Melting-points of the meta- and para-isomers of anisylpinacolone Srinivasan S. Kuduva, 1 Jagarlapudi A. R. P. Sarma, 2 Amy K. Katz, 3 H. L. Carrell 3 and Gautam R. Desiraju 1 * 1 School of Chemistry, University of Hyderabad, Hyderabad 500 046, India 2 Molecular Modelling Group, Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India 3 Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111, USA Received 20 March 2000; revised 29 June 2000; accepted 3 July 2000 ABSTRACT: The generally higher melting-point of a para-disubstituted benzene relative to the corresponding meta- isomer has been ascribed to the fact that, being more symmetrical, it can pack more tightly. Exceptionally, it was observed that whereas m-anisylpinacolone melts at 58.0 °C, the para-isomer melts lower at 39.5 °C. In this work we have attempted to understand this apparent anomaly. The crystal structures of both isomers were determined and the packing analysed. Energy calculations of the static structures and molecular dynamics (MD) simulations at temperatures just below the respective melting-points were performed. The structure analyses indicate that the intermolecular contacts are comparably weak in the two cases, and do not appear to be the direct cause of the melting- point difference. Thermal motion analysis, packing energies and MD simulations on minicrystals indicate the importance of both enthalpic and entropic factors in the melting behaviour of the two isomers. The higher melting point of the meta-isomer could originate from both a smaller DS f and higher DH f relative to the para-isomer. Copyright  2000 John Wiley & Sons, Ltd. Additional material for this paper is available from the epoc website at http://www.wiley.com/epoc KEYWORDS: anisylpinacolone; melting-point; crystal structure; intermolecular interactions; packing energy; enthalpy; entropy; molecular dynamics INTRODUCTION Determination of melting-points is a simple experimental technique, used to establish compound purity, but the melting phenomenon itself has always been an enigma to structural chemists. 1–3 Can one correlate molecular structure with melting-point? If so, how? These questions have practical significance but are difficult to answer because the rationalization of a melting-point requires a thorough understanding not only of the strength and nature of the various intermolecular interactions in the crystal, but also of other factors such as the size, shape and symmetry of the molecule. However, some general- izations may be useful: (1) hydrogen bonding increases the melting-point; (2) the melting-point increases with increasing size of the molecule; (3) for disubstituted benzenes the para-isomer has a higher melting-point than the meta-isomer. The hydrogen bond is a strong intermolecular interaction and is highly electrostatic, even with some covalent character. Therefore, it is associated with an increase in melting-point. An increase in molecular size will lead to an increase in the van der Waals interactions and this results in a higher melting- point. Finally, the relatively more symmetrical para- isomer of a disubstituted benzene supposedly packs more JOURNAL OF PHYSICAL ORGANIC CHEMISTRY J. Phys. Org. Chem. 2000; 13: 719–728 Copyright  2000 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2000; 13: 719–728 *Correspondence to: G. R. Desiraju, School of Chemistry, University of Hyderabad, Hyderabad 500 046, India. E-mail: desiraju@uohyd.ernet.in Contract/grant sponsor: NIH; Contract/grant number: CA10925. epoc