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Methods Used to Study Tautomerism

Tautomerism can be studied by various chemical and physical techniques, In principle, it is possible to obtain significant results from chemical evidence, but in practice this is very difficult, and physical methods are much more useful. Chemical methods are discussed first and emphasis is placed on the dangers inherent in their application. It [Pg.320]

The chemical methods can be subdivided into two interrelated groups (a) those which depend on the reactivity of a particular structural feature, e.g., a carbon-carbon double bond or an enolic hydroxyl group, that is present in only one of the tautomeric forms and (b) those which involve relating the structures of reaction products to the structures of the starting materials. [Pg.321]

Methods of the first type have been used for both qualitative and quantitative investigation. An important limitation is that the rates of interconversion of the tautomeric forms must be small as compared with those of the test reaction (s). The method is further complicated since the test reactions are sometimes complex and it is difficult to be certain that only one tautomer is reacting. An even more fundamental objection is that much chemical evidence is based on incorrect reaction mechanisms. Thus, the formation of condensation products (30) with aldehydes has repeatedly been quoted as evidence for structures of type 31 and against type 32,. whereas if 31 does react with an aldehyde it must either first tautomerize to 32 or ionize to 33. [Pg.321]

Bromine titration has been applied to several heteroaromatic compounds, but it is not a reliable method. The assumption is often made that oxo structures react very slowly with bromine whereas the hydroxy forms react rapidly. Thus, 3,4-diphenylisoxazol-5-one when freshly dissolved in ethanol was found to react with 0.5 mole of bromine, but after standing it reacted with almost 1 mole. These observations led to the conclusion that the solid was in the CH [Pg.321]

Compounds containing a reasonable proportion of an enolie hydroxyl group, i.e., C=C—OH, usually give a deep color with ferric chloride, and this has often been used as a qualitative test. In this way, 2-hydroxythiophene has been shown to exist, at least in part, in the hydroxy form,  [Pg.322]


No seetion eorresponding to The Chemieal Methods Used to Study Tautomerism (76AHCS1, p. 12) has been ineluded in the present ehapter be-eause it is now obsolete, but a seetion about Tautomerism and Reaetivity has been added (Seetion X). The elassifieation and the preeautions required for the study of tautomerism diseussed in the earlier edition [76AHCS1, pp. 14-20] are still valid. [Pg.24]

It must be stressed that a statement that benzotriazole protonates on N(3) or that l-methyl-4-aminopyrazole does on the amino group, means only that this is the dominant species in an equilibrium. Experimentally, the tautomeric equilibrium constant between cations can be determined by the general methods used to study tautomerism. Even pK s can be used, if the second protonation of quaternary salts as fixed derivatives are measured. [Pg.225]

II. Chemical Methods Used to Study Tautomerism. m. Physical Methods Used to Study Tautomerism. ... [Pg.5]

In general, physical methods have been used to study tautomerism more successfully than chemical methods, and, of the physical methods, those involving measurements of basicities and ultraviolet spectra are the most important, followed by those involving measurement of infrared and proton resonance spectra. An attempt is made here to delineate the scope and to indicate the advantages and disadvantages of the various methods. A short review by Mason of the application of spectroscopic methods appeared in 1955. Recently a set of reviews on the applications of physical methods to heterocyclic chemistry has appeared, which treats incidentally the determination of tautomeric structure. [Pg.325]

If the refractivity of the pure tautomeric constituents is known, the composition of the equilibrium mixture can be determined. This method has been used to study, for example, the keto and enol tautomers of ethyl acetoacetate. So far it has not been applied to heterocyclic compounds in this series the isolation of the pure... [Pg.337]

Our previous treatment (76AHCS1, p. 12) contained a section called Chemical Methods to Study Tautomerism where the relationship between tautomerism and reactivity was discussed. Today, nobody uses chemical methods to study tautomerism. However, a great many reactions are carried out on tautomeric heterocycles, although few papers contain new insights on that topic. Authors desiring to explain reactivity results based on tautomerism must take great care to verify that the substrate is in the neutral form AH and not as a conjugated anion A or cation HAH, which are usually devoid of tautomerism. They must also realize that most frequently the reaction path from tautomers to products in-... [Pg.58]

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A, radius to study tautomeric equilibria in the 3-hydroxyisoxazole system (the keto tautomer 13 is referred to as an isoxazolone). AMI predicts 13 to be 0.06 kcal/mol lower in energy than 14 in the gas phase. However, the AMI dipole moments are 3.32 and 4.21 D for 13 and 14, respectively. Hydroxy tautomer 14 is better solvated within the D02 model, and is predicted to be 2.6 kcal/mol lower in energy than 13 in a continuum dielectric with e = 78.4. Karelson et al. note, however, that the relative increase in dipole moment upon solvation is larger for 13 than for 14 (aqueous AMI dipole moments of 5.05 and 5.39 D, respectively). This indicates that the relative magnitude of gas-phase dipole moments will not always be indicative of which tautomer will be better solvated within a DO solvation approach — the polarizability of the solutes must also be considered. In any case, the D02 model is consistent with the experimental observation [266] of only the hydroxy tautomer in aqueous solution. [Pg.40]

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A radius to study tautomeric equilibria in the 4-hydroxyisoxazole system (they did not specify which hydroxyl rotamer they examined). Tautomer 17 predominates in aqueous solution. Although AMI predicts 16 to be about 10 kcal/mol more stable in the gas-phase than 17, its dipole moment is only predicted to be 0.68 D. Tautomer 17 has a predicted dipole moment of 2.83 D in the gas-phase. With the small cavity, the two dipole moments increase to 0.90 and 4.56 D, respectively, and this is sufficient to make 17 0.3 kcal/mol more stable than 16 in solution. Zwitterion 18 is much better solvated than either of the other two tautomers, but AMI predicts its gas-phase relative energy to be so high that it plays no equilibrium role in either the gas phase of solution. [Pg.41]

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A radius to study tautomeric equilibria in the 2-, 4-, and 5-hydroxyoxazole systems (the keto tautomers are referred to as oxazolones). Tautomers illustrated above in parentheses were not considered and hydroxyl rotamers were not specified. In the first two systems, tautomers 22 and 25 are predicted by AMI to be about 14 kcal/mol more stable than the nearest other tautomer in their respective equilibria. Differences in tautomer solvation free energies do not overcome this gas-phase preference in either case, and the oxazolones are predicted to dominate the aqueous equilibrium, as is observed experimentally [266],... [Pg.43]

Photoelectron spectra (PE) experimental of some 4-nitropyrazoles, nitroimidazoles, [1119, 1405] and nitrobenzimidazoles [1193, 1406] have been recorded and interpreted in terms of semiempirical AM-1 method. PE spectroscopy is not a widely used method to study tautomeric equilibria in the gas phase although it can give excellent results. PE spectra data and 6-31G/6-31G calculations show that in the gas phase tautomers 4-nitro- and 5-nitroimidazole have the similar energy [1301], However in water, 4-nitroimidazole is much more stable (8AG°=3.5 kcal/mol >99% at 25°C.) than the 5-nitro tautomer. The authors [1301] show that this is conditioned by solvation effect. Probably it is connected with the large difference in dipole moments of the tautomers (see Table 3.72). [Pg.365]

The Monte Carlo method can also be used to study the effect of solvent on the position of tautomeric equilibrium (Metropolis et al., 1953). This method models a dilute solution as N solvent molecules (N — 102) and 1 solute molecule. The fundamental requirement for a Monte Carlo simulation of tautomer solvation is a set of pair potentials for the solvent-solvent and solvent-solute interactions because approximately 106 config-... [Pg.110]

Proton resonance spectroscopy has been used to study the tautomerism of 4-hydroxypyridine and its 1-oxide, with results in agreement with those obtained by other physical methods discussed here. Resonance spectroscopy also indicated that the cations of 4-hydroxypyridine, 1-methyl-4-pyridone and 4-methoxypyridine are of the type (32), that of 4-hydroxy-pyridine 1-oxide as (33), and that 2-pyridone cation is protonated on... [Pg.145]

The latter troublesome methodology of synthesizing frozen tautomeric structures can be readily replaced by the theoretical computation of the NMR parameters 5 and J in the certain tautomers. Ah initio MO and DFT calculation programs with several methods on various levels of theory are available. To consider the solvent a number of solvent models can be employed as weU. Though good structures can be obtained easily by all relevant methods of sufficient level, the computation of chemical shifts, and especially coupling constants, is usually not that easy and often requires special basis sets (see Chapter 13 and special literature). In summary, NMR parameters of tautomers can be computed nowadays with analytical precision and can be adequately used to study quantitatively tautomeric equilibria. [Pg.105]

Nuclear magnetic resonance (NMR) continues to be the method of choice to study tautomerism in solution with low temperature studies becoming more common due to the use of dipolar aprotic solvents of low melting point, such as DMY-dj [16] and HMPA-iij g [17]. The main limitation of the use of NMR is due to it being a slow method that often needs the use of model compounds, whereas, UV-Vis spectroscopy is very fast and tautomers are seen... [Pg.2]


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