Concomitant Polymorphism in 3-Acetylcoumarin: Role of Weak C-H‚‚‚O and C-H‚‚‚π Interactions Parthapratim Munshi,† K. N. Venugopala,‡ B. S. Jayashree,‡ and Tayur N. Guru Row*,† Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India, and Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy, Bangalore 560 027, India Received February 2, 2004;
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 6 1105-1107
Revised Manuscript Received March 29, 2004
ABSTRACT: An analysis of structural features associated with polymorphism in 3-acetylcoumarin has been made in terms of morphology, infrared spectroscopy, crystal structure, powder X-ray diffraction, and differential scanning calorimetric measurements. The appearance of concomitant polymorphs is found to depend on the crystallization temperature in the 1:1 chloroform/hexane solvent system. C-H‚‚‚O and C-H‚‚‚π interactions stabilize one form in a head to head configuration, while only C-H‚‚‚O interactions stabilize the other in a head to tail configuration of the molecules in the crystal lattice. Coumarins feature in several areas of synthetic chemistry, medicinal chemistry, and photochemistry. Several substituted coumarin derivatives find application in the dye industry1,2 and have been used to develop LASER dyes.3 Coumarins exhibit antiviral activity4 and antimicrobial activity,5 and constitute the well-known antibiotic Novobiocin.6 In our continued effort to map charge densities from different substituted coumarins using accurate highresolution X-ray diffraction data,7,8 we have synthesized 3-acetylcoumarin9 (Scheme 1) (IUPAC name: 3-acetyl-2H1-benzopyran-2-one) and have discovered concomitant polymorphism10 during crystallization experiments. Polymorphism is the ability of a chemical substance to exist in at least two different crystal forms, which usually display different physical and chemical properties.11 Several coumarin dyes, such as coumarin 138,12 comarin 152,13 coumarin 153,14 and coumarin 31415 exhibit polymorphism. Concomitant polymorphs have also been identified in 4-styrylcoumarin16 and its 3-fluoro derivative.17 It is interesting to note that kinetic factors govern crystal nucleation and growth and serve as a key factor in generating polymorphic modifications.18-20 It is desirable to have a clear understanding of polymorphism particularly in the context of syntheses of drugs and pharmaceuticals.21,22 Appearance of concomitant polymorphs is a well-recognized phenomena,10 which depends on the subtle interplay between kinetic and thermodynamic factors.23 Scheme 1. Molecular Diagram of 3-Acetylcoumarin
Freshly synthesized 3-acetylcoumarin was recrystallized from glacial acetic acid at room temperature, resulting in large chunky pale yellow prismatic crystals (Figure 1a) after 2 days. Since the crystals were too large for data collection, recrystallization from a mixture of (1:1) chloroform-n-hexane was attempted, resulting in the appearance of crystals of two different morphologies (colorless needles and pale yellow prismatic) at a temperature of ∼5 °C (refrigerated) (Figure 1b). Several crystallization experiments at ∼5 °C with varying ratios of the solvent systems * To whom correspondence should be addressed. E-mail: ssctng@ sscu.iisc.ernet.in. † Indian Institute of Science. ‡ Al-Ameen College of Pharmacy.
(1:2, 1:3, 1:4, 1:5, etc.) also resulted in concomitant polymorphs. However, when the sample was crystallized at ambient temperature (∼23 °C), only needles appeared for all solvent ratios (Figure 1c). This clearly indicates that the needle form is indeed a metastable phase of 3-acetylcoumarin. Powder X-ray diffraction (PXRD) indicated that the prismatic form (form A) is distinct from the needle form (form B) with the highest intensities at 2θ ) 26.76° and 9.34°, respectively.24 It is of interest to note that the PXRD pattern is entirely different after 120 days of storage of form B. However, the single crystal retains the same structure of form B as seen from its diffraction pattern. It appears from these observations that on grinding the crystals after a long period of storage a new polymorphic form25 might be generated. Subsequent characterization using other physical and spectroscopic techniques was done on crystals rather than on powders because of this feature. The melting point of the two different forms is within 1-2 degrees, and differential scanning calorimetry (DSC) supports this observation. However, the two forms are easily distinguishable: form A melts at 397 K (124 °C), while form B shows a small exothermic peak at 390 K (117 °C) with a slightly suppressed melting point at 395 K (122 °C).24 Results from infrared spectroscopy (IR), which provide yet another graphic mapping of the atomic forces binding the crystal along with powder pattern, clearly indicate that the two forms are different. The acyl-carbonyl stretching frequency is lowered to 1679 cm-1 in form B as compared to the 1685 cm-1 in form A, pointing out subtle differences in intermolecular interactions between the two forms.24 Single-crystal X-ray diffraction experiments were conducted on both crystalline forms at 90 K.24,26 Figure 2a,b shows the packing in the crystalline lattice is mainly through C-H‚‚‚O interactions. However, there is an additional C-H‚‚‚π interaction between two independent molecules in the asymmetric unit in form A (Table 1). These two molecules appear in the crystal structure with significant conformational differences at the acetyl group [C1-C2-C10-C11 ) -6.7(2)° and -10.4(2)°, respectively]. There are three pairs of C-H‚‚‚O interactions (Figure 2a, Table 1), one connecting similar molecules and other two connecting dissimilar molecules, resulting in an essentially head to head configuration generating a sheet like structure. Further, a C-H‚‚‚π interaction (Figure 2a, Table 1) provides the link between neighboring sheets resulting in a 3D network. An additional stabilizing π-π interaction is present (Figure 2c) with a separation distance of 3.339
10.1021/cg049948l CCC: $27.50 © 2004 American Chemical Society Published on Web 05/29/2004
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Figure 1. (a) Morphology of form A. (b) Morphology of form A and form B at ∼5 °C depicting concomitant polymorphism. (c) Morphology of form B at ∼23 °C.
Å between the two independent molecules together with a π-π interaction between the identical molecules at a separation distance of ∼3.390 Å generating infinite stacks along the crystallographic direction [101]. Form B is stabilized via C-H‚‚‚O interactions, but the major difference is the head to tail configuration in the crystal lattice. This arrangement results in the generation of molecular chains in the ac plane (Figure 2b), with the atom O(3) forming a bifurcated C-H‚‚‚O interaction (Table 1). These 2D chains interestingly are not linked either to each other in the ac plane or to the neighboring chains via C-H‚‚‚π like in form A. However, a π-π interaction with a separation distance of 3.341 Å (Figure 2b) provides additional stability to the dimers and holds the chains in the crystallographic direction [110]. To conclude, the appearance of concomitant polymorphism and the subsequent experimental verification of the formation of form A and form B in terms of subtle
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Figure 2. (a) Packing of the molecules in form A showing C-H‚‚‚O and C-H‚‚‚π interactions generating a “sheet” structure in the bc plane with acetyl groups pointing to the left of the figure in a “head to head” alignment. Cg1 is the centroid of the ring C(4)C(9). For clarity, hydrogen atoms not participating in the interactions have been omitted and only representative molecules are included to show exclusively C-H‚‚‚π interactions. (b) Packing of the molecules in form B showing the nature of π-π interactions and C-H‚‚‚O interactions generating a “chain” structure in the ac plane. Hydrogen atoms not participating in the interactions have been omitted for clarity. (c) Packing of the molecules in form A showing the nature of π-π interactions along [101].
differences in intermolecular interactions involving weak C-H‚‚‚O and C-H‚‚‚π interactions are significant. Form A appears with head to head stacking being favored during nucleation, while form B prefers a head to tail stacking. It is interesting to note that such large rearrangement in packing features is brought by a reorganization in weak C-H‚‚‚O interactions assisted by a C-H‚‚‚π interaction in form A. It is interesting to note that the presence of C-H‚‚‚π amounts to a partial charge transfer,27 which explains the pale yellow color of form A. The ability of weak
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Table 1: Geometry of the C-H‚‚‚X Interactions in Form A and Form B cryst form
C-H‚‚‚Xa
form A C(5)-H(5)‚‚‚O(2)a C(5A)-H(5A)‚‚‚O(2A)b C(6)-H(6)‚‚‚O(1A)c C(6A)-H(6A)‚‚‚O(1)d C(4)-H(4)‚‚‚O(3A)e C(4A)-H(4A)‚‚‚O(3)f C(11A)-H(9A)‚‚‚Cg(1)g form B C(3)-H(3)‚‚‚O(3)i C(4)-H(4)‚‚‚O(3)i C(7)-H(7)‚‚‚O(1)ii
r(H‚‚‚Xa) Å
r(C‚‚‚Xa) ∠(C-H‚‚‚Xa) Å (°)
2.517(15) 2.544(15) 2.518(14) 2.498(14) 2.632(15) 2.609(15) 2.868(1) 2.499(18) 2.593(19) 2.484(19)
3.467(3) 3.469(3) 3.382(2) 3.390(2) 3.587(2) 3.551(2) 3.590(1) 3.360(3) 3.454(3) 3.453(3)
163.0(12) 161.5(12) 151.9(12) 154.8(12) 168.2(12) 160.2(12) 130.6 152.7(14) 146.1(13) 169.9(15)
a X ) O or the centroid [Cg(1)] of the corresponding aromatic ring. Symmetry codes: ax, y + 1, z; bx, y - 1, z; c-x + 1, -y + 1, -z + 1; d-x + 1, -y, -z + 1; e-x, -y + 1, -z + 2; f-x, -y, -z + 2; gx, y, z + 1. i-x + 1, -y - 1, -z + 2; ii-x + 2, -y + 1, -z + 2.
interactions to control packing of molecular moieties to generate different patterns as seen above suggests their importance in crystal engineering. It is obviously clear that such weak interactions are prolific in molecular assemblies providing both directionality and flexibility in the crystal lattice. Further studies on the mapping of the charge density distributions followed by a topological analysis of the regions in C-H‚‚‚O and C-H‚‚‚π interactions are currently in progress. Acknowledgment. P.M. thanks the CSIR, India, for a senior research fellowship. We thank DST-IRHPA, India, for the CCD facility at IISc., Bangalore. Supporting Information Available: Experimental PXRD pattern (Figure S1a,b), DSC plot (Figure S2), IR spectra (Figure S3), ORTEP at 90 K (Figure S4a,b) ,and torsion angles (Table S1) of both forms of 3-actylcoumarin. X-ray crystallographic information files (CIF) are available for both forms. This material is available free of charge via the Internet at http://pubs.acs.org.
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(8) Munshi, P.; Guru Row, T. N. Acta Crystallogr. 2003, B59, 159. (9) Knoevenagel, F. Ber 1898, 31, 732. (10) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem. 1999, 111, 3646-3669; Angew. Chem., Int. Ed. 1999, 38, 34403461. Concomitant polymorphs crystallize simultaneously from the same solvent and in the same crystallizing flask under identical crystal growth conditions. (11) McCrone, W. C. In Physics and Chemistry of the Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Eds.; Wiley-Interscience: New York, 1965; Vol. 2, pp 725-767. (12) Jasinski, J. P.; Woudenberg, R. C. Acta Crystallogr. 1995, C51, 107-109. (13) Jasinski, J. P.; Paight, E. S. Acta Crystallogr. 1994, C50, 1928-1930. (14) Yip, B. B.; Moo, F. M.; Lok, K. S.; Fun, H. K.; Sivakumar, K. A. Acta Crystallogr. 1996, C52, 477-481. (15) Honda, T.; Fujii, I.; Hirayama, N.; Aoyama, N.; Miike, A. Acta Crystallogr. 1996, C52, 395-397. (16) Narasimha Moorthy, J.; Venkatesan, K. Bull. Chem. Soc. Jpn. 1994, 67, 1-6. (17) Vishnumurthy, K.; Guru Row, T. N.; Venkatesan, K. Photochem. Photobiol. Sci. 2002, 1, 799-802. (18) Threlfall, T. L. Analyst 1995, 120, 2435-2460. (19) Desiraju, G. R. Science 1997, 278, 404-405. (20) Caira, M. R. Top. Curr. Chem. 1998, 198, 164-208. (21) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193200. (22) Henck, J. O.; Bernstein, J.; Ellern, A.; Boese, R. J. Am. Chem. Soc. 2001, 123, 1834-1841. (23) Thallapally, P. K.; Jetti, R. K. R.; Katz, A. K.; Carrell, H. L.; Singh, K.; Lahiri, K.; Kotha, S.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2004, 43, in press, private communication. (24) See Supporting Information for PXRD, DSC, IR, and ORTEP. (25) Characterization of the new polymorph, which has different IR and PXRD patterns (approximate cell dimensions: a ) 8.004, b ) 9.204, c ) 16.682 Å and R ) 83.08°, β ) 76.65°, γ ) 85.99°) is currently under investigation. (26) Crystal data: Form A: chemical formula C11H8O3, formula weight 188.17, triclinic, space group P1 h , a ) 7.496(4), b ) 9.653(6), c ) 12.002(7) Å, R ) 85.740(9)°, β ) 86.097(9)°, γ ) 81.728(9)°, V ) 855.5(9) Å3, Z ) 4, Fcalc ) 1.461 g cm-3, T ) 90.0(2) K, µ ) 0.107, reflections measured 8718, independent reflections 3382, observed reflections [I > 2σ(I)] 3176, R1 ) 0.0370, wR2 ) 0.1043 for all data. Form B: chemical formula C11H8O3, formula weight 188.17, monoclinic, space group P21/n, a ) 11.325(7), b ) 3.987(2), c ) 18.773(11) Å, β ) 86.097(9)°, V ) 847.5(8) Å3, Z ) 4, Fcalc ) 1.475 g cm-3, T ) 90.0(2) K, µ ) 0.108, reflections measured 5933, independent reflections 1664, observed reflections [I > 2σ(I)] 1329, R1 ) 0.0579, wR2 ) 0.1248 for all data. (27) Umezawa, Y.; Tsuboyama, S.; Takahashi, H.; Uzawa, J.; Nishio, M. Tetrahedron 1999, 55, 10047-10056.
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