Introducing Students to Mechanochemistry via Environmentally

Laboratory Experiment Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

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Introducing Students to Mechanochemistry via Environmentally Friendly Organic Synthesis Using a Solvent-Free Mechanochemical Preparation of the Antidiabetic Drug Tolbutamide Evelina Colacino,*,† Gandrath Dayaker,‡ Alain Morère,† and Tomislav Frišcǐ ć*,‡ †

Department of Chemistry, Faculty of Sciences, University of Montpellier, Montpellier 34090, France Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal H3A 0B8, Canada

‡

J. Chem. Educ. Downloaded from pubs.acs.org by EAST CAROLINA UNIV on 03/13/19. For personal use only.

S Supporting Information *

ABSTRACT: The implementation of environmentally friendly, solvent-free mechanochemical synthesis in an undergraduate chemistry teaching laboratory is described. As a model reaction, the experiment addresses the catalytic mechanochemical synthesis of a small library of sulfonylureas, including a known active pharmaceutical ingredient, tolbutamide. The experiment introduces students to mechanochemistry, and the use of automated ball milling as a solvent-free synthetic methodology with a choice of two instruments: a mixer mill and a planetary ball mill. The isolation and purification of final products is achieved simply by washing with water and characterization is performed through powder X-ray diffraction. As milling reactions under wet and dry conditions lead to the formation of two diverse polymorphs of tolbutamide, this experiment also provides an opportunity to discuss topics relevant to solid-state pharmaceutical materials science, such as crystal packing of molecules and polymorphism, and it is an illustration of the emergent field of medicinal mechanochemistry in an undergraduate teaching laboratory. KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Graduate Education/Research, Organic Chemistry, Hands-On Learning/Manipulatives, Medicinal Chemistry, X-ray Crystallography, Green Chemistry, Synthesis, Catalysis

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synthesis of nanoparticles.7,16−20 Importantly, recent work has demonstrated the ability to synthesize increasingly complex active pharmaceutical ingredients (APIs)21−24 through solventfree mechanochemical techniques, paving the way for the development of “medicinal mechanochemistry”,25 an efficient solution to the demands of the pharmaceutical industry for new, cleaner, and more efficient synthetic methodologies.2 A recent contribution to medicinal mechanochemistry is the copper-catalyzed coupling of sulfonamides with isocyanates, which provides a simple, rapid route to pharmaceutically relevant sulfonyl-ureas. In particular, the reaction enables the simple and fast synthesis of the first- and second-generation sulfonyl-urea antidiabetic drugs tolbutamide, chloropropamide, and glibenclamide without the use of a solvent.26 Importantly, the mechanochemical catalytic procedure is also one step shorter and more material-efficient than industrial procedures, which usually require a two-step process in which the sulfonamide reactant is first deprotonated using stoichiometric or excess base (e.g., NaOH or K2CO3), and then the in situ formed salt is reacted with the isocyanate reagent. Con-

INTRODUCTION The development of cleaner, safer, and more efficient chemical transformations is one of major challenges of modern research and industrial chemistry, which are facing the need for sustainable manufacture of chemical products (new medicines, functional materials, etc.).1 The need for such development was voiced over a decade ago by pharmaceutical industries,2 and is reflected in the increasingly important role of Green Chemistry in chemical research and manufacture.3 In particular, recent years have witnessed the emergence of a “benign-by-design”4 approach to chemical synthesis, which requires the implementation and organization of synthetic strategies and methodologies in accordance with the guidelines for improving sustainability.5,6 In the context of cleaner and safer chemical synthesis, mechanochemistry7,8 (i.e., chemical reactions and material transformations induced by mechanical force, such as grinding,9 milling, stretching, or shearing) has recently emerged as a highly successful approach to conduct solvent-free synthesis in diverse areas. As evidenced by recent review articles, the applications of mechanochemistry range from organic chemistry and screening for new pharmaceutical materials (e.g., polymorphs, cocrystals, and salts)10,11 to inorganic,12 organometallic,13 and coordination chemistry;14 the synthesis of metal−organic frameworks (MOFs);15 and the © XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: June 22, 2018 Revised: February 20, 2019

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DOI: 10.1021/acs.jchemed.8b00459 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

clean procedure that does not require organic solvent or chromatographic purification. The pedagogical goals of the experiments and the associated discussion are the following:

sequently, this recently demonstrated coupling reaction provides an excellent opportunity to organize a laboratory teaching experiment that introduces mechanochemistry, Green Chemistry, and different aspects of solid-state and pharmaceutical science into university chemistry teaching laboratories. The reactions in this experiment were adapted from a previously published26 mechanochemical reaction procedure that uses a laboratory mixer mill (MM) and further developed by students in a laboratory course for use with a larger-scale planetary ball mill (PM). Both types of apparatus achieve the grinding and mixing of the reactant substances through the motion of the milling media (i.e., balls of particular size and composition, e.g., steel, agate, or zirconia) in a rapidly oscillating (MM) or rotating (PM) vessel. Although mechanochemical reactions can often be performed by manual grinding using a mortar and pestle,11 recent successes and popularization of mechanochemistry have been accomplished through the use laboratory ball mills as they provide the benefits of long and reproducible operating times and containment of the reaction mixture in a closed vessel, thus reducing exposure of the reacting mixture to air and moisture and allowing control over the intensity of mechanochemical agitation through the choice of different milling parameters and milling media. More details on the operation and control of chemical reactivity in a ball mill can be found in recent reviews and research articles.27,28 The herein described experiment uses the catalytic preparation of sulfonylureas to illustrate a chemical protocol that strives for minimal environmental impact by utilizing mechanochemistry and eliminating the need for bulk organic solvents. The reactions involve the coupling of p-toluenesulfonamide with various isocyanates in the presence of a copper catalyst (copper(I) chloride, CuCl), which is performed in a mixer or planetary ball mill. Reactions are conducted by milling in the presence of a small amount of liquid phase (nitromethane, CH3NO2, which was selected because of its nonhygroscopic nature and relatively high boiling point, both of which facilitate reproducible and safe work in a laboratory involving many students) in a process known as liquid-assisted grinding (LAG).29 One exception is the reaction with nbutylisocyanate, which can be conducted both by LAG and by dry (neat) milling in order to obtain different polymorphs of the API tolbutamide. The amount of liquid used to facilitate the LAG reactions is expressed as η, which is the ratio of added liquid volume to combined mass of reactants, expressed in microliters per milligram (μL/mg). The η parameter provides a convenient way to compare mechanochemical reactions (η between 0 and ca. 1 μL/mg) with slurry reactions (η between ca. 1 and ca. 6 μL/mg) and reactions in homogeneous solution (η typically larger than 6 μL/mg). Importantly, the hallmark of LAG reactivity, compared with slurry or solution reactions, is that it enables chemical transformations regardless of reactant solubility.22 The reactions lead to high yields of sulfonylureas after 2 h of milling, after which the copper-based catalyst is converted into a water-soluble complex by another period of brief (10 min) milling with a small amount of aqueous disodium ethylenediaminetetraacetate dihydrate (Na2H2EDTA·2H2O). The resulting product is then washed with water and recovered by vacuum filtration, producing pure sulfonylureas as off-white powders, whereas the copper catalyst is converted to a water-soluble EDTA complex and eliminated into the filtrate. The experiment is an example of a simple,

(i) to develop an introduction to and awareness of the emergent mechanochemical methodologies and techniques, especially in the context of making chemical transformations cleaner, faster, and simpler; (ii) to encourage the students (and instructors!) to “think chemistry differently”30 by replacing solution-based chemistry with solvent-free procedures and to question the role of and need for solvents in chemical transformations; (iii) to illustrate how the use of volatile organic compounds and solvents in general can be avoided or minimized without having to suffer from slow reactivity or low reaction yields; (iv) to overcome the barriers facing the adoption of mechanochemistry and ball milling in teaching synthetic chemistry; (v) to show how mechanochemical-reaction conditions can be varied to change the reaction outcome (e.g., to generate different polymorphs of tolbutamide by switching from neat milling to LAG); and (vi) to encourage a discussion on the parameters of mechanochemical reactivity that influence product formation or reactivity, such as the size and materials of the reaction vessel (jar) and milling media (balls), the frequency of milling (for MM) and rotation speed (for PM), the reaction time, and others.27,28 The pedagogic goals were assessed not only by the success of the students in performing the reactions (e.g., in the form of product purity and yield) but also from the answers to questions asked during the laboratory session and from the evaluation of their laboratory reports, in which the students (i) described the importance of solvent-free syntheses, with a special emphasis on mechanochemistry by automated ball milling, particularly in comparison with solution procedures or manual grinding using a mortar and pestle; (ii) explained the general principles underlying this methodology, while describing the advantages and drawbacks of mechanochemical procedures in performing organic synthesis; (iii) highlighted the differences between different milling devices in term of product yield; (iv) tested different process parameters to optimize the reactions and critically analyze the results; and (v) compared their results with those obtained by all of the other pairs of students using different isocyanates. Students performed a catalytic coupling reaction between stoichiometric amounts of p-toluenesulfonamide 1 and four different isocyanates, 2a−d(Table 1). The reaction was catalyzed by CuCl via LAG with nitromethane (CH3NO2) as the grinding liquid; the ratio of liquid volume to combined weight of reactants was set to η = 0.25 μL/mg (Table 1).26 The reaction was mechanically activated using a mixer mill (MM, operated at 30 Hz) or a planetary ball mill (PM, operated at 450 rpm) for 2 h, which was sufficient for complete consumption of the starting materials. The reaction workup consisted of the removal of copper-based catalyst by a complexation reaction carried out by adding disodium dihydrogen ethylenediaminetetraacetate dihydrate (Na2H2EDTA·2H2O) and water (3 mL) directly to the jar B




Table 1. Representative Student Results for the CuCatalyzed Mechanochemical Coupling of pToluenesulfonamide (1) and Alkylisocyanates 2a−d To Afford Sulfonylureas 3−6a

type of mill and yield (%) compound

R−

MM

PM

3 4 5 6

CH3CH2− CH(CH3)2− PhCH2− CH3(CH2)3−

98 86 73 70 (75)b

65 84 75 74

a

The formal symbol for mechanochemical-reaction conditions was adopted from Rightmire and Hanusa.13 bThe reaction was performed without nitromethane (neat grinding).

Figure 1. Comparison of PXRD patterns. (a) PXRD pattern for compound 6 obtained by neat milling. (b) Simulated PXRD pattern for polymorph 1 of tolbutamide (based on CSD code ZZZPUS01). (c) PXRD pattern for compound 6 obtained by LAG. (d) Simulated PXRD pattern for polymorph 2 of tolbutamide (based on CSD code ZZZPUS15)

and milling for 10 min at lower intensity (25 Hz for MM or 400 rpm for PM, Table 1). The use of n-butylisocyanate as the reactant leads to the formation of tolbutamide (compound 6), a known firstgeneration antidiabetic drug, providing an opportunity to create a connection to medicinal chemistry and pharmaceutical materials science. In particular, the analysis of tolbutamide samples prepared by neat (dry) ball milling and liquid-assisted grinding by powder X-ray diffraction reveals two different patterns. Comparison of the patterns to those simulated for reported structures of tolbutamide found in the Crystal Structure Database (CSD) reveals that neat milling leads to the formation of tolbutamide polymorph 1, the less thermodynamically stable form (kinetically favored), with orthorhombic symmetry (corresponding to CSD codes ZZZPUS01, ZZZPUS02, ZZZPUS04, ZZZPUS14, ZZZPUS17, ZZZPUS18, ZZZPUS19, and ZZZPUS20), whereas LAG yields the more thermodynamically stable polymorph 2 with monoclinic symmetry, which is stable from 0 to ca. 353 K and hence at room temperature31 (corresponding to CSD codes ZZZPUS05, ZZZPUS15, and ZZZPUS21; Figure 1). It is well-known that introducing or switching the liquid additive in a mechanochemical reaction can lead to the formation of different polymorphs of a product (suggesting that the reaction conditions in ball milling are displaced from equilibrium), and also that different polymorphs of a drug can exhibit different pharmaceutically relevant properties (e.g., solubility, dissolution rate, tabletability, etc.).29,32 Consequently, conducting powder-X-raydiffraction (PXRD) analysis of the synthesized compound, 6, provides the laboratory instructor with an opportunity to introduce the students to the topics of polymorphism, the importance of the discovery of new solid forms of drugs, as well as the use of PXRD in the analysis of organic solid-state materials.33 Indeed, manufacturers are required to submit PXRD patterns to regulatory agencies when seeking approval for new drugs. This experiment is designed for one 4 h laboratory period in the fall semester, for undergraduate students attending the last year of chemistry. It provides opportunities for students to review basic concepts in organic chemistry (coupling reactions, chemistry of sulfonamides and isocyanates, catalysis, spectral and crystallographic interpretation, and medicinal chemistry); to become familiar with mechanochemistry as a modern

technology for performing organic synthesis in a more sustainable way; and to compare the reactivity of each isocyanate as a function of the type of mill (MM or PM) and the technical parameters used, as are taught in Green Chemistry courses.

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EXPERIMENTAL SECTION Students worked in pairs to prepare the same compounds by using both a mixer mill (MM) and a planetary ball mill (PM). As each ball mill has two milling stations, the students can perform two experiments simultaneously. As an alternative to MM and PM (Supporting Information, p S8), it is worth noting that some of the pioneering work in molecular mechanochemistry has been performed using the less sophisticated Wig-L-Bug mixers34 (dentistry mills). Alternatively, it is possible to rent or borrow the mixing mills directly from the manufacturers or share it across different departments. Finally, it is also possible to explore other types of setups for ball milling based on commonly available laboratory equipment. An example is the “vortex milling” technique developed by the MacGillivray group,35 which utilizes a conventional vortexing mixer in combination with glass or plastic vials containing the sample to be milled along with commercial BBs as the milling media. The use of nitromethane (CH3NO2) as the grinding-liquid additive in LAG is due to its stability in air, relatively high boiling point (100 °C), and low tendency to absorb moisture upon exposure to air, in contrast to other nonprotic liquid additives such as acetonitrile and acetone. These properties facilitate safe and reproducible work in laboratories involving many students with differing laboratory skills. However, in the absence of nitromethane, it is possible to use acetone, acetonitrile, ethylmethyl ketone, or other nonprotic solvents. Experiment Using a Mixer Mill

The reactions using a mixer mill were conducted at the 0.5 mmol scale, with the reactants placed in a stainless-steel jar with a 10 mL volume, containing 5 stainless-steel balls as the milling media (Ø 7 mm, weight for one ball: 1.3 g). The C



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RESULTS AND DISCUSSION These experiments gave the students practical experience with mechanochemistry, with a particular application for the preparation of a marketed drug, tolbutamide, with almost no waste, apart from that resulting from product purification using EDTA-based complexation and washing with water. Each pair of students obtained a sulfonylurea product prepared by two different milling devices and processing parameters. The approach provides an illustration of a simple experimental procedure that does not call for dry or inert conditions or for sophisticated glassware. Students were found to follow the previously published procedure using MM26 without major problems and were also able to adapt it to a PM protocol with no need for additional optimization. All the reactions went to completion, and the method proved to be general also for reactions using isocyanate reactants, which were not used in the original research report. 26 The experiments were conducted twice by 10 undergraduate students in a 4 h laboratory period during two fall semesters. In general, we observed that the initial setting up of the experiment took around 30 min, and the workup after the reaction was done lasted ca. 15 min. During the actual milling, students had the time and opportunity to look for spectral data and references in the literature and begin preparing the experimental laboratory report. The 1H NMR and 13C NMR spectra were used as proof of purity of the compounds. The postlaboratory report (which involved the accuracy of structural determination, comments on product purity, and postlab questions) completed the pedagogical goals. All students correctly answered the finalexam question on the use of mechanochemistry for organic synthesis, providing critical thinking on selected examples.

reactions were shaken at a frequency of 30 Hz for 2 h and then for 10 min at a frequency of 25 Hz during workup. Experiment Using a Planetary Mill (PM)

The reactions using a planetary mill were done on 1 mmol scale, by placing reactants in a 12 mL zirconium oxide jar containing 50 zirconium oxide balls (Ø 5 mm, weight for one ball: 1.38 g). The mill was operated at 450 rpm for 2 h for the catalytic reaction and again for 10 min at 400 rpm during workup. p-Toluenesulfonamide (1 equiv), alkylisocyanate (1 equiv), CuCl (5 mol %, 0.05 equiv), and CH3NO2 (η = 0.25 μL/mg) were milled for 2 h at the specified frequency or rotation speed. After the reaction, Na2H2EDTA·2H2O (20 mg) and deionized water (3 mL) were added to the green-colored crude mixture (Supporting Information, Figure S2), which was then milled for a further 10 min at the specified frequency or rotation speed. The resulting white product (Figure S3) was collected by vacuum filtration, washed with deionized water (10 mL × 2) to remove the copper catalyst in the form of a water-soluble EDTA complex, and dried in vacuo over P4O10. Comparative yields were calculated, and for each sample, 1H NMR, 13C NMR, and LC/MS spectra were recorded, and melting points were measured during the laboratory period. Data were analyzed and rationalized in the following weeks and incorporated in reports, which also included the original spectra from the analyses performed. Representative student 1 H and 13C NMR spectra are provided in the Supporting Information (pp S10−S17).

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HAZARDS p-Toluenesulfonamide is not a hazardous substance according to Regulation (EC) No. 1272/2008. Ethyl, isopropyl, and nbutyl isocyanate are flammable, lachrymator liquids causing acute toxicity if inhaled, swallowed, or adsorbed through the skin or eyes. No components of these reagents are considered by the International Agency for Research on Cancer (IARC) to be either persistent, bioaccumulative, and toxic (PBT) or very persistent and very bioaccumulative (vPvB) at levels of 0.1% or higher. Benzylisocyanate is flammable and irritating to the eyes, respiratory system, and skin. Copper(I) chloride causes acute toxicity if inhaled, as well as skin irritation and serious eye damage. It is very toxic to aquatic life with longlasting damage. No component of these last two products that is present at levels greater than or equal to 0.1% is identified as a probable, possible, or confirmed human carcinogen by IARC. Nitromethane is a flammable liquid that is harmful if swallowed. It has been reported to be possibly carcinogenic according to IARC and U.S. Environmental Protection Agency (EPA) classifications. Ethylenediaminetetraacetic acid disodium salt dihydrate is harmful if inhaled, potentially causing damage to the respiratory tract through prolonged repeated exposure. The hazards of products 3−5 are unknown; therefore, they should be handled as hazardous in the cases of inhalation, skin or eye contact, and ingestion. Compound 6 (tolbutamide) is not a hazardous substance or mixture according to Regulation (EC) No. 1272/2008 with an LD50 of 2.490 mg/kg (oral in rat). The entire experiment has to be conducted in accordance with good industrial hygiene and safety practices, always wearing eye protection and gloves.

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CONCLUSION The feedback of the students was extremely positive: they realized that milling is a powerful technology to perform organic synthesis at reduced energy costs, while avoiding large solvent uses. Specifically, the students learned (i) how to prepare their experiments on the basis of published results (MM experiments); (ii) how to search for relevant literature, including experimental information needed to evaluate their results (when available); (iii) how to highlight mechanisms and topics related to complexation reactions; and (iv) how to reason when the protocols need to be adapted, specifically when switching from the original MM procedure to a PM experiment. Moreover, the experiments stimulated the curiosity of the students: each group (two students) documented carefully the results and communicated reciprocally to compare the yields obtained when performing the syntheses with other isocyanates. They were interested in learning and practicing different approaches to solution synthesis, in particular because of the straightforwardness of the experimental procedure and workup. These experiments were also useful in that they required the use of essential skills such as spectral interpretation, percent yield calculation, and analysis of powder XRD spectra. Conducting solvent-free milling experiments in teaching laboratories could help a new generation of chemists to think outside of the box, increase their awareness of the environmental impact of chemical transformations and laboratory operations, and encourage daily environmentally-friendly behavior in chemistry laboratories.36 D



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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.8b00459. Spectral data and notes for students and instructors and 1 H and 13C NMR characterizations for all products (PDF, DOCX)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Evelina Colacino: 0000-0002-1179-4913 Tomislav Frišcǐ ć: 0000-0002-3921-7915 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to acknowledge the undergraduate students from the course “Synthèse Appliquée, Séparation, Analyse (SASA)” in the Faculty of Science of the University of Montpellier, France, who conducted these experiments and the Chemistry Department (Faculty of Science of the University of Montpellier) for financial support. We would especially like to thank Laurent Bernaud and Arnaud Folliard (University of Montpellier) for all the help setting up the necessary laboratory equipment. T.F. and G.D. acknowledge the support of an NSERC Discovery Grant (RGPIN-2017-06467) and an E. W. R. Steacie Memorial Fellowship (SMFSU 507347-17).

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Introducing Students to Mechanochemistry via Environmentally

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