Nitrogen nucleophiles, addition steric effect

The pKa of a nitrogen is a convenient measure of its nucleophilicity in proton addition steric effects are unimportant. All other types of electrophilic attack at nitrogen are sensitive in varying degrees to steric effects from a-substituents. (Exception certain ring formation reactions as in metal chelation.)... 

The importance of steric effects in determining the oxidation state of the product can be illustrated by a thioether linkage, eg (57). If a methyl group is forced to be adjacent to the sulfur bond, the planarity required for efficient electron donation by unshared electrons is prevented and oxidation is not observed (48). Similar chemistry is observed in the addition of organic nitrogen and oxygen nucleophiles as well as inorganic anions. 

Steric effects on the nucleophile, aniline, were clearly evident. Rate constants for bimolecular attack of 2,6-dimethyl- 70a, 2,6-diethyl- 70b, and 3,5-dimethylaniline 70c at 308 K indicate that the ort/zo-substituted anilines react more than an order of magnitude slower at the same temperature (Table 7). Structure 70c must be able approach the reactive nitrogen more closely.42,43 A comparison of the rate constants for reaction of aniline 72c, /V-methyl- 71a and /V-phenylaniline 71b provides further evidence of steric effects although the very small rate constant for the diphenylamine could also be accounted for by reduced nucleophilicity on account of lone pair resonance into the additional phenyl ring. 

The stability of azole carbenes can be attributed to electronic factors which operate in both the Tran d CT-frameworks (92JA5530). In the TT-framework, electron donation into the carbene out-of-plane p-orbital by the electron-rich system moderates the typical electrophilic reactivity of carbenes. In the o-framework, additional stability for the carbene electron pair may be gained from the o-electron-withdrawal effects on the carbene center by the more electronegative nitrogens, which moderates the carbene nucleophilic reactivity. The combination of these a- and TT-effects serves to increase the singlet-triplet gap and stabilize the singlet carbene over the more reactive triplet state. For carbenes with bulky substituents (tert-butyl, 1-adamantyl, etc.) steric effects provide additional stabilization. 

PyCH=CHPy however, only a slight effect was observed. Further, no difference between the rates of the second quater-nization step of l,3-(bis-4-pyridyl)propane and l,2-(bis-4-pyridyl)-ethane was detected. These results indicate that inductive effects do not contribute significantly to the relative nucleophilicity of the second amino function. Steric effects are also eliminated by the failure of the additional methylene spacer to influence the second quaternization rate. Fuoss et al. concluded that the rate decreases observed between the first and second quaternization steps in the model compounds could be attributed to a volume field effect, i.e.,an electrostatic effect produced at the site of the second nitrogen by the positive charge on the initially quaternized nitrogeh. 

The donor properties of nitrogen-containing systems make these nucleophiles excellent participants in substitution reactions of oxiranes (Equation 16). The major issue for additions to unsymmetrical epoxides is one of regioselec-tivity. Both steric and electronic effects within the electrophile and the nucleophile can play a significant role in these... 

The rule is bard to use because we do not have a good value for the p/fa of the product of the addition of hydroxide. Steric hindrance from R raises the pA abH of un alkoxide anion (poorer intermolecular solvation), whereas the inductive/field effect from the nitrogen should lower the p/ifabH- If these effects balance out, the tetrahedral intermediate product of nucleophilic attack would have a pATabH of about 13 (HOCH2OH is pKa 13.3). 

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