Nitrile group, directing effect

Nitriles will direct lithiation with non-nucleophilic bases such as LiTMP, particularly in conjuction with another nitrile group . The nitriles presumably act by an acidifying effect alone—no intramolecular N-Li coordination is possible in the intermediate (Scheme 60). 

A directing effect of a methyl group at the allylic stereocenter, located between the nitrile oxide and the alkene moieties, on the stereochemistry of cycloaddition was found with the carbon analogues (Scheme 6.46 and Table 6.14) (18,256). 

As apposed to this, co-catalysis by benzophenone - as well as by all benzophenones with electro-donating groups - noticeably increases HQ selectivity (ref. 7). This para-directing effect is notably reinforced by polar aprotic solvents with basicity less than that of benzophenone co-catalyst (nitriles, sulfolane, propylene carbonate...) (ref. 8). 

Similar results are obtained with other functional groups, such as nitriles, e.g., with compound 123S. In this case, the ethoxycarbonyl group has no directing effect, but does exert an influence on the hydrogenation rate. The 4x-ethoxycarbonyl isomer 12 (R1 = CH3 R2 = COOF.t) is reduced much more slowly than its 4/ -epimer (R1 = COOF.t R2 = CH,). In fact, the rates of these two reductions are so different that it is possible to completely saturate the olefinic double bond of the 4/i-isomer in a mixture of both epimers without any significant reduction of the 4a-isomer (12, R1 = CH3 R2 = COOEt)35. 

Limited examples of substituted alkyl radical clocks are available. Fortunately, some calibrated clocks that are available have rate constants in the middle ranges for radical reactions and should be useful in a number of applications. Examples of clocks based on the 5-exo cyclization of the 5-hexenyl radical are shown in Table 2. The data for the series of radicals 2-1 and 2-2 [17, 32, 34, 35] are from indirect studies, whereas the data for radicals 2-3 and 2-4 [3, 35-38] are from direct LFP studies. The striking feature in these values is the apparent absence of electronic effects on the kinetics as deduced from the consistent values found for secondary radicals in the series 2-1 and 2-3. The dramatic reduction in rate constants for the tertiary radical counterparts that contain the conjugating ester, amide and nitrile groups must, therefore, be due to steric effects. It is likely that these groups enforce planarity at the radical center, and the radicals suffer a considerable energy penalty for pyramidalization that would relieve steric compression in the transition states for cyclization. 

The capacity to effect direct insertion of a C-O or C-N multiple bond into a carbon-palladium bond has been exploited in a Pd(OAc)2-mediated cyclization reaction of alk)fnes containing tethered aldehyde, ketone or nitrile groups. Such processes can result in the formation of tetrahydrofurans incorporating a... 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

Many aspects of intramolecular nitrile oxide cycloadditions are similar to those of the intermolecular ones. Due to the proximity of the reacting groups, however, there are also several items that differ significantly. While HOMO-LUMO interactions and steric effects direct the intermolecular nitrile oxide cycloaddition to 1-alkenes to produce 5-substituted isoxazolines, the intramolecular cases often show a different behavior. With most of them, regioselectivity is determined by geometric constraints and cycloadditions occur in the exo mode to furnish the annulated bicycle (Scheme 6.42). 

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