Reactions of Carboxylic Acids and Their Derivatives ١٩ دقيقه

Reactions of Carboxylic Acids and Derivatives

Reduction of Carboxylic Acids to Alcohols

• Carboxylic acids can be reduced to alcohols using a strong reducing agent.
• Lithium aluminum hydride (LiAlH4) is commonly used.
• LiAlH4 provides H^- (hydride) which attacks the delta plus carbon (\delta^+) of the carbonyl group.
• The reaction involves treating the carboxylic acid with LiAlH4 followed by quenching with aqueous acid.
• Overall reaction: RCOOH \xrightarrow{1. LiAlH4, 2. H3O^+} RCH_2OH
• The hydrogens added to the carbon come from LiAlH4, while the hydrogen on the oxygen comes from the aqueous acid.
• Reaction is high yielding.
• The hydride does not attack carbon-carbon double bonds because they are electron-rich and repel the electron-rich hydride.

Conversion of Carboxylic Acids to Acid Chlorides

• Carboxylic acids can be converted into acid chlorides using thionyl chloride (SOCl_2).
• Chloroform (CHCl_3) is used as a solvent.
• Reaction: RCOOH + SOCl2 \rightarrow RCOCl + SO2 + HCl
• The reaction produces sulfur dioxide gas (SO_2) and hydrochloric acid (HCl) as byproducts.
• High yielding reaction useful for forming acid chlorides, which are reactive intermediates.

Conversion of Carboxylic Acids to Esters

• Carboxylic acids react with alcohols to form esters in the presence of an acid catalyst.
• This is a condensation reaction where water is lost.
• The hydrogen comes from the alcohol, and the OH comes from the carboxylic acid.
• General reaction: RCOOH + R'OH \xrightarrow{H^+} RCOOR' + H_2O
• Example: Benzoic acid + Ethanol \xrightarrow{H2SO4} Ethyl benzoate + Water

Nucleophilic Acyl Substitution

• Carboxylic acid derivatives (acyl group bonded to Y, where Y is a leaving group) undergo nucleophilic substitution.
• The nucleophile attacks the carbonyl carbon, breaking the pi bond.
• The electrons from the oxygen then reform the pi bond and kick off the leaving group (Y).
• If Y is a good leaving group, the reaction is effective.
• Halogens are good leaving groups.

Example: Acid Chloride with Water

• Water attacks the carbonyl carbon of the acid chloride.
• A tetrahedral intermediate is formed.
• The electrons push back down and kick off chloride ion (Cl^-).
• The oxygen is initially protonated, but a base deprotonates it to give the carboxylic acid.

Reactivity of Carboxylic Acid Derivatives

• Acid halides (acyl chlorides and bromides) are very reactive because the halogen withdraws electrons, making the carbonyl carbon more electrophilic.
• Acid anhydrides ((RCO)_2O) are also quite reactive because RCOO^- is a good leaving group.
• Esters (RCOOR') are less reactive because OR' is not a great leaving group.
• Amides (RCONR_2) are relatively stable. This stability is important for biological molecules like proteins, which contain amide bonds.
• Reactivity order: Acid Halides > Acid Anhydrides > Esters > Amides

Conversion Between Carboxylic Acid Derivatives

• More reactive derivatives can be converted into less reactive ones.
• Acid chlorides can be converted into anhydrides, esters, and amides.
• Anhydrides can be converted to esters and amides.
• Esters can be converted to amides (with some difficulty).
• It is difficult to go in the reverse direction (e.g., amide to acid chloride).

Acid Chlorides as Versatile Reagents

• Acid chlorides are important reagents due to their high reactivity.
• They can be readily prepared from carboxylic acids using thionyl chloride.

Reactions of Acid Halides

• Hydrolysis: React with water to give carboxylic acids.
• Alcoholysis: React with alcohols to form esters.
• Aminolysis: React with ammonia or amines to form amides.
• Reduction: Can be reduced to primary alcohols (via aldehydes).

Hydrolysis of Acid Halides

• Acid halides react violently with water to yield carboxylic acids.
• They are lacrimators (irritate the eyes) because they react with water in the eyes to produce HCl.
• Mechanism: Water attacks the carbonyl carbon, electrons from the oxygen are pushed back down, kicking off the halogen. A base deprotonates the protonated oxygen, yielding the carboxylic acid.

Formation of Esters from Acyl Chlorides

• Esters can be produced in good yield from acyl chlorides and alcohols, often with a base like pyridine present.
• Less bulky alcohols react more efficiently due to reduced steric hindrance.
• This method is generally more efficient than Fischer esterification (acid-catalyzed).

Formation of Amides from Acid Chlorides

• Amides can be obtained from acid chlorides and ammonia or primary/secondary amines.
• Tertiary amines do not work because they lack a proton to be removed.
• Two equivalents of the amine are typically used; one equivalent reacts with the acyl chloride, and the other deprotonates the intermediate.

Formation of acetate esters fom Acetic anhydride

• Acetic anhydride is an excellent reagent for forming acetate esters.

Esters: Properties and Synthesis

• Esters are important in fragrances, flavors, and medicines (e.g., aspirin).
• They can be efficiently prepared using acyl chlorides or anhydrides.

Synthesis Methods

• Carboxylic acid \xrightarrow{SOCl_2} Acid chloride \xrightarrow{R'OH, base} Ester
• Carboxylic acid + Alcohol \xrightarrow{H^+} Ester (Fischer esterification, limited by alcohol choice)
• Carboxylic acid \xrightarrow{base} Carboxylate anion \xrightarrow{R'X} Ester (limited to primary alkyl halides)

Reactivity of Esters

• Esters are less reactive than acid chlorides and anhydrides because the OR group is not a good leaving group.
• Esters can undergo:
  • Hydrolysis (acid or base catalyzed) to carboxylic acids and alcohols.
  • Reaction with ammonia or amines to form amides (less efficient).
  • Reduction to primary alcohols.

Ester Hydrolysis

• Hydrolysis in the presence of acid or base gives the carboxylic acid and alcohol.
• Base-catalyzed hydrolysis (saponification) yields the carboxylate salt, which then requires acidification to obtain the free carboxylic acid.
• Saponification is used to make soaps from fats (esters of glycerol with long-chain fatty acids).
• Mechanism: Nucleophilic acyl substitution. Hydroxide attacks the carbonyl carbon, forming a tetrahedral intermediate, and then the OR group is kicked off.
• In acid conditions: A series of logical steps occurs (mechanism not required to be memorized).

Reduction of Esters

• Reduction with lithium aluminum hydride yields two alcohols.
• The hydride attacks the carbonyl group, breaking the carbonyl-oxygen bond.
• The hydrogens from the hydride end up on the carbon, and the hydrogens from the acid workup end up on the oxygens.
• Mechanism: Hydride attacks the carbonyl carbon, OR' is kicked off forming an aldehyde, then hydride attacks the aldehyde to give an alkoxide. Acid workup protonates the alkoxide to give the second alcohol.

Amides: Formation and Properties

• Amides are prepared from acid chlorides and ammonia (primary amide), monosubstituted amines (secondary amide), or disubstituted amines (tertiary amide).
• Amides are less reactive than acid chlorides, esters, and anhydrides.
• The amide linkage is stable, which is important for the biological function of proteins.

Amides: Reactions

• Amides can be reduced to amines (similar to ester reduction).
• They can be hydrolyzed in aqueous acid or aqueous base to give the carboxylic acid and the corresponding amine (requires forcing conditions).
• Heating in either aqueous acid or base is required for hydrolysis.