In the Laboratory edited by
Green Chemistry
Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036
Microwave-Assisted Heterocyclic Chemistry for the Undergraduate Organic Laboratory
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Robert Musiol, Bozena Tyman–Szram, and Jaroslaw Polanski* Department of Organic Chemistry, University of Silesia, Katowice 40-007, Poland; *
[email protected] Important contributions of microwave techniques to organic synthesis has been observed in recent years. Microwaveassisted organic synthesis (MAOS) allows not only for the improvement of reaction yields but also decreases reaction time, and simplifies product purification (1–4). Last, but not least, it offers us an environmentally friendly way of practicing and teaching chemistry. However, classical textbooks for organic chemistry laboratory only rarely provide experimental procedures that make use of this established technique. Few published examples for undergraduate student courses (5–9) can be used with great success. Heterocyclic compounds are described in most introductory organic chemistry textbooks. However, the importance of these compounds is not limited to organic chemistry. We can find such structures among drugs and everyday articles,
which always stimulates student interest. We chose to examine benzimidazoles, succinic anhydride, phthalimide, piperazinedione, quinoxaline, hydantoin, and benzoxazinone. The importance of the aforementioned compounds can be illustrated by some examples of their applications. Thus, benzimidazoles are useful antimicrobial (10) and antiparasitic agents in veterinary treatment (11). Succinic anhydride is an important reagent in organic synthesis, which could also be further functionalized (multistep synthesis) by students in a laboratory course. Phthalimides are efficient inhibitors of many enzymes and are utilized in the treatment of inflammatory diseases (12). Piperazinedione could be an intermediate for the synthesis of phenylahistin or many other biologically important compounds (13, 14). The quinoxaline system is significant for the chemistry of echinomycine antibiotics (15),
Table 1. A List of Compounds Synthesized in the Microwave Oven Compound
Structure NH2
Benzimidazole
O
+ H
NH2
Yield (%)
N
60
3 x 1 min, 180 W
95
3 x 1 min, 550 W
98
3 min 45 sec, 850 W
97
3 min, 300 W
88
2 min, 1000 W
44
2 min 30 sec, 180W
86
3 min, 850 W
O
O O
Succinic anhydride
N
Al2O3
OH
OH
Reaction Conditions
+
Ac2O
O O
OH
O
O O O
Phthalimide
+
H2N
N
NH2
O
O
H2N
Piperazine-2,5-dione
COOH
N
HOOC
O
NH2
NH2
N
O
N
O
N
+
2,3-Diphenylquinoxaline
NH2
O
5,5-Diphenylhydantoin H2N
NH2
O
O
N
O
Ph Ph
N
+
O
Benzoxazinone
O NH2 OH
632
O
+
Journal of Chemical Education
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+
O
O O
O N O
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In the Laboratory
hydantoins an their analogues were described as potent anticonvulsive agents (16), and benzoxazinones are used as inhibitors of HIV-1 reverse transcriptase and other antiviral drugs (17). This prompted us to design new, environmentally friendly experiments for synthesis of these compounds that can be performed in an undergraduate laboratory. The following examples of microwave experiments for an undergraduate organic chemistry course have been developed in our laboratory and are used routinely by students during our laboratory classes. In all syntheses we used a neat or dry media (solid-phase) technique. In this technique the reaction is performed without any solvents, and reagents are reacted after mixing them together (neat) or following adsorption on a carrier surface (e.g., Al2O3). Such a prepared sample is then irradiated and, after the reaction is completed, the product is washed out from the carrier (10). In our experience, solid-phase and neat techniques have been found to be useful in improving the safety of students’ activities in the organic chemistry laboratory. Furthermore, short reaction and product purification times allowed us to avoid student boredom. Additionally microwave-assisted solid-phase reactions help to reduce or eliminate toxic solvents and reduce quantities of wastes. This not only makes the experiments inexpensive and safe but also aims into green chemistry features. The experiments can be performed with simple, inexpensive glassware (most of the reactions are run in open vessels). The reactions should be done in an microwave oven designed for laboratory use and safe from possibilities of explosion. Generally, the synthetic procedure consists of microwave irradiation in the open vessel at the specified power. In the case of substrates of low stability at high temperature, microwave processing can be performed in a pulse manner, with a break after each irradiation. After isolation, a product can be further purified by crystallization. The yields are high, and the quantity of waste is significantly reduced. Table 1 shows the reaction conditions and average yields obtained by students. Hazards 2-Phenylenediamine is toxic in contact with skin or eyes. Formic acid is corrosive and causes burns. Diethyl ether, ethanol, acetone, and petroleum ether are flammable. Benzil, acetic anhydride, phthalic anhydride, succinic acid, 2-aminobenzoic acid, and methylene chloride can cause skin or eye irritation. Students should wear gloves and avoid contact with skin, eyes, or clothing and breathing the vapor. The microwave oven should be placed in a fume hood and must be designed for laboratory use. W
Supplemental Material
Instructions for the students and notes for the instructor are available in this issue of JCE Online.
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