Noah Vinter
Tosylate is a product of the conversion of an alcohol group into a sulfonic ester. Tosylates are excellent leaving groups in nucleophilic substitution reactions. The conversion of an alcohol to a tosylate is a well-established process in organic chemistry. Tosylation of hydroxyl-functionalized substrates is an important transformation to activate hydroxyl groups, yielding substrates for further nucleophilic substitution. The preparation of the tosylate is similar to the reaction of an alcohol with thionyl chloride, SOCl2. The tosylate ester undergoes subsequent reactions (typically SN1 or SN2) as part of a multiple-step synthesis.
| Characteristics | Values |
|---|---|
| Conversion of Alcohol to Tosylate | Tosylate ester undergoes subsequent reactions (SN1 or SN2) as part of a multiple-step synthesis |
| Tosylate Synthesis | Tosyl chloride, an amine, and a proper catalyst in an organic solvent |
| Tosylate Reaction | Tosylate coupled with NMI forms a highly reactive N-sulfonylammonium intermediate |
| Tosylate Reaction with Alcohol | A substitution reaction on sulfur, leading to the formation of O-S and breakage of S-Cl |
| Tosylate Reaction with Benzyl Alcohol | Corresponding chlorides are formed instead of tosylates |
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What You'll Learn
Using mesyl chloride (MsCl) or tosyl chloride (TsCl)
The conversion of an alcohol to a tosylate or mesylate is a common process in organic chemistry. The poor leaving group of alcohols can be overcome by converting the hydroxyl group to a tosylate ester, an excellent leaving group. The tosylate ester then undergoes subsequent reactions (typically SN1 or SN2) as part of a multiple-step synthesis.
One method to convert an alcohol to a tosylate or mesylate is by using mesyl chloride (MsCl) or tosyl chloride (TsCl). The neutral alcohol performs a substitution reaction on sulfur, leading to the formation of O-S and the breakage of S-Cl. The charged alcohol is then deprotonated, leading to the formation of the neutral mesylate or tosylate. It is important to note that the stereochemistry is unchanged during this process.
The use of MsCl or TsCl allows for the conversion of OH into a better leaving group, avoiding the issues of rearrangements and racemization. Alkyl tosylates or mesylates can perform all the substitution and elimination reactions of alkyl halides as they contain a good leaving group.
The preparation of the tosylate is similar to the reaction of an alcohol with thionyl chloride (SOCl2). In tosylation, the lone pair of the alcohol attacks the sulfur in TsCl. However, this does not occur with MsCl due to the presence of a benzene ring, which causes steric hindrance.
Thiols and amines, particularly amines, can react with MsCl and TsCl. Therefore, when synthesizing a molecule with multiple functional groups, it is crucial to have only one reactive functional group present, protecting the others through deactivation.
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Understanding the substitution reaction on sulfur
The conversion of an alcohol to a tosylate ester involves a substitution reaction on sulfur. This process transforms the hydroxyl group (OH) of an alcohol into a better leaving group, such as a tosylate or mesylate, which is more reactive in nucleophilic substitution reactions. The preparation of a tosylate is similar to the reaction of an alcohol with thionyl chloride (SOCl2) or phosphorous tribromide (PBr3).
In the substitution reaction on sulfur, the neutral alcohol performs a nucleophilic attack on the sulfur, replacing the chloride and leading to the formation of an O-S bond and the breakage of the S-Cl bond. This step is facilitated by the addition of a base like pyridine, which deprotonates the intermediate and speeds up the formation of the tosylate ester. The resulting OH group is now a good leaving group, which can be displaced by another nucleophile.
The advantage of using tosylates or mesylates is that they avoid the problems associated with rearrangements and racemization that can occur with certain secondary alcohols in nucleophilic substitution reactions. By replacing the OH group on the sulfur with an inert organic group (R group) that lacks an acidic proton, the desired substitution reaction is more likely to occur instead of an acid-base reaction.
Tosylates and mesylates are excellent leaving groups due to resonance delocalization of the developing negative charge on the leaving oxygen. They are also useful in converting alcohols into alkyl halides, which are better substrates for nucleophilic substitution reactions. The larger size of tosylate molecules can be advantageous for handling, as they convert liquid alcohols into solids, although this also makes their preparation slower and reduces their reactivity in substitution reactions compared to mesylates.
Overall, the substitution reaction on sulfur involving tosylates and mesylates offers a versatile approach to converting alcohols into good leaving groups, avoiding issues with stereochemistry and reactivity, and enabling a range of subsequent nucleophilic substitution reactions.
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Deprotonation of the charged alcohol
The conversion of an alcohol to a tosylate ester is a useful process that allows the poor leaving group of alcohols to be transformed into an excellent leaving group. This is achieved by reacting the alcohol with tosyl chloride (TsCl) or para-toluene sulfonyl chloride (Ts-Cl), leading to the formation of O-S and the breakage of S-Cl.
The deprotonation of the charged alcohol is a critical step in this process. Deprotonation, or dehydronation, involves the removal of a proton (H+) from a Brønsted–Lowry acid in an acid–base reaction. In the context of converting a tosylate to an alcohol, deprotonation of the charged alcohol leads to the formation of the neutral mesylate or tosylate.
The deprotonation process results in the formation of the conjugate base of the acid. In the case of alcohol deprotonation, the conjugate base is the negatively charged alkoxide or alkoxy ion (alkoxide). This alkoxide ion is a much stronger nucleophile than the original alcohol. The increased nucleophilicity is due to the enhanced electron density on the alkoxide ion compared to the alcohol.
The specific base used for deprotonation depends on the acidity of the compound. For compounds that are not particularly acidic and do not readily give up their protons, stronger bases than common hydroxides are required. Hydrides, for example, are potent deprotonating agents. The choice of base is guided by the pKa value of the compound, which indicates its relative ability to give up a proton. A lower pKa value suggests that the compound is more acidic and will more readily transfer its proton to a base.
It is important to note that the deprotonation of alcohols can be a complex process. The concept of "complete deprotonation" can be confusing, as it refers to the extent of deprotonation for all molecules in a reaction rather than the deprotonation of individual molecules. Additionally, the stability of the conjugate base formed during deprotonation is a critical factor in determining the feasibility of the deprotonation step.
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Tosylation of hydroxyl-functionalized substrates
Tosylation refers to the process of selectively introducing a tosyl group to hydroxyl groups in organic compounds, often with the help of a base or other catalysts, resulting in the formation of tosylates. The tosylate ester undergoes subsequent reactions (typically SN1 or SN2) as part of a multiple-step synthesis.
The preparation of the tosylate is similar to the reaction of an alcohol with thionyl chloride, SOCl2. The treatment of alcohols with tosyl chloride, an amine, and a proper catalyst in an organic solvent is a conventional method to prepare tosylates. The resulting sulfonic esters can then be transformed into many other groups with an appropriate nucleophile, such as alkali azides, thiocyanates, sulfonates, and amines.
For example, the synthesis of extended functional-group-derivatized POVs involves tosylation of pentaerythritol-derivatized hexavanadate to prepare azide/bromide-functionalized hexavanadates. The reaction of pentaerythritol-derivatized hexavanadate, tosyl chloride, DMAP, and Et3N with a molar ratio of 1:2.2:2:2.85 in an acetonitrile solution after heating at 50 °C for 2 days led to the formation of compound 1.
In another example, the laboratory synthesis of isopentenyl diphosphate, a 'building block' molecule used by nature for the construction of isoprenoid molecules such as cholesterol and b-carotene, was accomplished by first converting the alcohol into an organic tosylate, then displacing the tosylate group with an inorganic pyrophosphate nucleophile.
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Using tosyl chloride with NMI
When using tosyl chloride (TsCl) with an organic base like N-methylimidazole (NMI), it's important to understand the underlying chemistry and the specific role of each reagent. Here's a detailed explanation:
Understanding Tosyl Chloride (TsCl)
Tosyl chloride, also known as toluenesulfonyl chloride or TsCl, is a reagent used in organic chemistry to introduce a tosyl group (tosyl being short for toluenesulfonyl) into a molecule. The tosyl group is derived from toluene, a simple aromatic compound, and it has a unique ability to act as a "leaving group" in subsequent chemical reactions. This is a crucial concept in organic chemistry, where certain groups of atoms can be replaced by other groups, leading to the formation of new compounds.
The Role of N-Methylimidazole (NMI)
N-methylimidazole, or NMI, is an organic base. In this context, an organic base helps to facilitate chemical reactions by accepting or donating electrons, creating a more favourable environment for the reaction to proceed. Specifically, NMI acts as a catalyst in this reaction, enhancing the nucleophilicity of the oxygen anion by abstracting a proton, thus promoting the formation of the desired product.
The Reaction Mechanism
Now, let's delve into the step-by-step process of what happens when you use tosyl chloride with NMI:
- Formation of Tosylate Ester: When an alcohol is treated with tosyl chloride, it undergoes a substitution reaction. The hydroxyl group (OH) of the alcohol reacts with the tosyl chloride, leading to the formation of a tosylate ester. This is a crucial step as it converts the poor leaving group of the alcohol (the hydroxyl group) into an excellent leaving group, the tosylate group.
- Deprotonation: After the formation of the tosylate ester, deprotonation occurs. This means that the charged alcohol molecule loses a proton (H+), resulting in the formation of a neutral molecule, often facilitated by the presence of a base like NMI.
- Substitution and Elimination Reactions: The resulting tosylate is a versatile intermediate. It can undergo a variety of substitution and elimination reactions with different nucleophiles, allowing for the synthesis of a wide range of compounds.
Solvent Selection
The choice of solvent is critical when performing this reaction. Water, for instance, is not suitable because it will hydrolyze the tosyl chloride. Instead, a non-polar, non-nucleophilic solvent that is compatible with your substrate should be used. Chlorinated solvents or ethers are commonly chosen for this purpose.
Precautions and Variations
It's important to note that the reaction of alcohols with tosyl chloride does not always lead to the formation of tosylates. In certain cases, chlorides may be formed instead, particularly with substituted benzyl alcohols. Additionally, the stereochemistry of the reaction is typically unchanged, but this may vary depending on the specific reaction conditions and other reagents used.
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Frequently asked questions
The first step is to treat the alcohol with tosyl chloride, an amine, and a proper catalyst in an organic solvent.
The second step is to displace the tosylate group with an inorganic pyrophosphate nucleophile.
In a study by Jia et al., tosylation of an alcohol was followed by nucleophilic substitution to successfully synthesize various natural products or drugs.
Treatment of alcohols with tosyl chloride does not always lead to the formation of tosylates. In some cases, the corresponding chlorides may be formed instead.
