Grignard reagents are powerful carbon nucleophiles used to form new carbon-carbon bonds in organic chemistry. This cheat sheet helps students predict products from reactions between reagents and common electrophiles such as aldehydes, ketones, esters, epoxides, and carbon dioxide. It also summarizes why dry conditions are required and which functional groups are incompatible.
Students need this reference because Grignard reactions combine mechanism, product prediction, and functional group recognition.
Key Facts
- A Grignard reagent has the general formula , where is an alkyl, aryl, or vinyl group and is , , or .
- Grignard reagents are commonly formed by reacting an alkyl or aryl halide with magnesium metal in dry ether: .
- The carbon attached to magnesium is strongly nucleophilic and basic because the bond is polarized as .
- Reaction of with formaldehyde followed by acid workup gives a primary alcohol: .
- Reaction of with an aldehyde followed by acid workup gives a secondary alcohol: .
- Reaction of with a ketone followed by acid workup gives a tertiary alcohol: .
- Reaction of with followed by acid workup gives a carboxylic acid with one extra carbon: .
- Water, alcohols, carboxylic acids, amines, and terminal alkynes destroy Grignard reagents by proton transfer: .
Vocabulary
- Grignard reagent
- An organomagnesium halide with the formula that acts as a strong nucleophile and strong base.
- Nucleophile
- An electron-rich species that donates an electron pair to form a new bond with an electrophilic atom.
- Electrophile
- An electron-poor species that accepts an electron pair, such as the carbonyl carbon in .
- Carbonyl addition
- A reaction in which a nucleophile adds to the carbon atom of a carbonyl group .
- Acid workup
- The final protonation step, often using , that converts an alkoxide intermediate into an alcohol.
- Compatible functional group
- A functional group that does not rapidly react with or protonate a Grignard reagent under the reaction conditions.
Common Mistakes to Avoid
- Using wet glassware or protic solvent is wrong because , , and other proton sources convert into before it can add to a carbonyl.
- Forgetting the acid workup is wrong because the immediate product after carbonyl addition is an alkoxide such as , not the neutral alcohol .
- Adding only one equivalent to an ester is often wrong because esters usually react with equivalents of to form a tertiary alcohol after two additions.
- Predicting oxidation state changes is wrong because Grignard carbonyl addition forms a new bond and protonates oxygen, but it is not classified as a simple oxidation or reduction in typical product prediction.
- Ignoring acidic functional groups in the substrate is wrong because groups such as , , , and terminal quench by acid-base reaction.
Practice Questions
- 1 Predict the major organic product after reacts with and is then treated with .
- 2 What alcohol forms when reacts with acetone, , followed by acid workup?
- 3 How many equivalents of are needed for complete reaction with equivalent of ethyl acetate, , and what class of alcohol is produced after workup?
- 4 A molecule contains both a ketone and an alcohol group. Explain why direct treatment with may fail to give the expected carbonyl addition product.
Understanding Grignard Reagents Reference
The key to these reactions is the difference in electron sharing within the carbon to magnesium bond. Magnesium attracts the bonding electrons much less strongly than carbon. This leaves the carbon electron rich and ready to make a bond to an electron poor atom.
In a carbonyl compound, the oxygen pulls electron density away from the carbonyl carbon. The Grignard carbon attacks that carbonyl carbon, while the electrons from the carbon oxygen double bond move onto oxygen.
This creates an alkoxide, which is an oxygen with a negative charge bound to magnesium. The later acid treatment simply gives that oxygen a hydrogen and turns the alkoxide into an alcohol.
A reliable product prediction method is to mark the carbon attached to magnesium, then treat it as the incoming carbon group. Draw that group attached to the carbonyl carbon. Next, change the carbon oxygen double bond into a single carbon oxygen bond, then place an OH group on oxygen after workup.
Count the carbon groups attached to the alcohol carbon in the final structure. Formaldehyde has no carbon groups attached before reaction, so it gives a primary alcohol. An aldehyde has one, so it gives a secondary alcohol.
A ketone has two, so it gives a tertiary alcohol. This counting method is usually safer than trying to memorize separate product pictures.
Some electrophiles need extra care because the first addition changes the molecule before the reaction is finished. Esters react with two equivalents of a Grignard reagent. The first attack produces a temporary intermediate that loses an alkoxide group and becomes a ketone.
A second Grignard group then attacks that ketone. The final alcohol carbon therefore contains two identical groups from the Grignard reagent. Epoxides behave differently.
The Grignard carbon opens the strained three membered ring by attacking one ring carbon. With simple epoxides, attack usually occurs at the less crowded carbon.
After workup, the oxygen becomes an alcohol. This reaction can extend a carbon chain by two carbons when ethylene oxide is used.
Dry glassware and dry solvent matter because a Grignard reagent reacts faster with an available acidic hydrogen than with many intended electrophiles. Even a small amount of water can convert the carbon group into an ordinary hydrocarbon, wasting the reagent. Students should scan every reactant for bonds such as oxygen hydrogen, nitrogen hydrogen, sulfur hydrogen, or the hydrogen on a terminal alkyne.
These groups can stop the planned reaction. In multistep synthesis, this is why chemists may protect an alcohol first, carry out the carbon bond forming step, then restore the alcohol later. In lab work, ether solvent helps stabilize the magnesium species, while moisture from air remains a practical source of failure.