Steric hindrance electrophilic substitution

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

The rate also decreases with an increase in the chain length of the alkene molecule (hex-l-ene > oct-1-ene > dodec-l-ene). Although the latter phenomenon is attributed mainly to diffusion constraints for longer molecules in the MFI pores, the former (enhanced reactivity of terminal alkenes) is interesting, especially because the reactivity in epoxidations by organometallic complexes in solution is usually determined by the electron density at the double bond, which increases with alkyl substitution. On this basis, hex-3-ene and hex-2-ene would be expected to be more reactive than the terminal alkene hex-l-ene. The reverse sequence shown in Table XIV is a consequence of the steric hindrance in the neighborhood of the double bond, which hinders adsorption on the electrophilic oxo-titanium species on the surface. This observation highlights the fact that in reactions catalyzed by solids, adsorption constraints are superimposed on the inherent reactivity features of the chemical reaction as well as the diffiisional constraints. 

Electrophilic substitution at the anthraquinone ring system is difficult due to deactivation (electron withdrawal) by the carbonyl groups. Although the 1-position in anthraquinone is rather more susceptible to electrophilic attack than is the 2-position, as indicated by jt-electron localisation energies [4], direct sulphonation with oleum produces the 2-sulphonic acid (6.3). The severity of the reaction conditions ensures that the thermodynamically favoured 2-isomer, which is not subject to steric hindrance from an adjacent carbonyl group, is formed. However, the more synthetically useful 1-isomer (6.7) can be obtained by sulphonation of anthraquinone in the presence of a mercury(II) salt (Scheme 6.4). It appears that mercuration first takes place at the 1-position followed by displacement. Some disulphonation occurs, leading to the formation of the 2,6- and 2,7- or the 1,5- and 1,8-disulphonic acids, respectively. Separation of the various compounds can be achieved without too much difficulty. Sulphonation of anthraquinone derivatives is also of some importance. 

Relatively few bisindole derivatives having unnatural aromatic substituents have been prepared. The most reactive aromatic center to electrophilic substitution is certainly at C-12, where steric hindrance is minimized and electron density favors stabilization of positive charge. Treatment of vinblastine (1) with less than 1.0 equiv of bromine in dichlo-romethane results in selective bromination at C-12 to give 12 -bromovin-blastine (5) (45,46). If excess bromine is employed, then bromination in the dihydroindole ring is also observed, and mixtures of (5) and 12, 17-dibromovinblastine (6) are obtained (46). 

Under mild conditions nitration and acetylation of hexahelicene give the 5-nitro-and 5-acetyl substitution product as the main product in about 50% yield. In both cases another monosubstitution product is formed, which was identified tentatively by NMR as the corresponding 8-substituted hexahelicene. From the relative rates of detritiation (krel) or the partial rate factors (f) given in Table 27, it seems more probable, however, that the 7-isomers are formed as the side product, as the positional reactivity order of detritiation is C(5) >C(7) >C(8) >C(1) >C-(4) >C(6) >C(2) > C-(3). The preferred reactivity at C(5), found in electrophilic substitutions, is predicted by all the simple Hiickel parameters, whereas the next two positions are correctly predicted by Nr and Lr. Judging from Nr-, Fr- and Lr-values the C-(l) position does not experience much steric hindrance in the H-exchange. Relative to some other positions (C(4), C(6)) its reactivity is higher than expected. The Mulliken overlap population predicts, however, the highest reactivity for C(l) and leaves room for the supposition that this position is considerably masked. 

Palladium-mediated substitutions of silylated allylic compounds are not subject to steric hindrances. The silicon atom exerts control over the reaction site snch thaty-substitution results [64]. While the electrophiles are unavoidably disjoint with respect to the acceptor silicon, one of the two limiting forms, i.e., the a-silylcarbenium ion, is much more unfavorable (a-a arrangement) and therefore its population is expectedly low. 

The replacement of methyl groups on acetylacetone by /-butyl groups causes a massive increase in steric hindrance to electrophilic substitution. The chromium(III) chelate of dipivaloylmethane can be chlorinated and nitrated only very slowly by means of forcing conditions (equation 68).281... 

An increase in steric hindrance at the /-position appears to favour a-substitution in equations 76 and 80, compared to /-substitution in equations 75 and 79. However, this does not explain the a-substitution in equation 78. Polla and Frejd148 attribute the a-substitution shown in equation 80 to protiodesilylation followed by electrophilic alkylation of the resulting olefin. 

Since the electrophile is introduced adjacent to the NH protective group, substantial steric hindrance may be encountered in the following reaction steps. In case of the dimethylsulfamoyl protected imidazole-5-carboxaldehyde, a rapid isomerisation to the 4-substituted product can be induced catalytically by traces of triethylamine or by mere standing at RT for several days42. The effect of steric hindrance by the protective group was also observed in the reduction of ethyl dimethylsulfamoyl-imidazolecarboxylate with DIBAH. The 5-isomer could not be reduced, whereas the 4-isomer is reduced easily to the imidazole carboxaldehyde under the standard conditions49. 

When hydrogen abstraction or electrophilic addition reactions may be inhibited by multiple halogen substitutions or steric hindrance, a hydroxyl radical can be reduced to a hydroxide anion by an organic substrate shown in Equation (7.28) ... 

If steric hindrance is important we should see evidence for this in the effect substitutents in the olefin have on the orientation ratio (see Table 14). The first feature to notice about Table 14 is that the methyl and trifluoromethyl substituent groups have similar directive effects towards the three electrophilic radicals. This is in sharp contrast to electrophilic ionic addition where, for... 

However, as a nucleophile s base strength and steric hindrance increase, its basicity tends to be accentuated. If there are abstractable protons at the p-position of the electrophile, an elimination pathway can compete with the nucleophilic substitution. 

Notice that the three key reactions work brilliantly in this synthesis the hydrogenation of 113 is totally stereoselective and very high yielding while the two electrophilic substitutions on the pyrrole are perfectly regioselective acylation of 108 controlled by steric hindrance and alkylation of 112 controlled by electronic preference and because it is intramolecular. 

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