11.14
Preparation and Reactions of Thiols
Thiols are prepared using the hydrosulfide anion as a nucleophile in a nucleophilic substitution reaction with alkyl halides. For instance, bromobutan…
Thiols are a class of sulfur-containing organic compounds with an –SH functional group.
They are usually prepared from alkyl halides via an SN2 reaction with a sulfur nucleophile such as a hydrosulfide anion.
For example, 1-bromobutane reacts with sodium hydrosulfide to give 1-butanethiol.
Here, the hydrosulfide anion exerts a strong nucleophilic attack on the carbon bearing the halide group, thus displacing the halide ion in an SN2 manner and forming the thiol.
However, this synthesis method does not work well because the product thiol can undergo a second SN2 reaction with the alkyl halide, generating sulfide as a by-product.
This limitation can be overcome by using a thiourea as the nucleophile. Thiourea displaces the halide ion on the alkyl halide to form an alkyl isothiourea salt intermediate.
The salt then undergoes hydrolysis with an aqueous base and yields thiol as a product.
Thiols readily undergo oxidation to form disulfides, sulfinic, and sulfonic acids owing to the multiple oxidation states of the sulfur atom.
The oxidation of thiols to sulfonic acid via sulfinic acid requires strong oxidizing agents such as hydrogen peroxide or potassium permanganate.
Oxidation of thiols to disulfides can occur with mild oxidizing agents, such as molecular bromine or iodine in base.
For instance, bromine in aqueous sodium hydroxide oxidizes two equivalents of ethanethiol to diethyl disulfide.
The reaction proceeds with the deprotonation of the thiol by the hydroxide ion, generating a thiolate ion.
Subsequently, the thiolate ion acts as a strong nucleophile and attacks the molecular bromine in an SN2 reaction, displacing a bromide ion.
Finally, a second thiolate ion exerts a nucleophilic attack on the electrophilic sulfur in the second round of SN2 reaction to give a disulfide product.
The oxidation of thiols to disulfides is reversible, and the resulting disulfide can be easily reduced back to the thiols using reducing agents such as hydrochloric acid and zinc.
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Q1: How are thiols prepared from alkyl halides?
Thiols are prepared through nucleophilic substitution reactions with alkyl halides. The hydrosulfide anion acts as a strong nucleophile, attacking the carbon bearing the halide group and displacing it in an SN2 mechanism. For example, 1-bromobutane reacts with sodium hydrosulfide to produce 1-butanethiol. This method is straightforward but has limitations due to unwanted side reactions.
Q2: Why does the direct hydrosulfide method produce sulfide byproducts?
The thiol product can undergo a second SN2 reaction with excess alkyl halide, generating sulfide as a byproduct. This occurs because the thiol remains reactive in the presence of the halide reagent. Using thiourea as the nucleophile overcomes this limitation by forming an alkyl isothiourea salt intermediate that hydrolyzes cleanly to thiol without further reaction.
Q3: What is the thiourea synthesis method for preparing thiols?
Thiourea displaces the halide ion on the alkyl halide to form an alkyl isothiourea salt intermediate. This salt then undergoes hydrolysis with aqueous base to yield thiol as the final product. This two-step process avoids the sulfide byproduct problem because the intermediate is stable and does not react further with excess alkyl halide.
Q4: How do thiols oxidize to disulfides?
Thiols oxidize to disulfides through a reversible redox reaction. Mild oxidizing agents like molecular bromine or iodine in base facilitate this conversion. The thiol is first deprotonated to form a thiolate ion, which then attacks bromine in an SN2 reaction. A second thiolate ion attacks the electrophilic sulfur to form the disulfide product.
Q5: What oxidizing agents convert thiols to sulfonic acids?
Strong oxidizing agents such as hydrogen peroxide or potassium permanganate oxidize thiols to sulfonic acids via an intermediate sulfinic acid. This multi-step oxidation requires powerful oxidants because it involves multiple changes in the sulfur oxidation state. The sulfur atom's ability to access multiple oxidation states makes these transformations possible.
Q6: Why must thiols be stored in an inert atmosphere?
Thiols are highly susceptible to air oxidation, readily forming disulfides when exposed to atmospheric oxygen. The weak S–S bond in disulfides, approximately half the strength of other covalent bonds, makes this oxidation thermodynamically favorable. Storing thiols under inert gas prevents unwanted oxidation and maintains product purity.
Q7: Can disulfides be converted back to thiols?
Yes, disulfides can be easily reduced back to thiols using reducing agents such as hydrochloric acid in the presence of zinc. This reduction reverses the oxidation process, demonstrating the reversible nature of thiol-disulfide interconversion. This redox equilibrium is important in biochemistry and synthetic applications.