Microwave Assisted Synthesis

Presented by:

Nivedita Singh

Medicinal Chemistry

IInd Sem

2

Flow of contents

• Definition

• Principle

• Advantages

• Thermal and non thermal effects

• Applications

• Pyrex v/s SiC

• Conclusion

3

Definition

Preparation of a desired

compound from available

starting materials via some

(multi-step) procedure,

involving microwave

irradiation.

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A green chemistry approach

Green chemistry is the utilization of a set of principles that

reduces or eliminates the use or generation of hazardous

substances in the design, manufacture and application of

chemical products.

Out of the 12 principles of green chemistry, the following are

taken care through MW synthesis

• Prevention of waste

• Less hazardous chemical synthesis

• Design for energy efficiency

• Inherently safer chemistry for accident prevention

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Principle

• Microwave irradiation(0.3-300 GHz)

Microwave radiationElectric

component

Dipolar polarization Ionic conduction

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Dipolar Polarization• Loss Tangent (Energy Dissipation Factor) – a measure of the ability to absorb microwave energy and convert it into thermal energy (heat)• Derived from Maxwell’s equation tanδ = ε”/ε’• ε” = loss factor• ε’ = dielectric constant• Reaction medium with high tanδ value efficient absorption

rapid heating

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According to Arrhenius equation:

k =A*e-Ea/RT

Rule of Thumb: for every 10°C increase in temperature the rate of reaction becomes twice

80 °C 90 °C 100 °C 110 °C 120 °C 130 °C 140 °C 150 °C 160 °C

8 hr 4 h 2 hr 1 hr 30 min 15 min 8 min 4 min 2 min

Increasing temperature

Decreasing reaction time

Ionic conduction• Due to translational motion of electric charges when an electric field is applied• Ions cause increased collision rate and convert kinetic energy to heat

Tetrahedron 2001, 9225

8

Advantages

• faster reactions

• less byproducts

• pure compounds

• absolute control over reaction parameters

• selective heating / activation of catalysts

• low energy input (max=300w, typical reaction ~20w)

• green solvents (H2O, EtOH, acetone) used

• less solvent usage ( 0.5-5mL per reaction)• software-supported experiment documentation

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Thermal effects

• k =A*e

• Loss tangent factor

• Superheating effects of solvents at atmospheric pressure

• Selective heating of microwave absorbing reagents and

catalysts

• Elimination of wall effects

-Ea/RT

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Non thermal effects

Polar reaction mechanism

Interaction of electric field with reaction medium

molecules

Orientation of molecules

Increase in polarity from ground state to transition state

Lowering of activation energy

Increase in reactivity

Angew. Chem. Int. Ed. 2004, 6250-6259

11

Applications

• Heck reaction

• Suzuki reaction

• Negishi and Kumada reaction

• Multicomponent reactions

• Solid phase synthesis

• Reactions in the absence of solvents

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Heck reaction

Most important C-C bond forming reaction

BrNC

X

COOH

NC

X

COOHPd(OAc)2, P(o-tolyl)3Et3N, MeCN

MW, 180oC, 15 min

Pd(OAc)2, P(o-tolyl)3 can be replaced by Pd/C catalystIonic liquids[bmim]PF6 can be used as green solvents• efficient interaction with microwaves• rapid heating• less pressure build-up• high recyclability

Org. Process Res. Dev. 2003, 707-716

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Suzuki reaction

Palladium catalyzed cross coupling of aryl halides with boronic acids

X

R'

(HO)2B

R''

R' R''

Pd(OAc)2, TBAB, Na2CO3H2O

MW, 150oC, 5 min

TBAB – phase transfer catalystFacilitates solubility of organic substrates and activation of boronic acids

J. Org. Chem. 2005, 3864-3870

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Negishi and Kumada reaction

Cl

OMeBrMgPdCl2(PPh3)2, THF

MW, 175oC, 10minOMe

CN

ZnBr

Br

O

H

CN

O

H

PdCl2 (PPh3)2, THF

MW, 160oC, 1 min

Org. Process Res. Dev. 2003, 707-716

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Multicomponent reactions

H H

O

R1

N

R2

H

Ar Me

O

Ar N

R2

R1

Odioxane

MW, 180oC, 10 min

Cl NH

Me

MeNH2, H2O

MW, 150oC, 5 min

Solid phase synthesis

• significant rate enhancement (10 min vs. 48 h)

• less material strain of solid support

• reduction of reagent excess

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Cl

MW, 200oC, 15 minO

R-COOH, Cs2CO3, NMP O

O

O

R

NH

Fmoca, b, c

HO

HN

NH

HN

NH2

R3

OR2

OR1O

O

a - deprotection with piperidine at RTb - HATU, iPr2NEt, DMF, MW, 110OC, 20 minc - TFA, RT, 2 hr

Conti..

Angew. Chem. Int. Ed. 2004, 6268-6273

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Reactions in the absence of solvents

NH2 NHR

ROHRaney Ni

MW, 30min

COOMe

MW, 3minHO-nC8H17

O O

nC8H17

KF-Al2O3

Ph

O

H

H2C

CN

CN

Ph

CN

CN

silica

MW, 150oC, 3 min

Angew. Chem. Int Ed. 2004, 6250-6252

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Microwave transparent pyrex v/s microwave absorbing SiC

NC Br

OBu

O NC

OBu

O

Pyrex: 82%SiC: 84%

Pd/C, Et3N, TBAB

MW, 191oC, 30 min

Angew. Chem. Int. Ed. 2009, 8321-8324

Advantages of SiC:• high melting point• high microwave absorbtivity• thermal conductivity• thermal effusivity• better control over exothermic reactions

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• corrosion resistant• differentiates thermal from non – thermal effects

time

temp

Pyrex

SiC

N

N

N

NMeMe

Bu

BuBr

Br

Pyrex or SiC

MW, 100o C,10min

Temperature profile for synthesis of [bmim]Br using pyrex and SiC reaction vials

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Conclusion

• Introduction of this technology in discovery efforts can

help streamline process improvements in research and

development.

• Microwave technology has become easy for medicinal

chemists to apply in a beneficial and reproducible manner,

providing a green technology that is widely embraced.

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THANK YOU