Torsional and Electronic Factors Control the C−H⋅⋅⋅O Interaction

The precise role of non-conventional hydrogen bonds such as the C-H⋅⋅⋅O interaction in influencing the conformation of small molecules remains unresolved. Here we survey a series of β-turn mimetics using X-ray crystallography and NMR spectroscopy in conjunction with quantum calculation, and conclude that favourable torsional and electronic effects are important for the population of states with conformationally influential C-H⋅⋅⋅O interactions. Our results also highlight the challenge in attempting to deconvolute a myriad of interdependent noncovalent interactions in order to focus on the contribution of a single one. Within a small molecule that is designed to resemble the complexity of the environment within peptides and proteins, the interplay of different steric burdens, hydrogen-acceptor/-donor properties and rotational profiles illustrate why unambiguous conclusions based solely on NMR chemical shift data are extremely challenging to rationalize.