Carboxylic Acids and Carboxylic Acid Deriva3ves Nucleophilic Acyl Subs0tu0on (Addi0on- Elimina0on) 1
Carboxylic Compounds Acyl group bonded to X, an electronega3ve atom or leaving group Includes: X = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates) 2
Nomenclature of Carboxylic Acids In systema3c nomenclature, the carbonyl carbon is C- 1. In common nomenclature, the carbon next to the carbonyl is the alpha-carbon. 3
Nomenclature of Carboxylic Acids 4
Nomenclature of Acyl Halides (Acyl Chlorides and Acyl Bromides) 5
Nomenclature of Acid Anhydrides 6
Nomenclature of Esters and Carboxylate Ion Salts state the subs3tuent apached to the O delete ic acid add ate 7
Nomenclature of Lactones (Cyclic Esters) 8
Nomenclature of Amides 9
Nomenclature of Lactams (Cyclic Amides) 10
Nomenclature of Nitriles 11
Physical Proper3es 12
Amides and Nitriles Have Rela3vely High Boiling Points 13
General Reac3on PaPern Nucleophilic acyl subs3tu3on Why this Chapter? Carboxylic acids (deriva3ves) are among the most widespread of molecules. A study of them and their primary reac3on nucleophilic acyl subs3tu3on is fundamental to understanding organic chemistry 14
If the Incoming Nucleophile (Z) is a Weaker Base Than the Base in the Reactant (Y) The weakest base is eliminated from the tetrahedral intermediate. If the incoming nucleophile (Z) is a weaker base than the base in the reactant (Y), the reactants will be reformed. 15
If the Incoming Nucleophile (Z) is a Stronger Base Than the Base in the Reactant (Y) The weakest base is eliminated from the tetrahedral intermediate. If the incoming nucleophile (Z) is a stronger base than the base in the reactant (Y), a new product will be formed. 16
If the Two Groups Have Similar Basici3es A mixture of reactants and products is obtained. 17
Reac3on Coordinate Diagrams 18
The Class to which a Carbonyl Group Belongs Depends on the Basicity of the Group APached to the Acyl Group 19
The Rela3ve Reac3vi3es Depend on the Basicity of the Subs3tuent APached to the Leaving Group 20
Rela3ve Reac3vity of Carboxylic Acid Deriva3ves Nucleophiles react more readily with unhindered carbonyl groups More electrophilic carbonyl groups are more reac3ve to addi3on (acyl halides are most reac3ve, amides are least) The intermediate with the best leaving group decomposes fastest 21
Subs3tu3on in Synthesis We can readily convert a more reac3ve acid deriva3ve into a less reac3ve one Reac3ons in the opposite sense are possible but require more complex approaches 22
General Reac3ons of Carboxylic Acid Deriva3ves Water is a reagent used to make carboxylic acids Alcohols is a reagent used to make esters ammonia or an amine are used to make an amide hydride source is used to make an aldehyde or an alcohol Grignard reagent is used to make a ketone or an alcohol 23
Nucleophilic Acyl Subs3tu3on Reac3ons of Carboxylic Acids Must enhance reac3vity Convert OH into a beper leaving group Specific reagents can produce acid chlorides, anhydrides, esters, amides 24
Conversion of Carboxylic Acids into Acid Chlorides Reac3on with thionyl chloride, SOCl 2 25
Mechanism of Thionyl Chloride Reac3on Nucleophilic acyl subs3tu3on pathway Carboxylic acid is converted into a chlorosulfite which then reacts with chloride 26
Conversion of Carboxylic Acids into Acid Anhydrides Acid anhydrides can be derived from two molecules of carboxylic acid by strong hea3ng to remove water 27
Conversion of Carboxylic Acids into Esters Methods include reac3on of a carboxylate anion with a primary alkyl halide 28
Fischer Esterifica3on Hea3ng a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid 29
Mechanism of the Fischer Esterifica3on The reac3on is an acid- catalyzed, nucleophilic acyl subs3tu3on of a carboxylic acid When 18 O- labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18 O- labeled but the water produced is unlabeled 30
Reac3on of a Carboxylic Acid with an Amine A carboxylic acid is an acid and an amine is a base, so an acid- base reac3on occurs. 31
Hea3ng the Product of the Acid Base Reac3on Forms an Amide 32
Mechanism of Amide Forma3on from Carboxylic Acids 33
Dicarboxylic Acids 34
The Two pk a Values of Dicarboxylic are Different Why? The neighboring COOH group withdraws electrons and lowers the first pk a. Electrosta3c interac3on between like charges raises the second pk a. 35
Dicarboxylic Acids Lose Water When Heated if They Can Form a Five- or Six- Membered Ring 36
Ace3c Anhydride (or Acetyl Chloride) Catalyzed Anhydride Forma3on 37
Deriva3ves of Carbonic Acid 38
Chemistry of Acid Halides Acid chlorides are prepared from carboxylic acids by reac3on with SOCl 2 Reac3on of a carboxylic acid with PBr 3 yields the acid bromide 39
Reac3ons of Acid Halides Nucleophilic acyl subs3tu3on Halogen replaced by OH, by OR, or by NH 2 Reduc3on yields a primary alcohol Grignard reagent yields a ter3ary alcohol 40
Reac3ons of Acyl Chlorides 41
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 42
Conversion of Acid Halides to Esters Esters are produced in the reac3on of acid chlorides with alcohols in the presence of pyridine or NaOH. This is called Alcoholysis The reac3on is beper with less steric bulk 43
Two Equivalents of Amine are Required 44
Conversion of Acid Halides into Amides: Aminolysis Amides result from the reac3on of acid chlorides with NH 3, primary (RNH 2 ) and secondary amines (R 2 NH) The reac3on with ter3ary amines (R 3 N) gives an unstable species that cannot be isolated HCl is neutralized by the amine or an added base 45
Reduc3on: Conversion of Acid Chlorides into Alcohols LiAlH 4 reduces acid chlorides to yield aldehydes and then primary alcohols 46
Reac3on of Acid Chlorides with Organometallic Reagents Grignard reagents react with acid chlorides to yield ter3ary alcohols in which two of the subs3tuents are the same 47
Forma3on of Ketones from Acid Chlorides Reac3on of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li + R 2 Cu - Addi3on produces an acyl diorganocopper intermediate, followed by loss of Rʹ Cu and forma3on of the ketone 48
Chemistry of Acid Anhydrides Prepared by nucleophilic acyl subs3tu3on of a carboxylate with an acid chloride 49
An Acid Anhydride is Formed When Water is Lost from Two Molecules of a Carboxylic Acid 50
Reac3ons of Acid Anhydrides 51
The Mechanism 52
Reac3ons of Acid Anhydrides Similar to acid chlorides in reac3vity 53
Acetyla3on Ace3c anhydride forms acetate esters from alcohols and N- subs3tuted acetamides from amines 54
Chemistry of Esters Many esters are pleasant- smelling liquids: fragrant odors of fruits and flowers Also present in fats and vegetable oils 55
Prepara3on of Esters Esters are usually prepared from carboxylic acids 56
Reac3ons of Esters Less reac3ve toward nucleophiles than are acid chlorides or anhydrides Cyclic esters are called lactones and react similarly to acyclic esters 57
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 58
Mechanism of Ester Hydrolysis Hydroxide catalysis via an addi3on intermediate 59
Aminolysis of Esters Ammonia reacts with esters to form amides 60
Reduc3on: Conversion of Esters into Alcohols Reac3on with LiAlH 4 yields primary alcohols 61
Mechanism of Reduc3on of Esters Hydride ion adds to the carbonyl group, followed by elimina3on of alkoxide ion to yield an aldehyde Reduc3on of the aldehyde gives the primary alcohol 62
Reac3on of Esters with Grignard Reagents React with 2 equivalents of a Grignard reagent to yield a ter3ary alcohol 63
Chemistry of Amides Amides are abundant in all living organisms proteins, nucleic acids, and other pharmaceu3cals have amid func3onal groups 64
Prepara3on of Amides Prepared by reac3on of an acid chloride with ammonia, monosubs3tuted amines, or disubs3tuted amines 65
Reac3ons of Amides Hea3ng in either aqueous acid or aqueous base produces a carboxylic acid and amine Acidic hydrolysis by nucleophilic addi3on of water to the protonated amide, followed by loss of ammonia 66
Basic Hydrolysis of Amides Addi3on of hydroxide and loss of amide ion 67
Reduc3on: Conversion of Amides into Amines Reduced by LiAlH 4 to an amine rather than an alcohol Converts C=O CH 2 68
Mechanism of Reduc3on Addi3on of hydride to carbonyl group Loss of the oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine 69
Uses of Reduc3on of Amides Works with cyclic and acyclic Good route to cyclic amines 70
Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Deriva3ves Nucleophilic carboxyl subs3tu3on in nature ooen involves a thioester or acyl phosphate Acetyl CoA s are most common thioesters in nature 71
Polyamides and Polyesters: Step- Growth Polymers Reac3ons occur in dis3nct linear steps, not as chain reac3ons Reac3on of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide A diol with a diacid leads to a polyester 72
Polyamides (Nylons) Hea3ng a diamine with a diacid produces a polyamide called Nylon Nylon 66 is from adipic acid and hexamethylene- diamine at 280 C 73
Polyesters The polyester from dimethyl terephthalate and ethylene glycol is called Dacron and Mylar to make fibers 74
Synthesis of Nitrile Na CN + R Br RCN + NaBr O R :O: N H H Cl S Cl R O O S N H Cl H B R O O S N H Cl B R C N: O + S + O Cl 75
Synthesis of a Carboxylic Acid 76
Acid- Catalyzed Hydrolysis of a Nitrile 77
The Mechanism 78
HYDROLYSIS OF NITRILES TO THE CORRESPONDING CARBOXYLIC ACIDS: The mechanism for the acid-catalyzed conversion of nitriles into carboxylic acids has already been given. However, the use of the base-catalyzed conversion of nitriles into carboxylic acids still does not tolerate the presence of acid-sensitive functional groups because the final step in this sequence is the acid-catalyzed hydrolysis of the primary amide formed by the initial base-catalyzed process. R C N: + OH R C H O H N: R (Why, can it be? It's... C N: it's...it's REGENERATION of the CATALYST!!!!) H :O: H 3 O :O: R OH O H R NH 2 O H H (Can you say, "Tautomerize?") 79
Reduc3on of Nitrile R C N: + H R :N: C H 1) H 2) H 3 O H 2 O R NH 2 :O: R H 80
Synthesis of Ketone R C N: + R' MgBr R :N: MgBr C R' H 3 O R :O: R' + NH 3 81