Tautomers and Equilibrium

Classify each of the following compounds as aromatic, antiaromatic, PROBLEM 1.8 or nonaromatic. 

Tautomers are isomers that differ in the arrangement of single and double bonds and a small atom, usually hydrogen. Under appropriate reaction conditions, such isomers can equilibrate by a simple mechanism. 

Equilibrium exists when there are equal rates for both the forward and reverse processes of a reaction. Equilibrium usually is designated by halfheaded arrows shown for both the forward and reverse reactions. If it is 

The keto and enol forms of aldehydes and ketones represent a common example of tautomerism. The tautomers interconvert by an equilibrium process that involves the transfer of a hydrogen atom from oxygen to carbon and back again. 

To avoid confusing resonance structures and tautomers, use the foiiowing criteria  

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Norcaradiene (255) and cycloheptatriene (256) are related as valence tautomers and equilibrium is weighted heavily in favour of the monocyclic component recently, 255 has... 

The last example is somewhat more complicated since four isomers (two tautomers and two conformations) are present at equilibrium (Figure 9) (78BSB189). The experimental value (3.73 D, Table 3) establishes the predominance of the 3-azido tautomer but does not allow the determination of the conformational equilibrium other methods (Section 4.04.2.3.4(v)) are necessary to establish definitely the Z conformation (43b). 

In a neutral azole, the apparent rate of formation of an A-substituted derivative depends on the rate of reaction of a given tautomer and on the tautomeric equilibrium constant. For example, with a 3(5)-substituted pyrazole such as (199), which exists as a mixture of two tautomers (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)] is a function of the rate constants Ha and fcs, as well as of the composition of the tautomeric mixture (Scheme 16) <76AHC(Si)l). 

Repeat your analysis for tautomeric equilibria between 4-hydroxypyridine and 4-pyridone, 2-hydroxypyrimidine and 2-pyrimidone and 4-hydroxypyrimidine and 4-pyrimidone. For each, identify the favored (lower-energy) tautomer, and then use equation (1) to calculate the ratio of tautomers present at equilibrium. Point out any major differences among the four systems and rationalize what you observe. (Hint Compare dipole moments and electrostatic potential maps of the two pyridones and the two pyrimidones. How are these related to molecular stability )... 

Tautomers are defined as isomers which are readily interconvertible. It is clear that the distinction between tautomerism and ordinary isomerism is very vague indeed, and that it depends on the interpretation of the adverb readily. It is customary to designate as tautomers those isomers whose half-lives (with respect to interconversion) are under ordinary circumstances less than the times required for laboratory operations to be carried out (some minutes or hours), so that the separation of the isomers from the equilibrium mixtures is difficult. The distinction between tautomers and ordinary isomers has no molecular significance whatever, since it is dependent on the accidental ordinary rate of human activity. 

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

The values of 3/(NH,H) coupling constant observed for imine proton can be helpful in detection of the proton transfer processes and determination of mole fractions of tautomers in equilibrium. For NH-form, this value is close to 13 Hz, lower values usually indicate the presence of tautomeric equilibrium. It should be mentioned that the values below 2.4 Hz have not been reported. The chemical shift of C—OH (C-2 for imines, derivatives of aromatic ortho-hydroxyaldehydes or C-7 for gossypol derivatives) carbon to some extent can be informative, however, this value depends on type of substituents and should be interpreted with caution. 

In 5 (6) -substituted benzofuroxans, there are a number of reasons for the preference for a tautomer at equilibrium. Nevertheless, the presence of an electron-withdrawing group in 5(6)-substituted benzofuroxans frequently favors the 6- tautomer over the 5- tautomer. In 4(7)-substituted benzofuroxans the steric interactions between the substituent and the N+-CT moiety play important roles, and thus the 4-isomer is frequently favored at equilibrium. 

The one-electron chemistry of enols has been intensively studied by Schmit-tel [108]. He has shown that the thermodynamic stability order of the ketone tautomer and the enol tautomer in the solution phase is inverted upon one-electron oxidation [109, 110]. Therefore enols are much more easily oxidized than the corresponding ketone tautomer. Supposing that the enolization is faster than the electron transfer, it ought to be possible to oxidize the enol present in small amounts beside the ketone in the equilibrium mixture. The following cyclization reactions are as useful approach to the chemistry of enol radical cations and can be considered as the a-umpolung of ketones. 

Rate and equilibrium constant measurements for the enolization of 3-phenylcoumaran-2-one (82) in aqueous dioxane indicate an enol content of ca 0.1%, a pKg, of 8.9 (6.0 for the enol tautomer), and a fairly symmetrical transition state for enolate anion formation the Brpnsted Pb = 0.52 Below pH 5, enolization is independent of pH, occurring via O-protonation of the enolate. 

Enolization and ketonization kinetics and equilibrium constants have been reported for phenylacetylpyridines (85a), and their enol tautomers (85b), together with estimates of the stability of a third type of tautomer, the zwitterion (85c). The latter provides a nitrogen protonation route for the keto-enol tautomerization. The two alternative acid-catalysed routes for enolization, i.e. O- versus Af-protonation, are assessed in terms of pK differences, and of equilibrium proton-activating factors which measure the C-H acidifying effects of the binding of a proton catalyst at oxygen or at nitrogen. 

The various tautomers and rotamers of alloxan have been examined in detail by the MNDO method and it is predicted that the keto form is most important in the gas phase, although in solution the monohydroxy forms are also thought to contribute. A mass spectral study has been used to investigate the enol-keto tautomeric equilibria of a series of substituted salicylaldehyde and 2-hydroxynaphthaldehyde Schiff bases. In neutral, ethanolic solutions, the cis- and trans-tm forms of 4,5-dimethyl-2-(2 -hydroxyphenyl)imidazoles (393) and (394) have been found to exist in equilibrium in the ground state. However, in neutral aqueous solutions, the trans-eao and keto forms (394) and (395) were the only species detected. Deuterium isotope effects on... 

The most powerful method currently available for the quantitative determination of ring-chain equilibrium constants is H-NMR spectroscopy. Often, two pairs of indicator signals of both tautomeric forms have been used, thereljy increasing the accuracy of equilibrium-constant determination. For structural analysis of the tautomers and quantitative measure-... 

The A-benzoylhydrazones of acylpinacolines 75 (R = alkyl R = H R = r-Bu R" = Ph) in solution form equilibria involving the participation of two hydrazone (75A- and Z) tautomers, one or two enhydrazine (75A -E and Z) tautomers, and one cyclic (75B) tautomers (84ZOR1371). Here, clear evidence is presented characterizing the influence of the steric effect of the substituent on the C = N bond an increase in the steric demands in the series R = H < Me < t-Pr < t-Bu shifts the equilibrium toward the cyclic tautomer 75B. When R = H, this tautomer is absent but when R = r-Bu, the equilibrium is shifted entirely in favor of 75B. 

Structural isomers existing in rapid equilibrium are tautomers and the equilibrium reaction is tautomerism. The above is a keto-enol tautomerism. 

Figure 11.2 4-Pyridone is considerably more polar than its hydroxypyridinc tautomer, and its extended n system also renders it highly polarizable. As a resiill, polar solvents shift the equilibrium between the two strongly to the right in comparison to the gas phase...

Some of the reagents used in olefin epoxidation can be applied in the direct oxidation of arenes to arene oxides. Benzene oxide, however, like other arene oxides, exists in equilibrium with oxepin, its valence tautomer, and has not been isolated. Existence of benzene oxides as intermediates can be concluded from observations like the NIH shift discussed above.752,753... 

Apart from structural factors annular tautomerism is strongly influenced by the aggregate state of the compound. Gas-phase and solid state studies of tautomerism have received much attention recently because of the development of methods such as X-ray crystallography, CPMAS NMR, microwave spectroscopy, etc. Low temperature H NMR is the simplest and most straightforward method to determine Kx it only requires that proton transfer be slow enough to observe separate signals for both tautomers, and that the equilibrium is not shifted too much towards one of the tautomers (about 5% of the minor tautomers seems the limit). More detailed information on tautomerism of key azole systems is given below. 

In the majority of cases, the equilibrium lies predominantly in favor of the carbonyl tautomer, and for this reason these compounds are considered in the present section. (Most amino and mercapto analogues, while also tautomeric, exist predominantly as such, and they are therefore considered as substituted aromatic compounds.)... 

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