Hydrogen Bond Hierarchy: Persistent Phenol···Chloride Hydrogen Bonds in the Presence of Carboxylic Acid Moieties
datasetposted on 02.09.2015, 00:00 authored by Naga Kiran Duggirala, Geoffrey P. F. Wood, Addison Fischer, Łukasz Wojtas, Miranda L. Perry, Michael J. Zaworotko
Crystal engineering strategies have been delineated during the past decade for the design of multi-component molecular crystals (molecular cocrystals, MCCs). However, the same depth of understanding has not yet been established for cocrystals that are comprised of at least one ionic compound (ionic cocrystals, ICCs). We address this long known but understudied class of cocrystals through the use of organic cation chloride salts as cocrystal formers with carboxylic acids and phenols. Such ICCs are of particular interest for both fundamental and applied reasons. With respect to the former, carefully selected molecular cocrystal formers (coformers) enable systematic study of the hierarchy of hydrogen bonds. With respect to the latter, chloride anions, phenol groups, and carboxylic acid moieties are prevalent in biologically active drug substances and nutraceuticals. In this contribution, we evaluated the propensity to form chloride···carboxylic acid vs chloride···phenol hydrogen bonds (supramolecular heterosynthons) through a combination of Cambridge Structural Database (CSD) data mining and the structural characterization of 12 novel ICCs, including 4 hydrates containing carboxylic acids, phenol groups, and chloride anions. Our analysis of these 12 ICCs and the 9 relevant entries (including 4 hydrates) archived in the CSD reveals that charge-assisted hydrogen bonds between phenol moieties and chloride anions persist even in the presence of carboxylic acid moieties, which form carboxylic acid dimers in 11/21 crystal structures. Carboxylic acid···chloride supramolecular heterosynthons occur in just 4/21 structures. These observations are supported by lattice energy calculations and hydrogen bond strengths derived from density functional theory calculations. That phenol groups are better suited than carboxylic acid moieties to form ionic cocrystals with chloride salts has important implications for the design of drug substances with improved properties since chloride salts are so prevalent as drug substances. This observation also questions the widespread reliance upon pKa values to predict hydrogen bond strengths.
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4 hydrates12 novel ICCschloride saltsHydrogen Bond Hierarchyhydrogen bond strengthscarboxylic acidscocrystal formersCSDcarboxylic acid moietiesphenol groupslattice energy calculationsdrug substanceschloride anionsMoietiesCrystal engineering strategiesCambridge Structural Databaseform carboxylic acid dimerscation chloride saltsMCC