1. Dr. Wolf's CHM 201 & 202 20-1 Chapter 20 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution

2. Dr. Wolf's CHM 201 & 202 20-2 20.1 Nomenclature of Carboxylic Acid Derivatives

3. Dr. Wolf's CHM 201 & 202 20-3 Acyl Halides RCOX name the acyl group and add the word chloride, fluoride, bromide, or iodide as appropriate acyl chlorides are, by far, the most frequently encountered of the acyl halides

4. Dr. Wolf's CHM 201 & 202 20-4 Acyl Halides CH 3 CCl O acetyl chloride 3-butenoyl chloride O H2CH2CH2CH2C CHCH 2 CCl OCBr F p-fluorobenzoyl bromide

5. Dr. Wolf's CHM 201 & 202 20-5 Acid Anhydrides when both acyl groups are the same, name the acid and add the word anhydride when the groups are different, list the names of the corresponding acids in alphabetical order and add the word anhydride RCOCR'OO

6. Dr. Wolf's CHM 201 & 202 20-6 Acid Anhydrides acetic anhydride benzoic anhydride benzoic heptanoic anhydride CH 3 COCCH 3 OO C 6 H 5 COCC 6 H 5 OO C 6 H 5 COC(CH 2 ) 5 CH 3 OO

7. Dr. Wolf's CHM 201 & 202 20-7 EstersEsters name as alkyl alkanoates cite the alkyl group attached to oxygen first (R') name the acyl group second; substitute the suffix -ate for the -ic ending of the corresponding acid RCOR'O

8. Dr. Wolf's CHM 201 & 202 20-8 EstersEsters CH 3 COCH 2 CH 3 O ethyl acetate methyl propanoate 2-chloroethyl benzoate O CH 3 CH 2 COCH 3 COCH 2 CH 2 Cl O

9. Dr. Wolf's CHM 201 & 202 20-9 Amides having an NH 2 group identify the corresponding carboxylic acid replace the -ic acid or -oic acid ending by -amide. RCNH 2 O

10. Dr. Wolf's CHM 201 & 202 20-10 Amides having an NH 2 group CH 3 CNH 2 Oacetamide 3-methylbutanamideO (CH 3 ) 2 CHCH 2 CNH 2 CNH2CNH2CNH2CNH2Obenzamide

11. Dr. Wolf's CHM 201 & 202 20-11 Amides having substituents on N name the amide as before precede the name of the amide with the name of the appropriate group or groups precede the names of the groups by the letter N- (standing for nitrogen and used as a locant) RCNHR' Oand RCNR' 2 O

12. Dr. Wolf's CHM 201 & 202 20-12 Amides having substituents on N CH 3 CNHCH 3 O N-methylacetamide N-isopropyl-N-methylbutanamide CN(CH 2 CH 3 ) 2 O N,N-diethylbenzamide O CH 3 CH 2 CH 2 CNCH(CH 3 ) 2 CH 3

13. Dr. Wolf's CHM 201 & 202 20-13 NitrilesNitriles add the suffix -nitrile to the name of the parent hydrocarbon chain (including the triply bonded carbon of CN) or: replace the -ic acid or -oic acid name of the corresponding carboxylic acid by -onitrile or: name as an alkyl cyanide (functional class name) RCN

14. Dr. Wolf's CHM 201 & 202 20-14 NitrilesNitriles CH 3 C N ethanenitrile or: acetonitrile or: methyl cyanide C6H5CC6H5CC6H5CC6H5CN benzonitrile N C CH 3 CHCH 3 2-methylpropanenitrile or: isopropyl cyanide

15. Dr. Wolf's CHM 201 & 202 20-15 20.2 Structure of Carboxylic Acid Derivatives

16. Dr. Wolf's CHM 201 & 202 20-16 The key to this chapter is the next slide. It lists the various carboxylic acids in order of decreasing reactivity toward their fundamental reaction type (nucleophilic acyl substitution). The other way to read the list is in order of increasing stabilization of the carbonyl group.

17. Dr. Wolf's CHM 201 & 202 20-17 CH 3 C OCl O OCCH 3 O CH 3 C O SCH 2 CH 3 CH 3 C O OCH 2 CH 3 CH 3 C O NH 2 Most reactive Least reactive Least stabilized Most stabilized

18. Dr. Wolf's CHM 201 & 202 20-18 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: RC O X –RC O X + RC O X +–

19. Dr. Wolf's CHM 201 & 202 20-19 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 RC O X RC O X + RC O X +––

20. Dr. Wolf's CHM 201 & 202 20-20 Orbital overlaps in carboxylic acid derivatives  orbital of carbonyl group

21. Dr. Wolf's CHM 201 & 202 20-21 Orbital overlaps in carboxylic acid derivatives lone pair orbital of substituent

22. Dr. Wolf's CHM 201 & 202 20-22 Orbital overlaps in carboxylic acid derivatives electron pair of substituent delocalized into carbonyl  orbital

23. Dr. Wolf's CHM 201 & 202 20-23 acyl chlorides have the least stabilized carbonyl group delocalization of lone pair of Cl into C=O group is not effective because C—Cl bond is too long Acyl Chlorides C O R Cl C O R Cl + –

24. Dr. Wolf's CHM 201 & 202 20-24 RCCl O least stabilized C=O most stabilized C=O

25. Dr. Wolf's CHM 201 & 202 20-25 lone pair donation from oxygen stabilizes the carbonyl group of an acid anhydride the other carbonyl group is stabilized in an analogous manner by the lone pair Acid Anhydrides C R O O C O R O +–C R O O C R

26. Dr. Wolf's CHM 201 & 202 20-26 RCOCR' OO RCCl O least stabilized C=O most stabilized C=O

27. Dr. Wolf's CHM 201 & 202 20-27 Sulfur (like chlorine) is a third-row element. Electron donation to C=O from third-row elements is not very effective. Resonance stabilization of C=O in thioesters is not significant. Thioesters +–C R O SR' O C R SR'

28. Dr. Wolf's CHM 201 & 202 20-28 RCOCR' OO RCCl O least stabilized C=O most stabilized C=O RCSR' O

29. Dr. Wolf's CHM 201 & 202 20-29 lone pair donation from oxygen stabilizes the carbonyl group of an ester stabilization greater than comparable stabilization of an anhydride or thioester Esters +–C R O OR' O C R OR'

30. Dr. Wolf's CHM 201 & 202 20-30 RCOCR' OO RCCl O RCOR' O least stabilized C=O most stabilized C=O RCSR' O

31. Dr. Wolf's CHM 201 & 202 20-31 lone pair donation from nitrogen stabilizes the carbonyl group of an amide N is less electronegative than O; therefore, amides are stabilized more than esters and anhydrides Amides +–C R O NR' 2 O C R NR' 2

32. Dr. Wolf's CHM 201 & 202 20-32 amide resonance imparts significant double-bond character to C—N bond activation energy for rotation about C—N bond is 75-85 kJ/mol C—N bond distance is 135 pm in amides versus normal single-bond distance of 147 pm in amines Amides +–C R O NR' 2 O C R NR' 2

33. Dr. Wolf's CHM 201 & 202 20-33 RCOCR' OO RCCl O RCOR' O RCNR' 2 O least stabilized C=O most stabilized C=O RCSR' O

34. Dr. Wolf's CHM 201 & 202 20-34 very efficient electron delocalization and dispersal of negative charge maximum stabilization Carboxylate ions O C R – O –C R O O

35. Dr. Wolf's CHM 201 & 202 20-35 RCOCR' OO RCCl O RCOR' O RCNR' 2 O RCO – O least stabilized C=O most stabilized C=O RCSR' O

36. Dr. Wolf's CHM 201 & 202 20-36 Reactivity is related to structure RCOCR' OO RCCl O RCOR' O RCNR' 2 OStabilization very small small large moderate Relative rate of hydrolysis 10 11 10 7 < 10 -2 1.0 The more stabilized the carbonyl group, the less reactive it is.

37. Dr. Wolf's CHM 201 & 202 20-37 Nucleophilic Acyl Substitution In general: O C R X + HY O C R Y + HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

38. Dr. Wolf's CHM 201 & 202 20-38 RCOCR' OO RCCl O RCOR' O RCNR' 2 O RCO – O RCSR' O most reactive least reactive a carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table

39. Dr. Wolf's CHM 201 & 202 20-39 20.3 General Mechanism for Nucleophilic Acyl Substitution

40. Dr. Wolf's CHM 201 & 202 20-40 Nucleophilic Acyl Substitution O C R X + HNu O C R Nu + HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

41. Dr. Wolf's CHM 201 & 202 20-41 General Mechanism for Nucleophilic Acyl Substitution involves formation and dissociation of a tetrahedral intermediate O C R X HNu C ROHX Nu O C R Nu -HX Both stages can involve several elementary steps.

42. Dr. Wolf's CHM 201 & 202 20-42 General Mechanism for Nucleophilic Acyl Substitution first stage of mechanism (formation of tetrahedral intermediate) is analogous to nucleophilic addition to C=O of aldehydes and ketones O C R X HNu C ROHX Nu

43. Dr. Wolf's CHM 201 & 202 20-43 General Mechanism for Nucleophilic Acyl Substitution second stage is restoration of C=O by elimination O C R X HNu C R OH X Nu O C R Nu -HX complicating features of each stage involve acid-base chemistry

44. Dr. Wolf's CHM 201 & 202 20-44 General Mechanism for Nucleophilic Acyl Substitution O C R X HNu C R OH X Nu O C R Nu -HX Acid-base chemistry in first stage is familiar in that it has to do with acid/base catalysis of nucleophilic addition to C=O.

45. Dr. Wolf's CHM 201 & 202 20-45 General Mechanism for Nucleophilic Acyl Substitution O C R X HNu C R OH X Nu O C R Nu -HX Acid-base chemistry in second stage concerns form in which the tetrahedral intermediate exists under the reaction conditions and how it dissociates under those conditions.

46. Dr. Wolf's CHM 201 & 202 20-46 The Tetrahedral Intermediate tetrahedral intermediate (TI) C R O X Nu H C R O X Nu H H + Conjugate acid of tetrahedral intermediate (TI + ) O C R X Nu – Conjugate base of tetrahedral intermediate (TI – )

47. Dr. Wolf's CHM 201 & 202 20-47 Dissociation of TI—H + C R O X Nu H H + + B—H + C O RNu +X H B

48. Dr. Wolf's CHM 201 & 202 20-48 Dissociation of TI B C R O X Nu H + B—H + C O RNu +X –

49. Dr. Wolf's CHM 201 & 202 20-49 Dissociation of TI – C O RNu +X – C R O X Nu –