Acceleration and Regioselectivity Switching in 1,3-Dipolar Cycloaddition Reactions Confined in A Bis-Calix[4]pyrrole Cage

Abstract

We report the results of our investigations on the role of the octa-imine bis-calix[4]pyrrole cage 1 in mediating confined 1,3-dipolar cycloaddition reactions of a series of 4-azido(alkyl)-pyridine-N-oxides (alkyl = null, Me, Et; 2a-c) with 1-(2-propynyl)-4(1H)-pyridinone (4). We performed 1H NMR binding studies of the different substrates with the octa-imine cage, evidencing the formation of thermodynamically and kinetically highly stable inclusion homo-complexes featuring 1:1 and 2:1 stoichiometry. We used simulated speciation profiles and performed ITC experiments to thermodynamically characterize the formed complexes. Adding mixtures of an azido-derivative with the propynyl-pyridinone in a solution of cage 1 resulted in the formation of the expected 1:1 and 2:1 homo-complexes, and allowed the detection and characterization of the corresponding ternary hetero-complexes (Michaelis) in solution, 2•4⊂1. The azide-alkyne cycloaddition reactions are significantly accelerated by confinement of the reactants in cage 1. We assessed the reactions’ acceleration factor by determining their effective molarities (EM = kintra/kbulk). We derived the kintra values from the best-fit computer simulation of an elaborated theoretical kinetic model to the experimental kinetic data. The determined EM values range from 2000 to 70 M depending on the length of the azido(alkyl) spacer. Notably, we observed a complete switching in the regioselectivity of the confined cycloaddition reactions. That is, the confined reaction is stereoselective for the 1,4-isomer of the triazole adduct of the 4-azido pyridine-N-oxide derivative 2a, but turns stereoselective for the 1,5-counterpart for the azido(methyl) and azido(ethyl) derivatives, 2b and 2c. We used the computed DFT structures of the inclusion complexes to rationalize our findings.