Formation and Trapping of the Thermodynamically Unfavoured Inverted-Hemicucurbituril
2019-04-11T15:05:43Z (GMT) by
Amplification of a thermodynamically unfavoured macrocyclic product through the directed shift of the equilibrium between dynamic covalent chemistry library members is difficult to achieve. We show for the first time that during condensation of formaldehyde and cis-N,N'-cyclohexa-1,2-diylurea formation of inverted-cis-cyclohexanohemicucurbituril (i-cis-cycHC) can be induced at the expense of thermodynamically favoured cis-cyclohexanohemicucurbituril (cis-cycHC). The formation of i-cis-cycHC is enhanced in low concentration of the templating chloride anion and suppressed in excess of this template. We found that reaction selectivity is governed by the solution-based template-aided dynamic combinatorial chemistry and continuous removal of the formed cycHC macrocycles from the equilibrating solution by precipitation. Notably, the i-cis-cycHC was isolated with 33% yield. Different binding affinities of three diastereomeric i-cis-, cis-cycHC and their chiral isomer (R,R)-cycHC for trifluoroacetic acid demonstrate the influence of macrocycle geometry on complex formation.