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Synlett 2025; 36(11): 1514-1519
DOI: 10.1055/a-2538-2843
letter

Photochemical Aerobic Sulfide Oxidation in Cοmplex Environments – from Alcoholic Beverages to Vinegar

Manos V. G. Lantzanakis
,
Charikleia I. Karaousta
,
Stamatis K. Serviou
,
Naya A. Stini
,
Elpida Skolia
,
Ierasia Triandafillidi
,
Anastasia Bota
,
Vera P. Demertzidou 
,
Christoforos G. Kokotos

The authors gratefully acknowledge the Hellenic Foundation for Research and Innovation (HFRI) for financial support through a grant, which is financed by the 1st Call for HFRI Research Projects to Support Faculty Members and Researchers and a procurement of high-cost research equipment grant (grant number 655).
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Abstract

Throughout the years, various photochemical processes have been developed in common organic solvents and attempts to find greener solutions have provided excellent results. Yet, escaping from common organic solvents has become a challenge. Herein, we present a photochemical aerobic oxidation of sulfides, where commercially available drinks or products are used as the solvent under catalyst-free conditions.


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Key word

photochemistry - aerobic oxidation - sulfides - sulfoxides - alcoholic beverages

The oxidation of sulfides is the most widely used method to achieve highly valued sulfoxides. Sulfoxides are key structural motifs in pharmaceutical compounds, such as modafinil,[1] sulindac[2] and omeprazole.[3] The oxidation of sulfides has been studied extensively in the past, employing various oxidative systems, employing organometallic reagents,[4] organocatalysts[5] or biocatalysts,[6] as well as various oxidation systems, including H2O2 [7] or O2.[8] Nonetheless, there is still room for improvement in advancing the efficacy and environmental sustainability of these transformations.

Since the seminal report on the oxidation of sulfides in 1865,[9] this useful transformation has been studied thoroughly. Metal-catalyzed protocols have been very informative,[10] providing mechanistic insight, while organocatalytic examples have taken a stand to promote environmentally friendlier methodologies.[11] However, even the ‘greener’ protocols, utilizing the activation of hydrogen peroxide, can still be characterized as waste-intensive, in comparison to more recent advancement in oxidation techniques. The undeniably most environmentally benign method to avoid such waste is the use of molecular oxygen as the oxidizing agent, particularly when harnessed through photoinitiated techniques.[12]

Photochemistry has heavily impacted a variety of transformations in organic chemistry. This advancement gained momentum, after MacMillan, Stephenson, and Yoon presented seminal reports on photoredox catalysis back in 2008.[13] However, the potential of photochemical transformations employed for the oxidation of sulfides dates back in 1962, when Schenck presented the first photochemical oxidation of sulfides.[14] After this contribution, a plethora of protocols has been introduced in the literature. Metal-oriented[8] [15] or heterogenous photocatalysts[8,16] have been implemented successfully in the aerobic oxidation of sulfides, while photoorganocatalytic systems have also made a commendable impact in this transformation.

Photoorganocatalysis has provided the available means to use small organic molecules to further increase the green character of this oxidative transformation.[8] [17] A plethora of naturally occurring compounds have shown photochemical properties, especially in oxidative transformations and sulfoxidations. Prime examples are flavins and their derivatives that have been explored thoroughly by Cibulka and Zhao.[18] Emodin and cercosporin, two naturally occurring molecules, have also exhibited successful results, as photocatalysts,[19] while organic dyes, such as rose bengal, BODIPY dyes, or perilene diimides, are all examples that have successfully accelerated the oxidation of sulfides.[20] Finally, even smaller organic compounds have been used for this oxidation with thioxanthone and its derivatives being key examples.[21] An interesting approach to this transformation was the use of a more complex system, consisting of CF3SO2Na and bis(2-butoxyethyl)ether, from He and his colleagues,[22] while other catalytic approaches constitute the use of known photocatalysts, anchored on carbon-oriented or other recyclable materials.[23] The Kokotos group has utilized their knowledge in photochemical oxidations,[24] reporting new methods to oxidize sulfides in the past 4 years.[25]

An even greener approach to photochemical transformations is the promotion of reactions under catalyst-free conditions. Albini and coworkers first reported a catalyst-free protocol for sulfide oxidation under UV irradiation[26] and in 2021, Sun and his coworkers oxidized aryl-alkyl sulfides under blue LED irradiation.[27] The Kokotos group has also made significant strides in advancing catalyst-free methodologies, particularly with their 2022 publication on sulfide oxidation (Scheme [1, 2]).[28] With our previous work in mind and inspired by the use of beverages from Wennemers as media in enantioselective organocatalytic reactions (Scheme [1, 1]),[29] we present herein an aerobic catalyst-free photochemical sulfide oxidation, utilizing alcoholic beverages as the solvent for the aerobic photochemical oxidation of sulfides (Scheme [1, 3]).

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Scheme 1 Use of complex environments for chemical transformations, catalyst-free photochemical sulfide oxidation and this work

Building on our previous work,[28] which provided a catalyst-free protocol, and utilizing a variety of over-the-counter available products as possible solvents, we initiated the optimization experiments (Tables 1 and 2). Phenyl methyl sulfide (1a) was used as the model compound for aryl-alkyl sulfides and dodecyl methyl sulfide (1j) for alkyl-alkyl compounds. Driven by the irradiation screening conducted in our previous catalyst-free sulfoxidation study,[28] we opted for 370 nm irradiation, which was proven to be the most efficient, whereas for irradiation in higher wavelengths, the addition of a catalyst was crucial for the reaction progression.[28] Additionally, we conducted reactions on water and in ethanol, as an initial screening, to assess the reaction conditions on more commonly used solvents that are representative relative to the complex environments that were used later.

Table 1 Aerobic Photochemical Oxidation of Aryl-Alkyl Sulfides in Complex Solvent Environment

Entry

Solvent

Yield of 2a (%)a

 1

H2O

27

 2b

EtOH

97

 3

cola

50

 4

carbonated orange juice

 5

 5

energy drink

67

 6

soda

13

 7

beer

 7

 8

apple cider

 3

 9

wine

15

10

commandaria

 2

11

limoncello

 2

12

Jägermeister

38

13

dry gin

38

14

white rum

63

15

vodka

52

16

tequila

62

17

whiskey

59

18

ouzo

14

19

raki

68

20

vinegar

43

21

apple cider vinegar

50

22b

white rum

88

23c

white rum

 2

24d

white rum

28

25b

tequila

82

26b

whiskey

59

27b

raki

63

a Yield determined by 1H NMR spectroscopy via internal standard.

b The reaction mixture was irradiated for 5 h.

c The reaction mixture was irradiated under CFL Lamps for 5 h.

d The reaction mixture was irradiated under sunlight for 5 h.

In the case of phenyl methyl sulfide, water proved to be inefficient in promoting the reaction, while ethanol provided promising results (Table [1], entries 1 and 2). Afterwards, we explored a variety of beverages as solvents. Carbonated media, such as carbonated orange juice or soda did not provide the desired product in good yields, while cola, on the other hand, facilitated the reaction up to 50% yield (Table [1], entries 3, 4, and 6). Energy drinks provided very good results, although the existence of flavonoids (known for their photocatalytic properties in aerobic photochemical oxidations) may account for this outcome (Table [1], entry 5). Wanting to avoid the use of a possible photocatalytic pathway, we chose to exclude energy drinks from further consideration, however, this observation is worth mentioning. We then turned to alcoholic beverages, where examples with low concentration in alcohol, such as beer, wine, commandaria, or limoncello, did not lead to notable results (Table [1], entries 7–11). In contrast, solvents that contain 30–40% v/v alcohol proved to be the most effective, with whiskey, raki, white rum, or tequila being the most efficient (Table [1], entries 12–19). Vinegar and apple cider vinegar were also utilized, but the afforded results came second to those mentioned before (Table [1], entries 20 and 21). In the cases of the four most promising solvents, we increased the reaction time to 5 h, instead of 3 h, and this led to greater results, particularly in the case of white rum that ended up as the optimal medium for the aryl-alkyl substrates (Table [1], entries 22, 25–27). It has to be mentioned that the higher yield obtained for the sulfoxide in rum can be justified by the combination of ethanol with water in rum, since the addition of water in the photochemical aerobic oxidation of sulfides is known to suppress overoxidation to sulfone, since the generated sulfoxide is stabilized via hydrogen bonding with water.[28] This hypothesis was validated by performing control experiments in ethanol or ethanol/water systems, where no overoxidation product was obtained in neither case. Furthermore, efforts to circumvent the use of UV irradiation by performing experiments under sunlight or CFL irradiation were unsuccessful (Table [1], entries 23 and 24). Another crucial factor for reaction efficiency is the UV/Vis absorption spectra of the ‘solvent’. It turned out that the beverages that are more efficient for the developed transformation, have a lower absorption in the area of irradiation (see the Supporting Information).

Dodecyl methyl sulfide (1j) was utilized in a similar manner to phenyl methyl sulfide to optimize the reaction conditions for the case of alkyl-alkyl substrates (Table [2]). In this case, only tequila, dry gin, and whiskey performed exceptionally well, with tequila being the best environment for the reaction to take place (Table [2], entries 13, 16, and 19). Sunlight and CFL irradiation yielded only trace amount of sulfoxide 2j (Table [2], entries 17 and 18).

Table 2 Aerobic Photochemical Oxidation of Alkyl-Alkyl Sulfides in Complex Solvent Environment

Entry

Solvent (1 mL)

Yield of 2j (%)a

 1

H2O

14

 2

EtOH

95

 3

cola

17

 4

carbonated orange juice

10

 5

energy drink

69

 6

soda

12

 7

beer

10

 8

apple cider

 6

 9

wine

18

10

commandaria

 5

11

limoncello

 6

12

Jägermeister

65

13

dry gin

81

14

white rum

22

15

vodka

13

16

tequila

89

17b

tequila

traces

18c

tequila

 5

19

whiskey

85

20

ouzo

42

21

raki

46

22

vinegar

 –

23

apple cider vinegar

35

a Yield determined by 1H NMR spectroscopy via internal standard.

b The reaction mixture was irradiated under CFL Lamps.

c The reaction mixture was irradiated under sunlight.

With the optimal alcoholic beverage for both the oxidation of aryl-alkyl substrates and alkyl-alkyl substrates in hand, we observed the behavior of various substrates in these environments (Scheme [2]). Starting with the aryl alkyl substrates, we extended the alkyl carbon chain of phenyl methyl sulfide from one to four or eight carbons and the reaction took place effortlessly, while introducing a cyclic chain did not impact the yield heavily (Scheme [2, 2a–d]). In contrast, substrates containing the allyl or propargyl moiety proved to be exceptionally sensitive in the employed conditions, thus these resulted in low yields (Scheme [2, 2e] and 2f). Finally, oxygen-containing functionalized motifs performed very well in the tequila environment (Scheme [2, 2g–i]). The alkyl-alkyl substrate scope required extended reaction times, while also providing yields lower than expected, in comparison to our previous work, except for dodecyl methyl sulfide and dibenzyl sulfide (Scheme [2, 2j] and 2n). Specifically, extending the alkyl chain of dodecyl methyl sulfide and cyclic aliphatic sulfides were not favorable towards oxidation in the complex medium, leading to low yields (Scheme [2, 2k–q]). Sulfides containing benzylic positions were also not as productive, but provided results worth mentioning (Scheme [2, 2l–n]). The oxidation of the Boc-protected natural amino acid methionine was successful, after 40 h of irradiation and the case of an aryl-aryl substrate, diphenyl sulfide, is also reported, where 60 h of irradiation were needed to achieve 18% yield (Scheme [2, 2r] and 2o). This is a worth-mentioning result based on the mechanism of action. Finally, the precursor sulfide of modafinil was synthesized, following previously known procedures.[30] Specifically, the synthesis of modafinil (Scheme [2, 4c]) started with the reaction of benzhydrol (Scheme [2, 4a]) with thioglycolic acid in trifluoroacetic acid. Afterwards, the crude reaction mixture reacted with thionyl chloride in benzene, followed by treatment of the generated acid chloride with concentrated ammonium hydroxide to afford the precursor sulfide of modafinil (Scheme [2, 4b]). Finally, we employed our protocol to oxidize sulfide 4b to generate modafinil in 20% yield after 7 h of irradiation (Scheme [2, 4c]). The protocol was further applied to the gram-scale photooxidation of sulfide 1a, successfully yielding sulfoxide 2a with an isolated yield of 62%, after extended reaction time (120 h).

Zoom Image
Scheme 2 Substrate scope for the photochemical aerobic oxidation of sulfides in white rum or tequila

During our previous publication,[28] we studied thoroughly the mechanistic pathways for the catalyst-free UVA-irradiated oxidation of sulfides. Utilizing quenching studies, UV/Vis studies and fluorescence quenching studies and combining knowledge previously mentioned in literature, we managed to pinpoint the possible interactions and the reactive oxidizing agents that occur in the cases of each type of substrate.

Therefore, we can safely assume that the mechanism of this reaction is identical to the one reported in our previous work, where under irradiation at 370 nm, sulfide oxidation takes place under aerobic conditions.[28] The mechanistic pathway is a mixed one between an EnT (energy transfer) and a SET (single-electron transfer) pathway (Scheme [3]).[28] In the first case, the sulfide is irradiated and excited to its singlet excited state and via intersystem crossing (ISC) to its triplet excited state, where it can interact with molecular oxygen to produce singlet oxygen. Singlet oxygen is known to oxidize sulfides, by reacting with them and leading to the preferred sulfoxides via intermediate I. In the mechanistic pathway B, the sulfide is irradiated and brought to its excited state, from which it can react with molecular oxygen to form intermediate II. This intermediate can react with molecular oxygen to lead to intermediate III that can react with another molecule of sulfide to lead to the corresponding sulfoxide. The case of 2o is interesting, some diaryl sulfides can be oxidized only by following the second mechanism.

Zoom Image
Scheme 3 Proposed reaction mechanism

In conclusion, we introduce a methodology for the oxidative transformation of sulfides to sulfoxides that can occur, when over-the-counter products are used, like beverages, alcoholic drinks, or vinegar, as the solvent. Thus, we can expand the possible pool of available solvents for oxidative transformations, utilizing publicly available products or solvents, while avoiding toxic commonly used solvents. Hopefully, this work can broaden the horizons of modern chemistry into utilizing more easily available reactants to produce highly valued compounds, while reducing the environmental impact of the used protocols.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2538-2843.
  • Supporting Information

Corresponding Author

Christoforos Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens
Panepistimiopolis 15771, Athens
Greece   

Publication History

Received: 03 January 2025

Accepted after revision: 12 February 2025

Accepted Manuscript online:
12 February 2025

Article published online:
01 April 2025

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   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Use of complex environments for chemical transformations, catalyst-free photochemical sulfide oxidation and this work
Zoom Image
Scheme 2 Substrate scope for the photochemical aerobic oxidation of sulfides in white rum or tequila
Zoom Image
Scheme 3 Proposed reaction mechanism