At the pH of blood, 7.4, more than 99.9% of methylamine, CH3NH2, carries an extra proton as the methylammonium ion, CH3NH3+. Ethanol, a molecule of about the same size, stays neutral. The difference is the lone pair on nitrogen. How available that pair is decides almost everything on this page: how strong a base an amine is, how good a nucleophile it is, and whether its nitrogen can act as a leaving group. Across the compounds on this page, pKaH runs from about 14 down to about −10.
Nitrogen’s lone pair
Start with the shape. The nitrogen in methylamine has three bonds, one to carbon and two to hydrogen, plus one lone pair. These four electron groups point toward the corners of a tetrahedron, so the nitrogen is sp3 (Molecular geometry). Only three of the corners hold atoms, so the molecule is a trigonal pyramid: the three atoms form the base, the nitrogen sits above them, and the bond angles are close to 107°. The lone pair fills the fourth corner and points away from all three bonds.
That exposed pair is what makes an amine a base. When a proton arrives, the pair becomes a fourth N–H bond and the nitrogen takes on a positive charge. Because the amine accepts a proton, it is a Brønsted base. Because it does so by donating an electron pair, it is also a Lewis base (Lewis acids/bases). Both names describe one property of the same pair.
The strength of a base is read from its conjugate acid, the ion it becomes after taking the proton. Methylammonium has a pKa of 10.6. Chemists usually quote this as the amine’s pKaH, meaning the pKa of its conjugate acid, and a higher pKaH means a stronger base (pKa). Most simple amines have pKaH values between 10 and 11. Water’s pKaH is −1.7, the pKa of H3O+, so an amine is a far stronger base than water or an alcohol.
That is why an amine in the body is almost entirely protonated. It is also why most drugs that contain an amine are sold as hydrochloride salts, R–NH3+ Cl−. The salt dissolves in water, while the neutral amine, called the free base, often does not.
The same pair also makes an amine a nucleophile, a species that donates an electron pair to an electron-poor atom, usually carbon. Basicity and nucleophilicity are different measurements, though. Basicity describes where an equilibrium settles; nucleophilicity describes how fast an attack happens (Nucleophiles). Diisopropylamine, [(CH3)2CH]2NH, shows the difference. Its pKaH is 11.1, at the top of the usual range, yet it attacks carbon far more slowly than a less crowded amine such as diethylamine.
The reason is size. A proton is tiny, and it slips past the two isopropyl groups to reach the lone pair. A carbon arrives carrying its own groups, and they bump into the methyl groups of the two isopropyls. Crowding slows the attack on carbon but barely affects the transfer of a proton.
You have met this amine before. Remove its N–H proton with butyllithium and you get lithium diisopropylamide, LDA, the bulky base that Alpha hydrogens & enolates used to make enolates without adding to the carbonyl. LDA keeps the same crowding, so it removes protons readily but rarely attacks carbon.
Salt formation also gives a simple way to separate an amine from a neutral compound. Dissolve the mixture in ether and shake it with aqueous HCl. Ether is less dense than water, so it forms the top layer. The amine takes a proton and becomes R–NH3+ Cl−. That salt is ionic, so it moves into the water layer, while the neutral compound stays in the ether.
Next, drain the water layer into a clean flask and add NaOH to it. Hydroxide takes the proton back, the free amine re-forms, and shaking this basic water with fresh ether draws the amine out of it. Two extractions separate the amine from the neutral compound without chromatography. A carboxylic acid can be pulled from a similar mixture the opposite way, with aqueous NaHCO3 (Carboxylic acids).
An amine whose nitrogen carries three different groups looks as if it should be chiral, with the lone pair as the fourth group. In practice it is not, because the pyramid turns itself inside out through a flat transition state, like an umbrella in the wind. This flip is called nitrogen inversion, and it turns each form into its mirror image.
The flip is fast because no bond breaks. Its barrier is about 6 kcal/mol for ammonia and a little higher for most amines, so at room temperature each molecule flips millions of times a second or more. A carbon stereocenter would have to break a bond to invert, at a cost of roughly 80 kcal/mol or more, so its two mirror-image forms never interconvert and can be kept apart.
Alkyl groups: a small effect, and a tangled one
Compare ammonia with its methyl derivatives in water. The pKaH values are 9.2 for ammonia, 10.6 for methylamine, 10.7 for dimethylamine and 9.8 for trimethylamine. The first methyl raises the basicity, the second barely changes it, and the third lowers it: a rise, then a fall.
In the gas phase, with no solvent, the order is clean: NH3 < CH3NH2 < (CH3)2NH < (CH3)3N. Each alkyl group pushes a little electron density through its σ bond toward the nitrogen, an effect called induction (Factors affecting acidity). That density helps the nitrogen carry the positive charge of the ammonium ion, so each methyl added makes a stronger base.
Water adds a second effect. Water forms hydrogen bonds to the N–H hydrogens of an ammonium ion, and those bonds stabilize it. Stabilization by the surrounding solvent is called solvation. Every methyl that replaces an N–H hydrogen removes one of those hydrogen bonds. Solvation therefore favors the less substituted ions while induction favors the more substituted ones, and in water the two effects roughly cancel.
Resonance donation: the big drop in basicity
Cyclohexylamine and aniline both have an NH2 group on a six-carbon ring. In cyclohexylamine the ring is saturated, with no double bonds; in aniline it is a benzene ring. Cyclohexylamine has a pKaH of 10.7 and aniline has a pKaH of 4.6, so aniline is about a million times less basic.
Aniline’s nitrogen sits right next to the ring’s π system, so its lone pair is delocalized into the ring: shared with the ring by resonance instead of held on nitrogen alone. Curved arrows move the pair into the C–N bond and push ring electrons onto the two ortho carbons and the para carbon. The ortho carbons are the ring carbons next to the one that carries the NH2, and the para carbon is the one opposite it.
A proton on nitrogen would lock the lone pair into an N–H bond, and the three structures with charge in the ring could no longer be drawn. Aniline would lose that resonance stabilization. Paying that cost makes protonation much less favorable, so the equilibrium lies far toward neutral aniline.
An amide is the extreme case. In acetamide, CH3CONH2, the nitrogen lone pair is delocalized into the neighboring C=O, and the second structure puts the negative charge on oxygen (Esters & amides). The conjugate acid of an amide has a pKa of about 0, about ten powers of ten below an alkylamine’s. An amide is essentially non-basic.
The same delocalization explains more than basicity. It makes the amide nitrogen flat rather than pyramidal, and it makes rotation about the C–N bond slow. It also leaves the carbonyl carbon less electron-poor, so an amide is the least reactive acid derivative. Amide nitrogen is a very poor leaving group too, but for a different reason: it would have to leave as a strongly basic anion. Peptide bonds, which hold proteins together, are amides, and these effects make them very stable.
Strong acid can still protonate an amide, and the proton goes on the carbonyl oxygen, not on nitrogen. With the proton on oxygen, the nitrogen pair still feeds the C=O, so the positive charge is shared by oxygen and nitrogen. With the proton on nitrogen, the pair is used up in the new N–H bond, and the cation can be drawn only one way.
So the amide pKaH of about 0 belongs to the ion with the proton on oxygen. The ion with the proton on nitrogen has a pKa of about −7. The amide nitrogen itself is therefore far less basic than the quoted value of about 0 suggests.
Pyridine and pyrrole: two aromatic nitrogen rings
Pyridine and pyrrole are both aromatic rings that contain one nitrogen (Aromaticity). Pyridine is a six-membered ring, like benzene with one CH replaced by N. Pyrrole is a five-membered ring whose nitrogen carries an H. Their pKaH values are 5.2 and about −4, nine powers of ten apart, and the whole difference is where the nitrogen lone pair sits.
Pyridine’s lone pair sits in an sp2 orbital in the plane of the ring, pointing outward. It is not part of the aromatic π system, so a proton can take it without disturbing the aromaticity. That is why pyridine is a base at all.
Pyridine is still a weaker base than an alkylamine, because an sp2 orbital holds its electrons more tightly than an sp3 one. An sp2 orbital has more s-character: it is one part s to two parts p, against one part s to three parts p for sp3. An s orbital keeps its electrons closer to the nucleus, and electrons held closer are less available to a proton. This is the orbital factor from Factors affecting acidity, now acting on a base.
The same factor runs through a whole series of nitrogens. An sp3 amine such as methylamine has a pKaH of 10.6. An sp2 nitrogen, as in pyridine (5.2) or an imine (the nitrogen of a C=N), is less basic. An sp nitrogen, as in a nitrile (C≡N), is barely basic at all, with a pKaH of about −10.
A strained ring can shift the s-character as well. Aziridine is a three-membered ring of two carbons and an N–H nitrogen. To close a ring with angles of about 60°, the ring bonds use orbitals with extra p-character, which leaves extra s-character for the lone pair. Aziridine (pKaH 8.0) is therefore a weaker base than an open-chain secondary amine such as dimethylamine (10.7).
Pyrrole is different in kind. Its nitrogen lone pair sits in a p orbital and supplies two of the six π electrons that make the ring aromatic. A proton on that nitrogen would pull the pair out of the ring and destroy the aromaticity, at a cost of about 20 kcal/mol, so pyrrole’s nitrogen essentially never takes a proton. In very strong acid the proton goes onto the ring carbon next to nitrogen instead, and the pKaH of about −4 describes that carbon-protonated ion.
When resonance makes a nitrogen more basic
Resonance can also raise basicity. Acetamidine, CH3C(=NH)NH2, has a pKaH of 12.4, higher than any simple alkylamine. It is an amidine: one carbon carries both a C=N and an NH2. The proton goes on the sp2 nitrogen of the C=N. In the cation that forms, the NH2 lone pair can push into the C–N bond, so the positive charge is shared equally by the two nitrogens.
Guanidine, (H2N)2C=NH, has a third nitrogen on the same carbon, and its pKaH is about 13.6. Its cation, guanidinium, shares the charge over all three nitrogens, which makes guanidine an unusually strong neutral base. Arginine, one of the amino acids that make up proteins, carries a guanidine group on its side chain, and that group stays protonated at every pH found in a cell.
Rank by basicity: 4-nitroaniline, aniline, 4-methoxyaniline and cyclohexylamine. The 4 means the group sits on the para carbon, opposite the NH2.
Step 1. Cyclohexylamine has no resonance at all, so it is the most basic (10.7). The three anilines all share their lone pair with the ring, so they sit several powers of ten lower.
Step 2. Among the anilines, the para group fine-tunes the value. A methoxy group donates electron density into the ring and pushes some of it back toward nitrogen, so 4-methoxyaniline (5.3) is a little more basic than aniline (4.6). A nitro group withdraws strongly and draws the lone pair further into the ring, so 4-nitroaniline (1.0) is the least basic.
Answer. Cyclohexylamine > 4-methoxyaniline > aniline > 4-nitroaniline. Resonance sets the tiers and substituents order the compounds within a tier, the same pattern Carboxylic acids showed for substituted benzoic acids.
Procaine, a local anesthetic, has two nitrogens. One is an NH2 on a benzene ring whose para carbon carries an ester, C(=O)O. The other is a diethylamino nitrogen, N(CH2CH3)2, at the end of a two-carbon chain on the ester oxygen. Add one equivalent of HCl. Where does the proton go?
Step 1 — list the candidates. There are two nitrogens, so the question is which one wins.
Step 2 — ask whether each lone pair is delocalized. The diethylamino nitrogen is bonded to three sp3 carbons and nothing else, so nothing competes for its lone pair. The ring nitrogen shares its pair with the ring, and the ring passes it on to the ester’s C=O, so that pair is largely spent.
Step 3 — put numbers on it. The diethylamino nitrogen has a pKaH of about 9 and the ring nitrogen one of about 2.5. They differ by more than six powers of ten, so the choice is clear.
Answer. The proton goes on the diethylamino nitrogen and stays there at the pH of the body. Procaine hydrochloride is the salt of that nitrogen. The same check works for most basic drugs: find the plain alkylamine nitrogen, because that is the one the salt is made from.
The question to ask
To rank nitrogen compounds by basicity, ask first whether the lone pair is delocalized, and if so, into what. The table collects the main cases on this page, from most to least basic. Hybridization and induction then settle the close calls.
| Compound | pKaH | Lone pair |
|---|---|---|
| alkylamine | 10–11 | fully available |
| ammonia | 9.2 | available, no donors |
| pyridine | 5.2 | available but sp² |
| aniline | 4.6 | into the ring |
| amide | ~0 | into the carbonyl |
| pyrrole | ~−4 | part of the aromatic sextet |
What carries forward
How available the lone pair is also decides how an amine reacts. A free pair makes a good nucleophile and a delocalized one does not. Amine reactions builds on that and uses the difference on purpose: turning an amine into an amide makes its nitrogen far less reactive. The pair also ties back to Ortho/meta/para directing effects: an NH2 group strongly activates a benzene ring and directs to ortho and para through the same donation that makes aniline a million times weaker as a base.