Stereoelectronic effects nucleophilic addition

The presence of a stereogenic center on the aldehyde can strongly inlinence the diastereoselectivity in allylboration reactions, especially if this center is in the a-position. Predictive rules for nucleophilic addition on snch a-snbstitnted carbonyl substrates such as the Felkin model are not always snitable for closed transition structures.For a-substituted aldehydes devoid of a polar substituent, Roush has established that the minimization of ganche-ganche ( syn-pentane ) interactions can overrule the influence of stereoelectronic effects. This model is valid for any 3-monosubstituted allylic boron reagent. For example, althongh crotylboronate (E)-7 adds to aldehyde 39 to afford as the major prodnct the diastereomer predicted by the Felkin model (Scheme 2), " it is proposed that the dominant factor is rather the minimization of syn-pentane interactions between the Y-snbstitnents of the allyl unit and the a-carbon of the aldehyde. With this... 

The most likely explanation is as outlined in Scheme 3. Following a well-known stereoelectronic effect , wherein addition of nucleophiles to triple bonds places the developing new lone pair trans to the incoming nucleophile, a fast addition of azide ion to the diazonium ion would give the Z-diazoazide (21) which cannot form a pentazole. This is analogous to the stable imidoyl azide of tetrazole chemistry. Rapid loss of N2 from this produces the first N2 evolution. 

It has however been suggested by Cieplak (9) that the stereochemistry of nucleophilic addition to cyclohexanone is determined by a combination of steric and stereoelectronic effects. According to this interesting model, steric hindrance favors the equatorial approach while electron donation favors the axial approach. The stereoelectronic effect favors the axial approach because the axial C —H bonds next to the carbonyl group (C — Ha and Cn-Ha) are better electron donors than the Cn-C-j and Cc-Cfi a bonds (cf 7A 7 and 7A-8). J... 

Interestingly, the crystal structures of 8-methoxy-l-naphtonitrile and 8-nitro-1-naphtonitrile have been determined by X-ray analysis by Procter, Britton, and Dunitz (24). The structure of the methoxy derivative corresponds to 61 where the exocyclic C —0 bond is bent inward (toward the nitrile group), the exocyclic C-CN bond is bent outward (away from the methoxy group). The C-C = N bond angle is 174° instead of 180°. A similar observation has been made with 8-nitro-l-naphtonitrile. Crystals of this compound contain two symmetry independent molecules which differ in structure. Both show a bent C CN bond and a short 0—C = N distance Icf. 62), but the orientation of the nitro group is different with the result that in one molecule the 0i—Cii distance is 2.69 A whereas in the other, it is 2.79 A. This analysis is in complete agreement with the theoretical calculations and the experimental results presented above. Thus, it can be concluded that the nucleophilic addition on triple-bond (and the reverse process) is strongly influenced by stereoelectronic effects which favor the anti mode of addition. 

We have already discussed in Chapter 2 that nucleophilic addition to a carbonyl group is controlled by stereoelectronic effects. Both X-ray data and theoretical calculations indicate a clearly defined path (cf. p.32) for the attack of a nucleophile on a carbonyl group. Baldwin (1) has also used a vector analysis approach to predict the stereochemistry of the addition products. 

The reaction of nucleophiles with the conformationally rigid piperidinium ion lj>, like that with cyclic oxonium ions, can also be controlled by stereoelectronic effects. On that basis, the addition of a nucleophile on the upper face of Jjj must lead to the boat-like intermediate whereas that from the lower face must lead to the chair-like intermediate V7. The transition state leading to must be less favorable than that leading to Yl and product V7 should therefore be favored. 

Stereoelectronic effects should also play an important role in the nucleophilic 1,4-additions of anions to conjugated systems. These effects should therefore influence the Michael reaction as well as the hydrocyanation of a,6-unsaturated ketones. Studies on these reactions provided evidence that the kinetically controlled addition of a nucleophile to a cyclohexenone derivative is indeed subject to stereoelectronic effects. 

The addition of a nucleophile Y to a triple-bond as in 2 can take place to give a product anion where the entering nucleophile is trans (2) or cis (3J to the non-bonded electron pair. Stereoelectronic effects should therefore affect product formation. 

In a probe for the presence of stereoelectronic effects in nucleophilic addition to 12 sterically unbiased ketones, calculations have identified subtle bond length differences in the C-Nu bond of the diastereomeric alcohol products, where Nu- = H-or Me-.304 The calculated differences are weak (<1%) but consistent the bond is longer in the major product, acting as a fossil record of the TS. Using microscopic reversibility, the easier bond to cleave (the longer one) is the easier to form. The effect bears comparison with the kinetic anomeric effect in sugars, where such bond length differences in calculation are borne out in X-ray crystal structures. 

The diastereoselectivity of the first two reactions shown in Scheme 2.19 [68] can also be interpreted as a result of a stereoelectronic effect. Although the diastereoselectivity of additions to enones is usually governed by steric effects, which lead to an addition of the nucleophile from the sterically less demanding side of the double bond (as in the third reaction in Scheme2.19 for additional examples, see Refs [69, 70]), the first two reactions shown in Scheme 2.19 are, surprisingly, syn-selective. Cyclopentenones [68, 71] and cycloheptenones [72] can also react with the same syn-diastereoselectivity. 

In contrast to the reaction of 1,2-anhydrosugar, C-glycosylation of 1,6-anhydropyranose requires a strong Lewis acid in order to open the anhydro bridge, generating the corresponding oxocarbenium cation (O Eq. 6). Addition of nucleophiles to the cation could be controlled by the stereoelectronic effect, chelation between the nucleophile and the Lewis acid coordinated to the hydroxyl group, or intramolecular delivery of nucleophiles as shown below. 

The reaction of endocyclic enamines with a,p-unsaturated ketones to afford cu-fused hydroindolones or hydroquinolones constitutes a complementary and highly useful annulation sequence developed extensively by Stevens and coworicers, see the reaction of (5) to give (6) in Scheme 7. ° The importance of stereoelectronic effects is highlighted in the reaction of (7) with methyl vinyl ketone, which provided only the alkylated product (8) and none of the expected ci5-hydroindolone (9)." The failure of intermediate (8) to cyclize in this case was attributed to nonbonded interactions between the aryl group and the side chain. This destabilizing allylic interaction s disfavors formation of conformer (10), the intermediate required for antiperiplanar addition of the enol nucleophile (Scheme 8). Cyclization via the alternate conformation would require a double boat-like transition state. 

Two of the factors that determine the reactivity of tethered ir-nucleophiles in Mannich-type cycliza-tions have been emphasized stereoelectronic effects and reaction medium effects. The stereoelectronics of orbital overlaps between the ir-nucleophile and the iminium electrophile are best evaluated by considerations such as antiperiplanar addition trajectories and Baldwin s rules for ring formation. The critical importance of the reaction medium has received serious attention only recently. However, it already appears clear that Tr-nucleophiles that would lead, upon cyclization, to relatively unstable carbocations can have their reactivity markedly increased by carrying out the cyclization in the presence of a nucleophilic solvent or additive which, by nucleophilic participation, can obviate the formation of high energy cyclic carbenium ion intermediates. 

It is known that the 2-cyclohexenone system exists, principally, as two rapidly exchanging envelope (also called sofa) conformations (93, 94). Conjugate addition of a nucleophile can occur to either face of the 2-cyclohexenone. Parallel or anti-parallel (with respect to the axial substituent at C4) attack is possible in principle, however, a nucleophile must approach from an axial direction for satisfying the requirement of the stereoelectronic effect. Anti-parallel attack leads to a favorable chair-like intermediate, whereas parallel attack leads to an unfavorable boat-like intermediate in each case. In an anti-parallel attack, the newly introduced nucleophile forms a frarcs-diaxial arrangement found in a chair conformation. Conversely, parallel attack leads to a syn-diaxial arrangement found in a boat conformation. Therefore, anti-parallel attack is favored as this leads to a lower energy intermediate. 

By shedding light on the critical role of stereoelectronic effects involved in the intramolecular addition of a nucleophile to an activated a, p-unsaturated ester, these studies may have contributed to a refinement of the transition state model normally used to rationalize such reactions. Furthermore, these studies may provide an... 

Anomeric and double anomeric effects in phosphates The unusual stereoelectronic properties of negatively charged oxygen as a source of donor orbitals play a role in the formation of tetrahedral intermediates in nucleophilic addition/substitution at carbonyl. It also has important consequences for phosphate transfer reactions - one of the key types of chemical events in biology. 

The addition of nucleophiles to cyclic acetals and hemiacetals is an efficient method to access substituted THFs in high diastereoselectivity which is, in general, predictable and can be explained by stereoelectronic effects (1999JA12208). In this transformation, the intermediate is an oxocarbe-nium, which preferentially adopts an envelope conformation, and the nucleophile attacks on the inside face of the envelope. In the presence of a methyl at C3, the conformer possessing pseudoequatorial substituents is favored and the, 2>-trans product is obtained as the major product (63 64) (Scheme 33). It is worthy of note that when an alkoxy group is present at C3, the 1,3-ds product, resulting from an inside attack on the diaxial conformer, is favored (65 66) (Scheme 33). 

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