6.4. Local Environments Affect Reactivity

Acidity/basicity and electrophilicity/nucleophilicity are strongly influenced by the local environment. Exactly how this occurs is complex and involves several different factors such as electron density, non-covalent interactions, and polarizability.

Consider the acidity of acetic acid (ethanoic acid) in different solvents (Table 6.1). Several parameters correlate with the changes in pK_a, but the most obvious is the polarity of the solvent. When the acid reacts it forms a pair of ions. Polar solvents are better able to stabilize these charges (see Solvent Effects for a similar effect) which favours their formation and increases the acidity. The more polar the solvent, the more acidic acetic acid is; the less polar the solvent, the less acidic acetic acid is.

Table 6.1 – pK_a Values for Acetic Acid (Ethanoic Acid) in Various Solvents.

Acetic acid is not miscible with (will not dissolve in) very non-polar solvents such as hexane. The solvent is so different in terms of polarity that they cannot be combined. Following the trend, the acidity would be dramatically decreased as formation of the ions would be disfavoured.

Enzymes use the same principle to adjust the acidity/basicity and/or electrophilicity/nucleophilicity of compounds and side chains inside them. While the effects are not normally as dramatic, enzymes are special because the acid/base/electrophile/nucleophile is FORCED to be where it is; instead of simply not “dissolving”, the compound is forced into a specific local environment which affects its reactivity.

Consider the acidity of the protonated side chain of lysine (as part of a peptide polymer) in different local environments (Scheme 6.6). Under typical conditions (e.g. the side chain floating in water) the pK_a of the acid is approximately 10.7. At physiological pH the vast majority of the compound (>99%) will be protonated; the side chain will exist exclusively as a cationic acid.

Scheme 6.6 – Comparison of Acidity of Protonated Lysine Side Chain in Two Local Environments.

The same side chain placed in a local environment inside an enzyme can behave very differently. Consider a pocket within an enzyme filled with many alkyl side chains (e.g. alanine, valine, leucine, etc.). The local environment is very non-polar. The side chain of lysine cannot leave the environment because it is covalently attached to the rest of the amino acids and folded inside the enzyme. In the local environment’s conditions the pK_a of the acid is approximately 5.3 (~250,000x more acidic). At physiological pH the majority of the compound (ca. 80%) will be deprotonated; the side chain will exist in equilibrium, with the majority as a neutral base. Base catalysis with the side chain is now possible because of the local environment.

Finally, consider the acidity of the side chain of serine (as part of a peptide polymer) in a specific local environment (Scheme 6.4 above). Under typical conditions (e.g. the side chain floating in water) the pK_a of an alcohol functional group is approximately 16. It is not nearly acidic enough to be deprotonated by histidine. However, the local environment (the exact orientation of the side chains relative to each other, the presence and exact location of water, the ionic charge of the nearby deprotonated aspartic acid, and the other side chains nearby [not shown]) allows this reaction to occur. The catalysis is made possible only by the enzyme controlling the local environment in a very specific way.