charette group - literature meeting january 31 st , 2011

Charette Group - Literature MeetingCharette Group - Literature MeetingJanuary 31January 31stst, 2011, 2011

Chemical Kinetics and Chemical Kinetics and Recent Applications of Calorimetry inRecent Applications of Calorimetry in

Organic Chemistry and Process DevelopmentOrganic Chemistry and Process Development

A + B C +D

William S. Bechara

Atibaia, S.-P., Brazil Laval, Qc, Canada

Atibaia

Brasil

1

Atibaia, S.-P., Brazil Laval, Qc, Canada

Atibaia Laval

Montreal

Laval

Brasil

1

Chemical Kinetics

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 edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

1

Chemical Kinetics

HeatHeat

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 edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

1

Chemical Kinetics

CalorimetryCalorimetry

HeatHeat

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 edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

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

3

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 edition, 30-72, 862-943. c) Laidler, K. J. The World of Physical Chemistry 1995, Oxford University, 562-678.

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

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

6

Omnical – SuperCRCSmall 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

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

8

Omnical – SuperCRCResearcher Software WinCRC Turbo

A + B C + D

The Software WinCRC Turbo collects raw data and convert them into reaction rates.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 reactiona) 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

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, 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.

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.

Raw Data to Corrected Curve – Tau CorrectionTau 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.

11

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.

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 = ΔHrxn V r⋅ ⋅

qΔHrxn

Vrnv

= 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

Heatflow Reaction progress

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

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 pointt0 = initial time of the reaction t f = final time of the reactionq = reaction heat raten = number of moles of reagent

t0 t tf

Heatflow

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

Reaction Order Versus Concentration

rk

[X]x,yx+y

tdt

= 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, 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

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.

16

First Order

Ex. N2O5 2NO2 + ½ O2

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.

17

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.

18

Second Order

Ex. 2CH3CHO 2CH4 + 2 CO

Concentration of a Reactant versus Time

Rate of Reaction versus Reactant Concentration

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.

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

rk

[X]

= reaction rate= reaction rate constant= concentration of reactant

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

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.

21

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.

Reaction Order - Summary

Zero-Order First-Order Second-Order nth-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 mol1-n·Ln-1·s-1

22

23

Catalyzed Reaction Kinetics Versus Concentration

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)

Michaelis-Menten Lineweaver-BurkMichaelis-Menten Lineweaver-Burk

Derivation

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.

24

Calorimetry/Chemical Kinetics Summary

q = ΔHrxn V r⋅ ⋅

25

Studies of Catalytic Reactions Problem 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

timea) 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 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 High concentrations in one reagent may dramatically influence the

chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the

relative abundance of the catalytic species. ”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 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 High concentrations in one reagent may dramatically influence the

chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the

relative abundance of the catalytic species. ”relative abundance of the catalytic species. ” What do we do?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 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 High concentrations in one reagent may dramatically influence the

chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the chemistry of the catalytic cycle, i.e., shifting the rate-limiting step and the

relative abundance of the catalytic species. ”relative abundance of the catalytic species. ” What do we do? - Let’s see some examplesWhat 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.

27

Calorimetry in Organic Chemistry

28

Mechanism Study Versus Diamine Ligand

IHN

OCuI (5 mol%)

Ligand (10 mol%)

K3PO4, Tol, 90 °C, 2hN

O

+NHMe

NHMe

99%

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.

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.

R1 X

CuI (1-10 mol%)Ligand (5-20 mol%)

K3PO4, Tol 90-110 °C

R1 N+NHMe

NHMe

R2

R3HN

R3

R2X = Cl, Br, IR1 = Ar, Het

R2 = Ar, Het, COR

R3 = H, Ar, Alkyl

Ligand

N N

O

S

ONH2

98% 97%

N

98%

O

N

OH

95%OMe

H H

N

91%

N N

72%

>55 examplesGood to excellents yields

Ph

N

91%

N

O

N

NN

O

86%

HN

O

98%

N

N

OPh

86%

HO

O

N

62%

H

NH2N

Ph

O

N

75%

NH2

Ot-BuO

Ph

30

Plausible Mechanism

N Cu NR2

R2

R1

O

R1O

Cu XN

N

Cu NR2

R1O

I

Major Speciesat Low [Diamine]

Major Speciesat High [Diamine]

NR2

R1O

Ar-Y

R3

Cuprate Cu-amidate Cu-diamine

Cu-X+ Diamine (Ligand)

+ Amide+ Ar-Y

X, Y = Halogen

via

Cu NR2

R1O

N

N

Cu YN

N

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

Calorimetry and GC Conversion Comparison

Agreement between Agreement between the two methods the two methods

Heat FlowHeat Flowis proportionalis proportional

to reactionto reactionconversionconversion

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.

32

Reaction Rate Versus Diamine Loading

Reaction Conditions : Amide (0.8 M) ArX (0.4 M), CuI (0.02 M).

Saturation afterSaturation after0.1 M of diamine0.1 M of diamine

(5:1) diamine:Cu (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.

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.

34

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.

35

Reaction Rate Versus Base Loading

Zero-order kinetics in [K3PO4]. It is also important to note that the ΔHrxn for all of these experiments does not change significantly.

ΔHΔHrxnrxn = 163 ± 2 kJ/mol = 163 ± 2 kJ/mol

As a average for the 6 As a average for the 6 different rate analysis. 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.

36

Reaction Rate Versus Ar-X Loading

Green vertical lines indicate that the reaction rate linearlydecreases at 0.5M of [amide] with different concentrations of ArI and

diamine, confirming the first order dependence on [ArI]. The reaction ratedecreases 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.

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 M0.8 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.

38

Reaction Rate

IHN

OCuI (5 mol%)

Ligand (10 mol%)

K3PO4, Tol, 90 °CN

O

+NHMe

NHMe

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.

Cu NR2

R1O

N

N

Cu-amidate

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

N Cu NR2

R2

R1

O

R1O

Cu NR2

R1O

N

NCu X

N

N

Cu NR2

R1O

I

Major Speciesat Low [Diamine]

Major Speciesat High [Diamine]

NR2

R1O

k1Ar-Y

R3

Cuprate Cu-amidate Cu-diamine

K1 K2

Cu-X+ Diamine (Ligand)

+ Amine or Amide+ Ar-Y

X, Y = Halogen

via

Without diamine, Without diamine, there is no reaction there is no reaction

from 0 to 90 °C.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.

40

Reaction RateN Cu N

R2

R2

R1

O

R1O

Cu NR2

R1O

N

NCu X

N

N

Cu NR2

R1O

I

Major Speciesat Low [Diamine]

Major Speciesat High [Diamine]

NR2

R1O

k1Ar-Y

R3

Cuprate Cu-amidate Cu-diamine

K1 K2

X, Y = Halogen

via

41

Reaction RateN Cu N

R2

R2

R1

O

R1O

Cu NR2

R1O

N

NCu X

N

N

Cu NR2

R1O

I

Major Speciesat Low [Diamine]

Major Speciesat High [Diamine]

NR2

R1O

k1Ar-Y

R3

Cuprate Cu-amidate Cu-diamine

K1 K2

X, Y = Halogen

via

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

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 Diamine Loading

Amide 0.7 MArX 0.6 M

Amide 1.0 MArX 0.6 M

Amide 0.9 MArX 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], K1[amide]<<1 and the resting state of the catalyst shifts toSpecies 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

Reaction Rate

N Cu NR2

R2

R1

O

R1O

Cu NR2

R1O

N

NCu X

N

N

Cu NR2

R1O

I

Major Speciesat Low [Diamine]

Major Speciesat High [Diamine]

NR2

R1O

k1Ar-I

R3

Cuprate Cu-amidate Cu-diamine

K1 K2

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], K1[amide]<<1 and the resting state of the catalyst shifts toSpecies Cu-diamine, giving first-order kinetics in both [ArI] and [Amide]

and zero-order kinetics in [diamine].

45

Copper-Amidate

Experimental and calorimetric studies establish both the Experimental and calorimetric studies establish both the chemical and kinetic competency of Cu(I)-amidate chemical and kinetic competency of Cu(I)-amidate

intermediate in the C-N bond formation. ”intermediate in the C-N bond formation. ”

CuHN

O Toluene

rt+

Cu N

O

2

Quant.

Cu N

OAr-I

Toluenert, 0 °C

N

O

X

Cu N

O Ar-IDiamine

Toluenert, 0 °C

N

O

Cu NR2

R1O

N

N

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

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.

N Cu NR2

R2

R1

O

R1O

Cu NR2

R1O

N

NCu X

N

N

Cu NR2

R1O

I

Major Speciesat Low [Diamine]

Major Speciesat High [Diamine]

NR2

R1O

k1Ar-I

R3

Cuprate Cu-amidate Cu-diamine

K1 K2

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.

47

Diamine Ligand Comparison

Reaction Conditions : Amide (0.8 M) , Ar-X (0.4 M), CuI (0.02 M).

NHMe

NHMe

NHMe

NHMe

3 4

Cu NN

Nkcat

ArIToluenert, 90 °C

N

OO

- Ligand 4 is faster- Ligand 4 is faster

- Ligand 3 has a higher affinity to Cu(I).- 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.

48

Electronic Effect with Hammett Equation

Hammett EquationHammett Equation

Electron-deficient Electron-deficient

analogues facilitate more analogues facilitate more

rapid turnover ratesrapid 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.

49

Reaction Optimization

CuI (5 mol%)Ligand (20 mol%)

Cs2CO3 (2 equiv)DMF, 25 °C

+H2N

5

I HN

5

Finding best ligand for the coupling reaction

by calorimetric studies of conversions

O O O O

t-Bu

O

t-Bu

ONEt2

O

OH

Ligands :

a ) Shafir. A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-8743. SI..

50

Reaction Optimization

L4 reaches complete conversion after 40 min L4 reaches complete conversion after 40 min while L2 after 2h while L2 after 2h

a ) Shafir. A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742-8743. SI..

51

Reaction Optimization

Ph MO O

Ph+

Rh.

solvent30 or 50 °C

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..

52

Reaction Optimization

(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.

S

HO

1

Ph MO O

Ph+

Rh.

solvent30 or 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..

53

Reaction Order Determination

Determination of reaction order in catalyst by calorimetry.

R

O

ROH

OH

R

O

+-

Cat.

H2O+

Cat.

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

“ The rate doubles for every increase in catalyst loading by a factor ofThe reaction is second order in catalyst throughout the entire course of the reaction. ”

2

2

a) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, SI.

55

Reaction Order Determination

[cat] (M)[cat] (M)

Rate • 2

2[cat]

“ The rate doubles for every increase in catalyst loading by a factor ofThe reaction is second order in catalyst throughout the entire course of the reaction. ”

2

a) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, SI.

56a) 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 – GrotonThe 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

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

Results Comparison

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

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

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

Thermal stability of NaBH4 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 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.

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

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 SuperCRCHeat of dissolutionof 0.21 g NaBH4in 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.

Finally!!!

Thank you!!!

62a) 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

63a) 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

64a) 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 EquationArrhenius Equation

A = frequency factor for the reaction, R = universal gas constantT = temperature (K), k = reaction rate constant

65a) Laidler, Keith, J. (1993). The World of Physical Chemistry. Oxford University Press. ISBN 0-19-855919-4.

Calorimetry

qΔUΔTCV

= reaction heat rate= change in internal energy = change in temperature = heat capacity at constant volume

66

Reaction rate

(fast equilibrium)

(slow equilibrium)

(fast equilibrium)

1a) 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,[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.”