Микроволновая химия как концепция зеленой химии

Green Chemistry: Microwave
Assisted Organometallic
Reaction
Green Chemistry
To promote innovative chemical technologies
that reduce or eliminate the use or generation of
hazardous substances in the design, manufacture,
and use of chemical products.
What does the Chemical Industry do
for us?
Green chemistry
is about
•
•
•
•
•
•
Waste Minimisation at Source
Use of Catalysts in place of Reagents
Using Non-Toxic Reagents
Use of Renewable Resources
Improved Atom Efficiency
Use of Solvent Free or Recyclable Environmentally
Benign Solvent systems
Green 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 is also called…
 A new approach to designing chemicals and chemical
transformations that are beneficial for human health and
the environment
 An innovative way to design molecules and chemical
transformations for sustainability
Meeting the needs of the current generation without
compromising the ability of future generations to meet
their own needs
 Benign by design
 Pollution prevention at the molecular level
What is Green Chemistry?
• Green chemistry is the study of how to
design chemical products and processes
in ways that are sustainable and not
harmful for humans and the environment.
• Three components: catalysis, solvents,
non-toxic
• 12 principles of green chemistry
Green Chemistry Is About...
Waste
Materials
Hazard
Risk
Energy
Cost
Why do we need Green Chemistry ?
• Chemistry is a very prominent part of our
daily lives.
• Chemical developments also bring new
environmental problems and harmful
unexpected side effects, which result in
the need for ‘greener’ chemical products.
• A famous example is the pesticide DDT.
The 12 Principles of Green Chemistry (1-6)
1. Prevention
It is better to prevent waste than to treat or clean up waste after it has been created.
2. Atom Economy
Synthetic methods should be designed to maximise the incorporation of all materials
used in the process into the final product.
3. Less Hazardous Chemical Synthesis
Wherever practicable, synthetic methods should be designed to use and generate
substances that possess little or no toxicity to people or the environment.
4. Designing Safer Chemicals
Chemical products should be designed to effect their desired function while minimising
their toxicity.
5. Safer Solvents and Auxiliaries
The use of auxiliary substances (e.g., solvents or separation agents) should be made
unnecessary whenever possible and innocuous when used.
6. Design for Energy Efficiency
Energy requirements of chemical processes should be recognised for their environmental
and economic impacts and should be minimised. If possible, synthetic methods should be
conducted at ambient temperature and pressure.
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable Feedstocks
A raw material or feedstock should be renewable rather than depleting whenever technically
and economically practicable.
8 Reduce Derivatives
Unnecessary derivatization (use of blocking groups, protection/de-protection, and temporary
modification of physical/chemical processes) should be minimised or avoided if possible,
because such steps require additional reagents and can generate waste.
9 Catalysis
Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.
10 Design for Degradation
Chemical products should be designed so that at the end of their function they break down into
innocuous degradation products and do not persist in the environment.
11 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.
12 Inherently Safer Chemistry for Accident Prevention
Substances and the form of a substance used in a chemical process should be chosen to
minimise the potential for chemical accidents, including releases, explosions, and fires.
What is “Green”?
Sustainable
 Kinder and gentler to people and the planet
Green Chemistry
The cost of using
hazardous materials:
Conventional Heating vs
Alternative Energy Source
Conventional Heating
 Bunsen burner
Oil bath
Heating mantle
Alternative Energy Sources
Microwave
Ultrasound
Sunlight / UV
 Electonchemistry
Clean Chemical Synthesis Using
Alternative Reaction Methods
Alternative Energy Sources
Microwave
Ultrasound
Sunlight / UV
AlternativeReactionMedia/Solvent-free
Supercritical Fluids
Ionic Liquids
Water
Polyethylene glycol (PEG)
Solvent free
Microwaves in Synthesis
History or how it all began…
•
While fire is now rarely used in synthetic chemistry, it was not until Robert
Bunsen invented the burner in 1855 that the energy from this heat source
could be applied
• There is some controversy about the origins of the microwave power cavity
called the magnetron – the high-power generator of microwave power.
The British were particularly forward-looking in deploying radar for air defense
with a system called Chain Home which began operation in 1937.
Originally operating at 22 MHz, frequencies increased to 55 MHz.
1921 was published by A.W. Hull the earliest description of the magnetron,
a diode with a cylindrical anode
1940 It was developed practically by Randall and Booth at the University of
Birmingham in England ; they verified their first microwave
transmissions: 500 W at 3 GHz.
A prototype was brought to the United States in September of that year to define
an agreement whereby United States industrial capability would undertake the
development of microwave radar.
1940 the Radiation Laboratory was established at the Massachusetts
Institute of Technology to exploit microwave radar. More than 40 types of
tube would be produced, particularly in the S-band (i.e. 300 MHz). The growth
of microwave radar is linked with Raytheon Company and P.L. Spencer who
found the key to mass production.
History or how it all began…
• 1946 Dr. Percy Spencer-the magnetron inventor; he
has found a variety of technical applications in the
chemical and related industries since the 1950s, in
particular in the food-processing, drying, and
polymer
• surprisingly, microwave heating has only been
implemented in organic synthesis since the mid1980s.
• Today, a large body of work on microwave-assisted
synthesis exists in the published and patent literature.
• Many review articles, several books and information on
the world-wide-web already provide extensive coverage
of the subject.
• 1969 “ Carrying out chemical reactions
using microwave energy ” J.W.
Vanderhoff – Dow Chemical Company US
3,432,413
• 1986 “The Use of Microwave Ovens for
Rapid Organic Synthesis” Gedye, R. N. et
alTetrahedron Lett. 1986, 27, 279
• 1986 “Application of Commercial
Microwave Ovens to Organic Synthesis”
Giguere, R. J. and Majetich, G. Tetrahedron
Lett. 1986, 27, 4945
Energy Use in Conventional
Chemical Processes
Heating
 Stirring
 Piping
 Transporting
 Cooling
Problem of Conventional Heating
You heat what you don’t want to heat.
Solvents
for
reactions,
apparatus:
heated up and cool it down.
Double energy penalty without any
apparent “benefit”.
Energy Consumptions
Three ways to get the reaction done, but different energy bills to pay
Microwaves
• MW reactors operate at 2.45 GHz.
• Electric field oscillates at 4.9 x 109 times/sec –
10oC/sec heating rate.
Electromagnetic Spectrum
Neas, E.; Collins, M. Introduction to Microwave Sample Preparation: Theory
and Practice, 1988, p. 8.
Schematic of a Microwave
E= electric field
H= magnetic field
l= wavelength (12.2 cm for 2450 MHz)
c= speed of light (300,000 km/s)
Microwaves Application in
Heating Food
1946: Original patent (P. L. Spencer)
1947: First commercial oven
1955: Home models
1967: Desktop model
1975: U.S. sales exceed gas ranges
1976: 60% of U.S. households have
microwave ovens
Spectrum Electromagnetic
•
•
•
•
•
Electric field component
Responsible for dielectric heating
Dipolar polarization
Conduction
Magnetic field component
Microwaves – Dipolar Rotation
•
Polar molecules have intermolecular forces which give any motion of the
molecule some inertia.
•
Under a very high frequency electric field, the polar molecule will attempt to
follow the field, but intermolecular inertia stops any significant motion before
the field has reversed, and no net motion results.
•
If the frequency of field oscillation is very low, then the molecules will be
polarized uniformly, and no random motion results.
•
In the intermediate case, the frequency of the field will be such that the
molecules will be almost, but not quite, able to keep in phase with the field
polarity.
•
In this case, the random motion resulting as molecules jostle to attempt in
vain to follow the field provides strong agitation and intense heating of the
sample.
•
At 2.45 GHz the field oscillates 4.9 x 109 times/s which can lead to heating
rates of 10 °C per second when powerful waves are used
MW Heating Mechanism
Noconstraint
Continuous electric
field
Two mechanisms:
 Dipolar rotation / polarization
Ionic Conduction mechanism
Alternating electric field
Withhigh frequency
Microwave Dielectric Heating
Mechanisms
Conduction Mechanism
Dipolar Polarization
Mechanism
Dipolar molecules try to
align to an oscillating field
by rotation
Ions in solution will move
by the applied electric
field
Mingos, D. M. P. et al., Chem. Soc. Rev. 1991, 20, 1 and 1998, 27, 213
Microwave vs Oil-bath Heating
J.-S. Schanche, Mol. Diversity 2003, 7, 293.
www.personalchemistry.-com; www.biotage.com.
Conventional Heating by
Conduction
Conductive
heat
Heating by
convection
currents
Slow and
energy
inefficient
process
temperature on the outside surface is
in excess of the boiling point of liquid
Direct Heating by Microwave
Irradiation
•Solvent/reagent
absorbs MW
energy
• Vessel wall
transparent to
MW
•Direct in-core
heating
•Instant on-off
Inverted temperature gradients!
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Food!
Cooking Chemistry ???
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R. Gedye et al.,
Tetrahedron Lett. 1986, 27, 279.
Publications on MW-Assisted
Organic Synthesis
7 Synthetic Journals: J.Org.Chem.,Org.Lett.,Tetrahedron Lett.,Tetrahedron,
Synth.Commun., Synlett, Synthesis
All Journals (Full Text): Dedicated instruments only (Anton Paar, Biotage, CEM,
Milestone, Prolabo)
Industrial /Chemical / Applications of
Microwave Heating
Food Processing
+ Defrosting
+ Drying / roasting / baking
+ Pasteurization
Drying Industry
+ Wood, fibers, textiles
+ Pharmaceuticals
+ Brick / concrete walls
Polymer Chemistry
+ Rubber curing, vulcanization
+ Polymerization
Ceramics/Materials
+ Alumina sintering
+ Welding, smelting, gluing
Plasma
+ Semiconductors
Waste Remediation
+ Sewage treatment
Analytical Chemistry
+ Digestion
+ Extraction
+ Ashing
Biochemistry / Pathology
+ Protein hydrolysis
+ PCR, proteomics
+ Tissue fixation
+ Histoprocessing
Medical
+ Diathermy, tumor detection
+ Blood warming
+ Sterilization (Anthrax)
+ Drying of catheters
Books on MicrowaveAssisted Synthesis
(ACS Professional Reference Book) H. M.
Kingston, S. J. Haswell (eds.)
􀂃 Fundamentals of Microwave
Application
􀂃 Alternative Laboratory Microwave
Instruments
􀂃 Chemistry Applications
􀂃 Biochemistry Applications
􀂃 Laboratory Microwave Safety
Microwaves in Organic and
Medicinal Chemistry
Kappe, C. O. and Stadler, A.
Wiley-VCH, Weinheim, 2005,
ISBN: 3-527-31210-2
410 pages, ca 1000 references,
Hayes, B. L.,
CEM Publishing,
Matthews, NC,
2002
Books on MicrowaveAssisted Synthesis
Lidstöm, P.;
Tierney, J. P.
(Eds.),
Blackwell
Scientific,
2005
Loupy Andre (Ed.)
Wiley-VCH, Weinheim, 2003,
ISBN: 3-527-30514-9
523 pages, 2000 refs.
Book (2 volumes) WileyVCHA.
Loupy edit
Second Edition
(2006) 22 Chapters
Books on Microwave-Assisted Synthesis
Astra Zeneca Research
Foundation Kavitha Printers,
Bangalore, India, 2002
azrefi@astrazeneca.com
Practical Microwave Synthesis for Organic Chemists Strategies, Instruments, and Protocols
Edition - 2009, X, 310 Pages, Hardcover, Monograph
Microwave Ovens
Monomodal instrument
Piccoli volumi processabili
- Onde Stazionarie (Hot Spots)
- Difficoltà nello Scale-up
+ Alta densità d’energia
Images adapted from: C.O. Kappe, A. Stadler: Microwaves in
Organic and Medicinal Chemistry, Wiley, 2005
Multimodal instrument
+ Alta densità d’energia (maggior potenza
disponibile)
+ Maggiori volumi processabili (cavità a
MW più grande)
+ No Onde Stazionarie (No Hot-spots)
+ Semplice Scale-up
- Volume minimo processabile
Monomodal Vs. Multimodal
Monomodal Vs. Multimodal
Thermal Effects
•More
efficient
energetic
coupling
of
solvent
with
microwaves promotes higher rate of temperature increase
• Inverted heat transfer, volumetric
• “Hot spots” in monomode microwaves
• Selective on properties of material (solvents, catalysts,
reagents, intermediates, products, susceptors)
Recent Applications of MicrowaveAssisted Synthesis-MAOS
Hydrolysis of benzamide
thermal: 1 h, 90 % yield (reflux)
MW: 10 min, 99 % yield (sealed vessel)
R. Gedye, F. Smith, K. Westaway, H. Ali, L. Baldisera,
L. Laberge, J. Rousell, Tetrahedron Lett. 1986, 27,
279–282. R. J. Giguere, T. L. Bray, S. M. Duncan,
G. Majetich, Tetrahedron Lett. 1986, 27, 4945–4958.
The first reports on the use of microwave heating to accelerate organic chemical
transformations (MAOS) were published by the groups of Richard Gedye (and
Raymond J. Giguere/George Majetich in 1986. In those early days, experiments
were typically carried out in sealed Teflon or glass vessels in a domestic
household microwave oven without any temperature or pressure measurements.
The results were often violent explosions due to the rapid uncontrolled heating of
organic solvents under closed-vessel conditions.
Solvent-free Reactions or Solid-Solid
Reactions
“No reaction proceeds without solvent”
Aristotle
Green chemistry
enabled advancement
Solventless syntheses
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o
u t t h e u s e o f solvents
has developed
intoapowerful
methodology as it
reduces the amount of
toxic waste produced and
therefore becomes less
harmful to the
environment
Solvent-free Organic Synthesis
Best solvent is no solvent!
• Clean and efficient synthesis
• Economic and environmental impact
• Fast reaction kinetics
Adolf von Baeyer
Synthesis of Indigo
Towards
benign
synthesis
with
remarkable
Versatility
G. W. V. Cave, C. L.
Raston, J. L. Scott
Chem.Commun.
2001, 2159
Solid-State General Oxidation with
with Urea H2O2 Complex
R. S. Varma and K. P. Naiker, Org. Letters, 1999, 1, 189.
Solvent-free Oxidative Preparation
of Heterocycles
Kumar, Chandra Sekhar, Dhillon, Rao, and Varma,Green Chem., 2004, 6, 156-157.
Solvent-free Synthesis of ß-Keto
Keto Sulfones Ketones
Kumar, Sundaree, Rao and Varma,Tetrahedron Letters, 2006, 47, 4197-4199.
Solvent-free Reduction
F. Toda et al. Angew. Chem. Int. Ed. Engl., 1989, 28, 320and Chem. Commun.,
1989, 1245.
Carbon-Carbon Bond Formation
Toda, Tanada, Iwata, J. Org. Chem., 1989, 54, 3007.
Solventless Photo Coupling and
Photo Rearangements
Y. Ito, S. Endo, J. Am. Chem. Soc. 1997, 119, 5974.
Shin, Keating, Maribay, J. Am. Chem. Soc. 1996, 118, 7626.
Solvent - Free Condensation
Z. Gross, et al., Org. Letters, 1999, 1, 599.
Solid-State Preparation
of Dumb-bell-shaped C120
Wang, Komatsu, Murata, Shiro, Nature 1997, 387, 583
Advantages of Solid Mineral Supports
(Alumina, Silica and Clay)
 Good dispersion of active (reagent) site can lead
to significant improvement of reactivity–large
surface area.
 The constraints of the (molecular dimensions)
pores and the characteristics of the surface
adsorption can lead to useful improvement in
reaction selectivity.
 Solids are generally easier and safer to handle
than liquids or gaseous reagents.
 Inexpensive, recyclable and environmentally
benign nature.
Solid-supported Solventless
Reactions
• Microwave irradiation of solventless
reactions with inorganic mineral supports
such as alumina, silica, or clays have
resulted in faster reactions with higher
yields with simplified separation.
R. S. Varma, Tetrahedron, 2002, 58, 1235.
R. S. Varma, Green Chem., 1999, 1, 43.
Supported Reactions
Using Microwaves
E. Gutterrez, A. Loupy, G. Bram, E. Ruiz-Hitzky, Tetrahedron Lett. 1989, 30, 945.
Microwave-Assisted Deacetylation
on Alumina
Varma et al.: J. Chem. Soc., Perkin Trans. 1, 999 (1993)
Deprotection of Benzyl Esters via
Microwave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al.: Tetrahedron Lett., 34, 4603 (1993)
Solid State Deoximation with Ammonium
Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma, Meshram: Tetrahedron Lett., 38, 5427 (1997)
Solid State Cleavage of
Semicarbazones/Phenylhydrazones with Amm.
Persulfate–Clay using Microwave and Ultrasonic
Irradiation
Varma, Meshram: Tetrahedron Lett., 38, 7973 (1997)
Solid Supported Solvent-free
Oxidation under MW
Varma et al., Tetrahedron Lett., 1997, 38, 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde: olefinic moiety remains
intact and the aldehyde functionality is reduced in a facile reaction.
Varma et al., Tetrahedron Lett., 1997, 38, 4337
Hydrodechlorination under
continuous MW
Pillai, Sahle-Demessie, Varma: Green Chemistry, 6, 295 (2004)
Synthesis of Heterocyclic
Compounds
Varma et al.: J. Chem. Soc. Perkin Trans 1, 4093 (1998)
Varma, J. Heterocycl. Chem., 36, 1565 (1999)
Synthesis of Heterocyclic
Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
R2
8
R1
7
6
1
N
5 4
2
3
R3
Heterocyclic systems, 10- p electronics
Structure of many naturals alkaloids : (-) slaframine, (-) dendroprimine,
indalozine, coniceine
Key intermediates in indolizidines, bisindolizines, ciclofans, ciclazines synthesisbiologic actives compounds
Why interest for indolizinic products
Strong fluorescent properties
luminiscent products
 Potentially fluorescents marker
 Potentially laser“scintillaters”
 Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
 Biologic actives products
Ligands for estrogen receptors
Possible inhibitory activity for phospholipase A2
“Calcium-entry” blockers
• Bioorg. & Med. Chem. Lett., 16, 59, 2006
•Tetrahedron, 61, 4643, 2005
• Bioorg. & Med. Chem., 10, 2905, 2002
• J. Org. Chem., 69, 2332, 2004
• Dyes and Pigments, 46, 23, 2000
•J. of Luminiscence, 82, 155, 1999
Indolizines by irradiation with
microwaves, in MCR
R2
O
Br +
R
+ R1
Al2O3
R2 Mw
R1
N
N
R=Ph, p-Tolil, Stiril,
COR
AcO
R1= H, COOMe
R2= COOEt, COOMe
U. Bora, A. Saikia, R. C. Boruah – Organic Lett., 5 (4), 435, 2003;
O
R1
Cl
+
R2
2% [Pd(PPh3)2Cl2
4% CuI
20 echiv. Et3N, THF, t.c., 2h
EtOOC
R1=Ph, 4-OMe-C6H4
R2= Ph
Br
N
Br
N
O
O
EtOOC
N
OMe
R2
COR 1
N
OMe
R2
COR 1
Asymmetric indolizines, by irradiation with microwaves, in MCR
A. Rotaru, I. Druţă, T. Oeser, T. Muller – Helv. Chim. Acta, 88, 1798, 2005;
Synthesis of new indolizines
 [3+2] dipolar cycloaddition of symmetrical or non-symmetrical 4,4’-bipyridiniummethyne-ylids with actives alkynes, symmetrical or non-symmetrical :
-
-
R1
X
N CH2
X
C CH2 N
O
C
R2
O
TEA
- 2 HX
anhydrous solvents
R1
C CH
O
N
C
N
2 R'O OC
N
CH
C
O
C
C
R1
COO R'
R2
CH
N
O
CH
C R2
O
H
C
N
N
2 H C C COOR'
I
C C
COOR'
N
C
O
H
C
C
R2
O
H
COOR'
II R1
C
C
R2
O
COOR'
N
H
R1= COOR', C6H4Y
R2=COOR', C6H4Y
R'=CH3, C2H5
Y=H, NO 2, OCH3, CH3, Cl, Br
X=Br, Cl
C
O
R'OOC
COOR'
R1
R1
C
(A)
N
COOR'
N
C
O
R'OOC
C
R2
O
COOR'
H
(B)
H
•I. Druţă, R. Dinică, E. Bâcu, I. Humelnicu – Tetrahedron, 54, 10811, 1998
•R. Dinică, C. Pettinari – Heterocycl. Comm., 07(4), 381, 2001
•A. V. Rotaru, R. P. Dănac, I. Druţă – J. Heterocyclic Chem., 41, 893, 2004
•A. Rotaru, I. Druţă, T. Oeser, T. Muller – Helv. Chim. Acta, 88, 1798, 2005
Synthesis of new substituted pyridiniumindolizines
 Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl
propiolate
I
I
H3C N
(9a-d)
I
I
KF/NMP
N
H3C N
R -HI
H3C N
N
O
R
H O
O
(10a-d)
HC C COO
a: R= OCH3
b: R= C6H5
c: R= p-C6H4-OCH3
d: R= p-C6H4-NO2
N
R
NO2
NMP
95o C, 30 min
I
II
I
H3C N
I
O
N
H3C N
O
N
R
R
O
O
O
O
NO2
NO2
-2[H]
-2[H]
6'
I
5'
H3C N
5
3'
4
3
N
4' 7
1'
2'
6
8
9
1
11
O
(A)
2
O
10 R
I
H3C N
O
N
R
O
O
O
(B)
NO2
(15a-d)
NO2
Indolizine synthesis in solid phase, under
microwaves
R
R2
R
C
R1
CH2
N X
N
a) (C2H5)3N in C6H6
sau N-metilpirolidona
R1
C
+ 2
b) microunde,
KF alumina
C
R2
N
N
X
R2
CH2
C
R
R1
2R
N
N
X
microunde,
KF alumina
R
C
N
R
N
C
R
+
2 R2 C
C
R1
R1
R2
R1
R2
Monoindolizine synthesis in solid
phase, under microwaves
CH3
CH3
a) KF/Al2O3
MW
10 min, 95oC
I N
+ HC
C COOC 2H 5
I N
b)Et3N/NMP
50-60 oC, 6-9h
O
N
N
I
c)KF/Al2O3
95oC, 10 min
O
OC2H5
O
R
R
(9a-d)
(12a-d)
a: R= OCH3
b: R= C6H5
c: R= p-C6H4-OCH3
d: R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Solution
Solid phase
Microwaves
Comp.
Time
(min)
T
(°C)
h
(%)
Time
(min)
T
(°C)
h
(%)
Time
(min)
T
(°C)
h
(%)
12a
480
50
63
10
95
57
10
95
84
12b
480
50
61
10
95
50
10
95
77
12c
480
55
71
10
95
52
10
95
85
12d
480
60
53
10
95
47
10
95
71
• B. Furdui, R. Dinică, I. Druţă, M. Demeunynck –Synthesis, 16, 2640, 2006
Benefits of MW-Assisted Reactions
• Higher temperatures (superheating / sealed
vessels)
• 􀂃 Faster reactions, higher yields, any solvent
(bp)
• 􀂃 Absolute control over reaction parameters
• 􀂃 Selective heating/activation of catalysts,
specific effects
• 􀂃 Energy efficient, rapid energy transfer
• 􀂃 Can do things that you can not do
conventionally
• 􀂃 Automation / parallel synthesis – combichem
MW-Assisted Solvent-free Three
Component Coupling:
Formation of Propargylamines
Ju, Li and Varma, QSAR & Combinatorial Science, 2004, 23, 891
Solvent-free Synthesis of Ionic
Liquids
Varma, Namboodiri, Chem. Commun., 2001, 643.
Varma, Namboodiri, Pure Appl. Chem., 2001, 73, 1307.
Namboodiri, Varma, Chem. Commun., 2002, 342.
MW Synthesis of
Tetrahalideindate(III)-based IL
Kim and Varma. J. Org. Chem., 2005, 70, 7882.
PEG, a Biodegradable “Solvent”
•
•
•
•
•
•
•
•
•
•
•
􀂃 PEG has been applied in bioseparations.
􀂃 PEG is on the FDA’s GRAS list, (compounds Generally
Recognized as Safe) and has been approved by the FDA for
Internal consumption.
􀂃 PEG is weakly, immunogenic, a factor which has enabled
the development of PEG–protein conjugates as drugs.
􀂃 Aqueous solutions of PEG are biocompatible and are
utilized in tissue culture media and for organ preservation.
􀂃 PEGs are nonvolatile
􀂃 PEG has low flammability
􀂃 PEG is biodegradable
J. Chen, S. K. Spear, J. G. Huddleston, R.D. Rogers, Green Chem.. 2005, 7, 64.
Suzuki Cross-Coupling Reaction
in PEG Accelerated by Microwaves
V. Namboodiri, R. S. Varma: Green Chemistry, 2001, 3, 146.
Advantages of Present Approach
 PEG offers a convenient recyclable reaction
medium
 Good substitute for volatile organic solvents
 The microwave heating offers a rapid and clean
alternative at high solid concentration and
reduces the reaction times from hours to
minutes
 The recyclability of the catalyst makes the
reaction economically and potentially viable for
commercial applications
Water as a “cleaner” solvent
•
•
•
•
•
•
•
Water is not a popular choice of solvent,
reactivity in heterogeneous aqueous media is
not very well understood
But It brings biochemistry and organic
chemistry closer together in the beneficial use
of water as the reaction medium, it is abundant,
inexpensive and clean.
Cu (I) Catalyzed Click Chemistry
P. Appukkuttan, W. Dehaen, V. V. Fokin, E. Van der Eycken.
Org. Lett. 2004, 6, 4223.
N-alkylation of Amines
using Alkyl Halides
Ju, Y.; Varma, R. S., Green Chem. 2004, 6, 219-221.
Aqueous N-alkylation of Amines
using Microwave Irradiation
Ju, Y.; Varma, R. S., Green Chem. 2004, 6, 219-221.
Why Amines and Heterocycles ?
MW Synthesis of N-Aryl
Azacycloalkanes
Ju; Varma, Tetrahedron. Lett., 2005, 46, 6011.
Ju; Varma, J. Org. Chem., 2006, 71, 135.
Choice of Reaction Media
MW -assisted one-pot synthesis of
triazoles
Designing a “greener” synthesis
•
•
•
•
•
Plan!
Maximize convergence
Consider using renewable starting materials
Avoid super toxic reagents
Strive for high atom economy
– Use catalytic over stoichiometric
– Avoid auxiliaries and protecting groups
• Consider greener solvents
• Minimize number of purifications
Take Aways
• “Green chemistry” is not so far away from
what we do everyday
– High yields
– Minimal number of steps
– Minimize number of purifications
• Green principles to keep in mind
– Strive for atom economy
– Consider the toxicity and necessity of
reagents and solvents
Green Chemistry Opportunities
Conferences
– Annual ACS Green Chemistry and
Engineering Conference
– Annual Gordon Conferenece, Green
Chemistry
• Funding
– PRF green chemistry grants
– NSF green chemistry grants
– EPA funding
Conclusion
Not a solution
to all environmental problems But
Green chemistry
the most fundamental approach to
preventing pollution.
• Today, a large body of work on microwaveassisted synthesis exists in the published
and patent literature.
• Many review articles, several books and
information on the world-wide-web already
provide extensive coverage of the subject.
Lead References
• Lidström, P.; Tierney, J.P.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225
• Hayes, Brittany, L. Microwave Synthesis.
Chemistry at the Speed of Light. North Carolina:
CEM Publishing, 2002.
• Tierney, J.P., and P. Lidström, ed. Microwave
Assisted Organic Synthesis. Oxford: Blackwell
Publishing Ltd, 2005.
• de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem.
Soc. Rev. 2005, 34, 164.
Lead References
reviews
A. Loupy, A. Petit, J. Hamelin, F. Texier- Boullet, P. Jacquault, D. Math_,
Synthesis1998, 1213–1234; R. S. Varma, Green Chem. 1999, 43–55; M.
Kidawi, Pure Appl. Chem. 2001, 73, 147–151; R. S. Varma, Pure Appl.
Chem. 2001, 73, 193–198; R. S. Varma, Tetrahedron 2002, 58, 1235–1255;
R. S. Varma, Advances in Green Chemistry: Chemical Syntheses Using
Microwave Irradiation, Kavitha Printers, Bangalore, 2002. A. K. Bose, B. K.
Banik, N. Lavlinskaia, M. Jayaraman, M. S. Manhas, Chemtech 1997, 27,
18–24; A. K. Bose, M. S. Manhas, S. N. Ganguly, A. H. Sharma, B. K.
Banik, Synthesis 2002, 1578–1591. C. R. Strauss, R. W. Trainor, Aust. J.
Chem. 1995, 48, 1665–1692; C. R. Strauss, Aust. J. Chem. 1999, 52, 83–
96; C. R. Strauss,
References
books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed.: C. O. Kappe),
Kluwer, Dordrecht, 2003 (a special issue of Mol. Diversity 2003, 7, pp 95–307);
Stadler, C. O. Kappe, Microwave-Assisted Organic Synthesis (Eds.: P. Lidstr_m, J. P.
Tierney), Blackwell Publishing, Oxford, 2005 (Chapter 7).
A. Loupy (Ed.), Microwaves in Organic Synthesis, Wiley-VCH, Weinheim, 2002.
B. L. Hayes, Microwave Synthesis: Chemistry at the Speed of Light, CEM Publishing,
Matthews, NC, 2002.
P. Lidstrom, J. P. Tierney (Eds.), Microwave- Assisted Organic Synthesis, Blackwell
Publishing, Oxford, 2005.
For online resources on microwave-assisted organic synthesis (MAOS), see:
www.maos.net.
THANK
YOU
FOR YOUR ATTENTION!
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