1. 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
2

3. Definition
Preparation of a desired
compound from available
starting materials via some
(multi-step) procedure,
involving microwave
irradiation.
3

4. 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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5. Principle
• Microwave irradiation(0.3-300 GHz)
Microwave
radiation
Electric
component
Dipolar Ionic
polarization conduction
5

6. 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
6

7. 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
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
Increasing temperature
80 °C 90 °C 100 °C 110 °C 120 °C 130 °C 140 °C 150 °C 160 °C
8 hr 4h 2 hr 1 hr 30 min 15 min 8 min 4 min 2 min
Decreasing reaction time
Tetrahedron 2001, 9225 7

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
8

9. Thermal effects
-Ea/RT
• 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
9

10. Non thermal
effects
Interaction of Polar reaction
electric field with mechanism
reaction medium
molecules Increase in polarity
from ground state
Orientation of
to transition state
molecules
Lowering of
activation energy
Increase in
reactivity
Angew. Chem. Int. Ed. 2004, 6250-6259
10

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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12. Heck reaction
Most important C-C bond forming reaction
NC Br NC COOH
Pd(OAc)2, P(o-tolyl)3
Et 3N, MeCN
COOH
MW, 180oC, 15 min
X X
Pd(OAc)2, P(o-tolyl)3 can be replaced by Pd/C catalyst
Ionic 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 12

13. Suzuki reaction
Palladium catalyzed cross coupling of aryl halides with boronic
acids
X (HO)2 B
Pd(OAc)2, TBAB, Na2CO3
H2O
MW, 150oC, 5 min
R' R''
R' R''
TBAB – phase transfer catalyst
Facilitates solubility of organic substrates and activation of
boronic acids
J. Org. Chem. 2005, 3864-3870 13

14. Negishi and Kumada reaction
CN
CN Br
PdCl2 (PPh3) 2, THF
H MW, 160oC, 1 min
ZnBr
H
O
O
Cl
PdCl2(PPh3)2, THF
BrMg OMe OMe
MW, 175oC, 10min
Org. Process Res. Dev. 2003, 707-716
14

15. Multicomponent reactions
O
O H O dioxane
R2
N MW, 180oC, 10 min Ar N
H H R1 R2 Ar Me
R1
Solid phase synthesis
Me
Cl N
MeNH2, H2O H
MW, 150oC, 5 min
• significant rate enhancement (10 min vs. 48 h)
• less material strain of solid support
• reduction of reagent excess
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16. Conti..
O
Cl R-COOH, Cs2CO3, NMP O R
MW, 200oC, 15 min
O O
O R1 O R3
Fmoc H H
a, b, c N N
N
H HO N NH 2
H
O R2 O
a - deprotection with piperidine at RT
b - HATU, iPr2NEt, DMF, MW, 110OC, 20 min
c - TFA, RT, 2 hr
Angew. Chem. Int. Ed. 2004, 6268-6273
16

17. Reactions in the absence of solvents
NH 2 NHR
Raney Ni
ROH
MW, 30min
O O
COOMe nC 8H 17
KF-Al2O3
HO-nC8H17
MW, 3min
O CN
CN
silica
Ph H 2C Ph
MW, 150oC, 3 min
H CN
CN
Angew. Chem. Int Ed. 2004, 6250-6252
17

18. Microwave transparent pyrex v/s microwave
absorbing SiC
O
O NC
NC Br
Pd/C, Et 3N, TBAB OBu
MW, 191oC, 30 min
OBu
Pyrex: 82%
SiC: 84%
Advantages of SiC:
• high melting point
• high microwave absorbtivity
• thermal conductivity
• thermal effusivity
• better control over exothermic reactions
Angew. Chem. Int. Ed. 2009, 8321-8324 18

19. • corrosion resistant
• differentiates thermal from non – thermal effects
Me
Me Pyrex or SiC N
N
BuBr
MW, 100o C,10min N
N Br
Bu
Pyrex
Temperature
temp SiC profile for
synthesis of
[bmim]Br using
pyrex and SiC
reaction vials
time 19

20. 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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