Regio- and Stereoselectivity in 1,3-Dipolar Cycloadditions: Activation Strain Analyses for Reactions of Hydrazoic Acid with Substituted Alkenes.

We quantum chemically explore and analyze 1,3-dipolar cycloadditions of hydrazoic acid and methyl azide with a number of substituted alkenes R-HC=CH2 (R = CH3, OH, OCH3, NH2, CN, and NO2) by using dispersion-corrected DFT at wB97XD/ 6-311++G(d,p). Our purpose is to uncover the physical factors behind the computed trends in reactivity, regioselectivity (1,4 vs. 1,5 addition), and preferred stereochemistry (endo vs. exo). To this end, we use the activation strain model (ASM) and quantitative molecular orbital (MO) theory. One of our main findings is that introducing electron-donating groups in the dipolarophile, R = CH3, OH, OCH3, or NH2, favors the 1,5-cycloaddition. On the other hand, the presence of electron-withdrawing groups, R = CN or NO2, leads to 1,4-addition. Besides, we find a general preference for endo addition, a result that consolidates the endo rule. Trends in the regiochemistry are dictated by the inverse and regular HOMO–LUMO gap, respectively, between dipole and dipolarophile. [ABSTRACT FROM AUTHOR]