Sulfonates and sulfonyl halides

The reactions of p-nitrophenyl toluenesulfonate (147) and 2,4-dinitrophenyl toluene-sulfonate (148) with a wide range of oximate ions (p/fa = 7-13) in 10% aqueous ethanol at 25 °C have been studied. For oximate ions with p/fa 9.0, the reactivity of the oximes tends toward that of alcoholate ions and their a-effect disappears [as was also shown with /7-nitrophenyl diethyl phosphate (128) and ethyl jo-nitrophenyl ethylphosphonate (129)]. The reason for this is the unfavourable solvation effects of 

A multi-factor kinetic model of the hydrolysis in aqueous dioxane of sterically hindered arenesulfonyl chlorides has been reported.Correlation equations have been developed (i) for the acid hydrolysis of aromatic sulfonyl chlorides in which contributions by substituents of resonance effects are highly significant, and (ii) for 

Fluorescein (149) reacts with phenylsulfonyl chloride in DMF to yield the chloro compound (150). The proposed pathway involves initial conversion of the phenolic hydroxyl group to its phenylsulfonate, and then displacement of the sulfonate group by the chloride ion liberated in the first step. The latter step presumably involves acid-catalysed addition of chloride ion at the site of sulfonate attachment to give the gm-substituted compound (151), which upon rearomatization of ring A expels benzene sulfonate ion to give the chloro compound (150). 

New hydrolytic rate data in aqueous dioxane mixtures of 2-methyl- and 2,4,6-trimethyl-phenylsulfonyl bromide (152) have been compared witli existing data of 4-methylphenylsulfonyl bromide. Kinetic studies of the sulfonylation of aniline in MeCN by a series of bridged disulfonyl chlorides (153), (154) and (155) have been reported. 

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TABLE 6. Sulfones from unsaturated systems and sulfonyl halides R S02X by radical routes... 

TABLE 9. Sulfones R S02X from different C-nucleophiles and sulfonyl halides... 

Esters of aliphatic and aromatic sulfonic acids are conveniently prepared in high yields from alcohols and sulfonyl halides. A basic medium is required. By substituting sodium butoxide for sodium hydroxide in butanol, the yield of n-butyl p-toluenesulfonate is increased from 54% to 98%. Ethyl benzenesulfonate and nuclear-substituted derivatives carrying bromo, methoxyl, and nirro groups are prepared from the corresponding sulfonyl chlorides by treatment with sodium ethoxide in absolute ethanol the yields are 74-81%. Pyridine is by far the most popular basic medium for this reaction. Alcohols (C -Cjj) react at 0-10° in 80-90% yields, and various phenols can be converted to aryl sulfonates in this base. "... 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

Van Dyke Tiers, G., The chemistry of flnorocarbon sulfonic acids. I. Preparation of anhydrides and sulfonyl halides, 7. Org. Chem., 28,1244,1963. 

Sulfur, Selenium and Tellurium Derivatives. TMSCF3 reacts with elemental sulfur, selenium or tellurium in the presence of a fluoride anion, leading to trifluoromethylthiolates, seleniates or tellurates, respectively.Aryltrifluoromethyl-sulfides, sulfoxides and sulfones were obtained from the corresponding arylsulfenyl, sulfinyl and sulfonyl halides, respectively, by treatment with TMSCF3 and TASF. The reaction of disulfides and diselenides with TMSCF3 and TBAF gave trifluoromethyl thioethers and selenoethers, respectively (eq 26). The same procedure can also be carried out from thiocyanates and selenocyanates. 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

TABLE 5. Survey of sulfonyl halide additions to unsaturated systems and hydrogen halide eliminations to unsaturated sulfones... 

Normally, reactive derivatives of sulfonic acids serve to transfer electrophilic sulfonyl groups259. The most frequently applied compounds of this type are sulfonyl halides, though they show an ambiguous reaction behavior (cf. Section III.B). This ambiguity is additionally enhanced by the structure of sulfonyl halides and by the reaction conditions in the course of electrophilic sulfonyl transfers. On the one hand, sulfonyl halides can displace halides by an addition-elimination mechanism on the other hand, as a consequence of the possibility of the formation of a carbanion a to the sulfonyl halide function, sulfenes can arise after halide elimination and show electrophilic as well as dipolarophilic properties. 

Besides radical additions to unsaturated C—C bonds (Section III.B.l) and sulfene reactions (see above), sulfonyl halides are able to furnish sulfones by nucleophilic substitution of halide by appropriate C-nucleophiles. Undesired radical reactions are suppressed by avoiding heat, irradiation, radical initiators, transition-element ion catalysis, and unsuitable halogens. However, a second type of undesired reaction can occur by transfer of halogen instead of sulfonyl groups283-286 (which becomes the main reaction, e.g. with sulfuryl chloride). Normally, both types of undesired side-reaction can be avoided by utilizing sulfonyl fluorides. 

Although the oxidation of thiols with chlorine or bromine in the presence of water gives sulfonyl halides or sulfonic acids, the reaction of thiols with a stoichiometric amount of BTMA Br3 and sodium hydroxide in dichloromethane-water at room temperature gives disulfides in good yields (Fig. 29) (ref. 37). 

This reaction, parallel with 10-77, is the standard method for the preparation of sulfonyl halides. Also used are PCI3 and SOCI2, and sulfonic acid salts can also serve as substrates. Sulfonyl bromides and iodides have been prepared from sulfonyl hydrazides (ArS02NHNH2, themselves prepared by 10-126) by treatment with bromine or iodine.Sulfonyl fluorides are generally prepared from the chlorides, by halogen exchange. 

Reduction of Sulfonyl Halides and Sulfonic Acids to Thiols... 

As a consequence of facile homolytic cleavages, sulfonyl halides (I > Br > Cl F unsuitable) are able to add to unsaturated C—C systems. To prevent (or reduce) competing polymerizations, the additions of sulfonyl chlorides have been recommended to be carried out in the presence of copper(I/II) salts (Asscher-Vofsi reaction ). Comprehensive surveys have been published on the resulting j8-halogeno sulfones (or their vinyloguous compounds) as well as on their dehalogenation products (vinyl sulfones, 1-sulfonyl-l, 3-dienes, etc.). Table 5 reviews a series of sulfonyl halide additions and facile hydrogen halide eliminations. 

In the early solution phase syntheses of oligonucleotides, coupling of phosphate diesters was used. A mixed 3 -ester with one aryl substituent, usually o-chlorophenyl, was coupled with a deprotected 5 -OH nucleotide. The coupling reagents were sulfonyl halides, particularly 2,4,6-tri-i-propylbenzenesulfonyl chloride,53 and the reactions proceeded by formation of reactive sulfonate esters. Coupling conditions... 

The reactions represented by (191) are all nucleophilic substitutions occurring at a sulfonyl sulfur. Besides cpdisulfones substitutions of this kind are also of frequent occurrence in the chemistry of many other types of sulfonyl derivatives such as sulfonyl halides, aryl esters of sulfonic acids, etc., and many of the general aspects of their behaviour and mechanism have been examined in considerable detail. Most of the remainder of this section will be devoted to consideration of the results of such studies. 

General Reaction Chemistry of Sulfonic Acids. Sulfonic acids may be used to produce sulfonic acid esters, which are derived from epoxides, olefins, alkynes, allenes, and ketenes, as shown in Figure 1 (10). Sulfonic acids may be converted to sulfonamides via reaction with an amine in the presence of phosphorus oxychloride [10025-87-3], POCl3 (11). Because sulfonic acids are generally not converted direcdy to sulfonamides, the reaction most likely involves a sulfonyl chloride intermediate. Phosphorus pentachloride [10026-13-8] and phosphorus pentabromide [7789-69-7] can be used to convert sulfonic acids to the corresponding sulfonyl halides (12,13). The conversion may also be accomplished by continuous electrolysis of thiols or disulfides in the presence of aqueous HQ [7647-01-0] (14) or by direct sulfonation with chlorosulfuric acid. Sulfonyl fluorides are typically prepared by direct sulfonation with fluorosulfuric acid [7789-21-1], or by reaction of the sulfonic acid or sulfonate with fluorosulfuric acid. Halogenation of sulfonic acids, which avoids production of a sulfonyl halide, can be achieved under oxidative halogenation conditions (15). 

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