Nucleophiles

Every bond-forming step in an organic mechanism starts with a nucleophile - an electron-rich species that attacks an electron-poor center. Alcohols attack carbonyls. Amines attack alkyl halides. Water attacks carbocations. Grignards attack esters. Your mental model for nucleophiles is the engine of mechanism.

A nucleophile is simply a Lewis base acting in a bond-forming step. The term shifts the focus from “this molecule donates electrons” (the Lewis view) to “this molecule attacks an electrophile to form a new bond” (the mechanism view). Same species, different role.

Three Features of a Strong Nucleophile

What makes one nucleophile more reactive than another? Three factors:

1. Charge - a negatively charged species is usually a better nucleophile than its neutral form. Hydroxide (OH⁻) beats water (H₂O). Alkoxide (RO⁻) beats alcohol (ROH). Amide (NH₂⁻) beats amine (NH₃). Having a full negative charge means a full lone pair is ready to donate.
2. Basicity - more basic = more nucleophilic, in most cases. A strong base is willing to donate its lone pair, whether to a proton (basicity) or to a carbon (nucleophilicity). The two properties track together for most species in common solvents.
3. Atom polarizability / size - in protic solvents, bigger and more polarizable atoms are better nucleophiles because their electron cloud deforms more easily to form a new bond. This is the effect that reverses the expected order for halides in water.

Charge: Anions Beat Neutrals

The rule: the anion is almost always a better nucleophile than its neutral conjugate acid. HO⁻ >> H₂O. RO⁻ >> ROH. H₂N⁻ >> H₃N. HS⁻ >> H₂S. RCOO⁻ >> RCOOH.

Why? An anion has its lone pair fully available. A neutral molecule has the same lone pair but distributed over different orbitals, some of which are tied up with the proton.

Practical takeaway: when you see a neutral nucleophile (water, alcohol, amine), check if there is a base nearby that could deprotonate it. If yes, the anion is the real attacker. If no (acidic or neutral conditions), the neutral species attacks directly.

Basicity Usually Predicts Nucleophilicity - But Not Always

In a single column (same atom), basicity and nucleophilicity track almost perfectly:

• F⁻ is more basic than Cl⁻ (conjugate acid HF pKa 3, HCl pKa −7). In an aprotic solvent, F⁻ is also a better nucleophile.
• OH⁻ is more basic than RCOO⁻ (water pKa 15.7 vs. carboxylic acid pKa 4). OH⁻ is a better nucleophile.

Across a row, the same relationship holds:

• NH₂⁻ (amide) > OH⁻ (hydroxide) > F⁻ (fluoride). Both basicity and nucleophilicity decrease across a row.

When Basicity and Nucleophilicity Diverge

Two situations break the link:

Steric bulk destroys nucleophilicity but not basicity. Tert-butoxide (tBuO⁻) is a strong base - its conjugate acid (tert-butanol) has pKa ~18. But tBuO⁻ is a terrible nucleophile because the three methyl groups on the adjacent carbon physically prevent it from approaching an electrophilic carbon. Students running an SN2 reaction avoid tBuO⁻ because it will do E2 (removing a proton from the periphery) instead of attacking carbon. LDA (lithium diisopropylamide) is another bulky strong base used specifically because it cannot act as a nucleophile.

Protic solvents invert nucleophilicity down a group. In protic solvents (those with O-H or N-H bonds: water, alcohols), small anions like F⁻ are heavily hydrogen-bonded. The solvent shell physically surrounds the anion and reduces its ability to attack. Larger anions (I⁻, Br⁻) are less tightly solvated because the charge is spread over a larger surface, so they remain more reactive. In protic solvents, nucleophilicity is: I⁻ > Br⁻ > Cl⁻ > F⁻ - the exact opposite of their basicity ranking.

In aprotic solvents (those without O-H or N-H: DMSO, DMF, acetone, acetonitrile), there is no strong hydrogen bonding to the anion. The “naked” anion is free to attack, and nucleophilicity tracks basicity: F⁻ > Cl⁻ > Br⁻ > I⁻. This matters for SN2 reactions and is a classic MCAT distinction.

Common Nucleophiles Ranked

A rough ranking that covers most MCAT reactions (in a standard polar aprotic solvent):

1. Carbanions (R⁻) - essentially infinite nucleophilicity, unstable as free species but delivered by Grignards and organolithiums.
2. Hydride (H⁻) - from LiAlH₄ and NaBH₄ reagents. Attacks carbonyls.
3. Amides (R₂N⁻), alkoxides (RO⁻), hydroxide (OH⁻), sulfides (RS⁻) - “strong” nucleophiles that are also strong bases.
4. Amines (R₃N), alcohols (ROH), sulfides (R₂S) - neutral nucleophiles; good enough for SN2 with reactive substrates.
5. Water, carboxylates, halides - weaker neutral or weakly charged nucleophiles.

Sulfur nucleophiles are underappreciated: they are bigger and more polarizable than oxygen analogs, so they are often better nucleophiles even when they are weaker bases. HS⁻ attacks alkyl halides faster than HO⁻ in many cases.

Solvent Effects in Detail

DMSO (dimethyl sulfoxide) is the classic polar aprotic solvent - it dissolves the cations (via its oxygen lone pairs) but cannot hydrogen-bond to anions. This leaves the nucleophile anion free to attack.

Soft vs. Hard Nucleophiles

A related concept: hard nucleophiles are small, high-charge-density species (F⁻, OH⁻, NH₃) that prefer to attack “hard” electrophiles (H⁺, small carbocations, strongly polarized carbonyls). Soft nucleophiles are larger, more polarizable species (I⁻, RS⁻, CN⁻) that prefer “soft” electrophiles (large alkyl halides, conjugate additions to Michael acceptors). The rule: hard prefers hard, soft prefers soft. This explains why soft sulfur nucleophiles are great for Michael additions (1,4-addition to enones) while hard alkoxides prefer direct carbonyl attack (1,2-addition).

Nucleophile vs. Base in Elimination

The same molecule can act as a nucleophile (attacks carbon, forms a bond) or as a base (attacks a proton on an adjacent carbon, causes elimination). The distinction matters:

• Small, strong-base nucleophiles (MeO⁻, EtO⁻) tend to do both. Product mix depends on substrate.
• Bulky strong bases (tBuO⁻, LDA) only do elimination.
• Weak, polarizable nucleophiles (I⁻, RS⁻) prefer substitution (act as nucleophile, not base).
• Polar aprotic solvent + strong nucleophile = SN2. Protic solvent + weak nucleophile + heat = SN1/E1.

This choice is drilled in Ch 5.10.

Next: what makes a good electrophile - the partner on the other side of every mechanism arrow.