Prototropy

Annular tautomerism (e.g. 191 192) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (191 R = H) and pyrazole (193 R=H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. However, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (195) than in (196), and UV spectral comparisons show that indazole exists predominantly as (195). 

The situation is more complex for triazoles and tetrazoles where other effects such as lone-pair repulsions intervene see discussion in (76AHC(S 1)296). 

Structure of Five-membered Rings with Two or More Heteroatoms Table 42 Annular Tautomerism of Azoles  

Pyrazole Imidazole v-Triazole s-Tri azole Tetrazole Equivalent Equivalent 1,2,5 1,2,3 1.2.4 1,3,4 1.2.3.4 1,2,3,5 b Electron-withdrawing group prefers 3-position Electron-withdrawing group prefers 4-position 

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. 

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Although the thermodynamic aspects of acylotropy are well documented, there have been few kinetic studies of the process. The activation barrier is much higher than for prototropy and only Castells et al. (72CC709) have succeeded in observing a coalescence phenomenon in H NMR spectra. At 215 °C in 1-chloronaphthalene the methyl groups of N-phenyl-3,5-dimethylpyrazole-l-carboxamide coalesce. The mechanism of dissociation-combination explains the reversible evolution of the spectra (Scheme 9). 

Tautomerism has been discussed in Section 4.04.1.5.2. It concerns prototropic tautomerism and the decreasing order of stability is (hydrazone) >A (azo)> A (enehydrazine). The isomerization A -> A occurs via a A -pyrazoline (65BSF769). Pyrazolidones and amino-A -pyrazolines exist as such. The only example of non-prototropic tautomerism deals with the isomerization (403) —> (404) (74CJC3474). This intramolecular process is another example (Section 4.04.1.5) of the thermodynamic analogy between prototropy and metallotropy. 

Knoevenagel condensation, 3, 674 2H-Chromene, 4-alkyl-prototropy, 3, 642 2H-Chromene, 3-bromo-synthesis, 3, 668... 

Anionotropy and prototropy are, obviously, processes that mutually oppose each other. The more polar the C—OH bond in (5), i.e., the more the equilibrium (5) (4) will favor (4) [or in other words, the... 

The possible use of Si NMR for the study of the prototropy and sily-lotropy of pyrazoles has been explored (98MRC110). Another paper reports the use of P NMR for establishing that 3-phenyl-4-benzoylisoxazol-5-one is hydrogen-bonded to tri-n-octylphosphine as the NH-tautomer [96MI(14)653j. 

For 3-acetylthiotetronic acid the same type of tautomerization process (90 91, 92 93 as a result of prototropy between internal tautomers 90, 91 92, 93, rotation of the side-chain group, between external tautomers) was observed as for the corresponding 3-acetyl-tetronic acids ( H NMR, NMR) [76JHC533 78BCJ651 79JCS (P2)1605],... 

As has already been pointed out for 3-acyl-tetronic and -thiotetronic acids, the corresponding 3-acyl-tetramic acid can exist as internal tautomers (136 137,138 139) as a result of prototropy between the two oxygen atoms and as external tautomers (136,137 138,139) as a result of rotation of the side-chain acyl group. 

Annular prototropie tautomerism of 1,2,3-triazole (v-triazole) and its C-substituted derivatives involves the equilibrium of three possible isomers 24a-24c. In the ease of the parent eompound (R = H), 24a and 24c are degenerate isomers (Seheme 11). 

Tautomeric rearrangements of transition-metal complexes with azole ligands are relatively scarce. The fluxional behavior of the rhodium complex 43 with a neutral 3,5-dimethylpyrazole was explained as the result of rapid processes of metallotropy and prototropy occurring simultaneously (Scheme 24) [74JOM(C)51],... 

Products of cyclization of 5-aminoethylene benzotriazole derivatives with eliminated prototropy of the azole ring can be alkylated on the nitrogen atom of the pyridone and then hydrolyzed to the corresponding acids (76JAP(K)1, 89FA619). The prepared compounds 167-169 and their salts were tested against bacteria (no data) (76JAP(K)1). 

Dihydro-2/7- 74 and -4//-l,2-oxazines and thiazines 75 are interrelated by prototropy, being enamines and imines, respectively. In the case of oxazines, the imine form 75 is favored, and there are several well established examples of this system, including the parent heterocycle 75 (X = O) [84MI2]. No tautomeric equilibrium between the 2H and 4H forms has been observed under normal conditions in solution or in the solid state. However, the formation of intermediate 2H isomers 77 was proposed both for the conversion of 3-phenyl-5,6-dihydro-4//-l,2-oxazine 76 (R = Ph, r = R = H) into 2-phenylpyrrole(89TL3471) under strong basic conditions and for thermal decomposition of cyclopentene-fused 1,2-oxazine 76... 

Diylide 1, by reaction with a phosphorus electrophile, Ph2PCl, lead instantaneously via a nucleophilic substitution and intramolecular prototropy to the formation of functionalized monoylides 10 (Scheme 11). 

Nucleophilic addition to a, -unsaturated sulfones has long been known. For example, treatment of divinyl sulfone with sodium hydroxide has been known to afford bis( -hydroxyethyl) sulfone "", while the reaction of a- and -naphthyl allyl sulfones and allyl benzyl sulfone " with alkali hydroxide or alkoxide gave -hydroxy or alkoxy derivatives. In the latter reaction, the allyl group underwent prototropy to the 1-propenyl group, which in a subsequent step underwent nucleophilic attack . Amines, alcohols and sulfides are known to add readily to a, -unsaturated sulfones, and these addition reactions have been studied widely. In this section, the addition of carbon nucleophiles to a, ji-unsaturated sulfones and the reactions of the resulting a-sulfonyl carbanions will be examined. 

Tautomerism, strictly defined, could be used to describe the reversible interconversion of isomers, in all cases and under all conditions. In practice, the term has increasingly been restricted to isomers that are fairly readily interconvertible, and that differ from each other only (a) in electron distribution, and (b) in the position of a relatively mobile atom or group. The mobile atom is, in the great majority of examples, hydrogen, and the phenomenon is then referred to as prototropy. Familiar examples are / -ketoesters, e.g. ethyl 2-ketobutano-ate (ethyl acetoacetate, 23), and aliphatic nitro compounds, e.g. nitro-methane (24) ... 

Lowry concluded with a discussion of "dynamic isomerism," which might be of three kinds transfer of (1) a radical (2) a hydrogen ion or proton or (3) an electron. The latter two categories he called "prototropy" and "electrotropy."64 Physical proofs for the ionic hypothesis were among Lowry s topics... 

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