Mechanistic and Kinetic Factors of ortho-Benzyne Formation in Hexadehydro-Diels-Alder (HDDA) Reactions.

Jan Maier,Todd B Marder

doi:10.1002/chem.202100608

Abstract

With the rapid development of the hexadehydro‐Diels‐Alder reaction (HDDA) from its first discovery in 1997, the question of whether a concerted or stepwise mechanism better describes the thermally activated formation of ortho‐benzyne from a diyne and a diynophile has been debated. Mechanistic and kinetic investigations were able to show that this is not a black or white situation, as minor changes can tip the balance. For that reason, especially, linked yne‐diynes were studied to examine steric, electronic, and radical‐stabilizing effects of their terminal substituents on the reaction mechanism and kinetics. Furthermore, the influence of the nature of the linker on the HDDA reaction was explored. The more recently discovered photochemical HDDA reaction also gives ortho‐arynes, which display the same reactivity as the thermally generated ones, but their formation might not proceed by the same mechanism. This minireview summarizes the current state of mechanistic understanding of the HDDA reaction.

Highlights

The highly reactive ortho-benzyne intermediate has fascinated chemists since it was first proposed in 1927 by Bachmann and Clarke (Figure 1a).[1]
In 2014, the group of Houk investigated the influence of activating substituents at the diynophile on the hexadehydroDiels-Alder reaction (HDDA) reaction.[17]
In addition to their main focus on the linker, they were able to confirm experimentally the increase of reactivity of the HDDA cyclization by about five orders of magnitude when an alkynyl substituent is attached to the diynophile

Summary

Introduction

The highly reactive ortho-benzyne intermediate has fascinated chemists since it was first proposed in 1927 by Bachmann and Clarke (Figure 1a).[1]. In order to generate o-benzyne free from any additional reactive substrates, possibly disturbing the follow-up reactions, a different approach than elimination from substituted benzene precursors had to be developed. In 1997, Johnson[9] and Ueda,[10] independently, found linked yne-diynes (Figure 1e) to be suitable precursors for the formation of o-arynes. The mechanism of those thermally triggered intramolecular reactions, known as hexadehydroDiels-Alder (HDDA) reactions,[11] became the subject of discussion. The historic development of the discussion of whether a concerted or stepwise mechanism better describes the thermal HDDA reaction of linked yne-diynes, as well as potential factors influencing the reaction mechanism and kinetics, will be reviewed in chronological order . For general overviews of the many applications of the HDDA reaction, see the two most recent reviews and references therein.[12]

Thermal HDDA reaction

Photochemical HDDA reaction

Conflict of Interest