Honors Cup Synthetic ProposalExpected yield: 50% 3.50 gExpected yield: 40% 1.16 gExpected yield: 50% .6 gHonors Cup Synthetic ProposalSection: 291Group Members: Corina Mommaerts, Brittne Halford, Thomas FaiTitle: Preparation of Benzocaine (ethyl-p-aminobenzoate) from p-acetotoluidideIntroduction: Benzocaine is one of many widely used anesthetics from a family of esters. These esters are synthesized from the organic acid para-aminobenzoic acid (PABA) and ethanol, which are also present in folic acid and vitamin B10. This essential drug is found in the liquid, gel, lozenge,lotion, eardrop and aerosol spray forms. It used as a temporary topical anesthetic that numbs the nerve endings near the surface of the skin where applied. Physicians throughout the world prescribe benzocaine for people 4 months and older. Benzocaine is frequently synthesized from p-nitrotoluene. This pathway involves many reduction steps of the nitro group. However because of our small scale needs we have found a procedure that involves the synthesis from p-acetotoluidide. P-acetotoluidide is oxidized by magnesium sulfate to produce p-aminobenzoic acid, which is then heated with hydrochloric acid to create an amino acid. Ethanol is added in the subsequent step to esterify the amino acid and produce our desired product, benzocaine.Reference:"Benzocaine." Drugs.com. invisalign. 05 Feb. 2005 <http://www.drugs.com/cons/Benzocaine.html>.Overall synthetic reaction scheme: O ONH2NH2O OHNHO OHONHOKMnO4MgSO47H2O / H2OHCl, NH3(aq)CH3COOHCH3CH2OHconc. H2SO4Step 1 Synthetic transformation 1:NHO OHONHOKMnO4MgSO47H2O / H2OExperimental 1 In a 1 L beaker or flask, add 7.6 g (.052 mol) p-acetotoluidide, 20 g (.08 mol) magnesium sulfate hydrate (MgSO4 · 7H2O) and 500 mL H2O. Heat to about 85 degrees C. Prepare a solution of 20.4 g KMnO4 (.128 mol) in 80 mL of boiling water. While stirring the p-acetotoluidide solution vigorously, add the permanganate solution slowly over 30 minutes. Afterall the permanganate has been added, swirl vigorously. Filter off the manganese dioxide precipitate from the hot solution using a fluted filter, and wash with water. If the solution is still purple from the permanganate, add 1 mL ethanol, boil until color has been discharged, and filter again. Cool the solution and acidify to pH 3-4 with 20% aqueous sulfuric acid. Filter with suction and dry. *we scaled the reaction to 400%. Expected yield: 50% 3.50 gSafety, disposal and green issues 1:P-acetotoluidideEngineering Controls: Use adequate ventilation to keep airborne concentrations low. Handling: Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use with adequate ventilation. Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Keep container tightly closed. Avoid ingestion and inhalation. Storage: Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from incompatible substances. Potassium PermanganateHandling: Wash thoroughly after handling. Remove contaminated clothing and wash before reuse. Use only in a well-ventilated area. Minimize dust generation and accumulation. Do not getin eyes, on skin, or on clothing. Keep container tightly closed. Avoid contact with clothing and other combustible materials. Do not ingest or inhale. Do not store near combustible materials. Discard contaminated shoes. Storage: Keep away from sources of ignition. Do not store near combustible materials. Keepcontainer closed when not in use. Store in a tightly closed container. Store in a cool, dry, well-ventilated area away from incompatible substances. Hazardous Decomposition Products: Irritating and toxic fumes and gases, oxygen, oxides of potassium, oxides of manganese. Other: Harmful to aquatic life in very low concentrations P-acetamidobenzoic acidChemical Stability: Stable under normal temperatures and pressures. Conditions to Avoid: Incompatible materials, dust generation, excess heat. Incompatibilities with Other Materials: Oxidizing agents. Hazardous Decomposition Products: Carbon monoxide, oxides of nitrogen, irritating and toxicfumes and gases, carbon dioxide. Ecotoxicity: Bacteria: Phytobacterium phosphoreumStep 2Synthetic transformation 2: NH2O OHNHO OHOHCl, NH3(aq)CH3COOHExperimental 2 Weigh 3.0 g (.0219 mol) p-acetaminobenzoic acid and add to 15 mL 18% hydrochloric acid in a 50-mL round bottom flask. Attach a condenser and reflux for 25-30 minutes. Cool the mixture and add half its volume of cold water. Make the solution slightly basic (pH 7-8 measured with wide-range pH paper) with 10% aqueous ammonia. For each 30 mL of solution, add 1 mL glacial acetic acid. Stir vigorously and cool solution in an ice bath. Initiate crystallization with glass rod. Filter with suction and dry. Expected yield: 40% 1.16 gSafety, disposal and green issues 2:P-aminobenzoic acid Handling: Should be used in areas with adequate ventilation and away from fire. Storage: Should be stored away from oxidizing agents and containers should remain closed. Container may explode when heated and produce poisonous and corrosive gases. Disposal: Pollutes waterways. Whatever cannot be saved for recovery or recycling should be managed in an appropriate and approved waste disposal facility.Step 3 Synthetic transformation 3:O ONH2NH2O OHCH3CH2OHconc. H2SO4Experimental 3 In a 25-mL round-bottom flask, mix 1.0 g (.0075 mol) p-aminobenzoic acid, 7.5 mL of absolute ethanol, and .75 mL (.0075 mol) of concentrated sulfuric acid. Attach a condenser and heat under reflux for 1 hr. Cool to room temperature and neutralize with foaming sodium carbonate (can check with litmus paper). Next, extract with dichloromethane (2 x 5-mL). Extract the combined organic layers with two 15-mL portions of water and dry over anhydrous magnesium sulfate. Remove the organic solvent and recrystallize from methanol-water. *We scaled the reaction to 150%.*Also, we figured we could use the Rotovap to remove the dichloromethane instead of distillation, which required a steam bath. Expected yield: 50% .6 gSafety, disposal and green issues 3:BenzocaineHandling: Remove contaminated clothing and wash before reuse. Use with adequate ventilation.Minimize dust generation and
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