Microwave vs. Conventional Organic Synthesis

Research will be limited to:
- Method: Microwave-assisted synthesis vs. conventional heating
- Scope: Organic reactions
- Metrics: Yield, time, reproducibility

Strategy: I will conduct a comparative analysis focusing on quantitative data regarding yield, reaction time, and reproducibility between microwave-assisted organic synthesis (MAOS) and conventional thermal heating. The search will target systematic reviews and meta-analyses that provide head-to-head comparisons across various organic reaction classes (e.g., Suzuki coupling, Diels-Alder, esterification) to determine if the 'microwave effect' is purely thermal or kinetic, and how it impacts experimental reproducibility.
Queries:
- microwave-assisted vs conventional heating organic synthesis yield time comparison
- reproducibility of microwave-assisted organic synthesis vs oil bath heating
- meta-analysis microwave-assisted organic reactions yield time efficiency
- kinetic comparison microwave vs conventional heating organic chemistry reproducibility
- statistical analysis microwave-assisted synthesis vs thermal heating organic reactions

Executing 5 concurrent searches:
- microwave-assisted vs conventional heating organic synthesis yield time comparison
- reproducibility of microwave-assisted organic synthesis vs oil bath heating
- meta-analysis microwave-assisted organic reactions yield time efficiency
- kinetic comparison microwave vs conventional heating organic chemistry reproducibility
- statistical analysis microwave-assisted synthesis vs thermal heating organic reactions

Found 10 papers. Key excerpts:

Recent developments on microwave-assisted organic synthesis of nitrogen- and oxygen-containing preferred heterocyclic scaffolds. — Ghanshyam Tiwari et al., 2023

A natural product is a substance found in the nature, and can be in the form of heterocycles or other moieties. 1 Natural products have had a great influence on the developments of medicines and materials for treatment of cancer, bacterial infections, autoimmune diseases and inflammation. 2 Nature is a major source for organic molecules in the form of secondary metabolites, which can be used for the development of novel therapeutics. Most of the drugs based on chemical scaffolds isolated from plants, marine organisms, microbes and other natural sources serve as treatments of various diseases. Natural products have also been used for commercial purposes such as cosmetics, dietary supplements, and many other edible products. 3,4
New pharmaceuticals and many effective medications were initially developed as semi-synthetic analogues of compounds found in nature. 5 Natural products are very diverse in terms of three-dimensional (3D) chemical space and exhibit unique biological functions. This is inferred from the idea that virtually all natural compounds have some capability for receptor binding. 6,7
Thus, the design and synthesis of natural products and natural product-inspired heterocyclic molecules have been of interest to medicinal chemists and chemical biologists because these molecules have significant roles in the drug-development process. 8–10 Common heterocycles are found in natural products, especially in alkaloids, polyketals, vitamins and propanoids. 11 Isatin, coumarin, quinoline, isoquinoline, pyrimidine, pyrazole, and pyrazolopyrimidine are heterocyclic motifs found widely in bioactive natural products as well as in pharmaceutical agents. Molecules derived from these scaffolds, such as coumarin derivatives, show various biological activities. Calanolide A is a coumarin based anti-HIV drug. 12 Warfarin is a coumarin-based anticoagulant drug which is mainly used to prevent blood clots. 13 Chloroquine is a quinoline-based antimalarial drug and recently used to treat COVID-19. 14 Hydroxychloroquine is also a quinoline-based antimalarial drug. 15 Nintedanib is an isatin derivative, currently used as an anticancer drug. 16 The pyrazolopyrimidine derivative zaleplon is used as treatment of insomnia in humans by decreasing the activity of the brain. 17 Sildenafil is a pyrazolopyrim

idine-based drug mainly used in the treatment of erectile disfunction in humans 18 ( Fig. 1 ).
Various techniques are available to efficiently synthesize these heterocyclic scaffolds and derivatives, including electrochemical synthesis, metal-free synthesis, photochemical synthesis, solvent-free synthesis, ultrasonication, solvothermal synthesis, ball milling, and many more. 19–21 Some reactions under thermal conditions can take from a few hours to a few days. 22 In recent times, various techniques and methods have enabled chemical reactions to be undertaken efficiently and in less time. As a result, a new approach has been developed to serve as an energy source for performing efficient chemical synthesis. 23–26 This approach involves the use of microwave energy, which is harnessed through a microwave reactor.
A microwave reactor is an apparatus designed for carrying out microwave-assisted organic synthesis. It is important to note that this type of reactor is slightly different from the conventional household microwave oven. 27 The microwave reactor comprises a microwave emitter, a pressure controller, and a rotor with safety controls that are fitted with the reactor. 28 The microwave emitter in the reactor emits microwave energy, which is absorbed by the reactants in the reaction vessel, leading to a heating effect. 29 The pressure controller is responsible for regulating the pressure within the reactor, ensuring that it remains at the desired level. The rotor helps to distribute the reactants evenly within the reactor, enhancing the efficiency of the reaction. 30
Over the past few decades, there has been a remarkable surge in the utilization of microwave energy. This had led to the introduction of novel and revolutionary applications in various fields, such as organic synthesis, heterocycle synthesis, polymer chemistry, 31,32 material sciences, 33 nanotechnology, and biochemical processes. 34,35 Notably, microwave irradiation has displayed the potential to significantly reduce processing time, amplify the reaction yield, as well as enhance the purity and properties of products, thereby surpassing traditional methods. 36 This advancement, known as microwave-assisted organic synthesis (MAOS), relies on the efficient heat transfer achieved through dielectric heating, and is primarily dependent on the absorption capacity of the solvent or reagents for microwave energy. 37
Dielectric heating provides a crucial advantage over conventional heating methods as microwaves directly interact with dipoles or ionic molecules present in the reaction mixture, allowing energy transfer to occur in less than a nanosecond (10 −9 s), leading to an

instantaneous temperature rise. 38–40 Additionally, microwave irradiation facilitates volumetric heating by directly coupling the electromagnetic field with molecules in the reaction mixture, thereby minimizing or completely avoiding wall effects. 41 This introduction outlines the promising and transformative possibilities that microwave energy offers in advancing research and development across various scientific domains. 42
Overall, the microwave reactor is an essential tool for conducting MAOS, providing a reliable and efficient energy source for various chemical reactions. Therefore, this approach has proven to be useful in obtaining a diverse library of heterocyclic molecules inspired by natural products that exhibit improved pharmacological properties. Thus, microwave irradiation has been identified as a crucial technique in organic synthesis and drug-discovery processes. This review highlights recent advancements in the synthesis of quinoline, pyrazolopyrimidine, coumarin, isatin and their derivatives under MAOS.
The review covers a wide range of microwave-assisted synthetic reactions, including Suzuki–Miyaura cross-coupling, Friedlander synthesis, copper-catalyzed four-component synthesis, and the synthesis of isatin-β-thiocarbohydrazones and quinoline fused 1,4-benzodiazepines. This breadth of coverage allows readers to gain insight into the diverse applications of microwave-assisted synthesis in different chemical transformations. We provide specific examples of successful reactions, the catalysts used, reaction conditions, and isolated yields. These examples enable researchers to understand the practical aspects of microwave-assisted synthesis. It highlights the advantages of microwave-assisted synthesis over conventional heating methods. It emphasizes the significant time savings, improved yields, and higher selectivity achieved through microwave irradiation, making it a more attractive option for various chemical reactions. The review offers valuable perspectives on the potential areas of research and improvement in microwave-assisted synthesis and discusses the need for a deeper mechanistic understanding, exploration of new reactions, “green” and sustainable chemistry applications, scale-up challenges, and the combination of microwave technology with other techniques.
Thus, this review offers a comprehensive, well-referenced, and forward-looking perspective on microwave-assisted synthesis. It goes beyond theoretical discussions and provides concrete examples and practical benefits, making it a valuable resource for researchers and practitioners in the fields of synthetic chemistry and materials science.
Nitrogen-containing heterocyclic motifs are abundant in natural products and natural product-derived drug molecules. 43,44 Therefore, chemical synthesis of these scaff

Microwave assisted synthesis of five membered nitrogen heterocycles. — Gopinadh Meera et al., 2020

Heterocycles are vital targets in organic synthesis especially nitrogen containing ones because of their notable presence in natural products and their wide variety of applications in pharmaceutical industries. Nitrogen containing five membered heterocycles include pyrroles, pyrrolidines, oxazoles, indoles, pyrazoles etc. Among which pyrrole was found to be the most important one.
Pyrroles are nitrogen containing five membered heterocycles whose structural moiety appears in a variety of pharmaceuticals and a large number of biologically active natural products, and also acts as the key factor throughout the total synthesis of these molecules. 1 The major part of porphyrin rings is pyrrole and its derivatives which act as building blocks in chlorophyll, heme, vitamin B 12 , and bile pigments. 2 Pyrrole containing pharmaceutical compounds acts as fungicides, antibiotics, anti-inflammatory drugs, 3 cholesterol reducing drugs, anti-tumor agents, 4 anti-microbial 5 and many more. Not only in pharmaceuticals but also in polymer chemistry, pyrroles are used as an efficient catalyst for polymerization process, used as corrosion inhibitor, 6 preservative, solvent for resin, terpenes, in metallurgical process. 7 In recent years pyrroles and its derivatives are successfully implemented as organic conducting materials also. 8
There are a variety of protocols available for the synthesis of pyrroles. Paal–Knorr synthesis, Knorr synthesis, Hantzsch pyrrole synthesis are some of them. The major disadvantages regarding these protocols are they are carried out in presence of acid catalyst in organic solvent medium and the protocols are time consuming ones. Since the constantly changing environment demands a sensible and sustainable chemistry organic synthesis also started to follow green principles. As part of that microwave irradiation introduced in place of conventional heating technique.
Microwave irradiation, one of the most effective nonconventional activation methods, has been illuminating organic synthesis over the last 30 years. 9 Substantial deceleration of reaction time (hours to minutes) and greater yield rendered this alternative heating source an attractive chemical synthesis method. This thermal control provides fine tuning of the parameters of the reaction and less chemical waste. Advantages such as elimination of side reactions and cost-effective response have also increased the popularity of microwave-assisted reactions. The first microwave-irradiated synthetic reaction was reported in 1969, but experiments performed by

Gedye and Giguere made it more popular. 10 The interaction of microwave energy with organic molecule is due to dielectric heating and the efficient interaction of polar molecules such as ethanol, water, acetonitrile, etc. with microwaves leads to rapid heat generation. The convection mode of microwave heating increases the reaction rate whereas the external heating source of traditional heating slows down the transfer of energy and hence the reaction rate. 11 Usual domestic ovens were used in the early stages of microwave irradiated chemical synthesis while nowadays we have sophisticated monomods and multimodes.
The major advantages of implementing microwave heating over conventional heating technique are shorter reaction time, higher yield under milder reaction conditions, neat reactions worked well under microwave irradiation, higher purity of the products formed, and suppression in the rate of by-product formation. All these features make microwave assisted reactions more towards a greener and environment-friendly process.
In the past few years microwave irradiation is found to be applied in the synthesis of nitrogen containing five membered heterocycles in a large scale. And it is observed that most of these protocols were carried out either in water or under solvent-free conditions. Here, in this review we summarize the developments in microwave assisted synthesis of pyrroles, pyrrolidine, indoles, quinoline and its derivatives in the past five years.
Feller and Imhof developed a microwave mediated Ru catalyzed four component (primary amine 2 and α,β-unsaturated aldehyde 1 with ethylene and carbon monoxide) reaction pathway for the synthesis of substituted pyrroles and chiral γ-lactams ( Scheme 1 ). 12 As compared to the conventional heating method, this protocol took lesser reaction time and the precatalyst (Ru 3 (CO) 12 ) loading was also found to be lower.
A new methodology for microwave assisted multicomponent reaction for the synthesis of substituted pyrrole derivatives 6 from sodium diethyl oxaloacetate 5, aromatic aldehydes 4 and primary amines 2 was reported by Komiotis and coworkers ( Scheme 2 ). 13 They studied the scope of this reaction in a variety of substrate molecules under optimized reaction conditions (sodium diethyl oxaloacetate (1 equiv.), amine (1 equiv.) and aldehyde (1 equiv.) in ethanol under MW, 100 W) and obtained average to good yields. From the

pharmacological studies conducted, they found that some of the substituted pyrroles show excellent cytostatic and antiviral activities.
Vyankatesh and coworkers designed a new microwave assisted protocol for the synthesis of 2-amino-4,5-diphenylpyrrole-3-carbonitriles 10 from a heterocyclic compound with substituted anilines 8 ( Scheme 3 ). 14 Under optimized reaction conditions (benzoin 7 (2.12 g, 0.01 mol), 8 and conc. HCl (6–8 drops), ethanol (40 mL), malononitrile (1.66 mg, 0.01 mol), pyridine (1.5 mL), MW, 240 W, 25 min), they explored the applications and limitations of this protocol and obtained good yields. From the pharmacological studies they found that some of the pyrrole derivatives show excellent in vitro anti-inflammatory activity.
There are few reports on synthesis of pyrrole using enaminones ( in situ generated) with phenacyl bromide 12, recently in 2018 Chawla et al. designed a new methodology for the microwave assisted synthesis of imidazole substituted pyrroles through a one pot synthesis ( Scheme 4 ). 15 Under the optimized reaction conditions they studied a number of substrates and obtained good to excellent yields.
In 2015 Zhang and coworkers developed an efficient microwave assisted three component (2, α-bromoacetophenone 15 and ethyl acetoacetate 16) one-pot synthesis of N -substituted 2-methyl-1 H -pyrrole-3-carboxylate derivatives 17 ( Scheme 5 ). 16 Here substituted phenacyl bromides are used for studying the scope of the reaction. This protocol is both catalyst- and solvent-free and the substrate scope studies are carried out under the optimized reaction conditions (15 (1.0 mmol), 16 (2.5 mmol) and 2 (1.0 mmol), MW, 450 W, Neat) in various amines, different α-bromoacetophenone and ethylacetoacetate and obtained good yields.
In that same year similar kind of a protocol was reported by Reddy and coworkers. They proposed a new protocol for microwave assisted synthesis of trisubstituted pyrroles 20 from substituted β-amino unsaturated ketone 19 and substituted phen

Microwave-Assisted Post-Ugi Reactions for the Synthesis of Polycycles. — Liangliang Song et al., 2022

Since the emergence of mono-mode reactors, microwave-assisted chemistry has been increasingly utilized in organic synthesis over the years [ 1 , 2 , 3 ]. For mono-mode reactors, the electromagnetic irradiation is centralized directly via an accurately programmed wave guide onto the reaction tube, which is fixed at a designed distance from the radiation source. Mono-mode reactors could provide designed and accurate microwave irradiation, avoiding undesired and useless waves. As alternative heating source, microwave irradiation has obtained more attention because of high efficiency and reproducibility [ 1 , 2 , 3 ]. Microwave heating shortens reaction time from hours to minutes or seconds, offering a more rapid method through uniform and efficient heating than conventional heating. This is generally accompanied with significant decrease of energy consumption, promoting the efficiency and yield of the desired products, and reducing the level of side products [ 4 , 5 , 6 ].
The Ugi four-component reaction (Ugi-4CR) was discovered by Ugi in 1959 and assembles an amine, an acid, an aldehyde or a ketone, and an isocyanide into α-acylaminoamides through a one-pot reaction [ 7 ]. The Ugi-4CR has become one of the highly explored reactions for forming multifunctional adducts, due to the mild reaction conditions, wide scope, and high variability [ 8 , 9 , 10 ]. Notably, the Ugi-4CR gives a chance for a variety of post-transformations by modifying the four components, usually in two operational steps [ 11 , 12 , 13 ]. The post-Ugi reactions are well suited for the construction of important heterocycles, macrocycles, polymers, and other compounds in drug discovery and natural product synthesis.
As microwave irradiation and post-Ugi reactions possess their respective advantages over other protocols, merging strategies show high value in synthetic chemistry. Through the combination of microwave irradiation and post-Ugi reactions, various polycycles have been efficiently and sustainably synthesized. In this minireview, we wish to highlight the recent advances of microwave-assisted post-Ugi reactions for the synthesis of polycycles ( Scheme 1 ). For the sake of clarity, we have divided this minireview into the following sections: (a) copper catalysis, (b) palladium catalysis, (c) other transition metal catalysis, and (d) transition metal-free catalysis.
In 2013, Liu

and co-workers developed a copper-catalyzed intramolecular arylation of Ugi-adducts [ 14 ]. Under microwave heating, diverse tetracyclic benzo[ e ][1,4]diazepines were synthesized within 40 min in high yields and with excellent chemoselectivities ( Scheme 2 ). Then they changed the amine and acid components, giving a series of new Ugi-adducts [ 15 ]. By using the same conditions in 30 min, the Ugi-adducts were performed to deliver various 5,6-dihydroindolo[1,2- a ]quinoxalines with excellent yields and chemoselectivities ( Scheme 3 ).
Van der Eycken’s group reported a post-Ugi copper-catalyzed intramolecular Ullmann coupling in 2014 ( Scheme 4 ). Microwave assistance promoted the diversity-oriented formation of 4 H -benzo[ f ]imidazo[1,4]diazepin-6-ones with high yields, in 30 min [ 16 ]. Ugi-adducts derived from imidazole-4-carbaldehyde and imidazole-2-carbaldehyde reacted smoothly to give the corresponding products. Notably, substrates derived from C-2 or C-5 substituted imidazole-4-carbaldehyde failed to deliver the corresponding products due to the decomposition of the starting materials.
In 2016, a microwave-assisted intramolecular Ullmann etherification was established by Dai and co-workers for the efficient construction of dibenz[ b,f ][1,4]oxazepine scaffold. When optimizing the reaction conditions, it was found that conventional heating gave 75% yield after 48 h, while microwave irradiation delivered 64% yield in 30 min, dramatically speeding up the reaction ( Scheme 5 ). Under the optimal reaction conditions of microwave irradiation, they explored the substrate limitation ( Scheme 6 ). By using 2-bromobenzoic acids or 2-bromobenzaldehydes, the diverse 6/7/6-fused tricyclic heterocycles were synthesized from Ugi-adducts via copper-catalyzed Ullmann coupling in 30 min [ 17 ]. In contrast with their previous report through copper-catalyzed Goldberg amidation of Ugi-adducts [ 18 ],

this reaction exhibited excellent chemoselectivity to undergo Ullmann etherification under microwave assistance.
Gracias and co-workers described a microwave-assisted intramolecular Heck cyclization of Ugi-adducts in 2004 [ 19 ]. Through palladium catalysis, highly functionalized N-heterocyclic scaffolds were synthesized with excellent yields in 2 h ( Scheme 7 ).
In 2007, Judd’s group reported a sequenced RCM/Heck reaction of diverse Ugi-adducts [ 20 ]. Under the assistance of microwave heating, various bridged bicyclic lactams were prepared with high yields and diastereoselectivities in 40 min ( Scheme 8 ). Compared to the homogeneous palladium catalyst Pd(Ph 3 P) 2 Cl 2 , the immobilized palladium catalyst FibreCat 1032 showed similar performance for all cases. This method could also give [4.3.2] the bicycloundecane scaffold in high yield and diastereoselectivity, leading to a mixture of the alkene regioisomers ( Scheme 8 b). The more constrained indole RCM product afforded the bridged indole scaffold with excellent selectivity ( Scheme 8 c). Interestingly, by using microwave heating, the indole RCM product delivered the saturated bridged bicyclic lactam with high diastereoselectivity using FibreCat 1032 and sodium formate ( Scheme 8 d).
Under microwave irradiation, palladium and copper catalysts showed distinctly different catalytic properties [ 14 , 15 ]. Highly selective C3-arylation of Ugi-adducts was achieved by Liu’s group in 2013 [ 14 ]. Under microwave-assisted palladium catalysis, various benzo[5,6]azepino[3,4- b ]indoles were constructed with high yields in 1 h ( Scheme 9 ). Subsequently, the same group employed this strategy using the Ugi-adducts derived from 2-halogenated anilines instead of 2-halogenated benzoic acids [ 15 ]. With the assistance of microwave irradiation, diverse indole-fused 6,7-dihydroindolo[2,3- c ]quinolines were obtained with high yields in 2 h ( Scheme 10 ).
In 2018, Sieburth and Al-Tel discovered a zinc-catalyzed microwave-assisted post-U

Aqueous microwave assisted novel synthesis of isothiocyanates by amine catalyzed thionation of isocyanides with Lawesson's reagent — Sodeeq Aderotimi Salami et al., 2023

1. IntroductionIsothiocyanates are an important class of chemical compounds that have been discovered as subunits in both naturally occurring and biologically active compounds. Many isothiocyanate analogues possessing the isothiocyanate motif have been synthesized for possible medical applications after it was discovered that naturally occurring isothiocyanates play a key role in the cancer chemo preventive activities of these plant species [Citation1Dufour V, Stahl M, Baysse, CC. The antibacterial properties of isothiocyanates. Microbiology (United Kingdom). 2015;161;229–243, doi:10.1099/mic.0.082362-0. [Crossref], [PubMed], [Web of Science ®], [Google Scholar],Citation2Wong R, Dolman SJ. Isothiocyanates from tosyl chloride mediated decomposition of in situ generated dithiocarbamic acid salts. J Org Chem. 2007;72:3969–3971. doi:10.1021/jo070246n. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. Many epidemiological studies have discovered a connection between eating cruciferous vegetables like broccoli and a lower cancer risk. The bioactive components of these cruciferous vegetables have been found to lower the expression of numerous cancer-related biomarkers in humans [Citation3Stoner GD, Morse MA. Isothiocyanates as inhibitors of esophageal cancer. In: Dietary phytochemicals in cancer prevention and treatment. Springer, WTI Frankfurt; 1996. p. 13–23. [Crossref], [Google Scholar]]. The beneficial health effects of cruciferous vegetables are believed to be caused by the isothiocyanate (ITC) compounds, which are prevalent in these foods and are widely known for their ability to prevent cancer [Citation4Ho E, Clarke JD, Dashwood RH. Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. J Nutr. 2009;139(12):2393–2396. [Crossref], [Google Scholar]] Scheme 1. Aqueous microwave assisted novel synthesis of isothiocyanates by amine catalyzed thionation of isocyanides with

Lawesson's reagentAll authorsSodeeq Aderotimi Salami, Vincent J. Smith & Rui W. M. Krausehttps://doi.org/10.1080/17415993.2022.2164196Published online:09 January 2023Scheme 1. Some natural isothiocyanates found in cruciferous vegetables: sulforaphane (SFN), phenethylisothiocyanate (PEITC), benzyl isothiocyate (BITC) and allyl isothiocyanate (AITC).Display full sizeScheme 1. Some natural isothiocyanates found in cruciferous vegetables: sulforaphane (SFN), phenethylisothiocyanate (PEITC), benzyl isothiocyate (BITC) and allyl isothiocyanate (AITC).Alkyl and aryl isothiocyanates are important synthetic intermediates that have been employed as significant precursors for heterocycles such us thiohydantoins, thiopyrimidones, thioquinazolones, mercaptoimidazoles, thioamidazolones, pyridinethiones, pyrrolidine, and benzothiazine [Citation5Blanco-Ania D, Valderas-Cortina C, Hermkens PHH, et al. Synthesis of dihydrouracils spiro-fused to pyrrolidines: druglike molecules based on the 2-arylethyl amine scaffold. Molecules. 2010;15:2269–2301. doi:10.3390/molecules15042269. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. Given the importance of isothiocyanates and their numerous applications, a variety of synthetic techniques have been developed. Although many synthetic methods for the preparation of isothiocyanates have been reported from amines [Citation6Hodgkins JE, Ettlinger MG. The synthesis of isothiocyanates from amines. J Org Chem. 1956;21:404–405. doi:10.1021/jo01110a006. [Crossref], [Web of Science

®], [Google Scholar]], dithiocarbamates [Citation7Bian G, Shan W, Su W. A one-pot preparation of isothiocyanates from amines using two phosgene substitutes: bis-(trichloromethyl) carbonate and trichloromethyl chloroformates. J Chem Res. 2005;9:585–586. doi:10.3184/030823405774308862. [Crossref], [Google Scholar]], organic halides [Citation8Cho CG, Posner GH. Alkyl and aryl isothiocyanates as masked primary amines. Tetrahedron Lett. 1992;33:3599–3602. doi:10.1016/S0040-4039(00)92512-7. [Crossref], [Web of Science ®], [Google Scholar]], olefins [Citation9Kitamura T, Kobayashi S, Taniguchi H. Photolysis of vinyl halides. reaction of photogenerated vinyl cations with cyanate and thiocyanate ions. J Org Chem. 1990;55:1801–1805. doi:10.1021/jo00293a025. [Crossref], [Web of Science ®], [Google Scholar]], and aldoximes[Citation10Kim JN, Jung KS, Lee HJ, et al. A facile one-pot preparation of isothiocyanates from aldoximes. Tetrahedron Lett. 1997;38:1597–1598. doi:10.1016/S0040-4039(97)00121-4. [Crossref], [Web of Science ®], [Google Scholar]]. The most widely utilized method in the literature is the decomposition of dithiocarbamates using heavy metals [Citation11Bian G, Qiu H, Jiang J, et al. A new method for the synthesis of isothiocyanates from dithiocarbamates or alkyl amines using chlorosilanes as decomposition reagents phosphorus, sulfur silicon. Relat Elem. 2007;182:503–508. doi:10.1080/104265006009

Microwave-assisted organic synthesis of nucleoside ProTide analogues. — Cinzia Bordoni et al., 2019

Microwave-Assisted Organic Synthesis (MAOS) has been widely used in the last 40 years in the organic chemistry field to solve problems such as low yield, long reaction time, side reactions and to synthesise libraries of compounds more efficiently. A number of articles report the optimisation of a variety of transformations exploiting the thermal/kinetic effect of the microwave irradiation (MWI) to enhance the reaction rate. 1,2 A few examples include Mitsunobu reaction, 3 Suzuki coupling, 4 Buchwald–Hartwig amination. 5 Prodrug nucleotide (ProTide) technology was originally designed by Professor Chris McGuigan and co-workers at Cardiff University in the early 1990s. 6 A ProTide consists of a nucleoside where the negative charge on the monophosphate moiety has been masked with an amino acid ester and an aryl group (5′-aryloxyphosphoramidate) to deliver nucleotide analogues into the cell and to overcome nucleoside drug resistance. 7 The ProTide approach has been successfully applied clinically: Sofosbuvir, Tenofovir alafenamide and Acelarin are clear examples of ProTide based drugs used in the treatment of different cancer and viral diseases. 8 Interestingly, only one review drives the attention on the challenges in their synthetic preparation. 9 Herein, we focus particularly on the final step of the ProTide synthesis: the nucleoside phosphoramidation, such as the coupling of the 5′-hydroxy moiety in the ribonucleoside with the phosphoramidating reagent. The two synthetic approaches commonly applied to perform this coupling are reported in Scheme 1 . 10 The first approach ( Scheme 1 , condition (a)) relies on the use of a strong base to activate the nucleophile according to the Uchiyama method. 11 In the second method ( Scheme 1 , condition (b)), activation of the phosphoramidochloridate is performed by N -1-methylimidazole (NMI). 9,12
Although both methodologies have been extensively used to synthesise several nucleoside prodrugs, a few limitations occur: poor solubility of the parent nucleoside; low yield (10–42%); 13 longer reaction time (4–48 hours); 8,14,15 lack of 5′-selectivity which leads to the formation of unwanted

3′,5′- O , O -phosphoramidates (bis) by-products, when X is an hydroxyl group and Y is either an hydroxy or hydrogen atom ( Scheme 1 ). 9
Also, appropriate protection of the sugar hydroxyl groups and/or of the nucleobase offers a solution to those limitations, although it is not amenable to high throughput chemistry. Additionally, protection/deprotection steps will require various conditions and protecting groups depending on the different ribonucleoside and phosphoramidating reagent. Besides, deprotection must be optimised to be compatible with the ProTide moiety. While common synthetic procedures for the synthesis of ProTide do not take into account the chirality at the phosphorous atom, a paper by Pertusati focuses on the development of a diastereoselective ProTide synthesis. 14
Although, a suitable catalytic system to predominantly deliver the Sp diastereoisomer via copper catalysis was identified, the new synthetic methodology still suffers from long reaction time (8–12 h) and modest yields (12–66%). 14
Sommadossi and co-workers reported the use of the Grignard method to synthesise a series of ProTide at 0 °C over long reaction time (15–18 h) and modest yields (16–55%). 15 Recently, Simmons and co-workers reported an optimised procedure to regioselectively obtained the 5′-phosphoramidate prodrugs of the ribonucleoside: although their methodology was extensively validated on different pharmaceutically relevant ProTide, it still suffers from long reaction times (20–48 hours). 16 In this work, we aimed to develop a MAOS methodology to obtain only the 5′-ProTide in good yield over shorter reaction time, without 3′,5′- O , O -phosphoramidates (bis-ProTide) by-products formation, and without additional protection/deprotection steps exploiting the cooling-while-heating (Power Max option) 17,18 on a CEM Discover LabMate microwave synthesizer for both the two aforementioned synthetic procedures reported in Scheme 1 . The cooling-while-heating MW technology further irradiates the reaction mixture with microwave power without overheating by simultaneously cooling down the reaction vessel with compressed air. The target temperature is

constant during the microwave irradiation experiment. As aforementioned, the phosphoramidation reaction proceeds very slowly in conventional heating and with modest yield at 0 and 25 °C. Then, we monitored the profile of the conventionally heated reaction at higher temperature, such as 55 °C. Preliminary experiments demonstrated that in conventional heating, a further increase in temperature would have not been compatible with long reaction times required to observe the formation of the desired product. When the reaction mixture was irradiated under standard MWI method at 55 °C (fixed power, 100 W), there was not a beneficial effect on the formation of the desired product (microwave power absorbed by reaction mixture was 6 W). We then repeated the same experiment using the temperature fixed mode: we fixed the temperature at 55 °C and the MW irradiated the reaction mixture with as much power as the reaction mixture was able to absorb. Having observed the formation of the desired product, we then tried to optimise the MWI conditions. We initially exploited the effect of a 10 °C increase under MWI (fixed temperature mode, dynamic method) and monitor how the percentage of conversion to the desired product was influenced (microwave power absorbed in cooling-while-heating experiment was 100 W). Then, we investigated the effect of different solvents on both solubility and microwave power absorption (using both low and high microwave absorbing solvents), different reaction times and temperatures under conventional and MW heating. Reactions in conventional heating or under microwave irradiation were performed using the same number of equivalents of reagents, the same molarity for the solution of the reaction mixture, in closed vessel and under anhydrous conditions to avoid any effects of air/moisture stability of reagents, and evaporation of solvents. Finally, we compared the yields and the reaction times for each experiment in the same experimental conditions under both conventional heating and microwave irradiation.
To exemplify the potential of the application of the MWI to the nucleoside phosphoramidation, we started our studies using the protected adenosine (17) for the initial model reaction. 19
The, we confirmed the compatibility of our microwave based approach using several phosphoramidating agents, exploring different leaving groups ( para -nitrophenolate, chlorine atom, phenol) and ester moiety (benzyl, iso-propyl), as reported in Table 1 .
Reaction conditions: (a

Microwave-assisted FLP-catalyzed hydrogenations. — S Tussing et al., 2016

Introduction

The reduction of organic molecules by frustrated Lewis pairs (FLP) using molecular hydrogen (H 2 ) has emerged to be a powerful tool for organic synthesis. 1 Electron-deficient as well as electron-rich compounds have been successfully hydrogenated 2 and even asymmetric reductions of prochiral substrates were achieved. 3 Usually such reactions are conducted in closed reaction systems e.g. thick-walled vials, pressure tubes including NMR-tubes or steel bomb autoclaves. The appropriate reactor must be selected with regard to the required H 2 - pressure. The closed reaction systems are typically heated in oil baths or with heating jackets above the boiling point of the solvent. 4 The same specifications hold true for microwavereactors including the advantage of the fast equilibration of the temperature and inverted temperature gradients. 5 Microwave-assisted transition-metal catalyzed hydrogenations and transfer hydrogenations were reported 6 rendering this method attractive for FLP-catalyzed hydrogenations. Interestingly, the application of microwave heating in FLP-catalyzed hydrogenations has not been reported yet.
Herein we report the first microwave-assisted FLP-catalyzed hydrogenation of imines, heterocycles, enamines, silyl enol ethers, nitroolefins, malonates and olefins. This study focuses on the comparison of hydrogenations conducted under conventional and microwave heating. Therefore reported catalyst systems (Lewis acids 1-3 and Lewis bases 4-8, Chart 1) and known substrates susceptible to FLP-catalyzed hydrogenation were investigated.

Results and discussion

We initiated our studies with the well-established FLP-catalyzed hydrogenation of N-benzylidene-tertbutyl amine 1c,7 (9) using conventional and microwave heating. A solution of imine 9 in toluene (0.2 M) and 5 mol% B(C 6 F 5 ) 3 was prepared and split into two identical thick walled glass vessels. The vessels were sealed and pressurized with 4 bar of hydrogen. One sample was immersed into a preheated oil bath and the second sample was introduced into a CEM microwave reactor with a power setting to 150 W. Both reactions were heated to 80 degC for the indicated time (see Table 1).
Chart 1 Lewis acids and Lewis bases for FLP-mediated hydrogen activation.

The hydrogenation product 10 was obtained with both heating methods however in very different yields. The reaction using microwave irradiation gave the product in 60% yield after 10 minutes while using conventional heating furnished only 22% yield. The microwave-assisted reaction went to full conversion with prolongation of the reaction time to 20 minutes while the oil bath heated reaction provided 10 in 47% yield. We attribute this significant rate increase to more efficient heating of the reaction by microwave irradiation.
Encouraged by these results we investigated other substrates bearing polarized double bonds in the microwave-assisted reaction. We selected substrates, which are susceptible to FLPcatalyzed hydrogenation under conventional heating and compared them with yields obtained from microwave experiments.
The standard conditions for the hydrogenations using microwave-assisted and conventional heating were benzene as solvent (0.2 M), 4 bar hydrogen and 150 W power-level in CEM Discover microwave reactor with external IR temperature control or a preheated oil-bath respectively. 12 For best comparability thermal as well as microwave-assisted hydrogenations were conducted under identical conditions using stock-solutions, identical glassware, temperature, hydrogen pressure and reaction time. The reactions were stopped after 10 to 120 minutes and the yields were determined by 1 H NMR with hexamethylbenzene as internal standard. The results are summarized in Table 2. Generally, all substrates underwent FLPcatalyzed hydrogenation under microwave conditions most of them with pronounced rate acceleration. In accord with our observations for imine 9 we found two-fold rate increase for imines 11a and 11b (entries 1 and 2). The imine 11c underwent hydrogenation in comparable yields and diastereoselectivity irrespective of the heating method (entry 3). Particularly, the hydrogenation of nitrogen-containing heterocycles benefits from microwave-assisted heating (entries 4-7). The hydrogenation of acridin (11d), 8-methyl-quinolin (11e) and 2-methyl-quinoline (11f ) proceeded in significantly higher yields (72-99%) compared to the reactions with conventional heating (7-68%). Notably, indol 11g was reduced in 57% yield in 40 minutes at 140 degC with only 4 bar of hydrogen pressure under microwave conditions whereas the hydrogenation was not achieved using conventional heating (entry 7). Although yields for the reaction using conventional heating were not reported 2e the decrease of the required pressure by

almost 100 bar renders the application of microwave-assisted FLP-hydrogenation of indoles as very promising. We also investigated the core hydrogenation of diphenylamine with 20 mol% catalyst loading (11h). 4b However, even under forcing conditions only traces of the product could be observed irrespective of the heating techniques (entry 8). The electron-rich double bond in enamines 7b and silyl enol ethers 3c,9,13 were reduced in good to excellent yields in only 10 to 40 minutes (entries 9-11). Again the microwave-assisted reactions provided the products in shorter reaction times compared to reactions using conventional heating. Densely functionalised malonates 10,14 were hydrogenated in quantitative yield in 2 h at 80 degC (entry 12) compared to 12 h at room temperature. However, direct comparison of the reactions using microwave and conventional heating after 40 minutes revealed identical reaction rates using the FLP-catalyst 3/7 for transient hydrogen activation. Such electronically modified FLP-catalysts e.g. consisting of less Lewis-acidic boranes B(C 6 F 3 H 2 ) 2 (2) and B(C 6 F 2 H 3 ) 3 (3) or less electron-releasing phosphine 8, display highly reversible H 2 -activation at room temperature or below according to eqn (1). 11
According to an almost ergoneutral reaction the temperature increase shifts the equilibrium to the left side resulting in reduced concentrations of the H 2 -activation products. 7c,10,11,15 Consequently, substrates e.g. nitroolefins or olefins (entries 13 and 14), which require the application of highly reversible FLP-catalysts are less susceptible to microwave-assisted hydrogenations and conventional heating provides higher yields. The reduction of nitroolefin 11m was achieved in 60% at 50 degC, but only 32% yield was obtained if the reaction was conducted at 80 degC (entry 13). Similar reactivity was observed for the hydrogenation of the olefin 11n (entry 14). Nevertheless, microwave-assisted FLP-catalyzed hydrogenations are highly valuable for reactions, which require heating leading to a significant rate increase.

Conclusions

In summary we have shown that microwave-assisted heating significantly accelerates FLP-catalyzed hydrogenations rendering this methodology as useful tool in

Microwave-Assisted Synthesis of 2-Methyl-1 — Rosa Bellavita et al., 2022

1. IntroductionThe indole nucleus is a very widespread motif used in drug discovery and found in many pharmacologically active compounds [1,2]. Bioactive indole-based molecules have been isolated from plants, bacteria, fungi, and marine products, such as tryptamine and serotonin derivatives [3,4], bufotenine [3], ergot and vinca alkaloids [5,6]. In addition, a large pool of drugs containing the indole ring was approved by the Food and Drug Administration (FDA) as antiviral, anticancer, antimalarial, and antitubercular agents [7,8]. Some of these molecules are mainly featured by axially chiral indole-based units [9,10], which are typical building blocks present in natural alkaloids, chiral phosphine ligands, and catalysts [11,12].The construction of the traditional indole core may occur through conventional strategies, such as those described by Fischer [13], Julia and Bartoli [14,15], or through organometallic catalyzed cross-coupling C–N/C–C bond formations [16,17], which are highly versatile and suitable for indole derivatization. The catalytic asymmetric approaches can be also used to access chiral indole-based compounds [18]. These substituted indole derivatives can be considered key intermediates for the synthesis of molecules of medicinal chemistry interest (Figure 1). For instance, 3-nitroindoles are essential structural moiety for the development and synthesis of novel antidiabetic agents [19], whereas halogenated indoles represent a key structural moiety of human 15-lipoxygenase-1 inhibitors [20], and indole-3-carboxylic acids, along with their related esters, are key moieties for mast cell tryptase inhibitors [21]. As part of chiral-indole-based skeletons, there are chiral tryptamines that constitute bioactive molecules acting in the central nervous system [22], while many axially chiral indoles have proved potent anticancer activity [23].An efficient route to obtain indole-3-carboxylate derivatives from several substituted anilines has been developed by Wurtz et al. by performing palladium-catalyzed intramolecular oxidation [24]. This strategy involves the use of four players: (i) a copper source, (ii) a

ligand, (iii) a base, and (iv) an N-aryl enamine, to efficiently get a series of 2-methyl-1H-indole-3-carboxylate derivatives [24]. Starting from this study and considering the numerous advantages the microwave (μW)-assisted synthesis has over the traditional organic synthesis, which includes reduction of reaction time, improved conversions, and cleaner product formation [25,26,27,28], we have explored the palladium-catalyzed oxidative cyclization reaction for the preparation of several indole-3-carboxylate derivatives via μW-heating technology. Previously, μW-heating has been exploited for the preparation of indole analogs in the classical reaction of Fischer [28], and other transition metal-mediated cyclizations, leading to final products yields >80% and excellent purity (>90%) [29]. In this light, we have synthesized N-aryl enamine carboxylates starting from commercially available anilines bearing different electron-withdrawing (-NO2, -Cl, -Br) and donating groups (-CH3, -OPh) (Scheme 1), then converted into their corresponding indoles under both μW-assisted and conventional heating conditions by palladium-catalyzed oxidation. By varying both the amount of oxidant agent (copper source) and the type of solvent, 2-methyl-1H-indole-3-carboxylate derivatives have been obtained with improved yields (>90%) and strikingly reduced reaction time with respect to conventional conditions. 2. Materials and Methods 2.1. Materials and General ProceduresAll solvents and commercial reagents were purchased from Sigma-Aldrich (Saint Louis, MO, USA). TLC sheets (silica gel 60 F254 with plates 5 × 20, 0.25 mm) were purchased from Merck (Kenilworth, NJ, USA). High-resolution MS analysis (positive mode) was performed on a Thermo LTQ Orbitrap XL mass spectrometer (Thermo-Fisher, San Josè, CA, USA) through the infusion of compounds 11–28 into the ESI source using MeOH as solvent. 1H (700, 600, and 400 MHz) and 13C (175 and 125 MHz). NMR spectra were recorded on a Bruker Avance Neo spectrometer equipped with an RT-DR-BF/1H

-5 mm-OZ SmartProbe (Bruker BioSpin Corporation, Billerica, MA, USA); chemical shifts (δH and δC) were referenced to the residual CHCl3 signal (δH = 7.26 and δC = 77.0). High-performance liquid chromatography (HPLC) analyses were performed on a Knauer K-501 instrument endowed with a Knauer K-2301 RI detector purchased from LabService Analytica s.r.l., (Anzola dell′Emilia, Italy). Microwave-assisted reactions were performed on an Initiator+ microwave apparatus purchased from Biotage (Bergamo, Italy). The instrument was set on the high-absorption level operating at a frequency of 2.45 GHz with a continuous irradiation power (0–300 W) and a standard absorbance level of 300 W. 2.2. Synthesis of Enamine Derived Compounds 11–19Each substituted aniline (1–9, 2.00 mL, 22.0 mmol) was stirred together with methyl acetoacetate (CH3COCH2COOCH3, 10, 2.37 mL, 22.0 mmol, 1 eq) and 10% acetic acid (CH3CO2H, 250 μL) into an oven-dried round bottom flask, at room temperature (rt). After 12 h, the crude material was washed with water and extracted with ethyl acetate (EtOAc). The organic phase was washed with water (×3), brine (×3), dried over Na2SO4, filtered, and evaporated under reduced pressure. All enamine intermediates (11–19) were obtained with high yield, ranging from 93–96%, and stored at 4–6 °C. Compounds 11–19 were confirmed by 1H and 13C spectroscopic as well as by HRMS (ESI) analyses.Methyl-(Z)-3-(phenylimino)butanoate) (11): white crystals (4.03 g, 96%); 1H NMR (CDCl3): 10.4 (-NH, brs); 7.32 (2H, t, J = 15 Hz); 7.15 (1H, t, J = 15Hz); 7.10 (2H, d, J = 8 Hz); 4.

Recent Advances in Microwave-Assisted Copper-Catalyzed Cross-Coupling Reactions — Younis Baqi, 2020

1. IntroductionCarbon–carbon (C–C) and carbon–heteroatom (C–X) bond formations through cross-coupling reactions represents as one of the most useful strategy in the synthetic organic chemistry, hence many procedures and methodologies have been developed and published in the literature. Elemental copper (Cu) is the first transition metal element used to catalyze the formation of C–C and C–X bond. The first report of copper in catalyzing C–C bond formation was proposed by Fritz Ullman in 1901. Followed by the modification of the classical Ullmann reaction to include C–X bond, was reported by Ullman and Goldberg in the years from 1903 to 1906. The progress was followed by Cadiot-Chodkiewicz coupling reaction in 1957, Castro-Stephens coupling reaction in 1963, and Corey-House synthesis in 1967. In the 1970s, the cross coupling reaction entered a new era by introducing palladium (Pd) as one of the most powerful noble metal in the cross-coupling reactions. Many important chemical transformations to generate new organic molecules have been developed and these reactions being named after the person who discovered it, including Kumada and Heck (1972), Sonogashira (1975), Negishi (1977), Stille (1978), Suzuki (1979), Hiyama (1988), and Liebeskind-Srogl (2000). Despite the great advances in utilizing palladium as catalyst, copper is still very much used as one of the important catalyst, being non-noble metal, which is cheap and available in the most organic synthetic laboratories globally. However, in comparison with palladium, copper catalyzed reactions are often suffering from the tolerance to cover variety of functional groups as well as the stability of starting materials and products due to the essentially required harsh reaction conditions such as high temperatures—typically 150–200 °C—and for the extended reaction time from several hours to few days [1,2,3,4].Upon the discovery of microwave technology, as an alternative heating source for organic reactions, it has gained much attention due to its high efficiency, reproducibility, and shortening the reaction time. This fulfills the requirements of green chemistry reactions as well as reducing solvents consumption, reaction temperature, and the extended reaction time to less than an hour, while many reactions are being done in few to several minutes. This is usually accompanied with significant reduction of energy consumption,

raising the efficiency and yield of the desired product, through lowering the level of side reactions [5,6]. Therefore, the discovery of the microwave heating in organic chemistry has revived the application of copper in cross-coupling reaction to access novel organic compounds via the formation of new C–C and C–X bonds.This review article is aiming to highlight the recent advances and perspectives of copper-catalyzed cross-coupling C–C and C–X bond formation under controlled microwave heating. Although it covers the most recent methodologies published in the last decade, but priority will be given to the protocols bearing transformation of wide-range of substrates, emphasizing on their utility and restrictions to simplify the further development of this very attractive area of research. 2. Copper-Catalyzed Cross-Coupling Reactions under Microwave Irradiation 2.1. Ullmann-Type Cross-Coupling ReactionsUllmann coupling reaction is the first reported cross-coupling reaction that uses a transition metal as catalyst. It has been developed by Fritz Ullmann for the synthesis of symmetrical biaryl compounds via the generation of new Ar–Ar (C–C) bond starting from an aryl halide and mediated by elemental copper (Cu0) [7]. In the next few years, Ullmann reaction has been modified to involve the coupling of aryl halides and various nucleophiles for the generation of other carbon–heteroatom (C–X) bonds, such as C–N, C–O, and C–S [8,9,10,11].For the last 20 years, Müller and coworkers are been interested in the synthesis of diverse range of anthraquinone derivatives for their pharmacological activity as antagonists for purinergic P2 receptors as well as ectonucleotidases inhibitors [12,13,14,15,16,17,18,19,20]. However, the anthraquinone chemistry undergo Ullmann coupling reaction under classical conventional heating were very much limited to the activated amines and anilines with significant low yield and extended reaction times for up to 48 h under harsh reaction conditions. Baqi, Y. et al. were the first to systematically investigate the effect of microwave irradiation on the Cu-catalyzed Ullmann coupling reaction using three different oxidation states of copper, namely elemental copper (0) powder (Cu),

copper(I) chloride (CuCl), and copper (II) sulfate (CuSO4). The three oxidation states of copper (0, I, and II) were investigate, in a comparison manner, under conventional heating and microwave technology [21,22]. The most significant achievement was when they employed a catalytic amount (5 mol%) of elemental copper in phosphate buffer (NaH2PO4 and Na2HPO4) at pH 6–7, as solvent under microwave irradiation, Scheme 1. The developed protocol has been successfully employed for the synthesis of a small library (about 200 compounds) of amino- and anilino-anthraquinones, where most of these compounds were previously inaccessible under classical Ullmann reaction using conventional heating.The generality of this protocol was further examined on other aryl halide scaffold and found to be useful. For example, Georg and his coworkers have employed the above mentioned protocol for the synthesis of 8-anilinonaphthalene-1-sulfonic acid derivatives. Similarly they have found that the use of elemental copper in phosphate buffer to be superior over other used copper based catalysts [23]. However, the reaction has relatively taken longer time, about 60–90 min, compared to the same reactions being performed under microwave heating. The product was obtained in low to good yields, Scheme 2. This low yield is probably due to the halide used, a chloride ion being less effective leaving group compared with bromide ion, while the presence of a carbonyl function in the anthraquinone core might have a direct impact on the stabilization of the intermediate generated in the catalytic cycle through possible coordination bond between the free lone pair on the oxygen atom of the carbonyl group and copper surface thus facilitate the reaction towards the desired product in shorter reaction time, therefore, it may minimize any competitive side reactions, which is the main cause of losing the yields.Park, A.R. and Yum, E.K. have developed microwave assisted synthesis of isoquinolines using copper(I) oxide (Cu2O) [24]. They have systematically optimized the reaction using different kind and equivalent of the catalyst, base, solvent, and reaction time. They have concluded that the optimal conditions for N-arylation of isoquinolines were using catalytic amount (10 mol %) of Cu2O, in the presence of Cs2CO3 as a base

Changing Perspectives on the Strategic Use of Microwave Heating in Organic Synthesis — Prof. Gregory B. Dudley et al., 2017

Introduction

Brief History of Microwave Heating in Organic Synthesis

While speaking on the topics of microwave chemistry, selective heating, and theories governing chemical kinetics, we have mused on occasion that organic chemists have been cooking with conventional (convective) heating methods since Prometheus stole fire from Mount Olympus and gave it to humankind. Microwave heating, in contrast, is comparatively new and poorly understood. Physical organic theories on reaction kinetics have emerged and developed, over decades or centuries, based exclusively on conventionally heated experiments. In contrast, the heating properties of low-energy "microwave" electromagnetic radiation were discovered by accident at Raytheon in the 1940s; the first microwave ovens became generally available in the 1970s; and the first reported examples of heating preparative organic reactions in a microwave oven came out in the mid-1980s, roughly a generation ago. Moreover, experiments designed to evaluate and refine theories of chemical kinetics are typically conducted under rigorously defined and controlled conditions. In contrast, the reaction parameters under microwave heating are often hard to measure, control, and quantify. Some of the microwaveheated reactions we have studied might fairly be described as teetering on the edge of chaos: thermal energy is created and transferred dynamically throughout the process, and temperature profiles are changing rapidly both in time and space. One should expect the unexpected. The unique behaviors of these systems cannot always be described by simple Arrhenius kinetics, but they can be advantageous for chemical synthesis. A more sophisticated analysis and understanding of microwave dielectric heating and dynamic thermal energy transfer processes is needed to take maximum advantage of emerging microwave heating technology.
Synthetic chemistry is inarguably an experimental science. Observation trumps expectation when it comes to chemical reactivity. Immediately following the first reported examples, chemists enthusiastically began an empirical assessment of various types of reactions under microwave heating. Reactions conducted in polar solvents originally seemed to show the most promise. In many cases, observations associated with microwave heating seemed to be inconsistent with conventionally heated experiments. Inexplicable changes in rate, yield, and product distribution were widely reported, and the legend of non-thermal microwave effects was born.
Theorists were quick to point out that many of the observations, interpretations, and/or hypotheses associated with so-called non-thermal or athermal microwave effects were physically implausible.

As dedicated microwave reactors became available, and temperature and pressure measurements inside the microwave cavity became more reliable, these preliminary observations were generally found to have been compromised by underestimating the solution temperature of reaction mixtures under microwave heating. Nonetheless, synthetic chemists have remained intrigued by the possible strategic value of microwave heating for chemical synthesis, and an apocryphal lore -that some reactions just work better under microwave heating -has unabatingly persisted. Synthetic chemistry, though firmly grounded in theory, remains an empirical science.
The tactical value of microwave energy as a convenient heating method for modern chemical synthesis is well recognized. Especially for small-scale reactions, microwave reactors can provide rapid heating to temperatures (and pressures) that cannot easily be achieved with conventional heating. The resulting process intensification can be tactically useful, although in principle the microwave reactor is not strategically necessary for such outcomes. In fact, many if not all of the tactical virtues of microwave heating can similarly be achieved using flow chemistry, which also offers rapid heating of small reaction volumes, with the added benefits of continuous processing. The strategic value of microwave heating is widely recognized in other fields. That is, microwave heating is applied in other lines of research and technology to achieve outcomes that are not possible or less efficient with conventional heating. This strategic value is derived from the unique volumetric heating characteristics of microwave energy as well as the ability to heat components of a mixture selectively. Moisture control of industrial production lots is supremely important for a reproducible product that maintains quality and profit margin standards. The food industry specifically has acknowledged the value of the rapid, volumetric nature of microwave heating by standardizing professionally recognized methods for loss on drying moisture analysis. [10,11] Microwave-based methods can produce more accurate and precise values compared to conventional methods through the uniformity of heating and permeation of energy into a sample. These same characteristics of rapid, volumetric heating have offered benefit to the field of trace metals analysis. Microwave acid digestion methods provide accelerated ramp-up and cool-down times as compared to conventional heating protocols, nearly independent of sample load. [12,13,14] This valuable acceleration of sample throughput has led to United States standardization around a recommended, microwave-based method for this type of sample preparation when analyzing pharmaceutical products. Another strategic feature, the selective heating characteristic of microwave energy (Figure 1), has benefited the fields of molecular extraction, heterogenous

catalysis, and materials synthesis. Because components of a system absorb different amounts of microwave energy (and so heat at differential rates), micelles and/or components containing a high concentration of polar, ionic, or otherwise strongly absorbing components (compared to the surrounding solution) can be effectively disrupted. This leads to a rapid and more complete extraction as compared to conventional heating methods. Some extraction methods use this selective heating in conjunction with additives to accelerate phasetransfer and allow for the use of more environmentally friendly solvents. This phenomenon was previously observed and documented in heterogeneous catalysis, providing a reaction rate enhancement when compared to the same bulk temperature of a conventionally heated reaction.

Modern Methods and Theory

One school of thought regarding the potential role of microwave heating in organic chemistry is that microwave heating offers tactical but not strategic value in chemical synthesis: "heating is just that... heating, whether by microwave or conventional methods." Dedicated microwave reactors offer powerful practical/tactical advantages in terms of convenient and rapid heating to high temperatures and pressures than may be difficult or impossible to attain Gregory B. Dudley is the Eberly Family Distinguished Professor of Chemistry and Chair of the C. Eugene Bennett Department of Chemistry at West Virginia University in Morgantown, WV. The current mission of his research program is to impact the drug discovery and development processes by contributing fundamental knowledge in organic chemistry, including new strategies, tactics, and research tools for best practices in organic synthesis.

Albert E. Stiegman is Professor of Chemistry and Biochemistry at Florida

State University in Tallahassee, FL. His primary research interests are in microwave chemistry, heterogeneous catalysis, and optical polymers, especially high refractive index composite polymer materials based on thiol-ene chemistry. Prof Stiegman was a graduate student at Columbia, a postdoctoral scholar at Caltech, and a member of the Jet Propulsion Lab before joining the faculty at FSU in 1994. conventionally; in this regard the microwave oven has been described as "the Bunsen burner of the 21st century." Implicit in this general paradigm are the assumptions that (a) the benefits of microwave heating are capped at the theoretical limits of the Bunsen burner, and (b) all reaction behavior can ultimately be described in terms associated with the measured bulk temperature and pressure of the system. Indeed, the vast majority of experiments in microwave chemistry can

Furfural Synthesis from d-Xylose in the Presence of Sodium Chloride: Microwave versus Conventional Heating — Christos Xiouras et al., 2016

Introduction

Furfural is a valuable platform chemical derived from renewable lignocellulosic biomass and agricultural surpluses. It has several uses, such as an extraction solvent for aromatic compounds or as a precursor for synthesizing specialty chemicals and liquid fuels. As one of a few non-petroleum-derived chemicals, it can play a vital role in the transition from fossil fuel resources to a more sustainable bio-based industry. Furfural synthesis usually involves the acid hydrolysis of the pentosan fraction of biomass into pentoses (C-5 sugars), such as xylose or arabinose, and the subsequent dehydration of the pentoses to furfural. The two reactions can take place in the same vessel under similar conditions, with the xylose dehydration to furfural as the rate limiting step. Currently, furfural is produced in industry by an energy intensive process using superheated steam to heat the reaction and mineral acids such as HCl and H 2 SO 4 as reaction catalysts. [2,4] Organic acids such as acetic acid can also be used and would be more desirable from an environmental standpoint, but they usually lead to lower furfural yield. Furfural product yields are generally limited to 45-55 % owing to the occurrence of side reactions that give rise to degradation products. New processes for furfural production can potentially circumvent the yield limitations, lower the energy requirements and minimize the large waste streams associated with the conventional process. In this way, the full potential of furfural as a biomass-derived intermediate could be exploited as a replacement for oil derivatives. Such intensified processes may be based on chemical activation through alternative energy forms (e.g., microwave heating). In many organic syntheses, microwave heating leads to reduced reaction times and higher reaction efficiency in aqueous systems compared to conventional heating. As a result, toxic organic solvents and catalysts may be replaced with more benign aqueous systems. [5,6] Marcotullio and De Jong have shown that the presence of Cl A ions in aqueous acidic solutions could significantly enhance the dehydration reaction rate of d-xylose under conventional heating and improve the selectivity and furfural yield. Another study investigated the effect of microwave heating on furfural yield using d-xylose in aqueous HCl solutions. Microwave heating showed no effect on the reaction

kinetics of xylose dehydration. However, several studies of the dehydration of C-5 and C-6 sugars to furfural and 5-hydroxymethylfurfural (5-HMF), respectively, claim significant enhancement of the reaction rate under the presence of ions and microwave heating compared to conventional (e.g., oil-bath) heating. Synergistic effects of ions and microwave heating, leading to higher furfural yield, have also been reported. A discussion of several studies comparing microwave and conventional heating for the synthesis of furfural and 5-HMF from C-5 and C-6 sugars, respectively, is presented in the Appendix. The presence of ions in aqueous solutions is known to enhance electromagnetic energy dissipation and consequently, increase the dielectric heating rate. The rapid temperature increase could explain some of the observed yield enhancements. However, ions participate in the dehydration chemistry as well; therefore, nonthermal microwave effects (i.e., increase in the number of ef-We investigate the existence of specific/nonthermal microwave effects for the dehydration reaction of xylose to furfural in the presence of NaCl. Such effects are reported for sugars dehydration reactions in several literature reports. To this end, we adopted three approaches that compare microwave-assisted experiments with a) conventional heating experiments from the literature; b) simulated conventional heating experiments using microwave-irradiated silicon carbide (SiC) vials; and at c) different power levels but the same temperature by using forced cooling. No significant differences in the reaction kinetics are observed using any of these methods. However, microwave heating still proves advantageous as it requires 30 % less forward power compared to conventional heating (SiC vial) to achieve the same furfural yield at a laboratory scale.
fective collisions or lowering of activation energy owing to the direct interaction of the electromagnetic field with the polar species) have also been put forward to explain the kinetic rate enhancement of these reactions. Nevertheless, it is known that the existence of such effects is largely speculative.
In this study, the application of microwave-assisted heating combined with the use of NaCl salt for the dehydration of xylose in dilute aqueous acidic solutions was investigated and the results were compared to conventionally heated experiments reported in the literature. In addition, the existence of nonthermal microwave effects was investigated in an experimental microwave setup that allows the

simulation of conventional heating while maintaining all the other process parameters the same (bulk and wall temperature, heating rate, reactor geometry, and stirring rate). Finally, the rate constants of the pseudo-first order reactions of xylose conversion to furfural and xylose and furfural conversion to byproducts were determined under the two heating modes.

Results and Discussion

Indirect comparison of microwave and conventional heating using varying amounts of NaCl

Microwave heating in combination with NaCl was investigated for the dehydration reaction of xylose to furfural. Three different NaCl concentrations (2, 3.5 and 5 wt %, or 342, 599 and 856 mm, respectively), close to those found in seawater, were studied in dilute aqueous HCl solutions (50 mm HCl concentration, initial xylose concentration: 35 mm) at 200 8C. The conditions of these experiments are similar to a previous study, which used a conventionally heated autoclave reactor. This way, an indirect comparison between the two modes of heating can be made. The results of these experiments in terms of the time evolution of the xylose and furfural concentrations are presented in Figure 1.
Based on the experimental results, it appears that NaCl has a significant catalytic effect on the reaction under microwave heating leading to complete xylose conversion within 1000 s in all cases. The maximum experimental furfural yields were 73, 76, and 72 %, for NaCl concentrations of 2, 3.5 and 5 wt %, respectively. Even though increasing the NaCl concentration within the evaluated range does not seem to significantly affect the furfural yield and selectivity, the reaction rate is increased considerably. Conversely, prolonged residence times, particularly at higher NaCl concentrations, seem to slightly decrease the furfural concentration. This can possibly be explained by the higher concentration of furfural or xylose-to-furfural intermediates that may undergo (enhanced) side reactions under these conditions. The first order rate constants k 1 , k 2 , and k 3 were derived based on the experimental data and are presented in Table 1. The estimated rate constants (Entries 1-3, Table 1) reveal that increasing salt concentration, at a constant acidity, leads to an almost proportional increase in both k 1 and k 2 , implying that both xylose reactions (towards