Introduction
The success of the aldol condensation and the Claisen condensation depends upon the fact that the value of the equilibrium constant for deprotonation of a carbon atom adjacent to a carbonyl group is such that significant concentrations of nucleophilic and electrophilic carbons are present in the reaction mixture simultaneously:
The reaction conditions required to effect an aldol or a Claisen condensation place a limit on our ability to effect direct alkylation of simple aldehydes, ketones, and esters. For example, suppose you wanted to prepare 2-butanone by methylation of acetone as shown in Equation 1.
While this reaction might look feasible on paper, the desired outcome is precluded by competition from both the aldol condensation and the Sn2 reaction shown in Equation 2.
In other words, nucleophilic aliphatic substitution competes with deprotonation; direct attack of the hydroxide ion on the methyl carbon of methyl bromide is preferred to attack at one of the methyl hydrogens of acetone. With other alkyl halides other pathways are possible. For example, with ethyl bromide both Sn2 and E2 reactions are viable alternatives, as indicated in Equation 3:
Complications such as those shown in Equations 2 and 3 have led chemists to develop other approaches to alkylation of aldehydes, ketones, and esters. This topic examines two of those alternatives.
Direct Alkylation
Perhaps the simplest way to effect direct alkylation of a simple aldehyde, ketone, or ester is to eliminate the possibility of aldol or Claisen condsations by converting essentially all the the starting material to its conjugate base. To do this requires a base that is stronger than hydroxide or alkoxide ion. One base that works well is lithium diisopropyl amide, LDA, the conjugate base of diisopropyl amine. This material is easily prepared by either of the two methods outlined in Scheme 1.
Scheme 1
Preparation of LDA
Treatment of diisopropyamine with n-butyl lithium involves an acid-base reaction that has an equilibrium constant of approximately 1012. A solution of n-BuLi in THF is added to a solution of diisopropyl amine in the same solvent under an inert atmosphere at -78oC.
The lower reaction in Scheme 1 involves addition of lithium metal to an excess of diisopropyl amine. This reaction is also generally performed at low temperatures under an inert atmosphere. It is analogous to the preparation of alkoxide ions by treatment of an alcohol with sodium, potassium, or lithium metal. LDA is available commercially, both as a solid and in solutions of known concentration.
Regardless of its source, LDA is a sterically hindered, non-nucleophilic base that readily abstracts a hydrogen atom from the a-carbon of aldehydes, ketones, and esters. Equation 4 provides a representative, yet informative, example of alkylation of a siimple ketone.
The isomeric products result from attack of either the C-2 enolate or the C-6 enolate on the methyl iodide. The product distribution depends on the reaction conditions.
Load the JME Molecular Editor Exercise 1A Draw the structure of the C-2 enolate. Don't include the Li ion.
Exercise 1B Draw the structure of the C-6 enolate. Don't include the Li ion.
Exercise 2 Which enolate ion is more stable? the C-2 enolate the C-6 enolate
Exercise 3 Which product is kinetically favored? 2,2-dimethylcyclohexanone 2,6-dimethylcyclohexanone
The product distribution in reaction 4 provides an indirect measure of the relative amounts of the alternative enolate ions. A more direct measure is avaliable from experiments in which the enolate ion is "trapped" by reaction with a silylating reagent such as chlorotrimethylsilane. The Si-O bond is especially strong, and as Equation 5 indicates, reactions of enolate ions with this reagent occur exclusively at the oxygen atom.
Exercise 4 Draw the structure of the kinetically controlled product of the following reaction:
Equations 6 and 7 provide two additional examples of alkylation reactions of compounds that have a pKa of approximately 20.
In reaction 7, the pKa of the hydrogen atom alpha to the nitrile group is approximately 25, not as acidic as alpha protons in aldehydes, ketones, and esters, but acidic enough that the equilibrium constant for deprotonation of the starting material is about 1013.
Exercise 5 Draw the structure of the major product in each of the following alkylation reactions. If you do not expect a reaction to occur, draw the structure of the starting material.
Alkylation of 1,3-Dithianes
In our discussion of the nucleophilic addition of alcohols to aldehydes and ketones, we saw that the reaction of diols with aldehydes and ketones produces cyclic acetals and cyclic ketals. One example is shown in Equation 8.
It should not come as a surprise that treatment of an aldehyde with a dithiol generates a cyclic thioacetal. Scheme 2 illustrates this parallel in general terms.
Scheme 2
Generation of Cyclic Thioacetals
This reaction is of synthetic interest because of the change in acidity of the aldehydic hydrogen that occurs when the aldehyde is converted to the corresponding cyclic thioacetal. While the pKa of an aldehydic proton is approximately 45, it drops to approximately 32 in the cyclic thioacetal. Hence, deprotonation of the cyclic thioacetal with LDA is essentially complete; Keq being approximately 106. Scheme 3 presents a resonance-based interpretation of the greater acidity of cyclic thioacetals.
Scheme 3
Resonance to the Rescue
Because sulfur has empty 3d orbitals, the negative charge that initially resides on the carbon atom may be delocalized onto both adjacent sulfur atoms. This stabilizes the conjugate base, making deptotonation of the cyclic thioacetal feasible. A comparable acid-base reaction is not possible in cyclic acetals because the conjugate base is not stabilized by resonance; the oxygen atoms do not have d orbitals available to accomodate electron density.
Exercise 6 What other reaction have we considered where the conjugate base of a carbon-acid is stabilized by delocalization of electron density into empty 3d orbitals?
What makes the chemistry outlined in Schemes 2 and 3 noteworthy, is the fact that the electronic nature of the carbon atom has changed from being electrophilic in the aldehyde to being nucleophilic in the conjugate base of the cyclic thioacetal. This is noteworthy because the the direct alkylation of aldehydes by the reaction postulated in Equation 9 is not possible:
However, the transformation suggested in Equation 9 may be accomplished indirectly by the 3-step sequence shown in Scheme 3.
Scheme 3
There's More Than One Way to Skin a Cat
The last step of this sequence, the work-up, involves hydrolysis of the thioacetal, a process that is facilitated by the Lewis acid mercuric chloride.
Exercise 7 Draw the structure of the product in each of the following reactions. If you do not expect a reaction to occur, draw the structure of the aldehyde or ketone from which the dithiane was prepared.
