Lidocaine Synthesis Lab report PDF

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Lidocaine Synthesis Introduction: The purpose of this experiment was to synthesis the local anesthetic, lidocaine. The experiment consisted of a two-step process occurring over three weeks. The first step of the process was to produce the amide N-(2,6-dimethylpentyl) chloroacetamide by acylation substitution reaction (SNAc) of an amine. This reaction consisted of 2,6-dimethylaniline and the acid chloride, chloroacetyl chloride mixed with acetic acid to get the end product. The product from this first step is isolated using vacuum filtration. The second step of this experiment synthesizes lidocaine by a SN2 reaction. This step takes N-(2,6-dimethylpentyl) chloroacetamide with dimethylamine. This reaction produces a lidocaine hydrochloride. Since it produces a hydrochloride and not lidocaine freebase, a workup acid- base reaction is needed. Then liquidliquid extraction and vacuum filtration is used to isolate the product. The last week of the experiment took the lidocaine free base and purified it using re-crystallization. Recrystallization takes a compound and dissolves it in a solvent which is then slowly cooled to produced crystals in a pure form. The first week’s product was a white paste and the weight of the product (N-(2,6dimethylpentyl) chloroacetamide obtained was 160 mg (0.16 g) with a 40% yield. Part two produced 5 mg of lidocaine freebase and 40% yield again, and part three produced 16 mg of the purified product. Reaction:

Procedures: The procedures followed for all three steps can be found in Poulos, Z. J. “Organic Chemistry II: Synthetic Organic Experiments for the Health Science Major,” Spring 2022: Hayden-McNeil: Plymouth, MI, 2019, pp 66-67, 70-74 and 74-76. Some changes that were made to the experiment were in part one the amounts of products were not doubled and part three no vacuum filtration was used. Data and Calculations: Part 1 synthesis: To find the limiting reagents calculating the number of moles of dimethylaniline and chloroacetyl chloride is needed. Moles of dimethylaniline: 0.243 g / 121.18 g/mol = 0.00200 moles (2.00 = limiting reagent) Moles of chloroacetyl chloride: 0.249 g / 112.949 g/mol = 0.002205 moles (2.20) Tared Tin dish Tin dish with product (chloroacetamide) Actual weight of dry product

0.413 g 0.573 g 0.573 – 0.413 = 0.16 g or 16 mg

(chloroacetamide) Moles of dimethylaniline 0.002 (2.00) Moles of chloroacetyl chloride 0.0022 (2.20) Theoretical Yield Part 1: 0.002 moles dimethylaniline x 197.66 g/mol N(2,6-dimethylphenyl) chloroacetamide = 0.395 g or 395 mg Percent yield: 160 mg / 395 mg x 100 = 40%

Part 2 synthesis: To find limiting reagents calculating the number of moles of chloroacetamide and diethylamine is needed. Moles of chloroacetamide: 160 mg x mmol/ 197.66 g/mol = 0.809 Moles of diethylamine: 418.4669 mg x mmol/ 73.14 g/mol = 5.71 moles Tin Dish Tared Tin Dish with Product Actual Weight of Product mL of diethylamine

0.408 g 0.413 g 0.413 g – 0.408 g = 0.005 g or 5 mg 0.8095 x 5.00 equiv. = 4.0474 x 73.14 = 296.0235 / 0.7074

= 418.4669 mg or 0.418 mL Theoretical Yield Part 2: 0.809 moles chloroacetamide x 234.34 g/mol lidocaine freebase = 189 mg Percent yield: (189 mg/468 mg) x 100 = 40%

Chemistry Discussion: Mechanism: Nucleophilic Acyl Substitution: SNAc – Acid Chloride to Amide

Mechanism: Backside (180) Nucleophilic Substitution (Sn2) to Lidocaine freebase/lidocaine hydrochloride

In the first mechanism (SNAc), the steps consist of the aniline nitrogen lone pair act as the nucleophile and add into the carbonyl carbon of the acid chloride. The electronegative oxygen and chlorine carbon atoms will pull electron density toward then. The second step is when an

intermolecular proton transfer occurs and the third step with the tetrahedral intermediate collapses. The last step consists deprotonation of the protonated amide which gives the 2 amide product. The second mechanism (Sn2) consists of the bond breaking of the nucleophilic 2 amine attacks the 1 alkyl chloride from the backside at 180 degrees to the leaving group, the chloride ion. As the bond forms, the C-Cl bond breaks. Since Et2NH is not a strong nucleophile and toluene if not polar aprotic, the reaction will need sufficient heating to proceed and produce dimethylammonium chloride as the by product. Using an excess of diethylamine, will allow for one molecule of Et2NH to act as the nucleophile, with the second molecule acting as the base. A fast acid-base reaction will occur between lidocaine hydrochloride and diethylamine which will produce lidocaine freebase and dimethylammonium chloride. Since lidocaine freebase is the desired product of this reaction, liquid-liquid extraction will then be needed to remove the dimethylammonium chloride. Discussion and Conclusion: This lab consisted of three different parts over the span of three weeks. The purpose of the first week’s lab was to produce the product N-(2,6-dimethylphenyl) chloroacetamide. This was done by weighing about 246 mg of 2,6-dimethylaniline and mixing it with 2 mL of glacial acetic acid, HOAc, and 175 uL of chloroacetyl chloride. This was then swirled and heated for about four minutes. Next, the solution of 600 mg sodium acetate in 8 mL of water was made and mixed in with previous mixture prepared in the flask. This was cooled in an ice bath for about five minutes and then vacuum filtrated in order to collect and weigh the product. This product was a white paste. The second week’s lab consisted of taking the melting point of the previous week’s lab. After this the next step was to calculate the 5.00 molar equivalents of diethylamine (0.418 mL).

The dry product from part one was placed into a 10.0 mL flask and 5.0 mL of toluene and 0.418 mL of diethylamine was added to the flask. This was then reflux condensed for 90 minutes. Once this was complete, the reaction was transferred, and 0.5 mL of n-hexane was added. Liquidliquid extraction was then performed to get the lidocaine freebase layer. 2 mL of 3 M HCl was and to the tube and the aqueous layer with the lidocaine and HCl was extracted, this step was repeated again. The final tube with the lidocaine and HCl was then cooled in an ice-water bath and 30 wt.% KOH was added to freebase the lidocaine and HCl. After ten minutes, vacuum filtration was skipped, and the crystals were extracted by hand. The final product set to dry and it was crystals. In this part, the diethylamine was the product and the proton scavenger which helps moved the reaction forward. The last part of the lab was to purify the lidocaine. The product from the last lab was weighed, then the process of recrystallization was performed. The crystals were transferred into a flask and 1 mL of n-pentane for every 100 mg of crude product was added (5 mL). The flask was then heated until the crystals dissolved and was then cooled in an ice-water bath for about 15 minutes. After this, it was then vacuum filtrated for two minutes and the product was scraped and weighed. The melting point for step one was between 149C- 151C and for step two it was between 68C- 71C, but was melted at around 68C. This shows that the product obtained was pure. Both of the yields calculated were 40%. This is relatively low and can be due to human error while the experiment was being done. One source of error could have come from the liquid-liquid extraction and some of the organic layer could have been picked up which could cause products to not be correct. IR and NMR of lidocaine IR spectrum for lidocaine recrystallized produced a N-H amine stretch at 3224 cm -1, C-H sp2 aromatic stretch at 2968 cm -1, C-H sp3 at 2799 cm -1, aromatic C=C at 1661 cm-1 and C=O at

1491 cm -1. HNMR showed carbon at 8.8 ppm was a singlet, carbon at 7.2 ppm was a singlet, carbon at 3.2 ppm was a singlet, carbons at 2.8, 2.7, 2.6, 25.5 ppm was a quartet, carbon at 2.2 ppm was a singlet, and carbon at 1.2, 1.1, 1.0 was a triplet. CNMR shows nine peaks occurring at 170.2 ppm (singlet), 134-135 ppm (doublet), 128.2-127 ppm (doublet), a triplet at 77.1 ppm, a singlet at 57.5 ppm, a singlet at 48.9 ppm, a singlet at 18.5 ppm, and another singlet at 12.659 ppm....