Green Chemistry
`
`In the Laboratory
`
`edited by
`Mary M. Kirchhoff
`ACS Green Chemistry Institute
`Washington, DC 20036
`
`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
`
`W
`
`Chemists have been painstakingly searching for an ulti-
`mate solvent for organic reactions that possesses the follow-
`ing criteria: good chemical and thermal stabilities, low vapor
`pressure, low toxicity, high fluidity, wide liquid range, good
`solubility for a wide range of organic and inorganic reagents,
`and readily recyclable. Recent research has shown that room
`temperature ionic liquids (RTILs) are potentially promising
`recyclable replacements for traditional volatile organic sol-
`
`+N
`
`N
`
`R
`imidazolium
`
`+
`
`N R
`
`pyridinium
`
`Figure 1. Some examples of cations commonly used for synthesiz-
`ing ionic liquids.
`
`O
`
`R
`
`H
`
`aldehyde
`
`+
`
`NH3
`(or derivatives)
`
`+
`
`O
`
`R⬘
`
`ketone
`
`R⬙
`
`H + or OH −
`
`R
`
`O
`
`H2N
`
`R⬘
`
`R⬙
`β-aminoketone
`
`Scheme I. The Mannich reaction.
`
`www.JCE.DivCHED.org • Vol. 83 No. 6 June 2006 • Journal of Chemical Education
`
`943
`
`vents for organic reactions (1–5). RTILs are ionic compounds
`that exist in the liquid state at ambient temperature (6). These
`substances are usually composed of large organic cations hav-
`ing bulky substituents or with the positive charges delocal-
`ized over a number of atoms (Figure 1). They are considered
`as “designer solvents” because ideally one can synthesize an
`ionic liquid having the desired properties by making the right
`choices for the cation and anion.
`The Mannich reaction is a three-component condensa-
`tion reaction in which a compound having active hydrogen
`atoms reacts with an aldehyde and an amine derivative un-
`der either acidic or basic conditions (Scheme I) (7–8). It is
`frequently used for the synthesis of pharmaceuticals and natu-
`ral products such as alkaloids, steroid hormones, antibiotics,
`and vitamins (7). Recent research has shown that Mannich
`reactions can also be carried out effectively in Brønsted acidic
`ionic liquids (9).
`Owing to the limitations of time and facilities associ-
`ated with undergraduate laboratory courses, most of the ex-
`periments for undergraduate teaching are designed to fit into
`a single laboratory session with little room left for student-
`oriented explorations. In order to help students leap the gap
`between undergraduate laboratory experience and the inde-
`pendent working environment in postgraduate studies, we
`have offered an advanced elective laboratory course apart from
`the core curriculum for those students who might wish to
`undertake postgraduate studies in synthetic chemistry. The
`synthesis of RTILs and their application to the Mannich re-
`actions described herein is a project-based experiment devel-
`oped to be part of that advanced program.1 This project
`provides a valuable opportunity for students to experience
`the latest innovative ideas in chemical research.
`
`Experiment and Results
`
`The project took four 4-hour laboratory sessions for
`completion. The experimental work included:
`(i) preparation of the RTIL 1-butyl-3-methyl-
`imidazolium tetrafluoroborate, [bmim][BF4], 2;
`(ii) investigation of the efficiency of [bmim][BF4]
`as a recyclable reaction medium for the Mannich
`reactions;
`(iii) spectroscopic characterization of the reaction
`products.
`
`R⬘
`
`R
`P+
`
`R⬘
`
`R⬙
`
`R⬘
`
`+
`
`NR
`
`R⵮
`ammonium
`
`R⬙
`
`R⵮
`phosphonium
`
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`In the Laboratory
`
`A
`
`N
`
`N
`
`1-methylimidazole
`
`n-BuCl
`
`CH3CN, N2
`80 (cid:176)C, 48 h
`
`B
`
`Cl −
`
`n-Bu
`
`NaBF4
`
`2H O
`r.t., 1.5 h
`
`N
`
`N
`
`[bmim][Cl]
`1
`
`N
`
`+
`
`N
`
`BF4
`
`−
`
`n-Bu
`
`[bmim][BF4]
`2
`
`Ph
`
`O
`
`NH
`
`O
`
`O
`
`+
`
`Ph
`
`H
`
`+
`
`NH
`4OAc
`
`[bmim][BF4]
`
`30oC, 24 h
`
`Ph
`
`benzaldehyde
`
`3-pentanone
`
`ammonium
`acetate
`
`3,5-dimethyl-2,6-
`diphenyl-4-piperidone
`3
`
`Scheme II. (A) Synthesis of [bmim][BF4] and (B) the Mannich reaction of benzaldehyde, 3-pentanone, and ammonium acetate in [bmim][BF4],
`where bmim+ is 1-butyl-3-methylimidazolium cation.
`
`Scheme III (12–13). 3-Pentanone, benzaldehyde, and am-
`monium acetate underwent a double Mannich reaction in a
`stoichiometry of 1:2:1 to give the cyclic tetrasubstituted 4-
`piperidone 3.
`
`O
`
`OH
`
`O
`
`HN
`
`H
`
`NH4OAc
`
`Ph
`
`HO
`
`Ph
`
`O
`
`Ph
`
`N
`
`Ph
`
`H
`
`PhCHO
`
`Ph
`
`NH2
`
`δ = 3.62 ppm
`3JHH = 10.4 Hz
`
`Ph
`HN
`Ph
`
`CH3 O
`
`H
`
`CH3
`
`H
`
`3
`
`OH
`
`Ph
`
`N
`
`Ph
`
`H
`
`Scheme III. Proposed reaction mechanism for the formation of 3.
`
`The reaction scheme is depicted in Scheme II.
`Preparation of the Ionic Liquid
`The procedures were adopted from the literature (9–11)
`with minor modifications and the details are available in the
`Supplemental Material.W The ionic liquid [bmim][BF4] was
`synthesized in the first laboratory session by the quaterniza-
`tion of 1-methylimidazole with 1-chlorobutane, followed by
`an anion-exchange reaction (anion metathesis) of the result-
`ing intermediate [bmim][Cl] with NaBF4.2 [bmim][BF4] was
`obtained as a clear pale-yellow oily liquid in 71% yield with
`respect to the amount of 1-methylimidazole used. The 1H
`and 13C NMR spectra obtained for the products were con-
`sistent with those reported in the literature (11).
`Ionic Liquid as a Recyclable Reaction Medium
`The Mannich reaction was carried out in the second ses-
`sion.3 A mixture of benzaldehyde (20 mmol), 3-pentanone
`(10 mmol) and ammonium acetate (10 mmol) in 2.5 g of
`[bmim][BF4] was stirred at 30 ⬚C for 24 h, and 3 was iso-
`lated as white needle-shaped crystals in 63% yield. The effi-
`ciency of this new reaction medium was compared with a
`traditional solvent—ethanol. Repeating the Mannich reac-
`tion in ethanol at room temperature for 24 hr gave 3 in 52%
`yield.
`Ionic liquids have the advantage of being readily recy-
`clable. Up to 95% of ionic liquid could be recovered after
`washing the mother liquor of the reaction mixture with di-
`ethyl ether and concentrating. The Mannich reaction was re-
`peated twice using the recycled ionic liquid in the third and
`fourth laboratory sessions, and no significant decrease in ac-
`tivity was observed among the three reaction cycles.4
`Spectroscopic Analysis and Structural Elucidation
`Students were required to identify the molecular struc-
`ture of the Mannich product from the spectroscopic data, as
`well as stoichiometry and mechanism of the reaction. A
`mechanism proposed for the formation of 3 is shown in
`
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`The students obtained the NMR and mass spectra of
`compound 3 during the second laboratory session under the
`assistance of a laboratory technician. The high resolution (ac-
`curate mass) mass spectrum shows a molecular ion peak at
`m兾z = 279.16184, which is consistent with the molecular
`formula of 3 [(C19H21N1O1)+, theoretical mass = 279.1618].
`The 1H NMR spectrum of 3 (obtained with a 300 MHz
`spectrometer) provided a good exercise on stereochemistry
`analysis for students. In a rigid system like a substituted cy-
`clohexane or piperidone, the stereochemistry of the substitu-
`ents can be determined from the coupling constants of the
`vicinal protons according to the Karplus equation (14–15).5
`The doublet at δ = 3.62 ppm has a 3JHH value of 10.4 Hz,
`suggesting that the methine protons are occupying the axial
`positions of the cyclic piperidone. The bulky substituents oc-
`cupy the less sterically crowded equatorial positions.
`
`Hazards
`
`The experiments should be performed in well-ventilated
`fume hoods. Acetonitrile, 1-chlorobutane, diethyl ether, and
`3-pentanone are highly flammable, and they should be kept
`away from ignition sources. Deuterochloroform is a mutagen
`and suspected to be carcinogenic. Dichloromethane is volatile
`and a probable human carcinogen. Sodium tetrafluoroborate,
`1-methylimidazole, and trifluoroacetic acid are corrosive. Ben-
`zaldehyde, 3-pentanone, and 1-chlorobutane are irritating.
`Acetonitrile and trifluoroacetic acid are toxic. Nitrile-type pro-
`tective gloves must be put on when handling these compounds.
`Exposures by inhalation or skin contact should be avoided.
`[Editor’s Note: CLIPs are available in J. Chem. Educ. for
`dichloromethane (2004, 81, 1415) and benzaldehyde (2005,
`82, 1770).]
`Students must be very careful and under the supervi-
`sion of experienced instructors when operating vacuum mani-
`folds. 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.
`
`Discussion
`
`This mini project provided a valuable opportunity for
`students to work on a current research area and to experi-
`ence research-oriented work associated with postgraduate
`studies. Those students who carried out this project attained
`a sense of accomplishment, as the synthesis of piperidone
`derivatives by double Mannich reactions in RTILs has not
`been reported in the literature. This mini project can be modi-
`fied into different versions of various lengths and difficulties
`in order to fit into different situations. For example, instruc-
`tors may provide students with an ionic liquid and let them
`work only on the Mannich reaction, ionic liquid recovery,
`and structural elucidation if the experiment has to fit into a
`single laboratory session. The ionic liquid [bmim][BF4] can
`be conveniently synthesized in a hundred-gram scale. This
`project, on the other hand, can be readily extended: another
`group of students in the same course carried out the Mannich
`reaction in another ionic liquid6 and with several other sub-
`strates. The experimental details and results are available in
`the Supplemental Material.W
`
`In the Laboratory
`
`Ionic liquids offer new opportunities for organic chem-
`ists because of their unparalleled physical and chemical prop-
`erties. They have negligible vapor pressure and form biphasic
`systems with many organic solvents, which made them readily
`recyclable and facilitated the isolation of products and recov-
`ery of precious catalysts (4). Ionic liquids have also demon-
`strated interesting and unusual chemical reactivity that are
`sometimes unparalleled in traditional organic solvents. They
`are attracting growing attention within the green chemistry
`community. Instructors, however, have to alert students to
`keep a critical mind about the possible problems associated
`with the practical uses of RTILs in large scales. The potential
`environmental impacts and the toxicity associated with these
`ionic liquids are so far unclear (16). Ionic liquids are gener-
`ally more expensive than the traditional solvents, and efficient
`methods are needed for their recovery. Furthermore, despite
`their ability to be recycled, the syntheses of RTILs are costly
`in terms of the expense and complexity of the starting mate-
`rials and a substantial quantity of organic solvent is consumed
`in the recycling processes. These issues should be properly
`addressed before RTILs can be widely adopted as the “green”
`alternatives for traditional solvents by the chemical industries.
`Students were asked to perform a literature survey and include
`a critical evaluation in their project reports on the advantages
`and disadvantages of these new reaction media. This encour-
`aged students to read current research literature.
`
`WSupplemental Material
`
`The student handout, detailed experimental procedures,
`notes for instructors, NMR and mass spectra, and the spec-
`troscopic data interpretations are available in this issue of JCE
`Online.
`
`Notes
`
`1. The course typically has an enrollment of 6–9 junior-level
`students divided in groups of three. This project was successfully
`carried out by a group of three students in 2004.
`2. Students came at a prearranged time 2 days before the first
`laboratory session to set up the reaction for [bmim][Cl], which took
`about 45 minutes.
`3. Students came at a prearranged time on the day before and
`set up the reaction.
`4. Results from the first, second, and third cycles are 63%,
`53%, and 60%, respectively (isolated yields after recrystallization
`from 95% ethanol).
`5. The Karplus equation: 3Jab = J0cos2φ − 0.28 (0⬚ ≤ φ ≤ 90⬚)
`and 3Jab = J180cos2φ − 0.28 (90⬚ ≤ φ ≤ 180⬚), where φ is the dihe-
`dral angle between the H⫺C⫺C´ and C⫺C´⫺H plane and J0 and
`J180 are constants dependent on the actual substituents on the car-
`bon atoms (14–15).
`6. The students used 1-butyl-3-methylimidazolium p-
`toluenesulfonate, [bmim][tsa].
`
`Literature Cited
`
`1. Hu, A.; Ngo, H. L.; Lin, W. Angew. Chem., Int. Ed. Engl.
`2004, 43, 2501–2504.
`2. Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002,
`102, 3667–3692.
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`In the Laboratory
`
`3. Welton, T. Chem. Rev. 1999, 99, 2071–2084.
`4. Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. Engl. 2000,
`39, 3772–3789.
`5. Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.;
`Wiley–VCH: Weinheim, Germany, 2003.
`6. Adams, D. J.; Dyson, P. J.; Tavener, S. J. Chemistry in Alter-
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`7. Tramontini, M.; Angiolini, L. Mannich Bases: Chemistry and
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`8. (a) Kleinman, E. F. The Bimolecular Aliphatic Mannich and
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`
`Green Chem. 2004, 6, 75–77.
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`H. D. Broker, G. A.; Rogers, R. D. Green Chem. 2001, 3,
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`11. Dupont, J.; Consorti, C. S.; Suarez, P. A. Z.; de Souza, R. F.
`Org. Synth. 1999, 79, 236–243.
`12. March, J. Advanced Organic Chemistry: Reactions, Mechanisms,
`and Structure, 4th ed.; Wiley: New York, 1992; pp 900–902.
`13. Vatsadze, S. Z.; Krainova, Y. V.; Kovalkina, M. A.; Zyk, N. V.
`Chem. Heterocycl. Compd. 2000, 36, 1185–1191.
`14. Silverstein, R. M.; Bassler. G. C.; Morrill, T. C. Spectrometric
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`Son: New York, 1998; pp 2–60, 144–216.
`15. Williams, D. H.; Fleming, I. Spectroscopic Methods in Organic
`Chemistry, 5th ed.; McGraw-Hill: London, 1995; pp 63–169.
`16. Swatloski, R. P.; Holbrey, J. D.; Memon, S. B.; Caldwell, G.
`A.; Caldwell, K. A.; Rogers, R. D. Chem. Commun. 2004,
`668–669.
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