SCH 206 Carboxylic acid derivatives Nucleophilic acyl substitution reaction Among the most important reactions of carboxylic acids are those that convert the carboxyl group into other acid derivatives by a nucleophilic acyl substitution reaction. O O O R1 Cl H R N R O R O R2
O O O R' R O R' R O Dr. Solomon Derese 57 Acyl chloride SCH 206 Preparation of acyl chlorides Acid chlorides can not be prepared by reaction between carboxylic acid and HCl. This is because the carbonyl carbon is not electrophilic enough to be attacked by chloride and also the fact that the hydroxyl group is a bad leaving group. X
We use PCl5 (an acid chloride of phosphoric acid), PCl3 (an acid chloride of phosphorous acid), SOCl2 (Thionyl chloride), an acid chloride of sulfurous acid, or oxalyl chloride, an acid chloride of oxalic acid.
Dr. Solomon Derese 58 SCH 206
PCl3
PCl5
O
Cl Cl
O
Dr. Solomon Derese 59 SCH 206 Good Good electrophile Very reactive Leaving Group
Dr. Solomon Derese 60 Reaction of acyl chlorides SCH 206 Acyl chlorides are the most reactive of acyl compounds towards nucleophiles. Lower molecular weight saturated acyl chlorides react explosively with water, and even more rapidly with stronger nucleophiles.
Because of their reactivity and the ease with which they can be prepared from carboxlylic acids, acyl chlorides are the most commonly used starting materials for the synthesis of carboxylic acid derivatives in general.
Dr. Solomon Derese 61 SCH 206
O R'OH NR1R2H O H2O [H] R OH Hydrolysis R Cl Acid chloride
O SOCl2 R OH Most nucleophilic acyl substitution reactions of acyl chlorides are irreversible.
Dr. Solomon Derese 62 Hydrolysis: Conversion into acids SCH 206 Acyl chlorides are hydrolyzed by water to give the corresponding carboxylic acid.
H2O N Pyridine scavenges the HCl O
OH
Dr. Solomon Derese 63 Alcoholysis: Ester formation SCH 206
In most cases this reaction is carried out in the presence of a base such as triethylamine, pyridine which will scavenge the acid (HCl).
Dr. Solomon Derese 64 Ammonlysis: Conversion into amides SCH 206
The reaction is carried out using an excess of the amine, which serves to remove the acid (HCl) as a salt. Example
DEET, the active ingredient in the most widely used insect repellents, is effective against mosquitoes, fleas, and ticks. Dr. Solomon Derese 65 SCH 206 Ammonolysis reactions carried with NaOH are sometimes referred to as Schotten – Baumann reaction.
Trimetozine (Opalene, Trimolide, Trioxazine) is a sedative that has been marketed in Europe since 1959. It also has mild tranquilizing effects and has been used in the treatment of anxiety.
Dr. Solomon Derese 66 Application: Nylon 6,6 SCH 206 The search for a synthetic fiber with properties similar to silk led to the discovery of nylon a polyamide. There are several different kinds of nylon, but the most well known is called nylon 6,6. It can be synthesized from two six-carbon monomers (hence its name)—adipoyl chloride (ClOC-(CH2)4- COCl) and hexamethylenediamine (H2N(CH2)6NH2).
Dr. Solomon Derese 67 Reduction: Conversion into alcohols SCH 206
Example
The aldehyde intermediate can be isolated if the less powerful reducing agent, LiAlH (Ot-Bu)3. Example
Dr. Solomon Derese 68 Reaction with aromatic compounds SCH 206 The Friedel Crafts acylation O O
R Cl R R' R' AlCl3 Acyl benzene Reaction with Organometallic reagents Grignard reagent
Organolithiums react similarly to give tertiary alcohols.
Dr. Solomon Derese 69 SCH 206 Organocopper (R2CuLi) (Gilman) reagents Less reactive than Grignard/organolithium reagent and yield ketones rather than tertiary alcohols.
Example
The ester functional group is not affected. Dr. Solomon Derese 70 SCH 206 Summary of the reactions of acid chlorides O
O OH R NR1R2 ) s s e c Li R R" R OR' x '
e R ( r R' 2 o R R'OH 1 r R gB Pyridine H 'M 2. H O N R 2 O 1. O O H2O R'2CuLi R OH Pyridine R R' R Cl
1. LiAlH4 2. H O 2 OH LiAlH(OtBu) O 3 AlCl3 R H H R O
R H Dr. Solomon Derese 71 Assignment 21 SCH 206 I. How do you achieve the following transformation?
II. Qiana, a polyamide fiber with a silky texture, has the following structure. What are the monomer units used in the synthesis of Qiana?
Dr. Solomon Derese 72 Acid anhydrides SCH 206
The 2nd most reactive carboxylic acid derivatives. Preparation of acetic anhydrides From acid chlorides
Most commonly used bases are pyridine and triethylamine.
Dr. Solomon Derese 73 Example SCH 206
Mechanism O
O
O Cl O O
O
Dr. Solomon Derese 74 Reactions of acid anhydrides SCH 206 The chemistry of anhydrides is similar to that of acid chlorides except that anhydrides react more slowly, but the kind of reactions the two groups undergo are the same.
Dr. Solomon Derese 75 Examples SCH 206
Dr. Solomon Derese 76 Esters SCH 206 O R' R O Alcohol component Acid component
Many simple low molecular weight esters are pleasant smelling liquids that are responsible for the fragrant odors of fruits and flowers.
Dr. Solomon Derese 77 Commercial applications of esters SCH 206 The characteristics fruity smell of esters lead to their use in artificial fruit essences. O O
O O Methyl 3-methylbutanoate Propyl propionate
O O
O O Butyl acetate 3-Methylbutyl acetate
O O
O O Methyl octanoate Benzyl butanoate
78 Dr. Solomon Derese Preparation of esters SCH 206 Fisher esterification General reaction
Catalyzed by conc. H2SO4 or HCl. Equilibrium reaction and yield can be increased by: a) Use of excess of acid or alcohol b) Removing water from the reaction mixtures as it is formed.
Dr. Solomon Derese 79 Mechanism SCH 206
H O
H R O O R1 H
Dr. Solomon Derese 80 SCH 206 Carboxylic acids whose molecules have a hydroxyl group on a g- or d- carbon undergo intramolecular esterification to give cyclic esters (Lactones) known as g- or d- lactones. Example O OH H3O O O R H O R Hydroxy acid -Lactone
Dr. Solomon Derese 81 SCH 206 From acid chlorides/acid anhydride/carboxylic acid salts General reaction
Williamson ester synthesis
Dr. Solomon Derese 82 Diazomethane esterification SCH 206
Diazomethane, CH2N2, which is best drawn as a hybrid of two contributing structures, can be used to synthesize esters from carboxylic acid. H N N H
O H C N N H 2 R O
Example
Dr. Solomon Derese 83 Reactions of Esters SCH 206
Dr. Solomon Derese 84 Hydrolysis of Esters SCH 206
Examples
Reversible, Why?
Irreversible, Why? Dr. Solomon Derese 85 Soaps Saponification SCH 206
Ester hydrolysis in base All soaps are salts of fatty acids. The main difference between soaps is the addition of other ingredients that do not alter their cleaning properties: dyes for color, scents for a pleasing odor, and oils for lubrication. Soaps that float are aerated so that they are less dense than water.
Dr. Solomon Derese 86 Transesterification SCH 206
Transesterification is the conversion of an ester into another ester by heating it with an excess of either an alcohol or a carboxylic acid in the presence of an acid or a base catalyst. In an equilibrium reaction, either the alcohol or the acid portion of the original ester is removed.
Dr. Solomon Derese 87 Example SCH 206
The equilibrium is shifted to the right by allowing the low boiling alcohol to distil from the reaction mixture.
Dr. Solomon Derese 88 Biodiesel SCH 206
Biodiesel is produced from renewable sources such as vegetable oils and animal fats and is a cleaner replacement for petroleum. It is nontoxic and biodegradable. It has physical properties similar to those of petroleum diesel.
Dr. Solomon Derese 89 Assignment 22 SCH 206
Draw a stepwise mechanism for each reaction.
Dr. Solomon Derese 90 Assignment 23 SCH 206 I. The following reactivity order has been found for the saponification of p-substituted methyl benzoates:
Y = NO2 > Br > H > CH3 > OCH3 How can you explain this reactivity order? Where would you expect Y = CHO and Y = NH2 to be in the reactivity list?
II. When ethyl benzoate is heated in methanol containing a small amount of HCl, methyl benzoate is formed. Propose a mechanism for the reaction.
Dr. Solomon Derese 91 Reduction of Esters SCH 206
The aldehyde intermediate can be isolated if 1 equivalent of the less reactive reducing agent diisobutylaluminum hydride (DIBAH) is used instead of LiAlH4. The reaction is carried out at -78°C to avoid further reduction to the alcohol.
Dr. Solomon Derese 92 SCH 206
Dr. Solomon Derese 93 Assignment 24 SCH 206 I. Predict the major product(s) for each of the following reactions:
II. Explain why ester A is more reactive than ester B in nucleophilic substitution.
Dr. Solomon Derese 94 Amides SCH 206
No free rotation across the C-N bond Preparation of amides From acid chlorides
Dr. Solomon Derese 95 From acid anhydrides SCH 206
From esters
Dr. Solomon Derese 96 From carboxylic acids SCH 206 Carboxylic acids react with aqueous ammonia to form ammonium salts:
An ammonium carboxylate Because of the low reactivity of the carboxylate ion toward nucleophilic substitution reaction, further reaction does not usually take place in aqueous solution.
Dr. Solomon Derese 97 SCH 206 Amides are of great importance in life. The linkages that join individual amino acids together to form proteins are primarily amide linkages. Proteins/peptides are formed by reacting the carboxyl group of one amino acid with the amino group another amino acid. amide linkages
As a consequence, much research has been done to find convenient and mild ways for amide synthesis. Dialkylcarbodiimides (R-N=C=N=R), for example dicyclohexylcarbodiimide (DCC), are especially useful reagents for amide synthesis. Dr. Solomon Derese 98 SCH 206
OH N
R O C N
Diclohexylcarbodiimide (DCC) H R O N The carbonyl carbon is now more C electrophilic than the carboxyl and O N the bad leaving group –OH is replaced by a good leaving group.
Dr. Solomon Derese 99 O SCH 206
R2 R N H R + 1 H N O C
N
H O N OH C R2 R N + N
R1
Dr. Solomon Derese 100 Assignment 25 SCH 206 The following reaction will not happen as shown.
a. Show what would happen instead. b. How could you obtain the desired product? Show the reagents to be used and the structures of any intermediates.
Dr. Solomon Derese 101 Reactions of amides SCH 206 Hydrolysis Amides are hydrolyzed in either acidic or alkaline solution. In either case, the acid or base is a reactant, not a catalyst, and must be used in a 1.1 molar ratio or in excess.
This property is at most important in biological systems for the stability of proteins. If the amide could hydrolyze easily we wont even be able to touch water.
Dr. Solomon Derese 102 Reduction SCH 206
Mechanism
Dr. Solomon Derese 103 Assignment 26 SCH 206 I. Predict the major product(s) for each of the following reactions:
II. Propose a mechanism for each of the following transformations:
Dr. Solomon Derese 104 Nitriles SCH 206 Preparation of nitriles I. From dehydration of amides
Dr. Solomon Derese 105 SCH 206 Mechanism O
S R Cl Cl O
H2N
R
N O
H S Cl O
Example
Dr. Solomon Derese 106 SCH 206
SN2 reaction of cyanide ion with primary alkyl halides
Example
Dr. Solomon Derese 107 Reactions of nitriles SCH 206 Hydrolysis of nitrites
Reduction of nitriles
NH2 1. LiAlH4 2. H2O R C N or R H H H2 / Pd/C
Dr. Solomon Derese 108 Mechanism SCH 206 H
R C N Al H H H
H R N C H H Example
Dr. Solomon Derese 109 SCH 206 Reaction with organometalic reagents
An alternative to Friedel-Crafts acylation
Dr. Solomon Derese 110 SCH 206 H H2O N R H C
R'
H O
R R'
NH3
O
+ NH4 R R'
Dr. Solomon Derese 111 Assignment 27 SCH 206 I. Predict the major product(s) for each of the following reactions:
1. NaCN CN 1. LiAlH a) 4 b) Br 2. MeMgBr 2. H2O 3. H3O
CN c) 1. EtMgBr 2. H2O
3. LiAlH4
4. H3O
Dr. Solomon Derese 112 SCH 206 II. Propose a mechanism for the following transformation:
III. Propose an efficient synthesis for each of the following transformations:
Dr. Solomon Derese 113 SCH 206 IV. Identify compounds A-M in the following reaction sequence.
Dr. Solomon Derese 114 SCH 206 Reduction of carboxylic acid General reaction
Dr. Solomon Derese 115 Example SCH 206
BH3 / THF O
HO
Selectively reduces carboxylic acids in the presence of aldhydes/ketones and esters
Dr. Solomon Derese 116 SCH 206 Decarboxylation of β-keto acids and β- diacids Acids whose molecules have a carbonyl group one carbon removed from the carboxyl group, called β- keto acids, decarboxylate readily when they are heated to 100-150°C. O O
H R O H H - Ketoacid
Dr. Solomon Derese 117 SCH 206 There are two reasons for this ease of decarboxylation. 1) When the carboxylate ion decarboxylate, it forms a resonance stabilized enolate anion: O O O
H H R O R H H - Ketoacid H
O
H R
H
Dr. Solomon Derese Resonance stabilized anion 118 SCH 206 II. The decarboxylation takes place though a stable six - membered cyclic transition state. O R R O
H R OH R O b-Keto carboxylic acid
Example
Dr. Solomon Derese 119 Assignment 28 SCH 206 Write the organic product(s) and reaction mechanism of the following reaction:
Dr. Solomon Derese 120