Acid-base Pre-equilibria

In this solvent the reaction is catalyzed by small amounts of trimethyl-amine and especially pyridine (cf. 9). The same effect occurs in the reaction of iV -methylaniline with 2-iV -methylanilino-4,6-dichloro-s-triazine. In benzene solution, the amine hydrochloride is so insoluble that the reaction could be followed by recovery. of the salt. However, this precluded study mider Bitter and Zollinger s conditions of catalysis by strong mineral acids in the sense of Banks (acid-base pre-equilibrium in solution). Instead, a new catalytic effect was revealed when the influence of organic acids was tested. This was assumed to depend on the bifunctional character of these catalysts, which act as both a proton donor and an acceptor in the transition state. In striking agreement with this conclusion, a-pyridone is very reactive and o-nitrophenol is not. Furthermore, since neither y-pyridone nor -nitrophenol are active, the structure of the catalyst must meet the conformational requirements for a cyclic transition state. Probably a concerted process involving structure 10 in the rate-determining step... 

The rate and activation parameters have been determined for the reaction of potassium methanethiolate with various 2-fluoro- and bromo-pyridines. Although an ortAo-methyl group did not activate the 2- position in 2-bromo- or 2-fluoro-pyridine towards attack by the methanethiolate ion, deactivation of the ortho rather than the para position was observed. At 110°C for the bromo-compounds Ao-Me Xp-Me = 3-9, while Ao-Br A -Br = 2-2. The results have been compared with those obtained using methoxide and benzenethiolate anions in methanol. The relative rates observed in HMPA are the same as those in methanoP . Thio-phenol reacts faster than its anion with a bromopyridine, in methanol, due to a rapid acid-base pre-equilibrium in which the pyridine is protonated. An o-MeO substituent accelerates the replacement of Br, and a small increase is also noted on going from MeOH to DMSO as solvenpii. 

The most direct interpretation, then, is that these reactions proceed by an Sn2 mechanism. However, the rate law in itself does not necessarily establish the reaction mechanism, because there may be other plausible mechanisms also consistent with the observed rate law. It is important that this point be emphasized and, fortunately, the discussion here illustrates how this can happen and how it then becomes necessary to design experiments to rule out some of the possible mechanisms. Garrick suggests a acid-base pre-equilibrium, Eq. (28), followed by the dissociation of the conjugate base, Eq. (29), and subsequent addition of the solvent, Eq. (30). 

Pre-equilibria. The base hydrolysis of trifluoroacetanilide is complicated by an acid-base equilibrium 22... 

Although these effects are often collectively referred to as salt effects, lUPAC regards that term as too restrictive. If the effect observed is due solely to the influence of ionic strength on the activity coefficients of reactants and transition states, then the effect is referred to as a primary kinetic electrolyte effect or a primary salt effect. If the observed effect arises from the influence of ionic strength on pre-equilibrium concentrations of ionic species prior to any rate-determining step, then the effect is termed a secondary kinetic electrolyte effect or a secondary salt effect. An example of such a phenomenon would be the influence of ionic strength on the dissociation of weak acids and bases. See Ionic Strength... 

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. 

Pre-equilibrium ionization of E generates the more reactive anion Ee, which may be protonated on carbon by the general acid water in the rate-determining step, Equation (6). For pH values well below piff, the concentration cH is much greater than K, which may thus be neglected in the denominator of Equation (6). The rate of this reaction is then inversely proportional to cH , i.e., proportional to cOHe. This apparent base catalysis saturates at pH values above p f , when E is converted to E . The concentration cH then becomes much smaller than and may be neglected in the denominator of Equation (6). 

The MEMED technique has been used to study the hydrolysis of aliphatic acid chlorides in a water/l,2-dichloroethane (DCE) solvent system [3]. It was shown unambiguously that the reaction proceeds via an interfacial process and shows saturation kinetics as the concentration of acid chloride in the DCE increases the data were well fitted to a model based on a pre-equilibrium involving Langmuir adsorption at the interface. First-order rate constants for interfacial solvolysis of CH3(CH2) COCl were 300 150(n = 2), 200 100(n = 3) and 120 60 s-1( = 8). 

Although free radical reactions are found less often in solution than in the gas phase, they do occur, and are generally handled by steady state methods. There are also organic and inorganic reactions that involve non-radical intermediates in steady state concentrations. These intermediates are often produced by an initial reversible reaction, or a set of reversible reactions. This can be compared with the pre-equilibria discussed in Section 8.4, where the intermediates are in equilibrium concentrations. The steady state treatment is also used extensively in acid-base catalysis and in enzyme kinetics. 

When a base catalyzed reaction with proton transfer in the first step is carried out in D20 solution, the substrate exchanges its acidic hydrogen with the deuterium of the solvent before the reaction takes place if the mechanism is fast pre-equilibrium proton transfer with subsequent slow step. If, on the other hand, hydrogen exchange does not occur prior to the reaction, it may be concluded that proton transfer is the rate-determining step. 

The halogenation of ketones is also general acid catalysed. The mechanism usually consists of a rapid pre-equilibrium protonation of the carbonyl group followed by a slow proton transfer from carbon to the base catalyst [41]. The enol thus produced reacts rapidly with halogen. The overall mechanism is similar to mechanism (7) described earlier and the observed rate coefficient is a product of the equilibrium constant for protonation of the carbonyl group and the rate coefficient for the proton transfer from carbon, and therefore does not refer to a single proton transfer step. 

The rate-determining step always corresponds to protonation or deprotonation of a carbon atom, while equilibration of oxygen acids with their conjugate bases is established rapidly. This fact can be used to determine the acidity constants of enols, ynols and ynamines by flash photolysis, Kf, either kinetically, from downward bends in the pH rate profiles indicating a pre-equilibrium, or from the changes of the transient absorption in solutions of different pH (spectrographic titration). Such studies have provided some remarkable benchmark numbers, such as the acidity constant of phenylynol (pKf < 2.1),476 phenylynamine (pKf < 18.0)477 and its pentafluoro derivative (pKf = 10.3),478 and of the carbon acid 2,4-cyclohexadienone, pKf = —2.9 475 The enolization constant of 2,4-cyclohexadienone is pKE = 12.7. 

Activation of Metal-bound Water In this mechanism, a metal ion, usually a zinc, complexes a water molecule and lowers its pfCa from 14 to values perhaps as low as 7 or 8, thus readily producing a nucleophilic metal-bound hydroxide anion [68, 69]. Proton transfer thus occurs in a pre-equilibrium step and does not participate, in the form of general acid-base catalysis, in the rate-limiting step. 

If we find experimentally kD > kH in a catalyzed reaction, then an acid-base equilibrium must always be involved in the kinetic scheme. If the reaction involves only one proton transfer, then the converse is also true for catalysis by hydrogen ions, i.e., if kB > fcD, then there is no pre-equilibrium. On the other hand, in a reaction involving two successive proton transfers the pre-equilibrium and the subsequent proton... 

If we assume that k2 is independent of the isotopic composition then k /k is less than unity because K /K < K /K owing to water being the weaker acid. Of course this approach will not work for acids less acidic than water and since the deuteroxide ion in deuterium oxide is a stronger base than hydroxide we are unable to distinguish between the pre-equilibrium mechanism (Eqn. 20) and one involving direct hydroxide attack (Eqn. 22 - see Table 3). 

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