1. 19.6 Substituents and Acid Strength

2. standard of comparison is acetic acid (X = H) Substituent Effects on Acidity X CH 2 COH O K a = 1.8 x 10 -5 pK a = 4.7

3. Substituent Effects on Acidity alkyl substituents have negligible effect X CH 2 COH O X KaKaKaKa pKapKapKapKaH CH 3 CH 3 (CH 2 ) 5 1.8 x 10 -5 4.7 1.3 x 10 -5 4.9 4.9

4. Substituent Effects on Acidity electronegative substituents increase acidity X CH 2 COH O X KaKaKaKa pKapKapKapKaH F Cl 1.8 x 10 -5 4.7 2.5 x 10 -3 2.6 1.4 x 10 -3 2.9

5. Substituent Effects on Acidity electronegative substituents withdraw electrons from carboxyl group; increase K for loss of H + X CH 2 COH O

6. Substituent Effects on Acidity effect of electronegative substituent decreases as number of bonds between X and carboxyl group increases X CH 2 COH OX KaKaKaKa pKapKapKapKa H 1.8 x 10 -5 4.7 1.4 x 10 -3 2.9 1.0 x 10 -4 4.0 ClCH 2 Cl 3.0 x 10 -5 4.5 ClCH 2 CH 2

7. 19.7 Ionization of Substituted Benzoic Acids

8. Hybridization Effect KaKaKaKa pKapKapKapKa 6.3 x 10 -5 4.2 5.5 x 10 -5 4.3 1.4 x 10 -2 1.8 COH O H2CH2CH2CH2C CH COH O COH O HC C sp 2 -hybridized carbon is more electron- withdrawing than sp 3, and sp is more electron-withdrawing than sp 2

9. pK a Substituentorthometapara H4.24.24.2 CH 3 3.94.34.4 F3.33.94.1 Cl2.93.84.0 CH 3 O4.14.14.5 NO 2 2.23.53.4 Table 19.3 Ionization of Substituted Benzoic Acids COHOX effect is small unless X is electronegative; effect is largest for ortho substituent

10. 19.8 Dicarboxylic Acids

11. Dicarboxylic Acids one carboxyl group acts as an electron- withdrawing group toward the other; effect decreases with increasing separation Oxalic acid Malonic acid Heptanedioic acid 1.2 2.8 4.3 COHOHOCO pKapKapKapKa HOCCH 2 COH OO HOC(CH 2 ) 5 COH OO

12. 19.9 Carbonic Acid

13. Carbonic Acid HOCOHO CO 2 + H2OH2OH2OH2O 99.7%0.3%

14. Carbonic Acid HOCOHO CO 2 + H2OH2OH2OH2O HOCO – O H+H+H+H+ +

15. Carbonic Acid HOCOHO CO 2 + H2OH2OH2OH2O HOCO – O H+H+H+H+ + overall K for these two steps = 4.3 x 10 -7 CO 2 is major species present in a solution of "carbonic acid" in acidic media

16. Carbonic Acid HOCO – O – OCO – O H+H+H+H+ + K a = 5.6 x 10 -11 Second ionization constant:

17. 19.10 Sources of Carboxylic Acids

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

19. 19.11 Synthesis of Carboxylic Acids by the Carboxylation of Grignard Reagents

20. Carboxylation of Grignard Reagents RX Mg diethyl ether RMgX CO2CO2CO2CO2 H3O+H3O+H3O+H3O+ RCOMgX O RCOH O converts an alkyl (or aryl) halide to a carboxylic acid having one more carbon atom than the starting halide

21. RMgX C O MgX+ –––– H3O+H3O+H3O+H3O+ diethyl ether O – R C O O R C OH O Carboxylation of Grignard Reagents

22. Example: Alkyl Halide CH 3 CHCH 2 CH 3 (76-86%) 1. Mg, diethyl ether 2. CO 2 3. H 3 O + CH 3 CHCH 2 CH 3 Cl CO2HCO2HCO2HCO2H

23. Example: Aryl Halide (82%) 1. Mg, diethyl ether 2. CO 2 3. H 3 O + CH 3 CO2HCO2HCO2HCO2H Br

24. 19.12 Synthesis of Carboxylic Acids by the Preparation and Hydrolysis of Nitriles

25. Preparation and Hydrolysis of Nitriles RX RCOH O 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 S N 2 mechanism – C N RCRCRCRC N SN2SN2SN2SN2 H3O+H3O+H3O+H3O+ heat + NH 4 +

26. Example NaCN DMSO (77%) H2OH2OH2OH2O H 2 SO 4 heat (92%) CH 2 Cl CH 2 CN CH 2 COH O

27. Example: Dicarboxylic Acid BrCH 2 CH 2 CH 2 Br NaCN H2OH2OH2OH2O H 2 O, HCl heat (77-86%) NCCH 2 CH 2 CH 2 CN (83-85%) HOCCH 2 CH 2 CH 2 COH OO

28. via Cyanohydrin 1. NaCN 2. H + (60% from 2-pentanone) H2OH2OH2OH2O HCl, heat CH 3 CCH 2 CH 2 CH 3 O OH CNCNCNCN OH CO2HCO2HCO2HCO2H