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Organic Chemistry 2 Unit 9: Amines

Amines are organic bases and nucleophiles; their basicity depends on hybridization, resonance and induction, and their reactions, from Gabriel synthesis to diazonium chemistry, let chemists install nitrogen and swap aromatic substituents.

Covers: Structure, classification and naming of amines, Basicity of amines and the effect of structure, Acid–base extraction and protonation state, Synthesis of amines, Hofmann elimination and Hofmann rearrangement, Arenediazonium salts and Sandmeyer reactions, Amines as nucleophiles: amides and azo coupling

Study guide

Amines are derivatives of ammonia classified by the number of carbons on nitrogen: primary (RNH₂), secondary (R₂NH), tertiary (R₃N) and quaternary ammonium ions (R₄N⁺), which have no lone pair. Nitrogen is sp³ and roughly pyramidal with a lone pair that makes amines bases and nucleophiles. Simple amines are named with the suffix -amine (propan-1-amine, N-methylethanamine) or as alkylamines. Amines with three different groups on N are not resolvable, because nitrogen inversion interconverts the two pyramidal forms rapidly. Primary and secondary amines form hydrogen bonds through N–H, so they boil higher than ethers of similar mass but lower than alcohols. Basicity is compared using the pKa of the conjugate acid (pKaH): the higher the pKaH, the stronger the base.

Alkylamines (pKaH about 10 to 11) are stronger bases than ammonia (9.25) because alkyl groups donate electron density. Arylamines are much weaker: aniline's pKaH is about 4.6, because its lone pair is delocalized into the ring. Electron-withdrawing ring substituents, especially para NO₂, make arylamines even weaker, while donating groups such as para OCH₃ make them slightly stronger. Hybridization matters too: piperidine (sp³ N, pKaH 11.1) is far more basic than pyridine (sp² N, 5.2), because more s-character holds the lone pair closer to the nucleus. Amides are essentially non-basic because their lone pair is delocalized into the carbonyl, and pyrrole's lone pair is part of its aromatic sextet. At pH 7.4, an alkylamine with pKaH 10.6 is more than 99.9% protonated.

Because amines are bases, they can be separated from neutral compounds by extraction. Shaking an ether solution with aqueous HCl converts the amine into a water-soluble ammonium chloride, which moves into the aqueous layer; adding NaOH regenerates the free amine. Direct alkylation of ammonia or amines with alkyl halides gives mixtures, because each product is as nucleophilic as or more nucleophilic than the starting amine. Cleaner routes include the Gabriel synthesis (potassium phthalimide, SN2 with a primary halide, then hydrazine or hydrolysis) for primary amines; reduction of nitriles and amides with LiAlH₄; reduction of nitroarenes with Sn/HCl or H₂/Pd to anilines; reductive amination of aldehydes and ketones with NaBH₃CN; and the Hofmann rearrangement, in which a primary amide treated with Br₂ and NaOH loses its carbonyl carbon as CO₂ to give an amine with one fewer carbon.

Amines can be turned into leaving groups. In the Hofmann elimination, exhaustive methylation with excess CH₃I gives a quaternary ammonium iodide, Ag₂O exchanges iodide for hydroxide, and heating causes E2 elimination of trimethylamine. Unlike most E2 reactions, it gives mainly the less substituted (Hofmann) alkene, because the bulky, positively charged leaving group makes the transition state carbanion-like and favors removal of the most accessible, most acidic β-hydrogen. Primary arylamines react with nitrous acid (NaNO₂ and HCl at 0 to 5 °C) to form arenediazonium salts, ArN₂⁺. Because N₂ is an excellent leaving group, the diazonium group can be replaced: CuCl, CuBr or CuCN give ArCl, ArBr or ArCN (Sandmeyer reactions), KI gives ArI, HBF₄ with heat gives ArF, warm water gives phenol, and H₃PO₂ replaces it with H.

Diazonium chemistry makes substitution patterns that direct EAS cannot. The powerful ortho/para-directing NH₂ group can be used to place substituents and then removed or replaced. For example, aniline with excess Br₂ gives 2,4,6-tribromoaniline, and diazotization followed by H₃PO₂ gives 1,3,5-tribromobenzene, a meta pattern impossible to make by direct bromination. To moderate the NH₂ group, acetylate it to an amide (–NHCOCH₃), which is still ortho/para-directing but less activating, and hydrolyze it afterward. Arenediazonium ions are also weak electrophiles that attack strongly activated rings such as phenols and anilines, usually at the para position, giving brightly colored azo compounds (Ar–N=N–Ar') used as dyes. Amines also react with acid chlorides to form amides and with sulfonyl chlorides to form sulfonamides.

Key ideas

• Amine basicity comes from the nitrogen lone pair and is measured by the pKa of the conjugate acid.
• Alkylamines are stronger bases than ammonia; arylamines, amides and pyrrole are much weaker.
• Protonation makes amines water-soluble, which is the basis of acid–base extraction.
• Direct alkylation over-alkylates; Gabriel synthesis, reductions and reductive amination give clean amines.
• Hofmann elimination gives the less substituted alkene; Hofmann rearrangement removes one carbon.
• Arenediazonium salts let N₂⁺ be replaced by Cl, Br, CN, I, F, OH or H.
• Using NH₂ as a temporary directing group enables substitution patterns direct EAS cannot make.

Formulas and rules

Common mistakes

• Comparing base strength with the pKa of the amine's N–H instead of the pKa of its conjugate acid.
• Calling amides basic because they contain nitrogen.
• Expecting clean monoalkylation when NH₃ is treated with an alkyl halide.
• Predicting the Zaitsev product for a Hofmann elimination.
• Forgetting that the Hofmann rearrangement shortens the carbon chain by one carbon.

Before the test, make sure you can

• Classify and name primary, secondary, tertiary and quaternary amines.
• Rank amines and related nitrogen compounds by basicity and explain the ranking.
• Use pKaH and pH to predict how much of an amine is protonated.
• Design an extraction to separate an amine from a neutral compound.
• Choose a clean synthesis for a given primary, secondary or tertiary amine.
• Predict Hofmann elimination and Hofmann rearrangement products.
• Use diazonium reactions to plan syntheses of substituted benzenes.

Words to know

Primary amine

An amine with one carbon group on nitrogen, RNH₂.

Secondary amine

An amine with two carbon groups on nitrogen, R₂NH.

Tertiary amine

An amine with three carbon groups on nitrogen, R₃N.

Quaternary ammonium ion

R₄N⁺, a nitrogen bonded to four carbons with a permanent positive charge and no lone pair.

pKaH

The pKa of an amine's conjugate acid; a higher pKaH means a stronger base.

Arylamine

An amine with nitrogen bonded to an aromatic ring, such as aniline; weakly basic due to resonance.

Nitrogen inversion

Rapid flipping of an amine's pyramidal geometry that prevents resolving most chiral amines.

Acid–base extraction

Separation of amines from neutral compounds by protonating them into an aqueous acid layer.

Gabriel synthesis

Preparation of primary amines by alkylating potassium phthalimide and then releasing the amine.

Hofmann elimination

E2 elimination of a quaternary ammonium hydroxide that gives mainly the less substituted alkene.

Hofmann rearrangement

Conversion of a primary amide into an amine with one fewer carbon using Br₂ and NaOH.

Arenediazonium salt

ArN₂⁺ X⁻, formed from an arylamine and nitrous acid; N₂ is an excellent leaving group.

Sandmeyer reaction

Replacement of a diazonium group by Cl, Br or CN using a copper(I) salt.

Azo coupling

Electrophilic attack of a diazonium ion on an activated arene, forming a colored Ar–N=N–Ar' compound.

Sulfonamide

RSO₂NR'₂, formed from a sulfonyl chloride and an amine; the basis of sulfa drugs.

Acetanilide

C₆H₅NHCOCH₃, the amide of aniline used to moderate the NH₂ group's activating effect.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.