Controlled tautomerism

Figure 12.15 Controlled tautomerism in 2-(4 -hydroxyphenylazo)benzoic add and derivatives.

Although the systems considered in this section do not exhibit controlled tautomerism, they show a promising concept for E/Z isomerization switching, where the tautomeric process is believed to play an important role. 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

A parallel exists between the results of protonation and alkylation of pyrazolones since there is an alkyl derivative for each tautomer. The main difference is that the percentage of the different tautomers is thermodynamically controlled whereas that of alkyl derivatives is kinetically controlled. One has to remember that the alkyl derivatives thus obtained are the fixed compounds used in tautomeric studies. 

The same arguments can be applied to other energetically facile interconversions of two potential reactants. For example, many organic molecules undergo rapid proton shifts (tautomerism), and the chemical reactivity of the two isomers may be quite different It is not valid, however, to deduce the ratio of two tautomers on the basis of subsequent reactions that have activation energies greater than that of the tautomerism. Just as in the case of conformational isomerism, the ratio of products formed in subsequent reactions will not be controlled by the position of the facile equilibrium. 

Up to the present the principal interest in heteroaromatic tautomeric systems has been the determination of the position of equilibrium, although methods for studying fast proton-transfer reactions (e.g., fluorescence spectroscopy and proton resonance ) are now becoming available, and more interest is being shown in reactions of this type (see, e.g., references 21 and 22 and the references therein). Thus, the reactions of the imidazolium cation and imidazole with hydroxyl and hydrogen ions, respectively, have recently been demonstrated to be diffusion controlled. ... 

Keto-enol tautomerism, 264, 842-844 Kiliani, Heinrich, 994 Kiliani-Fischer synthesis, 994-995 Kimbail, George, 216 Kinetic control, 491 Kinetics, 362... 

The tautomerization is induced by cobalt(II) which forms the thermodynamically more stable metalatcd hydroporphyrins from which the cobalt can be removed using trifluoroacctic acid under kinetic control. Experiments with porphyrinogen and hexahydroporphyrin show that the porphyrinogen-hexahydroporphyrin equilibrium can be shifted by complexation of porphyrinogen with metal ions to the more stable metal hexahydroporphyrins and that metal-free hexahydroporphyrins tautomerize back to the more stable metal-free porphyrinogens.29... 

The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the forma tion of the unusual trans adducts 53, have been explained by the facts that (i) Diels-Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

Pearlman, R.S., Khashan, R., Wong, D., and Balducci, R. ProtoPlex User-control over tautomeric and protonation state. 224th ACS National Meeting, Boston, MA, 2002. 

Since a knowledge of the correct tautomeric form of the pyrimidines is a requisite for understanding the mode of binding to active sites, as well as nucleic acid structure and modification, the formulae of the conventionally-named 2- and 4-hydroxypyrimidines are presented in the correct lactam, or pyrimidone, form in this chapter. Other physical properties of the pyrimidines, such as dissociation constants, protonation sites, and distribution coefficients, are presented in cases where there is a known relation to drug activity. Biogenesis and enzyme control mechanisms are discussed where they relate to an understanding of inhibitor action. 

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