Intrinsic Barriers for the Reactions of an Oxocarbenium Ion in Water

Abstract

The nucleophile addition reactions of R-methyl benzyl carbocations with Lewis bases are fast and are generally perceived to be thermodynamically favorable processes. 2,3 By contrast with proton-transfer reactions at carbon, 4-6 there has been little consideration of whether these reactions of unstable carbocations are intrinsically fast, or whether they are fast simply because they are energetically favorable. This distinction requires a knowledge of the intrinsic barrier to the reaction in the absence of a thermodynamic driving force. We report here intrinsic rate constants of (k MeOH ) o ) 1 × 10 8 M -1 s -1 and (k p ) o ) 450 s -1 for the nucleophilic addition of methanol to the acetophenone oxocarbenium ion 2H + and deprotonation of 2H + by solvent water, respectively (Scheme 1). These intrinsic rate constants correspond to intrinsic barriers of Λ MeOH ) 6.5 kcal/mol and Λ p ) 13.8 kcal/mol for the nucleophile addition and proton-transfer reactions, respectively. Table 1 summarizes the rate and equilibrium constants for the formation and reaction of 1, 1H + , 2, and 2H + in water at 25°C (Scheme 1). The literature values 7,8 of k MeOH ) 3 × 10 6 M -1 s -1 and k H ) 1600 M -1 s -1 give K add ) 1900 for the addition of methanol to 2H + to give 1. The value of pK a ) -6.2 for protonated acetophenone dimethyl ketal 1H + was estimated starting from pK a ) -2.52 for protonated dimethyl ether. 9 The equilibrium constant for the addition of methanol to 2H + to give 1H + can then be calculated as (K add ) H ) K add /K a ) 0.0012 M -1 (Scheme 1). The first-order rate constant for the cleavage of 1H + to give the oxocarbenium ion 2H + can be calculated as k solv ) k H K a ) 2.5 × 10 9 s -1 . This is smaller than the rate constant of ∼10 10 s -1 for the thermodynamically favorable deprotonation of 1H + by solvent water to regenerate 1, 11 so that 1 and 1H + are essentially at chemical equilibrium during the acid-catalyzed cleavage of 1. This is in agreement with the conclusions of earlier studies that 1H + is an intermediate of the stepwise, specific-acidcatalyzed hydrolysis of ketals, 12 which is the microscopic reverse of nucleophilic addition of methanol to 2H + to form 1.The rate constants for protonation of R-methoxystyrene 2 by hydronium ion and acetic acid in water at 25°C and I ) 1.0 (KCl) were determined by published methods 13 as (k H ) alk ) 80 M -1 s -1 and k AcOH ) 0.13 M -1 s -1 , respectively. Figure 1 shows the effect of increasing concentrations of acetate ion on the ratio of the yields of R-methoxystyrene 2 and acetophenone from the acid-catalyzed cleavage of acetophenone dimethyl ketal 1 in water at pH 7.0 (10 mM phosphate buffer) at 25°C and I ) 1.0 (KCl). 14 The data were fit to eq 1 to give k AcO /k HOH ) 0.0034 M -1 for partitioning of 2H + between deprotonation by acetate ion to give 2 and nucleophilic addition of solvent water to give, ultimately, acetophenone. 15 This partitioning ratio can be combined with the value of 5 × 10 7 s -1 for k HOH , 7 to give k AcO ) 1.7 × 10 5 M -1 s -1 as the abs...

The generation and reactions of quinone methides

“…129,132,133,137,139 The very large intrinsic barriers for nucleophile additions to 48 are consistent with the notion that this electrophile is an extreme example of a benzylic-type carbocation, where extensive delocalization of charge away from the quinone carbon is driven by the resulting relief of destabilizing polar interactions between the electrophilic carbon and the electron-deficient α-CF 3 groups. Consequently, the neutral, non-aromatic resonance form B makes a exceptionally large contribution to the structure of 48 (Scheme 48).…”

Toward a Detailed Understanding of Base Excision Repair Enzymes: Transition State and Mechanistic Analyses of N-Glycoside Hydrolysis and N-Glycoside Transfer

“…165,166 The study of glycosylase mechanisms has often focused on understanding the nature of oxacarbenium ions and how their formation is stabilized by specific interactions with enzymes.…”

Influence of N7 Protonation on the Mechanism of the N-Glycosidic Bond Hydrolysis in 2‘-Deoxyguanosine. A Theoretical Study

“…In fact, the Gibbs free energy barrier of this process is only 1.3 kcal/mol, which is not surprising since the high electrophilic character of oxacarbenium ions makes them undergo nucleophilic attack with almost no barrier. 48,49 The second step of the process implies also the protonation of the N3 position on the guanine. Note that in this case we do not obtain the canonical tautomer of guanine but a different one which lies 4.8 kcal/mol above it, in good agreement with previous theoretical results at the B3LYP level.…”