微流控芯片在两相有机合成中的应用研究
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摘要
微流控学(Microfluidics)是在微米级结构中操控纳升至皮升体积流体的技术与科学，是近十年来迅速崛起的新交叉学科。流体在微流控芯片微米级通道中，由于尺度效应导致了许多不同于宏观体系的特点，促进了微流控芯片在有机合成反应中的发展。
第一章将对微流控芯片微反应器的特点、微流控芯片反应器中常用的流体驱动技术、微通道中流体的混合及在有机合成反应中的研究现状进行综述。
第二章首次在玻璃流流控芯片中进行了Claisen-Schmidt缩合反应的研究，讨论了两相间的接触面积对反应速率和转化率的影响。实验表明，在相同实验条件下，微流控芯片中合成苄叉丙酮得到转化率比常规反应容器高，且反应时间短。在宽度分别为300μm和500μm微通道中反应8 min，苯甲醛的转化率分别能达到94％和80％。而在玻璃烧瓶中，快速搅拌下反应8 min，转化率还不到60％。实验中观察到，在相同流速下，不互溶两相在通道内形成的流形与通道尺寸有关，通道尺寸小(300μm)易形成塞流，通道尺寸宽(500μm)易形成层流，塞流比层流转质速度快。实验结果表明，在微流控芯片中进行有机合成反应的研究，具有反应速度快，试剂消耗量少，实验室污染轻等优点。
第三章首次提出了采用负压进样装置控制反应物以低流量通过微通道进行合成反应的进样方法，克服目前微量注射泵设备昂贵和电渗泵输液量难以控制等缺点。研制了一种密闭性能良好的接口。负压进样装置由一个微型真空泵，一个负压瓶，一个电接点真空表，以及微型调节阀和接口组成。大大简化了在微流控芯片上进行有机合成反应的进样设备。在玻璃微流控芯片中进行了对甲氧基苯甲醛和盐酸羟胺反应生成对甲氧基苯甲醛肟的相转移反应，测定了反应时间对转化率的影响，并与常规方法进行了比较。实验结果说明了负压进样结合微流控芯片进行合成研究具有价廉，流量稳定等优点。
第四章系统地研究了流体流速、微通道宽度和进样通道构形对微流控芯片内不互溶液-液两相流体流形的综合影响。实验结果说明，目前常用的毛细管数(Ca)不能准确地说明不相互溶两相流体在微通道内的流形。首次报道了除Ca外，流体在微流控玻璃芯片通道内形成的流形还和通道尺寸、通道构形有关。通过对芯片进样通道构形的不断优化，使形成塞流的微通道宽度和流体的临界流速大大增加，从而加快了不互溶两相间的传质速度。实验结果说明，在宽度500μm的带部分细管双T和十字型微通道内，两相间的传质速度比Y型微通道中快13-15倍。在微通道中用环己酮和盐酸羟胺为原料合成环己酮肟，在50mm／s的流速下反应18 s，在Y形芯片上得到产物的转化率为20％，而在带部分细管的十字形芯片上转化率高达70％。
第五章首次在装有C18的微流控芯片反应器中进行了Edman降解反应，用顺序注射系统提高了Edman降解的自动化程度。对固体吸附材料的选择、顺序注射程序的设计和优化、影响Edman降解反应的因素进行讨论。实验结果说明在微流控芯片反应器中进行Edman降解反应，具有需要试剂和样品量少，反应速度快等特点，可以得到蛋白质或多肽N-端氨基酸残基结构的准确信息，在蛋白质组学的研究中有一定的应用前景。
Microfluidics is the science and technology of systems that process or manipulate small (10~(-9) to 10~(-18) litres) amounts of fluids, using channels with dimensions of tens to hundreds of micrometres. Compared to macroscale laboratory techniques, microfluidic reactors have a number of advantages over conventional chemical processes, which would be expected to promote highly effective chemical reactions in the microchip.
In the chapter 1, the main feature of microfluidic reactors、the method to drive liquid through the microchannels, the method for mixing liquids in microchennels and the organic synthesis reactions carried out in microfluidics reactors were reviewed.
In the chapter 2, the Claisen-Schmidt reaction was carried out in glass microfluidic chips with two Y-shaped inlets. The effect of interfacial area on the rate of phase transfer reaction was studied and discussed. 93% and 80 conversions were obtained after 8 min reaction in microchannels in width of 300 and 500μm, respectively. In comparison, 60% conversion was obtained in a bulk reaction with vigorous stirring. Even the reaction time was doubled to 16 min, only 73% conversion could be achieved. It has been observed that by introducing the reactants into microchannels at the same linear flow rate of 12.0 cm/min, slug flow was formed reproducibly in the 300-μm wide microchannel and laminar flow was formed in the 500-μm wide microchannel. Slug flow provides faster mass transfer than laminar flow. The demonstrated advantages of organic synthesis in microfluidic chip included faster reaction rate, less consumption of reactants and labor contaminant, which proved microfluidic chip to be a powerful tool for synthetic applications.
In the chapter 3, a novel experiment system and method for organic synthesis in a microfluidic chip was developed, in which a negative pressure delivery device was used to drive reactants through the microchannels at a constant low flow rate. The negative pressure delivery device consists of a micro-vacuum air pump, a buffer vessel, a regulating value, a vacuum gauge and a newly developed interface to ensure airtight. The phase-transfer reaction for synthesis of 4-methoxy- benzaldehyde oxime from 4-methoxybenzaldehyde and hydroxylammonium chloride was carried out in glass microfluidic chips by using the developed negative pressure system. The effect of reaction time on yield was determined and compared with the standard batch system. The developed experiment system and method for organic synthesis in a microfluidic chip has been proved to be easy to operation, flow-stable and inexpensive, compared to the conventional sampling methods, such as using micro-pump and electroosmotic flow.
In the chapter 4, the effect of flow rate, dimension of the microchannels and inlet shape of the microfluidic chip on the flow pattern inside the microchannel was systematically studied. It has been found that not only Capillary number, which was usually used to characterize the flow pattern inside the microchannel, but also dimension of the microchannels and inlet shape of the microfluidic chip also affect the flow pattern. Experiments showed that slug flow offers a simple method of achieving rapid mixing. It was easy to form slug flow in the smaller channels and low flow velocity. By optimization of the inlet shape of the microchannels, the threshold velocity for forming slug flow in the larger (500μm in width) channels has greatly improved. Rapid mass transfer between organic and aqueous phases in optimized microfluidic reactors with double T and crossing inlets was realized, which is 13-15 fold faster than conventional reactors with Y inlet. 70% conversion for synthesis of cyclohexane oxime from cyclohexanone and hydroxylammonium chloride was obtained after 18 s reaction at the flow rate of 50 mm/s in large microchannels (500μm in width) in the suggested microfludic reactors. In comparison, only 20% conversion was obtained in the conventional reactors with Y inlet.
In the chapter 5, Edman degradation reaction was carried out in microfluidic chip packed with C18 beads as reaction cartridge, which was automatically manipulated by a sequential injection system. The program for sequential injection system, the column material for adsorption of protein or peptide and the temperature for Edman degradation reaction were optimized. Experiment results showed that the N-terminal residue of protein or peptide can be obtained by Edman degradation in microfluidic chip with the advantages of faster reaction rate, less consumption of protein or peptide.
第一章将对微流控芯片微反应器的特点、微流控芯片反应器中常用的流体驱动技术、微通道中流体的混合及在有机合成反应中的研究现状进行综述。
第二章首次在玻璃流流控芯片中进行了Claisen-Schmidt缩合反应的研究，讨论了两相间的接触面积对反应速率和转化率的影响。实验表明，在相同实验条件下，微流控芯片中合成苄叉丙酮得到转化率比常规反应容器高，且反应时间短。在宽度分别为300μm和500μm微通道中反应8 min，苯甲醛的转化率分别能达到94％和80％。而在玻璃烧瓶中，快速搅拌下反应8 min，转化率还不到60％。实验中观察到，在相同流速下，不互溶两相在通道内形成的流形与通道尺寸有关，通道尺寸小(300μm)易形成塞流，通道尺寸宽(500μm)易形成层流，塞流比层流转质速度快。实验结果表明，在微流控芯片中进行有机合成反应的研究，具有反应速度快，试剂消耗量少，实验室污染轻等优点。
第三章首次提出了采用负压进样装置控制反应物以低流量通过微通道进行合成反应的进样方法，克服目前微量注射泵设备昂贵和电渗泵输液量难以控制等缺点。研制了一种密闭性能良好的接口。负压进样装置由一个微型真空泵，一个负压瓶，一个电接点真空表，以及微型调节阀和接口组成。大大简化了在微流控芯片上进行有机合成反应的进样设备。在玻璃微流控芯片中进行了对甲氧基苯甲醛和盐酸羟胺反应生成对甲氧基苯甲醛肟的相转移反应，测定了反应时间对转化率的影响，并与常规方法进行了比较。实验结果说明了负压进样结合微流控芯片进行合成研究具有价廉，流量稳定等优点。
第四章系统地研究了流体流速、微通道宽度和进样通道构形对微流控芯片内不互溶液-液两相流体流形的综合影响。实验结果说明，目前常用的毛细管数(Ca)不能准确地说明不相互溶两相流体在微通道内的流形。首次报道了除Ca外，流体在微流控玻璃芯片通道内形成的流形还和通道尺寸、通道构形有关。通过对芯片进样通道构形的不断优化，使形成塞流的微通道宽度和流体的临界流速大大增加，从而加快了不互溶两相间的传质速度。实验结果说明，在宽度500μm的带部分细管双T和十字型微通道内，两相间的传质速度比Y型微通道中快13-15倍。在微通道中用环己酮和盐酸羟胺为原料合成环己酮肟，在50mm／s的流速下反应18 s，在Y形芯片上得到产物的转化率为20％，而在带部分细管的十字形芯片上转化率高达70％。
第五章首次在装有C18的微流控芯片反应器中进行了Edman降解反应，用顺序注射系统提高了Edman降解的自动化程度。对固体吸附材料的选择、顺序注射程序的设计和优化、影响Edman降解反应的因素进行讨论。实验结果说明在微流控芯片反应器中进行Edman降解反应，具有需要试剂和样品量少，反应速度快等特点，可以得到蛋白质或多肽N-端氨基酸残基结构的准确信息，在蛋白质组学的研究中有一定的应用前景。
Microfluidics is the science and technology of systems that process or manipulate small (10~(-9) to 10~(-18) litres) amounts of fluids, using channels with dimensions of tens to hundreds of micrometres. Compared to macroscale laboratory techniques, microfluidic reactors have a number of advantages over conventional chemical processes, which would be expected to promote highly effective chemical reactions in the microchip.
In the chapter 1, the main feature of microfluidic reactors、the method to drive liquid through the microchannels, the method for mixing liquids in microchennels and the organic synthesis reactions carried out in microfluidics reactors were reviewed.
In the chapter 2, the Claisen-Schmidt reaction was carried out in glass microfluidic chips with two Y-shaped inlets. The effect of interfacial area on the rate of phase transfer reaction was studied and discussed. 93% and 80 conversions were obtained after 8 min reaction in microchannels in width of 300 and 500μm, respectively. In comparison, 60% conversion was obtained in a bulk reaction with vigorous stirring. Even the reaction time was doubled to 16 min, only 73% conversion could be achieved. It has been observed that by introducing the reactants into microchannels at the same linear flow rate of 12.0 cm/min, slug flow was formed reproducibly in the 300-μm wide microchannel and laminar flow was formed in the 500-μm wide microchannel. Slug flow provides faster mass transfer than laminar flow. The demonstrated advantages of organic synthesis in microfluidic chip included faster reaction rate, less consumption of reactants and labor contaminant, which proved microfluidic chip to be a powerful tool for synthetic applications.
In the chapter 3, a novel experiment system and method for organic synthesis in a microfluidic chip was developed, in which a negative pressure delivery device was used to drive reactants through the microchannels at a constant low flow rate. The negative pressure delivery device consists of a micro-vacuum air pump, a buffer vessel, a regulating value, a vacuum gauge and a newly developed interface to ensure airtight. The phase-transfer reaction for synthesis of 4-methoxy- benzaldehyde oxime from 4-methoxybenzaldehyde and hydroxylammonium chloride was carried out in glass microfluidic chips by using the developed negative pressure system. The effect of reaction time on yield was determined and compared with the standard batch system. The developed experiment system and method for organic synthesis in a microfluidic chip has been proved to be easy to operation, flow-stable and inexpensive, compared to the conventional sampling methods, such as using micro-pump and electroosmotic flow.
In the chapter 4, the effect of flow rate, dimension of the microchannels and inlet shape of the microfluidic chip on the flow pattern inside the microchannel was systematically studied. It has been found that not only Capillary number, which was usually used to characterize the flow pattern inside the microchannel, but also dimension of the microchannels and inlet shape of the microfluidic chip also affect the flow pattern. Experiments showed that slug flow offers a simple method of achieving rapid mixing. It was easy to form slug flow in the smaller channels and low flow velocity. By optimization of the inlet shape of the microchannels, the threshold velocity for forming slug flow in the larger (500μm in width) channels has greatly improved. Rapid mass transfer between organic and aqueous phases in optimized microfluidic reactors with double T and crossing inlets was realized, which is 13-15 fold faster than conventional reactors with Y inlet. 70% conversion for synthesis of cyclohexane oxime from cyclohexanone and hydroxylammonium chloride was obtained after 18 s reaction at the flow rate of 50 mm/s in large microchannels (500μm in width) in the suggested microfludic reactors. In comparison, only 20% conversion was obtained in the conventional reactors with Y inlet.
In the chapter 5, Edman degradation reaction was carried out in microfluidic chip packed with C18 beads as reaction cartridge, which was automatically manipulated by a sequential injection system. The program for sequential injection system, the column material for adsorption of protein or peptide and the temperature for Edman degradation reaction were optimized. Experiment results showed that the N-terminal residue of protein or peptide can be obtained by Edman degradation in microfluidic chip with the advantages of faster reaction rate, less consumption of protein or peptide.
引文
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