Design and Preparation of Co‐crystals Utilizing the ${{\bf R}{{ \bf 2\hfill \atop \bf 4\hfill}}}$ (8) Hydrogen‐Bonding Motif

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 ${{\rm{R}}_4^2 (8)}$ 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 ${{\rm{R}}_4^2 (8)}$ motif.