微观不均一性合成(Microheterogeneous Synthesis)，是通过将合成化学的一般原理与单分子混合物科学原理进行结合，来构建具有微观不均一性特征的分子的一种新型化学合成技术。其基本原理是通过等概率随机合成方法，构建一个具有较大数目的可能异构体的结构空间体系，当该空间的可能异构体数目远远超过实际合成的样品中的分子数目时，所合成的样品将以很大的概率呈单分子混合物状态存在，这样，就实现了微观不均一性分子的合成，这一合成过程，就是一个典型的微观不均一性合成过程。

        图1详细展示了微观不均一性合成的基本过程。

图1 微观不均一性合成的一般原理与方法

    例如，以环糊精为骨架，利用其可以方便地发生全酰基化或全烷基化反应的特性，可以方便地构建环状结构的单分子混合物模型，如图2所示。其中的烷基或酰基部分有极为丰富的设计空间。所得到的单分子混合物可以方便地用现有的分离纯化及结构表征技术进行纯化、分析。这一合成方案的最大亮点在于非常简便，只需要一步反应即可构建一个复杂的环状结构的单分子混合物体系。

图2 微观不均一性合成的一个具体实例

English version

Microheterogeneous Synthesis: Principles and Method

  Microheterogeneous synthesis is a novel chemical synthesis technique that constructs molecules with microheterogeneous characteristics by integrating general principles of synthetic chemistry with the single-molecule mixture science^1,2. Its fundamental principle involves constructing a structural space system with a large number of possible isomers through an equal-probability random synthesis method. When the number of possible isomers in this space far exceeds the number of molecules in the actual synthesized sample, the synthesized sample will exist with a high probability as a single-molecule mixture. This achieves the synthesis of microheterogeneous molecules, representing a typical microheterogeneous synthesis process.

     Figure 1 details the fundamental process of microheterogeneous synthesis.

Figure 1: General Process of Microheterogeneous Synthesis

For example, using cyclodextrin as a scaffold and leveraging its ability to readily undergo total acylation or alkylation reactions, it is possible to conveniently construct a single-molecule mixture model with a cyclic structure, as shown in Figure 2. The alkyl or acyl moieties offer an extremely rich design space. The resulting single-molecule mixture can be easily purified and analyzed using existing separation, purification, and structural characterization techniques. The greatest advantage of this synthetic approach lies in its remarkable simplicity: a complex cyclic monomolecular mixture system can be constructed in a single reaction step.

Figure 2: A Specific Example of Microheterogeneous Synthesis

References

1.     Tang, Y. Single-Molecule Mixture: A Concept in Polymer Science. Int. J. Mol. Sci. 2024, 25, 7571.

2.     Tang, Y. Microheterogeneity and Single-Molecule Mixture Science: An Introduction. arXiv:2408.14485