D. A. Evans Kinetic Thermodynamic Acidity of Ketones Chem 206 a Kinetic Acidity: Rates of proton removal Consider enolization of the illustrated ketone under non-equilibrating conditions Kinetic Equilibrium Ratios of Enolates Resulting from Enolization with LDA Subsequent Equilibration HB ①Me KA K At Kinetic Ratios Ratios Kinetic Ratios Equilibrium Ratios LINR 87)(13) Equilibrium tic acidity refers to the rate of proton removal. e.g. k a vS kb. For example, (14 99)(1) ing the above energy diagram you would say that Ha has a lower kinetic acidity HB. As such, the structure of the base (hindered vs unhindered) employed Kinetic Ratios Equilibrium lays a role in determining the magnitude of k a and k b. For the case shown above, Ratios AG#A will increase more than a as the base becomes more hindered since the proton H a resides in a more sterically hindered environment. The example shown below shows the high level of selectivity which may be achieved with the sterically a Note that alkyl substitution stabilizes the enolate(Why??). This effect hindered base lithium diisopropylamide( LDA) shows up in the equilibrium ratios shown above hEnce, enolization under" kinetic control with LDA allows you to produce the less-substituted enolate while subsequent equilibration by simply heating the enolate mixture allows equilibration to the more substituted N一LH Kinetic Ratio 99:1 Equilibrium Ratio 10: 90O O Me O O Me HB HB Me OLi LiNR2 O Me HB HA HB LiNR2 H H H Me O H H Me OLi OLi Me H H O H H H H O C3H7 CH3 O O C3H7 CH3 Ph CH3 O O CH3 Ph THF K A – K LiNR2 B – A – OLi Me HA HB B – N Me Me Me Me Li D. A. Evans Kinetic & Thermodynamic Acidity of Ketones Chem 206 ■ Kinetic Acidity: Rates of proton removal Consider enolization of the illustrated ketone under non-equilibrating conditions: kA kB Kinetic acidity refers to the rate of proton removal. e.g. k A vs k B . For example, in reading the above energy diagram you would say that HA has a lower kinetic acidity than H B . As such, the structure of the base (hindered vs unhindered) employed plays a role in determining the magnitude of k A and k B . For the case shown above, D G ‡ A will increase more than D G ‡ B as the base becomes more hindered since the proton H A resides in a more sterically hindered environment. The example shown below shows the high level of selectivity which may be achieved with the sterically hindered base lithium diisopropylamide (LDA). Reaction Coordinate Energy DG ‡ B DG ‡ A B ‡ A ‡ Kinetic Ratio 99 : 1 LDA Equilibrium Ratio 10 : 90 ■ Note that alkyl substitution stabilizes the enolate (Why??). This effect shows up in the equilibrium ratios shown above. Kinetic & Equilibrium Ratios of Enolates Resulting from Enolization with LDA & Subsequent Equilibration (99) (1) Kinetic Ratios Equilibrium Ratios (90) (10) (2) (98) Kinetic Ratios (34) (66) Equilibrium Ratios (13) (87) Kinetic Ratios (53) (47) Equilibrium Ratios (16) (84) Kinetic Ratios (87) (13) Equilibrium Ratios Equilibrium Ratios (99) (1) Kinetic Ratios (14) (86) ■ Hence, enolization under "kinetic control with LDA allows you to produce the less-substituted enolate while subsequent equilibration by simply heating the enolate mixture allows equilibration to the more substituted enolate. –78 °C