What are Oxygen Nucleophiles? 

Oxygen being an electron rich species with a lone pair electron, can act as a good nucleophile. Typically, oxygen nucleophiles can be found in these compounds- water, hydroxides and alcohols. 

What are Nucleophiles?

In organic chemistry, a nucleophile is a species which is electron rich and forms a bond with an electrophile which means that in order for an atom/molecule to be nucleophilic, it has to possess a negative charge or a partial negative charge.   

A nucleophile refers to an electron-rich species which has an affinity towards any positively charged species (i.e., electrophiles) and is able to form bonds readily with the electrophile.

Nucleophilicity 

The comparison of the nucleophilic character of various nucleophiles is known as the nucleophilicity. It is basically the nucleophilic strength of that species. 

Nucleophiles undergo a set of characteristic reactions called the nucleophilic substitution reactions wherein an electron rich nucleophile is seen attacking a positively charged entity (or partial positively charged entity) and forms a bond with it leading to replacement of a certain ‘leaving group’. 

Coming to oxygen nucleophiles, we are aware that oxygen belongs to group VI of the periodic table and hence possess at least one lone pair of electrons in a lot of compounds they are present in. Since that they are electron rich species, they are nucleophiles. Further, these nucleophiles are capable to donate the electrons towards bond formation and during this process, they also act as Lewis bases. 

Typically oxygen nucleophiles can be observed in water, hydroxides and alcohols.

Note-  Water, itself, is a weak nucleophile, therefore, it is often present in necessary acidic or basic conditions to facilitate the reactions whereas hydroxides are strong nucleophiles.  

One set of nucleophilic substitution reactions are called ‘solvolysis’ where the nucleophile acts as a solvent. The solvolysis reactions with water as the nucleophilic solvent are collectively called ‘hydrolysis’. Hydrolysis reactions result in the formation of two fragments from one substrate (initial substrate is hydrolysed to form two fragments).  

Examples- Amide gets hydrolysed to give amine and carboxylic acid, esters get hydrolysed to give carboxylic acid and alcohol. 

The solvolysis reactions with alcohol as the nucleophilic solvent are collectively called ‘alcoholysis’. Example includes alcoholysis of methanol with triglycerides giving glycerol and methyl ester of the fatty acid. 

We know that carbonyl compounds (aldehydes/ketones) are subjected to a number of nucleophilic addition reactions and one of them is the reaction with hydroxide (water) to yield hydrates and upon reaction with alcohols yield acetals and hemiacetals. 

Hydrates 

• Carbonyl compounds react with water under acidic conditions and form hydrates. 

Note- Any substance in union with water forms the respective hydrate. 

• As previously mentioned, water is a weak nucleophile. So, it is necessary to have acidic conditions.  
• The formation of hydrates from carbonyl compounds is an example of a nucleophilic addition reaction.  
• When water (in acid medium) is involved, the reaction proceeds with the formation of the activated carbonyl group (the oxygen of the carbonyl group gets protonated). But, when hydroxide is involved, the reaction proceeds without the need for the formation of an activated carbonyl group and rather proceeds via an alkoxide intermediate. This is because of the fact that hydroxide is a stronger nucleophile than water. 
• Hydrates are too unstable and they exist in constant equilibrium with the initial compound. 
• The product that is formed is a hydrate with 2 diol groups attached to the same carbon and is hence called a germinal diol (gem-diol). 

Acetals and Hemiacetals

• When the nucleophilic addition reaction of a carbonyl compound is facilitated by an alcohol, acetals and hemiacetals are formed. 

• Hemiacetal is only an intermediate in the formation of an acetal but is of equal significance. 

• An acetal is formed when the starting carbonyl compound is an aldehyde whereas a ketal is formed when the starting compound in ketone. 

• The kind of product formed upon alcohol reacting with a carbonyl compound depends on the amount of alcohol added. If excess alcohol is added, the product formed will be an acetal and if a stoichiometric amount of alcohol is added, the product is a hemiacetal. 

Mechanism of Formation of Acetal and Hemiacetal 

1. The acid catalyst (H⁺) protonates the oxygen of the carbonyl group due to its polarity.  This step is called activation of the carbonyl group. 

2. The nucleophile (which is the oxygen atom of the alcohol), donates its lone pair of electrons to the carbon (the carbonyl carbon). A bond is now formed between the oxygen and carbon. To satisfy carbon’s valency, the pi bond between the carbon and oxygen in the carbonyl breaks and the oxygen ends up with a lone pair of electrons. 

3. The nucleophilic oxygen of alcohol now gets a positive charge and loses a proton to claiming back its lone pair of electrons. As a result, a hemiacetal is now formed. 

4. Further, the hemiacetal’s -OH donates its electrons to a proton  H⁺ and goes on to form water and exits the reaction.  

5. Further, the oxygen from the -OR uses the lone pair on its oxygen to form a pi bond between its oxygen and carbon. To this carbon, the oxygen of another alcohol molecule binds and it loses a proton to yield an acetal. 

Key takeaways         

• What makes oxygen nucleophilic? 
• What compounds possess nucleophilic oxygen? (classification) 
• Significance of oxygen nucleophiles. 

• Some important reactions involving oxygen nucleophiles. 
• Applications  

Context and Applications 

This topic is a prerequisite for the completion of certain undergraduate and graduate courses, especially for Bachelors and Masters of Chemistry and Biochemistry as well as in Chemical Engineering. 

Practice Question 

Q. We know that carbonyl compounds (aldehydes and ketones) contain a carbon in the carbonyl groups which is electrophilic since the oxygen is highly electronegative, it polarises the bond and attracts the electron density towards itself. But however, it is established that it is the carbon that is nucleophilic and not the oxygen. So, the alpha carbon of enols and enolates presents itself as nucleophilic, we know. What causes this low reactivity of oxygen? Shouldn’t the oxygen carbon pi bond be easily susceptible to attacks by reagents? 

Answer-  

During the conversion of the carbonyl compound from keto to enol / enolate form, it results in the formation of an intermediate wherein the alpha carbon acts as a nucleophile.  

The oxygen of the carbonyl group does act as a nucleophile but it is strongly dependent on the conditions of the reaction. In addition, enolates can react as a nucleophile through either the α -carbon or the oxygen. This depends on the kind of electrophile involved and the solvent used.