# Probing substrate binding and release events in iridium-catalysed hydrogen isotope exchange reactions

## TL;DR

This study explores how different directing groups affect the binding and release of substrates in iridium-catalyzed hydrogen isotope exchange reactions.

## Contribution

The paper identifies three distinct substrate classes based on their binding and labelling behavior during catalysis.

## Key findings

- Pyridine and pyrimidine exhibit a single-binding/dual labelling process in hydrogen isotope exchange.
- Ketone, nitro, and ester groups show a binding/labelling/dissociation pathway with d1 to d2 conversion.
- Three substrate classes with different behaviors were identified, requiring tailored reaction design.

## Abstract

Directed, metal-catalysed C–H activation reactions rely on the binding of a Lewis basic functional group to the metal centre to ensure precise control of regioselectivity. However, groups that bind the metal centre too strongly have the potential to decrease turnover frequency and inhibit productive catalysis. Herein, we have used kinetic studies of iridium-catalysed hydrogen isotope exchange reactions, with NMR spectroscopy and mass spectrometry as the analytical techniques, to investigate the binding and release behaviour of a representative series of monosubsituted aromatic systems bearing a Lewis basic directing group. It was found that pyridine and pyrimidine exhibit anomalous behaviour, with a single-binding/dual labelling process dominating, or at least being competitive with, a binding/labelling/dissociation pathway. In contrast, with other directing groups (e.g. ketone, nitro, ester) initial formation of an appreciable population of d1-isotopologue is observed, and this is subsequently converted to the corresponding d2-isotopologue, suggesting a mainly binding/labelling/dissociation pathway. These data reveal three classes of substrate with rather different behaviour and for which reaction design and optimisation needs to be approached rather differently.

Mass spectrometry and computational chemistry show that, in iridium-catalysed hydrogen isotope exchange, some directing groups lead to doubly-deuterated products after one binding event, while others undergo dissociation and subsequent re-binding.