Nucleophilic addition reaction trajectory

Obviously, the nature of the organocopper reagent is an important factor with respect to the stereochemical outcome of the cuprate addition. This is nicely illustrated for the cuprate addition reaction of enoate 75 (Scheme 6.15). Here, lithium di-n-butylcuprate reacted as expected by way of the modified Felkin-Anh transition state 77 (compare also 52), which minimizes allylic A strain, to give the anti adduct 76 with excellent diastereoselectivity [30]. Conversely, the bulkier lithium bis-(methylallyl)cuprate preferentially yielded the syn diastereomer 78 [30, 31]. It can be argued that the bulkier cuprate reagent experiences pronounced repulsive interactions when approaching the enoate system past the alkyl side chain, as shown in transition state 77. Instead, preference is given to transition state 79, in which repulsive interactions to the nucleophile trajectory are minimized. 

It seems that the repulsive steric interactions play a more dominant role in regioselectivity of aryne reactions than is sometimes realized. In fact, it has been argued that in nucleophilic addition to arynes, the transition state is reached early, while the incipient bond is still very much extended. Consequently, steric effects were considered not to be of great importance.80 81 It should, however, be noted that the dehydro bond orbitals are so oriented that the optimal approach trajectory for the nucleophile lies in the... 

The excellent control observed with the P,S- and certain N,S-ligands is believed to be mainly electronic in origin [85-88, 90-92, 94, 95]. When a tt-allyl system possesses two different coordinating atoms, the nucleophilic attack is expected to occur trans to the better Jt-acceptor, since the electronic density of the allylic system is lowest at this position. In these cases, the phosphorus and the nitrogen atoms are better Jt-acceptors than the sulfur which is a good donor but weak acceptor. In some cases, the sulfur atom is considered to be the better acceptor [90]. In addition, it has been proposed that the selectivity arises from subtle steric interactions that predispose attack on the allyl unit of the reaction intermediate with a preferred reaction trajectory [93]. 

MeLi-TiCU or PbEt4-TiCl4 ° reagents show high Cram selectivities in addition reactions to 2-phe-nylpropanal. An explanation was presented by Heathcock for the selectivities achieved by the Lewis acid promoted additions compared to simple organometal additions. In the latter cases, a trajectory is followed that brings the nucleophiles closer to H rather than to R, and asymmetry in R is transferred... 

Fig. 6.40. Eschenmoser s interpretation of glycolaldehyde phosphate aldomerisation reactions [37] It is generally appreciated... that the BUrgi-Dunitz trajectory... for nucleophilic addition to C = 0 groups must be taken into account as steric interactions between reaction center substituents are evaluated. The drawings in (this figure) remind the reader why. While it can be difficult to weigh the contributions of the four relevant interactions for an aldehyde/ketone-enolate pair, the problem for the case of an aldehyde/aldehyde-enolate pair turns out to have a unique solution the one indicated in (this figure), where none of the interacting substituents is juxtaposed with a non-H-atom partner ...

Such simplified analysis, based on the dominant two-electron stabilizing interaction between FMOs, is commonly used for understanding stereoelectronic preferences in intermolecular interactions. In particnlar, the preferred trajectories of nucleophilic additions or substitutions optimize the overlap of incoming nucleophile HOMO with the a and it LUMO of the target (vide infra. Figure 2.38). On the other hand, in electrophilic reactions, the favorable 2e-interaction involves the electrophile LUMO and the target HOMO. 

The trajectory of nucleophilic attack upon the double bond of VIII is quite close to that of the addition of nucleophiles to the carbonyl bond. For the addition reaction of the hydride-ion (Y = H) to ethylene (R = Z = H), and propene (R = CH3) the angle d is 123° (according to the ab initio 3-21G calculations in Ref. [23]. The driving force of the reaction is the charge transfer from the electron lone pair orbital of the nucleophile Y to the 7i -orbital of olefine. The latter has, unlike the orbital n Q (see Fig. 4.1), no loop on the a-atom of carbon and is delocalized, which diminishes the overlap integral and thereby the energy of interaction AE from Eq. (4.10) of the nucleophile with alkene as compared to the energy of interaction with the carbonyl... 

Chiral a-methyl aldehydes (43) show exceptional diastereofacial preferences in their Lewis acid mediated reactions with enol silanes (equation i6) 2i 25c-26-64 selected data are reported in Table 8. The reason for this selectivity may be due to an approach trajectory of the nucleophile closer to the stereocenter when the carbonyl group is bound to the Lewis acid. Additions to chiral a-alkoxy aldehyde (48) were studied with both nonstereogenic (equation 17 Table 9) and stereogenic enol silanes (equation 18 Table 10). (Stereogenic and nonstereogenic are defined according to Mislow and Siegel.) ... 

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. 

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