Fundamentals · 8 min read

Nucleophiles, electrophiles and leaving groups: what makes a reaction go

Every polar organic reaction is an electron-rich species meeting an electron-poor one. If you know what makes each partner reactive, you can predict what will happen even for a reaction you have never seen.

Nucleophiles: the electron donors

A nucleophile has a lone pair or a π bond available to share. Several factors raise nucleophilicity:

Negative charge: HO⁻ is a stronger nucleophile than H₂O; RO⁻ more than ROH.
Lower electronegativity across a row: the less tightly an atom holds its lone pair, the more freely it donates. R₃C⁻ > R₂N⁻ > RO⁻ > F⁻.
Larger, more polarisable atoms (in protic solvent): I⁻ > Br⁻ > Cl⁻, and RS⁻ > RO⁻, because the large atom is less tightly solvated and its electrons are easily distorted.
Less steric hindrance: methoxide is a better nucleophile than tert-butoxide, even though they have similar basicity.
Solvent: in polar aprotic solvents the nucleophile is less caged, so anions are far more reactive than in water or alcohols.

Not every nucleophile is an anion. Amines, phosphines (as in the Wittig reaction), enolates (Base-catalyzed aldol addition of acetaldehyde), organometallics (Grignard addition to acetaldehyde) and π bonds (in Friedel–Crafts reactions) are all common.

Electrophiles: the electron acceptors

An electrophile has an electron-poor atom that can accept a pair. The usual types:

Carbonyl carbons (C=O): polarised, with a partial positive on carbon. Aldehydes are more reactive than ketones because they are less hindered and have only one electron-donating alkyl group. See Hydride adds to acetaldehyde's carbonyl.
Carbons bearing a leaving group (alkyl halides, sulfonates, protonated alcohols): SN2, SN1.
Conjugated acceptors (α,β-unsaturated carbonyls): the β-carbon is electrophilic in the Michael addition.
Cations: carbocations, oxocarbenium ions, iminium ions (for instance in the Mannich reaction).
Activated aromatic rings: electron-poor rings with a good leaving group undergo nucleophilic aromatic substitution.

Carbonyl reactivity follows how much positive charge sits on carbon and how well the leaving group can depart afterwards. That is why acid chlorides react far faster than amides: the chloride is both a better leaving group and does less to donate electron density back to the carbonyl.

Leaving groups: the part that departs

A good leaving group is a stable species once it has taken the bonding electrons. The best guide is the pKa of its conjugate acid: lower pKa means a better leaving group.

Leaving group	Conjugate acid	Approx. pKa	Quality
TsO⁻, MsO⁻, TfO⁻	Sulfonic acids	−3 to −14	Excellent
I⁻, Br⁻, Cl⁻	HI, HBr, HCl	−10, −9, −7	Very good
H₂O	H₃O⁺	−1.7	Good (needs acid first)
F⁻	HF	3	Poor
HO⁻, RO⁻	H₂O, ROH	15 to 16	Very poor
H⁻, R⁻	H₂, RH	> 35	Essentially never

This explains why acid is added to alcohol reactions: protonation turns the poor leaving group HO⁻ into water. It also explains why alcohols are converted to tosylates or halides, for instance in the Appel reaction, before substitution.

The solvent as a hidden reagent

Polar protic (water, alcohols, carboxylic acids): hydrogen bond to anions and to leaving groups. They slow strong anionic nucleophiles and help ionisation. Good for SN1 and E1.
Polar aprotic (DMSO, DMF, acetonitrile, acetone, THF): dissolve salts but do not bond tightly to anions. Good for SN2 and for reactions of strongly basic reagents.
Non-polar (hexane, toluene): used when reagents are neutral or when ion pairs must be minimised, for example in the Diels–Alder cycloaddition.

Bringing it together

To predict a reaction, ask: What is the best nucleophile present? What is the most electrophilic site? Is there a good leaving group, or can one be made in situ? Which solvent and temperature are used? You will often find the answer is just "the strongest nucleophile attacks the most electrophilic carbon, and the best leaving group leaves".

Practise in the interactive app Browse all 345 reactions