Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution

McMurry Chapter 21

 

Acid Derivatives

n     

Similar chemistry - very different reactivity

 


Typical Reaction

n     
For acids, acid/base reaction

 


n     
For acid derivative, acyl substitution

Nomenclature - Acid Halides

n      Acid Halides

n       Drop the “ic acid” from the acid name and add “yl halide”

n      
Or drop “carboxylic acid” from the acid name and add “carbonyl halide”

 

 

 

 


Nomenclature - Anhydrides


n      Anhydrides

n      

Name the two acids and and the word “anhydride”.

Nomenclature - Amides

n      Name the groups that are attached to the nitrogen and place an N before the name.

n     

Use the name of the acid, drop “ic acid” and add “amide”

Nomenclature - Esters

n      Name the alkyl group attached to the oxygen

n     

Drop the “ic acid” from the name of the acid and add “ate”.

Nomenclature - Nitriles

n      Use the suffix of the alkane and add “nitrile”


 

 


n      Use the acid name, drop the “-ic acid” and add “-onitrile”


Acyl Substitution

n      Common reaction of acid derivatives

 

Relative Reactivity

n      Steric congestion about carbonyl carbon slows the reaction.

 



 

 

 

 

Electronic Effect

n     

Better leaving group more reactive.

 


n      A less reactive group can be made from a more reactive one.

Preparations

n     

Acid halides are key to the preparation of other acid derivatives.

 

 

 

 

 

 


Preparation of Other Acid Derivatives

n     
Start with the acid halide


Examples

What would happen?

n     

Predict the products of the following reactions.
Were you right?

Fischer Esterification

n     
Acid catalyzed reaction of an acid and and alcohol.

Mechanism of Fischer Esterification

n      Important mechanism (learn it!)

 

 

 

 

 

 

 

 

 

 

 

Fischer Esterification is an Equilibrium Reaction

n      How do you shift equilibria?

                        [RCOOR’][H2O]

             Keq =

                        [RCOOH][R’OH]

n       Load up reactants

n       Remove products

 

Acid Halides

n      The most reactive of the acid derivatives

n     

Best prepared from the acid and SOCl2

Major Reactions of Acid Halides

n      Acyl substitution

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reaction with H2O

n      Acyl Substitution

 

 

 

 

 

 

 

 

 

 

 

 

n      Acid chlorides are destroyed by water

Reaction with Alcohols

n      Same as with water

 

 

 

 

 

 

 

 

n      Primary alcohols react fastest; tertiary slowest.

 

 

 

 

 

Reaction with Amines

n      Aminolysis - same mechanism


 

 


n      Schotten-Baumann Reaction

 

 

 

 

 

Reduction of Acid Halides

n      LiAlH4 gives the alcohol

 

 

 

 

 

Mechanism

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Could we stop at the Aldehyde?

n     

A reagent that would reduce acid halides but not aldehydes. Less reactive than LiAlH4

n      At low temperature this reagent allows the isolation of aldehydes

Organometallics

n      Grignard reactions give tertiary alcohols  

 

2

 

 

 

n      Copper reagents give ketones

 

 

 

 

Acid Anhydrides

n       Preparation

n        From acid halides and carboxylate salts

 

 

 

 

n       Industrial preparation of acetic anhydride

 

 

 

 

 

 

 

 

 

 

 

 

 

Reactions of Acid Anhydrides

n       Very similar to acid halides

 

 

 

 

 

 

 

 

 

 

 

 

Two Important Reactions

n       Aspirin & Acetaminophen

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Esters

n       Frequently found in nature as fragrance and flavor compounds.

 

 

 

 

 

 

Fats as Esters

n       Triesters of glycerol

 

 

 

 

n-Butyl Phthalate

n       Many plastics are brittle. To make them more pliable n-butyl phthalate is added.

 

 

 

 

 

Preparation of Esters

n    Fischer Esterification of Acids

 

 

n    From Acid Halides


 

 

 

Bonus Reaction (not in book)

n    Diazomethane

n   Very unstable

 

 

 

 

 

n   Very good method to make methyl esters

Reactions of Esters

n       Hydrolysis - acid or base catalyzed

n        Acid catalysis is the reverse of the Fischer Esterification

 

 

 

Saponification

n       Base catalyzed hydrolysis is called “saponification”

 

 

 

 

 

 

 

Mechanism?

n       Acyl substitution

 

 

 

 

 

 

 

 

 

 

 

 

 

Ester Reduction

n    LiAlH4 reduces esters smoothly to the primary alcohol.

 

 

 

n    Since acids react violently with LAH they are often converted to esters before reduction.

Aminolysis

n    Reaction with amines

 

 

 

 

 

n    Notice the amine reacted, not the alcohol. Why?

Esters and Grignard Reagents

n       We have seen this reaction

n        (review is a “good thing”)

 

 

 

 

 

 

Amides

n       Prepared from acid halides, anhydrides, and esters.

 

 

 

 

 

 

 

 

 

Amide Hydrolysis

n      Relatively unreactive toward water.

n       Acid and base catalyzed

 

 

 

 

 

Amide Reduction

n       LAH reduces amides to the amine

n        Very good amine preparation.

 

 

 

 

 

Nitrile Chemistry

n       Oxidation state of nitriles is the same as acids.

n       Prepared by SN2 with NC-

 

 

 

 

 

Dehydration of Amides

n       Priamary amides with thionyl chloride

 

 

 

 

 

Reaction of Nitriles

n       Hydrolysis

 

 

 

n       Mechanism?

Reduction

n       Primary amine preparation

 

 

 

 

Could we subvert the reduction?

n       Partial reduction with a less reactive reagent; DIBAL

 

 

 

 

 

 

 

 

 

 

 

 

Nitriles and Grignard Reagents

n       Ketone preparation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Thiol Ester

n       Very important biochemically

n        Acetyl Coenzyme A

 

 

 

 

n        Acetylating agent. Two carbon building block

Polyamides and Polyesters

n       Important as fibers

n        Nylon

 

 

 

 

n        Polyester

 

 

 

 

Polyamides

n       Nylon

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Preparation

n       Acid chloride method

n        Low MW, poor properties

 

 

 

 

 

 

 

 

 

 

 

Industrial Preparation

n       Two step

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Industrial Preparation of Polyester

n       Trans esterification

 

 

 

 

 

 

 

 

 

Polycarbonate Polymers

n       Carbonates

 

 

 

 

n       Lexan

 

 

 

 

 

 

 

 

Spectroscopy

n     IR

n    Acid Halides                 1810 cm -1

n    Acid Anhydrides                       1820, 1760 cm -1

n    Acid Ester                     1735 cm -1

n    Acid Amides                 1690 cm -1

n    Nitriles                          2250 cm-1

Aromatic systems 30 cm-1 lower.

NMR

n       Proton

n        Protons next to the carbonyl occur about 2.2 ppm

n       Carbon

n        Acid 177 Ester 170

n        Acid Halide 170 Anhydride 166

n        Amide 172 Nitrile 117

n        Ketone 205 Aldehyde 201