process intensification in green synthesis

Green Process Synth 1 (2012): 79–107 © 2012 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/greenps-2011-0003

Review

Process intensifi cation in green synthesis

Vimal Kumar 1 and Krishna Deo Prasad Nigam 2, *

1 Department of Chemical Engineering , Indian Institute of Technology, Roorkee , India 2 Department of Chemical Engineering , Indian Institute of Technology, Delhi , India , e-mail: [email protected]; [email protected]

* Corresponding author

Abstract

In the past few decades there has been an extensive increase in the research for green synthesis processes due to environmen-tal concerns, industrial safety and sustainable development, which makes it an attractive alternative to the conventional synthesis processes. The interest of researchers in the green synthesis processes highlights the importance of understand-ing the mechanism and the fundamental differences between the different processes. The number of publications in the fi eld of “ Green Synthesis ” in journals, proceedings, patents, etc. has increased by almost 20 times from 2001 to 2010. The published reports are mainly concerned with green synthesis with catalytic processes, less harmful solvents and process intensifi ed techniques. In the present article, the technologi-cal development efforts in the area of green synthesis are summarized. Various techniques for green synthesis process intensifi cation are discussed, e.g., mixers, microreactors, spin disc reactor, oscillated fl ow reactors, microwave irradiation, ultrasonication, multifunctional membranes and coiled fl ow inverter. The applications of green synthesis processes for biofuel, nanoparticle, ionic liquids and pharmaceutical pro-duction are also discussed.

Keywords: green synthesis; microreactors; microwave-assisted synthesis; motionless mixers; process intensifi cation; ultrasound-assisted synthesis.

1. Introduction

In the past two decades, overall chemical production has shifted from commodity chemicals to fi ne and speciality chemicals. Chemical production has grown by 9.3 % world-wide in 2010 (Figure 1 ). The large volume of chemical pro-duction expresses the importance of the chemical industry in our day-to-day life as well as each nation ’ s economy. By contrast, the large production of chemicals has led to several issues for industrialists as well as researchers with regard to

environmental issues, such as toxic discharge, depletion of non-renewable resources, short-term and long-term problems due to the exposure of chemicals and safety issues to the pub-lic. Owing to severe market competitiveness and the huge environment impact from chemical production processes, the worldwide chemical industry is facing challenges of stringent environmental regulations. Researchers and engineers are working towards processes that are clean, safe, energy effi -cient and competitive with market needs. The newly proposed processes should be environmentally friendly, use minimum energy, be recyclable and reuse and meet all the objective requirements of the chemical industry processes.

To further explore the green synthesis processes and fulfi ll the need of the chemical industry, process technologies which are energy effi cient, environmentally friendly and have low residence time, higher heat and mass transfer coeffi cient, etc. are needed to be developed. Since Ramshaw [1, 2] pioneered the concept of process intensifi cation, there have been several technologies proposed by a number of researchers which are environmentally friendly as well as energy effi cient. The pro-cess intensifi cation technologies deal with the process miniatur-ization, energy effi ciency and inherent safety, improved product quality and reduction in capital cost. The aim of the process intensifi ed technologies is to develop and use multifunctional devices for performing heat and mass transfer, separation, extraction and mixing operations. Therefore, to develop an intensifi ed process, all the unit operation systems are required to be intensifi ed, i.e., reactors, mixers, heat exchangers, distilla-tion columns, separators. The process intensifi cation technolo-gies are not only limited to the development of miniaturized equipments but also to the development of intensifi ed methods of processing, i.e., the use of microwave and ultrasonic radia-tion as an energy source, e.g., the continuous microwave reac-tor, microwave batch reactor, etc. One of the oldest technologies in process intensifi cation is the high gravity (HIGEE) contactor, which is also known as rotating packed bed (RPB), developed by Ramshaw in 1979, where the packing in a packed bed rotates (RPB) at high speed to give high acceleration to liquid (of the magnitude of 2000 – 1000 m s -2 ). The phenomenon of forcing liquid out towards the periphery of the bed forms thin fi lms over the packing and leads to high mass transfer coeffi cient. Guo et al. [3] developed a crossfl ow RPB – where the gas fl ows axi-ally and the liquid fl ows radially into the packing. Another simi-lar confi guration of RPB is the spinning basket reactor, where a supported catalyst or packing is placed in a basket that rotates at high speed in a pool of liquid, creating very high liquid-solid mass transfer. HIGEE technology is used for different applica-tions, e.g., nanoparticle synthesis, polymerization (isobutylene isoprene rubber), methylene diphenyl diisocyanate production,

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80 V. Kumar and K.D.P. Nigam: Process intensifi cation in green synthesis

15

12

13.0%

10.1%

Asia (excl. Japan) EU Japan SouthAmerica

UnitedStates

8.8%

6.4%

5.0%

World average (9.3%)9

6

3

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Figure 1 Chemical production in 2010 excluding pharmaceuticals (compared with the previous year). (Source: http://report.basf.com/2010/en/managementsanalysis/globaleconomy/chemicalindustry.html).

Improvedcontrol

Improvedprocessflexibility

Advantages ofprocess

intensification

Improvedintrinsicsafety

Reducedfootprints

Rapid gradechange

Shortresidence

time Minimaldownstreamseparation

Energysufficient

Zero waste

Lowinventory

Figure 2 Advantages of process intensifi cation.

deoxygenation of water, desulfurization, etc. Another example of process intensifi cation technology is the reactive distillation process, where in the module both the reaction as well as separa-tion takes place simultaneously, i.e., it works as a reactor as well as distillation column.

The process intensifi cation approach also substantially improves the safety of a process by reducing the volume of hazardous chemicals in signifi cant amounts in a miniaturized device. The process intensifi cation (PI) approach results in the conversion of a batch process into a continuous process, especially in the case of exothermic reactions where a high amount of heat can be continuously removed during the pro-cess [4] . Some of the advantages of process intensifi cation technologies are shown in Figure 2 .

For green chemistry, to carry out hazardous exothermic chemical reactions process intensifi cation technologies are an ideal vehicle. With the help of PI technologies, green synthe-sis can utilize the opportunities provided by sonochemistry,

microwave irradiation, phase-transfer and heterogeneous catalysis, supercritical chemistry and ionic liquids. Green chemistry can be enhanced by using intensifi ed technologies, e.g., microwave reactors, microreactors, multifunctional mem-branes, ultrasonic irradiation systems, catalytic plate reactors, spinning disc reactors, oscillatory baffl e reactors, HEX reac-tors (Figure 3 ). Often the reactant concentrations and operat-ing conditions are limited due to heat/mass transfer and mixing operations of the reactor as well as high temperature and pres-sure restrictions which result in poor selectivity/conversion and downstream separation processes. PI technologies offer the use of higher reactant concentration and severe operating conditions, which signifi cantly infl uence the kinetics, selectiv-ity and inventory. Therefore, PI technologies offer a range of exciting processing conditions for researchers and engineers to try out chemistry that could not be considered in the past.

By contrast, miniaturization of green synthesis processes using intensifi ed technologies offers smaller footprints and reduces the size of the chemical plants [5] . Furthermore, chemical plants can be made mobile due to smaller sizes and thereby offer the opportunity for distributed manufacturing of chemicals. This will also reduce the transportation of chem-icals and hence will improve the safety of the process and reduce energy consumption. The PI approach is also benefi cial in improving energy effi ciency in intensifi ed unit operations, especially where there is an overwhelming concern on non-renewable energy resources and greenhouse gas emissions. Therefore, it is necessary to further develop PI technologies that will utilize energy in an effi cient manner. By enhancing heat and mass transfer, the energy consumptions can be sig-nifi cantly reduced in unit operations. There are several case studies reported by numerous researchers considering inten-sifi ed technologies which clearly illustrate the benefi ts of PI technologies, e.g., a gas-liquid reaction using static mixers and hypochlorous acid production in a rotating packed bed [6] . Keller and Bryan [7] have suggested that future develop-ment in chemicals and process industries will be dictated by PI technologies.



V. Kumar and K.D.P. Nigam: Process intensifi cation in green synthesis 81

Microreactor Mixers Spinningdisk reactor

Rotatingpacked bed

Multifunctionalmembranes

Microwaveirradiation

Ultrasoundirradiation

Ultrasoniccleaning bath

Ultrasonicprobe

Ultrasoniccontinuousflow reactor

Continuousflow reactor

Batch reactorDigital reactor

HEX reactor

Catalyzedpellet reactor

Coiled flowinverter

Oscillatingbaffled flow

reactor

Static mixer

Vortex mixer

Impinging jetmixer

Processintensification

Figure 3 Process intensifi cation techniques for green synthesis.

In the present article, fi rst, the analysis of research articles published in different journals is reported in Section 2. Then, the application of green synthesis for the production of bio-fuels, pharmaceuticals, production of nanoparticles and ionic liquids is discussed in Section 3. In Section 4, the applica-tions of PI technologies (microreactors, microwave, ultra-sonic, ionic liquids, multifunctional membranes, mixers and spin disc reactors) for green synthesis processes are summa-rized. The aim of the present article is to provide information about the various technologies available in the fi eld of process intensifi cation for green synthesis.

2. Analysis of literature on green synthesis

(in terms of publications, conference papers

and others)

In the past two decades, research in the fi eld of “ Green chem-istry ” or “ Green synthesis ” has received worldwide attention

due to the environmental and safety concerns in the industry as well as in the academic fi eld. In the present article, an analy-sis is carried out to understand the present and future trends of green synthesis. The rise and propagation of appearances of green synthesis in technical journals has been quantifi ed from the 2001 to 2011. For the analysis of journal publications, SCOPUS ( http://www.scopus.com ) has been considered. In the past 10 years, the number of papers published under the headings “ Green chemistry ” and “ Green synthesis ” has shown an extensive growth. Approximately 38,000 reports have been published by the scientifi c community out of which there are 32,921 research articles, 2567 review articles, 2196 con-ference proceedings, etc., obtained on SCOPUS. A trend of research articles regarding publication year is seen in Figure 4 . It can be seen that there is a nearly 15 times increase in research article publications in the year 2010 as compared to 2001, which itself indicates the interest shown by the scien-tifi c community in the past decade. The largest majority of the authors were from academia.

6000

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3000

2000

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2291

2909

3461

4351

5119 5002

1000

02001

Num

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f pub

licat

ions

2002 2003 2004 2005 2006Year

2007 2008 2009 2010 2011

Figure 4 Number of publications per year for “ Green chemistry ” and “ Green synthesis ” from 2001 to 2011.




Spain, 1255Italy, 1132

Iran, 1359

France, 1381

UnitedKingdom,

1547Germany, 1567

Japan, 1996

India, 3203

United States, 3370

China, 6592

Figure 5 Number of publications per country for “ Green chemistry ” and “ Green synthesis ” from 2001 to 2011.

Table 1 Number of publications from various journals (top 15).

Journal Number of publications

% (out of 27,939)

Green Chemistry 1859 6.65 % Tetrahedron Letters 1147 4.11 % Chemical Communications 664 2.38 % Tetrahedron 600 2.15 % Journal of Physical Chemistry 584 2.09 % Synthetic Communications 580 2.08 % Journal of Molecular Catalysis 566 2.03 % Journal of Organic Chemistry 534 1.91 % Advanced Synthesis and Catalysis 489 1.75 % Chemistry A European Journal 489 1.75 % Synlett 471 1.69 % Applied Catalysis A General 447 1.60 % Catalysis Communications 429 1.54 % Industrial Engineering Chemistry 424 1.52 % Organic Letters 383 1.37 %

Country distribution (Figure 5 ) shows that the highest number of research article publications in “ Green chemistry ” or “ Green synthesis ” is from China (n = 6592). Furthermore, it can be seen that the number of publications on “ Green chem-istry ” or “ Green synthesis ” from the USA (n = 3370) and India (n = 3203) are similar in numbers. For “ Green chemistry ” or “ Green synthesis ” publications, there are fi ve European coun-tries in the top 10 and Germany is leading in terms of the highest number of publications.

The leading journals in terms of total number of research publications and percentage of their own publications for the period 2001 – 2011 are reported in Table 1 for “ Green chem-istry ” or “ Green synthesis ” . It can be seen from Table 1 that the highest number of publications is reported in Green Chemistry (6.65 % of the total number of publications). Table 1 includes the 15 top journals where work on “ Green chem-istry ” or “ Green synthesis ” has been published. The topics of research were examined in more detail for “ Green chemistry ” or “ Green synthesis ” . It was observed that the highest number

of publications were dominated by research in catalysis, fol-lowed by ionic solvents, solvents, techniques based on irradia-tion, etc.

3. Application of green synthesis processes

3.1. Biofuels

Biodiesel or fatty acid methyl ester is produced from vege-table oil and alcohol in the presence of catalyst (acidic or basic). FAME is a biodegradable, non-toxic and environ-mentally friendly fuel used in diesel vehicles as BD20 (20 % biodiesel in fossil fuel). In the biodiesel production process, initially the vegetable oil and alcohol resulted in a biphasic system and hence mass transfer resistance is higher. Similarly after the reaction the product and byproduct are not soluble, hence the mass transfer resistance is higher. Also, it requires the removal of the catalyst and glycerin from the fi nal desired product.

Using the concept of green synthesis, Saka and Kusidianan [8 – 12] and Warabi et al. [13] carried out biodiesel production using supercritical methanol. This process exhibits advan-tages over the alkaline catalysis method, as it is a simple non-catalytic process, avoiding the removal of catalyst from the product and reducing wastewater. Hegel [14, 15] reported that methanol and oil forms a single phase in the supercritical state in a tubular reactor. Bertoldi et al. [16] carried out production of fatty acid ethyl esters from soybean oil transesterifi cation in supercritical ethanol and carbon dioxide as a cosolvent in a tubular reactor. The temperature and pressure were varied from 300 ° C to 350 ° C and 7.5 to 20 MPa, with an oil-to-ethanol molar ratio ranging from 1:10 to 1:40 and cosolvent to substrates mass ratio from 0:1 to 0.5:1. Considerable reac-tion yields were achieved at 350 ° C, 10 MPa, oil-to-ethanol molar ratio of 1:40 and using a CO 2 to substrate mass ratio of 0.05:1. It is shown that the use of a tubular reactor with small inner diameter can provide high reaction conversions in short residence times. Wang et al. [17] and Chen et al. [18]




studied the production of biodiesel in a batch reactor with stir-ring and a continuous vertical tubular reactor. Zhou et al. [19] extended their work and carried out biodiesel synthesis in a vertical tubular reactor made of stainless steel. They reported that the effect of temperature is very signifi cant on the yield of methyl ester. At high temperature ( ∼ 300 ° C), methyl ester decomposes, therefore the yield of methyl ester decreases. However, the operating conditions required by the supercriti-cal method (high temperature and pressure) make the process unsafe and it cannot be carried out with visual observation. Harvey et al. [20] carried out transesterifi cation reactions in an oscillating fl ow reactor (OFR) in a pilot-scale plant, using rapeseed oil and methanol as the feedstocks, and NaOH as the catalyst (Figure 6 ). A good to excellent yield of biodiesel at a lower residence time was obtained using the OFR.

Since the inception of ionic liquids they have been used in a large number of chemical reaction types [21, 22] . The advan-tages of the use of ionic liquid for chemical synthesis are that: (i) these solvents are non-volatile except at low pressures and high temperatures; (ii) their properties can be designed such that these solvents can be separated easily from the product of a reaction; and (iii) the ionic liquid can be designed in such a way that it can have required ionic property (acidity or alka-linity), can be recovered intact at the end of a reaction and recycled, therefore not creating any ionic liquid waste. The property of ionic liquids can be altered so that it can have Br ø nsted acidity and therefore ionic liquid can be used to catalyze esterifi cation and transesterifi cation reactions.

Verkade [23] carried out transesterifi cation reactions to produce biodiesel using 1-butyl-3-methylimidazolium tet-rafl uoroborate as ionic liquid. The combination of sodium methoxide dissolved in a neutral ionic liquid was used for the methanolysis of soybean oil. However, it has been reported that the combination of ionic liquid-reagent is not stable due to methanolysis of the tetrafl uoroborate anion and release of fl uoride ions. Kim et al. [24] added trifl ic acid or 4-tol-uenesulfonic acid to ionic liquid to catalyze the reaction of free fatty acids (FFAs) with ethanol. However, they failed to mention that the combination of some of the ionic liquid/acid is unstable and could lead to the formation of hydro-fl uoric acid, which is a hazardous chemical to work with. A

combination of K 2 CO 3 or H 2 SO 4 and 1-butyl-3-methylim-idazolium bis{(trifl uoromethyl)sulfonyl}amide ([C 4 mim][NTf 2 ]) was used by Lapis et al. [25] for the transesterifi cation reaction of soybean oil with primary and secondary alcohols. After completion of the reaction, a two-phase system of biod-iesel and a glycerol-methanol-ionic liquid-catalyst phase was obtained. It has been reported that the use of tetrafl uoroborate and hexafl uorophosphate ionic liquids should be avoided due to their decomposition. For the production of biodiesel in ionic liquids, acid-catalyzed chemistry considering acidic ionic liq-uid is reported by several researchers. Wu et al. [26] prepared biodiesel using fat and alcohols in the presence of an ionic liquid, where the cation of the ionic liquid had a SO 3 H group (i.e., sulfoalkylimidizoliums, sulfoalkylpyridiniums, sulfoal-kyltriphenylphosphoniums or sulfoalkylammonium salts). The reaction mixture resulted in a biphasic system, where the top layer contained the product, and the ionic liquid-catalyst remained in the bottom layer. Yi et al. [27] and Zhang et al. [28] used similar ionic liquids to transesterify waste oil or soybean oil with methanol for biodiesel production. An acidic anionic ionic liquid, 1-H-3-methylimidazolium hydrogen sul-fate, was used by Li et al. [29] for the transesterifi cation of rapeseed oil with methanol for biodiesel synthesis.

Ionic liquids containing metal complexes having Lewis acidic characteristics, which have similar chemistry as in the case of Br ø nsted-acidic ionic liquids, was also used for biodiesel synthesis. Neto et al. [30] used the tin complex [Sn(3-hydroxy-2-methyl-4-pyrone) 2(H 2 O) 2 ], immobilized in 1-butyl-3-methylimidazolium tetrachloroindate [bmim][InCl 4 ] as ionic liquid for biodiesel synthesis from alcoho-lysis of soybean oil. Wang and Bao [31] used aluminum(III) chloride as ionic liquids for the transesterifi cation reactions. However, it has been reported that Lewis acid ionic liquids suffer from the disadvantage that they form a biphasic sys-tem, can lead to metal wastes, are not stable in the presence of alcohols and liberate HCl. Basic catalysts mixed with ionic liquids were also used for biodiesel synthesis but they are only suitable for transesterifi cation reactions. Zhang et al. [32] used hydroxide salts of ammonium cations or sodium hydroxide dissolved in ionic liquids for biodiesel synthesis using animal or vegetable fats. A mixture of sodium methoxide and lithium diisopropylamide was used for transesterifi cation reactions [33] . Abbott et al. [34] used a mixture of ionic liquid, ethanol and KOH for the transesterifi cation reaction. The disadvan-tage with ionic liquids is that they are more expensive than some of the catalysts and conventional solvents.

Another method of green synthesis of biodiesel is the use of enzyme-catalyzed esterifi cation and transesterifi cation reac-tions, which have the advantage that strong acids and bases are not required and the synthesis is safe and non-corrosive. Talukder and Wu [35] synthesized biodiesel from oils or fats using an immobilized enzyme to catalyze the reaction. Ku et al. [36] used enzyme catalyst with ionic liquids as solvent and additive in the reaction of alcohols with plant or animal fats and oils. It was reported that the problems of low stability of enzyme and decrease of enzyme activity in organic solvents can be resolved with the presence of ionic liquid. The biodie-sel is synthesized with the methanolysis of soybean oil using

Bulk flow ofproduct out

Bulk flow ofreactants in

Oscillatory flowsuperimposed onbulk flow by piston

Figure 6 The oscillatory fl ow reactor. (Source: Harvey et al. [20] ; reprinted with kind permission from American Chemical Society. Copyright (2003). )




23 ionic liquids with immobilized Candida antarctica lipase catalyst [37] . An 80 % FAME yield was achieved after 12 h at 50 ° C in 1-ethyl-3-methy-limidazolium trifl uoromethanesul-fonate ([C 2 mim][OTf]). Gamba et al. [38] used Pseudomonas cepacia lipase supported in 1-butyl-3-methylimidazolium bis(trifl uoromethylsulfonyl)amide ionic liquid for biodiesel synthesis from the transesterifi cation reaction of soybean oil. It was observed that without loss of catalytic activity and selectivity the recovered ionic liquid/enzyme catalytic system can be recycled at least four times. Earle et al. [39] used seven different acidic and basic ionic liquids for biodiesel synthesis at room temperature. It was reported that the acid- or base-catalyzed transesterifi cation of animal fat with methanol requires higher reaction temperatures (typically 90 – 160 ° C) for rapid reactions.

3.2. Production of nanoparticles

Nanomaterials exhibit novel properties due to their small size, such as quantum size effect, non-linear optical properties, etc. Therefore, nanomaterials have extensive applications, e.g., in microelectronic materials, bacteriostatic materials, catalytic materials or magnetic recording materials, photodetection and biomedical applications (DNA detection). For example, silver nanoparticles can be used as antibacterial and biosensor materials in biomedical applications. Because of the number of applications in various fi elds, nanoparticle production has become an interesting research focus by a size-controlled or shape-controlled procedure. The demand of decreasing the thickness of conductive fi lms and width of printed circuits is growing in the electronic industry. Therefore, it is required that the silver nanoparticles diameter in the conductive paste is small as far as possible. In chemical industry, the silver nano-particles are used as catalytic material. The catalytic activity of silver nanoparticles is dependent on their shape, structure, size distribution and chemical-physical environment. He et al. [40] and Wang et al. [41] reported that the shape, size and size distribution of silver particles can be controlled by adjusting the reaction conditions such as reducing agent, stabilizer and different synthetic methods. In the past few years, different process intensifi cation technologies are used for the prepara-tion of nanoparticles.

For the synthesis of nanoparticles, various methods are reported in the literature, such as microwave-assisted syn-thesis, ultrasonic-assisted reduction, chemical reduction, template method, photocatalytic reduction, biochemical reduction, microemulsion method, etc. These methods can be used to prepare nanoparticles of different diameter and morphology by controlling reaction conditions. The chemical reduction technique is used for the production of large quanti-ties of nanoparticles in short time periods [42 – 45] . However, chemical synthesis of nanoparticles resulted in aggrega-tion of particles which tend to form large particles which can be avoided by using surfactants, polymers and stabiliz-ing ligands. To prevent agglomeration generally polymeric materials are used as protective agents. By choosing different stabilizers it is possible to manipulate the shape and size of silver nanoparticles. Therefore, for a certain application or

to obtain a particular shape and size, a particular protective agent should be used. Using the chemical reduction technique El-Rafi e et al. [46] synthesized silver nanoparticles (AgNPs) in an alkaline aqueous solution of silver nitrate (AgNO 3 )/hydroxypropyl starch (HPS). HPS is a water soluble/bio-compatible starch derivative which is used as both a reduc-ing agent for silver ions and a stabilizing agent. The diameter range obtained from for well-stabilized AgNPs varies from 6 to 8 nm. The advantage of this technique is that the AgNPs were prepared without any organic solvents or other reduc-ing agents. Using polyoxometalates (POMs) as a reducing agent, Li et al. [47] performed, at room temperature, an eco-friendly synthesis of Pt nanoparticle-decorated carbon nano-tubes. In the synthesis, POMs are not only used as a reducing agent but they are also employed as bridging molecules. In the pharmaceutical industry, it is important to synthesize the nanosized particles with antibacterial properties. Guzman et al. [48] synthesized the silver nanoparticles with the chemical reduction technique from aqueous solutions of silver nitrate, containing a mixture of hydrazine hydrate and sodium citrate as reductants and sodium dodecyl sulfate as a stabilizer. They reported reasonable bactericidal activity against Escherichia coli , Pseudomonas aeruginosa and Staphylococcus aureus . The nanoparticles were synthesized with membranes contain-ing reactive nanoparticles (Fe and Fe/Pd) immobilized in a polymer fi lm (polyacrylic acid, PAA-coated polyvinylidene fl uoride, PVDF membrane) using a biodegradable, non-toxic green reducing agent (green tea extract, i.e., polyphenols) [49] . The synthesized particles are protected from oxidation and aggregation, which increases their stability and longev-ity. During chemical synthesis of nanoparticles, toxic chemi-cal agents are used which are hazardous for health and the environment. In some reactions, sodium citrate and reducing sugar are used as reducing agents, which are inexpensive and non-toxic; however, the reaction takes a longer time and takes place under higher temperature.

Further microwave and ultrasonic irradiation and photo-induction techniques are used for nanoparticle synthesis. Owing to its unique reaction effects (such as rapid volumetric heating and reaction rate), microwave-assisted synthesis is widely used for nanoparticle synthesis. However, it is diffi -cult to achieve a narrow distribution of silver particles. The limitation of particle aggregation in the chemical reduction method can be overcome by using the reverse microemul-sion (i.e., reverse micelle) technique, where uniform and size controllable nanoparticles can be achieved. In addition, this technique is useful in obtaining nanoparticles with desired diameters [50] . The microemulsion technique is composed of a ternary mixture of water, surfactant and oil or a quater-nary mixture of water, surfactant, co-surfactant and oil. For the formation of microemulsion different types of surfactants are used, including cationic surfactants such as cetyltrimeth-ylammonium bromide (CTAB), anionic surfactants such as bis(2-ethylhexyl)sulfosuccinate (AOT), sodium dodecyl ben-zene sulfonate (SDBS) and lauryl sodium sulfate (SDS), and non-ionic surfactants such as Triton X-100, etc.

The biological reduction technique is a promising method for nanoparticle synthesis because of its advantages such as




suffi cient material sources, mild reaction conditions, good dispersion of nanoparticles, requiring less amounts of chemi-cal additives and producing less poisonous byproducts. The synthesis of silver nanoparticles is generally carried out with two mechanisms: (i) enzymatic and (ii) non-enzymatic reduc-tion. Yeary et al. [51] used a thermophilic bacterial strain for synthesizing the magnetite nanoparticles (Fe 3 O 4 ) outside of bacterial cells by reducing a magnetite precursor contain-ing Fe ions. Yeast has also been used for the preparation of non-toxic CdS (cadmium sulfi de) nanocrystallites [52] . The biological reduction technique is an environmentally friendly process and therefore there is huge interest in the synthesis of silver nanoparticles using biological routes. However, the reaction time for the nanoparticle preparation is very long and therefore the reduction rate is very slow. For example, in some cases for the synthesis of silver nanoparticles using fungi [53, 54] or bacteria [55 – 57] , the time for completion of the reaction ranges from 24 to 120 h. It is the main disadvan-tage of the biosynthesis method as compared to the chemical methods for nanoparticle synthesis.

Abdel-Halim and Al-Deyab [58] utilized the hydroxypro-pyl cellulose for green and effi cient synthesis of silver nano-particles. Hydroxypropyl cellulose samples were prepared through alkalization of cellulose followed by etherifi cation reaction with propylene oxide. The obtained hydroxypro-pyl cellulose samples were used in the preparation of silver nanoparticles through reduction of silver nitrate. Antony et al. [59] compared the antibacterial effi cacy of silver nanopar-ticles (AgNPs) fabricated by biological (a mangrove plant, Rhizophora apiculata ) and chemical means (glucose). It has been reported that the synthesized AgNPs were effi cient against the bacterial strains.

3.3. Production of ionic liquids

The preparation of ionic liquids on a large scale is limited to batch operation employed for the alkylation step. Waterkamp et al. [60] presented a process to intensify the synthesis of 1-butyl-3-methylimidazolium bromide ([BMIM]Br) by using a continuously operating microreactor system (Figure 7 ). The reaction unit is composed of a microstructured mixer of 450 mm channel width and with an inner diameter ranging from 2 to 6 mm, allowing a production rate of 9.3 kg [BMIM]Br per day. The strongly exothermic alkylation was thermally controlled even at elevated temperatures leading to high reaction rates in a solvent-free modus. Even at high tem-peratures ( ∼ 85 ° C) the product purity achieved was more than 99 % . Compared to the batch operation, the microstructured unit resulted in more than 20-fold increase of the space-time yield.

4. Technologies for green synthesis

4.1. Microreactor technology

One of the objectives of process intensifi cation is the minia-turization of the devices/equipments. The manufacturing of chemicals at the microscale resulted in the development of

Vortex mixer(shown in inset)

Mixedreactantoutlet

Reactant 2

Reactant 1

Figure 7 A vortex type mixer (shown in inset) with working prin-ciple. (Source: Jiménez-González and Constable [61].)

compact devices for performing a range of unit operations (such as mixing, reaction, separation and extraction) over a wide range of process parameters. The miniaturization of pro-cess equipments has resulted in the enhancement in heat and mass transfer processes within submillimeter-scale devices due to less residence time, plug fl ow behavior and higher surface-to-volume ratio. In addition, the miniaturization of equipments gives the advantages of high degree of control over the exothermic reactions or reactions carried out under runaway conditions and low inventory environment.

There are different structures used for microreactor designs, the most commonly used are microchannels and microplate geometries. The devices developed using the concept of miniaturization can also provide an intrinsically safe envi-ronment (depends on case by case and operating process con-ditions) for both catalyzed as well as non-catalyzed reactions. Burn and Ramshaw [62] carried out a nitration reaction in a poly(tetrafl uoroethene) (PTFE) capillary reactor where rapid heat transfer rates allow stronger acid concentration to be used at lower temperatures, which resulted in decreased organic oxidization byproducts. Owing to higher heat and mass trans-fer, microreactors are not only used for chemical synthesis but also used for heat transfer applications. To remove the heat of reaction from the source almost as rapidly as it is gen-erated, Phillips and Edge [63] developed a HEX reactor at the BHR Group (UK). They successfully demonstrated HEX reactor technology in the reduction of byproduct formation for an exothermic organic reaction (Figure 8 ). The reaction between 1- and 2-naphthol with diazotized sulfanilic acid is performed in an HEX reactor which resulted in four different dye products. The rate of formation of each dye product was different from one another by several orders of magnitude. The product distribution was precisely controlled with no side products, whereas in the case of a traditional batch reactor a mixture of dyes was observed. The BHR Group (USA) devel-oped a “ shell and tube ” reactor, where static mixer elements are inserted in the fl exible tubes. The confi guration is capable of operating over a wide range of process parameters. Direct fl uorination of toluene is an exothermic process and the heat




released cannot be controlled with conventional reactors. Therefore, the reaction has to be slowed down, and reaction takes a long time to complete.

Using a miniature bubble column reactor, Chambers et al. [64] carried out the Bayer-Villiger oxidation of cyclohexanol to cyclohexanone with fl uorine and aqueous formic acid (5 % water) and reported 60 % conversion at 88 % selectiv-ity. Kikutani et al. [65] and Fletcher et al. [66] carried out synthesis of organic chemicals in a reactor on a chip, where reactants were fl owing in parallel to one another, crossing in a complex and multileveled network. Kikutani et al. [65] , using a phase transfer catalyst, prepared a small (2 × 2) library in a chip microreactor by reacting 3-nitrobenzoyl chloride and 3,5-dinitrobenzoyl chloride, each with dl -1-phenylethylam-ine and 4-amino- l -benzylpiperidine. Using a chip reactor, Fernandez-Saurez et al. [67] developed, at GlaxoSmithKline (GSK), a 2 × 2 library for a domino reaction, composing of Knoevenagel condensation that gave an intermediate that immediately underwent an intramolecular hetero-Diels-Alder reaction with inverse electron demand. For the drug appli-cation, Garcia-Egido et al. [68] synthesized a 3 × 7 library using the Knorr reaction of 1,3-dicarbonyl compounds and hydrazincs under ring closure to pyrazoles. Similar size libraries were used for kinetic data extraction for the asym-metric syntheses and screening of homogeneous catalysts under multiphase conditions.

To control the rate of reaction in exothermic reactions, the plate microchannel reactors have been used for the removal of heat during the reaction. The high heat removal rate in plate microchannel reactors is due to a short residence time and a large surface-to-volume ratio [69, 70] . These reactors can be operated at high pressures, therefore low-boiling reactants and solvents can be maintained in the liquid phase even at high temperatures (e.g., at or above 100 ° C), thereby high reaction rates can be achieved at higher temperatures. The effi cient mixing and shortened residence time in plate microchannel reactors reduces side product formations and hence resulted in more yields and conversion with no side products. Krtschil et al. [71] carried out the aqueous-based Kolbe-Schmitt syn-thesis with resorcinol and phloroglucinol using these reactors and reported that the reaction time is decreased by several orders of magnitude (by a factor of ∼ 2000).

Lob et al. [72] carried out a bromination reaction of thio-phene in a microreactor rig, using pure bromine and aromatic without any catalyst at room temperature. The reaction using a microreactor operation led to high selectivities for the bro-mination of 2,5-dibromo-thiophene (at approximately com-plete conversion) and yields up to 86 % , which is higher than the conventional batch reactor (50 – 77 % yield). In addition, the reaction time was reduced from approximately 2 h (batch reactor) to <1 s (microreactor). In 2005, a continuous pilot plant with a microstructured mixer-reactor was installed in Xi ’ an, China for the production of nitroglycerin, which is used as a medicine for acute cardiac infarction. As nitroglyc-erin synthesis is an explosive reaction, with the use of the microstructured mixer-reactor a production rate of 15 kg h-1 was obtained without any safety problems [70] .

The direct combination process for hydrogen peroxide synthesis is chemically simple and environmentally benign, but the handling of the explosive gas mixture of hydrogen and oxygen over an active palladium catalyst is limited due to safety reasons. The team of Matsumoto at the National Institute of Advanced Industrial Science and Technology developed a multichannel microchemical reactor with packed-bed catalyst (Figure 9 A) to carry out the exother-mic reaction of hydrogen and oxygen at hydrogen/oxygen ratios in the explosive regime at pressures of 2 – 3 MPa. They tested different catalysts for H 2 O 2 synthesis and found that Pd/TiO 2 yielded highly concentrated ( > 10 % ) hydrogen perox-ide (Figure 9B). It was reported that the microreactor resulted in signifi cant enhancement in mass transfer as compared to the conventional reactors (source: http://www.aist.go.jp/aist_e/latest_research/2010/20101111/20101111.html).

For achieving effi cient heat transfer in exothermic and endothermic reactions, Charlesworth [73] developed the cata-lyzed plate reactor (CPR) technology. Zanfi r and Gavriilidis [74] performed the steam reforming of methane in a catalytic plate reactor (Figure 10 A). It was reported that the size of the steam reformer can be reduced by two orders of magni-tude. The CPR can be used for any specialty applications, as the channel walls can be coated with suitable catalysts, mod-erators and promoters. For example, a reaction that normally takes place in the presence of a base to activate a homogeneous catalyst was carried out in a microreactor without any addi-tion of the base. When compared to the conventional reactors, CPR has a higher heat transfer coeffi cient, a short diffusion distance and less pressure drop, therefore the heat transfer in the CPR is mostly due to the conduction and independent of the gas superfi cial velocities. These advantages resulted in smaller, lighter reactors (Figure 10B). The methane reform-ing and Fisher-Tropsch synthesis using CPR technology has also been reported by a research group from Newcastle University (UK). Owing to its compactness and the fact that the reaction can be carried out under low temperature conditions, the microreactor technology is advantageous for eliminating NOx emission into the environment.

Prasad et al. [75] carried out the preparation of chiral dihydrobenzofuran epoxide with microreactor technologies using Jacobsen asymmetric epoxidation and sharpless asym-metric dihydroxylation followed by epoxidation. Bristol-

Plates

Reaction zones

Microchannels/flow patterns

Heat transferzones

Figure 8 Typical HEX reactor (reaction zones are darker than the heat transfer zones). (Source: Jiménez-González and Constable [61].)




Myers Squibb/New Brunswick (USA) further investigated the process and transferred to the large scale. Several highly exothermic reactions have been carried out in the commer-cial Cytos ® microreactors. The applicability of the microre-actor was proven in a variety of organic syntheses reactions (nitration reactions, lithium halide exchanges, acylations and Grignard reactions). The yield obtained for few reactions using Cytos ® microreactors and the conventional reactors are given below:

single bond formation (microreactor – 88 % , conventional • reactor – 63 % ), double bond formation (microreactor – 87 % , conventional • reactor – 61 % ), and heteroaromatic synthesis (microreactor – 98 % , convention-• al reactor – 74 % ).

Several other reactions which have been performed using commercially available Cytos ® microreactors (100 × 150 mm in size) are: (i) six-stage synthesis of ciprofl oxacin, (ii)

nitration of toluene with highly explosive acetyl nitrate, (iii) nitration of pyridine- n -oxide at high temperature, and (iv) nitration of 2-methylindole. Furthermore, it has been demon-strated that six Cytos ® microreactors running in parallel are equivalent to a miniplant for the synthesis of a dye with a capacity of 30 t year -1. Researchers at Johnson and Johnson used the Cytos ® microreactor to access large quantities of synthetically useful intermediates synthesized under poten-tially hazardous reaction conditions.

Some of the examples of microreactor technology applica-tions are as follows: production of ethylene oxide (which is a highly exothermic reaction) in the presence of silver catalyst in a poly(methyl methacrylate)-nickel microreactor, hydroge-nation of alkenes and alkynes in the presence of Pd-catalyst, photoreactions, enzymatic reactions, synthesis of cyanobi-phenyls using Suzuki reaction, HCN preparation under high temperature, partial oxidation of methane to syngas in the presence of catalyst, and selective oxidation and hydrogena-tion reactions.

Reforming gases

Combustiongases

Gas in,exothermic reaction

Gas in,endothermic reaction

B

AExothermic catalyst

Endothermic catalyst

Plate

Plate

Plate

Heat

Figure 10 (A) Catalytic plate reactor combined exothermic and endothermic reactions and (B) a catalytic plate reactor system (manufactured by Chart energy and chemicals, Wolverhampton, UK). (Source: http://pig.ncl.ac.uk/catalytic_plate_reactors.htm.)

12BA10

8642

0.1 mm

0.1 mm0.1 mm

10 mm H2O

2/w

t%

0Pd/TiO2

(Developedcatalyst)

Pd/Al2O3(Commercial

catalyst)

Figure 9 (A) Multichannel microreactor used for the synthesis of hydrogen peroxide and (B) comparison between the newly devel-oped catalyst (Pd/TiO 2 ) and commercially available conventional catalysts (Pd/Al 2 O 3 ). (Source: http://www.aist.go.jp/aist_e/latest_research/2010/20101111/20101111.html)




Schwesinger et al. [76] investigated the Suzuki reaction to describe the conversion of 3-bromobenzaldehyde with 4-fl uorophenyl boronic acid in the presence of a dissolved Pd catalyst. It has been demonstrated that by using a microstruc-tured reactor the yield could be increased from 50 % to 90 % , as compared to the conventional mode (Figure 11 ). Jahnisch et al. [77] investigated the fl uorination of toluene (using either CH 3 CN or CH 3 OH as solvent) in a falling-fi lm microreactor. The performance of the falling-fi lm microreactor is compared with the conventional laboratory-scale bubble column. A higher selectivity for the formation of monofl uorinated tol-uene and space-time yields in a falling-fi lm microreactor is reported when compared to the conventional bubble column (Figure 12 ). Ehrich et al. [78] used the falling-fi lm microre-actor for the photochlorination of toluene-2,4-diisocyanate using both a nickel and an iron reaction plate. They com-pared the performance of the falling-fi lm reactor performance with the conventional batch reactor (Figure 13 ). A signifi cant increase in selectivity is reported in the falling-fi lm micro-reactor as compared to the conventional reactors for similar conversions.

Kestenbaum et al. [79] used a multiplate-stacked micro-structured reactor made of polycrystalline silver foil and reported the space-time yield as 0.78 t h-1 m -3 , which is signifi cantly higher as compared to the industrial reactor, 0.13 – 0.26 t h-1 m -3 . The performance of different microre-actors for ethylene oxide synthesis is reported in Table 2 in terms of residence time, temperature and pressure, and the partial pressures of ethylene and oxygen in the ethylene oxide process. In a microstructured reactor (of size 200 × 200 µ m 2 and 700 × 300 µ m 2 ), Kursawe and Honicke [80] reported safe working within the explosion regime for ethylene oxide syn-thesis. It was reported that the thickness of the Ag coating on Al had a strong infl uence on the conversion and selectiv-ity behavior (Figure 14 ). The selectivities up to 60 % were reported for conversion of ethylene from 5 % to ≈ 30 % .

0

10

20

30

40

50

60

70

80

90

0 20 40 60 80 100

Sel

ectiv

ity (%

)

Conversion (%)

Nickel plate

Iron plate

Batch reactor

CH3 CH2ClNCO

NCO

NCO

NCO

Cl2, hν

Figure 13 Selectivity (S) vs. conversion (X) for the photochlorina-tion of toluene-2,4-diisocyanate (Ehrich et al. [78] ) .

90

100

Microreactor/mixer module

70

80

50

60 Laboratory reactor

30

40Yie

ld (%

)

10

20

00 5 10 15

F BOH

OH+ Br

CHO

CHO

F[Pd(PPh3)4]

NaOH, DMF

20 25 30Time (min-1)

Figure 11 Comparison of yield in a laboratory reactor with a micromixer/residence time module combination for Suzuki reaction (Schwesinger et al. [76] ) .

45

50

35

40Microreactor

25

30

15

20Sel

ectiv

ity (%

)

Laboratory bubble column

Me Me Me MeF10% F2 in N2

MeCN, -15°C FF

+ +5

10

00 10 20 30 40 50 60

Conversion (%)

Figure 12 Fluorination of toluene in a laboratory bubble column and falling-fi lm microreactor (Jahnisch et al. [77] ).

During aldehyde synthesis with the oxidation of alcohol, the formation of hot spot is a major issue which overshot the set operating temperature. For formaldehyde synthesis this was not signifi cant; however, for the aldehyde synthesis both the reactants and products were unstable and, there-fore, thermally induced side reactions took place. Warz et al. [81] solved this problem by using a microstructured reactor and successfully obtained selectivity up to 96 % at a conversion of 55 % , without the formation of hot spot. It was reported that in a single-tube reactor long residence time reduces selectivity; however, in a multitubular reactor with many short tubes, signifi cantly shorter residence times can be achieved with acceptable heat transfer (conversion 50 % , selectivity 85 % , hot spot 60 ° C) (Figure 15 ). Wie ß meier and




Table 2 Comparison of process parameters and reactor yield for ethylene oxide synthesis for oxygen-based industrial process and three multiple-stacked microreactors (Lase-LIGA, Etche and Aluchrom). (Source: Kestenbaum et al. [79] .)

Operating parameters Industrialprocess

Microreactor(Laser-LIGA)

Microreactor(etched)

Microreactor(Aluchrom)

C 2 H 4 concentration (vol % ) 15 – 40 1.5 – 6 3 – 15 15O 2 concentration (vol % ) 5 – 9 10 – 41 5 – 85 85CH 4 concentration (vol % ) 1 – 60Temperature ( ° C) 220 – 275 240 – 290 240 – 290 270Pressure (bar) 10 – 22 5 2 – 20 5Typical residence time (s) 0.9 – 1.8 0.1 – 0.2 0.1 – 1.5 1.2C 2 H 4 conversion ( % ) 7 – 15 2 – 15 5 – 20 2 – 6Selectivity ( % ) 80 44 – 69 38 – 69 42 – 58Space-time yield (t h-1 m-3) 0.13 – 0.26 (reactor) 0.01 – 0.07 (foils), 0.03 – 0.13 (foils), 0.01 – 0.06 (foils),

0.14 – 0.78 (channels) 0.18 – 0.67 (channels) 0.08 – 0.36 (channels)

0

10

20

30

40

50

60

0 10 20 30 40 50

H2C=CH2 O

O

O2

Ag, Ag/Al2O3

∆H=-105 kJ mol-1

∆H=-1327 kJ mol-1

∆H=-1223 kJ mol-11/2 O2 5/2 O2

3 O2

H2C=CH2

CO2+H2O

Sel

ectiv

ity (e

thyl

ene

oxid

e, %

)

Conversion (%)

1400 nm

800 nm

400 nm

50 nm

Ag-nanoparticles

Figure 14 (A) Selectivity (S) vs. conversion (X) for ethylene oxide synthesis in an Ag/Al microstructured reactor for different Ag-layer thickness. Process parameters: temperature = 250 ° C, pressure = 3 bar, composition of ethylene = 20 vol % ethylene in oxygen, and time = 0.23 – 2 s. (B) Oxidation reaction for ethylene to ethylene oxide and enthalpies of complete oxidation and epoxidation (Kursawe and Honicke [80] ) .

Honicke [82] carried out hydrogenation of cis , trans , trans -1,5,9-cyclododecatriene using a conventional grain-shaped catalyst in both a fi xed-bed reactor and in a microstructured housing with fi tted microchanneled plates (Figure 16 ). Both the fi xed-bed reactor and microreactors were compared in terms of their selectivity/conversion ratio. In the con-ventional fi xed-bed reactor the selectivity was decreased from 62 % to 44 % for the conversion range of 80 – 100 % . Furthermore, the selectivity was improved up to 73 % in a foil-fi xed bed reactor. In the case of microstructured reac-tors, the selectivity obtained was of 84 % with complete conversion. Wolfrath et al. [83] carried out thermal dehy-drogenation of propane over a Pt-Sn/g-Al 2 O 3 catalyst fi la-ment (3 – 10 mm in diameter). Figure 17 shows the propane conversion propene selectivity for a fi lament-based catalyst and a conventional powder catalyst. A conversion up to 30 % propane was reported and selectivities up to 96 % were achieved.

The advantages and disadvantages of microreactor tech-nology are listed in Table 3 .

4.2. Motionless mixer technology

One of the main unit operations to intensify the reaction and separation processes is mixing. For green synthesis, processes mixing is a very important factor in intensifying the chemical reaction and synthesis processes. Proper mixing minimizes the concentration and temperature gradients and it avoids the sec-ondary and runaway reactions. Numerous mixer designs are reported in the open literature and are classifi ed into two main categories: active and passive. In the case of active mixing, energy input for mixing is derived from an external source, whereas in the case of passive mixing fl ow energy is utilized to restructure the fl ow in a way that results in improved mix-ing. Although active mixers produce excellent mixing, there are often diffi culties in fabricating and maintaining them.




84

86

88

90

92

94

96

98

48 50 52 54 56 58 60

Sel

ectiv

ity (%

)

Conversion (%)

Microstructured reactor

Multitubular reactor

Figure 15 Selectivity (S) vs. conversion (X) for selective oxida-tion of an alcohol to an aldehyde in a short multitubular reactor and a multiplate-stacked microstructured reactor (Warz et al. [81] ) .

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.8 0.9 1.0

Sel

ectiv

ity (C

DE

)

Conversion (CDT+CDO)

Microstructured reactor

Fixed cut coils

Fixed bed wires

Conventional Pb2O3 fixed bed

Figure 16 Comparison for the hydrogenation of cis , trans , trans -1,5,9-cyclododecatriene (CDT) to cyclodecene (CDE) in a conven-tional Pd/Al 2 O 3 fi xed-bed reactor, fi xed beds of wires small cut foils and microstructural reactor (Wie ß meier and Honicke [82] ).

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140

Con

vers

ion

Time (min)

X(propane): microstructured catalyst

X(propane): conventional catalyst

S(propane): microstructured catalyst

S(propane): Conventional catalyst

Sel

ectiv

ity

Figure 17 Selectivity (S) and conversion (X) vs. time for dehydro-genation of propane in a fi lament-based catalyst and a conventional powder catalyst. Process parameters: temperature = 550 ° C, pres-sure = 0.14 MPa, space velocity = 116 1 h-1, and time = 3.1 s). (Wolfrath et al. [83]) .

Passive mixers are attractive because of their ease of operation and manufacture. Passive mixers such as static, vortex and jet mixers are sometimes also known as motionless mixers, need no mechanical energy input into the mixer itself (i.e., there are no blades, rotating shaft, seals, etc.). The process intensifi ca-tion fi eld is ever expanding and new technologies are being constantly developed. Therefore, the discussion here is not meant to be comprehensive.

When considering green synthesis processes, small size and rapid mixing in a device offers signifi cant advantages for

runaway, exothermic and fast reactions. The green synthesis chemical reactions with improved selectivity and high yields have already been successfully demonstrated with the use of high-intensity gas-liquid mixers [84] , rotor/stator mixers [85] and tubular reactors with static mixers [86] . Jim é nez-Gonz á lez and Constable [61] described a vortex mixer for continuous operation. The mixing was so effi cient that the solvents (e.g., methylcyclohexane) are not required for the process.

Yasui et al. [87] developed a new passive-type micromixer based on the baker ’ s transformation and reported fast mix-ing of a protein solution. They reported the complete mixing of a fl uorescein isothiocyanate (FITC) solution ( D = 2.6 × 10 -10 m 2 s-1) within 51 ms and an IgG solution ( D = 4.6 × 10 -11 m 2 s-1) within 306 ms with the microfl uidic baker ’ s transfor-mation (MBT) device with having 10.4 mm mixing length. Its mixing speed is 70-fold higher for a FITC solution and 900-fold higher for an IgG solution than the mixing speed by the microchannel without MBT structures.

Penth [88, 89] at Synthesechemie (Heusweiler, Germany) developed a jet mixer confi guration where different jets col-lide and become intensely mixed. In the jet mixer, confi gura-tion reactants are sprayed as liquid jets through a diamond or sapphire nozzle (with openings between 60 and 350 mm). In this device, the gas is introduced from the side of the cham-ber to remove the reaction mixture from the reactor. In this confi guration, the fl uids coincide outside of the mixer and become mixed within a short length of time. Further fouling does not takes place within the microchannels, as reactants do not come into contact with each other but instead mix in an open space and are transported by an adjustable gas stream. Werner et al. [90] carried out the formation of a quaternary amine from 4,4 ′ -bipyridyl and bromoacetic acid ethyl ester in the impinging jet mixer, where solids are formed during the




reaction. It was reported that the reaction could be carried out up to 8 h continuously with a yield of 75 % , which is higher as compared to the batch operation. The impinging jet mixer prevents solid formation within the mixer and can be arranged in a vertical arrangement.

The research group at BHR developed a shell and tube reconfi gurable reactor where static mixer elements were inserted in the tubes (Figure 18 ). Flexible static mixing ele-ments are used over wide operating conditions. The reactor can be scaled up by adding more elements and increasing length. For the production of glycidyl ether, the reactor with static mixing elements was used to pre-mix the alcohol and chloroalkylepoxide stoichiometrically before the main reac-tor. The reactor consists of two twisted tubes in a helix format to create strong internal circulation (radial mixing) to enhance heat transfer at low Reynolds numbers. The fast preparation 1,3-diol monoesters has been carried out in microreactors with the rapid water-free method in the presence of monoal-coholates of 1,3-diols as catalysts [91] . The new process with the microstructured reactor resulted in fast and clean reactions as compared to the old process which uses several inorganic catalysts. The obtained yields were very high and minimum amounts of side products were observed.

Table 3 Advantages and disadvantages of microreactors.

Advantages Disadvantages

Higher heat transfer (rapid heating and cooling desired in a reaction), Controlled exothermic and runaway reactions, Low to high operating pressure, Narrower residence time distribution, High surface area to volume ratio, Compact size, and Higher selectivity and yield (reduced possibility of side reactions), Safe due to low reactants and products involved in the reactor.

Presence of solid in microreactor leads to clogging and fouling, Low fl ow rates, Less product per reactor.

Reactant in

Reactant out

Shell fluid in

Shell fluid out

Static mixer elements

Figure 18 Reactor with static mixer elements (residence times 25 – 30 min, 20 bar, -250 ° C, single-ended or double-ended design).

4.3. Microwave technology

The microwave wavelength varies from 1 mm to 1 m which is similar to the frequencies in RADAR and telecommuni-cation devices. For microwave chemistry applications the wavelength of 12.2 cm (which corresponds to the frequency of 2450 MHz) is readily available. The microwave energy is not transferred by the conduction and convection process; however, energy being imparted to a substance is a complex process and involves several aspects. There are two main mechanisms by which material dissipates microwave energy, namely dipolar polarization and ionic conduction. In the dipolar polarization method, when a substance having dipole moment subjected to the electromagnetic radiation it will attempt to align itself with the electromagnetic fi elds by rota-tion. This resulted in rotation in molecules, which generates heat. The effi cacy of this method depends on the dielectric relaxation time, which further depends on temperature and viscosity of the sample. Another dissipation mechanism is the ionic conduction, where migration of dissolved ions takes place due to the oscillating electric fi eld. Heat is generated due to frictional losses, which depends on the size, charge and conductivity of the ions as well as on their interactions with the solvent. Compounds such as water, ethanol and acetonitrile tend to heat readily under microwave irradiation due to their high dielectric constants. However, compounds such as aromatic and aliphatic hydrocarbons or compounds with no net dipole moment (e.g., carbon dioxide, dioxan and carbon tetrachloride) do not go readily under microwave irra-diation. The microwave may be considered a more effi cient source of heating than conventional steam or oil baths as energy is directly transferred to the reaction medium rather than through the wall of the reaction vessel.

Using microwave-assisted technologies the reaction time is considerably shortened, a heating rate of ≈ 10 ° C s-1 can be achieved. There are several studies available which report improved reaction selectivity and yields using microwave heating. However, the interpretation of microwave-heated reaction is diffi cult due to the high heating rate especially in the fast reactions. In the case of heterogeneous reac-tions, if the reaction temperature is not monitored or mea-sured precisely this may result in a problematic situation. In the case of enzymatic processes, the reaction takes place faster as compared to the conventional process under




similar temperature conditions; however, the infl uence of microwaves has been reported [92 – 94] . The kinetics for the enzymatic catalyzed reaction was not determined due to this reason and the approach resulted in misleading data regarding rate. In the following section, the different PI confi gurations used for microwave-assisted synthesis are discussed.

4.3.1. The continuous microwave reactor (CMR) The fi rst continuous microwave reactor (CMR) was designed and developed by Cablewski et al. [95] to carry out reactions in organic solvents (Figure 19 ). In a microwave cavity it is diffi cult to obtain uniform energy distribution and temperature control and to monitor, due to its electromagnetic fi elds, behavior. The CMR system is composed of a microwave cavity fi tted with a coil (continuous microwave reactor) fabricated from a microwave-transparent material, metering pump and pressure gauge at the inlet end, and a heat exchanger and pressure regulating valve at the effl uent end. Pressure regulating was provided at the inlet and effl uent ends to monitor and control the pressures. For monitoring and controlling temperatures, thermosensors were provided at the inlet and effl uent ends and after the heat exchanger. The heat exchanger was installed for rapidly cooling of the reaction mixture after it exits the irradiation zone. The CMR system was designed in such a way that it can withstand highly corrosive materials such as corrosive acids and bases, and therefore the contact between metal and reaction mixtures was minimized. To control the fl ow rate and temperature for heating and cooling of reactions, feedback microprocessor control was installed. For safety aspects, fail-safe parameters were implemented in the software so that if temperature exceeds the maximum allowable temperature the unit would shut down. For the reaction coil perfl uoroalkoxy (PFA), Tefl on16 or quartz tubing were used because they are chemically inert, microwave-transparent and allow physical observation of the reaction mixture in the microwave zone. As PFA Tefl on tubing of 3 mm (l/8 in.) inner diameter and 6 mm (l/4 in.) outer diameter could be used satisfactorily at 200 ° C and 1400 kPa, therefore the maximum allowable operating temperature and pressure were limited to these values. A commercial CRM unit has a

volume of 120 ml in the microwave zone, 80 ml in the cooling zone with a pump which can produce fl ow rates up to 100 ml min-1, therefore the residence time in the microwave zone are typically varied from 2 to 10 min [96, 97] .

Strauss and Trainor [98] carried out several reactions using CMR in the presence of solvents which include nucleophilic substitution, addition reactions, esterifi cations, transesterifi -cations, acetalizations, base- and acid-catalyzed hydrolyses, isomerizations, oximations, decarboxylations, eliminations and name (Michael addition, Hofmann degradation, Williamson ether synthesis, Claisen rearrangement, Mannich, Finkelstein, Baylis-Hillman, Diels-Alder and Knoevenagel) reactions. It was shown that for several volatiles, it is possible to carry out reactions in the CMR at temperatures up to 100 ° C higher than the boiling point of the solvent at atmospheric pressure. This resulted in rapid reaction and the reaction time reduced by up to three orders of magnitude as compared to conventional heating. In the case of homogeneous reaction mixtures [99, 100] , it was reported that the enhancement in rate resulted from the elevated temperature rather than from microwave heating.

The preparation of the acetonide of glycerol takes 21 – 36 h with a conventional method and resulted in a 87 – 90 % of isopropylideneglycerol yield [101] , whereas using CMR technology the reaction was 1000 – 1800 times faster and a comparable yield was obtained. For the oximation of Ph 2 CO reaction with batchwise microwave irradiation, Gedye et al. [102] reported a 68 % yield of benzophenone oxime after 2 min of heating, whereas when the same reaction was carried out with a similar proportion of reagents and solvents CMR technology resulted in 93 % yield within 1.5 min of reaction time.

CMR technology was used for the Williamson synthesis of BnOPh, a yield 67 % was obtained within reaction time of 1.5 min at 144 – 7 ° C using MeOH as solvent, whereas in the case of conventional continuous microwave heating a conver-sion of 49 % within a reaction time of 10 min was reported by Chen et al. [103] . Furthermore, as compared to the batchwise techniques [102, 104] , in CMR it was reported that there is no waiting time for the pressure and temperature to decrease before accessing the reaction mixture. It is highly advanta-geous for reactions that require heat but produce thermally

PS °C

°C

°C

°C6

10

66

87

9

5

6

1

2

34

1. Reaction mixture2. Pump3. Pressure sensor4. Microwave cavity5. Reaction coil

6. Temperature sensor7. Heat exchanger8. Pressure control valve9. Electronic key pad and display

10. Product mixture

Figure 19 Schematic diagram for continuous microwave reactor. (Source: Cablewski et al. [95] ; reprinted with kind permission from American Chemical Society. Copyright (1994). )




labile products. In addition, sample analysis from the reac-tion can be carried out while (or before) fresh material is pro-cessed. Some of the advantages offered by CMR technology are shown in Table 4 .

Although there are several advantages with CRM technol-ogy, it has, however, numerous limitations. The CMR tech-nique would not be appropriate when:

solids or highly viscous liquids are to be heated (due to • the blockages brought about by the presence of insoluble solids), the reaction requires low temperature conditions through-• out, and materials or reactions which are incompatible with • microwave energy (e.g., metals or reactions involving pre-dominantly non-polar organics) are to be employed.

Bagley et al. [105] designed a new continuous microwave reactor based on fl ow cell feature to make optimum use of the cavity and to be able to monitor the temperature of the fl ow cell directly using the instrument ’ s in-built IR sensor (Figure 20 ). The cell-based CMR unit has a glass tube reactor with a capacity of 10 ml fi tted with a custom-built steel head. The unit is fi lled with sand ( ∼ 10 g) between two drilled frits to minimize dispersion and effectively create a lattice of micro-channels, charged with solvent ( ∼ 5 ml volume), sealed using PTFE washers and connected to an HPLC fl ow system with a back-pressure regulator (Figure 20, inset). The fl ow cell was inserted into the microwave cavity. Before introducing reagents into the reactor the unit was irradiated and stabilized at the required reaction temperature through moderation of microwave power. The advantages of this system over the available coils are as follows: online measurement of the fl ow cell temperature, no additional and expensive equipment required (e.g., HPLC pump) and it has the potential to carry out heterogeneous as well as homogeneous reactions simply by immobilizing a catalyst on the support in the glass tube.

The performance of the cell-based microwave CF reactor has been characterized in two well-precedented microwave-assisted reactions operating under continuous fl ow (CF)

processing: (i) the hydrolysis of chloromethyl-thiazole to give hydrochloride, (ii) a Fischer indole synthesis of hydrazine and cyclohexanone in acetic acid, and (iii) synthesis of pyridines based upon the Bohlmann-Rahtz (B-R) reaction; in all cases sand is used as the packing agent. For indole synthesis a yield of 85 – 91 % was achieved at 150 ° C, processing 1 g in 15 – 30 min. Bagley et al. [105] carried out microwave organic syn-thesis of pyridine 6 using different glass tubes and heating coils (Table 5 ) and demonstrated that a glass tube CF reac-tor offers (i) improved heating effi ciency, (ii) the potential for operation on a large scale, (iii) successful transfer from batch to CF processing, and (iv) improved performance over commercial Tefl on heating coils. It was reported that a higher processing rate can be achieved with a glass tube reactor as a faster fl ow rate can be maintained without compromising the reaction temperature and yield.

4.3.2. The microwave batch reactor (MBR) Cablewski et al. [95] designed, developed and discussed the advantages of continuous microwave reactor (CMR). However, CMR technology may not be appropriate for kinetics studies, or when solids or highly viscous liquids are to be heated. However, it is more suitable for chemical processing or process optimization than once-only synthetic reactions on a small scale. These limitations of CMR technology has resulted in the development of a new microwave batch reactor (MBR). The MBR unit is composed of a stirrer, thermosensors, pressure monitoring and controlling devices, which has the maximum operating limit as 200 ° C and 1 MPa [100] . However, this MBR technology lacks the capability for withdrawing samples during a reaction and the post-reaction cooling. Therefore to upgrade this, Raner et al. [106] developed a more advanced laboratory-scale MBR, where samples can be withdrawn online and the unit can be operated at higher temperature and pressure (Figure 21 ). The MBR unit has a capacity of 20 – 100 ml, with upper operating limits of 260 ° C and 10 MPa (100 atm). The following reactions were carried out to investigate the performance of MBR unit: oxidation, elimination, esterifi cations, hydrolysis of a tertiary

Table 4 Advantages of continuous microwave reactor technology.

Rapid heating as compared to conventional heating, resulted in short time for heating up and cooling down reaction mixtures.(a) No substantial heating in the irradiation chamber while the reaction mixture is heated directly, also heating ceases immediately as the (b) power is turned off. Important for safety aspects. The continuous fl ow process allows quick removal from the reaction and cooling zone.(c) Irradiation results in minimal temperature gradients across the coil and therefore the temperature of the material on the wall of (d) the reaction vessel is not signifi cantly different from that in the body of the liquid. Pyrolysis on the inner wall of the tube is thus minimized. Reactions require high temperatures and higher boiling solvents can be carried out under pressure at these temperatures, but in lower (e) boiling solvents, therefore facilitating work-up. Low boiling reactants can be heated to high temperatures under the applied pressure and then cooled before exiting the pressurized (f) zone. Therefore, the losses of volatiles from the reactors are minimized. Reactions can be sampled and analyzed while material is being processed due to fl ow-through processing. If required, reaction mix-(g) tures can be subjected to multiple passes through the CMR, or the conditions changed during a run. Owing to the continuous nature of the system, reactions carried out in the laboratory can be scaled up easily.(h) Moderate to high temperature reactions can be carried out in a vessel fabricated from an inert material (e.g., PFA Tefl on, PTFE or (i) quartz). This would be benefi cial where reactants or products are incompatible with metals or borosilicate glass.




amide, etherifi cation, isomerization, Hofmann elimination, α -iodination of a carboxylic acid, Claisen rearrangement, aminoreductone formation and Willgerodt reactions. The MBR unit is advantageous as it has capability for rapid heating and quenching of reaction mixtures, a stirrer for mixing and to ensure minimal temperature gradients within the sample, elimination of wall effects, direct measurement of the reaction temperature and pressure, valving and plumbing to facilitate sample introduction and withdrawal during the heating period, rapid cooling post-reaction, and a facility for conducting reactions under an inert gas atmosphere. Safety aspects were considered during the design of the MBR unit. For rapid synthesis of molecules for drug discovery, a robotically operated MBR unit with capacity of 2 – 3 ml was designed and manufactured by Personal Chemistry (Uppsala, Sweden).

Nakamura et al. [107] carried out polycondensation of lactic acid using three different types of MW reactors (SMW-087, SMW-101 and SMW-114) designed by Shikoku Instrumentation Co. Ltd. (Takamatsu, Kagawa, Japan). Each reactor system has different capacities (Table 6 ). The SMW-087, commercially known as µ Reactor, is a multimode MW instrument with a 2.45 GHz magnetron (maximum power 700 W) and 21.5 l cavity (Figure 22 ). It consists of a glass reaction vessel with maximum reaction volume as 70 ml. The SMW-101 is made of a cylindrical heavy glass wall reac-tion vessel placed in a 69-l cavity made of stainless steel. Its maximum reaction volume, reaction temperature and the MW output power are 300 ml, 400 ° C and 1500 W at 2.45

GHz, respectively. The top of the cylindrical vessel is closed by a stainless steel cover perforated with fi ve holes, allowing overhead stirring, temperature measurements, gas injection and vacuum pumping in the reaction vessel (Figure 23 ). With a 366-l maximum cavity size, SMW-114 is a bench-scale MW reactor in anticipation of a pilot plant (Figure 24 ). Its maxi-mum reaction volume and MW power output are 30 l and 6000 W, respectively. Similar to the SMW-101, the reaction vessel in SMW-114 has a fi ve-neck separation fl ask equipped (for overhead stirring, temperature and pressure measure-ments, and vacuum pumping) with a bottom outlet which is used to extract the resulting product.

Bergamelli et al. [108] carried out six pharmaceutical reactions (Newman-Kwart rearrangement, ortho Claisen rearrangement, an acid-catalyzed benzofuran formation, an alkylation reaction, a Heck reaction and a nucleophilic aro-matic substitution reaction) in a commercial microwave batch reactor, the Milestone FlowSYNTH, Milestone (Italy) ( www.milestonsrl.com) (Figure 25 ). It is a 1600-W multimode microwave reactor with a magnetron which is able to deliver power in 1 W increment. The reaction chamber consists of a PTFE tube of 200 ml capacity protected by a quartz-fi ber reinforced polyetheretherketone (PEEK) sheath and is verti-cally mounted in the microwave cavity. A steel frame pro-vides the required mechanical strength. The reaction mixture is pumped by a high-pressure membrane pump from the base upwards through the column to the top where a chiller unit then rapidly cools it. An Archimedean screw provides plug-fl ow characteristics within the column. This is fi tted with

HPLC pump

Reagents IR sensor Product

IR sensor

Drilled porous frit

MW

Sand

Drilled porous frit10 ml glass

pressure tube

Steel head

Outflowinflow

MW

MW cavity

MW MW

Back pressureregulator

Figure 20 Continuous fl ow microwave reactor and fl ow cell. (Source: Bagley et al. [97] .)

Table 5 Sealed tube and continuous fl ow processing. (Source: Bagley et al. [105] .)

Flow rate (ml min-1) Isolated yield ( % ) Residency time (min)

Sealed tube (batch experiment) > 98 2CF coil (continuous fl ow processing in a Tefl on heating coil) 1 > 98 5

1.5 85 3.3CF glass tube (continuous fl ow processing in a glass tube reactor 1 > 98 3charged with send) 1.5 > 98 2




1. Pressure transducer2. Pressure relief valve3. Sample addition/removal port4. Fiber-optic thermometer5. Cold-finger

6. Retaining cylinder7. PTFE reaction vessel8. Top flange, and 9. Magnetic stirrer bar

108

3

P

91

11

2

4

1312

5

7

6

1. Reaction vessel2. Top flange

A

B

3. Cold-finger4. Pressure meter5. Magnetron

10. Fiber-optic thermometer11. Load matchingdevice12. Waveguide13. Multimdal cavity (applicator)

6. Forward reverse power meters7. Magnetron power supply8. Magnetic stirrer9. Computer

5

81 2 3 4

7

6

9

Figure 21 Schematic diagrams of (A) microwave batch reactor and (B) reaction vessel. (Source: Raner et al. [106] ; reprinted with kind permission from American Chemical Society. Copyright (1995). )

Table 6 Characteristics of the multimode MW reactors. (Source: Nakamura et al. [107]. )

SMW-087 ( µ Reactor,specialized in polycondensation)

SMW-101 SMW-114

Cavity size/ W mm × D mm × H mm (volume) 320 × 320 × 210 (21.5 l) 500 × 460 × 300 (69 l) 750 × 750 × 650 (366 l)Maximum reaction volume 70 ml 300 ml 30 lMaximum output power (W) 700 (1 magnetron) 1500 (1 magnetron) 6000 (1 magnetron)Impedance matching – Three stub E-H tunertemperature controller Fiber-optic thermometer

(1 position)Fiber-optic thermometer (1 position)

Fiber-optic thermometer (2 positions)

Maximum reaction temperature ( ° C) 250 400 250Minimum pressure (without reagent) (Pa) 30 30 100Extra control Temperature controlled by PID and power constant control

PID, poportional-integral-derivative controller.

three Wefl on baffl es which also aid heating. The reaction mixture then exits through a back pressure regulator which regulates the pressure of the system/solvent, although in prin-ciple it is not required when operating below the solvent boil-ing point. The entire system is monitored and controlled by

computer interface, wherein data can also be collected. The MBR unit can operate up to maximum temperature and pres-sure up to 230 ° C and 30 bar (435 psi), respectively. The pump can operate at fl ow rates between 10 and 200 ml min-1, i.e., up to one column volume per minute or 12 l h-1. In addition,




Figure 22 µ Reactor showing the entire instrument. (Source: Nakamura et al. [107] ; reprinted with kind permission from American Chemical Society. Copyright (2010). )

Figure 23 SMW-101 MW reactor showing the entire instrument (left) and the reaction cavity (right). (Source: Nakamura et al. [107] ; reprinted with kind permission from American Chemical Society. Copyright (2010). )

the FlowSYNTH reactor can process slurries when operat-ing below the solvent boiling point. However, in practice, the back pressure regulator is required when operating near or above the solvent boiling point, and when other volatile reac-tion components are present. In these cases, slurries cannot be processed because the back pressure regulator contains a frit which is easily blocked by solids (or formation of solids during the reaction).

4.4. Ultrasonic technology

Mason and Cintas [109] have mentioned that there are three methods for the introduction of ultrasound into a reacting

system: (i) immersed reactor in a tank of sonicated liquid (e.g., fl ask dipped into a cleaning bath), (ii) an ultrasonic source directly immersed into the reaction medium (e.g., probe placed in a reaction vessel), and (iii) reactor constructed with ultra-sonically vibrating walls (e.g., a tube operating through radial vibrations). Of all three operation modes the fi rst two are used extensively in the chemical laboratory. The majority of these systems rely on the piezoelectric transducer as a source of ultrasonic power and all three suffer from the disadvantage that optimum performance is obtained at a fi xed frequency (20 kHz for commercial probe systems and 40 kHz for baths) that depends on the particular transducer employed.

4.4.1. The ultrasonic cleaning bath The ultrasonic cleaning bath is the most widely available and cheapest source of ultrasonic irradiation for the chemical laboratory. Although the ultrasonic bath can be used as a reaction vessel; however, it is not preferred due to the problems involved with chemical attack of the bath walls and with the containment of any evolved vapors and gases. Normally the glass reaction vessels are immersed into the ultrasonic bath (Figure 26 A). Therefore, conventional apparatus can be immersed directly into the bath and an inert atmosphere can be achieved readily and maintained throughout a sonochemical reaction. In ultrasonic baths it is important to establish the optimum position for the reaction vessel in the bath both vertically (due to the discrete wavelength of sound in water) and horizontally (in terms of the position of the vessel with respect to the transducers on the base). Water with a small amount of surfactants is normally used as the coupling medium in the bath, which limits the upper temperatures of operation to a maximum of just below 100 ° C. In ultrasonic baths it is important to monitor the temperature inside the reaction vessel because it is always a few degrees above the bath temperature due to localized ultrasonic heating.




Figure 24 SMW-114 MW reactor showing the entire instrument (left) and the reaction cavity (right). (Source: Nakamura et al. [107] ; reprinted with kind permission from American Chemical Society. Copyright (2010). )

A. Back pressure valveB. Reactor outletC. Column-stirrer motorD. Water-cooled jacketE. ReactorF. Control terminalG. High pressure pumpH. Water chiller

A B

Figure 25 The Milestone FlowSYNTH reactor for (A) continuous and (B) batch processing. Photo courtesy of Milestone (Italy). (Source: Bergamelli et al. [108] ; reprinted with kind permission from American Chemical Society. Copyright (2010). )

Stainless steel tank

Ultrasonic transducersbonded to base

Optionalheaters

Water+surfactant

Reaction mixtureA B

Generator

Screw fitting atnull point

Replaceable tip

Detachable horn

Upper fixedhorn booster

Casing containingtransducer element

Figure 26 The ultrasonic (A) cleaning bath and (B) probe for sonochemistry.




Recently, Joshi et al. [110] synthesized the bis(indol-3-yl)methanes with the reaction of indole with various aldehydes in water using ultrasound irradiation at ambient temperature using 1-hexenesulfonic acid sodium salt as catalyst. The time, yields and solvent used for the benzaldehyde reaction with 1H-indole in the presence of 1-hexenesulfonic acid sodium salt (10 mol % ) with and without ultrasonic waves is shown in Table 7 . It can be seen from Table 7 that in the presence of water as solvent maximum yield is obtained for both with ultrasonication (i.e., in 45 min) and without ultrasonication (i.e., in 120 min).

4.4.2. The ultrasonic probe In the ultrasonic probe systems the energy is directly introduced into the system rather than rely on its transfer from the water bath and the reaction vessel walls. This is achieved by introducing the ultrasonically vibrating tip of a sonic probe into the reaction itself (Figure 26B). The part of the probe system that conducts and amplifi es the vibrational energy from the transducer into the reaction is the acoustic horn. This has advantages over an ultrasonic bath including:

control of ultrasonic power delivered to the reaction, • high powers achieved from the ultrasonic streaming (from • the tip of the probe), and provides bulk mixing without the need for additional stir-• ring. Therefore, mechanical stirring is not required.

Most modern units have a pulse facility, allowing the opera-tor to sonicate reactions repeatedly for fractions of a second. This gives adequate time for bulk cooling between sonic pulses. However, it is more expensive than the bath and it is signifi cantly less convenient in use, especially in terms of the glassware required. Special seals are required if the horn is to be used in any reactions that involve refl ux, inert atmospheres or the pressure above (or below) ambient. The cavitation, which is the source of chemical activation, is also the source of a common problem with probe systems – tip erosion – which occurs despite the fact that most probes are fabricated of tita-nium alloy, which is very hard. There are two unwanted side effects associated with erosion: metal particles may erode from the tip and contaminate the reaction mixture, and the physical shortening of the horn causes a loss of effi ciency (eventually it will become too short to be tuned to the ultrasonic frequency used). The later problem is avoided by the use of screw-on tips

for the probe in the form of studs, which eliminates the need for a costly replacement of the whole horn.

4.4.3. Ultrasonic continuous reactor Cintas et al. [111] developed a fl ow US-reactor comprising three transducers (21.5 kHz) placed in the bottom of the chamber and attached to a high-quality titanium alloy plate (100 × 325 × 0.9 mm) (Figure 27 ) for biodiesel production from vegetable oil and methanol. Transducers consist of high-effi ciency pre-stressed piezoelectric rings (diameter = 50 mm) compressed between two ergal blocks. The frequency is tunable between 17 and 45 kHz with an optimal effi ciency at 21.5 kHz. Power can be varied up to a maximum of 900 W, corresponding to a mean value of 3 W cm -2 at the emitting surface and is monitored by a true reading wattmeter. The whole circuit comprises a 5-l cylindrical tank with mechanical stirrer and a peristaltic pump (power = 30 W). The fl ow reactor operates in the following manner: the cylindrical tank is thermostated (temperature range 0 – 90 ° C) by a fl ow of silicone oil through the external jacket and the internal coil. In the working system, the 0.5-l gastight sonication chamber is completely full of circulating liquid, whereas the 5-l tank can work up to a minimum volume of 0.1 l as the aspiration pipe ends very close to the bottom. The peristaltic pump draws fl uid from the tank and propels it through the sonication compartment. Two thermocouples monitor the temperature at different points of the system: (1) at the outlet from the sonication chamber and (2) in the tank. The temperature of the thermostated silicon oil is controlled by an external thermostat system. At optimum fl ow rate of 55 ml min-1, the transesterifi cation was performed at three different power levels, namely 500, 600 and 700 W. The best power/conversion ratio was observed at 600 W, which resulted in maximum temperature of 49 – 50 ° C and gave total conversion to methyl esters after 1 h fl ow.

Zhou et al. [112] designed two types of structures for the sonochemistry reactors (Figure 28 ), consisting of a cylindri-cal tube and a single transducer (Figure 28A) or a transducer at each end (Figure 28B). In each case the tube is an integral multiple of the half wavelength in its material, and it has the inlet and outlet of the liquid near its ends. Liquid fl ows into the tube from the inlet and is processed inside the tube. The reactor shown in Figure 28B has a similar structure as that shown in Figure 28A, but is driven by transducers at two ends. Thus, the former can generate stronger ultrasound.

Table 7 Hexenesulphonic acid sodium salt (10 mol%) catalyzed reaction of benzaldehyde with 1H-Indole in presence as well as absence of ultrasonic waves (source: Joshi et al. [110].)

Entry Solvent With Ultra sonication(reaction time-45 min)

Without Ultra sonication(reaction time-120 min)

Isolated yield (%) Isolated yield (%)

1 Toluene 25 202 Dichloromethane 34 283 Acetonitrile:water (8:2) 65 534 Methanol 72 605 Ethanol 78 706 Water 94 85




A

1. Sonication chamber

5

2

4 1

11

3

8

10

9

6

7

8. Thermostatting liquid 9. Peristaltic pump10. Inlet11. Outlet

7. Mechanical stirrer

3. Titanium plate

5. Air cooling6. Tank

4. Screwed cover

2. US transducers

B

Figure 27 Flow diagram for continuous fl ow reactor (A) top view of bath and (B) probe for sonochemistry. (Source: Cintas et al. [111] ; published with kind permission from Elsevier . )

Although the above two reactors have different structures, their operating principles are same. The piezoelectric trans-ducers supply longitudinal vibration from the tube ’ s ends to the tube in which the longitudinal vibration is effectively transformed into transverse radial vibration so that ultrasonic energy is emitted from the cylindrical tube and ultrasound is focused to form a high-intensity ultrasonic fi eld inside the tube. The whole vessel wall of the tubular focused sono-chemistry reactor can radiate ultrasound, so its radiating area is larger and its electroacoustic transfer effi ciency is higher than those of a common sonochemistry reactor. The designed tubular sonochemistry reactor can run in a mode of continu-ous fl ow, and its length can be up to 2 m.

Mo et al. [113] optimized the reaction conditions for the synthesis of bis(indolyl)methanes under ultrasonication based preparation using a Kunshan KQ-250B ultrasonic reactor with a frequency of 40 kHz and a power 250 W. The various sol-vents, catalysts used for the preparation of bis(indolyl)meth-anes are summarized in Table 8 . The ionic liquids [bmim]BF 4 , [bmim]Br and [bmim]Cl, reported lower yields (0 – 39 % ) for this reaction, whereas the highest yield (97 % ) was obtained with [(CH 2 ) 4 SO 4 HMIM][HSO 4 ] within a shorter time (0.5 h) period. This may be due to the strongest Br ø nsted acid char-acteristics of [(CH 2 ) 4 SO 4 HMIM][HSO 4 ] among other ionic liquids. It can also be seen that in the absence of a catalyst a reaction did not take place.

4.5. Spinning disc reactor technology

Jachuck [114] developed an innovative device known as the spinning disc reactor (SDR) technology. The SDR technology utilizes the effects of centrifugal force and is capable of pro-ducing highly sheared thin fi lms (Figure 29 ) on the surfaces of rotating discs/cones. The technology is composed of smooth,

Lead wire

Piezoelectrictransducer

Liquid inlet Liquid inlet

Liquid outletLiquidoutlet

A B

Hollowcylindrical tube

Figure 28 A tubular focused sonochemical reactor driven by a (A) single transducer and (B) transducer at each end. (Source: Zhou et al. [112].)

grooved or meshed (depending on throughput requirement and applications) surface. The design parameters of SDR technol-ogy are as follows: the diameter of the disc varies from 0.06 to 0.5 m and the rotational speeds may range from 0.34 to 10,000 g (or 100 to 6000 rpm) (typically around 1500 rpm). The advantages of SDR technologies are as follows:

the development of thin liquid fi lm resulted in intense mixing, • narrower residence time distribution, • plug fl ow characteristics, and • high heat and mass transfer coeffi cients. •

Jachuck and Ramshaw [115] used the SDR technology for various heat and mass transfer application and reported high mixing intensity and heat and mass transfer effi cien-cies by providing an appropriate fl uid mixing environment




to achieve faster reaction kinetics. Owing to the above advantages of SDR technology, Boodhoo and Jachuck [116] used it to perform free-radical and condensation polymer-ization reactions (fast precipitation and catalyzed organic reactions). The application of SDR technology has resulted in time savings for the polymerization of styrene. Wilson et al. [117] performed a catalytic reaction in the presence of zinc trifl ate as catalyst using SDR technology for the rear-rangement of α -pinene oxide to campholenic aldehyde. For the same amount of feed the conversion using SDR tech-nology was 95 % (time 17 s), whereas for the batch reactor it is 50 % (time 900 s); and the yield was 71 % with SDR technology, whereas with the batch reactor it was 42 % . The study suggested that by using SDR technology, it is pos-sible to achieve faster reaction rates, improved yield and

elimination of the downstream separation process for cata-lyst recovery.

Oxley reported fi ve different reactions using spinning disc technology: (i) phase-transfer Darzen ’ s process, (ii) crystal-lization study, (iii) Knoevenagel reaction, (iv) condensation process, (v) elimination reaction, and (vi) exothermic con-densation. For a phase-transfer-catalyzed (ptc) Darzen ’ s reac-tion, as compared to the conventional batch processes, SDR technology reduced 99.9 % reaction time, 99 % inventory and 93 % impurity level. In the case of recrystallization, uniform particle size distribution and a mean size of around 3 µ m was obtained. It was reported the SDR technology will result in 8 ton year-1 of production capacity.

In a novel rotor-stator spinning disc reactor, Meeuwse et al. [118] reported that the mass transfer coeffi cient

Adjustable track

Gas inlet

Internally cooled/heated spinning disc

Inert gas Inert gas

Sample foranalysis

Cooling water jacket

Turbulence promoter

Reactor cover

To scrubber

Liquid feed

Inlet path of cooling/heating fluidOutlet path of cooling/heating fluid

Figure 29 Spinning disc reactor (SDR) schematic. (Source: Jachuck et al. [114] ; reprinted with kind permission from John Wiley & Sons. Copyright (2007). )

Table 8 Indoles (1mmol) and 4-chlorobenzaldehyde (2mmol) reaction under different solvents, catalysts, methods at 25-30 ºC (source: Mo et al. [113].)

Method Solvent Catalyst Catalyst quantity (mol%)

Reaction time (h)

Isolated yield (%)

High speed stirring Ethanol (C2H5OH) None 24 0Ultra sonication Ethanol (C2H5OH) None 24 0Ultra sonication Ethanol (C2H5OH) [bmim]BF4 20 2 39Ultra sonication Ethanol (C2H5OH) [bmim]Br 20 2 39Ultra sonication Ethanol (C2H5OH) [bmim]Cl 20 2 0Ultra sonication Ethanol (C2H5OH) [Hmim]HSO4 20 1 87Ultra sonication Ethanol (C2H5OH) [(CH2)4SO4 HMIM][HSO4] 20 0.5 97Ultra sonication Ethanol (C2H5OH) [(CH2)4SO4 HMIM][HSO4] 1 1.5 79Ultra sonication Ethanol (C2H5OH) [(CH2)4SO4 HMIM][HSO4] 5 1 91Ultra sonication Ethanol (C2H5OH) [(CH2)4SO4 HMIM][HSO4] 10 0.5 97Ultra sonication Ethanol (C2H5OH) [(CH2)4SO4 HMIM][HSO4] 10 0.5 95a

High speed stirring Ethanol (C2H5OH) [(CH2)4SO4 HMIM][HSO4] 10 1 88Ultra sonication Water (H2O) [(CH2)4SO4 HMIM][HSO4] 10 1 90Ultra sonication Water (H2O) [(CH2)4SO4 HMIM][HSO4] 10 0.5 82Ultra sonication CH3CN [(CH2)4SO4 HMIM][HSO4] 10 1.5 86Ultra sonication ClCH2CH2Cl [(CH2)4SO4 HMIM][HSO4] 10 2 91

a [(CH2)4SO4HMIM][HSO4] was refused.




( k GL a GL ) is one order of magnitude higher than the conven-tional reactor system; however, the energy input is around three orders of magnitude higher (Figure 30 ). Meeuwse et al. [118] estimated the ratio of gas-liquid mass transfer coeffi cient to the energy dissipation ( k GL a GL / E d ) for a rotor with a different radius. For example, for a rotor with 0.135 m the rate of gas-liquid mass transfer per unit of energy dis-sipation ( k GL a GL / E d ) is around 0.4 ml 3 MJ -1 and 1.1 ml 3 MJ -1 for a rotor with 0.066 m radius. Whereas in the case of stirred tank reactor with a Rushton stirrer the rate of gas-liquid mass

Cocurrent packed bed

Bubblecolumn

Micro packed bed

Solidfoam

Rotor-statorspinning discreactor

Stirred tank

Countercurrentpacked bed

Energy dissipation rate (W m-3R)

10110-3

10-2

10-1

k GLaGL

(m3 L m

-3 R s

-1)

100

101

102 103 104 105 106 107

Figure 30 Volumetric mass transfer coeffi cient vs. energy dissipa-tion in different multiphase reactors. (Source: Meeuwse et al. [118] , Stemmet et al. [119] , Trambouze and Euzen, [120] ; reprinted with kind permission from John Wiley & Sons. Copyright (2012). )

transfer per unit of energy dissipation is around 80 ml 3 MJ -1 [121] . From Figure 23 is can also be seen that the mass trans-fer coeffi cient is higher as compared to the conventional equipment [ 118–120 ]. The higher mass transfer coeffi cients in the rotor-stator spinning disc reactor can have a signifi -cant infl uence on the selectivity in the case of competitive or consecutive reactions. Furthermore, small volume or reactor size in the case of the rotor-stator spinning disc reactor can increase the safety of a process, feasible to work at higher pressures.

4.6. Oscillatory fl ow reactor

NiTech Solutions Ltd. (East Kilbride, Scotland, UK) devel-oped a continuous oscillatory baffl ed tubular reactor (COBR) that can achieve plug fl ow at very low Reynolds numbers [122] . The COBR is composed of a tubular device with peri-odically spaced orifi ce baffl es superimposed with fl uid oscilla-tions. The interaction between the oscillating fl uid and baffl es creates vortices, which results in effi cient and uniform mixing in the gap between the two baffl es. The device is effective at low volumetric fl ow rates (i.e., Reynolds numbers < 300). The schematic of a COBR is shown in Figure 31 . The advantages of the COBR are as follows:

The complete mixing in radial direction eliminates the • mass gradients of reactants build-up and allows instant contact between reactants, which leads to faster reactions. Elimination of heat and mass gradient resulted in shorter residence time. A comparison for time comparison is shown in Table 9 between stirred tank reactor (STR) and COBR. The reaction process is safe as no large pumps, and storage • tanks are required for the transportation of reactants. This also resulted in saving of energy. Uniform solid suspension and conveying along the tubu-• lar reactor. Ni [122] at NiTech mixed a toxic solid with an

Orifice

BafflesHeating/cooling

jacket

40 mmdiameter

Inputs ofreactants

Flow meter

Oscillation

Pump

TankLiquid

Product

Figure 31 Schematic of a continuous oscillatory baffl ed reactor (COBR). (Source: Ni [122] .)




Table 9 Comparison of overall reaction time between STR and COBR ™ . (Source: Ni [122].)

Process Batch STR COBR ™

A fi ne chemical 6 h 30 minA polymer 8 h 45 minA specialty chemical 12 h 40 minOne stage reaction of an API 10 h 20 minA sugar based product 30 min 15 minCoagulation 1 h 10 s

COBR, continuous oscillatory baffl ed tubular reactor; API, active pharmaceutical ingredient.

aqueous liquid in COBR and STR (batch reactor). The mix-ing time reported for 3000 l mixture was 12 h for the STR, whereas with the COBR it was 10 s at the rate of 6 l min-1.

4.7. Multifunctional membrane technology

The application of membranes in the green synthesis process is relatively a new method to simultaneously carry out reac-tion and separation processes [123] . A module of cross-corru-gated membranes is shown in Figure 32 , where both reaction and separation processes can be simultaneously carried out in a miniaturized module. The membrane is designed so that it will allow a desired species to pass through it (e.g., the product of organic synthesis), while holding another (e.g., a byproduct or unreacted feed). Here, the rate of transport of reactant or product is controlled by keeping apart the miscible fl uids. Reuben and Sjoberg [124] reported that, with a phase-transfer catalyst, multifunctional membrane technology can be used for performing organic reactions in pharmaceutical, cosmetics, agricultural, chemical and food industries. In an early study by Starks [125] , it was reported that on reacting 1-chloroctane with aqueous cyanide produced 1-cyanooctane

2 mm

1 mm

Figure 32 Cross-corrugated membrane. (Source: Hall et al. [123] ; reprinted with kind permission from Elsevier. Copyright (2001). )

in the presence of quaternary ammonium salt and the reaction was complete within a few hours, whereas in the absence of phase transfer catalyst there was no reaction.

Similarly encouraging results were reported for the oxida-tion reaction of benzyl alcohol in the presence of tetrabutylam-monium salts using cross-corrugated membrane technology. It was reported that there was a ≈ 90 % conversion with cross-corrugated membranes, whereas with the fl at membrane the conversion was ≈ 50 % . Therefore, from these encouraging results it can be proposed that multifunctional membrane technology can be advantageous for other reactions such as alkylation, esterifi cation, oxidations/reductions, epoxidation, condensation reactions, polymerization, etc.

Membranes comprising reactive nanoparticles (Fe and Fe/Pd) immobilized in a polymer fi lm (polyacrylic acid, PAA-coated polyvinylidene fl uoride, PVDF membrane) were used for the preparation of nanoparticles [49] . The membrane supported nanoparticles were successfully used for the degradation of a common and highly important pol-lutant, trichloroethylene (TCE). The rate of TCE degra-dation was found to increase linearly with the amount of Fe immobilized on the membrane. To compare the green reducing agent, Fe and Fe/Pd nanoparticles were synthe-sized in membranes using sodium borohydride as a reduc-ing agent. Initially the mass transfer coeffi cient values for this case (for Fe) were one order of magnitude higher than the tea extract synthesized nanoparticles; the rapid oxida-tion reduced their reactivity to <20 % within four cycles. However, in the case of green tea extract nanoparticles, the initial reactivity in the membrane domain was preserved even after 3 months of repeated use. Although chemical reduction techniques have many advantages, there are also several disadvantages.

4.8. Coiled fl ow inverter (CFI) technology

Saxena and Nigam [126] developed an innovative device based on the principle of fl ow inversion. The working prin-ciple of the coiled fl ow inverter (CFI) is multiple fl ow inver-sion which is effectively achieved by changing the direction of centrifugal force by 90 ° in coiled tubes. The device con-sists of 90 ° bends inserted in coils, with equal space before and after the bend (Figure 33 ). A single unit of CFI has sev-eral consecutive 90 ° bends and coils depending on the num-ber of applications of the device (Figure 34 A). The random mixing in the cross-sectional plane is achieved due to helical coils and complete fl ow inversion because of bending, which results in complex secondary fl ows in a plane normal to the principal fl ow direction. By shifting the plane of curvature from one bend to the next, one can induce a class of trajecto-ries in one bend, and then deform it to another type in the next bend, and so on. It shows that if the direction of centrifugal force is changed by any angle, the plane of vortex formation also rotates with the same angle. This phenomenon of cross-sectional mixing has been found to enhance the advection of passive scalars and therefore improve the effi ciency, leading to homogenization in the fl uid volume and thus better mix-ing [128] . In comparison to conventional mixers and heat




At the endof straighthelix

d p Direction ofcentrifugal force

Direction ofcentrifugal force

After thefirst bend

After thesecond bend

15°

From inlet

Outlet Dc

Ly

Lz

Figure 33 Coiled fl ow inverter confi guration and fl ow patterns at various bends. (Source: Ghorai et al. [127] ; reprinted with kind permission from American Chemical Society. Copyright (2008). )

exchangers, it has a 2-fold advantage: it intensifi es the con-vective transfer processes (i.e., increased heat and mass trans-fer coeffi cients) and provides increased transfer area per unit volume of space. In CFIs, Kumar and Nigam [129, 130] and Mridha and Nigam [131] reported 20 – 30 % enhancement in the heat transfer coeffi cient as compared to the conventional coiled tube heat exchangers and 50 – 60 % as compared to the conventional straight tube heat exchangers. Kumar et al. [132] and Mandal et al. [133] carried out heat transfer experi-ments on a pilot-plant scale using CFI confi guration as heat exchanger (Figure 34b) and reported a signifi cant enhance-ment in the heat transfer as compared to the conventional heat exchangers (Figure 35 A). Vashisth and Nigam [127, 134, 135] reported the performance of CFI confi guration as a mul-tiphase reactor for biphasic reaction applications (e.g., bio-fuel synthesis). Mridha et al. [136] reported the liquid-liquid mixing of the oil-water system in a CFI confi guration (Figure 35B). The mixing performances and pressure drop in CFI was compared with the straight tube, coiled tube and helical ele-ment mixer (HEM) for Reynolds number varying from 98 to 1020. It was reported that there is a signifi cant enhancement in mixing of two liquids with negligible pressure drop in CFI

as compared to a coiled tube as well as a HEM. Recently, Mridha et al. [137] investigated the free radical polymeriza-tion of styrene in the CFI reactor. It was reported that the CFI reactor has a better degree of polymerization as compared to the straight tube. It was proposed that this confi guration can be used as a microfl uidic reactor which can help in achieving a better control over the free radical polymerization.

5. Summary and future perspective of process

intensifi cation in green synthesis

In chemical industry, chemical handling and processing is a great concern as it involves large volumes and safety con-cerns. Green synthesis of chemicals resulted from the con-tribution of researchers and engineers from multidisciplinary fi elds towards sustainable development with a signifi cant reduction of the impact on the environment. In past few decades volumes of research have been published and tech-niques were developed for the green synthesis processes. In the present work, an analysis of green synthesis of chemicals from a particular database has been carried out ( www.scopus.

A B

Figure 34 (A) coiled fl ow inverter as mixer/reactor and (B) coiled fl ow inverter as heat exchanger.




Inlet

B

A

Straight tube Straight coiled tube CFI

L=1.33 m

L=2.67 m

L=4.01 m

OutletL=5.34 ma b c

200

180

160

140

120

100

80

60

40

20

2000

Straight tube (Seader and Tate’s equation)Coiled tube [Shchukin (1969)]

Qs=1000 l h-1; water

Qs=2000 l h-1; waterQs=2000 l h-1; water

Qs=620 Nm3 h-1; airProposed empirical correlation

Qs=750 Nm3 h-1; air

Qs=1500 l h-1; waterQs=1500 l h-1; water

Qs=800 l h-1; water

4000 6000 8000 10,000

Reynolds number

Nus

selt

num

ber

12,000 14,000 16,000 18,000

Figure 35 (A) Heat transfer coeffi cient comparison in coiled fl ow inverter (CFI), coiled tube and straight tube (source: Kumar et al. [132] ) and (B) scalar concentration distribution of liquids fl owing at v = 2 ms-1 at different axial distances in straight, coiled and CFI tubes. (Source: Mridha et al. [136] ; reprinted with kind permission from American Chemical Society. Copyright (2011). )

com ). The trend of publications in different research journals was analyzed for the years 2001 – 2010, and for country and sources. It is observed that there is an extensive growth in the fi eld of green chemistry from the year 2003 onward. It is also observed that research in the fi eld of green chemistry is not limited only to synthesis but also involves various unit opera-tions, e.g., separation, extraction, absorption, etc.

Process intensifi cation holds great promise for green synthesis. To intensify the green synthesis processes, vari-ous techniques were developed which do not alter synthesis processes, such as microwave and ultrasonic irradiation, intensifi ed mixers, spin disc reactors, multifunctional mem-branes, coiled fl ow inverter, etc. The implementation of process intensifi cation techniques resulted in the improve-ment in green synthesis processes without damaging the environment and requiring less capital cost. An analysis of various technologies to intensify the green synthesis

process was carried out, e.g., microwave irradiation, sono-chemical method, mixers, oscillating fl ow reactor, spin disc reactor, multifunctional membranes, etc. Green syn-thesis using process intensifi ed techniques has shown sig-nifi cant differences in terms of yield and energy effi ciency and environmental impact. For example, silver nanopar-ticle synthesis was carried out with various intensifi cation technologies and it was found that there is a signifi cant difference in both particle diameter and morphology (from chemical methods the particle size obtained was below 10 nm and with microemulsion methods a desired specifi c size of particles can be obtained). Both microwave-assisted irradiation and miniaturized technologies have resulted in signifi cant enhancement in the product yields within less time. However, there are certain limitations, e.g., handling of solids in both microreactor and microwave-assisted irradiation technologies. Technologies such as oscillating tubular reactors and the HEX reactor (BHR group) offer narrower residence time distributions with higher heat transfer coeffi cients as compared to the conventional batch vessels and have already been used for fi ne chemical prep-arations. Spinning disc reactors and the rotor-stator spin-ning disc reactor can be effectively used to perform fast polymerization reactions as they offer very high surface area-to-volume ratios, and mass transfer coeffi cients The small reactor size or volume of the spinning disc reactor can increase the safety of a process and is feasible to work at higher pressures.

Higher yields or conversions of one component over another, selectivity of a reaction, less side product, fast reac-tions and safety during the process should be motivation enough for process industries to become interested in pro-cess intensifi ed techniques (e.g., microstructured reactors, microwave- or ultrasound-based techniques, spinning disc reactors, oscillated fl ow reactor, coiled fl ow inverter, mul-tifunctional membranes, etc.). Although there is extensive work available on green synthesis using process intensifi ed devices, process-based green synthesis, green synthesis with process intensifi ed devices on a pilot-plant scale, demonstra-tion of hazardous/explosive reactions in process intensifi ed techniques are some more examples of areas that could be exploited by both academia and industry. Furthermore, focus on the combination of traditional and non-traditional methods for green synthesis is needed. The limitation of handling of solids and large volumes is another aspect which needs to be addressed. It is expected that the present review will contrib-ute to the further development of process intensifi cation tech-nologies in the fi eld of green synthesis, and will also provide new direction for improvement in the existing green synthesis technologies.

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3630–3638.




Prof. Krishna Nigam joined the faculty of Chemical Engi-neering, Indian Institute of Technology Delhi in 1976 and served in various capaci-ties. Prof. Nigam also served as Managing Director of The Foundation for Innovation & Technology Transfer (FITT). He has authored more than 120 research publications in peer reviewed international

journals. He is on the Editorial Board of many Elsevier journals, e.g. Chemical Engineering Research and Design, Chemical Engineering and Processing-Process Intensifi ca-tion, Education for Chemical Engineer and is a Guest Editor for special issues of Chemical Engineering Science. He has also been invited to join the International Advisory Panel of Chemical Engineering Science. He is the recipient of presti-gious Humboldt Research Award from Germany for the year 2011, a rare distinction making him the 15th Indian recipient of Senior Humboldt Fellowship.

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[137] Mridha MM, Serra C, Hoarau Y, Nigam KDP. Microfl uid. Nanofl uid. 2011, 10, 415–423.

Received October 26, 2011; accepted January 5, 2012

Dr. Vimal Kumar studied at Indian Institute of Technology, and obtained PhD degree in the fi eld of chemical engineering in 2008. Since 2007, he has worked in Dow Chemicals International Pvt. Ltd, Pune, India. In 2009, he obtained postdoctoral fellow-ship from Concordia University, Montreal, Quebec, Canada for two years. In the year 2011 he joined the Department

of Chemical Engineering, Indian Institute of Technology Roorkee, India. Dr. Kumar has authored or co-authored 14 research articles in the peer-reviewed journals, one chapter in Encyclopedia of Chemical Processing, 16 articles in both national and international conferences and several research reports for the industry.



process intensification in green synthesis

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