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Lecture 3 Regioselective Formation of Enolates

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Lecture 3 Regioselective Formation of Enolates Lecture 3 Regioselective Formation of Enolates Objectives: By the end of this lecture you will be able to: 1) recognise the difference between thermodynamic and kinetic enolates and be able to form both types selectively; 2) form enolates regioselectively from α-bromo ketones and from enones. Kinetic versus Thermodynamic Control Consider the following unsymmetrically substituted ketone. Protons can be abstracted from either side of the carbonyl group leading to two different enolate products. It is clearly important to be able to control the site of enolate formation; ideally we would like to have two sets of reaction conditions for selectively accessing either enolate. Although the pKa difference between the two sites is only 1-2 units, this difference, when combined with the differing steric accessibilities of the α-protons, is usually sufficient to be able to selectively form the kinetic enolate. NOTE: the more substituted enolate is not always the thermodynamically more stable enolate; in some cases steric hindrance can destabilise the more substituted enolate. In these cases, the kinetic and thermodynamic enolate are the same product. A number of variables can affect the regioselectivity of an enolisation. These include the solvent, the base, the countercation and the reaction temperature. factors favouring the formation of factors favouring the formation of the the kinetic enolate thermodynamic enolate aprotic solvents e.g. THF, Et2O (no acidic proton protic solvents e.g. ROH which have slightly more to encourage the reverse reaction) acidic protons than the enolate and favour formation of the enol and tautomerisation to the ketone (i.e. the reverse reaction) strong bases e.g. LDA (which generate a weak weaker bases which provide a relatively strong i conjugate acid (e.g. Pr2NH) specifically one conjugate acid. which is less acidic than the α-C−H in the carbonyl compound). oxophilic cations e.g. Li+ low temperature (e.g. -78 °C) higher temperature short reaction times long reaction times All these conditions suppress equilibration and All these conditions encourage the reverse ensure the reaction is effectively irreversible. reaction and maximise the chances of forming the thermodynamic product. Formation of the Kinetic Enolate Formation of the Thermodynamic Enolate Other Methods of Regioselective Enolate Formation It is not always necessary to rely on kinetic or thermodynamic control for forming enolates. In many cases chemical modification of pre-existing functionality (especially α,β-unsaturated ketones) can be used to regioselectively introduce the enolate. Example 1. Enolates from α−bromo ketones Example 2. Enone reduction Example 3. Conjugate addition of soft nucleophiles such as cuprates to enones. Summary For unsymmetrical ketones the issue of regioselective enolisation becomes important. Usually one enolate will be the kinetic product, the other the thermodynamic product. The kinetic enolate is fairly easy to prepare; typical conditions are LDA, -78 °C in THF. The thermodynamic enolate is not as easy to generate, and conditions need to be sought which ideally allow equilibration between the two enolates to maximise the chances of forming the thermodynamic product. An alternative method for regioselective enolisation is to use pre-existing functionality to prepare the enolate in a way that avoids the use of a deprotonation step. α-Bromo ketones and α,β- unsaturated ketones are very useful starting materials for this purpose..
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