Acidity of a-hydrogens

Alkyl hydrogen atoms bonded to a carbon atom in a a (alpha) position relative to a carbonyl group display unusual acidity. While the pK_a values for alkyl C-H bonds is typically on the order of 40-50, pK_a values for these alpha hydrogens is more on the order of 19-20. This can most easily be explained by resonance stabilization of the product carbanion, as illustrated in the diagram below.

In the presence of a proton source, the product can either revert back into the starting ketone or aldehyde or can form a new product, the enol. The equilibrium reaction between the ketone or aldehyde and the enol form is commonly referred to as "keto-enol tautomerism". The ketone or aldehyde is generally strongly favored in this reaction.

Aldol Condensation

The acidity of a-hydrogens is a crucial component of the formation of aldols. The general mechanism for aldol condensation is shown below. In the first step of this reaction, the acidic proton of an aldehyde is abstracted by a base. The resonance-stabilized carbanion then attacks a second aldehyde molecule at the carbonyl carbon (which bears a partial positive charge due to the electronegativity of the oxygen atom). This reaction results in formation of a new carbon-carbon bond (shown in red). The negative charge initially located on the a-carbon atom moves to an oxygen atom. This oxygen anion can then abstract a proton to form the aldol (aldehyde-alcohol) product.

While this reaction can also be performed with ketones, the equilibrium usually strongly favors starting material.

The aldol product typically can easily be dehydrated to form a conjugated enal (alkene-aldehyde). A possible mechanism for this reaction is shown below. Only a catalytic amount of base is required. Since base is required for formation of the aldol, the enal product is often the major product of the aldol condensation reaction.

Crossed Aldol Condensation

While in principle it should be possible to obtain aldol (or enal) products by simply mixing two different aldehydes in the presences of base, this typically leads to a complicated mixture of products. However, this reaction can be practical if one of the aldehydes doesn't contain any a-hydrogens. Consider the following reaction:

The benzaldehyde molecule doesn't contain any acidic hydrogen atoms, so it cannot condense via an aldol reaction. While the 3-pentanone could form a dimeric compound, aldol products obtained from ketones generally revert back to starting material. However, loss of the acidic hydrogen followed by attack of the more reactive aldehyde carbonyl carbon results in a stable product.

Aldol Cyclization reactions

If a compound contains two carbonyl groups, the molecule can undergo a reaction with itself to give a cyclic product. While many products can be envisioned, some general guidelines are available to assist in prediction of the major product.

• Aldehydes are generally more reactive than ketones. If both functional groups are present, the aldehyde carbonyl group will typically be attacked by the carbanion.
• Products resulting in 5- or 6-membered rings are preferred over all other ring sizes.

To illustrate the application of these ideas, consider the reaction of 6-heptanonal (6-oxyheptanal). The acidic hydrogens are shown in red.

Since this molecule contains both a ketone and an aldehyde, the reaction is most likely to proceed with attack at the aldehyde carbonyl carbon. (While deprotonation of the CH₂ group next to the aldehyde can occur, the resulting carbanion would have to attack to ketone, so the green arrow shown above can be eliminated). Acidic hydrogen atoms flank both sides of the ketone. However, loss of one of the CH₃ protons followed by attack of the aldehyde (magenta arrow) would lead to formation of a seven-membered ring. Therefore, the major reaction pathway is expected to be the reaction shown below.