THIOL OXIDATION a Slippery Slope the Oxidation of Thiols — Molecules RSH Oxidation May Proceed Too Predominates

RESEARCH HIGHLIGHTS

Nature Reviews Chemistry | Published online 25 Jan 2017; doi:10.1038/s41570-016-0013

THIOL OXIDATION A slippery slope The oxidation of thiols — molecules RSH oxidation may proceed too predominates. Here, the maximum of the form RSH — can afford quickly for intermediates like RSOH rate constants indicate the order − − − These are many products. From least to most to be spotted and may also afford of reactivity: RSO > RS >> RSO2 . common oxidized, these include disulfides intractable mixtures. Addressing When the reactions are carried out (RSSR), as well as sulfenic (RSOH), the first problem, Chauvin and Pratt in methanol-d , the obtained kinetic reactions, 1 sulfinic (RSO2H) and sulfonic slowed the reactions down by using isotope effect values (kH/kD) are all but have (RSO3H) acids. Such chemistry “very sterically bulky thiols, whose in the range 1.1–1.2, indicating that historically is pervasive in nature, in which corresponding sulfenic acids were no acidic proton is transferred in the been very disulfide bonds between cysteine known to be isolable but were yet rate-determining step. Rather, the residues stabilize protein structures, to be thoroughly explored in terms oxidations involve a specific base- difficult to and where thiols and thiolates often of reactivity”. The second problem catalysed mechanism wherein an study undergo oxidation by H2O2 or O2 in was tackled by modifying the model acid–base equilibrium precedes the order to protect important biological system, 9-mercaptotriptycene, by rate-determining nucleophilic attack − − − structures from damage. Among including a fluorine substituent to of RS , RSO or RSO2 on H2O2. the oxidation products, sulfenic serve as a spectroscopic handle. The If the environment deviates even

acids are particularly reactive and bulky 9-mercapto-10-fluorotrip- slightly from being pH neutral, H2O2 their existence is often only putative. tycene — featuring thiol and fluoro (and alkylhydroperoxides, which are However, Jean-Philippe Chauvin and groups at the sp3-hybridized bridge- mimics of lipid peroxides) will react Derek Pratt report in Angewandte head carbons — is readily prepared with the sulfenic acid/sulfenate faster Chemie International Edition the from the tert-butyl thioether, which than the thiol/thiolate, reflecting the direct observation of a sulfenic acid as in turn is formed by the Diels–Alder slippery slope that is thiol oxidation. the initial product in thiol oxidation. reaction of 9-tert-butylthio-10- For biology to use sulfenic acids

Oxidizing a thiol with H2O2 — the fluoroanthracene with benzyne. it must overcome this bias to curb quintessential reactive oxygen species What of the oxidation of overoxidation during protein folding, in both laboratories and in living 9-mercapto-10-fluorotriptycene? cell signalling or peroxide detoxifi-

systems — is simple to perform Treatment with H2O2 in buffered cation. The results of Chauvin and but difficult to understand because methanol sequentially converts the Pratt point to biomolecules having many products can form. Indeed, thiol to the corresponding sulfenic, finely tuned regions — including sulfinic and sulfonic acids. Each residues affecting hydrogen bonding species gives rise to a well-resolved and local pH — proximal to thiols 19F NMR resonance, with more oxi- that can in some cases reverse the dized species appearing at successively innate reactivity bias. Pratt now plans lower field. Monitoring the reaction to investigate “if sulfenic acids are mixture allows determination of a involved in other oxidations of thiols, rate constant for each of the three including those induced by ozone, successive oxidations, which are first as well as singlet and triplet oxygen. order in both the sulfur compound These are common reactions, but

and H2O2. The kinetics agree with have historically been very difficult

rates observed when H2O2 is added to study”. Yet, history has long smiled to authentic samples of thiol, sulfenic on fundamental research of this ilk, and sulfinic acid. which places us closer to uncovering The observed reactivities also the many secrets sulfur still keeps. mesh well with the pKa values of the thiol, sulfenic and sulfinic acid David Schilter (11.6, 12.8 and 4.3, respectively). ORIGINAL ARTICLE Chauvin, J.-P. R. & Pratt, D. A. The reaction rate for each of the On the reactions of thiols, sulfenic acids, and oxidations increases with pH up to sulfinic acids with hydrogen peroxide. Angew. a plateau at which pH exceeds pKa Chem. Int. Ed. http://dx.doi.org/10.1002/ anie.201610402 (2016) Rachael Tremlett/Macmillan Publishers Limited and the oxidizable conjugate base