Topological Analysis of Charge Density Distribution in Concomitant Polymorphs of 3-Acetylcoumarin, A Case of Packing Polymorphism Parthapratim Munshi and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560012, India ReceiVed September 20, 2005; ReVised Manuscript ReceiVed December 9, 2005 ABSTRACT: Detailed investigation of the charge density distribution in concomitant polymorphs of 3-acetylcoumarin in terms of experimental and theoretical densities shows significant differences in the intermolecular features when analyzed based on the topological properties via the quantum theory of atoms in molecules. The two forms, triclinic and monoclinic (Form A and Form B), pack in the crystal lattice via weak C-H‚‚‚O and C-H‚‚‚π interactions. Form A results in a head-to-head molecular stack, while Form B generates a head-to-tail stack. Form A crystallizes in P1 h (Z′ ) 2) and Form B crystallizes in P2 1 /n (Z′ ) 1). The electron density maps of the polymorphs demonstrate the differences in the nature of the charge density distribution in general. The charges derived from experimental and theoretical analysis show significant differences with respect to the polymorphic forms. The molecular dipole moments differ significantly for the two forms. The lattice energies evaluated at the HF and DFT (B3LYP) methods with 6-31G** basis set for the two forms clearly suggest that Form A is the thermodynamically stable form as compared to Form B. Mapping of electrostatic potential over the molecular surface shows dominant variations in the electronegative region, which bring out the differences between the two forms. Introduction Polymorphism in molecular crystals has received considerable attention in recent years particularly from the point of view of “drug design”, 1,2 which demands an unequivocal characterization of all possible crystalline forms of a drug material. It is in this context that the studies of concomitant polymorphism (in which crystallization occurs simultaneously from the same solvent and in the same crystallizing flask under identical crystal growth conditions) in a given material gains paramount significance. In general, polymorphs are classified into three major categories based on the geometry of molecular assembly in the crystal lattice. Of these, conformational polymorphism, which involves changes at the molecular level, occurs predominantly in flexible molecules. In the case of rigid molecules, the differences occur mainly in the packing motifs directed by the intermolecular interactions, which results in packing polymorphism. The third category is a consequence of the presence of solvent molecules in the crystal lattice, referred to as pseudo or solvato-morphism, which involves large changes in crystal density and packing. A significant number of molecules exhibit polymorphism, as can be seen from an analysis of the entries in the Cambridge Structural Database (CSD). 3 In the recent literature, several careful studies have been made to evaluate the role of the solvent in the formation of polymorphism. These highlight the impor- tance of the kinetics in solution rather than the formation of molecular assemblies. 4 In the case in which specific thermo- dynamic conditions result in a crystallization process, which has nearly similar rates in kinetics, two or more polymorphs may appear resulting in the phenomena of concomitant poly- morphism. 2,5 The nearly equivalent crystal energetics involved in the generation of concomitant polymorphs provides excellent and demanding benchmarks for theoretical and computational models. 6 One of the important questions that arises is to understand the energetics involved in concomitant polymor- phism on the basis of the specific intermolecular interactions. Determination of the lattice energy in the vicinity of the molecule, either by appropriate computational (theoretical) methods or by careful analysis of the charge density distribution via accurate experimental measurements, may provide the appropriate answer. Charge density analysis is an attractive tool to study a wide range of problems of physical and chemical interest. 7 All ground-state properties are unique functionals of the charge density based on the Hohenberg-Kohn theorem, 8 which provides pointers to the importance of charge density features in molecular crystals. An understanding of the phenomena of polymorphism in terms of charge density distributions has received some interest in recent times 9-12 with the realization that geometrical arrangements in crystal lattices are significantly guided by thermodynamic and kinetic factors. In literature, the study of polymorphic structures from the charge density point of view are rare with only one experimental electron density study on two markedly different molecular conformations of famotidine 9 and two other cases of packing polymorphs, one on p-nitrophenol 10 and the other on 5-nitrouracil. 11 There is just one example of an inorganic polymorph [antimony (III) oxide] studied via charge density analysis. 12 In the case of packing polymorphism, the contribution to the difference in the total lattice energy arises mainly from intermolecular interactions, and such values can only be quantitatively evaluated either from experimental or theoretical charge densities. The appearance of concomitant polymorphs presents an ideal case for charge density analysis since the conclusions based on electrostatic potentials, lattice energies, and interaction pathways could provide insights into the subtle interplay between the thermo- dynamic and the kinetic factors. Here we report the first case study of concomitant polymor- phism in 3-acetylcoumarin in terms of the topological analysis of charge densities derived from both experimental and theoreti- cal studies. 3-Acetylcoumarin crystallizes concomitantly in two forms as earlier reported by us, 13 and the intermolecular interactions are essentially C-H‚‚‚O and C-H‚‚‚π, which are responsible for arranging a head-to-head stacking in Form A and a head-to-tail stacking in Form B. Interestingly, Form A provides an opportunity to study a system with two crystallo- * To whom correspondence should be addressed. Professor T. N. Guru Row, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore - 560012, India. Tel: +91-80-22932796. Fax: +91-80- 23601310. E-mail: ssctng@sscu.iisc.ernet.in. CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 3 708 - 718 10.1021/cg050484g CCC: $33.50 © 2006 American Chemical Society Published on Web 02/10/2006