flow chemistry: a useful method for performing hazardous exothermic chemistry in a safer manner
TRANSCRIPT
Flow chemistry: A useful
method for performing
hazardous exothermic
chemistry in a safer manner
Richard [email protected]
What is flow chemistry?
Performing a reaction continuously, typically on small scale,
through either a coil or fixed bed reactor.
OR
PumpReactor Collection
Mixing (batch vs. flow)
Flow reactors can achieve homogeneous mixing and uniform heating in microseconds (suitable for fast reactions)
Kinetics In Flow Reactors
• In a microfluidic device with a constant flow rate, the concentration of the reactant decays exponentially with distance along the reactor.
• Thus time in a flask reactor equates with distance in a flow reactor
X
A
dX/dt > 0
dA/dt < 0
Miniaturization: Enhanced temperature control Large surface/volume rate
• Microreactors have higher surface-to-volume ratio than macroreactors, heat transfer occurs rapidly in a flow microreactor, enabling precise temperature control.
Yoshida, Green and Sustainable Chemical Synthesis Using FlowMicroreactors, ChemSusChem, 2010
Heating Control
Batch Flow
- Lower reaction volume. - Closer and uniform temperature control
Outcome:
- Safer chemistry.- Lower possibility of exotherm.
- Larger solvent volume. - Lower temperature control.
Outcome:
- More difficult reaction control. - Higher possibility of
exotherm.
Heating Control
Lithium Bromide Exchange
Batch
Flow
• Batch experiment shows temperature increase of 40°C.• Flow shows little increase in temperature.
Ref: Thomas Schwalbe and Gregor Wille, CPC Systems
Reactants
Products
By-products
Traditional Batch Method
Gas inlet
Reactants
Products
By-products
Batch vs. Flow: Enhanced selectivity
Low reactant concentrationElimination of the productsElution of gaseous by-product
Flow Method
Industry perception
Small scale: Making processes safer Accessing new chemistry Speed in synthesis and
analysis Automation
Large scale: Making processes safer Reproducibility-less batch
to batch variation Selectivity
Why move to flow?
Hydrogenation
• Current hydrogenation processes have many disadvantages:
Need hydrogen cylinder-tough safety regulations Separate laboratory needed! Time consuming and difficult to set up Catalyst addition and filtration is hazardous Parr has low temperature, low pressure capability Analytical sample obtained through invasive means. Mixing of 3 phases inefficient - poor reaction rates
• Benefits• Safety• No filtration necessary • Enhanced phase mixing
Catalyst System-CatCart®
Aldoxim reductionAldehyde reduction
0
5
10
15
20
25
30
t /m
in
Flow
Batch
0
200
400
600
800
1000
1200
t /
min
Alkylation Suzuki-Miyaura Azide synthesis Sonogashirareaction
Flow
Batch
Initial Experiments
Hydrogen generator cell Solid Polymer Electrolyte
High-pressure regulating valves
Water separator, flow detector, bubble detector
H-Cube Pro Overview
• HPLC pumps continuous stream of solvent • Hydrogen generated from water electrolysis• Sample heated and passed through catalyst• Up to 150°C and 100 bar. (1 bar=14.5 psi)
NH
O2N
NH
NH2
Hydrogenation reactions: Nitro Reduction Nitrile reduction Heterocycle Saturation Double bond saturation Protecting Group hydrogenolysis Reductive Alkylation Hydrogenolysis of dehydropyrimidones Imine Reduction Desulfurization
O2N NO2
OHH2N NH2
OH
Conditions: 1% Pt/C, 70 bar, 100°C, residence time 17sResults: 100% conversion, 100% yield
Nitro group reductions
Low TemperatureChemistry
What is ozonolysis?
Ozonolysis is a technique that cleaves double and
triple C-C bonds to form a C-O bond.
Ozonolysis in Industry
Biologically active natural product
Synthesis of a Key intermediate for Indolizidine 215F
S. Van Ornum et al, Chem. Rev.106, 2990-3001 (2006)
Oxandrolone, anabolic steroid used to promote weightgain following extensive surgery, chronic infection
Why ozonolysis is neglected?
• Highly exothermic reaction, high risk of explosion • Normally requires low temperature: -78°C.• In addition, the batchwise accumulation of ozonide
is associated again with risk of explosion• There are alternative oxidizing agents/systems:
• Sodium Periodate – Osmium Tetroxide (NaIO4-OsO4)
• Ru(VIII)O4 + NaIO4
• Jones oxidation (CrO3, H2SO4)
• Swern oxidation
• Most of the listed agents are toxic, difficult, and/or expensive to use.
Ozonolysis in a 16–channel–microreactor (Wada, Jensen, MIT)
Y Wada, K F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036-8042
Set-up of the Ice Cube Modular System
Ozone Module: generates O3 from O2 100 mL/min, 10 % O3.
Pump Module – 2 Rotary Piston Pumps. Excellent chemical compatibility.
Reactor Module: 2 Stage reactor. -70°C-+80°C.Teflon tubing.
Versatile: 2 options
A
BC
AB
C
D
Pre-cooler/Mixer Reactor
-70-+80ºC
-70-+80ºC -30-+80ºC
Potential Apps: Azide, Lithiation, ozonolysis, nitration, swern oxidation
Quench Reactant
T (°C) Solvent Vrea (ml/min)
vQuen (ml/min)
Quench c (M)
O3
(%)X (%) OH
(%)C=O(%)
RT Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 72 0 95
0 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 60 0 97
-20 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 65 0 97
RT Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 67 0 99
0 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 70 0 99
-20 Ethanol 1 1 (2-3 eq) Thiourea 0.05 16 63 0 99
Carbonyl is the productOther quenching agents for carbonyl production: PPh3, DMS
O
O
M=192 g/mol M=152 g/mol
OH
M=154g/mol
O-Cube™ – H-Cube® - ReactIR™ ozonolysis of decene
Ozonolysis Quenching withH-Cube®
T = -30 ºC
CSM = 0.02 M (in EtOAc)
O3 excess = 30 %
T = -30 ºC to r.t.
p = 1 bar
Cat: 10 % Pd/C
React IR™
O-Cube and ReactIR are trademarks of ThalesNano Inc. and Mettler Toledo International Inc., respectively, H-Cube is registered trademark of ThalesNano Inc.
H2 10%Pd/C
ThalesNano lab based chemistry-unpublished
Ozonide eluted into cool vial under N2
Diazotization and azo-coupling in Ice Cube
Vflow (ml/min)A - B - C
T (°C) τ (1. loop, min) τ (2. loop, min) Isolated Yield (%)
FM79-1 0.4 0 2.12 3.33 91FM79-2 0.9 0 0.94 1.48 91FM79-3 0.6 0 1.42 2.22 85FM79-4 0.9 10 0.94 1.48 85FM79-5 1.5 10 0.56 0.88 86FM79-6 1.5 15 0.56 0.88 98FM79-7 1.2 15 0.71 1.11 84FM79-8 1.8 15 0.47 0.74 86
NH2 N N+ Cl-NaNO2
HCl
O-
NaOH
N N
OH
AnilineHCl sol. Pump A
Pump BNaNO2 sol.
Pump C
Phenol NaOH sol.
Novel scaffold synthesis from explosive intermediates
Nitration of Aromatic Alcohols
OH OH
NO2
NO2
O2N
Phenol
Pump A Pump B Temperature (oC)
Loop size (ml)
Conversion (%) Selectivity (%)
SolutionFlow rate (ml/min) Solution
Flow rate (ml/min)
ccHNO3 0.41g PG/15ml
ccH2SO4 0.4 5 - 10 7 1000 (different products)
1.48g NH4NO3/15ml ccH2SO4 0.7
1g PG/15ml ccH2SO4 0.5 5 - 10 13 100 100
1.48g NH4NO3/15ml ccH2SO4 0.5
1g PG/15ml ccH2SO4 0.5 5 - 10 13 50 80 (20% dinitro)
70% ccH2SO4 30% ccHNO3 0.6
1g PG/15ml ccH2SO4 0.5 5 - 10 13 (3 bar) 100 100
70% ccH2SO4 30% ccHNO3 0.6
1g PG/15ml ccH2SO4 0.5 5 - 10 13 (1 bar) 80
70 (30% dinitro and nitro)
ThalesNano’s other cryogenic, continous flow applications
Swern Oxidation
Cryogenic operating conditions (< - 60°C), limit its utility for scale up operations in batch.
Temperature (°C) OAC Solution (ml/min) Alcohol and DMSO Solution (ml/min) Conversion (%) Selectivity (%)
-30 0.96 1.9 100% 100%
-20 0.96 1.9 100% 100%
-10 0.96 1.9 100% 100%
0 0.96 1.9 100% 60%
OH ODMSO, Oxalyl-Chloride
Quench: TEA
Ice-Cube Flow Reactor
Using TFAA as a DMSO activator seems to afford even higher temperatures.
No chloromethyl-methyl-sulfide production at higher Temps.
THANK YOU FOR YOUR ATTENTION!!
ANY QUESTIONS
Booth 1422