Polymorphism in 1-(4-Fluorophenyl)-3,6,6-trimethyl-2phenyl-1,5,6,7-tetrahydro-4H-indol-4-one: A Subtle Interplay of Weak Intermolecular Interactions Deepak Chopra,† K. Nagarajan,‡ and Tayur N. Guru Row*,†
CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 3 1035-1039
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560012, Karnataka, India, HIKAL India Limited, Bannerghatta Road, Bangalore-560078, Karnataka, India Received October 11, 2004;
Revised Manuscript Received December 1, 2004
ABSTRACT: An understanding of structural features associated with polymorphism in an anti-implantation agent has been made in terms of morphology, single-crystal structure, powder X-ray diffraction, and differential scanning calorimetric measurements. Polymorph 1 (P1) crystallizes from a solution in dichloromethane/hexane in monoclinic, noncentro symmetric P21 (as plates), whereas the second polymorph (P2) crystallizes from a solution in EtOH/ acetone in tetragonal, centro symmetric P42/n (as blocks). P1 is stabilized by C-H‚‚‚O and C-H‚‚‚π intermolecular interactions forming molecular chains, while P2 is stabilized by C-H‚‚‚O and C-H‚‚‚π dimers and a not so common F‚‚‚F intermolecular interaction. Introduction Polymorphism, as defined by McCrone1 is “a solid crystalline phase of a given compound resulting from the possibility of at least two crystalline arrangements of that compound in the solid state”. The phenomenon of polymorphism has been discussed in detail in the literature,2 and an analysis of all the entries in the Cambridge Structural Database3 reveals that a large number of molecules are found to exhibit polymorphism. The occurrence of polymorphic modifications in molecular compounds is manifested not just as a consequence of minimum free energy of the crystalline phases but also by kinetics of crystal nucleation and growth.4 Conformational polymorphs5 are generated if the molecular conformation is different from one polymorph to the other; packing polymorphs6 are those in which the molecules of similar conformation pack in different crystal lattices and solvatomorphs (pseudopolymorph)2,7 which crystallize including solvents in the crystal lattice. Concomitant polymorphs8,9 are formed in cases in which there is an overlap of such domains forcing the polymorphs to crystallize simultaneously from the same solvent and in the same crystallization flask under identical crystal growth conditions. Formation of a particular polymorph with desired properties is of immense interest in drug industry since the drug activity of a material might change abruptly from one polymorph to another.2 The appearance and disappearance of polymorphs such as, for example, the 1:1 complex of benzocaine and picric acid10 bring out the subtle differences in metastable polymorphic forms. It is possible to define the experimental conditions for a substance to crystallize in terms of solvent, temperature, rate of evaporation, and cooling which defines an occurrence domain.11 Davey et al.12 have analyzed the role of the solvent-induced self-assembly of a given * To whom correspondence
[email protected]. † Indian Institute of Science. ‡ HIKAL India Limited.
should
be
addressed.
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molecule from organic solvents and the generation of prenucleation aggregates. Studies related to polymorphism in 2,4,6-tri-nitrotoluene13 grown from two different solvents brings out the features of metastability, kinetics, and nucleation in the formation of different conformations of the same molecule. Organic crystals depicting nonlinear optical (NLO) properties have been extensively studied involving the design and synthesis of stable chromophore molecules to crystallize in noncentrosymmetric crystal forms.14-16 Careful crystallization studies using different solvents have led to both morphological and structural changes suggesting the possibility of obtaining good NLO coefficients in the structures such as 2-methyl-4-nitroaniline (MNA).17 Substituted indol-4-ones are anti-fertility agents and have been used for the inhibition of implantation activity in rats.18 In this article, we discuss the polymorphism in 1-(4-fluorophenyl)-3,6,6-trimethyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4-one based on solvent variation and the subsequent subtle changes in intermolecular interactions. Experimental Section The compound 1-(4-fluorophenyl)-3,6,6-trimethyl-2-phenyl1,5,6,7-tetrahydro-4H-indol-4-one was synthesized according to the procedure given in the literature.18 Efforts were made to crystallize the compound in different solvent systems, like DCM/hexane, EtOAc/hexane, acetone, and acetone/EtOH to evaluate the influence of change in polarities of the solvents. Single crystals of the polymorph 1 (P1) were consistently grown from a solution of dichloromethane and hexane (1:2) by a slow evaporation process at ∼10 °C in a refrigerator and those of the second polymorph (P2) were similarly obtained from a solution of acetone/EtOH (1:1). Images of the crystals representing the morphologies of P1 and P2 were recorded on an Olympus SZX12 optical microscope equipped with an optical polarizer and an Olympus DP11 digital camera (Figure 1). The crystals of P1 are obtained as plates, while those of P2 are obtained as well-defined blocks. The single-crystal diffraction data were collected on a Bruker AXS Smart Apex CCD diffractometer at 293(2) K. The X-ray generator was operated at 50 kV and 35 mA using MoKR radiation. Data were collected with ω scan width of 0.3°. A total of 606 frames were
10.1021/cg049656k CCC: $30.25 © 2005 American Chemical Society Published on Web 01/22/2005
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Figure 1. Images highlighting the different morphologies of the two forms. (a) Plates and (b) blocks. Table 1. Crystal Data of the Polymorphs P1 and P2 crystal size (mm) morphology formula formula weight temperature/K wavelength (Å) crystal system space group a (Å) b (Å) c (Å) R (°) β (°) γ (°) volume (Å3) Z density (g/mL) µ (1/mm) F (000) θ (min, max) h, k, l (min, max) no. refln measured no. unique reflns no. of parameters Flack parameter R_all R_obs wR2_all wR2_obs ∆Fmax (e Å-3) ∆Fmin (e Å-3) GoF
0.18 × 0.05 × 0.16 plates C23H22F1N1O1 347.4 293(2) 0.7107 monoclinic P21 7.752(4) 11.222(6) 11.082(6) 90.00 107.236(8) 90.00 920.81(25) 2 1.25 0.083 367.9 1.9,24.7 (-9,9), (-13,13), (-13,13) 6362 2901 323 0.4 (9) 0.039 0.033 0.077 0.074 +0.11 -0.14 1.022
0.28 × 0.25 × 0.20 blocks C23H22F1N1O1 347.4 293(2) 0.7107 tetragonal P42/n 18.343(6) 18.343(6) 11.472(7) 90.00 90.00 90.00 3859.94(28) 8 1.20 0.079 1471.8 1.6,25.3 (-22,19), (-22,22), (-13,13) 27957 3523 323 0.055 0.046 0.126 0.119 +0.27 -0.23 1.208
collected in three different settings of φ (0°, 90°, 180°) keeping the sample-to-detector distance fixed at 6.03 cm and the detector position (2θ) fixed at -25°. The data were reduced using SAINTPLUS,19 and an empirical absorption correction was applied using the package SADABS.20 XPREP20 was used to determine the space group. The crystal structure was solved by direct methods using SIR9221 and refined by full matrix least-squares method using SHELXL9722 present in the program suite WinGx (Version 1.63.04a). 23 Molecular diagrams were generated using ORTEP-32,24 and the packing diagrams were generated using CAMERON.25 Geometrical calculations were done using PARST9526 and PLATON.27 All the hydrogen atoms were located from a difference Fourier map, and their positional coordinates and isotropic thermal parameters were refined. Details of data collection and refinement are given in Table 1. The experimental powder X-ray diffraction patterns on the crushed crystals of both the polymorphs as well as the powdered sample were recorded on a Siemens powder X-ray diffractometer (D5005) operating at 30 kV/25 mA using CuKR
Table 2. Relevant Torsion Angles torsion angle/°
polymorph 1
polymorph 2
C9-N1-C1-C15 O1-C3-C4-C5 C8-C3-C4-C5 C3-C4-C5-C6 C4-C5-C6-C7 C9-N1-C7-C8 C5-C6-C7-C8 C6-C7-C8-C3 C4-C3-C8-C7 C7-N1-C9-C14 C7-N1-C9-C10 N1-C1-C15-C16 N1-C1-C15-C20
3.8(3) -148.9(2) 33.2(3) -55.1(2) 46.4(2) 179.8(2) -20.8(3) -2.2(3) -3.5(3) 58.1(3) -124.6(2) -131.2(2) 52.0(3)
-175.3(1) -152.4(2) 30.7(2) -53.6(2) 47.2(2) 175.8(1) -22.6(2) -1.6(2) -1.8(2) 62.3(2) -118.1(2) -135.8(2) 47.3(2)
radiation in reflection mode.28 These diffraction patterns provide an unambiguous proof for the existence of two polymorphs P1 and P2. Further, there is no indication of concomitant polymorphism. The simulated powder pattern obtained from single-crystal data further confirms the formation of the two polymorphs.28 These polymorphs were also characterized by DSC studies on a Mettler Toledo STARe system with heating/cooling rates of 5 °C/min.28 The NLO activity of the polymorph crystals and also of the powdered samples were measured based on the Kurtz and Perry29 technique using a Quanta DCR3 LASER (1064 nm) and a photodiode used as detector. 1064 nm was cut off by a CuSO4 solution and BG38 filter. Urea in both the powdered and single crystal form were used as standards for evaluating NLO activity.
Results Single-crystal data were collected on both the polymorphs at 293(2) K, and all the hydrogen atoms were located from a difference Fourier map. Table 2 lists all the torsion angles in P1 and P2. Table 3 lists all the significant intermolecular interactions in P1 and P2. Figure 2a,b illustrates the ORTEP of the polymorphs P1 and P2, while Figure 3a,b highlights the corresponding packing diagrams illustrating the intermolecular interactions. Polymorph 1 (P1). The crystal structure was solved and refined in the monoclinic noncentric space group P21 with Z ) 2. The saturated cyclohexane ring of the indole moiety has an envelope conformation with atom C5 deviated from the plane by +0.628(2)Å formed by C3, C4, C6, C7, and C8. The two phenyl rings are twisted out of the plane [C7-N1-C9-C10 ) -124.6(2)°
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Table 3. Intermolecular Interactionsa Polymorph 1 D-H‚‚‚A
D-H/Å
D‚‚‚A/Å
H‚‚‚A/Å
∠D-H‚‚‚A/°
C19-H19‚‚‚O1a C17-H17‚‚‚Cg1b
0.92(3) 0.92(3)
3.389(4) 3.445(4)
2.60(3) 2.81(3)
144(2) 127(2)
D-B‚‚‚A
D-B/Å
D‚‚‚A/Å
B‚‚‚A/Å
∠D-B‚‚‚A/°
C10-H10‚‚‚O1c
0.94(2) 0.97(2) 1.00(2) 1.360(3)
3.470(2) 3.413(3) 3.800(3) 3.918(3)
2.64(2) 2.46(2) 2.81(2) 2.868(3)
148(2) 167(2) 165(2) 133(2)
Polymorph 2
C14-H14‚‚‚O1d C4-H4B‚‚‚Cg1e C12-F1‚‚‚F1f
a Symmetry codes: Polymorph 1: (a) x, +y, +z - 1, (b) -x + 1, -1/2 + y, 1 - z. Polymorph 2: (c) -y + 1, x - 1/2, z - 1/2, (d) -x + 1, -y, -z + 2, (e) -x, 1 - y, -z, (f) -x + 3/2, -y - 1/2, z.
Figure 3. (a) Packing diagram of P1 showing C-H‚‚‚O molecular chains along the crystallographic ‘c’ axis; hydrogen atoms not participating in the interaction are excluded for clarity. (b) Packing diagram of P2 showing F‚‚‚F intermolecular contact and C-H‚‚‚O intermolecular interactions.
Figure 2. (a) ORTEP of P1 (Plates) drawn with 50% ellipsoidal probability. (b): ORTEP of P2 (Blocks) drawn with 50% ellipsoidal probability.
and N1-C1-C15-C16 ) -131.2(2)°] containing the indole moiety. The angle between the indole ring [N1C1-C2-C8-C7] and the phenyl rings C9-C10-C11C12-C13-C14 and C15-C16-C17-C18-C19-C20 are 56.47(7)° and 52.26(7)°, respectively. The dihedral angles between the two planes passing through the 1-phenyl and 2-phenyl rings are 56.41(6)°. The molecules assemble in the crystal lattice via intermolecular C-H‚‚‚O chains along the crystallographic c-axis (Figure 3a). In addition, intermolecular C-H‚‚‚π interactions form molecular chains, which are
related by a 21 screw axis of symmetry providing additional stability to the packing of molecules (Figure 4a). The SHG signal strength for the crystals of this polymorph is 0.88 times that of urea when the crystal is mounted along the a-axis exposing the (011) plane for the incident radiation. The corresponding SHG value for the polycrystalline powder sample is 0.75 times that of urea. Polymorph 2 (P2). The crystal structure was solved and refined in the tetragonal space group P42/n with Z ) 8. The atom C5 is deviated by -0.629(3) Å from the plane formed by the atoms C3, C4, C6, C7, and C8 resulting in an envelope conformation. The relative torsion angles of the phenyl rings from that of the indole moiety are C7-N1-C9-C10 ) -118.1(2)° and N1-C1C15-C16 ) -135.8(2)° respectively. The corresponding dihedral angle between the planes passing through the 1-phenyl and 2-phenyl rings is 61.34(6)°. The molecules pack in the unit cell via two C-H‚‚‚O intermolecular interactions involving the hydrogen atoms H14 and H10, the former generating a molecular dimer that packs via a head-to-tail arrangement (Figure 3b). These are further stabilized by C-H‚‚‚π intermolecular interactions generating dimeric molecular motifs
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Figure 5. Region representing the intermolecular F‚‚‚F contact in P2.
Discussion It may be concluded from the above studies that the prenucleation aggregates assemble in different supramolecular configurations depending on the use of solvent combinations. Indeed, careful studies done on the crystallization of 2,6-dihydroxybenzoic acid from solutions in toluene and chloroform have demonstrated the induction of morphological features associated with weak intermolecular interactions.12 However, since P1 and P2 are polymorphs of a fairly complex molecule, it is not easy to formulate a mechanism for polymorph induction based on solvent polarity. On the basis of the nature of packing and the features of intermolecular interactions, it can be seen that P1 crystallizes as plates owing to C-H‚‚‚O interactions forming a chain along the c-axis with the second dimension of the plate facilitated via C-H‚‚‚π interactions running along the 21 screw axis. The blocks of P2 are formed mainly influenced by the presence of interactions involving fluorine and C-H‚‚‚O built around the 42 screw axis. Possibly the solvent combination of acetone/ethanol provides the required polarity to the prenucleation aggregate to have these weak but highly directional interactions to develop along the 42 screw axis. Figure 4. (a) C-H‚‚‚π molecular chains related by a screw axis (21) in P1. (b). Molecular dimers involving C-H‚‚‚π intermolecular interaction in P2.
(Figure 4b). C-H‚‚‚O chains related by a 4-fold screw axis hold these dimers. The most important observation is the participation of the fluorine atom in a short intermolecular contact [F‚‚‚F ) 2.868(3) Å]. To our knowledge this is the first example of a short F‚‚‚F contact, which does not involve a center of symmetry [-x + 3/2, -y - 1/2, z] to form the short contact directly. Indeed, short F‚‚‚F contacts have been observed to occur only across a center of symmetry in structures reported earlier.30,31 There are two F‚‚‚F contacts, which develop across each other using the center of symmetry at (1/4, 1/4, 1/4) in P2, but the distances [6.307(3) Å] are very much larger than the van der Waals sum (Figure 5). Further studies on mapping the charge density in the molecule followed by a topological analysis of the regions highlighting the presence of F‚‚‚F interaction are currently in progress.
Conclusion These structural studies suggest that polymorphism could appear as a solvent-induced feature. Concrete evidence from kinetic studies might allow one to explore the causes for the formation of different polymorphs, but at the moment such an analysis is not feasible in these complex frameworks. A systematic survey of solvent-mediated polymorph generation in systems of this type, which involves crystal structure studies of several substituted indoles in terms of careful modeling studies and charge density analyses are currently being pursued to get further insights into the nature of these packing modes. The appearance of unusual but significant interactions, such as, for example, F‚‚‚F in this study provides additional impetus for such studies. Acknowledgment. D.C. thanks CSIR, India, for JRF, Mily Bhattacharya for doing the SHG measurements, and Mr. Padaikanta for DSC measurements. We thank DST-IRHPA, India, for data collection on the CCD facility at IISc, Bangalore.
Subtle Interplay of Weak Intermolecular Interactions Supporting Information Available: Experimental X-ray powder diffraction patterns (Figure S1a,b,c), simulated powder patterns (Figure S2a,b) and DSC plot (Figure S3a,b) of both forms. Single-crystal X-ray crystallographic information (CIF) is available for both forms. This material is available free of charge via the Internet at http://pubs.acs.org.
References (1) 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. (2) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, Great Britain, 2002. (3) July 1, 2004, release of Cambridge Structural Database contains 322 421 entries of which 10145 contain the qualifier “Polymorph”. (4) Kuleshova, L. N.; Antipin, M. Yu. Crystallogr. Rep. 2002, 47, 268-280. (5) Bernstein, J. Conformational Polymorphism in Organic Solid State Chemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987; Vol. 32. (6) Choudhury, A. R.; Islam, K.; Kirchner, M. T.; Mehta, G.; Guru Row, T. N. J. Am. Chem. Soc. 2004, 126(39), 1227412275. (7) Threlfall, T. L. Analyst 1995, 120, 2435. (8) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440. (9) Munshi, P.; Venugopala, K. N.; Jayashree, B. S.; Guru Row, T. N. Cryst. Growth Des. 2004, 4, 1105. (10) Henck, J.-O.; Bernstein, J.; Ellern, A.; Boese, R. J. Am. Chem. Soc. 2001, 123, 1834. (11) Sato, K.; Boistelle, R. J. Cryst. Growth 1984, 66, 441. (12) Davey, R. J.; Blagden, N.; Righini, S.; Alison, S.; Quayle, M. J.; Fuller, S. Cryst. Growth Des. 2001, 1, 59. (13) Vrcelj, R. M.; Sherwood, J. N.; Kennnedy, A. R.; Gallagher, G.; Gelbrich, T. Cryst. Growth Des. 2003, 3, 1027.
Crystal Growth & Design, Vol. 5, No. 3, 2005 1039 (14) Chemla, D. S.; Zyss, J. Nonlinear Optical Properties of Organic Molecules and Crystals; Academic: New York, 1987; Vols. 1 and 2. (15) Kadirvelraj, R.; Bhattacharya, S.; Guru Row, T. N. New J. Chem. 1996, 20, 1165. (16) Kadirvelraj, R.; Umarji, A. M.; Robinson, W. T.; Bhattacharya, S.; Guru Row, T. N. Chem. Mater. 1996, 8, 2313. (17) Hall, S. R.; Kolinsky, P. V.; Jones, R.; Allen, S.; Gordon, P.; Bothwell, B.; Bloor, D.; Norman, P. A.; Hursthouse, M.; Karaulov, A.; Baldwin, J.; Goodyear, M.; Bishop, D. J. Cryst. Growth 1986, 79, 745. (18) Nagarajan, K.; Tawalker, P. K.; Shah, R. K.; Mehta, S. R.; Nayak, G. V. Ind. J. Chem. 1985, 24b, 98. (19) SMART (V 5.628), SAINT (V 6.45a), XPREP, SHELXTL, Bruker AXS Inc. Madison, Wisconsin, USA, 2004. (20) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi A. J. Appl. Crystallogr. 1993, 26, 343-350. (21) Sheldrick, G. M. SADABS, University of Go¨ttingen, Germany, 1997. (22) Sheldrick, G. M. SHELXL97, Program for Crystal Structure Refinement, University of Go¨ttingen, Germany, 1997. (23) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837. (24) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565. (25) Watkin, D. M.; Pearce, L.; Prout, C. K. CAMERON, A Molecular Graphics Package, Chemical Crystallography Laboratory, University of Oxford, England, 1993. (26) Nardelli, M. J. Appl. Crystallogr. 1995, 28, 569. (27) Spek, A. L. Acta Crystallogr. 1990, A46, C34. (28) See Supporting Information for PXRD, Simulated PXRD, and DSC. (29) Kurtz, S. K.; Perry. T. T. J. Appl. Phys. 1968, 39, 3798. (30) Choudhury, A. R.; Urs, U. K.; Nagarajan, K.; Guru Row, T. N. J. Mol. Struct. 2002, 71, 605. (31) Choudhury, A. R.; Guru Row, T. N. Cryst. Growth Des. 2004, 4, 47.
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