Nucleophilic Substitution

In chemistry, nucleophilic substitution is a type of chemical reaction in which one nucleophile electron donor replaces another as a covalent substitute of some atom. In the examples given here, this is a carbon atom, but this is far from the only possibility.

An example of nucleophilic substitution is the hydrolysis of an alkyl bromide, R-Br, under alkaline conditions, where the attacking nucleophile is the OH^- and the leaving group is Br^-.

R-Br + OH^- → R-OH + Br^-

In 1935, Edward D. Hughes and Sir Christopher Ingold proposed a theory proposing that there were two mechanisms at work, both of them competing with each other. The two main mechanisms of nucleophilic substitution are called S_N1 and S_N2. S stands for chemical substitution, N stands for nucleophilic, and the number represents the kinetic order of the reaction.

S_N2

In the S_N2 reaction, the addition of the nucleophile and the elimination of leaving group take place simultaneously somewhat similarly as in the case of the E2 mechanism.

S_N2 occurs where the central carbon atom is easily accessible to the nucleophile. When the central carbon is too highly substituted, steric hindrance is so strong that SN2 is rendered close to impossible. The rate is second order, depending on both the nucleophile and the substrate concentrations. The nucleophile enters on the opposite side of the carbon to the leaving group, so a stereocenter is inverted by an SN2 reaction. Thus SN2 has the following specificities.

• It is a one-step process of substitution.
• Typical of methyl and primary substituted halides due to low steric hindrance. (Secondary substituted reacts only when with a strong nucleophile).
• The reaction rate is influenced by both the substrate and the nucleophile. :rate = k[RX][Nu^-]
• Stereospecificity when the carbon is chiral.

eg. CH₃Br + OH^- → CH₃OH + Br^-

The carbon hybridization of the certain alkyl halide goes from sp³ to sp² and then back to sp³ during the transition state. Such hybridization draws similarity with the E2 mechanism.

S_N1

S_N1 tends to be important when the central carbon atom is surrounded by bulky groups, both because such groups interfere sterically with the SN2 reaction (discussed above) and because highly substituted central carbon forms stable carbocations (the first reaction in the scheme below).

Contrary to S_N2, S_N1 reaction takes place in two steps. The rate of the overall reaction is essentially equal to that of carbocation formation, which does not involve the attacking nucleophile. Thus the overall rate depends on the concentration of the substrate only. S_N1 has the following specificities.

• It is a two-step process of substitution. The first step is rate-determining
• Typical of tertiary and some secondary substituted halides due to high steric hindrance. (Secondary substituted reacts only when with a weak nucleophile)
• The reaction rate is influenced only by the substrate concentration. :rate = k[RX]

1. (CH₃)₃CBr --> (CH₃)₃C⁺ + Br^-
2. (CH₃)₃C⁺ + H₂O --> (CH₃)₃C-OH₂⁺
3. (CH₃)₃C-OH₂⁺ + H₂O --> (CH₃)₃COH + H₃O⁺

This gives the overall reaction

(CH₃)₃C-Br + OH^- → (CH₃)₃C-OH + Br^-

Because the intermediate carbocation, R⁺, is planar, the central carbon is not a stereocenter, even if it was a stereocenter in the original reactant, so the original configuration at that atom is lost. Nucleophilic attack can occur from either side of the plane, so the product may consist of a mixture of two stereoisomers in the event of the molecule chirality. In fact, if the central carbon is the only stereocenter in the reaction, racemization will occur.

The nucleophile

The nucleophile by definition acts as a Lewis base. Even though, the nucleophile is often an anion there are exceptions. Neutral nucleophilic reactions such as with alcohols ROH and water HOH are named solvolysis. Nucleophilicity nucleophile strenght represent how fast a Lewis base replaces a leaving group. Anions are stronger nucleophile than neutral ions. Also, the more basic is the ions (high pK_a) the more reactive they are. Polarizability is also important in the determination of the nucleophilicity. Larger atoms contain more electrons; therefore distortion is easier so they are more nucleophilic. eg. I^- is more nucleophilic than F^-

Example

In the example below, the oxygen of the hydroxide ion donates an electron to bond with the carbon at the end of the bromopropane molecule. The pair of electrons in the carbon-bromine bond is given up to the bromine, which leaves as the bromide ion Br^-:

- - - - - - Taken from section nucleophile

Reaction rate

Initially, the rate of the nucleophilic substitution was a little puzzling as the rate followed the pattern :

CH₃X > primary > secondary < tertiary

The reaction kinetics changed from second order to first order.

The S_N1 and S_N2 reactions are influenced by different factors

S_N1 reactivity rates follow the trend CH₃X < primary < secondary < tertiary

S_N2 reactivity rates follow the trend CH₃X > primary > secondary > tertiary

The total reactivity is the sum of the two rates.

File:Sn2 Sn1 Graph.png

A graph showing the relative reactivities of the different alkyl halides towards S_N1 and S_N2 reactions.