Crystal-Structure Prediction DOI: 10.1002/ange.201007488 Molecule VI, a Benchmark Crystal-Structure-Prediction Sulfonimide: Are Its Polymorphs Predictable?** H.C. Stephen Chan, John Kendrick, and Frank J. J. Leusen* Many organic compounds are known to crystallize in more than one distinct crystal structure, a phenomenon known as polymorphism, [1] which can cause problems but also offers exploitation opportunities because of the variation in physical properties among polymorphs. The ability to predict the crystal structures of a compound would make a significant contribution to crystal engineering. In 1988, John Maddox commented that the general failure in crystal-structure prediction (CSP) remained as “one of the continuing scandals in physical sciences”. [2] Since then, steady progress has been made. To assess the technological advances in CSP, a series of blind tests was organized by the Cambridge Crystallographic Data Centre. In the 2007 blind test a new approach correctly predicted, for the first time, all four target structures. [3] This result was achieved using a DFT(d) method which combines density functional theory simulations and an empirical correction for dispersive forces. [4] Recently, we used the same methodology to re-evaluate the lattice energies and energy rankings of the experimental structures and all submitted predictions in the 1999, 2001, and 2004 blind tests, with very encouraging results. [5] None of the 2001 blind-test participants had predicted the then only known experimental structure (form I, a Z’ = 1 structure) of molecule VI (6-amino-2- phenylsulfonylimino-1,2-dihydropyri- dine, see Scheme 1). [6] Two additional polymorphs, forms II [7] (a Z’ = 2 struc- ture) and III [8] (a Z’ = 1 structure), were discovered after the 2001 blind test. Neither of these new structures had been reported by the blind-test participants. It was concluded that CSP had failed because the observed polymorphs were kinetically favored and the methods used in CSP are designed to locate thermodynamically favored forms. [7–9] These findings have led to comments on the state of CSP [9–11] and it was suggested that “structure prediction, which would be most valuable for Scheme 1. The molecu- lar structure of mole- cule VI from the 2001 blind test. Figure 1. Superpositions of the experimental (black) and the predic- ted (white) structures of a) form I, b) form II, and c) form III. All images are viewed along the b axis. See also Supporting Information. [*] H. C. S. Chan, Dr. J. Kendrick, Dr. F. J. J. Leusen School of Life Sciences, University of Bradford Bradford, BD7 1DP (UK) Fax: (+ 44) 1274-236155 E-mail: f.j.j.leusen@bradford.ac.uk [**] We thank Avant-garde Materials Simulation for providing a courtesy license to the GRACE software package and the School of Life Sciences at the University of Bradford for funding this project. Molecule VI is 6-amino-2-phenylsulfonylimino-1,2-dihydropyridine. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201007488. Angewandte Chemie 3035 Angew. Chem. 2011, 123, 3035 –3037  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim