and the crystal-to-detector distance was fixed at 45 mm during the data collection. Cell refinement and data integration and reduction were carried out using the program CrysAlisPro.16 The crystal structure was solved by direct methods and refined using SHELXS9717 accessed by the WinGX package.18 All hydrogen atoms were located from the difference Fourier map and, in a later stage, fixed to standard X-ray bond length values and refined using a riding atom model. The crystals of 2 showed a rotational twinning owing to the similarity in a and c cell parameters, which was treated with the twin law [0 0 1 0-1 0 1 0 0], and the twin domain was refined to a BASF value of 0.24873.

in the Chemical Abstract Service Registry (CAS no: 57653-26-6). Besides, the charge density features of fenobam also have been explored in the context of a potential “carbon bonding” motif in one of its polymorphs.11 In the present study, we have used chemical derivatization as a means to experimentally “simulate” the preferred tautomeric form under the conditions of altered electronegativity of the attached functional groups and consequent generation of different supramolecular environments. Recently, chemical substitution has been shown to be an effective method to scan over the complex supramolecular structural landscape,12 whereas our attempt is to utilize the possible variety of supramolecular milieu achieved via chemical derivatization to understand the intramolecular conformational and tautomeric features of this potential drug molecule. In this direction, eight derivatives of fenobam, (1) m-fluorofenobam, (2) o-fluorofenobam, (3) p-fluorofenobam, (4) thiofenobam, and its fluorinated derivatives (5) o-fluorothiofenobam, (6) m-fluorothiofenobam, (7) p-fluorothiofenobam, and (8) o,p-difluorothiofenobam, were synthesized, and crystal structures have been analyzed using singlecrystal X-ray diffraction (systematic names have been given in the Experimental Section). In the crystal structures of the present series of compounds, it is found that the conformational features of thiofenobam and its analogues follow a trend different from that observed in polymorphs of fenobam and its fluoro analogues. This has been rationalized in terms of the hierarchy of intramolecular C−H···O, C−H···N, and C−H···S hydrogen bonds supported by the computational energy calculations. It is known in the literature that such weak hydrogen bonds have the potential to control molecular conformations13 and to form supramolecular synthons in a cooperative fashion14,15 (which are sometimes energetically comparable to strong hydrogen bond motifs15). Our observations in the present series of compounds substantiate the conformation locking potential of weak hydrogen bonds. In addition, supramolecular synthons present in these crystal structures and the positional disorder (arising from hydrogen−fluorine isosteric nature) observed in o,p-difluorothiofenobam have been discussed. The stabilizing roles of weak C−H···O, C−H···N, C−H···F, C−H···Cl, and C−H···S hydrogen bonds in crystal packing have been quantified by Hirshfeld surface analysis.

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EXPERIMENTAL SECTION

Synthesis of 1-m-Fluorophenyl-3-(1-methyl-4-oxo-2imidazolidinylidene)urea (Fluorofenobam) and Analogues. To a suspension of creatinine (0.005 mol) in 15 mL of dry 1,4-dioxane was added m-fluorophenylisocyanate (0.005 mol) (Supporting Information, Scheme S1). The mixture was heated to 90−95 °C for 2 h. The solution was filtered, and the filtrate was cooled. Ice and ice−water were added to the filtrate. A white solid precipitate was filtered off. After recrystallization from acetone− methanol (1:1), the pure product 1-m-fluorophenyl-3-(1-methyl4-oxo-2-imidazolidinylidene)urea (1) was obtained (mp 170−171.6 °C). Similarly, (2) 1-o-fluorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea (mp 174−176 °C) and (3) 1-p-fluorophenyl-3(1-methyl-4-oxo-2-imidazolidinylidene)urea (mp 192−194 °C) were obtained. Synthesis of 1-m-Chlorophenyl-3-(1-methyl-4-oxo-2imidazolidinylidene)thiourea (Thiofenobam) and Analogues. To a suspension of creatinine (0.005 mol) in 15 mL of dry dimethylformamide (DMF) was added m-chlorophenylisothiocyanate (0.005 mol) (Supporting Information, Scheme S2). The mixture was heated to 90−95 °C for 2 h. The solution was filtered, and the filtrate was cooled. Ice and ice−water were added to the filtrate. A reddish orange solid precipitate was filtered off. After recrystallization from acetone−methanol (1:1), the pure product 1-m-chlorophenyl-3(1-methyl-4-oxo-2-imidazolidinylidene)thiourea (4) was obtained

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RESULTS AND DISCUSSION

Crystal structures of the eight analogues of fenobam are described in this section with reference to their molecular conformation, tautomeric form adopted, and the preferred supramolecular synthons. Atom color scheme in crystal packing diagrams is same as that in the ORTEPs. The ORTEPs are given in Figure 2a−h. The details of crystal structure solution and refinement are given in Table 1. The intra- and intermolecular interactions are listed in Table S1 in the Supporting Information. Crystal Structure of m-Fluorofenobam Monohydrate, 1. m-Fluorofenobam crystallizes in monoclinic space group P21/n as a monohydrate. The proton H3 attached to atom N3 (located from the difference Fourier map) suggests the intramolecular N3−H3···O1 hydrogen bond and the preferred tautomeric form in this structure. Further, the intramolecular C6H6···O1 hydrogen bond offers near planar geometry, as shown in Figure 2a. Thus, the molecular conformation is quite similar to that found in polymorphs of fenobam. This conformation offers 3759

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Figure 2. ORTEPs representing 50% probability ellipsoids of (a) m-fluorofenobam monohydrate, (b) o-fluorofenobam, (c) p-fluorofenobam, (d) thiofenobam, (e) o-fluorothiofenobam, (f) m-fluorothiofenobam, (g) p-fluorothiofenobam, and (h) the disordered o,p-difluorothiofenobam.

Crystal Structure of o-Fluorofenobam, 2. o-Fluorofenobam crystallizes in monoclinic space group P2/c, with Z′ = 2. Both the symmetry independent molecules adopt the tautomer II with intramolecular N−H···O hydrogen bonds. Owing to the presence of a F atom in the ortho position, the molecules assume a nonplanar conformation as different from 1. The amide

the N2 acceptor site and N1−H1 donor site for the water mediated intermolecular N−H···Ow and Ow−H···N hydrogen bonds that interlink the amide dimers formed via centrosymmetric N−H···O hydrogen bonds (Figure 3a). The supramolecular tapes thus formed are further interlinked by water molecules that act in a D2A fashion (double donor-single acceptor19). 3760

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Table 1. Crystallographic and Structure Refinement Details compound formula formula weight temperature (K) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z, Z′ density (g cm−3) μ (mm−1) F (000) hmin, max kmin, max lmin, max no. of unique reflections no. of parameters R_all, R_obs wR2_all, wR2_obs Δρmin, max (e Å−3) GOF compound formula formula weight temperature (K) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z, Z′ density (g cm−3) μ (mm−1) F (000) hmin, max kmin, max lmin, max No. of unique reflections No. of parameters R_all, R_obs wR2_all, wR2_obs Δρmin, max (e Å−3) GOF

m-fluorofenobam monohydrate (1)

o-fluorofenobam (2)

p-fluorofenobam (3)

C11H11FN4O2·H2O C11H11FN4O2 C11H11FN4O2 268.25 250.24 250.24 100(2) 100(2) 100(2) monoclinic monoclinic monoclinic P21/n P2/c P21/n 7.3445(4) 15.543(2) 7.3349(6) 20.5258(11) 9.3327(13) 11.5936(12) 8.2780(4) 15.610(2) 13.2131(14) 90 90 90 108.157(6) 94.655(5) 98.451(6) 90 90 90 1185.78(11) 2256.9(5) 1111.41(19) 4, 1 8, 2 4, 1 1.503 1.473 1.495 0.122 0.116 0.118 560 1040 520 −8, 9 −19, 19 −9, 9 −24, 25 −11, 6 −14, 13 −10, 10 −19, 19 −8, 16 2327 3146 2406 189 328 168 0.045, 0.037 0.11, 0.058 0.088, 0.047 0.094, 0.089 0.138, 0.121 0.117, 0.102 −0.29, 0.37 −0.33, 0.38 −0.30, 0.25 1.082 0.961 0.984 o-fluorothiofenobam (5) m-fluorothiofenobam (6) p-fluorothiofenobam (7) C11H11FN4OS 266.31 100(2) monoclinic P21/n 6.9043(4) 22.585(2) 7.8390(4) 90 101.721(5) 90 1196.88(14) 4 1.478 0.277 552 −8, 7 −21, 25 −9, 9 2340 164 0.036, 0.032 0.085, 0.083 −0.27, 0.20 1.059

C11H11FN4OS 266.31 100(2) triclinic P1̅ 10.274(5) 10.634(5) 11.610(5) 76.056(5) 80.353(5) 72.148(5) 1165.7(9) 4, 2 1.517 0.284 552 −12, 12 −13, 13 −14, 14 4581 327 0.053, 0.041 0.099, 0.092 −0.27, 0.42 1.032

C11H11FN4OS 266.31 100(2) triclinic P1̅ 6.9739(7) 8.0248(9) 11.1959(13) 102.503(10) 93.913(9) 107.93(1) 575.83(12) 2, 1 1.536 0.288 276 −8, 8 −9, 9 −13, 13 4303 172 0.093, 0.067 0.186, 0.174 −0.37, 0.35 1.058

thiofenobam (4)

C11H11ClN4OS 282.76 100(2) monoclinic P21/c 7.547(5) 7.400(5) 21.602(5) 90 96.919(5) 90 1197.6(12) 4, 1 1.568 0.486 584 −9, 9 −9, 9 −26, 26 2351 164 0.043, 0.038 0.101, 0.098 −0.27, 0.38 1.069 o,p-difluorothiofenobam (8) C11H10F2N4OS 283.29 100(2) triclinic P1̅ 7.1849(4) 7.8890(5) 11.9796(6) 86.705(4) 73.633(4) 68.392(5) 604.91(6) 2, 1 1.555 0.290 290 −8, 8 −9, 9 −14, 14 2378 182 0.031, 0.029 0.075, 0.074 −0.24, 0.23 1.100

hydrogen bond, as shown in Figure 2c. The catemeric molecular chains formed via N1−H1···O2 hydrogen bonds are further interlinked via C3−H3···O1 hydrogen bonds and CO···CO dipolar interactions (Figure 3c). Crystal Structure of Thiofenobam, 4. Thiofenobam crystallizes in monoclinic space group P21/c. The tautomer II is preferred in this compound too, and the proton H3n is involved in the intramolecular N−H···S hydrogen bond.

catemers formed via N−H···O hydrogen bonds stabilize the packing (Figure 3b). The crystal packing is further supported by weak C−H···O, C−H···F, and F···F interactions. Crystal Structure of p-Fluorofenobam, 3. p-Fluorofenobam crystallizes in monoclinic space group P21/n. The proton H3 attached to atom N3 suggests tautomer II, stabilized via an intramolecular N3−H3···O1 hydrogen bond. The planar molecular geometry is ensured by an intramolecular C6−H6···O1 3761

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C3−H3···Cl1(2.964 Å), and surrogate short H···H contact (2.418 Å) (Figure 4b). It is to be noted that, in the crystal structure of thiofenobam, the H3N proton is not involved in any intermolecular hydrogen bonding and the specific tautomeric preference is stabilized solely by the intramolecular hydrogen bonds discussed above. Crystal Structure of o-Fluorothiofenobam, 5. o-Fluorothiofenobam crystallizes in monoclinic space group P21/n. The intramolecular N3−H3···S1 hydrogen bond dictates the tautomeric prefrence, as in the case of thiofenobam. However, the molecule exhibits nonplanar geometry like in the case of 2. The molecules form N−H···O chains along the crystallographic c axis that are interlinked via weak C3−H3···F1 and C2−H2···S1 interactions, as shown in Figure 5a. Interestingly, a centrosymmetric molecular dimer is formed via C−H···π interaction where the C10−H10a donor is oriented toward the acceptor π-electron density of the CS bond with C−H···S and C−H···C interaction distances of 2.765 and 2.725 Å, respectively. A surrogate C10−H10a···F1 interaction adds stability to this dimer. Crystal Structure of m-Fluorothiofenobam, 6. m-Fluorothiofenobam crystallizes in triclinic space group P1̅ with Z = 4 and Z′ = 2. The tautomeric preference adopted by the molecule is clear from the ORTEP (Figure 2f). The conformations of both the molecules in the asymmetric unit are nearly planar. As in the case of 4, conformation is arrested by the intramolecular N3−H3···S1 and N7−H7···S2 hydrogen bonds on one end and by C6−H6···N2 and C17−H17···N6 hydrogen bonds on the other side (of the two residues in the asymmetric unit). The carbonyl oxygen atoms act as a bifurcated acceptor to the intermolecular N−H···O and C−H···O hydrogen bonds, resulting in an R21(6) motif forming zigzag molecular chains. These chains are interlinked via C−H···F interactions to form a supramolecular sheetlike assembly, as shown in Figure 5b. Along directions perpendicular to these molecular sheets, packing is mainly facilitated by C−H···π (H···C 2.82 Å) and C−H···S (2.953 Å) interactions. Crystal Structure of p-Fluorothiofenobam, 7. p-Fluorothiofenobam crystallizes in monoclinic space group P1̅ with Z = 2. It exists in the same tautomeric form as the one present in compounds 1−6, and the molecular conformation is similar to 4. Conformational locking is ensured by the intramolecular N3−H3···S1 and C3−H3···N2 and C17−H17···N6 hydrogen bonds. Similar to thiofenobam, the molecules of 7 form a centrosymmetric thioamide dimer synthon with an additional C5−H5···S1 interaction. These dimers are interconnected via C10−H10···O1 interactions, resulting in a chainlike assembly (Figure 5c). These chains are further packed via a variety of interactions: (i) a F···F interaction of type I geometrical characteristics with a F···F distance of 2.939 Å and a C−F···F angle of 102.7°, (ii) an N−H···F hydrogen bond (2.46 Å) where the F atom interacts with a proton attached to the ring N atom, (iii) a C−H···π interaction resulting in centrosymmetric molecular dimers formed with a C10−H10a···C5 distance of of 2.89 Å and an angle of 125.7°, and (iv) a C11−H11c···N1 interaction (2.74 Å, 159°). Crystal Structure of o,p-Difluorothiofenobam, 8. o,p-Difluorothiofenobam crystallizes in monoclinic space group P1̅ with Z = 2. The tautomeric preference exhibited by the molecule and the intramolecular N−H···S hydrogen bond are shown in the ORTEP (Figure 2g). The molecule adopts a nonplanar conformation with the F and H atoms at the ortho positions of the phenyl ring exhibiting positional disorder.

The molecular conformation is strikingly different from that of fenobam and the fluoro analogues. The molecule exhibits two intramolecular interactions that lock the molecular conformation: (i) N3−H3N···S1 and (ii) C6−H6···N2 hydrogen bonds. Further, the sulfur atom acts as a bifurcated hydrogen bond acceptor to form N−H···S and C−H···S hydrogen bonds, resulting in a centrosymmetric thioamide dimer synthon, as shown in Figure 4a. Crystal packing is supported by the π···π

Figure 3. (a) Formation of amide dimers and water mediated interlinking in 1, (b) amide catemer chain formed via N−H···O and N−H···N hydrogen bonds in 2, and (c) N−H···O hydrogen bond chains interlinked via CO···CO dipolar interactions in 3.

stacking along the crystallographic a axis (C···C distance of 3.356 Å) and surrogate C−H···π interactions. The structure is further stabilized by weak intermolecular interactions, such as C10−H10a···O1 (2.608 Å), C11−H11a···Cl1 (2.989 Å), 3762

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Figure 4. (a) Thioamide dimer synthon with an additional C−H···S interaction, and (b) crystal packing mediated via C−H···Cl and C−H···O interactions in 4.

τ2, τ3, and τ4. The relative stabilities of the conformations have been compared using Gaussian 09 calculations carried out with the B3LYP method and 6-311++G** basis set. The structural optimization starting from the crystal geometry was followed by single-point calculations at specific dihedral angles of these different conformations. The energy values for these conformations suggest that τ1 > τ2 (with an energy difference of 3 kcal/mol) and τ4 > τ3 in stability order (energy difference of 7.8 kcal/mol) and are in accordance with the hydrogen bond hierarchy argument discussed above. Notably, all three ortho-fluoro analogues (2, 5, and 8) discussed in this study exhibit a nonplanar conformation. It should also be noted that the intermolecular interactions such as N−H···O and N−H···S hydrogen bonds may also have significant roles in guiding the molecular conformations. For instance, the formation of thioamide dimer synthons with a pair of centrosymmetric N−H···S hydrogen bonds (Figure 4a) necessitates the τ4 conformation for thiofenobam analogues. It must be cautioned that the conformational analysis carried out in this study pertains to the crystal forms that are so far identified from a preliminary set of crystallization experiments (see the Supporting Information for PXRD patterns of the bulk samples). However, given that the parent compound fenobam exhibits five crystal forms,10 the possibility of polymorphs and even conformational polymorphs cannot be disregarded. On the basis of the conformation analysis, electrostatic potential (esp) surfaces have been plotted over the observed molecular conformations of fenobam, fluorofenobam, and thiofenobam, the three major chemical varieties of this class of antidepressants (Figure 8). The esp surfaces were generated using the Tonto interface of Crystal Explorer22 at the HF/STO-3G level and plotted with an isovalue of 0.05 e/au3. The esp plots indicate the possible differences in the binding modes of these molecules in their active sites and, hence, suggest different biological activity profiles. Hirshfeld Surface Analysis: Conservation of Interaction Proportions. Hirshfeld surface analysis21was carried out to gain a quantitative understanding of the varying levels of contribution from the weak intermolecular interactions, such as C−H···F, C−H···Cl, and C−H···S, and the prominent ones, such as N−H···O, N−H···S, and C−H···O hydrogen bonds, in these crystal structures. This partitioning scheme based on electron density weighted molecular surfaces, usually used to compare polymorphic structures, has been employed here to analyze the differences and similarities in the contributions

Such a disorder, resulting from the isosteric nature of F and H, has been discussed in our earlier reports.20 Consequently, the H atom in the ortho position has not been included in the structural model, and the F atom (F 2d) occupies the position. The crystal packing is facilitated by the N−H···O hydrogen bond chains, and such antiparallel chains are interlinked via CO···CO dipolar interactions, as shown in Figure 6a. As in the case of 3, a C−H···π interaction (with the C10−H10a donor oriented toward the acceptor π-electron density of the CS bond) is characterized by C−H···S and C−H···C interaction distances of 2.79 and 2.80 Å, respectively. Interestingly, a very short F···F contact distance of 2.663 Å is observed in this model, stabilizing a molecular chain along the crystallographic a axis (Figure 6b). This “pseudo F···F interaction” is an artifact of the positional disorder discussed above. It can be assumed to be a C−H···F chain formed with flip-flopped ortho-fluorophenyl rings, the statistical average of which gives rise to the delusion of a short F···F contact (as in the case of the ortho-fluoro N-acyl thiourea derivative reported by us earlier21). Conformational Features and the Role of Hydrogen Bonding Hierarchy. The molecular conformations observed for the known polymorphs and hydrates of fenobam and its analogues show a systematic trend with respect to the available intramolecular hydrogen bonding motifs. The conformation is invariably locked at one end of the molecules via N−H···O or N−H···S hydrogen bonds. On the other end, fenobam and thiofenobam derivatives have two distinct conformations possible, as given in Figure 7. These conformations offer the formation of intramolecular R11(6) motifs via C−H···O or C−H···N hydrogen bonds for fenobam based compounds (τ1 and τ2). For thiofenobam analogues, similar motifs are possible via C−H···S (τ3) or C−H···N (τ4) hydrogen bonds, respectively. The common crystal engineering wisdom that a C−H···O hydrogen bond is preferred over a similarly oriented C−H···N hydrogen bond can be employed here to rationalize the conformational preference similar to τ1 in polymorphs of fenobam and its fluoro analogues. Likewise, the thiofenobam derivatives (except the ortho-fluorosubstituted ones) show conformations similar to τ4, owing to the fact that a C−H···S hydrogen bond is weaker than a similarly oriented C−H···N hydrogen bond. These arguments have been further supported by gas-phase computational calculations with conformations τ1, 3763

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Figure 7. Possible molecular conformations locked by various weak intramolecular hydrogen bonds.

from corresponding weak interactions in different derivatives of fenobam (the difluoroderivative has not been included, owing to the disorder). It should be noted that the contributions of individual interaction types to the net crystal packing are estimated in terms of Hirshfeld surface sharing and not in terms of interaction energy. The fingerprint analysis shows very similar features of individual contributions such as the H···O interaction (arising from N−H···O and C−H···O hydrogen bonds) and the N···H interaction in fenobam and fluorofenobam. It may be noted that, in the fenobam series of compounds, there are two oxygen atoms acting as hydrogen bond acceptors contributing to the H···O interaction in the Hirshfeld surface analysis, whereas, in the thiofenobam series, this contribution is partitioned between H···O and H···S interactions. Hence, for the sake of comparison between various interaction contributions, the H···O interaction contribution of the fenobam series has been compared against the total contribution from both the H···O interaction and the H···S interaction in the thiofenobam series. Interestingly, the H···Cl interaction contribution in fenobam matches closely with the corresponding H···F contribution in fluorofenobam, and the same is the case with other interactions, such as C···C, C···H, and H···H. Likewise, all the thiofenobam derivatives exhibit striking similarity in their corresponding interactions with each other (Figure 9 and Table S2 in the Supporting Information). An interesting observation here to note is that, though the chemical derivatization did not result in isostructurality in these crystal structures, there exists a notable similarity in the relative contributions from the corresponding weak interactions. This suggests that the analogous interactions (e.g., H···F and H···Cl) are replaced in compensating proportions irrespective of the supramolecular variety and conformational differencesleading

Figure 5. (a) Crystal packing of 5, viewed down the crystallographic a axis; N−H···O chains are interconnected via C−H···F and C−H···S interactions; (b) molecular chains formed via N−H···O, C−H···O, and C−H···S hydrogen bonds, interlinked via C−H···Cl interactions, resulting in a sheetlike assembly in 6; and (c) zigzag chains formed by thioamide dimer synthon and C−H···O interactions in 7.

Figure 6. (a) Molecular chains formed via N−H···O hydrogen bonds interconnected via CO···CO dipolar interactions and C−H···O hydrogen bonds in 8 and (b) crystal packing showing the “pseudo F···F” contacts involving disordered F atoms and the C−H···π(CS) interactions. 3764

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Figure 8. Electrostatic potential surface plots of (a) fenobam, (b) fluorofenobam, and (c) thiofenobam.

Figure 9. Similarity in the contribution of analogous intermolecular interactions in the structures discussed in this study.

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to a “conservation of analogous intermolecular interaction proportions”.

ACKNOWLEDGMENTS T.N.G.R. thanks DST, India, for a J.C. Bose fellowship. S.P.T. thanks UGC, India, for a Senior Research Fellowship and Dr. Alexandre Sobolev for discussions.

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CONCLUSIONS The trends observed in the known polymorphs of fenobam and its eight analogues discussed in this study suggest that the tautomer II is comparatively quite stable and is the preferred form. The correlation between the weak hydrogen bonding preferences and the molecular conformations gives valuable clues into the solution-state geometry of these drug molecules. The argument that hydrogen bonding hierarchy guides the conformation has been supported by gas-phase computational calculations of stabilization energies associated with different molecular conformations. Detailed solution-state NMR spectroscopic studies to verify this output from the “experimental simulation” will be among the future steps of this work. Interestingly, the observed difference in conformational features of fenobam and thiofenobam correlates well with the preliminary results obtained from the antianxiety activity studies: that fenobam shows promising activity, whereas thiofenobam is inactive. The results of those experiments conducted on mice will be reported in a future communication.

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DEDICATION Dedicated to Prof. Mark Spackman on the occasion of his 60th birthday.

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ASSOCIATED CONTENT

* Supporting Information S

Detailed procedures for the synthesis of compounds 1−8, hydrogen bond tables, Hirshfeld fingerprint analysis table, and crystallographic information (CCDC 1001753−1001760). This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +91-80-22932796. Fax: +91-80-23601310 (T.N.G.R.). Notes

The authors declare no competing financial interest. 3765

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