Effect of Weak Sulfur Interactions and Hydrogen Bonds in the Folded

CRYSTAL GROWTH & DESIGN

Effect of Weak Sulfur Interactions and Hydrogen Bonds in the Folded or Unfolded Conformation of bis[2-(1H-Benzimidazol-2-yl)phenyl]disulfide Derivatives

2007 VOL. 7, NO. 10 2031-2040

Adriana Esparza-Ruiz,† Adriań Penã-Hueso,† Julio Hernańdez-Dıáz,‡ Angelina Flores-Parra,*,† and Rosalinda Contreras*,† Departamento de Quı´mica, CinVestaV, Me´ xico, A.P. 14-740, Me´ xico D.F., 07000 Me´ xico, and Facultad de Ciencias Quı´micas, UniVersidad de Colima, A.P. 28400, Coquimatla´ n, Colima, Me´ xico ReceiVed May 31, 2007; ReVised Manuscript ReceiVed July 30, 2007

ABSTRACT: Syntheses and structural study of the new compounds bis[2-(1H-benzimidazol-2-yl)phenyl]disulfide (1) and bis[2(3H-benzimidazol-1-ium-2-yl)-phenyl]disulfide sulfate (2), and their corresponding bis-hydrogen sulfate (3), bis-dihydrogen-phosphate (4), bis-tetrafluoroborate (5) and bis-perchlorate (6), are reported. X-ray diffraction analyses of 2-6 and three pseudo-polymorphs of 1 have shown that the conformation of 1 is the result of sulfur weak N f S intramolecular interactions, where the sulfur atom is acting as a Lewis acid. Nitrogen protonation changes the elongated conformation of 1 into a folded conformation for 2-4 and a semifolded conformation in compounds 5 and 6 with the assistance of intramolecular π-π stacking and hydrogen bonds, which bridge the two halves of the molecules. All disulfides adopt chiral conformations in the solid state; the ensemble of these chiral conformations is racemic. They present polymeric arrays with multiple cooperative stabilizing intermolecular and intramolecular interactions like π-interactions, O f S, C(π) f S, N(π) f S, F f S, and H-bonds. Introduction It is known that crystal structures are the result of interplay and cooperation between strong and weak intermolecular interactions. The X-ray diffraction analyses of crystals allow us to study the molecular and supramolecular architecture and evaluate the role of the weak interactions in the solid state, which are related with atomic distances shorter than the sum of the van der Waals radii (∑rvdW) but longer than covalent bond lengths. The study of weak interactions in molecular materials is of increasing general interest because of its relevant role in crystal engineering, supramolecular chemistry, and physicochemical properties. The intramolecular interactions determine the preferred conformation of molecules, whereas the intermolecular are fundamental in molecular recognition, self-organization of biomolecules, and drug design, among other applications.1-7 A disulfide bridge has been found in a reversible covalent crosslinking bond present in native proteins and has an important role in the stability, structure, and folding of proteins, as well as in their design and engineering.8-11 Aromatic disulfides12-14 and diselenides15,16 related to compounds studied here have been reported previously; they are also of interest in the design of ordered intermolecular arrays. Sulfur aromatic compounds are also important molecules in structural analyses, e.g., rigid thiols have been used for the study of π-π stacking interactions in gold materials Au(111).17 Sulfur organic compounds bearing Y f S interactions, where Y is an electron donor atom, are now reported as controlling the solid-state structure of molecules and molecular conglomerates in many different compounds,18-31 examples of S f S,18,29-31 N f S,14,29,31 and O f S12,19-23,27,28,31 interactions are known, the latter has biological relevance.20,21,23,27,31 These interactions are also found in polythiophenes, which have shown important electrical and electroluminiscent properties.28 The * Corresponding author. E-mail: [email protected]. † Cinvestav. ‡ Universidad de Colima.

Figure 1.

sulfur behaves as a Lewis acid when a donor atom approaches it following the axis of one of the two bonds X-S or S-Z, which allows the lone pair interaction with the sulfur antibonding unoccupied (LUMO) orbital. However, the divalent sulfur could have a role as electron donor with another atom if it is found in a perpendicular axis to the plane of the sulfur bonds X-S-Z, whereas one of the sulfur lone pairs occupies the p orbital,24,25 Figure 1. We have been currently investigating weak and cooperative interactions in nitrogenated aromatic heterocycles bearing chalcogen groups29,30 and have found that their sp2 aromatic rigid frameworks, along with the interaction between lone pairs and acidic C-H and N-H protons, determine their preferred conformation and intermolecular associations. In this context, herein, we report the preparation of the new compounds bis[2-(1H-benzimidazol-2-yl)phenyl]disulfide (1, and bis[2-(3Hbenzimidazol-1-ium-2-yl-)phenyl]disulfide sulfate (2), and their corresponding bis-hydrogen sulfate (3), bis-dihydrophosphate (4), bis-tetrafluroborate (5), and bis-perchlorate (6) and the structural analyses performed by X-ray diffraction. In this paper, their conformations and intermolecular associations due to the diverse cooperative intra- and intermolecular interactions as H-bonds, π-interactions, and particularly, the effect of the sulfur contacts with other electron donor or acceptor atoms are discussed. Experimental Section General. Assignment of 1H (300 MHz) and 13C NMR data was performed using 2D 1H/1H COSY, 1H/13C HETCOR, and 1H/13C COLOQ experiments. IR spectra were taken in KBr disc using a FT

10.1021/cg070498h CCC: $37.00 © 2007 American Chemical Society Published on Web 09/12/2007

2032 Crystal Growth & Design, Vol. 7, No. 10, 2007

Esparza-Ruiz et al.

Table 1. Crystal Data and Structure Refinement for Compounds 1a-1c (for all compounds, r ) γ ) 90°, and Z ) 4)

empirical formula fw T (K) wavelength (Å) cryst syst space group a (Å) b (Å) c (Å) β (deg) V (Å3) Fcalcd (mg/m3) µ (mm-1) F(000) cryst size (mm3) cryst color θ range limiting indices no. of reflns collected no. of independent reflns R(int) completeness to θ no. of obsd reflns Tmax, Tmin GOF on F2 R (all data) wR (all data) Final R1 Final wR2

1a

1b

1c

C26H18N4S2‚C4H8O 522.69 293 0.71073 monoclinic P121/n1 10.2181(2) 18.9535(4) 14.0549(4) 104.4620(10) 2635.74(11) 1.317 0.233 1096 0.5 × 0.08 × 0.05 colorless needle 3.69 to 27.48 -12 e h e 13; -24 e k e 24; -18 e l e 16 23910 5966 0.092 25.55°, 99.1% 2800 0.9884, 0.9815 1.0046 0.1137 0.0518 0.0469 (I > 2.5σ) 0.051

C26H18N4S2‚C3H6O 508.67 293 0.71073 monoclinic P121/n1 10.1475(2) 18.4674(4) 14.4251(4) 102.5570(10) 2638.57(11) 1.28 0.231 1064 0.3 × 0.08 × 0.08 light yellow prism 3.53 to 27.49 -12 e h e 12; -23 e k e 23; -18 e l e 18 11304 5963 0.014 26.67°, 99.6% 3470 0.9817, 0.9817 1.0238 0.0802 0.0798 0.0401 (I > 3σ) 0.0536

2(C26H18N4S2)‚2(C2H6OS)‚2(H0.8O0.4)‚H2O 1089.88 193 0.71073 monoclinic C12/c1 15.1789(2) 17.9938(3) 20.1523(3 103.5820(10) 5350.19(14) 1.353 0.31 2280 0.5 × 0.4 × 0.3 yellow prism 3.53 to 27.88 -19 e h e 19; -23 e k e 23; -26 e l e 26 12033 6350 0.01 27.05°, 99.6% 4055 0.9112, 0.8833 1.0637 0.0775 0.0775 0.0447 (I > 3σ) 0.0603

Table 2. Crystal Data and Structure Refinement for 2-4 (for all compounds, r ) γ ) 90°, Z ) 4 for 2-4 and Z ) 8 for 5 and 6) 2

3

4

5

6

empirical formula

C26H20N4S2O4S4(H2O)

C26H20N4S22(HO4S)3(H2O)

C26H20N4S22(BF4)

C26H20N4S22(ClO4)

fw T (K) wavelength (Å) xryst syst space group a (Å) b (Å) c (Å) β (deg) V (Å3) Fcalcd (mg/m3) µ (mm-1) F(000) cryst size (mm3) cryst color θ range limiting indices

620.73 293 0.71073 monoclinic P121/a1 12.3227(2) 15.3082(3) 15.0663(3) 90.3842(8) 2842.02(9) 1.451 0.317 1296 0.5 × 0.25 × 0.1 light blue prism 1.35-8.70 -15 e h e 15; -20 e k e 20; -20 e l e 20 14 078 7236

700.79 173 0.71073 monoclinic P121/a1 12.3785(2) 17.2285(3) 14.3959(3) 90.0890(10) 3070.11(10) 1.516 0.375 1456 0.38 × 0.25 × 0.2 dark green prism 1.41-27.80 -15 e h e 15; -22 e k e 22; -18 e l e 18 14 396 7204

C26H20N4S22(H3O4P) 2(H2O4P)H2O 860.58 293 0.71073 monoclinic P121/n1 16.1376(3) 10.1240(2) 21.9122(5) 94.0160(10) 3571.16(13) 1.601 0.409 1776 0.5 × 0.15 × 0.1 colorless prism 1.52-28.72 -20 e h e 20; -13 e k e 13; -29 e l e 29 17 888 9104

626.21 293 0.71073 monoclinic C2/c 15.2486 (2) 9.84440 (10) 36.7475 (6) 93.5419 (6) 5505.75 (13) 1.511 0.273 2544 0.3 × 0.25 × 0.05 green prism 1.11-27.45 -18 e h e 18; -12 e k e 12; -47 e l e 47 11 500 6173

651.5 293 0.71073 monoclinic C2/c 15.5145 (2) 9.88650 (10) 36.5057 (5) 94.0650 (10) 5585.31 (12) 1.549 0.44 2672 0.4 × 0.4 × 0.18 green plate 1.12-28.76 -19 e h e 19; -13 e k e 12; -49 e l e 49 11 962 7006

0.058 27.26°, 99.6% 3261 0.9688, 0.9239 1.0295 0.1418 0.1344 0.0554 (I > 2.5σ) 0.0643

0.055 25.66°, 99.4% 4050 0.9277, 0.9104 1.0556 0.1061 0.0792 0.0550 (I > 3σ) 0.0549

0.096 27.28°, 99.6% 3670 0.9405, 0.9599 1.0484 0.1512 0.2557 0.0477 (I > 2.5σ) 0.0549

0.068 25.25°, 99.0% 2626 0.9864, 0.934 1.0392 0.1790 0.2277 0.0773 (I > 2.0σ) 0.08

0.044 26.17°, 98.5% 3328 0.9239, 0.8387 1.0523 0.1380 0.1064 0.066 (I > 2.5σ) 0.0803

no. of reflns collected no. of independent reflns R(int) completeness to θ no. of obsd reflns Tmax, Tmin GOF on F2 R (all data) wR (all data) final R1 final wR2

Spectrum GX Perkin-Elmer spectrometer. EI mass spectra were performed in a Hewlett-Packard HP 5989A spectrometer. Melting points were determined on a Melt Temp II equipment in an open capillar tube and they are not corrected. Elemental analyses were carried out in a Flash 1112 Thermo Finnigan analyzer. Crystallographic Study. Data were measured on a Nonius Kappa CCD instrument with a CCD area detector using graphite-monocro-

mated Mo KR radiation. Intensities were measured using φ + ω scans, (Tables 1 and 2). Crystals obtained from MeOH/THF (1a), acetone (1b), and DMSO (1c) contained one molecule of compound 1 and one of THF, acetone, or DMSO, respectively. Compounds 2 and 3 crystallized from MeOH/THF, 4-6 from methanol. In the asymmetric unit of 1c, in addition to the DMSO molecule, there is also one-half of a molecule of H2O, the oxygen atom being in a special position. The

Conformation of bis[2-(1H-Benzimidazol-2-yl)phenyl]disulfide Scheme 1.

Synthesis of Compounds 1-5

Table 3. Select Bond Lengths (Å) for Compounds 1b and 2-6

C2-N1 C2-N3 C8-N1 C9-N3 C11-S16 C18-S17 C25-N24 C25-N26 C31-N24 C32-N26 S16-S17

1b

2

3

4

5

6

1.357 (3) 1.321 (3) 1.384 (3) 1.387 (3) 1.790 (2) 1.783 (3) 1.363 (3) 1.318 (3) 1.370 (3) 1.396 (3) 2.041 (1)

1.336 (5) 1.334 (5) 1.376 (5) 1.383 (5) 1.776 (4) 1.779 (4) 1.333 (5) 1.331 (5) 1.384 (5) 1.383 (5) 2.049 (2)

1.333(4) 1.333(4) 1.396(4) 1.391(4) 1.783(3) 1.779(3) 1.337(4) 1.329(4) 1.384(4) 1.379(4) 2.055(1)

1.332 (6) 1.332 (5) 1.377 (6) 1.392 (5) 1.784 (5) 1.783 (5) 1.329 (5) 1.337 (5) 1.389 (5) 1.379 (5) 2.054 (2)

1.332 (8) 1.332 (8) 1.391 (9) 1.380 (8) 1.782 (7) 1.778 (6) 1.335 (7) 1.334 (6) 1.386 (7) 1.384 (7) 2.047 (3)

1.332 (6) 1.340 (5) 1.389 (6) 1.369 (6) 1.789 (5) 1.778 (4) 1.338 (5) 1.327 (5) 1.375 (5) 1.387 (5) 2.056 (2)

atomic numbering for 1-6 is shown in Scheme 1. All structures were solved using direct methods using SHELX-97,32 and the refinement (based on F2 of all data) was performed by full matrix least-squares techniques with Crystals 12.84.33 All non-hydrogen atoms were refined anisotropically. For 1-6, all hydrogen atoms were located using a difference map. For 1a, the two NH hydrogen atoms were refined and all others restricted to fit ideal positions. For 1b, the position of all hydrogen atoms was refined. For 1c, the proton of the water molecule was located in the difference map and its position refined. For 2 only the positions of the OH and NH hydrogen atoms were refined, except of those bonded to O41. For 3 only hydrogen atoms of the organic part were refined, the water molecule was disordered. For 4, all hydrogen atoms were allowed to ride. For 5 they were restricted to fit

Crystal Growth & Design, Vol. 7, No. 10, 2007 2033 ideal positions. For 6 the four N-H protons were refined. Selected bond lengths and angles are presented in Tables 3 and 4. Crystallographic data (excluding structure factors) have been deposited in the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 635407 (1a), 635408 (1b), 635409 (1c), 635410 (2), 635411 (3), 646858 (4), 647415 (5), and 648719 (6). Copies of the data can be obtained, free of charge, on applications to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail: [email protected]). bis-[2-(1H-Benzimidazol-2-yl)phenyl]disulfide] (1). A mixture of 2-mercapto-benzoic acid (5.0 g, 32.4 mmol) and o-phenylenediamine (3.5 g, 32.4 mmol) was stirred in concentrated polyphosphoric acid (50 g) at 220 °C for 6 h. The hot mixture was poured into vigorously stirred cold water (300 mL). A green precipitate was obtained after neutralization with aqueous NH4OH and then filtered and dissolved in EtOH; slow evaporation gave green crystals. Crystallization in DMSO, EtOH, acetone, or a 1:1 mixture of MeOH/THF gave in all cases a pale green solid (11 g, 75%). After being washed with THF, pure compound 1 was obtained as a colorless solid. Mp 274 °C. NMR (DMSO-d6, rt) 1H: 7.69 (H4, H7), 7.26 (H5, H6), 7.79 (H12), 7.42 (H13), 7.41 (H14), 7.98 (H15). 13C: 150.7 (C2), 115.2 (C4, C7); 122.5 (C5, C6), 139.8 (C8, C9), 128.3 (C10), 136.4 (C11), 126.1 (C12), 130.2 (C13), 126.3 (C14), 129.1 (C15). IR (KBr), ν (cm-1): 1621, 1590, 739. MS: m/z (%) [M]+ 450(1), 448(3), 418(100). Anal. Calcd for C26H18N4S2‚2(CH3)2SO: C, 59.38; H, 4.98; N, 9.23. Found: C, 59.42; H, 4.79; N, 9.55. bis[2-(3H-Benzimidazol-1-ium-2-yl-)phenyl]disulfide sulfate (2). Compound 1 (1 g, 2.22 mmol) and H2SO4 (0.12 mL, 2.22 mmol) were added to an equimolar mixture of MeOH/THF (50 mL) and the suspension was stirred until all solids were dissolved. The solvent was slowly evaporated and 3 days later, blue pale crystals were obtained (1.17 g, 85%). Mp 260 °C. NMR (DMSO-d6, rt) 1H: 7.77 (H4, H7), 7.45 (H5, H6), 7.77 (H12), 7.51 (H13), 7.49 (H14), 7.92 (H15), NH and OH (4.75). 13C: 148.8 (C2), 115.1 (C4, C7); 124.6 (C5, C6), 135.3 (C8, C9), 126.3 (C10), 136.4 (C11), 128.5 (C12), 131.9 (C13), 127.8 (C14), 130.7 (C15). IR (KBr), ν(cm-1): 1626, 1592, 1112, 757. MS: m/z (%) [M]+/2 226(13), 224(100). Anal. Calcd for C26H20N4S2‚SO4‚ 4H2O: C, 50.31; H, 4.55; N, 9.03. Found: C, 50.04; H, 4.63; N, 9.05. bis[2-(3H-Benzimidazol-1-ium-2-yl-)phenyl]disulfide bis-(hydrogensulfate) (3). Compound 1 (1 g, 2.22 mmol) was dissolved in an equimolar mixture of MeOH/THF (50 mL), and 1.2 mL (22.2 mmol) of concentrated sulfuric acid was then added. The mixture was stirred until a dark green solution was obtained. The resulting solution was slowly evaporated at rt, and green crystals were filtered and washed with 2 mL of methanol (1.22 g, 79%). Mp 258 °C. NMR data of 2 and 3, dissolved in DMSO-d6, are identical: IR (KBr), ν(cm-1): 1627, 1592, 1114, 758. MS: m/z (%) [M]+/2 226(5), 224(100), 192(3). Anal. Calcd for C26H20N4S2‚2HSO4‚5H2O: C, 42.38; H, 4.38; N, 7.60. Found: C, 42.24; H, 4.07; N, 7.65. bis[2-(3H-Benzimidazol-1-ium-2-yl-)phenyl]disulfide bis-dihydrogen-phosphate (4). Compound 1 (200 mg, 0.44 mmol) was dissolved

Table 4. Selected Bond Angles (deg) for Compounds 1b and 2-6

C2-N1-C8 N1-C2-N3 N1-C2-C10 N3-C2-C10 C2-N3-C9 C4-C9-N3 C10-C11-S16 C12-C11-S16 C11-S16-S17 S16-S17-C18 C25-N24-C31 C19-C25-N24 C19-C25-N26 N24-C25-N26 C25-N26-C32 C30-C31-N24 N24-C31-C32 C27-C32-N26 C31-C32-N26 S17-C18-C19 S17-C18-C23

1b

2

3

4

5

6

107.5(2) 112.4(2) 121.2(2) 126.2(2) 105.1(2) 130.3(2) 118.2(2) 122.5(2) 106.0(1) 105.5(1) 108.0(2) 121.2(2) 126.9(2) 112.1(2) 105.5(2) 133.3(2) 105.2(2) 130.9(2) 109.2(2) 118.9(2) 122.2(2)

109.5 (3) 108.5 (3) 126.8 (3) 124.8 (3) 109.3 (3) 131.8 (4) 122.0 (3) 119.1 (3) 101.3 (1) 101.1 (1) 108.6 (3) 126.4 (3) 124.1 (3) 109.5 (3) 108.9 (3) 132.0 (4) 106.6 (3) 132.3 (4) 106.3 (3) 122.4 (3) 118.6 (3)

109.1(2) 109.1(3) 127.0(3) 123.9(3) 109.3(3) 131.9(3) 122.3(2) 118.9(2) 101.7(1) 100.5(1) 109.3(3) 127.5(3) 123.5(3) 109.0(3) 109.3(3) 132.4(3) 106.6(3) 132.1(3) 106.3(3) 122.2(2) 119.0(2)

109.5(3) 108.5(4) 128.8(4) 122.7(4) 109.3(4) 131.7(4) 122.1(4) 118.2(4) 102.5(2) 100.6(2) 110.0(3) 128.0(4) 123.6(4) 108.2(4) 109.5(3) 132.1(4) 105.5(4) 132.4(4) 106.7(4) 122.3(4) 118.6(4)

110.4 (6) 107.5 (7) 125.3 (6) 127.1 (6) 110.1 (6) 132.8 (8) 122.9 (6) 118.6 (5) 103.7 (2) 104.2 (2) 110.0 (5) 124.8 (5) 127.7 (5) 107.5 (5) 110.4 (5) 132.3 (6) 106.2 (5) 131.7 (5) 105.9 (5) 123.4 (5) 117.4 (5)

110.4 (4) 107.5 (4) 125.3 (4) 127.1 (4) 110.5 (4) 132.9 (5) 122.6 (4) 117.6 (4) 102.9 (2) 104.2 (1) 109.7 (3) 124.5 (3) 127.6 (3) 107.9 (3) 110.3 (3) 132.3 (4) 106.7 (3) 132.4 (4) 105.3 (3) 123.4 (3) 117.2 (3)


Esparza-Ruiz et al.

Figure 2. View of enantiomers in disulfide 1.

Figure 3. Solid-state structures 1a-1c have similar conformations, shown here. Figure 5. Perpendicular view of the thiophenylene planes in 1a and 1b. evaporated at rt, and green crystals were filtered and washed with 2 mL of methanol, (246 mg, 85%), dec at 224 °C. IR (KBr), ν (cm-1): 1625, 1588, 1120, 755, 622. NMR (DMSO-d6, rt) 1H: 7.83 (H4, H7), 7.62 (H5, H6), 7.69 (H12), 7.56 (H13), 7.59 H(14), 7.89 (H15), NH and OH (5.20). 13C: 147.6 (C2), 114.7 (C4, C7); 126.7 (C5, C6), 131.9 (C8, C9), 125.2 (C10), 136.2 (C11), 132.1 (C12), 133.7 (C13), 129.8 (C14), 132.6 (C15). EM: m/z (%) [M]+ - 452(1). Anal. Calcd for C26H20N4S2‚2ClO4: C, 47.93; H, 3.09; N, 8.60. Found: C, 47.64; H, 3.38; N, 8.57.

Results and Discussion

Figure 4. View of the dimer formed by six cooperative interactions in crystals 1a and 1b. The N-H protons have a bifurcated bond with nitrogen (h) and sulfur (i), (1a, N‚‚‚H 2.1 Å and S‚‚‚H 3.0 Å; 1b, N‚‚‚H 2.06 Å and S‚‚‚H 2.95 Å) and two S‚‚‚C(π) interactions (l) [1a and 1b 3.34 Å, (∑rvdW) S‚‚‚C(π) 3.5 Å]. in MeOH (40 mL), then 0.25 mL (4.44 mmol) of phosphoric acid were added. The mixture was stirred until a dark green solution was obtained. The resulting solution was slowly evaporated at rt, filtered, and washed with 2 mL of methanol. Colorless crystals were obtained (240 mg, 63%). Mp 202 °C. NMR (DMSO-d6, rt) 1H: 7.68 (H4, H7), 7.28 (H5, H6), 7.74 (H12), 7.40 (H13), 7.38 H(14), 7.91 (H15), NH and OH (7.33). 13C: 150.2 (C2), 115.7 (C4, C7); 123.5 (C5, C6), 138.3 (C8, C9), 128.2 (C10), 136.7 (C11), 127.1 (C12), 131.0 (C13), 127.2 (C14), 130.0 (C15). ν (cm-1): 1628, 988. MS: m/z (%) [M]+ 226(38), 194(4), 98(84), 81(100). Anal. Calcd for C26H20N4S2‚2H2PO4‚3H3PO4‚ 3H2O: C, 31.40; H, 3.95; N, 5.63. Found: C, 31.41; H, 3.71; N, 5.63. bis[2-(3H-Benzimidazol-1-ium-2-yl-)phenyl]disulfide bis-tetrafluoroborate (5). Compound 1 (1 g, 2.22 mmol) was dissolved in MeOH (100 mL) and BF3‚OEt2 0.56 mL (4.44 mmol) was added; the solvent was evaporated at rt and light brown crystals were formed (1.1 g, 79%). Mp 258-260 °C. IR (KBr), ν (cm-1): 1627, 1591, 1083, 754. MS: m/z (%): [M]+ - 2 450(1), 418(4), 274(3) 254 (100) 224 (64). Anal. Calcd for C26H20N4S2‚2BF4: C, 49.87; H, 3.22; N, 8.95. Found: C, 49.86; H, 3.51; N, 9.27. bis[2-(3H-Benzimidazol-1-ium-2-yl-)phenyl]disulfide bis-perchlorate (6). Compound 1 (200 mg, 0.44 mmol) was dissolved in MeOH (50 mL) and HClO4‚0.28 mL (4.44 mmol) was added. The solvent was

Disulfide 1 was prepared by reaction of 2-mercaptobenzoic acid and o-phenylenediamine in concentrated polyphosphoric acid and neutralized with NH4OH. The precipitate was filtered and dissolved in EtOH to give green crystals. The SH group of the reaction intermediate 2-(1H-benzimidazol-2-yl)benzenethiol was oxidized to disulfide in the reaction medium to afford compound 1, which was characterized by NMR experiments. Pseudo-polymorph crystals were obtained from MeOH:THF (1: 1) (1a) and acetone (1b) and a third different crystal from DMSO (1c); the three were submitted to X-ray diffraction analyses. Addition of 1 equiv of sulfuric acid to a MeOH:THF solution of compound 1 afforded the crystalline sulfate derivative 2, whereas the same reaction with 10 equiv of concentrated sulfuric acid gave the bis-(hydrogen-sulfate) 3, which crystallized from MeOH:THF. Addition of 10 equiv of phosphoric acid to compound 1 gave the corresponding bis-dihydrophosphate (4). Reaction of 2 equiv of BF3‚OEt2 in methanol afforded compound 5 and the reaction with 10 equiv of perchloric acid gave compound 6. Compounds 1-6 were analyzed by NMR, IR, mass, and X-ray diffraction, Scheme 1. The reactions of compound 1 with protonic acids or BF3 in the presence of moisture afforded the protonated benzimidazolium heterocycles as was confirmed by IR and NMR, with the exception of the phosphoric acid, which was not strong enough to completely protonate the benzimidazole in solution. Mass spectra gave only the peak for the mass or half of the mass of the disulfide cation. The discussion of this paper is mainly focused on the solid-state structures.

Conformation of bis[2-(1H-Benzimidazol-2-yl)phenyl]disulfide

Crystal Growth & Design, Vol. 7, No. 10, 2007 2035

Figure 6. Crystal structure 1c shows that each water molecule is linked by four disulfide molecules; the N-H-O-H-N angle is 114° and H-O-H 100.0°. Each water proton has a OH‚‚‚N bond (2.00 Å) and H‚‚‚S (2.95 Å), whereas the oxygen from water is bonded by two N-H protons.

Figure 7. Structure 1c shows intermolecular π-stacking between aromatic rings, the distance between centroids is 3.7 Å. Figure 9. Planes of the intramolecular stacked rings in 2; the angles between planes are 21.84 and 16.55. Angles of similar planes for compound 3 are 14.8 and 12.3°.

Figure 8. Folded conformation of compounds 2-4, and the distance between ring centroids for 3.

Solid-State Structures. Compound 1. The conformation of 1 is very similar in crystals 1a-1c. The C-S-S bond angles (1a, 105.4 and 105.2°; 1b, 105.5 and 105.9°; and 1c, 104.8 and 105.0°) indicate that the sulfur atoms have sp3 hybridization. The C-S-S-C bonds have torsional angles close to 90° (88.51, 1a; 87.53, 1b; and 89.36, 1c), which correspond to a staggered conformation of the S-S bond. This conformation avoids repulsion between sulfur bonds and lone pairs and gives chiral structures (C2 group, the C2 axis passing through the center of the S-S bond), as expected, both enantiomers were found in all crystals, Figure 2. The connected benzimidazole and thiophenylene rings in each half of compound 1 are not coplanar; for

example, in 1b, dihedral angles between the planes depicted by the mentioned rings are 36.4 and 37.7 Å. An important fact in the crystalline structures 1a-1c (Figure 3) was the finding that the four atoms N3‚‚‚S16-S17‚‚‚N26 are in a linear arrangement (the corresponding N-S-S angles are in the range of 170-177°). The distance between each sulfur atom and the imidazole nitrogen is very short, (N‚‚‚S distances are 2.96 and 2.97 Å for 1a, 2.97 and 2.96 for 1b, and 2.84 and 2.95 for 1c, whereas the van der Waals radii (∑rvdW) is S‚‚‚‚N ) 3.85 Å29). These arrays correspond with a linear N-S-S-N hypervalent four-center, six-electron bonds (n(N) f σ*(S-S) r n(N)),31 the orbital interaction occurs between the lone pair of the nitrogen atoms and the antibonding orbital of the sulfur atoms.31 A similar system for four sulfur atoms was depicted,13 as well as a disulfide bearing intramolecular S‚‚‚N interactions.14 The conformation of 1 is not only dictated by the nitrogensulfur interactions, but also by two cooperative C-H‚‚‚S hydrogen bonds (i and h, Figure 3) perpendicular to the plane described by C-S-S bonds; in this position, the sulfur atom is acting as a Lewis base. The H‚‚‚S contacts (2.69 and 2.69 Å for 1a, 2.65 and 2.70 Å for 1b, 2.63 and 2.74 Å for 1c) are shorter than the reported distance of the highest incidence of


Figure 10. Conformation of disulfides 5 and 6. For 5, the distance between the ring centroids is shown, the angles between the planes of benzimidazole and thiophenylene rings are 49.7 and 36.7°, whereas those for 6 are 50.2 and 35.4°.

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Figure 12. Crystal of 2 is formed by a diprotonated disulfide plus a sulfate and four water molecules. Sulfur atoms have four H-bonds: S16‚‚‚H1 3.0, S17‚‚‚H24 2.91, S16‚‚‚H12 2.82, and S17‚‚‚H23 2.81 Å. Each molecule of 2 is bonded by a sulfate ion through four H-bonds: H26‚‚‚O37 1.92, H15‚‚‚O37 2.63, H3‚‚‚O37 2.06, and H4‚ ‚‚O34 2.70 Å. The water molecules form H-bonds O39‚‚‚H24 1.95 and O38‚‚‚H1 1.96 Å. There are two O f S short distances: O39‚‚‚ S17 3.17 and S16‚‚‚O38 3.45 Å.

Figure 11. Spacefill representation for the extended conformation of compound 1 (up-left), folded conformation of 2-4 (up-right) and mixed conformation of 5-6, (down).

Figure 13. O‚‚‚S short contacts and H-bonds in the solid-state structure of compound 3.

CH‚‚‚S contacts (3.21 Å).35 Despite the fact that C-H‚‚‚S bonds are rarely reported, their relevance has been recognized.35-41 A dimeric structure is present in the crystal structures 1a and 1b, which is formed by six weak cooperative intermolecular interactions: two short contacts S‚‚‚C(π) (l), and two bifurcated N-H hydrogen bonds,41-42 one with the imidazolic nitrogen (h) and another with the sulfur atom (i), Figure 4. Thiophenylene rings form a π-stacking; a view perpendicular to the interacting planes is shown in Figure 5. It is reported that in nitrogen heterocycles, the π-stacking occurs with some deviation of the angle between planes (between 16 and 40°) as well as with some displacement.7 It has been also proposed that the atomic distance value is a better criterion for the determination of the π interactions, considering that strong interactions occurs if the atomic distances are around 3.3 Å, whereas weak interactions predominate between 3.6 and 3.8 Å.7 In the same context, it is reported that the ideal distance for C-H‚‚‚π contacts is 2.9 Å.43 A polymeric array is found for 1c, a water molecule is binding four disulfides molecules by strong hydrogen bonds, Figure 6. Each water molecule presents six stabilizing interactions, each

oxygen atom is linked by two N-H protons (2.14 Å), and each O-H proton is bonded by one imidazole nitrogen (2.00 Å) and one sulfur atom (2.95 Å). Structure 1c shows an intermolecular network formed by two types of π-stacking, one approaching two thiophenylene groups and another one between the benzimidazole and the thiophenylene, Figure 7. Compounds 2-6. Crystals of compounds 2-6 contain the diprotonated disulfide, in 2, with a sulfate and four water molecules; in 3, with two hydrosulfates and three water molecules; in 4, with two dihydrophosphates, two molecules of phosphoric acid and one molecule of water; in 5, with two tetrafluoroborates; and in 6, with two perchlorates. Disulfides 2-4 have a folded conformation that approaches the two aromatic halves of the molecule, giving two π-stacking interactions; the distance between the ring centroids varies in the range of 3.5-3.9 Å, Figure 8. The stacking occurs between oblique planes as is shown in Figure 9.7 On the other hand, compounds 5 and 6 present a semifolded conformation with half of the molecule folded and a benzimidazole oblique, as shown in Figure 10.



Figure 14. Phosphoric acid and phosphate S‚‚‚‚O interactions and H-bonds in compound 4.

Figure 16. Hydrogen bonds formed in compound 6 with the perchlorate anions.

Figure 17. π-Stacking in compound 2.

Figure 15. N-H and C-H fluorine H-bonds in compound 5. Two BF4- molecules are bridging the aromatic rings.

In compounds 2-6, the S-S bonds also have a staggered conformation; the C11-S16-S17-C18 torsional angles values are in the range of 77.6-80.3° for 2-4 and 96.4-96.5° for 5 and 6, respectively. As a consequence, the conformations of all six compounds are chiral (C2 point group for 2-4, and C1 for 5 and 6). A comparison between the different conformers of compounds 1, 2-4, and 5-6 is shown in Figure 11. The sulfur angles (S16-S17-C18 101.1° (2) 100.5° (3), 100.6° (4), 104.2° (5), 104.2 (6) and C11-S16-S17 101.3° (2), 100.5° (3), 102.5° (4), 103.7° (5), 102.9 (6)) are closer for compounds 2-4 than for 1a-1c, as a consequence of the folded conformation, Compounds 5 and 6 are like those of 1a-1c (104.8-105.9°).

In compounds 2-6, the N-H protons form weak bonds with sulfur (2.7-3.0 Å, Figures 12-15). The folded conformation found in 2-4 is also favored by two N-H hydrogen bonds (N3 and N26) with the oxygen of the sulfate ion in 2 (H3‚‚‚ O37 2.06, H26‚‚‚O37 1.92 Å, Figure 12), an oxygen of a water molecule in 3 (H3‚‚‚O43 1.98 and H26‚‚‚O43 2.08 Å, Figure 13), an oxygen of a phosphoric acid in 4 (H3‚‚‚O34 1.91 and H3‚‚‚O34 1.82 Å, Figure 14), fluorine atoms of two BF4tetrafluoroborates in 5 (CH12‚‚‚F37 2.81; NH24‚‚‚F37 2.13; CH30‚‚‚F35 2.66 Å, Figure 15), and finally, oxygen atoms of two perchlorate groups in 6 (one chlorate has four hydrogen bonds and a second two), Figure 16. Other interesting sulfur weak interactions were found in compounds 2-4. In compound 2, two water molecules are close to the sulfur atoms with O‚‚‚‚S distances (3.45 and 3.17 Å, ∑rvdW is 3.77 Å),34 and at the same time, the oxygen atoms are forming a cooperative strong N-H‚‚‚O bond with N1 (1.96 Å) and N24 (1.95 Å), Figure 12. In compound 3, a similar situation is produced; in this case, the disulfide group has short distances with two bisulfate anions; one of the sulfur atoms (S17) shows


Esparza-Ruiz et al.

Figure 18. A linear array is formed in compound 3, by a symmetric π-stacking, through the benzimidazole groups, between alternating enantiomers.

Figure 19. A spacefill representation of the linear array of disulfides in compound 4.

Figure 20. Inter- and intramolecular distances between centroids in compound 5. Distances between C22 of one disulfide with C23 (3.39 Å) and C32 (3.30 Å) of other two molecules. The angle between the planes of intramolecularly interacting rings is 8.6°.

two bifurcated interactions with two oxygen atoms of one hydrosulfate (3.13 and 3.48 Å), whereas the second approaches another sulfur atom in a distance of 3.16 Å, Figure 13. Also,

Figure 21. π-Interactions in compound 6.

cooperative strong H-bonds are formed between the oxygen atoms and the corresponding N-H groups (H1‚‚‚O39 1.94 and H24‚‚‚O36 2.28 Å, Figure 13). In compound 4, a phosphoric acid molecule has a role to join the two halves of the molecule, a phosphoric acid molecule and a dihydrophosphate are close to the disulfide, forming strong N-H‚‚‚O bonds (1.90 and 2.01 Å). Two oxygen atoms of the phosphates have contacts with the sulfur (3.28 and 3.47 Å). An O-H proton of the phosphoric acid shows a H-bond with sulfur (O-H‚‚‚S, 2.79 Å), Figure 14. Compounds 5 and 6 have isomorphous crystals so they have a similar array. In those compounds, two BF4- or two ClO4help to stack the two halves of the cation, forming several hydrogen bonds with N-H and C-H protons; some of them are bifurcated and cooperative, Figures 15 and 16. Fluorine atoms have short distances with the sulfur (3.55, 3.5, and 3.35 Å; ∑rvdW radii S, F is 3.71).34 In compound 6, there are three short contacts between sulfur and oxygen atoms (3.33, 3.49, and 3.56 Å; ∑rvdW 3.77 Å).34 Compounds 2-4 form chains through intermolecular stacking of benzimidazole groups. They form a head to tail parallel alignment, which allows the imidazole electron deficient ring to be stacked in front of the more electron-rich phenylene ring,7 as shown for compound 2, Figure 17. The intramolecular stack of thiophenylene rings and the benzimidazole are not parallel because of the effect of the nitrogen atoms.7 For compound 3, the distances between centroids in intramolecular contacts are 3.9-3.7 Å, whereas between molecules, the rings are parallel (distance between centroids is 3.6 Å), Figure 18. In compound 4, the disulfide forms a linear alignment in zigzag, Figure 19. The distance between the ring centroids is



lecular, intermolecular, and interionic sulfur interactions: the sulfur acting as a Lewis acid and receiving electron density from nitrogen, oxygen, and fluorine atoms, as well as from π-electrons of nitrogen and carbon atoms. The rigid aromatic framework of the molecules allows the formation of linear polymeric arrays by diverse and strong π-stacking. It has been found that the water, hydrogen sulfate, sulfate, dihydrogen phosphate, tetrafluoroborate, and perchlorate form several cooperative and polyfurcated intermolecular weak bonds. The staggered disulfide bond conformation produces chiral structures, giving associated pairs of enantiomers in the solid state.

Figure 22. Hydrogen bonds formed between two phosphoric acids, two dihydrophosphates, and one water molecule in the crystal structure of compound 4.

Figure 23. Lattice formed by the association of two phosphoric acids, two dihydrophosphates, and a water molecule in the crystal of compound 4.

3.7 and 3.8 Å for intramolecular stacking and 3.6 Å for intermolecular stacking. Compounds 5 and 6 also have intermolecular and intramolecular π-interactions, Figures 20 and 21. An interesting finding in the crystal structure of 4 was the water, phosphoric acid, and phosphate organization in planes forming a lattice with holes. The superposition of the planes form diagonal channels where the disulfide molecules are aligned in long chains. Figure 22 shows the hydrogen bonds connecting the phosphates, the phosphoric acid, and a water molecule, whereas Figure 23 shows the corresponding lattice. Conclusions The solid-state analyses of bis[2-(1H-benzimidazol-2-yl)phenyl]disulfide and bis[2-(3H-benzimidazol-1-ium-2-yl-)phenyl]disulfide sulfate, and its corresponding bis-hydrogen sulfate, bis-dihydrophosphate, bis-tetrafluroborate, and bisperchlorate, have shown that the disulfides conformation in the solid is dictated by several diverse and cooperative weak interactions. The protonation of imidazole nitrogen atoms changes dramatically their conformation. In the pseudo-polymorphous of the neutral molecule 1, two strong N‚‚‚S interactions determine the conformation by forming a linear array N-S-S-N, which corresponds to a hypervalent four-center, six-electron bond (n(N) f σ*(S-S) r n(N)). It has been found that disulfide shows multiple cooperative bonds between low acidic protons and Lewis basic atoms. Several π stacking between aromatic groups have important roles in ordering molecular architectures. Noteworthy findings are the intramo-

Acknowledgment. Authors wish to thank Conacyt-Me´xico for the Ph.D. scholarships of A. E.-R. and A. P-H. References (1) Custelcean, R.; Jackson, J. E. Chem. ReV. 2001, 101, 1963. (2) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford University Press: New York, 1997. (3) Giacovazzo, C. Fundamentals of Crystallography, 2nd ed.; Oxford University Press: Oxford, U.K., 2002. (4) Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Elsevier: New York, 1989. (5) Scheiner, S. Molecular Interactions: From Van der Waals to Strongly Bound Complexes; John Wiley & Sons: New York, 1997. (6) Desiraju, G. R. Chem. Commun. 2005, 2995. (7) Janiak, C. J. Chem. Soc., Dalton Trans. 2000, 3885. (8) Meinhold, D.; Beach, M.; Shao, Y.; Osuna, R.; Coloń, W. Biochemistry 2006, 45, 9767. (9) Vaz, D. C.; Rodrigues, J. R.; Sebald, W.; Dobson, C. M.; Brito, R. M. M. Protein Sci. 2006, 15, 33. (10) Swaisgood, H. E. Biotechnol. AdV. 2005, 23, 71. (11) Gupta, A.; van Vlijmen, H. W. T.; Singh, J. Protein Sci. 2004, 13, 2045. (12) Kucsman, A Ä .; Kapovits, I.; Pa´rkańyi, L.; Argay, G.; Ka´lmań, A. J. Mol. Struct. 1984, 125, 331. (13) Nakanishi, W.; Hayashi, S.; Arai, T. Chem. Commun. 2002, 2416. (14) Mugesh, G.; Singh, H. B.; Butcher, R. J. Eur. J. Inorg. Chem. 1999, 1229. (15) Tomoda, S.; Iwaoka, M.; Yakushi, K.; Kawamoto, A.; Tanaka, J. J. Phys. Org. Chem. 1988, 1, 179. (16) Nakanishi, W.; Hayashi, S.; Toyota, S. J. Org. Chem. 1998, 63, 8790. (17) Dou, R.-F.; Ma, X-C.; Xi. L.; Yip, H. L.; Wong, K. Y.; Lau, W. M.; Jia, J.-F.; Xue, Q.-K.; Yang, W.-S.; Ma, H.; Jen, A. K.-J. Langmuir 2006, 22, 3049. (18) Ren, X. M.; Nishihara, S.; Akutagawa, T.; Noro, S.; Nakamura, T. Inorg. Chem. 2006, 45, 2229. (19) Ganguly, N. C.; Datta, M.; Ghosh, K.; Bond, A. D. CrystEngComm. 2005, 7, 210. (20) Wu, S.; Greer, A. J. Org. Chem. 2000, 65, 4883. (21) Burling, F. T.; Goldstein, B. M. J. Am. Chem. Soc. 1992, 114, 2313. (22) Iwaoka, M.; Takemoto, S.; Tomoda, S. J. Am. Chem. Soc. 2002, 124, 10613. (23) Bernardi, F. Csizmandia, I. G; Mangini, A. Organic Sulfur Chemistry; Elsevier: New York, 1985. (24) Guru Row, T. N, Parthasarathy, R. J. Am. Chem. Soc. 1981, 103, 477. (25) Rosenfield, R. E., Jr.; Parthasarathy, R.; Dunitz, J. D. J. Am. Chem. Soc. 1977, 99, 4860. (26) Oae, S. Organic Sulfur Chemistry, Structure and Mechanism; CRC Press: Boca Raton, FL, 1991; pp 19-35. (27) Goldstein, B. M.; Takusagawa, F.; Berman, H.; Srivastava, P. C.; Robins, R. K. J. Am. Chem. Soc. 1983, 105, 7416. (28) Pomerantz, M.; Cheng, Y. Tetrahedron Lett. 1999, 40, 3317. (29) Tellez, F.; Cruz, A.; Lo´pez-Sandoval, H.; Ramos-Garcıá, I.; Gayosso, M.; Castillo-Sierra, R. N.; Paz-Michel, B.; No¨th, H.; Flores-Parra, A.; Contreras, R. Eur. J. Org. Chem. 2004, 4203. (30) Garcıá-Hernańdez, Z.; Flores-Parra, A.; Grevy, J. M.; RamosOrganillo, A.; Contreras, R. Polyhedron 2006, 25, 1662. (31) Iwaoka, M.; Takemoto, S.; Okada, M.; Tomoda, S. Bull. Chem. Soc. Jpn. 2002, 75, 1611. (32) Sheldrick, G. M. SHELX 97-2 Users Manual; University of Go¨ttingen: Go¨ttingen, Germany, 1977. (33) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J. Appl. Cryst. 2003, 36, 1487.

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Effect of Weak Sulfur Interactions and Hydrogen Bonds in the Folded

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