Expt 8: Preparation of Lidocaine, Part 2, from α- Chloro-2,6-dimethylacetanilide and Diethylamine

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1 Expt 8: Preparation of Lidocaine, Part 2, from α- Chloro-2,6-dimethylacetanilide and Diethylamine ITRDUCTI This step of the synthesis involves the reaction of α-chloro-2, 6-dimethylacetanilide, prepared in the previous part (Experiment 6) and used without further purification, with excess diethylamine, ( C 2 ) 2. α-chloro-2,6-dimethylacetanilide 2 ( C 2 ) 2 diethylamine Lidocaine + ( C 2 ) 2 2 diethylammonium chloride verall, this transformation is an -alkylation reaction in which the diethylamine (a secondary amine) reacts with the α-chloroamide, formed in Part 1, to form a tertiary amine (Lidocaine). Mechanistically, this is an example of an S 2 reaction, with diethylamine serving as the nucleophile and α-chloro-2, 6-dimethylacetanilide serving as the electrophile. α-chloro carbonyl compounds are especially reactive electrophiles for the S 2 reaction due to electron delocalization in the planar transition state. The nitrogen lone pair of the aniline is donating electron density to the carbonyl group. If substitution were to occur at the carbonyl carbon, it would disrupt this resonance stabilization associated with the amide linkage. In addition to serving as the nucleophile, diethylamine serves as a base to scavenge as it forms during the reaction. Therefore at a minimum, two equivalents of diethylamine are required per mole of acetanilide used. The initial product of the S 2 reaction is actually an ammonium salt, namely the hydrochloride salt of lidocaine. By using diethylamine as the reaction solvent, it is used in excess (more than 2 equivalents) and an acid-base equilibrium is established to form the free base of lidocaine along with diethylammonium chloride. After the reaction is complete, the diethylammonium chloride can be removed by simple filtration, and the excess diethylamine will be removed easily by evaporation since it has a low boiling point (55ºC). 1

2 At this point, the compounds remaining in the reaction mixture are (1) traces of diethylamine, (2) any unreacted α-chloro-2, 6-dimethylacetanilide and (3) Lidocaine, the desired product. In order to isolate Lidocaine, you will perform a series of liquid-liquid extractions. First the mixture is treated with aqueous hydrochloric acid solution, which converts lidocaine to its water-soluble hydrochloride salt; any residual diethylamine is similarly converted to diethylammonium chloride. Both of these compounds are watersoluble, but the unreacted α-chloro-2,6-dimethylacetanilide is not, and it can be removed by filtration. Soluble in solution Reaction Mixture 2 ( C 2 ) 2 2 Insoluble in solution The acidic filtrate is then neutralized and made basic (p ~14) with aqueous potassium hydroxide, liberating lidocaine from its water-soluble hydrochloride salt and reconverting diethylammonium chloride to diethylamine. Lidocaine can then be extracted from the basic aqueous layer with several portions of petroleum ether, which is a mixture of low-boiling hydrocarbons. The diethylamine, which is slightly soluble in water, will be left behind in the aqueous layer. K 2 insoluble in basic aqueous solution, but soluble in pet ether ( C 2 ) 2 2 ( C 2 ) 2 slightly soluble in basid aqueous solution The petroleum ether organic extracts containing Lidocaine are then combined and washed with several portions of cold water to remove any inorganic salts or traces of diethylamine. The petroleum ether organic layer is dried with anhydrous potassium 2

3 carbonate (K 2 C 3 ), to remove any residual water and treated with decolorizing charcoal to remove colored impurities. These solids are removed by filtration and the filtrate is left to evaporate in the hood until the next lab period to give solid Lidocaine. The separation scheme depicts all of the filtration steps and those in the series of liquid/liquid extractions: crude reaction mixture vacuum filtration solid residue upon evaporation 3M aqueous solid acidic solution 8M aqueous K basic solution Extraction with petroleum ether aqueous layer petroleum ether organic layer 3

4 REAGET/PRDUCT TABLE: Reagents MW (g/mol) MP (ºC) BP (ºC) Density diethylamine a-chloro-2,6-dimethylacetanilide petroleum ether Products MW (g/mol) MP (ºC) BP (ºC) Density lidocaine EXPERIMETAL PRCEDURE: FR YUR SAFETY 1.Since diethylamine is volatile, you must transfer it to the conical vial in the hood in order to avoid inhaling this compound. 2. Lidocaine is a local anesthetic that can be absorbed through the skin. Wear gloves at all times when handling this compound. WEEK E: 1. btain a clean, dry large sample vial from your locker. Check that the cap you selected for the vial has a lid liner in place to seal the vial shut. Preweigh the cap and empty sample vial. Transfer all of the remaining α-chloro-2, 6-dimethylacetanilide (after taking IR for Expt 6A) from the previous step (Expt 6A) to the vial. Reweigh the vial to determine the mass of α-chloro-2, 6-dimethylacetanilide added to the vial. 2. Add 5 ml of diethylamine to the large sample vial containing the α-chloro-2, 6- dimethylacetanilide. Using a spatula, stir to mix thoroughly, then cap the vial tightly and place in locker until the next lab period. (ED DAY 1) WEEK TW: 3. Set up a vacuum filtration apparatus using a 50 ml filter flask, the porcelain irsch funnel hat has been provided for you, and a micro filter paper. The filter flask should be clamped so that it is inside an empty 250 ml beaker, which will be used to hold a water bath. This apparatus will be used to vacuum filter your reaction mixture in the large sample vial from Step Use a 5 ml syringe to obtain 5 ml of petroleum ether from the hood. Make sure the shield is on the needle and take it back to your bench. 5. Turn the vacuum to your filtration apparatus on to about half strength (T full strength) and wet the micro filter paper with a few drops of petroleum ether to seat the paper. Check to make sure that the vacuum is actually pulling through the funnel (gently place your hand on top of the funnel to see if the vacuum is on). 4

5 6. CAUTI: You must do this next step VERY SLWLY due to the low boiling point of diethylamine and the reduced pressure in the filter flask. Pour the reaction mixture SLWLY into the irsh funnel. As the solution starts to filter through the irsh funnel, it will flash up in the filter flask. If you pour too quickly, the liquid containing your product will be sucked through the side arm of the filter flask in the vacuum line! The filtrate/filter flask will become cold (due to the evaporation of the diethylamine) and it may even form some ice on the outside of the flask. 7. After all of the liquid from the reaction mixture has been filtered, rinse the reaction sample vial up to five times with ~1 ml portions of diethylamine using the 5 ml syringe (obtained in Step 4). With each portion, try to rinse the reaction vial well each time so all solid material will be transferred to the irsh funnel. 8. nce filtration is complete and the filter flask is cold, turn on the vacuum full strength and fill the 250 ml beaker with room temperature (not hot!) water up to the level of the side arm of the filter flask. Allow the vacuum to remain on for at least 30 minutes, to evaporate off the diethylamine from your filtrate. 9. While waiting, obtain 3-4 ml of 3M and 3 ml of 8M K, in separate large labeled sample vials, and place them in an ice bath to cool. 10. After the diethylamine has evaporated, the inside of the filter flask should contain a solid, which is a mixture of Lidocaine and any unreacted α-chloro-2,6- dimethylacetanilide. The irsch funnel also has a solid in it, which is the diethylammonium chloride that formed over the course of the reaction. Turn off the vacuum, remove the irsch funnel and obtain a crude weight on the diethylammonium salts. The crude weight of the by-product salt may be used to calculate an approximate yield of your Lidocaine. Rinse the irsh funnel several times with water to clean it. It does not have to be completely dry before you use it again. 11. Turn on your hot plate to a heat setting of for use later in Step Add the 3-4 ml of the cold 3M to the contents of the filter flask. ALL of the solids inside the flask should dissolve in the acidic solution so try to add the aqueous down the sides of the filter flask, and gently swirl the mixture. Any solid that does not dissolve is unreacted α-chloro-2, 6-dimethylacetanilide. If the reaction was nearly complete, very little (if any) solid should be observed. If solid is observed, see your instructor. 13. Transfer the contents of the filter flask to a large sample vial and rinse the filter flask with 2 ml of water, which should also be added to the large sample vial also. ean the filter flask prior to the next step. 14. Re-set up the vacuum filtration apparatus again with the porcelain irsch funnel (do not forget the microfilter paper). Vacuum filter the acidified reaction mixture through the irsch funnel into the clean filter flask. Wash the large sample vial with 3 ml of 3 M and pour it through the funnel as well. 5

6 15. Discard any filtered solid in the solid organic waste and transfer the contents of the filter flask to a clean, large sample vial (labeled Vial #1). Place Vial #1 in a small beaker containing an ice-water bath, and keep it in the ice-water bath, while you add about 3 ml of 8M aqueous potassium hydroxide solution to the vial, and stir with a microspatula or a glass stirring rod to ensure thorough mixing. Test the basicity of the solution with p paper (remember T to dip the p paper directly into the solution but instead transfer a drop of the solution to the p paper using a glass stirring rod). If the p is less than 14, add additional K solution drop-wise (with stirring) until the p is 14. The contents of the vial will appear milky and if any crystals form, they will be removed in the next step. Remove the vial from the ice bath and allow it to warm to room temperature. 16. TE: In this step, you may find it convenient to label and/or number the vials in order to keep track of them. Fill a clean, dry large sample vial about 2/3 full with petroleum ether for use in the following extractions and label the vial petroleum ether. Add about 4 ml of petroleum ether to the original cold Vial #1, cap it tightly (make sure the cap has an insert in it to ensure a tight seal), and shake it gently (wear gloves!) with frequent venting. All of the solids that formed in the previous step MUST be dissolved before performing the next separation. Do not attempt to separate until everything is dissolved. Using a Pasteur pipette, remove the lower aqueous layer and transfer it to a second large, clean vial (Vial #2). Keep the upper layer in Vial #1 (it contains most of your product, Lidocaine). Repeat this procedure (the removal of Lidocaine) one more time by extracting the basic aqueous layer in Vial #2 with another 4 ml portion of petroleum ether (cap it, shake it, vent it, let the layers separate again). Remove the lower, basic aqueous layer and place it in a large sample vial (Vial #3, an aqueous basic waste vial). Vial #2 now contains the upper layer, with more of your product. At the completion of these extractions, you will have two large sample vials (Vial #1 and Vial #2), each of which contains petroleum ether extracts with Lidocaine. Combine the two petroleum ether extracts (total volume ~ 8 ml) together into the same sample vial by transferring the contents of Vial #2 into Vial #1). The third large vial (Vial #3) will contain aqueous basic waste and it should be saved and used for further waste collection until product is obtained. 17. Add about 3 ml of ice water to the combined petroleum ether extracts in Vial #1. Cap the vial and shake it vigorously. Allow the layers to separate and carefully remove the bottom waste layer with a Pasteur pipette, and place the lower aqueous layer in the waste beaker (Vial #3). Repeat this washing process of Vial #1 with an additional 3 ml portion of ice water, again placing the aqueous layer in Vial #3. 6

7 18. Add enough anhydrous K 2 C 3 to just cover the bottom of Vial #1 containing the petroleum ether and Lidocaine. Cap the vial, and gently swirl the mixture. If some of the drying agent does not move freely when swirled, add a little more of drying agent. The petroleum ether layer should appear clear, not cloudy. Then add a couple of microspatulas of decolorizing carbon to the vial, cap it, and swirl it gently. Remove the cap and warm the vial on the hot plate until the petroleum ether is slightly warmed. ote that this only takes a minute or so - do not over-heat the vial or walk away, as the petroleum ether can boil over, and you will lose your product in a violent eruption on the hot plate! Remove the vial from the hot plate and allow it to cool briefly to room temperature. 19. Pre-weigh a clean, dry large sample vial WITUT A CAP (Vial #4). Perform a gravity filtration (short stem funnel and fluted filter paper) to remove the drying agent and the decolorizing carbon, collecting the filtrate in the pre-weighed Vial #4. Wash Vial #1 with an additional 4 ml portion of petroleum ether and pour this also through the funnel, collecting it in Vial #4. Rinse the fluted filter paper well and also the inside of the glass funnel so all rinses are collected in Vial 4. Any white, cloudy crystal formations on the glass are Lidocaine (your product!!) and should be rinsed into Vial #4. Vial #4 now contains all of your Lidocaine, along with petroleum ether. 20. Label a 30 ml beaker with your name and carefully place Vial #4 in a 30 ml beaker (to prevent Vial #4 from spilling). Vial #4 should remain uncapped. See your instructor regarding which designated hood you must leave the beaker/vial #4 in until the next laboratory period. The ether will evaporate during this time. 21. ean and return to the bench top all equipment provided for you: porcelain irsch funnel with black adapter cone, 50 ml filter flask, 250 ml beaker and 5 ml syringe. 22. In the next lab period, reweigh the large sample vial to determine the mass of the Lidocaine and then scrape down the sides of the vial to loosen the crystals and get a melting point and IR (if desired) on your crystals. and in product, properly labeled. WASTE DISPSAL Place the aqueous basic extracts and the water extracts in the aqueous basic waste container. Carefully clean all of the equipment used in this experiment and return to its appropriate place (instructor or lab locker/station). CALCULATIS 1. Calculate the moles of α-chloro-2, 6-dimethylacetanilide that was used. 2. Calculate the theoretical yield of lidocaine. 3. Calculate the percent yield of lidocaine for this second step (Part B). 4. Calculate the overall percent yield (Parts A and B) by multiplying the percent yields together as in this example: If the yield from Part A was 80% (0.80) and the yield from Part B was 20% (0.20), then the overall yield is [0.80 x 0.20] x 100 or 16%. 7

8 %Transmittance Wavenumbers (cm-1) Date: Wed Dec 16 10:51: (GMT-05:00) diethylamine Scans: 4 Resolution: 4.000

2 (CH 3 CH 2 ) 2 NH diethylamine

2 (CH 3 CH 2 ) 2 NH diethylamine Experiment: (Part B) Preparation of Lidocaine from α-chloro-2,6-dimethylacetanilide and Diethylamine ITRDUCTI This step of the synthesis involves the reaction of α-chloro-2, 6- dimethylacetanilide, prepared