Tetrahedral intermediate, and

Step 3 The product of step 2 is the conjugate acid of the tetrahedral intermediate It transfers a proton to water giving the neutral form of the tetrahedral intermediate and regenerating the acid catalyst... 

All these facts—the observation of second order kinetics nucleophilic attack at the carbonyl group and the involvement of a tetrahedral intermediate—are accommodated by the reaction mechanism shown m Figure 20 5 Like the acid catalyzed mechanism it has two distinct stages namely formation of the tetrahedral intermediate and its subsequent dissociation All the steps are reversible except the last one The equilibrium constant for proton abstraction from the carboxylic acid by hydroxide is so large that step 4 is for all intents and purposes irreversible and this makes the overall reaction irreversible... 

Hydrolysis. Esters are cleaved (hydroly2ed) into an acid and an alcohol through the action of water. This hydrolysis is cataly2ed by acids or bases. The mechanistic aspects of ester hydrolysis have received considerable attention and have been reviewed (16). For most esters only two reaction pathways are important. Both mechanisms involve a tetrahedral intermediate and addition-elimination reactions i7i7... 

The reactions of the specific classes of carbonyl compounds are related by the decisive importance of tetrahedral intermediates, and differences in reactivity can often be traced to structural features present in the tetrahedral intermediates. 

When the leaving group is better, breakdown can occur directly from A. This is the case when R"0 is a phenolate anion. The mechanism also depends upon the pH and the presence of general acids and bases because the position of the equilibria among the tetrahedral intermediates and their rates of breakdown are determined by these factors. 

Imine formation and enamine formation appear different because one leads to a product with a C=N bond and the other leads to a product with a C=C bond. Actually, though, the reactions are quite similar. Both are typical examples of nucleophilic addition reactions in which water is eliminated from the initially formed tetrahedral intermediate and a new C=Nu bond is formed. 

Transfer of a proton from one oxygen atom to another yields a second tetrahedral intermediate and converts the OH group into a good leaving group. 

Figure 7-6. Mechanism for catalysis by an aspartic protease such as HIV protease. Curved arrows Indicate directions of electron movement. Aspartate X acts as a base to activate a water molecule by abstracting a proton. The activated water molecule attacks the peptide bond, forming a transient tetrahedral Intermediate. Aspartate Y acts as an acid to facilitate breakdown of the tetrahedral intermediate and release of the split products by donating a proton to the newly formed amino group. Subsequent shuttling of the proton on Asp X to Asp Y restores the protease to its initial state.

The pentacoordinate intermediate is the analog of the tetrahedral intermediate, and stable phosphoranes are the analogs of ortho esters and related species in carbon chemistry. Ph3P(OPh)2 and P(OPh)5 were reported in 1959, and in 1958 a general synthesis of pentaalkoxy phosphoranes containing an unsaturated five-membered ring was reported. In 1964 a synthesis of pentaethoxyphosphorane was devised which led to the preparation of a number of saturated and unsaturated pentaalkoxy... 

Such is the richness and intellectual vibrancy of the field of RI chemistry that an additional book was needed to cover silicon, germanium and tin centered RFs, as well as tetrahedral intermediates and topics of increasing importance such as quantum mechanical tunelling, conical intersections, solid-state chemistry, and combustion chemistry. These topics are covered in this new book. 

Initial theoretical studies focused on steps (1) and (2). Several model systems were examined with ab initio calculations.1191 For the reaction of methyl amine with methyl acetate, it was shown that the addition/elimi-nation (through a neutral tetrahedral intermediate) and the direct displacement (through a transition state similar to that shown in Figure 5a) mechanisms for aminolysis had comparable activation barriers. However, in the case of methyl amine addition to phenyl acetate, it was shown that the direct displacement pathway is favored by approximately 5 kcal/mol.1201 Noncovalent stabilization of the direct displacement transition state was therefore the focus of the subsequent catalyst design process. 

Few relevant data are available. Both equilibrium and rate constants have been measured for very few reaction series in solution, but comparisons are possible for lactone and thiolactone formation, and for a few anhydrideforming reactions (Tables 4 and 5). For lactone formation (Table 4) the EM for the rate process is of the same order of magnitude as that derived from the equilibrium constant data, and in some cases actually exceeds it (though only in one case by an amount clearly greater than the estimated uncertainty which is nominally a factor of 4 for these ratios). Lactonization generally involves rate-limiting breakdown of the tetrahedral intermediate, and the transition state is expected to be late and thus close in structure to the conjugate acid of the lactone. 

Transition metal ions cause a dramatic increase in the rate of hydrolysis of /Madam antibiotics [75][133][134], For example, copper(II) and zinc(II) ions increase the rate of alkaline hydrolysis ca. 108-fold and 104-fold, respectively [76], It has been suggested that the metal ion coordinates with both the carboxylate group and the /3-lactam N-atom of penicillins (A, Fig. 5.20). This complex stabilizes the tetrahedral intermediate and, thus, facilitates cleavage of the C-N bond catalyzed by the HO ion [74] [75], Such a model appears applicable also to clavulanic acid, imipenem, and monobactams, but it re-... 

Fig. 5.20. Modes of coordination of transition metal ions with /3-lactam antibiotics. Complex A In penicillins, the metal ion coordinates with the carboxylate group and the /3-lactam N-atom. This complex stabilizes the tetrahedral intermediate and facilitates the attack of HO-ions from the bulk solution. Complex B In benzylpenicillin Cu11 binds to the deprotonated N-atom of the amide side chain. The hydrolysis involves an intramolecular attack by a Cu-coordinated HO- species on the carbonyl group. Complex C In cephalosporins, coordination of the metal ion is by the carbonyl O-atom and the carboxylate group. Because the transition state is less stabilized than in A, the acceleration factor of metal ions for the hydrolysis of cephalosporins is lower than for penicillins. Complex D /3-Lactams with a basic side chain bind the metal ion to the carbonyl and the amino group in their side chain. This binding mode does not stabilize the tetrahedral transition complex and, therefore, does not affect the rate of... 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

A complete study of the basic hydrolysis of pyrazolidinone (196) by ab initio calculations at RHF/6-31+GV/RHF/6-31-fG" and MP2/6-31-bGV/MP2/6-31- -G levels has been carried out. The alkaline hydrolysis has been studied through a Z ac2 mechanism, characterized by a nucleophilic attack of the hydroxyl group on the carbonyl of the y-lactam ring, formation of the tetrahedral intermediate, and cleavage of the C(2)-N(3) bond to yield the final reaction product. ... 

Enzymes with oxyanion holes are now known to catalyze a wide range of reactions with substrates that have a carbonyl moiety. The examples discussed in this chapter include thioesters, oxygen esters, peptides, and ketones (Figure 4.1). Two classes of high-energy intermediates with oxyanions are generated in these reactions (Table 4.3), a tetrahedral intermediate and an enolate. These reactions are... 

Table 4.3 The oxyanion hole geometry for selected tetrahedral intermediates and enolate intermediates. 

A very well-studied example is the oxyanion hole in serine proteases. In chymot-rypsin the oxyanion hole is formed by main chain NH groups of two peptide units, Glyl93 and Serl95 [36]. More generally, the classical oxyanion hole stabilizes the negatively charged oxyanion of a tetrahedral intermediate and is formed by two main chain peptide NH groups (cf Scheme 4.3). 

Attack by Nu on the trigonal acyl C leads to a stable, uncrowded, tetrahedral intermediate (and transition state), with an octet of e s on C. The sulfonyl S is already tetrahedral, and attack by Nu gives a less stable, more crowded, intermediate (and transition state), with a pentavalent S having ten e s, as shown ... 

Transition state analogues are essentially stable molecules which resemble, in geometry and in charge distribution, metastable intermediates of the enzymic reaction. The actual transition state of the reaction will be close in structure to the metastable intermediate, and will quite likely vary slightly between different substrates accepted by the same enzyme. There will not be a unique transition state for all transformations catalysed by one particular enzyme, neither of course will there be a unique transition state for different enzymes catalysing the hydrolysis of peptide links in a protein. There will nevertheless be some similarities in mechanism, and so structures containing a tetrahedral centre have been designed to inhibit a variety of proteinases, where a tetrahedral intermediate is always presumed. Differences exist in the pathway to, and breakdown of, the tetrahedral intermediate, and its stabilization, between thiol and serine proteinases, zinc proteinases, and aspartic proteinases. 

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