Principles of Flow Chemistry

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 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 Batch vs Flow Operations

Batch Chemistry Flow Chemistry

reagents A

B A C Flow Reactor Product B •Workup C •Isolation Product

Reactants added, reacted, and isolated discretely Reactants added, reacted, and isolated continuously Anatomy of a Flow Reactor

Reagent Delivery Mixing Reactor Quench Pressure Collection Regulator

Reagent A

Product C

Reagent B Anatomy of a Flow Reactor

Reagent Delivery Mixing Reactor Quench Pressure Collection Regulator

Reagent A

Product C

Reagent B

Mixing/Reactor Unit Structure Heat/Mass Transfer & Safety Properties Beneficial Reaction Outcomes Mixing Units

T-Shaped Mixer Split and Recombine Multilaminar

Reynolds Number Einstein–Smoluchowski Equation 2 ρD υ inertial forces L Re = h = tm = µ viscous forces D

t = characteristic mixing time ρ = fluid density Dh = hydraulic diameter m υ = fluid velocity μ = dynamic viscosity L = diffusion distance D = molecular diffusivity Types of Reactors

Chip Reactor Coil Reactor Packed Bed Reactor

•Best heat transfer properties •Most widely used in synthetic •Best for heterogeneous catalysts chemistry •Low throughput •Simulates high effective molarity •Inner diameter 0.01”–1/16” of catalyst Flow Profiles

Slug Flow

transverse interfaces Taylor Flow Thin Film

Laminar Flow

longitudinal interface

Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42. Key Parameters

Reagent A Quench

c1 υ1 Product C

V, T P Reagent B

c2 υ2

Molar Flow Rates n = cυ

concentration

Residence Time concentration time V time τ = υ •Parabolic reaction profile results in residence time distribution

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 Mixing Rate vs Reaction Rate

Damköhler Number

χD 2 characteristic mixing time Da = t = 4τD reaction time

2 3 sec 5 sec χ = kinetic coeffiecient Dt = channel diameter τ = residence time D = diffusivity

For Da > 1 : Reaction faster than mixing For Da < 1 : Mixing faster than reaction 10 sec 30 sec

What happens when the reaction rate outpaces the rate of mixing? 3 min Concentration Gradients

A + B C + B S

Da > 1 Da < 1

•C primarily is formed •Significant side products as C reacts with B

Damköhler Number characteristic mixing time Da = reaction time Manipulation of the Damköhler Number

•Batch Strategy: Slow down reaction rate

Damköhler Number Arrhenius Rate Law Eyring Equation

–Ea/(RT) k T –ΔG‡/(RT) characteristic mixing time k = Ae B e Da = k = reaction time h

•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

OMe OMe OMe CO2Me CO2Me -78ºC MeO2C MeO2C CO2Me + N N + N N N Bu Bu Bu Bu Bu MeO OMe MeO OMe MeO OMe

Da > 1 Da < 1

Yoshida, J.-i. J. Am. Chem. Soc. 2005, 127, 11666–11675. Manipulation of the Damköhler Number

•Flow Strategy: Accelerate mixing rate

OMe OMe OMe CO2Me CO2Me -78ºC MeO2C MeO2C CO2Me + N N + N N N Bu Bu Bu Bu Bu MeO OMe MeO OMe MeO OMe

Mixer % Mono-alkylated % Di-alkylated

Batch 36 31

T-Shaped 36 31

SAR-type 50 14

Multilamination type 92 4

Yoshida, J.-i. J. Am. Chem. Soc. 2005, 127, 11666–11675. Synthesis of Verubecestat

O O n-HexLi S Me NPMB Me

A O Li O O O O Li S S S t-Bu NH O O S t-Bu H2C NPMB t-Bu N N O O Me S Me NPMB Br Me S AcOH Me NPMB Br F Me -65ºC Br F Me F D B C 73% yield, 92:8 d.r.

• Both lithiated A and C are capable of deprotonating B O AcOD S N t-Bu • True kinetic selectivity of nucleophilic addition masked Br by ineffiecient mixing in batch CH2D F • Authors hypothesized that increased rate of mixing in 99% D incorporation flow may contribute to higher conversions and yield

Thaisrivongs, D. A. and Naber, J.R. Org. Process Res. Dev. 2016, 20, 1997–2004. Synthesis of Verubecestat

O O S Me NPMB O Me Li O O S N t-Bu 0.75 M (1.5 equiv) S H2C NPMB Br n-HexLi Me -10ºC Me 0.75 M (1.5 equiv) -10ºC F τ1 τ2 0.5 M (1 equiv)

O Li S t-Bu N O O AcOH Me S 1.0 M (2 equiv) NPMB Br F Me

O S t-Bu NH O O Pump Rate Total Flow Rate τ1 (ms) τ2 (ms) % Conversion Me S NPMB 1 4 304 25 55 Br F Me 5 20 61 5.0 86 8 32 38 3.1 88 10 40 30 2.5 87 Thaisrivongs, D. A. and Naber, J.R. Org. Process Res. Dev. 2016, 20, 1997–2004. Hypothetical Side Reactions

Decomoposition

Starting Material Intermediate Product

Intramolecular Reaction Outpacing Intermediate Decomposition

α-Elimination Productive + LiX Li X H H Chemistry

I Cl 2 equiv 310 ms Li Cl H H

-40ºC MeLi OH 2 equiv Cl

1 equiv

Luisi, R. Adv. Synth. Catal. 2015, 357, 21–27. Outpacing Intermediate Decomposition

α-Elimination Productive + LiX Li X H H Chemistry

I Cl 2 equiv 310 ms Li Cl H H

-40ºC MeLi OH 2 equiv Cl

1 equiv

Luisi, R. Adv. Synth. Catal. 2015, 357, 21–27. Hypothetical Side Reactions

Decomoposition

Starting Material Intermediate Product

Intramolecular Reaction Outpacing Intramolecular Reactions

O O Anionic Fries Rearrangement

O R O R O OLi OLi O OE O E E E Li R R R

O O O

Et2N O 1) PhLi Et2N O O MeO O O + I 2) ClCO Me 2 OMe NEt2

Residence Time (ms) Unrearranged Rearranged 628 0 91 377 20 74 220 45 51 55 73 21 4 87 4 0.33 91 0 Yoshida, J.-i. Science 2016, 352, 691 − 694. Outpacing Intramolecular Reactions

O O Anionic Fries Rearrangement

O R O R O OLi OLi O OE O E E E Li R R R

O O O

Et2N O 1) PhLi Et2N O O MeO O O + I 2) ClCO Me 2 OMe NEt2

Residence Time (ms) Unrearranged Rearranged 628 0 91 377 20 74 220 45 51 55 73 21 4 87 4 0.33 91 0 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

Adiabatic Temperature Rise Ratio of Heat Exchange

cs,0(–ΔHR) –rΔHRdh heat generation rate T = β = = Δ ad heat removal rate ρCp 6hinΔTad “worst case scenario” ΔHR= reaction enthalpy hin = heat-transfer coefficient cs,0 = inlet concentration ρ = fluid density dh = diameter ΔTad = adiabatic temperature rise ΔHR= reaction enthalpy Cp= specific heat Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42. Heat Exchange in Flow

Ratio of Heat Exchange heat exchange in microreactor –rΔHRdh heat generation rate β = = heat removal rate 6hinΔTad

ΔHR= reaction enthalpy hin = heat-transfer coefficient dh = diameter ΔTad = adiabatic temperature rise h

dh •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

Curtin-Hammett Selectivity Product Formation/Degradation

Degradation of Selectivity Degradation of Product

ΔΔG‡ ΔΔG‡ flow flow batch batch ‡ ‡ ‡ ΔG 2 ‡ ΔG 2 ΔG 1 ΔG 1

SM I1 I2 P

Energy P1 Energy SP P2 Intermediate Degradation

βB = 6.3 (exotherm faster Br Li E than heat transfer) BuLi E+

Br Br Br βF = 0.2 (heat removed effectively)

Br Li

Time Br Br Temp BuLi H

MeOH

Yoshida, J.-i. J. Am. Chem. Soc. 2007, 129, 3046–3047. 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

Arrhenius Rate Law k = Ae –Ea/(RT)

Eyring Equation

k T –ΔG‡/(RT) k = B e h

•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) Reaction Vessel Pressure Rating (bar) acetonitrile 82 2 mL screw-cap vial 10 1-butanol 118 0.2–30 mL microwave tubes 30 chloroform 61 dimethylformamide 153 250 mL screw-cap flask ~4 1,4-dioxane 101 polymer-based tubing ~10 ethanol 79 stainless steel tubing >100 ethyl acetate 77 methanol 65 methylene chloride 40 •Batch reactors are limited by the boiling N-methyl-2-pyrrolidinone 202 point of the solvent 2-propanol 82 •Microwave tubes cannot be scaled beyond tetrahydrofuran 65 30 mL toluene 111 water 100 •With stainless steal tubing, virtually any temperature with any solvent can be achieved Examples of High Temperature Reactions

Diels-Alder Reaction Nucleophilic Aromatic Substitution

O Toluene (2.0 M) Me CN Toluene (2.0 M) Me CN 250ºC, 60 bar N N 250ºC, 60 bar N Cl N Me Me H 0.8 mL/min 0.8 mL/min O

Claisen Rearrangement Fisher Indole Synthesis O O OH Toluene (0.1 M) AcOH/IPA (0.5 M) NH 200ºC, 75 bar 240ºC, 100 bar N 5.0 mL/min H 1.0 mL/min NH2

Newman-Kwart Rearrangement

S NMe2 O NMe2

O DME (0.15 M) S

300ºC, 80 bar MeO MeO 1.0 mL/min Kappe, C. O. Eur. J. Org. Chem. 2009, 1321–1325. Gaseous Reagents in Flow

Bubble Flow For many gas-liquid reactions, mass transfer is rate-determining

Slug Flow gas phase liquid phase increasing gas flow rate concentration

interface Annular Flow Henry’s Law

p = kHc

p = partial pressure c = concentration

kH = temperature-dependent constant Gilmore, K. and Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893. Gaseous Reagents in Flow

Mass Transfer Efficiency For many gas-liquid reactions, mass transfer is rate-determining kLa

kL = mass transfer coefficient a = interfacial area

gas phase liquid phase type of reactor interfacial area (m2/m3)

5 mL RB Flask 141 concentration

50 mL RB Flask 66 interface

250 mL RB Flask 38 Henry’s Law

tube reactors 50–700 p = kHc

gas–liquid microchannel 3400–18000 p = partial pressure c = concentration

kH = temperature-dependent constant Gilmore, K. and Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893. Biphasic Mass Transfer

CN Et3BnNCl CN Br KOH (aq), 80ºC, 9.8 min

2 3 Aqueous:Organic (v/v) Organic Slug Length (µm) Interfacial Area (m /m ) kLa % Conversion

1.0 467 3000 0.24 40

2.3 330 4500 0.36 74

4.0 295 5100 0.41 92

6.1 265 5900 0.47 99

Schouten, J.C. Ind. Eng. Chem. Res. 2010, 49, 2681–2687. Gas Diffusion vs Reaction Rate

gas film Hatta Number liquid phase gas phase 2 liquid film liquid m–1 n km,n(cA,i) (cB,bulk) DA Ha = √ m+1 concentration kL Compares the rate of reaction in the liquid interface film to the rate of diffusion through the film

Ha > 3 Ha < 0.3 Instantaneous reaction Slow reaction happens at interface happens in bulk phase Nöel, T. Top. Organomet. Chem. 2016, 57, 1–42. Photon Transport Phenomenon

Beer–Lambert Law A = εcl

A = absorbance ε = extinction coefficient c = concentration l = path length

Berry, M.B.; Booker-Milburn, K.I. J. Org. Chem. 2005, 70 (19), 7558–7564. Handling of Hazardous Reagents

Fluorine Chlorine Diazomethane Phosgene

O F F Cl Cl H2C N N Cl Cl

• Generate and consume hazardous reagents instantaneously

•Minimize total concentration of hazardous reagents

Precursor Hazardous Reagent

Activator Product

Substrate Handling of Diazomethane

Methylation [2+3] Cycloaddition Cyclopropanation Homologation

O O H2 O C N Cl OMe N NPh Ph C Ph CO2Me H2 C H2 O

Diazald NO KOH N H2C N N Tos Me Diazald

aqueous waste

KOH O

PMDS membrane OMe reactor Acetic Acid

Ki, D.-P. Angew. Chem. Int. Ed. 2011, 20, 5952–5955. Handling of Phosgene

Triphosgene O O DIPEA O R1 OH Cl3CO OCCl3 Cl Cl

R2 0.5 sec DIPEA, DMF

Ph Triphosgene O 4.3 sec R1 OAllyl N H Ph R2 O

OAllyl H2N O

•Epimerization is reduced by reducing residence time

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 H N N N N N O H O OH O 5 mol% + H 40 hours DMSO, RT 77% yield, 74% ee NO2 NO2

Flow Conditions H N N N N N O H O OH O 5 mol% 20 min + H DMSO, 60ºC 79% yield, 75% ee

NO2 NO2

Arvidsson, P.I. Eur. J. Org. Chem. 2005, 4287–4295. Seeberger, P.H. Angew. Chem. Int. Ed. 2009, 48, 2699–2702. Flask vs Flow

Adiabatic Temperature Rise

ΔTad = 1.3 ºC

Worst case scenario in batch: 61.3ºC

Rates of Heat Transfer -2 βB = 1 x 10 β = 4 x 10-4 “It may simply be a case of comparing apples with F oranges, combined with the dangers inherent in inferring conclusions based on simple end-point analysis in the absence of time-course data.”

Blacker, J. Armstrong, A. Cabral, J.T. Blackmond, D.G. Angew. Chem. Int. Ed. 2010, 49, 2478–2485. 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? Batch Chemistry unfortunately not no Is the reaction safe in batch? yes Is the reaction reported in batch at an acceptable yes level with respect to yield, scale, and reaction time? no yes Is one of the reagents a gas? no Does a preciptate drive the equilibrium in the desired direction? yes no yes Is one reagent/catalyst a solid? yes no Flow Chemistry yes Is the reaction fast (<1 min)? no yes Is selectivity affected by temperature? no

yes Does the reaction need to be high heat in order to achieve a reasonable reaction rate? no yes Is the reaction photochemically driven? Seeberger, P.H. Chem. Rev. 2017, 117, 11796–11893. Additional Reading

The Hitchhiker’s Guide to Flow Chemistry Plutschack, 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 Synthesis Nöel,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 Synthesis Hartman, R.L.; McMullen, J.P.; Jensen, K.F. Angew. Chem. Int. Ed. 2011, 50, 7502–7519.