One synthetic reaction that creates new carbon chains is the use of enol or enolate. The α-carbon of the carbonyl group (the carbon next to the carbonyl carbon) plays an important role, and due to its high acidity, it has a tendency to be pulled out of the proton (H+) by a base.

Therefore, the carbons next to the carbonyl group are the starting points and enols or enolates are formed. It can then be alkylated by adding the compound you want to react with to create a new carbon chain.

For the synthesis of enolates, which is important in organic chemistry, you must understand in advance the reagents to be used and the regioselectivity of the reaction. Of course, you also need to learn about the reaction mechanism.

There are several reactions in the field of enols and enolates that are important in organic chemistry, such as Claisen condensation, aldol reaction and Michael addition. In order to learn these synthetic reactions, we need to understand the nature of the alpha carbon of the carbonyl group, so we will explain what the properties are.

The Alpha Carbon of the Carbonyl Group Is Highly Acidic

Compounds with carbonyl groups react in a variety of ways. In the case of carbonyl groups, the carbon and oxygen atoms are connected by a double bond, allowing electrons to be transferred to the oxygen atom.

Therefore, in the presence of a nucleophile, the carbonyl carbon is attacked. This is called a nucleophilic addition reaction.

However, in a carbonyl compound, the hydrogen atom of the adjacent carbon atom can be pulled out. When the protons are extracted by the base, the following compounds are formed.

Importantly, it can give rise to carbanions. Because of the presence of the carbanion, it is an unstable substance. But because it can write a resonance structure, when the proton is pulled out by a strong base, you get this molecule. This molecule is called an enolate.

Because enolates can write a resonance structure, the hydrogen atom next to the carbonyl group are highly acidic, and making it easy for a base to pull out a proton (H+).

The carbon next to the carbonyl group is called the α-carbon. The carbonyl group is used as the starting point for the α, β, and γ positions, as shown below.

In enolate, the alpha carbon of the carbonyl compound is an important factor. The formation of enolate ions as intermediates leads to a variety of chemical reactions.

Keto-Enol Tautomerism and Enol/Enolate

In carbonyl compounds, the normal state is called the keto form. However, when a strong base is present, an enolate is created. This is called keto-enol tautomerism. The reaction mechanism is as shown earlier.

A compound with a C=O structure is the keto form. On the other hand, if the -OH is attached to an alkene, it is called the enol form. Due to keto-enol tautomerism, both keto and enol forms can change their forms.

In the enol form, if the compound has the structure of -OH, it is called enol. On the other hand, if an oxygen atom has a negative charge, it is called an enolate. They are as follows.

Between enol and enolate, it is the enolate that is more important. Enolate is produced as a result of the withdrawal of protons by a strong base.

Enolate, Which Is Nucleophilic and Creates Carbon Bonds in the SN2 Reaction

Why is enolate important in organic chemistry? That’s because the α-carbon of enolate is negatively charged and has nucleophilic properties as a carbanion.

As mentioned above, enolate is generated by using a strong base. Subsequently, the enolate, as a nucleophilic agent, undergoes the SN2 reaction. The following nucleophilic substitution can create new carbon chains.

First, enolate is synthesized by adding a base as a reagent. Then, the SN2 reaction proceeds by adding an alkyl halide.

Do not add an alkyl halide until after the enolate is formed by the addition of the base. The next reaction must proceed after the enolate has been synthesized. Also, the amount of base to be added is one equivalent. If the base is present in the solution, it is more likely to react with the alkyl halide.

Large Steric Hindrance and Bulky Base LDA Is Important for Enolate Formation

However, carbonyl groups are known to be highly reactive. The addition of a base causes nucleophiles to attack the carbonyl carbons, resulting in the following nucleophilic addition reactions.

When does the nucleophile not attack the carbonyl carbons, but rather the formation of enolates? The answer is when a bulky base is used.

In many cases, bulky bases are used in the formation of enolates. One such strong base is, for example, LDA (lithium diisopropylamide). LDA is a compound with the following structure.

With such a bulky base, the steric hindrance is large. Therefore, it cannot nucleophilic attack the carbonyl carbon.

Instead, it is possible to pull out the hydrogen atom attached to the alpha carbon of the carbonyl group. This is because the proton pullout is less affected by steric hindrance.

A bulky base also has the advantage that when an alkyl halide is added to a solution, it is difficult to react due to steric hindrance. It is important to use a reagent that is a strong base but cannot be nucleophilic in order to generate enolates.

-NaH (sodium hydroxide) is also used in strong bases

Alternatively, NaH (sodium hydroxide) can also be used as a strong base to produce enolates, because although NaH is a strong base, it is not nucleophilic.

NaH is not a bulky base. Rather, it is a very small molecule. However, its small orbitals and lack of nucleophilicity make it highly important in enolate synthesis.

Can Alkylation with Electron-Withdrawing Groups Such as Cyano and Nitro Groups

Note that ketones and aldehydes are not the only functional groups for which anions are generated by strong bases. Not only carbonyl groups but also other electron-withdrawing groups can be synthesized as enolate equivalents of compounds with anionic properties by strong bases.

Examples of electron-withdrawing groups include the following.

  • Cyano group (-CN)
  • Nitro group (-NO2)
  • Ester (-COO-)
  • Amide (=CO-NR2)

Because they are electron-withdrawing, the alpha carbon is highly acidic, as is the alpha carbon of the carbonyl group. Therefore, by adding a strong base, we can synthesize enolate equivalents with a carbanion. For example, it is as follows.

When an electron-withdrawing group is present in a molecule, not just ketones and aldehydes, the proton attached to the α-carbon is pulled out of the molecule.

Regioselectivity Is Important in Ketone Alkylation

There is one problem in the formation of enolates in compounds with electron-withdrawing groups, including ketones. That is regioselectivity. Which part of the α-hydrogen is pulled out and becomes anionic is important.

For example, in ketones, there are two places where the protons are pulled out, as shown below.

The reason why regioselectivity is so important in the use of enolate for alkylation is that two compounds may be formed. Therefore, we need to understand how enolates are synthesized.

Thermodynamic Control: Acidity and Alkene Stability Determine the Position of the Reaction

There are two ideas in enolate positional selectivity. One of them is thermodynamic control of regioselectivity. In short, the lower the activation energy required to make a compound react, the more likely it is to react preferentially.

One of the most obvious thermodynamic control of regioselectivity is the difference in acidity. For the α-carbon of the carbonyl group, only one of the carbonyl groups is alkylated at different levels of acidity. For example, in the following compounds where the carbonyl group is present on both sides of the α-carbon, only one enolate is formed by the addition of a strong base.

If there are two carbonyl groups next to each other, it is easy to predict that they will be more acidic. Therefore, due to the positional selectivity in thermodynamic control, only one compound is obtained.

-Compounds with Many Substituents Tend to Be Stable

However, compounds with carbonyl groups on both sides are rare. So how can we predict which compounds will be generated?

When a compound makes a double bond, the compound is synthesized in such a way that a polysubstituted alkene is formed. This is called the Saytzeff rule. There is an order to the stability of alkenes, as shown below.

The double bond contains a π bond, which extends perpendicular to the bond. As a result, the π orbitals are parallel to the neighboring C-H bond, and the molecular structure is stabilized by weakly sharing electrons. This is called hyperconjugation.

Therefore, the more substituents there are in an alkene, the more stable the structure of the alkene will be.

The same is true for enolate formation. When enolates are synthesized, intermediates with stable structures are preferentially formed. As a result, enolates are synthesized in such a way that many alkyl chains are attached to the double bond.

For example, when NaH (sodium hydride) is added, the enolate formed is as follows.

When considering positional selectivity in thermodynamic control, the Saytzeff rule allows us to predict the positional selectivity of the enolate.

Kinetic Control: Use of Bulky Bases to Synthesize Fewer Substituents

Is it possible to synthesize enolates so that the substituents are fewer alkenes? By using a bulky base, a compound can be synthesized to have fewer substituents.

In the case of a strong base such as NaH, which has no steric hindrance, a multi-substituted enolate is generated due to the thermodynamic control of regioselectivity, as explained earlier. On the other hand, when a bulky strong base such as LDA is used, a proton with few substituents is easily pulled out due to steric hindrance.

Considering the stability of polysubstituted alkenes, as mentioned above, enolates with more substituents are easier to produce in terms of activation energy. However, because of the steric hindrance, when using a bulky base, the proton to be pulled out first will be the part with fewer substituents.

This is the reason for kinetic control. The greater the steric hindrance of the strong base used, the fewer substituents the enolate has to be synthesized. For example, the following synthesis proceeds under kinetic control.

The regioselectivity of the enolate depends on the reagent used. When a small strong base such as NaH is used, the reaction proceeds under thermodynamic control. On the other hand, when a bulky strong base such as LDA is used, the reaction proceeds in the kinetic control due to steric hindrance.

Enolate Synthesis of Electron-Withdrawing Groups Such as Ketones

The alpha carbon of the carbonyl group is known to be highly acidic. Therefore, enolates can be synthesized by using a strong base. Organic synthesis using enolates is very convenient because new alkyl chains can be synthesized by the SN2 reaction by adding alkyl halides.

In order to proceed with synthetic reactions using these compounds, you must understand the difference between enol and enolate. You also need to learn what strong bases will allow you to synthesize enolates without the nucleophilic addition reaction occurring.

In addition, one of the problems in the synthesis of enolates is always the regioselectivity: small bases, such as NaH, produce enolates with many substituents, while bulky bases, such as LDA, produce enolates with fewer substituents.

The synthetic reactions of enol and enolate are widely involved in the synthesis of important organic chemical reactions such as Claisen condensation and aldol reaction. Be sure to understand these reactions beforehand, as we have explained the basics of understanding them.