Date of Award

5-2013

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor

Alice E. Bruce

Second Committee Member

Mitchell R.M. Bruce

Third Committee Member

François G. Amar

Abstract

Thiol disulfide exchange is of fundamental importance in biochemistry, including protein folding, cellular redox balance, enzyme regulation, and oxidative cell-signaling pathways. The thiophilic metals, zinc(II) and gold(I), have the potential to alter thiolate disulfide exchange. Zinc(II) is a biologically important metal ion, while the isoelectronic ion, gold(I), has been used to treat rheumatoid arthritis.

NMR spectroscopic techniques are used to study the kinetics and mechanism of gold(I) and zinc(II) thiolate disulfide exchange: LMSR + R'SSR' → LMSR' + RSSR' (where LM = Ph3PAu and Tp*Zn; R = p-CH3C6H4; R' = p-ClC6H4 and p-O2NC6H4). The method of initial rates establishes an overall second order rate law; first order in metal thiolate and disulfide. Kinetics data in six solvents, DMSO-(d6, DMF-d7, CD3CN, CD3COCD3, CD2Cl2 and THF-d8 are analyzed using an integrated form of a second order rate law. The disulfide with the more electron withdrawing group, (O2NC6H4S)2, reacts faster than (ClC6H4S)2 in all solvents. For example, the rate constants for the reaction of Ph3PAuSR and (O2NC6H4S)2 vary from 9.61 xl0-4 M-1s-1 in THF-d8 to 3.36 M-1s-1 in DMSO-d6. For gold(I) and zinc(II), exchange rates are faster in high dielectric solvents KINETIC ANALYSIS OF METAL ASSISTED-THIOLATE DISULFIDE compared to low. This trend is opposite to that of thiolate disulfide exchange in the absence of metals. Zinc(II) thiolate disulfide exchange is approximately three times faster than gold(I).

2D (1H-1H) ROESY and NOESY NMR experiments provide evidence of close association between metal thiolate [gold(I) and zinc(II)] and disulfide. The association complex intermediate is stabilized in higher dielectric solvents.

Two different side reactions were investigated in DMSO solution. GC-MS and UV-vis spectrophotometry were used to measure the amount of an impurity, dimethylsulfide, present in all samples of DMSO tested, at ca. 0.5 mM concentrations. The reaction of DMS with (O2NC6H4S)2 is explained and accounted for in the kinetic analysis.

Another side reaction involved formation of Ph3PO, which depends on the reactants, the substituent group of the disulfide, and the water content of the solvents. The experimental results establish that formation of Ph3PO is slower than gold thiolate disulfide exchange and is negligible during the time frame of the kinetic experiments.

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