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A greener approach to aspirin synthesis using microwave irradiationIn the Laboratory
Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036 A Greener Approach to Aspirin Synthesis
Using Microwave Irradiation
Ingrid Montes,* David Sanabria, Marilyn García, Joaudimir Castro, and Johanna Fajardo
Department of Chemistry, University of Puerto Rico, San Juan, Puerto Rico 00931-3349; *email@example.com
The synthesis of aspirin has been a popular experiment pose. Recently, the synthesis of analgesic drugs has been em- in organic chemistry teaching laboratories and even in some ployed to demonstrate the advantages of microwave-assisted introductory chemistry laboratories (1). Many laboratory text- synthesis in terms of purity, yield, and reaction time (6). For books have included procedures for aspirin synthesis to study this reason, an experiment was designed so that the students carbonyl nucleophilic substitution reactions under acidic or could determine the best conditions for synthesizing aspirin basic conditions (2, 3). However, these traditional experi- under microwave irradiation (Scheme I).
ments use a cookbook recipe approach that does not allow As opposed to the previously cited experiments (2, 3, 6, the student to use critical reasoning to thoroughly understand 12), this experiment helps the student determine the effect the reaction.
of the catalyst in terms of reaction time, purity, yield, and Recently, there has been a growing interest in the use of secondary products formation under microwave conditions.
microwave technology for organic synthesis. The use of mi- The use of microwave heating instead of conventional heat- crowave induced heating offers certain advantages, such as ing is a green-chemistry aspect that will be introduced to the shorter reaction times, controlled heating and cooling (by student in this synthesis. This experiment also attempts to placement of an in-line heat exchanger adjacent to the mi- familiarize the student with the process of searching refer- crowave heating zone or by direct contact between a cold fin- ence materials related to origin, status, and future challenges ger and the reaction mixture), and reduction of secondary of green chemistry. In addition, this experiment has an products (4–11). Microwave ovens offer a clean and some- appendixthat includes some important concepts about mi- times cheaper alternative to oil baths for many organic reac- crowave irradiation, such as overheating effects, dielectric tions. The popularity of microwave heating has been extended heating, and the role that a catalyst plays when using this to research applications and recently even to academic teach- technology (5, 10). ing laboratories (6, 12–14). It has been proven that micro-wave heating is effective in solvent-free reactions as well as in reactions that do not utilize catalysts (5, 6, 10, 11, 15). Inaddition, reactions under solvent-free conditions offer the The experiment is conducted over two laboratory additional advantage of avoiding the use of solvents that can periods, where the student works individually in the prepa- sometimes be expensive, toxic, or difficult to remove and dis- ration of aspirin from salicylic acid and acetic anhydride. Asa safety precaution, the reaction is carried out in a fume hoodusing a domestic microwave oven (Kenmore Elite Model565.61582, 1200 W) as a heat source, which is also located inside the fume hood. A different catalyst for the reaction isassigned to each student: there are four acid catalysts, four basic catalysts and one student works without a catalyst. Inthis way, nine students work individually, but they need to pool their results to reach a conclusion regarding the cata- lysts' effect.
To a clean and dry 50-mL beaker, salicylic acid (5 mmol) and acetic anhydride (15 mmol) are added. Then, the assignedcatalyst is added. If the assigned catalyst is liquid, add one drop and if it is solid, add 0.02–0.04 g. The catalysts to beused are: H 2SO4, H3PO4, MgBr2 OEt2, AlCl3, CaCO3, NaOAc, NEt3, and 4-N,N-dimethylaminopyridine (DMAP).
The reaction mixture is placed in a microwave oven for two minutes at 80% power. Then, the mixture is removed from the microwave oven, stirred, and again placed in the micro- wave for two minutes at 80% power. After this period, mi-crowave irradiation is continued and the reaction mixture is acetylsalicylic acid monitored every five minutes using thin-layer chromatogra- phy (TLC) with a stationary phase of silica gel and a mobile Scheme I. Preparation of acetylsalicylic acid.
phase of hexane–ethyl acetate (8:2 v兾v). The ferric chloride In the Laboratory
3) test (used to identify the presence of phenols) also is used to identify the presence of salicylic acid in the reactionevery five minutes. The initial reaction mixture forms a slurry Some individuals can be allergic to aspirin. Acetic an- that after microwave irradiation becomes a homogeneous so- hydride is a toxic, irritating, and lachrymatory substance.
lution. The formation of solids indicates the presence of the Some of the catalysts used in the experiment (DMAP, H2SO4, product. Once the solids are formed, the students carry out H3PO4, AlCl3 MgBr2, NEt3) may cause severe skin and eyes a procedure for polymer removal, an unwanted side-prod- burns or are highly corrosive. The solvents that are used in uct, if the catalyst is an acid, or acidify the medium first if the experiment (toluene, ethyl acetate, diethyl ether, acetone, the catalyst is a Brønsted base. After this procedure, the stu- hexane, petroleum ether) are flammable liquids. Students dents must recrystallize the product using the available sol- must consult the Material Safety Data Sheet (MSDS) for each vents, which include acetone, diethyl ether, petroleum ether, of these reactants before beginning the experiment. Before and toluene. Solubility tests can be done to determine the proceeding with the experiment, the students must be in- best solvents for recrystallization.
formed of the appropriate disposal of chemical wastes and Through the solubility tests, and corroborated with the warned of additional precautions to be taken when working literature, toluene is the best solvent for the recrystallization with chemical substances and the microwave oven. These ex- of aspirin. After recrystallizing the solid product, the students periments must be carried out inside a fume hood. Home isolate the product using vacuum filtration. The solid prod- microwave ovens may cause explosions when flammable sol- uct is dried, weighed, and the yield and melting points are vents are heated in open containers or when liquids or solids determined. Aspirin crystals are characterized using tech- are heated in closed containers not designed for high pres- niques such as NMR, FTIR and UV–vis. The students are sures. In this experiment the microwave is protected in a encouraged to work with spectral NMR viewers and simula- hood, but it would be preferable to use a laboratory micro- tion software, where chemical shifts and multiplicities can be confirmed for aspirin. The suggested software to be usedis "1H-NMR VIEWER" version 8.0, a freeware that can be found at the ACD兾Labs Web page (16), although any otherspectrum visualization package compatible with the jcamp This experiment was initially designed to study the ef- file format and NMR spectral simulation capabilities can be fect of the catalysts on the synthesis of aspirin, refer to the used. Once the student generates the predicted proton spec- Supplemental MaterialW for these results. For this laboratory trum, it can be compared with the experimental proton spec- experience the results proved that the best catalysts, in terms tral data obtained for aspirin. The spectroscopic data obtained of reaction time, were the Brønsted acids, similar to the re- from this synthesis are available in the Supplemental sults reported previously (1, 2). Subsequently, a procedure for the acid-catalyzed synthesis of aspirin using microwave To improve the green chemistry aspects of this experi- irradiation was reported in the literature (6, 12). Based on ment, the recrystallization step can be eliminated. The crude this finding, it was understood that the original experiment might material obtained for each reaction is washed with 25 mL of be modified and extended by applying microwave irradiation, cold water to remove the excess acetic anhydride. Then, the in a research-like approach producing the results in Table 1. product is filtered and dried in a preheated oven at 80 ⬚C.
Analysis of these results reveals the effect of microwave The melting point and yield must be determined. Finally, irradiation in relation to the reaction time, polymer forma- NMR and other spectroscopic methods are used to charac- tion, product purity and yield. Table 1 shows that under mi- terize the crude product (Table 1).
crowave irradiation, the results are similar to those traditionallyreported for acid catalysis, in terms of polymer formation andreaction time (2, 3, 12). The results under basic catalysis, how-ever, are completely different from those obtained from aspi- rin synthesis without microwave irradiation, in terms of reaction time, polymer formation, and yield. For example, the reaction using calcium carbonate (CaCO3) did not work with conventional heating (without microwave irradiation), but was completed in five minutes and a 77% yield was ob- tained under microwave irradiation. The experimental data also show that Brønsted acids produced lower yields when compared to Brønsted bases as catalysts. Initially, this may appear contradictory, because traditional experiments estab- lish that acid catalysts are more effective than basic catalysts, given the nature of the leaving group in the reaction mecha- nism (2). When a carbonyl nucleophilic substitution reac- tion is carried out in an acidic medium, the leaving group is acetic acid, which is a better leaving group than the acetate ion that is generated in a basic medium (2, 3). As can be observed from Table 1, the use of sulfuric and phosphoric acid as catalysts produced low yields owing to the formation of polymers. The polymers must be removed using a saturated In the Laboratory
solution of sodium bicarbonate, which is later acidified to best reaction medium in terms of purity and yield. In addi- recover the aspirin (2). In addition, it can be observed from tion, these results show that the yields using Brønsted acids the experimental results that Lewis acids can also be used as are moderate. This tendency was also observed under micro- catalysts. In the case of AlCl3 the yields were good and no wave irradiation using the recrystallization procedure. Inter- polymer formation was observed.
estingly, calcium carbonate (CaCO3) shows the best yields What seems very interesting is the comparison of the among the studied basic catalysts.
results of the reaction without any catalyst. In the absence of According to the literature, if there is an increase in the catalyst, without microwave irradiation, no reaction is ob- polarity of the medium or charge separation in the reaction served. On the other hand, under microwave irradiation the transition state, a faster reaction is observed under microwave reaction is completed in 10–13 minutes without polymer for- irradiation, because the transition state is stabilized, decreas- mation producing the highest yield (80%). This unexpected ing the activation energy (5, 10, 15). It is expected that the experimental result provides a good opportunity to introduce students will consider a reaction mechanism that proposes a green chemistry, emphasizing the importance of the atom charge separation in the reaction transition state, similar to economy principle (17, 18). By omitting the use of solvents the one presented in Scheme II.
for recrystallization in the previous procedures we can also Once the experiment is completed, the students form introduce the solvent-free principle (Table 1). "Green chem- groups to discuss results and to explain the effect of the cata- istry is the design of chemical products and processes that lyst on the reaction. Discussion questions are provided to the reduce or eliminate the use and generation of hazardous sub- students to guide their reasoning (refer to the Supplemental stances (18, 19)." The design of environmentally benign Msing these questions as a guide, the student products and processes may be guided by 12 principles, might conclude that CaCO3 could be the best catalyst, be- among them atom economy and solvent-free reactions. Atom cause in just 5 minutes they can obtain aspirin in 77% and economy stresses that synthetic methods should be designed 92% yield (Table 1), while without catalyst in 10–13 min- to maximize the incorporation of all materials used in the utes they can obtain the same product in 80% and 97% yield.
process into the final product, while the solvent-free reac- This conclusion is correct as long as the reaction time is con- tion principle stresses that the use of auxiliary substances (e.g., sidered. However, if you want to guide the student to con- solvents, separation agents, etc.) should be made unneces- sider some aspects of green chemistry such as solvent-free sary wherever possible and innocuous when used (19). reaction and atom economy, then the student should arrive The results obtained from the synthesis of aspirin un- at the conclusion that the best practical condition for aspi- der microwave irradiation via the solvent-free approach, in- rin synthesis is without catalyst. Students must also explain, dicate that the product yield for each catalyst is increased in terms of reaction mechanisms, why the formation of the when compared with the recrystallized product yields (Table product is favored even when there is no catalyst present, and 1). These differences in yields could be due to the loss of the role of the microwave radiation in the reaction.
some product during the recrystallization step. When the syn- Overall, the experiment affords a good opportunity for thesis of aspirin is carried out in the absence of a catalyst, groups to compare their experimental results and reach gen- although the reaction is slower, this condition provides the eral conclusions that individuals would find difficult to ob- Scheme II. Reaction mechanism suggested for the synthesis of aspirin under microwave condition without catalyst.
In the Laboratory
tain. This experience also shows the students that research leads to new findings that can create alternatives to traditionalmethods. The experiment also presents a good opportunity 1. Olmsted, J., III. J. Chem. Educ. to emphasize the importance of green chemistry. Moreover, 2. Eaton, D. C. Laboratory Investigations in Organic Chemistry, this experiment allows the students to critically assess the ad- 1st ed.; Mc Graw-Hill: New York, 1989; pp 299–309.
vantages and disadvantages offered by the use of microwave 3. Williamson, K. L. Macroscale and Microscale Organic Experi- technology in the synthesis of aspirin. One of the advantages ments, 1st ed.; D. C. Heath and Company: Toronto, 1989; the students can appreciate is that pure aspirin can be syn- pp 296–301.
thesized in short times. On the other hand, because this ex- 4. Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665–
periment does not provide the necessary time for the students to optimize their reaction conditions, which is critically im- 5. Lidström, P.; Tierney J.; Wathey, B.; Westman, J. Tetrahedron portant (especially for industry), they must carry out their 2001, 57, 9225–9283.
reaction using a given time, power, and amount of catalyst.
6. Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman, M.; Manhas, M. S. CHEMTECH 1997, 18–24.
7. Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei, K.; Urbanczyk-Lipkowska, Z. Heterocycles 1990, 30, 741–769.
This experiment provides a learning experience for the 8. Bose, A. K.; Manhas, M. S.; Banik, B. K.; Robb, E. W. Res. students because it familiarizes them with the application of Chem. Intermed. 1994, 20, 1–11.
new approaches and technologies to a classic experiment in 9. Badami, S.; Mathew, A. M.; Thomas, S.; Purushotham, V.; a research-like fashion. It also offers a learning experience and Mathew, G.; Sharma, S. V.; Suresh, B. Pharm. Chemistry 2003,
a challenge for the instructor as we continue to develop new 37, 4. (ac- experiences to teach the students, including new alternatives cessed Jan 2005).
and "greener" experimental methodologies for traditional syn- 10. Loupy, A. Microwaves in Organic Synthesis, 1st ed.; Wiley-VCH thetic procedures.
Verlag GmbH & Company KGaA: Weinheim, Germany, 2002; pp 61–143.
11. Tanaka, K. Solvent–Free Organic Synthesis, 1st ed.; Wiley-VCH We gratefully acknowledge support from University of Verlag GmbH & Company KGaA: Weinheim, Germany, Puerto Rico-Río Piedras Campus Institutional funds (FIPI), 2002; pp 301–319.
National Science Foundation Grant DUE-9354432, and 12. Mirafzal, G. A.; Summer, J. M. J. Chem. Educ. Howard Hughes Program (University of Puerto Rico-Río Piedras Campus). We are also grateful to José A. Prieto, 13. Creswell, S. L.; Haswell, S. J. J. Chem. Educ. Rolando Oyola, Rafael Arce (University of Puerto Rico-Río Piedras Campus), Patricia Shapley (University of Illinois at 14. Ardon, M.; Hayes, P. D.; Hogarth, G. J. Chem. Educ. Urbana-Champaign) and to the 2001–2005 majors organic chemistry laboratory students at UPR-Río Piedras for their 15. Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M.
participation in the implementation of this experiment.
Pure Appl. Chem. 2001, 73, 161–166.
16. Download ACD/Labs Freewar 17. Hjeresen, D. L.; Schutt, D. L.; Boese, J. M. J. Chem. Educ. Detailed instructions and further discussion of back- ground (including microwave information) for the students 18. Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35,
and notes for the instructor are available in JCE Online.
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