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1658 Journal of Chemical Education • Vol. 83 No. 11 November 2006 • www.JCE.DivCHED.org

Organic reactions leading to the synthesis of nitrogenheterocycles afford students the opportunity to apply reac-tions learned in the classroom to new examples in the labo-ratory. Several experiments have been described in which amechanism can be developed from the reaction of aldehydesand ketones with nitrogen nucleophiles, such as the synthe-sis of 2,5-dimethyl-1-phenylpyrrole (1). Experiments of thissort mimic the research experience in that students are notsimply performing an illustration of a reaction from the text-book. Instead, they perform a reaction, use spectral data toconfirm the product’s structure, and develop possible mecha-nisms based on reactions learned in the classroom. We wishto describe an experiment in which students perform themicroscale synthesis of lophine or 2,4,5-triphenylimidazolevia a microwave-mediated reaction and use molecular mod-eling results to arrive at a mechanism for the synthesis oflophine.

A synthesis of lophine has been described by Pickeringas a prelude to its use in a kinetics experiment (2). Pickering’sprotocol, based on Davidson’s modification (3) of the origi-nal synthesis by Radziszewski (4), requires gram quantitiesof reagent, large quantities of solvent, and reaction times ofgreater than 1 hour. Recently, however, a microwave-medi-ated synthesis of imidazoles was described (5). We haveadapted this method to our second-year organic laboratoriesusing a Milestone START Microwave Lab Station, allowing16 students in the lab to simultaneously perform the reac-tion in less than 20 minutes.

The advantages of microwave-assisted organic synthesishave been reviewed elsewhere (6, 7). In short, they includeshorter reaction times, the possibility of performing reactionsat temperatures above the boiling point of the reaction sol-vent, and, on some occasions, elevated reaction yields. A num-ber of recent publications indicate that rate acceleration bymicrowave irradiation is simply due to more efficient heat-ing of the reaction mixture (8). But, some evidence suggeststhat an unknown microwave effect may occur when solutionsof high ionic concentration are irradiated (9). Although com-mercially available microwave ovens that were designed forkitchen use were initially used (10–14), single-mode micro-wave reactors that allow temperature control through pulsedirradiation are much safer to use. The Milestone system fur-ther reduces the likelihood of the failure of a reaction vesselthrough the use of pressure tubes fitted with caps that re-lease pressure above 1.5 bars (1.5 × 105 Pa).

Experiment

The reaction involves the heating of benzaldehyde,benzil, and ammonium acetate in glacial acetic acid undermicrowave irradiation in a 1.5 bar pressure tube (Scheme I).A pressure-release cap vents vapors from the tube in the eventthat the internal pressure rises above 1.5 bar, reducing the

likelihood of the vessel rupturing. This allows the reactionto be performed at slightly above the temperature of reflux-ing glacial acetic acid without the danger of the reaction boil-ing to dryness. The crude crystalline product forms uponaddition of concentrated ammonia upon workup and recrys-tallization (Scheme I).

The reaction is operationally simple to conduct. Equalmolar quantities of benzaldehyde and benzil (0.50 mmol ofeach, 51 µL and 105 mg, respectively) were dissolved in 5mL of glacial acetic acid and 385 mg (5.0 mmol) of ammo-nia was added. When the mixture was homogenous, the pres-sure tube was capped and irradiated to raise the temperaturefrom room temperature to 120 �C over 10 minutes and thento 125 �C over 5 more minutes. After cooling in an ice bath,6 mL of concentrated ammonia was added to precipitate theproduct, which was collected and recrystallized fromethanol�water. Student yields ranged from 2% to 90% withan average recovery of 38%. The crude product was moistand tended to form clumps. The slow rate of dissolution inhot ethanol caused some students to use more than the mini-mum quantity of solvent, reducing the yield of recrystallizedproduct.

Although we employed a single-mode microwave ovendesigned for chemical synthesis, the expense of these instru-ments may limit their availability. So, we also developed a ver-sion of this experiment for use in a conventional microwaveintended for kitchen use. Since sealed glassware in kitchenmicrowave ovens creates a significant explosion hazard, weperformed the reaction in a 50 or 100 mL-beaker that wastopped with a watch glass that held a piece of dry ice. Thegap near the beaker’s pouring spout allowed for release of gasesthat might create pressure and the dry ice cooled vapors tolimit their escape. By reducing the power of the microwaveoven to 30% and heating for 10 minutes, we were able toachieve comparable yields of the identical product. It is im-portant to note that different models of microwave ovens havedifferent heating characteristics and the conditions we devel-oped may require some adjustment in other models.

Hazards

The experiment presents no significant hazards as de-scribed. Routine laboratory procedures such as the use ofgoggles and gloves should be followed. Specific reagent haz-

Microwave-Mediated Synthesis of Lophine: WDeveloping a Mechanism To Explain a ProductR. David Crouch,* Jessica L. Howard, Jennifer L. Zile, and Kathryn H. BarkerDepartment of Chemistry, Dickinson College, Carlisle, PA 17013; *crouch@dickinson.edu

Scheme I. Reaction under microwave irradiation in a 1.5 bar pres-sure tube to produce lophine.

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www.JCE.DivCHED.org • Vol. 83 No. 11 November 2006 • Journal of Chemical Education 1659

ards include the use of concentrated ammonia and glacialacetic acid, which are corrosive, and benzil, benzaldehyde,and ammonium acetate, which are irritants.

However, owing to the lack of temperature and pressure regu-lation in kitchen microwave ovens, it is critical that sealed glass-ware not be used. The possibility of superheating of aqueoussolvents in a kitchen microwave oven also requires that carebe taken to ensure that the beaker has cooled to near roomtemperature before removing it from the oven. (The STARTsystem uses an automated cool-down period to ensure thatthe reaction mixture has cooled to room temperature.) And,since kitchen microwave ovens are not designed to handlevolatile compounds, flammable solvents should not be placednear or in the oven.

Results

The 13C NMR spectrum of the recrystallized productshows signals in the aromatic region (between 125–150 ppm)with no evidence of carbonyl carbons. This leads students toconclude that the carbonyl carbons of benzil and benzalde-hyde have been transformed into carbons of an aromatic ring.The 1H NMR spectrum provides confirmation that the prod-uct contains only aromatic hydrogens. After students drewthis conclusion, the structure of the product was provided.Although some were able to arrive at a structure, most stu-dents required this help.

With a structure in hand, a mechanism for this reactioncan be developed using the chemistry of imines. Althoughmost students were able to arrive at a basic mechanism ontheir own, a series of questions can be posed that will helplead students to a mechanism (Scheme II). Ammoniumacetate�acetic acid act as a source of NH3 and students rec-ognize that a reaction with benzaldehyde to form an imineis likely. The imine can then react with a ketone of benzil.Another equivalent of NH3 must then react. But which ofthe two electrophilic carbons will be attacked?

Molecular modeling using Spartan leads students to thecompletion of the mechanism. Computational analysis of the

neutral intermediate 1 indicates that the carbonyl carbon ismore susceptible to nucleophilic attack than the imine’s car-bon. But under the reaction conditions, it is likely that ei-ther the imine’s nitrogen or the carbonyl’s oxygen will beprotonated. Computational results indicate that the carbonyl’soxygen bears a slightly more negative charge. Thus, it is likelythat the actual intermediate encountered by the nucleophilicNH3 is structure 2, which forms a second imine followed bycyclization. Deprotonation leads to the formation of the fi-nal product, lophine.

This experiment is relatively brief. Reaction setup to iso-lation of pure product is about one hour. We have studentssimultaneously perform the synthesis of 2,5-dimethyl-1-phenylpyrrole (1) using conventional heating in a sand bath.After setting up the conventional reaction, the microwave-mediated synthesis of lophine can be completed before thefirst reaction is complete. Another option is to have studentsperform the conventional synthesis of lophine (2) along withmicrowave-assisted organic synthesis to gain a full apprecia-tion of the advantages of this new technique. Both experi-ments can be easily completed in a normal lab period.

Summary

The experiment provides students with the opportunityto experience microwave-assisted organic synthesis, an emerg-ing technology in synthetic chemistry, while developing a newmechanism using previously-learned reactions. By examin-ing the nature of the reactants and with the aid of informa-tion provided by molecular modeling, they can arrive at areasonable mechanism to explain its formation.

Acknowledgments

The support of the Arnold and Mabel Beckman Foun-dation through the Beckman Scholars Program is gratefullyacknowledged. We also thank Dickinson College for fundstoward the purchase of the Milestone START Microwave LabStation.

Scheme II. Mechanism to form lophine.

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WSupplemental Material

Instructions for the students, notes for the instructor,and 1H and 13C NMR spectra are available in this issue ofJCE Online.

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