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Article

Photochemical Acylation of 1,4-Naphthoquinone with Aldehydes Under Continuous-Flow Conditions

by
Madyan A. Yaseen
1,2 and
Michael Oelgemöller
1,3,*
1
College of Science and Engineering, James Cook University, Townsville, QLD 4811, Australia
2
College of Education, University of Samarra, Samarra 34010, Salah Al-Deen, Iraq
3
Faculty of Chemistry and Biology, Hochschule Fresenius gGmbH—University of Applied Science, 65510 Idstein, Germany
*
Author to whom correspondence should be addressed.
Organics 2025, 6(1), 9; https://doi.org/10.3390/org6010009
Submission received: 4 January 2025 / Revised: 21 January 2025 / Accepted: 12 February 2025 / Published: 14 February 2025
Browse Figures
Versions Notes

Abstract

:
A series of photoacylations of 1,4-naphthoquinone with various aldehydes and using Pyrex-filtered UVB light was conducted under continuous-flow conditions. Acetone served as a triplet photosensitizer and convenient solvent that kept all materials in solution and could be easily removed. The corresponding acylated 1,4-naphthohydroquinone photoproducts were obtained in acceptable to excellent yields of 30–90% with residence times of just 70 min. The photoacylation process was successfully coupled with in-line oxidation to obtain acylated 1,4-naphthoquinones.

Graphical Abstract

1. Introduction

Naphthoquinones and their derivatives are important natural products, synthesis intermediates, and biologically active compounds of interest to the chemical industry [1,2,3,4]. Due to their favorable photophysical properties, the photochemistry of quinones has also been intensively studied, and a variety of photochemical transformations have consequently been developed [5,6,7,8,9]. The photoacylation of 1,4-quinones with aldehydes, for example, represents a straightforward access to acylated 1,4-hydroquinones from readily available starting materials (Scheme 1) [10,11,12]. Due to its easy reaction protocol, the transformation has been used as a key step in the synthesis of a variety of biologically active compounds [13,14,15,16]. However, the strong absorption of the photoproducts typically causes a significant decrease in light usability (noticeable in a drop in quantum yield [17]), which necessitates exhaustive irradiation times and can lead to photodecomposition or secondary acylation [18,19]. An excess amount of aldehyde is also used to suppress dimerization of the quinones [20].
Most of the experimental procedures are performed using conventional batch or chamber reactors equipped with mercury lamps [21,22]. These traditional conditions commonly demand prolonged irradiation times due to poor light penetration and mixing or cause decomposition of light-sensitive photoproducts due to over-irradiation [23,24]. Recently, continuous flow chemistry has been developed as a new process technology for the on-site and on-demand synthesis of chemical products [25,26,27]. Flow operation inside narrow inner structures has proven especially beneficial for preparative photochemistry [28,29,30,31,32]. As a result, photochemical transformations are now routinely performed under continuous-flow conditions even on larger scales [33]. Despite this, only three flow-photochemical studies involving quinones have been reported so far [34,35,36]. Of these, photoacylations were conducted in a machined microchip [35] or in an improvised solar trough reactor [36]. This study thus investigated photoacylations of 1,4-naphthoquinone in a simple capillary reactor, of which some transformations were furthermore coupled with in-series oxidation.

2. Materials and Methods

2.1. General Information

All solvents and reagents were commercially available (Merck Life Science Pty Ltd., Bayswater, VIC, Australia, or Thermo Fisher Scientific Australia Pty Ltd., Scoresby, VIC, Australia) and were used without purification. 1,4-Naphthoquinone was purified by sublimation prior to use. Aldehydes were stored under nitrogen to prevent autooxidation [37].
Continuous-flow irradiations were conducted in an in-house reactor system equipped with a single UVB fluorescent tube (G8T5E, Ushio Inc., Tokyo, Japan) [38]. Tandem photoacylation–oxidations were performed in a modified version of this reactor. The plunger cartridge was loosely filled with a mixture of freshly prepared Ag2O (10 g) [39] and anhydrous sodium sulfate (10 g). Additional information and pictures of the reactors can be found in the Supplementary Materials.
Column chromatography was carried out in Pyrex glass columns using Scharlau silica gel 60 (particle size 0.06–0.2 nm) and 70–230 mesh ASTM as a stationary phase. Mixtures of cyclohexane and ethyl acetate (4:1) were used as the mobile phase.
Melting points were measured in open capillaries using a Tathastu or Gallenkamp melting point apparatus and are uncorrected.
NMR spectra were recorded on a Bruker 400 AscendTM (1H: 400 MHz and 13C: 100 MHz) equipped with an auto-sampler. NMR spectra were processed using the MestReNova software (Version 6.0.2-5475, Mestrelab Research S.L., Santiago de Compostela, Spain) and the residual solvent peak as an internal standard. Samples were prepared in CDCl3 (δ = 7.26/77.3 ppm ppm), DMSO-d6 (δ = 2.50/39.5 ppm) and acetone-d6 (δ = 2.09/30.6 ppm). NMR-spectra of all photoacylation products can be found in the Supplementary Materials.
Mass spectra were recorded using direct injection on a Shimadzu LCMS-2020 equipped with a DUIS ion source. Ions were subsequently detected in positive mode and/or negative mode within a mass range of m/z 100–500. The mobile phases were aqueous solutions of HPLC-grade methanol or acetonitrile with 0.1% formic acid added. All experimental event sequences were controlled, and processing was performed using LabSolutions for LCMS-2020 software. Alternatively, MS spectra were recorded on a Finnigan MAT 312 (EI, 70 eV) with an SS 300 data system.
Infrared spectra were recorded on a Perkin Elmer Spectrum One FT-IR Spectrometer as thin films. Spectra were recorded in the range of 600–4000 cm−1.

2.2. General Procedure for Photoacylations Under Continuous-Flow Conditions

The cooling fans and fluorescent tube of the in-house flow reactor were started, and the capillary tube was flushed with acetone. A solution of 1,4-naphthoquinone (0.5 mmol) and aldehyde (2.5 mmol) in acetone (25 mL) was degassed with nitrogen for 5 min, drawn into a precision syringe, and pumped at a flow rate of 0.071 mL/min through the reactor tube. The capillary tube was subsequently flushed with approx. 15 mL of acetone. The reaction mixture and wash acetone portions were collected in an amber round-bottom flask. The solvent was removed by evaporation, and the residues were subjected to repeated trituration using cyclohexane and sonication or to column chromatography.

2.3. General Procedure for Tandem Photoacylation–Oxidation Reactions

Following the same general procedure as described above, a previously degassed solution of 1,4-naphthoquinone (0.5 mmol) and aldehyde (2.5 mmol) in acetone (25 mL) was pumped through the tandem reactor at a flow rate of 0.071 mL/min. The reaction mixture and all acetone washings were evaporated to dryness, and the residues were subjected to repeated trituration using cold diethyl ether or to column chromatography.

2.4. Spectroscopic Details

All photoacylation and oxidation products are known, and their spectroscopic details matched previously described data.
1-(1,4-Dihydroxynaphthalen-2-yl) butan-1-one (3a) [40]. Yellow solid. M.p.: 144–145 °C (Lit. 145–146 °C). 1H-NMR (400 MHz, CDCl3): δ = 13.78 (s, 1H, OH), 8.46 (d, J = 8 Hz, 1H, CHarom), 8.10 (d, J = 8.2, 1H, CHarom), 7.68 (ddd, J = 8.3, 1.4 Hz, 1H, CHarom), 7.58 (ddd, J = 8.2, 1.3 Hz, 1H, CHarom), 7.03 (s, 1H, CHarom), 5.07 (br s, 1H, OH), 2.96 (t, J = 7.4 Hz, 2H, CH2), 1.82 (sxt, J = 7.4 Hz, 2H, CH2), 1.05 (t, J = 7.4 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 206.0, 157.6, 143.0, 129.8, 129.5, 126.7, 126.3, 124.8, 121.7, 111.9, 105.6, 40.8, 18.2, 14.0. MS (DUIS): m/z = 231 [M++H]. MS (EI): m/z = 230 [M+], 213, 187 (100%), 172, 157, 131, 116, 102, 77, 51. IR (neat): ῦ = 3325, 2878–2965, 1632, 1588, 1464, 1378, 1325, 1293, 1201, 1136, 1070, 1041, 868, 818, 763.
1-(1,4-Dihydroxynaphthalen-2-yl) propan-1-one (3b) [10]. Yellow solid. M.p.: 175–177 °C (Lit. 178–179 °C). 1H-NMR (400 MHz, acetone-d6): δ = 13.68 (s, 1H, OH), 8.64 (br s, 1H, OH), 8.39 (d, J = 8.3 Hz, 1H, CHarom), 8.21 (dd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.70 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.60 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.20 (s, 1H, CHarom), 3.10 (q, J = 7.3 Hz, 2H, CH2), 1.22 (t, J = 7.3 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 206.3, 157.4, 143.0, 129.8, 129.4, 126.7, 126.4, 124.8, 121.6, 111.7, 105.5, 32.1, 8.5. MS (DUIS): m/z = 217 [M++H]. MS (EI): m/z = 216 [M+, 100%], 202, 187, 159, 131, 103, 77, 51. IR (neat): ῦ = 3396, 3356, 2980, 2915, 1635, 1590, 1472, 1380, 1304, 1207, 1073, 802, 760.
1-(1,4-Dihydroxynaphthalen-2-yl) heptan-1-one (3c) [41]. Yellow solid. M.p.: 133–134 °C (Lit. 135–136 °C). 1H-NMR (400 MHz, CDCl3): δ = 13.77 (s, 1H, OH), 8.45 (d, J = 8.3 Hz, 1H, CHarom), 8.09 (d, J = 8.3 Hz, 1H, CHarom), 7.67 (ddd, J = 8.3, 1.4 Hz, 1H, CHarom), 7.57 (ddd, J = 8.3, 1.4 Hz, 1H, CHarom), 7.02 (s, 1H, CHarom), 5.15 (br s, 1H, OH), 2.96 (t, J = 7.4 Hz, 2H, CH2), 1.77 (quin, J = 7.4 Hz, 2H, CH2), 1.46–1.24 (br m, 6H, 3 × CH2), 0.90 (t, J = 6.9 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 206.2, 157.5, 143.1, 129.8, 129.5, 126.6, 126.3, 124.7, 121.7, 111.9, 105.9, 38.9, 31.8, 29.2, 24.7, 22.7, 14.2. MS (DUIS): m/z = 271 [M+-H]. MS (EI): m/z = 272 [M+, 100%], 254, 225, 202, 187, 172, 158, 131, 103, 77, 55. IR (neat): ῦ = 3425, 3348, 2860–2952, 1635, 1590, 1467, 1375, 1296, 1191, 1138, 1070, 1023, 876, 760.
1-(1,4-Dihydroxynaphthalen-2-yl) dodecan-1-one (3d) [36]. Yellow solid. M.p.: 105–106 °C (Lit. 130–133 °C). 1H-NMR (400 MHz, CDCl3): δ = 13.78 (s, 1H, OH), 8.46 (d, J = 8.4 Hz, 1H, CHarom), 8.10 (d, J = 8.4 Hz, 1H, CHarom), 7.67 (ddd, J = 8.4, 1.3 Hz, 1H, CHarom), 7.57 (ddd, J = 8.4, 1.2 Hz, 1H, CHarom), 7.02 (s, 1H, CHarom), 5.16 (br s, 1H, OH), 2.95 (t, J = 7.5 Hz, 2H, CH2), 1.77 (quin, J = 7.5 Hz, 2H, CH2), 1.45–1.20 (br m, 16H, 8 × CH2), 0.88 (t, J = 6.8 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 206.2, 157.6, 143.0, 129.8, 129.5, 126.7, 126.4, 124.8, 121.6, 111.8, 105.7, 38.9, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 24.8, 22.8, 14.3. MS (DUIS): m/z = 341 [M+-H]. MS (EI): m/z = 342 [M+, 100%], 324, 239, 225, 202, 187, 172, 157, 131, 103, 77, 55. IR (neat): ῦ = 3338, 2957, 2917, 2849, 1635, 1588, 1401, 1293, 1075, 763.
1-(1,4-Dihydroxynaphthalen-2-yl) buten-1-one (3e) [36]. Reddish solid. M.p.: 169–170 °C (Lit. 164–165 °C). 1H-NMR (400 MHz, DMSO-d6): δ = 14.13 (s, 1H, OH), 9.76 (s, 1H, OH), 8.31 (d, J = 8.3 Hz, 1H, CHarom), 8.13 (d, J = 8.3 Hz, 1H, CHarom), 7.72 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.61 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.20 (s, 1H, CHarom), 7.18–7.15 (m, 2H, 2 × CH=), 2.05 (d, J = 4.1 Hz, 3H, CH3). 13C-NMR (100 MHz, acetone-d6): δ = 194.3, 158.7, 146.5, 145.5, 130.9, 130.3, 127.2, 126.9, 126.7, 124.8, 123.1, 113.0, 105.3, 18.7. MS (DUIS): m/z = 229 [M++H]. IR (neat): ῦ = 3302, 1630, 1578, 1514, 1474, 1441, 1390, 1299, 1221, 1140, 1076, 1062, 959, 893, 810, 762.
(1,4-Dihydroxynaphthalen-2-yl)(4-methylphenyl)methanone (3f) [36]. Orange-brown solid. M.p.: 154–155 °C (Lit. 167–169 °C). 1H-NMR (400 MHz, acetone-d6): δ = 13.55 (s, 1H, OH), 8.66 (br s, 1H, OH), 8.45 (d, J = 8.4 Hz, 1H, CHarom), 8.23 (d, J = 8.4 Hz, 1H, CHarom), 7.74 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.69–7.62 (m, 3H, CHarom), 7.42 (d, J = 7.8 Hz, 2H, CHarom), 7.02 (s, 1H, CHarom), 2.47 (s, 3H, CH3). 13C-NMR (100 MHz, acetone-d6): δ = 201.8, 158.0, 145.2, 143.1, 136.6, 130.5, 130.0, 129.8, 127.3, 126.8, 124.9, 123.2, 112.9, 108.0, 21.5. MS (DUIS): m/z = 279 [M++H]. MS (EI): m/z = 278 (M+), 263, 187, 186 (100%), 158, 139, 131, 130, 119, 105, 102, 91, 76. IR (neat): ῦ = 3293, 1632, 1580, 1551, 1393, 1286, 1249, 1073, 828, 755.
(1,4-Dihydroxy-2-naphthalenyl)bis(p-tolylmethanone) (5) [36]. Orange solid. M.p.: 169–170 °C (Lit. 169–170 °C). 1H-NMR (400 MHz, acetone-d6): δ = 12.26 (s, 2H, OH), 8.52 (m, 2H, CHarom), 7.03 (m, 2H, CHarom), 2.37 (s, 6H, 2 × CH3). 13C-NMR (100 MHz, acetone-d6): δ = 198.7, 154.2, 144.0, 138.3, 131.2, 129.7, 129.5, 129.4, 125.2, 112.6, 21.5. MS (DUIS): m/z = 397 [M++H]. IR (neat): ῦ = 3330, 2969–2919, 1738, 1658, 1592, 1495, 1454, 1372, 1281, 1229, 1216, 1117, 1034, 996, 901, 814, 749.
(1,4-Dihydroxynaphthalen-2-yl)(4-chlorophenyl)methanone (3g) [36]. Brownish solid. M.p.: 207–208 °C (Lit. 189–190 °C). 1H-NMR (400 MHz, CDCl3): δ = 13.43 (s, 1H, OH), 9.98 (s, 1H, OH), 8.13 (d, J = 8.3 Hz, 1H, CHarom), 8.03 (d, J = 8.6 Hz, 1H, CHarom), 7.72 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.66 (d, J = 8.6 Hz, 2H, CHarom), 7.62 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.50 (d, J = 8.6 Hz, 2H, CHarom), 7.45 (d, J = 8.6 Hz, 1H, CHarom), 6.82 (s, 1H, CHarom). 13C-NMR (100 MHz, CDCl3): δ = 199.5, 159.1, 142.9, 138.2, 136.7, 131.7, 130.5, 130.4, 129.7, 129.1, 128.9, 126.9, 126.3, 124.9, 121.9, 111.4, 107.7. MS (DUIS): m/z = 299 [M++H]. IR (neat): ῦ = 3295, 2554, 1677, 1633, 1580, 1545, 1425, 1398, 1294, 1200, 1110, 1076, 998, 843, 757.
(1,4-Dihydroxynaphthalen-2-yl)(furan-2-yl)methanone (3h) [11]. Orange solid. M.p.: 188–189 °C (Lit. 188.5–189 °C). 1H-NMR (400 MHz, acetone-d6): δ = 13.87 (s, 1H, OH), 8.82 (broad s, 1H, OH), 8.44 (d, J = 7.8 Hz, 1H, CHarom), 8.24 (d, J = 8.3 Hz, 1H, CHarom), 8.02 (m, 1H, CHarom), 7.81 (s, 1H, CHarom), 7.75 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.64 (ddd, J = 8.3, 1.3 Hz, 1H, CHarom), 7.56 (m, 1H, CHarom), 6.82 (m, 1H, CHarom). 13C-NMR (100 MHz, acetone-d6): δ = 185.1, 159.0, 153.2, 148.6, 145.7, 139.9, 130.6, 127.3, 126.8, 124.9, 123.1, 121.6, 113.5, 112.2, 106.2. IR (neat): ῦ = 3299, 3132, 2852, 1634, 1560, 1459, 1387, 1301, 1275, 1197, 1123, 1076, 1030, 914, 886, 751.
2-Butanoyl-1,4-naphthoquinone (6a) [19]. Orange-brownish solid. M.p.: 66–67 °C (Lit. 64–66 °C). 1H-NMR (400 MHz, CDCl3): δ = 8.10 (dd, J = 8.9 Hz, 1H, CHarom), 7.83–7.75 (m, 3H, CHarom), 7.07 (s, 1H, CHquin), 2.92 (t, J = 7.3 Hz, 2H, CH2), 1.72 (sxt, J = 7.3 Hz, 2H, CH2), 0.99 (t, J = 7.3 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 200.9, 185.1, 183.5, 146.2, 136.7, 134.6, 134.5, 131.9, 127.0, 126.4, 45.5, 17.2, 13.8. MS (EI): m/z = 229 (M+1), 210, 200, 185, 157 (100%), 129, 101, 76, 50, 39. IR (neat): ῦ = 3041, 2965, 2933, 2875, 1664, 1588, 1454, 1346, 1293, 1251, 1225, 1041, 931, 868, 776, 713.
2-Propanoyl-1,4-naphthoquinone (6b) [19]. Orange-brown solid. M.p.: decomposition >50 °C (Lit. 84–85 °C). 1H-NMR (400 MHz, CDCl3): δ = 8.10 (dd, J = 9.0 Hz, 1H, CHarom), 7.84–7.73 (m, 3H, CHarom), 7.09 (s, 1H, CHquin), 2.97 (q, J = 7.2 Hz, 2H, CH2), 1.19 (t, J = 7.2 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 200.2, 184.1, 182.5, 145.3, 136.2, 134.1, 134.0, 131.3, 126.5, 126.0, 37.4, 8.4. MS (EI): m/z = 215 (M+1), 196, 187, 168, 157 (100%), 129, 101, 76, 50, 39. IR (neat): ῦ = 2978, 2936, 1661, 1588, 1341, 1296, 1251, 1220, 941, 773.
2-Dodecanoyl-1,4-naphthoquinone (6d) [42]. Yellow solid. M.p.: 62–64 °C (Lit. 65–66 °C). 1H-NMR (400 MHz, CDCl3): δ = 8.10 (m, 2H, 2 × CHarom), 7.81 (m, 2H, 2 × CHarom), 7.08 (s, 1H, CHquin), 2.93 (t, J = 7.2 Hz, 2H, CH2), 1.68 (q, J = 7.2 Hz, 2H, CH2), 1.20–1.40 (br m, 16H, 8 × CH2), 0.88 (t, J = 6.8 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3): δ = 201.2, 185.1, 183.5, 146.2, 136.7, 134.7, 134.5, 131.9, 131.9, 127.0, 126.5, 43.7, 32.1, 29.8, 29.7, 29.6, 29.5, 29.2, 23.7, 22.8, 14.3. IR (neat): ῦ = 2959, 2917, 282, 1693, 1667, 1590, 1296, 1249, 786, 715.
2-Crotonyl-1,4-naphthoquinone (6e) [43]. Brownish oily solid. 1H-NMR (400 MHz, CDCl3): δ = 8.15–8.06 (m, 2H, 2 × CHarom), 7.82–7.77 (m, 2H, 2 × CHarom) 7.01 (s, 1H, CHarom), 7.00–6.91 (m, 1H, CH=), 6.53 (dd, J = 15.7 Hz, 1H, CH=), 2.05 (dd, J = 6.9 Hz, 3H, CH3).

3. Results and Discussion

3.1. Photoacylations Under Continuous-Flow Conditions

3.1.1. In-House Capillary Reactor

The reactor setup has been described in detail earlier [38]. The device consisted of a fluorinated ethylene propylene (FEP, λ ≥ 240 nm [44]) capillary tightly wrapped around a Pyrex (λ ≥ 300 nm [21]) cylinder with a single 8 W fluorescence tube in its center. The reaction mixture was transferred through the capillary tubing with a syringe pump and collected in an amber flask.

3.1.2. Optimization Study

The photoacylation of 1,4-naphthoquinone (1) in the presence of butyraldehyde (2a) was selected as a model reaction (Scheme 2) for process optimization. Irradiations were initially conducted under direct excitation conditions of 1 with UVB light (λ = 300 ± 25 nm) to shorten the reaction time [45]. Previously degassed solutions of the starting materials (0.5 mmol of 1 and 2.5 mmol of 2a in 25 mL of solvent) were pumped through the flow reactor, and the conversion rates of the crude product mixtures were determined by 1H-NMR analysis (Table 1). Most of the batch laboratory procedures reported use benzene [11,40] or trifluorotoluene (TFT) [10,46] as a reaction medium from which the polar acylated naphthohydroquinone products commonly precipitate during irradiation. While this feature minimizes photodegradation of the desired products, it may cause clogging, pressure buildup, and rupture of the flow reactor tube or fittings [47]. The polar aprotic acetonitrile was thus initially chosen as the solvent to determine the best residence time for high conversions.
In acetonitrile, all reactions proceeded cleanly and selectively with acceptable losses during workup [48]. Residence times of 25, 50, and 70 min already achieved good to high conversion rates of 82, 87, and 90% and isolated yields for 3a of 70, 78, and 86% (entries 1–3), respectively. A further increase to 100 min only marginally increased the conversion to 92% and subsequently the yield to 90% (entry 4). Additional experiments in other solvents were thus conducted with a fixed residence time of 70 min. The reaction proceeded with excellent conversions of 96 and 95% and subsequently yields of 88 and 90% in acetone and chloroform (entries 5 and 6). Despite high conversions of >90%, photoreduction of 1 to 1,4-naphthohydroquinone (4) by hydrogen-abstraction from the solvent became competitive in tert-butyl alcohol [49] (entry 7) and ethyl acetate [50] (entry 8). Acetone was subsequently chosen for further studies due to its low toxicity, excellent solvation properties, and ease of removal [51]. In contrast to all other solvents, acetone also acted as a triplet sensitizer (T1 = 332 kJ/mol vs. 1: T1 = 241 kJ/mol [52]) [53], as similarly demonstrated with benzophenone [54].

3.1.3. Photoacylations with Other Aldehydes

The photoacylation in acetone was subsequently conducted with a series of aliphatic, unsaturated, aromatic, and heteroaromatic aldehydes 2a–h (Scheme 3). Using a general residence time of 70 min, acceptable to high yields of the photoproducts 3a–h of 30–90% were achieved in all cases without any undesired photoreduction to 4 (Table 2).
Short-chain aliphatic aldehydes furnished the desired acylated naphthohydroquinones 3a–c after simple evaporation, drying, and trituration with cyclohexane (entries 1–3). In the case of the non-volatile and oily dodecylaldehyde, the reaction achieved an incomplete conversion of 64%, from which the desired photoproduct 3d could be isolated in 34% yield (53% based on conversion) by column chromatography (entry 4) [48]. The photoacylation of crotonaldehyde readily furnished product 3e again in a yield of 72% without isomerization of the double bond (entry 5) [55]. In the case of p-tolualdehyde, the diacylated product 5 was additionally obtained in a yield of 12%, along with the mono-acylated compound 3f in 66% (entry 6). While bisacylation products have been previously reported, the mechanism of their formation remains largely unknown [12,19]. In contrast, p-chlorobenzaldehyde selectively furnished the corresponding mono-acylated product 3g in a high yield of 80% (entry 7). The heteroaromatic furfural achieved a somewhat lower yield of 3h of 30% due to the need for chromatographic purification (entry 8) [48]. In their 1H-NMR spectra, all photoproducts 3a–h showed a characteristic sharp singlet peak between 13.5 and 14.2 ppm for the newly formed hydroxy group at C-1, which is locked in an intramolecular hydrogen bond with the acyl-carbonyl group. For the bisacylation product 5, steric hindrance caused a distortion of this hydrogen bond, which subsequently shifted to 12.26 ppm instead.

3.2. Tandem Photoacylation–Oxidation Reactions Under Continuous-Flow Conditions

Individual continuous-flow processes can be easily combined in series through telescoping [56]. The photoacylation was thus coupled with a thermal oxidation step using silver (I) oxide to obtain the corresponding acylated 1,4-naphthoquinone derivatives (Scheme 4) [57]. Both processes have been separately conducted in flow in the past [35,36,58].

3.2.1. In-House Tandem Capillary Reactor

The capillary reactor was modified to allow for in-flow oxidation (Figure 1). The effluent stream of the photoreactor module entered a plunger cartridge against gravity from the bottom. All connecting tubes were masked with black shrinking tube. The cartridge was loosely loaded with solid Ag2O and anhydrous sodium sulfate, and the product solution was collected externally in an amber flask.

3.2.2. Tandem Photoacylation–Oxidation Reactions with Selected Aldehydes

Maintaining the advantageous residence time for light exposure of 70 min, previously degassed solutions of 1,4-naphthoquinone (1; 0.5 mmol) and selected aldehydes (2a,b,d,e; 2.5 mmol) in acetone (25 mL) were pumped through the tandem reactor. The desired acylated naphthoquinones 6a,b,d,e were subsequently obtained as colorful solids and in yields of 15–94% after a total residence time of under 2 h each (Table 3). Due to their known sensitivity towards spontaneous thermal reduction [46], the dried acylated naphthoquinones were stored in the dark and under nitrogen. The identity of the compounds was confirmed by the presence of three carbonyl singlet peaks between 180 and 205 ppm in their respective 13C-NMR spectra.
Organics 06 00009 g001
Figure 1. In-house tandem photochemical–thermal continuous-flow reactor during operation.
Figure 1. In-house tandem photochemical–thermal continuous-flow reactor during operation.
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In line with the decoupled flow-photoacylation, butyraldehyde and propionaldehyde achieved complete conversions of 1 and furnished the desired acylated naphthoquinones 6a and b in high yields of 94 and 76% (entries 1 and 2), respectively. Likewise, the long-chained dodecylaldehyde only accomplished an incomplete consumption of 1 of 61%, which resulted in a low yield of 6d of 15% (25% based on conversion) due to significant losses during workup and isolation (entry 3) [48]. For crotonaldehyde, near-complete consumption of 1 was again noted, and the tandem process produced compound 6e in 75% yield.
Despite its improvised design, the flow device showed excellent performance for stand-alone or coupled operation. The narrow FEP tubing with an inner diameter of just 0.8 mm enabled superior light penetration for photoacylation. Although the capillary coil only covered approximately ⅓ of the arc length of the central fluorescent tube, its inside–out irradiation design permitted efficient light utilization. The flow reactor is easily constructed from readily available components and only utilizes a single 8 W fluorescent tube. In comparison, the corresponding batch protocols demand prolonged reaction times of several hours to achieve similar conversions or yields [10,11,12,40,46].

4. Conclusions

In conclusion, a series of photoacylations of 1,4-naphthoquinone with various aldehydes was successfully realized under continuous-flow conditions in an in-house reactor. The simple procedure furnished the corresponding acylated 1,4-naphthohydroquinones in acceptable to high yields with residence times of just 70 min. In-series coupling with thermal oxidation in a tandem reactor enabled the direct synthesis of acylated 1,4-naphthoquinones in reasonable to excellent yields and total residence times of under 2 h. The easy reaction protocols of both processes may be readily scaled up [59] or conducted more efficiently in a purpose-designed flow module [60].

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/org6010009/s1: Experimental details, procedures, and NMR spectra. Figure S1: In-house continuous-flow capillary reactor during operation. Figure S2: In-house tandem photochemical–thermal continuous-flow reactor during operation.

Author Contributions

M.A.Y. conducted the research and collected the data; M.O. secured the funding, supervised the research, and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the College of Science and Engineering at James Cook University through a Competitive Research Training Grant.

Data Availability Statement

All data are available upon request from the corresponding author.

Acknowledgments

M.A.Y. thanks the Ministry of Higher Education and Scientific Research of Iraq for a Ph.D. Scholarship.

Conflicts of Interest

The authors declare no conflicts of interest.

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Organics 06 00009 sch001
Scheme 1. Photoacylation of 1,4-quinones with aldehydes.
Scheme 1. Photoacylation of 1,4-quinones with aldehydes.
Organics 06 00009 sch001
Organics 06 00009 sch002
Scheme 2. Photoacylation of 1,4-naphthoquinone with butyraldehyde as a model system for process optimization.
Scheme 2. Photoacylation of 1,4-naphthoquinone with butyraldehyde as a model system for process optimization.
Organics 06 00009 sch002
Organics 06 00009 sch003
Scheme 3. Photoacylation of 1,4-naphthoquinone with various aldehydes.
Scheme 3. Photoacylation of 1,4-naphthoquinone with various aldehydes.
Organics 06 00009 sch003
Organics 06 00009 sch004
Scheme 4. Tandem photoacylation–oxidation to acylated 1,4-naphthoquinones.
Scheme 4. Tandem photoacylation–oxidation to acylated 1,4-naphthoquinones.
Organics 06 00009 sch004
Table 1. Experimental results of the optimization study with Pyrex-filtered UVB light.
Table 1. Experimental results of the optimization study with Pyrex-filtered UVB light.
EntrySolventResidence Time (min)Conversion (%) 1Yield of 3a (%) 2
1acetonitrile258270
2acetonitrile508778
3acetonitrile709086
4acetonitrile1009290
5acetone709688
6chloroform709590
7tert-butyl alcohol7092 (22 3)55
8ethyl acetate7091 (16 3)53
1 Determined by 1H-NMR analysis (±3%). 2 After trituration with cyclohexane. 3 Amount of photoreduction product 4 in crude product mixture.
Table 2. Experimental results of photoacylations with various aldehydes (residence time of 70 min).
Table 2. Experimental results of photoacylations with various aldehydes (residence time of 70 min).
EntryRYield of 3 (%)
1C3H790 (a) 1
2C2H571 (b) 1
3C6H1375 (c) 1
4C11H2334 (d) 2/64 3
5E-CH3CH=CH72 (e) 1
6p-MeC6H466 (f) 2/12 (5) 2,4
7p-ClC6H480 (g) 1
8Organics 06 00009 i00130 (h) 2
1 After trituration with cyclohexane. 2 After column chromatography. 3 Conversion of 1 as determined by 1H-NMR analysis (±3%). 4 Amount of bisacylation product 5.
Table 3. Experimental results of tandem photoacylation–oxidations with selected aldehydes (total residence time of under 2 h).
Table 3. Experimental results of tandem photoacylation–oxidations with selected aldehydes (total residence time of under 2 h).
EntryRYield of 6 (%)
1C3H794 (a) 1
2C2H576 (b) 1
3C11H2315 (d) 1/61 2
4E-CH3CH=CH75 (e) 1
1 After trituration with cold diethyl ether. 2 Conversion of 1 as determined by 1H-NMR analysis (±3%).
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Yaseen, M.A.; Oelgemöller, M. Photochemical Acylation of 1,4-Naphthoquinone with Aldehydes Under Continuous-Flow Conditions. Organics 2025, 6, 9. https://doi.org/10.3390/org6010009

AMA Style

Yaseen MA, Oelgemöller M. Photochemical Acylation of 1,4-Naphthoquinone with Aldehydes Under Continuous-Flow Conditions. Organics. 2025; 6(1):9. https://doi.org/10.3390/org6010009

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Yaseen, Madyan A., and Michael Oelgemöller. 2025. "Photochemical Acylation of 1,4-Naphthoquinone with Aldehydes Under Continuous-Flow Conditions" Organics 6, no. 1: 9. https://doi.org/10.3390/org6010009

APA Style

Yaseen, M. A., & Oelgemöller, M. (2025). Photochemical Acylation of 1,4-Naphthoquinone with Aldehydes Under Continuous-Flow Conditions. Organics, 6(1), 9. https://doi.org/10.3390/org6010009

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