Configurationally Stable Atropisomeric Acridinium Fluorophores

Arylated heterocyclic fluorophores are particularly useful scaffolds for numerous applications, such as bioimaging or synthetic photochemistry. While variation of the substitution pattern at the heterocycle and aryl groups allows dye modulation, the bond rotational barriers are also strongly affected. Unsymmetrically substituted ring systems of rotationally restricted arylated heterocycles therefore lead to configurationally stable atropisomeric fluorophores. Herein, we describe these characteristics by determining the properties and configurational stability of atropisomeric, tri-ortho-substituted naphthyl-acridinium fluorophores. A significant barrier to rotation of >120 kJ mol^–1 was measured, which renders these dyes and related compounds distinct atropisomers with stereoisomer-specific properties over a broad temperature range.

Key words

atropisomerism - heterocycles - fluorophores - acridinium salts - barrier to rotation

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References and Notes

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9 General Procedure for the Double Directed ortho-MetalationTo a solution of bis(3-methoxyphenyl)-amine (160 μmol) in n-hexane (2.0 mL) was added a solution of n-butyllithium in hexanes (176 μL, 1.49 mol L^–1, 320 μmol) at RT. The mixture was stirred 6 h at 65 °C. The reaction mixture was directly used in the next step.
10 General Procedure for the Transformation of Esters into Acridinium SaltsTo the reaction mixture of the metalated aryl aniline in n-hexane (160 μmol) at –20 °C was added a solution of carboxylic acid ester (100 μmol) in anhydrous THF (0.60 mL), and the reaction mixture was allowed to warm to RT over 12 h. Aqueous HBr (1.00 mL, 48%) was added, followed by water (20 mL), and the mixture was extracted by CHCl₃/i-PrOH (4 × 10 mL; 85:15). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Column chromatography using 100% CH₂Cl₂ to CH₂Cl₂/MeOH (100:2 to 100:3 to 100:4) provided the product.
11 (±)-3-(Dimethylamino)-1,8-dimethoxy-9-(naphthalen-1-yl)-10-phenylacridinium bromide salt (4a)Prepared according to the above general procedures using 5-methoxy-N ¹-(3-methoxyphenyl)-N ³,N ³-dimethyl-N-phenylbenzene-1,3-diamine (55.8 mg, 160 μmol) and methyl 1-naphthoate (18.6 mg, 100 μmol). Purification provided a brown-red solid (14.4 mg, 26%, HPLC purity: 89% at 400 nm, decomp. at 131 °C): R_f = 0.12 (CH₂Cl₂/MeOH, 10:1); IR (neat): ν_max = 3369w, 2925w, 2361w, 1623s, 1598s, 1497s, 1475s, 1427m, 1377m, 1349s, 1255s, 1168w, 1102s, 972m, 785s, 768s, 707m. ¹H NMR (500 MHz, CDCl₃): δ = 7.95 (1 H, d, ³ J = 8.2 Hz, C5′H), 7.87–7.91 (3 H, m, C4′H, C3′′H, C5′′H), 7.79–7.81 (1 H, m, C4′′H), 7.60 (1 H, t, ³ J = 8.4 Hz, C6H), 7.46–7.52 (4 H, m, C3′H, C6′H, C2′′H, C6′′H ), 7.41–7.42 (1 H, m, C8′H), 7.34–7.37 (1 H, m, C7′H), 7.09 (1 H, d, ³J = 6.9 Hz, C2′H), 6.64 (1 H, d, ³J = 8.0 Hz, C7H), 6.57 (1 H, d, ³ J = 8.8 Hz, C5H), 6.32 (1 H, d, ⁴J = 1.2 Hz, C2H), 5.48 (1 H, d, ⁴J = 1.3 Hz, C4H), 3.14 (3 H, s, C1OCH₃), 3.12 (6 H, br, N(CH₃)₂), 2.99 (3 H, s, C8OCH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 161.1 (C1), 159.8 (C8), 157.3 (C3), 155.1 (C9), 145.3 (C4a), 142.0 (C10a), 140.0 (C1′), 138.7 (C1′′), 136.4 (C6), 132.2 (C4′a), 132.2 (C3′′), 132.1 (C8′a), 132.0 (C5′′), 131.1 (C4′′), 128.1 (C5′), 128.1 (C2′′), 128.0 (C6′′), 127.0 (C4′), 126.0 (C7′), 125.6 (C6′), 125.1 (C8′), 124.9 (C3′), 121.9 (C2′), 116.4 (C9a), 115.3 (C8a), 109.7 (C5), 106.0 (C7), 95.9 (C2), 89.1 (C4), 56.8 (C1OCH₃), 56.2 (C8OCH₃), 41.2 (N(CH₃)₂). ESI-MS: m/z calcd for C₃₃H₂₉N₂O₂ ⁺: 485.2224; found: 485.2226 [M⁺]. Luminescence spectroscopy (in MeCN): λ_abs1: 504 nm; λ_abs2: 431 nm; λ_abs3: 311 nm; ε_abs1: 8.5·10³ L cm mol^–1; ε_abs2: 1.6·10⁴ L cm mol^–1; ε_abs3: 4.1·10⁴ L cm mol^–1; λ_em(exc 495 nm): 590 nm; Stokes shift: 86 nm; E_0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E_1/2(P*/P^–): +1.36 V; E_1/2(P/P^–): –0.86 V.
12 (±)-3-(Dimethylamino)-9-(4-fluoronaphthalen-1-yl)-1,8-dimethoxy-10-phenylacridinium bromide salt (4b)Prepared according to the above general procedures using 5-methoxy-N ¹-(3-methoxyphenyl)-N ³,N ³-dimethyl-N-phenylbenzene-1,3-diamine (55.8 mg, 160 μmol) and methyl 4-fluoro-1-naphthoate (20.4 mg, 100 μmol). Purification gave a brown red solid (20.1 mg, 34%, HPLC purity: 93% at 400 nm, decomp. at 134 °C): R_f = 0.14 (CH₂Cl₂/MeOH, 10:1). IR (neat): ν_max = 2934w, 1623s, 1598s, 1503s, 1469s, 1429m, 1348m, 1256s, 1233m, 1166w, 1098s, 1036w, 907w, 767s, 707m. ¹H NMR (500 MHz, CDCl₃): δ = 8.22 (1 H, d, ³ J = 8.8 Hz, C5′H), 7.87–7.91 (2 H, m, C3′′H, C5′′H), 7.78–7.81 (1 H, m, C4′′H), 7.55–7.61 (2 H, m, C6′H, C6H), 7.46–7.52 (2 H, m, C2′′H, C6′′H), 7.43–7.44 (2 H, m, C7′H, C8′H), 7.17–7.21 (1 H, m, C3′H), 7.01–7.04 (1 H, m, C2′H), 6.64 (1 H, d, ³ J = 7.9 Hz , C7H), 6.57 (1 H, d, ³ J = 8.8 Hz, C5H), 6.36 (1 H, d, ⁴ J = 1.2 Hz, C2H), 5.48 (1 H, d, ⁴ J = 1.2 Hz, C4H), 3.20 (3 H, s, C1OCH₃), 3.12 (6 H, br, N(CH₃)₂), 3.04 (3 H, s, C8OCH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 160.9 (C1), 159.6 (C8), 158.0 (d, ² J_CF = 251 Hz, C4′), 157.3 (C3), 154.0 (C9), 145.3 (C4a), 142.1 (C10a), 138.7 (C1′′), 136.3 (C6), 135.9 (d, ⁴ J_CF = 4.8 Hz, C1′), 133.5 (d, ³ J_CF = 4.7 Hz, C8′a), 132.2 (C3′′), 132.0 (C5′′), 131.1 (C4′′), 128.1 (C2′′), 128.0 (C6′′), 127.1 (C7′), 126.0 (C6′), 125.2 (d, ⁴ J_CF = 2.6 Hz, C8′), 122.6 (d, ² J_CF = 17.0 Hz, C4′a), 121.6 (d, ³ J_CF = 8.2 Hz, C2′), 120.6 (d, ³ J_CF = 5.1 Hz, C5′), 116.8 (C9a), 115.3 (C8a), 109.8 (C5), 108.5 (d, ² J_CF = 20.4 Hz, C3′), 105.9 (C7), 96.2 (C2), 89.2 (C4), 56.9 (C8OCH₃), 56.2 (C1OCH₃), 41.0 (N(CH₃)₂). ¹⁹F NMR (471 MHz, CDCl₃): δ = –124.6. ESI-MS: m/z calcd for C₃₃H₂₈FN₂O₂ ⁺: 503.2128; found: 503.2129 [M⁺]. Luminescence spectroscopy (in MeCN): λ_abs1: 501 nm; λ_abs2: 430 nm; λ_abs3: 311 nm; ε_abs1: 5.9·10³ L cm mol^–1; ε_abs2: 1.0·10⁴ L cm mol^–1; ε_abs3: 2.9·10⁴ L cm mol^–1; λ_em(exc 496 nm): 591 nm; Stokes shift: 90 nm; E_0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E_1/2(P*/P^–): +1.37 V; E_1/2(P/P^–): –0.85 V.
13 General Procedure for the Preparation of the leuco-Form A solution of dye 4a or 4b in EtOH (10.0 μmol, ca. 0.01 mol L^–1) was treated with a suspension of sodium borohydride in EtOH (ca. 0.2 mol L^–1) until the intense red color faded. The solution was concentrated in vacuo, extracted with Et₂O (3 x 10 mL) and washed with water (20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the leuco-form 5a and 5b, respectively: Guin J. Besnard C. Lacour J. Org. Lett. 2010; 8: 1748
14 1,8-Dimethoxy-N,N-dimethyl-9-(naphthalen-1-yl)-10-phenyl-9,10-dihydroacridin-3-amine (5a)Prepared according to the above general procedure.R_f = 0.62 (CH₂Cl₂100%). IR (neat): ν_max = 3361w, 3194w, 2922s, 2853m, 1632w, 1592m, 1468m, 1258m, 1090m, 1021m, 909w, 798s, 733m, 700m. ¹H NMR (600 MHz, CDCl₃): δ = 8.98 (1 H, d, ³ J = 8.7 Hz, C8′H), 7.75 (1 H, d, ³ J = 8.0 Hz, C5′H), 7.69 (1 H, dd, ³ J = 7.3 Hz, ⁴ J = 0.7 Hz, C2′H), 7.63–7.66 (2 H, m, C3′′H, C5′′H), 7.55–7.58 (2 H, m, C4′H, C7′H), 7.48–7.52 (3 H, m, C2′′H, C4′′H, C6′′H), 7.41–7.44 (1 H, m, C6′H), 7.27–7.30 (1 H, m, C3′H), 6.82–6.85 (1 H, m, C6H), 6.61 (1 H, s, C9H), 6.25 (1 H, d, ³ J = 8.0 Hz, C7H), 5.92 (1 H, d, ³ J = 8.4 Hz, C5H), 5.74 (1 H, d, ⁴ J = 2.2 Hz, C2H), 5.28 (1 H, d, ⁴ J = 2.2 Hz, C4H), 3.43 (3 H, s, C8OCH₃), 3.43 (3 H, s, C1OCH₃), 2.66 (6 H, s, N(CH₃)₂); see ref. 17. ¹³C NMR (151 MHz, CDCl₃): δ = 158.4 (C1), 157.6 (C8), 149.9 (C3), 147.1 (C1′), 142.6 (C10a), 142.6 (C4a), 141.8 (C1′′), 133.2 (C4′a), 131.4 (C2′′, C6′′), 131.1 (C8′a), 130.5 (C3′′, C5′′), 128.1 (C4′′), 127.8 (C5′), 127.2 (C2′), 126.5 (C6), 126.1 (C8′), 126.0 (C3′), 125.7 (C4′), 124.6 (C6′), 124.3 (C7′), 115.7 (C8a), 107.7 (C5), 105.1 (C9a), 102.6 (C7), 92.8 (C4), 89.7 (C2), 55.2 (C1OCH₃), 55.1 (C8OCH₃), 40.5 (N(CH₃)₂), 30.2 (C9). ESI-MS: m/z calcd for C₃₃H₃₁N₂O₂ ⁺: 487.2380; found: 487.2376 [M + H⁺]. The enantiomers were separated on a Chiracel^® OD-H column (4.6 mm x 150 mm; 5 µm; Art. Nr. 14324) using a 1.0 mL/min flow of n-heptane/i-PrOH 95:5: 5.57 and 6.75 min.
15 9-(4-Fluoronaphthalen-1-yl)-1,8-dimethoxy-N,N-dimethyl-10-phenyl-9,10-dihydroacridin-3-amine (5b)Prepared according to the above general procedure. R_f = 0.74 (CH₂Cl₂ 100%); IR (neat): ν_max = 2926s, 1610s, 1468s, 1311w, 1249s, 1091m, 909w. ¹H NMR (600 MHz, CDCl₃): δ = 8.96 (1 H, d, ³ J = 8.8 Hz, C8′H), 8.04 (1 H, d, ³ J = 8.4 Hz, C5′H), 7.61–7.66 (3 H, m, C7′H, C3′′H, C5′′H), 7.57–7.60 (1 H, m, C2′H), 7.49–7.53 (2 H, m, C6′H, C4′′H), 7.46–7.47 (2 H, m, C2′′H, C6′′H), 6.94–6.98 (1 H, m, C3′H), 6.83–6.86 (1 H, m, C6H), 6.53 (1 H, s, C9H), 6.25 (1 H, d, ³ J = 8.0 Hz, C7H), 5.91 (1 H, d, ³ J = 8.3 Hz, C5H), 5.74 (1 H, d, ⁴ J = 2.2 Hz, C2H), 5.27 (1 H, d, ⁴ J = 2.2 Hz, C4H), 3.44 (3 H, s, C1OCH₃), 3.43 (3 H, s, C8OCH₃), 2.67 (6 H, s, N(CH₃)₂); see ref. 17. ¹³C NMR (125 MHz, CDCl₃): δ = 158.3 (C1), 157.5 (C8), 156.8 (d, ¹ J_CF = 247 Hz, C4′), 149.9 (C3), 143.1 (d, ⁴ J_CF = 4.5 Hz, C1′), 142.6 (C10a), 142.5 (C4a), 141.7 (C1′′), 132.1 (d, ³ J_CF = 4.1 Hz, C8′a), 131.4 (C2′′, C6′′), 130.5 (C3′′, C5′′), 128.1 (C4′′), 126.7 (d, ³ J_CF = 8.4 Hz, C2′), 126.6 (C6), 126.1 (d, ⁴ J_CF = 2.4 Hz, C8′), 125.5 (C7′), 124.9 (d, ⁴ J_CF = 1.3 Hz, C6′), 122.8 (d, ² J_CF = 15.4 Hz, C4′a), 119.9 (d, ³ J_CF = 6.3 Hz, C5′), 115.4 (C8a), 109.6 (d, ³ J_CF = 19.5 Hz, C3′), 107.7 (C5), 104.8 (C9a), 102.6 (C7), 92.7 (C4), 89.6 (C2), 55.1 (C8OCH₃), 55.0 (C1OCH₃), 40.5 (N(CH₃)₂), 30.0 (C9). ¹⁹F NMR (471 MHz, CDCl₃): δ = –126.8. ESI-MS: m/z calcd for C₃₃H₃₀FN₂O₂ ⁺: 505.2286; found: 505.2293 [M + H⁺]. The enantiomers were separated on a Chiracel^® OD-H column (4.6 mm x 150 mm; 5 µm; Art. Nr. 14324) using a 1.0 mL/min flow of n-heptane/i-PrOH 95:5: 5.37 and 6.43 min.
16 NOE enhancements observed between C9H of the acridinium and C8′H of the naphthyl group suggest the structure of the major diastereomer to be rac-5 as shown in Scheme 3.
17 General Procedure for the Oxidation of the leuco-Form A solution of leuco-form 5a or 5b (5.00 μmol) in CH₂Cl₂ (2.0 mL) was treated at RT with an excess of chloranil and the mixture stirred until the red color persisted. The mixture was washed with water (2.0 mL) and 1 M HBr (2 x 1.0 mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by chromatography over silica gel with 100% CH₂Cl₂ and CH₂Cl₂/MeOH (100:5) to provide acridinium bromide salt 4a or 4b: Sakabe M. Asanuma D. Kamiya M. Iwatate RJ. Hanaoka K. Terai T. Nagano T. Urano Y. J. Am. Chem. Soc. 2013; 135: 409

18a λ_abs: 425 nm; λ_em: 501 nm; E_1/2(P*/P^–): +2.06 V, E_1/2(P/P^–): –0.57 V vs. SCE: Tsudaka T. Kotani H. Ohkubo K. Nakagawa T. Tkachenko NV. Lemmetyinen H. Fukuzumi S. Chem. Eur. J. 2017; 23: 1306
18b λ_abs: 412 nm, λ_em: 550 nm; E_1/2(P*/P^–): +1.62 V and E_1/2(P/P^–): –0.84 V vs. SCE: Joshi-Pangu A. Lévesque F. Roth HG. Oliver SF. Campeau L.-C. Nicewicz D. DiRocco DA. J. Org. Chem. 2016; 81: 7244

19a Aliquots treated by NaBH₄ allowed the measurement of change in ee% by HPLC over time for rate of racemization (k_rac ), the barrier to rotation (ΔG ^‡ _393K) and the racemization half-life (t _1/2) determination.
19b Rickhaus M. Jundt L. Mayor M. Chimia 2016; 70: 192
19c Lotter D. Neuburger M. Rickhaus M. Häussinger D. Sparr C. Angew. Chem. Int. Ed. 2016; 55: 2920 ; and page S34 of the related Supporting Information

20 Witzig RM. Lotter D. Fäseke VC. Sparr C. Chem. Eur. J. 2017; 23: 12960
21 The results reported in this publication form part of a patent application: Fischer C. Sparr C. EP 17188288, 2017