Diels-Alder cycloaddition reactions, solvent effects

While studies of reactions in supercritical fluids abound, only a few researchers have addressed the fundamental molecular effects that the supercritical fluid solvent has on the reactants and products that can enhance or depress reaction rates. A few measurements of reaction rate constants as a function of pressure do exist. For instance, Paulaitis and Alexander (1987) studied the Diels Alder cycloaddition reaction between maleic anhydride and isoprene in SCF CO2. They observed bimolecular rate constants that increased with increasing pressure above the critical point and finally at high pressures approached the rates observed in high pressure liquid solutions. Johnston and Haynes (1987) found the same trends in the... 

Further examples of Diels-Alder cycloaddition reactions with small or negligible rate solvent effects can be found in the literature [531-535], The thermolysis of 7-oxabicyclo[2.2.1]hept-5-ene derivatives is an example of a solvent-independent retro-Diels-Alder reaction [537]. For some theoretical treatments of the solvent influence on Diels-Alder cycloaddition reactions, which, in general, confirm their small solvent-dependence, see references [536, 797-799]. 

The Diels-Alder cycloaddition reaction of maleic anhydride with isoprene has been studied in supercritical-fluid CO2 under conditions near the critical point of CO2 [759]. The rate constants obtained for supercritical-fluid CO2 as solvent at 35 °C and high pressures (>200 bar) are similar to those obtained using normal liquid ethyl acetate as the solvent. However, at 35 °C and pressures approaching the critical pressure of CO2 (7.4 MPa), the effect of pressure on the rate constant becomes substantial. Obviously, AV takes on large negative values at temperatures and pressures near the critical point of CO2. Thus, pressure can be used to manipulate reaction rates in supercritical solvents under near-critical conditions. This effect of pressure on reacting systems in sc-fluids appears to be unique. A discussion of fundamental aspects of reaction kinetics under near-critical reaction conditions within the framework of transition-state theory can be found in reference [759],... 

The Diels-Alder cycloaddition reaction is a concerted reaction, with no change in the charge density upon going from reactants to the activated complex and finally to the products. Therefore, from the Hughes-Ingold approach, litde solvent effect is expected upon these reactions. In spite of this, dramatic solvent effects are often observed when a non-symmetric dienophile is used, and a mixture of products is formed. For instance, the reaction of methyl acrylate with cyclopentadiene gives a mixture of two products (see Scheme 10.61. 

In addition to activation by Lewis acids, the Diels-Alder reaction has also been shown to undergo dramatic acceleration in certain reaction media. Breslow, for example, noted that water as a solvent can lead to substantive rate enhancement (Equation 2) [21]. The cycloaddition reaction of cyclopen-tadiene and methyl vinyl ketone (19) shows a more than 700-fold rate increase in water relative to that in isooctane. Additionally, when Diels-Alder cycloaddition reactions are conducted in water with LiCl or /1-cyclodextrin (18) as additives, further rate increases are observed (2.5-fold over water and 1800 over isooctane). It was suggested that this phenomenon was the result of hydrophobic effects, leading to mutual aggregation of the diene and dienophile [21, 22]. 

Solvent effect on rate constants. In this section, the rate constant will be predicted qualitatively in CO2 for the Diels-Alder cycloaddition of isoprene and maleic anhydride, a reaction which has been well-characterized in the liquid state (23,24). In a previous paper, we used E data for phenol blue in ethylene to predict the rate constant of the Menschutkin reaction of tripropylamine and methyliodide (19). The reaction mechanisms are quite different, yet the solvent effect on the rate constant of both reactions can be correlated with E of phenol blue in liquid solvents. The dipole moment increases in the Menschutkin reaction going from the reactant state to the transition state and in phenol blue during electronic excitation, so that the two phenomena are correlated. In the above Diels-Alder reaction, the reaction coordinate is isopolar with a negative activation volume (8,23),... 

Not only Diels-Alder cycloadditions but also 1,3-dipolar cycloaddition reactions can be subject to hydrophobic rate enhancements. For example, the reaction of C,N-diphenylnitrone with di-n-butyl fumarate at 65 °C to yield an isoxazolidine is about 126 times faster in water than in ethanol, while in nonaqueous solvents there is a small 10-fold rate decrease on going from n-hexane to ethanol as solvent - in agreement with an isopolar transition-state reaction [cf. Eq. (5-44) in Section 5.3.3] [858]. Because water and ethanol have comparable polarities, the rate increase in water cannot be due to a change in solvent polarity. During the activation process, the unfavourable water contacts with the two apolar reactants are reduced, resulting in the observed rate enhancement in aqueous media. Upon addition of LiCl, NaCl, and KCl (5 m) to the aqueous reaction mixture the reaction rate increases further, whereas addition of urea (2 m) leads to a rate decrease, as expected for the structure-making and structure-breaking effects of these additives on water [858]. 

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

Microwaves were shown to affect both reactivity and selectivity. The effect on yield is rather limited in the Diels-Alder reaction and found to be higher in the Michael addition. This process was even more favored by use of acetic acid as the solvent. These results can be explained by the natural assumption that the transition state leading to Michael addition (M) much more polar than that leading to Diels-Alder cycloaddition (DA). 

The Diels-Alder cycloadditions were the first organic reactions for which it was shown that the aqueous medium, when compared to organic solvents, has a beneficial effect on both the reactivity and selectivity of the reaction. ... 

QM/MM applications with Cope elimination reactions [663], numerous Diels-Alder cycloadditions and dimerizations, Claisen rearrangements and electro-cyclic ring openings [664-668] indicate that effects coimected with the molecular nature of the solvent influence their reaction rates as well. At first glance this is astmiishing since these reactions are assumed to be rather nonpolar. Again, only the... 

Alternatively, authors have repeatedly invoked the internal pressure of water as an explanation of the rate enhancements of Diels-Alder reactions in this solvent ". They were probably inspired by the well known large effects of the external pressure " on rates of cycloadditions. However, the internal pressure of water is very low and offers no valid explanation for its effect on the Diels-Alder reaction. The internal pressure is defined as the energy required to bring about an infinitesimal change in the volume of the solvents at constant temperature pi = (r)E / Due to the open and... 

Most Diels-Alder reactions, particularly the thermal ones and those involving apolar dienes and dienophiles, are described by a concerted mechanism [17]. The reaction between 1,3-butadiene and ethene is a prototype of concerted synchronous reactions that have been investigated both experimentally and theoretically [18]. A concerted unsymmetrical transition state has been invoked to justify the stereochemistry of AICI3-catalyzed cycloadditions of alkylcyclohexenones with methyl-butadienes [12]. The high syn stereospecificity of the reaction, the low solvent effect on the reaction rate, and the large negative values of both activation entropy and activation volume comprise the chemical evidence usually given in favor of a pericyclic Diels-Alder reaction. 

Diels-Alder reactions of vinylpyrazoles 45 and 46 only occur with highly reactive dienophiles under severe conditions (8-10 atm, 120-140 °C, several days). MW irradiation in solvent-free conditions also has a beneficial effect [40b] on the reaction time (Scheme 4.11). The indazole 48, present in large amounts in the cycloaddition of 45 with dimethylacetylenedicarboxylate, is the result of an ene reaction of primary Diels-Alder adduct with a second molecule of dienophile followed by two [l,3]-sigmatropic hydrogen shifts [42]. The MW-assisted cycloaddition of 46 with the poorly reactive dienophile ethylphenyl-propiolate (Scheme 4.11) is significant under the classical thermal reaction conditions (140 °C, 6d) only polymerization or decomposition products were detected. 

The aqueous medium also has beneficial effects on the diastereoselectivity of the Diels-Alder reactions. The endo addition that occurs in the classical cycloadditions of cyclopentadiene with methyl vinyl ketone and methyl acrylate is more favored when the reaction is carried out in aqueous medium than when it is performed in organic solvents (Table 6.4) [2b, c]. 

The Diels-Alder reaction can be greatly enhanced by high pressure (Chapter 5) but the effect of pressure is generally weaker in aqueous medium than in organic solvent. Results of high pressure-mediated Diels-Alder reactions of furans and acrylates in water and dichloromethane are reported in Table 6.6 [32]. In aqueous medium the cycloadditions occur with lower yields and less diastereoselectivity than in dichloromethane and, in some cases, addition-substitution reactions were observed. 

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