Preparation method of photo-induced diketoacid compound derived difree radicals for dynamic nuclear polarization

Abstract

The invention relates to the technical field of chemical synthesis, electron paramagnetic resonance and dynamic nuclear polarization, and particularly discloses a preparation method of photo-induced diketoacid compound derived difree radicals for dynamic nuclear polarization. The preparation method comprises the following steps: firstly designing and synthesizing a double-free-radical precursor, namely a double-alpha-ketonic acid compound connected by using a proper group, and then obtaining a proper illumination condition to carry out light induction, so that the two alpha-ketonic acid structures generate free radicals through light excitation, thereby obtaining the light-induced double free radicals containing two lactic acid-like carbon free radicals. The double free radicals obtained by the method have the advantages of light-induced free radicals, and can be directly removed by heating and melting in the application process of melting DNP, so that the free radical scavenging operation is avoided. The invention provides a new thought for synthesis of double free radicals.

Description

Technical Field

[0001] The invention relates to the technical fields of chemical synthesis, electron paramagnetic resonance and dynamic nuclear polarization (DNP), and in particular to a method for preparing a photoinduced diketoate compound-derived diradical that can be used for dynamic nuclear polarization. Background Art

[0002] Dynamic nuclear polarization (DNP) is a technique that transfers the high polarization of electrons to nuclei to enhance nuclear magnetic resonance (NMR) sensitivity. The polarization mechanism involves the interaction between free electrons and nuclei, so the source of the free electrons plays a central role in determining the overall efficiency of the DNP polarization process. The electron-donating substance, also known as a polarizing agent, is typically a free radical. Commonly used free radicals include stable monoradicals, diradicals, thermally responsive polymer radicals, radicals from silicon-based nanoporous materials, and photoinduced radicals.

[0003] The polarization mechanism of diradicals is mainly the cross-polarization effect, which is considered to be the most effective polarization transfer mechanism in DNP, and therefore can show better polarization performance than single radicals. Gómez et al. synthesized the PTM-TEMPO diradical using the following steps (see Equation 1), achieving a polarization efficiency superior to that of either PTM or TEMPO radicals alone. In 2017, LFPinto et al. synthesized the BDPAesterTEMPO radical using the following steps (Equation 2), achieving a 50,000-fold enhancement, surpassing the polarization efficiency of the PTM-TEMPO diradical. However, this diradical is always accompanied by a certain amount of monoradical 4, making it difficult to completely separate it during the synthesis process.

[0004]

[0005] Synthesis of stable diradical PTM-TEMPO (Formula 1)

[0006]

[0007] Synthesis of Stable Diradical BDPAesterTEMPO of Formula 2

[0008] Literature also reports the synthesis of diradicals such as the TOTAPOL, AMUPOL, and TEKPOL series, which link two TEMPO groups, and the TEMTriPol series, as DNP polarizers. These are all stable diradicals. While they possess excellent polarization properties, the synthesis of stable diradicals is challenging. During the synthesis process, the activity of both radicals must be maintained simultaneously, or one radical must be present to generate the other, resulting in a complex process. Furthermore, stable radicals used in molten DNP accelerate sample relaxation, shortening the polarization lifetime. Therefore, they must be removed after polarization. This process is time-consuming and can introduce new impurities, hindering DNP applications. Photoinduced radicals offer an effective solution to this problem. Photoinduced radicals are generated in situ from radical precursors at low temperatures (typically liquid nitrogen) by irradiation with ultraviolet or visible light. These radicals polarize the nuclei at liquid helium temperatures and are subsequently quenched due to thermal instability during sample heating and melting, resulting in a directly generated hyperpolarized sample free of radicals. This process does not require separation or filtration, has a longer polarization retention time, is low-cost, and highly safe, and avoids the scavenging process of stable free radicals. Photoinduced free radical precursors generally contain an α-dicarbonyl structure. This is because this structure can induce electron transfer through photoexcitation to produce free radicals that are stable at low temperatures. Although excitation may also induce some photolysis to a certain extent, it is only a side reaction. The free radical precursors reported in the literature are generally α-keto acid molecules. The typical photoinduced free radical precursor is pyruvate. The process of pyruvate photoinduced free radical generation is shown in Formula 3, where (Lactic acid-like carbon radicals) are stable at liquid nitrogen temperatures and can be used as DNP polarizing agents. However, no photoinduced diradicals have been reported so far.

[0009]

[0010] Formula 3: Mechanism of free radical generation by pyruvic acid under ultraviolet light Summary of the Invention

[0011] In view of the above-mentioned deficiencies in the prior art, the present invention aims to provide a method for preparing diradicals derived from light-induced diketoate compounds that can be used for dynamic nuclear polarization.

[0012] The concept of the present invention is as follows: first, a diradical precursor is designed and synthesized - a diα-ketoacid compound connected by a suitable group, and then suitable lighting conditions are obtained for photoinduction, so that both α-ketoacid structures generate free radicals through photoexcitation, thereby obtaining a light-induced diradical containing two lactic acid-like carbon radicals (see Formula 4).

[0013]

[0014] Formula 4 diα-keto acid free radical precursor generates diradical

[0015] Based on the reported stable diradical synthesis, a certain distance must be maintained between the two radical units for the diradical to exist stably, thus ruling out the possibility of two α-keto acid structures being directly connected. The conjugated π-bond structure of the aromatic ring can further stabilize the free radical, so a structure containing an aromatic ring is a suitable linking group. Furthermore, since the free radicals generated by the para-position connection of two α-keto acids with a single benzene ring easily recombine to form a 1,4-cyclohexadiene-3,6-dimethylethylene structure (see Equation 5), the possibility of the two α-keto acid structures being connected via a benzene ring is ruled out.

[0016]

[0017] The diradicals connected by the benzene ring of formula 5 recombine to form 1,4-cyclohexadiene-3,6-dimethylethylene structure

[0018] In order to achieve the above object, the technical solution adopted by the present invention is:

[0019] A photoinduced diradical and a diradical precursor thereof, wherein the structural formulas of the photoinduced diradical and the diradical precursor are respectively as follows:

[0020] Wherein the linking group is selected from any one of the following groups:

[0021]

[0022] wherein X=H, F or Cl; m is 0, 1, 2, 3 or 4, and n is 0, 1, 2, 3 or 4;

[0023] Y=H, F or Cl; X1=O or S.

[0024] Preferably, the linking group is selected from any one of the following groups:

[0025]

[0026] The method for preparing the light-induced diradicals comprises the following steps:

[0027] (1) Preparation of diradical precursor diketo acid compound:

[0028] S1: Compound M1 undergoes a Suzuki coupling reaction (Suzuki reaction) or a direct arylation (CH activation) reaction with Compound M2 or Compound M3, and the resulting coupling product is oxidized with selenium dioxide to obtain the diradical precursor diketo acid compound; or

[0029] S2: Compound N1 undergoes a Suzuki coupling reaction with Compound N2, the resulting coupling product is deprotonated with sodium methoxide, and undergoes a nucleophilic acyl substitution reaction with dimethyl oxalate to obtain the diradical precursor diketo acid compound;

[0030]

[0031] Wherein, X=H, F or Cl; X1=O or S; Y=H, F or Cl;

[0032] (2) dissolving the diradical precursor obtained in (1) in a solvent to obtain a diradical precursor solution, freezing the diradical precursor solution into microbeads in liquid nitrogen, and irradiating the microbeads with light to obtain photoinduced diradicals.

[0033] Furthermore, in step (1):

[0034] Under an inert atmosphere, using toluene and ethanol as solvents, compound M1 and compound M2 (or compound N1 and compound N2) undergo a coupling reaction in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium at 90-110° C. for 6-10 hours to obtain the diradical precursor diketo acid compound; or

[0035] Under an inert atmosphere, compound M1 and compound M3 are dissolved in N,N-dimethylacetamide, and a coupling reaction is carried out under the action of potassium acetate and palladium acetate. The reaction is carried out at 100-140° C. for 18-24 hours to obtain the diradical precursor diketo acid compound;

[0036] The molar ratio of compound M1, compound M2, sodium carbonate, and tetrakis(triphenylphosphine)palladium is 1:1.5:6.4:0.04; the molar ratio of compound N1, compound N2, sodium carbonate, and tetrakis(triphenylphosphine)palladium is 1:1.5:6.4:0.04; the molar ratio of compound M1, compound M3, potassium acetate, and palladium acetate is 1:2:2:0.02;

[0037] The coupling product is oxidized by selenium dioxide, which comprises: using pyridine as a solvent, mixing the coupling product and selenium dioxide in a molar ratio of 1:4, and reacting at 85-95° C. for 13-15 hours under an inert atmosphere.

[0038] The coupling product is deprotonated with sodium methoxide and reacts with dimethyl oxalate to undergo a nucleophilic acyl substitution reaction, which comprises the following steps: using anhydrous tetrahydrofuran as a solvent, mixing the coupling product with sodium methoxide and dimethyl oxalate in a molar ratio of 1:4:4, and reacting at 60-70° C. for 6-8 hours under an inert atmosphere.

[0039] Furthermore, in step (2):

[0040] The solvent is a mixture of ethanol and water in a volume ratio of 9:1 to 1:1.

[0041] The concentration of the diradical precursor solution is 0.02-1 mol / L.

[0042] Specifically, the steps for obtaining light-induced diradicals by illumination are as follows: taking a suitable volume of diradical precursor solution and dropping it into liquid nitrogen to freeze it into microbeads; taking a number of microbeads and placing them into a finger-shaped quartz Dewar flask filled with liquid nitrogen, and then using a light source with a suitable wavelength range to irradiate the microbeads immersed in liquid nitrogen for a certain period of time to obtain light-induced diradicals.

[0043] The light-induced biradicals and the light-induced biradicals prepared by the above method are used as melt dynamic nuclear polarization polarizers.

[0044] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0045] 1. This method avoids the inherent chemical problems of the aforementioned stable diradical synthesis process. It does not require maintaining the activity of one free radical while activating another free radical, or maintaining the activity of two free radicals during the synthesis process. It only requires obtaining the free radical precursor according to conventional organic synthesis and then directly irradiating the diradical in a single step.

[0046] 2. The diradicals obtained by this method have the advantage of being photoinduced free radicals, and can be directly removed by heating and melting during the application of melt DNP, thus avoiding the free radical scavenging operation.

[0047] 3. There is no report on this type of light-induced diradicals at present. The present invention provides a new idea for the synthesis of diradicals. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The NMR of compound 1 1 H spectrum.

[0049] Figure 2 The NMR of compound 1 13 C spectrum.

[0050] Figure 3 This is the ESR comparison diagram of free radicals generated by compound 1 and its corresponding monoketo acid and monoketo acid physical mixture induced by ultraviolet light.

[0051] Figure 4 This is a comparison of the ESR of free radicals generated by compounds 1, 2, 3 and benzoylformic acid under ultraviolet light induction.

[0052] Figure 5 This is a comparison of the ESR of free radicals generated by compounds 1 and 4 and 4-fluorobenzoylformic acid under ultraviolet light induction.

[0053] Figure 6This is a comparison chart of the secondary integral values ​​of free radical signals generated after compound 1 and its corresponding monoketo acid and monoketo acid are physically mixed and induced by ultraviolet light.

[0054] Figure 7 This is the ESR comparison chart of free radicals generated by ultraviolet light induction after compound 1-a and its corresponding monoketo acid and physical mixing of monoketo acid.

[0055] Figure 8 This is a comparison chart of the secondary integral values ​​of free radical signals generated by compound 1-a and its corresponding monoketo acid and the physical mixture of the monoketo acid induced by ultraviolet light.

[0056] Figure 9 This is the ESR comparison diagram of free radicals generated by ultraviolet light induction after compound 1-b and its corresponding monoketo acid and monoketo acid are physically mixed.

[0057] Figure 10 This is a comparison chart of the secondary integral values ​​of free radical signals generated by compound 1-b and its corresponding monoketo acid and the physical mixture of the monoketo acid and induced by ultraviolet light.

[0058] Figure 11 This is the ESR comparison diagram of free radicals generated by ultraviolet light induction after compound 1-c and its corresponding monoketo acid and physical mixing of monoketo acid.

[0059] Figure 12 This is a comparison chart of the secondary integral values ​​of the free radical signal generated by compound 1-c and its corresponding monoketo acid and the physical mixture of the monoketo acid induced by ultraviolet light.

[0060] Figure 13 The NMR of compound 2 1 H spectrum.

[0061] Figure 14 The NMR of compound 2 13 C spectrum.

[0062] Figure 15 The NMR of compound 3 1 H spectrum.

[0063] Figure 16 The NMR of compound 3 13 C spectrum.

[0064] Figure 17 The NMR of compound 4 1 H spectrum.

[0065] Figure 18 The NMR of compound 4 13 C spectrum.

[0066] Figure 19 The NMR of compound 5 1 H spectrum.

[0067] Figure 20 The NMR of compound 5 13 C spectrum.

[0068] Figure 21 This is a comparison of the ESR of free radicals generated by compound 5 and 2-oxo-4-phenylbutyric acid under ultraviolet light induction.

[0069] Figure 22 This is a comparison chart of the secondary integral values ​​of the free radical signals generated by compound 5 and its corresponding monoketo acid induced by ultraviolet light.

[0070] Figure 23 The NMR of compound 6 1 H spectrum.

[0071] Figure 24 The NMR of compound 6 13 C spectrum.

[0072] Figure 25 This is the ESR comparison diagram of free radicals generated by compound 6 and its corresponding monoketo acid and physical mixing of monoketo acid induced by visible light.

[0073] Figure 26 This is a comparison chart of the secondary integral values ​​of the free radical signal generated by compound 6 and its corresponding monoketo acid and the physical mixture of the monoketo acid induced by visible light.

[0074] Figure 27 The UV-visible absorption spectra of compound 6 and its corresponding monoketo acid. DETAILED DESCRIPTION

[0075] The present invention will be described in detail below with reference to specific embodiments and accompanying drawings, but this should not be construed as limiting the scope of protection claimed in the claims of the present invention.

[0076] Example 1:

[0077]

[0078] Synthesis steps of light-induced diradical precursor compound 1 of formula 6

[0079] Synthesis of compound 1-2:

[0080] The reaction raw materials, compound 1-1 and compound B, were both commercially available.

[0081] 542.5 mg (2.5 mmol) of 3-bromo-4-fluorobenzophenone (Compound 1-1) was weighed and dissolved in 17.5 mL of toluene. Subsequently, 8 mL of 2.0 M sodium carbonate solution was added, and 8 mL of anhydrous ethanol solution containing 615 mg (3.75 mmol) of acetylphenylboronic acid (Compound B) was added. The reaction system was purged with nitrogen, and then 115.5 mg of tetrakistriphenylphosphine palladium (4% mol) was added. The reaction system was purged with nitrogen again, and the reaction temperature was set to 100 ° C. and refluxed for 8 hours.

[0082] After the reaction is completed, the reaction solution is cooled to room temperature, and 30 mL of water and 30 mL of ethyl acetate are added for extraction. The extraction is repeated three times, and the organic phases are combined. The organic phase is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated by a normal phase silica gel column with a mobile phase of 0-100% petroleum ether / dichloromethane to obtain 610 mg of a white solid with a yield of about 95%. By nuclear magnetic 1 H spectrum and 13 The C spectrum characterizes its structure and the data are assigned as follows:

[0083] 1 H NMR (500MHz, DMSO-d6) δ8.15(dd,J=7.6,2.3Hz,1H),8.13–8.05(m,3H),7.82–7.74(m,2H),7.53(dd,J=10.5,8.6Hz,1H),2.65(d,J=4.4Hz,6H).

[0084] 13 C NMR (126MHz, DMSO-d6) δ198.06,197.07,163.32,161.30,139.18,136.80,134.44(d,J=3.3Hz),131.81(d,J =4.5Hz), 131.10 (d, J = 9.8Hz), 129.73 (d, J = 3.0Hz), 129.03, 127.94 (d, J = 14.0Hz), 117.38, 117.20, 27.31.

[0085] Synthesis of compound 1:

[0086] Dissolve 280 mg of compound 1-2 in 9 mL of pyridine and add 440 mg of selenium dioxide (4 eq). Replace the reaction system with nitrogen and set the reaction temperature to 90°C for 14 hours. During the reaction, the reaction solution gradually changes from colorless to yellow-green.

[0087] After the reaction is completed, the reaction solution is cooled to room temperature, filtered through diatomaceous earth, and the filter residue is washed with pyridine. Subsequently, it is concentrated under reduced pressure to remove pyridine. 80 mL of ethyl acetate and 50 mL of 1 M hydrochloric acid are added to the concentrated crude product, and it is completely dissolved by stirring or ultrasound. It is extracted three times with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 220 mg of yellow-white solid compound 1. By nuclear magnetic 1 H spectrum and 13 C spectrum characterizes its structure (see Figure 1-2 ).

[0088] The data is attributed as follows:

[0089] 1 H NMR (600MHz, DMSO-d6) δ8.15(dd,J=7.5,2.3Hz,1H),8.13–8.06(m,3H),7.85(dd,J=8.3,1.5Hz,2H),7.62(dd,J=10.3,8.6Hz,1H).

[0090] 13 C NMR (151MHz, DMSO-d6) δ188.54,187.04,166.25,165.68,164.08,162.37,140.43,133.27 (d, J=10. 4Hz), 132.92 (d, J = 4.5Hz), 132.13, 130.42, 130.26, 129.80, 128.39 (d, J = 13.9Hz), 118.16, 118.00.

[0091] ESR detection and comparison of compound 1 after generating free radicals:

[0092] A 20 mM solution of Compound 1 was prepared using a 1:1 ethanol / water mixture as the solvent. A 20 mM monoketoacid solution, a 20 mM benzoylformic acid solution, a 20 mM 4-fluorobenzoylformic acid solution, and a 20 mM benzoylformic acid / 4-fluorobenzoylformic acid mixed monoketoacid solution were also prepared for comparison. Both benzoylformic acid and 4-fluorobenzoylformic acid were commercially available.

[0093] 5 μL of 20 mM compound 1 solution was pipetted into a 100 mL flat-bottomed Dewar flask filled with liquid nitrogen to freeze it into microbeads with a diameter of about 2 to 3 mm. Four microbeads were transferred into a finger-shaped quartz Dewar flask and illuminated with a wavelength range of 280 nm to 450 nm and a power of 40 W / cm 2The microbeads were irradiated with a broadband light source for 300 seconds. The irradiated microbeads were transferred to a 5mm ESR detection quartz tube at liquid nitrogen temperature and subjected to X-band ESR testing at -150°C (modulation field amplitude mod = 0.05, signal amplification factor amp = 100). The same operation was performed on the other three comparison samples. The ESR test results are shown in Figure 2. Figure 3 shown.

[0094] Depend on Figure 3 The ESR peak of the free radical generated by photoinduced benzoylformic acid is a singlet. The ESR peak of the free radical generated by photoinduced 4-fluorobenzoylformic acid is split due to hyperfine coupling of the para-F, showing multiple peaks. The ESR peak of the free radical corresponding to the physical mixture of two monoketo acids is close to the superposition of the two free radical signals. The main peak of the free radical generated by compound 1, which is a chemical bond connecting two monoketo acids, is a singlet. Subtle splitting can be observed on both sides of the main peak. Its peak shape is different from the free radical peaks obtained from the monoketo acid and the physical mixture of two monoketo acids. It is preliminarily speculated that the generated free radical is a diradical.

[0095] In order to clarify whether the change in the peak shape of the ESR of compound 1 after photoinduced free radical generation compared with the monoketo acid is due to the direct interaction between the fluorine atom in the molecular structure and the benzoylformic acid free radical, or the result of the combined action of the 4-fluorobenzoylformic acid free radical and the benzoylformic acid free radical, compounds 2, 3, and 4 (structural formula see formula 7, synthesis method and NMR characterization see below) with similar structures to compound 1 but containing only one keto acid were designed and synthesized for comparison. According to the above method, 20mM solutions of compounds 2, 3, and 4 were prepared, microbeads were prepared, and ESR tests were performed after photoinduction. The test results are as follows Figure 4-5 shown.

[0096]

[0097] Formula 7: Structural formula of compounds 2, 3, and 4

[0098] like Figure 4 As shown, when the molecular structure contains fluorine atoms but can only generate single free radicals through the benzoylformic acid structure (see the structural formulas of compounds 2 and 3), its ESR spectrum shows the same single peak characteristics as benzoylformic acid. Figure 5The results showed that when the molecular structure contains a benzene ring but can only generate a single free radical through the 4-fluorobenzoylformic acid structure (see the structural formula of compound 4), the free radical peak shape is exactly the same as that of the 4-fluorobenzoylformic acid free radical. These experimental results indicate that the peak shape of the free radical generated by compound 1 is not caused by the interaction between the fluorine atom in the structure and the benzoylformic acid free radical, nor is it caused by the interaction between the benzene ring and the 4-fluorobenzoylformic acid free radical. Instead, it is the result of the interaction between the benzoylformic acid free radical and the 4-fluorobenzoylformic acid free radical. This further proves that the free radical generated by compound 1 upon photoinduction is a diradical.

[0099] The free radical concentration is proportional to the quadratic integral value of the ESR signal intensity. The quadratic integral values ​​of the free radical ESR signals generated by compound 1 and its corresponding monoketo acid and monoketo acid physical mixture were compared. The results are as follows Figure 6 As shown, it shows that the concentration of free radicals generated by compound 1 at the same concentration is higher than that of its corresponding two monoketo acids and their physical mixtures, which also indirectly verifies that the photoinduced free radicals generated by compound 1 are diradicals.

[0100] Furthermore, compounds 1-a, 1-b, and 1-c (structural formula shown in Formula 8, synthesis method is the same as compound 1) with the same molecular formula as compound 1 were designed and synthesized for comparison. According to the above method, 20mM solutions of compounds 1-a, 1-b, and 1-c were prepared, microbeads were prepared, and ESR tests were performed after light induction (modulation field amplitude mod was 0.05, signal amplification factor amp was 100). The test results are shown in the figure below. Figure 7-12 shown.

[0101]

[0102] Formula 8: Structural formula of compounds 1-a, 1-b, and 1-c

[0103] Depend on Figure 7 It can be seen that the ESR peaks of the free radicals generated by 3-fluorobenzoylformic acid and benzoylformic acid after light induction are both single peaks. The free radical ESR peaks corresponding to the physical mixture of the two monoketo acids are also single peaks. The signal intensity and signal quadratic integral value ( Figure 8 ) is higher than the superposition of two single free radicals. The free radical generated by compound 1-a, which connects two monoketo acids by chemical bonds, is basically the same as that under physical mixing. The ESR peak shape is a single peak, and the signal intensity and signal quadratic integral value ( Figure 8 ) is slightly higher than physical mixing.

[0104] Overall comparison of the photoinduced free radical generation between 2-fluorobenzoylformic acid, benzoylformic acid, and their physical mixture and chemically bonded diketo acid compound 1-b ( Figure 9) is similar to the situation corresponding to 3-fluorobenzoylformic acid. The ESR peak of the free radical generated by 2-fluorobenzoylformic acid after light induction is a single peak, and the peak width is slightly wider than that of 3-fluorobenzoylformic acid. The ESR peak of the free radical generated by the physical mixture of the two monoketo acids and the chemically bonded diketo acid compound 1-b is a single peak, and the signal intensity of the physical mixture and the signal quadratic integral value ( Figure 10 ) is close to the superposition of two single free radicals. The signal intensity and signal quadratic integral value of chemically bonded diketo acid compound 1-b ( Figure 10 ) are higher than those of physical mixtures.

[0105] Compound 1-c and compound 1 are both obtained by chemically connecting 4-fluorobenzoylformic acid and benzoylformic acid. The difference is the position of the connecting bond and F. Therefore, the overall comparison of the photoinduced free radical generation of compound 1-c corresponding to the monoketo acid and the monoketo acid physical mixture ( Figure 11-12 ) is similar to the corresponding situation of compound 1. The ESR signal peak of the free radical generated by the physical mixture is the superposition of two single free radicals, and the signal intensity and signal quadratic integral value are slightly lower than the superposition of two single free radicals. The signal intensity and quadratic integral value of the chemically bonded diketo acid compound 1-c are both higher than those of the physical mixture and the superposition of two single free radicals. The slight difference is that the ESR peak of compound 1-c shows a single peak, and the fission similar to compound 1 is not observed.

[0106] In general, the concentrations of free radicals generated by these three diketonate compounds connected by chemical bonds are basically the same as the corresponding comparison results of compound 1, that is, the concentration of diketonate compounds is higher than the superposition of the physical mixture and the two single free radicals, indicating that the type of free radicals generated by light-induced by these three diketonate compounds is the same as that of compound 1, all of which are diradicals.

[0107] Appendix: Synthesis and NMR characterization of compounds 2, 3, and 4

[0108]

[0109] Synthesis steps of compound 2 of formula 9

[0110]

[0111] Synthesis steps of compound 3 of formula 10

[0112]

[0113] Synthesis steps of compound 4 of formula 11

[0114] The synthesis steps of compounds 2, 3, and 4 are shown in Formula 9-11. The specific operation steps refer to the synthesis of compound 1. 1 H spectrum and 13The structures of these three compounds were characterized by C spectroscopy (see Figure 13-18 The reaction raw materials, compounds 2-1, 3-1, 4-1, compounds B and C, were all commercially available.

[0115] NMR assignment of compound 2:

[0116] 1 H NMR (600MHz, DMSO-d6) δ13.24(s,1H),8.12(dd,J=7.6,2.3Hz,1H),8.09–8.03(m,3H),7.84(dd,J=8.4,1.5Hz,2H),7.52–7.47(m,1H).

[0117] 13 C NMR(151MHz,DMSO-d6)δ188.57,166.58,166.29,163.04,161.35,140.92,132.55(d,J=4.53Hz),13 1.95, 130.36, 130.16 (d, J = 3.02Hz), 128.44 (d, J = 1.51Hz), 127.57 (d, J = 14.0Hz), 117.43, 117.28.

[0118] NMR assignment of compound 3:

[0119] 1 H NMR (600MHz, DMSO-d6) δ8.07–8.01(m,2H),7.83–7.76(m,2H),7.61(td,J=7.9,1.7Hz,1H),7.52–7.47(m,1H),7.38–7.32(m,2H).

[0120] 13 C NMR(151MHz,DMSO-d6)δ188.72,166.47,160.38,158.74,141.91,131.56,131.31(d,J=7.3Hz ), 130.26, 130.11 (d, J = 3.1Hz), 127.28 (d, J = 12.4Hz), 125.66 (d, J = 4.8Hz), 116.87, 116.72.

[0121] NMR assignment of compound 4:

[0122] 1 H NMR (600MHz, DMSO-d6) δ8.09–8.00(m,2H),7.62–7.56(m,3H),7.56–7.51(m,2H),7.50–7.46(m,1H).

[0123] 13 C NMR(126MHz,DMSO-d6)δ186.84,165.49,163.91,161.87,133.78,132.46(d,J=5.3Hz),131.7 0(d,J=10.1Hz),129.38(d,J=14.7Hz),129.19(d,J=3.3Hz),128.87,128.60,117.55,117.36.

[0124] Example 2:

[0125]

[0126] Synthesis steps of light-induced diradical precursor compound 5 of formula 12

[0127] Synthesis of compound 5-3:

[0128] The synthesis steps of compound 5-3 refer to the synthesis of compound 1-2 in Example 1. The raw materials compounds 5-1 and 5-2 were obtained from commercial sources.

[0129] NMR assignment of compound 5-3:

[0130] 1 H NMR (600MHz, Chloroform-d) δ7.56–7.46(m,4H),7.31–7.21(m,4H),3.70(s,6H),3.01(t,J=7.8Hz,4H),2.73–2.62(m,4H).

[0131] 13 C NMR (151MHz, Chloroform-d) δ173.35,139.48,138.97,128.70,127.10,51.67,35.65,30.57.

[0132] Synthesis of compound 5:

[0133] Dissolve 490 mg (1.5 mmol) of compound 5-3 in 15 ml of anhydrous tetrahydrofuran, add 324 mg (6 mmol, 4 eq) of sodium methoxide and 708 mg (6 mmol, 4 eq) of dimethyl oxalate. Replace the reaction system with nitrogen, set the reaction temperature to 65°C, and reflux the reaction solution for 6 hours. During the reaction, precipitation of a yellow oil was observed.

[0134] After the reaction, the mixture was cooled to room temperature and the tetrahydrofuran solvent was evaporated using a rotary evaporator. 30 ml of 4 M hydrochloric acid and 30 mL of ethyl acetate were then added to the cooled crude product in sequence. The upper organic phase was separated, washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to obtain a yellow oil.

[0135] The yellow oil was mixed with 15 ml of 4M hydrochloric acid and refluxed at 100°C for 6 hours. The resulting reaction solution was cooled to 4°C and filtered at the same temperature to obtain an off-white solid compound 5. 1 H and 13 C NMR characterization of its structure (see Figure 19-20 ), and data attribution was performed.

[0136] NMR assignment of compound 5:

[0137] 1 H NMR (700MHz, DMSO-d6) δ7.57–7.53(m,4H),7.32–7.28(m,4H),3.17(t,J=7.5Hz,4H),2.86(t,J=7.5Hz,4H).

[0138] 13 C NMR (176MHz, DMSO-d6) δ196.05,162.95,140.15,138.24,129.30,126.90,40.27,28.45.

[0139] ESR detection and comparison of compound 5 after generating free radicals:

[0140] A 100 mM solution of compound 5 was prepared using a 1:1 ethanol / water mixture as the solvent. 100 mM and 200 mM solutions of 2-oxo-4-phenylbutyric acid were also prepared for comparison. 2-oxo-4-phenylbutyric acid was commercially available.

[0141] 5 μL of 100 mM compound 5 solution was pipetted into a 100 mL flat-bottomed Dewar flask filled with liquid nitrogen to freeze it into microbeads with a diameter of about 2 to 3 mm. Four microbeads were transferred into a finger-shaped quartz Dewar flask and illuminated with a wavelength range of 280 nm to 450 nm and a power of 40 W / cm 2 The microbeads were irradiated with a broadband light source for 300 seconds. The irradiated microbeads were transferred to a 5mm ESR detection quartz tube at liquid nitrogen temperature and subjected to X-band ESR testing at -150°C (modulation field amplitude mod = 0.1, signal amplification factor amp = 20). The same operation was performed on 100mM and 200mM 2-oxo-4-phenylbutyric acid solutions. The ESR test results are shown in Figure 2. Figure 21 shown.

[0142] Depend on Figure 21 It can be seen that the ESR peaks of the free radicals generated by photoinduction of 100mM and 200mM 2-oxo-4-phenylbutyric acid are both double peaks, with only differences in signal strength. The main peak of the ESR peak of the free radical generated by photoinduction of compound 5 is double peaks, but splitting can be observed. Its peak shape is generally different from that of 2-oxo-4-phenylbutyric acid. This shows that compound 5 should generate a diradical, and the change in its peak shape is most likely caused by the electron dipole interaction between the two free radicals. In addition, the free radical signal intensity and signal quadratic integral value ( Figure 22 ) is significantly greater than that of 100mM and 200mM 2-oxo-4-phenylbutyric acid, indicating that its concentration is also higher, which also indirectly verifies that compound 5 generates a diradical.

[0143] Example 3:

[0144]

[0145] Synthesis steps of light-induced diradical precursor compound 6 of formula 13

[0146] Synthesis of compound 6-3:

[0147] The starting materials, compounds 6-1 and 6-2, were obtained commercially. 2.985 g (15 mmol) of p-bromoacetophenone compound 6-1, 2.268 g (30 mmol) of 2-acetylthiophene compound 6-2, 22.45 mg of palladium acetate (2% mol), and 2.925 g (30 mmol) of potassium acetate were dissolved in 40 mL of anhydrous N,N-dimethylacetamide (DMA). The reaction system was purged with nitrogen, the temperature was set to 120°C, and the reaction was refluxed for 20 hours. During the reaction, the reaction solution gradually changed from yellow to dark brown.

[0148] After the reaction, the reaction solution was cooled to room temperature, and 120 mL of water, 200 mL of ethyl acetate and 50 mL of dichloromethane were added for extraction, which was repeated three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was separated by a normal phase silica gel column with a mobile phase of 0-100% petroleum ether / dichloromethane to obtain 1.376 g of white solid compound 6-3 with a yield of about 37.6%. By nuclear magnetic resonance 1 H spectrum and 13 Its structure was characterized by C spectrum.

[0149] NMR assignment of compound 6-3:

[0150] 13C NMR (176MHz, DMSO-d6) δ197.65,191.24,150.09,144.48,137.26,137.14,135.61,129.66,127.11,126.57,27.24,26.91.

[0151] 1 H NMR (700 MHz, DMSO-d6) δ 8.03–8.00 (m, 2H), 7.98 (d, J = 4.0 Hz, 1H), 7.93–7.89 (m, 2H), 7.80 (d, J = 4.0 Hz, 1H), 2.60 (d, J = 1.4 Hz, 3H), 2.56 (s, 3H). Synthesis of compound 6:

[0152] The preparation method of compound 6 is the same as the method for preparing compound 1 from compound 1-2 in Example 1. The product is a yellow solid with a yield of about 86%. 1 H spectrum and 13 C spectrum to characterize its structure (see Figure 23-24 ), and data attribution was performed.

[0153] NMR assignment of compound 6:

[0154] 1 H NMR (700MHz, DMSO-d6) δ8.13(d,J=4.1Hz,1H),8.08–8.05(m,2H),8.05–8.02(m,2H),7.90(d,J=4.1Hz,1H).

[0155] 13 C NMR (176MHz, DMSO-d6) δ188.09,178.84,166.14,163.68,152.58,140.08–137.44(m),132.65,131.05,128.06,127.34.

[0156] ESR detection and comparison of compound 6 after generating free radicals:

[0157] A 20 mM solution of compound 6 was prepared using a 1:1 ethanol / water mixture. A 20 mM monoketoacid solution, a 20 mM benzoylformic acid solution, a 20 mM 2-thiophene glyoxylic acid solution, and a 20 mM monoketoacid mixed solution, a 20 mM 2-thiophene glyoxylic acid / benzoylformic acid mixed solution, were also prepared for comparison. Both 2-thiophene glyoxylic acid and benzoylformic acid were commercially available.

[0158] 5 μL of 20 mM compound 6 solution was pipetted into a 100 mL flat-bottomed Dewar flask filled with liquid nitrogen to freeze it into microbeads with a diameter of about 2 to 3 mm. Four microbeads were transferred into a finger-shaped quartz Dewar flask and illuminated with a wavelength of 405 nm and a power of 36 W / cm 2 Narrow band light source (under the same conditions, the narrow band light source has a wavelength range of 280nm-450nm and a light power of 40W / cm 2 The microbeads were irradiated with a wide-band light source (the concentration of free radicals generated by the wide-band light source is higher) for 300 seconds. The irradiated microbeads were transferred to a 5mm ESR detection quartz tube at liquid nitrogen temperature and subjected to X-band ESR testing at -150°C (modulation field amplitude mod = 0.05, signal amplification factor amp = 100). The same operation was performed on the other three comparison samples. The ESR test results are shown in Figure 2. Figure 25 shown.

[0159] Depend on Figure 25 It can be seen that the ESR peak shape of the free radical generated by benzoylformic acid after photoinduction is a single peak; the ESR peak shape of the free radical generated by 2-thiophene glyoxylic acid after photoinduction is affected by the hyperfine coupling of the S atom and is split, showing multiple peaks; the free radical ESR peak shape corresponding to the two physically mixed compounds is close to the superposition of the two free radical signals. The free radical ESR signal generated by compound 6, in which two monoketo acids are connected by a chemical bond, is a single peak after photoinduction. Unlike the physical mixture sample of 2-thiophene glyoxylic acid and two monoketo acids, no fine splitting is observed, which may be caused by the interaction between the two free electrons of the generated diradical. At the same concentration, the free radical signal intensity generated by compound 6 is higher than that of its corresponding monoketo acid 2-thiophene glyoxylic acid, benzoylformic acid and the physical mixture of the two. The quadratic integral of the free radical ESR signal intensity was also compared (see Figure 26 ), it can be seen that the concentration of free radicals generated by compound 6 at the same concentration is higher than that of its corresponding two monoketo acids and physical mixtures, which also indirectly verifies that the photoinduced free radicals generated by compound 6 are diradicals.

[0160] The concentration was 4×10- 5 The UV-visible absorption spectra of compound 6 solution, benzoylformic acid solution and 2-thiophene glyoxylic acid solution of M are shown in Figure 27 , it can be seen that the UV-visible absorption peak of compound 6 is closer to the visible light range.

Claims

1. A photoinduced diradical and its diradical precursor, characterized in that: The structural formulas of the photoinduced diradical and diradical precursor are shown below: Wherein the linking group is selected from any one of the following groups: wherein X=H, F or Cl; m is 0, 1, 2, 3 or 4, and n is 0, 1, 2, 3 or 4; Y=H, F or Cl; X1=O or S.

2. The photoinduced diradical and diradical precursor thereof according to claim 1, characterized in that: The linking group is selected from any one of the following groups:

3. The method for preparing the light-induced diradical and diradical precursor thereof according to any one of claims 1 to 2, characterized in that: The steps include: (1) Preparation of diradical precursor diketo acid compound: S1: Compound M1 undergoes a Suzuki reaction or a direct arylation reaction with Compound M2 or Compound M3, and the resulting coupling product is oxidized with selenium dioxide to obtain the diradical precursor diketo acid compound; or S2: Compound N1 and Compound N2 undergo a Suzuki reaction, the resulting coupling product is deprotonated with sodium methoxide, and undergoes a nucleophilic acyl substitution reaction with dimethyl oxalate to obtain the diradical precursor diketo acid compound; Wherein, X=H, F or Cl; X1=O or S; Y=H, F or Cl; (2) dissolving the diradical precursor obtained in (1) in a solvent to obtain a diradical precursor solution, freezing the diradical precursor solution into microbeads in liquid nitrogen, and irradiating the microbeads with light to obtain photoinduced diradicals.

4. The preparation method according to claim 3, characterized in that In step (1): Under an inert atmosphere, using toluene and ethanol as solvents, compound M1 and compound M2, or compound N1 and compound N2, undergo a coupling reaction in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium at 90-110° C. for 6-10 hours to obtain the diradical precursor diketo acid compound; or Under an inert atmosphere, compound M1 and compound M3 are dissolved in N,N-dimethylacetamide, and a coupling reaction is carried out under the action of potassium acetate and palladium acetate. The reaction is carried out at 100-140° C. for 18-24 hours to obtain the diradical precursor diketo acid compound.

5. The preparation method according to claim 3, characterized in that The molar ratio of compound M1, compound M2, sodium carbonate, tetrakistriphenylphosphine palladium or compound N1, compound N2, sodium carbonate, tetrakistriphenylphosphine palladium is 1:1.5:6.4:0.04; the molar ratio of compound M1, compound M3, potassium acetate, and palladium acetate is 1:2:2:0.

02.

6. The preparation method according to claim 3, characterized in that In step S1, the coupling product is oxidized with selenium dioxide, comprising: using pyridine as a solvent, mixing the coupling product and selenium dioxide in a molar ratio of 1:4, and reacting at 85-95° C. for 13-15 hours under an inert atmosphere; and / or In step S2, the coupling product is deprotonated with sodium methoxide and undergoes a nucleophilic acyl substitution reaction with dimethyl oxalate, which comprises: using anhydrous tetrahydrofuran as a solvent, mixing the coupling product with sodium methoxide and dimethyl oxalate in a molar ratio of 1:4:4, and reacting at 60-70° C. for 6-8 hours under an inert atmosphere.

7. The preparation method according to claim 3, characterized in that In step (2): the solvent is a mixture of ethanol and water in a volume ratio of 9:1 to 1:1; and / or The concentration of the diradical precursor solution is 0.02-1 mol / L.

8. The preparation method according to claim 3, characterized in that In step (2), the step of obtaining light-induced diradicals by illumination is as follows: taking a suitable volume of diradical precursor solution and dropping it into liquid nitrogen to freeze it into microbeads; taking a number of microbeads and placing them into a finger-shaped quartz Dewar flask filled with liquid nitrogen, and then using a light source of a suitable wavelength range to irradiate the microbeads immersed in liquid nitrogen for a certain period of time to obtain light-induced diradicals.

9. Use of the photoinduced biradical according to any one of claims 1 to 2 or the photoinduced biradical prepared by the method according to any one of claims 3 to 8 as a polarizer for melt dynamic nuclear polarization.

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