Grignard Reagents
A Grignard reagent (R-MgX) is a carbon-magnesium bond so polarized that the carbon behaves like a carbanion. This makes Grignards the most versatile C-C bond-forming reagents in undergraduate organic chemistry - they attack aldehydes, ketones, esters, epoxides, and CO₂, creating new alcohols (or carboxylic acids from CO₂) with an extended carbon chain.
The MCAT loves Grignard synthesis because it combines mechanism, stereochemistry, and multi-step reasoning into one compact problem. Know the reagent, know the substrate, and you can predict the product every time.
Formation of a Grignard Reagent
To make a Grignard, you combine an alkyl (or aryl) halide with magnesium metal in dry ether:
R-X + Mg⁰ → R-Mg-X (in ether or THF)
- Works for most halides (Cl, Br, I; F is too unreactive).
- Works for 1°, 2°, 3° alkyl groups and aryl halides.
- Solvent MUST be dry (water-free) ether, tetrahydrofuran (THF), or similar aprotic ether.
- Any water, alcohol, or acidic proton will destroy the Grignard before it can react with the intended substrate.
The magnesium inserts into the C-X bond, giving an organomagnesium halide. The C-Mg bond is highly polarized (carbon is δ⁻, magnesium is δ⁺), so the carbon behaves like a carbanion.
The Core Reaction: Attack on Carbonyls
Grignards attack carbonyls (C=O) in a simple two-step process:
Step 1: The carbanionic carbon of R-MgX attacks the electrophilic carbonyl carbon. The C=O pi bond breaks, electrons flow to oxygen. Result: a magnesium alkoxide intermediate.
Step 2 (workup): Acidic aqueous workup (dilute HCl, NH₄Cl, or H₂O) protonates the alkoxide to give the alcohol product. Magnesium halide salt is a byproduct.
What You Get from Each Carbonyl
The product of a Grignard addition depends on which carbonyl you attack:
| Starting carbonyl | Grignard addition → alcohol type | Example |
|---|---|---|
| Formaldehyde (HCHO) | 1° alcohol | CH₃MgBr + HCHO → CH₃CH₂OH (ethanol) |
| Aldehyde (RCHO) | 2° alcohol | CH₃MgBr + CH₃CHO → (CH₃)₂CHOH (isopropanol) |
| Ketone (R₂C=O) | 3° alcohol | CH₃MgBr + CH₃COCH₃ → (CH₃)₃COH (tert-butanol) |
| Ester (RCOOR’) | 3° alcohol (double addition) | CH₃MgBr (2 equiv) + CH₃COOCH₃ → (CH₃)₃COH |
| Acyl halide, anhydride | Ketone → then 3° alcohol (double addition) | |
| Epoxide | Primary alcohol (ring-opened) | CH₃MgBr + ethylene oxide → CH₃CH₂CH₂OH (1-propanol) |
| CO₂ | Carboxylic acid | CH₃MgBr + CO₂ → CH₃COOH (after workup) |
Double Addition: Esters and Acid Halides
Esters (and acid halides, anhydrides) react with TWO equivalents of Grignard reagent because the initial addition produces a tetrahedral alkoxide that can eject the OR’ (or Cl) leaving group, forming an intermediate ketone. That ketone then accepts a second Grignard addition, giving the final 3° alcohol.
Net result: CH₃COOC₂H₅ + 2 CH₃MgBr → (CH₃)₃COH (tert-butanol) + CH₃CH₂O⁻MgBr⁺.
On the MCAT, if you see an ester + excess Grignard, the product is a 3° alcohol with two identical R groups from the Grignard on the carbonyl carbon.
Ring Opening of Epoxides
Grignards attack epoxides at the less substituted carbon (backside-attack-like, SN2-style) due to steric considerations. The epoxide O becomes an alkoxide, which gives an alcohol on workup.
CH₃MgBr + ethylene oxide (CH₂CH₂O as a 3-membered ring) → CH₃CH₂CH₂O⁻MgBr⁺ → CH₃CH₂CH₂OH after workup.
This is a powerful C-C bond forming method with a built-in two-carbon extender (the epoxide) - often easier than double-Grignard or Wittig alternatives.
Why Grignards Are Destroyed by Water
A Grignard has a carbanionic carbon. That carbon is intensely basic - the pKa of an alkane C-H is about 50, so the corresponding carbanion is an extremely strong base. Any acidic proton - water (pKa 15.7), alcohol (pKa 16), carboxylic acid (pKa 4-5), amine N-H (pKa 38), terminal alkyne (pKa 25) - will donate a proton to the Grignard immediately, converting R-MgX to R-H.
Practical consequences:
- Reaction mixtures must be completely dry before Grignard formation or use.
- If the substrate itself has an acidic proton (a hydroxyl, amine, or terminal alkyne), it will quench the Grignard. You need to protect those groups first.
- Workup with water is done AT THE END, after the Grignard has added to the intended carbonyl.
Organolithium Reagents: The Grignard’s Cousin
R-Li (organolithium) reagents behave similarly to Grignards but are even more reactive. They are made by reacting alkyl halides with lithium metal:
R-X + 2 Li → R-Li + LiX
n-Butyllithium (n-BuLi) is a common strong base in synthesis. Because it is an even stronger base than a Grignard, it can deprotonate terminal alkynes, amines, and similar weakly acidic species - useful when you need to generate a specific anion.
Other key organometallics:
- Gilman reagents (R₂CuLi): softer nucleophiles, do 1,4-conjugate addition on enones (Michael addition). Covered in Ch 7.
- Lithium diisopropylamide (LDA): a strong bulky base used for enolate formation. Not a nucleophile itself (too bulky).