Cycloaddition reactions pressure effects

Cycloaddition reactions of (E)-l-acetoxybutadiene (18a) and (E)-l-methoxy-butadiene (18b) with the acrylic and crotonic dienophiles 19 were studied under high pressure conditions [9] (Table 5.1). Whereas the reactions of 18a with acrylic dienophiles regioselectively and stereoselectively afforded only ortho-enJo-adducts 20 in fair to good yields, those with crotonic dienophiles did not work. Similar results were obtained in the reactions with diene 18b. The loss of reactivity of the crotonic dienophiles has been ascribed to the combination of steric and electronic effects due to the methyl group at the )S-carbon of the olefinic double bond. 

Scheeren and coworkers used the pressure effect for a powerful domino process consisting of three cycloadditions [2], to form up to six bonds and eight stereogenic centers in a single operation. At 15 kbar and 50 °C, the reaction of a mixture of 10-1 (1 equiv.) and 10-2 (3 equiv.) led to tricyclic nitroso acetals 10-5,10-6 and 10-7 in a 1 3 1 ratio via the first [4+2]-cycloadduct ( )-10-3 and the second [4+2]-cycloadduct ( )-10-4. The final step in this sequence is a [3+2]cycloaddition (Scheme 10.1). 

The observation that the transition state volumes in many Diels-Alder reactions are product-like, has been regarded as an indication of a concerted mechanism. In order to test this hypothesis and to gain further insight into the often more complex mechanism of Diels-Alder reactions, the effect of pressure on competing [4 + 2] and [2 + 2] or [4 + 4] cycloadditions has been investigated. In competitive reactions the difference between the activation volumes, and hence the transition state volumes, is derived directly from the pressure dependence of the product ratio, [4 + 2]/[2 + 2]p = [4 + 2]/[2 + 2]p=i exp —< AF (p — 1)/RT. All [2 + 2] or [4 + 4] cycloadditions listed in Tables 3 and 4 doubtlessly occur in two steps via diradical intermediates and can therefore be used as internal standards of activation volumes expected for stepwise processes. Thus, a relatively simple measurement of the pressure dependence of the product ratio can give important information about the mechanism of Diels-Alder reactions. 

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... 

Diels-Alder reactivity of thiophene and benzothiophene remains poorly understood. AMI semiempirical studies examining the activation of thiophene for this thermally allowed [4+2] cycloaddition process have shown that the usual synthesis approaches (use of highly reactive dienophiles, substitution on thiophene, increased reaction pressures) have only small effects on rate enhancement. However, use of the corresponding S-methylthiophenium salts, which have little aromaticity, should provide excellent activation for Diels-Alder reactions of thiophenes even with poor dienophiles such as ethylene <95JHC483>. This AMI approach has been applied to examine Diels-Alder reactions of benzo[6] and benzo[c]thiophenes the theoretical data agree with experimental results <95JCS(P1)1217>. 

A clear correlation between the stabilisation of the endo-transition structure and the size of substituent at the 2-position of an 1-oxa-1,3-butadiene is again seen in the cycloaddition of the N-acetyl-enaminoketone 8-20 to 8-12. As expected, the reaction of 8-20 a to give 8-21 a and 8-22 a shows only a very small AAV, whereas with growing bulkiness of R as in 8-20 b and 8-20 c an increase of AAV is observed with the formation of the trans-cycloadduct 8-22 as the major product under high pressure. Because of the pressure effect it can clearly be deduced that 8-22 is formed via an endo-Z-anti-transition structure, presumably due to a strong hydrogen bond in the (Z)-diastereomer and a steric discrimination of the ( )-diastereomer of 8-20. However, an exo-E-anti-transition structure would give the same product (Fig. 8-7) [548]. 

Grosch B, Orlebar CN, Herdtweck E, Kaneda M, Wada T, Inoue Y, Bach T (2004) Enantioselective [4+2]-cycloaddition reaction of a photochemically generated o-quinodimethane Mechanistic details, association studies, and pressure effects. Chem Eur J 10 2179-2189... 

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 first part of this chapter deals with the effects of high pressure on cycloaddition reactions, particularly the Diels-Alder reaction, which is the most important cycloaddition reaction. The second part will illustrate applications of pressure to nucleophilic substitutions, condensations and other reactions (miscellaneous reactions), such as Mannich, Heck, ene, SeAr, Wittig, Horner-Wadsworth Emmons and multicomponent Strecker reactions. 

Thiophene (30) does not usually undergo Diels-Alder reaction under thermal and Lewis acid catalysed conditions but it has been reported that under high pressure (2.0 GPa) it reacts with maleic anhydride (31) in reasonable yield (47%) (Scheme 7.8). It was recently observed that the reaction yield is strongly improved (77%) if the cycloaddition reaction is carried out in perfluorohexane at 0.8 GPa the fluorophobic effect plays a crucial role in rate enhancement... 

Furyl derivatives 76, with an allylether or allylamine-type linkage to a methylenecyclopropane framework, readily undergo high pressure-promoted intramolecular cycloaddition" to give spirocyclopropane tricyclic products 77. No cycloaddition reaction occurred at ambient pressure and the products were mostly tar and polymers. Lewis acid catalysis was only marginally successful (Scheme 7.18). At 1.0 GPa and a slightly elevated temperature (60-70 °C) the intramolecular Diels-Alder reaction occurs readily and is exo-diastereo-selective. To quantify the pressure effect on the kinetics the volumes of activation were determined. 

Jenner has investigated the effect of kinetic pressure on some nitro Michael and Henry reactions and has concluded that, although the kinetic effect is less than that reported for [4 -I- 2] cycloadditions, high pressure is a valuable tool... 

A similar pressure effect on regioselectivity was reported for palladium-catalyzed [3-I-2]-cycloadditions [19]. In the reaction of the trimethylenemethane (TMM) precursor 61 with the alkene 62 the two regioisomeric cycloadducts 63 and 64 are possible while 64 is mainly formed at 1 bar, the only product observed at 10 kbar is 63. A possible explanation of this dramatic change in selectivity could be the increased rate of the bimolecular reaction of 65 and 62 to give 63 compared to the unimolecular isomerization of the TMM complexes 65 and 66. Thus, the kineti-cally formed complex 65 is effectively trapped under pressure by the alkene 62. 

The importance of steric bulk in the transition structure in order to obtain a large AAV can also be seen in the cycloaddition of 78 and 61a to give the cycloadducts 79 and 80 described by Boger et al. [47]. In this reaction the pressure effect on the stereoselectivity seems to be negligible since the endo/exo ratio of 5.7 1.0 was observed to be the same at 0.62 and 1.3 GPa. This is in good agreement with the lower steric demand of the oxabutadiene (78) compared to 60a. 

A negligible pressure effect on the diastereoselectivity was also observed for the cycloaddition of the enamine carbaldehyde (81a) carrying an electron-withdrawing group at position 3 and 61a to yield the dihydropyrans 82 and 83 (Scheme 8.21). This reaction was again studied by direct quantitative infrared spectroscopy up to 300 MPa between 45 and 95 °C in different solvents. The activation volume was found to be —(25.1 1.7) cm mol in dichloromethane and —(25.0 + 1.8) cm mol in isodurene. Thus, in this reaction solvent polarity had no influence on the pressure dependence of the rate coefficient in addition, the ratio of the two diastereo-meric products is not changed under high pressure thus the AAV value is very small (AAV < 1 cm mol ). 

Pressure effects on the diastereoselectivity can also be observed for intramolecular cycloadditions such as the hetero-Diels-Alder reaction of 90, even though the AAV are smaller compared to intermolecular reactions (Scheme 8.23). The kinetics were again measured by on-line FT-IR spectroscopy and the stereoselectivity by HPLC. At atmospheric pressure in toluene under reflux the reaction of 90 led to a 5.2 1 ratio of the diastereomeric cycloadducts 91 and 92 in 93 % yield. Increasing pressure favors the formation of the cis-adduct 91, which is probably formed via an endo-E-syn transition structure. Interestingly, in the ground state of 90 the Z-configuration is more stable and it is therefore assumed that isomerization of the Z- to the B-double bond occurs prior to the cycloaddition [51]. From the slope of the plot of ln(91/92) versus pressure, AAV is calculated to be -(1.6 + 0.2) cm mol with the individual values for AV = -(19.4 + 0.2) and AV = —(17.9 0.6) cm mol at 343 K. Although the AV values are relatively low in comparison with data reported for other intramolecular Diels-Alder reactions e.g. 

Over the last 10 years, a burst of publications and reviews has been focused on the translation of different types of organic reactions towards the solid phase. The difficulty of transferring certain key reactions to the solid phase has stimulated solution phase library synthesis approaches which may be more effective. Cycloaddition reactions allow straightforward and often stereoselective construction of cyclic systems, which can serve as templates for further derivatization. Therefore, cycloaddition reactions play a key role in combinational chemistry sequences. The translation of cycloaddition reactions, especially 1,3-dipolar- [2] and Diels-Alder reactions [3] to the solid phase has been extensively studied. Although the benefits of high pressure for all type of cycloaddition reactions (e.g. [4 + 2] 1,3-dipolar, [2 + 2]) have been very well illustrated in past decades, the application of high pressure to solid phase cycloaddition reactions is still in its infancy. 

One of the main reasons is probably related to the small rate constant increase in the low pressure range (0-300 MPa) even for fairly pressure-dependent reactions such as pericyclic cycloadditions. The kinetic effect is derived from the relationship of Evans and Polanyi in the transition state theory as ... 

Catalyzed and uncatalyzed homo-Diels-Alder reactions behave mechanistically in the same way as Diels-Alder reactions. However, in the presence of a Lewis catalyst two competing processes, the homo-Diels-Alder reaction and the [2 + 2] cycloaddition, take place. The smaller absolute value of AV observed for the [2 + 2] cycloaddition is good evidence of a stepwise process. In this case, the size of the pressure effect depends on the possibility of electrostriction due to the polarity of the transition state [14],... 

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