Nucleophilic addition reaction

The different reactions we learn in organic chemistry are not just limited to books. If you delve a little you will get to know these reactions happen in our common day to day life or it may be a part of the processes living organisms undergoes. Similarly, different nucleophile and the corresponding reactions help in the biological synthesis of compounds in metabolic processes of living organisms.

Browse more Topics under Aldehydes Ketones Carboxylic Acids

• Chemical Reactions and Uses of Carboxylic Acids
• Methods of Preparation of Carboxylic Acids
• Nomenclature and Structure of Carbonyl Group
• Nomenclature and Structure of Carboxyl Group
• Oxidation
• Physical properties of Aldehydes, Ketones and Carboxylic Acids
• Preparation of Aldehydes
• Preparation of Aldehydes and Ketones
• Preparation of Ketones
• Reactions due to Alpha-Hydrogen
• Reduction
• Uses of Aldehydes and Ketones

The reactions also form part of the pharmaceutical preparation processes in industries and academia. The reaction helps in the formation of new complex organic chemicals. Therefore, nucleophilic addition reactions are central to organic chemistry.

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Nucleophilic Addition Reactions

We will be able to convert multiple bonds into different functional groups with the help of addition reactions. The reaction will help to convert the unsaturated compounds to saturated and more functional species. In this topic, we will go through a series of very important reactions occurring due to nucleophilic addition reactions. Usually, electrophilic addition reactions take place in an alkene. Contrary to this, aldehydes and ketones undergo nucleophilic addition reaction.

Mechanism of Nucleophilic Addition Reaction

We know that carbonyl carbon demonstrates sp² hybridization and together the structure is coplanar. A nucleophile acts on the polar carbonyl’s electrophilic carbon atom perpendicular to the orbital demonstration sp² hybridization of the carbonyl carbon structure.

However, on the attack of the nucleophile, the hybridization of the carbon atom changes from sp² hybridization of sp³ hybridization thereby forming tetrahedral alkoxide intermediate complex. This intermediate complex will take a proton from reaction medium to produce an electrically neutral compound. Hence, the reaction results in the addition of nucleophile and hydrogen in the carbon-oxygen double bond.

Aldehyde and ketones demonstrate polar nature. Moreover, these compounds have a higher boiling point in comparison to hydrocarbons. However, aldehydes and ketones have lower boiling points in comparison to alcohols. The many reactions involving aldehydes and ketones are sufficient for different synthesis reactions.

However, the majority of characteristics reactions of aldehydes and ketones involve a nucleophilic addition to the carbonyl group. The general equation of the aldehyde and ketone are

Reactivity of Aldehydes and Ketones

Aldehydes are more reactive and readily undergo nucleophilic addition reactions in comparison to ketones. Aldehydes demonstrate more favourable equilibrium constants for addition reactions than ketones because of electronic and steric effect. In the case of ketones, two large substituents are present in the structure of ketones which causes steric hindrance when the nucleophile approaches the carbonyl carbon.

However, aldehydes contain one substituent and thus the steric hindrance to the approaching nucleophile is less. Moreover, electronically aldehydes demonstrate better reactivity than ketone. This is because ketones contain two alkyl groups which decrease the electrophilicity of carbonyl carbon atom more than aldehydes.

The rate determining step with respect to base-catalyzed nucleophilic addition reaction and acid-catalyzed nucleophilic addition reaction is the step in which the nucleophile acts on the carbonyl carbon.

However, protonation process occurs in the carbonyl oxygen after nucleophilic addition step in case of acid catalysis conditions. The carbocation character of carbonyl structure increases due to protonation and thus makes it more electrophilic. Various nucleophilic addition and nucleophilic addition-elimination reactions are

Addition of Hydrogen Cyanide (HCN)

Aldehydes and ketones undergo reaction with HCN to produce cyanohydrins. The reaction progresses very slowly by using pure hydrogen cyanide. Hence, base as a catalyst helps to speed up the reaction. This is because catalysis helps in the generation of cyanide ion (CN) which acts as a stronger nucleophile and adds to carbonyl compounds to produce the corresponding cyanohydrin. Cyanohydrins are important synthetic intermediates.

Mechanism of the Reaction

Due to the electronegativity difference in carbon atoms and oxygen atoms, the C=O bond demonstrates a polar behaviour. This, in turn, results in gaining of partial negative charge on the oxygen atom and partial positive charge on the carbon atom. The partial positive charge of the carbon atom will attract the cyanide ion of H⁺CN⁻. The double bond of C=O will break and a new C-CN bond development occurs. Furthermore, the unstable oxygen will attract the H⁺ of Hydrogen cyanide.

Addition of Sodium Hydrogen Sulphite

Addition of Sodium Hydrogen Sulphite to aldehydes and ketones will result in the formation of the addition of products. The equilibrium position of the reaction for aldehydes will be on the right-hand side but the equilibrium position of the reaction for will be on the left-hand side because of the steric effect.

The hydrogen sulphite compound form from the sodium hydrogen sulphite addition is water soluble. Therefore, it can be converted back to parent carbonyl compound by treatment of the compound with dilute mineral acid or alkali. The reaction is also useful for the purification and separation processes of aldehydes.

Addition of Alcohols

Aldehydes undergo reaction with the monohydric alcohol to produce hemiacetals or alkoxyalcohol intermediate. The hemiacetal will further undergo reaction with an alcohol to produce gem-dialkoxy compound or acetal. The reaction is carried out in the presence of dry hydrogen chloride. On application of similar conditions, ketone undergoes reaction with ethylene glycol to produce cyclic compounds or ethylene glycol ketals.

The dry hydrogen chloride present in the reaction protonates the oxygen atom present in the carbonyl structure thereby increasing the electrophilicity of the carbonyl carbon. Thus, it helps in the nucleophilic attack of ethylene glycol. Further hydrolysis of acetals and ketals with mineral acids (aqueous) will help in retrieval of respective aldehydes and ketones.

Let’s see few examples of aldehydes and ketones and the resulting acetals and ketals. Aldehyde reacts with dihydric alcohols (ethane-1,2-diol) to produce cyclic acetals.

Similarly, ketones react with dihydric alcohols to produce cyclic ketals. Dry HCl gas helps in shifting the equilibrium of the reaction to the right-hand side. Furthermore, hydrolysis of acetals and ketals and aqueous mineral acids help in retrieving the aldehydes and ketones.

Addition of Grignard Reagents

Grignard Reagents or R-MgX demonstrates polar nature. In this compound, the carbon atom is electronegative in nature and the Mg atom is electropositive in nature. The polar nature of the Grignard Reagents helps the compound reacts with aldehydes and ketone to produce additional products. The addition products undergo decomposition reaction to give alcohol with water or dilute sulphuric acid.

Necessary Points to Note in this Reaction

If Grignard Reagent reacts with formaldehyde (HCHO), the reaction will form primary alcohol as the product.

If the reagent reacts with aldehydes other than HCHO, the reaction will produce secondary alcohols.

Ketone reaction with the reagent will produce tertiary alcohols.

Addition of Ammonia and Derivatives

Many nucleophiles like ammonia and derivatives of ammonia (H₂N-Z) can also be added to the carbonyl group of aldehydes and ketones. The reaction of ammonia and its derivatives is reversible and the reaction happens in the presence of acid to form addition products. The reaction equilibrium will help the product formation because of fast dehydration of the intermediate complex. Thus, the reaction finally forms the compound >C=N-Z. In the structure >C=N-Z, Z can be alkyl, OH, aryl, NH₂, NHCONH₂, C₆H₅NH, etc.

Acid catalysts

Generally, we use weak acids as catalysts in the addition reaction of aldehydes and ketones with ammonia and its derivatives. The carbonyl group in aldehydes or ketone contains lone pair which reacts with weak acids. Refer to the example below. The product formed in the reaction will show resonance.

The resonance of the product will increase the positive charge on carbonyl carbon. This makes the carbon prone to a nucleophile attack thus favouring the reaction. However, the reaction is possible pH 4 to 5 only. Hence, the reaction is pH dependent.

The reason for a restricted pH is because if the pH is very low then the ammonia derivative will form their respective salts due to their basic nature and at the same time will lose their nucleophilic nature. If the pH is high then the carbonyl group will not be able to undergo sufficient protonation.

Few reactions with different derivatives of ammonia are given below

• NH₂OH (hydroxylamine)
• NH₂-NH₂ (hydrazine)
• C₆H₅NHNH₂ (phenylhydrazine)
• NH₂CONH₂ (Semicarbazide)

Hydroxylamine

Aldehydes and ketones undergo reaction with hydroxylamine (NH₂OH) and lead to the formation of oximes.

Hydrazine

Aldehydes and ketones undergo reaction with hydrazine (NH₂−NH₂) thereby forming hydrazones.  Additionally, aldehydes and ketones can also undergo reaction with phenylhydrazines (C₆H₅NHNH₂) to produce phenylhydrazones.

2,4-DNP Test

This test can produce different precipitate depending on the basis of compounds. Aldehydes and ketones can undergo reaction with 2,4-dinitrophenylhydrazine to form a yellow, orange or red precipitate. This reaction helps to differentiate and identify aldehydes and ketones from other compounds. The reaction is also known as 2,4-DNP test or Brady’s test.

Aliphatic aldehydes and ketones produce yellow precipitate upon reaction with 2,4-dinitrophenylhydrazine. We obtain red precipitate on the reaction of aromatic aldehydes and ketones.

Semicarbazides

Aldehydes and ketones undergo reaction with semicarbazide (NH₂CONH₂) to produce semicarbazones.

Solved Examples for You

Question: Formaldehyde reacts with ammonia to give a white solid, Hexamethylenetetramine (methenamine). Identify the correct formula of Hexamethylenetetramine

1. (CH₂)₆N₄
2. (CH₂)₃N₃(NO₂)₃
3. NH₂OH
4. N₂H₄

Solution: Option 1 (CH₂)₆N₄