Understanding the mechanism and regioselectivity of the copper(i) catalyzed [3 + 2] cycloaddition reaction between azide and alkyne: a systematic DFT study

Abstract

The copper(i) catalyzed azide-alkyne [3 + 2] cycloaddition (32CA) reaction and its uncatalyzed version have been studied for systematic understanding of this relevant organic transformation, using DFT calculations at the B3LYP/6-31G(d) (LANL2DZ for Cu) computational levels. In the absence of a copper(i) catalyst, two regioisomeric reaction paths were studied, indicating that the 32CA reaction takes place through an asynchronous one-step mechanism with a very low polar character. The two reactive channels leading to 1,4- and 1,5-regisomer present similar high activation energies of 18.84 and 18.51 kcal mol^-1, respectively. The coordination of copper(i) to alkyne produces relevant changes in this 32CA reaction. Analysis of the global and local electrophilicity/nucleophilicity allows explaining correctly the behaviors of the copper(i) catalyzed cycloaddition. Coordination of the copper to alkyne changes the mechanism from a non-polar one-step mechanism to a polar stepwise one, as a consequence of the high nucleophilic character of the dinuclear Cu(i)-acetylide complex. Parr and Fukui functions and Dual Descriptor correctly explain the observed regioselectivity by means of the most favorable two-center interaction that takes place along the 1,4 reaction path.

Scheme 1. Uncatalyzed thermal (A) and copper(i) catalyzed (B) azide–alkyne 32CA reaction.

Fig. 1. Early CuAAC mechanism proposed by Sharpless and Fokin.

Fig. 2. Recent CuAAC mechanism proposed by Fokin.

Fig. 3. Local nucleophilicites N_k, (in eV in blue) and local electrophilicites ω_k (in eV in red) calculated using Parr function.

Fig. 4. Calculated energy (kcal mol⁻¹) barriers for the uncatalyzed thermal azide–alkyne 32CA reaction in absence of copper(i) species.

Fig. 5. Optimized geometries of the regioisomeric TSs, TS14 and TS15, associated with the uncatalyzed 32CA reaction of methyl azide and propyne. The distances are given in Å.

Fig. 6. Schematic representation (energy (kcal mol⁻¹) vs. reaction coordinate) of the reaction of copper(i)-catalyzed 32CA between methyl azide and propyne (bold numbers for gas phase and numbers between brackets for water as reaction medium).