Questions: Grignard and Organolithium Reagents in Synthesis

Question 1

A chemist wants to prepare a Grignard reagent from a molecule that also contains a free carboxylic acid group. What happens when she attempts to form the reagent?

• A. The Grignard forms normally; the carboxylic acid is too far from the reaction site to interfere
• B. The Grignard reagent is destroyed by the acidic proton of the carboxylic acid before it can react with the intended electrophile
• C. The carboxylic acid is reduced to an aldehyde by the organometallic reagent
• D. The reaction proceeds in ethanol solvent, which stabilizes both functional groups

Answer: (B)

Grignard and organolithium reagents are destroyed by any protic source — including carboxylic acids, alcohols, water, and terminal alkynes — because these acidic protons react with the carbanion-like reagent immediately. The –COOH proton (pKa ~5) is far more acidic than the carbon being metalated, so the Grignard is instantly protonated and deactivated. Functional groups containing N–H or O–H bonds must be protected before attempting to form or use organometallic reagents.

Question 2

A Grignard reagent RMgBr is added to an ester (R'COOR''). What is the final product after acidic workup?

• A. A secondary alcohol with one R group from the Grignard
• B. A tertiary alcohol with two R groups from the Grignard
• C. An aldehyde, because esters are reduced by one oxidation state
• D. A primary alcohol, because esters react more mildly than ketones

Answer: (B)

Ester addition proceeds in two steps: the Grignard attacks the carbonyl of the ester, and the alkoxide leaving group departs to produce a ketone intermediate. This ketone is more reactive toward nucleophilic addition than the original ester, so a second equivalent of Grignard attacks immediately. After acidic workup, the product is a tertiary alcohol carrying two identical R groups from the Grignard. This two-addition sequence is why Grignard + ester always gives a tertiary alcohol — you cannot stop at the ketone stage under normal conditions.

Question 3

Organolithium reagents are more reactive and less selective than Grignard reagents because the C–Li bond is more ionic, giving the carbon a stronger partial negative charge.

• T. True
• F. False

Answer: True

The C–Li bond is more polarized than the C–Mg bond because lithium is a smaller, less electronegative metal, making the bond more ionic in character. This stronger carbanion-like character makes organolithium reagents faster to react and less discriminating about which electrophiles they attack — they will add to functional groups (like certain amides) that Grignard reagents leave alone. When precise selectivity is needed, RMgX is preferred; when maximum nucleophilicity is needed, RLi is the choice.

Question 4

A Grignard reaction can be successfully carried out in a slightly damp flask if the reaction is performed quickly, since water primarily slowly decomposes the reagent.

• T. True
• F. False

Answer: False

Grignard and organolithium reagents react with water immediately and completely — there is no window where the reaction is 'slow enough' to tolerate moisture. Even trace water destroys the reagent by protonating the carbon nucleophile. This is why Grignard reactions require rigorously dried glassware, anhydrous solvents (dried ether or THF), and an inert atmosphere. The reaction of RMgX with water is essentially instantaneous, not slow. Any moisture contamination before or during the reaction results in failure.

Question 5

Why do Grignard and organolithium reagents require anhydrous, aprotic conditions, and what happens at the molecular level when a protic solvent is present?

Model answer: Grignard and organolithium reagents carry a strongly nucleophilic carbon that behaves as a carbanion. Protic solvents (water, alcohols) have O–H bonds whose protons are far more electrophilic than the carbonyl carbons these reagents are designed to attack. The carbanion immediately abstracts the proton, forming a simple alkane (R–H) and a magnesium or lithium alkoxide — destroying the C–metal bond entirely. Because this proton transfer is faster than carbonyl addition, even trace moisture converts the entire reagent to an unreactive alkane before it can form the desired C–C bond.

The key is the kinetic competition: proton transfer from O–H to a carbanion is among the fastest reactions in organic chemistry (essentially diffusion-controlled), while nucleophilic addition to a carbonyl is slower. Any protic source wins the competition, irreversibly converting the valuable organometallic reagent into a worthless alkane. This is also why terminal alkynes (R–C≡C–H, pKa ~25) destroy Grignard reagents despite being relatively weak acids — the carbanion of RMgBr is basic enough to deprotonate them.