Carboxylic Acids & Their Derivatives: Acid Strength, Substituent Effects, and Key Reactions

Carboxylic Acids & Their Derivatives

Learning Outcomes

• Draw the chemical structure and name organic compounds using common name and IUPAC nomenclature.

• Illustrate the physical and chemical properties of carboxylic acids and their derivatives.

Acid Strength and Substituent Effects

Carboxylic acids exhibit variable acidity influenced by the nature and position of substituents. Two main effects govern their acid strength:

• Inductive Effect: Transmission of charge through a chain of atoms by electrostatic induction.

• Mesomeric Effect: Electron withdrawing or releasing properties of substituents based on resonance structures.

Inductive Effect

• Substituents and their position relative to the carboxyl group affect acidity.

• Electron-withdrawing groups (EWG) stabilize the carboxylate ion, increasing acidity.

• Electron-donating groups (EDG) destabilize the carboxylate ion, decreasing acidity.

General Dissociation Equation:

$\mathrm{R{-}C(O)OH} + \mathrm{H_2O} \rightleftharpoons \mathrm{R{-}C(O)O^-} + \mathrm{H_3O^+}$

Electron-Withdrawing Groups (EWG)

• EWGs (e.g., -F, -Cl, -Br, -CN, -NO2) attract electrons, stabilizing the carboxylate anion and increasing acidity.

• Halogen substitution at the α-carbon increases acidity.

Acid	pKa
CH3COOH	4.76
CH2ICOOH	3.18
CH2BrCOOH	2.90
CH2ClCOOH	2.86
CH2FCOOH	2.59

• Mono-halogenated acetic acids are ~100x more acidic than acetic acid.

• Acidity increases with halogen electronegativity.

Multiple Halogen Substitution

• Increasing the number of halogen substituents further increases acidity.

Acid	pKa
CH3COOH	4.76
ClCH2COOH	2.86
Cl2CHCOOH	1.48
Cl3CCOOH	0.70

• Trichloroacetic acid is 7000x more acidic than acetic acid.

Position of Substitution

• Acidity decreases as the EWG moves farther from the carboxyl group.

Acid	pKa
CH2CH2CHClCOOH	2.83
CH3CHClCH2COOH	3.98
CH2ClCH2CH2COOH	4.52
CH3CH2CH2COOH	4.82

• Inductive effect diminishes with increasing distance from the carboxyl group.

Aromatic Carboxylic Acids

• Both inductive and mesomeric effects influence acidity.

• Substituent position matters: ortho effect > para effect.

R (para)	pKa	R (ortho)	pKa
-H	4.2	-	-
-NO2	3.4	-NO2	2.2
-Cl	4.0	-Cl	2.9

Electron-Donating Groups (EDG) on Aromatic Carboxylic Acids

• EDGs (-OH, -OCH3, -CH3) destabilize the carboxylate anion, decreasing acidity.

-R	-OH	-OCH3	-CH3	-H
4.48	4.46	4.34	4.19	4.19

Mesomeric Effect

The mesomeric effect increases the acidity and stability of carboxylate anions by delocalization of π electrons.

• Resonance in carboxylate anion stabilizes the negative charge.

• Important for drugs such as sulphonamides, succinimides, and barbiturates.

Resonance Structure:

$\mathrm{R{-}COO^-} \rightleftharpoons \mathrm{R{-}COO^-}$ (delocalized charge over both oxygens)

Acidity of Sulphonamides, Sulphonic Acids, Succinimides, Barbiturates

Sulphonamide Antibiotics

• First effective therapeutic agents for bacterial infections.

• Competitive inhibitors of dihydropteroate synthetase (DHPS), blocking folate synthesis.

• Relatively insoluble in water; sodium salts are soluble.

• Sulfur atom linked to benzene ring; para-NH2 substitution affects activity.

• Stability of sulfonamide anion (pKa ≈ 10) upon dissociation makes them suitable as drugs.

Sulphonic Acid

• Commonly used in drug molecules.

• Benzenesulphonic acid: pKa = 0.7 (strong acid due to stable sulfonate anion).

Antiseizure Succinimides

• Primary agents for treating seizures (e.g., ethosuximide, phensuximide, methsuximide).

• Cyclic imides (C4H5NO2), acidic due to mesomeric effect from carbonyl groups flanking nitrogen.

• Charge delocalization stabilizes the anion (pKa ≈ 9.6).

Anesthetic Barbiturates

• Used for anxiety, insomnia, and seizure disorders; clinical anesthesia (sodium thiopental, thiamylal, methohexital).

• Derivatives of barbituric acid (2,4,6-trioxohexahydropyrimidine), with O or S at 2-position.

• Acidic due to mesomeric effect; charge delocalization stabilizes the anion (pKa ≈ 7.8).

Reactions of Carboxylic Acids

Salt Formation: Salts of Carboxylic Acids

• Carboxylic acid salts: anionic compounds with carboxylate ion as the negative ion.

• Water solubility: carboxylic acid salts >> carboxylic acids.

• Drugs often marketed as acid salts to enhance solubility.

• Naming: cation name + acid name (ending -ic replaced by -ate).

Compound	Structure
Sodium p-chlorobenzoate	ClC6H4COO-Na+
Potassium hydrogen hexanedioate	HOOC(CH2)4COO-K+

• Used as food preservatives (benzoate, sorbate, propionate salts).

Reduction: Conversion to Alcohols

• Reduction increases hydrophilicity by forming hydroxyl groups.

• Aldehydes, ketones, and carboxylic acids can be reduced to alcohols.

Reduction Equations:

Ketones: $\mathrm{R{-}C(O){-}R'} \xrightarrow{LiAlH_4/EtOH~or~THF} \mathrm{R{-}CH(OH){-}R'}$

Carboxylic acids: $\mathrm{R{-}C(O)OH} \xrightarrow{LiAlH_4/EtOH~or~THF} \mathrm{R{-}CH_2OH}$

• Example: Warfarin reduction to p-(trifluoromethyl)benzyl alcohol.

Formation of Acid Chlorides

• Carboxylic acids are converted to acid chlorides using reagents such as SOCl2, PCl3, or PCl5.

• Acid chlorides are intermediates for esters and amides.

General Reaction:

$\mathrm{R{-}C(O)OH} + \mathrm{SOCl_2} \rightarrow \mathrm{R{-}C(O)Cl} + \mathrm{SO_2} + \mathrm{HCl}$

• SOCl2 is preferred due to gaseous by-products.

Acid	Acid Chloride	Reagent
3-phenylpropanoic acid	3-phenylpropanoyl chloride	SOCl2
Oleic acid	Oleoyl chloride	PCl5
Butanoic acid	Butanoyl chloride	PCl3

Formation of Esters

• Esters are formed by heating carboxylic acid with alcohol in the presence of a strong acid catalyst (HCl or H2SO4).

• Equilibrium can be shifted by excess reactants or removal of water.

• Fischer Esterification:

$\mathrm{R{-}C(O)OH} + \mathrm{R'OH} \xrightarrow{H^+,~heat} \mathrm{R{-}C(O)OR'} + \mathrm{H_2O}$

• Example: Benzoic acid + methanol → methyl benzoate + water

$\mathrm{C_6H_5COOH} + \mathrm{CH_3OH} \xrightarrow{HCl,~heat} \mathrm{C_6H_5COOCH_3} + \mathrm{H_2O}$

References

• Carey FA. Organic Chemistry. 9th ed. McGraw Hill, 2014.

• Hart H, Craine LE, Hart DJ. Organic Chemistry - A Short Course. 13th ed. Brooks Cole, 2012.

• Solomons TWG, Fryhle CB. Organic Chemistry. 11th ed. Wiley, 2014.

• Bruice PY. Organic Chemistry. 6th ed. Prentice Hall International, 2011.

• McMurry J. Fundamentals of Organic Chemistry. 7th ed. Brooks Cole, 2011.

• McMurry J. Organic Chemistry. 8th ed. Brooks Cole, 2012.

• Brown WH, Foote CS, Iverson BL. Organic Chemistry. 6th ed. Thomson Brooks Cole, 2015.

• Wade LG. Organic Chemistry. 8th edition, Pearson, 2013.

Additional info: This guide expands on the lecture notes by providing definitions, equations, and context for the effects of substituents on acidity, the role of resonance, and the main reactions of carboxylic acids and their derivatives, suitable for college-level Organic Chemistry study.