Honors Cup Synthetic Proposal (250 I-Wed PM-W08)

Transcription

1 Honors Cup Synthetic Proposal (250 I-Wed PM-W08) Group Members: Franzblau, Rachel; Johns, Jeremy; Yadav, Hans Title: Synthesis of Cinnamaldehyde Introduction: Cinnamaldehyde, a major part of cinnamon oil, has been used for flavoring in many different food products, as a fragrance in perfumes and also as a fungicide. It is also currently being investigated for its antibacterial properties. Cinnamaldehyde occurs naturally in the bark of the Cinnamomum zeylanicum tree, which grows only in Sri Lanka and southern India. There is also the Cinnamomum cassia tree, which grows in China that produces a cinnamon-like flavoring and smell in its bark, however cinnamaldehyde is only found naturally in the Cinnamomum zeylanicum. Cinnamon as has been used as far back as 2000 BC as a spice and a fragrance, and trade in cinnamon flourished, bringing cinnamon even to ancient Rome, where the mperor Nero burned it at his wife s funeral after he allegedly murdered her. verall synthetic reaction scheme: Step 1 C CHCl2 + CH 1.1 R:CrCl2, S:THF, 3 h, reflux 1.2 R:HCl, S:H2 95% NT: stereoselective, Reactants: 2, Reagents: 2, Solvents: 2, Steps: 1, Stages: 2 Step 2 R:AlH(Bu-i)2, S:THF, S:Me, -70 C; 30 min, -70 C H NT: Reactants: 1, Reagents: 1, Solvents: 2, Steps: 1, Stages: 1 Step 3 H + Mn electrolytic Reagent S:Hexane 100% CH NT: electrolytic Mn2, Reactants: 1, Reagents: 1, Solvents: 1, Step s: 1, Stag es: 1

2 Synthetic transformation 1: H Cl t 1) CrCl 2 2) HCl Cl thyl Dichloroacetate Benzaldehyde 1) THF 2) H 2 t thyl trans-cinnamate xperimental 1 The slurry of Mn* (2.5 mmol, 8.5 ml) in THF was added to a stirred solution of ethyl 1,1-dichloroacetate (0.6 mmol, 0.08 g) and the corresponding aldehyde (0.5 mmol) in THF (2 ml) under a nitrogen atmosphere. The mixture was refluxed for 3 h before it was quenched with HCl 3 M. The organic material was extracted with diethyl ether (3 x 20 ml), the combined organic extracts were washed sequentially with HCl 3 M (2 x 10 ml), NaHC3 (saturated, 2 x 20 ml), Na2S23 (saturated, 2 x 20 ml), and brine (2 x 20 ml) and dried over Na 2 S 4. Solvents were removed in vacuo. Purification by flash column chromatography on silica gel (hexane/ac 10/1) provided pure compound 5 [thyl transcinnamate]. The slurry of Mn with THF should be replaced with 2.5 mmol CrCl 2 in a solution of 20 ml THF. Also, if under time constraints, purification by column chromatography may be skipped. To synthesize a product of 0.625g the following measurements were modified: CrCl2: 0.322mmol THF: 0.05mL thyl-1,1-dichloroacetate: 0.064g Benzaldehyde: 0.658g xpected yield: 95 % g Safety, disposal and green issues 1: thyl Dichloroacetate: Harmful if inhaled Benzaldehyde: Harmful if ingested; Avoid contact with skin THF: Highly flammable; Irritating to eyes and respiratory system o Keep away from flame; Do not pour down drain CrCl 2 : Irritating to eyes, respiratory system and skin o If in contact with eyes, flush with water and find medical help HCl: Causes burns; Irritating to respiratory system o In case contact with eyes, flush with water and find medical help; Keep in original container When handling any of the above chemicals, always wear gloves, goggles, and protective clothing. For chemicals like ethyl dichloroacetate, THF, and CrCl 2, make sure to use under a hood. Proper disposal of the above compounds should follow suit with the safe disposal regulations already established in the laboratory.

3 Synthetic transformation 2: thyl trans-cinnamate 1)DIBAL THF Hexane 2) MeH Cinnamyl Alcohol H xperimental 2 A solution of DIBAL-H 1 M in hexanes (106 ml, 106 mmol) was added slowly to a solution of (9 g, 41 mmol) in THF (150 ml) under argon and the resultant mixture was stirred at 80 C for 4 hours. The reaction was quenched with MeH (30 ml) at 80 C, stirred for 1 hour then water (14 ml) was added. Celite was added and the resulting granular suspension was filtered through a celite plug and the residue washed with ethyl acetate. The filtrate was then concentrated to yield the alcohol. (5.8g, 80%). Use the following measurements instead (for scaling purposes): Hexane: 9.1mL MeH: 2.58mL DIBAL-H: 0.774g Water: 1.2mL THF: 12.9mL Instead of using an Argon atmosphere, use a Nitrogen atmosphere. Also, do not stir for 4 hours, stir as long as possible, then leave it in the drawer until the next lab and then quench it with MeH. Use dry ice to reach the necessary -80 C for the reaction to occur. xpected yield: 80 % g Safety, disposal and green issues 2: thyl trans-cinnamate: Skin and eye irritant DIBAL-H: Causes eye burns, skin and respiratory irritation and digestive burns if ingested Hexane: Mild irritant THF: Should not have prolonged exposure to air; Can form explosive peroxides; Use a nitrogen environment MeH: Do not ingest or inhale, skin irritant Celite: Highly flammable; Irritant to skin, eyes, and repiritory system Cinnamyl Alcohol: Not harmful Dispose comounds properly in correctly labeled waste containers. Use goggles and keep chemicals away from eyes and mouth- can irritate the skin. Wear protective clothing as precautionary measures against skin irritation from chemicals such as hexane, MeH, and celite.

4 Synthetic transformation 3: H Mn Hexane Cinnamyl alcohol electrolytic manganese dioxide Cinnamaldehyde xperimental 3: 6.88g (79.2 mmol) of electrolytic manganese dioxide were placed in a three-necked round bottom flask and flushed with nitrogen. A solution of g (3.894mmol) of cinnamyl alcohol and 96 ml of hexane were added to the three-necked round bottom flask at 0 C. The mixture was stirred at 0 C for 3 hours. The mixture was then filtered and the filtrate was concentrated to give the final product, cinamaldyhde. All values had to be increased by a factor of 6 to generate the needed 0.5 grams of product. xpected yield: 100 % g Safety, disposal, and green issues: Manganese dioxide: xidizer. Contact with other materials may cause fire. Harmful if swallowed or inhaled and affects the lungs, central nervous system, blood and kidneys. May cause irritation to eyes and respiratory tract. If there is skin exposure, wash the exposed area with water and soap. Hexane: Highly flammable and readily forms explosive mixtures with air. xposure to skin and/or eyes may cause moderate irritation and discomfort. Vapors can cause dizziness, headaches, excitation, and/or central nervous system depression. Cinnamaldehyde: Harmful if swallowed or inhaled. Can cause irritation to the skin, eyes and respiratory tract. May cause an allergic skin reaction. The liquid and vapor phases are combustible. Cinnamyl alcohol: Hazardous in case of skin and/or eye contact, inhalation and ingestion. Slightly flammable. Use goggles, gloves, lab aprons and a fume hood while working with these chemicals. Waste materials can be disposed of in their appropriate waste containers in the lab.

5 verall budget: Chemical Supplier Cost Amt. Needed Total THF Sigma-Aldrich $0.05/mL 13.4 ml $0.67 Hexane Sigma-Aldrich $0.06/mL ml $6.31 DIBAL-H Sigma-Aldrich $1.10/g g $0.85 MeH Sigma-Aldrich $0.04/mL 2.58 ml $0.10 Celite Sigma-Aldrich $0.03/g Unknown Unknown Chromium (II) Sigma-Aldrich $10.00/g 0.04 g $0.40 Chloride Mn Sigma-Aldrich $0.13/g 6.88 g $0.89 (electrolytic) HCl Sigma-Aldrich $0.02/mL 20 ml $0.40 Nitrogen gas Benzaldehyde Sigma-Aldrich $0.03/g g $0.02 thyl Sigma-Aldrich $0.90/g g $0.06 dichloroacetate NaHC 3 Sigma-Aldrich $0.04/g 40 ml $1.60 Na 2 S 2 3 Sigma-Aldrich $0.07/g 40 ml $2.80 Na 2 S 4 Sigma-Aldrich $4.23/g Unknown Unknown Brine 40 ml Total costs per synthesis: $14.10 Notes: Water and nitrogen, due to their relative availability in the lab, were not included in the pricing. In addition, brine was not included in the pricing because of its simple to make combination of the basic compounds H 2 and NaCl. The amounts of Na 2 S 4 and Celite were not given by the references, so they were not included in the budget. References Step 1: Concellon, J. M.; Rodriguez-Solla, H.; Diaz, P.; Llavona, R. J. rg. Chem. 2007, 72, Step 2: Sauerberg, P.; Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Fleckner, J.; lsen, G. S.; Jeppesen, C. B.; Wulff,. M.; Pihera, P.; Havranek, M.; Polivka, Z.; Pettersson, I. Bioorganic & Medicinal Chemistry Letters 2007, 17, Step 3: Tsuboi, S.; Ishii. N., Sakai, T.; Tari, I.; Utaka, M. The Bulletin of the Chemical Society of Japan 1990, 63,