Endo:exo- selectivity

Theoretical work by the groups directed by Sustmann and, very recently, Mattay attributes the preference for the formation of endo cycloadduct in solution to the polarity of the solvent Their calculations indicate that in the gas phase the exo transition state has a lower energy than the endo counterpart and it is only upon introduction of the solvent that this situation reverses, due to the difference in polarity of both transition states (Figure 1.2). Mattay" stresses the importance of the dienophile transoid-dsoid conformational equilibrium in determining the endo-exo selectivity. The transoid conformation is favoured in solution and is shown to lead to endo product, whereas the cisoid conformation, that is favoured in the gas phase, produces the exo adduct This view is in conflict with ab initio calculations by Houk, indicating an enhanced secondary orbital interaction in the cisoid endo transition state . 

In summary, it seems that for most Diels-Alder reactions secondary orbital interactions afford a satisfactory rationalisation of the endo-exo selectivity. However, since the endo-exo ratio is determined by small differences in transition state energies, the influence of other interactions, most often steric in origin and different for each particular reaction, is likely to be felt. The compact character of the Diels-Alder activated complex (the activation volume of the retro Diels-Alder reaction is negative) will attenuate these eflfects. The ideas of Sustmann" and Mattay ° provide an attractive alternative explanation, but, at the moment, lack the proper experimental foundation. 

In 1961 Berson et al. were the first to study systematically the effect of the solvent on the endo-exo selectivity of the Diels-Alder reaction . They interpreted the solvent dependence of the endo-exo ratio by consideririg the different polarities of the individual activated complexes involved. The endo activated complex is of higher polarity than the exo activated complex, because in the former the dipole moments of diene and dienophile are aligned, whereas in the latter they are pointing in... 

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. 

Woodward and Baer in 1948 " ". These authors noticed a change in endo-exo selectivity when... 

Three years after the Breslow report on the large effects of water on the rate of the Diels-Alder reaction, he also demonstrated tliat the endo-exo selectivity of this reaction benefits markedly from employing aqueous media . Based on the influence of salting-in and saltirg-out agents, Breslow pinpoints hydrophobic effects as the most important contributor to the enhanced endo-exo... 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

In conclusion, the special influence of water on the endo-exo selectivity seems to be a result of the fact that this solvent combines in it three characteristics that all favour formation of the endo adduct (1) water is a strong hydrogen bond donor, (2) water is polar and (3) water induces hydrophobic interactions. 

The reaction between 2.4 and 2.5 yields four products two enantiomeric endo products and two enantiomeric exo products. In this section the effect of the solvent, the Lewis-acid and the substituents on the endo-exo selectivity are described. Chapter 3 will mainly focus on aspects dealing with the enantioselectivity of the reaction. 

Table 2,8, Solvent effect on the endo-exo selectivity (% endo -% exo) of the nncatalysed and Cu" -ion catalysed Diels-Alder reaction between 2,4c and 2,5 at 25°C.

In Chapter 2 the Diels-Alder reaction between substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-ones (3.8a-g) and cyclopentadiene (3.9) was described. It was demonstrated that Lewis-acid catalysis of this reaction can lead to impressive accelerations, particularly in aqueous media. In this chapter the effects of ligands attached to the catalyst are described. Ligand effects on the kinetics of the Diels-Alder reaction can be separated into influences on the equilibrium constant for binding of the dienoplule to the catalyst (K ) as well as influences on the rate constant for reaction of the complex with cyclopentadiene (kc-ad (Scheme 3.5). Also the influence of ligands on the endo-exo selectivity are examined. Finally, and perhaps most interestingly, studies aimed at enantioselective catalysis are presented, resulting in the first example of enantioselective Lewis-acid catalysis of an organic transformation in water. 

The effect of ligands on the endo-exo selectivity of Lewis-acid catalysed Diels-Alder reactions has received little attention. Interestingly, Yamamoto et al." reported an aluminium catalyst that produces mainly exo Diels-Alder adduct. The endo-approach of the diene, which is normally preferred, is blocked by a bulky group in the ligand. 

In contrast, investigation of the effect of ligands on the endo-exo selectivity of the Diels-Alder reaction of 3.8c with 3.9 demonstrated that this selectivity is not significantly influenced by the presence of ligands. The effects of ethylenediamine, 2,2 -bipyridine, 1,10-phenanthroline, glycine, L-tryptophan and L-abrine have been studied. The endo-exo ratio observed for the copper(II)-catalysed reaction in the presence of these ligands never deviated more than 2% from the endo-exo ratio of 93-7 obtained for catalysis by copper aquo ion. 

Analogously, the effect of micelles on the rate of the unimolecular retro Diels-Alder reaction has been studied. Also here only a modest retardation" or acceleration" is observed. Likewise, the presence of micelles has been reported to have a modest influence on an intramolecular Diels-Alder reaction . Studies on the endo-exo selectivity of a number of different Diels-Alder reactions in micellar media lead to comparable conclusions. Endo-exo selectivities tend to be somewhat smaller in micellar solutions than in pure water, but still are appreciably larger than those in organic media In contrast, in microemulsions the endo-exo selectivity is reduced significantly" ... 

First of all, given the well recognised promoting effects of Lewis-acids and of aqueous solvents on Diels-Alder reactions, we wanted to know if these two effects could be combined. If this would be possible, dramatic improvements of rate and endo-exo selectivity were envisaged Studies on the Diels-Alder reaction of a dienophile, specifically designed for this purpose are described in Chapter 2. It is demonstrated that Lewis-acid catalysis in an aqueous medium is indeed feasible and, as anticipated, can result in impressive enhancements of both rate and endo-exo selectivity. However, the influences of the Lewis-acid catalyst and the aqueous medium are not fully additive. It seems as if water diminishes the catalytic potential of Lewis acids just as coordination of a Lewis acid diminishes the beneficial effects of water. Still, overall, the rate of the catalysed reaction... 

This thesis describes a study of catalysis of Diels-Alder reactions in water. No studies in this field had been reported at the start of the research, despite the well known beneficial effects of acpieous solvents as well as of Lewis-add catalysts on rate and endo-exo selectivity of Diels-Alder reactions in organic solvents. We envisaged that a combination of these two effects might well result in extremely large rate enhancements and improvements of the endo-exo selectivity. 

As expected, the solvent has a significant effect on the endo-exo selectivity of the uncatalysed Diels-Alder reaction between 1 and 2. In contrast, the corresponding effect on the Lewis-acid catalysed reaction is small. There is no beneficial effect of water on the endo-exo selectivity of the catalysed Diels-Alder reaction. The endo-exo selectivity in water is somewhat diminished relative to that in ethanol and acetonitrile. 

The endo exo selectivity for the Lewis acid-catalyzed carbo-Diels-Alder reaction of butadiene and acrolein deserves a special attention. The relative stability of endo over exo in the transition state accounts for the selectivity in the Diels-Alder cycloadduct. The Lewis acid induces a strong polarization of the dienophile FMOs and change their energies (see Fig. 8.2) giving rise to better interactions with the diene, and for this reason, the role of the possible secondary-orbital interaction must be considered. Another possibility is the [4 + 3] interaction suggested by Singleton... 

P/Z equilibrium 233 enantioselectivity 216 endo 153 endo isomer 217 endo/exo ratio 303 endo/exo selectivity 217 mt-shikimic acid 30 ethyl vinyl ether 220 exo 153 exo-endo 303 exo-selective 13... 

A study of the Diels-Alder reaction was carried out by Earle et al. [42]. The rates and selectivities of reactions between ethyl acrylate (EA) and cyclopentadiene (CP) in water, 5 m lithium perchlorate in diethyl ether (5 m EPDE), and [BMIM][PE(3] were compared. The reactions in the ionic liquid [BMIM][PE(3] were marginally faster than in water, but both were slower than in 5 m EPDE [42, 43] (see Table 5.1-1 and Scheme 5.1-18). It should be noted that these three reactions give up to 98 % yields if left for 24 hours. The endo. exo selectivity in [BMIM][PE(3] was similar to that in 5 M EPDE, and considerably greater than that in water (Table 5.1-1). 

By using unactivated K-10 montmorillonite in the absence of solvent, the endo-exo selectivity of the cycloadditions of acrolein and methyl vinyl ketone with cyclopentadiene and cyclohexadiene is low [8] (Table 4.2, entry 3), while highly reactive dienophiles such as 1,4-benzoquinone and N-phenyl... 

Earle and coworkers [54] have performed Diels-Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except [BMIMJPF4, and gave almost quantitative yields after 18-24h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. 

Similar results were obtained [55] for the Diels-Alder reaction between cyclopentadiene and methyl acrylate carried out in [EMIM]BF4 at 20 °C for 72 h. In [EMIMjX (X = OTf, NO3, PFg) the reaction yields were lower [55]. The best yields and the highest endo/exo selectivity were obtained in [FtNHsJNOs [56],... 

Mataka and coworkers further studied the exo/endo selectivity of outside attack products in the reactions of 96 and 97 with A-(5-X-phenyl)maleimides [56]. They found that the endo/exo selectivity is markedly dependent on the electronic nature of the substituent X (Scheme 47). The electro-withdrawing substituents such as NOj and Cl enhance enrfo-selectivity. The relative order of the enr/o-selectivity is NOj > Cl > H > OCH3. 

The optically active a-sulfinyl vinylphosphonate 122 prepared in two different ways (Scheme 38) is an interesting reagent for asymmetric synthesis [80]. This substrate is an asymmetric dienophile and Michael acceptor [80a]. In the Diels-Alder reaction with cyclopentadiene leading to 123, the endo/exo selectivity and the asymmetry induced by the sulfinyl group have been examined in various experimental conditions. The influence of Lewis acid catalysts (which also increase the dienophilic reactivity) appears to be important. The 1,4-addition of ethanethiol gives 124 with a moderate diastereoselectivity. 

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