AIN SHAMS UNIVERSITY SECOND YEAR

PHARMACY
FACULTY OF PHARMACY
1ST SEMESTER
DEPARTMENT OF PHARMACEUTICAL
CHEMISTRY

MICROWAVE IN
ORGANIC
SYNTHESIS

EDITED BY

4.Shimaa Sayed
1.Doha Ashour
Mohammad 262
Abdulwahab 267
5. Shimaa Abd Elmged
2. Aliaa Adel Abdulsalam
Ibrahem 264
278
6. Shimaa Ali Saad
3. Fatma Abd El-Aziz
265
INDEX

MICROWAVE IN ORGANIC SYNTHESIS

1 INTRODUCTON 3

2 GENERAL BRINCIBLES 4
THEORY OF MICROWAVE HEATING

1 DIPOLAR POLARIZATION 5

2 CONDUCTION MECHANISM 5

3 SUPERHEATING EFFECT 6

4 SPECIFIC MW EFFECT 7

5 MW EFFECT ON SELECTIVITY OF REACTION 8

6 MW- Accelerated Homogeneous Catalysis 9

APPLICATIONS 10
CONCLUSION 17
REFERENCES 18

2
Introduction
In 1986 Richard Gedye and coworkers published a short
communication in Tetrahedron Letters, entitled "The Use Of Microwave
Ovens for Rapid Organic Synthesis" which for the first time described
the utilization and advantages of microwave irradiation for organic
synthesis . In this original publication four different types of reactions
were studied, including the hydrolysis of benzamide to benzoic acid
under acidic conditions (Scheme 1). Considerable rate increases (5 -
1000 fold) were observed for all investigated transformations when
compared to classical thermal reflux conditions. The same year, an
independent study by the groups of Giguere and Majetich describing
similar rate-enhancements in microwave-promoted Diels-Alder,
Claisen, and ene reactions was published in the same journal .

Scheme 1

The advantages of using microwave dielectric heating for performing

organic reactions were soon realized by many different groups and as
a consequence the amount of articles describing high-speed chemical
synthesis promoted by microwave irradiation has grown quickly from
~200 in 1995 to ~1000 in 2001. In addition an unusually large
number of review articles and commentaries (~60) has been published
on this subject covering various aspects of microwave-assisted
synthesis

Importantly, many of the early microwave-assisted reactions, such as

the process shown in Figure 1, were carried out in sealed Teflon or
glass vessels using unmodified domestic household ovens . Due to the
nature of microwave dielectric heating accurate temperature
measurements using conventional means of temperature
determination during the irradiation process were not possible at the
time. Therefore the reasons for the observed rate-enhancements were
in many cases not fully understood and led to a lot of speculation and
fierce debate on the existence of so-called non-thermal or specific
microwave effects .

Today, a variety of dedicated microwave reactors for chemical

synthesis are commercially available that incorporate built-in magnetic
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stirring, direct temperature control of the reaction mixture with the aid
of fluoroptic probes, shielded thermocouples or IR sensors, and
software that enables online temperature/pressure control by
regulation of microwave output power

4
General Principles

• Electromagnetic Spectrum MW have wavelengths 1mm - 1m , frequencies

of 0.3 - 300 GHz.

• To avoid interfernce with telecommunication, cellular phones and radar, by

International convention most domestic and commercial MW heating operate
at wavelength of 12.2 cm, 2.45 GHz.

• MW can be divided in an electric field and a magnetic field component and

the former is responsible for heating.

• MW is generated by vacuum tubes, magnetron, multimode or mono-mode

Commercial ovens - multimode, distribution of electric field is not
homogeneous.

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 Theory of Microwave Heating

Dipolar Polarization:
• For MW heating to occur the matrix should be dipolar or ionic

Polar solvents e.g. water, DMF, CH2Cl2 with a dipole moment, i.e. high
dielectric constant are MW-active whereas non-polar solvents like toluene,
diethyl ether, benzene are MW-inactive.

• In the presence of an electric field - dipole moment tend to align parallel

to the applied field by rotation.

• If the electric field oscillates, the dipole realigns and rotates in respond to
the alternate electric field.

• The molecules are extremely agitated, the molecular friction and collisions
give rise to dipolar heating, ~10 oC per second.

• Note - gases are not microwave active because the rotating molecules are
far apart

• MW heating occurs via dipolar polarization or conduction mechanism

Conduction Mechanism:
• This applies for ions in solutions.

• The ions will move through the solution under the influence of an electric
field, the increased collision rate generates heat.

• Heat generated is stronger than the dipolar mechanism, e.g. tap water will
have higher temperature than distilled water at the same MW radiation
power.

• Problem - non polar solvents are MW-inactive.

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Superheating effect:
• The combination of temperature and frequency of the MW
causes the loss tangent to increase.
This causes the heating rate to increase during MW heating by
limiting the formation of
"Boiling nuclei". Superheating may result in a raised of boiling
point by up to 26 oC
• This phenomenon is believed to be responsible for the rate
increases in solution phase MW reaction.

• MW produces efficient internal energy transfer (in situ

heating)
Compared to the wall heat transfer in the conventional
Thermal heating. As a result the tendency for seed formation
(The initiation of boiling) is reduced and superheating is possible.

• Temperature profiles of MW flash-heated palladium catalyzed

alkylation in acetonitrile (bp, 81- 82oC).
The reaction was performed in Septum-sealed Pyrex vessels.

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Is There A Specific MW effect ?
• Since the introduction of MW in organic chemistry in 1986, the
main debate still reamains,what alter the outcome of the
synthesis.

Is it merely a thermal or a specific MW effect?

Arrhenius Equation

k = Ae^(-Ea/RT)

• Does not decrease reaction (Ea) but Increases pre-exponential

factor (A )

The pre-exponential factor, A, describes the molecular mobility

and depends on the frequency of vibrations of the molecules.
Since, MW induces an increase in molecular vibrations, it's been
proposed that this factor, A, can also be affected

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MW effect on selectivity of reactions:
• Since MW can interact with a polar TS. The product formed via
a more polar TS will be favored

• Regioselectivity in Cycloaditions of C70 fullerene under MW can

be altered.

Classical heating: ODCB, 120 min, 32% yield 46%

46% 8%

MW : ODCB, 120W, 30 min, 39% yield 50%

50% 0%

• Theoretical studies suggest that under kinetic control, 1a and 1b

have a more polar TS.

N.B: ODCB is ( - o-dichlorobenzene).

9
MW- Accelerated Homogeneous Catalysis
Homogeneous palladium-catalyzed reactions:

1-Heck coupling :

2-Sonogashira Coupling:

3-Suzuki Cross Coupling:

10
4- Stille Coupling:

Applications
Acetals and ketals are readily deprotected under neutral
conditions in the presence of acetone and indium(III)
trifluoromethanesulfonate as catalyst at room temperature
or mild microwave heating conditions to give the
corresponding aldehydes and ketones in good to excellent
yields.

1)

Palladium-phosphinous acids catalyze the microwave-

assisted conjugate addition of arylsiloxanes to a wide range
of α,β-unsaturated substrates in water. The described
procedure eliminates the need for stoichiometric additives
and an excess of arylsiloxane, and does not require an inert
atmosphere.

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2)

Gold N-heterocyclic carbene complexes, in conjunction with

a silver salt, were found to efficiently catalyze the
rearrangement of allylic acetates under both conventional
and microwave-assisted heating. The steric hindrance of the
ligand bound to gold was found crucial as only extremely
bulky ligands permitted the isomerization.

3)

Hoveyda-Grubbs catalyst in combination with BF3·OEt2

efficiently promotes tandem cross metathesis intramolecular
aza-Michael reaction between enones and unsaturated
carbamates resulting in the creation of β-amino carbonyl
units. The use of microwave irradiation dramatically
accelerates the process, but also inverts the
stereoselectivity in the addition process.

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4)

An effective and mild microwave-assisted route to 2-

substituted benzofurans directly from carboxylic acids allows
the preparation of α-alkyl-2-benzofuranmethanamines from
N-protected α-amino acids without racemization in good
yields.
5)

A Lewis acid catalyzed and solvent free procedure for the

preparation of imides from the corresponding anhydrides
uses TaCl5-silica gel as Lewis acid under microwave
irradiation.

6)

A series of primary alcohols and aldehydes were treated with

iodine in ammonia water under microwave irradiation to give
the intermediate nitriles, which without isolation underwent
[2 + 3] cycloadditions with dicyandiamide and sodium azide
to afford the corresponding triazines and tetrazoles in high

13
yields.

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7)

Zirconium(IV)-catalyzed exchange processes of dialkyl

carbonates and carbamates in the presence of amines gave
carbamates and ureas using 2-hydroxypyridine (HYP) and 4-
methyl-2-hydroxyquinoline (MeHYQ) as catalytic additives,
respectively. A microwave acceleration effect was observed
in Zr(IV)-catalyzed carbamate-urea exchange.

8)

A one-pot reaction between nitriles, hydroxylamine and

Meldrum’s acids under microwave irradiation and solvent-
free conditions gives 3,5-disubstituted 1,2,4-oxadiazoles in
good to excellent yields.

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9)

The Gewald reaction of PEG-bound cyanoacetic ester,

elemental sulfur, DIPEA and carbonyl compounds carried out
under microwave irradiation afforded PEG-supported
thiophenes, which were acylated and treated with 1% KCN in
methanol to give free thiophenes in good yields. This
synthetic method is simple and mild.

10)

Addition of Grignard reagents to pyridine N-oxides in THF at

room temperature and subsequent treatment with acetic
anhydride at 120°C afforded 2-substituted pyridines in good
yields. By exchanging acetic anhydride for DMF in the
second step, 2-substituted pyridine N-oxides were obtained,
enabling the synthesis of 2,6-disubstituted pyridines.

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11)

Lawesson’s reagent is an efficient promoter in the solvent-

free microwave-assisted synthesis of 2-substituted
benzoxazoles and benzothiazoles from carboxylic acids and
2-aminophenol or 2-aminothiophenol, respectively. Various
aromatic, heteroaromatic and aliphatic carboxylic acids react
under the conditions developed with good yields.

12)

Trapping of β,γ-alkynyl aldehydes, generated in situ by

treatment of alkynyloxiranes with a catalytic amount of
Sc(OTf)3 or BF3·OEt2, by a variety of allyl nucleophiles affords
homopropargylic homoallylic alcohols in good yield and
selectivity. Subsequent enyne metathesis gives
functionalized vinylcyclopentenols.

17
13)

A novel and efficient synthesis of pyrimidine from β-formyl

enamide involves samarium chloride catalysed cyclisation of
β-formyl enamides using urea as source of ammonia under
microwave irradiation.

14)

]A very simple and efficient, microwave-assisted procedure

is reported for the synthesis of 1,3-diarylimidazolinium
chlorides by cyclization of N,N′-diarylethylenediamines
dihydrochlorides with triethyl orthoformate.

15)

N-Vinylpyridinium and -trialkylammonium tetrafluoroborate

salts represent a new class of electrophilic coupling partner
for Pd(0)-catalyzed Suzuki cross-coupling reactions with
various boronic acids in high yields. The crystalline, air-
stable, and nonhygroscopic salts are easily prepared from
activated acetylenes and pyridinium or trialkylammonium
tetrafluoroborates.
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 conclusion
1-MW provides an interesting alternative for
heating chemical reactions.

2- The drastic rate enhancement observed

confims the usefulness of the MW technique.

3-Solvent-free reactions under MW -

promising future

4-The availability of commercial MW

instrument for organic chemistry make this
technique a routine use in the laboratory.

5- The existence of a specific MW effect is

still a debate.

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 References:

• www.organic-chemistry.org/topics/microwave-
synthesis.shtm

• www.mdpi.org

• www.euchems-torino2008.it/download/WTL-
I.3HLehmann.pdf

• en.wikipedia.org/wiki/Microwave_chemistry

• www.chemistry-conferences.com

• www.microwavesynthesis.net

• www.biotage.co.jp

• www.cem.de

• www.encyclopedia.com

• www.jasco.hu

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