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 Aut!onoma de M!exico, Batalla del 5 de Mayo esq. Fuerte de Loreto,
Ej!ercito de Oriente, 09230 M!exico, D.F., M!exico
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 Spec-
troscopy, Synthesis

O 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
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 proce-
through research projects.1!3 To this end, a nontraditional dure, frequently advising students against the idea that they must
advanced undergraduate organic chemistry laboratory course “follow instructions step-by-step” to achieve success. This inter-
was developed. The project-oriented system consists of half- action is intended to promote a critical process that allows
semester research projects (about eight 4-h lab sessions) that students to design their own work plan and gives them self-
involve the multistep synthesis of a variety of classical pharma- confidence. The dialogue between the students and instructor
ceutical drugs, with methodologies usually adapted from primary may be time-consuming, but the instructors must be aware of the
literature. One of these projects is described; the multistep work the students are carrying out, making sure that the students
synthesis of two local anesthetic drugs, benzocaine and prilo- know, before initiating each step, how they are going to do it,
caine, from a common three-step sequence starting from toluene why, and what to expect.
that requires the student to formulate a hypothesis and to design At the beginning of the course, pharmaceuticals are assigned to
experiments to test it. 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
’ LABORATORY DYNAMICS the assigned drug. This search (typically 1950 through 1980)
Students work singly or in pairs, with different projects. Each frequently renders several nonrecoverable papers or patents, so it
instructor is in charge of up to 10 students. The semester work is sometimes necessary to discuss alternatives, and then plan the
starts with three to five simple experiments, presented in a project and design experimental work based on nondetailed
nonconventional laboratory manual (more accurately, a labora- procedures outlined in CA, turning the process into authentic
tory guide) that includes: (i) an introduction describing the work laboratory research. Laboratory limitations (time, materials, and
system; (ii) 40 experimental proposals (each featuring a reaction equipment) are taken into account in choosing a synthetic
scheme, main objective, procedure references, a study guide, strategy, as well as in designing each experiment; nonetheless,
prelab questions, and notes, as well as IR and NMR spectra); and additional support from a research laboratory is sometimes
(iii) 10 appendixes addressing topics such as the lab notebook, necessary for reagents and facilities, which facilitates the teaching!
experimental design, microscale, waste disposal, bibliographic research link. Students learn that, even for the reproduction
research, and laboratory rules (the original version of this of methodology from a formal paper, adaptations or modifica-
manual, in Spanish, is included in the Supporting Information). tions may be necessary, so they are encouraged to initially explore
Before conducting each experiment, students search for
information, discuss it with the instructor, and outline a labora-
tory work plan, generating a grade that will be averaged with the Published: October 13, 2011

Copyright r 2011 American Chemical Society and

Division of Chemical Education, Inc. 147 dx.doi.org/10.1021/ed100838a | J. Chem. Educ. 2012, 89, 147–149
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 This project, undertaken by two students as a team, illustrates
of the expected global yield, the quantity of starting material several classic reaction types and involves many common labora-
is calculated to obtain about 1 g of final product. Students tory techniques. Most importantly, it requires students to design
typically encounter chemical transformations that have not been a methodology for the conversion of the nitrotoluene isomer
covered in lecture, highlighting the importance of qualified mixture obtained in the first step (part A, Scheme 1) into the
laboratory instructors, as well as good communication with starting material for each local anesthetic. The methodology is
lecture instructors. based on a hypothesis, which can easily be verified, concerning
More than the successful culmination of the synthesis, the the different reactivity of the corresponding amines.
learning process and the interest the students demonstrate in Nitration of toluene is a classical example of an electrophilic
understanding their experiments are valued. For each experi- aromatic substitution on an activated benzene ring, which affords a
ment, a grade is assigned on the basis of (i) preliminary oral mixture of nitrotoluene isomers in varying ratios depending on the
evaluation (correlation between theory and practice, planning of specific conditions. In this project, students have employed the
the experiment), (ii) performance in the lab (attention to lab classical sulfuric/nitric method by adapting a laboratory procedure
guidelines, time management, responsibility, ethics, etc.), and published in this Journal,7 leading to a mixture of o-, m-, and
(iii) proper documentation in a lab notebook. A final-term report p-nitrotoluene (MNT) isomers (1) in a typical ratio of about 59:4:36,
is assigned on the synthesis and other features (bibliographic respectively, with yields of 62!80%. An alternative nitration
research, pharmacology, analysis) of the target drug to encourage method, which students have reproduced, employs in situ gen-
the students to have a comprehensive view of the prepared erated acetyl nitrate.8 Because the separation of the MNT isomers
compound. Oral reports to the class are given by the students is too difficult to accomplish in the laboratory,9 the isomeric ratio is
who carried out the most interesting or successful projects. established by GC or HPLC analysis and the mixture is used as the
starting material for the synthesis of target products.
’ PROJECT DESCRIPTION Reduction of the MNT mixture by catalytic hydrogen transfer
(ammonium formate, Pd/C, AcOEt)10 affords a mixture of
The multistep divergent synthesis of two local anesthetics,
prilocaine hydrochloride (5) and benzocaine (8), with a com- toluidine isomers, from which the p-toluidine may be selectively
mon initial three-step reaction sequence starting from toluene is acetylated, owing to its reduced steric demand. After discussing
described as an example project (Scheme 1). Local anesthetics, the steric properties of the toluidines with the instructor, the
which reversibly block nerve impulses, can be divided into two students in charge of the project must propose a hypothesis
main groups, esters (e.g., cocaine, benzocaine, procaine, tetra- regarding which of the isomers will be the most reactive toward
caine) and amides (e.g., lidocaine, prilocaine, bupivacaine), by an acylating agent, develop a work plan to verify it, and a strategy
the functional group that connects the hydrophobic group (generally that allows them to isolate both main products, o-toluidine and
an aromatic ring) and the hydrophilic group (frequently a p-methylacetanilide. To achieve this, students treat the dried
secondary or tertiary amine group).4 Side effects of local anes- solution of the toluidine isomer mixture, at 0 !C, with one molar
thetics are common; a metabolite of benzocaine is p-amino equivalent (as to the amount of p-isomer theoretically present in
benzoic acid, which is associated with allergic reactions, and a break- the mixture) of acetic anhydride. TLC analysis of the reaction
down product of prilocaine, o-toluidine, can produce methemoglo- mixture allows a clear differentiation of all compounds involved
binemia. Also, prilocaine has been reported to induce apoptosis (see the Supporting Information). Following dilute HCl extrac-
in osteoblastic cells.5 Prilocaine is used as a racemate, although tion, p-methylacetanilide (3) is isolated and purified by one of
isomers differ in potency and in toxicity.6 the students as the starting material for benzocaine synthesis.
148 dx.doi.org/10.1021/ed100838a |J. Chem. Educ. 2012, 89, 147–149
Journal of Chemical Education LABORATORY EXPERIMENT

The o-toluidine hydrochloride solution (2) is used by the other ’ ASSOCIATED CONTENT
student for prilocaine hydrochloride synthesis.
The synthesis of prilocaine hydrochloride (5) from 2 (part B bS Supporting Information
in Scheme 1) is accomplished through modifications of the Background information, experimental procedure with notes
described methodologies11 to suit the laboratory conditions for instructors, safety hazards, list of chemicals, gas and HPLC
and small scale. The o-toluidine hydrochloride solution (2) is chromatograms, NMR spectra. The lab manual (in Spanish)
buffered to pH = 5!6 (NaOH and AcONa) and cooled to 5 !C used in our course is included in a separate compressed file. This
before adding 2-chloropropionyl chloride to afford chloro- material is available via the Internet at http://pubs.acs.org.
amide 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 simplified by ’ AUTHOR INFORMATION
allowing a solution of 4 in n-propylamine to stand for two days at
room temperature, followed by treatment of the isolated base Corresponding Author
product with gaseous HCl, either lab generated12 or by the use of a *E-mail: [email protected].
commercially available hydrogen chloride/2-propanol solution.
Typical yields of 5 from 4 are around 60!80 %. ’ ACKNOWLEDGMENT
By omitting several isolation and purification steps, this set of We are grateful to Santiago Capella Vizcaíno, from Facultad de
operations may be considered a telescoping synthesis. This is a Química, UNAM, and Ma. de los A ! ngeles Pe~na, from Instituto de
green chemistry strategy, where one reactant goes through Química, UNAM, for chromatographic and 1H NMR analysis,
multiple transformations without isolation of intermediates, respectively. We also thank the students David Arias, Araceli
and is aimed to reduce the number of unit operations, in this Guevara, Ram!on V!azquez, Claudia Almaz!an, Sarahí Barrag!an,
way saving time, reducing environmental burden (solvents, Neftalí Rivera, and Manuel L!opez-Ortiz, who enthusiastically
energy, etc.), reducing the need to manipulate toxic materials, participated in this project.
and increasing yield.13
Benzocaine (8) is prepared from p-methylacetanilide (3) (part
C in Scheme 1) in a three-step reaction sequence, involving ’ REFERENCES
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’ CONCLUSIONS
This project was developed and refined 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 scientific practice.
149 dx.doi.org/10.1021/ed100838a |J. Chem. Educ. 2012, 89, 147–149