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

Deem, Madeleine C.; Cai, Isabelle; Derasp, Joshua S.; Prieto, Paloma L.; Sato, Yusuke; Liu, Junliang; Kukor, Andrew J.; Hein, Jason E.

doi:10.1021/acscatal.2c05045

Cited by 10 publications

(12 citation statements)

References 83 publications

(149 reference statements)

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“…Temporal concentrations were determined by GC-FID analysis of a series of samples taken at regular intervals from the reaction mixtures using n- dodecane as an internal standard. To ensure that in situ formation of the rhodium NHC complex does not introduce a source of variability that could potentially affect the kinetic analysis, isolated complex 1 was used throughout our kinetic studies …”

Section: Resultsmentioning

confidence: 99%

Mechanistic Investigation of the Rhodium-Catalyzed Transfer Hydroarylation Reaction Involving Reversible C–C Bond Activation

Lutz,

Roediger,

Rivero-Crespo

et al. 2023

J. Am. Chem. Soc.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Investigation of the Rhodium-Catalyzed Transfer Hydroarylation Reaction Involving Reversible C–C Bond Activation

Lutz,

Roediger,

Rivero-Crespo

et al. 2023

J. Am. Chem. Soc.

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“…Encouraged by the ease of implementation and accuracy of our approach, we hypothesized that parallel NIR monitoring could be applied to more complex, kinetic investigations such as initial rate kinetics and variable time-normalization analysis (VTNA) . These experiments are often performed to assess robustness and derisk further development as early as possible (e.g., to confirm catalytic activity and identify product inhibition and catalyst deactivation).…”

Section: Results and Discussionmentioning

confidence: 99%

RIPPLY: Real-TIme Parallel Progress AnaLYsis of Organic Reactions Using Near-Infrared Spectroscopy

van Putten,

De Smet,

Lefort

2023

Org. Process Res. Dev.

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High-throughput experimentation (HTE) is an important tool in pharmaceutical process research and development. However, most of the current HTE workflows do not monitor reaction progress and, therefore, provide no information on kinetic regimes (induction, deactivation, etc.). Here, we describe the development of a parallel reaction monitoring technique for micromole-scale organic reactions using near-infrared spectroscopy and multivariate semi-NMF analysis (Non-negative Matrix Factorization). This workflow produces qualitative reaction progress profiles or semiquantitative concentration profiles without the need for time-consuming calibration. Advantageously, simultaneous analysis of parallel reactions improved confidence in the black box multivariate analysis and allowed a direct comparison of predicted and measured final compositions. Two test reactions were successfully monitored using our new approach. Coincidentally, our study led to the identification of a new ketone transfer hydrogenation catalyst. Finally, initial rate kinetics and VTNA (Variable Time Normalization Analysis) experiments were successfully performed using the new technique.

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“…To verify the quench, it is sufficient to analyze the same solution again after a sufficiently long time interval. The area count should not change …”

Section: Kinetic Characterizationmentioning

confidence: 99%

How to Develop Organometallic Catalytic Reactions in the Pharmaceutical Industry

Farina¹

2023

Org. Process Res. Dev.

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From a careful analysis of the recent literature, it seems clear that many transition-metal-catalyzed processes used in API synthesis are developed without resorting to any kind of kinetic analysis. Even acknowledging that some of these processes were developed for early development projects and did not need to be thoroughly optimized, the lack of kinetic work is surprising. This Perspective suggests that, in addition to the utilization of modern technologies such as high-throughput experimentation (HTE) and classical optimization tools such as Design of Experiments (DOE), a modest level of kinetic analysis is necessary to develop truly effective catalytic reactions. We offer some basic theoretical considerations and suggest some rather simple tools which can be employed to integrate kinetic analysis of catalytic steps into API development.

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

Cited by 10 publications

References 83 publications

Mechanistic Investigation of the Rhodium-Catalyzed Transfer Hydroarylation Reaction Involving Reversible C–C Bond Activation

Mechanistic Investigation of the Rhodium-Catalyzed Transfer Hydroarylation Reaction Involving Reversible C–C Bond Activation

RIPPLY: Real-TIme Parallel Progress AnaLYsis of Organic Reactions Using Near-Infrared Spectroscopy

How to Develop Organometallic Catalytic Reactions in the Pharmaceutical Industry

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