Site-selective C(sp3)–H functionalization with gaseous reagents using Hydrogen Atom Transfer photocatalysis in flow

Introduction

An essential part of synthetic organic chemistry is the conversion of raw materials into highly complex molecules. While traditionally this has been achieved through the conversion of functional groups, Nature has developed strategies to deliberately functionalize C–H bonds in organic molecules.

Current Challenges

Mimicking Nature’s machinery, chemists have developed a diverse set of powerful C–H bond functionalization strategies. However, undirected and selective C–H bond functionalization is still very challenging, and it remains “a dream reaction” for the community.

Proposed Approach

Herein, I propose a novel approach that combines both chemical and technological tools. This approach is based on a continuous-flow photocatalytic Hydrogen Atom Transfer (HAT) that uses cheap decatungstate to activate these C(sp3)–H bonds selectively.

Reaction Classes

Four different reaction classes will be developed which forge:

1. C=O bonds using O2
2. C–NO bonds using NO
3. C–SO2X bonds using SO2
4. C–CO2H bonds using CO2

These reagents are cheap and atom-efficient. All these methods provide useful functional handles which can be seamlessly engaged in other transformations.

Methodology and Applications

I will show that our methodology can be used to enable the late-stage diversification of bioactive molecules, establishing a new way of retrosynthetic thinking. Furthermore, I propose to exploit the intrinsic ability of HAT to abstract a hydrogen from volatile alkanes, such as methane, to generate the corresponding carbon-centered radicals.

Cross-Coupling Transformations

These nucleophilic radicals will be engaged in various cross-coupling transformations, including enantioselective variants.

Technological Impact

Moreover, I envision that a combination of continuous-flow, automation technology, and machine learning will provide a much-needed technological impact. This will enable the development of unique screening tools for the reproducible functionalization of organic molecules.

Conclusion

The synthetic methods and technological tools will provide a breakthrough in the selective functionalization of strong C(sp3)–H bonds in both gaseous alkanes and biologically active molecules.