Nucleophilic Substitution Reactions

How do we get from a halogenoalkane to a molecule such as an alcohol, nitrile or amine? These are all examples of nucleophilic substitution reactions.

• This article is about nucleophilic substitution reactions in organic chemistry.
• We'll define nucleophilic substitution before looking at the differences between nucleophilic and electrophilic substitution reactions.
• After that, we'll turn our attention to halogenoalkane nucleophilic substitution reactions, focusing on their mechanism and reactivity.
• We'll then consider stereochemical aspects of nucleophilic substitution reactions.
• This will be followed by examples of nucleophilic substitution reactions. These include reactions with the hydroxide ion, the cyanide ion, ammonia, and silver nitrate solution.
• We'll end by discussing the importance of nucleophilic substitution reactions.

Nucleophilic substitution reaction definition

Let's break the term nucleophilic substitution down a little. First, substitution.

Next, let's look at nucleophilic. It refers to nucleophiles.

Nucleophiles are chemical species that react by donating a lone pair of electrons to an electron-deficient species to form a covalent bond. Nucleophiles are all negatively or partially negatively charged (which we represent using the delta symbol, δ) and feature a lone pair of electrons.

By looking more closely at the term nucleophile, we can form a picture of what these species actually are. -phile comes from the Greek word philos, which means to love, and nucleo- refers to nuclei, which are the positively charged areas of atoms. Therefore, nucleophiles must ‘love’ positive regions - they are attracted to them.

Examples of nucleophiles include:

• The cyanide ion, :CN^-.
• The hydroxide ion, :OH^-.
• Ammonia, NH₃.

Difference between nucleophilic and electrophilic substitution reactions

You'd be forgiven for getting nucleophilic substitution mixed up with a similar term: electrophilic substitution. Whilst the two types of reactions have some features in common, they involve very different species. It is important that you know the difference between them:

• Nucleophilic substitution reactions involve an attack by a nucleophile, an electron-pair donor.
• Electrophilic substitution reactions, on the other hand, involve an attack by an electrophile, an electron-pair acceptor.

Examples of electrophiles include:

• Hydrogen halides, HX.
• The nitronium ion, NO₂⁺.

However, both nucleophilic substitution and electrophilic substitution are still examples of substitution reactions. This means that they swap one functional group in an organic molecule for a different functional group.

Halogenoalkane nucleophilic substitution reactions

We know that halogenoalkanes are polar molecules (explore Halogenoalkanes to refresh your memory). Because the halogen atom in the C-X bond is a lot more electronegative than the carbon atom, it attracts the shared pair of electrons towards itself. Electrons are negatively charged. This makes the halogen atom partially negatively charged and leaves the carbon partially positively charged.

C-X bond polarity. StudySmarter Originals

Nucleophiles, which we now know ‘love’ positive regions, can attack this partially charged carbon atom, in an example of a nucleophilic substitution reaction.

Halogenoalkane nucleophilic substitution reaction mechanism

Nucleophilic substitution reactions of halogenoalkanes all follow one of two similar mechanisms. The mechanism used depends on the classification of the halogenoalkane.

• Primary halogenoalkanes react using an SN₂ mechanism. The S stands for substitution, the N stands for nucleophilic, and the number 2 lets us know that the initial reaction step involves two species: the halogenoalkane and the nucleophile.
• Tertiary halogenoalkanes react using an SN₁ mechanism. Once again, the S and N stand for substitution and nucleophilic, but this time the number 1 tells us that the initial reaction step involves just one species: the halogenoalkane itself.
• Secondary halogenoalkanes use a mixture of both the SN₁ and the SN₂ mechanisms.

The overall equation for both mechanisms is the same:

RCH₂X + Nu^- → RCH₂Nu + X^-

Stereochemical aspects of nucleophilic substitution reactions

Above, we saw how nucleophilic substitution can have an SN₁ or SN₂ mechanism. These two different mechanisms produce products with different stereochemical aspects:

• SN₂ mechanisms produce just one product. The bonds in this product are inverted compared to the bonds in the original reacting molecule.
• SN₁ mechanisms produce two enantiomers. Enantiomers are stereoisomers with the same structural formulae but different arrangements of atoms around a central carbon. These two enantiomers are produced in a 50:50 mixture known as racemic mixture, or a racemate.

We've shown these stereochemical aspects using a halogenoalkane nucleophilic substitution reaction:

Stereochemical aspects of the products of nucleophilic substitution reactions. StudySmarter Originals

Notice how in the SN₂ mechanism above, the bonds in the product are inverted compared to the original reacting molecule. Compare this to the SN₁ mechanism, which produces two different enantiomer products. One of the products is inverted, whilst the other keeps the original arrangement of bonds.

Examples of nucleophilic substitution reactions

Let's now move on to examples of nucleophilic substitution. We'll focus on nucleophilic substitution reactions involving halogenoalkanes.

Halogenoalkanes can react with the hydroxide ion, cyanide ion and ammonia molecule in nucleophilic substitution reactions. These reactions all use either the SN₂ or SN₁ mechanism that we looked at earlier, depending on the classification of the reacting halogenoalkane. Remember:

• Primary halogenoalkanes use an SN₂ mechanism.
• Tertiary halogenoalkanes use an SN₁ mechanism.
• Secondary halogenoalkanes use both an SN₂ and SN₁ mechanism.

Nucleophilic substitution reaction with the hydroxide ion

Halogenoalkanes react with aqueous sodium or potassium hydroxide (NaOH or KOH) to form an alcohol (ROH) and a halide ion (X^-). Alcohols have the hydroxyl functional group (-OH) and are represented by the general formula C_xH_2x+1OH. The potassium/sodium ion acts as a spectator ion and is not shown in the mechanism.

Let’s look at the conditions for nucleophilic substitution with hydroxide ions. Halogenoalkanes do not readily mix with water, so ethanol is used as a solvent for the substitution reaction. The mixture is warmed under reflux to increase the rate of reaction:

• Warming the mixture increases the kinetic energy of the molecules. This means that not only do they move faster and so have more collisions, but on average they also have more energy when they collide. This means that they are more likely to have the activation energy needed for a reaction. There will be a higher proportion of successful collisions and thus a faster reaction.
• Reflux is a reaction technique that involves heating the mixture in a sealed vessel. When volatile components in the mixture evaporate, they are trapped in a condenser and cannot escape out of the system, and instead condense back into the container. We can reach higher temperatures and carry the reaction out over a longer period. This increases the opportunity for a successful reaction.

For example, bromoethane (CH₃CH₂Br) reacts with potassium hydroxide to form ethanol (CH₃CH₂OH) and a bromide ion. The bromide ion then reacts with the potassium ion to form potassium bromide. This can be shown by the following overall equation:

CH₃CH₂Br + KOH → CH₃CH₂OH + KBr

Another example is the nucleophilic attack of 2-chloro-2-methylpropane (CH₃CCl(CH₃)CH₃) by sodium hydroxide, forming 2-methylpropan-2-ol (CH₃COH(CH₃)CH₃) and sodium chloride. Here's the equation:

CH₃CCl(CH₃)CH₃ + NaOH → CH₃CCl(CH₃)CH₃ + NaCl

Nucleophilic substitution reaction with the cyanide ion

Potassium or sodium cyanide (KCN or NaCN) react with halogenoalkanes in ethanolic solution to form a nitrile (RCN) and a halide ion. Nitriles have the functional group -CN, which contains a C≡N triple bond. Once again, the reaction mixture is heated under reflux. This nucleophilic substitution reaction is important industrially as it increases the length of the carbon chain.

For example, chloromethane (CH₃Cl) heated in ethanolic potassium cyanide produces ethanenitrile (CH₃CN) and a chloride ion. The chloride ion then reacts with potassium to form potassium chloride. The overall equation is as follows:

CH₃Cl + KCN → CH₃CN + KCl

Nucleophilic substitution reaction with ammonia

The reaction between halogenoalkanes and an excess of ammonia (NH₃) produces a primary amine (RNH₂), a halide ion and an ammonium ion (NH₄⁺). Amines are ammonia derivatives, where one or more of the hydrogen atoms has been replaced by an alkyl group.

Ammonia, a primary amine and the ammonium ion. StudySmarter Originals

We saw earlier in the article that although ammonia is not a negative ion, it is still a nucleophile. It contains a partially negatively charged atom, N^δ-, with a lone pair of electrons. When the nitrogen atom donates its lone pair of electrons to the carbon atom, the nitrogen atom becomes positively charged. This isn’t great for the molecule - it wants to be neutral, as that’s a lot more stable. To solve this problem, it kicks out a hydrogen atom, but keeps the bonded pair of electrons. The hydrogen atom is now a positive ion, and reacts with a second molecule of ammonia to form a positive ammonium ion. This positive ammonium ion can then react with the bromide ion produced in the substitution reaction, forming an ammonium salt. Overall, the reaction requires two moles of ammonia for each mole of halogenoalkane.

The reaction is carried out heated in ethanolic solution, in a sealed container under pressure.

For example, bromoethane (CH₃CH₂Br) and ammonia react together to form ethanamine (CH₃CH₂NH₂), a bromide ion, and an ammonium ion. The ammonium ion reacts with the bromide ion to form an ammonium salt, ammonium bromide (NH₄Br):

CH₃CH₂Br + 2NH₃ → CH₃CH₂NH₂ + NH₄Br

Nucleophilic substitution reaction with silver nitrate solution

Let's now consider the reaction of halogenoalkanes with silver nitrate solution (AgNO₃(aq)) mixed with ethanol. We use this process to identify the halogen present in the halogenoalkane. The ethanol acts as a solvent and allows everything to dissolve, whilst the water in the silver nitrate solution acts as the nucleophile, producing an alcohol, a hydrogen ion (H⁺), and a halide ion (X^-). The halide ion then reacts with the silver nitrate to form a coloured precipitate, and the colour of the precipitate gives us the identity of the halogen.

Because this reaction produces a visible precipitate, it is a great way to compare the relative rates of reaction of different halogenoalkanes:

• Iodoalkanes produce a precipitate much faster than chloroalkanes. As we explored earlier in the article, this is because the C-X bond enthalpy decreases as you move down the halogen group in the periodic table, making the halogenoalkane more reactive and leading to a faster rate of reaction.
• Tertiary halogenoalkanes produce a precipitate much faster than primary halogenoalkanes. This is because tertiary halogenoalkanes use the SN₁ mechanism, whilst primary halogenoalkanes use the SN₂ mechanism. The SN₁ mechanism is a lot quicker than the SN₂ mechanism, leading to a faster rate of reaction.

Importance of nucleophilic substitution reactions

Finally, we'll discuss the importance of nucleophilic substitution reactions.

• They allow us to swap one functional group for another in certain organic molecules. This makes them important stepping stones in industrial processes.
• Particular nucleophilic substitution reactions, specifically the reaction with the cyanide ion (:CN^-), increase the length of the carbon chain. This is quite tricky in organic chemistry.