Isolation and Derivatization of Sucralose from an Artificial Sweetener

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

pubs.acs.org/jchemeduc

Isolation and Derivatization of Sucralose from an Artificial Sweetener to Provide a Hands-On Laboratory Experiment Emphasizing Synthesis and Purification Paige J. Monsen and Frederick A. Luzzio* Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, United States

J. Chem. Educ. Downloaded from pubs.acs.org by IDAHO STATE UNIV on 04/01/19. For personal use only.

S Supporting Information *

ABSTRACT: A laboratory experiment is detailed that entails the separation and derivatization of the artificial sweetener sucralose from a commercially available sweetener mixture. The experiment utilizes 1 g packets of a sucralose-based artificial sweetener and involves the separation of the synthetic sweetener from the more polar bulk additives by differential solubility. The semipure trichlorosucrose is then acetylated with acetic anhydride and purified using extraction and mini-column chromatography. The isolation, extraction, and chromatography can be followed by thin-layer chromatography in conjunction with 1H and 13C NMR spectroscopy for ascertaining purity during the process as well as final structural confirmation. The experiment is designed to utilize two 4 h laboratory periods, including any spectral work, and employs the laboratory apparatuses found in most undergraduate organic laboratories. During the experiment, the students learn separation by solubility, filtration, extraction, thin-layer and column chromatography, and acetylation of a carbohydrate to make a characterizable derivative. The usefulness of obtaining 1H and 13C NMR spectra as applied to structural analysis of carbohydrates and their derivatives is demonstrated. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Synthesis, Thin Layer Chromatography, Chromatography, NMR Spectroscopy, Carbohydrates

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INTRODUCTION Very few consumer products take center stage in the food and drink market like non-nutritive “artificial” sweeteners. Also known as sugar substitutes, these compounds are found in “diet” or “sugar-free’’ soft drinks, juices, ice creams, yogurts, jellies, candies, chewing gums, and bakery items. The sweeteners are also available as individually packaged commodities for addition to coffee, tea, or wherever one desires to avoid the caloric intake of natural sugar. Despite the differences in taste as compared with natural sugar, many consumers use artificial sweeteners out of necessity for health reasons, such as diabetes or weight control. The three major artificial sweeteners are saccharin, aspartame, and sucralose (Figure 1). Interestingly, the three sweeteners fall into three distinctly different classes of compounds, and each elicits an intensely sweet taste. Saccharin is a nitrogen−oxygen heterocycle, aspartame is a dipeptide (methyl)ester, and sucralose is a sugar derivative. Sucralose, 4,1′,6′-trideoxy-4,1′,6′-trichlorogalactosucrose (1), is a derivative synthesized from sucrose whereby three of the hydroxy groups of the natural sugar are replaced with three chlorine groups, resulting in a product with two primary chlorine groups and one secondary one. An © XXXX American Chemical Society and Division of Chemical Education, Inc.

Figure 1. Three major artificial sweeteners on the market.

inversion of the hydroxy group on carbon 4 gives a chlorine group in the galacto position (Figure 2). Sucralose was synthesized by Tate and Lyle in 1976 and introduced as a food-additive candidate after a great deal of research went into its synthesis and purification with the goal of yielding a safe product for consumers.1,2 Sucralose itself is 450−650 times sweeter than sucrose, and a sucralose-based packet contains roughly 1% of the sweetening agent with two other major ingredients, dextrose and maltodextrin, which are bulking agents.3 Sucralose was approved by the FDA in 1998 Received: June 7, 2018 Revised: March 18, 2019

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DOI: 10.1021/acs.jchemed.8b00413 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Table 1. Pedagogical Goals Questions To Be Answered in the Experiment What properties of the three compounds found in the sweetener packet allow for successful separation, in relation to the solvent used? What is the mechanism of the acetylation reaction performed on the artificial sugar? How is the pyridine removed from the reaction mixture? How does performing TLC help determine reaction completeness? How has the polarity of the compound changed after performing an acetylation on the sugar? How does one expect to know when the desired compound elutes from the column? What characteristic peaks should be observed in the NMR spectra that confirm acetylation at all five hydroxy positions?

Figure 2. Synthetic derivative 1, sucralose, synthesized from natural sugar.

and has since become the top artificial sweetener available to consumers. Sucralose-based table-top sweeteners were used by 65.52 million Americans in 2017, whereas the second-mostused artificial sweetener, saccharin, was used by less than half that number at 29.74 million.4 Saccharin was the first sugar substitute available for human consumption. Made in 1885 by Remsen and Fahlberg, it was primarily used during the World Wars before becoming available to public consumers.5 A 1970 report linking saccharin to bladder cancer caused the compound to be placed on the U.S. National Toxicology Program’s Report on Carcinogens list from 1981 to 2000, leading to its temporary removal from market.6 While saccharin was momentarily removed from the market, the dipeptide aspartame gained FDA approval in 1996 as an allpurpose sweetening additive.3 The experiment described herein employs a commercially available sucralose-based artificial sweetener as a foundation for an experiment designed for a second-semester organic laboratory course. The experimental design allows students to perform a traditional classroom experiment and utilizes chromatography for both monitoring reaction progress and purifying the crude product. Upon obtaining pure material, the students can confirm the product structure using NMR spectroscopy. The sucralose experiment complements previous experiments that involve the isolation of natural products, such as the isolation of (−)-menthol from peppermint oil and parthenolide from Tanacetum parthenium, as well as the chromatographic analysis of peppermint and spearmint leaf extracts.7−9 Because a carbohydrate is a reactant, the product’s 1 H NMR spectrum can be slightly complex for secondsemester organic students to analyze; therefore, NMR spectra are used only to confirm that five acetate groups are present in the product. This experiment can also be tailored for students in an advanced organic-chemistry lab, where NMR spectroscopy is emphasized. Instructors can add 2D-NMR spectroscopy experiments (e.g., DEPT, COSY, HSQC, etc.) so students can fully characterize the product. Whether this experiment is utilized for a second-semester lab or is altered to fit a more advanced class, the core learning outcomes are kept consistent.

Experiment Part I II, postlab II, prelab II, prelab II III, prelab IV, postlab

experiment whereby the students successfully extract sucralose from a commercially available product, execute acetylation on the artificial sugar, perform a purification to yield product, and analyze the product by NMR spectroscopy and melting-point analysis. When faced with the laboratory experiment and questions, most students succeed at correlating the conceptual objectives to the actual experiment performed. Because this experiment is designed to be a 2 week experiment, the students can analyze the data obtained from the reaction together with the first TLC performed and use these observations as preparation for the purification steps the following week (Week 2). After completing this experiment, students should feel comfortable utilizing multiple organic-chemistry skills while performing in the lab, tasks that are often found in research laboratories. Students focus on executing the techniques required as well as interpreting the information provided from TLC and spectral data. Keeping the pedagogical goals as the foundation of the learning objective, students • perform an acetylation reaction of all five hydroxy positions of a carbohydrate; • prepare, load, and use a gravity column to successfully purify a crude reaction product; • conduct TLC as a means of analyzing a reaction product and as a way to test a fraction’s purity; • successfully develop a TLC plate and visualize with a panisaldehyde stain; and • correctly choose the pure fractions and prepare the product for spectral analysis. The success of the students in accomplishing the pedagogical goals and learning outcomes is performed in a formative manner. Prelab and postlab worksheets are provided to guide students toward understanding the underlying concepts. The prelab lecture involves class participation in which students are asked for verbal responses, and instructors demonstrate and review the core lab techniques to ensure students are familiar with the required practical skills. Further assessment is completed by a written report. The success of the experiment is not based on yield but on the student’s ability to obtain a pure product and correlate the theoretical concepts that are taught in class with basic laboratory practice.

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PEDAGOGICAL GOALS AND LEARNING OUTCOMES The experiment described involves a simple chemical reaction surrounded by fundamental organic-chemistry techniques and spectral application. Students complete the necessary skills in the positive learning setting of a teaching laboratory and connect classroom learning to a hands-on exercise. The practical engages students through the use of an everyday product (a sweetener packet) with the integration of multiple concepts and techniques to provide the experience and excitement that is present in a research setting. The pedagogical goals are listed in Table 1 and encompass an

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EXPERIMENTAL OVERVIEW The sucralose experiment is designed for undergraduate students who have completed a semester of an introductory organic-chemistry laboratory. The experiment utilizes basic B




packed their columns and are prepared to perform the purification steps, they load 2 onto the columns and begin separation. The purity of each fraction is tested with TLC, and the pure fractions are collected when the solvent is removed by a rotary evaporator. Removal of the solvent with a rotary evaporator does not result in crystals; therefore, students crystallize the product by trituration with a small amount of cold hexane and subsequent cooling to obtain pure, white crystals. Experimental data (TLCs, melting points, and NMR spectra) as well as instructor notes on any modifications are provided in the Supporting Information.

organic-chemistry techniques to isolate, derivatize, and characterize sucralose from a commercially available sweetener mixture.10 After the experiment was optimized by the instructor, it was performed by 11 second-year undergraduate students who had completed at least one semester of introductory organic-chemistry laboratory. These students were invited to our research laboratory to complete the experiment in two lab periods. After reproducibility, successfulness, and learning objectives were confirmed by the select group, the experiment was implemented into four sections of a second-semester organic-chemistry laboratory course, with each section ranging from 10 to 16 students. The students completed the experiment over two lab periods of 4 h each. The experiment is separated into two parts, where different pedagogical goals and learning objectives are met. Within the Supporting Information is a detailed experimental procedure and list of chemicals and supplies needed to complete the experiment. 1. First lab period. I. Extraction of sucralose from the more polar additives in a sucralose-based artificial sweetener packet. II. Acetylation reaction of sucralose, including the workup of the reaction product to yield a crude product. III. TLC and visualization of the crude product using p-anisaldehyde stain. 2. Second lab period. IV. Purification of the crude product by gravity column chromatography using TLC to follow separation of components. V. Characterization by melting point as well as obtaining of 1H and 13C NMR spectra. Students complete Parts I, II, and III of the experiment during the first lab meeting where they first extract sucralose (1) from commercially available packets by differential solubility using a solution of acetone−ethyl acetate (98:2, v/ v). After solvent removal, a clear, syruplike product results that is the starting material for Part II. Students acetylate 1 using acetic anhydride (300 μL, 3.18 mmol, excess) and pyridine (0.5 mL, 6.21 mmol, excess) with stirring at room temperature (75 min, Scheme 1). After the reaction is complete, the

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HAZARDS

Suitable personal-protection equipment such as eye protection, a lab coat, and gloves are worn when working with the materials in this experiment. Sucralose is approved by the FDA for use in commercial food products; however, ingestion is prohibited in the laboratory and extremely large amounts (gram sizes) may be harmful if swallowed. All organic solvents and reagents are treated as flammable and harmful if inhaled, swallowed, or absorbed through the skin. n-Hexane is a neurotoxin and is handled with extreme care with proper disposal (pentane may be used in place of hexane). A wellventilated fume hood is recommended during the acetylation of sucralose (exothermic). Precautions are taken when using aqueous hydrochloric acid, which is corrosive. The panisaldehyde TLC stain contains sulfuric acid, and other organic reagents and solvents are handled with gloves and treated as flammable and harmful irritants. Silica gel is an inhalation hazard, and the generation of dust is avoided. Dichloromethane (used only in the student learningexperience group) is very hazardous to skin (irritant) and eyes, and inhalation is avoided (carcinogen!). Hazards are not fully known for the product, acetylated sucralose, and it is treated as an irritant, so contact with skin, eyes, and mouth is avoided. Do not taste the product. Deuterochloroform (CDCl3) is a volatile irritant that is a suspected carcinogen and is handled with extreme care. A more detailed list of hazardous substances is available in the Supporting Information on pages S4−S5.

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RESULTS AND DISCUSSION Sucralose was separated from bulking agents in the sweetener by differential solubility. Combinations of diethyl ether, chloroform, dichloromethane, hexane, acetone, and ethyl acetate were tested for the relative solubility of the packet contents, and it was discovered that the slightly less polar sucralose is soluble in acetone−dichloromethane (95:5, v/v) or acetone−ethyl acetate (98:2, v/v). The initial group utilized acetone−dichloromethane; however, because of the hazards associated with dichloromethane, the acetone−ethyl acetate solution was used when introducing the experiment to the undergraduate organic laboratory sections. Both solvent options are equally effective, the choice of which depends on the instructor’s discretion and department policies. The extraction demonstrated how differential solubility is used to separate one compound from others, thereby providing a purer starting material for the acetylation. The removal of the less polar sucralose from the more polar dextrose and maltodextrin gives purer product, which results in easier purification of the final product. All 11 students who composed the learning-

Scheme 1. Extracted 1 Undergoing Acetylation in the Presence of Acetic Anhydride and Pyridine at All Five Hydroxy Positions to Yield 2

workup consists of various washes to remove the pyridine and obtain a dry, crude product, 4,1′,6′-trideoxy-4,1′,6′-trichlorogalactosucrose pentaacetate (2). Before removal of the ethyl acetate, TLC is performed on the crude product using a panisaldehyde stain to visualize the product spots and to ensure the reaction was successful. Parts IV and V entail the purification of 2 and its characterization. The students purify 2 using gravity column chromatography on silica gel. Once students have successfully C




about concepts and techniques used to complete the experiment. Upon the completion of the reaction, the students advanced to the workup, in which they removed pyridine from a reaction mixture. Knowledge of acid−base chemistry helps the students correlate this topic to the experimental process. The protonation of the pyridine nitrogen with hydrochloric acid gives the ionic aqueous-soluble pyridinium ion. Removal of pyridine is important before performing TLC on the product because the pyridine causes “tailing” and “streaking” on the TLC plate during development, which results in poor visualization. TLC was performed immediately following filtration of the drying agent, with the product dissolved in ethyl acetate. Students used this opportunity to confirm product formation and visualize the polarity change of the compound after the transformation of the hydroxy groups to acetate groups.15 The students’ TLC plates of the crude product show their main product, 2, as the denser spot with the highest Rf, with two lighter spots running lower on the plate (Figure 3a). The lower-running spots are most likely acetylated dextrose or maltodextrin that was not fully separated at the beginning. Students visualized this transformation on their TLC plates and correlated this to polarity changes, a crucial pedagogical goal. Prelaboratory questions (see the Supporting Information) prepared the students for the expected observations. Students were provided questions about chromatography based on polarity to probe their thoughts on what they observed on their TLC plates following the completion of the reaction. Students also used inductive reasoning to postulate what other compounds could be found in the crude product. The instructor confirmed that each student obtained an effective TLC plate to ensure success of the following purification lab period. All students effectively completed Parts I, II, and III within the 4 h time block. All 53 students of the undergraduate course obtained reaction product and successfully executed TLC indicating product 2. The students visualized the polarity changes that resulted from transforming all hydroxy groups to acetate groups, and noted that the major product is the most nonpolar spot on the TLC plate, and the other spots are chromatographically separable byproducts. Purification of crude 2 is performed with mini-column chromatography.16 The students came prepared to the second

experience group successfully isolated sucralose in a reasonable yield (Table 2).11 All 53 students in the second-semester Table 2. Results of Students from the Learning-Experience Group

Student

Crude Sucralose Extracted from Packets (g)

Pure Acetylated Sucralose Obtained after the Columna (g)

Percent Yield of Pure Acetylated Product (%)

Melting Rangeb (°C)

1 2 3 4 5 6 7 8 9 10 11

0.143 0.105 0.152 0.162 0.162 0.156 0.156 0.185 0.169 0.152 0.164

0.069 0.099 0.117 0.128 0.142 0.143 0.110 0.119 0.107 0.113 0.079

32 62 50 52 57 58 46 42 41 49 32

95−97 97−100 97−100 97−99 96−99 94−96 96−100 96−99 95−97 96−98 98−100

a

The mass of the product is relative to the amount of extracted starting material from the packets (100−200 mg). bLiterature melting point, 99−101 °C.12

course successfully extracted sucralose from the packets. The excess amount of reagents in the reaction step resulted in acetylation of any unwanted dextrose and maltodextrin. The acetylated dextrose and sucralose products have similar polarities and Rf values, resulting in complicated chromatographic purification. Consequently, for a successful purification, the importance of the extraction step was stressed. When reacted with acetic anhydride and pyridine, sucralose undergoes acetylation of all five hydroxy groups at room temperature (Scheme 1).13,14 The reaction is air stable, utilizes inexpensive reagents, and occurs rapidly, making it ideal for a teaching laboratory. To ensure that students successfully conduct the required practical skills, the instructor utilized the period during the reaction to demonstrate TLC-development techniques and how to pack a gravity-chromatography column, two new skills for the students enrolled in this course. This is also an opportune time for students to ask questions

Figure 3. Representative student TLC performed during the experiment using 1:1 hexane−ethyl acetate and staining with p-anisaldehyde. (a) TLC plate of crude 2 before purification (left) and starting material (right). (b) TLC plate after column chromatography of two different fractions: fraction containing pure 2 (left) and fraction containing impure product (right). D




Table 4. 1H NMR Assignments of Acetylated Product, 2

lab meeting with an idea of which spot represented the desired product and where it would elute during column chromatography. Although students should have been instructed on how to load, pack, and perform the gravity column during the previous lab meeting, instructors should briefly review the general procedure, concepts, and safety before the students begin. Column conditions were optimized before testing by the learning group in which all students successfully loaded and packed their own columns. Compound 2 is the most nonpolar compound found within the crude mixture and eluted first from the column. Students utilized TLC as a means of visualizing which fractions contained pure product versus which had multiple products within them (Figure 3b). It was stressed that the goal of the experiment was to obtain pure product for characterization, not to obtain the best yield. Although students found the column chromatography challenging at first, the overall feedback following the completion of the column was that it successfully provided students with pure product that could be visualized immediately with TLC. A more detailed account of the fractions collected and TLC performed is in the Supporting Information. Following the collection of pure fractions and the removal of the eluent, the product was crystallized from the semidry syrup by trituration with cold hexane and cooling. The white crystals precipitated further, and the hexane was removed by either a rotary evaporator or vacuum filtration to obtain pure compound. The learning group obtained pure, white crystals using the rotary evaporator (Table 2), and the students enrolled in the organic lab course successfully obtained pure product after vacuum filtration (Table 3). It was decided to use vacuum filtration with the students in the organic course because of the limited availability of rotary evaporators.

Proton Assignment H-1 H-2 H-3 H-4 H-5 H-6 H-1′a H-1′b H-3′ H-4′ H-5′ H-6′ −OAc (5 × CH3)

δ (ppm) 5.65 5.28 5.28 4.54 4.54 4.22 3.69 3.57 5.67 5.39 4.22 3.74 2.07−2.14

3

JH−H (Hz)

3

d, J1−2 < 1 m m m m m d, 3J1′a−1′b = 12.4 d, 3J1′b−1′a = 12.4 d, 3J3′−4′ = 6.4 d, 3J4′−3′ = 6.4, 3J4′−5′ = 6.4 m d, 3J6′−5′ = 6.0 

Table 5. Distribution of Melting-Point Data from the Second-Semester Organic-Chemistry Course Melting-Point Range (°C)

Number of Students

96−98 98−100 100−102

3 45 4

Table 3. Results of Students from the Second-Semester Organic-Chemistry Course Section

Average Crude Percent Yield Before Column (%)

Average Percent Yield of Pure 2 After Column (%)

1 2 3 4

54 62 59 51

32 42 45 35

Figure 4. Acetate regions of both the 1H and 13C NMR spectra of 2. (a) Expanded region showing five separate acetate methyl peaks integrating to 15 protons total. (b) Expanded region showing five separate carbonyl peaks.

Using gravity column chromatography, 52 of 53 students isolated enough pure product to obtain a melting point as well as 1H and 13C NMR spectra. The melting points obtained by the learning-experience group were consistent with the literature value (Table 2). Pure products collected also displayed the expected 1H and 13C NMR peak assignments (Table 4).17 The students in the second-semester laboratory sections had sufficient time to obtain melting points and spectral data. All melting points (Table 5) and NMR spectra were consistent with expected results. The pedagogical goal in this practical is for students to confirm that all hydroxy groups were replaced with acetate groups. Figure 4 shows an expansion of the acetate regions of both the 1H and 13C NMR spectra. The students identified peaks that correlated with the five acetate groups and concluded that the reaction progressed to completion. Visualization and assignment of both the 1H and 13C NMR spectra as well as the results of student NMR spectra are in the Supporting Information.

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CONCLUSION We have developed a functional, straightforward experiment that is appropriate for undergraduate organic teaching laboratories with an emphasis on chromatography and carbohydrate chemistry. The techniques involve isolation, synthesis, purification, and spectral analysis. Students are introduced to a handful of useful techniques, including the separation of similar compounds using solubility characteristics, chromatography to both monitor a reaction and purify a product, and NMR spectroscopy to confirm the outcome of a chemical reaction. The experiment highlights the importance of thin-layer chromatography in monitoring the progress of a reaction as well as following the purification of a compound through column chromatography. For teaching laboratories without access to an NMR spectrometer, the spectral data E




(−)-Menthol from Peppermint Oil and Its Conversion to (−)-Menthyl Acetate. J. Chem. Educ. 2015, 92 (10), 1736−1740. (8) Walsh, E. L.; Ashe, S.; Walsh, J. J. Natures Migraine treatment: Isolation and structure elucidation of parthenolide from Tanacetum parthenium. J. Chem. Educ. 2012, 89 (1), 134−137. (9) Pelter, L. S. W.; Amico, A.; Gordon, N.; Martin, C.; Sandifer, D.; Pelter, M. W. Analysis of Peppermint Leaf and Spearmint Leaf Extracts by Thin-Layer Chromatography. J. Chem. Educ. 2008, 85 (1), 133−134. (10) Sucralose has been the topic of educational articles in this Journal: (a) Heider, E. C.; Valenti, D.; Long, R. L.; Garbou, A.; Rex, M.; Harper, J. K. Quantifying Sucralose in Water-Treatment Wetlands: Service-Learning in the Analytical Chemistry Laboratory. J. Chem. Educ. 2018, 95 (4), 535−542. (b) Ellis, J. W. Overview of Sweeteners. J. Chem. Educ. 1995, 72 (8), 671−675. (11) It should be noted that the separated sucralose will not be 100% pure; there will be some residual “bulking agent” that may be extracted along with the sucralose. (12) Wen, H.-L.; Fang, Z.-J.; Wu, Z.-S.; Xie, M.-Y. 6(Acetoxymethyl)-5-chloro-2-[(2R, 3R, 4R, 5S)-3,4-diacetoxy-2,5-bis(chloromethyl)-2,3,4,5-tetrahydrofuran-2-yloxy]-3,4,5,6-tetrahydro2H-pyran-3,4-diyldiacetate toluene solvate. Acta Crystallogr. 2006, E62, o1157−o1159. (13) The amount of reagents used was optimized before students performed experiments. This is in regard to the fact that students will extract different amounts of sucralose (starting material) from the sweetener packets. On the basis of student results, this can be an amount from 0.105 to 0.185 g. The optimized amounts of reagents were calculated to ensure excess was used. (14) Mann, T. D.; Mosher, J. D.; Wood, W. F. Preparation of Sucrose Octaacetate A Bitter-Tasting Compound. J. Chem. Educ. 1992, 69 (8), 668−669. (15) Brinkman, U.A. Th.; De Vries, G. Small-Scale Thin-Layer Chromatography. J. Chem. Educ. 1972, 49 (8), 545−546. (16) Davies, D. R.; Johnson, T. M. Isolation of Three Components from Spearmint Oil: An Exercise in Column and Thin-Layer Chromatography. J. Chem. Educ. 2007, 84 (2), 318−320. (17) Tachrim, Z. P.; Wang, L.; Yoshida, T.; Muto, M.; Nakamura, T.; Masuda, K.; Hashidoko, Y.; Hashimoto, M. Comprehensive Structural Analysis of Halogenated Sucrose Derivatives: Revisiting the Reactivity of Sucrose Primary Alcohols. ChemistrySelect 2016, 1 (1), 58−63.

could be provided to students, and IR spectroscopy could be performed in order to show the loss of hydroxy groups and the presence of carbonyls. The range of concepts and skills incorporated in the experiment allows the instructor to tailor the focus in specific areas of the experiment to better fit the course objectives and level of the students. For example, the laboratory exercise can be modified for an upper-level spectroscopy course by having students perform 2D NMR experiments to fully establish proton and carbon assignments. Feedback and formal evaluations from students confirmed that this practical was successful in fulfilling the pedagogical goals of the experiment.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.8b00413. Detailed instructions for the separation, acetylation, purification, and characterization procedures; instrument and materials lists; student exercises; and a reproduction of spectra obtained (PDF, DOCX)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Frederick A. Luzzio: 0000-0002-9903-0781 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS P.J.M. thanks the University of Louisville for a Graduate Assistantship. Jarrid M. Ronnebaum is acknowledged for his assistance.

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REFERENCES

(1) (a) Jenner, M. R.; Waite, D.; Jackson, G.; Williams, J. C. Process for the Preparation of 4,1,6-trichloro-4,1,6-trideoxygalactosucrose. U.S. Patent 4362869, Dec 7, 1982. (b) Hough, L.; Phadnis, S. P.; Khan, R. A. Sweeteners. U.S. Patent 4435440, March 6, 1984. (c) Khan, R. A.; Sankey, G. H.; Simpson, P. J.; Vernon, N. M. Chlorination of Sugars. U.S. Patent 5136031, Aug 4, 1992. (d) Navia, J. L.; Walkup, R. E.; Vernon, N. M.; Wingard, R. E., Jr. Sucralose Pentaester Production. U.S. Patent 5298611, March 29, 1994. (2) (a) Hough, L.; Phadnis, S. P. Enhancement in the Sweetness of Sucrose. Nature 1976, 263 (5580), 800. (b) Hough, L. The Sweeter Side of Chemistry. Chem. Soc. Rev. 1985, 14, 357−374. (3) Ager, D. J.; Pantaleone, D. P.; Henderson, S. A.; Katritzky, A. R.; Prakash, I.; Walters, D. E. Commercial, Synthetic Nonnutritive Sweeteners. Angew. Chem., Int. Ed. 1998, 37 (13−14), 1802−1817. (4) U.S. Population: Which Brands of Sugar Substitutes Do You Use Most Often?; Statista, 2018. https://www.statista.com/statistics/ 278629/us-households-most-used-brands-of-sugar-substitutes/.html (accessed March 2019). (5) (a) Fahlberg, C.; Remsen, I. Ueber die Oxydation des Orthotoluolysulfamids. Ber. Dtsch. Chem. Ges. 1879, 12 (1), 469− 473. (b) Walter, G. J.; Mitchell, M. L. Alternative Sweeteners; Marcel Dekker: New York, NY, 1986. (6) Bryan, G. T.; Erktürk, E.; Yoshida, O. Production of Urinary Bladder Carcinomas in Mice by Sodium Saccharin. Science 1970, 168 (3936), 1238−1240. (7) Egan, M.; Connors, É . M.; Anwar, Z.; Walsh, J. J. Nature’s Treatment for Irritable Bowel Syndrome: Studies on the Isolation of F


Isolation and Derivatization of Sucralose from an Artificial Sweetener

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