Nucleophilic addition steric effects

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 coordinately saturated ring compounds owe their stabilities to both additional steric effects and the unavailability of sites for electrophilic or nucleophilic attack. A clear discrimination between the relative influence of these factors is often difficult, but the fact that (H2NBH2)3 is unaffected by boiling water while (HNBHjj is rapidly hydrolyzed must be largely a consequence of the latter. 

A summary of ring activation would not be complete without mention of steric effects. Since nucleophilic attack occurs in a plane perpendicular to that of the aromatic ring, substitutions are not usually very sensitive to the bulk of orf/io-substituents. However, steric hindrance by an ortho-methyl substituent may be observed as the steric requirements of the nucleophile increase. Thus, the introduction of a 6-methyl group in l-chloro-2,4-dinitrobenzene causes rate decreases by factors of 14, 22, and 276 in reactions with methoxide, aniline, and piperidine, respectively. The first two figures are attributable to the electronic effect of the methyl substituent, but with piperidine, an additional steric effect is apparent [50]. 

For unsymmetrically substituted oxiranes, the situation is more complex, since attack of the nucleophile at the oxirane C-O bonds may proceed via SNl-hke or SN2-like processes giving rise to regioselective product formation in addition, steric effects (i.e., accessibility of the oxirane carbons) play a significant role [8]. 

Steric and electronic effects influence the rate of nucleophilic addition to a proton ated carbonyl group m much the same way as they do for the case of a neutral one and protonated aldehydes react faster than protonated ketones... 

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. 

In addition to steric effects, there are other important substituent effects which determine both the rate and mechanism of nucleophilic substitution reactions. It was... 

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

The regioselectivity in radical addition reactions to alkenes in general has successfully been interpreted by a combination of steric and electronic effects1815,47. In the absence of steric effects, regiochemical preferences can readily be explained with FMO theory. The most relevant polyene orbital for the addition of nucleophilic radicals to polyenes will be the LUMO for the addition of electrophilic orbitals it will be the HOMO. Table 10 lists the HOMO and LUMO coefficients (without the phase sign) for the first three members of the polyene family together with those for ethylene as calculated from Hiickel theory and with the AMI semiempirical method48. 

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. 

In this chapter, both intermolecular and intramolecular electrophilic [1] and nucleophilic additions [2, 3] to allenes will be discussed. For electrophilic addition, the regio- and stereoselectivity depend on the steric and electronic effects of the substituents on the allenes and the nature of the electrophiles. However, nucleophilic addition usually occurs at the central carbon atom with very limited exceptions. 

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