Mechanistic aspects of thiol additions to Michael acceptors: Insights from computations

Abstract

Computational studies have delivered valuable mechanistic insights into thiol Michael additions, which are important C S bond-forming reactions used in biological and materials chemistry. The field has delivered a wealth of understanding about the ways in which substituents, catalysts, and the local environment influence the addition pathway. Several mechanistic scenarios are now recognized, differing with respect to the energies and timing of the bondforming processes. While technical challenges still exist, the field has advanced to such an extent that full-scale simulations of the additions of Michael acceptors to protein thiol groups are now possible.

A mechanistic study of thiol addition to N-acryloylpiperidine

“…Protonation of this enolate intermediate leads to the thioether product. These transition structures are similar to those previously reported by Roseli et al , 17 where the C β –S bond length is >2.2 Å and the S–CH 3 bond eclipses the CC bond. 19…”

“…Protonation of this enolate intermediate leads to the thioether product. These transition structures are similar to those previously reported by Roseli et al, 17 where the C β -S bond length is >2.2 Å and the S-CH 3 bond eclipses the CvC bond. 19 DFT calculations previously reported by Flanagan et al predicted a barrier of 29.5 kcal mol −1 for the addition of methanethiol to AcrPip.…”

“…The α-carbons of enolates are highly basic and will readily abstract a proton from many bases. 17 Computationally, we identified multiple mechanisms by which the AcrPip enolate can abstract a proton from the aqueous solvent, including one low energy path where the solvent was modelled as a cluster of 11 water molecules within the continuum model. The barrier to this reaction step was 9.8 kcal mol −1 , which is significantly lower than the rate limiting addition step.…”

Benchmarking in silico Tools for Cysteine pKa Prediction

“…[6][7][8][9][10][11][12][13][14][15][16] The nucleophilicity of a Cys residue is dependent on the ionization state of the side chain, with the deprotonated thiolate form (-S -) being more nucleophilic than its protonated thiol form (-SH). The reactivity and susceptibility of a Cys residue towards deprotonation and chemical protein modification is complex; 15,[17][18][19][20] however, pKa provides information about the relative stability of both the neutral and charged states. Cysteines with low pKa's have readily accessible thiolates that are prone to covalent chemical modification by electrophilic inhibitors (Figure 1).…”

Thia-Michael addition: the route to promising opportunities for fast and cysteine-specific modification

“…6, pink curve). 58 The reaction dependency on the pK a of the thiol may be negated by using a strong nucleophile as a catalyst instead of a base (Scheme 2b). The process of nucleophile-catalyzed thia-Michael reaction starts with the attack of a nucleophilic catalyst to the CvC double bond affording an intermediate zwitterion.…”