Reactions of Organic Disulfides and Gold(I) Complexes

Gold-thiolate/disulfide exchange reactions of (p-SC6H4Cl)2 with Ph3PAu(SC6H4CH3), dppm(AuSC6H4CH3)2, and dppe(AuSC6H4CH3) 2 were investigated. The rate of reactivity of the gold-thiolate complexes with (p-SC6H4Cl)2 is: dppm(AuSC6H4CH3)2>> dppe(AuSC6H4CH3)2>Ph2PAu (SC6H4CH3). This order correlates with conductivity measurements and two ionic mechanisms have been evaluated. 1H NMR experiments demonstrate that in the reaction of dppm(AuSC6H4CH3)2 with (p-SC6H4Cl)2, the mixed disulfide, ClC6H4SSC6H4CH3, forms first, followed by the formation of (p-SC6H4CH3)2. The rate law is first order in (pp-SC6H 4Cl)2 and partial order in dppm(AuSC6H4CH3)2. Results from electrochemical and chemical reactivity studies suggest that free thiolate is not involved in the gold-thiolate/disulfide exchange reaction. A more likely source of ions is the dissociation of a proton from the methylene backbone of the dppm ligand which has been shown to exchange with D2O. The implications of this are discussed in terms of a possible mechanism for the gold-thiolate/disulfide exchange reaction.

INTRODUCTION Gold in the +1 oxidation state is a soft metal and is therefore expected to have less affinity for the "hard" sulfur in disulfides than for the "soft" sulfur in thiolates. However, there are several reports in the literature that demonstrate that gold(I) can react with simple organic disulfides as well as the disulfide bonds in proteins. 2. 3 The reaction of gold(I) and disulfides is potentially significant for the biochemistry of gold(I) drugs because of the importance of disulfide bonds in stabilizing protein structure and moderating biochemical reactions. There is added significance for rheumatoid arthritis where oxidative stress is believed to result in an increase in disulfide bonds in oroteins? b Several years ago, we began a program to study whether phosphine gold(I) thiolate complexes would react with organic disulfides. 4 This study was motivated by the observation that dppm(AuSCsH4CHa) undergoes the gold-thiolate/disulfide exchange reaction shown in eq. 1.4, There are LL(AuSCH4CHz)= + (p-SC.H4CI)= LL(AuSCsH4CI) + (p-SCsH4CHa)2 (1) (LL dppm, dppe) 2 LAuSCH,CH + (p-SCH4CI) 2 LAuSCsH4CI + (p-SCH4CH)= (2) (L PPh3) several features that make this reaction noteworthy. It occurs at room temperature in N=-purged CH=CI or CHCI solution while thiol-disulfide exchange reactions generally require elevated temperatures (100 C), the presence of O, or prior deprotonation of the thiol.Another interesting feature is that the corresponding reactions of disulfides and the mononuclear complex, Ph3PAu(SCeHCH3), or the binuclear complex, dppe(AuSCeH4CHa)=, with a longer bisphosphine backbone, do not readily occur under similar conditions. 4.s These observations prompted us to undertake a more thorough investigation of the goid-thiolate/disulfide exchange reactions as shown in eqs. and 2. tetrahydrofuran, was measured in the cell prior to addition of the gold sample. Gold complexes were weighed out in 5-10 mg increments. After addition of sach increment, the conductance was measured.

MATERIALS AND METHODS
Typically, a total of 40-60 mg of compound was used. All measurements were made in the air and at room temperature.

RESULTS AND DISCUSSION
The gold-thiolate/disulfide exchange reactions, shown in eqs. 1-2, can be monitored by H NMR. s,, In the reaction of dppm(AuSCH4CH)= with disulfide (eq 1), the mixed disulfide, CICsH4SSCsH4CHs begins forming immediately upon mixing. After 20 minutes, 35% of (p-SCsHCI)= is converted into CICeH4SSCeHCH3. Although the reaction is initially fast, it gradually slows down so that after 1.5 hours, conversion of (p-SCH,CI)2 to CICeH4SSCeH4CH is 50% complete and after 15 hours, it is 65% complete (see Table 1). The symmetrical disulfide, (p-SCeH4CH)=, and the symmetrical gold product, dppm(AuSCeHCI)=, also form later in the reaction. In contrast, reaction of PhzPAu(SCeH,CHz) or dppe(AuSCH4CH) with (p-SCeH,=CI)= under similar conditions produces no detectable amount of CICeHSSCeH4CH [or (p-SCeHCH3)z] during the first several hours. A small amount of reactivity is seen only over a long time period.
Rate Studies. Monitoring the H NMR spectra at different initial concentrations of gold-thiolate and disulfide, allows for an estimation of the rate of reaction, s'' The rate law for the reaction of dppm(AuSCHCH) with (p-$CHCI) is first order in disulfide but is only partial order in dppm(AuSCHCH). TM The partial order of the gold complex indicates the possibility of a pre-equilibrium whereby only a fraction of the gold complex present in solution is active towards the gold-thiolate/disulfide exchange reaction.  Conductivity. To aid our interpretation of the rate data, we performed conductivity measurements :n a series of complexes including Ph3PAu(SC6H4CH3), dppe(AuSC6H4CH3), and dppm(AuSC6H4CH3)=. 5,1,11 As shown in Table 1, the conductivity of dppm(AuSCHCH3)= in CH=CI= is an order of magnitude larger than the mononuclear complex and 5 times greater than the dppe complex. All complexes exhibit weak electrolyte behavior. In Figure 1, the conductivity of dppm(AuSC6H,CH3)= is shown in comparison to [Au(cis-dppee)2][PF6], a 1:1 electrolyte. This comparison allows us to estimate th'at the percent ionization of dpprn(AuSCHCH)= in CH=CI= is about 10%. a The correlation of the rate of the gold-thiolate/disulfide exchange reaction with conductivity led us to consider mechanisms involving ionic intermediates. H P--Au-SR Pathway a in Scheme would explain the data because thiolate/disulfide exchange reactions readily occur in solutions.containing free thiolate. '" However, three lines of evidence suggest that this pathway is not important in the initial reactivity observed in the gold-thiolate/disulfide exchange reaction.
The first line of evidence involves electrochemical tests for free thiolate. Cyclic voltammetry experiments on dppm(AuSC6HCH)2 show that there are two irreversible oxidation waves at +0.6 V and +1.6 V vs.
SCE. 1 The first oxidation wave has been assigned as a sulfur-based oxidation on the thiolate ligand. In contrast, the free thiolate, p-thiocresolate, oxidizes irreversibly at 0 V vs. SCE. 15 Therefore if a thiolate ligand was dissociating from the gold complex (pathway a) it should be possible to detect it by oxidation. Figure 2 shows the results of two bulk electrolysis experiments conducted on solutions of dppm(AuSCeH4CH) = in 1.0 M TBAH/CHzCI=. Figure a shows the total coulombs passed vs. time for a bulk electrolysis experiment done at +0.3 V vs. SCE using a Pt mesh working electrode. Them is no sign of oxidation and the cyclic voltammogram of the solution is identical to that prior to electrolysis. For comparison, Figure l b shows the bulk electrolysis conducted at +1.1 V vs. SCE (after the first oxidation wave for dppm(AuSCH4CH), but before the second) in which a significant amount of oxidation occurs.
The cyclic voltammogram of this solution shows that the first oxidation wave at +0.6 V has disappeared, but the peak at +1.6 V is still present. Another test for free thiolate made use of the reaction between (CH30)3PO and thiolate, which is known to be rapid (eq. 3). 16 When (CH30)PO is added to dppm(AuSC6H4CHz)= in d6-dmso (in an approximate 1:4 molar ratio), there is no reaction even after one week. 1 (CHO)PO + "$CH,OH --, (CHO)PO=" + CH=SCH,CH Shaw and coworkers have studied ligand scrambling reactions of R3PAu(CN) to form (R3P)=Au* and Au(CN)2-. These reactions are unusual because they do not require the presence of excess ligand. 17 We tested our complexes for the presence of ligand scrambling to see if that might be contributing to the conductivity and reactivity with disulfide. Thus if a thiolate ligand was dissociating from the gold complex, then in a mixture of two different dinuclear gold complexes (which have very similar molar conductivities) the thiolate ligands should exchange as shown in equation 4. This exchange would be detected by a shift dppm(AuSCH,CH)= + dppm(AuSC-ICI)= 2 dppm(AuSCH,CH)(AuSCH,CI) (4) in the meta hydrogens on the aromatic ring of the thiolate, relative to the pure samples. However, the H NMR spectrum of a 1"1 mixture of dppm(AuSCeH4CH)2 and dppm(AuSCeH4CI)2 in CD=CI2 shows that the doublet peaks centered at 6.87 and 6.97 ppm, assigned to the meta-ring hydrogens in SCH,CH and SC6H4CI, respectively, do not shift and are identical to the chemical shifts for each complex alone. '1 An interesting feature in the H NMR spectrum of dppm(AuSC6H4CH)= is that the methylene hydrogens on the dppm ligand appear as a broad triplet at 3.7 ppm (in CD=CI=) and the chemical shift is concentration dependent. ,1 This suggests that there is an equilibrium between two species involving the methylene hydrogens on the dppm ligand. To test this hypothesis, two equivalents of D=O were added tc a solution of dppm(AuSC6H4CHa)2 in CDCI=. After 3 hours the methylene hydrogens on the dppm liganc have decreased by one-half and after 12 hours, the triplet signal has disappeared. Thus, pathway b ir Scheme appears to be a better explanation for the ionic intermediates present in solutions ol dppm(AuSCHCH).
There are several examples in the literature that illustrate the acidity of the methylene hydrogens in oordinated dppm.However, deprotonation of a dppm ligand generally requires a strong base. An important feature of the dinuclear gold complex, dppm(AuSCHCH)2, is that it exists in solution as a mixture of gold-gold bonded and nonbonded conformers. 4' The activation barrier for interconversion of these two conformers is about 10 kcal/mole, which agrees with other estimates of the gold-gold bond strength. TM Our results suggest that the auriophilic Au-Au interaction in dppm(AuSCHCH)2 perturbs the electronic structure enough to effect the acid-base properties of the methylene protons in dppm. Indeed there is precedent in the literature for this type of effect. Fackler, Schmidbaur, and coworkers recently reported that the basicity of a nitrogen atom in a TPA ligand bound to gold(I) is greater when there is a stronger Au-Au interaction. Thus the solid state Au-Au interaction is 0.2 shorter in (TPA)AuCI vs. ITPA-HCI)AuCI (where TPA is 1,3,5-triza-7-phosphaadamantane).
Pathway b in Scheme also explains the reactivity with disulfide if the anionic gold complex is ctivated towards disulfide exchange. It is known that increasing the electron density on a transition metal omplex activates it toward oxidative addition. = In addition, many transition metals undergo oxidative ddition reactions with organic disulfides. A plausible mechanism that accounts for both the conductivity ;f dppm(Au$CHCH) and reactivity with disulfide is shown in Scheme II (where R = CH,CH and R* = 3eHCI). The gold-gold interaction influences the acid-base properties of the dppm ligand and we propose :hat an anionic intermediate forms which is activated toward reaction with disulfide. Scheme II shows 'oxidative addition" of disulfide occurring at one gold center, followed by "reductive elimination" of mixed isulfide and concomitant formation of the mixed gold complex. Small molecules, such as CHal and I, are (nown to oxidatively add across two gold(I) atoms in dinuclear complexes. However, if disulfide ;xidatively adds across the golds in this case, it would lead to an equal probability of formation of ymmetrical and mixed disulfides. Oxidative addition to one gold center is more consistent with the experimental results because the mixed disulfide forms significantly earlier in the reaction than does the symmetrical disulfide, (p-SCeH4CH3)=. Finally, it is interesting and somewhat unusual that the oxidative addition product is unstable and apparently immediately undergoes reductive elimination of disulfide. =='z We assume that the reaction is govemed by the formation of the most thermodynamically stable disulfide and gold-thiolate bonds. We are continuing to investigate the role of auriophilic Au-Au interactions in the deprotonation of the dppm ligand as well as in the reaction with disulfides.