Reaction with Neat Reactants

Organic reactions under microwave conditions, including cycloadditions, frequently involve solvent-free dry media procedures. The reaction is performed between neat reagents, at least one of which must be a liquid and polar substance. These are liquid-liquid or liquid-solid systems the latter implies the solid is soluble in the liquid phase or at least that the liquid counterpart is adsorbed on the solid, so reaction occurs at the interface [3e, 32a]. Because of the absence of solvent, the radiation is absorbed directly by the reagents, so the effect of the microwaves is more marked. As a result, high overall yields and purity of the desired products are usually obtained more quickly. 

De la Hoz et al. describe several of the advantages of microwave irradiation by this method in Diels-Alder and 1,3-dipolar reactions of ketene acetals [41]. A specific improvement is the absence of polymerization of the ketene acetals. The same 

Using these procedures, the most important advantages are simplification of reaction work-up, because the products are isolated directly from the crude reaction mixture. In addition, rates of neat reactions are markedly accelerated compared with microwave activation with solvents or classical reflux conditions with the same solvents. The reduced reactivity observed using solvent can be associated to the limitation of the reaction temperature reaction (at maximum, the boiling point of the solvent) and the dilution. 

In the second example, Hamelin et al. [47] reported the first microwave-assisted solvent-free catalyzed conditions for generation of nitrile oxide intermediates 17. In this work, a mixture of methyl nitroacetate 16 (as 1,3-dipole precursor), dimethyl acetylene dicarboxylate (DMAD) 18 (as dipolarophile), and p-toluene sulfonic acid (PTSA) as catalyst (10% w/w) was irradiated neat for 30 min. The reaction was performed in an open vessel from which water was continuously removed [48]. In this manner, the desired isoxazole adduct 19 was obtained in excellent yield (91%). 

In the past few years, Garrigues et al. have reported two papers dealing with graphite-supported, solvent-free dry media conditions as a powerful technique 

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Fig. 2.7 Fluorous phase catalytic hydroboration. The procedure involves stirring the catalyst (0.1 mol%) in the fluorous phase with neat reactants at 40-45 °C, the cooling on completion of reaction and extracing with THF.

Another problem is the very high concentrations of reactants present in the low-conversion region. The correct derivation of any rate expression such as Eqs. 2-20 and 2-22 requires the use of activities instead of concentrations. The use of concentrations instead of activities assumes a direct proportionality between concentration and activity. This assumption is usually valid at the dilute and moderate concentrations where kinetic studies on small molecules are typically performed. However, the assumption often fails at high concentrations and those are the reaction conditions for the typical step polymerization that proceeds with neat reactants. A related problem is that neither concentration nor activity may be the appropriate measure of the ability of the reaction system to donate a proton to the carboxyl group. The acidity function ho is often the more appropriate measure of acidity for nonaqueous systems or systems containing high acid concentrations [Ritchie, 1990]. Unfortunately, the appropriate ho values are not available for polymerization systems. 

The preceding demonstration, All Things Being Equal, was intended to illustrate three significant subtleties concerning chemical reactions. The first is that although we often symbolize chemical reactions with neat little arrows pointing from reactants to products. 

PTC reactions, especially under microwave irradiation, have been discussed at length recently [14b] and are not included in this chapter. Reactions between neat reactants, with and without soHd inorganic supports and with microwave assistance are described herein with the salient advantages of the processes as they relate to environment, energy consumption, and recycHng of materials. 

Heropoulos et al. (2007) reported bromination reaction (ultrasound and microwave-assisted) of various alkylaryls with NBS (N-bromosuccinimide), either neat or in water with diverse chemoselectivity. Thus, only ring substitution occurs in water with ultrasound, whereas with microwaves both side-chain a-bromination as well as ring substitution occurs. In presence of water, microwaves promote side-chain a-bromination and ring substitution, both. With neat reactant, side-chain a-brominated form was obtained as the major product. 

The fate of the ion pair iatermediate depends on the stmcture of the amine and the reaction conditions. Certain tertiary amines, eg, dimethylaruline (DMA), react with specific diacyl peroxides such as diben2oyl peroxide (BPO) to generate free radicals at ca 20°C. Some reactions, eg, DMA—BPO, are explosive when neat reactants are mixed. Primary and secondary amines do not yield free radicals. 

A typical reason for longer reaction times in the plant is slower overall heat removal rates. And a typical case is batch hydrogenation, with a neat reactant or in solvent. Here all reactants are charged before the batch reaction is initiated. Typical set of reactions is ... 

The feedstreams can consist of either neat reactants or their solutions. When the feedstreams consist of solutions, the reaction mixture is pumped into a polymerization vessel where the reaction that started in the mixing head proceeds to its conclusion. The polymer is subsequently precipitated from solution, separated, dried, and pelletized. Solvent-free mixtures of reactants are pumped directly to a mold where polymerization proceeds. In this case, other additives, such as, fillers or fire retardants, are co-mixed with the reactants in the mixing head. These additives are permanently incorporated into the finished molding. 

The immobilization of Pd(acac)2 as hydrogenation catalyst in the ionic liquids [BMIM][BF4] and [BMIM][PF6] was reported by Dupont et al. in 2000 [70]. These authors compared the biphasic hydrogenation of butadiene with the homogeneous system with all reactants being dissolved in CH2C12, with the reaction in neat butadiene and with a heterogeneous system using Pd on carbon as catalyst. 

The problems encountered in the catalytic transfer of highly hydrophilic anions from aqueous solutions into the organic phase can be countered by the use of anhydrous solid salts the organic reactant is dissolved in the organic solvent or, if liquid, may be used neat. Solid liquid two-phase reactions using ammonium salts have widespread application (see, for example, the many examples cited in later chapters) frequently with shortened reaction times, lower reaction temperatures, and higher yields [e.g. 66, 67] and are generally superior to solidrliquid reactions catalysed by crown ethers [68]. The process is particularly useful in base-initiated reactions with fluorides, hydroxides or carbonates. 

Solvent-free conditions can be employed according to three main methods (a) using only neat reactants (b) reactants adsorbed onto solid supports or (c) reactants in the presence of phase transfer catalysts (in the case of anionic reactions). Besides the apparent potential benefits in solvent usage, reactions can be conducted conveniently and rapidly, often without temperature measurement in domestic microwave ovens. However, they now are often carried out under more precisely controlled conditions using monomode reactors initially introduced by the former French manufacturer Prolabo. Nowadays, several systems are available that provide facilities for the accurate measurement and monitoring of temperature throughout the reaction by modulation of emitted power with an infrared detector or an optical fibre. 

On the other hand, different mechanisms can operate when autoxidation is performed with Co in acetic acid as a solvent. Under these conditions, Co3+ is a very strong oxidant, capable of reacting directly with the hydrocarbon reactant instead of the hydroperoxide, resulting in unusual regioselectivities and other patterns that deviate from classical free radical chemistry (5). The previously stated considerations, and particularly the distinction between reactions in neat hydrocarbon and in acetic acid, have an important bearing on any strategy for immobilization of Co autoxidation catalysts. 

To extend the comparison between homogeneous and supported systems, we have carried out kinetic measurements on the reactions of polymer-supported [Rh(CO)2I2] complexes with Mel. In order to monitor the reactions in situ, polymer films were inserted between the windows of a conventional infrared liquid cell, fitted with a thermostatted jacket. The cell was then filled with neat Mel or a solution of Mel in CH2C12, and transmission spectra recorded directly through the polymer film immersed in the Mel solution. An example of a series of spectra recorded in this way is shown in Figure 5. The absorption bands of [Rh(CO)2I2] are replaced cleanly by those of the product acetyl complex, [Rh(CO)(COMe)I3], with the high frequency band of the reactant almost coinciding with the terminal v(CO) band of the product. 

The only example of a reaction between two solids, under solvent-free and catalyst-free environment, was demonstrated by Varma et al. when the reaction of neat 5- or 8-oxobenzopyran-2(177)-ones with a variety of aromatic and heteroaromatic hydrazines provided rapid access to several synthetically useful heterocyclic hydrazones (Scheme 5) via the formation of a eutectic melt below the melting point of either of the reactants. ... 

Intermolecular Diels-Alder or hetero Diels-Alder reactions have been greatly improved by using microwave technology - again with higher reaction rates and improved yields [3j]. Remarkable improvements in rate acceleration and selectivity enhancement for a variety of intermolecular Diels-Alder reactions have also been accomplished in the past two decades by application of catalysts such as Lewis acids. Recently, many such examples have been reported under microwave conditions in polar solvents or ionic liquids as energy-transfer medium. These reactions have also been developed in open vessels by adsorption of the reactants on mineral solid supports or using neat reactants. 

A similar MW strategy has been used to synthesize a set of pyrimidinones (65-95%) via the Biginelli condensation reaction in a household MW oven and has been successfully applied to combinatorial synthesis [139]. More recent examples describe a convenient synthesis of highly substituted pyrroles (60-72%) on silica gel using readily available a, 3-unsaturated carbonyl compounds, amines, and ni-troalkanes [140], and the use of neat reactants under solvent-free conditions to generate Biginelli and Hantzsch reaction products with enhanced yields and shortened reaction times [141]. 

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