Solvent Effects on Tautomeric Equilibria

3 Solvent Effects on Tautomeric Equilibria 4.3.1 Solvent Effects on Keto/Enol Equilibria [36-43,134] 

In general, 1,3-dicarbonyl compounds, which include y9-dialdehydes, y9-ketoaldehydes, y -diketones, and y -ketocarboxylic esters, can exist in solution or as the pure compound in three tautomeric forms the diketo form (4a), the cw-enoUc (4b), and the trans-enolic form (4c). 

Open-chain 1,3-dicarbonyl compounds are observed in the tran -enolic form only in rare cases [41] (for examples, see references [44, 45]). When the trans -enolic form is excluded, the keto/enol equilibrium constant Ki is given by Eq. (4-23). 

In solution, open-chain 1,3-dicarbonyl compounds enolize practically exclusively to the czls-enolic form (4b), which is stabilized by intramolecular hydrogen bonding. In contrast, cyclic 1,3-dicarbonyl compounds e.g. cycloalkane-1,3-diones [46]), can give either trans-Qnols (for small rings) or czk-enols (for large rings). As the diketo form is usually more dipolar than the chelated cu-enolic form, the keto/enol ratio often depends on solvent polarity. This will be discussed in more detail for the cases of ethyl acetoacetate and acetylacetone [47-50, 134, 135]. 

The equilibrium constants, measured by NMR spectroscopy, of ethyl acetoacetate and acetylacetone [47, 48, 134] (Table 4-2) indicate a higher enol content for these czx-enolizing 1,3-dicarbonyl compounds in apolar aprotic than in dipolar protic or dipolar aprotic solvents. 

---

The list of publications in the obituary of the organic chemist Otto Dimroth (1872-1940)139 has eleven papers that are classified as physikalisch-organische Chemie. They are mainly about tautomerism, intramolecular rearrangements, and solvent effects on tautomeric equilibria. One paper,140 published in 1933, deals with relationships between reaction velocities and oxidation-reduction potentials for quinone systems and it is evident that Dimroth was a pioneer in developing linear free-energy relationships. He was Professor in Wurzburg from 1918 to 1940. 

Among many examples of the solvent effects on chemical equilibria and reactions, the solvent effect on tautomerization has been one of the most extensively studied. Experi-... 

Several excellent reviews and chapters in books that are specifically devoted to the general applications of N NMR spectroscopy to structural studies are currently available. The interested reader is referred to these reviews for more detailed treatment. Most attention has been focused on isotropic chemical shifts and their relationship to the elucidation of structure, the importance of solvent effects, and tautomeric equilibria. The combination of a large range of chemical shifts - approximately 600 ppm for organic molecules (—1200 ppm for -NO... 

Neglecting solvent effects is extremely hazardous. Equilibria and kinetics can be dramatically altered by the nature of the solvent For example, the rate of nucleophilic substitution reactions spans 20 orders of magnitude in going from the gas phase to polar and nonpolar solvents. A classical example of a dramatic solvent effect on equilibrium is the tautomerism between 1 and 2. In the gas phase, the equilibrium lies far to the left, while in the solution phase, 2 dominates because of its much larger dipole moment." Another classical example is that the trend in gas-phase acidity of aliphatic alcohols is reverse of the well-known trend in the solution phase in other words, in the solution phase, the relative acidity trend is R3COH < R2CHOH < RCH2OH, but the opposite is true in the gas phase. ... 

M. M. Karelson, A. R. Katritzky, M. Szafran, and M. C. Zerner,/. Chem. Soc., Perkin Trans. 2, 195 (1990). A Theoretical Treatment of Solvent Effects on the Tautomeric Equilibria of Five-Membered Rings with Two Heteroatoms. 

Like reaction rates, the effect of solvent polarity on equilibria may be rationalized by consideration of the relative polarities of the species on each side of the equilibrium. A polar solvent will therefore favour polar species. A good example is the keto-enol tautomerization of ethyl acetoacetate, in which the 1,3-dicarbonyl, or keto, form is more polar than the enol form, which is stabilized by an intramolecular H-bond. The equilibrium is shown in Scheme 1.3. In cyclohexane, the enol form is slightly more abundant. Increasing the polarity of the solvent moves the equilibrium towards the keto form [28], In this example, H-bonding solvents will compete with the intramolecular H-bond, destabilizing the enol form of the compound. 

In conjugated molecules one or other of the possible protonation sites may be more or less favoured by solvation effects and for this reason sites of protonation are often solvent dependent. In some instances, similar stability of two possible cations results in tautomeric equilibria and these too may be solvent dependent. Just as solute-solvent interactions have an effect on the relative stability of two possible cations formed from a conjugated molecule, so in solid salts stability relationships depend on the mode of packing of ions, which determines interactions with the nearest neighbours. Therefore the types of cation observed in solid salts are not necessarily the most stable ones in solution. 

Burawoy, A., and A. R. Thompson The Effect of Solvents on the Tautomeric Equilibria of 4-Arylazo-l-Naphthols and the ortho-Effect. J. chem. 

The effect of solvent polarity on chemical systems including reaction rates and equilibria can be quite significant. In general, it is necessary to consider the relative polarities of the reactants and products. In equilibria, a polar solvent will favour the more polar species. A good example is the keto-enol tautomerization of ethyl acetoacetate shown in Figure 1.9. The keto tautomer is more polar than the enol tautomer and therefore the equilibrium lies to the left in polar media such as water Table 1.11. 

Results obtained using the various discrete models applied to 2- and 4-oxopyridines are summarized in Table VI. Similar data for continuum models are summarized in Table VII. All methods used to estimate the effect of solvent on the position of these tautomeric equilibria are qualitatively correct in that they all show greater stabilization of the lactam form in agreement with experiment. Quantitatively the various discrete models yield a disappointing array of results. For 2-oxopyridine several methods yield relative polyhydration energies close to the experimental value but then predict the same or lower relative polyhydration energy for the 4-oxopyridine system, a direction opposite to that found experimentally. 

---