N-Heterocyclic carbene organocatalysis in
structured ternary fluids

Abstract

Organocatalysis offers numerous advantages for sustainable chemistry including a high atom
economy, non-hazardous chemical syntheses, and unique catalytic modes of action. However,
its use often relies on crude oil derived solvents such as DCM, THF, and toluene.
N-heterocyclic carbenes (NHCs) are one of the largest and most diverse classes of
organocatalysts. There are limited examples of NHC-organocatalysis in water, due to the poor
solubility of NHC pre-catalysts and substrates. Asymmetric organocatalysis in aqueous media
is also challenging, since the intermolecular interactions between the chiral catalyst and
substrate are hindered, due to competing solvent interactions.
This project investigates the use of structured ternary fluids (STFs) as alternative solvent media
for NHC-organocatalysis. STFs are comprised of water, a water-immiscible solvent, and a third
co-solvent that is miscible with both. STFs offer significant potential within NHC
organocatalysis, presenting a compromise between fully aqueous media and ecotoxic organic
solvent media.
The benzoin condensation (BC) has been carried out in various water, toluene and propan-2-ol
(WTP) STF compositions and monitored through 1H and 19F NMR spectroscopy. Key
parameters, including the initial rate of reaction, the apparent equilibrium constant (Kapp), and
the equilibrium concentration of p-fluorobenzoin were used to optimise conditions. A 10:40:50
(mass %) water: toluene: propan-2-ol WTP STF gave the best performance, achieving a 46%
isolated yield of p-fluorobenzoin. This optimised system also tolerated a range of aromatic
aldehydes with electron-donating and electron-withdrawing substituents on the phenyl ring.
Dynamic light scattering (DLS) experiments confirmed that STF integrity (average particle
diameter ≈ 2 – 10 nm) remained intact during the BC. Oxidation to the side product p
fluorobenzil was minimised by argon degassing, however this also reduced the yield of p
fluorobenzoin (30% versus 46%).
Parallel studies using water, ethyl acetate, and propan-2-ol (WEP) STFs showed the use of a
70:5:25 (mass %) water: ethyl acetate: propan-2-ol system was optimal, with an isolated yield
of 70% p-fluorobenzoin, which was comparable to fully aqueous systems (71%), while also
offering enhanced substrate solubility. This optimised WEP STF system also tolerated a range
of aromatic aldehydes with electron-donating and electron-withdrawing substituents on the
phenyl ring.
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The impact of stirring (since this may disrupt STF integrity) and nanostructuring on the BC
within WEP STFs was evaluated. Stirring was found to have no adverse effect on STF
performance. Furthermore, homogeneously mixed non-STF WEP solutions showed reduced
conversion to p-fluorobenzoin (maximum 85%) compared to WEP STFs (up to > 99%),
suggesting that STF nanostructuring favours the BC.
The Stetter reaction was successfully performed in both optimised WTP and WEP STFs,
achieving up to an 83% isolated yield in a 70:5:25 (mass %) water: ethyl acetate: propan-2-ol
WEP STF system, demonstrating the suitability of STFs for broader NHC-organocatalytic
transformations.
The asymmetric BC reaction using a chiral NHC catalyst in WEP and WTP STFs produced
enantiomeric excesses ranging from 86% to 88%, similar to those observed in conventional
solvents, suggesting the use of STFs has limited stereochemical influence upon the asymmetric
BC.
Finally, the synthesis of achiral and chiral triazolium NHC salts has been investigated.
However, owing to the challenging silylation of tertiary alcohols, the synthesis of a chiral NHC
salt was unsuccessful.