H ₂ O ₂ /HBr assisted metal-free oxidative debenzylation of 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane: optimization of reaction parameters via central composite design

This study systematically investigated the metal-free oxidative debenzylation of 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane to 2,6,8,12-tetraacetyl- 2,4,6,8,10,12-hexaazaisowurtzitane using an H2O2/HBr system was systematically optimized by response surface methodology. A face-centered central composite design enabled reliable modeling of the reaction within experimentally feasible boundaries. The resulting quadratic model showed high statistical significance and predictive accuracy, with analysis of variance confirming that H2O2 concentration, H2O2 equivalents, HBr equivalents, and reaction temperature all significantly influence the reaction outcome. Notably, reaction temperature exhibited a pronounced curvature effect, defining an optimal operational window beyond which the yield decreased. Numerical optimization predicted optimal conditions of approximately 60% H2O2, 20 equivalents of H2O2, 10 equivalents of HBr, and a reaction temperature of ~53 °C, corresponding to a predicted yield of about 79%. Experimental validation under these conditions provided reproducible yields of 76–77%, confirming the robustness and reliability of the developed model. Overall, this work establishes an efficient, metal-free, and environmentally compatible strategy for the oxidative debenzylation of TADBIW under mild conditions.