Grignard Reagent - A Powerful, Versatile Nucleophile1

Reading Assignment: Smith, J.G. Organic Chemistry; McGraw Hill Review 20.1-20.2A, Read 20.2B,
20.9-20.11 Review recrystallization: http://orgchem.colorado.edu/Technique/Procedures/Crystallization/
Crystallization.html

Introduction
Organometallic reagents play a very important and diverse role in organic chemistry. Organometallic
compounds are defined as compounds that contain a carbon-metal bond, where the metal can be one of the main
group elements, such as magnesium or lithium or a transition metal, such as palladium, iridium, etc.
Organometallic compounds are used as reagents in molar ratios or they can be used as catalysts, species that are
not consumed in the reaction, but simply help to lower the energy of a transition state making a reaction
possible.

Organomagnesium halides, also known as Grignard reagents, are some of the earliest known organometallic
compounds. These reagents are typically prepared by combining an alkyl halide with magnesium metal in an
ethereal solvent. The reaction is thought to occur at the surface of the magnesium metal via a free radical
mechanism as shown below (Fig. 1). One electron is transferred from the magnesium metal (Mg0) to the alkl
halide (RX). The resultant carbon-based and magnesium halide radicals combine to form a covalent bond. An
ethereal solvent is required (most often diethyl ether, Et2O, or tetrahydrofuran, THF). These Lewis basic
solvents stabilize the Grignard reagent and carry it away away from the metal surface, thus allowing for reaction
of another alkyl halide.

- +
R X R + Mg+ X R Mg+X
Mg = R MgX = R:
X = Cl, Br, I
R = alkyl, aryl,
alkenyl, alkynyl

Figure 1. Mechanism of Grignard Formation

The bond between carbon and magnesium is covalent, but highly polarized so that the carbon has significant
negative charge build-up. Therefore, the carbon reacts as if it was a carbanion and is a strong base and a great
nucleophile.
Because the Grignard Reagent is so strongly basic one must be careful not to attempt to form or use the reagent
in the presence of acids such as water, alcohols, carboxylic acids or even amines and alkynes. Recall, acid-
base chemistry happens fast!
RMgBr + H A RH + A MgBr

HA = H 2O, ROH,
RCO 2H, R 2NH,
or RC CH

Example:

MgBr + CH 3OH H + OCH3 + MgBr BrMgOCH 3

Figure 2. Grignard Reagent as a Base.

Because the Grignard reagent is a source of nucleophilic carbon it provides synthetic and medicinal chemists an
outstanding tool for creating carbon-carbon bonds. The Grignard reagent can add to a wide range of
electrophiles including, but not limited to epoxides, ketones, aldehydes, acid chlorides, esters, carbon dioxide
and nitriles (Figure 3.). Though Victor Grignard earned the Nobel Prize for his work developing the reagent
over 100 years ago it remains important today. A quick search in SciFinder reveals over 23,000 articles
containing the Grignard reagent; 635 were published in 2014-2015.

Grignard Addition to an Aldehyde: Nucleophilic Addition

O O MgBr OH
H 3O+
R'MgBr + R H R H R H
Et 2O R' R'

Grignard Addition to an Acid Chloride: Nucleophilic Substitution then Addition

O O MgBr OH
H 3O+
2 eq. R'MgBr + R Cl R R' R R
Et 2O R' R'

Figure 3. Examples of Grignard Reagents as Nucleophiles

Grignard reagents are useful in the synthesis of many important molecules. The example shown below features
the addition of vinylmagnesium bromide (the vinyl Grignard reagent) to an aldehyde. The secondary alcohol
isolated after the acidic work up was taken on to synthesize analogs of N-acetylcholchinol. These molecules are
useful as a vasculature disrupting agents/anti-cancer drugs.2

O OH

MeO 1. 3 eq. MgBr MeO

OTES OTES
THF, -78 oC,3h
MeO MeO
OMe 2. H 3O+ OMe

Figure 4. Grignard Reagent Used in the Synthesis of Vasculature Disrupting Agent/Anticancer Drug

In todays experiment everyone will prepare the Grignard reagent phenylmagnesium bromide, PhMgBr (figure
4) by refluxing bromobenzene and magnesium metal in diethyl ether.
Br Mgo MgBr

CH3CH2OCH2CH3
phenylmagnesium
bromide

Figure 4. Preparation of the Phenyl Grignard Reagent

The class will then be split into 3 groups. Each group will be assigned a slightly different electrophile to react
with the phenylmagnesium bromide (figure 5). Can you predict the product of each reaction?
O
MgBr H 2SO 4

CH 3CH2OCH2CH 3 H 2O

benzophenone

O
MgBr H 2SO 4
OCH3
CH 3CH2OCH2CH 3 H 2O

methyl benzoate

MgBr H 2SO 4
O C O
CH 3CH2OCH2CH 3 H 2O
carbon dioxide

Figure 5. Phenylmagnesium Bromide Reacts with Benzophenone, Methyl Benzoate, and Carbon Dioxide
The Grignard reagent is destroyed by water that is present in the air, adhered to glassware, or dissolved in
solvents. In addition, it reacts with oxygen to form peroxides. Therefore, the Grignard Reagent must be
formed and used under strictly air- and moisture-free conditions. The glassware to be used for this reaction has
been dried in an oven at 120 oC overnight to remove moisture from the glass surface. Use caution handling
hot glassware! Dry, inert nitrogen (N2) will be bubbled through the glassware as it cools and as the reaction
approaches reflux. This will create an air-free system and will prevent moisture from redepositing on the
glassware as it cools down. Because diethyl ether is highly hygroscopic (what does that mean?) anhydrous
ether will be stored over molecular sieves. It is extremely important that each lab section take care to keep all
stock bottles and individual aliquots of diethyl ether tightly covered to minimize exposure to atmospheric
moisture.

Occasionally the preparation of the Grignard reagent is slow to start because the magnesium metal surface is
often coated with magnesium oxide, formed from the reaction of the metal with air. Grinding the metal turnings
before adding them to the reaction flask should help to expose some the metal surface. Sonicators are also
useful for this purpose because they produce ultrasonic waves, which physically remove the magnesium oxide.
A clean surface can also be exposed chemically by adding small amounts of iodine or ethylene dibromide.

Safety Precautions:
Bromobenzene and benzophenone are irritants. Benzophenone is a suspect carcinogen. Handle in the hood
with gloves.
Methylbenzoate is harmful if swallowed.
Diethyl ether and bromobenzene are flammable and methyl benzoate is combustible; keep these reagents away
from sources of high heat and open flame.
Magnesium is a flammable solid and releases a flammable gas when in contact with water. Keep away from
sparks and open flame. Extinguish fire with sand or dry powder.
Carbon dioxide sublimes at -78oC. Handle carefully with gloves to prevent frostbite.
All needles should be disposed of in the RED SHARPS CONTAINERS ONLY. Do NOT attempt to recap the
needle before discarding. Disposing of the needles in any other container will result in a zero for the
experiment.
Hydrochloric acid is highly corrosive. For skin or eye contact rinse with water for 15 minutes.
EXPERIMENTAL

Chemicals:..............................................................................................Waste disposal
Magnesium turnings, 0.33 g.........................................................................Solid waste
Bromobenzene, 1.1.5 mL.........................................................................Organic waste
Diethyl ether, anhydrous, 8 mL ...............................................................Organic waste
Diethyl ether, ordinary, 5-20 mL .............................................................Organic waste
Methyl benzoate, 0.61 mL....................................................................Organic waste
Dry ice, 0.45 g..................................................................................................Sublimes
Benzophenone, 1.6 g................................................................................Organic waste
3M HCl, 5-10 mL..............................................................................Inorganic waste
6M HCl, 3-10 mL..................................................................................Inorganic waste
3% NaOH, 20 mL..............................................................................Inorganic waste

Procedure
This experiment is one of the longest of the semester. It is essential that you plan ahead and work efficiently so
that you finish on time.

Preparation of phenylmagnesium bromide (Grignard reagent)

1) Before retrieving the glassware from the oven, first gather together two orange septa and one needle. Be
sure that a needle is attached to the end of your nitrogen line. If not, obtain a second needle and attach it
firmly. Check to be sure the nitrogen has been turned on at the main valve by turning on the nitrogen at
your hood. You should notice bubbling in the glass bubbler attached to the nitrogen line. If not,
please tell your TA know.

2) Right before you collect glassware from the oven, obtain 0.33g of magnesium metal turnings.

3) One partner should collect a reaction tube from the oven (handle carefully with a paper towel - it will be
HOT). The other partner should quickly grind the magnesium in a mortar and pestle to expose fresh
metal surface. Pour the magnesium turnings in the reaction tube then quickly attach the orange rubber
septa to both opening. Attach the reaction tube to the clamp. Turn on the nitrogen and insert the needle
into the small round circle in the center of the rubber septum. Add a second, open needle to the orange
septum to allow an opening for the air to be displaced as nitrogen is being introduced.
4) Wrap the top of the reaction tube with a pipe cleaner soaked in ethanol. The formation of the Grignard
reagent is exothermic and therefore the chance exists for a runaway reaction. Keep a cool water bath
nearby at all times in case the reaction requires rapid cooling.

5) Measure 4 mL of anhydrous (dry) diethyl ether with a disposable 5 mL syringe and deliver to a clean,
dry test tube (or Erlenmeyer flask). Carefully measure 1.15 mL of bromobenzene with a 2 mL
disposable syringe and add to the test tube/Erlenmeyer flask containing the ether, then swirl to mix.
Immediately draw the up the entire volume of the ethereal bromobenzene solution into the 5 mL syringe
to minimize exposure to the moisture in the air. Fit the syringe with a needle.

6) Slowly add enough bromobenzene/ether solution to just cover the Mg turnings via syringe through the
rubber septum. DO NOT ADD ALL OF THE BROMOBENZENE SOLUTION AT ONCE, as the
reaction may get out of control.

7) Swirl the reaction vessel gently in the palm of your hand, being careful not to push the magnesium up
onto the sides of the flask. The heat from your palm may help to initiate the reaction.

8) Observe carefully for the start of the reaction signaled by bubbling (even when the reaction flask is
pulled away from the heat), or the appearance of a brownish grey cloudy precipitate (more common).
The formation of small bubbles at the surface of the magnesium will be noticeable. If the reaction does
not start after about 2-3 minutes you may try one of the following:
! Crush the magnesium by quickly and carefully removing the rubber septum. Insert a
clean dry glass stirring rod into the reaction tube to pulverize the magnesium, which has
been softened. Take care not to poke the rod through the bottom of the reaction tube by
holding the reaction tube firmly against the bench top to apply counter pressure.
! Add ONE OR TWO small iodine crystals (more is NOT better).
! Heat the reaction mixture gently in the sand bath.
! Add a few more drops of bromobenzene/ether.

9) Once you observe evidence that the reaction has started continue to add the bromobenzene/ether solution
to the magnesium suspension drop-wise at a rate of 1-3 drops per second. If the condensation line does
not remain in the lower third of the condenser, slow the addition. Heating should not be necessary since
the reaction is sufficiently exothermic to allow the solvent to boil without additional heating. However,
 if the reaction slows down add more bromobenzene or heat with the sand bath. It is important to
maintain the reflux once the reaction has started.

10) Maintain a gentle reflux for 10-15 minutes after all of the bromobenzene solution has been added. Keep
an eye on the solvent volume in the flask. If the volume decreases below the original volume or you
notice that the mixture is thick and gelatinous add more dry diethyl ether. After 10 minutes of reflux
allow the mixture to cool to room temperature.

Addition of Electrophiles

Option 1: Benzophenone

1) During the 15 minute reflux remove a 25 mL Erlenmeyer flask (Or test tube) from the oven. Careful!!
Hot glass looks the same as cool glass! Cover with an orange septum and cool under nitrogen. (It is
safe to remove the nitrogen line from the reaction tube because the reaction is at reflux. This means that
the reaction mixture is blanketed in the solvent vapors.)

2) Weigh out 9 mmol of benzophenone. Crush with a spatula to a fine powder (this will assist the
dissolution). Add the powder to the Erlenmeyer flask. Add 4 mL anhydrous Et2O via a clean and dry
disposable 5 mL syringe. Swirl the flask well until the benzophenone is completely dissolved. Draw
the entire volume into a syringe, fit with a needle and set aside until needed.

3) Once the solution of phenylmagnesium bromide has reached room temperature, add the benzophenone
solution to the Grignard reagent fast drop-wise with shaking. Add the benzophenone/ether at a rate
sufficient to maintain a gentle ether reflux. Keep a cold bath around to slow reaction if it gets out of
control. Once the benzophenone solution has been completely added to the Grignard reagent allow the
solution to reflux for an additional 10 minutes. The reaction mixture will turn a rose color and may
begin to solidify. Do your best to continue stirring, with a clean, dry stir rod or spatula if necessary. You
may add more ether if necessary.

Quenching the Reaction Mixture

11) Cool to room temperature then pour the reaction mixture a small beaker and cool it on ice. If unreacted
magnesium turnings are visible leave them behind in the reaction tube, then dispose of in the special
 magnesium solid waste container. To the reaction mixture, add drop-wise with stirring about 5-6 mL of
3M hydrochloric acid. Take care not to add too quickly as reaction may be vigorous. Add a few
milliliters of the acid and ~5 mL ether to the reaction tube, swirl in order to dissolve any solid and add
this solution to the beaker.

12) If two layers are not clearly evident add more ether (anhydrous ether no longer necessary - use
ordinary ether from this point forward) and/or water to dissolve all solid precipitates. Expect a total
volume of approximately 50 mL. The result should be two perfectly clear, though not necessarily
colorless layers. Whenever you are doing an extraction and three layers are apparent, the middle layer is
an emulsion and can often be removed by adding more of one or both of the solvents and gentle
swirling. Any bubbling seen at the interface or in the lower layer is leftover magnesium reacting with
the hydrochloric acid. Transfer the two layers to a separatory funnel, rinse with ether and water to aid in
transfer. Where do you expect the product to be? Which layer is on top? Organic or Aqueous? Never
throw away any layers until you have your product in hand. Drain the aqueous layer into a small beaker.
Shake the ether layer with an equal volume of saturated aqueous sodium chloride solution (brine) in
order to move any remaining water. Carefully drain the entire aqueous layer.

13) Pour the ether layer out of the top of the separatory funnel into an Erlenmeyer flask and dry with
anhydrous calcium chloride pellets. Swirl the flask periodically over 5-10 minutes to complete the
drying process. Remove the drying agent by filtering. Rinse the flask with several portions of ether to
facilitate transfer.

14) Transfer the solution to a pre-weighed round bottom flask. Remove the solvent on the rotary
evaporator. Keep in mind that the round bottom flask should not be filled greater than 1/3 - 1/2 full
when placed on the rotary evaporator. Transfer to a larger round bottom flask or evaporating in two
portions may be necessary.

15) After all of solvent has been removed weigh the flask and record the mass of your crude product.
Purification of the product.

16) Trituration (grinding) of the crude product with hexanes will remove non-polar impurities. Stir and
grind the crystals with 1.5 mL hexanes with gentle warming. Use a Pasteur pipet to remove as much of
the solvent as possible (Where is your product? Recall, the goal here is to remove non-polar impurities.)

17) Optional: Recrystallization will remove any impurities that remain. Dissolve the crystals in the smallest
possible quantity of warm ether in a small beaker. Add 1.5 mL hexanes. Place the beaker on the
hotplate set at a low setting. Concentrate the solution until you notice it turns slightly cloudy. (Is it ok
if all of the solvent is evaporated? What happens to the impurities that were dissolved in the solvent if it
is completely evaporated?) Remove the solution from the hotplate and allow to cool to room
temperature. Place the beaker in an ice/water bath to promote complete crystallization. Collect the
crystals via suction filtration. Continue to filter for several minutes to draw air through the crystals to
promote drying.

18) Determine the weight and melting point. Analyze your product by IR and prepare a sample for NMR
analysis (15 mg product/0.5 mL CDCl3 - fill to 5 cm mark). Calculate percent yield for your product.
Add your product to the correct product collection vial in the hood.

Clean your glassware thoroughly and be sure to return the reaction tube, Erlenmeyer flasks or large test
tubes to the appropriate shelf in the oven!

Option 2: Methyl benzoate

Same as above except use methyl benzoate instead of benzophenone. Two equivalents of the PhMgBr will add
to the methyl benzoate. Therefore, use 4.5 mmol of the liquid methyl benzoate.

Option 3: Carbon Dioxide

1) Atmospheric moisture condenses on the surface of dry ice. Before using it in a reaction, wipe the
surface of the dry ice with a clean, dry paper towel to remove any frost. Place it in a beaker covered by
a watch glass until you are ready to use it.

2) When the phenylmagnesium bromide has been prepared and the mixture has stopped refluxing,
 remove the nitrogen line, open needle and septum and pour the entire contents slowly but steadily over
2 g of dry ice contained in a 50 mL beaker - try to leave as much of the unreacted magnesium metal
behind in the reaction tube. Rinse the reaction tube with a 2-3 mL of anhydrous ether to aid in transfer
and add that to the reaction mixture (again without transferring the magnesium). Cover the reaction
mixture with a watch glass, stirring periodically, until the excess dry ice has completely sublimed. The
Grignard product will appear as a viscous glassy mass. If the mass is too viscous to stir, add an
additional 5-10 mL of ether or more if needed.

Quenching the Reaction Mixture

3) To the beaker containing the reaction mixture, add 10 mL of crushed ice/water. Remove any unreacted
Mg turnings with a spatula and discard in the special magnesium solid waste container. Add slowly and
carefully ~3 mL of 6M HCl (multiple concentrations available - read the label carefully). Take care not
to add too quickly as reaction may be vigorous. Stir the mixture thoroughly. If solids persist add more
ether and/acid until all solids have dissolved. Test the pH with Litmus paper. If the pH is not between
0-1 add additional acid drop-wise until you reach this level.

4) Transfer the two layers to a separatory funnel, rinse with ether and water to aid in transfer. Where do
you expect the product to be? Which layer is on top? Organic or Aqueous? Never throw away any
layers until you have your product in hand. Drain the aqueous layer into a small beaker. Drain the
organic layer into a separate labeled container. Return the aqueous layer to the separatory funnel and
extract two times with 10 mL portions of Et2O (ordinary, not anhydrous).

5) Place the combined organic layers back into the separatory funnel and extract with two-10 mL portions
of 5% aqueous sodium hydroxide. A reaction is actually taking place in this step! What is it? In which
layer would you expect to find most of your product in this step? This is important - discuss this with
your TA before moving on.

6) Combine the aqueous extracts in a beaker and heat briefly to ~50 oC to remove any residual ether.

7) Acidify to pH = 1 or less with 6M HCl. Cool in an ice/water bath to aid in precipitation.

8) Isolate the precipitated solid by suction filtration. Weigh the solid.

Purification of the Product

9) (Optional) Recrystallize the crude product from water: Heat up approximately 50 mL of water to
boiling on a hotplate (be sure to add boiling stones). Dissolve the crude product in the minimum amount
of hot water. Be sure to add the hot water to the crude product and swirl over the hotplate. Do not allow
the water to cool down or too much water will be added and your product will not precipitate out. Once
the solid has been completely dissolved set the flask on the bench top to cool. Once you see solid begin
to precipitate place the beaker in an ice/water bath to complete the cooling.

10) Isolate the solid by vacuum filtration. Continue to filter for several minutes to draw air through the
crystals to promote drying.

Analysis of the product

11) Determine the weight and melting point. Analyze your product by IR and prepare a sample for NMR
analysis (15 mg product/0.5 mL CDCl3). Calculate percent yield for your product. Add your product
to the correct product collection vial in the hood.

Pre-Lab Notebook
Objective:
! Include a statement of the main objective of this experiment.

! Include the reaction (using structures) and mechanism for formation of the Grignard reagent from
bromobenzene and magnesium metal.

! Show the mechanism and predict the products of the reaction of phenylmagnesium bromide with
benzophenone, methyl benzoate and CO2.

! Include a mechanism for the formation of two common by-products: benzene and biphenyl. Indicate
the steps necessary to minimize formation of these by-products.
 Table of reagents and products: include the reagents/products from the table below and also include columns
for actual amounts used (g or mL) and (mol).
Actual
Molecular weight, Density, Actual amounts,
mp/bp, oC Amounts,
g/mol g/mL mmol
g or mL
Bromobenzene 157.02 130 (bp) 1.491
Mg metal 24.3
Benzophenone 182.21 48 (mp)
Methyl benzoate 136.14 199 (bp) 1.08
Dry ice (solid CO2)
Diethyl ether 34.5 (bp) 0.708
Product
Biphenyl (colorless crystals) 154.21 72

In-Lab Notebook:
Observations- record EXACT amounts of reagents used (use table similar to one shown above), detailed
observations, and any changes you have made to the written procedure.

Calculations- Show complete calculation of percent yield and percent recovery (if recrystallization
performed).

All information above should be written directly into your lab notebook. The duplicate pages will be turned
in with the rest of your lab report.

Post-Laboratory Report:

Prepare an oral presentation to be presented during lab the week of February 27-March 3.
Prepare a PowerPoint or Keynote presentation (or use similar software) with your lab partner.
The presentation should be approximately 15 minutes long.
Reactions and mechanisms should be created using Chem Draw.
You will sign up for a one hour slot during your lab period in which you will present. Link will be
provided on Canvas.
Include at least the following:
1. Main objective.
2. Include one example of the Grignard reaction in the recent literature to highlight why this
reaction is so useful. Use SciFinder to find a recent article. In your presentation highlight the
importance of the work described in the paper and how the Grignard Reaction contributes to the
overall goal of the work. Draw the Grignard reaction using Chem Draw. Be sure to fully
 reference the article on the slide. Use the Chem Resources lab handout or the ACS Style Guide
for formatting guidelines.

3. Include the following reactions and correct/modified mechanisms:

Preparation of phenyl magnesium bromide from bromobenzene and magnesium metal.
Reaction and mechanisms of phenylmagnesium bromide with benzophenone, methyl benzoate
and carbon dioxide (followed by acidic work up). Compare and contrast the mechanisms.
What is similar and what differs about the mechanisms?
Mechanism of formation of biphenyl and benzene. Discuss what you did to prevent formation
of both of these molecules. How did you attempt to remove any biphenyl that may have
formed during the reaction?
Show the reaction and mechanism of phenylmagnesium bromide with a different carbon-based
electrophile. You may choose the electrophile. It should not belong to the ketone or ester
functional group class or be CO2.
Which product did you isolate and how pure is it? Identify any of the impurities that are
present. Use mp data, IR and 1H NMR results to back up all of your claims. Note I am
leaving out specific instructions regarding the information you should include in this
discussion. Use what you have learned in previous experiments to determine which pieces of
information are useful. This should be a thorough discussion with claims backed up by
evidence.
What was your percent yield? What could you do differently next time to improve on the
percent yield?
Do not include the details of the procedure in your report, unless there were deviations that
caused your experiment to give unusual results.
Be sure to include pictures of your labeled IR and NMR spectra in your presentation and
discuss the IMPORTANT peaks.
Be creative! Have fun with this. Use your own style and tell a story. Do not just use the
instructions above as a checklist.

References: 1. Epstein, W.W., Seidel, J.L., Young, C.S. Chem 2325 Organic Chemistry II Laboratory; Hayden
McNeil: Plymouth, 2013. 2. Colombel, V., Baudoin, O. J. Org. Chem., 2009, 74 (11) pp 4329-4335.