--
r
186
Part 1 Experiments
Cleanup:
Place all solutions containing bromine in the container for
halogenated waste. Place the solutions from the reference cuvet in the
container for flammable (organic) waste.
Optional
Experiments
Devise and carry out a procedure to isolate and purify the organic product(s) from one of these bromination reactions. You will need to begin the
synthesis with at least 1 g of the aromatic compound for a macroscale
synthesis or 200 mg of the aromatic compound for a microscale synthesis.
Synthesis of a
Bromination Product
Bromination of Phenol
If you had brominated phenol in this experiment, what sort of rate
would you expect? Test your prediction by running the experiment with
a phenol solution.
Reference
1. Casanova, J. J. Chern.Educ. 1964,41, 341-342.
Questions
~
1. How does the measurement of the absorbance
of Brz give a measurement of the relative rates
of bromination in this experiment?
2. Account for the relative rates that you experimentally determined by considering the structures of the aromatic compounds.
(
Experiment
18
3. What should the products of bromination be in
each reaction?
4. Predict the relative reactivities of the following
three compounds when subjected to bromination conditions: methoxybenzene (anisole), benzene, nitrobenzene.
)
ACYLATION AND ALKYLATION
OF AROMATIC COMPOUNDS
Investigate a variety of Friedel-Crafts reactions and purify the products by column chromatography or recrystallization.
The Friedel-Crafts acylation and alkylation of aromatic compounds are
specific examples of electrophilic aromatic substitution, which was discussed in Experiment 17. Friedel-Crafts reactions, named after the French
and American chemists who discovered their synthetic importance over
100 years ago, lead to carbon-carbon bond formation. Acyl and alkyl
groups can be substituted on aromatic rings by using acid catalysts, such
as HzS04' H3P04, and HF, or Lewis acids, such as AICl3 and BF3'
Experiment
18
Acylation
and
187
Alkylation
Friedel-Crafts chemistry is big business. For example, about 9 billion
pounds of ethylbenzene are produced in the United States each year by
the reaction of benzene and ethene in the presence of either a protic or a
Lewis acid catalyst. Most of it is dehydrogenated to form styrene, from
which polystyrene (Experiment 29.1) is made:
acid
O
~
I
Benzene
_catalyst
+ H2C-CH2)
Ethene
C~CH3
()
~
- H2
~
I
CH=CH2
()
~
Ethylbenzene
I
Styrene
In a Friedel-Crafts alkylation the alkyl electrophile can be prepared
by many methods; the traditional one in undergraduate laboratories has
been treatment of an alkyl halide with a Lewis acid, commonly aluminum trichloride or iron(ID) chloride. We will first review electrophilic
alkylation, with a focus on the processes occurring in Experiments 18.2
and 18.3, followed by a discussion of the acylation of ferrocene to produce acetylferrocene (Experiment 18.1).
In both 18.2 and 18.3, the electrophile is the tert-butyl cation. This
cation is especially easy to produce because it is tertiary and thus
more stable than either a secondary or a primary cation. Using benzene
as the substrate, a simple rendition of the substitution (alkylation) mechanism is:
o
-H+
+
6~'
(CHJ,c+ ,
Delocalized
cationic intermediate
tert-Butylbenzene
(1,1-dimethylethyl) benzene
The delocalized cationic intermediate corresponds to three localized resonance forms:
OC~~
+
Delocalized intermediate
Resonance
oCHJ']
forms
The process of delocalization, or distribution, of the positive charge over
a large portion of the ring system stabilizes the cationic intermediate.
When a proton is lost, the highly stable aromatic ring is regenerated.
Any additional groups on the benzene ring that stabilize the positive
charge increase the rate of substitution. Moreover, the ability of such substituents to stabilize or destabilize positive charge can be used to predict
the ability of a group to direct the substitution to either an ortho, meta, or
para position. In Experiment 18.3, an alkoxy group (OR) provides an electronegative atom that has a nonbonding pair of electrons and is attached
188
Part 1 Experiments
directly to the ring. This atom donates electrons to the ring, a process that
stabilizes a positive charge.
Q
E
Para substitution product
Thus, the "extra" resonance provided by the alkoxy group facilitates
additional charge distribution, stabilizing the positive charge of the intermediate. Moreover, the direct interaction of the alkoxy group with positive charge causes electrophilic attack to occur in the para (as above) or
ortho position.
Another type of Friedel-Crafts reaction is the acylation of aromatic compounds. In this electrophilic aromatic substitution reaction, an acyl derivative, such as an acyl chloride or acyl anhydride,
reacts with the aromatic compound in the presence of acids, such
as AICl3 or H3P04. The product of the acylation reaction is an aromatic ketone:
o
o
II
CCH
~
O ()
~
I
CH]CCI)::::7
AICI] ~
3
I
Experiment 18.1 uses the novel aromatic compound ferrocene,
an organometallic compound that is composed of two planar fivemembered rings that "sandwich" an iron ion:
The ferrocene sandwich compound can be named Fe('I1s-CsHsh, where
the Greek letter '11(eta) means that each ligand bonds to the metal atom
through all five carbon atoms of the ring.
Ferrocene was originally made in 1951 by treating sodium cyclopentadienide with iron(II) chloride:
FeCl2 + 2
Ferrous
chloride
~
Na+ ~(CSHS)2Fe
Sodium
cyclopentadienide
+ 2NaCl
Ferrocene
Experiment
189
18 Acylation and Alkylation
Ferrocene can be thought of as a compound formed by the bonding
Of an Fe2+ cation to two cyclopentadienide ligands, each bearing a negative charge. Each cyclopentadienide anion is aromatic because it has six
7T-electrons:
c.-
0-- O--etc.
Q
u_
6 7T-electrons
Because the rings in ferrocene are aromatic, they readily undergo electrophilic aromatic substitution reactions, such as the acylation reaction in
Experiment 18.1.
18.1
.
Acylationof Ferrocene
Acetylate a colored organometallic compound
chromatography.
and purify itby column
~
W
+
Fe
CH-3
/O
CH3-C
@
@r
'
'-.l..-/
C ~O
H3PO.
C -CH
3
'
Fe
~
@
'0
Ferrocene
Acetic anhydride
mp 173°C
MW 186.0
bp 139.5°C
yellow-orange color
density 1.08 g . mL-1
+ CH,COOH
Acetylferrocene
mp 85-86°C
MW102.1
MW 228.1
orange-red color
This Friedel-Crafts acylation of ferrocene produces acetylferrocene
by using acetic anhydride in the presence of a catalytic amount of phosphoric acid. A frequently used catalyst for such acylations is aluminum
trichloride, but in this particular acylation that catalyst complicates the
process by producing a disubstituted product: l,l'-diacetylferrocene. The
milder catalyst, phosphoric acid, works better. It generates the acylium
ion electrophile by protonation followed by loss of acetic acid:
0
-
II
3
[ HC/'
C
H3PO.
] 20
Acetic anhydride
~
cJ'H
cJ'H
I
II
C
C
'"
HC/+"cf
3
0
'cH
I
~
3
HC/
3
C~
"""0
Acetic acid
+
O~
C~
CH3
Acylium ion
electrophile
190
Part 1 Experiments
3500
3000
2500
Wavenumber
2000
1500
1000
500
(em-')
FIGURE 18.1 IR spectrum of acetylferrocene(in CHCl3).
The electrophile then attacks the ring, a reaction resulting in substitution
of the acetyl group for a ring proton:
Acetylferrocene can be characterized by examining its IR (Figure 18.1)
and IH NMR (Figure 18.2) spectra. Note the intense carbonyl stretching
vibration in the IR spectrum at about 1660 em-I. The IH NMR spectrum
of ferrocene shows 10 equivalent aromatic protons as a singlet at about 8
4.15. The IH NMR spectrum of acetylferrocene (Figure 18.2) shows the
acetyl methyl group as a 3H singlet at 8 2.42. The unsubstituted ring
yields a 5H singlet at 8 4.22, and the substituted ring reveals a pair of 2H
signals as apparent triplets, one at 84.5 and the other near 84.8.
( m icroscale )
Procedure*
Techniques
Thin-Layer Chromatography: Technique 10
Column Chromatography: Technique 12
IR Spectrometry: Spectrometric Method 1
NMR Spectrometry: Spectrometric Method 2
"This procedure was developed by David Alberg, Department of Chemistry, Carleton
College,Northfield, MN.
---0
Experiment
4.7
5.0
4.5
191
18 Acylation and Alkylation
4.0
4.6
3.5
4.5
3.0
2.5
2.0
1.5
1.0
.5
0.0
~
FIGURE18.2 IH NMR spectrum (300 MHz) of acetylferrocene (in COCl3).
SAFETY
INFORMA nON
Ferrocene is relatively nontoxic, but avoid contact with the skin.
The product, acetylferrocene, is highly toxic. Wear gloves and
avoid contact with skin, eyes, and clothing.
Acetic anhydride is corrosive and a lachrymator (causes tears).
Wear gloves and avoid contact with skin, eyes, and clothing. Dispense it in a hood.
Concentrated (85%) phosphoric acid is irritating to the skin and
mucous membranes. Wear gloves. If you spill any phosphoric acid
on your skin, wash it off immediately with copious amounts of
water.
Aqueous sodium hydroxide solutions are corrosive and cause
burns. Solutions as dilute as 9% (2.5 M) can cause severe eye
injury. Avoid contact with skin, eyes, and clothing.
Hexane and diethyl ether are extremely volatile and flammable.
Alumina (Al203) is a lung irritant. Avoid breathing the dust.
Preparation of
Acetylferrocene
Fit a dry 5-mL round-bottomed
flask with the support-rod
nector and a drying tube containing anhydrous
flexible con-
calcium chloride [see
Technique 3, Figure 3.6b (omit the air condenser)]. Keep the drying tube
on the flask except while you are adding reagents. Place 200 mg (1.07
mmol) of ferrocene and 2.0 mL (21 mmol) of acetic anhydride in the
r
192
Part 1 Experiments
flask. Swirl the flask to mix these reagents. Slowly add 0.4 mL of
85% phosphoric acid (about 10 drops with a Pasteur pipet; the exact
amount is not critical). Put the drying tube on the flask and swirl
Acetylferrocene
will appear as
an orange-red spot (Rf = 0.3),
and any remaining ferrocene
appears as a yellowish spot at
Rf = 0.9.
the reaction mixture to thoroughly mix the reagents. Heat the flask on a
steam bath or in a beaker of boiling water for 10 min with occasional swirling.
Remove the flask from the heat source and check the progress of the
reaction by thin-layer chromatography on silica gel plates [see Technique 10]. Also spot the plate with a 2% solution of ferrocene in ether.
Use 25: 75 (v / v) anhydrous diethyl ether / hexane as the TLC elution solvent. A UV lamp allows you to visualize traces of ferrocene. A trace
amount of ferrocene is likely; but if you can see a substantial yellow spot
of ferrocene without the aid of the UV lamp, heat your reaction mixture
for an additional 2-5 min. If the amount of ferrocene is minimal, cool
the reaction flask for a total of 10 min.
Pour the reaction mixture over about 10 g of ice in a 50-mL beaker.
Use an additional 1 or 2 mL of water to complete the transfer of your
mixture to the ice. Partially neutralize the mixture by adding 5 mL of
6 M sodium hydroxide in at least three portions. Determine the pH with
pHydrion paper or other pH paper. Continue adding 6 M NaOH dropwise until the pH is 7-8. Swirl the beaker after each addition to mix the
contents. Cool the mixture to room temperature and collect the product
by vacuum filtration on a Hirsch funnel. Use a few milliliters of water to
complete the transfer of the tarry solid. With the vacuum on, pull air
over the crude product on the Hirsch funnel for 15 min to dry the product while you prepare for the column chromatography.
Purification by Column
Chromatography
Assemble all the equipment
and reagents that you will
need for the entire
chromatography procedure
before you begin to prepare
the column.
Large-volume Pasteur pipets,
available from Fisher
Scientific, catalog no.
13678-8, have a capacity
of 4 mL.
Read this procedure completely and review Technique 12 before you
undertake this part of the experiment.
Obtain about 25 mL of hexane in a 50-mL Erlenmeyer
fitted
with
a cork.
Transfer
your
air-dried
crude' product
flask
to a 13
x
100 mm test tube and add about 1 mL of hexane. Much of the material
will not dissolve in the hexane. Spot a thin-layer plate with this hexane
mixture, then set the test tube and the thin-layer plate aside while you
prepare the column.
Obtain a large-volume Pasteur pipet to use as the chromatography
column and pack a small plug of glass wool down into the stem, using a
wood applicator stick or a thin stirring rod. Clamp this pipet in a vertical
position and place a 25-mL Erlenmeyer flask underneath it to collect the
hexane that you will be adding to the column. Weigh approximately 3 g
retiultthealuminais
Ivered
with solventat
alltimesduring the
2tographic
procedure.
nayseeafaint yellow
n thehexanesolution
ting infraction 1; the
i duetoferrocene that
did not react.
Experiment
18 Acylation and Alkylation
193
of Activity III alumina in a tared 50-mL beaker; add enough hexane to
make a thin slurry. Transfer the alumina slurry to the column, using a
regular Pasteur pipet. Continue adding slurry until the column is twothirds full of alumina. Fill and drain the column four or five times with
hexane to pack it well (do not let the hexane level fall below the top of
the alumina). The eluted hexane can be reused for this purpose. After the
alumina is packed, add a 2-3 mm layer of sand above the alumina by
letting it settle through the hexane.
Allow the hexane level to almost reach the top of the alumina, and
place a flask labeled fraction 1 under the column. Transfer your crude
product mixture to the top of column, using a Pasteur pipet and as many
small portions of hexane (do not use the eluted hexane) as necessary to
transfer all of your material. When all of the crude product is on the column and the hexane level is just above the top of the alumina, elute the
column with 15 mL of hexane.
Next elute with 10 mL of 50:50 (v/v) hexane/anhydrous
diethyl
ether solution. You will see the orange-red acetylferrocene move rapidly
down the column. Collect the eluent in fraction 1 until you see the
orange-red solution in the column tip, then quickly change the collection
flask to a clean, tared 50-mL Erlenmeyer flask labeled "Fraction 2." Continue adding 50: 50 hexane / ether until the orange-red product has
eluted from the column. (This elution requires about 10-15 mL of 50:50
hexane / ether.) Spot fraction 1, fraction 2, and pure ferrocene on the same
thin-layer plate that you have already spotted with your crude acetylferrocene. Develop the thin-layer plate as you did previously. Record the
results in your notebook.
Recover your purified acetylferrocene by evaporating
the solvent
from fraction 2 on a steam bath or with a stream of nitrogen or air in a
hood. Alternatively, if a rotary evaporator is available, transfer fraction 2
to a tared 25- or 50-mL round-bottomed flask and remove the solvent
under reduced pressure. Weigh your purified product, calculate the percent yield, and determine the melting point of your acetylferrocene. Prepare a sample for NMR or IR analysis as directed by your instructor.
Assign all the major peaks, but do not try to analyze the complex splitting patterns.
Cleanup:
The aqueous filtrate from the crude product may be washed
down the sink or placed in the container for aqueous inorganic waste.
Pour any remaining TLC solvent and fraction 1 into the container for
flammable (organic) waste. Place the thin-layer plates and the alumina
from the column in the container for inorganic solid waste.
194
Part 1 Experiments
Questions
1. Any
diacetylferrocene produced in this reaction
remains near the top of the column under the
chromatographic conditions used in this experiment. Explain the order of elution of ferrocene
and acetylferrocene, and why the diacetylferrocene is retained by the column.
3. Explain how the NMR spectrum of ferrocene
supports
the assigned sandwich structure
rather than a structure in which the iron atom is
bound to only one carbon atom of each ring.
2. In the NMR spectrum of most aromatic compounds, the aromatic protons exhibit a chemical
shift of {) = 7-8 ppm. However, in ferrocene,
the chemical shift of the aromatic protons is
{) = 4.15 ppm. Explain what factors cause the
upfield shift.
5. There is only one isomer known for diacetylferrocene when each cyclopentadienide ring is
monosubstituted. Explain why other isomers
are not found.
4. Why is the acetylation of acetylferrocene faster
on the unsubstituted cyclopentadienide ring?
@J
Synthesis of 4,4' -Di- tert-Butylbiphenyl
Investigate
halide.
a classic Friedel-Crafts
CH3
CH3
+
I
H C-C-CI
3
Biphenyl
mp 69°(
MW 154.2
I
reaction using AICl3 and an alkyl
AICI]
>
CH]NO,
CH3
2-(hloro-2 -methyl propane
(tert-butyl chloride)
bp 51 O(
MW 92.6
.
~
HC-t~t-CH
31~1
CH3
CH3
3
CH3
4,4' -Di-tert-butylbiphenyl
mp 128-129°(
MW 266.4
density 0.85 g . mL-1
In this experiment an electrophile is produced by treating tert-butyl chloride with aluminum trichloride. Because aluminum trichloride has only
six electrons in its valence shell, it is electron deficient and has Lewis acid
properties. Therefore, aluminum trichloride will coordinate with tertbutyl chloride, leading to abstraction of chloride anion from the alkyl
halide to give the tert-butyl cation
The electrophilic tert-butyl cation then attacks biphenyl, and a combination of electronic and steric effects causes para substitution in both
rings: