Amines and Diazonium Salts

Adrenaline and ephedrine, both built around a secondary amino group, raise blood pressure; Novocain, a synthetic amine, numbs a dentist's patient; Benadryl, an antihistamine, carries a tertiary amino group; quaternary ammonium salts work as surfactants in everyday soaps and shampoos. Every one of these compounds is an amine, a derivative of ammonia with one, two, or all three of its hydrogens replaced by an alkyl or aryl group, and every one of them inherits ammonia's own defining feature: a nitrogen with an unshared pair of electrons, ready to accept a proton or donate into a new bond. Push a primary aromatic amine one specific step further, and it becomes a diazonium salt instead, unstable, short-lived, and precisely for that reason genuinely useful, a synthetic intermediate that can be swapped for practically any other group a chemist wants, including the extended, coloured -N=N- linkage that gives azo dyes their colour. This chapter follows nitrogen through both roles.

Nitrogen in an amine, exactly like nitrogen in ammonia itself, is sp3 hybridised, three of its four hybrid orbitals overlapping with hydrogen or carbon and the fourth holding its own unshared electron pair, and the resulting shape is pyramidal, not flat, the lone pair occupying real space and pushing the other three groups closer together than a perfect tetrahedron would allow. That repulsion measurably narrows the C-N-E bond angle, E standing for whichever carbon or hydrogen sits opposite, below the ideal 109.5 degrees, down to 108 degrees in trimethylamine specifically. Amines are classified the same way haloalkanes and alcohols already were, by substitution count rather than by which specific carbon is involved this time: replacing one ammonia hydrogen gives a primary amine, RNH2 or ArNH2; replacing a second gives a secondary amine, RNHR'; replacing the third gives a tertiary amine, RNR'R''; and an amine is called simple when every substituent is identical and mixed when they differ.

Common names simply prefix the alkyl group's own name onto amine, methylamine for CH3NH2, with di or tri appended when a secondary or tertiary amine repeats the same group. IUPAC names replace an alkane's final -e with -amine instead, methanamine for CH3NH2, and when a molecule carries more than one amino group, locants mark each -NH2 position with the parent chain's own -e retained before the multiplying prefix, ethane-1,2-diamine for H2N-CH2-CH2-NH2. Naming a secondary or tertiary amine's own substituents on nitrogen itself uses the locant N specifically, CH3NHCH2CH3 becoming N-methylethanamine, and (CH3CH2)3N becoming N,N-diethylethanamine. Arylamines, where the -NH2 sits directly on a benzene ring, take aniline as both the accepted common and IUPAC name for the simplest case, C6H5NH2, though the fully systematic IUPAC alternative, benzenamine, replaces arene's own final -e with -amine exactly as the aliphatic naming scheme does.

Nitro compounds reduce cleanly to amines with hydrogen gas over finely divided nickel, palladium or platinum, or with a metal in acidic medium, and iron scrap with hydrochloric acid is the preferred combination industrially, since the iron(II) chloride by-product hydrolyses back to release fresh hydrochloric acid as the reaction proceeds, keeping the whole process self-sustaining on only a small initial acid charge. Ammonolysis offers a second, more direct route: an alkyl or benzyl halide, refluxed with ethanolic ammonia in a sealed tube at 373 K, undergoes ordinary nucleophilic substitution, the halogen swapped for an amino group, in the reactivity order iodide fastest, chloride slowest; but the primary amine formed is itself nucleophilic enough to attack a second molecule of alkyl halide, and the secondary amine formed that way attacks a third, so ammonolysis, left uncontrolled, yields a genuine mixture of primary, secondary and tertiary amine plus a quaternary ammonium salt, workable in practice only by using a large excess of ammonia to keep the primary amine the dominant product. Nitriles and amides supply cleaner, single-product alternatives: lithium aluminium hydride, or catalytic hydrogenation, reduces a nitrile straight to a primary amine, a route specifically useful for extending a carbon chain by exactly one carbon since the nitrile itself already carries an extra carbon in its own -CN group; the same reducing agent converts an amide to an amine just as directly.

Uncontrolled ammonolysis's messy-mixture problem has a genuine solution: the Gabriel phthalimide synthesis builds a primary amine cleanly, one molecule at a time, by first converting phthalimide to its potassium salt with ethanolic potassium hydroxide, alkylating that salt with an alkyl halide, and finally hydrolysing the product to release the pure primary amine, no secondary or tertiary contamination possible along the way, though aromatic primary amines are specifically off-limits to this route, since an aryl halide simply will not undergo the nucleophilic substitution the phthalimide anion needs. The Hofmann bromamide degradation reaction runs in the opposite direction on the carbon count: an amide, treated with bromine in aqueous or ethanolic sodium hydroxide, undergoes migration of its own alkyl or aryl group from the carbonyl carbon directly onto the nitrogen atom, and the resulting amine carries exactly one carbon fewer than the amide it started from, a controlled, single-product way to shorten a chain by precisely one carbon, the practical mirror image of the nitrile-reduction route's own chain-lengthening trick.

Lower aliphatic amines are gases carrying a distinctly fishy odour, aliphatic primary amines with three or more carbons are liquid, and heavier ones are solid, while aniline and other arylamines, colourless when fresh, darken on storage as atmospheric oxidation slowly sets in. A primary amine's own nitrogen-hydrogen bonds let it hydrogen-bond directly to a second amine molecule, and since a primary amine carries two such hydrogens against a secondary amine's one, that intermolecular association runs strongest in primary amines, weaker in secondary, and vanishes entirely in tertiary amines, which have no N-H hydrogen left to offer at all, producing the clean order primary greater than secondary greater than tertiary for the boiling points of isomeric amines. Amines mix with water too, hydrogen-bonding directly with water molecules, though nitrogen's own electronegativity, 3.0 against oxygen's 3.5, makes that hydrogen bond measurably weaker than an alcohol's own, and amine solubility fades with growing alkyl bulk exactly as an alcohol's does, heavier amines ending up essentially insoluble.

Amines react with acids to form ammonium salts, water-soluble but insoluble in organic solvents like ether, a solubility switch useful enough to serve as a genuine separation technique for pulling amines out of a non-basic organic mixture; treating that salt with a strong base like sodium hydroxide simply regenerates the free amine again. This acid-base behaviour reflects amines' own nature as Lewis bases, nitrogen's unshared electron pair ready to accept a proton, and that basicity is quantified through the equilibrium constant Kb, or more conveniently its negative logarithm pKb, the smaller the pKb the stronger the base, ammonia itself sitting at 4.75. Whether a substituted amine is stronger or weaker than ammonia comes down to how well the resulting substituted ammonium cation is stabilised relative to the neutral amine: an alkyl group's own electron-releasing character pushes extra density onto nitrogen, making its lone pair more available for protonation, and further stabilises the resulting cation by spreading its positive charge outward, both effects making aliphatic amines measurably stronger bases than ammonia itself, pKb values generally between 3 and 4.22.

In the gas phase, with no solvent involved at all, basicity follows the inductive effect exactly as expected, more alkyl groups meaning more electron release meaning a stronger base: tertiary greater than secondary greater than primary greater than ammonia, a clean, predictable ladder. In aqueous solution, that same ladder scrambles, and the reason is solvation: a substituted ammonium cation is stabilised not only by the alkyl group's own electron release but also by hydrogen-bonding with surrounding water molecules, and a bulkier cation, more heavily hindered by its own alkyl groups, cannot solvate nearly as effectively as a smaller one can, so the trend followed in water is genuinely: primary greater than secondary greater than tertiary, the inductive-effect order inverted by solvation, at least as a starting expectation. A further complication awaits even this reversed rule: small methyl groups create little steric hindrance to hydrogen bonding, but a somewhat bulkier ethyl group creates enough to shift the balance again, which is exactly why methylamine's own aqueous ordering, (CH3)2NH greater than CH3NH2 greater than (CH3)3N greater than NH3, differs from ethylamine's, (C2H5)2NH greater than (C2H5)3N greater than C2H5NH2 greater than NH3, a genuine three-way tug of war between inductive effect, solvation, and steric hindrance, with no single rule ever fully dominating on its own.

Aniline's own pKb runs surprisingly high, meaning surprisingly weak, and the reason lies in exactly where its nitrogen's lone pair actually sits: attached directly to the ring, that lone pair delocalises into the aromatic system by resonance, aniline itself a genuine hybrid of five distinct resonance structures, and that delocalisation leaves the lone pair considerably less available for protonation than an ordinary aliphatic amine's own, undelocalised pair. The anilinium ion formed after protonation, by contrast, manages only two Kekule resonance structures, since the nitrogen's lone pair is now fully tied up in the new N-H bond and no longer free to delocalise at all, and a species with fewer resonance structures is correspondingly less stabilised; since aniline itself gains far more stabilisation from its five structures than the anilinium ion gains from its two, protonating aniline costs relatively more energy than protonating ammonia does, making aniline measurably weaker as a base than even plain ammonia. Substituents on the ring tune this further, exactly the way they have every other time this pattern has appeared in this thread: an electron-releasing group like -OCH3 or -CH3 pushes extra density back toward nitrogen and strengthens the base, while an electron-withdrawing group like -NO2, -SO3H, -COOH or a halogen pulls density away and weakens it further still.

Primary and secondary amines, aliphatic or aromatic, react with acid chlorides, anhydrides and esters by nucleophilic substitution, replacing a hydrogen on nitrogen with an acyl group to give an amide, acylation, the reaction generally run alongside a base stronger than the amine itself, pyridine, to mop up the hydrogen chloride released and pull the reaction forward; benzoyl chloride reacts the same way, in what is specifically called benzoylation. A carboxylic acid reacting with an amine at ordinary room temperature, by contrast, stops short of forming an amide at all, producing only a simple ammonium salt instead, amide formation from a carboxylic acid needing the extra push of real heat, exactly as established for carboxylic acid chemistry itself. Primary amines carry one further, genuinely distinctive reaction: heated with chloroform and alcoholic potassium hydroxide, a primary amine, aliphatic or aromatic, converts to a foul-smelling isocyanide, the carbylamine reaction, and since secondary and tertiary amines simply do not respond to this treatment at all, it doubles as a clean, reliable diagnostic test for a primary amine specifically.

Nitrous acid, generated in situ from sodium nitrite and a mineral acid, reacts differently with each class of amine and each type of substrate: a primary aliphatic amine forms a genuinely unstable alkyldiazonium salt that immediately breaks down, releasing nitrogen gas quantitatively alongside an alcohol, a reaction precise enough to be used for estimating amino acids and proteins by measuring exactly how much nitrogen comes off; a primary aromatic amine, treated the same way but kept cold at 273 to 278 K, instead forms a genuinely useful, if still short-lived, arenediazonium salt. Benzenesulphonyl chloride, Hinsberg's reagent, supplies the single most complete distinguishing test in this entire chapter: a primary amine reacts to give a sulfonamide still carrying one N-H hydrogen, rendered acidic enough by the adjacent electron-withdrawing sulfonyl group to dissolve in alkali; a secondary amine reacts to give a fully N,N-disubstituted sulfonamide with no N-H hydrogen left at all, insoluble in alkali as a direct result; and a tertiary amine, with no hydrogen on nitrogen to begin with, does not react with Hinsberg's reagent at all, three amine classes, three cleanly distinct outcomes, from one single reagent.

The -NH2 group's own resonance donation pushes extra electron density specifically to the ortho and para positions, making aniline both powerfully activated and strictly ortho/para-directing in electrophilic aromatic substitution, so powerfully activated, in fact, that bromine water reacts at room temperature with no catalyst needed at all, substituting all three available ortho/para positions at once to give a white precipitate of 2,4,6-tribromoaniline directly. Direct nitration runs into a genuinely different problem: aniline's strongly acidic nitrating mixture protonates the amine itself into anilinium ion, which is meta-directing rather than ortho/para, so straightforward nitration gives a messy blend of tarry by-products alongside a substantial, unwanted meta-nitroaniline fraction. Both problems share the same fix: acetylating the amine first, with acetic anhydride, converts the powerfully activating -NH2 into the far milder -NHCOCH3, the nitrogen's own lone pair now delocalising into the acetyl group's carbonyl instead of the ring, tempering the ring's reactivity enough for controlled, predominantly para-selective substitution, after which simple hydrolysis regenerates the free amine again. Aniline shares one further, absolute limitation with every carboxylic acid already met in this thread: it cannot undergo Friedel-Crafts reactions at all, since the aluminium chloride Lewis acid catalyst simply forms a salt with the amine's own basic nitrogen, leaving a positively charged, now strongly deactivated ring with nothing left to activate.

A diazonium salt carries the general formula ArN2+X-, aryl bonded through nitrogen's own diazonium group to a counter-ion like chloride, bromide or hydrogensulphate, and is made by diazotisation: treating a primary aromatic amine with sodium nitrite and hydrochloric acid at a carefully controlled 273 to 278 K, warmer conditions causing the salt to decompose before it can even be used. Aliphatic diazonium salts are simply too unstable to isolate at all, breaking down essentially the moment they form, but an arenediazonium salt survives briefly in cold solution, its own positive charge delocalised by resonance across the attached aromatic ring, which is exactly the stabilisation an aliphatic diazonium salt's own alkyl group can never provide. Benzenediazonium chloride itself is a colourless, water-soluble crystalline solid, stable enough cold but reactive once warmed, and decomposing readily in the dry state, while benzenediazonium fluoroborate, by contrast, is water-insoluble and genuinely stable at room temperature, a useful practical difference exploited directly in one of this chapter's own preparative routes.

A diazonium salt's own reactions sort cleanly into two families, whether its own nitrogen ends up leaving or staying. When nitrogen leaves, it escapes as gas, and the diazonium group itself, an outstanding leaving group, is displaced by whatever nucleophile is offered: copper(I) salts introduce chloride, bromide or cyanide directly onto the ring, the Sandmeyer reaction, or the related but generally lower-yielding Gattermann reaction using copper powder with the corresponding halogen acid instead; potassium iodide alone, with no catalyst needed at all, introduces iodine; fluoroboric acid precipitates the diazonium fluoroborate, which decomposes on heating to release aryl fluoride; mild reducing agents like hypophosphorous acid or plain ethanol replace the diazonium group with plain hydrogen, reducing the ring back to an arene; gentle warming to 283 K hydrolyses the salt straight to phenol; and diazonium fluoroborate heated with aqueous sodium nitrite and copper installs a nitro group in the diazonium's own former place. Every one of these routes reaches a position ordinary electrophilic substitution genuinely cannot: aryl fluorides and iodides resist direct halogenation entirely, and a cyano group cannot displace a chlorine already on the ring by nucleophilic substitution, yet a diazonium salt reaches every one of these outcomes cleanly. When nitrogen instead stays, the diazonium salt couples with an electron-rich partner like phenol or aniline at that partner's own para position, forming an extended, conjugated -N=N- linkage between two aromatic rings, an azo compound, and it is exactly that extended conjugation that gives azo compounds their distinctive, often vivid colour, the basis of an entire class of synthetic dyes.