Directed Intermolecular Association by Complementary Molecular Edges in 6-Methoxycoumarin Paul W. Baures,* Jeremy R. Rush, Scott D. Schroeder, and Alicia M.
Beatty†
Department of Chemistry, Kansas State University, Manhattan, Kansas 66506
CRYSTAL GROWTH & DESIGN 2002 VOL. 2, NO. 2 107-110
Received December 7, 2001
ABSTRACT: The design of complementary hydrogen bonding interactions between molecules is often used in crystal engineering and other molecular recognition research. Herein we report the ability of complementary molecular edges in 6-methoxycoumarin (1) to form CH‚‚‚O interactions and thereby direct intermolecular association of this compound. Cocrystallization experiments between 2-methoxynaphthalene (2) and coumarin (3) yield a powdery eutectic at a 1:1 stoichiometry but provide no indication of whether similar intermolecular edge interactions between 2 and 3 are stable in solution. The lack of net secondary interactions in the intermolecular association of 1 does not prevent edge-directed association between CH‚‚‚O groups. Indeed, fumaric acid monoethyl ester (4) associates through edge-directed CH‚‚‚O interactions in the solid-state with seemingly unfavorable secondary interactions. The use of complementary edges capable of associating through CH‚‚‚O interactions may serve as useful molecular recognition elements by themselves or within the context of other predictable intermolecular forces. Hydrogen bonding interactions such as OH‚‚‚O and NH‚‚‚O associations are powerful tools for directing molecular recognition between molecules and are widely employed in crystal engineering1 and drug design.2 These electrostatic forces are subject to secondary interactions with either favorable or unfavorable contributions that can thereby affect the overall stability of the aggregate.3 Interactions of the CH‚‚‚O type have also been employed for molecular recognition in the context of crystal engineering,4 but are less widely employed in drug design despite the recognition of their widespread occurrence in biological systems.5 Coumarins are polyoxygenated phytochemicals with diverse biological activities.6 Selected coumarins also serve as useful fluorescent dyes.7 These compounds are known to bind to a wide variety of macromolecules,6 yet little is known about the molecular recognition forces that dominate these interactions. In this paper, we report the self-association of 6-methoxycoumarin (1) in the solid-state through CH‚‚‚O interactions between complementary molecular edges. The strength of this association was probed by cocrystallization experiments between 2-methoxynaphthalene (2) and coumarin (3). In addition, the X-ray crystal structure of fumaric acid monoethyl ester (4) was determined and found to contain analogous edge associations despite seemingly unfavorable secondary interactions. These structures support the hypothesis that CH‚‚‚O interactions between complementary molecular edges can be predictable molecular recognition forces in the presence of other strong and equally predictable interactions. In addition, this work supplements known coumarin crystal structures with similar self-association as models for postulating the role of edge interactions in the molecular recognition of coumarins in biological systems. Compound 1 was synthesized by modification of a known procedure6,8 from 2-hydroxy-5-methoxybenzal* To whom correspondence should be addressed. E-mail: baures@ ksu.edu. † Currently at the University of Notre Dame.
dehyde.9 Crystals of 1 were grown from chloroform, and the single-crystal X-ray structure was determined.10 Previously, only unit cell parameters were known for this coumarin derivative.11 Compounds 2-4 were purchased from ACROS and used as received. Crystals of 4 were grown from methanol for X-ray analysis.12 The intermolecular association of 1 in the solid-state is shown in Figure 1. The coumarin associates via the formation of three intermolecular CH‚‚‚O interactions (3.43, 3.49, and 3.44 Å) between the two longest molecular edges to form a linear tape motif (Figure 1a). The one-dimensional tapes are further associated in a second dimension through CH‚‚‚O interactions between the carbonyl oxygen to the C3-H bond (3.37 Å) as well as vdW contacts between methyl groups (4.06 Å) in the 010 plane (Figure 1b). The 010 planes also stack (3.23 Å) through partial overlap of the coumarin rings (Figure 1c). We attribute the self-association of 1 to be controlled by the three CH‚‚‚O interactions formed between complementary molecular edges. In making this assessment, we have considered that the C‚‚‚O distance should be less than or approximate to 3.56 Å.4,5d,13 Although distance and geometric criteria for these interactions have been and continue to be debated, this is the mean distance reported from a recent Cambridge Structural Database (CSD) analysis with sp2-hybridized C-H donors and carbonyl acceptors.14 To determine whether the sum of these three interactions would be sufficient to associate two independent molecules, we examined the possibility of cocrystallization between 2-methoxynaphthalene (2) and coumarin (3). Samples with varying molar percentages of each component were prepared in chloroform.15 Differential
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Figure 3. A comparison of the X-ray powder diffraction data collected on compounds 2 and 3 as well as for the solid formed from a slow evaporation of a 1:1 stoichiometric mixture of 2 and 3.
Figure 4. Intermolecular CH‚‚‚O directed edge-association of 7-methoxy-4-methylcoumarin in the solid-state.19
Figure 1. (a) Molecular packing of 1 via intermolecular association of molecular edges through complementary CH‚‚‚O interactions. (b) A nearly perpendicular view showing the molecules coincident with the 010 plane. (c) The packing interactions between 010 planes showing partial overlap between two molecular edges and the relative absence of overlap of the other two edges.
Figure 2. Phase diagram describing the beginning of the melt (bottom) and the end of the melt (top) that was generated from the DSC data for compositions containing 2 (right), 3 (left), and mixtures containing percentages of each.
scanning calorimetry (DSC) was used to create a binary phase diagram illustrating the composition of the resulting solids (Figure 2).15 The DSC data supports the formation of a eutectic with 1:1 stoichiometry. The observed melting points for 2 and 3 are 72-77 °C and 68-71 °C, respectively, whereas the new solid has a melting point range of 42-50 °C. The other stoichiometries of 2 to 3 in these mixtures resulted in a broadened melting range and evidence of the eutectic composition being formed in all of the mixed samples. The solids from the cocrystallizations were powders unsuitable for single-crystal X-ray analysis but which were suitable for analysis by X-ray powder diffraction.
The X-ray powder diffraction data from 2, 3, and from a mixture having 1:1 stoichiometry of 2 to 3 are shown in Figure 3. The mixed sample contains only peaks identifiable in either parent compound, and the mixture is therefore best defined as being a eutectic rather than a cocrystal with a unique solid-state. This difference may be subtle in some cases, however, as a mechanical mixture of two solids is not necessarily the same as a eutectic.16 Cocrystallization directed by CH‚‚‚O edge interactions has been previously shown to occur between two different molecules, although the acidity of the C-H donor was greater in comparison to this work.17 The lack of cocrystallization to yield 2‚3 is possibly due to the similarity of molecular size and shape between these two compounds that could result in substitutions for one another as a cocrystalline aggregate forms or as the aggregates of either parent are formed. Coumarins form a variety of packing motifs in the solid-state. Similar edge associations to those formed in 1 have been among the intermolecular interactions previously observed in coumarin X-ray structures. For example, a CH‚‚‚O associated interaction has been noted for the coumarin 311 laser dye in the solid-state.18 The same intermolecular packing motif is also found in 7-methoxy-4-methylcoumarin, and this structure is used to illustrate this set of interactions (Figure 4).19 This motif is also present in other 4-methylcoumarins,11,20 where there are not competing strong interactions such as OH‚‚‚O hydrogen bonds from phenolic functional groups. Secondary forces have been previously shown to influence the formation and stabilization of intermolecular hydrogen bonding associations,3 yet no favorable secondary interactions would be predicted for the association found in 1.
Directed Intermolecular Association in 6-Methoxycoumarin
Figure 5. Two potential intermolecular edge associations for fumaric acid monoethyl ester with (a) the s-trans configuration of the carboxylic acid and (b) the s-cis configuration of the carboxylic acid. The s-trans configuration was found in the crystalline state.
Figure 6. Intermolecular interactions in the molecular packing of the crystal structure of 4.
The crystal structure of 4 was determined both to further probe the importance of secondary interactions in CH‚‚‚O directed edge associations and to support the predictability of CH‚‚‚O interactions in the presence of a stronger intermolecular force. The formation of a carboxylic acid dimer to yield an R22 (8) motif would be expected to be the strongest force directing association of the molecules in 4 (Figure 5).21 The s-cis or s-trans conformations in both an R,βunsaturated ester and an R,β-unsaturated acid are nearly equivalent energetically.22 Thus, these conformations may be influenced by both the local structure of a molecule in solution as well as the packing interactions that result in the solid-state. Association of the acid dimers through complementary CH‚‚‚O edge interactions could be dictated by the conformation of the alkene bond or a preference by the oxygen atoms participating in the CH‚‚‚O associations or both. Regardless, the secondary interactions resulting from the alternate donor and acceptor groups would be predicted to be unfavorable in either an s-trans (Figure 5a) or an s-cis (Figure 5b) conformation of the acid functional group. The size and shape of oxygenated molecules can influence their solid-state packing arrangement and the strength of their intermolecular associations,23 although size and shape differences are expected to be negligible between the similar packing possibilities shown in Figure 5. A representation of the crystal packing of 4 (Figure 6) shows that edge association occurs in the manner represented by Figure 5a. The carboxylic acid directs
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the formation of a strong hydrogen bonded dimer with OH‚‚‚O hydrogen bonds of 2.67 Å. The crystal packing of 4 also has three CH‚‚‚O interactions (3.36, 3.55, and 3.58 Å) that meet or approximate the distance criteria for these associations.4,5d,13 This supports the premise that CH‚‚‚O edge interactions can contribute to subsequent intermolecular association following the interaction of more strongly directing functional groups. Moreover, the seemingly unfavorable secondary interactions in 4 do not prevent edge association, just as observed in a previous cocrystal with a similar pattern of CH‚‚‚O interactions.17 It is too early to discern whether secondary interactions are in general less significant to intermolecular associations directed by CH‚‚‚O interactions than they are to stronger hydrogen bonding interactions. However, it seems reasonable that the comparatively long distances of the CH‚‚‚O interactions and the smaller bond polarizations for CH groups would result in a correspondingly smaller influence of secondary interactions. In summary, CH‚‚‚O interactions between complementary molecular edges can organize intermolecular association of molecules in the solid-state. These edges can also associate in the presence of stronger interactions, such as those formed by carboxylic acid dimers, provided the stronger association does not block the complementary edges from subsequent association. Secondary interactions do not appear to prevent the association of edges through CH‚‚‚O interactions, although their influence is not yet fully known. Acknowledgment. The crystallographic assistance of John Desper is appreciated. This work was supported by the National Science Foundation Grant EPS-9550487 with matching support from the state of Kansas. The financial support of the Department of Chemistry at Kansas State University is also greatly appreciated. Supporting Information Available: X-ray crystallographic information files (CIF) and tables with X-ray structural information for 1 and 4 are available. This material is free of charge via the Internet at http://pubs.acs.org.
References (1) (a) Aakero¨y, C. B.; Seddon, K. R. Chem. Soc. Rev. 1993, 397407. (b) Subramanian, S.; Zaworotko, M. J. Coord. Chem. Rev. 1994, 137, 357-401. (c) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311-2327. (d) Aakero¨y, C. B. Acta Crystallogr. 1997, B53, 569-586. (e) Anthony, A.; Desiraju, G. R.; Jetti, R. K. R.; Kuduva, S. S.; Madhavi, N. N. L.; Nangia, A.; Thaimattam, R.; Thalladi, V. R. Cryst. Eng. 1998, 1, 1-18. (f) Braga, D.; Grepioni, F. Acc. Chem. Res. 2000, 33, 601-608. (2) For examples of drug design hydrogen bond considerations, see (a) Bo¨hm, H.-J.; Klebe, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2588-2614. (b) Hubbard, R. E. Curr. Opin. Biotechnol. 1997, 8, 696-700. (c) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359-1472. (d) Wlodawer, A.; Vondrasek, J. Annu. Rev. Biophys. Biomol. Struct. 1998, 27, 249-284. (3) (a) Jorgenson, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008-2010. (b) Murray, T. J.; Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010-4011. (c) Zimmerman, S. C.; Murray, T. J. Philos. Trans. R. Soc. London A 1993, 345, 49-56. (d) Gardner, R. R.; Gellman, S. H. Tetrahedron 1997, 53, 9881-9890. (e) Beijer, F. H.; Kooijman, H.; Spek, A. L.;
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(4) (5)
(6) (7)
(8) (9)
(10)
(11)
Crystal Growth & Design, Vol. 2, No. 2, 2002 Sijbesma, R. P.; Meijer, E. W. Angew. Chem., Int. Ed. Engl. 1998, 37, 75-78. Desiraju, G. R. Acc. Chem. Res. 1996, 29, 441-449. (a) Wahl, M. C.; Sundaralingam, M. Trends Biochem. Sci. 1997, 22, 97-102. (b) Pascard, C. Acta Crystallogr. 1995, D51, 407-417. (c) Glusker, J. P. Acta Crystallogr. 1995, D51, 418-427. (d) Desiraju, G. R.; Steiner, T. In The Weak Hydrogen Bond in Structural Chemistry and Biology; Desiraju, G. R., Steiner, T., Eds.; Oxford University Press: New York, 1999; pp 343-440. Murray, R. D. H.; Me´ndez, J.; Brown, S. A. The Natural Coumarins. Occurrence, Chemistry and Biochemistry; John Wiley & Sons Ltd.: New York, 1982; pp 131-161. (a) Mukherjee, P. S.; Karnes, H. T. Biomed. Chromatogr. 1996, 10, 193-204. (b) Shobini, J.; Mishra, A. K.; Sandhya, K.; Chandra, N. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2001, 57, 1133-1147. (c) Nakamura, K.; Hanna, I. H.; Cai, H.; Nishimura, Y.; Williams, K. M.; Guengerich, F. P. Anal. Biochem. 2001, 292, 280-286. (d) Takakusa, H.; Kikuchi, K.; Urano, Y.; Higuchi, T.; Nagano. T. Anal. Chem. 2001, 73, 939-942. Perkin, W. H. J. Chem. Soc. 1868, 21, 53-63. The synthetic procedure is provided in the Supporting Information. mp 98.5-100 °C [Lit. (see ref 24) 98-99 °C]; 1H NMR [CDCl , Lit. (see ref 25) δ 7.67 (d, J ) 9.6 Hz, 1 3 H), 7.25 (d, J ) 8.0 Hz, 1 H), 7.12 (dd, J ) 8.0 Hz, J ) 3.0 Hz, 1 H), 6.92 (d, J ) 3.0 Hz, 1 H), 6.43 (d, J ) 9.6 Hz, 1 H), 3.86 (s, 3 H)]. Crystal Data for 1: C10H8O3, Mr ) 176.16, orthorhombic, Pnma, a ) 6.771(2) Å, b ) 6.454(2) Å, c ) 18.797(5) Å, R ) β ) γ ) 90°, V ) 821.4(4) Å3, Z ) 4. Data for 1 was collected at -70 °C on a Siemens P4 four-circle diffractometer with a Bruker SMART 1000 CCD to provide 688 reflections [Fo > 4σ(Fo)] out of 996 total reflections for final values of R ) 0.041 and Rw ) 0.059. Gnanaguru, K.; Ramasubbu, N.; Venkatesan, K.; Ramamurthy, V. J. Org. Chem. 1985, 50, 2337-2346.
Baures et al. (12) Crystal Data for 4: C6H8O4, Mr ) 144.12, triclinic, P-1, a ) 5.182(1) Å, b ) 5.850(1) Å, c ) 11.505(2) Å, R ) 91.28(1), β ) 99.12(1), γ ) 90.44(1)°, V ) 344.3(1) Å3, Z ) 2. Data for 4 was collected at -70 °C on a Siemens P4 four-circle diffractometer with a Bruker SMART 1000 CCD to provide 1321 reflections [Fo > 4σ(Fo)] out of 1515 total reflections for final values of R ) 0.042 and Rw ) 0.046. (13) Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982, 104, 50635070. (14) Steiner, T.; Desiraju, G. R. Chem. Commun. 1998, 891892. (15) The cocrystallization procedure and DSC collection parameters are provided in the Supporting Information. The DSC traces are also provided as Supporting Information. (16) (a) Rai, U. S.; Shekhar, H. Thermochim. Acta 1991, 175, 215-227. (b) Rai, U. S.; Rai, R. N. J. Therm. Anal. 1998, 53, 883-893. (17) Biradha, K.; Sharma, C. V. K.; Panneerselfvam, K.; Shimoni, L.; Carrell, H. L.; Zacharias, D. E.; Desiraju, G. R. J. Chem. Soc., Chem. Commun. 1993, 1473-1475. (18) Gavezzotti, A. Crystallogr. Rev. 1998, 7, 5-121. (19) Moorthy, J. N.; Venkatesan, K. J. Mater. Chem. 1992, 2, 675-676. (20) Vishnumurthy, K.; Guru, T. N.; Venkatesan, R. K. Tetrahedron 1998, 54, 11235-11246. (21) (a) Leiserowitz. L. Acta Crystallogr. 1976, B32, 775-802. (b) Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126. (22) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. In Basic Organic Stereochemistry; Eliel, E. L., Wilen, S. H., Doyle, M. P., Eds.; John Wiley & Sons: New York, 2001; p 394. (23) Gavezzotti, A. J. Phys. Chem. 1991, 95, 8948-8955. (24) Gu¨nther, H.; Prestien, J.; Joseph-Nathan, P. Org. Magn. Reson. 1975, 7, 339-344. (25) Joseph-Nathan, P.; Domı´nguez, M.; Ortega, D. A. J. Heterocycl. Chem. 1984, 21, 1141-1144.
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