Teaching Green Chemistry & Engineering Concepts in the Undergraduate Organic Laboratory via Biginelli and Hantzsch Reactions

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1 Teaching Green Chemistry & Engineering Concepts in the Undergraduate rganic Laboratory via Biginelli and antzsch Reactions A.P. Dicks*, E. Aktoudianakis and S. Styler Department of Chemistry University of Toronto Green Chemistry and Engineering Conference, 23 rd June

2 Today s Presentation CM 343: rganic Synthesis Techniques Green chemistry principles/reactions The Biginelli & antzsch reactions: traditional versus modern comparisons Solvent-free cautionary notes & reactor design Conclusions 2

3 CM A New Course rganic Synthesis Techniques: enrollment 30-40, first taught in Spring 2008 Not required by any specific program: mix of CM specialists/majors/minors Course driven by new experiments: (a) replacing organic solvents with water (b) solvent-free reactions (c) catalytic reactivity 3

4 (ne f The) 12 Green Chemistry Principles Use safer solvents and reaction conditions: Avoid using solvents, separation agents, or other auxiliary chemicals many reactions faster in absence of solvent good pedagogical examples exist (e.g. aldol, Wittig, Michael, Claisen, oxidation, reduction reactions) 4

5 The Biginelli Reaction (1893) N N 2 N 2 Cl, Et heat, 3 hours N Nifedipine N N a 3,4-dihydropyrimidone 5

6 The Traditional Biginelli Reaction (2001) N N 2 Cl, Et heat, 1.5 hours R.D. Crouch et al. N J. Chem. Educ. 2001, 78, 1104 N microscale, 58% average yield 6

7 The Modern Biginelli Reaction (1) Many recent attempts to accelerate and improve yield of Biginelli reaction Lewis acid catalysis (rather than Cl) Adapt methodology for CM 343, compare modern with traditional from green perspective in the same lab session 7

8 The Modern Biginelli Reaction (2) 2 N + + N 2 ZnCl 2, no solvent heat, 15 minutes adapted from Q. Sun et al. N Synthesis 2004, 1047 N microscale, 65% average yield 8

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10 Comparing Methodologies (1) Two students per fumehood: one performs traditional method (ave. yield = 62%), other performs modern method (ave. yield = 65%) Alternatively, one student runs both reactions simultaneously if equipment permits... Analysis for adherence to Green Chemistry Principles (GCP)... 10

11 Comparing Methodologies (2) Modern strategy: eliminates solvent and reduces need for significant reactant excess: GCP avoid using auxiliary chemicals Modern strategy: six-fold rate acceleration: GCP increase energy efficiency Modern strategy: GCP maximize atom economy... 11

12 Comparing Methodologies (3) Theoretical atom economy: C 7 6 Mol. Wt.: C C C 3 C C C + 3 C Mol. Wt.: N N C C 4 N 2 Mol. Wt.: catalyst (Cl or ZnCl 2 ) Atoms in red finish in desired product N N C N 2 3 Mol. Wt.: [(M of desired product)/σ(m of reactants)] * 100 = 87.8% (for both methods) 12

13 Comparing Methodologies (4) Experimental atom economy - traditional : [( obtainable product mass)/ Σ(mass of reactants utilized)] * 100 Compound GMW Amount Added mmol benzaldehyde µl = g 2.5 ethyl acetoacetate µl = g 3.8 urea g % ethanol ml concentrated Cl drops Total reactant mass (exc. catalyst) = = g Product mass = g (if 100% yield) Experimental atom economy = (0.650/0.909) x 100% = 71.5% 13

14 Comparing Methodologies (5) Experimental atom economy - modern : [( obtainable product mass)/ Σ(mass of reactants utilized)] * 100 Compound GMW Amount Added mmol benzaldehyde µl = g 2 ethyl acetoacetate µl = g 2 urea g 3 zinc (II) chloride mg % ethanol Total reactant mass (exc. catalyst) = = g Product mass = g (if 100% yield) Experimental atom economy = (0.520/0.651) x 100% = 79.9% 14

15 Comparing Methodologies (6) Ultimate measure of reaction efficiency: take into account chemical yield and experimental atom economy Reaction = chemical yield (%) * experimental efficiency atom economy (%) Traditional = 45% Modern = 52% 15

16 Featured In JCE Compounds highlighted as Featured Molecules in J. Chem. Educ. June 2009 E. Aktoudianakis et al. J. Chem. Educ. 2009, 86,

17 A Modern antzsch Reaction aq. + 2 R + N 4 +. C 3 C - heat, 10 minutes no catalyst R = Me, Et R N R adapted from M. Zolfigol et al. Synlett 2004, 827 semi-microscale, 60% average yield 17

18 Interest In antzsch Products N 2 N N N nifedipine lacidipine diludine first generation dihydropyridine calcium-channel blocker second generation dihydropyridine calcium-channel blocker antioxidant, powerful stabilizer of vitamin A in edible oils 1,4-dihydropyridine ring a privileged structure 18

19 Not Quite Solventless aq. + 2 R + N 4 +. C 3 C - heat, 10 minutes no catalyst R = Me, Et R R strictly not a solvent-free reaction: small amount of water present N Traditional antzsch reactions: reflux in Et, 1 hr.++ 19

20 What Constitutes a Solvent-Free Reaction? Tom Welton (Green Chem. 2006, 8, 13): a dry solid-phase reaction is solvent-free, also a reaction where there is liquid present, but it is not acting as a solvent (i.e. nothing is dissolved in it) is also solvent-free. 20

21 Careful What We Teach ur Students! + µw, catalyst + Salicylic acid (5 mmol) mixed with acetic anhydride (15 mmol) and irradiated in presence of catalyst aspirin I. Montes et al. J. Chem. Educ. 2006, 83,

22 Important Purpose f Solvent Acts as a heat sink for exothermic reactions Proceed with caution! Industrial scale-up issues exist problems with thermal runaways, how is this managed? 22

23 Reactor Design Spinning disk reactor for irradiated reactions B. Dunk et al. Green Chem. 2000, 2, G13 Polymerization reactions possible under UV irradiation Thin reaction films generated by rotating reactor surface Microreactors another option - reaction components mixed in small diameter channels - control heat transfer and unwanted side reactions 23

24 Conclusions To really appreciate green improvements, students compare synthetic methods themselves Solvent-free reactivity a reality in the 2nd/3rd-year ug organic lab Important segue to solventless problems and reactor design strategies to overcome them 24

25 Acknowledgements CM 299Y 2005/06: $$$: Elton Chan Chemistry Lecturer Amanda Edward Scholar Fund (CM 299Y) Isabel Jarosz Vicki Lee Chemistry Teaching Leo Mui Fellowship Program (CTFP) Sonya Thatipamala 25

26 Publications Type Dicks into the JCE Index Database Author Field rganic experiments available from