Deprotonation rate-limiting

Citrate synthase catalyzes the metabolically important formation of citrate from ace-tyl-CoA and oxaloacetate [68]. Asp-375 (numbering for pig CS) has been shown to be the base for the rate-limiting deprotonation of acetyl-CoA (Fig. 5) [69]. An intennediate (which subsequently attacks the second substrate, oxaloacetate) is believed to be formed in this step the intermediate is thought to be stabilized by a hydrogen bond with His-274. It is uncertain from the experimental data whether this intermediate is the enolate or enol of acetyl-CoA related questions arise in several similar enzymatic reactions such as that catalyzed by triosephosphate isomerase. From the relative pK values of Asp-375... 

We mention Williams work briefly here because it may also explain Blangey s observations strongly basic primary amines unequivocally form 7V-nitrosoanilinium ions in strongly acidic media. In contrast to the rate-limiting deprotonations of the less basic aromatic and heteroaromatic nitrosoamine cations discussed in this section, the TV-nitroso cation of a strongly basic amine deprotonates extremely slowly. Therefore, the nitroso rearrangement, the Fischer-Hepp reaction, competes effectively with the 7V-deprotonation. 

There are two cases in which the general base catalysis observed for an azo coupling reaction is due not to a rate-limiting proton transfer from the o-complex (Scheme 12-66) but to deprotonation of the coupling component when the species involved in the substitution is formed. These reactions are shown in Schemes 12-71 H I... 

In the azo coupling of nitroethane (Machacek et al., 1968 a, 1968 b already discussed in Sec. 12.7) the forward step of Scheme 12-71 corresponds to the formation of the nitroethane anion. This step is a rate-limiting deprotonation and is therefore general base-catalyzed. 

In the azo coupling reaction of acetoacetanilide (Dobas et al., 1969b) the reaction steps of Schemes 12-71 and 12-72 constitute a steady-state system, i.e., Arx [B] < Ar [HB+] == 2[Ar —NJ] A 2 — 0 with a fast subsequent deprotonation (Scheme 12-73). As with nitroethane, this reaction is general base-catalyzed because the ratedetermining step is the formation of the anion of acetoacetanilide (Scheme 12-71). In contrast to the coupling of nitroethane, however, the addition of the diazonium ion (Scheme 12-72) is rate-limiting. The overall kinetics are therefore between zero-order and first-order with respect to diazonium ion and not strictly independent of [ArNJ ] as in the nitroethane coupling reaction. 

The formation of the Wheland intermediate from the ion-radical pair as the critical reactive intermediate is common in both nitration and nitrosation processes. However, the contrasting reactivity trend in various nitrosation reactions with NO + (as well as the observation of substantial kinetic deuterium isotope effects) is ascribed to a rate-limiting deprotonation of the reversibly formed Wheland intermediate. In the case of aromatic nitration with NO, deprotonation is fast and occurs with no kinetic (deuterium) isotope effect. However, the nitrosoarenes (unlike their nitro counterparts) are excellent electron donors as judged by their low oxidation potentials as compared to parent arene.246 As a result, nitrosoarenes are also much better Bronsted bases249 than the corresponding nitro derivatives, and this marked distinction readily accounts for the large differentiation in the deprotonation rates of their respective conjugate acids (i.e., Wheland intermediates). 

Regarding the first problem, the most elemental treatment consists of focusing on a few points on the gas-phase potential energy hypersurface, namely, the reactants, transition state structures and products. As an example, we will mention the work [35,36] that was done on the Meyer-Schuster reaction, an acid catalyzed rearrangement of a-acetylenic secondary and tertiary alcohols to a.p-unsaturatcd carbonyl compounds, in which the solvent plays an active role. This reaction comprises four steps. In the first, a rapid protonation takes place at the hydroxyl group. The second, which is the rate limiting step, is an apparent 1, 3-shift of the protonated hydroxyl group from carbon Ci to carbon C3. The third step is presumably a rapid allenol deprotonation, followed by a keto-enol equilibrium that leads to the final product. 

The SB-GA mechanism consists of a rapid equilibrium deprotonation of the ZH intermediate, followed by rate-limiting, general acid-catalysed leaving-group departure from the anionic cr-complex Z via the concerted transition state, 2. The derived expression for this mechanism is equation 4, where fctBH is the rate coefficient for acid-catalyzed expulsion of L from Z and K3 is the equilibrium constant for the reaction ZH Z- + BH. 

Several reaction mechanisms are possible for the cleavage of A-(hydroxy-methyl) intermediates [214], In the case of derivatives of amides and imines, the reaction is base-catalyzed, with the rate-limiting step being deprotonation of the A-(hydroxymethyl) compound (which has a pKa of ca. 13 Fig. 

In the unlikely event that k2 > k, Atqh = mAt, and the act of deprotonation becomes rate limiting, affording powerful evidence for the necessity of (4.44) in the base reaction. Changes of rds with conditions show up in changing values of Ai/ (but surprisingly not AV ) with temperature (Sec. 2.6). 

In Eqn. (4.48), when Ar i > k, proton transfer is a pre-equilibrium and when A j < k, the act of deprotonation becomes rate-limiting. Since these processes are likely to have different heats of activation, in the intermediate region, A , = Atj, the heat of activation is changing and the Eyring plot will be curved. See Sec. 2.6. 

We conclude that the neutral substrate enters 1 to form a host-guest complex, leading to the observed substrate saturation. The encapsulated substrate then undergoes encapsulation-driven protonation, presumably by deprotonation of water, followed by acid-catalyzed hydrolysis inside 1, during which two equivalents of the corresponding alcohol are released. Finally, the protonated formate ester is ejected from 1 and further hydrolyzed by base in solution. The reaction mechanism (Scheme 7.7) shows direct parallels to enzymes that obey Michaelis-Menten kinetics due to the initial pre-equilibrium followed by a first-order rate-limiting step. 

Diazotization is a complex reaction (Scheme 1). When performed in acidic media with sodium nitrite, NOx or nitrosyl halides, its kinetics are dependent upon the acidity of the medium in media with a Hammett acidity constant (-H0) from — 1 to 3 the reaction rate increases with acidity and the formation of the nitroso cation is the rate-limiting step, in more acidic media (-H0 > 4) the reaction rate decreases when acidity increases and the deprotonation of intermediate 6 is the rate-limiting step.6-9... 

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