r

186 Part 1 Experiments

Cleanup: Place all solutions containing bromine in the container forhalogenated waste. Place the solutions from the reference cuvet in thecontainer for flammable (organic) waste.

Optional Experiments

Synthesis of aBromination Product

Devise and carry out a procedure to isolate and purify the organic prod-uct(s) from one of these bromination reactions. You will need to begin thesynthesis with at least 1 g of the aromatic compound for a macroscalesynthesis or 200 mg of the aromatic compound for a microscale syn-thesis.

If you had brominated phenol in this experiment, what sort of ratewould you expect? Test your prediction by running the experiment witha phenol solution.

Bromination of Phenol

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 ratesof bromination in this experiment?

2. Account for the relative rates that you experi-mentally determined by considering the struc-tures of the aromatic compounds.

3. What should the products of bromination be ineach reaction?

4. Predict the relative reactivities of the followingthree compounds when subjected to bromina-tion conditions: methoxybenzene (anisole), ben-zene, nitrobenzene.

( Experiment 18 )ACYLATION AND ALKYLATIONOF AROMATIC COMPOUNDS

Investigate a variety of Friedel-Crafts reactions and purify the prod-ucts by column chromatography or recrystallization.

The Friedel-Crafts acylation and alkylation of aromatic compounds arespecific examples of electrophilic aromatic substitution, which was dis-cussed in Experiment 17. Friedel-Crafts reactions, named after the Frenchand American chemists who discovered their synthetic importance over100 years ago, lead to carbon-carbon bond formation. Acyl and alkylgroups can be substituted on aromatic rings by using acid catalysts, suchas HzS04' H3P04, and HF, or Lewis acids, such as AICl3 and BF3'

--

Experiment 18 Acylation and Alkylation 187

Friedel-Crafts chemistry is big business. For example, about 9 billionpounds of ethylbenzene are produced in the United States each year bythe reaction of benzene and ethene in the presence of either a protic or aLewis acid catalyst. Most of it is dehydrogenated to form styrene, fromwhich polystyrene (Experiment 29.1) is made:

Oacid

()C~CH3

()CH=CH2

I

_catalystI

- H2

I+ H2C-CH2) ~~ ~ ~

Benzene Ethene Ethylbenzene Styrene

In a Friedel-Crafts alkylation the alkyl electrophile can be preparedby many methods; the traditional one in undergraduate laboratories hasbeen treatment of an alkyl halide with a Lewis acid, commonly alu-minum trichloride or iron(ID) chloride. We will first review electrophilicalkylation, with a focus on the processes occurring in Experiments 18.2and 18.3, followed by a discussion of the acylation of ferrocene to pro-duce acetylferrocene (Experiment 18.1).

In both 18.2 and 18.3, the electrophile is the tert-butyl cation. Thiscation is especially easy to produce because it is tertiary and thusmore stable than either a secondary or a primary cation. Using benzeneas the substrate, a simple rendition of the substitution (alkylation) mech-anism is:

o(CHJ,c+ ,

-H++

6~'tert-Butylbenzene

(1,1-dimethylethyl) benzene

Delocalized

cationic intermediate

The delocalized cationic intermediate corresponds to three localized res-onance forms:

OC~~ oCHJ']+

Resonance formsDelocalized intermediate

The process of delocalization, or distribution, of the positive charge overa 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 positivecharge increase the rate of substitution. Moreover, the ability of such sub-stituents to stabilize or destabilize positive charge can be used to predictthe ability of a group to direct the substitution to either an ortho, meta, orpara position. In Experiment 18.3, an alkoxy group (OR) provides an elec-tronegative 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 thatstabilizes a positive charge.

QE

Para substitution product

Thus, the "extra" resonance provided by the alkoxy group facilitatesadditional charge distribution, stabilizing the positive charge of the inter-mediate. Moreover, the direct interaction of the alkoxy group with posi-tive charge causes electrophilic attack to occur in the para (as above) orortho position.

Another type of Friedel-Crafts reaction is the acylation of aro-matic compounds. In this electrophilic aromatic substitution re-action, an acyl derivative, such as an acyl chloride or acyl anhydride,reacts with the aromatic compound in the presence of acids, suchas AICl3 or H3P04. The product of the acylation reaction is an aro-matic ketone:

oo II

O~

()CCH

I CH]CCI)::::7 I 3~ AICI] ~

Experiment 18.1 uses the novel aromatic compound ferrocene,an organometallic compound that is composed of two planar five-membered rings that "sandwich" an iron ion:

The ferrocene sandwich compound can be named Fe('I1s-CsHsh, wherethe Greek letter '11(eta) means that each ligand bonds to the metal atomthrough all five carbon atoms of the ring.

Ferrocene was originally made in 1951 by treating sodium cyclo-pentadienide with iron(II) chloride:

FeCl2 + 2~ Na+ ~(CSHS)2Fe + 2NaClFerrous Sodium Ferrocene

chloride cyclopentadienide

Experiment 18 Acylation and Alkylation 189

Ferrocene can be thought of as a compound formed by the bondingOf an Fe2+ cation to two cyclopentadienide ligands, each bearing a nega-tive charge. Each cyclopentadienide anion is aromatic because it has six7T-electrons:

c.-0-- O--etc.Q u_

6 7T-electrons

Because the rings in ferrocene are aromatic, they readily undergo elec-trophilic aromatic substitution reactions, such as the acylation reaction inExperiment 18.1.

18.1 .

Acylationof FerroceneAcetylate a colored organometallic compound and purify itby columnchromatography.

WFe

@Ferrocene

mp 173°CMW 186.0

yellow-orange color

+CH- ~O @r

~

3 C '-.l..-/ C -CH' 3

C/O H3PO. '

H3-C ~ Fe

'0 @ + CH,COOHAcetic anhydride

bp 139.5°CMW102.1

density 1.08 g . mL-1

Acetylferrocene

mp 85-86°CMW 228.1

orange-red color

This Friedel-Crafts acylation of ferrocene produces acetylferroceneby using acetic anhydride in the presence of a catalytic amount of phos-phoric acid. A frequently used catalyst for such acylations is aluminumtrichloride, but in this particular acylation that catalyst complicates theprocess by producing a disubstituted product: l,l'-diacetylferrocene. Themilder catalyst, phosphoric acid, works better. It generates the acyliumion electrophile by protonation followed by loss of acetic acid:

[

0

]

- cJ'H 0 cJ'HII H3PO. I II I O~C ~ C '" C ~ C~ + C~

HC/' 0 HC/+"cf 'cH HC/ """0 CH3 2 3 3 3 3

Acetic anhydride Acetic acid Acylium ion

electrophile

m icroscale )Procedure*

190

(

Part 1 Experiments

3500 3000 2500 2000

Wavenumber (em-')

1500 1000 500

FIGURE 18.1 IRspectrumof acetylferrocene(in CHCl3).

The electrophile then attacks the ring, a reaction resulting in substitutionof 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 stretchingvibration in the IR spectrum at about 1660 em-I. The IH NMR spectrumof ferrocene shows 10 equivalent aromatic protons as a singlet at about 84.15. The IH NMR spectrum of acetylferrocene (Figure 18.2) shows theacetyl methyl group as a 3H singlet at 8 2.42. The unsubstituted ringyields a 5H singlet at 8 4.22, and the substituted ring reveals a pair of 2Hsignals as apparent triplets, one at 84.5 and the other near 84.8.

Techniques Thin-Layer Chromatography: Technique 10Column Chromatography: Technique 12IR Spectrometry: Spectrometric Method 1

NMR Spectrometry: Spectrometric Method 2

"This procedure was developed by David Alberg, Department of Chemistry, CarletonCollege,Northfield, MN.

---01

Preparation ofAcetylferrocene

Experiment 18 Acylation and Alkylation 191

4.7 4.6 4.5

5.0 4.5 3.54.0 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 andavoid 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. Dis-pense it in a hood.

Concentrated (85%) phosphoric acid is irritating to the skin andmucous membranes. Wear gloves. If you spill any phosphoric acidon your skin, wash it off immediately with copious amounts ofwater.

Aqueous sodium hydroxide solutions are corrosive and causeburns. Solutions as dilute as 9% (2.5 M) can cause severe eyeinjury. 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.

Fit a dry 5-mL round-bottomed flask with the support-rod flexible con-

nector and a drying tube containing anhydrous 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

r192

Acetylferrocene will appear as

an orange-red spot (Rf = 0.3),and any remaining ferrocene

appears as a yellowish spot at

Rf = 0.9.

Purification by ColumnChromatography

Assemble all the equipment

and reagents that you will

needfor the entire

chromatography procedure

before you begin to preparethe column.

Large-volume Pasteur pipets,

available from Fisher

Scientific, catalog no.13678-8, have a capacity

of4 mL.

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

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 occa-

sional swirling.

Remove the flask from the heat source and check the progress of the

reaction by thin-layer chromatography on silica gel plates [see Tech-

nique 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 sol-

vent. 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 mixturefor 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 drop-

wise 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 prod-

uct while you prepare for the column chromatography.

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 flask

fitted with a cork. Transfer your air-dried crude' product to a 13 x100 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 3g

retiultthealuminaisIveredwith solventatalltimesduring the

2tographicprocedure.

nayseeafaint yellown thehexanesolution

ting infraction 1; thei 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 aregular Pasteur pipet. Continue adding slurry until the column is two-thirds 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 byletting 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 col-

umn and the hexane level is just above the top of the alumina, elute thecolumn 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." Con-

tinue 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 acetyl-

ferrocene. Develop the thin-layer plate as you did previously. Record theresults 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 ahood. Alternatively, if a rotary evaporator is available, transfer fraction 2to a tared 25- or 50-mL round-bottomed flask and remove the solvent

under reduced pressure. Weigh your purified product, calculate the per-

cent yield, and determine the melting point of your acetylferrocene. Pre-

pare 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 split-ting patterns.

Cleanup: The aqueous filtrate from the crude product may be washeddown the sink or placed in the container for aqueous inorganic waste.Pour any remaining TLC solvent and fraction 1 into the container forflammable (organic) waste. Place the thin-layer plates and the aluminafrom the column in the container for inorganic solid waste.

194 Part 1 Experiments

Questions1. Any diacetylferrocene produced in this reaction

remains near the top of the column under thechromatographic conditions used in this experi-ment. Explain the order of elution of ferroceneand acetylferrocene, and why the diacetyl-ferrocene is retained by the column.

2. In the NMR spectrum of most aromatic com-pounds, the aromatic protons exhibit a chemicalshift of {)= 7-8 ppm. However, in ferrocene,the chemical shift of the aromatic protons is{)= 4.15 ppm. Explain what factors cause theupfield shift.

-

3. Explain how the NMR spectrum of ferrocenesupports the assigned sandwich structurerather than a structure in which the iron atom is

bound to only one carbon atom of each ring.

4. Why is the acetylation of acetylferrocene fasteron the unsubstituted cyclopentadienide ring?

5. There is only one isomer known for diacetyl-ferrocene when each cyclopentadienide ring ismonosubstituted. Explain why other isomersare not found.

@JSynthesis of 4,4' -Di- tert-Butylbiphenyl

Investigate a classic Friedel-Crafts reaction using AICl3 and an alkylhalide.

CH3I AICI]

+ H C-C-CI >

3 I CH]NO,

CH32-(hloro-2 -methyl propane

(tert-butyl chloride)

bp 51 O(MW 92.6

density 0.85 g . mL-1

Biphenylmp 69°(

MW 154.2

CH3 . ~ CH3

HC-t~t-CH31~1 3

CH3 CH34,4' -Di-tert-butylbiphenyl

mp 128-129°(MW 266.4

In this experiment an electrophile is produced by treating tert-butyl chlo-ride with aluminum trichloride. Because aluminum trichloride has onlysix electrons in its valence shell, it is electron deficient and has Lewis acidproperties. Therefore, aluminum trichloride will coordinate with tert-butyl chloride, leading to abstraction of chloride anion from the alkylhalide to give the tert-butyl cation

The electrophilic tert-butyl cation then attacks biphenyl, and a com-bination of electronic and steric effects causes para substitution in bothrings: