2′,7′-Dimethyl-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one

Abstract

A synthetic route to 2′,7′-dimethyl-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one has been described using methanesulfonic acid in place of reagents described in protocols from the early 20th century. A full NMR assignment has been made and X-ray crystallography has been used to characterise the title compound for the first time.

1. Introduction

Reactions of phenols with phthalic anhydride under strongly acidic conditions has long been known as a general method for the preparation of phenolphthalein-based dyes (3,3-bis(4-hydroxyaryl)isobenzofuran-1(3H)-ones) [1,2]. For example, it is known that heating 2-methylphenol with a mixture of phthalic anhydride and zinc chloride affords cresolphthalein (3,3-bis(4-hydroxy-3-methylphenyl)isobenzofuran-1(3H)-one 1) [3]; this compound is often used as an acid-base indicator [1,2]. It has also been reported that the use of 4-methylphenol under the same conditions results in the formation of fluoran 2 as the product rather than an isomer (3) of cresolphthalein (Scheme 1) [3]. These results align with an earlier study that found that fluoran 2 is the product of strongly heating a mixture of phthalic anhydride, 4-methylphenol, and boric acid [4].

Alternative methods for the preparation of phenolphthalein analogues have become available since the original studies that were conducted in the early 20th century. In recent years, methanesulfonic acid and methanesulfonic acid/niobium(V) chloride mixtures have been found to be useful replacements for concentrated sulfuric acid and mixtures containing zinc chloride or aluminium chloride [1,5]. Methanesulfonic acid is a readily available replacement for concentrated sulfuric acid, it is liquid at room temperature, and it is a less potent oxidising agent than concentrated sulfuric acid. Classical methods for the synthesis of 3,3-bis(4-hydroxyaryl)isobenzofuran-1(3H)-ones (such as 1) and corresponding xanthene derivatives often require temperatures significantly greater than 100 °C; in contrast, the same reactions in methanesulfonic acid often readily proceed when heated below 100 °C [1,5]. The reaction of 2-substituted phenols with phthalic anhydride in hot methanesulfonic acid affords the corresponding 3,3-bis(4-hydroxyaryl)isobenzofuran-1(3H)-one products in good yield [1]. Furthermore, it has been shown that the reaction of 3-substituted phenols with phthalic anhydride in hot methanesulfonic acid (containing 0.25 equivalents of niobium(V) chloride) affords fluoran 4 (Scheme 2) rather than 3,3-bis(2-hydroxy-4-methylphenyl)isobenzofuran-1(3H)-one [6].

In this work, we describe a short study to examine whether 2′,7′-dimethyl-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one (2) or 3,3-bis(2-hydroxy-5-methylphenyl)isobenzofuran-1(3H)-one (3) is the isolable product from the reaction of phthalic anhydride and 4-methylphenol under milder conditions than reported in older studies [3,4]. Our findings align with the outcome of closely related reactions from the earlier 20th century; fluoran 2 was the sole isolated product (Scheme 3), and this compound has been characterised using X-ray crystallography for the first time.

Fluoran 2 can be made by other methods; for example, a recent study has demonstrated that compound 2 can be produced from the reaction of phthalic anhydride with 4,4′-oxybis(methylbenzene) (di-p-tolyl ether) in the presence of trifluoromethanesulfonic acid (Scheme 4) [7]. The reaction pathway has been investigated by in situ NMR experiments and computational (DFT) studies; these conditions can also be used to prepare a selection of spirocyclic xanthene products.

2. Results

2.1. Synthesis and Spectroscopy

The reaction of 4-methylphenol with phthalic anhydride in hot methanesulfonic acid (90 °C) proceeds over 4 h. The crude product is then easily isolated by filtration after the reaction is quenched with water and sodium bicarbonate. The crude material is usually obtained as a tan coloured solid; however, it can readily be recrystallized from hot acetone. The melting point was determined to be 251–253 °C; this observation is consistent with earlier studies [3,4]. The isolated yield in this case is 28%, this is very similar to the results reported by Copisarow in 1920; in that instance, fluoran 2 was obtained in 26% yield [3]. It is apparent from our work that heating the reagents in methanesulfonic acid does not offer a significant improvement in terms of % yield from the earlier protocol [3]. It is likely that the reaction did not procced to completion and that unreacted phthalic anhydride and 4-methylphenol were removed during the purification steps. Most previous reports of fluoran 2 were published prior to the introduction of modern spectroscopic techniques; however, there is one recent paper that includes ¹H and ¹³C NMR spectra [7]. In this work, a full assignment of the structure has been made using 2D NMR techniques, and a full set of assigned spectra is provided in the supporting information document (Supporting Information—Figures S1–S5). The ATR-IR spectrum of fluoran 2 has also been obtained (Supporting Information—Figure S6); this shows a distinctive signal at 1756.8 cm⁻¹ consistent with the γ-lactone carbonyl group [8].

In contrast to cresolphthalein (1) [1], fluoran 2 is insoluble in aqueous solutions of sodium hydroxide and the solution does not become red/pink in colour. However, a report from 1902 suggested fluoran 2 is reactive under acidic conditions, since it would likely exist as oxonium ion 5 in concentrated sulfuric acid (98%) [9]. The observation at the time was that the addition of concentrated sulfuric acid to fluoran 2 afforded a clear yellow solution. This outcome was attributed to the formation of the conjugated resonance stabilised species such as 5 (Scheme 5). Our results align with the original observation regarding the colour of the strongly acidic solution, and it was found that the solution emits yellow light when illuminated with a 405 nm violet laser (Figure 1).

2.2. The Crystal Structure of 2

Crystals of 2 suitable for X-ray diffraction were isolated by the slow cooling of a saturated solution of 2 in dimethyl sulfoxide. The data confirm the structure of 2 is in agreement with the spectroscopic assignment.

The structure shows (Figure 2) only slight distortion from the ideal tetrahedral angles at the spiro carbon (C3), ranging from the smallest angle of 101.94(9)° in the constrained isobenzofuranone ring (C4−C3−O2), to 114.14(9)°. The C−O bond lengths are of typical length, 1.3608(14) and 1.4912(13) Å, and the C=O distance is typical of isobenzofuranones at 1.2026(14) Å. Unsurprisingly, given the linkage of the two rings at the spiro carbon, the xanthene group adopts a planar conformation (mean deviation from plane 0.037 Å). The interplanar angle between the xanthene and isobenzofuranone rings is 87.679(14)°.

The structure displays several non-classical intermolecular CH···O interactions. A pair of interactions are found between both H6 and H7 with O2 at H···O distances of 2.65 and 2.55 Å (C···O separations of 3.2503(14) and 3.1986(15) Å), respectively, resulting in 1D chains running along the crystallographic a-axis (Figure 3). Two sets of dimer-forming CH···O interaction are also seen; between H5 and O11 and between H22 and O1, at H···O distances of 2.45 Å (C···O separations of 3.3715(15) and 3.3875(15) Å) (Figure 4). The dimer-forming interactions result in the chains of molecules being linked into two-dimensional sheets in the ab-plane (Figure 3).

In summary, the first X-ray crystal structure of 2′,7′-Dimethyl-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one (2) has been obtained and full ¹H and ¹³C NMR assignments have been made. The title compound was prepared by heating a mixture of phthalic anhydride, 4-methylphenol, and methanesulfonic acid. This method produces results that align with studies conducted in the early 20th century that employed more forcing conditions to prepare fluoran 2.

3. Experimental Section

Melting points were recorded on an Stuart Scientific SMP3 melting point apparatus and are uncorrected. IR spectra were recorded on a Nicolet Summit FTIR instrument with Everest diamond ATR accessory. NMR spectra were obtained for ¹H at 400 MHz and for ¹³C at 100 MHz using a Bruker AVIII_HD 400 instrument. Spectra were run at 25 °C in d₆-DMSO. Chemical shifts are reported in ppm to the high frequency of the reference, and coupling constants J are reported in Hz. The HRMS data were acquired from the University of St Andrews Mass Spectrometry Service.

• 2′,7′-Dimethyl-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one

A stirred mixture of 4-methylphenol (0.36 g, 3.3 mmol) and phthalic anhydride (0.30 g, 2.0 mmol) in methanesulfonic acid (1.00 g, 0.68 mL, 10.0 mmol) was heated to 90 °C in a boiling tube for 4 h. Upon cooling to room temperature, water (20 mL) was added, and the resulting mixture was triturated with a glass rod until a tan-coloured solid was formed. The supernatant liquid was neutralised by the portionwise addition of solid sodium bicarbonate. The crude product was filtered off under suction, washed with water (2 × 5 mL), and recrystallized from acetone. A colourless crystalline solid was formed; this was filtered off under suction and washed with ice-cold acetone (2 × 2 mL) to afford product 2 (0.15 g, 28%), mp 251–253 °C (lit. [4] 250–252 °C). IR (ATR) 3059.4, 3016.8 (ArCH), 2920.3 (CH₃), 1756.8 (C=O), 1610.5, 1486.3, 1106.7 cm⁻¹; ¹H NMR (400 MHz, d₆-DMSO); 8.06 (1H, ddd, J = 7.4 Hz, 1.4, 0.8 Hz, ArH), 7.80 (1H, td, J = 7.5, 1.4 Hz, ArH), 7.75 (1H, td, J = 7.5, 1.1 Hz, ArH), 7.29–7.33 (4H, m, ArH), 7.27 (1H, dt, J = 7.5, 0.9 Hz) ArH), 6.60 (2H, dt, J = 1.7, 0.9 Hz, ArH), 2.17 (6H, s, CH₃); ¹³C NMR (100 MHz, d₆-DMSO); 169.3 (C=O), 153.5 (ArCq), 148.9 (ArCq), 136.4 (ArCH), 133.6 (ArCq), 132.3 (ArCH), 130.8 (ArCH), 127.7 (ArCH), 125.7 (ArCq), 125.5 (ArCH), 124.4 (ArCH), 118.7 (ArCq), 117.4 (ArCH), 82.2 (Cq), and 20.6 (CH₃). HRMS (ESI+) m/z (%) Calcd. for C₂₂H₁₆O₃Na 351.0992, found 351.0998 [M+Na] (100).

Colourless X-ray quality crystals of 2 were grown by slow cooling of a sample dissolved in dimethyl sulfoxide.

• X-ray Structure Determination of 2

X-ray diffraction data were collected at 100 K using a Rigaku MM-007HF High Brilliance Microfocus RA generator/confocal optics with XtaLAB P200 diffractometer [Cu Kα radiation (λ = 1.54187 Å), Tokyo, Japan]. Data were collected (using a calculated strategy) and processed (including correction for Lorentz, polarisation, and absorption) using CrysAlisPro [10]. The structure was solved by dual-space methods (SHELXT) [11] and refined by full-matrix least squares against F² (SHELXL-2019/3) [12]. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model. All calculations were performed using the Olex2 interface [13].

Crystal data for C₂₂H₁₆O₃, M = 328.35 g mol⁻¹, colourless plate, crystal dimensions 0.15 × 0.05 × 0.01 mm, monoclinic, space group P2₁/n (No. 14), a = 7.72260(6), b = 12.79542(10), c = 16.74757(13) Å, β = 91.3986(7) °, V = 1654.40(2) ų, Z = 4, D_calc = 1.318 g cm⁻³, T = 100 K, 31,448 reflections measured, 3426 unique (R_int = 0.0644), which were used in all calculations. The final R₁ [I > 2σ(I)] was 0.0426 and wR₂ (all data) was 0.1227, with a goodness of fit on F² of 1.095. Data have been deposited at the Cambridge Crystallographic Data Centre as CCDC 2441124. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/structures.