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CHAPTER1 3 Thiol-disulfideinterchange RAJEEVASINGH lmmunoGen,lnc., 748 Sidney St.,Cambrtdge, MA 02139 and GEORGEM WHITESIDES Departmentof Chemistry,Harvard university,12 oxford St.,Cambridge, MA02138 I. INTRODUCTION 634 II. METHODS USED IN FOLLOWING THIOL-DISULFIDE INTERCHANGE 636 A. Spectroscopic(UV, NMR) Assays 636 B. EnzymaticAssays 631 C. AssaysBased on Chromatography 638 III. MECHANISM 638 A. Products 638 B. Dependenceon Solution pH, and on the pK" Valuesof Thiols 638 C. Kinetics 639 1. Rate law 639 2. Br/nsted relation 640 3. Substituent effects 641 a. Steric 641 b. Acidity 642 c. Charge 642 d. Hydrogen bonding 642 e. Reactionsinvolving cyclic disulfides 643 4. Solvent effects 643 5. Gas-phasestudies 645 6. Catalysis 645 7. Comparison with selenolate-diselenideinterchange 646 D. Transition State Structure 646 E. TheoreticalCalculations on Thiol-Disulhde Interchanse 646 F. MechanisticUncertainties . 641 SupplementS: The ,hr^irnrv of sulphur-containinllfunctional aroups Edited by S. Patai and Z. Rappoport O 1993John Wiley & Sons Ltd 633 634 R. Singh and G. M. Whitesides IV. EQUILIBRIUMIN THIOL DISULFIDE INTERCHANGE - REACTIONS 6-l A. Equilibria Involving Monothiols 641 B. Equilibria Involving a,co-Dithiols 648 V. APPLICATIONSOF THIOL-DISULFIDE INTERCHANGE IN BIOCHEMISTRY 654 u. CONCLUDING REMARKS 655 VII. ACKNOWLEDGMENTS 656 VIII. REFERENCES 656 I. INTRODUCTION Thiol-disulfrde interchangeis the reaction of a thiol (RSH) with a disulfide(R'SSR'), with formation of a new disulfide (RSSR')and a thiol (R'SH) derived from the original disulfide(equation 1). The reactionis unique in organic chemistry:although it involves the cleavageand formation of a strong covalent bond (the S-S bond; bond energy ca 60 kcal mol 1),it occurs reversiblyat room temperaturein water at physiological pH (ca 7)1-a.The reaction is moderately fast: a typical value of the observed rate constant is ca 10M-1min-r at pH 7 and room temperatures.The half-lifefor the reactionis ca 2h for mM concentrationsof thiol and disulfidein aqueoussolution at pH 7. and for alkanethiolswith normal valuesof pK^ (ca9-10). The yield of the reactionis quanti- tative if side-reactions-such as air oxidation of thiol to disulfide,and cleavageof disulfidebonds at high pH-are preventedr. RSH + R,SSR,= RSSR,+HSR, (I) - Thiol-disulfide interchangeis an Sr2 reaction.Thiolate anion (RS ) is the active if solution is made acidict.The reaction nucleophileand the reactioncan be stopped the -zo. is overall second-order:first-order each in thiolate and in disulfide(equations ) 4f In this chapter, we will distinguish between rhlol-disulfide interchange(the overall observedprocess, equation 1),and thiolate-disulfideinterchange (the reaction of thiolate anion with disulfide,equation 3). The two processesdiffer according to the extent to which thiol is dissociatedto thiolate anion under the reactionconditions. RSH = RS + H+ (pK^*t") (2) _SR, RS_+ R,SSR,= RSSR,+ (3) * H + SR' = HSR' (pK"*'tt) (4) 2s Thiolate-disulhde interchange is base catalyzed2l and involves the backside nucleophilicattack of thiolate anion along the S-S bond axis of the disulfide26.It showsless sensitivity to solventthan most S"2 reactionsinvolving oxygenand nitrogen nucleophilesls.The rates of thiolate-disulfideinterchange in polar aprotic solvents (DMSO, DMF) are fasterby a factor of approximately 103than rates in polar protic solvents(water, methanol). For comparison,the rate enhancementfor oxyanions(which s aremore highlysolvated than thiolates)1on moving from protic to polar aproticsolvents is 106-107. Biologicallyimportant moleculescontaining the thiol or the disulfidegroup are widely distributedin naturel'2,and the unique position of thiols and disulfidesin biochemistry 3. hasbeen reviewed in severalexcellent books and articlest The thiol-containingamino acid cysteine-is presentin proteinsand peptides;examples include glutathione2- and trypanothione2s-30.Several cofactors coenzymeA, dihydrolipoamide,coenzyme M (-O3SCH2CH2SH)3r containthe essentialthiol functionalityl'2.The disulfidebonds 635 = 0 =f - .F -10 c 50 a) lTl q q) C LLJ 30 20 r0 0 -r0 0 30 60 90 120 150 180 Dihedralangle (HSSH or CSSC) ')of FIGURE 1. Relativeenergy lkJmol HSSH and MeSSMeas a function of the dihedralangle ({, RSSR):( ) MM2 (85);(--) 6-31G* [M. Aida and C. Nagata, Theor. Chint. Acta,70,73 11986)J,(- -) SCF and MP2 [C. J. Marsdenand B. J. Smith,J. Pht's. -) Chem.,92,347(1988)l; (- - OPLS [W L. Jorgensen,J. Ph1,s. Chem.,90, 6379 (1986)1. Reprinted with permission from Reference16. Copyright (1990)American Chemical Society 636 R. Singh and G. M. Whitesides betweencysteine residues are important tertiary and quarternarystructural clcntcnrr in proteins(especially extracellular proteins) such as immunoglobulins,enzymes, horntor.rc.. procollagenand albuminl-3. The cleavageof the disulfidebond(s) of many proteins1e .g. deoxyribonucleaseI) resultsin loss of activity32.Thiol-disulfide interchangemay plal a role in metabolic regulation of enzymatic activities3'::':+.76. activitiesof several chloroplastenzymes such as fructose-1,6-biphosphatase,NADP-malate dehydrogenase, sedoheptulose-1,7-biphosphatase, NADP-glyceraldehyde-3-phosphate dehydrogenase and phosphoribulokinaseare enhancedby reduction of their specificdisulfide bonds by photogeneratedreducing equivalents transferred via ferredoxinand thioredoxin3''rs-'17. The cleavageof disulfide bonds of B-adrenergicand other cell surfacereceptors by thiols activatesthe receptorin a manner similar to binding of agonist3s'3e. The thiol functional group is essentialfor activity of many enzymesl'2such as thiol proteases (papain, ficin, bromelain)a0,B-ketoacylthiolaseal-a3, enolaseaa, creatine kinase,glyceraldehyde-3-phosphate dehydrogenase, phosphofructokinase and adenylate kinaser-3'11.These enzymes are inactivein mixed disulfideform, and can be reactivated using strongly reducing thiols (e.g. dithiothreitol, lV,ly''-dimethyl-N,lV'-bis(mercapto- acetyl)hydrazine)l1'18.A thiolate anion may be involved in methanogenesisby 2elle redox couplingwith a Ni cofactorin methyl coenzymeM reductase3t.The reactivethiol functionalityis maskedas a trisulfidein the potent DNA-cleavageagents-calichemycin and esperimicin4s-48.The rate-determiningstep in the unmaskingof theseDNA-cleavage agentsis the cleavageof the trisulhdeby a thiol (e.g.glutathione)48. The thiolate anion formedundergoes intramolecular Michael-type attack on an enonesystem, which in turn facilitatesthe ring closureof the enediynemoiety to form the reactivearomatic diradical. Thiolate anion is a strong nucleophileand a good leavinggroup becauseof its high polarizability and low degreeof solvation.The thiol group is lessstrongly hydrogen- bonded,and the thiolate anion is lesssolvated, than the alkoxide anion. The value of pKu of the SH group of butanethiol in DMSO (ca 17)is 7 units higher than in water (ca 10);the correspondingpKu value for the OH group of butanol is 12 units higher in DMSO (ca28) than in water (cctI6)ae-s1. The optimum CSSC dihedral angle in the disulfide bond is ca90 (Figure l). The energy barrier to rotation around CSSC bond is c'u7.5 kcalmol-1 s2. Five-membered cyclic disulfidesare strainedand have a CSSC dihedral angle of ca 30. s3.Sulfur shows concatenation:molecular sulfur S, exists as an eight-memberedring; organosulfur compoundscontaining tri- and polysulfidelinkages (RS"R) are found in natureand have beencharacterizedsa's s. This chapter focuseson the physical-organicaspects of the thiol-disulfide interchange reaction.The biochemicalaspects of the reaction are only lightly touched upon here, and we recommendReferences 1-3 to the readerfor a detailedreview of the biochemistrv. II. METHODSUSED IN FOLLOWINGTHIOL-DISULFIDE INTERCHANGE A. Spectroscopic(UV, NMR) Assays The kinetics of thiol disulfide interchange reactions involving formation of a chromophoric thiolate are convenientlyfollowed by UV spectroscopy.The reactionof thiolates with excessEllman's reagent [EllS-SEll, 5,5'-Dithiobis(2-nitrobenzoicacid)] is usedfor quantitativeestimation of thiol by measuringthe absorptiondue to Ellman's thiolate(EllS ) at 412nm (equation5)so-su. Reactions of thiols with 4,4'-dipyridyldisulfide and 2,2'-dipyridyl disulfide generatechromophoric thiols: 4-thiopyridone (r3z+n-: t 19600M cm- 1)and 2-thiopyridone(e.o.,_ : 8080M- 1cm t) respectivelyso-t'u. The kinetics and equilibria of reactions involving cyclic five- and six-membered disulfidescan be followed at 330nm and 290 (or 310nm) respectively.Five-membered 13. Thiol-disulfide interchanse 637 RS_.,;b,_, el'o*o, Ellman's Reagent EIIS-SEII (5) ---* RS-S + OrN EIIS E4r2n^:13600 M tcm-t cyclic disulfides absorb in the UV region at 330nm (e:147M tcm t) and six- membered disulfides absorb at 290nm (e: 290M tcm t) or 3l0nm (e:110M I a-- tys,s:,63-6s. 1H NMR spectroscopycan be used to determinethe position of equilibria in thiol disulfideinterchange reactionsro'13'18, and to follow the kineticsof the reactions(either in the reactingsystem or after quenchingwith acid)18'6668. This method is usefulwhere the methyleneprotons e and p to the sulfur in the reactantsand products differ in chemical shift and can be integratedaccurately. Dynamic lHNMR lineshapeanalysisls'1'and spin-transfermethodse'6e have beenused to determinethe rate constantsof degenerate intermolecularthiolate-disulfide interchangereactions: RS- + RSSR: RSSR+ RS Analysisof 1H NMR lineshapes,where the resonancesare exchange-broadened,is useful for determining the ratesof fast degenerateintermolecular interchangereactions between thiolatesand
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    M. L. Gallego-Diez et al.; Revista Facultad de Ingeniería, No. 79, pp. 138-149, 2016 Revista Facultad de Ingeniería, Universidad de Antioquia, No. 79, pp. 138-149, 2016 Validation of a methodology to determine Benzene, Toluene, Ethylbenzene, and Xylenes concentration present in the air and adsorbed in activated charcoal passive samplers by GC/ FID chromatography Validación de una metodología para la determinación de la concentración de Benceno, Tolueno, Etilbenceno y Xilenos, presentes en muestras aire y adsorbidos en captadores pasivos de carbón activado, mediante cromatografía GC/FID Mary Luz Gallego-Díez1*, Mauricio Andrés Correa-Ochoa2, Julio César Saldarriaga-Molina2 1Facultad de Ingeniería, Universidad de Antioquia. Calle 67 # 53- 108. A. A. 1226. Medellín, Colombia. 2Grupo de Ingeniería y Gestión Ambiental (GIGA), Facultad de Ingeniería, Universidad de Antioquia. Calle 67 # 53- 108. A. A. 1226. Medellín, Colombia. ARTICLE INFO ABSTRACT: This article shows the validation of the analytical procedure which allows Received August 28, 2015 determining concentrations of Benzene (B), Toluene (T), Ethylbenzene (E), and Xylenes (X) Accepted April 02, 2016 -compounds known as BTEX- present in the air and adsorbed by over activated charcoal by GC-FID using the (Fluorobenzene) internal standard addition as quantification method. In the process, reference activated charcoal was employed for validation and coconut -base granular charcoal (CGC) for the construction of passive captors used in sample taken in external places or in environmental air. CGC material was selected from its recovering capacity of BTEX, with an average of 89.1% for all analytes. In this research, BTEX presence KEYWORDS in air samples, taken in a road of six lines and characterized for having heavy traffic, in Validation, activated Medellín city (Antioquia, Colombia), was analyzed.
  • THIOL OXIDATION a Slippery Slope the Oxidation of Thiols — Molecules RSH Oxidation May Proceed Too Predominates

    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.