Fundamentals · 8 min read

Acids, bases and pKa: predicting which way a step goes

Almost every mechanism contains a proton transfer. Knowing which proton is acidic, and which base is strong enough to remove it, tells you what happens first and what the reagents are for.

The one rule: a reaction goes toward the weaker acid

An acid–base equilibrium favours the side with the weaker acid and weaker base. A lower pKa means a stronger acid, and each pKa unit is a factor of ten in the equilibrium constant. If you compare the pKa of the acid you have (HA) with the pKa of the conjugate acid of the base you add (BH⁺), the difference tells you how far the reaction goes.

If the base's conjugate acid has a higher pKa than the acid you are deprotonating, the proton transfer is favourable.
If the two pKa values are within about 1–2 units, you get a mixture, which can still be useful if the next step is irreversible.
A difference of 10 or more means the transfer is essentially complete in one direction.

Approximate pKa values worth remembering

You do not need exact numbers, only the ordering and the rough gaps. These values are approximate and depend on solvent.

Group	Example	Approx. pKa
Protonated ketone or alcohol	R₂C=OH⁺, ROH₂⁺	−2 to −7
Hydronium	H₃O⁺	−1.7
Carboxylic acid	CH₃CO₂H	about 4.8
Ammonium ion	R₃NH⁺	about 10–11
Phenol	PhOH	about 10
1,3-Dicarbonyl C–H	CH₂(CO₂Et)₂	about 9–13
Water, alcohols	H₂O, EtOH	about 16
Aldehyde or ketone α-C–H	CH₃COCH₃	about 19–20
Ester α-C–H	CH₃CO₂Et	about 25
Terminal alkyne C–H	HC≡CR	about 25
Amine N–H	(iPr)₂NH	about 36
Alkane C–H	CH₄	about 50

What makes a conjugate base stable?

A stronger acid has a more stable conjugate base. Four factors, roughly in this order, decide stability. They are often summarised as ARIO: Atom, Resonance, Inductive effects, Orbital.

Atom. Negative charge is more stable on the more electronegative atom across a row (O⁻ is better than N⁻, which is better than C⁻) and on the larger atom down a column (I⁻ is better than F⁻, RS⁻ better than RO⁻ for stability, which is why thiols are more acidic than alcohols).
Resonance. Charge spread over several atoms is stabilised. This is why a carboxylate is far more stable than an alkoxide, and why the α-hydrogen of a carbonyl compound is acidic: the enolate puts charge on oxygen as well as carbon.
Inductive effects. Nearby electron-withdrawing groups (halogens, carbonyls, nitro groups) stabilise a negative charge through the σ framework. Trichloroacetic acid is much stronger than acetic acid for this reason.
Orbital. A lone pair in an orbital with more s character is held closer to the nucleus. That is why an sp carbanion (alkyne) is more stable than sp² or sp³, giving pKa values of about 25, 44 and 50.

Using this to choose reagents

Enolate formation. To turn a ketone (pKa about 20) fully into its enolate you need a base whose conjugate acid has a pKa well above 20, such as LDA (diisopropylamine, pKa about 36). With sodium ethoxide (ethanol, pKa about 16) the equilibrium lies on the side of the ketone, so only a small amount of enolate is present. That is exactly what you want for an equilibrium process like the aldol reaction and Claisen condensation, and exactly what you do not want when you need to alkylate cleanly.

The Claisen driving force. The Claisen condensation works with only ethoxide because the final product, a β-ketoester, has an α-hydrogen between two carbonyls (pKa about 11). Ethoxide removes it irreversibly, which pulls the whole sequence to completion. Look for this "final deprotonation" in the Dieckmann condensation condensation too.

Grignard reagents and acidic protons. A Grignard reagent is a carbon base with a conjugate-acid pKa of about 50. It will deprotonate water, alcohols, carboxylic acids and terminal alkynes faster than it adds to a carbonyl. That is why Grignard reactions need dry solvents and why an alcohol must be protected before you add RMgX.

Acid catalysis: protonate first, then react

Acid catalysts work by making an electrophile more electrophilic or a leaving group better. Protonating the carbonyl oxygen puts a positive charge on the carbon framework and lowers the barrier for a weak nucleophile (see Base hydrolysis (saponification) of an ester and Fischer esterification). Protonating an alcohol turns OH⁻, a poor leaving group (conjugate acid pKa about 16), into H₂O, a good one (conjugate acid pKa about −1.7), which makes SN1 and acid-catalysed hydration possible.

Leaving groups and pKa

A good leaving group is a weak base, so the pKa of its conjugate acid predicts leaving-group ability. I⁻, Br⁻, Cl⁻ and sulfonates (conjugate acid pKa from −3 to −7) leave readily, while HO⁻, RO⁻ and H₂N⁻ do not, unless they are first protonated or converted into sulfonates or other activated groups. This connects to the choice between substitution and elimination in the SN1, SN2, E1 and E2 guide.

A quick method for any step

Mark every acidic proton in the substrate and rank them by approximate pKa.
Look at the base you are adding and the pKa of its conjugate acid.
The most acidic proton that the base can remove is the one that moves, unless a faster, kinetic pathway competes.
Ask whether the resulting charge is stabilised by resonance. If it is, the proton transfer is plausible.

With practice you stop looking up numbers and start recognising that "this base is too weak" or "this base will deprotonate everything" before you draw the first arrow.

Practise in the interactive app Browse all 345 reactions