Chem. Educator 2014, 19, 347–350
347
A “Green” Approach to Synthesis of trans-4-Methoxycinnamic acid in
the Undergraduate Teaching Laboratory
Kristopher J. Keuseman* and Nicole C. Morrow
Department of Natural & Applied Sciences, Mount Mercy University, Cedar Rapids, Iowa 52402,
kkeuseman@mtmercy.edu
Received August 5, 2014. Accepted September 25, 2014.
Abstract: A green Knoevenagel reaction is described utilizing microwave irradiation. Students prepare trans-4methoxycinnamic acid from malonic acid and 4-methoxybenzaldehyde (p-anisaldehyde) with ammonium acetate
as a catalyst under solvent-free conditions. The product is purified by recrystallization and analyzed by proton
NMR. The proton NMR spectrum allows students to determine the substitution pattern of the benzene ring and
relative stereochemistry of the double bond through examination of the splitting pattern and coupling constants.
The principles of green chemistry are demonstrated through use of low hazard reactants and reagents. The
solvents used in purification of the product are derived from renewable resources and are biodegradable.
Furthermore, the use of solvent-free conditions and microwave heating demonstrate resource conservation and
waste reduction techniques.
O
Introduction
O
+
Carbonyl condensation reactions are often an important
topic in second-semester sophomore organic chemistry. In the
laboratory portion of the course, Aldol, Claisen, Dieckmann
and Knoevenagel reactions [1] are often used to illustrate
carbonyl chemistry. As part of our ongoing lab development,
we sought a new experiment to teach carbonyl chemistry. Of
the numerous possible target molecules, cinnamic acid and its
derivatives stood out to us because of its biochemical
relevance to lignin, which is a biopolymer that helps
strengthens cell walls [2]. As part of the “shikimate pathway”
[2], cinnamic acid is an important intermediate in plant
metabolism. Cinnamic acids are also useful starting
compounds for organic synthesis. The broad-spectrum
antibiotic chloramphenicol [3] can be synthesized from a
cinnamic acid derivative. The synthesis of cinnamic acid has
previously been explored in the sophomore organic chemistry
laboratory. In 1990 Kolb et al. [4] published a microscale
experiment using benzaldehydes and malonic acid. The authors
report satisfactory yields (50–80%) using the Verely-Doebner
modification of the classic Knoevenagel reaction using
pyridine and β-alanine to catalyze the reaction under reflux.
Similarly, Harwood and co-workers describe a similar reaction
using pyridine and piperidine [5]. In our hands the reaction
described by Harwood and co-workers worked well, but we
were not satisfied with the use of hazardous reagents (pyridine
and piperidine are toxic and corrosive; pyridine is also
considered a carcinogen). Therefore, we sought a more “green”
application of the Knoevenagel reaction for our students.
Kumar et al. reported [6] that cinnamic acids could be formed
under solvent-free conditions using ammonium acetate as a
catalyst with microwave irradiation (Scheme 1). Ammonium
acetate is advantageous as a catalyst for the Knoevenagel
reaction in the teaching environment because it’s a
nonhazardous, inexpensive solid. Furthermore, use of solventfree conditions and microwave irradiation are both
advantageous from the standpoint of green chemistry [7]: the
HO
O
O
H
OH
MeO
NH4 OAc
W
OH
MeO
Scheme 1.
lack of solvent prevents production of unnecessary waste and
microwave irradiation can often accomplish reactions in a
fraction of the time needed with conventional heating using
much less energy. The reaction outlined by Kumar et al.
appeared to fulfill the requirements for our lab experiment, so
we used it as the basis for further work on its application to the
teaching environment. The present report outlines the use of
solvent-free Knoevenagel condensation under microwave
irradiation in the undergraduate organic laboratory. The
procedure is a modification of the published procedure of
Kumar and coworkers [6].
Experimental Procedure
General: Microwave irradiation (µW) was performed using an
Amana Radarange household microwave oven model RS415T
produced in 1990 (frequency = 2450 MHz, maximum power = 1500
W). Melting points (uncorrected) were determined using a Mel-Temp
melting point apparatus fitted with a Fisher Scientific digital
temperature probe. All reagents were used as received from the
supplier. Absolute ethanol was 200 proof ethyl alcohol (Fisher
Scientific) and 95% ethanol was 190 proof ethyl alcohol (EMD).
Proton NMR data was collected on an Anasazi Ef 90 FT-NMR
operating at 90.019 MHz. Samples for NMR experiments were
prepared using approximately 40 mg of compound in ca. 0.5 mL of
DMSO-d6, to which was added one drop of tetramethylsilane (TMS).
Infrared spectroscopy was conducted using a Thermo Scientific
Nicolet iS5 instrument; data was collected by attenuated total
reflection (ATR).
E-3-(4-Methoxyphenyl)prop-2-enoic
acid
(trans-4methoxycinnamic acid) [830-09-1]. Malonic acid [141-82-2], 3.6 g
(35 mmol), and 2.7 g (35 mmol) of ammonium acetate [211-162-9]
were ground together in a mortar and pestle until a sticky solid was
formed without large clumps of either reactant. This solid was
transferred to a 125- or 250-mL Erlenmeyer flask. 4-
© 2014 The Chemical Educator, S1430-4171(14)12588-6, Published 11/05/2014, 10.1333/s00897142588a, 19140347.pdf
348
Chem. Educator, Vol. 19, 2014
Methoxybenzaldehyde (p-anisaldehyde, [123-11-5]), 4.5 mL (37
mmol), was added to the solid reactants and swirled by hand until the
mixture began liquefying, was homogeneous, and evenly coated the
bottom of the flask. A small beaker (50-, 80- or 100-mL) was inverted
over the top of the flask to act as a loose cover.
The reaction mixture was placed in a 1000-mL beaker containing
ca. 200 mL of chromatographic-grade alumina. The Erlenmeyer flask
was pushed down into the alumina powder so that the level of the
alumina outside the flask was at or above the level of reactants inside
the flask. The beaker containing the alumina and reaction flask was
then placed inside the microwave oven, which was located inside a
fume hood. The reaction was heated with microwave irradiation for 3
minutes at power setting 1 (10% irradiation time). The reaction
became a honey-colored viscous liquid with the formation of bubbles
during the reaction. The viscous liquid quickly solidified on cooling to
give a waxy, yellow, opaque solid. In some instances the reaction
mixture formed a solid during heating.
To isolate the product, the yellow-orange crude product was
completely dissolved in a minimum amount of hot glacial acetic acid
(ca. 8 mL) on a hot plate. Three-times the volume of 95% ethanol (ca.
24 mL) was subsequently added after the solution was removed from
the hot plate. The crude product began to precipitate on cooling to
room temperature; precipitation was completed in an ice-water bath
(solution was cooled to  5 °C). The resulting yellow solid was
isolated through vacuum filtration, washed with cold 95% ethanol and
immediately purified by recrystallization or air dried until the next lab
period. A spectroscopic quality product was obtained by purifying the
compound through recrystallization from 95% or absolute ethanol.
Typical student chemical yield was 0.70–1.5 g (11–24%), off-white to
orange crystalline solid (needles); melting point, 181–184 °C (abs.
ethanol). 1H-NMR (DMSO-d6, 90 MHz, ): 3.81 (s, 3H, methoxy
group), 6.40 (d, J = 16 Hz, 1H, vinylic H), 6.98 (d, J = 8.7 Hz, 2H,
CH arom.), 7.58 (d, J = 16 Hz, 1H, vinylic H), 7.65 (d, J = 8.7 Hz,
2H, CH arom.). IR (ATR): ca. 2550 cm–1( OH), 1672 cm–1 (ν C=O),
821 cm–1 ( oop-arom.).
Results and Discussion
Microwave energy has become a very useful tool for
synthetic chemistry [8], but it presents some challenges for the
undergraduate laboratory course. It is best practice to use a
microwave reactor specifically designed for chemical
synthesis, however, these units are often cost-prohibitive. To
minimize the risks associated with use of a domestic
microwave oven, we have chosen to use low-hazard, highboiling compounds and an open reaction vessel to prevent
pressure build-up. We also placed the reaction in a bed of
alumina powder [9] to moderate the temperature. Instead of
using benzaldehyde, we chose to use 4-methoxybenzaldehyde
(p-anisaldehyde) because of its lower hazard level. According
to section 2 of the Safety Data Sheet (SDS) available from
Sigma-Aldrich, benzaldehyde is a flammable liquid and toxic
[10], whereas 4-methoxybenzaldehyde is listed as not
hazardous [11].
Kumar and coworkers report near quantitative yield (98%)
[6] for synthesis of 4-methoxycinnamic acid under microwave
irradiation; however, our results do not confirm this finding.
We have found that typical student yields (before
recrystallization from ethanol) are 2.25–3.65 g (36–58%).
Despite this, the average student can still perform this reaction
on the 35 millimole-scale with reasonable success using
normal laboratory glassware. Because of the simplicity of the
reaction set-up, short reaction time and simple work-up, this
experiment generally does not take a full 3-hour lab period. In
our program this experiment is conducted when a previous
Keuseman et al.
experiment needs to be completed or another experiment is
also begun, to fill the lab period.
During the development stage for this lab experiment we
found that increasing the microwave irradiation time beyond 3
minutes had little effect on product yield, but the increased
time produced a product that is much darker in color. Because
household microwave ovens can vary considerably in
performance, we recommend that the experiment be repeated
by the instructor to adjust the irradiation time and power
settings to the specific oven used.
Our initial investigations repeated the procedure of Kumar et
al. by pouring the still-liquid reaction mixture into water after
the irradiation period was complete. In our experience, this
would be somewhat difficult in a teaching lab because the
product often solidifies very soon after removal from the
microwave (or is a solid when removed). If the product has
solidified, water can be poured onto the product and triturated
with a glass rod prior to suction filtration. In either case, an
insoluble substance is commonly present in the crude product
necessitating gravity filtration during recrystallization [6] from
ethanol. With the aqueous treatment the recrystallized product
is varying shades of yellow or orange with melting point 181183 °C (95% ethanol). Ultimately, we determined that the
aqueous work-up was of little benefit.
To simplify the procedure we eliminated the aqueous workup and crystallized the crude product directly after microwave
irradiation from hot glacial acetic acid and ethanol. The crude
product is completely soluble in hot acetic acid, but addition of
three-times its volume of ethanol begins precipitation of the
product. Cooling to room temperature and then further to  5
°C in an ice-water bath provides the product. After
precipitation from acetic acid-ethanol, the compound melted at
173–182 °C. Recrystallization from absolute (or 95%) ethanol
raises the melting point to 181–184 °C. A search of the current
literature found a wide range of melting points reported for 4methoxycinnamic acid: Aslam et al. [12] reported 169–173 °C,
while Gupta and coworkers [13] reported 198–200 °C. For
comparison purposes during development of this experiment,
4-methoxycinnamic acid was also synthesized as described by
Harwood and co-workers [5] (Scheme 2).
O
O
piperidine
+
HO
O
O
H
OH
MeO
OH
pyridine, 
MeO
Scheme 2.
After two recrystallizations from absolute ethanol, the product
was a white needle-shaped crystalline solid having a melting
point of 180–183 °C. A mixed melting point of this product
with 4-methoxycinnamic acid synthesized using the current
procedure was 180–182 °C. Despite the differences in color
between the products of reactions in Scheme 1 and Scheme 2,
the mixed melting point data suggests that the identity and
purity of the samples is the same.
Product identity was further established by proton NMR
spectroscopy. Recrystallized samples of product synthesized
by students (via Scheme 1) were analyzed and compared to the
recrystallized product synthesized using the procedure of
Harwood and co-workers (Scheme 2) [5], as well as literature
[14] data. The proton NMR spectra of samples synthesized in
our lab and by our students (see Supporting Data) are
consistent with the spectral data reported by Duarte and coworkers [14], except in the absence of the carboxyl proton
© 2014 The Chemical Educator, S1430-4171(14)12588-6, Published 11/05/2014, 10.1333/s00897142588a, 19140347.pdf
A “Green” Approach to Synthesis of trans-4-Methoxycinnamic acid...
Chem. Educator, Vol. 19, 2014
349
product is a para disubstituted benzene derivative, because the
protons are observed as a pair of doublets.
Conclusion
Synthesis of trans-4-methoxycinnamic acid as outlined here
can be used to strengthen the organic chemistry laboratory
curriculum by providing an example of a carbonyl
condensation reaction and illustrate principles of green
chemistry [7]. Other possible educational opportunities of this
experiment include: recrystallization, melting point and mixed
melting points, Infrared spectroscopy and proton NMR
acquisition and interpretation. The product compound is of
relevance to biochemistry, natural products chemistry and
medicinal chemistry, thus providing an opportunity for “buyin” with students having interest in these subjects.
Figure 1. 1H-NMR (90 MHz) spectrum showing overlap (in box)
between vinyl and aromatic protons in 4-methoxycinnamic acid; the
upfield peaks correspond to the signals for the other pair of aromatic
protons (6.98 ppm, J = 8.7 Hz) and the other vinyl proton (6.40 ppm,
J = 16 Hz).
signal from spectra taken in our lab. The phenomena of
hydrogen bonding and proton exchange make observation of
carboxyl protons (and other acid hydrogens) difficult and
chemical shift values unpredictable [15]. As a result, under the
conditions used to record our spectra, the signal of the acidic
carboxyl proton was not sufficiently intense or too broad (large
halfwidth) [15] to be observed. The presence of the carboxylic
acid functional group can be established by the IR spectrum.
The spectrum shows a broad signal centered around 2550 cm–1
corresponding to the O–H stretch of a carboxylic acid. Due to
conjugation with the -system, the C=O stretch of the carboxyl
group is shifted to lower frequency and is found at 1672 cm–1.
The IR spectrum also supports the para substitution pattern of
the aromatic ring, characterized by the strong absorption band
at 821 cm–1 attributed to the out-of-plane bending mode [16].
The proton NMR spectrum of 4-methoxycinnamic acid is
not complicated and can be interpreted by students. The most
confusing aspect of the spectrum is the overlap of signals in
the aromatic region in the 90 MHz spectrum [17]. The overlap
of the benzylic vinyl proton and the signal for a pair of
aromatic protons presents an opportunity to apply knowledge
of H-H coupling constants (Figure 1). Normally the coupling
constant for vinyl hydrogens is large (about 16 Hz), whereas
the coupling constant between aromatic hydrogens in this case
is about half as much (ca. 8.7 Hz). Even without dividers or
numerical values (in Hz) for these peaks, some students can
visually compare the coupling constants in the overlap region
to the other well-resolved peaks and determine which peaks
are part of each doublet in the overlap region. The magnitude
of the coupling constant between the vinyl protons is also
useful in establishing the geometry of the C=C bond. Typically
the coupling constants for vinyl protons are quite dependent on
relative stereochemistry: for cis protons 3J = 6–15 Hz and for
trans protons 3J = 11–18 [16]. The observed coupling constant
of 16 Hz for 4-methoxycinnamic acid, therefore, indicates a
predominantly trans geometry in the purified product. Finally,
one more point of interpretation can be made from this
spectrum, namely, the substitution pattern of the benzene ring.
The splitting pattern of the aromatic protons indicates that the
Acknowledgements. The authors would like to thank the
organic chemistry students who helped develop this laboratory
experiment and Dr. Joe Nguyen for assistance in manuscript
preparation. We would also like to thank Mount Mercy
University, the R. J. McElroy Trust and the Roy J. Carver
Charitable Trust for generous direct and indirect financial
support.
Supporting Materials. One supporting file is available.
(http://dx.doi.org/10.1333/s00897142588a).
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© 2014 The Chemical Educator, S1430-4171(14)12588-6, Published 11/05/2014, 10.1333/s00897142588a, 19140347.pdf
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© 2014 The Chemical Educator, S1430-4171(14)12588-6, Published 11/05/2014, 10.1333/s00897142588a, 19140347.pdf