Nucleophiles hyperconjugation

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Secondary isotope effects at the position have been especially thoroughly studied in nucleophilic substitution reactions. When carbocations are involved as intermediates, substantial /9-isotope effects are observed. This is because the hyperconjugative stabliliza-... 

In addition to the nucleophilic displacement of the halogen atom, subsequent substitution of the heteroarylium moiety has been observed in numerous cases. Tliese substitution reactions beneht from the increasing importance of the negative hyperconjugation (Scheme 13). Such a pathway has been intensively exploited to synthesize (fused) hve-, six-, and seven-membered heterocycles. 

Addition reactions at the alkyne bonds are dealt with in the section on alkenylstannanes that are produced. The alkynyl-tin bond is more readily cleaved by both electrophiles and nucleophiles than is the alkenyl- or alkyl-tin bond. Strong electrophiles such as halogens or halogen acids attack at the z/Mzi-position of the triple bond to give a /3-stannyl cation that is stabilized by C-Sn hyperconjugation, but this is followed by cleavage of the C-Sn bond (Equation (83)). 

As mentioned above, the reactivity of alkoxyallenes is governed by the influence of the ether function, which leads to the expected attack of electrophiles at the central carbon C-2 of the cumulene. However, the alkoxy group also activates the terminal double bond by its hyperconjugative electron-withdrawing effect and makes C-3 accessible for reactions with nucleophiles (Scheme 8.3). This feature is of particular importance for cyclizations leading to a variety of heterocyclic products. The relatively high CH-acidity at C-l of alkoxyallenes allows smooth lithiation and subsequent reaction with a variety of electrophiles. In certain cases, deprotonation at C-3 can also be achieved. 

Substituted snoutan-9-ones (61a) undergo nucleophilic additions with the same facial selectivity as the corresponding norsnoutanones (61b). However, the selectivity is markedly reduced, apparently owing to electrostatic effects in (61a), and hyperconjugative interactions in (61b). ... 

More often, however, fluorocarbanions are intermediates in reactions of fluoroalkenes,35 e.g. by addition of nucleophiles, especially fluoride. Deprotonation of hydrofluorocarbons also yields the anion. Whereas a-fluorination destabilizes the anion, /J-fluorination is essentially stabilizing. The latter effect may be assisted by so-called fluorine-nonbond resonance (negative anionic hyperconjugation) which has been discussed in diverse ways supported by some,3 but criticized by others.2 31... 

The relative rates of insertion into the OH bond of methanol and addition to 2-methylbut-2-ene indicate that the jS-thiophosphinoylcarbene (59) has enhanced nucleophilicity.66 This was interpreted as being due to hyperconjugative electron... 

Solvolysis of 15 in 97% trifluoroethanol gave a secondary isotope effect of 1.17, which indicates a vertically stabilized transition state. Thus the highly unsymmetrical dihedral dependence of silicon participation can almost entirely be attributed to the hyperconjugation model with little non-vertical involvement of the silicon nucleophile. 

Hyperconjugation appears to be the dominant factor governing the diastereoselectivity of the hydrochlorination of 5-substituted 2-methyleneadamantanes 3 (Table 2)36. However, the product distribution for epoxidation suggests that the stereochemical course of electrophilic additions not mediated by carbocations is most likely regulated by direct field effects36. Note that, unlike in the previous reactions, the facial selectivity in this case reflects the preference for the nucleophilic attack on the corresponding carbocation. 

Natural bond orbital analysis of early and late TSs has been carried out to explore the factors involved in tt-selectivity of nucleophilic addition to carbonyls.209 Cieplak s o —r o hyperconjugation hypothesis (where o is the incipient bond) is not supported by the results for early TSs, and evidence in favour of Felkin-Anh s o er hypothesis is weak. Late TSs are devoid of o 7r(t=() interactions here, the Cieplak model may be applicable. 

The arguments used above to explain the diastereoselectivity of the two first reactions in Scheme 2.19 on the basis of hyperconjugation of incipient antibonding orbitals are analogous to that used to explain the reactivity of phosphites (Scheme 2.12). This form of hyperconjugation was also used by Cieplak to explain jt-facial diastereoselection in the addition of nucleophiles to ketones [38, 74], The third reaction of Scheme 2.19 clearly shows that the diastereoselectivity of these reactions is responsive to small structural changes and are, therefore, hardly predictable. 

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