Carboxylic Acid Derivatives - Acid Halides, Esters | Organic Chemistry 2

Carboxylic acid derivatives are studied in this chapter: nomenclature, properties and relative reactivity of carboxylic acid derivatives, nucleophilic acyl substitution, chemistry of acid halides: preparation, hydrolysis and reactions of acid halides, chemistry of esters: preparation, hydrolysis and reactions of esters.

Nomenclature of Carboxylic Acid Derivatives

Nomenclature:

The names of carboxylic acid derivatives are formed from the names of the parent carboxylic acids.
The order of precedence of functional groups is:
 

 

  • Acid halides:

The -oic acid ending of the corresponding carboxylic acid is replaced by -oyl halide (halide = fluoride, chloride, bromide, iodide).

 

  • Esters:

The alkyl chain R' is named as a substituent. This is followed by the name of the parent chain (RCO) where the -oic acid ending of the corresponding carboxylic acid is replaced by -ate.

 

  • Acid Anhydrides:

The acid ending of the corresponding carboxylic acid is replaced by anhydride. Unsymmetrical anhydrides are prepared from two different carboxylic acids and are named by listing both acids alphabetically followed by anhydride.

 

  • Amides:

The -oic acid ending of the corresponding alkane is replaced by -amide. Substituents on nitrogen are indicated as prefixes preceded by N- or N,N- (when 2 similar groups are present). When an amide moiety is connected to a ring, the suffix carboxylic acid is replaced by carboxamide.

 

Properties of Carboxylic Acid Derivatives

Physical properties:

  • Polarity: The carbonyl bond (C=O) is short, strong and highly polar due to the electronegativity difference between carbon and oxygen ⇒ significant dipole moment.
  • Solubility: Carboxylic acid derivatives are soluble in organic solvents. Molecules with less than 6 carbons are soluble in water, favored by the formation of hydrogen bonds with water.
  • Boiling and melting points: Similar to other polar compounds of comparable molecular weight and shape, except for 1o and 2o amides, which can form intermolecular hydrogen bonds and thus have higher boiling and melting points.

 

Geometry and orbitals:

The carbon of the C=O bond of carboxylic acid derivatives is sp2 hybridized ⇒ trigonal planar geometry. 

 

Absorption spectroscopy:

  • 13C NMR: δ ~ 160-185 ppm
    The carbonyl group of a carboxylic acid derivative is highly deshielded.
  • IR absorptions: 1650-1850 cm-1 (intense band, C=O stretching).
    The exact position of the signal in IR spectroscopy depends on the nature of the carbonyl group ⇒ IR can be used to determine the carbonyl group in an unknown compound.

 

 

Acidity on the α-carbon:

H on an α-carbon of the carbonyl bond is acidic. The pKa depends on the electronegativity of L ⇒ the lower the electronegativity, the higher the pKa.
Acyl halides: pKa ~ 16; Carboxylic anhydrides: pKa ~ 20; Esters: pKa ~ 25; Amides: pKa ~ 30

Reactivity of Carboxylic Acid Derivatives

Stability of carboxylic acid derivatives:

Carboxylic acid derivatives (RCOZ) are stabilized by delocalization of electron density due to the lone pair of electrons on Z ⇒ 3 resonance structures contribute to the resonance hybrid.
 


The more basic Z is, the more it donates its electron pair, the more each of the resonance structures contributes to the hybrid, and thus the more stable RCOZ is ⇒ the stability of carboxylic acid derivates increases with the basicity of Z.

 

Relative reactivities:
 

Nucleophilic Acyl Substitution

Reactivity of carboxylic acid derivatives:

Similar to the reactivity of aldehydes and ketones ⇒ the carbonyl group is electrophilic and can be attacked by a nucleophile.
However, there is a critical difference: carboxylic acid derivatives have a heteroatom that can act as a leaving group ⇒ when a nucleophile attacks a carboxylic acid derivative, it replaces the leaving group. This type of reaction is called a nucleophilic acyl substitution.

 

Nucleophilic acyl substitution:
 

Mechanism:

Substitution at the carboxy carbon occurs by addition-elimination in 2 distinct steps.

  1. Nucleophilic attack on the carbonyl group to form a tetrahedral intermediate.
  2. Loss of the leaving group to re-form the carbonyl group.



The better the leaving group, the more reactive RCOZ is in nucleophilic acyl substitution ⇒ more reactive acyl compounds (acid chlorides and anhydrides) can be converted to less reactive ones (carboxylic acids, esters, amides). The reverse is usually not true.

 

Synthetic strategy:

For -COOH, the addition-elimination process is complicated because of the poor leaving group (HO-). To favor this process, carboxylic acids can be converted to one of its derivatives (e.g., acyl halides) with a better leaving group.

Preparation of Acid Halides and Hydrolysis

Synthesis of acid chlorides:
 

Mechanism:

  • Part 1: Conversion of the OH group into a better leaving group.
  1. Nucleophilic attack of the carboxylic acid on the thionyl chloride.
  2. Loss of the leaving group, a chloride ion.
  3. Loss of a proton to form a neutral compound with an excellent leaving group (-OSOCl).


     
  • Part 2: Substitution of the leaving group by Cl.
  1. Nucleophilic attack of a chloride ion on the carbonyl group to form a tetrahedral intermediate.
  2. Loss of the leaving group to re-form the carbonyl group. The leaving group is decomposed to form SO2 gas and a chloride ion.

 

Synthesis of acyl bromides:
 

 

Hydrolysis of acid chlorides:
 

Mechanism:

  1. Nucleophilic attack of water on the carbonyl to form a tetrahedral intermediate.
  2. Loss of the leaving group, a chloride ion, to re-form the carbonyl group.
  3. Loss of a proton to generate the carboxylic acid.

This reaction produces HCl as a by-product, which can cause undesired reactions ⇒ Pyridine is usually used during this reaction to scavenge the HCl.

Reactions of Acid Halides

Alcoholysis of acid chlorides:
 

Mechanism:

Analogous to acid chloride hydrolysis. Pyridine is used as a base to neutralize the generated HCl.

 

Aminolysis of acid chlorides:
 

Mechanism:

Analogous to acid chloride hydrolysis. Pyridine is not used in this reaction because ammonia (or amines) is a sufficiently strong base to neutralize the generated HCl ⇒ 2 equivalents are required: one for the nucleophilic attack, the other to neutralize HCl.

 

Reduction of acid chlorides

  • With lithium aluminium hydride (alcohols formation):
     

Mechanism:

  1. Nucleophilic attack of the hydride ion on the carbonyl to form a tetrahedral intermediate.
  2. Loss of the leaving group, a chloride ion, to re-form the carbonyl group.
  3. Second nucleophilic attack by hydride to form an alkoxide.
  4. Protonation of the alkoxide to form an alcohol.

 

  • With lithium tri(t-butoxy) aluminium hydride (aldehydes formation):
     

 

Mechanism:

Lithium tri(t-butoxy) aluminium hydride reacts more rapidly with acid chlorides than with aldehydes ⇒ using only 1 equivalent of this reagent will convert acid chlorides to aldehydes with excellent yields.

  1. Nucleophilic attack of the hydride ion on the carbonyl to form a tetrahedral intermediate.
  2. Loss of the leaving group, a chloride ion, to re-form the carbonyl group.

 

Reactions with organometallic reagents

  • Synthesis of alcohols:
     

Mechanism:

Acid chlorides are converted into alcohols with the introduction of 2 alkyl groups from the Grignard reagent.

  1. Nucleophilic attack by the Grignard reagent to form a tetrahedral intermediate.
  2. Loss of the leaving group, a chloride ion, to re-form the carbonyl group.
  3. Second nucleophilic attack by the Grignard reagent to form an alkoxide.
  4. Protonation of the alkoxide to form an alcohol.

 

  • Synthesis of ketones:
     

 Mechanism:

Gilman reagent reacts more rapidly with acid chlorides than with ketones ⇒ using only 1 equivalent of this reagent will convert acid chlorides to ketones with excellent yields.

  1. Nucleophilic attack by the Gilman reagent to form a tetrahedral intermediate.
  2. Loss of the leaving group, a chloride ion, to re-form the carbonyl group.

Preparation of Esters

Preparation via SN2 reactions:
 

Mechanism:

  1. Deprotonation of the carboxylic acid with a strong base to form a carboxylate ion.
  2. Nucleophilic attack of the carboxylate ion on the alkyl halide in an SN2 process to form an ester.

Tertiary halides do not react due to steric hindrance.

 

Preparation via Fischer esterification:
 

Mechanism:

Acid catalyzed esterification.

  1. Protonation of the carbonyl group to make it even more electrophilic.


     
  2. Nucleophilic attack of the alcohol on the carbonyl group.
  3. Deprotonation to form a neutral tetrahedral intermediate.


     
  4. Protonation of the OH group to make it a better leaving group.
  5. Loss of the leaving group, water, to re-form the carbonyl group.
  6. Deprotonation to form an ester.


Fischer esterification is reversible ⇒ ester hydrolysis. According to Le Chatelier's principle, ester formation can be favored either by using an excess of the alcohol or by removing water as it is formed.

 

Preparation via acid chlorides:
 

Mechanism:

Analogous to acid chloride hydrolysis. Pyridine is used as a base to neutralize the generated HCl.

Hydrolysis of Esters

Saponification:
 

Mechanism:

  1. Nucleophilic attack of the hydroxide on the carbonyl group.
  2. Loss of the leaving group, an alkoxide ion, to re-form the carbonyl.
  3. Deprotonation of the carboxylic acid with the alkoxide ion to form a carboxylate ion (shifting the equilibrium in favor of product formation).
  4. After the reaction is complete, protonation of the carboxylate ion in the presence of an acid.

 

Acid-catalyzed hydrolysis:
 

Mechanism:

Reverse Fischer esterification favored by using an excess of water.

  1. Protonation of the carbonyl group to make it even more electrophilic.
  2. Nucleophilic attack of water on the carbonyl.
  3. Deprotonation to form a neutral tetrahedral intermediate.
  4. Protonation of the alkoxy group to make it a better leaving group.
  5. Loss of the leaving group, an alcohol, to re-form the carbonyl group.
  6. Deprotonation to form a carboxylic acid.

Reactions of Esters

Aminolysis of esters
 

Mechanism:

Analogous to aminolysis of acid chlorides.
Esters are less reactive than acid chlorides ⇒ slower reactions with amines. Preparation of amides is more efficient by reaction with acid chlorides than with esters.

 

Reduction of esters

  • With lithium aluminium hydride (alcohols formation):
     

Mechanism:

  1. Nucleophilic attack of the hydride ion on the carbonyl to form a tetrahedral intermediate.
  2. Loss of the leaving group, an alkoxide ion, to re-form the carbonyl group.
  3. Second nucleophilic attack by hydride to form an alkoxide.
  4. Protonation of the alkoxide to form an alcohol.

 

  •  With diisobutylaluminium hydride - DIBAL-H (aldehydes formation):
     

Mechanism:

  1. Nucleophilic attack of the hydride ion on the carbonyl to form a tetrahedral intermediate.
  2. Loss of the leaving group, an alkoxide ion, to re-form the carbonyl group.

DIBAL-H (also known as DIBAL or DIBAH) is a strong, bulky reducing agent ⇒ partial reduction of esters.  Using only 1 equivalent of DIBAL-H at low temperature will prevent further reduction of the aldehyde formed.

 

Reactions with organometallic reagents:
 

Mechanism:

Reduction of the ester into alcohol with the introduction of 2 alkyl groups from the Grignard reagents.

  1. Nucleophilic attack by the Grignard reagent to form a tetrahedral intermediate.
  2. Loss of the leaving group, an alkoxide ion, to re-form the carbonyl group.
  3. Second nucleophilic attack by the Grignard reagent to form an alkoxide.
  4. Protonation of the alkoxide to form an alcohol.

Check your knowledge about this Chapter

Carboxylic acid derivatives are characterized by the substitution of the hydroxyl group (-OH) in the carboxylic acid functional group with other atoms or groups of atoms, such as a halogen (in acid halides), an alkoxy group (in esters), an amino group (in amides), or an alkyl or aryl group (in anhydrides). The general structure of carboxylic acid derivatives can be represented as RCOZ, where R is a hydrocarbon group and Z is a substituent that distinguishes the derivative from a simple carboxylic acid.

The priority for naming carboxylic acid derivatives is in the following order: carboxylic acids > acid chlorides > acid anhydrides > esters > acid halides > amides.

When naming an acid anhydride derived from a simple carboxylic acid, the following steps are followed:

  1. Identify the carboxylic acids that form the anhydride. If they are the same, use the name of the acid followed by the word 'anhydride'. For example, acetic anhydride from acetic acid.
  2. If the anhydride is formed from two different carboxylic acids, name both acids alphabetically and add the word 'anhydride' at the end. For example, acetic formic anhydride.

Carboxylic acid derivatives generally have lower boiling points than carboxylic acids of comparable molecular weight, largely because they do not form intermolecular hydrogen bonds as extensively as carboxylic acids do. Carboxylic acids engage in strong dimeric hydrogen bonding, which significantly raises their boiling points and gives them the ability to dissolve many polar substances. In contrast, while derivatives like esters, amides, and anhydrides can participate in hydrogen bonding, it is typically weaker and less extensive than in carboxylic acids. Amides, however, can exhibit high boiling points due to strong hydrogen bonding as hydrogen acceptors, but they do not form dimers like acids.

Electron-withdrawing groups increase the reactivity of carboxylic acid derivatives towards nucleophilic acyl substitution reactions: these groups stabilize the intermediate tetrahedral complex by dispersing the negative charge that forms during the reaction. They also make the carbonyl carbon more electrophilic by pulling electron density away from it, thus making it more susceptible to attack by nucleophiles.

Acid chlorides are more reactive than esters due to the high electronegativity of the chlorine atom, which pulls electron density away from the carbonyl carbon, making it more susceptible to nucleophilic attack. Additionally, the chlorine atom is a better leaving group than the alkoxide group in esters, facilitating nucleophilic acyl substitution reactions.

The general mechanism for nucleophilic acyl substitution in carboxylic acid derivatives involves two key steps:

  1. Nucleophilic attack on the carbonyl carbon, forming a tetrahedral intermediate.
  2. Elimination of the leaving group, which reforms the carbonyl and completes the substitution.

In the first step, the nucleophile attacks the electrophilic carbonyl carbon, which is highly reactive due to the partial positive charge. This creates a tetrahedral intermediate with a negative charge on the oxygen atom. In the second step, a leaving group, which is often a better leaving group than the nucleophile, departs, and the carbonyl functionality is restored. This mechanism is common in reactions involving carboxylic acids, anhydrides, esters, and amides.

Acid chlorides can be prepared from carboxylic acids by treating the acid with a chlorinating agent such as thionyl chloride (SOCl2), phosphorus trichloride (PCl3), or phosphorus pentachloride (PCl5). The reaction generally proceeds via nucleophilic acyl substitution where the hydroxyl group of the carboxylic acid is replaced by a chlorine atom, releasing SO2 and HCl with SOCl2, or POCl3 and HCl with PCl3/PCl5. This reaction is favored due to the formation of these volatile byproducts, which drive the reaction to completion.

Pyridine is frequently used in reactions involving acid chlorides because its basic nature helps to neutralize the HCl by-product generated during the formation of the desired product and the elimination of the chloride ion. This prevents the formation of other by-products.

The use of lithium tri(t-butoxy) aluminium hydride allows the selective reduction of acid chlorides to aldehydes without over-reduction to primary alcohols.

  • Grignard reagents react with acyl chlorides, leading to the formation of alcohols through two nucleophilic additions.
  • Organocuprates, commonly known as Gilman reagents, react with acyl chlorides to afford ketones. The process involves cuprate addition to the carbonyl carbon.

This selectivity allows chemists to tailor reactions for the desired outcome, whether it involves alcohol or ketone synthesis, providing a valuable tool in organic synthesis strategies.

Fischer esterification involves the nucleophilic attack of the alcohol oxygen on the electrophilic carbonyl carbon of the carboxylic acid, followed by proton transfer and elimination of water.

In the preparation of esters, particularly during esterification where carboxylic acids react with alcohols, a catalyst, typically a strong acid like sulfuric acid or hydrochloric acid, is used to increase the reaction rate. The catalyst provides a more favorable pathway for the reaction by protonating the oxygen of the carbonyl group in the carboxylic acid, making it more electrophilic and thus more reactive towards the nucleophilic alcohol. Additionally, the catalyst assists in shifting the equilibrium toward product formation, which is essential since esterification is a reversible reaction.

The Dean-Stark apparatus is employed to separate and collect water produced during esterification, driving the equilibrium towards ester formation by Le Chatelier's principle.

The specific conditions that favor ester hydrolysis involve the presence of either acidic or basic catalysts, along with suitable temperature. Acid-catalyzed hydrolysis typically requires the addition of a strong acid, such as sulfuric acid (H2SO4), while basic hydrolysis, known as saponification, involves the use of an alkali, commonly sodium hydroxide (NaOH). The reaction is often performed under elevated temperatures to accelerate the hydrolysis process. The combination of the catalyst and elevated temperature promotes nucleophilic attack of water or alkoxide ion on the ester, resulting in the cleavage of the ester bond and formation of carboxylic acids (under acidic conditions) or carboxylate salts (under basic conditions).

 

Both LiAlH4 and diisobutylaluminium hydride (DIBAL-H) are reducing agents commonly used for the reduction of esters. However, LiAlH4 is more reactive and can reduce esters all the way to primary alcohols, while DIBAL-H is milder and typically stops at the aldehyde stage, allowing controlled reduction to aldehydes without further reduction to primary alcohols.