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Synlett 2018; 29(16): 2176-2180
DOI: 10.1055/s-0037-1610233
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© Georg Thieme Verlag Stuttgart · New York

Configurationally Stable Atropisomeric Acridinium Fluorophores

Christian Fischer
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland   Email: christof.sparr@unibas.ch
,
Christof Sparr  *
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland   Email: christof.sparr@unibas.ch
› Author Affiliations

We gratefully acknowledge the Swiss National Science Foundation (BSSGI0-155902/1), the University of Basel, and the NCCR Molecular Systems Engineering for generous financial support.
Further Information

Publication History

Received: 15 June 2018

Accepted after revision: 13 July 2018

Publication Date:
03 August 2018 (online)

 
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In Memoriam Kurt Mislow.

Published as part of the Cluster Atropisomerism

Abstract

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.


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Key words

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

Absorption and emission characteristics, brightness, excited-state life times and redox potentials are important attributes for fluorophores used in imaging, synthetic photochemistry, and other applications.[1] Modulation of these properties is typically achieved by altering the substitution pattern of an established arylated heterocyclic fluorophore scaffold. However, these adjustments also impact the symmetry and the conformational behavior of fluorophores such as fluorescein- and rhodamine-derivatives (Scheme [1, a] vs. b).[2] [3] With three or four ortho-substituents, rotation is typically sufficiently hindered in both directions to provide atropisomers that are configurationally stable at ambient temperature and under physiological conditions. Conjugation to a typical biomolecule or other moieties with stereocenters would hence provide diastereoisomers, and in cases of racemic atropisomers, diastereoisomeric mixtures, which can lead to misinterpretation or unnecessarily perplexing analyses. Furthermore, utilizing the rotationally restricted dyes as probes for biological samples may also result in atropisomer-specific interactions as with other distinct stereoisomers, such as bioactive compounds.

Furthermore, isomer-specific chiroptical properties and biological activities can be expected, as observed in the helically shaped [4]heterohelicenium dyes (DMQA, Scheme [1, c]) pioneered by Laursen and Lacour.[4]

Considering the stereodynamic behavior of the acridinium dye obtained from the twofold nucleophilic aromatic substitution with 1-phenylethylamine, featuring a barrier to rotation about the C(sp3)–N(sp2) bond of ΔG ‡ 298 K = 51.4 kJ mol–1, (Scheme [1, d]),[5] [6] we anticipated that acridinium dyes with a tri-ortho-substitution with respect to the aryl–­heterocycle bond would provide configurationally stable atrop­isomers at ambient temperature.

Zoom Image
Scheme 1 Commonly used symmetric a) rhodamine B and fluorescein, b) racemic ATTO 647 dyes. c) Helical chiral DMQA salt. Acridinium salts: d) C–N stereodynamic acridinium salt, e) configurationally stable atropisomeric acridinium fluorophore with hindered rotation about the C(sp2)–C(sp2) bond.

To investigate the conformational behavior, we envisaged their synthesis directly from carboxylic acid esters by employing 1,5-bifuctional organometallic reagents, thus allowing expeditious variation of the C9-substituent.[7] [8] Furthermore, by the double directed ortho-metalation (dDoM) strategy,[7] an unsymmetrically substituted acridinium system with 1,9-dimethoxy-peri-substitution is readily accessible without a preceding halogenation and halogen–metal exchange (Scheme [1, e]). Moreover, we expected that the di-peri-substitution of the acridinium moiety and the 1-naphthyl group from the corresponding carboxylic acid methyl ester would further increase the barrier to rotation about the C(sp2)–C(sp2) bond and thus lead to configurationally stable atropisomeric fluorophores. With the presence of the NMe2 group, we anticipated a bathochromic shift in absorption and emission as well as an attenuation of the redox properties.[7] [8a]

Zoom Image
Scheme 2 Double directed ortho-metalation on tertiary amine 1 allows the synthesis of 1,5-bifunctional organolithium reagent 2. Ensuing addition to ester 3a or 3b and in situ dehydration using aq. HBr allows the direct transformation into atropisomeric acridinium bromide salts.

To prepare the configurationally stable acridinium atrop­isomers, unsymmetrically substituted triarylamine 1 was treated with n-butyllithium in n-hexane at 65 °C to form 1,5-bifunctional organolithium reagent 2 by a dDoM (Scheme [2], top).[7] [9] The addition of 2 to methyl 1-naphthoates 3a and 3b and subsequent treatment with aqueous ­hydrobromic acid thus provided racemic acridinium ­bromide salts 4a and 4b concisely, but with low yields of 26% and 34%, respectively (Scheme [2], bottom).[10] [11] [12]

With tri-ortho-substituted acridinium dyes in hand, we set out to investigate their configurational stability by separating the racemic mixtures into their atropo-enantiomers. By reduction with NaBH4, the dyes 4 were effortlessly converted into their corresponding leuco-forms 5 with a dia­stereomeric ratio of 97:3 (Scheme [3]). Interestingly, HPLC analysis on a chiral stationary phase established that the C(sp3)–N(sp2) bond of leuco-form 5 is sufficiently rotationally ­restricted to allow separation by chromatography at ambient temperature (Chiracel® OD-H, n-heptane/i-PrOH = 95:5).[13] [14] [15] Notably, the separated enantiomers of the leuco-form 5 showed pronounced configurational stability over several days and were also chemically inert to aerobic oxidation at room temperature. To prepare enantioenriched acridinium dyes 4a and 4b, we hence employed chloranil and individually reoxidized the separated enantiomers of the leuco-form 5.[17] A 90:10 enantiopurity of the dyes 4a and 4b was obtained by this method (determined by HPLC analysis of leuco-form samples prepared as previously).

Zoom Image
Scheme 3 Reduction of the racemic dye 4a and 4b by NaBH4,[16] followed by separation and individual oxidation with chloranil gives access to both enantiomers of the atropisomeric fluorophore in 90:10 e.r.

We next investigated the properties of the enantioenriched dyes 4a and 4b by UV and ECD spectroscopy and found pronounced Cotton effects around 240, 260, and 310 nm (Figure [1]).[10] [11] Strong bathochromic shifts in absorption and emission spectra and alleviated redox potentials of the diamino-substituted acridinium salts as compared to the Fukuzumi acridinium- (MesMeAcr) or 9-mesityl-1,3,6,8-­tetramethoxy-10-phenylacridinium salt were measured.[11,12,18] Furthermore, a remarkable configurational ­stability of the atropisomeric acridinium fluorophores was determined in racemization experiments of 4a and 4b in cyclohexanol at 120 °C (Table [1]).[19] In both cases, the tri-ortho-substitution leads to an exceptional configurationally stability and significant bond-rotational barriers of ΔG ‡ 298 K = 124 kJ mol–1 and ΔG ‡ 298 K = 127 kJ mol–1.[20]

Zoom Image
Figure 1 ECD spectroscopy of both enantiomers of 4a (red) and 4b (blue, full lines, y-axis: Δε) and the corresponding UV spectrum (dashed lines, y-axis:ε) and normalized emission spectrum (dotted lines).

Table 1 Determination of the Configurational Stability of Atropisomeric Acridinium Dyes 4a and 4b

Dye

k rac [s–1]

t 1/2 (393 K) [min]

ΔG ‡ 393 K [kJ mol–1]

4a

6.00·10–4

19

124

4b

2.16·10–4

54

127

Having confirmed the high configurational stability of atropisomeric acridinium dyes, applications for novel optical materials, diastereomerically enriched conjugates or atropisomer-specific bioimaging probes are anticipated. Furthermore, fluorophore modulation, particularly at the acridinium 9-position, is readily achieved by the directed ortho-metalation strategy for the formation of 1,5-bifunctional organometallic reagents.

In conclusion, substitution of heterocyclic fluorophores such as acridinium dyes strongly impacts their conformational behavior and hence provides an avenue towards atropisomers with a notable configurational stability over a broad temperature range. Having evaluated the bond rotational barriers, atropisomeric fluorophores can be strategically implemented into diagnostic tools, imaging, material sciences or photocatalysis. Current efforts in our group focus on the stereoselective synthesis of atropoisomeric fluorophores and their applications.[21]


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Acknowledgment

We thank PD Dr. D. Häussinger and K. Atz for assistance with NMR spectroscopy and Prof. O. S. Wenger and Prof. M. Mayor for the use of their equipment to acquire photophysical and electrochemical data.

  • References and Notes

    • 2a Heagy MD. Chemosensors: Principles, Strategies, and Applications . In New Fluorophore Design . Wang B. Anslyn EV. John Wiley and Sons; Hoboken, NJ: 2011: 253
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    • 2b 11th ed. The Molecular Probes® Handbook. Johnson I. Spence MT. Z. Life Technologies Corporation; Carlsbad, CA: 2010
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    • 2c Zilles A. Arden-Jacob J. Drexhage K.-H. Kemnitzer NU. Hammers-Schneider M. WO 2005003086, 2005
    • 2d Kolmakov K. Belov VN. Wurm CA. Harke B. Leutenegger M. Eggeling C. Hell SW. Eur. J. Org. Chem. 2010; 3593
  • 6 Ōki M. In Topics in Stereochemistry: Recent Advances in Atropisomerism . Allinger NL. Eliel EL. Wilen SH. John Wiley and Sons; Hoboken, NJ: 1983: 1-82
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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): Rf  = 0.12 (CH2Cl2/MeOH, 10:1); IR (neat): νmax = 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): λabs1: 504 nm; λabs2: 431 nm; λabs3: 311 nm; εabs1: 8.5·103 L cm mol–1; εabs2: 1.6·104 L cm mol–1; εabs3: 4.1·104 L cm mol–1; λem(exc 495 nm): 590 nm; Stokes shift: 86 nm; E0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E1/2(P*/P–): +1.36 V; E1/2(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): Rf  = 0.14 (CH2Cl2/MeOH, 10:1). IR (neat): νmax = 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 JCF = 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 JCF = 4.8 Hz, C1′), 133.5 (d, 3 JCF = 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 JCF = 2.6 Hz, C8′), 122.6 (d, 2 JCF = 17.0 Hz, C4′a), 121.6 (d, 3 JCF = 8.2 Hz, C2′), 120.6 (d, 3 JCF = 5.1 Hz, C5′), 116.8 (C9a), 115.3 (C8a), 109.8 (C5), 108.5 (d, 2 JCF = 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): λabs1: 501 nm; λabs2: 430 nm; λabs3: 311 nm; εabs1: 5.9·103 L cm mol–1; εabs2: 1.0·104 L cm mol–1; εabs3: 2.9·104 L cm mol–1; λem(exc 496 nm): 591 nm; Stokes shift: 90 nm; E0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E1/2(P*/P–): +1.37 V; E1/2(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
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  • 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.Rf  = 0.62 (CH2Cl2100%). IR (neat): νmax = 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. Rf  = 0.74 (CH2Cl2 100%); IR (neat): νmax = 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 JCF = 247 Hz, C4′), 149.9 (C3), 143.1 (d, 4 JCF = 4.5 Hz, C1′), 142.6 (C10a), 142.5 (C4a), 141.7 (C1′′), 132.1 (d, 3 JCF = 4.1 Hz, C8′a), 131.4 (C2′′, C6′′), 130.5 (C3′′, C5′′), 128.1 (C4′′), 126.7 (d, 3 JCF = 8.4 Hz, C2′), 126.6 (C6), 126.1 (d, 4 JCF = 2.4 Hz, C8′), 125.5 (C7′), 124.9 (d, 4 JCF = 1.3 Hz, C6′), 122.8 (d, 2 JCF = 15.4 Hz, C4′a), 119.9 (d, 3 JCF = 6.3 Hz, C5′), 115.4 (C8a), 109.6 (d, 3 JCF = 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
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    • 18a λabs: 425 nm; λem: 501 nm; E1/2(P*/P–): +2.06 V, E1/2(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
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    • 18b λabs: 412 nm, λem: 550 nm; E1/2(P*/P–): +1.62 V and E1/2(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
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    • 19a Aliquots treated by NaBH4 allowed the measurement of change in ee% by HPLC over time for rate of racemization (krac ), 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
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    • 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
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  • 20 Witzig RM. Lotter D. Fäseke VC. Sparr C. Chem. Eur. J. 2017; 23: 12960
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  • 21 The results reported in this publication form part of a patent application: Fischer C. Sparr C. EP 17188288, 2017
    PubMed

  • References and Notes

    • 2a Heagy MD. Chemosensors: Principles, Strategies, and Applications . In New Fluorophore Design . Wang B. Anslyn EV. John Wiley and Sons; Hoboken, NJ: 2011: 253
      Search in Google Scholar
    • 2b 11th ed. The Molecular Probes® Handbook. Johnson I. Spence MT. Z. Life Technologies Corporation; Carlsbad, CA: 2010
      Search in Google Scholar
    • 2c Zilles A. Arden-Jacob J. Drexhage K.-H. Kemnitzer NU. Hammers-Schneider M. WO 2005003086, 2005
    • 2d Kolmakov K. Belov VN. Wurm CA. Harke B. Leutenegger M. Eggeling C. Hell SW. Eur. J. Org. Chem. 2010; 3593
  • 6 Ōki M. In Topics in Stereochemistry: Recent Advances in Atropisomerism . Allinger NL. Eliel EL. Wilen SH. John Wiley and Sons; Hoboken, NJ: 1983: 1-82
    Search in Google Scholar
  • 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): Rf  = 0.12 (CH2Cl2/MeOH, 10:1); IR (neat): νmax = 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): λabs1: 504 nm; λabs2: 431 nm; λabs3: 311 nm; εabs1: 8.5·103 L cm mol–1; εabs2: 1.6·104 L cm mol–1; εabs3: 4.1·104 L cm mol–1; λem(exc 495 nm): 590 nm; Stokes shift: 86 nm; E0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E1/2(P*/P–): +1.36 V; E1/2(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): Rf  = 0.14 (CH2Cl2/MeOH, 10:1). IR (neat): νmax = 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 JCF = 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 JCF = 4.8 Hz, C1′), 133.5 (d, 3 JCF = 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 JCF = 2.6 Hz, C8′), 122.6 (d, 2 JCF = 17.0 Hz, C4′a), 121.6 (d, 3 JCF = 8.2 Hz, C2′), 120.6 (d, 3 JCF = 5.1 Hz, C5′), 116.8 (C9a), 115.3 (C8a), 109.8 (C5), 108.5 (d, 2 JCF = 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): λabs1: 501 nm; λabs2: 430 nm; λabs3: 311 nm; εabs1: 5.9·103 L cm mol–1; εabs2: 1.0·104 L cm mol–1; εabs3: 2.9·104 L cm mol–1; λem(exc 496 nm): 591 nm; Stokes shift: 90 nm; E0,0: 2.22 eV. Cyclic voltammetry (in MeCN, vs. SCE): E1/2(P*/P–): +1.37 V; E1/2(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
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  • 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.Rf  = 0.62 (CH2Cl2100%). IR (neat): νmax = 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. Rf  = 0.74 (CH2Cl2 100%); IR (neat): νmax = 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 JCF = 247 Hz, C4′), 149.9 (C3), 143.1 (d, 4 JCF = 4.5 Hz, C1′), 142.6 (C10a), 142.5 (C4a), 141.7 (C1′′), 132.1 (d, 3 JCF = 4.1 Hz, C8′a), 131.4 (C2′′, C6′′), 130.5 (C3′′, C5′′), 128.1 (C4′′), 126.7 (d, 3 JCF = 8.4 Hz, C2′), 126.6 (C6), 126.1 (d, 4 JCF = 2.4 Hz, C8′), 125.5 (C7′), 124.9 (d, 4 JCF = 1.3 Hz, C6′), 122.8 (d, 2 JCF = 15.4 Hz, C4′a), 119.9 (d, 3 JCF = 6.3 Hz, C5′), 115.4 (C8a), 109.6 (d, 3 JCF = 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
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    • 18a λabs: 425 nm; λem: 501 nm; E1/2(P*/P–): +2.06 V, E1/2(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
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    • 18b λabs: 412 nm, λem: 550 nm; E1/2(P*/P–): +1.62 V and E1/2(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
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    • 19a Aliquots treated by NaBH4 allowed the measurement of change in ee% by HPLC over time for rate of racemization (krac ), 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
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    • 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
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  • 20 Witzig RM. Lotter D. Fäseke VC. Sparr C. Chem. Eur. J. 2017; 23: 12960
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  • 21 The results reported in this publication form part of a patent application: Fischer C. Sparr C. EP 17188288, 2017
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Zoom Image
Scheme 1 Commonly used symmetric a) rhodamine B and fluorescein, b) racemic ATTO 647 dyes. c) Helical chiral DMQA salt. Acridinium salts: d) C–N stereodynamic acridinium salt, e) configurationally stable atropisomeric acridinium fluorophore with hindered rotation about the C(sp2)–C(sp2) bond.
Zoom Image
Scheme 2 Double directed ortho-metalation on tertiary amine 1 allows the synthesis of 1,5-bifunctional organolithium reagent 2. Ensuing addition to ester 3a or 3b and in situ dehydration using aq. HBr allows the direct transformation into atropisomeric acridinium bromide salts.
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Scheme 3 Reduction of the racemic dye 4a and 4b by NaBH4,[16] followed by separation and individual oxidation with chloranil gives access to both enantiomers of the atropisomeric fluorophore in 90:10 e.r.
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Figure 1 ECD spectroscopy of both enantiomers of 4a (red) and 4b (blue, full lines, y-axis: Δε) and the corresponding UV spectrum (dashed lines, y-axis:ε) and normalized emission spectrum (dotted lines).