Organic Structure & Electron Movement · Section 13 of 64

Nucleophiles

Practice this — interactive lesson

Every reaction in this course has a species that brings the electrons and a species that receives them. This section is about the first half of that pair. Once you can look at a flask of reagents and say "that one is the nucleophile," you know where the tail of your first arrow goes, and the mechanism has begun.

What it is

A nucleophile — literally "nucleus-loving" — is any species with an available electron pair it can donate to form a new bond. That pair can come from a lone pair, from a full negative charge, or from a pi bond. Nucleophiles seek out electron-poor centers, which is where the name comes from: they are attracted to positively charged nuclei.

Three families cover nearly everything you will meet. Anions: hydroxide (HO⁻), alkoxides (RO⁻), cyanide (⁻CN), thiolates (RS⁻), halides, hydride donors, carbanions. Neutral molecules with lone pairs: water, alcohols, ammonia, amines, phosphines. Pi bonds: alkenes, alkynes, and aromatic rings, which are weak nucleophiles but genuinely nucleophilic, and which supply the entire reactivity of Modules 7 and 13.

An anionOH−hydroxide, alkoxide, cyanide,thiolate, a carbanionfull charge — strongestA neutral molecule with a lone pairNRRRwater, alcohols, ammonia,amines, phosphinesno charge — middlingA π bondCCalkenes, alkynes,aromatic ringsweak, but genuinely nucleophilic
The three places a donatable electron pair comes from. Learn to spot all three on sight, because finding the nucleophile is where the tail of your first arrow goes. The third one is the one beginners miss: a pi bond has no charge and no lone pair, but its electrons stick out of the molecular plane where something can reach them — and that fact carries the whole of Modules 7 and 13.

What makes one stronger

Nucleophilicity is about how readily a species hands over its electron pair. Four factors control it.

Charge. A negatively charged species is a stronger nucleophile than its neutral counterpart, every time. HO⁻ beats H₂O; RO⁻ beats ROH; H₂N⁻ beats NH₃. A full negative charge means loosely held, readily available electron density. This is why deprotonating an alcohol before using it is such a common first step — it converts a mediocre nucleophile into a strong one.

Electronegativity, running backwards. Across a row of the periodic table, nucleophilicity decreases as electronegativity increases: H₃C⁻ > H₂N⁻ > HO⁻ > F⁻. A more electronegative atom holds its electrons more tightly and is therefore less willing to share them. This surprises people, because electronegativity usually predicts reactivity in the other direction — but it is exactly the same physics read the other way round.

Sterics. A nucleophile has to physically reach the atom it attacks. Bulky groups around the nucleophilic atom slow it down, sometimes drastically, and this is what separates nucleophilicity from basicity (below).

Polarizability. Down a column, nucleophilicity increases: I⁻ > Br⁻ > Cl⁻ > F⁻. This one needs its own explanation.

Two words worth pinning down: protic, and polarizable

A protic solvent has an O–H or N–H bond and can donate hydrogen bonds — water, methanol, ethanol, acetic acid. An aprotic solvent has no such bond — acetone, DMSO, DMF, acetonitrile, THF. Both kinds can be highly polar; the only question is whether an O–H or N–H is available for hydrogen bonding. The distinction is one of the most consequential in Module 6.

Polarizable describes how easily an atom's electron cloud can be distorted. A large atom like iodine holds its outermost electrons loosely and far from the nucleus, so that cloud deforms readily: it can reach out toward an electrophile before the atoms are close, and it can spread a negative charge over a large volume. A small atom like fluorine holds its electrons tightly and close in, and its cloud barely budges. Big and loose means polarizable; small and tight means not. This single property returns for leaving-group ability and for acidity trends down a group.

Solvent matters too — and it can reverse the order

In a polar protic solvent such as water or methanol, small highly charged anions get caged by a tight shell of hydrogen bonds. Fluoride, small and charge-dense, is held so firmly that stripping the solvent off it costs more than the reaction gains, and its nucleophilicity collapses. Iodide, large and diffuse, is only loosely solvated and moves freely. So in water the halide order is I⁻ > Br⁻ > Cl⁻ > F⁻, the exact opposite of what electronegativity alone would suggest.

In a polar aprotic solvent such as DMSO or DMF, there are no O–H bonds to cage anything. These solvents solvate cations well and anions poorly, leaving the anion effectively naked and much more reactive. The order flips back to the intrinsic one: F⁻ > Cl⁻ > Br⁻ > I⁻, and every anion is a stronger nucleophile than it was in water — often by several orders of magnitude.

Polar PROTIC — water, methanolH–OH–OH–OH–OH–OH–OFF⁻ — small, charge-densea tight, costly cageH–OH–OH–OH–OH–OH–OII⁻ — big, diffusebarely held, free to moveso in water: I⁻ > Br⁻ > Cl⁻ > F⁻Polar APROTIC — DMSO, acetoneFnakedInakedno O–H bond to donate, so nothing cages an anion —every one of them is far more reactive hereso in DMSO: F⁻ > Cl⁻ > Br⁻ > I⁻
Why there is no such thing as a nucleophilicity ranking without a solvent attached. A protic solvent has O–H bonds, so it wraps a small charge-dense anion like fluoride in a tight shell of hydrogen bonds that must be paid to remove before fluoride can attack anything. Iodide, big and diffuse, is barely held and moves freely — so in water the order runs backwards. Switch to an aprotic solvent with no O–H to donate and every anion is left naked, far more reactive, and back in the order electronegativity predicted. If a question names a solvent, that is the information you need, not scene-setting.
There is no single nucleophilicity ranking. Any list of nucleophile strengths is implicitly a list in a particular solvent. If an exam question gives you a solvent, that is not scene-setting; it is the information you need to answer. Polar protic reverses the halide order relative to polar aprotic.
Worked example — why the same reaction runs faster in acetone

Sodium iodide displacing bromide from 1-bromobutane runs in acetone, a polar aprotic solvent. Switch to methanol and the same reaction slows by roughly three orders of magnitude.

Nothing about the substrate changed. In methanol, iodide is surrounded by hydrogen-bonded solvent that must be stripped away before it can attack; in acetone there is nothing to strip. Solvent is a reagent in SN2 chemistry, not a background detail.

Nucleophilicity is not basicity

These two ideas track together often enough to be confused, and they are genuinely different.

Basicity is thermodynamic: it measures where a proton-transfer equilibrium sits, and it is quantified exactly by pKa (Module 3). Nucleophilicity is kinetic: it measures how fast a species attacks carbon. One is about the position of an equilibrium; the other is about the rate of a reaction.

Sterics is what pries them apart. tert-Butoxide is a stronger base than hydroxide — it is happy to take a proton, which is a small exposed target — but a much weaker nucleophile, because its three methyl groups cannot get close enough to a crowded carbon. This is not a curiosity; it is a tool. When you want elimination rather than substitution in Module 6, you deliberately choose a bulky base for exactly this reason.

Hydroxide, HO⁻OHsmall and exposedgood base · good nucleophiletert-Butoxide, (CH₃)₃CO⁻OCCH₃CH₃CH₃the same pair, behind three methylsstronger base · far weaker nucleophile
Two alkoxides carrying the same lone pair, pulled apart by nothing but shape. Basicity asks where a proton-transfer equilibrium settles; nucleophilicity asks how fast the species reaches a carbon. tert-Butoxide is the stronger base of the two — and a far worse nucleophile, because a proton is a bare nucleus it can reach around its own methyls to grab, while a crowded carbon it cannot. Reagents are chosen on exactly this distinction all through Module 6.A proton is a bare nucleus — tiny, and reachable past anything. A carbon is not. That single difference is why Module 6 reaches for a bulky base when it wants elimination.

Polarizability pries them apart in the other direction. Iodide is an excellent nucleophile and a terrible base. Thiolate (RS⁻) is a stronger nucleophile than alkoxide (RO⁻) while being a much weaker base. Any time a reagent is "a good nucleophile but a weak base," it will favour substitution over elimination.

Every mechanism starts with finding the nucleophile — it is where the tail of your first arrow goes. And often the first step of a synthesis is manufacturing a better one: deprotonating methanol to methoxide converts a middling neutral nucleophile into a strong anionic one, which is why "NaOMe" appears in so many reaction conditions.

What carries forward

The strong-nucleophile / weak-base versus strong-base / bulky distinction is what decides SN2 against E2 in Module 6, and it is one of the most heavily tested judgements in the course. Nucleophile identity determines the product in nucleophilic addition (Module 9) and acyl substitution (Module 10). And the recognition that a pi bond is a nucleophile is the starting point for every alkene and aromatic reaction you will see.