AmmoniaAmmonia--Free Birch Reductions Using Free Birch...
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Ammonia Ammonia-Free Birch Reductions Using Free Birch Reductions Using Stabilized Sodium In n Stabilized Sodium In n-Silica for Safer, More Silica for Safer, More Michael J. Costanzo, Mitul N. Patel, Kathryn A. Petersen, and Paul F. Vogt Sustainable Synthesis Sustainable Synthesis June 2009
Transcript of AmmoniaAmmonia--Free Birch Reductions Using Free Birch...
AmmoniaAmmonia--Free Birch Reductions Using Free Birch Reductions Using Stabilized Sodium In nStabilized Sodium In n--Silica for Safer, More Silica for Safer, More
Michael J. Costanzo, Mitul N. Patel, Kathryn A. Petersen, and Paul F. Vogt
Sustainable SynthesisSustainable Synthesis
June 2009
About SiGNa ChemistryAbout SiGNa Chemistry
A chemical technology company with a growing portfolio ofA chemical technology company with a growing portfolio of“GREEN” products and processes for
improved efficiency and a cleaner environmentimproved efficiency and a cleaner environment
Alternative Energy:Cl H f t f b d f i d t i l d t bl f l• Clean H2 from water for a broad range of industrial process and portable fuel cell applications
Green Industrial Processes:Green Industrial Processes:• Improved industrial efficiency and yield with critical cost reduction using green chemical processing
Clean Technology:• Cleaner burning conventional petroleum‐ and bio‐based fuels• Remediation of hazardous environmental contaminants
SiGNa Technology OverviewSiGNa Technology Overview
H Fuel Technology SiGNa’s Scientific CouncilH2 Fuel Technology
H2 gas produced from waterRoom‐temp. operation, no catalystNear instant start‐stop functionalityN t i b d tNon‐toxic by‐productsProducts: Reagents (NaSi) and fuel systemsApplications: Fuel cells and industrial H2
“Green” Catalysts
JL Dye Sir JM ThomasKnighted in
1991
RH Grubbs2005 Nobel Prize
Chemistry
GD Stucky
Green Catalysts
Low cost and scalableRenewable starting materialsEnvironmentally‐friendly operation
Specialty Chemicals
Non‐toxic by‐productsProducts: EP Catalyst and AlPOsApplications: EPDM rubber and ethylene
Stable in dry air / safe to handleRetains chemical power of base alkali metalFree‐flowing conductive powderNon‐toxic by‐productsNon toxic by productsProducts: M‐SG, OrganoLi‐AG, and MH‐SGApplications: Chemical manufacturing, desulfurization, and remediation (PCBs)
Desulfurization
Applications of SiGNa MaterialsApplications of SiGNa Materials
Desulfurization
Dissolving Metal ReductionsChemical Reductions
Fuel Cells and Alternative Energy
Hydrogen Generation
Palladium Replacement
LAH Replacement
Solvent Drying and Purification
Olefin Isomerization
Carbon‐Carbon Bond forming
PCB/CFC Remediation and Freon Conversion
Deuterium and Radio‐label Incorporation
Bond forming Reactions
Alkali Metals React with WaterAlkali Metals React with Water
Overview of SiGNa’s TechnologyOverview of SiGNa’s Technology
Metals solvated in nano‐structured porous oxides
Alkali metal silica materials (M‐SG); capacity up to 40 wt.%
Stable in dry air / Safer to handle / easier to transport
Free‐flowing powders
Reducing power of the parent metal/alloy retained
Non‐toxic by‐products and waste streams
SiGNa’sSiGNa’s Commercial PipelineCommercial Pipeline
CONCEPT FEASIBILITY VALIDATION LAUNCH
ChemicalsStage I M‐SG
OrganoLi‐AGM+H‐‐SG
Stage II M‐SG
M+H‐‐SG
Alt. Fuels NaSi
Fuel System
Catalysts EP CatalystAlPOsBio‐Zeolites
The Birch ReductionThe Birch Reduction
Birch, A. J. J. Chem. Soc. 1944, 430.Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1.
• Alternative to hydrogenation that yields cyclohexadienes.• Carried out in liquid ammonia with dissolved Na Li or K• Carried out in liquid ammonia with dissolved Na, Li or K.• Metal cation and a solvated electron are formed.• Mixture contains stoichiometric amounts of an alcohol
Problems include:• Handling of alkali metal and ammonia gasC i• Cryogenic temperatures
• Special design of the equipment• Choice and handling of materials • Operations waste treatment and both safety and economic issues• Operations, waste treatment, and both safety and economic issues
The Classical Birch ReductionThe Classical Birch Reduction
Typical Reaction Conditions:
• Phenanthrene was dissolved in THF• Solution was added to refluxing ammonia at ‐33 oC• Lithium metal (3 5 equivalents) was added to the mixture• Lithium metal (3.5 equivalents) was added to the mixture• Reaction quenched with ethanol then water then warmed to rt• Desired product is isolated in 57% yield
“Lithium wire was wiped free ofoil and washed with hexaneimmediately before use…….”
The SiGNa Birch ReductionThe SiGNa Birch Reduction
SiGNa’s Reaction Conditions:
• Phenanthrene and Na‐SG(I) (3.5 equivalents) are charged to a round bottom flaskTHF i dd d d th i t i l d t 0 oC• THF is added and the mixture is cooled to 0 oC
• tert‐Butanol (1.75 equivalents) is added in one portion• Reaction is allowed to warm to room temperature
D i d d i i l d i 60% i ld• Desired product is isolated in 60% yield
NO LIQUID AMMONIA!NO LIQUID AMMONIA! NO CRYOGENIC TEMPERATURES!NO CRYOGENIC TEMPERATURES!
NO PYROPHORIC REAGENTS!NO PYROPHORIC REAGENTS!
MM--SG Reaction ParametersSG Reaction Parameters
Temp (Temp (°°C)C) Prod (%)Prod (%)Temp. (Temp. ( C)C) Prod. (%)Prod. (%)-78 90
0 81
Similar conversions were observed with:
2 0 to 7 5 equivalents of metal0 81
22 82
2.0 to 7.5 equivalents of metalStage I with Na, Na2K and K2Nat‐butanol and t‐amyl alcohol
40 87
reflux 81
MM--SG Solvent CompatibilitySG Solvent Compatibility
SolventSolvent Prod. (%)Prod. (%) SolventSolvent Prod. (%)Prod. (%)( )( )THF 81
Me-THF 85
( )( )Cyclohexane 83
Heptane 82Me THF 85
Dioxane 76
MTBE 75
Heptane 82
DME 67
EtOA 0MTBE 75
DMSO 3
EtOAc 0
NMP 19
Toluene 84 t-Amyl-OH (neat) 2
Polycyclic Aromatic HydrocarbonsPolycyclic Aromatic Hydrocarbons
SiGNa’s safer and more practical modification of the classic Birchreduction that avoids the use of liquid ammonia and cryogenic temperatures
Entry Substrate Major Product Rxn Equiv. Time (h)Na-SG(I)
Prod./Yield (%)Na/NH3 (lit.)
Prod./Yield (%)
1 3 5 2 0 96 / 70 / 851 3.5 2.0 96 / 70 - - / 85
2 2.0 1.0 87 / 83 - - / 97
3 3 5 2 5 99 / 94 - - / 963 3.5 2.5 99 / 94 / 96
Aromatic HydrocarbonsAromatic Hydrocarbons
Entry Substrate Major Product Rxn Equiv Time (h)Na-SG(I)
Prod./Yield (%)Na/NH3 (lit.)
Prod./Yield (%)( ) ( )
1 3.5 2.0 100 / 83 - - / 80-90
2 3 5 2 0 100 / 82 / 80 902 3.5 2.0 100 / 82 - - / 80-90
3 14 24 9 / - - - - / 63
Aryl EthersAryl Ethers
Entry Substrate Major Product Rxn Equiv Time (h)Na-SG(I)
Prod./Yield (%)Na/NH3 (lit.)
Prod./Yield (%)Prod./Yield (%) Prod./Yield (%)
1 14 24 30 / - - - - / 74
2 3 5 24 12 / - - - - / 19OMe
2 3.5 24 12 / - - - - / 19
3 3.5 24 68 / 43 - - / - -
4 14 24 85 / 68 / 74
OMe
4 14 24 85 / 68 - - / 74
5 5.6 24 - - / 56 - - / - -
6 3.5 2.5 92 / 80 - - / 74(liq. NH3)
Polycyclic Aromatic Polycyclic Aromatic HeterocyclesHeterocycles
Entry Substrate Major Product Rxn Equiv Time (h)Na-SG(I)
Prod./Yield (%)Na/NH3 (lit.)
Prod./Yield (%)
1 5 6 24 / 58 / 69Et
1 5.6 24 - - / 58 - - / 69
2 14 48 94 / 62 - - / 15
OH
3 3.5 2.0 89 / 38 - - / - -
4 3.5 2.0 77 / 40 - - / 89
Case Study Case Study –– Birch Reduction Birch Reduction
Goal: Develop a manufacturing process for a Birch reduction of a steroid that does not require liquid ammonia and cryogenic temperaturesp
Results: Conditions were developed which used SiGNa materials in THF at 0 °C without the use of liquid ammonia.
Minimized the amount undesired side-products and comparable yields and purities were observed.
Eliminated the expensive part of the client’s regular Birch reduction which was the required cooling capacity of the reaction and ammonia recycle.
Lowered the client cost of goods by 18% –ll d th t d t liallowed them access to a new product line
Birch with Deuterium IncorporationBirch with Deuterium Incorporation
SiGNa’s Reaction Conditions:
• Phenanthrene and Na‐SG(I) (3.5 equivalents) are charged to a round bottom flask and stirred
• THF is added and the mixture is cooled• THF is added and the mixture is cooled• Reaction is allowed to warm to room temperature and quenched with D2O
• Desired product is isolated in similar yields and purities• Desired product is isolated in similar yields and purities• NMR integrations shows deuterium incorporation product in 81% yield
When performing a reduction with SiGNa materials,When performing a reduction with SiGNa materials,When performing a reduction with SiGNa materials, When performing a reduction with SiGNa materials, any Cany C‐‐H bond formed can be also be converted into a CH bond formed can be also be converted into a C‐‐D bondD bond
SodiumMetal (Na0) in Water: SiGNa Na‐SG in Water:
SiGNa’sSiGNa’s Competitive AdvantageCompetitive Advantage
Sodium Metal (Na ) in Water: SiGNa Na‐SG in Water:
SiGNa’s alkali metals solvated in nano‐structured porous oxides:
Significantly simplifies processes while mitigating risks
Potential to Save $MMs for Each Process!!
Generates non‐toxic by‐products and waste streams
Potential to Save $MMs for Each Process!!
SiGNa SiGNa DeprotectionsDeprotections
Deallylation Debenzylation
Desulfonation
f f ONandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefenfeld, M.; Vogt, P. F.; Jackson, J. E. Organic Letters 2008, 10 (23), 5441.
Case Study Case Study –– Palladium ContaminationPalladium Contamination
Goal: Develop a deprotection step which minimized palladium in the API and that does not require a resin treatment or other precious metal removal stepprecious metal removal step
Results: Desired deprotection was achieved using SiGNa materials to give target API in comparable yields and purities to Pd/Cgive target API in comparable yields and purities to Pd/C hydrogenolysis route.
Palladium content of API, inherently, was 0 ppm. No extra work up steps or purifications were required.
New route removed regulatory hurdle to filling New Drug ApplicationApplication.
Lowered the client’s cost of goods by 24% –Increased productivity by 50%
Order SiGNa Materials TodayOrder SiGNa Materials Today
www.alfa.com
Prod. No. Product Name Size44893 Stage I Sodium-Silica Gel 5g, 25g, 100g44894 Stage II Sodium-Silica Gel 5g, 25g, 100g44892 Stage I Na2K-Silica Gel 5g, 25g, 100g44890 St g I K N Sili G l 5g 25g 100g44890 Stage I K2Na-Silica Gel 5g, 25g, 100g
www.sigmaaldrich.com
Prod. No. Product Name Size660167 Stage I Sodium-Silica Gel 5g, 25g, 100g660175 Stage II Sodium-Silica Gel 5g, 25g, 100g660159 Stage I Na2K-Silica Gel 5g, 25g, 100g660140 Stage I K2Na-Silica Gel 5g, 25g, 100g
To purchase development and commercial volumes of SiGNa materials or for technical support, please contact SiGNa Chemistry directly at
