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. What are the dangers of working with benzenesulfonyl chloride?

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from http://physchem.ox.ac.uk/MSDS/BE/benzenesulfonyl_chloride.html

Safety data for benzenesulfonyl chloride

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General
Synonyms: benzenesulphonyl chloride
Molecular formula: C6H5SO2Cl
CAS No: 98-09-9
EC No:
Physical data
Appearance: colourless oily liquid
Melting point: 15 C
Boiling point: 251 C
Vapour density: 6.0 (air = 1)
Vapour pressure:
Density (g cm-3): 1.38
Flash point:
Explosion limits:
Autoignition temperature:
Water solubility: negligible
 
Stability
Stable. Incompatible with water, strong oxidizing agents, strong bases, methyl formamide, dimethyl sulfoxide.
Toxicology
Toxic. May be fatal if swallowed, inhaled or absorbed through the skin. Corrosive - causes burns. Eye, skin and respiratory irritant. Readily absorbed through the skin. Chronic exposure may lead to liver damage.
Toxicity data
(The meaning of any abbreviations which appear in this section is given here.)
ORL-RAT LD50 1960 mg kg-1
IPR-RAT LD50 76 mg kg-1
IHL-RAT LC50 32 ppm/1h

Risk phrases
(The meaning of any risk phrases which appear in this section is given here.)


Transport information
Personal protection
Safety glasses, gloves, good ventilation.
Safety phrases
(The meaning of any safety phrases which appear in this section is given here.)


Please take necessary precautions Antoncho!!

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2. Can anyone advise SWIM how to quickly and mildly destroy SO2 (so as to make further work-up of postreaction mixtr a more tolerable xperience)

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Let fumes go through washing bottle w/ NaOH-sol. ?

[1,2] RSH + 3 X2 + 2 H2O __> RSO2X + 5 HX

[2] RSSR + 5 X2 + 4 H2O __> 2 RSO2X + 8 HX

[3] R3Al __ +SO2 __> (R-SO-O)3Al __ +Cl2 __> RSO2Cl + AlCl3

          NH2                               NH2
         /                                 /
[4] RS-C(+) + 3 Cl2 + 2 H2O __> RSO2Cl + ClC(+) + 4 HCl _H2O_> CO2 + 2 (NH4+ + Cl-) 
         \                                 \ 
          NH2                                NH2                      


[1]Duglass, I.B.; Johnson, T.B.: J. Amer. chem. Soc. 60 (1938) page 1486
[2]Duglass, I.B.; Farah, B.S.; Thomas, E.C.: J. org. Chemistry 26 (1961) page 1996
[3]Patent US3134809(1964)
[4]Johnson, T.B.; Sprague, J.M.: J. Amer. chem. Soc. 58 (1936) page 1348
   Sprague, J.M.; Johnson, T.B.: J. Amer. chem. Soc. 59 (1937) page 1837

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Yield         81%
Reagents      bentonite clay, aq. HNO3	
Solvent       hexane	
Time          5 hour(s)	
Other         Heating

Other nitration rxns give mixtures of isomeres, mostly ortho.

The 4-nitrotoluene is subsequenttly reduced to 4-methylaniline. For this type of reaction there's 100's of high yield variations out there, don't know what the latest trend is around here.

[1]Bahulayan, Damodaran; Narayan, Gopinathan; Sreekumar, Vellalath; Lalithambika, Malathy; SYNCAV; Synth.Commun.; EN; 32; 23; 2002; 3565 - 3574.

Scheme 7:
cmpd. 15 is 4-[4-(-4-Triflouromethyl-phenyl)-thiazol-2-yl]-phenylamine hydrobromide

cmpds 3,20,21 and 18 result from substitution of the -NH2 in 15 with R.

3 : R=SO2Cl
18: R=SO3H
20: R=SO2Br
21: R=Cl

Thus, treatment of the hydrobromide salt of aniline 15 with sodium nitrite in a mixture of glacial acetic acid and aqueous hydrochloric acid afforded the corresponding diazonium salt. Treatment of the resulting slurry with sulfur dioxide and copper salts afforded a mixture of sulfonyl halides 3 and 20, which crystallized directly from the reaction mixture. Some undesired aryl chloride 21 and bromide 14 (via a Sandmeyer reaction) as well as sulfonic acid 18 were also generated, but these were all removed in the crystallization.

Further optimization of these conditions was pursued to ensure that this process can be performed safely.

Diazotization of 15 occurs rapidly to afford a bright, yellow diazonium salt, much of which is out of solution. Thermal analyses of these solids showed their potential for extremely rapid, exothermic decomposition. In contrast, in solution, only slow and low energy decompositions were observed. Thus, a process was developed in which all of the diazonium salt remained in solution and in which the chlorosulfonylation reaction was executed at or below room temperature. The solubility of the diazonium salt in several water miscible organic solvents was found to decrease in the following order: DMF>THF, acetonitrile>acetone> dioxane. Further evaluation demonstrated that acetonitrile was the best solvent for our process.

For the chlorosulfonylation step, both copper(I) and copper(II) salts (chlorides, bromides, acetates and triflates) were effective in catalyzing the reaction with sulfur dioxide. With copper(I) salts the reaction was generally faster and more vigorous than with copper(II) salts. The latter were preferred since they allowed better control of temperature and foaming, which is caused by the liberation of nitrogen during this step. Aryl chloride 21 and sulfonic acid 18 are the principal side products in this reaction. Optimization studies showed that minimizing the amount of water and increasing the SO2 concentration reduces the formation of 18 and 21, respectively (Table 2).

Entry Equiv. SO2   Rxn time (h) 3vs21   3yield, A% purity
1      2.2         23            4/l      75%   94.9 A%
2     10.0          7           13/1      90%   97.8 A%
3     16.0          3           18/1      92%   98.2 A%
4     32.0          3           36/l      93%   99.1 A%

 The reaction rate, yield and purity of the product increased as more SO2 was used. On the other hand, it is also important to keep the excess of corrosive SO2 to a minimum. Thus, we arrived at an optimum charge of --20 equiv. Of SO2. The gas can be introduced by either adding a 30% solution in acetic acid (saturated) or by passing gaseous SO2 into the reaction mixture directly. On larger scale condensation of the gas can be conveniently achieved by introduction into a closed vessel at a pressure of 5 psig at 5°C. Emission of SO2 can be controlled by using a caustic scrubber in the venting lines of the reaction vessel and water for the bay scrubber.

Under optimum conditions, a mixture of 3 and 20 was produced in a 2.6:l ratio and 84% overall yield starting with the HBr salt of aniline 15, which was prepared from readily available bromoketone 6 (F3C-PhCOCH2Br). The use of a mixture of sulfonyl halides was inconsequential for the next step. Pure sulfonyl chloride could be prepared by using either the HCl salt of 15 (prepared from chloroketone 7) or its free base. Pure sulfonyl bromide 20 could be prepared by running the reaction with concentrated HBr instead of concentrated HCl. Detailed hazard evaluation showed that our optimum process was operationally safe. Subsequent reaction of aniline free base 15 on multi-kg scale afforded sulfonyl chloride 3 in a reproducible 90% overall yield and excellent purity.

Table 3. Diazotization: acetonitrile, acetic, HCl, 1.2 equiv. NaNO2, 5°C Chlorosulfonylation: 21-33 equiv. SO2, 1.26 equiv. CuCl2, RT age

Substrate       Product                   Yield
para-toluidine  toluenesulfonylchloride   99%
etc...

In an effort to demonstrate the scope of our newly developed diazotization/chlorosulfonylation procedure we examined five other anilines (Table 3). In each case, corresponding sulfonyl chloride was isolated in high yield and purity (>98%) after filtration of the crude reaction mixtures. Impurities were rejected to the acetonitrile-rich mother liquors and recrystallization of the products was not necessary. The procedure is most likely safe in these cases too since all diazonium salts were completely solubilized. In the case of aniline 28 some diazonium salt was out of solution. It is projected that some additional development on a case-by-case basis can circumvent this potential problem.

In conclusion the diazotization/chlorosulfonation reaction outlined above provides the most practical and economic approach to sulfonyl chloride 3. All operations are performed in the 5-25°C range, and inexpensive and readily available reagents are used. The desired product can be isolated directly from the crude reaction mixture via a simple filtration. Importantly, starting with regioisomerically pure aniline 15 guarantees the production of pure sulfonyl chloride 3. It should be noted that solubilization of the diazonium salt intermediate significantly reduces the potential hazard of working with this high-energy species. Indeed, this process has been safely scaled up to prepare multi-kg quantities of sulfonyl chloride 3 in high yield and purity.

4-[4-(-4-Triflouromethyl-phenyl)-thiazol-2-yl]-phenylsulfonylchloride.

From 15.HBr salt: the aniline hydrobromide salt 15 (50 g, 0.125 mol) was suspended in 500 mL of acetonitrile and cooled over an ice bath. Concentrated HCl (200 ml.) was added to afford a creamy mixture. A solution of NaNO2 (10.3 g, 0.150 mol) in 25 mL of water was added via an addition funnel over 10 min. The temperature rose to 10°C during the addition, and an HPLC assay after 25 min showed complete conversion to the diazonium salt. A 30 wt% saturated solution of SO2 in acetic acid (300 mL) was poured into the reaction mixture. Then, a solution of CuCl2*2H2O (10.6 g) in 25 mL of water was added. In a few minutes, the dark solution yielded thick brown precipitates. Over time, tan solids of the sulfonyl chloride formed. After stirring for 2.5 h these solids were filtered and rinsed 250 mL of acetic acid, 200 mL l:l mixture of acetic acid/water and 800 mL of water. The solids were dried to afford sulfonyl chloride 3 (44 g, 92.5% pure, 81% yield) as a light yellow solid. This product was a 72:28 mixture of sulfonyl chloride and sulfonyl bromide, as determined by titration.

From 15 free base: in a glass pressure vessel, aniline freebase 15 (16.04 g, 50 mmol) was dissolved in 400 mL of acetonitrile at room temperature, and 40 mL of acetic acid was added. Concentrated HCl (40 mL) was added slowly over 2 min to afford a thick slurry, which was cooled to 5°C. A solution of NaNO2 (4.14 g, 60 mmol) in 10 mL of water was added over 1 min, and the resulting solution was stirred for 20 min at 5°C. The vessel was pressurized over 35 min with SO2 gas (88.7 g, l.38 mol) from a cylinder to 5 psig, keeping the temperature at <10'C. Then, a solution of CuCl2.2H20 (8.52 g, 50 mmol) in 10 mL of water was added. The temperature was allowed to rise to 18°C over 10 min and the mixture was stirred for 4 h at room temperature. The slurry was filtered and rinsed sequentially with 50 mL of acetonitrile, 150 mL of water, and 50 mL of acetonitrile. The solids were vacuum dried overnight to afford sulfonyl chloride 3 (18.6 g, 99.5% pure, 91% yield).

4.2.15. 4-Benzoyl-benzenesulfonyl chloride (23) (representative procedure).

4-Aminobenzophenone 22 (3.94 g, 20.0 mmol) was dissolved in 160 mL of acetonitrile and after cooling to 0-5°C, 16 mL of acetic acid and 8 mL of concentrated HCl were added. To the mixture was added NaNO2 (l.66 g, in 3 mL water) over 10 min at < 5°C. After stirring 20 min, SO2 gas (42 g) was bubbled in over 40 min keeping the mixture <7°C. A solution of CuCl2 (3.4 g, 25 mmol) in water (3 mL) was added and the mixture was allowed to warm and stir for 16 h at room temperature. The mixture was concentrated to 80 mL and was cooled to 0-5°C. The solids were filtered, washed with 20 mL of water, and dried to afford sulfonyl chloride 23 (5.27 g, 94% yield) as a pink solid; mp 96-97°C. 1H NMR (400 MHz, CDCl3): S 7.55 (m, 2H), 7.66 (m, lH), 7.82 (m, 2H), 8.00 (m, 2H), 8.17 (m, 2H). 13C NMR (100 MHz, CDCl3): S 127.0, 128.7, 130.l, 130.7, 133.6, 136.0, 143.5, 146.6, 194.5. Anal. Calcd for C13H9ClO3S (280.73): C, 55.62; H, 3.23; Cl, 12.63; S, 11.42. Found: C, 55.55; H, 3.23; Cl, 12.54; S, 11.25.
4.2.14.

Full Ref:  Ikemoto, Norihiro; Liu, Jinchu; Brands, Karel M. J.; McNamara, James M.; Reider, Paul J.; TETRAB; Tetrahedron; EN; 59; 8; 2003; 1317 - 1326.

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