Nucleophilic cleavage of the sulfur-sulfur bond by phosphorus nucleophiles. III. Kinetic study of the reduction of a series of ethyl aryl disulfides with triphenylphosphine and water

Overman, Larry E.; PETTY, S. T.

doi:10.1021/jo00907a016

Cited by 38 publications

(19 citation statements)

References 2 publications

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“…The calculated activation free energy of the first step of reduction of Et 2 S 2 with PPh 2 CH 3 and PPh 3 in H 2 O are 15.7 and 19.2 kcal/mol, respectively, versus 14.9 and 17.1 kcal/mol measured in 0.1 M NaOH in H 2 O/dioxane (3:1 mol). [49][50][51] We calculated the restoring forces of the local coordinate, f l in each conformer of Et 2 S 2 as fl cl /l l , 3 where l l is (force-dependent) compliance of local coordinate l, and l cl is the coupling coefficient 58 between this coordinate and the constrained distance. All compliances were derived from analytical Hessians computed at force f. Calculations with B3LYP/6-311 þ G(d) and B3LYP/6-311 þ þ G(3df, 2pd) basis sets resulted in nearly identical force-extension curves and the relationship between the stretching and local forces of the ensemble of Et 2 S 2 ( Supplementary Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The strain-free mechanism is shown in Fig. 3a; [49][50][51][52] of this intermediate to the disulphide requires a thiolate nucleophile, which can be (partially) protonated by acid, reduction of disulphides by phosphines is one of the few reactions in which the rate constant for the formation of a highly unstable reaction intermediate can be measured. By comparing this rate constant derived from the pH-dependence of the reduction rate of an unstrained disulphide with the one derived from the rate versus force correlations for a series of strained disulphides using the model in Fig.…”

Section: Strategymentioning

confidence: 99%

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Model studies of force-dependent kinetics of multi-barrier reactions

et al. 2013

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According to transition state theory, the rate of a reaction that traverses multiple energy barriers is determined by the least stable (rate-determining) transition state. The preceding ('inner') energy barriers are kinetically 'invisible' but mechanistically significant. Here we show experimentally and computationally that the reduction rate of organic disulphides by phosphines in water, which in the absence of force proceeds by an equilibrium formation of a thiophosphonium intermediate, measured as a function of force applied on the disulphide moiety yields a usefully accurate estimate of the height of the inner barrier. We apply varying stretching force to the disulphide by incorporating it into a series of increasingly strained macrocycles. This force accelerates the reduction, even though the strain-free rate-determining step is orthogonal to the pulling direction. The observed rate-force correlation is consistent with the simplest model of force-dependent kinetics of a multibarrier reaction.

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Section: Methodsmentioning

confidence: 99%

Section: Strategymentioning

confidence: 99%

Model studies of force-dependent kinetics of multi-barrier reactions

et al. 2013

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“…Model studies show that reduction of disulfides by phosphines is initiated by rate-limiting formation of a thiophosphonium salt (1,(8)(9)(10)(11). Subsequent, rapid, hydrolysis releases the second thiol fragment and the phosphine oxide (Scheme 1).…”

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confidence: 99%

New Water-Soluble Phosphines as Reductants of Peptide and Protein Disulfide Bonds: Reactivity and Membrane Permeability

et al. 2004

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Tris(2-carboxyethyl)phosphine (TCEP) is a widely used substitute for dithiothreitol (DTT) in the reduction of disulfide bonds in biochemical systems. Although TCEP has been recently shown to be a substrate of the flavin-dependent sulfhydryl oxidases, there is little quantitative information concerning the rate by which TCEP reduces other peptidic disulfide bonds. In this study, mono-, di-, and trimethyl ester analogues of TCEP were synthesized to evaluate the role of carboxylate anions in the reduction mechanism, and to expand the range of phosphine reductants. The effectiveness of all four phosphines relative to DTT has been determined using model disulfides, including a fluorescent disulfide-containing peptide (H(3)N(+)-VTWCGACKM-NH(2)), and with protein disulfide bonds in thioredoxin and sulfhydryl oxidase. Mono-, di-, and trimethyl esters exhibit phosphorus pK values of 6.8, 5.8, and 4.7, respectively, extending their reactivity with the model peptide to correspondingly lower pH values relative to that of TCEP (pK = 7.6). At pH 5.0, the order of reactivity is as follows: trimethyl- > dimethyl- > monomethyl- > TCEP >> DTT; tmTCEP is 35-fold more reactive than TCEP, and DTT is essentially unreactive. Esterification also increases lipophilicity, allowing tmTCEP to penetrate phospholipid bilayers rapidly (>30-fold faster than DTT), whereas the parent TCEP is impermeant. Although more reactive than DTT toward small-molecule disulfides at pH 7.5, all phosphines are markedly less reactive toward protein disulfides at this pH. Molecular modeling suggests that the nucleophilic phosphorus of TCEP is more sterically crowded than the thiolate of DTT, contributing to the lower reactivity of the phosphine with protein disulfides. In sum, these data suggest that there is considerable scope for the synthesis of phosphine analogues tailored for specific applications in biological systems.

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“…1a). [5][6][7][8][9] These investigations pointed out the critical role played by water in the reduction process, [5][6][7]9 and the higher propensity of aryl disulfides or mixed alkyl aryl disulfides over alkyl disulfides to be cleaved by triphenylphosphine.…”

Section: Mainmentioning

confidence: 99%

Thiol catalysis of selenosulfide bond cleavage by a triarylphosphine

Firstova

Melnyk

Diemer

2022

Preprint

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The arylthiol 4-mercaptophenylacetic acid (MPAA) is a powerful catalyst of selenosulfide bond reduction by the triarylphosphine 3,3′,3′′-phosphanetriyltris(benzenesulfonic acid) trisodium salt (TPPTS). Both reagents are water-soluble at neutral pH and are particularly adapted for working with unprotected peptidic substrates. Contrary to trialkylphosphines such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP), TPPTS has the advantage of not inducing deselenization reactions. We believe that the work reported here will be of value for those manipulating selenosulfide bonds in peptidic or protein molecules.

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Nucleophilic cleavage of the sulfur-sulfur bond by phosphorus nucleophiles. III. Kinetic study of the reduction of a series of ethyl aryl disulfides with triphenylphosphine and water

Cited by 38 publications

References 2 publications

Model studies of force-dependent kinetics of multi-barrier reactions

Model studies of force-dependent kinetics of multi-barrier reactions

New Water-Soluble Phosphines as Reductants of Peptide and Protein Disulfide Bonds: Reactivity and Membrane Permeability

Thiol catalysis of selenosulfide bond cleavage by a triarylphosphine

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