Chemie | Biochemie | Medizin
Mara Robinson, 2005 | Muri, AG
This paper presents an optimization of the oxidation of para-methylacetanilide to para-acetamidobenzoic acid, a key step in the synthesis of the local anesthetic benzocaine. While an aqueous solution of the starting compound was heated, the oxidant (KMnO4) was added slowly. At the end of the reaction, the reaction mixture was filtered and the precipitated MnO2 discarded. The filtrate was acidified, whereupon the product crystallized and was isolated by filtration.
Three parameters were varied as part of the intended optimization: (i) reaction temperature, (ii) reaction time, and (iii) the amount of oxidizing agent. Additional adjustments were made to the experimental setup and the work-up procedure to improve efficiency. Varying the temperature in the range of 70 °C to 100 °C gave an optimum yield at around 90 °C. For reaction times between 15 and 120 minutes, yields peaked at 80-90 minutes. The amount of KMnO4 was varied from 1.6 to 2.65 equivalents, with an optimum yield between 2.4 and 2.5 equivalents. Our findings suggest that minor adjustments to reaction conditions can significantly improve product yield and purity, while diminishing the environmental impact by reducing the production of heavy metal waste (MnO2).
Introduction
This project focuses on optimizing the yield of the oxidation of para-methylacetanilide to para-acetamidobenzoic. It is investigated how the tuning of reaction parameters can make the synthesis more efficient and environmentally friendly.
Methods
Starting from a standard procedure, the oxidation reaction was repeatedly carried out in three series, one reaction parameter being varied per series. The parameters were (i) temperature (+/- 85 °C), (ii) reaction time (+/- 30 minutes), and (iii) the amount of KMnO4 used (+/- 2.5 equivalents). After work-up of each reaction and isolation of the crystalline product, its mass/yield was determined and plotted against the varied parameter. Analysis of these plots led to the determination of an optimum value for each parameter.
Results
When the reaction was carried out according to a literature procedure (85 °C, for 30 min, with 2.5 equiv. of KMnO4), a product yield of 57% was obtained. Higher temperatures generally led to better yields, the highest yield (65%) being achieved at 90–100 °C. Reaction times between 60 and 90 minutes produced the best results (67% yield), shorter or much longer times gave lower yields. There is a strong correlation between oxidant amount and yield, the highest value (68%) being found at 2.5 eq. KMnO4. The use of fluted filter paper was more effective in the work-up than vacuum filtration, and a three-neck flask plus dropping funnel improved safety as compared to an Erlenmeyer flask.
Discussion
The results mostly confirmed the initial assumptions: temperature, reaction time and the amount of oxidant clearly affected the yield of the oxidation reaction. Higher temperatures and reaction times as well as larger amounts of KMnO4 led to higher yields compared to the reference procedure.
Some irregularities in the trends of the data (temperature, equivalents of KMnO4) show that a larger number of reaction runs, combined with a better control of external factors, should produce more consistent and reliable results. However, limited time and initial inexperience affected consistency of the collected data.
Within the scope of this work, it was unfortunately not possible to assess the purity of the product. Four product samples were analyzed a posteriori by NMR spectroscopy in a university laboratory, underlining the importance of this aspect.
Conclusions
The yield of a key step in the synthesis of benzocaine was increased from an initial 57% to 68% by adjusting the parameters reaction temperature, reaction time, and amount of oxidizing agent. In addition, the replacement of several pieces of equipment also had a positive impact on yield. From an environmental perspective, this work helps to achieve an optimal product yield without generating unnecessary amounts of heavy metal waste (MnO2).
Future work could include testing of environmentally benign oxidants (e.g. oxygen in combination with a catalyst, hydrogen peroxide, bleach), specialized equipment such as ultrasonicators to enhance solubilization of the organic starting material in water, or pressure vessels to achieve even higher temperatures.
Würdigung durch den Experten
Prof. Dr. Carlo Thilgen
This project, which focused on optimizing a specific step in the synthesis of benzocaine, had a clearly defined and evaluable goal. Mara Robinson chose a classic approach involving variations in temperature, reaction time, and molar ratios of the reactants, that can be easily implemented in a school laboratory. Remarkably, she was able to make some improvements to this well-described reaction. The work impresses with the diligence and discipline shown in the numerous experiments, the self-critical evaluation of the results, and the comprehensible presentation.
Prädikat:
sehr gut
Sonderpreis von Life Sciences Switzerland (LS2)
Neue Kantonsschule Aarau
Lehrer: Michael Nussbaum