Dimorphic Forms in a Non-Centrosymmetric Environment from a Prochiral Molecule: Cooperative Interplay of Strong Hydrogen Bonds and Weak Intermolecular Interactions Deepak Chopra and T. N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560012, Karnataka, India Received April 22, 2005;
CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 5 1679-1681
Revised Manuscript Received August 3, 2005
ABSTRACT: 4-Fluoro-N-(2-fluorophenyl) benzamide, a prochiral molecule, exhibits dimorphic behavior. This feature has been analyzed in terms of morphology, X-ray single-crystal structure analysis, differential thermal analysis, and measurement of second harmonic generation (SHG) in both forms, which crystallize in noncentric space groups. The dimorphs have different morphologies, a major form as needles and a minor form as thin plates, occurring concomitantly in the same crystallization setup. The plates crystallize in the monoclinic space group P21, while the needles are in the orthorhombic space group Pca21. Strong N-H‚‚‚O hydrogen bonds and weak but highly directional C-H‚‚‚F interactions acting cooperatively are responsible for the observed symmetry steering the molecules to pack in noncentric environments. Polymorphism is a widely recognized and observed phenomenon with both fundamental and commercial ramifications brought about by the subtle interplay of kinetic and thermodynamic factors and often mediated through the involvement of both strong hydrogen bonds and weak intermolecular interactions.1 Understanding the cooperativity between the different intermolecular interactions that characterize a polymorph from its sibling is without a doubt the key to the synthesis of novel supramolecular materials with desired properties.1 In this context, hydrogen bonding interactions, either strong or weak, have always been the cynosure in the field of crystal engineering. However, there has always been ambiguity in the role of organic fluorine as a hydrogen-bond acceptor, and this has been a matter of active interest.2 Intense research is currently being carried out in the field of bioactive compounds of pharmaceutical and agrochemical interest,3-5 and efforts are being made to evaluate the importance of organic fluorine in such compounds.6,7 In our ongoing research on the role of fluorine in weak, but highly directional interactions, we report here the crystal structure of 4-fluoro-N-(2-fluorophenyl)benzamide (Scheme 1), which crystallizes concomitantly as dimorphs. The compound 4-fluoro-N-(2-fluorophenyl)benzamide was synthesized by the reaction of m-fluorobenzoyl chloride and o-fluoroaniline. The compound was isolated by a solvent extraction procedure. A small portion of the resulting product was added to a 5.0 mL beaker and dissolved in a 1:1 ratio of a mixture of EtOAc/hexane to obtain crystals by a slow evaporation method at ∼2 °C. On complete evaporation, it was observed that crystals of two different morphologies (Figure 1), the major product as needles and the other minor product as very thin plates, appear concomitantly. Crystals of the same morphology were carefully isolated under a polarizing microscope. Melting points of the two samples are different, and DTA experiments allow for the two forms to be easily distinguishable. On the basis of the DTA traces, it is deduced that the needle form melts at 401.7 K (128.7 °C), while the plate form melts with a small peak at 396.6 K (123.6 °C) and a suppressed melting point at 399.7 K (126.7 °C).8 It is of interest to note that further purification of the compound using column chromatography and recrystallization from EtOAc/hexane resulted in only the needle form crystals. These needles were finely powdered, and powder diffraction patterns were recorded.8 * To whom correspondence should be addressed. E-mail: ssctng@ sscu.iisc.ernet.in.
Figure 1. Morphological changes observed on concomitant crystallization of needle and plate forms at ∼2 °C.
Scheme 1. Molecular Diagram of 4-Fluoro-N-(2-fluorophenyl) benzamide
Single-crystal X-ray diffraction experiments9-11 on both the morphologies was performed at 100 K. The needles and plates were found to crystallize in noncentric space groups Pca21 and P21, respectively.12-13 A search14 through the Cambridge Structural database (CSD Version 5.26, November 2004 and an update on February 2005)15,16 to identify the distribution of all noncentric polymorphic structures in the crystal systems common to organics (triclinic, monoclinic, and orthorhombic) was carried out to assess the propensity of occurrence of common space
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Crystal Growth & Design, Vol. 5, No. 5, 2005
Communications Table 1. Intermolecular Interactions D-H Å
D-H‚‚‚A
D‚‚‚A Å
H‚‚‚A ∠D-H‚‚‚A Å (deg)
Polymorph 1: Plate N1-H13‚‚‚O1 0.82(4) 2.935(3) 2.23(4) 143(3) C10-H10‚‚‚F1 0.93 3.175(4) 2.59 121 C3-H3‚‚‚F2
0.93(4) 3.204(4) 2.42(4)
142(3)
Polymorph 2: Plate N1-H12‚‚‚O1 0.88(3) 2.946(3) 2.14(3) 151(3) C3-H3‚‚‚F1 0.94(3) 3.368(4) 2.59(3) 140(2) C9-H9‚‚‚F2 C5-H5‚‚‚O1
0.95(4) 3.332(4) 2.40(4) 0.90(4) 3.429(4) 2.60(4)
168(3) 153(3)
symmetry codes x, +y + 1, +z x + 1/2, -y + 1, z -x + 1/2, y + 1, z + 1/2 x + 1, y, z -x, y - 1/2, -z+1 x - 1, y - 1, z x + 1, y + 1, z
Table 2. SHG Data on Crystals of the Two Dimorphsa
a
Figure 2. CSD analysis showing the distribution of polymorphic compounds in noncentric space groups until the space group number ) 46 (gaps indicate no hits for the corresponding space group number). Only noncentric space groups have been plotted.
Figure 3. (a) Packing of molecules in the needle form. Dotted lines depict N-H‚‚‚O hydrogen bonds and C-H‚‚‚F intermolecular interactions. Hydrogen atoms not participating in interactions are omitted for clarity. (b) Packing of molecules in the plate form. Dotted lines depict N-H‚‚‚O hydrogen bonds and C-H‚‚‚F intermolecular interactions. Hydrogen atoms not participating in interactions are omitted for clarity.
groups in polymorphism (Figure 2). The most common space group was found to be P212121 (space group No. 19; no. of hits: 221) with P21 (space group No. 4; no. of hits: 172) placed second, while Pna21 (space group No. 33; no. of hits: 62) and Pca21 (space group No. 29; no. of hits: 43) are third and fourth on the list. Further analysis indicates that only four cases of polymorphism17 have been reported so far in the literature with this combination of space groups (Pca21 and P21), and just one of them is reported to be concomitant.18 It is noteworthy that in the present study the solid-state conformation of the molecule in both forms is similar, and hence this example is a rare case of packing polymorphism among concomitant noncentric dimorphs. Figure 3a,b highlights the intermolecular features
morphology
incident energy (mJ)
output signal intensity (mJ)
needle plate
10 5.5
39 475
Laser source: Nd:YAG.
associated with the packing of molecules in the crystal lattice. Strong N-H‚‚‚O hydrogen bonds parallel to the crystallographic b axis along with participation of two C-H‚‚‚F intermolecular interactions related by a and c glide planes, respectively, involving both fluorine atoms result in the formation of molecular chains in the needle form (Table 1; Figure 3a). In contrast, in the plate form the N-H‚‚‚O hydrogen-bonded chains run parallel to the a axis. Also, both the fluorine atoms are involved in generating two well-directed C-H‚‚‚F intermolecular interactions. The strong N-H‚‚‚O hydrogen bond along with a C-H‚‚‚O hydrogen bond in addition to one of the C-H‚ ‚‚F interactions form planar sheets, which in turn are held by the second C-H‚‚‚F interaction resulting in a screwlike packing arrangement along the b axis (Table 1; Figure 3b). A CSD search19 on the C (sp2, phenyl)-H‚‚‚F-C (sp2, phenyl) interactions, in which the distance H‚‚‚F is varied from 2.1 to 3.2 Å, indicates that the maxima in the histogram (Figure 4a) is between 2.6 and 2.7 Å and is highly directional (Figure 4b). In a recent study20 based on charge density analysis, a well-defined “region of overlap” between hydrogen bond and van der Waals interactions has been identified to lie between 2.75 and 2.85 Å in internuclear separation distance between the H atom and the acceptor atom. The values of the H‚‚‚F distance and the associated angular restriction suggest that the C-H‚‚‚F interaction could indeed be classified as a weak hydrogen bond. Charge density analysis on several compounds containing C-H‚‚ ‚F interactions is expected to quantify this observation. SHG measurements on the crystals of the two forms show that both are NLO active, the SHG intensity of the plate form being an order of magnitude more intense than the needle form (Table 2). It is noteworthy that the incident energy had to be lowered in the case of the plate sample to record the magnitude of the SHG intensity within the recorder limits. The observed differences in intensities could be in accordance with the arrangement of molecules in the two crystal lattices. In the plate form, the molecule has polarization vectors oriented along the b axis, and the resultant is of large magnitude but in the needle form because of the presence of glide planes in two orthogonal directions; the polarization components cancel out resulting in a SHG signal of lower intensity. It is of significance to note that the two forms differ from each other (needle and plate) only in terms of different weak but highly directional C-H‚‚‚F interactions (Figure 3a,b) despite the presence of a strong N-H‚‚‚O hydrogen bond in the crystal lattice. The noncentric crystal environ-
Communications
Crystal Growth & Design, Vol. 5, No. 5, 2005 1681 two polymorphs are available free of charge via the Internet at http://pubs.acs.org.
References
Figure 4. (a) CSD analysis showing the distribution of H‚‚‚F intermolecular distances, keeping the angularity constant (140180°). (b) CSD analysis highlighting the geometry of C-H‚‚‚F intermolecular interaction, the distance H‚‚‚F being kept constant in the range 2.6-2.7 Å.
ments generated in a prochiral molecule suggest the importance of kinetic factors influencing the nucleation conditions. The energetics involved in such environments needs critical evaluation of the nature of intermolecular interactions acting in the solvent-solute media. Further studies to evaluate the role played by fluorine in a series of differently substituted fluorobenzanilides with special emphasis on unraveling the nature of the interactions in terms of charge density analysis are currently underway. Acknowledgment. We thank Professor Goverdhan Mehta for allowing us to use the synthesis facilities in his laboratory. We thank Department of Science and Technology, India, for funding and providing the CCD facility under the IRHPA-DST program. We also thank Arun Umarji, Girish Kunte, Pushpendu Das, Sampa for DTA and SHG measurements and Saikat Sen for helping in synthesizing the compound. D.C. thanks CSIR, India, for Junior Research Fellowship and Dr. Angshuman Ray Choudhury for useful comments and suggestions. Supporting Information Available: Powder XRD for the pure material (Figure S1), simulated XRD patterns (Figure S2a,b), DTA plots (Figure S3a,b), ORTEP plot for the two forms at 100 K (Figure S4a,b), and a table highlighting the molecular geometry (Table S1). The X-ray crystallographic information files for the
(1) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon Press: Oxford, 2002. (2) Dunitz, J. D. ChemBioChem 2004, 5, 614. (3) Bohm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Sander, U. O.; Stahl, M. ChemBiochem 2004, 5, 637. (4) Jeschke, P. ChemBioChem 2004, 5, 570. (5) Leroux, F. ChemBioChem 2004, 5, 644. (6) Choudhury, A. R.; Guru Row, T. N. Cryst. Growth Des. 2004, 4, 47. (7) Hulme, A. T.; Price, S. L.; Tocher, D. A. J. Am. Chem. Soc. 2005, 127, 1116. (8) See Supporting Information for PXRD on pure material, simulated powder patterns for the dimorphic forms, DTA, and ORTEP at 90 K. (9) Bruker 2000, SMART (Version 5.625), SAINT (Version 6.45a); Bruker AXS Inc.: Madison, Wisconsin, USA. (10) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. SIR92. A program for crystal structure solution. J. Appl. Crystallogr. 1993, 26, 343. (11) Sheldrick, G. M. SHELXL97, Program for crystal structure refinement; University of Go¨ttingen, Germany, 1997. (12) Crystal data (needle): chemical formula C13H9NOF2, formula weight 233.2, orthorhombic Pca21, a ) 25.563(1), b ) 4.969(3), c ) 8.250(4), Z ) 4, F(calc) ) 1.48 g/cm3, T ) 100(2) K, µ ) 0.118 mm-1, reflections measured ) 7419, unique reflections ) 1959, reflections observed [I > 2σ(I)] ) 1547, R1_obs ) 0.054, wR2_obs ) 0.123. (13) Crystal data (plates): chemical formula C13H9NOF2, formula weight 233.2, monoclinic P21, a ) 4.962(1), b ) 5.486(1), c ) 19.174(5) Å, β ) 91.759(4)°, Z ) 2, F(calc) ) 1.48 g/cm3, T ) 100(2) K, µ ) 0.119 mm-1, reflections measured ) 4017, unique reflections ) 1914, reflections observed [I > 2σ(I)] ) 1545, R1_obs ) 0.044, wR2_obs ) 0.097. (14) CSD search was performed first for the word “polymorph” (search 1). Then individual searches were done for all the noncentric space groups in triclinic, monoclinic, and orthorhombic crystal systems only (Search 2). Searches for each noncentric space groups were then combined with the word “polymorph” and the resulting search was performed. The “no. of hits” obtained by this procedure was used to obtain data for the histogram. The specified search options were 3D coordinates determined, R-factor < 10%, no disordered structures, not polymeric, no ions, no powder structures, and only ORGANICS. Further, a search was initiated with the key words “polymorph” (search 1), “form” (search 2), “modification” (search 3) and “phase” (search 4) as well. Then individual searches were done for the noncentric space groups P21 and Pca21 (searches 5 and 6). Searches for the individual noncentric space groups were then combined with the word “polymorph”, “form”, “modification”, and “phase”, and the resulting search was performed. The results were then compared manually, and the reference codes common to both space groups were selected. (15) Allen, F. H. Acta Crystallogr. 2002, B58, 380. (16) Allen, F. H.; Motherwell, W. D. S. Acta Crystallogr. 2002, B58, 407. (17) The reference codes for the four cases are HADNOP, HADNOP01, POCPUS, POCPUS01, QIKFIZ, QIKFIZ01, YERRUI01, and YERRUI02. (18) Blake, A. J.; Gould, R. O.; Halcrow, M. A.; Schroder, M. Acta Crystallogr. 1993, B49, 773. (19) CSD search done for C (sp2, phenyl)-H‚‚‚F-C (sp2, phenyl) fragment in which the C-H‚‚‚F distance is varied from 2.1 to 3.2 Å, keeping the angularity constant (range 140-180°). In the second search, the distance is kept constant between 2.6 and 2.7 Å (maxima in the histogram) and the angularity was varied from 140 to 180°. The specified search options were 3D coordinates determined, R-factor < 7.5%, no disordered structures, not polymeric, no ions, no powder structures, and only ORGANICS. (20) Munshi, P.; Guru Row, T. N. J. Phys. Chem. A 2005, 109, 659.
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