Thiol-based michael-type addition. A systematic evaluation of its controlling factors. Issue 47 (20th November 2020)

• Record Type: Journal Article
• Authors: Gennari, Arianna; Wedgwood, Jennifer; Lallana, Enrique; Francini, Nora; Tirelli, Nicola
• Is Part Of: Tetrahedron. Volume 76:Issue 47(2020)
• Publication Date: 2020-11-20
• Subjects: Bioconjugation -- Hammett equation -- Retro michael -- Acrylates -- Methacrylates -- Acrylamides -- Methacrylamides -- Maleimides -- Cysteine; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2020.131637
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: This paper is about the factors controlling kinetics and product stability of this popular bioconjugation reaction. We demonstrate that a) thiol pKa, i.e. the amount of thiolates, is the only determinant of the reaction kinetics for the nucleophile; b) product degradation occurs primarily via hydrolysis (not thiol exchange), and is more prominent for the most rapidly reacting electrophiles. In terms of molecular design, acrylamides and low pKa thiols appear as the reaction partners that provide the best compromise for stability and reaction rate. Graphical abstract: Image 1 Highlights: Thiolate concentration is the determinant of thiol Michael-type reactivity. Retro-Michael (= thiol exchange) appears to be relevant only for maleimides. Hydrolysis is more likely for acceptors that accelerate the reaction (e.g. esters). Acrylamides + acidic thiols offer the best combination of stability + reactivity.