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Chapter 4: Alcohols and Alkyl Halides



Summary | Alcohols | Alky halides | Nucleophilic Substitution Reactions | Radical Substitution Reactions | Preparations of Alkyl Halides | Self Assessment | Quiz |


Nucleophilic Substitution reactions

Chapter 4: Alcohols and Alkyl Halides

Nucleophilic substitution at sp3 C
Nucleophilic substitution reactions are an important class of reactions that allow the interconversion of functional groups, for example R-OH ® R-Br.

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

Curly arrows for S<sub>N</sub>2
There are two fundamental events in these substitution reactions:
  1. formation of the new bond to the nucleophile
  2. breaking of the bond to the leaving group
Depending on the relative timing of these events, two different mechanisms are possible:

SN1 mechanism

SN1 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:

reaction coordinate diagram for a two step process 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.

reaction coordinate diagram for an S<sub>N</sub>1
General case
SN1 reaction

The following issues are relevant to the SN1 reactions of alcohols:

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

In an SN1 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 SN1 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 SN1 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 SN1 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

planar carbocation 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.

Nu can attack either face of a C+ giving products that are mirror images

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. 
 
 
 
 

 

Carbocations

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

[carbocation stability order]
This is because alkyl groups are weakly electron donating due to hyperconjugation and inductive effects. Resonance effects can further stabilize carbocations when present.

Structure:
 
A simple representation of a carbocation
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.
Computer model of CH3+

Reactivity:

electrostatic potential of CH3+ (side view) 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.
 

electrostatic potential of CH3+ (top view)

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 SN1
2. Eliminations via the E1
3. Additions to alkenes and alkynes (HX, H3O+)

 

 

SN2 mechanism

SN2 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.
 
 

reaction coordinate diagram for a concerted process 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.
 

reaction coordinate diagram for an S<sub>N</sub>2
General case
SN2 reaction

The following issues are relevant to the SN2 reactions of alcohols:

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

For alcohols reacting with HX, methyl and 1o systems are more likely to react via an SN2 reaction since the carbocations are too high energy for the SN1 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 SN2 reaction. More reactive nucleophiles will favor an SN2 reaction.

Stereochemistry
When the nucleophile attacks in an SN2 reaction,  it is on the opposite side to the position of the leaving group. As a result, the reaction will proceed with an inversion of configuration.
 
 
SN2 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. 
 

S<sub>N</sub>2 mechanism for the reaction of ROH with HX
Step 2:
Simultaneous formation of C-Br bond and cleavage of the C-O bond allows the loss of the good leaving group, a neutral water molecule, to give a the alkyl bromide. This is the rate determining step.


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