Distortion/Interaction Energy Control of 1,3-Dipolar Cycloaddition Reactivity

Abstract

Huisgen's 1,3-dipolar cycloaddition reactions, extraordinarily versatile methods for heterocycle synthesis, are now used in materials chemistry, drug discovery, and chemical biology. 1,2 The 1,3-dipoles range from the familiar atmospheric components, ozone and nitrous oxide, to the synthetically valuable azides of click chemistry fame. 1 Frontier molecular orbital (FMO) theory has provided a powerful model for the qualitative understanding of reactivity and regioselectivity, based upon electronic properties of isolated reactants. 3 Conceptual density functional theory has also provided a qualitative way to rationalize reactivity patterns. 4 Chemically accurate theoretical thermochemistries ((1 kcal/mol) are now available using the CBS-QB3 method. 5 Three of the most important classes of dipoles defined by Huisgen, the diazonium (DB), nitrilium (NB), and azomethine betaines (AB), shown below, were explored. 2 The CBS-QB3 ∆H q and ∆H rxn were computed for the reactions of 1-9 with ethylene and acetylene. 6

A Molecular Electron Density Theory Study of the Reactivity of Azomethine Imine in [3+2] Cycloaddition Reactions

“…when more distorted the TS is with respect to the separated reagents, higher the activation energy. This finding, which is a computational assertion of Hammond's postulate [9], does not resolve the question why the activation energies of these 32CA reactions depend on the geometry deformations [7,8].…”

“…On the order hand, unlike the non-polar Diels-Alder reaction between butadiene 9 and ethylene 3, which has a high activation energy of ca. 25 kcal·mol -1 [35], the non-polar 32CA reactions between TACs and ethylene 3 have activation energies that range from 1 to 15 kcal·mol -1 [7,8]. Note that ethylene 3 is a poor electrophile and a poor nucleophile that cannot participate in polar reactions.…”

“…While A-TACs such as I are bent, P-TACs such as II have a linear structure (see Scheme 1). [7,8]. The applicability of this model was checked in 32CA reactions of nine different TACs, three A-TACs 1a-c and six P-TACs 2a-f, with ethylene 3 and acetylene 4 (see Scheme 2) [7,8].…”

“…[7,8]. The applicability of this model was checked in 32CA reactions of nine different TACs, three A-TACs 1a-c and six P-TACs 2a-f, with ethylene 3 and acetylene 4 (see Scheme 2) [7,8]. that the distortion energy of the reagents towards the transition state structure (TS) is the major factor controlling the reactivity differences of TACs.…”

Metal‐Free 1,5‐Regioselective Azide–Alkyne [3+2]‐Cycloaddition

“…[9,23] Recently, Houk and co-workers reported that the energy to distort 1,3-dipoles and dipolarophiles to their transition state geometries is related to the activation energies of these kinds of 1,3-dipolar cycloaddi- tion. [24] In addition, Houk has also shown by DFT calculations that the mechanism of 1,3-dipolar cycloadditions of phenyl azide and cyclooctyne derivates are concerted and nearly synchronous. This observation is supported by the performed calculations.…”