Exp t 14 The Preparation of a Heterocyclic Compound 3 Carbethoxycoumarin Adapted by Anderson Blecker Chia Follweiler Haywood Amy Bollinger R Minard PSU 92 from Microscale Syntheses of Heterocyclic Compounds by R Al awar and G Wahl Jr J Chem Ed 67 265 1990 Revised 3 26 02 Introduction Cyclic organic compounds can be classified as either carbocyclic i e the ring systems contain all carbons or heterocyclic in which the ring systems contain other hetero atoms such as nitrogen oxygen sulfur etc in addition to carbon atoms Many heterocycles have important pharmaceutical properties The structures of two biologically important heterocycles are shown below S Na CH2 H NH O S H N O H H CH3 CH3 N N O O CH2 CH sodium pentothal CH3 CH3 CH an anesthetic barbiturate 2 COOH Penicillin G an antibiotic CH2 CH3 A subclass of heterocyclic compounds are fused ring heterocycles These compounds contain a benzene ring fused to a heterocyclic ring Some examples are shown below N H2 O CH2 CH2 N CH3 N CH3 N H N N dimethyltryptamine a hallucinogen N O H N H S H O Luminol a chemiluminescent substance O O Saccharin an artificial sweetner In this experiment you will be synthesizing a fused ring heterocycle 3 carbethoxycoumarin which is an example of a class of heterocyclic compounds called coumarins 8 7 6 5 O 12 3 4 O Coumarin the parent heterocycle a flavoring O O O O O OC2H 5 3 Carbethoxycoumarin your synthetic goal OH O Warfarin a rat poison Exp t A very important coumarin compound is Warfarin which is a powerful anticoagulant In low doses it is used as a blood thinner in humans with high blood pressure It is applied at higher concentrations to corn or other grains and sold as a rodenticide When eaten by rats or mice the higher concentrations of Warfarin cause them to bleed internally To replace body fluid losses the rodents move out of grain storage areas into the outdoors in search of water Thus they are less likely to die within the grain elevator which is obviously a much less disgusting situation The Warf in Warfarin stands for Wisconsin Alumni Research Fund which makes a bundle from the patent it holds on this compound The synthesis of the 3 carbethoxycoumarin heterocycle involves an aldol condensation reaction between salicylaldehyde and diethyl malonate base catalyzed condensation H C2H 5O O O O O H salicylaldehyde OC2H 5 diethyl malonate piperidine or triethylamine O O O OC2H 5 3 Carbethoxycoumarin mp 92 94 C The aldol condensation is described in Organic Chemistry by McMurry or any large organic textbook Prelab Exercises 1 Draw the step by step mechanism use arrow pushing for the synthesis of 3 carbethoxycoumarin from salicylaldehyde and diethyl malonate Hint the mechanism involves both an aldol condensation and a transesterification step 2 Why are the hydrogens on the a carbon of diethyl malonate acidic enough to be removed by the base piperidine Draw all pertinent resonance structures 3 What advantage s could there be for using piperidine rather than hydroxide as a base Cautions Piperidine is toxic salicylaldehyde is a toxic irritant and glacial acetic acid is a corrosive agent Be careful when handling these chemicals Synthesis Place 1 1 mL salicylaldehyde and 1 7 mL diethyl malonate into a 25 mL round bottom flask with a 1 2 inch magnetic stir bar Add 4 mL ethanol 20 drops piperidine and 4 drops of glacial acetic acid Connect the flask to a water condenser Fill a plastic drying tube with Drierite Common Shelf using a glss wool plug at each end to hold the pellets in Connect this drying tube at the top of the condensor using the glass red rubber thermometer adapter from your kit Reflux the solution for 2 hours using a heating mantle no sand and continuous stirring Isolation and Purification Let the solution cool slowly to room temperature then cool in an ice bath Stir the solution for 5 minutes in the ice bath after crystals first appear Vacuum filter off the solid using a Buchner funnel with the two pieces of filter paper in it Rinse out residual crystal from the flask with cold ethanol and add to solid in the funnel Allow the crystals to dry until the next laboratory period Weigh the dry crystals on the filter paper and determine the percent yield and the melting point If the melting point is low recrystallize from 95 ethanol Cleaning Up Dispose of all filtrates down the drain with lots of water Final Report Include the spectrum from the analysis method assigned with the structure and interpretation written directly on it Answer these questions at the end of the report 1 What is the purpose of using the water condensor and drying tube 2 Why is the hydrogen on carbon 4 of the product so far downfield in the proton NMR 3 A solution of 3 carbethoxycoumarin was refluxed in a solution of NaOH and water What product s would you expect to form from the reaction Synthetic Experiment PreLab Grading Sheet Name s TA Date PreLab For Exp t 14 The Preparation of a Heterocyclic Compound 3 Carbethoxycoumarin Possible Points Date Name Desk Experiment Title abbreviated after 1st pg Section TA Name 4 Summary 8 Goals 8 Reactions structures conditions diagrams 14 Completeness of Chemical Data Table s 14 Chromatographic Behavior Comparison 16 Spectral Features Comparison 12 Work up Explanation of the product isolation and purification process 12 PreLab Questions 12 TOTAL FOR PRELAB Missed Points 100 Date Handed in General Comments Total Points Synthetic Experiment Final Report Grading Sheet Name TA Date Final Report For Exp t 14 The Preparation of a Heterocyclic Compound 3 Carbethoxycoumarin Possible Points Name Date Experiment Title abbreviated after 1st page and every page numbered 4 OBSERVATIONS and DATA Overall organization readability completeness 8 Data Weighing data molecular weights moles density volumes Rf s Missed Points 12 Product analysis conditions i e weight of sample and KBr for IR solvent and field strength for NMR ionization mode for MS solvent and wavelength range for UV Vis Yield Show yield calculations with limiting reagent clearly stated Purity Record melting points color TLC analyses or other indicators of purity RESULTS AND DISCUSSION Overall organization readability completeness Results Achievement of goals 12 8 16 Product Analysis Data Quality and Interpretation Structure s drawn on each Spectrum or Chromatogram Interpret all NMR peaks including impurities or major IR or MS peaks Explain how spectra confirm product identity Discuss all UV Vis lmax in terms of conjugation 24 See Lab Guide