1

Nucleophilic Addition to Carbonyl:

Grignard Reaction with an Aldehyde.
Instructor : Dilusha Harischandra ,PhD

Student: Betty Weiss

2
Lab SYNT 718: Nucleophilic Addition to Carbonyl: Grignard Reaction
with an Aldehyde.
by : Betty Weiss
Date of experiment:
January 25, 2016

INTRODUCTION
THE GRIGNARD REACTION
In 1912 the Nobel Prize in Chemistry was awarded to Victor Grignard for his work.
Investigation into the reactions of organic halides with magnesium. This reaction is valuable for its
ability to form carbon-carbon bonds. The Grignard reagents are formed from the reaction of an alkyl
halide with magnesium metal in anhydrous ether. The carbon of the Grignard reagent can function as
both as strong base and a strong nucleophile. However, due to the high reactivity of these Grignard
reagents, great care must be taken to keep the reaction as free from air and water as possible.
OBJECTIVE
To perform and prepare the Grignard reagentisopropyl-magnesium bromide from 2-bromopropane.
The Grignard reagent reacts with 4-methoxybenzaldehyde to form a secondary alcohol,1(4methoxyphenyl)-2-methylpropa-1-ol. The Grignard product should be purified by recrystallization
and characterized by TLC, IR and NMR.
CHEMICAL REACTION

Br
+

Mg

ether

MgBr

Cl
CH3CHCH2CH3

Mg

MATERIALS
50 ml beaker
100 ml beaker
250 ml beaker
5 Erlenmeyer flask (25, 50 & 250 ml)
Bunsen burner
capillary tubes
condenser with tubing cotton
filter funnel
fluted filter paper
25 ml graduated cylinder
pH paper
Pasteur pipet,w/latex bulb
hot plate
125 ml separatory funnel
silica gel TLC plate
REAGENTS AND PROPERTIES
1.

2-bromopropane

ether

MgCl
CH3CHCH2CH3

4
C3H7Br (Isopropyl Bromide)
MM: 122.99 g/mol
BP: 59C
Hazard: Highly flammable liquid and vapor may damage fertility of unborn child.
2.

CaCl2 Calcium chloride, anhydrous

MM: 110.99 g/mol
Hazard: Harmful if swallowed, may cause respiratory irritation, can cause severe skin burns and eye
damage.
3.

(C2H5)2O Diethyl ether, anhydrous

dried 99.5 % (GC) , 0.0075% water
MM: 74.12 g/mol
BP : 34.6C
Hazard: Colorless, highly volatile flammable liquid, it has narcotic properties, can cause temporary
dependence.
Previously used as a general anesthetic in early 1840s.
4.

(C2H5)2O Diethyl ether, solvent grade (ASC grade 98 %, contains ~ 2% ETOH)

5
MM: 74.12 g/mol
BP: 34.6C
Hazard: Is sensitive to light and air, tending to form explosive peroxide, vapor is heavier than air.
Diethyl ether inhibits the metabolic oxidation of ETOH, can cause false positive results on Drug
Screens.
When shaken under absolutely dry conditions ether can generate enough static electricity to start a fire.
5.

I (Atomic number 53), the name is from Greek meaning violet, purple due to the color of elemental
iodine vapor.
MM: 253.8 g/mol
MP: 113C
BP: 184C
Highly soluble Iodine ion I, as other halogens free iodine occurs mainly as diatomic molecule I2. Has
low toxicity and easy attachment to organic compounds, used in X ray contrast.

Ioflupane 123 I (DaTscan) purification by HPLC, contrast agent used with SPECT
for detecting dopamine transporters in Parkinsons diseases (GE-Healthcare, (Amersham). I worked on
the project from Sept.2010-April.2011. Highly radioactive material!
Approved by FDA in Jan.2011, production in London, (Amersham), purification performed in
Arlington Heights, project funded by M.J. Fox.

6
6.

Mg (Magnesium) solid,atomic number 12

MM: 24.3 g/mol
BP: 1091C
Magnesium is the eleventh most abundant element by mass in the human body,ions are essential to all
cells . They interact with polyphosphate coumponds such as, ATP,DNA and RNA.
7.

Magnesium sulfate, anhydrous

MM: 120.37 g/mol

Colorless crystal used as an anticonvulsant, treating low magnesium levels and maintaining the proper
amount of magnesium in the body when used as part of intravenous feedings. It is also used in
pregnant women to control seizures due to certain complications of pregnancy, severe toxemia, preclamsia and to control high blood pressure, encephalopathy and seizures in children who have sudden,
acute nephritis.
Magnesium sulfate is a mineral. It works by replacing magnesium in patients who have low
magnesium levels in the body due to illness or treatment with certain medicines. Magnesium sulfate
may also be used to treat seizures by decreasing certain nerve impulses to muscles.
8.

7
4-methoxybenzaldehyde (4-Anisaldehyde)
C8H8O2
MM: 136.15 g/mol
BP: 248C
MP: -1C
Very soluble in alcohol, benzene and ether, insoluble in water, acetone and chloroform .GC/MS top
peaks 135,136,77 m/z. Organic compound that is commonly encountered in the fragrances both
synthetic and natural. Clear liquid with strong aroma.
9.
1-(4-methoxyphenyl)- 2 methylpropan-1-ol (product)
C11H16O2

MM: 180.21g/mol
BP: 264 C
10.
1 M Phosphoric Acid

MP: 0C

BP: 100C
Hazard: Nonflammable, corrosive, may cause irritation, redness, pain, burns to the skin. Inhalation
may cause respiratory problems.
11.
NaCl (Sodium Chloride)

MM: 58.44 g/mol

MP: 801C
BP: 1413 C
Hazard: Irritant
12.
5% NaOH

MM: 39.99 g/mol

BP: 1388C
MP: 318C
Hazard: Corrosive, toxic, can cause burns/corrosion to the skin.
METHODS AND CALCULATIONS

Prepare the reflux apparatus and dry the glassware in the oven
Weight 0.3632 g Mg turnings
Add 3-4 crystals of iodine to the flask
Heat the reflux apparatus to flood with iodine vapor (my observation dark purple vapor

becomes clear)
Weight 1.4836g (1.13ml) of 2-bromopropane and dissolve in 10 ml of anhydrous diethyl ether
Add 2-bromopropane solution to the magnesium turnings & reflux to make the Grignard

reagent
Poor the solution through the condenser into a flask and stir at medium speed while boiling
Prepare hot water bath, immerse the flask until the water level is even with the reaction
mixture level in the flask, warm it for 10-15 min to complete the formation of Grignard reagent
Allow solution to cool to room temperature
Weight 0.6962 g of 4-methoxybenzaldehyde( p-anisaldehyde) into dry 25 ml Erlenmeyer flask
and add 10 ml of anhydrous diethyl ether directly pouring from the container
Add the solution to the condenser over 10-15 min intervals in a 0.5 ml portions and stir gently
Warm the solution for 10 min and allow to cool to room temperature
Isolate the product by pouring the mixture into ice water and acidify with 1M H3PO4 until

mixture is acid to pH paper (pH 2.0 verified by instructor)

Separate the layers by liquid/liquid extraction
Extract the product into ether & wash it with 5% NaOH & 10 ml of saturated NaCl solution
Dry the ether layer with 2.0 g of anhydrous MgSO4, gradually until solution is not cloudy
Use the hot water bath to distill the ether from the product
Weight the product and label it as Grignard Product
Characterize the product by using TLC,IR and NMR method

RESULTS AND CONCLUSIONS

Empty vial: 6.189g
Vial with a product: 6.733g
Grignard Product: 0.544 g
TLC (THIN LAYER CHROMATOGRAPHY)
Thin-layer chromatography, also known as TLC is a simple and inexpensive analytical
technique useful in identifying the purity of a compound, and also can help identify the quantity of
compounds in a mixture of less than ten micrograms. This is performed by testing the same mixture in

10
a number of different solutions and comparing the Rf values (distance compound traveled/distance
eluent traveled). TLC is comprised of two different phases, the first is a stationary phase in which
suitable absorbent takes in the compound mixture and is usually polar.
The second is a mobile phase in which an eluent (a gas or a liquid) migrates up the TLC silica
gel plate, and is usually nonpolar. If the compound is more attracted to the non-polar eluent then the
compounds will migrate farther up the TLC plate, and if the compound is less attracted to the polar
adsorbent than it will not migrate far. The farther the compound migrates with the eluent, the larger
the Rf value will be. The Rf value of a compound in one eluent may not be enough to identify one
unknown compound, it usually will need to be tested in multiple eluents to be properly identified such
as benzene or methylene chloride solvent.
The principle of TLC method is known for more than 100 years. The real break-through of TLC
as an analytical method (HPTLC) known as high performance thin layer chromatography, also known
as planar chromatography came about 35 years ago as a consequence of the pioneering work of Egon
Stahl. TLC method has gained increasing importance as an analytical separation technique, which is
probably due the effects of instrumentation and automation.

Place 0.1ml of product into 2.0 ml vial and add 1.9 ml of anhydrous diethyl ether and cap it
Spot the standard 4-methoxybenzaldehyde one time and the unknown sample two times on
TLC silica gel plate and let the spot to air dry, mark your sample with pencil
Prepare developing chamber, obtain 5 ml of dichloromethane, cut a piece of filter paper and
place it inside the chamber wall
Poor 5 ml of eluent into chamber and moisten the filter paper & form a layer 3-4 mm deep at
the bottom
Place the spotted silica TLC plate into the dichloromethane developing chamber and seal with a
clamping chamber lid
The solvent migrates up the silica gel plate, carrying with it components at different rates
After developing the plate, remove it from the chamber and immediately mark the eluent front
with a pencil line
Visualize under UV light, mark the spots and calculate the Rf (Retention factor)

Rf = distance migrate by substance/ distance migrate by solvent

11

Figure 1: Displaying product spotted twice; in the

middle is the standard, migration by polarity under
UV light 254 nm
Solvent: Dichloromethane
Rf std: 5.0/6.5 = .769
Rf product: 4.8/6.5 = .738
IR (INFRARED SPECTROSCOPY)
Infrared (IR) spectroscopy is an excellent method of the identification of organic functional groups.
Its often used to confirm presence or absence of a specific functional group in a compound, as well as
compound purity. Additionally it can be also used as a preliminary indicator of types of functional
groups that are present in the unknown sample # 13

12

Figure 2: Unknown # 13
Displaying IR spectrum of major peak OH group at 3500 cm-1, (H-bonded) broad spectrum with
strong intensity, stretching vibration

13

Figure 3: Displaying a product a secondary alcohol, 1-(4-methoxyphenyl)-2-methylpropan-1-ol

IR spectrum at 3454 cm-1 OH group, at 2973 cm-1 showing strong intensity with 2,3 bands
CH3,CH2&CH group (alkenes)
Since most organic compounds have C-H bonds absorption in the range of 2850- 3000 cm-1 is due to
sp 3 C-H stretching; absorption above 3000 cm-1 is from sp2 C-H stretching or sp C-H is near
3000cm-1. Spectrum from 1030-1462 cm-1 showing bending vibrations, medium intensity CH2&CH3
deformation. Absorption from 1511-1601 cm-1, showing medium-strong intensity, bending vibrations
NH2 scissoring 1 amines.

Figure 4: Displaying IR Spectrum of p-anisaldehyde (4-Methoxybenzaldehyde),the noticeable spectra

14
broadens in
the 3000 cm
-1 region,
with
medium
intensity
which
indicates a

benzaldehyde

15

Figure 5: 4-methoxybenzaldehyde (p-anisaldehyde)

Organic compound, consist of benzene ring with an aldehyde and methoxy group. Its a clear liquid
with strong aroma, widely used in pharmaceutical industry.
NMR (NUCLEAR MAGNETIC RESONANCE)
NMR is one of the most important diagnostic tools available to organic chemist. This method provides
information as to the relative positions and numbers of spin active nuclei in a compound ,this tool can
be used to identify the structural features of a molecule. NMR can be used a s analytical tool to define
product ratios, purity complete chemical structure in a short period of time. Determination of peak
integration is performed by measuring the line height of each integral plot of the spectrum and divided
by lowest value to get relative peak intensities. Next step is to determine the chemical shift of each
resonance in the spectrum. Important is also to determine the splitting of each resonance in the
spectrum.

16

17

Figure 6: Displaying NMR of p- anisaldehyde , first signal is 3H of CH3, second is a doublet

of two H of aromatic ring ortho to O atom, third is a doublet of two H of aromatic ring ortho

18
to CHO group, last is a lone H of CHO.
This lab and its technique seemed to me to be the easiest to understand I have performed it
several years and I found it a bit easier. The only error made in this lab with my lab partner Saul
was by spotting the TLC standard, please see figure 1,it should have been diluted.
The percent yield of the product is: .544/0.9 *100 = 60 %
The purpose of adding anhydrous MgSO4 is to make Grignard Reagent (electron transfer from
magnesium to bromobenzene, carbonation occurs).If the steps are omitted in the procedure no
reaction will occur. The first side product is biphenyl (Ph-Ph), the second is benzene (PhH),resulting from protonation of carbonation, so if there is any water in the solvent or
glassware or if moist air is allowed to enter the reaction mixture, some of the carbonation will
be pronated. The last problem could be unreacted starting material( Ph-Br,Mg or ester) ,which
didnt happen in our case. Overall the procedure and results were success.
REFERENCE
Stahl, Egon. Thin layer chromatography, 2 edition. Springer-Verlag Berlin, Reprint. 1988.
nd

19

20

21