Understanding the Mechanism and Stereoselectivity of Fe-catalyzed Carbene Insertion Reactions using Computational Tools

Abstract

Transition-metal and enzyme-catalyzed carbene insertion reactions are key methods for constructing C–X (X=N, O, S) and C–C bonds, primarily using catalysts such as Rh, Pd, Au, Cu, and Fe. While most of these give high reaction yields and enantiomeric excess (ee), Fe often exhibits low enantioselectivity, limiting its use. This underutilization is connected to a lack of mechanistic insights and challenges in controlling stereoselectivity, raising questions about whether the low ee results from a mechanistic glitch or the ligand design. The current thesis involves a mechanistic study of Fe-catalyzed carbene insertion reactions using various computational tools. It deals with understanding the active species involved in these reactions, along with the formation of some interesting, unusual complexes during the reactions. Subsequently, we have extended our understanding of two-component carbene insertion reactions to multi-component reactions. We began by thoroughly investigating the mechanistic pathways for C(sp2)–H insertion reactions, addressing the challenge of achieving good ee with Fe. We propose a new metal-associated enol pathway that also accounts for the low selectivity. We further examined the unusual case of a highly enantioselective Fe-catalyzed O–H insertion reaction, where we show that non-covalent interactions along with the catalyst framework are crucial for attaining high enantioselectivity. Next, we explored the active species in an Fe(III) catalyzed carbene insertion reaction, considering the apparent advantages of Fe(III) over Fe(II). Our DFT calculations reveal the participation of oxidized bridged carbenoids, challenging the notion that such species are dead ends. We then studied the role of axial ligands and metals in heme-based artificial metalloenzymes. Next, we applied the understanding of two-component carbene insertion reactions to multi-component reaction catalyzed by Rh(I) complex. The in-depth mechanistic understanding of metal-catalyzed reactions presented in the thesis will help design better catalysts by emphasizing the metal enol binding.