Predictions of substituent effects in thermal azide 1,3-dipolar cycloadditions: implications for dynamic...

Substituent effects in 1,3-dipolar cycloadditions of azides with alkenes and alkynes were investigated with the high-accuracy CBS-QB3 method. The possibilities for noncatalytic activation and the reversibility or irreversibility of these reactions was explored; the possibilities for uses in dynamic combinatorial chemistry (DCC) or click chemistry were explored. The activation enthalpies for reactions of ethylene and acetylene with hydrazoic acid, formyl, phenyl-, methyl-, and methanesulfonylazides exhibit modest variation, with Delta H++ ranging from 17 to 20 kcal/mol. A detailed study of formylazide cycloadditions with various alkenes and alkynes reveals a narrow range of activation enthalpies (17-21 kcal/mol). The activation enthalpies for the reactions of azides with alkenes and alkynes are similar. FMO theory and distortion/interaction energy control have been used to rationalize the rates and regiochemistries of cycloadditions involving alkene dipolarophiles. Significantly, triazoles, formed from alkynes, are 30-40 kcal/mol more stable than tetrazolines formed from alkenes. On the basis of initial reactant concentrations, kinetic and thermodynamic values are suggested for the identification of reversible reactions that approach equilibrium over 24 h, as well as for fast irreversible reactions. Although azide cycloadditions are suitable for irreversible chemistry and are typically unsuitable for reversible applications, theoretical procedures established by these studies have provided guidelines for the prediction of useful reversible libraries.