Solvatomorphism in 3-Fluorobenzoylaminophenyl 3-Fluorobenzoate: A Subtle Interplay of Strong Hydrogen Bonds and Weak Intermolecular Interactions Involving Disordered Fluorine Deepak Chopra and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560012, Karnataka, India
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 6 1267-1270
ReceiVed February 16, 2006; ReVised Manuscript ReceiVed April 5, 2006
ABSTRACT: 3-Fluorobenzoylaminophenyl 3-fluorobenzoate crystallizes in dimorphic forms, generated by a delicate balance of strong and weak intermolecular forces, one form containing a trapped cyclohexane molecule in the crystalline lattice. Both forms crystallize as triclinic systems with centrosymmetric space group P1h. The supramolecular features in both forms is guided by control of strong N-H‚‚‚O hydrogen bonds, weak but directional C-H‚‚‚O and C-H‚‚‚F interactions involving disordered fluorine, and isotropic C-H‚‚‚π and aromatic π‚‚‚π stacking interactions that differentiate the packing in the two forms. The extent of disorder associated with organic fluorine is different in both forms. Pseudo-polymorphism or solvatomorphism, defined as crystalline forms of a compound that differ in the species or stoichiometry of a trapped solvent molecule, has been recognized to be of great importance in the pharmaceutical industry.1 It affords opportunities to study the effect of solvents on the molecular assembly consisting of host molecules where the solvent is a guest.2 However, the implication of solvent incorporation, although it changes the crystal structure resulting in a new polymorphic form, on the subsequent biological activity is yet to be understood. Currently, in the literature a number of reports discuss this aspect of polymorphism.3 The term pseudo-polymorph was first suggested by McCrone, and even though in the pharmaceutical literature4 this is accepted there are several “for” and “against” views expressed in recent times.5 The design and synthesis of new materials with desired chemical and physical properties have been of interest, and this involves the generation and study of structural motifs in crystals, which is essentially guided by precise topological control through the manipulation of weak intermolecular interactions.6 There are a rich variety of intermolecular interactions that serve as tools in engineering such molecular assemblies.7 The well-known interactions involving hydrogen bonds are O-H‚‚‚O, N-H‚‚‚O, O-H‚‚‚N, and N-H‚‚‚N.8 Interactions involving halogens, especially, chlorine and bromine, have been analyzed in terms of the strength of their interaction.9 Organic fluorine and its role as a hydrogen-bond acceptor is of recent interest,10 and we have observed concomitant polymorphism in 4-fluoro-N-(2-fluorophenyl) benzamide, both polymorphs being noncentric in nature.11 In this case, it has been demonstrated that both strong N-H‚‚‚O hydrogen bonds and weak but highly directional C-H‚‚‚F interactions acting cooperatively are responsible for the observed symmetry, and hence they steer the molecules to pack in noncentric environments. Isotropic van der Waals interactions also play an important role in generating different molecular assemblies. Extension of such features of introduction of weak intermolecular interactions through the incorporation of solvents is of interest, and hence the title compound has been prepared. 3-Fluorobenzoylaminophenyl 3-fluorobenzoate was synthesized by dimethyaminopyridine (DMAP)12 catalyzed coupling of m-fluorobenzoyl chloride and m-amino phenol in dry dichloromethane (Figure 1). The compound purified from column chromatography was dissolved using a library of solvents such as dichloromethane/hexane, chloroform/hexane, ethyl acetate/hexane, ethyl acetate/cyclohexane, acetonitrile, and dioxan. Powder diffraction and IR measurements were also performed to confirm formation of the compound.13 Simulated powder diffraction pattern of the two forms obtained after complete solution of the crystal structures is also given.13 All the crystals were screened and checked * To whom correspondence
[email protected].
should
be
addressed.
E-mail:
Figure 1. Synthesis of the title compound.
Figure 2. (a) ORTEP of Form I drawn with 30% ellipsoidal probability. Dotted lines indicate intramolecular hydrogen bonds. (b) ORTEP of Form II (asymmetric unit) drawn with 30% ellipsoidal probability. Dotted lines indicate intramolecular hydrogen bonds.
for the existence of polymorphism. It was observed that all crystals obtained from different solvents had the same unit cell (Form I)
10.1021/cg060082o CCC: $33.50 © 2006 American Chemical Society Published on Web 04/25/2006
1268 Crystal Growth & Design, Vol. 6, No. 6, 2006
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Table 1. Intermolecular Interactions in the Two Forms Form I D-B‚‚‚A
D-B/Å
D‚‚‚A/Å
B‚‚‚A/Å
∠D-B‚‚‚A/°
symmetry
C13-H13‚‚‚O1 N1-H1N‚‚‚O3a C9-H9‚‚‚O3 C3-H3‚‚‚O3 C18-H18‚‚‚O1 C5-H5‚‚‚F2A C1-H1‚‚‚F2B
0.93 0.74(2) 0.93 0.93 0.93 0.93 0.93
2.849(4) 3.063(3) 3.400(4) 3.197(4) 3.412(3) 3.466(6) 3.256(6)
2.28 2.34(2) 2.70 2.41 2.70 2.58 2.57
120 167(3) 133 143 134 160 131
x, y, z -x, -y, -z + 1 -x, -y, -z + 1 -x, -y, -z + 1 -x, -y + 1, -z + 2 -x + 1, -y, -z + 2 -x + 1, -y - 1, -z + 1
Form II
b
D-B‚‚‚A
D-B/Å
D‚‚‚A/Å
B‚‚‚A/Å
∠D-B‚‚‚A/°
symmetry
C13-H13‚‚‚O1 N1-H1N‚‚‚O3a C9-H9‚‚‚O3 C3-H3‚‚‚O3 C18-H18‚‚‚O1 C5-H5‚‚‚F2A C10-H10‚‚‚F2A C16-H16‚‚‚Cg2b
0.93 0.88(2) 0.93 0.93 0.93 0.93 0.93 0.93
2.853(3) 2.980(3) 3.418(3) 3.189(3) 3.278(3) 3.392(6) 3.503(4) 3.782(3)
2.26 2.12(2) 2.75 2.60 2.46 2.66 2.60 2.96
121 166(2) 130 122 147 136 165 147
x, y, z -x + 2, -y, -z + 1 -x + 2, -y, -z + 1 -x + 2, -y, -z + 1 -x + 1, -y + 1, -z + 1 -x + 2, -y, -z x, y, z + 1 x + 1, y, z
a The amino hydrogen was located from a difference Fourier map and refined isotropically. The remaining hydrogens were fixed in geometrical positions. Cg2 is the center of gravity of the phenyl ring.
Table 2. Molecular Conformation: Relevant Torsion Angles torsion angle
Form I (°)
Form II (°)
HF/6-31G**(°)
C5-C4-C7-N1 C4-C7-N1-C8 C7-N1-C8-C13 C13-C12-O2-C14 C12-O2-C14-C15 O2-C14-C15-C16
-163.4(3) 175.4(3) -14.2(5) -82.7(3) -178.4(2) -14.6(4)
-154.7(4) 174.3(4) -8.8(6) -77.1(4) -176.2(3) 174.2(3)
-150.3 -179.6 5.13 -106.5 178.5 179.6
except in the case of crystals obtained from solvent combinations of ethyl acetate/cyclohexane (Form II). Single-crystal data14 for the two forms were collected on a BRUKER AXS diffractometer15 at 290(2) K. The molecular structure of these forms (Form I and II) is as shown in Figure 2, panels a and b, respectively. The crystal structure is stabilized by intra- and intermolecular hydrogen bonds of type N-H‚‚‚O and C-H‚‚‚F interactions. In addition, aromatic π‚‚‚π stacking interactions also provide additional stability (Table 1). The molecular conformation in the molecule in the two forms is nearly the same (Table 2). However, comparison of the experimental values of some of the torsion angles with theoretical values obtained from ab initio HF/6-31G** calculations16 suggests that the conformation observed experimentally is different from that of the optimized geometry (Table 2). Crystal Structure of Form I. This form crystallizes in the triclinic space group P1h with Z ) 2 with no solvent trapped in the crystal lattice and a density of 1.42 g/cm3. One of the fluorine atoms F1 is fully occupied, whereas the atom F2 is disordered over two sites F2A and F2B, the occupancy of the fluorine atom F2A refining to 0.466(4). The molecular conformation is stabilized through a well-defined intramolecular C-H‚‚‚O hydrogen bond involving the hydrogen atom H13 [Etter’s symbol19: S(6)]. It is of interest to note that only the disordered fluorine atoms F2A and F2B involving acidic hydrogen atoms H1 and H5 participate in the formation of C-H‚‚‚F intermolecular interactions, both generating dimers across the center of symmetry, forming “chains of dimers” along the crystallographic c axis form [Etter’s symbol: R22(8)] (Figure 3a). N-H‚‚‚O dimers involving the hydrogen atom H1N [Etter’s symbol: R22(16)], which are further held by C-H‚‚‚O intermolecular interactions (involving hydrogens H3, H9, H18) forming molecular dimers (Etter’s symbol for the corresponding graph set motif being R22(16) for H3, H9 and R22(26) for H18, respectively), provide a link between the molecules held by C-H‚‚‚F dimers (Figure 3a,b). This packing is further stabilized by aromatic π‚‚‚π stacking interactions between the phenyl rings [C8-C13 (Cg1), C15-C20 (Cg2)] separated by a stacking distance of 4.117(3) and 4.202(3) Å, respectively (Figure 3b).
Figure 3. (a) Packing of molecules in the crystal lattice of Form I. N-H‚ ‚‚O, C-H‚‚‚O, C-H‚‚‚F dimers are indicated as dotted lines. (b) Aromatic π‚‚‚π interactions along with the presence of C-H‚‚‚O and C-H‚‚‚F dimers in Form I.
Crystal Structure of Form II. This form crystallizes in the triclinic space group P1h with Z ) 2. The density is 1.33 g/cm3,
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Figure 4. Molecular packing in Form II containing the chair form of solvent cyclohexane.
Crystal Growth & Design, Vol. 6, No. 6, 2006 1269 The conformation of the molecule is once again locked through a well-defined intramolecular C-H‚‚‚O hydrogen bond involving hydrogen atom H13. Form II is stabilized by N-H‚‚‚O hydrogenbonded dimers involving the hydrogen atom H1N [Etter’s symbol: R22(16) (Figure 5a). These dimers are further stabilized by C-H‚‚ ‚O intermolecular interactions involving the hydrogen atoms H3, H9 [Etter’s symbol: R22(16)] and H18 [Etter’s symbol: R22(26)] (Figure 5a). These dimers are in turn held by weak intermolecular interactions involving fluorine atom F2A of the type C-H‚‚‚F using hydrogen atom H10 in forming molecular chains parallel to the crystallographic c axis involving the atom F2A [Etter’s symbol: C(10)], and these are further stabilized by formation of additional C-H‚‚‚F dimers, involving the acidic hydrogen H5 [Etter’s symbol: R22(8)] (Figure 5a). In addition, weak C-H‚‚‚π intermolecular chains using hydrogen H16 and phenyl ring [C8-C13 (Cg2)] forms molecular chains along the crystallographic a axis (Figure 5b) along with isotropic van der Waals involving aromatic phenyl rings [C1-C6 (Cg1), C15-C20 (Cg3)] with a stacking distance of 4.004(2) and 4.164(2) Å, respectively (Figure 5b). It is to be noted that the atom F1 in Form I also did not participate in any intermolecular interactions. The presence of the cyclohexane moiety rearranges the molecules resulting in an entirely different mode in the crystal lattice. It is thus the changes in the pattern of C-H‚‚‚F interactions acting in cooperation with isotropic aromatic π‚‚‚π interactions that steer the packing of molecules into different crystalline environments. Since the molecules enclose the cyclohexane moiety located at the center of symmetry generating a framework structure, Form II was heated to exclude the cyclohexane moiety. However, on heating of the sample to 120 °C, the framework structure loses crystallinity. In conclusion, a subtle interplay among strong, weak, and isotropic interactions appears to control the packing motifs in both solvated and unsolvated forms of 3-fluorobenzoylaminophenyl 3-fluorobenzoate. It is of interest that stabilization of the lattice is achieved through interactions involving disordered fluorine. Acknowledgment. We thank DST, India, for data collection on the CCD set up under the IRHPA-DST program. We thank Professor Goverdhan Mehta for use of his laboratory facilities. D.C. thanks CSIR, India, for the award of a junior research fellowship. Supporting Information Available: Experimental powder pattern (Figure S1), simulated powder X-ray patterns (Figure S2a,b), and IR pattern (Figure S3); crystallographic information as deposited CIF files (284960 and 284961); single-crystal X-ray crystallographic information (CIF) file. This material is available free of charge via the Internet at http://pubs.acs.org.
References
Figure 5. (a) Packing of molecules in the crystal lattice of Form II. N-H‚ ‚‚O, C-H‚‚‚O, and C-H‚‚‚F dimers along with the C-H‚‚‚F building the chain are shown as dotted lines. (b) Aromatic π‚‚‚π interactions along with presence of C-H‚‚‚π molecular chains in Form II.
which is significantly lower than that of Form I. The cyclohexane molecule is trapped in the crystal lattice at the center of symmetry (Figure 4). It is noteworthy that both the fluorine atoms F1 and F2 are disordered over two sites F1A and F1B in the case of F1 and F2A and F2B in the case of F2 with the final occupancy of the fluorine atoms F1A and F2A refining to 0.787(4) and 0.891(5), respectively.
(1) Nangia, A.; Desiraju, G. R. Chem. Commun. 1999, 605. (b) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440. (c) Milton, C.; Howard, J. A. K.; Madhavi, N. N. L.; Nangia, A.; Desiraju, G. R.; Allen, F. H. Wilson, C. C. Chem. Commun. 1999, 1675. (d) Pedireddi, V. R.; Prakasha Reddy, J. Tetrahedron Lett. 2003, 44, 6679. (e) Yin, Z.; Li, Z.; Yu, A.; He, A.; Cheng, J.-P. Tetrahedron Lett. 2004, 45, 6803. (2) Tanifuji, N.; Kobayashi, K. CrystEngComm 2001, 3, 1. (b) Raj, S. B.; Muthiah, P. T.; Rychlewska, U.; Warzajtis, B. CrystEngComm 2003, 5, 48. (3) Schmuck, C.; Wienand, W. J. Am. Chem. Soc. 2003, 125, 452. (b) Schmuck, C.; Heil, M. Org. Lett. 2001, 3, 1253. (c) Schmuck, C. J. Org. Chem. 2000, 65, 2432. (d) Schmuck, C. Eur. J. Org. Chem. 1999, 2397. (4) Haleblian, J. K.; McCrone, W. C. J. Pharm. Sci. 1975, 64, 1269. (5) (a) Rogers, R. D. Cryst. Growth Des. 2003, 3, 869. (b) Desiraju, G. R. Cryst. Growth Des. 2004, 4, 1089. (c) Seddon, K. R. Cryst. Growth Des. 2004, 1087. (d) Bernstein, J. Cryst. Growth Des. 2005, 5, 1661. (e) Nangia, A. Cryst. Growth Des. 2006, 6, 2. (6) Dethlefs, K. M.; Hobza, P. Chem. ReV. 2000, 100, 143. (7) Lehn, J. M. Science. 1993, 260, 1762. (8) Steiner, T. Cryst. ReV. 1996, 6, 1. (9) Ramasubbu, N.; Parthasarathy, R.; Murray- Rust, P. J. Am. Chem. Soc. 1986, 108, 4308.
1270 Crystal Growth & Design, Vol. 6, No. 6, 2006 (10) Dunitz, J. D. ChemBioChem 2004, 5, 614. (b) Bohm, H. J.; Banner, D.; Bendels. S.; Kansy, M.; Kuhn, B.; Muller, K.; Sander, U. O.; Stahl, M. ChemBioChem. 2004, 5, 637. (c) Jeschke, P. ChemBioChem 2004, 5, 570. (d) Leroux, F. ChemBioChem 2004, 5, 644. (11) Chopra, D.; Guru Row, T. N. Cryst. Growth Des. 2005, 5, 1679. (12) Penney, J. M. Tetrahedron Lett. 2004, 45, 2667. (13) Supporting Information contains PXRD (pure solid), simulated powder X-ray patterns [Form (I) and Form (II)] and IR pattern of the synthesized compound. (14) Single-crystal data were reduced using SAINTPLUS,15 and an empirical absorption correction was done using SADABS15. Space group was determined using XPREP.15 The crystal structure was solved using SIR 9217 and refined using SHELXL.18 Crystal Data (Form I): chemical formula ) C20H12NO3F2, formula weight ) 352.3, triclinic ) P1h, a ) 9.207(6) Å, b ) 9.775(6) Å, c ) 10.656(4) Å, R ) 106.630(10)°, β ) 95.219(11)°, γ ) 113.286(10)°, Z ) 2, F(calc) ) 1.42 g/cm3, T ) 290(2) K, µ ) 0.111 mm-1, R (int) ) 0.018, reflections measured ) 7749, unique reflections ) 2389, reflections observed [I > 2σ(I)] ) 2117, R1_obs ) 0.052, wR2_obs ) 0.136, ∆Fmax (e Å-3) ) 0.28, ∆Fmin (e Å-3) ) -0.17, GOF ) 1.053. Crystal data (Form II): chemical formula ) C23H17NO3F2, formula weight ) 393.4, triclinic ) P1h, a ) 7.904(1) Å, b ) 10.222(2) Å, c ) 12.435(2) Å, R ) 95.269(3)°, β ) 95.215(3)°, γ ) 96.239(10)°, Z ) 2, F(calc) ) 1.32 g/cm3, T ) 290(2)K, µ ) 0.100 mm-1, R(int) ) 0.030, reflections measured ) 9502, unique reflections ) 3435, reflections observed [I > 2σ(I)] ) 2381, R1_obs ) 0.060,
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(15) (16)
(17)
(18) (19)
wR2_obs ) 0.130, ∆Fmax (e Å-3) ) 0.16, ∆Fmin (e Å-3) ) -0.13, GOF ) 1.071. Bruker 2000. SMART (Version 5.625), SAINT (Version 6.45a). Bruker AXS Inc., Madison, Wisconsin, USA. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.11.3; Gaussian, Inc.: Pittsburgh, PA, 1998. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. SIR92. A program for crystal structure solution. J. Appl. Cryst. 1993, 26, 343. Sheldrick, G. M. SHELXL97. Program for crystal structure refinement. University of Go¨ttingen, Germany, 1997. Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126.
CG060082O
