Carboxyl Derivatives

1. Carboxyl Derivatives Classes shown, formally, via dehydration.

2. Structure: Acid Chlorides • The functional group of an acid halide is an acyl group bonded to a halogen. • The most common are the acid chlorides. • To name, change the suffix -oic acidto -oyl halide.

3. Related: Sulfonyl Chlorides • Replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride.

4. Structure: Acid Anhydrides • Two acyl groups bonded to an oxygen atom. • The anhydride may be symmetrical (two identical acyl groups) or mixed (two different acyl groups). • To name, replace acid of the parent acid by anhydride.

5. Acid Anhydrides • Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.

6. Esters • The functional group of an ester is an acyl group bonded to -OR or -OAr. • Name the alkyl or aryl group bonded to oxygen followed by the name of the acid. • Change the suffix -ic acid to -ate.

7. Esters; Lactones • Lactone: A cyclic ester. • name the parent carboxylic acid, drop the suffix -ic acid and add -olactone.

8. Amides • The functional group of an amide is an acyl group bonded to a nitrogen atom. • drop -oic acidfrom the name of the parent acid and add -amide. (For the common acid name, drop -icof the acid name and add -amide.) • an alkyl or aryl group bonded to the N: name the group and show its location on nitrogen by N-. ethanamide

9. Amides: resonance

10. Amides; Characteristics

11. Amides; Lactams • Lactams: A cyclic amides are called lactams. • Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam. Indicates where the N is located.

12. Imides • The functional group of an imide is two acyl groups bonded to nitrogen. • Both succinimide and phthalimide are cyclic imides.

13. Related: Nitriles • The functional group of a nitrile is a cyano group • IUPAC names: name as an alkanenitrile. • common names: drop the -ic acidand add -onitrile.

14. Acidity of N-H bonds • Amides are comparable in acidity to alcohols. • Water-insoluble amides do not react with NaOH or other alkali metal hydroxides to form water-soluble salts. • Sulfonamides and imides are more acidic than amides.

15. Acidity of N-H bonds • Effect of neighboring carbonyl groups. 1.0

16. Acidity of N-H • Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.

17. Acidity of N-H bonds • Imides are more acidic than amides because 1. the electron-withdrawing inductive of the two adjacent C=O groups weakens the N-H bond, and 2. More resonance delocalization of the negative charge.

18. Lab related: Sulfonamides (Hinsberg) Experimental test to distinguish primary, secondary and tertiary amines. 1 soluble insoluble 2 insoluble 3 soluble In base In acid Reaction replaces one H with the sulfonyl group. In an H remains it is soluble in base. Aq. base

19. Characteristic Reactions: Ketones & Aldehydes • Nucleophilicacyl Addition: Protonation makes carbonyl better electrophile. Ok with poor nucleophile. Carbonyl weaker electrophile. Need good nucleophile.

20. Characteristic Reactions: Derivatives • Nucleophilicacyl substitution:An addition-elimination sequence resulting in substitution of one nucleophile for another. Dominant for derivatives due to good leaving group (Y), uncommon for ketones or aldehydes.

21. Characteristic Reactions Poor bases make good leaving groups. • Halide ion is the weakest base and the best leaving group; acid halides are the most reactive toward nucleophilic acyl substitution. • Amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution.

22. Water and Acid Chlorides • Low-molecular-weight acid chlorides react rapidly with water. • Higher molecular-weight acid chlorides are less soluble in water and react less readily.

23. Water and Anhydrides • Low-molecular-weight anhydrides react readily with water to give two molecules of carboxylic acid. • Higher-molecular-weight anhydrides also react with water, but less readily.

24. Mechanism- Anhydrides • Step 1: Addition of H2O to give a TCAI. (Addition) Acid makes carbonyl better electrophile.

25. Mechanism- Anhydrides • Step 2: Protonation and collapse of the TCAI. (Elimination) Acid sets up better leaving group.

26. Water and Esters • Esters are hydrolyzed only slowly, even in boiling water. • Hydrolysis becomes more rapid if they are heated with either aqueous acid or base. • Hydrolysis in aqueous acid is the reverse of Fischer esterification. • acid catalyst protonates the carbonyl oxygen and increases its electrophilic character toward attack by water (a weak nucleophile) to form a tetrahedral carbonyl addition intermediate. • Collapse of this intermediate gives the carboxylic acid and alcohol.

27. Mechanism: Acid/H2O - Esters (1o and 2oalkoxy) • Acid-catalyzed ester hydrolysis. Acid makes carbonyl Better electrophile. Acid sets up leaving group.

28. Mechanism: Reaction with Acid/H2O – Esters (3oalkoxy) But wait!!!!!!! water alcohol

29. Reaction with Base/H2O - Esters • Saponification: The hydrolysis of an esters in aqueous base. • Each mole of ester hydrolyzed requires 1 mole of base • For this reason, ester hydrolysis in aqueous base is said to be base promoted.

30. Mechanism of Reaction with Base/H2O – Esters • Step 1: Attack of hydroxide ion (a nucleophile) on the carbonyl carbon (an electrophile). (Addition) • Step 2: Collapse of the TCAI. (Elimination) • Step 3: Proton transfer to the alkoxide ion; this step is irreversible and drives saponification to completion.

31. Acidic Reaction with H2O - Amides • Hydrolysis of an amide in aqueous acid requires one mole of acid per mole of amide. • Reaction is driven to completion by the acid-base reaction between the amine or ammonia and the acid.

32. Basic Reaction with H2O - Amides • Hydrolysis of an amide in aqueous base requires one mole of base per mole of amide. • Reaction is driven to completion by the irreversible formation of the carboxylate salt.

33. Mechanism: Acidic H2O - Amides • Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.

34. Acidic H2O - Amides • Step 2: Addition of water (a nucleophile) to the carbonyl carbon (an electrophile) followed by proton transfer gives a TCAI. • Step 3: Collapse of the TCAI and proton transfer. (Elimination)

35. Mechanism: Reaction with Basic H2O - Amides Amide hydroxide ion Dianion!

36. Acidic H2O and Nitriles • The cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion. • Protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid. • Keto-enol tautomerism gives the amide. Acid + Ammonium ion

37. Basic H2O and Nitriles • Hydrolysis of a cyano group in aqueous base gives a carboxylic anion and ammonia; acidification converts the carboxylic anion to the carboxylic acid.

38. Synthesis: Reaction with H2O - Nitriles • Hydrolysis of nitriles is a valuable route to carboxylic acids.

39. NMgX NH N RC RCR' RCR' Synthesis: Grignards + Nitriles ->ketone 1 R'MgX H2O diethylether • Grignard reagents add to carbon-nitrogen triplebonds in the same way that they add to carbon-oxygen double bonds. • The product of the reaction is an imine.

40. NMgX NH N RC RCR' RCR' O RCR' Synthesis: Grignards + Nitriles ->ketone 2 R'MgX H2O diethylether H3O+ Imines hydrolyzed to ketones.

41. Reaction of Alcohols and Acid Halides • Acid halides react with alcohols to give esters. • Acid halides are so reactive toward even weak nucleophiles such as alcohols that no catalyst is necessary. • Where the alcohol or resulting ester is sensitive to HCl, reaction is carried out in the presence of a 3° amine to neutralize the acid.

42. Reaction with Alcohols, Sulfonic Esters • Sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol. • The key point here is that OH- (a poor leaving group) is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.

43. Reaction of Alcohols and Acid Anhydrides • Acid anhydrides react with alcohols to give one mole of ester and one mole of a carboxylic acid. • Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group.

44. Reaction of Alcohols and Esters • Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification.

45. Reaction of Ammonia, etc. and Acid Halides • Acid halides react with ammonia, 1° amines, and 2° amines to form amides. • Two moles of the amine are required per mole of acid chloride.

46. Reaction of Ammonia, etc. and Anhydrides. • Acid anhydrides react with ammonia, and 1° and 2° amines to form amides. • Two moles of ammonia or amine are required.

47. Ammonia, etc. and Esters • Esters react with ammonia and with 1° and 2° amines to form amides. • Esters are less reactive than either acid halides or acid anhydrides. • Amides do not react with ammonia or with 1° or 2° amines.

48. Acid Chlorides with Salts • Acid chlorides react with salts of carboxylic acids to give anhydrides. • Most commonly used are sodium or potassium salts.

49. Interconversions of Acid Derivatives

50. Grignard and an Ester.Look for two kinds of reactions. Substitution Any alcohol will do here. But where does an ester come from? Acid chloride Perhaps this carboxylic acid comes from the oxidation of a primary alcohol or reaction of a Grignard with CO2. Addition