Nucleophilic Substitution Reaction

Core Concepts

In this article, you will learn about different types of the nucleophilic substitution reaction and how the nucleophilic substitution mechanism works. We’ll also cover what distinguishes SN2 vs. SN1, with some practice problems for you at the end!

Topics Covered in Other Articles

Important Vocabulary

Nucleophile – a negatively-charged group that searches for a positive charge (nucleophilic translates to nucleus lover!)
Electrophile – a positively-charged group that searches for a negative charge (electrophile translates to electron lover!)
Leaving Group – a group attached to the main carbon that leaves the molecule in a substitution reaction
Nucleus – the positively-charged center of an atom
Bimolecular – a reaction whose rate depends on the concentrations of two or more reactants
Unimolecular – a reaction whose rate depends on the concentration of one reactant

What is the Nucleophilic Substitution Reaction?

Nucleophilic substitution is an organic chemistry reaction that involves an electron-rich (negatively-charged) nucleophile and an electron-deficient (positively-charged) electrophile. In this reaction, the electron-rich nucleophile attacks an electron-deficient atom, replacing one of its functional groups. After the nucleophile bonds with the electrophile, a functional group becomes the leaving group.

These reactions are driven by electronegativity, where the nucleophile seeks a positive nucleus to negate its high negative charge. With an electron-rich lone pair, the nucleophile is unstable independently. As the nucleophile is most stable when bonded to an electrophile, the nucleophile always initiates the attack and starts the reaction.

Nucleophilic Substitution Mechanism

For a nucleophilic substitution, the reaction must include a negatively-charged group and a positively charged group (usually an sp3-hybridized carbon atom). This mechanism can be considered similar to Bronsted-Lowry Acid-Bases: a proton acceptor and a proton donor. The positively charged group must also be attached to a potential leaving group, as more than four single bonds on a carbon atom create an unstable molecule.

During a nucleophilic attack, the reaction can be either unimolecular or bimolecular. Also, based on whether the molecule is an R or S-enantiomer, a backside nucleophilic attack can result in an inversion or retention of configuration. Thus, these characteristics are the difference between an SN1 and SN2 mechanism – two different forms of nucleophilic substitution reaction.

SN1 vs. SN2 Reactions

Shown below is an example of a unimolecular SN1 reaction:

An SN1 Nucleophilic Substitution Reaction — An SN1 Reaction

In this SN1 reaction, the leaving group detaches from the main molecule, forming a carbocation reactionary intermediate. An SN1 reaction is unimolecular, meaning the reaction rate depends on one reactant’s concentration. After the leaving group detaches from the molecule, the nucleophile attacks the compound and forms the product.

Moreover, after the nucleophile forms the product, all stereospecificity is lost, meaning that the direction the nucleophile attacks in doesn’t matter. Through this SN1 reaction, the product was formed with nucleophilic attack that did not alter the molecule’s stereochemistry.

Shown below is an example of a bimolecular SN2 reaction:

An SN2 Nucleophilic Substitution Reaction — An SN2 Reaction

Unlike an SN1 reaction, an SN2 reaction begins with the nucleophilic attack. The nucleophile attacks the carbon from the backside. As the nucleophile forms bonds with the carbon, a transition state forms where the leaving group breaks its bond and leaves the molecule. Finally, the leaving group then detaches, thus forming the final product; the molecule’s stereochemistry becomes inverted from the nucleophile’s backside attack.

The main differences between SN1 and SN2 reactions is how and when the nucleophile attacks – such as whether the leaving group detaches first or once the nucleophile attacks. The SN1 reaction is a unimolecular reaction that depends only on the nucleophile’s concentration. The SN2 reaction is a bimolecular reaction that depends on both the nucleophile and electrophile’s concentrations. Also, within the products, the SN2 reaction creates an inverted chemical structure, and affects the molecule’s stereochemistry, while the SN1 maintains the original stereochemistry.

Different Types of Nucleophilic Substitution

Along with the processes behind SN1 vs. SN2, nucleophilic substitution reactions can be further categorised into what molecular groups are being substituted. Subsequently, we will cover two different nucleophilic substitution reactions involve the acyl group and the aromatic ring group.

Nucleophilic Acyl Substitution

As another example, nucleophilic acyl substitution involves a nucleophile reacting with an acyl group, and leaving behind a carbonyl compound. This reaction can proceed in both acidic and basic conditions, and involves both SN1 and SN2.

Shown below is an example of a nucleophilic acyl substitution occurring within acidic conditions, where the acyl group is first protonated by the acidic conditions.

Acyl Substitution

Nucleophilic Aromatic Substitution

Another example of a nucleophilic acyl substitution involves an aromatic ring functional group. Similarly to an acyl substitution, an aromatic ring substitution involves a substituent on an aromatic ring being replaced with the nucleophile. The nucleophile attacks any carbon on the aromatic ring and then replaces the leaving group. Aromatic substitutions usually undergo SN2 substitution, as an aromatic ring intermediate is too reactive and possesses too high energy to be formed. In conclusion, every aromatic substitution begins with a nucleophilic attack and is a multi-step process.

Shown below is an example of a nucleophilic aromatic substitution.

Review Problems

As we’ve covered key concepts behind nucleophilic substitution reactions and their variations, try some of these practice problems below. Solutions are also attached, and be sure to check your answers!

In an SN1 mechanism, what reactionary intermediate remains after the leaving group detaches?
What kind of nucleophilic substitution mechanism is the reaction of 1-fluoro-4-nitrobenzene with sodium methoxide?
Would a carboxylic acid group (R’-COOH) act as a strong or weak nucleophile?

Answers:

A Carbocation Intermediate – As the carbocation has a positive charge on the carbon atom, this thus creates an unstable and reactive substance.
Nucleophilic Aromatic Substitution – the reaction of an aromatic ring group (1-fluoro-4-nitrobenzene) with a strong nucleophile (sodium methoxide).
A Weak Nucleophile – as a polar protic solvent, carboxylic acid is not a strong nucleophile due to its H+ proton. However, in some reactions, carboxylic acid can still behave as a nucleophile.