jake ganley group meeting july 8, 2018...jake ganley group meeting july 8, 2018 principles of flow...
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Jake Ganley
Group Meeting
July 8, 2018
Principles of Flow Chemistry
Principles of Flow Chemistry
1. Introduction to Flow Chemistry
2. Mass Transport Phenomena
3. Heat Transfer Phenomena
4. Novel Process Windows & Safety Considerations
5. Conclusions
Principles of Flow Chemistry
1. Introduction to Flow Chemistry
2. Mass Transport Phenomena
3. Heat Transfer Phenomena
4. Novel Process Windows & Safety Considerations
5. Conclusions
A
B C
reagents
Product
•Workup•Isolation
Flow Reactor
A
BC
Product
Batch Chemistry Flow Chemistry
Reactants added, reacted, and isolated discretely Reactants added, reacted, and isolated continuously
Batch vs Flow Operations
Reagent A
Reagent B
Product C
Reagent Delivery Mixing Reactor Quench PressureRegulator
Collection
Anatomy of a Flow Reactor
Reagent A
Reagent B
Product C
Reagent Delivery Mixing Reactor Quench PressureRegulator
Collection
Mixing/Reactor Unit Structure Heat/Mass Transfer & Safety Properties Beneficial Reaction Outcomes
Anatomy of a Flow Reactor
T-Shaped Mixer Split and Recombine Multilaminar
Re =ρDh υµ
=inertial forcesviscous forces
Reynolds Number Einstein–Smoluchowski Equation
tm =L2
D
ρ = fluid density Dh = hydraulic diameterυ = fluid velocity μ = dynamic viscosity
tm = characteristic mixing time
L = diffusion distance D = molecular diffusivity
Mixing Units
Types of Reactors
Chip Reactor Coil Reactor Packed Bed Reactor
•Best heat transfer properties
•Low throughput
•Most widely used in synthetic chemistry
•Inner diameter 0.01”–1/16”
•Best for heterogeneous catalysts
•Simulates high effective molarity of catalyst
Laminar Flow
Slug Flow
longitudinal interface
transverse interfaces Taylor Flow Thin Film
Flow Profiles
Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42.
Reagent A
Reagent B
Product Cc1
c2
υ1
υ2
V, T P
Quench
Residence Time
τ =υ
V
conc
entr
atio
n
conc
entr
atio
n
time time
•Parabolic reaction profile results in residence time distribution
Molar Flow Ratesn = cυ
Key Parameters
Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42.
Principles of Flow Chemistry
1. Introduction to Flow Chemistry
2. Mass Transport Phenomena
3. Heat Transfer Phenomena
4. Novel Process Windows & Safety Considerations
5. Conclusions
Da =χDt
2
4τD=
characteristic mixing timereaction time
Damköhler Number
χ = kinetic coeffiecient Dt2 = channel diameter
τ = residence time D = diffusivity
3 sec 5 sec
10 sec 30 sec
3 min
For Da > 1 : Reaction faster than mixing
For Da < 1 : Mixing faster than reaction
What happens when the reaction rate outpaces the rate of mixing?
Mixing Rate vs Reaction Rate
•C primarily is formed •Significant side products as C reacts with B
Da =characteristic mixing time
reaction time
Damköhler Number
A B C B S+ +
Da > 1 Da < 1
Concentration Gradients
Manipulation of the Damköhler Number
Da =characteristic mixing time
reaction time
Damköhler Number
•Batch Strategy: Slow down reaction rate
k = Ae
Arrhenius Rate Law
k =
Eyring Equation–ΔG‡/(RT)–Ea/(RT) kBT
he
•Expensive to cool large reactors to cryogenic temperatures
•Small temperature gradients can degrade selectivity for highly exothermic reactions
•Longer overall operation time
Manipulation of the Damköhler Number
•Flow Strategy: Accelerate mixing rate
T-Shaped Mixer Split and Recombine Multilaminar
Manipulation of the Damköhler Number
•Flow Strategy: Accelerate mixing rate
A B C B S+ +
Da > 1 Da < 1
Manipulation of the Damköhler Number
•Flow Strategy: Accelerate mixing rate
Da > 1 Da < 1
OMe
OMeMeOBu
NCO2Me -78ºC
OMe
OMeMeOBuN
MeO2C
BuNCO2Me
OMe
OMeMeOBuN
MeO2C+ + N
Bu
CO2Me
Yoshida, J.-i. J. Am. Chem. Soc. 2005, 127, 11666–11675.
Manipulation of the Damköhler Number
•Flow Strategy: Accelerate mixing rate
OMe
OMeMeOBu
NCO2Me -78ºC
OMe
OMeMeOBuN
MeO2C
BuNCO2Me
OMe
OMeMeOBuN
MeO2C+ + N
Bu
CO2Me
Mixer
Batch
T-Shaped
SAR-type
Multilamination type
% Mono-alkylated % Di-alkylated
36 31
50 14
36 31
92 4
Yoshida, J.-i. J. Am. Chem. Soc. 2005, 127, 11666–11675.
MeS
NPMBMe
O O n-HexLi
SNPMBMe
OO
F
BrN
Me
SO
t-Bu NMe
FBr
SNPMBMe
O OSO
t-Bu
LiNH
Me
FBr
SNPMBMe
O OSO
t-Bu
AcOH
H2C
Li
73% yield, 92:8 d.r.
-65ºC
AcOD
F
BrN
CH2D
SO
t-Bu
• Both lithiated A and C are capable of deprotonating B
• True kinetic selectivity of nucleophilic addition masked by ineffiecient mixing in batch
• Authors hypothesized that increased rate of mixing in flow may contribute to higher conversions and yield
A
B CD
99% D incorporation
Synthesis of Verubecestat
Thaisrivongs, D. A. and Naber, J.R. Org. Process Res. Dev. 2016, 20, 1997–2004.
MeS
NPMBMe
O O
n-HexLi
SNPMBMe
OO
F
BrN
Me
SO
t-Bu
NMe
FBr
SNPMBMe
O OSO
t-Bu
Li
NHMe
FBr
SNPMBMe
O OSO
t-Bu
AcOH
H2C
Li
0.5 M (1 equiv)
0.75 M (1.5 equiv)
0.75 M (1.5 equiv)
1.0 M (2 equiv)
-10ºCτ1
-10ºCτ2
Pump Rate Total Flow Rate τ1 (ms) τ2 (ms) % Conversion158
10
4203240
304613830
255.03.12.5
55868887
Synthesis of Verubecestat
Thaisrivongs, D. A. and Naber, J.R. Org. Process Res. Dev. 2016, 20, 1997–2004.
Hypothetical Side Reactions
Starting Material Intermediate
Decomoposition
Intramolecular Reaction
Product
Outpacing Intermediate Decomposition
Li XH H LiX+
α-Elimination Productive Chemistry
I Cl2 equiv
MeLi2 equiv
O
H
1 equiv
OHCl
310 ms Li Cl H H
-40ºC
Luisi, R. Adv. Synth. Catal. 2015, 357, 21–27.
Outpacing Intermediate Decomposition
Li XH H LiX+
α-Elimination Productive Chemistry
I Cl2 equiv
MeLi2 equiv
O
H
1 equiv
OHCl
310 ms Li Cl H H
-40ºC
Luisi, R. Adv. Synth. Catal. 2015, 357, 21–27.
Hypothetical Side Reactions
Starting Material Intermediate
Decomoposition
Intramolecular Reaction
Product
Outpacing Intramolecular Reactions
O
O
RLiE
O
O
RE
O OLi
R
OLi O
RE
OE O
R
Anionic Fries Rearrangement
Et2N
O
OI
1) PhLi
2) ClCO2Me
O
O
Et2N O
OMe
O O
NEt2
O
MeO+
Residence Time (ms) Unrearranged Rearranged628 0 91377 20 74220 45 5155 73 214
0.338791
40
Yoshida, J.-i. Science 2016, 352, 691 − 694.
Outpacing Intramolecular Reactions
O
O
RLiE
O
O
RE
O OLi
R
OLi O
RE
OE O
R
Anionic Fries Rearrangement
Et2N
O
OI
1) PhLi
2) ClCO2Me
O
O
Et2N O
OMe
O O
NEt2
O
MeO+
Residence Time (ms) Unrearranged Rearranged628 0 91377 20 74220 45 5155 73 214
0.338791
40
Yoshida, J.-i. Science 2016, 352, 691 − 694.
Principles of Flow Chemistry
1. Introduction to Flow Chemistry
2. Mass Transport Phenomena
3. Heat Transfer Phenomena
4. Novel Process Windows & Safety Considerations
5. Conclusions
Temperature Gradients
ΔTad =cs,0(–ΔHR)
ρCp
Adiabatic Temperature Rise
“worst case scenario”
ρ = fluid densitycs,0 = inlet concentrationΔHR= reaction enthalpy Cp= specific heat
β =–rΔHRdh
6hinΔTad
Ratio of Heat Exchange
dh = diameter
ΔHR= reaction enthalpy hin = heat-transfer coefficient
ΔTad = adiabatic temperature rise
=heat generation rateheat removal rate
Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42.
Heat Exchange in Flow
h
dh
β =–rΔHRdh
6hinΔTad
Ratio of Heat Exchange
dh = diameter
ΔHR= reaction enthalpy hin = heat-transfer coefficient
ΔTad = adiabatic temperature rise
=heat generation rateheat removal rate
heat exchange in microreactor
•Increasing surface area to volume ratio increases heat exchange efficiency
Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42.
Consequences of Temperature Gradients
What are the consequences of temperature gradients?
Consequences of Temperature Gradients
ΔΔG‡
I1 I2
P1P2
Degradation of Selectivity
flow
batchΔG‡
1ΔG‡
2
ΔΔG‡
P
SP
Degradation of Product
flow
batchΔG‡
1ΔG‡
2
Curtin-Hammett Selectivity Product Formation/Degradation
Energy Energy
SM
Intermediate Degradation
Br
Br
Li
Br
E
Br
BuLi E+
Time
Temp
Li
Br
MeOH
BuLi
Br
Br
H
Br
Yoshida, J.-i. J. Am. Chem. Soc. 2007, 129, 3046–3047.
βB = 6.3 (exotherm faster than heat transfer)
βF = 0.2 (heat removed effectively)
Principles of Flow Chemistry
1. Introduction to Flow Chemistry
2. Mass Transport Phenomena
3. Heat Transfer Phenomena
4. Novel Process Windows & Safety Considerations
5. Conclusions
Temperature vs Reaction Rate
k = Ae
Arrhenius Rate Law–Ea/(RT)
k =
Eyring Equation–ΔG‡/(RT)kBT
he
•When reactions are prohibitively slow, heating will accelerate the rate
•Frequently reactions can be heated in batch to a temperature that allows for a reasonable reaction time
Gilmore, K. and Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893.
Boiling Points of Common Solvents
Solvent Boiling Point (ºC)acetonitrile 821-butanol 118chloroform 61dimethylformamide 1531,4-dioxane 101ethanol 79ethyl acetate 77methanol 65methylene chloride 40N-methyl-2-pyrrolidinone 2022-propanol 82tetrahydrofuran 65toluene 111water 100
Reaction Vessel Pressure Rating (bar)
2 mL screw-cap vial 10
0.2–30 mL microwave tubes
250 mL screw-cap flask
polymer-based tubing
stainless steel tubing
30
~4
~10
>100
•Batch reactors are limited by the boiling point of the solvent
•Microwave tubes cannot be scaled beyond 30 mL
•With stainless steal tubing, virtually any temperature with any solvent can be achieved
Examples of High Temperature Reactions
Me
Me
CN Toluene (2.0 M)
250ºC, 60 bar0.8 mL/min
Me
Me
CN
DME (0.15 M)
300ºC, 80 bar1.0 mL/min
MeO
NMe2S
O
MeO
S
O NMe2
O OHToluene (0.1 M)
240ºC, 100 bar1.0 mL/min NH2
NH
O
NH
AcOH/IPA (0.5 M)
200ºC, 75 bar5.0 mL/min
N Cl NH
O Toluene (2.0 M)
250ºC, 60 bar0.8 mL/min
N NO
Diels-Alder Reaction Nucleophilic Aromatic Substitution
Claisen Rearrangement
Newman-Kwart Rearrangement
Fisher Indole Synthesis
Kappe, C. O. Eur. J. Org. Chem. 2009, 1321–1325.
Gaseous Reagents in Flow
Bubble Flow
Slug Flow
Annular Flow
increasing gas flow rate
p = kHcHenry’s Law
p = partial pressure
kH = temperature-dependent constant
c = concentration
Gilmore, K. and Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893.
gas phase liquid phase
concentration
interface
For many gas-liquid reactions, mass transfer is rate-determining
Gaseous Reagents in Flow
p = kHcHenry’s Law
p = partial pressure
kH = temperature-dependent constant
c = concentration
Gilmore, K. and Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893.
gas phase liquid phase
concentration
interface
For many gas-liquid reactions, mass transfer is rate-determiningkLa
Mass Transfer Efficiency
kL = mass transfer coefficienta = interfacial area
type of reactor
5 mL RB Flask
50 mL RB Flask
250 mL RB Flask
tube reactors
gas–liquid microchannel
interfacial area (m2/m3)
141
66
38
50–700
3400–18000
Biphasic Mass Transfer
CN CN
Bu
BrEt3BnNCl
KOH (aq), 80ºC, 9.8 min
Aqueous:Organic (v/v) Organic Slug Length (µm) Interfacial Area (m2/m3) kLa % Conversion
1.0
2.3
4.0
6.1
467
330
295
265
0.24
0.36
0.41
0.47
3000
4500
5100
5900
40
74
92
99
Schouten, J.C. Ind. Eng. Chem. Res. 2010, 49, 2681–2687.
Gas Diffusion vs Reaction Rate
gas phase liquid phase
concentration
interface
gas
film
liqui
d fil
m
Ha = √ 2m+1
km,n(cA,i)m–1(cB,bulk)nDA
kL
Hatta Number
Compares the rate of reaction in the liquid film to the rate of diffusion through the film
Ha > 3Instantaneous reaction happens at interface
Ha < 0.3Slow reaction
happens in bulk phase
Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42.
Photon Transport Phenomenon
Beer–Lambert LawA = εcl
A = absorbance ε = extinction coefficientc = concentration l = path length
Berry, M.B.; Booker-Milburn, K.I. J. Org. Chem. 2005, 70 (19), 7558–7564.
Handling of Hazardous Reagents
Diazomethane PhosgeneFluorine Chlorine
H2C N NF F Cl ClO
Cl Cl
• Generate and consume hazardous reagents instantaneously
•Minimize total concentration of hazardous reagents
Precursor
Activator
Substrate
Product
Hazardous Reagent
Handling of Diazomethane
O
OMe NPhN
NCH2
O
O
H2C
Ph CO2MePh
O
CH2
Cl
Methylation [2+3] Cycloaddition Cyclopropanation Homologation
Diazald
Acetic Acid
aqueous waste
NON
Tos Me
KOHH2C N N
Diazald
O
OMe
KOH
PMDS membrane reactor
Ki, D.-P. Angew. Chem. Int. Ed. 2011, 20, 5952–5955.
Handling of Phosgene
O
Cl3CO OCCl3
DIPEA
TriphosgeneO
Cl Cl
H2NO
OAllyl
PhNH
O
OAllyl
Ph
R1
O
OHR2
DIPEA, DMF
Triphosgene OR1
R2
•Epimerization is reduced by reducing residence time
0.5 sec
4.3 sec
Takahashi, T. Angew. Chem. Int. Ed. 2014, 53, 851–855.
Principles of Flow Chemistry
1. Introduction to Flow Chemistry
2. Mass Transport Phenomena
3. Heat Transfer Phenomena
4. Novel Process Windows & Safety Considerations
5. Conclusions
Flask vs Flow
Flask Conditions
OH
O O OHNH
N NN
HN
DMSO, RT+
5 mol%
Flow Conditions
OH
O O OHNH
N NN
HN
DMSO, 60ºC+
5 mol%
40 hours77% yield, 74% ee
20 min79% yield, 75% ee
Arvidsson, P.I. Eur. J. Org. Chem. 2005, 4287–4295. Seeberger, P.H. Angew. Chem. Int. Ed. 2009, 48, 2699–2702.
NO2
NO2 NO2
NO2
Flask vs Flow
Blacker, J. Armstrong, A. Cabral, J.T. Blackmond, D.G. Angew. Chem. Int. Ed. 2010, 49, 2478–2485.
“It may simply be a case of comparing apples with oranges, combined with the dangers inherent in inferring conclusions based on simple end-point analysis in the absence of time-course data.”
Adiabatic Temperature Rise
ΔTad = 1.3 ºC
Worst case scenario in batch: 61.3ºC
βB = 1 x 10-2 βF = 4 x 10-4
Rates of Heat Transfer
Conclusions
•Flow chemistry has emerged as a tool for synthetic organic chemists
•The decision to implement a flow vs batch process is highly context specific
•Flow can potentially provide higher yield and selectivity by reducing concentration and temperature gradients
•Flow setups allow chemists to reach novel process windows with regards to temperature, pressure, and photon flux, potentially accelerating reaction rates
•Flow chemistry does not improve every process!
Is flow chemistry the answer to the ultimate questions of life, the universe, and whether or not Rob can actually dunk?
Is the reaction safe in batch?
Is the reaction reported in batch at an acceptable level with respect to yield, scale, and reaction time?
Is one of the reagents a gas?
Does a preciptate drive the equilibrium in the desired direction?
Is one reagent/catalyst a solid?
Is the reaction fast (<1 min)?
Is selectivity affected by temperature?
Does the reaction need to be high heat in order to achieve a reasonable reaction rate?
Is the reaction photochemically driven?
unfortunately not
Batch Chemistry
Flow Chemistry
yes
no
no
no
no
no
no
no
no
yes
yes
yes
yes yes
yes
yes
yes
yesSeeberger, P.H. Chem. Rev. 2017, 117, 11796–11893.
Additional Reading
The Hitchhiker’s Guide to Flow ChemistryPlutschack, M.B.; Pieber, B.; Gilmore, K.; Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893.
Beyond Organometallic Flow Chemistry: The Principles Behind the Use of Continuous-Flow Reactors for SynthesisNöel,T.; Su, Y.; Hessel, V. Top. Organomet. Chem. 2016, 57, 1–42.
Deciding Whether to Go with the Flow: Evaluating the Merits of Flow Reactors for SynthesisHartman, R.L.; McMullen, J.P.; Jensen, K.F. Angew. Chem. Int. Ed. 2011, 50, 7502–7519.