Nucleophilic substitution will be explored in much more detail in chapter 8.

What does the term "nucleophilic substitution" imply ?

A nucleophile is an the electron rich species that will react with an electron poor species.
A substitution implies that one group replaces another

1. formation of the new bond to the nucleophile
2. breaking of the bond to the leaving group

• Bond breaking to form a carbocation preceeds the formation of the new bond : S_N1 reaction
• Simultaneous bond formation and bond breaking : S_N2 reaction

S_N1 mechanism

S_N1 indicates a substitution, nucleophilic, unimolecular reaction, described by the expression rate = k [R-LG]

This pathway is a multi-step process with the following characteristics:

• step 1: rate determining (slow) loss of the leaving group, LG, to generate a carbocation intermediate, then
• step 2: rapid attack of a nucleophile on the electrophilic carbocation to form a new s bond

	Multi-step reactions have intermediates and several transition states (TS).  In an SN1 there is loss of the leaving group generating an intermediate carbocation which then undergoes a rapid reaction with the nucleophile. The reaction profiles shown here are simplified and do not include the equilibria for protonation of the -OH.
General case		SN1 reaction

The following issues are relevant to the S_N1 reactions of alcohols:

Effect of R-
Reactivity order :   (CH₃)₃C-  >  (CH₃)₂CH-   >  CH₃CH₂-  >  CH₃-

In an S_N1 reaction, the key step is the loss of the leaving group to form the intermediate carbocation. The more stable the carbocation is, the easier it is to form, and the faster the S_N1 reaction will be. Some students fall into the trap of thinking that the system with the less stable carbocation will react fastest, but they are forgetting that it is the generation of the carbocation that is rate determining.

More about carbocations

-LG
The only event in the rate determining step of the S_N1 is breaking the C-LG bond. For alcohols it is important to remember that -OH is a very poor leaving. In the reactions with HX, the -OH is protonated first to give an oxonium, providing the much better leaving group, a water molecule (see scheme below).

Nu
Since the nucleophile is not involved in the rate determining step of an S_N1 reaction, the nature of the nucleophile is unimportant.  In the reactions of alcohols with HX, the reactivity trend of HI > HBr > HCl > HF is not due to the nucleophilicity of the halide ion but the acidity of HX which is involved in generating the leaving group prior to the rate determining step.

Stereochemistry

In an SN1, the nucleophile attacks the planar carbocation. Since there is an equally probability of attack on either face there will be a loss of stereochemistry at the reactive center and both possible products will be observed.

Since a carbocation intermediate is formed, there is the possibility of rearrangements (e.g. 1,2-hydride or 1,2-alkyl shifts) to generate a more stable carbocation (see later).  This is usually indicated by a change in the position of the halide compared to that of the original -OH group, or a change in the carbon skeleton of the product when compared to the starting material.
 

SN1 MECHANISM FOR REACTION OF ALCOHOLS WITH HBr Step 1: An acid/base reaction. Protonation of the alcoholic oxygen to make a better leaving group. This step is very fast and reversible.  The lone pairs on the oxygen make it a Lewis base.        Step 2: Cleavage of the C-O bond allows the loss of the good leaving group, a neutral water molecule, to give a carbocation intermediate. This is the rate determining step (bond breaking is endothermic)          Step 3: Attack of the nucleophilic bromide ion on the electrophilic carbocation creates the alkyl bromide.

Stability:
The general stability order of simple alkyl carbocations is: (most stable) 3^o > 2^o > 1^o > methyl (least stable)

Structure:
 

Alkyl carbocations are sp2 hybridized, planar systems at the cationic C center.  The p-orbital that is not utilized in the hybrids is empty and is often shown bearing the positive charge since it represents the orbital available to accept electrons.

Reactivity:

As they have an incomplete octet, carbocations are excellent electrophiles and react readily with nucleophiles. Alternatively, loss of H+ can generate a p bond.  The electrostatic potential diagrams clearly show the cationic center in blue, this is where the nucleophile will attack.

Rearrangements:
Carbocations are prone to rearrangement via 1,2-hyride or 1,2-alkyl shifts if it generates a more stable carbocation

Reactions involving carbocations:
1. Substitutions via the S_N1
2. Eliminations via the E1
3. Additions to alkenes and alkynes (HX, H₃O⁺)

S_N2 mechanism

S_N2 indicates a substitution, nucleophilic, bimolecular reaction, described by the expression rate = k [Nu][R-LG]

This pathway is a concerted process (single step) as shown by the following reaction coordinate diagrams, where there is simultaneous attack of the nucleophile and displacement of the leaving group.
 
 

	Single step reactions have no intermediates and single transition state (TS).  In an SN2 there is simultaneous formation of the carbon-nucleophile bond and breaking of the carbon-leaving group bond, hence the reaction proceeds via a TS in which the central C is partially bonded to five groups.  The reaction profiles shown here are simplified and do not include the equilibria for protonation of the -OH.
General case		SN2 reaction

The following issues are relevant to the S_N2 reactions of alcohols:

Effects of R-
Reactivity order :  CH₃-  >  CH₃CH₂-  >  (CH₃)₂CH-  >  (CH₃)₃C-

For alcohols reacting with HX, methyl and 1^o systems are more likely to react via an S_N2 reaction since the carbocations are too high energy for the S_N1 pathway to occur.

-LG
Once again the leaving group is a water molecule formed by protonation of the -OH group. -OH on its own is a poor leaving group.

Nu
Since the nucleophile is involved in the rate determining step, the nature of the nucleophile is very important in an S_N2 reaction. More reactive nucleophiles will favor an S_N2 reaction.