Supramolecular Architectures in 5,5′-Substituted Hydantoins: Crystal

Aug 30, 2010 - Computer programs used: MOGUL(53) run on the CSD. The molecular-orbital optimization for compounds 1−3 with Dmol3 corroborates the ...
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DOI: 10.1021/cg100706n

Supramolecular Architectures in 5,50 -Substituted Hydantoins: Crystal Structures and Hirshfeld Surface Analyses

2010, Vol. 10 4476–4484

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Basab Chattopadhyay,† Alok K. Mukherjee,‡ N. Narendra,§ H. P. Hemantha,§ Vommina V. Sureshbabu,§ Madeliene Helliwell, and Monika Mukherjee*,† †

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Department of Solid State Physics, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India, ‡Department of Physics, Jadavpur University, Kolkata 700032, India, § Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Bangalore-560 001, India, and Department of Chemistry, University of Manchester, Manchester M13 9PL, United Kingdom Received May 27, 2010; Revised Manuscript Received August 9, 2010

ABSTRACT: A series of three 5,50 -substituted hydantoin derivatives (1-3) were synthesized, and their crystal structures were solved using single-crystal synchrotron/powder-crystal X-ray diffraction data with a detailed analysis of Hirshfeld surfaces and fingerprint plots facilitating a comparison of intermolecular interactions in building different supramolecular architectures. A comparison of supramolecular assembly in the compounds with that in similar 5,50 -substituted hydantoins in the Cambridge Structural Database (CSD) has been presented. The crystal packing in compounds 1-3 containing complementary hydrogen bonding groups, i.e. the amino NH donors and carbonyl O acceptors, exhibits three types of supramolecular synthons. In the dipropyl substituted hydantoin (1), intermolecular N-H 3 3 3 O hydrogen bonds with only one carbonyl O atom acting as a double acceptor generate a one-dimensional C11(4)C11(4)[R22(8)] network propagating along the [100] direction, while in 3, a 5-spiro fused hydantoin, the cyclic R22(8) motifs self-organize through pairs of N-H 3 3 3 O hydrogen bonds to form a C22(9)[R22(8)][R22(8)] framework running along the [1-10] direction. The molecular assembly in 2, with a dibutyl substitution at the hydantoin C-5 position, produces R44(17) synthons, which are edge-fused to form two-dimensional molecular sheets in the (100) plane. The formation of a supramolecular architecture built with an R44(17) synthon is unprecedented among the substituted hydantoin structures in the CSD.

Introduction Noncovalent molecular interactions such as hydrogen bonding and aromatic π-stacking form the basis for the design of supramolecular assemblies in organic crystals.1,2 Molecular functionalities, e.g. amino, hydroxyl, carbonyl, and ester, play an important role in determining the spatial relationship between neighboring molecules, leading to repetitive hydrogen bond patterns or supramolecular synthons.3,4 Many of the synthons in molecular compounds involve N-H 3 3 3 O, N-H 3 3 3 N, O-H 3 3 3 O, and O-H 3 3 3 N hydrogen bonds, which provide the requisite robustness and reproducibility to create new solid-state structures.5-7 Compounds with highly symmetrical, rigid frameworks are versatile scaffolds, because they can hold together interactive functional groups for the formation of a variety of one-dimensional, twodimensional, or three-dimensional architectures based on multiple noncovalent interactions.8-10 It is useful to design new compounds comprising a rigid core with multiple donor atoms and having different types of substitutions and to study their structural features as well as the interplay of noncovalent interactions in building possible supramolecular assemblies. This would undoubtedly enhance our understanding of the factors that may be responsible for perturbing the usual hydrogen bond motif characteristic of the rigid core in the system under investigation. In this respect, the hydantoin or imidazolidine-2,4-dione motif, possessing equal numbers of N-H donors and CdO acceptors, and present in a number of *Corresponding author. Telephone: þ91 33 2473 4971 ext 312. Fax: þ91 33 2473 2805. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 08/30/2010

natural products,11,12 constitutes an ideal structural component with a rigid core. Hydantoin derivatives such as phenytoin, mephenythoin, norantoin, methetoin, and ethotoin are used as anticonvulsive drugs.13,14 Among other medicinally useful properties exhibited by 5-substituted hydantoins, antiviral, antidepressant, antithrombic, and anticancer activities,15,16 inhibition of platelet aggregation, human aldose reductase, and human leukocyte clastase are worth mentioning.17,18 Synthetically, hydantoins are also important precursors to amino acids, via either acid-, base-, or enzyme-catalyzed hydrolysis.19,20 A search of the Cambridge Structural Database (version 5.31, November CSD 2009 release)21 with both hydantoin NH groups unsubstituted and sp3 hybridization at the C5 position yielded 68 hits (excluding duplicate structure determinations), 35 of which had a 5,50 -spiro-fusion, with the remaining 33 containing different substituent groups at the 5,50 -positions, except in BEPNIT22 and PHYDAN,23 where the C5 atom had symmetrical substitutions by either methyl or phenyl groups. A symmetrical aliphatic chain (propyl, butyl, etc.) substitution at the 5,50 positions is, however, yet to be reported. In general, single-crystal X-ray diffractometry is the method of choice when it comes to structure determination. For many compounds of scientific interest, including the chain substituted hydantoins, single crystals of appropriate size and quality cannot always be grown within a reasonable time scale that make them amenable to X-ray structure analysis. With the recent developments in direct-space approaches for structure solution,24-27 ab initio crystal structure analysis can nowadays be accomplished from X-ray powder diffraction data,28-31 r 2010 American Chemical Society

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although significant challenges may arise when the molecule possesses considerable flexibility or there are multiple molecules in the asymmetric unit. In this paper, the synthesis and structural characterization of three 5,50 -substituted hydantoin derivatives (Scheme 1) using X-ray powder and synchrotron single-crystal diffraction data are described, along with the DFT calculations, as a part of our wider strategy aimed at providing a library of 5,50 substituted hydantoin molecules capable of forming different types of supramolecular assemblies.32 An investigation of close intermolecular contacts between the molecules via Hirshfeld surface analysis is also presented in order to reveal subtle differences and similarities of hydantoin molecules in the three crystal structures. Experimental Section Synthesis. A mixture of a solution of appropriate ketone (0.1 mmol) [4-heptanone in (1), 5-nonanone in (2), and cyclopentanone in (3)] in 50% aqueous methanol (50 mL), KCN (0.3 mmol), and (NH4)2CO3 (0.5 mmol) was refluxed for 6-7 h. The resulting solution was concentrated to half of its volume under vacuum and cooled to 0 °C in an ice bath. The precipitate was filtered off, washed with ice-cold water, and air-dried. Slow evaporation of a 1:1 water/ methanol solution of the crude product yielded the title hydantoin derivatives (1, 2, and 3) in microcrystalline forms. Compound 1. Yield 84%, mp 198 °C. Anal. HR-MS Calcd for C9H16N2NaO2, 207.1109; found, 207.1117 [M þ Na]. IR (cm-1): 3330-3180, 1728, 1710. 1H NMR (300 MHz, DMSO-d6): δ 0.92 (t, J = 4.5 Hz, 6H), 1.42 (m, 4H), 1.88 (t, J = 4.0 Hz, 4H), 5.80 (br, 1H), 8.71 (br, 1H) ppm. 13C NMR (200 MHz, DMSO-d6): δ 12.8, 16.8, 32.5, 63.4, 157.8, 174.2 ppm. Compound 2. Yield 86%, mp 160 °C. Anal. HR-MS Calcd for C11H20N2NaO2, 235.1422; found, 235.1418 [M þ Na]. IR (cm-1): 3340-3200, 1730, 1710. 1H NMR (300 MHz, DMSO-d6): δ 0.82 (t, J = 6.3 Hz, 6H), 1.12-1.29 (m, 4H), 1.44-1.52 (m, 4H), 2.01 (t, J = 3.8 Hz, 4H), 5.20 (br, 1H), 7.41 (s, 1H) ppm. 13C NMR (200 MHz, DMSO-d6): δ 13.5, 21.8, 26.8, 33.0, 66.4, 154.6, 175.2 ppm.

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Compound 3. Yield 85%, mp 204 °C. Anal. HR-MS Calcd for C7H10N2NaO2, 177.0640; found, 177.0648 [M þ Na]. IR (cm-1): 3220-3160, 1780, 1740. 1H NMR (300 MHz, DMSO-d6): δ 1.71-1.77 (m, 4H), 1.92-2.12 (m, 4H), 6.21 (s, 1H), 7.84 (br, 1H) ppm. 13C NMR (200 MHz, DMSO-d6): δ 23.8, 34.2, 69.5, 155.9, 173.2 ppm. X-ray Powder Diffraction. X-ray powder diffraction data of compounds 1-3 were collected on a Bruker D8 Advance powder diffractometer using monochromatic Cu KR1 radiation (λ = 1.54056 A˚) selected with an incident beam germanium(111) monochromator. The diffraction patterns were recorded at 293(2) K with a step size of 0.02° (2θ) and counting time of 20 s/step in the angular range 8.0-100.0° (2θ) for 1 (3.0-100.0° for 2 and 3), using the Bragg-Brentano geometry. The indexing of the powder pattern of 1 using the program TREOR33 showed an orthorhombic unit cell with a = 7.167(1), b = 13.964(1), and c = 10.957(3) A˚ [M(20) = 49, F(20) = 84 (0.003343, 72)]. Statistical analysis of the X-ray powder data using the FINDSPACE module of EXPO200434 indicated Pnma as the most probable space group, which was confirmed by a successful structure determination. For compound 2, although the powder XRD pattern (see Figure S1 in the Supporting Information) could be indexed on a monoclinic unit cell with a = 9.327(8), b = 9.575(4), c = 7.556(3) A˚, and β = 113.73(8)° [M(20) = 23, F(20) = 47 (0.014188, 30)], our attempts to solve the structure from powder XRD data were not successful. For compound 3, however, the powder XRD pattern (see Figure S2 in the Supporting Information), which contained only one low angle (2θ) peak of very large relative intensity and a few small peaks with significant broadening (fwhm ≈ 0.2°), could not be indexed reliably. The crystal structures of 2 and 3 were

Scheme 1

Figure 1. Final Rietveld refinement plot of C9H16N2O2 (1). Table 1. Crystal Data and Structure Refinement Parameters for C9H16N2O2 (1), C11H20N2O2 (2), and C7H10N2O2 (3) chemical formula Mr temperature (K) crystal system, space group, Z a, b, c (A˚) R, β, γ (deg) volume (A˚3) D (Mg/m3) wavelength (A˚) μ (mm-1) F(000) crystal size (mm) diffractometer no. of measured, independent, and observed reflections Rint, θmax data/restraints/parameters Rp/R1 Rwp/wR(I) χ2/S

1

2

3

C9 H16 N2 O2 184.24 293(2) orthorhombic, Pnma, 4 7.1577(5), 13.9721(9), 11.0211(10) 90, 90, 90 1102.2(2) 1.110 1.54056

C11 H20 N2 O2 212.29 150(2) monoclinic, Pc, 2 9.3072(12), 9.5775(12), 7.5116(9) 90, 113.735(1), 90 612.95(13) 1.150 0.69450 0.079 232 0.30  0.06  0.04 Station 9.8, SRS 10758, 1371, 1370

C7 H10 N2 O2 154.17 150(2) triclinic, P1, 2 6.028(2), 6.086(2), 11.003(4) 91.834(4), 93.626(4), 115.228(4) 363.6(2) 1.408 0.69450 0.105 164 0.25  0.04  0.02 Station 9.8, SRS 3671, 2009, 1756

0.0635, 26.74 1371/2/140 0.0433 0.1135 1.096

0.0211, 30.41 2009/0/140 0.0449 0.1262 1.090

Bruker D8 Advance

592/33/98 0.0477 0.0687 1.671

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-0.010 -0.005 0.020 -0.010 0.002 -0.006 -0.003 0.012 2.9 -1.3 0.2 0.5 0.5 0.1 0.4 0.7 0.1 0.2 -1.1 -0.036 0.002 -0.026 -0.025 -0.002 -0.024 -0.019 -0.023 -0.3 -2.1 2.3 -2.0 -0.1 -1.0 1.1 -0.4 -1.1 0.1 -0.7 -0.004 -0.021 0.022 -0.008 0.005 -0.010 0.013 0.003 3.6 -1.7 0.0 0.8 0.7 -0.3 0.7 0.6 -0.2 0.9 -0.3 -0.006 -0.007 0.020 -0.014 0.000 -0.010 0.013 0.030 3.7 -2.0 0.4 0.7 0.8 -0.5 0.7 0.6 -0.5 -0.4 1.3 1.346(3) 1.209(3) 1.402(2) 1.362(3) 1.225(3) 1.520(3) 1.473(3) 1.513(5) 129.6(2) 123.3(3) 107.0(2) 111.8(2) 126.7(2) 125.7(2) 107.7(2) 100.6(2) 112.8(2) 113.9(2) 111.7(2) 1.376 1.223 1.425 1.385 1.222 1.561 1.476 1.552 129.1 125.9 104.9 113.6 126.6 127.1 106.3 100.4 114.7 111.9 112.3

Computer programs used: MOGUL53 run on the CSD. a

1.375 1.223 1.425 1.385 1.223 1.557 1.477 1.544 129.3 125.8 104.9 113.6 126.6 127.1 106.3 100.6 114.5 112.7 112.6

1.340(1) 1.225(1) 1.400(1) 1.360(1) 1.222(1) 1.524(1) 1.457(1) 1.532(2) 128.9(1) 123.7(1) 107.2(1) 111.5(1) 126.5(1) 126.1(1) 107.38(9) 100.73(9) 113.07(9) 107.2(9) 112.9(1)

1.376 1.223 1.426 1.385 1.224 1.548 1.476 1.555 129.2 125.8 104.9 113.5 126.6 127.1 106.3 101.1 114.2 107.1 113.6

1.35(2) 1.23(2) 1.38(2) 1.37(2) 1.22(2) 1.53(1) 1.46(9) 1.51(4) 126(1) 125(2) 107(1) 111(1) 126(1) 126(1) 107(1) 100(1) 113(1) 111(3) 113(1)

-0.032 0.000 -0.025 -0.029 -0.002 -0.041 -0.003 -0.012 0.6 -2.9 2.5 -1.9 0.2 -1.6 1.4 0.2 -2.2 -0.3 1.0

-0.029 -0.014 -0.023 -0.023 0.002 -0.037 -0.004 -0.030 0.3 -2.5 2.1 -1.8 0.1 -1.4 1.4 0.0 -1.7 1.2 -0.9

XRD-MOGUL

3

XRD-DFT XRD-MOGUL

2

XRD-DFT XRD-MOGUL

1

XRD-DFT MOGUL (mean) DFT 3 XRD DFT 2 XRD DFT

1.344(2) 1.223(3) 1.400(2) 1.356(3) 1.220(4) 1.520(3) 1.473(3) 1.540(1) 129.7(2) 123.0(2) 107.4(2) 111.7(1) 126.8(2) 125.5(2) 107.7(2) 100.6(1) 112.5(1) 111.6(7) 113.34(6)

where rivdW and revdW are the van der Waals radii of the atoms. The value of dnorm is negative or positive depending on intermolecular contacts being shorter or longer than the van der Waals separations. The parameter dnorm displays a surface with a red-white-blue color scheme, where bright red spots highlight shorter contacts,

N1-C2 C2-O2 C2-N3 N3-C4 C4-O4 C4-C5 C5-N1 C-Cmean O2-C2-N1 O2-C2-N3 N3-C2-N1 C4-N3-C2 O4-C4-C5 O4-C4-N3 C5-C4-N3 N1-C5-C4 C2-N1-C5 C-C-Cmean C-C-Nmean

ðd i - rvdW Þ ðd e - rvdW Þ e i þ vdW rvdW ri e

XRD

d norm ¼

bonds/angles

1

finally solved via single crystal X-ray analysis using synchrotron data. The agreement between the simulated powder pattern based on single-crystal analysis and the observed X-ray powder profile (see Figure S1 in the Supporting Information) for 2 indicates that the crystal structure corresponds to the bulk phase. A similar conclusion can be drawn for 3, although a high degree of preferred orientation is apparent in the observed X-ray powder diffraction profile (see Figure S2 in the Supporting Information). The crystal structure of 1 was solved by global optimization of the structural models in direct space using the simulated annealing technique as implemented in the program DASH.35 Rietveld refinement36 was carried out using the program GSAS37 with an EXPGUI38 interface. The background was described by the shifted Chebyshev function of the first kind with 36 points regularly distributed over the entire 2θ range. The lattice parameters, background coefficients, and profile parameters were refined initially, followed by the refinement of the positional coordinates of nonhydrogen atoms with soft constraints on the bond lengths and bond angles, and a planar restraint for the hydantoin fragment. A fixed isotropic displacement parameter of 0.04 A˚2 for all non-hydrogen atoms was maintained. Hydrogen atoms were placed in the calculated positions with a common Biso value of 0.06 A˚2. In the final stages of refinement, a preferred orientation correction using the generalized spherical harmonic model (order 12) was applied. The final Rietveld refinement converged to Rp = 0.0477 and Rwp = 0.0687 with an excellent agreement between the observed and the calculated powder patterns (Figure 1). Single Crystal X-ray Diffraction. Since the single crystals of 2 and 3 were too thin and weakly diffracting, intensity data were collected at 150(2) K with synchrotron radiation (λ = 0.69450 A˚) from Station 9.8 at SRS Daresbury Laboratory using a Bruker SMART APEX CCD diffractometer. Data reduction was performed using the SAINT39 software. An empirical absorption correction SADABS39 was applied. Structures were solved by the direct methods incorporated in SHELXS-9740 and refined by the full-matrix least-squares methods based on F2 using SHELXL-97.40 For a successful structure refinement of 2, a twin law (-1 0 -1/0 -1 0/0 0 1) had to be applied. The refined twin fraction value of 0.500(4) indicates the presence of two nearly overlapping monoclinic domains. The displacement parameters of all non-H atoms were treated anisotropically. The H-atoms in 2 were located from difference Fourier maps and allowed to ride on the parent atom with fixed isotropic thermal parameters [Uiso(H) = 1.2Ueqv(N/C) for NH and CH2 groups and Uiso(H) = 1.5Ueqv(C) for CH3 groups]. In 3, the H-atoms located from the difference Fourier map were refined isotropically. Crystal data and relevant refinement parameters of 1-3 are summarized in Table 1. Computational Details. The isolated molecule DFT calculations were performed with full geometry optimization without any symmetry restriction. All calculations were carried out using the Dmol3 code41 in the framework of a generalized-gradient approximation (GGA).42 The starting atomic coordinates were taken from the final X-ray refinement cycle. The geometries of the molecules were optimized using the hybrid exchange-correlation functional BLYP43,44 and a double numeric plus polarization (DNP) basis set. Hirshfeld Surface Analysis. Hirshfeld surfaces45-47 and the associated 2D-fingerprint48-50 plots were calculated using CrystalExplorer,51 which accepts a structure input file in CIF format. Bond lengths to hydrogen atoms were set to typical neutron values (C-H = 1.083 A˚, N-H = 1.009 A˚). For each point on the Hirshfeld isosurface, two distances de, the distance from the point to the nearest nucleus external to the surface and di, the distance to the nearest nucleus internal to the surface, are defined. The normalized contact distance (dnorm) based on de and di is given by

Chattopadhyay et al.

Table 2. Selected Bond Distances (A˚) and Bond Angles (deg) for C9H16N2O2 (1), C11H20N2O2 (2), and C7H10N2O2 (3)a21

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Figure 2. ORTEP diagrams of C9H16N2O2 (1), C11H20N2O2 (2), and C7H10N2O2 (3).

interaction

Table 3. Hydrogen Bonds and C-H 3 3 3 O Interactions in C9H16N2O2 (1), C11H20N2O2 (2), and C7H10N2O2 (3) D-H/A˚ H 3 3 3 A/A˚ D 3 3 3 A/A˚ D-H 3 3 3 A/deg symmetry code

(1) N1-H1 3 3 3 O2 N3-H3 3 3 3 O2 C6-H6A 3 3 3 O4

0.86 0.86 0.93

1.95 2.02 2.69

2.790(3) 2.863(3) 3.582(3)

166 167 162

-1/2 þ x, 1/2 - y, 3/2 - z 1 /2 þ x, 1/2 - y, 3/2 - z -1/2 þ x, -y þ 1/2, -z þ 1/2

(2) N1-H1 3 3 3 O2 N3-H3 3 3 3 O4 C6-H6A 3 3 3 O4

0.86 0.86 0.97

2.06 1.97 2.66

2.826(3) 2.827(3) 3.583(3)

147 173 159

x, -y þ 1, z - 1/2 x, -y, z þ 1/2 x, -y, þz - 1/2

(3) N1-H1 3 3 3 O2 N3-H3 3 3 3 O4 C9-H9B 3 3 3 O2 C6-H6B 3 3 3 O2

0.93(2) 0.93(2) 0.96(2) 0.97(2)

1.93(2) 1.97(2) 2.63(2) 2.69(2)

2.843(1) 2.890(1) 3.278(2) 3.298(2)

167(2) 174(2) 125(2) 121(2)

-x, -y þ 1, -z þ 1 -x þ 1, -y, -z þ 1 -x þ 1, -y þ 1, -z þ 1 -x, -y, -z þ 1

Figure 3. Formation of the parallel C11(4)C11(4)[R22(8)] network in C9H16N2O2 (1). H-atoms of the propyl chains are omitted for clarity. white areas represent contacts around the van der Waals separation, and blue regions are devoid of close contacts.

Results and Discussion The asymmetric unit of 1 crystallizing in the orthorhombic space group Pnma (Table 1) consists of half of the hydantoin moiety (lying on the mirror plane) and one propyl chain (Figure 2). The orientation of the -(CH2)2CH3 chain with respect to the hydantoin fragment in 1 is established by the dihedral angle of 57.9(3)°, between the two planar fragments. As expected, the hydantoin moieties in 2 and 3 (Figure 2) are essentially planar with a rms deviations of 0.02 and 0.01 A˚ in

2 and 3, respectively. In 2, the dibutyl chain (C6-C13), with the maximum deviation of 0.057(3) A˚ for the C10 atom from the least-squares plane through the chain atoms (C6-C13), is twisted with respect to the hydantoin ring; the dihedral angle between the hydantoin and dibutyl moieties is 86.8(1)°. The cyclopentane ring in 3 adopts a half-chair conformation with ring puckering parameters52 Q=0.407(2) A˚ and j= 340.7(2)°, respectively. The bond lengths (Table 2) of the hydantoin fragment in 1-3 agree well with the mean values of relevant bond distances obtained with MOGUL53 from searches based on related molecular fragments run on the CSD. The presence of a spiro center (C5) explains the

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Table 4. Supramolecular Synthons in 5,50 -Substituted Hydantoin Structures Retrieved from the CSD with Space Groups Given in Parenthesesa C11(4)C11(4)[R22(8)] CSD ref code (space group) compound (1) (Pnma) BEPNIT (P212121) ADUQOF (P212121) NIWRAN (Pbca) AHORIY (P212121)

HPHCMS (P21)

XERTUJ (P21)

OGUVIV (P21)

a

substituents (R1,R2)/R R1 = propyl, R2 = propyl R1 = methyl, R2 = methyl R1 = methyl, R2 = ethyl R1 = methyl, R2 = fluorophenyl R1= isobutene, R2 = 4-methoxy-2,2dimethyltetrahydrofuro[3,4-d][1,3]dioxole R1 = phenyl, R2 = phenyl(7,7dimethyl-2oxobicyclo[2.2.1] heptan-1-yl) methanesulfonate R=2,2,4,6tetramethyltetrahydro-3aH[1,3]dioxolo[4,5-c]pyran R=tert-butyl1,2,3,4,5,6,7,8octahydroanthracen1-ylcarbamate

C22(9)[R22(8)] [R22(8)] CSD ref code (space group) compound (3) (P1) QOPYOK (P21/c) OCSHYD (C2/c) UGEYIO (P1) BCOCHY (C2/m)

GRNSHY (P1)

substituents (R1,R2)/R R = cyclopentane R = cyclohexane R = cyclooctane R = ((cyclobutylmethoxy)methyl)benzene R = bicyclo(3.3.0)octane

fused R33(12) rings CSD ref code (space group) LABTIR (P212121) PHYDAN (Pn21a) PIPVAL (P21) DAFFIZ (P212121)

substituents (R1,R2)/R R1 = phenyl, R2 = ethyl R1 = phenyl, R2 = phenyl R1 = hydroxyl, R2 = ethyl acetate R = 6-fluorochroman

R = 9-phenethyl-9-azabicyclo[3.3.1]nonane

R = spiro-fused ring substitution at the 5-position; R1, R2 are substitutions at the 5,50 -positions, respectively.

lengthening of the C4-C5 distance [1.520(3)-1.525(2) A˚] in 1-3. The C-N bond distance (Table 2) involving the spirocarbon atom (C5) reveals that the N1-C5 bond is σ in character, while the other C-N bonds show dominantly π character due to the π-electron delocalization in the hydantoin fragment. Bending of one of the two carbonyl bonds is common in hydantoin derivatives. In 1-3, the O2-C2-N1 angle [129.0(1)-129.7(2)°] is significantly greater than O2C2-N3 [123.0(2)-123.8(1)°], while the equivalent bond angles around C4 are practically identical [125.5(2)-126.8(2)°]. The asymmetry of exterior bond angles around the C2 atom can be attributed to the fact that the N3 atom shares its lone pair between the C2 and C4 atoms, while the N1 atom is involved in a π-resonance with the C2-O2 carbonyl group only. This observation is in accordance with the different acidic properties of two NH residues in hydantoin derivatives, with N3-H3 being more acidic than N1-H1.54,55 As a consequence of the asymmetric π-electron clouds on N1C2 and N3-C2 and of the latter bond being more electron rich, the lone pair residing on O2 could experience a repulsion causing the observed bending of O2 toward N3. The molecular-orbital optimization for compounds 1-3 with Dmol3 corroborates the near equality of CdO distances (Table 2). The DFT calculation generally yields longer bond lengths compared to the crystallographic values; the largest difference between the calculated and experimentally determined distances is 0.041 A˚ for the C4-C5 bond in 1 (Table 2). The difference between the observed and calculated bond distances can be attributed to the inadequacies of the DFT method and also the fact that theoretical calculations have been carried out with isolated molecules in the gaseous phase whereas the experimental values correspond to the crystalline state in which the packing forces play a significant role. The atomic charges estimated from Mulliken population analysis

appear to be consistent with electronegativity. The net charges on O2 [-0.477 in 3 to -0.478 in 1] and O4 [-0.451 in 1 to -0.461 in 2] suggest that more negative charge is received by the atom O2 than by O4. The molecular packing in compounds 1-3 exhibits strong intermolecular N-H 3 3 3 O hydrogen bonds and weak C-H 3 3 3 O interactions (Table 3). The N-H 3 3 3 O hydrogen bonds facilitate self- assembly of hydantoin molecules, forming different types of supramolecular architectures in 1-3; additional reinforcement within each framework is provided by the CH...O interactions. In 1, the amino N1 atom in the molecule at (x, y, z) acts as a donor to the carbonyl O2 atom of the molecule at (-1/2 þ x, 1/2 - y, 3/2 - z), whose amino N3 atom in turn donates a proton to the O2 atom in the molecule at (x, y, z), thus generating an R22(8) ring (Table 3 and Figure 3); the oxygen atom (O4) of another possible carbonyl (C4dO4) acceptor remains unused in the hydrogen bonding pattern, except for forming a weak interaction with the C-atom (C6) of the propyl group. The one-dimensional N-H 3 3 3 O hydrogen bonded network propagates along the [100] direction and can be represented using the graph-set notation56,57 as C11(4) C11(4)[ R22(8)]. The spreading of parallel chains separated by 11.0 A˚ in 1 is such that the hydantoin sites in the neighboring chains are oriented toward each other in the same way as the hydrophobic propyl groups (Figure 3). A search of the CSD for 5,50 -disubstituted hydantoin structures with a similar hydrogen bonding pattern returned seven hits (Table 4), where the electron-rich O2 atom simultaneously accepts both N1H1 3 3 3 O2 and N3-H3 3 3 3 O2 hydrogen bonds, while the other carbonyl oxygen atom (O4) of hydantoin does not take part in any classical hydrogen bonding. Incidentally, except the present compound (1) and NIWRAN,58 the other six entries in Table 4 exhibiting a C11(4) C11(4)[R22(8)] synthon belonged to the Sohnke space groups.

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Figure 4. Two-dimensional molecular sheet with fused R44(17) rings in C11H20N2O2 (2). H-atoms of the butyl chains are omitted for clarity.

Figure 5. Parallel C22(9)[R22(8)] [R22(8)] motifs propagating along the [1-10] direction in C7H10N2O2 (3).

Intermolecular N1-H1 3 3 3 O2 (x, -y þ 1, z - 1/2) and N3H3 3 3 3 O4 (x, -y, z þ 1/2) hydrogen bonds link the molecules in 2 into zigzag polymeric C11(4) chains propagating along the [001] direction. Two pairs of N-H 3 3 3 O hydrogen bonds interconnect four hydantoin molecules, forming an R44(17) synthon (Figure 4) of dimension 6.3 A˚  7.8 A˚. The R44(17) rings are edge-fused to generate a two-dimensional molecular assembly in the (100) plane. The parallel molecular sheets in 2 are stacked along the crystallographic a-axis with an interlayer separation of 9.3 A˚. The formation of an R44(17) synthon built by hydantoin molecules is unprecedented in the literature. A CSD search among the 5,50 -substituted hydantoins for an Rnm(X) synthon (m,n > 2 and X > 8) involving more than two molecules returned only four hits, having the CSD ref-codes DAFFIZ,59 LABTIR,60 PHYDAN,23 and PIPVAL.61 In all cases, the supramolecular synthon was, however, R33(12). In 3, pairs of N1-H1 3 3 3 O2 (-x, -y þ 1, -z þ 1) and N3-H3 3 3 3 O4 (-x þ 1, -y, -z þ 1) hydrogen bonds between molecules related by inversion and translation generate centrosymmetric R22(8) dimeric rings M and N centered at (0, 1/2, 1/2)

and (1/2, 0, 1/2), respectively. The R22(8) rings are alternately linked into an infinite one-dimensional MNMN... polymeric chain propagating along the the [1-10] direction (Figure 5) with a graph-set description of C22(9)[R22(8)][R22(8)]. The adjacent polymeric chains are separated by 3.3 A˚ (Figure 5). A similar hydrogen bonding pattern has been reported in the experimental62 as well as the predicted63 (results of a third blind test of crystal structure prediction) structures of unsubstituted hydantoin molecules (CSD code PAHYON) and also in five 5,50 -spiro-substituted hydantoin systems in the CSD (Table 4). It is interesting to note that all of them, including the present compound 3, crystallize in centrosymmetric space groups. The Hirshfeld surfaces of substituted (1-3) and unsubstituted (4)62 hydantoin compounds are illustrated in Figure 6, showing surfaces that have been mapped over a dnorm range of -0.5 to 1.5 A˚. The dominant interactions between amine N-H and carbonyl O atoms in 1-4 can be seen in the Hirshfeld surfaces as the bright red areas marked as a and b in Figure 6. The light red spots labeled as c are due to C-H 3 3 3 O interactions

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Figure 6. Hirshfeld surfaces for C9H16N2O2 (1), C11H20N2O2 (2), C7H10N2O2 (3), and C3H4N2O2 (4) (unsubstituted hydantoin, CSD code PAHYON).

Figure 8. Relative contributions of various intermolecular contacts to the Hirshfeld surface area in C9H16N2O2 (1), C11H20N2O2 (2), C7H10N2O2 (3), and some related structures retrieved from the CSD.

Figure 7. Fingerprint plots: full (left) and resolved into O 3 3 3 H/ H 3 3 3 O contacts for C9H16N2O2 (1), C11H20N2O2 (2), C7H10N2O2 (3), and C3H4N2O2 (4) (unsubstituted hydantoin, CSD code PAHYON) showing percentages of O 3 3 3 H/H 3 3 3 O contacts contribution to the total Hirshfeld surface area of molecules.

(Figure 6). Other visible spots in the Hirshfeld surfaces correspond to H 3 3 3 H contacts. The N-H 3 3 3 O intermolecular interactions appear as two distinct spikes in the 2D fingerprint plots (Figure 7), labeled correspondingly as a and b. Prominent pairs of sharp spikes of almost equal lengths in the region 1.6 A˚ < (de þ di) < 2.4 A˚ in the fingerprint plots (Figure 7) are characteristics of nearly equal N(donor) 3 3 3 O(acceptor) distances (2.84 ( 0.05 A˚) and a cyclic hydrogenbonded Rnm(X) synthon.64 The upper spike a (Figure 7) corresponds to the donor spike (amino H-atoms from hydantoin interacting with O-atoms of the carbonyl groups), with the lower spike b being an acceptor spike (O-atoms from hydantoin interacting with the H-atoms of NH groups). The points in the (di, de) regions of (1.5 A˚, 1.2 A˚) and (1.2 A˚, 1.5 A˚) in the fingerprint plots of 1-3 are due to C-H 3 3 3 O interactions (Figure 7). A significant difference between the molecular interactions in three hydantoin derivatives (1-3) and the unsubstituted hydantoin (4)62 in terms of H 3 3 3 H interactions is reflected in the distribution of scattered points in the fingerprint plots, which spread only up to di = de= 2.1 A˚ in 4 compared to di = de = 2.4 A˚ in 1, di = de = 2.6 A˚ in 2, and di = de = 2.2 A˚ in 3. The relative contribution of the different interactions to the Hirshfeld surface was calculated for 1-3 as well as a number of unsubstituted and 5,50 -substituted hydantoins (Figure 8) available in the CSD. Due to varying the number and the types of carbon containing substituents, they are not directly comparable across the compounds, but it offers some insight into the effect of different substituents on the hydantoin backbone. No significant C-H 3 3 3 π or π-π interactions are observed in 1-3, with C 3 3 3 H close contacts varying from

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0.9% in 3 to 2.6% in 1. In the unsubstitued hydantoin (4), the H 3 3 3 H interactions contribute 21.8% and the O 3 3 3 H interactions account for 56.5% to the Hirshfeld surface area (Figures 7 and 8). With different aliphatic and aromatic substituents at the hydantoin C5-position, the contribution of H 3 3 3 H interactions to the Hirshfeld surface increases steadily up to well over 70% in 2 with a corresponding decrease in the contribution of O 3 3 3 H interactions to 22% in OGUVIV.65 Figure 8 indicates that the molecular interactions in 5,50 -substituted hydantoins are predominantly of the H 3 3 3 H and O 3 3 3 H types, which can account for 90-98% of the Hirshfeld surface area, whereas in the unsubstituted hydantoin62 the corresponding fraction is less than 80%. The contribution of O 3 3 3 H interactions varies from 22.1% in OGUVIV65 to 44.8% in BEPNIT22 and can be attributed to various substitutions on the hydantoin moiety, which in turn facilitates the formation of different supramolecular synthons, leading to diverse crystal packing arrangements. Hydrogen bond synthon energy was calculated with the program DMol3 at the BLYP level using the DNP basis set. Different synthons were built from the structures of 1-3 obtained by X-ray analysis with their hydrogen atom positions corrected. The synthon energy (ΔE) was estimated as the difference between the N-H 3 3 3 O bonded dimers (1 and 3) or tetramer (2) and the sum of the isolated monomer energies, and so it only included the interactions within the complex, i.e. N-H 3 3 3 O hydrogen bonds but not the C-H 3 3 3 O interactions.66 The ΔE values of -18.7, -16.9, and -21.3 kcal/ mol for compounds 1, 2, and 3 are consistent with the observation that the synthon types C11(4)C11(4)[R22(8)] in 1 and C22(9)[R22(8)][R22(8)] in 3 are energetically more favorable and consequently relatively abundant in 5-substituted hydantoins. This fact is also corroborated by the relatively higher contribution of O-H interactions to the Hirshfeld surfaces of 1 and 3 than that in compound 2. Conclusions In the crystal structures of 5,50 -substituted hydantoins (1-3), multiple N-H 3 3 3 O hydrogen bonds lead to different types of supramolecular architectures, which is interesting and significant from a crystal engineering point of view. The series highlights the subtleties of crystal packing with the variation of substitutions in the hydantoins despite the presence of similar hydrogen bond functionalities. The hydantoin (1), with a symmetrically substituted dipropyl chain, exhibits a one-dimensional C11(4)C11(4)[R22(8)] network, in which only one carbonyl O atom takes part in the intermolecular hydrogen bonding, whereas in 3, with a spiro substitution at the C(5) position, both N-H 3 3 3 O hydrogen bonds are involved in building a C22(9)[R22(8)][R22(8)] framework. The dibutyl substituted hydantoin (2), on the contrary, generates twodimensional molecular sheets of fused R44(17) rings, a synthon unprecedented in this class of compounds. These structures add to the range of known hydantoin structures, which, taken with the hypothetical structures for the unsubstituted hydantoin generated in the third blind test of crystal structure prediction, show that the hydantoin functional group can adopt a range of supramolecular motifs. Acknowledgment. Financial support from the University Grants Commission, New Delhi, and the Department of Science and Technology, Government of India, New Delhi, through the DRS (SAP-II) and FIST programs for purchasing

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the X-ray powder diffractometer in the Department of Physics, Jadavpur University, is gratefully acknowledged. Supporting Information Available: Three crystallographic files (CIF); observed and simulated X-ray powder diffraction patterns. This material is available free of charge via the Internet at http:// pubs.acs.org.

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