Effect of Fluorination on Molecular Conformation in the Solid State: Tuning the Conformation of Cocrystal Formers

We present a detailed analysis of the effect of fluorination on the conformation of perfluorosuccinic acid in the solid state, using database analysis, crystal structure determination, and computational analysis of molecular conformations. Our results indicate that perfluorosuccinic acid exhibits strikingly different conformational preferences to its hydrocarbon analogue despite similarity in molecular size. This difference in conformational behavior also extends to the pair of adipic and perfluoroadipic acids. A search of the Cambridge Structure Database indicates that our analysis is valid for neutral molecules, salts, cocrystals, and metal organic materials, suggesting fluorination as a general means to modify the shape of a molecular building block without changing its size. The difference in molecular shape between hydrocarbon and perfluorocarbon molecules is expected to lead to significant differences in solid-state structures of the resulting materials. We illustrate this by comparing the structures of new multicomponent crystals involving the model pharmaceutical ingredient caffeine and perfluorosuccinic or perfluoroadipic acid with the structures of analogous crystals based on the hydrocarbon diacids. Unlike hydrocarbon-based succinic and adipic acids which provide structurally similar hydrogen-bonded cocrystals and inclusion hosts with caffeine, perfluorosuccinic acid provides a salt and perfluoroadipic acid yields a cocrystal. Combined crystal structure analysis, solid-state and solution NMR analysis, single molecule conformational analysis, and calculations of acid dissociation energies indicate that the different solid-state behaviors of perfluoro- and hydrocarbon acids toward caffeine should be interpreted as a result of their distinct conformational properties rather than differences in pK(a) values.