Structure−Reactivity Relationships and Intrinsic Reaction Barriers for Nucleophile Additions to a Quinone Methide:  A Strongly Resonance-Stabilized Carbocation

Abstract

Second-order rate constants k Nu (M-1 s-1) were determined for addition of a wide range of nucleophiles to the simple quinone methide 4-[bis(trifluoromethyl)methylene]cyclohexa-2,5-dienone (1) to give the nucleophile adduct 1-Nu in water. Equilibrium constants were determined for the overall addition of HBr and HI to 1 to give H-1-Nu, and the data were used to calculate equilibrium constants for the addition of Br- and I- to 1, and to estimate equilibrium constants for the addition of Cl- and AcO-. The values of log k Nu show a linear correlation with the Ritchie nucleophilicity parameter N + with a slope s = 0.92 ± 0.10 that is essentially the same as the electrophile-independent value of 1.0 for highly resonance-stabilized carbocations. Marcus intrinsic barriers Λ of 12.4, 13.9, 15.4, and 19.8 kcal/mol are reported for the addition of I-, Br-, Cl-, and AcO- to 1, respectively. The thermodynamic barriers ΔG° and intrinsic barriers Λ for addition of Br-, Cl-, and AcO- to 1 are 8.4 ± 1.0 and 5.2 ± 0.2 kcal/mol larger, respectively, than the corresponding barriers for addition of these nucleophiles to the triphenylmethyl carbocation. It is concluded that, by the criterion of its chemical reactivity, 1 behaves as a highly resonance-stabilized carbocation. Values of N + = 4.0, 2.2, 1.2 and 0.60, respectively, are reported for I-, Br-, Cl-, and AcO-, which do not form stable adducts to Ritchie electrophiles. The slope of 2.0 (r = 0.98) for the linear correlation between Ritchie (N +) and Swain−Scott (n) nucleophilicity parameters shows that there is substantially greater bonding between the nucleophile and carbon at the transition state for nucleophile addition to sp2-hybridized carbon than for addition to sp3-hybridized carbon. Azide ion and nucleophiles with a nonbonding electron pair(s) at atoms adjacent to the nucleophilic site (α-effect nucleophiles) exhibit significant positive deviations from this correlation.

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

“…Hepatotoxicity likely related to the formation of several chemical species in liver, among which QM 70, has also been described for the antidiabetic drug troglitazone (69) which is subjected to metabolization in this organ (see Fig. 9) [81].…”

“…Finally, another drop in the reactivity was obtained with allylic substituents, for which reactions with nucleophiles break the resonance between the cyclic quinoid system and the double bond. Those substituents influence not only the rate of formation of this QM, but also its stability (half-life) and its electrophilicity, which directly influence its reactivity [69]. These structural considerations indicate that all QM species do not have the same reactivity towards biological nucleophiles, either in terms of potency or selectivity.…”

“…FRs are more reactive and are able to induce chemical and structural modifications in many cellular components, such as DNA, proteins and lipids. QMs react in qualitatively and quantitatively different ways than FRs: they are less reactive and more selective towards the kind of nucleophile they will bind to [69]. In contrast, they have the same features as alkylating agents.…”

“…They react with DNA (mainly the N7 of guanine) but also with other nucleophiles, among which, thiol-containing compounds are the most important. As strong electrophiles, QMs are, of course, prone to the same reactions, as it has been proven for example with celastrol (5) [68,69]. QMs have also been compared to free radicals (FRs) that act as chemical modifiers of the intracellular contents.…”

Auf dem Weg zu einer allgemeinen Nucleophilie‐Skala?

“…Bunting und Mitarbeiter berichteten beispielsweise, dass die Geschwindigkeitskonstanten der Reaktionen von Methyl-p-nitrosulfonaten mit 60 Aminen linear mit den entsprechenden Reaktivitäten gegen 4-Vinylpyridinium-Ionen korrelierten. [44] Analoge Reihungen der Nucleophilie wurden auch gegen Carbokationen und Halogenalkane bemerkt; Richard und Mitarbeiter stellten fest, [45] dass nur N 3 À und a-Effekt-Nucleophile stark von der linearen Korrelation zwischen Ritchies N + -und Swain-Scotts n-Konstanten abweichen (Abbildung 5).…”