Effects 4-position substitution

Radical chlorination reactions show a substantial polar effect. Positions substituted by electron-withdrawing groups are relatively unreactive toward chlorination, even though the substituents may be potentially capable of stabilizing the free-radical intermediate " ... 

Substituents with -I,+M effects such as halogen show a similar orientation effect to that of alkyl groups. If the substituent is in the 2-position, substitution occurs at C-5 if it is in position 3, substitution occurs preferentially at C-2 or if steric requirements of the group or electrophile intervene, then substitution occurs at C-5. 

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

It can be seen from resonance structures (2) to (4) that a — I — M-substituent deactivates the 3- and 5-position most strongly in electrophilic substitution. If this deactivation of the 5-position is strong enough to overcome the activating effects of the sulfur in the 5-position, substitution will be directed to the 4-position to an increasing extent. Tirouflet and Fournari studied the nitration of 2-substituted thiophenes of this type. The analysis was carried out polarographically, and the percentage of 4-isomer was as follows ... 

The effect of substitutents at the C3 and C6 positions of the azepine ring is much more dramatic in that they force the 1//-azepine into a competing [6 + 2] Tt-cydoaddilion at the Cl —Cl positions.6 1 In fact, at room temperature [6 + 2] cycloaddition by a kinetically controlled, non-concerted, ionic process appears to be dominant, since on treating a mixture of ethyl 3,6-dimethyl- and ethyl 2,5-dimethyl-l//-azepine-l-carboxylate with less than a molar equivalent of ethenetctracarbonitrile, only the [6 + 2] cycloadduct 10 of the 3,6-dimethyl-l//-azepine is formed. 

Structure activity relationships, i.e., the total pattern of change in a biological activity as a function of chemical structure, typically derived from a comparison within a chemical series so that the biological effects of substitution at each structural position may be determined and correlated. 

With the method applied it is possible to take into account substitution effects both in the A and C monomers, as explained elsewhere (12). The substitution effect factor Kjj indicates the factor by wKTch the reaction rate between monomer I and any other monomer L is multiplied for each previous bond formed between monomers I and J (i.e. first-shell substitution effects (7)). For positive substitution effects Kjj is larger than 1, for negative effects it is smaller than 1. 

The results obtained with different amines cannot be explained merely on the effects of amine basicity. Thus, to obtain complete hydrogenation of Q to DHQ, the basicity has to be tailored by other factors such as the steric hindrance of the amine and its electronic interaction with the catalyst active sites this seems to be favored by the presence of an electron-rich aromatic ring. Of note, the positive effect of substituted aromatic amines, with a 49% DHQ yield being obtained for ethylanilines, is independent of the substituent position of the alkyl group. 

With substituents such as OH and OMe that have unshared electron pairs, an electron-donating, i.e. base-strengthening, mesomeric effect can be exerted from the o- and p-, but not from the m-position, with the result that the p-substituted aniline is a stronger base than the corresponding w-compound. The m-compound is a weaker base than aniline itself, due to the electron-withdrawing inductive effect exerted by the oxygen atom in each case. As so often, the effect of the o-substituent remains somewhat anomalous, due to direct interaction with the NH2 group by both steric and polar effects. The substituted anilines are found to have related pAa values as follows ... 

Donor dopants are impurity ions of a higher valence than that of the parent ions, as when small amounts of Nb2Os are incorporated into Ti02, so that Nb5+ substitutes for Ti4+. The donor species has an effective positive charge, Nb j, in this example. 

Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

Concerning steric factors, 43 is attacked in the most hindered position ( inverse effect of substitution ) likewise, 39 is attacked at the most hindered carbon. Obviously, the transition states for the formation of 44 or 50 show limited sensitivity to the degree of substitution, and the relief of ring strain is a more significant factor than the steric hindrance in the transition state. On the other hand, steric factors are important in systems such as P-phellandrene radical cation 40 which is attacked at the xo-methylene carbon (most easily accessible), or the tricyclane radical cation 56 which is attacked at the less hindered 3° carbon further removed from the dimethyl-substituted bridge (approach a). Both reactions also benefit Irom the formation of the most highly substituted, hyperconjugatively stabilized free radicals. 

The data on the reactivities of trichloroethylene and tetrachloroethylene further illustrate the competitive effects of substitutions on the 1- and 2-positions of ethylene. Trichloroethylene is more reactive than either of the 1,2-dichloroethylenes but less reactive than vinylidene chloride. Tetrachloroethylene is less reactive than trichloroethylene—analogous to the difference in reactivities between vinyl chloride and 1,2-dichloroethylene. The case of polyfluor-oethylenes is an exception to the generally observed large decrease in reactivity with polysubstitution. Tetrafluoroethylene and chlorotrifluoroethylene show enhanced reactivity due apparently to the small size of the fluorine atoms. 

Fluorination in the electrophilic 2-, 4-, and 6-positions is effected by substitutions of other halides, and this is normally performed by nucleophilic displacement with fluoride ion <1994HC(52)1>. Hydrofluoric acid can also be used, and in the case of 2,4-dichloro-5-trichloromethylpyrimidine 111, replacement of all five chlorine atoms occurred, to give 2,4-difluoro-5-trifluoromethylpyrimidine 112, which was subsequently hydrolyzed to give 5-tri-fluoromethyluracil 113 <1996JFC(77)93>. 

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