Variable Temperature LED–NMR: Rapid Insights into a Photocatalytic Mechanism from Reaction Progress Kinetic Analysis

Abstract

A multitude of techniques are available to obtain a useful understanding of photocatalytic mechanisms. The combination of LED illumination with nuclear magnetic resonance spectroscopy (LED–NMR) provides a rapid, convenient means to directly monitor a photocatalytic reaction in situ. Herein, we describe a study of the mechanism of an enantioselective intermolecular [2 + 2] photocycloaddition catalyzed by a chiral Ir photocatalyst using LED–NMR. The data-rich output of this experiment is suitable for same-excess and variable time normalization analyses (VTNA). Together, these identified an unexpected change in mechanism between reactions conducted at ambient and cryogenic temperatures. At −78 °C, the kinetic data are consistent with the triplet rebound mechanism we previously proposed for this reaction, involving sensitization of maleimide and rapid reaction with a hydrogen-bound quinoline within the solvent cage. At room temperature, the cycloaddition instead proceeds through intracomplex energy transfer to the hydrogen-bound quinolone. These results highlight the potential sensitivity of photocatalytic reaction mechanisms to the precise reaction conditions and the further utility of LED–NMR as a fast, data-rich tool for their interrogation that compares favorably to conventional ex situ kinetic analyses.

Best Practices for the Collection of Robust Time Course Reaction Profiles for Kinetic Studies

“…The data processing and interpretation required for graphical kinetic analyses are simple, but the process of gathering robust and reliable time course data suitable for these techniques can be difficult. Time course data is often generated via in situ analytical instruments, including NMR, 20 FT-IR, 21 UV−vis, 25 and Raman 26 spectroscopy. These technologies provide near-continuous real time trends.…”

“…Obtaining reaction profiles of different excess, same excess, and product inhibition experiments is an essential step in this process. , Rate constants, order in reaction components, catalyst deactivation, and product inhibition can be probed using RPKA or VTNA. These methodologies are amenable for analysis of complex catalytic reactions at or near the desired operating conditions, allowing delineation of subtle mechanistic details that may be missed by initial rate methodologies. − RPKA and VTNA provide insights on the kinetic behavior over the entirety of the reaction, compared to initial rate studies, which may not represent the reaction as a whole and therefore limit the level of reaction understanding. , Several review articles explaining how RPKA and VTNA can be applied have been published. We point readers to these articles for a basic understanding of and best practices for applying these data interpretation techniques.…”

“…If reaction calorimetry is used, then high conversion of the starting material to product is necessary. Kinetic studies require access to reliable and trustworthy time course data. ,, A baseline understanding of a system is needed to have confidence in the conclusions drawn from the kinetic studies. Failing to understand factors such as order of addition or intermediate formation can result in erroneous conclusions and misinterpreted data.…”

In situ Reaction Monitoring in Photocatalytic Organic Synthesis

“…Next, rate laws for the title reaction at different temperatures were constructed from reaction profiles using variable time normalization analysis (VTNA) [53] . Therefore, multiple reaction profiles are collected by strategically changing the concentration of a single ingredient of the reaction mixture (“different excess” experiments).…”

The Catalysis Laboratory at Merck: 20 Years of Catalyzing Innovation

“…Critically, LED-NMR spectroscopy was a capability built in anticipation of pipeline opportunities, and its availability provided the requisite data to move forward with the photocatalytic bromination process for belzutifan ( 70 ) highlighted above . Furthermore, because of the accessibility of this tool, it has now been deployed across a variety of settings, including academic laboratories …”