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Sodium Hypochlorite Pentahydrate Crystals (NaOCl·5H2O): A Convenient and Environmentally Benign Oxidant for Organic Synthesis Masayuki Kirihara,*,† Tomohide Okada,‡ Yukihiro Sugiyama,‡ Miyako Akiyoshi,§ Takehiro Matsunaga,§ and Yoshikazu Kimura*,∥ †
Department of Materials and Life Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan ‡ R&D Department of Chemicals, Nippon Light Metal Company, Ltd., 480 Kambara, Shimizu-ku, Shizuoka 421-3203, Japan § Research Center for Explosion Safety, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8565, Japan ∥ Research and Development Department, Iharanikkei Chemical Industry Co. Ltd., 5700-1 Kambara, Shimizu-ku, Shizuoka 421-3203, Japan S Supporting Information *
ABSTRACT: The novel oxidant of sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals is now available for industrial and laboratory use. It is superior to conventional aqueous sodium hypochlorite solutions (aq. NaOCl). The crystalline material is 44% NaOCl and contains minimal amounts of sodium hydroxide and sodium chloride, and the aqueous solution, which is prepared from NaOCl·5H2O and water, has a pH of 11−12. Examples of the selective organic synthesis using NaOCl·5H2O involve the oxidations of primary and secondary alcohols, selective oxidations to sulfoxide and sulfone, oxidative cleavage of disulfide to sulfonyl chloride and bromide, oxaziridine synthesis, and oxidative dearomatization of phenols.
1. INTRODUCTION
We expected that NaOCl·5H2O is a superior substitute of aq. NaOCl and found several new types of oxidation reactions of organic molecules which had not been successful using conventional aq. NaOCl. In addition, a high volume efficiency of reactions, good stability in storage, and unnecessity pH adjustment prior to use afforded simple methods for organic synthesis. Several oxidation reactions were found to occur as shown in Scheme 1.
In this review, novel production on a commercial basis of sodium hypochlorite pentahydrate (NaOCl·5H2O) and its application for organic syntheses is described. Although NaOCl·5H2O itself has been known since 1919 in the literature,1 nothing has been supplied on an industrial scale. In 2013, Nippon Light Metal Co. in Japan was the first to put sodium hypochlorite pentahydrate (NaOCl·5H2O) crystals on the market in the world.2,3 As the organic synthesis using NaOCl·5H2O as an oxidant has never been reported, we examined the performance of the NaOCl·5H2O compared to a conventional aqueous NaOCl solution (aq. NaOCl). Oxidation using aq. NaOCl4 is one of the most promising methods in process chemistry, because diluted aq. NaOCl is nonexplosive and inexpensive, and the postoxidation waste is harmless and nontoxic sodium chloride (NaCl). However, there are still some drawbacks when using the conventional aq. NaOCl as an oxidant of organic compounds. The process has an inherently poor volume efficiency because the concentration of conventional aq. NaOCl is only 8−13% (higher concentrations of the NaOCl solution are known to be unstable). Moreover, the pH of conventional aq. NaOCl is very high (∼13; as adjusted with free NaOH to maintain stability), and the pH must sometimes be adjusted lower to speed up the rate or prevent decomposing the starting materials and/or products. Furthermore, conventional aq. NaOCl is not stable enough, and the deteriorated NaOCl sometimes produces unsuccessful synthetic reactions. © 2017 American Chemical Society
2. SODIUM HYPOCHLORITE PENTAHYDRATE (NaOCl·5H2O)2,5 As shown in Figure 1, NaOCl·5H2O consists of pale yellow crystals having the melting point of 25−27 °C. Notable features of NaOCl·5H2O include: (1) the NaOCl content is about 44 wt % (the following expressed as %; 3−4 times higher concentration versus conventional aq. NaOCl), (2) simple stoichiometric calculations, easy and accurate mass determination due to the crystalline nature of the compound, (3) the pH of aqueous solutions is ∼11−12 since the solution contains less than 0.04−0.08% NaOH, and (4) the crystals are stable for 1 year below 7 °C. Currently, NaOCl·5H2O crystals are commercially available from several companies including us.3 Received: September 1, 2017 Published: October 23, 2017 1925
DOI: 10.1021/acs.oprd.7b00288 Org. Process Res. Dev. 2017, 21, 1925−1937
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Scheme 1. Synthetic Applications of NaOCl·5H2O
the conventional aq. NaOCl is pH 13 and oxidations are faster due to the lower pH, vide infra. The stability of the product was evaluated at several temperatures (Figure 2). These NaOCl·5H2O crystals, which contain 44% of NaOCl, are stable at lower temperatures. However, the product gradually decomposed under an ambient temperature. Further evaluation revealed that the NaOCl·5H2O crystals are quite stable in refrigerator. The concentration of NaOCl of the crystals is almost unchanged (44.2% → 43.7%) even after 360 days at 7 °C (Figure 2). This means that 99% of the NaOCl was maintained (Table 1). This is in sharp contrast to the conventional aqueous NaOCl solution, whose concentration gradually drops to 11.3% from 13.6% of original concentration under the same condition. This means that 17% of NaOCl content decomposed during storage. Because of the instability of the conventional aq. NaOCl, titration is required to determine the exact concentration before use. On the contrary, the accurate mass of NaOCl·5H2O can be easily measured using a balance (Figure 3). 3.3. Safety Assessment of NaOCl·5H2O.6 According to the testing method of explosives based on the Japanese Industrial Standards (JIS K 4810), the BAM friction test and the drop hammer test have been applied to the product (NaOCl·5H2O) (Table 2). The results of both tests were negative at classification 7 for the BAM friction test and 8 for the drop hammer test. This means that NaOCl·5H2O is not an explosive compound under typical conditions. Differential scanning calorimetry (DSC) has been done at a heating rate of 5 °C/min contacting with several materials [stainless (SUS304H), titanium, low-density polyethylene (LDPE), high-density polyethylene (HD-PE), and polypropylene (PP)] in glass ampule, and the results are shown in Figures 4 and 5.
Figure 1. NaOCl·5H2O crystals. Reproduced with permission from ref 5. Copyright 2016 Elsevier.
3. COMMERCIAL SYNTHESIS OF SODIUM HYPOCHLORITE PENTAHYDRATE (NaOCl·5H2O) CRYSTALS2,5 3.1. Development of the Industrial Preparation of NaOCl·5H2O. Several preparation methods for NaOCl·5H2O have already been proposed;1 however, industrial applicable methods to prepare high-purity NaOCl·5H2O crystals are unknown. We have recently found specified crystallization conditions for high-purity NaOCl·5H2O crystals based on the NaCl−NaOCl−H2O ternary phase diagram. On the basis of these findings, we have established an original method for manufacturing NaOCl·5H2O (Scheme 2)2 and have been supplying this product to the market. Chlorine gas is added to a 45−48% NaOH solution to prepare a highly concentrated NaOCl solution. After removing of the precipitated NaCl by filtration, the filtrate is cooled to around 12 °C to precipitate the NaOCl·5H2O crystals, which are collected by centrifugal filtration. 3.2. Property of NaOCl·5H2O. Analysis shows that the prepared NaOCl·5H2O contains only 0.1−0.5% NaCl and 0.04−0.08% NaOH. That is, the crystals prepared using this new method contain less free NaOH as well as less NaCl than the conventional aq. NaOCl. In addition, an aqueous solution of this product has a more ideal pH of 11−12, whereas that of Scheme 2. Industrial Preparation of NaOCl·5H2O
1926
DOI: 10.1021/acs.oprd.7b00288 Org. Process Res. Dev. 2017, 21, 1925−1937
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Figure 2. Stability of NaOCl·5H2O at several temperatures.
Table 1. Stability of NaOCl·5H2O Crystals and Conventional Aq. NaOCl at 7 °C
a
substance
original concentration
NaOCl·5H2O
44.2%
aq. NaOCl
13.6%
Table 2. Sensitivity Test of NaOCl·5H2O Based on JIS K 4810
concentration 1 year later 43.7%a (98.9% of the original concentration) 11.3%b (83.1% of the original concentration)
test
condition
result
JIS grade
friction drop hammer
limiting load: 353 N limiting impact energy: 24.5 J
negative negative
Class 7 Class 8
360 days later. b361 days later. Data are from ref 5.
The sharp peak was observed at 100 °C in DSC measurement with SUS304H. This result means that stainless steel reacts with NaOCl·5H2O; thus, stainless vessels cannot be used as reactors. On the other hand, titanium did not react with NaOCl·5H2O, and thus the reaction of NaOCl·5H2O can be performed in titanium vessels as well as glass wares. The DSC data of NaOCl·5H2O with these resins (LD-PE, HD-PE, and PP) showed that all of them were not affected by NaOCl·5H2O at ambient temperatures.
4. OXIDATION OF ALCOHOLS5,7 The synthesis of aldehydes or ketones by oxidation of the corresponding primary or secondary alcohols is one of the most important reactions in organic synthesis, and a high number of methods has been reported.8 However, there are only a few methods that can be industrially applied, because most of the existing oxidations have serious drawbacks such as toxic or explosive property of the oxidants. The oxidation of alcohols using conventional aq. NaOCl catalyzed by TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)9 or AZADO (2-azaadamantane N-oxyl)10 have been reported.
Figure 4. DSC data with SUS304H and titanium.
They appear to be economically and environmentally benign methods without the use of a metal catalyst.
Figure 3. Advantage of NaOCl·5H2O crystals on conventional aqueous NaOCl. 1927
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Table 3. Comparison with NaOCl·5H2O Crystals and Conventional Aqueous NaOCl
run
NaOCl
1 2 3 4 5 6 7
NaOCl·5H2O aq. 13% NaOCl NaOCl·5H2O aq. 13% NaOCl NaOCl·5H2O NaOCl·5H2O aq. 13% NaOCl
a
nitroxyl radical (mol %)
time (h)
yield (%)a
TEMPO (1) TEMPO (1) TEMPO (0.1) 1-Me-AZADO (1) 1-Me-AZADO (1)
24 27 1 22 3 1 24
78 9 97 11 99 100 99
Determined by GC analysis using an internal standard method.
Table 4. Effect for Quaternary Ammonium Salts and Acid in the Presence of TEMPOa
yield of 2-octanone (%)b run
Figure 5. DSC data with resins.
X (equiv)
additive
0.5 h
1
However, the process has an inherently poor volume efficiency because the concentration of the conventional aq. NaOCl solution is up to only 13%. Moreover, at the pH of the conventional aq. NaOCl (about 13), the reactions are very slow; thus, the pH must be lowered (pH 8−9) with aqueous sodium hydrogen carbonate (aq. NaHCO3) to increase the rate.9b NaOCl·5H2O is expected to overcome these mentioned drawbacks. 4.1. Optimization of the Reaction Conditions. The oxidations of 2-octanol were initially examined using NaOCl· 5H2O crystals or the conventional aq. 13% NaOCl in dichloromethane (CH2Cl2) in the presence of 5 mol % tetrabutylammonium hydrogen sulfate (Bu4NHSO4) without pH adjustment with aq. NaHCO3 in the presence or absence of TEMPO or 1-Me-AZADO. The results are summarized in Table 3. In all cases, the NaOCl·5H2O crystals (runs 1, 3, 5, and 6) showed more excellent results than those of the aq. 13% NaOCl (runs 2, 4, and 7). We first postulated that the role of Bu4NHSO4 was as a phase transfer catalyst; however, it turned out to act as an acid based on the results shown in Tables 4 and 5. As shown in Table 5, the addition of Bu4NHSO4 to the 13% aq NaOCl (prepared from NaOCl·5H2O) dramatically reduced the pH value (9.6). On the basis of the results, the oxidation effectively occurred below pH 10. As mentioned below, the use of NaHSO4 in place of Bu4NHSO4 gave excellent results for the oxidation of 2octanol (Scheme 3). Next, we examined the reaction with concentrated aq. NaOCl which can be prepared by dissolving NaOCl·5H2O crystals with water. We also confirmed that the concentration of a NaOCl solution higher than 20% is stable for a few days for the reaction. However, almost no concentration effect was observed at 13, 20, and 31% aq. NaOCl. On the other hand, the
2 3
HSO4 0.005 Br 0.05
4 5
Cl 0.05 Cl 0.05
6
Cl 0.05
7
NaHSO4·H2O, 0.05 equiv NaHSO4·H2O, 0.05 equiv + H2O, 0.2 mL NaHSO4·H2O, 0.05 equiv + H2O, 0.2 mL
1h
2h
3h
21 h
0.1
0.1
0.1
0.2 (23 h)
40
73
98
6
14
25
3 19
10 25
10
97
99
46
98
87 (22 h) 73 69
a
2-octanol (10 mmol), NaOCl·5H2O (12 mmol), TEMPO (0.1 mmol), Bu4NX (0.05−0.5 mmol), CH2Cl2 (30 mL). bYields were determined by GC using an internal standard method.
Table 5. pH of 13% aq. NaOCl (Prepared from NaOCl· 5H2O) with Quaternary Ammonium Salts 13% aq. NaOCla 50 50 50 50 a
mmol mmol mmol mmol
quaternary ammonium salt
pH
none Bu4NHSO4 (2.5 mmol) Bu4NBr (2.5 mmol) Bu4NCl (2.5 mmol)
11.3 9.6 11.4 11.2
Prepared from NaOCl·5H2O and ion-exchanged water.
use of the solid NaOCl·5H2O crystals dramatically increased the oxidation (Figure 6). The precise reason is not clear, but it may appear that a high concentration of the primary oxidant HOCl forms on the surface of the crystalline solid. The solvent effects were examined (Table 6), and ethyl acetate was found to be as good of a reaction solvent as dichloromethane. 1928
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Na2SO3 followed by extraction with ethyl acetate and distillation of the residue to produce 2-octanone (23.2 g, 91% yield). As an improved method, NaHSO4 was used instead of Bu4NHSO4. In method A, 2-octanol was dropwise added to the reaction mixture. In method B, 30% NaOCl prepared from NaOCl·5H2O was dropwise added to the mixture. Both methods gave high yields of the desired 2-octanone within 1 h (Scheme 5). NaOCl·5H2O can be used in a slurry or highly concentrated solution. 4.2. TEMPO-Catalyzed Oxidation of Several Alcohols with NaOCl·5H2O. The optimized TEMPO-catalyzed oxidation with NaOCl·5H2O was applied to various primary alcohols (10 mmol) (Table 7). Use of an equimolar amount of NaOCl· 5H2O gave the corresponding aldehydes in good yields. This optimized method using NaOCl·5H2O gives encouraging results with TEMPO. It is notable that the reaction of primary alcohols having a heteroaromatic moiety (pyridine, thiophene) effectively produced the desired aldehydes. The oxidations of secondary alcohols were then examined (Table 8). Both the TEMPO- and 1-Me-AZADO-catalyzed oxidations of sterically hindered secondary alcohols were reported to give poor yields of the ketones using the conventional aq. NaOCl without pH adjustment using aq. NaHCO3. In contrast, the optimized method using NaOCl· 5H2O gave excellent results with TEMPO even in the reaction of sterically hindered alcohols (menthol and 2,6-dimethyl-4heptanol). Notably, the cheap TEMPO is useful as a catalyst for the oxidations. For the oxidation of alcohols using the conventional aq. NaOCl catalyzed by TEMPO, primary alcohols are known to be easier and faster oxidized than secondary alcohols.9 Actually, the oxidation of an equimolar mixture of a primary alcohol (1nonanol) and a secondary alcohol (2-nonanol) using the conventional aq. NaOCl catalyzed by 4-MeO-TEMPO was reported to afford 90% nonanal and 10% 2-nonanone in the literature.9b Conversely, the reaction of an equimolar mixture of 1octanol and 2-octanol with NaOCl·5H2O in the presence of TEMPO provided octanal in 47% yield and 2-octanone in 44% yield after 0.5 h. The 4-MeO-TEMPO catalyzed reaction exhibited a similar result (Table 9). Thus, the oxidation rates for primary and secondary alcohols under these conditions are not very different. These results suggest that the reaction mechanism of the nitroxyl radical catalyzed oxidation of alcohols using NaOCl· 5H2O is different from the oxidation using the conventional aq. NaOCl. The oxidation of alcohols with NaOCl·5H2O/ TEMPO/Bu4NHSO4 occurs under acidic to neutral conditions (Scheme 3 vide supra).5 We proposed a plausible mechanism involving intermediate B with hydride transfer (Scheme 6)5 based on the mechanism which was reported by Bobbitt et al. as an alternative for the TEMPO oxidation of alcohols under neutral or acidic conditions.11 Taking intermediate B into account, steric hindrance of the bulky secondary alcohols is likely relaxed, permitting the oxidation to occur. The interaction between the lone pair of the nitrogen atom and the hydrogen atom of the hydroxyl group in the alcohol plays an important role in this reaction mechanism.
Scheme 3. Proposed Mechanism for the TEMPO-Catalyzed Oxidation of Alcohols with NaOCl·5H2O (Reproduced with Permission from Ref 5. Copyright 2016 Elsevier)
Figure 6. Reaction of 2-octanol with several concentrations of aqueous NaOCl prepared from NaOCl·5H2O crystals and water; NaOCl·5H2O crystals (○); aq. 31% NaOCl (△); aq. 20% NaOCl (□); aq. 13% NaOCl (◇) ; conventional aq. 13% NaOCl (×). 2-Octanol (10 mmol), NaOCl·5H2O (12 mmol), Bu4NHSO4 (0.5 mmol), TEMPO (0.1 mmol), CH2Cl2 (30 mL), and appropriate water.
Table 6. Results for the Oxidation of 2-Octanol in Several Solvents
yieldb of 2-octanone (%) solvent
temperature (°C)
1h
2h
3h
4h
CH2Cl2 EtOAc C6H5CH3 C6H5CF3 CH3CN AcOH
5 5 5 5 5 r.t.
97 61 38 30 53 18
97 90 55 54 78
98 87 53 90
95 52 90
a
2-Octanol (10 mmol). bYields were determined by GC using an internal standard method.
A large-scale (26.0 g of 2-octanol, 0.2 mol) example of the oxidation of 2-octanol was examined in ethyl acetate (Scheme 4). To maintain the reaction temperature below 20 °C, 2octanol was dropwise added for 15 min to a mixture of all reagents cooling in an ice−water bath. After stirring for 45 min at 0−20 °C, the reaction mixture was quenched with aqueous
5. OXIDATION OF ORGANOSULFUR COMPOUNDS 5.1. Selective Oxidation of Sulfides to Sulfoxides.12 Sulfoxides are important and useful compounds in organic 1929
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Scheme 4. Large-Scale Oxidation of 2-Octanol in Ethyl Acetate
Scheme 5. Solvent-Free Oxidation of 2-Octanol Catalyzed by NaHSO4·H2O
As we described in the previous chapters, the main difference between NaOCl·5H2O and aq. NaOCl is their pH values. Therefore, the reactivities of NaOCl·5H2O and conventional aq. NaOCl were compared while altering the pH with HCl or NaOH (Table 10). At pH 11, the reaction rapidly proceeded to selectively afford the desired sulfoxide (runs 1, 2). At pH 13, on the other hand, the reaction was not complete after 4 h, and a significant amount of overoxidized sulfone was produced along with the desired sulfoxide (runs 3, 4). As we had surmised, the selectivity of this reaction depends on the basicity of the reaction mixture. These results show that the ideal pH range for the selective production of the sulfoxide is 10−11. Although the conventional aqueous NaOCl adjusted to pH 11 with HCl can provide the desired sulfoxide in high yield, as a practical oxidant, it has some drawbacks (low concentration, unstable, etc.) as we mentioned in the earlier chapters. In addition, it is very important to add the correct amount of oxidant in order to prevent overoxidation during the selective oxidation of sulfides to the corresponding sulfoxides. However, during storage of the conventional aq. NaOCl, the NaOCl concentration gradually decreases, even when it is stored in a refrigerator. Therefore, titration is required to determine the exact concentration before use. If a higher concentration of the NaOCl solution is desired (e.g., 20 wt % NaOCl, as demonstrated in Table 13 entry 2, for gram-scale synthesis), it can be prepared from crystalline NaOCl·5H2O and water. This would be useful in large-scale syntheses due to the need for a high volume efficiency and reduced wastewater.
synthesis, because they are frequently used as the intermediates for the construction of several important organic molecules. In addition to this, there are many biologically important compounds containing a sulfoxide moiety. They are mainly prepared by the oxidation of the corresponding sulfides; however, it is sometimes difficult to stop the oxidation at the sulfoxide stage. Consequently, several selective sulfide oxidations have been developed to more effectively synthesize sulfoxides.13 Although they provide the desired sulfoxides in high yields, some are accompanied by large amounts of undesirable waste derived from the oxidants. As we emphasized in the introduction, NaOCl has several merits as an environmentally benign oxidant. Despite these merits, NaOCl has seldom been used for the synthesis of sulfoxides from sulfides, because it is difficult to selectively obtain the desired sulfoxides without producing the overoxidized sulfone. The use of TEMPO as a catalyst has been required to obtain the sulfoxides in high yields.14 We expected that the oxidation of sulfides with NaOCl·5H2O might be an excellent method for the selective preparation of sulfoxides. 5.1.1. Optimization of the Reaction Conditions. The reactions of thioanisole with 1.1 equiv of NaOCl (conventional 12 wt % aq. NaOCl solution or NaOCl·5H2O crystals) in acetonitrile were examined in the absence of a catalyst (Scheme 7). In the case of the NaOCl·5H2O crystals, the desired sulfoxide was selectively obtained in 18 min. Conversely, the conventional aq. NaOCl reacted more slowly with the sulfide to produce the sulfoxide in 79% yield accompanied by a certain amount of the overoxidized sulfone. 1930
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Table 7. Selective Syntheses of Aldehydes from Primary Alcoholsa
Table 9. Oxidation of an Equimolar Mixture of 1-Octanol and 2-Octanol with NaOCl·5H2O Catalyzed by a Nitroxyl Radicala
a
nitroxyl radical
time (h)
octanal
2-octanone
TEMPO 4-MeO-TEMPO
0.5 1.0
47% (2.35 mmol) 48% (2.40 mmol)
44% (2.20 mmol) 37% (1.85 mmol)
Yields were determined by GC using an internal standard method.
Scheme 6. Plausible Reaction Mechanism
a
Substrate: 10 mmol. bYields were determined by GC using an internal standard method. cTEMPO 10 mol %. d1-Me-AZADO was used instead of TEMPO.
sulfoxide in high yield with a shorter reaction time (run 1) among the several experimental conditions as shown in Table 11. The acetonitrile/water ratios were variable to afford similar results between 5:1 and 50:1 (Table 12). In the absence of
Consequently, NaOCl·5H2O is much more convenient than aqueous NaOCl for such applications. The survey of the solvent effects on the reaction of thioanisole with NaOCl·5H2O revealed that acetonitrile is appropriate solvent for this reaction. It selectively provided the Table 8. Results for the Oxidation of Secondary Alcoholsa
a
All the reactions were performed without pH adjustment using aq. NaHCO3. bYields were determined by GC using an internal standard method. Numbers in parentheses refer to isolated yields. 1931
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Scheme 7. Reaction of Thioanisole with NaOCl
Table 11. Reaction of Thioanisole (Sulfide) with NaOCl· 5H2O in a Mixture of Various Organic Solvents and Water
1
H NMR ratios (%) (CH3 protons)
water (run 5), the reaction did not reach completion even after 20 h affording the sulfoxide in an unsatisfactory yield accompanied by a significant amount of the sulfone. Since NaOCl·5H2O crystals are hard to dissolve in pure acetonitrile, the reaction proceeds very slowly. 5.1.2. Selective Synthesis of Sulfoxides from the Reaction of Sulfides with NaOCl·5H2O. The optimized oxidation of sulfides with 1.1 equiv of NaOCl·5H2O in aqueous acetonitrile was used for the synthesis of various sulfoxides (Table 13). The desired sulfoxides were selectively obtained in high yields in all cases. It is notable that an alkene moiety (entry 6) and a pyridine ring (entry 12) were inert under these reaction conditions. 5.2. Efficient Synthesis of Sulfones from Sulfides.15 Synthetic studies of the sulfone by the oxidation of sulfides with NaOCl·5H2O and conventional aq. NaOCl were examined. Under similar conditions to sulfoxide synthesis, using 2.4 equiv of NaOCl·5H2O gave the desired sulfone in 78% yield along with α-chlorinated compounds. After the solvent survey, aromatic hydrocarbons were found to be optimal solvents to give excellent results as shown in Table 14. The reaction of several sulfides with 13 wt % NaOCl prepared from NaOCl·5H2O and water in toluene produced the desired sulfones in good yields in most cases (Table 15). A plausible reaction mechanism is shown in Scheme 8. The sulfur atom of sulfide is chlorinated by hypochloric acid, and the chlorine atom of A is substituted for oxygen to form the sulfoxide. The sulfur atom of the sulfoxide is similarly oxidized to produce the sulfone. In polar solvents, alkali species readily dissolve in the reaction mixture and cause α-deprotonation of sulfoxides and/or sulfones. The resulting α-carbanions react
run
solvent
time (h)
sulfide
sulfoxide
sulfone
1 2 3 4 5 6 7
CH3CN CH2Cl2 CH2Cl2 + 5 mol % Bu4HSO4 EtOAc EtOAc + 5 mol % Bu4NHSO4 toluene toluene + 5 mol % Bu4NHSO4
0.3 24 3.5 24 3 24 4
0 50 13 8 13 42 38
98 43 68 69 68 4 7
2 7 19 23 19 54 55
Table 12. Optimization for the Ratio of Acetonitrile to Water
1
H NMR ratios (%) (CH3 protons)
run
CH3CN:H2O (v/v)
time
sulfide
sulfoxide
sulfone
1 2 3 4 5
5:1 10:1 20:1 50:1 100:0
15 min 15 min 15 min 15 min 20.5 h
0 3 2 3 20
98 96 97 96 72
2 1 1 1 8
with hypochloric acid to form the chlorinated byproducts. On the other hand, alkali species are hard to dissolve in nonpolar organic phase containing reactants and products; therefore, productions of the chlorinated byproducts are suppressed. 5.3. Synthesis of Sulfonyl Chlorides from Disulfides or Thiols.16 Sulfonyl chlorides are very important compounds in organic synthesis as precursors to sulfonic esters, sulfonamides, sulfonic anhydrides, sulfonic hydrazide, sulfonyl azide, and so forth. The representative method for the preparation of sulfonyl chlorides is the oxidative chlorination of disulfides or thiols.17
Table 10. Reactivity of NaOCl·5H2O and Conventional Aqueous NaOCl Solutions
1
H NMR ratios (%) (CH3 protons)
run
NaOCl
pH
time
sulfide
sulfoxide
sulfone
1 2 3 4 5 6 7 8
prepared from NaOCl·5H2O conventional aqueous solution + HCl prepared from NaOCl·5H2O + NaOH conventional aqueous solution prepared from NaOCl·5H2O + HCl prepared from NaOCl·5H2O + HCl prepared from NaOCl·5H2O + HCl prepared from NaOCl·5H2O + HCl
11 11 13 13 10 9 8 7
20 min 20 min 4h 4h 20 min 20 min 4h 4h
1 0 18 5 1 8 37 38
99 97 66 79 98 88 8 7
0 3 16 16 1 4 55 55
1932
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Table 13. Reaction of Sulfides with NaOCl·5H2O in Aqueous Acetonitrile
Table 15. Synthesis of Sulfones from Sulfides
a Sulfide (10 mmol), toluene (30 mL). bSulfide (10 mmol), toluene (10 mL). c1 mol % of (C8−10)3NMeCl was used. dAccompanied with the sulfoxide (partially oxidized compound) (41%). eGC yield by using an internal standard. fIsolated yield.
Scheme 8. Plausible Reaction Mechanism for the Oxidation of Sulfides to Sulfoxides and Sulfones
a
CH3CN (10 mL) and H2O (2 mL) were used. bThioanisole (2.48 g, 20 mmol), aqueous 20.6% NaOCl (7.59 g, 21 mmol) from NaOCl· 5H2O, and CH3CN (100 mL) were used. A water bath (ca. 20 °C) was used to control the reaction temperature for a gram-scale synthesis. cDichloromethane was added to dissolve the sulfide in the solvent. Bu4NHSO4 (0.05 equiv) was also added.
Many reagents are proposed though there are some issues such as being toxic, hazardous, explosive, or relatively expensive. An environmentally benign and economical preparation method of sulfonyl chloride is therefore in great demand. We expected that NaOCl·5H2O could oxidize and chlorinate disulfides or thiols to effectively form the corresponding sulfonyl chlorides.18 5.3.1. Optimization of the Reaction Conditions. A search for the appropriate solvent found only acetic acid (Table 16). To occur the oxidative chlorination from disulfide to sulfonyl
chloride, 5 equiv of HOCl is necessary based on the following experiment. The mechanism is assumed in the original document.16
Table 14. Solvent Effect for the Oxidation of Thioanisole by NaOCla
GC area %b run
solvent
time (h)
sulfoxide
sulfone
chloromethyl sulfoxide
chloromethyl sulfone
1 2 3c 4 5 6 7
acetonitrile toluene toluene chlorobenzene 2-chlorotoluene dichloromethane ethyl acetate
6 6 3 4 2 6 2
8 0 3 0 0 36 0
78 99 94 99 98 62 63
5
