Grignard Reaction

Organic Chemistry II

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Overview

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA

This experiment will demonstrate how to properly carry out a Grignard reaction. The formation of an organometallic reagent will be demonstrated by synthesizing a Grignard reagent with magnesium and an alkyl halide. To demonstrate a common use of a Grignard reagent, a nucleophilic attack onto a carbonyl will be performed to generate a secondary alcohol by forming a new C-C bond.

Cite this Video

JoVE Science Education Database. Organic Chemistry II. Grignard Reaction. JoVE, Cambridge, MA, (2017).

Principles

The Grignard reaction is a method for forming carbon-carbon bonds between alkyl/aryl halides and carbonyls like aldehydes, ketones, or esters. This Nobel-Prize-winning chemistry consists of two steps: Grignard reagent formation and subsequent Grignard addition onto a carbonyl to construct a new carbon-carbon bond. A Grignard reagent is an organometallic compound, specifically an organomagnesium compound. The synthesis of a Grignard reagent requires an alkyl or aryl halide (chlorides, bromides, or iodides) and magnesium. In this step, the electrophilic (an electrophile is electron deficient and accepts electrons) alkyl halide is transformed into a nucleophilic (a nucleophile is electron rich and donates electrons) carbanion-like compound. The second step of the Grignard reaction entails a nucleophilic addition of the Grignard reagent onto a carbonyl. After this step, a new carbon-carbon bond is formed and the carbonyl is transformed into an alcohol. It is important to perform both steps under moisture-free conditions otherwise the Grignard reagent used will react with water, and no desired Grignard or C-C bond formation results. The Grignard reaction is an important and widely used tool that allows synthetic chemists to take any alkyl or aryl halide and transform it into an organomagnesium compound, which can be used to construct carbon-carbon bonds.

Figure 1

Procedure

Figure 2

1. Grignard Reagent Formation

  1. Flame-dry a round bottom flask equipped with a magnetic stir bar.
  2. Add magnesium (Mg, 1.1 equiv.) to the round bottom flask.
  3. 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.
  4. Cool the reaction mixture to 0 °C with an ice-water bath
  5. Slowly add a THF (1 M) solution of allyl bromide (1 equiv.) to the round bottom flask with magnesium.
  6. After adding the solution of allyl bromide, stir the reaction mixture for 3 h at room temperature.

2. Nucleophilic Addition

  1. 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.
  2. Slowly add the THF solution of the Grignard reagent (allyl-magnesium bromide) to the trans-cinnamaldehyde solution.
  3. After the addition, warm the reaction mixture to room temperature by removing the ice-water bath and stir for 4 h.
    1. Monitor the reaction progress via TLC by looking for the disappearance of trans-cinnamaldehyde.
  4. After reaction completion, cool the mixture to 0 °C with an ice-water bath.
  5. Slowly quench the reaction with a saturated aqueous solution of ammonium chloride (NH4Cl).
  6. Transfer the mixture into a separatory funnel and extract the aqueous layer with ethyl acetate 3x.
  7. Combine the organic layers and wash with water and brine (a saturated aqueous solution of NaCl).
  8. Dry the organic layer with anhydrous MgSO4, filter, and evaporate the solvent via rotatory evaporation.
  9. 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.

You've just watched JoVE's introduction to the Grignard reaction. You should now understand the principles of the Grignard reaction, how to perform an experiment, and some of its applications. Thanks for watching!

Results

The purified product should have the following 1H NMR spectrum: 1H NMR δ 7.23-7.39 (m, 5H), 6.60 (d, J = 16.0 Hz, 1H), 6.23 (dd, J = 6.4 Hz, 1H), 5.84 (m, 1H), 5.14-5.20 (m, 2H), 4.35 (q, J = 6.4 Hz, 1H), 2.37-2.43 (m, 2H), 1.9 (br s, 1H).

Applications and Summary

This experiment has demonstrated how to synthesize a Grignard reagent from an aryl/alkyl halide and how to use the Grignard reagent to perform a nucleophilic addition onto a carbonyl compound to construct a new carbon-carbon bond.

The Grignard reaction is widely applied in the synthetic chemistry world, and is used in university research labs, national laboratories, and pharmaceutical companies. Simple Grignard reagents are commercially available, but often times unique and specialized Grignard reagents are required. The Grignard reaction allows synthetic chemists to access the necessary compounds from aryl or alkyl halides. In addition to performing nucleophilic additions onto carbonyls, Grignard reagents can be used as nucleophiles in combination with a large variety of other electrophilic compounds. An example of a specialized Grignard reagent can be found in the synthesis of phorboxazole A, a natural product that exhibits potent anti-bacterial, anti-fungal, and anti-proliferative properties.

Figure 3
Figure 1. Phorboxazole A

Another way to generate Grignard reagents is via magnesium-halogen exchange. This method uses a premade Grignard reagent instead of using magnesium to generate the desired Grignard. The most commonly used Grignard reagents for magnesium-halogen exchange are i-PrMgCl and i-PrMgBr, both of which are commercially available. Magnesium-halogen exchange has been shown to exhibit broad functional group tolerance1. As a result, this method has proven to be a useful way to generate highly functionalized Grignard reagents. Alkyl/aryl halides with functional groups that typically react with Grignard reagents can be used to make Grignard reagents via magnesium-halogen exchange. Esters, nitriles, and alkyl chlorides remain intact during magnesium-halogen exchange. In addition, iodides can selectively undergo magnesium-halogen exchange in the presence of bromides.

Figure 4

Figure 2. Magnesium-Halogen Exchange

Grignard reagents typically act as nucleophiles and add onto carbonyl compounds, but side reactions can occur depending on the nature of the Grignard and carbonyl used. A common side reaction is a Wurtz coupling, where the Grignard reagent couples to itself to form a dimer. Sterically bulky Grignards or carbonyls can make the nucleophilic addition challenging. Potential outcomes with sterically bulky substrates are the absence of an addition or reduction of the carbonyl viaΒββ-hydride transfer. The presence of enolizable protons in the carbonyl can also make nucleophilic addition challenging due to competitive carbonyl enolization. A common way to suppress these side reactions and promote nucleophilic addition is to use lanthanide salts, especially CeCl3, as additives. Lanthanide salts are oxophilic (attracted to oxygen), and therefore they coordinate to the carbonyl oxygen and increase the electrophilicity of the carbonyl. It is expected that addition of cyclopentyl MgCl into cyclohexenone would give the tertiary alcohol, but instead the carbonyl is reduced to give the secondary alcohol. This side reaction can be suppressed in favor of the desired Grignard addition by adding LaCl3.

Figure 5
Figure 3. Lanthanide Salt Promoted Grignard Addition

References

  1. Angew. Chem. Int. Ed.,2003, 42, 4302.

Figure 2

1. Grignard Reagent Formation

  1. Flame-dry a round bottom flask equipped with a magnetic stir bar.
  2. Add magnesium (Mg, 1.1 equiv.) to the round bottom flask.
  3. 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.
  4. Cool the reaction mixture to 0 °C with an ice-water bath
  5. Slowly add a THF (1 M) solution of allyl bromide (1 equiv.) to the round bottom flask with magnesium.
  6. After adding the solution of allyl bromide, stir the reaction mixture for 3 h at room temperature.

2. Nucleophilic Addition

  1. 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.
  2. Slowly add the THF solution of the Grignard reagent (allyl-magnesium bromide) to the trans-cinnamaldehyde solution.
  3. After the addition, warm the reaction mixture to room temperature by removing the ice-water bath and stir for 4 h.
    1. Monitor the reaction progress via TLC by looking for the disappearance of trans-cinnamaldehyde.
  4. After reaction completion, cool the mixture to 0 °C with an ice-water bath.
  5. Slowly quench the reaction with a saturated aqueous solution of ammonium chloride (NH4Cl).
  6. Transfer the mixture into a separatory funnel and extract the aqueous layer with ethyl acetate 3x.
  7. Combine the organic layers and wash with water and brine (a saturated aqueous solution of NaCl).
  8. Dry the organic layer with anhydrous MgSO4, filter, and evaporate the solvent via rotatory evaporation.
  9. 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.

You've just watched JoVE's introduction to the Grignard reaction. You should now understand the principles of the Grignard reaction, how to perform an experiment, and some of its applications. Thanks for watching!

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