The Resolution of Ibuprofen, 2-(4'-Isobutylphenyl)propionic Acid

McCullagh, James V.

doi:10.1021/ed085p941

Cited by 13 publications

(16 citation statements)

References 7 publications

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“…This helps students appreciate the often-subtle effects the 3-dimensional shape of a molecule can have on a reaction. In addition to providing students with a wet-lab approach to stereochemistry, undergraduates will be exposed to some of the unique benefits of heteroatom NMR spectroscopy.…”

Section: Discussionmentioning

confidence: 99%

A Wet-Lab Approach to Stereochemistry Using ³¹P NMR Spectroscopy

Fenton

Sculimbrene

2011

J. Chem. Educ.

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b S Supporting Information N MR spectroscopy can be a particularly useful tool in assessing the enantiopurity or stereochemical identity of certain optically active reagents. For example, derivitizing chiral alcohols and amines with Mosher's acid is used extensively to elucidate their enantiomeric purity or absolute configuration. 1 Undergraduate-ready modifications of this same procedure have even been described within the pages of this Journal. 2 These methods, which are typically analyzed using either 1 H or 19 F NMR spectroscopy, rely on the coupling of optically active materials with chiral auxiliaries to generate diastereomeric products whose chemical shifts are often distinguishable using conventional NMR technology.However, Mosher's methodology is not the only procedure that has been used to assess the enantiopurity of chiral alcohols with NMR. In 1985, Feringa and co-workers demonstrated that the enantiomeric ratio of alcohols could be determined without the use of a chiral auxiliary coupling reagent. 3 Their method relies on the coupling of two molecules of a chiral alcohol with PCl 3 , an achiral phosphorous-bearing center (Scheme 1). The resulting dialkyl phosphonate can be chiral or meso depending on the configuration of the two alcohols that reacted. The dialkyl phosphonate is then analyzed by 31 P NMR to determine the number and ratio of phosphorous products present. The enantiomeric purity of each alcohol is then determined based on the integration of these diastereomeric peaks in the 31 P NMR spectrum. The large spectral window in 31 P NMR in comparison to 1 H NMR easily facilitates resolution of diastereomeric peaks.We sought to develop a laboratory experiment that would introduce second-semester or advanced organic laboratory students to the stereochemical intricacies of coupling optically active or racemic mixtures of chiral alcohols to an achiral center. We envisioned that the synthesis of di-sec-phenethyl phosphonate from either racemic, (R)-, or (S)-sec-phenethyl alcohol depicted in Scheme 1 could successfully accomplish our goal. The laboratory begins with a modified Michaelis-Abruhov reaction for the synthesis of a dialkyl phosphite. 4 The resulting dialkyl phosphite readily tautomerizes to the dialkyl phosphonate, which presents the students with an interesting tautomerization that occurs between the P(III) and P(V) phosphorous forms. This could serve as a point of departure for discussing keto-enol equilibrium concentrations: much as the keto form predominates, so too does the P(V) dialkyl phosphonate. 5 After acquiring the 31 P NMR spectra and making molecular models of their product, students are asked to interpret their results paying careful attention to stereochemistry. ' SUMMARY OF PROCEDUREDi-sec-phenethyl phosphonate is synthesized according to a modified literature procedure. 6 Students are divided into one of three groups, and each of these groups is assigned either racemic, (R)-, or (S)-sec-phenethyl alcohol. Students dissolve their respective sec-phenethyl alcohol (2.5 mmol,...

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Section: Discussionmentioning

confidence: 99%

A Wet-Lab Approach to Stereochemistry Using ³¹P NMR Spectroscopy

Fenton

Sculimbrene

2011

J. Chem. Educ.

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“…23 etc. Em substâncias com o grupo funcional ácido carboxílico próximo ao centro estereogênico, como nas amostras em questão, uma maneira clássica de se fazer a resolução da mistura racêmica é através da preparação dos correspondentes sais 4,6,8 ou outros derivados diasteroisoméricos dos ácidos utilizando um reagente quiral. 10 Como já indicado, optou-se por preparar amidas diastereoisoméricas e isto foi feito pela reação entre o (±)-ibuprofeno e (S)-(-)-a-metilbenzilamina (4) na presença de N,N'-dicicloexilcarbodi-imida (DCC) 24 (Esquema 1).…”

Section: Algumas Considerações Sobre Moléculas Quirais E Separação Deunclassified

“…Assim, enquanto inúmeros experimentos são propostos envolvendo extrações, sínteses ou análises de substâncias opticamente ativas, [4][5][6] ainda faltam propostas de experimentos que tratem da resolução de enantiômeros. [7][8][9][10] Neste contexto, uma das classes de fármacos quirais mais populares hoje em dia e que pode ser perfeitamente utilizada para tal fim é a dos anti-inflamatórios derivados do ácido propiônico, conhecidos como profenos, como o ibuprofeno (1), o naproxeno (2) e o cetoprofeno (3) (Figura 1). No caso do ibuprofeno (1), o enantiômero (S)-(+) é o que apresenta maior afinidade pelas proteínas plasmáticas e, como consequência, melhor ação farmacológica.…”

Section: Introductionunclassified

Resolução do ibuprofeno: um projeto para disciplina de química orgânica experimental

Romero¹,

Baptistella²,

Coelho³

et al. 2012

Quím. Nova

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Recebido em 29/2/12; aceito em 3/4/12; publicado na web em 2/7/12 RESOLUTION OF IBUPROFEN: A PROJECT FOR AN EXPERIMENTAL ORGANIC CHEMISTRY COURSE. A practical and didactic sequence of experiments was proposed to illustrate the stereochemistry concept, optically active compounds, resolution of racemates, and use of the NMR technique, including 2D-COSY for identification of organic compounds, on a laboratory course for undergraduate students. The sequence was: extractions of racemic ibuprofen and chiral naproxen from commercial tablets; syntheses of diastereoisomeric amides reacting chiral (S)-(-)-a-methylbenzylamine with (±)-ibuprofen; separation and determination of absolute configuration of amides by 1 H NMR spectroscopy and GC analysis, and hydrolysis of amides to obtain (+)-and (-)-ibuprofen.Keywords: resolution of ibuprofen; stereochemistry; NMR Spectroscopy. INTRODUÇÃOSubstâncias opticamente ativas com atividades farmacológicas sempre foram excelentes alvos para ilustrar a importância dos conhecimentos de estereoquímica em disciplinas de graduação. Desde o clássico caso da ação deletéria da (S)-talidomida 1 até os mais recentes lançamentos de inibidores enzimáticos, 2 os docentes podem encontrar nos livros texto ou na literatura em geral inúmeros exemplos para se aprofundar nos ensinamentos de um dos mais fascinantes tópicos da química. Nas disciplinas de química orgânica teórica em cursos de graduação, o assunto estereoquímica é, na maioria das vezes, muito bem tratado, inclusive com o uso, em classe, de modelos moleculares e de programas computacionais que facilitam o entendimento por parte dos alunos.3 Por outro lado, nas disciplinas experimentais, ainda se notam lacunas no tratamento de alguns dos itens abordados por esse assunto. Assim, enquanto inúmeros experimentos são propostos envolvendo extrações, sínteses ou análises de substâncias opticamente ativas, 4-6 ainda faltam propostas de experimentos que tratem da resolução de enantiômeros.7-10 Neste contexto, uma das classes de fármacos quirais mais populares hoje em dia e que pode ser perfeitamente utilizada para tal fim é a dos anti-inflamatórios derivados do ácido propiônico, conhecidos como profenos, como o ibuprofeno (1), o naproxeno (2) e o cetoprofeno (3) (Figura 1). No caso do ibuprofeno (1), o enantiômero (S)-(+) é o que apresenta maior afinidade pelas proteínas plasmáticas e, como consequência, melhor ação farmacológica.11 No entanto é conhecido, por testes biológicos realizados in vivo, que a enzima epimerase 2-arilpropionil--CoA é capaz de converter o (R)-(-)-ibuprofeno no seu enantiômero mais ativo (S)-(+).12 Desta forma, devido ao alto custo envolvido na síntese de um enantiômero puro, os profenos são comercializados na forma racêmica, com exceção do naproxeno (2), disponível no mercado apenas como o isômero (S)-(+), devido à ação hepatotóxica do enantiômero (R)-(-). 13Com base nesse conjunto de informações e considerando o nosso interesse em sequências reacionais adequadas a uma disciplina de química orgânica experimental, 14 foi elabora...

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“…These concepts are often encountered in experimental laboratory activities in which students determine the enantiomeric purity of a compound and calculate the enantiomeric excess . These chirality measurements are often performed in teaching laboratories using polarimetry or nuclear magnetic resonance (NMR) spectroscopy . While these two instrumental techniques diversify a student’s knowledge base, a third instrumental technique, mass spectrometry, is also suitable for enantiomeric excess determination. , …”

Section: Introductionmentioning

confidence: 99%

Chiral Analysis by Tandem Mass Spectrometry Using the Kinetic Method, by Polarimetry, and by ¹H NMR Spectroscopy

Fedick

Bain

et al. 2017

J. Chem. Educ.

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The goal of this laboratory exercise was for students to understand the concept of chirality and how enantiomeric excess (ee) is experimentally determined using the analysis of ibuprofen as an example. Students determined the enantiomeric excess of the analyte by three different instrumental methods: mass spectrometry, nuclear magnetic resonance spectroscopy, and optical polarimetry. This laboratory exercise introduced mass spectrometry into the first-semester organic chemistry curriculum. Further, it allowed the students to compare and contrast the analytical figures of merit for each technique, a topic usually discussed later in chemistry courses. The ee resolution, sensitivity, limits of detection, and required sample preparation were considered. Furthermore, this laboratory experiment taught students how to use the kinetic method for chiral analysis by mass spectrometry, a new technique in a student laboratory exercise. Students’ knowledge of how to select the appropriate technique for enantiomeric excess determination was broadened, as was their knowledge of the general concept of chirality, as seen in their laboratory reports and exit interviews.

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The Resolution of Ibuprofen, 2-(4'-Isobutylphenyl)propionic Acid

Cited by 13 publications

References 7 publications

A Wet-Lab Approach to Stereochemistry Using ³¹P NMR Spectroscopy

A Wet-Lab Approach to Stereochemistry Using ³¹P NMR Spectroscopy

Resolução do ibuprofeno: um projeto para disciplina de química orgânica experimental

Chiral Analysis by Tandem Mass Spectrometry Using the Kinetic Method, by Polarimetry, and by ¹H NMR Spectroscopy

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The Resolution of Ibuprofen, 2-(4'-Isobutylphenyl)propionic Acid

Cited by 13 publications

References 7 publications

A Wet-Lab Approach to Stereochemistry Using 31P NMR Spectroscopy

A Wet-Lab Approach to Stereochemistry Using 31P NMR Spectroscopy

Resolução do ibuprofeno: um projeto para disciplina de química orgânica experimental

Chiral Analysis by Tandem Mass Spectrometry Using the Kinetic Method, by Polarimetry, and by 1H NMR Spectroscopy

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A Wet-Lab Approach to Stereochemistry Using ³¹P NMR Spectroscopy

A Wet-Lab Approach to Stereochemistry Using ³¹P NMR Spectroscopy

Chiral Analysis by Tandem Mass Spectrometry Using the Kinetic Method, by Polarimetry, and by ¹H NMR Spectroscopy