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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.
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
5
Principle
• Microwave irradiation(0.3-300 GHz)
Microwave radiationElectric
component
Dipolar polarization Ionic conduction
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
7
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
9
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
10
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
12
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
13
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
14
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
15
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
16
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
17
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
18
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
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.
21
THANK YOU