Electrophilic catalysis mechanisms

It has also been argued10,40 that the second mechanism (rapid, reversible interconversion of II and IV) cannot be general. The basis for this contention is the fact that electrophilic catalysis is rare in nucleophilic aromatic substitution of non-heterocyclic substrates, an exception being the 2000-fold acceleration by thorium ion of the rate of reaction of 2,4-dinitrofluorobenzene with thiocyanate... 

During the insertion mechanism, the metal is inserted into the carbon-oxygen bond. The insertion is promoted by a strong metal—oxygen interaction. It is thought that unreduced metal ions may play an important role in the insertion mechanism (electrophilic catalysis). The type of the catalyst, the method of preparation, and the additives can influence the concentration and stability of these ions. 

Electrophilic catalysis may play an important role in the case of the similar benzylic carbon, too. For an O-benzyl system, it was found in a 1997 experiment that palladium oxide is a much more effective catalyst than palladium metal when the catalyst has been prereduced with chemical reducing agents. This finding shows very clearly that the electrophilic character of the unreduced metal ions plays an important role in the hydrogenolysis of the benzyl C—O bonds. Additional support for this mechanism is the fact that a small amount of butylamine can inhibit the hydrogenolysis of the benzyl C—O bond. 

In principle, reactions which are subject to electrophilic catalysis by protons can be catalysed by metal ions also (e.g. Tee and Iyengar, 1988 Suh, 1992). However, metal ions may function in other ways, such as to deliver a hydroxide ion nucleophile to the reaction centre (e.g. Dugas, 1989 Chin, 1991), and it is often difficult to decide between kinetically equivalent mechanisms without resorting to extensive (and intensive) model studies. Use of the Kurz approach may help to resolve such ambiguities, as shown below. 

The effect is interpreted as evidence of the operation of the homo-/hetero-conjugate mechanism. The authors presume that for the mechanism given by equation 1, for additives P which are much less basic than the nucleophile N, electrophilic catalysis also occurs both with the hetero-conjugate N+HP formed between the conjugate acid of the nucleophile, N, and P, as well as with the homo-conjugate Nu+HNu. For more basic additives, electrophilic catalysis is possible by the species PH+ and its homo-conjugate PHP+153 162 182. 

A hydroxoaqua copper complex containing N, N, N, A -tetramethyl-1,2-diamino-ethane (250) is an excellent catalyst for the hydrolysis of sarin, O-isopropyl methylphosphonofluoridate (251), and diethyl p-nitrophenyl phosphate (252 R = Et). The mechanism of the reaction probably involves bound hydroxide attacking the phosphoryl group with concomitant electrophilic catalysis by copper. 

This mechanism explains much of the experimental evidence obtainedhfrom studies of the solvolysis of acyl chlorides, but it may not be in agreement (as was pointed out to Minato by a referee) with the linear relationship between electrophilic catalysis observed in the solvolysis of certain acid chlorides would possibly be explained by a simpler mechanism such as the SN1 or hydration-ionisation mechanism. However, it is of interest to see how the mechanism applies to acetyl, benzoyl and mesitoyl chlorides. For acetyl chloride, kY and k-Y would be very large and the rate would approximate to... 

Electrophilic catalysis by Lewis acids is also observed here no ambiguity arises with general acid catalysis, as Lewis acids and proton acids are not the same. An interesting example is the strong catalysis of thiolester hydrolysis by mercuric and silver ions. These soft acids presumably coordinate with the sulfur and, by virtue of the consequent electron withdrawal, make the carbonyl group much more susceptible to attack in the addition mechanism, or, in favorable cases, promote unimolecular SN1 cleavage of the sulfur-carbon bond.122... 

Kinetic evidence for the involvement of a-hydroxydialkylnitrosamines (142) in the pH-independent solvolysis of the a-(acyloxy)dialkylnitrosamines (141) has been obtained.120 The aminolysis in benzene of 0-(2,4-dinitrophenyl)-/7,/ -disubstituted benzophenone oximes (143) with pyrrolidine and piperidine are third order in amine.121 Hir st s mechanism involving electrophilic catalysis operates and can explain the various effects observed. The bis(pentamethylphenyl)-A-isopropylketenimine (144) undergoes pre-equilibrium /V-protonation in aqueous acetonitrile followed by water attack. An inverse solvent isotope effect and the observation of the diol (145) confirm this.122... 

Nucleophilic and electrophilic catalysis occur when a nucleophile or electrophile reacts with the substrate to form an adduct which provides a more favourable alternative mechanism to that of the uncatalysed reaction. The intermediate can be formed as a transient species present in only a small concentration compared with the reactant or product, or it can build up to a measurable concentration. In this section, we exemplify the techniques used in their investigation using nucleophilic reactions. The same techniques can be used for reactions undergoing electrophilic catalysis, mutatis mutandis. 

Three O-substituted benzophenone oximes (29 X = OMe, F, Cl) have been subjected to aminolysis by pyrrolidine and piperidine, in benzene solution." Kinetics were third order in amine, and involved two routes one accelerates with a rise in temperature, the other decelerates. Of the many mechanisms proposed for this reaction in non-polar media, the results support Hirst s mechanism of electrophilic catalysis in this instance. 

There is extensive evidence from site-directed mutagenesis and other studies of enzymes that catalyze proton transfer that acidic and basic amino side chains and, in some cases, metal cations, are required for the observation of efficient catalysis. However, catalysis of the deprotonation of a-carbonyl by small molecule analogs of these side chains, and by metal cations is generally weak. Relatively little attention has been directed towards understanding the mechanism for the enhancement of Bronsted acid/base and electrophilic catalysis for enzyme-catalyzed reactions... 

In view of the apparent convergent evolution of mechanism in the serine and cysteine protease family, it is interesting that two phosphodiesterases that require Ca + for catalytic activity by virtue of presumed electrophilic catalysis via direct coordination to the anionic phosphoryl oxygens of the substrate have evolved conceptually similar (general basic catalysis) but structurally distinct solutions to the problem of phosphodiester hydrolysis. 

The proposed mechanism is essentially electrophilic catalysis mediated by the active site zinc atom. The mechanism is valid in the pH region... 

The main features of the reaction mechanism for YADH are in all probability essentially the same as in LADH. The structural similarities of the catalytic domain, including the catalytic zinc and its protein ligands, are strong indications that both enzymes perform electrophilic catalysis mediated by zinc. Involvement of zinc in the catalytic action of YADH was suggested almost 20 years ago (365,366,452), but evidence for a direct participation has been obtained only recently (329,449). 

So far in this chapter, the chemical biology reader has been introduced to examples of biocatalysts, kinetics assays, steady state kinetic analysis as a means to probe basic mechanisms and pre-steady-state kinetic analysis as a means to measure rates of on-catalyst events. In order to complete this survey of biocatalysis, we now need to consider those factors that make biocatalysis possible. In other words, how do biocatalysts achieve the catalytic rate enhancements that they do This is a simple question but in reality needs to be answered in many different ways according to the biocatalyst concerned. For certain, there are general principles that underpin the operation of all biocatalysts, but there again other principles are employed more selectively. Several classical theories of catalysis have been developed over time, which include the concepts of intramolecular catalysis, orbital steering , general acid-base catalysis, electrophilic catalysis and nucleophilic catalysis. Such classical theories are useful starting points in our quest to understand how biocatalysts are able to effect biocatalysis with such efficiency. 

Figure 8.51 Mechanisms of three types of bio-cataLyst that employ electrophilic catalysis as part of their mechanistic paths to successful bio-catalysis. All substrates are shown in red. Electrophilic catalysis is brought about by the use of pyridoxal phosphate, a natural cofactor for electrophilic catalysis operations.

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