Fishing for intermediates

Evidence for the Baylis Hillman mechanism provided by advanced techniques.

Researchers in Brazil have used advanced mass spectrometry techniques to prove the mechanism of an increasingly popular synthetic reaction. Mass spec has revolutionised biomolecular analysis in recent years. Gentle ionisation techniques combined with gas phase fragmentation, high resolution detection and tandem applications have made the methodology a driving force in high throughput fields like proteomics, and now the technique is being turned to the study of small organic molecules.

Groups led by Fernando Coelho and Marcos Eberlin, both at the Universitz of Campinas, studied the Baylis Hillman reaction, a coupling between an activated alkene and an electrophile using Lewis base catalysis. Although the reaction was patented in 1972 and has been widely used in synthesis, there had been only a little evidence to back up the hypothetical mechanism involving a four-step catalytic cycle with three zwitterionic intermediates.

Predicting that each of these intermediates would be in equilibrium with its protonated form in methanolic solution, the researchers used electrospray ionisation mass spectrometry (ESI-MS) to ’fish’ for these ions. They delivered the reaction mix to the electrospray outlet using a microsyringe and observed cationic species corresponding to all of the proposed intermediates represented as major peaks only a few minutes after the start of the reaction.

Further structural analysis using collision-induced dissociation (CID) of the ions and tandem analysis confirmed that all of the intermediates of the hypothetical reaction cycle can be observed and characterised experimentally. The researchers are now planning to extend their studies to include similar reactions catalysed by Lewis acids.

Michael Gross