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 <i>cis</i>-<i>N,N'</i>-cyclohexa-1,2-diylurea formation of <i>inverted-cis</i>-cyclohexanohemicucurbit[6]uril
(<i>i-cis</i>-cycHC[6]) can be induced at
the expense of thermodynamically favoured <i>cis</i>-cyclohexanohemicucurbit[6]uril
(<i>cis</i>-cycHC[6]). The formation of <i>i-cis-</i>cycHC[6] 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[6] macrocycles
from the equilibrating solution by precipitation. Notably, the <i>i-cis</i>-cycHC[6] was isolated with 33%
yield. Different binding affinities of three diastereomeric <i>i-cis</i>-, <i>cis</i>-cycHC[6] and their chiral isomer (<i>R,R</i>)-cycHC[6] for trifluoroacetic acid demonstrate the influence of
macrocycle geometry on complex formation.