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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.

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Presentation on theme: "Charette Group - Literature Meeting January 31 st, 2011 Chemical Kinetics and Recent Applications of Calorimetry in Organic Chemistry and Process Development."— Presentation transcript:

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

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

3 1 Atibaia, S.-P., Brazil  Laval, Qc, Canada Atibaia  Laval Montreal Laval Brasil 

4 1 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, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

5 1 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, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

6 1 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 Calorimetry Calorimetry Heat a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

7 2 Calorimetry... From Heat Joseph Black  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. a) Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry 2008, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

8 3 Calorimetry  Indirect Calorimetry : calculates the heat that living organisms produce from their production of CO 2, nitrogen waste (ammonia or urea), or from their consumption of O 2.  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, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

9 4 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, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

10 5 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, 3 rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678. d) http://www.omnicaltech.com

11 6 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 7 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 8 Omnical – SuperCRC Researcher Software WinCRC Turbo The Software WinCRC Turbo collects raw data and convert them into reaction rates. Rate of Reaction = Increase in concentration of products Time in which change takes place the speed of a reaction a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 9 Differential Scanning Calorimeter - Super CRC  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. Reaction Time Heat Course of reaction Software WinCRC Turbo + Physical Theories a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 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. Tau Correction Raw Data to Corrected Curve – Tau Correction 10 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.

16 11 Reaction Calorimetry a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 12 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 = ΔH rxn ⋅ V ⋅ r q ΔH rxn 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 Heat flow Reaction progress a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 13 Conversion Analysis via Calorimetry  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 t = specific time point t 0 = initial time of the reaction t f = final time of the reaction q = reaction heat rate n = number of moles of reagent t 0 t t f Heat flow a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 14 Reaction Order Versus Concentration 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 aA + bB pP + qQ a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 15 First Order A P a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 16 First Order Ex. N 2 O 5  2NO 2 + ½ O 2 Concentration of a Reactant versus Time Rate of Reaction versus Reactant Concentration a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 17 Second Order or a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 18 Second Order Ex. 2CH 3 CHO  2CH 4 + 2 CO Concentration of a Reactant versus Time Rate of Reaction versus Reactant Concentration or a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 19 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 Chemistry 2003, 7 th edition, 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 20 Zero Order Concentration of a Reactant versus Time Rate of Reaction versus Reactant Concentration a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 21 Reaction Order - Summary a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 Zero-OrderFirst-OrderSecond-Ordernth-Order Rate Law Integrated Rate Law Units of Rate Constant (k) Linear Plot to determine k Half-life Units of k mol·L -1 ·s -1 s -1 mol -1 ·L·s -1 mol 1-n ·L n-1 ·s -1 22

28 23 Catalyzed Reaction Kinetics Versus Concentration K M = Michaelis constant (M) = affinity of substrate to catalyst (enzyme). The higher the K M, the lower the affinity V = current reaction rate (M min -1 ) V max = maximum reaction rate (M min -1 ) Michaelis-Menten Lineweaver-Burk Derivation a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7 th edition, 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 24 Calorimetry/Chemical Kinetics Summary q = ΔH rxn ⋅ V ⋅ r

30 25  Problem 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 time 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.

31 26  More Problems 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 26  More Problems 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 26  More Problems 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 27 Calorimetry in Organic Chemistry  Academic Organic Chemistry - Mechanism and chemical kinetics  Stephen L. Buchwald - Reaction order in catalyst  Eric N. Jacobsen - Reaction optimization  Tamejiro Hiyama 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 28 Mechanism Study Versus Diamine Ligand  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]. ”  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? 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 29 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 30 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 31 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, [K 3 PO 4 ] 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 32 Reaction Rate Versus Diamine Loading Reaction Conditions : Amide (0.8 M) ArX (0.4 M), CuI (0.02 M).  Saturation after 0.1 M of diamine (5:1) diamine:Cu 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 33 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 34 Reaction Rate Versus Base Loading  The reaction rate exhibits nearly zero-order kinetics in [K 3 PO 4 ] 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 35 Reaction Rate Versus Base Loading  Zero-order kinetics in [K 3 PO 4 ]. It is also important to note that the ΔH rxn for all of these experiments does not change significantly. ΔH rxn = 163 ± 2 kJ/mol As a average for the 6 different rate analysis. 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 36 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 37 Reaction Rate Versus Amide Loading  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]. 0.6 M 0.93 M 0.8 M 0.7 M 0.6 M 0.93 M 0.8 M 0.7 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.

45 38 Reaction Rate  Cu-diamine : first-order  ArI : first-order  K 3 PO 4 : 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 39 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 40 Reaction Rate

48 41 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 42 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 43 Reaction Rate Versus Diamine Loading Amide 0.7 M ArX 0.6 M Amide 1.0 M ArX 0.6 M Amide 0.9 M ArX 0.4 M [Amide] 0.6 M [Amide] 0.7 M [Amide] 0.9 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], K 1 [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.

51 44 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. 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], K 1 [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].

52 45 Copper-Amidate  Experimental and calorimetric studies establish both the chemical and kinetic competency of Cu(I)-amidate intermediate in the C-N bond formation. ” Quant. 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.

53 46 Summary of Cu-Amidate Study  At hight concentrations of the diamine : oxidative insertion to the aryl iodide to become the rate-limiting step.  At low concentrations of diamine, however, the catalyst resides as a multiply ligated species, which requires the dissociation of an amide through diamine coordination to generate the active copper(I) amidate.  These results show that both the diamine and the amide play vital roles in the rate at which the N-arylation occurs.  The diamine serves to prevent multiple ligation of the amide forming the Cuprate. (Soluble) 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.

54 47 Diamine Ligand Comparison Reaction Conditions : Amide (0.8 M), Ar-X (0.4 M), CuI (0.02 M). - Ligand 4 is faster - Ligand 3 has a higher affinity to Cu(I).  Good cat. : ( Kcat and Km)  Good cat. : ( Kcat and Km) 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.

55 48 Electronic Effect with Hammett Equation Hammett Equation  Electron-deficient analogues facilitate more rapid turnover rates 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.

56 49 Reaction Optimization  Finding best ligand for the coupling reaction by calorimetric studies of conversions Ligands : a ) Shafir. A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-8743. SI..

57 50 Reaction Optimization  L4 reaches complete conversion after 40 min while L2 after 2h a ) Shafir. A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-8743. SI..

58 51 Reaction Optimization  Determination of reaction conditions by calorimetric studies of conversions a ) Nakao, Y.; Chen, J.; Imanaka, H.; Hiyama, T.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 9137-9143. SI..

59 52 Reaction Optimization (a) PhB(OH) 2 (67 mM) [Rh(OH)(cod)] 2 (2.7 mM) B(OH) 3 (536 mM). 1,4-dioxane/H 2 O (10/1) at 30 °C. (b) 1 (67 mM) [Rh-(OH)(cod)] 2 (2.7 mM) 1,4-dioxane at 50 °C. (c) 1 (67 mM) [Rh(OH)(cod)] 2 (2.7 mM) THF at 30 °C. (d) PhSi(OMe) 2 (67 mM) [Rh(cod)(MeCN) 2 ]BF 2 (2.7 mM) 1,4-dioxane/H 2 O (10/1) at 50 °C. 1 a ) Nakao, Y.; Chen, J.; Imanaka, H.; Hiyama, T.; Ichikawa, Y.; Duan, W.-L.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 9137-9143. SI..

60 53 Reaction Order Determination  Determination of reaction order in catalyst by calorimetry. Cat. a) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, SI.

61 54 Reaction Order Determination “ The rate doubles for every increase in catalyst loading by a factor of The reaction is second order in catalyst throughout the entire course of the reaction. ” a) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, SI.

62 55 Reaction Order Determination [cat] (M) Rate 2 [cat] “ The rate doubles for every increase in catalyst loading by a factor of The reaction is second order in catalyst throughout the entire course of the reaction. ” a) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, SI.

63 56 a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125. b) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. Calorimetric Studies at Pfizer – Groton  The heat of reaction is an important parameter in the safe, successful scale-up of chemical processes.  Reaction heat data is used to predict potential risks or runaway reactions with temperature rising within exothermic reactions.  Pfizer global process safety network provides a heat of reaction for all processes run in kilo laboratories, pilot plant, and manufacturing facilities.  Pfizer uses 2 methods used to determine reaction heats: 1 - Experimental measurement - Small scale calorimetry – Omnical SuperCRC 2 - Estimation techniques - Physical theories and equations

64 57 Results Comparison a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125.

65 58 Results Comparison a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125.

66 59 Results Comparison a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125.

67 60 Safety Evaluation of Sodium Borohydride In which solvent would you dissolve kg of NaBH 4 ? DMF or DMA a) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763. c) Liu, Y.; Schwartz, J. J. Org. Chem. 1993, 58, 5005.

68 60 Safety Evaluation of Sodium Borohydride In which solvent would you dissolve kg of NaBH 4 ? DMF or DMA a) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763. c) Liu, Y.; Schwartz, J. J. Org. Chem. 1993, 58, 5005.

69 60 Safety Evaluation of Sodium Borohydride  Thermal stability of NaBH 4 was examined in DMA and in DMF by accelerating rate calorimeter (ARC) and a SuperCRC reaction microcalorimeter. In which solvent would you dissolve kg of NaBH 4 ? DMF or DMA a) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763. c) Liu, Y.; Schwartz, J. J. Org. Chem. 1993, 58, 5005.

70 61 Safety Evaluation of Sodium Borohydride a) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763. c) Liu, Y.; Schwartz, J. J. Org. Chem. 1993, 58, 5005.

71 61 Safety Evaluation of Sodium Borohydride a) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763. c) Liu, Y.; Schwartz, J. J. Org. Chem. 1993, 58, 5005.

72 61 Safety Evaluation of Sodium Borohydride Omnical SuperCRC Heat of dissolution of 0.21 g NaBH4 in 1.7 mL DMA : - Temperature rise : 28 °C - Specific heat : 2J/(g ·K) - Dissolution energy : 56 J/g a) Shimizu. S. et al. Org. Process. Res. Dev. 2010, 14, 1518–1520. b) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763. c) Liu, Y.; Schwartz, J. J. Org. Chem. 1993, 58, 5005.

73 Finally!!! Thank you!!!

74 62 a) Pelletier, G.; Bechara, W. S.; Charette, A. B., J. Am. Chem. Soc. 2010, 132, 12817. b) Barbe, G; Charrette, A. B. J. Am. Chem. Soc. 2008, 130, 18. Catalytic Reactions [B] = [B]o - [A]o + [A] [B] = ["excess"] + [A] ["excess"] = [B]o - [A]o

75 63 a) Pelletier, G.; Bechara, W. S.; Charette, A. B., J. Am. Chem. Soc. 2010, 132, 12817. b) Barbe, G; Charrette, A. B. J. Am. Chem. Soc. 2008, 130, 18. Calorimetry

76 64 a) Pelletier, G.; Bechara, W. S.; Charette, A. B., J. Am. Chem. Soc. 2010, 132, 12817. b) Barbe, G; Charrette, A. B. J. Am. Chem. Soc. 2008, 130, 18. Rate Constant Versus Temperature Arrhenius Equation A = frequency factor for the reaction, R = universal gas constant T = temperature (K), k = reaction rate constant

77 65 a) Laidler, Keith, J. (1993). The World of Physical Chemistry. Oxford University Press. ISBN 0-19-855919-4. Calorimetry q ΔU ΔT C V = reaction heat rate = change in internal energy = change in temperature = heat capacity at constant volume

78 66 Reaction rate (fast equilibrium) (slow equilibrium) (fast equilibrium)

79 1 a) Pelletier, G.; Bechara, W. S.; Charette, A. B., J. Am. Chem. Soc. 2010, 132, 12817. b) Barbe, G; Charrette, A. B. J. Am. Chem. Soc. 2008, 130, 18. Reaction Rate Versus Catalyst Loading Reaction conditions: [CuI] = 0.01 - 0.04 M, [Diamine] = 0.04 - 0.22 M, [ArX] 0 = 0.4 M, [Amide] = 0.8 M, [K 3 PO 4 ] 0 = 1.0 M, 2 mL of toluene, 90 °C. At low [Diamine] : (Cu:diamine = 1:2). At high [Diamine] : (Cu:diamine = 1:7). “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 visually convenient conversions to see that this is the case.”


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