Investigating C S···I Halogen Bonding for Cocrystallization with

Article pubs.acs.org/crystal

Investigating CS···I Halogen Bonding for Cocrystallization with Primary Thioamides Kevin S. Eccles,† Robin E. Morrison,† Abhijeet S. Sinha,† Anita R. Maguire,‡ and Simon E. Lawrence*,† †

Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Center, University College Cork, Cork, Ireland ‡ Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Center, University College Cork, Cork, Ireland S Supporting Information *

ABSTRACT: Cocrystallization utilizing halogen bonding involving the thiocarbonyl functional group of a series of primary aromatic thioamides has been investigated. The well-known organoiodide 1,4-diiodotetrafluorobenzene was utilized as the halogen bond donor and the CS···I halogen bond was established as a robust supramolecular synthon in these systems. Weak N−H···S hydrogen bonding involving the thioamides influences the overall supramolecular architectures, meaning that there is a diverse range of structural motifs and cocrystal stoichiometries observed. The majority (60%) of the cocrystals obtained have a 2:1 ratio of thioamide/organiodide with the latter present over an inversion center. The higher ratio of organoiodide seen in the other cocrystals is achieved by additional I···I and I···π halogen bonding. The CS···I halogen bond is replaced by N···I halogen bonding in the one cocrystal containing a pyridyl-substituted thioamide. The ability of the thioamides to form cocrystals and the strength of the halogen bond were influenced by the nature of the substituents on the aromatic ring, with derivatives containing electron donating groups most likely to form cocrystals. Calculated molecular electrostatic potential values on the sulfur atom in the thioamides corroborate these experimental results.

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INTRODUCTION

become widely used in the construction of multicomponent molecular crystals.20,21

The formation of multicomponent crystalline materials has been the focus of many research groups within the past few years.1−3 Initially hydrogen bonding was exploited for cocrystal formation, primarily because classical hydrogen bonding involving electronegative oxygen and nitrogen donor atoms has both strength and directionality.4,5 The amide/acid hydrogen bonded dimer, exemplified by cocrystals involving isonictotinamide with carboxylic acids, is one of the most successful examples of this approach.6−9 Other noncovalent interactions have been explored for the formation of multicomponent systems, including halogen bonding10,11 and π···π stacking.12,13 More recently, interest has centered on the interplay between halogen bonding and hydrogen bonding.14−17 Similar to hydrogen bonding, halogen bonding has both strength and directionally, with the strength of the molecular interactions dependent on the halogen atom involved.18,19 The polarizability of the halogen atom is important as it leads to the formation of a positive sigma hole on the halogen atom, effectively meaning that iodine exhibits stronger halogen bonding than bromine and chlorine. The presence of electron withdrawing fluorine atoms in close proximity to the iodine atom enhances the positive charge on the halogen atom and explains why fluorinated organoiodides such as 1,4-diiodotetrafluorobenzene, 1 (Figure 1), have © XXXX American Chemical Society

Figure 1. The well-known organoiodide 1,4-diiodotetrafluorobenzene, 1.

Within the past few years, the ability of sulfur functional groups such as sulfoxides and sulfinamides to act as coformers via either hydrogen or halogen bonding has been investigated because of the interaction with the electronegative oxygen atom in the sulfinyl group.22−28 Switching attention to the sulfur atom itself, there have been reports of halogen bonding involving thiourea, thiophene, and tetrathiafulvalene derivatives.29−31 The electron distribution on the sulfur atom is more diffuse and anisotropic relative to the oxygen atom,32 meaning Received: April 14, 2015 Revised: June 3, 2015

A

DOI: 10.1021/acs.cgd.5b00513 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Table 1. Crystallographic Data 2.1 formula MW, g mol−1 crystal system space group, Z a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Dc, g cm−3 μ, mm−1 2θ range, deg T, K total reflns unique reflns Rint obs reflns, I > 2σ(I) no. parameters no. restraints R1 [I > 2σ(I)] wR2 [all data] S Δρmax, Δρmin, e Å−3 formula MW, g mol−1 crystal system space group, Z a, Å b, Å c, Å α, deg β, deg γ, deg V, Å3 Dc, g cm−3 μ, mm−1 2θ range, deg T, K total reflns unique reflns Rint obs reflns, I > 2σ(I) no. parameters no. restraints R1 [I > 2σ(I)] wR2 [all data] S Δρmax, Δρmin, e Å−3 formula MW, g mol−1 crystal system space group, Z a, Å b, Å c, Å α, deg

C13H7F4I2NS 539.06 triclinic P1,̅ 2 5.774(4) 10.168(8) 13.264(10) 88.77(2) 84.79(2) 82.25(2) 768.4(10) 2.33 4.26 1.54−26.93 151 17584 3257 0.036 2858 198 1 0.021 0.045 1.02 0.53, −0.69 β-52.1 C22H18F4I2N2S2 704.32 monoclinic C2/c, 4 28.2332(14) 10.7096(6) 8.1690(4) 90 91.1780(10) 90 2469.5(2) 1.89 2.76 1.44−26.41 296 14088 2537 0.035 2212 155 2 0.023 0.059 1.06 0.65, −0.42

22.13

32.1

C32H14F12I6N2S2 1479.97 triclinic P1,̅ 1 6.2654(5) 10.9683(10) 15.3237(13) 80.406(3) 81.396 (3) 79.248 (3) 1012.44 (15) 2.43 4.79 1.36−26.33 300 10857 4033 0.034 3161 245 0 0.029 0.092 1.01 0.68, −0.71

C22H18F4I2N2S2 704.32 triclinic P1,̅ 1 8.1916(4) 8.6229(4) 9.6939(5) 97.9080(10) 93.2950(10) 112.0730(10) 624.05(5) 1.87 2.73 2.14−26.52 296 13984 2575 0.069 2302 154 1 0.035 0.094 1.19 0.99, −1.03

62.1

72.1

84.13

C22H18F4I2N2O2S2 736.32 monoclinic P21/n, 2 10.746(3) 6.1830(16) 18.780(5) 90 98.107(7) 90 1235.3(6) 1.98 2.77 2.07−26.54 100 7175 2532 0.056 2310 163 0 0.032 0.087 1.06 2.16, −1.46 154.13

C22H18F4I2N2O2S2 736.32 monoclinic P21/n, 2 6.7544(8) 9.9221(12) 18.4744(18) 90 93.261(3) 90 1236.1(2) 1.98 2.77 2.33−26.44 100 7126 2485 0.043 2015 163 2 0.029 0.055 1.01 0.50, −0.59

C50H36F12I6N4O4S4 1874.51 triclinic P1̅, 1 5.8460(10) 13.270(2) 20.334(4) 71.991(4) 83.885(4) 79.176(4) 1471.5(4) 2.12 3.39 1.64−26.38 100 32433 5919 0.088 5552 379 2 0.027 0.072 1.11 1.65, −1.35 172.1

C46H24Cl4F12I6N4S4 1892.13 triclinic P1̅, 1 4.2868(4) 13.6897(13) 25.474(3) 105.469(2)

C20H12Cl2F4I2N2S2 745.16 monoclinic P21/c, 2 12.0308 (17) 9.2912 (11) 11.6550 (16) 90 B

α-52.1

42.1 C22H18F4I2N2S2 704.32 monoclinic P21/c, 2 10.4324(7) 5.4480(3) 21.0125(14) 90 102.340(2) 90 1166.67(13) 2.01 2.92 1.98−26.44 100 7052 2400 0.064 2103 154 2 0.026 0.052 0.95 0.93, −1.12 102.1

C22H18F4I2N2S2 704.32 triclinic P1,̅ 2 7.9155(4) 11.2629(6) 15.2608(9) 69.6170(10) 81.5520(10) 76.4080(10) 1236.45(12) 1.89 2.76 1.43−26.46 292 28660 5038 0.035 4174 307 0 0.024 0.057 1.04 0.45, −0.63 12.1

C20H12F4I2N4O4S2 766.28 monoclinic P21/n, 2 5.1924(7) 14.745(2) 16.356(3) 90 98.258(5) 90 1239.3(3) 2.05 2.77 1.87−25.18 300 18967 2220 0.045 1793 171 2 0.025 0.088 1.28 0.39, −0.43

C13H6F5I2NS 557.05 triclinic P1̅, 2 6.2828(3) 10.9161(5) 12.9878(6) 110.5560(10) 96.2050(10) 102.9010(10) 795.83(6) 2.33 4.13 2.08−25.82 294 8688 3025 0.119 2402 208 2 0.038 0.085 0.91 0.89, −0.71 182.1

C18H12F4I2N4S2 678.26 monoclinic P21/c, 2 13.7819 (16) 7.0458 (8) 11.6222 (12) 90

DOI: 10.1021/acs.cgd.5b00513 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Table 1. continued 154.13 β, deg γ, deg V, Å3 Dc, g cm−3 μ, mm−1 2θ range, deg T, K total reflns unique reflns Rint obs. reflns, I > 2σ(I) no. parameters no. restraints R1 [I > 2σ(I)] wR2 [all data] S Δρmax, Δρmin, e Å−3

172.1

91.027(2) 96.835(2) 1428.6(2) 2.20 3.67 1.56−25.92 286 26560 5371 0.046 3941 339 2 0.039 0.181 1.24 1.80, −2.59

107.790 (4) 90 1240.5 (3) 2.00 2.96 1.78−25.07 300 11553 2181 0.040 1785 154 1 0.029 0.093 1.16 0.94, −0.51

obtained from the retreating solvent line before the solvent had completely evaporated showed they were the same in all cases except for the cocrystals involving the thioamide 5 (see below). For each combination of thioamide and 1, six solvents were investigated: CH2Cl2, EtOH, EtOAc, MeCN, acetone, and toluene (see Supporting Information). Physical Measurements. IR was recorded on a PerkinElmer Fourier transform infrared (FT-IR) spectrophotometer either as KBr discs or untreated using an ATR fitting. Melting points were measured on an Electrothermal 9100 melting point apparatus and are the values provided in the Experimental Section. Differential scanning calorimetry (DSC) data were collected using a TA Instruments Q1000. Microanalysis was performed by the microanalysis laboratory, University College Cork, on either a PerkinElmer 240 or an Exeter Analytical CE440 elemental analyzer. PXRD data were collected using a STOE STADI MP diffractometer with Cu Kα1 radiation, and calculated PXRD patterns were generated from the appropriate crystallographic information files, as described previously.40 In some cases weak diffraction was observed, which is mainly due to the small sample size. Single-crystal X-ray diffraction data were collected using a Bruker SMART X2S diffractometer for 22.13, 102.1, 172.1, and 182.1, and using a Bruker APEX II DUO using Mo Kα radiation for the remaining crystals, as described previously.41 All calculations and refinement were made using the APEX software,42 containing the SHELX suite of programs,43 and diagrams were prepared using Mercury version 3.3.44 The detailed crystallographic data and structure refinement parameters for these compounds are summarized in Table 1. The thioamide hydrogen atoms were found and refined, where possible, and the other hydrogen atoms were placed in calculated positions and allowed to ride on the parent atom. A suitable single structure of 3.1 cocrystal could not be obtained. Crystals were grown from a variety of different solvents, and numerous single X-ray diffraction experiments were attempted. In all cases, crystals of 3.1 were intergrown with crystals of 32.1, and it was not possible to separate the diffraction spots and obtain a publishable structure. To check if the crystal structures of α-52.1 and β-52.1 were different, the Niggli values were calculated using PLATON:45 α-52.1: 7.915, 11.263, 15.261 Å and 69.62, 81.55, 76.41°; β-52.1: 8.169, 10.710, 15.098 Å and 69.23, 88.90, and 90.00°. Preparation of pure α52.1 proved difficult. Crystals were harvested from ethanol before the solvent had completely evaporated to reduce contamination due to the presence of minor traces of β-52.1. Similarly, it was not possible to obtain pure crystals of 84.13 from solution based crystallization experiments; all attempts were contaminated with one or both coformers. Molecular Electrostatic Potential Calculations. Charge calculations were performed using Spartan’14 (Wavefunction, Inc., Irvine,

that intermolecular interactions involving sulfur are likely to be weaker and less predictable than their oxygen counterparts. The thioamide functional group RC(S)NR′R″ is the sulfur analogue of the amide functional group but has been largely ignored from a cocrystallization perspective, even though it possesses a significant hydrogen bond donor.33 Analysis of the crystal landscape of primary aromatic thioamides has revealed both similarities and differences in relation to their amide analogues and suggests that thioamides also have the potential to act as coformers.34 This work included thioamides containing the pyridyl functional group, which has itself been commonly utilized for halogen bonding.10,11 A search of the Cambridge Structural Database (CSD)35,36 reveals that there are 64 multicomponent systems that contain a N−CS···I interaction. The interaction involves molecular iodine for the only two examples that involve the thiocarbonyl of a thioamide group;37,38 no reports of thioamides with organoiodides exist. Consideration of these factors led us to investigate the cocrystallization of a series of primary aromatic thioamides with 1. We were interested in seeing whether the CS···I interaction would form a robust supramolecular synthon and exploring the competition between the CS···I and N···I halogen bonding, as well as the interplay between halogen bonding and weak hydrogen bonding in these systems.

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182.1 97.938 (4) 90 1117.8 (2) 2.02 3.05 1.49−25.27 300 10392 1998 0.039 1526 145 2 0.034 0.115 1.15 0.86, −0.47

EXPERIMENTAL SECTION

Materials. The thioamides 2, 7, 8, 14, 17, 18, and 20 were obtained from Sigma-Aldrich and used as received. The other thioamides were synthesized by thiolation of the aromatic amide using Lawesson’s reagent. 34,39 Solvents were obtained from commercial sources, dried, and distilled before use. Grinding Experiments. Mechanical grinding experiments were conducted in a Retsch MM400 Mixer mill, equipped with stainless steel 5 mL grinding jars and one 5 mm stainless steel grinding ball per jar. The mill was operated at a rate of 30 Hz for 20 min. The thioamide/1 ratios investigated were 4:1, 2:1, 1:1, and 1:2, and 0.2 mmol of the thioamide was used. In all cases, a powdered material was isolated and analyzed by powder X-ray diffraction (PXRD) and IR (see Supporting Information). Solution Crystallization. On the basis of the stoichiometric ratio determined from the neat grinding experiments, the thioamide (∼ 0.1−0.2 mmol) and 1 were mixed together in the solid state, dissolved, and allowed to stand at room temperature until the solvent had completely evaporated, typically 3−9 days. Analysis of crystals C

DOI: 10.1021/acs.cgd.5b00513 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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2.51. Found: C, 28.35; H, 1.12; N, 2.39. IR (KBr) νmax/cm−1: 1605, 1617 (CS). 2-Chlorothiobenzamide: 1,4-Diiodotetrafluorobenzene 4:3 Cocrystal, 154.13. Compound 15 (0.068 g, 0.4 mmol) and 1 (0.120 g, 0.3 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 95−97 °C. Anal. Calcd for C46H24Cl4F12I6N4S4: C, 29.20; H, 1.28; N, 2.96. Found: C, 30.11; H, 1.34; N, 2.87. IR (KBr) νmax/cm−1: 1622 (CS). 4-Chlorothiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 172.1. Compound 17 (0.034 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 97−100 °C. Anal. Calcd for C20H12Cl2F2I4N2S2: C, 32.23; H, 1.62; N, 3.76. Found: C, 32.39; H, 1.49; N, 4.13. IR (KBr) νmax/cm−1: 1621 (CS). Pyridine-2-carbothioamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 182.1. Compound 18 (0.027 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 96−99 °C. Anal. Calcd for C18H12F4I2N4S2: C, 31.88; H, 1.78; N, 8.26. Found: C, 31.89; H, 1.75; N, 7.92. IR (KBr) νmax/cm−1: 1582, 1602 (CS).

CA). All molecules were geometry optimized using density functional theory (DFT) B3LYP/6-311+G** ab initio calculations, with the maxima and minima in the electrostatic potential surface (0.002 e au−1 isosurface) determined using a positive point charge in vacuum as a probe. Thiobenzamide/1,4-Diiodotetrafluorobenzene 1:1 Cocrystal, 2.1. Compound 2 (0.013 g, 0.1 mmol) and 1 (0.040 g, 0.1 mmol) were used. Yellow crystals were obtained in quantitative yield, mp 83−87 °C. Anal. Calcd for C13H7F4I2NS: C, 28.96; H, 1.31; N, 2.60. Found: C, 29.22; H, 1.34; N, 2.94. IR (KBr) νmax/cm−1: 1628 (CS). Thiobenzamide/1,4-Diiodotetrafluorobenzene 2:3 Cocrystal, 22.13. Compound 2 (0.027 g, 0.2 mmol) and 1 (0.120 g, 0.3 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 84−86 °C. Anal. Calcd for C32H14F12I6N2S2: C, 25.97; H, 0.95; N, 1.89. Found: C, 26.20; H, 0.98; N, 1.90. IR (KBr) νmax/cm−1: 1614 (CS). 2-Methylthiobenzamide/1,4-Diiodotetrafluorobenzene 1:1 Cocrystal, 3.1. Compound 3 (0.015 g, 0.1 mmol) and 1 (0.040 g, 0.1 mmol) were used and colorless crystals were obtained, mp 111−113 °C. Anal. Calcd for C14H9F4I2NS: C, 30.40; H, 1.64; N, 2.53. Found: C, 30.43; H, 1.64; N, 2.21. IR (KBr) νmax/cm−1: 1623 (CS). 2-Methylthiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 32.1. Compound 3 (0.030 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Colorless crystals were obtained in a quantitative yield, mp 97−99 °C. Anal. Calcd for C22H18F4I2N2S2: C, 37.52; H, 2.58; N, 3.98. Found: C, 37.75; H, 2.62; N, 3.94. IR (KBr) νmax/cm−1: 1618 (CS). 3-Methylthiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 42.1. Compound 4 (0.030 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 91−95 °C. Anal. Calcd for C22H18F4I2N2S2: C, 37.52; H, 2.58; N, 3.98. Found: C, 37.92; H, 2.39; N, 4.24. IR (KBr) νmax/cm−1: 1605 (CS). 4-Methylthiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, α Form, α-52.1. Compound 5 (0.030 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Colorless crystals were obtained from ethanol before the solvent had completely evaporated, mp 112−115 °C. Anal. Calcd for C22H18F4I2N2S2: C, 37.52; H, 2.58; N, 3.98. Found: C, 37.48; H, 2.48; N, 3.85. IR (KBr) νmax/cm−1: 1604 (CS). 4-Methylthiobenzamide/1,4-dDiiodotetrafluorobenzene 2:1 Cocrystal, β Form, β-52.1. Compound 5 (0.030 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Colorless crystals were obtained in a quantitative yield, mp 123−126 °C. IR (KBr) νmax/cm−1: 1611 (C S). 2-Methoxythiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 62.1. Compound 6 (0.033 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Colorless crystals were obtained in a quantitative yield, mp 126−127 °C. Anal. Calcd for C22H18F4I2N2O2S2: C, 35.89; H, 2.46; N, 3.80. Found: C, 35.54; H, 2.32; N, 3.47. IR (KBr) νmax/cm−1: 1571, 1596, 1610 (CS). 3-Methoxythiobenzamide/1,4-dDiiodotetrafluorobenzene 2:1 Cocrystal, 72.1. Compound 7 (0.033 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Colorless crystals were obtained in a quantitative yield, mp 82−85 °C. Anal. Calcd for C22H18F4I2N2O2S2: C, 35.89; H, 2.46; N, 3.80. Found: C, 36.39; H, 2.42; N, 3.74. IR (KBr) νmax/cm−1: 1578, 1603, 1627 (CS). 4-Methoxythiobenzamide/1,4-Diiodotetrafluorobenzene 4:3 Cocrystal, 84.13. Compound 8 (0.067 g, 0.4 mmol) and 1 (0.120 g, 0.3 mmol) were used and colorless crystals were obtained, mp 112− 115 °C. IR (KBr) νmax/cm−1: 1614, 1599 (CS). 3-Nitrothiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 102.1. Compound 10 (0.036 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 163−165 °C. Anal. Calcd for C20H12F4I2N4O4S2: C, 31.35; H, 1.58; N, 7.31. Found: C, 31.53; H, 1.68; N, 6.96. IR (KBr) νmax/cm−1: 1645 (CS). 2-Fluorothiobenzamide/1,4-Diiodotetrafluorobenzene 2:1 Cocrystal, 122.1. Compound 12 (0.032 g, 0.2 mmol) and 1 (0.040 g, 0.1 mmol) were used. Yellow crystals were obtained in a quantitative yield, mp 92−94 °C. Anal. Calcd for C13H6F5I2NS: C, 28.03; H, 1.09; N,

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RESULTS Initial cocrystallization screening was carried out by neat grinding the two coformers in different ratios of the thioamide and 1. IR analysis of the thiocarbonyl group for the different ratios used allowed cocrystals to be identified due to shifts in the thiocarbonyl stretching frequency,46 Table 2, and PXRD Table 2. Thiocarbonyl Frequency, νCS, in the Coformers and the Cocrystals thioamide

νCS, cm−1

2

1622

3

1616

4 5

1636 1624

6 7 8 10 12 15 17 18

1623 1636 1626 1644 1607, 1630 1610, 1622 1614, 1632 1600

cocrystal 2.1 22.13 3.1 32.1 42.1 α-52.1 β-52.1 62.1 72.1 84.13 102.1 12.1 154.13 172.1 182.1

νCS, cm−1 1628 1614 1623 1618 1605 1604 1611 1610, 1627, 1614, 1645 1617, 1622 1621 1602,

1596, 1571 1603, 1578 1599 1605

1582

analysis assisted in determining cocrystal composition. This was particularly important as 1 is a flat, symmetrical, coformer that can fit into a crystalline lattice either with the complete molecule in the asymmetric unit or located over an inversion center. These two different possibilities can lead to stoichiometric cocrystals.26 On the basis of the IR and PXRD analysis, slow evaporation of solutions of the coformers, in the correct ratios, was then undertaken, and the material obtained was analyzed by IR, PXRD, DSC, and, where possible, single crystal X-ray diffraction. In total, 15 cocrystals involving 12 coformers were obtained from the 19 coformers investigated, Figure 2. While a detailed polymorphic screen was not undertaken, two crystal forms of the 52.1 cocrystal were obtained which were different based on their Niggli values. The β form was obtained from the majority of experiments, while the α form was only obtained from the retreating solvent line during the evaporative crystallization from ethanol. This is in D

DOI: 10.1021/acs.cgd.5b00513 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 2. Thioamides, 2−20, investigated for cocrystallization with 1. Blue indicates successful cocrystallization.

agreement with previous studies on evaporative crystallization, which have shown the initial formation of metastable forms near the solvent/air interface,47−50 and suggests the α form is metastable. The α form also has a lower melting point than the beta form. The DSC data for 32.1 has two peaks, the higher of which corresponds to the melting of 3.1. The difficulties encountered in isolating pure 84.13 are reflected in the DSC data, suggesting the presence of multiple forms. For all other cocrystals, the DSC data indicate the presence of only one phase. Single Crystal Analysis. The 15 cocrystal structures have been divided into two different categories. Category One, containing nine structures, possesses a 2:1 ratio of thioamide and 1. In each case, the asymmetric unit contains one thioamide molecule and one-half molecule of 1, which is located over an inversion center. The six structures in Category Two display a variety of different stoichiometries of thioamide and 1 (4:3, 1:1, and 2:3), which contain more organoiodide, 1, than seen in the structures in Category One. The anticipated CS···I halogen bond is present in all of the cocrystals except for 182.1, which displays the familiar N···I halogen bond involving the pyridyl nitrogen atom,4 Table 3. The structures exhibit hydrogen bonding involving either one or both of the thioamide hydrogen atoms, Table 4. Diagrams showing the various intermolecular interactions present in these structures are provided in the Supporting Information. Category One. The crystal structures 32.1, 42.1, α-52.1, β52.1, 62.1, 72.1, 102.1, 172.1, and 182.1 belong to Category One. In addition to the expected halogen bonding there is N− H···S hydrogen bonding from one of the thioamide hydrogen atoms to the thiocarbonyl sulfur atom. For 42.1, β-52.1, and 172.1 this gives rise to C(4) hydrogen bonded chains, as illustrated for 172.1 in Figure 3, whereas in α-52.1 the hydrogen bonded chains involve alternating symmetry inequivalent molecules. In 172.1 the second thioamide hydrogen atom is

Table 3. Details of the Halogen Bonding Observed in the Cocrystals cocrystal 2.1 22.13

32.1 42.1 α-52.1 β-52.1 62.1 72.1 84.13

102.1 12.1 154.13

172.1 182.1

halogen bond type

distance, Å

angle at I,°a

RIYb

CS···I I···π CS···I I···I I···π CS···I CS···I CS···I CS···I CS···I CS···I CS···I CS···I CS···I I···I CS···I CS···I I···I CS···I CS···I CS···I CS···I Npy···I

3.260(3) 3.429 3.3054(16) 3.6932(7) 3.85 3.4833(11) 3.2679(8) 3.154(2) 3.1874(9) 3.1738(9) 3.2066(13) 3.2112(11) 3.2619(9) 3.2471(9) 3.8325(8) 3.3750(15) 3.3486(15) 3.6889(6) 3.4930(17) 3.4050(17) 3.4891(17) 3.2907(14) 3.215(4)

173.10(7) 160.21 175.49(14) 169.17(15) 171.8 171.94(9) 174.83(9) 176.38(10) 178.70(9) 176.07(9) 176.48(9) 173.41(10) 175.93(8) 170.95(8) 172.34(8) 173.11(13) 175.04(13) 170.61(15) 165.56(14) 167.12(19) 168.12(14) 177.81(13) 171.99(14)

0.862 0.874

0.922 0.865 0.834 0.843 0.840 0.848 0.850 0.865 0.859 0.893 0.871 0.924 0.901 0.923 0.871 0.911

a Angle at N for 182.1. bRIY = d/(RI + RY).51 The distance between the atoms is d. RI and RY are the van der Waals radii of iodine and Y (sulfur or nitrogen) respectively.52

involved in N−H···F hydrogen bonding;54 however, for 42.1, α52.1, and β-52.1, while not formally involved in any hydrogen bonding, it fills some of the space near one of the fluorine atoms of 1. E

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Table 4. Details of the Hydrogen Bonding Observed in the Cocrystals cocrystal 2.1 22.13 32.1 42.1 α-52.1

β-52.1 62.1

72.1 84.13

102.1 12.1 154.13 172.1 182.1 a

atoms N9−H9A···S8 N9−H9B···S8 N9−H9B···S8 N9−H9B···S8 N9−H9A···S8 N19−H19B···I30 N19−H19A···S8 N9−H9A···S18 N9−H9A···S8 N9−H9A···S8 N9−H9A···S8 N9−H9B···I15 N9−H9B···O10 N9−H9A···S8 N9−H9B···O10 N9−H9B···F30 N9−H9B···S8 N9−H9A···S8 N20−H20A···S19 N9−H9A···S8 N9−H9B···O11 N9−H9B···S8 N9−H9A···F10 N9−H9B···S8 N19−H19B···S8 N9−H9A···F16 N9−H9B···S8 N9−H9B···S8

D−H, Å 0.83(3) 0.838(18) 0.86 0.843(19) 0.850(18) 0.84(4) 0.79(4) 0.82(4) 0.857(18) 0.864(18) 0.81(5) 0.85(5) 0.85(5) 0.852(19) 0.847(19) 0.86(4) 0.86(4) 0.86(4) 0.78(3) 0.859(19) 0.833(19) 0.82(2) 0.84(2) 0.85(4) 0.86 0.85(2) 0.83(6) 0.858(19)

H···A, Å

D···A, Å

2.56(4) 2.65(3) 2.68 2.55(2) 2.60(2) 3.19(4) 2.70(4) 2.68(4) 2.64(2) 3.00(3) 2.66(5) 3.14(4) 1.94(5) 2.95(3) 2.19(2) 2.61(4) 2.72(4) 2.56(4) 2.70(3) 2.56(2) 2.34(3) 2.82(2) 2.24(6) 2.60(4) 2.59 2.47(4) 2.79(6) 2.82(4)

3.381(4) 3.297(4) 3.518(5) 3.365(3) 3.417(3) 3.896(4) 3.491(4) 3.495(4) 3.463(3) 3.565(3) 3.452(4) 3.681(3) 2.609(4) 3.600(3) 3.023(4) 3.259(3) 3.438(3) 3.408(3) 3.277(3) 3.389(4) 3.086(6) 3.628(6) 2.683(7) 3.431(8) 3.446(7) 3.118(5) 3.599(5) 3.453(4)

θ, deg 169(3) 135(3) 173.9 163(4) 160(3) 143(3) 172(3) 174(3) 161(3) 125(3) 165(4) 124(3) 135(4) 134(3) 168(4) 133(3) 141(3) 170(3) 132(3) 163(4) 150(4) 168(6) 113.(5) 167(8) 170.5 133(5) 166(5) 132(4)

thioamide motifa R22

(8) dimer and C(4)

R22 (8) dimer R22 (8) dimer C(4) N−H···S catemersb

C(4) R22 (8) dimer, D

R22 (8) dimer, D R22 (8) dimer and C(4) C(4), Dc

R22 (8) dimer R22 (8) dimer, D R22 (8) dimer C(4) R22 (8) dimer and C(4)

53 b

Motif described by Etter’s graph set notation. Each crystallographically independent molecule is involved in a D hydrogen bond with the independent molecule at the unitary level, giving rise to C(4) chains at the binary level. cThe two crystallographically independent molecules have different motifs.

Figure 3. CS···I halogen bonding joining two C(4) hydrogen bonded chains together in 172.1, left, and the capped R22 (8) dimer in 102.1, right.

The pyridyl functional group has been commonly utilized for halogen bonding.10,11 In this work, only the ortho-derivative cocrystallized. The structure of 182.1 contains the expected N··· I halogen bonding along with centrosymmetric R22 (8) hydrogen bonded thioamide dimers, Figure 4. Category Two. The crystal structures of 2.1, 22.13, 3.1, 84.13, 12.1, and 154.13 belong to Category Two. The crystal structure of 2.1 contains CS···I halogen bonding and I··· π interactions,26 which in combination with the centrosymmetric R22 (8) dimer and C(4) chains hydrogen bonding, results in a bridging ladder motif, Figure 5. The related cocrystal 22.13 is very similar to the 2.1 cocrystal, with the extra half molecule of

For 32.1, 62.1, 72.1, and 102.1 one of the thioamide hydrogen atoms participates in N−H···S hydrogen bonding giving rise to centrosymmetric R22 (8) dimers, as seen for 102.1 in Figure 3. In the case of 32.1, the other thioamide hydrogen atom forms C− H···π interactions55 with a neighboring molecule, while in 62.1 it is the ortho-methoxy oxygen atom which results in a S(6) hydrogen bond. In 72.1, the second thioamide hydrogen atom forms a C(7) catemer with the oxygen of a neighboring thioamide, and there is distortion out of the plane of the dimers (6.6°). The oxygen atoms of the nitro group cap the dimer via N−H···O hydrogen bonding and join the dimers together via a C(8) along the b axis in 102.1. F

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DISCUSSION

There are four different types of halogen bonding seen in this cocrystal study, viz. CS···I, N···I, I···I, and I···π. The latter three interactions all occur within expected values.10,26 The CS···I halogen bond anticipated at the outset of this work is present in all the cocrystals except for 182.1, which displays the well-known N···I pyridine halogen bond. This is consistent with the theoretical studies on halogen bonding.31 The RIY parameter, Table 3, allows comparison of different halogen bonded systems and has been calculated using the method of Lommerse et al.51 Graton and co-workers used this approach in their crystallographic and theoretical study on the geometry and occurrence of halogen bonds which examined Csp-I, Csp2I, and Csp3-I interacting with N, P, O, S, Se, and C.31 They found that the I···S distances were longer, and hence weaker, than other types of halogen bonding for Csp2-I. A significant proportion of the sulfur-containing systems in their CSD study were thioureas (mean normalized I···S distance of 3.39 Å), and they attributed this weakening to competing N−H···S hydrogen bonding involving the thiocarbonyl sulfur atom. In contrast Rissanen and co-workers observed a very short CS···I halogen bond to a cationic iodonium in a charge transfer complex involving 2-imidazolidinethione.58 In the present study, the primary thioamides have a greater range of I···S distances, Table 3, than seen for the thiourea containing systems.29,30 Significantly shorter distances are seen with electron donating substituents on the aromatic ring, and only the cocrystals containing ortho-substituted chloro and methyl derivatives have longer I···S distances. The seven thioamide derivatives for which cocrystallization was not observed have substituents with electron withdrawing character. In all the cocrystals, the sulfur is involved in N−H···S hydrogen bonding in addition to the halogen bonding, Table 5, and therefore it seems unlikely that the hydrogen bonding is significantly influencing the I···S distance, in contrast with Graton’s findings on thioureas.31 To investigate this further, molecular electrostatic potentials (MEPs) were calculated for the thioamide coformers; see Supporting Information. The MEP values on the sulfur atom are enhanced by the presence of electron donating groups on the aromatic ring (3−8) and diminished by the electron withdrawing groups (9−20). The higher the surface potential value on the sulfur atom, the greater is its propensity

Figure 4. R22 (8) dimer in 182.1 with halogen bonding involving the pyridyl nitrogen atom.

1 located over an inversion center and bridging the ladder motif via additional I··I halogen bonding, Figure 6. In this case the second thioamide hydrogen atom is not involved in hydrogen bonding. There is an intermolecular S···S contact between neighboring dimers that is consistent with the literature.56,57 The crystal structure of 12.1 consists of one molecule of 12 and two crystallographically unique half molecules of 1 located over inversion centers. There are R22 (8) hydrogen bonded dimers, with S···S contacts, in combination with CS···I and I···I halogen bonding. The crystal structures of 84.13 and 154.13 both contain two independent thioamide molecules with one full molecule and one-half molecule of 1, the latter located over the inversion center. In 84.13 the full molecule of 1 is involved in two unique CS···I halogen bonds to two different, crystallographically equivalent, thioamide molecules. The molecule of 1 over the inversion center bridges two other molecules of 1 via I··I halogen bonding, Figure 7. One of the crystallographically independent thioamide molecules is involved in a R22 (8) dimer and C(4) hydrogen bonding to itself. The other independent thioamide molecule forms N−H···S C(4) hydrogen bonds to itself, with the second thioamide hydrogen atom capped by the methoxy oxygen of a symmetrically inequivalent thioamide molecule. There are three unique CS···I halogen bonds in the structure of 154.13, and the two crystallographically unique thioamide molecules each hydrogen bond to themselves to form centrosymmetric R22 (8) dimers.

Figure 5. Ladder motif, left, and CS···I and I···π halogen bonding, right, present in 2.1. The centroid of the aromatic ring of the thioamide is shown in red for clarity. G

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Figure 6. R22 (8) dimer, left, and CS···I, I···π, and I···I halogen bonding observed in 22.13, right. The centroid of the aromatic ring of the thioamide is shown in red for clarity.

Figure 7. Interactions observed in 84.13: (a) centrosymmetric R22 (8) dimer involving one independent thioamide, (b) C(4) capped by the methoxy oxygen involving the other independent thioamide, and (c) CS···I and I···I halogen bonding.

motifs are common features in the solid state structures of the thioamides themselves. For the six thioamides with an oxygencontaining substituent (methoxy or nitro), four form cocrystals and three of these display moderate N−H···O hydrogen bonding utilizing the second thioamide hydrogen atom. The exception is the 84.13 cocrystal containing the para-methoxy derivative. This structural study indicates that an activated halogen-bond donor such as 1 is likely to be very competitive for a CS moiety, even in the presence of other hydrogen-bond donors

to act as a better halogen-bond acceptor, as is evidenced by shorter I···S bond distances in 3−8, Table 3. The cutoff surface potential value at which cocrystallization is/is not observed is approximately 133−135 kJ mol−1 for these thioamides; however, the cocrystals 102.1 and 12.1 are the exception to this, the reasons for which are unclear. In all cases, in addition to the halogen bonding, at least one of the thioamide hydrogen atoms is involved in weak N−H···S hydrogen bonding, resulting in the presence of the C(4) catemer or R22 (8) dimer motif in all of the cocrystals. These H

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This interaction was displaced by the well-known N···I halogen bonding in the one example obtained with a pyridyl-substituted thioamide. The cooperative effect of the dominant halogen bonding interaction, in combination with the weak N−H···S hydrogen bonded motifs characteristic of thioamides, gave rise to a diverse range of supramolecular architectures. Interestingly, the strength of the halogen bond is independent of the hydrogen bonding which is present at the same atomic site (the thiocarbonyl sulfur atom), in contrast to the related thiourea functional group. Instead, it is the nature of the substituents on the aromatic ring that influences the strength of the halogen bond, including whether cocrystallization occurs. Cocrystallization was observed in all cases for thioamides bearing electron donating groups on the aryl ring with reduced success using electron withdrawing groups. This systematic study which has combined hydrogen and halogen bonds will enable synthetic strategies for the assembly of complex heteromeric molecular architectures.

Table 5. Nature of Intermolecular Interactions Involving the Thiocarbonyl Sulfur Atom cocrystal

nature of Interaction

# interactions to S

2.1 22.13 3.1 32.1 42.1 α-52.1a

N−H···S (x2), I···S N−H···S, I···S, S···S

3 3

N−H···S, I···S N−H···S, I···S N−H···S, I···S N−H···S, I···S N−H···S (x2), I···S N−H···S, I···S N−H···S, I···S N−H···S (x2) N−H···S, I···S (x2) N−H···S, I···S N−H···S, I···S, S···S N−H···S, I···S N−H···S, I···S (x2) N−H···S, I···S N−H···S (x2)

2 2 2 2 3 2 2 2 3 2 3 2 3 2 2

β-52.1 62.1 72.1 84.13a 102.1 12.1 154.13a 172.1 182.1 a

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ASSOCIATED CONTENT

S Supporting Information *

X-ray crystallographic information in CIF format, DSC, IR, and PXRD data, and additional figures. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00513. The crystallographic data have been deposited with the Cambridge Crystallographic Data Center, CCDC numbers 1059444−1059457. The data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

Two symmetry independent sulfur atoms.

and acceptors. The structures presented in this study are primarily assembled via a complementary interplay between hydrogen and halogen bonds as structure determining features, although other weak interactions also play a part in the supramolecular assembly. Another feature of the CS···I halogen bonding is the range of different angles and orientations found in the cocrystals, as shown in Figure 8, which shows an overlay of the thioamide functional group with the iodine atom and parent carbon atom. The range of angles observed, along with the distances in Table 3, suggest that while CS···I halogen bonding is significant, there is little directional control exhibited by the CS···I supramolecular synthon.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +353 21 490 3143. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This publication has emanated from research conducted with the financial support of IRCSET under Grant Numbers PD/ 2012/2652 and EPSPG/2011/146 (in collaboration with Bruker UK), Science Foundation Ireland under Grant Numbers 12/RC/2275 and 05/PICA/B802/EC07, and UCC 2013

CONCLUSIONS The primary thioamide functional group has been utilized to form a range of cocrystals via CS···I halogen bonding with successful cocrystallization observed for 12 of the 19 coformers, suggesting this is a relatively robust supramolecular synthon.

Figure 8. Spatial representation of the CS···I halogen bonding in the cocrystals; side-view, left, and top view looking down the SC bond, right. Atoms omitted for clarity. The structures have been overlaid with the N, C, and S atoms of the thioamide functional group in the same position for each cocrystal. The colors used for the halogen bond indicate the angle at the sulfur (CŜI): red, CŜI < 95°; green, 95° < CŜI < 100°; blue 100° < CŜI < 120°. I

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Strategic Research Fund. We thank Bruker for their help and support in this work.

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