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Principles of Flow Chemistry 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 O H 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 O H 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 Br 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.
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