Lidocaine Synthesis

Introduction
The purpose of this lab is to synthesize Lidocaine from 2,6-dimethylaniline, using diethyl amine, 2-chloroacetyl chloride, acetic acid, and toluene. The Lidocaine was made by adding 2,6-dimethylaniline to 2-chloroacetyl chloride in acetic acid. Sodium acetate is added in order to make the compound soluble. The product is dried, then treated with diethyl amine and toluene. This is refluxed using a water-cooled reflux condenser. The vapor is condensed by the cold water as the compound is being heated. A separatory funnel is used to separate the organic layer, and the product is recrystallized for TLC, GC/MS, and melting point analysis.
Pre-Lab
1. What is the limiting reagent in step 1? What is the theoretical yield of amide 1 in figure 3?
The amine is the limiting reagent. The theoretical yield is 4.81 grams of amide 1.
2. What is the theoretical yield of Lidocaine? Base calculations on 2,6-dimethylaniline.
The theoretical yield of lidocaine is 5.71 grams.
3. How many molar equivalents of diethyl amine are used in step 2
Roughly 3 molar equivalents of diethyl amine are used in step 2.
Procedure
An ice water bath for 100 mL of water was prepared. It was noted that gloves had to be put on at this time. 3.0 mL of 2,6-dimethylaniline in a 10 mL graduated cylinder. Then, a larger cylinder was used to measure out 15 mL of glacial (concentrated) acetic acid. This was poured into a 125 mL Erlenmeyer flask. Both graduated cylinders were rinsed thoroughly with acetone several times. The 2,6-dimethylaniline was added via a Pasteur pipet to the acetic acid. The graduated cylinder was rinsed with acetone and left to air dry. 2 mL of 2-chloroacetyl chloride was measured and poured into the Erlenmeyer flask. A thermometer was placed to record any temperature change during this process. A large graduated cylinder was used to measure out 25 mL of .333 M Sodium Acetate directly to the Erlenmeyer flask. The temperature increased from 30 to 32 degrees Celsius. 60 mL of cold water was added directly into the flask. Using a glass stir rod, the mixture was stirred for roughly 10 minutes. The product was isolated using vacuum filtration via a Buchner funnel. A few small portions of cold water was rinsed and pressed dry with another sheet of filter paper. The 50 mL RB flask was then weighed (35.252g). The pressed dry amide was added to the flask and reweighed toe be 38.388 grams. 2.5 mL of diethylamine, 25 mL of toluene, and boiling chips were added to the flask. The diethylamine reacted in the graduated cylinder, meaning that it was not properly rinsed. Smoke and a white precipitate formed. Another, clean graduated cylinder was used to measure and pout the diethylamine. A water-cooled reflux condenser was attached to the round bottomed flask. The water was turned on slowly, and the assembly was lowered into the sand bath. This was refluxed for 60 minutes, then cooled to room temperature slowly. The mixture was transferred into a separatory funnel and washed with 150 mL of water in 3 portions. Then, the organic layer extraction took place with 40 mL of 3 M HCl in 2 portions. The aqueous layer was placed into an Erlenmeyer flask. The organic layer was washed with 20 mL of water. This aqueous layer was placed into an Erlenmeyer flask yet again. A thermometer was added and the flask was cooled in an ice bath till the solution reached 10 degrees Celsius. In small portions, 3 M Sodium Hydroxide was added in portions and in excess of 50 mL. During this process, the temperature was supposed to be kept below 20 degrees Celsius. Sodium Hydroxide was added until the pH strip turned dark green. The actual test strip turned lime green, then dark blue with a minimal addition of sodium hydroxide. The compound was later taken for GC and MS analysis. The melting point of the final product was also measured.
Data/Calculations
TLC of Lidocaine Sample

Rf Value
Rf Value
2,6-dimethylaniline
0.51
-
Co-spot recrystallized
0.35
0.5
Authentic Lidocaine
0.28
-

Melting Point of Sample

Melting Point (Celsius)
Lidocaine (actual)
68
Lidocaine (sample)
62-64

3.136 g of amide 1
3.136/4.81 * 100 = 65.2 % yield of amide 1
The yield of lidocaine was inconclusive, as most of product was lost due to spill. The product was recrystallized, but a significant loss from this spill resulted in an inaccurate percent yield.
Conclusion
The sample of lidocaine before recrystallization was spilled. Because of this error, a majority of the product was lost, and very little was left for recrystallization. The spill occurred before the recrystallization, but after the GC/MS sampling. However, the amide lost significantly more than what was expected in terms of percent yield. The percent yield of the lidocaine cannot be salvaged, but the purity of the product can be determined by the GC/MS sampling.
The GC/MS sampling determined a high purity. The Gas Chromatography showed a purity of 97.89% of Lidocaine. There was a small amount of impurity that was determined to be pentanone. The mass spectrometry confirmed the two compounds by running the sample peak against other known results, and a 97% match was found for lidocaine std. The impurity peak had a 94% similarity to 2-pentanone. It is not entirely known why 2-pentanone was found in the sample, but could be due to some rare decomposition of lidocaine.
The melting point was found to be in a range roughly 6 degrees below the expected resulted. This demonstrates a lack of purity of the compound, but could have also been due to the spill. Whatever product remained still had a small portion of what remained on the ground at the lab station. The purity of the lidocaine was, however, backed up by the GC (as previously explained). The TLC component of the lab further supported the presence of lidocaine. The Rf values for the co-spot showed a distinct separation of the lidocaine sample and the 2,6-dimethylanaline. The Rf value for the sample lidocaine had a slightly higher value and was more non-polar. This could have been due to the tailing, which broadened the range of polarity for the compound. The existence of 2-pentanone in solution could have also increased the non-polarity slightly.
Post-Lab Questions
1.
2. Diethyl ether could be used as well, as its non-polarity is favored in SN2 reactions. However, a polar aprotic solvent would be ideal in order to increase the rate of the reaction. Non-polar still are unaffected by the nucleophile, so the effect is similar, yet diminished.
3. The reflux condenser cools the vapor of the solution, so the cold water must be pumped through the bottom (where the heating takes place)
4.
a.
b.
5. A molar equivalent of 2 or greater of diethylamine is required for each 2,6-dimethylaniline. At least one is used for the reaction, and the other is used by the formation of diethylammonium chloride.
6.
7. Tailing could have occurred as a result of too high a concentration. The compound could have also been decomposing. This was seen in the purity test, as pentanone was found in the sample.