Synthesis of the Commercial Fragrance Compound Ethyl 6

Laboratory Experiment pubs.acs.org/jchemeduc

Synthesis of the Commercial Fragrance Compound Ethyl 6‑Acetoxyhexanoate: A Multistep Ester Experiment for the SecondYear Organic Laboratory James V. McCullagh* and Sophia P. Hirakis Department of Chemistry & Biochemistry, Manhattan College, Riverdale, New York 10471-4098, United States S Supporting Information *

ABSTRACT: This synthesis of ethyl 6-acetoxyhexanoate (Berryflor) is designed as an experiment for use in a second-year organic chemistry course focusing on the synthesis and reaction of esters. The compound is described as having a raspberry-like odor with jasmine and anise aspects. A two-step procedure for its synthesis beginning with inexpensive ε-caprolactone is described. The first step involves an acid-catalyzed transesterification of the lactone to form ethyl 6-hydroxyhexanoate. Ethyl 6-hydroxyhexanoate is converted to the desired compound via acetylation under mildly basic conditions to give ethyl 6-acetoxyhexanoate in good yield. The product is characterized using 1H NMR spectroscopy, IR spectroscopy, gas chromatography, thin layer chromatography, and by comparison to commercial samples.

KEYWORDS: Esters, Synthesis, Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Consumer Chemistry, Hands-On Learning/Manipulatives compound is commonly used in fine fragrance applications as well as in cosmetics and soaps.18 In this procedure, students prepare the target diester 3 via a two-step synthesis. It is a modification and expansion of the work presented in the Givuadan patent16 (Scheme 1). Rather than starting from the moderately expensive ethyl 6hydroxyhexanoate 2 as was outlined in the patent, this synthesis is backed up one step to form 2 from the inexpensive and readily available ε-caprolactone 1. Then the patent’s use of an acid-catalyzed acetylation is substituted with a base-catalyzed (NaHCO3) acetylation, which, in small scale testing, was shown to yield a much purer product in higher overall yield. Upon completion the student should be able to

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he synthesis of fragrance compounds is of popular interest in organic laboratory courses. With these experiments, in a safe laboratory setting, students can directly observe the practical applications of organic reactions learned in lecture class. For this reason, the preparation of fragrance compounds is found in numerous laboratory texts1−7 as well as in a large portion of synthetic experimental literature.8−15 However, many of these experiments involve the use the same reaction: a Fischer esterification to produce a variety of simple pleasantsmelling esters.1−12 These include isoamyl acetate (banana aroma),1,2,4,6,7 methyl salicylate (wintergreen aroma),7 butyl acetate (banana and pear aroma),2,3 octyl acetate (orange aroma),2,4 pentyl acetate (banana aroma),2,4 isobutyl propionate (rum aroma),5 hexyl acetate (pear aroma),2 and methyl cinnamate (strawberry aroma).1 The synthesis of ethyl 6acetoxyhexanoate (Berryflor) (Scheme 1) is set apart from such experiments because it combines the use of two different esterforming reactions not often encountered in organic laboratory experiments: the transesterification of ε-caprolactone followed by an acetylation of the ester alcohol intermediate produced in the first step. Ethyl 6-acetoxyhexanoate is a commercial fragrance compound produced by the Givaudan Corporation that is sold under the commercial name Berryflor. The synthesis of this and related fragrance compounds from ethyl 6-hydroxyhexanoate was first described in Givaudan’s patent [U.S. patent 4,668,433] in 1987.16 The product is a clear, pale-yellow liquid at room temperature described as having a floral, fruity, raspberry-like odor with jasmine, anise, and balsamic aspects.16−18 The © XXXX American Chemical Society and Division of Chemical Education, Inc.

• Demonstrate an understanding of the synthesis of esters through the transesterification and acetylation reactions • Show how ring opening of cyclic precursors can be used in the synthesis of linear products • Apply the use of thin layer chromatography to monitor a reaction • Demonstrate the use of IR and 1H NMR spectroscopy to identify their products • Demonstrate the use of gas chromatography to analyze product purity Received: October 21, 2016 Revised: May 28, 2017

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DOI: 10.1021/acs.jchemed.6b00778 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Scheme 1. Synthesis of Ethyl 6-Acetoxyhexanoate (Berryflor)

in dust can cause irritation to the respiratory and gastrointestinal tract. Potassium permanganate can form dangerous mixtures when exposed to some organics or sulfuric acid and therefore needs to be disposed of in a separate waste container. When conducting this experiment, students should work in a well-ventilated fume hood to avoid breathing any toxic vapors. Because several of the chemicals are corrosive or irritants, disposable butylnitrile gloves should be worn during the whole experiment. As always in the organic chemistry lab, students should wear appropriate eye protection.

To check if students have achieved these learning outcomes, observation of their practical laboratory skills and formal lab reports are used. See the Supporting Information for a suggested report setup and grading rubric.

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EXPERIMENTAL OVERVIEW The synthesis can be completed in two lab periods of 3 h by students working individually. The first step of the synthesis is the conversion of ε-caprolactone to ethyl 6-hydroxyhexanoate. ε-Caprolactone and ethanol (excess) along with a catalytic amount of sulfuric acid are refluxed until the reaction is completed, as determined by TLC (hexane/acetone 4/1 eluent; KMnO4 stain). The reaction typically is complete in less than 1 h. After neutralization with sodium bicarbonate, excess ethanol is evaporated. The desired product is separated from the inorganic salt byproducts by extraction using methyl tert-butyl ether and water. Methyl tert-butyl ether was chosen instead of the more common diethyl ether because it does not show a tendency to form explosive peroxides during storage. The organic layer is dried over anhydrous sodium sulfate, and methyl-tert-butyl ether is evaporated to isolate compound 2. The second step of the synthesis is the conversion of compound 2 to compound 3. The product from the first step, excess acetic anhydride, and sodium bicarbonate are refluxed until the reaction is completed (TLC: hexane/acetone 4/1 eluent; KMnO4 stain). The reaction is typically complete in less than 1 h. A small amount of water is added to convert the excess acetic anhydride to acetic acid. The reaction is diluted with water and methyl tert-butyl ether. Solid sodium bicarbonate is added to neutralize the acetic acid. Additional extractions of the organic layer with saturated sodium bicarbonate solutions are used to ensure all the acetic acid was removed. The organic layer was dried over anhydrous sodium sulfate, and solvent was evaporated to give the diester 3. The product of each step is characterized by 1H NMR and IR spectroscopy and gas chromatography. For a detailed procedure, see the student handout in the Supporting Information.

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RESULTS AND DISCUSSION The synthesis of Berryflor has been used as an experiment in the second semester of a second-year organic chemistry laboratory class of 2014 with a total of 29 students. The experiment required two, 3 h lab sessions to complete including product analysis (TLC, 1H NMR, IR spectroscopy, and gas chromatography). All of the students finished the experiment and isolated the target compound in reasonable to excellent yield and with good purity. The average yield for the first step was 77% with a range of 30−96% yield. The second step proceeded with an average yield of 72% with a range of 52−100% yield. In each case, the values at the lower end of the yield range were due to student mishaps such as spills and extraction errors, which were not attributed to the experimental procedure. The overall average yield for the two-step process was 55%. The product was analyzed using thin layer chromatography, gas chromatography, IR spectroscopy, and 1H NMR spectroscopy and compared to spectra from a commercial sample of the products and literature data.19,20 TLC confirmed that the reactions had run to completion and were consistent with a clean reaction. Gas chromatographs were comparable to those of a commercial sample and showed high levels of purity greater than 95% based on GC areas. The IR and 1H NMR spectra of student samples were consistent with the products and exactly matched the spectra of a commercial sample of ethyl 6-acetoxyhexanoate. By observing students performing the experiment and by examination of their lab reports, it was seen that the vast majority (96%) of students were able to use TLC to determine when their reactions were complete. Most of the students either correctly (76%) or mostly correctly (24%) analyzed the IR spectra of compounds 2 and 3 according to their lab reports. This included successfully recognizing the O−H (3400 cm−1), sp3-hybridized C−H (2940−2860 cm−1), CO (1735 cm−1), and C−O (1100−1300 cm−1) peaks expected for the alcohol, alkyl and ester groups present in compound 2 and the sp3hybridized C−H (2940−2860 cm−1), CO (1738 cm−1), and C−O (1164, 1240 cm−1) peaks expected for the alkyl and ester groups present in compound 3. The most common problem students had was picking the C−O stretching peaks from within the fingerprint region of their IR spectra. A majority of students either correctly (76%) or correctly with minor errors (17%) calculated the expected chemical shifts of compounds 2

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HAZARDS The solvents used in this experiment, methyl tert-butyl ether, ethanol, deuterated chloroform, and acetone, are flammable solvents of moderate toxicity. Hexane is suspected to be neurotoxic; heptane or cyclohexane could be used as a safer alternative. Sulfuric acid and acetic anhydride are corrosive and toxic. ε-Caprolactone is an eye and skin irritant and is moderately toxic. Ethyl 6-hydroxyhexanoate and ethyl 6acetoxyhexanoate (Berryflor) are moderate skin irritants, and gloves should be used when using these compounds. Potassium permanganate is corrosive and strongly irritating to skin and eyes. Students must wear disposable butylnitrile gloves and safety goggles when handling potassium permanganate solutions. Work in a hood when preparing potassium permanganate solutions to avoid breathing in dust. Breathing B




Scheme 2. Transesterification Ring Opening of ε-Caprolactone

Scheme 3. Formation of Polycaprolactone under Low Ethanol Concentration

and 3 using 1H NMR correlation tables in their textbook and then correctly assigned the peaks in their NMR spectra as judged by their lab reports.1 Close to three-quarters (72%) of the students were capable of determining the purity of their products by the single peak seen in the gas chromatographs of their samples of 2 and 3. Of the remaining students, 21% analyzed their gas chromatographs with only minor errors. Their most common error was to confuse the solvent peak from syringe washing as an impurity in their sample. Most

students demonstrated their understanding of transesterification and acetylation reaction as determined by examining the mechanism section of their lab reports. For the transesterification mechanism, 86% of the students presented a totally correct mechanism, and 10% gave a mechanism that was mostly correct with only minor errors. For the acetylation mechanism, 72% of the students presented a correct mechanism, and 7% presented a mechanism that was mostly correct containing only minor errors. From this, it can be seen C




from a lactone, through an ester intermediate. This experiment uses ester starting materials and ester intermediates and produces ester products using atypical esterification methods. The experiment is from esters, to esters, through esters, by esters. The experiment received considerable positive feedback from the students who appreciated the fact that they were making a commercially relevant compound and enjoyed the pleasant raspberry smell of Berryflor. Student feedback included written comments such as “I enjoyed the final product, for it had a sweet fruity smell and I find it interesting that what I made is most likely in a lotion I have in my own room”; “I found this experiment to be a fairly challenging experiment and I enjoyed doing it because I enjoy making products that smell nice”; “Berryflor is used in making cosmetics and perfumes due to the great smell it has. Preparing Berryflor in a two step process was successful, challenging and honestly fun.” and “Berryflor has a distinct smell similar to that of raspberry and jasmine. In smelling our product, we did see there is a distinct smell similar to that of actual Berryflor.”

that from an experimental and pedagogical standpoint, the experiment was largely successful. The students were able to complete the two-step synthesis and obtain Berryflor in moderate to good yield and high purity. The experiment also successfully instructed students how esterification via the transesterification and acetylation reactions works. Additionally, it reinforced students’ skills using TLC, gas chromatography, and IR and 1H NMR spectroscopy. A positive aspect of the experiment is that the reagents used in this experiment are all inexpensive. Based on current prices (March 2017) of the reagents at Fisher Scientific and VWR International, for example, on a per student basis, the costs for the following reagents were ε-caprolactone $0.11, ethanol $0.38, and acetic anhydride $0.08. The reagents used in this experiment are actually less expensive than the solvent, methyl tert-butyl ether, used for extractions, which cost approximately $0.80 per student. Overall, the total cost of this experiment was quite reasonable compared to other organic laboratory experiments. From a pedagogical standpoint, there are several key concepts that this experiment demonstrates to students. The experiment is an excellent overview of the chemistry of esters. In fact, the starting materials, intermediate, and product of the synthesis are all esters. In the first step, a transesterification with ethanol is used to ring open a lactone to produce an ester alcohol intermediate 2. Next, an acetylation reaction is used to convert the intermediate 2 into the desired diester 3. The two synthetic steps encountered in this experiment are atypical of an ester synthesis laboratory experiment. The commonly used Fischer esterification is replaced by a transesterification and acetylation. The nucleophilic attack of ethanol on a cyclic precursor (Scheme 2) to form a linear product is not a synthetic manipulation that most students will think of on their own in the synthesis of the target compound. This synthesis introduces the strategy of using a ring opening reaction on a cyclic intermediate to produce a linear product with functional groups on both ends. Additionally, the first step of this synthesis demonstrates how reaction conditions can be rationally adjusted to maximize product yield. It is known that in the presence of protic or Lewis acids, ε-caprolactone will polymerize to form polycaprolactone 421−23 (Scheme 3). The ratio of the desired product 2 to the side product polycaprolactone 4 was determined by the reaction rates of ethanol and 2 with εcaprolactone. In order to maximize the yield of ethyl-6hydroxyhexaonate 2 in the first step, a large excess of ethanol is used. Excess ethanol increases the probability that an εcaprolactone molecule reacted with ethanol rather than a molecule of ethyl-6-hydroxyhexanoate 2.

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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.6b00778. Detailed experimental procedure, instructor’s notes, as well as representative student gas chromatographs, IR and 1H NMR spectra, and TLC plates (PDF, DOC)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

James V. McCullagh: 0000-0003-0072-9603 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The author would like to acknowledge Donald Clarke and the Fordham University Chemistry Department for generously donating their time and the use of their Bruker Advance 400 NMR spectrometer to obtain the high-field NMR spectra shown in the supplemental section.

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REFERENCES

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CONCLUSION The synthesis of Berryflor relates concepts learned in organic lecture to real-world applications. It is a cost-effective, multistep synthetic route toward a commercial fragrance compound. In addition to giving any laboratory a sweet-smelling aroma, this experiment is an excellent example of ester chemistry. The transesterification/lactone ring opening and acetylation reactions used are not ester-forming reactions commonly encountered in second-year organic lab experiments. The experiment explores the chemistry of the ester functional group in much greater depth than a typical Fischer esterification experiment, showing students a way to synthesize a diester D




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Synthesis of the Commercial Fragrance Compound Ethyl 6

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