Isostructurality in crystalline oxa-androgens: a case of Cndash;Ondash;Hmiddot;middot;middot;O and Cndash;Hmiddot;middot;middot;O interaction mimicry and solid solution formation

摘要

O O O O O O 1 OH 2 Isostructurality in crystalline oxa-androgens: a case of Cndash;Ondash;Hmiddot;middot;middot;O and Cndash;Hmiddot;middot;middot;O interaction mimicry and solid solution formation Addlagatta Anthony,a Mariusz Jaskoacute;lski,*b Ashwini Nangia*a and Gautam R. Desirajua a School of Chemistry, University of Hyderabad, Hyderabad 500 046, India. E-mail: ansc@uohyd.ernet.in b Institute of Bio-organic Chemistry, Polish Academy of Sciences and Department of Crystallography, A. Mickiewicz University, Poznan, Poland Received (in Cambridge, UK) 24th August 1998, Accepted 13th October 1998 A Cndash;Hmiddot;middot;middot;O interaction in 2-oxa-4-androstene-3,17-dione is replaced by a Cndash;Ondash;Hmiddot;middot;middot;O hydrogen bond in the isostructural 6a-hydroxy analogue, and these compounds form a binary solid solution, showing the similarity of these two crystal structures. As part of an ongoing study on androgens1 and their 2-oxa analogues,2 the crystal structures of 2-oxa-4-androstene- 3,17-dione 13 and 6a-hydroxy-2-oxa-4-androstene-3,17-dione 22 were determined.Crystals of these compounds were obtained from EtOAcndash;MeOH mixtures. Both these lactones were found to have similar crystal structures. Isostructurality in steroids has been studied previously for compounds that are related by an exchange of functional groups or by epimerisation. Thus, the pairs of compounds gamabufotalin/arenobufagin, cinobufagin/ cinobufotalin and digitoxigenin/digirezigenin form solid solutions which are isostructural with the respective individual components while the crystal structures of epimeric 5a- and 5bandrostane- 3a,17b-diol are similar, if only to a slightly lesser degree.4 The conformation of the oxa-steroid skeletons in 1 and 2 are identical.dagger; Accordingly, the crystal structures of 1 and 2 were scrutinised further.Dagger; Both 1 and 2 adopt the same monoclinic space group, P21 and the value of the a-axis parameter is nearly equal (6.2321 and 6.2214 Aring;). This is the direction of the hydrogen bond interactions and an inspection of Fig. 1ndash;3 is instructive. In hydroxy lactone 2, O6ndash;H and C6ndash;H are hydrogen bonded to the lactone carbonyl atom O3 of different screw-axis related molecules, thereby forming chains of alternating Ondash;Hmiddot;middot;middot;O (1.86 Aring;) and Cndash;Hmiddot;middot;middot;O (2.38 Aring;) hydrogen bonds5 (Fig. 1 and 3). Effectively, O6 behaves as an Ondash;Hmiddot;middot;middot;O donor and O3 as a bifurcated acceptor. In lactone 1, the C6 methylene hydrogens are linked to the O3 atom of 21-related molecules to give chains of Cndash;Hmiddot;middot;middot;O hydrogen bonds (2.38 and 2.67 Aring;) (Fig. 2 and 3). The metrics of these hydrogen bonded chains along 100 in the two structures are given in Fig. 3, from which it is clearly seen that the shorter of the Cndash;Hmiddot;middot;middot;O hydrogen bonds in 1 behaves as a surrogate of the Cndash;Ondash;Hmiddot;middot;middot;O bond in 2. We note that the near equality of the a-axis parameter in the two structures allows for the replacement of four links between translationally related O3 atoms in 1 (two weak Omiddot;middot;middot;H interactions and two Cndash;H bonds) by five links in 2 (strong Omiddot;middot;middot;H interaction, weak Omiddot;middot;middot;H interaction, Cndash;H bond, Cndash;O bond and Ondash;H bond).When a 1:1 mixture of 1 and 2 was crystallised from EtOAcndash; MeOH, crystals 3Dagger; were obtained in the space group P21 with cell dimensions very similar to those of pure 2. Structure solution and refinement with partial positional occupancy for O6 yielded a converged model with partial occupancies of 0.28 and 0.720(6) for 1 and 2 respectively, showing that 3 is a binary solid solution.sect; While there are examples of equivalence between Nndash;Hmiddot;middot;middot;O and Cndash;Hmiddot;middot;middot;O hydrogen bonds in isostructural crystals,6 the formation of solid solution has not been reported in these cases.Additionally, interaction mimicry between Cndash;Ondash;Hmiddot;middot;middot;O and Cndash;Hmiddot;middot;middot;O is a novel occurrence. The present example is therefore unprecedented and offers valuable clues regarding crystal packing in general. Fig. 1 Hydrogen bonding in hydroxy lactone 2 along 100 to show the O6ndash;Hmiddot;middot;middot;O3 and C6ndash;Hmiddot;middot;middot;O3 interactions between 21-related molecules. Oxygen atoms are shaded.Fig. 2 Hydrogen bonding in lactone 1 along 100 between C6-methylene H-atoms and the carbonyl O3 atom of different 21-related molecules. Oxygen atoms are shaded. Notice the identity of a-axis and the similarity in hydrogen bonded chains and arrangement of molecules in the structure shown here and in Fig. 1. Chem. Commun., 1998, 2537ndash;2538 2537O H H O O H H H H O O O d H q H O H H O H H O D 3 3 6 a b 4 5 7 7 5 5 6 2 4 4 2 Firstly, this example shows the equivalence of Ondash;Hmiddot;middot;middot;O and Cndash;Hmiddot;middot;middot;O hydrogen bonding and confirms yet again that the structure directing effects of these two interactions can often be the same.It is noteworthy that the C6 H-atoms in D4-steroids are allylic in nature and, as such, activated as Cndash;H donors.7 Secondly, the formation of a solid solution in such cases is per se noteworthy. Binary solid solution formation is the most stringent criterion for isostructurality8 and occurs here because 1 and 2 have similar overall molecular shapes and also because the hydrogen bonds and recognition patterns in the structureforming domain, that is along 100, are virtually identical.These patterns are the supramolecular synthons9 4 and 5 and they play a significant structural role in all three crystals. Thirdly, the fact that the 3 adopts the structure of 2 rather than that of 1 could be ascribed to the larger size of the OH group compared to the H substituent,10 while the excess of 2 over 1 in the solid solution might be because of the relative strengths of Ondash;Hmiddot;middot;middot;O and Cndash;Hmiddot;middot;middot;O hydrogen bonds in the individual structures.11 Finally, we note that solid solution formation occurs for this pair of compounds 1 and 2 even though the b, c and b parameters are significantly different.While the unit cell similarity index P8,12 is fortituously close to zero (P = 0.002), this index could be misleading here. Since the monoclinic axial lengths are quite different (9.926 and 12.050 Aring;), the other packing features in the crystals, in this case the general coordination arrangements of molecules, are different leading to a degree of isostructurality index,8,12 I21 D of only 75.Despite this, solid solution formation has been observed leading to the thought that isostructurality along one direction is sufficient to observe mimicry effects,13 if that direction is important as a structure determinant. The implications of such lsquo;one-dimensional isostructuralityrsquo; have a bearing on the analysis of similarities in crystal packing that are mediated by robust supramolecular synthons.14 Such synthons could play an active role during all stages of crystallisation events from nucleation to growth to the final appearance of a single crystal.We acknowledge Professor U. Wrzeciono and Dr A. Gzella (K. Marcinkowski University of Medical Sciences, Poznan) for X-ray facilities. A. A. thanks CSIR for a fellowship.This research was supported by D. S. T. (SP/S1/G25/91) and in part under the Indo-Polish D.S.T.-K.B.N. exchange scheme (INT/ POL/POC/96-98/P22). M. J. thanks H. H. M. I. for support. Notes and references dagger; This was determined from an overlay diagram which shows an overall rms deviation of 0.075 Aring;. Dagger; Crystal data for 1: C18H24O3, M = 288.37, mp 185ndash;186 deg;C, monoclinic, space group P21, a = 6.2321(3), b = 9.9264(6), c = 12.8120(8) Aring;, b = 97.079(5)deg;, V = 786.54(8) Aring;3, Z = 2, Dc = 1.218 g cm23, KM-4 diffractometer, T = 293 K, Cu-Ka, wndash;2q scan mode, 1597 unique reflections, 1434 with I 2s(I), no absorption corrections.Structure solution and refinement with standard methods (SHELXS86 and SHELX97); H-atoms fixed, final R = 0.0342 (observed), 0.0412 (all), wR = 0.0865 (observed), 0.0919 (all). For 2: C18H24O4, M = 304.37, mp 244ndash;246 deg;C, monoclinic, space group P21, a = 6.2214(7), b = 12.050(1), c = 10.888(1) Aring;, b = 103.07(1)deg;, V = 795.10(14) Aring;3, Z = 2, Dc = 1.271 g cm23, KM-4 diffractometer, T = 293 K, Cu-Ka, wndash;2q scan mode, 1514 unique reflections, 1458 with I 2s(I), no absorption corrections. Structure solution and refinement with standard methods (SHELXS86 and SHELX97); H-atoms fixed, final R = 0.0359 (observed), 0.0378 (all), wR = 0.1013 (observed), 0.1033 (all).For 3: solid solution of 1 and 2, (C18H24O3)0.28 + (C18H24O4)0.72, M = 299.89, mp 244ndash;245 deg;C, monoclinic, space group P21; a = 6.2246(7), b = 12.014(1), c = 10.915(1) Aring;, b = 103.09(1)deg;, V = 795.04(14) Aring;3, Dc = 1.252 g cm23, KM-4 diffractometer, T = 293 K, Cu-Ka, wndash;2q scan mode, 1542 unique reflections, 1497 with I 2s(I), no absorption corrections.Structure solution and refinement with standard methods (SHELXS86 and SHELX97); H-atoms fixed, final R = 0.0321 (observed), 0.0334 (all), wR = 0.0862 (observed), 0.0880 (all). CCDC 182/1056. sect; The presence of 1 and 2 in single crystals of 3 was further confirmed by IR analysis and their ratio was found to be in the range 3:7 to 4:6 by 1H NMR integration. 1 A. Anthony, M. Jaskoacute;lski, A. Nangia and G.R. Desiraju, Acta Crystallogr., 1998, C54, in the press. 2 A. Nangia and A. Anthony, Ind. J. Chem., 1997, 36B, 1113. 3 A. A. Frimer, J. Hameiri-Buch, S. Ripshtos and P. Gilinsky-Sharon, Tetrahedron, 1986, 42, 5693. 4 G. Argay, A. Kaacute;lmaacute;n, B. Ribaacute;r, S. Vladimirov and D. Zivanov-Stakic, Acta Crystallogr., 1987, C43, 922; A. Kaacute;lmaacute;n, G. Argay, D. Zivanov- Stakic, S.Vladimirov and B. Ribaacute;r, Acta Crystallogr., 1992, C48, 812; A. Kaacute;lmaacute;n, L. Paacute;rkaacute;nyi and G. Argay, Acta Crystallogr., 1993, B49, 1039. 5 G. R. Desiraju, Acc. Chem. Res., 1996, 29, 441; T. Steiner, Chem. Commun., 1997, 727. 6 Z. Berkovitch-Yellin and L. Leiserowitz, Acta Crystallogr., 1984, B40, 159; T. Steiner, G. Koellner, K. Gessler and W. Saenger, J. Chem. Soc., Chem. Commun., 1995, 511; L. J. W. Shimon, M. Vaida, L. Addadi, M. Lahav and L. Leiserowitz, J. Am. Chem. Soc., 1990, 112, 6215. 7 V. R. Pedireddi and G. R. Desiraju, J. Chem. Soc., Chem. Commun., 1992, 988. 8 A. Kaacute;lmaacute;n, Adv. Mol. Struct. Res., 1997, 3, 189. 9 G. R. Desiraju, Angew. Chem., Int. Ed. Engl., 1995, 34, 2311. 10 A. I. Kitaigorodskii, Molecular Crystals and Molecules, Academic Press, New York, 1973, pp 108ndash;110. 11 G. A. Jeffrey, An Introduction to Hydrogen Bonding, OUP, New York, 1997, p. 12. 12 J. S. Rutherford, Models Chem., 1997, 134, 395. 13 W. Jones, C. R. Theocharis, J. M. Thomas and G. R. Desiraju, J. Chem. Soc., Chem. Commun., 1983, 1443. 14 A. Nangia and G. R. Desiraju, Top. Curr. Chem., 1998, 198, 57. Communication 8/06607H Fig. 3 Supramolecular synthons 4 and 5 in the structures of 1 and 2 along 100. The geometrical parameters (d, D, q) of the hydrogen bonds with normalised Ondash;H and Cndash;H distances are for 4: C6ndash;aHmiddot;middot;middot;O3: 2.38, 3.381(4) Aring;, 154deg; and C6ndash;bHmiddot;middot;middot;O3: 2.67, 3.693(4) Aring;, 157deg;; 5: O6ndash;aHmiddot;middot;middot;O3: 1.8602(5), 2.831(4) Aring;, 171deg; and C6ndash;bHmiddot;middot;middot;O3: 2.38 Aring;, 3.409(4) Aring;, 158deg;. a and b refer to the bottom and top faces of the somewhat flattened steroid skeleton. 2538 Chem Commun., 1998, 2537ndash;2538