Acceleration and Selectivity of 1,3-Dipolar Cycloaddition Reactions Included in a Polar [4 + 2] Octa-imine Bis-calix[4]pyrrole Cage

We describe the quantitative
self-assembly (>90%) of a [4 + 2]
octa-imine cage (1) in a CDCl3:CD3CN 9:1 solvent mixture containing 0.5% of acetic acid. Cage 1 is based on two identical aryl-extended calix[4]pyrrole
units linked through eight dynamically reversible imine bonds. Cage 1 forms thermodynamically and kinetically highly stable inclusion
complexes featuring 1:1 and 2:1 stoichiometry with suitable para-substituted pyridine-N-oxides. The
ability of 1 for the pairwise inclusion of two different
pyridine-N-oxides led us to investigate its properties
as a reactor vessel. The coinclusion of 4-azido pyridine-N-oxide and 4-ethynyl pyridine-N-oxide did not produce
a detectable acceleration of their 1,3-dipolar cycloaddition reaction.
Conversely, the coinclusion in cage 1 of the same alkyne
dipolarophile with 4-azido(alkyl) pyridine-N-oxides
(alkyl= methyl, ethyl) produced significant reaction acceleration.
We quantified the reactions’ acceleration with an effective
molarity (EM) of ∼103 M, corresponding to the more
prominent reported value of a bimolecular 1,3-dipolar cycloaddition
reaction in a molecular vessel by directly detecting the ternary Michaelis
complex. The included reactions are quantitative and regioselective,
yielding exclusively the 1,4-disubstituted triazole isomers. We propose
that the selectivity of 1 in accelerating the included
1,3-dipolar cycloadditions is related to (a) the entropy gain provoked
by the reaction’s inclusion, (b) the rigidity of the container,
and (c) the spatial fixation of the polar knobs (pyridine-N-oxide) carrying the reacting groups in its two functionalized
hemispheres. The two latter characteristics render the distance between
the reacting groups (azido and ethynyl) almost fixed by design, thus
allowing or not achieving the transition state’s geometry.
We support our hypothesis with the help of DFT calculations of the
inclusion complexes’ structures.