HY Kemian laitos Orgaanisen kemian laboratorio Orgaanisen kemian työt II Organiska kemiarbeten II 18.11. 2015
2 Contents 4-Bromoacetanilide. 3 4-Bromoaniline 5 Benzhydrol.... 6 Benzophenone.....8 1-Phenyl-1-penten-3-one 9 It is assumed that students who attend the course Organic chemistry laboratory II know the basic organic chemistry methods (how to reflux, extract, filter, distil, and recrystallize etc.)
3 4-Bromoacetanilide 4-Bromoacetanilide is used as a starting material for 4-bromoaniline. Literature: Naik, S., Bhattacharjya G., Kavala, V. R., and Patel, B. K.; Mild and eco-friendly chemoselective acylation of amines in aqueous medium, ARCIVOC, 2004 (i) 55-63. Cardinal, P., Greer, B., Luong, H., and Tyagunova, Y.; A multistep synthesis of incorporating a green bromination of an aromatic ring, J. Chem. Educ. 89, (2012) 1061 1063 (modified). Preparation of acetanilide (N-Phenylacetamide) Reagents: Equipment: 2 ml of aniline 250 ml erlenmeyer flask 3.2 ml of acetic anhydride magnetic stirring apparatus suction filtration apparatus Aniline (2 ml) and water (100 ml) are mixed and stirred in an erlenmeyer flask. Add to this heterogeneous mixture 6 M HCl (6-10 ml) until the ph is ca. 1. 1 The resulting homogenous solution is cooled in an ice bath and acetic anhydride (3.2 ml) is added followed by solid NaHCO 3 until the ph is ca. 6 1 evolution of CO 2 has ceased (requires 4-6 g of NaHCO 3). Isolation The precipitated product is filtered with a Büchner funnel and washed with a little ice-cold water. Let the product dry on a watch glass overnight.
4 Run a TLC from your product and aniline (1:2 EtOAc : CH 2Cl 2). Determine the melting point and run IR spectrum. 1. Check with ph paper p-bromoacetanilide Reagents Equipment 2.9 g of acetanilide 100 ml round-bottomed flask 5.4 g of NaBr magnetic stirring apparatus 20 ml of EtOH (95%) suction filtration apparatus 15 ml of acetic acid recrystallization apparatus 11.6 ml of NaClO (ca.14%) Place previously made acetanilide (2.9 g) and NaBr (5.4 g) in a 100 ml round-bottomed flask. Add ethanol (20 ml) and acetic acid (15 ml) and stir the mixture in an ice bath until the temperature of the mixture is <5 C. Add 14 % NaClO (11.6 ml) and stir 1 minute in an ice bath. 1 Remove the ice bath and stopper the flask with a cork and allow the reaction to warm up to room temperature over 15 minutes. Cool the reaction in an ice bath and quench the reaction by adding 10% sodium thiosulfate solution to remove any unreacted bromine. 2 Add 40 ml of 2 M NaOH. The precipitated product is filtered with a Büchner funnel and recrystallized in a small round-bottomed flask from minimum amount of 1:1 ethanol:h 2O. Calculate the yield starting from aniline. The yield of the product is 45%. Determine the melting point and run IR spectrum and 1 H NMR spectrum. Questions 1. What may be observed? 2. What may be observed? 3. Why is the amine group of aniline protected as an amide before bromination? 4. Why are these two reactions good examples of green chemistry procedures?
5 4-Bromoaniline Reagents: Equipment: 2.0 g of 4-bromoacetanilide reflux apparatus 30 ml of ethanol (95%) magnetic stirrer 30 ml of 4 M HCl separatory funnel suction filtration apparatus Dissolve 4-bromoacetanilide(2.0 g) in 30 ml of ethanol in a 100 ml round-bottomed flask. Add 4 M HCl (30 ml) and reflux the mixture. The reaction time needed is checked with TLC at hourly intervals (eluent 2:1 CH 2Cl 2: EtOAc). 1 Cool the solution in an ice-bath and make the solution basic by adding 2 M NaOH. 2 The mixture is extracted three times with 20 ml of diethyl ether. The organic phase is washed three times with water and dried with Na 2SO 4 and the solvent is evaporated. The crude product is recrystallized in a small round-bottomed flask from minimum amount of 1:1 EtOH:H 2O. The yield of the product is 85%. Determine the melting point and run IR spectrum and 1 H NMR spectrum. Question: 1. How is the reaction followed by TLC? How do you prepare the sample for TLC? 2. Check with ph paper.
6 Benzhydrol Literature: Preparation of Grignard reagent Hünig, Märkl & Säuer, Integriertes Organisches Practicum, p. 306. Preparation of benzhydrol: H.D. Durst & G. W. Gokel, Experimental Organic Chemistry, McGraw-Hill, Inc. 1980, USA, p. 281. Benzhydrol is used as a starting material for benzophenone. Reagents Safety notes Equipment 6.0 ml freshly distilled benzaldehyde Perform experiment in hood. reflux apparatus with three-neck 7.6 ml of bromobenzene Extinguish all flames flask and CaCl 2-tube 1.5 g of magnesium before opening any solvent dropping funnel vessel. Ether is flammable and a distillation apparatus powerful narcotic separation/extraction suction filtration apparatus The experiment is started with the preparation of a Grignard reagent from bromobenzene. Note that any moisture hinders the start of the reaction. Therefore, all the reagents, solvents and equipment have to be absolutely dry. First prepare enough dry ether according to instructions (eg. T. Simonen: Orgaanisen kemian työmenetelmistä ja työturvalllisuudesta sekä orgaanisesta analytiikasta, p. 130 in Finnish. Also note the safety instructions for handling of sodium, p. 147). Dry the glassware in the oven over night and cool the hot glassware with Ar-gas. Use CaCl 2-tubes to protect the apparatus from dampness. Benzaldehyde must be distilled in vacuum before use. Place Mg-tunings (1.5 g) and dry ether (6 ml) into the reaction flask. Mix bromobenzene (7.6 ml) in dry ether (12 ml) and transfer the solution into a dropping funnel. Without stirring add about 1/10 of the bromobenzene solution to the reaction flask. If the reaction does not start immediately, careful warming or addition of a catalyst (eg. a crystal of iodine) can help. A sign that the reaction has started is that the reaction mixture turns dimly grey and, as the reaction is exothermic, the ether starts to boil. Once the reaction has started, the reaction mixture is stirred and the rest of the bromobenzene is slowly added in such a way that the reaction mixture does not boil too vigorously. When all the bromobenzene has been added, stirring is continued for about 15 minutes at room temperature. Finally the reaction mixture is refluxed for 20 minutes. Let the reaction mixture cool to room temperature.
7 Mix 6.0 ml of freshly distilled benzaldehyde and 25 ml of dry ether and transfer the solution into the dropping funnel which was used for the bromobenzene in preparing the Grignard reagent. Add slowly the benzaldehyde solution into the reaction flask. During the addition, a vigorous reaction will occur and the solution will reflux. Dropwise addition maintains a controlled reaction. During the addition a precipitate may form in the reaction solution. After all the aldehyde solution has been added, reflux the mixture on a water bath for 30 minutes. Just before the reflux period is complete, prepare an acid solution by pouring 50 ml of 10% aqueous sulphuric acid into a 250 ml Erlenmeyer flask containing approximately 50 g of cracked ice. Pour about 10 ml of this solution into a graduated cylinder for later use. Cool the reaction mixture to room temperature and pour it into the Erlenmeyer flask containing the very cold acid. When the addition is compete, stir vigorously so that the ether and aqueous acid solutions thoroughly mix and all salts hydrolyze. Now add the reserved 10 ml of acid solution to the reaction flask to hydrolyze any remaining salts (use a small amount of solvent ether if necessary to dissolve most of the material). When the hydrolysis of all the salts in both containers is complete, transfer the combined solutions to the separatory funnel. Close the separatory funnel with a stopper and gently shake the mixture. Draw off the lower acid layer and wash the remaining ether layer once with 25 ml water, twice with 25 ml saturated sodium bicarbonate solution, and finally with two 25 ml portions of saturated NaCl-solution (brine). Dry the organic phase with Na 2SO 4. After filtering the drying agent away, evaporate the ether. After all the ether has been removed, add 75 ml hexane and heat the solution to reflux on a water bath. Cool the solution to room temperature, then continue to cool the solution in an ice-bath until the internal temperature is approximately 10 C. Filter the crystalline material on a Büchner funnel. (Note: Benzhydrol tends to form an oil as the solution cools in the ice-bath. If a source of seed crystals is available, several should be added while cooling. It also helps to swirl the flask vigorously immediately). The crude benzhydrol is purified by recrystallization from hexane as described above. The product is collected on a Büchner funnel and washed with cold hexane. The material is then air dried. Pure benzhydrol has a melting point of 67 to 69 C. The yield of pure material should be 7 g. Analyze the product by thin-layer chromatography. Thin-layer chromatography of the crude product (silica gel, dichloromethane) shows benzhydrol and a small amount of benzaldehyde. Thin-layer chromatography of the purified material (same conditions) shows only benzhydrol. Record the melting point and run 1 H NMR- and IR-spectrum of the pure product. No benzaldehyde (C=O peak at about 1700 cm -1 ) is detected in the IR spectrum of pure benzhydrol. Questions 1. Why does benzaldehyde contain benzoic acid after a long period of storage? 2. Why is H 2SO 4 added? 3. What drying agent can be used and what cannot?
8 Benzophenone Literature: H. D. Durst & G. W. Gokel, Experimental Organic Chemistry, Mc-Graw-Hill, Inc., 1980, USA, p.352. Mirafzal, G.A. and Lozeva, A.M., Tetrahedron Letters, 1998, 39, 7263. Reagents Safety notes Equipment 5 g of benzhydrol NaOCl is concentrated bleach 250 ml Erlenmeyer flask 50 ml of 10% sodium and skin contact should separation/extraction hypochlorite be avoided. It is a strong oxidizing ice bath 500 mg of tetra- agent TLC equipment butylammonium reflux apparatus hydrogensulphate Place magnetic stirring bar, 5 g (0.027 mol) benzhydrol, and 50 ml ethyl acetate in a 250 ml Erlenmeyer flask. Add 50 ml concentrated NaOCl solution (swinging pool bleach, 10% aqueous NaOCl), followed by 500 mg tetrabutylammonium hydrogensulfate. 1 Stir the mixture vigorously for 1 h. If the flask begins to heat up, place it in an ice-water bath until its temperature returns to ambient. The mixture should be maintained at room temperature or ambient temperature throughout the reaction. Run a TLC chromatogram (silica gel, CH 2Cl 2) every half an hour to see how far the reaction has proceeded. After the stirring period is over, transfer the mixture to a separatory funnel. Separate the layers and wash the ethyl acetate solution once with 25 ml water, then twice with 25 ml 5% sodium bicarbonate, and finally once with 25 ml saturated NaCl-solution. Evaporate the ethyl acetate with rotary evaporator. Dissolve the residue in 25 ml methyl alcohol and while stirring with a magnet, gently warm the solution (not over 45 C). Add water a little at a time with continued heating until the solution turns cloudy (usually 9 to 10 ml will suffice). Allow the solution to cool so that benzophenone deposits as an oil and then crystallizes. Vigorous swirling and the addition of a seed crystal assist the crystallization. Cool the aqueous methanol solution in an ice-bath and filter. Approximately 4.5 g of crude benzopheone should be obtained. The crude material may be recrystallized from aqueous methyl alcohol or from petroleum ether (b. p. 65to 75 C). The recrystallized product will have a m. p. of 46-48 C and weight approximately 3.75 g (which corresponds to a 75% yield).
9 Run a thin-layer chromatogram of the purified product (silica gel, dichloromethane). Record the melting point and run an IR-spectrum of the pure product. Question: 1. Explain what does the phase transfer catalyst do in this experiment. 1-Phenyl-1-penten-3-one Literature: Hünig, Märkl & Säuer, Integriertes Organisches Practicum For the mechanism see for example Clayden, Greeves, Warren and Wothers, Organic Chemistry Reagents Equipment 15.1 g of 2-butanone round-bottomed flask 8.2 ml of freshly distilled magnetic stirrer benzaldehyde separation / extraction 83 ml of 2M NaOH oil pump solid state distillation apparatus suction filtration apparatus In a round-bottomed flask mix 8.2 ml of freshly distilled benzaldehyde (bp. 62 C/10 mmhg), 15.1 g of 2- butanone (bp. 80 C) and 83 ml 2M NaOH. The mixture is stirred vigorously with a magnetic stirrer for 24 h. The Organic phase is separated in a separatory funnel and the water phase is extracted twice with 25 ml of ether. The combined organic phases are washed thoroughly with water until they show a neutral reaction. After drying with Na 2SO 4, most of the ether is evaporated. The residue is purified by distilling in a solid state distillation apparatus in vacuo using an oil pump, the boiling point is expected to be at the region 80-120 C/10-2 mmhg) The distillate is crystallized by the addition of ice cold petroleum ether b(bp. 40-60 C). After the mixture has been stored for one hour in the fridge, the crystalline product is filtered by suction filtration. The yield is recoded to be 62%. Record the melting point and run IR and 1 H NMR spectra of the product.