Cycloaddition Reactions: Design Principles from Quantum Chemical Analyses

Cycloaddition reactions provide facile access to cyclic compounds with a high atom economy. As such, these reactions have found applications in almost all fields of chemistry, including organic synthesis, material science, medicinal chemistry, and biological chemistry. In particular, the most studied and useful concerted cycloadditions (pericyclic reactions) are the Diels-Alder reaction and 1,3-dipolar cycloaddition. A systematic understanding of the reactivity, regio- and stereo-selectivity of pericyclic reactions is a prerequisite for the rational design of these reactions. This thesis is dedicated to a study of four critical factors that are used to tune the reactivity of pericyclic reactions: the heteroatom, geometry of the reactant, catalyst, and external electric field. These factors are studied by performing computational studies on four representative Diels-Alder reactions or 1,3-dipolar cycloadditions using DFT calculations and quantum chemical analyses, including the activation strain model (ASM), energy decomposition analysis (EDA) and quantitative Kohn-Sham molecular orbital (KS-MO) theory. Our findings based on these analyses furnish fundamental insights into how these internal and external factors alter the reactivity of cycloaddition reactions.