Carboxylic Acids and Carboxylic Acid Derivatives

Overview of Carboxylic Acids and Their Derivatives

Carboxylic acids and their derivatives form a closely related family of functional groups centered around the carboxyl group. They are among the most important classes of organic compounds in both nature and industry (fats, amino acids, many drugs, fragrances, polymers).

A carboxylic acid has the functional group

$$
\ce{-COOH} \quad \text{(often written as } \ce{-CO2H} \text{)}
$$

More explicitly, the carboxyl group is

$$
\ce{R-COOH} \equiv \ce{R-C(=O)-OH}
$$

where R is an alkyl, aryl, or other carbon-containing substituent.

Carboxylic acid derivatives are compounds in which the OH of the carboxyl group is replaced by another group, but the carbonyl–based structure remains:

$$
\ce{R-C(=O)-Z}
$$

where Z is a heteroatom‑containing group (not simply OH) that can, in suitable conditions, be replaced by other nucleophiles. Typical carboxylic acid derivatives include:

• Acid halides: $\ce{R-COX}$ (usually $\ce{X = Cl}$)
• Acid anhydrides: $\ce{(RCO)2O}$
• Esters: $\ce{R-COOR'}$
• Amides: $\ce{R-CONH2}$, $\ce{R-CONHR'}$, $\ce{R-CONR'2}$
• Nitriles (often included): $\ce{R-CN}$

All of these are interconvertible under appropriate conditions and are related by the concept of nucleophilic acyl substitution.

Structure and Properties of Carboxylic Acids

Electronic Structure of the Carboxyl Group

In the carboxyl group $\ce{R-COOH}$:

• The carbonyl carbon is $sp^2$ hybridized and electrophilic (partial positive charge).
• The carbonyl oxygen and the hydroxyl oxygen bear partial negative charges.
• The $\ce{C=O}$ and $\ce{C-O}$ bonds are strongly influenced by resonance between two major contributors:

$$
\ce{R-C(=O)-OH <-> R-C(-O^-)=OH^+}
$$

Consequences:

• The two C–O bonds have partial double-bond character, so the C–O(H) bond is shorter and stronger than in simple alcohols.
• The carboxylate anion $\ce{R-COO^-}$ is resonance-stabilized, with the negative charge delocalized over both oxygens:

$$
\ce{R-COO^- <-> R-C(-O^-)=O}
$$

This resonance stabilization is crucial for their acidity.

Acidity of Carboxylic Acids

Carboxylic acids are significantly more acidic than alcohols. Typical $pK_a$ ranges:

• Simple aliphatic carboxylic acids: $pK_a \approx 4$–5
• Simple alcohols: $pK_a \approx 16$–18

Key reasons (without re-deriving general acid–base theory):

• The conjugate base $\ce{R-COO^-}$ is stabilized by resonance.
• Inductive effects from substituents on R can further stabilize or destabilize the carboxylate.

Substituent Effects on Acidity (Qualitative)

• Electron‑withdrawing groups (EWG) such as $\ce{-Cl}$, $\ce{-NO2}$, $\ce{-CF3}$ near the carboxyl group increase acidity:
• They pull electron density away, stabilizing the negative charge in $\ce{R-COO^-}$.
• Example: $\ce{ClCH2COOH}$ is more acidic than $\ce{CH3COOH}$.
• Electron‑donating groups (EDG) such as $\ce{-CH3}$, $\ce{-OCH3}$ generally decrease acidity:
• They push electron density toward the carboxylate, destabilizing the negative charge.

Physical Properties and Hydrogen Bonding

Carboxylic acids can form strong hydrogen bonds:

• As donors: via the acidic $\ce{O–H}$.
• As acceptors: via the carbonyl oxygen.

In the pure liquid (and often in the gas phase), many simple carboxylic acids form dimers, held together by two hydrogen bonds:

$$
\ce{2 R-COOH <-> R-COOH···HOOC-R}
$$

Consequences:

• Relatively high boiling points compared to alcohols and other compounds of similar molar mass.
• Smaller carboxylic acids (up to about 4 carbons) are miscible or soluble in water due to hydrogen bonding with water; solubility decreases with increasing hydrophobic alkyl chain length.

Typical Examples and Nomenclature Hints

• Formic acid $\ce{HCOOH}$ (systematic: methanoic acid)
• Acetic acid $\ce{CH3COOH}$ (ethanoic acid)
• Propionic acid $\ce{CH3CH2COOH}$ (propanoic acid)
• Benzoic acid $\ce{C6H5COOH}$ (benzenecarboxylic acid)

In systematic IUPAC naming (details of nomenclature are part of the general naming chapter):

• The parent chain includes the carboxyl carbon.
• Suffix: -oic acid (or -carboxylic acid for ring systems).

Types and Structures of Carboxylic Acid Derivatives

All classical carboxylic acid derivatives can be written as $\ce{R-C(=O)-Z}$. Their differences lie in Z, which controls reactivity and typical uses.

Acid Halides (Acyl Halides)

General formula:

$$
\ce{R-COX}, \quad \text{commonly } \ce{X = Cl}
$$

Features:

• Very reactive toward nucleophiles.
• The halogen is a good leaving group; the $\ce{C=O}$ is strongly activated.
• Typically liquids or low‑melting solids; many are moisture‑sensitive and fume in air.

Nomenclature pattern: alkanoyl halide (e.g. ethanoyl chloride) or acyl halide (e.g. acetyl chloride).

Acid Anhydrides

General structure (symmetrical case):

$$
\ce{(RCO)2O} \equiv \ce{R-CO-O-CO-R}
$$

They can also be mixed anhydrides (two different acyl groups).

Features:

• Reactivity is high, but typically less than acid chlorides.
• Viewed as the functional combination of two carboxylic acids with loss of water.

Nomenclature pattern: alkanoic anhydride (e.g. ethanoic anhydride).

Esters

General structure:

$$
\ce{R-COOR'}
$$

Where R and R' can be alkyl or aryl groups.

Features:

• Often have pleasant fruity or floral odors.
• Less reactive than acid chlorides and anhydrides, but more reactive than amides toward many nucleophiles.
• Can engage in hydrogen bonding as acceptors (via $\ce{C=O}$), but not as donors (no $\ce{O–H}$ on the carbonyl oxygen).

Nomenclature pattern: alkyl alkanoate (e.g. methyl ethanoate for $\ce{CH3COOCH3}$).

Amides

General structure:

$$
\ce{R-CONH2},\ \ce{R-CONHR'},\ \ce{R-CONR'2}
$$

Features:

• The nitrogen lone pair can delocalize into the carbonyl, giving significant resonance stabilization and partial double‑bond character in the C–N bond.
• As a result, amides are generally much less reactive (towards nucleophilic substitution) than other derivatives.
• May form strong hydrogen bonds (primary and secondary amides), leading to relatively high melting/boiling points.

Nomenclature pattern: alkanamide (e.g. ethanamide; common name: acetamide).

Amides are key structural elements of peptides and proteins (peptide bond).

Nitriles (as Carboxylic Acid “Equivalents”)

General formula:

$$
\ce{R-CN}
$$

Features:

• Contain a carbon–nitrogen triple bond.
• Can often be hydrolyzed to carboxylic acids (via amide intermediates), thus functioning as synthetic equivalents of carboxylic acids.
• The cyano carbon is electrophilic; the nitrile nitrogen is relatively weakly basic.

Nomenclature pattern: alkanenitrile (e.g. ethanenitrile; common name: acetonitrile).

Reactivity Patterns: Nucleophilic Acyl Substitution

The central reaction type for carboxylic acids and their derivatives is nucleophilic acyl substitution.

General Mechanism Concept (Qualitative)

A nucleophile Nu⁻ attacks the electrophilic carbonyl carbon in $\ce{R-C(=O)-Z}$:

1. Nucleophilic addition to the carbonyl:
   $$
   \ce{R-C(=O)-Z + Nu^- -> R-C(OH)(Nu)-Z^-}
   $$
2. Elimination of a leaving group Z⁻ (or neutral ZH) to restore the carbonyl:
   $$
   \ce{R-C(OH)(Nu)-Z^- -> R-C(=O)-Nu + Z^-}
   $$

Overall:

$$
\ce{R-C(=O)-Z + Nu^- -> R-C(=O)-Nu + Z^-}
$$

This is distinct from simple nucleophilic addition to carbonyls that cannot easily eliminate a leaving group (e.g. aldehydes, ketones).

Relative Reactivity of Derivatives

Different Z groups lead to different reactivities, which can be conveniently ordered (most to least reactive toward nucleophilic acyl substitution):

$$
\text{Acid halides} > \text{Acid anhydrides} > \text{Esters} \approx \text{Carboxylic acids} > \text{Amides}
$$

Nitriles follow somewhat different patterns but, in terms of “conversion back to an acid,” they are among the least reactive.

Factors influencing reactivity:

• Quality of the leaving group: better leaving group → higher reactivity.
• Resonance stabilization of the starting material: more resonance → often lower reactivity (amides are strongly stabilized).
• Inductive and steric effects.

This reactivity order underlies common interconversion sequences (e.g. making less reactive derivatives from more reactive ones is usually easy; the reverse is harder and often impossible without strong conditions).

Preparative Interconversions (Overview)

Only the most typical and conceptually important transformations are outlined here, without detailed mechanisms.

Formation of Carboxylic Acids

Carboxylic acids can be obtained by oxidation or by hydrolysis of derivatives.

Common synthetic routes include:

• Oxidation of primary alcohols or aldehydes (covered elsewhere).
• Hydrolysis of nitriles:
  $$
  \ce{R-CN + 2 H2O -> R-COOH + NH3}
  $$
  (usually acid- or base‑catalyzed; often proceeds via an amide).
• Hydrolysis of esters:
• Acidic hydrolysis (reversible):
  $$
  \ce{R-COOR' + H2O <=> R-COOH + R'-OH}
  $$
• Basic hydrolysis (saponification) (essentially irreversible due to formation of a carboxylate salt):
  $$
  \ce{R-COOR' + OH^- -> R-COO^- + R'-OH}
  $$

Formation of Acid Derivatives from Carboxylic Acids

Typical conversions (representative, not exhaustive):

• To acid chlorides: by chlorinating agents (e.g. thionyl chloride, $\ce{SOCl2}$):
  $$
  \ce{R-COOH + SOCl2 -> R-COCl + SO2 + HCl}
  $$
• To esters: via Fischer esterification (acid-catalyzed reaction of a carboxylic acid with an alcohol):
  $$
  \ce{R-COOH + R'-OH <=> R-COOR' + H2O}
  $$
• To anhydrides: by dehydration of two carboxylic acid molecules or via reaction of an acid with an acid chloride (mixed anhydrides).
• To amides: often via the more reactive acid chloride:
  $$
  \ce{R-COCl + 2 NH3 -> R-CONH2 + NH4Cl}
  $$

Direct reaction of $\ce{R-COOH}$ with $\ce{NH3}$ or amines under dehydrating conditions can also produce amides.

Interconversion of Derivatives

A few important general trends:

• More reactive → less reactive derivatives:
• $\ce{R-COCl}$ or anhydride $\to$ ester, amide, carboxylic acid.
• Example: $\ce{R-COCl + R'OH -> R-COOR' + HCl}$
• Less reactive → more reactive is usually not possible by simple nucleophilic acyl substitution; stronger activating or specialized reagents are required, and such transformations are more limited.

Characteristic Reactions of Carboxylic Acids

Beyond acid–base behavior (discussed in the acids–bases chapter), carboxylic acids show a few typical transformations:

Salt Formation

With bases, carboxylic acids form carboxylate salts:

$$
\ce{R-COOH + NaOH -> R-COO^- Na^+ + H2O}
$$

These salts are usually more water‑soluble than the free acids. Many natural fatty acids are present as carboxylate salts in biological or industrial contexts.

Reduction (Overview)

Carboxylic acids and their derivatives can be reduced to different products, depending on the reagent (details of reagents and mechanisms belong in broader reaction chapters):

• Strong hydride donors (e.g. complex hydrides) can reduce:
• Esters and acids → primary alcohols.
• Amides → amines (after loss of the oxygen atom equivalent).

Reduction chemistry of $\ce{C=O}$ groups is central to many synthetic strategies.

Characteristic Reactions of Carboxylic Acid Derivatives

Each derivative features characteristic nucleophilic acyl substitution reactions. Only the key patterns are mentioned here.

Hydrolysis

All classical derivatives can, under suitable conditions, be hydrolyzed back to carboxylic acids (or their salts):

• Acid chlorides:
  $$
  \ce{R-COCl + H2O -> R-COOH + HCl}
  $$
• Anhydrides:
  $$
  \ce{(RCO)2O + H2O -> 2 R-COOH}
  $$
• Esters (see above; acid or base-catalyzed).
• Amides (require relatively harsh conditions: strong acid or base, elevated temperature):
  $$
  \ce{R-CONH2 + H2O -> R-COOH + NH3}
  $$

Nitriles:
$$
\ce{R-CN + 2 H2O -> R-COOH + NH3}
$$

Transesterification (Ester–Ester Exchange)

An ester can react with an alcohol to give a new ester:

$$
\ce{R-COOR' + R''-OH <=> R-COOR'' + R'-OH}
$$

Typically acid or base catalyzed. This is widely used in modifying fats and in biodiesel production.

Aminolysis of Esters and Anhydrides

Esters and anhydrides react with ammonia or amines to form amides:

• Ester:
  $$
  \ce{R-COOR' + NH3 -> R-CONH2 + R'-OH}
  $$
• Anhydride:
  $$
  \ce{(RCO)2O + NH3 -> R-CONH2 + R-COO^- NH4^+}
  $$

Reactions of Acid Chlorides

Due to their high reactivity, acid chlorides readily undergo nucleophilic acyl substitution with a variety of nucleophiles:

• With water: hydrolysis to acid (see above).
• With alcohols: formation of esters.
• With ammonia or amines: formation of amides.
• With carboxylates: formation of anhydrides.

These reactions are central in the laboratory synthesis of less reactive derivatives.

Biological and Practical Significance

Carboxylic acids and their derivatives are ubiquitous:

• Fatty acids and esters:
• Long-chain carboxylic acids (fatty acids) and their glycerol esters form fats and oils.
• Saponification of fats produces soap (carboxylate salts).
• Amino acids and peptides:
• Amino acids contain both amine and carboxylic acid functional groups.
• Peptide bonds are specialized amides linking amino acids in proteins.
• Metabolic intermediates:
• Many key metabolites (e.g. pyruvate, citrate, lactate) are carboxylic acids or their derivatives.
• Thioesters (a special type of ester where Z = SR') such as acetyl‑CoA play a central role in energy metabolism.
• Polymers and materials:
• Polyesters and polyamides (e.g. nylon) are built from diacids and diols or diamines, respectively.
• Many synthetic fibers, plastics, and resins derive from carboxylic acid derivatives.
• Fragrances and flavors:
• Simple esters are widely used as artificial flavorings and fragrances (fruit-like aromas).
• Some short-chain acids and their esters are responsible for characteristic smells in foods and natural products.

Understanding the structures, properties, and interconversions of carboxylic acids and their derivatives is thus a foundation for both organic synthesis and biochemistry.