colinbrennan.pdf
TRANSCRIPT
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Dr Colin Brennan, Process Studies Group
30 October 2012
Mechanistic Chemistry from Lab to Plant
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Outline
● Introduction – what does the title mean?
● Who we are, what we do & how we do it
● Examples to exemplify
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Syngenta – a leading global agribusiness
● Global agribusiness spanning crop
protection, seeds and seed care
with 26000 employees worldwide
“Bringing plant potential to life“
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Bringing Plant Potential to Life
70% of Scotch Whisky is produced by
Syngenta barley
80% of every Guinness drunk starts life
with Syngenta barley
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Syngenta – a leading global agribusiness
● Global agribusiness spanning crop
protection, seeds and seed care
with 26000 employees worldwide
● Science examples to ensure we
have sustainable excellence in
process & product development &
manufacture
“Bringing plant potential to life“
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Technology &
Engineering
PSG
Central Hub UK
Spokes in strategic
development sites
Production & Supply
Process Studies Group (Technology and Projects)
•AI process technology
•Formulation development & technology
•Analytical & Regulatory characterisation
•Seeds processing & production technology
•Engineering & project management
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Technology &
Engineering
PSG
Central Hub UK
Spokes in strategic
development sites
Production & Supply
Process Studies Group (Technology and Projects)
•AI process technology
•Formulation development & technology
•Analytical & Regulatory characterisation
•Seeds processing & production technology
•Engineering & project management
Physical Organic ChemistryOrganic Chemistry
Catalysis
Process EngineeringScale Up/Scale Down
Particle and Colloid Science
Surfactant and Colloid Science
•solution physical chemistry•physical organic/mechanisms
•solids/particle science•crystallisation & crystal science•solids separation/crystallisation
• Physical Property Estimation& Measurement
• Reactor Engineering• Phase Separation
Targeted in-depth understanding
Targeted = Differentiated Added Value & Relevance
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What do chemists and engineers do?
Chlorine approx 5-10ml/min
via mass flow controller
Pressure Indicator
(Bourdon gauge)
To vacuum via scruber
flow~3000ml/min
Catalytic Chlorination of Isophalonitrile to
Chlorophalonil
Stainless Steel Lab Reactor
Glass Desublimer Recovery
Nitrogen 10-50ml/min
via mass flow controller
AG Wardman
18.01.07
3/8" fitting
(3/8 tube stub welded to base of 1" tube)
T.I
Nitrogen 15ml/min
via mass flow controller
Lagging around
and between
sections
1" 1/2"
Reactor Section
1/4" tube(packed with carbon catalyst)
I.P.N. Evaporator
Section(190 Celsius IPN flow 0.3- 0.5g/hr)
(300- 400 Celcius)
11"
Upper lagged section heated
with electric heating tape
Lagging P.I.
T.I
P.I.
P.I.
Quartz wool (catalsyt support)
Coiled 1/8" copper tube (thermal conduction)
Heating block
Carbon catalyst
Steel sleeve (thermal conduction)
P.I
.
B19 Quickfit coneViton tubing
id - approx 20mm
T.I
Glass wool plug
B19 Quickfit cone
Gap ~2mm
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What do chemists and engineers do?
0
10
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30
40
50
60
70
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90
100
0 1 2 3 4 5 6 7
Co
nc
hours
Lab Reaction
Product
Chlorine approx 5-10ml/min
via mass flow controller
Pressure Indicator
(Bourdon gauge)
To vacuum via scruber
flow~3000ml/min
Catalytic Chlorination of Isophalonitrile to
Chlorophalonil
Stainless Steel Lab Reactor
Glass Desublimer Recovery
Nitrogen 10-50ml/min
via mass flow controller
AG Wardman
18.01.07
3/8" fitting
(3/8 tube stub welded to base of 1" tube)
T.I
Nitrogen 15ml/min
via mass flow controller
Lagging around
and between
sections
1" 1/2"
Reactor Section
1/4" tube(packed with carbon catalyst)
I.P.N. Evaporator
Section(190 Celsius IPN flow 0.3- 0.5g/hr)
(300- 400 Celcius)
11"
Upper lagged section heated
with electric heating tape
Lagging P.I.
T.I
P.I.
P.I.
Quartz wool (catalsyt support)
Coiled 1/8" copper tube (thermal conduction)
Heating block
Carbon catalyst
Steel sleeve (thermal conduction)
P.I
.
B19 Quickfit coneViton tubing
id - approx 20mm
T.I
Glass wool plug
B19 Quickfit cone
Gap ~2mm
b
plant
a
plant
plantL
b
lab
a
lab
labLA
Q
V
Pak
A
Q
V
Pak
3
6.0
3
,
,1190
11.0
1317
m
W
m
m
m
W
T
T
V
P
V
P a
b
labvessel
plantvessel
plantlab
Wmm
WV
V
PP lab
lab
lab 19.1001.01190 3
3
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What do mechanistic chemists (& the engineers in Process Studies) do?
● Help bridge the gap between reaction & reactor design
- Quantitative information & qualitative insight
- Fundamental information
- What is our scientific hypothesis?
- Design of experiments versus “mini-processes”
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11
Process development - what sometimes (usually?!) happens
Think
Charge materials
Stir to react
Test for completion
Workup
Analyse yield
Good resultSTOP
Poorresult
The end result is a little like playing the lottery:
you might get lucky but can take many goes
Even if you are lucky in the lab will it always work?
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Interview Question
0
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100
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nc
hours
Lab Reaction
Product
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Interview Question
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Lab Reaction
Product
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Lab Reaction
Product
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Interview Question
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hours
Lab Reaction
Product
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hours
Lab Reaction
Product
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hours
Lab Reaction
SM
Product
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Interview Question
0
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40
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100
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nc
hours
Lab Reaction
Product
0
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30
40
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100
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Co
nc
hours
Lab Reaction
Product
0
10
20
30
40
50
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70
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90
100
0 1 2 3 4 5 6 7
Co
nc
hours
Lab Reaction
SM
Product
0
10
20
30
40
50
60
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Co
nc
hours
Lab Reaction
SM
?
Product
?
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0
0.5
1
1.5
2
2.5
3
3.5
4
0 10 20 30 40 50 60 70 80
Co
nce
ntr
atio
n o
f oC
BC
N, A
mid
e, o
CPA
A (m
ol/
L)
time (mins)
oCPAA
Amide
oCBCN
t = 15.5 mins, Note: Single phase
End of Rxn, Single Aq phase
t= 0.5 mins, Two Phase, Assume Aq
continuous
t = 9.5 mins, Note: gassing
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Hypothesis
● The chemical reaction that we want
A + B C
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● Mass balance including inorganics
A + B C + Inorganics
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● The reactions we don’t want
A + B C + Inorganics
DECOMPOSITION
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● What really are the reactive species?
A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
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● We may have some reversible processes
A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
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● What is our continuous phase?
● What phase is the desired reaction occurring in?
A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
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Heterogeneous Systems
● What other phases are present?
● What physical processes do we have?
A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B Pre-B
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Heterogeneous Systems
● Can we remove our product to a “none-reacting” phase?
A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B Pre-B
C
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Heterogeneous Systems
● Remembering the “inorganics”, is there another reactant or catalyst that
we routinely forget?
A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B Pre-B
C
D D
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Process & Product Design
● Design, Development & Delivery of Processes for the Manufacture of
Active Ingredients & Formulated Products
- The majority of industrial chemical processes are not single solvent
homogeneous systems.
- “Two-thirds” of processes surveyed involve two or more phases
during reaction, and over a third involve three or more phases”
● Design, Development & Delivery of Products to End Application
- The majority of product applications are heterogeneous either in their
product form (formulation) or their application (product-substrate
interactions)
JH Atherton, JM Double, B Gourlay, “Survey of PI Equipment Requirements in the Fine Chemicals & Pharmaceuticals Sector”
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Process Studies Activities
Stage 1: Research Stage 2: Evaluation Stage 3: Development Stage 4: Life Cycle
NEW PRODUCT DEVELOPMENT LIFE CYCLE TECHNOLOGY MANAGEMENT
AI Development
Formulation Development
AI-Formulation Interface
Redesign: AI & 2nd Generation Formulations
AI ELS
Formulation Technology
Manufacturing Support
Strategic Enabling Technology & Capability
AI Generic Defence
including IP
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Process Studies Activities
Stage 1: Research Stage 2: Evaluation Stage 3: Development Stage 4: Life Cycle
NEW PRODUCT DEVELOPMENT LIFE CYCLE TECHNOLOGY MANAGEMENT
AI Development
Formulation Development
AI-Formulation Interface
Redesign: AI & 2nd Generation Formulations
AI ELS
Formulation Technology
Manufacturing Support
Strategic Enabling Technology & Capability
AI Generic Defence
including IP
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Scale of Operation
Time of Operation
Early Late
Prevent & Direct Cure & Control
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Modern Coupling Reactions
X
R
R
NR2
Buchwald-HartwigAmination
R
R2R3
C-C formation
with C-H bonds
OR
R
C-O Bondformation
R
R
HeckReaction
CONu
R
Carbonylation
R
R
Sonogoshira
RStille, Kumada, Negishi, Suzuki
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Example 1: Process Development
● Information to help develop the manufacturing process
- Speed to market with minimum risk
- Cost, capacity, quality…
● Early quantitative information & mechanistic insight
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Mechanisms of Pd Coupling Reactions
InternalOn-line/at-line analysisDynamic Modelling
ExternalBlackmond, Imperial
CapabilityMechanisms & Development
of Homogeneous Catalysed Processes
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-50
0
50
100
150
200
250
60 80 100 120 140 160
He
at
(mW
)
Time (mins)
Integrated peak area
=236 KJ/mol (Aryl-Cl)
Integrated peak area
=21 KJ/mol (Aryl-Cl)
X
R
R
NR2
Buchwald-HartwigAmination
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Catalyst Stability. Literature Example
Singh, Steiter, Blackmond, Buchwald. J.Am.Chem.Soc.2002,124,14104-14114
Br
NH2
NH
+Pd(BINAP)
NaOtAm
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Mechanisms of Pd Coupling Reactions
Br
CF3
N
NH2
Ph Ph
N
NH
Ph Ph
CF3
NH2
NH
CF3
+
Pd(AcO)2
BINAP
in toluene
with Na-tert-BuO+ +
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 20 40
Time (min)
Heat (
mW)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 20 40
Time (min)
Heat (
mW)
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Proposed Mechanism
oxidative addition
reductive elimination
reaction with amine and base
Br
CF3
Pd
P
PBr
CF3
PdP
P
Pd
P
P P
P
Pd PRHN
P
CF3
CF3
NH
R
NaBr+ROH
NaOR+H2NR
Hartwig, J.F., Blackmond, D.G., Buchwald, S.L. & al., J Am Chem Soc., 128 (11): 3584-3591 Mar 22 2006
catalyst resting state
catalyst resting state
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Proposed Mechanism
oxidative addition
reductive elimination
reaction with amine and base
Br
CF3
Pd
P
PBr
CF3
PdP
P
Pd
P
P P
P
Pd PRHN
P
CF3
CF3
NH
R
NaBr+ROH
NaOR+H2NR
Hartwig, J.F., Blackmond, D.G., Buchwald, S.L. & al., J Am Chem Soc., 128 (11): 3584-3591 Mar 22 2006
catalyst resting state
catalyst resting state
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Proposed Mechanism
oxidative addition
reductive elimination
reaction with amine and base
Br
CF3
Pd
P
PBr
CF3
PdP
P
Pd
P
P P
P
Pd PRHN
P
CF3
CF3
NH
R
NaBr+ROH
NaOR+H2NR
Hartwig, J.F., Blackmond, D.G., Buchwald, S.L. & al., J Am Chem Soc., 128 (11): 3584-3591 Mar 22 2006
catalyst resting state
catalyst resting state
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more reactive
forms a more stable
intermediate
Reactivity vs Population
Br
CF3
N
NH2
Ph Ph
N
NH
Ph Ph
CF3
NH2
NH
CF3
+
Pd(AcO)2
BINAP
in toluene
with Na-tert-BuO+ +
NH2
N
Ph Ph
NH2
Competitive Reactions hexylamine
reaction
benzophenone
reaction
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more reactive
forms a more stable
intermediate
Reactivity vs Population
Br
CF3
N
NH2
Ph Ph
N
NH
Ph Ph
CF3
NH2
NH
CF3
+
Pd(AcO)2
BINAP
in toluene
with Na-tert-BuO+ +
NH2
N
Ph Ph
NH2
Competitive Reactions
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 20 40
Time (min)
He
at
(mW
)
What is more important?
hexylamine
reaction
benzophenone
reaction
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0
100
200
300
400
500
600
0 10 20 30 40 50
Time (min)
He
at
(mW
)Competitive Reaction
Ferretti, AC, Mathew JS, Ashworth, I,
Purdy, M, Brennan, C, Blackmond DG,
Adv. Synt. Cat., 350, 1007 (2008)
Less reactive benzophenone
hydrazone reacts first
… followed by the more reactive hexylamine
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0.0
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40 50 60
Time (min)
Co
nve
rsio
nCompetitive Reaction
N
NH2
Ph Ph
NH2
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Br
CF3
Pd
P
P
Br
CF3
PdP
P
Pd
P
P P
P
Pd
P
P
CF3
N
H
Pd
P
P
CF3
N H
N
Ph Ph
N H
N
Ph
Ph
CF3
N
CF3
H
path a path b
hexylamine + base
benzophenone
hydrazone + base
+
21 babatotal kArXkrrr
ba kArXk 12 for reactivity
2
1
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Benzylamination Process
ArCl + PhCH2NH2 ArNHCH2Ph + BH+Cl-B
PdL2
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Benzylamination Process
● Reaction stops
● Needs high levels of Pd to keep it going
- COST
● Yields lower than wanted or expected
ArCl + PhCH2NH2 ArNHCH2Ph + BH+Cl-B
PdL2
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Benzylamination Process
● Reaction stops
● Needs high levels of Pd to keep it going
- COST
● Yields lower than wanted or expected
● Process chemists believed the catalyst was degrading
ArCl + PhCH2NH2 ArNHCH2Ph + BH+Cl-B
PdL2
ArH
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Back to our hypothesis
Ar
Cl
Ar
NH Ph
H
Ar
N+
Ph
H
HH
L2PdIIX2
L2Pd0
L2PdII
L2PdII
L2PdII
M+tBuO-
tBuOH
MCl
+
Cl-
ArCl
ArNHCH2Ph
PhCH2NH2
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48
Hypothesis
Ar
Cl
Ar
NH Ph
H
Ar
N+
Ph
H
HH
H
NH2+Cl-
Ph H
NH
Ph
H
NH
Ph
L2PdIIX2
L2Pd0
L2PdII
L2PdII
L2PdII
M+tBuO-
tBuOH
MCl
+
Cl-
ArCl
ArNHCH2Ph
PhCH2NH2
ArH
ArH
+ + BH+Cl-B
+
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49
Ar
Cl
Ar
NH Ph
H
Ar
N+
Ph
H
HH
Ar
N+
Ar'
H
H
Ar
N
Ar'
H
H
NH2+Cl-
Ph H
NH
Ph
H
NH
Ph
L2PdIIX2
L2Pd0
L2PdII
L2PdII
L2PdII
M+tBuO-
tBuOH
MCl
+
Cl-
ArCl
ArNHCH2Ph
L2PdII
Cl-
L2PdII
M+tBuO-
tBuOH
PhCH2NH2
ArH
ArH
+ + BH+Cl-B
+
Imine (or amine) by-productscomplexing the active Pd?
MCl
+
Accumulated Intermediate
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50
Experiments to get the data, fit to our hypothesis
Expt. UKNB674/18
0
2
4
6
8
10
12
14
16
18
0 100 200 300 400Reaction Time (mins)
mM
ols
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Acc
ounta
bil
ity /
Sel
ecti
vit
y
T=140 OC, 0.001 mmol cat/g, feed time 75 min
Expt. UKNB674/25
0
5
10
15
20
25
0 100 200 300 400Reaction Time (mins)
mM
ols
T=150 OC, 0.001 mmol cat/g, feed time 75 min
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51
Predict from our understanding
0
0.0005
0.001
0.0015
0.002
0.0025
0.003
0.0035
0.004
130 135 140 145 150 155 160
Temperature (OC)
Min
imu
m c
ata
lyst
am
ou
nt
(mm
ol/g
)
0
200
400
600
800
1000
1200
1400
1600
1800
130 135 140 145 150 155 160Temperature (
OC)
Le
ng
ht
of
the
sta
ge
(m
in)
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52
Example 2: Scale Up to Manufacture - Multi-Phase/Multi-Scale
● Information to ensure the process scales & continual improvement
- Minimise risk of initial manufacture
- Maximise future opportunities
● Quantitative scale predictive information, process control &
improvement
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53
Example 2: Solid-Liquid Heterogeneous System for Ai Intermediate
CNNC
H2O + + Na+Br-
NaOH
NaOH
NMP
H2O NaBr
CNNC
Na+(-)
CNNC
Ar
CNNC
Ar
CNNC
Na+
(-)
ArBr
NaOH
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54
Homogeneous Pd Coupling Reaction
CNNC
H2O + + Na+Br-
NaOH
NaOH
NMP
H2O NaBr
CNNC
Na+(-)
CNNC
Ar
CNNC
Ar
CNNC
Na+
(-)
ArBr
NaOH
L Ar
L NucPdII
L Ar
L XPdII
Pd source
[L2Pd0]
catalyst activation
ArNucArX
Nuc-X-
oxidative addition
ligand exchange
reductive elimination
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55
Rate of Formation of Product Anion
CNNC
-0.05
0.15
0.35
0.55
0.75
0 20 40 60 80 100 120
Time (min)
Ab
so
rba
nce
at
32
8 n
m
0
0.2
0.4
0.6
0.8
1
250 300 350 400
Wavelength (nm)
Ab
so
rba
nce
t=0
t=4
t=8
t=12
t=16
t=20
t=24
t=28
t=32
0
0.1
0.2
0.3
0 5 10 15 20
Time (min)
Ab
so
rba
nce
at
32
8n
m
Pellet
Pearl
Powder
Pellet + water
pKa in NMP = 12.6
pKa in NMP = 6.8
Ar
CNNC
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56
CNNCCNNC
Ar
HCNNC
Ar
CNNC
H(-)
(-)
++
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57
CNNCCNNC
Ar
HCNNC
Ar
CNNC
H(-)
(-)
++
CNNC
H2O + + Na+Br-
NaOH
NaOH
NMP
H2O NaBr
CNNC
Na+(-)
CNNC
Ar
CNNC
Ar
CNNC
Na+
(-)
ArBr
NaOH
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58
NOA407855 Stage 5 - Comparison of Coupling Exotherms (t=0 at start
of DEMBB Addn.)
130
135
140
145
0 20 40 60
Time (min)
Te
mp
(°C
)
STD
Low Agi
Conversion 77% versus 97%
CNNCCNNC
Ar
HCNNC
Ar
CNNC
H(-)
(-)
++
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59
Example 3: Full Scale Manufacturing – what to do with the Pd?
● Information to support long term sustainable manufacture
- Continual improvement & optimisation
- Step change technology
- License to operate
● Quantitative information for the fate of the Pd
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60
Removal of the Pd
● Early description of mechanistic understanding to reduce the Pd level
● How do we remove (and recover) the Pd that is there?
- Measure it
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61
Carbon adsorption
● Simple C adsorption isn’t very good
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62
Surface modified carbon
Richard Compton,
Oxford
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63
From the physical chemistry to the engineering design
● Batch example
● Required C per unit volume treated
● Required C to treat 600kg water with 0.02%w/w Pd
0
200
400
600
800
1000
1200
1400
1600
1800
2000
0 10 20 30 40 50 60 70 80 90 100
R (% removal of Pd)
S/V
(g
ca
rbo
n/L
tre
ate
d w
ate
r)
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
0 10 20 30 40 50 60 70 80 90 100
R (% removal)
Re
qu
ire
d c
arb
on
(kg
)
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64
Cross-Linked Chitosan
-200
0
200
400
600
800
1000
1200
1400
1600
0 1000 2000 3000 4000 5000
[Pd
] / p
pm
Time / mins
1000 ppm Pd Loadings onto commercial scavengers compared with Crosslinked chitosan
Johnson Matthey scavenger
105pp FB
269pp
CrossLinked Chitosan
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65
Some thoughts
● We live in a heterogeneous world
● Speed & intensity of development is continually increasing
- Need to understand more earlier to help predict & direct
• Prevention vs cure
- Need earlier foresight & awareness of implications at scale
• Not just for initial manufacture but also for long term compliant &
economic production
● For process design we have to understand these principles – the real
application, “plant”, is scale and environment sensitive
● To do this successfully requires a multi-disciplinary approach between
people who may speak different languages
● This skill is transferable
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66
Air
Deposit
Cuticle
Intracellular
Extracellular
StomataCont. Phase
CrystallineWax
AmorphousWax
AI Solid 1 AI Solid 2
Ai(d)
H2OSurfactant
Solvent
Ai(c)
AI(e)
AI(i)To Plant
F
F
F
C1 C2 C3 C4
hv O2H2O Isom
WaterPhysicalLoss (Rain)
MX M+X-
SurfactantH2O Solvent
Sub-Wax Cuticle
Met 2
Met 1
Active Site
Active Site
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67
Acknowledgements
● Numerous Syngenta colleagues in Process Studies (both past &
present) who did the work
● External collaborators
● ICES and the organising committee for inviting me
● Audience
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68
Thank you