Microwave (MW) technology has got obvious edge and advantages over conventional methods of heating by virtue of which MW assisted methods are being employed to carry out various synthetic procedures successfully and effectively, which were otherwise encountering problems earlier. The noticeable features of MW technology like reduction of time for a chemical reaction, instantaneous and uniform heating, carrying out solvent free reactions and possibility of parallel chemical reactions has proved as a bonanza for the researchers particularly those who are involved in drug discovery and development processes like high-speed combinatorial and medicinal chemistry as well as industrial scale production of chemicals. The review encompasses the vital and salient characteristics, principles and mechanism and some significant chemical applications of this recently developed promising technology.
Conventional heating methods
Conductive heating has been a conventional approach and synthetic chemical reactions have been carried out successfully using such methods but problems like long reaction time, secondary reaction time, solvent use, excess components during chemical transformations have been major draw backs associated with such approaches. At the same time researchers find themselves helpless when quick experimental results are desirable to complete a project. In addition to this, such conventional approaches also pose problems to the researchers like instantaneous and uniform heating while carrying out the chemical transformations particularly when solvent free procedures are to be followed.
Salient features
However, with the advent of microwave synthesis, there is for the first time, a technology that will dramatically change the scenario of chemical synthesis by offering a new energy source, powerful enough to complete reactions in minutes, instead of hours or even days. With recent advances in technology and the development of an applications base, the organic chemist is now equipped with the tools and knowledge to be able to effectively apply microwave synthesis to any routine. The time saved by using microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry as well as industrial scale production of chemicals.
Since 1986, when Gedye and Giguere published their first article in tetrahedron letters on microwave-assisted syntheses in household microwave ovens, there has been a steadily growing interest in this research field. Since the use of microwaves comprises more than the simple application of a goal-oriented, innovative tool, it is crucial to be aware of the fundamentals of chemistry in the microwave field before investigating challenging reaction mechanisms.
A great number of applications associated with MW tech include sintering, drying, melting and defrosting have been reported in literature. Rapid developments in those fields still prevail today. Microwave radiation provides an alternative to conventional heating as it utilizes the ability of liquids or solids to transform electromagnetic energy into heat. The use of microwave irradiation has introduced several new concepts in chemistry, since the absorption and transmission of the energy is completely different from the conventional mode of heating. The MW tech has been applied to a number of useful R&D processes such as polymer tech, organic synthesis, application to waste treatment, drug release/targeting, ceramic and alkane decomposition. A microwave is a form of electromagnetic energy, which falls at the lower end of the electromagnetic spectrum and is defined in a measurement of frequency as 300 to 300,000 megahertz.
Principles & mechanism
A microwave apparatus involves heating in entirely different fashion. MW tech imparts instantaneous heating, as the process is independent of thermal conductivity of materials. Two fundamental mechanisms for transferring energy from microwave to substance being heated may be: Dipole rotation/dielectric heating and Ionic conduction.
Dipole rotation/dielectric heating
The mechanism by which matter absorbs microwave energy is called dielectric heating. In this context, an important property is the mobility of the dipoles and the ability to orient them according to the direction of the electric field. The orientation of the dipoles changes with the magnitude and the direction of the electric field. Molecules that have a permanent dipole moment are able to align themselves through rotation completely or at least partly with the direction of the field. Molecules can rotate in time with field frequencies of 106 Hz in gases or liquids. However; they cannot follow the inversion of the electric field at an indefinite time. Phase shifts and dielectric losses are the results. In this case, besides the dielectric coefficient (permittivity), the size (mass) of the excited molecules is also relevant. Field energy is transferred to the medium and electrical energy is converted into kinetic or thermal energy. Molecular friction is often cited as a model for this behaviour. For numerous polar substances, dielectric losses are observed in the microwave range. A simplified illustration of the heating mechanism of polar solvents by microwave radiation is provided in Fig. 1 for the example of a water molecule.
The fast changing electric field of the microwave radiation leads to a rotation of the molecules. Due to this process, "Internal friction" takes place in the polar medium, which leads to a direct and almost even heating of the reaction mixture. Because the change in the polarity of the electric field is faster than the rotation of the water molecules around its dipole centre, a phase shift results and energy is absorbed from the electric field. Reflections and refractions on local boundaries yield "hot spots" and may result in a "super-heating" effect. This effect can be described best as local overheating and is comparable to the delayed boiling of overheated liquids under conventional conditions. This effect is characteristically found only in unstirred solutions.
Ionic conduction
The second way to transfer energy is ionic conduction, which results if there are free ions or ionic species present in the substance being heated. The electric field generates ionic motion as the molecules try to orient to the field, causing rapid heating. The temperature of the substance also affects ionic conduction; as the temperature increases, the transfer of energy becomes more efficient. In a typical reaction coordinate, the process begins with reactants, which have a certain potential energy level. In order to complete the transformation, these reactants must be activated to a transition state. Once there, they quickly react and return to a lower energy state - the product for the reaction. Microwave energy provides the momentum to overcome the activation energy barrier and complete the reaction.
Energy transfer process
One of the most important aspects of microwave energy is the rate at which it heats. Microwaves transfer energy in 10-9 seconds, with each cycle of the electromagnetic energy. The kinetic molecular relaxation from this energy is approximately 10-5 seconds. The energy transfers faster than the molecules can relax, resulting in a non-equilibrium condition and high instantaneous temperatures that affect the kinetics of the system. This enhances the reaction rate, as well as the yields. Activated complexes do not normally exist long enough to have an opportunity to absorb microwave energy, although there is a number of stabilized intermediates, resident stabilized intermediates and other intermediates that are much longer lived. Many of these have lifetimes longer than 10-9 seconds, so the opportunity exists for them to couple directly with the microwave and be further enhanced. Most intermediates are highly polar species and many of them are even ionic in character, making them excellent candidates for microwave energy transfer.
Vital applications with suitable examples
Microwave enhanced chemical reactions can be faster by as much as 1,000-fold. This is based on experimental data, from numerous works, that have been performed over the last 15 years. Significant contribution of MW tech and its vital application may be summarized as below.
Raw materials from natural sources
Microwave technology provides an alternative source of energy that should be well suited for preparative extractions. Microwave assisted extraction of raw materials from natural sources offers numerous and obvious advantages over conventional methods of extraction like using Soxhlet apparatus.
A relevant example may be the extraction of trimyristine from nutmeg powder. Common unground nutmeg nuts contain between 10% and 40% of extractable substances. The main constituent of these substances is a triglyceride consisting of 90% myristic acid (saturated C14 carboxylic acid). Due to its solubility, trimyristine can be easily isolated by hot extraction with ethanol.
O-Alkylation of phenols
Another good example of microwave assisted chemical reaction is O-alkylation of phenols using polymer-supported reagents. It is a demonstration of the use of microwave energy for solid phase reactions. Increased yields and reduced reaction times (from 10-30 minutes compared to more than 22 hours from earlier published works) have been obtained using MW technology.
Biginelli synthesis of tetrahydropyrimidines
Various tetrahydropyrimidines have been synthesized via Biginelli synthesis. The main feature of this reaction is that it is a three-component reaction that again was successfully completed in a microwave with reaction times of 5 minutes at 170°C with good yields for the product.
Heck reaction of iodobenzene and 1-decene
Professor Wali and his group reported Heck reaction with iodobenzene and 1-decene and were able to get a complete reaction in approximately 10 minutes compared to 14 hours with conventional methods.
Solvent free reactions
In organic chemistry, Diels-Alder reactions are synthetically useful for the construction of sixmembered rings. This reaction type was one of the first performed in a microwave field. The reaction of fumaric acid diethyl ester with anthracene to the respective Diels-Alder adduct is a well-investigated and comparatively simple reaction. It proceeds in high yield under conventional conditions in the presence of equimolar amounts of anhydrous aluminium chloride as an activator.
Parallel chemical reactions
The technology of running parallel chemical reactions is an intensively investigated area of research. In general, there are two different methods for performing parallel synthesis in the microwave field:
(i) EXPLORER-System and EMRYS-Systems
(ii) ETHOS and Multiwave 3000
The first method allows for the use of small microwave cavities with high microwave density, for irradiation of solely the reactor (e.g. GC vial) and volumes of up to 50 ml. Short reaction times under controlled reaction conditions (temperature measurement via IR-sensor) are used for a step-by-step processing of a large number of assays.
The ETHOS system takes a different approach which allows for the simultaneous irradiation of several assays (sample volumes: 1-100 ml) in a larger microwave cavity under identical reaction conditions.
Conclusion
Microwave heating offers yet another exciting new opportunity, the possibility of returning to a sequential rather than a parallel format. In the last several years, there has been a shift to parallel synthesis, primarily due to the reaction times required for conventional heating. Microwave systems provide the opportunity to complete reactions in minutes, offering the option to return to more sequential formats. It is advantageous for MW technology helps in optimizing the synthetic reaction and also reduces the valuable substrates. This technology has also influenced the drug discovery and development process by minimizing the problems encountered in case of conventional methods of heating like long reaction time, secondary reaction time, solvent use, excess components during chemical transformations. MW technology offers obvious advantages like instantaneous and uniform heating along with integrated on-line control that guarantees safe operation and even on the technical scale, large number of synthetic reactions can be handled effectively.
Microwave assisted synthetic procedures are being preferred by researchers yet promising challenges particularly coordinating various reaction parameters during a synthetic process still ahead to exploit the applicability of MW technology to its full extent.
Fig. 1
(The authors are with D. J. College of Pharmacy, Niwari Road, Modinagar, U.P.)