Sulfur1

S

[7704-34-9]  · S  · Sulfur  · (MW 32.07)

(mild oxidizing agent used for the Willgerodt reaction2 and dehydrogenation of various organic compounds;3 its most recent use has been for the in situ generation of carbonyl sulfide4 from CO for the synthesis of thiocarbamates5 and other derivatives)

Physical Data: mp 119 °C; bp 444.6 °C; d 2.07 g cm-3.

Solubility: insol water; slightly sol alcohol, ether; sol carbon disulfide, benzene, toluene.

Form Supplied in: powder, flakes.

Handling, Storage, and Precautions: store in a closed bottle at ambient temperatures. Chronic inhalation of dust can cause irritation of the mucous membranes.

Willgerodt Reaction.

The first reaction of this type was carried out by Willgerodt6 on 1-acetylnaphthalene to give what was later identified as 1-naphthylacetamide (eq 1).7 This was accomplished by using an ammonium polysulfide solution in a sealed tube at 210-230 °C for 3 or 4 days. The corresponding acid salt always accompanied the amide. Another limitation is that the harsh conditions used in the original procedure gave yields of only 20-50%.

The Kindler8 modification of the reaction allows this to be carried out under anhydrous conditions at lower temperatures. The thioamide can be isolated and then hydrolyzed to the acid or reduced to the amine. Even with this important change, the reaction saw little application because it had to be carried out in an autoclave as in eq 2.9

The adoption of Morpholine as both the solvent and base led to a procedure that could be used at ambient pressure (eq 3).10a With the relatively mild temperatures (bp 129 °C), certain functionalities on the aryl ring like nitro, amino, hydroxy, and acetoxy groups can tolerate these conditions.10b

The original Willgerodt conditions found a use in converting aliphatic aldehydes and ketones to the amides in poor to moderate yields (eqs 4-7).11

This reaction can also be applied to unconventional substrates for conversion into thioamides (eq 8).12 It was found that methylphenylcarbinol, b-phenylethyl alcohol, b-phenylethyl acetate, and methylbenzylcarbinol failed to give appreciable amounts of amide when heated with a typical Willgerodt reagent at 160 °C. Unexpected results were seen with b-substituted acrylic acids (eqs 9 and 10).13 Apparently, the carboxyl group was eliminated to give an amide with one less carbon atom.

Other functionalities were found to allow the Willgerodt reaction to work on substrates that yield phenylacetamide in an attempt to elucidate the mechanism.14 Poor to good yields were obtained. A thorough review of this reaction was written by Carmack and Spielman in 1946.15

Dehydrogenation.

This reaction is another important use of elemental sulfur in organic chemistry. Sulfur is the reagent of choice for the dehydrogenation of hydroaromatic compounds because it is simpler than Selenium and may be preferred over selenium or catalytic dehydrogenation. The following example is from a systematic study that compared the three methods (eq 11).16

The dehydrogenation of aromatizable hydrocarbons works well enough to have been incorporated into an undergraduate experiment (eq 12).17

In this experiment it was necessary to use less than the theoretical amount of sulfur because the brilliantly blue product, guaiazulene, reacts with sulfur to form an intractable brown product.

More complex structures can be selectively dehydrogenated to give fair yields of products, as the example from Haede et al. illustrates (eq 13).18

Other heterocycles are good substrates for the dehydrogenation reaction (eqs 14-18).19-23

Carbonyl Sulfide Generation.

The use of Carbon Monoxide and sulfur leads to the generation of carbonyl sulfide (Carbon Oxysulfide), which is electrophilic enough to be attacked by nucleophiles present in the reaction mixture. A new synthesis of ureas based upon this intermediate was put forth (eq 19).24 This reaction starts out with each of the reactants in a different phase, liquid, gas, and solid, respectively. This simplifies the industrial process, and the in situ oxidation of carbon monoxide leads to a Phosgene synthon without the formation of ammonium salts as byproducts. In an experiment using only Ammonia, carbon monoxide, and sulfur in methanol, Franz and Applegath25 found carbonyl sulfide making up about 30% of the product gases when the reaction was run at 150 °C. Ammonium thiocarbamate was obtained in large quantities when the temperature of the reaction was held overnight at 25-30 °C with 700 psi of CO. The isocyanate group was detected by IR in an alcoholic solution of ammonium thiocarbamate (eq 20). This method has also been used to synthesize unsymmetrical ureas, with the authors postulating that aryl isocyanates are formed first which then react with primary or secondary alkyl amines to give the 1-aryl-3-alkyl- or 1-aryl-3-dialkylureas in good yield (eq 21).26

This sulfur-assisted carbonylation has also been applied to the synthesis of 4-hydroxycoumarins,27 which entails the direct formation of a C-C bond without a transition metal catalyst (eq 22).

This reaction has also been applied to the synthesis of S-alkyl carbonothioates, which requires the use of 1,8-Diazabicyclo[5.4.0]undec-7-ene and an alkylating agent (eq 23).28

Application to the synthesis of carbonates has been accomplished by inclusion of a stoichiometric amount of Copper(II) Chloride in the second step (eq 24).29

More complex heterocycles like 4-alkylidene-2-oxo-1,3-oxathiolanes have been synthesized by a related method (eq 25).30

The same group has developed a variation of this technique which provides the S,S-dialkyl dithiocarbonates from water, sulfur, carbon monoxide, and alkyl halides.31 The use of a catalytic amount of selenium provides a synthesis of S-alkyl thiocarbamates from amines, carbon monoxide, sulfur, and alkyl halides that can be carried out under ambient pressure (eqs 26 and 27).32 The intermediate (1) can undergo decomposition to carbonyl selenide which then undergoes facile exchange with sulfur to give carbonyl sulfide, which will then react as usual. At higher pressures of CO (10 atm) and 1 mol % selenium these authors can synthesize S-alkyl carbonothioates.33

Sulfide and Polysulfide-Derived Reactions.

The largest and broadest application of sulfur in organic synthesis is in the generation of sulfides and polysulfides from elemental sulfur. These polysulfides can act as nucleophiles, reductants, and oxidants. A brief survey of these various aspects of sulfides and polysulfides is in order.

Elemental sulfur is believed to dissociate in liquid ammonia according to the following series of equations (eq 28).

Sato obtained a mixture of products upon attempted reduction of 4-nitrotoluene in liquid ammonia (eq 29).34

The use of sulfur as an oxidant is more common and several examples exist. The oxidation of aromatic sulfinates with elemental sulfur in amines gives thiosulfonates almost quantitatively.35 Oxidation of benzylic carbons to aldehydes is observed with 4-nitrotoluene in a water-ethanol solvent at reflux (eq 30).36 The oxidation of both methyl groups of m- and p-xylene gave high yields of isophthalic and terephthalic acids in 87 and 96% yields, respectively (eqs 31 and 32).37

Strong nucleophiles are generated upon the reaction of excess ammonia and elemental sulfur. These have been used to prepare arenesulfinamides from S-(4-nitrophenyl) S-substituted phenyl sulfoximides (eq 33).38 The same conversion has been accomplished using 4-nitrophenyl substituted phenyl sulfoxides.39

The generation of anhydrous lithium sulfide is easily accomplished by reaction of two equivalents of Lithium Triethylborohydride with sulfur in THF at room temperature. This reacts well with a variety of electrophiles that require strictly anhydrous conditions to give good yields of products. The alkali metal disulfides are not commercially available and the methods for their preparation [Li0, NH3(l)] are difficult and give mixtures of polysulfide salts. The reaction of one equivalent of the hydride reagent with sulfur yields the lithium disulfide which gives high yields of disulfide products.40 More recently a phase transfer catalytic method of generating the disulfide in a water/chloroform mixture has been used with electrophiles that can tolerate the presence of water (eq 34).41

When sulfur reacts with Sodium Borohydride in an appropriate solvent such as THF, the sulfurated hydride NaBH2S3 is formed. The reagent is most useful for its special reactivity and not necessarily as a sulfurating agent (eqs 35 and 36). A synopsis of its range of reactions was published more than 20 years ago.42

Miscellaneous Reactions.

Sulfur will react with organometallic reagents to replace a metal-carbon bond with a sulfur-carbon bond. Since sulfur is divalent, a thiolate results which is generally not useful. In some cases, however, the thiolate is essential for further reactivity. The utility of lithium thioalkynolates in the synthesis of alkenes is outlined below (eqs 37 and 38).43

Using the same intermediate alkynylthiolates, one can prepare thioamides (eq 39).44 This sequence works for selenium derivatives as well.

A tetrahydrothiophene synthesis was accomplished by treating the carboalumination product of Triethylaluminum and terminal alkenes with sulfur (eq 40).45

Diazo compounds react with sulfur to give thioketones. Monothioanthraquinones can be synthesized from the reaction of 10-diazoanthrones with sulfur in DMF at 130-150 °C (eq 41).46

Sulfur is less reactive towards carbenes than selenium and so selenium is used in a catalytic fashion first to react with carbene-like compounds (isocyanides in this case), and then sulfur replaces the selenium to give an isothiocyanate (eq 42).47 Using this method, cyclohexyl isothiocyanate was synthesized in 89% yield using 5 mol % of Se and 1.2 equiv of S. The reaction could be run with 0.5 mol % Se with only a modest lengthening of the reaction time.

An unusual aspect of sulfur chemistry is the reaction of alkenes with elemental sulfur (eqs 43 and 44). The reaction of sulfur with norbornene in the presence of ammonia in DMF at 110 °C results in a selective and stereospecific sulfuration.48 The exo-3,4,5-trithiatricyclo[5.2.1.02,6]decane forms in about 86% yield.

Sulfur has also been used to oxidize inorganic compounds to increase their electrophilic nature. A simple synthesis of Triphenylphosphine that does not rely on organometallic reagents has been published by Olah (eq 45).49 This Friedel-Crafts reaction fails with Phosphorus(III) Chloride as well as its corresponding oxide. There exists an unfavorable disproportionation between triphenylphosphine, diphenylchlorophosphine, and phenyldichlorophosphine. The oxychloride does not give the triphenylphosphine oxide. The phosphorus sulfochloride gives the corresponding triphenylphosphine sulfide, which is easily reduced.

Olah also used Trifluoromethanesulfonic Acid catalysis for the electrophilic sulfuration of cycloalkanes.50 Elemental sulfur was heated in a stainless steel autoclave with excess cyclopentane in triflic acid at 150 °C for 12 h. This gave dicyclopentyl sulfide in 46% isolated yield (eq 46).


1. Juraszyk, H. CZ 1974, 98, 126.
2. Schwenk, E.; Papa, D. JOC 1946, 11, 798 and references cited therein.
3. Gill, N. S.; Lions, F. JACS 1950, 72, 3468.
4. Konishi, K.; Nishiguchi, I.; Hirashima, T. S 1984, 254.
5. Grisley, D. W., Jr.; Stephens, J. A. JOC 1961, 26, 3568.
6. Willgerodt, C. CB 1887, 20, 2467.
7. Willgerodt, C. CB 1888, 21, 534.
8. Kindler, K. LA 1923, 431, 187.
9. Kindler, K.; Li, T. CB 1941, 74, 321.
10. (a) Schwenk, E.; Bloch, E. JACS 1942, 64, 3051. (b) King, J. A.; McMillan, F. H. JACS 1946, 68, 2335.
11. Cavalieri, L.; Pattison, D. B.; Carmack, M. JACS 1945, 67, 1783.
12. Carmack, M.; DeTar, D. F. JACS 1946, 68, 2029.
13. Davis, C. H.; Carmack, M. JOC 1947, 12, 76.
14. Gerry, R. T.; Brown, E. V. JACS 1953, 75, 740.
15. Carmack, M.; Spielman, M. A. OR 1946, 3, 83.
16. Cocker, W.; Cross, B. E.; Edward, J. T.; Jenkinson, D. S.; McCormick, J. JCS 1953, 2355.
17. Fieser, L. F. Organic Experiments, 2nd ed.; Raytheon Education: Lexington, MA, 1968; pp 290-294.
18. Haede, W.; Fritsch, W.; Radscheit, K.; Stache, U. LA 1973, 5.
19. Piper, D. E.; Wright, G. F. JACS 1950, 72, 1669.
20. Hitchings, G. H.; Russell, P. B.; Whittaker, N. JCS 1956, 1019.
21. Wynberg, H. JACS 1958, 80, 364.
22. Grandberg, I. I.; Kost, A. N. JGU 1958, 28, 3102.
23. Asinger, F.; Diem, H.; Sin-Gun, A. LA 1961, 643, 186.
24. (a) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F. JOC 1961, 26, 3306. (b) Franz, R. A.; Applegath, F.; Morriss, F. V.; Baiocchi, F.; Bolze, C. JOC 1961, 26, 3309.
25. Franz, R. A.; Applegath, F. JOC 1961, 26, 3304.
26. Romanova, I. B.; Kutlukova, U.; Penskaya, L. V. JGU 1969, 39, 1884.
27. Mizuno, T.; Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N. S 1988, 257.
28. Mizuno, T.; Nishigushi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N. TL 1988, 29, 4767.
29. Mizuno, T.; Nakamura, F.; Egashira, Y.; Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N. S 1989, 636.
30. Mizuno, T.; Nakamura, F.; Ishino, Y.; Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N. S 1989, 770.
31. Mizuno, T.; Yamaguchi, T.; Nishiguchi, I.; Okushi, T.; Hirashima, T. CL 1990, 811.
32. Sonoda, N.; Mizuno, T.; Murakami, S.; Kondo, K.; Ogawa, A.; Ryu, I.; Kambe, N. AG(E) 1989, 28, 452.
33. Mizuno, T.; Nishiguchi, I.; Hirashima, T.; Ogawa, A.; Kambe, N.; Sonoda, N. TL 1990, 31, 4773.
34. Sato, R.; Takizawa, S.; Oae, S. PS 1979, 7, 229.
35. Sato, R.; Goto, T.; Takikawa, Y.; Takizawa, S. S 1980, 615.
36. Beard, H. G.; Hodgson, H. H. JCS 1944, 4.
37. Toland, W. G., Jr.; Hagmann, D. L.; Wilkes, J. B.; Brutschy, F. J. JACS 1958, 80, 5423.
38. Sato, R.; Saito, N.; Takikawa, Y.; Takizawa, S.; Saito, M. S 1983, 1045.
39. Sato, R.; Chiba, S.; Takikawa, Y.; Takizawa, S.; Saito, M. CL 1983, 535.
40. Gladysz, J. A.; Wong, V. K.; Jick, B. S. CC 1978, 838.
41. Hase, T. A.; Peräkylä, H. SC 1982, 12, 947.
42. Lalancette, J. M.; Fréche, A.; Brindle, J. R.; Laliberté, M. S 1972, 526.
43. Miyaura, N.; Yanagi, T.; Suzuki, A. CL 1979, 535.
44. Sukhai, R. S.; de Jong, R.; Brandsma, L. S 1977, 888.
45. Dzhemilev, U. M.; Ibragimov, A. G.; Zolotarev, A. P.; Tolstikov, G. A. IZV 1989, 38, 1324.
46. Raasch, M. S. JOC 1979, 44, 632.
47. Fujiwara, S.; Shin-Ike, T.; Sonoda, N.; Aoki, M.; Okada, K.; Miyoshi, N.; Kambe, N. TL 1991, 32, 3503.
48. Shields, T. C.; Kurtz, A. N. JACS 1969, 91, 5415.
49. Olah, G. A.; Hehemann, D. JOC 1977, 42, 2190.
50. Olah, G. A.; Wang, Q.; Prakash, G. K. S. JACS 1990, 112, 3697.

James A. Morrison

University of Wisconsin-Madison WI, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.