Supplemental Materials
`
`Mannich Reactions in Room Temperature Ionic Liquids (RTILs): An
`Advanced Undergraduate Project of Green Chemistry and Structural
`Elucidation
`
`Kendrew K. W. Mak*, Jane Siu, Y. M. Lai, and Pak-kei Chan
`
`Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong
`SAR, PRC.
`
`*kendrewmak@cuhk.edu.hk
`
`
`Table of Contents
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`Page
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`1. Experimental Procedure (Student Handouts)
`
`2.
`
`Instructor’s Notes
`
`3. List of Chemicals
`
`4. Spectra
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`2
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`10
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`22
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`23
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`1
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`Liquidia's Exhibit 1026
`IPR2020-00770
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`

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`Mannich Reactions in Room Temperature Ionic Liquids (RTILs): An
`Advanced Undergraduate Project of Green Chemistry and Structural
`Elucidation
`
`
`
`Student Handouts
`
`
`Background
`
`Chemists have been painstakingly searching for the ultimate solvent for organic
`
`reactions that possesses the following criteria: good chemical and thermal stabilities, low
`vapor pressure, low toxicity, high fluidity, wide liquidus range, good solubility for a wide
`range of organic and inorganic reagents, and are readily recyclable. Recent research has
`shown that room temperature ionic liquids (RTILs) are potentially promising recyclable
`replacements for traditional volatile organic solvents for organic reactions (1-5). RTILs
`are ionic compounds that exist in their liquid state at ambient temperature (6). These
`substances are usually composed of large organic cations having bulky substituents, or
`have the positive charge delocalized over a number of atoms (Figure 1). The bulkiness
`of the cations weakens the electrostatic attractions between the ions and therefore the
`melting points are significantly lowered. Table 1 lists the melting points of some
`commonly used ionic liquids. Ionic liquids are considered “designer solvents” because
`ideally one can get a particular ionic liquid having the desired properties by making the
`right choices for the cation and anion.
`
`
`+
`
`N
`
`R1
`
`N
`
`R2
`
`R2
`N+
`
`R3
`
`NR+
`
`R1
`R1
`R4
`R4
`Imidazolium
`Pyridinium
`Ammonium
`Phosphonium
`
`Figure 1. Some examples of cations commonly used for synthesizing ionic liquids.
`
`
`R2
`P+
`
`R3
`
`
`
`2
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`m.p. (oC)
`6
`
`-
`
`
`Ionic liquid
`
`N
`
`+
`
`H3C
`
`N
`
`+
`
`N
`
`H3C
`
`BF4
`C2H5
`
`N
`
`
`CF3SO3
`C2H5
`
`-9
`
`-
`
`
`ref
`7
`
`7
`
`Ionic liquid
`
`N
`
`+
`
`N
`
`H3C
`
`N
`
`+
`
`N
`
`H3C
`
`-
`
`BF4
`C4H9
`
`
`
`-
`
`PF6
`C6H13
`
`
`
`m.p. (oC)
`-81
`
`-61
`
`ref
`8
`
`8
`
`N
`
`+
`
`N
`
`-
`
`7
`
`7
`
`
`
`
`
`AlCl4
`
`C2H5
`H3C
`Table 1. The melting points of some commonly used ionic liquids
`
`The Mannich reaction is a three-component condensation reaction in which a
`
`compound having active hydrogen atoms reacts with an aldehyde and an amine under
`either acidic or basic conditions (9-10). The product is a beta-amino-carbonyl
`compound if the active-hydrogen bearing substrate is a ketone (Figure 2). A general
`mechanism for the acid-catalyzed Mannich reaction is depicted in Figure 3 (11). It is
`frequently used for the synthesis of pharmaceuticals and natural products such as
`alkaloids, steroid hormones, antibiotics, and vitamins (9).
`
`
`O
`
`R1
`
`H
`
`+
`
`NH3
`(or derivatives)
`
`O
`
`+
`
`R2
`
`R3
`
`H+ or OH-
`
`ketone
`aldehyde
`Figure 2. The Mannich reaction
`
`
`R1
`
`O
`
`H2N
`
`R2
`
`R3
`β-aminoketone
`
`O
`
`(ketone)
`
`H3C
`
`R"
`
`+ R'2NH
`
`O
`
`R
`H
`aldehyde
`
`R
`
`OH
`
`H
`NR'2
`
`H+
`- H2O
`
`+
`
`NR'2
`R
`H
`iminium ion
`
`OH
`
`(enol)
`
`H2C
`
`R"
`
`NR'2
`
`OH
`
`- H+
`
`NR'2
`
`O
`
`R
`
`R"
`
`R
`R"
`the Mannich product
`
`(beta-aminoketone)
`Figure 3. The mechanism of the Mannich reaction in acidic conditions
`
`
`
`
`3
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`In this project you will carry out the following investigations:
`
`(a)
`
`tetrafluoroborate,
`the RTIL 1-butyl-3-methylimidazolium
`Synthesis of
`[bmim][BF4], by the quaternization of 1-methylimidazole with 1-chlorobutane,
`followed by the anion-exchange reaction of the resulting [bmim][Cl] with
`NaBF4 (Figure 4).
`(b) Determine the activity of [bmim][BF4] for the Mannich reaction (Figure 4),
`and recover the RTIL.
`(c) Determine the activity of the recovered RTIL.
`(d) Compare the activity of the RTIL with the traditional organic solvent.
`(e)
`Identify the structure of the product obtained from the Mannich reaction from
`the reaction mechanism and spectroscopic data.
`
`
`
`
`
`
`Synthesis of the ionic liquid - [bmim][BF4]
`
`N
`
`N
`
`Cl
`
`CH3CN,
`80 oC, 48 h
`
`+
`
`N
`
`Cl-
`N nBu
`
`NaBF4
`H2O,
`r.t., 1.5 h
`
`1-methylimidazole
`
`[bmim][Cl] (1)
`
`+
`
`N
`
`-
`
`BF4
`N nBu
`
`[bmim][BF4] (2)
`
`Mannich reaction in ionic liquid
`
`O
`
`H
`
`+
`
`2
`
`O
`
`+ NH4OAc
`
`[bmim][BF4]
`30 oC, 24 h
`
`the product
`
`3
`
`* [bmim]+ = 1-butyl-3-methylimidazolium cation
`
`Figure 4. Synthesis of [bmim][BF4] and the Mannich reaction of benzaldehyde,
`3-pentanone and ammonium acetate in [bmim][BF4]
`
`
`Experimental Procedure
`
`A1. Synthesis of 1-butyl-3-methylimidazolium chloride, [bmim][Cl] (1) (12, 13)
`
`Caution: The experiment should be carried out in a well-ventilated fume hood.
`Acetonitrile, 1-chlorobutane and ethyl acetate are highly flammable and
`should be kept away from ignition sources. 1-Methylimidazole is corrosive
`and acetonitrile is toxic. Put on proper protective gloves and safety goggles.
`
`
`
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`Students must be very careful and under the supervision of experienced
`instructors when operating vacuum manifolds. Liquid nitrogen may cause
`severe cold burns in contact with skin. Proper protective gloves (e.g.
`Cryo-gloves from Aldrich) must be worn. Furthermore, liquid nitrogen is an
`asphyxiant and should be used in a well-ventilated area.
`
`
`
`All glassware must be dried thoroughly. To a 100-mL round-bottomed flask add
`10.0 g of 1-methylimidazole (122 mmol), 14.66 g of 1-chlorobutane (158 mmol) and 6.5
`mL of acetonitrile. Fit a water-condenser to the RB flask. Protect the reaction mixture
`from moisture and oxygen by a slow stream of nitrogen.1 Heat the reaction mixture
`under gentle reflux (ca. 80 °C) with stirring for 48 hours. Cool the mixture to room
`temperature and remove the residual starting materials by washing it three times with
`ethyl acetate: add 20 mL of ethyl acetate to the reaction mixture, stir the mixture
`vigorously for 1-2 min and allow the layers to separate. Ethyl acetate is immiscible with
`[bmim][Cl] and appears as the upper layer. Remove the upper layer carefully by
`decantation or with a dropper. Remove the residual volatile organic substances under
`reduced pressure (0.1 mmHg) at 60 °C for 10 minutes.2 The product is a low-melting
`white solid (m.p. 66-67 °C) and can be used to synthesize [bmim][BF4] without further
`purification.
`
`Notes:
`1.
`This can be accomplished by connecting the upper
`opening of the water condenser to a nitrogen inlet
`adapter. (See the figure). The nitrogen inlet
`adapter should be connected to (or integrated with)
`a bubbler filled with paraffin oil to regulate the
`internal pressure and ensure the gas flow is
`unidirectional.
`
`
`
`2.
`
`Liquid nitrogen cold traps must be used to condense the volatile substances and protect the
`vacuum-manifolds system from being contaminated.
`
`
`
`
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`A2. Synthesis of 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim][BF4] (2)
`(12, 13)
`
`
`Caution: Sodium tetrafluoroborate is corrosive and proper protective gloves should be
`worn. Dichloromethane is highly volatile and should be handed with care in
`a fume hood.
`
`
`
`Prepare an aqueous solution of sodium tetrafluoroborate (13.4 g, 122 mmol) in
`deionized water (48 mL) and add it slowly to the reaction product obtained from Part
`A1.3 Stir the mixture at room temperature for 1.5 hours. Remove water from the
`heterogeneous mixture4 by rotary evaporation and then under high-vacuum (0.1 mmHg)
`at 80 °C. To remove the co-product NaCl and residual water from the mixture, dilute
`the ionic liquid with 25 mL of CH2Cl2 and add 8.0 g of anhydrous MgSO4. Stir the
`mixture at room temperature for 10 minutes and filter the mixture. After concentrating
`the filtrate by rotary evaporation or under reduced pressure (0.1 mmHg) at 35 – 40 °C
`until constant weight, the ionic liquid [bmin][BF4] will be obtained as a light yellow
`viscous oily liquid. The ionic liquid obtained is sufficiently pure for use and further
`purification is not necessary.
`
`Notes:
`3. Aqueous solutions of sodium tetrafluoroborate react slowly with glass. Avoid prolonged storage of
`an aqueous NaBF4 solution in a glass container.
`4. Although the ionic liquid [bmim][BF4] is miscible with water, the NaCl present in the aqueous
`solution causes “salting-out” effects and therefore a two-phase liquid mixture is obtained.
`
`
`B. Mannich reaction of benzaldehyde, 3-pentanone and ammonium acetate in
`[bmim][BF4], and the recovery of the RTIL (14)
`
`
`Caution: 3-Pentanone and diethyl ether are highly flammable, and should be kept away
`from ignition sources. Both benzaldehyde and 3-pentanone are irritants, and
`exposure by inhalation or skin contact should be avoided.
`
`
`
`To a 25-mL round-bottomed flask add freshly purified benzaldehyde5 (2.12 g, 20
`mmol), 3-pentanone (0.861 g, 10 mmol), ammonium acetate (0.771 g, 10 mmol), and
`[bmim][BF4] (2.5 g). Stopper the flask and stir the mixture in a water bath at 30 °C for
`24 hours, and a white powdery precipitate will form gradually. To work-up the mixture,
`
`
`
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`dilute it with 20 mL of deionized water and stir the suspension for 5 minutes. Collect
`the white precipitate by vacuum filtration. Save the filtrate for recovering the ionic
`liquid. Purify the crude product by recrystallization from hot ethanol (ca. 15-20 mL)6
`and collect the product by vacuum filtration.
`
`
`To recover the ionic liquid, transfer the mother liquor collected from the reaction
`mixture into a separatory funnel and extract it with diethyl ether three times to remove
`the residual organic substances. Collect the aqueous solution and concentrate it by
`rotary evaporation and then under reduced pressure (0.1 mmHg) at 80 °C.
`
`Notes:
`5. Benzaldehyde undergoes slow air oxidation and should be freshly purified. It can be done by
`extracting benzaldehyde three times with a 10% aqueous Na2CO3 solution, drying it over anhydrous
`MgSO4, and filtering the mixture.
`6. The crude product may contain some unidentified white insoluble powdery impurities. To remove
`the insoluble impurities, either filter the hot ethanolic solution carefully by gravity filtration, or decant
`the mixture to collect the clear supernatant liquid.
`
`
`C. Determination of the activity of the recovered RTIL
`
`
`
`
`Repeat the Mannich reaction twice using the recovered RTIL, and compare the
`reaction yields among the three reaction cycles.
`
`D. Comparing the activity of the RTIL with a traditional organic solvent
`
`
`To a 25-mL round-bottomed flask add freshly purified benzaldehyde5 (2.12 g, 20
`mmol), 3-pentanone (0.861 g, 10 mmol), ammonium acetate (0.771 g, 10 mmol), and
`ethanol (2.5 mL). Stopper the flask and stir the mixture at room temperature for 24
`hours. Add 20 mL of deionized water and stir the suspension for 5 minutes. Collect
`the white precipitate by vacuum filtration and purify
`the crude product by
`recrystallization from hot ethanol (ca. 15-20 mL). Compare the reaction yield with that
`obtained from [bmim][BF4].
`
`
`
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`E. Structural identification of the reaction product
`
`
`Propose a detailed mechanism for the Mannich reaction and predict the molecular
`structure for the product. Pay attention to the relative amounts of the reagents used
`when you work out the reaction mechanism.
`
`Obtain the 1H NMR, 13C NMR and mass (both low resolution and high resolution)
`spectra for the recrystallized Mannich reaction product. Ask the laboratory technician
`for assistance since you are probably not very familiarized with the operation of these
`instruments. Analyze the spectra and use the spectroscopic data to support your
`proposed product structure. Assign the signals for the 1H and 13C NMR spectra.
`
`
`The Mannich reaction that you have carried out is a stereoselective reaction (16).
`Make use of the 1H NMR spectrum to identify the stereochemistry of the product.
`Briefly explain the observed stereochemistry in terms of the reaction mechanism.
`
`
`Sample Preparation for the NMR Experiment: Prepare the sample solution by
`dissolving about 10-15 mg of the recrystallized product in 0.6 mL of CDCl3 in a 5 mm
`NMR tube. (Wilmad-528-PP or Wilmad-507-PP).
`
`Project Report
`
`
`
`In the project report you should explain in detail how the molecular structure of the
`Mannich product is proposed from the reaction mechanism and the spectroscopic data.
`You are also required to write a discussion on the current developments in using RTILs
`as the reaction media for organic reactions, and compare the advantages and
`disadvantages of using these newly developed reaction media. Search the recently
`published scientific literature for the most up-to-date information for the discussion.
`
`Literature Cited
`
`1. Hu, A.; Ngo, H. L.; Lin, W. Angew. Chem. Int. Ed. 2004, 43, 2501-2504.
`2. Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667-3692.
`3. Welton, T. Chem. Rev. 1999, 99, 2071-2084.
`4. Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000, 39, 3772-3789.
`5.
`Ionic Liquids in Synthesis; Wasserscheid. P., Welton, T., Eds.; Wiley-VCH:
`
`
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`Weinheim, 2003.
`6. Adams, D. J.; Dyson, P. J.; Tavener, S. J. Chemistry in Alternative Reaction Media;
`John Wiley & Sons: West Sussex, 2004; pp. 75-94.
`7. Bonhôte, P.; Dias, A.-P.; Papageorgiou, N.; Kalyanasundaram. K.; Grätzel, M. Inorg.
`Chem. 1996, 35, 1168-1178.
`8. Suaraz, P. A. Z.; Einloft, S.; Dullius, J. E. L.; de Souza, R. F.; Dupont, J. J. Chim.
`Phys. 1998, 95, 1626-1639.
`9. Tramontini, M.; Angiolini, L. Mannich Bases: Chemistry and Uses; CRC Press:
`Florida, 1994.
`10. (a) Kleinman, E. F. The Bimolecular Aliphatic Mannich and Related Reactions. In
`Comprehensive Organic Syntheses, Vol.2; Trost, B. M., Flaming, I., Eds.; Pergamon
`Press: Oxford, 1991, pp 893-951. (b) Heaney, H. The Bimolecular Aromatic
`Mannich Reaction. In Comprehensive Organic Syntheses, Vol.2; Trost, B. M.,
`Flaming, I., Eds.; Pergamon Press: Oxford, 1991, pp 952-973.
`11. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th
`ed.; Wiley: New Work, 1992; pp 900-902.
`12. Huddleston, J. G.; Visser, A. E.; Reichert, W. M.; Willauer, H. D. Broker, G.. A.;
`Rogers, R. D. Green Chem. 2001, 3, 156-164.
`13. Dupont, J.; Consorti, C. S.; Suarez, P. A. Z.; de Souza, R. F. Org. Synth. 1999, 79,
`236-243.
`14. Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D. Green Chem. 2004, 6,
`75-77.
`15. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 2nd ed.;
`Pergamon Press: Oxford, 1988; p 91.
`16. Vatsadze, S. Z.; Krainova, Y. V.; Kovalkina, M. A.; Zyk, N. V. Chem. Heterocycl.
`Compd. 2000, 36, 1185-1191.
`
`
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`
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`

`Mannich Reactions in Room Temperature Ionic Liquids (RTILs): An
`Advanced Undergraduate Project of Green Chemistry and Structural
`Elucidation
`
`
`Instructors’ Note
`
`
`
`(Refer to the Students’ Handout for the Detailed Experimental Procedure)
`
`
`Background
`
`This project illustrates an interesting “Green” approach of organic synthesis. The
`
`experiment is about the synthesis of a commonly used room temperature ionic liquid –
`[bmim][BF4], and the application of this ionic liquid as a recyclable solvent for organic
`reactions. Since the applications of ionic liquids in organic reactions are gaining
`attention among the chemistry community, this project can arouse students’ interest in
`chemical research and reading research literature.
`
`
`In this project the students were asked to synthesize a commonly used room
`temperature ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]),
`investigate the effectiveness of this ionic liquid as a recyclable reaction solvent for the
`Mannich reaction, and compare the activity of this ionic liquid with a traditional organic
`solvent. Finally, the students were asked to identify the molecular structure of the
`Mannich reaction product by NMR spectroscopy and mass spectrometry.
`
`This project was designed for an advanced organic laboratory course for junior
`students and intended to be completed in four 4-hour laboratory sessions. Shown below
`is the suggested schedule for the project.
`
`
`Suggested schedule for the experiment
`2 days before the 1st session:
`Set up the reaction for [bmim][Cl] (45 minutes)
`1st session:
`Work-up the reaction mixture for [bmim][Cl]
`Synthesize the ionic liquid [bmim][BF4]
`The day before the 2nd session: Set up the Mannich reaction (30 minutes)
`
`
`
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`
`
`2nd session:
`
`Work-up the Mannich reaction mixture
`Recover the ionic liquid
`Obtain the 1H NMR, 13C NMR and mass spectra for the
`Mannich reaction product
`The day before the 3rd session: Set up the Mannich reaction with ethanol
`
`Set up the Mannich reaction with the recovered RTIL
`(2nd reaction cycle)
`3rd session:
`Work-up the two Mannich reaction mixtures
`Recover the ionic liquid
`
`
`The day before the 4th session: Set up the Mannich reaction with the recovered RTIL
`(3rd reaction cycle)
`4th session:
`Work-up the Mannich reaction mixture
`
`
`
`
`Instructors may also choose to provide students with the ionic liquid and let them
`work only on the Mannich reaction, ionic liquid recovering, and structural elucidation if
`the experiment has to be fitted into a single laboratory session. The ionic liquid
`[bmim][BF4] can be readily synthesized in a hundred-gram scale. Instructors may also
`provide students with photocopies of the NMR and mass spectra if the spectrometers are
`not available for undergraduate classes. The spectra can be found at the end of this Lab
`Documentation.
`
`Special equipment required for the experiment
`
`1. Vacuum-line manifolds system
`2. Mechanical rotary vane pump for the Vacuum-line Manifolds system (e.g. BOC
`Edwards RV8)
`3. Nitrogen gas supply
`
`
`
`
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`A. Synthesis of 1-butyl-3-methylimidazolium chloride, [bmim][Cl] (1)
`
`
`the quaternization of
`The synthesis of [bmim][Cl] was carried out by
`1-methylimidazole with 1-chlorobutane. It was accomplished by heating a mixture of
`1-methylimidazole and 1-chlorobutane in acetonitrile at 80 °C under nitrogen for 2 days.
`Students were asked to come at a prearranged time 2 days before their first lab session to
`set up the reaction, so they could work-up the reaction mixture to obtain [bmim][Cl] and
`carry out the anion exchange reaction for [bmim][BF4] in their first lab session.
`
`
`The procedure described in the students’ handout is a simplified version of the
`literature procedure (1-2). This simplified procedure can be fitted into a 4-hour
`laboratory session. 1-Methylimidazole, 1-chlorobutane and acetonitrile were used as
`received without purification. It is recommended to heat the mixture under a slow
`stream of nitrogen since the product [bmim][Cl] is hygroscopic and it may turn light
`brown if O2 is present. A photograph of the nitrogen inlet adapter is shown in the
`student handout.
`
`
`When the reaction was complete, the mixture was washed with ethyl acetate three
`times to remove acetonitrile and excess 1-chlorobutane. Ethyl acetate is immiscible
`with [bmim][Cl]. The upper ethyl acetate layer was removed by careful decantation or
`with a dropper. Do not use a separatory funnel as [bmim][Cl] is rather viscous.
`Finally, the residual volatile organic substances were removed under reduced pressure
`(0.1 mmHg) at 60 °C for 10 minutes. To minimize contamination of the vacuum-line
`manifolds system, liquid nitrogen cold traps were used for condensing and collecting the
`volatile organic substances. The product was isolated as a low-melting solid (m.p.
`66-67 °C).
`
`A2. Synthesis of 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim][BF4] (2)
`
`The anion exchange reaction was carried out by stirring an aqueous mixture of
`[bmim][Cl] and NaBF4 at room temperature for 1.5 hours. Water was removed from the
`mixture by rotary evaporation and then under high vacuum (0.1 mmHg) at 80 – 90 oC.
`Dichloromethane was added to precipitate the by-product NaCl, and MgSO4 was added
`to remove the residual water. The salts were removed by filtration and the solution was
`concentrated by rotary evaporation or under high vacuum. The ionic liquid [bmim][BF4]
`
`
`
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`

`was isolated as a pale yellow viscous liquid in about 70% yield (with regard to the
`amount of 1-methylimidazole used).
`
`
`Both [bmim][Cl] and [bmim][BF4] were characterized by 1H and 13C NMR
`spectroscopy. The 1H and 13C NMR spectra of [bmim][Cl] and [bmim][BF4] and
`detailed NMR signal assignments are available in this supplemental documentation.
`
`B. Mannich reaction of benzaldehyde, 3-pentanone and ammonium acetate in
`[bmim][BF4]
`
`Ph
`
`O
`
`NH
`
`O
`
`H
`
`+
`
`O
`
`+ NH4OAc
`
`[bmim][BF4]
`30 oC, 24 h
`
`Ph
`
`3,5-dimethyl-2,6-diphenyl-
`4-piperidone (3)
`
`
`
`2
`
`
`
`
`
`3-Pentanone and ammonium acetate were used as received without further
`purification. Benzaldehyde, on the other hand, undergoes slow air-oxidation and is
`usually contaminated with benzoic acid. It must be freshly purified by extraction three
`times with 10% aq. Na2CO3 and then dried over anhydrous MgSO4 (3).
`
`
`Mixing benzaldehyde, 3-pentanone and ammonium acetate in [bmim][BF4] gave a
`clear pale yellow liquid mixture with some NH4OAc remained undissolved. The
`Mannich product was formed as a white powdery precipitate after reacting at 30 °C for
`24 hours. The product was isolated by filtration, and the filtrate was saved for
`recovering the ionic liquid. The crude product was purified by recrystallization from
`hot ethanol, and needle-shape crystals were obtained in about 60 – 65% yield. The
`product was structurally characterized by 1H and 13C NMR spectroscopy, and mass
`spectrometry.
`
`Other useful physical data of compound 3: Melting point: 131 – 133 oC
`
`
` R
`f: 0.65 (n-hexane / ethyl acetate 5:1)
`
`
`
`
`
`
`
`
`The ionic liquid was recovered from the filtrate by the procedure as described in the
`student handout, and about 90% of the ionic liquid could be recovered each time.
`
`
`
`
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`C. Determination of the activity of the recovered RTIL
`
`
`
`
`To investigate whether [bmim][BF4] was recyclable, the Mannich reaction was
`repeated twice using the recovered ionic liquid. As only about 90% of [bmim][BF4]
`was recovered in each reaction cycle, a small amount of fresh ionic liquid was added in
`each time to make up to the required amount. Our trials demonstrated that the ionic
`liquid showed no apparent decrease in activity for three reaction cycles. The yields of 3
`obtained in these reactions were 54% and 60%, compared with 63% as obtained from the
`fresh ionic liquid.
`
`D. Comparing the activity of the RTIL with a traditional organic solvent
`
`
`As a control experiment for comparing the effectiveness of the ionic liquid with the
`traditional solvent, the Mannich reaction was also carried out in ethanol. 52% of 3 was
`obtained after reaction at room temperature for 24 hr, suggesting that the effectiveness of
`[bmim][BF4] is comparable with the traditional reaction media.
`
`
`E. Structural identification of the Mannich reaction product
`
`
`O
`
`Ph
`
`NH2
`4
`
`PhCHO
`
`Ph
`
`O
`
`NH
`
`Ph
`
`O
`
`OH
`
`HP
`
`h
`
`H
`
`HN
`
`Ph
`
`NH4OAc
`
`HO
`
`Ph
`
`OH
`
`Ph
`
`N
`
`HP
`
`h
`
`O
`
`N
`
`Ph
`
`5
`Figure 5. Proposed reaction mechanism for the formation of 3
`
`3-Pentanone, benzaldehyde and ammonium acetate underwent a double Mannich
`
`reaction in the stoichiometry of 1:2:1 and gave the cyclic tetrasubstituted piperidone 3,
`and the proposed mechanism is shown in Figure 5. The first Mannich reaction yielded a
`
`3
`
`
`
`
`
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`

`primary amine 4, which is capable of reacting with another molecule of benzaldehyde to
`intermediate 5.
`give
`the
`imine
` Finally,
`intramolecular cyclization gave
`the
`tetrasubstituted 4-piperidone 3.
`
`
`The EI (electron impact) mass spectrum of compound 3 shows a molecular ion peak
`at m/z = 279, which
`is
`consistent with
`the molecular
`formula of
`3,5-dimethyl-2,6-diphenyl-4-piperidone [C19H21NO]+. The molecular formula of the
`product was further confirmed by high-resolution mass spectrometry. The measurement
`gave a molecular ion peak at m/z = 279.16184, which is consistent with the calculated
`formula mass of [C19H21NO]+ (theoretical: 279.1618).
`
`
`
`The 1H and 13C NMR data of compound 3 are summarized in the following table.
`
`
`1H NMR (300 MHz, CDCl3):
`δ 0.83 (d, 6H, 3JHH = 6.61 Hz), 2.01 (bs, 1H), 2.82 – 2.90 (m, 2H),
`3.62 (d, 2H, 3JHH = 10.40 Hz), 7.23 – 7.38 (m, 6H), 7.40 – 7.50
`(m, 4H).
` 13C NMR (75 MHz, CDCl3):
`δ 10.5, 52.0, 68.8, 127.7, 127.9, 128.3, 141.9, 211.1.
`
`23
`
`O
`4
`
`1
`
`NH
`
`5 6
`
`
`
`The interpretation of the 1H NMR spectrum is straightforward (Figure 6). The
`multiplets at 7.23 – 7.50 ppm were assigned to the phenyl groups. The doublet at 0.83
`ppm was assigned to the methyl groups attached to positions 3 and 5 of the piperidone,
`and the doublet splitting was attributed to the spin-spin interaction with the methine
`protons at C-3 and C-5.
`
`
`The 1H signals at δ = 3.62 and 2.82 – 2.90 ppm are assigned to the methine protons
`at the positions 2/6 and 3/5, respectively. The assignments were deduced from their
`respective splitting patterns. A qd (quartet of doublets) pattern was expected for the
`protons located at positions 3 and 5, and this signal appeared as an unresolved multiplet
`at 2.82 – 2.90 ppm. The signal of the protons located at positions 2 and 6 appeared as a
`doublet, and the splitting was attributed to the spin-spin interaction with the protons at
`positions 3 and 5. Spin-coupling with the N-H proton was not observed. The broad
`singlet at δ = 2.01 was assigned to the N-H proton.
`
`
`
`
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`

`Figure 6. 1H NMR spectrum of compound 3
`
`
`
`The doublet at δ = 3.62 ppm has a 3JHH value of 10.4 Hz, suggesting that the
`methine protons occupied the axial positions of the cyclic piperidone. In the chair
`conformation of a six-membered ring, the equatorial positions are sterically less crowded
`than the axial positions, and therefore, the stereoisomer that having all the bulky
`substituents (methyl and phenyl) occupying the equatorial positions should be more
`thermodynamically favorable (4).
`
`
`O
`
`+
`
`O
`
`Ph
`
`H
`
`+ NH4OAc
`
`O
`
`PhCHO
`
`Ph
`
`NH2
`
`H
`
`Ph
`HN
`Ph
`
`CH3
`
`O
`CH3
`
`H
`
`3
`
`
`
`
`
`The interpretation of the 13C NMR spectrum is also straightforward. The simplicity
`of the spectrum suggested a highly symmetric molecular structure. The signal at 211
`ppm was assigned to the carbonyl carbon (C-4) and the four signals appearing from 128
`
`
`
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`

`to 142 ppm were assigned to the aromatic carbon atoms. The signals at 69 and 52 ppm
`were assigned to C-2/C-6 and C-3/C-5, respectively. C-2 and C-6 are attached to the
`electronegative nitrogen atom and are also subjected to the anisotropic effect of the
`neighboring phenyl groups. Therefore, their 13C signals are shifted downfield. Finally,
`the signal at 11 ppm was assigned to the methyl carbon atoms.
`
`F. Spectroscopic characterization of the ionic liquids
`
`1-Butyl-3-methylimidazolium chloride, [bmim][Cl] (1)
`
`The 1H and 13C NMR data of [bmim][Cl] are summarized in the following table.
`
`
`
`4
`
`
`
`3
`
`N
`
`2
`
`N+
`1
`
`5
`
`Cl-
`6
`
`7
`
`8
`
`
`
`1H NMR (300 MHz, DMSO-d6):
`δ, 0.84 (t, 3JHH = 7.34 Hz), 1.20 (sextet (overlapped qt), 2H, 3JHH =
`7.42 Hz), 1.73 (quintet (overlapped tt), 2H, 3JHH = 7.34 Hz), 3.88 (s,
`3H), 4.20 (t, 2H, 3JHH = 7.12 Hz), 7.87 (s, 1H), 7.95 (s, 1H), 9.71 (s,
`1H).
`13C NMR (75 MHz, DMSO-d6):
`δ 13.4, 18.9, 31.6, 35.8, 48.5, 122.5, 123.7, 137.0.
`
`The spectral data are consistent with the desired product. The 1H NMR spectrum
`has 3 singlet signals at 9.71, 7.95 and 7.87 ppm, which were assigned to the protons on
`the imidazole ring. The singlet at 3.88 ppm and the spin-coupled signals at 4.20 (H-5),
`1.73 (H-6), 1.20 (H-7) and 0.84 (H-8) ppm were assigned to the methyl and the butyl
`substituents, respectively. The proton signals of the n-butyl group were assigned
`according to their respective splitting patterns.
`
`
`The 13C NMR spectrum of [bmim][Cl] has 3 downfield signals between 122 – 137
`ppm. They were assigned to the three carbon atoms of the imidazole ring. The other
`five signals that appeared in the upfield region (13 – 48 ppm) were assigned to the methyl
`and the n-butyl substituents.
`
`
`The FAB (fast atom bombardment) mass spectrum of [bmim][Cl] has a base peak at
`m/z = 139, which is consistent with the 1-butyl-3-methylimidazolium cation [C8H15N2]+.
`
`
`
`
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`

`1-Butyl-3-methylimidazolium tetrafluoroborate, [bmim][BF4] (2)
`
`
`The NMR spectra of [bmim][BF4] were obtained from an acetone-d6 solution and
`the spectral data are summarized in the following table. The spectroscopic data were
`found to be consistent with the literature values (2).
`
`
`1H NMR (300 MHz, acetone-d6):
`δ 0.92 (t, 3JHH = 7.40 Hz), 1.36 (sextet (overlapped qt), 2H, 3JHH =
`7.48 Hz), 1.89 (quintet (overlapped tt), 2H, 3JHH = 7.47 Hz), 3.99 (s,
`3H), 4.32 (t, 2H, 3JHH = 7.29 Hz), 7.68 (s, 1H), 7.73 (s, 1H), 9.00 (s,
`1H).
`13C NMR (75 MHz, acetone-d6):
`δ 13.7, 20.0, 32.8, 36.5, 50.1, 123.3, 124.7, 137.6,
`
`3
`
`N
`
`2
`
`N+
`1
`
`5
`
`-
`
`BF4
`6
`
`8
`
`7
`
`
`
`4
`
`
`
`The interpretations of the NMR signals of [bmim][BF4] are similar to that of
`[bmim][Cl]. Changing the counter-anion has no significant effect to the NMR signals of
`the imidazolium cation.
`
`
`Similarly, the mass spectrum of [bmim][BF4] also has a base peak at m/z = 139,
`which is consistent with the 1-butyl-3-methylimidazolium cation [C8H15N2]+.
`
`G. Mannich reactions in other room temperature ionic liquids and of different
`substrates
`
`
`
`Another group of students enrolled in the course synthesized another room
`temperature ionic liquid (1-butyl-3-methylimidazolium p-toluenesulfonate, [bmim][tsa]),
`and carried out the Mannich reaction with it. They also tried the Mannich reactions with
`other substrates. The students found that [bmim][tsa] was less effective than
`[bmim][BF4] for the Mannich reaction. They also found that the double-Mannich
`reaction could be carried out with a variety of substrates. Changing the ketone to the
`sterically bulky dibenzyl ketone had only very slight effects on the reaction yield. The
`reaction yields obtained with different p-substituted benzaldehydes, on the other hand,
`were comparable with each other.
`
`
`
`
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`

`Synthesis of 1-butyl-3-methylimidazolium p-toluenesulfonate, [bmim][tsa] (6)
`CH3
`
`[bmim][Cl] (1)
`
`
`p-Toluenesulfonic acid (8.41 g, 44.2 mmol) was added in portions to an aqueous
`
`solution of [bmim][Cl] (7.69 g, 44.2 mmol in 16 mL of H2O) at 0 °C over a period of 5
`minutes. The mixture was stirred at room temperature for 1.5 hours. The mixture was
`concentrated by rotary evaporation, and then under high vacuum (0.1 mmHg) at 80 °C.
`12.47 g (91%) of a pale yellow oily liquid was obtained. 1H NMR (acetone-d6, 300
`MHz) δ 0.88 (t, 3H, J = 7.4 Hz), 1.30 (sextet, 2H, J = 7.5 Hz), 1.84 (quintet, 2H, J = 7.5
`Hz), 2.31 (s, 3H), 4.01 (s, 3H), 4.32 (t, 2H, J = 7.3 Hz), 7.15 (d, 2H, J = 7.9 Hz), 7.69 (d,
`2H, J = 8.0 Hz), 7.76 (t, 1H, J = 1.7 Hz), 7.82 (t, 1H, J = 1.7 Hz), 9.68 (s, 1H).
`
`Mannich reaction of 3-pentanone, benzaldehyde and ammonium acetate in [bmim][tsa]
`
`Ph
`
`O
`
`NH
`
`3 (33%)
`
`
`
`O
`
`H
`
`+
`
`2
`
`O
`
`+ NH4OAc
`
`[bmim][tsa]
`30 oC, 24 h
`
`Ph
`
`3-Pentanone (0.86 g, 10 mmol), benzaldehyde (2.12 g, 20 mmol) and ammonium
`
`acetate (0.77 g, 10 mmol) were mixed with 2.5 g of [bmim][tsa]. The mixture was
`stirred at 30 °C for 24 hours. 20 mL of water were added and the mixture was filtered
`to collect the white precipitate. 0.92 g (33%) of white crystals were collected after
`recrystallization from hot e