US EPA

1548962 

Journal Article 

Predictions of substituent effects in thermal azide 1,3-dipolar cycloadditions: Implications for dynamic combinatorial (reversible) and click (irreversible) chemistry 

Jones, GO; Houk, KN 

2008 

Yes 

Journal of Organic Chemistry
ISSN: 0022-3263
EISSN: 1520-6904 

73 

4 

1333-1342 

18211089 

10.1021/jo702295d 

WOS:000253152700018 

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(double dagger) 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.