Diels-Alder reactions conformational effects

Effect of Conformation on Rates of Diels-Alder Reactions 277... 

Jorgensen et al. [84] studied how solvent effects could influence the course of Diels-Alder reactions catalyzed by copper(II)-bisoxazoline. They assumed that the use of polar solvents (generally nitroalkanes) improved the activity and selectivity of the cationic copper-Lewis acid used in the hetero Diels-Alder reaction of alkylglyoxylates with dienes (Scheme 31, reaction 1). The explanation, close to that given by Evans regarding the crucial role of the counterion, is a stabilization of the dissociated ion, leading to a more defined complex conformation. They also used this reaction for the synthesis of a precursor for highly valuable sesquiterpene lactones with an enantiomeric excess superior to 99%. 

The catalysis of bimolecular reactions such as the Diels-Alder reaction can be realized effectively and specifically by abzymes such as 1E9. The antibody then acts as a template and maintains the two partners, diene and dienophile, in a position favorable to the formation of the TS that is in a boat conformation in this reaction (Figure 8). 

The Durham precursor route to polyacetylene is an excellent example of the application of organic synthesis to produce a precursor polymer whose structure is designed for facile conversion to polyacetylene. Durham polyacetylene was first disclosed by Edwards and Feast, working at the University of Durham, in 1980 227). The polymer (Fig. 6 (I)) is effectively the Diels-Alder adduct of an aromatic residue across alternate double bonds of polyacetylene. The Diels-Alder reaction is not feasible, partly for thermodynamic reasons and partly because it would require the polymer to be in the all m-conformation to give the required geometry for the addition to take placed 228). However, the polymer can be synthesised by metathesis polymerization of the appropriate monomer. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Dipole-dipole interactions have been used to assess the conformational populations of 2-haloketones (Eliel et al., 1965). With respect to SS, however, there are few applications in which these and related effects are considered. It is interesting that dipole induction and London dispersion effects were used some thirty years ago to account for the high endo over exo preference in the Diels-Alder reaction (Wassermann, 1965). Although effects are small for any pair of atoms, there are many closely packed atoms in a Diels-Alder transition state. At a carbon-carbon distance of 2-0 a between the atoms to be bonded, the energy favoring endo addition is 2-7 for dipole induction and 3-4 kcal/mole for dispersion in the reaction of cyclopentadiene with p-benzoquinone (Wassermann, 1965). These nonbonding attractive energies cooperate with the secondary HMO effects discussed earlier to lead to an endo product. 

In order to form the activated complex required for the formation of product D, rotational changes of the less dipolar anti-form A to the more dipolar s jn-conformer B are necessary, to give an activated complex C with more parallel bond dipoles, which is thus more dipolar and better solvated than the reactant molecule. In agreement with this explanation is the observation that the reverse refro-Diels-Alder reaction exhibits no large solvent effect, since the activated complex C is quite similar to the reactant D [807], A very subtle solvent effect has been observed in the Diels-Alder addition of methyl acrylate to cyclopentadiene [124], The polarity of the solvent determines the ratio of endo to exo product in this kinetically controlled cycloaddition reaction, as shown in Eq. (5-43). The more polar solvents favour endo addition. 

Scheme 11. Regioselectivity, stereospecifity, conformative effects and reaction rates of [4+2] cycloadditions (Diels-Alder reaction) of tlie silaetliene Me2Si=C(SiMe3>2 with organic dienes...

Whereas in the case of fra j-piperylene a [4+2] cycloadduct is formed with the standard silaethene, no such product is formed in the case of c/j-piperylene but only a [2+2] cycloadduct (Scheme 11) [26]. Obviously, the [4+2] cycloaddition proceeds here more slowly than the unfavored [2+2] cycloaddition. In this sense, silico Diels-Alder reactions are influenced by conformative effects of the organic dienes like Diels-Alder reactions [27] a displacement of the transoid/cisoid equilibrium in the direction of the transoid isomer on steric grounds decreases the rate of cycloadditions. 

The multipole expansion model has seen use in the examination of solvation effects on both reaction coordinates and conformational equilibria, including the isomerization of push-pull ethylenes o (e,g., nitroenamines), the ketene-imine [2-f 2]-cycloaddition to form p-lactam,24i and the Diels-Alder reaction.242,243 Again, only the ENP terms are considered in general. 

Grieco has used his aqueous imnicmium Diels-Alder procedure to effect a number of intramolecular reactions. In one case, diene aldehyde (83) was treated with ammonium chloride to afford a 2.2 1 mixture of isomeric Diels-Alder adducts (87) and (85) (Scheme 10). Since intermediate immonium ions (84)/(86) cannot participate in secondary orbital effects as is the case with A-acyl imines (c/. 80), these results are probably due to steric factors. It was suggested that adduct (85) derives from conformation (84) and adduct (87) comes from (86). Conformer (84) is favored since there is a severe eclipsing of Ha b in (86). A more detailed account of the stereochemical aspects of intramolecular Diels-Alder reactions can be found in Chapter 4.4. 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

We have also studied the solution conformations of CAB-complexed methacrolein and crotonaldehyde by use of NOE measurements (Table 1) [12]. These results are in agreement with the transition-state preference for the s-trans or s-cis conformation of a,/8-enals, on the basis of the enantioselectivity of the aldol and Diels-Alder reactions catalyzed by CAB. Finally, it has been established that the effective shielding of the si face of the CAB-coordinated a, -enal arises from /r-stacking of the 2,6-diisopropoxy-benzene ring and the coordinated aldehyde. 

Craig and coworkers have reported rate constants for the reaction of 2-substituted 1,3-butadienes with maleic anhydride in benzene at 25 °C their values are X, k Cl, 0,019 H, 0.19 Me, 0,57 Et, l.l5 /-Pr, 2.2 t-Bu, 5.6 OMe, 1.9. As the Diels-Alder reaction proceeds through the s-cis conformation of the diene, and substituents in the 2-and 3-positions can affect the fraction of the diene in this conformation, steric effects must be considered. The data set was correlated therefore with the CRS equation ... 

Branchadall and co-workers studied the effect of Lewis acid (AlCfO catalysis on the Diels-Alder reactions of methyl (Z)-(5)-4,5-(2,2-propylidenedioxy)pent-2-enoate (10) with cyclopentadiene, which usually exhibits a high level of syn-endo selectivity under the influence of the Lewis acid, at the B-LYP/6-31G level [16]. The most stable conformation of the complex IO-AICI3 revealed the significant difference with the structure of uncomplexed molecule, i.e., s-trans arrangement of the carbonyl group with respect to the carbon-carbon double bond (Fig. 1-3). 

We have recently argued [39] that facial selectivity in the Diels-Alder reactions of 5-substituted cyclopenta-1,3-dienes is a reflection of hyperconjugative effects a frontier orbital analysis is shown in Fig. 6-10 [40], The molecule adopts a conformation where the better electron-donating group (C-Me rather than C-X) hinders approach of the dienophile from that face. Overlap of the C-C (T-bond (a better donor than C-X) increases the energy of the diene HOMO. Furthermore overlap of the C-C (T -orbital with the diene LUMO yP reduces the energy of the... 

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