Alpha Carbonyl Chemistry

Mechanism for Keto-Enol Tautomerism

In acidic conditions, the mechanism for keto-enol tautomerism involves protonation of the carbonyl oxygen followed by deprotonation of the alpha hydrogen. In basic conditions, the mechanism for keto-enol tautomerism involves deprotonation of an alpha hydrogen and formation of a negatively charged enolate intermediate that is protonated on oxygen to form the enol.

Keto-enol tautomerism is the chemical equilibrium between a ketone or aldehyde and an enol. Because the presence of either acidic or basic conditions leads to tautomerism, there will be two different reaction mechanisms to consider—one for acidic conditions and one for basic conditions. Given that the only difference between tautomers is the location of a single proton, converting a ketone into an enol will involve two separate steps—introducing a proton (H+) and removing a proton (H+).

When diagramming the keto-enol tautomerization there are three crucial factors to determine:

1. Whether protonation or deprotonation occurs first

2. The location of protonation and deprotonation.

3. The reagents to use for the proton transfer steps.

Ketone Conversion

Conversion from a ketone to an enol involves both proton introduction and proton removal.
In basic conditions, an alpha proton (H+) (any proton joined to an alpha carbon) will be removed to form an enolate, which is an enol with a proton missing from the hydroxyl group. The enolate will then pick up a hydrogen to form the enol. In acidic conditions, the oxygen of the carbonyl will add H+ first, and then an alpha proton will be removed to form the enol form. The two steps that convert a ketone or aldehyde to the enol form can be reversed to re-form the keto form by converting the enol form back into the keto form.

Enol Conversion

Conversion from an enol to a ketone involves both proton introduction and proton removal.
Two separate steps are required to convert between a ketone or aldehyde and the enol form. One step is a protonation step, and the other step is a deprotonation step. To protonate means to add a hydrogen ion (H+) to form the conjugate acid of a compound. To deprotonate means to remove a hydrogen ion (H+) to form the conjugate base of a compound.

Steps in Keto-Enol Tautomerism

Proton transfer must be multistep in keto-enol tautomerism. The process involves transferring a proton to the oxygen atom and the double bond formation between carbon atoms.
Logically, it would seem to be simpler for the oxygen (O) of the carbonyl to directly remove an alpha proton to form the enol instead of going through a two-step process. A single-step mechanistic process that moves a hydrogen atom from one atom within a molecule to another atom within the same molecule is called an intramolecular proton transfer. However, the intramolecular proton transfer step cannot happen in the keto-enol tautomerism because the oxygen atom of the carbonyl is too far away from the alpha hydrogen of the alpha carbon.

Oxygen Proton Transfer

An intramolecular proton transfer that transfers a hydrogen atom from the alpha carbon to an oxygen atom does not occur because the distance between the oxygen of the carbonyl and the alpha carbon is too great.
A base-catalyzed reaction is a reaction that occurs under basic conditions with a proton acceptor. In the base-catalyzed reaction, a base such as hydroxide (OH{-}{\rm{OH}}) removes a proton from an alpha carbon to form an intermediate ion. The intermediate is a resonance hybrid of a carbanion (negatively charged carbon) and an enolate. An enolate is an anion formed when an alpha hydrogen in the molecule of an aldehyde or a ketone is removed as a hydrogen ion. The enolate form of the intermediate will protonate in the presence of water to form an enol. It is important to recognize that the resonance is not a separate step in the mechanism. The only two steps are the equilibrium reaction between the ketone and the enolate, and the equilibrium reaction between the enolate and the enol.

Base-Catalyzed Keto-Enol Tautomerism

The mechanism for base-catalyzed keto-enol tautomerism involves the formation of an intermediate ion that is a resonance hybrid of a carbanion and an enolate.
An acid-catalyzed reaction is a reaction that occurs under acidic conditions with a proton donor. In the acid-catalyzed reaction, an acid such as hydronium ion (H3O+) will protonate the oxygen of a carbonyl, which forms an intermediate ion. The intermediate is a resonance hybrid of a protonated carbonyl and a carbocation (positively charged carbon). The carbocation form of the intermediate will deprotonate in the presence of water to form an enol. As in the base-catalyzed reaction, the resonance is not a separate step in the mechanism. The only two steps are the equilibrium reaction between the ketone and the protonated carbonyl, and the equilibrium reaction between the protonated carbonyl and the enol.

Acid-Catalyzed Keto-Enol Tautomerism

The mechanism for acid-catalyzed keto-enol tautomerism also involves an intermediate protonated carbonyl.
When comparing the acid-catalyzed mechanism to the base-catalyzed mechanism, a major difference is the charge of the intermediates. The intermediate is negatively charged in basic conditions and positively charged in acidic conditions. The rest of the mechanism is similar for the two mechanisms. Each step involves a simple proton transfer. The key difference lies in the sequence of protonation and deprotonation. For acidic conditions, protonation comes first, followed by deprotonation. The resulting positively charged intermediate correlates with acidic conditions. For basic conditions, deprotonation comes first, followed by protonation. The resulting negatively charged intermediate correlates with basic conditions.

Acid Catalyzed Conversion of Enol to Ketone

In an acid-catalyzed keto-enol tautomerization, a proton is removed from the alcohol, and a proton is added to the alpha carbon.
An example of conversion of an enol into a ketone under acidic conditions is the conversion of 1-cyclohexen-1-ol (C6H9OH) to cyclohexanone (C6H10O). Since this reaction occurs in acidic conditions, a protonation step occurs first, and then a deprotonation step occurs after. Based on the order of protonation and deprotonation, the location of protonation and deprotonation can be determined. The protonation occurs on the double bond, creating a carbocation that has a protonated ketone resonance form. The protonated ketone is deprotonated to create the ketone product of the equilibrium. The first step has to be protonation of the double bond, not the hydroxyl (OH). This may seem a logical first step, but this protonation will not produce a ketone.

Protonating the Double Bond

When protonating (adding a proton to a group), a ketone will form only if the double bond is protonated. Ketone formation will not occur if the hydroxyl (OH{-}{\rm{OH}}) group is protonated.
When writing a mechanism for the keto-enol tautomerization in acidic conditions, H3O+ is used to protonate, and H2O is used to deprotonate, not OH and H3O+. There is a negligible amount of OH present under acidic conditions.

When writing a mechanism for the keto-enol tautomerization in basic conditions, OH is used to deprotonate, and H2O is used to protonate, not H3O+ and H2O . The pKa of the alpha carbon next to a carbonyl is around 19, about the same as an alcohol (pKa=16{\rm {p}}K_{\rm {a}}=16). The pKa of an alpha carbon between two carbonyls is around 9, as acidic as a phenol. These are both much more acidic than other CH{\rm{C{-}H}} bonds.

One of the important parts of alpha carbon chemistry is choosing the correct base to form the enolate. For the alpha carbon of a carbonyl, a base with a conjugate acid that has a pKa greater than 19 is needed, so NaH, LDA, and NaNH2 are often used instead of NaOH, NaOEt, and so on. For an alpha carbon between two carbonyls, any of these bases will work.