New Era In The Field Of Synthetic Chemistry: Microwave Assisted Synthesis

Raghvendra Dubey

Raghvendra Dubey

Microwave radiation, an electromagnetic radiation, is widely use as a source of heating in organic synthesis Microwaves have enough momentum to activate reaction mixture to cross energy barrier and complete the reaction.

The basic mechanisms observed in microwave assisted synthesis are polarization (mainly dipolar polarization) and conduction. The benefits of microwave synthesis including increasing speed, yield and clear chemistry with decreasing time, have provided the momentum for many chemists to switch from traditional heating method to microwave assisted chemistry.


Synthesis of new chemical entities is major bottleneck in drug discovery. The methods for synthesis (Heating process) of organic compounds has continuously modified from the decade. In 1855, Robert Bunsen invented the burner which act as a energy source for heating a reaction vessel, this was latter superseded by isomental, oil bath or hot plate, but the drawback of heating, though method remain same, one feasible solution is microwave assisted synthesis (MAOS), which is in many way superior to traditional heating.

Microwave heating refers the use of electromagnetic waves ranges from 0.01m to 1m wave length of certain frequency to generate heat in the material. These microwaves lie in the region of the electromagnetic spectrum between millimeter wave and radio wave i.e. between I.R and radio wave. They are defined as those waves with wavelengths between 0.01metre to 1meter, corresponding to frequency of 30GHz to 0.3 GHz. 16, 18, 19

Among the broad range of microwaves radiation, wavelength ranges from 0.01m to 0.25m are used by equipment known as microwave RADAR, which is used for telecommunications. In order to avoid interference of wavelength of this region (use for telecommunication region), the wavelength at which industrial and domestic microwave apparatus may be operated were regulated at both national and international level. In majority of countries, 2.450(+/-0.050) GHz is the major operating frequency for this purpose.1- 21


The basic principle behind the heating in microwave oven is due to the interaction of charged particle of the reaction material with electro magnetic wavelength of particular frequency. The phenomena of producing heat by   electromagnetic irradiation are ether by collision or by conduction, some time by both.

All the wave energy changes its polarity from positive to negative with each cycle of the wave. This cause rapid orientation and reorientation of molecule, which cause heating by collision. If the charge particles of material are free to travel through the material (e.g. Electron in a sample of carbon), a current will induce which will travel in phase with the field. If charge particle are bound within regions of the material, the electric field component will cause them to move until opposing force balancing the electric force.1-8

Heating Mechanism

In microwave oven, material may be heated with use of high frequency electromagnetic waves. The heating arises from the interaction of electric field component of the wave with charge particle in the material. Two basic principal mechanisms involve in the heating of material.

Dipolar Polarisation

Dipolar polarization is the phenomenon responsible for the majority of microwave heating. It depends upon nature (Polarity) of solvent and compound.  In polar molecule different electronegativities of individual atoms results permanent electric dipole which are sensitive to external electric fields and will attempt to align with them by rotation. This realignment is rapid for free molecule, but in liquid the instantaneous alignment is prohibited by the presence of other molecule. A limit is therefore place on the ability of the dipole to respond to a field, which affects the behavior of the molecule with different frequency of electric field. For e.g. under low frequency irradiation the dipole may react by aligning itself in phase with the electric field. Molecule will polarize uniformly, and no random motion result. Whilst some energy is gained in the molecule by this behavior, and some is lost in collisions, the overall heating effect is small. Under high frequency irradiation the polar molecule will attempt to follow the field, but intermolecular inertia stops any significant motion before the field has reversed, the dipole do not have sufficient time to respond the field, and so do not rotate. As no motion is induced in the molecules, no energy transfers take place, and therefore, no heating. In intermediate frequency the field will be such that the molecule is almost, but not quite, able to keep in phase with the field polarity. The microwave frequency is low enough that the dipoles have time to respond to the alternating field, and therefore to rotate, but high enough that the rotation does not precisely follow the field. As the dipole reoriented to align itself with the field, the field is already changing, and a phase difference causes energy to be lost from the dipole in random collisions, and to give rise to dielectric heating, shown in Figure 1

Figure 1 Microwave heating by dipolar polarization mechanism.

Microwave heating by dipolar polarization mechanism

Interfacial Polarization

Interfacial polarization is an effect, which is very difficult to treat in a simple manner, and easily viewed as combination of the conduction and dipolar polarization effects. This mechanism is important for system where a dielectric material is not homogenous, but consists of conducting inclusion of one dielectric in other.

Conduction Mechanism

Where the irradiated sample is an electrical conductor, the charge carries (electrons, ions, etc.) are moved through the material under the influence of electric field (E), resulting in a polarization (P), these induced currents will cause heating in the sample due to any electric resistance, shown in Figure 2. For a very good conductor, complete polarization may be achieved in approximately within 10-18 seconds. 19-35

Microwave heating by conduction mechanism

Figure 2 Microwave heating by conduction mechanism.

Requirement for Heating

The reaction vessel must be substantially transparent to the passage of microwaves e.g.- glass fiber, polypropylene. Heating of mixture does not proceed from the surface of the vessel. The vessel wall is almost at a lower temperature than the reaction mixture. In fact the vessel wall is effective route for heat loss from the reaction mixture

For microwave heating to occur, there must be some component of the reaction mixture that absorbs the penetrating microwave. Microwave radiation will penetrate in the reaction mixture and if they are absorbed, the energy will be converted into heat.

Interaction with matter

The microwave coupled directly with the molecules that are heating, leading to rise in temperature. In typical reaction co-ordinate the process begins with reactions, which have a certain potential energy level .In order to complete the transformation this reaction must be activated to a transitional state. Once reaching to that state, they quickly react and return to lower energy state (i.e. forms the product for the reaction). Microwave energy provides the momentum to overcome the activation energy barrier and complete the reaction.

In microwave heating, material (reactant) can absorb the energy, they can reflect the energy, or they can simply pass the energy, few material are either pure absorbs, pure reflects or completely transparent to microwaves. Polar molecules are generally good absorbent to microwave radiation.

Influence on reaction rate and yield

Microwave radiation will transfer energy in 10-9 seconds, with each cycle of the electromagnetic energy. Microwave heating affects the temperature parameters of rate equation. Most effects are due to high instantaneous heating of the substance above the normal bulk temperature. This is the primary factor in the observed rate enhancements.

K= reaction rate constant=Ae-Ea/RT           

The reaction rate constant A depends on two factors. First on the frequency of collisions that have the correct geometry for reaction to occur, and second on the fraction of the molecule that has minimum energy required overcoming activation barrier.

Microwave enhancement reaction can be faster by as much as 1,000 fold. Microwave energy shifts the chemical reaction from kinetic control to thermodynamic control because of availability of high energy. With the elevated energy generated by the transfer of microwave energy, reactions which require many hours or even days to complete, have been accomplished in a minutes. The kinetic molecular relaxation is approximately 10-5seconds. The energy transfers (in 10-9seconds) is faster than a molecule can relax (in 10-5seconds), resulting in a non-equilibrium condition and high instantaneous temperatures that affect the kinetic of system. This enhances the reaction rate, as well as the yields.

Differential Heating Effect

Different heating effects are due to the fact that the material or components of a reaction mixture can differ in their ability to absorb microwave. Differential absorption of microwave will lead to differential heating and localized thermal inhomogeneties.

Solvent and reactant absorb microwave equally- Increasing temperature can increase reaction rate, as in homogenous condition both solvent and reactant are heated equally in the system.

Solvent absorb microwave, reactant much less so -As solvent absorbs radiation they are directly heated by microwave. The bulk solvent, on heating, will in turn heat the reactant by conduction. Homogenous reaction condition can be established with thorough.

Reactants absorbs microwave, solvent much less so-As reactants absorb radiation, they are directly heated by microwave. In this case, the bulk solvent is heated by conduction obtained from the reactant.

Catalyst on microwave –Most of the catalysts absorbs microwave radiation, which enhance various catalytic and enzymatic activities. Catalytically activation (e.g. palladium) is generally used in many synthetic reactions.

Conventional vs Microwave Heating

Microwave heating is different from conventional heating in many respects. The mechanism behind microwave

Synthesis is quite different from conventional synthesis. Points enlisted in Table 1, differ the microwave heating from conventional heating.19-35

Table 1Difference between conventional and microwave assisted heating





Reaction mixture heating proceeds from a surface usually inside surface of reaction vessels

Reaction mixture heating proceeds directly inside mixture


The vessel should be in physical contact with surface source that is at a higher temperature source (e.g. mental, oil bath, steam bath etc.)

No need of physical contact of reaction with the higher temperature source. While vessel is kept in microwave cavities.


By thermal or electric source heating take place.

By electromagnetic wave heating take place.


Heating mechanism involve- conduction

Heating mechanism involve- dielectric polarization and conduction


Transfer of energy occur from the wall, surface of vessel, to the mixture and eventually to reacting species

The core mixture is heated directly while surface (vessel wall) is source of loss of heat


In conventional heating, the highest temperature (for a open vessels) that can be achieved is limited by boiling point of particular mixture.

In microwave, the temperature of mixture can be raised more than its boiling point i.e. superheating take place


In the conventional heating all the compound in mixture are heated equally

In microwave, specific component can be heated specifically.


Heating rate is less

Heating rate is several fold high

Microwave Reactors in organic synthesis

Microwave synthesis has started with a kitchen microwave with good results. Now a day many types of advanced microwave oven are introduce in the market. Advance microwave system consists of a microwave source (Magnetrons), a microwave cavity or an applicator (Multimode cavity or Single mode cavity, Figure 3), Mode Stirrer, Sensors probe (thermocouples or IR sensor) and Software with digital display.

Magnetrons are a vacuum tube in which electron are affected by magnetic and electric fields in such a way that they produce microwaves radiation (a type of electromagnetic radiation) of particular wavelength.

Microwave cavity or Applicator is also known as reactor. Two types of reactors are used for microwave assisted organic synthesis multimode reactors and monomode reactors. Domestic microwave ovens (multimode reactors) are the most common instruments used in organic synthesis since they are comparatively inexpensive and readily available. Lot of satisfying organic synthesis has been done with domestic microwave.

Multimode reactors provide a field pattern with areas of high and low field strength, commonly referred to as “hot and cold spots.” This non-uniformity of the field leads to the heating efficiency varying drastically between different positions of the sample. This draw back is overcome by the use of mode stirrer.

The mode stirrer is, typically a periodically moving metal vane that continuously changes the instantaneous field pattern inside the cavity. The shape of the vane and its movement is such that the microwave field is continuously stirred, and therefore the field intensity is homogeneous in all directions and all locations throughout the cavity. Therefore microwave-absorbing materials can be placed anywhere inside the cavity, because the field is homogeneous through out the cavity.

The single mode cavity, as the name implies, allows only a single mode to enter the cavity by waveguide. A properly designed Single mode cavity or reactor can prevent the formation of “hot and cold” spots. This advantage is very important in organic synthesis since the actual heating pattern can be controlled. Therefore, higher reproducibility and predictability are achieved.

In modern microwave reactors, preinstalled digital thermometers (sensors and probes) are used for temperature control via changing power and temperature. Moreover, some sophisticated ovens even interface with computers for reaction monitoring.36, 37

Figure 3 Single mode and Multimode cavity used in microwave synthesis

Single mode and Multimode cavity used in microwave synthesis


1. High efficiency of heating,

2. Reduction in unwanted side reaction (reaction Quenching),

3. Purity in final product,

4. Improve reproducibility

5. Environmental heat loss is save

6. Reduce wastage of heating reaction vessel

7. Selective heating i.e. heating selectively one reaction component.

8. Super heating: conventional heating is done from out side, therefore the core of solvent may be as much as 5C cooler than the edge, while in microwave, the core is 5C hotter than the outside, because of surface cooling, therefore in microwave, we can raise the boiling point of solvent by as much as 5C, an effect is known as super heating.

9. Green advantage

(i) Minimal amount of solvent is utilized; the reactants are absorbed into sponge like material (clay alumna) and are heated directly to generate the product.

(ii) Use of water (supercritical water) in organic reaction, instead of organic solvent, as water in microwave acts as an excellent solvent. Some compound that can’t be or difficult to prepare by conventional technique can easily prepare by microwave. E.g. Preparation of needle shaped iron oxide particle.

(iii) Direct and rapid nature of microwave heating cross-large kinetic behavior at an earlier stage of synthesis process.


1.In Organic Reaction -

Many reaction has yet performed through microwave heating this include Acetylation reaction38, Addition reaction39, Alkylation reaction40, Alkynes metathesis41, Allylation reaction42, Amination reaction43, Aromatic nucleophillic substitution reaction 44, Arylation reaction45, Carbonylation reaction46, Combinatorial reaction47, Condensation reaction48, Coupling reaction49, Cyanation reaction50, Cyclization reaction51, Cyclo-addition reaction52, Deacetylation reaction53, Dehalogenation reaction54, Diel’s-Alder reaction55, Dimerization reaction56, Elimination reaction39, Estrification reaction57, Enantioselective reaction58, Halogenation reaction59, Hydrolysis reaction60, Mannich reaction61, Oxidation reaction62, Phosphorylation synthesis63, Polymerization reaction64, Rearrangement reaction65, Reduction reaction66, Ring closing synthesis67, Solvent free reaction68, Transestrification reaction57, Transformation reaction69

2. Heterocyclic Nucleus Synthesis 70-

Microwave is used in synthesis of

Five-Membered Heterocyclic Rings- Pyrroles, Pyrazoles, Imidazoles, Oxazolines, Triazoles and Tetrazoles, Oxadiazoles, Isoxazolines and Pyrazolines

Benzo-Derivatives of Five-Membered Rings- Benz-imidazoles, Benz-oxazoles, and Benz-thiazoles, Indoles, ã-Carbolines,

Six-Membered Rings- Dihydropyridines, Dihydropyridopyrimidinones, Tetrazines, Dihydropyrimidines

Polycyclic Six-Membered Rings- Quinolines, Pyrimido [1, 2-a] pyrimidines

Heterocyclic C-Alkylations, Heterocyclic N-Alkylation’s, Nucleophilic Substitutions, Hetero-Diels-Alder Reactions, Intramolecular Reactions, Intermolecular Reactions, 1,3-Dipolar Cycloaddition Reactions70

3. Miscellaneous – Microwave assisted Extraction, Microwave Ashing, Microwave drying.


(1) Adam, D. Nature 2003, 421, 571-572.

(2) Blackwell, H. E.. Org. Biomol. Chem. 2003, 1, 1251-55.

(3) Sharma, S. V.; Rama-sarma, G. V. S.; Suresh, B. Indian. J. Pham. Scien. 2002, 64, 337-344.

(4) Johansson, H. Am. Lab.  2001, 33(10), 28-32.

(5) Bradley, D. Modern Drug Discovery 2001, 4, 32-36.

(6) Larhed, M.; Hall berg, A. Drug Discovery Today 2001, 6, 406-416.

(7) Wathey, B.; Tierney, J.; Lidrom, P.; Westman, J. Drug Discovery Today 2002, 7,373-380.

(8) Dzieraba, C. D.; Combs, A. P. Annual reports in medicinal chemistry, academic press, 2002, 37, 247-256.

(9) Gedye, R. N.; Smith, F.; Westaway, K.; Ali, H.; Baldisiera, L. Tetrahedron Lett. 1986, 27, 279-282.

(10) Roth, G.; Sarko, C. Drug Discovery and development 2001, 57-58.

(11)Berlan, J. Rad. Phys. Chem. 1995, 45, 581-589.

(12)Whittaker, G. New Scientist 1998, 34.

(13)Whittaker, G. In;

(14)Cumming, S. Green chem. 1999, 1, G94-G96.

(15)Richter, R. C.; Link, D.; Kingston, H. M. Chem. Soc. Rev. 1997, 26, 233-238.

(16)Galema, S. A. Chem. Soc. Rev., 1997, 26, 233-238.

(17)Fini, A.; Breccia, A. Pure Appl. Chem., 1999, 71, 573-579.

(18)Fourth International Electronic Conference on synthetic organic chemistry (ECSOC-4),,  sep.1-30, 2000.




(22)Westaway, K. C.; Gedye, R. J. Microwave Power Electromagnetic energy 1995, 30, 219-230.

(23) Kuhnert, N. Angrew Chem. Int. Ed. 2002, 41, 1863-1866.

(24)Gabriel, C.; Gabriel, S.; Grant, E. H.; Holstead, B. S. T.; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27, 213-23.

(25)Langa, F.; DelaCruz, P.; DelaHoz, A.; Diaz-Ortiz, A.; Diez-Barra, E. Org. Synth. 1997, 4, 373-86.

(26)Saillard, R.; Poux, M.; Berlan, J.; Audhvy-peaudecert, M. Tetrahedron 1995, 51, 4033-42.

(27)Stuerga, D.; Gaillard, P. Tetrahedron 1996, 52, 5505-10.

(28)Caddick, S. Tetrahedron 1995, 51, 10403-32.

(29)Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665-1692.

(30)Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman, M.; Manhas, M. S. Chemtech1997, 27, 18-124.

(31) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225-83.

(32)Nuchter.  M.; Ondruschka, B.; Lautenschlager, W. Chem. Eng. Techno. 2003, 26, 1208-1216.

(33)Nuchter.  M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128-141.

(34)Abramovitch, R. A.  Org. Prep. Proced. Int. 1991, 23, 685-711.

(35)Leadbeater, N. E. Chemistry World 2004, 1, 38-41.

(36)Raner, K. D.; Strauss, C. R.; Traineer, R. W.; Thorn, J. S. J. Org. Chem. 1995, 60, 2456-60.

(37)Barlow, S.; Morder, S. R. Adv. Funct. Mater. 2003, 1B, 517-18.

(38)Moghaddam, F. M.; Sharifi, A. Synth. Commun. 1995, 25, 2457-61.

(39)Mogilaiah, K.; Kavita, S.; Babu, H. R. Indian J. Chem. 2003, 42b, 1750-52.

(40)Abramovitch, R. A.; Shi, Q.; Bogdal, D. Synth. Commun. 1995, 25, 1-8.

(41)Miljanic, O. S.; Volhardt, K. P. C.; Whitener, G. D. Synlett. 2003, 1, 29-34.

(42)Motorina, I. A.; Parly, F.; Grierson, D. S. Synlett. 1996, 4, 389-91.

(43)Mccarroll, A. J.; Sandham, D. A.; Titumb, L. R.; Dek Lewis, A. K.; Cloke, F. G. N.; Davies, B. P.; Desantand, A. P.; Hiller, W.; Caddicks, S. Molecular Diversity 2003, 7, 115-23.

(44)Robeiro, G. L.; Khandikar, B. M.. Synth. Commun. 2003, 33, 10405-10.

(45)Wali, A.; Paillai, S. M.; Satish, S. Indian petrochemical Corp. Ltd. 1995, 294.

(46)Yamazaki, K.; Kondo, V.  J. Comb. Chem., 2003, 5, in press.

(47)Al-obeidi, F.; Austin, R. E.; Okonoya, J. F.; Bond, D. R. S. Mini-rev. Med. Chem. 2003, 3, 449.

(48)Kim, J. K.; Kwon, P. S.; Kwon, T. W.; Chung, S. K.; Lee, J. W. Synth. Commun. 1996, 26, 535-42.

(49)Burten, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373-76.

(50)Arevela, R. K.; Leadbeater, N. E. J. Org Chem.2003, 68, 9122-25.

(51)Crawford, K. R.; Bur, S. K.; Straub, C. S.; Padwa, A. Org. Lett. 2003, 5, 3337-40.

(52)Lerestif, J. M.; Perocheav, J.; Tonnard, F.; Bazareav, J. P.; Hamelin, J. Tetrahedron 1995, 51, 6757-74.

(53)Jaya Kumar, G.; Ajithabai, M. D.; Santhosh, B.; Veena, C. S.; Nair, M. S. Indian J. Chem. 2003, 42B, 429-31.

(54)Calinescu, I.; Calinescu, R.; Martin, D.I.; Radoiv, M. T. Res. Chem. Inter med. 2003, 29, 71-81.

(55)Mavoral, J. A.; Cativicla, C.; Garcia, J. I.; Pires, E.; Rovo, A. J.; Figueras, F. Appl. Catal. 1995, 131, 159-66.

(56)Santagoda, V.; Fiorino, F.; Perissuti, E.; Severino, B.; Terracciano, S.; Cirino, G.; Caliendo, G. Tetrahedron lett. 2003, 5, 2131-34.

(57)Roy, I.; Gupta, M. N. Tetrahedron Lett. 2003, 44, 1145-48.

(58)Diaz-Ortiz, A.; Dela Hoz, A.; Merrero, M. A.; Prieto, P.; Sanchez-Migallon, A.; Cassio, F. P.; Arriela, A.; Vivanco, S.; Foces, C. Molec. Divers. 2003, 7, 165-69.

(59)Jnagaki, T.; Fukuhara, T.; Hara, S. Synthesis 2003, 8, 1157-59.

(60)Plazl, I.; Leskovesek, S.; Kolooini, T. Chem. Eng. J. 1995, 59, 253-57.

(61)Lechmann, F.; Pilotti, A.; Luthman, K. Molec. Divers. 2003, 7, 145-52.

(62)Kiasat, A. R.; Kazemi, F.; Rastogi, S. Synth. Commun. 2003, 33, 601-06.

(63)Gospondinova, M.; Gredard, A.; Jeannin, M.; Chitanv, G. C.; Carpov, A.; Thiery, V.; Besson, T. Green chem. 2002, 4, 220-22.

(64)Vu, z. T.; Liu, L. J.; Zhuo, R. X. Polym. Chem. Ed. 2003, 41, 13-21.

(65)Srikrishana, A.; Kumar, P.P. Tetrahedron Lett. 1995, 36, 6313-16.

(66)Chattopadhyay, S.; Banerjee, S.K.; Mitra, A.K. J. Indian Chem. Soc. 2002, 79, 906-907.

(67)Garbacia, S.; Desai, B.; Lavastre, O.; Kappe, C. O. J. Org. Chem. 2003, 68, in press.

(68)Laurent, A.; Jacquault, P.; Di Martino, J. L.; Hamelin, J. J. Chem. Soc., Chem. Commun. 1995, 1101.

(69)Kad, G. L.; Kaur, I.; Bhandari, M.; Singh, J.; Kaur, J. J. Org. Proc. Res. Dev. 2003, 339-40.

(70)Katritzky, A. R.; Singh, S. K. ARKIVCO 2003, 13, 68-86 (

About Authors:

Raghvendra Dubey

Raghvendra Dubey
For Corespondence
3451, Type III, Bank Note Press, Colony, Dewas (M.P.) 455003,

Sumeet Dwivedi

Sumeet Dwivedi
Chordia Institute Of Pharmacy, Indore (M.P.) ,

Kushagra Mehta

Kushagra Mehta
School Of Pharmacy, Davv, Indore (M.P.)

Hemant Joshi

Hemant Joshi
Ujjain Institute Of Pharmceutical Sciencs, Ujjain (M.P.)

Volumes and Issues:  Reviews: