2 (CH 3 CH 2 ) 2 NH diethylamine

Transcription

1 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 in the previous part (Experiment 4A) and used without further purification, with excess diethylamine, ( C 2 ) 2.!-chloro-2,6-dimethylacetanilide 2 ( C 2 ) 2 diethylamine Lidocaine (4) + ( C 2 ) 2 2 diethylammonium chloride Diethyl amine serves three roles in this reaction: (a) as a nucleophile to displace chloride anion from C 2 in the α-chloro-2, 6-dimethylacetanilide by an S 2 type reaction; (b) as a base to absorb the that is formed in the nucleophilic substitution reaction leading to Lidocaine; and (c) as a solvent for the reaction. The reaction of α- chloro-2, 6-dimethylacetanilide with diethylamine represents another example of selection reaction because nucleophilic substitution occurs exclusively at the carbon alpha to the carbonyl. ucleophilic attack by the amine on the carbonyl carbon of the amide group is not favored relative to reaction at the carbon alpha to the carbonyl, which bears the chlorine atom. If substitution were to occur at the carbonyl carbon, it would disrupt the resonance associated with the amide linkage. Examination of equation (4) shows that a minimum of two moles of diethylamine is required for each mole of α-chloro-2, 6-dimethylacetanilide used. ne mole is needed for the S 2 reaction and a second mole absorbs the that is liberated in the substitution reaction; diethylammonium chloride, ( C 2 ) 2 2, is formed along with Lidocaine, and no is ever formed directly in the reaction. The mechanism for the substitution reaction between an alkyl halide and an amine may be found in lecture textbooks and/or discussed by your instructor. In this reaction, the starting chloroamide, α-chloro-2, 6-dimethylacetanilide, is placed in a vial with the diethylamine solvent/nucleophile and the solution is allowed to react in the vial. As the reaction proceeds, the formation of a salt, diethylammonium chloride, is observed. After several days, the solution is carefully vacuum filtered to 1

2 remove the salt and the excess diethylamine is removed by evaporation using the vacuum system. The compounds remaining in the filtration flask are: (a) traces of diethylamine, (b) any unreacted α-chloro-2, 6-dimethylacetanilide and (c) Lidocaine, the desired product. To isolate Lidocaine, the solids left behind by the evaporation process are dissolved by aqueous solution, which converts Lidocaine into its water-soluble hydrochloride salt. Diethylammonium chloride is formed from the reaction between aqueous and traces of unreacted diethylamine, and is soluble in aqueous solution. Any unreacted chloroamide, α-chloro-2, 6-dimethylacetanilide, is insoluble in aqueous and remains a solid that is removed from the acidic aqueous solution by a second vacuum filtration. Soluble in solution Reaction Mixture 2 ( C 2 ) 2 2 Insoluble in solution The extracts are made distinctly basic (p ~ 14) to liberate Lidocaine from its water-soluble hydrochloride salt and to reconvert diethylammonium chloride to diethylamine. Lidocaine is extracted from the basic aqueous solution with several portions of petroleum ether, which is a mixture of low-boiling hydrocarbons. 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 extracts containing the Lidocaine are combined and washed with several portions of cold water to remove traces of diethylamine and inorganic salts and bases. The petroleum ether layer is dried with anhydrous potassium carbonate (K 2 C 3 ), which is a basic drying agent that will not react with basic organic compounds 2

3 such as Lidocaine. This minimizes the loss of Lidocaine in the procedure. A little decolorizing carbon is then added to the petroleum ether solution to remove colored impurities. Gravity filtration is used to remove the drying agent and decolorizing charcoal. The ether is allowed to evaporate in the hood until the next lab period to give solid Lidocaine. REAGET/PRDUCT TABLE: Reagents MW (g/mol) MP (ºC) BP (ºC) Density diethylamine alpha-chloro-2, 6-dimethylacetanilide petroleum ether Product MW (g/mol) MP (ºC) lidocaine EXPERIMETAL PRCEDURE: FR YUR SAFETY Keep the bottle containing the diethylamine in the hood at all times. Take your reaction vial to the hood when adding diethylamine to it. 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 α-chloro-2, 6-dimethylacetanilide obtained from the previous step (Part A) to the vial. Reweigh the vial to determine the amount of α-chloro-2, 6-dimethylacetanilide added to the vial. 2. To the large sample vial containing the chloroamide, add 5 ml of diethylamine. Using a spatula, stir to mix thoroughly, cap tightly and place in locker until the next lab period. (ED DAY 1) 3. Set-up the porcelain irsh funnel and 50 ml filter flask provided for you, for a vacuum filtration. The filter flask should be clamped so it is placed down inside an empty 250 ml beaker, which will be used in Step 8 to hold a room temperature water bath. Make sure a microfilter paper is placed in the funnel. 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 dry diethyl amine from the hood. Make sure the shield is on the needle. Take it back to your bench. 5. Turn the vacuum on to about half strength (T full strength), wet the microfilter paper with a few drops of diethylamine to seat the paper and check that the vacuum is indeed pulling through the funnel (gently place your hand on top of the funnel to see if the vacuum is on). 3

4 6. Caution: You must do this next step VERY SLWLY into the filter for filtration to occur, 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 vacuum will suck up the liquid containing your product out the side arm of the filter flask and into the vacuum line! The filtrate/filter flask will quickly get cold and it may even form some ice on the outside of the flask. If/when that happens, don t worry it s expected. 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 (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 the filter flask is cold, turn on the vacuum full strength and fill the 250 ml beaker with room temperature water so the filter flask is submerged up to the filtration arm. Allow the vacuum to remain on for at least 30 minutes, to evaporate off the diethylamine from your filtrate. This will leave only crude Lidocaine and any unreacted chloroamide inside your filtration flask. 9. While waiting, obtain 3-4 ml of 3M and 3 ml of 8M K, in separate large sample vials, labeled appropriately. Place them in an ice bath to cool. 10. After the diethylamine has evaporated, the inside of the filtering flask should contain a solid, which would be your impure Lidocaine. The irsch funnel also has a solid in it, which are the by-product diethylammonium salts that formed during 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 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 into the filter flask. ALL solids inside the flask should dissolve in the acidic solution so try to wash down the sides of the filtering flask and gently swirl the flask so the acid comes in contact with all solids in order to dissolve them entirely. The possible solid that may 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 will be added to the large sample vial also. ean the filter flask prior to the next step. 14. Vacuum filter the acidified reaction mixture through the irsch funnel (do not forget the microfilter paper) into the clean filter flask. Wash the large sample vial with 3 ml of 3 M and pour it through the funnel. 4

5 15. Discard any filtered solid in the solid organic waste container and transfer the contents of the filter flask to a clean, large sample vial (Vial #1). Place the vial in a small beaker containing ice and water, and while in the ice-water bath, add about 3 ml of 8 M K solution to the vial, and stir with a spatula or a glass stirring rod to ensure thorough mixing. Test the basicity of the solution with p paper. If the p is not about 14, add K drop-wise and 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 back to room temperature. 16. TE: In this step, you may find it convenient to label and number the vials to avoid getting them mixed up. Fill a clean, dry large sample vial about two-thirds full with petroleum ether for use in the following extractions. Label the vial petroleum ether. Add about 4 ml of petroleum ether to the original cold vial (Vial 1) from Step 14, cap it tightly (make sure the cap has an insert in it so the seal will be good), 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 your product, Lidocaine. Repeat this procedure one more time by extracting the basic aqueous layer in Vial 2 with another 4 ml portion of petroleum ether. Remove the lower, basic layer and place it in a large sample vial (Vial 3, a waste container). 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 pouring Vial 2 into Vial 1). The third large vial (Vial 3) will contain aqueous basic waste and it should be saved until product is obtained. 17. Add about 3 ml of ice water to the combined petroleum ether extracts (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. Place the water in the waste beaker (Vial 3). Repeat this extraction process of vial 4 with an additional 3 ml portion of ice water, again placing the aqueous layer in Vial Add enough anhydrous K 2 C 3 to cover the bottom of Vial 1 containing the petroleum ether and Lidocaine. Cap and gently swirl the vial. If some of the drying agent does not move freely when the vial is swirled, add a little more of it. 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. This takes 5

6 just a minute or so. Don t over-heat, as the petroleum ether can boil over, sending decolorizing carbon all over your hot plate. (Don t walk away while this is heating, as the solution may erupt like a volcano.) Allow the vial to cool briefly to room temperature. 19. Pre-weigh a clean and dry large sample vial (Vial 4). Gravity filter the contents of Vial 1, using a short-stemmed glass funnel and fluted filter paper, into Vial 4. Wash the vial once with a 3-mL portion of petroleum ether (swirl around to help remove all traces of Lidocaine left behind), and pour this through the filter as well. Rinse the fluted filter paper well and also the inside of the glass funnel so all rinses are in Vial 4. Any white, cloudy crystal formations on the glass are Lidocaine and should be rinsed into Vial 4. Vial 4 now contains all of your Lidocaine, along with petroleum ether. 20. Place Vial 4 containing the petroleum ether and Lidocaine inside a 30 ml beaker labeled with your name, (to prevent Vial 4 from spilling), and leave it in the designated hood 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. Reweigh the large sample to determine the total weight of the Lidocaine and then scrape down the sides of the vial to obtain 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. 6

7 %Transmittance Wavenumbers (cm-1) Date: Wed Dec 16 10:57: (GMT-05:00) alpha-chloro-2,6-dimethylacetanilide Scans: 4 Resolution: 4.000

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

9 %Transmittance Wavenumbers (cm-1) Date: Unknown Lidocaine Scans: Resolution: Unknown

10 PPM 1 0

11 PPM