In the Laboratory
Methylation of Isobutyrophenone Using Potassium Triphenylmethide An Advanced Organic Chemistry Laboratory Experiment Fred J. Matthews Department of Chemistry, Austin Peay State University, Clarksville, TN 37044
Formation of carbon–carbon bonds is of fundamental importance in the syntheses of a variety of organic compounds, including terpenes and steroids. One of the methods available to produce this transformation is the alkylation of ketones, a reaction that is well documented in the chemical literature (1–4). A survey of experiments in organic laboratory texts and this Journal indicates a void in the area of alkylation reactions of simple ketones. This experiment provides a relatively simple procedure to fill this vacancy in the undergraduate organic chemistry laboratory literature. A variety of bases (5–7) have been used to convert ketones into their corresponding enolate anions that may then undergo an SN2 alkylation reaction with alkyl halides to produce new carbon–carbon bonds. Potassium triphenylmethide (tritylpotassium, 1) is a useful base in these reactions for several reasons: it is a strong base with a pKa value of 31.5, it is soluble in inert solvents, it reacts quickly to avoid aldol condensations and is not nucleophilic nor a reducing agent, and the red anion of 1 can be used as an indicator to determine when equivalent amounts of base and ketone have reacted to produce the enolate anion and colorless triphenylmethane. 1) DMSO/Ar or He (g) 2) (C6H5)3CH/DME 3) 40 °C/30 min
KH
– + (C6H5)3C: K
(1)
1
This experiment initially prepares tritylpotassium (1) from potassium hydride (eq 1), then uses base 1 to convert isobutyrophenone (2-methyl-1-phenyl-1-propanone, 2) into the anion and then into pivalophenone (2,2-dimethyl-1-phenyl-1-propanone, 3) (eq 2) (8, 9, and Matthews, F. J.; McDowell, M. V. R.; Huffman, J. W., submitted for publication in J. Tenn. Acad. Sci.). O
O CH(CH3)2
1) 1 / DME
C(CH3)3
(2)
2) MeI 2
3
Students are required to carry out the reactions under an inert atmosphere using a moisture-sensitive reactant and intermediates, to perform a variety of laboratory techniques, and to utilize several methods of analysis. This experiment, which takes 4–5 days, is considered suitable for the advanced organic chemistry laboratory and may be performed by individual students or a small group of students with close supervision.
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Experimental Procedure CAUTION. Potassium hydride1 (KH, 10, 11), lithium aluminum hydride1 (LAH, 12), and calcium hydride1 (CaH2, 11) react with moisture in the atmosphere to form hydrogen gas; contact with water may result in an explosion. Short term exposure of these hydrides to air has not presented a problem in our laboratories; however, it is recommended to use these hydrides in a vented safety hood. CAUTION . Methanol, hexanes, 1,2-dimethoxyethane (DME), and diethyl ether are flammable liquids and should be used in a vented safety hood (12). This experiment does not require flames when these solvents are present. CAUTION. Dimethylsulfoxide (DMSO) is irritating to the eyes, respiratory system, and skin, and is readily absorbed through the skin. Use gloves when handling DMSO and wash hands thoroughly afterwards (11). CAUTION. Methyl iodide is carcinogenic with many potential health problems (12). It should be used in a vented safety hood.
Glassware.2 The distillation of DME from LAH (apparatus A), preparation of base 1 (apparatus B), and alkylation of ketone 2 (apparatus C) must be performed under an inert atmosphere (Ar or He). Stirring is accomplished using magnetic stirring bars and stirring motors. Apparatus A is a single-neck 100-mL round-bottom flask (RBF) fitted with a 50-mL graduated addition funnel that is topped with a condenser containing a gas inlet adapter. Apparatuses B and C are three-necked 100-mL and 50-mL RBF, respectively, with a condenser topped with a gas inlet adapter attached to the central neck of each, and septa secured in the side necks. Each apparatus should be constructed quickly using dry, desiccator-cooled glassware and flushed with inert gas.
Step 1 – Purification and Preparation of Reagents and Solvents Hexanes. A minimum of 150 mL of reagent-grade hexanes (bp 68–72 °C) should be purified by simple distillation through clean oven-dried glassware. The distillate should be collected in a 250-mL RBF, sealed with a lightly greased glass stopper, and stored in a vented safety hood. The distillation forerun may contain the hexane–water azeotrope (bp 61.6 °C). 1,2-Dimethoxyethane (DME).3 To the 100-mL RBF of apparatus A containing 60 mL of DME slowly add small scoops of fresh LAH through a powder funnel until no hydrogen gas bubbles are emitted from the solvent. Reassemble apparatus A, open the stopcock of the addition funnel, place a shield in front of the apparatus, and heat the DME to reflux temperature for a minimum of 30 min. Close
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In the Laboratory the stopcock and collect 45 mL of dry DME (C AUTION: do not distill the DME to dry LAH in order to avoid explosive decomposition of the residual aluminate [13]) 4. Triphenylmethane. A minimum of 15 g of triphenylmethane (mp 94 °C) should be purified by recrystallization. The triphenylmethane is dissolved in methanol (1 g solid/ 15 mL solvent) and filtered, and the solution reduced to twothirds volume using a steam bath or hot-plate. Long white needlelike crystals form upon cooling. Following vacuum filtration, the crystals should be air-dried overnight; further drying under vacuum at room temperature for a minimum of 1 hour is recommended to remove all traces of solvent. Dimethylsulfoxide (DMSO).3 Distill 2 mL of DMSO (bp 189 °C/1 atm) from CaH2 using a 25-mL RBF with a short-path distillation apparatus under vacuum at a temperature below 70 °C. Use a pressure–temperature nomograph (15) to identify an appropriate pressure and temperature for this vacuum distillation. KH Oil-Dispersion (KH-od). The KH-od must be thoroughly mixed prior to step 2. A mechanical shaker is most convenient; other mixing methods include hand shaking or stirring with minimal exposure to the atmosphere. Isobutyrophenone (2). Commercially available isobutyrophenone (2, 10 mL minimum, bp 86 °C/4 mmHg) may be purified, if necessary, by vacuum distillation from a 50-mL RBF using a short-path distillation apparatus.
Step 2 – Preparation of Potassium Triphenylmethide (1) Potassium Hydride (KH). Flush Apparatus B with inert gas using a syringe needle inserted into either septum as a gas exit. Remove the gas exit needle, then lower the 100mL RBF and immediately place a glass stopper into the center neck. Weigh the empty RBF, then use a Pasteur pipet (with the tip removed) to quickly transfer sufficient KH-od to equal 35 mmol of KH;5 remove the glass stopper from the center neck only long enough to make the KH-od transfer. Reweigh the RBF containing the KH-od, then reassemble apparatus B and flush with inert gas (as previously described). Use a 50-mL syringe to add 30 mL of distilled hexanes to the RBF. Stir the mixture thoroughly, allow the solid to settle, and remove the majority of solvent using a syringe with a long needle. 6 Repeat the hexanes washing twice. While stirring the remaining KH slurry, flush apparatus B with inert gas (as previously described) to evaporate all remaining hexanes; the evaporation requires 30–60 min. Disassemble apparatus B as previously described and determine the mass (millimoles) of KH in the RBF. Triphenylmethane/DME Solution. Use the number of millimoles of KH to calculate the mass of one equivalent of triphenylmethane, then weigh a slight excess of triphenylmethane in a single-neck 100-mL RBF. Transfer to the flask 1 mL of dry DME7 for every mmol of triphenylmethane used, seal the flask with a glass stopper, and swirl to produce a homogenous solution. Tritylpotassium (1). Use a 1-mL glass syringe8 to add 5 drops of dry DMSO to the KH in the three-necked 100mL RBF of apparatus B. Bubbles should appear at the surface of the KH. Turn on the magnetic stirrer and slowly add the triphenylmethane/DME solution to apparatus B using a 50-mL glass syringe. Attach water hoses to the condenser and heat the red solution for 30 min at 40 °C.9, 10 Step 3 – Methylation of Isobutyrophenone (2) Methylation. A solution of 1.00 g (6.77 mmol) of freshly distilled 2 in 2.0 mL of dry DME is prepared in apparatus C using a three-necked 50-mL RBF. Turn on the magnetic stirrer and flush the apparatus with inert gas as
described above in step 2. Base 1 is added dropwise using a 25-mL glass syringe with an attached needle; the addition is complete when a red solution persists.10 The red mixture is stirred for 10 min, after which 1.0 mL (16 mmol, 2.4 equiv) of methyl iodide is added in one portion using a 1-mL glass syringe. The opaque white mixture is stirred for 30 min at room temperature and then quenched with 25 mL of distilled water. The reaction mixture is acidified by the dropwise addition of 12 M HCl and extracted three times with diethyl ether (25 mL each), and the combined ethereal extracts are washed with 75 mL of distilled water. The organic layer is dried with anhydrous sodium sulfate, filtered, and concentrated using a rotary evaporator (40 °C, water aspirator). Separation of Pivalophenone (3) from Triphenylmethane. The product mixture contains both pivalophenone (3) and triphenylmethane. The nonpolar triphenylmethane can be separated from polar 3 by three methods: 1. Simple column chromatography11 using silica gel and hexanes eluent will readily separate the triphenylmethane from product 3. Product 3 can then be eluted from the column using a diethyl ether–hexanes solvent system; progress of the chromatographic separation can be followed using silica gel TLC. 2. The insolubility of triphenylmethane in certain solvents (e.g. hexanes) at low temperatures (17) can be exploited to separate the bulk of the triphenylmethane from product 3. 3. Kugelrohr bulb-to-bulb distillation (98 °C/16 mmHg) readily separates product 3 from the triphenylmethane.
Step 4 – Identification of Pivalophenone (3) Product 3 can be readily separated from reactant 2 by GLC using an SE-30 column at 160 °C; 3 should have the longer retention time and this can be confirmed by performing GLC using distilled 2. GC/MS, 1 H-NMR, and 13C-NMR will readily differentiate between the reactant 2 and product 3. Although refractive index and IR for 2 and 3 are similar, these data should be collected to confirm the GC/MS and NMR data.12 Notes 1.Do not extinguish KH- or LAH-induced fires with water, dry chemical, or carbon dioxide fire extinguishers. For KH fires use only class D extinguishers, or smother with dry sand, dry clay, or dry powdered limestone (11). Use only powdered graphite, powdered salt, or powdered limestone to extinguish LAH fires (12). Extinguish CaH2 fires using only class D extinguishers or dry powder (11). For all other chemicals utilized in this experiment, one may use either foam, dry chemical, or water fire extinguishers ( 12). 2. Glassware used for apparatuses A, B, and C and the shortpath distillations of DMSO and 2 should be 14/20 size. The glassware must be cleaned, oven-dried overnight, and cooled in a desiccator to minimize the presence of any moisture. 3. To ensure purity and dryness of the DME and DMSO, the distillates should either be used as soon as possible in step 2 or stored under an inert atmosphere. 4. Destruction of excess LAH may be accomplished by the slow addition of 10% NaOH or NH4Cl to the remaining DME mixture. This process should be performed in a vented safety hood with a shield placed in front of the apparatus. The resulting granular Al 2O3 can be easily separated by filtration (14). 5. It is preferable to weigh the KH-od to provide an approximate mass of dry KH necessary for the formation of base 1, rather than to later transfer the dry, more reactive KH. 6. Destroy the KH in the hexanes wash by slowly adding ethanol to the hexanes mixture in a vented safety hood.
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In the Laboratory 7. DME volume is measured using the 50-mL graduated addition funnel of apparatus A. 8. All glass syringes and accompanying needles must be cleaned, oven-dried overnight, and cooled in a desiccator to minimize the presence of any moisture. 9. Use a 250-mL heating mantle filled with sand to heat the 100-mL RBF containing 1. The temperature may be estimated by submersing a thermometer bulb in the sand. 10. The concentration of 1 produced in step 2 can be determined by (i) titration of a 1-mL aliquot of water-quenched 1 with dilute HCl to a phenolphthalein end-point, (ii) comparison of proton NMR integration of a 1-mL aliquot of D2O-quenched 1 to that of nondeuterated triphenylmethane, or (iii) calculation from volume of 1 required to react with the measured quantity of 2 in step 3. 11. Prepare a slurry pack of silica gel in hexanes (50–100 g of silica gel per gram of product mixture) in a column with a lengthto-diameter ratio of 20:1 ( 16). Collect fractions with volume (mL) equal to mass (g) of silica gel used to prepare the column. Triphenylmethane produces a pink spot on TLC plates developed using iodine; product 3 yields a brown spot. Following elution of the hydrocarbon, volumes (mL) of diethyl ether/hexanes eluent (1:9, 2:8, 4:6, 8:2, then 10:0) equal to twice the mass (g) of silica gel in the column are used to elute product 3. 12. The experiment may be shortened by having the instructor or a laboratory assistant complete step 1, by performing only separation method 2 in step 3, and by conducting only GLC or GC/MS identification in step 4.
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Literature Cited 1. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA, 1972; pp 546–570. 2. Carruthers, W. Some Modern Methods of Organic Synthesis, 2nd ed.; Cambridge University: London, 1978; pp 12–30. 3. Caine, D. In Carbon–Carbon Bond Formation; Augustine, R. L., Ed.; Dekker: New York, 1979; Vol. 1, pp 85–352. 4. March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; pp 416–421. 5. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA, 1972; p 547. 6. Caine, D. In Carbon–Carbon Bond Formation; Augustine, R. L., Ed.; Dekker: New York, 1979; Vol. 1, pp 95–100. 7. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1968; Vol. 1, pp 915–916, 1037–1038, 1069, 1096, 1258, 1259. 8. Huffman, J. W.; Harris, P. G. Synth. Commun. 1977, 7, 137–141. 9. Matthews, F. J. M.S. thesis, Clemson University, May 1980. 10. Lenga, R. E., Ed. The Sigma-Aldrich Library of Chemical Safety Data, 2nd ed.; Sigma-Aldrich: Milwaukee, 1988; Vol. 2, pp 2870–2871. 11. Material Safety Data Sheet; Aldrich Chemical Co.: Milwaukee, 1995. 12. Hazardous Chemicals Data Book; Weiss, G., Ed.; Noyes Data: Park Ridge, NJ, 1980; pp 368, 437, 445, 505, 570, 598, 823, 1094. 13. Material Safety Data Sheet; Fisher Scientific: Fair Lawn, NJ, 1987. 14. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1968; Vol. 1, pp 583–584. 15. Gordon, A. J.; Ford, R. A. The Chemist’s Companion; Wiley: New York, 1972; p 36. 16. Shugar, G. J.; Ballinger, J. T. Chemical Technicians’ Ready Reference Handbook, 3rd ed; McGraw-Hill: New York, 1990; pp 831–832. 17. Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989; pp 1532–1533.
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