19.10 Sources of Carboxylic Acids

1. 19.10Sources of Carboxylic Acids

2. 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)

3. 19.11Synthesis of Carboxylic Acids by the Carboxylation of Grignard Reagents

4. 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+

5. •• •• O O •• •• diethylether R C R + O •• •• MgX MgX •• – •• O •• R C OH •• •• Carboxylation of Grignard Reagents d– C O •• •• H3O+

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

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

8. 19.12Synthesis of Carboxylic Acidsby thePreparation and Hydrolysis of Nitriles

9. 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, i.e. best with primary, then secondary…… tertiary gives elimination H3O+ RX heat SN2 + NH4+

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

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

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

13. 19.13Reactions of Carboxylic Acids:A Review and a Preview

14. Reactions of Carboxylic Acids Reactions already discussed • Acidity (Sections 19.4-19.9) • Reduction with LiAlH4 (Section 15.3) • Esterification (Section 15.8) • Reaction with Thionyl Chloride (Section 12.7)

15. Reactions of Carboxylic Acids New reactions in this chapter • a-Halogenation • Decarboxylation • But first we revisit acid-catalyzed esterificationto examine its mechanism.

16. 19.14Mechanism of Acid-Catalyzed Esterification

17. O H+ COH O COCH3 Acid-catalyzed Esterification (also called Fischer esterification) • Important fact: the oxygen of the alcohol isincorporated into the ester as shown. + CH3OH + H2O

18. Mechanism of Fischer Esterification • The mechanism involves two stages: • 1) formation of tetrahedral intermediate (3 steps) • 2) dissociation of tetrahedral intermediate (3 steps)

19. OH OCH3 C OH Mechanism of Fischer Esterification • The mechanism involves two stages: • 1) formation of tetrahedral intermediate (3 steps) • 2) dissociation of tetrahedral intermediate (3 steps) tetrahedral intermediate in esterification of benzoic acid with methanol

20. O COH OH OCH3 C OH First stage: formation of tetrahedral intermediate • methanol adds to the carbonyl group of the carboxylic acid • the tetrahedral intermediate is analogous to a hemiacetal + CH3OH H+

21. O COCH3 OH OCH3 C OH Second stage: conversion of tetrahedral intermediate to ester • this stage corresponds to an acid-catalyzed dehydration + H2O H+

22. Mechanism of formationoftetrahedral intermediate

23. CH3 •• O H O •• •• + H C O H •• •• Step 1

24. CH3 •• O H O •• •• + H C O H •• •• CH3 •• + H O O •• •• H C O H •• Step 1 ••

25. O H •• + H O C O H •• Step 1 •• H O •• • carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) C + •• ••

26. •• + H O CH3 C O •• •• H O H •• Step 2 ••

27. •• OH CH3 •• + C O •• H OH •• •• •• + H O CH3 C O •• •• H O H •• Step 2 ••

28. •• OH CH3 •• + CH3 C O •• O H •• •• OH •• •• H Step 3

29. •• OH CH3 •• + CH3 C O •• O H •• •• OH •• •• H •• OH CH3 •• CH3 C O •• + •• O H •• OH •• •• H Step 3

30. Tetrahedral intermediatetoester stage

31. •• OH •• •• C OCH3 •• O •• •• H Step 4

32. •• OH •• •• C OCH3 CH3 •• O O H •• •• •• H + H Step 4

33. •• OH •• •• CH3 C OCH3 •• + O •• •• O H •• H H •• OH •• •• C OCH3 CH3 •• O O H •• •• •• H + H Step 4

34. Step 5 •• OH •• •• C OCH3 •• + O H •• H

35. •• OH •• •• C OCH3 •• + O H •• H •• OH •• •• O C H •• H + •• OCH3 •• Step 5 +

36. •• •• + OH OH •• C C + •• •• OCH3 OCH3 •• •• Step 5

37. •• O •• •• CH3 H O C •• •• OCH3 •• •• + O C •• OCH3 •• Step 6 •• CH3 H O + H H

38. Key Features of Mechanism • Activation of carbonyl group by protonation of carbonyl oxygen • Nucleophilic addition of alcohol to carbonyl groupforms tetrahedral intermediate • Elimination of water from tetrahedral intermediate restores carbonyl group

39. 19.15Intramolecular Ester Formation:Lactones

40. Lactones • Lactones are cyclic esters • Formed by intramolecular esterification in acompound that contains a hydroxyl group anda carboxylic acid function

41. O O HOCH2CH2CH2COH O Examples • IUPAC nomenclature: replace the -oic acid ending of the carboxylic acid by -olide • identify the oxygenated carbon by number + H2O 4-hydroxybutanoic acid 4-butanolide

42. O O HOCH2CH2CH2COH O O O HOCH2CH2CH2CH2COH O Examples + H2O 4-hydroxybutanoic acid 4-butanolide + H2O 5-pentanolide 5-hydroxypentanoic acid

43. O O O O Common names a b a b • Ring size is designated by Greek letter corresponding to oxygenated carbon • A g lactone has a five-membered ring • A d lactone has a six-membered ring g g d g-butyrolactone d-valerolactone

44. Lactones • Reactions designed to give hydroxy acids often yield the corresponding lactone, especially if theresulting ring is 5- or 6-membered.

45. O O CH3CCH2CH2CH2COH 1. NaBH4 2. H2O, H+ O O H3C Example 5-hexanolide (78%)

46. O O CH3CCH2CH2CH2COH 1. NaBH4 OH O 2. H2O, H+ CH3CHCH2CH2CH2COH O O H3C Example via: 5-hexanolide (78%)