2.9. Reaction: Alpha (α) Alkylation
It is possible to add an alkyl group (R) adjacent to a carbonyl using an enolate nucleophile (Scheme 2.18). There are multiple ways of doing this, though the classical method is to form the enolate using LDA and then add an alkyl halide electrophile. This is sometimes referred to as α-alkylation (alpha-alkylation). The enolate must be generated before the addition of the electrophile. The reaction is normally written as two steps to indicate this.
Scheme 2.18 – Generalized Reaction Equation for Alpha-Alkylation.
The alkyl halide is typically an alkyl bromide or iodide. Some alkyl chlorides work, but many undergo competitive side-reactions. This approach will not work with alkyl fluorides.
In reality this method only works well with some alkyl halides, with many others affording poor-to-acceptable results. However, it is not always intuitive whether a given electrophile will work well or poorly for this reaction. Assume any given alkyl halide will work for this reaction unless otherwise indicated.
The mechanism for this reaction follows the standard sequence for irreversible enolate formation followed by nucleophilic attack of the enolate (Scheme 2.19). The strong base (LDA) reacts irreversibly with the acid (carbonyl-containing group) to remove a proton and generate the enolate. This greatly increases its nucleophilicity. Then the enolate (nucleophile) attacks the carbon of the alkyl halide (electrophile). This creates a new C-C bond and a salt (LiBr).
Scheme 2.19 – Reaction Mechanism for Alpha-Alkylation of Acetone with Bromomethane.
Recall that when multiple constitutional isomers are possible products of a reaction they are referred to as regioisomers (constitutional isomers that result from different atoms/groups going to different regions of the product).
For many reactions multiple regioisomers are possible. If the regioisomers are not formed in equal amounts, the reaction is described as being regioselective (selectively forming more of one regioisomer over the other(s)). A complete understanding of how regioselectivity can be controlled or achieved lies beyond the scope of this text. Instead, a brief explanation is sufficient to provide context.
Regioselectivity can be achieved if the reaction is fully reversible and there is a moderate to large energy difference between the products (the constitutional isomers). This is usually referred to as thermodynamic control because the control comes from being able to reach thermodynamic equilibrium.
Regioselectivity can be achieved if there is a moderate to large energy difference between transition states leading to the two products. This is usually referred to as kinetic control because the control comes from one pathway being kinetically faster than the other(s).
If the two sides of the carbonyl-containing molecule both contain alpha-hydrogens then multiple enolates may be formed (Scheme 2.20). These may be considered different regioisomer intermediates. Afterwards, the enolate irreversibly attacks the alkyl halide electrophile. Each regioisomer of the enolate would form a different regioisomer of the product.
Scheme 2.20 – Example of Possible Regioisomers in Alpha-Alkylation Reactions.
Because the enolate formation step is (functionally) irreversible, whatever regioisomer forms fastest will lead to the major product(s). Although alkenes are thermodynamically more stable with more substituents (see Regioselectivity – Zaitsev’s Rule) having more substituents also means there is more steric bulk close to the alpha hydrogen(s). This makes it slower for a base to get close enough to remove a proton (Scheme 2.21).
Scheme 2.21 – Example of Steric Bulk Affecting Regioselectivity for Enolate Formation Using LDA.
Because the base (LDA) is intentionally very large, with a large amount of steric bulk/interactions, the major regioisomer will be the one where the alkene has the fewest substituents (Scheme 2.22). The regioselectivity is the result of steric strain between the two molecules affecting the two possible acid-base reactions differently.
Scheme 2.22 – Determination of Major Product (Regioisomer) for Alpha-Alkylation of 2-Methylcyclohexan-1-one.
It is often possible to instead select for the other, thermodynamically more stable, regioisomer. However, this typically requires special conditions and/or reactants. Discussions of how to achieve this are typically left to advanced courses in enolate chemistry. All alpha-alkylation reactions follow kinetic control for regioselectivity in this text.
All stereoselectivity considerations for this reaction are identical to those for alpha-halogenation (see Section 2.7.3.). Assuming there are no pre-existing stereocentres in the starting material, the nucleophilic attack (enolate attacks alkyl halide) will not be stereoselective; if a new stereocentre is formed during this step, it will be formed as an equal mixture of both (R) and (S). If another stereocentre (or multiple stereocentres) exists then the resulting products will be diastereomers; the product is a non-one-to-one mixture of diastereomers. Predicting which diastereomer should be favoured is not required.
2.9.4. Variant: Enamine-Catalyzed Alpha (α) Alkylation
It is possible to add an alkyl group (R) adjacent to a carbonyl using a combination of an amine and an acid catalyst (Scheme 2.23). By far the most common combination of reagents used is pyrrolidine and acetic acid. Other amines and acids also work but are less commonly used.
Scheme 2.23 – Generalized Reaction Equation for Enamine-Catalyzed Alpha-Alkylation.
The primary benefit to this approach is avoiding the use of a strong base (LDA). Some carbonyl-containing molecules may have other functional groups that would be destroyed by the use of a very strong base.
The reaction forms an enamine as the nucleophile (Figure 2.13; see Section 2.9.4.1). Because nitrogen is less electronegative than oxygen the enamine is more reactive than an equivalent enol but still less reactive than an equivalent enolate.
Figure 2.13 – Comparison of Structure and Nucleophilicity of an Otherwise Equivalent Enol, Enamine, and Enolate.
Because it is less nucleophilic than an enolate enamine-catalyzed alpha-alkylation reactions actually work well with even fewer alkyl halide electrophiles. Again, it is not always intuitive whether a given electrophile will work well or poorly for this reaction. Assume any given alkyl halide will work for this reaction unless otherwise indicated.
This occurs in three main parts. The mechanism for this reaction is typically abbreviated due to its length.
It starts with acid-catalyzed enamine formation (Scheme 2.24). It is important to remember that acetic acid (CH3CO2H) is always contaminated with a small amount of water (H2O). The acid reacts with water to form hydronium (not shown). This is the active catalyst. First, the electrophile (carbonyl) gets activated by the catalyst. This greatly increases its electrophilicity. Second, the amine (nucleophile) attacks the activated carbonyl (electrophile). This forms a new bond and adds a lone pair to the oxygen. The solvent then removes a proton from the nitrogen (the former nucleophile) and places it on the desired leaving group, the oxygen. This greatly increases its leaving group ability. A lone pair of the nitrogen forms a π bond with the carbon, ejecting the leaving group (water). Water then removes an alpha hydrogen, regenerating the acid catalyst.
Then the enamine (nucleophile) attacks the carbon of the alkyl halide (electrophile). This creates a new C-C bond.
Third, the water hydrolyzes the imine. Water (nucleophile) attacks the carbon of the iminium (electrophile). This forms a new bond and adds a lone pair to the nitrogen. The acid then places a proton on the desired leaving group, the nitrogen. This greatly increases its leaving group ability. Water removes a proton from the oxygen (the former nucleophile) regenerating the catalyst. A lone pair of the oxygen forms a π bond with the carbon, ejecting the leaving group (amine). Finally, the amine removes a proton to generate the final product.
Scheme 2.24 – Reaction Mechanism for Enamine-Catalyzed Alpha-Alkylation of Acetone with Bromomethane.
The same major regioisomer as the standard alpha-alkylation is obtained (new group attached to less substituted position; see Section 2.9.2.). The enamine is not formed using a sterically bulky base. Instead, the regioselectivity is better attributed to the effects of steric interactions on the speed of the enamine attack on the alkyl halide.
All stereoselectivity considerations for this reaction are identical to those for alpha-halogenation (see Section 2.7.3.). Assuming there are no pre-existing stereocentres in the starting material, the nucleophilic attack (enamine attacks alkyl halide) will not be stereoselective; if a new stereocentre is formed during this step, it will be formed as an equal mixture of both (R) and (S). If another stereocentre (or multiple stereocentres) exists then the resulting products will be diastereomers; the product is a non-one-to-one mixture of diastereomers. Predicting which diastereomer should be favoured is not required.
