Electronic Conjugations 4311 In Aromatic Systems

Substituents in aromatic rings may influence each other in a number of ways depending on their chemical nature, mutual position, and the presence of other substituents. For example, methyl groups have relatively little electronic interactions with the aromatic ring and with each other. Their incremental contribution to the lipophilicity of, e.g., xylenes, is additive as expected and independent from their relative position (or-tho versus meta versus para). Such groups are "well-behaved" in lipophilic fragmental systems [7-10].

In contrast, many groups interact strongly by resonance with the aromatic ring, and these groups must necessarily interact with each other. Such interactions are particularly marked in ortho and para isomers. Substituents in ortho position may display a further, through-space level of interaction, namely internal H-bonds (which increase lipophilicity) or steric hindrance with out-of-plane rotation (which decreases lipophilicity). These electronic and steric interactions may strongly perturb the lipophilic increment of some substituents, rendering difficult the calculation of reliable log P values by fragmental systems. The use of correction factors may improve results in some cases, but with serious limitations due to large differences in substituent characteristics and intensity of interaction.

As an example, we present here a systematic study in which the lipophilicity of 75 disubstituted benzene derivatives (i.e., 25 triplets of ortho, meta and para isomers) was measured as capacity factors (log /cw) in reversed-phase HPLC (RP-HPLC) [11]. The substituents, e.g., CH3, CI, OH, NH2, OCH3, COOH, COOCH3, CONH2, S02CH3 and S02NH2, were combined pairwise in a variety of possibilities. Substituent constants were first determined from the corresponding monosubstituted benzenes, and used to predict the capacity factors of the 75 disubstituted benzenes. The differences between predicted and measured log kw values ranged from negligible (e.g., dimethyl-benzenes) to very high (e.g., nitrophenols). In about two thirds of cases, such interactions resulted in an increased lipophilicity compared with the expected value, while in about one-third of cases the measured capacity factors were lower than expected.

The measured and predicted capacity factors could be correlated by multiple linear regression (Eq. (8)):

log kexf> = 0.943(± 0.043) log ¿calc + 0.790(± 0.168) go + 0.255

(± 0.208) go0 + 0.297(± 0.050) Ia + 0.170(± 0.080)

where log kcxp and log kC3k are the experimental and calculated log kw values, respectively, pais a parameter expressing the mutual electronic influence of two substitutents in meta or para position, goa is the same parameter for ortho disubstitution, and Ia is an indicator of ortho effects taking the value of + 1 or + 2 in case of weak or strong in ternal H-bonds, and — 1 or — 2 in case of out-of-plane rotation producing loss of resonance.

Interestingly, Eq. (8) was challenged with a test set of 11 tri- and tetrasubstituted benzenes, with a good correlation between predicted and measured log kv values (r2 = 0.976).

4.3.1.2 Across Aliphatic Segments

Interactions of functional groups separated by aliphatic segments can be caused by a variety of effects, e.g., H-bonds between donor and acceptor (section 4.3.2.2), or hydrophobic interactions between two apolar moieties (section 4.3.3.1). In many cases, however, through-space interactions may be present, either between polar groups (section 4.3.2.1) or as result of internal electrostatic bonds (section 4.3.2.2 and 4.3.4.2). Indeed, electronic interactions that occur across aliphatic segments without involving a through-space/conformational component have seldom been reported in structure-lipophilicity relationship studies. In other words, the unambiguous characterization of hyperconjugation as a factor influencing lipophilicity is insufficiently documented in the literature.

An example is provided by oo-functionalized alkylbenzenes and alkylpyridines (Fig. 2), where some partly understood effects were seen [12, 13], In phenylalkanols and phenylalkylamines (Fig. 2), the lower homologs (benzyl alcohol and benzylamine) were more lipophilic by 0.11 log P unit than predicted from the sum of their fragmenta! constants. The higher homologs (n = 2-4) were slightly less lipohilic by 0.10. This suggests a modest influence on lipophilicity caused by hyperconjugation between the phenyl ring and the functional group, but across one carbon atom only.

As compared with phenylalkanols and phenylalkylamines, various pyridylakanols, pyridylalkylamines and pyridalalkanamides (where n = 1-5) showed large deviations from calculated log P values. The fact that these deviations were comparable in each triplet of a-, fi- and y-regioisomers excludes internal H-bond formation between the pyridyl nitrogen and the terminal functionality as the cause of such deviations. As for the phenyl analogs, but in a more marked way, the pyridyl analogs with n = 1 were more lipophilic than calculated (by an average of 0.46, 0.08 and 0.27 for the alcohols, amines and amides, respectively). This again could be due to some hyperconjugative effects. However, the clear difference between the OH, NH2 and CONH2 groups would tend to implicate additionally a through-space proximity effect between polar groups, i.e, between the pyridine ring and the terminal group. Such effects are discussed in section 4.3.2.1.

All higher homologs (n = 4 and 5) were markedly less lipophilic than calculated, but no explanation could be offered for such intramolecular effects.

Figure 2. Chemical structure of co-functionalized alkylbenzenes and alkylpyridines used as model compounds to assess the influence of intramolecular electronic interactions across aliphatic segments [11, 12].

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