Saccharin: a cheap and mild acidic agent for the synthesis of azo dyes via telescoped dediazotization

1 Introduction

The reduction of environmental, human health, and safety risks of chemicals and synthetic procedures is the foremost goal of green chemistry, which can be achieved by redesigning toxic molecules, synthetic routes, and industrial processes. Reducing the amount of waste generated in reactions, recycling certain reagents, improving energy efficiency, minimizing potential accidents, preparing the biodegradable or recyclable products, using sustainable raw materials, and avoiding molecules linked to toxicity are some routes in green chemistry. New catalysts, low-risk solvents, and reagents as well as new experimental processes are developed by green chemistry researches [1].

Azo compounds have gained broad applications in pharmaceutical, cosmetic, food, and dyeing/textile industry and analytical chemistry due to their specific physicochemical and biological properties. These compounds have shown potential in areas of nonlinear optics and electronics, drug delivery, chemosensors, liquid crystals, photochemical molecular switches, molecular shuttles, nanotubes, and optical storage media and in the preparation of protective eye glasses and filters [2]. Azo dyes also exhibit a variety of interesting antibiotic, antifungal, and anti-HIV activities [3]. The azo compounds were studied as a definitive diagnosis of Alzheimer’s disease via imaging of amyloid plaques in the brain of patients with Alzheimer’s disease [4].

Saccharin (Sac-H) (pKa=1.31) [5] is a cheap artificial sweetener and a calorie-free additive that was widely used in the food and drug industries [6]. The saccharin ring moiety has obtained considerable attention in the past decades as a key structural element in several biologically active compounds ranging from enzyme inhibitors to receptor ligands such as leukocyte elastase inhibitors and 5-HT1A agonists [7]. N-substituted saccharin derivatives proved to be atypical and selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results represent that most of them inhibited cancer-related human carbonic anhydrase viz. hCA XII and hCA IX, whereas they were poorly active against hCA II and hCA I [8], [9], [10], [11].

The azo coupling reaction is an important procedure for the synthesis of azo compounds because the variety of the coupling and diazo components can be used and an enormous range of possible azo compounds can be produced [2].

The ability to couple the unstable intermediates into a subsequent consuming reaction step drastically increases the safety profile of many organic transformations [1], [12], [13]. The arenediazonium salts have shown particular versatility as reactive intermediates, which are prepared and directly reacted in a subsequent process in flow synthetic processes [14], [15], [16], [17]. Most arenediazonium salts in dry state are potentially explosive chemicals; therefore, extreme care should be applied in handling/storing these intermediates, and it is well known that the nature of their counter-anion plays an important role on their stability [2], [18]. However, these arenediazonium salts have some drawbacks, and the development of an efficient and cost-effective reagent seems required.

Our ongoing researches are intended to develop new catalysts and reagents as well as procedures with higher energy efficiency to address an eco-friendly and sustainable method in organic transformations [19], [20], [21]. Recently, stable arenediazonium bis(trifluoromethane)sulfonimides were easily synthesized through diazotization of aniline derivatives with tert-butyl nitrite in the presence of bis(trifluoromethane)sulfonamide and glacial HOAc [22]. Bis(trifluoromethane)sulfonamide is commercially available but is expensive. Based on the structural similarity of o-benzenedisulfonimide and saccharin, we were interested to explore the potential of saccharin as an inexpensive and safe reagent for the generation of stable arendiazonium saccharin salts from aryl amines. To our pleasant surprise, the investigations clarified that this prediction is correct and the synthesis of azo coupling can be efficiently performed in high yield in one-pot synthesis by using stable arenediazonium saccharin intermediates. Then the diazotization reaction was followed with azo coupling reaction (Scheme 1). Tert-Butyl nitrite was chosen as the diazotizing reagent because it does not involve metal wastes as do NaNO₂ and therefore greatly lowers the risk of pollution and also sodium nitrite does not meet the requirements of green chemistry in strongly acidic solutions. The mixture of saccharin and neat acetic acid was utilized as a cheap and mild acidic medium, thus the aniline derivatives containing acid-sensitive functional group can be tolerated. In order to reduce the amount of waste, the diazonium intermediates were not isolated and purified; the reaction was done via the telescopic procedure.

Scheme 1:

Modified Knoevenagel’s method for synthesis of 4-hydroxy-3-[(E)-aryldiazenyl]-benzaldehyde derivatives via stable arenediazonium saccharinates.

2 Materials and methods

3 Results and discussion

The mixture of saccharin (Sac-H), glacial acetic acid, and tert-butyl nitrite in ethanol was slowly stirred for 10 min at low temperature (ice bath). Then aryl amine (1a–l) was added dropwise, and stirring was gently continued at low temperature until the aniline derivative disappeared (monitored by TLC and the color test of azo coupling with 2-naphthol). At a higher temperature, the reaction gave byproducts and several spots were observed on TLC. Finally, the arenediazonium saccharinate was added dropwise to the basic solution of 4-hydroxy benzaldehyde in ethanol to afforded azo products. After work-up, pure saccharin was recovered in 84–90% yield and was utilized to the synthesis of the diazonium saccharin salts. The arenediazonium saccharinate solutions (2a–l) were stable to be kept in the refrigerator (4°C) for 1 week without any loss of activity. When aniline was reacted under optimized conditions in the absence of saccharin, 3a was not obtained, and this proved that saccharin plays a much more important role in the present reaction (monitored by GC-MS).

Whitehead and Traverso [23] prepared 3-amino-1,2-benzisothiazole-1,1-dioxides by refluxing saccharin with excess alkyl or aralkyl amines (no aryl amines) boiling at least at 130°C for more than 8 h. To the best of the authors’ knowledge, there have been no reports presented on the reaction of saccharin and aryl amines at low temperature; however, a control experiment was carried out to investigate it. No 3-amino-1,2-benzisothiazole-1,1-dioxide was observed when saccharin, aniline, and glacial acetic acid were stirred in ethanol at room temperature for 1 h (GC-MS analysis), which signifies that the reaction did not proceed at all. Furthermore, it was reported that when thiosaccharin was treated with amines in methanol at room temperature, the alkyl or aryl ammonium saccharinates were obtained in good yields [24]. Therefore, it seems that aniline cannot act, as nucleophile attacks the C atom of the carbonyl group in saccharin to form 3-amino-1,2- benzisothiazole-1,1-dioxide.

In order to investigate the stability of the diazonium saccharinate in dry state, the dry 4-methoxyphenyldiazonium saccharinate (2j) was isolated in 88% yield in the diazotization step. This solid salt was dried at room temperature overnight and then was kept in the refrigerator (4°C) for 1 week. Then the basic solution of 4-hydroxybenzaldehyde was added to dry diazonium salt, which offered 78% yield of 4-hydroxy-3-[(E)-(4-methoxyphenyl)diazenyl]benzaldehyde (3j). It seems that extensive delocalization of the charge over the -CO-N-SO₂- framework, assisted by the withdrawing inductive effect of the benzene ring, makes [Sac]¯ anion and the corresponding salt highly resonance-stabilized [22].

Aryl amines (1a–l) containing electron-withdrawing and electron-donating substituents gave azo coupling products in good to excellent yields (Table 1, entries 2, 7, 9 and 10). As previously reported [22], there is no clear correlation between electronic effects of substituents on aromatic ring and reaction rate and yield (Table 1). It seems that electronic effect of the substituent at the first step is compensated in the second step (Table 1, entries 7, 9 and 2, 10). Steric effects of substituents on aryl amines decreased both the yield and the reaction rate; for example, ortho-substituent anilines and the sterically hindered aniline viz., 2,6-diisopropylaniline, offered lower yields within longer reaction times (Table 1, entries 3, 5 and 8). The hetero-anilines such as 3,4-(methylenedioxy) aniline and 4-morpholineoaniline also gave good yields under optimal conditions (Table 1, entries 11 and 12). The present method was successfully applied on a macro scale viz., 20 mmol of 4-methoxyaniline (1j) was converted into 4-hydroxy-3-[(E)-(4-methoxyphenyl)diazenyl]benzaldehyde (3j) in 75% isolated yield.

According to the plausible mechanism (Scheme 2), the nitoso cation (⁺N=O↔N≡O⁺) as a mild electrophile is produced from saccharin and tert-butyl nitrite in the first step. Then the nitrogen atom of aniline reacts with a nitoso cation (⁺N=O↔N≡O⁺) to form arenediazonium saccharin salt, which is greatly stabilized by resonance. The presence of such a delocalization was confirmed in the crystal structure of some of the sulfonamide salts [25]. Then an electrophilic substitution reaction occurs in the second step. 4-Hydroxybenzaldehyde activated in mild basic medium react with diazonium cation in [ArN₂]⁺[Sac]¯ salt followed by the loss of a proton to restore the aromaticity of the ring, and finally, the corresponding azo coupling product is afforded.

Scheme 2:

The diazotization process of aryl amines in presence of saccharin and tert-butyl nitrite, followed by azo coupling reaction with 4-hydroxybenzaldehyde.

In order to compare, the intermediates of 4-methoxybenzenediazonium 4-methylbenzenesulfonate, o-benzenedisulfonimide, and bis(trifluoromethane)sulfonimide were obtained in 32% [4], 89% [26], and 90% [22] yield, respectively, whereas 4-methoxyphenyldiazonium saccharinate (2j) offered to yield 81% with the same amounts of reactants in the present method. o-Benzenedisulfonimide and bis(trifluoromethane)sulfonamide worked well for the preparation of stable arenediazonium salts; however, these reagents are too expensive for large-scale application. On the other hand, the synthesis of o-benezenedisulfonimide is very laborious and demands expensive, toxic, and fatal reagents [27].

4 Conclusion

In summary, an efficient and cost-effective telescopic catalyst-free reaction to the synthesis of azo compounds was developed by using tert-butyl nitrite and a mixture of saccharin and glacial acetic acid in ethanol mixed solvent followed by the azo coupling reaction with 4-hydroxybenzaldehyde. The stable arenediazonium saccharinates were stored for long periods of time and then were used without any loss of activity and ascertained threads. The current method has advantages such as reduced waste, cost-effectiveness, simple experimental and environmentally benign procedure, and good yield of the products with potential use as azo-dyes, pigments, and therapeutic agents and the reactants in heterocyclic synthesis.