Crystal structures of two polymorphs of thiodiglycolamide via the formation of dimeric and catemeric hydrogen bonds

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Abstract

Thiodiglycolamide crystallizes in two different crystalline forms, triclinic and tetragonal, from methanol and dimethyl sulfoxide solvents respectively. While the triclinic form possesses dimeric hydrogen bond coupling between the adjacent amide molecules, the tetragonal form has a catemeric hydrogen bond pattern.

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Introduction

Polymorphism – crystallization of a compound into different crystalline forms from different solvents – in fact, is the phenomenon that laid the foundation for the development of solid-state organic chemistry with the identification of different photochemical reactivities in different polymorphs of trans-cinnamic acid crystals.^1–3 The pharmaceutical industry is one of the few areas to recognize the importance of the phenomenon as several drug molecules often crystallize in different polymorphs, with varying properties towards drug activity.^4–6 In this connection, the well-known and unprecedented Ranitidine patent case is a representative example.⁷ However, the phenomenon was often considered to be a nuisance in general chemistry as no definite means of either prediction or deliberate synthesis of the polymorhic forms were established, as exemplified by Dunitz and Bernstein recently in their article ‘Disappearing polymorphs’.⁸ Also, it is believed that the success of obtaining a new polymorph of a specific compound is proportional to the number of man-hours spent crystallizing the compounds (a test of patience!).⁹ As a result, synthesis of new polymorphic forms becomes practically unattainable in a target synthesis both in terms of economics as well as time-scales involved.

However, in a recent statistical analysis¹⁰ on known polymorphic structures, polymorphs of some compounds with multifunctional groups capable of interacting with each other have been found to be easily distinguishable from each other by the nature of intermolecular bonds, such as hydrogen bonds, formed by the constituent functional groups. For instance, 2,6-dihydroxybenzoic acid forms two polymorphs with different types of hydrogen bonds formed by OH and COOH groups as shown in Scheme 1. This suggests that deliberate synthesis of polymorphic structures is possible if the molecules possess a functional group capable of forming different types of intermolecular bonds. Indeed, it appears to be feasible, as noted from the analysis of the two polymorphic forms – triclinic and tetragonal – of thiodiglycolamide, obtained serendipitously in the process of co-crystallisation of the amide with 4,4′-bipyridyl, and these results are discussed in this article.

Scheme 1 Schematic representation of different kinds of hydrogen bond patterns in different polymorphs of a hydroxybenzoic acid.

Results and discussion

While the triclinic¹¹ form of 2 was obtained from a methanol solution, the tetragonal form was obtained from a dimethyl sulfoxide (DMSO) solution (for crystal data for 1 and 2 see Table 1). Packing analysis reveals the intriguing features for both of the structures with distinct differences in the packing arrangements. The two polymorphs form different kinds of N–H⋯O hydrogen bond couplings (see Scheme 2), leading to unique packing arrangements in each structure.

Scheme 2 Schematic representation of the difference in the hydrogen bonding network between the two polymorphs of thiodiglycolamide.

Table 1 Crystal data for 1 and 2^ab

	1	2
a Full-matrix, least square refinement on F^2. H atoms were obtained from Fourier difference maps. b Click b100890k.txt for full crystallographic data (CCDC 157832–157833).
Formula	C4H8N2O2S	C4H8N2O2S
Crystal dimensions/mm	0.30⊕×⊕0.20⊕×⊕0.25	0.25⊕×⊕0.20⊕×⊕0.25
Crystal geometry	Rod	Diamond
Crystal system	Triclinic	Tetragonal
Space group	P1̄	P41212
a/Å	5.142(1)	5.172(1)
b/Å	8.125(1)	5.172(1)
c/Å	8.221(1)	25.085(1)
α/°	83.75(1)	90
β/°	117.2(1)	90
γ/°	85.47(1)	90
U/Å^3	325.2(1)	670.9(2)
Z	2	4
T/K	293	293
F(000)	156	312
μ(Mo-Kα)/mm^−1	0.42	0.41
Number of reflections (independent)	1366 (736)	2904 (1944)
R 1	0.085	0.025
wR 2	0.170	0.070

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In the triclinic form, the adjacent molecules are held together by cyclic N–H⋯O hydrogen bond couplings generally known for amide compounds [Scheme 3(a)].¹² In addition, interestingly, the adjacent molecules form a cyclic dimer by connecting in a head-to-tail manner as shown in Fig. 1. The H⋯O distances observed are 2.05 and 2.17 Å. Other characteristics of these bonds are given in Table 2. These cyclic units, connected together by a centrosymmetric cyclic C–H⋯O hydrogen bond coupling, form a sheet structure in the two-dimensional arrangement. The corresponding H⋯O distance is 2.63 Å. In the three-dimensional arrangement, the sheets comprise cyclic networks stacked along [100] and connect together through typical N–H⋯O hydrogen bonds perpendicular to the cyclic hydrogen bond motif, involving the second hydrogen on the NH₂ group of the amide group. It is worthy of mention that this kind of packing arrangement, as well as being present in the formation of cyclic supermolecules, was noted earlier in a 1∶1 complex of thiodiglycolic acid and 4,4′-bipyrdiyl.¹³

Fig. 1 Formation of ring dimers via cyclic N–H⋯O hydrogen bonds in the triclinic form of thiodiglycolamide. Notice the C–H⋯O hydrogen bonds connecting the rings. Click image or 1.htm to access a 3D representation.

Scheme 3 Schematic representation of (a) dimeric hydrogen bond and (b) catemeric hydrogen bond patterns of CONH₂.

Table 2 Hydrogen bonding parameters for the triclinic^a and tetragonal^b polymorphic modifications of thiodiglycolamide

Hydrogen bond	X–H⋯O/Å	X⋯O/Å	X–H⋯O/°
a Shown as normal font. b Shown as bold font; X⊕=⊕N or C.
N–H⋯O	2.05	2.88	164
	2.17	3.02	170
	2.15	2.94	152
	2.26	2.95	137
C–H⋯O	2.63	3.35	131
	2.05	2.94	174
	2.26	2.95	130

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However, in the crystal structure of the tetragonal form, the adjacent molecules are held together by a single N–H⋯O hydrogen bond in a catemeric fashion (as shown in Fig. 2) with a H⋯O distance of 2.05 Å (Table 2), forming linear chains. These linear chains are further held together by a N–H⋯O hydrogen bond (H⋯O, 2.26 Å) formed by the second amide group. It is interesting to note that neither of the amide groups forms the generally known centrosymmetric coupling for the amide functional group.

Fig. 2 Linear chain arrangement between the adjacent molecules of thiodiglycolamide in the tetragonal form. Notice the formation single N–H⋯O hydrogen bonds, unlike the cyclic rings formed in the triclinic form. Click image or 2.htm to access a 3D representation.

The noted differences in the formation of different types of hydrogen bond couplings by the amide moiety has prompted a systematic study of these patterns. In this regard, a search performed on the Cambridge Structural Database (CSD),¹⁴ comprising of 207 507 crystal structures, (version 5.18) reveals quite interesting features. There is a total of 1070 entries containing the amide functional group (excluding organometallic compounds) for which three-dimensional coordinates are available. While 301 structures of these compounds possess a cyclic hydrogen bond pattern [Scheme 3(a)], the catemeric hydrogen bond pattern [Scheme 3(b)] is present in a nearly similar number of structures (245 structures), suggesting equal occurrence of both types of hydrogen bond pattern. A comparative study of the characteristics of both these types of hydrogen bond, shown in Fig. 3, further ascertains that these patterns are very similar with nearly equal mean H⋯O distances of 2.08 and 2.19 Å, respectively, for cyclic and catemeric hydrogen bonds. This intriguing hydrogen bond feature in the amide compounds suggests that amide functionality may be a better choice as steering group, if not the best, for the synthesis of polymorphic forms. In conclusion, it appears that the target synthesis of polymorphs could be carried out by employing the CONH₂ moiety, and that successful results could be obtained with other functional groups as well, provided that more precise knowledge of the interplay of intermolecular interactions formed by such functional groups is well understood (as exemplified recently by Allen et al.¹⁵ for various types of hydrogen bond formed by COOH).

Fig. 3 Scatter plots showing similarity between (a) cyclic hydrogen bond and (b) catemeric hydrogen bond patterns present in amide compounds.

Acknowledgements

I thank Dr Paul Ratnasamy and Dr K. N. Ganesh, respective Director and Head of the Division of Organic Chemistry, National Chemical Laboratory, Pune, India, for providing grant assistance for computational equipment used to carry out structure determinations.

References

1. (a) G. M. J. Schmidt, Pure Appl. Chem., 1971, 27, 647; (b) M. Lahav and G. M. J. Schmidt, J. Chem. Soc. B, 1967, 239.
2. G. R. Desiraju, Organic Solid State Chemistry, Elsevier, Amsterdam, 1987..
3. G. R. Desiraju, Crystal Engineering: The Design of Organic Solids, Elsevier, Amsterdam, 1989..
4. S. R. Byrn, Solid State Chemistry of Drugs, Academic Press, New York, 1982..
5. W. C. McCrone, Polymorphism in Physics and Chemistry of the Organic Solid State, Vol. 2, ed. D. Fox and M. M. Labes, Weinberger, Interscience, New York, 1965, p. 725..
6. (a) A. Nangia and G. R. Desiraju, Chem. Commun., 1999, 605; (b) R. J. Davey, N. Blagden, G. D. Potts and R. Docherty, J. Am. Chem. Soc., 1997, 119, 1767; (c) V. R. Thalladi, M. Muthuraman, A. Nangia and G. R. Desiraju, Acta Crystallogr., Sect. C, 1999, 55, 698.
7. W. H. Decamp, in Proceedings of 3rd International Workshop on Crystal Growth of Organic Materials, ed. A. S. Myerson, D. A. Green and P. Meenan, ACS series, Washington DC, 1996..
8. (a) J. D. Dunitz and J. Bernstein, Acc. Chem. Res., 1995, 28, 193; (b) T. Liad, in Comprehensive Medicinal Chemistry, ed. P. D. Kennewell, Pergamon, Oxford, 1990, vol. 5, p. 545..
9. M. R. Caira, in Design of Organic Solids, ed. E. Weber, Springer-Verlag, Berlin, 1998, p. 164..
10. A. Nangia and G. R. Desiraju, in Design of Organic Solids, ed. E. Weber, Springer, Berlin, 1998, pp. 57–95..
11. (a) Siemens, SMART System, Siemens Analytical X-Ray Instruments Inc., Madison, WI, 1995.; (b) G. M. Sheldrick, SHELXTL, Users Manual, Siemens Analytical X-Ray Instruments Inc., Madison WI, 1993..
12. Y. Weisinger-Lewin, F. Frolow, R. K. McMullan, T. F. Koetzle, M. Lahav and L. Leiserowitz, J. Am. Chem. Soc., 1989, 111, 1035.
13. V. R. Pedireddi, S. Chatterjee, A. Ranganathan and C. N. R. Rao, Tetrahedron, 1998, 54, 9457.
14. F. H. Allen and O. Kennard, Chem. Des. Autom. News, 1993, 8, 31.
15. F. H. Allen, W. D. S. Motherwell, P. R. Raithby, G. P. Shields and R. Taylor, New J. Chem., 1999, 23, 25.

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