Base-catalyzed, mechanisms for

Evidence against the covalent mechanism has been summarized by Mock, who has also proposed alternative general-base-catalyzed mechanisms for ther-molysin and carboxypeptidase A.143 He suggests that His-231 is the general base for thermolysin and the carboxy-terminal carboxylate for carboxypeptidase A. The one common feature of all the proposed mechanisms is the Zn2+ functioning as a Lewis acid to polarize the substrate. 

Figure 1. Schematic representation of the relationships between proposed catalytic and inhibitory mechanisms. A. Postulated general acid-general base catalyzed mechanism for substrate hydrolysis by an aspartyl protease. The water molecule indicated is extensively hydrogen bonded to both aspartic acid residues plus other sites in the active site (see Reference 16 for details). Hydrogen bonds to water are omitted here. B. Kinetic events associated with the inhibition of pepsin by pepstatin. The pro-S hydroxyl group of statine displaces the enzyme immobilized water molecule shown in Figure lA. Variable aspartyl sequence numbers refer to penicillopepsin (pepsin, Rhizopus pepsin), respectively.

WORKED PROBLEM 19.20 Write the products of the aldol condensations of the following compounds. Write both an acid- and a base-catalyzed mechanism for (b). 

Scheme 1.15 The base-catalyzed mechanism for the hydrothiolation of an activated C=C bond.

Bob s research interests and knowledge across chemistry were great. Throughout his career he retained an interest in biomimetic chemistry, specifically the study of metal ion-promoted reactions and reactions of molecules activated by metal ion coordination. His early interests in carbohydrate chemistry inspired him to study metal ion catalysis of both peptide formation and hydrolysis as well as studies in inorganic reaction mechanisms. He was particularly interested in the mechanisms of base-catalyzed hydrolysis within metal complexes and the development of the so-called dissociative conjugate-base (DCB) mechanism for base-catalyzed substitution reactions at inert d6 metal ions such as Co(III). 

Tautomerization can be induced through the addition of an acid or base. (See the previous section for details on tautomerism.) We begin here by investigating the racemization (the formation of both enantiomers) of the compound shown in Figure 11-5, and we use this reaction to investigate both the acid and base mechanisms. The acid-catalyzed mechanism is shown in Figure 11-6 and the base-catalyzed mechanism is shown in Figure 11-7. 

The hydrolysis of esters of the amino acid betaine (trimethylglycine), see Fig. 8, shows extraordinary strong pH dependence. In an alkahne environment the rate of hydrolysis is much higher for these substances than for esters in general, whereas they are more stable in an acidic environment [25,26]. In fact, betaine esters are generally hydrolyzed at a significant rate by the base-catalyzed mechanism even at neutral pH. 

Note how the key interaction boosting the catalytic effect is the protonation of the carbonyl group on the TG. Such catalyst-substrate interaction increases the electrophilicity of the adjacent carbonyl carbon atom, making it more susceptible to nucleophilic attack. Compare this to the base-catalyzed mechanism where the base catalyst takes on a more direct route to activate the reaction, creating first an alkoxide ion that directly acts as a strong nucleophile (Figure 4). Ultimately, it is this crucial difference, i.e., the formation of a more electrophilic species (acid catalysis) v.s. that of a stronger nucleophile (base catalysis), that is responsible for the differences in catalytic activity. 

Figure 13.8 Variation of hydrolysis half-life at 25°C for several carboxylic acid esters as a function of solution pH due to changing contributions of the acid-catalyzed, neutral, and base-catalyzed mechanisms.

The tautomerization of an enol to a ketone is catalyzed by either acid or base. In the acid-catalyzed mechanism, H+ is added in the first step (see Figure 11.6). In the base-catalyzed mechanism, H+ is removed in the first step. Show the steps in the mechanism for the base-catalyzed tautomerization. 

The same base-catalyzed mechanism accounts for the profile obtained in deuteriation of the 2-position of quinoline (Fig. 2.10), with the reaction occurring on the cation [7 JCS(B)4]. This mechanism is found at an ex-... 

The following box summarizes the base-catalyzed and acid-catalyzed mechanisms for nucleophilic addition, together with their reverse reactions. 

Acid-catalyzed transesterification and Fischer esterification take place by nearly identical mechanisms. Transesterification can also take place by a base-catalyzed mechanism, but all attempts at base-catalyzed Fischer esterification (using OR", for example) seem doomed to failure. Explain why Fischer esterification cannot be catalyzed by base. 

Enamines with good 7r-acceptor substituents at Cp, including conjugated enamines of the type just described, can hydrolyze by a base-catalyzed mechanism probably stepwise nucleophilic vinylic substitution at Ca (see equations 34 and 41). The generality of this mechanism has yet to be demonstrated, but it is strongly implied for compounds 35 and 37 (R = N02), and less dramatically for 37 (R = Br). 

No other adducts are formed, and the endo/exo diastereomeric ratio is essentially the same for all of these methods. Further, the existence of an acid catalyzed mechanism for cycloaddition can be explicitly excluded by using an excess of a hindered amine base (2,6-di-tert-butylpyridine, DTBP) in the aminium salt induced reaction and by examining the results of an authentic acid catalyzed reaction (using, for example, triflic acid). In the former case, the same endo and exo adducts are formed in virtually the same relative amounts, but in the latter case neither of these adducts is formed. It is worth noting that acid catalyzed reactions have indeed sometimes been observed under typical aminium salt conditions [70], but these have never been observed, nor would they be expected, under PET conditions. Finally, in the instance where cation radicals are generated by the aminium salt method, the intervention of substrate cation radicals can usually be verified by the addition of the reduced form of the catalyst, i.e., the neutral triarylamine, to the reaction mixture. 

The precise mechanisms by which thiirane 1,1-dioxides are converted stereospecifically into alkenes and SO2 (or products derived from SO2) are not clearIn typical Ramberg-Backlund reactions both thermal and base-catalyzed mechanisms are likely to be in operation, with the latter generally predominating. The importance of the base-catalyzed pathway accounts for the fact that thiirane 1,1-dioxides... 

Figure 13 Chemical models for the radical isomerization process in the action of DDH. At the top is a base-catalyzed mechanism by way of a ketyl radical as the key intermediate. At the bottom is an acid-catalyzed mechanism by way of a radical cationic intermediate.

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