Stoichiometric first-order reactions, substrate

Corey also pointed out that 16 reflects the transition-state of an enzyme-substrate complex. Its formation was later supported by the observation of Michaelis-Menten-type kinetics in dihydroxylation reactions and in competitive inhibition studies [37], This kinetic behavior was held responsible for the non-linearity in the Eyring diagrams, which would otherwise be inconsistent with a concerted mechanism. Contrary, Sharpless stated that the observed Michaelis-Menten behavior in the catalytic AD would result from a step other than osmylation. Kinetic studies on the stoichiometric AD of styrene under conditions that replicate the organic phase of the catalytic AD had revealed that the rate expression was clearly first-order in substrate over a wide range of concentrations [38],... 

Equation 2.6 has been established for well-defined conditions pseudo first-order in substrate (but any order in chiral auxiliary, stoichiometric or catalytic) and no change of mechanism during the course of the reaction, for example, no autoinduction by the products. Reactions with chiral catalysts are especially susceptible to auto-induction. It is then useful to give the calculated x values with an indication of the correspondence between conversion and ee j or eCp j [1 Ij. We advise running experiments for at least two values of conversion and subsequent verification that the X values obtained are identical or similar. If not, this can indicate a change in the structure of the reagent during the reaction or a non-first-order reaction in substrate. TTie extrapolation of x at initial conversion is a characteristic value for a... 

Having established that 1 catalyzes the hydrolysis of orthoformates in basic solution, the reaction mechanism was probed. Mechanistic studies were performed using triethyl orthoformate (70) as the substrate at pH 11.0 and 50 °C. First-order substrate consumption was observed under stoichiometric conditions. Working under saturation conditions (pseudo-0 order in substrate), kinetic studies revealed that the reaction is also first order in [H+] and in [1]. When combined, these mechanistic studies establish that the rate law for this catalytic hydrolysis of ortho-formates by host 1 obeys the overall termolecular rate law rate = k[H+][Substrate][l], which reduces to rate = k [H ][l] at saturation. 

Several kinds of evidence indicate that the reactions are catalytic rather than stoichiometric. When the reaction is followed to completion, linear first order plots are obtained for at least 90% of the reaction 7>. At the ratio of substrate to polymer employed, about 1 1 by weight, nonlinear first order plots would be predicted for a stoichiometric reaction. When a second aliquot of substrate is added after completion of the reaction, the first order rate constant noted with the second aliquot is essentially identical to that of the original7). The liberation of acetate and p-nitrophenol in equimolar proportions is also consistent with an inference of catalysis 7>. 

True catalysis was proven by three criteria (Table XI see p. 381). When three successive equimolar aliquots of OAA were reacted to completion with an equivalent amount of polymer (on a lysine residue basis), identical rates ( 7 relative %) were observed with each aliquot (Table XI). A progressive drop in rate would be expected from a stoichiometric reaction (33). Second, linear first-order plots were obtained from the interaction of equimolar amounts of substrate and polymer nonlinear plots would be predicted for a stoichiometric reaction (34-36). Third, in the experiments of Table XI at least three equivalents of COg were liberated for each equivalent of lysine residue present. The importance of avoiding an excess of polymer, in order to employ the first two criteria, was pointed out. 

A limited number of mechanistic studies of stoichiometric amide hydrolysis reactions promoted by Zn(II) complexes have been reported. Groves and Chambers reported studies of the zinc-mediated hydrolysis of an internal amide substrate wherein amide carbonyl coordination to the zinc center is not possible (Scheme 15).93 Examination of the rate of this reaction as a function of pH (6.5-10.5) yielded a kinetic pKa = 9.16. First-order rate constants at 70 °C (/i = 0.5 (NaC104)) for the Zn-OH2 and Zn-OH-mediated amide hydrolysis reactions differed by a factor of 100 when the data was fit to Equation (1) for the proposed mechanism shown in Scheme 16. The activation parameters determined for this reaction (Ai7 = 22(1) kcal mol-1 and AS = — 18(3) eu) are consistent with an intramolecular hydrolysis process wherein a zinc-bound hydroxide acts as an intramolecular nucleophile to attack the amide carbonyl in the ratedetermining step. 

Subscripts T, W, and M indicate the stoichiometric, aqueous, and micellar concentrations, respectively, of the organic reactant or substrate, S, and square brackets indicate concentration in moles per liter of total solution volume. Equation (1) defines the observed rate as the sum of the rates of reaction in the aqueous and micellar pseudophases where kyv,k tv A/ observed, aqueous, and micellar first-order rate constants,... 

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

---