Trifunctional organocatalysts that closely mimic natural enzymes can significantly increase reaction rates, say chemists in Japan.

Tadashi Ema, Takashi Sakai and co-workers at Okayama University in Japan have made highly active organocatalysts by combining the reactivity of three separate organic components. Mimicking the catalytic triad structure found inside many enzyme active sites, the three components work cooperatively, accelerating a test reaction 3.7 million-fold.

Ema's catalysts were inspired by lipase, an enzyme known to work through a catalytic triad. 'With precise information about the structures and reaction mechanism of lipases, we decided to test our abilities to mimic the active site,' said Ema. The resulting trifunctional organocatalyst has a nucleophilic OH group, a pyridine moiety, and either a urea or thiourea group.

Ema tested his catalysts using the transesterification reaction, a synthetic transformation often applied to organic molecules to switch one ester side chain for another. The catalyst's hydroxyl group, boosted in reactivity by the adjacent pyridine, initiates the reaction by attacking the ester group in vinyl trifluoroacetate - and the urea group stabilises the resulting intermediate through hydrogen bonding.

Adding the catalyst increased the rate of reaction up to 3.7 million times, depending on the exact substrate used. For comparison, Ema also made three bifunctional control catalysts each missing a different one of the three components - and found all three to be essentially inactive.

'The observed rate accelerations are impressive,' said Ben List, who develops organocatalysts at the Max-Planck Institute in Mülheim an der Ruhr, Germany. 'The authors have elegantly combined previously developed organocatalysis motifs to make a highly active and promising new organocatalyst type. Designing an asymmetric version is clearly the next logical step, which I look forward to.'

Ema agrees that, along with further tuning the catalyst structure to boost reactivity levels even closer to those of enzymes, the next target will be to develop the catalyst for asymmetric synthesis.

James Mitchell Crow