Intramolecular NH···S Hydrogen Bonding in the Zinc Thiolate Complex [Tm^Ph]ZnSCH₂C(O)NHPh:  A Mechanistic Investigation of Thiolate Alkylation as Probed by Kinetics Studies and by Kinetic Isotope Effects

Abstract

The zinc thiolate complex [Tm(Ph)]ZnSCH2C(O)N(H)Ph, which features a tetrahedral [ZnS4] motif analogous to that of the Ada DNA repair protein, may be obtained by the reaction of Zn(NO3)2 with [Tm(Ph)]Li and Li[SCH2C(O)N(H)Ph] ([Tm(Ph)] = tris(2-mercapto-1-phenylimidazolyl)hydroborato ligand). Structural characterization of [Tm(Ph)]ZnSCH2C(O)N(H)Ph by X-ray diffraction demonstrates that the molecule exhibits an intramolecular N-H...S hydrogen bond between the amide N-H group and thiolate sulfur atom, a structure that is reproduced by density functional theory (DFT) calculations. The thiolate ligand of [Tm(Ph)]ZnSCH2C(O)N(H)Ph is subject to alkylation, a reaction that is analogous to the function of the Ada DNA repair protein. Specifically, [Tm(Ph)]ZnSCH2C(O)N(H)Ph reacts with MeI to yield PhN(H)C(O)CH2SMe and [Tm(Ph)]ZnI, a reaction which is characterized by second-order kinetics that is consistent with either (i) an associative mechanism or (ii) a stepwise dissociative mechanism in which the alkylation step is rate determining. Although the kinetics studies are incapable of distinguishing between these possibilities, a small normal kinetic isotope effect of kH/kD = 1.16(1) at 0 degrees C for the reaction of [Tm(Ph)]ZnSCH2C(O)N(H*)Ph (H* = H, D) with MeI is suggestive of a dissociative mechanism on the basis of DFT calculations. In particular, DFT calculations demonstrate that a normal kinetic isotope effect requires thiolate dissociation because it results in the formation of [PhN(H)C(O)CH2S]- which, as an anion, exhibits a stronger N-H...S hydrogen bonding interaction than that in [Tm(Ph)]ZnSCH2C(O)N(H)Ph. Correspondingly, mechanisms that involve direct alkylation of coordinated thiolate are predicted to be characterized by kH/kD < or = 1 because the reaction involves a reduction of the negative charge on sulfur and hence a weakening of the N-H...S hydrogen bonding interaction.

Further insights into the mechanism of the reaction of activated bleomycin with DNA

“…5). The frequencies of bending modes have been shown to contribute significantly to the normal secondary isotope effect observed for S N 2 reactions in alkyl and ethyl halides (17)(18)(19)(20). In our computational model, the O-H stretch and OH ip bend are clean modes that are easily mapped in the H/D-substituted reactant and TS complexes.…”

Applications of tripodal [S3] and [Se3] L2X donor ligands to zinc, cadmium and mercury chemistry: organometallic and bioinorganic perspectives

“…74,75 In this regard, the thiolate copmplexes [Tm R ]ZnSCH 2 C(O)N(H)Ph (R = Ph, Bu t ), which incorporate an N-H hydrogen bonding functionality, provide a more refined structural analogue for the Ada protein. 71b, 76 The presence of hydrogen bonding interactions within [Tm R ]ZnSCH 2 C(O)N(H)Ph was confirmed by X-ray diffraction, as illustrated in Figure 13. Selected data pertaining to the hydrogen bonding interactions are summarized in Table 3 In an effort to discern further details concerned with the nature of alkylation reactions involving [Tm R ]ZnSR derivatives, a series of kinetics studies were performed for the reaction of [Tm Ph ]ZnSCH 2 C(O)N(H)Ph with MeI (Scheme 14).…”

“…Selected data pertaining to the hydrogen bonding interactions are summarized in Table 3 In an effort to discern further details concerned with the nature of alkylation reactions involving [Tm R ]ZnSR derivatives, a series of kinetics studies were performed for the reaction of [Tm Ph ]ZnSCH 2 C(O)N(H)Ph with MeI (Scheme 14). 76 However, the derived kinetics were incapable of distinguishing between associative and dissociative reaction mechanisms. Specifically, although the kinetics indicate a second order rate law, such an observation does not prove that the mechanism is associative because a dissociative reaction can also exhibit second order kinetics if re-coordination of RS − to the zinc center competes with alkylation by MeI.…”

Nucleophilicity of zinc-bound thiolates

“…[15] The influence of the nature of the metal cation on the nucleophilicity of p-toluenethiolate has been studied both experimentally and by DFT computation, revealing that nickel-and zinc-thiolate complexes are more reactive than ironand cobalt-thiolate complexes. [16] In the case of zinc complexes, both the composition of the ligand set, [17][18][19][20] in terms of donating capability and steric hindrance, and the presence of hydrogen bonding towards the reactive thiolate [21][22][23][24] have been shown to modulate the reactivity against electrophiles.…”

“…In the case of zinc-bound thiolates, several studies provide the rate constants of their reaction against electrophile but it is difficult from these data to have a general view of their relative nucleophilicities as the experimental conditions are not the same. [19,21,23,24,29] Such a determination would however be of great significance in order to evaluate the relative reactivity of enzymes and to determine which thiolate is reactive in zinc active sites including more than one cysteinate.…”