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Teaching Green Chemistry & Engineering Concepts in the Undergraduate Organic
Laboratory via Biginelli and Hantzsch Reactions
A.P. Dicks*, E. Aktoudianakis and S. Styler
Department of ChemistryUniversity of Toronto
Green Chemistry and Engineering Conference, 23rd June 2009
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Today’s Presentation
CHM 343H: Organic Synthesis Techniques
Green chemistry principles/reactions
The Biginelli & Hantzsch reactions: “traditional versus modern” comparisons
“Solvent-free” cautionary notes & reactor design
Conclusions
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CHM 343H - A New Course
Organic Synthesis Techniques:enrollment ∼ 30-40, first taught in Spring 2008
Not required by any specific program: mix of CHM specialists/majors/minors
Course driven by new experiments:
(a) replacing organic solvents with water(b) “solvent-free” reactions (c) catalytic reactivity
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(One Of 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 examplesexist (e.g. aldol, Wittig,Michael, Claisen, oxidation,reduction reactions)
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The Biginelli Reaction (1893)
O
OO
O
NH2
O
H2N
H
+ +
NH
NH
O
O
O
+ 2H2O
HCl, EtOHheat, 3 hours
a 3,4-dihydropyrimidone
NH
O
O
O
O
NO2
Nifedipine
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The “Traditional” Biginelli Reaction (2001)
O
OO
O
NH2
O
H2N
H
+ +
NH
NH
O
O
O
+ 2H2O
HCl, EtOHheat, 1.5 hours
microscale, 58% average yield
R.D. Crouch et al.
J. Chem. Educ. 2001, 78, 1104
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The “Modern” Biginelli Reaction (1)
Many recent attempts to accelerate and improve yield of Biginelli reaction
Lewis acid catalysis (rather than HCl)
Adapt methodology for CHM 343H, compare “modern” with “traditional” from green perspective in the same lab session
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The “Modern” Biginelli Reaction (2)
O
OO
O
NH2
O
H2N
H
+ +
NH
NH
O
O
O
+ 2H2O
ZnCl2, no solventheat, 15 minutes
microscale, 65% average yield
adapted from Q. Sun et al.
Synthesis 2004, 1047
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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)...
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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”...
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Comparing Methodologies (3)
Theoretical atom economy:
O
CC
CO
CH3
O
O
H2C
H3CN
CO
NH
H H
HHH
H
+ +
catalyst (HClor ZnCl2)
NH
NH
O
O
O
+ 2H2O
C7H6OMol. Wt.: 106.12
CH4N2OMol. Wt.: 60.06
C6H10O3Mol. Wt.: 130.14
C14H16N2O3Mol. Wt.: 260.29
[(M of desired product)/Σ(M of reactants)] * 100
= 87.8% (for both methods)
Atoms in red finish in desired product
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Comparing Methodologies (4)
Experimental atom economy - “traditional”:
[(“obtainable” product mass)/ Σ(mass of reactants utilized)] * 100
Compound GMW Amount Added mmolbenzaldehyde 106.12 254 µL = 0.265 g 2.5ethyl acetoacetate 130.14 484 µL = 0.494 g 3.8urea 60.06 0.150 g 2.595% ethanol 46.07 1 mLconcentrated HCl 36.46 2 drops
Total reactant mass (exc. catalyst) = 0.265+0.494+0.150 = 0.909 gProduct mass = 0.650 g (if 100% yield)Experimental atom economy = (0.650/0.909) x 100% = 71.5%
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Comparing Methodologies (5)
Experimental atom economy - “modern”:
[(“obtainable” product mass)/ Σ(mass of reactants utilized)] * 100
Compound GMW Amount Added mmolbenzaldehyde 106.12 203 µL = 0.212 g 2ethyl acetoacetate 130.14 254 µL = 0.259 g 2urea 60.06 0.180 g 3zinc (II) chloride 136.3 57 mg 0.4295% ethanol 46.07
Total reactant mass (exc. catalyst) = 0.212+0.259+0.180 = 0.651 gProduct mass = 0.520 g (if 100% yield)Experimental atom economy = (0.520/0.651) x 100% = 79.9%
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Comparing Methodologies (6)
Ultimate measure of reaction efficiency: take into account chemical yield and experimental atom economy
“Traditional” = 45%“Modern” = 52%
Reaction = chemical yield (%) * experimentalefficiency atom economy (%)
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Featured In JCE
E. Aktoudianakis et al. J. Chem. Educ. 2009, 86, 730
Compounds highlighted as “Featured Molecules” in J. Chem. Educ.
June 2009
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A “Modern” Hantzsch Reaction
R = Me, Et
H
O
OO
OR NH4+.
CH3COO-H+ +
NH
O
OR
heat, 10 minutes
aq. 2
O
O R
no catalyst
semi-microscale, 60% average yield
adapted from M. Zolfigol et al.
Synlett 2004, 827
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Interest In Hantzsch Products
NH
O
O
O
ONO2
nifedipine
NH
O
O
O
O
diludine
NH
O
O
O
O
lacidipine
O
O
antioxidant, powerfulstabilizer of vitamin Ain edible oils
first generationdihydropyridinecalcium-channelblocker
second generationdihydropyridinecalcium-channelblocker
1,4-dihydropyridine ring a “privileged structure”
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Not Quite Solventless
R = Me, Et
H
O
OO
OR NH4+.
CH3COO-H+ +
NH
O
OR
heat, 10 minutes
aq. 2
O
O R
no catalyst
strictly not a solvent-free reaction: small amount of water present
“Traditional” Hantzsch reactions: reflux in EtOH, 1 hr.++
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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”.
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Careful What We Teach Our Students!OH
O
OH OO
O
OO
OH
O
O
OH
+
+
µW, catalyst
aspirinI. Montes et al.
J. Chem. Educ. 2006, 83, 628
Salicylic acid (5 mmol) mixed with acetic anhydride (15 mmol) and irradiated in presence of catalyst
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Important Purpose Of 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?
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Reactor Design
Spinning disk reactor for irradiated reactionsB. Dunk et al.
Green Chem. 2000, 2, G13
Polymerization reactions possible under UV irradiation
Thin reaction films generated by rotatingreactor surface
Microreactors another option - reactioncomponents mixed in small diameter channels - control heat transfer andunwanted side reactions
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Conclusions
To really appreciate green improvements, students compare synthetic methods themselves
Solvent-free reactivity a reality in the 2nd/3rd-yearug organic lab
Important segue to solventless problems and reactor design strategies to overcome them
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Acknowledgements
CHM 299Y 2005/06: $$$:
Elton Chan Chemistry Lecturer Amanda Edward Scholar Fund (CHM 299Y)Isabel Jarosz Vicki Lee Chemistry Teaching Leo Mui Fellowship Program (CTFP)Sonya Thatipamala
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Publications
Type “Dicks” into the JCE Index Database “Author Field”
adicks@chem.utoronto.ca
Organic experiments available from 2003 - 2009
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