SNS - Organic Chemistry - Carboxylic Acid Derivatives Flashcards
Carboxylic Acid Derivatives
Compounds in which the -OH of the -COOH has been replaced with -X, -OCOR, -NH2 or -OR to form acyl halides, anhydrides, amides or esters respectively
Readily undergo nucleophilic substitution (including hydrolysis) and other substitution and addition reactions
Acid Halides
Synthesis
Most common are the acid chlorides, although acid bromides and iodides are occasionally seen.
Prepared by reaction of the carboxylic acid with SOCl2 to produce SO2 and HCl as side products
PCl3 or PCl5 can also be used
Acid Halides
Reactions
- Nucleophilic Substitution - (a) Hydrolysis, (b) Conversion to esters, (c) Conversion to amides
- Other - (a) Friedel Crafts acylation, (b) Reduction
Acid Halides
Reactions
Nucleophillic Acyl Substitution
- Hydrolysis
- Conversion into esters
- Conversion into amides
Acid Halides
Reactions
Nucleophilic Acyl Substitution
Hydrolysis
The simplest reaction of acid halides is their conversion back to carboxylic acids
React very rapidly with water to form the corresponding acid along with HCl
Acid Halides
Reactions
Nucleophilic Acyl Substitution
Conversion Into Esters
By reaction with alcohols
Same type of nucleophilic attack as found in hydrolysis leads to the formation of a tetrahedral intermediate with the -OH oxygen as the nucleophile.
Chloride is displaced and HCl released as the side product
Acid Halides
Reactions
Nucleophilic Acyl Substitution
Conversion Into Amides
Nucleophilic amines such as ammonia attack the carbonyl group displacing chloride
The side product is ammonium chloride, formed from excess ammonia and HCl
Acid Halides
Reactions
Other
- Friedel Crafts Acylation
- Reduction
Acid Halides
Reactions
Other
Friedel Crafts Acylation
Aromatic rings can be acylated via Friedel Crafts
Electrophilic aromatic substitution mechanism, with the attacking reagent an acylium ion formed by the reaction of an acid chloride with AlCl3 or another Lewis acid
Product is an alkyl aryl ketone
Acid Halides
Reactions
Other
Reduction
Can be reduced to alcohols or selectively reduced to the intermediate aldehydes
Catalytic hydrogenation in the presence of a ‘poison’ like quinoline permits the latter transformation
Anhydrides
Condensation dimers of carboylic acids
General formula RCOOCOR
Anhydrides
Synthesis
Synthesised by reaction of an acid chloride with a carboxylate salt
Certain cyclic anhydrides can be formed simply by heating carboxylic acids. Reaction is driven by the increased stability of the newly formed ring, hence only the five and six membered ring anhydrides are easily made. In this case, the -OH of one -COOH acts as a nucleophile attacking the carbonyl on the other -COOH
Anhydrides
Reactions
React under the same conditions as acid chlorides, but as they are slightly more stable, they are slightly less reactive. Reactions are slower and produce a carboxylic acid as a side product instead of HCl.
Cyclic anhydrides are also subject to these reactions, which cause ring opening at the anhydride group along with the formation of the new functional groups
- Hydrolysis
- Conversion into amides
- Conversion into esters and carboxylic acids
- Acylation
Anhydrides
Reactions
Hydrolysis
Converted into carboxylic acids when exposed to water
Leaving group is a carboxylic acid
Anhydrides
Reactions
Conversion Into Amides
Cleaved by ammonia, producing amides and ammonium carboxylates
Even though the leaving group is actually a carboxylic acid, the final products are an amide and the ammonium salt of a carboxylate anion
Anhydrides
Reactions
Conversion Into Esters and Carboxylic Acids
React with alcohols to form esters and carboxylic acids
Anhydrides
Reactions
Acylation
Occurs readily with AlCl3 or other Lewis acids catalysts
Proceeds via electrophilic aromatic substitution
Amides
Nomenclature
General formula RCONR2
Named by replacing the -oic acid ending with -amide
Alkyl substituents are listed as prefixes and their location specied with the letter N, for example N-methylpropanamide
Amides
Synthesis
Generally synthesised by:
- Reaction of acid chlorides with amines
- Reaction of acid anhydrides with ammonia
Amides
Reactions
- Hydrolysis
- Hofman Rearrangement
- Reduction
Amides
Reactions
Hydrolysis
Can be hydrolysed under acidic conditions via nucleophilic substitution to produce carboxylic acids or basic conditions to form carboxylates
Under acidic conditions the carbonyl oxygen becomes protonated, making the carbon atom more susceptible to nucleophiic attack
Amides
Reactions
Hofman Rearrangement
Converts amides to primary amines with the loss of the carbonyl carbon
Mechanism involves formation of a nitrene (nitrogen anaog of a carbene). The nitrene is attached to the carbonyl group and rearranges to form an isocyanate which under the reaction condition is hydrolysed to the amine
Amines
Reactions
Reduction
Can be reduced with LAH to the corresponding amine
Differs from the product of the Hofman rearrangement in that no carbon atom is lost
Esters
Synthesis
- Mixtures of carboxylic acids and alcohols will condense into esters, liberating water under acidic conditions
- Can also be obtained by reaction of acid chlorides or anhydrides with alcohols. Phenolic (aromatic) esters are produced in the same manner, although the aromatic acid chlorides are less reactive than aliphatic acid chlorides, so base must be added as a catalyst
Esters
Reactions
- Hydrolysis
- Conversion into Amides
- Transesterification
- Grignard Addition
- Condensation
- Reduction
Esters
Reactions
Hydrolysis
Can be hydrolysed to yield carboxylic acids and alcohols
Can take place under either acidic or basic conditions - similar except under basic conditions the C=O oxygen isn’t protonated and the nucleophile is OH-
Esters
Reactions
Conversion Into Amides
Nitrogen bases such as ammonia will attack the electron-deficient carbonyl carbon atoms, displacing alkoxide to yield an amide and an alcohol side product
Esters
Reactions
Transesterification
Alcohols can act as nucleophiles and displace the alkoxy groups on ester
Process transforms one ester into another
Esters
Reactions
Grignard Reactions
These reagents (RMgX) add to the carbonyl groups of esters to form ketones.
These ketones are more reactive than the original esters and are readily attacked by more Grignard reagents
Two equivalents of Grignard reagent can thus yield tertiary alcohols via nucleophilic substiution reaction
The intermediate ketone can be isolated only if the alkyl groups are sufficiently bulky to prevent further reaction
Esters
Reactions
Condensation
Claisen condensation - in the simplest case, two moles ethyl acetate react under basic conditions to form a beta-keto ester, ethyl-3-oxobutanoate (acetoacetic ester)
Proceeds by addition of an enolate anion o the carbonyl group of another ester followed by displacement of ethoxide ion
Analogous mechanism to that of aldol condensation
Esters
Reactions
Reduction
May be reduced to primary alcohols with LAH but not NaBH4
Allows for selective reduction in molecules with multiple functional groups
