[Back] [Mount Allison Biology] [Mount Allison University] [Mount Allison Search]

Chemistry 2131:
Organic Chemistry for the Life Sciences (3)

The Aldol Reaction

• to date we have concentrated on the attack of nucleophiles at the electron deficient carbonyl carbon. There is another property of carbonyl containing compounds that leads to interesting chemistry. This is the acidity of the alpha hydrogen
• the alpha carbon is defined as the carbon atom adjacent to the carbonyl carbon (be it on an aldehyde, ketone, or carboxylic acid derivative). The hydrogen atoms attached to this carbon atom are called alpha hydrogens
• the hallmark of alpha hydrigens is their increased acidity relative to normal alkyl hydrogens. If one remembers that the pKa of ethanol (the hydroxyl hydrogen) is around 16, the pKa of an ordinary alkyl hydrogen is around 45, then it is of note that the alpha hydrogen of a carbonyl compound has a pKa of around 20.
• there are two major reasons for this increased acidity. First, there is an electronic consideration. The electron withdrawing inductive effect of the adjacent carbonyl group polarizes the C-H bond down towards the carbon atom. In effect this makes the proton easiear to remove
• the second reason is a resonance stabilization effect. The anion (a carbanion) that is formed is resonance stabilized. The unshared electron pair can form a double bond to the carbonyl carbon, pushing the carbonyl pibond up onto the carbonyl oxygen atom. Thus the negative charge is shared over two atoms.
• the anion formed by deprotonation of the alpha carbon is called an enolate anion. The reason is fairly clear, the resonance form with the negative charge on the oxygen is essentially a deprotonated enol

2. The Aldol Reaction:

• one of the very important reactions of enolate ions is the formation of a new carbon-carbon bond through an aldol reaction. The reaction has the name aldol because the product can have a hydroxyl group and an aldehyde group. To be more specific, the product is a beta-hydroxyaldehyde or a beta-hydroxyketone.
• let's look at the mechanism. The first step is to generate the enolate anion. This is done by treating the carbonyl containing compound with a strong base such as hydroxide. The hydroxide removes an alpha hydrogen from a molecule of aldehyde or ketone. The anion is a potent nucleophile
• next, this carbanion attacks the electron deficient carbonyl carbon of another molecule of aldehyde or ketone. The electrons of the pi bond are pushed up onto the carbonyl oxygen.
• this gives a TCAI. In the final step of the reaction the alkoxide abstracts a proton from water, to give an alcohol addition product and regenerate the base catalyst.
• the beta-hydroxy aldehydes and ketones are easily dehydrated to give alpha-beta unsaturated aldehydes or ketones
• in the base catalysed reaction, a second alpha hydrogen is removed from the product. This anion is resonance stabilized.
• the electron pair can go to make a double bond between the alpha and beta carbons, pushing off a hydroxyl group.
• the dehydration can be acid catalyzed as well, in this case the hydroxyl is first protonated, then the alpha hydrogen is lost, and the electrons go to form a double bond pushing off water.
• equilibrium constants for the aldol reaction generally favour the reactants. However, the equilibrium constants for the dehydration reaction are large, so this pulls the reaction to the right
• aldol reactions can be done intramolecularly.