Group Meeting Presentation

12/02/2010Continuous flow reactors for

gas/liquid chemical processes

Graham Sandford

Department of Chemistry, Durham University

1

Durham

Rob Spink

Darren Holling

Jelena Trmcic

Takashi Nakano

Mark Fox

Chris McPake

Jess Breen

Prof. Richard D. Chambers

Funding

BNFL

DU Quota

Asahi Glass Co. (Japan)

Asahi Glass Co. (Japan)

Crystal Faraday / EPSRC Partnership

AWE CASE

Pfizer CASE

Flow Chemistry Projects : 1995 - present

Organofluorine Chemistry

Fluorine may effect physiological properties of molecules

Commercially very valuable for life-science products

N

O

N

FOH

O

NH

Ciprofloxacin (Bayer)

CF3

O NH

CH3

Prozac (Eli Lilley)

N

N

F

O

H

O

H

5-FU (anti-cancer)

How do we introduce fluorine into organic systems ?

2

Carbon-Fluorine bond formation

3

Nucleophilic Fluorinating agents

Electrophilic fluorinating agents

C XF

C F

X = leaving group

C HF

C F

For large scale low-cost manufacture

HFN

SF3

KF Et4NF Et3N.3HF etc.

etc.F2

N

N

CH2Cl

F

2 BF4N

F

BF4

HF KF F2

Selective Direct Fluorination – Use of F2

F2 is now a viable reagent for synthetic organic chemistry

Replacement of Hydrogen by Fluorine

Reviews

• S.T. Purrington and B.S. Kagen, Chem Rev., 1986, 86, 997.

• R.J. Lagow and J.L. Margrave, Prog. Inorg Chem., 1979, 26, 161.

• J. Hutchinson and G. Sandford, Top. Curr. Chem., 1997, 193, 1.

• G. Sandford, J. Fluorine Chem., 2007, 128, 90.

C H

F2

C F

4

Problems with using F2

Heat of Reaction

Require : efficient coolingdilute F2 in N2

polar (MeCN) or acidic (HCOOH) reaction media

Possibility of aerosol formation

Safety on a large scale ?

C H + F2 C F

H = - 430 kJmol-1

+ HF

5

Selective direct fluorination – batch process

Direct fluorination of b-ketoesters first carried out at Durham on 1 g scale

Industrial Application

Scale-up to 100s kg within 5 years for pharmaceutical production

Adapt to a continuous flow process on the industrial scale ??

OO

OEt

OO

OEt

F

(76%)10% F2 in N2

HCOOH, 5 - 10oC

NN

NN N

OH

F

F

F

V oriconazoleanti-fungal agentPfizer

OO

OMe

OO

OMe

F

10% F2 in N2

HCOOH, 5 - 10oC

6

Pfizer, OPRD, 2001, 5, 28

Tetrahedron, 1996, 52, 1

Flow reactors for Direct Fluorination

Potential advantages:

Low inventories of F2 in contact with reagents gives increased safety

Efficient mixing across phase boundary (gas/liquid)

More efficient heat exchange

Large surface/volume ratio gives excellent gas/liquid interface

‘Scale-out’ rather than scale up

Good manufacturing practice (GMP) – lab. conditions are the same as

the commercial plant

7

Single Channel Gas/Liquid Flow reactor

• Single groove cut into the surface of a nickel block (0.5 mm wide; 10 cm long)

• Kel-F viewing window

• Top-plate

• Reagents introduced via tubes cut through viewing plate

• Coolant channels through nickel block

Chem. Commun., 1999, 883 8

Single Channel Gas/Liquid Flow reactor

Chem. Commun., 1999, 883

Substrate

inlet

F2/N2

inletProduct

outlet

Cooling

coils

Substrate

inletF2/N2

inlet

Product

outlet

9

Gas/Liquid ‘pipe flow’

Gas

Liquid

Direction of flow

Direction of flow

• ‘Plug flow’ not observed

• ‘Pipe flow’ permits maximum phase interface

10

Selective fluorination – 1,3-Dicarbonyls

11Lab. Chip, 2001, 1, 132;

OEt

O O 10% F2 in N2, f low

HCO2H, 0 - 5oC OEt

O O

OEt

O O

OEt

O O

F F F

F

F

+ +

71% 12% 3%

Difluorination observed but mono-fluorinated product separated and purified

Lab Chip, 2005, 5, 1132

O O

F

O

OEt

O

F

78%

76%

OEt

O O

F Cl

74%

O

O O

F

83%

OEt

O O

F

68%

O O

F

76%

O O

F

91%

O O

F Cl

86%

Selective fluorination – 1,3-Dicarbonyls

12Chem. Eng. Tech, 2005, 28, 344

Fluorination of diethyl malonate gives mixtures

Meldrum’s acid preferred

10% F2 in N2, f low

MeCN, 0 - 5oCO O

O O

O O

O O

F

O O

O O

O O

O O

O O

O OF

F

F F

2% 11%

46% 16%

+ others

10% F2 in N2, f low

MeCN, 0 - 5oCO O

O O

O O

O O

O O

O O

F F F

+EtOH

work-up

O O

O O

F

O O

O O

F F89%, 2 : 1

+

(quantitative)

Selective fluorination - Aromatics

13

1,4-Disubstituted aromatic systems

Lab. Chip, 2001, 1, 132

10% F2 in N2, f low

HCO2H, 0 - 5oC

OCH3

NO2

OCH3

NO2

OCH3

NO2

F F F

+ + others

77% 11%

Mono-fluorinated product separated and purified

OCH3

F

CN

74%

OH

F

NO2

71%

CH3

F

CN

75%

OCH3

F

CHO

82%

Alternative to multi-step Balz-Schiemann processes

Selective fluorination - Aromatics

14

10% F2 in N2, f low

HCO2H, 0 - 5oC

CH3

NO2

NO2

CH3

NO2

NO2

F

(70%)

OCH3

NO2

NO2

F

79%

Cl

NO2

NO2

F

57%

F

NO2

NO2

F

62%

J. Fluorine Chem, 2007, 28, 29

Deactivated 1,3-disubstituted aromatic systems

Gas/liquid – liquid/liquid processes

15

Sequential fluorination-cyclisation for fluoropyrazole formation

Gas/liquid Oxidation using HOF

16

F2 can be used to ‘enable’ other difficult transformations such as oxidation processes

F2 + H2O HOF.MeCNMeCN

HOF.MeCN complex half life of ~3 h at rt

Extremely powerful oxygen transfer agent

Many oxidation reactions possible

No heavy metal by-products

S. Rozen, J. Org. Chem., 1992, 57, 7342

S. Rozen, Eur. J. Org. Chem. 2005, 2433

MeOOC

MeOOC

COOMe

COOMe

HOF.MeCN

1 min, rt

(80%)

MeOOC

MeOOC

COOMe

COOMeO

No reaction using DMDO or H2O2

Difficult to scale up in batch processes due to instability

Gas/liquid Oxidation using HOF

17

Can we synthesise and use HOF.MeCN in one continuous flow process ?

Collectproduct

HOF.MeCN

Substrate

F2 in N2

H2O, MeCN

Gas/liquid – liquid/liquid sequential flow reaction

Low inventory of HOF.MeCN : Safer process

Gas/liquid Oxidation using HOF

1818

Continuous flow oxidation using in situ generated HOF.MeCN

Applicable to large scale synthesis using continuous flow techniques

Gas/liquid Oxidation using HOF

19

Conditions

• Alkene - 2.0 mmol h-1

• HOF.MeCN - 2.0 mmol h-1

• Run time - 60 mins @ rt

• Reaction path length - 30 cm

• Yields calculated using 1H NMR

Tetrahedron Lett., 2009, 50, 1674

Gas/liquid Oxidation using HOF

20Chim. Oggi. 2010, 28, 3

Gas/liquid Oxidation using HOF

21

F

F

F

NH2

F

F

F

F

F

NO2

F

F

F2 in N2, H2O, MeCN

r.t.

Cont inuous f low

Flow rates:

10% F2 in N2 (4.8 mmol h-1)

H2O in MeCN (166 mmol h-1)

amine (2.0 mmol h-1)

73%

CF3

F

F

NO2

F

F

Br

F

Br

NO2

F

F

Br

F

F

NO2

F

F

40% 62% 51%

NO2

61%

F

NO2

F

F

F

NO2

F

F

61%

74%

NO2

61%

F

F

F

NO2

59%

F

F

Scale-out to 3-channels

• A nickel plate with three grooves/channels etched into the surface

• Viewing and top plates

Lab Chip, 2001, 1, 132 22

Scale-out challenges

• Difficult integration of microchannels supplied from one feed-stock

• No pre-cooling of gas or liquid substrates

• Uniform supply of feedstocks to channels

• Simple design for daily production and maintenance

23

Multi-channel reactor concept

Base block fitted

with ‘reservoir’ holes

Channel plate

Top plate

Substrate

inlets

Product

outlet

‘Slots’ to allow fluids from

reservoirs to channels

24Lab. Chip, 2005, 5, 191

Multi-channel reactor – base block

• Machined Stainless steel

• 3 reservoirs for substrates

and product collection

• Slits leading from reservoirs

to top of the plate

• Screw and cooling channel fittings

25

Multi-channel reactor – channel plates

• 0.5 mm thick stainless steel

• 0.5 mm wide channels

• Number of channels per plate as

required

• Fitted with crew holes to attach to base

block

9-channel plate

27 channel plate

26

Multi-channel reactor – Final design

• External cooling of stainless steel

block

• Sealing gaskets

• Various multi-channel plates (3, 9,

27 channels)

• Kel-F sealing plate for observation

• Mounted vertically

27

Multi-channel reactor - operation

28Lab. Chip, 2005, 5, 191

Multi-channel reactor – fluorination

OO

OEt

OO

OEt

F

F2/N2 (v:v)

HCO2H

8-10oC

0.5 mlh-1ch-1 (1.8 mmolh-1ch-1)

16.2 mmolh-1 (2.11gh-1)

10 mlmin-1ch-1

10% F2 in N2 83% conv. 87% yield

20% F2 in N2 93% conv. 94% yield

• Approx. 2 g product per channel per hour

29Lab. Chip, 2005, 5, 191

Multi-channel reactor - operation

• Inexpensive to construct using standard machine shop techniques

• Easy to maintain and replace corroded plates – F2 is corrosive !

• Versatile – ready interchange of channel plates (£2 per plate)

• Ability to synthesise useful amounts of product (100 g overnight)

• Better performance than bulk, less waste

30

Conclusions

Gas/liquid continuous flow reactors for effective direct fluorination processes

• 1,3-Dicarbonyl derivatives (diketones, ketoesters, diesters)

• Aromatic systems

Continuous flow oxidation reactions using HOF generated in situ

Convenient, multi-channel flow reactors for applications to manufacturing

31