Jake Ganley Group Meeting July 8, 2018...Jake Ganley Group Meeting July 8, 2018 Principles of Flow Chemistry Principles of Flow Chemistry 1. Introduction to Flow Chemistry 2. Mass

Jake Ganley

Group Meeting

July 8, 2018

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






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







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


•Flow Strategy: Accelerate mixing rate

T-Shaped Mixer Split and Recombine Multilaminar



A B C B S+ +

Da > 1 Da < 1



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.



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


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.






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


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


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


βB = 6.3 (exotherm faster than heat transfer)

βF = 0.2 (heat removed effectively)






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)


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)


N Cl NH

O Toluene (2.0 M)


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


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



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


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


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.






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.

Documents

Jake Ganley Group Meeting July 8, 2018...Jake Ganley Group Meeting July 8, 2018 Principles of Flow Chemistry Principles of Flow Chemistry 1. Introduction to Flow Chemistry 2. Mass