【作者】 张景；

【导师】 董泽元；

【作者基本信息】 吉林大学 ， 高分子化学与物理， 2022， 博士

【摘要】 自组装过程在自然界中以各种各样的形式出现,从分子水平上的蛋白质折叠和脂双层的形成,再到地球上整个生物系统的建立,自组装过程均贯穿其中。生物体通过非共价相互作用将多种不同的构筑基元组装到一起,形成具有特定结构和功能的生物大分子,例如核酸(DNA、RNA),蛋白质和多肽等。而这些天然的生物大分子,它们都具有极其复杂但精确的空间立体结构,这些复杂但是精密的结构既离不开自组装过程的精准控制,又赋予了生物大分子特殊的性质和独特的功能。其中,作为重要遗传物质的脱氧核糖核酸(DNA)承载着生命体的遗传信息,DNA碱基序列在配对过程中的任何变化都可能会给识别、复制和传递过程带来不精确性,进而可能会影响到人体的正常功能的发挥。受自然界启发,长期以来,科学家们一直渴望利用自组装的手段来实现人造物体的非共价精准合成,以达到甚至超越生物大分子的高度复杂性和特定功能性,这就需要对构筑基元进行精确的设计,对自组装过程进行精准的控制。对于人工合成的体系而言,实现复杂且有序的结构的精准合成仍然存在着很大的挑战。目前,大多数研究采用的是通过共价合成的方法实现精准合成,例如点击化学的方法之所以备受化学家们的推崇是因为这种方法具有高效率和高选择性的优势,但是这种方法只适用于极少数的反应。相比之下,基于非共价作用的合成具有方法多种多样、构筑基元简单、容易合成和功能化等一系列优点。本论文的研究内容是基于非共价相互作用的精准合成。在众多的非共价相互作用中,金属配位作用由于键能强和明确的方向性,在大多数情况下被用来作为驱动力组装形成有序的结构。然而,在生命系统内,只有很少量的金属元素存在,氢键是构成蛋白质、核酸、多糖等生物大分子的基本作用力,可以说,分子之间的识别和作用过程都离不开氢键的参与。DNA中的鸟嘌呤(G)与胞嘧啶(C)两个碱基之间通过三重氢键作用进行配对,腺嘌呤(A)与胸腺嘧啶(T)之间通过二重氢键作用进行碱基配对,最终形成双螺旋结构。氢键作用具有显著的方向性、可逆性和饱和性,以及一定的结合强度,可以作为组装的驱动力用于复杂的、具有特定结构和功能的超分子体系的构筑。抱着向生物体系学习的态度,化学家们构建了一系列多重氢键自组装体系。但是,多重氢键自组装体系的稳定性往往会受到多种因素的影响,比如氢键位点的数目、二级静电相互作用、氢键单元的变构等。组装基元是自组装结构的分子基础,组装基元的结构稳定性与精确性会直接影响到自组装结构的精准合成。因此,我们希望能够找到有效的方法来解决控制多重氢键驱动力的稳定性问题,发展出多重氢键作用位点精确排列的组装基元,为精准超分子结构的构筑提供基于多重氢键的非共价合成工具。具体的工作内容如下:1.控制多重氢键实现超分子结构精准化多重氢键体系中的脲基嘧啶酮(UPy)体系,由于该体系有一定的互补性,并且具有原料廉价易得、合成简单、容易衍生、结合能力强等多个优点,因此,UPy分子作为一种重要的构筑基元可以通过多重氢键驱动力来构建各种超分子结构。同时,该体系具有一个不可忽略的重要特征,那就是在非极性或弱极性溶剂中,存在着由两种不同的质子互变异构体形成的氢键二聚体的平衡,分别是4[1H]-嘧啶酮异构体和嘧啶-4-醇异构体,前者通过自互补的四重氢键作用形成DDAA-AADD型二聚体,后者则形成DADA-ADAD型二聚体。由于这类体系中酮-烯醇互变异构现象的固有存在,使得基于这种构筑基元所构建的超分子组装体中不可避免地存在各种互变异构体,这就无法保证超分子结构的精准合成,给研究带来很多复杂的问题。在这一部分工作中,我们提出了一种合理并且简单的超分子策略来预组织UPy分子的二聚行为,即利用分子内氢键作用来限制质子的分子内移动,解决酮-烯醇互变异构问题,固定氢键位点以特定的方式排列,得到的UPy衍生物1完全以酮式结构形成DDAA-AADD型氢键复合物。根据Jorgensen的二级静电作用理论,以DDAA-AADD型四重氢键作用的二聚体由于具有两重净吸引的二级静电作用,要比DADA-ADAD型二聚体表现出更高的稳定性和更强的结合能力。之后,我们合成了含有两个分子1的构筑基元5,我们发现构筑基元5在溶液中完全通过DDAA-AADD四重氢键作用形成明确的超分子结构。而没有分子内氢键作用来稳定结构的参比分子则表现出了更复杂的聚集行为。在这里,我们控制UPy体系多重氢键作用位点的精确排列,为构筑精准的超分子结构提供了明确的非共价合成工具。2.基于多重氢键构筑水介质中二维组装体除了DDAA-AADD型四重氢键体系外,另外一类具有DADA-ADAD型氢键位点的自互补四重氢键体系也常被用来构建超分子结构。在上一部分工作中,我们成功地利用超分子策略控制了UPy体系的DDAA-AADD二聚。在上一部分工作的基础上,我们希望能够利用同样的策略实现单一的DADA-ADAD四重氢键作用模式。于是,在这部分工作中,我们通过分子内氢键作用有效地控制了UPy分子的烯醇式互变异构体,无论是在溶液中还是固态下,都完全形成DADAADAD型氢键复合物。与第一部分工作不同的是,我们在这里得到的UPy衍生物不仅可以通过精确控制的四重氢键作用发生二聚,还可以与引入的芳香基团经历π-π作用从而稳定氢键作用的二聚。目前,大多数基于氢键作用的研究是在有机溶剂中进行的,这是因为水分子作为一种竞争分子会严重地干扰自组装过程。为了实现结构的精确控制和高度稳定,许多重要的生物过程(例如DNA组装、蛋白质折叠)都会通过形成疏水区域来保护方向性的氢键作用不受水分子的影响。令人激动的是,我们发现在这部分工作中设计合成的烯醇式单体分子在自组装的过程中会不断地形成类似于“三明治”结构的区域,四重氢键作用正好被包埋在芳香堆积形成的疏水区域内发生二聚,从而躲避水分子的干扰。研究表明,我们发展出了多重氢键作用位点精确排列的构筑基元,进一步实现了水介质中多重氢键驱动的稳定有序组装,为在水中基于氢键的精确组装提供了有效策略。3.氢键驱动的二维单层结构的可控组装二维单层纳米结构是一类重要的材料,具有大的比表面积和丰富的活性位点,有着多种潜在的应用。在没有模板或者受限空间的情况下,制备单层的二维纳米结构仍然是一个挑战。在前面一部分工作中,我们提供了结构明确的多重氢键基元,实现了片层结构的精准构筑。在这部分工作中,我们希望可以通过控制多重氢键驱动力的方向来操控组装过程,构筑具有特定空间排列的单层自组装结构。于是,我们以2,5-双(氨基)对苯二甲酸酯为前驱体,其晶体结构显示,存在很强的分子内和分子间氢键相互作用,在此基础上我们在两端引入亮氨酸部分来提供另一个方向上的氢键驱动力,设计合成了分子1。分子1作为构筑基元在自组装的过程中,其氢键驱动力具有特定的空间取向,可以沿x轴和y轴两个方向组装形成具有特定空间排列的二维单层结构。通过各种显微成像的研究以及和参比分子的自组装结构进行对比,说明在自组装过程中通过控制氢键驱动力的空间取向,能够实现二维单层结构的可控组装。在这部分工作中我们构建的这种单层纳米片具有较大的比表面积,为进一步的化学修饰和功能化提供了充足的空间。更多还原

【Abstract】 Self-assembly occurs in nature in various forms,from protein folding and lipid bilayer formation at the molecular level to establishing entire biological systems on Earth.Organisms assemble diverse building blocks through non-covalent interactions to form biological macromolecules with specific structures and functions,such as nucleic acids(DNA,RNA),proteins,and polypeptides.These natural biological macromolecules all have extremely complex but precise spatial structures.These delicate structures are indispensable from the precise control of the self-assembly process,and endow the biological macromolecules with special properties and unique functions.Among them,deoxyribonucleic acid(DNA),as a crucial genetic material,carries the genetic information of living organisms.Any changes in the DNA base sequence pairing process will bring inaccuracy to the process of identification,replication,and transmission,which may affect the normal function of the human body.Inspired by nature,scientists have long been eager to achieve the non-covalent and precise synthesis of artificial objects by employing self-assembly,so as to reach or even surpass the high complexity and specific functionality of biological macromolecules,which require the delicate design of building elements and precise control of the selfassembly process.For synthetic systems,achieving precise synthesis of complex and ordered structures is still a big challenge.At present,most studies use covalent synthesis to achieve precise synthesis.For instance,click chemistry,with high efficiency and selectivity,is highly recommended by chemists.Nevertheless,this method only works for a handful of reactions.In contrast,the synthesis based on non-covalent bonds has plenty of advantages,such as diverse methods,simple building blocks,easy synthesis,and functionalization.The research content of this thesis is the precise synthesis based on non-covalent interactions.Among the numerous non-covalent interactions,metal coordination interactions are used as the driving force to assemble into ordered structures in most cases due to their strong bond energy and good directionality.However,in living systems,only trace amounts of metallic elements exist.Hydrogen bonding is the basic driving force for the formation of biological macromolecules such as proteins,nucleic acids and polysaccharides.Hydrogen bonds are thought to be essential in recognition and molecular interactions.In DNA,guanine(G)and cytosine(C)pair through triple hydrogen bonds,while adenine(A)and thymine(T)pair through double hydrogen bonds,ultimately forming a double helix.Hydrogen bonding has significant directionality,reversibility and saturation,as well as a certain bonding strength,which can be used as a driving force of assembly for the construction of complex supramolecular systems with specific structures and functions.Intending to learn from biological systems,chemists have constructed a series of self-assembled systems with multiple hydrogen bonds.However,the stability of self-assembly systems with multiple hydrogen bonding is often affected by various factors,such as the number of hydrogen bonding sites,secondary electrostatic interactions,and allostery of hydrogen bonding units.Building blocks are the molecular basis of self-assembly structures,and the accuracy of building blocks will directly affect the precise synthesis of self-assembled structures.Therefore,we hope to find an effective method to solve the problem of how to control the stability of the hydrogen bonding interactions,and develop a definite building unit with multiple hydrogen bonding sites,to accurately synthesize complex supramolecular structures.The detailed work are as follows:1.Precision of supramolecular structures by controlling multiple hydrogen bonding interactionsMultiple hydrogen-bonding ureidopyrimidinone(UPy)units have certain complementarity,cheap raw materials,easy derivatization,strong dimerization ability,and many other advantages.Therefore,the UPy unit can be used as an important building block to build various supermolecular structures driven by multiple hydrogen bonding interactions.Meanwhile,an important feature that cannot be ignored of this system is that there is an equilibrium of two different kinds of proton tautomers in nonpolar or weak polar solvent.They are the 4[1H]-pyrimidinone(keto)isomer and the pyrimidin-4-ol(enol)isomer,respectively.The former forms DDAA-AADD dimer through self-complementary quadruple hydrogen bonding interactions,while the latter forms DADA-ADAD dimer.Because of the existence of the inherent tautomerization of this heterocyclic ring-based system,there are various isomers in supramolecular assemblies based on this building block,which makes supramolecular structures very complicated in essence.In this part,we propose a reasonable and simple supramolecular strategy to pre-organize the dimerization behavior of UPy molecule,that is,using intramolecular hydrogen bonding interactions to limit the intramolecular movement of proton,control keto-enol tautomerism,and fix the hydrogen bonding sites to arrange in a specific way,thus the UPy derivative 1 exists as only a 4[1H]-pyrimidinone tautomer in solution and in the solid state,which gives rise to the generation of a single DDAA-AADD dimeric array.According to Jorgensen’s theory of secondary electrostatic interactions,the DDAA-AADD dimer with quadruple hydrogen bonding interactions shows higher stability and stronger binding ability than the DADA-ADAD dimer because of the two secondary electrostatic attraction interactions.Then,we synthesized the building block 5 containing two molecule 1,and found that the building block 5 self-assembled into ordered supramolecular structure with exclusive DDAA-AADD dimeric arrays in solution.Here,we have controlled the precise arrangement of hydrogen bonding sites of the UPy system,and provided a specific multiple hydrogen bonding driving force for the precise synthesis of selfassembled structures.2.Construction of two-dimensional assemblies in aqueous media based on multiple hydrogen bondsIn addition to the quadruple hydrogen bonding system with DDAA-AADD dimeric array,another kind of self-complementary quadruple hydrogen bonding system with DADA-ADAD type hydrogen bonding sites is also often used to construct supramolecular structures.In the previous work,we have successfully controlled the DDAA-AADD dimerization of the UPy system through a supramolecular strategy.Based on the previous work,we hope to realize the DADA-ADAD dimerization of UPy system with the same strategy.Therefore,in this part,we effectively controlled the enol isomer of UPy molecule through the weak intramolecular hydrogen bonding interactions,and formed DADA-ADAD dimeric array in both solution and solid state.Unlike the work in part 1,the UPy derivative we obtained here not only undergos the dimerization through precisely controlled quadruple hydrogen bonding interactions,but also undergos π-π interactions with the introduced aromatic group to stabilize hydrogen-bonded dimmers.Currently,most studies based on hydrogen bonding were carried out in organic solvents,because water molecules as competitive molecules can severely interfere with the self-assembly process.To achieve precise structural control and high stability,many important biological processes(e.g.DNA assembly,protein folding)protect directional hydrogen bonding imteractions from water molecules by forming hydrophobic regions.Excitingly,we found that the enol monomer molecule designed and synthesized in this part would continuously form a region similar to the sandwich structure during the self-assembly process,and the quadruple hydrogen bonding interactions would be just shielded in the hydrophobic region formed by aromatic stacking interactions and resulting in dimerization,thus avoiding the interference of water molecules.This research shows that we have synthesized a definite multiple hydrogen-bonded building block,which further realizes the precise self-assembly driven by multiple hydrogen bonds in aqueous medium.3.Controllable assembly of two-dimensional monolayered structures driven by hydrogen bonding interactionsTwo-dimensional monolayered nanostructures are important materials with large specific surface area and abundant active sites,which have many potential applications.The preparation of monolayered two-dimensional nanostructures remains a challenge without templates or confined space.In the previous part of this work,we provide a kind of multiple hydrogen bonding unit with definite structure,and realize the precise construction of the sheet structures.In this part,we hope to control the assembly process by controlling the direction of multiple hydrogen bonding driving force,and construct a single layer self-assembled structure with specific spatial arrangement.Therefore,we took 2,5-bis(amino)terephthalate as the precursor,the crystal structure shows that the molecule has strong intramolecular and intermolecular hydrogen bonding interactions.On the basis of its structural characteristics,we designed and synthesized molecule 1by introducing leucine at both ends to provide hydrogen bonding interactions in the other direction.In the process of self-assembly,the building block 1 has a specific spatial orientation of its hydrogen bonding driving forces,which can be assembled along the x-axis and y-axis to form a two-dimensional monolayered structure with specific spatial arrangement.Through various microscopic imaging experiments and comparison with the self-assembled structure of reference molecule,it is proved that controllable self-assembly of two-dimensional monolayered structure can be realized by controlling the spatial orientation of hydrogen bonding driving forces during the self-assembly process.In this part,we have successfully constructed the monolayered nanosheets with large specific surface area,which provides ample scope for further chemical modification and functionalization.更多还原