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A collaborative workshop was held in May 1999 at the Cambridge Crystallographic Data Centre to test how well currently available methods of crystal structure prediction perform when given only the atomic connectivity for an organic compound. A blind test was conducted on a selection of four compounds and a wide range of methodologies representing, the principal computer programs currently available were used. There were 11 participants who were allowed to propose at most three structures for each compound. No program gave consistently reliable results. However, seven proposed structures were close to an experimental one and were classified as "correct". One compound occurred in two polymorphs, but only one form was predicted correctly among the calculated structures. The basic problem with lattice energy based methods of crystal structure prediction is that many structures are found within a few kJ mol(-1) of the global minimum. The fine detail of the force-field methodology and parametrization influences the energy ranking within each method. Nevertheless, present methods may be useful in providing a set of structures as possible polymorphs for a given molecular structure.

A procedure to adapt electron densities of isolated molecules for the evaluation of intermolecular energies, first introduced in paper 1 (Gavezzotti, A. J. Phys. Chem. B 2002, 106, 4145) is here improved for polarization energy and extended to dispersion and repulsion terms. Dispersion is evaluated from atomic polarizabilities distributed over the electron density, using an average ionization potential taken as the energy of the highest occupied molecular orbital, in a London-type inverse sixth-power formulation. Repulsion is evaluated from the overlap between electron densities. The method, called semiclassical density sums (SCDS), requires only four disposable numerical parameters and allows a complete evaluation of intermolecular interaction energies for a rather wide range of molecular systems. Calculations on molecular dimers, in comparison with results obtained by high-level quantum chemical methods, show that SCDS energies are quite reliable, at a fraction of the computational cost. The sublimation energies of many organic crystals are well reproduced by the corresponding calculated lattice energies, which include significant polarization contributions. The method allows a partitioning of intermolecular interactions over molecular pairs in crystals; this in turn allows for the first time a quantitative assessment of the relative importance of Coulombic, repulsion, and dispersion energies in the interaction between atom groups and in crystal packing in general, often contradicting some current views based on intuitive or even semiquantitative electrostatic models that do not include penetration terms.

A total of 204 pairs of different crystal structures for the same organic molecule (polymorphs), determined at room conditions, were retrieved from the Cambridge Structural Database. Crystallographic, chemical, and pharmaceutical aspects of the phenomenon were considered. Correlations between differences in density, calculated packing energy, and lattice-vibrational entropy, and other crystal properties, are presented. Indices to quantify conformational polymorphism and differences in coordination sphere in the crystal are proposed. Differences in lattice-vibrational entropy between polymorphs are seldom, if ever, large enough to equal or to exceed differences in packing energy (enthalpy) at room temperature. Although few experimental estimates of energy differences between polymorphs are available, the overall results and some detailed comparisons with calculated lattice energies confirm the good performance of the parameters of the crystal potential. A tentative polymorph for aspirin is proposed by a structure generation procedure. The occurrence of polymorphism in organic crystals is very frequent, if the proper temperature range is explored, but at room conditions, the appearance of several polymorphic forms is not as pervasive as it is sometimes said to be.