1. 1Spring, 2011 Organic Chemistry II Carboxylic Acid Derivatives Dr. Ralph C. Gatrone Department of Chemistry and Physics Virginia State University

2. Spring, 20112 Chapter Objectives Nomenclature Nomenclature Properties Properties Preparation Preparation Reactions Reactions Spectroscopy Spectroscopy

3. Spring, 20113 Carboxylic Derivatives Functional Groups we will consider are: Functional Groups we will consider are:

4. Spring, 20114 Carboxylic Derivatives Chemistry is similar Chemistry is similar Chemistry is dominated by one reaction Chemistry is dominated by one reaction

5. Spring, 20115 Nomenclature 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 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. Spring, 20116 Nomenclature Acid Anhydrides, RCO 2 COR’ If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid For substituted monocarboxylic acids: use bis- ahead of the acid name For substituted monocarboxylic acids: use bis- ahead of the acid name Unsymmetrical anhydrides— cite the two acids alphabetically Unsymmetrical anhydrides— cite the two acids alphabetically

7. Spring, 20117 Nomenclature Esters, RCO 2 R Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate” Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate”

8. Spring, 20118 Nomenclature Amides, RCONH 2 With unsubstituted  NH 2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide With unsubstituted  NH 2 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 If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide

9. Spring, 20119 Examples Try these Try these

10. Spring, 201110 Examples Answers Answers

11. Spring, 201111 Properties Amides have higher boiling point than other derivatives due to H-bonding Amides have higher boiling point than other derivatives due to H-bonding Esters have pleasant odors associated with fruits and flavors Esters have pleasant odors associated with fruits and flavors Acid halides have pungent odors due to hydrolysis to HCl or HBr Acid halides have pungent odors due to hydrolysis to HCl or HBr

12. Spring, 201112 Stability Amides more stable than Amides more stable than Esters, more stable than Esters, more stable than Acid anhydrides, more stable than Acid anhydrides, more stable than Acid halides Acid halides Esters and amides are commonly found in natural materials. Esters and amides are commonly found in natural materials. Amides make up foundation of animals Amides make up foundation of animals Acid halides and anhydrides don’t exist in nature Acid halides and anhydrides don’t exist in nature

13. Spring, 201113 Stability

14. Spring, 201114 Relative Reactivity of Carboxylic Acid Derivatives Nucleophiles react more readily with unhindered carbonyl groups 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) 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 The intermediate with the best leaving group decomposes fastest

15. Spring, 201115 General Reactions of Carboxylic Acid Derivatives

16. Spring, 201116 Reactions of Carboxylic Acids OH is poor leaving group OH is poor leaving group Must enhance reactivity Must enhance reactivity Specific reagents can produce acid chlorides, anhydrides, esters, amides Specific reagents can produce acid chlorides, anhydrides, esters, amides

17. Spring, 201117 Acids to Acid Chlorides Reaction with thionyl chloride, SOCl 2 Reaction with thionyl chloride, SOCl 2

18. Spring, 201118 Acids to Acid Anhydrides Heat cyclic dicarboxylic acids that can form five- or six-membered rings Heat cyclic dicarboxylic acids that can form five- or six-membered rings Acyclic anhydrides are not generally formed this way - they are usually made from acid chlorides and carboxylic acids Acyclic anhydrides are not generally formed this way - they are usually made from acid chlorides and carboxylic acids

19. Spring, 201119 Acids to Esters Carboxylate anion with a primary alkyl halide Carboxylate anion with a primary alkyl halide

20. Spring, 201120 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 Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid

21. Spring, 201121 Esterification using Diazomethane Reaction only provides the methyl ester Glassware must be polished (no ground glass joints)

22. Spring, 201122 Acids to Amides Direct reaction cannot be done Direct reaction cannot be done Due to acid base reaction that occurs first Due to acid base reaction that occurs first

23. Spring, 201123 Acids to Amides Must make OH a better leaving group Must make OH a better leaving group Generally done in the laboratory via the acyl halide Generally done in the laboratory via the acyl halide Can also use dicyclohexylcarbodiimide to activate the OH Can also use dicyclohexylcarbodiimide to activate the OH

24. Spring, 201124 Chemistry of Acid Halides Acid chlorides are prepared from carboxylic acids by reaction with SOCl 2 Acid chlorides are prepared from carboxylic acids by reaction with SOCl 2 Reaction of a carboxylic acid with PBr 3 yields the acid bromide Reaction of a carboxylic acid with PBr 3 yields the acid bromide

25. Spring, 201125 Reactions of Acid Halides Nucleophilic acyl substitution Nucleophilic acyl substitution Halogen replaced by  OH, by  OR, or by  NH 2 Halogen replaced by  OH, by  OR, or by  NH 2 Reduction yields a primary alcohol Reduction yields a primary alcohol Grignard reagent yields a tertiary alcohol Grignard reagent yields a tertiary alcohol

26. Spring, 201126 Acid Halides into Acids (Hydrolysis) Acid chlorides react with water to yield carboxylic acids Acid chlorides react with water to yield carboxylic acids HCl is generated during the hydrolysis: a base is added to remove the HCl HCl is generated during the hydrolysis: a base is added to remove the HCl

27. Spring, 201127 Acid Halides to Anhydrides Acid halides react with carboxylate anions Acid halides react with carboxylate anions

28. Spring, 201128 Acid Halides to Esters Esters are produced in the reaction of acid chlorides react with alcohols in the presence of pyridine or NaOH Esters are produced in the reaction of acid chlorides react with alcohols in the presence of pyridine or NaOH The reaction is better with less steric bulk The reaction is better with less steric bulk

29. Spring, 201129 Acid Halides into Amides Amides result from the reaction of acid chlorides Amides result from the reaction of acid chlorides –with NH 3, –primary amines (RNH 2 ) –secondary amines (R 2 NH) The reaction with tertiary amines (R 3 N) gives an unstable species that cannot be isolated The reaction with tertiary amines (R 3 N) gives an unstable species that cannot be isolated HCl is neutralized by the amine or an added base HCl is neutralized by the amine or an added base

30. Spring, 201130 Acid Chlorides into Alcohols LiAlH 4 reduces acid chlorides to yield primary alcohols through the aldehyde (not isolated) LiAlH 4 reduces acid chlorides to yield primary alcohols through the aldehyde (not isolated)

31. Spring, 201131 Acid Halides with Organometallics Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same

32. Spring, 201132 Acid Chlorides to Ketones Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li + R 2 Cu  Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li + R 2 Cu  Reaction of an acid chloride with organocadmium reagent Reaction of an acid chloride with organocadmium reagent

33. Spring, 201133 Chemistry of Acid Anhydrides Prepared by carboxylate nucleophile with an acid chloride Prepared by carboxylate nucleophile with an acid chloride

34. Spring, 201134 Reactions of Acid Anhydrides Similar to acid chlorides in reactivity Similar to acid chlorides in reactivity

35. Spring, 201135 Anhydrides to Esters or Amides Anhydrides form esters with alcohols Anhydrides form esters with alcohols Anhydrides form amides with amines Anhydrides form amides with amines

36. Spring, 201136 Anhydrides: More Selective than Acid Halides Anhydrides react with amines in presence of alcohols, Not so acid chlorides Anhydrides react with amines in presence of alcohols, Not so acid chlorides

37. Spring, 201137 Chemistry of Esters Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers Also present in fats and vegetable oils Also present in fats and vegetable oils

38. Spring, 201138 Preparation of Esters Esters are usually prepared from carboxylic acids Esters are usually prepared from carboxylic acids

39. Spring, 201139 Reactions of Esters Less reactive toward nucleophiles than are acid chlorides or anhydrides Less reactive toward nucleophiles than are acid chlorides or anhydrides Cyclic esters are called lactones and react similarly to acyclic esters Cyclic esters are called lactones and react similarly to acyclic esters

40. Spring, 201140 Esters into Carboxylic Acids An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol

41. Spring, 201141 Soap Ester (Fat) hydrolysis into carboxylate anion Ester (Fat) hydrolysis into carboxylate anion

42. Spring, 201142 Esters to Amides Ammonia reacts with esters to form amides Ammonia reacts with esters to form amides Reaction is easier from the acid chloride Reaction is easier from the acid chloride

43. Spring, 201143 Esters into Alcohols: Reduction Reaction with LiAlH 4 yields primary alcohols Reaction with LiAlH 4 yields primary alcohols

44. Spring, 201144 Reduction of Esters LAH is reducing agent of choice LAH is reducing agent of choice NaBH 4 does not reduce esters NaBH 4 does not reduce esters H 2 does not reduce esters H 2 does not reduce esters BH 3 – THF does not reduce esters BH 3 – THF does not reduce esters DIBAH reduces esters to the aldehyde DIBAH reduces esters to the aldehyde

45. Spring, 201145 Esters with Grignard Reagents Reacts with 2 equivalents of a Grignard reagent to yield a tertiary alcohol Reacts with 2 equivalents of a Grignard reagent to yield a tertiary alcohol

46. Spring, 201146 Chemistry of Amides Prepared by reaction of an acid chloride with ammonia, primary amines, or secondary amines Prepared by reaction of an acid chloride with ammonia, primary amines, or secondary amines Amides are the least reactive of derivatives Amides are the least reactive of derivatives

47. Spring, 201147 Reactions of Amides Heating in either aqueous acid or aqueous base produces a carboxylic acid and the amine Heating in either aqueous acid or aqueous base produces a carboxylic acid and the amine

48. Spring, 201148 Amides into Amines Reduced by LiAlH 4 to an amine rather than an alcohol Reduced by LiAlH 4 to an amine rather than an alcohol Converts C=O  CH 2 Converts C=O  CH 2

49. Spring, 201149 Reduction of Amides Works with cyclic and acyclic Works with cyclic and acyclic Good route to cyclic amines Good route to cyclic amines

50. Spring, 201150 Amides to Nitriles

51. Spring, 201151 Amide to Amine The Hoffmann Rearrangement Preparation of amine with loss of a carbon Preparation of amine with loss of a carbon

52. Spring, 201152 Infrared Spectroscopy Acid chlorides: 1800cm -1 Acid chlorides: 1800cm -1 Acid anhydrides: 1820 and 1760cm -1 Acid anhydrides: 1820 and 1760cm -1 Esters: 1735cm -1 Esters: 1735cm -1 Amides: 1650 - 1690cm -1 depending on N substitution Amides: 1650 - 1690cm -1 depending on N substitution

53. Spring, 201153 NMR Spectroscopy Carbon-13 NMR Carbon-13 NMR Difficult to assign with certainty Difficult to assign with certainty

54. Spring, 201154 NMR Spectroscopy Proton NMR Proton NMR Protons adjacent to C=O resonate near 2  Protons adjacent to C=O resonate near 2  Identity of the C=O cannot be determined Identity of the C=O cannot be determined