Continuous flow synthesis and separation of mandelic acid enantiomers in a modular microfluidic system

Abstract

Mandelic acid enantiomers are key precursors in the synthesis of valuable chiral products. However, separating enantiomers in reasonable amounts is a challenging task despite advances in chiral chromatography and other discontinuous and expensive techniques. To tackle these problems, we designed and tested a modular microfluidic system working in a fully continuous flow regime. The system consists of two modules, namely (i) a packed-bed microreactor (PBR) with immobilized enzyme lipase and (ii) a membrane microseparator driven by an imposed electric field. The immobilized catalyst converts a racemic substrate, methyl mandelate, into mandelic acid enantiomers. The enzyme preferentially synthesizes (R)-(−)-mandelic acid within minutes. The product stream from PBR is fed into a membrane microseparator operated in a counter-current regime. An inserted dialysis membrane and an orthogonally applied electric field completely separate the electrically charged enantiomers from their mixture with unreacted and uncharged methyl mandelate within 1.5 min. Under improved reaction and separation conditions, approximately 1 g of (R)-(−)-mandelic acid are produced per day with almost 60 % enantiomeric excess. Moreover, the productivity of this system is easily scalable without compromising its excellent reaction-transport characteristics.