Diels normal electron demand

Diels-Alder reactions can be divided into normal electron demand and inverse electron demand additions. This distinction is based on the way the rate of the reaction responds to the introduction of electron withdrawing and electron donating substituents. Normal electron demand Diels-Alder reactions are promoted by electron donating substituents on the diene and electron withdrawii substituents on the dienophile. In contrast, inverse electron demand reactions are accelerated by electron withdrawing substituents on the diene and electron donating ones on the dienophile. There also exists an intermediate class, the neutral Diels-Alder reaction, that is accelerated by both electron withdrawing and donating substituents. 

Figure 1.1. Orbital correlation diagram illustrating the distinction between normal electron demand (leftside) and inverse electron demand (right side) Diels-Alder reactions.

Hydrogen bonding of water to the activating group of (for normal-electron demand Diels-Alder reactions) the dienophile constitutes the second important effect". Hydrogen bonds strengthen the electron-withdrawing capacity of this functionality and thereby decrease the HOMO-LUMO gap... 

The fact that good correlations are observed with d" rather than with a, is indicative of a strong infiuence of the substituent through a direct resonance interaction with a positive charge in the reacting system. The p-values are positive, which is expected for substituted dienophiles in a normal electron demand Diels-Alder reaction. Furthermore, the p-values do not exceed unity and are not significantly different from literature values reported for the uncatalysed reaction. It is tempting to... 

More complete interpretations of Diels-Alder regioselectivity have been developed. MO results can be analyzed from an electrostatic perspective by calculating potentials at the various atoms in the diene and dienophile. These results give a more quantitatively accurate estimate of the substituent effects. Diels-Alder regioselectivity can also be accounted for in terms of HSAB theory (see Section 1.2.3). The expectation would be that the most polarizable (softest) atoms would lead to bond formation and that regioselectivity would reflect the best mateh between the diene and dienophile termini. These ideas have been applied using 3-2IG computations. The results are in agreement with the ortho rule for normal-electron-demand Diels-Alder reactions. ... 

The FMOs of acrolein to the left in Fig. 8.2 are basically slightly perturbed butadiene orbitals, while the FMOs of protonated acrolein resemble those of an allyl cation mixed in with a lone-pair orbital on the oxygen atom (Fig. 8.2, right). Based on the FMOs of protonated acrolein, Houk et al. [2] argued that the predominant interaction in a normal electron-demand carbo-Diels-Alder reaction is between the dienophile LUMO and diene HOMO (Fig. 8.1, left). This interaction is greatly... 

The two transition states in Figs 8.5 and 8.6 correspond in principle to a metal-catalyzed carho-Diels-Alder reaction under normal electron-demand reaction conditions and a hetero-Diels-Alder reaction with inverse electron-demand of an en-one with an alkene. The calculations by Houk et al. [6] indicated that with the basis set used there were no significant difference in the reaction course. 

We are now able to understand the Lewis acid-catalyzed normal electron-demand carbo-Diels-Alder reaction from a theoretical point of view. The calculated influence of the Lewis acids on the reaction rate, regio- and stereoselectivity in an... 

The basic concept of activation in hetero-Diels-Alder reactions is to utilize the lone-pair electrons of the carbonyl and imine functionality for coordination to the Lewis acid. The coordination of the dienophile to the Lewis acid changes the FMOs of the dienophile and for the normal electron-demand reactions a decrease of the LUMO and HOMO energies is observed leading to a better interaction with... 

Normal electron-demand controlled hetero-Diels-Alder reactions... 

Normal Electron-demand Hetero-Diels-Alder Reactions... 

Extensive studies by Gorman and Gassman have shown that an allyl cation can be a 27r-electron component in a normal electron-demand cationic Diels-Alder reaction and, since a carbocation is a very strong electron-withdrawing group, the allyl cation is a highly reactive dienophile [19a, 21]. 

Since the reactivity depends on the lowest HOMO-LUMO energy separation that can be achieved by the reacting partners, all the factors, steric and electronic, that lower the HOMO-LUMO distance increase the reaction rate and, as a consequence, allow the reactions to be carried out under mild conditions. Thus the normal electron-demand Diels-Alder reaction between 1,4-benzoquinone and 1,3-butadiene (Equation 2.2) proceeds at 35 °C almost quantitatively. 

The combination of thionation by Lawesson s reagent [98] of oxoenamino-ketones 96 with normal electron-demand Diels-Alder reaction of conjugated aldehydes allows a variety of thiopyrans 97 to be synthesized by a regio-selective and chemoselective one-pot methodology [99] (Equation 2.28). Thionation occurred at the more electrophilic ketonic carbonyl group. O O... 

They reported that the DFT calculations of 114 at the B3LYP/6-31G level showed that the ji-HOMO lobes at the a-position are slightly greater for the syn-n-face than for the anti face. The deformation is well consistent with the prediction by the orbital mixing rule. However, the situation becomes the reverse for the Jt-LUMO lobes, which are slightly greater at the anti than the syn-n-face. They concluded that the iyn-Jt-facial selectivity of the normal-electron-demand Diels-Alder reactions... 

Terrier et al. have widely described Bfxs 4-nitro-substituted participating in a series of Diels-Alder processes. Bfx 4-nitro-substituted system could participate as diene, C = C - C = C system, or heterodiene, C = C - NO2 system, in an inverse electron demand reaction [62,63] or as dienophile, C = C or N = O systems, in a normal electron demand reaction [64-68]. Fxs have been reported as 1,3-dipole through the substructure C = - 0 reacting with... 

The reactions of 4-nitrobenzodifuroxan 242 with a series of common dienes, such as cyclopentadiene, cyclohexa-diene, isoprene, 2,3-dimethylbutadiene, and 1-acetoxybutadiene, with ethoxymethyleneacetylacetone were found to proceed very readily to afford stable cycloadducts, which are the result of highly stereoselective normal electron-demand (NED) Diels-Alder reactions. Due to the additional activation provided by the two adjacent furoxan rings, the nitroalkene double bond of compound 242 is also prone to undergo NED reactions with less reactive dienic structures, such as the enol form of ethoxymethyleneacetylacetone and the in situ generated 2-ethoxy-4-(2-furfur-yl)buta-l,3-diene <2004TL1037, 2005T8167>. 

In contrast to the above-mentioned cydoadditions, normal electron demand Diels-Alder reactions exclusively form products where the terminal C=C bond of the allene was attacked by the diene. For example, cydoaddition of N-allenylsulfeni-mide 281 with cydopentadiene (282) affords norbornene derivative 283 (Eq. 8.37) [148]. 

The interactions of the occupied orbitals of one reactant with the unoccupied orbitals of the other are described by the third term of the Klopman-Salem-Fukui equation. This part is dominant and the most important for uncharged reaction partners. Taking into account that the denominator is minimized in case of a small energy gap between the interacting orbitals, it is clear that the most important interaction is the HOMO-LUMO overlap. With respect to the Diels-Alder reaction, one has to distinguish between two possibilities depending on which HOMO-LUMO pair is under consideration. The reaction can be controlled by the interaction of the HOMO of the electron-rich diene and the LUMO of the electron-poor dienophile (normal electron demand) or by the interaction of the LUMO of an electron-poor diene and the HOMO of an electron-rich dienophile (inverse electron demand cf Figure 1). 

Lewis acid catalysis enormously enriches the scope of Diels-Alder reactions, but it is limited to reagents containing Lewis basic sites, i.e. functional groups with lone pairs such as carbonyl, amino, ether or nitro close to the reaction centre. As we have seen in the discussion about the FMO aspects of Lewis acids, the major reason for catalysis is the reduction of the HOMO-LUMO gap. In case of Diels-Alder reactions with normal electron demand, it follows that the coordination of the Lewis acid lowers the LUMO energy of the dienophile. Such interactions are only possible if there is a spatial proximity or an electronic conjugation between the coordinated Lewis basic site and the reaction centre. Fortunately, in nearly every Diels-Alder reaction one of the reagents, mostly the dienophile, meets this requirement. 

The appreciable rate effects in water are generally overpowered by the large accelerations found for Lewis acid catalysis in normal electron demand Diels-Alder... 

Although Diels-Alder reactions can occur in the unsubstituted case, the reaction is most successful when the diene and the dienophile contain substituents which exert a favorable electronic influence [19]. In the normal electron demand case, the most favorable interactions are between dienes with electron-donating groups and dienophiles with electron-withdrawing groups. Cases have been reported in which inverse electron demand occurs and the electronic nature of the diene and dienophile are reversed [20], [21], [22]. This case of inverse electron demand is accounted for in the system. 

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 stereoselective normal electron demand Diels-Alder reaction of chiral 13-diaza-13-butadienes 42, derived from acyclic carbohydrates, with diethyl azodicarboxylate 2 yields the corresponding functionalized l,23,6-tetrahydro-133,4-tetrazines 43. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1 3 - Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation <99JOC6297>. 

The reactivities of the diene and dienophile in a Diels-Akier reac tion are highly dependent on their electronic structures.15 In the case of a Dieh-Alder reaction with normal electron demand, the dienophile is substituted with an electron acceptor Z, whereas the dienophile carries an electron donor X. The reaction in question follows this pattern. Increased reactivity in such a case can be rationalized with the frontier orbital theory of hukui and HouL according to which the energy difference between the (HOMO) of the diene and the lowest unoccupied molecular orbital (LUMO) of the dienophile is reduced in a favorable way by the substituents. 

Diels-Alder Reactions with Normal Electron Demand... 

The stereocontrolled synthesis of a-hydroxyakylated piperidines, a motif frequently encountered in natural products, represents a difficult synthetic challenge that was recently tackled by Hall and co-workers using the aza-variant of the Vaultier-Lallemand three-component reaction described in Scheme 12.14 [62]. One interesting feature of this reaction is the use of hydrazines, as masked amines, which allows the hetero-Diels-Alder reaction to operate on a normal electron demand manifold. Toure and Hall recently applied this powerful MCR to the asymmetric synthesis of (—)-methyl dihydropalustramate 192 [91], a degradation product and postulated biosynthetic precursor of (+)-palustrine (Scheme 12.27) [92]. 

Diels-Alder reactions of the type shown in Table 15.1, that is, Diels-Alder reactions between electron-poor dienophiles and electron-rich dienes, are referred to as Diels-Alder reactions with normal electron demand. The overwhelming majority of known Diels-Alder reactions exhibit such a normal electron demand. Typical dienophiles include acrolein, methyl vinyl ketone, acrylic acid esters, acrylonitrile, fumaric acid esters (irans-butenedioic... 

An increase in reactivity also can be observed in Diels-Alder reactions with normal electron demand if a given dienophile is reacted with a series of more and more electron-rich dienes. The reaction rates of the Diels-Alder reactions of Figure 15.22 show that the substituents MeO > Ph > alkyl are such reactivity-enhancing donors. The tabulated rate constants also show that a given donor substituent accelerates the Diels-Alder reaction more if located in position 1 of the diene than if located in position 2. 

---