Transcript J. Am. Chem. Soc. 2005

Chemical Kinetics and
Recent Applications of Calorimetry in
Organic Chemistry and Process Development
William S. Bechara
Charette Group - Literature Meeting
January 31st, 2011
Atibaia, S.-P., Brazil  Laval, Qc, Canada
Atibaia
Brasil
Atibaia, S.-P., Brazil  Laval, Qc, Canada
Atibaia

Laval
Brasil

Laval
Montreal
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, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th
1
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.
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 Chemistry 2003, 7th
1
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.
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 Chemistry 2003, 7th
1
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.
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.
Joseph Black
 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, 3rd edition, Wiley, 322-404. b) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th
2
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.
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 Chemistry 2003, 7th
3
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.
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 Chemistry 2003, 7th
4
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.
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 Chemistry 2003, 7th
5
edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678. d) http://www.omnicaltech.com
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
6
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
7
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, 7th 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.
8
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 Chemistry 2003, 7th 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.
9
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.
10
Reaction Calorimetry
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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.
11
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
q
ΔHrxn
V
r
n
v
=
=
=
=
=
=
Heat
flow
Reaction progress
reaction heat rate
heat of reaction (enthalpy)
the reaction volume
reaction rate
number of moles of limiting reagent
stoichiometric coefficient of the limiting reagent
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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.
time
12
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
t0
tf
q
n
= specific time point
= initial time of the reaction
= final time of the reaction
= reaction heat rate
= number of moles of reagent
Heat
flow
t0
t
tf
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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.
13
Reaction Order Versus Concentration
aA + bB
r
k
[X]
x,y
x+y
t
dt
=
=
=
=
=
=
=
pP + qQ
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 Chemistry 2003, 7th 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.
14
First Order
A
P
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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.
15
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 Chemistry 2003, 7th 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.
16
Second Order
or
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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.
17
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 Chemistry 2003, 7th 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
Pseudo First Order
r = k[A][B]  second order
If [B] : constant
r = reaction rate
k = reaction rate constant
[X] = concentration of reactant
• Catalyst (that does not degrade within the reaction time)
• In excess [B]>>[A]
r = k’[A]
where k’ = k [B]0
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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
Zero Order
Concentration of a Reactant
versus Time
Rate of Reaction versus
Reactant Concentration
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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
Reaction Order - Summary
a) Atkins, P.; De Paula, J. Physical Chemistry 2003, 7th 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
Reaction Order - Summary
Zero-Order
First-Order
Second-Order
mol·L -1·s-1
s-1
mol-1·L·s-1
nth-Order
Rate Law
Integrated
Rate Law
Units of Rate
Constant (k)
Linear Plot to
determine k
Half-life
Units of k
mol1-n·Ln-1·s-1
22
Catalyzed Reaction Kinetics Versus Concentration
Michaelis-Menten
Lineweaver-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 Chemistry 2003, 7th 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.23
Calorimetry/Chemical Kinetics Summary
q = ΔHrxn⋅ V ⋅ r
24
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.
Rate
• Initial rate measurements (before saturation).
• Pseudo first order approximations.
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
25
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.
26
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.
26
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.
26
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
27
Mechanism Study Versus Diamine Ligand
 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.
28
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
29
al. J. Am. Chem. Soc. 2004, 126, 3529-3533. f) Buchwald, S. L. et al. J. Am. Chem. Soc. 2010, 132, 6205–6213.
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.
30
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.
31
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.
32
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.
33
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.
34
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.
35
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.
36
Reaction Rate Versus Amide Loading
0.6 M
0.7 M
0.8 M
0.93 M
0.93 M
0.8 M
0.7 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.
37
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.
38
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.
39
Reaction Rate
40
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.
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.
42
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.
43
Reaction Rate
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.
44
Copper-Amidate
Quant.
 Experimental and calorimetric studies establish both the
chemical and kinetic competency of Cu(I)-amidate
intermediate in the 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.
45
Summary of Cu-Amidate Study
 The diamine serves to prevent
multiple ligation of the amide
forming the Cuprate. (Soluble)
 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.
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
Diamine Ligand Comparison
- Ligand 4 is faster
Reaction Conditions :
Amide (0.8 M) , Ar-X (0.4 M), CuI (0.02 M).
- Ligand 3 has a higher affinity to Cu(I).
 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.
47
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.
48
Reaction Optimization
Ligands :
Finding best ligand for the coupling reaction
by calorimetric studies of conversions
a ) Shafir. A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-8743. SI..
49
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..
50
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..
51
Reaction Optimization
1
(a) PhB(OH)2 (67 mM)
[Rh(OH)(cod)]2 (2.7 mM)
B(OH)3 (536 mM).
1,4-dioxane/H2O (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]BF2 (2.7 mM)
1,4-dioxane/H2O (10/1) at 50 °C.
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..
52
Reaction Order Determination
Cat.
 Determination of reaction order in catalyst by calorimetry.
a) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, SI.
53
Reaction Order Determination
2
“ The rate doubles for every increase in catalyst loading by a factor of 2
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.
54
Reaction Order Determination
2.5
2
1.5
Rate • 2
1
0.5
[cat]
2
0
0
0.005
0.01
0.015
0.02
[cat] (M)
0.025
0.03
0.035
“ The rate doubles for every increase in catalyst loading by a factor of 2
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.
55
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
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.
56
Results Comparison
a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125.
57
Results Comparison
a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125.
58
Results Comparison
a) Weisenburger, G. A. et al. Org. Process. Res. Dev. 2007, 11, 1112–1125.
59
Safety Evaluation of Sodium Borohydride
In which solvent would you dissolve kg of NaBH4?
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.
60
Safety Evaluation of Sodium Borohydride
In which solvent would you dissolve kg of NaBH4?
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.
60
Safety Evaluation of Sodium Borohydride
In which solvent would you dissolve kg of NaBH4?
DMF
or DMA
 Thermal stability of NaBH4 was examined in DMA and in DMF
by accelerating rate calorimeter (ARC) and a SuperCRC reaction
microcalorimeter.
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.
60
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.
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.
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.
61
Finally!!!
Thank you!!!
Catalytic Reactions
[B] = [B]o - [A]o + [A]
[B] = ["excess"] + [A]
["excess"] = [B]o - [A]o
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.
62
Calorimetry
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.
63
Rate Constant Versus Temperature
Arrhenius Equation
A = frequency factor for the
reaction,
R = universal gas constant
T = temperature (K),
k = reaction rate constant
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.
64
Calorimetry
q
ΔU
ΔT
CV
=
=
=
=
reaction heat rate
change in internal energy
change in temperature
heat capacity at constant volume
a) Laidler, Keith, J. (1993). The World of Physical Chemistry. Oxford University Press. ISBN 0-19-855919-4.
65
Reaction rate
(fast equilibrium)
(slow equilibrium)
(fast equilibrium)
66
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,
[K3PO4]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.”
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.
1