Expt 6: Preparation of Lidocaine, Part 1 Local anesthetics are an important class of clinical drugs that provide targeted numbing and pain relief when applied to specific areas of the body. This is in contrast to general anesthetics, which affect the entire body by inducing a state of unconsciousness. n the of the most notorious anesthetics is cocaine, an alkaloid isolate from coca plats, which has been used for thousands of years by the indigenous peoples of South America for treating pain. Concerns about the addictive nature of cocaine and its cardiovascular toxicity led to the development of a large number of synthetic local anesthetics, all of which retain the -caine suffix (as they are structural analogs of cocaine). 3 C cocaine 2 benzocaine 2 procaine (novocaine) bupivacaine Lidocaine prilocaine Perhaps the most well known of these local anesthetics is procaine (sold under the trade name novocaine), which is widely used in dentistry. Structurally, all of these compounds are either amino esters (cocaine, benzocaine, and procaine) or amino amides (bupivacaine, lidocaine and prilocaine), and they can therefore be synthesized using carbonyl chemistry. In this experiment, you will carry out the first step in the two-step synthesis of the local anesthetic lidocaine, as depicted in the reaction scheme below: 2 C 2 2,6-dimethylaniline α-chloro-2,6- dimethylacetanilide ( C 2 ) 2 heat Lidocaine 1
The first step is a nucleophilic acyl substitution reaction between 2,6-dimethylaniline and a-chloroacetyl chloride to form an amide bond. The second step is an S 2 reaction between diethylamine and the a-chloroamide to form lidocaine. Experiment 6, Part 1: Preparation of a-chloro-2, 6- dimethylacetanilide from 2,6-dimethylaniline. EXPERIMETAL VERVIEW: Although there are many useful methods for synthesizing amides, one of the simplest is the reaction of an amine with an activated carboxylic acid derivative. In this experiment, you will use this method to prepare a-chloro-2, 6-dimethylacetanilide as depicted in the reaction scheme below: 2 + C 2 (2) 2,6-dimethylaniline α-chloroacetyl chloride α-chloro-2,6-dimethylacetanilide In this reaction, the activated carboxylic acid derivative is a-chloroacetyl chloride (the alpha prefix indicates that the chlorine atom is attached to the carbon adjacent to the carbonyl group). Even though acid chlorides are the most reactive of the carboxylic acid derivatives, amides can also be formed using acid anhydrides or even esters as the electrophilic component. Since acid chlorides hydrolyze in the presence of water, great care must be taken to exclude moisture from the reaction mixture. It is worthwhile to note that even though a-chloroacetyl chloride contains two electrophilic sites, substitution occurs selectively at the carbonyl group. The origin of this chemoselectivity can be attributed to both electronic effects and sterics. Electronically, the carbon atom in the carbonyl group is more electrophilic since it is bonded to more electron-withdrawing substituents. Moreover, the sp 2 -hybridization of the carbon atom in the carbonyl group enforces a planar geometry, which is more sterically accessible for nucleophilic attack. The amine component in this reaction is 2,6-dimethylaniline; note that aniline is the common name given to amines containing an aryl (aromatic ring) substituent. Due to resonance delocalization of the lone pair on nitrogen, anilines are much weaker bases and nucleophiles than amines containing only alkyl substituents. For example, the anilinium ion [(Ph 3 ) +, the conjugate acid of aniline] has a pka of 4.6 whereas the 2
triethylammonium ion [(Et 3 ) +, the conjugate acid of triethylamine] has a pka of 10.8. If you recall from Bronsted-Lowry Acid/Base theory, the stronger the conjugate acid, the weaker the base. The solvent in this reaction is glacial acetic acid ( glacial means 100%, no water, anhydrous), which may seem like an unusual choice since carboxylic acids react with amines (including anilines) to form salts. nce protonated, the amine is no longer nucleophilic and cannot participate in the desired nucleophilic substitution reaction. owever, note that the pka of acetic acid is 4.8, which is very close to the pka we would expect for the conjugate acid of 2,6-dimethylamine. Therefore, only ~50% of the 2,6- dimethylaniline will be in the protonated form at equilibrium, meaning that there will still be free 2,6-dimethylaniline available to react with the acid chloride. Based on LeChatlier s Principle, as you remove the 2,6-dimethylaniline from the solution to form the desired product, the equilibrium shown below must shift backwards to form more 2,6-dimethylaniline. 2 + C 3 acetate salt C This acetate salt by-product is water-soluble so should any remain at the end of the reaction, it will dissolve and be washed away from the product. As the reaction proceeds, the strong acid (pka = -8) is formed as a by-product, and this will quantitatively protonate any unreacted 2,6-dimethylaniline to form the hydrochloride salt, as shown below: 2 + - 3 hydrochloride salt As in the other side reaction with acid, LeChatlier s Principle will allow this reaction equilibrium to shift backwards to provide more 2,6-dimethylaniline. Unlike the previous acid-base reaction, if this hydrochloride salt by-product remains at the end of the reaction, it would contaminate the desired a-chloro-2, 6-dimethylacetanilide, as both are insoluble in cold acetic acid. This co-precipitation is avoided by adding an aqueous 3
solution of sodium acetate to the warm reaction mixture. Since sodium acetate is a weak base, it will help neutralize any residual, forming acetic acid and a. C a + - C + a sodium acetate acetic acid Water also changes the polarity of the solvent mixture, causing the desired a-chloro-2, 6-dimethylacetanilide to precipitate from solution while the conjugate acid of 2,6- dimethylaniline remains in solution. The product is then collected by vacuum filtration, washed with water, and allowed to dry until the next lab period. This material can be used in the second step of the procedure to prepare lidocaine. REAGET/PRDUCT TABLE: Reagents MW (g/mol) MP (ºC) BP (ºC) Density a-chloroacetyl chloride 112.94-22 105-106 1.418 2,6-dimethylaniline 121.18 10-12 214 (739mm g) 0.984 glacial acetic acid 60.05 16.2 117-118 1.049 Products MW (g/mol) MP (ºC) BP (ºC) Density a-chloro-2,6-dimethylacetanilide 197.66 145-146 EXPERIMETAL PRCEDURE FR YUR SAFETY 1. a-chloroacetyl chloride is a noxious, toxic and highly corrosive chemical and must be kept in the hood. When it is used, transfer it to the conical vial in the hood (Step 3). 2. Wear gloves at all times when handling a-chloroacetyl chloride. If any should come into contact with your skin, immediately rinse the area with cold running water. 3. Acetic acid is corrosive and a lachrymator; wear gloves when measuring out this compound. 1. eat a 50-mL beaker containing about 40 ml of water and a couple of boiling stones on the hot plate set to about 3 until the water is gently boiling. This beaker will be used as a hot water bath. 2. Take a clean, dry, pre-weighed 5 ml conical vial with spin vane with cap to the hood and add 0.50 ml of 2, 6-dimethylaniline to the vial. Reweigh this capped vial to determine the mass of 2, 6-dimethylaniline you added to it. Add approximately 1 ml 4
of glacial acetic acid to the same vial. Stir this mixture gently with the tip of a clean microspatula, to ensure the contents in the vial are thoroughly mixed. 3. Take a clean dry pre-weighed small sample vial with cap to the hood and add 0.50 ml of a-chloroacetyl chloride. Cap the vial and reweigh this capped sample vial to determine the mass of a-chloroacetyl chloride that was added. Add approximately 1 ml of glacial acetic acid to this vial and gently stir the mixture with the tip of a clean microspatula, to ensure that the contents of the vial are thoroughly mixed. 4. Take the 5 ml conical vial containing 2,6-dimethylaniline in glacial acetic acid mixture to the hood, and transfer the a-chloroacetyl chloride/glacial acetic acid mixture to the 5 ml conical vial. Attach an air condenser to the conical vial, clamp the apparatus on the air condenser and lower the conical vial so it is about halfway immersed in the hot water bath. (See Section A.3 and Figure A.3) Begin magnetic stirring, and after the water starts to boil, continue heating for about 30 minutes. Place the small sample vial that had contained the a-chloroacetyl chloride/glacial acetic acid in the dirty vial beaker in the hood. 5. Cool the reaction mixture to room temperature by placing the conical vial (with the air condenser still attached) in a beaker of cold tap water. In the hood, remove the air condenser and pour the contents of the reaction vial into a clean, dry 30-mL beaker. Add approximately 6.5 ml of 0.4 M aqueous sodium acetate solution (measured with a graduated cylinder) all at once to the beaker. At this point, the a-chloro-2, 6-dimethylacetanilide should precipitate from solution. Stir the mixture with a glass-stirring rod, and cool the beaker in an ice water bath for about 5 minutes. 6. Collect the solid by vacuum filtration using a irsch funnel (see Section A.2, Figure A.2). Add approximately 1 ml of ice-cold water to the beaker that contained the reaction mixture, swirl it gently, and pour it over the solid in the irsch funnel. Wash the product with an addition 1 ml portion of ice-cold water, and continue to pull vacuum for ten minutes to remove as much of the water as possible. Break up the solid with a clean microspatula and leave the funnel containing the product in a small beaker in your locker to dry until the next laboratory period, when you will record the mass. Recrystallization of the product (if instructed to do so) 7. Transfer your product into a small clean, dry beaker. Add 20 ml diethyl ether. Carefully warm this mixture on your hot plate (start with a heat setting of 2-3). Swirl it and use a glass stirring-rod to break up the solid, allowing the ether to boil 5
gently for a minute or two. It may not all dissolve, but it is important that the solid particles all mix well with the hot ether. 8. Cool your beaker on an ice bath for several minutes. Prepare a irsch funnel for vacuum filtration (make sure the irsch funnel is clean and dry and that the filtrate from the previous steps has been discarded properly). Vacuum-filter the cooled mixture to collect the product (use an additional 1 ml of cold ethyl ether to help transfer all the material from the beaker and rinse the product) 9. Keep the vacuum applied to the filter flask and filter containing the solid for about 10 minutes to remove as much solvent as possible. Break up any large chunks periodically to allow the product to dry well. 10. Allow the product to dry until the next lab period by placing your irsch funnel in a beaker in your personal locker. In the next lab period, record the mass of product. You will also measure the melting point and take an IR spectrum. WASTE DISPSAL Place the filtrate contained in the filter flask in the aqueous acid waste bottle. Carefully wash all the equipment used in this experiment and return it to your locker. CALCULATIS 1. Calculate the mmoles (millimoles) of 2,6-dimethylaniline used. 2. Calculate the mmoles of a-chloroacetyl chloride used. 3. Determine which compound is the limiting reagent. 4. Calculate the theoretical yield of a-chloro-2, 6-dimethylacetanilide. 5. Calculate the percent yield of a-chloro-2, 6-dimethylacetanilide. 6
85 80 75 70 65 60 55 %Transmittance 50 45 40 35 30 25 20 15 10 5 4000 3500 3000 2500 2000 1500 1000 Wavenumbers (cm-1) Date: Wed Dec 16 10:44:59 2009 (GMT-05:00) 2,6-dimethylaniline Scans: 4 Resolution: 4.000
90 85 80 75 70 65 60 55 %Transmittance 50 45 40 35 30 25 20 15 10 5 0 4000 3500 3000 2500 2000 1500 1000 Wavenumbers (cm-1) Date: Wed Dec 16 10:49:17 2009 (GMT-05:00) alpha-chloroacetyl chloride Scans: 4 Resolution: 4.000
85 80 75 70 65 60 %Transmittance 55 50 45 40 35 30 25 20 15 4000 3500 3000 2500 2000 1500 1000 Wavenumbers (cm-1) Date: Wed Dec 16 10:57:23 2009 (GMT-05:00) alpha-chloro-2,6-dimethylacetanilide Scans: 4 Resolution: 4.000