Electrophilic catalysis

ELECTRON TRANSEER REACTIONS ELECTRON TRANSPORT ELECTROPHILE ELECTROPHILICITY NUCLEOPHILE ELECTROPHILIC CATALYSIS ELECTROPHILICITY NUCLEOPHILICITY ELECTROPHILE ELECTROPHILIC SUBSTITUTION REACTION Electrophoretic mobility,... 

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. 

In the field of homogeneous catalysis, electrophilic metals [palladium(II), plati-num(II), rhodium(II), iridium (I), ruthenium(II), cobalt(I), titanium(II) and gold(I)] activate alkynes under mild conditions [2-8]. When an alkyne behaves as a ligand, there are four orbitals that can participate in the bonding (Fig. 1.1) [4]. The in-plane orbitals, Try and n, are responsible for a donor interaction (M <- L donation) and a 7r-acceptor interaction (M L back-donation) respectively. The orthogonal, out-of-plane orbitals, and n , are engaged in the M <- L 7t donation and the d symmetry M L back-donation respectively. This latter interaction can be neglected, due to the weak overlap of the orbitals. 

An example of an intermolecular aldol type condensation, which works only under acidic catalysis is the Knoevenagel condensation of a sterically hindered aldehyde group in a formyl-porphyrin with a malonic ester (J.-H. Fuhrhop, 1976). Self-condensations of the components do not occur, because the ester groups of malonic esters are not electrophilic enough, and because the porphyrin-carboxaldehyde cannot form enolates. 

Data are lacking on the mechanisms of these reactions, but knowledge of other series suggests that the first step is attack of the exocyclic sulfur of 66 on the exocyclic sulfur of 67 converted into an electrophilic center by catalysis (Scheme 31). 

Under conditions of acid catalysis the nucleophilic addition step follows protonation of the carbonyl oxygen Protonation increases the carbocat ion character of a carbonyl group and makes it more electrophilic... 

Miscellaneous Reactions. Some hydantoin derivatives can serve as precursors of carbonium—immonium electrophiles (57). 5-Alkoxyhydantoins are useful precursors of dienophiles (17), which undergo Diels-Alder cycloadditions under thermal conditions or in the presence of acid catalysis (58). The pyridine ring of Streptonigrine has been constmcted on the basis of this reaction (59). 

Reactions with Aldehydes and Ketones. An important use for alkylphenols is ia phenol—formaldehyde resias. These resias are classified as resoles or aovolaks (see Phenolic resins). Resoles are produced whea oae or more moles of formaldehyde react with oae mole of pheaol uader basic catalysis. These resias are thermosets. Novolaks are thermoplastic resias formed whea an excess of phenol reacts with formaldehyde under acidic conditions. The acid protonates formaldehyde to generate the alkylating electrophile (17). 

SuIfona.tlon, Sulfonation is a common reaction with dialkyl sulfates, either by slow decomposition on heating with the release of SO or by attack at the sulfur end of the O—S bond (63). Reaction products are usually the dimethyl ether, methanol, sulfonic acid, and methyl sulfonates, corresponding to both routes. Reactive aromatics are commonly those with higher reactivity to electrophilic substitution at temperatures > 100° C. Tn phenylamine, diphenylmethylamine, anisole, and diphenyl ether exhibit ring sulfonation at 150—160°C, 140°C, 155—160°C, and 180—190°C, respectively, but diphenyl ketone and benzyl methyl ether do not react up to 190°C. Diphenyl amine methylates and then sulfonates. Catalysis of sulfonation of anthraquinone by dimethyl sulfate occurs with thaHium(III) oxide or mercury(II) oxide at 170°C. Alkyl interchange also gives sulfation. 

Affinity Labels. Active site-directed, irreversible inhibitors or affinity labels are usually substrate analogues that contain a reactive electrophilic functional group. In the first step, they bind to the active site of the target enzyme in a reversible fashion. Subsequentiy, an active site nucleophile in close proximity reacts with the electrophilic group on the substrate to form a covalent bond between the enzyme and the inhibitor, typically via S 2 alkylation or acylation. Affinity labels do not require activation by the catalysis of the enzyme, as in the case of a mechanism-based inhibitor. 

The acid-catalyzed additions of bromide and chloride ion to thiiranes occurs readily, with halide preferentially but not exclusively attacking the most substituted carbon atom of the thiirane. The reaction of 1-substituted thiiranes with acetyl chloride shows a slight preference for halide attack at the less substituted carbon atom (80MI50601). For further discussion of electrophilic catalysis of halide ion attack see Section 5.06.3.3.2. The reaction of halogens with thiiranes involves electrophilic attack on sulfur (Section 5.06.3.3.6) followed by nucleophilic attack of halide ion on carbon. 

The transition state for the rapid hydrolysis of the monoanion has been depicted as involving an intramolecular general acid catalysis by the carboxylic acid group, with participation by the anionic carboxylate group, which becomes bound at the developing electrophilic center... 

Molecular chlorine is believed to be the active electrophile in uncatalyzed chlorination of aromatic compounds. Simple second-order kinetics are observed in acetic acid. The reaction is much slower in nonpolar solvents such as dichloromethane and carbon tetrachloride. Chlorination in nonpolar solvents is catalyzed by added acid. The catalysis by acids is probably the result of assistance by proton transfer during the cleavage of the Cl-Cl bond. ... 

Electrophilic catalysis is catalysis by an electrophile (Lewis acid) acting as an electron-pair acceptor. For example, metal ions catalyze the decarboxylation of dimethyloxaloacetic acid. ... 

The factors in carboaromatic nucleophilic displacements summarized in this section are likely to be characteristic of heteroaromatic reactions and can be used to rationalize the behavior of azine derivatives. The effect of hydrogen bonding and of complexing with metal compounds in providing various degrees of electrophilic catalysis (cf. Section II, C) would be expected to be more extensive in heteroaromatics. 

The azinones and their reaction characteristics are discussed in some detail in Section II, E. Because of their dual electrophilic-nucleophilic nature, the azinones may be bifunctional catalysts in their own formation (cf. discussion of autocatalysis below) or act as catalysts for the desired reaction from which they arise as byproducts. The uniquely effective catalysis of nucleophilic substitution of azines has been noted for 2-pyridone. 

Nucleophilic chlorination of 1,5-naphthyridine mono- and di-N-oxides yields 2-chloro- and 2,6-dichloro-naphthyridines via electrophilic catalysis of the reaction of intermediates such as 430 with chloride ion. An interesting example of electrophilic catalysis is the... 

E. Treibs Views on the Nature of the Acid Catalysis of Electrophilic Substitution in Pyrroles.298... 

Surely these views are not very plausible, depending as they do on the formation of such an improbable system as (23). How much more simple is it to view acid catalysis as involving enhancement of the electrophilic character of the reagent. Thus, in the formaldehyde condensation, it is protonated formaldehyde,... 

Traces of bases such as methylimidazole in the final ionic liquid product can play an unfavorable role in some common applications of ionic liquids (such as bipha-sic catalysis). Many electrophilic catalyst complexes will coordinate the base in an irreversible manner and be deactivated. 

The author anticipates that the further development of transition metal catalysis in ionic liquids will, to a significant extent, be driven by the availability of new ionic liquids with different anion systems. In particular, cheap, halogen-free systems combining weak coordination to electrophilic metal centers and low viscosity with high stability to hydrolysis are highly desirable. 

The fact that ionic liquids with weakly coordinating anions can combine, in a unique manner, relatively high polarity with low nucleophilicity allows biphasic catalysis with highly electrophilic, cationic Ni-complexes to be carried out for the first time [26]. 

---