# Molecular Dynamics Investigation of the Reactivity of Alkyl Radicals in Transition Metal-Catalyzed Transformations > **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2024 · $100,008 ## Abstract Project Summary/Abstract Computations reveal valuable information about organic reactions including those catalyzed by transition metals. Organic chemists can map out potential energy surfaces using density functional theory (DFT) and gain insight into the mechanism of a transformation. Using transition state theory, the reactivity and selectivity of a reaction can be explained by these studies. However, reactions with selectivity that cannot be explained by energy calculations performed with DFT may require the use of quasi-classical molecular dynamics simulations. One transformation where this type of modeling is vital is in the Michael addition and nickel cross-couplings using Watson's pyridinium salts. Despite the best experimental efforts, the Michael addition forms many byproducts in addition to product and the nickel cross-coupling gives only byproduct. The aim of this project is to study the dynamic behavior of alkyl radicals from a series of pyridinium salts and use this knowledge to enable reaction design. While the barrier computed by DFT for the alkyl radical to undergo Michael addition is lower in energy than recombination with the pyridine, a greater amount of byproduct is observed experimentally. This lack of agreement between DFT calculations and experiments points to a need for modeling of dynamic effects. I propose that the generation of the alkyl radical via C–N bond breaking of the pyridinium salt is an ambimodal transition state, which does not follow the intrinsic reaction coordinate (IRC) pathway to the alkyl radical but rather recombines with the pyridine, forming byproduct instead of the statistically favored product. I propose that the nature of the pyridine substitution pattern will affect the distribution of products, with more electron-withdrawn pyridines favoring radical addition. After verifying that more electron-rich, sterically hindered pyridines will favor productive reaction, the escape of the alkyl radical from the solvent cage will be modeled. A detailed understanding of the lifetime of the alkyl radical in solvents of varying polarity is needed, with the hypothesis being that more polar solvent leads to a more stable radical which is more likely to undergo further chemistry. This study is accessible solely through molecular dynamics simulations, an underexplored area that is vital to reaction design in systems with ambimodal transition states. Using the training and information gained in this study, in the R00 phase, I will develop chemistry to expand on existing methods of three-component coupling processes of C-aryl glycosides in which molecular complexity can rapidly be generated from a simple scaffold. These methods are vital to future drug design with the goal of lowering drug cost by simplifying the synthetic pathway to access certain drugs as well as using earth-abundant metals like nickel and iron in the R00 phase. ## Key facts - **NIH application ID:** 10948150 - **Project number:** 1K99GM155549-01 - **Recipient organization:** UNIVERSITY OF PENNSYLVANIA - **Principal Investigator:** Madeline Rotella - **Activity code:** K99 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $100,008 - **Award type:** 1 - **Project period:** 2024-08-01 → 2026-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10948150 ## Citation > US National Institutes of Health, RePORTER application 10948150, Molecular Dynamics Investigation of the Reactivity of Alkyl Radicals in Transition Metal-Catalyzed Transformations (1K99GM155549-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10948150. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*