Influence of polarity on the scalability and reproducibility of solvent-free microwave-assisted reactions

Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not.     

Microwave-assisted reactions in heterocyclic compounds with applications in medicinal and supramolecular chemistry

Microwave irradiation has been successfully applied in organic chemistry. Spectacular accelerations, higher yields under milder reaction conditions and higher product purities have all been reported. Indeed, a number of authors have described success in reactions that do not occur under conventional heating and modifications in selectivity (chemo-, regio- and stereoselectivity) have even been reported. Recent advances in microwave-assisted combinatorial chemistry include high-speed solid-phase and polymer-supported organic synthesis, rapid parallel synthesis of compound libraries, and library generation by automated sequential microwave irradiation. In addition, new instrumentation for high-throughput microwave-assisted synthesis continues to be developed at a steady pace. The impressive speed combined with the unmatched control over reaction parameters justifies the growing interest in this application of microwave heating. In this review we highlight our recent advances in this area, with a particular emphasis on cycloaddition reactions of heterocyclic compounds both with and without supports, applications in supramolecular chemistry and the reproducibility and scalability of organic reactions involving the use of microwave irradiation techniques.     

Highly regioselective Wittig reactions of cyclic ketones with a stabilized phosphorus ylide under controlled microwave heating

Significant base and temperature effects on the Wittig reactions of cyclohexanones with (carbethoxymethylene)triphenylphosphorane under microwave irradiation were observed. For the Wittig reactions carried out in a domestic microwave oven under solvent-free conditions, the initially formed exo-olefin products isomerized into the thermodynamically more stable endo-olefins due to uncontrolled high reaction temperature. In sharp contrast, under controlled microwave heating, both exo- and endo-olefins have been selectively synthesized by accurately regulating the reaction temperature with or without a base.     

Microwave-induced organic reaction enhancement (more) chemistry: Techniques for rapid,safe and inexpensive synthesis

Synthetic organic reactions have been conducted under microwave irradiation in open vessels in unaltered domestic microwave ovens. Reaction times vary from a few seconds for sub-milligram reactions to about 15 minutes for reactions carried out on a scale of hundreds of grams. Promising results have been obtained for several condensations, as well as the Bischler-Napieralski reaction, the Wolff-Kishner reduction, free radical dehalogenation reactions, and other standard synthetic operations. Rapid catalytic transfer hydrogenation using ammonium formate as the source of hydrogen has been conducted at about 100-130 °C under microwave irradiation. Meaningful, safe and inexpensive synthetic experiments for undergraduate and pre-college students have been developed and tested. The MORE chemistry techniques make it possible to use simple apparatus and very short reaction times. Commercial microwave ovens are now essential equipment in our research and teaching laboratories [1-3]. These ovens are relatively inexpensive, easy to move from one laboratory and set up in another, and safe to operate. Glass, plastics, and ceramics are essentially transparent to microwaves whereas many organic compounds are dipolar in nature and absorb microwave energy readily. We have found that untraditional experimental arrangements are possible for conducting a wide variety of organic reactions in open vessels inside domestic microwave ovens. Depending on the quantity of reactants, most reactions (on a scale of milligrams to several grams) can be completed in minutes instead of hours. One important element of our “Microwave-induced Organic Reaction Enhancement” (MORE) chemistry is the proper choice of a microwave energy transfer agent as the reaction medium.     

Microwave-assisted SNAr reaction of 2,4,6-trichloro-1,3,5-triazine for the rapid synthesis of C3-symmetrical polycarboxylate ligands

The microwave-assisted S_NAr reaction of 2,4,6-trichloro-1,3,5-triazine with various unprotected amino acids was developed for the synthesis of C₃-symmetrical polycarboxylate ligands which can be used as structural directing units in metal-organic frameworks. The reactions were performed in water using a domestic microwave oven as the heating device. In comparison to the reactions performed under conventional heating, the reactions under microwave irradiation proceeded much more rapidly within 20 min to afford the desired ligands in comparative yields to those obtained by conventional heating.     

CARO'S ACID SUPPORTED ON SILICA GEL. PART 7: A VERSATILE REAGENT FOR THE AROMATIZATION OF HANTZSCH 1,4-DIHYROPYRIDINES UNDER NON-AQUEOUS CONDITION AND MICROWAVE IRRADIATION

Efficient oxidation of 1,4-dihydropyridines with Caro's acid on silica gel is achieved under nonaqueous conditions and in a domestic microwave oven. The reactions under microwave irradiation were shorter in duration and higher in yields than the reactions in conventional method, confirming the potentiality of microwave heating in aromatization of Hantzsch 1,4-dihydropyridines.     

Microwave-promoted synthesis of chiral pyridinium salts

The synthesis of several chiral pyridinium salts via Zincke’s reaction can be easily accomplished by domestic microwave oven irradiation. Yield enhancements, reduction of reaction time, and less racemization were observed under microwave heating when compared to conventional heating in similar conditions.     

One-pot and efficient synthesis of triazolo[1,2-a]indazole-triones via reaction of arylaldehydes with urazole and dimedone catalyzed by silica nanoparticles prepared from rice husk

A novel synthesis of triazolo[1,2-a]indazole-1,3,8-trione derivatives by reaction of urazole, dimedone and aromatic aldehydes under conventional heating and microwave irradiation and solvent-free conditions using silica nanoparticles prepared from rice husk ash as catalyst is described. The new method features high yields, multicomponent reactions and environmental friendliness.     

微波与有机化学反应的选择性

本文综述了微波辅助下有机化学反应的选择性,包括化学选择性、区域选择性、顺反选择性、非对映选择性、对映选择性,与传统加热条件下反应选择性的区别。讨论了微波对有机化学反应选择性的影响。从文献报道的结果来看,虽然观察到了一些反应在微波照射与加热条件下显示出不同的选择性,但绝大部分例子并不是在严格相同的条件下进行的对比,还有一些虽然做了对比研究,但却忽略了温度的影响。对于绝大多数例子,微波产生的选择性的差别似乎都可以用热效应来解释。可以认为微波辅助的反应中基本不存在特殊的"非热效应"。微波辅助技术可以通过改变反应温度来实现改变某些反应的选择性。希望本文对微波效应和微波对有机反应加速效应的本质的理解提供一些有用信息。     

Environmentally Friendly Methods for Syntheses of New Aromatic Bisesters

Two environmentally friendly methods, one in liquid and the other in solid phase, for preparation of phenyl bisesters (bearing alkylating groups) under microwave (MW) irradiation are presented. The MW remarkably enhanced the rate of acceleration for esterification: the reaction time decreased dramatically, the reaction conditions are milder, and the consumed energy decreased considerably. In the most cases, in the liquid phase under MW irradiation, the yields are better, in some cases substantially (almost 75%). In the solid phase under MW irradiation, the yields are moderate to good compared to the liquid phase but excellent compared to conventional heating. Both methods are fast, general, and facile, but because the solid-phase reactions are solvent-free, we consider this one to be the most suitable for synthetic chemistry. A comparative study of MW and conventional heating was done.     

Out of the oil bath and into the oven--microwave-assisted combinatorial chemistry heats up

The application of microwave irradiation to expedite solid-phase organic reactions could be the tool that allows combinatorial chemistry to deliver on its promise--providing rapid access to large collections of diverse small molecules. Herein, several different approaches to microwave (MW)-assisted solid-phase reactions and library synthesis are introduced, including the use of solid-supported reagents, multicomponent coupling reactions, solvent-free parallel library synthesis, and spatially addressable library synthesis on planar solid supports. The future impact of MW-assisted organic reactions on solid-phase and combinatorial chemistry could prove to be immense, and methods for further improvement of this strategic combination of technologies are highlighted.     

Facile Access to Mono-Cinchona Alkaloid-Derived Ligands

Two facile accesses to mono-cinchona alkaloid-derived ligands, by conventional heating conditions and solvent-free microwave irradiation, are described. 1,4-Dichlorophthalazine (PHAL) or 3,6-dichloropyridazine (PYDZ) reacted with quinine (QN), cinchonine (CN), or cinchonidine (CND) by using CaH₂ as acid-bonding reagent in DMF at 90–100°C to provide mono-cinchona alkaloid-derived ligands 2a–f (87–95%) in 1.5 h. However, the coupling reactions were performed under solvent-free microwave conditions to yield 2a–f (64–89%) within 15 min.     

Molecular Iodine–Catalyzed,Mild, Effective,Ecofriendly, Microwave-Assisted,One-Pot Synthesis of 5-Arylmethylidene-2-phenyloxazol-4-ones (Azalactones) Under Solvent-Free Conditions

Fourteen azalactones have been synthesized in excellent yields under solvent-free conditions by heating an aldehyde, hippuric acid, and acetic anhydride in the presence of molecular iodine as a catalyst in a microwave oven. The short reaction time, cleaner reaction, and easy workup make this protocol practical and economically attractive.     

Microwave Accelerated Cycloaddition Reactions of Nitrile Oxides and Allylic Alcohols

The application of microwaves in promoting the cycloaddition reactions of allyl alcohols with nitrile oxides using a domestic microwave oven and a focused monomode microwave reactor have demonstrated that not only was the reaction time substantially reduced, but also the reaction yields were significantly improved over the conventional stirred reactions. Microwave irradiation alters the regioselectivity of the cycloaddition reaction which favors the non‐hydrogen‐bond directed cycloadduct, isoxazoline 4 .     

Methylation of 1,8-dihydroxy-9,10-anthraquinone with and without use of solvent-free technique

A convenient and environmentally friendly solvent-free procedure has been developed for dimethylation of 1,8-dihydroxy-9,10-anthraquinone with excellent yield. A highly selective monomethylation of 1,8-dihydroxy-9,10-anthraquinone in refluxing tetraglyme makes monomethylated peri-dihydroxy-9,10-anthraquinones easily available. Alternatively, irradiation in a domestic microwave oven has been employed for the solvent-free monomethylation of 1,8-dihydroxy-9,10-anthraquinone.     

Microwaves in organic synthesis. Thermal and non-thermal microwave effects

Microwave irradiation has been successfully applied in organic chemistry. Spectacular accelerations, higher yields under milder reaction conditions and higher product purities have all been reported. Indeed, a number of authors have described success in reactions that do not occur by conventional heating and even modifications of selectivity (chemo-, regio- and stereoselectivity). The effect of microwave irradiation in organic synthesis is a combination of thermal effects, arising from the heating rate, superheating or "hot spots" and the selective absorption of radiation by polar substances. Such phenomena are not usually accessible by classical heating and the existence of non-thermal effects of highly polarizing radiation--the "specific microwave effect"--is still a controversial topic. An overview of the thermal effects and the current state of non-thermal microwave effects is presented in this critical review along with a view on how these phenomena can be effectively used in organic synthesis.     

Natural organic acids promoted Beckmann rearrangement: Green and expeditious synthesis of amides under solvent-free conditions

Naturally occurring organic acids are reported to be highly efficient promoters of the Beckmann rearrangement. Citric, oxalic, tartaric, malic, succinic, malonic, and fumaric acids efficiently promote the Beckmann rearrangement under solvent-free conditions and thermal and microwave irradiation. Tartaric acid was found to be the best promoter of the Beckmann rearrangement under conventional conditions as well as under microwave irradiation. Compared with conventional heating, microwave irradiation provides higher reaction rate and slightly higher yields.     

Microwave assisted synthesis of novel organomercurials in ‘dry media’

New organomercurials of benzoquinone, barbituric acid and thiobarbituric acid with substituted aryl mercuric chloride have been synthesised using microwave irradiation under dry conditions in a domestic microwave oven in a few minutes with improved yields as compared to conventional heating. These organomercurials have a 1:1 stoichiometric ratio of aryl mercury and benzoquinone/barbituric acid/thiobarbituric acid moiety.     

Microwave-assisted asymmetric organocatalysis. A probe for nonthermal microwave effects and the concept of simultaneous cooling

A series of five known asymmetric organocatalytic reactions was re-evaluated at elevated temperatures applying both microwave dielectric heating and conventional thermal heating in order to probe the existence of specific or nonthermal microwave effects. All transformations were conducted in a dedicated reactor setup that allowed accurate internal reaction temperature measurements using fiber-optic probes. In addition, the concept of simultaneous external cooling while irradiating with microwave power was also applied in all of the studied cases. This method allows a higher level of microwave power to be administered to the reaction mixture and, therefore, enhances any potential microwave effects while continuously removing heat. For all of the five studied (S)-proline-catalyzed asymmetric Mannich- and aldol-type reactions, the observed rate enhancements were a consequence of the increased temperatures attained by microwave dielectric heating and were not related to the presence of the microwave field. In all cases, in contrast to previous literature reports, the results obtained either with microwave irradiation or with microwave irradiation with simultaneous cooling could be reproduced by conventional heating at the same reaction temperature and time in an oil bath. No evidence for specific or nonthermal microwave effects was obtained.     

A mild and simple synthesis of N-aryl substituted toluenesulfamides under solvent-free conditions

N- aryl substituted benzenesulfamides are often used as heating-sensitive recording material1, thermal printing material2, sensitizer3 and developer4. Moreover, some of the benzenesulfamides have antifungal activities5. Many methods have been described for preparation of sulfamides. They are used to carry out in solvent8 or in solid phase condition9. These methods required solvent or solid support and even required heating or cooling. At the same time, the process of these methods is complex. Now we have developed a new method to prepare N-aryl substituted toluenesulfamides under solvent-free conditions.In recent years, solvent-free technology has gained popularity in organic synthesis. For instance,solidstate reaction and microwave reaction have received considerable attention. Solvent-free synthesis of amides has been reported10-11. This technology has many advantages such as high efficiency and selectivity, easy separation and environmental acceptability. All these merits are in accord with green chemistry's requirements of energy-saving, high efficiency and environmental benefits.In our paper, we used a simple and efficient method for preparing N-aryl substituted toluenesulfamides under solvent-free conditions, as a replacement for classic solvent, which gives many environmental benefits.All reactions were completed at room temperature by co-grinding in an agate mortar for 3-20min and the results are shown in Table 1.In conclusion, we have developed an efficient and convenient method of preparation N-aryl substituted toluenesulfamides in high yields. It symbols an improvement for synthesis of benzenesulfamides.