Keto-enol tautomerism describes the chemical equilibrium between a keto form (a ketone or an aldehyde) and an enol (an alcohol) in a molecule. This dynamic equilibrium involves the migration of a hydrogen atom and the relocation of a double bond. A compound containing a carbonyl group (C=O) is normally in rapid equilibrium with an enol tautomer, which contains a pair of doubly bonded carbon atoms adjacent to a hydroxyl (−OH) group, C=C-OH. In keto-enol tautomers, the enol form is the one with the alcohol, and the keto form is the one with the ketone.
Understanding Tautomerization
Chemists use the term “tautomerization” to describe the process of two molecular structures that interconvert under a state of dynamic equilibrium. Tautomers are rapidly interconverted constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently located double bond. Put differently, consider a Molecule A with some functional group X. In Molecule A, group X attaches to site A. However, there exists another suitable location for group X to attach, called site B. Sometimes, group X moves from site A to site B, which changes Molecule A to Molecule B, its tautomer. Once at site B, group X can also move back to site A. When you have a whole bunch of Molecule A, such as a mole dissolved in solvent, it will constantly convert to Molecule B and back again. However, the relative proportions of Molecule A and Molecule B remain consistent, because eventually, their rates of conversion will cancel out.
General Keto-Enol Tautomerization
The interconversion between keto and enol forms involves the movement of a proton from an α-carbon (a carbon atom adjacent to the carbonyl group) to the oxygen atom of the carbonyl group, with a simultaneous shift of the double bond.
The Keto Form
The keto form is characterized by a carbonyl group (C=O), where a carbon atom is double-bonded to an oxygen atom. In the context of monosaccharides, the keto form can take the form of an aldose, which is a straight-chain version of a monosaccharide.
The Enol Form
The enol form is characterized by a carbon-carbon double bond (C=C) adjacent to a hydroxyl group (-OH). The name "enol" is derived from the combination of "ene" (indicating the presence of a double bond) and "ol" (indicating the presence of an alcohol).
Read also: Mechanism of Keto-Enol Shift
Mechanism of Keto-Enol Tautomerization
Keto-enol tautomerization is catalyzed by both acids and bases. The mechanism differs slightly depending on whether it is acid-catalyzed or base-catalyzed.
Acid-Catalyzed Tautomerization
Protonation of the Carbonyl Oxygen: The reaction begins with the protonation of the carbonyl oxygen by an acid. This protonation increases the electrophilicity of the carbonyl carbon. To form an enol, an acid protonates a lone electron pair on the carbonyl.
Deprotonation of the α-Carbon: A base (often the conjugate base of the acid catalyst) then deprotonates an α-carbon, leading to the formation of a double bond between the α-carbon and the carbonyl carbon, and the regeneration of the acid catalyst. Then, the acid’s conjugate base deprotonates the ɑ-carbon.
Base-Catalyzed Tautomerization
Deprotonation of the α-Carbon: The reaction begins with the deprotonation of an α-carbon by a base. This generates a carbanion, which is resonance-stabilized by the adjacent carbonyl group. To form an enol, a generic Brønsted-Lowry base deprotonates the ɑ-carbon. This drives the pi electrons of the carbonyl to form an alkene pi bond with the deprotonated carbon.
Protonation of the Oxygen: The carbanion then abstracts a proton from a suitable acid (often the solvent), leading to the formation of the enol. To form a ketone, the base deprotonates the hydroxide, liberating a lone electron pair. These electrons then form a carbonyl, pushing a lone electron pair to the ɑ-carbon.
Read also: Regioselectivity in alkyne hydration
Factors Affecting Equilibrium
The equilibrium between keto and enol forms is influenced by several factors, including:
- Stability of the Enol Form: The stability of the enol form is enhanced by factors such as conjugation, hydrogen bonding, and aromaticity.
- Steric Effects: Steric hindrance around the carbonyl group can destabilize the keto form, favoring the enol form.
- Solvent Effects: Polar solvents tend to stabilize the more polar keto form, while nonpolar solvents may favor the enol form.
Equilibrium Considerations
The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence for the presence of the minor tautomer comes from the chemical behavior of the compound. Often, Molecule A has more stability than Molecule B, meaning that Molecule A outnumbers B at equilibrium. This unequal state of equilibrium occurs commonly in tautomer pairs, including between ketones and enols. Generally, ketones are favored heavily over enols in many of the most common molecular structures.
Structural Trends and Stability
One such structural trend holds that ɑ-carbons with more non-hydrogens have more stability as enols. For instance, if the ɑ-carbon has a methyl structure, with three hydrogens, it has less stability forming an enol than a methylene ɑ-carbon, which has two hydrogens. However, there exist some molecules in which the enol form predominates over the ketone. One such example are 1,3-dicarbonyl molecules, which frequently form from certain aldol condensations. In these molecules, an enol can form, shuffling a hydrogen to the oxide ion. This new hydroxide structure stabilizes from the adjacent carbonyl providing a hydrogen bond. Aromatic enols also tend to have stability, as aromaticity offers such stability that it outweighs that of ketones. Specifically, enols are favored when the resulting alkene completes an aromatic electron cycle.
Enolate Anions
Enolate anions are important intermediates in many organic reactions, including aldol condensations and alkylation reactions.
Formation of Enolate Anions
Enolate anions are formed by the deprotonation of an α-carbon of a carbonyl compound using a strong base. For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25) in a non-hydroxylic solvent before any alkyl halides are added to the reaction system.
Read also: The Chemistry of Keto-Enol Forms
Common Bases for Enolate Formation
Some bases that have been used for enolate anion formation are:
- NaH (sodium hydride, pKa > 45)
- NaNH2 (sodium amide, pKa = 34)
- LiN[CH(CH3)2]2 (lithium diisopropylamide, LDA, pKa 36)
Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF.
Considerations for Base Selection
Certain other strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application, one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid.
Keto-Enol Tautomerism in Monosaccharides
In monosaccharides, keto-enol tautomerism involves the interconversion between the open-chain form and cyclic forms. The C5 hydroxyl group cyclizes when it attacks the C1 carbonyl. Monosaccharides exist in a chemical equilibrium as two isomers in keto-enol tautomerism.