Disproportionation of 2-(phenyldithio)benzoic acid (2) to phenyl disulfide and 2,2'-dithiodibenzoic acid is much faster for the salt than for the acid. Among the facts which suggest that the o-carboxylate moiety of the salt anchimerically facilitates disproportionation are the following: an increase in rapidity with increasing pH near pH 7; decreased rapidity for the meta isomer; lack of a marked effect of dilution; inhibition of disproportionation by A-ethylmaleimide (through trapping of benzenethiolate ion) but acceleration by addition of thiolate ion; accordance with expectation as to the relative rapidity of disproportionation of other dithiobenzoic acids; and, evidence for existence and consistent reactions of o-sulfenobenzoic acid anhydride (5a) as an unstable intermediate generated by anchimeric displacement of benzenethiolate ion by the o-carboxylate moiety.o-(2-Protoaminoethyldithio)benzoate ( 1) is active as an antiradiation drug.2 That the methyl ester, the meta isomer, and the para isomer of 1 showed no significant antiradiation activity2a led us to suspect anchimeric involvement of the carboxylate moiety of 1 with the disulfide linkage. In a similar vein, inactivity of the cyclohexyl analog of l2b is understandable, since this analog is believed to have trans substituents, which should resist anchimeric involvement. This suspicion of anchimeric involvement was strengthened during work with a phenyl counterpart (2) of 1, since the sodium salt of 2 (3) disproportionated far more readily to the two symmetrical disulfides than did 2 itself (eq l).This paper further supports the probability of such an anchimeric involvement in the reaction of eq 1.The extent of disproportionation of 2 proved to be highly dependent on the pH of the solution (Table I).At pH 14 disproportionation is 95% complete in 0.6 hr (calculated as usual).4 *Attack of the hydroxyl ion on(1) (a) Paper XXX:

o-Ca,rboxyphenyl o-carboxybenzenethiolsulfonate (4) was prepared easily in 77-92% yield from o-mercaptobeneoiic acid in one step using chlorine or sulfuryl chloride. It reacted readily in ethanol or pH 7 buffer to give unsymmetrical o-carboxyphenyl disulfides (5-IS), in yields exceeding 55%, with primary, secondary, and tertiary alkanethiols, an arenethiol, a heterocyclic thiol, and with mercapto amino acids. Other routes to these disulfides were inferior. The formation of o-carboxyphenyl disulfides affords a promising means of purifying and characterizing thiols, since typical compounds differ considerably in melting point and tlc Rr value, can be titrated with standard base, and can resist disproportionation well. Furthermore, the thiol can be regenerated by reduction either with sodium borohydride or dithiothreitol under mild conditions or recovered as the disulfide by disproportionation of the unsymmetrical disulfide. The o-carboxyphenylthio moiety seems promising for latentiating pharmacologically active thiols; it also reversibly blocks the sulfhydryl groups of an enzyme, although thus far it shows no advantages over Ellman's reagent.Earlier work, in a continuing study of disulfides,2 suggested that the o-carboxyphenylthio moiety, o-HO2CCs-H4S-(l), is a promising latentiating groupa for radioprotective thiols.6," It also suggested that salts of unsymmetrical disulfides containing moiety 1 showed an interesting instability.6 While looking further into these matters, we realized that moiety 1 had attractive potentialities for latentiation of other medicinally significant thiols, for purification, characterization, or resolution of thiols, and for working with biochemically important thiol groups such as those of proteins. Relevant to many of these purposes were the presence of the carboxyl group and the probability of easy removal of moiety l . This paper reports a study of some of these potentialities.We found earlier that o-mercaptobenzoic acid (2)6 or its disulfide (3)15 could be converted by chlorine-acetic acid-water in the Douglass-Farah reaction' to the thiolsulfonate (4). The 4 reacted with aminothiols to give compounds like 5-15 (eq l).5p6With thiophenol as RSH, instead of an aminothiol, the reaction of eq 1 still proceeded cleanly, without added base at room temperature. As Table I shows, o-carboxyphenyl phenyl disulfide ( 5 ) precipitated in 85% yield. One recrystallization gave 5 of' analytical purity in 74% yield.Attempts to prepare 5 by treating o-carboxybenzenesulfenyl chloride (prepared from 2 with chlorine) with thiophenol gave 5 in 48% yield; o-carboxybenzenesul-* To whom correspondence should be addressed.(1) (a)

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Die Disproportionierung der 2‐(Phenyldithio)‐benzoesäure (I) zu den symmetrischen Disulfiden (II) und (III) wird durch eine Salzbildung an (I) wesentlich beschleunigt, z.B. unter Annahme von Zwischenstufen der Art (IV) und (V).