Nucleophilicity steric effects

Garbon-13 NMR shifts correlate with reactivities . Transition states may vary with the nucleophile . Steric effects of substituents are predictable reaction at an occupied position is slow , and the seven-membered ring series is slower than the six. 

The equation does not take into account such pertubation factors as steric effects, solvent effects, and ion-pair formation. These factors, however, may be neglected when experiments are carried out in the same solvent at the same temperature and concentration for an homogeneous set of substrates. So, for a given ambident nucleophile the rate ratio kj/kj will depend on A and B, which vary with (a) the attacked electrophilic center, (b) the solvent, and (c) the counterpart cationic species of the anion. The important point in this kind of study is to change only one parameter at a time. This simple rule has not always been followed, and little systematic work has been done in this field (12) stiH widely open after the discovery of the role played by single electron transfer mechanism in ambident reactivity (1689). 

Equation 4 can be classified as S, , ie, substitution nucleophilic bimolecular (221). The rate of the reaction is influenced by several parameters basicity of the amine, steric effects, reactivity of the alkylating agent, and solvent polarity. The reaction is often carried out in a polar solvent, eg, isopropanol, which may increase the rate of reaction and make handling of the product easier. 

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. 

Mechanistically the rate-determining step is nucleophilic attack involving the hydroxide ion and the more positive siUcon atom in the Si—H bond. This attack has been related to the Lewis acid strength of the corresponding silane, ie, to the abiUty to act as an acceptor for a given attacking base. Similar inductive and steric effects apply for acid hydrolysis of organosilanes (106). 

Alkyl groups under nonacidic conditions sterically deflect nucleophiles from C, but under acidic conditions this steric effect is to some extent offset by an electronic one the protonated oxirane opens by transition states (Scheme 40) which are even more 5Nl-like than the borderline Sn2 one of the unprotonated oxirane. Thus electronic factors favor cleavage at the more substituted carbon, which can better support a partial positive charge the steric factor is still operative, however, and even under acidic conditions the major product usually results from Cp attack. 

The more stable the LUMO, the stronger is the interaction with the HOMO of the approaching nucleophile. The observed (Cram s rule) stereoselectivity is then a combination of stereoelectronic effects ftiat establish a preference for a perpendicular substituent and a steric effect that establishes a preference for the nucleophile to approach from the direction occupied by the smallest substituent. 

Examples of effects of reactant stmcture on the rate of nucleophilic substitution reactions have appeared in the preceding sections of this chapter. The general trends of reactivity of primaiy, secondary, and tertiaiy systems and the special reactivity of allylic and benzylic systems have been discussed in other contexts. This section will emphasize the role that steric effects can pl in nucleophilic substitution reactions. 

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

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

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. 

Protecting groups are generally formed by nucleophilic attack on the carbonyl group and the rate of this process is determined by steric and electronic factors associated with the ketone. In steroid ketones steric effects are usually more important due to the rigid tetracychc skeleton. 

Hydrolysis of an enamine yields a carbonyl compound and a secondary amine. Only a few rate constants are mentioned in the literature. The rate of hydrolysis of l-(jS-styryl)piperidine and l-(l-hexenyl)piperidine have been determined in 95% ethanol at 20°C 13). The values for the first-order rate constants are 4 x 10 sec and approximately 10 sec , respectively. Apart from steric effects the difference in rate may be interpreted in terms of resonance stabilization by the phenyl group on the vinyl amine structure, thus lowering the nucleophilic reactivity of the /3-carbon atom of that enamine. 

This approach to carbonyl protection uses the relative differences in basicity and the differences in steric effects to protect selectively either the more basic carbonyl group or the less hindered carbonyl group from reactions with nucleophiles such as DIB AH and MeLi. ... 

The selective reaction of anionic 3,6-dichloro-4-sulfanilamidopy-ridazine with excess methanolic methoxide at the 3-position is another indication of the absence of major steric effects in most nucleophilic substitutions, as a result of the direction of nucleophilic attack (cf. Section II, A, 1). The selectivity at the 3-position is an example of the interaction of substituent effects. The sulfonamide anion deactivates both the 3-chloro (ortho direct deactivation) and... 

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. 

The chemoselectivity of the other alkenes of Table 1 is more variable. It appears that bulky substituents favour bromide over methanol attack of the bromonium ion, since dibromlde increases from 39 to 70 % on going from methyl to tert-butyl in the monosubstituted series. The same trend is observed in the disubstituted series with a contraction of the chemoselectivity span (37 to 43 % on going from methyl to teH-butyl) for the trans isomers. Since the solvated bromide ion can be viewed as a nucleophile larger than methanol, the influence of steric effects, important in determining the regioselectivity, does not seem very significant as regards the chemoselectivity. This result has been interpreted in terms of a different balance between polar and steric effects of the substituents on these two selectivities. 

It occasionally happens that a reaction proceeds much faster or much slower than expected on the basis of electrical effects alone. In these cases, it can often be shown that steric effects are influencing the rate. For example, Table 9.2 lists relative rates for the Sn2 ethanolysis of certain alkyl halides (see p. 390). All these compounds are primary bromides the branching is on the second carbon, so that field-effect differences should be small. As Table 9.2 shows, the rate decreases with increasing P branching and reaches a very low value for neopentyl bromide. This reaction is known to involve an attack by the nucleophile from a position opposite to that of the bromine (see p. 390). The great decrease in rate can be attributed to steric hindrance, a sheer physical blockage to the attack of the nucleophile. Another example of steric hindrance is found in 2,6-disubstituted benzoic acids, which are difficult to esterify no matter what the resonance or field effects of the groups in the 2 or the 6 position. Similarly, once 2,6-disubstituted benzoic acids are esterified, the esters are difficult to hydrolyze. 

When Z is SOR or SO2R (e.g., a-halo sulfoxides and sulfones), nucleophilic substitution is retarded. The SnI mechanism is slowed by the electron-withdrawing effect of the SOR or SO2R group,and the Sn2 mechanism presumably by the steric effect. 

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