A computational study on the reaction mechanism and energetics of Markovnikov and anti-Markovnikov addition in alkyne hydrothiolation reactions

Exploring the Versatility of the Covalent Thiol–Alkyne Reaction with Substituted Propargyl Warheads: A Deciding Role for the Cysteine Protease

“…A radical-mediated thiol–yne mechanism was quickly excluded because covalent adduct formation was not prevented by absence of light and/or addition of radical scavengers and would have resulted in the anti-Markovnikov-type thiovinyl bond adduct with terminal C1 carbon ( Scheme 1 A). 30 , 31 Ekkebus et al 27 and Sommer et al 28 both propose a proximity-driven in situ thiol(ate)–alkyne addition that involves direct nucleophilic attack of the catalytic cysteine thiol(ate) to the alkyne internal C2 carbon ( Scheme 1 B). However, it was not possible to exclude the possibility that nucleophilic addition actually occurs with a more reactive allenic isomer, present at the enzyme active site in equilibrium with the unreactive terminal alkyne ( Scheme 1 C).…”

“…Excluded because this would form anti-Markovnikov-type product with alkyne C1 carbon atom. 30 , 31 (B) Proximity-driven in situ thiol(ate)–alkyne addition. 27 , 28 Direct nucleophilic attack on internal C2 alkyne by cysteine thiol is supported by mutagenesis experiments with SENP1; only catalytic Cys603 was essential to form covalent adduct with SUMO2-Prg.…”

“…The covalent thiol–alkyne addition forming a Markovnikov-type thiovinyl adduct is a newly discovered reaction for which several reaction mechanisms have been proposed (Scheme ). A radical-mediated thiol–yne mechanism was quickly excluded because covalent adduct formation was not prevented by absence of light and/or addition of radical scavengers and would have resulted in the anti-Markovnikov-type thiovinyl bond adduct with terminal C1 carbon (Scheme A). , Ekkebus et al and Sommer et al both propose a proximity-driven in situ thiol­(ate)–alkyne addition that involves direct nucleophilic attack of the catalytic cysteine thiol­(ate) to the alkyne internal C2 carbon (Scheme B). However, it was not possible to exclude the possibility that nucleophilic addition actually occurs with a more reactive allenic isomer, present at the enzyme active site in equilibrium with the unreactive terminal alkyne (Scheme C). , Alternatively, Arkona et al propose an enzyme-templated stepwise reaction with stabilization of a secondary carbanion intermediate in the oxyanion hole to overcome the thermodynamically unfavored bond formation (Scheme D).…”

Computationally unraveling the mechanism and selectivity of five and six membered N‐heterocyclic carbene‐catalyzed alkyne hydrochalcogenation

“…Kinetic information studies using AUTOF program identified INT as TDI and TS2 as TDTS and the calculated energetic span (δE) for the reaction were 29.99 and 20.87 kcal/mol for cis and trans addition pathways respectively. When compared with the reported (∆G) values for uncatalyzed gas phase acetylene hydrothiolation reaction (49.61 kcal/mol), it was clear that NHC lowered the free energy barrier by 19.62 and 28.74 kcal/mol respectively for cis and trans addition pathways 47 …”

“…When compared with the reported (ΔG) values for uncatalyzed gas phase acetylene hydrothiolation reaction (49.61 kcal/mol), it was clear that NHC lowered the free energy barrier by 19.62 and 28.74 kcal/mol respectively for cis and trans addition pathways. 47 S C H E M E 1 Envisioned pathway for NHC catalyzed acetylene hydrochalcogenation reaction A similar pathway for IH catalyzed acetylene hydroselenation reaction has also been unraveled. Characterized reaction points of the pathway showed only some minute geometric changes, inherent to switching methanethiol with methaneselenol.…”