In the Laboratory edited by
Green Chemistry
Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036
An Approach Towards Teaching Green Chemistry Fundamentals
W
Susan D. Van Arnum Chemistry Department, Union County College, Cranford, NJ 07016;
[email protected] Waste prevention is a central component to the concept of green chemistry. From a process-chemistry perspective, this tenet has consequences not only for selection of route and reagent, but also for the use of auxiliary substances such as solvents and separation reagents (1). Because waste prevention requires a certain level of sophisticated understanding of chemistry, one way to introduce the concept of green chemistry at the undergraduate level is to begin with assessing the quantity of waste produced in a chemical process. This laboratory experiment describes a virtual experiment that focuses on the critical analysis of chemical processes and utilizes a recently described system of metrics as the basis for the experiment (2). The system of metrics calculates the total quantity of waste produced per quantity of product and analyzes the individual contribution of solvent, reagents, auxiliary substances, and water with respect to the quantity of product produced. A more advanced treatise on this subject has recently appeared (3). Process development involves an analysis of a current process, design of an experimental plan, and the execution of the experimental work. The experimental work forms the basis for a new process and then, these steps are repeated (Figure 1). This methodology is the algorithm of process chemistry and of process optimization; this algorithm is repeated until the desired process characteristics are achieved. This experiment is an exercise in process optimization in which waste minimization is the desired target. More advanced experimental methods in process optimization such as statistical design of experiments could be introduced in this context (4). For photochemical processes and their utilization as an approach towards environmentally-benign chemical processes, typical experimental variables for the optimization of tradi-
tional chemical processes and photochemical processes have recently been described and contrasted and could also be included in this discussion (5). Hazards This dry laboratory experiment does not utilize any chemicals and therefore there are no known hazards. Results and Discussion During the course of studies on the photochemistry of endo-bicyclo[2.2.1]hept-5-en-2-yl(5-methyl-3-isoxazolyl)methanone (6), a straightforward, multigram synthesis of 3acetyl-5-methylisoxazole (3) was required and we have recently described a one-pot, solvent-free preparation of 3 (7). The synthesis is atom efficient and although the conversion of 2,5-hexanedione (1) to 3 is close to 100%, the isolated yield is lower. This is reflective of product losses during the extraction and purification steps. The synthesis of 3 involves the hydrochloric acid-catalyzed nitrosation of 1 by ethyl nitrite (Scheme I) (7). The synthesis of 3 by this method is a two-step process and involves initial nitrosation of 1 to form the intermediate hexane-2,3,5-trione-3-oxime (2). Cyclization and dehydration of 2 yields 3. Both of these processes are acid-catalyzed.
O
O EtONO HCl
N
O 1
O OH 2
Environmental-impact analysis
Process
−H2O HCl
Proposal O N
Exp
r e ri m e n t a l w o
k
O 3
Figure 1. Algorithm of process development.
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+ C2H5OH
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Scheme I. Reaction of 2,5-hexanedione (1) and ethyl nitrite to form 3-acetyl-5-methylisoxazole (3) through an intermediate, hexane2,3,5-trione-3-oxime (2).
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In the Laboratory Table 1. Spreadsheet for the Preparation of 3-Acetyl-5-methylisoxazole at 67% Yield Compound
Source or Use
Molar Mass/ (g mol ᎑1)
Volume/ mL
2,5-Hexanedione
Starting Mat.
114.15
43.99
Density/ (g mL᎑1)
Amount/ mol
Mass/ g 42.80
0.973
0.375
12 N HCl
Catalyst
36.46
4.5
1.18
0.055
Ethyl nitrite
Reagent
75.06
---
---
0.79
Diethyl ether
5.31 59.30
Solvent
74.12
25 0
0.706
---
Sodium bicarbonate
Extraction
84.01
---
---
0.179
177 14.25
Sodium chloride
Extraction
58.44
---
---
---
17.50
Sodium chloride
Byproduct
58.44
---
---
0.055
8.51
Carbon dioxide
Byproduct
44.01
---
---
0.055
2.42
20 0
Water
Extraction
18.01
Water
Byproduct
18.01
Magnesium sulfate
Desiccant
120.04
Ethyl alcohol
Byproduct
3-Acetyl-5-methylisoxazole
Product
46.07 125.01
To evaluate this procedure, the quantities of the input materials and the product are required. The procedure describes the input material and these values can be transposed into Table 1. In addition to the compound name, the molar mass, the density, and the volume of a substance, the quantity of each substance used or produced in the process is calculated and the source or use of the substance identified. There are two byproducts in the reaction, ethyl alcohol and water, and three byproducts as a consequence of the neutralization of the hydrochloric acid catalyst, sodium chloride, water, and carbon dioxide (Table 1). The laboratory is also an exercise in stoichiometry as the student needs to calculate the quantities of different products that are produced in the reaction and in the workup procedure (8). Through this analysis, the student will identify the reason for the use of these different substances. With this realization, a student can develop different alternatives that could eliminate their use and reduce the quantity of waste. The same exercise could be conducted by the student using a different nitrosating agent, such as isoamyl nitrite, or for the ethyl nitrite procedure, this process could be analyzed for the synthesis of 100 grams or 100 kg of 3. A separate approach would be to construct this experiment as a project case study, in which the goal of a project is to reduce the overall waste in the process by, for example, 20%. This approach would be worthwhile, but waste reduction should be not considered as incremental, and the best process would be one in which the yield of the process was 100% and no waste was generated. If the 20% reduction approach is used, the caveat that attainment of this goal is only a milestone in total waste reduction should be presented as well. The environmental-impact analysis for this process is shown in Table 2 at the current yield of 67% and at a theoretical yield of 100%. A step is a discrete chemical transformation or a purification or isolation operation. A stage is a series of steps. The conversion of 1 to 3 consists of two steps, but the number of stages for the synthesis is only one. From an environmental perspective, the fact that there are two
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1
---
6.75
1
0.375
---
---
---
10.00
0.79
0.375
17.27
---
0.251
31.30
21.86 ---
200 6.75
chemistry steps for a one-stage process would suggest that there is some level of chemical complexity in this synthesis. The total number of stages reflects the number of synthetic steps and the purification steps that are needed to prepare the final product in acceptable purity. Because a one-stage, two-step process would indicate that the workup procedure
Table 2. Environmental-Impact Analysis for the Preparation of 3-Acetyl-5-methylisoxazole Process Characteristic
67% Yield
Product name
100% Yield
3-Acetyl-5-methyl 3-Acetyl-5-methyl isoxazole isoxazole
Literature reference
7
7
Number of chemical steps
2
2
Number of purification steps
1
1
Number of stages Overall Yield
2
2
67%
100%
Lists of solvent used
Diethyl ether
Diethyl ether
List of reagents with known environmental, safety, or health problems
Diethyl ether
Diethyl ether
Overall mass solvent per unit mass final product
5.65
3.78
Overall mass water per unit mass final product
6.39
4.27
Overall mass input material per unit mass final product
3.40
2.27
Total mass waste per unit mass final product
15.44
10.32
Additional Comments
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Ethyl nitrite is a gas; Ethanol is produced in the process; A reusable solid-phase acid catalyst may be beneficial.
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In the Laboratory
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Conclusion In summary, a useful metrics system for the assessment of the environmental impact of chemical processes is utilized to illustrate several of the principles of green chemistry. In addition to the example for the nitrosation of 2,5-hexanedione (1), the use of this metrics system in conjunction with
18 16 14
Waste Mass Product Mass
has been eliminated for one of the steps, a comparative analysis between one-stage and two-stage processes would show that the process that had the fewest number of stages would be the most environmentally benign. The list of solvent includes those solvents that are used in the process. Diethyl ether, used in the extraction process, is the only solvent used in this example. Because of its low flash point and its propensity to form peroxides, diethyl ether is considered a hazardous substance to use on a preparative scale. Ethyl nitrite should be evaluated for its potential as a hazardous substance; however, the substance is not readily commercially available and because of this, in practice, another alkyl nitrite would be substituted. Hazardous substances are highlighted in this analysis as their safer substitutes would always be a component of a process development study. The total quantity of solvent per quantity of product is equal to the mass of diethyl ether that is used per mass of product produced. The quantity of waste produced by this input material is related to the yield. The higher the yield in the process, the smaller the quantity of the solvent that will be used. Ways to increase yield could be to minimize product losses in the aqueous waste streams and to maximize the efficiency of the distillation process. For this experiment, this value is equal to 177 g of diethyl ether divided by 31.30 g of 3, or 5.65. For this process, water is used in the extraction procedure and is produced as a byproduct in the reaction and during the neutralization of the hydrochloric acid. For this analysis, only the total quantity of water that is used in the extractions is considered and the quantity of wastewater produced per quantity of product is calculated. In this example, this value is equal to 200 g water divided by 31.30 g of 3, or 6.39. The total quantity of input material is equal to the sum of the quantities of the reagents and the catalyst and the quantities of auxiliary substances such as sodium bicarbonate, sodium chloride, and magnesium sulfate. Hydrochloric acid is considered as a catalyst. This total is summed and divided by the quantity of product produced. For the present analysis, this value is equal to the sum of 5.31 g of hydrochloric acid, 59.30 g of ethyl nitrite, 14.25 g of sodium bicarbonate, 17.50 g of sodium chloride and 10.00 g of magnesium sulfate divided by 31.30 g of 3, or 3.40. The total quantity of waste that is produced per quantity of product produced is the sum of the three quantities just discussed. As illustrated in Figure 2, the quantity of waste can be dramatically reduced by improvements in the isolated yield. The waste mass intensity is the ratio of the quantity of waste produced per mass of product produced. The overall process is described in the flow diagram shown in Figure 3. This flow diagram would be helpful as an instructional aid for the identification of the input and output materials and the operations that yield an output material or a subsequent process stream. For this dry laboratory experiment, students are required to answer 14 questions (see the Supplemental MaterialW). For question 6, Tables 1 and 2 need to be completed for the isoamyl process at a 100% yield. These results are then compared to the ethyl nitrite process at the same yield.
67% yield 100% yield
12 10 8 6 4 2 0
solvents
water usage
input materials
total waste
Source of Waste Figure 2. Waste mass intensity as a function of yield improvement.
Input
Operation
Output
2,5-Hexanedione Hydrochloric acid Ethyl nitrite
Charge
Excess ethyl nitrite
Diethyl ether Sodium bicarbonate Water
Extract
Sodium bicarbonate Sodium chloride Carbon dioxide Water
Sodium chloride Water
Extract
Sodium chloride Water
Magnesium sulfate
Dry
Magnesium sulfate
Evaporate
Diethyl ether Ethanol
Distill
3-Acetyl-5methylisoxazole
Figure 3. Flow diagram for the synthesis and purification of 3-acetyl5-methylisoxazole.
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In the Laboratory
laboratory experiments in green chemistry (8–10) would provide for reinforcement in both the theory and practice of green chemistry (7, 11–13). 3. 4.
Acknowledgments We thank Ronald R. Sauers of Rutgers University for the initial review of this manuscript. We thank the J.L.R. Morgan Fellowship Fund of Rutgers University and the Garden State Graduate Fellowship Commission for financial support. W
5. 6. 7. 8.
Supplemental Material
Uses and other preparations for 3-acetyl-5-methylisoxazole, the procedure for the environmental-impact analysis, and student exercises are available in this issue of JCE Online.
9. 10. 11.
Literature Cited
12.
1. Anastas, P. T.; Warner, J. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 2000. 2. Constable, D. J. C.; Curzons, A. D.; Freitas dos Santos, L. F.;
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Geen, G. R.; Hannah, R. E.; Hayler, J. D.; Kitteringham, J.; McGuire, M. A.; Richardson, J. E.; Smith, P.; Webb, R. L.; Yu, M. Green Chem. 2001, 3, 7–9. Andraos, J. Org. Proc. Res. Dev. 2005, 9, 149–163. Van Arnum, S. D.; Moffet, H.: Carpenter, B. K. Org. Proc. Res. Dev. 2004, 8, 769–776. Sauers, R. R.; Van Arnum, S. D.; Scimone, A. A. Green Chem. 2004, 6, 578–582. Sauers, R. R.; Hagedorn, A. A., III; Van Arnum, S. D.; Gomez, R. P.; Moquin, R. V. J. Org. Chem. 1987, 52, 5501–5505. Sauers, R. R.; Van Arnum, S. D. J. Heterocycl. Chem. 2003, 40, 665–668. Song, Y.-M.; Wang, Y.-C.; Geng, Z.-Y. J. Chem. Educ. 2004, 81, 691–692. Pohl, N.; Clague, A.; Schwarz, K. J. Chem. Educ. 2002, 79, 727–729. Harper, B. A.; Rainwater, J. C.; Birdwhistell, K.; Knight, D. A. J. Chem. Educ. 2002, 79, 729–731. Colom, J.; Llobet, A.; Pla-Quintana, A.; Roglans, A. J. Chem. Educ. 2002, 79, 731–735. Santos Santos, E.; Cruz Gavilan Garcia, I.; Lejarazo Gomez, E. F. J. Chem. Educ. 2004, 81, 232–238. Cann, M. C.; Dickneider, T. A. J. Chem. Educ. 2004, 81, 977– 981.
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