Dr Vivek Polshettiwar was born in Mangli (India) in 1979. He obtained his Ph.D. (2005) under the supervision of Prof. M. P. Kaushik from Jiwaji University and DRDE, Gwalior. He investigated nanostructured silica-catalysis, with Prof. J. J. E. Moreau and Prof. P. Hesemann in 2006 during his postdoctoral research at ENSCM, Montpellier (France). He also worked as project leader in Jubilant Chemsys, Noida for short time.. Then he moved to the U. S. Environmental Protection Agency (2007-2009) to research nano-catalysis and MW-assisted new synthetic methods for green chemistry with Prof. R. S. Varma. Currently, he is working as senior research scientist at KAUST catalysis center directed by Prof. J. M. Basset. His research interests are in the area of advanced nano-materials for perfect catalysis. He has over 50 publications including various review articles and book chapters.

Prof. Rajender S. Varma was born in India (Ph.D., Delhi University 1976). After postdoctoral research at Robert Robinson Laboratories, Liverpool, UK, he was a faculty member at Baylor College of Medicine and Sam Houston State University prior to joining the US Environmental Protection Agency in 1999. He has over 35 years of research experience in management of multi-disciplinary programs that include nanomaterials and development of environmentally friendlier alternatives for synthetic methods using microwaves, and ultrasound etc. He has published over 300 scientific papers and has been awarded 6 US Patents.

Aqueous Microwave Assisted Chemistry

Synthesis and Catalysis

By Vivek Polshettiwar, Rajender S. Varma

The Royal Society of Chemistry

Copyright © 2010 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-038-9

Contents

About the Authors, xii,
Chapter 1 Fundamentals of Aqueous Microwave Chemistry Vivek Polshettiwar and Rajender S. Varma, 1,
Chapter 2 Metal-catalyzed Reactions in Water under MW Irradiation Victorio Cadierno, Pascale Crochet and Sergio E. García-Garrido, 10,
Chapter 3 Microwave-assisted Coupling Reactions in Aqueous Media Aziz Fihri and Christophe Len, 55,
Chapter 4 Microwave-assisted Synthesis of Bio-active Heterocycles in Aqueous Media Vivek Polshettiwar and Rajender S. Varma, 91,
Chapter 5 Microwave-assisted Enzymatic Reactions in Aqueous Media Hua Zhao, 123,
Chapter 6 Microwave-assisted Synthesis of Polymers in Aqueous Media Catherine Marestin and Régis Mercier, 145,
Chapter 7 Microwave-assisted Synthesis of Nanomaterials in Aqueous Media Babita Baruwati, Vivek Polshettiwar and Rajender S. Varma, 176,
Subject Index, 217,

CHAPTER 1

Fundamentals of Aqueous Microwave Chemistry

VIVEK POLSHETTIWAR AND RAJENDER S. VARMA

Sustainable Technology Division, National Risk Management Research Laboratory, U.S. Environmental Protection Agency, 26 W. Martin Luther King Dr., MS 443, Cincinnati, Ohio 45268, USA

1.1 Introduction

The first chemical revolution changed modern life with excellent amenities and services, but also created the serious problem of environmental pollution. Now, 150 years later, we need to develop the concept of ‘green chemistry’ to help safeguard human life. The core principle of this concept is to protect the environment, not by cleaning it up, but by discovery of new chemistry and chemical processes that avert pollution. The concept of green chemistry prompts the chemical and pharmaceutical industries to consider the impact on human life when new chemicals are produced and introduced into our society. Thus, we can develop innovative pathways by rethinking chemical design from the ground up, to create products that stimulate our economy and lifestyles, without damaging our environment and surroundings. Green chemistry has emerged as a discipline that permeates all aspects of chemistry.

A myriad of drugs are required by society in short periods of time. To achieve this goal, medicinal chemists have been under increased demands to produce bio-active drug molecules, because of the high molecular complexity in drug discovery processes accompanied by time constraints. The central focus of pharmaceutical green chemistry is the development of efficient and environmentally benign synthetic protocols.

1.2 Green Chemistry Approach

Green chemistry is a vast and multifaceted field. The principles of green chemistry can be used to evaluate the greenness of a particular synthetic protocol. These principles deal with several issues, such as preventing the use of volatile and toxic solvents, the quantity and reusability of catalyst and reagents employed, the use of benign chemicals, atom-economic synthetic methods with a minimum number of chemical steps (which selectively generate the desired product without producing any by-products), energy efficient and mild reaction conditions, and chemical waste produced (Figure 1.1). It is not anticipated that any synthetic protocol will satisfy all green chemistry principles, but the more it satisfies the greener the process will be.

Solvents play a key role in deciding the environmental fate of a chemical process and have a huge impact on its cost, safety and health issues. The volatile and highly flammable solvents that are commonly used are the foremost source of ecological pollution and are rapidly rising on the green chemistry agenda. The use of reaction solvents, however, cannot be avoided as they are necessary for various steps such as the mixing of reactants, harmonized supply of heat and energy, and also in some cases to control the regio- and chemoselectivity of reactions.

There are assorted approaches for the development of environmentally friendly methods. The replacement of toxic reaction solvents with benign media is one of the best ways to make a protocol greener. While solvent replacement is a successful approach, it alone may not be enough. The entire development process must be well thought out, considering factors such as atom economy, energy efficiency and use of benign and naturally available renewable resources, and the solvent should be only one part of this. In addition, toxic solvents should not only be avoided during reaction but also after completion of the reaction; their use for isolation and purification of products (which involves the use of excess amounts per mass of final products) should be prevented or minimized.

Toxic solvents can be replaced by various non-conventional alternatives with superior ecological, health and safety properties, such as:

• bio-solvents: solvents produced from renewable resources, e.g. ethanol produced by fermentation of sugar-containing feeds and starchy feed materials;

• supercritical fluids, e.g. CO2;

• benign ionic liquids that have low vapor pressure and restrain release into the environment;

• fluorous and re-generable biphasic media.

1.3 Water as Green Solvent

To reduce the environmental impact resulting from the use of toxic solvents in chemical production, the identification and use of “green” solvents is a top priority. A solvent-free process is another answer, as one of the green chemistry principles states that the use of no toxic solvent makes the protocol green; however, this is not true in every case, and in fact this is how we misinterpret these principles. This particular green chemistry principle is only valuable if the developed solvent-free protocol works at the industry level (or at least the pilot plant level). Simply carrying out the reactions at small scale in the laboratory has no value as, at the bench-scale, small amounts of reactants can be mixed without solvent, but this is not feasible at the kilogram level, where a lack of reaction medium may lead to overheating of the reaction mixture because of the inadequate heat- and mass-transfer.

Biphasic technologies, using fluorous and ionic liquids along with aqueous systems and supercritical carbon dioxide, have formed the main thrust of this green solvent movement. However, the cost and toxicity of ionic liquids are prohibitive. Water appears to be a better option because of its abundant, nontoxic, non-corrosive, and non-flammable nature. In addition, water can be contained because of its relatively higher vapor pressure as compared to organic solvents, making it a green and sustainable alternative.

The major difficulty with using water as a solvent is the insolubility of most of organic reactants, making reaction mixtures heterogeneous. One way to overcome this is by using phase-transfer catalysts, but their expensive nature means that the resulting method is not economical. Product isolation from aqueous reaction mixture is another critical issue. Usually, evaporation of water is an option, but this is not an energy-efficient technique. Interestingly, these challenges can be tackled successfully by using the microwave (MW) heating technique for reactions in aqueous medium.

1.4 Why Microwaves?

Conventional processes of chemical synthesis are orders of magnitude too slow to satisfy the current demand for the generation of new compounds. Although the fields of combinatorial and automated chemistry have emerged to meet this burgeoning demand, most of these techniques generate considerable quantities of chemical waste. Chemists have been under growing pressure to develop new methods that are rapid and environmentally benign. One of the alternatives is the use of nano-catalysis in conjunction with non-conventional MW heating technology. The efficiency of MW flash-heating has resulted in dramatic reductions in reaction times – from days to minutes – that are potentially important in process chemistry for the expedient generation of fine chemicals. In the last few years, MW-assisted chemistry has blossomed into a mature and useful technique for various applications. Although MW-assisted reactions in conventional solvents have developed rapidly, the center of attention has now shifted to environmentally benign processes, which use nano-catalysts and greener solvents such as water.

MW-enhanced chemistry is based on the efficiency of the interaction of molecules in a reaction mixture (substrates, catalyst and solvents) with electromagnetic waves generated. This process mainly depends on the specific polarity of molecules. Since water is polar it has good potential to absorb microwaves and convert them into heat energy, consequently accelerating the reactions in an aqueous medium as compared to results obtained using conventional heating. This can be explained by two key mechanisms: dipolar polarization and ionic conduction of water molecules (Figure 1.2 below). Irradiation of a reaction mixture in an aqueous medium by MW results in the dipole orientation of water molecules and reactants in the electric field.

1.4.1 Thermal Effect

Dielectric heating ensues from the tendency of dipoles (mostly water molecules in addition to reactants) to follow the inversion of alternating electric fields and induce energy dissipation in the form of heat through molecular friction and dielectric loss, which allows more regular repartition in reaction temperatures compared to conventional heating (Figure 1.2).

Antonio and Deam recently proposed a new hypothesis based on enhanced diffusion that stated “If the transport of an active species is a rate limiting step in a reaction (such as for diffusion limited reactions), and if microwave enhances the diffusion of that species, then overall reaction rate would change under microwave heating compared with conventional heating”. Notably, various organic reactions can be carried out in an aqueous medium using MW irradiation without using any phase-transfer catalyst (PTC). This is because water at higher temperature behaves as a pseudo-organic solvent, as the dielectric constant decreases substantially and an ionic product increases the solvating power towards organic molecules to be similar to that of ethanol or acetone.

1.4.2 Non-thermal Effect

Non-thermal effects have been envisaged to have several origins, including thermodynamic parameters. Molecular shake-up and movement are other factors that have contribute to the MW effect. Such effects can also occur from the interactions of microwaves and reactants, like thermal effects. It is very difficult to isolate non-thermal effects from thermal effects.

Perreux and Loupy have researched non-thermal effects on the basis of the reaction medium (polar and non-polar) and the polarity of the transition state. They have established that the MW effect increases in non-polar solvents and solvent-free reactions and reactions with polar transition states. This effect has also been demonstrated by Polshettiwar and Kaushik using a “tighter ion pair effect” in aminolysis of enolizable esters. They observed that reactions involving tighter ion pairs (e.g. C6H11NH–K+) had higher reaction rates, indicating more MW-specific effect, than reactions involving less tight ion pairs (e.g. C6H5NH–K+). This may be due to delocalization of negative charge on the aromatic ring of aniline (as compared to aliphatic cyclohexyl amine), making the transition state less polar.

Miklavc has observed a decrease in activation energy during MW-assisted decomposition of sodium bicarbonate. The exposure of substrates (dielectric materials) to microwaves induced rapid rotation of the molecules. This in turn generated heat due to friction and also increased the probability of contact between reactant molecules, thus enhancing the reaction rate by reducing the activation energy. In continuation of this work, Cross et al. found an increase in molecular mobility in the presence of microwaves. The increase in the rate of reactions was due to an increase in the Arrhenius pre-exponential factor (A) (Equation 1.1):

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (1.1)

where, γ = number of neighbor jump sites, λ = jump distance and Γ = jump frequency.

As per Equation (1.1), the Arrhenius pre-exponential factor (A) depends on the frequency of vibration of the atoms at the reaction interface and therefore is affected by MW irradiations.

Kappe and co-workers have performed an in depth study of this MW effect in ring-closing metathesis and Biginelli reactions. They observed no considerable difference between conventional heating and microwave heating. This conclusion is only true for these two reactions and cannot be generalized. The subject of a non-thermal specific MW effect is still divisive and not absolutely known.

In addition to these microwave “thermal effect” and “non-thermal effect”, there are some additional advantages of using microwaves for aqueous protocols.

1.4.3 Selectivity towards Water

MW heating depends on the composition and structure of molecules (i.e. their dielectric properties) and this property can facilitate selective heating. Micro- waves initiate rapid intense heating of polar molecules such as water, while non- polar molecules do not absorb the radiation and in turn do not contribute to heating. Strauss and Hallberg have demonstrated that this selective heating can be exploited to develop a high yield rapid MW protocol using a two-phase (polar–non-polar) solvent system. They determined that the use of water was advantageous in MW chemistry and expedited the protocol with more energy efficiency.

1.4.4 Selectivity towards Catalyst

Selective heating can be exploited in heterogeneous catalysis protocols. This was demonstrated in the MW-assisted rapid molybdenum-catalyzed allylic reaction by Larhed and his co-workers, and in the case of oxidation of alcohol using Magtrievet by Bogdal et al. They established that polar catalysts absorbed extra energy and heated at higher temperatures than the overall reaction temperature, making the protocol more energy efficient.

1.4.5 Catalyst as Susceptors

Susceptors are materials that efficiently absorb MW irradiation and transfer the generated thermal energy to molecules in the vicinity that are weak microwave absorbers. Although transmission of the energy occurs through conventional mechanisms, it is more rapid than conventional heating. Kappe and Leadbeater, pioneers in the field of MW chemistry, have used silicon carbide and ionic liquid, respectively, as susceptors, and determined that addition of these materials to the reaction mixture enhanced its overall capacity to absorb MWs and significantly reduced the required MW energy. The addition of these materials as susceptors to the reaction mixture, however, adds to the overall cost of the protocol and makes it expensive. Ideally, if nanomaterials can play a dual role of catalyst and susceptor then all the interesting advantages related to it can be enjoyed without the need for additional material as a susceptor. This can be achieved by using a nano-catalyst, such as a polar ferrite-based material, which can act not only as a catalyst but also as a susceptor.

1.4.6 Stability of Catalyst

Since MW-assisted reactions are rapid, the residence time of nano-catalyst at high temperature is minimal. Catalytic processes with shorter reaction times safeguard the catalyst from deactivation and decomposition, consequently increasing the overall competence of the catalyst, as well as the entire protocol.

1.5 Conclusion

It appears that the approach of fusing the MW technique with water (as a benign reaction medium) can offer an extraordinary synergistic effect with greater potential than these two individual components in isolation. The advantages of aqueous MW chemistry in rapid and greener synthesis of fine chemicals, polymers and nanomaterials as well as in enzymatic and nanocatalysis are illustrated in various chapters of this book.

CHAPTER 2

Metal-catalyzed Reactions in Water under MW Irradiation

VICTORIO CADIERNO, PASCALE CROCHET AND SERGIO E. GARCÍA-GARRIDO

Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica “Enrique Moles” (Unidad Asociada al CSIC), Facultad de Química, Universidad de Oviedo, Julián Clavería 8, 33006, Oviedo, Spain

2.1 Introduction

Over the past two decades, increasing environmental concerns have triggered the development of new synthetic protocols that minimize the generation of chemical wastes. In this context, remarkable research endeavors have focused on the replacement of traditional organic solvents, which are generally toxic, flammable and non-renewable, by water. Besides its inherent advantages (harmless, non-flammable, abundant, renewable, inexpensive), fulfilling the requirements of the Green Chemistry principles, the use of water as solvent can also provide a notable difference in reactivity. In this sense, its high polarity combined with the hydrophobic effects enables water to enhance reaction rates and selectivities of some organic processes. Therefore, it is not surprising that in recent years a plethora of studies devoted to the development of metalcatalyzed organic transformations in pure water or aqueous biphasic media have been reported, with some of them disclosing highly efficient eco-friendly synthetic protocols.

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