Chemical Horizons: Research and Development

The world is rapidly evolving due to advancements in science, technology, and research. Chemical Sciences, in particular, have played a pivotal role in driving these changes. Over the course of seven chapters, this book attempts to highlight some significant advancements in this discipline. Our extreme contributors to this book deserve a great deal of praise for their efforts. These are the chapters that make up this edited book.
Chapter 1- A Mini Review on Green Synthesis of Dihydropyrimidinones/thiones via Biginelli Reaction by Dr. Murshida Karim
Chapter 2- Carbon Nanomaterials for Renewable Energy Applications by Dr. Monmi Saikia and Trisha Dutta
Chapter 3- Tert-amino effect: Synthesis of nitrogen heterocycles by Dr. Biswajita Baruah
Chapter 4- Assessment of Antioxidant Potential of some Indigenous Medicinal Vegetables of Northeast India by Dr. Manas Pratim Boruah
Chapter 5- A facile method for synthesis of triazoles using copper nano particles supported on Montmorillonite by Dr. Mitali Chetia
Chapter 6- Artemisinin is a Sesquiterpene lactone: Remedy for Malaria and Cancer by Dr. Bishwajit Saikia
Chapter 7- A study of some important medicinal plants in Manipur by Dr. Malabika Borah and Mr. Ankur Choudhury
We extend our sincere gratitude to the contributors of each chapter, whose invaluable contributions form the backbone of this book. We hope this book will ignite the passion of aspiring researchers and motivate them to delve deeper into the realm of science.

Preface

Contributors

Chapter 1 A Mini Review on Green Synthesis of Dihydropyrimidinones/thiones via Biginelli Reaction……..

Dr. Murshida Karim

Chapter 2 Carbon Nanomaterials for Renewable Energy Applications

Dr. Monmi Saikia and Trisha Dutta

Chapter 3 Tert-amino effect: Synthesis of nitrogen heterocycles

Dr. Biswajita Baruah

Chapter 4 Assessment of Antioxidant Potential of some Indigenous Medicinal Vegetables of Northeast India

Dr. Manas Pratim Boruah

Chapter 5 A facile method for synthesis of triazoles using copper nano particles supported on Montmorillonite

Dr. Mitali Chetia

Chapter 6 Artemisinin is a Sesquiterpene lactone: Remedy for Malaria and Cancer

Dr. Bishwajit Saikia

Chapter 7 A study of some important medicinal plants in Manipur….

Dr. Malabika Borah and Mr. Ankur Choudhury

Preface

The world is rapidly evolving due to advancements in science, technology, and research. Chemical Sciences, in particular, have played a pivotal role in driving these changes. Over the course of seven chapters, this book attempts to highlight some significant advancements in this discipline. Our extreme contributors to this book deserve a great deal of praise for their efforts.

Chapter 1- Dihydropyrimidinones (DHPMs)/thiones are valuable organic compounds with significant medicinal applications. Researchers are increasingly focused on developing green and efficient synthetic methods for these compounds in the last few years. This review summarizes five recent green methodologies for synthesizing DHPMs/thiones through the Biginelli reaction using microwave irradiation, ultrasound irradiation, grinding method, solvent-free conditions and water as a solvent. The author of this chapter discusses these green approaches which offer promising alternatives to traditional methods of producing these valuable chemical compounds.

Chapter 2- In this chapter, the author emphasizes the critical need to prioritize research on sustainable and renewable energy sources, given the exhaustion of non-renewable resources and their detrimental effects harmful impact on the environment. The advancement of technologies like fuel cells, lithium-ion batteries, solar cells, and supercapacitors has been driven by this focus. To further improve the efficiency of these energy storage systems, researchers have explored the use of nanostructured carbon-based materials, including graphene and carbon nanotubes (CNTs). These nanomaterials exhibit remarkable characteristics, such as high electron conductivity and extensive surface area, which greatly enhance the charge storage capacity and response times of electrodes in lithium-ion batteries, fuel cells, and supercapacitors. This chapter of the book outlines recent progress in the application of CNTs, graphene, and nanohybrid composites to optimize the electrode materials for sustainable energy storage systems. By incorporating these nanomaterials, researchers aim to develop high-performance, long-lasting, and environmentally friendly energy solutions. By integrating these nanomaterials, researchers aspire to create high-performance, durable, and environmentally sustainable energy solutions.

Chapter 3- This chapter explores the significance of nitrogen-containing, a class of organic compounds with nitrogen atoms within their ring structures. These compounds play a crucial role in both material science and pharmaceuticals due to their unique chemical properties and biological activities. Their prevalence in drug formulations and versatility in chemical applications underscore their importance in advancing both health and technology. As research continues to unveil new derivatives and applications, these compounds are likely to remain at the forefront of scientific innovation. In this article, a unique method for creating nitrogen-containing heterocycles is discussed. The study makes use of the tert-amino effect, which is the special reactivity of tert-amino groups. Through comprehension of the mechanism underlying this action, scientists can effectively create a wide variety of heterocyclic molecules. This study provides important information for expanding the field of heterocyclic chemistry and improving synthetic approaches.

Chapter 4- The chapter 4 focuses on the antioxidant properties of three indigenous leafy vegetables from North East India: Polygonum microcephallum D. Don, Oxalis corniculata, and an unspecified Achyranthes species. The antioxidant activity of these plants was assessed using the DPPH radical scavenging method.

Chapter 5- A novel catalytic system for azide-alkyne cycloaddition processes is covered by the author in chapter 5. An ionic liquid was used to immobilize copper nanoparticles on Montmorillonite clay. A highly effective catalyst was created by this combination, which produced good yields of 1,4-disubstituted 1,2,3-triazoles from a range of alkynes and azides. The ionic character of the ionic liquid and the negatively charged silicate sheets of montmorillonite work in concert to increase catalytic activity.

Chapter 6- The Chinese medicinal plant Artemisia annua L. yields a chemical called artemisinin, which has transformed the treatment of malaria because of its strong antimalarial properties and minimal toxicity. Artemisinin loses a great deal of strength when the peroxide bridge, which is essential to its effectiveness, is absent. A promising class of chemicals with stronger antimalarial and anticancer properties than their monomeric counterparts are artemisinin dimers, which are formed by linking two artemisinin molecules. The action of these dimers is strong even at very low concentrations. The prospective possibility of Artemisinin dimers for the creation of new antimalarial and anticancer medications are discussed by the author in chapter 6.

Chapter 7- North East India, particularly Manipur, is renowned for its rich biodiversity and abundance of medicinal plants. In chapter 2, the author's research attempts to investigate the traditional knowledge of different tribes in Manipur regarding the use of ethnobotanical plants for treating various ailments and diseases. By understanding these traditional practices, researchers hope to uncover valuable insights into potential new medicines and therapies.

We extend our sincere gratitude to the contributors of each chapter, whose invaluable contributions form the backbone of this book. We are also thankful to our family and friends for their unwavering support and encouragement. We hope this book will ignite the passion of aspiring researchers and motivate them to delve deeper into the realm of science.

Neither the editor nor the publisher is responsible for the data, results and comments reported by the respective authors on the book.

December, 2024 Dr. Devajani Boruah

Dhemaji, Assam, India

Contributors

Dr. Murshida Karim, Associate Professor, Department of Chemistry, B. N. College, Dhubri, Assam, India, [e-mail]

Dr. Biswajita Baruah, Assistant Professor, Department of Chemistry, Pandu College, Ghy-12, Assam, India, [e-mail]

Dr. Malabika Borah, Assistant Professor, Department of Chemistry, B. N. College, Dhubri, Assam, India , [e-mail]

Mr. Ankur Choudhury, Department of Chemistry, B. N. College, Dhubri, Assam, India, [e-mail]

Dr. Monmi Saikia, Assistant Professor, Department of Chemistry, Eastern Karbi Anglong College, Sarihajan, Karbi Anglong, Assam, India , [e-mail]

Dr. Bishwajit Saikia, Assistant Professor, Department of Chemistry, Digboi College, Digboi, Assam, India, [e-mail]

Ms. Trisha Dutta, Assistant Professor, Department of Chemistry, Eastern Karbi Anglong College, Sarihajan, Karbi Anglong, Assam India, [e-mail]

Dr. Mitali Chetia, Assistant Professor, Department of Chemistry, Moridhal College, Dhemaji, Assam, India, [e-mail]

Dr. Manas Pratim Boruah, Assistant Professor, Department of Chemistry, Dhemaji College, Dhemaji, Assam, India, [e-mail]

Chapter 1 A Mini Review on Green Synthesis of Dihydropyrimidinones/thiones via Biginelli Reaction

Murshida Karim

Department of Chemistry, B. N. College, Dhubri, Assam, India

E-mail: [e-mail]

Abstract

Dihydropyrimidinones (DHPMs)/thiones can be considered as fascinating class of organic compounds due to their involvement in various medicinal activities. The longing for green and efficient route for the synthesis of Dihydropyrimidinones/thiones remain a growing area of interest for the researchers. In this present mini review, we have tried to compile research works conducted regarding the green synthesis of Dihydropyrimidinones (DHPMs)/thiones. Here, we have focused five recent green methodologies for the synthesis of Dihydropyrimidinones/thiones via Biginelli reaction using microwave irradiation, ultrasound irradiation, grinding method, solvent free condition and water as a solvent in concise manner.

Keywords: Green Synthesis, Biginelli reaction, DHPMs, synthesis

Introduction

A multi-component reaction (MCR) is a chemical reaction where three or more components react to form a single product [1, 2]. In MCRs, more than two reactants combine in a successive manner to give a highly selective product [1, 2]. All the components are taken together in one pot in a multi component reaction [1, 2]. It is one of the important approach and key methodology to synthesize the valuable heterocycles in organic chemistry [3]. MCR was known since 1850 and Strecker synthesis of α-amino acids is generally known as the first MCR [4]. Biginelli reaction is one of the important multi component reaction, developed by Pietro Biginelli in 1893 to synthesize 3,4-dihydropyrimidin-2-(1 H)-one (DHPMs) [5]. The classical Biginelli reaction involves the acid-catalyzed, three-component reaction between benzaldehyde, ethyl acetoacetate (EAA), and urea in ethanol at reflux condition (Figure 1).

DHPMs have been drawing attention of the Chemists world due to their bioactivities such as calcium channel inhibitors, antimicrobial, antihypertensive, antitumor, antiviral, anti-inflammatory, cardiovascular, antimalarial, antioxidant, anti-epileptic etc. (Figure 2) [6,7,8, 9].

The original method suffers several drawbacks such as low yield of products in the case of substituted and aliphatic aldehydes, harsh reaction conditions and long reaction time [5, 10]. Due to their important biological activities, the synthesis of Biginelli compounds under wide range of reaction conditions with several improvements in the experimental procedures have been reported in recent years. Though many procedures have been developed for the synthesis of Biginelli compounds still a simple and efficient method is the thirst to solve the environmental pollution problems. In addition to traditionally used Brønsted acids as catalyst, a number of green methodologies have been reported in the literature over the last two decades to solve the environmental pollution issues. This mini literature review is planned to review concisely the synthesis of Biginelli compounds via various green methodologies.

Review of Literature

This literature review is mainly focus on the recent research work that have been reported in the scientific literature on the synthesis of Biginelli compounds. In this mini literature review, we have focused five recent green methodologies for Biginelli reaction using microwave irradiation, ultrasound irradiation, grinding method, solvent free condition and using water as a solvent in concise manner as follows:

Biginelli reaction using microwave irradiation

Chemical reactions under thermal conditions are better achieved by the use of Microwave irradiation. It promotes rapid heat transfer and allows reactions very much faster in comparison to conventional heating methods. As a result, it often increases the yield of the product in shorter time with lower energy usage [11]. Microwave irradiation has been widely studied and used for Biginelli reaction in the presence or absence of a solvent [12].

A. Kuraitheerthakumaran et al. have developed a new efficient method for the synthesis of 3,4-dihydropyrimidin-2(1 H)-ones/thiones using lanthanum oxide as a catalyst under solvent free condition via microwave irradiation (Scheme 1) [13]. They optimised the reaction condition and best results were achieved with 10 mmol of ethyl acetoacetate, 10 mmol of benzaldehyde/substituted benzaldehydes, 15 mmol of urea/thiourea and 10 mol % La2O3 at 320 W microwave irradiation for 20-60 seconds. It was found that 10 mol % La2O3 was sufficient to promote the reaction and no product obtained when the reaction was carried out at room temperature for a long time even in the presence of 20 mol % La2O3. In absence of La2O3, the reaction did not proceed even at higher irradiation.

Illustrations are not included in the reading sample

K. K. Pasunooti and his research group have developed an efficient and environmentally friendly procedure for the synthesis of 3,4-dihydropyrimidin-2-(1 H)-ones in excellent yields via microwave-assisted multi-component reaction (Scheme 2) [14]. They used Cu(OTf)2 in catalytic amounts and the process does not require work-up or column purification. 1 mmol of aldehydes, 1 mmol of ethyl acetoacetate, 1.5 mmol of urea, 0.02 mmol of Cu(OTf)2 and 2 mL of EtOH were added for the formation of DHPMs. Mild reaction conditions, lower catalyst loading, no by-products and easy purification process makes the mentioned reaction more convenient.

Illustrations are not included in the reading sample

Glycine nitrate (GlyNO3) amino acid ionic liquid initiated multicomponent Biginelli reaction for the synthesis of Dihydropyrimidinones has been reported by N. Sharma and his co-worker (Scheme 3) [15]. The ionic liquid is inexpensive, biodegradable and green catalyst and can be reused for more than ten consecutive reactions without significant loss of its catalytic activity. They optimized reaction condition and best results were obtained with 0.25 mmol of substituted benzaldehyde, 0.25 mmol of dicarbonyl compound, 0.75 mmol of urea or thiourea, 0.1 mmol of glycine nitrate and 3 ml of ethanol solvent.

An efficient green method has been developed by E. Kolvari and his research group for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones in solvent-free condition by using a magnetically separable and easily recyclable nano-γ-Fe2O3-SO3H catalyst under thermal or microwave conditions (Scheme 4) [16].

Illustrations are not included in the reading sample

The combination of magnetic iron nanoparticles and microwave technique is the first example for multicomponent reaction. An additional greener aspect of this reaction is easy magnetic separation of the catalyst after completion of the reaction.

The introduction of the guanidine moiety via Biginelli reaction into heterocyclic systems leads to the discovery of novel compounds with attracting pharmacological properties [17]. At first, Kappe and his team reported the direct three-component Biginelli reaction in 2001 with guanidine hydrochloride to give the corresponding 2-aminodihydropyrimidines [18]. F. Felluga and his research group modified the methodology of Biginelli reaction with guanidine hydrochloride in ethanol under microwave irradiation. (Scheme 5) [19]. They optimized the reaction conditions by using various solvents, time and temperature. The best results were obtained with ethanol solvent, 120 °C temperature and time ten minutes. No reactions were observed in water and poor yields are obtained in other solvents or solvent free condition.

Illustrations are not included in the reading sample

Biginelli reaction using Ultrasound irradiation

Sonochemistry plays a new trend in organic chemistry and offers a versatile and more environmentally friendly conditions for a large variety of reactions. Thus, a large number of organic reactions can be carried under ultrasonic irradiation with high yields and short reaction times [20]. Ultrasound irradiation (20 KHz-10 MHz) is a powerful technique to accelerate the organic reactions and it not only reduce the reaction time but also improves the reaction efficiency [21]. Ceric ammonium nitrate catalysed condensation of an aldehyde, β-ketoester and urea in methanol to afford the corresponding 3,4-dihydropyrimidin-2(1 H)-ones in excellent yields under sonication have been reported by J. S. Yadav and his co-worker (Scheme 6) [22]. The efficacy of other oxidants such as manganese (III) acetate and FeCl 3 were also studied for this reaction. Among these catalysts, CAN was found to be superior in terms of conversion and reaction time. Similar results were also obtained using 10% Oxone in methanol under identical reaction conditions.

Illustrations are not included in the reading sample

Ultrasound accelerated synthesis of 3,4-dihydropyrimidin-2-ones catalysed by NH2SO3H in ethanol have been reported by J.T.Li and his research group [23]. They carried out the experiment with different ratios of aldehyde, b-keto ester, urea, catalyst and the best results were obtained with the molar ratio 1:1.1:1.5:0.75 in aqueous ethanol at 25-30°C under 25 kHz ultrasound irradiation. (Scheme 7).

Illustrations are not included in the reading sample

P.G. Mandhane et al. have reported the sonochemical synthesis of 3,4-dihydropyrimidin-2(1 H)-ones catalyzed by using thiamine hydrochloride (Vitamin B1) as solid acid catalyst in water under ultrasound irradiation within 15-25 min (Scheme 8) [24]. It is well-known that thiamine hydrochloride (VB1) is a cheap and non-toxic reagent. The structure of VB1 contains a pyrimidine ring and a thiazole ring linked by a methylene bridge. They used 2 mmol of substituted aldehydes, 2 mmol β-keto ester, 3 mmol of urea and 5 mol % thiamine hydrochloride for the formation of 3,4-dihydropyrimidin-2-(1H)-ones. The mentioned method offers the following advantages: Green synthesis without using organic solvents, short reaction time and improve reaction yield.

Illustrations are not included in the reading sample

An ultrasonic assisted chlorosulphonic acid promoted multicomponent reaction for the synthesis of 3, 4-dihydropyrimidin-2(1H)-ones by the condensation of substituted benzaldehydes, diketone/β-ketoester and urea/ thiourea, at ambient temperature under solvent-free condition have been reported by G. M. Nazeruddin and his co-worker (Scheme 9) [25]. In the mentioned method products can be easily isolated by simple workup such as dilution and filtration of the precipitated product (DHPMs).

Illustrations are not included in the reading sample

S. Kakaei and his co-workers have successfully developed an efficient and versatile protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones by the condensation of aldehydes, ethyl acetoacetate, urea/thiourea using holmium chloride as a catalyst under solvent free condition with ultrasound irradiation as the energy source (Scheme 10) [26]. They received the optimal conditions at a molar ratio: benzaldehyde, ethyl acetoacetate and urea at a molar ratio of 1:1:1.5 with addition of 8 mol% HoCl3 in 80 °C for 1 hour.

Illustrations are not included in the reading sample

Biginelli reaction using Grinding

The use of mortar-pestle for organic transformation is popularly known as grindstone chemistry and was introduced by Toda et al. in the last century [27]. The technique offers solvent-free or solvent-less reactions, often works in the absence of a catalyst and avoids an extensive work-up step [28]. Gradually, it became an effective tool for a variety of organic reactions including Michael addition [29] Aldol condensation [30], Claisen-Schmidt condensation [31], Wittig reaction [32] etc.

Synthesis of tetrahydropyrimidinone derivatives via Biginelli reaction using ‘Grindstone Chemistry Technique’ have been reported by A. K. Bose and his group (Scheme 11) [33]. They have used an inexpensive and common organic chemical, p-toluene sulfonic acid (p-TSA) as a catalyst for the Biginelli reaction.

Illustrations are not included in the reading sample

An efficient and inexpensive route for the synthesis of Dihydropyrimidinones via Biginelli reaction catalysed by CuCl2.2H2O and Conc. HCl under solvent free condition have been reported by V. N. Pathak and his group (Scheme 12) [34]. They have used ‘Grindstone Chemistry Technique’ for the synthesis of Biginelli compounds. They have tried with various molar ratios of the catalyst to optimize the amount of catalyst requirement and maximum product yield. The best results were obtained with 40 mol% catalyst. 10 mmol of aromatic aldehyde, 10 mmol of EAA, 20 mmol of urea/thiourea, 5 mmol of CuCl2.2H2O and few drops of conc. HCl was used for the synthesis of DHPMs.

Illustrations are not included in the reading sample

An efficient protocol for the synthesis of 3,4-dihydropyrimidin-2-(1 H)-ones via Biginelli reaction from an aldehyde, b-ketoester and urea/thiourea, using nickel chloride pentahydrate has been described by U. B. More (Scheme 13) [35]. They have carried out the synthesis in solvents, namely ethanol and water under reflux condition. They have also carried out the same reactions under solvent free conditions via grinding. The grinding method was found to be better on the basis of yield and purity of products.

Illustrations are not included in the reading sample

Biginelli reaction under grinding condition was first reported by Bose and co-workers using p-TSA as catalyst. Traditional method for Biginelli reactions generally require a large excess of one of the reagents, large amounts of catalyst, high temperatures, long reaction time and occasionally the presence of co-catalyst. To overcome these problems A. Khaskel et al. focused on the search of a catalyst that would be useful in grindstone methodology[36]. They had chosen L-tyrosine as a catalyst and performed Biginelli reaction (Scheme 14) with 4-methoxybenzaldehyde (1 mmol), urea (1 mmol) and methyl acetoacetate (1 mmol) in presence of L-tyrosine (10 mol %) as catalyst under solvent free grinding condition. This model reaction afforded compound with 87% yield and the reaction is optimum under grinding method using 10 mol% L-tyrosine at room temperature.

Illustrations are not included in the reading sample

J. Safari et al reported Biginelli type reaction in the presence of Fe3O4-CNT nanocomposites as catalyst under solvent-free conditions via grinding method (Scheme 15) [37]. They reported green and high yielding methodology for the synthesis of 4, 6-diaryl-3, 4-dihydropyrimidine-2(1H)-ones from readily available aldehydes, acetophenone, and urea in the presence of Fe3O4–CNTs via grinding under solvent-free condition. The above mentioned three components one-pot reactions proceeded smoothly and rapidly to afford the product in excellent yields.

Illustrations are not included in the reading sample

Biginelli reaction using solvent free condition

Now a days, the solvent free reaction has attracted much attention to increase the environmental consciousness in chemical research and industry [38]. Solvent-free synthesis of dihydropyrimidinones via Biginelli protocol catalyzed by zinc chloride have been developed by

Q. Sun and co-worker (Scheme 16) [38]. The best result was achieved by carrying out the reaction with 0.2:1:1:1.5 mole ratios of zinc chloride, benzaldehyde, ethyl acetoacetate and urea at 80 °C for 20 minutes under solvent-free conditions.

Illustrations are not included in the reading sample

J. S. Yadav et al. developed a novel, efficient and simple synthetic protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones via Biginelli reaction of an aldehydes, β-dicarbonyl compounds and urea/thiourea using L-proline as the catalyst under solvent free condition (Scheme 17) [39]. They have used 10 mol% of L-proline under solvent-free condition at ambient temperature and in addition no additive or protic/ Lewis acid is necessary in this procedure. Another important feature of the mentioned protocol is that a variety of functional groups survive under the reaction condition.

Illustrations are not included in the reading sample

Ce(NO3)3·6H2O catalyzed solvent-free three-component Biginelli reaction of an aldehyde, a β-keto ester or β-diketone and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2(1 H)-ones or thiones in excellent yields has been reported by M. Adib and his research group (Scheme 18) [40]. The reactions of several activated and deactivated aromatic and aliphatic aldehydes with a β-keto ester (or β-diketone) and urea using catalytic amount of Ce(NO3)3·6H2O produced a range of 3,4-dihydropyrimidin-2(1 H)-ones and their thio analogs in excellent yields under solvent-free conditions at 80 ºC.

Illustrations are not included in the reading sample

M. S. Wu et al. have modified the Biginelli reaction and employed p-aminobenzene sulphonic acid catalyst for the synthesis of Biginelli adducts under solvent-free conditions (Scheme 19) [41]. A mixture of 1 mmol aromatic aldehydes, 1 mmol ethyl acetoacetate, 3 mmol of urea/thiourea and 0.1 mmol anhydrous p-aminobenzene sulphonic acid was used for the preparation of Biginelli adduct. Excellent yields with short reaction time, no side reactions and easy experimental and simple isolation procedure make this an important alternative to other catalysts commonly used in the Biginelli reaction.

Illustrations are not included in the reading sample

The synthesis of 3,4-dihydropyrimidin-2-(1 H)- one/thione derivatives via Biginelli protocol of aryl aldehydes, urea/thiourea and ethyl/methyl acetoacetate in the presence of ZnSO4.7H2O as an efficient and inexpensive catalyst under solvent-free conditions have been reported by F. Mohamadpour (Scheme 20) [42]. A mixture of aldehyde derivatives (1.0 mmol) and urea/thiourea (1.5 mmol), ethyl/methyl acetoacetate (1.0 mmol) were heated in the presence of ZnSO4.7H2O (25 mol %) under solvent-free conditions at 80 °C for appropriate time. This protocol has several advantages such as readily available and non-toxic catalyst, short reaction times, good to high yields, solvent-free conditions, facile reaction profiles and simple work-up.

Illustrations are not included in the reading sample

Biginelli reaction using water as solvent

Water is considered as one of the best solvent among all the greener solvents. Organic reactions via aqueous medium and without using harsh chemicals are of great interest for the chemists [43]. It accelerates the polar reactions by activating both electrophiles and nucleophiles. Biginelli reactions in aqueous media has been explored by many researchers using different methodologies.

V. Polshettiwar et al. used the polymer supported polystyrene sulfonic acid (PSSA) as a catalyst for the synthesis of various substituted 3,4-dihydropyrimidin-2(1H)-ones using Biginelli protocol in water (Scheme 21) [44]. They studied the condensation in water under microwave irradiation. They also tested the reactions without any catalyst under microwave irradiation conditions in aqueous media but no reaction was observed at 80°C and 100 ° respectively. They reported poor yields with Lewis acids and Nafion-H whereas acetic acid gave moderate yield. However, PSSA efficiently catalysed this reaction and afforded high yields of the desired product.

Illustrations are not included in the reading sample

S. K. Kundu et al. reported aqueous zinc tetrafluoroborate catalyzed one-pot Biginelli condensation for the synthesis of 3,4-Dihydropyrimidine-2-(1-H)ones derivatives at room temperature (Scheme 22) [45]. 2 mmol of ethyl acetoacetate, 2 mmol of benzaldehyde, 2.4 mmol of urea along with aqueous solution (40 % W/V) of zinc tetra fluoroborate was used for the preparation of Biginelli compounds. Operational simplicity, aqueous media, mild reaction conditions, high yield and inexpensive catalyst makes the mentioned procedure advantageous.

Illustrations are not included in the reading sample

Synthesis of 3,4-dihydropyrimidinones using Biginelli protocol in presence of water without additional solvent and acid catalyst under conventional heating, microwave irradiation/ultrasound have been reported by S. Singhal and his research team (Scheme 23) [46]. They have used 2 mmol of aldehyde, 2 mmol of urea, 2mmol of β-dicarbonyl compound and 0.5 ml of water followed by microwave irradiation (750 W, 2 min) for the formation of 3,4-Dihydropyrimidine-2-(1-H)ones. Water was found to be vital in the mentioned synthetic process and the reactions were found to proceed faster under microwave irradiation/ultrasound in comparison to conventional heating and afforded products in high yields.

Illustrations are not included in the reading sample

Synthesis of a variety of 3,4-dihydropyrimidin-2(1H)-ones via Biginelli protocol using ammonium carbonate as a solid ammonia source in aqueous media have been reported by F. Tamaddon et al. (Scheme 24) [47]. They used 2 mmol of aromatic aldehydes, 2 mmol of alkyl acetoacetate and 2.5 mmol of urea/thiourea followed by the addition of a catalytic amount of (NH4)2CO3 (30 mol %) in 1 mL of H2O for the preparation of 3,4-dihydropyrimidin-2(1H)-ones.

Illustrations are not included in the reading sample

Synthesis of 3,4-Dihydropyrimidine-2-(1-H)ones derivatives via Biginelli reaction using aromatic aldehyde with urea and a β-dicarbonyl compound in presence of HCl at a temperature of 90 °C in water solvent have been reported by Y. M. Shams and his team (Scheme 25) [48]. The effect of solvents, temperature and amount of acid on the reaction yield was investigated. They have reported that the maximum yield of the reaction was obtained with 20 mol% HCl in water solvent at a temperature of 90 °C for 30 minutes. The mentioned synthetic method has several advantages such as high reaction yield, shorter reaction time, no requirement for additional solvent, no intermediate separation, and environmental compatibility of the catalyst.

Conclusion

In conclusion, this mini review has summarized recent advances in the synthesis of 3,4-Dihydropyrimidine-2-(1-H)ones derivatives via Biginelli reaction related to green chemistry. Here, we have made efforts to compile five recent green methods that have been reported in the literature. This literature review will be very useful to the researcher working in this field, and it would be helpful to search a new green, efficient and economical method.

References

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11. S Panda, S., Khanna, P., and Khanna, L., 2012. Biginelli reaction: A green perspective. Current Organic Chemistry, 16(4), 507-520.

12. Stadler, A., Kappe, C. O., 2000. Microwave-mediated Biginelli reactions revisited. On the nature of rate and yield Enhancements. J. Chem. Soc., Perkin Trans., 2, 1363-1368; Hügel, H. M., 2009. Microwave multicomponent synthesis. Molecules, 14, 4936-4972.

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Chapter 2 Carbon Nanomaterials for Renewable Energy Applications

Trisha Dutta and Monmi Saikia

Department of Chemistry, Eastern Karbi Anglong College, Sarihajan, Karbi Anglong-782480 Assam

E-mail: [e-mail] , [e-mail]

Abstract

The study on sustainable and renewable energy should take precedence over other areas due to the growing global usage of non-renewable energy resources (such as fossil fuels) and the release of harmful gases. Fuel cells, lithium-ion batteries, solar cells, and supercapacitors are just a few of the sustainable energy production and storage technologies that have been made possible by this goal. These devices, with high specific power, long cycle life, portability, and ease of fabrication, have been able to secure worthy positions in the field of energy science and technology. Over the last decades, attempts have been taken to use nanostructured carbon-based materials, like graphene and carbon nanotubes (CNTs), with the aim of improving the efficiency of the abovementioned energy storage systems. This book chapter focuses on the latest developments in the application of CNTs, graphene, or nanohybrid fillers to increase the efficiency of the electrode materials of these sustainable energy storage devices. Furthermore, these nanomaterials' strong electron conductivity and high surface area improved the capacity of lithium-ion batteries, fuel cells, and supercapacitors to store charge as well as their electrode response rates.

Keywords: technology, non-renewable energy, carbon nanotubes, Fuel cells,

Introduction

Background and Significance

The escalated demand for variegated purposes such as heating, transportation, and electrical energy sources has caused the global community to confront with an energy crisis because of the increasing growth of the world’s population and technological advancement. This causes the strain of fossil fuels such as natural gas, coal, crude oil, etc., and their excess consumption might lead to various adverse consequences, that is, climate change, environmental damage, as well as shortage and depletion risks in the upcoming years; this has drawn extensive attention toward clean sustainable and renewable energy alternatives [1]. Energy harvesting could therefore furnish a route for incessant power supply and battery replacement. One of the most propitious energy sources for self-powered systems can be classified into two categories: ambient and external sources. Those sources which are available in the surroundings free of costs affected by location, time, and weather conditions and characterized by their unpredictability, non-controllability, and unique conversion efficiency. External sources, in contrast, are explicitly employed in the environment, predictable, and controllable [2]. Various energy sources available in the environment include electromagnetic, waves, solar and wind energy, nuclear power, thermal energy etc. which can be used to harness energy [3,4]. One of the most important step towards the manufacture of wireless and portable devices is power supply miniaturization [5]. Nanogenerators (NGs) have been introduced as several-to-few/one centimeter-sized mini-plants has the ability to convert various forms of primary energy into electricity without expensive apparatuses for operation, much complications, and large-scale production to replace batteries thereby making a remarkable contribution to the conversion of waste energy in the environment into viable electricity which would be efficient to power low electronic devices [6]. Therefore, different types of NGs were then introduced which could extend hands as one of the solutions to the evolving demand of energy. These NGs were based on various physical effects such as electromagnetic, piezoelectric (PE), triboelectric (TE), and pyroelectric (PYE) effects; could be integrated into larger systems as power suppliers; or perform different applications independently as self-powered devices [7,8]. In the recent scenario, applying nanotechnology in the renewable energy field acts efficiently in improving energy efficiency, storage, and conversion [9]. As carbon nanomaterials are attributed with unique characteristics like enhanced and facile tunable electrochemical, electrical, and optical properties; low cost for large-scale production; chemical stability; ease of interactions and functionalization; high electrical and thermal conductivity; large surface-to-volume ratio and reactivity, these are widely adopted in various applications [10-12]. Owing to the miscellaneous structures, that is their tunable surface chemistry and versatile surface and dimensionality ranging from 0D to 3D of carbon nanomaterials, these can be used as both matrices and functional additives [13]. Ultimately, the properties like the nano-dimensionality, nanostructure, unlimited tunable, structural and electronic properties, excellent sustainability, and availability have resulted to significant roles in the fields of charge-transfer systems and trending energy sources [14]. Hence, the carbon nanomaterials hold substantial potential for the purpose of energy harvesting from the environment.

General Classification of Carbon Nanomaterials

One of the most multifaceted elements displaying all the three hybridization states: sp, sp[2], and sp[3]. The diversity in bonding creates variegated and numerous possibilities for carbon allotropes with different geometries and shapes, from linear to trigonal planar to tetrahedral and other shapes. sp[3] hybridized carbon atoms undergo formation of sigma bonds while sp[2], and sp[3] hybridized carbons possess delocalized electrons that generate frames of conjugated π bonds. This versatility in bonding results in a significant variety of geometries and chemical and physical properties. Carbon nanomaterials flexibly range in size and dimension, from 0D hollow, spherical fullerenes and carbon nanodots to 1D carbon nanotubes (CNTs) and graphene nanoribbons, to 2D planar monolayer graphene, to 3D multilayered graphite and nanodiamond. The above mentioned carbon allotropes are based on sp[2] carbon while diamond and graphite are two natural carbon allotropes formed by sp[3] and sp[2] hybridized carbons, respectively. In contrast, some are laboratory-prepared and are mainly predicted and designed based on theoretical calculations and experimental investigations [15].

Use of Carbon nanomaterials in energy Harvesting

Carbon nanomaterials-based piezoelectric energy harvesting

One effect which can be explained by the electric polarization of a material under external mechanical force, inducing electric potential upon deformation of the material is piezoelectricity [16]. It is much useful in sensing, energy harvesting, transducing, and actuating applications. Piezoelectric Nanogenerators (PENGs) finds promising applications for low energy devices such as medical implanted devices, wearable electronics, microelectronic systems which display advantages of small size, strong versatility, high adaptability to the environment and portable installation[17]. Some commonly used PENG materials include inorganic zinc oxide (ZnO), gallium nitride (GaN), and organic poly(vinylidene fluoride) (PVDF) [16]. The classic bulk PENG materials display several disadvantages such as a complicated crystal structure, and poor electrical conductivity and chemical composition. This creates an unidirectional conductive Schottky barrier thereby restricting the electron transfer/mobility and hence causes difficulty in applying in miniaturized and high electric output systems under normal conditions and traditional circuit connections. Nonetheless, PENG materials on the nanoscale level have the ability to overcome these limitations owing to their simple chemical composition and crystal structure present in their easily controlled purity, size, and morphology via physical/chemical methods [18]. The randomly oriented dipoles of a PENG material need to be aligned for better electric output and higher performance. This can be achieved through either of the two pathways: a) Using high-electric-field-based poling b) chemically depositing conductive nanofillers [19].

As nanofillers, carbon nanomaterial-based nanofillers occupied their position amongst the best positions due to their attractive mechanical, thermal, and electrical properties. They are equipped with unique electrical properties and special properties such as their high aspect ratio, unique shape, environmental stability, nanoporous architecture, superconductivity, light weight, high stiffness, and axial strength. These characteristics make them suitable for behaving as nanofillers which can be utilized as either organic or inorganic polymer, to be added or mixed into the active PENG matrix in order to enhance the electrical performance of the device. [20,21,22]

Carbon nanomaterials-based triboelectric energy harvesting

Active contribution to triboelectrification and charge transfer processes is carried out by carbon nanomaterials. Depending on the counter TENG material and the difference in work functions and electronegativity, which tells about the imbalanced electron sharing in the adhesive electron cloud, Carbon nanomaterial films can tune itself either triboelectrically positive or negative [23, 24]. Prominent attention has been gained by TENGs owing to their advantages of low cost, high energy-conversion efficiency, light weight, simple design, reliability, easy scalability, high power output, and environmental friendliness [25]. TENGs operated through four basic operation modes where all of them follow the same electricity generation principle: vertical contact-separation, lateral sliding (in-plane), single-electrode, and freestanding TENG layer modes [26]. It actually converts mechanical energy in the environment into electricity through two processes: contact electrification (triboelectrification) and electrostatic induction. The two main parts of TENG device comprises of active TENG layers (positive and negative) and conducting electrodes [27]. Mechanical energy in the environment is converted into electricity by TENG through two processes: contact electrification (triboelectrification) and electrostatic induction. This effect can be described by the periodic contact/separation of two distinct materials as TENG layers that drive electrons to flow from one electrode to another in the direction of high to low electrochemical potential based on the electronegativity difference [18]. Determination of energy conversion performance of TENG devices is based on the surface charge transfer during periodic contact/separation. The surface charge transfer during periodic contact/separation plays a major role in the TENG outputs, which shows the significance of the material composition and TENG system design [28]. Various strategies have been applied in order to escalate the charge transfer at the contacted surfaces’ interface and the overall performance of TENGs, which aims at either the TENG active material, such as the (1) TENG material type, (2) TENG material modification, (3) charge injection through polarization or corona charging, and (4) device structure optimization, or electrode materials which require highly conductive materials such as rigid metals (aluminum (Al), nickel (Ni), gold (Au), copper (Cu), indium tin oxide (ITO), and magnesium (Mg)) limited by their corrosion and inapplicability for flexible devices, and carbon nanomaterials such as graphene and CNTs [27]. The electronegativity of the negative layer, depending on the functional group content; is the primary factor determining the surface chemical potential difference. Higher the electronegativity value, higher is the tendency to attract electrons and yield higher electric outputs. Some other governing factors are the surface contact area, porosity, and roughness of the two contacted materials, which are functions of the morphology and composition. The dielectric constant, measuring the capacitance and charge trapping capability of the material, should be increased in order to provide larger charge densities/surface potentials and consequently improve charge transfer tendencies and output current [29]. In the current scenario, 2D materials have secured its position as excellent TENG building components and tend to be located near the negative TENG side of the TE series [30]. 2D lamellar materials have also displayed its excellency in trapping the potential via the interlayer contribution to trapping and stacked structures [29]. In a nutshell, carbon nanomaterials possess the properties which would fulfil most of the previously mentioned factors and played the roles of a contacting/friction layer, TENG film components, and electrodes.

Electricity generation from water/carbon nanomaterials interface

An attention-grabbing renewable energy approach is the one generated from the motion of liquids on solid media [31]. The fact got proven experimentally when CNTs were used for electricity generation from fluid flow [32]. Hence, it was also confirmed that moving droplets of ion-containing water over graphene or the flow of ionic and nonionic liquids inside or outside CNTs or over graphene can induce potential differences along the flow direction, thereby producing electricity. The generation of electricity was also carried out by water evaporation or moisture adsorption onto the carbon nanomaterial films. When CNT, carbon black film, graphene, and their derivatives came into interaction with water, low -power electricity has been observed. Variegated working principles of blue energy harvesting devices have been put forwarded such as pseudo-capacitive effects, friction with moving liquids, drifting of absorbed ions, Coulombic drag, electron drag, streaming potentials, waving potentials, fluctuating asymmetric potentials, evaporation potentials, adsorption potentials even though only electrons, water molecules, and/or ions are involved in the energy conversion process. Carbon nanomaterial-based energy harvesters can be classified into three categories based on the stimulus type which includes sliding droplets, flowing water and phase change processes. These carbon nanomaterial-based systems are activated by the motion of sliding droplets, waves, rain, shaking flowing or circling water, and phase change processes, which involve processes like evaporation of water and adsorption of moisture [31]. The unique characteristics of carbon nanomaterials involve delocalized π-electron rich networks, diverse forms, high conductivities, and chemical stability which makes them suitable for activities like establishing proper interfacial behaviors with ionic liquids at the liquid/solid interface. The key to maximizing the electrokinetic potential for the generation of electricity is the presence of the strong cation-π interaction between the π-electron-rich structure of the carbon nanomaterial’s aromatic system and electrolytes. [33]

Carbon nanomaterials-based thermal energy harvesting

Electricity can be harnessed from heat; an important energy source in our day-to-day life. It can be executed by making use of transducers or materials that can convert thermal energy present in the surroundings into electrical energy via the Seebeck/T effect. It can also be implemented to power small electronic devices and systems. The wide spectrum of accessed thermal energy distribution, the simplicity of the TNG apparatus, the direct conversion of solar/thermal energy or waste heat into effective electrical power with reduced harmful greenhouse emissions, no hazardous working fluids or noisy forms the basis of the benefit behind using thermoelectricity. [34]

The underlying principle behind TNG technology lies in the built-in temperature gradient between two spaces with different temperatures, a cold part and a hot one, accompanied by the formation of an electric field and a potential difference [18]. The focal principle is traced back to the formation of a hole-electron pair in a semiconductor material in response to a temperature gradient across the TNG device. In order to harness the harvested energy, it is necessary to use interface circuits which has the ability to convert and store or directly feed the generated energy to power any external load [35]. The module for TNG is made up of alternating legs of p-type and n-type materials connected thermally in parallel and electrically in series [36]. Materials used include commercial bismuth telluride (Bi2Te3), thallium-doped lead telluride alloy (PbTe), antimony telluride (Sb2Te3), and CNT membranes. In commercial TNG devices, Bi2Te3 has been used for decades but the limitations of these devices lie in their low efficiency (only 16%) because of the poor thermal resistivity and high heat flow of the active Bi2Te3 material [37, 38]. Materials having high electrical conductivity and Seebeck coefficient and, most notably, low thermal conductivity is suitable for the fabrication of an ideal high-performance TNG device. Various inorganic TNGs are found to have greater efficiencies and voltages only at elevated temperatures, but they display relatively high-power outputs and densities compared to organic TNGs. But these also suffer from drawbacks such as high cost, brittleness, toxicity, and poor processability, prohibiting their widespread use. On the other hand, the carbon nanomaterial-based TNG devices such as CNT [38], p-n CNT fiber[39], p-n CNT Buckypapers [40], p-n CNT/PANI [41] , p-n CNT[42], Pyrene/CNT[43], p-PPT aerogel and n-CNT [44] etc reveal better performances and potential in order to harvest low-grade heat, such as from the human body and automobiles, at a low range of 300–400 K. Also, similar to organic TNGs, these devices also offer advantages such as ease of fabrication, cost-effectiveness, and broad range applicability, especially in flexible and stretchable devices [36].

Application of Carbon Nanomaterials

The 1970s energy crisis catalyzed the creation of energy-saving technologies and renewable energy sources. These programs were later trimmed back as supply caught up with demand. After ten years, the pollution risks prompted efforts to reduce and reverse the environmental damage caused by the mining, transportation, and use of fossil fuels. A shift towards more sustainable and renewable energy sources is necessary due to climate change and the depletion of fossil fuels. Different forms of renewable energies like geothermal, solar, wind power, biofuel, and hydropower have been nurtured by human being. Of all the carbon-neutral energy sources available, sunlight is the most abundant. Consequently, solar or photovoltaic cell-based technologies are crucial because they can capture sun energy. Researchers are once again focusing on developing sustainable energy sources and improving renewable energy systems due to growing worries about the continuous use of fossil fuels and its impact on climate change [45]. To effectively address global warming and the limited supply of fossil fuels, we must make significant progress in energy storage and conversion technologies [45,46]. To fulfill the world's future energy requirements, effective energy storage technologies must be developed, particularly at a time when energy costs are rising and more people require access to electricity. Energy storage devices, which store extra energy and release it during periods of high demand, can increase supply system efficiencies. The creation of energy storage devices that will assist in resolving the energy storage and conversion conundrums facing humanity will require further advancements in engineering and material science [47, 48]

In this context, carbon nanomaterials, like carbon nanotubes (CNTs) [49, 50] and graphene [51, 52] and in some cases polymer nanocomposites have been recognized as ideal candidates for utilization in advanced energy storage devices. Carbon nanoparticles can be utilized as electrodes for fuel cells, solar cells, lithium-ion (Li-ion) batteries, and supercapacitors [53. 54].

Illustrations are not included in the reading sample

Figure 1: A schematic illustration exhibiting the application of carbon nanomaterials in various energy storage systems

The extraordinary properties of CNTs, such as excellent electrical conductivity, high entanglements, good thermal conductivity, and high resilience, have resulted in extensive application as catalyst-supporting materials in fuel cells [55, 56, 57].

Supercapacitors

Creating very efficient supercapacitors has emerged as one of the most promising areas of academic and industrial study in this new era. Currently, a great deal of research is being done on using carbon nanomaterials as supercapacitor electrodes. Supercapacitors are made up of two solid/porous electrodes that are in contact with an electrolyte and a separator, just like regular capacitors.

Illustrations are not included in the reading sample

Figure 2: A schematic illustration of a supercapacitor. (Source: Wikipedia)

While an electrolytic capacitor accumulates charges on the two conductors, which are separated by a dielectric, a supercapacitor stores charges at the interfacial region between the electrolyte solution and the electrode. It can be observed from Figure 2 that there exist porous dielectric materials that prevent the transport of charges between the electrodes. The basic difference between these two types of capacitors is in their charge transfer and storage aspects, i.e., a pseudo capacitor follows faradaic charge-transfer laws, whereas an ELDC obeys the non-faradaic charge-transfer mechanism. It was found that in case of ELDC, the storage of electrical energy remains electrostatic without any electron transfer, resulting in the formation of a Helmholtz layer. Usually, supercapacitors can be divided into two classes (a) pseudo capacitors and (b) electrical double-layer capacitors.

To increase the energy storage capacity of supercapacitors, the porous architectures of graphene and carbon nanotubes (CNTs) were investigated. Significant improvements in the specific capacitance of supercapacitor electrodes have been demonstrated by freestanding mats of entangled multiwalled carbon nanotubes (MWCNTs) with H2SO4 electrolyte [58]. Studies on the impact of randomly oriented and vertically aligned CNTs on the specific capacitance of the supercapacitor electrodes have been conducted [59, 60]. Mesoporous carbon spheres with carbon nanotubes implanted in them have been created to act as electrodes in an aqueous electrolyte. This has been done to increase the porosity and enhance the electrical conductivity of the carbon spheres [61]. Random SWCNTs networks have also shown significant value of specific capacitance in the presence of KOH electrolyte with a power density of 20 kWkg-[1] and an energy density of 10 Whkg-[1] . It was also found that Polypyrrole (PPy)/CNT composite was prepared by utilizing CVD-grown CNTs on ceramic foam, followed by PPy coating by chemical polymerization [62] . Polyaniline (PAni), with carbon porous material having a high surface area, exhibited a high specific capacitance and an improved cycle life. PAni composites, i.e., PAni/graphene, PAni/carbon nanofibers (CNFs), and PAni/CNT, produced higher specific capacitance values compared to PAni [63, 64, 65, 66]. The properties of nickel oxide (NiOx)-based nanoparticles have been analyzed, which were formed by the process of self-assembly on poly(ethylene imine) (PEI)-CNTs composites as substrate with the aid of microwave radiation improvement in the electrocatalytic performance of the electrode [67]. PEI-functionalized CNTs proved to be effective in facilitating the uniform dispersion of nanoparticles on CNTs. Additionally, it has been noted that the specific capacitance, specific surface area, and rate performance of CNTs were enhanced by controlled KOH activation and nitrogen doping with melamine, as well as by a stable performance even after 1000 cycles [68]. SWCNTs-coated mesoporous cellulose fibers prepared by “dip-absorption-polymerization” method followed by infiltration and in situ polymerization of aniline have been used as an electrode in supercapacitors [69].

Solar Cells

Solar cell devices are those which use solar energy as the only fuel and produce electrical charges by photovoltaic effect, so that these can move freely in semi-conductors and finally through an electric load [70]. A photovoltaic (PV) cell, commonly called a solar cell, is a nonmechanical device that converts sunlight directly into electricity. Some PV cells can convert artificial light into electricity. Sunlight is composed of photons, or particles of solar energy.

Illustrations are not included in the reading sample

Figure 2: Working of solar cell (Source: Wikipedia)

A solar cell involves direct harvesting of sunlight into solar energy using small photovoltaic cells [71]. From the advent of the first solar cell, which was a silicon (Si)-based cell [72], this has gained enormous attention from research communities [73] The first generation of solar cells was produced on silicon wafers either using monocrystalline or polycrystalline silicon crystals [74, 75] Usually, silicon wafers have a thickness of 350 μm, whereas the second-generation thin-film solar cells possess a thickness of 1 μm. The second-generation solar cells are amorphous silicon, CdTe, and copper indium gallium diselenide (CIGS) [76, 77] The most recent and promising generation of solar cells consists of concentrated solar cells, polymer-based solar cells, dye-sensitized solar cells, nanocrystal-based solar cells, and perovskite-based solar cells. Over the last decades, organic materials like conducting polymers have been used as ideal candidates for the photovoltaics in solar cells. Concentrated solar cells, polymer-based solar cells, dye-sensitized solar cells, nanocrystal-based solar cells, and perovskite-based solar cells make up the most recent and promising generation of solar cells. Organic materials, like as conducting polymers, have been employed as excellent candidates for solar cell photovoltaics throughout the past few decades. However, employing organic photovoltaics has certain drawbacks. CNTs have been utilised to increase polymer photovoltaics' efficiency. CNTs contribute to the enhancement of the thermal, chemical, optoelectronic, and charge conduction characteristics of the cells. It has been discovered that nitrogen doping improves the performance of graphene-based supercapacitor electrodes. According to certain reports, doping graphene with nitrogen improves electron transport, which in turn helps electrodes made of graphene function better [78, 79, 80, 81].

The most promising solar cell technologies of the present period are DSSC (Dye-Sensitized Solar Cells) and QDSC (Quantum Dot Solar Cell) because of their adaptability, simplicity in production, and efficiency in absorbing dispersed sunlight. CNTs have been used in photoanodes of DSSC and QDSC due to their high specific surface area and enhanced charge transport [82-86] . Researchers have investigated the role of carbon nanomaterials, like CNTs and graphene, in enhancing the performance of solar cells [87, 88]. The most popular photoanode for use in DSSC is TiO2, because of its large specific surface area. However, the trapping of electrons caused by the grain boundaries in TiO2's porous structure limits the material's potential as a photoanode [89-91]. In the case of a PEO/CNTs composite electrolyte, the introduction of CNTs into the poly(ethylene oxide) (PEO) matrix improved the conductivity and other features of a solid-state DSSC's performance [92].

Fuel Cells

Fuel cells are environmentally friendly energy-storing devices, possessing low or no emission threat and high energy conversion and power density [93]. The polymer electrolyte membrane (PEM) fuel cell is mainly used for low-temperature mobile applications [93, 94]. Their slow electrode kinetics resulted in a significant amount of costly and scarce catalyst materials (especially Pt metal) being used [95]. Similar to batteries, fuel cells also convert chemical energy to electrical energy producing heat and water as a by-product [96, 97]. In the case of fuel cells, the fuel is fed to the anode side of the cell, while the oxidant is fed to the cathode side of the cell [94]; electrochemical reactions take place at the two electrodes [98]. Electrons are generated at the anode and are then transferred to the cathode through the external circuit to produce electricity. Several attempts have been made in the past few decades to increase the efficiency of fuel cells by substituting novel and alternative catalysts for the most advanced Pt metal. This is because Pt is very expensive and hard to come by, which makes it difficult for fuel cell devices to go on sale. In addition, several novel catalytic supports have been created to replace the conventional carbon black. These consist of various nanoparticles that aid in enhancing the catalyst's performance as well as carbon nanomaterials like graphene and carbon nanotubes (CNTs). CNTs-based fuel cells have been found to possess high catalytic activity and high quality of transmission and production of large current densities [98, 99]. CNTs have been applied as supporting materials for both the anode and the cathode of the fuel cells [100, 101]. Several aspects make CNTs a more preferred candidate over other materials, which include higher crystalline nature, higher chemical stability, better electrical and thermal properties, and a 3D structure favoring sufficient space for reaction.

Illustrations are not included in the reading sample

Figure 3: A schematic illustration of a fuel cell

Lithium-Ion Batteries

Battery technology has also advanced significantly to keep up with the development of computers. From nickel-cadmium (NiCd), which is utilized for mobile computing and wireless communications, to nickel metal hydride (NiMH), and ultimately to high-capacity Li-ion batteries. The challenge for developing new-generation Li-ion batteries depend on the advancement of electrodes and electrolytes which can withstand hundreds of charge-discharge cycles with minimum capacity fading. The challenge for developing new generation Li-ion batteries depends on the advancement of electrodes and electrolytes which can withstand hundreds of charge-discharge cycles with minimum capacity fading. Depending on whether the battery is charging or discharging, Li-ions are intercalated and de-intercalated into the anode and cathode of the Li-ion battery cell. The mobility of the Li-ions that are exchanged between the electrodes through electrolytes and the flow of electrons in the external circuits determine whether the electrodes are charging or discharging. Li-ion batteries are in greater demand because of their high volumetric energy, high power density, low self-discharge, and extended cycle life [102, 103].

Illustrations are not included in the reading sample

Figure 4: Schematic diagram of Lithium-ion Battery

It is therefore crucial to consider the cause of the enhancement in nanomaterial-based energy storage devices' performance. When bulk materials are switched to nanoscale materials, the efficiency of the energy storage or conversion devices increases significantly because the electrode/electrolyte contact area increases and increases the rate of electrode reactions.

The density of mobile defects at the space charge region increases with a rise in interfacial area and grain boundaries, ultimately endowing the nanomaterials with exceptional electrochemical characteristics.

Conclusion And Future Perspectives

Supercapacitors, fuel cells, solar cells, and Li-ion batteries are examples of innovative, cutting-edge energy storage technologies that have been developed in response to the growing demand for clean, renewable energy for the next generation of sustainable societies. Conducting polymers and carbon nanomaterials like graphene and carbon nanotubes have managed to establish a strong foothold in the field of energy storage devices. Nevertheless, there are many obstacles in the way of expanding and commercializing these nanomaterial-infused energy generation and storage technologies. Consequently, current research has concentrated on employing CNTs and graphene to enhance the effectiveness and performance of these devices. Conducting polymer composites based on graphene and CNTs are thought to be a promising option for next-generation solar cells. Although these polymer composites are inexpensive, quickly made, and flexible, their use in solar cells is currently limited by the acceptor-donor issue with conducting polymers. CNTs and graphene are excellent candidates for use in solar cells due to their effective photon-absorbing capacity, capacity to produce photocarriers, strong photovoltaic characteristics, and ability to segregate charge carriers to form heterojunctions with conducting polymers. Supercapacitors are more powerful than regular batteries, but they have lower energy densities overall. It has been discovered that a supercapacitor's capacitance depends on several additional parameters in addition to the specific surface area of the CNTs, including the synthesis, pore size, pore size distribution, and posttreatment of the CNTs.

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Chapter 3 Tert -amino effect: Synthesis of nitrogen heterocycles

Dr. Biswajita Baruah

Department of Chemistry, Pandu College, Ghy-12, Assam

E-mail: [e-mail]

Abstract

This article explores the novel application of the tert -amino effect in the synthesis of nitrogen-containing heterocycles. By leveraging the unique reactivity of tert -amino groups, the study demonstrates a highly efficient method for constructing a diverse range of nitrogen heterocycles, which are crucial in pharmaceuticals and material science. The research highlights the mechanism behind the tert -amino effect and its impact on reaction pathways, offering a detailed analysis of how this effect facilitates the formation of various heterocyclic compounds. The findings provide valuable insights into optimizing synthetic routes and expanding the scope of heterocyclic chemistry.

Keywords: heterocyclic chemistry, tert -amino effect, pharmaceuticals, nitrogen

Top of FormBottom of Form

Introductions

The tert-amino effect is an important concept in organic chemistry that describes the unique reactivity of tertiary amines (tert -amino groups) when positioned near electron-withdrawing groups, such as double or triple bonds. This phenomenon is characterized by the ability of the tertiary amine's lone pair of electrons to participate in nucleophilic attacks, leading to a variety of structural rearrangements and cyclization reactions. Meth-Cohn and Suschizky [1] introduced the term "tert -amino effect" to describe the cyclization reactions of some ortho-substituted N,N-dialkylanilines in a more broad way. There are three possible approaches to ring closure of ortho-substituted N,Ndialkylaniline derivatives, depending on the characteristics of A=B (Scheme 1). Ring closure occurs in the initial path (a) between the tert -nitrogen atom and the ortho-substituted. The reactions that involve one of the α-methylene groups connected to atom A are included in the second path (b), which finally results in the production of five-membered rings. A six-membered ring was formed via a similar reaction between methylene groups and atom B in the third channel (c). Pinnow [2] recorded the first reaction of this kind in 1895. When compounds with unsaturated ortho substitutes react, the majority of the early instances feature groups containing one or more heteroatoms, such as nitroso [3], nitro [4-5], azo [6], amine [7], azomethine [8–10], carbonyl [11–13], or thiocarbonyl moieties as the ortho substituents [14].

The tert -amino effect and related 1,5- hydride transfer/subsequent ring closure have attracted much attention due to its unique features to afford N-heterocycles. These reactions, in particular, are the most concerning because of their remarkable step/atom economy and high efficiency, which have drawn a lot of attention due to their dependable capability.

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The field of nitrogen-based heterocyclic chemistry is a distinct and valuable area within the applied fields of organic chemistry. A substantial portion of this field's research is focused on creating new compounds and composites. Over the past 20 years, these molecules have drawn more and more attention. Numerous organic synthesis methods have been developed with their assistance, and they have found extensive applications in the chemical sciences [15-19]. Numerous widely distributed N-heterocyclic compounds in nature have physiological and pharmacological characteristics and are building blocks of numerous biologically significant molecules, such as vitamins, nucleic acids, medications, dyes, agrochemicals, and antibiotics [20-24]. They also play a crucial role in the synthesis of numerous pharmacologically active compounds. N-heterocyclic substances such as purines, pyrimidines, etc. are also constituents of the base pairs of DNA and RNA, which are guanine, cytosine, adenine, and thymine. The rapidly developing domains of organic and medicinal chemistry, as well as the pharmaceutical business, have given rise to the popularity of these nitrogen-containing heterocyclic compounds with unique properties and uses [25-27]. Moreover, the electron-rich nitrogen heterocycle can easily form a variety of weak interactions in addition to being able to take or donate a proton with ease. Certain intermolecular forces, like the formation of hydrogen bonds, dipole-dipole interactions, hydrophobic effects, van der Waals forces, and π-stacking interactions of nitrogen compounds, have made nitrogen compounds more important in medicinal chemistry because they enable them to bind with a wide range of biological targets' enzymes and receptors. The structural features of their derivatives are beneficial since they exhibit broad bioactivities.

Through the tert -amino effect-promoted rearrangement of isothiocyanate derivatives, Xinyu Xeng et. al. developed a novel and effective process for the synthesis of benzimidazothiazepines and benzimidazothioethers [28]. The desired product might be made on a gram scale, and the reaction has a broad scope with total atom economy. Notably, a straightforward oxidation process can easily transform the end product into the benzimidazothiazepine dioxide species. Furthermore, this reaction expanded on the idea of tert -amino effect reactions that occur without a hydride transfer event and react at the tertiary nitrogen center.

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To optimize the reaction conditions, 1-(2-isothiocyanatophenyl)pyrrolidine was first chosen as a model substrate. Initial research on the catalyst was done using xylene as the solvent under reflux. The result indicated that in the absence of a catalyst, no reaction took place. However, the expected benzimidazothiazepine product 2a was produced in 67% yield when Sc(OTf)3 was employed as a Lewis acid catalyst. Motivated by this outcome, the authors proceeded to examine numerous other metal triflates; nevertheless, none of them outperformed the initial Sc(OTf)3.

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The authors explored different substrate scopes and established that this transition can generally withstand a wide variety of substrates, and a wide range of benzimidazo[1,3]thiazepines can be generated. Smooth reactions between isothiocyanates with different electron-donating (methyl, methoxy, amine) and electron-withdrawing (halogen, trifluoromethyl) groups on the phenyl ring produced the target products 2b - 2o in good to high yields (60–98%) (Scheme 3). Notably, the electron-withdrawing group typically displayed high reaction efficiency.

Prajapati et. al. reported the synthesis of new fused pyrazolinoquinolizine and 1,4-oxazinopyrazoline derivatives by using a tertiary amine effect strategy (Scheme 4) [29]. A variety of fused heterocycles is obtained by the Knoevenagel condensation of 5- tert- amino-3-methyl-1-phenylpyrazolone-4-carboxal-dehyde with active methylene compounds such as malononitrile and cyanoacetamide followed by cyclization using anhydrous zinc chloride. 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde 2 was the model compound employed in this work. It had previously been produced via chloroformylation of pyrazolone 1 under Vilsmeier conditions. Since nucleophiles can easily replace the 5-chloro atom in 2, the reaction with several cyclic sec-amines, such as pyrrolidine, piperidine, and morpholine, produced a smooth conversion to the 5- tert -amino derivatives 3. The corresponding pyrazolin-5-ylmethylenemalononitriles 4a were then obtained by using these in the Knoevenagel condensation reactions with malononitrile. These cyclized in the presence of anhydrous zinc chloride to yield the corresponding pyrazolinoquinolizines 6a and 1,4-oxazinopyrazolines 6e in refluxing toluene.

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The plausible mechanism of the reaction is given in Scheme 5. The reaction continues with the Knoevenagel products 4 in the rate-determining phase undergoing a 1,5(4 →5) hydride shift before cyclization to generate a 6-membered ring product 6, despite their inability to isolate any intermediates.

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The first instance of a catalytic enantioselective hydride shift/ring closure reaction cascade was disclosed by Sandip Murarka and his colleagues [30]. High levels of enantioselectivity and good yields are produced from ring-fused tetrahydroquinolines (Scheme 6).

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The extent of the reaction was investigated at the optimal conditions. On the fundamental substrate framework, several substitution patterns are well tolerated (products 2a - e). Starting materials made from b-carboline and N-Me-b-carboline underwent a successful rearrangement to produce products 2f and 2g with great stereoselectivity and good yields. Good yields were obtained for products 2h and 2i, which contain seven- or eight-membered azacycles, but their enantio- and diastereoselectivity were diminished (Scheme 6).

Employing the tertiary amino effect reaction approach, Baruah and colleagues reported the synthesis of a number of novel classes of spirosubstituted pyrido[2,3-d]pyrimidines (Scheme 7) [31].

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The reaction's generality was established by synthesizing a range of cyclic and acyclic tertiary amino uracil derivatives 2a–d from 1, and combining them with N,N-dimethylbarbituric acid/N-methylbarbituric acid 4a–b under thermal conditions with ethanol as solvent and diisopropylethylamine as a base, This produced a good to the excellent yield of diverse annelated spirosubstituted pyrido[2,3-d]pyrimidines 5b–h. The elemental analysis and spectroscopic data allowed for the determination of the compounds' structures. The results of the investigation showed that 6-pyrrolidinouracils have relatively high reactivity and excellent product yields. The least reactive, however, are 6-morpholino uracils, and the product yields are poor.

The first organocatalytic synthesis of tetrahydroquinoline derivatives using 1,5-hydride transfer/ring closure sequences was disclosed (Scheme 8).

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The usage of organocatalysts in the transformation of 1 to 2 was examined by the author. They hypothesized that derivatives of cinnamon aldehyde 1 serve as excellent acceptors since they can be activated by secondary amine catalysts that can produce iminium ion A. It is anticipated that this iminium ion activation will boost the hydroxide transfer to alkene (Scheme 8).

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Seidel and co-workers developed a synthesis of cyclic aminals by “ tert-amino effect ” strategy catalyzed by Brønsted acids (Scheme 9) [32]. The aminobenzaldehyde was treated with amines (aniline or benzylamine) in the presence of various Brønsted and Lewis acids in diverse solvents and temperatures to successfully form cyclic aminals. When aniline was used, triflic acid (TfOH 20 mol %) in EtOH under refluxing conditions provided the best yield. Other aromatic amines with different substituents and heterocyclic amines gave a modest yield of products. Interestingly, when 4-cyanoaniline was used, the reaction proceeded at room temperature with a 50% yield.

The use of heterocyclic amines such as 2-aminopyridine formed a lower yield, which might be due to the available multiple protonation sites, interfering with the catalytic process. However, 1.2 equiv. of trifluoroacetic acid (TFA) in EtOH was required in refluxing conditions when benzylamine was used in the reaction. Other aliphatic amines also provided reasonable yield under this condition. The reaction was then performed with α-methylbenzylamine which offered a mixture of diastereomers, and with tryptamine gave a mixture of the normal desired product along with the major product resulting from the Pictet-Spengler reaction. Aminobenzaldehydes having cyclic amines with benzylic α-C-H bonds were mostly found reactive. 1,3-Dibenzyl-2-phenyl-1,2,3,4-tetrahydroquinazoline obtained from 2-(dibenzylamino)benzaldehyde formed the product in low yield due to the instability of the product formed. An interesting reaction of 2-pyrrolidinyl acetophenones with 4-bromoaniline furnished a mixture of diastereomers proving aminoacetophenones to be a feasible substrate for the transformation.

In the probable mechanism, the o -aminobenzaldehyde first forms the iminium ion intermediate A in the presence of the acid which after 1,5-hydride shift gives intermediate B. Finally, the elimination of a proton furnished the cyclic aminal product (Scheme 10).

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Akiyama and his team synthesized quinazolines in refluxing benzene using p -toluenesulfonic acid (p -TSA) as a catalyst in 2009 (Scheme 11) [33]. The reaction gave a reasonable yield of products when various substituted anilines were employed. However, the o -substituted anilines gave a lower yield due to steric hindrance. When aliphatic cyclic amines were used in o -formylamine component, products were obtained at higher temperatures (under reflux in toluene) which is due to the reduced 1,5-hydride transfer ability of these substrates.

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Zhi et. al. disclosed an interesting synthesis of oxadiazepine derivatives via 1,5-hydride shift/cyclization of cyclic amine (it may be pyrrolidine- or tetrahydroisoquinoline) having nitrone moiety (Scheme 12) [34]. The reaction was

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performed in dichloroethane (DCE) solvent catalyzed by Lewis acid AlCl3 under heating conditions. Different substituted nitrones were employed in the reaction which produced a good yield except when nitro-substituted nitrone was used which gave only a 20% yield. Nitrones containing amine moieties such as piperidine and morpholine did not react under these conditions. A one-pot reaction was also carried out by reacting 2-(pyrrolidin-1-yl)benzaldehyde and N-arylhydroxylamine generating nitrone in situ, furnishing the desired product but in a little lower yield. A plausible mechanism is depicted in which a [1,5]-hydride shift takes place in the nitrone, generating an intermediate iminium ion. Then an intramolecular attack occurs by the oxygen anion of the nitrone to iminium carbon forming the desired cyclized product (Scheme 13).

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Conclusions

The tert -amino effect represents a significant and versatile tool in the field of organic chemistry, particularly in the synthesis of complex molecules. By leveraging the unique reactivity of tertiary amines in the presence of electron-withdrawing groups, chemists can induce a range of rearrangements, cyclizations, and other transformations that might otherwise be challenging to achieve. This effect is especially valuable in the synthesis of heterocyclic compounds, which are crucial components in a wide variety of biologically active molecules, including pharmaceuticals and agrochemicals. The ability to form pyrroles, indoles, and other nitrogen-containing rings efficiently through the tert -amino effect has made it a cornerstone in medicinal chemistry, where the rapid construction of complex molecular frameworks is often required. Moreover, the tert -amino effect has found applications beyond just molecule construction. Its influence extends into materials science, where new functional materials can be created, often with unique electronic, optical, or mechanical properties due to the specific structures generated through this effect. The ongoing exploration and utilization of this effect continue to open new avenues for innovation, pushing the boundaries of what can be achieved in molecular design and synthesis.

References

1. Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem. 1972, 14, 211.

2. Pinnow, J. Ber. Dtsch. Chem. Ges. 1895, 28, 3039.

3. Seebach, D.; Enders, D. Angew. Chem. 1975, 87, 1.

4. Fielden, R.; Meth-Cohn, O.; Suschizky, H. J. Chem. Soc., Perkin Trans. I, 1973, 696.

5. Gluhareva, T.V.; Morzherin, Yu.Yu.; Mokrushin, V.S. Chem. Heterocycl. Comp. (Engl. Transl.) 2000, 36, 107.

6. Kirschke, K.; Möller, A.; Schmitz, E.; Kuban, R.J.; Schulz, B. Tetrahedon Lett. 1986, 27, 4281.

7. Martin, J.; Meth-Cohn, O.; Suschitzky, H. Tetrahedron Lett. 1973, 4495.

8. Tea Gokou, C.; Pradere, J.P.; Qiuniou, H. Synth. Commun. 1986, 16, 79.

9. Akiba, M.; Kosugi, Y.; Takada, T. J. Org. Chem. 1978, 43, 4472.

10. Suschitzky, H.; Walrond, R.E.; Hull, R. J . Chem. Soc., Perkin Trans. I, 1977, 47.

11. Falci, K.J.; Franck, R.W.; Smith, G.P. J. Org. Chem. 1977, 42, 3317.

12. Fokin, E.P.; Russkikh, V.V. Zhur.Org. Khim. 1966, 2, 907.

13. Nijuis, W.H.N.; Verboom, W.; Harkema, S.; Reinhoudt, R. Recl. Trav. Chim. Pays-Bas 1989, 108, 147.

14. Verboom, W.; Reinhoudt, D.N. Rec. Trav. Chim. Pay-Bas 1990, 109, 311.

15. Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. J. Org. Chem. 2013, 78, 3636–3646.

16. Santos, C.M.M.; Freitas, M.; Fernandes, E. Eur. J. Med. Chem. 2018, 157, 1460–1479.

17. Kalaria, P.N.; Karad, S.C.; Raval, D.K. Eur. J. Med. Chem. 2018, 158, 917–936.

18. Kerru, N.; Bhaskaruni, S.V.H.S.; Gummidi, L.; Maddila, S.N.; Maddila, S.; Jonnalagadda, S.B. Synth. Commun. 2019, 49, 2437–2459.

19. Kerru, N.; Singh, P.; Koorbanally, N.; Raj, R.; Kumar, V. Eur. J. Med. Chem. 2017, 142, 179–212.

20. Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013, 113, 2958–3043.

21. Kerru, N.; Maddila, S.; Jonnalagadda, S.B. Curr. Org. Chem. 2019, 23, 3156–3192.

22. Ju, Y.; Varma, R.S. J. Org. Chem. 2006, 71, 135–141.

23. Zarate, D.Z.; Aguilar, R.; Hernandez-Benitez, R.I.; Labarrios, E.M.; Delgado, F.; Tamariz, J. Tetrahedron 2015, 71, 6961–6978.

24. Leeson, P.D.; Springthorpe, B. Nat. Rev. Drug Discov. 2007, 6, 881–890.

25. Fang, W.Y.; Ravindar, L.; Rakesh, K.P.; Manukumar, H.M.; Shantharam, C.S.; Alharbi, N.S.; Qin, H.L. Eur. J. Med. Chem. 2019, 173, 117–153.

26. Kerru, N.; Singh-Pillay, A.; Awolade, P.; Singh, P. Eur. J. Med. Chem. 2018, 152, 436–488.

27. Smith, B.R.; Eastman, C.M.; Njardarson, J.T. J. Med. Chem. 2014, 57, 9764–9773.

28. Geng, X.; Liu, S.; Wang, W.; Qu, J.; Wang, B. J. Org. Chem. 2020, 85, 12635-12643.

29. Prajapati, D.; Borah, K.J. Beilstein. J. Org. Chem. 2007, 3, 43, doi:10.1186/1860-5397-3-43.

30. Murarka, S.; Deb, I.; Zhang, C.; Seidei, D. J. Am. Chem. Soc. 2009, 131, 13226–13227

31. Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2009, 50, 243–245.

32. Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem., 2009, 74, 419-422.

33. Mori, K.; Ohshima, Y.; Ehara, K.; Akiyama, T. Chem. Lett., 2009, 38, 524-525.

34. Chang, Y.-Z.; Li, M.-L.; Zhao, W.-F.; Wen, X.; Sun, H.; Xu, Q.-L. J. Org. Chem., 2015, 80, 9620-9627.

Chapter 4 Assessment of Antioxidant Potential of some Indigenous Medicinal Vegetables of North East India

Dr. Manas Pratim Boruah

Department of Chemistry, Dhemaji College, Dhemaji-787057 Assam, India

E-mail: [e-mail]

Abstract

Radical scavenging abilities of three indigenous leafy vegetables of North East India viz., Polygonum microcephallum D. Don, Oxalis corniculata and an unidentified Achyranthes species have been assessed by DPPH radical scavenging method. On calculating % inhibition, it was observed that among hexane, ethylacetate and methanol extracts, the methanol extracts of all have shown the highest radical scavenging activity.

Keywords: Indigenous medicinal vegetables, antioxidant potential, DPPH, radical scavenging abilities.

Introduction

Oxidative stress, caused by free radicals and other reactive oxygen species (ROS) such as singlet oxygen, superoxide radicals, hydroxyl radicals and hydrogen peroxide which are inevitable by-products of physiological redox reactions, is now considered as the main etiological agent involved in the progressive deterioration of cell structures. ROS may modify all biological molecules. The main consequences of oxidative stress are lipid peroxidation, protein oxidation and DNA damage (Maciejewaska et al, 2002). Oxidative damages mediate the pathogenesis of many chronic diseases, such as atherosclerosis, Parkinson’s diseases, Alzheimer’s diseases, cancers and other degenerative diseases (Halliwell & Grootyeld, 1987; Lim & Murtijaya, 2007; Aruoma, 1994; Gerber, Boutson-Ruault, Hercberg, Riboli, Scalber. & Siess, 2002; Kris-Etherton, Hecker, Bonanome, Coral, Brinksoki, Hilpert et al,2002; Seratini, Bellocco, Wolk & Ekstrom, 2002 and Di Matteo & Esposito, 2003). Under normal circumstances, natural antioxidants defenses e.g., glutathione peroxidase catalase and superoxide dismutase (SOD) (Cadenas & Packer,1996) etc. are sufficient neutralize ROS and there is a balance between prooxidant and antioxidant. However, when there is an imbalance between these two, resulting in “Oxidative Stress”, dietary antioxidants including food additives are required (Chan, Lim, Wong, Lim, Tan, Lianto and Yang, 2009).

Antioxidants are not only produced by our body to combat ROS but are also important as food additives. They can either be synthetic or naturally occurring. Many synthetic antioxidants possess carcinogenic activity,so natural antioxidants are getting importance as they are safer and also possess antiviral, anti-inflammatory, anti-cancer, antimutagenic, anti-tumour and hepatoprotective properties (Kris-Etherton et al, 2002; Madsen & Berteslen,1995 ). Natural antioxidants have already been isolated from plant materials like leafy vegetables, fruits, seeds, cereals and algae (Pokorny, 1991). Fruits and vegetables having different antioxidant compounds such as vitamin C, vitamin E and carotenoids; whose activities have been established in recent years. Flavonoids and other phenolic compounds present in foods of plant origin are also potential antioxidants (Salah, Milar, Paganga, Tijburg, Bolwell & Rice-Even, 1996). The antioxidants preserve an adequate function of immune cells against homeostatic disturbances (De la Fuenta & Victor, 2000). Metabolic activation of carcinogen is a free radical dependent reaction. DNA damage, caused by free radicals, plays a critical role in carcinogenesis (Feig, Reid & Loeb, 1994; Guylon & Kensler, 1993). The potentially cancer-inducing oxidative damage might be prevented or limited by dietary antioxidants found in fruits and vegetables (Dasgupta & De, 2006). The phytochemicals in common fruits and vegetables can have complementary and overlapping mechanism of action, including scavenging of oxidative agents, stimulation of the immune system, regulation of gene expression in cell proliferation and apoptosis, hormone metabolism and antibacterial and antiviral effects (Waladkhani & Clemens, 1998).

North East India is a home for a large number of medicinal plants. People of this region have diverse food habits, which include many medicinal vegetables and preserved food items. Some of these plants are used not just in case of specific diseases, but also as good for general health. This type of plants has not attracted much attention of researchers, but it is pertinent to study their antioxidant activities, as these are believed to enhance resistance to various diseases. During the present study, we have evaluated the antioxidant potential of various leafy vegetables used by the people of Upper Assam.

Materials and methods

Plant materials

The leafy vegetables were collected from their natural habitats from nearby areas of Dhemaji College, Assam. The freshly cut plants were sorted out and shade dried for few days and then at 60[0] in an oven and kept in a dessicator. For these also, the plant parts were collected from nearby areas of Dhemaji College. These have also been dried in shade first and then at 60[0] in an oven. Details of the plants/ plant parts/ preserved form and traditional uses are given in Table-1.

Table - 1: Plants and plant products used for the study

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Reagents

Folin-Ciocalteu reagent, 1, 4-diaminobenzene, 1, 1-diphenyl-2-picryl hydrazyl (DPPH) was purchased from Sigma Chemicals. Hexane, ethylacetate and methanol were of AR grade of RANKEM. All solvents were purified prior to use according to standard procedure.

Extraction

100g of each of the dried plants were made into powder form. 10g of dried powder was extracted with three solvents, hexane, ethyl acetate and methanol respectively. This extraction was carried out with the help of Soxhlet apparatus. The extracts were concentrated in rotavapor apparatus (Buchi, Fiawil, Switzerland) at approximately 40[0]c.

Evaluation of antioxidant activity by DPPH radical scavenging assay

Radical scavenging effects of all the plant extracts on DPPH radical (Sigma-Aldrich Chemie, Steinheim, and Germany) have been recorded using UV-Visible spectrophotometer. When 1, 1-diphenyl-2-picryl hydrazyl (DPPH), a purple-coloured, stable free radical reacts with an antioxidant, it is reduced and the purple-coloured free radical is then changed to the yellow-coloured 1, 1-diphenyl-2-picrylhydrazine. The experiments were performed in the following way (Brand-Williams et al, 1995; Molyneux, P., 2004)

The stock solution of the extracts was prepared by dissolving 300 mg of crude dry extract in 10 ml of methanol. The solution of 0.004 g of 1, 1-diphenyl picryl hydrazyl (DPPH) in 10 ml (~1 mM) of methanol was prepared daily, before UV measurement. From this stock solution, for each measurement, 200 ml of DPPH stock solution was taken and made up to 3 ml by adding methanol to make a test solution (0.07 mM). The absorbance of the test solution is recorded at 517 nm. Antioxidant effect of plant extract is studied by adding 100 ml, 200 ml and 300 ml of the stock solution of the extract, separately to a test solution of DPPH. The solutions were kept in dark for 15 min., 30 min., and 1 h respectively at room temperature and then the decrease in absorption was measured. Absorption of blank solution containing the same amount of DPPH in methanol was recorded daily. Radical scavenging activity was calculated by the following formula – % inhibition = [(A_B-A_A)/A_B] X 100

Where A_B = absorption of blank samples (t = 0 min.)

A_B = absorption of tested extract solution (t = 15 min, 30 min and 1 hr)

Preliminary screening of phenolic contents

To determine the presence of polyphenols in the plant, Folin Ciocalteu Test has been performed. The test was performed as follows.

Folin-Ciocalteu Test for polyphenols

5 ml of each of hexane, ethylacetate and methanol solution of plant extract was taken in a test tube separately and added Folin-ciocalteu reagent and NaOH (30 %) to each test tube. Shaked well and stood for few minutes. The presence of phenol developed a blue colour.

Results and discussion

The results of DPPH[0] inhibition (%) by different medicinal vegetables and by different preserved food additives were summarized in Table-2 and Table-3 respectively.

Table-2 presents the results of DPPH radical scavenging activity of three leafy medicinal vegetables using three different solvents, viz., hexane, ethyl acetate (EtOAc) and methanol (MeOH) respectively. From the Table, it was observed that the methanol extracts of all showed highest DPPH radical scavenging activity. The methanol extracts of these leafy vegetables almost completely inhibited DPPH absorption. (O. corniculata- 88.27%, A. species- 96.78% and P. microcephallum- 92.62%). These percentages can be considered as a full absorption inhibition of DPPH, because after completing the reaction, the final solution always possesses same yellowish colour and therefore its absorption inhibition compared to colourless methanol solution can’t reach 100%.

Ethyl acetate and hexane extracts were considerably less effective radical scavengers compared to methanolic extracts. Ethyl acetate extracts were found to be more active against the DPPH radical than that of hexane extracts.

The results provided in the Table-2 demonstrate that among the leafy medicinal vegetables, the highest antiradical activity was exhibited by the Achyranthes species and the activity was highest in the methanol extract (Fig-1).

Table-2: (%) inhibition of DPPH[0] of leafy medicinal vegetables extracts (at 30 min.) with standard deviation (SD)

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Fig-1: Graphical representation of Antioxidant activity of different plant extracts

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Preliminary screening for phenolic contents

In all the plant samples under investigation, presence of phenolic contents is observed. Again, in the methanol extracts of the plant samples the test was intensely positive (Table 4).

Table 4: Presence of phenolic contents in plant materials

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+ = responded to the test feebly, ++ = positive response is observed

+++ = intensely positive response

Conclusion

The results of this study showed that the methanol extract of each of the sample showed presence of phenolic contents. The samples under study have significantly high antiradical activity on DPPH radical. In all but one sample methanol extract has the highest antiradical activity. So, in these cases phenolic contents might be the main responsible for the antioxidant activity.

Reference

Aruoma, O. I., (1994). Nutrition and health aspects of free radicals and antioxidants. Food and Chemical Toxicology, 32, 671-683.

Brand–Williams, W., Cuvelier, M. E. and Berset, C. (1995). Lebensm – Wiss. Technol, 28, 25-30.

Cadenas, E. & Packer, L. (2002). Handbook of antioxidants. New York; Mercel Dekker.

Dasgupta, N. and De, B. (2007). Antioxidant activity of some leafy vegetables of India. A comparative study. Food Chem. 101, 471-474.

De la Fuenta, M. & Victor, M. (2000). Antioxidants as modulators of immune function. Immunology and Cell Biology, 78, 49-54.

Di Matteo V. & Esposito E. (2003) Biochemical and therapeutic effect of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease and amyotropik lateral sclerosis. Current Drug Target CN, and Neurological Disorder. 2: 95-107.

Fieg, D. I., Reid, T. M. & Loeb, L. A. (1994). Reactiv oxygen species in tumorigenesis. Cancer Research, 54(Supply 7), 1890-1894.

Gerber M., Boutson-Ruault M. C., Hercberg S., Riboli E., Scalber A. & Siess M. H. (2002). Food and cancer: state of the art about the protective effect of fruits & vegetables. Bulletin du Cancer. 89(3) 293-312.

Guylon, K. Z. & Kensler, T. W. (1993). Oxidative mechanism in carmogenesis. British Medical Bulletin, 49, 523-544.

Halliwel B. and Grootveld M. (1987). The measurement of free radical reactions in humans. FEBS Letters. 213, 9-14.

Kris-Etherton P. M., Hecker K. D., Bonanome A., Coral S. M., Brinksoki A.E., Hilpert K.F., et al (2002). Bioactive compounds in foods, their role in the prevention of cardiovascular diseases and cancer. American Journal of Medicine. 113 (9B), 715-885.

Lim Y. Y., Murtijaya.(2007). Antioxidant properties of Phyllanthus Amorus extracts as affected by different drying method. Food Chem, 40, 1664-1669

Maciejewska, V., Polkowska-Kowalezyle, L., Swiezewska, E. and Szhokopinska, A. (2002). Plastoquinone: possible involvement in plant disease resistance. Acta Biochemica Polonica, 49, 775-780.

Madsen H. & Bertelsen G. (1995). Spices as antioxidants. Trends in Food Science & Technology. 6: 271-277

Molyneux, P. (2004). The use of the stable free radical diphenylpicrylhydrazyl (DPPH) for estimating antioxidant activity. Songklanakarin. J. Sci. Technol, 26(2): 211-219.

Pokorny J. (1991). Natural antioxidants for food use. Trends in Food Science & Technology. 2: 233-227.

Salah N. Miller N J., Paganga G., Tijburg J., Bolwell G. P., & Rice-Even C. (1995). Polyphenolic flavonols as scavenging of aqueous phase radicals and as chain-breaking antioxidants. Archieves of Biochemistry and Biophysics. 322(2). 339-346.

Seratini M., Bellocco R., Wolk A. & Ekstrom A.M. (2002). Total antioxidant potential of fruits and vegetables and risk of gastric cancer. Gastroenterology. 123 (4) 985-991.

Van Acker S. A. B.E., Van den Vijgh W. J. F. & Bast F. (1996). Structure of antioxidant activity of flavonoids . Free Radical Biology and Medicine. 20 (3), 331-342.

Waladkhani, A., & Clemens, M. R. (1998). Effect of dietary phytochemicals on cancer development. International Journal of Moleculer Medicine, 7, 747-753.

Chapter 5 A facile method for synthesis of triazoles using copper nano particles supported on Montmorillonite

Dr. Mitali Chetia

Department of Chemistry, Moridhal College

E-mail: [e-mail]

Abstract

Cu Nanoparticles immobilized on Montmorillonite by ionic liquid have been used in azide-alkyne cycloaddition reaction. MMT possesses negatively charged, two-dimensional silicate sheets that are separated by interlayer cationic species, and ILs are composed entirely of ions. Therefore the combination of the two may provide a new way to prepare highly efficient catalysts. The catalytic system results in very excellent yields of 1,4-disubstituted 1,2,3-triazoles from the cycloaddition of various azides and alkynes.

Illustrations are not included in the reading sample

Keywords: Montmorillonite, Ionic liquid, Water, room temperature, copper nanoparticles

Introduction

Montmorillonite (MMT) is one type of naturally occurring clay which can be structurally defined as layers of negatively charged two-dimensional silicate sheets that are separated by interlayer cationic species with a high exchange ability for other cations.[1] Such layered materials have been used as host materials for the preparation of composites and have potential applications in catalysis, separation, and the optical and electrical fields.[2] For MMT-based catalysts, the catalytic nanoparticles are generally intercalated into the interlayer spaces or deposited on the outer surfaces of MMT with the aid of surfactants or polymers.[3],[4]

In recent years, room-temperature ionic liquids (ILs) have attracted much attention due to their unusual properties, especially their extremely low vapor pressure, high thermal and good chemical stability, and excellent solvent power for organic and inorganic compounds, and they have been widely utilized as environmentally benign solvents for different processes, including chemical reactions[5] and separations.[6] ILs are also attractive media to stabilize metal nanoparticles.[7] In a literature, Pd nanoparticles immobilized on the molecular sieve SBA-15 by 1,1,3,3-tetramethylguanidinium lactate have been found to exhibit high catalytic activity for hydrogenation reactions.[8]

In 2006, Shiding Miao and co-workers reported a highly efficient heterogeneous catalyst for the hydrogenation of benzene where, Ru nanoparticles were immobilized on montmorillonite by ionic liquids.[9]

We have developed copper nanoparticles immobilised on montmorillonite K10 clay by [BMIM]OH ionic liquid and applied this composite as a heterogeneous catalyst for the synthesis of 1,2,3-triazoles from azide-alkyne cycloaddition reaction.

Preparation of the catalyst

For the preparation of the catalyst, at first the ionic liquid was prepared and then copper was immobilised on IL-MMT composite.

Synthesis of 1-Butyl-3-methylimidazolium hydroxide, [Bmim]OH ionic liquid

[Bmim]OH is a basic ionic liquid and it can be prepared in two steps. In the first step, 1-methyl imidazole (10 ml, 125.46 mmol) and 1-bromobutane (20ml, 192.29 mmol) were mixed in a round bottom flask and stirred at 70 [0]C for 48 hours. The reaction mixture was heated until two phases were formed. The top phase, containing the unreacted starting material was decanted and ethyl acetate was added to the vessel. The reaction mixture was washed with ethyl acetate thrice. This results in the formation of slightly yellow product, i.e. [Bmim]Br ionic liquid.

Then, to a solution of [Bmim]Br (17.6 g, 80 mmol) in methylene chloride (50 mL), potassium hydroxide (4.6 g, 80 mmol) was added and the mixture was stirred vigorously at room temperature for 10 h. The reaction mixture was then filtered, and the filtrate was evaporated to obtain the crude [Bmim]OH. The crude product was washed with diethyl ether (2x20 mL) and dried at 90 [0]C for 10h yielding [Bmim]OH as a brown viscous liquid.

Illustrations are not included in the reading sample

Scheme 1: Synthesis of [Bmim]OH ionic liquid

Immobilisation of copper on IL-MMT support

To prepare the catalyst about 1.0 g of MMT was dispersed in an aqueous solution of the [Bmim]OH IL by stirring for about 4 h. The molar ratio of IL to MMT was 1.1:1. The MMT was then separated from the solution by centrifugation and was treated again with an aqueous solution of the IL. This procedure was repeated three times. The IL-exchanged MMT was then washed several times with distilled water. Then to a water solution of the prepared product (IL-MMT), CuSO4 was added and stirred at room temperature for half an hour. Now, 50% solution of hydrazine hydrate was added to it for half an hour and the reaction was allowed to run at room temperature for 3h. The prepared catalyst was now washed with water several times and collected by centrifugation. The catalyst was characterised by different analysis.

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Figure 2: Preparation of the catalyst

Results and discussion

We applied this supported heterogeneous catalyst for carrying out CuAAC reactions leading to the regioselective formation of 1,2,3-triazoles.

Cycloaddition of various azides and alkynes with our condition

After the determination of the best reaction condition, CuAAC reactions were carried out with various azides and alkynes. Under this reaction condition, various alkynes, both aromatic and aliphatic, react with different azides to afford 1,2,3-triazoles in good to excellent yields.

Table 1. Scope of cycloaddition reaction of different azides and alkynesa

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Reagents and reaction conditions: azide (1 mmol), alkyne (1.1 mmol), catalyst (25 mg, 1.18 mol%) in 3 ml water at room temperature

Recyclability of the catalyst

For the useful applications of heterogeneous systems, the lifetime of the catalyst and its level of reusability are highly significant factors. To determine whether our catalyst fulfils its applicability or not, a set of experiments were performed for the cycloaddition of phenyl azide and phenylacetylene using the recycled Cu@IL-MMT catalyst. After the completion of the first reaction, the product was extracted and the catalyst was recovered easily by centrifugation. A fresh reaction was then performed with new reactants under the same conditions. The results obtained in our experiment confirmed that it was possible to recycle and reuse the catalytic system for a minimum of four cycles without losing any catalytic activity.

Experiment for examining the heterogeneity of the catalyst

To establish the heterogeneity of the catalyst, the following technique was used, which confirmed that during the reaction progression, metal loss from the solid surface to the reaction medium did not occur. To perform this test, an experiment was carried out for the cycloaddition of benzyl azide (1 mmol) and phenyl acetylene (1.1 mmol) in the presence of the catalyst using water as the solvent. The reaction was allowed to run for 15 minutes. The reaction progression was then noted, and the catalyst was removed from the reaction mixture. The catalyst free reaction mixture was then allowed to run for an additional 15 minutes. It was observed that there was no reaction progress after the removal of the catalyst, which clarifies that our catalyst does not undergo any loss of metal from the solid support during the reaction, proving its useful applicability to a wide extent.

Table 2: Recyclability of the catalyst

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Conclusions

We have developed copper immobilised on montmorillonite clay by ionic liquid which can serve as an efficient heterogeneous catalyst for the cycloaddition of azides and alkynes in order to form the important and useful heterocyclic compound 1,4-disubstituted 1,2,3-triazoles. It is a benign system with the use of water as solvent and room temperature reaction condition. Thus the system provides us a time effective, benign procedure for the desired cycloaddition. The easy recoverability and reusability of the supported catalyst prove the heterogeneity of the system. Thus, we can be hopeful that our system will be applicable for greater prospects of various scientific areas.

References

1. a) Dale, J.; Kowalska, M.; Cocke, D. L. Chemosphere. 1991, 22, 769-798; b) Sterte, J. Clays Clay Miner. 1986, 34, 658-664
2. a) Pinnavaia, T. J. Science. 1983, 220, 365-371; b) Gil, A.; Gandia, L. M.; Vicente, M. A. Catal. Rev. Sci. Eng. 2000, 42, 145-212; c) “Pillared Clays”: Burch, R. in Catalysis Today, Vol. 2, Elsevier, New York, 1988, p. 185; d) Valverde, J. L.; de Lucas, A.; SMnchez, P.; Dorado, F.; Romero, A. Appl. Catal. B 2003, 43, 43-56; e) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.; Rao, K. K. Angew. Chem. Int. Ed. 2005, 44, 322-325; f) Veisz, B.; Király, Z.; Tóth, L.; Pécz, B. Chem. Mater. 2002, 14, 2882-2888; g) Nikalje, M. D.; Sudalai, A. Tetrahedron 1999, 55, 5903-5908; h) Dolmazon, D.; Aldea, R.; Alper, H. J. Mol. Catal. A: Chem. 1998, 136, 147-151; i) Shao, L. X.; Shi, M. Adv. Synth. Catal. 2003, 345, 963-966; j) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Gnaneshwar, D. Adv. Synth. Catal. 2002, 344, 938-940; k) Han, Z. H.; Zhu, H. Y.; Bulcock, S. R.; Ringer, S. P. J. Phys. Chem. B 2005, 109, 2673-2678
3. Király, Z.; Veisz, B.; Mastalir, Á.; Köfaragó, Gy. Langmuir, 2001, 17, 5381-5387
4. Papp, S.; Szél, J.; Oszkó, A.; Dékány, I. Chem. Mater. 2004, 16, 1674-1685
5. a) Welton, T. Chem. Rev. 1999, 99, 2071-2084; b) Wasserscheid, P.; Keim, W. Angew. Chem. 2000, 112, 3926-3945; c) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72, 1391-1398; d) “Ionic Liquids as Green Solvents: Progress and Prospects”, ACS Symp. Ser. 2003, 856.
6. Blanchard, L. A.; Hancu, D.; Beckman, E. J.; Brennecke, J. F. Nature 1999, 399, 28.
7. a) Dupont, J.; Fonseca, G. S.; Umpierre, A. P.; Fichtner, P. F. P.; Teixeira, S. R. J. Am. Chem. Soc. 2002, 124, 4228-4229; b) Zhou, Y.; Antonietti, M. J. Am. Chem. Soc. 2003, 125, 14960-14961; c) Kim, K. S.; Demberelnyamba, D.; Lee, H. Langmuir 2004, 20, 556-560
8. Huang, J.; Jiang, T.; Gao, H.; Han, B.; Liu, Z.; Wu, W.; Chang, Y.; Zhao, G. Angew. Chem. 2004, 116, 1421-1423
9. Miao, S.; Liu, Z.; Han, B.; Huang, J.; Sun, Z.; Zhang, J.; Jiang, T. Angew. Chem. Int. Ed. 2006, 45, 266 –269

Chapter 6 Artemisinin is a Sesquiterpene lactone: Remedy for Malaria and Cancer

Dr. Bishwajit Saikia

Assistant Professor, Department of Chemistry, Digboi College, Digboi

E-mail: [e-mail]

Abstract

Artemisinin is a sesquiterpene lactone endoperoxide isolated in 1971 from the Chinese medicinal plant Artemisia annua L. Due to their potent antimalarial activity, low toxicity and fast action, artemisinin and its derivatives have gained importance over the years as a new generation antimalarial drug, especially in the treatment of multi-drug-resistant malaria strains. Structure-activity studies have shown that the peroxide group is essential for the antimalarial activity and the absence of this peroxy bridge, e.g. deoxyartemisinin, lead to complete loss of potency. Artemisinin dimers are a new class of artemisinin derivatives obtained by connection two artemisinin molecules without destroying their endoperoxide linkages. This class of molecules has been reported to have much better antimalarial and anticancer activities than many of the monomers. Artemisinin dimers are gaining importance in the recent years because of their profound antimalarial and anticancer activity even at very low concentration. This chapter have projected artemisinin dimers as having lots of promise for development of new anticancer and antimalarial drug candidates.

Keywords: Artemisia annua, mosquito, antimalarial drug, anticancer activity

Introduction

In spite of an effective and safe vaccine therapy against malaria, mosquito borne infectious disease caused by protests of the genus Plasmodium becomes a global health problem in the world, especially the third world. Moreover, because direct antimalarial therapy is not yet perfectly developed, it is important to discover the lead compounds for novel anti-malarial agents from the potential library. Artemisinin, the first and last naturally occurring 1,2,4-trioxane originated from Artemisia annua, L.[1] and its derivatives are a potent class of antimalarial drugs. The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant. Furthermore, artemisinin and many of its analog possess not only antiparasitic effect against Plasmodium falciparum, Schistosoma japonicum and Clonorchis sinensi but also immune-modulation effects, and antitumor activities.[2] Artemisinin, the key ingredient obtained from Artemisia annua in a maximum yield of 0.1%, has a long history of use as an antimalarial remedy. Artemisinin has been extensively researched for malaria, and has been used on over a million patients, mostly in China and Vietnam. It is very helpful for drug resistant malaria. Artemisinin contains an internal peroxide group. Due to this group, reactive oxygen is already present in the molecule. This belief agrees with the observations that derivatives of artemisinin lacking the peroxide moiety, are devoid of antimalaria activity.[3] The major active principal was first isolated in 1972, and investigators at the Walter Reed Army Institute of Research located and crystallized the active component in 1984.[4] However, artemisinin with an endoperoxide linkage is a sensitive molecule for large scale derivatization. Fortunately, it was found that the carbonyl group of artemisinin 1, can be easily reduced to dihydroartemisinin 2 in high yields using sodium borohydride, which has in turn led to the preparation of a series of semi-synthetic first-generation analogues included oil soluble artemether 3, arteether 4, water soluble sodium artesunate 5, and sodium artelinate 6. Due to their potent antimalarial activity, low toxicity and fast action, artemisinin and its derivatives (2-5) have gained importance over the years as a new generation antimalarial drug, especially in the treatment[5] of multi-drug-resistant malaria strains (Figure 1).

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Figure 1

Recently, there was a report about anti-HBV activity of artemisinin 1 and artesunate 5 based on the screening by using HBV-transferred HepG2 cell. Structure-activity studies have shown that the peroxide group is essential for the antimalarial activity and the absence of this peroxy bridge, e. g. deoxyartemisinin, 7 lead to complete loss of potency[6].

Mode of Action of Artemisinin for antimalarial activity

The entry of the malaria parasites into their human host is through a mosquito bite. They first enter the liver and replicate there for two weeks, before beginning a cycle of red-blood-cell invasion, followed by growth, replication and red-cell destruction that leads to the symptoms of the disease. The artemisinin drugs are known to act specifically during this blood stage. Artemisinin contains an endoperoxide moiety and several authors have suggested the production of carbon centered free radicals arising from this due to Ferrous iron (Fe[2]+) catalyzed cleavage of this bridge; forming highly reactive free radicals.[7] The theory has been that these artemisinin-derived carbon centered radicals chemically modify and inhibit a variety of parasite molecules, resulting in parasite death.[8]

Many researchers believe that the artemisinin per se is not antimalarial, but rather act as ‘prodrugs’, requiring generation of antimalarially active intermediates after encounter with ferrous iron. It has long been believed that Fe[2]+-haem, which is a rich source of intracellular Fe[2]+, is responsible for activating artemisinin inside the parasite. During its growth and replication inside the red blood cell, the parasite ingests and degrades up to 80% of host-cell haemoglobin in a compartment called a food vacuole. This releases Fe[2]+-haem, which is oxidized to Fe[2]+-haematin and then aggregates within the food vacuole into an ordered crystalline pigment called haemozoin. It is believed that the antimalarial effect of artemisinin was due to its entry into the food vacuole of the parasite and its interaction with Fe[2]+-haem. The free radicals thus generated from artemisinin inside the food vacuole, inhibit several key parasite compounds and eventually result in parasite death.

Hynes and coworkers[9] observed that some artemisinin derivatives are resistant to Fe[2]+ activation. These and similar findings by others led them to reject the iron activated theory. The work of Krishna and colleagues on P. falciparum using a fluorescently labeled artemisinin derivative ruled out the earlier idea of artemisinin accumulation in parasite food vacuole. They suggested that instead artemisinin is spread throughout the parasite. By presenting evidence that the artemisinin work through irreversibly inhibiting metabolic enzyme-the malarial calcium-dependent ATPase (PfATP6). PfATP6 is very similar to a mammalian ATPase, which, as its name suggests, is located in a membrane-enclosed intracellular compartment called the sarco/endoplasmic reticulm (ER). In the parasite, the ER is situated outside the food vacuole (throughout the parasite cytoplasm) - the same location as the proposed site of artemisinin action. Once inside the parasite, artemisinin is activatd by free iron, or another iron-dependent process that occus close to PfATP6 in the endoplasmic reticulum. The activated artemisinin specifically and irreversibly binds and inhibits PfATP6, and inhibits parasite growth.[10]

Mode of action of Artemisinin for anticancer activity

In the mid-1990s[11] selective cytotoxicity of artemisinin derived peroxides towards cancer cells also became known. Cancer cells require much iron to assist their rapid proliferation and indeed, human cancer cells are known to be richer than normal human cells in receptor for transferen, an iron transporting protein. Most cancer cells express higher cell surface concentration of transferrin receptors than normal cells and have high rates of iron intake via transferring receptors. Efforts to explore the molecular mechanism of action of these monomeric 1,2,4-trioxanes towards tumour cells have established a correlation between a trioxane’s potency and m -RNA gene expression, cell doubling time and the portion of cells in different cell cycle phases. According to Moore and his coworkers, a unique structure bearing endoperoxide could be a trigger for the generation of active oxygen radical via homolytic cleavage of the weak oxygen peroxide bond accelerated by higher ferrous iron concentration of the cancer cells which may cause selective and preferential damage to vital cellular structure of the relatively active cancer cells. The anticancer mode of action of artemisinin although are less studied and known, recent studies reveal radical alkylation and inhibition of G1 cycle for anticancer activity.[12]

In recent years some dimeric trioxanes have been synthesized which possessed very high anticancer activities.[13] Recently Posner’s group reported synthesis of a series of second-generation orally active antimalarial artemisinin derived trioxane dimers with excellent efficacy. In view of the excellent antimalarial and anticancer activity exhibited by several of such artemisinin demers, a change of interest has been witnessed on this class of compouns which resulted quite a few publications reporting synthesis and biological activity of this new class of compounds during the last one decade or so. In this short review we will discuss synthesis and biological activities of different artemisinin dimers reported so far with an aim to provide a general account on this subject. For convenience the discussion will be divided into two broad catagories, via (i) oxa dimers and (ii) carbon dimers.

In the mid 1990’s selective cytotoxicity of artemisinin derived peroxide towards cancer cells also becomes known. The majority of derivatives of artemisinin prepared so far are through C-10 and the members through C-13 are relatively less. Artemisinin dimers are a new class of artemisinin derivatives obtained by joining two artemisinin molecules without destroying their endoperoside linkage. This class of molecules have been reported to have much better antimalarial and anticancer activities than many of the monomers.[21] Since the pioneering work of Beekman et al.[14] a small group of chemists have ventured into this field and synthesized several classes of artemisinin dimrs with varying degree of bioactivity and quite a few of them are in different stages of development as drug candidates.

Artemisinin, being a very sensitive molecule, restricts wide-spread derivatization for library synthesis for further clinical development. So far majority of the derivatization of artemisinin were carried out on the C-10 acetal and to a lesser extent on C-13 carbon via artemisitene a natural analogue of artemisinin which also co-exists with artemisinin in Artemisia annua and also can be synthesized from artemisinin via a selenoxide elimination route. Several authors also have been able to hydroxylate unactivated carbons (C-4, C-5, C-6 & C-7) of the artemisinin molecule using some green methods such as microbial fermentation.[15] A key advantage of these endoperoxides containing anti-malarial agents, which have been used for nearly two decades, is the absence of drug resistance.

Artemisinin dimers are a new class of semi-synthetic compounds obtained by joining two Artemisinin (or its derivatives) molecules without affecting the 1,2,4-trioxane-ring system. This class of compounds is gaining importance in recent years because of their profound antimalarial and anticancer activity even at very low concentrations. These reports have projected artemisinin dimers as having lots of promise for development of new anticancer and antimalarial drug candidates.

Huisgen 1,3-dipolar cyclo-addition[16] between azides and terminal alkynes, popularly known as click chemistry, is an important and generally accepted methodology to synthesize various biologically important molecules comprising of the triazole ring system. Keeping this in mind and with an attempt to enhance the biological activity of the trioxane dimers we are planning to synthesize a whole new series of artemisinin dimers employing the above-mentioned cycloaddition reactions.

Evidence for Fe (IV) = O in the Molecular Mechanism of Action of Artemisinin

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Figure 2

Artemisinin C-10 oxa dimers as Potent Antimalarial and Anticancer Agents

Anderson and his coworkers reported the X-ray structure of the first artemisinin derived dimer 9 in 1989,[17] however their dimer was devoid of the endoperoxide linkage. In 1996, El-Feraly’s group reported synthesis and X-ray structure of apparently the same dimer 10 starting from deoxydihydroartemisinin 8. The dimer 10 is remarkably different from the C2 -symmetrical dimer 9, which was suggested as a possible metabolite of arteether 4. Dimer 9 was prepared by treating deoxydihydroartemisinin 8 with p- toluenesulfonic acid in dry toluene. It was reported to have a symmetrical structure with both C-12 and C-12′ possessing inverted stereochemistry.

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Beekman and his coworkers made a comparative study on the cytotoxicity of dimer 11 with few other anticancer agents such as Artemisinin 1, Artemisitene 12, Eupatoriopicrin 13, Cisplatin and Deoxorubicin on murine Ehrlich ascites (EN19) and a human HeLa S3 cancer cell line using the MTT and the clonogenic assay. While the clonogenic assay detects actual cell death, the MTT assay cannot distinguish between growth inhibition and cell killing. The endoperoxides artemisinin and the dimer of dihydroartemisinin showed much higher cytotoxicity in the MTT assay compared with the clonogenic assay.[18]

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The relative cytotoxicity of these compounds as reported by these authors are given in Table 1.1

Table 1. IC50 values (µm) of artemisinin, the dimer of dihydroartemisinin, artemisitene, eupatoriopicrin, cisplatin, and doxorubicin for EN19 and HeLa cells as measured by the MTT and clonogenic assays (CA) with either 10[4] or 10[4] cell/mL.

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Woerdenbag and his coworkers studied the cytotoxicity of the ether-linked dimers of dihydroartemisinin and observed that the cytotoxic effect on EN2 cells was dependent to some extent on the stereochemistry of the ether linkage, the non-symmetrical dimer 14 being more active than the symmetrical dimer 15. They also observed that the non-symmetrical dimer of deoxydihydroartemisinin 8 lacking the endoperoxide bridge was also effective in the MTT assay, although less cytotoxic than 14 and 15. Similarly the symmetrical dimer 10 was less effective than 9. These authors are of the opinion that endoperoxide bridge is not crucial for cytotoxicity to the tumor cells but contribute to the cytotoxic effect apparently exerted by the ether linkage of the dimers.[19]

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Posner, Murray and his co-workers[20] synthesized a series of tetracyclic and tricyclic dimers, several of which exhibited potent and potentially therapeutically valuable in vitro antimalarial, antiproliferative, and antitumer activities. Among all the simplified trioxane dimers synthesized by these authors, the ether dimer 16 (a - e) (IC50 = 1.9 nM) are more antimalarially active than artemisinin 1 (IC50 = 10 nM) in vitro against chloroquin sensitive Plasmodium falciparam (NF54) parasites.

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The chemical synthesis of these dimers as reported by these authors was done as per equation 1.1 from the corresponding trioxane alcohol, where acidic conditions were used for assembly of the lactol acetal dimers 16.

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Conclusion

The Artemisia annua has been using as a source of the malarial drug since ancient times. At present, artemisinin and its derivatives are prepared industrially in a semi-synthetic way. The 1,2,4-endoperoxide bridge of artemisinins is responsible for its antimalarial activity. It was found that mutation at Kelch13 protein of P. falciparum is the root cause of ART-resistance. Clinical trial data published on the literature showed that the artesunate is more favorable than quinine or artemether to treat severe falciparum malaria. Artemisinins also show some activity against certain cancer cells. Oxidative stress, DNA damage and repair, and various types of cell deaths are the main mechanism of action in how artemisinins work as anticancer drugs. Besides antimalarial and anticancer activities, artemisinins are beneficial in viral diseases, schistosomiasis, ocular diseases, inflammations, and respiratory problems.

References

1. Klayman et al. Science 1985, 228, 1049-1055.

2. Jung et al. Curr. Meed. Chem. 2004, 11, 1265-1284.

3. Lin et al.J. Med. Chem., 1992, 35, 1639-1642.

4. Jeyadevan et al. J. Med. Chem. 2004, 47, 1290-1298.

5. Avery et al. J. Med. Chem. 1993, 36, 4264-4275.

6. (a) Gu et al. Acta Pharmacol. Stn. 1980, 1, 48-50; (b) Brossi et al. J. Med. Chem. 1988, 31, 645-650.

7. Meshnick et al. Microbiol. Rev. 1996, 60, 301-315.

8. Robert et al. Chem. Int. 2001, 40, 1954-1957.

9. Haynes et al. Angew. Chem. Int. Ed. 2004, 43, 1381-1385.

10. O’Neill et al. Nature 2003, 424, 957-961.

11. Krishna et al. Drug Resistant Updates 2004, 7, 233-244.

12. Moore et al. Cancer Lett. 1995, 98, 83-87.

13. Dadava et al. Cancer Lett. 2002, 179, 151-165.

14. Beekman et al. Planta Medica 1998, 64, 615-619.

15. Parshikov et al. Pharmaceutical Biology, 2005, 43, 579-582.

16. Huissen et al. Chem. Berl. 1967, 100, 2494-2507.

17. Flippen-Anderson et al. Acta Crystallogr. 1989, C45, 292-294.

18. Beekman et al. Phytotherapy Research 1996, 10, 140-144.

19. Woerdenbag et al. J. Nat. Prod. 1997, 60, 325-330.

20. Posner et al. Bio. & Med. Chem. 1997, 5, 1257-1265.

Chapter 7 A study of some important medicinal plants in Manipur

Dr. Malabika Borah and Ankur Choudhury

Department of Chemistry, Bhola Nath College, Dhubri-786001, Assam

E-mail: [e-mail] , [e-mail]

Abstract

North East India is considered as the biodiversity hotspots in the whole world. Among this NE region, Manipur has been known as a treasure house of medicinal plants. The present study is an attempt to survey and understand the wide range of ethnobotanical plants used by different tribes of Manipur as medicines in the treatment of various ailments and diseases.

Keywords: Manipur, ethnobotanical plants, treatment, medicine

Introduction

India is known for its significant inheritance of natural and therapeutic knowledge. Indigenous medicinal plant resources of different ethnic communities play an important role in the healthcare systems of different parts of the world. Progress in scientific validation of traditional knowledge-based herbal medicines and ethno-botanical plants has resulted in a continuous increase in demand for plant-based medicine, cosmetics and food supplements in both national and international market[1],[2].

NE region in India covers around 50% of India’s total plant diversity and harbours 40% of India’s endemic plant species[3],[4]. NE India comprises of the states of Arunachal Pradesh, Sikkim, Mizoram, Assam, Manipur, Nagaland, Meghalaya and Tripura[5]. It is interesting to note that one-third of the flora of North-East India is endemic to this region only. Along with this, the region hosts more than 200 tribes of different ethnic groups with distinct cultural entities and rich indigenous traditional medicine knowledge. The inhabitants hugely depend on available plant resources for their livelihood and for the treatment of common ailments. However, the practice of ethno-medicine is declining very fast because of the modernization, westernization and decrease of knowledgeable people[6].

Manipur is situated in the eastern-most corner of Northeast India. It has comparatively smaller forest areas and have less alpine forest and therefore lesser scope for commercial cultivation and trade of medicinal plants. With about 3,268 km[2] of area covered by bamboo forests, Manipur is one of India’s largest bamboos producing states including the highly demanded Ayurvedic bamboo product like Banslochan or Tabasheer[7],[8]. It has a central valley (Imphal valley) inhabited by the Meitei and Meitei pangal whereas the hilly areas are inhabited by 30 different tribes of Naga and Kuki [9]. About 1,535 species of medicinal and aromatic plants have already been recorded so far from Manipur among which about 400 species are used by majority of people for their primary health care needs as well as in the treatment of various ailments[8],[10],[11]. Some lists of important commercially important medicinal plants found in Manipur are given in table 1[8]-[12].

Table 1: List of medicinal plants reported in Manipur along with their application

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Acorus calamus, from Acoraceae family, is highly abundant in Manipur and finds its use in different health care products that claim prevention of flatulence and loss of appetite, as anti-lice and hair strengthner and also as a support for healthy functioning of nervous and digestive system[8],[12]. Similarly, Aegle marmalos, is used for healthy bowel functions, anti-inflammation, against cough, loss of appetite, anorexia, hyperacidity, gastric problems, relief from constipation, indigestion, respiratory problems, diarrhoea etc[8],[9]. Curcuma longa Linn., from family Zingiberaceae, is found to contain 6.8-7.5% of curcumin which finds its use in different pharmaceutical products for joint support, treatment of osteoarthritis, anti-inflammatory, pain and modulation of energy metabolism[8],[13].

Again, Hydnocarpus kurzii, from family Achariaceae, is reported to have various cyclopentenic fatty acids and is used in Dabur and Alvia products against mild dermatitis and itching and also as moisturizer for skin, improves skin tone and gives rejuvenating glow to the skin[8],[14]. Similarly, Singh and Huidrom studied Justicia adhatoda, locally known as Nongmangkha, which is mainly used by Meitei and Meitei-Pangal community for cold and cough, fever, asthma and dysentery. They reported a total of 29 compounds in it (Fig. 1) including nine glycosides and three favonoids[15],[16].

Similarly, G e et al. investigated the different phytochemicals present in Melia azedarach Linn., locally known as Siikhasii and reported two new tetracyclic triterpenoids from the barks of the plant which may be responsible for its action against diabetes[17]. The structure of the terpenoids is shown in fig. 2. Similar studies were done in Taxus wallichiana Zucc. and reported to have several diterpenoids which may be responsible for its activity in cough and cancer[8],[12],[18].

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Figure 1. Structures of the phytochemicals present in Justicia adhatoda [16]

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Figure 2. Structures of the terpenoids present in Melia azedarach Linn. [17]

Conclusion

The study reveals that there is a large number of important medicinal plants used in the formulation of various herbal products available Manipur. However, there are concerns about sustainable collection methods and to do this, there is a need to collect various traditional practices of medicinal plants with well documentation and need to share these traditional practices. This traditional knowledge could help in the scientific discovery of important drugs to cure long standing diseases[18]. Further works on more taxonomic and systematic molecular based studies of the bioresources are needed to better understand and identify the active chemical compounds for finding any superior quality attributes[8].

References

1. S. Ravi, N. Bharadvaja, Curr. Pharm. Biotechnol. 2019, 20, 1172-1180.

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About the editor

Illustrations are not included in the reading sample

Dr. Devajani Boruah (b. 1980) was born and brought up at Dhakuakhana, a subdivision of Lakhimpur district of Assam. She received her M.Sc., M.Phil and Ph.D from Dibrugarh University, Assam. She is working as an Assistant Professor & HoD in the Department of Chemistry, Silapathar Science College, Silapathar, Dhemaji, Assam. She published a good number of research papers in nationally and internationally reputed research journals. Besides, Dr. Boruah is the author of the book “ Interaction of Amino Acids with Transition Metal Ions” and editor of the two books- “Recent Advances in Scientific Research” and “Recent Advances in Chemical Research”. Her area of interest are inorganic synthesis and catalysis.

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Details

• Author: Dr. Devajani Boruah (ed.) (Editor)
• Publication Year: 2024
• Pages: 114
• Catalog Number: V1547275
• ISBN (eBook): 9783389098172
• ISBN (Book): 9783389098189
• Language: English
• Tags: chemical horizons research development