Structural Factors Influencing Intramolecular Interactions

The previous sections have presented a number of possibilities by which various moieties in a molecule may interact to influence the partitioning behavior of the solute. In a schematic manner, such interactions depend on the following factors:

Table 3. The influence of geometric factors and molecular states on intramolecular interactions expressed in lipophilicity

Structural factors

Interactions Regio- Tautom- Diastereo- Conforma- Ionization isom- erism isomerism tional erism isomerism

Electronic conjugations

• Across aliphatic segments +

Interactions involving polar groups

Electronic conjugations

• Across aliphatic segments +

Interactions involving polar groups

• Proximity effects between two

+

+

+

+

neutral polar groups

• Internal H-bonds

+

+

+

+

+

• The case of zwitterions

+

+

+

+

• Hydrophilic collapse

+

+

+

+

+

• Proximity effects between polar

+

+

+

+

and nonpolar groups

Steric/hydrophobic interactions

• Shielding of polar groups

+

+

+

+

+

• Hydrophobic interactions

+

+

+

• Hydrophobic collapse

+

+

+

• the chemical and physico-chemical nature of the moieties, e.g., their high or low polarity;

• their distance from each other;

• the nature and number of interconnecting atoms.

In other words, a number of structural factors (geometric factors and molecular states) will influence intramolecular interactions and hence solubility and partitioning. Various possibilities are schematized in Table 3, some of which will be briefly discussed below.

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