Crystal-Packing-Driven Enrichment of Atropoisomers

Angewandte Chemie - International Edition

5 years ago

Crystal-Packing-Driven Enrichment of Atropoisomers

Natavan Dudkina, Joseph P. Campbell, Jianing Li, Danielle L. Gray, Toby J. Woods, Mona Sharafi, Sinu C. Rajappan, Severin T. Schneebeli

Crystal-packing forces can have a significant impact on the relative stabilities of different molecules and their conformations. The magnitude of such effects is, however, not yet well understood. Herein we show, that crystal packing can completely overrule the relative stabilities of different stereoisomers in solution. Heating of atropoisomers (i.e. “frozen-out” conformational isomers) in solution leads to complex mixtures. In contrast, solid-state heating selectively amplifies minor (<25 mole %) components of these solution-phase mixtures. We show that this heating strategy is successful for compounds with up to four rotationally hindered σ bonds, for which a single stereoisomer out of seven can be amplified selectively. Our results demonstrate that common supramolecular interactions—for example, [methyl⋅⋅⋅π] coordination and [C−H⋅⋅⋅O] hydrogen bonding—can readily invert the relative thermodynamic stabilities of different molecular conformations. These findings open up potential new avenues to control the folding of macromolecules. Turn up the amplification: Solid-state heating of a mixture containing seven atropostereo-isomers converts almost all its components into a single product. This process takes place, even though the amplified stereoisomer represents only a minor (<25 mol %) component of the mixture at equilibrium in solution. Favorable crystal-packing interactions induce the high selectivity observed in this process.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201701876