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