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

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

The Claisen Condensation

• we have already looked in detail at the aldol reaction. This reaction relies on the increased acidity of alpha hydrogens on aldehydes and ketones. Remember that this increased acidity is due to two contributing factors: the pulling of electrons from the alpha C-H bonds towards the electron deficient carbonyl carbon and the resonance stabilization of the carbanion formed when deprotonation takes place.
• thus in the presence of a strong base, a strong nucleophile is generated by this deprotonation event. Nucleophilic addition can occur in the case of the aldehyde and ketone to give a beta-hydroxy aldehyde or ketone.
• a similar reaction can occur with esters, the Claisen condensation, to give beta-ketoesters
• this reaction is highly analogous to the aldol reaction, but as one would expect for a carboxylic acid derivative, nucleophilic substitution rather than addition takes place
• again, this reaction relies on the acidity of the alpha hydrogens of the ester. The pKa for these hydrogens is about 22, just a little higher than the pKa of aldehyde or ketone alpha hydrogens
• there is a little trick here. If we were to use the strong base, hydroxide, that we used for an aldol reaction you would get alkaline hydrolysis of the ester bond. Remember saponification? To get around this one tends to use non-aqueous bases such as sodium ethoxide in ethanol or sodium methoxide in methanol
• the first step in the process is the removal of an alpha hydrogen by the base. Can you identify an alpha hydrogen? It's the one on the carbon directly beside the carbonyl carbon.
• the resulting anion, an enolate is resonance stabilized.
• the pKa of ethanol, the parent alcohol of ethoxide is 16, whereas the pKa of the alpha hydrogen is around 22. So, which way does the equilibrium lie? towards the ethoxide rather than the enolate. This means that there will be way more ester than enolate at any one time.
• when a little enolate is formed, the carbanion can attack the carbonyl of the ester to give a TCAI, with the carbonyl oxygen accepting the electron pair of the pi bond.
• to resolve the reaction, we get the reformation of the pi bond with the pushing off of alkoxide to generate the substitution product, a beta-keto ester
• the equilibrium of the reaction lies far to the left, favouring the reactants over the products. The reaction is driven to the right though, because the beta-ketoester is a stronger acid than the alcohol, so the alkoxide formed is rapidly protonated to alcohol, and is thus removed, pulling the reaction to the right
• why should a beta-keto ester be a stronger acid than an alcohol? There is one carbon atom in a beta-keto ester that is alpha to two carbonyls, this makes the hydrogen on it very acidic
• one can recover the protonated form by a mild acid work up (not strong enough to hydrolyse the ester bond)

2. The Diekmann Condensation:

• one variation of the Claisen reaction is the Diekmann Condensation. This is an intramolecular Claisen reaction which gives a 5 or six membered ring
• let's look at the example of diethyl hexandioate mixed with sodium ethoxide. The first step is the removal of an alpha hydrogen to give a resonance stabilized enolate ion.
• the carbanion attacks the other carbonyl group, pushing the electrons up onto the carbonyl oxygen to give a TCAI
• the electrons come back down to reform the pi bond and push off ethoxide. You end up with 2-oxocyclopentane carboxylate

3. Biological Example- the Biosynthesis of Terpenes:

• Claisen and aldol condensations are widely used in the biological world for the synthesis of new carbon-carbon bonds. Organic chemists go to great lenghts to make new carbon carbon bonds, and often have to tear their hair out to get the desired stereochemical product
• since you have been sitting here sleeping through the first part of the class, your body has broken countless C-C bonds and built others. Effortlessly (essentially, at least you probably didn't notice)
• let's look at some reactions used to generate the base terpene units, isoprene
• biological systems usually build up bigger molecules using 2-carbon units, acetyl groups. This acetly group is usually activated by having it covalently attached to a Coenzyme A molecule through a thioester linkage
• in a reaction catalysed by the enzyme thiolase two acetyl-CoA molecules are brought together to give acetoacetyl-CoA. One acetly-CoA is deprotonated to give an enolate. This attacks the other acetyl-CoA to give a TCAI. The electrons come back down to regenerate the carbonyl and to push off Co-A-SH (picks up a proton from water as it leaves) and generates acetoacetyl-CoA.
• the next step is an aldol reaction. The enzyme is 3-hydroxyl-3-methylglutaryl-CoA synthase. A new enolate is formed on a new molecule of acetyl-CoA. The carbanion attacks the keto group of acetoacetyl-CoA to give a TCAI. Two things happen to the intermediate. First the CoA is hydrolysed from the new acetyl group and the alkoxide becomes protonated to give the addition product. The product is (S)-3-hydroxy-3-methylglutaryl CoA
• because of the chiral environment of the enzyme only the S isomer is made
• so, now we have made a 6 carbon unit. The pathway continues on to generate in a couple more steps, isopentenyl pyrophosphate which is the activated form of isoprene.