What is flow chemistry?

Flow chemistry is a process in which a reaction is run Continuously

in a flowing stream rather than in batch production

Comparison between traditional chemistry and flow chemistry

Reaction Stoichiometry:

In traditional chemistry this is defined by the concentration of chemical

reagents and their volumetric ratio. In flow chemistry this is defined by

The concentration of the chemical reagents and the ratio of their flow rate

Residence time:

In traditional chemistry this is determined by how long a vessel is kept at

given temperature. In flow the volumetric residence time is used given

by the ratio of the volume of the reactor and the overall flow rate

What is residence time?

Residence time of a reagent is defined as the amount of time

that the reaction is cooled or heated.

Residence time = reactor volume/flow rate

Continuous flow reactors: a perspective

Advantages:

1. Improved thermal management

2. Mixing control

3. Application of the extreme reaction conditions

Principles of green chemistry:

1. Prevention of waste

O

OHO

NH2

Solvent -freeN

OH

reaction temp : 65 oC

reaction time : 5.1 min

yield : 91%

Green chem., 2012, 14, 38-54

2. Atom economy

O

toluene

OH

reaction temp : 240 oC

pressure : 100 bar

yield : 95%

O

O

OMeCN

O

O

O

H

Hreaction temp : 60 oC

Green chem., 2012, 14, 38-54

N

N

N

O

OO

N

N

N

O

OO

O CCl3

NH

electon-withdrawing group

Smallest unit of benzylimidate

N

N

N

O

OO

N

N

N

Cl

ClCl

NaOH (3.4 eq)BnOH (7.8 eq)

0 to 50 oC, 2.5 h

81%

Org. Lett., 2012, 14, 5026-5029

3. Less hazardous chemical synthesis

Synthetic methods should be designed to use and generate Substances

that possess no toxicity to humans and to the environment as well

4. Designing for safer chemicals

Chemical products should be designed to effect their desired function

while minimizing their toxicity

5. Safer solvents and auxiliaries

The use of auxiliary substances should be avoided

6. Design for energy efficiency

Energy requirements of chemical process should be recognized

for their environmental and economic impacts and should be

minimized

7. Use of renewable feedstocks

A raw material should be renewable whenever technically and

economically practical

8. Reduce derivatives

Unnecessary derivatisation must be avoided because such steps

can generate waste

9. Catalysis

Catalytic processes are superior to stoichiometric reagents

10. Real-time analysis for pollution prevention

In- process monitoring and control to minimize the formation of

hazardous substances

11. Inherently safer chemistry for accidental prevention

Substances used in a chemical process must be chosen to minimize

The potential for chemical accidents

Org. process. Res. Dev. 2004, 8, 455

N

MeO

MeO

O

H

-Oxomaritidine

A flow process for the multi-step synthesis of the alkaloid

natural product: Oxomaritidine

Chem. commun., 2006, 2566-2568

Chem. commun., 2006, 2566-2568

1. Product obtained with >90% purity by H NMR

2. 40% isolated yield overall (phenolic oxidation gave 50% yield

3. Natural product can be obtained in less than 1day

4. Only obtained 20 mg of (±)-oxomaritidine

NMeO

MeO

NH

MeO

MeO

HO HO

10% Pd/C, THF

flow hydrogenation

Efficient reduction of imines to amines

Continuous flow-through reduction of imines into amines

Continuous flow-through reduction of imines into amines

H-Cube flow hydrogenator

H-Cube Flow Hydrogenator front panel

NMeO

MeO

OH

N

N

OH

N O

O

N N

OH

quant. quant.

quant. quant.

Flow hydrogenation scope

Bestmann-Ohira reagent for the formation of alkynes

and triazoles

Flow synthesis of terminal alkynes:

Two-step formation of triazoles from alkynes

Three step synthesis of triazole 5 from alcohol 3

Vapourtec R2+/R4

flow system

Multi-step synthesis strategies

Chem.sci., 2010, 1, 675-680

Generation and reaction of o-bromophenyllithium

Br

Br

PhCHOin THF

n-BuLiin hexane

TMSClin THF

TMS

Ph

OH

tR= 0.82 s

-78 oC -78 oC

tR= 6.93 s tR= 0.49 s

0 oC

tR= 0.49 s

0 oC

= the introduction of an input stream to the reactor network

tR= residence time in the reactor

n-BuLiin hexane 74%

J. Am. Chem. Soc. 2007, 129, 3046

Generation of kilogram quantities of 3-methoxybenzaldehyde

BrtR= 0.82 s

0 oC

= the introduction of an input stream to the reactor network

tR = residence time in the reactor

n-BuLiin hexane

tR= 0.15 s

0 oC

H NMe2

O

in THF

MeO

MeO

O

H

88%

59 g/h throughput1.4kg produced in 24h

Difficult to reproduce on kilogram scales using batch methods (24% yield, -40 oC)

Continuous flow synthesis of ibuprofen

tR= 5 min

150 oC

= the introduction of an input stream to the reactor network

tR = residence time in the reactor

TfOH5 equiv

tR= 2 min

50 oC

20 equiv KOHin MeOH/H2O

1 equiv PhI(OAc)24 equiv HC(OMe)3

in MeOH

65 oC

tR= 3 min

O

OHHO

O

Angew. Chem. Int. Ed. 2009, 48, 8547

Synthesis of a Mur ligase inhibitor

N

tR= 20 min

100 oC

tR= 15 min

75 oC

N

OH

NH2

HO

O

Br

O

N O

HN

HN

CO2Me

OH

H2N

HN

CO2Me

HOBt, EDC(1.2equiv in DMF)

(2.0 equiv in DMF)

1 equiv in DMF

1.2 equiv in DMF

Org. Lett., 2010, 12, 412

Curtious rearrangement of Carboxylic acids

Org. Biomol. chem., 2007, 5, 1559-1561

3+2 cycloaddition of actylenes with azides

N

NN

HO

NO2

N

NNN

NN

S

O

O

91%85%

93%

NNN

HO

85%

Conclusions

large quantities of synthetically use intermediates can be accessed

through flow chemistry

Multiple reactors in tandem can be used to build molecular complexity

Micro reactors have the potential to increase reaction efficiency

It is better to prevent waste than cleanup after creation!!!