Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

Transcription

1 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

2 Carboxylic Acid Derivatives Carboxylic acid derivatives. Acyl chloride Acid anhydride Ester Amide Nucleophilic acyl substitution

3 19.1 Nomenclature of Carboxylic Acid Derivatives

4 Nomenclature of Acid Chlorides Replace the -ic acid ending of the IUPAC name of the corresponding carboxylic acid by yl chloride. The suffix -carbonyl chloride is used for attachments to rings other than benzene Pentanoyl chloride 3-Butenoyl chloride p-fluorobenzoyl chloride Cyclopentanecarbonyl chloride

5 Nomenclature of Acid Anhydrides When both acyl groups are the same, the word acid in the corresponding carboxylic acid is replaced by anhydride. When the two acyl groups are different, their corresponding carboxylic acids are cited in alphabetical order. Acetic anhydride Benzoic heptanoic anhydride

6 Nomenclature of Esters The alkyl group and the acyl group of an ester are specified independently. Esters are named as alkyl alkanoates. Ethyl acetate 2-Chloroethyl benzoate Methyl propanoate

7 Nomenclature of Amides When naming amides, replace the -ic acid or -oic acid of the corresponding carboxylic acid with -amide. Substituents are listed in alphabetical order. Substitution on nitrogen is indicated by the locant N-. 3-Methylbutanamide N-Ethyl-3-methylbutanamide N-Ethyl-N,3-dimethylbutanamide

8 Nomenclature of Nitriles Substitutive names add the suffix -nitrile to the name of the parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also be named by replacing the -ic acid or -oic acid ending of the corresponding carboxylic acid with -onitrile. The suffix -carbonitrile is used when a CN group is attached to a ring. Ethanenitrile Acetonitrile 5-Methylhexanenitrile 4-Methylpentyl cyanide Cyclopentanecarbonitrile Cyclopentyl cyanide

9 19.2 Structure and Reactivity of Carboxylic Acid Derivatives

10 Stabilization of the Carbonyl

11 Stabilization of the Carbonyl This is a resonance effect. Acid chlorides. Ineffective; poor orbital overlap

12 Stabilization of the Carbonyl Acid Anhydrides. Esters. Less effective; since both carbonyls compete

13 Stabilization of the Carbonyl Amides. most effective; nitrogen less electronegative supports the positive charge better Restricted rotation. Significant C-N double bond character.

14 Structure and Bonding of Amides Formamide is planar. overlap of the 2p orbital of N and the p orbital of the carbonyl group allows delocalization of the nitrogen unshared pair.

15 19.3 Nucleophilic Acyl Substitution Mechanisms

16 Addition-elimination. Acyl Substitution Mechanisms Effect of ph on the tetrahedral intermediate. Low ph High ph

17 Elimination-addition. Acyl Substitution Mechanisms Uncommon sometimes observed with acyl chlorides.

18 S N 2-like reaction. Acyl Substitution Mechanisms

19 19.4 Nucleophilic Acyl Substitution in Acyl Chlorides

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22 19.5 Nucleophilic Acyl Substitution in Acid Anhydrides

23 Acyl Substitution of Acid Anhydrides The nucleophile connects to one acyl group. The other acyl is the leaving group. Acetyl chloride undergoes hydrolysis about 100,000 times more rapidly than acetic anhydride at 25 C. Hydrolysis in aqueous base.

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25 Mechanism of Substitution in an Anhydride Reaction Equation. Step 1. Nucleophilic attack. Step 2. Expulsion of acetate.

26 19.6 Physical Properties and Sources of Esters

27 Physical Properties of Esters Esters are moderately polar with dipole moments of D. Boiling points. 2-Methylbutane Methyl acetate 2-Butanol mol wt 72 bp 28 C mol wt 74 bp 57 C mol wt 74 bp 99 C

28 Physical Properties of Esters Some esters have pleasing odors. Butyl acetate pear Methyl salicylate wintergreen Ethyl cinnamate sex pheromone male oriental fruit moth (R)-(Z)-5-Tetradecen-5-olide sex pheromone female Japanese beetle

29 Physical Properties of Esters Long chain esters are glycerol triesters, triacylglycerols, or triglycerides. Tristearin, found in animal and vegetable fats Phosphatidylcholine Fats and oils are mixtures of glycerol triesters. Fats are solids at room temperature; oils are liquids. The long-chain carboxylic acids obtained from fats and oils by hydrolysis are known as fatty acids.

30 19.7 Reactions of Esters: A Preview

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34 19.8 Acid-Catalyzed Ester Hydrolysis

35 Acid Catalyzed Ester Hydrolysis Reaction equation. Carried out in the presence of a generous excess of water. Example.

36 Mechanism of Acid Catalyzed Hydrolysis Reaction Equation. Step 1. Protonation. Step 2. Nucleophilic attack.

37 Mechanism of Acid Catalyzed Hydrolysis Step 3. Deprotonation. Step 4. Protonation.

38 Mechanism of Acid Catalyzed Hydrolysis Step 5. Loss of methanol. Step 6. Deprotonation.

39 Mechanism and Isotopic Labeling 18 O labeling experiments confirms the tetrahedral intermediate. Since the hydroxyl groups are equivalent either could be protonated and lost as water.

40 19.9 Ester Hydrolysis in Base: Saponification

41 Ester Hydrolysis in Base: Saponification Reaction equation. Example. To isolate the free acid the carboxylate must be acidified.

42 Saponification Saponification means soap making. For thousands of years the saponification of triglycerides in animal fats have yielded soaps Glycerol Potassium carboxylate salts

43 Ester Hydrolysis in Base: Saponification Reaction equation. Rate.

44 Ester Hydrolysis in Base: Saponification Possible mechanisms. S N 2 Nucleophilic acyl substitution Bond between O and alkyl group R breaks Bond between O and acyl group RC=O breaks

45 Ester Hydrolysis in Base: Saponification 18 O labeling experiments eliminate one of these mechanisms. The label goes from ester to alcohol. Cannot be S N 2! Stereochemical studies support this.

46 Ester Hydrolysis in Base: Saponification The reaction. Mechanism. Step 1. Nucleophilic addition.

47 Ester Hydrolysis in Base: Saponification Step 2. Dissociation. Step 3. Proton transfer and deprotonation.

48 19.10 Reaction of Esters with Ammonia and Amines

49 Reaction of Esters with Ammonia and Amines Reaction equation. Examples. (The amine must be secondary or primary)

50 19.11 Reaction of Esters with Grignard and Organolithium Reagents and Lithium Aluminum Hydride

51 Reaction of Esters with Grignard Reagents Reaction equation. Two equivalents of the nucleophile are added and an alcohol formed. Example.

52 Reaction of Esters with Grignard Reagents Mechanism. Second equivalent of Grignard reacts with the ketone as described earlier. Organolithium reagents react in the same way.

53 Reaction of Esters with Lithium Aluminum Hydride Mechanism. The aldehyde is then rapidly reduced to the primary alcohol.

54 19.12 Amides

55 Physical Properties of Amides Short C-N bond and restricted rotation about C-N. Electron delocalization. More polar than esters with dipole moment in the range of D. Hydrogen bonding in the solid state.

56 Compared to acetic acid. Physical Properties of Amides

57 Acidity of Amides Amides are weaker acids than carboxylic acids since N is less electronegative.

58 Synthesis of Amides Synthesis from acid chlorides, acid anhydrides, and esters.

59 Common mechanism. Synthesis of Amides

60 19.13 Hydrolysis of Amides

61 Hydrolysis of Amides Amides are fairly stable in water but hydrolyzed in the presence of strong acid or base. Reaction equation. Example.

62 Mechanism of Amide Hydrolysis in Acid Reaction equation. Mechanism. Step 1. Protonation. Step 2. Nucleophilic addition.

63 Mechanism of Amide Hydrolysis in Acid Step 3. Deprotonation Step 4. Protonation.

64 Mechanism of Amide Hydrolysis in Acid Step 5. Dissociation. Step 6. Proton transfer.

65 Hydrolysis of Amides Reaction equation in base. Example.

66 Mechanism of Amide Hydrolysis in Base Reaction equation. Mechanism. Step 1. Nucleophilic addition. Step 2. Protonation.

67 Mechanism of Amide Hydrolysis in Acid Step 3. Protonation. Step 4. Dissociation. Step 5. Deprotonation.

68 19.14 Lactams

69 Lactams Lactams are more stable than lactones and b-lactams are the best known antiobiotics: penicillins and cephalosporins. N-Methylpyrrolidone e-caprolactam

70 b-lactam Antibiotics In 1945 Fleming, Florey, and Chain received the Nobel Prize for Physiology or Medicine. PenicillinG originated in a strain obtained from a rotting cantaloupe in Peoria and was the first penicillin made on a large scale Penicillin G Cephalexin

71 b-lactam Antibiotics β-lactams act by deactivating an enzyme, transpeptidase, required for the biosynthesis of bacterial cell walls. Active form of transpeptidase Penicillin G Inactive ester of transpeptidase

72 19.15 Preparation of Nitriles

73 Preparation of Nitriles Dehydration of amides. Reaction equation. Examples.

74 Preparation of Nitriles

75 19.16 Hydrolysis of Nitriles

76 Nitriles are also hydrolyzed in aqueous acid or base. This is an irreversible reaction. Hydrolysis of Nitriles Reaction equation. Example.

77 Hydrolysis of Nitriles In base the carboxylate is formed and an acidification step is added to isolate the carboxylic acid. Reaction equation in base. Example.

78 Nitrile Hydrolysis in Basic Solution Reaction equation. Mechanism. Step 1. Nucleophilic attack.

79 Nitrile Hydrolysis in Basic Solution Step 2. Protonation. Step 3. Deprotonation. Step 4. Protonation.

80 19.17 Addition of Grignard Reagents to Nitriles

81 Addition of Grignard Reagents to Nitriles Addition of Grignards gives imines which are hydrolyzed to ketones. Reaction equation. Example.

82 19.18 Spectroscopic Analysis of Carboxylic Acid Derivatives

83 IR Spectroscopy Typical C=O stretching frequencies are given cm cm -1 and 1815 cm cm cm -1

84 1 H NMR Spectroscopy Chemical shift differences of the protons adjacent to the carbonyl or bonded to the O of an ester are important. The chemical shift of the N H proton of amides appears in the range δ 5 8 and is often very broad.

85 Mass Spectrometry Common cation radical cleavage patterns are:

86 Other Spectroscopy 13 C NMR. Carbonyl carbon appears in the range δ The Carbon of a C N group appears near δ 120. UV-Vis. The n π* absorption (l max ) : 235 nm 225 nm 207 nm 214 nm