Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions

1. Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions

2. Carboxylic Compounds • Acyl group bonded to Y, an electronegative atom or leaving group • Includes: Y = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates)

3. General Reaction Pattern • Nucleophilic acyl substitution

4. 21.1 Naming Carboxylic Acid Derivatives • Acid Halides, R-CO-X • Derived from the carboxylic acid name by replacing the -ic acidending with -ylor the -carboxylic acidending with –carbonyland specifying the halide

5. Naming Acid Anhydrides, RCO2COR' • If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid (for symmetrical anhydrides) • From substituted monocarboxylic acids: use bis- ahead of the acid name • Unsymmetrical anhydrides— cite the two acids alphabetically

6. Naming Amides, RCONH2 • With unsubstitutedNH2 group. replace -oic acid or -ic acidwith -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

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

9. 21.2 Nucleophilic Acyl Substitution • 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

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

11. 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

12. General Reactions of Carboxylic Acid Derivatives • water˝ carboxylic acid • alcohols˝esters • ammonia or an amine˝ an amide • hydride source ˝ an aldehyde or an alcohol • Grignard reagent ˝a ketoneor an alcohol

13. 21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids • Must enhance reactivity • Convert OH into a better leaving group • Specific reagents can produce acid chlorides, anhydrides, esters, amides

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

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

16. i. Conversion of Carboxylic Acids into AcidAnhydrides • 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

17. ii. Conversion of Carboxylic Acids into Esters • Methods include reaction of a carboxylate anion with a primary alkyl halide

18. 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

19. 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

20. Fischer Esterification: Detailed Mechanism 1 3 4 2

21. iii. Conversion of Carboxylic Acids into Amides The reaction can not be achieved easily by direct reaction between carboxylic acids and amines as the latter is a base and results in the formation of un-reactive carboxylate anion. In practice, amides are usually prepared by treating the carboxylic acid with dicyclohexylcarbodiimide (DCC) to activate it, followed by addition of the amine. The overall reaction is the formation of the amide linkage (-CO-NH-) and the water molecule is added to the DCC converting it into dicyclohexylurea.

22. iv. Conversion of Carboxylic Acids into Alcohols The reaction can be achieved by either LiAlH4, a strong reducing agent, converting the (-COOH) into (-CH2-OH) OR BH3/THF, followed by treatment with dilute acid solution, which is a more milder reducing agent, which will reduce ONLY the (COOH) into (CH2-OH) and leaving any other group in the molecule unaffected at the given reaction condition. This is an advantageous selective reduction reaction.

23. 21.4 Chemistry of Acid Halides • Acid chlorides are prepared from carboxylic acids by reaction with SOCl2 • Reaction of a carboxylic acid with PBr3 yields the acid bromide

24. 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

26. i. 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

27. ii. Conversion of Acid Halides to Esters • Esters are produced in the reaction of acid chlorides with alcohols in the presence of pyridine or NaOH • The reaction is better with less sterically hindered (OH) groups.

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

29. iv. Reduction: Conversion of Acid Chlorides into Alcohols • LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols

30. v. Reaction of Acid Chlorides with Organometallic Reagents (GR) • Grignard Reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same

31. vi. Formation of Ketones from Acid Chlorides • Reaction of an acid chloride with a lithium diorganocopper (Gilman reagent), Li+ R2Cu • Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone

32. vii. Conversion of Acid Halides to Anhydrides • Reaction between metal carboxylate and acide halides facilitated the preparation of anhydrides at much lower temperatures than the direct sever heating method to eliminate H2O molecule. • This method is also a very useful route to prepare unsymmetrical anhydrides.

33. 21.5 Chemistry of Acid Anhydrides • Prepared by nucleophilic acyl substitution of an acid chloride with a carboxylate anion. • Both symmetrical and unsymmetrical acid anhydrides are prepared by this method.

34. Reactions of Acid Anhydrides • The chemistry of acid anhydrides is similar to that of acid chlorides. Although anhydrides react more slowly than acid chlorides.

35. Acetylation • Acetic anhydride forms acetate esters from alcohols and N-substitutedacetamides from amines

37. 21.6 Chemistry of Esters • Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers that are naturally occuring. • Also present in fats and vegetable oils

38. The chemical industry uses esters for a variety of purposes e.g. ethyl acetate is a commonly used solvent, dioctyl phthalate DOP or diisooctyl phthalate DIOP has been used for along time as a plasticizer for PVC, beside other dialkyl phthalate.

39. Preparation of Esters • Esters are usually prepared from carboxylic acids

40. Reactions of Esters • Less reactive toward nucleophiles than are acid chlorides or anhydrides, see the reactivity chart!!!. • Cyclic esters are called lactones and react similarly to acyclic esters -Valerolactone

41. i. 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. • Alkaline hydrolysis of esters is the basic reaction for soapindustry which in fact is made by boiling animal fat with a base to hydrolyze the ester linkages giving alcohol and metal-carboxylate salt (soap).

42. Mechanism of Ester Hydrolysis under basic condition • Hydroxide anion is the nucleophilic attacking species. 1 3 2 4

43. Evidence from Isotope Labelling • 18O in the ether-like oxygen in ester winds up exclusively in the ethanol product • None of the label remains with the propanoic acid, indicating that saponification occurs by cleavage of the C–OR bond rather than the CO–R bond

44. Mechanism of Ester Hydrolysis under acidic condition

45. ii. Conversion of Ester into Alcohols • Esters (cyclic and acyclic) are easily reduced completely by treatment with LiAlH4/ether to yield primary alcohols. • Controlled or partial reduction of esters (cyclic and acyclic) is possible if 1equivalent of [DIBAH/toluene, -78 C, followed by treatment with H3O+] was applied.

47. Mechanism of Reduction of Esters • Hydride ion adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde • Reduction of the aldehyde gives the primary alcohol

48. Partial Reduction to Aldehydes • Use one equivalent of diisobutylaluminum hydride (DIBAH = ((CH3)2CHCH2)2AlH)) instead of LiAlH4 • Low temperature to avoid further reduction to the alcohol

49. iii. Aminolysis of Esters • Ammonia, primary and secondary amines react with esters to form amides. The reaction is not very common as this preparation is usually carried out by reacting the more reactive species, like acid chloride, instead.

50. iv. Reaction of Esters with Grignard Reagents: conversion into alcohols • React with 2 equivalents of a Grignard reagent to yield a tertiary alcohol