Honors Cup Synthetic Proposal Section: 251 Group Members: Alan Harrell Thomas Wong David Ross Cheri Pascoe Title: Sythesis of Menadione Introduction: Vitamin K3, menadione, is a polycyclic aromatic ketone and is the synthetic form of Vitamin K. Vitamin K is used by the body to control blood clotting and is naturally found in asparagus, coffee, bacon and green tea. Some people even believe it promotes longevity. The advantage of the drug is its water-solubility, which allows it to be the agent of choice in Vitamin K deficiencies. However, large doses of this supplement for newborn babies has been known to cause adverse outcomes including hemolytic anemia, neonatal brain or liver damage, and possible mutagenic effects. Overall synthetic reaction scheme: 1CCHCO2HHC CCOOR: H2SO4S: MeOHStep 1 Synthetic transformation 1: (Chemdraw picture of first transformation) 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): Prepared from 3-methyl-2butanoic acid by acid catalysed esterification. H2SO4 was used in heated test tubes with the alcohol. The ester formed a thin layer on the surface while excess alcohol and acid remain in the solution. The layer can then be removed.Expected yield: 43% g (One needs .0655 g of this to achieve * product in experimental 3. At 43% yeild one needs .152g.) Safety, disposal and green issues 1: MeOH Safety Info: Flammable, toxic if in contact with skin or if swallowed. Precautions: Keep container tightly closed, Keep away from sources of ignition - No smoking, wear suitable protective clothing and gloves Sulfuric Acid (H2SO4) Safety Data: Corrosive; causes severe burns Precautions: 26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice 30: Never add water to this product 45: In case of accident or if you feel unwell, seek medical advice immediately MgSO4 Safety data: 23: Do not breathe gas/fumes/vapor/spray (appropriate wording to be specified by the manufacturer) 24/25: Avoid contact with skin and eyesStep 2 Synthetic transformation 2: Et2NCOCHCMeMe+PhBr1.1 R: C6H11 (i-Pr) NLi S: THF S: N2 1.2 S: THFOHMe64% 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): Multiply by .394 of all mass and volume to get * product in experimental 3. At -78 degrees Celsius, in a round bottom flask, under nitrogen, 5mmol N,N-Diethylsenecioamide (in 20mL tetrahydrofuran (THF)) was added to a solution of 17.5mmol lithium di-isopropylamide (prepared from a 1.2M solution of 17.5mmol butyl-lithium in hexane, and 17.5mmol N-isopropycyclohexylamine) in 30mL tetrahydrofuran. The solution was stirred at -78 degrees Celsius for one hour and then allowed to warm to -20 degrees Celsius (ten minutes). 10mmol of bromobenzene in 10mL tetrahydrofuran was injected into the solution. The reaction mixture was stirred overnight at room temperature, quenched with saturated ammonium chloride and 10% HCl. It was then left to evaporate. The residue was extracted with CHCl3 and dried over Na2SO4 and evaporated to give a brown oil. The oil was column chromographed using n-hexane as the eluate, giving .52g 3-methyl-1-naphthol. Expected yield: 55 % .52 g To get * product in 3rd experimental you will need .111 g of 3-methyl-1-naphthol. At 55% yield you need .204g of this product Safety, disposal and green issues 2: Tetrahydrofuran Safety Info: Flammable; Irritant to eyes and respiratory system; Explosive, Precautions: avoid sources of ignition, take precaution against smoking, or static discharges, wear protective clothing and glovesLithium diisopropylamide Safety Statements: 14: Reacts violently with water 17: Spontaneously flammable in air 34: Causes burns Hazard Codes: Flammable, Coorosive Monobromobenzene Safety Info: Skin Irritant; dangerous for environment; Precautions: avoid release to the environment Ammonium chloride Warnings: Irritating to eyes, harmful if swallowed MgSO4 Safety data: 23: Do not breathe gas/fumes/vapor/spray (appropriate wording to be specified by the manufacturer) 24/25: Avoid contact with skin and eyes Step 3 Synthetic transformation 3: OHOOR: cosalenR: O2S: DMF3Experimental 3 (notes if this transformation is not exactly the one reported in literature (e.g. on a different scale) and how it was modified): (Times all scalar quantities of mass and volume in this experimental by 3.73 to get *product) 1.90mmol of 3-methyl-1-naphthol and 60mg salcomine were dissolved in 15mL dimethylformamide (DMF) in the dark in a round-bottom flask, allowing oxygen gas to flow over it for 3 hours. 50mL H2O was added and the mixture was extracted three times with benzene (using a separatory funnel). The combined organic layers were washed with water, dried over MgSO4 and then evaporated. The resulting brown solid was column chromatographed using silica gel to give menadione as yellow crystals. Expected yield: 64 % 0.210 g (.50 grams of menadione is 64% of .782 g product*) Safety, disposal and green issues 3: N,N'-Bis(salicylidene)ethylenediamine cobalt(II) salt Safety Info: Irritant Precautions: 26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice 27: Take off immediately all contaminated clothing 28: After contact with skin, wash immediately with plenty of ... (to be specified by the manufacturer) 29: Do not empty into drains 30: Never add water to this product 33: Take precautionary measures against static discharges 35: This material and its container must be disposed of in a safe way 36: Wear suitable protective clothing 37: Wear suitable gloves 38: In case of insufficient ventilation, wear suitable respiratory equipment 39: Wear eye/face protectionDMF Safety Info: 20: Harmful by inhalation 21: Harmful in contact with skin 22: Harmful if swallowed 23: Toxic by inhalation 24: Toxic in contact with skin 25: Toxic if swallowed 26: Very Toxic by inhalation 27: Very Toxic in contact with skin 28: Very Toxic if swallowed 29: Contact with water liberates toxic gas 30: Can become highly flammable in use 31: Contact with acids liberates toxic gas 32: Contact with acids liberates very toxic gas 33: Danger of cumulative effects 34: Causes burns 35: Causes severe burns 36:
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