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Charette Group - Literature Meeting January 31 st , 2011

Chemical Kinetics and Recent Applications of Calorimetry in Organic Chemistry and Process Development. William S. Bechara. Charette Group - Literature Meeting January 31 st , 2011. Atibaia , S.-P., Brazil  Laval, Qc, Canada. Atibaia. Brasil.

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Charette Group - Literature Meeting January 31 st , 2011

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  1. Chemical Kinetics and Recent Applications of Calorimetry in Organic Chemistry and Process Development William S. Bechara Charette Group - Literature Meeting January 31st, 2011

  2. Atibaia, S.-P., Brazil  Laval, Qc, Canada Atibaia Brasil

  3. Atibaia, S.-P., Brazil  Laval, Qc, Canada Atibaia Laval Brasil  Laval Montreal

  4. Chemical Kinetics •  Reaction kinetics is the study of rates of chemical processes, reaction's mechanism, transition states and allows the construction of mathematical models that can describe the characteristics of a chemical reaction. •  A reaction rate is the amount of substance reacted or produced per unit time. Its how fast or slow a chemical reaction takes place. • The Reaction Rate is influenced by : • The nature of the reaction • (activation energy, enthalpy, etc) • Temperature • Concentration • Pressure • Order • Solvent, Catalyst • Stirring, Surface Area a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678.

  5. Chemical Kinetics •  Reaction kinetics is the study of rates of chemical processes, reaction's mechanism, transition states and allows the construction of mathematical models that can describe the characteristics of a chemical reaction. •  A reaction rate is the amount of substance reacted or produced per unit time. Its how fast or slow a chemical reaction takes place. • The Reaction Rate is influenced by : • The nature of the reaction • (activation energy, enthalpy, etc) • Temperature • Concentration • Pressure • Order • Solvent, Catalyst • Stirring, Surface Area Heat a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678.

  6. Chemical Kinetics •  Reaction kinetics is the study of rates of chemical processes, reaction's mechanism, transition states and allows the construction of mathematical models that can describe the characteristics of a chemical reaction. •  A reaction rate is the amount of substance reacted or produced per unit time. Its how fast or slow a chemical reaction takes place. • The Reaction Rate is influenced by : • The nature of the reaction • (activation energy, enthalpy, etc) • Temperature • Concentration • Pressure • Order • Solvent, Catalyst • Stirring, Surface Area Heat Calorimetry a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678.

  7. Calorimetry... From Heat • Calorimetry :Calor (Latin) means Heat. • Heat : A form of energy associated with the motion of atoms or • molecules and capable of being transmitted. •  Adding heat to matter increases its speed and pressure. •  First defined by Joseph Black, a Scottish Physician. • Calorimetry is the science of measuring the heat exchange • of chemical reactions or physical changes. • The first Calorimeter was used in 1782-83 by • Antoine Lavoisier and Pierre-Simon Laplace. Joseph Black a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678.

  8. Calorimetry • Indirect Calorimetry : calculates the heat that living organisms produce • from their production of CO2, nitrogen waste (ammonia or urea), • or from their consumption of O2. • Direct Calorimetry : measures the • heat of a organism (or a reaction) placed • directly inside the calorimeter. a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678.

  9. Calorimeters • • Basic Calorimeter (Thermometer) • Measures the total heat of a reaction. • • Differential Scanning Calorimeter (Omnical SuperCRC) • Measures the total heat of a reaction versus time comparing it to the heat flow of a reference vessel.  Provides a more accurate heat flow of the reaction. • • Bomb Calorimeters • Measures the heat of combustion. • • Calvet-Type Calorimeter • Complex calorimeter used for large scale. • • Constant-Pressure Calorimeter • • Isothermal Titration Calorimeter • The heat of reaction is used to follow a titration experiment. a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678.

  10. Differential Scanning Calorimeter - Super CRC • • Sample Compartment : All reagents, reactants, catalyst, additives, etc. • • Reference Compartment : All reagents except for starting material (product). a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.c) Laidler, K. J. The World of Physical Chemistry1995, Oxford University, 562-678. d) http://www.omnicaltech.com

  11. Omnical – SuperCRC • Small Scale Microcalorimeter Provides : • • Total heat released by chemical reaction. • • Reaction kinetics and thermodynamics. • • Heat capacity. • • Instantaneous concentrations of reactants/products • • Thermochemical conversion. • • Accurate representations of large scale reaction • processes in early phase development. • • Scalable heat release rate profile. • • Safety screening with potential hazardous events and non-scalable factors. • It accurately maps out chemical pathways prior to scale-up because it generates • scalable heat flow that matches real process reactions, saving both money & time. a) Omnical SuperCRC Users Guide. b) http://www.omnicaltech.com

  12. Omnical – SuperCRC • Reaction Calorimeter Specifications :  • • Temperature range from -100°C to +200°C. • • 1 microwatt sensitivity. • • Pressure reactors up to 1000 psi. • • 1400 rpm internal magnetic stirring. • • Visual observation through a borescope. • • Automated syringe pump dosing. • • Generates real kinetics that match other analytical instruments (GC/HPLC). a) Omnical SuperCRC Users Guide. b) http://www.omnicaltech.com

  13. Omnical – SuperCRC • Researcher Software WinCRC Turbo • The Software WinCRC Turbo collects raw data and convert them into reaction rates. Increase in concentration of products Time in which change takes place Rate of Reaction = the speed of a reaction a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) http://www.omnicaltech.com d) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. e) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  14. Differential Scanning Calorimeter - Super CRC • Software WinCRC Turbo + Physical Theories Course of reaction Heat Reaction Time • A reaction calorimeter is a calorimeter in which a chemical reaction is initiated • within a closed insulated container. Reaction heats (absorbed or emitted) are measured • and the heat flow is obtained by integrating heat versus time. a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) http://www.omnicaltech.com d) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. e) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  15. Raw Data to Corrected Curve – Tau Correction Tau Correction : Calibration performed by applying a known quantity of heat in the thermocouple, allowing for the response of the instrument to be corrected using the WinCRC software. The tau corrected data curve is a plot of heat flow (mJ s-1 or mW) versus time. a) Omnical SuperCRC Users Guide b) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc.2004, 126, 1360-1362, SI.

  16. Reaction Calorimetry a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) http://www.omnicaltech.com d) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. e) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  17. Reaction Rate and Physical Theories • - The data acquired from the Calorimeter is : •  Quantity of heat measured in energy units (Joules or calories) versus time. •  These data lead to the heat flow or heat rate (mJ s-1 or watts) . •  The heat rate is proportional to the reaction rate : q = ΔHrxn⋅ V ⋅ r Heat flow Reaction progress q ΔHrxn V r n v = reaction heat rate = heat of reaction (enthalpy) = the reaction volume = reaction rate = number of moles of limiting reagent = stoichiometric coefficient of the limiting reagent time a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  18. Conversion Analysis viaCalorimetry • Fraction conversion and instantaneous concentrations of reactants/products • can all be calculated with the ratio or corresponding integration.  area under the heat flow to any time point t  the total area under the heat flow curve Heat flow t = specific time point t0 = initial time of the reaction t f = final time of the reaction q = reaction heat rate n = number of moles of reagent t0 t tf a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  19. Reaction Order Versus Concentration aA + bB pP + qQ r k [X] x,y x+y t dt = reaction rate = reaction rate constant = concentration of reactant = order of reaction for each reactant = order of reaction = t = derivative versus time a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  20. First Order A P a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  21. First Order Concentration of a Reactant versus Time Rate of Reaction versus Reactant Concentration Ex. N2O5 2NO2 + ½ O2 a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  22. Second Order or a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  23. Second Order or Concentration of a Reactant versus Time Rate of Reaction versus Reactant Concentration Ex. 2CH3CHO  2CH4 + 2 CO a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  24. Pseudo First Order • r = k[A][B]  second order • If [B] : constant • • Catalyst (that does not degrade within the reaction time) • • In excess [B]>>[A] • r = k’[A] where k’ = k [B]0 r k [X] = reaction rate = reaction rate constant = concentration of reactant a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  25. Zero Order Concentration of a Reactant versus Time Rate of Reaction versus Reactant Concentration a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  26. Reaction Order - Summary a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Omnical SuperCRC Users Guide. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  27. Reaction Order - Summary mol·L -1·s-1 s-1 mol-1·L·s-1 mol1-n·Ln-1·s-1

  28. Catalyzed Reaction Kinetics Versus Concentration Michaelis-MentenLineweaver-Burk Derivation KM = Michaelis constant (M) = affinity of substrate to catalyst (enzyme). The higher the KM, the lower the affinity V = current reaction rate (M min-1) V max = maximum reaction rate (M min-1) a) Atkins, P.; De Paula, J. Physical Chemistry2003, 7thedition, 30-72, 862-943.b) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, Wiley, 322-404. c) Jacobsen, E. N. et al. J. Am. Chem. Soc.2004, 126, 1360-1362, SI. d) Buchwald, S. L. et al.J. Am. Chem. Soc.2005, 127, 4120-4121, SI.

  29. Calorimetry/Chemical Kinetics Summary q = ΔHrxn⋅ V ⋅ r

  30. Studies of Catalytic Reactions  Problem • Mechanistic studies on catalytic reactions are typically complicated due to : • • More than one reactant. • • Multi-step reactions involved in the process. • • Various states that a catalytic species may exist, either within the catalytic cycle • or external to it. • • Potential slow formation of active catalyst (induction period). • • Solubility of reactants. • • Many parameters are often not constant during a reaction. • Solutions : • • Studies are performed under constant volume and pressure to simplify analysis. • • Initial rate measurements (before saturation). • • Pseudo first order approximations. Rate a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense. time

  31. Pseudo First Order  More Problems • • Pseudo first order approximations. • r = k[A][B]  second order • - With a reactant in excess • [B] >> [A] • r = k’[A] •  “ High concentrations in one reagent may dramatically influence the • chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the • relative abundance of the catalytic species. ” a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  32. Pseudo First Order  More Problems • • Pseudo first order approximations. • r = k[A][B]  second order • - With a reactant in excess • [B] >> [A] • r = k’[A] •  “ High concentrations in one reagent may dramatically influence the • chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the • relative abundance of the catalytic species. ”  What do we do? a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  33. Pseudo First Order  More Problems • • Pseudo first order approximations. • r = k[A][B]  second order • - With a reactant in excess • [B] >> [A] • r = k’[A] •  “ High concentrations in one reagent may dramatically influence the • chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the • relative abundance of the catalytic species. ”  What do we do? - Let’s see some examples a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121, SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  34. Calorimetry in Organic Chemistry • Academic Organic Chemistry • Mechanism and chemical kinetics  Stephen L. Buchwald • Reaction order in catalyst  Eric N. Jacobsen • Reaction optimization  TamejiroHiyama and Tamio Hayashi •  Stephen L. Buchwald • Application in Process development • Comparison of chemical kinetics obtained by : • Calorimeter  Pfizer • Physical theories and equations • Estimation of hazardous or runaway reactions

  35. Mechanism Study Versus DiamineLigand  What is the role of the diamine ligand in this Cu(I) catalysed C-N bound formation reaction?  What is the reaction order in each of the reactants? Since this current study is focused on determining the precise role of the diamine ligand in this reaction, the reaction rate was examined as a function of [diamine]. ” a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  36. Copper Catalyzed C-N Bond Formation a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense. c) Buchwald, S. L. et al. J. Am. Chem. Soc. 2001, 123,7727-7729. d) Buchwald, S. L. et al. J. Am. Chem. Soc. 2002, 124, 11684-11688. e) Buchwald, S. L. et al. J. Am. Chem. Soc. 2004, 126, 3529-3533. f) Buchwald, S. L. et al. J. Am. Chem. Soc. 2010, 132, 6205–6213.

  37. Plausible Mechanism a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  38. Calorimetry and GC Conversion Comparison Agreement between the two methods  Heat Flow is proportional to reaction conversion Reaction Conditions: [3,5-dimethyliodobenzene]0 = 0.4 M, [2-pyrrolidinone]0 = 0.8 M, [K3PO4]0 = 1.0 M, [CuI]0 = 0.02 M, [trans-N,N'-dimethyl-1,2-cyclohexanediamine]0 = 0.04 M in 2.0 mL of Toluene at 363 K. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  39. Reaction Rate Versus Diamine Loading  Saturation after 0.1 M of diamine (5:1) diamine:Cu Reaction Conditions : Amide (0.8 M) ArX (0.4 M), CuI (0.02 M). a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  40. Reaction Rate Versus Cu:Diamine Loading  In both cases the reaction rate displays first-order dependence on catalyst concentration throughout the entire course of the reaction. The reaction rate linearly increases with the catalyst concentration while maintaing a constant Cu:diamine ratio. Vertical lines indicate the linear increasing. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  41. Reaction Rate Versus Base Loading The reaction rate exhibits nearly zero-order kinetics in [K3PO4] a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  42. Reaction Rate Versus Base Loading ΔHrxn = 163 ± 2 kJ/mol As a average for the 6 different rate analysis.  Zero-order kinetics in [K3PO4]. It is also important to note that the ΔHrxn for all of these experiments does not change significantly. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  43. Reaction Rate Versus Ar-X Loading • Green vertical lines indicate that the reaction rate linearly • decreases at 0.5M of [amide] with different concentrations of ArI and • diamine, confirming the first order dependence on [ArI]. The reaction rate • decreases constantly for different [ArI] at the same [amide]. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  44. Reaction Rate Versus Amide Loading 0.6 M 0.93 M 0.7 M 0.8 M 0.8 M 0.7 M 0.93 M 0.6 M  At low [diamine], the reaction rate becomes inhibited at higher [amide]. At high [diamine], the reaction rate actually increases as the [amide] increases. At low [diamine], the positive-order rate dependence on [1,2-diamine] corresponds to the inverse dependence on [amide] and at high [diamine] the zero-order rate dependence on [diamine] corresponds to the positive-order dependence on [amide]. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  45. Reaction Rate • Cu-diamine : first-order • ArI : first-order • K3PO4 : zero-order • Amide : It depends on the [diamine] • There exists a direct correlation between the reaction rate. • dependence on [1,2-diamine] and the dependence on [amide]. • Further analysis of reaction rate versus [amide] is required. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  46. Reaction Rate  Without diamine, there is no reaction from 0 to 90 °C. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  47. Reaction Rate

  48. Reaction Rate a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  49. Reaction Rate a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

  50. Reaction Rate Versus Diamine Loading Amide 0.7 M ArX 0.6 M [Amide] 0.7 M [Amide] 0.6 M Amide 1.0 M ArX 0.6 M [Amide] 0.9 M Amide 0.9 M ArX 0.4 M Inverse dependence on [amide] at low [diamine]. At high [diamine], a straight-line relationship is observed between the function rate/[Amide] versus [ArI]. Under high [diamine], K1[amide]<<1 and the resting state of the catalyst shifts to Species Cu-diamine, giving first-order kinetics in both [ArI] and [Amide] and zero-order kinetics in [diamine]. a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2005, 127, 4120-4121. SI. b) Strieter, E. R.; Buchwald, S. L. Thesis Defense.

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