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This is a great personal favourite because it illustrates a clear link between two worlds that I enjoy working in – quantum chemistry and crystal structures.  Both of these are rich sources of information about drug-like molecules. A particular challenge that both face is whether they are relevant to the behavior of molecules in solution.  In this paper, the question of whether the two at least agree with one another is addressed and is pleasingly positive – as you can see in the figure in which the curve is the energy variation with dihedral angle (computed at the RHF/STO-3G level) and the columns are the frequency that each dihedral range is observed in crystal structures.  This evolved towards the MOGUL tool from the Cambridge Crystallographic Database Centre.  A follow up (DOI: 10.1039/c2ce25585e) probed the extent to which the solid state influences the observed torsional preferences in crystal structures and found this to be an infrequent concern.  For those interested in understanding the conformational preferences of molecules the approaches presented here are a great starting point.  Presumably if the preferences hold in the gas phase (in the quantum calculations) and the solid state (in crystal structures) there is a high likelihood of a similar preference prevailing in solution.


Comparison of conformer distributions in the crystalline state with conformational energies calculated by ab initio techniques. Allen, F. H.; Harris, S. E.; Taylor, R.  J. Comput.-Aided. Mol. Design 1996, 10, 247-254.


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