Synthesis of the Sweetener Dulcin from the Analgesic Tylenol

Abstract

Undergraduate organic chemistry students typically show the greatest interest in laboratory experiments utilizing familiar substances or compounds with a definite and readily understood function, such as analgesics, sweeteners, or flavorings. Considering the common use of experiments involving the analgesic aspirin, it is surprising that there have been few synthetic procedures developed for the high school or undergraduate laboratory involving acetaminophen (I) (1-3). This is notable because numerous experiments, concepts, and techniques can be directly linked with acetaminophen and its derivatives and would facilitate integration of its use in a broader pedagogical strategy. 1 This report describes the conversion of the analgesic acetaminophen to the artificial sweetener dulcin (IV). The experimental sequence is suitable for both high school and undergraduate laboratories and can be performed on either a micro or macro scale. Phenacetin (II), also a physiologically active analgesic, is an intermediate isolated during the sequence (2, 4 ). Consequently, the procedures described can be adopted as a multistep synthesis of dulcin from acetaminophen or, alternatively as one-period conversions of either acetaminophen to phenacetin or phenacetin to dulcin. A Williamson-type synthesis of aromatic ethers is featured in the former transformation, while the latter demonstrates an amide hydrolysis followed by a nucleophilic addition reaction of an aryl amine with an isocyanate. 2 The procedure described offers numerous advantages over previously reported methods, making the experiment suitable for student laboratories. Yields are high and crude products are commonly isolated with sufficient purity that refinement before analysis or use in subsequent reactions is optional. Reaction conditions are optimized to provide adequate time for product purification and characterization within each 3-hour laboratory period. Finally, halogenated solvents are eliminated and the experiment can be run if desired on a single Tylenol tablet, thus significantly minimizing chemical use and wastes.

Preparing 4-Ethoxyphenylurea Using Microwave Irradiation: Introducing Students to the Importance of Artificial Sweeteners and Microwave-Assisted Organic Synthesis (MAOS)

“…Crude yields before recrystallization typically ranged from 80% to 100% compared to the literature value of 82−90% when the mixture was heated for 45−90 min. 10 The average yields for the recrystallized product observed from comparing classes performing the traditional procedure versus the microwave procedure were slightly improved from 29% for the heating mantle procedure to 39%. The range of yields obtained by students using the MAOS method was 10−86% (see the instructor's notes in the Supporting Information).…”

“…9 There are different procedures that can be used to synthesize dulcin including a multistep synthesis from acetaminophen requiring two laboratory periods. 10 By contrast, the method described here uses microwave irradiation, requires just one laboratory session, and parallels the traditional synthesis of dulcin involving the reaction of p-phenetidine (p-ethoxyaniline) with isocyanic acid (Scheme 1). 11 The instability of isocyanic acid requires its in situ formation from ammonium cyanate which exists in equilibrium with urea under acidic conditions (Scheme 2).…”

Síntese dos analgésicos paracetamol e fenacetina e do adoçante dulcina: um projeto para química orgânica experimental

“…Em um béquer de 1000 mL contendo 74,0 g de gelo picado, num banho de gelo, foram adicionados lentamente 24,5 mL de ácido sulfúrico concentrado e em seguida 5,93 g da N-fenil-hidroxilamina (2). A solução foi diluída com 490 mL de água e aquecida até a ebulição.…”

“…Assim, visando a elaboração de experimentos para uma disciplina experimental avançada de química orgânica no perí-odo noturno, com uma carga horária semanal de 6 h (4+2 h), pensou-se em projetos de síntese que envolvessem seqüências de 4 a 6 etapas com as seguintes características: compatibilidade com o tempo disponível, produtos de fácil purificação e caracterização, possibilidade de manipulação em escala semi-micro ou micro e, principalmente, experimentos que permitissem aos alunos a sedimentação de conceitos básicos, com exemplos envolvendo aspectos de suas vidas cotidianas. Foi publicado recentemente um experimento para laboratório de ensino envolvendo a preparação da dulcina 2 , um adoçante sintético, a partir do analgésico acetaminofeno, conhecido também como paracetamol. No entanto, a seqüência mostrada (parte experimental disponível apenas por assinatura da revista "online", a qual, segundo informações, não é feita por nenhuma biblioteca do Brasil) não funcionou como descrito, e os resultados não se reproduziram.…”

A Multistep Synthesis for an Advanced Undergraduate Organic Chemistry Laboratory

“…Moreover, the synthesis of a product with novel applications can usually make the laboratory course more attractive to students. A number of articles offering multistep syntheses of compounds with biological significance have appeared (1)(2)(3)(4)(5). Wilen and co-workers (6) outlined a four-step procedure to prepare polystyrene from benzene.…”