Exp t 435 Enamine Reactions 2 Acetylcyclohexanone st Adapted by R Minard and M DeGrazia from Pavia P D Lampman G M Kritz G S Organic Laboratory Techniques 1 ed Harcourt Brace Company 1998 Introduction Hydrogens on the a carbon of ketones aldehydes and other carbonyl compounds are weakly acidic and are removed in a basic solution Equation 1 Although resonance stabilizes the conjugate base A in such a reaction the equilibrium is still unfavorable because of the high pKa about 20 of a carbonyl compound O R R OH R R R O R O A H2O 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 1 is low because of the unfavorable equilibrium Equation 1 while the concentration of the completing 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 O R R R X R X R 2 O Small Amount HO R X ROH Competing Reaction X Large Amount Acylation O R R HO O O R O O Cl R Cl 4 R R O R Cl 3 R Cl OH Competing Reaction 5 Large Amount Adol condensation R O R R O R R O R R O R R OH R R O R 6 Formation and Reactivity of Enamines Enamines are prepared easily from carbonyl compounds for example cyclohexanone and a secondary amine for example pyrrolidine by an acid catalyzed addition elimination reaction An excess of the amine can be used to shift the equilibrium to the right O H H N HO N H H N H H H2 0 Enamine An enamine has the desirable property of being nucleophilic carbon alkylation is more important than nitrogen alkylation and is easily alkylated N N N R R X X N R X N Alkylation minor X C Alkylation major The key point is that the resonance hybrid B is like the resonance hybrid A shown in Equation 1 However B has been produced under nearly neutral conditions so that it is the only nucleophile present N O N O R R R R B A 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 acid catalyzed hydrolysis N R O H H2O R H N Examples of Enamine Reactions N O H2 O N RX R R O N R Cl N O H2 O O Alkylation O C R R Acylation O N O N O O O H2 O H O O HX 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 Michael addition O O O base O O O H O Aldol condensation O O O O base O O 1 H 2 H 2O 8 1 5 4 O 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 Pre lab Question 1 The enamine formed from pyrrolidine and 2 methylcyclohexanone has the A structure What reason can you give for the less substituted enamine being formed instead of the more substituted enamine B N N CH3 CH3 H A B The Experiment In this experiment pyrrolidine reacts with cyclohexanone to give the enamine This enamine is used to prepare 2acetylcyclohexanone O H N SO3H N p Toluenesulfonic acid Cyclohexanone Pyrrolidine N O Enamine O N O Acetic anhydride O O N O H O 2 O 2 Acetylcyclohexanone Precautions and 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 work up and column chromatography The yields in these reactions are low less than 50 partly due to reduced reaction periods necessary to fit the experiment into convenient 3 hour laboratory periods Procedure Part A Preparation of the Enamine Obtain a 14 20 50 mL round bottom flask a 14 20 condenser and a microscale distillation kit from the stockroom Place 3 2 mL of cyclohexanone into a preweighed 50 mL round bottom flask and determine the weight of the material transferred Add 15 mL of toluene and a stir bar to the flask clamp the flask in a heating mantle no sand above a magnetic stirrer Place about 0 1g of ptoluenesulfonic acid monohydrate in the mixture In your hood transfer 4 0 mL of pyrrolidine to this flask using a 1 mL pipettor 4 times Attach the water condenser Move the apparatus to the back of the hood to minimize pyrrolidine vapors from entering the lab Using a heating mantle heat under reflux for 30 minutes with stirring Purification by Distillation Allow the reaction to cool somewhat and assemble a simple distillation by inserting the microscale distillation head Cool the receiving flask in an ice bath to prevent the noxious vapors of pyrrolidine from being released into the room Distill the mixture until the temperature reaches 108 to 110 C 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 2acetylcyclohexanone 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 in your hood Rinse out flask in hood drain Part B Preparation of 2 Acetylcyclohexanone Dissolve 3 2 mL of acetic anhydride in 5 0 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