via microwaves - university lesson
TRANSCRIPT
Green Chemistry and Microwave Assisted Green Chemistry and Microwave Assisted Synthesis: From Theory to PracticesSynthesis: From Theory to Practices
Perugia - May 8, 2012
Dipartimento di Chimica e Tecnologia del FarmacoDipartimento di Chimica e Tecnologia del FarmacoUniversità degli Studi di PerugiaUniversità degli Studi di Perugia
MM AA
SS CC
LabLab
Laboratory of Medicinal and Advanced Synthetic ChemistryLaboratory of Medicinal and Advanced Synthetic Chemistry
MM AA
SS CC
LabLab
Laboratory of Medicinal and Advanced Synthetic ChemistryLaboratory of Medicinal and Advanced Synthetic Chemistry
Emiliano Rosatelli, Sezione Chim. Farm. IEmiliano Rosatelli, Sezione Chim. Farm. I
OverviewOverview
Green chemistry: concept and principles
Microwave assisted synthesis• Mechanism of microwave induced heating• “Greenness” of microwave synthesis• Examples
Chemists are molecular designers: they design and synthesize new
molecules and new materials
Role of a Synthetic (Medicinal) ChemistRole of a Synthetic (Medicinal) Chemist
Molecular target selection
Screen to identified lead
SAR-potency-selectivityCellular efficacy
In vivo efficacyPatent
ADME
Scale-upFormulation
ClinicalFDA
Safety
Role of a Synthetic Chemistry in Drug DevelopmentRole of a Synthetic Chemistry in Drug DevelopmentObstacles in Drug DevelopmentObstacles in Drug Development
From Concept to Pharmacy
Role of Chemistry in Environmental ProblemsRole of Chemistry in Environmental Problems
Chemistry produces waste and contributes to
environmental pollution
necessity of environmentally sustainable chemistry
GREEN CHEMISTRY
Green Chemistry = ResponsibilityGreen Chemistry = Responsibility
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
GREEN CHEMISTRY
The term green chemistry was coined by Paul Anastas in 1991.
What’s Green Chemistry?What’s Green Chemistry?
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.
Green Chemistry Is About…Green Chemistry Is About…
Use of catalyst in place of reagents
Using non-toxicreagents
Waste minimisation as source
Use of renewable resources
Use of solvent free or recyclable environmentally
benign solvent systems
Improved atom efficiency
Materials
Hazard
Waste
Risk
Cost
Energy
reducingreducing
1. Pollution Prevention2. Atom Economy3. Less Hazardous Chemical Synthesis4. Designing Safer Chemicals5. Safer Solvents and Auxiliaries6. Design for Energy Efficiency7. Use of Renewable Feedstocks8. Reduce Derivatives9. Catalysis10. Design for Degradation11. Real-Time Analysis for Pollution Prevention12. Inherently Safer Chemistry for Accident Prevention
The 12 Principles of Green ChemistryThe 12 Principles of Green Chemistry
1. Pollution Prevention1. Pollution Prevention
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”
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
Recycling or reuse of raw materials
2. Atom Economy2. Atom Economy
+
Raw materials Product
High atom economy
Waste(by-products)
+
Raw materials Product
+
Low atom economy
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!”
Whenever practicable, synthetic methodologies should be designed to use and generate substances that possess little
or no toxicity to human health and the environment.
3. Less Hazardous Chemical Synthesis3. Less Hazardous Chemical Synthesis4. Designing Safer Chemicals4. 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
The use of auxiliary substances (solvents, separation agents, etc.) should be made unnecessary whenever
possible and, when used, innocuous.
5. Safer Solvents and Auxiliaries5. Safer Solvents and Auxiliaries
Organic solventsVolatiles
Difficult to dispose
Toxic
Flammable Corrosive
Solvents should be natural, non-toxic, cheap, and readily available (green solvent)
Solvent-less system, water-based reaction
Using of supercritical fluid or ionic liquids
6. Design for Energy Efficiency6. Design for Energy Efficiency
Energy requirements should be recognized for their environmental and economic impacts and
should be minimized.
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.
7. Use of Renewable Feedstocks7. Use of Renewable Feedstocks
A raw material or feedstock should be renewable rather than depleting whenever technically and
economically practical.
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..
8. Reduce Derivatives8. 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.
Catalytic reagents are superior to stoichiometric reagents
Uncatalyzed
Catalyzed Less feedstock
9. Catalysis9. Catalysis
Less waste
Less energy consumption
Catalysts improve the efficiency of reaction
10. Design for Degradation10. Design for Degradation
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.
Avoiding certain chemical structures:• halogenated moieties• some heterocycles• quaternary carbons• tertiary amines
Favoring the chemical biodegradation (insertion of amides or esters)
11. Real-Time Analysis for Pollution Prevention11. Real-Time Analysis for Pollution Prevention
Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control
prior to the formation of hazardous substances.
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.
12. Inherently Safer Chemistry for Accident Prevention12. Inherently Safer Chemistry for Accident Prevention
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).
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.
Chemical accidents are generally very dangerous and with harmful consequences.
IDEAL CHEMICALSYNTHESIS
Renewable materials
Energy efficiency
Safer chemicals
Less hazardous
Atom economy
Waste prevention
Reduce steps
Catalysis
Green Chemical SynthesisGreen Chemical Synthesis
HOW TO ACHIEVE THIS GOAL?
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
Clean Chemical Synthesis Using Alternative Reaction MethodsClean Chemical Synthesis Using Alternative Reaction Methods
Classical Batch ProtocolClassical Batch Protocol
A + B = CExample:
A B
1) Addition of raw materials
A+B = CB+C = D
AB ∞
2) Mixing & Heating
A
BCD
3) Extraction
A
B
C
pure C
4) Purification
Green Chemistry - Enabled TechnologiesGreen Chemistry - Enabled Technologies
Flow chemistry Micro-Wave Reactors Automated Chromatographic System
Chemical synthesis Chemical engineeringnew approaches
Automated Combinatorial Synthesizer
Automated Parallel Synthesizer
3) Extraction
A B
A+B = CB+C = D
AB ∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A
B
C
pure C
4) Purification3) Extraction
A B
A+B = CB+C = D
AB ∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A B
A+B = CB+C = D
AB ∞∞∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A
B
C
pure C
4) Purification
A
B
C
pure C
4) Purification
Micro-Wave assisted synthesis
Green Chemistry - Enabled TechnologiesGreen Chemistry - Enabled Technologies
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.
MICROWAVE ASSISTED MICROWAVE ASSISTED SYNTHESISSYNTHESIS
FAST AND HOMOGENEOUS HEATING OF IRRADIATED MATERIAL
Wavelenght (λ): 0.1 cm - 100 cm Frequency (ν) : 300 MHz - 300 GHz
What About Microwaves?What About Microwaves?
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)
What About Microwaves?What About Microwaves?
Magnetic fieldMagnetic fieldElectric fieldElectric field
heating
ionic conductiondipolar polarization
Not responsible of heating
MicroWaves – Heating by Ionic ConductionMicroWaves – Heating by Ionic Conduction
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.
+
--
--
-
-+
--
- --
-
-
-
-
-
+
+
+
+
Absence of electric field Electric field
ions
MicroWaves – Heating by Dipolar PolarizationMicroWaves – Heating by Dipolar Polarization
molecules with dipole ≠ 0
• 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
Polarized by an applied electric field
unpolarized
Microwaves – Heating by Dipolar PolarizationMicrowaves – 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.
Microwave Microwave vsvs Conventional Heating Conventional Heating
Sample mix
Heat conduction
Convection currentsConvection currentsSample mix Sample mix
Microwave heating
Sample mix
Microwave irradiationHeat conduction
flame oil bath heating mantle microwaves
Conventional Heating Conventional Heating vsvs Alternative Energy Source Alternative Energy Source
Conventional Heating• Bunsen burner• Oil bath• Heating mantle
• You heat what you don’t want to heat (flask, vessel, reactor).• Necessity of heated up and cool down solvents for reaction and apparatus
Alternative Energy Sources• Microwave• Ultrasound• Sunlight / UV• Electrochemistry
Lower energy consumption
Three ways to get the reaction done, but different energy bills to pay
Energy ConsumptionEnergy Consumption
Energy consumption of the synthesis
oil bath heating mantlemicrowaves
• Homogeneity of heating.• Speed of heating.• Clean, reproducible and easily automated.
Advantages of the Microwave HeatingAdvantages of the Microwave Heating
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
Non-thermal effects have not be proven
Super Heating Effects and Hot Spots Super Heating Effects and Hot Spots
• High increase of rate of reactions with respect to conventional heating: additional non-thermal effects?
• 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
• Ionic bond: 7.6 eV• Covalent [C-H]: 4.28 eV• Hydrogen bond: 0.04 – 0.44 eV• Brownian motion: 1.7 x 10-2 eV• Microwaves: 1.6 x 10-3 eV
Reaction MediumReaction Medium
Solvent Dieletric costant (ε) tan δ Boiling point
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
Greenness of Microwave SynthesisGreenness 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.
Domestic Microwave Instrument
MagnetronWaveguide
Feed
Oven Oven CavityCavity
Microwave ApparatusMicrowave Apparatus
Laboratory Microwave SystemsLaboratory Microwave Systems
Advances in Laboratory Microwave SystemsAdvances in Laboratory Microwave Systems
Laboratory Microwave Systems – In Line ControlLaboratory Microwave Systems – In Line Control
Industrial Microwave ReactorsIndustrial Microwave Reactors
Microwave pilot plan
Industrial microwave reactor for large-scale production
Industrial Microwave ReactorsIndustrial Microwave Reactors
List of Organic Reactions Carried Out by Microwave IrradiationList of Organic Reactions Carried Out by Microwave Irradiation
• Reactions in liquid phaseReactions 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-transferReactions in phase-transfer• Saponifications of hindered esthers• Decarboxilations
• Solvent-free reactionsSolvent-free reactions• Aliphatic nucleophilic substitutions• Hydrolisis of esters and amides• Dehydration of alchols• Oxidation of alchols
Microwave Relevance in ChemistryMicrowave Relevance in Chemistry
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Example of Microwave Assisted SynthesisExample of Microwave Assisted Synthesis
OH
OH
HOH
O
O
OH
OH
HOH
OH
ONaOH, MeOH
60 °C, 8 hYield: 100%
NaOH, MeOHμW, 100 °C, 15 min
Yield: 100%
1 2
Drug Production by Microwaves Assisted SynthesisDrug Production by Microwaves Assisted SynthesisExample: Sildenafil (Viagra®)Example: Sildenafil (Viagra®)
OEtCO2H
OEtCO2H
O2SN
N
NNH2N
O
H2N
NN
H2NO
NH
OEt
O2SN
N
ON
NHN
O
NH
EtO
O2SN
N
1 3
2
4 5
tBuOK, BuOH85° C, 10 h
EtONa, EtOHMW, 120° C, 10 min
Yield: 100%
91%
Conclusions 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.
Diapositive in coda
2. Atom Economy2. Atom Economy
+
Raw materials Product
High atom economy
Waste(by-products)
+
Raw materials Product
+
Low atom economy
atomeconomy
(%)
Molecular Weight(desired product)Molecular Weight
(all reactants)
= 100x
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!”
3) Extraction
A B
A+B = CB+C = D
AB ∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A
B
C
pure C
4) Purification3) Extraction
A B
A+B = CB+C = D
AB ∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A B
A+B = CB+C = D
AB ∞∞∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A
B
C
pure C
4) Purification
A
B
C
pure C
4) Purification
Flow chemistry
Green Chemistry - Enabled TechnologiesGreen Chemistry - Enabled Technologies
3) Extraction
A B
A+B = CB+C = D
AB ∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A
B
C
pure C
4) Purification3) Extraction
A B
A+B = CB+C = D
AB ∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A B
A+B = CB+C = D
AB ∞∞∞
A
BCD
1) Addition of raw materials
2) Mixing & Heating
A
B
C
pure C
4) Purification
A
B
C
pure C
4) Purification
Automated Chromatographic System
Green Chemistry - Enabled TechnologiesGreen Chemistry - Enabled Technologies
Microwaves – Heating by Dipolar PolarizationMicrowaves – 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.
Microwave Apparatus: MagnetronMicrowave 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.
Microwave Apparatus: Waveguide FeedMicrowave 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.
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.
Microwave Apparatus: Oven CavityMicrowave Apparatus: Oven Cavity
Greenness of Microwave Synthesis:Greenness of Microwave Synthesis:Solvent-Free SynthesisSolvent-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.
Reaction vesselReaction 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 and reflection of rays. 10 ml 35 ml
flame oil bath heating mantle microwaves
Conventional Heating Conventional Heating vsvs Alternative Energy Source Alternative Energy Source
Conventional Heating• Bunsen burner• Oil bath• Heating mantle
• You heat what you don’t want to heat (flask, vessel, reactor).• Necessity of heated up and cool down solvents for reaction and apparatus
Conventional Heating Conventional Heating vsvs Alternative Energy Source Alternative Energy Source
Alternative Energy Sources• Microwave• Ultrasound• Sunlight / UV• Electrochemistry
Lower energy consumption
flame oil bath heating mantle microwaves