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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
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.
LABORATORY EXPERIMENT
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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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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