A Practical, Large-Scale Synthesis of Pyrene-2-Carboxylic Acid

Abstract

Pyrene-2-carboxylic acid is a versatile intermediate for introducing the unusual 2-pyrenyl unit into functional organic molecules. A classical preparation for this molecule has been revised and improved to give a robust and efficient three-step process. The method has been applied on a multigram scale to give pyrene-2-carboxylic acid in >70% overall yield from pyrene.

Key words

condensed aromatic compounds - electrophilic aromatic substitution - ring closure - ring opening - Haller–Bauer cleavage

• References and Notes

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• 21 Preparation of 1-(o-Carboxybenzoyl)pyrene (2): AlCl₃ (15.4 g, 116 mmol) was added to a suspension of pyrene (9.4 g, 46 mmol) and phthalic anhydride (6.9 g, 46 mmol) in anhyd CH₂Cl₂ (280 mL) under N₂ atmosphere. The mixture was heated under reflux for 3 h. The solvent was then evaporated and the residue was cooled to 0 °C and suspended in H₂O (500 mL). The pH of the solution was adjusted to 0–1 by adding concd aq HCl (20 mL), and the solid was isolated by filtration, washed with ice water (2 × 150 mL) and dried by addition–evaporation of toluene. The solid was suspended in glacial AcOH (500 mL) and heated at 130 °C for 5 min, after which the insoluble material was removed by hot filtration and washing with hot glacial AcOH (3 × 50 mL). The filtrate was poured into ice water (1 L) and the resulting solid was isolated by filtration, washed with ice water (2 × 100 mL) and dried by addition–evaporation of toluene to give 2 (15.96 g, 45.6 mmol, 98%) as a bright yellow powder; mp 224–225 °C (Lit.⁹ mp 225–226 °C); R_f = 0.35 (CH₂Cl₂–MeOH, 10:1). FTIR (ATR): 3039, 2910, 2786, 2617, 2546, 2492, 1714, 1591, 1578, 1234, 941, 838, 708 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 13.01 (br s, 1 H, COOH), 9.18 (d, ³ J = 9.2 Hz, 1 H, H-10), 8.41 (d, ³ J = 9.2 Hz, 1 H, H-9), 8.40 (br d, J = 7.6 Hz, 2 H, H-6, H-8), 8.32 (d, ³ J = 9.1 Hz, 1 H, H-5), 8.21 (d, ³ J = 8.1 Hz, 1 H, H-3), 8.18 (d, ³ J = 9.1 Hz, 1 H, H-4), 8.15 (t, ³ J = 7.6 Hz, 1 H, H-7), 7.99 (br d, J = 7.6 Hz, 1 H, H-6′), 7.83 (d, ³ J = 8.1 Hz, 1 H, H-2), 7.77 (ddd, J = 7.6, 7.2, 1.2 Hz, 1 H, H-4′), 7.71 (ddd, J = 7.6, 7.2, 1.2 Hz, 1 H, H-5′), 7.63 (br d, J = 7.2 Hz, 1 H, H-3′). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 198.7 (CO), 167.5 (COOH), 142.9 (C-2′), 133.5 (C-3a), 132.1 (C-4′), 131.1 (C-1), 130.8 (C-1′), 130.6 (C-5a), 130.3 (C-5′), 130.0 (C-8a), 129.9 (C-5), 129.8 (C-10a), 129.7 (C-6′), 129.5 (C-9), 128.9 (C-2), 128.5 (C-3′), 127.2 (C-4), 126.8 (C-7), 126.7 (C-6), 126.3 (C-8), 125.1 (C-10), 124.1 (C-3a¹), 123.9 (C-3), 123.3 (C-5a¹). HRMS (ESI^–): m/z [M – H]^– calcd for C₂₄H₁₃O₃: 349.0870; found: 349.0881.
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• 23 Preparation of 1,2-Phthaloylpyrene (3): 1-(o-Carboxy-benzoyl)pyrene (2; 16.0 g, 45.7 mmol) was suspended in chlorobenzene (300 mL) under N₂ atmosphere, and PCl₅ (14.44 g, 69.3 mmol) and AlCl₃ (9.58 g, 71.9 mmol) were added. The resulting dark green mixture was heated under reflux for 2.5 h. The solvent was removed by evaporation and the residue was cooled to 0 °C and suspended in H₂O (450 mL). The dark red precipitate was collected by filtration, washed with H₂O (4 × 100 mL), toluene was added and evaporated (3 × 200 mL), and the resulting solid was further dried in vacuo (overnight) to give 3 (15.5 g, ca. quantitative). This material appeared pure by ¹H NMR and was used directly in the next step. Trace amounts of a highly coloured contaminant were removed by flash chromatog-raphy (CH₂Cl₂–hexane, 1:1 → CH₂Cl₂–MeOH, 10:1) to give a sample for characterisation; mp 255–256 °C (Lit.⁹ 254 °C); R_f = 0.51 (EtOAc–hexane, 1:4). FTIR (ATR): 3119, 3024, 2804, 1716, 1661, 1615, 1443, 1392, 620 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 9.87 (d, ³ J = 9.8 Hz, 1 H, H-10), 8.90 (s, 1 H, H-3), 8.34 (dd, J = 7.6, 0.9 Hz, 1 H, H-3′), 8.28 (dd, J = 7.6, 0.9 Hz, 1 H, H-6′), 8.24 (d, ³ J = 9.8 Hz, 1 H, H-9), 8.21 (d, ³ J = 7.5 Hz, 1 H, H-8), 8.18 (d, ³ J = 7.5 Hz, 1 H, H-6), 8.13 (d, ³ J = 8.9 Hz, 1 H, H-5), 8.09 (d, ³ J = 8.9 Hz, 1 H, H-4), 8.02 (t, ³ J = 7.5 Hz, 1 H, H-7), 7.80 (dt, J = 7.5, 1.2 Hz, 1 H, H-4′), 7.75 (dt, J = 7.5, 1.2 Hz, 1 H, H-5′). ¹³C NMR (125 MHz, CDCl₃): δ = 185.9 [C-1(CO)C-2′], 184.3 [C-2(CO)C-1′], 136.2 (C-2′), 135.0 (C-3a), 134.4 (C-4′), 133.5 (C-5′), 133.1 (C-1′), 132.0 (C-2), 131.9 (C-9), 131.8 (C-5a), 131.7 (C-10a), 131.2 (C-5), 131.0 (C-8a), 128.3 (C-4), 127.8 (C-7), 127.7 (C-3a¹), 127.6 (C-3′), 127.5 (C-6), 127.1 (C-8), 126.8 (C-6′), 126.5 (C-10), 124.3 (C-1), 124.2 (C-3), 123.8 (C-5a¹). HRMS (EI⁺): m/z [M]⁺ calcd for C₂₄H₁₂O₂: 332.0837; found: 332.0842.
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• 28 Preparation of Pyrene-2-carboxylic Acid (4): Crude 3 (10 g) was suspended in 1,2-dimethoxyethane (140 mL). H₂O (3 equiv per carbonyl group, 3.3 mL, 180.6 mmol) was added, then potassium tert-butoxide (10 equiv per carbonyl group, 67.6 g, 602 mmol) was added portionwise with vigorous stirring to ensure that a fine suspension was maintained throughout the addition. The mixture was vigorously stirred under reflux for 7 h and the solvent was evaporated. The residue was cooled to 0 °C, suspended in H₂O (1 L), and acidified to pH 1–2 with concd aq HCl. The resulting solid was removed by filtration, suspended in H₂O (2 L), stirred overnight, collected by filtration, washed with H₂O (2 × 250 mL) and dried in vacuo. The material was ground into a fine powder then slowly added to CH₂Cl₂–MeOH (1:1, 250 mL), forming a suspension. Silica (30 g) was then added and the mixture was concentrated to dryness. The resulting fine powder was carefully loaded (band height = 1.8 cm) on a short column (diameter = 6.5 cm, ca. 300 mL, silica gel, height = 5 cm) packed with CH₂Cl₂–hexane (1:1). Pyrene (1; 0.79 g, 3.9 mmol, 13% from 2) and starting diketone 3 (0.96 g, 2.9 mmol, 10% from 2) eluted with CH₂Cl₂–hexane (1:1, 500 mL) and CH₂Cl₂ (1.5 L), respectively. The polarity of the eluent was increased to 10% MeOH in CH₂Cl₂ (150 mL per 2.5% increment) and finally to CH₂Cl₂–MeOH–30% aq NH₃ (90:9:1, 2 L) to elute the product. Elution of diketone 3 (bright yellow/orange fluorescence) and product 4 (dark purple fluorescence) could be monitored by irradiating the column with a 365 nm UV lamp. Pyrene-2-carboxylic acid (4; 5.46 g, 22.2 mmol, 75% from 2) was obtained as a light grey solid; mp 326 °C (Lit.⁹ 326 °C); R_f = 0.33 (CH₂Cl₂–MeOH, 10:1). FTIR (ATR): 2596, 1685, 1305, 1247, 896, 840, 820, 704 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.31 (br s, 1 H, COOH), 8.86 (s, 2 H, H-1, H-3), 8.33 (d, ³ J = 7.6 Hz, 2 H, H-6, H-8), 8.31 (d, ³ J = 9.2 Hz, 2 H, H-4, H-10), 8.24 (d, ³ J = 9.2 Hz, 2 H, H-5, H-9), 8.13 (t, ³ J = 7.6 Hz, 1 H, H-7). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 167.8 (COOH), 131.2 (C-5a, C-8a), 130.5 (C-3a, C-10a), 128.1 (C-2), 128.0 (C-5, C-9), 127.7 (C-4, C-10), 127.3 (C-7), 125.8 (C-3a¹), 125.5 (C-1, C-3, C-6, C-8), 123.3 (C-5a¹). HRMS (ESI^–): m/z [M – H]^– calcd for C₁₇H₉O₂: 245.0608; found: 245.0615.