Dr Mark Wood (University of Exeter, UK) and colleagues at biopharma company UCB Celltech have investigated the extent to which deuterium can be used as a protecting group for carbon-hydrogen bonds in radical-based intramolecular hydrogen atom transfer processes. Dr Wood tells us more about the work in the short interview below. 



Please explain, for the non-specialist, the significance of your article 
The article describes the first systematic studies into the effectiveness of deuterium as a "protecting group" for carbon-hydrogen bonds in synthetically important radical reactions that involve hydrogen atom transfer, by determining the extent to which the primary kinetic isotope effect can control this process. Whilst there are many examples in the literature of such a methodology being used to probe the rate-determining step in reaction mechanisms, there are very few reports of this strategy actually being used in synthetic applications, despite the fact that an isotope effectively represents the simplest possible protecting group for a covalent bond. Given the vital importance of nitrogen-containing molecules and the increasingly common use of radical techniques in their preparation, we chose to study the methodology in the "real world" context of the generation of synthetically valuable, carbon-centred radicals adjacent to nitrogen atoms. 

The results obtained show clearly, through straightforward experiments, the fact that such a protecting group approach can only be applied successfully when the synthetically useful radical intermediate generated by hydrogen atom removal, or more correctly, the transition state leading to it, has a relatively low level of electronic stabilisation. Not only do these experiments show, therefore, the extent to which deuterium can be used to prevent unwanted hydrogen atom abstraction in a synthetic procedure, they also very importantly highlight the care that must be taken in interpreting kinetic isotope effect data in mechanistic studies if stabilised radical intermediates are involved. The studies also shed light on the (often controversial) issue of "captodative" radical stabilisation. 

What has motivated you to conduct this work? 
There has been significant recent interest in the use of deuterium for blocking deprotonation reactions effected by strong bases but despite the plethora of mechanistic investigations into radical reactions based on similar use of the primary kinetic isotope effect, there were very few literature reports of related synthetic procedures taking advantage of such a simple approach to carbon-hydrogen bond protection. With reports of extremely high kinetic isotope effects being observed for hydrogen atom transfer processes where the reaction mechanism involves predominantly quantum mechanical tunnelling, we felt that it was timely to carry out systematic, fundamental investigations into the extent to which these well-established studies are relevant in the field of synthetic chemistry. 

Where do you see this work developing in the future? 
One of the important "spin-offs" from this work is the possibility of using the morpholinone systems in which hydrogen or deuterium atom transfer occurs through either a stabilised or non-stabilised transition state, to probe directly the significance and real extent of captodative stabilisation of carbon centred radicals. 

Fundamental studies into the effectiveness of deuterium for the protection of carbon-hydrogen bonds against carbene insertion can also be envisaged. As for the radical chemistry, only a handful of literature reports exist describing the use of such a protecting group approach in the synthetically useful chemistry of these other key reactive intermediates. 

Are there any particular challenges facing future research in this area? 
Future important challenges in this area include the incorporation of such a protecting group approach into a synthetic scheme in which the isotope label can be recovered in the form of a simple molecule that can be recycled. Systems in which the reaction products derived from hydrogen atom transfer are significantly structurally different from those obtained from deuterium transfer also need to be devised in order to emphatically highlight the usefulness of the approach underpinned by these studies.