INTRODUCTION:

The need for different organic compound libraries for drug discovery, biomaterial development, automated library screening, proteomics etc has supported the emergence of innovative technologies for rapid combinatorial organic synthesis using Microwave Assisted Organic Reactions¹. Conventionally, attaining the highest yield and product selectivity were the governing factors of chemical synthesis.

Little consideration was given to the usage of multiple reagents in stoichiometric quantities, which often were not incorporated into the target molecule and would result in significant side products. However, in a balanced chemical reaction, a simple addition or cycloaddition incorporates all atoms of the starting materials into the final product. Recognizing this fundamental phenomenon, in 1991². Trost presented a set of coherent guiding principles for evaluating the efficiency of specific chemical processes, termed the atom economy, which has subsequently been incorporated into the ‘‘Twelve Principles of Green Chemistry’’ and has altered the way many chemists design and plan their synthesis³. The advent of microwave assisted technology in organic chemistry dates back to the mid 1980s and since the 1990s there has been a significant increase in the number of publications on Microwave Assisted Organic Reactions (MAOS) due to increased benefits associated with the process. The promotion of microwave assisted reactions in organic chemistry has improved the speed, reduced cost, reduced energy spent making it a sustainable process and is widely reffered as “green chemistry” measures whose applications are promoted today to minimize the use of non-renewable resources as well as polluting solvent, to reduce generation of secondary products which are often toxic and to reduce the emission of harmful gases⁴. Microwave assisted reactions in organic chemistry achieve the same by ensuring facilitation of faster reactions under bulk conditions as well as promoting reduction of reaction time. Reactions play the most fundamental role in synthesis. The ideology of Green Chemistry calls for the development of new chemical reactivities and reaction conditions that can potentially provide benefits for chemical syntheses in terms of resource and energy efficiency, product selectivity, operational simplicity, and health and environmental safety⁵. Solvents are auxiliary materials used in chemical synthesis. They are not an integral part of the compounds undergoing reaction, yet they play an important role in chemical production and synthesis. By far, the largest amount of ‘‘auxiliary waste’’ in most chemical productions is associated with solvent usage. In a classical chemical process, solvents are used extensively for dissolving reactants, extracting and washing products, separating mixtures, cleaning reaction apparatus, and dispersing products for practical applications. Although the invention of various exotic organic solvents has resulted in some remarkable advances in chemistry, the legacy of such solvents has led to various environmental and health concerns. Consequently, as part of Green Chemistry efforts, various cleaner solvents have been evaluated as replacements⁶.

The new approach introduces in green chemistry synthesis, dealing out and relevance of chemical material in such a way as to minimize the risk to environment and health of human⁷. This advanced access is well called:

1 Eco-friendly chemistry

2 Clean chemistry

3 Atom economy

4 Benign design chemistry

Evolution of Microwave Chemistry:

Microwave synthesis is considered as an important approach toward green chemistry, because this technique is more eco-friendly. Due to its ability to couple directly with the reaction molecule and by passing thermal conductivity leading to a rapid rise in the temperature, microwave irradiation has been used to improve many organic synthesis. Microwave technology originated in 1946, when Dr. Percy Le Baron Spencer, while conducting laboratory tests for a new vacuum tube called a magnetron (device that generates an electromagnetic field), accidentally discovered that a candy bar in his pocket melted on exposure to microwave radiation⁸. Dr. Spencer developed the idea further and established that microwaves could be used as a method of heating. Subsequently, he designed the first microwave oven for 18 domestic use in 1947. Since then, the development of microwave radiation as a source of heating has been very gradual⁹.

Principles of Green Chemistry:

Green science is an exceedingly compelling way to deal with contamination a version as it applies creative logical answers for certifiable natural circumstances. The accompanying 12 standards of Green Chemistry give an approach to scientific experts to execute green chemistry¹⁰.

Waste Control:

It is perfect to forestall squander than to take care of waste after it has been produced.

Atom effectiveness:

Engineered planning must intended to enhance the all supplies utilized as element of procedure into product.

Application of non- destructive of reagents:

This incorporates the utilization of reagents and manufactured strategies that decreases the hazard and delivers eco-accommodating items that has no awful effect on human and atmosphere.

Safer Chemicals Scheming:

Chemicals and reagents should accomplish their coveted ability while limiting their harmfulness.

Safer Solvents and Auxiliaries:

Broadly utilized solvents in unions are lethal and unstable – liquor, benzene (known cancercausing), CCl₄, CHCl₃, perchloroethylene, CH₂Cl₂. These have now been supplanted by more secure green solvents.

Design for Energy Efficiency:

Vitality requirements of synthetic procedures must perceive for their ecological and monetary effects and should to be limited.

Use of Renewable Feed stocks:

It is wanted to use crude materials and feedstock that are sustainable, however in fact and monetarily practicable. Referring to the case of sustainable feedstock which incorporate agrarian items and exhausting feedstock incorporate crude supplies that are extracted from non-renewable energy sources (oil, gaseous petrol or coal).

Shorter combinations:

Superfluous derivatization should be limited or managed a strategic space if possible and such strides require additional reagents and can produce squander.

Use of Catalytic instead of Stoichiometric reagents:

Impetuses are utilized as a part of little sums and can complete a solitary response commonly as are desirable over stoichiometric reagents, which are utilized as a part of overabundance and work. This will improve the selectivity, lessen the temperature of a change, diminish waste produced by reagent and conceivably keep away from undesirable side responses prompting a spotless innovation.

Design for dreadful conditions:

Compound items ought to be planned so that toward the finish of their capacity they separate into harmless corruption items and don't hold on in nature.

Techniques to control pollution:

Different techniques require developing for actual-time, in-process monitoring and control formation of hazardous substances.

Use of Safer Chemicals and Process:

Substances and the form of a substance used in a chemical process should be chosen so as to minimize the potential of chemical accidents, including releases, explosions, and fires¹¹.

Mechanism of microwave heating:

Microwave absorbing materials are of almost important for microwave chemistry and three main different mechanisms are involved for their heating namely:

Dipolar polarization:

Dipolar polarization can generate heat by either interaction between polar solvent molecules such as water, methanol and ethanol; or interaction between polar solute molecules such as ammonia and formic acid. The key requirement for dipolar polarization is that the frequency range of the oscillating and field should be appropriate to enable adequate inter-particle interaction. If the frequency range is very high, intermolecular forces will stop the motion of a polar molecule before it tries to follow the field, resulting in inadequate inter-particle interaction. On the other hand, if the frequency range is low, the polar molecule gets sufficient time to align itself in phase with the field. Microwave radiation has the appropriate frequency (0.3-30 GHz) to oscillate polar particles and enable enough inter-particle interaction. This makes it an ideal choice for heating polar solutions¹².

Conduction mechanism:

The conduction mechanism generates heat through resistance to an electric current. The oscillating electromagnetic field generates an oscillation of electrons or ions in a conductor, resulting in an electric current. This current faces internal resistance, which heats the conductor. Major limitation of the method is that it is not applicable for materials with high conductivity, since such materials reflect most of the energy that falls on them. The oscillating electromagnetic field generates an oscillation of electrons or ions in a conductor, resulting in an electric current. This current face internal resistance, which heats the conductor. A solution containing ions, or even a single isolated ion with a hydrogen bonded cluster, in the sample the ions will move through the solution under the influence of an electric field, resulting in expenditure of energy due to able to believe that the more polar the solvent, the more readily the microwave irradiation is absorbed and the higher the temperature obtained. Where the irradiated sample is an electrical conductor, the charge carriers (electrons, ions, etc.) are moved through the material under the influence of the electric field, resulting in a polarization¹³.

Interfacial polarization:

It is important for heating systems that comprise a conducting material dispersed in a nonconducting material. For example, consider the dispersion of metal particles in sulphur. Sulphur does not respond to microwaves and metals reflect most of the microwave energy they are exposed to, but combining the two makes them a good microwave-absorbing material. However, for this to take place, metals have to be used in powder form. This is because, unlike a metal surface, metal powder is a good absorber of microwave radiation. It absorbs radiation and is heated by a mechanism that is similar to dipolar polarization. The environment of the metal powder acts as a solvent for polar molecules and restricts the motion of ions by forces that are equivalent to inter-particle interactions in polar solvents. It absorbs radiation and is heated by a mechanism that is similar to dipolar polarization. The environment of the metal powder acts as a solvent for polar molecules and restricts the motion of ions by forces that are equivalent to inter-particle interactions in polar solvents. These restricting forces under the effect of an oscillating field induce a phase lag in the motion of ions, resulting in random motion of ions and ultimately heating of the system¹⁴.

Effects of Solvents:

Every solvent and reagent will absorb microwave energy differently. They each have a different degree of polarity within the molecule, and therefore, will be affected either more or less by the changing microwave field. A solvent that is more polar, for example, will have a stronger dipole to cause more rotational movement in an effort to align with the changing field. A compound that is less polar, however, will not be as disturbed by the changes of the field and, therefore, will not absorb as much microwave energy. Unfortunately, the polarity of the solvent is not the only factor in determining the true absorbance of microwave energy, but it does provide a good frame of reference. Most organic solvents can be broken into three different categories: low, medium, or high absorber. The low absorbers are generally hydrocarbons while the high absorbers are more polar compounds, such as most alcohols¹⁵.

Microwave Synthesis Apparatus:

The apparatus for microwave assisted synthesis include; single-mode microwave ovens, and multi-mode microwave ovens.

Single-mode apparatus:

These apparatuses can process volumes ranging from 0.2 to about 50 ml under sealed-vessel conditions, and volumes around 150 ml under open-vessel conditions. Single-mode microwave ovens are currently used for small-scale drug discovery, automation and combinatorial chemical applications. The factor that governs the design of a single-mode apparatus is the distance of the sample from the magnetron. This distance should be appropriate to ensure that the sample is placed at the antinodes of the standing electromagnetic wave pattern. One of the limitations of single-mode apparatus is that only one vessel can be irradiated at a time. The differentiating feature of a single-mode apparatus is its ability to create a standing wave pattern, which is generated by the interference of fields that have the same amplitude but different oscillating directions. This interface generates an array of nodes where microwave energy intensity is zero, and an array of antinodes where the magnitude of microwave energy is at its highest¹⁶.

Multi-mode microwave apparatus:

Multi-mode apparatus is the deliberate avoidance of generating a standing wave pattern inside it. The goal is to generate as much chaos as possible inside the apparatus. The greater the chaos, the higher is the dispersion of radiation, which increases the area that can cause effective heating inside the apparatus. As a result, a multi-mode microwave heating apparatus can accommodate a number of samples simultaneously for heating, unlike single-mode apparatus where only one sample can be irradiated at a time. Owing to this characteristic, a multimode heating apparatus is used for bulk heating and carrying out chemical analysis processes such as ashing, extraction, etc. In large multi-mode apparatus, several litres of reaction mixture can be processed in both open and closed-vessel conditions. The goal is to generate as much chaos as possible inside the apparatus. The greater the chaos, the higher is the dispersion of radiation, which increases the area that can cause effective heating inside the apparatus. As a result, a multi-mode microwave heating apparatus can accommodate a number of samples simultaneously for heating, unlike single-mode apparatus where only one sample can be irradiated at a time¹⁷.

Significance of Microwave Assisted Reactions:

Significance of microwave assisted organic synthesis are:

Better yield and higher purity:

Less formation of side products are observed using microwave irradiation, and the product is recovered in higher yield. Consequently, also the purification step is faster and easier. For example, microwave synthesis of aspirin results in an increase in the yield of the reaction, from 85 % to 97 %¹⁸.

Green synthesis:

Reactions conducted using microwaves are cleaner and more eco-friendly than conventional heating methods. Microwaves heat the compounds directly; therefore, usage of solvents in the chemical reaction can be reduced or eliminated. Synthesis without solvent, in which reagents are absorbed on mineral support, has a great potential as it offers an eco-friendly green protocol in synthesis. The use of microwaves has also reduced the amount of purification required for the end products of chemical reactions involving toxic-reagents¹⁹.

Reproducibility:

Reactions with microwave heating are more reproducible compared to the conventional heating because of uniform heating and better control of process parameters. The temperature of chemical reactions can also be easily monitored²⁰.

Faster reaction:

Based on experimental data it has been found that microwave-enhanced chemical reaction rates can be faster than those of conventional heating methods by as much as 1,000-fold. The microwave can use higher temperatures than conventional heating system, and consequently the reactions are completed in few minutes instead of hours, for instance, synthesis of fluorescein, which usually takes about 10 hours by conventional heating methods, can be conducted in only 35 minutes by means of microwave heating²¹.

Applications:

Microwave-assisted synthesis can be suitably applied to the drug discovery process. Some of applications are:

Organic Synthesis:

Organic synthesis is the preparation of a desired organic compound from available starting materials. Microwave assisted organic synthesis has been the one of the most researched applications of microwaves in chemical reactions. Chemists have successfully conducted a large range of 33 organic reactions. These includes:

1 Diels-Alder reaction

2 Heck reaction

3 Suzuki reaction

4 Mannich reaction

5 Hydrogenation of [beta]-lactams

6 Hydrolysis

7 Dehydration

8 Esterification

9 Cycloaddition reaction

Microwave-assisted organic synthesis is being widely applied in the pharmaceuticals industry, particularly for developing compounds in the lead optimization phase of drug development. In this phase, chemists use diverse synthetic techniques to develop candidate drugs from lead compounds.

Organic synthesis at atmospheric pressure:

Microwave-assisted organic reactions can be conveniently conducted at atmospheric pressure in reflux conditions e.g. Diels-Alder reaction of maleic anhydride with anthracene. In the presence of diglyme (boiling point 162ºC), this reaction can be completed in a minute, with a 90% yield. However, the conventional synthetic route, which uses benzene, requires 90 minutes. High boiling solvents are preferred in microwave assisted organic synthetic reactions.

Organic synthesis at elevated pressure:

Microwaves can be used to directly heat the solvent in sealed microwave-transparent containers. The sealed container helps in increasing the pressure in the reactor, which facilitates the reaction that will take place at much higher temperatures. This results in a substantial increase in the reaction rate of microwave-assisted organic. However, increase in the reaction rate of any chemical synthesis depends on three factors: volume of the vessel, the solvent to 34 space ratio, and the solvent boiling point.

Organic synthesis in dry media:

Microwaves have been applied to organic synthesis in dry media, using solid supports (i.e. alumina, montmorillonite clay, alkali metal fluoride doped alumina and silica.) Microwave radiation, based on solid supports, has been highly successful in reducing the reaction time for condensation, acetylation and deacetylation reactions, for example, deacetylation of a protected compound such as alcoholic acetate held on a support material. The microwave assisted reaction could be completed within two to three minutes, compared to conventional oil-bath heating at 75 ºC for 40 hours²².

Inorganic Synthesis:

Synthesis of ceramic products by microwave processing of ceramic materials has reached a high degree of maturity. In ceramic production industry, the removal of solvent or moisture is a critical step in the generation of ceramic products. Initially, the use of microwaves was limited to the effective removal of solvents from solid samples. It is estimated that for materials with a water content below 5%, microwave drying is efficient than conventional drying methods. However, over the past few years, the utility of microwaves has increased due to other advantages. It has been proven that microwave heating provides better uniform heating than conventional heating methods²³.

Synthesis of Nanotechnology products:

Synthesis of silver nanoparticles from silver nitrate employing starch as the reductant as well as stabilizing agent has been carried out under direct heating, controlled heating and microwave irradiation. The microwave irradiation was considered as better for reduction of silver ions to silver nanoparticles. It also afforded smaller particle sizes and particle size distribution. Compared to conventional methods, microwave assisted synthesis was faster and provided particles with an average particle size of 12 nm. Nanostructures with smaller sizes, narrower size distributions, and a higher degree of crystallization were obtained under microwave heating than those in conventional oil-bath heating. The gold nanoparticles have been prepared by microwave high-pressure procedure with alcohol as the reducing agent. A method has been reported for microwave-assisted non-aqueous synthesis of zinc oxide nanoparticles. Particularly the fast reaction rates, better product yields and the possibility to automatically combine different experimental parameters makes microwave assisted synthesis suitable for the studies of the influences of the reaction conditions on the morphology and sizes of zinc oxide nanoparticles particles, which determine its properties and applications²⁴.

Polymer Synthesis:

The use of polar reactants in polymerization reaction results in controlled synthesis and a combination of this with direct heating of reactants makes microwave heating an economically viable option. Using microwave radiation in curing has greatly increased the rate of the reactions. It has been found that the rate of a curing reaction, using microwaves, is not dependent on the power applied but on the way the pulse is applied. Controlled solvent-free synthesis and modification in polymer materials can be rapidly and effectively done with the help of microwave heating using large scale reactors. The first microwave assisted organic synthesis of Poly Lactic Acid was carried out with SnOct as catalyst by using toluene as a solvent. Applications of microwave chemistry for intercalation compounds have been tested recently. Intercalation compounds comprise organic or organometallic compounds that are incorporated between layers of oxides and sulphides. Conventional heating methods for the preparation of intercalation compounds, such as the intercalation of pyridine or its derivatives are slow and have limitations w.r.t. the yield obtained²⁵.

Extraction:

Microwave extraction has proved to be more effective and efficient than its conventional counterpart, the Soxhlet extraction method. The Soxhlet extraction, which is a standard technique, is a continuous solvent extraction method²⁶. Extraction systems are used to conduct routine solvent extractions of soils, sediments, sludge, polymers and plastics, pulp and paper, biological tissues, textiles and food samples. Experiments have proved that microwaves, in comparison with the Soxhlet extraction, use a lesser volume of solvent and sample and perform extraction at a much faster rate²⁷.

CONCLUSION:

Microwave assisted synthesis is a new approach that through application and extension of the principles of inexperienced chemistry will contribute to property development. Many technologies that meet green chemistry objectives already exist and offer immediate opportunities to reduce environmental burdens and enhance economic performance. Current microwave reactors are able to translate small scale microwave chemistry from milligram or gram scale to multi-kilogram scale using batch or continuous-flow processing. However, many of the benefits of small scale microwave chemistry are lost when the processes performed in larger batch reactors. The incorporation of green chemistry and related approaches into the training of current and potential science students increases the effectiveness of recruitment and retention efforts in this crucial field. Research investments beyond current "pilot program" levels are needed from both government and industry to empower and enable the development and utilization of green chemistry technologies by the broad spectrum of private-sector interests. Several new analytical methodologies de-scribed that are complete in step with inexperienced chemistry rules. They are helpful in conducting chemical processes and in analysis of their effects on the setting. The advantages of this enabling technology have also been exploited in the context of multistep total synthesis and medicinal chemistry/drug discovery and have additionally penetrated related fields such as polymer synthesis, nanotechnology and biochemical processes. Green chemistry, also known as sustainable chemistry that has grown substantially since it fully emerged a decade ago. In the future, with lower costs, microwave synthesizers will become an integral part of and a standard technology in most synthetic laboratories and will continually make valuable impact on both organic synthesis and drug discovery. It is the design, development, and implementation of chemical products and processes to reduce or eliminate the use and generation of substances hazardous to human health and the environment.

ACKNOWLEDGEMENT:

I express my sincere thanks to Vice-principal Prof. Dr. S. K. Mohite for providing me all necessary facilities and valuable guidance extended to me.

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Received on 25.05.2020 Modified on 17.06.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(3):191-197.

DOI: 10.5958/0975-4377.2020.00033.6