In this tutorial you will learn all about the preparation and uses of Grignard Reagents in organic chemistry. You will also become familiarized with the various types of Grignard reactions, and how they can be used in synthesis reactions.
Topics Covered in Other Articles
What are Grignard Reagents?
A Grignard reagent is also called an organomagnesium halide, because it is formed by reacting an alkyl halide with magnesium. Grignard reagents have the formula R – Mg – X. Like other organometallic compounds, Grignard reagents are incredibly nucleophilic and reactive, as well as incredibly basic. They are extremely versatile and used to form carbon-carbon bonds, and generally build up the carbon skeleton.
Forming Grignard Reagents
To form a Grignard reagent, react an alkyl halide with magnesium metal in an ether solvent (to ensure the reagent is stable). It is important to remember that the actual Grignard reagent is present in solution, and not generally found as a single molecule.
Primary, secondary, tertiary, vinyl, and alkyl halides can all react to form Grignard reagents. The most common halides in these reagents are iodine and bromine; recall the reactivity of the alkyl halides: R – I > R – Br > R – Cl > R – F
Important Grignard Reactions
Grignard reagents have many fascinating reactions with different functional groups including: aldehydes, ketones, formaldehyde, carboxylic acid derivatives, and epoxides.
Grignard Reagent + Aldehyde → Secondary Alcohol
Because of their nucleophilicity, Grignard reagents attack easily with a variety of carbonyl compounds. The first example of this is the aldehyde.
In the first step below, the Grignard reagent attacks the carbonyl to form an alkoxide salt.
In the Step 2, after the first reaction has finished, water or some other dilute acid protonates the alkoxide to produce the secondary alcohol. This is often called “Acid Workup.”
Grignard Reagent + Ketone → Tertiary Alcohol
Reactions with ketones are nearly identical that with aldehydes; the only difference is that ketones have a second function group (denoted R3) attached to the carbonyl instead of the H. This means that Grignard reagents and ketones will react to form tertiary alcohols.
Grignard Reagent + Ester → Tertiary Alcohol
Grignard reagents have fascinating reactions with esters, and actually react twice to produce a tertiary alcohol.
The Grignard reaction first attacks one time to form a tertiary alkoxide, similar to the reaction with ketones and aldehydes. But immediately after, the -OR acts as a leaving group to form a a new ketone with the Grignard R group.
But the reaction is not yet complete! Recall that Grignard reagents are present in a solution, so there are many R-MgX ions present. We already learned that they attack ketones to form a tertiary alcohol. The Grignard reacts once more to form an alkoxide in Step 2, and then the molecule undergoes Acid Workup in Step 3.
See how the final product is a tertiary alcohol, with a di-substitued R1 group, due to the dual reactive nature of Grignards with esters.
This reaction can also be done identically with acid chlorides, where the alkyl halide serves as the leaving group in the first reaction.
Grignard Reagent + Formaldehyde → Primary Alcohol
Once more, reactions with formaldehyde are similar to that of ketones and aldehydes, except that a formaldehyde has two hydrogens attached to the carbonyl instead of any functional group.
Grignard Reagent + Epoxide → Ring Opening
Grignard Reagents attack the less hindered end of the epoxide as an “Sn2 like” reaction. This opens up the epoxide and leads to a planar molecule, as shown below:
Don’t React With Carboxylic Acids!
Since Grignard reagents react with a variety of functional groups, one might try to react them with carboxylic acids; however, because carboxylic acids are strong acids, and Grignards are strong bases, the Grignard is irreversibly protonated instead!
See the topics below for some in-depth reading into the specific properties of the individual functional groups which engage with Grignard reagents:
- Carboxylic Acids
- Acid Chlorides
- Alkyl Halides