Formulation science


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7PY015: Natural Products and Medicinal Chemistry.
Workshop Activity for Week 33
Synthesis and modification of benzocaine
Benzocaine is a local anaesthetic used for pain relief in the mouth, ears and other areas as well as in some cough medications. Its relatively simple structure means that it is easily synthesised and here it will be prepared by Fischer esterification of 4-aminobenzoic acid (or p-aminobenzoic acid – PABA).

The experiment is in three parts; firstly the synthesis of a sample of benzocaine and secondly an extension activity where you asked to prepare a sample of N-acetylbenzocaine from your original product. In parts 1 & 2 you will be asked to collect sufficient evidence to confirm that you have made the expected product. Further evidence will be gathered in Part 3.
Please note that you are asked to write a full report and complete the background reading and extension questions included in this protocol as part of the assessment for the module. Assessment criteria and other details are included at the back of this document.
You may find it helpful to watch the video Synthesis of benzocaine and Running a TLC Plate before you come to the laboratory. It will help to give you an overview of this experiment.
You MUST wear a lab coat, safety spectacles and latex gloves throughout this experiment.
Part 1: Synthesis of benzocaine:
Place 4-aminobenzoic acid (3.0g) in a 100 mL round bottom flask and then add absolute ethanol (20 mL) followed by the careful addition of sulfuric acid (3.0 mL), with cooling in ice bath as a safety precaution. Place 2-4 anti-bumping granules in the flask and then assemble a condenser and place the flask in a suitable heating mantle. Heat under reflux for 90 minutes, and then stop the reaction. Cool the reaction mixture to room temperature, then in a fresh ice/water bath, and then remove the condenser and stand the flask safely on a flat surface using a cork ring. Carefully add some ice (about 20-30 g) to the flask and then pour in slowly 12.0 mL of 10% NaOH solution (aqueous). Mix well and using a plastic teat pipette as a dropper, test the pH on a small piece of universal indicator paper. Check that the pH lies between 6 and 8 and if not, adjust by adding small quantities of 1M HCl or 1M NaOH as required. Now transfer the flask contents to a 500 mL glass beaker, rinsing with distilled water and dilute to 500 mL. Stir well and filter off the white solid using a Buchner funnel and vacuum pump. When as dry as possible (no drips coming through the filter) remove the white solid product onto a clean pre-weighed watch glass and leave the powder to dry in the drying cabinet at around 70oC for up to an hour.
Record the yield and transfer the product to a labelled glass jar with a screw top.
Retain enough material (~50 mg) so that you may fully characterise your product from part A.
Part 2: Acetylation of benzocaine:
In this part of the experiment you will attempt to prepare a sample of N-acetylbenzocaine. Follow the instructions carefully as acetic (ethanoic) anhydride is a lachrymator, and is corrosive and irritating to the eyes and skin.
Weigh approximately 1.0 g of your benzocaine product from part 1 into a test tube. Working in a fume cupboard, add ethanoic anhydride (3ml approx.) using a disposable plastic teat pipette. The graduations on the pipette are a suitably accurate measure of volume for this purpose. Now clamp your test tube (still in the fume cupboard) in an upright position with sufficient clearance to allow a micro-Bunsen burner underneath. Using a very low flame and sufficient gap, heat the mixture gently until the acetic anhydride begins to reflux on the walls of the tube. This must be controlled very carefully so that nothing actually boils out of the tube. Keep the refluxing going for about 15 minutes. Turn off the flame and allow the mixture to cool. When cool to the touch, pour the tube contents into about 25 mL of cold water in a 100 mL conical flask. Swirl the flask and add small amounts of solid sodium hydrogen carbonate to dispose of the excess acetic anhydride. Stop when no more evolution of carbon dioxide is apparent. You should now have a solid product which you now may filter under vacuum and collect.
Isolate the solid in exactly the same way as in part 1 and wash with a little cold water while under vacuum filtration.

Dry your crude product at 700C and record the yield.
Record the yield and transfer the product to a labelled glass jar with a screw top.
You may now fully characterise your product from part B.
Part 3: Evaluating the success of parts 1 & 2:
A) Using the TLC plate provided, spot samples of PABA, benzocaine and your crude N-acetylbenzocaine, labelling each spot clearly in pencil. Run your TLC plate using neat diethyl ether as the eluent. Visualise your spots under UV light. Take a photograph of your TLC plate to include in your report. Record the Rf values of PABA, benzocaine and N-acetylbenzocaine from your TLC plate.
B) Record the melting points of your two products.
C) Record a FTIR spectrum of your two products.
D) Prepare NMR samples by weighing approximately 5-10 mg of each product into a small sample vial and dissolving in 0.5-0.6 mL CDCl3 (deuterated chloroform). Use a glass Pasteur pipette to transfer your sample solutions to an NMR tube under supervision. The 1H and 13C NMR spectra may then be collected.
E) Record an LCMS spectrum of your two products.

The Report:
NB: Microgram Journal, Volume 7, Number 1 (March 2010) is available on WOLF
1. Write up a full report detailing this experiment in such a way that others could repeat your work reliably if required. You may wish to use the article by Casale and Nguyen (Microgram Journal, Volume 7, Number 1 (March 2010)) as a guide to the style that would be acceptable. You may adapt parts of the experimental details given in this lab booklet, but remember that a past, passive tense should be used, as in the cited article. Use clear section headings and equations and tables where relevant.
2. Ensure that you use all of your analytical data obtained from part 3 to confirm that you have successfully synthesised benzocaine and if possible, N-acetylbenzocaine. Comment on the yields and purity of your samples. For each compound you have synthesised, report your analytical data associated with the compound in RSC format. Include your spectra in your report as an appendix and cite any literature data which you use as evidence.

3. Address the following in your discussion:
a) Suggest mechanisms for the synthesis of and acetylation of benzocaine under the conditions used.
b) Explain concisely, but in detail, how you would expect aspirin to react with benzocaine if the two substances are stored as an intimate mixture. Do you think that Casale and Nguyen are correct in their conclusions and was their data sufficient to support their arguments? (Maximum 500 words please).
NB: This report with extension questions will be used as part of the assessment for 7PY015.
Please hand in to Dr Mark Honey (with assessment criteria page included) on or before 26/04/2018. Submit your document via email as a word document so that suitable feedback may be given. Marks will be deducted if the report is considered too long and repetitive.

School of Applied Sciences: Pharmacy Department
7PY015: Natural Products and Medicinal Chemistry.
Practical Report: Synthesis and modification of benzocaine.
STUDENT NAME:………………………………………………
Assessment: This report will be assessed according to the following criteria:
Grade 0-5% 10% 15% 20%
Presentation Poor. Not clear. Satisfactory but several areas for improvement. Mostly good but some parts inconsistent. Clear, easy to follow. Well laid out.
Use of English Poor, hard to follow, many errors. Satisfactory but several areas for improvement. Mostly good but some weak spelling and grammar. Very good. Clear, concise and free from repetition.
Answers to Question Answers missing or nonsensical Misses main points or confused Most points covered satisfactorily Well thought out, clear answers
References None included/inappropriate Some given but not consistent or clear Mostly good, some inconsistencies Well cited and properly listed (Harvard system used).
Scientific Content & Results Poor. Data missing & weak arguments Satisfactory. Main points included & discussed, but gaps. Mostly good, some inconsistencies & weaknesses Well-reasoned arguments & well presented data.

Sample Solution

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