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    Ep Oxidation

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    Calvin Syw
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    COATS Diastereospecific Synthesis of an Epoxide An Introductory Experiment in Organic Synthetic and Mechanistic Chemistry James A. Ciaccio Fordham University, Bronx, NY 10458 ‘The role of epoxides as a synthetically useful class of ‘compounds has been widely established (7, 2), and epoxide chemistry is presented in all modern undergraduate or- ‘ganic textbooks, However, neither their reactions nor their Preparation are common subjects of undergraduate or- {ganic laboratory experiments.’ This paper describes an op- rationally straightforward, two-step epoxide synthesis, that ean be presented to students in the form of two ‘mechanistic “puzzles” that probe the stereoselectivity of ‘two important reactions: halohydrin formation from alke- res and epoxide formation via intramolecular Williamson ‘ther synthesis, It complements the increasing number of puzzle-oriented undergraduate experiments combining synthesis and mechanistic discovery that continue to ap- pear in this Journal (4). ‘Alkenes are the most common starting material for the preparation of epoxides, Treatment of an alkene with aqueous N-bromosuccinimide (NBS) affords a bromohy- drin (1) that, upon treatment with base, eliminates HBr to {form an epoxide (2) via intramolecular nucleophilic substi- ‘ution (eq 1). base ‘The first question posed to the student asks whether or not the bromohydrin formation is stereoselective. In the present experiment, ¢rans-stilbene (3) is treated with NBS ‘and Hy0 in dimethyl sulfoxide (DMSO) (eq 2) to afford one of two possible diastereomers: + erythro 2-bromo-12-diphenylethanol (0, mp 83-84°C 6) 1+ threo bromo-,2-diphenvlethanal(S),mp 61-52°C (6)(eq2) Ho Pt wes.Ho Spe Hy o=C owso” eH Hep on py DMSO” pt . mg 3 a 5 @ [Because the melting point ranges for the two possible dias- tereomeric products are separated by 30 °C, only a melting- “There are suprisingly few pubished undorgradua involving epoxides, daspte thor extensive use in research (1). For texample, searching through issues of this Joural dating trom 1989 to the presen, | found only si undergraduate experiments () that involve etter the preparation 0” reaction of epoxies. point determination is noeded to establish that the product is the erythro bromohydrin (4) (Analogously the threo bro- mohydrin (5) can be prepared from cis.stilbene (6) "The second question asks whether the nucleophilic dis placement of bromide that occurs when 4 is treated with base proceeds with inversion of configuration, to afford (b-trans-stilbene oxide (6) (mp 65-87 °C), or with reten- tion of configuration, to afford (+-cis-stilbene oxide (7) (mp 38-40 °C) (eq 3). Again, the diastereospecificty of the reac- tion can be established simply by determining the melting- point range of the product. oH Pr 2 9g HER RO eouen of He OH preg COHORT pH pen 4 6 7 ® Experimental Procedure '* Caution: Students should be required to wear gloves when ‘working with either NBS or DMSO because bth are skin lrrwante ‘This experiment was carried out by 62 students enrolled in the first-somester organic chemistry laboratory course at Fordham University. A single 4-h lab period was sched- uled for the synthesis and isolation of the crude bromoby’ din, and the crystallization was carried out as an addi- tional task along with the following week's experiment. ‘The conversion of the bromohydrin to epoxide was carried out by 11 students during an additional 2-h period. ‘All the reagents for this experiment were used as re- ceived from the supplier (Aldrich) without additional puri- fication, TLO analyses were carried out using Hard Layer Siliea Gel GHLF Uniplates with inorganic binder (Anal- tech). The protocol for the bromohydrin synthesis was adapted from a procedure reported by Langman and Dal- ‘ton in Organic Syntheses (5). Synthesis of (:}-erythro-2-Bromo-1,2-diphenylethanol (4) trans-Stilbene (1.0 g, 5.5 mmol) was placed in a 50-mL Erlenmeyer flask followed by water 10.5 mL! and DMSO (15 mL) to afford a clear, colorless solution. Additional DMSO may be added or the solution may be warmed over 1 steam bath to dissolve the alkene. Students then treated the DMSO solution of the alkene at room temperature with 2 molar equivalents of NBS (requiring a calculation ‘on their part) in small portions over several minutes, "The resulting clear, bright-orange solution was gently swirled over 30 min, then poured into a large beaker con- taining 50 mi. of ice-cold water. The resulting milky white slurry was transferred to a separatory funnel where it was diluted with 20 mL. of water and extracted with 40 mL of ‘diethyl ether. Any undissolved solid was removed by vac- Volume 72 Number 11 November 1995 1037 vum-fltering the contents of the separatory funnel through a thin layer of Celite. Enough ether may evapo- rate during vacuum filtration to cause the product to pre- cipitate, and some students had to add more ether to redis solve it ‘The layers were then separated, and the aqueous layer ‘was extracted with an additional 30 mL of ether. The com- bined ether layers were washed once with 50 mL of water, once with 50 ml. of saturated brine, dried over anhydrous ‘MSOs, and gravity-filtered into’a 100-mL round-bot- tomed flask, Because our labs are not equipped with rotary evaporators, the ether was removed by simple distillation until less than 5 ml remained in the pot. Removal of Solvent ‘The remaining solvent was removed as follows. Once cooled to room temperature, the distillation apparatus was disassembled, and a ground-glass thermometer adapter ‘was connected to the pot. The narrow tip of a medicine Gropper was inserted through the rubber portion of the adapter, and the other end was connected by vacuum tub- ing toa water aspirator via a water trap. The vacuum was slowly applied to full strength while gently swirling the flask. The average yield of erude erythro-2-brome-1,2- Giphenylethanol students received was approximately 1.0 (66% yield); if earried out carefully, yields approaching 1 g can be obtained. Reerystalization from a minimum amount (20-40 mL) of high-boiling petroleum ether af- forded an average recovery of 0.37 g (24% yield); melting points ranges were nearly all around 81-82 °C (83-84 °C Tit), Invariably, @ small amount of solid remained undis- solved during the reerystallization, and hot filtration or de- canting the hot solution was often necessary. Students should be warned of this undissolved solid in advance so they would avoid treating the crude bromohydrin with Wo much petroleum ether ‘Synthesis of (t)-trans-Stlbene Oxide (6) ‘The dry, purified bromohydrin (150 mg, 0.54 mmol) was placed in a 20 x 150-mm test tube followed by anhydrous po- tassium carbonate (125 mg, 0.90 mmol, powder, ~825 mesh) and methanol (2 mL). The resulting turbid solution was mixed at frequent intervals by vigorously agitating the corked tube. TLC on silica gel (elution with 20:1 (vx) petro- Jeum ether: ethyl acetate) of an aliquot taken directly from, the reaction mixture after approximately 6 min clearly re- vealed spots at R 0.85 (epoxide) and Ry 0.20 (bromohydrin), Both spots are visible under UV light and ean also be visual- ized by briefly submerging the platein a 20% solution of phos- ‘phomolybdic acid in ethanol (Aldrich) followed by heating the plate with a heat gun or hy placing the glass TLC plate face ‘up on a hot plate standing in the hood, ‘When the reaction was complete by TLC, 3 mLof water was added to the tube followed by 7 mL of petrcleum ether. (When, diethyl ether was used to isolate the epoxide from the reac- tion mixture after water treatment, a small amount of water ‘was extracted along with the epoxide, affording a damp prod: ‘uct upon removal of solvent. Extraction of the epoxide into petroleum ether avoided that problem), ‘The layers were then thoroughly mixed by rapidly and repeatedly drawing them into a long Pasteur pipet and re- Teasing them back into the tube. The top, organic layer con- taining the epoxide was then transferred to a second 20 x 150-mm test tube using a Pasteur pipet and treated with anhydrous MgSOs. After filtering away the drying agent, the solvent was removed under vacuum to afford trans” stilbene oxide in an average yield of 60 mg (55%); reerys- tellization was unnecessary because the melting point ranges of the crude epoxide samples were all around 64-65, °C (65-67 °C lit 1038 Jounal of Chemical Education Results and Discussion Both reactions are diastereospecifi, affording accept- able yields of solid products whose melting points are ‘widely different from their respective diastereomers, The students experienced little difficulty in carrying out either of the preparations, so all of them correctly identified the bromohydrin as ()erythro-2-bromo-1,2-diphenylethanol (4) and the epoxide as (t-trans-stilbene oxide '6) by virtue of their products’ melting-point ranges and, for the epox- ide, "H_ NMR analysis in comparison with’a commercial sample of 6, The majority of erude bromohydrin samples were somewhat impure (melting-point ranges varied from 78-79 °C to 55-61 °C) due to the presence of DMSO and possibly some unreacted 3. Vigorous washing of the combined ether iayers with water before treatment, with MgSOs was effective in re- ‘moving essentially all of the DMSO. Apparently. most stw- dents wore a bit careless in recrystallizing their erude bro- mohydrins (the average percentage recovery was 37%); if carried out carefully, up to 70% of the original mass can be recovered. The more assiduous students concentrated down their mother liquors and obtained 50 mg or more of comparatively pure bromohyéirin as second crop. TLC Monitoring ‘The progress of the epoxide formation is easily moni tored by TLC analysis. The reaction is usually complete within 10-16 min, giving the student enough time to carry. ut a single analysis before all of the bromohydrin is con- sumed, The R/s of the bromohydrin and epoxide are far enough apart to allow an easy distinction, and students were instructed to co-spat the reaction mixture aliquot, along with their bromohydrin and a commercial sample of 6 on the same plate in order to identify the spots. NMR as a Stereochomical Probe In order to rigorously establish the relative stereochemis- tuy of the epoxide, students obtained HNMR spectra oftheir products on a Varian EM-360 60-MHe instrument, under the supervision of an instructor who prepared their samples. Be- cause the epoxide protons are homotopic and the chemical shifts of the pheny! protons are fortuitously equivalent, the NMR spectrum consists of two singlets, The chemical shift of the epoxide-ring protons are the most diagnostic feature; the trans epoxide protons appear at 3.85 ppm, whereas the cis, epoxide protons appear at 4.35 ppm. Further analysis using “C NMR would serve notonly as another stereochemical probe (the epoxide earbons of 6 ap- pear at 63 ppm, whereas those of 7 appear at 60 ppm) but also as an excelient example of the effect of molecular sym- metry on C spectra. Students should try to explain why their 14-carbon bromohydrin, which has 10 peaks in its SC NMR spectrum, affords # 14-carbon epoxide with only five "¥C peaks. It is not necessary for students to obtain spectra of the cis epoxide themselves because they appear (along with that pf the trans epoxide) in The Aldrich Li brary of °C and 'H FENMR Spectra, Course Convenience ‘This ‘project” is particularly suited to a large lab course. + Both stops can be run on a very small scale, reducing mate rial costs and increasing lab safety + Common lab glassware and equipment are used ‘No sophisticated instrumentation is needed; melting point

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