1. Chapter 10 Carboxylic Acids and Derivatives: Nucleophilic Acyl Substitution Reactions
Suggested Problems: 33-5,38-42,44-5,49-50,55-7,59,61-2

2. The Importance of Carboxylic Acids and Their Derivative
Most abundant organic compounds in both the laboratory and living organisms

3. 10.1 Naming Carboxylic Acids and Derivatives
Carboxylic Acids, RCO2H
If derived from open-chain alkanes, replace the terminal -e of the alkane name with -oic acid
The carboxyl carbon atom is C1

4. Alternative Names
Compounds with –CO2H (carboxyl group) bonded to a ring are named using the suffix -carboxylic acid
The CO2H carbon is not itself numbered in this system
Use common names for formic acid (HCOOH) and acetic acid (CH3COOH) – see Table 10.1

5. Naming Acid Halides RCOX
Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide

6. Naming Acid Anhydrides, RCO2COR'
If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid
Unsymmetrical anhydrides— cite the two acids alphabetically

7. Naming Amides, RCONH2
With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide
If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide

8. Naming Esters, RCO2R′
Name R′ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate”

9. Naming Nitriles, RCN
Closely related to carboxylic acids named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon numbered C1

10. Naming Nitriles, RCN
Complex nitriles are named as derivatives of carboxylic acids.
Replace -ic acid or -oic acid ending with -onitrile

11. 10.2 Occurrence and Properties of Carboxylic Acids and Derivatives
Carboxylic acids form hydrogen bonds, existing as cyclic dimers held together by two hydrogen bonds
Strong hydrogen bonding causes much higher boiling points than the corresponding alcohols

12. Esters Widespread in nature
Simple esters are pleasant smelling liquids
Ester linkage present in many biologically important molecule

13. Amides Widespread in nature: proteins, nucleic acids
Least reactive of the common acid derivatives

14. 10.3 Acidity of Carboxylic Acids
Carboxylic acids transfer a proton to water to give H3O+ and carboxylate anions, RCO2, but H3O+ is a much stronger acid
The acidity constant, Ka,, is about 10-5 for a typical carboxylic acid (pKa ~ 5)

15. Substituent Effects on Acidity
Electronegative substituents promote formation of the carboxylate ion

16. Substituent Effects on Acidity
Weaker than mineral acids
Stronger than alcohols or phenol

17. Substituent Effects on Acidity
Strength depends on the stability of the anion produced upon deprotonation

18. 10.4 Synthesis of Carboxylic Acids
Oxidation of a substituted alkylbenzene with KMnO4 gives a substituted benzoic acid (see Section 5.8)

19. From Alcohols
Oxidation of a primary alcohol or an aldehyde with CrO3 in aqueous acid

20. Hydrolysis of Nitriles
Hot acid or base yields carboxylic acids
Conversion of an alkyl halide to a nitrile (with cyanide ion) followed by hydrolysis produces a carboxylic acid with one more carbon (RBr  RCN  RCO2H)
Best with primary halides because elimination reactions occur with secondary or tertiary alkyl halides

21. 10.5 Nucleophilic Acyl Substitution Reactions
Carboxylic acid derivatives have an acyl carbon bonded to a group –Y that can leave
A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution

22. Comparison to Aldehydes and Ketones
Consequence of structure
Aldehydes and ketones do not have a leaving group

23. Relative Reactivity of Carboxylic Acid Derivatives
Nucleophiles react more readily with unhindered carbonyl groups
More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least)
The intermediate with the best leaving group decomposes fastest

24. Substitution in Synthesis
We can readily convert a more reactive acid derivative into a less reactive one
Reactions in the opposite sense are possible but require more complex approaches

25. General Reactions of Carboxylic Acid Derivatives
Water is a reagent used to make carboxylic acids
Alcohols is a reagent used to make esters
Ammonia or an amine are used to make an amide
Hydride source is used to make an aldehyde or an alcohol
Grignard reagent is used to make a ketone or an alcohol

26. 10.6 Carboxylic Acids and Their Reactions
Must enhance reactivity
Convert –OH into a better leaving group
Specific reagents can produce acid chlorides, anhydrides, esters, amides

27. Conversion of Carboxylic Acids into Acid Chlorides
Reaction with thionyl chloride, SOCl2

28. Mechanism of Thionyl Chloride Reaction
Nucleophilic acyl substitution pathway
Carboxylic acid is converted into a chlorosulfite which then reacts with chloride

29. Fischer Esterification
Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid

30. Mechanism of the Fischer Esterification
The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid
When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled

31. Amide Formation
Difficult to prepare directly from a carboxylic acid and an amine
—OH group must be activated by making it a better nonacidic leaving group
Activation by DCC (dicyclohexylcarbodiimide) followed by the addition of the amine

32. Mechanism of Amide Formation from Carboxylic Acids

33. Conversion of Acids into Alcohols
LiAlH4 reduces acids to yield aldehydes and then primary alcohols
Aldehyde is an intermediate that is not isolated

34. 10.7 Acid Halides and Their Reactions
Acid chlorides are prepared from carboxylic acids by reaction with SOCl2
Most reactive of the acid derivatives and can be converted into many other substances

35. Reactions of Acid Halides
Nucleophilic acyl substitution
Halogen replaced by –OH, by –OR, or by –NH2
Reduction yields a primary alcohol
Grignard reagent yields a tertiary alcohol

36. Hydrolysis: Conversion of Acid Halides into Acids
Acid chlorides react with water to yield carboxylic acids
HCl is generated during the hydrolysis: a base is added to remove the HCl

37. Conversion of Acid Halides to Esters
Esters are produced in the reaction of acid chlorides with alcohols in the presence of pyridine or NaOH. This is called alcoholysis
The reaction is better with less steric hinderance

38. Conversion of Acid Halides into Amides: Aminolysis
Amides result from the reaction of acid chlorides with NH3, primary (RNH2) and secondary (R2NH) amines
The reaction with tertiary (R3N) amines gives an unstable species that cannot be isolated
HCl is neutralized by the amine or an added base

39. 10.8 Acid Anhydrides and Their Reactions
Prepared by nucleophilic acyl substitution of a carboxylate with an acid chloride

40. Reactions of Acid Anhydrides
Similar to acid chlorides in reactivity

41. Acetylation
Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines

42. 10.9 Esters and Their Reactions
Esters are usually prepared from carboxylic acids

43. Reactions of Esters

44. Hydrolysis: Conversion of Esters into Carboxylic Acids
An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol

45. Mechanism of Ester Hydrolysis
Hydroxide catalysis via an addition intermediate

46. Saponification
Hydrolysis of an ester in basic solution

47. Reduction: Conversion of Esters into Alcohols
Reaction with LiAlH4 yields primary alcohols

48. Reaction of Esters with Grignard Reagents
React with 2 equivalents of a Grignard reagent to yield a tertiary alcohol

49. 10.10 Amides and Their Reactions
Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines

50. Conversion of Amides into Acids
Heating in either aqueous acid or aqueous base produces a carboxylic acid and amine
Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia

51. Reduction: Conversion of Amides into Amines
Reduced by LiAlH4 to an amine rather than an alcohol
Converts C=O  CH2

52. 10.11 Nitriles and Their Reactions
Nitriles and carboxylic acids both have a carbon atom with three bonds to an electronegative atom, and contain a  bond
Both are electrophiles

53. Preparation of Nitriles
Reaction of alkyl halides with NaCN
Simplest method via SN2 reaction

54. Mechanism of Dehydration of Amides
Nucleophilic amide oxygen atom attacks SOCl2 followed by deprotonation and elimination

55. Reactions of Nitriles
RCºN is strongly polarized with an electrophilic carbon atom
Attacked by nucleophiles to yield sp2-hybridized imine anions

56. Reactions of Nitriles

57. Hydrolysis: Conversion of Nitriles into Carboxylic Acids
Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia (or an amine)

58. Conversion of Nitriles to Amines
Reduction of a nitrile with LiAlH4 gives a primary amine
Similar to the reduction of an ester to give a primary alcohol

59. Conversion of Nitriles to Ketones
Grignard reagents added to nitriles to produce intermediate imine anions
Subsequent hydrolysis yields ketones

60. 10.12 Biological Carboxylic Acid Derivatives: Thioesters and Acyl Phosphates
Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate
Acetyl CoA’s are most common thioesters in nature

61. 10.13 Polymers from Carbonyl Compounds: Polyamides and Polyesters
Reactions occur in distinct linear steps (step-growth polymers), not as chain reactions (chain-growth polymers)
Reactions between difunctional molecules
Reaction of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide
A diol with a diacid leads to a polyester

62. 10.13 Polymers from Carbonyl Compounds: Polyamides and Polyesters

63. Polyamides (Nylons)
Heating a diamine with a diacid produces a polyamide called Nylon®
Nylon 66® is from adipic acid and hexamethylene-diamine at 280°C

64. Polyesters
The polyester from dimethyl terephthalate and ethylene glycol is called Dacron® and Mylar® and used to make fibers

65. Biodegradable Polymers
Polymers which can readily be broken down by natural processes
Examples: in landfills by soil microorganisms or hydrolysis of surgical sutures