EXPERIMENT 7

FRIEDEL-CRAFTS ACETYLATION
CHEMISTRY

63
 FERROCENE CHEMISTRY

AIMS OF THIS PRACTICAL

1. To demonstrate Friedel-Crafts acetylation of an inorganic aromatic system.
2. To illustrate the effect Lewis acids of different strength have on the outcome of
the reaction.
THEORY
Ferrocene was first prepared in 1951. There were many ideas put forward about its
structure.

Fe Fe2 Fe

(1) (2) (3)

Figure 1: Refinement of structure of Ferrocene
One of the first was that as it contained Fe (II), it must have two rings linked to the Fe (II)
by two Fe-C σ−bonds (1). However, IR and NMR studies showed that the molecule
consisted of two 5-membered rings around a central Fe (II) atom. The cyclopentadienyl
anion has six π-electrons and is aromatic (2).

There are eight valance electrons from the iron atom and five from each of the two rings,
resulting in a total of 18 electrons. These combine to give six bonding and three non
bonding molecular orbitals as illustrated in figure 2. This has led to the actual structure
(3), i.e. all carbons interact equally with the iron atom.

Ferrocene undergoes electrophilic aromatic substitution reactions, e.g. halogenation,

Friedel-Crafts acylations and acylations, in the same manner as benzene. In this
experiment you will look at a Friedel-Crafts acetylation to illustrate the aromatic nature
of the rings. Since ferrocene is more nucleophilic than benzene, it is easier to acetylate. In
this experiment you will use two different Lewis acids and two different acetylating
reagents to see what effect this has on the outcome of the reaction.

As an extra part to this experiment or as an experiment in its own right, you can
synthesise Fenbufen (information on this can be found after the instructions for the main
experiment).

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Figure 2 – MO diagram of Ferrocene

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Experimental Procedure

CHECK THERE IS NO WATER PRESENT IN THE REACTION

VESSEL AS A VIOLENT REACTION CAN OCCUR.

Working in a pair, one person do part A and the other person do part
B.

Part A
To a 100 ml 3-necked flask, containing a stirrer bar, add ferrocene (0.56g, 3 mmol),
acetic anhydride (0.92g, 9 mmol) and dichloromethane (15 ml). Flush the system with
nitrogen for roughly 5 minutes, while stirring the mixture. Using a syringe, add boron
trifluoride etherate (1.42g, 10 mmol) dropwise to the mixture and leave the solution to
stir for 30 minutes under a nitrogen atmosphere.

When washing the syringe, wash with plenty of methanol, ESPECIALLY THE
FIRST RINSE.

Using a syringe, remove a few μL of the reaction mixture and place into a vial. Dilute
this sample with dichloromethane (1ml). Using TLC analysis (chloroform/ methanol
(99:1)), check for the presence of any unreacted starting material. If any starting
material is present, leave the reaction for a further 15 minutes and repeat the TLC.

Dilute the reaction mixture with dichloromethane (10 ml). Attach a dropping funnel to
the reaction vessel (make sure the tap is closed) and add water (50 ml). Place a stopper
into the dropping funnel. Cautiously add the water dropwise. Pour the resulting biphasic
mixture into a separatory funnel and remove the organic layer. Wash the organic layer
with water (3 x 10 ml) and dry over anhydrous magnesium sulphate. Filter the drying
agent and wash it with dichloromethane to remove the red product, before concentrating
the solution on a rotary evaporator. Add dichloromethane (5 ml) and cyclohexane (10 ml)
to the solution and cool in an ice bath, while scratching the flask. Filter the crystals that
form using suction filtration.

Record the yield, melting point, IR and 1H NMR spectra of your product.

Part B

To a 100 ml 3-necked flask, containing a stirrer bar, quickly add anhydrous aluminium
chloride (1.33g, 10 mmol), followed by dichloromethane (25 ml) ferrocene (0.56g, 3
mmol). Flush the system with nitrogen for roughly 5 minutes, while stirring the mixture.
Using a syringe, add acetyl chloride (0.78g, 10 mmol) dropwise to the solution and leave
it to stir for 30 minutes under a nitrogen atmosphere.

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When washing the syringe, wash with plenty of methanol, ESPECIALLY THE
FIRST RINSE. Please note that a little methanol WILL cause a violent reaction
with acetyl chloride.

Using a syringe, remove a few μL of the reaction mixture and place into a vial. Dilute
this sample with dichloromethane (1ml). Using TLC analysis (chloroform/ methanol
(99:1)), check for the presence of any unreacted starting material. If any starting
material is present, leave the reaction for a further 15 minutes and repeat the TLC. If
more than one spot present, consult a demonstrator.

Dilute the reaction mixture with dichloromethane (10 ml). Attach a dropping funnel to
the reaction vessel (make sure the tap is closed) and add water (50 ml). Place a stopper
into the dropping funnel. Cautiously add the water dropwise. Pour the resulting biphasic
mixture into a separatory funnel and remove the organic layer. Wash the organic layer
with water (3 x 10 ml) and dry over anhydrous magnesium sulphate. Filter the drying
agent and wash it with dichloromethane to remove the red product, before concentrating
the solution on a rotary evaporator. Add dichloromethane (5 ml) and cyclohexane (10 ml)
to the solution and cool in an ice bath, while scratching the flask. Filter the crystals that
form using suction filtration.

Record the yield, melting point, IR and 1H NMR spectra of your product.

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 Preparation of Fenbufen

AIMS OF THIS PRACTICAL

3. To demonstrate Friedel-Crafts acetylation of an aromatic system to produce a
drug precursor.

THEORY

In this experiment, the industrially practical synthesis of the non-steroidal anti-

inflammatory drug (NSAID) Fenbufen will be carried out by reaction of biphenyl with
succinic anhydride. Several Lewis acid catalysts (e.g. SnCl2, BF3.OEt2) have been shown
to be effective for the acylation of aromatic substrates with acid chlorides and
anhydrides; in this case aluminium chloride will be used. The transformation is shown in
the reaction scheme below:
O

OH
O
O O AlCl3
+
O
dichloroethane
rt

Fenbufen (once converted to its active form in the liver) works by blocking the action of
an enzyme called cyclo-oxygenase (COX). Cyclo-oxygenase is involved in the
production of various chemicals in the body, some of which are prostaglandins.
Prostaglandins are produced in response to injury or certain diseases and cause pain,
swelling and inflammation. Thus, by stopping the production of prostaglandins, fenbufen
relieves inflammation and pain (e.g. in arthritis, tendonitis, dislocations and fractures).
Since the isolation of salicylic acid from willow bark in 1829, NSAIDs have become an
extremely important class of pharmaceuticals for the treatment of pain, with aspirin and
ibuprofen being the most prominent members of this group.

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Experimental Procedure

Carry out a COSHH assessment before you start this experiment (Seek advice from
a demonstrator). This must be written up before you can proceed.

Check all glassware is dry before commencing the experiment. Reaction must be
performed in a fume hood.

To a 100 ml 3-necked round bottom flask containing a stirrer bar, equipped with a
pressure equalising dropping funnel, a thermometer and a nitrogen balloon, add succinic
anhydride (1.0 g) and 1,2-dichloroethane (20 ml). Cool the resulting solution to 0ºC using
an ice/water bath, and then add aluminium chloride (1.5 g).

Aluminium chloride should be weighed out in a fume hood as reaction with

moisture in the air evolves HCl vapour.

In a 25 ml conical flask, dissolve biphenyl (1.54g) in 1,2-dichloroethane (5 ml) and add

the solution to the dropping funnel. Add the biphenyl solution dropwise to the reaction
mixture, ensuring the temperature does not exceed 15ºC. The reaction mixture will
change colour, first to a deep yellow, then green and finally blue/black. When the
addition is complete, remove the ice bath and leave the reaction to stir for 2 hours. Check
for the disappearance of biphenyl by TLC (pet. ether, neat).

To a 100 ml 2-necked round bottom flask containing a stirrer bar and fitted with a
thermometer, add water (25 ml) and conc. HCl (2.5 ml) and cool to 0ºC using an
ice/water bath. Add the reaction mixture slowly, ensuring that stirring is maintained
(extra water, e.g. 10-15 ml, can be added to aid stirring). The colour will disappear and an
off-white precipitate Fenbufen will form. Stir the mixture for 15 mins at 0ºC, checking
the stirring regularly. Recover the precipitate by suction filtration, and wash with pet.
ether (2 x 10 ml). Transfer the solid to a pre-weighed dish and desiccate overnight under
vacuum.

When dry, record the mass of your product and calculate the yield. Recrystallise from hot
ethanol and record melting point, IR and NMR.

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 FERROCENE CHEMISTRY

Ac2O / BF3.Et2O Fe AcCl / AlCl3

REAGENTS (quantities g/ml mmol)

PART A
FERROCENE

BORON TRIFLUORIDE

ACETIC ANHYDRIDE

DCM

CYCLOHEXANE

PART B
FERROCENE

ALUMINUM CHLORIDE

ACETYL CHLORIDE

DCM

CYCLOHEXANE

SAFETY INFORMATION
FERROCENE R : 11-22 HIGHLY FLAMMABLE
S : 16 KEEP AWAY FROM SOURCES OF IGNITION

BORON TRIFLUORIDE R : 10-34-20/22-48/23-52/53 FLAMMABLE

(ETHERATE SOLN.) S : 26-45 CAUSES BURNS
IF FEELING UNWELL CONTACT A MEDIC
DANGER OF SERIOUS HEALTH DAMAGE WITH PROLONGED EXPOSURE

ACETIC ANHYDRIDE R : 10-34 FLAMMABLE

S : 26-45 CAUSES BURNS
CYCLOHEXANE R : 11-38-50/53-65-67 HIGHLY FLAMMABLE
S : 26-45 WEAR GLOVES

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ALUMINUM CHLORIDE R : 34 WEAR GLOVES
S : 7/8-26-28-36-45 CAUSES BURNS

ACETYL CHLORIDE R : 11-14-34 HIGHLY FLAMMABLE

S : 9-16-26-45 CAUSES BURNS

Other compounds see safety page

METHOD (BRIEF DESCRIPTION OF PROCEDURE)

YIELD and MELTING POINT

PART A
Product weight = g

% Yield = product weight/ rmm product x 100 =

ferrocene weight/ rmm ferrocene

mp = ْc

PART B
Product weight = g

% Yield = product weight/ rmm product x 100 =

ferrocene weight/ rmm ferrocene

mp = ْc

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OBSERVATIONS (IF ANY)

TLC ANALYSIS

solvent
front
S = STARTING Rf =
MATERIAL

M = MIXTURE Rf =

P = PRODUCT Rf =

origin
S M P

NMR DATA
PART A

PART B

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CONCLUSIONS

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 SYNTHESIS OF FENBURFEN

DRAW REACTION SCHEME HERE !!

USE THE FOLLOWING HEADINGS FOR YOUR OWN WRITE UP.

1. REAGENTS (quantities, g/ml mmol)

2. SAFETY INFORMATION (use catalogues in prep. Room)

3. METHOD (BRIEF DESCRIPTION OF PROCEDURE)

4. YIELD AND MELTING POINT

5. OBSERVATIONS (IF ANY), TLC plates

6. IR and NMR DATA

7. CONCLUSIONS

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Questions on Ferrocene Chemistry

1. Explain why ferrocene is about 105 more reactive than benzene to acylation.
2. Why does ferrocene not undergo electrophilic substitution with concentrated
euphoric acid, nitric acid or bromine?
3. Compare and contrast the chemical and physical properties of ferrocene and
cyclopentadienyl sodium.

Questions for Fenbufen

1. Explain why the limitations of the Friedel-Crafts alkylation’s reaction, and why
the acylation reaction is synthetically more useful.
2. Where would you expect electrophilic substitution to occur in the following
substances:

OMe NO2 NH2

Cl Br

Br

3. Suggest a synthesis of 4-chloro-1-nitro-2-propylbenzene from benzene.

Cl

NO2

1-Chloro-4-nitro-2-propylbenzene

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