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 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

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 coneViton tubing

id - approx 20mm

T.I

Glass wool plug

B19 Quickfit cone

Gap ~2mm

9

What do chemists and engineers do?

0

10

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30

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50

60

70

80

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

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 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?

12

Interview Question

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90

100

0 1 2 3 4 5 6 7

Co

nc

hours

Lab Reaction

Product

13

Interview Question

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90

100

0 1 2 3 4 5 6 7

Co

nc

hours

Lab Reaction

Product

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90

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0 1 2 3 4 5 6 7

Co

nc

hours

Lab Reaction

Product

14

Interview Question

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10

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30

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90

100

0 1 2 3 4 5 6 7

Co

nc

hours

Lab Reaction

Product

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Co

nc

hours

Lab Reaction

Product

0

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20

30

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50

60

70

80

90

100

0 1 2 3 4 5 6 7

Co

nc

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

Co

nc

hours

Lab Reaction

Product

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Co

nc

hours

Lab Reaction

Product

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Co

nc

hours

Lab Reaction

SM

Product

0

10

20

30

40

50

60

70

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90

100

0 1 2 3 4 5 6 7

Co

nc

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

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

17

Hypothesis

● The chemical reaction that we want

A + B C

18

● Mass balance including inorganics

A + B C + Inorganics

19

● The reactions we don’t 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 & 2nd 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 & 2nd 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

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

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

InternalOn-line/at-line analysisDynamic Modelling

ExternalBlackmond, Imperial

CapabilityMechanisms & Development

of Homogeneous Catalysed Processes

33

-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

34

Catalyst Stability. Literature Example

Singh, Steiter, Blackmond, Buchwald. J.Am.Chem.Soc.2002,124,14104-14114

Br

NH2

NH

+Pd(BINAP)

NaOtAm

35

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)

36

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

37

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

38

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

39

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

40

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

41

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

42

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

43

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

44

Benzylamination Process

ArCl + PhCH2NH2 ArNHCH2Ph + BH+Cl-B

PdL2

45

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

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 + PhCH2NH2 ArNHCH2Ph + BH+Cl-B

PdL2

ArH

47

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

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

+

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

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

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)

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

CNNC

H2O + + Na+Br-

NaOH

NaOH

NMP

H2O NaBr

CNNC

Na+(-)

CNNC

Ar

CNNC

Ar

CNNC

Na+

(-)

ArBr

NaOH

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

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

56

CNNCCNNC

Ar

HCNNC

Ar

CNNC

H(-)

(-)

++

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

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(-)

(-)

++

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 isn’t 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

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

)

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

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

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

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