Fairlamb Research Group

Catalysis, Synthetic and Mechanistic Chemistry

Metal Catalysis: C-X and C-H Bond Activation

Our research group has developed synthetic methodologies allowing the C-H functionalization of various heteroaromatic compounds. We are particularly interested in the involvement of Pd nanoparticles as catalysts for these particular reactions. For example, we have demonstrated that piperidine lowers the reduction potential at Pd(II) leading to the more rapid generation of Pd nanoparticles in the C-H functionalization of nucelosides.  We also have interests in studying the C-H activation reactions of 2-pyrones and related coumarins

(a) Arylation of amino acids, peptides and proteins

We are currently working on methodologies allowing the selective C-H bond functionalisation of amino acids such as tryptophan derivatives. 

Lead references: Org. Biomol. Chem. 2015, 13, 8298 and Chem. Commun. 2014, 50, 3052.

(b) Mechanism of C-H bond activation involving manganese(I)

Over the last 3 years we have been examining the role of manganese(I) carbonyls in C-H bond activation reactions, using a combined experimental and computations approach. The project is in collaboration with Dr. Jason Lynam and Simon Duckett.

Our first paper in the Mn catalysis field has been reported in Angew. Chem. Int. Ed. 2016, in press.  See Departmental News Item.

We are currently working on a number of Mn-mediated processes, particularly mechanistic aspects.

(b) Mechanism of C-H bond activation at fluoroaromatics

We are currently working with Prof. Robin Perutz on mechanistic aspects of C-H bond activation involving fluorinated aromatic substrates. In our first joint paper together we revealed that there is no obvious ortho-fluorine effect in the cyclopalladation of suitable fluorinated benzyl amines. A difference is seen in products containing either bridging chloride or acetate ligands.  For the former we see para-selective cyclopalladaton and for the latter we see no regiochemical preference. 

Lead reference: Organometallics 2015, 34, 4376.

(c) Involvement of Pd nanoparticles in C-H bond activation processes

We are currently exploring the role played by palladium nanoparticles in a variety of cross-coupling reactions. We are particularly interested in the formation of Pd clusters and the hybrid homogeneous-heterogeneous phase. 

In a recent paper we have compared the catalyst efficacy of homogeneous and heterogeneous palladium catalysts in the direct arylation of common heterocycles. See, Synlett 2016, 27, 1211.

(d) Catalytic C-H functionalisation in unprotected nucleosides:  

C-modified non-natural nucleosides are used as fluorescent markers, light sensors, therapeutic agents, novel ligands for metals and supramolecular building blocks. These analogues allow biomolecular structure and biochemical mechanisms to be probed, which in turn provides the impetus to develop more efficient synthetic routes to structurally distinct purine nucleosides.  In the reaction scheme opposite is shown an efficient approach which allows the arylation of 2'-deoxyadenosine selectively at the 8-position in the purine ring system. The process is mediated by a Pd(0) active catalyst species, most likely nanoparticulate, derived from the Pd(II) precatalyst - "Pd(OAc)2".

We are currently working on the mechanism of this transformation which is complex.  Our working hypothesis is shown in the mechanistic scheme opposite.  The requirement for stoichiometric Cu(I) is inriguing, as is the potential involvement of Cu-carbene intermediates and D

General reaction scheme illustrating the arylation of a fully unprotected nucleoside (2'-deoxyadenosine).  The process is completely selective for the C8 hydrogen. 

Proposed reaction mechanism for the arylation process mediated by Pd and Cu. 

X-ray structure of 8-naphthyl-2'-deoxyadenosine.

 Lead reference: J. Org. Chem. 2009, 74, 5810. 

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