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

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.