Products of Diels-Alder reactions

Predict the products of Diels-Alder reactions, and determine which Diels-Alder reaction will give a specific synthetic product. 

Figure 7 Main products of Diels-Alder reactions...

Q 1. Cyclopentadiene reacts with acrylic ester to give products of Diels—Alder reaction. What are the interacting frontier molecular orbitals ... 

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

The Diels-Alder reaction provides us with a tool to probe its local reaction environment in the form of its endo-exo product ratio. Actually, even a solvent polarity parameter has been based on endo-exo ratios of Diels-Alder reactions of methyl acrylate with cyclopentadiene (see also section 1.2.3). Analogously we have determined the endo-exo ratio of the reaction between 5.1c and 5.2 in surfactant solution and in a mimber of different organic and acpieous media. These ratios are obtained from the H-NMR of the product mixtures, as has been described in Chapter 2. The results are summarised in Table 5.3, and clearly point towards a water-like environment for the Diels-Alder reaction in the presence of micelles, which is in line with literature observations. 

The Diels-Alder cycloaddition reaction (Section 14.4) is a pericvclic process that takes place between a diene (four tt electrons) and a dienophile (two tr electrons) to yield a cyclohexene product. Many thousands of examples of Diels-Alder reactions are known. They often take place easily at room temperature or slightly above, and they are stereospecific with respect to substituents. For example, room-temperature reaction between 1,3-butadiene and diethyl maleate (cis) yields exclusively the cis-disubstituted cyclohexene product. A similar reaction between 1,3-butadiene and diethyl fumarate (trans) yields exclusively the trans-disubstituted product. 

A number of Diels Alder reactions have been investigated in supercritical media and some of them will be illustrated. Most of the research has been focused on the influence of the pressure, which greatly influences the density of the fluid, on the kinetic aspects and on the product distribution of the reaction. 

In the synthesis of 2,2,5-trisubstituted tetrahydrofurans, a novel class of orally active azole antifungal compounds, Saksena95 reported that the key step of Diels-Alder reaction in water led to the desired substrate virtually in quantitative yields (Eq. 12.34), while the same reaction in organic solvent resulted in a complicated mixture with only less than 10% of the desired product being isolated. This success made the target compounds readily accessible. 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

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. 

The advantages of using ionic liquids as solvents for Diels-Alder reactions are exemplified by the scandium triflate catalysed reactions [14] in [bmim][PFg], [bmim][SbF6] and [bmim][OTf] for the reaction shown in Scheme 7.6. Whilst the nature of the anion seems to have little effect, all these solvents give rate enhancements for a range of Diels-Alder reactions compared to when the reactions are carried out in dichloromethane (DCM). Also, the selectivity towards the endo product is higher than in conventional solvents. As well as the enhanced rates and selectivities, the products can also be removed by extraction with diethyl ether and the ionic liquid and catalyst can immediately be reused. Experiments... 

FIGURE 2. The Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. The selectivity leading to the endo-product (endo-selectivity of Diels-Alder reactions) is rationalized by secondary orbital interactions in the endo-transition state... 

The explanation of the regiospecificity of Diels-Alder reactions requires knowledge of the effect of substituents on the coefficients of the HOMO and LUMO orbitals. In the case of normal electron demand, the important orbitals are the HOMO on the diene and the LUMO on the dienophile. It has been shown that the reaction occurs in a way which bonds together the terminal atoms with the coefficients of greatest magnitude and those with the coefficients of smaller magnitude [18]. The additions are almost exclusively cis and with only a few exceptions, the relative configurations of substituents in the components is kept in the products [19]. 

The isopropylation of anthracene gave similar results to that of naphthalene.84 The selectivities for 2-isopropylanthracene (2-IPA) and 2,6-diisopropylanthra-cene (2,6-DIP A) over HM(25) were as high as 91% and 47%, respectively. On the other hand, the selectivities over HY were as low as 59% and 8% for both products. The Diels-Alder reaction of anthracene with propylene occurred at higher temperatures to yield large amounts of the adducts such as 11 -methyl-9, lO-dihydro-etano-anthracene. However, their formation was prevented by the addition of a small quantity of water. 

In striking contrast with these two previous examples of 1,3-dipolar cycloaddition catalyzed by encapsulation, the EMs calculated for particular examples of Diels-Alder reactions catalyzed by Rebek s softball [25] or by Sanders [26] cyclophane, which was selected from a dynamic combinatorial library (DCL), are lower than the actual reactant concentration calculated from the volumes of the molecular cavities. Probably, the Diels-Alder reactions have more stringent orientational requirements than the 1,3-dipolar cycloaddition. The reactants of the Diels-Alder reactions, when encapsulated or included, spend a significant amount of time in ternary complexes displaying a non-productive mutual orientation. 

Large negative values of Av (-25 to -50 cm3/mol) have been found in the investigation of Diels-Alder reactions, such as the dimerization of cyclopentadiene (Table 3.2-1, b). The cyclic transition state has a compact structure similar to the reaction products. Av is only a little smaller than the volume change between the initial- and the product-structures, indicating a late transition state. 

No reaction has been found with simple vinylpyrroles and TCNE. Nevertheless, there are examples of Diels-Alder reaction of some protoporphyrins with this dienophile. It was first reported [73JCS(P1)1424] that compound 184 reacted with TCNE in refluxing chloroform, giving the cycloadduct 185 in 56% yield. A later study reexamined the reaction and found more complicated chemistry (80JOC5196). In initial experiments, reactions of TCNE with protoporphyrin di-ter/-butyl ester were shown to give three major products, 186,187, and 188 but depending on the conditions of the reaction, time, solvent or amount of TCNE, the results were different. The authors also characterized compounds 189 and 190. 

A large number of Diels-Alder reactions have been reported for arsabenzenes 86,87). In all cases, 1,4-addition of the dienophile is found. However, there is some indirect evidence that 2,5-addition can also take place. Heating the dimethyl acetylene-dicarboxylate-adduct 48 to > 250° gives small quantities of dimethyl phthalate 49 87>. This product may be formed by reversion to starting materials followed by readdition to form transient 50 which rapidly loses HCAs to give 49. However, the major product of pyrolysis of 48 is Alder-Richart cleavage to substituted arsabenzene 51. 

A number of reactions are known, however, in which more extensive rearrangements of bonds occur and which involve cyclic intermediates or products. The Diels-Alder reaction is a classical example of this. In the normal Diels-Alder reaction a Ci s-1,3-diene reacts with an ethylene derivative (dienophile) to form a cyclohexene ... 

Butadienes with alkyl substituents in the 2-position favor the formation of the so-called para-products (Figure 15.25, X = H) in their reactions with acceptor-substituted dienophiles. The so-called mefa-product is formed in smaller amounts. This regioselectivity increases if the dienophile carries two geminal acceptors (Figure 15.25, X = CN). 2-Phenyl-1,3-butadiene exhibits a higher para -selectivity in its reactions with every unsymmetrical dienophile than any 2-alkyl-1,3-butadiene does. This is even more true for 2-methoxy- 1,3-butadiene and 2-(trimethylsilyloxy)-l,3-butadiene. Equation 15.2, which describes the stabilization of the transition states of Diels-Alder reactions in terms of the frontier orbitals, also explains the para "/"meta "-orientation. The numerators of both fractions assume different values depending on the orientation, while the denominators are independent of the orientation. 

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