THIOL CATALYSIS OF GEOMETRIC ISOMERIZATION OF BENZALDEHYDE SEMI-CARBAZONE BY NUCLEOPHILIC-ADDITION

The isomerization of (Z)- to (E)-benzaldehyde semicarbazone is catalyzed by aliphatic and aromatic thiols. The proposed reaction mechanism involves rate-determining formation of a tetrahedral addition intermediate which undergoes fast bond rotation, nitrogen inversion, and/or proton exchange, followed by loss of thiol to generate the isomeric semicarbazone. The reaction, which provides a convenient method for measuring rates of nucleophilic addition of thiols to a carbon-nitrogen double bond in a system where equilibrium formation of the tetrahedral addition intermediate is highly unfavorable, has been used to investigate the detailed mechanism of this addition reaction in water at 25 °C. Addition of strongly basic thiols to the semicarbazone follows the rate law kthiol = kRS-[RSk] + kRSH[RSH]; for weakly basic thiols krsh is large and kRS- cannot be detected. Rate constants, kRS-, show little or no dependence on the pKa of the thiol (β ≤ 0.13) for thiols of pKa 7.9-10.3. Rate constants, kRHS, for thiols of pKa ≥ 5.5 follow a Brønsted-type relationship with a slope of log kRHS vs. pKa of -1.1, consistent with a mechanism involving rate-determining addition of the thiol anion to the protonated semicarbazone with βnuc approximately 0. For less basic thiols (pKB 2.7-5.5) the slope of log kRHS vs. pKa is ca. -0.65, corresponding to βnuc for the anion of 0.35. For strongly basic thiols the βnuc of 0 and calculated rate constants for anion attack on the protonated semicarbazone are consistent with a rate-determining diffusion-controlled reaction of RS, s- with the protonated semicarbazone, a “one-encounter” mechanism with rate-determining reorganization of the complex formed upon protonation of the semicarbazone by the thiol, or rate-determining semicarbazone protonation by H3O+ in the presence of “spectator” thiol anion. The value of βnuc ~0.35 for weakly basic thiols may reflect a change in rate-determining step or curvature in the Brønsted-type plot that results from a change in transition-state structure corresponding to significant carbon-sulfur bond formation for the poorer nucleophiles. © 1979, American Chemical Society. All rights reserved.