Nucleophilic Addition Reactions

What is Nucleophilic Addition Reaction?

Nucleophilic addition reaction is simply a chemical addition reaction in which a nucleophile creates a sigma bond (σ) with an electron-deficient species. Such reactions are considered to be very important in organic chemistry because they enable the conversion of carbonyl groups into several functional groups. In general, nucleophilic addition reaction of carbonyl compounds take place by the following steps-

  • Electrophilic carbonyl carbon forms a sigma bond with the nucleophile.

  • The carbon-oxygen pi bond is then broken, forming an alkoxide intermediate (the bond pair of electrons are passed to the oxygen atom).

  • The subsequent protonation of the alkoxide results in a derivative of alcohol.

The carbon-oxygen dual bond is specifically attacked by strong nucleophiles to give rise to an alkoxide. However, where weak nucleophiles are used, the carbonyl group must be activated, seeking the help of an acid catalyst for a nucleophilic addition reaction to happen.

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Here, the carbonyl group has a coplanar structure, and its carbon is sp2 hybridized. Although, the attack of the nucleophile on the C=O group results in the breakage of the pi bond. Now, the carbonyl carbon is sp3 hybridized and forms a sigma bond with the nucleophile. As represented above, the resulting alkoxide intermediate has a tetrahedral geometry.

Why Does Carbonyl Compounds Undergo Nucleophilic Addition?

The carbon-oxygen bond is polar in nucleophilic addition of carbonyl compounds. Owing to the relatively higher electronegativity of the oxygen atom, the electron density becomes higher near the oxygen atom. This results in generating a partial negative charge on the oxygen atom and a partial positive charge on the carbon atom.

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Because carbonyl carbon holds a partial positive charge, it behaves like an electrophile. The partial negative charge on the oxygen atom can stabilize by introducing an acidic group. The proton is donated by the acid to the carbonyl oxygen atom and neutralizes the negative charge.

Relatively, aldehydes are more reactive to nucleophilic addition reactions compared to ketones. This is because the adjacent R groups stabilize the secondary carbocations formed by the ketones. The primary carbocations produced by aldehydes are less stable than secondary carbocations formed by ketones and are thus more vulnerable to nucleophilic attacks.

Mechanism of Nucleophilic Addition Reaction of Carbonyl Compounds

The general mechanism of nucleophilic addition reaction involved in two steps.

Step 1 - Nucleophilic attack on carbonyl

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Step 2 - Leaving group is removed

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Even though nucleophilic addition to aldehydes and ketones contain a carbonyl, their chemistry is different in a distinct manner because they don’t contain a suitable leaving group. Once the tetrahedral intermediate forms, both aldehydes and ketones cannot reform carbinyl. Due to this, aldehydes and ketones typically undergo nucleophilic additions, but no substitutions.

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The relative reactivity of carboxylic acid derivatives to nucleophilic substitution is related to the ability of the electronegative group to activate carbonyl. The more electronegative leaving groups withdraw the electron density from carbonyl, increasing its electrophilicity thereby.

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Nucleophilic Addition Reaction of Aldehyde and Ketone

Aldehydes are highly reactive and readily undergo nucleophilic addition reactions compared to ketones. Aldehydes demonstrates many favourable equilibrium constants for addition reactions than ketones due to the electronic and steric effect.

Aldehydes present more favorable equilibrium constants for additional reactions than ketones due to electronic and steric results. Concerning the ketones case, two large substituents contain in the ketone structure, which causes steric hindrance when the nucleophile approaches the carbonyl carbon.

After all, aldehydes comprise one substitute, and thus the steric hindrance to the approaching nucleophile is comparatively less. In contrast, electronically aldehydes exhibit better reactivity than ketone. It is because ketones contain two alkyl groups that reduce the carbonyl carbon atoms' electrophilicity rather than aldehydes.

The rate-determining step with regards to the base-catalyzed nucleophilic addition reaction and the acid-catalyzed nucleophilic addition reaction is the step, wherein the nucleophile works on carbonyl carbon.

Moreover, the protonation process happens in carbonyl oxygen after a nucleophilic addition step in the case of acid catalysis conditions. The carbocation character of the carbonyl structure increases due to protonation and thus makes it further electrophilic.

Reactions of Grignard Reagents with Aldehydes and Ketones

Grignard reagent has a formula - RMgX. 

Where ‘X’ is a halogen, and ‘R’ is an aryl or alkyl (depending on a benzene ring) group. For instance, we shall take R to be an alkyl group.

A typical Grignard reagent might be CH3CH2MgBr.

Preparation of a Grignard Reagent

All grignard reagents are made by adding halogenoalkane to little bits of magnesium in a flask with ethoxyethane (called either “diethyl ether” or just "ether"). The flask is fitted with a reflux condenser, and the mixture is warmed at a water bath for 20 - 30 minutes.

CH₃CH₂Br + Mg \[\overset{ethoxy ethane}{\rightarrow}\] CH₃CH₂MgBr

It is to note that everything must perfectly be dry because Grignard reagents can undergo reactions with water.

Any reactions using the Grignard reagent are carried out with mixture formed from this reaction and we cannot separate it out in any other ways.

These are the reactions of the double bond carbon-oxygen, and therefore aldehydes and ketones react in just the same way - all these changes are the groups that happen to attach with the carbon-oxygen double bond. All these changes are groups that happen to be attached to the double bond of carbon-oxygen.

It's easier to understand what's going on when looking closer at the general case (using ‘R’ groups instead of specific groups). And then, slotting in various real groups as and when you need to. Also, the ‘R’ groups can be either hydrogen or alkyl in any combination.

The Grignard reagent adds across the carbon-oxygen double bond in the first stage, as seen below.

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Then, the dilute acid is added to this to hydrolyse it.

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Therefore, alcohol is formed. One of the significant uses of Grignard reagents is the ability to produce complicated alcohols easily.

Which type of alcohol you get depends on the carbonyl compound you started with, it means what R and R' are.

FAQ (Frequently Asked Questions)

1. Explain Nucleophilic Addition Reaction with Monohydric Alcohols?

Aldehydes and ketones undergo nucleophilic external reactions with monohydric alcohols to create hemiacetals. The acetal is obtained following a further reaction with another molecule of alcohol. Because alcohols are weak nucleophiles, the reaction needs an acid catalyst to activate the carbonyl group towards a nucleophilic attack.

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The reason being the hemiacetals can undergo hydrolysis to produce reagents (alcohol and carbonyl compounds), the water produced during the reaction needs to be removed. During this reaction, carbonyl oxygen is protonated due to the nucleophilic attack by alcohol. Now, the nucleophilic alcohol is deprotonated to produce the hemiacetal. The same reaction can be repeated to obtain acetal.

2. Explain the Nucleophilic Reaction with Primary Amines.

The reaction between the primary amines and aldehydes or ketones generates imine derivatives along with water. The same can be seen below.

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Firstly, the nucleophilic nitrogen of the amine attacks carbonyl carbon. The carbon-oxygen double bond is thus broken, and a new sigma bond of carbon-nitrogen is formed. The proton is now being transferred from the amine to the oxygen atom. In the next step of this nucleophilic addition reaction, the OH group is further protonated, and the water is removed.

Now, the carbon atom forms a double bond with the nitrogen that belongs to the amine. This nitrogen is now deprotonated to afford the necessary imine product.