Appendix B — pKa Reference Table
The single most important reference in this book. Acid-base reasoning underlies mechanism (Ch 3), substitution/elimination (Chs 10-12), carbonyl chemistry (Chs 25-29), and biochemistry (Chs 33-34). Keep this open.
pKa convention — pKa = −log₁₀ Ka. Lower pKa = stronger acid. The pKa of an acid HA tells you how readily it gives up H⁺; the pKaH of a base B tells you the pKa of its conjugate acid BH⁺.
The 16-point rule — water's pKa is ~15.7. Any acid with pKa < 15.7 is fully deprotonated by hydroxide; any with pKa > 15.7 is not. Plan synthetic deprotonations from this.
Predicting acidity — the ARIO framework (Ch 3 recap)
When comparing two acids, work through these four factors in order:
- A — Atom. The atom carrying the negative charge after deprotonation. Across a row, more electronegative → more stable anion → stronger acid (HF > H₂O > NH₃ > CH₄). Down a column, larger atom → more diffuse charge → more stable anion → stronger acid (HI > HBr > HCl > HF for protic acid; RSH > ROH).
- R — Resonance. Delocalization stabilizes the conjugate base. Carboxylic acid (pKa 4-5) vs alcohol (pKa 16-18) — the carboxylate has two equivalent resonance structures, the alkoxide does not. Phenol (10) vs cyclohexanol (17) — same logic.
- I — Induction. Electron-withdrawing groups stabilize negative charge through σ bonds. Trichloroacetic acid (0.7) vs acetic acid (4.76) — three Cl atoms pull electron density away. The effect falls off rapidly with distance (α >> β >> γ).
- O — Orbital. The hybridization of the atom holding the charge. More s character → electrons held closer to nucleus → more stable anion → stronger acid. Hence terminal alkyne (sp, pKa 25) >> alkene (sp², 44) >> alkane (sp³, 50).
Worked micro-example — why is the α-C-H of nitromethane (pKa 10) more acidic than the α-C-H of acetaldehyde (pKa 17)? Both have resonance stabilization of the anion. But nitro has two electronegative oxygens (more inductive pull) plus better resonance (both O share the negative charge), so the carbanion is much more stabilized.
Strong acids (pKa < 0 — fully dissociated in water)
| Acid | pKa |
|---|---|
| FSO₃H (fluorosulfonic) | −15 |
| CF₃SO₃H (triflic, TfOH) | −14 |
| HI | −10 |
| HClO₄ | −10 |
| HBr | −9 |
| HCl | −7 |
| H₂SO₄ (1st ionization) | −3 |
| HSO₃CF₃·BH₃ super acids | ≪ −15 |
| H₃O⁺ (hydronium) | −1.7 |
| HNO₃ | −1.4 |
| p-TsOH (tosic) | −2.8 |
| CH₃SO₃H (mesylic) | −2 |
| TFA (CF₃COOH) | 0.2 |
| Picric acid (2,4,6-trinitrophenol) | 0.4 |
| Trichloroacetic acid | 0.7 |
Super acids (TfOH, HFSO₃) protonate ethers, ketones, and even some alkenes. TFA, TsOH, MsOH are the workhorse acids of synthesis — strong enough to catalyze but easy to handle.
C-H acids (carbon as the acidic site)
The pKa range here spans 50 orders of magnitude. Substituents determine everything.
Plain alkyl, alkenyl, alkynyl C-H
| Acid | pKa | Notes |
|---|---|---|
| CH₄ | ~50 | sp³ |
| Ethane, propane | 50-51 | sp³ |
| Cyclopropane C-H | 46 | small ring strain |
| CH₂=CH₂ (vinyl) | 44 | sp² |
| Benzene C-H | 43 | sp² aromatic |
| HC≡CH | 25 | sp |
| RC≡CH (terminal alkyne) | 25 | classic; NaNH₂ deprotonates |
Allylic and benzylic
| Acid | pKa |
|---|---|
| Propene allylic CH₃ | 43 |
| Toluene benzylic CH₃ | 43 |
| Diphenylmethane (Ph₂CH₂) | 32 |
| Triphenylmethane (Ph₃CH) | 31.5 |
| Cyclopentadiene | 16 |
| Indene | 20 |
| Fluorene | 22.6 |
Cyclopentadiene's pKa = 16 because the conjugate base is aromatic (6 π e⁻ in 5-membered ring). This is a powerful illustration of resonance stabilization (Ch 20).
α to a single carbonyl
| Acid | pKa | Notes |
|---|---|---|
| α-C-H of aldehyde (RCH₂CHO) | 17 | |
| α-C-H of ketone (RCH₂COR) | 19-21 | acetone 20 |
| α-C-H of ester (RCH₂CO₂R) | 25 | |
| α-C-H of amide (RCH₂CONR₂) | 26-30 | |
| α-C-H of acid (RCH₂COOH, neutral) | 25 | (COOH itself is pKa 4) |
| α-C-H of acyl chloride | ~15 | acidic but acid chloride is too reactive |
α to a nitrile, nitro, or sulfone
| Acid | pKa |
|---|---|
| α-C-H of nitrile (CH₃CN) | 25 |
| α-C-H of nitro (CH₃NO₂) | 10 |
| α-C-H of sulfone (CH₃SO₂R) | 25 |
| α-C-H of sulfoxide | 33 |
| α-C-H of phosphonate ((EtO)₂P(O)CH₃) | 28 |
| α-C-H of nitrile + ester (NC-CH₂-CO₂R) | 9 |
| α-C-H of two nitros (CH₂(NO₂)₂) | 4 |
Doubly activated (β-dicarbonyl-style)
These are pre-formed enolates at biological pH.
| Acid | pKa |
|---|---|
| Pentane-2,4-dione (acetylacetone, acac) | 9 |
| Malonic acid ester (CH₂(CO₂Et)₂, diethyl malonate) | 13 |
| β-ketoester (CH₃COCH₂CO₂Et, ethyl acetoacetate) | 11 |
| Meldrum's acid | 4.97 |
| Cyclohexane-1,3-dione | 5.3 |
| Dimedone | 5.2 |
| Barbituric acid | 4.0 |
| NC-CH₂-CN (malononitrile) | 11 |
| (NC)₃CH | −5 |
N-H acids
Amines, amides, sulfonamides
| Acid | pKa |
|---|---|
| NH₃ | 38 |
| RNH₂ (alkyl amine) | ~35-36 |
| (i-Pr)₂NH (diisopropylamine; gives LDA) | 36 |
| 2,2,6,6-tetramethylpiperidine (TMP) | 37 |
| HMDS (hexamethyldisilazane, (Me₃Si)₂NH) | 26 |
| Aniline (PhNH₂) | 30 |
| 1° amide N-H (RCONH₂) | 17 |
| 2° amide N-H (RCONHR') | 17-18 |
| Imide N-H (succinimide) | 9.5 |
| Imide N-H (phthalimide) | 8.3 |
| Sulfonamide N-H (RSO₂NH₂) | 10 |
| Sulfonamide N-H (RSO₂NHR') | 11 |
| Carbamate N-H (RNHCO₂R') | 17-25 |
| Pyrrole N-H | 17 |
| Indole N-H | 17 |
| Imidazole N-H | 14.4 |
| Tetrazole N-H | 4.9 |
O-H acids
Water, alcohols, alkoxides
| Acid | pKa |
|---|---|
| H₂O | 15.7 |
| MeOH | 15.5 |
| EtOH | 16 |
| i-PrOH | 17 |
| t-BuOH | 18 |
| HFIP ((CF₃)₂CHOH, hexafluoroisopropanol) | 9.3 |
| TFE (CF₃CH₂OH, trifluoroethanol) | 12.5 |
| HOCH₂CH₂OH (ethylene glycol) | 14.2 |
The fluorinated alcohols are unusually acidic — and unusually polar without being nucleophilic. HFIP is the solvent of choice for stabilizing cations.
Phenols (substituent effects, Hammett-relevant)
| Phenol | pKa |
|---|---|
| Phenol | 10.0 |
| p-Methylphenol (p-cresol) | 10.3 |
| p-Methoxyphenol | 10.2 |
| p-Cl-phenol | 9.4 |
| p-Br-phenol | 9.3 |
| p-CN-phenol | 8.0 |
| p-NO₂-phenol | 7.2 |
| m-NO₂-phenol | 8.4 |
| 2,4-dinitrophenol | 4.0 |
| 2,4,6-trinitrophenol (picric) | 0.4 |
| 2-naphthol | 9.5 |
| 1-naphthol | 9.3 |
| Catechol (1,2-diOH) | 9.5, 13 |
p-NO₂ stabilizes the phenoxide by resonance (the oxygen and nitro share the negative charge); m-NO₂ only by induction, hence weaker effect. This is the prototype Hammett system (Ch 21, Ch 24).
Carboxylic acids — substituent effects
| Acid | pKa |
|---|---|
| HCOOH (formic) | 3.77 |
| CH₃COOH (acetic) | 4.76 |
| CH₃CH₂COOH (propionic) | 4.87 |
| (CH₃)₃CCOOH (pivalic) | 5.0 |
| ClCH₂COOH | 2.85 |
| Cl₂CHCOOH | 1.35 |
| Cl₃CCOOH | 0.65 |
| FCH₂COOH | 2.59 |
| BrCH₂COOH | 2.90 |
| NCCH₂COOH | 2.45 |
| HOCH₂COOH (glycolic) | 3.83 |
| CH₃OCH₂COOH | 3.53 |
| HOOC-COOH (oxalic) | 1.27, 4.27 |
| HOOC-CH₂-COOH (malonic) | 2.85, 5.7 |
| HOOC-(CH₂)₂-COOH (succinic) | 4.21, 5.64 |
Substituted benzoic acids (Hammett dataset)
| Acid | pKa | σₚ |
|---|---|---|
| Benzoic acid | 4.20 | 0 (reference) |
| p-OCH₃-PhCOOH | 4.47 | −0.27 |
| p-CH₃-PhCOOH | 4.37 | −0.17 |
| p-F-PhCOOH | 4.14 | +0.06 |
| p-Cl-PhCOOH | 3.98 | +0.23 |
| p-Br-PhCOOH | 4.00 | +0.23 |
| p-CF₃-PhCOOH | 3.66 | +0.54 |
| p-CN-PhCOOH | 3.55 | +0.66 |
| p-NO₂-PhCOOH | 3.41 | +0.78 |
| m-OCH₃-PhCOOH | 4.09 | +0.12 |
| m-NO₂-PhCOOH | 3.45 | +0.71 |
These pKa values, plotted against σ values, give Hammett ρ = 1.00 by definition (Ch 21, Ch 24 for free-energy relationships).
Other O-H
| Acid | pKa |
|---|---|
| Hydroperoxide R-O-OH | 11-12 |
| Peracid R-C(=O)-OOH | 8.2 |
| Oxime R₂C=N-OH | 11-12 |
| Hydroxamic acid RC(=O)NHOH | 9 |
| Sulfonic acid R-SO₃H | −2 to 1 |
| Sulfinic acid R-SO₂H | 2-3 |
| Phosphonic acid RPO(OH)₂ | 1-3, 6-8 |
S-H, Se-H acids
| Acid | pKa |
|---|---|
| H₂S | 7.0 |
| RSH (alkyl thiol) | 10-11 |
| PhSH (thiophenol) | 6.6 |
| Cysteine side chain | 8.3 |
| H₂Se | 3.9 |
| RSeH | ~5 |
Thiols (pKa 10) are far more acidic than alcohols (pKa 16), because S is larger and more polarizable than O. They are also better nucleophiles (Ch 33 — cysteine in active sites).
H-X (hydrohalic, hydrogen)
| Acid | pKa |
|---|---|
| HF | 3.2 |
| HCl | −7 |
| HBr | −9 |
| HI | −10 |
| H₂ | 35 |
pKaH of common protonated functional groups (basicity reference)
To compare basicities, look up the pKa of the conjugate acid (pKaH). Higher pKaH = stronger base.
| Base B | Conjugate acid BH⁺ | pKaH |
|---|---|---|
| Cl⁻ | HCl | −7 |
| ROR (ether) | R-O(H)R⁺ | −3.5 |
| RSR (sulfide) | RS(H)R⁺ | −5 |
| R-CHO | R-CH=OH⁺ | −7 |
| R-CO-R' (ketone) | R-C(OH)⁺-R' | −7 |
| R-CO-OR' (ester) | protonated ester | −6.5 |
| R-CO-OH (acid) | R-C(OH)₂⁺ | −6 |
| R-CO-NR'₂ (amide on O) | iminol-type | −0.5 |
| ROH (alcohol) | ROH₂⁺ | −2 |
| H₂O | H₃O⁺ | −1.7 |
| HSO₄⁻ | H₂SO₄ | −3 |
| HF | H₂F⁺ | −10 |
| RC≡N (nitrile) | RC≡NH⁺ | −10 |
| ArNH₂ (aniline) | ArNH₃⁺ | 4.6 |
| Pyridine | pyridinium | 5.2 |
| Imidazole | imidazolium | 7.0 |
| Histidine side chain | imidazolium | 6.0 |
| RNH₂ (1° amine) | RNH₃⁺ | 10-11 |
| R₂NH (2° amine) | R₂NH₂⁺ | 10-11 |
| R₃N (3° amine) | R₃NH⁺ | 9-11 |
| Et₃N (triethylamine) | Et₃NH⁺ | 10.75 |
| DBU (1,8-diazabicycloundecene) | DBU-H⁺ | 12 |
| DBN | DBN-H⁺ | 13.5 |
| Proton sponge (1,8-bis(NMe₂)naphthalene) | protonated | 12.3 |
| TMG (tetramethylguanidine) | guanidinium | 13.6 |
| Guanidine | guanidinium | 13.6 |
| Arginine side chain (guanidinium) | — | 12.5 |
| t-BuO⁻ | t-BuOH | 18 |
| HO⁻ | H₂O | 15.7 |
| MeO⁻ | MeOH | 15.5 |
| NH₂⁻ | NH₃ | 38 |
| i-Pr₂N⁻ (LDA) | i-Pr₂NH | 36 |
| n-Bu⁻ (n-BuLi as base) | n-BuH | 50 |
| t-Bu⁻ (t-BuLi) | t-BuH | 53 |
| Ph⁻ (PhLi) | benzene | 43 |
| Me⁻ (MeLi) | CH₄ | 50 |
| H⁻ (NaH) | H₂ | 35 |
| HMDS⁻ (LiHMDS/NaHMDS/KHMDS) | HMDS | 26 |
Choosing a base — practical guide
| Job | Base of choice | Why |
|---|---|---|
| Deprotonate R-COOH | NaHCO₃, K₂CO₃, NaOH | pKa 4-5, easy |
| Deprotonate phenol | NaOH, K₂CO₃ | pKa 10 |
| Deprotonate β-dicarbonyl (pKa 9-13) | NaOEt, NaOMe, NaH | enolate cleanly formed |
| Deprotonate simple ester (pKa 25) | LDA | needs strong, non-nucleophilic |
| Deprotonate simple ketone (pKa 20) | LDA at low T (kinetic) or NaOR (thermodynamic) | controls regiochemistry (Ch 27) |
| Deprotonate terminal alkyne (pKa 25) | NaNH₂ in NH₃(l) or n-BuLi | classic |
| Deprotonate alcohol (pKa 16-18) | NaH, Na⁰, K⁰ | irreversible, gas off |
| Deprotonate amide N-H (pKa 17) | NaH | clean |
| Deprotonate aryl/vinyl C-H | n-BuLi, t-BuLi, LDA + TMEDA | directed metalation |
| Deprotonate alkane sp³ C-H (pKa 50) | not feasible with standard bases | use radical instead |
The "1 pKa unit" rule — for a useful equilibrium, you want pKa(base's conjugate acid) − pKa(acid being deprotonated) ≥ 1, ideally ≥ 4. So to deprotonate ester (pKa 25) you want a base with pKaH ≥ 29 — LDA at 36 works.
Why LDA over NaH — LDA is bulky and non-nucleophilic. NaH would also deprotonate the α-C-H thermodynamically, but Na⁺ as counterion is loose and the enolate can attack the H₂ that's bubbling off or do other side reactions. LDA gives kinetic enolate (Ch 27).
Why n-BuLi over t-BuLi — n-BuLi is cheap, stable in hexanes, and pKaH ~50. t-BuLi is more reactive (and pyrophoric) but useful for halogen-lithium exchange at low T.
KOtBu vs NaOEt — t-BuOK is bulky and gives Hofmann (less-substituted) alkene in E2 (Ch 12). NaOEt is small, gives Zaitsev.
Henderson-Hasselbalch — quick math
For a weak acid HA ⇌ A⁻ + H⁺:
pH = pKa + log([A⁻] / [HA])
| pH − pKa | [A⁻] / [HA] | % deprotonated |
|---|---|---|
| −2 | 1:100 | 1% |
| −1 | 1:10 | 9% |
| 0 | 1:1 | 50% |
| +1 | 10:1 | 91% |
| +2 | 100:1 | 99% |
Implication for biochem (Ch 33) — at physiological pH 7.4, an acid with pKa 4.7 (carboxylic acid) is > 99.5% deprotonated; an amine (pKaH 10) is > 99.5% protonated. This is why proteins carry net charge.
Buffer table — common biological buffers (Ch 33-34)
| Buffer | Useful pKa range | pKa at 25°C |
|---|---|---|
| Glycine (carboxyl) | 2.0-3.5 | 2.34 |
| Citric acid | 3.0-6.0 | 3.13, 4.76, 6.40 |
| Acetate | 3.8-5.8 | 4.76 |
| MES | 5.5-6.7 | 6.10 |
| Phosphate (pKa₂) | 6.2-8.2 | 7.20 |
| HEPES | 6.8-8.2 | 7.55 |
| Tris | 7.0-9.0 | 8.07 |
| Bicarbonate (pKa₁) | 5.5-7.0 | 6.35 |
| Glycine (amino) | 8.6-10.6 | 9.60 |
| CAPS | 9.7-11.1 | 10.40 |
Amino acid side-chain pKa (Ch 33 cross-reference)
| Amino acid | Group | Side-chain pKa | Charge at pH 7.4 |
|---|---|---|---|
| Asp (D) | β-COOH | 3.65 | −1 |
| Glu (E) | γ-COOH | 4.25 | −1 |
| His (H) | imidazolium | 6.00 | mostly 0 (10% +) |
| Cys (C) | -SH | 8.33 | mostly 0 |
| Tyr (Y) | phenol | 10.07 | 0 |
| Lys (K) | ε-NH₃⁺ | 10.53 | +1 |
| Arg (R) | guanidinium | 12.48 | +1 |
| Ser, Thr | -OH | ~16 | 0 |
| α-COOH (backbone, free amino acid) | — | ~2.0 | −1 |
| α-NH₃⁺ (backbone, free amino acid) | — | ~9.5 | +1 |
In a folded protein, microenvironment can shift these by 2-4 pKa units. A buried Asp can have pKa = 7. This is how enzyme active sites work (Ch 34).
Print this, keep it at your desk. Read down it once a week until the numbers feel obvious. Every mechanism question you face will reduce, eventually, to a pKa comparison.