Grignard Reaction
Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate how to properly carr…
1. Grignard Reagent Formation
- Flame-dry a round bottom flask equipped with a magnetic stir bar.
- Add magnesium (Mg, 1.1 equiv.) to the round bottom flask.
- Add a small amount of iodine (I2, a few crystals). Addition of iodine is to help remove any MgO on the surface of the Mg. Removing MgO allows for Mg and the aryl/alkyl halide to come in contact and react. Sonication or addition of methyl iodide or 1,2-dibromoethane can also help with initiation.
- Cool the reaction mixture to 0 °C with an ice-water bath
- Slowly add a THF (1 M) solution of allyl bromide (1 equiv.) to the round bottom flask with magnesium.
- After adding the solution of allyl bromide, stir the reaction mixture for 3 h at room temperature.
2. Nucleophilic Addition
- In a separate flame-dried round bottom flask, add trans-cinnamaldehyde (0.85 equiv.) and THF (0.5 M with respect to trans-cinnamaldehyde) and cool to 0 °C.
- Slowly add the THF solution of the Grignard reagent (allyl-magnesium bromide) to the trans-cinnamaldehyde solution.
- After the addition, warm the reaction mixture to room temperature by removing the ice-water bath and stir for 4 h.
- Monitor the reaction progress via TLC by looking for the disappearance of trans-cinnamaldehyde.
- After reaction completion, cool the mixture to 0 °C with an ice-water bath.
- Slowly quench the reaction with a saturated aqueous solution of ammonium chloride (NH4Cl).
- Transfer the mixture into a separatory funnel and extract the aqueous layer with ethyl acetate 3x.
- Combine the organic layers and wash with water and brine (a saturated aqueous solution of NaCl).
- Dry the organic layer with anhydrous MgSO4, filter, and evaporate the solvent via rotatory evaporation.
- Purify the crude residue via flash column chromatography.
The Grignard reaction is a useful tool for the formation of carbon-carbon bonds in organic synthesis.
This reaction was discovered more than a century ago by a French Chemist named Victor Grignard for which he was rewarded a Nobel Prize in 1912.
The Grignard reaction consists of two steps. The first step is reacting an organohalide with magnesium metal, usually present in the form of turnings. This leads to in situ formation of an organomagnesium halide A.K.A. Grignard reagent.
The second step is the reaction between this reagent and a carbonyl-containing compound like aldehyde, ketone, or ester, and depending on the compound used, a secondary or tertiary alcohol, composed of organic portions from both the reagent and the carbonyl-containing compound, is produced.
In this video, we will show a step-by-step protocol for preparing allylmagnesium bromide, a frequently used Grignard reagent in chemistry labs. This will be followed by the procedure for reacting this reagent with trans-cinnamaldehyde to obtain a secondary alcohol. Lastly, we will look at a couple of applications of this reaction.
Prior to addition of the reagents, flame-dry a 50-mL flask and stir bar to remove all traces of water, then cool to room temperature under an atmosphere of nitrogen. This is critical as Grignard reagents are very sensitive to moisture.
Next, add oven-dried magnesium turnings and a few crystals of iodine which will facilitate initiation of the reaction by removing any magnesium oxide coating from the metal. Subsequently, add 24 mL of anhydrous THF.
Place the flask in an ice-water bath to mitigate the heat produced, and with stirring, slowly add allyl bromide via syringe. Then remove the flask from the ice-water bath and allow the reaction mixture to reach room temperature. To ensure completion of the reaction, use gas chromatography to monitor the consumption of allyl bromide.
Once the Grignard reaction is ready for use, prepare for the next step in the reaction. Add to a flame-dried 200-mL flask and stir bar trans-cinnamaldehyde and 30 mL of anhydrous THF, and stir under a nitrogen atmosphere. This is important as in the presence of moisture the Grignard reagent will be destroyed, and will not react with the carbonyl-containing compound.
Stir the trans-cinnamaldehyde solution at 0 degrees, and insert a double-tipped needle into the headspace, with the other end inserted into the headspace of the flask containing the Grignard reagent. Remove the nitrogen-filled balloon from the cinnamaldehyde, and add a nitrogen line to the Grignard flask.
Apply positive pressure with the nitrogen line to transfer the Grignard reagent into the cinnamaldehyde. After the addition is complete, replace the double-tipped needle with a balloon attachment, remove the cold bath, and stir at room temperature. To determine whether the reaction is complete, use thin layer chromatography to monitor the consumption of trans-cinnamaldehyde.
Once it has been determined that the reaction is complete, cool the mixture to 0 degrees, and, while stirring, carefully add 30 mL of saturated aqueous ammonium chloride solution and 50 mL of ethyl acetate. Separate the layers using a separatory funnel, and extract the aqueous layer with three 50-mL portions of ethyl acetate. Combine the organic extracts in the separatory funnel, and wash with 50-mL saturated aqueous sodium chloride solution.
Remove traces of water from the combined organic layers by adding approximately 500 mg of magnesium sulfate, then filter off the solid and rinse with additional ethyl acetate. Concentrate the mixture under reduced pressure, and purify the crude material using flash column chromatography.
To verify the structure of the product, dissolve 2 mg of the dried material in 0.5 mL deuterated solvent and analyze by proton NMR.
Now that we have seen an example laboratory procedure, let's see some useful applications of the Grignard reaction.
Phorboxazole A is a natural product that is shown to exhibit potent antibacterial, antifungal, and antiproliferative properties, prompting efforts in developing synthetic procedures for its manufacture. The Grignard reaction is used in a key step of this synthesis, in which an oxazolyl-methylmagnesium bromide attacks a lactone carbonyl to form a hemiketal intermediate. While the Grignard Reaction is widely applied, side reactions can occur depending on the nature of substrate, and should be taken into account when designing a new synthesis.
For example, if the substrate is a hindered carbonyl, the Grignard reagent can react as a base, deprotonating the substrate, and yielding an enolate. Upon work up, the starting material is recovered. Alternatively, a beta-hydride elimination reaction can take place, leading to the reduction of the carbonyl to alcohol.
To suppress these side reactions, lanthanide salts such as cerium(III) chloride are added to the reaction, where the salts coordinate with the carbonyl oxygen, enhancing the carbonyl electrophilicity. This in turn enables the Grignard reagent to add to the carbonyl to give the desired product and decreases the rate of unwanted products.
For instance, in the reaction between cyclopentylmagnesium chloride and cyclohexenone, the beta-hydride elimination product dominates, if no cerium three chloride is added. However, when the same reaction is performed in the presence of the cerium salt, the desired addition product is obtained in high yield.
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Q1: What is a Grignard reagent and how is it formed?
A Grignard reagent, or organomagnesium halide, forms when an organohalide reacts with magnesium metal turnings. This organometallic reagent is created in situ and serves as a nucleophile in subsequent reactions. The formation requires anhydrous conditions and an inert atmosphere since Grignard reagents are extremely sensitive to moisture and will be destroyed in its presence.
Q2: Why must glassware be flame-dried before preparing a Grignard reaction?
Flame-drying removes all traces of water from the flask and stir bar, which is critical because Grignard reagents are highly sensitive to moisture. Any residual water would destroy the reagent and prevent it from reacting with the carbonyl-containing compound. An inert nitrogen atmosphere must also be maintained throughout the procedure to protect the reagent.
Q3: What is the role of iodine in initiating a Grignard reaction?
Iodine crystals facilitate initiation of the Grignard reaction by removing the magnesium oxide coating from the metal surface. This oxide layer can inhibit the reaction between magnesium and the organohalide. By removing this coating, iodine enables efficient contact between the magnesium metal and the alkyl halide, allowing the reaction to proceed smoothly.
Q4: How does the Grignard reagent react with carbonyl compounds to form alcohols?
The Grignard reagent acts as a nucleophile and attacks the electrophilic carbonyl carbon in aldehydes, ketones, or esters. This nucleophilic attack forms a new carbon-carbon bond, creating an intermediate that yields a secondary or tertiary alcohol upon workup. The alcohol product contains organic portions from both the Grignard reagent and the carbonyl compound.
Q5: What side reactions can occur with hindered carbonyl substrates in Grignard reactions?
With hindered carbonyls, the Grignard reagent can act as a base, deprotonating the substrate to form an enolate and recovering starting material. Alternatively, beta-hydride elimination can occur, reducing the carbonyl to an alcohol instead of producing the desired addition product. Lanthanide salts like cerium(III) chloride suppress these side reactions by coordinating with the carbonyl oxygen and enhancing its electrophilicity.
Q6: How are Grignard reaction products purified and characterized?
After workup with ammonium chloride and ethyl acetate, the organic layers are washed with saturated sodium chloride solution and dried with magnesium sulfate. The crude material is purified using flash column chromatography. Product structure is verified by dissolving the dried material in deuterated solvent and analyzing by proton NMR to confirm the desired carbon-carbon bond formation.
Q7: What are practical applications of the Grignard reaction in organic synthesis?
The Grignard reaction is used in synthesizing complex natural products like phorboxazole A, which exhibits antibacterial, antifungal, and antiproliferative properties. In this synthesis, an oxazolyl-methylmagnesium bromide attacks a lactone carbonyl to form a hemiketal intermediate. The reaction's ability to form new carbon-carbon bonds makes it invaluable for constructing complex organic molecules in pharmaceutical and materials research.