Double Proton Migrations

A synchronous transfer of two protons, which in reaction (9.14) competes with a two-step process, is in some cases the predominant proton exchange mechanism. Such double proton migrations play an important role in many chemical and biochemical reactions in which the steric hindrances impeding proton transfer in a substrate molecule are removed thanks to the double proton exchange between substrate and enzyme [79]. The double proton transfers determine the mechanism of the bifunctional acid-base catalysis[80, 81]. The interest in the mechanism of double proton migrations in the H-bound complexes became especially keen after Lowdin [82] advanced in 1963 the hypothesis to the effect that it is precisely such processes in the DNA molecules that underlie the nature of spontaneous mutations. 

Nondegenerate double proton migrations between a solute molecule and the molecules of the solvent (water) may determine the mechanism of intermolecular proton transfers that give rise to a new tautomeric form. Thus, using the relaxation method of temperature jump, it was found [97] that the tauto-merization of 6-methoxy-2-pyridone proceeds as a nondissociative concerted process of bifunctional interaction with one molecule of water ... 

The double proton migrations can occur also in intramolecular reactions, for example, in diotropic systems [52]. These comprise the compounds whose transition into a tautomeric form requires the transfer of two migrants (such as the protons), and, in terms of the classic structural notions, this transfer must be concerted since a single transfer would result in the formation of a nonclassic structure of the zwitterionic or biradical type. A simplest example of such systems is provided by the molecule of the oxalic acid for which, depending on the nature of the stationary point on the PES that corresponds to a structure with one transferred proton, two in principle different reaction mechanisms may be realized ... 

It should be noted in conclusion that the above-considered (Sect. 9.2.5) double proton migrations may also be regarded as typical multibond reactions. The rule cited above is actually quite applicable to these reactions. At the same time, given a favorable stereochemistry, a concerted synchronous mechanism may be realized for some systems of this type. Analysis of the factors that may provide for the possibility of such exceptions in the case of this and some other multibond reactions would be of particular interest for understanding the nature of cooperative processes. 

In chlorination, loss of a proton can be a competitive reaction of the cationic intermediate. This process leads to formation of products resulting from net substitution with double-bond migration ... 

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

The regiochemistry of the Heck reaction is determined by the competitive removal of the (3-proton in the elimination step. Mixtures are usually obtained if more than one type of (3-hydrogen is present. Often there is also double-bond migration that occurs by reversible Pd-H elimination-addition sequences. For example, the reaction of cyclopentene with bromobenzene leads to all three possible double-bond isomers.146... 

Novel alkenylphosphonium salts were subjected to the Wittig reaction (Scheme 12). Allylic deprotonation took place for phosphonium salts possessing such protons, and the olefination proceeded after double bond migration. In cases where such protons were absent, allene formation was observed. 

Certain epoxy steroids, however, yielded dienes rather than ketones, apparently by proton loss from the initially generated csrboninm ion, subsequent elimination of water from the resultant allylic alcohol, and finally double-bond migration. Among epoxides... 

The other mechanism proceeds by enolization followed by proton-induced double-bond migration. 

Mechanism The reaction involves converting a ketone to the corresponding hydrazone A, which undergoes a base-catalyzed double bond migration (tautomerization) of the initially formed hydrazone to an azo-isomer B, and the loss of N2 then follows to give carbanion C. Finally, an alkane derivative is formed by protonation of carbanion C (Scheme 6.30). 

Not all terpene synthases catalyse complex reactions. Isoprene synthase converts DMAPP to the hemiterpene (G5), isoprene (Fig. 5.1), a comparatively simple process involving the ionization of the diphosphate group, followed by double-bond migration and proton elimination (Silver and Fall, 1991). Present in chloroplasts in both stromal and thylakoid-bound forms, isoprene synthase is a homodimer that differs from other terpene synthases in many properties, such as subunit architecture, optimum pH and kinetic parameters... 

This subject has already arisen in connection with the stabilities of olefinic bonds at various positions in the steroid nucleus (p. 14) and as a side-reaction in certain hydrogenation processes. Rearrangements of allylic systems will be covered in Chapter 9, and photolytic reactions in Chapter ii. We are concerned here with the double-bond migrations which involve carbonium ions generated by protonation of simple olehns. 

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