Chapter 20 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

1. Chapter 20Carboxylic Acid Derivatives:Nucleophilic Acyl Substitution

2. 20.2Structure and ReactivityofCarboxylic Acid Derivatives

3. Stability and Reactivity of Carboxylic Acid Derivatives The key to managing the information inthis chapter is the same as always:structure determines properties. The key structural feature is how well thecarbonyl group is stabilized. The key property is reactivity in nucleophilicacyl substitution.

4. Mostreactive Leaststabilized O O O O O O CH3C CH3C CH3C CH3C CH3C Cl NH2 SCH2CH3 OCH2CH3 OCCH3 Leastreactive Moststabilized

5. – – •• •• •• O O O •• •• •• •• •• + •• •• RC X RC X RC X + Electron Delocalization and the Carbonyl Group • The main structural feature that distinguishes acyl chlorides, anhydrides, thioesters, esters and amides is the interaction of the substituent with the carbonyl group. It can be represented in resonance terms as:

6. – •• •• •• O O O •• •• •• •• •• + •• •• RC X RC X RC X + Electron Delocalization and the Carbonyl Group • The extent to which the lone pair on X can be delocalized into C=O depends on: • 1) The electronegativity of X. • 2) How well the lone pair orbital of X interacts with the  orbital of C=O. –

7. Orbital Overlaps in Carboxylic Acid Derivatives • orbital of carbonyl group

8. Orbital Overlaps in Carboxylic Acid Derivatives • Lone pair orbitalof substituent

9. Orbital Overlaps in Carboxylic Acid Derivatives • Electron pair of substituent is delocalized into carbonyl orbital.

10. •• O •• R C Cl •• •• •• Acyl Chlorides – •• O •• •• • Acyl chlorides have the least stabilized carbonylgroup. • Delocalization of lone pair of Cl into C=O group isnot effective because C—Cl bond is too long. R C + Cl •• ••

11. O RCCl Least stabilized C=O Most stabilized C=O

12. – •• •• •• •• O O O O •• •• •• •• •• + •• C C C C O O R R R R •• •• Acid Anhydrides • Lone pair donation from oxygen stabilizes carbonyl group of an acid anhydride. • The other carbonyl group is stabilized in an analogous manner by the lone pair. • However, since both carbonyl groups compete for the same lone pair, stabilization of each is reduced.

13. O RCCl O O RCOCR' Least stabilized C=O Most stabilized C=O

14. – •• •• O O •• •• •• + •• C C SR' SR' R R •• •• Thioesters • Sulfur (like chlorine) is a third-row element. • Electron donation to C=O from third-row elementsis not very effective. • Resonance stabilization of C=O in thioesters isnot significant.

15. O RCCl O O RCOCR' O RCSR' Least stabilized C=O Most stabilized C=O

16. – •• •• O O •• •• •• + •• C C OR' OR' R R •• •• Esters • Lone pair donation from oxygen stabilizes carbonyl group of an ester. • Stabilization greater than comparable stabilizationof an anhydride or thioester.

17. O RCCl O O RCOCR' O O RCOR' RCSR' Least stabilized C=O Most stabilized C=O

18. – •• •• O O •• •• •• + •• C C NR'2 NR'2 R R Amides • Lone pair donation from nitrogen stabilizes carbonyl group of an amide. • N is less electronegative than O; therefore, amides stabilized more than esters and anhydrides.

19. – •• •• O O •• •• •• + •• C C NR'2 NR'2 R R Amides • Amide resonance imparts significant double-bondcharacter to C—N bond. • Activation energy for rotation about C—N bondis 75-85 kJ/mol. • C—N bond distance is 135 pm in amides versusnormal single-bond distance of 147 pm in amines.

20. O RCCl O O RCOCR' O O O RCOR' RCSR' RCNR'2 Least stabilized C=O Most stabilized C=O

21. – •• •• O O •• •• •• – •• C C O O R R •• •• •• •• Carboxylate Ions • Very efficient electron delocalization and dispersalof negative charge. • Maximum stabilization.

22. O RCCl O O RCOCR' O O O RCOR' RCSR' RCNR'2 O RCO– Least stabilized C=O Most stabilized C=O

23. Relative rateof hydrolysis O 1011 RCCl O O 107 RCOCR' O 1.0 RCOR' O < 10-2 RCNR'2 Reactivity Is Related to Structure Stabilization • The more stabilized the carbonyl group, the less reactive it is. very small small moderate large

24. •• •• O O •• •• C C R R X Y Nucleophilic Acyl Substitution In general: • Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). + HY + HX

25. O RCCl O O RCOCR' O O O RCOR' RCSR' RCNR'2 O RCO– Most reactive A carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table. Least reactive

26. 20.3General MechanismforNucleophilic Acyl Substitution

27. •• •• O O •• •• C C R R X Nu Nucleophilic Acyl Substitution • Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). + HNu + HX

28. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Involves formation and dissociationof a tetrahedral intermediate. Both stages can involve several elementary steps.

29. •• OH O HNu •• R C C Nu R X X General Mechanism for Nucleophilic Acyl Substitution First stage of mechanism (formation of tetrahedralintermediate) is analogous to nucleophilic additionto C=O of aldehydes and ketones.

30. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Second stage is restoration of C=O by elimination. Complicating features of each stage involve acid-base chemistry.

31. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in first stage is familiar in thatit has to do with acid-base catalysis of nucleophilic addition to C=O.

32. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in second stage concernsform in which the tetrahedral intermediate existsunder the reaction conditions and how it dissociatesunder those conditions.

33. Tetrahedral intermediate (TI) H H •• •• O O •• •• •• – •• •• •• R R O •• •• C C C R Nu Nu •• Nu X X Conjugate acid of tetrahedral intermediate (TI-H+) Conjugate base of tetrahedral intermediate (TI–) + X H •• The Tetrahedral Intermediate

34. O B •• •• •• H X + +B—H + •• C R Nu •• Dissociation of TI—H+ •• O H •• R H X C + Nu ••

35. •• O H O •• R B •• X C •• •• Nu •• •• – + X +B—H + •• •• C R Nu •• Dissociation of TI

36. •• – O O •• •• R X C •• •• Nu •• •• – + X •• •• C R Nu •• Dissociation of TI–

37. 20.4Nucleophilic Substitutionin Acyl Chlorides

38. O O (CH3)2CHCOH (CH3)2CHCCl Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride(12.7) SOCl2 + + SO2 HCl heat (90%)

39. O RCCl O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acyl Chlorides

40. O O O O RCOCR' RCCl R'COH H O O via: R OCR' C Cl Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to giveacid anhydrides: + + HCl

41. O O CH3(CH2)5CCl CH3(CH2)5COH O O CH3(CH2)5COC(CH2)5CH3 Example + pyridine (78-83%)

42. O O RCOR' RCCl H O via: R OR' C Cl Reactions of Acyl Chlorides Acyl chlorides react with alcohols to give esters: + + R'OH HCl

43. O O C6H5COC(CH3)3 C6H5CCl Example pyridine + (CH3)3COH (80%)

44. O O RCNR'2 RCCl H O via: R NR'2 C Cl Reactions of Acyl Chlorides Acyl chlorides react with ammonia and aminesto give amides: + + R'2NH + HO– H2O + Cl–

45. O O C6H5CN C6H5CCl HN Example NaOH + H2O (87-91%)

46. O O RCOH RCCl O O RCO– RCCl Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): + + H2O HCl + + 2HO– Cl– + H2O

47. O O RCOH RCCl H O R OH C Cl Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): + + H2O HCl via:

48. O O C6H5CH2COH C6H5CH2CCl Example + + H2O HCl

49. O C6H5CCl Reactivity • Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. C6H5CH2Cl Relative rates ofhydrolysis (25°C) 1,000 1

50. 20.5Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides • Anhydrides can be prepared from acyl chlorides