Aerobic (Alcohol) Oxidation in Flo...Aerobic (Alcohol) Oxidation in Flow Challenges in Catalysis for...
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Aerobic (Alcohol) Oxidation in Flow Challenges in Catalysis for Pharmaceuticals and Fine Chemicals V London, November 2016 Paul Alsters [email protected]
Transcript of Aerobic (Alcohol) Oxidation in Flo...Aerobic (Alcohol) Oxidation in Flow Challenges in Catalysis for...
Aerobic (Alcohol) Oxidation in Flow
Challenges in Catalysis forPharmaceuticals and Fine Chemicals V
London, November 2016
Paul Alsters
Page 1
Bulk chemicals (2009 figures)
The traditional stronghold of aerobic oxidation catalysisChemical Mton/year Air O2 HNO3 Cl2 ROOH H2O2
Terephthalic acid 44 •
Formaldehyde 19 •
Ethene oxide 18 •
1,2-Dichloroethane 18 • • •
Propene oxide 8 • • •
Cyclohexanone 6 • •
Vinyl acetate 6 • •
Acrylonitrile 6 •
Styrene (ex Propene oxide/Styrene) 5 • •
Phenol/Acetone 5 •
Phthalic anhydride 5 •
Acrylic acid 5 •
MTBE (ex Propene oxide/tButyl alcohol) 4 •
Adipic acid 3 •
Maleic anhydride 2 •
Hydrogen cyanide 2 •
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The renaissance of aerobic oxidation catalysis
From bulk to fine
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# Publications related to catalytic oxidationwith oxygen in journals on organic synthesis(SciFinder 31 July 2015)
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Cost & waste reduction: O2 for Pd catalyzed C-H activation
Cross-dehydrogenative arene-arene coupling
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DSM example on aerobic Pd catalyzed biaryl synthesis
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Cost & waste reduction: O2 for Cu catalyzed dehydrogenation
Cross dehydrogenative N-N coupling
Triazolo-pyridines, pyrazines,pyridazines, and pyrimidinesfrom guanidyl-N-heterocycles
Roche pharma: J. Org. Chem. 2015, 80, 1249
Aerobic Cu catalysis revolutionizes heterocycle synthesis
Young chemists award account by Shunsuke Chiba:"Cu-Catalyzed Aerobic Molecular Transformation of Imine and Enamine Derivatives forSynthesis of Azaheterocycles", Bull. Chem. Soc. Jpn. 2013, 86, 1400
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SimpleCu salt,Simpleligand
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Another revolution: (aerobic) carbocatalysis
Graphene:C
Grapheneoxide:CxOyHz
Graphiticcarbon
nitride:C3N4 B-doped N-doped
graphene: graphene:CxBy CxNyHz
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SimpleCarbo-
catalyst
Carbocatalysis: multi-purpose applications
Selected examples of unusual or useful reactions, survival of oxidation-sensitive groups,and/or demonstrated superiority over other tested oxidation methods
More organocatalysis: aerobic alcohol oxidations
From heterogeneous carbocatalysts to homogeneous nitroxyls
P.L. Anelli (TEMPO)Y. Iwabuchi (AZADOs; ABNOs)
Iwabuchi review: Chem. Pharm. Bull. 2013, 61, 1197Page 9
N ON OX R
N ON O
X
TEMPO R = X = H:R = Me, X = H:R = H, X = F:
AZADO1-Me-AZADO5-F-AZADO
norAZADO X = H2:X = O:
ABNOketoABNO
Kg availabilityfrom Nissan
2 Steps fromacetonedicarboxylic
acid
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Preparation and properties of ketoABNO
• Redox potential in MeCN vs ferrocene: 416 mV(cf AZADO: 188 mV; TEMPO: 239 mV)Þ suitable organocatalyst for electron-deficient alcohols
• a-Carbonyl methylene groups may reduce organocatalyststability under basic bleach conditions, but ketoABNO foundto be effective under (non-basic) aerobic conditions
Improved prep and aerobic oxidns: B. Karimi, ChemSusChem 2014, 7, 2735Redox potentials and aerobic oxidns: S.S. Stahl, ACS Catal. 2013, 3, 2612Aerobic oxidns of electron-deficient alcohols: M. Kanai, Adv. Synth. Catal.2015, 357, 2193
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Transition metal-like catalyst turnovers
Under "Anelli bleach" conditions for unactivated alcohols
Y. Iwabuchi, Chem. Pharm. Bull. 2011, 59, 1570
Nitroxyls as organocatalysts for aerobic alcohol oxidations
Dominated by two protocols
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Continuous flow!
Transition metal-like catalyst turnovers
Under "aerobic Cu" conditions for activated alcohols
M.J. Muldoon, Catal. Sci. Technol. 2014, 4, 1720
90% Conversion in 20 min at 40 bar air; unactivated secondary alcohols:several hrs at 0.1 mol%/RT/1 bar air (Cu cat decomposition at 40 bar!)
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"FOX" (flow oxidation) project goals
• Set-up of a safe, continuous flow system for catalyticaerobic oxidations, also based on pure oxygen besides air
• Implementation of online analysis (FT-IR)• Kick-off transformation: oxidation of primary and secondary
alcohols to industrially relevant aldehydes and ketones
Recent publications by S.S. Stahl on flow protocols for aerobic Cu/nitroxylcatalyzed alcohol oxidations:Org. Process Res. Dev. 2015, 19, 858 (elevated P&T using 100% O2 in a PTFEtube-in-shell membrane reactor)Org. Process Res. Dev. a.s.a.p. (process development together with Pfizer,Merck, and Lilly)Org. Process Res. Dev. 2013, 17, 1247 (elevated P&T using 9% O2/N2 in astainless steel or PTFE tube reactor)
Toleratessteric
bulkaround
alcoholTole
rate
sco
ordi
nati
nghe
tero
atom
s
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Remarkably broad scope of aerobic Cu/nitroxyl cat systems
S.S. Stahl, J. Am. Chem. Soc. 2013, 135, 15742
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Two relevant alcohol oxidations
Benzylic but bulkyEpoxone
Deactivated and bulky
Necessitates low cat costs!
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In house pilot plant experience on 220 lbs Epoxol oxidation
Potentially cheap lab alcohol ox methods failed on scale-up!
Replacing non-viable alcohol oxidation protocols withinexpensive, green aerobic protocols enableslarge-scale application of Epoxone technology
L• Bleach instead of periodate caused product and catalyst degradation• TEMPO + bleach (Anelli) not active (too hindered alcohol)• Stoichiometric chromate not feasible on large scale• NaIO4 offered acceptable cost because DSM was a periodate producer at the time
David J. Ager, Org. Process Res. Dev. 2007, 11, 44
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Implementation of online FT-IR analysis
Benzyl alcohol (704 cm-1) → benzaldehyde (1704 cm-1)
SwitchfromN2 to O2
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Design of the Taylor flow reactor
Pumping& mixing
gases
Pumping& mixingliquids
G/Lmixing:Taylorflow Cooler
DilutionwithN2
Reactor FT-IR
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Benzyl alcohol oxidation under Taylor flow conditions
Dependence on oxygen pressure
0.25 M BnOH; 25°C; O2/sub = 1; 2/2/2/5 CuOTf/bpy/TEMPO/NMI
ü Rate increases with oxygen pressureÞ Turnover-limiting oxidation of Cu(I) by O2
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yiel
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7.5 bar O2
19.5 bar N2/O2and 7.5 bar O2
19.5 bar pure O2
Taylor flow: slow rate with near-stoichiometric O2/sub = 0.5RCH2OH + 0.5 O2 è RCH(O) + H2O
Near stoichiometric O2/sub minimizes N2 dilution,but high O2/sub required for fast conversionPage 21
Pumping& mixing
gases
Pumping& mixingliquids
G/Lmixing:Taylorflow Cooler
DilutionwithN2
Reactor FT-IR
O2/sub= 2
O2/sub= 1
G slugs much smallerthan L slugs Þ G/Lmixing insufficient
Good Taylor flowÞ efficient G/Lmixing
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Design of the single phase reactor
Pumping& mixing
gases
Pumping& mixingliquids
P = 34 barG/solventpre-mixing Cooler
DilutionwithN2
FT-IR3D printedzig-zagreactor
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Zig-zag assures turbulent (non-laminar)flow despite the commercially relevantmillimeter diameter scale of the tube
3D printed zig-zag reactor
How it looks like:inside and outside
Red:Tracer that rapidly homo-genizes thanks to theturbulent flow athigh Reynoldsnumber
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3D printing by Selective Laser Melting: principleSLM produceshomogenous metalobjects directly from3D CAD data byselectively meltingfine layers of metalpowder with a laserbeam.
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3D printing by Selective Laser Melting: practice
Developed by ILT Fraunhofer Aachen (1995)
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Benzyl alcohol oxidation under various flow regimes
Taylor vs. single phase conditions
19 bar O2
33 bar O2
0.25 M BnOH; 25°C; 5/5/5/10 mol% CuOTf/bpy/TEMPO/NMI
ü Rate increases by using single phase conditionsü O2/sub can be lowered to 0.55 (10% excess)
2 phases
1 phase
O2/sub=1
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Oxidation of fenchyl alcohol as a model for Epoxol
Catalyst optimization: "more is better" except for NMI
Cf:
0.25 M Fenchyl alcohol; 60 min@70°C/1 bar O2 (balloon); 0.1 mol% ketoABNO
ü Optimum at 5 mol% NMI irrespective of NMI/Cu ratio
/bpy/bpy/bpy
/bpy
NMI (mol%)
ketoABNONMI
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Mechanism of Cu/nitroxyl aerobic alcohol oxidation
S.S. Stahl, J. Am. Chem. Soc. 2014, 136, 12166
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Oxidation of Epoxol under Taylor flow conditions
Molar O2/Epoxol ratio and oxygen pressure: "more is better"...?
7.5 bar O2 O2/sub = 1
0.2 M Epoxol; 25°C; 5/5/1/10 mol% CuOTf/bpy/ketoABNO/NMI
ü Rate hardly increases with molar O2/alcohol ratio and P(O2)Þ Turnover-limiting cleavage of the C−H bond
(Cf turnover-limiting oxidation of Cu(I) by O2 for BnOH)
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19.5 bar O2
7.5 bar O2
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Oxidation of Epoxol under single phase conditions
Conversion does not continuously increase with temperature
11 min 100°C
Catalyst degrades attoo high temperatures?
0.2 M Epoxol; 33 bar O2; O2/sub = 1; 7.5/7.5/0.25/10 mol% CuOTf/bpy/ketoABNO/NMI
ü Full conversion with 0.25 mol% ketoABNOwithin 17 min at 100°C
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Copper(I) source: triflate or iodide...?
MeCNCu + 2 HOTf è Cu(OTf)2 + H2 WO2012010752A1
ultrasound
MeCNCu + Cu(OTf)2 è 2 CuOTf SUM WO2011109878A1___________________________________________________________
2 Cu + 2 HOTf è 2 CuOTf + H2(as MeCN solution)
CuOTf CuI (S.S. Stahl, Org. Process Res. Dev. a.s.a.p.)
Requires bpy and NMI (besides nitroxyl) Requires only NMI (besides nitroxyl)
Fluoride source in waste water may beproblematic in some countries
Acceptable halide for waste water
No corrosion problems encounteredwhen using stainless steel reactor
Corrosive Þ PTFE reactor required (lessP&T robust and less heat conductive)
Too expensive as such, but expected tobe readily available as MeCN solutionfrom (ultrasonic) Cu + HOTf reaction
Readily commercially available
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Summary• Catalytic aerobic oxidation is finally escaping from its bulk chemical stronghold
and makes its way into fine chemicals/pharma manufacture• This trend is driven by the significant reductions of (raw materials) cost, waste
and number of steps enabled by new developments in aerobic oxidation catalysis• Example: aerobic Epoxolè Epoxone opens the door to broader large-scale
application of this versatile asymmetric epoxidation organocatalyst• Scalable, safe, and efficient aerobic processing is enabled by continuous flow
reactors, in particular zig-zag reactors for single phase conditions• 3D printing has enabled cost-efficient manufacture of flow reactors with full
freedom of design: create the ideal asset for demanding chemistry• Smooth integration in existing hardware, wide diversity of applications:Ø Cryogenic organometallic chemistryØ High temperature (‘in the melt’)Ø Catalytic (aerobic) oxidationsØ Catalytic hydrogenationØ NitrationsØ Cyclopropanations (‘Ethyl diazoacetate’)Ø PolymerizationsØ Azide Chemistry
Process R&D services via DSM InnoSyn®Interested? Contact: [email protected]
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AcknowledgementsDSM:Christine CzaudernaRuben van SummerenBert DielemansRaf Reintjens
Madison (Wisconsin):Janelle StevesShannon Stahl
