C-H Functionalisation EXPLAINED How do scientists make compounds conventionally? Carbon to hydrogen (C-H) bonds are the most abundant type of bond in organic molecules. In comparison to other chemical bonds found in molecules, C-H bonds are generally unreactive. As a result, scientists have found that directly reacting these bonds can be very challenging. Conventionally, to make complex molecules, scientists focus on the reactions of functional groups, which are generally more reactive than C-H bonds, making it easier to change the molecule using these groups. The process of making (or synthesising) complex molecules usually requires multiple steps to build the structure piece by piece, like a jigsaw puzzle. Functional groups are found in certain areas on a molecule, hence specific atoms are added in specific positions using the functional groups.
What is C-H functionalisation and what are the advantages of this type of reaction in comparison to conventional ways to make molecules? Unlike conventional methods used by organic chemists, C-H functionalisation does not rely on the reaction of functional groups. C-H functionalisation can be explained using the diagram below. Starting with the organic compound at the far left, this molecule contains multiple C-H bonds but one is shown just for simplicity. Selective C-H functionalisation reactions directly target a particular C-H bond in a molecule and the reaction results in the formation of a new chemical bond with a second organic chemical group, atom or group of atoms. C-H functionalisation can be advantageous compared to conventional methods. Firstly, reactions which target a specific C-H bond usually require less steps to form the desired product (with the new chemical bond). This is because usually a functional group must be pre-installed, creating a reactive point, allowing the desired organic group to be attached onto the molecule. Reducing the number of steps saves time and energy, whilst reducing the cost of chemicals required for each step. Furthermore, this reduces the amount of waste material produced in each reaction step, showing environmental and sustainable advantages of C-H functionalisation. New Chemical Bond
Chemical Bond
C
Organic compound
Catalyst, Light Energy
H
Organic group
C
How can C-H functionalisation be used in the discovery of new medicines and treatments? Medicinal chemists working in research and development teams in pharmaceutical companies have the overarching aim of synthesising molecules that have the desired chemical and biological properties to treat a target disease or condition. Medicinal chemists usually start from scratch and carry out multiple step synthesis to build up a molecule piece by piece. Once made, these molecules get submitted for biological testing to see if they are biologically active and have the right properties to become a medicine. If found to be biologically active, molecules with similar structures are made to see if they have improved properties. To make a molecule with one small change, such as a different chemical bond or atom, scientists usually have to start from the beginning again, building up this slightly different molecule step by step. In this context, C-H functionalisation can be used to facilitate this process, removing the need to start from scratch. By using C-H functionalisation reactions on the original, biologically active Molecule A (diagram below), we can access a range of other molecules with different chemical bonds. These different bonds can promote different chemical properties (such as solubility or activity), resulting in library of molecules that have the potential to become medicines, treatments and therapeutics. 1. Multiple steps are usually required to make target Molecule A which was found to have promising biological activity.
Molecule A
= C
C
H
2. C-H functionalisation of Molecule A to various different compounds with potential biological activity.
C C
New attached organic group
Compound Library
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