Lecture 19. Nucleophilic Acyl Substitution Y - + X - Y X R C X. April 2, Chemistry 328N

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1 Lecture 19 Nucleophilic Acyl Substitution X Y - - Y X X - Y April 2, 2019 hemistry 328N

2 Acid-catalyzed Esterification (also called Fischer esterification) H H 3 H H H 2 H 3 Please study the mechanism hemistry 328N

3 Decarboxylation of b-keto acids H H H H -H 2 --H 2 H H enol of a carboxylic acid Please study the mechanism too hemistry 328N

4 Practice Heat hemistry 328N

5 Practice these at home hemistry 328N

6 Acid hlorides The functional group is a carbonyl bonded to a chlorine atom Name derived from the parent acid by dropping ic acid and adding yl chloride --X Functional group of an acid halide H 3 l Acetyl chloride l Benzoyl chloride hemistry 328N

7 Acid hlorides Acid chlorides are most often prepared by treatment of a carboxylic acid with thionyl chloride - Sl 2 H 3 H 2 H 2 H Sl 2 H 3 H 2 H 2 l S 2 Hl Butanoic acid Thionyl Butanoyl chloride chloride hemistry 328N

8 Acid hlorides The mechanism divided into two steps. Step 1: The -H, is transformed into a chlorosulfite group, a great leaving group --H l-s-l S l Hl A chlorosulfite group hemistry 328N

9 Acid hlorides Step 2: attack of chloride ion gives a tetrahedral carbonyl addition intermediate, which collapses to give the acid chloride S l l - - S l l A tetrahedral carbonyl addition intermediate --l S 2 l - hemistry 328N

10 Nucleophilic Acyl Substitution with an anion as nucleophile X Y - - Y X X - Y This is a very IMPTANT general reaction. Understanding the mechanism allows one to explain and predict a large body of organic chemistry! hemistry 328N

11 The best leaving group wins What makes a leaving group good Stablility of the anion The conjugate bases of strong acids are greatleaving groups. hemistry 328N

12 eactions of Acyl hlorides l ' ' N' 2 hemistry 328N

13 hemistry 328N

14 eactions of Acyl hlorides Acyl chlorides react with carboxylic acids to give acid anhydrides: l 'H ' Hl H via: ' l hemistry 328N

15 Acid Anhydrides The functional group of an acid anhydride is 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 H 3 H 3 Acetic anhydride Benzoic anhydride H 3 - Acetic benzoic anhydride hemistry 328N

16 eactions of Acyl hlorides Acyl chlorides react with alcohols to give esters: l 'H ' Hl Please review the nomenclature of esters hemistry 328N

17 eactions of Acyl hlorides Acyl chlorides react with water (or base) to give carboxylic acids (carboxylate ion in base): Hydrolysis l H 2 H Hl l 2H l H 2 hemistry 328N

18 eactivity Acyl chlorides undergo nucleophilic acyl substitution much faster than the corresponding alkyl chlorides. elative rates of hydrolysis (25 ) 6 H 5 l 6 H 5 H 2 l 1,000 1 hemistry 328N

19 eactions of Acyl hlorides Acyl chlorides react with ammonia and amines to give amides: l ' 2 NH N' 2 l via: N' 2 l hemistry 328N

20 Example H 3 (H 2 ) 5 l H 3 (H 2 ) 5 H pyridine H 3 (H 2 ) 5 (H 2 ) 5 H 3 hemistry 328N

21 Example of acyl chloride reaction with amines to make amides 6 H 5 l HN NaH H 2 6 H 5 N hemistry 328N

22 Amides The functional group of an amide is an acyl group bonded to a nitrogen atom IUPA: drop -oic acid from the name of the parent acid and add -amide If the amide nitrogen is bonded to an alkyl or aryl group, name the group and show its location on nitrogen by N- H 3 NH 2 NH 2 H 3 NHH 3 Acetamide Benzamide N-Methylacetamide (a 1 amide) (a 1 amide) (a 2 amide) hemistry 328N

23 Amides yclic amides are called lactams Name the parent carboxylic acid, drop the suffix -ic acid, and add -lactam b H NH 3-Butanolactam (b-butyrolactam) b NH 6-Hexanolactam ( -aprolactam) hemistry 328N

24 Lactam Antibiotics hemistry 328N

25 eactions of Acid Anhydrides Acid anhydrides react with alcohols to give one mol of ester and one of carboxylic acid Phthalic anhydride H 3 HHH 2 H 3 2-Butanol (sec-butyl alcohol) H 3 HH 2 H 3 H sec-butyl hydrogen phthalate hemistry 328N

26 eactions of Esters Esters react with ammonia and amines to give amides: ' 2 NH N' 2 H H via: N' 2 hemistry 328N

27 eaction of Esters with Grignard eagents H 2 H 3 NaH - Na H 3 H hemistry 328N

28 eaction of Esters with H - Saponification H 2 H 3 NaH - Na H 3 H hemistry 328N

29 Saponification of Esters Hydrolysis of an esters is aqueous base is called saponification Each mol of ester hydrolyzed requires 1 mol of base; for this reason, ester hydrolysis in aqueous base is said to be base-promoted (not catalyzed) H 2 H 3 NaH - Na H 3 H Hydrolysis of an ester in aqueous base involves Nucleophilic acyl substitution hemistry 328N

30 Saponification of Fat H 2 H H 2 H 2 H NaH H H H 2 H - Na Fat glycerol Fatty Acid Salt "Soap" = H 3 (H 2 ) 16 H Stearic Acid H 3 (H 2 ) 7 H H(H 2 ) 7 H leic acid etc. hemistry 328N

31 Physical Properties Water solubility decreases as the relative size of the hydrophobic portion of the molecule increases hydrophilic region; increases water solubility hydrophobic region; decreases water solubility hemistry 328N

32 Soaps and Detergents Surface Active Agents = surfactants H 3 (H 2 ) 16 - N a Soap H 3 (H 2 ) 11 S 'Na Anionic detergent H 3 l H 2 N (H 2 ) 15 H 3 H 3 ationic Detergent hemistry 328N

33 hemistry 328N

34 hemistry 328N

35 Hydrolysis of Amides Hydrolysis of amides is also irreversible. In acid solution the amine product is protonated to give an ammonium salt. NH' H 2 H H 'NH 3 hemistry 328N

36 Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. This makes the reaction irreversible! NH' H 'NH 2 hemistry 328N

37 Hydrolysis of Amides in Acid Hydrolysis of amides in aqueous acid requires 1 mol of acid per mol of amide Ph 2-Phenylbutanamide H 3 H 2 HNH 2 H 2 Hl H 2 heat - H 3 H 2 HH NH 4 l Ph 2-Phenylbutanoic acid hemistry 328N

38 Hydrolysis of Amides in Acid Acid-catalyzed hydrolysis of an amide is divided into three steps Step 1: protonation of the carbonyl oxygen NH 2 H H H H NH 2 NH 2 esonance-stabilized cation H H 2 hemistry 328N

39 Hydrolysis of Amides in Acid Step 2: addition of H 2 to the carbonyl carbon followed by proton transfer H NH 2 H H H H NH 2 H proton transfer from to N H H NH 3 Tetrahedral carbonyl addition intermediate hemistry 328N

40 Hydrolysis of Amides in Acid Step 3: collapse of the intermediate coupled with proton transfer to give the carboxylic acid and ammonium ion H NH 3 H H H NH 3 H NH 4 hemistry 328N

41 Hydrolysis of Amides in Base Hydrolysis of an amide in aqueous base requires 1 mole of base per mole of amide H 3 NH N-Phenylethanamide NaH H 2 heat H 3 - Na Sodium acetate H 2 N Aniline hemistry 328N

42 Hydrolysis of Amides in Base Hydrolysis of an amide in aqueous base is divided into three steps Step 1: addition of hydroxide ion to the carbonyl carbon NH 2 - H Tetrahedral carbonyl addition intermediate - H NH 2 hemistry 328N

43 Hydrolysis of Amides in Base Step 2: collapse of the intermediate to form a carboxylic acid and ammonia - H NH 2 H H H NH 3 Tetrahedral carbonyl addition intermediate A very rare event Why??? - H hemistry 328N

44 Hydrolysis of Amides in Base Step 3: proton transfer to form the carboxylate anion and water. Hydrolysis is driven to completion by this acid-base reaction H - -H - H H hemistry 328N