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org/jchemeduc Laboratory Experiment

Paracetamol Synthesis for Active Learning of Amide Functional

Groups in Undergraduate Chemistry Laboratories
Fabián Garzón-Posse,* Yovanny Quevedo-Acosta, and Diego Gamba-Sánchez*
Cite This: J. Chem. Educ. 2022, 99, 2385−2391 Read Online

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ABSTRACT: Three different experiments that allow the synthesis of the drug paracetamol are described; such experiments were
designed for their implementation in undergraduate organic chemistry courses, considering the medical and economic importance of
paracetamol. The experience wants to show the students some “real world” applications of organic synthesis techniques. The
methods are based not only on the classical nucleophilic acyl substitution reaction but also on exploring innovative methodologies
which expand the understanding of the reactivity of several organic functional groups, such as direct amidation of carboxylic acids
under microwave heating and a transamidation reaction catalyzed by iron salts. The experiments allow students to obtain a
compound of high interest and explore different synthesis, purification, and identification approaches. They work with molecules of
biological significance and use various functional groups and organic synthesis techniques, including reflux heating, microwave
heating, thin-layer and flash column chromatography, and IR and NMR spectroscopy. These experiments create a context in which it
is possible to discuss various chemical concepts related to the reactivity of several functional groups. This is also to learn and
illustrate the role of a catalyst and solid support in chemical processes.
KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Hands-On Learning, Professional Development, Synthesis, Catalysis,
Amides

■ INTRODUCTION
Carbonyl compounds constitute one of the largest groups of
organic molecules, and their importance is evidenced in an
enormous number of scientific reports related to their
properties, reactivity, and applications.1 Similarly, in the
classroom, numerous approaches to teach relevant chemical
aspects of carbonyl compounds have been implemented.2
Among them, amides stand out due to their particular physical
and chemical properties, which distinguish them from
aldehydes and ketones and carboxylic acids and their
derivatives. Amides are also present in various molecules of
interest, such as polymers, drugs, and biomolecules.3 Addi-
tionally, amides are valuable starting materials for obtaining
natural products, pesticides, organic materials, and other
valuable chemicals (Figure 1).4 Conventional methods for
the synthesis of these types of molecules, both in laboratories
(in teaching or research processes) and in industries,
© 2022 American Chemical Society and
Division of Chemical Education, Inc.
2385
frequently involve using highly electrophilic carboxylic acid
derivatives and their subsequent reaction with a nucleophilic
amine.5 However, given the previously established importance
of the amide functional group, new methodologies for
obtaining this type of molecule are constantly explored by
the scientific community.6
One of the multiple medicaments that have the amide
functional group in its molecular structure and that has a
worldwide distribution, use, and social recognition is para-
cetamol (also known as acetaminophen), being one of the
Received: January 29, 2022
Revised: May 5, 2022
Published: May 23, 2022
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Journal of Chemical Education pubs.acs.org/jchemeduc
Figure 1. Representative bioactive amides.
antipyretic analgesics with the most significant global
circulation; paracetamol was prepared more than 140 years
ago; today, several billion doses of this drug are sold annually,
making it the most commonly dispensed pharmaceutical in the
USA. The standard synthetic approach used in paracetamol
synthesis at the industrial level is based on the acetylation of p-
aminophenol as the final stage.7 Even though the hepatotox-
icity of paracetamol is fully established, its analgesic
mechanism of action is still a matter of debate.8
In this sense, it is worth mentioning that the synthesis of
organic molecules for common uses and wide recognition in
society allows students to directly recognize applications in real
life of numerous laboratory procedures, making them
particularly attractive.9 In this scenario, the high medical,
clinical, and social recognition of paracetamol, its economic
importance, and its high distribution make its synthesis
particularly effective, emphasizing the “real world” applicability
of the experiments and connecting the teaching of several
experimental techniques of organic chemistry with topics of
current relevance.
This work reports three different methods for synthesizing
paracetamol in organic chemistry laboratory courses by third-
year undergraduate chemistry students. The goal of the
experiments is to allow students to analyze and compare
other ways to obtain a molecule of high interest and wide
distribution. We have optimized the classical nucleophilic acyl
substitution reaction experiment, and we also developed and
optimized two innovative methodologies, such as direct
amidation of carboxylic acids under microwave heating and a
transamidation reaction catalyzed by iron salts.10
The experiments allow students to obtain a compound of
high interest. At the same time, the students are permitted to
explore different approaches for the synthesis, purification, and
identification of molecules of biological interest through the
use of a diverse group of crucial organic synthesis techniques,
including reflux heating, microwave heating, liquid−liquid
extraction, thin-layer chromatography, column chromatogra-
phy, IR and NMR spectroscopy, etc. In parallel, these
experiments create a context in which it is possible to discuss
a great variety of chemical concepts relevant to the reactivity of
functional groups such as amine, hydroxyl, amide, carboxyl,
and anhydride, specifically analyzing the electronic character-
istics and the nucleophilic or electrophilic potential of each
functional group and relating it to the conditions necessary for
its transformation, along with the role of a catalyst and solid
support in chemical processes, among others.
In parallel, the implementation of three methods for the
synthesis of paracetamol can provide the opportunity to
analyze and compare the most appropriate alternative from the
perspective of green chemistry. Thus, students can explore
each method by taking criteria such as the atom economy,11
mass reaction efficiency,12 use of hazardous materials, and
production of waste.5b
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Laboratory Experiment
■ EXPERIMENTS
Acylation of p-Aminophenol in an Aqueous Medium
The first experiment involves the reaction of p-aminophenol
and acetic anhydride at 90 °C using water as the solvent
(Figure 2), allowing the selective acylation of the amino group
Figure 2. Acylation of p-aminophenol in water.
of the aromatic compound. The experiment is completed in 30
min, and it can be monitored by thin-layer chromatography.
After its completion, the mixture is extracted with ethyl acetate
or ethyl ether. The solvent is removed under reduced pressure
or evaporated; subsequently, a chromatography column using
ethyl acetate as the mobile phase allows the purification of the
paracetamol. Alternatively, the crude paracetamol can be
purified by recrystallization from water when the reaction is set
up using 500 mg of p-aminophenol. The product can be
identified by its melting point and IR spectroscopy or by 1H
nuclear magnetic resonance.
Pedagogical goals of the experiment include (a) the previous
identification and the subsequent comparison between the
different functional groups of nucleophilic character present in
p-aminophenol and their reactivity against the anhydride used,
and (b) a discussion about the possibility of using water as the
solvent, since for amino group acylation reactions nonreactive
organic solvents are usually used. To assess the students’
understanding of these concepts, they were asked to respond
to specific questions on the writeup sheet for the experiment.
For example, they were asked in previous sessions about the
electronegativity of nitrogen and oxygen and how this
influences the availability of the electrons that make the
amino and hydroxyl groups reactive. The students were also
asked about the eventual competition of the reaction between
acetic anhydride and water and the benefits in terms of the
environmental impact of using water as a solvent. See the
Supporting Information for an example of the writeup sheet for
this experiment. The previous lecture for this experiment
usually took 50 min, including the prelab quiz allotted.
Direct Amidation of Carboxylic Acids with Microwave
Heating and Supported with Silica Gel
The second experiment involves the reaction of a mixture of p-
aminophenol and glacial acetic supported on silica gel 60
(Figure 3). After homogenization, the reaction mixture is
transferred to a microwave tube and subjected to heating in a
CEM microwave; after 20 min at 200 W, the reaction mixture
is cooled and then filtered using ethyl acetate to remove the
silica gel, and the organic phase is washed with NaHCO3(sat)
and HCl (5%) and dried over anhydrous MgSO4. Finally, the
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Figure 3. Direct amidation of p-aminophenol under microwave
irradiation.
solvent is evaporated. In this way, the students can isolate the
paracetamol produced without further purification.
The pedagogical goals of the experiment focus on (a)
recognizing the need for the presence of silica gel in the
reaction medium to provide silanol groups, with these acting as
Brønsted acids activating acetic acid molecules,13 (b) the effect
of microwave heating on chemical reactions, and (c) knowing
the operation and basic handling of microwave irradiation
equipment currently used in organic synthesis laboratories. To
establish the previous concepts of the students regarding these
issues, in preceding sessions, they were asked about what
would be the main product of the chemical reaction if only
acetic acid and p-aminophenol were mixed in the absence of
silica gel and with conventional heating; also, they were asked
about how electromagnetic radiation in the length of
microwaves can interact with organic molecules and how this
radiation can promote chemical transformations. The students’
understanding of this concept can be assessed through
questions on the writeup sheet (see the Supporting
Information).
Iron(III)-Catalyzed Transamidation of Amides
The third experiment involves the reaction between p-
aminophenol and acetamide in the presence of a catalytic
amount of iron chloride hexahydrated, using toluene as solvent
(Figure 4). Ninety minutes of reflux heating provides
paracetamol, purified by filtration through a pad of Celite
and subsequent column chromatography.
Figure 4. Iron-catalyzed transamidation.
The pedagogical aims of this experiment include the
following: (a) to understand the reasons for the low reactivity
of amides in nucleophilic acyl substitution reactions and to
explain the reactivity problems to obtain paracetamol by the
direct reaction between acetamide and p-aminophenol and (b)
to establish the importance and possible role of iron(III) in the
reaction medium. To establish the concepts previously built by
the students, a series of questions were asked regarding the
reasons that explain the reactivity as electrophiles of various
functional groups derived from the carbonyl group: amides,
esters, acyl chlorides, anhydrides, acids, etc. See the Supporting
Information for an example of the writeup sheet for this
experiment.
■
HAZARDS
Appropriate protective measures include safety glasses, gloves,
and a lab coat to be constantly worn. The procedures must be
carried out in fume hoods.
1. Acylation of p-aminophenol in an aqueous medium.
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Laboratory Experiment
p-Aminophenol is toxic by contact, inhalation, and
ingestion. Acetic anhydride is flammable and toxic by
inhalation, contact, and ingestion.
2. Direct amidation with microwaves and supported with
silica gel.
Glacial acetic acid is a corrosive and flammable liquid.
Celite may cause damage to the lungs through
prolonged or repeated exposure if inhaled.
3. Iron(III)-catalyzed transamidation
Acetamide irritates the skin and is a possible
carcinogen; toluene is flammable and toxic by contact,
ingestion, and inhalation. The risks associated with using
p-aminophenol were already described in the first
experiment.
■
RESULTS AND DISCUSSION
General Discussion
Roughly 80 third-year undergraduate chemistry students have
performed these laboratory experiments. The experiments
were performed once a year for the last five years. Sessions
before the laboratory practice, in which the previous questions
corresponding to each experiment were implemented, had an
average duration of 50 min; students worked in groups of two
and typically set up the reaction and purification of
paracetamol in less than 5 h. Students were assigned one of
the three methods; once the reaction was finished, the product
was dried and weighed, the melting point was determined, and
1
H NMR spectroscopy and IR spectroscopy were analyzed.
The students shared yield information, and the average yield
was calculated for each method.
Based on data included in the Supporting Information, the
average yield for the acylation of p-aminophenol in an aqueous
medium was 66%. The average melting point range was 169 ±
7.6 °C for the paracetamol obtained. In comparison, the
average yield for the direct amidation with microwaves and
supported with silica gel experiment was 67%, with an average
melting point range of 169 ± 6.8 °C for the product. The
iron(III)-catalyzed transamidation experiment, for its part,
showed an average yield of 45% and an average melting point
range of 169 ± 5.9 °C for the product.
The analysis of the IR spectra makes it possible to identify
the characteristic vibration frequencies of the amide formed,
and the changes in the amino group of the initial amine are
also noticeable. The 1H NMR characterization of the reaction
product brings direct evidence of the transformation. Relevant
information such as the chemical shifts, multiplicity, and
coupling constants of the signals can be used to discuss the
effectiveness of the transformation and the purity of the
paracetamol obtained.
Overall, the students showed a participative and proactive
attitude in developing the theoretical and experimental
sessions of the practice. The oral presentations were complete,
and the analysis of 1H NMR and IR spectra was exhaustive; the
students appreciated synthesizing a highly recognized molecule
and showed their progress in implementing various organic
synthesis techniques, together with the development of skills
related to the spectroscopic component. See the Supporting
Information.
Acylation of p-Aminophenol in Aqueous Medium.
The development of the experiment allows the discussion of
various topics of interest; some of the concepts to be analyzed
in the prelaboratory session are
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a. The identification of functional groups with nucleophilic
character present in the p-aminophenol molecule and
the latent possibility of obtaining different molecules
from the reaction: for example, amides and esters, and at
the same time, the predominant tendency for N-
acylation.
b. The electrophilic character of the anhydride used and
the evaluation of the course of the reaction in the
presence of other carboxylic acid derivatives such as acid
chlorides, esters, etc. (seen from the ratio of N-acylation
vs O-acylation).
c. The influence of anhydride substituents on its reactivity,
considering that the electrophilicity of the carbonyl
group on this kind of molecules depends on the
substituent of the carbonyl group; for example, harsh
reaction conditions must be employed for the same kind
of chemical transformation if benzoic anhydride is used.
The possibility of monitoring the progress of the reaction
using thin-layer chromatography (which uses AcOEt as the
mobile phase) allows us to discuss the affinity to the stationary
phase of the initial amine and the amide formed. At the same
time, the evolution of the process is checked. Another aspect
that can be analyzed is the difference between the melting
points of the starting p-aminophenol (187 °C) and the
obtained amide (169 °C), which are the different intermo-
lecular forces responsible for this change.
Direct Amidation of Carboxylic Acids under Micro-
wave Irradiation. The synthesis of organic molecules by
microwave heating has gradually become a common strategy in
multiple industries and academic research laboratories.14
Likewise, its use in teaching laboratories is increasing.15 In
this sense, some of the concepts that can be discussed in the
sessions before the practice are
a. The role of silica gel as solid support and catalyst in the
reaction medium and the need for its presence to form
the desired product, due to its role as a proton transfer
agent (Brønsted acid), which makes the acetic acid a
suitable electrophile.
b. The different activating agents used to make carboxylic
acids more reactive on acyl substitutions reactions, such
as dicyclohexylcarbodiimide (DCC), diethyl azadicar-
boxylate (DEAD) or carbonyl diimidazole (CDI),
among others.
c. The differences between conventional heating of a
reaction mixture and microwave heating of the same
system.
d. The possibility of reaching high temperatures in a sealed
system, a fact that does not occur with traditional open-
vessel heating, whose limit is determined by the boiling
point of the solvent used.
e. The use of electromagnetic radiation in organic
chemistry and the usefulness of each range of wave-
lengths in specific techniques: microwaves to promote
reactions, IR and UV in characterization, visible
radiation in catalysis, and X-rays in diffraction.
Conventionally, the academic and industrial syntheses of
amides involve preparing and isolating electrophilic derivatives
of carboxylic acids and their nucleophilic acyl substitution
reaction with the respective nucleophilic amine.16 In this sense,
students are typically aware of methodologies such as the one
used in the first experiment described here or those related to
obtaining intermediate acyl chloride using reagents such as
2388
Laboratory Experiment
thionyl chloride or oxalyl chloride. On the contrary, this
experiment offers the possibility of directly getting the amide of
interest from carboxylic acid without previous derivatization.10a
This fact is one of the main points to analyze in the sessions
related to the practice. The experiment allows students to raise
hypotheses regarding how silica gel catalyzes the activation of
the acid to make it reactive against the amine. At the same
time, the use of microwave heating allows students to become
familiar with alternative technologies used in organic synthesis.
It also allows them to use a methodology that generates less
waste and is operationally more straightforward and more
effective than the traditional heating of reaction mixtures.17
Iron(III)-Catalyzed Transamidation. Transamidation is
an alternative way of obtaining amides that do not depend
directly on reacting an electrophilic derivative of a carboxylic
acid with a specific amine; instead, it is based on the direct
exchange of the nitrogen segment of an amide by direct
reaction with a nucleophilic amine; of course, the exchange
occurs mainly under the influence of a suitable catalyst or
activating agent given the low reactivity as an electrophile of
the starting amide.18 In this sense, several concepts related to
organic synthesis can be discussed:
a. The low reactivity in the nucleophilic acyl substitution
reactions of the amides and the subsequent need for a
catalyst that allows direct transformation due to the
electron-donating effect of the lone pair of nitrogen
atom over the carbonyl group.
b. The advantages of this transformation compared with
the more classical methodologies for obtaining amides,
owing to the possibility to use starting materials which
are not an obvious option for amide synthesis.
c. The concept of catalysis and its usefulness in obtaining
molecules of interest.
Transamidation provides a different alternative for obtaining
amides, establishing an unconventional disconnection to
synthesize this type of molecule.19 The scope of this
methodology in research laboratories has grown during the
last decades.20 However, to the best of our knowledge, there
are no practices of this methodology adapted to teaching
laboratories. This experiment allowed students to explore
alternative methodologies for the synthesis of amides that are
not directly related to the formation of electrophilic derivatives
of carboxylic acids; on the contrary, it is based on the initial
activation of the amide through its interaction with the metal
and the subsequent reaction of the initially formed metal−
amidate complex with the amine present in the reaction
medium.21
The experiments described herein allowed the students to
develop high-interest in medicinal compounds through three
different methodologies, offering an opportunity to experiment
with diverse essential classes of organic reactions. In these
laboratory experiments, the students needed to reflect on
important issues, such as the nucleophilicity of amines,
hydroxyl groups, and amides, the difference between the role
of a catalyst and solid support on a chemical reaction, and the
role of microwave heating in triggering chemical processes,
among others.
In addition, as previously established, the parallel imple-
mentation of three synthetic methods for the same target
molecule would allow students to determine the greenest
obtaining route by comparing specific data such as atom
economy, reaction mass efficiency, the toxicity of the starting
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J. Chem. Educ. 2022, 99, 2385−2391
Journal of Chemical Education
materials, activation by catalysis, green solvents, and among
other principles of the green chemistry,22 and those principles
may be used as a guide for adequate development of chemical
processes. In this sense, a specific way that can be used to
determine the greenest synthesis route would be the
compliance with each of the mentioned green chemistry
principles, evaluated through the so-called accomplished
principle index (API) (eq 1),23 which establishes how many
principles of the green chemistry apply for a specific synthetic
route and analyzes how many of those principles are
accomplished; thus, the greenest route will reach an API
value closest to 100. In lab reports, students can analyze the
three routes, compare the metrics, and propose the most
sustainable amide-forming reaction based on the data. All this
increases the relevance and potential pedagogical application of
the work.
number of principles of green chemistry completed
API = × 100
number of principles of green chemistry that apply
(1)
■ ASSESSMENT OF LEARNING OUTCOMES
The assessment of the learning objectives was established
through the analysis of the laboratory reports and the seminars
presented; those analyses were carried out using grading
formats, which were built based on a previously published
rubric24 and updated following more recent insights (see
Supporting Information).25 The grading rubrics were designed
to show the level of argumentation and the depth of the
analysis made by the students of various aspects directly related
to the experiments carried out and the educational aims of the
application of the different but complementary methods to
synthesize the same molecule. The evaluation of the various
sections of the laboratory reports and the seminars showed
that, in general terms, the students achieved the processes of
comprehension, argumentation, and analysis satisfactory. They
particularly appreciate the use of a known drug as the model
study subject; they argued an apparent disconnection between
previous lab practices and the real world; this is, indeed, a
significant achievement since it showed us that students are
more motivated and participants when they link the model
practices with daily life. The students were able to explain the
need for the specific experimental conditions necessary to carry
out the assigned transformations for the lab practices based on
the inherent reactivity of each of the substances (functional
groups) used as starting materials; they also succeeded in
correlating their results with the previously consulted
information; however, analyzing the general performance of
the students, the routes of amine acylation and direct
amination of carboxylic acids (topics commonly worked on
in the introductory theoretical sessions of reactivity in organic
chemistry) continue to be more recognizable and easier to plan
than the use of iron-catalyzed transamidation, with this being a
modern methodology and not immediately evident from the
perspective of the reactivity of the molecules involved. It is
worth mentioning that some students were also proactive in
consulting complementary information about green chemistry
practices and alternative sources of energy; they used those
opinions in the seminar presentation, trying to motivate their
classmates to be more aware of environmental issues. In
addition, students generally showed good appropriation of
solid support and catalyst concepts, identifying their
advantages and limitations. Finally, all of the students showed
pubs.acs.org/jchemeduc Laboratory Experiment
good criteria in choosing the purification conditions based on
thin-layer chromatography observations and a good level of
analysis of spectroscopic data.
■ CONCLUSIONS
Three laboratory experiments for the synthesis of paracetamol,
a widely used and distributed analgesic, were designed and
implemented for its development in an organic chemistry
laboratory session; this highlights the applicability in real
contexts of organic synthesis while showing the possibility of
applying various synthetic routes to obtain a specific molecule.
Each of the experiments provides a particular context from
which different relevant concepts in organic chemistry can be
discussed, for example: the reactivity of various functional
groups, nucleophilic acyl substitution reactions, chemo-
selectivity of organic reactions, and phenomena of heteroge-
neous catalysis, among others. At the same time, the
experiment allows an analysis of the electronic characteristics
and the nucleophilic or electrophilic potential of each
functional group, relating it to the optimal conditions for its
transformation. In addition, each of the experiments implies
the use by the students of various experimental techniques of
importance in organic synthesis. Finally, spectroscopic
techniques such as NMR or IR can be used to identify the
product formed and evaluate its purity.
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available at https://pubs.ac-
s.org/doi/10.1021/acs.jchemed.2c00080.
Detailed experimental procedures, student writeup
sheets, instructors’ notes, suggested mechanisms, and
product characterization (DOCX, PDF)
■ AUTHOR INFORMATION
Corresponding Authors
Fabián Garzón-Posse − Medical School, Juan N Corpas
University Foundation, 110311 Bogotá, Colombia;
Email: fabian.garzon@juanncorpas.edu.co
Diego Gamba-Sánchez − Laboratory of Organic Synthesis,
Bio and Organocatalysis, Chemistry Department,
Universidad de Los Andes, 111711 Bogotá, Colombia;
orcid.org/0000-0001-5432-5108;
Email: da.gamba1361@uniandes.edu.co
Author
Yovanny Quevedo-Acosta − Laboratory of Organic Synthesis,
Bio and Organocatalysis, Chemistry Department,
Universidad de Los Andes, 111711 Bogotá, Colombia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jchemed.2c00080
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors express their gratitude to the Chemistry
Department of the Universidad de Los Andes for financial
support and the Medical School of the Juan N Corpas
University Foundation, as well as Andrea Ojeda-Porras, Juan
Rueda-Espinoza, Paola Acosta-Guzmán, Camilo Mahecha-
2389 https://doi.org/10.1021/acs.jchemed.2c00080
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Journal of Chemical Education pubs.acs.org/jchemeduc
Mahecha, and Laura Adarve-Cardona, instructors in the
laboratory courses described herein at the Universidad de los
Andes.
■
REFERENCES
(1) (a) Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Diaster-
eoselective allylation of carbonyl compounds and imines: application
to the synthesis of natural products. Chem. Rev. 2013, 113 (7), 5595−
5698. (b) Bartolo, N. D.; Read, J. A.; Valentín, E. M.; Woerpel, K.
Reactions of Allylmagnesium Reagents with Carbonyl Compounds
and Compounds with CN Double Bonds: Their Diastereoselectiv-
ities Generally Cannot Be Analyzed Using the Felkin−Anh and
Chelation-Control Models. Chem. Rev. 2020, 120 (3), 1513−1619.
(c) Irrgang, T.; Kempe, R. Transition-metal-catalyzed reductive
amination employing hydrogen. Chem. Rev. 2020, 120 (17), 9583−
9674.
(2) (a) Gonçalves, I. L.; Davi, L.; Cidade Torres, F.; Faria Santos
Canto, R.; Eifler-Lima, V. L. Synthesis of 1-Phenylthiourea: An
Undergraduate Organic Chemistry Experiment Illustrating Carbonyl
Transformations. J. Chem. Educ. 2021, 98 (3), 986−990. (b) Mullins,
J. J.; Prusinowski, A. F. Microwave-Promoted Synthesis of a
Carbocyclic Curcuminoid: An Organic Chemistry Laboratory Experi-
ment. J. Chem. Educ. 2019, 96 (3), 606−609. (c) Nelson, D. J.;
Kumar, R.; Ramasamy, S. Comparing carbonyl chemistry in
comprehensive introductory organic chemistry textbooks. J. Chem.
Educ. 2015, 92 (7), 1171−1177. (d) McEvoy, J. P. Characterizing
carbonyls with Infrared spectroscopy: an introductory chemistry
experiment in a molecular bioscience program. J. Chem. Educ. 2014,
91 (5), 726−729.
(3) (a) Pattabiraman, V. R.; Bode, J. W. Rethinking amide bond
synthesis. Nature 2011, 480 (7378), 471−479. (b) Ghosh, T.; Jana,
S.; Dash, J. KO t Bu-Promoted Transition-metal-free transamidation
of primary and tertiary amides with amines. Org. Lett. 2019, 21 (17),
6690−6694. (c) Li, G.; Ji, C.-L.; Hong, X.; Szostak, M. Highly
chemoselective, transition-metal-free transamidation of unactivated
amides and direct amidation of alkyl esters by N−C/O−C cleavage. J.
Am. Chem. Soc. 2019, 141 (28), 11161−11172. (d) Humphrey, J. M.;
Chamberlin, A. R. Chemical synthesis of natural product peptides:
coupling methods for the incorporation of noncoded amino acids into
peptides. Chem. Rev. 1997, 97 (6), 2243−2266.
(4) (a) Ruider, S. A.; Maulide, N. Strong bonds made weak: towards
the general utility of amides as synthetic modules. Angew. Chem., Int.
Ed. 2015, 54 (47), 13856−13858. (b) Brown, D. G.; Bostrom, J.
Analysis of past and present synthetic methodologies on medicinal
chemistry: where have all the new reactions gone? Miniperspective. J.
Med. Chem. 2016, 59 (10), 4443−4458. (c) Carey, J. S.; Laffan, D.;
Thomson, C.; Williams, M. T. Analysis of the reactions used for the
preparation of drug candidate molecules. Org. Biomol. Chem. 2006, 4
(12), 2337−2347.
(5) (a) Sorrell, T. Organic Chemistry; University Science Books,
2006. (b) Fennie, M. W.; Roth, J. M. Comparing amide-forming
reactions using green chemistry metrics in an undergraduate organic
laboratory. J. Chem. Educ. 2016, 93 (10), 1788−1793.
(6) (a) Massolo, E.; Pirola, M.; Benaglia, M. Amide bond formation
strategies: Latest advances on a dateless transformation. Eur. J. Org.
Chem. 2020, 2020 (30), 4641−4651. (b) Valeur, E.; Bradley, M.
Amide bond formation: beyond the myth of coupling reagents. Chem.
Soc. Rev. 2009, 38 (2), 606−631. (c) Ojeda-Porras, A.; Gamba-
Sánchez, D. Recent developments in amide synthesis using non-
activated starting materials. J. Org. Chem. 2016, 81 (23), 11548−
11555.
(7) Joncour, R.; Duguet, N.; Métay, E.; Ferreira, A.; Lemaire, M.
Amidation of phenol derivatives: a direct synthesis of paracetamol
(acetaminophen) from hydroquinone. Green Chem. 2014, 16 (6),
2997−3002.
(8) Chiam, E.; Weinberg, L.; Bellomo, R. Paracetamol: a review with
specific focus on the haemodynamic effects of intravenous
administration. Heart Lung Vessel 2015, 7 (2), 121.
2390
Laboratory Experiment
(9) (a) Love, B. E.; Bennett, L. J. Two Approaches to the Synthesis
of Dimethyl Fumarate That Demonstrate Fundamental Principles of
Organic Chemistry. J. Chem. Educ. 2017, 94 (10), 1543−1546.
(b) Nahra, F.; Riant, O. Recruiting the students to fight cancer: total
synthesis of goniothalamin. J. Chem. Educ. 2015, 92 (1), 179−182.
(c) Young, D. M.; Welker, J. J.; Doxsee, K. M. Green Synthesis of a
Fluorescent Natural Product. J. Chem. Educ. 2011, 88 (3), 319−321.
(d) Withey, J. M.; Bajic, A. Operationally simple synthesis of N, N-
Diethyl-3-methylbenzamide (DEET) using COMU as a coupling
reagent. J. Chem. Educ. 2015, 92 (1), 175−178.
(10) (a) Ojeda-Porras, A.; Hernández-Santana, A.; Gamba-Sánchez,
D. Direct amidation of carboxylic acids with amines under microwave
irradiation using silica gel as a solid support. Green Chem. 2015, 17
(5), 3157−3163. (b) Becerra-Figueroa, L.; Ojeda-Porras, A.; Gamba-
Sánchez, D. Transamidation of Carboxamides Catalyzed by Fe(III)
and Water. J. Org. Chem. 2014, 79 (10), 4544−4552.
(11) Trost, B. M. The atom economya search for synthetic
efficiency. Science 1991, 254 (5037), 1471−1477.
(12) Curzons, A. D.; Constable, D. J.; Mortimer, D. N.;
Cunningham, V. L. So you think your process is green, how do you
know?Using principles of sustainability to determine what is
green−a corporate perspective. Green Chem. 2001, 3 (1), 1−6.
(13) Comerford, J. W.; Clark, J. H.; Macquarrie, D. J.; Breeden, S.
W. Clean, reusable and low cost heterogeneous catalyst for amide
synthesis. Chem. Commun. 2009, No. 18, 2562−2564.
(14) (a) Li, Y.; Radoiu, M.; Fabiano-Tixier, A.-S.; Chemat, F. From
Laboratory to Industry: Scale-Up, Quality, and Safety Consideration
for Microwave-Assisted Extraction. In Microwave-assisted Extraction for
Bioactive Compounds: Theory and Practice, Chemat, F., Cravotto, G.,
Eds.; Springer US, 2013; pp 207−229. (b) Kappe, C. O.; Dallinger, D.
The impact of microwave synthesis on drug discovery. Nat. Rev. Drug
Discovery 2006, 5 (1), 51−63. (c) Maramai, S.; Taddei, M. Microwave
Irradiation. Sustainable Organic Synthesis: Tools and Strategies; The
Royal Society of Chemistry, 2022; pp 488−521.
(15) (a) Reilly, M. K.; King, R. P.; Wagner, A. J.; King, S. M.
Microwave-assisted esterification: A discovery-based microscale
laboratory experiment. J. Chem. Educ. 2014, 91 (10), 1706−1709.
(b) Kappe, C. O.; Murphree, S. S. Microwave-assisted carbonyl
chemistry for the undergraduate laboratory. J. Chem. Educ. 2009, 86
(2), 227. (c) Martin, E.; Kellen-Yuen, C. Microwave-assisted organic
synthesis in the organic teaching lab: A simple, greener Wittig
reaction. J. Chem. Educ. 2007, 84 (12), 2004.
(16) (a) de Figueiredo, R. M.; Suppo, J.-S.; Campagne, J.-M.
Nonclassical routes for amide bond formation. Chem. Rev. 2016, 116
(19), 12029−12122. (b) Albeiicio, F.; Chinchilla, R.; Dodsworth, D.
J.; Najera, C. New trends in peptide coupling reagents. Org. Prep.
Proced. Int. 2001, 33 (3), 203−303. (c) Montalbetti, C. A.; Falque, V.
Amide bond formation and peptide coupling. Tetrahedron 2005, 61
(46), 10827−10852.
(17) Kappe, C. O.; Stadler, A.; Dallinger, D.; Mannhold, R.; Kubinyi,
H.; Folkers, G. Microwaves in Organic and Medicinal Chemistry; Wiley,
2013.
(18) Liu, Y.; Shi, S.; Achtenhagen, M.; Liu, R.; Szostak, M. Metal-
Free Transamidation of Secondary Amides via Selective N−C
Cleavage under Mild Conditions. Org. Lett. 2017, 19 (7), 1614−1617.
(19) Loomis, W.; Stumpf, P. Transamination and transamidation.
Der Stickstoffumsatz/Nitrogen Metabolism; Springer, 1958; pp 249−
261.
(20) Acosta-Guzmán, P.; Mateus-Gómez, A.; Gamba-Sánchez, D.
Direct transamidation reactions: mechanism and recent advances.
Molecules 2018, 23 (9), 2382.
(21) (a) Thomson, R. K.; Zahariev, F. E.; Zhang, Z.; Patrick, B. O.;
Wang, Y. A.; Schafer, L. L. Structure, bonding, and reactivity of Ti and
Zr amidate complexes: DFT and X-ray crystallographic studies. Inorg.
Chem. 2005, 44 (24), 8680−8689. (b) Kissounko, D. A.; Hoerter, J.
M.; Guzei, I. A.; Cui, Q.; Gellman, S. H.; Stahl, S. S. TiIV-mediated
reactions between primary amines and secondary carboxamides:
Amidine formation versus transamidation. J. Am. Chem. Soc. 2007,
129 (6), 1776−1783.
https://doi.org/10.1021/acs.jchemed.2c00080
J. Chem. Educ. 2022, 99, 2385−2391
Journal of Chemical Education pubs.acs.org/jchemeduc Laboratory Experiment

(22) Ribeiro, M. G. T.; Machado, A. A. Holistic metrics for

assessment of the greenness of chemical reactions in the context of
Chemical Education. J. Chem. Educ. 2013, 90 (4), 432−439.
(23) Duarte, R. C.; Ribeiro, M. G. T.; Machado, A. A. Using green
star metrics to optimize the greenness of literature protocols for
syntheses. J. Chem. Educ. 2015, 92 (6), 1024−1034.
(24) Erhart, S. E.; McCarrick, R. M.; Lorigan, G. A.; Yezierski, E. J.
Citrus Quality Control: An NMR/MRI Problem-Based Experiment. J.
Chem. Educ. 2016, 93 (2), 335−339.
(25) Tobajas, M.; Molina, C. B.; Quintanilla, A.; Alonso-Morales,
N.; Casas, J. A. Development and application of scoring rubrics for
evaluating students’ competencies and learning outcomes in Chemical
Engineering experimental courses. Education for Chemical Engineers
2019, 26, 80−88.

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