D A. Evans Weak Acids: Impact of Structure on Acidity Chem 206 a The General Reaction: lonization of a weak acid (pKa s o) Case ll: Carboxylic Acids vs Ketones H solvent H-C- Ka=4.8 Ka~19 electronegative than C X= NH(amide) Case IV: Carboxy lic Acids, Esters, Amides Ketones X= CH2(Ketoneester) R=CR3 0 0 R=NR2 Eto-C a The Question: How does one analyze the impact of structure on pKa? CH2-H CH2-H CH2-H ■ The Approach pKa-26 Ka~30 Ka~34 pKa>34<40 For equilibria such as that presented above, analyze the effect of stabilizing (or destabilizing) interactions on the more energetic The Analysis constituent which in this case is the conjugate base this series of compounds there are two variables to consider Case I: Carboxy lic Acids: Inductive Effects Inductive Effect: OEt>Me2N H3c but (0-?) Cl 0 Carboxylate ■ Resonance effect c-c stabilized by increased H electron-withdrawing CCl3 group he degree to which substituent X Ka=48 pKa=0.6 contributes"electron density into enolate represents a destabilizing interaction Trend: 0->Me 2N>OEt Case l: Carboxylic Acids: Inductive Effects Carbon Hybridization Resonance donation dominates inductive electron withdrawal as indicated by the data H-C-C-c→Hc〓c-c Carboxylate HC三C stabilized by increased Substituents on the a-carbon: Stabilization by either resonance induction or both is observed SP-hybridized carbon 0 pKa=4.9 Ph-C-CH2 CH3 Ph-C-CH2OCH3 Ph-C-CH2Ph Ph-C-CH2SPh pKa= 24.4 pKa= 22.9 a=177 Ka=17.1■ The Approach: ■ Resonance Effect: The degree to which substituent X: "contributes" electron density into enolate represents a destabilizing interaction: X C O – CH2 Resonance donation dominates inductive electron withdrawal as indicated by the data. ■ – + ●● R C O – CH2 C O O – R C C O CH2–H H H H C H H H C OH O O – R X C CH2 O – X R C O CH2–H Ph C O CH2CH3 C CH2OCH3 O Ph Ph C O CH2Ph C CH2SPh O Ph R X O – O R XH C C O O – Cl Cl Cl HC C C O – O EtO C O CH2–H C CH2–H O Me C CH2–H O Me2N – O C O CH2–H Cl C Cl Cl C OH O C C O OH H C R X H O C C O OH H H H C C O OH H H C H H H Trend: O– > Me2N > OEt ●● ■ Inductive Effect: OEt > Me2N > H3C but (O–?) In this series of compounds, there are two variables to consider: The Analysis: pKa ~ 26 pKa ~ 30 pKa ~ 34 pKa > 34 < 40 Case IV: Carboxylic Acids, Esters, Amides & Ketones: pKa = 4.8 pKa ~ 19 Carboxylate ion more stabile than enolate because O more electronegative than C Case III: Carboxylic Acids vs Ketones: pKa = 4.9 pKa = 1.9 Case II: Carboxylic Acids: Inductive Effects & Carbon Hybridization Carboxylate ion stabilized by increased electron-withdrawing SP-hybridized carbon Carboxylate ion stabilized by increased electron-withdrawing CCl3 group. pKa = 4.8 pKa = 0.6 Case I: Carboxylic Acids: Inductive Effects ■ The Question: How does one analyze the impact of structure on pKa ? R = NR2 R = OR R = CR3 X = O (carboxylic acid) X = CH2 (Ketone/ester) X = NH (amide) + solvent(H+ ) DG° DG° Energy Variables: ■ The General Reaction: Ionization of a weak acid (pKa 0) + solvent(H+ + solvent ) D. A. Evans Weak Acids: Impact of Structure on Acidity Chem 206 Stabilization by either resonance, induction, or both is observed: Substituents on the a-carbon: pKa = 24.4 pKa = 22.9 pKa = 17.7 pKa = 17.1 For equilibria such as that presented above, analyze the effect of stabilizing (or destabilizing) interactions on the more energetic constituent which in this case is the conjugate base