CN110759890B - 诺蒎烷基吲唑类银离子荧光探针及其制备方法 - Google Patents
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Abstract
本发明公开了一种诺蒎烷基吲唑类银离子荧光探针及其制备方法。本发明利用天然可再生资源β‑蒎烯衍生物诺蒎酮为原料,诺蒎酮与2‑吡啶甲酸甲酯进行克莱森缩合反应,制得3‑(2′‑吡啶甲酰基)诺蒎酮;3‑(2′‑吡啶甲酰基)诺蒎酮再与苯肼缩合环化,得到诺蒎烷基吲唑类化合物6,6‑二甲基‑2‑苯基‑3‑(2′‑吡啶基)‑4,5,6,7‑四氢‑2H‑5,7‑桥亚甲基吲唑。该化合物作为专一性荧光探针分子在检测银离子方面具有很好的应用。
Description
技术领域
本发明属精细有机合成技术领域,涉及诺蒎烷基吲唑类荧光探针分子及其制备方法和在检测银离子方面的应用。
背景技术
含银化合物作为一种分布广泛的资源大量应用于许多工业生产活动中,例如冶金行业、制药行业、电镀行业、食品行业。每年,含有大量银离子的工业污水流入河流湖泊中,而低浓度的银离子积累在海洋生物中,对作为食物链顶端的人类造成伤害。银离子对人类的神经***、肝脏、骨骼造成严重的影响,引起许多疾病的发生。因此银离子被定为毒性最高的一类金属离子。因此开发选择性高、灵敏性高的探测Ag+的方法,对于疾病病理学研究和环境保护具有重要的意义。
截止到目前为止,许多方法应用到Ag+的探测方面,例如:碘量滴定发,电化学分析发,原子吸收/发射光谱发,等离子体质谱法和荧光分析法。在这些分析方法中荧光分析方法作为一种简单的、快速的、高选择性、高灵敏性的方法被广泛使用于生物体内的离子检测。近年有许多关于有机荧光探针的合成和应用于Ag+检测的报道,例如:在2017年,以2,6-二苯基吡啶为结构用于Ag+的检测荧光探针被报道。同年,以乙酰硫脲为结构的Ag+荧光探针被报道。2017年,第一次应用石墨烯半导体量子点制作Ag+探针。因此用于Ag+检测的新型探针的合成也是一项重要的科学挑战。
同时,近年来也出现许多吡唑类化合物作为荧光探针的报道,例如:肼探针、Mn2+、Zn2+探针、F-探针、Zn2+探针、Fe3+探针。但没有关于诺蒎烷基吲唑类化合物应用于Ag+检测的报道。
发明内容
发明目的:针对现有技术中存在的不足。本发明的目的是提供一种诺蒎烷基吲唑类化合物的制备方法。本发明另一目的是提供该化合物在银离子低浓度下的检测应用。
技术方案:为实现上述发明目的,本发明采用的技术方案为:
诺蒎烷基吲唑类化合物,该化合物的结构式为:
所述的诺蒎烷基吲唑类化合物的制备方法,包括如下工艺步骤:
1)诺蒎酮与2-吡啶甲酸甲酯进行克莱森缩合反应,得到3-(2′-吡啶甲酰基)诺蒎酮。
2)3-(2′-吡啶甲酰基)诺蒎酮与苯肼进行缩合环化,得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑。
步骤1)中,诺蒎酮与2-吡啶甲酸甲酯进行克莱森缩合反应,具体的制备方法包括:
(1)将0.06mol氢化钠加入配有搅拌器、温度计和回流冷凝器的三口烧瓶中,氮气保护下缓慢注入8mL乙二醇二甲醚,0.02mol诺蒎酮溶于9mL乙二醇二甲醚后氮气保护下缓慢注入烧瓶中,升温控制反应温度在82℃,加热回流0.5h,0.024mol吡啶甲酸甲酯溶于9mL乙二醇二甲醚后氮气保护下缓慢注入烧瓶中,薄层色谱法跟踪反应进程,反应7~8h;
(2)反应液用100mL乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗涤至中性;有机相经无水硫酸钠干燥、过滤、浓缩回收溶剂,得到3-(2′-吡啶甲酰基)诺蒎酮粗产物;
(3)3-(2′-吡啶甲酰基)诺蒎酮粗提物经过柱层析(100~200目硅胶,洗脱液石油醚/乙酸乙酯比为10∶1),得到3-(2′-吡啶甲酰基)诺蒎酮。
步骤2)中,在10%醋酸作用下,3-(2′-吡啶甲酰基)诺蒎酮与苯肼进行缩合环化,制得6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑,具体的制备方法包括:
(1)将0.02mol 3-(2′-吡啶甲酰基)诺蒎酮、0.04mol苯肼、1ml10%醋酸和20mL乙醇依次加入配有搅拌器、温度计和回流冷凝器的三口烧瓶中,在回流状态下反应7~8h,用薄层色谱法跟踪反应进程。
(2)反应液用150~300mL乙酸乙酯萃取3次,合并萃取液,用蒸馏水洗涤至中性,再用饱和食盐水洗涤1次,有机相经无水硫酸钠干燥、过滤、浓缩回收溶剂,得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑粗产物;
(3)6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑粗产物经柱层析(100~200目硅胶,洗脱液石油醚/乙酸乙酯比为6∶1),得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑。
所述的诺蒎烷基吲唑类化合物能与银离子进行专一性络合,在365nm紫外光下溶液的荧光颜色由蓝色变为绿色,可用作银离子的荧光检测。荧光强度与银离子的浓度(在1.0-18×10-6M范围内)呈现线性关系,y=28.46x+306.49(R2=0.9927)。该化合物检测Ag+的最低浓度为:1.74×10-7M。
有益效果:与现有技术相比,本发明的利用天然可再生资源β-蒎烯衍生物诺蒎酮为原料制备新型的诺蒎烷基吲唑类化合物,该化合物对银离子具有选择性络合作用,溶液的荧光颜色由蓝色变为绿色,而且荧光强度与银离子的浓度(在1.0-18×10-6M范围内)呈现线性关系。该化合物可作为专一性荧光探针分子在检测银离子方面的具有很好的应用。
附图说明
图1为不同金属离子对6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑的荧光光谱影响图;
图2为不同外加金属离子对6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑与银离子形成的络合物的荧光强度的影响图;
图3为不同浓度的银离子对6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑的荧光光谱的影响图;
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
实施例1
诺蒎烷基吲唑类化合物的制备过程为:
具体步骤如下:
1)3-(2′-吡啶甲酰基)诺蒎酮的制备:
将0.06mol氢化钠加入配有搅拌器、温度计和回流冷凝器的三口烧瓶中,氮气保护下缓慢注入8mL乙二醇二甲醚,0.02mol诺蒎酮溶于9mL乙二醇二甲醚后氮气保护下缓慢注入烧瓶中,升温控制反应温度在82℃,加热回流0.5h,0.024mol吡啶甲酸甲酯溶于9mL乙二醇二甲醚后氮气保护下缓慢注入烧瓶中,薄层色谱法跟踪反应进程,反应7-8h。反应液用100mL乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗涤至中性,有机相经无水硫酸钠干燥、过滤、浓缩回收溶剂,得到3-(2′-吡啶甲酰基)诺蒎酮粗产物,经柱层析纯化(100~200目硅胶,洗脱液石油醚/乙酸乙酯比为10∶1),得到3-(2′-吡啶甲酰基)诺蒎酮。1H NMR(400MHz,CDCl3)δ:15.58(s,1H),8.68(dd,J=4.9,1.7Hz,1H),8.00(d,J=8.0Hz,1H),7.88~7.72(m,1H),7.35~7.30(m,1H),3.28~2.95(m,2H),2.59(dt,J=22.5,5.4Hz,2H),2.32(qt,J=5.9,2.6Hz,1H),1.49(d,J=9.9Hz,1H),1.35(s,3H),0.96(s,3H).13C NMR(100MHz,CDCl3)δ:209.55,169.51,150.69,149.01,135.67,131.29,123.24,104.89,54.84,39.77,39.61,28.07,27.66,25.79,21.54.HRMS(m/z):[M+H]+ calculated for C15H17NO2+H+,244.1259;found,244.1335。
2)诺蒎烷基吲唑类化合物的制备:
将0.02mol 3-(2′-吡啶甲酰基)诺蒎酮、0.04mol苯肼、1ml 10%醋酸和20mL乙醇依次加入配有搅拌器、温度计和回流冷凝器的三口烧瓶中,在回流状态下反应7~8h,用薄层色谱法跟踪反应进程。反应物用150~300mL乙酸乙酯萃取3次,合并萃取液,用蒸馏水洗涤至中性,再用饱和食盐水洗涤1次,有机相经无水硫酸钠干燥、过滤、浓缩回收溶剂,得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑粗产物,再经过柱层析纯化(100~200目硅胶,洗脱液石油醚/乙酸乙酯比为6∶1),得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑。1H NMR(400MHz,DMSO)δ:8.57~8.50(m,1H),7.81(ddt,J=7.8,5.6,1.9Hz,1H),7.38~7.32(m,2H),7.27~7.23(m,1H),7.19~7.15(m,4H),3.51~3.11(m,1H),2.87~2.76(m,2H),2.53~2.50(m,1H),2.29(dd,J=5.8,3.0Hz,1H),1.43~1.34(m,4H),0.74(d,J=3.3Hz,3H).13C NMR(100MHz,CDCl3)δ:153.67,150.00,149.37,148.36,139.50,136.13,129.08,127.16,124.01,121.86,120.74,113.46,41.79,41.37,41.08,32.28,27.02,26.32,21.69.HRMS(m/z):[M+H]+calculatedfor C21H21N3+H+,316.1785;found,316.1811。
实施例2
将固体6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑和不同的金属离子溶于4-羟乙基哌嗪乙磺酸(HEPES)缓冲溶液(20mM,pH=7.2,7/3(v/v)乙醇/水)中,配制成探针化合物浓度为1×10-6M和Ag+浓度均为1×10-5M的19种溶液。在激发波长为320nm的条件下测得不同金属离子存在下的荧光强度变化,如图1所示。结果表明,化合物对Ag+具有很强的荧光增强作用,最大吸收波长由455nm红移到505nm,紫外灯下荧光颜色由蓝色变成绿色,说明该化合物对Ag+具有较好的选择性。
实施例3
将配置好的6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑(1×10-6M)+Ag+(1×10-5M)的溶液(HEPES缓冲液,10mM,pH=7.2,50%(v/v)C2H5OH)中分别加入与Ag+等摩尔量的K+,Na+,Mg2+,Fe2+,Fe3+,Mn2+,Ca2+,Al3+,Pb2+,Cr2+,Co2+,Zn2+,Bi3 +,Ni2+,Pb2+,Cu2+,Sn2+,Ba2+,Ag+,在激发波长为320nm的条件下测得荧光光谱,结果如图2所示。当加入其他金属离子时,6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑-Ag+络合物的荧光强度未受到影响,说明其他金属离子未对化合物检测Ag+造成影响。
实施例4
将6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑溶于HEPES缓冲液(pH=7.4,10mM,50%(v/v)乙醇),配制成浓度为1×10-6M的溶液,同样将Ag+溶于HEPES缓冲溶液配成浓度为0、1、2、4、6、8、10、12、14、16、18、20、22×10-6M的溶液。测得不同浓度的Ag+对6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑的荧光光谱,如图3所示。结果表明,化合物在505nm左右的荧光强度明显增强,最大吸收波长由455nm红移到505nm,说明6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑可以作为检测Ag+的荧光探针。
Claims (5)
2.权利要求1所述的诺蒎烷基吲唑类化合物的制备方法,包括如下步骤:
1)诺蒎酮与2-吡啶甲酸甲酯进行克莱森缩合反应,得到3-(2′-吡啶甲酰基)诺蒎酮;
2)3-(2′-吡啶甲酰基)诺蒎酮与苯肼进行缩合环化,得到诺蒎烷基吲唑类化合物6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑。
3.根据权利要求2所述的诺蒎烷基吲唑类化合物的制备方法,其特征在于,步骤1)中,诺蒎酮与2-吡啶甲酸甲酯进行克莱森缩合反应得到3-(2′-吡啶甲酰基)诺蒎酮,具体的制备方法包括:
(1)将0.06mol氢化钠加入配有搅拌器、温度计和回流冷凝器的三口烧瓶中,氮气保护下缓慢注入8mL乙二醇二甲醚,0.02mol诺蒎酮溶于9mL乙二醇二甲醚后氮气保护下缓慢注入烧瓶中,升温控制反应温度在82℃,加热回流0.5h,0.024mol 2-吡啶甲酸甲酯溶于9mL乙二醇二甲醚后氮气保护下缓慢注入烧瓶中,薄层色谱法跟踪反应进程,反应7~8h;
(2)反应液用100mL乙酸乙酯萃取3次,合并有机相,用饱和食盐水洗涤至中性;有机相经无水硫酸钠干燥、过滤、浓缩回收溶剂,得到3-(2′-吡啶甲酰基)诺蒎酮粗产物;
(3)3-(2′-吡啶甲酰基)诺蒎酮粗产物经柱层析,得到3-(2′-吡啶甲酰基)诺蒎酮。
4.根据权利要求2所述的诺蒎烷基吲唑类化合物的制备方法,其特征在于,步骤2)的制备方法包括:
(1)将0.02mol 3-(2′-吡啶甲酰基)诺蒎酮、0.04mol苯肼、1ml 10%醋酸和20mL乙醇依次加入配有搅拌器、温度计和回流冷凝器的三口烧瓶中,在回流状态下反应7~8h,用薄层色谱法跟踪反应进程;
(2)反应液用150~300mL乙酸乙酯萃取3次,合并萃取液,用蒸馏水洗涤至中性,再用饱和食盐水洗涤1次,有机相经无水硫酸钠干燥、过滤、浓缩回收溶剂,得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑粗产物;
(3)6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑粗产物经柱层析,得到6,6-二甲基-2-苯基-3-(2′-吡啶基)-4,5,6,7-四氢-2H-5,7-桥亚甲基吲唑。
5.权利要求1所述的诺蒎烷基吲唑类化合物在制备检测银离子荧光探针中的应用,其特征在于,该化合物与银离子进行专一性络合,在365nm紫外光下溶液的荧光颜色由蓝色变为绿色。
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