Laboratory Experiment

pubs.acs.org/jchemeduc

Synthesis of the Commercial Fragrance Compound Ethyl

6‑Acetoxyhexanoate: A Multistep Ester Experiment for the Second-
Year 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

T 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 pleasant-
smelling 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 propio-
nate (rum aroma),5 hexyl acetate (pear aroma),2 and methyl
cinnamate (strawberry aroma).1 The synthesis of ethyl 6-
acetoxyhexanoate (Berryflor) (Scheme 1) is set apart from such
experiments because it combines the use of two different ester-
forming 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 com-
pound 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.
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 6-
hydroxyhexanoate 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
• 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
A DOI: 10.1021/acs.jchemed.6b00778
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Journal of Chemical Education
Scheme 1. Synthesis of Ethyl 6-Acetoxyhexanoate (Berryflor)
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.
■
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.
■
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 6-
acetoxyhexanoate (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 DOI: 10.1021/acs.jchemed.6b00778
Laboratory Experiment
in dust can cause irritation to the respiratory and gastro-
intestinal 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.
■ 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 sp3-
hybridized 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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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
C DOI: 10.1021/acs.jchemed.6b00778
students demonstrated their understanding of transesterifica-
tion and acetylation reaction as determined by examining the
mechanism section of their lab reports. For the trans-
esterification 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
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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 poly-
caprolactone 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 ε-
caprolactone. In order to maximize the yield of ethyl-6-
hydroxyhexaonate 2 in the first step, a large excess of ethanol is
used. Excess ethanol increases the probability that an ε-
caprolactone molecule reacted with ethanol rather than a
molecule of ethyl-6-hydroxyhexanoate 2.
■
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 reac-
tions 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 DOI: 10.1021/acs.jchemed.6b00778
Laboratory Experiment
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.”
■
*
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)
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: james.mccullagh@manhattan.edu.
ORCID
James V. McCullagh: 0000-0003-0072-9603
Notes
The authors declare no competing financial interest.
■
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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