Design and preparation of co-crystals utilizing the R(4)(2)(8) hydrogen-bonding motif

Chemistry : a European Journal
Joel BernsteinSebastian A Cirkel

Abstract

An investigation of the feasibility of utilizing a specific, and previously largely unrecognized, hydrogen-bonded synthon for the design and preparation of co-crystals is reported. Structural evidence (i.e., >12,000 instances) indicated the robustness of the cyclic R(4)(2)(8) hydrogen-bonded motif containing, in most cases, four individual (either identical or different) molecules, in which the donor substituent (e.g., an amine) can provide two hydrogen-bond donors, and the acceptor (e.g., a carbonyl oxygen) can provide two hydrogen-bond acceptors. The energetic robustness of the motif with respect to chemical substitution and charge on the component molecules was investigated and confirmed in a series of fully optimized calculations at the MP2/6-31+G(d) level. A proof-of-concept experiment to prepare a co-crystal between a prototypical ketone and a primary amine yielded the crystal structure reported herein, in which the hydrogen bonds between the co-crystal components indeed exhibit exclusively the designed and sought-after R(4)(2)(8) motif.

References

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Citations

Oct 23, 2014·Chemistry : a European Journal·Rachel GraingerJosep M Campanera
Feb 6, 2019·Acta Crystallographica. Section C, Structural Chemistry·Eynav KatsAndreas Lemmerer
Apr 22, 2015·The Journal of Pharmacy and Pharmacology·Neil FeederRobert Docherty
Jun 12, 2013·Journal of the American Chemical Society·Gautam R Desiraju

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