Alder s rule

The exo addition mode is expected to be preferred because it suffers fewer steric repulsive interactions than the endo approach however, the endo adduct is usually the major product because of stabilizing secondary orbital interactions in the transition state (Scheme 1.10). The endo preference is known as Alder s rule. A typical example is the reaction of cyclopentadiene with maleic anhydride which, at room temperature, gives the endo adduct which is then converted at... 

However, Diels-Alder reactions are well known to be exceptional, with maleic anhydride reacting with cyelopentadiene by way of an endo transition structure 2.110 to give what is called the endo adduct 2.111 as the major product. The exo adduct 2.112 is a very minor product, unless the mixture is heated for a long time, when reversal of the Diels-Alder reaction and readdition establish the thermodynamic equilibrium in its favour. The endo adduct is evidently the product of kinetic control, and the preference for it is called Alder s rule. 

MA cycloaddition to metalloles seems to be always stereospecific and, according to Alder s rule, the endo configuration has been attributed to the adduct125. When two different groups R1 and R2 are present (equation 43), the major adduct results from the sterically more suitable transition state, i.e. the more bulky group is preferentially syn with respect to the C=C bond of the norbornene6,67c. 

Figure 4.8 A molecular orbital interpretation of Alder s rule.

There is no contradiction. When electrons are withdrawn from a molecule, its LUMO energy is lowered and this FO becomes nearer to the partner s HOMO. According to rule 2, the reaction is then facilitated. It is exactly the same problem as with the Alder s rule and the reactions with inverse electron demand. 

Generalizing the Alder rule. After considering Alder s rule, we can naturally ask the following questions ... 

Ghosez and co-workers used standard electron-poor dienophiles (quinone, acrylonitrile, methyl acrylate, maleic anhydride) for their experiments, hence the choice of donor substituents to increase the electron density of the azadiene (Alder s rule). However, the intrinsically electron-deficient diene can only be made sufficiently nucleophilic by the presence of exceptionally good donors. The oxygen lone pair is relatively low-lying (a+ 2/3), so it does not confer sufficient reactivity for the oxime to react. AMI calculations validate this qualitative reasoning the oxime B HOMO lies at -9.47 eV versus -8.56 eV for A s HOMO. 

The analysis of Alder s rule showed that any substituent, donor or acceptor, will enhance the reactivity of a diene. Fowler s and Boger s dienes are more reactive than Ghosez s reagents because it is easier to increase the electrophilicity of an azadiene than to transform it into a nucleophile. 

Alder s rule suggests that the Boger and Fowler dienes should react more readily with electron-rich than electron-poor dienophiles. However, the global conclusion of rule 2 is that the reaction rate will increase as the frontier orbital gap between the reaction partners decreases. The most reactive dienes have very small HOMO-LUMO... 

Many examples of polycyclic alkene osmylations have been reported in the literature in connection with the syntheses of specific target molecules such as alkaloids, prostanoids, or steroids. However, carefully determined diastereomer ratios are usually not available. Due to the varied nature of these substrates, it is not possible to formulate definite rules for diastereo-face differentiation except in specific cases. Thus, for example, the exclusive exo reactivity of bridged systems such as bicyclo[2.2.1]heptene derivatives (norbornene-type) is well known as Alder s rule of exo addition63. 

Wiberg reported the Diels-Alder reaction of butadiene and cyclopropene [53] and Baldwin estimated from the reaction between cyclopropene and 1-deuteriobutadiene at 0°C that 99.4% of the formed cycloadduct was the endo isomer [54], There are many suggestions which attempt to explain endo selectivity in Diels-Alder reactions (Alder s rule [55]), but none are firmly established. According to Woodward and Hoffmann [56], the preference is the result of favorable Secondary Orbital Interactions (SOI) or secondary orbital overlap [57-59] between the diene and dienophile in the corresponding transition state structure. One can also find an explanation for the reaction preference in the difference between primary overlap [60], volumes of activation [61], and the polarity of the transition states [62]. Secondary orbital overlap between the diene and the dienophile does not lead to bonds in the adduct, but primary orbital overlaps do. 

As expected from Alder s endo rule, and justified by consideration of maximum accumulation of unsaturation in the transition state, secondary orbital interactions and dispersion forces, furan reacts with maleic anhydride in acetonitrile at 40 °C (78JOC518) to give initially... 

Alder s endo rule applies not only to cyclic dienes like cyclopentadiene and to disubstituted dienophiles like maleic anhydride, but also to open chain dienes and to mo no-substituted dienophiles diphenylbutadiene and acrylic acid, for example, react by way of an endo transition structure 2.113 to give largely (9 1) the adduct 2,114 with all the substituents on the cyclohexene ring cis, and equilibration again leads to the minor isomer 2.115 with the carboxyl group trans to the two phenyl groups. 

Alder s endo rule leads substituents in open-chain trans dienes to be alias on the cyclohexene ring. 

The Stereoselectivity of Diels-Alder Reactions. One of the most challenging stereochemical findings is Alder s endo rule for Diels-Alder reactions. The favoured transition structure 6.180 has the electron-withdrawing substituents in the more hindered environment, under the diene unit, giving the kinetically more favourable but thermodynamically less favourable adduct 6.181. Heating eventually equilibrates the adducts in favour of the exo adduct 6.182, by a retro-cycloaddition re-addition pathway. 

Endo versus exo geometry in the Diels-Alder reaction When the Diels-Alder reaction forms bridged bicyclic adducts and an unsaturated constituent is located on this bicyclic structure, the chief product is normally the kinetically favoured endo-isomer, Alder s endo rule. 

Alder s endo rule specifies a preference for endo (C) over exo (D) addition. However, this rule appears to be strictly applicable only to the addition of cyclic dienophiles (e.g. maleic anhydride, p-qui-nones) to cyclic dienes (e.g. cyclopentadienes). 

Corey-Winter olefin synthesis (I. I23.3-I234). Chong and Wiseman were able to demonstrate the transient existence of bicyclo[3.2.l]octenc-l (2, a bridgehead alkene which violates Bredt s rule) by application of the Corey-Winter olefin synthesis. Thus treatment of the thionocarbonatc (I) with triethyl phosphite at reflux (165°) fur 24 hr. in the presence of I,3-diphenyli obenzofurane (1, 342-343 2, 178-179) leads to the formation of two Diels-Alder adducts (3) and (4) derived from (2). 

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