Spring Organic Chemistry Experiment #3
Electrophilic Aromatic Substitution:
An Investigation of Directing Effects in EAS
Introduction
Friedel-Crafts alkylation and acylation represent two examples of the electrophilic
substitution reactions that are characteristic of aromatic compounds. The chemistry was
discovered in 1877 by Charles Friedel at the Ecole des Mines in France and by James Crafts at
M.I.T. Indeed, their discovery was groundbreaking because it has since led to one of the most
useful C-C bond forming reactions involving aromatic systems. The original synthesis involved
the alkylation of benzene by an alkyl chloride (e.g. 2-chloropropane) in the presence of
aluminum chloride as a Lewis acid catalyst (shown below) to generate cumene as the only
isolated product.
The proposed mechanism (that is now widely accepted) that explains this outcome is as follows:
Step #1
Cl
Cl
Cl
Al
Cl
Al
Cl
+
Cl
AlCl4
Cl
Cl
Step #2
active electrophile
(carbocation)
H
H
H
H
(antiaromatic)
(aromatic)
Step #3
H
H
H
H
H
H
Step #4
H
Cl
H
Cl
Al
Cl
Cl
The entire mechanism occurs in four steps: (1) generation of the active electrophile; (2) attack of
the elctrophile by the pi electrons of the aromatic ring; (3) resonance stabilization of the resulting
intermediate; and (4) regeneration of the aromatic system. The active electrophile in this
alkylation process is a carbocation intermediate that is derived from an alkyl halide. You should
read pages 679-696 in the Jones text before coming to lab.
This groundbreaking work has spurned others to continue the original work of Friedel and
Crafts. In particular, Professor George Olah at USC has derived most of the important details that
we now know about the chemistry of the Friedel-Crafts reaction. In fact, Olah won the 1994
Nobel Prize for his pioneering efforts in the electrophilic aromatic substitution chemistry
associated with the Friedel-Crafts reaction. Although this reaction is synthetically useful, it does
suffer from a variety of limitations (see pages 690-691 of Jones).
An important variation on the Friedel-Crafts alkylation is called a Friedel-Crafts
acylation. In contrast, the electrophile for the Friedel-Crafts acylation is an acylium ion
intermediate and it is derived from an acyl halide or an anhydride (i.e. acetyl chloride). The final
product obtained in this reaction is an acylated aromatic ring (note: an acyl group contains a
carbonyl and typically it’s a ketone).
Objective
In this experiment, we will be performing the Friedel-Crafts alkylation of m-xylene using
2-chloro-2-methylpropane in the presence of the Lewis acid catalyst, FeCl3.
Our goal is to use proton NMR analysis in order to determine the structure of our product.
However, we must first consider the possibilities. In other words, what structures are possible
given these starting materials and the known mechanism of the reaction? Well, if you know
something about the mechanism of the reaction and the effect that ring substituents can have on
the course of further ring substitution, then you should be able to predict ALL of the possibilities
(both favorable and unfavorable). I recommend that you check out Chemactivity #29 from the
purple book (in particular, see pages 253-261 and Table 6 on page 259). Once you have the
possibilities in front of you, you should be able to prioritize which ones are most favorable and
which are least favorable. So, your job (before lab) is to work through the mechanism (as best
you can) given the information above in order to derive all of the possible products. You should
then establish a hypothesis predicting which of the possible products most likely would form.
Finally, you should come to lab and conduct the experiment to either confirm or refute your
hypothesis.
Procedure
Place 0.9 mL of m-xylene and 0.75 mL of 2-chloro-2-methylpropane in a dry reaction
tube equipped with a rubber septum and the polyethylene tubing that leads to a second tube
containing a small wad of moist cotton (2-3 drops of water). Cool the mixture in an ice bath and
carefully add 40 mg of anhydrous iron (III) chloride. (Why does everything have to be
dry/anhydrous?) Replace the septum and let the reaction proceed. Record your observations
carefully.
Once the reaction subsides, remove the ice bath and allow the reaction to warm to room
temperature. Let the reaction go for an additional 15 minutes and then quench the reaction with
1.5 mL of water. Mix the solution well and then remove the aqueous layer with a Pasteur
pipette. Repeat this procedure two more times using 1 mL of saturated NaHCO3 solution,
followed by 1 mL of brine. Transfer the remaining solution to a clean reaction tube and dry with
anhydrous MgSO4.
Transfer the dried liquid to yet another reaction tube, add a small boiling chip, and heat
the mixture to its boiling point. Heat so the vapors rise to a level of about 3 cm in the reaction
tube. Draw the vapors into a Pasteur pipette and squirt this "distillate" into a final reaction tube
that you a holding in the same hand (instant microscale distillation). Continue until you have
distilled approximately half of the mixture.
Analyze your product by preparing a 20-30 mg sample for NMR analysis (1H, 13C, 13C
DEPT, and 1H-1H COSY) in the usual fashion using CDCl3/TMS as the solvent. In addition, use
the Spartan 04 molecular modeling software to build each of your proposed reaction products and
carry out molecular mechanics calculations to determine the relative steric energies for each
product. Finally, during lab, work through the mechanism for the Friedel-Crafts acylation
reaction (shown above) with your lab partner and discuss.