Diels-Alder reactions HOMO activation

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... 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

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... 

The ene reaction (or Alder reaction) is a cycloaddition which requires an activation energy higher than that of the Diels-Alder reaction [41]. Without a catalyst it usually occurs under pressure and/or at high temperature. The reaction with an allcene (ene) is much easier if the latter is more substituted (high HOMO) and the enophile is more electron-poor (low LUMO). 

The main stabilization in reactions with activated reaction partners, viz. when one partner is electron-rich and the other electron-poor, arises through interaction between the donor HOMO and the acceptor LUMO which are much closer in energy than the acceptor HOMO and the donor LUMO. Figure 2 illustrates which interactions between the frontier orbitals cause the main stabilization in normal, neutral and inverse Diels-Alder reactions. For example, the main stabilization in the reaction between an electron-rich diene and an electron-poor dienophile stems from the interaction of the diene HOMO with the dienophile LUMO. 

A combined system formed from Co(acac)3, 4 equiv of diethylalu-minum chloride, and chiral diphosphines such as (S,S)-CHIRAPHOS or (/ )-PROPHOS catalyzes homo-Diels-Alder reaction of norbomadiene and terminal acetylenes to give the adducts in reasonable ee (Scheme 109). Use of NORPHOS in the reaction of phenylacetylene affords the cycloadduct in 98.4% ee (268). It has been postulated that the structure of the active metal species involves noibomadiene, acetylene, and the chelating phosphine. The catalyzed cycloaddition may proceed by a metallacycle mechanism (269) rather than via simple [2+2 + 2] pericyclic transition state. 

The homo-Diels-Alder reactions of norbornadiene with dimethylacetylene dicarboxylate (DMAD) and TCNE are reported to have activation volumes of about - 30 cm3 cm-1 and classical examples have already been reviewed [10]. 

Dienophiles like phosphaalkyne 44a or activated alkynes and triphosphadewarbenzene 45 undergo a [2+2+2] homo-Diels-Alder reaction that leads to C3P4 cage 46. Cyclic dienophiles yield pentacycles (Scheme 13) <1997JOM(529)215, 1999S1363>. 

Alder Ene Reactions. Like the Diels-Alder reaction, Alder ene reactions usually take place only when the enophile has a Z-substituent, the regiochemistry is that expected from the interaction of the HOMO of the ene and the LUMO of the enophile, and Lewis acids increase the rate. All these points can be seen in the reaction of /3-pinene with the moderately activated enophile methyl acrylate, which takes place at room temperature in the presence of aluminium chloride, but which would probably not have taken place easily without the Lewis acid. 

The purely inductive electron-withdrawing character of a fluoroalkyl substituent activates alkenes in Diels-Alder reactions via the interaction of the HOMO of the diene and the LUMO of the fluoroalkyl-containing alkene. 

The Homo Diels-Alder Reaction of Norbomadiene with Acetylenes. [2 + 2+2] Cycloadditions of dienes such as norbomadiene with the double bonds in 1,4-position are called homo Diels-Alder reactions. Using an in situ catalyst (consisting of Co(acac)3-Et2AlCl-bis(diphenylphosphino)ethane) the products obtained with monosubstituted acetylenes, such as phenyl, i-propyl-, n-butyl-, t-butyl-, and trimethylsilylacetylene, are 4-substituted deltacyclenes. - In the formation of the polycyclic deltacyclene skeleton, six new stereo centers are generated in one step. Thus enantiocontrol by using optically active phosphine ligands as cocatalysts allows the synthesis of optically active cycloadducts, as shown for the reaction of norbomadiene with phenylacetylene to give 4-phenyldeltacyclene (eq 1). 

The Diels-Alder reaction of a diene and a dienophile has become one of the most powerful carbon-carbon bond-forming processes [81]. In normal Diels-Alder reactions of an electron-poor dienophile with an electron-rich diene, the main interaction is between the HOMO of the diene and the LUMO of the dienophile. Coordination of a Lewis acid to the dienophile reduces its frontier orbital energies, and this increases the rate of the reaction. Regio- and stereoselectivity are also markedly affected by the Lewis acid. Recent extensive studies on the design of chiral Lewis acids have led to fruitful results in the control of the stereochemistry of a variety of pericyclic reactions. Several chirally modified Lewis acids have been developed for the asymmetric Diels-Alder reaction [82,83] and spectacular advances have recently been achieved in this area. Various kinds of polymer-supported chiral Lewis acid have also been developed. Polymer-supported A1 Lewis acids such as 62 have been used in the Diels-Alder reaction of cyclopentadiene and methacrolein (Eq. 20) [84] as has polymer-supported Ti alkoxide 63 [84]. These Ti catalysts are readily prepared and have high activity in the Diels-Alder reaction. 

The appearance of the difference in MO energies in the denominator in eq. (15.1) suggests that a smaller gap between the-diene HOMO and diencophile LUMP in a Diels-Alder reaction should lower the activation energy. If the diene is made more... 

This nonpolar process with simultaneous bond formation was confirmed by solvent and pressure effects on the activation volume and kinetics of homo-Diels-Alder reactions. ... 

Tetracyanoethene is one of the most active and used dienophiles its cycloadditions, including homo-Diels-Alder reactions, have been reviewed in detail. Preparative homo-Diels-Alder reactions using this dienophile are presented in Table 1. 

When Danishefsky11 set out to synthesise ipalbidine 83, a Diels-Alder reaction of this imine 77 was an obvious approach. To get efficient reaction, it was necessary to use a diene 79 activated by two electron-donating ethers and to activate the imine with a Lewis acid. The orientation of 81 is as expected from the LUMO of the imine reacting with the HOMO of the diene. 

Dienes that contain electron-donating groups (activated dienes) are more reactive in Diels-Alder reactions than unsubstituted or electron-deficient dienes. In molecular orbital formalism, the substituents on the diene perturb the tT-electron density to cause an increase in the energy of the highest occupied molecular orbital (HOMO Figure 1). In a normal-demand Diels-Alder reaction this results in an increase in the interaction between the HOMO of the diene and the LUMO (lowest unoccupied molecular orbital) of the dienophile. This interaction, in turn, lowers the transition state energy of the reaction. Similar arguments have also been used to explain the increased reactivity of activated dienes towards heterodienophiles such as aldehydes. 

Activated dienes are also highly regioselective. This is due to the unsymmetrical polarization of the HOMO that is caused by the placement of substituents on the diene. The use of activated dienes is well documented in classical Diels-Alder reactions. They provide for high reactivity, good regioselectivity and introduce useful functionality into the cycloadducts."... 

Homo-Diels-Alder reactions of norbornadiene. In the presence of Ni(COD)2 and P(C6H5).i (1 2) norbornadicnes can react with activated alkencs at 80° to give [2 + 2 + 2] adducts. Preliminary studies of the rcgiosclectivity indicate that this homo-Diels-Aldcr reaction can be useful for synthesis of complex molecules. Thus reaction of methyl norbornadiene-2-carboxylatc with acrylonitrile results in only two... 

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