O-007C Procedure

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Oct 30, 2023

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© copyright C3XX Instructional Staff. Not to be used, copied or revised or shared without explicit written permission. O-0007C: Synthesis of Ethyl 4-Nitrobenzoate Learning Objectives 1. Learn to safely handle and transfer concentrated sulfuric acid; 2. Practice running a reaction under reflux conditions; 3. Practice using thin-layer chromatography to monitor reaction progress; 4. Practice using liquid-liquid extraction to separate the desired product from excess reagents and unreacted starting material; 5. Practice the technique of recrystallization to purify a solid; 6. Measure the FTIR-ATR spectrum of the purified product and compare to published values to determine the product structure. Introduction According to the DrugBank website (http://www.drugbank.ca/drugs/DB01086), benzocaine (ethyl 4- aminobenzoate) is a topical anesthetic used to numb the skin or mucous membranes. Its action occurs via binding to sodium channels of nerve membranes, which prevents the initiation and conduction of nerve impulses. It is the active ingredient in many “over -the- counter” pain relief products, such as Anbesol ® , an ointment that is used rubbed on a b aby’s gums to relieve the pain of teething and Cepacol ® Sore Throat Lozenges. Starting with the readily available 4-nitrobenzoic acid, there are two approaches to the synthesis of benzocaine. In the sequence shown below, the order of functional group interconversion is reduction followed by esterification. The advantages of this approach are 1) the reagents are inexpensive and 2) the reactions are simple to set up. The challenge of the above sequence lies in the difficulty of isolation of 4-aminobenzoic acid (also called para - aminobenzoic acid or PABA, which is an ingredient in some sunscreens). With both an acidic and a basic functional group in the same molecule, extremely careful control of the pH is necessary to avoid the formation of a water-soluble salt.

© copyright C3XX Instructional Staff. Not to be used, copied or revised or shared without explicit written permission. The key to avoid handling this unpleasant intermediate is using careful synthetic planning. Ethyl 4- aminobenzoate can also be prepared from 4-nitrobenzoic acid by reversing the order of the functional group conversions. The carboxylic acid can be converted into the ethyl ester under Fischer esterification conditions (excess ethanol using a catalytic quantity of mineral acid), and this is the topic of the present experiment. Conversion of the nitro group into an amine can be accomplished by catalytic hydrogenation (hydrogen gas in the presence of palladium on carbon), a reaction performed in experiment O-0007D. Such a strategy avoids altogether the zwitterionic 4-aminobenzoic acid encountered in the first route presented. Pre-lab Preparation 1) Read the experimental procedures for the lab. 2) Prepare your lab notebook according to the outlines presented in the Organic Laboratory Guidelines (available on Canvas). Chapter 4 of the lab text “Introductory Organic Laboratory Techniques, 2014 edition” also contains valuable information for the pre-lab preparation. Procedure To a sT 14 round bottom flask (RBF) containing a solution of 4-nitrobenzoic acid (3.0 mmol) in anhydrous ethanol (10 mL) at 0 ˚C and equipped with a condenser, is slowly added concentrated sulfuric acid ( 20.0 mmol). The reaction mixture is then heated to mild reflux and for 40 min. The reaction progress is monitored using thin layer chromatography (TLC), and the reaction is stopped when the starting material is consumed (to a max. of 2 h at reflux). The reaction mixture is cooled to ~25 ˚C (cold water bath), then diluted with water (15 mL). The crude reaction mixture is extracted with diethyl ether (3 x 15 mL). The combined organics are washed successively with water (3 x 10 mL), then with a 5% sodium bicarbonate solution (1 x 10 mL), and then with brine (1 x 10 mL). The combined organics are finally dried over anhydrous sodium sulfate, filtered and concentrated through rotary evaporation. The product is recrystallized from ethanol, and submitted in a tared and labelled beaker to the TA.

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