Nearly every reaction in this course so far has treated carbon as the electrophile. A carbonyl carbon is attacked; an alkyl halide is attacked; a protonated alkene is attacked. The nucleophile has almost always been a heteroatom — oxygen, nitrogen, a halide, a cyanide.
That is a real limitation, because a nucleophile supplies the new bond, and a heteroatom nucleophile can only ever attach a heteroatom. Building a carbon skeleton requires a nucleophile that is carbon.
Organometallic chemistry is the answer, and it comes from one observation about electronegativity.
Bond a carbon to a metal and the polarity flips
Carbon sits at 2.55 on the Pauling scale. Every metal you will meet here sits far below it — magnesium at 1.31, lithium at 0.98. So in a C–Mg or a C–Li bond, carbon is the more electronegative partner, and the shared electrons sit on carbon.
A deliberate reversal of a site's normal polarity is called umpolung, and organometallics are the cleanest example of it. An alkyl halide is an electrophile at carbon; insert magnesium into that C–X bond and the same carbon becomes a nucleophile. One step, opposite behavior.
It is worth being precise about how far this goes. The C–Mg bond is polar covalent, not ionic: a Grignard reagent is not a free carbanion floating in solution. But it behaves like one in every reaction you will write, so drawing R⁻ as the reactive species is a good model, and the curved arrow starts at the C–metal bond.
The family, in order of reactivity
| Reagent | Metal | Character |
|---|---|---|
| R–MgX | Mg | Grignard. Strongly nucleophilic, strongly basic. The workhorse. |
| R–Li | Li | Organolithium. More reactive and more basic than a Grignard. |
| R2CuLi | Cu | Gilman reagent. Softer and far more selective; adds 1,4 and couples. |
| R–ZnX | Zn | Mild enough to tolerate an ester in the same molecule. |
| R–B(OH)2 | B | Boronic acid. Barely nucleophilic on its own; needs a palladium catalyst. |
The ordering is not arbitrary. The bigger the electronegativity gap between carbon and the metal, the more carbanion-like the carbon, and the more reactive and less selective the reagent is. Lithium is the most electropositive of these, so RLi is the most aggressive; copper and boron are much closer to carbon, so their reagents are gentler and can be pointed at one site in a molecule that contains several.
The one thing that destroys all of them
A carbanion is the conjugate base of an alkane, and alkanes have pKa values around 50. That makes R⁻ one of the strongest bases in organic chemistry — strong enough to take a proton from essentially anything with an O–H, N–H or S–H bond, and from a terminal alkyne as well.
So an organometallic reagent and an acidic hydrogen cannot be in the same flask:
- Water (pKa 15.7) destroys it instantly, giving R–H and Mg(OH)X. Glassware and solvent must be dry.
- Alcohols (pKa ~16), carboxylic acids (pKa ~5) and amines (pKa ~35) all do the same.
- A terminal alkyne (pKa 25) is deprotonated rather than attacked.
This is not a side note; it is the single most common way a synthesis on paper fails in practice. If your substrate carries an O–H anywhere, the Grignard reacts with that proton and nothing else happens. The answer is to put the organometallic step earlier, or to protect the acidic group — which is exactly the argument the protecting-groups section makes.
The flip side is that this reaction is sometimes the point. Quenching an organometallic with D2O instead of water puts a deuterium exactly where the metal was, which is how a specific position gets labeled.
What carries forward
Carbon bonded to a metal is nucleophilic carbon, and that is what makes carbon skeletons buildable. The rest of this chapter is four ways to use it: the Grignard and organolithium reagents that attack carbonyls directly, the cuprates that add where a Grignard will not, and the palladium chemistry that joins two pieces neither of which is nucleophilic enough on its own.