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

Abstract

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 wB97X‐D/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.

Is DFT Accurate Enough to Calculate Regioselectivity? The Case of 1,3‐Dipolar Cycloaddition of Azide to Alkynes and Alkenes

“…In the other cases, especially for R=Me, low levels of regioselectivity are predicted. It is noteworthy that the qualitative regioselectivity predictions about the HN 3 +H 2 C=CH−R 1,3‐DCs based on the W n protocols agree, not only with recent B3LYP results, [12] but also with those based on the CNDO/2 MO coefficients published 50 years ago and the experimental data therein cited [6,7] …”

The 1,3‐Dipolar Cycloaddition: From Conception to Quantum Chemical Design

“…Vilhena et al computationally investigated the 1,3-DCA reaction of hydrozoic acid with various substituted alkenes (RÀ HC=CH 2 , where R = CH 3 , OH, OCH 3 , NH 2 , CN, and NO 2 ) at ωB97X-D/6-311 + + G(d,p). [10] Three main reactivity trends were observed. Firstly, dipolarophiles with electron-donating substituents exhibited a lower activation barrier for the 1,5-cycloaddition than for the 1,4-cycloaddition, whereas electron-withdrawing substituents switched the preference towards the 1,4cycloaddition (Scheme 3).…”

“…Vilhena et al . computationally investigated the 1,3‐DCA reaction of hydrozoic acid with various substituted alkenes (R−HC=CH 2 , where R=CH 3 , OH, OCH 3 , NH 2 , CN, and NO 2 ) at ωB97X‐D/6‐311++G(d,p) [10] . Three main reactivity trends were observed.…”

1,3-Dipolar Cycloadditions by a Unified Perspective Based on Conceptual and Thermodynamics Models of Chemical Reactivity

“…Experimentally and computationally, this cycloaddition reaction has been widely investigated during the last decades. − ,− Deeper insight into the factors controlling both its kinetic feasibility and orientation mode have emerged by means of several interpretative tools; e.g., the frontier molecular orbital (FMO) theory , indicates whether the reactions are or are not allowed by conservation of orbital symmetry in accordance with the Woodward–Hoffmann rules . Furthermore, FMO classifies the reactions as HOMO- or LUMO-controlled resembling the normal (NED) or inverse (IED) electron demand in Diels–Alder reactions, respectively, as the interaction originates between occupied orbitals of 13D with unoccupied orbitals of d or between unoccupied orbitals of 13D with occupied orbitals of d .…”