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U-M CHEM 215 - Honors Cup Synthetic Proposal

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Honors Cup Synthetic ProposalExpected yield: 70% 1.49 gExpected yield: 60 % 0.974gExpected yield: 80% 0.5 gTotal costs per synthesis (each step): $13.90Honors Cup Synthetic ProposalSection: 220Group Members: Angela Sandelin, Brian O’Keefe, Stephen Winter, and Lisa LentzTitle: A Three-Step Synthesis of methyl 4-hydroxybenzoate (Methyl Paraben)Introduction: (what makes your target interesting?)Methyl ParabenHOCOO CH3Why is this molecule interesting?Parabens are found as antifungal preservatives in many commercial products; they inhibit bacterial growth and reproduction, thus killing the bacteria. Some products in which parabens can be found include food, sunscreen, cosmetic products and shampoos. Since parabens functionto kill mold and fungi, they are also used in combination with bactericides in order to form largerranges in which antibiotics affect bacteria.Overall synthetic reaction scheme:1)OOCOHOHOCOHO2)OOCOHOOOCOO3)OOCOOHOCOOMeOOMePhClO CH3CH3H3CBFFFFplusAc2OCl OOOOHMethyl ParabenStep 1 Synthetic transformation 1:1)OOCOHOHOCOHOAc2OCl OOOOHExperimental 1 4-hydroxybenzoic acid (1.632g, 11.83 mmol) was treated with acetic anhydride [Ac2O] (1.136 ml, 11.83 mmol) in the absence of a solvent in an appropriately sized beaker at room temperature. The reaction was run under magnetic stirring in the presence of magnesium perchlorate [Mg(ClO4)2] (26.50 mg, 0.1183 mmol). The reaction was monitored with TLC every 30 minutes. The reaction was run to completion according to the results of the TLC plates. Reaction time lasted between one to two hours. The reaction, when complete, was extracted withDCM (dichloromethane) to afford the product: 4-acetoxybenzoic acid. A separatory funnel was used for the extraction and the organic layer was collected. The solvents were evaporated through the use of a rotary evaporator. The product was then characterized with H-NMR, C-NMR, TLC, and IR spectral analysis. The expected yield is 70%.Deviations from Cited Literature: The above procedure exactly follows the procedure outlined in the journal article (Tetrahedron 59 (2003)) except for the fact that the journal article proposed a scaled down version with only 2.5 mmol of each respective reagent (0.025 mmol of Mg(ClO4)2). They also have the reaction listed as affording 85% yield and taking one hour.Expected yield: 70% 1.49 gSafety, disposal and green issues 1:Safety Issues: The above reaction uses perchlorates, which can cause explosions when heated in the presence of combustible substances at high temperatures. Caution should be exercised, but since the reaction scheme does not involve combustible materials and was carried out at room temperatures (far below the melting point of 251 deg C of magnesium perchlorate) the potential hazards associated with perchlorates should not be a problem.Green Awareness: The reaction has favorable "Green" chemistry elements since it was preformed with out a solvent. This is particularly good for large scale reactions where solvents generate a tremendous amount of hazardous waste.Step 2Synthetic transformation 2:2)OOCOHOOOCOOO CH3CH3H3CBFFFFplusExperimental 2:To a suspension of 1.26g (8.50mmol) of trimethyloxonium tetrafluoroborate in 58.2mL of dichloromethane was added 7.73mmol of the carboxylic acid. The resulting suspension was stirred magnetically while 1.10g (8.50mmol) of N,N-diisopropylethylamine was introduced with a syringe. During the addition of the amine, a warming of the reaction mixture was observed. The flask was stoppered after the addition of the amine and the suspension was allowed to stir for two hours. After approximately 1 hour, virtually all of the originally undissolved oxonium salt had gone into solution. After two hours, the organic solution was extracted with three 50-mL portions of N hydrochloric acid, three 50-mL portions of 1 N potassium bicarbonate, and a singleportion of saturated sodium chloride. With maleic acid, fumaric acid, 2- butenoic acid, and citric acid, the HCl and the KHCO3 solutions were back-extracted due to the water solubility of the corresponding esters. The organic solution was then dried over anhydrous sodium sulfate and thesolvent was removed by evaporation under reduced pressure. The residue left was purified by short path distillation or recrystallization to afford the desired esters with purities of 95% or greater.Note: The experimental closely follows that of Raber experimental outlined in the J. Org. Chem. However, it has been scaled down (1 : .773, mol to mol) to achieve 500mg of the desired final product. Since the carboxylic acid used here is monoprotic, the instructions for diprotic and triprotic acids were left out. The exothermic nature of the addition of the amine and the cautions for larger scale reactions were dropped left out.Expected yield: 60 % 0.974gSafety, disposal and green issues 2:Trimethyloxonium salts are nonhygroscopic, and may be easily handled in air for a short period of time. The salt should be stored in -20 Celsius freezer and lasts for six months. This reaction did not contain any special green issues.Step 3 Synthetic transformation 3:3)OOCOOHOCOOMeOOMePhClMethyl ParabenExperimental 3 (notes if this transformation is not exactly the one reported in literature (e.g. on a different scale) and how it was modified):Ammonium formate (HCOONH4) (259.9 mg, 20.63 mmol) wax mixed thoroughly with silica gel (2.063 g, finer than 200 mesh) to form a powder. Methyl 4-acetoxybenzoate (0.8 g, 4.125 mmol) was then added and mixed. The mixture was taken in a glass test tube (length: 15 cm, diameter: 1.6 cm) and placed in the center of an alumina bath, which was made by using a 250 ml glass beaker three-quarters filled with alumina. The alumina bath was placed inside a microwave oven (BPL, BMO, 700T, 450 W) and the reaction mixture was irradiated for 6 minutes. The mixture was cooled, shaken with ethyl acetate (EtOAc) (41.25 ml) and filtered. The filtrate was concentrated to afford the deprotected product, methyl 4-hydroxybenzoate. The product was then characterized using 1H NMR.This experimental was altered from the one appearing in literature in that the scale has been increased 4.125 times the original. Also, the journal article reported that the reaction mixture should be irradiated for 2 minutes. The journal states that irradiating up to 6 minutes did not change the results, but irradiating longer caused the compounds to decompose. As we have a greater

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