Amines and Nitrogen-Containing Compounds

Amine Classification and Structure

Amines are classified by the number of carbon-containing groups attached to the nitrogen atom. A primary (1°) amine has one alkyl or aryl group bonded to nitrogen (RNH₂); examples include methylamine (CH₃NH₂), ethylamine, and aniline (C₆H₅NH₂). A secondary (2°) amine has two carbon groups (R₂NH); examples include dimethylamine and N-methylaniline. A tertiary (3°) amine has three carbon groups (R₃N); examples include trimethylamine and triethylamine. A quaternary ammonium salt has four carbon groups and a permanent positive charge (R₄N⁺ X⁻); tetramethylammonium chloride and choline are examples—these are not amines in the basic sense because they lack the nitrogen lone pair. The nitrogen atom in amines is sp³ hybridized, with a trigonal pyramidal geometry (bond angles ~107°, slightly less than the ideal tetrahedral 109.5° due to lone-pair repulsion). The lone pair occupies an sp³ orbital and protrudes from the pyramid apex, making it sterically accessible for protonation and nucleophilic attack. Amines with three different substituents on nitrogen are chiral at nitrogen, but nitrogen inversion—where the lone pair flips through the plane like an umbrella turning inside out—occurs rapidly at room temperature (barrier ~5-6 kcal/mol), causing enantiomers to interconvert unless the nitrogen is constrained (e.g., in a quaternary ammonium salt or a bridged bicyclic structure). The MCAT may ask about nitrogen inversion in a stereochemistry question. Amines are polar molecules: the C–N and N–H bonds are polar, and primary and secondary amines can form intermolecular hydrogen bonds (N–H···N), giving them higher boiling points than alkanes of similar molecular weight but lower than alcohols (O–H···O hydrogen bonds are stronger). Tertiary amines cannot donate hydrogen bonds and boil at lower temperatures than their primary and secondary isomers. Low-molecular-weight amines (methylamine, dimethylamine, trimethylamine) have a characteristic fishy odor; trimethylamine is responsible for the smell of rotting fish. In IUPAC nomenclature, primary amines are named by replacing the -e of the parent alkane with -amine (methanamine, ethanamine). For secondary and tertiary symmetrical amines, the prefix di- or tri- is used (dimethylamine). For unsymmetrical amines, the largest carbon group is the parent and the other groups are N-substituents (N-methylpropan-1-amine). Aromatic amines are named as derivatives of aniline.

Amine Basicity

The defining chemical property of amines is their basicity—the ability of the nitrogen lone pair to accept a proton. Amines are the most important organic bases on the MCAT, and their basicity is always reported as the pKa of the conjugate acid (the ammonium ion, RNH₃⁺). A higher pKa of the conjugate acid means a stronger base. Aliphatic amines have conjugate-acid pKa values in the range of 10–11, making them significantly stronger bases than ammonia (pKa of NH₄⁺ = 9.3). For comparison: carboxylic acids have pKa ~5, phenols ~10, alcohols ~16, and terminal alkynes ~25. The trend in basicity for aliphatic amines is: secondary (R₂NH) > primary (RNH₂) > tertiary (R₃N) ≈ ammonia. This trend results from a balance of two opposing factors: inductive electron donation (alkyl groups release electron density, stabilizing the positive charge on the ammonium ion) and solvation (more N–H bonds in the protonated form allow more hydrogen-bonding with water, stabilizing the protonated amine). Secondary amines benefit from two alkyl donors and still have one N–H for solvation; tertiary amines have three alkyl donors but zero N–H bonds, losing solvation stabilization and actually being slightly less basic than secondary amines in aqueous solution (pKa of (CH₃)₃NH⁺ ≈ 9.8 versus (CH₃)₂NH₂⁺ ≈ 10.7 in water). In the gas phase, where solvation is absent, basicity increases monotonically with alkyl substitution: tertiary > secondary > primary > ammonia, because the intrinsic inductive effect dominates. The MCAT expects you to recognize that aqueous basicity is the exam-relevant context. Aromatic amines (aniline and its derivatives) are dramatically less basic than aliphatic amines. Aniline has a conjugate-acid pKa of ~4.6, nearly six orders of magnitude weaker than cyclohexylamine (pKa ~10.6). The reason is resonance: the nitrogen lone pair in aniline is delocalized into the aromatic π system through p-orbital overlap. Protonation destroys this resonance stabilization because the lone pair is sequestered in the N–H σ bond, so aniline is far less willing to accept a proton. Resonance structures show the lone pair contributing electron density to the ortho and para positions of the ring—this is why the amino group is a powerful activating, ortho/para-directing substituent in electrophilic aromatic substitution. Substituent effects on aromatic amine basicity follow predictable trends: electron-donating groups (e.g., –OCH₃, –CH₃) increase basicity by further donating electron density to the ring and to nitrogen. Electron-withdrawing groups (e.g., –NO₂, –CF₃, –CN) decrease basicity by pulling electron density away. Nitroaniline isomers illustrate this dramatically: p-nitroaniline (pKa ~1.0), m-nitroaniline (pKa ~2.5), o-nitroaniline (pKa ~−0.3). Heterocyclic amines follow the same logic: pyridine (pKa ~5.2) is an aromatic imine—its nitrogen lone pair sits in an sp² orbital in the plane of the ring, NOT part of the aromatic π system, and is available for protonation. Pyrrole (pKa of conjugate acid ~0.4) has its nitrogen lone pair as part of the aromatic sextet—protonation destroys aromaticity, making pyrrole an extraordinarily weak base. This pyridine-versus-pyrrole distinction is a classic MCAT question: pyridine is basic (lone pair is external to the aromatic π system), pyrrole is not (lone pair is required for aromaticity). The MCAT also tests acid-base extraction: amines can be separated from other organic compounds by exploiting their basicity. Treating a mixture with aqueous acid (HCl) protonates amines to water-soluble ammonium salts (RNH₃⁺ Cl⁻), which partition into the aqueous layer and can be separated; subsequent treatment with base regenerates the free amine.

Amide Formation and Reactions of Amines

Amines react as nucleophiles, and the most biologically and synthetically important reaction is amide formation. When an amine attacks a carboxylic acid derivative—an acid chloride, an anhydride, or an ester—nucleophilic acyl substitution occurs, yielding an amide. The mechanism is directly analogous to the reactions of alcohols forming esters. Step 1: the amine nitrogen attacks the electrophilic carbonyl carbon, forming a tetrahedral intermediate with the nitrogen bearing a positive charge. Step 2: the tetrahedral intermediate collapses, expelling the leaving group (Cl⁻ from acid chlorides, RCO₂⁻ from anhydrides, OR⁻ from esters) and reforming the carbonyl π bond. Step 3: deprotonation of the nitrogen yields the neutral amide. Acid chlorides react vigorously with amines even at room temperature and do not require a catalyst. Esters require heating and often a catalyst. Amides are remarkably stable due to resonance: the nitrogen lone pair is delocalized into the carbonyl π system, creating a partial double bond between nitrogen and the carbonyl carbon (C–N bond has ~40% double-bond character). This resonance confers planarity to the amide functional group (the N and its three substituents are nearly coplanar with the carbonyl), restricts rotation about the C–N bond (barrier ~15-20 kcal/mol), and makes amides far less basic than amines (the conjugate acid of an amide has pKa ~−0.5 to 0, compared to ~10 for an amine). The restricted C–N rotation has profound consequences for protein structure: the peptide bond has partial double-bond character, meaning the six atoms of the peptide unit (Cα–C–N–Cα) are planar, restricting the conformational space available to the polypeptide backbone. The MCAT may test this in a biochemistry context. Amines participate in several other key reactions tested on the MCAT. Alkylation: amines react with alkyl halides via S_N2 to produce secondary and tertiary amines; overalkylation is a problem that leads to quaternary ammonium salts. The Gabriel synthesis is a controlled way to make primary amines without overalkylation: phthalimide is deprotonated, alkylated with an alkyl halide, and then cleaved with hydrazine (or base hydrolysis) to liberate the primary amine. Reductive amination: a carbonyl compound (aldehyde or ketone) reacts with ammonia or an amine to form an imine, which is then reduced in situ with NaBH₃CN or H₂/Pd to give a more-substituted amine. This is the most general and practical method for synthesizing secondary and tertiary amines. The Hofmann rearrangement (also called Hofmann degradation): a primary amide treated with Br₂ and strong base (NaOH) loses the carbonyl carbon as CO₂ and forms a primary amine with one fewer carbon atom. The mechanism proceeds through an isocyanate intermediate (R–N=C=O), which is hydrolyzed to the amine. This reaction is specific to primary amides and is a way to shorten a carbon chain by one atom while introducing an amine. The Hofmann elimination (exhaustive methylation): a primary amine is exhaustively methylated with excess CH₃I to form a quaternary ammonium iodide, then treated with Ag₂O/H₂O and heated to undergo E2 elimination. The regiochemistry is opposite to Zaitsev's rule (the Hofmann product is the less-substituted alkene) because the bulky –N(CH₃)₃⁺ leaving group favors removal of the less-hindered β-hydrogen. The MCAT may contrast Hofmann elimination (less-substituted alkene) with Zaitsev elimination (more-substituted alkene). Reaction of amines with nitrous acid (HNO₂, generated from NaNO₂ + HCl at 0–5°C) gives different products depending on the amine class: primary aliphatic amines give unstable diazonium salts that decompose immediately to carbocations (producing alcohols, alkenes, and rearranged products via S_N1). Primary aromatic amines give stable arenediazonium salts (Ar–N₂⁺) at 0–5°C, which are the gateway to Sandmeyer reactions (CuCl → ArCl, CuBr → ArBr, CuCN → ArCN), Schiemann reaction (HBF₄ → ArF), and azo coupling (with activated aromatic rings to form azo dyes). Secondary amines react with HNO₂ to form N-nitrosamines (yellow oils, carcinogenic). Tertiary amines form N-nitrosammonium salts. This differential reactivity was historically used as a chemical test (the Hinsberg test, though the MCAT rarely tests it explicitly).

Biological Nitrogen Compounds

The MCAT integrates amine and amide chemistry deeply into biochemistry, because nitrogen is central to every major class of biomolecules. Amino acids are the building blocks of proteins; each contains both an amine group (–NH₂) and a carboxylic acid group (–COOH). At physiological pH (~7.4), the amine is protonated (–NH₃⁺) and the acid is deprotonated (–COO⁻), giving amino acids their zwitterionic character. The α-amino group of one amino acid reacts with the α-carboxyl group of another to form a peptide bond—which is an amide linkage. The resonance of the peptide bond (C–N partial double bond) restricts rotation and enforces planarity of the peptide unit, which is the fundamental structural constraint of protein folding. The MCAT frequently tests this in the context of protein secondary structure: α-helices and β-sheets are stabilized by hydrogen bonding between the amide N–H (donor) and carbonyl C=O (acceptor) of peptide bonds along the backbone. Neurotransmitters are overwhelmingly amines. Dopamine is a catecholamine—a primary amine with a catechol (1,2-dihydroxybenzene) ring—synthesized from tyrosine via L-DOPA. Norepinephrine and epinephrine are secondary amines that act as hormones and neurotransmitters in the sympathetic nervous system. Serotonin (5-hydroxytryptamine) is a primary amine derived from tryptophan and regulates mood, sleep, and appetite. Histamine is a primary amine released by mast cells during allergic responses. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter—its amino group is at the γ position relative to the carboxylic acid. Acetylcholine is a quaternary ammonium compound (not strictly an amine) and the neurotransmitter at neuromuscular junctions; its synthesis from choline and acetyl-CoA and its degradation by acetylcholinesterase are core MCAT biochemistry. The nitrogenous bases of nucleic acids—adenine, guanine, cytosine, thymine, and uracil—contain nitrogen atoms incorporated into heterocyclic rings. Adenine and guanine are purines (fused pyrimidine-imidazole rings); cytosine, thymine, and uracil are pyrimidines. The nitrogen atoms in these rings participate in hydrogen bonding that governs Watson-Crick base pairing (A=T/U: two H-bonds; G≡C: three H-bonds). The nitrogen at position 9 of purines and position 1 of pyrimidines forms the N-glycosidic bond to ribose or deoxyribose, linking the base to the sugar-phosphate backbone—this bond is formally at the anomeric carbon position (analogous to an acetal). Nitrogen is also critical in cofactors and vitamins: pyridoxal phosphate (PLP, vitamin B₆) forms Schiff-base (imine) intermediates with amino acid substrates during transamination—the first step in amino-acid catabolism and a direct application of imine chemistry. Thiamine pyrophosphate (TPP, vitamin B₁) has a thiazolium ring with a nitrogen atom that stabilizes carbanion intermediates. Nicotinamide adenine dinucleotide (NAD⁺/NADH) contains a nicotinamide ring—an amide of nicotinic acid—that carries hydride equivalents in redox reactions. Alkaloids are a vast class of nitrogen-containing natural products produced by plants, many with potent pharmacological effects: morphine, codeine, caffeine, nicotine, atropine, quinine, and cocaine are all alkaloids. The MCAT may present alkaloid structures in passage-based questions and ask you to identify the amine functional group, predict its basicity, or consider its protonation state at physiological pH.

Diazonium Chemistry and Synthetic Applications

Diazonium chemistry is a unique reaction manifold of primary aromatic amines that the MCAT tests selectively—it is not a high-volume topic, but it appears frequently enough that you must recognize the transformations. When a primary aromatic amine (ArNH₂) is treated with nitrous acid (HNO₂, generated in situ from NaNO₂ + HCl at 0–5°C), the amino group is converted to a diazonium group (–N₂⁺). The arenediazonium salt (ArN₂⁺ X⁻) is stable at low temperature (0–5°C) because the positive charge is resonance-stabilized across the aromatic ring and the diazonium group. The diazonium group (–N₂⁺) is an excellent leaving group: N₂ gas is released, and the aromatic ring can then react with a nucleophile. This makes arenediazonium salts extraordinarily versatile synthetic intermediates—they convert the amino group into almost any other functional group on an aromatic ring. The Sandmeyer reaction uses copper(I) salts to effect substitution: CuCl gives aryl chlorides (ArCl), CuBr gives aryl bromides (ArBr), and CuCN gives aryl nitriles (ArCN, benzonitriles). The Schiemann reaction uses HBF₄ (fluoroboric acid) to convert the diazonium salt into an aryl fluoride (ArF)—one of the few reliable methods for introducing fluorine directly onto an aromatic ring. Replacement with H₃PO₂ (hypophosphorous acid) or ethanol reduces the diazonium group to a simple Ar–H (deamination). Hydrolysis in warm aqueous acid replaces the diazonium group with –OH, yielding a phenol. Reaction with KI gives the aryl iodide (ArI). These transformations are synthetic gold: you can nitrate benzene (HNO₃/H₂SO₄), reduce the nitro group to an amine (Sn/HCl or H₂/Pd), and then use diazonium chemistry to install Cl, Br, CN, F, I, OH, or H—effectively bypassing the limitations of direct electrophilic aromatic substitution for groups that cannot be introduced directly. The MCAT may ask a multistep synthesis question where the key step is a diazonium substitution. Azo coupling is another diazonium-based reaction: the arenediazonium ion acts as a weak electrophile and attacks an activated aromatic ring (phenol, aniline, or their derivatives) in an electrophilic aromatic substitution to form an azo compound (Ar–N=N–Ar′, where the –N=N– linkage is the azo group). Azo compounds are intensely colored because the azo group extends the conjugation of the π system, lowering the HOMO-LUMO gap into the visible region—they are used as dyes and indicators (methyl orange, for example, is an azo dye that changes color with pH). The MCAT may ask you to recognize the azo linkage in a structure or understand why azo compounds are colored. A critical distinction: primary aliphatic amines (RNH₂ + HNO₂) give unstable alkyldiazonium salts that decompose instantly to carbocations, which then undergo S_N1-style reactions (rearrangements, alcohol formation, alkene formation). This is essentially useless synthetically. The stability of arenediazonium salts arises specifically from resonance with the aromatic ring—without the aromatic ring, the diazonium group decomposes. The MCAT may test this distinction by asking what product forms when butylamine versus aniline reacts with nitrous acid.

How it works

Amine chemistry revolves around a single atomic feature: the nitrogen lone pair. That lone pair makes amines Brønsted bases (proton acceptors), Lewis bases (electron-pair donors), and nucleophiles (attackers of electrophilic carbons). The MCAT tests each of these roles in sequence. For basicity questions, start by identifying the hybridization and environment of the nitrogen: sp³ aliphatic amines are stronger bases than sp² aromatic amines because the sp³ lone pair is localized and available; sp² lone pairs in aromatic amines are delocalized and stabilized by resonance, so protonation is disfavored. Next, assess substituent effects: electron-donating groups on an aromatic amine increase basicity by feeding electron density to the already-electron-rich nitrogen; electron-withdrawing groups pull density away and decrease basicity. Then check for the classic trap: pyridine (lone pair in sp² orbital external to the π system, basic) versus pyrrole (lone pair part of the aromatic sextet, not basic). For nucleophilic reactions, the amine nitrogen attacks following the same mechanistic patterns as any nucleophile: S_N2 with alkyl halides (alkylation, with the complication of overalkylation), nucleophilic acyl substitution with acid derivatives (amide formation), and nucleophilic addition to carbonyls (imine/enamine formation). For the biological angle, trace every nitrogen atom in a biomolecule back to amine/amide chemistry: amino acids contain amine and carboxylic acid groups that form amide (peptide) bonds; neurotransmitters are amines that differ by one or two hydroxyl/methyl substituents; nitrogenous bases use nitrogen atoms for hydrogen bonding and glycosidic linkage; PLP forms imine intermediates with amino acid substrates. For synthesis questions, the key toolbox is: (1) Gabriel synthesis for primary amines without overalkylation, (2) reductive amination for secondary and tertiary amines, (3) Hofmann rearrangement to shorten an amide to an amine, (4) diazonium chemistry to convert an aromatic amine into almost any other functional group. The through-line is always: what state is the nitrogen in, where is its lone pair, and what electrophile does it attack?

How it works

Amine chemistry revolves around a single atomic feature: the nitrogen lone pair. That lone pair makes amines Brønsted bases (proton acceptors), Lewis bases (electron-pair donors), and nucleophiles (attackers of electrophilic carbons). The MCAT tests each of these roles in sequence. For basicity questions, start by identifying the hybridization and environment of the nitrogen: sp³ aliphatic amines are stronger bases than sp² aromatic amines because the sp³ lone pair is localized and available; sp² lone pairs in aromatic amines are delocalized and stabilized by resonance, so protonation is disfavored. Next, assess substituent effects: electron-donating groups on an aromatic amine increase basicity by feeding electron density to the already-electron-rich nitrogen; electron-withdrawing groups pull density away and decrease basicity. Then check for the classic trap: pyridine (lone pair in sp² orbital external to the π system, basic) versus pyrrole (lone pair part of the aromatic sextet, not basic). For nucleophilic reactions, the amine nitrogen attacks following the same mechanistic patterns as any nucleophile: S_N2 with alkyl halides (alkylation, with the complication of overalkylation), nucleophilic acyl substitution with acid derivatives (amide formation), and nucleophilic addition to carbonyls (imine/enamine formation). For the biological angle, trace every nitrogen atom in a biomolecule back to amine/amide chemistry: amino acids contain amine and carboxylic acid groups that form amide (peptide) bonds; neurotransmitters are amines that differ by one or two hydroxyl/methyl substituents; nitrogenous bases use nitrogen atoms for hydrogen bonding and glycosidic linkage; PLP forms imine intermediates with amino acid substrates. For synthesis questions, the key toolbox is: (1) Gabriel synthesis for primary amines without overalkylation, (2) reductive amination for secondary and tertiary amines, (3) Hofmann rearrangement to shorten an amide to an amine, (4) diazonium chemistry to convert an aromatic amine into almost any other functional group. The through-line is always: what state is the nitrogen in, where is its lone pair, and what electrophile does it attack?

Comparisons

• C/P (Basicity trends): Aliphatic amines (pKa ~10-11, conjugate acid) are stronger bases than aromatic amines (pKa ~4.6). Pyridine (pKa ~5.2, basic) vs. pyrrole (pKa ~0.4, NOT basic). Electron-donating groups increase basicity; electron-withdrawing groups decrease it.
• C/P (Nucleophilic reactions): Amines attack carbonyls to form imines (primary) and enamines (secondary). Amines attack acid chlorides/anhydrides/esters to form amides (nucleophilic acyl substitution). Alkylation via S_N2 with risk of overalkylation.
• C/P (Synthesis): Gabriel synthesis (primary amines without overalkylation), reductive amination (aldehyde/ketone → imine → amine), Hofmann rearrangement (amide → amine with loss of one carbon), Hofmann elimination (E2 with anti-Zaitsev regiochemistry).
• C/P (Diazonium chemistry): ArNH₂ + HNO₂/0-5°C → ArN₂⁺. Sandmeyer (CuCl, CuBr, CuCN), Schiemann (HBF₄ → ArF), azo coupling (→ ArN=NAr'). Arenediazonium salts are stable; alkyldiazonium salts decompose immediately.
• B/B (Amino acids and proteins): Amino acids are zwitterions at pH 7.4 (–NH₃⁺/–COO⁻). Peptide bond = amide; resonance restricts rotation and enforces planarity. Protein secondary structure (α-helices, β-sheets) stabilized by amide N–H···O=C hydrogen bonds.
• B/B (Neurotransmitters): Dopamine, norepinephrine, epinephrine, serotonin, histamine, GABA are all amines. Acetylcholine is a quaternary ammonium compound. Structure-function and synthesis from amino acid precursors.
• B/B (Nucleic acids): Purines (A, G) and pyrimidines (C, T, U) contain nitrogen heterocycles. Nitrogen atoms mediate Watson-Crick base pairing. N-glycosidic bond links base to sugar.
• B/B (Cofactors): PLP forms imine intermediates in transamination (amino-acid metabolism). NAD⁺/NADH contains a nicotinamide ring (amide). TPP contains a thiazolium nitrogen.

Common confusions

• Conflating aqueous vs. gas-phase basicity of amines: In water, secondary > primary > tertiary ≈ ammonia because solvation matters. In the gas phase, tertiary > secondary > primary > ammonia. The MCAT tests aqueous behavior.
• Forgetting that aniline is a much weaker base than aliphatic amines: the nitrogen lone pair is delocalized into the ring by resonance. Protonation destroys this resonance. Aniline (pKa ~4.6) vs. cyclohexylamine (pKa ~10.6)—a factor of one million.
• Pyridine vs. pyrrole basicity: pyridine's lone pair is in an sp² orbital in the ring plane (not part of aromaticity, available for protonation, pKa ~5.2). Pyrrole's lone pair is part of the 6π aromatic sextet (protonation destroys aromaticity, pKa ~0.4).
• Amide resonance and lack of basicity: the nitrogen lone pair in an amide is delocalized into the carbonyl, making amides essentially non-basic (pKa ~0). The C–N bond has partial double-bond character, restricting rotation—this is why peptide bonds are planar.
• Hofmann vs. Zaitsev regiochemistry: Hofmann elimination of quaternary ammonium hydroxides gives the LESS-substituted alkene (bulky leaving group favors less-hindered β-hydrogen). Zaitsev elimination gives the MORE-substituted alkene.
• Aliphatic vs. aromatic amines with HNO₂: primary aliphatic amines → unstable diazonium salts → carbocations → mixtures. Primary aromatic amines → stable arenediazonium salts at 0-5°C → Sandmeyer, Schiemann, azo coupling.
• Amine alkylation overcontrol: treating a primary amine with an alkyl halide gives a mixture of secondary, tertiary, and quaternary products. The Gabriel synthesis is the controlled alternative for primary amines only.
• Confusing Hofmann rearrangement (primary amide → primary amine with one fewer C, via isocyanate) with Hofmann elimination (exhaustively methylated amine → alkene via E2). Same name, completely different reactions.

Quick review

• Amine classification: 1° (RNH₂), 2° (R₂NH), 3° (R₃N), 4° ammonium (R₄N⁺). Nitrogen is sp³, pyramidal, with a lone pair.
• Basicity trend (aqueous): secondary > primary > tertiary ≈ ammonia. pKa of conjugate acid: aliphatic ~10-11, aniline ~4.6, amides ~0.
• Aromatic amines are weaker bases: nitrogen lone pair is delocalized into ring by resonance; protonation destroys resonance.
• Pyridine (pKa ~5.2) is basic; pyrrole (pKa ~0.4) is not. Pyridine's lone pair is external to aromaticity; pyrrole's lone pair is part of the sextet.
• Electron-donating groups increase amine basicity; electron-withdrawing groups decrease it. p-Nitroaniline pKa ~1.0.
• Amide formation: amine + acid chloride/anhydride/ester → amide (nucleophilic acyl substitution). Peptide bond = amide with resonance (C–N partial double bond).
• Amide resonance: N lone pair delocalizes into C=O. C–N bond has ~40% double-bond character, restricted rotation, planar geometry.
• Gabriel synthesis: phthalimide → deprotonate → alkylate → cleave → primary amine. No overalkylation.
• Reductive amination: aldehyde/ketone + NH₃ or amine → imine → reduce in situ (NaBH₃CN) → amine. General method for 2° and 3° amines.
• Hofmann rearrangement: primary amide + Br₂/NaOH → primary amine (one fewer C). Goes through isocyanate intermediate.
• Hofmann elimination: exhaustive methylation → quaternary ammonium salt → Ag₂O/heat → E2 to LESS-substituted alkene (anti-Zaitsev).
• Arenediazonium salts: ArNH₂ + NaNO₂/HCl, 0-5°C → ArN₂⁺. Sandmeyer (CuCl→ArCl, CuBr→ArBr, CuCN→ArCN), Schiemann (HBF₄→ArF), azo coupling (→ArN=NAr').
• Aliphatic amines + HNO₂: 1° → unstable R–N₂⁺ → carbocations → mixtures. 2° → N-nitrosamines. 3° → N-nitrosammonium salts.
• Amino acids at pH 7.4: zwitterions (–NH₃⁺/–COO⁻). Peptide bond = amide linkage.
• Neurotransmitters: dopamine, norepinephrine, serotonin, histamine = amines. Acetylcholine = quaternary ammonium.
• Nitrogenous bases: purines (A,G) and pyrimidines (C,T,U). N-glycosidic bond. H-bonding governs base pairing.