Diels-Alder reaction rate enhancement with

It has been established that alkoxy alkenylcarbene complexes participate as dienophiles in Diels-Alder reactions not only with higher rates but also with better regio- and stereoselectivities than the corresponding esters [95]. This is clearly illustrated in Scheme 51 for the reactions of an unsubstituted vinyl complex with isoprene. This complex reacts to completion at 25 °C in 3 h whereas the cycloaddition reaction of methyl acrylate with isoprene requires 7 months at the same temperature. The rate enhancement observed for this complex is comparable to that for the corresponding aluminium chloride-catalysed reactions of methyl acrylate and isoprene (Scheme 51). 

An ab initio MO calculation by Jorgensen revealed enhanced hydrogen bonding of a water molecule to the transition states for the Diels-Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile, which indicates that the observed rate accelerations for Diels-Alder reactions in aqueous solution arise from the hydrogenbonding effect in addition to a relatively constant hydrophobic term.7,76 Ab initio calculation using a self-consistent reaction field continuum model shows that electronic and nuclear polarization effects in solution are crucial to explain the stereoselectivity of nonsymmetrical... 

Although the early examples of the 4ir participation of heterodienes in [4 + 2] cycloaddition reactions describe their reactions widi electron-deficient aJkenes, e.g. the thermal dimerization of a,3 unsaturated carbonyl compounds, the introduction of one or more heteroatoms into the 1,3-butadiene framewoiic does convey electrophilic character to the heterodiene. Consequently, such systems may be expected to participate preferentially in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, or simple alkene and alkyne dienophiles. The complementary substitution of the heterodiene with one or more electron-withdrawing substituents further lowers the heterodiene Elumo, accelerates the rate of heterodiene participation in the LUMOdioie-conn-olled Diels-Alder reaction, and enhances the observed regioselectivity of the [4 + 2] cycloaddition reaction. ... 

Another alternative, LiNTfa, was also employed as Lewis acid catalyst (1 mol %) in the Diels-Alder reaction of CP with MVK in CH2CI2. The rate enhancement was moderate compared with that obtained with the other alkali earth and lanthanide metal imides Mg(NTf2)2, La(NTf2)3.H20, and Zn(NTfa)2 (Sch. 25) [73]. 

An early example of chiral alcohol-based hydrogen bonding catalysts is the work by Braddock and coworkers in which they used paracydophanediols (PHANOLs) as dual H-bond donors [65, 66]. Significant rate enhancements were obtained in the Diels-Alder reactions of dienes with a,P-unsaturated aldehydes and ketones and in the epoxide-opening reactions with amines. However, little or no asymmetric induction was obtained when a chiral PHANOL catalyst was used. 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

The rate constants for the catalysed Diels-Alder reaction of 2.4g with 2.5 (Table 2.3) demonstrate that the presence of the ionic group in the dienophile does not diminish the accelerating effect of water on the catalysed reaction. Comparison of these rate constants with those for the nonionic dienophiles even seems to indicate a modest extra aqueous rate enhancement of the reaction of 2.4g. It is important to note here that no detailed information has been obtained about the exact structure of the catalytically active species in the oiganic solvents. For example, ion pairing is likely to occur in the organic solvents. 

In contrast to SDS, CTAB and C12E7, CufDSjz micelles catalyse the Diels-Alder reaction between 1 and 2 with enzyme-like efficiency, leading to rate enhancements up to 1.8-10 compared to the reaction in acetonitrile. This results primarily from the essentially complete complexation off to the copper ions at the micellar surface. Comparison of the partition coefficients of 2 over the water phase and the micellar pseudophase, as derived from kinetic analysis using the pseudophase model, reveals a higher affinity of 2 for Cu(DS)2 than for SDS and CTAB. The inhibitory effect resulting from spatial separation of la-g and 2 is likely to be at least less pronoimced for Cu(DS)2 than for the other surfactants. 

Diels-Alder reactions Neutral ionic liquids have been found to be excellent solvents for the Diels-Alder reaction. The first example of a Diels-Alder reaction in an ionic liquid was the reaction of methyl acrylate with cyclopentadiene in [EtNH3][N03] [40], in which significant rate enhancement was observed. Howarth et al. investigated the role of chiral imidazolium chloride and trifluoroacetate salts (dissolved in dichloromethane) in the Diels-Alder reactions between cyclopentadiene and either crotonaldehyde or methacroline [41]. It should be noted that this paper describes one of the first examples of a chiral cationic ionic liquid being used in synthesis (Scheme 5.1-17). The enantioselectivity was found to be < 5 % in this reaction for both the endo (10 %) and the exo (90 %) isomers. 

The cycloadditions of cyclopentadiene 1 and its spiro-derivatives 109 and 110 with quinones 52, 111 and 112 (Scheme 4.20), carried out in water at 30 °C in the presence of 0.5% mol. of cetyltrimethylammonium bromide (CTAB), gave the endo adduct in about 3 h with good yield [72b]. With respect to the thermal Diels-Alder reaction, the great reaction rate enhancement in micellar medium (Scheme 4.20) can be ascribed to the increased concentration of the reactants in the micellar pseudophase where they are also more ordered. 

Water has physical hemical properties that are very different from those of other solvents [1] and its role in enhancing the reactivity and selectivity of some organic reactions is still a debated question. Recent experimental studies [3e, 9] and computer simulations [10] seem to indicate, at least with respect to the rate enhancement of aqueous Diels Alder reactions, that the main effects are due to the enforced hydrophobic interactions and hydrogen bond interactions. 

The rate enhancement of the Diels-Alder reaction in LP-NM has been attributed to the high dipole moment of nitromethane (3.40 D) in comparison with diethyl ether (1.33 D). 

The combination of Lewis-acid catalysis and sc-COi has also been investigated. One of these studies involved the AlCls-catalyzed Diels Alder reaction of isoprene and maleic anhydride in sc-COi at 67 °C and at 74.5-78.5 bar [89]. The reaction rate was enhanced with respect to the uncatalyzed reaction and an unconcerted two-step mechanism was suggested [89]. 

The effect of water molecules on pericyclic reactions can also be compared with the effects of Lewis acids on these reactions. The enhanced polarization of the transition state in these reactions would lead to stronger hydrogen bonds at the polar groups of the reactants, which will result in a substantial stabilization of the transition states in the same way Lewis acids do. A computer-simulation study on the Diels-Alder reaction of cyclopentadiene by Jorgensen indicated that this effect contributes about a factor of 10 to the rates.7... 

In the absence of catalytically active transition-metal ions, micelles impede the reaction. In contrast to SDS, CTAB, and C12E7, Cu(DS)2 micelles catalyze the Diels-Alder reaction with extremely high efficiency, leading to rate enhancements up to 1.8 x 106 compared to... 

The first report suggesting specific activation of an organic reaction by MW was that of Berlan et al. [28] who observed that some Diels-Alder reactions occurred more rapidly on MW heating than under conventional heating at the same temperature (95 °C). The reactions were performed in two different solvents, xylene and dibutyl ether and the rate enhancements were slightly higher in xylene, the less polar solvent. For example the rate enhancement of the reaction of 2,3-dimethyl-l,3-butadiene 21 with methyl vinyl ketone 22 was 8 times in xylene and 2.3 times in dibutyl ether, based on the half lives of the reactions. Reaction of anthracene 3 with diethyl maleate 23 in xylene (Scheme 4.12) resulted in an approximately fourfold rate in-... 

Diels-Alder reaction of methyl 2-acetamidoacrylate with cyclopentadiene in the presence of Si02-Al and Si02-Tl catalysts [53], Rate enhancement was not expressed quantitatively. Reaction conditions a stirred multi-mode tank microreactor, no solvent. 

In Scheme 14 the effect of pressure on Diels-Alder reactions with acyclic heterodienophiles or heterodienes is presented. The application of high pressure leads also in these reactions to an enhancement of rates and improvement of yields. The hetero-Diels-Alder reaction (entry 3) is a good example of the interplay between pressure and temperature. At high pressure the rate of reaction as well as the diastereoselectivity are increased. The pressure-induced acceleration allows the temperature of reaction to be lowered, which leads to a further increase of diastereoselectivity. 

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