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Dr Colin Brennan, Process Studies Group

30 October 2012
Mechanistic Chemistry from Lab to Plant
2
Outline
Introduction what does the title mean?
Who we are, what we do & how we do it
Examples to exemplify
3
Syngenta a leading global agribusiness
Global agribusiness spanning crop
protection, seeds and seed care
with 26000 employees worldwide

Bringing plant potential to life
4
Bringing Plant Potential to Life
70% of Scotch Whisky is produced by
Syngenta barley
80% of every Guinness drunk starts life
with Syngenta barley
5
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
6
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
7
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
Chemistry
Organic Chemistry
Catalysis
Process
Engineering
Scale 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
8
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 cone
Viton tubing
id - approx 20mm
T.I
Glass wool plug
B19 Quickfit cone
Gap ~2mm
9
What do chemists and engineers do?
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
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 cone
Viton tubing
id - approx 20mm
T.I
Glass wool plug
B19 Quickfit cone
Gap ~2mm
b
plant
a
plant
plant L
b
lab
a
lab
lab L
A
Q
V
P
a k
A
Q
V
P
a k |
.
|

\
|
|
.
|

\
|
= = |
.
|

\
|
|
.
|

\
|
= o o
3
6 . 0
3
,
,
1190
11 . 0
1
317
m
W
m
m
m
W
T
T
V
P
V
P
a
b
lab vessel
plant vessel
plant lab
=
|
|
.
|

\
|
=
|
|
.
|

\
|
|
.
|

\
|
=
|
.
|

\
|
W m
m
W
V
V
P
P
lab
lab
lab
19 . 1 001 . 0 1190
3
3
= =
|
.
|

\
|
=
10
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
11
11
Process development - what sometimes (usually?!) happens

Think
Charge materials
Stir to react
Test for completion
Workup
Analyse yield
Good result
STOP
Poor
result
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?
12
Interview Question
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
13
Interview Question
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
14
Interview Question
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
SM
Product
15
Interview Question
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
Product
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
SM
Product
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7
C
o
n
c
hours
Lab Reaction
SM
?
Product
?
16
0
0.5
1
1.5
2
2.5
3
3.5
4
0 10 20 30 40 50 60 70 80
C
o
n
c
e
n
t
r
a
t
i
o
n

o
f

o
C
B
C
N
,

A
m
i
d
e
,

o
C
P
A
A

(
m
o
l
/
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
17
Hypothesis
The chemical reaction that we want

A + B C
18
Mass balance including inorganics

A + B C + Inorganics
19
The reactions we dont want

A + B C + Inorganics
DECOMPOSITION
20
What really are the reactive species?

A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
21
We may have some reversible processes

A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
22
What is our continuous phase?
What phase is the desired reaction occurring in?

A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
23
Heterogeneous Systems
What other phases are present?
What physical processes do we have?

A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
Pre-B
24
Heterogeneous Systems
Can we remove our product to a none-reacting phase?

A + B C + Inorganics
DECOMPOSITION
Pre-A Pre-B
Pre-B
C
25
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
26
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
27
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 & 2
nd
Generation Formulations
AI ELS
Formulation Technology
Manufacturing Support
Strategic Enabling Technology & Capability
AI Generic Defence
including IP


28
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 & 2
nd
Generation Formulations
AI ELS
Formulation Technology
Manufacturing Support
Strategic Enabling Technology & Capability
AI Generic Defence
including IP


29
Scale of Operation
Time of Operation
Early
Late
Prevent & Direct Cure & Control
30
Modern Coupling Reactions
X
R
R
NR
2
Buchwald-Hartwig
Amination
R
R
2
R
3
C-C formation
with C-H bonds
OR
R
C-O Bond
formation
R
R
Heck
Reaction
CONu
R
Carbonylation
R
R
Sonogoshira
R
Stille, Kumada,
Negishi, Suzuki
31
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
32
Mechanisms of Pd Coupling Reactions
Internal
On-line/at-line analysis
Dynamic Modelling
External
Blackmond, Imperial
Capability
Mechanisms & Development
of Homogeneous
Catalysed Processes
33
-50
0
50
100
150
200
250
60 80 100 120 140 160
H
e
a
t

(
m
W
)

Time (mins)
Integrated peak area
=236 KJ/mol (Aryl-Cl)
Integrated peak area
=21 KJ/mol (Aryl-Cl)
X
R
R
NR
2
Buchwald-Hartwig
Amination
34
Catalyst Stability. Literature Example
Singh, Steiter, Blackmond, Buchwald. J.Am.Chem.Soc.2002,124,14104-14114
Br
NH
2
N
H
+
Pd(BINAP)
NaOtAm
35
Mechanisms of Pd Coupling Reactions
Br
CF
3
N
NH
2
Ph
Ph
N
N
H
Ph Ph
CF
3
NH
2
N
H
CF
3
+
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)
H
e
a
t

(
m
W
)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 20 40
Time (min)
H
e
a
t

(
m
W
)
36
Proposed Mechanism
oxidative addition
reductive elimination
reaction with amine and
base
Br
CF
3
Pd
P
P
Br
CF
3
Pd
P
P
Pd
P
P
P
P
Pd P
RHN
P
CF
3
CF
3
N H
R
NaBr+ROH
NaOR+H
2
NR
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
37
Proposed Mechanism
oxidative addition
reductive elimination
reaction with amine and
base
Br
CF
3
Pd
P
P
Br
CF
3
Pd
P
P
Pd
P
P
P
P
Pd P
RHN
P
CF
3
CF
3
N H
R
NaBr+ROH
NaOR+H
2
NR
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
38
Proposed Mechanism
oxidative addition
reductive elimination
reaction with amine and
base
Br
CF
3
Pd
P
P
Br
CF
3
Pd
P
P
Pd
P
P
P
P
Pd P
RHN
P
CF
3
CF
3
N H
R
NaBr+ROH
NaOR+H
2
NR
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
39

more reactive

forms a more stable
intermediate
Reactivity vs Population
Br
CF
3
N
NH
2
Ph
Ph
N
N
H
Ph
Ph
CF
3
NH
2
N
H
CF
3
+
Pd(AcO)
2
BINAP
in toluene
with Na-tert-BuO
+ +
NH
2
N
Ph
Ph
NH
2
Competitive Reactions
hexylamine
reaction
benzophenone
reaction
40

more reactive

forms a more stable
intermediate
Reactivity vs Population
Br
CF
3
N
NH
2
Ph
Ph
N
N
H
Ph
Ph
CF
3
NH
2
N
H
CF
3
+
Pd(AcO)
2
BINAP
in toluene
with Na-tert-BuO
+ +
NH
2
N
Ph
Ph
NH
2
Competitive Reactions
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
0 20 40
Time (min)
H
e
a
t

(
m
W
)
What is more important?
hexylamine
reaction
benzophenone
reaction
41
0
100
200
300
400
500
600
0 10 20 30 40 50
Time (min)
H
e
a
t

(
m
W
)
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
42
0.0
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40 50 60
Time (min)
C
o
n
v
e
r
s
i
o
n
Competitive Reaction
N
NH
2
Ph
Ph
NH
2
43
Br
CF
3
Pd
P
P
Br
CF
3
Pd
P
P
Pd
P
P
P
P
Pd
P
P
CF
3
N
H
Pd
P
P
CF
3
N
H
N
Ph
Ph
N
H
N
Ph
Ph
CF
3
N
CF
3
H
path a path b
hexylamine
+ base
benzophenone
hydrazone + base
+
| || | | | 2 1
b a b a total
k ArX k r r r + = + =
| |
b a
k ArX k >>
| | | | 1 2 >>
for reactivity
2
1
44
Benzylamination Process
ArCl + PhCH
2
NH
2
ArNHCH
2
Ph + BH
+
Cl
-
B
PdL
2
45
Benzylamination Process
Reaction stops
Needs high levels of Pd to keep it going
- COST
Yields lower than wanted or expected
ArCl + PhCH
2
NH
2
ArNHCH
2
Ph + BH
+
Cl
-
B
PdL
2
46
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 + PhCH
2
NH
2
ArNHCH
2
Ph + BH
+
Cl
-
B
PdL
2
ArH
47
Back to our hypothesis

Ar
Cl
Ar
N
H
Ph
H
Ar
N
+
Ph
H
H
H
L
2
Pd
II
X
2
L
2
Pd
0
L
2
Pd
II
L
2
Pd
II
L
2
Pd
II
M
+t
BuO
-
t
BuOH
MCl
+
Cl
-
ArCl
ArNHCH
2
Ph
PhCH
2
NH
2
48
Hypothesis
Ar
Cl
Ar
N
H
Ph
H
Ar
N
+
Ph
H
H
H
H
NH
2
+Cl-
Ph
H
NH
Ph
H
NH
Ph
L
2
Pd
II
X
2
L
2
Pd
0
L
2
Pd
II
L
2
Pd
II
L
2
Pd
II
M
+t
BuO
-
t
BuOH
MCl
+
Cl
-
ArCl
ArNHCH
2
Ph
PhCH
2
NH
2
ArH
ArH
+
+ BH+Cl-
B
+
49
Ar
Cl
Ar
N
H
Ph
H
Ar
N
+
Ph
H
H
H
Ar
N
+
Ar'
H
H
Ar
N
Ar'
H
H
NH
2
+Cl-
Ph
H
NH
Ph
H
NH
Ph
L
2
Pd
II
X
2
L
2
Pd
0
L
2
Pd
II
L
2
Pd
II
L
2
Pd
II
M
+t
BuO
-
t
BuOH
MCl
+
Cl
-
ArCl
ArNHCH
2
Ph
L
2
Pd
II
Cl
-
L
2
Pd
II
M
+t
BuO
-
t
BuOH
PhCH
2
NH
2
ArH
ArH
+
+
BH+Cl-
B
+
Imine (or amine) by-products
complexing the active Pd?
MCl
+
Accumulated
Intermediate
50
Experiments to get the data, fit to our hypothesis

Expt. UKNB674/18
0
2
4
6
8
10
12
14
16
18
0 100 200 300 400
Reaction Time (mins)
m
M
o
l
s
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
A
c
c
o
u
n
t
a
b
i
l
i
t
y

/

S
e
l
e
c
t
i
v
i
t
y
T=140
O
C, 0.001 mmol cat/g, feed time 75 min
Expt. UKNB674/25
0
5
10
15
20
25
0 100 200 300 400
Reaction Time (mins)
m
M
o
l
s
T=150
O
C, 0.001 mmol cat/g, feed time 75 min
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 (
O
C)
M
i
n
i
m
u
m

c
a
t
a
l
y
s
t

a
m
o
u
n
t

(
m
m
o
l
/
g
)
0
200
400
600
800
1000
1200
1400
1600
1800
130 135 140 145 150 155 160
Temperature (
O
C)
L
e
n
g
h
t

o
f

t
h
e

s
t
a
g
e

(
m
i
n
)
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

53
Example 2: Solid-Liquid Heterogeneous System for Ai
Intermediate
CN NC




H
2
O + + Na
+
Br
-

NaOH

NaOH

NMP
H
2
O

NaBr

CN NC
Na
+
(-)
CN NC
Ar
CN NC
Ar
CN NC
Na
+
(-)
ArBr
NaOH

54
Homogeneous Pd Coupling Reaction
CN NC



H
2
O + + Na
+
Br
-

NaOH

NaOH

NMP
H
2
O

NaBr

CN NC
Na
+
(-)
CN NC
Ar
CN NC
Ar
CN NC
Na
+
(-)
ArBr
NaOH


L Ar
L Nuc
Pd
II
L Ar
L X
Pd
II
Pd source
[L
2
Pd
0
]
catalyst activation
ArNuc
ArX
Nuc
-
X
-
oxidative addition
ligand exchange
reductive elimination
55
Rate of Formation of Product Anion
CN NC
-0.05
0.15
0.35
0.55
0.75
0 20 40 60 80 100 120
Time (min)
A
b
s
o
r
b
a
n
c
e

a
t

3
2
8

n
m
0
0.2
0.4
0.6
0.8
1
250 300 350 400
Wavelength (nm)
A
b
s
o
r
b
a
n
c
e
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)
A
b
s
o
r
b
a
n
c
e

a
t

3
2
8
n
m
Pellet
Pearl
Powder
Pellet + water
pKa in NMP = 12.6

pKa in NMP = 6.8

Ar
CN NC
56
CN NC
CN NC
Ar
H
CN NC
Ar
CN NC
H
(-)
(-)
+
+
57
CN NC
CN NC
Ar
H
CN NC
Ar
CN NC
H
(-)
(-)
+
+
CN NC




H
2
O + + Na
+
Br
-

NaOH

NaOH

NMP
H
2
O

NaBr

CN NC
Na
+
(-)
CN NC
Ar
CN NC
Ar
CN NC
Na
+
(-)
ArBr
NaOH

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)
T
e
m
p

(

C
)
STD
Low Agi
Conversion 77% versus 97%
CN NC
CN NC
Ar
H
CN NC
Ar
CN NC
H
(-)
(-)
+
+
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

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
61
Carbon adsorption
Simple C adsorption isnt very good
62
Surface modified carbon
Richard Compton,
Oxford
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

c
a
r
b
o
n
/
L

t
r
e
a
t
e
d

w
a
t
e
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)
R
e
q
u
i
r
e
d

c
a
r
b
o
n

(
k
g
)
64
Cross-Linked Chitosan










-200
0
200
400
600
800
1000
1200
1400
1600
0 1000 2000 3000 4000 5000
[
P
d
]

/

p
p
m

Time / mins
1000 ppm Pd Loadings onto commercial scavengers compared with
Crosslinked chitosan
Johnson Matthey scavenger
105pp FB
269pp
CrossLinked Chitosan
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
66
Air
Deposit
Cuticle
Intracellular
Extracellular
Stomata
Cont. Phase
Crystalline
Wax
Amorphous
Wax
AI Solid 1
AI Solid 2
Ai(d)
H2O Surfactant
Solvent
Ai(c)
AI(e)
AI(i)
To Plant
F
F
F
C1 C2 C3 C4
hv O2
H2O Isom
Water
Physical
Loss
(Rain)
MX M+X-
Surfactant
H2O
Solvent
Sub-Wax
Cuticle
Met 2
Met 1
Active
Site
Active
Site
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

68
Thank you

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