Step 1NOOHHNNOCH3OCH3NNCH3OO2NCH3ONNOCH3CH3H2NONNNNNOOCH3CH3H3CNaH/DMSO/CH3IHNO3H2SO4Fe/HClUracil1,3-dimethyluracil1,3-dimethyl-5-nitrouracil5-amino-1,3-dimethyluracilPartial synthesis of caffeine by the three step reaction starting with uracil and ending with 5-amino-1,3-dimethyluracilCaffeine(1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione)123Honors Cup Proposal Check:Section 211Natalie Clark, Antoinette Maniaci, Rui Zhang, Heechan ChaTarget molecule: 5-amino-1,3-dimethyluracil (an intermediate of caffeine)NNOCH3CH3H2NO5-amino-1,3-dimethyluracilWhy is this molecule interesting?We chose caffeine as our molecule because it is what keeps us awake in class by acting as a metabolic stimulant. We also found caffeine to be an interesting molecule for its addictive properties. As a six step synthesis is required to produce caffeine, we are proposing to make its 3rd step intermediate, starting withuracil and ending with 5-amino-1,3-dimethyluracil.Proposed three-step synthesis:Step 1 Synthetic transformation 1: (1)NOOHHNNOCH3OCH3NNaH/DMSO/CH3Iacil1,3-dimethyluracil1Ur(2) Experimental 1: A solution of uracil ( 9.895 g, 0.08835 mol) in DMSO ( 495 mL) was stirred overnight at room temperature. Four equivalents of sodium hydride (8.4g, 0.35 mol) were added carefully to the solution of uracil. Five equivalents ( 62.45 g, 0.44 mol) of methyl idodide was added slowly over a period of 10 min. The mixture was stirred for another 40 min and diluted with 158 mL of water to remove excess of hydide. The solution was then acidified with conc. HCl to pH 1-2. The product was then extracted with methylene chloride and washed with saturated bicarbonate solution until neutral. 14.34 grams was isolated after removing the dicholormethane. Expected yeild: 61% 14.34g Safety, disposal and green issues 1: There are multiple reagents to carry out this transformation, however, the method using NaH/DMSO/CH31 was the most 'earth friendly' while providing the best yeild. Step 2 Synthetic transformation 2: NNOCH3OCH3NNCH3OO2NCH3OHNO3H2SO41,3-dimethyluracil1,3-dimethyl-5-nitrouraci2l(3) Experimental 2 Compound 2 ( 1.33 g, 0.0095 mol) was added carefully to an equal volume of a mixture of fuming nitric and conc. sulfuric acid (4.66 mL) and stirred for 30 min at room temperature. The solution was then refluxed for an hour and added carefully to ice cold water (ca. 5 mL). The light yellow colored crystals of compound 3 were filtered, washed with ice cold water. Expected yeild: 64 % 10.97 g Safety, disposal, and green issues 2: No safety issues.Step 3 Stynthetic transformation 3 (4)NNCH3OO2NCH3ONNOCH3CH3H2NOFe/HCl1,3-dimethyl-5-nitrouracimino-1,3-dimethyluracil3l5-a(3) Experimental 3 0.83g (0.0045 mol) of 3 was dissolved in enough THF to form a 2M solution. Equal volume 1M HCl was added followed by 10 equiv. of (2.53 g) of active iron powder. The solution was refluxed for 30 min. The reduced product was extracted into methylene chloride after neutralizing with saturated bicarbonate solution. 70% yeild of 0.5g of reduced product 4 was formed. After purification of the product by flash chromatography on silica gel using ethyl acetate, the product was identified by IR and NMR. Expected yeild: 70 % 0.5 g Safety, disposal and green issues 3: No safety issues. Overall budget: Chemical Supplier Cost Amt. Needed Total 1. Uracil Aldrich 25g/$13.10 9.895g $5.18 2. NaH Aldrich 100g/$26.50 8.4g $2.23 3. DMSO Aldrich 500mL/$23.00 495mL $22.77 4. CH3I Aldrich 100g/$28.00 62.45g $17.49 7. Fuming Nitric Acid Aldrich 500mL/$363.40 2.33 mL $1.69 8. Sulfuric Acid Aldrich 100mL/$47.00 2.33 mL $0.47 9. THF Aldrich 2L/$76.40 10. Fe, powder Aldrich 250g/$45.30 25.33g $4.41 Total costs per synthesis: $54.24 References: 1. Zajac, M. A.; Zakrzewski, A. G.; Kowal, M. G.; Narayan, S. Synthetic Communications. 2003, 33, 3291-3297. 2. Gepner, B.; Kreps, L. J. Gen. Chem. USSR. 1946, 16,
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