Research

The formation of C–X (X = C(sp³), C(sp²), O, N, B, Si, and S) bonds through carbene insertion reactions is a well-sought strategy to synthesize novel compounds with high chemo-, regio-, and stereoselectivity. In this regard, metal-based (particularly early and late transition metal viz. Fe, Cu, Pd, Rh, Ru, Pd, Ag, Au, etc.) homogenous catalysts generally present the most efficient and step-economic strategies. Metal-carbenes or metal-carbenoids are generally the reactive intermediates, having a variety of reactivities, selectivities, and tolerance.

We are interested in computationally exploring and rationalizing the reaction mechanisms of these organic transformations in order to present a clear understanding of metal-carbene reactivity along with the development of stereochemical models. We are also interested in understanding ligand-modified catalyst architectures in this aspect and their role in modifying catalyst activity, with a special focus on multi-component reactions.

A brief summary of the problems we are currently working on:

1. Insertion into C–H bonds – where reactions proceed in a concerted or a radical-based stepwise manner.

2. Insertion into X–H bonds – where a stepwise mechanism is favored. The formation of metal-free species such as ylides/enols is typically invoked to account for low stereoselectivity. Using computational approaches, we aim to understand the mechanism and develop the stereochemical models.

3. Mechanisms of MCRs – where reactions may proceed in a direct or relay fashion. Alongside computational investigation, we utilize a combination of experimental methods, namely, isotopic labeling, cyclic voltammetry, in situ NMR, IR, and UV spectroscopy.

The intriguing realm of enzyme catalysis has been fascinating scientists since the last century. The remarkable rate enhancements rendered by enzymes have led to many theories – ground state destabilization (GSD), transition state stabilization (TSS), electrostatic preorganization, and many more. However, the exact reason for the exceptional catalytic power depends on various factors. Our research in this field involves elucidating enzymatic mechanisms to develop an understanding of how enzymes work and gain insight into their extraordinary catalytic power.

Stereodivergence in enzymes is a relatively underexplored field with only sporadic reports where enzyme modifications have led to the formation of all possible stereoisomers. Specific amino acid modifications have been utilized using Directed Evolution in the few successful examples reported. Our group is particularly interested in understanding the influence of these mutations on the stereochemical outcome in an attempt to achieve the holy grail of computationally predicting enhanced activity and selectivity.

To reveal the mechanistic underpinnings and to gain rational insights, we use state-of-the-art computational techniques, including DFT calculations, Docking, Molecular Dynamics (MD) simulations, QM cluster calculations, hybrid QM/MM, and Empirical Valence Bond Theory (EVB).