Substitution Reactions

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Substitution reactions are reactions that involve an electronegative or electron-withdrawing atom/group substituting another atom/group. The atom/group that is substituted is called the leaving group.

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


Electrophilic Substitutions

An electrophile is an electron poor species that acts as an electron acceptor in a reaction (thus acts as a lewis acid). In a electrophilic substitution occurs when an electrophile displaces a group on a molecule.

However, in Chemistry 123, the focus will be primarily on nucleophilic substitution reactions. Chemistry on electrophilic aromatic substitution will be discussed in detailed in Chemistry 204.


Nucleophilic Substitutions

A nucleophile is an electron rich species that donate electrons to a electrophile (therefore it is a lewis base). A nucleophile can be electrically neutral or it can be negatively charged, though a negatively charged species is generally more reactive than a neutral one (because it has a higher electron density). A nucleophile must have at least one lone pair to interact with the electrophile. Some good nucleophiles are thiolates, cyanides, alkoxides, halides and carboxylates. Alcohols and water make weaker nucleophiles because they are a weaker base.


What makes a "good" nucleophile? =

-Charge on the nucleophilic atom (OH- >H2O)

-Electonegativity of nucleophilic atom --> less electrophilic atoms share electrons better (OH- > F-)

-Bulkiness of Nucleophilic species ( less bulky nucleophiles can attack easier)

-Polarizability/size of nucleophilic atom ( SH- > OH- )


Consider the reaction

  • CH3Br + NaI --> CH3I + NaBr

In this case, I- is the nucleophile that donates electron density to the electrophile CH3Br.


There are two types of Nucleophilic Subsitutions SN1 and SN2 that concern us in Chemistry 123.


SN2

Bimolecular nucleophilic substitution abbreviated as SN2, involves the nuleophilic attack of on an electrophilic center and two molecules involved in the rate determining step.

The rate of reaction can be related by the second order kinetics

rate= k[Nu][E]

where [Nu] and [E] are the concentrations and k is the rate constant.

The nucleophilic attack and displacement of the leaving group occurs simultaneously to form a pentacoordinated transition state. The nucleophile attacks at a 180&deg angle, which gives the best overlap between the lone pairs of the nucleophile and &sigma* orbital of the C-X complex. The leaving groups is broken off in the opposite side. In light of this, if the backside of electrophile is sterically hindered, then SN2 reactions will not occur. Instead, SN1 or elimination reactions can take place.

For example:

  • SN2 displacement on tertiary compound is not possible.
  • SN2 nucleophilic attack will be faster on primary rather than secondary electrophiles because of less steric hinderance.

Furthermore, due to the backside attack, the stereochemistry of the new product will be the inverse of the original.


The weaker base the leaving group is the more stable it will be after it leaves. SN2 reactions are more favorable when the leaving group is a weak base because weaker bases (with a lower pKa) are more stable than stronger bases.

A CH3CH2F leaving group, for example, would not undergo substitution reactions as opposed to CH3CHI which would undergo substitution reactions readily. This because F2 are not as stable as I2.

SN1

SN1 indicates a substitution, nucleophilic, unimolecular R eaction, described by the expression rate = k [R-LG] (first order Kinetics). This implies that the rate determining step of the mechanism depends on the decomposition of a single molecular species(LG= Leaving group).

There are 3 steps that occur during an SN1 reaction:

  1. The leaving group leaves behind a carbocation (slow and reversible: rate determining step),
  2. The nucleophile attacks the carbocation
  3. If the nucleophile is neutral, then it will be deprotonated.

The formation of the carbocation causes the original stereochemistry of the carbon to be lost. Subsequent attack of the nucleophile is not stereochemically selective so a racemic mixture is formed as a result.

The following is a general reaction scheme of SN1 reaction:

Nu: + C-Lg --> Nu: C+Lg+ --> Nu-C + Lg

Where C is short a sp3 carbon of an alkane and Lg is the leaving group.

How does solvent effect the whether the reaction will be SN1 or SN2

A polar protic solvent will make nucleophiles less effective since the nucleophile will be stabilized by the solvent. A more stable nucleophile will have a lower tendency to undergo reactions. Polar Aprotic solvents like DMSO, THF, DMF favor the SN2 reactions.

For SN1 reactions a polar protic solvent is favoured because it stabilizes the carbocation intermediate. Water, alcohol, carboxylic acids, and amines are polar protic solvents.


Comparison of SN1 and SN2 Reactions
SN2 SN1
Preferred Nucleophile good, strong, nucleophile no effect
Preferred carbon centers 1&deg>2&deg>3&deg (unhindered) 1&deg
Preferred Solvent Polar Aprotic Polar Protic
Mechanism One rate determining step Two rate determining step
Leaving group good base(stable) good base(stable)
Stereochemistry reversed racemic mixture