Systematic study of synthesizing various heteroatom-substituted rhodamines from diaryl ether analogues

Article abstract of DOI:10.1016/j.saa.2020.118466

The dye rhodamine, as the most popular scaffold to construct fluorescent labels and probes, has been explored extensively on its structure-fluorescence relationships. Particularly, the replacement of the oxygen atom in the 10th position with heteroatoms obtained various new rhodamines with improved photophysical properties, such as brightness, photostability, red-shifted emission and fluorogenicity. However, the applications of heteroatom-substituted rhodamines have been hindered by difficult synthetic routes. Herein, we explored the condensation strategy of diaryl ether analogues and o-tolualdehyde to synthesize various heteroatom-substituted rhodamines. We found that the electron property and steric effect in the rhodamine 10th position determined the synthetic yield. It's concluded that this condensation method was more suitable for the synthesis of heteroatom-substituted rhodamines with small or electron-donating groups like rhodamine, S-rhodamine and Si-rhodamine. We hope these results will benefit the design and synthesis of heteroatom-substituted rhodamines.

Full text of DOI:10.1016/j.saa.2020.118466

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Systematic study of synthesizing various heteroatom-substituted
rhodamines from diaryl ether analogues
Fei Deng, Limin Liu, Wei Huang, Chunfang Huang, Qinglong
Qiao, Zhaochao Xu
PII:
S1386-1425(20)30444-3
https://doi.org/10.1016/j.saa.2020.118466
SAA 118466
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomolecular
Spectroscopy
To appear in:
Received date: 26 March 2020
Revised date:
8 May 2020
9 May 2020
Accepted
date:
Please cite this article as: F. Deng, L. Liu, W. Huang, et al., Systematic study of
synthesizing various heteroatom-substituted rhodamines from diaryl ether analogues,
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2018),
https://doi.org/10.1016/j.saa.2020.118466
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Systematic study of synthesizing various heteroatom-substituted
rhodamines from diaryl ether analogues
Fei Denga,b, Limin Liua,*, Wei Huanga, Chunfang Huanga, Qinglong Qiaob,*, Zhaochao Xub,*
aSchool of Chemistry and Chemical Engineering, Jinggangshan University, Ji'an, Jiangxi 343009,
China.
bCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of
Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
*Corresponding authors
E-mail addresses: zcxu@dicp.ac.cn (Z. Xu); qqlqiao@dicp.ac.cn (Q. Qiao); llm24@126.com (L.
Liu)
Abstract
The dye rhodamine, as the most popular scaffold to construct fluorescent labels and probes, has
been explored extensively on its structure-fluorescence relationships. Particularly, the replacement
of the oxygen atom in the 10th position with heteroatoms obtained various new rhodamines with
improved photophysical properties, such as brightness, photostability, red-shifted emission and
fluorogenicity. However, the applications of heteroatom-substituted rhodamines have been
hindered by difficult synthetic routes. Herein, we explored the condensation strategy of diaryl
ether analogues and o-tolualdehyde to synthesize various heteroatom-substituted rhodamines. We
found that the electron property and steric effect in the rhodamine 10th position determined the
synthetic yield. It’s concluded that this condensation method was more suitable for the synthesis
of heteroatom-substituted rhodamines with small or electron-donating groups like rhodamine,
S-rhodamine and Si-rhodamine. We hope these results will benefit the design and synthesis of
heteroatom-substituted rhodamines.
Keywords
Rhodamine; Heteroatom; Fluorescence; Friedel-Crafts reaction; Diaryl ether analogues
1. Introduction
The advance of fluorescence imaging is driving the revolution of fluorophores to get better
brightness, photostability, large stokes shift, near-infrared (NIR) spectrum, and fluorogenicity
[1-10]. Rhodamines, as the most popular scaffold in conventional confocal imaging, are among
the best choices for these purposes through rational modification [11-13]. Recently, substituting
the bridging oxygen atom of rhodamine with silicon atom has attracted great interests [14, 15].
The so-called Si-rhodamines red-shift the absorption and emission maximum into deep-red or NIR
region, facilitating tissue penetration and mitigating auto fluorescence during in vivo imaging.
Besides, the stronger electrophilic property of the 9th carbon atom in Si-rhodamine facilitate the

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construction of functional compounds, such as fluorogenic dyes [16-18], blinking dyes [19-22]
and fluorescent probes [23-26]. The success of Si-rhodamine also inspired the appearance of other
heteroatom-substituted rhodamines, such as B-rhodamine [27], P-rhodamine [28-30] and
Ge-rhodamine [31-33]. These heteroatom contained moieties in the rhodamine 10th position not
only tune the spectra, but also improve the photophysical properties, such as brightness and
photostability [34, 35].
Rhodamine was traditionally synthesized through the Friedel-Crafts reactions of
meta-aminophenol and phthalic anhydride (Scheme 1a). Unfortunately, this method resulted in a
mixture of 5'- and 6'-regioisomers via use of a 3-functionalized anhydride as starting material.
Latterly, an improved synthesis method was proposed by using the corresponding benzaldehydes
as anhydride replacements [36]. Compared to traditional O-rhodamine, syntheses of
Si-rhodamines were more complicated, including introducing silicon contained moiety and fusing
the pendent rings (Scheme 1b). As shown in route 1, the key intermediate Si-anthrone was
obtained through lithium-halogen exchange reaction followed by potassium permanganate
oxidation. Subsequently, the arylmetal nucleophile was added to a Si-anthrone with the formation
of Si-rhodamine [23, 31]. In addition to the long-step uses of active organometallic reagents, the
yield from diarylmethane to Si-anthrone was usually low (~ 30%), thus increasing the difficulty in
synthesis. Inspired by the improved method in O-rhodamine, route 2 was proposed. It partially
solved the problems in route 1 through the condensation of diaryl silyl ether and benzaldehydes
analogues [37]. However, the condensation conditions for Si-rhodamines were much harsher in
temperature and concentration compared to O-rhodamine. As presented in route 3, transfering the
diaryl silyl ether to electron-rich diarylmetal silyl ether would enable the milder synthesis [38, 39].
Besides, the diarylmetal silyl ether also connected diaryl silyl ether with Si-anthrone in route 4
[32].

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Scheme 1. Strategies for the synthesis of (a) O-rhodamines and (b) Si-rhodamines.
Due to the similarity in structures, these synthetic strategies for Si-rhodamine were applied to
other heteroatom-substituted rhodamines. Most of the reported heteroatom-substituted rhodamines
were synthesized according to the synthetic route 1 or 4, including S-rhodamine [40],
Se-rhodamine [41], Te-rhodamine [42], C-rhodamine [43], Ge-rhodamine [31], P-rhodamine [30]
and sulfone-rhodamine [44]. Besides, route 3 has also been reported to synthesize O-rhodamine,
N-rhodamine and P-rhodamine [39, 45]. However, the application of route 2 has rarely been
discussed. Considering the minimum synthesis steps and least organometallic reagents used, we
aimed to investigate this cost-effective strategy in detail. As shown in Scheme 2, five
heteroatom-substituted rhodamines with the spectra ranging from orange to NIR were synthesized
through the condensation of diaryl ether analogues (DAEAs) and o-tolualdehyde. Our results
indicated the synthetic yields were related to the substituted moiety in the rhodamine 10th position.
It suggested that this is a priority synthetic route for O-rhodamine, S-rhodamine, Si-rhodamine,
but not for P-rhodamine and sulfone-rhodamine.
Scheme 2. Synthesis of TMXR-methyl through the condensation of DAEA and o-tolualdehyde.

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2. Material and methods
2.1. Material and Instruments
Unless otherwise stated, all reagents and solvents for synthesis and detection were purchased from
commercial suppliers and used without further purification. All water used was from a Millipore
water purification system with a minimum resistivity of 18.0 MΩ·cm. Heteroatom-substituted
rhodamines were purified by Waters PREP150 preparative HPLC (XSelect C18, 30 mm × 150
mm). 1H NMR and 13C NMR spectra were recorded on a Bruker 400 spectrometer, using TMS as
an internal standard. Chemical shifts were given in ppm and coupling constants (J) in Hz. Mass
spectrometry data were obtained with a HP1100LC/MSD mass spectrometer and a LC/Q-TOF MS
spectrometer. UV-Vis absorption spectra were collected on an Agilent Cary60 UV-Vis
Spectrophotometer. Fluorescence measurements were performed on an Agilent CARY Eclipse
fluorescence spectrophotometer (Serial No. FL0812-M018).
2.2. Synthesis of DAEA-O
This compound was synthesized according to the literature [39].1H NMR (400 MHz, CDCl3) δ
7.15 (t, J = 8.0 Hz, 2H), 6.50 – 6.42 (m, 4H), 6.35 (ddd, J = 8.1, 2.2, 0.9 Hz, 2H), 2.92 (s, 12H).
MS (ESI) m/z: calcd. forC16H20N2O [M+H]+ 257.1654, observed 257.1685.
2.3. Synthesis of DAEA-S
The mixture of 3-iodide-N,N-diethylaniline (247 mg, 1 mmol), CuI (19 mg, 0.1 mmol), K2CO3
(138 mg, 1 mmol), Na2S·9H2O (144 mg, 0.6 mmol), and 2 mL DMF were stirred vigorously at
120 °C for 18 h under N2. The resulting mixture was cooled to RT and diluted with EtOAc (50
mL). After washing with water (2 × 25 mL) and brine (25 mL), the organic layers dried over
Na2SO4 and then concentrated under vacuum. The residue was purified by column
chromatography to give product (103 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J = 8.0 Hz,
2H), 6.81 – 6.72 (m, 2H), 6.69 (d, J = 7.6 Hz, 2H), 6.59 (dd, J = 8.4, 2.5 Hz, 2H), 2.90 (s, 12H).
13C NMR (100 MHz, CDCl3) δ 151.04, 136.44, 129.56, 119.05, 114.79, 111.20, 40.50. MS (ESI)
m/z: calcd. for C16H20N2S [M+H]+ 273.1425, observed 273.1433.
2.4. Synthesis of DAEA-Si
This compound was synthesized according to the literature [38].1H NMR (400 MHz, CDCl3) δ
7.26 – 7.19 (m, 2H), 6.93 (d, J = 2.7 Hz, 2H), 6.91 (d, J = 7.1 Hz, 2H), 6.76 (dd, J = 8.2, 2.5 Hz,
2H), 2.92 (s, 12H), 0.56 (s, 6H). MS (ESI) m/z: calcd for C18H26N2Si [M+H]+ 299.1944, observed
299.1965.
2.5. Synthesis of Compound 1
This compound was synthesized according to the literature [28].1H NMR (400 MHz, DMSO-d6) δ
8.62 (d, J = 12.0 Hz, 2H), 8.42 (d, J = 8.1 Hz, 2H), 8.30 (dd, J = 10.9, 7.7 Hz, 2H), 7.86 (td, J =

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8.0, 2.8 Hz, 2H), 2.31 (d, J = 14.1 Hz, 3H).
2.6. Synthesis of Compound 2
This compound was synthesized according to the literature [28].1H NMR (400 MHz, DMSO-d6) δ
7.12 (td, J = 7.6, 3.6 Hz, 2H), 6.89 (d, J = 13.1 Hz, 2H), 6.79 (dd, J = 10.9, 7.7 Hz, 2H), 6.68 (d, J
= 7.6 Hz, 2H), 5.33 (s, 4H), 1.82 (d, J = 13.1 Hz, 3H).
2.7. Synthesis of DAEA-PO
To a suspension of compound 2 (0.99 g, 4 mmol) and K2CO3 (4.42 g, 32 mmol) in DMF (40 mL)
added CH3I (2.0 mL, 32 mmol). The mixture was stirred for 12 h at 100℃. The reaction mixture
was cooled to RT and remove the solvent under vacuo. The residue was extracted with 100 mL
CH2Cl2 and washed with water (2 x 50 mL) and brine (50 mL). After drying over Na2SO4, the
organic layers were concentrated under vacuum and purified by column chromatography to give
product (0.93 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.33 – 7.24 (m, 2H), 7.19 (dt, J = 13.9, 1.9
Hz, 2H), 6.92 (dd, J = 11.5, 7.4 Hz, 2H), 6.87 – 6.78 (m, 2H), 2.97 (s, 12H), 1.97 (d, J = 13.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 150.39, 135.27, 134.28, 129.21, 129.07, 117.96, 115.23,
114.21, 114.11, 40.46, 17.21, 16.49. MS (ESI) m/z: calcd. for C17H23N2OP [M+H]+ 303.1626,
observed 303.1622.
2.8. Synthesis of Compound 3
To a stirred solution of diphenyl sulfone (2.18 g, 10 mmol) in 50 mL sulfuric acid, 1.73 mL nitric
acid was added slowly over 10 min at r.t. After stirring for 24 h, the mixture was poured on to ice,
deposit was filtered and washed with saturated NaHCO3 and brine, successively. Then the solid
1
was dried to afford product (2.99 g, 97%). H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 2.1 Hz,
2H), 8.58 – 8.50 (m, 4H), 7.96 (t, J = 8.1 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ 148.71,
141.68, 134.47, 132.54, 129.45, 123.19.
2.9. Synthesis of Compound 4
To a solution of Pd/C (0.16 g, 10% Pd/C) in 20 mL MeOH, compound 3 (1.54 g, 5 mmol) was
added. The mixture was stirred under the atmosphere of hydrogen at room temperature for 12 h.
Then the solution was filtered and concentrated under vacuum to afford the product (1.18 g, 95%).
1H NMR (400 MHz, DMSO-d6) δ 7.21 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 1.9 Hz, 2H), 6.95 (d, J =
7.7 Hz, 2H), 6.77 (dd, J = 8.0, 1.6 Hz, 2H), 5.67 (s, 4H). 13C NMR (100 MHz, DMSO-d6) δ
150.13, 142.49, 130.37, 118.47, 114.09, 111.63. MS (ESI) m/z: calcd. for C12H12N2O2S [M+H]+
249.0698, observed 249.0696.
2.10. Synthesis of DAEA-SO2
To a suspension of compound 4 (1.24 g, 5 mmol) and K2CO3 (5.53 g, 40 mmol) in DMF (50 mL)
added CH3I (2.5 mL, 40 mmol). The mixture was stirred for 12 h at 100℃. The reaction mixture

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was cooled to RT and remove the solvent under vacuo. The residue was extracted with 100 mL
CH2Cl2 and washed with water (2 x 50 mL) and brine (50 mL). After drying over Na2SO4, the
organic layers were concentrated under vacuum and purified by column chromatography to give
product (1.05 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.25 (dt, J = 19.7, 7.8 Hz, 6H), 6.80 (dd, J =
8.2, 2.0 Hz, 2H), 2.97 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 150.57, 142.45, 129.76, 116.10,
114.84, 110.19, 40.33. MS (ESI) m/z: calcd. for C16H20N2O2S [M+H]+ 305.1324, observed
305.1319.
2.11. General method to synthesize heteroatom-substituted rhodamines
The corresponding DAEA (0.5 mmol), o-tolualdehyde (300 mg, 2.5 mmol) and p-TsOH·H2O (95
mg, 0.5 mmol) were mixed in a sealable pressure tube. The tube was sealed tightly and heated at
140 °C for 8 h. After cooling to room temperature, the mixture was diluted with 2 mL MeOH, then
added chloranil (123 mg, 0.5 mmol) and stirred for 2 h. After filtration and removal of the solvent,
the residue was purified roughly by column chromatography on silica gel. An analytically pure
sample was obtained through further purification by preparative HPLC (30–90% MeOH/H2O +
0.5% v/v TFA). TMOR-methyl (191 mg, 81%).1H NMR (400 MHz, MeOD) δ 7.62 – 7.43 (m,
3H), 7.26 (dd, J = 7.6, 1.3 Hz, 1H), 7.20 (d, J = 9.5 Hz, 2H), 7.09 (dd, J = 9.5, 2.4 Hz, 2H), 6.96
(d, J = 2.4 Hz, 2H), 3.32 (s, 12H), 2.05 (s, 3H). 13C NMR (100 MHz, MeOD) δ 158.26, 157.81,
157.68, 135.83, 131.77, 130.95, 130.49, 129.89, 128.69, 125.89, 114.35, 113.33, 96.19, 39.59,
18.24. MS (ESI) m/z: calcd. for C24H25N2O+ [M]+ 357.1961, observed 357.1920. TMSR-methyl
(187 mg, 77%).1H NMR (400 MHz, MeOD) δ 7.51 (tt, J = 20.1, 7.4 Hz, 3H), 7.34 (dd, J = 10.8,
6.1 Hz, 4H), 7.20 (d, J = 7.5 Hz, 1H), 7.11 (dd, J = 9.7, 2.6 Hz, 2H), 3.30 (s, 12H), 1.97 (s, 3H).
13C NMR (100 MHz, MeOD) δ 159.89, 153.92, 144.33, 135.83, 135.35, 135.32, 130.36, 129.44,
128.79, 125.96, 118.44, 115.55, 105.41, 39.32, 18.02. MS (ESI) m/z: calcd. for C24H25N2S+ [M]+
373.1733, observed 373.1733. TMSiR-methyl (73 mg, 28%). 1H NMR (400 MHz, MeOD) δ 7.41
(ddd, J = 17.3, 11.8, 5.1 Hz, 1H), 7.18 – 7.01 (m, 1H), 6.77 (dd, J = 9.6, 2.8 Hz, 1H), 3.34 (s, 3H),
2.03 (s, 1H), 0.60 (d, J = 6.9 Hz, 1H). MS (ESI) m/z: calcd. for C26H31N2Si+ [M]+ 399.2251,
1
observed 399.2236. TMPOR-methyl (10 mg, 4%). H NMR (400 MHz, MeOD) δ 7.78 (dd, J =
15.9, 2.7 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 16.3, 8.0 Hz, 2H), 7.27 – 7.09 (m, 3H),
6.97 (dd, J = 9.7, 2.7 Hz, 2H), 3.46 (s, 12H), 2.15 – 1.97 (m, 6H). 13C NMR (100 MHz, MeOD) δ
164.01, 163.94, 155.40, 155.27, 139.93, 139.91, 139.85, 139.82, 138.88, 137.96, 136.01, 135.82,
135.52, 130.30, 130.17, 129.42, 129.39, 128.22, 125.74, 125.62, 122.57, 122.49, 122.41, 119.11,
119.03, 115.41, 40.09, 18.17, 18.02. MS (ESI) m/z: calcd. for C25H28N2OP+ [M]+ 403.1934,
1
observed 403.1939. TMSO2R-methyl (1 mg, 0.4%). H NMR (400 MHz, MeOD) δ 7.78 (t, J =
2.3 Hz, 2H), 7.58 – 7.38 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 7.11 (dd, J = 9.6, 1.6 Hz, 2H), 6.98
(ddd, J = 9.6, 2.6, 1.3 Hz, 2H), 3.46 (s, 12H), 2.10 (s, 3H). 13C NMR (100 MHz, MeOD) δ 159.72,
155.97, 144.34, 138.66, 136.03, 133.91, 130.45, 129.84, 128.88, 125.84, 118.93, 115.59, 112.02,
40.52, 18.09. MS (ESI) m/z: calcd. for C24H25N2O2S+ [M]+ 405.1631, observed 405.1632.
2.12. Computational methods
Geometry optimizations were performed at the B3LYP/6-31G level of theory, implemented in the
Gaussian 09 program [46]. Next, the molecular electrostatic potentials were generated using

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Multiwfn (version 3.7) [47] and VMD (version 1.9.3) [48].
3. Results and discussion
3.1. Design and synthesis of DAEAs
As the key intermediate to construct heteroatom-substituted rhodamines through the condensation
reaction, we initially investigated the synthesis of DAEAs (Scheme 3). The diaryl ether DAEA-O
was prepared through Ullmann reaction according to the previous method [39]. For diaryl sulfides
DAEA-S, copper-catalyzed carbon-sulfur bond formation was applied. Although the aryl
bromides could hardly react with Na2S·9H2O under the catalyzation of CuI, S-arylation through
aryl iodides was in excellent yields. The synthesis of diaryl silyl ether have been detailedly
described in previous reports [37, 38]. We used the Li/Br-exchange with n-BuLi and added
dichlorodimethylsilane to afford DAEA-Si successfully. DAEA-PO containing P(=O)Me moiety
was synthesized according to the similar procedure reported by Wang [28]. DAEA-SO2, as the
sulfone contained diaryl ether analogues, we originally intended to synthesize with reference to
DAEA-Si. Unfortunately, the addition of sulfuryl chloride after Li/Br-exchange failed to afford
DAEA-SO2. Realizing diphenyl sulfone was commercially available, we decided to synthesize
DAEA-SO2 with the procedure of introducing N,N-dimethyl. Similar to DAEA-PO, the specific
steps included nitration, reduction, and alkylation.
Scheme 3. Synthesis of DAEAs.
3.2. Design and synthesis of heteroatom-substituted rhodamines

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With these DAEAs in hand, we further investigated the key cyclization step to form the
heteroatom-substituted rhodamines. The condensation reactions of diaryl silyl ether and
benzaldehydes analogues have been discussed in detail by Wang [28, 37]. We applied the
optimized condition directly to synthesize the heteroatom-substituted rhodamines. Diaryl ether
analogues condensed with 5.0 equivalent of o-tolualdehyde in the presence of the catalyst of
p-toluenesulfonic acid. After 8h reaction at 140 ℃ in sealed tube, the condensed product was
further oxidized with chloranil to heteroatom-substituted rhodamine. As shown in Scheme 4,
DAEA-O and DAEA-S provided target products TMOR-methyl and TMSR-methyl with 81%
and 77% isolated yields, respectively. However, the condensation of DASE-Si and o-tolualdehyde
afforded a modest yield of TMSiR-methyl (28%). As for DAEA-PO and DAEA-SO2, the same
condensation condition could hardly provide target products TMPOR-methyl and
TMSO2R-methyl, with only 4% and 0.4% isolated yields. In the condensation process,
bis-nucleophilic DAEAs were anticipated to attack twice to the electron-poor o-tolualdehyde and
form the central C−C bonds of the dyes. We speculated the substituted moieties influenced the
nucleophilic properties of DAEAs and resulted the difference in reaction yields.
Scheme 4. Synthesis of TMXR-methyl.
3.3. Theoretical calculations
To further get insight into the relationship between the substituted moieties and reaction yields, we
carried out theoretical calculations on DAEAs. C4 and C8, as the unsubstituted and
electron-richest sites on each aromatic ring, were calculated to attack the electron-poor
o-tolualdehyde and form the central C−C bonds of the dyes (Fig. 1 and Table S1-5). Specifically,
the calculated electrostatic potential of C4 and C8 in DAEA-O were -20.82024 and -20.79005
kcal/mol respectively (Table 1). These values were slightly smaller than DAEA-S (-19.26014 and
-20.76527 kcal/mol), which indicated the stronger nucleophilic ability and higher reaction yield in
DAEA-O. Interestingly, DAEA-Si with lower reaction yield possessed much lower electrostatic

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potentials (-20.38024 and -22.93891 kcal/mol for C4 and C8 respectively) compared to DAEA-O
and DAEA-S. We attributed it to the steric effect. The substituted moiety in DAEA-Si was much
larger than DAEA-O and DAEA-S, which hindered the nucleophilic reaction. As for DAEA-PO
and DAEA-SO2, the steric effects of P(=O)Me and SO2 were similar to Si(Me)2 in DAEA-Si.
Besides, the strong electron-withdrawing properties of P(=O)Me and SO2 resulted much higher
electrostatic potentials in C4 and C8. These reasons prevented the nucleophilic reaction in
DAEA-PO and DAEA-SO2.
Fig. 1. Electrostatic potential surfaces of DAEAs.
Table 1. Electrostatic potential on C4 and C8 of DAEAs.
Electrostatic potential
Compound
DAEA-O
DAEA-S
Atom
(kcal/mol)
-20.82024
-20.79005
-19.26014
-20.76527
-20.38024
-22.93891
-19.86078
-19.85955
-13.58788
-13.58662
C4
C8
C4
C8
C4
C8
C4
C8
C4
C8
DAEA-Si
DAEA-PO
DAEA-SO2
3.4. Photophysical properties of heteroatom-substituted rhodamines
Fig. 2 shows the absorption and fluorescence spectra of the heteroatom-substituted rhodamines
synthesized in this work. Compared to TMOR-methyl and TMSR-methyl, the electron-donating
property and σ*–π* conjugation of SiMe2 red-shifted the absorption and fluorescence of

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TMSiR-methyl [28, 44]. Furthermore, TMPOR-methyl and TMSO2R-methyl possessing
electron-withdrawing moieties displayed much more red-shifted spectra [44]. The specific
photophysical properties of the dyes in aqueous solution were provided in Table 2.
Fig. 2. (a) Absorption and (b) emission spectra of various heteroatom-substituted rhodamines.
Table 2. Photophysical properties of heteroatom-substituted rhodamines.a
λabs
(nm)
549
571
647
688
703
ε
(M-1 cm-1× 105)
0.72
λflu
(nm)
570
592
661
709
734
Dye
Φf
TMOR-methyl
TMSR-methyl
TMSiR-methyl
TMPOR-methyl
TMSO2R-methyl
0.31b
0.33c
0.31d
0.16e
0.06e
0.61
1.10
0.98
0.62
a Measured in PBS (20 mM, pH 7.4).
b This value was taken from ref 27.
c Determinedusing R101 as standard (Φf = 0.91 in ethanol).
d This value was taken from ref 31.
e Determinedusing SiR700 as standard (Φf = 0.12 in PBS).
4. Conclusion
In summary, we have synthesized a series of heteroatom-substituted rhodamines through the
condensation of DAEAs and o-tolualdehyde. The electron-rich C4 and C8 in DAEAs were
anticipated to attack the electron-poor o-tolualdehyde and form the central C−C bonds of
rhodamine. The electron-withdrawing substituted moieties in DAEAs decreased the nucleophilic
ability of reaction sites and resulted the poor yields. Besides, the large substituted moieties in
DAEAs hindered the reaction and further decreased yields. Moreover, the spectra of these
rhodamines were determined by the substituted moiety in the 10th position. We hoped these results
will benefit the design and synthesis of heteroatom-substituted rhodamines.
Acknowledgments

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We acknowledge the financial support from National Natural Science Foundation of China
(21765011, 21878286, 21908216) and Department of Education of Jiangxi Province (GJJ190567).
References
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F. D. synthesized the compounds. Z. X. supervised the project. F. D., Q. Q. and Z. X.
wrote the paper. L

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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which
may be considered as potential competing interests:

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Graphical abstract

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Highlight
1. Five heteroatom-substituted rhodamines through the condensation of
diaryl ether analogues and o-tolualdehyde were systematically
synthesized.
2. The electron-donating moiety increased the nucleophilic ability of
diaryl ether analogues and facilitated the condensation reaction.
3. Rhodamines with strong electron-withdrawing moiety in the 10th
position hindered the condensation reaction and resulted the poor
yield.

Figure 1

Figure 2