Lecture 9

-Alkylation of Carbonyl Compounds

-Alkylation of ketones - via the enolate anion - can be a useful technique for extending or modifying the alkyl chain in aldehydes and ketones at the -carbon:

As we saw earlier a problem here is that the intermediate enolate can be a strong enough base to deprotonate the alkylated product at an -carbon. This yields a new enolate which can then itself be alkylated - hence mixtures which may be difficult to separate can be formed:

lkylation of -ketocarboxylic esters provides a clean alternative route to direct -alkylation of ketones:

The activating effect of the ester group increases the acidity of the 'doubly -' CH, directing alkylation to that carbon but di-alkylation is sterically inhibited. Following removal of the ester group by hydrolysis/decarboxylation the overall reaction is equivalent to - i.e. yields the same product as - clean -monoalkylation of acetone.

The strategy of using a -ketoester as a synthetic 'stand-in' for a ketone in alkylation reactions (in technical language, as a 'synthetic equivalent' of a ketone) can also be applied to carry out effective stepwisedi-alkylation- to ketone carbonyl:

Although the reactions discussed above involve several steps, the ability to exercise precise choice of mono- vs. di-alkylation and the ability to attach two different alkyl groups to the -carbon makes them significantly more useful than direct alkylation of the ketone enolate.

Revision: Indirect clean -monoalkylation of ketones via the Claisen condensation:

The activating effect of the ester group, increases the acidity of the 'doubly -' CH, directing alkylation to that carbon but sterically inhibiting di-alkylation. Following removal of the ester group by hydrolysis/decarboxylation the overall reaction is equivalent to - i.e. yields the same product as - clean -monoalkylation of acetone.

Some further examples of indirect ketone monoalkylation:

Malonic Ester Synthesis - A synthesis of -substituted carboxylic acids - equivalent to clean indirect mono- or di- -alkylation of acetic acid:

The CH2 hydrogens in diethylmalonate are 'doubly -' to the two ester carbonyl groups and therefore have enhanced acidity. One or two deprotonation/alkylation steps leads cleanly to monoalkylated or dialkylated products (compare the -ketoester chemistry just studied) Hydrolysis of both ester groups gives a -dicarboxylic acid which - like a -keto carboxylic acid - undergoes rapid decarbonylation to a monocarboxylic acid. The overall reaction is equivalent (i.e. gives the same product as) the clean indirect di--alkylation of acetic acid.

The Knoevenagel Condensation - The 'doubly -' enolate anion of diethyl malonate behaves as the nucleophile in an aldol-like reaction with an aldehyde or ketone forming an ,-unsaturated diester. Following hydrolysis and decarboxylation, the final product is an ,-unsaturated carboxylic acid. Here diethyl malonate acts as a synthetic equivalent of the enolate anion of acetic acid.

Tutorial Question:

In the base-catalysed Aldol-Claisen Condensation of a ketone and an ester the ketone behaves as the nucleophile and the ester behaves as the electrophile:

In the base-catalysed Knoevenagel Condensation of malonic ester and a ketone the ester behaves as the nucleophile and the ketone behaves as the electrophile:

How do you explain the difference?

Enamines - nitrogen analogues of enols:

Preparation of 3° enamines - acid-catalysed addition of a secondary amine to an enolisable ketone:

Reactivity of enamines:

-Alkylation of enamines - another synthetic equivalent of clean -monoalkylation of ketones:

Although a multi-step process, ketone alkylation via enamines may be more efficient than direct alkylation via the enolate.

Special properties of conjugated carbonyl compounds:

Carbonyl compounds in which other multiple bonds are conjugated with the C-O double bond are significantly more stable than their non-conjugated isomers. For this reason ,-unsaturated carbonyl compounds readily isomerise to the more stable conjugated ,-unsaturated isomers via enol (acidic conditions) or enolate (basic conditions) intermediates:

Acid catalysis:

-Unsaturated carbonyl compounds have two electrophilic carbon sites - the carbonyl carbon and the -carbon:

Addition reactions tto the C=C or C=O double bond alone are called 'normal' or 1,2 additions:

Addition reactions that involve the conjugated system as a whole are called 'conjugate additions' or 1,4 additions:

Note that here '1,2' and '1,4', do not refer to the numbering system for identifying carbon atoms in the systematic naming of the molecules. Examples of 1,4 (i.e. conjugate) addition:

This reaction looks like a 'normal' or 1,2 - although anti-Markownikov - addition of HCl to the C-C double bond. However the mechanism involves acid-catalysed 1,4-addition:

This apparent contradiction arises because 1,4-addition of HZ to the C=C-C=O structure yields an enol which then tautomerises to the corresponding keto form which has the same structure as would be produced by anti-Markovnikov 1,2-addition to the C=C bond.