WO2016173386A1 - 五取代四氢嘧啶在制备温度敏感荧光材料中的应用 - Google Patents

五取代四氢嘧啶在制备温度敏感荧光材料中的应用 Download PDF

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WO2016173386A1
WO2016173386A1 PCT/CN2016/078413 CN2016078413W WO2016173386A1 WO 2016173386 A1 WO2016173386 A1 WO 2016173386A1 CN 2016078413 W CN2016078413 W CN 2016078413W WO 2016173386 A1 WO2016173386 A1 WO 2016173386A1
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temperature
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朱秋华
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南方医科大学
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K9/00—Tenebrescent materials, i.e. materials for which the range of wavelengths for energy absorption is changed as a result of excitation by some form of energy
    • C09K9/02—Organic tenebrescent materials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01K—MEASURING TEMPERATURE; MEASURING QUANTITY OF HEAT; THERMALLY-SENSITIVE ELEMENTS NOT OTHERWISE PROVIDED FOR
    • G01K11/00—Measuring temperature based upon physical or chemical changes not covered by groups G01K3/00, G01K5/00, G01K7/00 or G01K9/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01K—MEASURING TEMPERATURE; MEASURING QUANTITY OF HEAT; THERMALLY-SENSITIVE ELEMENTS NOT OTHERWISE PROVIDED FOR
    • G01K11/00—Measuring temperature based upon physical or chemical changes not covered by groups G01K3/00, G01K5/00, G01K7/00 or G01K9/00
    • G01K11/20—Measuring temperature based upon physical or chemical changes not covered by groups G01K3/00, G01K5/00, G01K7/00 or G01K9/00 using thermoluminescent materials

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  • the invention relates to the technical field of temperature-sensing organic light-emitting materials, and particularly discloses the use of a compound having a penta-substituted tetrahydropyrimidine structure in preparing a temperature-sensitive fluorescent material.
  • the inventors in 201110129857.X disclose a compound having a penta-substituted tetrahydropyrimidine structure which has an aggregation-induced luminescence effect and can be used for organic electroluminescence or photoluminescence devices or chemical and bioluminescence sensors and probes.
  • some structures of penta-substituted tetrahydropyrimidines have allotropes, one of which The fluorescent color of the allotrope, that is, the wavelength is particularly sensitive to temperature changes, the temperature changes by 30 degrees, the fluorescence wavelength changes by 59 nm, and the fluorescence wavelength is more sensitive to temperature changes than the reported compound 2.
  • the pento-substituted tetrahydropyrimidine measurement temperature range is much wider than the existing organic small molecule fluorescent compound.
  • the temperature-sensitive material penta-substituted tetrahydropyrimidine is preferably: in the formula (I),
  • R 1 is selected from methyl or ethyl
  • R 2 is selected from the group consisting of phenyl, methylphenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl,
  • R 3 is selected from the group consisting of phenyl, bromophenyl, methoxyhydroxy substituted phenyl, bromophenyl, trifluoromethylphenyl, naphthyl, thienyl;
  • R 4 is selected from the group consisting of phenyl, methylphenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl.
  • the penta-substituted tetrahydropyrimidine compound has a linear temperature dependence of red-edge excitation wavelength (LTDE), and different excitation wavelengths can be selected in different temperature ranges.
  • LTDE red-edge excitation wavelength
  • a fluorescent temperature- and/or fluorescence intensity on-off mutation can be used to prepare a sensitive temperature-sensitive fluorescent material; the penta-substituted tetrahydropyrimidine compound has high temperature sensing sensitivity (temperature change 30K, emission wavelength change 59 nm, and/or temperature change) At 35K, the fluorescence intensity was changed by 10 times.
  • the penta-substituted tetrahydropyrimidine compound has a wide temperature range (0K to 450K).
  • FIG. 2 is a diagram showing an example of a linear relationship between a molecular structure of a small molecule organic compound 2 having a temperature-sensitive fluorescent material and an emission wavelength and a temperature in a polar solution;
  • 3 is a diagram showing an example of a reversible change in the molecular structure of a small molecule organic compound 3 and 4 having a temperature-sensitive fluorescent material and a change in solid-state fluorescence intensity or emission wavelength with temperature;
  • Figure 4 is a photograph showing the molecular structure of the penta-substituted tetrahydropyrimidine THP-1 of the present invention and its allotrope crystal THP-1g emitting green light (emitting wavelength: 496 nm);
  • Figure 6 shows the characteristics of sensitive on-off mutations in different temperature ranges using THP-1g fluorescence intensity when excited at different wavelengths. Accurate determination of temperature changes in different ranges.
  • A) and b) respectively THP-1g The linear relationship between the emission spectrum and the emission peak fluorescence intensity and temperature in the range of 80-120K under 420nm excitation; c) and d) are the emission spectra of THP-1g at 445nm excitation and 210-300K respectively. a linear relationship diagram of the power function of the emission peak fluorescence intensity versus temperature;
  • Figure 7 is a photograph showing the molecular structure of the penta-substituted tetrahydropyrimidine THP-1 of the present invention and its allotrope crystal THP-1b emitting blue light (emitting wavelength: 433 nm);
  • Figure 8 shows the linear dependence temperature of the THP-1b red edge excitation wavelength in the 90-300K measurement range.
  • the characteristics of (LTDREEW) and the fluorescence color and intensity at different wavelengths can be mutated in different temperature ranges, and the fluorescence intensity is linear with temperature.
  • Figure 10 is an emission spectrum of THP-1b with an excitation wavelength of 360 nm and a range of 4-298K;
  • FIG 11 is an emission spectrum of THP-1 ⁇ 12 at their respective maximum emission wavelengths (see Table 1) at 293K and 353K (THP-4b and THP-4g are allotropes);
  • Figure 12 is an emission spectrum of THP-4p (which is an allotrope of THP-4b and THP-4g) at its maximum emission wavelength (425 nm) at an emission wavelength of 298 and 410 K;
  • Figure 13 is an emission spectrum of ⁇ at its maximum emission wavelength (469 nm) at an emission wavelength of 293 K and 353 K.
  • Table 1 shows the molecular structure of the compound in the examples, the maximum emission wavelength ⁇ em, the ratio of the fluorescence intensity at the maximum emission wavelength of 80 ° C to the fluorescence intensity at the maximum emission wavelength of 20 ° C, I80/I20, and the melting point of the compound.
  • the compounds THP-1, THP-2 and THP-5-8, 10-12 are all disclosed in the aforementioned patents;
  • the compounds THP4g, THP4b and THP-4p are allotropes which we have separated from known compounds.
  • Their molecular structure and structural characteristic parameters are the same, except that the melting point and optical properties are different (the respective melting points and maximum emission wavelengths are shown in Table 1, the excitation spectra are shown in Figure 11 and Figure 12);
  • the compounds THP-3 and THP-9 are
  • the synthesis method can refer to the prior art, and the corresponding raw materials can be selected.
  • the properties and structural characteristics of the data are as follows:
  • the appropriate excitation wavelength can be selected, and the temperature in the range of 300-90K can be accurately determined by the sensitive on-off fluorescence change of THP-1g.
  • Example 1 using a low temperature fluorometer, accurately measured the temperature of 80-120 K with an excitation wavelength of 420 nm. As shown in Fig. 6a, the temperature changes by 35 degrees, and the fluorescence intensity of THP-1g changes by 10 times. At the same time, as can be seen from Fig. 6b, the fluorescence intensity has a good power function relationship with temperature, which can be sensitively and accurately determined from 80- Temperature in the range of 120K.
  • Example 2 using a low temperature fluorometer with an excitation wavelength of 445 nm, the temperature of 300-210 K can be accurately determined. As shown in Fig. 6c, the temperature changes by 90 degrees, and the fluorescence intensity of THP-1g changes by 14 times. At the same time, as can be seen from Fig. 6d, the fluorescence intensity has a good power function relationship with temperature, which can be sensitively and accurately determined from 300- Temperature in the range of 210K.
  • THP-1 blue fluorescent allotropes were measured by a low-temperature fluorometer from 300 to 90K every 30 degrees with the short-wavelength and long-wavelength fluorescent component maximum emission wavelengths.
  • the excitation spectrum of the crystal see Figure 7) (see Figure 8a), with two different red-edge excitation wavelengths as the emission spectrum ( Figures 8c and 8d).
  • the red edge excitation wavelength has a good linear relationship with temperature. That is, it has the characteristic of the red edge excitation wavelength linear dependence temperature (LTDREEW).
  • LTDREEW characteristic of the red edge excitation wavelength linear dependence temperature
  • Figures 8c, 8d and 8e that a suitable excitation wavelength is selected and a good linear relationship can be obtained over the measured temperature range.
  • Example 1 using a low temperature fluorometer, the excitation wavelength of 365 nm was selected to accurately determine the temperature of 120-80K. It can be seen from Fig. 9a that the temperature changes by 30 degrees (from 110 to 80K) and the maximum emission wavelength changes by 59 nm (from 433 to 492 nm), that is, from a substantially short-wavelength fluorescent component to a substantially long-wavelength fluorescent component. The change of the fluorescent component, that is, the change of the fluorescent color, can be directly observed by the naked eye. At the same time, as shown in Figure 9b, the two fluorescence intensity ratios of THP-1b have a very good power function relationship with temperature.
  • a 12-substituted tetrahydropyrimidine THP-1-12 and a commonly used excitation probe for measuring the critical micelle concentration of the surfactant were measured at 20 and 80 degrees by means of a temperature control device (The molecular structure of the compound, the maximum emission wavelength ⁇ em, the ratio of the fluorescence intensity at the maximum emission wavelength of 80 degrees to the fluorescence intensity at the maximum emission wavelength of 20 degrees I 80 /I 20 , and the melting point of the compound are shown in Table 1) to determine whether the compound has The LTDREEW characteristic and the red edge excitation wavelength sensitivity to temperature, that is, whether the red edge excitation wavelength is affected by temperature and the degree of temperature influence to determine whether the compound has the LTDREEW characteristic and the sensitivity of the red edge excitation wavelength to temperature.
  • the red-edge excitation wavelengths of 12 penta-substituted tetrahydropyrimidines are affected by temperature, that is, the LTDREEW property is
  • the excitation wavelength of the red edge is affected by the temperature.
  • Some red edge excitation wavelengths have different phase difference ( ⁇ ) of 9 nm, while some red edge excitation wavelengths only differ by ( ⁇ ) by 4 nm. Therefore, the measured penta-substituted tetrahydropyrimidines can be used for fluorescence temperature detection or fluorescence temperature imaging analysis like THP-1.
  • the excitation spectra of THP-4p (the molecular structure of the compound, the maximum emission wavelength ⁇ em, and the melting point of the compound are shown in Table 1) were determined by a low temperature fluorometer at 298 K and 410 K, such as Figure 12 shows the THP-4p near its melting point (153 ° C, ie 426 K), its red edge
  • the wavelength of the light still changes with temperature, that is, there is still a LTDREEW characteristic, and the ratio of the fluorescence intensity at the maximum emission wavelength at 410 K to the fluorescence intensity at the maximum emission wavelength at 298 K is 0.68.
  • This example shows that the red edge excitation wavelength of THPs is sensitive to temperature from 0K to its melting point, and still has strong fluorescence intensity at near melting point.
  • the excitation spectrum of the common fluorescent compound ruthenium was measured at 20 and 80 ° C by a conventional fluorometer through a temperature control device. As can be seen from Fig. 13, the red edge excitation wavelength of ruthenium is not affected by temperature, i.e., there is no LTDREEW property, which means that not all fluorescent compounds have LTDREEW characteristics.

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Abstract

本发明五取代四氢嘧啶在制备温度敏感荧光材料中的应用。所述五取代四氢嘧啶化合物具有红边激发波长线性依赖温度(linear temperature dependence of red-edge excitation wavelength,LTDREEW)的特性，以及选择不同的激发波长，可以在不同的温度范围内发生荧光颜色突变和/或荧光强度on-off变化，并且荧光强度比率或荧光强度与温度成很好的线性或幂函数关系，可以用作高灵敏度宽温度范围(0-450K)的温度感应荧光材料。

Description

五取代四氢嘧啶在制备温度敏感荧光材料中的应用 技术领域
本发明涉及温度感应有机发光材料技术领域，具体公开一种具有五取代四氢嘧啶结构的化合物在制备温度敏感荧光材料中的应用。
背景技术
温度是影响物理化学过程及生物代谢过程的一个最基本的物理参数。因此，无论是科学研究还是日常生活都离不开温度的检测，温度传感器约占世界传感器市场的75-80％(Review of Scientific Instruments 2000,71,2959-2978)。不同环境或研究对象温度的检测需要不同的温度传感器。随着分子生物学、蛋白组学、医学、科学仪器等学科和技术的快速发展，多种研究领域已深入到微观动态的检测过程，如对生物代谢过程及疾病的研究已深入到生物细胞内分子变化的过程(Nature medicine 2003,9,149-150)。这些发展对温度检测提出了新的挑战：实时及远距离检测微观环境的温度及温度分布。通过局部接触检测温度的传统传感器，如基于物质热胀冷缩体积变化的温度传感器、基于热电效应(Seebeck effect)设计的热电偶温度指示器等，已无法满足这些学科发展的需要。在这方面，具有超高灵敏度、极快响应速度、极高空间分辨率、安全远程检测等优点的荧光分子或纳米温度传感器受到了极大的关注(Chemical Society Reviews 2013,42,7834-7869)。
从理论上来说，所有荧光化合物的荧光都与温度有关，因为温度的改变一方面会带来原子或分子电子能级及电子振动能级分布的改变，从而改变荧光性质；另一方面温度的改变还会带来化合物体积的改变，从而影响原子或分子间的相互作用力，使荧光性质发生改变。但用作温度探针的荧光化合物却很少，因为作为温度探针的化合物需要满足灵敏度高、稳定性好、可逆等条件(Chemical Society Reviews 2013,42,7834-7869)。目前报道的温度感应荧光材料有高分子荧光化合物、有机小分子荧光化合物、有机金属配合物、量子点、有机、无机纳米材料等(Chemical Society Reviews 2013,42,7834-7869)。其中一些荧光温度探针已用于细胞内温度检测及成像研究，如高分子化合物1可以用于细胞内温度成像(Nature communications 2012,3,705)(图1)。
相对无机及高分子化合物荧光材料，有机小分子荧光材料的性能比较容易调控，这是因为他们具有如下特性：1)易通过结构修饰得到不同光学性能的化合物；2)易通过分子层面上的有序组装，以改变材料的性能；3)能够有目的地改变功能分子的结构，进行多种功能的组合和集成。另外，相对金属量子点、金属配合物等温度荧光探针，有机小分子温度荧光探针的毒性较低。但到目前为止，具有高灵敏度、宽温度范围的荧光探针是金属配合物、量子点和有机聚合物(Chemical Society Reviews 2013,42,7834-7869)。能作为温度探针的有机小分子种类也很少，其中绝大部分是溶液分子温度荧光探针，这类探针除了与温度有关外，还与溶液的极性、酸碱度有关，如图2中的化合物2，其化合物的荧光不仅与温度有关，还与溶剂的极性有关，只能检测一定极性溶液的温度，因此化合物2对温度的响应在极性的2-甲氧基乙基醚溶液中进行的(图2)(Angew.Chem.Int.Ed.2011,50,8072-8076)。这就限制了这类探针的应用，因为，理想的温度探针是只与温度有关，而其它环境因素无关。环境感应固态可逆荧光变化具有更广泛的用途，但固体荧光因温度刺激而发生可逆变化的化合物非常少。如图3中的化合物3的荧光强度可以通过改变温度发生可逆的变化(Nat Mater 2005,4,685-687)，化合物4的双色荧光可以通过改变温度发生可逆的变化(Chemical Communications 2012,48,10895-10897)。有机化合物的荧光不仅与分子结构有关，还与分子堆积方式有关。化合物3和化合物4对温度的感应是因为温度刺激会使它们的分子堆积方式发生可逆的变化。
发明人在201110129857.X中，公开了一种具有五取代四氢嘧啶结构的化合物，其具有聚集诱导发光效应，可以用于有机电致或光致发光器件或化学及生物荧光传感器和探针。
发明内容
本发明的目的是为了克服现有技术的不足，提供一种具有五取代四氢嘧啶结构的化合物在制备温度敏感荧光材料的应用。
本发明的上述目的通过如下技术方案予以实现：
五取代四氢嘧啶在制备温度敏感荧光材料中的应用，所述五取代四氢嘧啶具有如(Ⅰ)所示结构：
Figure PCTCN2016078413-appb-000001
式中：
R1选自C1-8直链或支链烷基或取代的C1-8烷基；
R2、R4各自独立选自C1-8直链或支链烷基、取代的C1-8烷基、C5-8环烷基、取代的C5-8环烷基、C5-6芳香基、取代的C5-6芳香基、C9-18稠环芳香基、取代的C9-18稠环芳香基、C5-6杂环基、取代的C5-6杂环基、C5-6芳杂环基或取代的C5-6芳杂环基；
R3选自C5-6芳香基、取代的C5-6芳香基、C9-18稠环芳香基、取代的C9-18稠环芳香基、C5-6芳杂环基或取代的C5-6芳杂环基。
优选地，所述五取代四氢嘧啶在制备化学和/或生物温度荧光传感器或探针中的应用。
随着深入研究分析，发明人意外发现，201110129857.X中的五取代四氢嘧啶化合物，不仅仅具有聚集诱导发光效应，还具有红边激发波长线性依赖温度(linear temperature dependence of red-edge excitation wavelength,LTDREEW)的特性，利用该特性，可以将该化合物用作高灵敏度、宽温度范围的温度荧光探针，拓展化合物的应用范围。LTDREEW特性是首次发现，选择合适的激发波长，在0K到化合物熔点的温度范围内，荧光颜色发生突变和/或荧光强度发生on-off变化，荧光强度比率或荧光强度与温度成很好的线性或幂函数关系，温度变化35度，荧光强度可发生10倍变化，荧光强度对温度变化的灵敏度比报道的化合物1高；某些结构的五取代四氢嘧啶具有同素异形体，其中一种同素异形体的荧光颜色即波长对温度变化尤其灵敏，温度变化30度，荧光波长变化59nm,荧光波长对温度变化的灵敏度比报道的化合物2高。另外，所述五取代四氢嘧啶测定温度范围远比现有的有机小分子荧光化合物宽。
作为一种优选方案，所述的温度敏感材料五取代四氢嘧啶，R1优选为C1-2烷 基。
作为一种优选方案，所述的温度敏感材料五取代四氢嘧啶，R2优选为C1-5直链或支链烷基、取代的C1-5烷基、C5-8环烷基、C5-6芳香基或取代的C5-6芳香基。
作为一种优选方案，所述的温度敏感材料五取代四氢嘧啶，R3优选为C5-6芳香基或取代的C5-6芳香基。
作为一种优选方案，所述的温度敏感材料五取代四氢嘧啶，R4优选为C1-5直链或支链烷基、取代的C1-5烷基、C5-8环烷基、C5-6芳香基或取代的C5-6芳香基。
作为一种优选方案，上述的取代基，优选为卤素、全卤代的C1-2烷基、卤代C1-4烷基、羟基、C1-6直链或支链烷氧基、硝基、氰基、氨基、C1-6单烷基氨基、C1-6二烷基氨基、C5-8单环烷基氨基、C5-6单杂环基氨基、C5-6单芳基氨基、C1-6烷基酰氨基、C5-6芳基酰氨基、氨基羰基、C1-6单烷基氨基羰基、C1-6二烷基氨基羰基、C1-6烷基酰基、C5-8芳基酰基、氨基砜基、C1-6单烷基氨基砜基、C1-6二烷基氨基砜基、C5-8芳基氨基砜基、C1-6烷基磺酰氨基、羧基、C1-6单烷基砜基、直链或支链烷基、C5-8环烷基、C5-8取代的环烷基、C2-4烯基、C2-4炔基、芳基C1-3烷基、C5-6芳香基、C5-6取代的芳香基、C9-18稠环芳香基、C5-6杂环基、C5-6芳杂环基或C9-18稠环芳杂环基。
作为一种优选方案，所述的温度敏感材料五取代四氢嘧啶，优选为：式(Ⅰ)中，
R1选自甲基或乙基；
R2选自苯基，甲基苯基，氯苯基，溴苯基，三氟甲基苯基，
R3选自苯基，溴苯基，甲氧基羟基取代的苯基，溴苯基，三氟甲基苯基，萘基，噻吩基；
R4选自苯基，甲基苯基，氯苯基，溴苯基，三氟甲基苯基。
与现有技术相比，本发明具有如下有益效果：
发明人发现，所述五取代四氢嘧啶化合物具有红边激发波长线性依赖温度(linear temperature dependence of red-edge excitation wavelength,LTDREEW)的特性，选择不同的激发波长，可以在不同的温度范围内发生荧光颜色和/或荧光强度on-off突变，可以制备灵敏的温度感应荧光材料；所述五取代四氢嘧啶化合物的温度感应灵敏度高(温度变化30K，发射波长变化59nm，同时/或者温度变 化35K，荧光强度改变10倍。)；所述五取代四氢嘧啶化合物的测定温度范围宽(0K到450K)。
附图说明
图1为现有的具有温度感应荧光材料的高分子有机化合物1示例.a)化合物1随温度变化的激发和发射光谱图.b)化合物1发射光谱峰值(564nm)处的荧光强度与温度的关系图；
图2为报道的具有温度感应荧光材料的小分子有机化合物2分子结构及其在极性溶液中发射波长与温度的线性关系图示例；
图3为报道的具有温度感应荧光材料的小分子有机化合物3和4分子结构及其固态荧光强度或发射波长随温度的变化发生可逆变化图示例；
图4为本发明所述五取代四氢嘧啶THP-1的分子结构及其发绿光(发射波长496nm)的同素异形体晶体THP-1g照片；
图5为在77-300K测定范围，THP-1g红边激发波长线性依赖温度(LTDREEW)的特性以及以不同波长激发时其荧光强度可以在不同的温度范围内发生on-off突变并与温度成线性关系的特性；a)随温度变化的激发光谱(发射波长为496nm，与带符号的线基本重合的虚线为循环温度下测定的激发光谱)；b)红边激发波长与温度的线性关系图(带黑色方块符号的直线)及以420nm激发，在90-210K范围的496nm处荧光强度与温度的线性关系图(带圆圈符号的直线)和以438nm激发，在180-300K范围的496nm处荧光强度与温度的线性关系图(带五角星符号的直线)；c)以420nm激发，在77-300K范围的发射光谱；d)以438nm激发，在150-300K范围的的发射光谱；
图6为利用THP-1g荧光强度在以不同波长激发时，可以在不同温度范围内发生灵敏的on-off突变的特性精确测定不同范围的温度变化.a)和b)分别为THP-1g在420nm激发下，在80-120K范围的发射光谱及发射峰荧光强度与温度的幂函数线性关系图；c)和d)分别为THP-1g在445nm激发下，在210-300K范围的发射光谱及发射峰荧光强度与温度的幂函数线性关系图；
图7为本发明所述五取代四氢嘧啶THP-1的分子结构及其发蓝光(发射波长433nm)的同素异形体晶体THP-1b照片；
图8为在90-300K测定范围，THP-1b红边激发波长线性依赖温度 (LTDREEW)的特性以及以不同波长激发时其荧光颜色和强度可以在不同的温度范围内发生突变，并且荧光强度与温度成线性关系的特性。a)随温度变化的激发光谱(带符号的线为发射波长为434nm的激发光谱，不带符号的实线为发射波长为510nm的激发光谱，与带符号的线基本重合的虚线为循环温度下测定的激发光谱)；b)图8a中三个不同发光强度处(图8a中三条平行线)的红边激发波长与温度的线性关系图；c)以365nm激发，在90-300K范围的发射光谱；d)以380nm激发，在90-300K范围的的发射光谱；e)以365nm激发，在90-210K范围的433nm处荧光强度与温度的线性关系图(带方块符号的直线)和以380nm激发，在180-300K范围的433nm处荧光强度与温度的线性关系图(带圆圈符号的直线)；
图9为利用THP-1b在以不同波长激发时，其荧光颜色和强度可以在不同的温度范围内发生突变的特性精确测定不同范围的温度变化。a)THP-1b在365nm激发下，在80-120K范围的发射光谱；b)433nm处的荧光强度与535nm处荧光强度之比与温度的幂函数关系图；
图10为THP-1b以360nm为激发波长，4-298K范围的发射光谱；
图11为温度293K和353K下，THP-1～12以各自最大发射波长(见表1)为发射波长的发射光谱(THP-4b和THP-4g为同素异形体)；
图12为温度298和410K下，THP-4p(为THP-4b和THP-4g的同素异形体)以其最大发射波长(425nm)为发射波长的发射光谱；
图13为温度293K和353K下，芘以其最大发射波长(469nm)为发射波长的发射光谱。
具体实施方式
下面结合具体实施例对本发明作进一步的解释说明，但具体实施例并不对本发明作任何限定。除非特别说明，实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。
表1为实施例中化合物的分子结构、最大发射波长λem、80℃最大发射波长处的荧光强度与20℃最大发射波长处的荧光强度之比I80/I20，以及化合物熔点。实施例中部分化合物已在201110129857.X中，未在201110129857.X中具体公开的化合物，我们给出相应的结构特征数据。
表1实施例中化合物的分子结构、最大发射波长λem、80℃最大发射波长处的荧光强度与20℃最大发射波长处的荧光强度之比I80/I20，以及化合物熔点
Figure PCTCN2016078413-appb-000002
Figure PCTCN2016078413-appb-000003
Figure PCTCN2016078413-appb-000004
a最大发射波长；b80度最大发射波长处的荧光强度与20度最大发射波长处的荧光强度之比。
其中，化合物THP-1、THP-2及THP-5～8,10～12均在前述专利中有公开；化合物THP4g、THP4b及THP-4p是我们从已知化合物中分离出来的同素异形体，它们的分子结构与结构特征参数都相同，只是熔点和光学性质不同(它们各自的熔点和最大发射波长见表1，激发光谱见图11和图12)；化合物THP-3、THP-9为新化合物，其合成方法可以参照现有技术，选用相应的原料即可，其性质与结构特征数据如下：
THP-3 Dimethyl 1,2,3,6-tetrahydro-1,3-diphenyl-2-(thiophen-2-yl)pyrimidine-4,5-dicarboxylate 35％yield,yellow solid,mp＝121.4–121.6℃；IR(KBr):νmax＝2949,1742,1702,1593,1495,1241,1110,1064,976,843,752,696cm-1；1H NMR(400MHz,CDCl3)δ＝7.47–7.02(m,13H),6.30(s,1H),4.33(d,J＝17.6Hz,1H),3.88(d,J＝17.6Hz,1H),3.72(s,3H),3.66(s,3H)ppm；13C NMR(101MHz,CDCl3)δ＝165.71,164.69,148.49,144.23,143.91,142.15,129.32,129.21,127.08,126.60,126.46,126.28,124.18,121.87,119.06,102.03,52.52,51.49,42.65ppm；MS(ESI):m/z 435(M+H+,27),248(100)；Anal.Calcd for C24H22N2O4S:C,66.34；H,5.10；N,6.45；Found:C,66.53；H,5.10；N,6.61
THP-9 Dimethyl 1,3-bis(4-bromophenyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate 24％yield,white solid,mp＝196.2–196.4℃；IR (KBr):νmax＝2951,2303,1740,1704,1606,1489,1325,1241,1114,893,748cm-1；1H NMR(400MHz,CDCl3)δ＝7.76–6.73(m,12H),6.04(s,1H),4.24(d,J＝18.4Hz,1H),3.72(s,3H),3.69(s,3H),3.53(d,J＝18.4Hz,1H)ppm；13C NMR(101MHz,CDCl3)δ＝165.21,164.33,148.06,143.06,141.45,132.55,132.37,127.28,126.30,125.05,120.69,119.75,114.53,103.19,79.53,52.83,51.68,42.66ppm；MS(ESI):m/z 653(M+H+,27),655(M+H+,53),326(100)；Anal.Calcd for C27H21Br2F3N2O4:C,49.57；H,3.24；N,4.28；Found:C,49.58；H,3.29；N,4.17
实施例1
(1)从300到77K，用低温荧光仪，以最大发射波长测五取代四氢嘧啶THP-1绿色荧光同素异形体(THP-1g，结构及晶体图见图4)的激发光谱(见图5a)，以两个不同的红边激发波长做发射光谱(图5c和5d)。由图5a和图5b中可以看出红边激发波长/荧光强度与温度有很好的线性关系，即具有红边激发波长线性依赖温度(LTDREEW)的特性。由图5c、5d和5b可以看出选择合适的激发波长，在测定温度范围内荧光强度与温度有很好的线性关系
(2)利用LTDREEW的特性，选择合适的激发波长，可以通过THP-1g灵敏的on-off荧光变化精确测定300-90K范围的温度。
实例1，用低温荧光仪，以420nm为激发波长准确测定80-120K的温度。如图6a所示，温度变化35度，THP-1g的荧光强度变化10倍，同时，从图6b可以看到，荧光强度与温度有很好的幂函数关系，可以灵敏精确地测定从80-120K范围内的温度。
实例2，用低温荧光仪，以445nm为激发波长，则可以准确测定300-210K的温度。如图6c所示，温度变化90度，THP-1g的荧光强度变化14倍，同时，从图6d可以看到，荧光强度与温度有很好的幂函数关系，可以灵敏精确地测定从300-210K范围内的温度。
实施例2
(1)从300到90K每隔30度，用低温荧光仪，分别以短波长和长波长荧光组分最大发射波长测五取代四氢嘧啶THP-1蓝色荧光同素异形体(THP-1b)(晶体图见图7)的激发光谱(见图8a)，以两个不同的红边激发波长做发射光谱(图8c和8d)。由图8a和图8b中可以看出红边激发波长与温度有很好的线性关系， 即具有红边激发波长线性依赖温度(LTDREEW)的特性。由图8c、8d和8e可以看出选择合适的激发波长，在测定温度范围内可以得到很好的线性关系。
(2)利用THP-1b的LTDREEW的特性以及双色荧光的特性，选择合适的激发波长，可以精确测定从0K到THP-1b熔点范围的温度。
实例1，用低温荧光仪，选择365nm的激发波长可以精确测定120-80K的温度。从图9a可以看到，温度变化30度(从110到80K)，最大发射波长变化59nm(从433到492nm)，即从基本为短波长荧光组分转变到基本为长波长荧光组分，这种荧光组分的改变，即荧光颜色的改变，肉眼就可以直接观察得到。同时，如图9b所示THP-1b两种荧光强度比率与温度呈非常好的幂函数关系。
实例2，用低温荧光仪，选择360nm的激发波长可以精确测定4-80K的温度。从图10可以看到，温度变化56度(从60到4K)，最大发射波长变化66nm(从434到500nm)，即从基本为短波长荧光组分转变到基本为长波长荧光组分，这种荧光组分的变化，即荧光颜色的变化，肉眼就可以直接观察得到。
实施例3
用普通荧光仪，通过控温装置，在20和80度下测定12个五取代四氢嘧啶THP-1-12和一个常用的测定表面活性剂临界胶束浓度的荧光探针芘的激发光谱(化合物的分子结构、最大发射波长λem、80度最大发射波长处的荧光强度与20度最大发射波长处的荧光强度之比I80/I20，以及化合物熔点见表1)，以判断化合物是否具有LTDREEW特性及红边激发波长对温度的敏感程度，即以红边激发波长是否受温度影响以及受温度影响程度的程度以判断化合物是否具有LTDREEW特性及红边激发波长对温度的敏感程度。如图11所示，12个五取代四氢嘧啶(THP-1-12，其中THP-4g和THP-4b为同素异形体)的红边激发波长均受温度影响，即都有LTDREEW特性，但红边激发波长受温度影响程度不同，有的红边激发波长相差(Δλ)差别有9nm，而有的红边激发波长只相差(Δλ)差别有4nm。因此，测定的五取代四氢嘧啶均像THP-1一样可以用于荧光温度检测或荧光温度成像分析。
实施例4
用低温荧光仪，在298K和410K下测定THP-4p(THP-4g和THP-4b的同素异形体(化合物的分子结构、最大发射波长λem、以及化合物熔点见表1)的激发光谱，如图12所示THP-4p在接近其熔点(153℃，即426K)时，其红边激 发波长仍然随温度变化，即仍然有LTDREEW特性，其在410K时最大发射波长处的荧光强度与298K时最大发射波长处的荧光强度之比为0.68。该实例说明THPs的红边激发波长在0K到其熔点范围内均对温度有敏感的响应，并且在近熔点时仍然有较强的荧光强度。
实施例5
用普通荧光仪，通过控温装置，在20和80℃下测定普通荧光化合物芘的激发光谱。如图13可以看出芘的红边激发波长不受温度的影响，即没有LTDREEW特性，这说明不是所有的荧光化合物具有LTDREEW特性。

Claims (8)

  1. 五取代四氢嘧啶在制备温度敏感荧光材料中的应用，其特征在于，所述五取代四氢嘧啶具有如(Ⅰ)所示结构：
    Figure PCTCN2016078413-appb-100001
    式中：
    R1选自C1-8直链或支链烷基或取代的C1-8烷基；
    R2、R4各自独立选自C1-8直链或支链烷基、取代的C1-8烷基、C5-8环烷基、取代的C5-8环烷基、C5-6芳香基、取代的C5-6芳香基、C9-18稠环芳香基、取代的C9-18稠环芳香基、C5-6杂环基、取代的C5-6杂环基、C5-6芳杂环基或取代的C5-6芳杂环基；
    R3选自C5-6芳香基、取代的C5-6芳香基、C9-18稠环芳香基、取代的C9-18稠环芳香基、C5-6芳杂环基或取代的C5-6芳杂环基。
  2. 根据权利要求1所述应用，其特征在于，所述五取代四氢嘧啶在制备化学和/或生物温度荧光传感器或探针中的应用。
  3. 根据权利要求1所述应用，其特征在于，R1为C1-2烷基。
  4. 根据权利要求1所述应用，其特征在于，R2为C1-5直链或支链烷基、取代的C1-5烷基、C5-8环烷基、C5-6芳香基或取代的C5-6芳香基。
  5. 根据权利要求1所述应用，其特征在于，R3为C5-6芳香基或取代的C5-6芳香基。
  6. 根据权利要求1所述应用，其特征在于，R4为C1-5直链或支链烷基、取代的C1-5烷基、C5-8环烷基、C5-6芳香基或取代的C5-6芳香基。
  7. 根据权利要求1所述应用，其特征在于，取代基选自选自下列基团：卤素、全卤代的C1-2烷基、卤代C1-4烷基、羟基、C1-6直链或支链烷氧基、硝基、氰基、氨基、C1-6单烷基氨基、C1-6二烷基氨基、C5-8单环烷基氨基、C5-6单杂环基氨基、 C5-6单芳基氨基、C1-6烷基酰氨基、C5-6芳基酰氨基、氨基羰基、C1-6单烷基氨基羰基、C1-6二烷基氨基羰基、C1-6烷基酰基、C5-8芳基酰基、氨基砜基、C1-6单烷基氨基砜基、C1-6二烷基氨基砜基、C5-8芳基氨基砜基、C1-6烷基磺酰氨基、羧基、C1-6单烷基砜基、直链或支链烷基、C5-8环烷基、C5-8取代的环烷基、C2-4烯基、C2-4炔基、芳基C1-3烷基、C5-6芳香基、C5-6取代的芳香基、C9-18稠环芳香基、C5-6杂环基、C5-6芳杂环基或C9-18稠环芳杂环基。
  8. 根据权利要求1所述应用，其特征在于，
    R1选自甲基或乙基；
    R2选自苯基，甲基苯基，氯苯基，溴苯基，三氟甲基苯基，
    R3选自苯基，溴苯基，甲氧基羟基取代的苯基，溴苯基，三氟甲基苯基，萘基，噻吩基；
    R4选自苯基，甲基苯基，氯苯基，溴苯基，三氟甲基苯基。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113563870A (zh) * 2021-08-30 2021-10-29 陕西科技大学 一种温敏有机聚集发光材料及其制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104845613B (zh) 2015-04-29 2017-01-04 南方医科大学 五取代四氢嘧啶在制备温度敏感荧光材料中的应用
CN105203041B (zh) * 2015-09-21 2017-11-10 南昌航空大学 一种宽带荧光积分强度比测量应变的方法
CN105713598B (zh) * 2016-03-07 2018-05-04 南方医科大学 五取代四氢嘧啶衍生物在制备具有压致荧光变色材料中的应用
CN105837513B (zh) * 2016-04-07 2018-10-26 南方医科大学 五取代四氢嘧啶衍生物在制备细胞成像染料中的应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250015A (zh) * 2011-05-19 2011-11-23 南方医科大学 聚集诱导发光的五取代四氢嘧啶及其制备方法和应用
CN103113282A (zh) * 2013-01-22 2013-05-22 天津理工大学 一种含吸电子基团半菁蓝素温敏分子光学探针的制备方法
CN103113283A (zh) * 2013-01-22 2013-05-22 天津理工大学 一种含给电子基团半菁蓝素温敏分子光学探针的制备方法
CN103411961A (zh) * 2013-07-15 2013-11-27 南方医科大学 一种测定表面活性剂临界胶束浓度灵敏的荧光点亮探针法
CN103483271A (zh) * 2013-09-10 2014-01-01 常州高特钛科新材料科技有限公司 氢键自组装超分子光聚合单体的制备及其方法
CN103755704A (zh) * 2014-01-08 2014-04-30 上海大学 温度敏感型树枝化苝及其制备方法
US20140342390A1 (en) * 2011-12-21 2014-11-20 The University Of Tokyo Temperature-sensitive fluorescent probe for introduction into cell
CN104845613A (zh) * 2015-04-29 2015-08-19 南方医科大学 五取代四氢嘧啶在制备温度敏感荧光材料中的应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250015A (zh) * 2011-05-19 2011-11-23 南方医科大学 聚集诱导发光的五取代四氢嘧啶及其制备方法和应用
US20140342390A1 (en) * 2011-12-21 2014-11-20 The University Of Tokyo Temperature-sensitive fluorescent probe for introduction into cell
CN103113282A (zh) * 2013-01-22 2013-05-22 天津理工大学 一种含吸电子基团半菁蓝素温敏分子光学探针的制备方法
CN103113283A (zh) * 2013-01-22 2013-05-22 天津理工大学 一种含给电子基团半菁蓝素温敏分子光学探针的制备方法
CN103411961A (zh) * 2013-07-15 2013-11-27 南方医科大学 一种测定表面活性剂临界胶束浓度灵敏的荧光点亮探针法
CN103483271A (zh) * 2013-09-10 2014-01-01 常州高特钛科新材料科技有限公司 氢键自组装超分子光聚合单体的制备及其方法
CN103755704A (zh) * 2014-01-08 2014-04-30 上海大学 温度敏感型树枝化苝及其制备方法
CN104845613A (zh) * 2015-04-29 2015-08-19 南方医科大学 五取代四氢嘧啶在制备温度敏感荧光材料中的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HUANG, LAN ET AL.: "Copper-induced fluorescence enhancement and particle-size decrease of a C-6 unsubstituted tetrahydropyrimidine racemate", RSC ADVANCES, vol. 3, no. 32, 10 May 2013 (2013-05-10), pages 13286 - 13292, XP055326447, ISSN: 2046-2069 *
ZHU, QIUHUA ET AL.: "A New Series of C-6 Unsubstituted Tetrahydropyrimidines: Convenient One-Pot Chemoselective Synthesis, Aggregation-Induced and Size-Independent Emission Characteristics", CHEMISTRY-A EUROPEAN JOURNAL, vol. 19, no. 4, 29 November 2012 (2012-11-29), pages 1268 - 1280, XP055326428, ISSN: 0947-6539 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113563870A (zh) * 2021-08-30 2021-10-29 陕西科技大学 一种温敏有机聚集发光材料及其制备方法
CN113563870B (zh) * 2021-08-30 2022-10-18 陕西科技大学 一种温敏有机聚集发光材料及其制备方法

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