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Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.fw001

Green Chemistry Experiments in Undergraduate Laboratories

Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.fw001

Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

ACS SYMPOSIUM SERIES 1233

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.fw001

Green Chemistry Experiments in Undergraduate Laboratories Jodie T. Fahey, Editor Mount Saint Mary College Newburgh, New York

Lynn E. Maelia, Editor Mount Saint Mary College Newburgh, New York

Sponsored by the ACS Division of Chemical Education

American Chemical Society, Washington, DC Distributed in print by Oxford University Press

Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.fw001

Library of Congress Cataloging-in-Publication Data Names: Fahey, Jodie T., editor. | Maelia, Lynn E. (Lynn Ellen), editor. | American Chemical Society. Division of Chemical Education. Title: Green chemistry experiments in undergraduate laboratories / Jodie T. Fahey, editor, Mount Saint Mary College, Newburgh, New York, Lynn E. Maelia, editor, Mount Saint Mary College, Newburgh, New York ; sponsored by the ACS Division of Chemical Education. Description: Washington, DC : American Chemical Society, [2016] | Series: ACS symposium series ; 1233 | Includes bibliographical references and index. Identifiers: LCCN 2016043970 (print) | LCCN 2016044489 (ebook) | ISBN 9780841231771 (alk. paper) | ISBN 9780841231764 () Subjects: LCSH: Green chemistry--Study and teaching (Higher) | Chemistry--Study and teaching (Higher) Classification: LCC TP155.2.E58 G74185 2016 (print) | LCC TP155.2.E58 (ebook) | DDC 540.78--dc23 LC record available at https://lccn.loc.gov/2016043970

The paper used in this publication meets the minimum requirements of American National Standard for Information Sciences—Permanence of Paper for Printed Library Materials, ANSI Z39.48n1984. Copyright © 2016 American Chemical Society Distributed in print by Oxford University Press All Rights Reserved. Reprographic copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Act is allowed for internal use only, provided that a per-chapter fee of $40.25 plus $0.75 per page is paid to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. Republication or reproduction for sale of pages in this book is permitted only under license from ACS. Direct these and other permission requests to ACS Copyright Office, Publications Division, 1155 16th Street, N.W., Washington, DC 20036. The citation of trade names and/or names of manufacturers in this publication is not to be construed as an endorsement or as approval by ACS of the commercial products or services referenced herein; nor should the mere reference herein to any drawing, specification, chemical process, or other data be regarded as a license or as a conveyance of any right or permission to the holder, reader, or any other person or corporation, to manufacture, reproduce, use, or sell any patented invention or copyrighted work that may in any way be related thereto. Registered names, trademarks, etc., used in this publication, even without specific indication thereof, are not to be considered unprotected by law. PRINTED IN THE UNITED STATES OF AMERICA Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.fw001

Foreword The ACS Symposium Series was first published in 1974 to provide a mechanism for publishing symposia quickly in book form. The purpose of the series is to publish timely, comprehensive books developed from the ACS sponsored symposia based on current scientific research. Occasionally, books are developed from symposia sponsored by other organizations when the topic is of keen interest to the chemistry audience. Before agreeing to publish a book, the proposed table of contents is reviewed for appropriate and comprehensive coverage and for interest to the audience. Some papers may be excluded to better focus the book; others may be added to provide comprehensiveness. When appropriate, overview or introductory chapters are added. Drafts of chapters are peer-reviewed prior to final acceptance or rejection, and manuscripts are prepared in camera-ready format. As a rule, only original research papers and original review papers are included in the volumes. Verbatim reproductions of previous published papers are not accepted.

ACS Books Department

Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.pr001

Preface Since the introduction of green chemistry principles in industrial processes, interest has continued to grow and green chemistry has started to take roots in educational laboratories of all disciplines of chemistry. Entire courses centered around green chemistry are becoming more prevalent. By introducing students to green chemistry at a collegiate level, they will better be prepared for industry, graduate schools, and also have a better appreciation for the environment. This symposium text will highlight some novel experiments that can be implemented in college laboratories. This book is based on a symposium held at the 2015 Northeast Regional Meeting of the American Chemical Society in Ithaca, NY. All presentations were positively received,especially the green chemistry talks. This interest was also apparent at the 250th National American Chemical Society Meeting in Boston, Massachusetts on August 17th, 2015. During the green chemistry symposium there was a strong interest in all presentations and how the experiments presented could be implemented into the undergraduate curriculum. The text includes experiments that cover range of green chemistry principles. Due to the nature of undergraduate organic chemistry, and the typical large number of students enrolled in the course from various majors, many of the experiments presented in this text have an organic chemistry focus. However, many of the experiments can be adapted to other disciplines of chemistry or can be used as a foundation for a Green Chemistry course. The experiments presented in this text utilize many of the 12 Principles of Green Chemistry. Each chapter presents an experiment that utilizes at least one, if not more, of these principles. This book is targeted for any professor who would like to introduce green or “greener” laboratory experiments for their students in any chemistry course regarless of level. Additionally, instructors wishing to create and implement a green chemistry course would also benefit from the material presented here. We hope these experiments serve to introduce students to the ideas, principles, and benefits of green chemistry and inspire educators to adopt more green chemistry principles in their course. We would like to thank the authors for their contributions, patience, and cooperation while the text was being reviewed. We also would like to thank the ACS for sponsoring the 2015 NERM symposium and supporting this text. We would like to thank the numerous reviewers for their hard work as well as the staff of the ACS Symposium Series. Lastly, this book would not be possible if not for the inspiration of Dr. Kimberly Pacheco. Dr. Pacheco taught organic chemistry at the University of Northern Colorado until her passing early this summer after a 9 year battle with ix Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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cancer. She was very passionate about organic chemistry and the many green initiatives in the field. She served as my mentor in graduate school and continued to collaborate with me throughtout my career. She was an editor and author of many ACS Symoposium series texts herself. It is in her memory that we submit this text.

Jodie T. Fahey Division of Natural Sciences Mount Saint Mary College 330 Powell Ave. Newburgh, New York 12550, United States [email protected] (e-mail)

Lynn E. Maelia Division of Natural Sciences Mount Saint Mary College 330 Powell Ave. Newburgh, New York 12550, United States [email protected] (e-mail)

x Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Chapter 1

Introduction

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J. Fahey* and L. Maelia Division of Natural Science, Mount Saint Mary College, Newburgh, New York 12550, United States *E-mail: [email protected]

This chapter outlines the development of green chemistry as an alternative way of considering chemical processes. It describes the principles that define green chemistry and explains how the following chapters utilize green chemistry concepts in the teaching laboratory.

Since the 1960s when it became evident that our environment could not sustain the insults of human activity, chemists have considered ways to mitigate their impact on the planet. Initially, concern was almost exclusively about removing toxic chemicals in the environment. Today, chemists’ concern for the environment is much more multidimensional, ranging from designing processes that use fewer and less toxic chemicals, to designing molecules that are themselves less toxic and that do not remain in the environment after they have outlived their usefulness. Greening a chemical reaction has become more than an afterthought, but is built into the entire process, from choosing the source for the reactants, to the disposition of the products, and along the way considering the quantity and toxicity of byproducts, the chemical and energy efficiency of the reaction, and the safety of the entire process. This change has been gradual, occurring slowly over time. Green chemistry, as we know it today, revolves around a set of twelve principles that were outlined by Anastas and Warner in 1998 (1): 1.

Prevention It is better to prevent waste than to treat or clean up waste after it has been created.

© 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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2.

Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product.

3.

Less Hazardous Chemical Syntheses Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment.

4.

Designing Safer Chemicals Chemical products should be designed to affect their desired function while minimizing their toxicity.

5.

Safer Solvents and Auxiliaries The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used.

6.

Design for Energy Efficiency Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure.

7.

Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable.

8.

Reduce Derivatives Unnecessary derivatization (use of blocking groups, protection/ deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.

9.

Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.

10. Design for Degradation Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment. 11. Real-Time Analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 2 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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12. Inherently Safer Chemistry for Accident Prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires. Just over twenty-five years ago, the United States Environmental Protection Agency (EPA) first introduced the term Green Chemistry (2). Since it’s introduction, green chemistry has infiltrated both industry and academia. In the early 90’s a course entitled, Introduction to Green Chemistry, was first taught at Carnegie Mellon University (3). By the late 90’s the University of Massachusetts at Boston established the first doctoral program in Green Chemistry (4). In 1997, the Green Chemistry Institute (GCI) was founded as an independent nonprofit organization to advance green chemistry principles in the scientific community. In 2001, the GCI joined forces with the American Chemical Society (ACS), the largest scientific society in the world, and became the ACS-GCI (5). The ACS-GCI employs a three pronged approach to expanding knowledge about green chemistry: via scientific research, educational outreach, and industry participation (6). 2016 marks the 20th anniversary of the annual Green Chemistry & Engineering Conference first sponsored by GCI. The first conference brought together industry leaders and government in an effort to make industrial processes more environmentally friendly. Subsequent conferences have expanded their reach to include students and green chemistry education. It is one of many national and international conferences with a green chemistry focus (7). While industry has seen the need and benefits of applying principles of environmental concern, green chemistry has more slowly been adopted by the education community. However, we are doing students a disservice if we send them off to industry, government, or graduate school without the knowledge and skills needed to protect the environment. A number of resources are available for instructors to learn about greening their curriculum. The ACS Green Chemistry site provides extensive lists of resources for both students and educators (8), as does the green chemistry site of the US Environmental Protection Agency (EPA) (9). There are a few texts and laboratory manuals devoted to green chemistry (10–15). This book builds on the work that has been done previously, and is a product of a chemical education symposium held at the 2015 Northeast Regional Meeting of the American Chemical Society in Ithaca, NY. In this book, we have compiled a number of ways that green chemistry can be incorporated into the undergraduate teaching laboratory. We begin with an overview of the green chemistry experiments in organic chemistry published since 2012, when Andrew Dicks’ “Green Organic Chemistry in Lecture and Laboratory” was published (10). The twelve green chemistry principles can be seen throughout the experiments described here. A common principle is one that is easily understood as a basic tenet of greening a chemical process: using less hazardous substances in chemical synthesis and using safer solvents for extractions and separations. By using safer starting materials, the experiments of Fahey and Bastin show how Principle 3, Less Hazardous Chemical Syntheses, can be applied. The experiments of Bastin, Manchanayakage, and Wissinger 3 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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all use fewer and/or safer solvents (Principle 5). The use of catalysts marks the work of Gross and Fahey (Principle 9), while the efficiency of the synthetic route is a focus of the experiments of Fishback and Manchanayakage (Principle 2). Wissinger’s experiment also uses renewable feedstocks (Principle 7) and designs products for ultimate degradation (Principle 10). Bastin’s chapter explains how students are actively involved in seeking green alternatives for their laboratory experiments. The chapter by Barcena encourages students to consider the toxicity of the chemicals used, even everyday chemicals with which students are familiar. These experiments can be adopted or adapted for use in the undergraduate laboratory, and provide ideas and inspiration for greening your own laboratory experiments.

References 1. 2. 3. 4.

5.

6.

7.

8.

9.

10. 11. 12. 13.

Anastas, P. T. ; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. Andraos, J.; Dicks, A. P. Green chemistry teaching in higher education: a review of effective practices. Chem. Educ. Res. Pract. 2012, 13, 69–79. Collins, T. J. Introducing green chemistry in teaching and research. J. Chem. Ed. 1995, 72, 965. American Chemical Society. ACS History of Green Chemistry, June 19, 2016. https://www.acs.org/content/acs/en/greenchemistry/what-is-greenchemistry/history-of-green-chemistry.html (accessed July 6, 2016). American Chemical Society. ACS History of Green Chemistry, June 21, 2016. https://www.acs.org/content/acs/en/greenchemistry/what-is-greenchemistry/history-of-green-chemistry.html (accessed June 26, 2016). American Chemical Society. ACS Green Chemistry Institute, June 24, 2016. https://www.acs.org/content/acs/en/greenchemistry.html (accessed June 26, 2016). American Chemical Society. Green Chemistry Conferences, June 25, 2016. https://www.acs.org/content/acs/en/meetings/ greenchemistryconferences.html (accessed June 26, 2016). American Chemical Society.. Students and Educators, June 21, 2016. https://www.acs.org/content/acs/en/greenchemistry/students-educators.html (accessed June 26, 2016). Environmental Protection Agency. Resources. [Online] April 19, 2016. [Cited: June 26, 2016] https://www.epa.gov/greenchemistry/ resources#education. Dicks, A. P., Ed.; Green Organic Chemistry in Lecture and Laboratory; CRC Press: Boca Raton, FL, 2012. Matlack, A. S.;Dicks, A. P. Problem-Solving Exercises in Green and Sustainable Chemistry; CRC Press: Boca Raton, FL, 2015. Henrie, S. A. Green Chemistry Laboratory Manual for General Chemistry; CRC Press: Boca Raton, FL, 2015. Matlack, A. S. Introduction to Green Chemistry, 2nd ed.; CRC Press: Boca Raton, FL, 2010. 4 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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14. Lancaster, M.. Green Chemistry: An Introductory Text, 2nd ed.; Royal Society of Chemistry: London, 2010. 15. Kirchhoff, M., Ryan, M., Eds.; Greener Approaches to Undergraduate Chemistry Experiments; American Chemical Society: Washington, DC, 2002.

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Chapter 2

Recent Progress in Green Undergraduate Organic Laboratory Design Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch002

Barbora Morra and Andrew P. Dicks* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6 *E-mail: [email protected]

Green chemistry principles have been highlighted and incorporated into the organic classroom and laboratory for over twenty years. In order to provide educators with the tools necessary to implement environmentally conscious modules into their own courses, this chapter summarizes innovative greener experiments published in the pedagogical literature since 2012. This select collection of examples serves as an introduction to Green Chemistry Experiments in Undergraduate Laboratories by describing green organic laboratories in the following three categories: (i) teaching experimental techniques; (ii) traditional verification experiments; and (iii) guided-inquiry activities.

Introduction Green, sustainable chemistry instruction has been on the radar of educators for more than twenty years. In 1995, Terry Collins outlined efforts at Carnegie Mellon University to introduce a lecture course entitled “Introduction to Green Chemistry” to advanced undergraduates and graduate students (1). Five years later, Reed and Hutchison described the environmentally responsible preparation of adipic acid as a teaching laboratory experiment, and stated that “we know of no published green experiments designed for use in the organic teaching laboratory” (2). In one 2006 Journal of Chemical Education editorial, John Moore wrote “any change in curriculum or in our approach to teaching chemistry requires time and effort on our © 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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parts, but incorporating green chemistry is a change that needs to be made, is being made by many, and is supported by the chemical industry”, and that “students trained in green chemistry principles will be better able to carry out their duties as industrial, government, or academic scientists and engineers” (3). The increasing public profile of environmental issues has undoubtedly led to many instructors rethinking their curricula to incorporate aspects of green chemistry. In 2011, one of us (A.P.D) edited a book for university and college teachers (“Green Organic Chemistry in Lecture and Laboratory”) (4). This publication summarizes efforts made in both practical and theoretical venues to introduce green principles to students at various academic levels. It includes a description of many undergraduate laboratory tasks that showcase green chemistry concepts (either deliberately or unwittingly!). However, it should be borne in mind that there are no “perfectly green” teaching experiments, but that incremental improvements are routinely possible. The current chapter provides an update to the aforementioned book by profiling new experiments published in the pedagogical literature since 2012. While not intended to be an exhaustive review, this chapter sets the scene for the remainder of Green Chemistry Experiments in Undergraduate Laboratories by providing specific examples of greener organic laboratories in the following areas: (i) teaching experimental techniques; (ii) traditional verification experiments; and (iii) guided-inquiry activities. Several experiments devised by the authors with undergraduate and graduate support at the University of Toronto are additionally included. It is hoped that this review contributes a snapshot of the current “state of the art”, and will provide impetus for educators to consider how they might introduce such procedures or indeed design some of their own.

Experiments Illustrating Fundamental Laboratory Techniques Gaining practical experience in the laboratory is a major learning objective in undergraduate chemistry education. It is in the laboratory that students improve their understanding of chemical transformations, develop technical skills, and are first introduced to the challenges of research. Some of the most common experiments conducted by novice learners are those highlighting fundamental practical techniques. The skills and confidence gained throughout introductory laboratory experiences lay the foundation that students rely upon when engaged in independent, problem-based experiments later in their education and careers. In recent years, many instructors have designed simple experiments that highlight conventional laboratory techniques with an emphasis on green chemistry principles. The specific contributions highlighted in this section introduce students to sustainable and safe practices during the early stages of their laboratory training, which encourages them to grow into environmentally responsible chemists. Just as importantly, students who eventually pursue a myriad of other scientific careers will benefit from this exposure.

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Extraction Soap-making is a popular experiment in introductory undergraduate laboratories as it highlights the utility of the saponification reaction with a real-world application (5–7). Sutheimer et al. recently updated this classic experiment to include an oil extraction from fresh avocados (8). The exercise has student pairs working together to peel, pit and macerate one avocado. The flesh is then extracted with a solution of ethyl acetate and isopropyl alcohol, which are safer and less toxic alternatives to petroleum ether, hexanes, or chlorinated solvents that are typically used. The fresh avocado oil is then combined with additional vegetable oils and saponified with aqueous sodium hydroxide solution, poured into molds, and left to cure for four to six weeks until ready to use. This fun procedure allows students to visualize the concepts behind extraction while recognizing aspects of green chemistry in the real-world application of soap production. Chromatography Two of the most fundamental separation techniques used in organic chemistry are column chromatography and thin-layer chromatography (TLC). A common undergraduate chromatography exercise involving the isolation of leaf pigments provides an excellent opportunity for students to visualize the colorful separation of biologically active molecules (9–15). As these experiments traditionally use halogenated or otherwise harmful solvents, Johnston et al. have developed a greener approach that employs safer solvents and recycling to minimize waste (16). Here, students use recycled acetone from a previous experiment to extract β-carotene, xanthophyll, and chlorophyll a pigments from spinach leaves. To minimize exposure to harmful solvents and limit waste production, they then utilize recycled alumina and a non-halogenated eluent system of hexanes and acetone to complete their column chromatography separation. Students support their findings through TLC and Rf comparison in order to verify the identity of each isolated pigment. Similar TLC studies of spinach and ruccola plant pigments have recently been developed, including a comparison of normal-phase (silica gel 60 with 7:3 n-hexane:acetone eluent) and reverse-phase (RP-18 silica with 2:3:5 n-hexane:acetone:ethanol eluent) chromatography (17). These activities nicely illustrate concepts of molecular polarity and retention in various mobile and stationary phases, while also employing an alternative solvent. Ethanol is a greener option than n-hexane, which among other hazards is suspected of damaging fertility. An eco-friendly modification of column chromatography has also been established by Dias and Ferreira, where the use of baking soda and potato starch as unconventional column adsorbents (instead of expensive and potentially harmful silica gel) is described (18). In this experiment, students perform an acetone extraction of plant pigments from red and green Stromanthesanguinea leaves and adsorb the chlorophyll, anthocyanin and carotenoid-rich solution onto the surface of potato starch. They proceed to load their crude sample onto a baking soda or potato starch column and separate each bioactive pigment using petroleum ether, 9 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

acetone, ethanol, or saturated aqueous sodium bicarbonate solution as eluents. The experiment takes advantage of the high concentration of colorful pigments in plants to demonstrate chromatographic techniques, while simultaneously reinforcing green chemistry through use of renewable feedstocks, reduction of waste, and by employing safer solvents and column adsorbents.

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Batch and Flow Methods Simeonov and Afonso have developed a modern undergraduate laboratory that introduces students to industrially useful separation technology utilized in the efficient synthesis and isolation of 5-hydroxymethylfurfural (HMF) (19). This 2,5-disubstituted furan was chosen as a target molecule in the experimental design as it is easily accessible from carbohydrates (a biorenewable resource) with potential applications in the biofuel and sustainable polymer industries (20). A key limitation in production of HMF is its efficient isolation, since it suffers from poor solubility in both aqueous and organic solvents. The experiment addresses this challenge by engaging students in batch and flow syntheses of HMF to explore the efficacy and environmental impact of each isolation method (Figure 1).

Figure 1. Green comparison of batch and flow syntheses of 5-hydroxymethylfurfural (HMF).

While working in small groups, some students perform a batch method which involves synthesis of HMF from fructose using heterogeneous acid catalysis and separation by precipitation from the reaction media. This approach also features a fully recyclable reaction medium, catalyst, and solvent while achieving a remarkable 90-97% yield of highly pure product. Other students concurrently explore the synthesis through a flow method which features homogeneous acid-catalyzed reaction conditions along with a similar precipitation method of isolating the product. This alternative protocol furnishes pure HMF with lower yields (average of 77%) compared to the batch method. After the laboratory session is complete, students evaluate class results to identify the superior method of HMF synthesis and isolation by considering the yield, purity, and E-factor for each process. This novel undergraduate experiment engages students in a synthetic challenge to prepare an industrially relevant biomolecule by comparing modern isolation techniques that stimulate discussion of green chemistry principles. 10 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Traditional Verification Laboratory Experiments This section presents a range of activities where students primarily follow a scripted procedure to learn about greener approaches. The experiments are organized into four major categories according to several of the Twelve Principles of Green Chemistry: safer solvents and auxiliaries, design for energy efficiency, less hazardous chemical syntheses, and catalysis. Additional green aspects of each experiment are highlighted where appropriate.

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Safer Solvents and Auxiliaries One of the Twelve Principles of Green Chemistry states that “the use of auxiliary substances (e.g. solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used” (21). Several recent teaching experiments have focused on this principle from two different perspectives: elimination of reaction solvents (i.e. solventless transformations (22, 23) and greener solvent replacements (24). Examples in both categories will be discussed here.

Solvent-Free Syntheses Goldstein and Cross have reported a solvent-free reductive amination reaction between a range of liquid aromatic aldehydes and two liquid benzylamine derivatives (Figure 2), which is part of an introductory undergraduate organic course (25).

Figure 2. Solventless formation of dibenzylamines via reductive amination. Each student or student pair identifies their specific dibenzylamine product formed by generating the corresponding hydrochloride salt and making melting point measurements. This cost-effective and efficient experiment requires reactant grinding at room temperature for a total of 45 minutes, using a mortar and pestle. In a similar vein, synthesis of β-citronellyl tosylate (a laundry detergent additive) was described where citronellyl alcohol is briefly ground with p-toluenesulfonyl chloride under basic conditions (26) (Figure 3). 11 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 3. Solvent-free tosylation of β-citronellol.

As a third example, Patterson et al. designed the preparation of a thiol-reactive sensor via a microscale, solventless Diels-Alder reaction that does not require heating or stirring (27). Student yields of the sensor typically range from 7-16 mg (30-70%). As the work-up and purification steps of these three syntheses are not solvent-free, an important opportunity exists to point out this drawback to students and that one should consider more than just the reaction itself from a green chemistry perspective (28).

Water as an Alternative Solvent The properties of water as a greener solvent choice and its use as such in undergraduate laboratories has previously been reviewed (29, 30). Since then, water was utilized as the solvent for a Hantzsch dihydropyridine synthesis and as a co-solvent with acetic acid for eventual pyridine formation (31). This multicomponent reaction additionally highlights other green features: (i) an atom-economical approach to synthesis; (ii) isolation and purification of products without the use of volatile organic solvents; and (iii) benign oxidation conditions using an iron catalyst and hydrogen peroxide rather than more traditional stoichiometric oxidants (as discussed under “A Transition Metal-Catalyzed Alcohol Oxidation”) (Figure 4).

Figure 4. Aqueous Hantzsch dihydropyridine and pyridine synthesis. 12 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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In contrast, Morsch and coworkers have developed an aqueous Wittig reaction where a variety of aldehydes are stirred with benzyltriphenylphosphonium chloride (highly toxic by ingestion and inhalation) in 10 M NaOH at room temperature (32). One specific aldehyde employed is cinnamaldehyde, which generates the corresponding conjugated diene in 30 minutes (Figure 5).

Figure 5. A Wittig reaction under aqueous basic conditions. Thirdly, Marks and Levine reported student preparation of dibenzylaniline via reaction between benzyl bromide and aniline in aqueous sodium bicarbonate/catalytic sodium dodecyl sulfate (33). It should however be noted that aniline has high chronic and acute aqueous toxicity, is a skin sensitizer and also a suspected carcinogen. These last two experimental examples highlight that “greener” procedures can still have “non-green” aspects associated with them in terms of undesirable chemical properties.

PEG-400 as an Alternative Solvent Polyethylene glycol (PEG) is an intriguing alternative solvent in which to undertake organic reactivity (34, 35). As polyethers, PEG solvents have very low toxicity and volatility, and are stable under a wide variety of reaction conditions (including high temperatures). They are also potentially recyclable. The latter feature was harnessed in the context of consecutive one-pot carbonyl condensation reactions, within both introductory and advanced undergraduate courses (36). PEG with a molecular weight of 400 (PEG-400) is used as the solvent for sequential Knoevenagel and Michael reactions under mild, organocatalytic conditions (Figure 6).

Figure 6. Consecutive Knoevenagel and Michael reactions in PEG-400. 13 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Both PEG-400 and the proline organocatalyst are readily recycled and available for further reactions. The experimental atom economy of this reaction is 96%, as no reagents are used in excess. Very recently, PEG-400 has also been employed as the solvent for an aza-Michael addition between methyl acrylate and diethylamine (37) (Figure 7). In this experiment, students analyze product spectra to deduce whether conjugate addition or nucleophilic acyl substitution has taken place, thus introducing a discovery-based element.

Figure 7. An aza-Michael reaction in PEG-400.

Design for Energy Efficiency Microwave-Enhanced Reactions The benefits of microwave heating in the undergraduate organic laboratory have been highlighted by Baar and coworkers (38, 39). Lengthy reflux times for traditional reactions can be dramatically reduced to minutes (or sometimes even seconds) by using microwaves. Latimer and Wiebe described three microwave-induced nucleophilic aromatic substitution reactions of 1-bromo-2,4-dinitrobenzene that are complete in five minutes (40) (Figure 8).

Figure 8. Microwave-enhanced nucleophilic aromatic substitution reactions of 1-bromo-2,4-dinitrobenzene. Students compare these reactions with those undertaken by refluxing in toluene/water for one hour in the presence of a phase-transfer catalyst. In each case the microwave reaction gives a higher yield using a greener solvent combination (ethanol/water). Microwave electrophilic aromatic substitution has also been explored in the context of phenol nitration (41). Here, nitric acid (the source of NO2+) is generated in situ by the reaction between copper(II) nitrate and acetic acid (Figure 9). 14 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 9. Electrophilic aromatic substitution of phenol via microwave heating. This convenient approach has a reaction time of one minute and forms a mixture of ortho- and para-disubstituted products that are separated by column chromatography or steam distillation. Keuseman and Morrow reported a solvent-free Knoevenagel condensation of malonic acid with 4-methoxybenzaldehyde in the presence of ammonium acetate (42). Microwave irradiation promotes formation of trans-4-methoxycinnamic acid in five minutes (Figure 10). Two additional recent examples of undergraduate microwave experiments are in the areas of soap/biodiesel production (43) and the Suzuki reaction (44).

Figure 10. Microwave-enhanced synthesis of trans-4-methoxycinnamic acid.

A Diels-Alder Reaction under Solar Irradiation In a very unusual approach, Amin et al. have designed a solar heat source from a satellite dish and used it to harness sunlight for the Diels-Alder reaction between anthracene and maleic anhydride (45) (Figure 11).

Figure 11. A Diels-Alder reaction heated by solar irradiation. Using round-bottomed flasks painted black to improve energy absorption, students obtain an average yield of 81% after solar heating in xylene for 30 minutes. This is comparable to an almost identical yield (80%) on using an electric hot plate for the same time period. From this experiment, undergraduates learn that the sun is a viable heating alternative to electrical sources which is a critical concept in the context of sustainability. 15 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

A Mechanochemical Charge Transfer Salt Synthesis

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Two solvent-free reactions that require mechanical grinding were previously discussed in this chapter. A third example of mechanochemistry that does feature a solvent (“liquid-assisted grinding”) concerns preparation of two polymorphs of a charge-transfer salt (46). Tetrathiafulvalene (TFF) is ground by students over 20 minutes with chloranil (CA), utilizing either water or acetone as the solvent. This approach negates any heating or stirring requirements. Water promotes formation of a black polymorph, whereas using acetone generates a green polymorph. These reactions have 100% atom economy and as essentially no waste is produced, the E-factor is very close to zero in each instance (Figure 12).

Figure 12. Polymorph synthesis via liquid-assisted grinding. Less Hazardous Chemical Syntheses Greener Reagents Significant progress has been made regarding incorporation of greener reagents into introductory and advanced organic teaching laboratories (47). In 2012, Geiger and Donohoe reported the oxidation of (–)-menthol to (–)-menthone using calcium hypochlorite as an environmentally friendly, nonhazardous and cost-effective oxidant (48) (Figure 13).

Figure 13. Alcohol oxidation using calcium hypochlorite. 16 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Advanced undergraduates isolate the ketone product in an average yield of 75%, and learn about circular dichroism spectroscopy as an analytical tool. In comparison, sodium hypochlorite was employed in conjunction with sodium bromide for the regioselective bromination of acetanilide (49). This safer reagent combination means that the typical use of molecular bromine in acetic acid is avoided (Figure 14).

Figure 14. Regioselective aromatic bromination of acetanilide. In a third publication, Lipshutz et al. discussed the use of a biodegradable and nontoxic surfactant (TPGS-750-M) to promote aqueous organic reactions within nanoscale micelles (50). One example is the highly atom-economical “click” reaction between benzyl azide and an aromatic alkyne (Figure 15). This [3 + 2] cycloaddition additionally features copper catalysis under energy-efficient reaction conditions.

Figure 15. An azide-alkyne “click” reaction profiling a biodegradable surfactant.

Sustainable Polymer Synthesis Two recent reports discuss sustainable polymer synthesis in the second-year undergraduate laboratory. Chan and coworkers described the generation of a biodegradable polycarbonate via ring-opening polymerization (ROP) of trimethylene carbonate using two organocatalysts (51) (Figure 16). Secondly, Schneiderman et al. outlined preparation of a block copolymer product as a transparent film (52). Two renewable resource monomers are used in this experiment which is run under mild, solventless and catalytic conditions. 17 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 16. Organocatalytic ROP generating a biodegradable polycarbonate. Catalysis An undergraduate catalytic chemistry course was described in 2013 where students undertake reactions under the general themes of organocatalysis, phase-transfer catalysis, transition metal catalysis and BrØnsted/Lewis acid catalysis (53). This course showcases experiments designed by undergraduates at the University of Toronto since 2001, and has been taken by over 300 students since its inception in 2008. Further aspects of the course will not be discussed in this section.

Transition Metal-Catalyzed Coupling Reactions The Suzuki reaction has recently been employed as a vehicle for teaching aspects of green chemistry (28). Hill and coworkers outlined a facile Suzuki coupling amenable to large undergraduate organic classes using an aqueous atomic absorption standard solution as the palladium source (54) (Figure 17).

Figure 17. Suzuki reaction using ultra-low Pd catalyst loading. The solution is commercially available and facilitates the reaction of three aryl boronic acids with six aryl bromides in less than 30 minutes at room temperature. A similar coupling reaction was reported to generate a biaryl under aqueous conditions utilizing catalytic Pd(OAc)2 (55). This strategy introduces 18 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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a problem-solving element as students work to identify the greenest approach given three potential reaction conditions. A traditional Suzuki reaction has even been performed by advanced high school students as part of a laboratory field trip with the goal of associating chemistry with the broader concept of sustainability (56). In 2015, a Ni-catalyzed Suzuki reaction was described for the first time from a pedagogical perspective (57). Undergraduates use inexpensive bis(tricyclohexylphosphine)nickel(II) dichloride in tert-amyl alcohol as a greener system with which to couple a heteroaryl bromide with two heteroarylboronic acids (Figure 18). Nickel has advantages over palladium for such reactions as Ni is a non-precious metal, is considerably cheaper, and is less toxic.

Figure 18. Nickel catalysis of a Suzuki reaction. The homocoupling of 1-methylimidazole under conditions of copper catalysis was disclosed by Ballard (58) and performed by introductory organic students at the University of Florida. The process employs in situ formation of a Grignard reagent which reacts with the metal catalyst (CuCl2) to form an organocopper intermediate. This intermediate subsequently reacts under aerobic conditions to form the dimerized product and regenerate the catalyst (Figure 19).

Figure 19. Dimerization of 1-methylimidazole using catalytic CuCl2.

Transition Metal-Catalyzed Alkene Hydrogenations Fry and O’Connor have outlined the facile hydrogenation of methyl transcinnamate using 0.5% Pd/Al(O)OH as the catalyst (59). Very good student yields are possible using this method (Figure 20).

19 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 20. Catalytic hydrogenation of methyl trans-cinnamate. Two further advantages are apparent from a green perspective: firstly, this reaction is undertaken using solvent-free conditions, and secondly the catalyst is (unusually) recoverable without a reduction in activity. The catalytic transfer hydrogenation of castor oil using Pd/C in limonene also facilitates discussion of several green chemistry metrics such as atom economy, reaction mass efficiency, E-factor and CO2 emissions (60).

Organocatalytic Reactions Synthesis of 1,3,4-triphenylcyclopentene was described by Snider via the carbene-catalyzed reaction of cinnamaldehyde with a chalcone (61). This modern procedure showcases application of organocatalysis where students initially prepare 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride as a heterocyclic carbene, and then use it to generate the product in a 10:1 trans/cis ratio under aqueous conditions (Figure 21). Copper N-heterocyclic carbene complexes have also been synthesized by upper-level undergraduates and utilized to perform atom-economical 1,3-dipolar cycloaddition reactions under solventless conditions (62).

Figure 21. Carbene-catalyzed formation of 1,3,4-triphenylcyclopentene.

A Transition Metal-Catalyzed Alcohol Oxidation A copper(I)/2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) catalyst has been used to effect oxidation of five benzylic alcohols to the corresponding aldehydes (63). This approach negates the traditional use of stoichiometric Crand Mn-based oxidants routinely discussed in introductory organic textbooks. The experiment is amenable to large laboratory groups, requires standard glassware, 20 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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and highlights contemporary research as molecular oxygen is the active oxidizing agent (Figure 22).

Figure 22. Benzylic alcohol oxidation under catalytic conditions.

Guided-Inquiry Laboratory Experiments Many recent reports have highlighted the value of guided-inquiry experiments within undergraduate organic chemistry education (64, 65). These contributions share similar learning objectives that include (i) enhancing student interest and proficiency in the laboratory; (ii) introducing real-world problems in a research-focused context; (iii) encouraging development of critical thinking and problem solving skills; and (iv) incorporating green chemistry initiatives. Despite this encouraging progress, guided-inquiry experiments are not widely undertaken due to the extensive time and cost requirements that are often necessary to design and implement them in the curriculum. Even with these challenges, numerous guided-inquiry organic experiments have been featured in the recent literature that emphasize sustainable principles. These contributions are highlighted in the following three categories: student-driven decision- making in target-oriented synthesis, discovery-based experiments, and collaborative laboratory case studies. Student-Driven Decision-Making in Target-Oriented Synthesis The environmental and economic benefits of practicing sustainable chemistry in academia and industry are becoming increasingly important. Green chemistry education must play a significant role within undergraduate curricula in order to foster responsible chemists that are better prepared to prevent further environmental damage. One of the most powerful methods of training future chemists in a laboratory setting is allowing students to participate in decision-making and experimental design. Despite the increase of organic laboratory experiments highlighting green chemistry, few prepare students for the multifaceted decision-making required in a research laboratory. Edgar et al. emphasized student-driven decision-making as a primary learning objective within a target-oriented laboratory where students are engaged in every step of the research process (66). This upper-level laboratory requires students to independently execute a synthesis of a unique azlactone 21 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

derivative while incorporating green chemistry principles into their experimental design (Figure 23).

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Figure 23. Incorporating green chemistry into an azlactone synthesis. Azlactones were selected as target molecules as they have utility in the preparation of medicinally significant biomolecules, and can be accessed through a variety of synthetic methods from readily available starting materials (67–69). Students are given two weeks to independently design a synthetic plan for their assigned azlactone complete with a retrosynthetic analysis, figures for all projected reactions, detailed experimental procedures with appropriate reference to the chemistry literature, a comprehensive list of reagents including a safety and cost analysis, and a discussion of how green chemistry principles are incorporated in the synthetic design. Once their proposals are approved for safety and cost by the course instructor, students independently embark on their three or four-step synthesis over two 4.5 h laboratory sessions. It is important to note that the course instructor and teaching assistants support students from a safety perspective but do not offer specific feedback on the chemical viability of their proposals or work performed in the laboratory. As some of the azlactone derivatives are not found in the literature, students find procedures based on similar target molecules and apply them appropriately. In the laboratory, students generally implement at least two green chemistry principles into their methodology. For example, some students substitute halogenated solvents with more sustainable non-halogenated options (e.g. naturally derived 2-methyltetrahydrofuran), while others exploit non-toxic reagents (e.g. NaHCO3 instead of triethylamine), catalysis, and energy efficient processes in order to limit the environmental impact of their synthesis. In general, students find this guided-inquiry activity to be a valuable learning experience as it offers insights into the challenges of conducting chemistry research while considering green principles. A similar research-based approach was outlined by Slade et al. in the development of a second-year organic chemistry laboratory that engages students in a target-based synthesis of a novel fluorous dye (70) (Figure 24).

Figure 24. Synthesis of a fluorous dye for use in affinity chromatography. 22 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Once synthesized, students explore the applications of the dye in fluorous affinity chromatography as a greener alternative to other solid-phase separation techniques (71). This type of affinity chromatography enables fluorous-tagged reagents and catalysts to be easily isolated in high purity for the purpose of recyclability. The main goal of this guided-inquiry project is to provide students with an authentic research experience that involves them in reaction design by adapting literature procedures. In addition, the project exposes students to a variety of advanced synthetic tools including microwave heating and Schlenk and degassing techniques. Early in the semester, students are introduced to the target molecule along with a suggested synthetic protocol which serves as a starting point from which they can begin their literature search. After several weeks, each student independently submits a proposal consisting of literature procedures for each transformation along with suggested modifications for use in the undergraduate teaching laboratory. Once each proposal is inspected for safety, cost, equipment availability, and time management considerations, students are given six consecutive laboratory sessions to execute their synthetic plan. Although students are able to complete some of the six-step synthesis, none have thus far been successful in making the final fluorous dye without any assistance. Despite this, students report having enjoyed the project as it offers a unique opportunity to make their own decisions and take ownership of their laboratory work. Multicomponent reactions are often valuable transformations from a green chemistry perspective. One such example, a Prins-Friedel-Crafts type reaction, has been implemented into a second-year undergraduate laboratory by Dintzner et al. (72) This atom-economical strategy for synthesizing a variety of tetrahydropyran derivatives showcases several green chemistry principles as it is performed using a natural and benign Montmorillonite K10 catalyst (Mont. K10) with limited waste production since the work-up is a simple filtration (Figure 25).

Figure 25. Montmorillonite K10-catalyzed multicomponent synthesis of functionalized tetrahydropyrans. This tetrahydropyran synthesis is executed in the teaching laboratory in two phases throughout the semester. The first phase (three laboratory sessions) consists of a typical verification-type experiment where students perform a Prins-Friedel-Crafts synthesis with benzene, and analyze their product using GC-MS, IR and 1H/13C NMR spectroscopy. The research component of the project takes place during the second phase (five laboratory sessions) where pairs of students use a unique aldehyde or ketone in a Prins-Friedel-Crafts reaction, applying the method from the control reaction. After independent analysis and discussion of their initial findings, students are encouraged to explore the reaction 23 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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in a direction that interests them. For example, students can decide to optimize their current reaction conditions or expand the scope of the methodology to include different arenes or carbonyl-containing starting materials, all while considering principles of green chemistry. This novel research-based laboratory exposes students to interesting multicomponent reactions and decision-making in the laboratory while developing environmentally conscious synthetic methodologies. With the intent to increase student engagement and to better prepare students for responsible chemistry research, Graham et al. designed a multiweek project as part of the second-year organic curriculum highlighting green practices within experimental design (73). This inquiry-based approach involves student pairs working collaboratively to improve a known reaction by applying green chemistry principles. Student teams begin the project by selecting a target reaction of interest from the literature and designing a modified variation that emphasizes sustainable practices. During this critical design phase, students meet with course instructors to determine whether their projected modifications demonstrate green chemistry principles, the plausibility of success, chemical and equipment availability, and safety precautions. While some students propose more ambitious changes to their reaction conditions, most suggest subtle modifications including solvent changes or omissions, employing a catalyst, or using safer reagents. Once course instructors approve the original "non-green" procedure (the control reaction) and the modified protocol, students work together to collect data for both the literature control method and the greener approach. Since each student is required to perform both reactions, teams obtain two sets of data for each protocol, which increases the reliability of the results and overall success rates. Once the experimental data is collected and analyzed, students compare the two reaction conditions based on the utility of the procedure towards product formation and reflect on the environmental implications of their modified process. This unique laboratory engages students in an independent experimental design project that reinforces the role of sustainable practices within organic synthesis. Overall, students report excellent improvement in conducting literature searches, applying knowledge to new situations, and understanding the concepts of green chemistry. A similar research-centric approach to student learning in the laboratory was implemented into the Simmons College introductory organic chemistry curriculum (74). The goal of this project is to support the development of higher-order thinking skills through a research-inspired experiment and to create a cohesive learning process from first-year introductory experiments through to fourth-year research projects. In order to engage novice learners, Lee et al. employed a green chemistry framework from which to base the experiments since students identify with sustainable principles in their own lives and are excited to extend that enthusiasm to include green chemistry research. The project involves first-year general chemistry and second-year organic chemistry students working collaboratively towards a common synthetic goal. The initial project design has first-year students working in small groups towards the development of environmentally friendly syntheses of commercially unavailable ketones. This requires extensive literature searches and student-driven decision-making to independently plan and perform a two-step protocol involving Grignard addition and oxidation reactions (Figure 26). 24 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 26. Collaborative undergraduate research projects. A unique collection of ketones is intended to serve as starting materials for the second-year organic chemistry laboratory as a method of minimizing waste, energy, and additional resources. Here, students are required to firstly identify and purify their unknown ketones and then explore the effect of chiral agents (e.g. partially-digested polylactic acid) in a reduction reaction. Similar to the first-year program, students propose purification, synthetic, and analytical methods that integrate green chemistry principles. Although the initial plan is highly collaborative, the workload is overly-ambitious for novice chemists. In most cases, first-year students are unable to complete the synthesis of their target ketones, causing students in the second-year program to use commercially available substrates. In addition, the reduction reactions performed in the second-year program are highly variable and problematic. Despite these shortcomings, the student experience and skills gained from the research project exceed instructor expectations. Throughout the process, students are immersed in every facet of conducting chemistry research which enhances their critical thinking and laboratory skills. Interestingly, the authors found that students do not explicitly comment on the “greenness” of their methods in reports or self-assessment surveys despite applying several principles of green chemistry throughout their synthetic plans. This suggests that green chemistry is seamlessly woven into the curriculum so that students do not associate organic chemistry and green chemistry as separate entities, but simply as a standard method of conducting research. Discovery-Based Experiments Advanced guided-inquiry experiments where students are required to undertake literature searches or independent experimental design may not always be suitable. This is especially the case when novice learners are involved, or due to logistical challenges associated with large classes. Discovery-based experiments offer a unique bridge between cookbook-style and advanced guided-inquiry laboratories by providing a puzzle for students to solve within a structured experimental framework. These types of laboratory activities can offer unique learning opportunities as students are exposed to the benefits and applicability of green chemistry principles in a more engaging manner. Serafin and Priest have recently implemented a green, discovery-based laboratory for second-year and upper-level organic chemistry students involving exploration of the Passerini reaction (75). This multicomponent transformation is performed with a variety of benzoic acid and benzaldehyde derivatives in water instead of typical organic solvents, which accelerates the reaction rate and allows full conversion in 25 minutes at room temperature. The experiment provides a 25 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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convenient method for synthesis of several α-acyloxy amide derivatives in high yield and purity while highlighting several sustainable principles including high atom economy, energy efficiency, and waste prevention. Two variations of the experiment are highlighted, which can be catered to the level of difficulty desired. In version A, students work in pairs and are provided with the identity of the benzoic acid and benzaldehyde derivatives. After synthesizing and isolating their unique α-acyloxy amide, they work together to confirm the structure of their product by applying knowledge of the transformation and a variety of spectroscopic data. Geared towards more advanced students, version B of the experiment explores the scope of the Passerini reaction with unknown starting materials. Students must perform the synthesis and analyze their product by melting point determination, MS spectrometry, and 1H NMR/IR spectroscopy. Here, students rely on their structural elucidation and problem-solving skills to determine the identity of their product. This discovery-based experiment nicely features a series of simple and environmentally friendly Passerini reactions that allow students to identify products through a variety of spectroscopic techniques and reflect on the green chemistry principles utilized in the process (Figure 27).

Figure 27. Passerini reaction scope. A second discovery-based experiment was recently developed by Morra at the University of Toronto for an introductory organic course that mimics a research environment. Students apply their chemistry knowledge to predict reaction outcomes but ultimately use a variety of spectroscopic techniques to elucidate the structure and analyze the purity of the products they obtain. The primary learning objective of this experiment is to bridge the gap between the classroom and research laboratory while introducing the role of reagent selection from a green chemistry perspective. The transformation explored is the bromination of 1,4-dimethoxybenzene with aqueous sodium bromide and Oxone®, which promotes complete conversion after 40 minutes of stirring in a fumehood at ambient temperature (Figure 28).

Figure 28. Bromination of 1,4-dimethoxybenzene. 26 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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This regioselective reaction yields pure 1,4-dibromo-2,5-dimethoxybenzene in high yield after extraction with ethyl acetate and recrystallization from 95% ethanol. In preparation for the experiment, students are instructed to review the general mechanism and regioselectivity of electrophilic aromatic substitution reactions, but the details of the reaction are not disclosed prior to the laboratory session. Since the exact transformation is not revealed, students are given the first 20-30 minutes of the laboratory session to familiarize themselves with the reaction, predict the six potential products, and discuss methods of structural elucidation. After isolation, students analyze their products by melting point determination, IR spectroscopy, 1H NMR spectroscopy, and thin layer chromatography to determine structure and purity. They are also required to consider the “greenness” of the transformation as it employs benign chemicals compared to traditional bromination protocols that use toxic and environmentally hazardous halogenated solvents and elemental bromine (Br2). A discovery-based microwave-assisted Fischer esterification experiment has been developed by Reilly et al. as an efficient method to prepare a wide variety of esters for the undergraduate organic chemistry laboratory (76) (Figure 29).

Figure 29. Microwave-assisted Fischer esterification reactions. Students performing this experiment apply their chemistry knowledge and critical-thinking skills to design an environmentally friendly procedure to prepare unique ester derivatives. After selecting an ester, students choose one of two microwave-assisted experimental procedures (either excess alcohol or excess carboxylic acid) by considering the physical properties of their unique starting materials (boiling point, melting point, solubility, etc.), cost, and green chemistry principles. Pure esters are isolated in modest to high yields after a liquid-liquid extraction with no further purification required. Students also characterize their ester products by IR and 1H NMR spectroscopy. This work provides an opportunity for students to discover the effects of varying simple reaction conditions while utilizing modern microwave technology to achieve a greener variation of a classic transformation. Collaborative Laboratory Case Studies Conventional undergraduate experiments often expose students to a particular chemical transformation or technique but rarely provide context in which that knowledge can be applied in a research setting. Case-based laboratories furnish an innovative solution by introducing students to a real-world problem that must be solved by using chemistry knowledge and reasoning abilities, often in a collaborative manner. 27 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Schaber et al. developed a case-based laboratory that invites second-year undergraduate students to play the role of laboratory technicians tasked with evaluating the efficacy of a new supercritical fluid extraction (SFE) technique compared to a traditional liquid extraction with an organic solvent (77). This study requires students to work in pairs during a three-hour laboratory session to explore the extraction of caffeine from tea leaves. While one student in each pair conducts the SFE technique with supercritical fluid CO2 (with 10% ethanol as a modifier), the other student performs a traditional liquid extraction using dichloromethane and alkaline water. Student pairs then share results and observations before deciding which extraction method is preferred. This case-based laboratory requires undergraduates to consider several variables including the isolated caffeine purity and percentage recovery of caffeine, as well as green chemistry principles when making their choice. Almost all students (95% of the class) endorse the SFE technique over traditional liquid extraction for high-volume requirements (>1000 extractions per year). While both techniques produce caffeine of high purity, the SFE method allows for a more complete recovery of caffeine while employing a greener approach (SFE offers 34-54% recovery while liquid extraction gives 14-30% recovery). Students successfully identify the environmental benefits of SFE compared to liquid extraction, since SFE generates less waste and employs safe, naturally occurring CO2 instead of halogenated solvents. At the University of Toronto, Morra and Tsoung have recently implemented a case-study experiment into the second-year organic chemistry curriculum that effectively bridges the gap between the classroom and research laboratory. In this guided-inquiry activity, students are given the opportunity to play the role of a process chemist employed by a pharmaceutical company working towards the synthesis of lysergic acid for the treatment of Parkinson’s disease (78). Students work as a team to optimize one of the key steps in the synthesis, a Sandmeyer reaction with 2-amino-3-nitrobenzoic acid. They accomplish this task by screening several reaction parameters including varying the type of acid used, reagent equivalents, reaction temperature, and iodide source (Figure 30).

Figure 30. Unoptimized Sandmeyer reaction in the synthesis of lysergic acid. In order to generate reliable data, several students examine the same reaction parameter (7-9 students per parameter). The progress of each reaction is monitored and an approximate purity determined with an in-process check (IPC). This common technique used in the pharmaceutical industry involves running a large collection of reactions for a pre-determined amount of time, solubilizing each mixture and analyzing the solutions directly using HPLC. This type of analysis is 28 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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efficient and accurate, and highlights several green principles as it prevents waste by avoiding typical reaction work-up and purification steps while conducting optimization studies. After the experiment is complete, a comprehensive set of data is posted on the course website and students evaluate the results to select the optimal Sandmeyer reaction conditions. Students are assessed on their ability to analyze the overall data and rationalize their choice based on reaction conversion and purity, while considering green chemistry principles. The two optimal reaction conversion and purity results are observed when the Sandmeyer reaction is performed with either hydrochloric acid or p-toluenesulfonic acid with three equivalents of sodium nitrite and potassium iodide at elevated temperatures (70 °C and 90 °C compared to 50 °C). Interestingly, most students select the 70 °C reaction temperature as part of their optimal parameters despite the fact that the 90 °C reaction temperature gives slightly better results (5% higher reaction conversion and 1% higher reaction purity). Students rationalize their choice by stating the results obtained from the two elevated temperatures are similar but the 70 °C reaction temperature has the added benefit of increased energy efficiency. This activity gives students a chance to work collaboratively with their peers towards a real research problem that requires green chemistry decision-making.

Conclusion Given the various contributions made by the authors reviewed in this chapter and elsewhere, there has been a surge towards highlighting sustainability and green chemistry principles in the undergraduate organic laboratory. These publications provide educators with the resources necessary to implement creative and innovative experiments into their own teaching laboratories as they cater to a wide variety of learners. Whether technique-focused, verification-driven, or guided-inquiry, instructors are able to choose examples of greener experiments that accommodate their specific resources, time restrictions, and student learning goals. Progress has also specifically been made in the area of teaching green chemistry metrics from an organic perspective (79–82). We anticipate that this chapter serves as an introduction to the exciting modernization of undergraduate organic experiments, and recognize that our pivotal role in the laboratory is to prepare students for careers in areas including research, industry, government and teaching. Accordingly, we hope the described experiments will inspire instructors to adopt greener practices at their own institutions in order to better prepare students for the varied challenges they will undoubtedly face in their future professions.

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Phanstiel, O.; Dueno, E.; Wang, Q. X. J. Chem. Educ. 1998, 75, 612–614. JCE staff J. Chem. Educ. 1999, 76, 192A–192B. Mabrouk, S. T. J. Chem. Educ. 2005, 82, 1534–1537. Sutheimer, S.; Caster, J. M.; Smith, S. H. J. Chem. Educ. 2015, 92, 1763–1765. Strain, H.; Sherma, J. J. Chem. Educ. 1969, 46, 476–483. Diehl-Jones, S. J. Chem. Educ. 1984, 61, 454–456. Mewaldt, W.; Rodolph, D.; Sady, M. J. Chem. Educ. 1985, 62, 530–531. Cousins, K. R.; Pierson, K. M. J. Chem. Educ. 1998, 75, 1268–1269. Lalitha, N. J. Chem. Educ. 1994, 71, 432. Horowitz, G. J. Chem. Educ. 2000, 77, 263–264. Quach, H. T.; Steeper, R. L.; Griffin, G. W. J. Chem. Educ. 2004, 81, 385–387. Johnston, A.; Scaggs, J.; Mallory, C.; Haskett, A.; Warner, D.; Brown, E.; Hammond, K.; McCormick, M. M.; McDougal, O. M. J. Chem. Educ. 2013, 90, 796–798. Sjursnes, B. J.; Kvittingen, L.; Schmid, R. J. Chem. Educ. 2015, 92, 193–196. Dias, A. M.; Ferreira, M. L. S. J. Chem. Educ. 2015, 92, 189–192. Simeonov, S. P.; Afonso, C. A. M. J. Chem. Educ. 2013, 90, 1373–1375. Rosatella, A. A.; Simeonov, S. P.; Frade, R. F. M.; Afonso, C. A. M. Green Chem. 2011, 13, 754–793. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998, p 30. Dicks, A. P. Elimination of Solvents in the Organic Curriculum. In Green Organic Chemistry in Lecture and Laboratory; Dicks, A. P., Ed.; CRC Press: Boca Raton, FL, 2012; pp 69−102. Dicks, A. P. Green Chem. Lett. Rev. 2009, 2, 87–100. Mui, L. Organic Chemistry in Greener Nonaqueous Media. In Green Organic Chemistry in Lecture and Laboratory; Dicks, A. P., Ed.; CRC Press: Boca Raton, FL, 2012; pp 131-164. Goldstein, S. W.; Cross, A. V. J. Chem. Educ. 2015, 92, 1214–1216. Mascarenhas, C. M. J. Chem. Educ. 2013, 90, 1231–1234. Patterson, A. L.; May, M. D.; Visser, B. J.; Kislukhin, A. A.; Vosburg, D. A. J. Chem. Educ. 2013, 90, 1685–1687. Dicks, A. P. J. Chem. Educ. 2015, 92, 405. Sauer, E. L. O. Organic Reactions under Aqueous Conditions. In Green Organic Chemistry in Lecture and Laboratory; Dicks, A. P., Ed.; CRC Press: Boca Raton, FL, 2012; pp 103−130. Dicks, A. P. Green Chem. Lett. Rev. 2009, 2, 9–21. Bucholtz, K. M.; Hugdahl, J. D.; Kiefer, A. M.; Kiefer, K. M.; Santa Maria, A. M. Chem. Educ. 2012, 17, 125–127. Morsch, L. A.; Deak, L.; Tiburzi, D.; Schuster, H.; Meyer, B. J. Chem. Educ. 2014, 91, 611–614. Marks, P.; Levine, M. J. Chem. Educ. 2012, 89, 1186–1189. Gu, Y. Green Chem. 2012, 14, 2091–2128. 30 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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35. Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green Chem. 2005, 7, 64–82. 36. Stacey, J. M.; Dicks, A. P.; Goodwin, A. A.; Rush, B. M.; Nigam, M. J. Chem. Educ. 2013, 90, 1067–1070. 37. Nigam, M.; Rush, B.; Patel, J.; Castillo, R.; Dhar, P. J. Chem. Educ. 2016, 93, 753–756. 38. Baar, M. R. Greener Organic Reactions under Microwave Heating. In Green Organic Chemistry in Lecture and Laboratory; Dicks, A. P., Ed.; CRC Press: Boca Raton, FL, 2012; pp 225−256. 39. Baar, M. R.; Gammerdinger, W.; Leap, J.; Morales, E.; Shikora, J.; Weber, M. H. J. Chem. Educ. 2014, 91, 1720–1724. 40. Latimer, D.; Wiebe, M. Green Chem. Lett. Rev. 2015, 8, 39–42. 41. Yadav, U.; Mande, H.; Ghalsasi, P. J. Chem. Educ. 2012, 89, 268–270. 42. Keuseman, K. J.; Morrow, N. C. Chem. Educ. 2014, 19, 347–350. 43. Pohl, N. L. B.; Streff, J. M.; Brokman, S. J. Chem. Educ. 2012, 89, 1053–1056. 44. Soares, P.; Fernandes, C.; Chavarria, D.; Borges, F. J. Chem. Educ. 2015, 92, 575–578. 45. Amin, S.; Barnes, A.; Buckner, C.; Jones, J.; Monroe, M.; Nurmomade, L.; Pinto, T.; Starkey, S.; Agee, B. M.; Crouse, D. J.; Swartling, D. J. J. Chem. Educ. 2015, 92, 767–770. 46. Wixtrom, A.; Buhler, J.; Abdel-Fattah, T. J. Chem. Educ. 2014, 91, 1232–1235. 47. Bastin, L. D. Environmentally Friendly Organic Reagents. In Green Organic Chemistry in Lecture and Laboratory; Dicks, A. P., Ed.; CRC Press: Boca Raton, FL, 2012; pp 165−198. 48. Geiger, H. C; Donohoe, J. S. J. Chem. Educ. 2012, 89, 1572–1574. 49. Cardinal, P.; Greer, B.; Luong, H.; Tyagunova, Y. J. Chem. Educ. 2012, 89, 1061–1063. 50. Lipshutz, B. H.; Boskovic, Z.; Crowe, C. S.; Davis, V. K.; Whittemore, H. C.; Vosburg, D. A.; Wenzel, A. G. J. Chem. Educ. 2013, 90, 1514–1517. 51. Chan, J. M. W.; Zhang, X.; Brennan, M. K.; Sardon, H.; Engler, A. C.; Fox, C. H.; Frank, C. W.; Waymouth, R. M.; Hedrick, J. L. J. Chem. Educ. 2015, 92, 708–713. 52. Schneiderman, D. K.; Gilmer, C.; Wentzel, M. T.; Martello, M. T.; Kubo, T.; Wissinger, J. E. J. Chem. Educ. 2014, 91, 131–135. 53. Dicks, A. P.; Batey, R. A. J. Chem. Educ. 2013, 90, 519–520. 54. Hill, N. J.; Bowman, M. D.; Esselman, B. J.; Byron, S. D.; Kreitinger, J.; Leadbeater, N. E. J. Chem. Educ. 2014, 91, 1054–1057. 55. Costa, N. E.; Pelotte, A. L.; Simard, J. M.; Syvinski, C. A.; Deveau, A. M. J. Chem. Educ. 2012, 89, 1064–1067. 56. Aubrecht, K. B.; Padwa, L.; Shen, X.; Bazargan, G. J. Chem. Educ. 2015, 92, 631–637. 57. Hie, L.; Chang, J. J.; Garg, N. K. J. Chem. Educ. 2015, 92, 571–574. 58. Ballard, C. E. J. Chem. Educ. 2013, 90, 1368–1372. 59. Fry, D.; O’Connor, K. Chem. Educ. 2013, 18, 144–146. 31 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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60. Alwaseem, H.; Donahue, C. J.; Marincean, S. J. Chem. Educ. 2014, 91, 575–578. 61. Snider, B. B. J. Chem. Educ. 2015, 92, 1394–1397. 62. Ison, E. A.; Ison, A. J. Chem. Educ. 2012, 89, 1575–1577. 63. Hill, N. J.; Hoover, J. M.; Stahl, S. S. J. Chem. Educ. 2013, 90, 102–105. 64. Schoffstall, A. M.; Gaddis, B. A. J. Chem. Educ. 2007, 84, 848–851and references therein. 65. Horowitz, G. J. Chem. Educ. 2007, 84, 346–353and references therein. 66. Edgar, L. J. G.; Koroluk, K. J.; Golmakani, M.; Dicks, A. P. J. Chem. Educ. 2014, 91, 1040–1043. 67. Moghanian, H.; Shabanian, M.; Jafari, H. C. R. Chim. 2012, 15, 346–349. 68. Rostami, M.; Khosropour, A.; Mirkhani, V.; Moghadam, M.; Tangestaninejad, S.; Mohammadpoor-Baltork, I. Appl.Catal., A 2011, 397, 27–34. 69. Parveen, M.; Ali, A.; Ahmed, S.; Malla, A. M.; Alam, M.; Silva, P. S. P.; Silva, M. R.; Lee, D. Spectrochim. Acta, Part A 2013, 104, 538–545. 70. Slade, M. C.; Raker, J. R.; Kobilka, B.; Pohl, L. B. J. Chem. Educ. 2014, 91, 126–130. 71. Ubeda, M. A.; Dembinski, R. J. Chem. Educ. 2006, 83, 84–92. 72. Dintzner, M. R.; Maresh, J. J.; Kinzie, C. R.; Arena, A. F.; Speltz, T. J. Chem. Educ. 2012, 89, 265–267. 73. Graham, K. J.; Jones, T. N.; Schaller, C. P.; McIntee, E. J. J. Chem. Educ. 2014, 91, 1895–1900. 74. Lee, N. E.; Gurney, R.; Soltzberg, L. J. Chem. Educ. 2014, 91, 1001–1008. 75. Serafin, M.; Priest, O. P. J. Chem. Educ. 2015, 92, 579–581. 76. Reilly, M. K.; King, R. P.; Wagner, A. J.; King, S. M. J. Chem. Educ. 2014, 91, 1706–1709. 77. Schaber, P. M.; Larkin, J. E.; Pines, H. A.; Berchou, K.; Wierchowski, E.; Marconi, A.; Suriani, A. J. Chem. Educ. 2012, 89, 1327–1330. 78. Somei, M.; Yoloyama, Y.; Murakami, Y.; Ninomiya, I.; Kiguchi, T.; Naito, T. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 2000; pp 191−257. 79. Gómez-Biagi, R. F.; Dicks, A. P. J. Chem. Educ. 2015, 92, 1938–1942. 80. Duarte, R. C. C.; Ribeiro, M. G. T. C.; Machado, A. A. S. C. J. Chem. Educ. 2015, 92, 1024–1034. 81. Ribeiro, M. G. T. C.; Yunes, S. F.; Machado, A. A. S. C. J. Chem. Educ. 2014, 91, 1901–1908. 82. Ribeiro, M. G. T. C.; Machado, A. A. S. C. J. Chem. Educ. 2013, 90, 432–439.

32 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Chapter 3

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Three Modules Incorporating Cost Analysis, Green Principles, and Metrics for a Sophomore Organic Chemistry Laboratory V. Fishback,* B. Reid, and A. Schildkret Department of Chemistry, University of Colorado Denver, Denver, Colorado 80217-3364, United States *E-mail: [email protected]

Green chemistry practices and metrics can be experienced by students without compromising the teaching of sophomore organic chemistry laboratory techniques. Organizing and analyzing cost and green metric data provides students an opportunity to apply critical thinking skills and see a connection to the chemical industry and to their own consumer use of chemicals. This chapter describes experiments, organized into three modules, illustrating green chemistry principles, incorporating green chemistry metrics and utilizing cost analysis. Two different epoxidation reactions of trans-Anethole are compared using green chemistry principles, atom economy, E-Factor and cost analysis metrics. In the second module, bromination and nitration reactions of toluene are compared using the same kind of analysis. In the third module, Barbier, Wittig and aldol carbon-carbon bond-forming reactions using different substrates are compared.

© 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Introduction The greening of organic chemistry teaching laboratories has produced numerous individual experiments that can be incorporated into the organic chemistry laboratory curriculum since the dawn of green chemistry principles twenty years ago. A recent green organic chemistry textbook (1) edited by Dicks includes an appendix listing 178 reactions adapted to highlight green chemistry principles and techniques such as solventless reactions, aqueous organic, and microwave assisted reactions. Current teaching practices in laboratory and lecture along with a discussion of barriers to implementing either a stand alone green chemistry course, or integrating green chemistry into an existing course, have been reviewed (2). In this review Andraos and Dicks specifically mention that cost analysis has received little attention in teaching laboratories. This curriculum includes a cost analysis of each reaction and includes the cost of waste disposal. In a recent survey of 130 undergraduate organic chemistry laboratories (3), less than 4% of the institutions considered any aspect of green chemistry methodologies important. Green chemistry can be viewed as one aspect of practicing chemistry rather than an actual subset of chemistry. Application of the principles of green chemistry, and use of a variety of metrics, applies to any area of experimental chemistry using chemicals. Pedagogical Background Bretz, Bruck and Towns (4), in their recent study of faculty goals for chemistry undergraduate teaching laboratories, found three primary goals: faculty would like students to learn (1) techniques and laboratory skills, (2) critical thinking skills and (3) written communication skills. A quote from one of their research participants sums up the situation “That's my fear of organic lab, is too often, it's a cooking class and if you end up with white solid at the end, you've been successful. And, and I don't think the students get much out of that.” Green chemistry was not mentioned as a separate item, although as expected, spectroscopy was a major skill faculty mentioned as important. They found the major barriers and limitations to implementation of these goals were: (1) concern with student preparation for laboratory, (2) the ability of the TAs to facilitate learning in laboratory and assess student work, and (3) faculty involvement and accountability with laboratory development and implementation. Our pedagogical thinking is aligned with the findings of Bretz, Bruck and Towns. Green chemistry as a topic is a vehicle to help facilitate goals 1-3 without undermining organic laboratory skills and spectroscopic analysis. In a subsequent study, Bretz, Bruck, Fay and Towns (5) analyzed faculty goals and grouped them into three domains: cognitive, affective and psychomotor. The three main affective goals were making connections to the real world, engaging in collaboration, and gaining independence. In this analysis, the authors also noted a lack of affective goals for organic chemistry faculty, as well as for those teaching other upper-level chemistry laboratory courses. Although the authors interviewed eleven faculty members who teach organic chemistry at a wide range of institution types, ranging from community colleges to research (R1) 34 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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universities, affective goals were not discussed or given any importance by these faculty. This was not the case for those who teach general chemistry who felt that these affective goals were very important. Incorporation of green chemistry into the organic laboratory curriculum certainly makes a connection to the real world for the students and also can be a vehicle for collaborative discussions and a prime driver of the collaborative domain. The majority of our students are interested in health care. Our students will be the future prescribers, users and designers of new pharmaceuticals. They will also be making and applying policy in their careers. Understanding green chemistry issues and applications is foundational if we want to move forward with a sustainable chemical industry at all levels. The pharmaceutical industry in general is the worst at waste production, producing from 25–100 kg of waste per kg of product. In contrast the oil refining industry produces the least amount of waste, less than 0.1 kg of waste per kg of product (6). Of course waste is not everything as the the main consumption of the oil industry’s product leads to greenhouse gas production versus the consumption of pharmaceuticals leading to improved health outcomes in patients. Being conscious of waste production in an organic laboratory and choosing to limit waste when there is a choice is the goal of the curriculum.

Institutional Background The University of Colorado at Denver is an urban commuter campus serving a wide range of students from traditional to post-baccalaurate career changing students. We have a large number of transfer students, both from community colleges and from other four year schools around the country. Our chemistry department has a very small Masters degree program and is dependent on advanced undergraduates to serve as teaching assistants for chemistry labs. We currently offer organic chemistry I and II laboratories every semester including summers. The organic chemistry II laboratories are not required for any of our chemistry majors. Chemistry majors take an honors version of organic II laboratory that focuses on research. Typically we teach eleven sections per year of the second semester laboratory with the students almost exclusively pre-health majors. The laboratory curriculum is divided up into modules. Organic chemistry laboratory II has four modules. The first is determination of an unknown, the rest are various reactions with green chemistry principles woven in. Having undergraduates as teaching assistants has its own set of challenges. We have a robust training program; the teaching assistants spend a forty-hour week training with us (TA Bootcamp) prior to the start of fall semester and do all of the unknowns. We then have mini-bootcamps prior to the start of each module. Not only do we have to train the teaching assistants on the reactions and laboratory techniques, but we also need to include the green chemistry principles and metrics since not all the teaching assistants have been exposed to this before. Even the students who have taken our laboratories prior to being teaching assistants often need a major refresher. Our curriculum design had to take into account a fluid student population and the background and capabilities of the teaching assistants. 35 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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The Curriculum The Twelve Principles (7) of green chemistry and how they apply specifically to the organic chemistry laboratory curriculum are summarized in Table 1. Atom economy (AE) and environmental factor (E factor) are the two prime green chemistry metrics used. The principles and the metrics drive the green analysis of the reactions. Atom economy (AE), developed by Trost (8) is defined as the molecular weight of the desired product divided by the molecular weight of all reactants. Environmental factor (E factor), developed and clarified over the years by Sheldon (9), is defined as kg waste/kg product. Waste is defined as all solvents, process aids (i.e. drying agents), organic compounds and inorganic compounds used in the reaction that are not incorporated into the product. Water is not considered in the E factor metric. Ideally, water should be considered, as aqueous waste added to the general wastewater has to be treated at the wastewater treatment plant. Aqueous waste collected and disposed of in the same manner as organic waste also incurs a disposal fee. Inclusion of water can lead to high E factors when comparing aqueous processes to non-aqueous processes, skewing a direct comparison. The energy used to operate stir plates, heating mantles and rotary evaporators is difficult to calculate and is ignored in the metric. The amount of energy used to conduct the reaction should also be factored in as it certainly adds to the cost. How to actually calculate the amount and cost of energy used for devices would be a welcome addition to the metric. The energy associated with waste disposal could be factored in as a separate item or rolled into the cost of waste disposal. One could also factor in whether the energy used came from a renewable or non-rewnweable source. The three modules presented here comprise the three green chemistry modules. The first is epoxidation reactions, the second electrophilic aromatic substitution reactions, and the third module is carbon-carbon bond-forming reactions. Introduction to green chemistry occurs at the beginning of the epoxidation module. The students read Green Chemistry: Theory and Practice (Anastas and Warner), the required textbook (7). We chose this book for its accessability, low cost and concise discussions.

Table 1. Twelve Green Principles (7) Principle

Organic Chemistry Laboratory Curriculum Application

1 Prevention (better to prevent waste than to treat or cleanup waste)

Minimize waste Calculate E factor for reaction. Choose reaction with a lower E factor.

2 Atom economy (maximize inclusion of starting materials into product)

Calculate atom economy for the reaction. Choose reaction with the highest atom economy. Continued on next page.

36 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Table 1. (Continued). Twelve Green Principles (7)

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Principle

Organic Chemistry Laboratory Curriculum Application

3 Less hazardous chemical syntheses (minimize the use of materials toxic to living beings or the planet)

Choose the least toxic reagents if there are multiple ways to synthesize a particular product.

4 Designing safer chemicals (the chemical needs to do it’s job - design it be less toxic)

Design a less toxic molecule for a particular purpose. (more of a lecture topic versus a laboratory topic).

5 Safer solvents and auxiliaries

Choose aqueous reactions or solventless reactions over solvent reactions. Choose the least toxic solvent if an organic solvent must be used.

6 Energy efficiency (minimize the amount of energy required)

Minimize the amount of heat and pressure needed to run a reaction.

7 Renewable feedstocks (renewable starting materials from plants or animals is preferred over starting materials derived from petroleum industry) 8 Reduce derivatives

Minimize protection/deprotection steps in organic syntheses.

9 Catalysis

A catalytic reagent in small quantities is preferable to a stoichiometric catalyst.

10 Design for degradation (natural decomposition into non -toxic byproducts when the compound is no longer needed.) 11 Real-time analysis for pollution prevention 12 Inherently safer chemistry

Safer laboratories for students. Minimize risk for exposure to chemicals, spills, explosions and fires.

The first module is two weeks and introduces the students to green analysis and cost analysis. The students epoxidate the same substrate two different ways and compare the two reaction pathways by doing a direct comparison cost-benefit and green chemistry analysis. During the second module, which is also two weeks, the students continue with cost and green chemistry analyses comparing two different electrophilic aromatic substitution reactions on the same substrate. In the last module, which is three weeks long, the students perform three carbon-carbon bond-forming reactions that each highlight one of the Twelve Principles. The students also compare the three reactions via a cost benefit and green analysis of each reaction. Before each laboratory period, students prepare a prelab and take a quiz online covering the week’s topic. During the preliminary unknowns 37 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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module, the quizzes focus on techniques. Beginning with the first green chemistry module, the quizzes incorporate material specific to the reactions being performed as well as material from the green chemistry text. Quiz questions include green chemistry principles applied to laboratory synthetic scenarios. The main metrics we incorporate into the curriculum are discussed during recitation in the context of how they apply to the reaction that week. Each module has one laboratory report. As part of the laboratory report, the students calculate specific green chemistry metrics for each reaction. Atom economy, E factor, reaction costs and waste costs are calculated and compared for each reaction in the module. The students also discuss the reactions using applicable green principles outlined in Table 1. Details for all the metrics are provided for the first module reactions, while summaries are provided for the second and third module reactions. The modules can be used as stand alone units or bundled together to form a seven week green organic laboratory curriculum that could be implemented in any standard sophomore level second semester organic chemistry laboratory program.

Green Reaction Chemistry Module 1 In our first green chemistry module, which occurs over a two week period, students compare the epoxidation of trans-anethole (1) using potassium peroxymonosulfate 2KHSO5 KHSO4 K2SO4 (2) (10) and epoxidation of 1 using meta-chloroperoxybenzoic acid (mCPBA) (11) to produce trans-Anethole oxide (3) as shown in Scheme 1. Having two distinct reactions for synthesizing 3 from 1 allows the student to directly compare the two reactions. Often when we perform synthetic steps we have a choice of reactions. Determining the best reaction, taking into consideration cost and green chemistry metrics, is the overall task for Module 1. For reagent 2, we use the salt tradenamed Oxone by Sigma-Aldrich, so refer to this reaction as epoxidation by Oxone. Potassium peroxymonosulfate is also used in spas. Spa suppliers sell it as “pool shock”. We have not tried those products. In the first week, students read about green chemistry in the text, read the paper from which the procedure is modified (10), write a standard organic chemistry prelab, take a quiz including green chemistry questions and complete the synthesis of 3 using 2.

Scheme 1. Epoxidation reactions for module 1.

38 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

We involve the students in a cost analysis as well as a green analysis. Ideally, cheaper and greener should win the day. We also ask them to take into account the percent yield. Of course students’ yields are not optimized as they would be in industry, but just a simple comparison can be illuminating. The cost of producing a gram of product in a low yield reaction can soar compared to a high yield one. For the prelab, we give the students the cost of materials per gram and have them calculate the total cost of running the reaction per gram of product based on obtaining a 100 percent yield. The students do two cost analyses, one for each reaction as part of their prelab. The cost analysis of materials for the two epoxidation reactions are combined and shown in Table 2 below. For liquids, the students use the density and are given the following assumptions and formula. For workup solutions, grams of solids used are calculated by (solution % X volume used)/(100% – solution %) assuming a weight to volume (w/v) solution. Saturated aqueous NaCl is assumed to be 26% w/v and saturated aqueous ammonium chloride is assumed to be 24% w/v. Once the students have completed the reaction, they adjust this cost analysis for the percent yield they obtained and include it in the module laboratory report.

Table 2. Cost Analysis for Epoxidation Reactions Reagent

Cost / Gram ($)

Amount used in Oxone Reaction (g)

Oxone Reaction Cost ($)

Amount used in mCPBA Reaction (g)

mCPBA Reaction Cost ($)

Acetone

0.33

23.73

7.83

-

-

trans-Anethole

1.41

1.48

2.09

0.74

1.04

mCPBA

0.78

-

-

2.00

1.56

Dichloromethane

0.28

-

-

59.63

16.70

Diethyl ether

0.12

42.36

5.08

-

-

Magnesium sulfate

0.17

0.50

0.09

0.50

0.09

Oxone

0.42

8.00

3.36

-

-

Sodium bicarbonate

0.12

4.00

0.48

-

-

Sodium carbonate

0.13

-

-

17.22

2.24

Sodium chloride

0.13

7.03

0.91

5.27

0.69

87.10 g

$19.84

85.358 g

$22.31

Totals

The theoretical yield for a 10 mmol reaction producing 3 from 2 is 1.64 grams. For the cost analysis, students can calculate the cost to produce one gram of 3 assuming a 100 percent yield as shown in eq 1. This is calculated by dividing the total reaction cost by the theoretical yield.

39 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Students can then adjust the cost using their percent yield for the final laboratory report as shown in eq 2. Assuming our student had a 25 percent yield, the reaction cost is divided by the theoretical product mass times the students’ percent yield.

We do not have the students calculate the AE as part of the Oxone epoxidation reaction prelab since determining which species to factor into the calculations is driven by the assumed reaction mechanism. This particular epoxidation mechanism is not discussed in standard sophomore organic chemistry textbooks so requires an in-class discussion. The students do include E factor and waste disposal calculations (assuming 100 percent yield) as part of each prelab. During recitation, the teaching assistants review the reaction mechanism and discuss which species should be involved in the AE calculation. The reaction mechanism for the Oxone epoxidation reaction is shown in Figure 1. Oxone reacts stoichiometrically with acetone to form dioxirane. Oxone is included in the AE calculation even though HSO5– is the only active portion of the 2 salt.

Figure 1. Mechanism of epoxidation of trans-anethole with Oxone. Atom economy is independant of the actual yield obtained in the reaction and is a property of the reaction. The general formula AE is shown in eq 3.

40 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

AE for the epoxidation of 1 by 2 is calculated by dividing the molar mass of the product 3 by the sum of the reagent molar masses 1 and 2 as shown in eq 4.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

The E factor for the reaction is the total mass of materials used in the reaction minus the mass of the product, divided by the mass of the product. Equation 5 outlines the E factor calculation assuming a 100 percent yield.

The E factor is dependent on the percent yield. For example, if the student obtained a 25 percent yield the E factor increases dramatically as demonstrated in eq 6.

The cost of waste disposal for organic and aqueous waste at our institution is $2.50 per pound which is $0.006 per gram of waste. The cost of waste disposal of the theoretical reaction per gram of product is the E factor times the cost of waste disposal per gram as shown in eq 7.

Students may then calculate the cost of waste disposal using their calculated E factor based on their individual reaction yield. Equation 8 shows the calculation for a student obtaining a 25 percent yield.

Adding in the cost of waste disposal gives a total cost of $12.39 per gram of product, assuming a 100 percent yield. With a yield of 25 percent, the total cost soars to $49.66. The students can easily see the impact of a low yield on the bottom line. The experimental procedure for each reaction gives a typical student yield, 41 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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however our students vary in abilities at running reactions and we expect a wide range in yields. In the second week, students epoxidate 1 with mCPBA. This is a standard epoxidation reaction covered in mechanistic detail in sophomore organic chemistry textbooks so students include this AE calculation in their prelab. Atom ecomomy for the epoxidation of 1 by mCPBA can be calculated according to eq 9.

The E factor can be calculated for the mCPBA epoxidation reaction of 1 according to equation 10 assuming 100 percent yield of 3 (0.82 g).

For the cost analysis, students can calculate the cost to produce one gram of 3 assuming a 100 percent yield as shown in eq 11. As mentioned in the previous section, this is calculated by dividing the total reaction cost by the theoretical yield.

As seen in the aforementioned calculations, the cost of waste disposal of the theoretical reaction per gram of product is equal to the E factor times the cost of waste disposal per gram as shown in eq 12.

The total cost of the actual reaction assuming 100 percent yield can be calculated by adding the cost of waste disposal to the cost of the reaction per gram of product as shown below in eq 13.

42 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

Comparing the two reactions directly, the reaction with the highest AE has the most reagent atoms incorporated into the product structure. The AE of epoxidation of 1 by mCPBA is superior to the AE of epoxidation of 1 by 2 (51% versus 36%). The lower the E factor for a reaction the less waste is produced and the more environmentally efficient the reaction. The E Factor of epoxidation of 1 by mCPBA is twice that of epoxidation of 1 by 2 assuming 100% yield (103 versus 51). The cost of running the epoxidation of 1 by mCPBA is over twice the cost of epoxidation of 1 by 2 ($27.79 versus $12.39). Epoxidation using 2 is aqueous, utilizing green principle 5 which is safer solvents and auxiliaries as described in Table 1. Overall the student should conclude that epoxidation of 1 with 2 is greener as well as cheaper than oxidizing 1 with mCPBA. Not every reaction requires the same skill level so some reactions produce a much higher yield than others for the student, which can affect their conclusions. Once the reaction metrics have been adjusted for their actual yield, students can appreciate the complexities of a cost benefit and green analysis.

Experimental Procedure for Epoxidation of 1 with Oxone (10) 30 mL DI water, and 8 g (13 mmol of active portion) 2 were added to a 100mL beaker and stirred for 20–25 mins. To a 100 mL round bottom flask on ice, a stir bar, 30 mL of acetone, 1.482 g of 1 (10 mmol), and 4 g (47.6 mmol) of solid pure NaHCO3 were added, stirred and cooled to ≈ 0 °C. The 2 solution was transfered to a separatory funnel and added dropwise to the round bottom flask containing 1. Once the addition of the 2 solution was complete, the mixture was stirred unheated for 30 minutes. The reaction mixture was filtered through filter paper into a separatory funnel. Remaining solids were washed with 10 mL diethyl ether and the wash added to the separatory funnel. The organic layer was extracted with diethylether (25 mL X 2), washed with DI H2O (1 X 20 mL), followed by brine wash (1 X 20 mL), dried over anhydrous MgSO4, and concentrated by rotary evaporation to yield a yellow oil. Typical yield 1.45 g (8.8 mmol, 88 %). FTIR: 3000–3100, 2836–3000, 1515, 1613, 1250 cm-1. 1H NMR (300 MHz, CDCl3, δ): 7.18 (dt, J = 9 Hz, J = 2 Hz, 2H, Ar–H ortho to oxirane), 6.87 (dt, J = 9 Hz, J = 2 Hz, 2H, Ar–H), 3.79 (s, 3H, OCH3), 3.44–3.54 (m, 1H, HCArO), 3.00–3.07 (m, 1H, HCCH3O), 1.43 (d, J = 5 Hz, 3H, CH3 on oxirane).

Experimental Procedure for Epoxidation of 1 with mCPBA (11) To a 100 mL or larger round bottom flask on ice equipped with a stir bar, 0.741 g 1 (5.0 mmol), 15 mL of CH2Cl2 and 30 mL of 10% Na2CO3 solution were added. In a beaker 2.0 g (8.15 mmol, 0.8 equivalents) of mCPBA were dissolved in 30 mL of CH2Cl2, transferred to a separatory funnel and added dropwise to the reaction mixture. After the addition was completed, the reaction mixture was stirred in the ice bath for an additional 20 minutes. A small amount of DI water was added to dissolve any solids and the liquid reaction mixture was transferred to a separatory funnel. The organic layer was washed with 10 % (Aq) Na2CO3 (5 43 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

X 25 mL) to remove 3-chlorobenzoic acid, washed with brine (1 X 15 mL), dried over anhydrous MgSO4, and concentrated by rotary evaporation to yield a yellow oil. Typical yield 0.71g ( 4.3 mmol, 86%). FTIR: 3000–3100, 2836–3000, 1515, 1613, 1250 cm-1. 1H NMR (300 MHz, CDCl3, δ): 7.18 (dt, J = 9 Hz, J = 2 Hz, 2H, Ar–H ortho to oxirane), 6.86 (dt, J = 9 Hz, J = 2 Hz, 2H, Ar–H), 3.78 (s, 3H, OCH3), 3.52 (d, J = 2 Hz, 1H, HCArO), 3.00–3.07 (m, 1H, HCCH3O), 1.43 (d, J = 5 Hz, 3H, CH3 on oxirane).

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

Green Reaction Chemistry Module 2 In module 2, the students compare bromination of toluene with n-bromosuccinimide (NBS) (12) with nitration of toluene with nitric acid (13) as shown in Scheme 2. In this example, the students are functionalizing toluene two different ways. During complex syntheses, sometimes a choice can be made for an intermediate functional group. In a situation like this, there would be a decision as to which reaction would be the best choice. The goal is to produce a mono substituted ortho or para-toluene. The students determine which reaction, bromination or nitration, is the cheapest and greenest.

Scheme 2. EAS Reactions for Module 2.

At this point the students are familiar with the green principles and the metrics. The students calculate the AE and reaction costs, E factor and waste disposal costs assuming a 100 percent yield as part of the prelab. The cost analysis for these two reactions is shown in Table 3. The suggested mechanism of NBS facilitated bromination is not discussed in the typical sophomore organic textbook and is included in Figure 2 for reference. 44 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Table 3. Cost Analysis for Electrophilic Aromatic Substitution Reactions Cost/ gram ($)

Amount used in Bromination Reaction (g)

Bromination Cost ($)

Amount used in Nitration Reaction (g)

Nitration Cost ($)

Acetonitrile

0.27

5.50

1.49

-

-

NBS

0.16

1.78

0.28

-

-

Dichloromethane

0.28

13.26

3.71

-

-

Diethyl ether

0.12

-

-

5.65

0.68

Ethyl acetate

0.09

2.71

0.24

-

-

Hexanes

0.14

4.61

0.65

-

-

Iron (III) chloride

0.38

0.16

0.06

-

-

Magnesium sulfate

0.17

0.50

0.09

-

-

Nitric acid

0.03

-

-

1.41

0.04

Sodium bicarbonate

0.12

-

-

1.11

0.13

Sodium chloride

0.13

3.51

0.46

3.51

0.46

Sodium thiosulfate

0.19

0.79

0.15

-

-

Sulfuric acid

0.02

-

-

1.84

0.04

Toluene

0.07

0.92

0.06

0.87

0.06

33.74

7.19

14.39

1.41

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Reagent

Totals

Figure 2. Mechanism for bromination of toluene with NBS. 45 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

n-Bromosuccinimide functions as a stoichiometric catalyst so is included in the AE. Iron (III) chloride (0.1 equivalents) is not included in the AE as it is a true catalyst. Nitration of toluene follows the standard EAS mechanism presented in textbooks. The green and cost metrics for both reactions in this module assuming 100 percent yield are summarized in Table 4.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

Table 4. Green and Cost Metrics of EAS Reactions Bromination of Toluene

Nitration of Toluene

Atom Economy (%)

63

85

E Factor

19

10

Cost of reaction/g of product ($)

4.20

1.10

Cost of reaction including waste disposal/g of product ($)

4.31

1.16

Nitration of toluene has a higher AE, lower E factor and is cheaper than bromination of toluene. Once the students perform the reactions they realize that bromination of toluene leads to the desired products, p-bromotoluene and o-bromotoluene while nitration of toluene does not. The problem with nitration, the students realize when they do the spectral analysis of their product, is that nitration is hard to control. A number of students observe considerable dinitrotoluene as well as some trinitrotoluene. These products are deemed unwanted therefore waste. The actual percent yield of the desired products has to be adjusted for this and result in an increased E factor and increased cost for the nitration reaction. Students can determine the percent of mononitrated toluene by comparing the integration of signals What appears on the surface as the green and cheaper choice turns out to be quite problematic once the students realize that they have no reliable way of actually obtaining a pure mono-nitrated toluene product.

Experimental for Bromination of Toluene 1.780 g n-Bromosuccinimide and 7.00 mL acetonitrile were added to a 50 mL round bottom flask charged with a stir-bar and fitted with a reflux condenser followed by addition of 0.162 g iron (III) chloride. The solution was stirred for 5 minutes at room temperature. The solution turned from yellow to dark red indicating the formation of the bromine complex. 1.065 mL toluene, using a microliter autopipettor, was added to the dark red solution and the reaction was stirred for 30 minutes at room temperature with monitoring via TLC, (30% ethyl acetate 70% hexanes). After reaction completion as determined by TLC, the reaction was quenched with 15 mL of 5% sodium thiosulfate. The solution was extracted with CH2Cl2 ( 2 X 10 mL), washed with DI water (1 X 10 mL), washed with saturated aq. NaCl solution (1 X 10mL) and dried over anhydrous 46 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

MgSO4. Solvent was removed by rotary evaporation yielding a yellow oil. Typical yield 0.97 g (5.7 mmol, 57%). FTIR: 3000–3088, 2864–3000, 1486, 1568, 801 (para), 747 (meta), 657 cm-1. p-Bromotoluene 1H NMR (300 MHz, CDCl3, δ): 7.36, d, J = 8Hz, 2H, ArH ortho to Br), 7.00–7.07 (m, 2H), 2.29 (s, 3H CH3) o-Bromotoluene: 7.52 (d, J = 8 Hz, 1H, ArH ortho to Br), 7.15–7.26 (m, 3H ArH), 2.39 (s, 3H, CH3).

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

Experimental for Nitration of Toluene 1.0 mL of concentrated nitric acid was added to a 25 mL round bottom flask immersed in an ice water bath charged with a magnetic stir bar. While stirring, 1.0 mL 18M sulfuric acid was added. 1.0 mL of toluene was added dropwise over a period of 5 minutes. The solution was stirred and the ice bath removed to allow the contents of the flask to reach room temperature. Stirring was continued at room temperature for 5 mins. The solution was transferred to a separatory funnel and quenched with 10 mL of water. The solution was extracted with diethyl ether (1 X 8 mL), washed with 10% (aq) sodium bicarbonate ( 1 X10 mL, washed with DI water (1 X 5 mL) and washed with sat aq NaCl (1 x 10 mL). The solvent was removed by rotary evaporation to yield a yellow oil. Typical yield 0.81 g (5.9 mmol, 63%). FTIR: 3080–3117, 2851–2931, 1599, 1513, 1340 cm-1. pNitrotoluene 1H NMR (300 MHz, CDCl3, δ): 8.11 (d, J = 9Hz, 2H), 7.33 (m, 2H), 2.47 (s, 3H); o-Nitrotoluene 1H NMR (300 MHz, CDCl3, δ): 8.37(dd, J = 8Hz, J = 1.2Hz, 1H), 7.97 (dd, J = 8Hz, J = 1.2Hz, 2H), 7.33 (m, 1H), 2.57 (s, 3H); di-Nitrotoluene 1H NMR (300 MHz, CDCl3, δ): 8.02 (d, J = 8Hz 2H), 7.61 (d, J = 8Hz, 1H), 2.59 (s, 3H); tri-Nitrotoluene 1H NMR (300 MHz, CDCl3, δ): 8.82 (d, J = 8Hz, 2H), 2.59 (s, 3H). Green Reaction Chemistry Module 3 In the last module of the semester, the students compare three carbon-carbon bond forming reactions, a Barbier reaction (14), a Wittig reaction (15) and an aldol reaction (16) shown in Scheme 3. In organic chemistry syntheses when carbon carbon bonds are formed, there can be choices in reaction types. In this module, students are exposed to different reaction types and different green principles in action. The Barbier is an aqueous version of a Grignard reaction. The use of an aqueous environment minimizes toxicity and waste disposal as classic Grignard reactions are usually conducted in an anhydrous environment with organic solvents. The Wittig reaction we chose illustrates the minimal use of solvents by being solventless, using grinding to induce contact between the reactants. Traditional Wittig reactions use organic solvents so incur higher waste costs. The aldol addition reaction is an example of a fantastically high AE reaction. The cost analyses for the specific Barbier, Wittig and aldol reactions are shown in Table 5 below. Keeping the reactions small, yet not microscale, keeps the costs for each reaction low yet the size allows for students to adequately practice their laboratory techniques. 47 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Table 5. Cost Analysis for Carbon-Carbon Bond Forming Reactions

48

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Reagent

Cost per Gram ($)

Amount Used in Barbier Reaction (g)

Barbier Cost ($)

Amount Used in Wittig Reaction (g)

Wittig Cost ($)

Amount Used in Aldol Reaction (g)

Aldol Cost ($)

Acetic acid

0.11

-

-

-

-

0.42

0.05

Acetone

0.11

-

-

-

-

0.47

0.05

Allyl bromide

0.14

0.66

0.09

-

-

-

-

Ammonium chloride

0.54

1.57

0.85

-

-

-

-

Benzaldehyde

0.25

0.52

0.13

-

-

1.70

0.42

BTPPCla

0.70

-

-

0.21

0.15

-

-

p-Bromo-benzaldehyde

1.83

-

-

0.10

0.17

-

-

Diethyl ether

0.12

28.24

3.39

-

-

-

-

Ethanol

0.14

-

-

3.95

0.55

35.19

4.93

Ethyl acetate

0.09

-

-

1.80

0.16

2.71

0.24

Hexanes

0.14

-

-

5.27

0.74

4.61

0.65

Magnesium sulfate

0.09

0.50

0.09

-

-

-

-

Sodium chloride

0.13

5.27

0.69

-

-

-

-

Sodium hydroxide

0.12

-

-

-

-

2.00

0.24

Tetrahydrofuran

0.12

0.89

0.11

-

-

-

-

Tripotassium phosphate

0.10

-

-

0.43

0.04

-

-

Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Zinc

Cost per Gram ($)

Amount Used in Barbier Reaction (g)

Barbier Cost ($)

0.18

0.40

0.07

38.05

5.41

Totals a

Amount Used in Wittig Reaction (g)

11.75

Wittig Cost ($)

1.81

BTPPCl = benzyltriphenylphosphonium chloride

49

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Reagent

Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Amount Used in Aldol Reaction (g)

Aldol Cost ($)

-

-

47.09

6.58

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Scheme 3. Carbon-carbon forming reactions for module 3.

The green and cost metrics for this module assuming a hundred percent yield for each reaction are summarized in Table 6 below. The students observe that carbon-carbon bond-forming varies in cost and in greenness.

Table 6. Metrics of Carbon-Carbon Bond Forming Reactions Barbier

Wittig

Aldol

Atom Economy (%)

65

45

86

E Factor

50

89

24

Cost of reaction/g of product ($)

7.30

13.92

3.52

Cost of reaction including waste disposal/ g of product ($)

7.60

14.46

3.66

The aldol has the highest AE (86 percent versus 65 percent for Barbier and 45 percent for Wittig), lowest E Factor (24 versus 50 for Barbier and a much higher 89 for the Wittig reaction) and is the most economical of the three reactions. The Wittig reaction is over four times the cost of the aldol reaction per gram of product. The solventless Wittig definitely adhering to Green Principle 1, prevention of waste as described in Table 1, unfortunately has the lowest AE, highest E Factor and is the most expensive reaction. If the only choice synthetically in an organic synthesis scheme is a Wittig reaction, then the solventless process is preferable over a Wittig reaction that uses a solvent. However, other options forming a carbon-carbon bond might be preferable. The Barbier reaction has a reasonable AE and E Factor for an organic reaction and as an aqueous reaction is preferable to performing a classical Grignard reaction requiring anhydrous and organic solvent conditions. Adding in the cost and green analysis adds another layer to the overall choice in organic synthesis pathways when considering synthesizing a target molecule.

50 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch003

Experimental for Barbier Reaction (14) To a 50 mL round bottom flask equipped with reflux condenser, 5 mL of aqueous saturated ammonium chloride solution, 1 mL of THF, 0.4 g of zinc powder, 0.500 mL of benzaldehyde (with auto pipet) and 0.470 mL of allyl bromide (with auto pipet) was added. The solution was stirred at RT for 45 minutes. 10 mL of diethyl ether was added to the solution followed by gravity filtration and transference to a separatory funnel. An additional 10 mL of DI H2O was added and the solution was extracted with diethyl ether (2 X 15 mL), washed with sat. aq NaCl (1 X 10 mL) and dried over anhydrous MgSO4. The solvent was removed by rotary evaporation yielding a yellow oil. Typical yield 0.26 g (1.75 mmol, 35%) FTIR: 3126–3631, 3000–3126, 2737–3000, 1698, 1584,1203 cm-1. 1H NMR (300 MHz, CDCl3, δ): 7.19–7.38 (m, 5H,ArH), 5.78 (ddt, J = 17Hz, J = 10Hz, J = 7Hz, 1H, internal vinyl), 5.13 (td, J = 10Hz, J = 1.2Hz, 2H, terminal vinyl), 4.70 (t, J = 6Hz, 1H, HCOH), 2.48 (td, J = 6Hz, J = 1.2Hz, 2H, CH2), 2.36 (s, 1H, OH).

Experimental for Wittig Reaction (15) A clean mortar was charged with 208 mg of benzyltriphenylphosphonium chloride, 95 mg of p-bromobenzaldehyde, and 425 mg of K3PO4. The solid mixture was ground vigorously with a pestle for 20 minutes, scraping down the sides every few minutes with a scoopula. The reaction was monitored by TLC every 5 minutes (1:4 ethyl acetate/hexanes). Upon reaction completion, 10 mL of water was added to the mortar and the insoluble materials were isolated via vacuum filtration yielding a white paste. Recrystallization (5 mL of hot ethanol) yielded a white solid. Typical yield 0.027 g (0.104 mmol, 20.3%) mp: 135.4–137.5 °C (lit (15). 135–137 °C) FTIR: 3000–3071, 1590, 1484, 1437, 537 cm-1. 1H NMR (300 MHz, CDCl3, δ): 7.51 (d, J = 8Hz, 2H), 7.49 (d, J = 8Hz, 2H), 7.38 (d, J = 8Hz, 2H), 7.36 (d, J = 8Hz, 2H), 7.29 (d, J = 12Hz, 1H), 7.13 (d, J = 16Hz, 1H), 7.05 (d, J = 16Hz, 2H).

Experimental for Aldol Reaction (16) To a 50 mL Erlenmeyer flask equipped with a stir bar, 2.0 g of NaOH, 15 mL DI water and 15 mL of ethanol were added. The solution was stirred to dissolve the NaOH. In a small beaker 8 mmol acetone was combined with 16 mmol benzaldehyde then added to the Erlenmeyer flask. The reaction mixture was stirred at room temperature for 30 minutes and monitored by TLC every 10 minutes (1:4 ethyl acetate, hexanes). When the reaction was complete, the flask was chilled in an ice bath to 4 °C. The resultant precipitated white crystalline product was isolated by vacuum filtration. Typical yield 0.41 g (1.75 mmol, 22%) mp: 111.9–113.1 °C (lit (17). 107–113 °C) FTIR: 3026–3105, 1647, 1587 cm-1. 1H NMR (300 MHz, CDCl3, δ): 7.77 (d, J = 15Hz, 2H), 7.64 (dd, J = 8Hz, J = 4Hz, 4H), 7.42 (d, J = 3Hz, 4H), 7.41 (d, J = 3Hz, 2H), 7.11 (d, J = 15Hz, 2H). 51 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Conclusion Green chemistry practices and metrics can be experienced by students without compromising the organic chemistry laboratory techniques that are highly desired. Organizing and analyzing cost and green metric data provides students an opportunity to delve deeper into the reactions and apply critical thinking skills. This kind of analysis provides students more of a real world case study than just a recipe and hopefully connects them more to issues present in chemical production that affect each one of us. Connection to the larger world hopefully makes the educational experience more meaningful and memorable. How green a process is is not a clear cut issue. Students see the subtleties and have to prioritize principles and metrics in order to do their evaluations of the reactions. Students need classroom discussion and clarity around the specific metrics used to evaluate reactions; currently there is no standarization in name or definition. The three modules can be used individually or as a block. Each module involves analyzing each reaction, what is green about the reaction, what is not green about the reaction, calculating and comparing the atom economy, the amount of waste produced and the cost of a reaction including waste disposal. This kind of analysis enhances critical thinking skills as well as written communication skills. Collaboration is fostered as students do not necessarily reach the same conclusions due to their different reaction yields. As students discuss their own results and conclusions in class with each other and with the TA, they hopefully see that conducting chemical experiments has more nuance than just following a recipe. Students can also connect the organic chemistry laboratory experience to the greater world through a green and cost reaction analysis. On the periodic course evaluations, students mention how they appreciated and enjoyed learning something totally new. Students are not exposed to green chemistry concepts in lecture at our institution. Most students we have spoken to have never had to think about cost or waste in relation to laboratory courses before. This is an area of chemical education we would like to explore in the future, documenting what green chemistry knowledge students bring with them to the course and what knowledge they take away. Hopefully they can see a connection to the chemical industry and to their own consumer use of chemicals. Documentation of this possible transference could be an exciting avenue of chemical education research.

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Dicks, A. P. (Ed.). Green Organic Chemistry in Lecture and Laboratory; CRC Press: Boca Raton, FL, 2011; pp 257–272. Andraos, J.; Dicks, A. P. Green chemistry teaching in higher education: a review of effective practices. Chemistry Education Research and Practice. 2012, 13, 69–79. Martin, C. B.; Schmidt, M.; Soniat, M. A survey of the practices, procedures, and techniques in undergraduate organic chemistry teaching laboratories. J. Chem. Educ. 2011, 88, 1630–1638. 52 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Bruck, L. B.; Towns, M.; Bretz, S. L. Faculty perspectives of undergraduate chemistry laboratory: Goals and obstacles to success. J Chem Educ. 2010, 87, 1416–1424. Bretz, S. L.; Fay, M.; Bruck, L. B.; Towns, M. H. What faculty interviews reveal about meaningful learning in the undergraduate chemistry laboratory. J. Chem. Educ. 2013, 90, 281–288. Sheldon Home Page. http://www.sheldon.nl/roger/efactor.html (accessed March 2016). P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998; pp 1–129. Trost, B. M. The atom economy--a search for synthetic efficiency. Science. 1991, 254, 1471–1477. Sheldon, R. A. The E factor: fifteen years on. Green Chem. 2007, 9, 1273–1283. Broshears, W. C.; Esteb, J. J.; Richter, J.; Wilson, A. M. Simple epoxide formation for the organic laboratory using oxone. J. Chem Educ. 2004, 81, 1018–1019. Centko, R. S.; Mohan, R. S. The Discovery-Oriented Approach to Organic Chemistry. 4. Epoxidation of p-Methoxy-trans-β [beta]-methylstyrene: An Exercise in NMR and IR Spectroscopy for Sophomore Organic Laboratories. J. Chem Educ. 2001, 78, 77–79. Smith, R. E.; McKee, J. R.; Zanger, M. The electrophilic bromination of toluene: Determination of the ortho, meta, and para ratios by quantitative FTIR spectrometry. J. Chem Educ. 2002, 79, 227–229. Russell, R. A.; Switzer, R. W.; Longmore, R. W. A multistep microscale synthesis based on an industrial process. J. Chem Educ. 1990, 67, 68–69. Coqueret, X.; Bourelle-Wargnier, F.; Chuche, J. 1, 4-Bridged pyrazolin5-ones from thermal ring enlargement of spiropyrazolium ylides. J. Org. Chem. 1985, 50, 909–910. Leung, S. H.; Angel, S. A. Solvent-free Wittig reaction: A green organic chemistry laboratory experiment. J. Chem Educ. 2004, 81, 1492–1493. Huck, L. A.; Leigh, W. J. A Better Sunscreen: Structural Effects on Spectral Properties. J. Chem Educ. 2010, 87, 1384–1387. Sigma-Aldrich Product Page. http://www.sigmaaldrich.com/catalog/ product/aldrich/43143?lang=en®ion=US&cm_sp=Insite-_prodRecCold_xviews-_-prodRecCold10-1 (accessed July 2016).

53 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Chapter 4

A Greener Organic Chemistry Course Involving Student Input and Design Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch004

Loyd D. Bastin* and Kaitlyn Gerhart Departments of Chemistry and Biochemistry, Widener University, One University Place, Chester, Pennsylvania 19013, United States *E-mail: [email protected]

When greening an organic chemistry laboratory, redesigning the course to educate students about green chemistry rather than simply greening the individual experiments is crucial. This chapter describes a process of redesigning the organic chemistry I laboratory from a microscale course into a green chemistry lab. An organic chemistry I laboratory course where the students learn key organic chemistry techniques, the principles of green chemistry, and to apply green chemistry concepts was developed. A feedback mechanism was designed to involve students in the development and greening of experiments. As a capstone experiment, a three step inquiry-based, green synthesis was devised. The capstone experiment requires the students to search the literature and find methods for performing a carbonyl reduction, alcohol dehydration, and alkene bromination. The student-researched methods are analyzed as a class exercise before the experiments are performed, and the class chooses the best method for each reaction.

© 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Introduction One of the major challenges facing society in the 21st century is environmental sustainability. How do we as a society continue to meet our demands and needs without compromising the ability of future generations to meet their needs (1)? Since a key component of an environmentally sustainable future is to decrease the amount of pollution and use of natural resources by chemical industries, chemists and engineers will play a key role in addressing the sustainability challenge. In order to combat the pollution and overuse of our natural resources, the chemical industry will need to develop new processes and products that use starting materials from renewable sources, develop new products that are biodegradable, and develop processes that generate less hazardous waste and use less hazardous substances. In order to provide scientists and engineers with the tools necessary to address these challenges, we must educate future generations about sustainability, green chemistry, and green engineering. Students need to understand the importance of environmental sustainability, the principles of sustainability (triple-bottom line and life cycle analysis), and how green chemistry can be a tool to address the challenge. Therefore, it is important for chemistry faculty to infuse sustainability and green chemistry into the curriculum. While there are a variety of textbooks available for organic chemistry courses (2–5) and multitudes of experiments published in the Journal of Chemical Education for organic chemistry courses, there are only two textbooks for a green organic chemistry laboratory course (6, 7). A number of green organic chemistry laboratory experiments have been published in the Journal of Chemical Education, but there are substantially fewer green experiments found in the Journal of Chemical Education than traditional organic chemistry experiments. However, the number of published green organic experiments is increasing and were recently summarized by Dicks (8) in a supplemental textbook for chemists who wish to incorporate green chemistry into the organic chemistry lecture and laboratory curriculum. Here we describe the design of an organic chemistry sequence that immerses the students in a laboratory experience where they learn to apply the principles of green chemistry (9). This goal is accomplished through a sequential and deliberate introduction to environmental contamination and chemical exposure, introduction to sustainability and green chemistry, and laboratory experiments that have been revised to be greener. Additionally, the students are asked to analyze the experiments using the twelve principles of green chemistry and several green chemistry metrics. Finally, the students are asked to provide suggestions to improve the greenness of each experiment. These suggestions were then investigated by a group of undergraduate research students for incorporation into the subsequent offering of the course. Widener University is a private, primarily undergraduate, regional metropolitan university with ~2900 undergraduate students. The chemistry department is an undergraduate only, ACS-approved department consisting of nine tenured and two non-tenure track faculty. The department graduates three to six chemistry majors per academic year, and many of our upper level courses are populated by of students majoring or minoring in chemistry, chemical engineering, 56 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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biochemistry, environmental science, and biology. The organic chemistry I course discussed here is taken by about 60 second year biology, chemical engineering, chemistry, biochemistry, and environmental science students each year. The four-credit lecture portion of the course consists of four 50 minute class periods each week. The laboratory portion is an additional one-credit course consisting of a 50 minute lab lecture and three hour laboratory session each week. The lab lecture hour convenes all 60 students at the same time and introduces the students to the experiments, techniques, lab notebook expectations, and green chemistry. There are five laboratory sections of organic chemistry I offered each fall semester with an enrollment between 14-16 per section. Since our revision of the course eight years ago, approximately 460 students have participated in the greening process described.

Design Process Previous to our redesign, the organic chemistry I laboratory experiments at Widener were performed on the microscale. While the microscale techniques successfully reduce waste and minimizes risk by reducing the chemist’s exposure to hazardous chemicals, this approach does not address the larger problems of hazardous waste disposal in industry and the potential large scale exposure of the environment to hazardous chemicals. Rescaling a reaction does not truly address the issue of hazardous waste disposal or the need for more environmentally friendly solvents, reagents, and reactions. Therefore, we transformed the organic chemistry I laboratory into a green organic chemistry laboratory. The redesign was guided by the goal to educate students about green chemistry rather than simply greening the individual experiments. Also, it was imperative to design the laboratory to incorporate the principles of green chemistry throughout the course regardless of whether the experiments have been completely “greened”. Our approach involved assessing the pedagogical value of current experiments performed in the organic chemistry I laboratory. We then interviewed science faculty to determine the skills/knowledge that students should obtain from the laboratory course. Using this information, we searched the current literature for green organic chemistry experiments that met revised course goals. As we found suitable experiments, the experiments were performed and evaluated for pedagogical value. We selected the experiments that met the revised course goals and included green chemistry concepts. Greening the organic chemistry laboratory accomplished several goals: (1) The experiments utilize safer starting materials, reagents, and products, (2) the students learn about renewable resources and recycling of reaction products, (3) the experiments use safer solvents, and (4) the waste generated is less hazardous.

Immersion of Students in the Greening Process When the experiments were implemented eight years ago, we intentionally designed a feedback loop into our course design. Hence, the experiments are continually evaluated and some have been improved based on student suggestions 57 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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over the past eight years. This feedback mechanism (Figure 1) requires the organic chemistry students to suggest modifications to the experiments as part of their laboratory reports. Although others have greened their organic chemistry lab courses (6, 10–13), our approach to the course offers a learning experience that ask the students to suggest modifications and be involved in the greening of the course and individual experiments. These modifications are then evaluated and researched by undergraduate students in the research lab. If these improvements are greener than the current experimental procedure, the experiment is modified and the students the following year use the modified procedure. As a result of these experiences, students are challenged to apply their knowledge, and in so doing, feel a sense of accomplishment and involvement far beyond what a typical lab provides.

Figure 1. Feedback mechanism to involve students in the greening process.

Experiments Solventless Aldol Condensation The first experiment of the organic chemistry I laboratory is a solventless aldol condensation (Figure 2) adapted from published experiments by Doxsee et al. (14) and Thompson (15). The experiment is used to introduce the concepts of solubility, recrystallization, filtration, melting point, and mixed melting point. Additionally, this experiment introduces the Twelve Principles of Green Chemistry (9). The experiment exhibits three green chemistry principles: atom economy, waste reduction via a solventless reaction, and catalysis. The experimental procedure is very green and we have not significantly modified the experimental procedure. Over the years, several students recommended a 58 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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multitude of suggestions for reducing our water usage during filtrations for this and subsequent labs in our course. Recently, we purchased two recirculating water aspirator systems to reduce our water usage in the organic laboratories.

Figure 2. Solventless aldol condensation.

Acid-Base Extraction The second experiment is a modified version of a traditional three component acid-base extraction (16). The students separate and purify 9-fluorenone, benzoic acid, and ethyl 4-aminobenzoate from a solid mixture containing the components (Figure 3). Diethyl ether is used as the extraction solvent instead of methylene chloride. The students are exposed to acid/base chemistry, liquid-liquid extraction, solubility, recrystallization, melting point, and mixed solvent recrystallization. The experiment highlights two green chemistry principles: safer solvents and safer organic components. In addition to using a less hazardous extraction solvent, the original procedure used p-dibromobenzene as the neutral component in the mixture. The p-dibromobenzene is more hazardous than 9-fluorenone if inhaled.

Figure 3. Components of mixture in acid-base extraction. 59 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Biosynthesis of Ethanol The third experiment is an adapted distillation experiment (17, 18). The experiment involves fermentation of molasses using Baker’s yeast followed by simple and fraction distillations to purify the ethanol product. The students learn simple distillation, fractional distillation, and gas chromatography. The experiment highlights three green chemistry principles: benign reagents, renewable feedstocks, and atom economy. Additionally, the ethanol can be used for later experiments.

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Friedel-Crafts Acylation

Figure 4. Friedel-Crafts acylation of ferrocene.

The fourth experiment of the semester is a Friedel-Crafts Acylation of ferrocene (Figure 4) adapted from Mohrig (19). The experiment was adapted to include small-scale column chromatography. The students learn column chromatography, thin-layer chromatography, melting point, and IR spectroscopy. The experiment highlights four green chemistry principles: atom economy, greener reagents, catalysis, and energy efficiency. This experiment can also be performed using recrystallization as the purification technique (18) to reduce waste from the chromatography solvents. However, the experiment requires an increase in scale (1.5g vs 200mg). We chose to use column chromatography so that the students are introduced to column and thin-layer chromatography using colored materials. As the students analyze the greenness of the first three experiments, they become more comfortable with the analysis and their suggestions for experiment modification start to improve around this point in the semester. Therefore, the fourth experiment provides an excellent example of how the students were involved in further greening of our initial experiment. Over the years, several students suggested the use of microwave heat rather than thermal heating. Initially, we were reluctant to incorporate the change into the laboratory because Widener does not own a reaction-grade microwave system. However, after learning of several successful experiments utilizing a household microwave, we tested the use of a household microwave as the heating source for the reaction. For the last six years, we have been able to safely perform the reaction in a 1000W household microwave with short 10-second heating cycles. The reaction typically requires three heating cycles. This change reduces the heating time from 30 minutes to 30 seconds. 60 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Spearmint Oil Separation

Figure 5. Components of spearmint oil mixture separated by column chromatography.

The fifth experiment was adapted from an experiment by Davies and Johnson (20). The experiment involves the separation of the colorless components of spearmint oil (Figure 5) via column chromatography. Since the components are colorless, the students are exposed to the monitoring of a column by thin-layer chromatography. Additionally, the students learn to use IR spectroscopy and TLC to determine the effectiveness of a column separation. The experiment exemplifies the use of greener solvents, but also provides an example of a greener experiment that needs further improvement. Our experiment uses a larger column in order to increase the yield of each component. The use of a larger column increases the amount of solvent and adsorbent thus generating more waste than the Davies’ procedure. The students suggested the replacement of ethyl acetate with 2-methyltetrahydrofuran as the polar component in the eluent. This change was made and a 5% 2-methyltetrahydrofuran in hexane eluent resulted in better separation than the original 5% ethyl acetate in hexane eluent. Unfortunately, 95% of the eluent remains hexane.

Synthesis As a capstone experiment for the organic chemistry I laboratory, we developed a three step inquiry-based, green synthesis. While there have been numerous inquiry-based experiments published (21–27), it is difficult to find multi-step green syntheses for the organic laboratory (28, 29). Since synthesis is a fundamental part of organic chemistry, we thought it was necessary to develop a multi-step green synthesis. This first semester capstone experiment requires the students to search the literature and find methods for performing a series of organic reactions. The student-researched methods are then analyzed for greenness as a class exercise before the experiments are performed, and the class chooses the best method for each reaction.

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Figure 6. General reaction scheme for the synthesis of 1,2-dibromo-1phenylpropane. During the course of this experiment, students are required to search organic textbooks, the Journal of Chemical Education, and the ACS website for procedures that accomplish each step of the synthesis (Figure 6). Only after the students have provided a procedure from the literature are they shown the default procedure developed for each reaction. When the students bring in their suggested procedures, the class reviews the cost effectiveness, safety, and greenness of each proposed method using the twelve principles of green chemistry and several metrics (percent yield, atom economy, E-factor, effective mass yield) as guides. By highlighting these different factors, the professor emphasizes the overall effectiveness of green methodologies and the students learn to analytically review procedures for a synthesis. If a student proposes a greener method that has not been previously investigated, the materials are ordered so that the student can perform their procedure the following week.

Experimental Details The instructor should view these experimental designs with flexibility. In order for this synthetic sequence to be effective, students need to be given the opportunity to experiment and research alternative methods for carrying out each step. It is strongly recommended that the laboratory have one rotary evaporator for every eight students. Each step should take the students no more than a three-hour lab period. Ideally, the students will obtain high yields so that several methods of characterization are possible. In our laboratory, students characterize the products by boiling point, melting point, and IR. By the end of the first semester organic laboratory, most students do not have a strong comprehension of IR. However, the spectra obtained during this experiment show very clear differences and allow the students to easily verify if their procedure is successful. 1H-NMR and 13C-NMR analysis could easily be introduced, if desired. 62 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Reduction

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The students find a number of suitable methods for the reduction of a ketone to a secondary alcohol. These methods include the use of carrots (30) and Baker’s yeast (31) as natural sources of reductases (Figures 7 and 8). These examples provide an excellent opportunity to discuss the advantages and disadvantages of enzymatic catalysis in synthesis. We have allowed students to try these two methods to demonstrate that the reductases are extremely selective and only catalyze the reduction of molecules with similar structural features.

Figure 7. Carrot-based enzymatic reduction of benzofuran-2-yl methyl ketone.

Figure 8. Baker’s yeast enzymatic reduction of ethyl acetoacetate.

The students also occasionally find a reduction method reported by O’Brien and Wicht using poly(methylhydro)siloxane (Figure 9) as the reducing agent (32). We have found this reagent effective for this reduction scheme in the research laboratory, but less effective in the teaching laboratory. Instead, we have opted for a revised sodium borohydride reduction (Figure 10) of the ketone (31). While the atom economy is much lower for this reaction compared to the enzymatic reductions, the percent yield is much greater than the O’Brien and Wicht procedure. This procedure also allows for the reuse of the ethanol produced in the fermentation of molasses experiment earlier in the semester, if desired. Additionally, the students suggested a couple of modifications to the experiment over the years. The students suggested using diethyl ether instead of methylene chloride as an extraction solvent to purify the reduction product. Therefore, they were allowed to attempt the work-up using diethyl ether. Overall, product yield shows that this solvent was not as effective as methylene chloride. In a later iteration of the course, a student suggested the use of cyclopentyl methyl ether (CPME) to replace methylene chloride as the extraction solvent. The students performed the experiment using CPME as the extraction solvent and found that the solvent produced similar yields and purity to methylene chloride extractions. While CPME is a greener solvent, there is an additional energy cost to remove CPME after extraction compared to methylene chloride. 63 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 9. Polymethylhydrosiloxane (PMHS) reduction of citronellal with catalytic fluoride provided tetrabutyl ammonium fluoride (TBAF) in tetrahydrofuran (THF).

Figure 10. Results of various reduction methods for propiophenone.

The reduction of propiophenone with sodium borohydride takes approximately fifteen minutes. However, the work up is time consuming. Neutralization of the sodium borohydride with hydrochloric acid is difficult and generates a fair amount of waste. This step produces copious amounts of hydrogen gas and the contents of the flask can easily overflow if the addition is not done slowly. Despite the lengthy work-up time, students can complete this step of the synthesis in a three-hour lab period. The percent yields obtained for this step average 80%. During the development of the synthesis, the identity of the product was verified by IR, refractive index, boiling point, and 1H-NMR. Students can see the difference between the alcohol product and the ketone by the disappearance of the carbonyl peak at 1680 cm-1 and the appearance of the hydroxyl peak at 3300 cm-1.

64 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Elimination Once students have obtained 1-phenyl-1-propanol, their next task is to eliminate the alcohol and form a double bond, creating trans-β-methylstyrene (Figure 11). The students typically find four procedures for this transformation. The most common method is the use of sulfuric acid (33, 34) as an aqueous catalyst for the dehydration reaction (Figure 11b). This procedure is the most familiar to the students since it is the reagent found in most organic chemistry textbooks. Many students also find a procedure using phosphoric acid (34–36) as the catalyst (Figure 11a) and typically have a sense that it is the greener reagent since it appears in Doxsee and Hutchison’s laboratory textbook (6). Occasionally, the students find the sulfuric/phosphoric acid mixture procedure (Figure 11c) in Pavia (37). The discussion of these three options typically revolves around a comparison of atom economy, percent yield, and reagent hazards. The atom economies are similar with the phosphoric acid version having a slightly higher atom economy. The percent yields of each method are also similar with the sulfuric acid version producing a slightly higher yield. With those two points in mind, there is no reason to choose the procedure that uses a mixture of the two acids. Thus, the choice is made largely based on a comparison of the acid hazards. Occasionally, a student will find Doyle and Plummer’s procedure that uses Nafion NR50 (Figure 11d), a recyclable solid phase acid catalyst (38). The recycling process adds substantial waste to the reaction; therefore, we opted to use the phosphoric acid procedure.

Figure 11. Elimination reagents. We use a modified version of the phosphoric acid catalyzed (Figure 11a) dehydration driven by distillation published by Doxsee and Hutchison (35). Our procedure has been modified in two ways to improve energy efficiency and reduce waste. Instead of using fractional distillation to drive and purify the alkene from the alcohol, we use simple distillation. This change reduces our distillation time by about one hour thus reducing our energy usage. Additionally, the simple distillation results in water being distilled with the alkene product. Since we have distilled a product/water mixture, there is no need to add additional water for the work-up used by Doxsee and Hutchison, thus we reduce our waste by about 5 mL per student. The product is sufficiently pure (determined by 1H-NMR) to carry out the final reaction, so we also eliminated the simple distillation used by Doxsee and Hutchison. The percent yield of trans-β-methylstyrene is around 80%. The 65 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

IR spectrum after this step shows the disappearance of the alcohol peak at 3300 cm-1 and a strengthening of double bond character in the 3080 cm-1 to 2850 cm-1 region.

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Bromination The final step of the synthesis calls for adding bromine across the alkene. The students typically find three procedures to accomplish this transformation (Figure 12). A nice green analysis of these bromination procedures was published by McKenzie et al. (39). McKenzie analyzes the atom economies, experimental atom economies, E-factor, effective mass yields, and hazards of the bromine in methylene chloride (Figure 12a), pyridinium tribromide in ethanol (Figure 12b), and hydrobromic acid with hydrogen peroxide in ethanol (Figure 12c) methods. Our class discussions also focus on these metrics, and we concluded, as does McKenzie et al. that the hydrobromic acid with hydrogen peroxide method is the greenest alkene bromination method.

Figure 12. Bromination reagents.

We developed a bromination procedure for trans-β-methylstyrene that was adapted from the McKenzie et al. procedure (Figure 12c). The procedure uses a combination of 49% hydrobromic acid in water and 30% hydrogen peroxide in water to release bromine into the ethanol solvent system. Students can clearly monitor the progress of the bromination through the solution’s color changes. Once the product is brominated, the excess acid is neutralized using sodium bicarbonate. The original procedure uses filtration to remove the product because the product is insoluble in ethanol and water. However, 1,2-dibromo-1-phenylpropane is soluble in both ethanol and water. Thus, we developed an extraction procedure using ethyl acetate and water to purify the product. The resulting oil can then be characterized. The IR spectra for this step can be distinguished by the weakening of double bond character in the trans-β-methylstyrene IR from the region of 3080 cm-1 to 2850 cm-1 and the appearance of a carbon-bromine peak at 575 cm-1. 66 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Conclusion The organic chemistry I laboratory described here provides a contemporary green organic chemistry laboratory experience. The lab gradually introduces students to the principles and metrics of green chemistry while exploring the technical skills of purification and characterization typically found in an organic chemistry I laboratory course. The laboratory design provides a framework for students to contribute to the development and redesign of green chemistry experiments. This approach has sparked interest in green chemistry research among chemistry, chemical engineering, and biology majors at our institution. The capstone synthesis experiment provides students with a chance to explore green methods for three reactions commonly discussed in organic chemistry lecture courses. Under the guidance of their professor, students learn to apply green chemistry principles by picking appropriate, safe, and green reagents for the synthetic steps.

Acknowledgments We would like to thank the following Biology and Chemistry faculty members from Widener University for their input on the topics and techniques that are important for their respective students to obtain from the organic chemistry laboratory: David Coughlin, Kelly Davis, Louise Liable-Sands, Scott Van Bramer, and Fran Weaver. Special thanks to Chris Annunziato, Kevin Blattner, Brandon Driscoll, Wayne Karnas, Andrew Montgomery, Alysha Moretti, Cassandra Pelton, and Michael Polen for their help testing and revising several experiments. Brandon Driscoll, Kristen Anderson, and Irina Knyazeva of the Chemistry Stockroom were also essential in the development and testing of several of the labs by helping us find chemicals, glassware, yeast, etc. Another special thanks to Irina Kynazeva and Krishna Bhat for their many suggestions and revisions to the experiments. We thank the Widener University Faculty Development Grant program and the Widener University Arts and Sciences Student Summer Research Housing Fellowship for funding.

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Williamson, K. L.; Minard, R. D.; Masters, K. M. Macroscale and Microscale Organic Experiments, 5th ed.; Houghton Mifflin Company: New York, 2007. Doxsee, K. M.; Hutchison, J. E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments; Thomson Brooks/Cole, 2004. Greener Approaches to Undergraduate Chemistry Experiments; Kirchhoff, M.; Ryan, M. A., Eds.; American Chemical Soceity: Washington, DC, 2002. Green Organic Chemistry in Lecture and Laboratory; Dicks, A. P., Ed.; CRC Press: New York, 2012. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. Goodwin, T. E. In Green Chemistry Education: Changing the Course of Chemistry; Anastas, P. T.; Levy, I. J., Parent, K. E., Eds.; ACS Symposium Series 1011; American Chemical Society: Washington, D.C., 2009; pp 37−53. Haack, J. A.; Hutchison, J. E.; Kirchhoff, M. M.; Levy, I. J. J. Chem. Educ. 2005, 82, 974–976. Goodwin, T. E. J. Chem. Educ. 2004, 81, 1187–1190. Kerr, M. E.; Brown, D. M. In Green Chemistry Education: Changing the Course of Chemistry; Anastas, P. T.; Levy, I. J., Parent, K. E., Eds.; ACS Symposium Series 1011; American Chemical Society: Washington, D.C., 2009; pp 19−36. Doxsee, K. M.; Hutchison, J. E. In Green Organic Chemistry - Strategies, Tools, and Laboratory Experiments; Thompson Brooks/Cole, 2004; pp 115−119. Thompson, J. E. Melting Point Study of a Solventless Reaction. http://greenchem.uoregon.edu/Pages/Overview.php?ID=143 (accessed November 1, 2008). Patterson, J.: Acid-Base Extraction. 2000. Thompson, J. E. Biosynthesis of Ethanol from Molasses. http:// greenchem.uoregon.edu/Pages/Overview.php?ID=86 (accessed July 5, 2007). Doxsee, K. M.; Hutchison, J. E. In Green Organic Chemistry - Strategies, Tools, and Laboratory Experiments; Thompson Brooks/Cole, 2004; pp 225−230. Mohrig, J. R.; Hammond, C. N.; Schatz, P. F.; Morrill, T. C. In Modern Projects and Experiments in Organic Chemistry: Miniscale and Standard Taper Microscale; 2nd ed.; W. H. Freeman and Company: New York, 2003; pp 171-176. Davies, D. R.; Johnson, T. M. J. Chem. Educ. 2007, 84, 318–320. Amburgey-Peters, J. C.; Haynes, L. W. J. Chem. Educ. 2005, 82, 1051–1052. Ball, D. B. J. Chem. Educ. 2006, 83, 101–105. Baru, A. R.; Mohan, R. S. J. Chem. Educ. 2005, 82, 1674–1675. Crouch, R. D.; Richardson, A.; Howard, J. L.; Harker, R. L.; Barker, K. H. J. Chem. Educ. 2007, 84, 475–476. Evans, T. A. J. Chem. Educ. 2006, 83, 1062–1064. Gaddis, B. A.; Schoffstall, A. M. J. Chem. Educ. 2007, 84, 848–851. 68 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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27. Mohrig, J. R.; Hammond, C. N.; Colby, D. A. J. Chem. Educ. 2007, 84, 992–998. 28. Fringuelli, F.; Piermatti, O.; Pizzo, F. J. Chem. Educ. 2004, 81, 874–876. 29. Cave, G. W. V.; Raston, C. L. J. Chem. Educ. 2005, 82, 468–469. 30. RavÌa, S.; Gamenara, D.; Schapiro, V.; Bellomo, A.; Adum, J.; Seoane, G.; Gonzalez, D. J. Chem. Educ. 2006, 83, 1049–1051. 31. Pohl, N.; Clague, A.; Schwarz, K. J. Chem. Educ. 2002, 79, 727–728. 32. O’Brien, K. E.; Wicht, D. K. Green Chem. Lett. Rev. 2008, 1, 149–154. 33. Mayo, D. W.; Pike, R. M.; Trumper, P. K. In Microscale Organic Laboratory: with multistep and multiscale syntheses, 4th ed.; John Wiley & Sons, Inc.: New York, 2000; pp 184−191. 34. Mohrig, J. R.; Hammond, C. N.; Schatz, P. F.; Morrill, T. C. In Modern Projects and Experiments in Organic Chemistry: Miniscale and Standard Taper Microscale, 2nd ed.; W. H. Freeman and Company: New York, 2003; pp 83−92. 35. Doxsee, K. M.; Hutchison, J. E. In Green Organic Chemistry - Strategies, Tools, and Laboratory Experiments; Thompson Brooks/Cole, 2004; pp 129134. 36. Lehman, J. W. In Microscale Operational Organic Chemistry: A ProblemSolving Approch to the Laboratory Course; Pearson/Prentice-Hall: Upper Saddle River, NJ, 2004; pp 162−171. 37. Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G. In Introduction to Organic Laboratory Techniques: A Microscale Approach, 4th ed.; Thomson Brooks/Cole, 2007; p 207. 38. Doyle, M. P.; Plummer, B. F. J. Chem. Educ. 1993, 70, 493–495. 39. McKenzie, L. C.; Huffman, L. M.; Hutchison, J. E. J. Chem. Educ. 2005, 82, 306–310.

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Chapter 5

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Synthesis and Characterization of Biodiesel from Used Cooking Oil: A Problem-Based Green Chemistry Laboratory Experiment E. M. Gross,*,1 S. H. Williams,2,3 E. Williams,3 D. A. Dobberpuhl,1 and J. Fujita1 1Department

of Chemistry, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, United States 2Energy Technology Program, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, United States 3Omaha Biofuels Cooperative, Omaha, Nebraska 68117, United States *E-mail: [email protected]

Students in a Green Chemistry laboratory course learned about clean energy and commercial-scale production of biodiesel from members of the Omaha Biofuels Cooperative. Students were presented with a “problem” to investigate several of the variables involved in synthesizing biodiesel from used cooking oil. Students were tasked to study a few of these variables, characterize their reaction products and report their findings. In this experiment, students investigated the following variables: oil identity, alcohol type, and catalyst amount and type. Students used both common biodiesel “field tests” and instrumental methods to characterize their biodiesel. Students learned how to communicate scientific results to both scientists and non-scientists via oral presentations, scientific reports and newspaper articles.

© 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Introduction An inquiry-based experiment for the synthesis of biodiesel from waste vegetable oil was developed for students at Creighton University. This laboratory experiment was part of a two credit hour Green Chemistry laboratory course. Students in the course had a one hour per week recitation along with three hours of laboratory time. The experiment was designed to be problem-based, with students performing considerable guided literature searching and experiment design. The experiment utilized five lab meetings – two for synthesis and two for characterization, and one day for presentations. There are a variety of biodiesel synthesis and characterization experiments in the chemical education literature. Students either synthesize biodiesel from vegetable oil and analyze their product (1–9) or perform an analysis of commercial biodiesel and biodiesel blends (10, 11). In designing the experiment described here, several of these experiments were consulted and many of the innovative ideas combined to design a project-based laboratory experiment. Students not only learned about clean energy in conducting these experiments, but also employed some of the twelve principles of green chemistry. Green chemistry considers human beings and the environment when designing a chemical reaction, experiment, or process. The ultimate goal is pollution prevention. There are twelve guiding principles of green chemistry. The two utilized by this experiment were Use catalysis and Use renewable feedstocks. The learning objectives for this experiment were for students to • • • • • • •

Discover how specific principles of green chemistry are utilized in a chemical synthesis. Obtain in-depth knowledge about a clean energy method. Successfully search the chemical literature. Compare “science” found on websites to science found in the chemical literature. Design and perform experiments in a thoughtful and efficient manner. Utilize “field” and instrumental biodiesel characterization methods. Effectively communicate scientific data and results to scientific and nonscientific audiences.

Laboratory Methods and Weekly Objectives On the first day of the unit, students were provided with an introduction to renewable energy and specifically biodiesel. A member of the Omaha Biofuels Cooperative (OBC), a local, community-scale, not-for-profit biofuels organization, provided demonstrations of transesterification reactions used for producing biodiesel from straight vegetable oil, and also from used cooking oil, and asked questions to stimulate thinking about the chemistry of this process. Students were given an assignment asking them to search the literature on the production of biodiesel from cooking oil and also to search the web for “recipes” commonly used by biodiesel “homebrewers”. Students were asked to compare 72 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

these two processes and to design a procedure for producing biodiesel from cooking oil. Additionally, they were asked to choose a variable in the reaction to investigate. During the first week of lab, students prepared biodiesel from neat or straight vegetable oil (SVO). The second week, they prepared biodiesel from used cooking oil, also called waste vegetable oil (WVO). Students worked in pairs and were required to determine the differences between these procedures and plan accordingly. Weeks three and four were devoted to characterization and week five for presentations.

Publication Date (Web): November 16, 2016 | doi: 10.1021/bk-2016-1233.ch005

Week 1: Synthesis from Straight Vegetable Oil A member of OBC provided a demonstration of the transesterification production of biodiesel from new vegetable oil, using an equipment setup developed by OBC specifically for such demo purposes. Students were then given a memo similar to the one used in reference 1. The memo was from OBC and provided a hypothetical scenario where OBC and Creighton University were partnering to develop an alternative fuel for the campus shuttle system. It discussed the environmental motivation for implementing alternative fuels into automobiles. The memo asked for the green chemistry students’ assistance. It asked them to first prepare biodiesel from neat vegetable oil, and then from waste vegetable oil that OBC had collected from local restaurants and processed for biofuel production. Students were also asked to investigate a variable in the reaction. The chemical reaction in Figure 1 was provided to students. The reaction is a transesterification of the triglycerides that make up cooking oil. The reaction products are glycerol and biodiesel, which is comprised of fatty acid methyl esters (FAMEs). In addition to background into the chemistry, students were given a worksheet similar to that reported in reference 1 to aid setting up calculations (Table 1). Some sample student numbers are shown in the table. Students were expected to arrive to lab with the table completed.

Figure 1. Transesterification of triglycerides in cooking oil to produce biodiesel. In this example, KOH or NaOH is used as the catalyst. 73 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Table 1. Synthesis of Biodiesel from Straight Vegetable Oil Method

mL of oil

Total grams of NaOH catalyst per liter of oila

mL of alcoholb

grams of catalyst for your reaction

Web reference (13)

100

5.0 g NaOH (0.50 % w/w)

20

0.50

Web reference (12)

100

3.5 g NaOH (0.38 % w/w)

20

0.35

a

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If KOH was used as catalyst; the mass was adjusted higher by a factor of 1.4. ~20% v/v methanol:oil, providing ~6:1 mol ratio to drive reaction forward.

b

Typically

Students located biodiesel synthetic methods both on the web (12, 13) and in the literature (3, 5, 14–19). They found the stepwise instructions in the web resources straightforward for designing the experimental steps. However, the web resources lacked in the chemical detail students desired. For example, the stoichiometry was not explained and the websites did not always use units in the calculations, as students were accustomed to doing. The literature articles were complementary in that they explained the stoichiometry and used scientific descriptions and units. With the combination of these sources, the students designed procedures as shown in Table 1 and as described in the next section. From reading the literature articles, especially the review articles (18, 19), students appreciated that optimization of these reactions is still an active area in scientific research. Reading these articles guided them in choosing variables to test, such as catalyst type and amount (w/w%).

Table 2. Chemical and Physical Data for Reagents and Products

a

Reagent

MW (g/mol)

Density (g/mL)

BP /flash (°C)

Vegetable oil

~882a

~0.91-0.92c

~200a

Methanol

32

0.791

64.7 / 11.1

Ethanol

46

0.789

78 / 12

NaOH

40

NA

NA

KOH

56

NA

NA

Mixed methyl esters product

~250-290b

0.86-0.90d

331/70.6b

glycerol byproduct

92

1.26

290

reference (18)

b

reference (17)

c

reference (20)

d

reference (19)

74 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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During their literature searching and preparation, students tabulated the chemical and physical data as shown in Table 2 (18–20). Literature references are shown for vegetable oil and biodiesel physical properties. Students found information for the more common chemicals at typical sources (e.g. Sigma-Aldrich, the CRC Handbook, or ChemSpider). This information aided in their preparation for the synthesis. Each student group determined a procedure for producing biodiesel from cooking oil. They were required to submit a list of required materials to the instructor one day prior to lab. At the beginning of lab, the class reviewed and discussed the procedures. The general steps that the students should determine for the synthesis are listed next.

Synthesis of Biodiesel from SVO 1. 2.

3. 4. 5.

6. 7. 8.

Heat oil to ~110 °C for 15 minutes to remove excess water. Water can react to produce unwanted soap. Cool to ~50 °C. Dissolve catalyst in alcohol (e.g. NaOH in methanol) as shown in Table 1 to produce methoxide. (Note that NaOH and sodium methoxide are highly caustic.) Carefully and slowly add methoxide to the vegetable oil and heat at ~50 °C for around 1 hour. Cool to room temperature, allowing layers to separate. Allow the layers to separate overnight in either a separatory funnel or graduated cylinder. This glassware facilitates viewing and separating of the layers. Remove the top (biodiesel) layer from the bottom (glycerol) layer. In a separatory funnel, wash the biodiesel layer with ~20 mL deionized water. Remove the water phase and store the washed biodiesel layer for testing.

Week 2: Synthesis of Biodiesel from Waste Vegetable Oil After successful synthesis of biodiesel from SVO, students were given an assignment (Figure 2) for preparing biodiesel from the WVO. The feedstock used cooking oil was provided by OBC, and had been processed to remove contamination of food particles, water, heavy waxes and polymerized oil. The key changes students noticed regarding the preparation of biodiesel from WVO was that using cooking oil for frying results in hydrolysis of triglyceride oils into di- and mono-glycerides, and releases free fatty acids (FFAs). As a result, the WVO was initially titrated to determine the FFA content. Students learned that the presence of FFAs could neutralize the base catalyst, requiring additional catalyst (NaOH or KOH) to neutralize the FFAs. They also discovered that the neutralization results in soap contamination in the reacted biodiesel. An example table for performing these calculations is also provided (Figure 2). Note that this table is for NaOH catalyst. If students use KOH catalyst, the mass should be increased by a factor of 1.4. 75 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 2. Week 2 Assignment - Literature Research and Lab Preparation. Note that a sample “answer” has been added to the table in question 1.

Synthesis of Biodiesel from WVO 1.

Free fatty acid titration: Dissolve 1.0 mL of WVO in 10.0 mL isopropyl alcohol. Titrate with 0.10% w/v NaOH to a pink phenolphthalein endpoint. (Note that students delivered the titrant from a 5 mL graduated syringe.) Enter titration number (mL of titrant) into table. Add this number, representing required additional catalyst, to the g/mL of 76 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

2. 9. 3.

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4. 5.

6. 7. 8.

stoichiometrically required catalyst. This is the total amount of catalyst to measure. Heat oil to ~110 °C for 15 minutes to remove excess water. Water can react to produce unwanted soap. Cool to ~50 °C. Dissolve catalyst (Step 1) in alcohol (e.g. NaOH in methanol) to produce methoxide. (Note that NaOH and sodium methoxide are highly caustic.) Carefully and slowly add methoxide to the WVO and heat at ~50 °C for around 1 hour. Cool to room temperature, allowing layers to separate. Allow the layers to separate overnight in either a separatory funnel or graduated cylinder. This glassware facilitates viewing and separating of the layers. Remove the top (biodiesel) layer from the bottom (glycerol) layer. Wash the biodiesel layer with ~20 mL deionized water. Remove and store the washed biodiesel layer for testing.

Weeks 3-4: Characterization Students were asked in the previous assignment to consider how they will characterize their biodiesel. They were requested to determine two “field tests” and two “laboratory tests” to characterize their biodiesel. Students performed literature and Internet searches to determine the various methods researchers (21–23) and home brewers (12, 13) use to characterize biodiesel. Students were reminded of the various instruments available to them. These instruments included gas chromatography with a flame ionization detector (GC-FID), gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), 1H-NMR, and viscometry. Most of the students had taken an instrumental analysis course and were familiar with the techniques from the course or from research experience. Protocols for using the instruments were available in the laboratory. Students who were unfamiliar with a technique were shown how to use an instrument. Chromatographic methods were developed prior to the course so that lab time could be spent on biodiesel characterization and not method development. For example, if a group chose GC-MS, they were given the parameters and instructions for the analysis. Most of the students tried to perform as many of the tests and characterization methods as possible during the two weeks allotted for characterization. They were curious as to how their reactions turned out and how the variable they investigated affected the results. The field tests students performed included: a quick titration for soap content (13) and a 90/10 test for reaction completion (a modified version by OBC of the common homebrewing 3/27 Biodiesel Conversion Test) (13). The laboratory characterization methods utilized included GC-FID, GC-MS, FTIR, 1H-NMR, and viscometry, which was also accepted as a field test. The various analytical tests and the information students determined for their reactions are listed in Table 3. References are provided for the characterization techniques (FTIR, viscometry, and 1H-NMR) that other undergraduate experiments involving biodiesel synthesis from vegetable oil also utilized. In addition to these methods, similar undergraduate experiments have utilized Karl Fischer titration for 77 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

water content (4), glycerol by periodic titration (3), high-performance liquid chromatography (10), thin-layer chromatography (6), optical activity (7), and flame tests (2).

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Table 3. Methods Utilized for Characterization of Biodiesel

a

Test

Field or Laboratory

Information obtained

Soap

Field

Soap content, quality of fuel

90/10

Field

Reaction completion

GC-FID

Laboratory

Product (fatty acid methyl ester) characterization

GC-MS

Laboratory

Product (fatty acid methyl ester) characterization

Viscositya

Laboratory

Reactant & product comparison Compare product to ASTM standards

FTIRb

Laboratory

Reactant & product comparison Reaction completion

1H-NMRc

Laboratory

Reactant & product comparison Reaction completion

references (1, 6, 11)

b

references (1, 4, 6–8, 10)

c

references (1, 2, 10)

Soap Test Soap is an unwanted byproduct that can be produced from the reaction between free fatty acids in the oil, excess water and catalyst. Soap can be produced during the reaction if there is excess water in the oil or too much catalyst added. Students found the soap test procedure at the Utah Biodiesel website (13) and followed the procedure below. Students delivered the titrant from a 5 mL syringe and observed a color change from blue to yellow at the end point (Figure 3). 1. 2. 3. 4. 5. 6.

Dissolve 10.0 g of biodiesel product in 100 mL of isopropyl alcohol (99%). Add 3-5 drops of 0.04% w/w bromophenol blue indicator. Solution appears blue. Titrate sample with 0.010 M HCl until the yellow end point. Record the volume (mL) of HCl delivered. Perform a “blank” titration of the isopropyl alcohol alone, and use the result to correct the sample titration result as necessary, Multiply the value from step four by 304 (NaOH catalyst) or 320 (KOH catalyst) to calculate the soap content in ppm.

78 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 3. Photograph of a biodiesel-isopropanol solution with bromophenol blue indicator before (left) and at the end point (right) when titrated with 0.010 M HCl for a soap test.

90/10 Test The 90/10 test is a scaled up version of the 3/27 test for reaction completion (13). This test allows for visualization and semi-quantitation of unreacted vegetable oil. If no unreacted oil is present in the tube, the sample is said to “Pass” the test. This is a necessary, but not sufficient, indicator of biodiesel reaction completeness. 1.

2.

3.

4.

Add 10 mL of biodiesel product to the graduated 100 mL conical centrifuge tube, followed by 90 mL of methanol, up to the 100 mL graduation. Shake the tube vigorously and allow layers to settle. If unreacted vegetable oil triglycerides are present, the mixture should separate into two layers. The biodiesel-methanol layer is colorless and on top. The unreacted oil settles to the bottom and appears yellow. (Figure 4) If unreacted oil is not present in the sample, a homogenous solution of methanol and FAME biodiesel will be present, transparent with a light yellowish tint. The volume of unreacted oil is determined by reading the volume of oil at the bottom. For example, the volume of unreacted oil in Figure 4A is ~1 mL. Multiply the volume of unreacted oil in mL by 10 for an approximation of the percentage (%) of reaction incompleteness.

79 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Figure 4. Results of a 90/10 test for reaction completion for WVO starting material with 0.5 % NaOH (A) and 1.0% NaOH (B). The top layer is biodiesel dissolved in methanol. The bottom layer is unreacted waste vegetable oil.

FT-IR 1H-NMR and Viscometry Some students chose to characterize their reaction using FTIR. They used a Thermo Avatar 370 Fourier Transform Infrared Spectrometer. Other groups chose to test and compare the viscosity of their products and starting material. They used a Canon-Fenske 150 viscometer in a water bath at 23.2°C. One group used a 1H-NMR (Varian Inova 300 MHz NMR) to evaluate their reaction. As 1H-NMR (1, 2, 10) FTIR (1, 4, 6–8, 10) and viscometry (1, 6, 11) have been used and reported in numerous undergraduate biodiesel synthesis experiments, this discussion will primarily focus on the GC-FID and GC-MS analysis methods, along with the two home biodieseler field tests that students employed.

Gas Chromatography Gas chromatography with flame ionization (GC-FID) or mass spectrometry (GC-MS) detection are common methods for fatty acid methyl ester (FAME) analysis, but have not been reported in the chemical education literature for characterizing the FAMES in biodiesel produced from vegetable oil. GC-MS has been reported in the chemical education literature for experiments characterizing biodiesel blends (24) and to measure FAMES in egg yolks (25), demonstrating that GC method development and optimization is straightforward for the FAME analysis and can be implemented for undergraduate students.

80 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

GC-MS Many students used GC-MS to characterize their reaction product. The GCMS used was an Agilent 5973 gas chromatograph with a mass selective detector. The column employed was a HP-5MS (30 m length, 0.250 mm i.d., 5% phenyl 95% dimethylpolysiloxane, 0.25 µm thickness). The method settings are listed below. Samples were diluted by a factor of 10-20 with cyclohexane and injected (1 µL) onto the instrument.

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Oven settings: Initial temperature: 190°C Initial time: 5 min Rate: 2°C/min Final temperature: 220°C Final temp time: 5 min Inlet settings: Inlet temperature: 250°C Split ratio: 1:50 Flow: 1.20 mL/min Detector temperature: 280°C

GC-FID Students also had the opportunity to analyze a sample of biodiesel provided by OBC. Students ran the sample on both the GC-MS and GC-FID and compared the results. This also allowed them to compare their results to biodiesel produced by “experts”. An Agilent 6850 gas chromatograph with a flame ionization detector was used to identify the biodiesel reaction product. The column and method parameters are reported here and student results are reported in the next section. The column was a Zebron ZB-Wax plus (30 m length, 0.53 mm i.d. (poly(ethyleneglycol) stationary phase, 1.0 µm thickness). To identify their peaks, students compared their peak retention times to an AOCS gas-liquid chromatography (GLC) reference mixture standard (#17A) from NuCheck Prep. The method settings are listed below. Samples were diluted by a factor of 10 with cyclohexane and injected (1.0 µL) onto the instrument. Oven settings: Initial temperature: 200°C Initial time: 6.0 min Rate: 10°C/min Final temperature: 230°C Final temp time: 5.0 min 81 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Inlet settings: Inlet temperature: 230°C Split ratio: 1:50 Flow: 1.20 mL/min Detector temperature: 230°C

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Results and Discussion All students compared their results as a function of using straight and waste vegetable oil as the feedstock. Each pair also chose a variable to examine in each reaction. Therefore, each group ended up performing four reactions. Each group then characterized their biodiesel products with a minimum of two field tests and two instrumental methods. Lab recitation time was used to discuss the results of the students’ literature searching for analytical characterization methods. The class discussed the various characterization techniques and the types of chemical or physical information that could be obtained. This activity has been taught in two iterations, allowing pairs of students to design their own inquiry and characterization. The reaction variables and characterization methods used by each pair of students are listed in Table 4. One pair did not have a successful reaction on the first day, so did not test a variable. However, they were able to prepare biodiesel from straight (SVO) and waste vegetable oil (WVO), and analyze their biodiesel and a sample provided by OBC. A sampling of student results for each test will be discussed.

Table 4. Reaction Variables Investigated and Characterization Methods Used by Students Group

Variable Investigated

Characterization

Variable 1

Variable 2

1

Oil type: corn vs sunflower (SVO)

Catalyst amount: (SVO & WVO)

Soap, 90/10 GC-MS FTIR

2

Catalyst type: KOH vs NaOH (canola SVO)

Catalyst type: acid vs base (WVO only)

90/10 Viscosity GC-MS GC-FID

3

SVO vs. WVO as feedstock (this group had some difficulties on the first day)

Soap, 90/10 GC-MS GC-FID Continued on next page.

82 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Table 4. (Continued). Reaction Variables Investigated and Characterization Methods Used by Students Group

Variable Investigated

Characterization

Variable 1

Variable 2

4

Alcohol identity: methanol vs. ethanola (NaOH catalyst)

SVO vs. WVO as feedstock

90/10, Viscosity FTIR 1H-NMR

5

Alcohol identity: methanol vs. ethanola (NaOH catalyst)

SVO vs. WVO as feedstock

Soap, 90/10 Viscosity GC-FID

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a

Note that using ethanol will produce fatty acid ethyl esters rather than fatty acid methyl esters.

Soap Test For base-catalyzed reactions, ASTM limits for soap testing in biodiesel are extrapolated from ASTM D4951 (which is for Na and K) to be 41 ppm (NaOH) and 66 ppm (KOH) (13). Failure of this test implies that the biodiesel was not suitably washed and residual soap was left in the fuel. Some students performed the soap test before and after the water wash step, to test the effectiveness of the wash. The results from Group 5’s methanol reaction (Table 5) show that the wash step removed soap, but that further washing would be required to lower soap levels below the 41 ppm limit. This group also performed the reaction with ethanol as a reactant. The soap levels were much higher, at the parts-per-thousand level. Other students’ post-wash results ranged from low ppm levels to ~150 ppm. Most students concluded that they could produce and wash biodiesel to contain acceptable levels of soap.

Table 5. Example of Student Soap Test Results Before and After Wash Step

a

Feedstock

ASTM Limit (Na)a

Unwashed

Washed

% Reduction

SVO Sunflower Oil

41 ppm

274 ppm

61 ppm

78%

WVO

41 ppm

669 ppm

137 ppm

80%

reference (13)

90/10 Test The 90/10 test quickly provides a measure of reaction completion by estimating the volume of unreacted oil in a biodiesel sample. Group 1 investigated two different NaOH catalyst amounts and performed the 90/10 test for reaction completion (Figure 4). The photograph shows that much more (~1.0 mL versus ~0.05 mL) unreacted WVO is present for the lower catalyst concentration. 83 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

GC-FID

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Students were provided with a sample of biodiesel from OBC. They were able to visually compare their sample (color, clarity) to this sample, but could also run some of the characterization tests on it and compare the results of the OBC sample to those of their own biodiesel sample. A GLC reference mixture was analyzed to match the retention times to specific FAMES in the sample. The results (Table 6) were semi-quantitative and the relative amount of each FAME was estimated from the peak area percent (PA%).

Table 6. GC-FID of Biodiesel Sample from OBC and NuCheck FAME Standard NuCheck

OBC Biodiesel sample

FAME ID

tr (min)a

PA%b

tr (min)

PA%

methyl myristate C14:0

1.78

1.02 (1.0)c

no peak

N/A

methyl palmitate C16:0

2.64

4.11 (4.0)

2.68

11.16

methyl stearate C18:0

4.22

3.09 (3.0)

4.26

4.22

methyl oleate C18:1

4.62

44.37 (45.0)

4.68

24.71

methyl linoleate C18:2

5.14

15.12 (15.0)

5.43

50.21

methyl alpha linolenate C18:3

6.01

3.12 (3.0)

6.15

7.03

methyl arachidate C20:0

7.00

3.08 (3.0)

no peak

N/A

methyl behenate C22:0

9.89

3.04 (3.0)

9.84

0.40

methyl erucate C22:1

10.33

19.80 (20.0)

10.22

0.16

methyl lignocerate C24:0

13.17

3.05 (3.0)

13.08

0.08

a tr = retention time; the standard.

b

PA% = peak area percent;

c

values in ( ) are the % by weight in

Group 5 chose sunflower oil for their SVO biodiesel synthesis. Upon completing the GC-FID FAME analysis, they looked up the literature values for triglycerides in sunflower oil (26). The students determined the relative amounts of fatty acid methyl and ethyl esters produced. Using peak area percents as an approximate abundance of fatty acids, their results agree within reason to the expected values (Table 7). This group also used GC-FID to characterize the 84 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

FAME components of their biodiesel sample produced from WVO (Table 8). The FAMEs were primarily derived from C16 and C18 fatty acids in the triglycerides in cooking oil.

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Table 7. GC-FID Analysis of Biodiesel Produced from Sunflower Oil

a

Identity

tr (min) (MeOH)

PA % (MeOH)

tr (min) (EtOH)

PA % (EtOH)

Expected rangea

methyl palmitate C16:0

2.63

6.54

2.81

5.79

4 – 9%

methyl stearate C18:0

4.17

5.00

4.50

5.93

1 – 7%

methyl oleate C18:1

4.48

28.16

4.86

27.08

14 - 40%

methyl linoleate C18:2

5.10

47.46

5.59

56.09

48 -74%

reference (26)

Table 8. GC-FID Analysis of Biodiesel Produced from Waste Vegetable Oil Identity

tr (min) (MeOH)

PA % (MeOH)

tr (min) (EtOH)

PA % (EtOH)

methyl palmitate C16:0

2.63

9.76

2.83

10.31

methyl stearate C18:0

4.18

3.81

4.52

4.08

methyl oleate C18:1

4.52

30.73

4.89

30.56

methyl linoleate C18:2

5.16

46.53

5.59

46.08

methyl alpha linolenate C18:3

5.99

6.31

6.48

6.19

GC-MS Many of the students chose GC-MS as a method to determine which FAMEs were present in their biodiesel sample. Students could compare their sample with the NuCheck standard mixture as described for the GC-FID. They also could use the mass spectral library to determine the identity of each peak. Figure 5 shows a chromatogram of a sample of biodiesel that Group 1 prepared from WVO using 1.0% NaOH catalyst. They observed four main peaks at retention times of 6.3, 9.8, 10.0 and 10.6 minutes. The peak area percents were determined for the four largest peaks for biodiesel produced from WVO using 1.0% and 0.5 % catalyst (Table 9). The names in parentheses were determined from comparison to the spectral 85 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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library. Although the soap test (Figure 4) indicated that the reaction using more catalyst was more complete, the reactions produced the same FAMEs in similar proportions.

Figure 5. Chromatogram from Group 1 of a biodiesel sample produced from WVO with 1.0% catalyst.

Table 9. GC-MS Peak Areas for FAMES in Biodiesel Produced from WVO FAME

tr (min)

PA percent 1.0% NaOH

PA percent 0.5% NaOH

C16:0 Hexadecanoic acid, methyl ester

6.3

7.22

4.53

C18:2 9,12-Octadecadienoic acid, methyl ester

9.8

46.87

46.93

C18:1 9-Octadecenoic acid, methyl ester

10.0

41.46

38.25

C18:0 Methyl stearate

10.6

4.45

4.53

86 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Instructor Notes Instructor Preparation – Transesterification Reaction

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This experiment uses chemicals and materials found in most chemical stockrooms, so preparation is straightforward. Instructors will need to purchase cooking oils and obtain waste vegetable oil from a restaurant or even from the on-campus dining hall. Solid particulates can be removed from waste oil by allowing them to settle or by filtering (27). Materials for the synthesis are listed below. Vegetable oil (a few varieties are helpful, if students wish to study oil type) Waste vegetable oil Methanol (ethanol and isopropanol, if students wish to study transesterification alcohol identity) KOH or NaOH catalyst (note purity for calculations) Phenolphthalein indicator, for FFA titration Isopropyl alcohol, for FFA titration 0.10 % w/v NaOH, for FFA titration 250 mL Erlenmeyer flasks for reaction 100 mL graduated cylinders Separatory funnels Thermometers Hot plates Mortar and pestle, for grinding up catalyst pellets Glass bottles, for storing biodiesel Instructor Preparation – Characterization If the students have had organic chemistry laboratory or an instrumental analysis course, they should be familiar with the common instrumental techniques used for biodiesel characterization. GC-FID, GC-MS and FTIR are fast, user-friendly methods that require minimal method development time. In addition to these instruments, the following supplies should be available to students. 100 mL tapered and graduated glass tube for 90/10 test (e.g. KIMAX centrifuge tube, oil and weathering, 100 mL, Sigma Aldrich #Z252263) bromophenol blue indicator (0.040% w/w), for soap test 0.010 M HCl, for soap test Cyclohexane, for diluting biodiesel prior to analysis Viscometer, if students choose to make viscosity measurements Student Preparation Because students had to establish their own procedures for the transesterification reaction, it was important that they successfully search the literature and outline their procedure before coming to lab. Giving them an 87 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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introduction to the reaction, along with assignments that provided guidance through specific questions to be addressed, helped students correctly determine a procedure. Students worked in pairs, which provided someone to double check ideas and calculations. Instructors could use either the beginning of lab time or a separate recitation section to review the students’ planned procedures. Some students may have difficulties interpreting the literature article they found, as was the case for Group 3 (Table 4). Alternatively, some students may find research articles that employ reagents not commonly found in lab. A planned procedural review time can avoid these misunderstandings. Students were also asked to provide a list of chemicals and materials to the instructor one day prior to lab. Although instructors can anticipate the reagents students will need, this requirement helped in the preparation and allowed the instructor to red flag potential erroneous procedures.

Grading Suggestions Students were evaluated on their written reports to OBC and oral presentations on the experiment. Because the laboratory assignment originated with a memo from the Omaha Biofuels Cooperative to the students, students were asked to provide a written summary of their results to the Omaha Biofuels Cooperative. The summaries were briefer than a full lab report, but contained all of the pertinent experimental details and a description and analysis of the data. The instructions provided to students are given below.

Instructions for Written Work Next week the class will get together discuss our results. You will turn in a “memo” communicating your results. You should start to think about how you will present your results and data. Below is a brief outline for your memo. 1. 2.

Brief motivation / background Chemical reactions and oil used a.

3. 4.

It will be helpful to determine the fatty acid pattern for the oil used. E.g. some helpful information may be found at J. Agricultural and Food Chemistry 1997, 45, 4748-52 (or similar references). Are there any correlations between oil type and fuel performance? What oil do you expect to predominate the WVO? Do your results correlate with this?

Variable studied (e.g. catalyst type, alcohol type) Results and Characterization a. b.

Of variable studied Of SVO versus WVO transesterification 88

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5.

Conclusions and Future experiments

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Oral Presentations Students also presented their results to the class in an oral presentation, given in a graduate school “group meeting” format. After providing a brief background and experimental description, they focused on data analysis and interpretation. Within a class, the student pairs each chose different variables to study, so it was interesting for them to learn about the various results. The rubric students were provided was a modified version of an oral presentation assessment form used by the Creighton University Chemistry Department. Each criterion (Table 10) was rated with a 1, 2 or 3 and awarded points accordingly. (1=less than adequate (< 7 pts), 2=adequate (7-8 pts), 3=more than adequate (9-10 pts). The students in the “audience” were also provided with rubrics to fill out for each presentation. This “assignment” kept them engaged and actively thinking about how to deliver a successful presentation.

Table 10. Criteria for Oral Presentations Content/Understanding 1. Is the title accurate? 2. Is the background information explained sufficiently to understand the talk? 3. Does the introduction address the significance of the topic? 4. Does the introduction clearly state the purpose or hypothesis of the work? 5. Are the experiments explained clearly? 6. Are the experimental observations or data effectively summarized and communicated? 7. Are the chemical principles of the work sufficiently explained? 8. Are the green chemistry principles utilized by the work sufficiently explained or addressed? 9. Are references appropriately cited within the talk? Presentation 10. Is the talk organized in a logical way? 11. Are the figures/data tables clearly legible and easy to interpret? 12. Does the presenter appear excited and interested in the work? Interaction 13. Can the presenter effectively discuss the experimental details of the work? 14. Can the presenter effectively discuss the chemical principles of the work? 15. Can the presenter answer questions and freely discuss ideas about the work?

Final Thoughts For their final evaluation, students in the class were required to write a newspaper style article (28) on one of the experiments from the course. Some of the students opted to write their article on the production of biodiesel from waste 89 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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vegetable oil. This assignment challenged students to describe scientific concepts, data and results to non-scientists. During the recitation, a faculty member from the journalism department presented information on communication of science and writing newspaper articles. Students were first given an assignment to determine for which newspaper they were going to write and to decide on their topic. A subsequent assignment provided them with instructions on writing their articles and deadlines for the rough draft and final paper. Students turned in a rough draft, received feedback and submitted their final papers at the end of the semester. In summary, students found the project-based experiment “challenging yet engaging” as indicated in end-of-course surveys. Students enjoyed the independent environment and designing their experiments. One student commented, “I really enjoyed the use of chemical instruments and designing our own experiments in this course.” Surveys showed unanimous responses “agreeing” to the statement “I enjoyed and learned a lot from the inquiry-based experiments where I was able to help design the experiments.” Allowing students to choose a reaction variable to investigate dramatically engaged their inner “chemist” and maintained their interest in the outcome of a project that lasted 5 weeks. Students received hands-on experience in a variety of inexpensive and quick “field” analytical tests along with sophisticated laboratory instrumentation such as GC-MS and FTIR. Of the four field trips/outside speakers, students ranked the OBC the highest in an end-of-semester survey. Student interaction with the community partner Omaha Biofuels Cooperative greatly enhanced the learning experience, both in terms of technical knowledge and in professional skills. An OBC representative was present during nearly all the lab meetings, particularly when the students were performing the biodiesel synthesis. Students were encouraged to ask for advice from OBC. During one lab meeting, one group decided to employ acid-catalyzed esterification. Upon watching the reaction during the lab period, which was clearly unsuccessful, OBC requested a copy of the students’ procedure for review. When provided, OBC recommended the students to study base-catalyzed transesterification, which is far more commonly used in home-brew biodiesel production due to simplicity. The final report Memo from the student group highlighted this interaction: “Our second purpose was to test the feasibility of making biofuels from waste vegetable oil (WVO) using base-catalyzed and acid-catalyzed methods. The field tests exemplify the fact that the production of biodiesel from WVO using a base-catalyzed reaction proved successful at a lab scale.” “… the acid-catalyzed reaction proved unsuccessful.” Using a format of Memos as initial instructions, and as the method of student report to Creighton University and Omaha Biofuels Cooperative, reinforced professional written communications in a commercial or industrial setting.

References 1.

Clarke, N. R.; Casey, J. P.; Brown, E. D.; Oneyme, E.; Donaghy, K. J. Preparation and Viscosity of Biodiesel from New and Used Vegetable Oil. J. Chem. Educ. 2006, 83, 257–259. 90 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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Bladt, D.; Murray, S.; Gitch, B.; Trout, H.; Liberko, C. Acid-Catalyzed Preparation of Biodiesel from Waste Vegetable Oil: An Experiment for the Undergraduate Organic Chemistry Laboratory. J. Chem. Educ. 2011, 88, 201–203. Bucholtz, E. Biodiesel Synthesis and Evaluation: An Organic Chemistry Experiment. J. Chem. Educ. 2007, 84, 296–298. Ault, A. P.; Pomeroy, R. Quantitative Investigations of Biodiesel Fuel Using Infrared Spectroscopy: An Instrumental Analysis Experiment for Undergraduate Chemistry Students. J. Chem. Educ. 2012, 89, 243–247. Yang, J.; Xu, C.; Li, B.; Ren, G.; Wang, L. Synthesis and Determination of Biodiesel: An Experiment for High School Chemistry Laboratory. J. Chem. Educ. 2013, 90, 1362–1364. Behnia, M. S.; Emerson, D. W.; Steinberg, S. M.; Alwis, R. M.; Dueñas, J. A.; Serafino, J. O. A Simple, Safe Method for Preparation of Biodiesel. J. Chem. Educ. 2011, 88, 1290–1292Uses potassium carbonate as a catalyst. Pohl, N. L.; Streff, J. M.; Brockman, S. Evaluating Sustainability: Soap versus Biodiesel Production from Plant Oils. J. Chem. Educ. 2012, 89, 1056–1571. de Oliveira, R. R.; das Neves, L. S.; de Lima, K. M. G. Experimental Design, Near-Infrared Spectroscopy, and Multivariate Calibration: An Advanced Project in a Chemometrics Course. J. Chem. Educ. 2012, 89, 1566–1571. Ryan, M. A., Tinnesand, M., Eds.; Biodiesel: Using Renewable Resources, Laboratory Experiment in Introduction to Green Chemistry; American Chemical Society: Washington, DC, 2002, pp 13−22. Feng, Z. V.; Buchman, J. T. Instrumental Analysis of Biodiesel Content in Commercial Diesel Blends: An Experiment for Undergraduate Analytical Chemistry. J. Chem. Educ. 2012, 89, 1561–1565. Wagner, E. P.; Koehle, M. A.; Moyle, T. M.; Lambert, P. D. How Green Is your Fuel? Creation and Comparison of Automotive Biofuels. J. Chem. Educ. 2010, 87, 711–713. Mike Pelly’s Biodiesel Method. http://journeytoforever.org/ biodiesel_mike.html (accessed March 18, 2016). Utah Biodiesel Supply. www.utahbiodieselsupply.com (accessed March 18, 2016). Wenzel, G.; Lammers, P. S. Boiling Properties and Thermal Decomposition of Vegetable Oil Methyl Esters with Regard to Their Fuel Stability. J. Agric. Food Chem. 1997, 45, 4748–4752. Uddin, M. R.; Ferdous, K; Uddin, M. R.; Khan, M. R.; Islam, M. A. Synthesis of Biodiesel from Waste Cooking Oil. Chem. Eng. Sci. 2013, 1, 22–26. Zheng, S.; Kates, M.; Dube, M. A.; McLean, D. D. Acid-catalyzed production of biodiesel from waste frying oil. Biomass Bioenergy 2006, 30, 267–272. Ozsezen, A. N.; Canakci, M.; Sayin, C. Effects of Biodiesel from Used Frying Palm Oil on the Performance, Injection, and Combustion Characteristics of an Indirect Injection Diesel Engine. Energy Fuels 2008, 22, 1297–1305. Ma, F.; Hanna, M. A. Biodiesel Production: A Review. Bioresource Technol. 1999, 70, 1–15. 91 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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19. Shahid, E. M.; Jamal, Y. Production of Biodiesel: A Technical Review. Renewable Sustainable Energy Rev. 2011, 15, 4732–4745. 20. Weast, R. C. CRC Handbook of Chemistry and Physics; Boca Raton, FL: CRC Press, 1988−1989; p F3. 21. Monteiro, M. R.; Ambrozin, A. R. P; Liao, L. M.; Ferreira, A. G. Critical Review on Analytical Methods for Biodiesel Characterization. Talanta 2008, 77, 593–605. 22. Pauls, R. E. A Review of Chromatographic Characterization Techniques for Biodiesel and Biodiesel Blends. J. Chromatog. Science 2011, 49, 384–396. 23. Knothe, G., Von Gerpen, J., Krahl, J., Eds.; The Biodiesel Handbook; AOCS Press: Champaign, IL, 2005. 24. Pierce, K. M.; Schale, S. P.; Le, T. M.; Larson, J. C. An Advanced Analytical Chemistry Experiment Using Gas Chromatography−Mass Spectrometry, MATLAB, and Chemometrics To Predict Biodiesel Blend Percent Composition. J. Chem. Educ. 2011, 88, 806–810. 25. Alty, L. T. Analysis of Fatty Acid Methyl Esters in Egg Yolk Using GC–MS. J. Chem. Educ. 2009, 86, 962. 26. British Pharmacopoeia Commission. Ph. Eur. Monograph 1371. British Pharmacopoeia 2005; The Stationary Office: Norwich, England, 2005. 27. Duda Diesel. http://www.dudadiesel.com/filtering.php (accessed June 20, 2016) 28. Shane, J. W.; Bennett, S. D.; Hirchl-Mike, R. Using Chemistry as a Medium for Energy Education: Suggestions for Content and Pedagogy in a Nonmajors Course. J. Chem. Educ. 2010, 87, 1166–1170.

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Chapter 6

Microwave-Assisted Aspirin Synthesis from Over-the-Counter Pain Creams Using Naturally Acidic Catalysts: A Green Undergraduate Organic Chemistry Laboratory Experiment J. T. Fahey,*,1 A. E. Dineen,1 and J. M. Henain1 1Division

of Natural Science, Mount Saint Mary College, 330 Powell Ave., Newburgh, New York 12550, United States *E-mail: [email protected]

The synthesis of aspirin using H2SO4 or H3PO4 is a common undergraduate organic laboratory experiment. Replacing these potentially harmful, strong acids with naturally acidic soft drinks or fruit juices demonstrates the use of green chemistry guidelines to undergraduate students. Isolation of methyl salicylate from over-the-counter pain creams, and subsequent conversion to aspirin was explored. Salicylic acid, obtained via hydrolysis of the methyl salicylate, was converted to aspirin using soft drinks or fruit juices as catalysts in a microwave synthesis. Average yields were 55%, but individual yields depended on the soft drink/juice used as a catalyst. The successful synthesis was tested with first-semester undergraduate organic chemistry students as a multi-week experiment. Results are discussed.

Introduction The traditional focus during the first-semester of organic chemistry is teaching various techniques used to synthesize organic molecules and performing simple synthesis reactions. In most organic chemistry laboratory manuals, synthesis reaction experiments are typically “cookbook” in nature, providing a specific list of instructions for the students to follow. Upon anecdotal observation, students do not show any personal interest/vestment in the experiments. The © 2016 American Chemical Society Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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hypothesis derived from this observation is that if the experiments could be made more memorable, applicable, and practical to students, their interest, and success would improve. One way of improving success is to have students synthesize a compound, i.e. aspirin, which many people use for pain relief, to reduce an elevated body temperature, or to reduce joint inflammation. The synthesis of aspirin is a common synthesis experiment performed in an undergraduate organic chemistry laboratory. Many organic chemistry laboratory manuals use conventional methods of aspirin synthesis from salicylic acid and acetic anhydride (Figure 1) utilizing acid catalysts (H2SO4 or H3PO4) under reflux to obtain high yields (1, 2).

Figure 1. The traditional synthesis of aspirin typical in undergraduate laboratory manuals. However, according to the Safety Data Sheets, sulfuric and phosphoric acids are highly corrosive and very hazardous in case of skin contact, and may produce burns (3, 4). After observing multiple students burn themselves using these acids, a safer, greener alternative was sought. In addition, a pathway for even higher yields was also sought. The initial idea was to replace the traditional reflux with microwave conditions, and to use naturally acidic sodas and juices as catalysts, replacing sulfuric or phosphoric acid. Microwave irradiation in organic synthesis has become common, offering benefits including improving product yields, decreasing reaction time, and improving efficiency while reducing cost (5). Microwave ovens used for irradiating chemical reactions can range from a standard household microwave oven to an industrial microwave specifically designed for chemical reactions in the organic chemistry laboratory. Microwave irradiation leads to new pathways to perform reactions, such as solvent free reactions (6) and the use of less hazardous materials (7). Green chemistry has increasingly become an area of interest both in industry and in academia. One of the primary goals of green chemistry is to eliminate or reduce the use of hazardous chemicals either by alteration of the experimental procedure or by substitution with less hazardous chemicals or water (8, 9). This proposed synthesis experiment is a greener approach to previous microwave synthesis experiments for aspirin as well as other analgesic drugs (10). The proven microwave syntheses of asprin used multiple catalysts, including H2SO4, H3PO4, MgBr2·OEt2, AlCl3, CaCO3, NaOAc, NEt3, and DMAP (11) 94 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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with yields of aspirin ranging from 55% to 97%. Initially, a greener synthesis of aspirin was investigated using an over-the-counter analgesic pain cream with methyl salicylate as an active ingredient (Figure 2) to provide salicylic acid for the reaction. Results showed that the extraction of methyl salicylate from Tylenol™ Precise pain cream (12) and the use of soda and juice catalysts allowed for a range of yields comparable to the traditional method, with applicability, practicality, memorability, and an increase in safety for the students.

Figure 2. Conversion of methyl salicylate isolated from pain cream to aspirin using natural catalysts and microwave irradiation. During the course of the research and despite initial success with this procedure, the production of Tylenol™ Precise pain cream was discontinued. Additional pain creams such as IcyHot® and Bengay® were investigated; however, they failed to produce pure aspirin in a comparable percent yield. Therefore, the research focused on the use of naturally acidic sodas and juices as catalysts in the conversion of salicylic acid to aspirin using microwave irradiation. Various techniques, concepts, and reactions are introduced to students during this experiment (whether pain cream or pure salicylic acid is used as a starting material). Students practice techniques including extraction, reflux, and melting point determination. Additionally, students are introduced to the concept of microwave chemistry and its benefits over conventional heating. If using pain cream as a starting material, students will also learn about base-promoted ester cleavage (methyl salicylate to salicylic acid) and acid-catalyzed esterification (salicylic acid to aspirin) reactions. Analysis of product using infrared (IR) spectroscopy and melting point apparatus provides students with further hands-on experience. Lastly, they are familiarized with green chemistry and its future in the scientific community.

Experimental Procedure When starting with pain cream, the experiment can be completed over four laboratory periods (one lab per week). The first week of the procedure calls for a synthesis of salicylic acid from methyl salicylate using OTC pain cream (Tylenol™ Precise). Students weigh approximately 17 g of Tylenol™ Precise pain cream and mix it vigorously with methanol. The mixture is then vacuum filtered to separate the inactive ingredients, and the filtrate (methyl salicylate and methanol) is then placed on a hot plate to evaporate the methanol solvent. Students use 95 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

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methyl tert-butyl ether (MTBE) as a solvent with a separatory funnel to separate the menthol and the methyl salicylate in the filtrate from each other. Once the extraction is complete, students let the methyl salicylate sit for one week (due to time constraints) and then weigh their product. During the second week, the methyl salicylate is refluxed in NaOH solution and then transferred, cooled, and acidified with HCl solution. A white precipitate (salicylic acid) should form, but scratching and letting the crystals sit over ice should further induce crystallization. The precipitate is then collected via vacuum filtration and left to dry until the following week. If pain cream is not available, the experiment can be started from this point using pure salicylic acid. Without the availability of the pain cream, the experiment can be shortened to two weeks. Approximately 1.4 g of salicylic acid is added to a microwave tube with 2.8 mL acetic anhydride and 5 drops of concentrated soda or juice catalyst (students carefully boil catalyst solution until half the original volume remains). For our experiment, each pair of students works with a different soda or juice (Table 1). The microwave used is a MARS CEM industrial chemical microwave. The aspirin synthesis is programmed to run at 400 Watts, 100% power. The microwave takes 5 minutes to ramp up to temperature and then is held at a constant temperature for 10 minutes (150 °C). After 10 minutes the microwave automatically cools the samples down for an additional 10 minutes; the reaction takes a total time of 25 minutes. Once out of the microwave, students’ mixtures are poured into beakers and allowed to cool. Water is added once the mixture is cool and crystallization is induced. The mixture is then allowed to sit until the following week.

Table 1. Soda and juice catalysts used by researcher and student groups Root Beer

Grapefruit Juice

Sierra Mist™

Coke™

Orange Juice

Mountain Dew™

Diet Coke™

Lemon Juice

Pineapple Juice

Orange Soda

Diet Pepsi™

Lime Juice

Sprite™

Red Bull™

Dr. Pepper™

Pepsi™

During the fourth week, students isolate aspirin crystals via vacuum filtration and rinse with cold water to ensure all crystals are collected. Aspirin crystals are allowed to sit under vacuum for 15-20 minutes to ensure dryness. Dry crystals are weighed and subjected to IR analysis (Perkin Elmer Spectrum 100 with Universal ATR Sampling Accessory) and melting point determination. Additionally, students perform a ferric chloride test for purity. To perform the ferric chloride test, students add a small amont of pure salicylic acid, synthesized salicylic acid, pure aspirin, synthesized aspirin, water, and sometimes commercial aspirin each to 6 separate test tubes. To each tube, 1 mL of 0.1% solution of ferric chloride is added. Students record the changes in color in the tubes, red/purple for phenols present (indicating salicylic acid) and yellow for no phenols (indicating aspirin). [Note: the prepared aspirin can give a purple color due to presence of unreacted salicylic acid.] 96 Fahey and Maelia; Green Chemistry Experiments in Undergraduate Laboratories ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Students have the option of doing a recrystallization to remove the impurities introduced from the soda or juice catalyst, which often cause discoloration in the aspirin. Recrystallization can be done with or without charcoal.

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Results and Discussion This experiment was designed to provide students with a more efficient, greener pathway to synthesize aspirin. Initially, the experiment was designed to start with an over-the-counter pain cream as the source of methyl salicylate. The methyl salicylate would then be converted to salicylic acid, the traditional starting material for the synthesis of aspirin. Various brands of pain creams were initially investigated for their potential use in the experiment. Since each brand of pain cream has varying percentages of methyl salicylate, it was thought those creams with higher percentages of the active ingredient would provide higher yields of salicylic acid. Bengay® was used and shown to work previously in an experiment in Experimental Organic Chemistry (1). (Note: the original procedure used Original Strength Bengay® which only contains methyl salicylate and menthol as active ingredients. Currently, only Extra Strength Bengay® is commercially available, which contains a third active ingredient, camphor.) Six common pain creams, all containing methyl salicylate as an active ingredient, were investigated: Bengay® Extra Strength, IcyHot®, Tylenol Precise™, Mentholatum®, Thera-gesic®, and Nature Plex®. Analysis of results (Table 2) shows that only Bengay®, IcyHot®, and Tylenol Precise™ produced salicylic acid that could be converted to aspirin. Mentholatum® produced a low yield of salicylic acid, not enough to continue the conversion to aspirin. Thera-gesic® and Nature Plex® both appeared to produce salicylic acid, however, upon further analysis with melting point and IR spectroscopy it was determined that both had large amounts of sodium acetate present but not salicylic acid as expected.

Table 2. Percent yields and melting point data for aspirin obtained from various over-the-counter pain creams

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Only salicylic acid derived from Bengay®, IcyHot®, and Tylenol Precise™ was used in the subsequent conversion to aspirin. All three were successful in conversion to aspirin as confirmed with IR spectroscopy. However, upon analysis of the melting points, only Tylenol Precise™ provided results close to the actual melting point of aspirin. The extremely low melting point obtained for aspirin obtained from Bengay® and IcyHot® confirmed that the conversion to pure aspirin was unsuccessful. It was hypothesized that the presence of camphor as a third active ingredient could have interfered with the conversion of methyl salicylate to salicylic acid, and the reported percent yield of salicylic acid included unreacted camphor. It may be possible that the camphor further interfered with the conversion of any produced salicylic acid to aspirin. Further research must be done to determine the exact effect of the camphor in the reactions as well as possible ways to remove the camphor at the start. Until this research can be conducted, Bengay® and IcyHot® were omitted from use. It was therefore determined that Tylenol Precise™ pain cream was the only choice that would allow for successful conversion to salicylic acid with subsequent conversion to aspirin in high yield and higher purity as confirmed by IR spectroscopy, melting point, and nuclear magnetic resonance (NMR) analysis. To make the experiment greener, various soda and fruit juices were used in place of concentrated phosphoric or sulfuric acids during the conversion of salicylic acid to aspirin. A student researcher performed the reaction using both pure salicylic acid and pain cream derived salicylic acid for comparison. The results with three of the soda/juices are presented in Table 3.

Table 3. Yields of aspirin made from pure salicylic acid and from salicylic acid extracted from Tylenol Precise™ pain cream using various sodas and juices as a catalyst Aspirin Yield (%): from Pure Salicylic Acid

Aspirin Yield (%): using Salicylic Acid prepared from Pain Cream

Orange Juice

81.40

73.62

Diet Pepsi™

78.86

69.43

Coke™

83.16

75.30

Catalyst

Although pure salicylic acid consistently produced significantly higher yields of aspirin (p