11.5 Organic Reactions & Functional-Group Reactivity

Functional Groups and Their Reactions

Quick Answer: A functional group is the reactive atom set in a molecule (–OH, –COOH, –NH2, C=O). The PA-CAT tests whether you can predict how each group reacts—especially the Bulletin sample-item mechanism: a carboxylic acid loses H+ to a base, forming an ionic carboxylate salt that dissolves readily in water.

Chemistry is 16% (~38 items) and Application is 54%, so expect items that give a starting material and a reagent and ask for the product, or that ask how a structural feature (an –OH, a C=O) changes solubility or reactivity.

Functional-Group Reference Table

The Bulletin Sample-Item Mechanism: Salt Formation and Solubility

A carboxylic acid (R–COOH) is a weak acid (typical pKa 4–5). With a strong base (NaOH) or a basic amine, it donates its acidic proton:

R–COOH + NaOH → R–COO⁻Na⁺ + H2O

The product is an ionic salt. The carboxylate anion and sodium cation organize water molecules via ion–dipole interactions, which are much stronger than the dipole–dipole and hydrogen-bond interactions of the neutral acid. Solubility jumps accordingly: benzoic acid (C6H5COOH) dissolves only ~3.4 g/L in cold water, but sodium benzoate dissolves ~630 g/L—almost 200× more. This is why sodium benzoate is a common preservative and why many drugs are formulated as sodium or potassium salts of a carboxylic-acid parent.

A parallel effect occurs with amines: a free amine is often poorly soluble, but its hydrochloride salt (R–NH3⁺Cl⁻, formed by R–NH2 + HCl) is highly water soluble. Many pharmaceuticals are marketed as hydrochloride salts for this reason.

Reaction Type Catalog

Substitution (SN1/SN2). A leaving group is replaced by a nucleophile. SN1: two steps via carbocation; favored by 3° substrates, polar protic solvents, weak nucleophiles. SN2: one concerted step with backside attack; favored by 1° substrates, polar aprotic solvents, strong nucleophiles; gives inversion of configuration.

Elimination (E1/E2). A base removes a β-hydrogen while a leaving group departs, forming an alkene. E2 is concerted and anti-periplanar; E1 goes through the same carbocation as SN1. Zaitsev's rule: the more substituted (more stable) alkene is the major product.

Nucleophilic addition to carbonyls. Aldehydes and ketones (no leaving group on the carbonyl carbon) undergo addition: R2C=O + RMgX → R3C–OMgX → R3C–OH (Grignard). Hydride reagents (NaBH4, LiAlH4) reduce carbonyls to alcohols.

Nucleophilic acyl substitution. Carboxylic-acid derivatives (acyl chlorides, anhydrides, esters, amides) have a leaving group on the carbonyl carbon, so addition is followed by elimination of the leaving group. Reactivity order reflects leaving-group stability: acyl chloride > anhydride > ester > amide.

Esterification (Fischer). R–COOH + R'–OH ⇌ R–COOR' + H2O, acid-catalyzed, reversible. Removing water or using excess alcohol shifts equilibrium to product.

Amide formation. Direct condensation of a carboxylic acid and an amine is unfavorable because the acid just protonates the amine. In practice, the acid is first activated (convert to acyl chloride or use a coupling reagent like DCC), then the amine attacks.

Worked Application Item

Question stem pattern: A drug candidate contains a –COOH group and has poor water solubility at physiological pH 7.4. Which modification most increases its solubility, and why?

Reasoning: At pH 7.4, using Henderson–Hasselbalch with pKa ≈ 4.5: ratio [A⁻]/[HA] = 10^(7.4 − 4.5) = 10^2.9 ≈ 794. The acid is essentially fully deprotonated already. If the free acid is still poorly soluble, the fix is to formulate it as the sodium or potassium salt, which provides the discrete cation that boosts ion–dipole solvation. Converting the acid to an ester would remove the charge and reduce solubility; converting to an amide likewise removes the ionic character. So the answer is form the sodium salt of the carboxylate, exploiting the acid-base chemistry plus ion solvation principle.