Carboxylic acid derivatives

Transcription

1 Carboxylic acid derivatives Nucleophilic acyl substitution reaction Among the most important reactions of carboxylic acids are those that convert the carboxyl group into other acid derivatives by a nucleophilic acyl substitution reaction. Cl 1 N 2 ' ' Dr. Solomon Derese 57

2 Acyl chloride Preparation of acyl chlorides Acid chlorides can not be prepared by reaction between carboxylic acid and Cl. This is because the carbonyl carbon is not electrophilic enough to be attacked by chloride and also the fact that the hydroxyl group is a bad leaving group. X We use PCl 5 (an acid chloride of phosphoric acid), PCl 3 (an acid chloride of phosphorous acid), SCl 2 (Thionyl chloride), an acid chloride of sulfurous acid, or oxalyl chloride, an acid chloride of oxalic acid. Dr. Solomon Derese 58

3 PCl 3 PCl 5 Cl Cl Dr. Solomon Derese 59

4 Very reactive Good Leaving Group Good electrophile Dr. Solomon Derese 60

5 eaction of acyl chlorides Acyl chlorides are the most reactive of acyl compounds towards nucleophiles. Lower molecular weight saturated acyl chlorides react explosively with water, and even more rapidly with stronger nucleophiles. Because of their reactivity and the ease with which they can be prepared from carboxlylic acids, acyl chlorides are the most commonly used starting materials for the synthesis of carboxylic acid derivatives in general. Dr. Solomon Derese 61

6 ydrolysis ' 2 Cl Acid chloride N 1 2 [] SCl 2 Most nucleophilic acyl substitution reactions of acyl chlorides are irreversible. Dr. Solomon Derese 62

7 ydrolysis: Conversion into acids Acyl chlorides are hydrolyzed by water to give the corresponding carboxylic acid. 2 N Pyridine scavenges the Cl Dr. Solomon Derese 63

8 Alcoholysis: Ester formation In most cases this reaction is carried out in the presence of a base such as triethylamine, pyridine which will scavenge the acid (Cl). Dr. Solomon Derese 64

9 Ammonlysis: Conversion into amides The reaction is carried out using an excess of the amine, which serves to remove the acid (Cl) as a salt. Example DEET, the active ingredient in the most widely used insect repellents, is effective against mosquitoes, fleas, and ticks. Dr. Solomon Derese 65

10 Ammonolysis reactions carried with Na are sometimes referred to as Schotten Baumann reaction. Trimetozine (palene, Trimolide, Trioxazine) is a sedative that has been marketed in Europe since It also has mild tranquilizing effects and has been used in the treatment of anxiety. Dr. Solomon Derese 66

11 Application: Nylon 6,6 The search for a synthetic fiber with properties similar to silk led to the discovery of nylon a polyamide. There are several different kinds of nylon, but the most well known is called nylon 6,6. It can be synthesized from two six-carbon monomers (hence its name) adipoyl chloride (ClC-(C 2 ) 4 - CCl) and hexamethylenediamine ( 2 N(C 2 ) 6 N 2 ). Dr. Solomon Derese 67

12 eduction: Conversion into alcohols Example The aldehyde intermediate can be isolated if the less powerful reducing agent, LiAl (t-bu) 3. Example Dr. Solomon Derese 68

13 eaction with aromatic compounds The Friedel Crafts acylation ' Cl ' AlCl 3 eaction with rganometallic reagents Acyl benzene Grignard reagent rganolithiums react similarly to give tertiary alcohols. Dr. Solomon Derese 69

14 rganocopper ( 2 CuLi) (Gilman) reagents Less reactive than Grignard/organolithium reagent and yield ketones rather than tertiary alcohols. Example The ester functional group is not affected. Dr. Solomon Derese 70

15 Summary of the reactions of acid chlorides N 1 2 ' Pyridine 2 Pyridine ' N 1 2 (excess) 'MgBr or 'Li ' 2 CuLi Cl ' " ' 1. LiAl AlCl 3 LiAl(tBu) 3 Dr. Solomon Derese 71

16 Assignment 21 I. ow do you achieve the following transformation? II. Qiana, a polyamide fiber with a silky texture, has the following structure. What are the monomer units used in the synthesis of Qiana? Dr. Solomon Derese 72

17 Acid anhydrides The 2 nd most reactive carboxylic acid derivatives. Preparation of acetic anhydrides From acid chlorides Most commonly used bases are pyridine and triethylamine. Dr. Solomon Derese 73

18 Example Mechanism Cl Dr. Solomon Derese 74

19 eactions of acid anhydrides The chemistry of anhydrides is similar to that of acid chlorides except that anhydrides react more slowly, but the kind of reactions the two groups undergo are the same. Dr. Solomon Derese 75

20 Examples Dr. Solomon Derese 76

21 Esters Acid component ' Alcohol component Many simple low molecular weight esters are pleasant smelling liquids that are responsible for the fragrant odors of fruits and flowers. Dr. Solomon Derese 77

22 Commercial applications of esters The characteristics fruity smell of esters lead to their use in artificial fruit essences. Methyl 3-methylbutanoate Propyl propionate Butyl acetate 3-Methylbutyl acetate Methyl octanoate Benzyl butanoate Dr. Solomon Derese 78

23 Preparation of esters Fisher esterification General reaction Catalyzed by conc. 2 S 4 or Cl. Equilibrium reaction and yield can be increased by: a) Use of excess of acid or alcohol b) emoving water from the reaction mixtures as it is formed. Dr. Solomon Derese 79

24 Mechanism 1 Dr. Solomon Derese 80

25 Carboxylic acids whose molecules have a hydroxyl group on a g- or d- carbon undergo intramolecular esterification to give cyclic esters (Lactones) known as g- or d- lactones. Example ydroxy acid 3 -Lactone Dr. Solomon Derese 81

26 From acid chlorides/acid anhydride/carboxylic acid salts General reaction Williamson ester synthesis Dr. Solomon Derese 82

27 Diazomethane esterification Diazomethane, C 2 N 2, which is best drawn as a hybrid of two contributing structures, can be used to synthesize esters from carboxylic acid. N N 2 C N N Example Dr. Solomon Derese 83

28 eactions of Esters Dr. Solomon Derese 84

29 ydrolysis of Esters Examples eversible, Why? Dr. Solomon Derese Irreversible, Why? 85

30 Soaps Saponification Ester hydrolysis in base All soaps are salts of fatty acids. The main difference between soaps is the addition of other ingredients that do not alter their cleaning properties: dyes for color, scents for a pleasing odor, and oils for lubrication. Soaps that float are aerated so that they are less dense than water. Dr. Solomon Derese 86

31 Transesterification Transesterification is the conversion of an ester into another ester by heating it with an excess of either an alcohol or a carboxylic acid in the presence of an acid or a base catalyst. In an equilibrium reaction, either the alcohol or the acid portion of the original ester is removed. Dr. Solomon Derese 87

32 Example The equilibrium is shifted to the right by allowing the low boiling alcohol to distil from the reaction mixture. Dr. Solomon Derese 88

33 Biodiesel Biodiesel is produced from renewable sources such as vegetable oils and animal fats and is a cleaner replacement for petroleum. It is nontoxic and biodegradable. It has physical properties similar to those of petroleum diesel. Dr. Solomon Derese 89

34 Assignment 22 Draw a stepwise mechanism for each reaction. Dr. Solomon Derese 90

35 Assignment 23 I. The following reactivity order has been found for the saponification of p-substituted methyl benzoates: Y = N 2 > Br > > C 3 > C 3 ow can you explain this reactivity order? Where would you expect Y = C and Y = N 2 to be in the reactivity list? II. When ethyl benzoate is heated in methanol containing a small amount of Cl, methyl benzoate is formed. Propose a mechanism for the reaction. Dr. Solomon Derese 91

36 eduction of Esters The aldehyde intermediate can be isolated if 1 equivalent of the less reactive reducing agent diisobutylaluminum hydride (DIBA) is used instead of LiAl 4. The reaction is carried out at -78 C to avoid further reduction to the alcohol. Dr. Solomon Derese 92

37 Dr. Solomon Derese 93

38 Assignment 24 I. Predict the major product(s) for each of the following reactions: II. Explain why ester A is more reactive than ester B in nucleophilic substitution. Dr. Solomon Derese 94

39 Amides No free rotation across the C-N bond Preparation of amides From acid chlorides Dr. Solomon Derese 95

40 From acid anhydrides From esters Dr. Solomon Derese 96

41 From carboxylic acids Carboxylic acids react with aqueous ammonia to form ammonium salts: Because of the low reactivity of the carboxylate ion toward nucleophilic substitution reaction, further reaction does not usually take place in aqueous solution. An ammonium carboxylate Dr. Solomon Derese 97

42 Amides are of great importance in life. The linkages that join individual amino acids together to form proteins are primarily amide linkages. Proteins/peptides are formed by reacting the carboxyl group of one amino acid with the amino group another amino acid. amide linkages As a consequence, much research has been done to find convenient and mild ways for amide synthesis. Dialkylcarbodiimides (-N=C=N=), for example dicyclohexylcarbodiimide (DCC), are especially useful reagents for amide synthesis. Dr. Solomon Derese 98

43 N C N Diclohexylcarbodiimide (DCC) The carbonyl carbon is now more electrophilic than the carboxyl and the bad leaving group is C N N replaced by a good leaving group. Dr. Solomon Derese 99

44 + N N 1 C 2 N N 2 + N C N 1 Dr. Solomon Derese 100

45 Assignment 25 The following reaction will not happen as shown. a. Show what would happen instead. b. ow could you obtain the desired product? Show the reagents to be used and the structures of any intermediates. Dr. Solomon Derese 101

46 eactions of amides ydrolysis Amides are hydrolyzed in either acidic or alkaline solution. In either case, the acid or base is a reactant, not a catalyst, and must be used in a 1.1 molar ratio or in excess. This property is at most important in biological systems for the stability of proteins. If the amide could hydrolyze easily we wont even be able to touch water. Dr. Solomon Derese 102

47 eduction Mechanism Dr. Solomon Derese 103

48 Assignment 26 I. Predict the major product(s) for each of the following reactions: II. Propose a mechanism for each of the following transformations: Dr. Solomon Derese 104

49 Nitriles Preparation of nitriles I. From dehydration of amides Dr. Solomon Derese 105

50 Mechanism Cl S Cl 2 N N Cl S Example Dr. Solomon Derese 106

51 S N 2 reaction of cyanide ion with primary alkyl halides Example Dr. Solomon Derese 107

52 eactions of nitriles ydrolysis of nitrites eduction of nitriles C N 1. LiAl or 2 / Pd/C N 2 Dr. Solomon Derese 108

53 Mechanism C N Al N C Example Dr. Solomon Derese 109

54 eaction with organometalic reagents An alternative to Friedel-Crafts acylation Dr. Solomon Derese 110

55 N C 2 ' ' N 3 ' + N4 Dr. Solomon Derese 111

56 Assignment 27 I. Predict the major product(s) for each of the following reactions: a) CN 1. LiAl b) Br 1. NaCN 2. MeMgBr 3. 3 c) CN 1. EtMgBr LiAl Dr. Solomon Derese 112

57 II. Propose a mechanism for the following transformation: III. Propose an efficient synthesis for each of the following transformations: Dr. Solomon Derese 113

58 IV. Identify compounds A-M in the following reaction sequence. Dr. Solomon Derese 114

59 eduction of carboxylic acid General reaction Dr. Solomon Derese 115

60 Example B 3 / TF Selectively reduces carboxylic acids in the presence of aldhydes/ketones and esters Dr. Solomon Derese 116

61 Decarboxylation of β-keto acids and β- diacids Acids whose molecules have a carbonyl group one carbon removed from the carboxyl group, called β- keto acids, decarboxylate readily when they are heated to C. - Ketoacid Dr. Solomon Derese 117

62 There are two reasons for this ease of decarboxylation. 1) When the carboxylate ion decarboxylate, it forms a resonance stabilized enolate anion: - Ketoacid Dr. Solomon Derese esonance stabilized anion 118

63 II. The decarboxylation takes place though a stable six - membered cyclic transition state. b-keto carboxylic acid Example Dr. Solomon Derese 119

64 Assignment 28 Write the organic product(s) and reaction mechanism of the following reaction: Dr. Solomon Derese 120