Flash ChemistryThe Concept and Some

Applications Jun-ichi Yoshida

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University,

Nishikyo-ku, Kyoto 615-8510, Japanyoshida@sbchem.kyoto-u.ac.jp

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Workshop “Novel process Windows in Chemical Engineering” Dec 10th 2009Osnabrück GERMANY

IntroductionFlask Chemistry Not Flash Chemistry

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The reason is probably, that the sizes of the flasks are similar to the size of our hands. However, the sizes of the flasks are not necessarily appropriate from a scientific view point.

We usually run reactions in a centimeter size flask in a chemistry laboratory. Why? Why this size?

Flask chemistry is a field of chemistry that is developed under constraints of flasks.

Reaction Time in Flask Chemistry

Because a time interval of minutes to hours is acceptable and convenient for human beings. In such a range of time, we can recognize how the reaction proceeds.

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Reactions in laboratory synthesis using flaks usually takes minutes to hours to obtain a product in a sufficient amount. Why? Why minutes to hours?

However, such time intervals are not necessarily appropriate from a scientific view point.

Time Efficiency of SynthesisConventional chemical synthesis has been using

“slow reactions”, because “fast reactions” are difficult to control (Reaction time: min ~ h).

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In order to achieve synthesis in highly time efficient manner, the use of much faster reactions in a controlled way is strongly needed.

Ugo Schiff (1834-1915)

Are you still using flasks for chemical synthesis ? University

of Florence

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Why fast chemical synthesis is needed?

• Demands for time efficient synthesis in laboratories and time efficient production in industry

• Fast synthesis for fast screening

• Needs for on site –on demand synthesis of chemicals

PET-Probe

S3

S2

S3

-eNu1 Nu1

Nu2

Nu3

S3 Nu2

S3 Nu3

S1

S3

S2

S2

S3

-eNu1 Nu1

Nu2

Nu3

S2 Nu2

S2 Nu3

S1

S2

S1

S2

S3

micro flow electrolysis cell

-eNu1 Nu1

Nu2

Nu3

S1 Nu2

S1 Nu3

S1

S1

........

....

........

....

........

....

S

Nu

: substrate

: carbon nucleophile

S : carbocation

micro flow electrolysis cell

micro flow electrolysis cell

combinatorial chemistry

Flash Chemistry

product

substrate

highly reactivereagent

reaction time:msec - sec

• Flash chemistry is a field of chemical synthesiswhere extremely fast reactions are conducted in ahighly controlled manner to produce desiredcompounds with high selectivity.

• The reaction time ranges from msec to sec.

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Flash chromatographyW. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923

Flash vacuum pyrolysis(vapor phase fast flow synthesis)

Flash laser photolysis (a tool for mechanistic studies for extremely fast reactions)

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“Flash” in Chemistry

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How to achieve flash chemistry ?

• fast reactions – highly reactive species

• thermal generation• photochemical generation• electrochemical generation• generation by organometallic chemistry

flow microreactor

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Why micro ?Problems inherent in conducting fast reactions in a preparative

scaleFast reactions are usually highly exothermic.Reactions are often faster than mass transfer.Therefore, kinetics does not work!

explosion

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Reaction Time and Reaction Regime

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Reaction Time and Reaction Regime

limited bymass and heattransfer

kineticregime

reactiontime

slow reactionsfast reactions

longshort min, hms, s

centimeter sizeflask or biggerreactor

micrometer sizereactor

The border shifts with the size of a reactor, because mass and heat transfer strongly depend on diffusion.

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Relation between Molecular Diffusion Time and Size

diffusion time diffusion path

• 0.0005 sec 1 μｍ (bacteria) • 0.05 sec 10 μｍ (cell) • 5 sec 100 μｍ• 500 sec 1000 mm (1 mm)

Theory of molecular diffusionDiffusion time ∝ (diffusion path)2

Theory of Brownian motion1905 Einstein

Experimental work1908-1912 Perrin

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Why flow microreactor?• To conduct fast reactions in a controlled

way, microreactors are essential. • Productivity of batch microreactors are too

small for synthesis. • For synthesis, flow microreactors are

essential. • Especially, flow microreactors for fast

reactions provide powerful tools for synthesis and production.

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fast

microflow

The Essence of Flash Chemistry

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Examples of Flash Chemistry• Organic Reactions

– halogenation– nitration– oxidation

• Inorganic Reactions– inorganic particle synthesis

• Organometallic Reactions– organolithium reactions– Grignard reactions

• Polymerization Reactions– cationic polymerization– anionic polymerization– radical polymerization

Flash chemistry enables use of short-lived highly reactive intermediates for synthesis

Highly reactive intermediates are unstable and are easy to decompose.

If such intermediates are transported to the next reactor within the lifetime, we can use them for the reaction before decomposition.

In flow microreactor systems, residence time can be greatly reduced by adjusting the length of micro channels and flow speed. 16

Residence time: The length of time that the solution remains inside the reactor

Merit of Flash Chemistry

Lithiation of an Epoxide without Decomposition of the Oxyranyllithium

Intermediate

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Nagaki, A.; Takizawa, E.; Yoshida, J. J. Am. Chem. Soc. 2009, 131, 1654

Example of Residence Time Control

Temperature – Residence Time Map the yield of the desired product

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Bath

tem

pera

ture

[o C]

tR: residence time of R1 (s)

-78 oC100806040200

0 5 10 15 20

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How does the reaction take place at -78 oC?

19Lithiation takes 20 sec.

If we increase the temperature,

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-48 oC100806040200

0

Yield (%)

5 10 15 20

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Further increase in the temperature

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Lithiation finishes within 1 sec at -48 oC, but the oxyranyllithium decomposes very quickly.

Esters survive in organolithiumreactions in flash chemistry.

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Nagaki, A.; Kim. H.; Yoshida, J. Angew. Chem. Int. Ed. 2008, 47, 7833.

temperature-residence time map(T-t map)

Esters cannot survive in organolithium reactions in flask chemistry

high time-solution analysis of reactions under preparative conditions

O

OMe

Br

s-BuLi

O

OMe

Li

MeOTf

O

OMe

Me

Me3SiOTfO

OMe

SiMe3

PhCHO

O

O

Ph

65%

82%

85%

Mission Impossible in Flask Chemistry!Generation and Reactions of Aryllithium

Bearing Methoxycarbonyl Group

methyl ester survives in organolithium reactions

Integrated Synthesis of o-Disubstituted Benzenes

Usutani, H.; Tomida, T.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3046

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Integrated Flow Microreactor System

Integrated flow microreactor system enables a straightforward transformation that is difficult to achieve by conventional method

ArylLi bearing NO2Isomerization or Not Isomerization

Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem. Int. Ed. 2009, 48, 8063

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Can flash chemistry be applied to industrial production ?

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Yes !

A Pilot PlantGrignard Exchange ReactionWakami, H.; Yoshida, J. Org. Process Res. Dev. 2005, 9, 787-791

Toray Hi-mixer

continuous operation20 oC residence time 5 sec14.7 kg/24 h

ConclusionSynthetic reactions can be much faster if they are released from the constraints of a flask.

Flash chemistry will make paradigm shift in laboratory chemical synthesis and industrial production

Reactions can be conducted at natural rates in a highly controlled manner without deceleration by virtue of characteristic features of microflow systems.

New synthetic transformations which are difficult to achieve using conventional flask chemistry can be achieved (straightforward synthesis without protecting groups).

The first book to describe this exciting new technique. First dedicated volume on this new concept in which extremely fast reactions are conducted in a highly controlled manner, and desired products are formed 'in a flash' and on a preparative scale.

Brings together research in reactive intermediates and microreactors into an integrated scheme for fast, controlled organic synthesis.

A key resource for those working in organic synthesis.

OUT NOW!

Flash ChemistryFast Organic Synthesis in Microsystems

Acknowledgement

Grant-in-Aid for Scientific Research, Japan Project of Micro-Chemical Technology for Production, Analysis, and

Measurement Systems (Micro Chemical Plants), NEDO, Japan Project of Development of Microspace and Nanospace Reaction Environment

Technology for Functional Materials, NEDO, Japan Group for Research on Automated Flow and Microreactor Synthesis (GRAMS),

Division of Synthetic Chemistry, Kinki Chemical Society

NEDO ProjectsProf. Shinji HasebeProf. Kazuhiro MaeProf. Mitsuo SawamotoProf. Nobuaki AokiDr. Takeshi IwasakiShigeki Hikage Dr. Tasuya KawaguchiToshiharu KuboyamaHideo WakamiYousuke Ushiogi

Staffs 6 StudentsDr. Aiichiro NagakiDr. Seiji SugaHirotsugu UsutaniYutaka TomidaHeejin KimEiji TakizawaNaofumi TakabayashiChika Matuo+ Many other students