1. CH-5 Organic Chemistry-2 Prepared By Dr. Khalid Ahmad Shadid & Prof Dr. Abdelfattah Haikal Islamic University in Madinah Department of Chemistry Carboxylic Acids and Their Derivatives Nucleophilic Addition–Elimination at the Acyl Carbon

2. 1.Introduction  Carboxylic Acid Derivatives

3. 2.Nomenclature and Physical Properties  Nomenclature of Carboxylic Acids ● Rules  Carboxylic acid as parent (suffix): ending with “–oic acid” Carboxylic Acids  Examples

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5. Carboxylate Salts  Nomenclature of Carboxylic Salts ● Rules  Carboxylate as parent (suffix): ending with “–oate”  Examples

6.  Acidity of Carboxylic Acids Most unsubstituted carboxylic acids have Ka values in the range of lit 10 -4 - 10 -5 (pKa 4-5). These relative acidities mean that carboxylic acids react readily with aqueous solutions of sodium hydroxide and sodium bicarbonate to form soluble sodium salts.

7. Carboxylic acids having electron-withdrawing groups are stronger than unsuhslituled acids. The chloroacetic acids, show the following order of acidities:  Stability of conjugate bases > > > > >>

8. The acid-strengthening effect of electron- withdrawing groups arises from a combination of inductive effects and entropy effects. The acid-strengthening effect decreases as distance between the electron-withdrawing group and the carboxyl group increases. > > > > > > > > >

9.  Dicarboxylic Acids Dicarboxylic acids are named as alkanedioic acids in the IUIPAC systematic or substitutive system.

10.  Esters The names of esters are derived from the names of the alcohol (with the ending - yl ) and the acid (with the ending - ate or - oate ). The portion of the name derived from the alcohol comes first.

11. Esters are polar compounds, but, lacking a hydrogen attached to oxygen, their molecules cannot form hydrogen bonds to each other. As a result, esters have boiling points that are lower than those of acids and alcohols of comparable molecular weight.

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13. Carboxylic Anhydrides  Nomenclature of Carboxylic Anhydrides ● Rules  Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word “anhydride”  Example

14.  Acyl Chlorides Acyl chlorides are also called acid chlorides. They are named by dropping - ic acid from the name of the acid and then adding - yl chloride. Acyl chlorides and carboxylic anhydrides have boiling points in the same range as esters of comparable molecular weight.

15.  Amides Amides that have no substituent on nitrogen are named by dropping - ic acid from the common name of the acid (or - oic acid from the substitutive name) and then adding - amide. Alkyl groups on the nitrogen atom of amides are named as substituents, and the named substituent is prefaced by N- or N, N-.

16.  Nitriles Carboxylic acids can he converted to nitriles and vice versa. In IUPAC substitutive nomenclature, acyclic nitriles are named by adding the suffix - nitrile to the name of the corresponding hydrocarbon. The carbon atom of the -C  N group is assigned number 1.

17. Preparation of Carboxylic Acids 1. By oxidative cleavage of alkenes ● Using KMnO 4 ● Using ozonolysis

18. 2. By oxidation of aldehydes & 1 o alcohols

19. 3. By oxidation of alkyl benzene

20. 4. By Oxidation of methyl Ketones 5. By oxidation of Cyanohydrines and other Nitriles

21. Nitriles can also be prepared by nucleophilic substitution reactions of alkyl halides with sodium cyanide. Hydrolysis of the nitrile yields a carboxylic acid with a chain one carbon atom longer than the original alkyl halide.

22. 6. By Carbonation of Grignard Reagent

23. Problem Show how each of the following compounds could be converted to benzoic acid. (a) Ethylbenzene(b) Acetophenone (c) Benzyl alcohol (d) Bromobenzene (e) Phenylethene (f) Benzaldehyde

24. Nucleophilic Addition-Elimination at the Acyl Carbon A characteristic reaction of aldehydes and ketones is one of nucleophilic addition to the carbon-oxygen double bond. Carboxylic acids and their derivatives are characterized by a nueleophilic addition-elimination mechanism that takes place at their acyl (carbonyl) carbon atoms.

25. It is after the initial nucleophilic attack has taken place that the two reactions differ. The tetrahedral intermediate formed from an aldehyde or ketone usually accepts a proton to form a stable addition product. In contrast, the intermediate formed from an acyl compound usually eliminates a leaving group; this elimination leads to regeneration of the carbon-oxygen double bond and to a substitution product. The overall process in the case of acyl substitution occurs, therefore, by a nucleophilic addition-elimination mechanism.

26. Nucleophilic Addition-Elimination at the Acyl Carbon  This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination mechanism

27. This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives Unlike carboxylic acids and their derivatives, aldehydes and ketones usually do not undergo this type of nucleophilic acyl substitution, due to the lack of an acyl leaving group A good leaving group Not a good leaving group

28. Acyl compounds react as they do because they all have good, or reasonably good, leaving groups (or they can be protonated to have good leaving groups) attached to the carbonyl carbon atom. An acyl chloride, for example, generally reacts by losing a chloride ion- a very weak base and thus a very good leaving group.

29. Relative Reactivity of Acyl Compounds The general order of reactivity of acid derivatives can be explained by taking into account the basicity of the leaving groups. When acyl chlorides react, the leaving group is a chloride ion, and when amides react, the leaving group is an amine (or ammonia). The chloride ions are the weakest bases and acyl chlorides are the must reactive acyl compounds. Amines (or ammonia) are the strongest bases and amides are the least reactive acyl compounds.

30. Acyl Chlorides synthesis of acyl chlorides (COCl) 2 Oxalyl chloride

31. Mechanism Oxalyl chloride

32. Reactions of Acyl Chlorides

33. Acyl chlorides also react with water and (even more rapidly) with aqueous base.

34. Mechanism

35. Carboxylic Acid Anhydrides Synthesis of Carboxylic Acid Anhydrides Carboxylic acids react with acyl chlorides in the presence of pyridine to give carboxylic acid anhydrides.

36. Sodium salts of carboxylic acids anhydrides Cyclic anhydrides dicarboxylic acid Cyclic anhydrides dicarboxylic acid

37. Reactions of Carboxylic Acid Anhydrides  Conversion of acid anhydrides to carboxylic acids by hydrolysis

38. Mechanism

39. Reactions of Carboxylic Acid Anhydrides Because carboxylic acid anhydrides are highly reactive they can be used to prepare esters and amides.

40. Esters Synthesis of Esters: Esterification Carboxylic acids react with alcohols to form esters through a condensation reaction known as esterification :

41. Mechanism

42. Acid-Catalyzed Ester Hydrolysis Esters from Acyl Chlorides

43. Esters from Carboxylic Acid Anhydrides

44. Cyclic anhydrides react with one molar equivalent of an alcohol to form compounds that are both esters and acids.

45. Base-Promoted Hydrolysis of Esters: Saponification

46. Lactones Carboxylic acids whose molecules have a hydroxyl group on a  or  carbon undergo an intramolecular esterification to give cyclic esters known as  or  - lactones. The reaction is acid catalyzed:

47. Lactones are hydrolyzed by aqueous base just as other esters are.

48. Amides Synthesis of Amides  Amides from Acyl Chlorides

49. Amides from Acyl Chlorides

50. Amides from Carboxylic Anhydrides

53.  Amides from Esters

54.  Amides from Carboxylic Acids and Ammonium Carboxylates

55.  Hydrolysis of Amides

56. Problem What products would you obtain from acidic and basic hydrolysis of each of the following arnides?

57.  Nitriles from the Dehydration of Amides Amides react with P 4 H 10 (a compound that is often called phosphorus pentoxide and written P 2 O 5 or with boiling acetic anhydride to form nitriles. dehydration

58.  Hydrolysis of Nitriles Catalyzed by both acid and base

59.  Examples

60.  Mechanism protonated nitrile protonated amide tautomer

61.  Mechanism

62. Lactams Cyclic amides are called lactams. The size of the lactam ring is designated by Greek letters in a way that is analogous to lactone nomenclature

63.  -Halo Acids The Hell-volhard-Zeliniski reaction Aliphatic carboxylic acids react with bromine or chlorine in the presence of phosphorus (or a phosphorus halide) to give  -halo acids through a reaction known as the Hell-Volhard-Zelinski (or HVZ) reaction.

64.   -Halo acids are important synthetic intermediates because they are capable of reacting with a variety of nucleophiles;

66. Decarboxylation of Carboxylic Acids The reaction whereby a carboxylic acid loses CO 2 is called a decarboxylation.

67. Acids whose molecules have a carbonyl group one carbon removed from the carboxylic acid group, called  -keto acids, decarboxylate readily when they are heated to 100-150°C. (Some  -keto acids even decarboxylate slowly at room temperature.)

68. 1. When the carboxylate anion decarboxylates, it forms a resonance-stabilized enolate anion:

69. 2. When the acid itself decarboxylates, it can do so through a six- membered cyclic transition state: This reaction produces an enol directly and, the enol then tautomerizes to a methyl ketone.

70.  Malonic acids also decarboxylate readily for similar reasons.

71. Chemical Tests for Acyl Compounds  Recall: acidity of

74. Summary of the Reactions of Carboxylic Acids and Their Derivatives

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