33 Part Three Properties and Reactions of Organic Compounds I QUESTIONS 1. Why was it possible to separate the product from sodium hydroxide using acetone? 2. The white solid that remains in the centrifuge tube after acetone extraction fizzes when hydrochloric acid is added, suggesting that sodium carbonate is present. How did this substance form? Give a balanced equation for its formation. Also give an equation for the reaction of sodium carbonate with hydrochloric acid. 3. Draw a mechanism for each of the three steps in the preparation of the 6-ethoxycarbonyl-3,5- diphenyl-2-cyclohexenone. You may assume that sodium hydroxide functions as a base and ethanol serves as a proton source. 4. Indicate how you could synthesis trans-chalcone. (Hint: See Experiment 38). -1 1 L J_ 6..,...,, 1 3 4 35 3 25 2 15 Wavenumbers 1 5 Infrared spectrum of 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone, KBr. EXPERIMENT 4 Enamine Reactions: 2-Acetylcyclohexanone Enamine reaction Column chromatography Keto-enol tautomerism Infrared and NMR spectroscopy Hydrogens on the a -carbon of ketones, aldehydes, and other carbonyl compounds are weakly acidic and are removed in a basic solution (equation I). Although resonance stabilizes the conjugate base A in such a reaction, the equilibrium is still unfavorable becau~e of the high pka (about 2) of a carbonyl compound.
Experiment 4 Enamine Reactions: 2-Acet ylcyclohexanone 331 (1) Typically, carbonyl compounds are alkylated (equation 2) or acylated (equation 4) only with difficulty in the presence of aqueous sodium hydroxide because of more important secondary side reactions (equations 3, 5, and 6). In effect, the concentration of the nucleophilic conjugate base species (A in equation I) is low because of the unfavorable equilibrium (equation 1 ), while the concentration of the competing nucleophile (OH- ) is very high. A significant side reaction occurs when hydroxide ion reacts with an alkyl halide by equation 3 or acyl halide by equation 5. In addition, the conjugate base can react with unreacted carbonyl compound by an aldol condensation reaction (equation 6). Enamine reactions, described in the next section, avoid many of the problems described here. Alkylation R II~ c. II I RCH 2 C-CHR + R-X ~ RCH 2 C-CHR + x- Small amount (2) HO~R_cx ~ ROH+Xlarge amount Competing reaction (3) Acylation R II II~ II I II RCH 2 C-CHR +RC-Cl~ RCH 2 -C-CH-CR +Cl._:...,/' Small amount (4) II ~ II HO~C-C l ~ RC- OH + Cl - large amount Competing reaction (5) Aldol condensation
332 Part Three Properties and Reactions of Organic Compounds FORMATION AND REACTIVITY OF ENAMINES Enamines are prepared easily from c:;arbonyl compounds (for example, cyclohexanone) and a secondary amine (for example, pyrrolidine) by an acid-catalyzed additionelimination reaction. An excess of the amine can be used to shift the equilibrium to the right: An enamine has the desirable property of being nucleophilic (carbon alkylation is more important than nitrogen alkyfation) and is easily alkylated: N Alkylation (minor) q Q A~ ~ R +x- u+ R~x~ u C Alkylation (major) The key point is that the resonance hybrid Bis like the resonance hybrid A shown in equation I. However, B has been produced under nearly neutral conditions so that it is the only nucleophile present. Q Q 6 ~ 6- (B) (A)
Experiment 4 Ena mine Reactions: 2-Acetylcyclohexanone 333 Contrast this situation to the one in equation 1 where hydroxide ion, present in a large amount, produces undesirable side reactions (equations 3 and 5). The alkylation step is followed by removal of the secondary amine by an acidcatalyzed hydrolysis: EXAMPLES OF ENAMINE REACTIONS Alkylation N N 6- RX 6R~6 R Acylation 6=- &II. N II (/ C-R R-C-CI H 2 II or R-C- cl R ~ C-R 6-6 N N II II _,,c, CH2 reaction) CH 2 = CHCOCH 3..._ OCH HiO CH 2 3 w Conjugate addition (Michael 6 CH2 _,,C, 'ch 2 II OCH3
334 Part Three Properties and Reactions of Organic Compounds ROBINSON ANNELATION (RING-FORMATION) REACTION Reactions that combine the Michael addition reaction and aldol condensation to form a six-membered ring fused on another ring are well known in the steroid field. These reactions are known as Robinson annelation reactions. An example is the formation of ~ 1. 9-2-octalone. Michael addition (conjugate addition) 7ccr 8 9~ 2 6 3 1 5 4 /!. " 9-2-ctalone Robinson annelation reactions can also be conducted by enamine chemistry. One advantage of enamines is that the unsaturated ketones are not easily polymerized under the mild conditions of this reaction. Base-catalyzed reactions often give large amounts of polymer. THE EXPERIMENT In this experiment, pyrrolidine reacts with cyclohexanone to give the enamine. This enamine is used to prepare 2-acetylcyclohexanone. Cyclohexanone Q I H Pyrrolidine Enamine
Experiment 4 Enamine Reactions: 2-Acetylcyclohexanone 335 O + N I H H+ 2-Acetylcyclohexanone Required Reading Review: Technique 7 Technique 12 Technique 14 Technique 19 Reaction Methods, Sections 7.1-7.4 Extractions, Separations, and Drying Agents, Sections 12.4 and 12.9 Simple Distillation, Section 14.3 Column Chromatography, Sections 19.6-19.1 Special Instructions Pyrrolidine and acetic anhydride are toxic and noxious. You must measure and transfer these substances in a hood. If you are not careful, the entire room will be filled with vapors of pyrrolidine, and it will not be pleasant to work in the laboratory. The enamine should be made during the first part of the laboratory period and used as soon as possible. Once the acetic anhydride has been added, the reaction mixture must be allowed to stand in your drawer for at least 48 hours to complete the reaction. The second period is used for the workup and column chromatography. The yields in these reactions are low (Jess than 5%), partly due to reduced reaction periods necessary to fit the experiment into convenient 3-hour laboratory periods. Suggested Waste Disposal Dispose of the distillates into the waste container designated for nonhalogenated organic solvents. All aqueous solutions produced in this experiment should be disposed of by pouring them into the container designated for aqueous waste.
336 Part Three Properties and Reactions of Organic Compounds Procedure PART A. PREPARATION OF ENAMINE Running the Reaction. Place 3.2 ml of cyclohexanone (MW = 98.1) into a preweighed 5-ml round-bottom flask and determine the weight of the material transferred. Add 15 ml of toluene to the flask. Place about.1 g of p-toluenesulfonic acid monohydrate in the mixture. In a hood, transfer 4. ml of pyrrolidine (MW= 71.1, d =.85 g/ml) to this flask from a bottle that has been cooled in ice to reduce its volatility. Add a boiling stone and assemble the apparatus shown in the figure. The purpose of the trap is to control the release of pyrrolidine into the laboratory room. Using a heating mantle, heat under reflux for 3 minutes. Distillation. Allow the reaction to cool somewhat and reassemble the apparatus for simple distillation (Technique 14, Figure 14.1, p. 734). Cool the receiving flask Clamp 5-mL roundbottom flask Apparatus for preparing the enamine.
Experiment 4 Ena mine Reactions: 2-Acetylcyclohexanone 337 in an ice bath to prevent the noxious vapors of pyrrolidine from being released into the room. Distill the mixture until the temperature reaches 18-11 ( (boiling point of toluene) and then stop the distillation. At this point, most of the remaining pyrrolidine and water have been removed. The enamine and toluene solvent remain in the distilling flask. Be sure you save this liquid for the next step. Allow the reaction mixture in the distilling flask to cool to room temperature. Remove the flask and prepare 2-acetylcyclohexanone as described in the next section. Proceed to the next step during this laboratory period. Pour the distillate, containing pyrrolidine, toluene, and water, into a suitable waste container. PART B. PREPARATION OF 2-ACETYLCYCLOHEXANONE Running the Reaction. In a hood, dissolve 3.2 ml of acetic anhydride (MW = 12.1, d = 1.8 g/ml) in 5. ml of toluene in a small beaker. Add this solution to the enamine solution contained in the round-bottom flask. Place a glass stopper in the flask, swirl it for a few minutes at room temperature, and allow the mixture to stand for at least 48 hours. Following this period, add 5. ml of water. Attach a condenser and heat the mixture under reflux for 3 minutes. Cool the flask to room temperature. Transfer the liquid to a separatory funnel. Add another 5. ml of water, stopper the funnel, shake it, and allow the layers to separate. The 2-acetylcyclohexane is contained in the upper toluene layer. Remove the lower aqueous layer and discard it. Extraction. Add 1 ml of 6 M hydrochloric acid to the toluene layer remaining in the funnel and shake the mixture to extract any nitrogen-containing contaminants from the organic phase. After allowing the layers to separate, remove the lower aqueous layer and discard it. Finally, shake the organic phase with 5. ml of water, remove the lower aqueous layer, and discard it. Pour the organic layer into a small Erlenmeyer flask and add 1 g of magnesium sulfate to dry the organic phase. When the liquid has become clear, transfer the dried organic phase from the drying agent and place it in a 25-ml round-bottom flask. Set up a simple distillation apparatus and remove most of the toluene (bp 11 C) by distillation. Stop the distillation when the temperature ' goes above 11 c. Pour the distillate containing toluene into a suitable waste con- 11 tainer. Transfer the remaining liquid in the distilling flask into ~ /du-/,,.,. Evaporate the toluene in a water bath afdbe.ut 7 C, using a stream of dry air dr ~ -v4~ nitrogen. Watch the liquid carefully during this procedure or your product may evapo- ~;J!y~q rate. When the toluene has all been removed, the volume of liquid will remain constant (2-2.5 ml). Save the yellow liquid residue for purification by column chromatography. ~C{ A Column Chromatography. Prepare a column for column chromatography using '--f-" a 2-cm length of 1-mm glass tubing with a constriction at one end (Technique 19, Section 19.7, p. 88). Place a piece of cotton in the column and gently push it into the constriction'. Pour 5. g of alumina slowly into the column while t apping the column constantly with a pencil or finger. 1 Obtain about 2 ml of methylene chloride. Use the methylene chloride to prepare the column, dissolve the crude product, and elute the purified product as described in the next paragraph. 1 Alumina: EM Science (No. AX 612-1 ). T he particle sizes are 8-2 mesh, and the material is Type F-2.
338 Part Three Properties and Reactions of Organic Compounds Dissolve the crude product in 2.5 ml of methylene chloride. Clamp the column above a 5-ml Erlenmeyer flask. Using a Pasteur pipet, add about 5 ml of the methylene chloride to the column and allow it to percolate through the alumina. Allow the solvent to drain until the solvent surface just begins to enterthe alumina. Add the crude product to the top of the column and allow the mixture to pass onto the column. Use about 5 ml of methylene chloride to rinse the centrifuge tube that contained the crude product. When the first batch of crude product has drained so that the surface of the liquid just begins to enter the alumina, add the methylene chloride rinse to the column. When the solvent level has again reached the top of the alumina, add more methylene chloride with a Pasteur pi pet to elute the product into the flask. Continue adding methylene chloride to the column until all the colored material has eluted off the column. Collect all the liquid that passes through the column as one fraction. Evaporation of Solvent. Preweigh a 15-ml centrifuge tube and transfer about half the liquid in the Erlenmeyer flask to the tube. Place the centrifuge tube in a warm water bath (about 5 () and evaporate t he methylene chloride with a light stream of air or nitrogen in a hood until the volume is about 3 ml. Transfer the remaining liquid in the Erlenmeyer flask to the c~ntrifuge tube and continue evaporating the methylene chloride to give the 2-acetylcyclohexanone as a yellow liquid. When the solvent has been removed, reweigh the tube to determine the weight of product. Calculate the percentage yield (MW = 14.2). At the option of the instructor, determine the infrared spectrum and/or the NMR spectrum. The NMR spectrum may be used to determine the percentage enol content for 2-acetylcyclohexanone. This compound is highly enolic, giving calculated values between 25 % and 7%. The enol content depends upon the time delay between when the compound was synthesized and when the enol content is measured. Solvent effects also influence the enol content. Submit the remaining sample to the instructor in a labeled vial with your laboratory report. Note: The percentage enol content can be calculated using the 6- MHz NMR spectrum reproduced in this experiment. The offset peak is assigned to the enolic hydrogen (integral height, 1 mm). The remaining absorptions at 1.5-2.85 ppm (integral height, 155 mm) are assigned to the 11 protons remaining in the enol structure and the 12 protons in the keto structure. Thus, 11 mm (1 x 11) of the 155-mm integral height is assigned to the enol structure. Eno I % = 11/155 = 71; keto % = 451155 = 29. At 3 MHz, one can integrate the enol hydrogen at 16 ppm and compare it to the methyl hydrogens at 2.15 ppm. At 6 MHz, the methyl groups are not clearly resolved. REFERENCES Augustine, R. L., and Caputa, J. A. "Ll 1. 9-2-ctalone." Organic Syntheses, Coll. Vol. 5 ( 1973): 869. Cook, A. G., ed. Enamines: Synthesis, Structure, and Reactions. New York: Marcel Dekker, 1969. Dyke, S. F. The Chemistry of Ena mines. London: Cambridge University Press, 1973.
Experiment 4 Enamine Reactions: 2-Acetylcyclohexanone 339 Mundy, B. P. "The Synthesis of Fused Cycloalkenones via Annelation Methods." Journal of Chemical Education, 5 ( 1973): 11. Stork, G., Brizzolara, A., Landcsman, H., Szmuszkovicz, J., and Terrell, R. "The Enamine Alkylation and Acylation of Carbonyl Compounds." Journal of the American Chemical Society, 85 ( 1963): 27. l.j_ }_ --j_..;_ I -+-- 1--r-- I _... 1_, - '- --+--. 1 -t -,-t- 4 35 3 25 2 15 Wavenumbers 1 Infrared spectrum of 2-acetylcyclohexanone. 8. 7. 6. 5. 4. 3. 2. 1. ppm(&) NMR spectrum of 2-acetylcyclohexanone, CDCl 3, offset peak shifted by 5 Hz.