Intrinsic catalytic activity of Brønsted acid ionic liquids for the synthesis of triphenylmethane and phthalein under microwave irradiation

Abstract

A microwave-irradiated, ionic liquid-catalyzed, solvent-free method for the synthesis of triphenylmethane and a phthalein derivative has been developed from different aldehydes or anhydrides and substituted phenols or N,N-diaryl amines, respectively. Short reaction time, ambient reaction conditions, recyclability of catalyst, simple work up and high yields are some of the striking features of the present protocol. The immobilized catalyst could be easily recovered by simple filtration and recycled for up to four cycles without significant decrease in the catalytic activity.

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Introduction

Phthalein, triphenylmethane and their analogues are vital heterocyclic motifs in dyes chemistry and have biological activities ranging from antibacterial, antiviral and anti-inflammatory, as well as being useful in photodynamic therapy.^1–9 Other useful applications of these heterocycles are as fluorescent materials for visualization of bio-molecules and in laser technologies.^10,11–13 Furthermore, these molecules find potential application in concurrent analytical assay expansion and measurement of intracellular pH while screening biologically active species for immunoassays, as biological probes, environmental sensors, molecular devices, ferric ion sensors, copper ion sensors and nerve gas sensors.^14–16 Due to this wide range of applications, the synthesis of phthalein and triphenylmethane-type compounds has received considerable attention in recent years.^15,16 A number of strategies have been reported for the preparation of triphenylmethane, fluorescein and rhodamine.¹⁷ Traditionally, Brønsted acids (H₂SO₄ or MeHSO₃), niobium pentachloride, zinc(II) chloride, alkali disulphates, HClO₄, hydrochloric acid, lead dioxide, manganese(IV) oxide, Lewis acids (BBr₃, AlCl₃ or ZnCl₂), TiCl₄, In(III) or mixtures thereof have been used in the synthesis of phthalein and triphenylmethane derivatives.^18–26 These methodologies have drawbacks such as prolonged reaction time (4–5 h), tedious catalyst preparation and work up, formation of inevitable side products, and exhaustive usage of energy sources and solvents, which result in a lower yield of the desired product. Considering all these factors and with an emphasis on human health and environmental protection, the development of an eco-friendly methodology for the synthesis of phthalein and triphenylmethane derivatives is in great demand.

Brønsted acid ionic liquids (BAILs) have been used in many areas due to their exclusive chemical and physical properties.²⁷ They display the useful features of solid acids and mineral liquid acids, hence they are a good alternative to traditional mineral liquid acids in chemical procedures. Brønsted acid ILs have potential as dual solvents–catalysts in organic reactions.²⁸ BAILs ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) have been successfully used in transesterification reactions,²⁹ cyclocondensations,³⁰ oxa-Michael addition reactions,³¹ and Prins reactions.³² Remarkably, the synthesis of triphenylmethane and phthalein derivatives using BAILs ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) as solvents–catalysts has not been reported yet.

In continuation of our previous research on fluorescent dyes and the development of green methodologies for the synthesis of heterocyclic compounds of biological importance,^32–34 herein the microwave irradiated synthesis in the presence of ionic liquids ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) is reported. This is an efficient and reusable solvent–catalyst system for the synthesis of triphenylmethane derivatives (Scheme 1). In order to further extend the utility of ILs, the synthesis of phthalein derivatives is reported in Scheme 2. The reaction was completed smoothly and purification of the product was fairly simple. ILs ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) were conveniently separated from the products and easily recycled for another set of reactions.

Scheme 1 Schematic representation of the synthesis of triphenylmethane.

Scheme 2 Schematic representation of the synthesis of phthalein.

Results and discussion

Optimisation of the catalyst

In our preliminary experiments, we carried out a reaction under solvent-free conditions as a model reaction (Scheme 3). The control reaction was carried out between phthalic anhydride 5a and resorcinol 4a under conventional as well as microwave heating in the presence of different solid acid catalysts, mineral liquid acid catalysts, ILs and in the absence of catalyst (Scheme 3, Table 1, entries1–8).

Scheme 3 Reaction conditions: (2 mmol) resorcinol and (1 mmol) phthalic anhydride in 5 mmol (1 mL) of IL under microwave irradiation (100 W) for 2 min or reflux at 100 °C for 60 min.

Table 1 Synthesis of 6a using different catalysts and solvent-free conditions.

Entry	Catalyst	Amount of catalyst (mmol)	Microwave^a		Conventional ^b
			Time (min)	Yield (%)	Time (h)	Yield (%)
a Reaction conditions: (2 mmol) resorcinol and (1 mmol) phthalic anhydride under microwave irradiation (100 W) in different catalyst. b Reaction conditions: (2 mmol) resorcinol and (1 mmol) phthalic anhydride reflux at 100 °C for 60 min in different catalyst. c Reaction carried out under solvent-free conditions (fused reaction).
1	Without catalyst	—	2	—	5	—
2	HCl	5	2	—	5	—
3	H2SO4	5	2	80	5	50
4	AlCl3^c	2^c	2	75	4	35
5	ZnCl2^c	2^c	2	75	4-5	45
6	TiCl4	2	2	—	5	—
7	([HNMP]^+ [CH3SO3]^−)	5	2	88	0.5	85
8	([HNMP]^+ [HSO4]^−)	5	2	87	0.5	87

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In this set we reacted the previously mentioned substrates in the presence of various catalysts viz. HCl, H₂SO₄, AlCl₃, ZnCl₂, TiCl₄, ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) at the same temperature. This set was used for the purpose of screening for the most efficient catalyst by observing their effects through reaction monitoring. Effects of the catalysts and microwave irradiation (80–100 W) on the synthesis of triphenylmethane and phthalein analogues are summarized in Table 1, entries 1–8. It was interesting to note that the ionic liquids ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) offer the best results (Table 1, entries 7–8) owing to their ability to activate the carbonyl groups of anhydrides or aldehydes. This increases the rate of formation of C–C bonds via electrophilic substitution, followed by intramolecular cyclization rationalised by a proposed mechanism (Fig. 1).

Fig. 1 Plausible mechanism for the synthesis of phthalein derivatives promoted by [HNMP]⁺ MeSO₃.

Optimisation of amount of ILs

We optimized the reaction conditions such as the amount of ionic liquid needed for the maximum yield of phthalein and triphenylmethane derivatives by using a model reaction (Table 1, Scheme 3). It was observed that the amount of ionic liquid plays a key role in catalyzing the formation of phthalein and triphenylmethane derivative (Scheme 3).

It was found that the optimum reaction rate and yield could be achieved with 5 mmol (1 mL) of the ionic liquid (IL) with and without microwave irradiation under solvent-free conditions. We applied these conditions to the synthesis of various phthalein and triphenylmethane derivatives (Table 2, entries 1–15).

Table 2 Ionic liquid mediated synthesis of phthalein and triphenylmethane derivatives with and without microwave irradiation.

Entry	Aldehyde	Substituted aniline or phenol	Product	Microwave		Conventional
				Time (min)/MW (W)	Yield (%)	T/°C	Time (min)	Yield (%)
1				2/80	97	80	30	90
2				3/80	87	80	60	85
3				2/80	84	80	60	78
4				2/80	86	60	60	82
5				5/80	88	80	40	79
6				2/80	80	100	60	68
7				2/80	78	78	60	73
8				2/100	89	100	60	85
9				2/100	90	100	60	85
10				2/100	97	80	30	83
11				3/100	78	120	30	73
12				5/100	80	100	30	74
13				5/100	79	120	70	65
14				5/100	74	120	70	70
15				5/100	78	120	70	73

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Optimisation of microwave and conventional heating

The synthesis of triphenylmethane and phthalein was optimised for catalysts ([HNMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻). The optimised microwave conditions were 80–100 W (9.6 × 10³–1.2 × 10⁴ J of heat) and conventional heating between 60–120 °C was investigated (Table 2, entries 1–15).

With regard to the work up, the procedures were very simple and included the addition of sufficient amounts of ice cold water at the end of the reaction. The product was separated by filtration. Finally the crude product was recrystallised from ethanol. As is evident from the results, ([HNMP]⁺ [CH₃SO₃]⁻) and ([NMP]⁺ [CH₃SO₃]⁻) were found to be effective solvents–catalysts for the synthesis of the above mentioned reactions (Table 2, entries 1–15).

Reusability of ILs ([NMP]⁺ [CH₃SO₃]⁻) and ([HNMP]⁺ [HSO₄]⁻) as catalysts

The recovery and reusability of catalysts (ILs) is a requirement for an eco-friendly catalytic process. In this protocol, we used ([HNMP]⁺ HSO₄⁻) and ([HNMP]⁺ [CH₃SO₃]⁻) as solvents as well as catalysts under both microwave and conventional heating conditions (Scheme 3). After completion, the reaction mixture was cooled to room temperature then poured into a mixture of crushed ice and water. The crude product was separated by filtration. The ionic liquid was then recovered by evaporating the water under reduced pressure. The recovered ionic liquid was reused for the next four cycles of the same reaction without significant loss of activity. (Fig. 2)

Fig. 2 Recyclability study on the reaction depicted in Scheme 3.

Experimental

All chemicals were commercially available and used without further purification. ¹H NMR and ¹³C NMR spectra were obtained on a Varian Mercury plus 300 MHz NMR spectrometer. Chemical shift values are expressed in δ units relative to tetramethylsilane (TMS) signal as the internal reference in CDCl₃. Data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, br = broad singlet, m = multiplet), coupling constant J (Hz).

Preparation of ionic liquid N-methyl-2-pyrrolidonium methyl sulphate ([HNMP]⁺ [CH₃SO₃]⁻)³⁵

Benzene (30 ml) was mixed with N-methyl-2-pyrrolidone (9.9 g, 0.1 mol) under vigorous stirring in a 100 mL flask. Then, methanesulphonic acid (9.6 g, 0.1 mol) was slowly added dropwise to the flask within 30 min in an ice bath. The reaction lasted for another 4 h at room temperature. Benzene was removed under reduced pressure and the product was further dried at 90 °C under 1–5 mmHg for 1 h. A light yellow viscous liquid [HNMP]⁺ [CH₃SO₃]⁻ was obtained (yield: 97%) (Fig. 3a).

Fig. 3 a: Schematic presentation of synthesis of N-methyl-2-pyrrolidonium methyl sulphate, b: Schematic representation of the synthesis of N-methyl-2-pyrrolidonium hydrogen sulphate.

Preparation of ionic liquid N-methyl-2-pyrrolidonium hydrogen sulphate ([HNMP]⁺ [HSO₄]⁻)³⁵

1-Methylpyrrolidone (0.2 mol) was placed in a 250 mL three necked flask with overhead stirrer. Concentrated sulphuric acid (0.2 mol) was slowly added dropwise to the flask within 40 min in an ice bath. The flask was then kept at 80 °C for 12 h to complete the reaction. The mixture was washed three times with ether to remove non-ionic residues and dried in vacuo by a rotary evaporator to obtain the viscous clear liquid ([NMP]⁺ HSO₄⁻) (Fig. 3b). The preparation and purification of ionic liquids were discussed by Z. S. Qureshi and et al.²⁸ and the products were used for further reactions as they were.

General procedure for the preparation of triphenylmethane and phthalein derivatives‡

Conventional method of synthesis of triphenylmethane (Table 2, entries 1–7) and phthalein derivatives (Table 2, entries 8–15). Triphenylmethane derivatives were synthesized by using ionic liquids (5 mmol, 1 mL). Substituted phenol/aryl amines (2 mmol) and different aldehydes (1 mmol) were heated at 60–120 °C for an appropriate time giving triphenylmethane (phthalein derivatives were synthesis by using phthalic anhydride instead of aldehydes) (Table 2, entries 1–15). All the reactions were monitored by thin layer chromatography. After completion of the reaction, cold water (10 mL) was added to the reaction mixture. Precipitation was achieved by further cooling for 30 min. The product was filtered and dried in the oven at 50 °C.

Microwave irradiation heating³⁶

A 700 W Electrolux (17 L) domestic microwave oven was used. It was modified to allow fitting of a condenser as described in the previous communication.³⁶ As mentioned in the above section, the same procedure was followed with a microwave oven being used as a heating source for various time periods between 2–5 min and 80–100 W for the synthesis of different derivatives.

Conclusions

In summary, we have demonstrated a new, efficient and practical procedure for the synthesis of triphenylmethane and phthalein derivatives. Results showed that ([HNMP]⁺ HSO₄⁻) and ([NMP]⁺ [CH₃SO₃]⁻) are efficient catalysts for the reaction of different aldehydes/anhydrides with different aryl amines/phenols. The advantages of our protocol are easy work up, fast reaction rates, mild reaction conditions, good yields, and reusability of ILs, which make the method an attractive and useful contribution to the existing methodologies.

Acknowledgements

Authors are thankful to the Indian Institute of Technology, Mumbai for recording NMR and Mass Spectra. Amol Chaudhari is thankful to the Centre of Advanced Studies University Grant Commission for financial support by way of a SAP fellowship.

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Footnotes

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c2ra21803h

‡ 4,4′-(Cyclohexylmethylene) bis (N,N-dimethylaniline) 3c (Table 2, entry 2): Yield: 85%. M.p. 150–152 °C. FT-IR (KBr, cm⁻¹): 3061, 2926, 1611, 1532, 1440, 1347. ¹H NMR (CDCl₃): δ 1.27–1.52 (m, 10H), 2.35 (m, 1H), 2.95 (s, 12H), 4.19 (d, 1H), 6.61 (d, 4H), 7.25 (d, 4H). ¹³C NMR (CDCl₃): δ 14.83, 133.90, 128.66, 128.54, 113.13, 112.99, 54.03, 41.61, 41.05, 32.35, 29.79, 25.57. 4,4′-(3-Methylpentane-1,1-diyl) bis (N,N-dimethylaniline) 3d (Table 2, entry 3): Yield: 84%. M.p. > 250 °C. FT-IR (KBr, cm⁻¹): 3070, 2915, 1465, 1375, 800. ¹H NMR (CDCl₃): δ 0.97 (t, 6H), 1.45 (m, 1H), 1.89 (t, 2H), 2.80 (s, 12H), 3.95 (d, 1H), 6.69 (d, 4H), 7.15 (d, 4H). ¹³C NMR (CDCl₃)δ 149.05, 148.86, 134.76, 130.62, 129.50, 129.40, 128.40, 128.31, 113.26, 113.13, 46.85, 45.51, 43.30, 41.19, 41.06, 41.00, 40.93, 39.96, 29.77, 25.57, 22.81.4,4′-(3-Phenylprop-2-ene-1,1-diyl)bis (N,N-dimethylaniline) 3f (Table 2, entry 5): Yield: 88%. FT-IR (KBr, cm⁻¹): 3065, 2924, 1611, 1470, 1532, 801. ¹H NMR (CDCl₃): δ 2.95 (s, 12H), 4.80 (d, 1H), 6.60 (d, 1H), 6.80 (d, 1H), 7.10 (m, 8H), 7.21–7.60 (m, 5H). ¹³C NMR (CDCl₃): δ 144.09, 136.34, 134.74, 130.08, 129.92, 128.48, 127.08, 116.78, 113.09, 52.79, 40.78. 2′,7′-Di(1H-benzo[d]imidazol-2-yl)-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1-9′-xanthen]-3-one) 6f (Table 2, entry 13): Yield: 79%. M. p. > 300 °C. FT-IR (KBr, cm⁻¹): 3432, 3324, 1768 , 1740, 1689, 1642, 1578 ,1550,1515, 1441, 1402, 1339 (C–N), 1252, 1190, 1130. Mass: m/z 564 (M⁺). ¹H NMR ((CD₃)₂SO, 300 MHz): δ 6.58 (s, 2H), 7.17 (d, 2H, J = 6.4 Hz), 7.34 (d, 2H, J = 6.4 Hz), 7.68 (d, 2H, J = 6.4 Hz), 7.72 (dd, 2H, J = 6.4 Hz; 14.9 Hz), 8.00 (s, 2H), 8.2–8.3 (d, 4H, J = 8.9 Hz), 8.4 (s, 2H), 11.3 (bs, 2H). ¹³CNMR ((CD₃)₂SO,75 MHz): 5.46, 166.00, 106.21, 11.92, 115.21, 115.39, 124.11, 25.83, 127.29, 130.74, 141.71, 151.73, 152.48, 152.93.

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