Organic Chemistry · Amines and Heterocycles
Basicity of Amines
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Amines are weak Brønsted–Lowry bases: the nitrogen lone pair accepts a proton from an acid, converting the amine into its Conjugate acid Product formed when a base gains a proton (RNH3+ from RNH2) Full entry →, an ammonium ion. The equilibrium is written for the general amine RNH2 as:
RNH2 + H2O ⇌ RNH3+ + OH-
Basicity is measured quantitatively by the acid dissociation constant of the conjugate acid, RNH3+, reported as pKa — chemists call this value the pKa of the conjugate acid, often written pKaH to avoid confusion. The key rule: the larger the pKaH, the stronger the base. Alkylamines have pKaH values near 10–11 (comparable to ammonia, 9.26), which makes them far stronger bases than anilines ( ≈ 4.6) or pyridines ( ≈ 5.3). Three factors control amine basicity: inductive effects (alkyl groups donate electron density), Solvation Stabilization of ions by surrounding solvent molecules Full entry →/hydrogen bonding (which flips the expected order in water), and Hybridization Mixing of atomic orbitals (sp3, sp2, sp) Full entry → (more s-character makes the lone pair less available).
Why this matters
- Drug ionization: Whether a drug exists as a neutral amine or a charged ammonium salt at body pH controls absorption, distribution, and receptor binding (Topic 5).
- Acid–base extraction: Amines are separated from neutral impurities by protonating them into water-soluble salts with acid, then regenerating the free amine with base — a routine lab and industrial technique.
- Biochemistry: The basic side chains of histidine and lysine sit in enzyme active sites; their protonation state at physiological pH determines catalysis.
- Alkaloid chemistry: Caffeine, nicotine, morphine, and quinine are amines whose isolation exploits pH-dependent protonation.
- Exams: Ranking basicity, predicting the effect of substituents, and identifying the dominant species at a given pH are classic test problems.
The college version
Core Concepts
The pKaH scale for bases
For the conjugate acid of a base B, the equilibrium is:
BH+ ⇌ B + H+ Ka = [B][H+][BH+]
and pKaH = -log10 Ka. A weak acid (large pKa) means the equilibrium lies far to the left — the protonated form BH+ is strongly favored, which is exactly what a strong base does. So for bases, larger pKaH = stronger base. Representative aqueous values: ammonia 9.26, methylamine 10.66, dimethylamine 10.73, trimethylamine 9.81, ethylamine 10.75, cyclohexylamine 10.64, aniline 4.60, pyridine 5.25, piperidine 11.2.
Inductive effects: alkyl groups push electron density
Alkyl groups are electron-donating relative to hydrogen. They push electron density toward nitrogen, stabilizing the positive charge on the ammonium conjugate acid:
CH3NH3+ is more stable than NH4+ ⇒ CH3NH2 (10.66) > NH3 (9.26)
Conversely, electron-withdrawing substituents (Cl, NO2, CN, OH, aryl) destabilize the positive charge and lower basicity. For example, 2-chloroethylamine is a much weaker base than ethylamine, and aniline (pKaH 4.60) is far weaker than cyclohexylamine (10.64) — a preview of Topic 4.
Solvation: why tertiary amines are NOT the strongest in water
If only induction mattered, more alkyl groups would always mean a stronger base, and the aqueous order would be 3°> 2°> 1°> NH3. Measured values in water are 2°> 1°> 3°> NH3 for the methylamines: dimethylamine 10.73 > methylamine 10.66 > trimethylamine 9.81 > ammonia 9.26. The reason is solvation: the conjugate acids R2NH2+ and RNH3+ have N–H bonds that donate hydrogen bonds to water, stabilizing the cation. Trimethylammonium (CH3)3NH+ has only one N–H and is more hindered, so its cation is less stabilized by solvent. In the gas phase (no solvent), the purely inductive order 3°> 2°> 1°> NH3 is observed. The medium matters — a classic exam trap.
Hybridization: sp³ beats sp² beats sp
The lone pair's availability depends on the orbital it occupies. An sp3 orbital (alkylamine) holds the lone pair loosely; an sp2 orbital (pyridine, 5.25) holds it tighter because more s-character means more electronegative; an sp orbital (nitriles) holds it tightest. Hence alkylamines ( ≈ 10–11) > pyridine (5.25) > nitrile nitrogen. A related special case: amides are not basic at all — the lone pair is delocalized into the adjacent carbonyl, and the nitrogen is planar.
Strong organic bases
Guanidine (pKaH ≈ 13.6) and amidines ( ≈ 12.5) are exceptionally strong bases because their conjugate acids are stabilized by resonance: the positive charge is delocalized over several nitrogen atoms. These are used when a strong, non-nucleophilic base is needed.
Common Confusions
| Do Not Confuse | With | Difference |
|---|---|---|
| "pKa of the amine" | pKaH (of its conjugate acid) | Tables quote the conjugate acid's pKa; for a base this is pKaH — larger means stronger base |
| Stronger base = smaller pKa | Larger pKaH | A stronger base has a weaker conjugate acid, hence a larger pKaH |
| Tertiary amines are always strongest | In water, 2°> 1°> 3° | Solvation of BH+ flips the gas-phase order; trimethylamine (9.81) < dimethylamine (10.73) in water |
| Amines are strong bases | Weak bases | They protonate only partially in water; pKaH ≈ 10–11 is "weak" on the acid–base scale |
| More alkyl groups = always more basic | Inductive vs. solvation vs. steric trade-offs | Each added alkyl group helps inductively but may hurt solvation and add steric bulk |
| Basicity and nucleophilicity are the same | Related but distinct | Basicity = proton affinity (thermodynamic); nucleophilicity = rate of attack on electrophilic carbon (kinetic) |
Eli explains
The same idea, in plain words
Explain it like I’m 10
An amine is like a catcher's mitt with an extra pair of hands (a lone pair) that grabs protons — that's what "being a base" means. How tightly it grabs depends on its friends: alkyl groups are generous teammates that push electron power toward nitrogen, so more alkyl friends usually means a stronger grip, but in water the charged "glove" also needs to hold hands with water molecules, which changes the ranking. If the lone pair is busy sharing with an aromatic ring (aniline) or locked in a tighter orbital (pyridine), the grip weakens. Chemists measure the grip with a number called pKaH: bigger number, stronger base.
Worked example
Example 1: Ranking basicity from pKaH values
Rank these bases from strongest to weakest, using the given pKaH values: piperidine 11.2, methylamine 10.66, ammonia 9.26, pyridine 5.25, aniline 4.60.
Rule: larger pKaH = stronger base.
piperidine (11.2) > methylamine (10.66) > ammonia (9.26) > pyridine (5.25) > aniline (4.60)
Why: piperidine and methylamine are alkylamines with sp3 N and electron-donating alkyl groups; ammonia lacks the alkyl donation; pyridine's lone pair sits in an sp2 orbital; aniline's lone pair is delocalized into the aromatic ring.
Example 2: Converting Ka to pKaH — show the formula first
The acid dissociation constant of methylammonium ion, CH3NH3+, is Ka = 2.3 × 10-11. Find pKaH of methylamine.
Formula first:
pKaH = -log10 Ka
Substitute and compute:
pKaH = -log10(2.3 × 10-11) = 11 - log10(2.3) = 11 - 0.36 = 10.64
Answer: pKaH ≈ 10.6. Because this exceeds ammonia's 9.26, methylamine is the stronger base — consistent with the inductive donation of the methyl group.
Example 3: Which species dominates at pH 7 — an applied preview
At physiological pH (7.0), is methylamine mostly protonated or mostly free base? Use the Henderson–Hasselbalch form for bases (full derivation in Topic 5):
pH = pKaH + log10[B][BH+]
Substitute pH = 7.0, pKaH = 10.66:
7.0 = 10.66 + log10[B][BH+] ⇒ log10[B][BH+] = -3.66
[B][BH+] = 10-3.66 ≈ 2.2 × 10-4
Answer: [BH+] ≈ 4600 × [B] — methylamine is essentially fully protonated (>99.9%) at pH 7. Aliphatic amines with pKaH ≈ 10–11 are protonated at physiological pH, which is why their salts are water-soluble and why pH control matters for drug absorption.
Key takeaways
- Basicity of an amine is quoted as pKaH = pKa of its conjugate acid; larger pKaH = stronger base.
- Key aqueous values: NH3 9.26; methylamine 10.66; dimethylamine 10.73; trimethylamine 9.81; aniline 4.60; pyridine 5.25; piperidine 11.2.
- Alkyl groups donate electron density → stabilize BH+ → increase basicity (methylamine > ammonia).
- Electron-withdrawing groups (Cl, NO2, CN, aryl) decrease basicity.
- In water the methylamine order is 2°> 1°> 3°> NH3 because of solvation of the ammonium cation; in the gas phase it is 3°> 2°> 1°> NH3.
- Hybridization order of basicity: sp3 > sp2 > sp; amides are nonbasic (lone pair delocalized into C=O).
- Guanidine ( ≈ 13.6) is a very strong base because its conjugate acid is resonance-stabilized.
Check yourself
6 review questions from the chapter. Try each one, then open the answer.
Define pKaH and state the direction: does a larger value mean a stronger or weaker base?
Show answer
pKaH is the pKa of the conjugate acid BH+. A larger value means a stronger base (weaker conjugate acid).
Why is methylamine (pKaH 10.66) a stronger base than ammonia (9.26)?
Show answer
The methyl group donates electron density inductively, stabilizing the positive CH3NH3+ ion relative to NH4+.
In water, why is dimethylamine a stronger base than trimethylamine, even though trimethylamine has more alkyl groups?
Show answer
Solvation: CH3NH3+ and (CH3)2NH2+ have multiple N–H bonds that hydrogen-bond to water, stabilizing the cation. (CH3)3NH+ has only one N–H and is more hindered, so it is less stabilized.
Which is the stronger base: pyridine (5.25) or aniline (4.60)? Give one structural reason.
Show answer
Pyridine (5.25) is stronger. Its lone pair is in an sp2 orbital but is not delocalized into the ring; aniline's lone pair is delocalized (resonance) into the aromatic ring, stabilizing the free base and weakening it.
Why is an amide nitrogen essentially nonbasic?
Show answer
The amide lone pair is delocalized into the adjacent carbonyl π system, so it is not available to accept a proton; amide nitrogen is also planar (sp2-like).
A base has Ka = 1.0 × 10-11 for its conjugate acid. What is its pKaH, and where does it rank versus ammonia (9.26)?
Show answer
pKaH = -log10(1.0 × 10-11) = 11.0. Since 11.0 > 9.26, this base is stronger than ammonia (comparable to piperidine).
Study tools & related lessonsKey vocabulary · Related
Key vocabulary
- Brønsted–Lowry base
- Species that accepts a proton (H+)
- Conjugate acid
- Product formed when a base gains a proton (RNH3+ from RNH2)
- pKaH
- pKa of the conjugate acid of a base; -log10 Ka
- Inductive effect
- Electron donation/withdrawal through σ bonds
- Solvation
- Stabilization of ions by surrounding solvent molecules
- Electron-withdrawing group (EWG)
- Substituent that pulls electron density (Cl, NO2, CN)
- Hybridization
- Mixing of atomic orbitals (sp3, sp2, sp)
- Resonance stabilization
- Delocalization of charge over multiple atoms
Sources & references
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