C-H Functionalisation

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What we do, in a lot more detail…

[this section is under construction]

Catalytic C-H functionalisation

Introduction to C-H functionalisation

Organic molecules are literally covered in C-H bonds and most of them are classically considered ‘inert’. (They’re rarely even drawn out explicitly.) Inventing and exploiting catalytic methods to react them (C-H functionalisation) is a major part of the future of organic synthesis. It allows the very direct and efficient introduction of valuable functionality to the desired position on a molecule, minimising the number of required steps and waste generated.

Figure 1: The general concept of catalytic C-H functionalisation.

The advantages of C-H functionalisation

C-H functionalisation brings many significant advantages over classical methods to produce organic molecules. These include:

  • Much shorter synthetic routes to desired molecules (lower cost, less waste)
  • Transformations that were completely impossible previously
  • Hugely reduced use of toxic or dangerous reagents

However, despite all these advantages, there is plenty of work ahead. C-H functionalisation reactions need to be regioselective (only the desired C-H bond should be substituted) and chemoselective (other valuable functionality should not be damaged in the process). There are many more C-H bonds and functional groups, potential catalysts and sets of conditions to develop to make this technology maximally useful for efficient organic synthesis.

Our work on C-H functionalisation

Our work makes use of homogeneous catalyst (catalysts that are in the same phase as the substrate – in this case, in solution). These are based on transition metal complexes (e.g. Ru or Ir). We have developed several protocols for selectively transforming C-H bonds in a variety of molecules. These include various heterocycles, which are found ubiquitously in biologically active compounds, and which are useful in developing new materials.

Figure 2: Selected molecules made via new C-H functionalisations developed in our group.

The reactions we have developed include C-H silylation (C-H bond is substituted for a silane) and C-H arylation reactions (C-H bond is substituted for an aryl group). The approach we take is to design the reactions in such a way as to make them unusually tolerant of other functional groups present on the molecule.

For example, our C-H silylation reaction requires no protecting groups for amine groups, which means we can convert molecules like tryptamine very efficiently to the silylated product (Figure 2, top left). This reaction works in the presence of a number of other sensitive groups that might ordinarily be lost using previously available methods. It also works on N-, O- and S- based heterocycles, too.

Our C-H arylation reaction is performed under oxidative conditions, which means that the catalyst does not harm valuable C-Br or C-I bonds. These are hugely useful for other transformations (e.g. Suzuki and Heck reactions) and it is therefore important to be able to “carry” them to further stages of a synthesis (Figure 2, bottom left). As an example of what our reaction can do, we used it to couple a tryptophan derivative with ferrocene. (Figure 2, bottom right). Ferrocene derivatives are hugely important in chemistry, including as anti-malarial and anti-cancer drugs, as the key units in chiral ligands and in many, many other applications.

Mechanistic investigations include identifying organometallic intermediates, multinuclear NMR studies and hydrogen/deuterium exchange reactions to determine, e.g. the how the key C-H activation step happens.