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LABORATORY EXPERIMENT

pubs.acs.org/jchemeduc

Synthesis of Two Local Anesthetics from Toluene: An Organic


Multistep Synthesis in a Project-Oriented Laboratory Course
Patricia Demare and Ignacio Regla*
Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autonoma de Mexico, Batalla del 5 de Mayo esq. Fuerte de Loreto,
Ejercito de Oriente, 09230 Mexico, D.F., Mexico

bS Supporting Information
ABSTRACT: This article describes one of the projects in the advanced undergraduate
organic chemistry laboratory course concerning the synthesis of two local anesthetic drugs,
prilocaine and benzocaine, with a common three-step sequence starting from toluene.
Students undertake, in a several-week independent project, the multistep synthesis of a
pharmaceutical drug, comprising instructor-guided tasks such as literature search, planning,
critical discussion, experimental design, observation, and results interpretation. In this
project, in addition to searching and using information found in primary and secondary
sources, students learn to design the methodology for several of the steps in the reaction sequence, bearing in mind safety and
environmental concerns.
KEYWORDS: Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives,
Problem Solving/Decision Making, Amines/Ammonium Compounds, Chromatography, Drugs/Pharmaceuticals, NMR Spectroscopy, Synthesis

ur academic approach is based on the premise that learning


is facilitated in a research environment, which involves
independent study, decision making, and problem solving
through research projects.1 3 To this end, a nontraditional
advanced undergraduate organic chemistry laboratory course
was developed. The project-oriented system consists of halfsemester research projects (about eight 4-h lab sessions) that
involve the multistep synthesis of a variety of classical pharmaceutical drugs, with methodologies usually adapted from primary
literature. One of these projects is described; the multistep
synthesis of two local anesthetic drugs, benzocaine and prilocaine, from a common three-step sequence starting from toluene
that requires the student to formulate a hypothesis and to design
experiments to test it.

lab work and report. In this preliminary evaluation, the instructor


inquires about the theoretical background of the experiment
(reaction type, mechanism, stoichiometry, etc.) and the procedure, frequently advising students against the idea that they must
follow instructions step-by-step to achieve success. This interaction is intended to promote a critical process that allows
students to design their own work plan and gives them selfcondence. The dialogue between the students and instructor
may be time-consuming, but the instructors must be aware of the
work the students are carrying out, making sure that the students
know, before initiating each step, how they are going to do it,
why, and what to expect.
At the beginning of the course, pharmaceuticals are assigned to
the students, who do a time-constrained bibliographic search
in Chemical Abstracts (CA), either in printed form or through
the SciFinder database, seeking information on syntheses for
the assigned drug. This search (typically 1950 through 1980)
frequently renders several nonrecoverable papers or patents, so it
is sometimes necessary to discuss alternatives, and then plan the
project and design experimental work based on nondetailed
procedures outlined in CA, turning the process into authentic
laboratory research. Laboratory limitations (time, materials, and
equipment) are taken into account in choosing a synthetic
strategy, as well as in designing each experiment; nonetheless,
additional support from a research laboratory is sometimes
necessary for reagents and facilities, which facilitates the teaching
research link. Students learn that, even for the reproduction
of methodology from a formal paper, adaptations or modications may be necessary, so they are encouraged to initially explore

LABORATORY DYNAMICS
Students work singly or in pairs, with dierent projects. Each
instructor is in charge of up to 10 students. The semester work
starts with three to ve simple experiments, presented in a
nonconventional laboratory manual (more accurately, a laboratory guide) that includes: (i) an introduction describing the work
system; (ii) 40 experimental proposals (each featuring a reaction
scheme, main objective, procedure references, a study guide,
prelab questions, and notes, as well as IR and NMR spectra); and
(iii) 10 appendixes addressing topics such as the lab notebook,
experimental design, microscale, waste disposal, bibliographic
research, and laboratory rules (the original version of this
manual, in Spanish, is included in the Supporting Information).
Before conducting each experiment, students search for
information, discuss it with the instructor, and outline a laboratory work plan, generating a grade that will be averaged with the
Copyright r 2011 American Chemical Society and
Division of Chemical Education, Inc.

Published: October 13, 2011


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dx.doi.org/10.1021/ed100838a | J. Chem. Educ. 2012, 89, 147149

Journal of Chemical Education

LABORATORY EXPERIMENT

Scheme 1. Divergent Synthesis of Prilocaine Hydrochloride (5) and Benzocaine (8)

uncertain procedures on a microscale. From a rough calculation


of the expected global yield, the quantity of starting material
is calculated to obtain about 1 g of nal product. Students
typically encounter chemical transformations that have not been
covered in lecture, highlighting the importance of qualied
laboratory instructors, as well as good communication with
lecture instructors.
More than the successful culmination of the synthesis, the
learning process and the interest the students demonstrate in
understanding their experiments are valued. For each experiment, a grade is assigned on the basis of (i) preliminary oral
evaluation (correlation between theory and practice, planning of
the experiment), (ii) performance in the lab (attention to lab
guidelines, time management, responsibility, ethics, etc.), and
(iii) proper documentation in a lab notebook. A nal-term report
is assigned on the synthesis and other features (bibliographic
research, pharmacology, analysis) of the target drug to encourage
the students to have a comprehensive view of the prepared
compound. Oral reports to the class are given by the students
who carried out the most interesting or successful projects.

This project, undertaken by two students as a team, illustrates


several classic reaction types and involves many common laboratory techniques. Most importantly, it requires students to design
a methodology for the conversion of the nitrotoluene isomer
mixture obtained in the rst step (part A, Scheme 1) into the
starting material for each local anesthetic. The methodology is
based on a hypothesis, which can easily be veried, concerning
the dierent reactivity of the corresponding amines.
Nitration of toluene is a classical example of an electrophilic
aromatic substitution on an activated benzene ring, which aords a
mixture of nitrotoluene isomers in varying ratios depending on the
specic conditions. In this project, students have employed the
classical sulfuric/nitric method by adapting a laboratory procedure
published in this Journal,7 leading to a mixture of o-, m-, and
p-nitrotoluene (MNT) isomers (1) in a typical ratio of about 59:4:36,
respectively, with yields of 62 80%. An alternative nitration
method, which students have reproduced, employs in situ generated acetyl nitrate.8 Because the separation of the MNT isomers
is too dicult to accomplish in the laboratory,9 the isomeric ratio is
established by GC or HPLC analysis and the mixture is used as the
starting material for the synthesis of target products.
Reduction of the MNT mixture by catalytic hydrogen transfer
(ammonium formate, Pd/C, AcOEt)10 aords a mixture of
toluidine isomers, from which the p-toluidine may be selectively
acetylated, owing to its reduced steric demand. After discussing
the steric properties of the toluidines with the instructor, the
students in charge of the project must propose a hypothesis
regarding which of the isomers will be the most reactive toward
an acylating agent, develop a work plan to verify it, and a strategy
that allows them to isolate both main products, o-toluidine and
p-methylacetanilide. To achieve this, students treat the dried
solution of the toluidine isomer mixture, at 0 C, with one molar
equivalent (as to the amount of p-isomer theoretically present in
the mixture) of acetic anhydride. TLC analysis of the reaction
mixture allows a clear dierentiation of all compounds involved
(see the Supporting Information). Following dilute HCl extraction, p-methylacetanilide (3) is isolated and puried by one of
the students as the starting material for benzocaine synthesis.

PROJECT DESCRIPTION
The multistep divergent synthesis of two local anesthetics,
prilocaine hydrochloride (5) and benzocaine (8), with a common initial three-step reaction sequence starting from toluene is
described as an example project (Scheme 1). Local anesthetics,
which reversibly block nerve impulses, can be divided into two
main groups, esters (e.g., cocaine, benzocaine, procaine, tetracaine) and amides (e.g., lidocaine, prilocaine, bupivacaine), by
the functional group that connects the hydrophobic group (generally
an aromatic ring) and the hydrophilic group (frequently a
secondary or tertiary amine group).4 Side eects of local anesthetics are common; a metabolite of benzocaine is p-amino
benzoic acid, which is associated with allergic reactions, and a breakdown product of prilocaine, o-toluidine, can produce methemoglobinemia. Also, prilocaine has been reported to induce apoptosis
in osteoblastic cells.5 Prilocaine is used as a racemate, although
isomers dier in potency and in toxicity.6
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Journal of Chemical Education


The o-toluidine hydrochloride solution (2) is used by the other
student for prilocaine hydrochloride synthesis.
The synthesis of prilocaine hydrochloride (5) from 2 (part B
in Scheme 1) is accomplished through modications of the
described methodologies11 to suit the laboratory conditions
and small scale. The o-toluidine hydrochloride solution (2) is
buered to pH = 5 6 (NaOH and AcONa) and cooled to 5 C
before adding 2-chloropropionyl chloride to aord chloroamide 4 (mp 112 113 C). Overall yields of 4 from toluene
(no isolated intermediates) are typically in the range from 12 to
26%. Synthesis of prilocaine hydrochloride (5) was simplied by
allowing a solution of 4 in n-propylamine to stand for two days at
room temperature, followed by treatment of the isolated base
product with gaseous HCl, either lab generated12 or by the use of a
commercially available hydrogen chloride/2-propanol solution.
Typical yields of 5 from 4 are around 60 80 %.
By omitting several isolation and purication steps, this set of
operations may be considered a telescoping synthesis. This is a
green chemistry strategy, where one reactant goes through
multiple transformations without isolation of intermediates,
and is aimed to reduce the number of unit operations, in this
way saving time, reducing environmental burden (solvents,
energy, etc.), reducing the need to manipulate toxic materials,
and increasing yield.13
Benzocaine (8) is prepared from p-methylacetanilide (3) (part
C in Scheme 1) in a three-step reaction sequence, involving
procedures described in this Journal14 and in several laboratory
instruction manuals (overall yields of about 12 to 22 %).

LABORATORY EXPERIMENT

ASSOCIATED CONTENT

bS

Supporting Information
Background information, experimental procedure with notes
for instructors, safety hazards, list of chemicals, gas and HPLC
chromatograms, NMR spectra. The lab manual (in Spanish)
used in our course is included in a separate compressed le. This
material is available via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION
Corresponding Author

*E-mail: regla@unam.mx.

ACKNOWLEDGMENT
We are grateful to Santiago Capella Vizcano, from Facultad de
 ngeles Pe~na, from Instituto de
Qumica, UNAM, and Ma. de los A
Qumica, UNAM, for chromatographic and 1H NMR analysis,
respectively. We also thank the students David Arias, Araceli
Guevara, Ramon Vazquez, Claudia Almazan, Sarah Barragan,
Neftal Rivera, and Manuel Lopez-Ortiz, who enthusiastically
participated in this project.
REFERENCES
(1) Horowitz, G. J. Chem. Educ. 2007, 84 (2), 346353.
(2) Reid, N.; Shah, I. Chem Educ. Res. Pract. 2007, 8 (2), 172185.
(3) Ruttledge, T. R. J. Chem. Educ. 1998, 75 (12), 15751577.
(4) Ostercamp, D. L.; Brunsvold, R. J. Chem. Educ. 2006, 83 (12),
18161820.
(5) Nakamura, K.; Kido, H.; Morimoto, Y.; Morimoto, H.; Kobayashi,
S.; Morikawa, M.; Haneji, T. Can. J. Anesth. 1999, 46 (5), 476482.
(6) Akerman, B.; Ross, S. Pharmacol. Toxicol. 1970, 28 (6), 445453.
(7) Russell, R. A.; Switzer, R. W.; Longmore, R. W. J. Chem. Educ.
1990, 67 (1), 6869.
(8) Blankespoor, R. L.; Hogendoorn, S.; Pearson, A. J. Chem. Educ.
2007, 84 (4), 697698.
(9) Zinnen, H. A., U.S. Pat. 4,620,047, October 28, 1986.
(10) Hanson, R. W. J. Chem. Educ. 1997, 74 (4), 430431.
(11) (a) Lofgren, N.; Tegner, C. Acta Chem. Scand. 1960,
14, 486490. (b) Lofgren, N. Tegner, C. P. U.S. Pat. 3,160,662, 1964.
(c) Brown, C. L., U.S. Pat. 3,646,137, 1972. (d) Reilly, T. J. J. Chem. Educ.
1999, 76 (11), 1557.
(12) Arnaiz, F. J. J. Chem. Educ. 1995, 72 (12), 1139.
(13) Clark, J. H. Nature Chem. 2009, 1, 1213.
(14) Kremer, C. B. J. Chem. Educ. 1956, 33 (2), 7172.

HAZARDS
All reactants, products, and solvents must be handled in a
manner consistent with the information available on their
Material Safety Data Sheets (MSDS). Eye protection and gloves
must be worn at all times and procedures must be conducted in a
fume hood. Nitrotoluene and toluidine isomers are skin irritants
and suspected carcinogens. Acetic anhydride is a lachrymator,
corrosive, and ammable. 2-Chloropropionyl chloride should
be handled with particular care as it is extremely corrosive,
lachrymator, water-reactive (generating HCl), and ammable.
Toluene, methanol, diethyl ether, hexane, ethyl acetate, and
isopropyl alcohol are all volatile, toxic, and ammable liquids;
particularly, diethyl ether should be kept away from sparks or re.
Propylamine is highly volatile, toxic, ammable, and irritating to
the skin and mucous membranes. Ammonium formate and
sodium acetate trihydrate are irritant to skin and eyes. Sodium
hydroxide is very caustic. Sulfuric, nitric, and hydrochloric acids
are corrosive to eyes, skin, and mucous membranes. Palladium on
carbon is pyrophoric when dry; it can cause re in contact with
combustible materials, such as organic solvents or lter paper.
Hydrogen chloride is extremely corrosive and irritating to eyes,
skin, and mucous membranes.
CONCLUSIONS
This project was developed and rened with the work of
students from several generations in our course. It requires the
design of a telescoping sequence for several of the synthetic steps,
as well as adaptations to previously reported syntheses, to suit
laboratory conditions. Students have described this project as
challenging and useful, as it has allowed them to practice a variety
of experimental techniques and reaction types, in addition to
exposing them to real scientic practice.
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dx.doi.org/10.1021/ed100838a |J. Chem. Educ. 2012, 89, 147149

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