Direct sulfonation

Fuming sulfuric acid (oleum) of 20% S03 strength is suitable for preparation of monosulfonated products [1-3] while for multiple sulfonation 30% (or more) SO3 is required [4-10], The phosphine is dissolved in cold oleum with protonation of the phosphorus atom therefore in cases when the phenyl rings are directly attached to the phosphorus (e.g. triphenylphosphine or the bis(diphenylphosphino)alkanes) sulfonation takes place in the 3-position. 

For monosulfonation of PPh3 the reaction mixture can be heated for a limited time [1-3] while multiple sulfonation is achieved by letting the solution stand at room temperature for a few days [4-10], In this simplest way of the preparation several problems may arise. Under the harsh conditions of sulfonation there is always some oxidation of the phosphine into phosphine oxide and phosphine sulfides are formed, too. Furthermore, selective preparation of TPPMS (1) or TPPDS (2) requires optimum reaction temperature and time and is best achieved by constantly monitoring the reaction by NMR [10] or HPLC [7], Even then, the product can be contaminated with unreacted starting material. However, 1 can be freed of both the non-sulfonated and the multiply sulfonated contaminants by simple methods, and in the preparation of TPPTS (3) contamination with PPh3, 1 or 2 is usually not the case. Direct sulfonation with fuming sulfuric add was also used for the preparation ofthe chelating diphosphines 34-38, 51, 52. 

Most of the problems of side reactions can be circumvented by using a mixture of unhydrous sulfuric acid (containing no free S03, a powerful oxidant) and orthoboric acid [4,8], The superacidic nature of this sulfonation mixture ensures complete protonation and the lack of free S03 excludes the possibility of oxidation. In addition, the number and position of the sulfonate groups can be more effectively controlled than by using oleum for 

In cases where the phenyl ring is not directly attached to a protonated phosphorus, sulfonation can be carried out in 95-100% H2S04 i.e. with no dissolved free S03 (28, 31, 42, 47, 49-51). 

In these syntheses based upon direct sulfonation, the reaction mixture should be neutralized at the appropriate reaction time this is usually achieved with concentrated NaOH or KOH solutions [1-3] with the concomitant production of lots of inorganic sulfates. The less soluble monosulfonated products can be crystallized and the raw products contain Na2S04 or K2S04. 

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Direct sulfonation of thiazole, as well as of 2-substituted thiazoles, leads mostly to substitution m the 5-position (330-332). 4-Thiazole sulfonic acid has been prepared through direct sulfonation of 2.5-dibromothiazole with subsequent Rane% Ni reduction (330). Sulfonation of 2.5-dimethyl- and 2-piperidyl-5-methylthiazoles affords the corresponding 4-sulfonic acids as barium salts (247). The 2-hydroxy group facilitates the sulfonation (201. 236). When the 4- and 5-positions are occupied direct sulfonation can occur in the 2-position. 5-hydroxyethyl-4-methyl-2-thiazole sulfonic acid has been prepared in this manner (7). 

In addition, and 2(S-is CC-olefins can be directly sulfonated to produce a-olefin sulfonate (AOS). AOS was formerly used as an efficient,... 

Table 3. Reagents for Direct Sulfonation and Sulfation Reactions ...

General Reaction Chemistry of Sulfonic Acids. Sulfonic acids may be used to produce sulfonic acid esters, which are derived from epoxides, olefins, alkynes, aHenes, and ketenes, as shown in Figure 1 (10). Sulfonic acids may be converted to sulfonamides via reaction with an amine in the presence of phosphoms oxychloride [10025-87-3] POCl (H)- Because sulfonic acids are generally not converted directiy to sulfonamides, the reaction most likely involves a sulfonyl chloride intermediate. Phosphoms pentachlotide [10026-13-8] and phosphoms pentabromide [7789-69-7] can be used to convert sulfonic acids to the corresponding sulfonyl haUdes (12,13). The conversion may also be accompHshed by continuous electrolysis of thiols or disulfides in the presence of aqueous HCl [7647-01-0] (14) or by direct sulfonation with chlorosulfuric acid. Sulfonyl fluorides are typically prepared by direct sulfonation with fluorosulfutic acid [7789-21-17, or by reaction of the sulfonic acid or sulfonate with fluorosulfutic acid. Halogenation of sulfonic acids, which avoids production of a sulfonyl haUde, can be achieved under oxidative halogenation conditions (15). 

In order to introduce an S03 group into long-chain fatty acids, direct sulfonation with sulfur trioxide had been suggested in 1962 [29], similar to the Hell-Volhard-Zelinskii reaction of the a-bromation studied by Watson [34], Ten years previously de Boer had reviewed this mechanism among others for lower aliphatic sulfocarboxylic acids [35]. The sulfonation process was proposed as a two-step mechanism. The first step is the rapid addition of the S03 into... 

In fact, one metal complex has already had considerable clinical application in PDT, although its regulatory approval status is not clear at present. The photosensitizer has the trade name PHOTOSENS and may be represented by structure (7). It is prepared by the direct sulfonation of chloroaluminum(III)-phthalocyanine, and the isolated material appears to contain a mixture of... 

The most studied of the water-soluble metallophthalocyanines (Zn, Al, Ga) are the sulfonic acids. These are prepared by cyclotetramerization of 4-sulfophthalic acid or its derivatives (Figure 6),246,247 or by the direct sulfonation (oleum) of the metallophthalocyanine.248 The latter method gives complex mixtures, since direct sulfonation occurs at both exo and endo positions. These mixtures may be separated by chromatographic methods (usually reverse-phase HPLC). Thus... 

With this last point in mind, the synthesis of mono-, bis- and tra-sulfonated triphenylphosphine will be described, but the same methodology can be applied to the preparation of other sulfonated arylphosphines. In general, these phosphines are made by direct sulfonation using fuming sulfuric acid (oleum) [21], The extent of sulfonation is determined by the SO3 strength, as well as factors such as the temperature and time of the reaction. The monosulfonated phosphine (tppms) is prepared using oleum of 20% SO3 strength, with typically 30% SO3 used... 

As will be described in Section 3.3.2.1, direct sulfonation also makes it considerably easier to generate sulfonated block copolymer polyarylenes. 

Hydroxy-phosphines undergo benzoylation with o-sulfobenzoic anhydride in the presence of bases (Na2C03 or BuLi) affording sulfobenzoylated phosphine products. In such a way several mono- and dihydroxy phosphines could be made soluble in water, exemplified by the chiral bisphosphines 53. It should be noted, that this general method allows the preparation of water-soluble sulfonated derivatives of acid-sensitive phosphines, such as DIOP, too, which are not accessible via direct sulfonation [56]. 

Sultones are often prepared by direct sulfonation of olefinic compounds or ketenes. This method, applied to differently substituted a-olefins, has... 

Sulfonic acids are conveniently made by oxidation of the corresponding thiones or disulfides. Direct sulfonation is best effected with chlorosulfonic acid. Direct thiation can be achieved with sulfenyl chlotides to give 5-thiopyrimi-dines in excellent yields. For example, the reaction of 6-hydroxy-4(l//)-pytimidinone [4,6(1//,5//)-pyrimidinedione] 72 with benzylsulfenyl chloride or 2-methoxyphenylsulfenyl chloride gave the respective 5-thio derivatives 73 in 96% and 97% yields <1993SC2363, 2001JME3355>. 

The directly sulfonated CDs were the second family of compounds studied. The substituent was introduced, after multiple synthetic steps, at the C6 position with a metabolically stable C-S bond. Like the sulfate derivatives, the sulfonates have the negative charge of the substituent in proximity to the carbohydrate backbone. 

The direct sulfonation with sulfuric acid discovered by Hanson et al. (18) is more effective. Another method by which the formation of phosphane oxide is strongly inhibited was published in 1995 the use of B(OH)3 in combination with sulfur trioxide hinders the oxidation and offers the possibility to control the number and the position of sulfonate groups (19). 

TABLE 1. REAGENTS FOR DIRECT SULFONATION AND SULFATION REACTIONS3... 

This procedure has an advantage over direct sulfonation in that sulfonyl chlorides usually are soluble in organic solvents and may be easily separated from the reaction mixture. Also, the sulfonyl chloride is a more useful intermediate than the sulfonic acid, but can be converted to the acid by hydrolysis if desired ... 

Compound 19 was obtained by direct sulfonation of Compound 1 with concentrated H2S04 at 25°C. The dimethylamino sulfone was prepared by chlorosulfonating and aminating DiPAMP as the bis-oxide followed by silane reduction. 

C. M. Suter and A. W. Weston, Direct Sulfonation of Aromatic Hydrocarbons and Their Halogen Derivatives, Org. React. 1946, 3, 141-197. 

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