Efficient green synthesis of monomethine cyanines via grinding under solvent-free conditions

1 Introduction

Monomethine cyanine dyes are an important class of organic compounds that have various valuable applications in biochemistry, molecular biology, biomedicine, structural biology, tumor imaging, dye-sensitized solar cells (as sensitizers), and other research fields [1–8].

The development of less hazardous synthetic methodologies for organic reactions is one of the most sought-after objectives in current research. For the synthesis of complex molecules employing environmentally friendly green methods, reactions carried out in aqueous media have received much attention [9]. However, there have been associated drawbacks as well, primarily owing to the reduced ability of water in solvating organic reactants, making the reaction mixture heterogeneous [10]. This difficulty can be overcome using reactions in dry media or under solvent-free conditions, as they provide an opportunity to work in an open vessel, thus avoiding the risk of the development of high internal pressure and the possibility of upscaling the reaction [11]. Grindstone chemistry has been shown to be a highly viable green and rapid method for the synthesis of organic compounds without the risk associated with the use of different solvents, including water. The proposed method does not require external heating, leading to energy- efficient synthesis, and may be observed as a more economically and ecologically constructive procedure in chemistry. Grindstone chemistry has been shown to be a very practical method for desktop- as well as kilogram-scale synthesis [12]. In this work, we report on a new and green synthetic approach for some monomethine cyanine dyes, as representatives, under solvent-free conditions at room temperature, as an environmentally benign synthesis of important and widely applicable class of organic compounds.

2 Materials and methods

2.3 Green synthesis

2.3.1 Green synthesis of monomethine cyanine dye 2:

By using agate mortar and pestle under a solvent-free condition at room temperature, the starting compound (1) (0.001 mol/0.509 g) and an equimolar ratio of 1-methylpyridiniumiodide salt (0.221 g), in the presence of two drops of piperidine, were grinded for 13 min. The reaction progress was monitored by means of TLC (alumina sheets) until consistent results were attained. The red dye paste was dissolved in 20 ml ethanol, refluxed for 30 min to optimize yield, and purified by means of column chromatography eluting with ethylacetate/hexane (20:80) to obtain a red dye (2) (Scheme 1).

Scheme 1:

(2): A=1-methylpyrid-4-yl. Conventional: 50 ml EtOH/1 ml piperidine, 4 h reflux (yield: 81%) [13]. Green: 13 min grinding/two drops piperidine +30 min reflux (yield: 93%). (3): A=1-methylquinol-4-yl. Conventional: 50 ml EtOH/1 ml piperidine, 4 h reflux (yield: 77%) [13]. Green: 13 min grinding, two drops piperidine at room temperature (yield: 94%).

(2) 5-Phenyl-2-methyl-3-(1-methylpyridin-4(1H)-ylidene)methyl)- 6-oxo-1-phenyl-5,6- dihydro-1H-[1,3,4]oxadiazino[6,5-c]isoquinolin-2-ium iodide

(Yield: 93%); M.P.: 253–255°C; Mol. F.: C₃₀H₂₅IN₄O₂; Mol. Wt.: 600.45; m/z (FABMS): 600.10; Elemental analysis: (Calculated %) 60.01; H, 4.20; I, 21.13; N, 9.33; O, 5.33; (Found %) C, 59.96; H, 4.29; I, 21.15; N, 9.23; O, 5.37; ¹H-NMR: 2.41 (s, 3H-CH₃), 2.88 (s, 3H N⁺-CH₃), 4.41 (s, 1H-CH=), 5.08 (d, 2H Pyr.), 6.27–7.43 (m, 16H-Ar); ¹³C-NMR: 29.00 (N-CH₃), 42.78 (N⁺-CH₃), 102.10–130.99 (19CH), 132.98–154.64 (7C), 157.90 (C=O), 163.34 (O-C=N).

2.3.2 Green synthesis of monomethine cyanine dyes 3, 5, and 7:

This synthesis was established by grinding, by means of agate mortar and pestle (0.001 mol), of the starting compounds 1, 4, and 6 (0.001 mol/ 0.509 g, 0.500 g, and 0.426 g), and an equimolar ratio of the 1-methylquinoliniumiodide salt (0.001 mol/0.271 g) under a solvent-free condition at room temperature for 13, 18, and 15 min, respectively. The mixtures were rinsed with two drops of piperidine catalyst with continuous grinding, and a reddish violet paste was formed. The reaction progress was monitored via TLC till the completion of the reactions. The resulting dyes were left to dry and purified by means of column chromatography eluting with ethylacetate/hexanes (25:75) (Schemes 1, 2, and 3).

Scheme 2:

Conventional: 30 ml EtOH/1 ml piperidine, 10 h reflux (yield: 65%) [14]. Green: 18 min grinding/two drops piperidine at room temperature (yield: 96%).

Scheme 3:

Conventional: 30 ml EtOH/1 ml piperidine, 8 h reflux (yield: 37%) [15]. Green: 15 min grinding/two drops piperidine at room temperature (yield: 90%).

(3) 2-Methyl-3-((1-methylquinolin-4(1H)-ylidene)methyl)-6-oxo-1,5-diphenyl-5,6-dihydro-1H-[1,3,4]oxadiazino[6,5-c]isoquinolin-2-ium iodide

(Yield: 94%); M.P.: 254–257°C; Mol. F.: C₃₄H₂₇IN₄O₂; Mol. Wt.: 650.51; m/z (FABMS): 650.12; Elemental analysis: (Calculated %) C, 62.78; H, 4.18; I, 19.51; N, 8.61; O, 4.92; (Found %) C, 62.68; H, 4.26; I, 19.48; N, 8.59; O, 4.99; ¹H-NMR: 2.50 (s, 3H-CH₃), 3.05 (s, 3H N⁺-CH₃), 4.58 (s, 1H-CH=), 5.43 (d, 1H-CH quin.), 6.41–8.23 (m, 19H-Ar); ¹³C-NMR: 29.69 (N-CH₃), 43.97 (N⁺-CH₃), 105.31–134.00 (21CH), 141.31–158.90 (9C), 159.98 (C=O), 164.11 (O-C=N).

(5) 6-Amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-3-((1-methylquinolin-4(1H)-ylidene)methyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazol-2-ium iodide

(Yield: 96%); M.P.: 181–183°C; Mol. F.: C₃₂H₂₈IN₅O₂; Mol. Wt.: 641.50; m/z (FABMS): 641.13; Elemental analysis: (Calculated %) C, 59.91; H, 4.40; I, 19.78; N, 10.92; O, 4.99; (Found %) C, 59.84; H, 4.46; I, 19.77; N, 10.91; O, 5.02; ¹H-NMR: 2.44 (s, 3H N-CH₃), 2.75 (s, 3H O-CH₃), 3.13 (s, 3H N⁺-CH₃), 3.58 (s, 1H-CH-), 5.43–8.19 (m, 18H Ar+Het+NH₂), 13C-NMR: 28.01 (-CH-), 38.10 (N-CH₃), 46.00 (O-CH₃), 55.21 (N⁺-CH₃), 107.11–176.23 (22C Ar-C+Het-C+CN+CNH₂).

(7) 6-Amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-3-((1-methylquinolin-4(1H)-ylidene)methyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazol-2-ium iodide

(Yield: 90%); M.P.: 177°C; Mol. F.: C₂₇H₂₆IN₃O₃; Mol. Wt.: 567.42; m/z (FABMS): 567.10; Elemental analysis: (Calculated %) C, 57.15; H, 4.62; I, 22.37; N, 7.44; O, 8.46; (Found %) C, 57.10; H, 4.64; I, 22.38; N, 7.40; O, 8.48; ¹H-NMR: 1.19 (t, 3H ethoxy-CH₃), 2.47 (s, 3H-O-C-CH₃), 3.31 (s, 3H N-CH₃), 3.83 (s, 3H N⁺-CH₃), 3.98 (q, 2H ethoxy-CH₂), 6.58–8.43 (m, 12H Ar+Het+-CH=), ¹³C-NMR: 14.10 (ethoxy-CH₃), 14.30 (-CH₃), 34.00 (N-CH₃), 36.20 (N⁺-CH₃), 59.30 (ethoxy-CH₂-), 107.30–141.20 (20C Ar-C+Het-C+-CH=), 151.40 (-O-C=), 169.80 (-C=O).

2.3.3 Green synthesis of monomethine cyanine dyes 9 and 11:

The starting compounds 8 and 10 (0.001 mol/0.512 g, 0.560 g), and a bimolar ratio of 1-methyl(ethyl)quinoliniumiodide salts (0.002/0.542 g, 0.570 g) were grinded under solvent-free conditions at room temperature in the presence of three drops of the piperidine catalyst for 16 and 20 min, respectively. The reaction mixture changed to a violet-colored paste during grinding, and the completeness of the synthesis was recognized by means of TLC. The dyes were left to dry and purified by means of column chromatography, eluting with ethylacetate/hexanes (30:70) (Schemes 1, 4, and 5).

Scheme 4:

Conventional: 50 ml EtOH/1 ml piperidine, 6 h reflux (yield: 80%) [16]. Green: 16 min grinding/three drops piperidine at room temperature (yield: 91%).

Scheme 5:

Het=1-ethylquinol-4-yl. Conventional: 100 ml EtOH/1 ml piperidine, 6 h reflux (yield: 69%) [17]. Green: 20 min grinding/three drops piperidine at room temperature (yield: 93%).

(9) 2,5,6-Trimethyl-7-(1-methylquinolin-4(1H)-ylidene)methyl)-3-(1-ethylquinolin-4-(1H)-ylidene)methyl)-1,5-dihydropyrazolo[4,3-e][1,3,4]oxadiazine-2,6-diium iodide

(Yield: 91%); M.P.: 201–203°C; Mol. F.: C₂₉H₃₀I₂N₆O; Mol. Wt.: 732.40; m/z (FABMS): 732.06; Elemental analysis: (Calculated %) C, 47.56; H, 4.13; I, 34.65; N, 11.47; O, 2.18; (Found %) C, 47.60; H, 4.14; I, 34.63; N, 11.42; O, 2.21; ¹H-NMR: 2.33 (s, 6H N-CH₃), 2.50 (s, 3H N-CH₃), 2.71 (s, 6H N⁺-CH₃), 3.77 (s, NH), 4.91 (s, -CH=), 5.38 (s, -CH=), 6.13–8.02 (m, 12H Ar+Het), ¹³C-NMR: 31.30 (N-CH₃), 31.6 (N⁺-CH₃), 38.30 (N⁺-CH₃), 45.10 (2N-CH₃), 105.9–117.10 (14-CH=), 136.40–158.00 (8-C=).

(11) 2,7-Diethyl-3,8-bis(1-ethylquinolin-4(1H)-ylidene)methyl)-5,10-dioxo-1,5,6,10-tetrahydrobenzo[1,2-e:4,5-e′]bis([1,3,4]oxadiazine)-2,7-diium iodide

(Yield: 97%); M.P.: 206°C; Mol. F.: C₃₆H₃₆I₂N₆O₄; Mol. Wt.: 870.52; m/z (FABMS): 870.09; Elemental analysis: (Calculated %) C, 49.67; H, 4.17; I, 29.16; N, 9.65; O, 7.35; (Found %) C, 49.68; H, 4.14; I, 29.11; N, 9.70; O, 7.37; ¹H-NMR: 1.21 (t, 6H 2CH₃, of 2Et-N), 1.32 (t, 6H 2CH₃, of 2Et-N), 3.70 (q, 4H 2N-CH₂-), 4.10 (q, 4H 2N-CH₂-), 6.39–8.30 (m, 16H Het+-CH=), ¹³C-NMR: 12.70–14.30 (4CH₃ of Et-N), 40.70–42.60 (4N-CH₂), 106.10 (2-CH=), 118.10–134.20 (12-CH=), 140.90–163.90 (12-C=), 168.10 (2-C=O).

3 Results and discussion

Generally, a successive synthesis of monomethine dyes proceeds via formation of a highly reactive anhydro base containing side-chain methylene carbanion that internally attacks an electron-deficient center at the quaternary heterocyclic salts. This type of reaction is common in organic chemistry and could be initiated via a base catalyst and a suitable amount of activation energy that is usually maintained by means of reflux.

The conventional method commonly involves reflux at a high temperature for several hours, excessive amounts of solvents, and a large amount of catalyst, resulting in dye with smaller yields than that obtained from the green method [13–17].

The green synthesis in our approach afforded the selected monomethine cyanine dyes including the same mechanism via grinding, which generates the required activation energy, but was adopted to prevent/minimize reflux, minimize the use of solvent, minimize the amount of catalyst, and optimize yield through an environmentally benign procedure.

The green synthesis of monomethine cyanine dye 2 is not completed via grinding at room temperature only, but also heating under reflux in a small amount of ethanol should be incorporated. This could be attributed to the course of such reaction, which was first initiated by the formation of a highly reactive methylene carbanion that internally attacked an electron-deficient center on the 4-position of the quaternized salt. The 4-position of the quinolinium moiety would be more electron deficient than that of the pyridinium, due to the presence of additional rings that increase and support the electron deficiency at the 4-position. This internal attack initiates the 4-position of the quinolinium moiety to react via grinding only, at room temperature, with the least activation energy. On the other hand, the 4-position of pyridinium moiety was less reactive toward nucleophilic attacks, thus requiring additional activation energy incorporated via a shorter reflux time to complete the synthesis. Although the developed green condition was not entirely sufficient to achieve monomethine cyanine dye 2 containing a 4-pyridyl group, the green context of the reaction course remained, resulting in minimized reflux and greater-than-ever reaction yield (Scheme 1).

The green synthesis of monomethine cyanine dye 5 was established via grinding only under solvent-free conditions at room temperature and in the presence of one drop of catalyst. The optimum yield of this synthesis and the short reaction time, as well as the high atom economy, strongly recommended the use of such methodologies for industrial purposes (Scheme 2).

Furthermore, the conventional synthesis of dye 7 involved more reflux time with low atom efficiency due to the poor yield in the presence of both the solvent and a considerable amount of catalyst. On the other hand, using the green methodology successively prevented and minimized the non-green components that were predominant in the conventional synthesis, and the green context of the new methodology was obviously present on the basis of the solvent-free condition, short reaction time, and simplicity of the method, increasing the yield and atom efficiency, minimizing hazards and the amount of catalyst, and saving energy, thus resulting in a high environmental impact (Scheme 3).

The current study not only focused on the green preparation of the analyzed monomethine dyes, but also showed applicability to other types of monomethine cyanine dyes. The green synthesis of monomethine cyanine dye 9 proceeded under the same condition, resulting in the prevention of the non-green components in its conventional synthesis and the preservation of the green context of the newly developed methodology (Scheme 4).

Although both the green conditions and the atom efficiency of such synthesis could be slightly changed, due to the structure variation of the prepared monomethine dyes, the overall green context of such synthesis remained predominant. In the green synthesis of dye 11, both the grinding time and the amount of catalyst slightly increased; however, the green context of the synthesis is still present in its optimum yield and high atom economy (Scheme 5).

The application of these green organic synthetic procedures is a relatively new emerging issue concerning atom efficiency and sustainability. This green synthesis, via grinding under solvent-free conditions at room temperature, has received great attention in recent years due to its capability to design alternatives, higher safety, energy efficiency, and less toxic routes toward the synthesis of highly important organic compounds. These routes have been associated with the rational utilization of various organic compounds for green preparations and benign synthetic methods, which have been broadly discussed. This article is not meant to provide an exhaustive overview of the green synthesis of monomethine cyanine dyes (2, 3, 5, 7, 9, and 11), but to present several pivotal aspects of synthesis with environmental concerns, the choice of grinding under a solvent-free condition at room temperature, and the development of energy-efficient synthetic methods. Moreover, if the reaction course could not be entirely maintained at room temperature, a modification should be made in future studies by incorporating benign means of supplying the activation energy.

The absorption spectra of the selected monomethine cyanine dyes were examined according to Refs. [13–17] and tabulated in Table 1.

4 Conclusion

The current work demonstrates an improvement over conventional synthetic pathways, which are not eco-friendly, utilize hazardous solvents, and not atom efficient in the sense that they do not meet the 12 green chemistry principles. The green methodology via grinding at room temperature and solvent-free conditions, adopted for the preparation of widely applicable organic compounds in various aspects of life, represents a benign method that enhances the atom efficiency of synthesis and minimizes the use of heat energy. The newly developed green pathway largely reduced the reaction time from several hours to a few minutes; provided a relatively high reaction yield; and launched a safe, solvent-free, less hazardous, energy-saving, sustainable, and environmentally friendly methodology. Also, this work opened a research window for future approaches in green synthetic chemistry via new benign methodologies with increased atom efficiency and environmental impact.