Existence of Individual Tautomers

Any doubt about the existence of individual tautomers is now long past some tautomers can be crystallized separately (desmotropy), and others can be observed simultaneously in the same crystal (Section V,D,2) in summary, tautomers are not intrinsically different from isomers. Maybe it is worth mentioning that even two identical tautomers can differ. This is the case for the two intramolecular hydrogen-bonded (IMHB) enol tautomers of acetylacetone and for many NH-azoles they correspond to a doublewell profile for the proton transfer with both wells having the same energy (autotrope). 

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Crystalline 2-methylimidazole exhibits different 13C (CPMAS) chemical shifts for C-4 and C-5 (125.0, 115.7 ppm). The average (120.3 ppm) is close to that reported for imidazole in deuterated DMSO (121.2 ppm). These results imply that solid state chemical shifts can be used instead of N-methyl models in tautomerism studies (87H(26)333). For imidazole the solid state l3C shifts are 137.6 (C-2), 129.3 (C-4), and 119.7 (C-5) (81JA6011). No proton exchange occurs in the solid, and the data support a structure resembling the crystal structure. Cooling imidazole solutions has not yet allowed the detection of individual tautomers, but by symmetry the compound exists in equal tautomeric forms, as does pyrazole (81CC1207). 

A purine base contains one pyrimidine and one imidazole ring connected via a shared (C4-C5) aromatic bond. One nitrogen atom in the purine base is generally protonated. Due to the presence of several nitrogen sites, several tautomers usually co-exist both in solution and in the solid state. The populations of individual tautomers are strongly influenced by the substitution of the piuine base, the temperature, the pH, the solvent, and the salt concentration. 

The concept of mesohydric tautomerism was advanced by Hunter and his associates in a series of papers which appeared between 1940 and 1950 (e.g., references 15 and 16). This concept was based on the fact that in all cases where the mobile hydrogen atom would be bonded to oxygen, sulfur, or nitrogen atoms in both possible tautomers, the individual forms had not been isolated. It was further established that many of these compounds were associated both in the liquid state and in solution, and it was concluded that the individual tautomers did not exist. The actual molecules were thought to be intermolec-ularly hydrogen-bonded, the mobile hydrogen atom being bonded equally to both of the hetero atoms. This concept has been useful and has led to clarification of the tautomerism which occurs in solids and... 

Very little is known concerning the simple, monocyclic 3-hydroxy-furans (cf. reference 15). Both the oxo and hydroxy forms of the substituted 3-hydroxyfurans 26 and 27 (R = H, CcHn) have been isolated/ but the individual tautomers slowly undergo interconversion. The enol forms give a positive reaction with ferric chloride, react rapidly with bromine, and form a peroxide with oxygen. From chemical evidence, the benzo derivatives of 3-hydroxyfuran, 28 and 29, appear to exist predominantly in the oxo form, and this is further supported by ultraviolet spectral data. Stefanye and Howard- ... 

All triazoles, tetrazoles, and unsymmetrically substituted imidazoles and pyrazoles can exist in two tautomeric forms, e.g., 1 2 and 3 4. However, attempts to isolate the individual tautomers have been unsuccessful, always leading to one isomer (for summaries of this aspect of the tautomerism of imidazoles, see references 1 and 2). Although the isolation of both tautomers of a number of com-... 

The experimental evidence for the existence of the corresponding tautomeric forms in solutions has been based on the study of their chemical reactivity and, to a lesser extent, on the study of tautomeric systems by means of physical methods. Not even an approximate quantitative evaluation can be presented by chemical experiments because of the different reaction rates of the individual tautomers at best, they can be used as negative evidence, viz., the absence of a certain tautomeric form in the reaction mixture can be assumed under the conditions used. The physico-chemical methods, due to low sensitivity, also did not give a satisfactory picture of the ratio of the corresponding tautomers.50... 

Das and Rout claim to have prepared the imino forms (143) of several 2-toluidino-l,3,4-thiadiazoles (145) by oxidation of the corresponding 4-tolylthiose micarbazones (144) with iodine or potassium ferricyanide in alkaline solution. Later, Ramachander and Srinivasan repeated this synthesis in similar systems, but they also prepared the tautomers (145) by oxidation of 144 with ferric chloride. It is highly unlikely that individual tautomers like 143 and 145 should exist as separate compounds, particularly as they have crystallized from the same solvent, ethanol. The only proofs for the structure 143 are sulfur analyses, but it is evident from the melting points that 143 is identical neither with 145 nor with the isomeric triazolinethiones. Menin et al. tried to repeat the preparation of 143, though without success. 

Compounds whose structures differ in the arrangement of hydrogen atoms and which are in rapid equilibrium are called tautomers. It is important to draw a distinction between resonance forms and tautomers. Whereas it is possible to obtain spectroscopic information on the existence of the individual tautomeric forms, resonance forms are not distinguishable. The difference can be illustrated by considering an amide (1.52). The resonance form (1.53) shows a difference in the position of charge, while the tautomer (1.54) shows a difference in the position of a hydrogen atom. 

Any evidence that the individual tautomers do exist discredits one basic notion of mesohydric tautomerism. Surely the relatively small perturbations of the A—H vibrational bending modes indicate that the H atom remains attached to A though H bonded to B. (See Section 3.4.1.) Possibly more obvious evidence is that offered by spectroscopic meaisurements which locate the H atom. Both neutron diffraction and proton magnetic resonance studies show that the proton is usually nearer one atom than the other. (See Section 9.3.)... 

Janniah and Guha18S>189 reported that 2-amino-l-thia-3,4-diazol-5-thione (158) exists in two forms the sterically-unaceeptable bridged structure 159 was postulated for one of these forms. Bambas190 suggests instead that the two forms may be the individual tautomers 160 and 161. The second explanation is hardly more probable than the first, and the whole problem needs reinvestigation. Certain related compounds with a substituted-amino group have been shown by ultraviolet spectral comparisons to exist in the thione form.190 ... 

Most of the hop resins contain -di- and p-tri-carbonyl functions which are enolized. It is seldom possible to isolate the individual tautomers but estimates of the relative proportions can be obtained by proton magnetic resonance (PMR) spectroscopy and other physical methods. Irrespective of the major component a tautomeric mixture can react in any form if, for example, a minor tautomer is consumed in a reaction it will be regenerated from the major tautomers, according to the equilibrium, until the reaction is complete. Thus phloroglucinol, the parent of the hop resin, exists almost entirely in the trienol form (17) but can react as cyclohexone-1,3,5 trione (18) to form a trioxime (19). 

This approach was mathematically developed by Bershtein and Ginsburg [12] and later used for the analysis of the tautomeric equilibrium in 2 [13]. The main problem here is to find real individual areas of absorbance. Usually the long-wavelength absorption maximum of the a form is strongly bathochromically shifted with respect to that of the b form, which means that the red-shifted part of this area is by itself individual. Finding an individual area for the b tautomer (if it exists at all) is complicated, because its absorbance strongly overlaps with that of the a form. Careful preprocessing of the spectral data is needed to prove the existence of the real individual absorbance of the enol tautomer [14]. 

It should be noted that virtually all 5-R-NH-unsubstituted tetrazoles, regardless of the substituent, exist in the crystalline state as individual 1 //-tautomers. Only losartan 29 containing a sterically strained (2 -tetrazol-5-ylbiphe-nyl-4-yl)methyl group was found to crystallize in the 2//-form stabilized by intermolecular O-H- N and N-H- -N hydrogen bonds <2004AXEol830>. 

In 1975, Weis and Mamaev153 showed that the 6-methyl-2,4-diphenyl dihydropyrimidine (MDHP) (20), which was obtained by condensation of benzylidene, acetone, and benzamidine, exists in solution in a tautomeric equilibrium of 6-methyl-2,4-diphenyl-1,4-dihydropyrimidine (20a) and 6-methyl-2,4-diphenyl-3,4-dihydropyrimidine (20b) [although the systematic nomenclature for structure 20b would be 4-methyl-2,6-diphenyl-1,6-dihy-dropyrimidine (see Section 111,8), we have retained the original nomenclature to provide a convenient comparison of the two tautomers]. This tautomerism was detected by spectral studies (NMR, IR, and UV) of solutions of 20. Thus the NMR spectra of the two individual tautomeric structures can be observed in dipolar aprotic solvents such as dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA).153... 

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