Temperature effects nucleophilic addition

Compared with the variety of existing carbon or nitrogen nucleophiles that were subjected to nucleophilic addition to there are few examples for phosphorus nucleophiles. Neutral trialkylphosphines turn out to be to less reactive for an effective addihon to Cjq even at elevated temperatures [114], Trialkylphosphine oxides show an increased reactivity. They form stable fullerene-substituted phosphine oxides [115] it is not yet clear if the reaction proceeds via a nucleophilic mechanism or a cycloaddition mechanism. Phosphine oxide addition takes place in refluxing toluene [115], At room temperature the charge-transfer complexes of with phosphine oxides such as tri-n-octylphosphine oxide or tri-n-butylphosphine oxide are verifiable and stable in soluhon [116],... 

Molecular dynamics simulations have been used to predict solvent and temperature effects in the nucleophilic addition of a-chiral carbonyl compounds.253 Prediction of diastereoselectivity break temperatures (i.e. inversion points) has been achieved with fair accuracy by comparison with experimental data on n-BuLi addition. Dramatic differences are seen for additions to 2-phenylpropanol in pentane solvent, compared with octane. 

The rate constants for addition of aliphatic alcohols and water to 19a decrease in the order MeOH > EtOH > H2O i-PrOH > t-BuOH in acetonitrile at 23 °C45, due to a combination of steric effects, nucleophilicity and acidity, all of which can be expected to affect the magnitudes of the individual rate constants involved in the mechanism for the reaction. The Arrhenius activation energy for addition of Z-BuOH to this silene, Ea = —1.7 0.4 kJmoP189, is closer to zero than that for MeOH addition, suggesting that the intracomplex product partitioning ratio is closer to 0.5 than is the case for the more reactive alcohol over the temperature range examined. It thus follows that the factor of ca 10 lower reactivity of t-BuOH compared to MeOH is mainly due to a reduction in the rate constant (kcj for initial complexation of the alcohol with the silene. 

The activating effect of Pd and Fe° toward nucleophilic addition to alkenes is powerful and allows addition of stabilized anions to simple alkenes at low temperatures. However, the only efficient catalytic processes are based on the addition of oxygen nucleophiles to alkenes activated by spontaneous coordination with Pd extensions of the Wacker process. 

Reference is in general made to . One example from the early 1990s is provided by the rearrangement of pyrazoles to pyrimidines, which can be effected under mild conditions, pH about 9, and room temperature, by the addition of an oxygen nucleophile to an exocyclic double bond (580) (Scheme 92). The intermediate betaine (581) subsequently suffers ring expansion with formation of 1,2-dihydropyrimidines (582) <92JOC4i5l>. 

Condensation of urea with carbonyl compounds A rapid and efficient MW-assisted synthesis of hydantoins and thiohydantoins was described by Muccioli et al. [117]. The most straightforward conditions for synthesis of phenytoin are the base-catalyzed condensation using benzil and urea, known as the Biltz synthesis (Eq. 33). MW activation of the Biltz synthesis of phenytoin improved both yield and reaction time. The first step consists in MW activation of the reaction of benzil with (thio)urea the second includes the conversion of the resulting 2-(thio)hydantoin to hydantoin using hydrogen peroxide. When reactions were performed at the same temperature under both reaction conditions, yields were by far better under the action of MW and emphasized the evident specific MW effects. These are perfectly expected when one considers the polar TS involved in the first step (nucleophilic addition of neutral NH2 group on carbonyl moiety). 

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