In the Laboratory

Microwave-Mediated Synthesis of Lophine:

Developing a Mechanism To Explain a Product

R. David Crouch,* Jessica L. Howard, Jennifer L. Zile, and Kathryn H. Barker

Department of Chemistry, Dickinson College, Carlisle, PA 17013; *[email protected]

Organic reactions leading to the synthesis of nitrogen

heterocycles afford students the opportunity to apply reactions learned in the classroom to new examples in the laboratory. Several experiments have been described in which a
mechanism can be developed from the reaction of aldehydes
and ketones with nitrogen nucleophiles, such as the synthesis of 2,5-dimethyl-1-phenylpyrrole (1). Experiments of this
sort mimic the research experience in that students are not
simply performing an illustration of a reaction from the textbook. Instead, they perform a reaction, use spectral data to
confirm the products structure, and develop possible mechanisms based on reactions learned in the classroom. We wish
to describe an experiment in which students perform the
microscale synthesis of lophine or 2,4,5-triphenylimidazole
via a microwave-mediated reaction and use molecular modeling results to arrive at a mechanism for the synthesis of
lophine.
A synthesis of lophine has been described by Pickering
as a prelude to its use in a kinetics experiment (2). Pickerings
protocol, based on Davidsons modification (3) of the original synthesis by Radziszewski (4), requires gram quantities
of reagent, large quantities of solvent, and reaction times of
greater than 1 hour. Recently, however, a microwave-mediated synthesis of imidazoles was described (5). We have
adapted this method to our second-year organic laboratories
using a Milestone START Microwave Lab Station, allowing
16 students in the lab to simultaneously perform the reaction in less than 20 minutes.
The advantages of microwave-assisted organic synthesis
have been reviewed elsewhere (6, 7). In short, they include
shorter reaction times, the possibility of performing reactions
at temperatures above the boiling point of the reaction solvent, and, on some occasions, elevated reaction yields. A number of recent publications indicate that rate acceleration by
microwave irradiation is simply due to more efficient heating of the reaction mixture (8). But, some evidence suggests
that an unknown microwave effect may occur when solutions
of high ionic concentration are irradiated (9). Although commercially available microwave ovens that were designed for
kitchen use were initially used (1014), single-mode microwave reactors that allow temperature control through pulsed
irradiation are much safer to use. The Milestone system further reduces the likelihood of the failure of a reaction vessel
through the use of pressure tubes fitted with caps that release pressure above 1.5 bars (1.5 105 Pa).

likelihood of the vessel rupturing. This allows the reaction

to be performed at slightly above the temperature of refluxing glacial acetic acid without the danger of the reaction boiling to dryness. The crude crystalline product forms upon
addition of concentrated ammonia upon workup and recrystallization (Scheme I).
The reaction is operationally simple to conduct. Equal
molar quantities of benzaldehyde and benzil (0.50 mmol of
each, 51 L and 105 mg, respectively) were dissolved in 5
mL of glacial acetic acid and 385 mg (5.0 mmol) of ammonia was added. When the mixture was homogenous, the pressure tube was capped and irradiated to raise the temperature
from room temperature to 120 C over 10 minutes and then
to 125 C over 5 more minutes. After cooling in an ice bath,
6 mL of concentrated ammonia was added to precipitate the
product, which was collected and recrystallized from
ethanolwater. Student yields ranged from 2% to 90% with
an average recovery of 38%. The crude product was moist
and tended to form clumps. The slow rate of dissolution in
hot ethanol caused some students to use more than the minimum quantity of solvent, reducing the yield of recrystallized
product.
Although we employed a single-mode microwave oven
designed for chemical synthesis, the expense of these instruments may limit their availability. So, we also developed a version of this experiment for use in a conventional microwave
intended for kitchen use. Since sealed glassware in kitchen
microwave ovens creates a significant explosion hazard, we
performed the reaction in a 50 or 100 mL-beaker that was
topped with a watch glass that held a piece of dry ice. The
gap near the beakers pouring spout allowed for release of gases
that might create pressure and the dry ice cooled vapors to
limit their escape. By reducing the power of the microwave
oven to 30% and heating for 10 minutes, we were able to
achieve comparable yields of the identical product. It is important to note that different models of microwave ovens have
different heating characteristics and the conditions we developed may require some adjustment in other models.
Hazards
The experiment presents no significant hazards as described. Routine laboratory procedures such as the use of
goggles and gloves should be followed. Specific reagent haz-

Experiment
The reaction involves the heating of benzaldehyde,
benzil, and ammonium acetate in glacial acetic acid under
microwave irradiation in a 1.5 bar pressure tube (Scheme I).
A pressure-release cap vents vapors from the tube in the event
that the internal pressure rises above 1.5 bar, reducing the
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Journal of Chemical Education

Scheme I. Reaction under microwave irradiation in a 1.5 bar pressure tube to produce lophine.

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In the Laboratory

ards include the use of concentrated ammonia and glacial

acetic acid, which are corrosive, and benzil, benzaldehyde,
and ammonium acetate, which are irritants.
However, owing to the lack of temperature and pressure regulation in kitchen microwave ovens, it is critical that sealed glassware not be used. The possibility of superheating of aqueous
solvents in a kitchen microwave oven also requires that care
be taken to ensure that the beaker has cooled to near room
temperature before removing it from the oven. (The START
system uses an automated cool-down period to ensure that
the reaction mixture has cooled to room temperature.) And,
since kitchen microwave ovens are not designed to handle
volatile compounds, flammable solvents should not be placed
near or in the oven.
Results
The 13C NMR spectrum of the recrystallized product
shows signals in the aromatic region (between 125150 ppm)
with no evidence of carbonyl carbons. This leads students to
conclude that the carbonyl carbons of benzil and benzaldehyde have been transformed into carbons of an aromatic ring.
The 1H NMR spectrum provides confirmation that the product contains only aromatic hydrogens. After students drew
this conclusion, the structure of the product was provided.
Although some were able to arrive at a structure, most students required this help.
With a structure in hand, a mechanism for this reaction
can be developed using the chemistry of imines. Although
most students were able to arrive at a basic mechanism on
their own, a series of questions can be posed that will help
lead students to a mechanism (Scheme II). Ammonium
acetateacetic acid act as a source of NH3 and students recognize that a reaction with benzaldehyde to form an imine
is likely. The imine can then react with a ketone of benzil.
Another equivalent of NH3 must then react. But which of
the two electrophilic carbons will be attacked?
Molecular modeling using Spartan leads students to the
completion of the mechanism. Computational analysis of the

neutral intermediate 1 indicates that the carbonyl carbon is

more susceptible to nucleophilic attack than the imines carbon. But under the reaction conditions, it is likely that either the imines nitrogen or the carbonyls oxygen will be
protonated. Computational results indicate that the carbonyls
oxygen bears a slightly more negative charge. Thus, it is likely
that the actual intermediate encountered by the nucleophilic
NH3 is structure 2, which forms a second imine followed by
cyclization. Deprotonation leads to the formation of the final product, lophine.
This experiment is relatively brief. Reaction setup to isolation of pure product is about one hour. We have students
simultaneously perform the synthesis of 2,5-dimethyl-1phenylpyrrole (1) using conventional heating in a sand bath.
After setting up the conventional reaction, the microwavemediated synthesis of lophine can be completed before the
first reaction is complete. Another option is to have students
perform the conventional synthesis of lophine (2) along with
microwave-assisted organic synthesis to gain a full appreciation of the advantages of this new technique. Both experiments can be easily completed in a normal lab period.
Summary
The experiment provides students with the opportunity
to experience microwave-assisted organic synthesis, an emerging technology in synthetic chemistry, while developing a new
mechanism using previously-learned reactions. By examining the nature of the reactants and with the aid of information provided by molecular modeling, they can arrive at a
reasonable mechanism to explain its formation.
Acknowledgments
The support of the Arnold and Mabel Beckman Foundation through the Beckman Scholars Program is gratefully
acknowledged. We also thank Dickinson College for funds
toward the purchase of the Milestone START Microwave Lab
Station.

Scheme II. Mechanism to form lophine.

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W

Supplemental Material

Instructions for the students, notes for the instructor,

and 1H and 13C NMR spectra are available in this issue of
JCE Online.
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