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Optimizing Selectivity in C-H Functionalization Through Computational Design

Final Report Summary - CHOPTOCOMP (Optimizing Selectivity in C-H Functionalization Through Computational Design)

A final report is attached in PDF format. A concise overview of the project work is as follows:

The project CHOPTOCOMP has sought to establish a new understanding of the synthetic functionalization of C-H bonds. These are present in abundance in organic molecules and utilizing them directly in synthesis presents an exciting opportunity to make molecules more quickly and more efficiently. The pharmaceutical, materials and agrochemicals industries all stand to benefit from developments in C-H functionalization, and in turn, society is rewarded with new and cheaper medicines and other useful molecules. The project has developed computational models which have elucidated mechanistic details for these processes, and in turn, has established computational predictions as a means to predict the outcome of synthetic experiments. This paves the way for more rational-based design of catalytic processes to achieve C-H functionalization reactions. The project led directly to a number of publications and presentations, and to the establishment of a new network of computational-experimental collaborations between researchers inside and outside of the E.U.

From computational modelling the project has delivered new chemical insights, directly contributing to new catalytic discoveries, and leading to publications in internationally-recognized journals and presentations at international meetings. In particular, the work has uncovered mechanistic details for the functionalization of cyclic structures containing heteroatoms such as oxygen or nitrogen - these substrates are of interest not only to academia, but also in pharmaceutical chemistry, a multi-billion dollar industry in Europe, where understanding site-selective functionalization is a key towards enhancing the efficiency of both discovery and process chemistry. Any enhancements in efficiency of synthetic processes in this arena are of potential value to pharmaceutical companies, and to patients in terms of cheaper medicines.

The project has developed a rationale for observed regioselectivity as a function of substrate and ligands, for a series of industrially useful reactions. Due to the abundance of C-H bonds, the challenge of site-selective activation limits the current applicability of C-H functionalization. We have tackled the effects of substrate and ligands and have explored the different mechanisms upon modification of both aspects in Pd-catalyzed C-H activation. In doing so, we anticipate that future developments of site-selective tranformations may be grounded in rationally-designed systems.

The Fellow was able to develop predictive computational methods for the optimization of C-H functionalization and additional modes of chemical reactivity. Since the discovery and optimization of chemical reactions often relies on screening and serendipity, the incorporation of computational or theoretical insights into this process are long overdue. We developed a model to account for site-selectivity in the arylation and alkenylation of heteroatom containing cyclic molecules, which has led to collaborations with experimentalists. New networks have been established between the host PI, the Fellow and groups working inside and outside of the E.U. Experimental groups we have been able to test the computational predictions experimentally relating to the optimization of ligands for transition metal catalysis. This work highlights the growing role of computation in synthetic chemistry, and how the ability to make testable predictions is able to enhance efficiency and selectivity of new reactions, to deliver new molecules.