Push-pull acid-base catalysis

Push-pull acid-base catalysis has been proposed to account for the proton switch mechanism which occurs in the methoxyaminolysis of phenyl acetate (Scheme 11.14) where a bifunctional catalyst traps the zwitterionic intermediate. A requirement of efficient bi-functional catalysis is that the reaction should proceed through an unstable intermediate which has p values permitting conversion to the stable intermediate or product by two proton transfers after encounter with the bifunctional catalyst the proton transfer with monofunctional catalysts should also be weak. 

The HIV-1 protease, like other retroviral proteases, is a homodimeric aspartyl protease (see Fig. 1). The active site is formed at the dimer interface, with the two aspartic acids located at the base of the active site. The enzymatic mechanism is thought to be a classic acid-base catalysis involving a water molecule and what is called a push-pull mechanism. The water molecule is thought to transfer a proton to the dyad of the carboxyl groups of the aspartic acids, and then a proton from the dyad is transferred to the peptide bond that is being cleaved. In this mechanism, a tetrahedral intermediate transiently exists, which is nonconvalent and which is mimicked in most of the currently used FDA approved inhibitors. 

Push-pull and bifunctional acid-base catalysis... 

In enzymes, the active site may possess acid and base groups intimately associated with the conjugate base and acid functions, respectively, of the complexed substrate the push-pull mechanism is possible but might not be a driving force. The halogenation of acetone in the presence of aqueous solutions of carboxylic acid buffers exhibits the rate law of Equation 11.2 where the third-order term, although small, has been shown to be significant and due to bifunctional concerted acid-base catalysis (Scheme 11.13) ... 

The impact of nucleophilic and electrophilic groups of the active center on the substrate at the contact area in the enzyme-substrate complex (the effect of synchronous intramolecular catalysis). The polyfunctional catalysis involves a great many processes push-pull mechanisms, processes involving a relay charge transfer, as well as a general acid-base catalysis. Presumably, the enzyme in the initial state of the enzymatic reaction already contains structural elements of the transition state and in this case the reaction must be thermodynamically more advantageous. 

Besides the effect of solvent polarity, the C=C rotation in many push-pull ethylenes is sensitive to acid catalysis (143). This is probably explained by protonation of the acceptor groups, for example, the oxygen atoms in C=0 groups (16), which increases their acceptor capacity. Small amounts of acids in halogenated solvents, or acidic impurities, may have drastic effects on the barriers, and it is advisable to add a small quantity of a base such as 2,4-lutidine to obtain reliable rate constants (81). Basic catalysis is also possible, but it has only been observed in compounds containing secondary amino groups (38). 

Atom Variations E2 Heteroatom Variants, Dehalogenation, Fragmentation Vinylogous Variations Sn2 and E2. 1,4 additions Extent of Proton Transfer Variations General Acid and General Base Catalysis of Additions and Eliminations, Summary by Media, Push-Pull Catalysis of Enolization... 

We ean also expect that enzyme active sites with appropriately positioned acidic and basic groups can easily do general acid, general base, and push-pull catalysis. 

This kind of catalysis is usually refered to as acid-base concerted (synchronous, or push-pull) bifunctional catalysis, which for brevity is expres.sed as acid-base bifunctional catalysis in some articles. 

The addition or removal of a proton can promote electron flow, i.e., bond formation and breakage, during the reaction. As far as enzymes are concerned, only general acid or base catalysis can occur, because enzymes have no means of concentrating or OH ions. A number of amino acid side chains can act as proton donors or acceptors, and in many Zn-dependent enzymes, such as carboxypeptidase. the metal ion acts as an effective Lewis acid to enhance polarization of the carbonyl moiety of the amide bond. Among the amino acids His (which has a pKa generally close to 7) plays an especially important role in enzyme catalysis, because at neutral pH, there is a good balance between its protonated and deprotonated forais. In most cases, enzymes have suitably positioned pairs of side chains to provide push and pull of electrons. 

Acyl Transfer Blfunctlcfnal Catalysis- Many mechanisms for enzjrme cataly-sls postulate cooperative ("push-pull") catalysis by an acid-base pair in the active site. The analogous bifunctional intramolecular catalysis has been widely sought the evidence presented generally consists of a maximum rate at a pH sufficiently acidic for the acid-catalytic function to be pro-tonated yet sufficiently basic for the base-catalytic function to be free. The hydrolysis of hexachlorophene monosuccinate (14). for example, exhibits such a rate maximum at pH 6.8 (between pK 5.20 for Che carboxyl group and... 

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