understanding enolate chemistry and the tishchenko...
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Dan WaddellJune 24, 2009
Understanding Enolate Chemistry and the Tishchenko
Reaction Under High Speed Ball Milling Conditions
12 Principles of Green Chemistry• Prevention
• Atom Economy
• Less Hazardous Chemical Syntheses
• Designing Safer Chemicals
• Safer Solvents and Auxiliaries
• Design for Energy Efficiency
• Use of Renewable Feed stocks
• Reduce Derivatives
• Catalysis
• Design for Degradation
• Real-time Analysis for Pollution Prevention
• Inherently Safer Chemistry for Accident Prevention
Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, p.30.
How to Prevent Waste
Non-Solvent Chemical Waste Methanol Toluene1,2-Dichloroethane Ethylene Glycol DichloromethaneXylenes Benzene n-hexaneAcetonitrile Cyclohexane Carbon DisulfideTetrachloroethylene Chloroform Carbon TetrachlorideDimethylformamide 1,4-Dioxane Pyridine
32%68%
Total Waste = 11.5 Billion Pounds
Total Solvent Waste = 3.7 Billion Pounds
EPA Toxic Release Index: 2005
Eliminate Organic Solvents
-Large volume used in industry
-Difficulty containing volatile compounds
- $$$$ Cost $$$$
http://www.epa.gov/triexplorer/chemicalquantity.htm
Why?
Why use solvents anyway?
Aristotle’s Conclusion:“No Coopora nisi Fluida”
“No reaction occurs in the absence of solvent”
Mack LabSPEX mixer/mill
Custom Vials
Path of BallA. Concas et al. / Chemical Engineering Science 61 (2006) 3746 – 3760
Mixer/Mill
My projects
Tishchenko Reaction
Carbon-carbon bond formation– Regio- and Stereoselectivity
Tishchenko Reaction
• Environmentally Friendly
– 100% atom economic
– Use of catalyst• Both reduce chemical
waste
• Industrially Relevant
– Create benzyl benzoate• Flavorings and
Fragrances
– Create ethyl acetate• Common organic solvent
Tishchenko Reaction
History1887: First reported by Claisen using sodium alkoxide1906: Tishchenko used aluminum alkoxides and broadened the scope of the reactions
Tishenko, V., J. Russ. Phys. Chem. Soc. 1906, 3 8 , 355.Claisen, L., Chem. Ber. 1887, 2 0 , 646.
Other catalysts have been applied to increase scope of the Tishchenko reaction
HSBM Tishchenko
Daniel C. Waddell and James Mack, An environmentally benign solvent-free Tishchenko reaction, Green Chem., 2009, 11, 79 – 82.
Aryl Aldehydes Continued
Daniel C. Waddell and James Mack, An environmentally benign solvent-free Tishchenko reaction, Green Chem., 2009, 11, 79 – 82.
Non-Aryl Aldehydes
H
OH
O
O
H
H
O
O
H
O
HPolymer
Formation
Mainly conjugate additon products
Daniel C. Waddell and James Mack, An environmentally benign solvent-free Tishchenko reaction, Green Chem., 2009, 11, 79 – 82.
O
OO
H
H
O
Other Tischenko Considerations
• Magnesium turnings can be used to catalyze the reaction– Magnesium vial under investigation
• Aluminum vial also catalyzes reaction– Create Aluminum Alkoxides (original catalyst
for these reactions)– Use HgCl2 and isopropanol
Second Project:Carbon-carbon bond formation
• Fundamental Organic Transformation
• Enolate Chemistry is arguably the easiest method
Prof. Dr. Burkhard König, Institut für Organische Chemie, Uni Regensburg
Solvent-Free Literature Precedent?
Mortarand
Pestle5 min
NaOH
O
H
O O
+
K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025–1074.
Ketone Electrophile 97%
C. L. Raston, J. L. Scott, Green Chem. 2000, 2, 49 – 52.
Probing SelectivityKinetic vs. Thermodynamic Control
• 2-methylcyclohexanone as a model system
HO
H
O–
O–
Thermodynamic enolate
Kinetic enolate
Kinetic vs. Thermodynamic
• Is this regioselectivity possible under HSBM conditions?– Prevailing thought:
• HSBM is an extremely high energy system• All reactions should proceed to the thermodynamic
product
• Test the system– Use KOH as a thermodynamic base– Use LiHMDS as a kinetic base N
SiSi
Li
Selectivity!O
BrO
Br
Br
+ + KOH1/8" ss ball
O
Br24% 5%
Thermodynamic Kinetic
O
Br
Br
+ +1/8" ss ball
HMDS
O
Br
O
Br10% 44%
Br
O
Br8%
Thermodynamic Kinetic
Daniel C. Waddell, Indre Thiel, S. Tyler Marcum and James Mack, Making kinetic and thermodynamic enolates via solvent-free high
speed ball milling, Green Chem., submitted.
Other Base Choices1/8" ss ball
BASE
Br
BrO
+ +1/8" ss ball
BASE
Br
BrO
+ +
O
Br Br
O
Br
O
Br
NaOH 76% 2%
LiOH
CsF/LiOH 9%9%50%
-/- -/- -/-
-/-
BASE
NaH0.6 equiv.
46% 2% -/-
LiHMDS0.9 equiv.
9% 19% -/-Daniel C. Waddell, Indre Thiel, S. Tyler Marcum and James Mack, Making kinetic and thermodynamic enolates via solvent-free high
speed ball milling, Green Chem., submitted.
Conclusions
• HSBM is a viable technique to create a paradigm shift in the way we perform organic reactions
• Tishchenko reaction is successful for a variety of aryl aldehydes
• Stereo- and regio-selectivite enolate chemistry is viable under HSBM conditions
Acknowledgements• Dr. James Mack• Mack Group• Indre Thiel
– Cincinnati REU Program• S. Tyler Marcum• Brandon Smith• NSF Scholars Program• University of Cincinnat
– University Research Council• NSF - 0548150