CN115584142A - 一种红色发光环状结构花菁染料及其合成方法 - Google Patents
一种红色发光环状结构花菁染料及其合成方法 Download PDFInfo
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
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- UIYBMOLHFWZYGN-UHFFFAOYSA-N 2-[phenyl(pyridin-2-yl)methyl]pyridine Chemical class C1=CC=CC=C1C(C=1N=CC=CC=1)C1=CC=CC=N1 UIYBMOLHFWZYGN-UHFFFAOYSA-N 0.000 claims description 11
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
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- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 description 1
- OHOQEZWSNFNUSY-UHFFFAOYSA-N Cy3-bifunctional dye zwitterion Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCN1C2=CC=C(S(O)(=O)=O)C=C2C(C)(C)C1=CC=CC(C(C1=CC(=CC=C11)S([O-])(=O)=O)(C)C)=[N+]1CCCCCC(=O)ON1C(=O)CCC1=O OHOQEZWSNFNUSY-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供一种红色发光环状结构花菁染料及其合成方法。但由于花菁染料结构中的单、双键能自由旋转,荧光量子效率低,且化学稳定性较差。本文设计、合成了一种新型的环状结构红光发射花菁染料,一方面保留传统花菁染料的D‑π‑A离子型共轭结构,另一方面通过成环限制其单、双键的自由旋转,提高荧光量子效率。实验结果表明,所合成的花菁染料具有高的摩尔吸光系数及荧光量子效率,且具有极高的化学稳定性,在低浓度的条件下即可对细胞染色,适用于荧光成像。
Description
技术领域
本发明涉及到有机染料合成技术领域,设计一种具有环状结构的花菁染料,具体为环状结构花菁染料的合成方法。
背景技术
花菁染料是荧光染料的一种,具有摩尔吸收系数大、光谱可调、易于功能化、生物安全性好的优点,在生物传感、荧光成像等领域有广泛的应用。通过共轭链长度的调节,花菁的光谱可以从可见光区一直延伸到近红外区,而长波长的光可有效地穿透皮肤组织、排除背景干扰,获得更为理想的灵敏度和分辨率。但是常规的花菁染料结构中的单、双键能自由旋转,从而引发非辐射跃迁,导致荧光量子效率低;另一方面,花菁染料的离子型D-π-A结构易受亲核试剂的进攻,破坏共轭结构,因此化学稳定性弱。近些年来,从事荧光染料的研究者做了大量的尝试,力图通过合理的分子设计增强荧光量子效率,而通过环化限制单双键旋转的方法获得了非常好的效果,荧光量子效率得到上百倍的提高。但由于合成难度大且难于功能化,因此并未能大量制备、实现商业化。由此,我们提出了一种新的合成方案,反应条件温和,原料价廉易得。首先,所设计的结构中保留传统花菁的共轭结构单元,并引入功能基团,再成环得目标分子。对其进行了结构表征,并研究了光物理性能和在荧光成像领域的应用。
发明内容
针对上述技术问题,本发明通过对花菁染料的推拉电子结构进行环化,限制其单、双键自由旋转;同时采用苯环取代单双键上的氢,可有效避免亲核试剂进攻,显著增强其化学稳定性,增大其荧光发射波长,并极大的提高荧光量子效率。该染料具有强的吸收和荧光发射性能,在织物着色、近红外荧光成像领域均具有良好的应用前景与发展潜力。为后续扩展新化合物、设计与制备高性能花菁染料提供了新研究思路及合成路线。
本发明提供一种环状结构花菁染料,该化合物的结构式为:
所述的环状结构花菁染料的合成方法包括如下步骤:
(1)在N2保护下,向反应瓶中加入CsF,Pd催化剂和KOH,室温条件下依次加入三苯基膦的甲苯溶液、间二甲苯、二(2-吡啶基)甲烷和溴苯衍生物,并加热至100-120℃回流反应2-5小时(优选为2~3h),得到的产物经有机溶剂萃取、干燥浓缩后得到二(2-吡啶基)-苯基甲烷衍生物;
(2)将步骤(1)中得到的二(2-吡啶基)-苯基甲烷中衍生物加入二溴甲烷,乙腈,K2CO3,并在氮气条件下回流过夜,得到的产物经冷却、旋蒸除去溶剂,柱层析提纯,得环状结构花菁染料。
所述的步骤(1)中所述的Pd催化剂为PdCl2(MeCN)2;即PdCl2与(MeCN)2形成的络合剂(J.R.Doyle,P.E.Slade,H.B.Jonassen.Inorg.Syn,1960,6,216-219.)。本发明的技术方案中三苯基膦也是实现反应过程的催化剂,在一些案例中发现当同时使用本案的Pd催化剂与三苯基膦时,其实现二(2-吡啶基)-苯基甲烷衍生物的这一中间产物的收率最高。单独使用本案的Pd催化剂时,也能实现本案的步骤(1)的反应,但催化效率略低于两种催化剂连用时的效率。但是当仅仅使用三苯基膦时,其催化效率令人极其不满意。
所述步骤(1)中有机溶剂为二氯甲烷、氯仿、乙酸乙酯的任意一种,优选二氯甲烷。
所述的步骤(1)中二(2-吡啶基)甲烷、溴苯衍生物的摩尔比为1:1.0-1.5;三苯基膦的添加量为原料摩尔总量的6%-8%;Pd催化剂的添加量为原料摩尔总量的2%-3%。
步骤(2)中所得到的二(2-吡啶基)-苯基甲烷衍生物与二溴甲烷、K2CO3的摩尔比为1:10-15:1-1.2。作为优选方案,所得到的二(2-吡啶基)-苯基甲烷衍生物与二溴甲烷、K2CO3的摩尔比为1:10:1。
本案中的又一核心关键性步骤是二溴甲烷与K2CO3的添加量。事实上,二溴甲烷的加入量为二(2-吡啶基)-苯基甲烷衍生物摩尔量的1倍时,几乎没有产物生成;加入5倍时,产率低于10%,只有在略过量的情况下(如二溴甲烷的加入量为二(2-吡啶基)-苯基甲烷衍生物摩尔量的10-15倍)时,其收率能提高到18%及以上。
当然,在不加K2CO3,亦可得到产物,但提纯后收率大致10%。
本发明的技术方案在已报道花菁染料的基础上,设计了一种新型环状结构的花菁化合物,采用核磁和高分辨率质谱对目标化合物进行表征。经光物理测试表明,化合物Cy1-Ph(R=H)具有较高的荧光量子效率和化学稳定性,并适用于对细胞进行染色和荧光成像。
附图说明
图1为实施例1制备得到的化合物Cy1-Ph(R=H)的核磁氢谱。
图2为实施例1制备得到的化合物Cy1-Ph(R=H)的核磁碳谱。
图3为实施例1制备得到的化合物Cy1-Ph的高分辨质谱。
图4为实施例1制备得到的化合物Cy1-Ph在不同溶剂中的吸收光谱。
图5为实施例1制备得到的化合物Cy1-Ph在不同溶剂中的荧光光谱。
图6为实施例1制备得到的化合物Cy1-Ph与商业化Cy3在加入亲核试剂(2-氨基苯硫酚)的化学稳定性对比。
图7为实施例1制备得到的化合物Cy1-Ph(2.5μm)对PANC-1染色后的荧光图像。
具体实施方式
实施例1
制备路线
制备方法
(1)在N2保护下,向反应瓶中加入CsF(0.61g,4mmol),PdCl2(MeCN)2(26mg,0.10mmol)和KOH(0.23g,4mmol),室温条件下依次加入三苯基膦(0.5mol/L,溶剂为甲苯,0.60mL,0.30mmol)、间二甲苯(4.0mL)、二(2-吡啶基)甲烷(340mg,2.0mmol)和溴苯(377mg,2.4mmol),并加热至120℃下回流3小时。冷却到室温后,水洗,二氯甲烷萃取,无水硫酸钠干燥,真空浓缩得到(2-吡啶基)-苯基甲烷衍生物(产率:75%);
(2)将步骤(1)中得到的二(2-吡啶基)-苯基甲烷中衍生物中加入二溴甲烷(3.50g,20.0mmol,10.0eq),乙腈(5.0mL),K2CO3(0.28g,2.0mmol,1.0eq)并回流过夜。冷却至室温后,旋蒸除去溶剂,柱层析提纯,得红色固体产物Cy1-Ph,产率18%。
1H NMR(400MHz,CDCl3):δ8.04(d,2H),7.57(m,5H),7.38(d,2H),6.95(t,2H),6.77(d,2H),6.19(s,2H)。13C NMR(100MHz,CDCl3):δ148.31,139.87,138.46,134.17,133.31,129.78,119.71,116.27,101.73,68.25。HRMS calcd for C18H15N2[M]+259.1230,found259.1229。氢谱、碳谱和质谱图如图1、2、3。
在本实施例的步骤(1)的另一合成过程中,只采用PdCl2(MeCN)2催化剂时,(2-吡啶基)-苯基甲烷衍生物的收率为75%
在本实施例的步骤(1)的另一合成过程中,只采用三苯基膦催化剂时,(2-吡啶基)-苯基甲烷衍生物的收率为0%
在本实施例的步骤(2)的另一合成过程中,不加K2CO3,亦可得到产物,Cy1-Ph提纯后收率为10%。
在本实施例的步骤(2)的另一合成过程中,二溴甲烷的加入量为1倍当量(2.0mmol)时,几乎没有Cy1-Ph产物生成;加入5倍当量(10.0mmol)时,Cy1-Ph产率低于10%。
实施例2
针对实施例1得到的化合物Cy1-Ph,分析其在不同溶剂中的荧光效果,测试步骤如下:将Cy1-Ph分别溶解于二氯甲烷、DMSO、甲醇中,配制浓度为1.0×10-5mol/L的溶液;再采用该溶液,利用紫外-可见分光光度计、荧光分光光度计测试所配制溶液的紫外-可见吸收光谱和荧光光谱,并以商业染料cy3为参照计算荧光量子效率(商业cy3在甲醇中的量子效率为2.4%,参考文献:王瑾瑾,花菁染料的合成及其应用探索,上海师范大学硕士论文,2019.)。
表1.化合物Cy1-Ph在不同溶剂中的光物理性质
对所制备的花菁染料在非极性溶剂中几乎不溶,因此在极性及中等极性溶剂中进行其光物理性质的测试。如图2和图3所示,化合物的最大吸收峰在580nm左右,其吸收波长几乎与溶剂的极性大小无关,但在极性溶剂中的摩尔吸光系数更高。而其荧光发射峰中心位于580nm左右,与商业化花菁染料cy3的发射波长接近。cy3有更长的共轭结构,推、拉电子之间的共轭链之间有3个,而我们所合成的Cy1-Ph中间1个,说明环状结构的花菁染料有利于增大荧光发射波长。同时,该化合物的荧光发射位置与与溶剂的极性大小无关。更为重要的是,该化合物具有较高的摩尔吸光系数及高的量子效率。常规的商业化花菁染料cy3在二氯甲烷中的量子效率不超过1%,而环状结构的cy1-Ph却接近80%,说明环状结构的花菁染料能极大的提高荧光量子效率。
实施例3
将Cy3、Cy1-Ph溶于DMSO,配制浓度为1.0×10-5mol/L的溶液;同时配制浓度为1.0×10-2mol/L的2-氨基苯硫酚的DMSO溶液。取3mL的染料溶液,逐渐加入一定比例的2-氨基苯硫酚溶液,分别测试加入前后的荧光光谱变化。
如图4所示,以商业化的Cy3作对照,对合成的两个化合物(1.0×10-5mol/L)进行了化学稳定性测试。我们通过加入不同当量的2-氨基苯硫酚后测试其荧光强度(I/I0)的变化,来对其化学稳定性进行评估。从图中可以看出环状结构的Cy1-Ph比商业化的Cy3染料具有更好的化学稳定性。
实施例4
将Cy1-Ph溶于1%的DMSO水溶液中,浓度为1.0×10-3mol/L。后往人源胰腺癌细胞PANC-1中加入2.5μM的染料,染色2小时后采用荧光显微镜拍照(λex=488nm)。
花菁染料Cy1-Ph有较好的水溶性、高的荧光量子效率及化学稳定性,适合做细胞成像的探针。将其溶于1%的DMSO中,采用较低的浓度(2.5μM)对人源胰腺癌细胞PANC-1进行染色,并用倒置荧光显微镜进行成像(λex=488nm)。如图5如示,花菁染料Cy1-Ph能很好的进入细胞,并发射强的红色荧光。
Claims (6)
3.根据权利要求2所述的环状结构花菁染料的合成方法,其特征在于,步骤(1)中所述的Pd催化剂为PdCl2与(MeCN)2形成的络合剂。
4.根据权利要求2所述的环状结构花菁染料的合成方法,其特征在于,步骤(1)中有机溶剂包括二氯甲烷、氯仿、乙酸乙酯的任意一种。
5.根据权利要求3所述的环状结构花菁染料中间体的合成方法,其特征在于,步骤(1)中二(2-吡啶基)甲烷、溴苯衍生物的摩尔比为1:1.0-1.5;三苯基膦的添加量为原料摩尔总量的6%-8%;Pd催化剂的添加量为原料摩尔总量的2%-3%。
6.根据权利要求2所述的环状结构花菁染料的制备方法,其特征在于,步骤(2)中所得到的二(2-吡啶基)-苯基甲烷衍生物与二溴甲烷、K2CO3的摩尔比为1:10-15:1-1.2。
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