Greener Oxidation of Benzhydrol: Evaluating Three Oxidation

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Greener Oxidation of Benzhydrol: Evaluating Three Oxidation Procedures in the Organic Laboratory Kelli S. Khuong* Department of Chemistry and Biochemistry, University of San Diego, San Diego, California 92110, United States S Supporting Information *

ABSTRACT: In one lab period, students individually conduct one of three published green oxidation reactions of benzhydrol. Each method employs a different oxidant (potassium permanganate, sodium tungstate/hydrogen peroxide, or bleach) and requires approximately the same amount of time to complete. In a subsequent lab period, using a combination of TLC, IR spectroscopy, and GC, students work in teams to compile results and determine the average yield and purity, cost, amount of waste, and greenness of the oxidation method that was performed. Ultimately, the three methods are compared to determine whether one method is superior to another in each of the categories listed above. KEYWORDS: Organic Chemistry, Laboratory Instruction, Alcohols, Aldehydes/Ketones, Green Chemistry, Oxidation/Reduction, Inquiry-Based/Discovery Learning, Second-Year Undergraduate

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his experiment compares the effectiveness and costs of different synthetic methods that accomplish the same transformation. All students perform an oxidation of benzhydrol to benzophenone using one of three published green methods.1−3 Each of the three methods requires approximately the same reaction time but employs a different oxidant (see Scheme 1).4 Students then work in teams to determine the Scheme 1. Conditions for Performing Three Green Oxidations of Benzhydrol

average yield and purity, cost, ease, and greenness5 of the oxidation reaction that they performed. Finally, students compare the three methods to determine if one of the three oxidation methods is a clear winner over the other two or whether the particular priorities of a given situation (say cost versus safety) would warrant the choice of different methods. Two 4 h lab periods are devoted to the experiment. © XXXX American Chemical Society and Division of Chemical Education, Inc.

EXPERIMENTAL OVERVIEW

Prior to week 1 of the experiment, students are divided into three teams, with each team focusing on one oxidation method. The background information provided to the students includes information about green chemistry and direct quotes from the three published articles about the benefits of the given method (see Supporting Information for all student handouts). Each oxidation method includes notable features highlighted below. The crude product is analyzed without further purification. Method 1, a potassium permanganate oxidation,1 features a solvent-free, solid/solid reaction mixture, heated for 1 h. The product is isolated by extraction, vacuum filtration, and evaporation of the solvent. Method 2, a peroxide oxidation,2 combines hydrogen peroxide and sodium tungstate (a catalyst) as oxidants, and no organic solvent is needed. An acidic phase transfer catalyst is required to shuttle the tungstate during the 1 h reflux. The product is isolated by extraction, filter pipet, and evaporation of the solvent. In method 3, commercial bleach is used as the oxidant, and a phase transfer catalyst is required.3 The reaction mixture is stirred (not heated) for 1 h. The product is isolated by extraction and evaporation of the solvent. In the first week of the experiment, each member of the team performs the assigned oxidation reaction and isolates the crude benzophenone. During the 1 h stir or reflux, the team calculates the cost of chemicals (scaled to 1 g of benzhydrol), calculates Received: June 12, 2016 Revised: November 21, 2016

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DOI: 10.1021/acs.jchemed.6b00433 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

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Table 1. Typical Yield, Purity, Cost, Mass Intensity, and Ease of Oxidizing Benzhydrol to Benzophenone by Methods 1−3 Oxidation Method

Average Yield, %

Range of Yields, %

Students Reporting Pure Product,a %

Reaction Cost,b USD

Theoretical Mass Intensity

Average Mass Intensityc

Method Is Easyd

Method 1: Permanganate Method 2: Peroxide Method 3: Bleach

50 40 70

15−100 0−90 10−100

50 30 80

1.75 0.98 1.30

21.1 10.4 34.1

42.2 26.0 48.7

yes no yes

a Indicated by TLC and GC. bScaled to 1 g of benzhydrol starting material. cUsing the average reaction yield and eq 1. dBased on student feedback during the week 2 discussion.

Table 2. Assessment of Green Principles for Oxidation Methods 1−3 Green Principle

Method 1: Permanganate Scorea

1 2

No hazardous waste (assessed by MI) No excess reagents or byproduct formation (assessed by excess of stoichiometric reagents) All substances have low risks to human health and environment (assessed by hazard rubric)

2 1

5

No solvent is used, or solvents have low risks to human health and environment

3, 1

6

Environmental temperature and pressure

7 8 9

All raw materials are renewable Derivatizations are not used Catalytic reagents with low risk to human health and the environment (assessed by hazard rubric) Substances are biodegradable All substances have low risks of chemical accident (assessed by hazard rubric)

3

10 12 Sumb a

1

Method 2: Peroxide Scorea

Reason Intermediate MI 3.1 equiv KMnO4; MnO2 byproduct Health and environmental hazards high

2

Reaction is solventless; isolation solvent high hazard 100 °C, ambient pressure

1 3 1

1 1

3 2 1

Lowest MI 1.14 equiv H2O2; innocuous byproducts Health and environmental hazards high

Method 3: Bleach Scorea 1 1 1

2

Reaction is solventless; isolation solvent high hazard 90 °C, ambient pressure

3

Not renewable No derivatives High hazard

1 3 1

Not renewable No derivatives High hazard

1 3 2

Not biodegradable High health and physical hazard

1 1


1 1

17

3, 1

Reason

19

1, 1

Reason Highest MI 3.3 equiv NaOCl; innocuous byproducts Health and environmental hazards high Reaction and isolation solvent high hazard Room temperature, ambient pressure Not renewable No derivatives Moderate hazard


16

1 = poorest green score, 3 = best green score. bMaximum greenness score is 33.

the mass intensity of the reaction (eq 1), and determines an appropriate TLC developing solvent for distinguishing between the benzhydrol and benzophenone using standards. Mass intensity (MI) is calculated by eq 1.6,7 This green metric was chosen to measure waste because it accounts for all reagents, catalysts, and solvents used in a reaction relative to the amount of product obtained. The ideal MI for a reaction is 1. MI =

∑ (mass of all materials used) mass of product

personal protective equipment, and work in a fume hood to minimize contact.

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RESULTS AND DISCUSSION This experiment has been performed by approximately 600 students (15 students per section, 10 sections per year) over a four-year period. The outcomes of the experiment have been similar from year to year, with one exception when the bleach oxidation showed poor conversion to product.

(1)

Experiment Outcomes for Methods 1−3

In the second week of the experiment, each team member analyzes the purity of their crude product by TLC, IR spectroscopy, and GC, and calculates percent yield. Team members then compile data to calculate average percent yield, purity, and mass intensity. Finally, all teams participate in a class discussion to compare the outcomes of the three oxidation methods.

The typical results for oxidation methods 1, 2, and 3 are summarized in Table 1. Individual student results, example cost calculations, and example MI calculations are included in the Supporting Information. Method 1, the permanganate oxidation, consistently worked well in the hands of students, although yields were lower than the “near quantitative” yield1 reported in the original article. The yield and purity appeared most dependent on how well the reactants were mixed prior to heating. Students found the procedure to be straightforward, with cleanup of the MnO2 residue using sodium bisulfite solution being the main complication. Method 2, the peroxide oxidation, was the most timeconsuming of the three, partly because more reagents were needed for the reaction mixture (including the difficult-tomeasure viscous liquid methyltrioctylammonium chloride) and because a filter pipet was required. As shown in Table 1, both average yield and purity were lower for method 2 than for 1 (the permanganate reaction) and lower than the >90% yield

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HAZARDS Chemicals required are benzhydrol, benzophenone, potassium permanganate, copper sulfate pentahydrate, hexanes, 30 wt % hydrogen peroxide, sodium tungstate, methyltrioctylammonium chloride, sodium hydrogen sulfate hydrate, sodium thiosulfate pentahydrate, diethyl ether, sodium hypochlorite, ethyl acetate, tetrabutylammonium bromide, and magnesium sulfate. See the Supporting Information for a complete listing of CAS numbers and hazard statements. Students should use standard safety precautions, handle all reagents while wearing B



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and purity reported in the original article.2 Of the three reactions, this one was the least reliable in the hands of students due to the higher number of reagents, the difficulty of maintaining the water bath temperature at 90 °C (higher temperature leads to hydrogen peroxide decomposition2), and the greater number of procedural steps. For the ease category, students reliably ranked reaction 2 as being the most difficult. Reaction 3, the bleach oxidation, consistently worked well (with one exception noted in the Supporting Information). It was the quickest reaction to set up, and the extraction sequence was easy to follow. It is no surprise that this is a method published in undergraduate laboratory manuals.8 Rapid, efficient stirring of the biphasic reaction mixture was important for high conversion. Overall, both yield and purity were highest for this method (and were in line with the original article, which reported 80% yield of pure benzophenone after recrystallization). However, nearly every student performing the bleach oxidation obtained a yellow crude product instead of the anticipated white solid.

has pros and cons, and that there remains much room for improvement in the greening of oxidation methods.

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CONCLUSION Although the oxidation of an alcohol is not novel, the format of this two-week experiment achieves many goals that a simple verification-type of procedure cannot accomplish. First, a student is responsible for the outcome of his/her individual reaction and is also working within a team to compile results. The large number of data points emphasizes the importance of having meaningful numbers when calculating yield or purity.11 Second, students are asked to address issues that often are overlooked in a typical organic laboratory (e.g., cost of reagents, amount of waste, and ease). Third, the experimental format is flexible so that additional green oxidation procedures could be incorporated into the comparative analysis.4 Fourth, green chemistry can promote social responsibility and engage students because it is a topic that resonates even for students whose primary interests lie outside of organic chemistry.12 Finally, the discussion of waste, safety, and energy efficiency drives home the message that green is a relative term with many facets that must be assessed independently of each other.

Green Outcomes for Methods 1−3

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After compiling data and completing the necessary calculations, all three teams participated in a full class discussion, guided by the instructor. For the quantitative metrics (yield, purity, cost, mass intensity) and perception of ease, each team simply reported its findings. For greenness, the instructor guided the teams regarding how to assess the 10 relevant green principles of chemistry (principles 4 and 11 are generally omitted because they deal with product design and analytical techniques). A prepared packet of SDSs, a hazard code rubric (used to categorize SDS hazard codes as low, moderate, or high risk), and a rubric for assessing each green principle was provided to each team (and can be found in the Supporting Information).9 Students used SDS hazard codes and the two rubrics to assign each method a score of 1, 2, or 3 for each green principle. Typical green principle scores and reasons for those scores are given in Table 2. Using this analysis, an oxidation method can earn a maximum greenness score of 33 and minimum greenness score of 11. For the three oxidation reactions, method 2 (peroxide oxidation, score 19) slightly outscored method 1 (permanganate oxidation, score 17) and method 3 (bleach oxidation, score 16). The Table 2 rubric for assessing green principles 3, 6−10, and 12 follows the green star assessment method reported by Ribeiro, Yunes, and Machado.9,10 The green star method ranks each principle using a 1, 2, or 3 score (1 = poorest green score and 3 = best green score), using a provided rubric. The green star method would have given all three oxidation methods the same score of “1” for principles 1, 2, and 5, so a different ranking system was developed for these principles. For principles 1 and 2 the three oxidations were simply compared relative to each other using the calculated mass intensity (principle 1) and excess of stoichiometric reagents (principle 2) instead of using the green star rubric. For principle 5, the role of solvent was considered separately for the reaction phase and the isolation phase of the procedure (to capture the fact that reaction 1 features a solid/solid reaction and reaction 2 is free of organic solvents). Overall, the class discussion on greenness underscored that many factors play a role in the development of greener synthetic methods, that each of the three oxidation methods

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00433. List of chemicals and hazards, student handouts, instructor notes, example calculations, green principle rubric, and sample data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kelli S. Khuong: 0000-0002-1080-1309 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS The author would like to thank USD’s organic chemistry team for helpful discussions in fine-tuning this experiment and the 2012−2016 organic chemistry students in the preparation and testing of this experiment.

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REFERENCES

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Greener Oxidation of Benzhydrol: Evaluating Three Oxidation

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