1. Green Chemistry and Microwave Assisted
Synthesis: From Theory to Practices
M A Lab
Emiliano Rosatelli, Sezione Chim. Farm. I S C
Laboratory of Medicinal and Advanced Synthetic Chemistry
Dipartimento di Chimica e Tecnologia del Farmaco
Università degli Studi di Perugia
Perugia - May 8, 2012
2. Overview
Green chemistry: concept and principles
Microwave assisted synthesis
• Mechanism of microwave induced heating
• “Greenness” of microwave synthesis
• Examples
3. Role of a Synthetic (Medicinal) Chemist
Chemists are molecular designers:
they design and synthesize new
molecules and new materials
4. Role of a Synthetic Chemistry in Drug Development
Obstacles in Drug Development
From Concept to Pharmacy
FDA
Clinical
Safety
Formulation
Scale-up
ADME
Patent
In vivo efficacy
Cellular efficacy
SAR-potency-selectivity
Screen to identified lead
Molecular target selection
5. Role of Chemistry in Environmental Problems
Chemistry produces waste
and contributes to
environmental pollution
necessity of
environmentally sustainable chemistry
GREEN CHEMISTRY
6. Green Chemistry = Responsibility
GREEN CHEMISTRY
Why is there no ‘Green Geology’ or ‘Green Astronomy’?
Because chemistry is the science that introduces new
substances into the world and we have a responsibility for their
impact in the world.”
Ronald Breslow
7. What’s Green Chemistry?
The term green chemistry was coined by Paul Anastas in 1991.
The green chemistry also called sustainable chemistry, is a
philosophy of chemical research and engineering that
encourages the design of products and processes that
minimize the use and generation of hazardous substances.
As a chemical philosophy, green chemistry can be applied to synthetic
chemistry, inorganic and organic chemistry, medicinal chemistry,
biochemistry, analytical chemistry, and even physical chemistry.
8. Green Chemistry Is About…
Waste minimisation
as source Waste
Use of catalyst in
place of reagents Materials
Using non-toxic
reagents reducing Hazard
Use of renewable
resources Risk
Improved atom
efficiency Energy
Use of solvent free or
recyclable environmentally Cost
benign solvent systems
9. The 12 Principles of Green Chemistry
1. Pollution Prevention
2. Atom Economy
3. Less Hazardous Chemical Synthesis
4. Designing Safer Chemicals
5. Safer Solvents and Auxiliaries
6. Design for Energy Efficiency
7. Use of Renewable Feedstocks
8. Reduce Derivatives
9. Catalysis
10. Design for Degradation
11. Real-Time Analysis for Pollution Prevention
12. Inherently Safer Chemistry for Accident
Prevention
10. 1. Pollution Prevention
Recycling or reuse of raw materials
Increase the efficiency of a process to
reduce the amount of waste and
pollution generated
Use of less toxic, non-toxic or renewable
substances as raw materials
It is better to prevent waste than to treat or clean up
waste after it is formed because:
“Always better to prevent than to cure”
11. 2. Atom Economy
Low atom economy
+ +
Waste
Raw materials Product (by-products)
High atom economy
+
Raw materials Product
Synthetic methods should be designed to maximize the
incorporation of all materials used in the process into the
final product
“Waste not, we don’t want it!”
12. 3. Less Hazardous Chemical Synthesis
4. Designing Safer Chemicals
Less hazardous reagents and chemicals
When possible, toxic or hazard chemicals
can be replaced by safer ones
Designing products that are safe and
non-toxic, preserving their function
Whenever practicable, synthetic methodologies should be
designed to use and generate substances that possess little
or no toxicity to human health and the environment.
13. 5. Safer Solvents and Auxiliaries
Difficult to dispose
Toxic Volatiles
Organic solvents
Flammable Corrosive
Solvent-less system, water-based reaction
Solvents should be natural, non-toxic, cheap, and readily
available (green solvent)
Using of supercritical fluid or ionic liquids
The use of auxiliary substances (solvents, separation
agents, etc.) should be made unnecessary whenever
possible and, when used, innocuous.
14. 6. Design for Energy Efficiency
Energy consumption contributes to pollution.
Unutilized energy may also be considered a waste
( 1st principle).
Reducing the energy barrier of the chemical
reaction and increasing its energy efficiency.
Reactions performed at room temperature.
Use of alternative energy sources as biofuels, solar power, wind power, hydro-
power, geothermal energy and hydrogen cells.
Energy requirements should be recognized for
their environmental and economic impacts and
should be minimized.
15. 7. Use of Renewable Feedstocks
90-95% of the products we use (plastics,
pharmaceuticals, energy) come from oil, a not
renewable resource.
A green chemistry approach provides the use of
renewable raw materials deriving from living
organisms:
• wood
• crops
• agricultural residue
• cellulose
• starch
• etc. etc..
A raw material or feedstock should be renewable
rather than depleting whenever technically and
economically practical.
16. 8. Reduce Derivatives
A conventional chemical process involves
several manipulations to transform the starting
material to the desired product.
Green chemistry approach provides to design
products in a simplified manner avoiding,
whenever possible, the blocking group,
protection/deprotection or temporary
modification of physical/chemical processes
Unnecessary derivatization should be avoided
whenever possible.
17. 9. Catalysis
Catalysts improve the efficiency
Uncatalyzed
of reaction
Less feedstock
Catalyzed
Less waste
Less energy consumption
Catalytic reagents are superior to
stoichiometric reagents
18. 10. Design for Degradation
Avoiding certain chemical structures:
• halogenated moieties
• some heterocycles
• quaternary carbons
• tertiary amines
Favoring the chemical biodegradation
(insertion of amides or esters)
Chemical products should be designed so that at the
end of their function they do not persist in the
environment and instead break down into innocuous
degradation products.
19. 11. Real-Time Analysis for Pollution Prevention
Real-time analysis is defined as the ability
to monitor a transformation and act
immediately upon it to prevent unwanted
outcomes, by-products formation and to
save energy.
It is the goal of green analytical chemistry to measure chemicals without
generating waste.
Analytical procedure must be safer to human health and the environment.
Analytical methodologies need to be further developed
to allow for real-time in-process monitoring and control
prior to the formation of hazardous substances.
20. 12. Inherently Safer Chemistry for Accident Prevention
Chemical accidents are generally very dangerous and
with harmful consequences.
The 12nd principle focuses on safety for the worker
and the surrounding community where an
industry/laboratory resides.
When designing a process, it is best to avoid highly
reactive chemicals that have potential to result in
accidents.
Substance and the form of a substance used in a chemical
process should be chosen so as to minimize the potential
for chemical accidents (releases, explosions, fires).
21. Green Chemical Synthesis
Atom economy
Waste prevention Less hazardous
Reduce steps IDEAL CHEMICAL Safer chemicals
SYNTHESIS
Catalysis Energy efficiency
Renewable materials
HOW TO ACHIEVE THIS GOAL?
22. Clean Chemical Synthesis Using Alternative Reaction Methods
Alternative Reaction Media/Solvent-free
• Supercritical Fluids
• Ionic Liquids
• Water
• Polyethylene glycol (PEG)
• Solvent free
Alternative Energy Sources
• Microwave
• Ultrasound
• Sunlight/UV
Alternative/Advanced Chemical Instrumentations
23. Classical Batch Protocol
Example: A + B = C
1) Addition of 2) Mixing & 3) Extraction 4) Purification
raw materials Heating
A
B
A A
C B B
D
C
D
B + C = A+ B
=C
∞
B A
pure C
24. Green Chemistry - Enabled Technologies
new approaches
Chemical synthesis Chemical engineering
Flow chemistry Micro-Wave Reactors Automated
Chromatographic System
Automated Automated
Combinatorial Synthesizer Parallel Synthesizer
25. Green Chemistry - Enabled Technologies
1) Addition of 2) Mixing & 3) Extraction 4) Purification
raw materials Heating
A
B
A A
C B B
D
C
=D
B+C A+B = C
B
∞ A
pure C
Micro-Wave assisted
synthesis
26. MICROWAVE ASSISTED
SYNTHESIS
Application of microwaves in organic chemistry was published for
first time in 1986. Now the microwave assisted synthesis has
emerged as new green and innovative tool in synthesis of organic
and inorganic compounds.
FAST AND HOMOGENEOUS HEATING
OF IRRADIATED MATERIAL
27. What About Microwaves?
Wavelenght (λ): 0.1 cm - 100 cm
Frequency (ν) : 300 MHz - 300 GHz
Waves Range of Frequency
Very-High Frequencies (VHF) 30 - 300 MHz
Ultra-High Frequencies (UHF) 300 - 3000 MHz
Super-High Frequencies (SHF) 3 - 30 GHz
Extremely-High Frequencies (EHF) 30 - 300 GHz
The microwaves used in domestic instruments and laboratory/industrial
equipments belong to the area of the UHF (2450 MHz,12.25 cm)
28. What About Microwaves?
Electric field Magnetic field
Not responsible
heating of heating
ionic conduction
dipolar polarization
29. MicroWaves – Heating by Ionic Conduction
+ -
ions
- -
- + - -
- -
+ +
- - + - -
-
- -
+ -
Absence of electric field Electric field
Charged particles oscillate under the influence of oscillating
electric field of microwaves and they collide with other
molecules and atoms. The kinetic energy of ions is lost in the
form of heat.
30. MicroWaves – Heating by Dipolar Polarization
unpolarized
molecules
with dipole ≠ 0
Polarized by an applied electric field
• The dipoles orient themselves according to the direction of the electrical field.
• The electrical field continuously changes.
• This movement of molecules results into the collision and friction between molecules
thus the kinetic energy is lost as thermal energy
31. Microwaves – Heating by Dipolar Polarization
Only polar materials exhibit microwave response and can be quickly
and efficiently heated.
Polar materials (like water) have an elevated value of dielectric
constant (ε) and the dielectric tangent (tan δ, capability to
absorb the microwave energy and convert it into heat).
Microwave heating effect is not a property of
an individual molecule but a collective
phenomenon of bulk.
33. Conventional Heating vs Alternative Energy Source
flame oil bath heating mantle microwaves
Conventional Heating • You heat what you don’t want to heat (flask, vessel,
• Bunsen burner reactor).
• Oil bath • Necessity of heated up and cool down solvents for
• Heating mantle
reaction and apparatus
Alternative Energy Sources
• Microwave
• Ultrasound Lower energy consumption
• Sunlight / UV
• Electrochemistry
34. Energy Consumption
Energy consumption of the synthesis
microwaves oil bath heating mantle
Three ways to get the reaction done, but different energy bills to pay
35. Advantages of the Microwave Heating
• Homogeneity of heating.
• Speed of heating.
• Clean, reproducible and easily automated.
Microwave heating is efficiently used to
force the organic chemical reactions!!!
• Under microwave irradiations, high and intense temperature can be
achieved very quickly.
• According to Arrhenius equation, K =A∙e(-Ea/R∙T)
Higher temperature = Higher reaction rate
36. Super Heating Effects and Hot Spots
• High increase of rate of reactions with respect to conventional heating:
additional non-thermal effects?
• Ionic bond: 7.6 eV
• Covalent [C-H]: 4.28 eV
Non-thermal effects • Hydrogen bond: 0.04 – 0.44 eV
have not be proven • Brownian motion: 1.7 x 10-2 eV
• Microwaves: 1.6 x 10-3 eV
• Under microwaves irradiation, solvents can be heated well above their
boiling points (super heating) for extended time.
• Microwaves interact directly with molecules of entire volume of
solvent leading to sudden and quick rise of temperature.
• Formation of hot spots in reaction mixture due to the change of
dielectric properties of substances
37. Reaction Medium
Dieletric
Solvent tan δ Boiling point
costant (ε)
Hexane 1.9 n.d. 69° C
Benzene 2.3 n.d. 80° C
Chloroform 4.8 n.d. 61° C
Acetic Acid 6.1 0.091 118° C
Ethyl Acetate 6.2 0.174 77° C
THF 7.6 0.059 66° C
Dichlorometane 9.1 0.047 40° C
Acetone 20.6 0.042 56° C
Ethanol 24.6 0.054 79° C
Methanol 32.7 0.941 65° C
Acetonitrile 36 0.659 81° C
DMF 36.7 0.062 153° C
DMSO 47 0.161 189° C
Water 80.4 0.123 100° C
38. Greenness of Microwave Synthesis
• Low energy consumption: homogeneity and speed of heating.
• Faster reaction: minutes instead of hours or days (low energy consumption).
• Atom economy: greater yield, lesser wastage.
• Green solvents: H2O, EtOH, methanol and acetone are strongly responsive to
microwave.
• Less or no solvent: possibility to carried out concentrated reaction. Possibility
of neat condition or supported reagents.
• Rapid conditions screening: integrated on-line control guarantees safe
operations.
45. List of Organic Reactions Carried Out by Microwave Irradiation
• Reactions in liquid phase
• Diels-Alder, etero- Diels Alder, Alder-Bong reactions
• Synthesis and hydrolisis of esters and amides
• Different aliphatic nucleophilic substitutions
• Oxidation of alchol
• Condensation of malonic esthers
• Cyclocondensations of varius eterocycle compounds
• Synthesis of organometallic compounds
• Reactions in phase-transfer
• Saponifications of hindered esthers
• Decarboxilations
• Solvent-free reactions
• Aliphatic nucleophilic substitutions
• Hydrolisis of esters and amides
• Dehydration of alchols
• Oxidation of alchols
47. Example of Microwave Assisted Synthesis
O O
OH NaOH, MeOH OH
O 60 °C, 8 h OH
Yield: 100%
HO OH NaOH, MeOH HO OH
H μW, 100 °C, 15 min H
Yield: 100%
1 2
48. Drug Production by Microwaves Assisted Synthesis
Example: Sildenafil (Viagra®)
OEt
O CO2H OEt
CO2H
H2N N
N
H2N O2S
N
N 2
1 3
O
H2 N O
OEt O N tBuOK, BuOH
EtO HN N
N 85° C, 10 h N
N 91%
H N
H
O2S EtONa, EtOH
N MW, 120° C, 10 min O2S
N
N Yield: 100%
N
4 5
49. Conclusions
Microwave assisted synthesis has become a common laboratory practice.
Microwave assisted technique offers a simple, clean, faster, efficient and safe
methods for chemical transformations.
In recent years the technical developments have enormously extended the
possibilities and the applicability of the microwave irradiation for the chemical
synthesis.
All the advantages related to the use of microwave in organic chemistry are
perfectly in harmony with the principles of green chemistry.
52. 2. Atom Economy
Low atom economy
+ +
Waste
Raw materials Product (by-products)
High atom economy
Molecular Weight
atom (desired product)
+ economy = x 100
Molecular Weight
(%)
(all reactants)
Raw materials Product
Synthetic methods should be designed to maximize the
incorporation of all materials used in the process into the
final product
“Waste not, we don’t want it!”
53. Green Chemistry - Enabled Technologies
1) Addition of 2) Mixing & 3) Extraction 4) Purification
raw materials Heating
A
B
A A
C B B
D
C
=D
B+C A+B = C
B
∞ A
pure C
Flow chemistry
54. Green Chemistry - Enabled Technologies
1) Addition of 2) Mixing & 3) Extraction 4) Purification
raw materials Heating
A
B
A A
C B B
D
C
=D
B+C A+B = C
B
∞ A
pure C
Automated
Chromatographic System
55. Microwaves – Heating by Dipolar Polarization
Only polar materials exhibit microwave response and can be quickly
and efficiently heated.
Polar materials (like water) have an elevated value of dielectric
constant (ε) and the dielectric tangent (tan δ, capability to
absorb the microwave energy and convert it into heat).
Gases cannot be heated by microwave due to larger inter-particle
distance (hence no friction).
In solids, where molecules can not move freely, no heating occurs by
microwaves.
Microwave heating effect is not a property of
an individual molecule but a collective
phenomenon of bulk.
56. Microwave Apparatus: Magnetron
• The cavity magnetron is a high-powered vacuum tube consisting of a cathode
and a anode placed in a magnetic field generated by a permanent magnet.
• Magnetron generates microwaves using the interaction of a stream of
electrons with the permanent magnetic field.
57. Microwave Apparatus: Waveguide Feed
• A waveguide feed is a rectangular channel having reflective walls which
allows the transmission of microwaves from magnetron to microwave cavity.
• It is made of sheet metal
• These walls prevent leakage of radiations and increase the efficiency of the
oven.
58. Microwave Apparatus: Oven Cavity
Microwave cavity
• Some area of oven cavity receives large amount of energy in the form of
electric energy and in some it is neglected. For smoothing the incoming
energy in the cavity, a stirred is usually used.
59. Greenness of Microwave Synthesis:
Solvent-Free Synthesis
• According to green chemistry principles, more interest has now been
focused solvent-free synthesis.
• Solvent-free synthesis represent a clean, economical, efficient and safe
approach that involve the exposure of neat reactants to MW irradiation
coupled with the use of supported reagents.
• The most commonly used supported reagents include mineral oxide as
aluminas, silicas, zeolites.
• The mineral oxides are very poor conductor of heat but they absorb
microwave radiation very effectively determining a significant
improvement in temperature, homogeneity and heating rates.
60. Reaction vessel
• The preferred reaction vessel for microwave is
a tall beaker loosely covered with a capacity
much greater than the volume of the reaction
mixture.
• Vessels are made of material transparent to
microwaves, such as teflon, polystyrene and
glass.
• No metallic container can be used as it gets
heated soon due to preferential absorption
10 ml 35 ml and reflection of rays.
61. Conventional Heating vs Alternative Energy Source
flame oil bath heating mantle microwaves
Conventional Heating
• You heat what you don’t want to heat (flask, vessel,
• Bunsen burner
reactor).
• Oil bath
• Necessity of heated up and cool down solvents for reaction
• Heating mantle
and apparatus
62. Conventional Heating vs Alternative Energy Source
flame oil bath heating mantle microwaves
Alternative Energy Sources
• Microwave
• Ultrasound Lower energy consumption
• Sunlight / UV
• Electrochemistry
