An In-depth Overview on the Williamson Synthesis Concept

Williamson synthesis is an organic procedure that results in the production of ether from deprotonated alcohol and an organohalide. Alexander Williamson invented this organic reaction in the year 1850. It includes an SN2 reaction between an alkoxide ion and the main alkyl halide. This reaction is significant in organic chemistry history since it contributed to the discovery of the composition of ethers. After a well-defined introduction to Williamson synthesis,you must be curious about the concept. So, let’s begin with knowing the reaction mechanism.

General Reaction Mechanism

The following is the general response mechanism:

R-OΘ+R’ —   X    →  R -O- R’ + X¯

The reaction created when sodium ethoxide and chloroethane are used together to create sodium chloride, and diethyl ether is an illustration. The reaction produced is:

[Na]+[C2H5O] − + C2H5Cl → C2H5OC2H5 + [Na]+[Cl]−

Mechanism of Williamson Synthesis

An SN2 bimolecular nucleophilic substitution mechanism governs the Williamson ether synthesis reaction. A backside assault of an electrophile by a nucleophile arises in an SN2 reaction process in a coordinated process. For the SN2 reaction, a suitable leaving group that is significantly electronegative, often a halide, must be present.

The nucleophile in the Williamson synthesis is an alkoxide ion (RO) that attacks the electrophilic carbon, including the leaving group. It is usually an alkyl halide or an alkyl tosylate. Since secondary and tertiary leaving points continue as an elimination reaction, the leaving point must be the primary carbon. Due to the steric hindrance, this process does not promote the creation of bulky ethers such as di-tert butyl ether and instead favours the production of alkenes.

Which Alkyl Halides are Effective in the Williamson Ether Synthesis?

An SN2 reaction is used in the Williamson Ether Synthesis. Because the SN2 reaction occurs in a single step in which the nucleophile makes a “backside attack” on the alkyl halide, steric hindrance is the “major barrier” for the SN2 mechanism. The rate of the SN2 mechanism was most significant for methyl halides, followed by primary, secondary, and tertiary. The Williamson Ether reaction follows the same process.

Williamson works well with methyl and primary alkyl halides as substrates.

Silver Oxide Ether Synthesis

A variant of the Williamson ether synthesis substitutes silver oxide (Ag2O) for the solid base. Since a strong base and the creation of an alkoxide intermediate are not required in this version, the circumstances are gentler than in the conventional introduction to Willamson synthesis. This reaction effectively transforms -OH groups on sugars to ethers.

Alkoxymercuration for Ether Synthesis

An alkoxymercuration product is formed when an alkene reacts with an alcohol in the trifluoroacetate mercury (II) salt presence [(CF3CO2)2Hg]. Demercuration with sodium borohydride (NaBH4) produces ether. Generally, this reaction enables the Markovnikov additions of alcohol to an alkene to produce ether. It should be noted that the alcohol reactant is employed as the solvent, and trifluoroacetate mercury (II) salt is utilised instead of mercuric acetate. Most 1o, 2o, and 3oalcohols may be utilised effectively in this process.

Intramolecular Williamson Ethers

The Williamson synthesis can also be used to make cyclic ethers. You’ll need a molecule with a hydroxyl group on one carbon as well as a halogen atom upon another. This compound will then undertake an SN2 mechanism with itself, producing a halogen anion and a cyclic ether. Another method of obtaining ethers is to transform halo alcohols into cyclic ethers.

This reaction is triggered by the dissociation of the hydrogen linked to the oxygen from an OH- anion. This causes the halogen to leave, resulting in the formation of a halogen radical and a cyclic ether. Ring size is another element in deciding if a cyclic ether will develop. Three-membered rings are the quickest, following five-membered, six-membered, four-membered, and finally eight-membered rings. Both entropic and enthalpic factors impact the respective rates of ring formation.

Contributions of Entropy and Enthalpy

The significant enthalpy impact on ring formation is the ring strain, although it is not the only factor influencing formation. Rings with the most significant strain might develop the slowest if that was the case. Due to entropy circumstances, this is not the tendency for ring development. Smaller rings have less entropy, rendering them more advantageous due to less molecular ordering.

However, ring creation does not participate in this process due to another phenomenon known as the proximity effect. According to the proximity effect, the nucleophilic section of the carbon chain is so proximal to the electrophilic carbon that only a minor ring strain is seen in the molecule’s initial state.

Side Reactions

The Williamson reactions frequently conflict with base-catalysed alkylating agent elimination. The type of the leaving group, and the reaction circumstances (especially the solvent and temperature), can significantly influence which is favoured. Specific alkylating agent compositions, in particular, can be especially vulnerable to removal. Because the aryloxide is an ambident nucleophile, the Williamson synthesis can conflict with alkylation whenever the nucleophile seems to be an aryloxide ion.

Conclusion

That’s everything there is to say on the matter for the time being. We have covered everything from the introduction to Williamson synthesis through the mechanism and side reactions. However, in the part of Williamson synthesis questions below, we have addressed specific concerns about the Williamson reaction. To have a better understanding, read them.