Question

provide background on nucleophilic substitution reactions in general and ambidentate nucleophiles specifically including a definition of the term and what factors are important in determining the product distribution. It would be helpful to include structures to reinforce your statements

Answer 1

Nucleophilic substitution in an organic/inorganic reaction refers to a reaction in which an electron rich substituent (nucleophile) selectively bonds with the positive or partially positive charge of an atom or a group of atoms to replace a leaving group. Example is shown below:

R-Br + OH⁻ → R-OH + Br⁻

There are two types of nucleophilic substitution reactions, SN1 and SN2 reactions. S stands for chemical substitution, N stands for nucleophilic, and the number represents the order of kinetic reaction.

In the S_N2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously. S_N2 occurs where the central carbon atom is easily accessible to the nucleophile (not hindered).

S_N1 reaction involves two steps. In the first step the leaving group leaves leading to the formation of carbocation. In the second step, a nucleophile (hard base) attacks the electron deficient center, leading to racemization. S_N1 reactions is favored when the central carbon atom of the substrate is surrounded by bulky groups, because such groups interfere sterically with the S_N2 reaction and also because a highly substituted carbon forms a stable carbocation.

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed on these centers. Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions. Examples are enolate ion with oxygen and carbon as two nucleophilic centers, phenolate, cyanide, thiocyanide, nitrite ions, amides etc.

The product of an ambident nucleophilic reaction is mainly governed by two factors:

a) Polarizability of nucleophile

b) Nature of solvent

Other factors influencing the product distribution are counterion, concentration, temperature, pressure, leaving group, and steric hindrance etc.

As a general rule, in SN1 mechanism a carbocation intermediate is a hard acid that prefers to be attacked by a hard base. E.g. attack by oxygen of enolate. On the other hand for SN2 mechanism the carbon at reaction center is softer acid and would be preferably attacked by carbon atom of enolate ion.

In protic solvents, the more electronegative atom is better solvated through hydrogen bonding than the less electronegative atom. Thus, the less electro negative atom is more prone to attack. In contrast, polar aprotic solvents offer no stabilization to either end of the nucleophile however, they stabilize the substrate cation by solvation. As a result of this, the extent of attack by the more electronegative atom increases.

The leaving group and counter positive ion of the nucleophile also influences mechanism of reaction and therefore influences the major product formed. For the alkylation of 2-hydroxyl pyridine (enolate ion) when the reaction is carried out with K+ as the counter ion, a SN2 mechanism is favored and the soft reaction center N atom participates in the reaction. On the other hand, if instead of K+ the counter ion is Ag+ then due to the ability of Ag+ to coordinate with the leaving group iodide ion, the reaction was found to favor SN1 mechanism and therefore O-acylation product was obtained as the major product.

Steric hindrance at the nucleophilic center may become predominating factor to decide point of attachment to substrate. For e.g. the alkylation of phenol with RI gives O-alkylated product. However, when the reaction center is crowded as in 2,6-dimethyl phenol then, the para alkyl substitution leading to C-alkylation is favored over O-alkylation.