Steric Effects on Nucleophilicity

The rate of an Sj 2 reaction is strongly affected by bulky groups near the reaction center, which hinder the approach of the nucleophile (Section 9.9). Therefore, the size of the nucleophile is also important. Steric crowding in the transition state increases with the size of the nucleophile. We find, for example, that the larger fert-butoxide ion is a poorer nucleophile in S 2 reactions than the smaller ethoxide ion. 

The order of basicities of alkoxides is opposite to the order of nucleophihcity. Thus, fert-butoxide ion is a stronger base than ethoxide ion. Steric hindrance has little effect on the ease of abstraction of a proton in acid-base reactions. Steric repulsions are less severe when the base approaches a small hydrogen atom than when it approaches the more crowded environment at a tetravalent carbon atom. 

BIOLOGICAL S 2 REACTIONS Glutathione is present at a concentration of about 1-5 mM in most animal cells. It partici- 

BYSULFUR CONTAINING hi several enzyme-catalyzed reactions. In some reactions, glutathione acts as a reducing agent. In 

Ml ir i irnnuii re others, its nucleophilic sulfhydryl group reacts with certain toxic intermediates that are produced when 

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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. 

As pyramidal amides5,32 their Sn2 reactivity with neutral nucleophiles like /V-methylaniline parallels that of a-haloketones with amines, which, as described in an earlier section, are also strongly affected by steric effects on the a -carbon.183 SN2 reactions are in general strongly and adversely influenced by steric effects and branching / to the reactive centre and the same appears to be true for /V-acyloxy-/V-alkoxyamides 30b and 29a-e. Broadly speaking, their mutagenic activity is affected similarly. 

Some studies have been made with bases of the type ArO , as this allows study of the effects of variation in basic strength (by introduction of p-substituents in C HsO ) without concomitant change in the steric requirements of the base. With a given base, transfer from a hydroxylic solvent, e.g. HjO or EtOH, to a bipolar aprotic one, e.g. HCONMej (DMF) or MejS —O (DMSO), can have a very pronounced effect as the strength of the base, e.g. OH, OR, is enormously increased thereby. This arises because the base has, in the latter solvents, no envelope of hydrogen-bonded solvent molecules that have to be stripped away before it can act as a base (c/ effect on nucleophilicity in S, 2, p. 81). Such change of solvent may result in a shift of mechanistic pathway from E1 to E2 for some substrate/base pairs. 

Amer. Chem. Soc., 95, 1897, 1900 (1975)]. Bunnett maintains that if the E2C transition state involves partial bonding of the base to C, steric effects on the E2C transition state should be similar to those on the Sn2 transition state. It is difficult to assess this argument because in the looser E2C transition state (see p. 366) the nucleophile would be farther away from the /-butyl group. For a further discussion of this controversy, see W. T. Ford, Accts. Chem. Res., 6, 410 (1973). 

Both polar and steric effects on the Sn-Cl bond influence the reaction. Higher electron deficiency of the tin atom in Me2SnCl2 is important, supporting the nucleophilic behavior of the R2Sn species. Methyldichlorostannanes, MeRSnCl2, always result in insertion into the Sn-Cl bond, but yields decrease with increasing bulkiness of R. 

Electronic and steric factors exert their impacts on this rearrangement. Thus, the rate of isomerization increased with electron depletion and decreased with electron enrichment of the pyrimidine ring. It was less facile when the triazole ring was substituted (89JHC687). Methyl groups with a positive mesomeric effect at C5 and/or C8 (16, R1 and or R3=Me) diminished the rate of acid-induced isomerization (pH 4) by retarding the approach of the nucleophile to C5 by electronic and (for C5) steric hinderance effects. Methyl groups at C3 and/or C7 (16, R and or R2=Me) exerted little electronic and no steric effects on C5, yet promoted the approach of the... 

Steric Effects on k0. At least two types of steric effects occur direct repulsion between the attacking nucleophile and the olefin and steric interference with the optimal tt overlap among X, Y, and the carbanionic carbon in the adduct. Both effects have their counterpart in proton transfers, but as long as R = H in R CHXY, these effects are small unless very bulky bases are used (32, 33). 

Steric Effects on Solvent Nucleophilicity. The N0Ts values (Table III) show that TFA is, by this measure, less nucleophilic than HFIP. As the rate ratios 2-AdOTs (CH3)2CHOTs in TFA and 97% HFIP were very similar, we initially proposed (17) that solvolyses of (CH3)2CHOTs in these two weakly nucleophilic solvents were kc processes. More detailed studies (4, 50) later showed that solvolyses of secondary tosylates in 100% HFIP were closer to limiting (kc) than those in TFA. This apparent reverse of the order of nucleophilicity could be caused by steric effects (50), which could also contribute to the lower precision of the iN/mY equation (5) in correlations of rate data for secondary substrates for example, for 2-propyl tosylate, solvolyses in TFE and HFIP are predicted to be slower than observed, whereas reaction in CF3C02H is predicted to be faster than observed (3). 

An example is the use of Z isomerization as a nucleophilicity probe. This process has practical advantages because it does not require the characterization of different products for each nucleophile, and the thermodynamics of the process is independent of the nucleophile. Table I gives the kinetic parameters for the amine-catalyzed (Z)-5 to ( )-5 isomerization (equation 1) (13, 14). The k2 values are easily interpreted in terms of electronic and steric effects on a rate-determining nucleophilic attack. However, the very low AHl values suggest that the observed rate constant is not kx but a more complex expression, and the internal rotation step krot may be ratedetermining. In view of this, this process should not be used as a probe. Very low activation enthalpies in several vinylic substitutions [e.g., AHx = 0.8-2.0 kcal mol-1 for the reaction of the para position of N,N-dialkylanilines with tricyanovinyl chloride in chloroform (15)] may also indicate a composite rate constant. 

Steric effects, on the other hand, do affect nucleophilicity. A bulky nucleophile cannot approach the back side of a carbon as easily as a less sterically hindered nucleophile can. Thus, the bulky ferf-butoxide ion, with its three methyl groups, is a poorer nucleophile than ethoxide ion even though ferf-butoxide ion is a stronger base. 

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