Suppose a protein side chain has a $\ce{-SH}$ group which is partially deprotonated to thiolate anion $\ce{-S -}$. This thiolate can perform a nucleophilic attack on a certain substrate.

Will the propensity of nucleophilic attack be reduced if the thiolate anion is in electrostatic interaction with a $\ce{NH3+}$ group of a basic amino acid? Or is the likelihood of nucleophilic attack independent of electrostatic effects?

P.S.- The $\ce{-S-}$ will probably be in eletrostatic interaction with H+ in the solution also. Maybe electrostatic interaction with $\ce{NH3+}$ will be more stable?

Core question: If a negative nucleophile is in electrostatic interaction, will it affect its nucleophilicity?


It would since the S atom is now negatively charged. However, S is a very poor hydrogen-bond acceptor as evidenced by its weak basicity (thiols are more acidic than alcohols). So this electrostatic effect will be greatly diminished if you compare with more basic nucleophiles like F- and O-. This is because sulfur larger and will be more polorizable making the localization of the negative charge more disperse around the atom and much weaker to form ion-ion interactions. It will still remain as a relatively powerful nucleophile, so you can expect side reactions.


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