Catalytic Organic Transformations in Fluorinated Solvents

Fluorinated solvents, notably fluorinated alcohols such as hexafluoroisopropanol (HFIP) and perfluoroalkylated media, have emerged as indispensable reaction media for a wide range of catalytic organic transformations. Their unique combination of high polarity, strong hydrogen-bond donating ability and low nucleophilicity enables acceleration of both acid- and metal-catalysed processes. In many cases, these solvents stabilise cationic intermediates, suppress unwanted side-reactions and improve chemo- and stereoselectivity. Key applications include Brønsted and Lewis acid catalysis, organocatalysis and transition-metal-mediated protocols. For example, HFIP can act as a non-innocent solvent by engaging in hydrogen-bond networks that lower activation barriers for electrophilic aromatic substitution, cyclisation cascades and dehydrative couplings. Fluorinated media also facilitate unconventional reagent activation, for instance by holding reactive carbocations in persistent solvent cages that enable downstream functionalisation. Beyond enhancing reaction kinetics, the adoption of these solvents contributes to more sustainable processes by often reducing catalyst loadings, enabling milder conditions and obviating the need for stoichiometric activators. Consequently, catalysed C–C and C–heteroatom bond-forming reactions in fluorinated solvents have seen rapid growth, with significant impacts on pharmaceutical synthesis, agrochemical development and material science.

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Catalytic Organic Transformations in Fluorinated Solvents publication trend

The graph below shows the total number of articles in catalytic organic transformations in fluorinated solvents across all publications each year (not limited to Nature Index journals).

Technical terms

Fluorinated solvent: A solvent containing one or more fluorinated groups, characterised by high polarity, low nucleophilicity and unique hydrogen-bonding properties.

Hexafluoroisopropanol (HFIP): A perfluorinated alcohol with strong hydrogen-bond donating ability, used to stabilise cationic intermediates and accelerate acid-catalysed reactions.

Hydrogen-bond donor (HBD): A molecule or solvent capable of donating a hydrogen bond, influencing solvation and the stability of charged or polar species.

Lewis acid: A substance that accepts an electron pair, commonly employed to activate substrates via coordination or generation of cationic intermediates.

Organocatalysis: Catalysis mediated by small organic molecules, which often rely on non-covalent interactions such as hydrogen bonding to activate substrates.

References

1. Synthesis of functionalised isochromans: epoxides as aldehyde surrogates in hexafluoroisopropanol. Chemical Science (2023).
2. Emerging unconventional organic solvents for C–H bond and related functionalization reactions. Chemical Society Reviews (2020).
3. Hydroarylation of enamides enabled by HFIP via a hexafluoroisopropyl ether as iminium reservoir. Chemical Science (2022).