CN116790134A - Near infrared small molecule dye and preparation method and application thereof - Google Patents

Near infrared small molecule dye and preparation method and application thereof Download PDF

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CN116790134A
CN116790134A CN202310743539.5A CN202310743539A CN116790134A CN 116790134 A CN116790134 A CN 116790134A CN 202310743539 A CN202310743539 A CN 202310743539A CN 116790134 A CN116790134 A CN 116790134A
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dye
near infrared
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张凡
王尚风
晏魁
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Fudan University
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Fudan University
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Abstract

The invention belongs to the technical field of biological materials, and particularly relates to a near infrared small molecule dye and a preparation method and application thereof. The near infrared micromolecule dye has the structure shown in the general formula A, has the absorption and emission wavelength of the near infrared region of 700-1700nm, has the characteristics of small molecular weight, good water solubility, excellent light stability, good cell permeability, simple synthesis, easy structure modification and the like, and can be widely applied to the biomedical fields such as cell marking and imaging, fluorescence operation navigation, multispectral imaging, photoacoustic imaging and the like; the partial structure in the small-molecule dye can be used as an activatable small-molecule optical probe for photoacoustic detection of peroxynitrite ions;

Description

Near infrared small molecule dye and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biological materials, in particular to the field of biomedical imaging detection, and particularly relates to a near infrared small molecule dye and a preparation method and application thereof.
Background
Near infrared dyes are a class of compounds with photon absorption and emission properties in the near infrared spectrum, and have wide application potential in the fields of medical diagnosis, biological imaging, material science and industry. The near infrared absorption dye can be used for photodynamic or photothermal treatment of various skin diseases, tumors and other diseases, and can also be used as a photoacoustic contrast agent for disease diagnosis; the near infrared emission dye can be used as a fluorescent contrast agent for surgical navigation to develop tissue structures or edges of disease focus and assist surgeons in surgical excision. In recent years, photons having wavelengths in the range of 700 to 1700nm are found to have more excellent biological tissue penetrating properties, and thus the demand for near infrared dyes that absorb and emit in this band in the biomedical field is increasing.
At present, near infrared dyes in the field are mainly developed around the traditional precursors of cyanines, fluorobopyrroles, squaraines, porphyrins, phthalocyanines, coumarins, rhodamine and the like. In order to extend the wavelength of the parent substance to the near infrared region, the current general strategy needs to make the molecular structure large by means of expanding conjugation, fusing hetero atoms and the like, which can lead to the reduction of the water solubility, biocompatibility and photostability of the dye, and simultaneously, the larger and more complex structure can make the synthesis difficult, so that the requirement of large-scale preparation is difficult to meet.
Therefore, it is necessary to find new near-infrared dye precursors, explore suitable synthesis methods, develop near-infrared dyes with good solubility and light stability, small molecular structure and long absorption and emission wavelength, and this will help to promote the application of near-infrared photon technology in medicine, bioscience and other fields, and provide new solutions for diagnostic and therapeutic fields.
Disclosure of Invention
The invention aims to provide a functional dye molecule with small molecular weight, good light stability and absorption emission peak wavelength in a near infrared region, and a preparation method and application thereof.
The near infrared micromolecule dye provided by the invention is a novel dye matrix based on a diaminofluorene cation structure, and is a functional dye molecule which has small molecular weight and absorption emission peak wavelength in a near infrared region and is obtained through substituent regulation on a matrix structure.
The invention firstly provides a brand new strategy to construct a near infrared dye matrix and a functional molecular system thereof. Specifically, the present invention relates to a method for manufacturing a semiconductor device.
Firstly, the conjugated structure of the traditional dye system is built based on the shock-aromatic rule, and the invention abandons the common method to build a novel anti-aromatic chromophore core based on fluorene cation skeleton;
secondly, introducing amino substituent groups with different electron supply capacities on a fluorene cation skeleton, and introducing a large-steric-hindrance aromatic ring structure at a position 9 of a fluorene ring to synthesize a series of diamine fluorene cation dyes with different absorption and emission wavelengths and excellent chemical stability;
finally, the dye molecules with fluorescent marks or photoacoustic sensing functions are obtained through functional modification on the dye molecules.
The anti-aromatic diamido fluorene cation series dye has ideal near infrared absorption and emission properties in water and organic solvents, shows excellent light stability and chemical stability, has molecular weight smaller than other series dye molecules with similar properties, is easy to chemically modify, and shows excellent biocompatibility. Therefore, the dye has bleaching resistance in long-time cell staining fluorescence imaging and fluorescent contrast agent function as a liver and gall metabolism and kidney metabolism removal way, and also has the advantages of obtaining a novel activatable micromolecular photoacoustic probe through functionalization and having the photoacoustic detection effect on peroxynitrite cations.
The structural general formula of the near infrared small molecule dye provided by the invention is shown as the following formula, or a salt thereof, or an enantiomer, a diastereoisomer, a tautomer or a solvate thereof:
wherein:
X - is an anion, including ClO 4 - 、PF 6 - 、BF 4 - 、Cl - 、Br - 、I - 、CH 3 COO - 、CF 3 COO - 、CF 3 SO 3 - And CH (CH) 3 SO 3 - ；
R 1 、R 2 、R 3 、R 4 Each independently selected from H, cl-C6 alkyl, substituted aryl and substituted acyl;
R 5 ，R 6 each independently selected from H, C1-C6 alkyl, C1-C6 perfluoroalkyl, and C1-C6 alkoxy;
R 7 independently selected from any one of H, C-C6 alkyl, and groups of formula I-IV:
the curve mark is a substitution position;
the maximum absorption wavelength of the near infrared small molecule dye is between 800 and 1150nm, and the maximum emission wavelength is between 900 and 1250 nm; the molecular weight is between 299 Da and 603 Da.
In some embodiments, as shown in formula A, wherein R 1 And R is 2 Optionally substituted N-membered nitrogen containing heterocycles may be formed with the N to which they are attached, N being an integer from 4 to 7, including silacyclobutanyl, pyrrolidinyl, piperidinyl, cyclohexylimino, or indolinyl;
the R is 3 And R is 4 Optionally substituted N-membered nitrogen containing heterocycles may be formed with the N to which they are attached, N being an integer from 4 to 7, including silacyclobutanyl, pyrrolidinyl, piperidinyl, cyclohexylimino, or indolinyl;
wherein, preferably, the n-membered nitrogen-containing heterocycle contains an epoxy atom, and more preferably, the n-membered nitrogen-containing heterocycle is morpholinyl.
In some embodiments, typical compounds of formula a have the structure shown below as formulas B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, or B12:
in the formulae B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12, R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 And R is 18 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate.
Wherein,,
in the formula B5, R 8 And R is 9 Each independently H or C1-C6 alkyl;
in the formula B10 and the formula B11, R 10 、R 11 、R 12 、R 13 And R is 14 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate;
in the formula B12, R 15 、R 16 、R 17 And R is 18 Each independently selected fromH, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen and sulfonate;
on the other hand, the invention synthesizes near infrared small molecule dye based on the parent structure of the general formula A, and the structure is shown as the following formulas C1 and C2:
in the formulae C1 and C2, R 19 Independently selected from any one of the groups represented by the formulas V-VIII:
the near infrared small molecule dye can be used as an activatable small molecule optical probe, and the activatable small molecule optical probe can generate change of optical signals before and after activation.
In other embodiments, the near infrared small molecule dyes provided by the invention have the structure shown in the following formulas D1-D18:
in some specific embodiments, the near infrared small molecule dyes provided by the invention have a maximum absorption wavelength between 800 and 1150nm and a maximum emission wavelength between 900 and 1250 nm. In other embodiments, the near infrared small molecule dyes provided herein have a molecular weight between 299 Da and 603 Da.
Another object of the present invention is to provide a general simple preparation method of the compound of formula a, comprising the steps of:
step one, performing Buchwald-Hartwig carbon-nitrogen coupling reaction on a compound shown in the formula (1) and an amino compound to obtain a compound shown in the formula (2);
step two, a compound shown in the formula (2) undergoes nucleophilic addition reaction under the action of a phenyllithium reagent or a phenyl Grignard reagent, and then undergoes acid catalysis to obtain a compound shown in the general formula A;
in the first step, the compound shown in the formula (1) and an amino compound undergo a Buchwald-Hartwig carbon-nitrogen coupling reaction to obtain a compound shown in the formula (2), and the method comprises the following steps:
under the protection of inert gas, heating and stirring a compound shown in a formula (1) and an organic amine compound in an organic solvent environment by using a palladium catalyst, a phosphine ligand and a base as catalysts to obtain a compound shown in a formula (2);
wherein the organic amine compound is selected from one or more of the formulae IX-XX:
wherein,,
R 8 and R is 9 Each independently H or C1-C6 alkyl;
R 10 、R 11 、R 12 、R 13 and R is 14 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate;
R 15 、R 16 、R 17 and R is 18 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate;
the organic solvent is selected from one or more of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, trichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, diethyl ether and 1, 4-dioxane;
the palladium catalyst is selected from one or more of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium and palladium acetate;
the alkali is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate and potassium phosphate;
the phosphine ligand is selected from one or more of tri-tert-butyl phosphine, triphenylphosphine and tri-n-butyl phosphine.
In the second step, the compound shown in the formula (2) is subjected to nucleophilic addition reaction under the action of a phenyllithium reagent or a phenylGrignard reagent, and then is subjected to acid catalysis to obtain a compound shown in the general formula A, which comprises the following steps:
under the action of a phenyllithium reagent or a phenyl Grignard reagent, the compound shown in the formula (2) takes ethers as a reaction solvent, and reacts at room temperature under the catalysis of an acid catalyst through nucleophilic addition reaction to obtain a compound shown in the general formula A;
wherein the phenyllithium reagent is represented by formula XXI:
R 5 ，R 6 each independently selected from H, C1-C6 alkyl, C1-C6 perfluoroalkyl, and C1-C6 alkoxy;
R 7 independently selected from any one of H, C-C6 alkyl, and groups of formula I-IV:
the curve mark is a substitution position;
the phenyl Grignard reagent is a Grignard reagent corresponding to a phenyllithium reagent;
the ether solvent is tetrahydrofuran or diethyl ether;
the acid catalyst is perchloric acid or trifluoroacetic acid.
In addition, the invention also provides application of near infrared multispectral fluorescence imaging based on the general formula A.
Wherein the near infrared multispectral fluorescent imaging comprises near infrared living body multispectral fluorescent imaging.
Specifically, the near infrared living body multispectral fluorescence imaging also comprises application of multichannel living body viscera fluorescence imaging of small animals, and more specifically comprises application of at least two of the formulas D1-D18 in multichannel living body viscera fluorescence imaging of small animals.
Furthermore, the invention also provides a method for detecting peroxynitrite (ONOO) in photoacoustic based on the small molecular probe type C1 and the small molecular probe type C2 - ) Application in ions.
The functional dye molecule provided by the invention has the characteristics of small molecular weight, good water solubility, excellent light stability, good cell permeability, simple synthesis, easy structure modification and the like, has the absorption and emission wavelength in a near infrared region of 700-1700nm, and can be widely applied to biomedical fields such as cell marking and imaging, fluorescence surgical navigation, multispectral imaging, photoacoustic imaging and the like; the partial structure in the small molecule dye can be used as an activatable small molecule optical probe for photoacoustic detection of peroxynitrite ions.
Drawings
FIG. 1 shows the absorption and emission spectra of the anti-aromatic aminofluorene cationic dyes 1a-14a (see examples 1-15 for details) in methylene chloride.
FIG. 2 shows the ratio of the activatable small molecule probe 18a (see example 19) to peroxynitrite (ONOO) - ) The ions produce changes in absorption and emission spectra in response.
FIG. 3 is a graph of dye 3a (see examples 3, 20 for details) and a control commercial near infrared dye Cy7-Cl used to dye Endothelial (EC) cells followed by excitation with 808nm laser, 2X 10 4 mW/mm 2 The power density and the exposure time of 100ms continuously shoot the contrast condition of the signal to noise ratio of the cell fluorescence imaging images collected before and after 1000 frames.
FIG. 4 shows the results of near infrared multispectral fluorescence imaging of multiple organs of mice using dyes 2a and 15a (see examples 2, 16, 21 for details).
FIG. 5 shows the pair of peroxynitrite (ONOO) in a mouse brain injury model with an activatable small molecule probe 18a (see more fully examples 19 and 22) - ) Photoacoustic imaging detection results of ions.
Detailed Description
The invention is illustrated by the following specific examples, but the invention is by no means limited to these examples, in order to make the objects, technical solutions and advantages of the invention more apparent. The following examples are given for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention. It should be noted that any modification, substitution or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Example 1:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 1a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 1
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), tert-butyl carbamate, dipalladium tris (dibenzylideneacetone), tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 1. 1 H NMR(400MHz,CDCl 3 )δ7.72(d,J＝1.5Hz,2H),7.53(d,J＝8.1Hz,2H),7.11(dd,J＝8.1,1.9Hz,2H),6.82(s,2H),1.54(s,18H)； 13 C NMR(101MHz,CDCl 3 )δ152.24(C),145.62(C),144.42(C),129.77(C),125.23(C),117.75(C),110.31(C),28.42(CH3)；
(2) Synthesis of dye 1a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 1 was added and allowed to warm to room temperature, stirred for 30 minutes, then quenched with excess water, extracted with dichloromethane, and washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and removed by rotary evaporationThe solvent was removed by rotary evaporation, and the dye 1a was obtained by column chromatography separation (dichloromethane: methanol=50:1). Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 1 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ8.68(s,4H),7.33–7.18(m,3H),6.95(s,2H),6.59(d,J＝8.4Hz,2H),6.18(d,J＝8.4Hz,2H),2.16(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ172.07(C),160.87(C),147.57(C),135.41(C),134.64(C),131.10(C),129.86(C),128.87(C),128.37(C),114.44(C),114.15(C),20.31(CH3)；HRMS(ESI)calcd for C 21 H 19 N 2 [M] + 299.1543,found 299.1694。
example 2:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 2a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 2
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), methyl-carbamic acid tert-butyl ester, tri (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a mol ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 2. 1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝8.0Hz,2H),7.47(d,J＝1.7Hz,2H),7.15(dd,J＝8.0,1.9Hz,2H),3.32(s,6H),1.50(s,18H)； 13 C NMR(101MHz,CDCl 3 )δ154.23(C),149.79(C),144.66(C),131.24(C),124.97(C),124.64(C),117.18(C),81.42(C),37.20(CH3),28.46(CH3)；
(2) Synthesis of dye 2a
Anhydrous anaerobic operation2, 6-dimethyl bromobenzene was dissolved in tetrahydrofuran solvent and stirred at-78 ℃ for 5 minutes, then n-hexane solution of n-butyllithium was added dropwise, and stirring was continued for 30 minutes. Adding anhydrous tetrahydrofuran solution of the intermediate 2, heating to room temperature, stirring for 30 minutes, adding excessive water for quenching, extracting with dichloromethane, washing with saturated saline water for 3 times, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation to obtain oily substance, adding mixed solvent of trifluoroacetic acid and dichloromethane (volume ratio is 1:1), stirring for 3 hours at room temperature, removing the solvent by rotary evaporation, and separating by column chromatography (dichloromethane: methanol=50:1) to obtain dye 2a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 2 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ9.11(s,2H),7.26–7.21(m,1H),7.19(d,J＝1.2Hz,2H),7.11(d,J＝7.6Hz,2H),6.61(d,J＝8.7Hz,2H),6.06(dd,J＝8.7,1.3Hz,2H),3.09(s,6H),2.17(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ171.59(C),159.38(C),146.59(C),135.65(C),133.93(C),131.10(C),129.95(C),129.32(C),127.88(C),114.50(C),109.90(C),30.98(CH3),20.29(CH3)；HRMS(ESI)calcd for C 23 H 23 N 2 [M] + 327.1856,found 327.1960。
example 3:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 3a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 3
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), tetrahydrofuran solution of dimethylamine, dipalladium tris (dibenzylideneacetone), tri-tert-butylphosphine and sodium tert-butoxide are mixed according to the mole ratio of 1:4:0.025:0.075:6, charging, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, then removing solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collectingThe solid was collected to give intermediate 3. 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝8.4Hz,2H),6.75(d,J＝2.2Hz,2H),6.43(dd,J＝8.4,2.3Hz,2H),3.09(s,12H)； 13 C NMR(101MHz,CDCl 3 )δ191.76(C),154.59(C),146.19(C),125.34(C),124.47(C),110.38(C),103.19(C),40.72(CH3)；
(2) Synthesis of dye 3a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. Adding anhydrous tetrahydrofuran solution of the intermediate 3, heating to room temperature, stirring for 30 minutes, adding excessive 10% perchloric acid solution, stirring for 10 minutes, precipitating precipitate, filtering, and collecting solid to obtain dye 3a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 3 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝2.1Hz,2H),7.24(d,J＝7.5Hz,1H),7.13(d,J＝7.6Hz,2H),6.58(d,J＝8.9Hz,2H),6.08(dd,J＝8.9,2.1Hz,2H),3.44(s,12H),2.22(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ158.36(C),147.72(C),135.39(C),132.95(C),129.20(C),127.71(C),113.62(C),111.21(C),42.17(CH3),20.09(CH3)；HRMS(ESI)calcd for C 25 H 27 N 2 [M] + 355.2169,found 355.2269。
example 4:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 4a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 3
The synthesis of intermediate 3 is described in example 3;
(2) Synthesis of dye 4a
Anhydrous and anaerobic operation, dissolving 2, 6-dimethoxy bromobenzene in tetrahydrofuran solvent, stirring at-78deg.C for 5 min, and dropwise addingThe n-hexane solution of n-butyllithium was stirred for 30 minutes. The anhydrous tetrahydrofuran solution of intermediate 3 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 4a. Wherein the feeding mole ratio of the 2, 6-dimethoxy bromobenzene, the n-butyl lithium and the intermediate 3 is 1:1:0.5. 1 H NMR(400MHz,DMSO)δ7.49(t,J＝8.4Hz,1H),7.44(d,J＝2.1Hz,2H),6.84(d,J＝8.5Hz,2H),6.78(d,J＝9.0Hz,2H),6.33(dd,J＝9.0,2.1Hz,2H),3.73(s,6H),3.34(s,12H)； 13 C NMR(101MHz,DMSO)δ158.53(C),157.76(C),147.30(C),133.99(C),133.58(C),129.92(C),112.23(C),112.14(C),105.49(C),56.67(CH3),42.06(CH3)；HRMS(ESI)calcd for C 25 H 27 N 2 O 2 [M] + 387.2067,found 387.2234。
example 5:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 5a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 4
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), diethylamine, tris (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 4. 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝8.4Hz,2H),6.72(d,J＝2.3Hz,2H),6.43(dd,J＝8.5,2.3Hz,2H),3.47(q,J＝7.1Hz,8H),1.24(t,J＝7.1Hz,12H)； 13 C NMR(101MHz,CDCl 3 )δ191.38(C),152.27(C),146.46(C),125.63(C),123.92(C),109.90(C),102.55(C),44.98(CH2),13.01(CH3)；
(2) Synthesis of dye 5a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. The anhydrous tetrahydrofuran solution of intermediate 4 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 5a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 4 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.65(s,2H),7.27–7.22(m,1H),7.13(d,J＝7.7Hz,2H),6.58(d,J＝8.9Hz,2H),6.09(s,2H),3.75(d,J＝6.4Hz,8H),2.23(s,6H),1.37(t,J＝7.1Hz,12H)； 13 C NMR(101MHz,CDCl 3 )δ156.73(C),148.18(C),135.66(C),133.13(C),131.20(C),129.32(C),127.88(C),113.40(C),110.92(C),47.19(CH2),20.33(CH3),13.97(CH3)；HRMS(ESI)calcd for C 29 H 35 N 2 [M] + 411.2795,found 411.2924。
example 6:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 6a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 5
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), azetidine, dipalladium tris (dibenzylideneacetone), tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain an intermediate 5. 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝8.0Hz,2H),6.39(s,2H),6.11(d,J＝8.1Hz,2H),4.01(t,J＝7.1Hz,9H),2.42(p,J＝7.0Hz,5H)； 13 C NMR(101MHz,CDCl 3 )δ155.43(C),145.78(C),125.21(C),124.89(C),109.04(C),102.06(C),51.81(CH2),16.67(CH2)；
(2) Synthesis of dye 6a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. The anhydrous tetrahydrofuran solution of intermediate 5 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 6a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 5 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.34(s,2H),7.23(d,J＝7.4Hz,1H),7.12(d,J＝7.6Hz,2H),6.55(d,J＝8.6Hz,2H),5.78(d,J＝8.6Hz,2H),4.49(t,J＝7.6Hz,8H),2.60–2.47(m,4H),2.19(s,6H)； 13 C NMR(101MHz,DMSO)δ156.66(C),146.28(C),135.50(C),132.48(C),129.81(C),128.91(C),128.42(C),111.43(C),110.71(C),53.46(CH2),20.25(CH3),16.22(CH2)；HRMS(ESI)calcd for C 27 H 27 N 2 [M] + 379.2169,found 379.2245。
example 7:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 7a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 6
Anhydrous anaerobic operation, 3, 6-dibromofluorenone (compound 1), 3-difluoroazetidine, tris (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine, sodium tert-butoxide were added in a molar ratio of 1:4:0.025:0.075:6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, then removing solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain an intermediate6。 1 H NMR(400MHz,CDCl 3 )δ7.50(d,J＝8.1Hz,2H),6.46(d,J＝1.9Hz,2H),6.23(dd,J＝8.1,2.0Hz,2H),4.35(t,J＝11.6Hz,8H)； 13 C NMR(101MHz,CDCl 3 )δ191.34(C),153.52(C),145.73(C),126.51(C),125.63(C),115.68(C),111.08(C),103.63(C),63.23(CH2)；
(2) Synthesis of dye 7a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. The anhydrous tetrahydrofuran solution of intermediate 6 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 7a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 6 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.36(d,J＝2.1Hz,2H),7.26(t,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,2H),6.63(d,J＝8.6Hz,2H),5.82(dd,J＝8.6,2.1Hz,2H),4.87–4.68(m,8H),2.20(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ178.35(C),157.17(C),148.14(C),135.34(C),134.53(C),131.39(C),130.43(C),129.95(C),128.14(C),114.48(C),113.34(C),110.91(C),64.40(CH2),20.29(CH3)；HRMS(ESI)calcd for C 27 H 23 F 4 N 2 [M] + 451.1792,found 451.2016。
example 8:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 8a comprises the following structural formula and specific synthetic route:
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the method comprises the following specific steps:
(1) Synthesis of intermediate 7
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), tetrahydropyrrole, tris (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075:6, feeding, dissolving in toluene, inThe reaction was carried out at 60℃for 12 hours, diluted with methylene chloride after cooling, insoluble matters were removed by filtration, then the solvent was removed by rotary evaporation to obtain a crude product, which was washed with ethyl acetate, filtered, and the solid was collected to obtain intermediate 7. 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝8.3Hz,2H),6.63(d,J＝2.1Hz,2H),6.30(dd,J＝8.3,2.2Hz,2H),3.48–3.36(m,8H),2.12–1.98(m,8H)； 13 C NMR(101MHz,CDCl 3 )δ191.67(C),151.93(C),146.10(C),125.26(C),123.93(C),110.14(C),103.21(C),48.02(CH2),25.54(CH2)；
(2) Synthesis of dye 8a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 7 was added and allowed to warm to room temperature, stirred for 30 minutes, an excess of 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 8a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 7 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.56(d,J＝1.8Hz,2H),7.24(dd,J＝8.1,7.1Hz,1H),7.12(d,J＝7.7Hz,2H),6.55(d,J＝8.8Hz,2H),5.97(dd,J＝8.8,1.7Hz,2H),3.81(s,8H),2.21(s,6H),2.09(t,J＝6.6Hz,8H)； 13 C NMR(101MHz,CDCl 3 )δ172.57(C),155.62(C),147.49(C),135.42(C),132.66(C),131.06(C),129.52(C),129.06(C),127.65(C),114.47(C),111.73(C),50.19(CH3),25.14(CH2),20.04(CH2)；HRMS(ESI)calcd for C 29 H 31 N 2 [M] + 407.2482,found 407.2552。
example 9:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 9a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 8
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), piperidine, tris (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 8. 1 H NMR(400MHz,CDCl 3 )δ7.49(d,J＝8.4Hz,2H),6.97(s,2H),6.65(dd,J＝8.4,1.8Hz,2H),3.45–3.33(m,8H),1.75–1.61(m,12H)； 13 C NMR(101MHz,CDCl 3 )δ191.44(C),155.81(C),146.03(C),125.67(C),125.39(C),113.16(C),106.06(C),49.32(CH2),25.64(CH2),24.49(CH2)；
(2) Synthesis of dye 9a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. The anhydrous tetrahydrofuran solution of intermediate 8 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 9a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 8 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.83(s,2H),7.28–7.22(m,1H),7.13(d,J＝7.6Hz,2H),6.62(d,J＝8.9Hz,2H),6.30(s,2H),3.86(s,8H),2.21(s,6H),1.89–1.73(m,12H)； 13 C NMR(101MHz,CDCl 3 )δ
157.23(C),148.06(C),135.71(C),133.09(C),131.27(C),129.61(C),129.31(C),127.89(C),113.74(C),111.38(C),50.53(CH2),27.01(CH2),24.50(CH2),20.34(CH3)；HRMS(ESI)calcd for C 31 H 35 N 2 [M] + 435.2795,found 435.3144。
example 10:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 10a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 9
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), hexamethyleneimine, dipalladium tris (dibenzylideneacetone), tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 9. 1 H NMR(400MHz,CDCl 3 )δ7.47(d,J＝8.4Hz,2H),6.75(d,J＝2.2Hz,2H),6.45(dd,J＝8.5,2.3Hz,2H),3.64–3.50(m,8H),1.89–1.77(m,8H),1.62–1.52(m,8H)； 13 C NMR(101MHz,CDCl 3 )δ153.38(C),146.35(C),125.52(C),123.97(C),109.74(C),102.43(C),49.90(CH2),27.73(CH2),27.02(CH2)；
(2) Synthesis of dye 10a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 9 was added and allowed to warm to room temperature, stirred for 30 minutes, an excess of 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 10a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 9 is 1:1:0.5. 1 H NMR(400MHz,DMSO)δ7.63(d,J＝2.2Hz,2H),7.32(dd,J＝8.3,6.9Hz,1H),7.23(d,J＝7.7Hz,2H),6.63(d,J＝9.0Hz,2H),6.43(dd,J＝9.1,2.2Hz,2H),3.87(t,J＝5.5Hz,8H),2.17(s,6H),1.80(s,9H),1.55(s,8H)； 13 C NMR(101MHz,DMSO)δ170.44(C),157.22(C),147.57(C),135.51(C),133.26(C),131.25(C),129.88(C),129.15(C),128.42(C),113.09(C),112.47(C),
52.24(CH3),27.74(CH2),26.21(CH2),20.37(CH2)；HRMS(ESI)calcd for C 33 H 39 N 2 [M] + 463.3108,found 463.3435。
example 11:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 11a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 9
Reference example 10 for synthesis of intermediate 9;
(2) Synthesis of dye 11a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethoxy bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyl lithium, and stirring for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 9 was added and allowed to warm to room temperature, stirred for 30 minutes, an excess of 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 11a. Wherein the feeding mole ratio of the 2, 6-dimethoxy bromobenzene, the n-butyl lithium and the intermediate 9 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝2.2Hz,2H),7.39(t,J＝8.4Hz,1H),6.72(d,J＝9.0Hz,2H),6.65(d,J＝8.5Hz,2H),6.10(dd,J＝9.0,2.2Hz,2H),3.91–3.72(m,8H),3.77(s,6H),1.95–1.84(m,8H),1.60–1.55(m,8H)； 13 C NMR(101MHz,CDCl 3 )δ166.42(C),158.50(C),157.17(C),148.24(C),134.13(C),132.63(C),130.34(C),112.11(C),110.58(C),109.75(C),104.53(C),
56.24(CH3),52.21(CH2),27.90(CH2),26.61(CH2)；HRMS(ESI)calcd for C 33 H 39 N 2 O 2 [M] +
495.3006,found 495.3227。
example 12:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 12a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 10
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), N-methylaniline, dipalladium tris (dibenzylideneacetone), tri-tert-butylphosphine and sodium tert-butoxide are mixed according to the mol ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 10. 1 H NMR(400MHz,CDCl 3 )δ7.46(d,J＝8.3Hz,2H),7.43–7.37(m,4H),7.25–7.18(m,6H),6.83(d,J＝2.1Hz,2H),6.57(dd,J＝8.3,2.1Hz,2H),3.40(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ191.47(C),154.00(C),147.78(C),145.82(C),130.02(C),126.36(C),125.87(C),125.45(C),125.26(C),114.40(C),106.80(C),40.96(CH3)；
(2) Synthesis of dye 12a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 10 was added and allowed to warm to room temperature, stirred for 30 minutes, an excess of 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated, filtered, and the solid was collected to give dye 12a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 10 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.60(d,J＝2.2Hz,2H),7.50(dd,J＝10.5,4.8Hz,4H),7.43–7.36(m,2H),7.26–7.20(m,4H),7.09(d,J＝7.7Hz,2H),6.98(s,1H),6.42(d,J＝8.9Hz,2H),5.88–5.85(m,2H),3.83(s,6H),2.22(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ175.57(C),158.99(C),148.63(C),144.83(C),135.45(C),133.12(C),131.07(C),130.47(C),129.62(C),128.76(C),128.23(C),127.97(C),126.73(C),114.20(C),114.10(C),43.23(CH3),20.35(CH3)；HRMS(ESI)calcd for C 35 H 31 N 2 [M] + 479.2482,found 479.2677。
example 13:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 13a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 11
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), diphenylamine, tris (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 11. 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝8.2Hz,2H),7.33–7.27(m,8H),7.16–7.07(m,12H),7.01(d,J＝1.9Hz,2H),6.77(dd,J＝8.2,2.0Hz,2H)； 13 C NMR(101MHz,CDCl 3 )δ191.01(C),153.53(C),146.82(C),145.34(C),129.70(C),128.60(C),125.71(C),125.27(C),124.52(C),121.40(C),113.45(C)；
(2) Synthesis of dye 13a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 11 was added and allowed to warm to room temperature, stirred for 30 minutes, an excess of 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated, filtered, and the solid was collected to give dye 13a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 11 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.45(t,J＝7.7Hz,8H),7.34(t,J＝7.4Hz,4H),7.26–7.22(m,9H),7.13(d,J＝7.6Hz,2H),6.75(d,J＝2.0Hz,2H),6.63(d,J＝8.8Hz,2H),6.22(dd,J＝8.8,1.8Hz,2H),2.28(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ175.99(C),158.30(C),147.34(C),143.64(C),135.63(C),134.39(C),133.64(C),130.47(C),130.08(C),128.70(C),128.17(C),127.62(C),118.48(C),116.80(C),20.60(CH3)；HRMS(ESI)calcd for C 45 H 35 N 2 [M] + 603.2795,found 603.3048。
example 14:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 14a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 12
Anhydrous and anaerobic operation, 3, 6-dibromofluorenone (compound 1), indoline, tris (dibenzylideneacetone) dipalladium, tri-tert-butylphosphine and sodium tert-butoxide are mixed according to a molar ratio of 1:4:0.025:0.075: and 6, feeding, dissolving in toluene, reacting for 12 hours at 60 ℃, cooling, diluting with dichloromethane, filtering to remove insoluble substances, removing the solvent by rotary evaporation to obtain a crude product, washing the crude product with ethyl acetate, filtering, and collecting solids to obtain the intermediate 12. 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝8.2Hz,2H),7.34(d,J＝2.0Hz,2H),7.31(d,J＝8.0Hz,2H),7.24(d,J＝7.3Hz,2H),7.17(t,J＝7.7Hz,2H),7.04(dd,J＝8.2,2.0Hz,2H),6.87(t,J＝7.4Hz,2H),4.10(t,J＝8.3Hz,4H),3.19(t,J＝8.3Hz,4H)； 13 C NMR(101MHz,CDCl 3 )δ149.14(C),145.68(C),145.35(C),132.37(C),127.57(C),127.42(C),125.57(C),125.54(C),120.73(C),115.52(C),110.33(C),107.83(C),52.46(CH2),28.28(CH2)；
(2) Synthesis of dye 14a
And (3) performing anhydrous and anaerobic operation, dissolving 2, 6-dimethyl bromobenzene in tetrahydrofuran solvent, stirring for 5 minutes at the temperature of minus 78 ℃, then dropwise adding n-hexane solution of n-butyllithium, and stirring for 30 minutes. Adding anhydrous tetrahydrofuran solution of intermediate 12, heating to room temperature, stirring for 30min, adding excessive 10% perchloric acid solution, stirring for 10 min, precipitating, filtering,the solid was collected to give dye 3a. Wherein the feeding mole ratio of the 2, 6-dimethyl bromobenzene, the n-butyllithium and the intermediate 12 is 1:1:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.87(s,2H),7.43(d,J＝8.1Hz,2H),7.35–7.26(m,5H),7.19–7.09(m,4H),6.91(d,J＝8.9Hz,2H),6.71(d,J＝8.8Hz,2H),4.67(t,J＝7.5Hz,4H),3.30(t,J＝7.4Hz,4H),2.27(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ172.23(C),153.17(C),147.80(C),142.61(C),136.93(C),135.75(C),132.87(C),132.50(C),129.66(C),128.29(C),128.07(C),126.50(C),125.93(C),117.30(C),116.73(C),114.39(C),54.74(CH3),28.63(CH2),20.49(CH2)；HRMS(ESI)calcd for C 37 H 31 N 2 [M] + 503.2482,found 503.2802。
example 15:
the dyes 1a to 14a of the general formula A prepared in examples 1 to 14 above were respectively prepared as a DMSO solution having a concentration of 20mM as a mother solution, and then respectively diluted into methylene chloride solutions having a concentration of 20. Mu.M, and their ultraviolet-visible absorption spectra and fluorescence emission spectra were scanned and plotted as shown in FIG. 1. The relevant photophysical properties are shown in table 1. The near infrared absorption peak and emission peak of the dye of the general formula A series are between 800 and 1200 nm.
TABLE 1 photophysical Properties of dyes of the general formula A series 1a-14a
Example 16:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 15a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 13
Anhydrous and anaerobic operation, 2, 6-dimethyl-1, 4-dibromobenzene (compound 2) was dissolved in tetrahydrofuran solvent, stirred at-78 ℃ for 5 minutes, then n-hexane solution of n-butyllithium was added dropwise, and stirring was continued for 60 minutes. Di-tert-butyl dicarbonate was dissolved in anhydrous tetrahydrofuran, the reaction system was added dropwise, and the mixture was warmed to room temperature and stirred for 12 hours. Adding water for quenching reaction, extracting with dichloromethane, drying with anhydrous sodium sulfate, rotary evaporating to remove solvent, and separating by column chromatography (pure petroleum ether) to obtain intermediate 13. Wherein the feeding mole ratio of the compound 2, n-butyllithium and di-tert-butyl dicarbonate is 1:1:1, a step of;
(2) Synthesis of intermediate 3
The synthesis of intermediate 3 is described in example 3;
(3) Synthesis of dye 15a
In an anhydrous and anaerobic operation, intermediate 13 was dissolved in tetrahydrofuran solvent and stirred for 5 minutes at-78 ℃, then n-pentane solution of t-butyllithium was added dropwise and stirring was continued for 30 minutes. An anhydrous tetrahydrofuran solution of intermediate 3 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was isolated, filtered and the solid was collected. The solid was dissolved in a mixed solvent of trifluoroacetic acid and dichloromethane (volume ratio: 1:1), stirred at room temperature for 3 hours, the solvent was removed by rotary evaporation, and column chromatography was performed (dichloromethane: methanol=50:1) to obtain dye 15a. Wherein the feeding mole ratio of the intermediate 13 to the tertiary butyl lithium to the intermediate 3 is 1:2:0.5. 1 H NMR(400MHz,DMSO)δ7.79(s,2H),7.62(d,J＝1.7Hz,2H),6.65(d,J＝9.0Hz,2H),6.37(dd,J＝9.0,1.7Hz,2H),3.38(s,12H),2.21(s,6H). 13 C NMR(101MHz,DMSO)δ169.03(C),167.70(C),158.07(C),146.97(C),136.31(C),135.88(C),132.79(C),131.96(C),129.14(C),128.78(C),113.62(C),113.04(C),42.31(CH3),20.20(CH3).HRMS(ESI)calcd for C 26 H 27 N 2 O 2 [M] + 399.2067,found 399.2165。
example 17:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 16a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 13
Reference example 16 for synthesis of intermediate 13;
(2) Synthesis of intermediate 2
The synthesis of intermediate 2 is described in example 2;
(3) Synthesis of dye 16a
In an anhydrous and anaerobic operation, intermediate 13 was dissolved in tetrahydrofuran solvent and stirred for 5 minutes at-78 ℃, then n-pentane solution of t-butyllithium was added dropwise and stirring was continued for 30 minutes. Adding anhydrous tetrahydrofuran solution of the intermediate 2, heating to room temperature, stirring for 30 minutes, adding excessive water for quenching, extracting with dichloromethane, washing with saturated saline water for 3 times, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation to obtain oily substance, adding mixed solvent of trifluoroacetic acid and dichloromethane (volume ratio is 1:1), stirring at room temperature for 3 hours, adding toluene, repeatedly rotary evaporating to remove the solvent, precipitating with diethyl ether and petroleum ether, and washing to obtain dye 16a. Wherein the feeding mole ratio of the intermediate 13 to the tertiary butyl lithium to the intermediate 2 is 1:2:0.5. 1 H NMR(400MHz,DMSO)δ9.29(s,2H),7.78(s,2H),7.20(s,2H),6.65(d,J＝7.8Hz,2H),6.23(d,J＝8.5Hz,2H),3.07(s,6H),2.22(s,6H)； 13 C NMR(101MHz,DMSO)δ169.18(C),167.68(C),159.42(C),147.03(C),136.32(C),135.82(C),133.45(C),131.95(C),129.09(C),128.77(C),31.17(CH3),20.20(CH3)；HRMS(ESI)calcd for C 24 H 23 N 2 O 2 [M] + 371.1754,found 371.1864。
example 18:
the preparation of the anti-aromatic diamine fluorene cation fluorescent dye 17a comprises the following structural formula and specific synthetic route:
the method comprises the following specific steps:
(1) Synthesis of intermediate 14
2-bromo-5-iodo-1, 3-xylene (compound 3) was dissolved in diisopropylamine, bis (triphenylphosphine) palladium dichloride, cuprous iodide and trimethylsilyyne were added, and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed 3 times with water, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the residue was separated by column chromatography (pure petroleum ether) to give intermediate 14. Wherein the feeding mole ratio of the compound 3, the bis (triphenylphosphine) palladium dichloride, the cuprous iodide and the trimethylsilyyne is 1:0.03:0.06:1.2;
(1) Synthesis of intermediate 15
Intermediate 14 was dissolved in methanol and potassium carbonate was added and stirred at room temperature for 12 hours. The reaction solution was diluted with water, extracted 3 times with diethyl ether, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give intermediate 15. Wherein the feeding mole ratio of the intermediate 14 to the methanol is 1:2;
(2) Synthesis of intermediate 3
The synthesis of intermediate 3 is described in example 3;
(3) Synthesis of dye 17a
In an anhydrous and anaerobic operation, intermediate 15 was dissolved in tetrahydrofuran solvent and stirred for 5 minutes at-78 ℃, then n-hexane solution of n-butyllithium was added dropwise and stirring was continued for 30 minutes. The anhydrous tetrahydrofuran solution of intermediate 3 was added and allowed to warm to room temperature, stirred for 30 minutes, excess 10% perchloric acid solution was added, stirred for 10 minutes, precipitate was separated out, filtered, and the solid was collected to give dye 17a. Wherein the feeding mole ratio of the intermediate 15 to the n-butyllithium to the intermediate 3 is 1:2:0.5. 1 H NMR(400MHz,CDCl 3 )δ7.64(s,2H),7.27(s,2H),6.54(d,J＝8.9Hz,2H),6.08(d,J＝8.9Hz,2H),3.44(s,12H),3.11(s,1H),2.19(s,6H)； 13 C NMR(101MHz,CDCl 3 )δ172.04(C),158.60(C),147.82(C),136.04(C),132.92(C),131.93(C),131.46(C),129.59(C),123.17(C),113.94(C),111.47(C),83.23(C),78.26(CH),42.40(CH3),20.12(CH3)；HRMS(ESI)calcd for C 27 H 27 N 2 [M] + 379.2169,found379.2277。
example 19:
preparation of activatable small molecule probe 18a and ONOO - The response situation is studied, and the structural formula and the specific synthetic route of the compound are as follows:
the method comprises the following specific steps:
compound 4 was dissolved in dry THF, stirred under ice bath and triethylamine and triphosgene were added and stirring continued for 4 hours. The reaction solution was filtered with celite, and the solvent was removed by rotary evaporation to give an oily chloroformate intermediate. Dye 2a was further dissolved in dichloromethane, N-Diisopropylethylamine (DIPEA) was added under ice bath and stirred for 5 minutes. The chloroformate intermediate was dissolved in methylene chloride and added dropwise to the solution of dye 2a, stirring was continued for an additional 30 minutes. After the reaction, the reaction mixture was diluted with methylene chloride and washed with 0.1M hydrochloric acid, dried over anhydrous sodium sulfate, and most of the solvent was removed by rotary evaporation, followed by precipitation of the crude product by addition of a large amount of diethyl ether. The precipitate was separated by preparative high performance liquid chromatography (methanol/water, 0.1% trifluoroacetic acid added) to give dye 18a. Wherein the feeding mole ratio of the compound 4, triethylamine, triphosgene, dye 2a and dipea is 1.5:2.25:0.75:1:4. 1 H NMR(400MHz,CDCl 3 )δ8.03–7.75(m,2H),7.47–7.29(m,3H),7.21–7.06(m,2H),6.91(dd,J＝48.3,8.6Hz,2H),6.80–6.57(m,3H),6.42(d,J＝9.0Hz,1H),5.24(s,2H),3.47(s,3H),3.29(s,3H),2.17(s,6H).HRMS(ESI)calcd for C 31 H 29 BN 2 O 4 [M+H] + 505.2299,found505.2292；
dye 18a has a response to ONOO - And eliminates the removed phenylboronic acid group through cascade connection, has no near infrared absorption and emission, and responds to ONOO - The resulting dye 2a has an absorption emission in the near infrared and is thus a responsive ONOO - And (3) a probe. ONOO for dye 18a - In response, dye 18a was formulated as a 50. Mu.M 1 XPBS solutionRespectively adding ONOO with concentration of 5-25 mu M - The solution and the change in absorbance spectrum of the dye was collected using an ultraviolet-visible spectrophotometer. Then add 25. Mu.M ONOO - And no ONOO was added to the sample of (C) - And the fluorescence emission of both samples was measured by a near infrared fluorescence spectrometer. The results are shown in FIG. 2, which shows dye 18a vs. ONOO - Has good response effect.
Example 20:
ultra-stable long-time cell staining imaging experiments of anti-aromatic diamine fluorene cation fluorescent dye. Dye 3a is taken as an example.
The method comprises the following specific steps:
endothelial cells were incubated overnight in 35 mm dishes, diluted with dye 3a to 1. Mu.M in 1 XPBS, and a commercial near infrared dye Cy7-Cl was selected as a control, also diluted to 1. Mu.M in 1 XPBS. After 30min of each staining, each was washed 3 times with 1×pbs solution and imaged under a near infrared two-zone fluorescence microscope, respectively. The excitation wavelength is 808nm, and fluorescence signals with the wavelength of more than 1000nm are collected. With excitation power of 5W (power density 2X 10) 4 mW/mm 2 ) The exposure time is 100ms, and 1000 frames of signals are continuously collected, and the change condition of the signal to noise ratio of the cell fluorescence signal in each frame is respectively plotted, and the result is shown in fig. 3. The signal-to-noise ratio of the cell fluorescence signal of the commercial near infrared dye Cy7-Cl is sharply reduced within a period of several seconds after 5W power irradiation, the light stability is weaker, and the dye 3a still well maintains the good imaging signal-to-noise ratio after repeated exposure for up to 1000 times under the same imaging condition, so that the dye has higher light stability.
Example 21:
two-channel mouse organ fluorescence imaging experiment of anti-aromatic diamine fluorene cation fluorescent dye. Dyes 2a,15a have significantly different absorption spectra and large differences in oil water partition coefficients (LogD), so that different metabolic conditions can be present in mice and fluorescent signals from the two dyes can be distinguished by multispectral unmixing. Dye 2a,15a is taken as an example. The method comprises the following specific steps:
dye 2a and dye 15a are respectively prepared into DMSO solutions with the concentration of 20mM as mother solutions, firstly, the dye is diluted into 1 XPBS solution with the concentration of 20 mu M in a 2mL centrifuge tube, the 1 XPBS solution is placed under a near infrared camera, respectively excited by lasers with the same power of 730nm, 808nm and 940nm in sequence, fluorescent signals with the wavelength of more than 1000nm are collected, and the collected simulated spectrum is used as a reference spectrum for subsequent multichannel unmixing. Then, the two dye mother solutions were diluted to 1mM with 1 XPBS, respectively (2 a additionally added with 5% F127). Taking a Balb/c mouse with 6-8 weeks of age, performing anesthesia, unhairing, injecting 100 mu L of the two dye solutions respectively through tail veins, after metabolism for 5 minutes, adopting excitation and acquisition conditions which are completely the same as those of reference spectrum acquisition, sequentially exciting with 730nm, 808nm and 940nm under a near infrared camera, collecting fluorescent signals with the wavelength of more than 1000nm, and unmixing the obtained image result by using in-vitro acquisition reference spectrum as described above. The results are shown in FIG. 4. The visible dye successfully realizes fluorescence imaging of multiple organs, can successfully analyze fluorescence signals from different dyes, and has good application value of multicolor fluorescence imaging of living organisms.
Example 22:
application of anti-aromatic diamine fluorene cation response type probe to ONOO (oxide-nitride-oxide) excessively generated in mouse brain injury process - Is provided. Dye 18a has ONOO - Response capability, can realize OFF-ON type response in near infrared photoacoustic imaging, and can further realize ONOO in living body by unmixing signals of deoxidized/oxyhemoglobin in living body through multispectral photoacoustic signals - And (5) detecting. Taking dye 18a as an example, the specific steps are as follows:
a Balb/c mouse of 6-8 weeks old was anesthetized, and then a head of one side of the mouse was hit with a depth of 1.5 mm by dropping a 40g metal block from a height of 20cm, and a brain injury model was produced, and the head of the other side was intact as an autologous control. After 12 hours, a photoacoustic signal of 680nm to 970nm was collected by intravenous injection of 200. Mu.L of 1 XPBS solution of dye 18a at a concentration of 200. Mu.M and placed in a small animal photoacoustic imaging system after 30 minutes. Photoacoustic using system preset deoxygenated/oxygenated hemoglobin standard spectrum and pre-acquired dye 2aThe spectrum is spectrally resolved as a reference spectrum for multispectral unmixing and the photoacoustic signal of the dye 2a generated in response is identified. The results are shown in FIG. 5. It can be seen that the probe molecule successfully realizes ONOO in living body - Has the potential of being further expanded into a novel small molecular probe platform for various living body sensing and analysis applications.

Claims (11)

1. A near infrared small molecule dye characterized by having a structure represented by the general formula a, and further comprising a salt thereof, or an enantiomer, diastereomer, tautomer, or solvate thereof:
wherein:
X - is an anion, including ClO 4 - 、PF 6 - 、BF 4 - 、Cl - 、Br - 、I - 、CH 3 COO - 、CF 3 COO - 、CF 3 SO 3 - And CH (CH) 3 SO 3 - ；
R 1 、R 2 、R 3 、R 4 Each independently selected from H, cl-C6 alkyl, substituted aryl and substituted acyl;
R 5 ，R 6 each independently selected from H, C1-C6 alkyl, C1-C6 perfluoroalkyl, and C1-C6 alkoxy;
R 7 independently selected from any one of H, C-C6 alkyl, and groups of formula I-IV:
the curve mark is a substitution position;
the maximum absorption wavelength of the near infrared small molecule dye is between 800 and 1150nm, and the maximum emission wavelength is between 900 and 1250 nm; the molecular weight is between 299 Da and 603 Da.
2. The near infrared small molecule dye of claim 1, wherein R 1 And R is 2 Forms an optionally substituted N-membered nitrogen containing heterocyclic ring with the N to which they are attached, N being an integer from 4 to 7, said N-membered nitrogen containing heterocyclic ring comprising a silacyclobutanyl, pyrrolidinyl, piperidinyl, cyclohexylimino, or indolinyl group;
the R is 3 And R is 4 Forms an optionally substituted N-membered nitrogen containing heterocyclic ring with the N to which they are attached, N being an integer from 4 to 7, said N-membered nitrogen containing heterocyclic ring comprising a silacyclobutanyl, pyrrolidinyl, piperidinyl, cyclohexylimino or indolinyl group.
3. The near infrared small molecule dye of claim 1, having the structure of any one of the following formulas B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12:
wherein R is 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 And R is 18 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate.
4. The near infrared small molecule dye of claim 3, wherein:
in B5, R 8 And R is 9 Each independently selected from H or C1-C6 alkyl;
in B10 and B11, R 10 、R 11 、R 12 、R 13 And R is 14 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate;
in B12, R 15 、R 16 、R 17 And R is 18 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate.
5. The near infrared small molecule dye of claim 1, wherein the structure is selected from any one of the following formulas C1 and C2:
wherein R is 19 Independently selected from any one of the groups represented by the formulas V-VIII:
6. the near infrared small molecule dye of claim 1, wherein the structure is selected from any one of the following formulas D1-D18:
7. a method for preparing the near infrared small molecule dye as claimed in any one of claims 1 to 6, comprising the following specific steps:
step one, performing Buchwald-Hartwig carbon-nitrogen coupling reaction on a compound shown in the formula (1) and an amino compound to obtain a compound shown in the formula (2);
step two, a compound shown in the formula (2) undergoes nucleophilic addition reaction under the action of a phenyllithium reagent or a phenyl Grignard reagent, and then undergoes acid catalysis to obtain a compound shown in the general formula A;
the reaction formula is as follows:
8. the method of manufacturing according to claim 7, wherein:
in the first step, the compound shown in the formula (1) and an amino compound are subjected to Buchwald-Hartwig carbon-nitrogen coupling reaction to obtain a compound shown in the formula (2), and the method comprises the following steps:
under the protection of inert gas, heating and stirring a compound shown in a formula (1) and an organic amine compound in an organic solvent environment by using a palladium catalyst, a phosphine ligand and a base as catalysts to obtain a compound shown in a formula (2);
wherein the organic amine compound is selected from one or more of the formulae IX-XX:
wherein,,
R 8 and R is 9 Each independently H or C1-C6 alkyl;
R 10 、R 11 、R 12 、R 13 and R is 14 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate;
R 15 、R 16 、R 17 and R is 18 Each independently selected from H, optionally substituted C1-C6 alkyl, C1-C6 perfluoroalkyl, C1-C6 alkoxy, carboxyl, halogen, and sulfonate;
the organic solvent is selected from one or more of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, trichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, diethyl ether and 1, 4-dioxane;
the palladium catalyst is selected from one or more of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium and palladium acetate;
the alkali is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, cesium carbonate and potassium phosphate;
the phosphine ligand is selected from one or more of tri-tert-butyl phosphine, triphenylphosphine and tri-n-butyl phosphine;
in the second step, the compound shown in the formula (2) is subjected to nucleophilic addition reaction under the action of a phenyllithium reagent or a phenylGrignard reagent, and then is subjected to acid catalysis to obtain a compound shown in the general formula A, wherein the method comprises the following steps:
under the action of a phenyllithium reagent or a phenyl Grignard reagent, the compound shown in the formula (2) takes ethers as a reaction solvent, and reacts at room temperature under the catalysis of an acid catalyst through nucleophilic addition reaction to obtain a compound shown in the general formula A;
wherein the phenyllithium reagent is represented by formula XXI:
R 5 ，R 6 each independently selected from H, C1-C6 alkyl, C1-C6 perfluoroalkyl, and C1-C6 alkoxy;
R 7 independently selected from any one of H, C-C6 alkyl, and groups of formula I-IV:
the curve mark is a substitution position;
the phenyl Grignard reagent is a Grignard reagent corresponding to a phenyllithium reagent;
the ether solvent is tetrahydrofuran or diethyl ether;
the acid catalyst is perchloric acid or trifluoroacetic acid.
9. Use of the near infrared small molecule dye of any one of claims 1-6 in near infrared multispectral fluorescence imaging.
10. The use according to claim 9, wherein at least two of the formulae D1-D18 are used for multichannel in vivo fluorescence imaging of small animal organs.
11. The use of the near infrared small molecule dye of claim 5 in photoacoustic detection of peroxynitrite ions.
CN202310743539.5A 2023-06-21 2023-06-21 Near infrared small molecule dye and preparation method and application thereof Pending CN116790134A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3000833A (en) * 1959-01-26 1961-09-19 American Cyanamid Co Color salts of fluoren-9-ols as infrared absorbers
JPS495636A (en) * 1972-05-06 1974-01-18
US3925077A (en) * 1974-03-01 1975-12-09 Horizons Inc Photoresist for holography and laser recording with bleachout dyes
US3954468A (en) * 1974-08-27 1976-05-04 Horizons Incorporated Radiation process for producing colored photopolymer systems
US4761396A (en) * 1986-02-12 1988-08-02 Kanzaki Paper Manufacturing Co., Ltd. Heat-sensitive recording material
US20210159420A1 (en) * 2019-11-21 2021-05-27 Samsung Display Co., Ltd. Organic electroluminescence device and amine compound for organic electroluminescence device
CN113735759A (en) * 2021-09-26 2021-12-03 长春海谱润斯科技股份有限公司 Diamine derivative and organic electroluminescent device thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3000833A (en) * 1959-01-26 1961-09-19 American Cyanamid Co Color salts of fluoren-9-ols as infrared absorbers
JPS495636A (en) * 1972-05-06 1974-01-18
US3925077A (en) * 1974-03-01 1975-12-09 Horizons Inc Photoresist for holography and laser recording with bleachout dyes
US3954468A (en) * 1974-08-27 1976-05-04 Horizons Incorporated Radiation process for producing colored photopolymer systems
US4761396A (en) * 1986-02-12 1988-08-02 Kanzaki Paper Manufacturing Co., Ltd. Heat-sensitive recording material
US20210159420A1 (en) * 2019-11-21 2021-05-27 Samsung Display Co., Ltd. Organic electroluminescence device and amine compound for organic electroluminescence device
CN113735759A (en) * 2021-09-26 2021-12-03 长春海谱润斯科技股份有限公司 Diamine derivative and organic electroluminescent device thereof

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