19.6 Substituents and Acid Strength

1. 19.6Substituents and Acid Strength

2. O CH2COH X Substituent Effects on Acidity standard of comparison is acetic acid (X = H) pKa = 4.7

3. O CH2COH X X X pKa pKa Alkyl groups have negligible effect Electronegative groups increase acidity H H 4.7 4.7 4.9 2.6 CH3 F CH3(CH2)5 Cl 2.9 4.9 Substituent Effects on Acidity

4. O CH2COH X Substituent Effects on Acidity • electronegative substituents withdraw electrons from carboxyl group; increase K for loss of H+

5. CH3CH2CHCO2H 2.8 Cl CH3CHCH2CO2H 4.1 Cl 4.5 Effect of electronegative substituent decreasesas number of bonds between it and carboxyl group increases. pKa ClCH2CH2CH2CO2H

6. 19.7Ionization ofSubstituted Benzoic Acids

7. pKa O 4.2 COH O 4.3 COH H2C CH O 1.8 COH HC C Hybridization Effect • sp2-hybridized carbon is more electron-withdrawing than sp3, and sp is more electron-withdrawing than sp2

8. O X COH Table 19.3 Ionization of Substituted Benzoic Acids • effect is small unless X is electronegative; effect is largest for ortho substituent pKa Substituent ortho meta para H 4.2 4.2 4.2 CH3 3.9 4.3 4.4 F 3.3 3.9 4.1 Cl 2.9 3.8 4.0 CH3O 4.1 4.1 4.5 NO2 2.2 3.5 3.4

9. 19.8Dicarboxylic Acids

10. O O 1.2 HOC COH O O HOCCH2COH 2.8 O O 4.3 HOC(CH2)5COH Dicarboxylic Acids pKa Oxalic acid • one carboxyl group acts as an electron-withdrawing group toward the other; effect decreases with increasing separation Malonic acid Heptanedioic acid

11. 19.9Carbonic Acid

12. O O + HOCO– H+ HOCOH overall K for these two steps = 4.3 x 10-7 Carbonic Acid • CO2 is major species present in a solution of "carbonic acid" in acidic media + H2O CO2 99.7% 0.3%

13. O HOCO– O –OCO– Carbonic Acid Second ionization constant: Ka = 5.6 x 10-11 + H+

14. 19.10Sources of Carboxylic Acids

15. Synthesis of Carboxylic Acids: Review • side-chain oxidation of alkylbenzenes (Section 11.13) • oxidation of primary alcohols (Section 15.10) • oxidation of aldehydes (Section 17.15)

16. 19.11Synthesis of Carboxylic Acidsby theCarboxylation of Grignard Reagents

17. O RCOMgX O RCOH Carboxylation of Grignard Reagents • converts an alkyl (or aryl) halide to a carboxylic acid having one more carbon atom than the starting halide Mg CO2 RMgX RX diethylether H3O+

18. •• •• O O •• •• diethylether R C R + O •• •• MgX MgX •• – •• H3O+ O •• R C OH •• •• Carboxylation of Grignard Reagents – C O •• ••

19. CH3CHCH2CH3 CH3CHCH2CH3 Example: Alkyl Halide 1. Mg, diethyl ether 2. CO2 3. H3O+ Cl CO2H (76-86%)

20. CH3 CH3 Br CO2H Example: Aryl Halide 1. Mg, diethyl ether 2. CO2 3. H3O+ (82%)

21. 19.12Synthesis of Carboxylic Acidsby thePreparation and Hydrolysis of Nitriles

22. O – N C •• •• RC N RCOH •• Preparation and Hydrolysis of Nitriles • converts an alkyl halide to a carboxylic acid having one more carbon atom than the starting halide • limitation is that the halide must be reactive toward substitution by SN2 mechanism H3O+ RX heat SN2 + NH4+

23. CH2Cl CH2CN H2O H2SO4 O heat CH2COH (77%) Example NaCN DMSO (92%)

24. H2O, HCl heat O O (83-85%) HOCCH2CH2CH2COH Example: Dicarboxylic Acid BrCH2CH2CH2Br NaCN H2O NCCH2CH2CH2CN (77-86%)

25. OH O CH3CCH2CH2CH3 CH3CCH2CH2CH3 CN H2O OH HCl, heat CH3CCH2CH2CH3 CO2H (60% from 2-pentanone) via Cyanohydrin 1. NaCN 2. H+