Computational Study and Kinetic Analysis of the Aminolysis of Thiolactones

Abstract

The aminolysis of three differently α-substituted γ-thiolactones (C4H5OSX, X = H, NH2, and NH(CO)CH3) is modeled based on CBS-QB3 calculated free energies corrected for solvation using COSMO-RS. For the first time, quantitative kinetic and thermodynamic data are provided for the concerted path and the stepwise path over a neutral tetrahedral intermediate. These paths can take place via an unassisted, an amine-assisted, or a thiol-assisted mechanism. Amine assistance lowers the free energy barriers along both paths, while thiol assistance only lowers the formation of the neutral tetrahedral intermediate. Based on the ab initio calculated rate coefficients, a kinetic model is constructed that is able to reliably describe experimental observations for the aminolysis of N-acetyl-dl-homocysteine thiolactone with n-butylamine in THF and CHCl3. Reaction path analysis shows that for all conditions relevant for applications in polymer synthesis and postpolymer modification, an assisted stepwise mechanism is operative in which the formation of the neutral tetrahedral intermediate is rate-determining and which is mainly amine-assisted at low conversions and thiol-assisted at high conversions.

Synthesis of Thiol‐Containing Oligopeptides via Tandem Activation of γ‐Thiolactones by Silver‐DABCO Pair

“…Previous computational studies of the γ-thiolactone aminolysis by simple amines indicated that the reaction mainly proceeds through an assisted stepwise mechanism. [24] However, since the presence of silver(I) and DABCO in our study showed a significant increase in the reactivity of γ-thiolactone, another reaction pathway must be operating. A tentative mechanism was proposed to rationalize the various results summarized in Table 1 (Scheme 2).…”

Unveiling α-Etherification Effects on the Aminolysis of α,α-Difluoroacetate Enables the Aminolysis Post-polymerization Modification of α,α-Difluoro-α-(aryloxy)acetate-Containing Polymers

“…In our previous report, a self-catalytic pathway was proposed for the aminolysis reaction of α,α-difluoroacetate units. According to the report, an additional amine molecule catalyzes the proton transfer from the nucleophile amine to the leaving alcohol group in an analogous process to that described by Espeel, Reyniers, and their co-workers for the aminolysis of thiolactones . Because this tendency was also implied in our experiments, to shed light on the effect of the α-etherification on the α,α-difluoroacetate units, its role in the self-catalytic pathway must be considered.…”

Protected thiol strategies in macromolecular design

“…This was not further investigated, but an explanation can be found in a later publication from Reyniers and co-workers discussing the aminolysis of thiolactones [247]. Using different diamines, polyamide-like structures with symmetrically distributed sidechains bearing thiol groups could be obtained.…”