Honors Cup Synthetic ProposalExpected yield: 60 % 14.4 gExpected yield: 60 % 7.7 gExpected yield: 75 % 3.15 gHonors Cup Synthetic Proposal Section: 290 Group Members: Yue Ming Wu, Mikhail Lomize, Mike Kemper Title: Synthesis of Flavone Introduction: (what makes your target interesting?) Flavone is the parent molecule of a number of naturally occurring yellow pigments found primarily in primroses. Other flavone derivatives are found in a variety of plants. Flavones have a variety of uses in medicine. Many citrus flavones have an antiproliferative effect on human cancer cells (Manthey, J.A.; Guthrie, N. J. Agric. Food Chem. 2002, 50, 5837-5943.). Other flavones, specifically one extracted from mad-dog skullcap, have been shown to bind to serotonin receptors, and could be useful in treating depression, sleep disorders, migraines, pain, or memory impairment (Gafner, S. et al. J. Nat. Prod., 2003, 66, 535-537.). Other skullcap flavones have been shown to bind to the benzodiazepine site on the GABA receptor. These have a minor stress relieving effect, without acting as a muscle relaxant or sedative (Huang, X. et al. J. Med. Chem., 2001, 44, 1883-1891.). The target molecule in this case is the archetypal flavone. Overall synthetic reaction scheme: (a Chemdraw or similar drawing of all three steps)OHOOHOOOOOOOClOpyridineOH- (100 degrees Celsius)H+ (200ml of glacial acetic acid and 8ml of concentrated sulfuric acid)Step 1 Synthetic transformation 1: (Chemdraw picture of first transformation) OHOOOClOpyridine Experimental 1 (notes if this transformation is not exactly the one reported in literature (e.g. on a different scale) and how it was modified): Place 10.2g (0.075 mol) of o-hydroxyacetophenone in14.7g (12mL, 0.105 mol) of benzoyl chloride and 15mL of dry, redistilled pyridine. Mix the solution by shaking. After shaking for 20 minutes, pour the solution into 360 mL of 1 M-hydrochloric acid with 150g of crushed ice. Filter the product and wash it with 15mL of ice-cold methanol, then with 15mL of water. Recrystallize it from 18mL of methanol. Cool the product in ice. Collect the product by filtration. The expected yield is 60%, 14.4g. The product for the first step is called “o-benzoyloxyacetophenone,” no characterization data can be found. Please note that the experiment is scaled down so that it is 30% of the original experiment. Expected yield: 60 % 14.4 g Safety, disposal and green issues 1: o-hydroxyacetophenone is irritating to eyes and skin. Benzoyl chloride is toxic by inhalation, harmful if swallowed, irritating to respiratory system and skin, causes serious damage to eyes, may cause cancer. In case of accident or feeling unwell, seek medical advice immediately. Pyridine is highly flammable. It is also harmful if inhaled, if contacted by skin, and if swallowed. HCl is corrosive, it causes burns, and is irritating to respiratory system. Methanol is highly flammable, toxic by inhalation. One must keep it away from sources of ignition, wear protective gears, keep the container tightly closed, seek medical advice immediately in case of unwell. These chemicals must be disposed in appropriate containers.Step 2 Synthetic transformation 2: (Chemdraw picture of second transformation) OHOOOOOOH- (100 degrees Celsius) Experimental 2 (notes if this transformation is not exactly the one reported in literature (e.g. on a different scale) and how it was modified): Dissolve 9.6 g (0.04 mol) of benzoyloxyacetophenone in 36mL of dry pyridine and heat the solution to 50 degrees Celsius. Powder 3.4g (0.06 mol) of potassium hydroxide in and heat it in the oven at 100 degrees Celsius. Add the powdered potassium hydroxide to the benzoyloxyacetophenone solution and stir it for 15 minutes. Cool the reaction mixture to room temperature. Add 50 mL of 10 percent aqueous acetic acid while stirring the solution. Filter the pale yellow precipitate. Dry the precipitate in the oven at 50 degrees Celsius. The pure product can be obtained by crystallization from methanol. The expected yield is 80%, 7.7g. The product for the second step is called “o-hydroxydibenzoylmethane,” no characterization data can be found. Please note that the experiment is scaled down so that it is 20% of the original experiment. Expected yield: 60 % 7.7 g Safety, disposal and green issues 2: Potassium hydroxide is a base, so if it gets into water or soil, it will raise the pH. Some plants cannot tolerate soil that has high pH, potassium hydroxide has potential for destroying plant life. However, some plants thrive in high pH soil, so it could benefit other plants. If potassium hydroxide gets into an ecosystem in a significant amount, it could dramatically alter the livelihood of plant life, thus impacting the entire ecosystem. Glacial acetic acid is extremely corrosive, and can cause severe burns. Potassium hydroxide and glacial acetic acid should be disposed in appropriate containers and be neutralized.Step 3 Synthetic transformation 3: (Chemdraw picture of third transformation) OHOOOOH+ (200ml of glacial acetic acid and 8ml of concentrated sulfuric acid) Experimental 3 (notes if this transformation is not exactly the one reported in literature (e.g. on a different scale) and how it was modified): Dissolve 3.6g of (0.015 mol) of o-hydroxydibenzolymethane in 20mL of glacial acetic acid. Add 0.8 mL of concentrated sulfuric acid while shaking. Reflux the mixture on a boiling water bath for 1 hour with intermittent shaking. Pour the mixture while stirring to 0.1kg of crushed ice and allow the ice to melt. Filter the precipitate, wash it with water until it is no longer acidic(about 0.2 liters). Dry it in the oven at 50 degrees Celsius. The product flavone can be purified by recrystalization from light petroleum. The expected yield is 3.15g, 75% expected yield. The end product is flavone. HNMR:(8.235, 7.405, 7.680, 7.554, 8.15, 1.71, 0.56, 7.22, 0.91, 8.25, 6.82, 7.914, 7.503, 7.539, 1.84, 7.23, 0.56, 2.36, 0.56, 7.23, 2.36, 0.04,7.35, 7.35) Please note that the experiment is scaled down so that it is 10% of the original experiment. Expected yield: 75 % 3.15 g Safety, disposal and green issues 3: Sulfuric acid is a highly corrosive chemical, so if it gets into water or soil, it harms aquatic life as well as plant life. Furthermore, it can contaminate drinking water sources for humans. It should be disposed in the acid container and be