Push-pull catalysis

Polgar, L., 1987. The mechanism of acdon of aspardc protea.ses involves push-pull catalysis. FEBS Letters 219 1-4. 

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. 

The STRAIN AND DISTORTION model for catalysis involves pushing, pulling, or twisting a bond that is to be made or broken during the reaction. Parts of the substrate not involved directly in the chemical reaction are required to hold the substrate on the enzyme in the distorted form. The distortion and strain make it easier to reach the transition state. 

Two-Step (Push-Pull, Ping-Pong) Mechanisms Two-step mechanisms are typical of chemical catalytic processes, as opposed to redox catalysis processes, that are discussed and exemplified in Section 6.2. The first step following the generation at the electrode of the active form of the catalyst, Q, is the formation of an adduct, C, with the substrate A (Scheme 2.11). C requires an additional electron transfer to regenerate the initial catalyst, P. There are then two main possibilities. One is when C is easier to reduce (or oxidize in oxidative processes) than P. The main route is then a homogeneous electron... 

This is an example of acid catalysis and the effect is to pull electrons away from the leaving group. Often both acid catalysis and nucleophilic attack are involved in enzyme-catalysed reactions in what are known as push-pull mechanisms. 

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). 

The regiochemistry observed in the EGA-catalyzed displacement of methoxyl group with nucleophiles is promising For example, the carbenium ion formed from compound 29 in methanolic solution is trapped to produce the thermodynamically stable compound 30. However, in CHjClj, a concerted push-pull mechanism ( push by nucleophile and pull by EGA) is operative leading to the exclusive formation of 31. 1-Menthone 32 can be acetalized by EGA catalysis without epimerization at C-2... 

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

In the 1950s, the push-pull mechanism whereby a proton is donated by one centre and received at another was considered as a major contributor to enzyme catalysis and to give rise to third-order terms in non-enzymic reactions. Third-order terms were observed in organic solvents but in water they are of minor importance because of the solvating power of this solvent for ions and polar centres. 

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) ... 

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. 

As a further elaboration of the "push-pull mechanism [106], the structures of the transition states for enolisation have been considered in more detail. With acid catalysis the O HA bond is considered to be well-developed i.e. short... 

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. 

Fats and carbohydrates are metabolized down to carbon dioxide via an acetyl unit, CH3C=0, which is attached to a coenzyme, HSCoA, as a thioester called acetyl CoA. Acetyl CoA enters the citric acid cycle and eventually is converted to two molecules of carbon dioxide. The first step in the citric acid cycle is the aldol of acetyl CoA with oxaloacetate (Fig. 8.6). What is so elegant about this aldol is that the acidic and basic groups within the enzyme s active site provide a route that avoids any strongly acidic or basic intermediates. The enzyme accomplishes an aldol reaction at neutral pH, without an acidic protonated carbonyl or basic enolate intermediate via push-pull catalysis (Section 7.4.3). 

Cyclocondensation. Two different processes depend on the catalysis of MesSiOTf in the construction of a cyclohexanopyrrole intermediate for a synthesis of goniomitine. It assists the cleavage of a push-pull cyclopropane ring and the condensation with a nitrile unit. 

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. 

Base catalysis of piperidino-demethoxylation of 2-methoxy-3-nitrothiophene was discussed in CHEC-I <84CHEC-I(4)74i>. The study has been extended to the reaction of 2-methoxy-5-methyl-3-nitrothiophene with pyrrolidine and piperidine <93JCR(S)440>. The push-pull nature inherent in the 2-methoxy-3-nitrothiophene system apparently makes the methoxy group a sluggish nucleofuge hence the need for catalysis. The displacement of bromine in 2-bromo-3,5-dinitrothiophene by various meta- and przra-substituted anilines also appears to be base-catalyzed <90JCS(P2)2153>. 

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. 

Phosphinocarbene or 2 -phosphaacetylene 4, which is in resonance with an ylide form and with a form containing phosphoms carbon triple bond, is a distillable red oil. Electronic and more importantly steric effects make these two compounds so stable. Carbene 4 adds to various electron-deficient olefins such as styrene and substituted styrenes. Bertrand et al. have made excellent use of the push-pull motif to produce the isolable carbenes 5 and 6, which are stable at low temperature in solutions of electron-donor solvents (THF (tetrahydrofuran), diethyl ether, toluene) but dimerizes in pentane solution. Some persistent carbenes are used as ancillary ligands in organometallic chemistry and in catalysis, for example, the ruthenium-based Grubbs catalyst and palladium-based catalysts for cross-coupling reactions. 

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