Effect of the Nucleophile

S_N1 Effect of Nucleophile Structure

Under typical reaction conditions, the S_N1 reaction is independent of the nature of the nucleophile since it is not involved in the rate determining step.

S_N2 Effect of Nucleophile Structure

The effect of the nucleophile structure on rate of S_N2 substitution is complex.  Many factors can influence a nucleophile's reactivity, including solvent choice, concentration and other additives (e.g. crown ethers).

Nucleophiles can be basic and as such its very common to relate the two.  However, it is important to note the differences between bases and nucleophiles.  Nucleophilicity is a kinetic phenomenon measured by the rate at which a Nu attacks a compound.  Basicity is an equilibrium property measured by the position of equilibrium in an acid-base reaction.  Nucleophilicity is more concerned with kinetics and attack trajectories, and as such are sensitive to sterics (their own and the electrophile they react with).

• Within a period (row), nucleophilicity parallels basicity
  CH₃^- > NH₂^- > OH^- > F^-  (electrostatic charge interaction important)
• Within a family, larger atoms are better nucleophiles (polarizability)
  I^- > Br^- > Cl^- >F^- or R₂Se > R₂S > R₂O or R₃P > R₃N  (HOMO/LUMO interaction important)
• With the same nucleophilic atom but different charge type, nucleophilicity parallels basicity
  OH^- > H₂O or SH^- > H₂S (electrostatic charge interaction important)
• Nucleophilicity parallels basicity
  OH^- > CH₃COO^- (electrostatic charge interaction important)

Two distinct types of interactions control the reactions of nucleophiles and electrophiles; 1) HOMO/LUMO and 2) electrostatic interactions.  In nucleophilic substitution at aliphatic carbons the HOMO/LUMO interactions appear to be most important.

HOMO-LUMO Interactions

We have discussed in the past that when reactions occur the electrons must come from some source that has electrons and this is called HOMO (Highest Occupied Molecular Orbital).  Likewise the electrons must have somewhere to go (a sink) and this is the LUMO (Lowest Unoccupied Molecular Orbital).  If there is a large energy difference between the HOMO and LUMO then this transfer of electrons is difficult.  On the contrary, if the HOMO/LUMO are similar in terms of energy, the transfer can more readily occur.

Consider the competing reaction of HS^- and HO^- with an electrophile.  Both of these species have sp³ hybrid orbitals as their HOMO which are essentially the lone pair electrons.  Since the HOMO of the HS^- is higher in energy because of its filled 3sp³, it can more easily donate its electrons in to the LUMO of the electrophile.  This concept can be used to explain the following trend I^- > Br^- > Cl^- >F^- or R₂Se > R₂S > R₂O or R₃P > R₃N.

Electrostatic Interaction

Electrostatic interactions are simply the attraction of oppositely charged species.  In addition to HOMO/LUMO interactions, this is important in the reaction of nucleophiles with protons and carbonyls.  To understand the lack of importance of electrostatic interactions in nucleophilic substitution at aliphatic carbons, consider the reaction of the iodide (I^-) nucleophile.  The electronegativity difference between carbon (2.55) and iodide(2.66) is rather small (ΔEN=0.11), however I^- is known to be one of the best nucleophiles.  On the other hand, the fluorine as electronegativity of 3.98, but is notoriously a terrible nucleophile.  Thus, the electrostatic interactions play only a small part in nucleophilic substitution at aliphatic carbons.