Synthesis of Two Local Anesthetics from Toluene: An Organic Multistep Synthesis in a Project-Oriented Laboratory Course

Abstract

ercito de Oriente, 09230 M exico, D.F., M exico b S Supporting InformationO 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. 1À3 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. ' LABORATORY DYNAMICSStudents work singly or in pairs, with different projects. Each instructor is in charge of up to 10 students. The semester work starts with three to five 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 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 selfconfidence. 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 o...

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“…Benzocaine (BENZ), the ethyl ester of p-aminobenzoic acid, is a local anesthetic commonly used in human medicine and one of the most used for fish anesthesia [10,14,15]. Its anesthetic effects are desirable for teleost fish due to fast induction, short half-life, and rapid recovery time [16].…”

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“…PABA -para-aminobenzoic acid VDSCs -voltage-dependant sodium channels PPD -paraphenylendiamine introduced to the market in 1902 under the name "Anästhesin", according to Auterhoff (4) and Demare and Regla (5). It is also known under several other names: ethyl aminobenzoate, ethyl 4-aminobenzoate, 4-aminobenzoic acid ethyl ester, and p-aminobenzoic acid ethyl ester.…”

“…Benzocaine acts to inhibit the voltage-dependant sodium channels (VDSCs) on the nerve membrane, stopping the propagation of the action potential and blocking the local nerve impulses. It is absorbed in very small quantities by the membrane and is hydrolyzed by plasma pseudocholinesterases to metabolites containing PABA, which is highly allergenic and responsible for anaphylactic reactions (5).…”

An idea to explore: A collaboration and cross training in an extended classroom‐based undergraduate research experience between primarily undergraduate and research‐intensive institutions

“…Advanced synthesis laboratories have typically followed several formats. Some are designed to synthesize a specific target or targets such as chrysanthemic acid, insect pheromones, or local anesthetics . Others utilize a common intermediate (hypervalent iodine), pathway (Prins−Friedel−Crafts‐Type Reaction), or precursor (N‐Heterocyclic Carbene) to make diverse compounds.…”