Nucleophilic Substitution of Alkyl Sulfonates

A few other classes of organic compounds undergo nucleophilic substitution reactions analogous to those of alkyl halides the most important of these are sulfonates. 

Sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid are strong acids, comparable in acidity with sulfuric acid. 

Alkyl sulfonates are derivatives of sulfonic acids in which the proton of the —OH group is replaced by an alkyl group. They are prepared by treating an alcohol with the appropriate sulfonyl chloride, usually in the presence of pyridine. 

Alkyl sulfonates resemble alkyl halides in their ability to undergo elimination and nucleophilic substitution. Those used most frequently are the p-toluenesulfonates, commonly known as tosylates and abbreviated as ROTs. 

As shown in Table 8.6, alkyl tosylates undergo nucleophilic substitution at rates that are even faster than those of the corresponding iodides. Iodide is the weakest base and the best leaving 

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A similar strategy in aqueous media has now been applied to the nucleophilic substitution of alkyl halides or tosylates using readily available alkali azides, thiocyanates or sulfinates under microwave irradiation. The approach afforded safe and efficient preparation of azides, thiocyanates and sulfones (Scheme 23) (Ju et al., personal communications). 

The sulfonyl halides (ArSOjCl) convert the alcohol into a sulfonate (ArSOjOR), which is a better leaving group than the hydroxyl group. This allows a range of nucleophilic substitutions to be carried out, many of which parallel those found with alkyl halides. Alkyl halides such as iodides are formed by the nucleophilic substitution of the sulfonate by an iodide ion. The reaction in this case proceeds with inversion of configuration. Treatment of the sulfonate esters with bases such as sodium methoxide or collidine (2,4,6-trimethylpyridine), or even just heating them, can lead to the elimination of toluene-4-sulfonic acid and the formation of an alkene. 

Copper complexes have been used as reagents and as catalysts for the formation of carbon-carbon bonds. The most utilized reactions mediated by copper have been couplings of alkyl halides and sulfonates because copper complexes were unique for many years as reagents that would mediate the nucleophilic substitution of alkyl and aryl nucleophiles with alkyl halides. In recent years, work has been conducted to develop copper-catalyzed versions of cross couplings with aryl halides to address the issues of the cost of palladium catalysts. Although few examples of these processes currently rival those catalyzed by palladium complexes, they do illustrate the potential of copper complexes to catalyst these types of cross-coupling processes. 

The mechanisms by which sulfonate esters undergo nucleophilic substitution are the same as those of alkyl halides Inversion of configuration is observed m 8 2 reac tions of alkyl sulfonates and predominant inversion accompanied by racemization m 8 1 processes... 

In the special case of nucleophilic substitution at a sulfonic ester RS020R where R is alkyl, R —O cleavage is much more likely than S—O cleavage because the OSOiR group is such a good leaving group (p. 353).1730 Many of these reactions have been considered previously (e.g., 0-4, 0-14, etc.), because they are nucleophilic substitutions at an alkyl carbon atom and not at a sulfur atom. However, when R is aryl, then the S—O bond is much more likely to cleave because of the very low tendency aryl substrates have for nucleophilic substitution.1731... 

The dicyclopentadienyl metal compounds undergo Friedel-Crafts alkylation and acylation, sulfonation, metalation, arylation, and formyla-tion in the case of ferrocene, dicyclopentadienyl ruthenium, and dicyclopentadienyl osmium, whereas the others are unstable to such reactions ( ). Competition experiments (128) gave the order of electrophilic reactivity as ferrocene > ruthenocene > osmocene and the reverse for nucleophilic substitution of the first two by n-butyl lithium. A similar rate sequence applies to the acid-catalysed cleavage of the cyclopentadienyl silicon bonds in trimethylsilylferrocene and related compounds (129), a process known to occur by electrophilic substitution for aryl-silicon bonds (130). 

The preparation of fluorinated carbohydrates via nucleophilic displacement of the. sulfonate group of the corresponding sulfonates by fluoride is a well-known rcaction " however, potassium fluoride, which was used to prepare the first alkyl fluoride type of sugar derivative, has been progressively replaced by the alkylamine fluorides (.see Section 1.1.4.2.1.2.). The substitution of relatively unhindered primary mesylates or tosylates in cxocyclic positions of carbo-... 

Many of the convenient methods of preparing alkyl halides are based on the reactions of alcohols with reagents such as thionyl chloride and phosphorus pentachloride. These are dealt with in more detail in Section 2.3 on alcohols. The nucleophilic substitution of an alkyl methanesul-fonate or toluene-4-sulfonate with a sodium or potassium halide is a useful method. 

The sulfone is a versatile functional group comparable to the carbonyl functionality in its ability to activate molecules for further bond construction, the main difference between these two groups being that the sulfone is usually removed once the synthetic objective is achieved. The removal most commonly involves a reductive desulfonylation process with either replacement of the sulfone by hydrogen (Eq. 1), or a process that results in the formation of a carbon-carbon multiple bond when a P-functionalized sulfone, for example a (3-hydroxy or (3-alkoxy sulfone, is employed (Eq. 2). These types of reactions are the Julia-Lythgoe or Julia-Paris-Kocienski olefination processes. Alkylative desulfonylation (substitution of the sulfone by an alkyl group, Eq. 3), oxidative desulfonylation (Eq. 4), and substitution of the sulfone by a nucleophile (nucleophilic displacement, Eq. 5) are also known. Finally, p-eliminations (Eq. 6) or sulfur dioxide extrusion processes (Eqs. 7, 8 and 9) have become very popular for the... 

Alkyl and 2-Alkenyl Halides or Sulfonates Ring Opening of Cyclic Amines and Ethers Addition onto Carbon-Carbon Multiple Bonds Addition onto Heteroconjugated Multiple Bonds Nucleophilic Substitution of 1-Alkenyl Halides Nucleophilic Addition onto Arenes and Hetarenes Substitution of Halo-, Alkoxy-, and Metalloarenes or -hetarenes Addition onto Nonaromatic Carbon-Nitrogen Multiple Bonds Addition onto Carbonyl Compounds... 

Nucleophilic Substitution of Optically Active l-Alkoxy(polyfluoro)alkyl Sulfonates... 

An advantage that sulfonate esters have over alkyl halides is that their prepara tion from alcohols does not involve any of the bonds to carbon The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group Thus the configuration of a sulfonate ester is exactly the same as that of the alcohol from which It was prepared If we wish to study the stereochemistry of nucleophilic substitution m an optically active substrate for example we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared... 

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