Authors
Professor Xiaoqi Yu
Sichuan University
College of Chemistry
No. 29 Wangjiang Road
610064 Chengdu
China
Professor Ji Zhang
Sichuan University
College of Chemistry
No. 29 Wangjiang Road
610064 Chengdu
China
Cover
(Foreground image) © cdascher/Gettyimages;
(Background image) © Ensuper/Shutterstock
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Although macrocyclic organic compounds have been studied for nearly half a century, the discovery and study of novel macrocyclic compounds continue to be of high importance to chemists, especially in the field of supramolecular chemistry. The awarding of two separate Nobel prizes over the past 30 years is an evidence for this assertion. First, the 1987 Nobel Prize in Chemistry was awarded to American chemists Charles J. Pedersen and Donald J. Cram, along with French chemist Jean-Marie Lehn, for their development and use of molecules with structure-specific interactions of high selectivity. The macrocyclic molecules developed by these pioneering researchers may help people to achieve the goal of finding synthetic organic chemicals with functions similar to natural proteins. The most recent Nobel Prize in Chemistry (2016), awarded to Jean-Pierre Sauvage, J. Fraser Stoddart, and Bernard L. Feringa for the design and synthesis of molecular machines, is also highly reliant on the facile synthesis and host–guest properties of macrocyclic organic compounds. The most commonly known functional macrocyclic compounds are crown ethers, which were developed by Professor Charles J. Pedersen in 1967. Macrocyclic polyamines are a family of aza-crown ethers. The nitrogen atoms on the macrocycle make the molecules allow for greater flexibility with regard to modifications and performance. In this book, some properties and applications of macrocyclic polyamines, which may not be possessed by crown ethers, are described and reviewed.
Macrocyclic polyamines are a class of cyclic crown ether-like organic compounds that possess more than two nitrogen atoms in the ring. Because the nitrogen atoms in the cyclic structures can be modified with different functional groups to form various derivatives with different physical and chemical properties, these derivatives can be used over a diverse collection of areas. Although macrocyclic polyamines have been studied for decades, books or chapters focusing on their synthesis and applications are relatively rare. Herein, we aim to summarize some research advances of macrocyclic polyamines including the following contents: the properties of and synthetic methods toward macrocyclic polyamines, chemical nucleases based on macrocyclic polyamines, derivatives of macrocyclic polyamines as nano-vector materials, macrocyclic polyamines derivatives for bio-imaging, chemical sensors based on macrocyclic polyamines, as well as several other applications. This text includes most of the studies involving macrocyclic polyamines and their derivatives, and we believe that it may be used as a reference for the researchers in related fields.
It would have been impossible for us to write a comprehensive monograph on so many aspects of macrocyclic polyamines without support from many coworkers and colleagues. Accordingly, we would like to thank all the people who worked together so enthusiastically on this book, including Drs Shan-Yong Chen (Chapter 2), Qiang Liu (Chapter 3), Wen-Jing Yi (Chapter 3), Li-Jian Ma (Chapter 5), Kun Li (Chapter 6), and Shan-Shan Yu (Chapter 7). We are also grateful to funding agencies such as the National Natural Science Foundation of China for supporting our research about this project
Xiao-Qi Yu and Ji Zhang
Chengdu, P. R. China
May 2017
Macrocyclic polyamines (MPAs) are important complexing agents for cations, anions, and neutral molecules. In this book, MPAs are defined as having at least three nitrogen atoms and nine atoms in the ring. Although polyazamacrocycles containing amide and imine functional groups cannot be named amines strictly, these macrocycles are also included here. According to the functional groups in the ring, MPAs can be divided into aliphatic MPAs, aromatic-containing MPAs, macrocyclic polyimines, macrocyclic polyamides, and cryptands.
In an aliphatic macrocycle, all carbon and hetero atoms are sp3-hybridized. Cylen and cyclam are the most used aliphatic MPAs. One or more nitrogen atoms can be substituted with other heteroatoms, such as oxygen or sulfur, to afford heteroatom-substituted MPAs (compound 1-1).
To adjust the rigidity of MPAs, aromatic motifs such as benzene and pyridine are introduced. Most aromatic-containing MPAs have a linker between the aromatic motif and the nitrogen atom (compounds 1-2 and 1-3). Modern transition metal catalysis enables the direct combination of the aromatic motif with the nitrogen atom through the formation of CAr−N bonds (compound 1-4).
Macrocyclic polyimines have at least one imine bond in the ring. Because aliphatic macrocyclic Schiff bases have rather low hydrolytic stability, they often complex with a suitable metal template (compound 1-5). Aromatic-containing macrocyclic polyimines are hydrolytically stable to a certain extent in the absence of a template (compound 1-6).
Macrocyclic polyamides have at least one amide bond in the ring (compounds 1-7 and 1-8). Macrocyclic polyamides possess the dual features of cyclic peptides and MPAs. Amide-containing macrocycles are usually prepared by cyclocondensation of acids with amines or coupling of the amide-containing precursors.
Cryptands (compound 1-9) are three-dimensional analogs of crown ethers but offer much better selectivity and strength of binding. Spherical cryptands (compound 1-10) can be described as twice-bridged azamacrocycles.
Except for the nitrogens on the aromatic ring, the amino groups on MPAs are mainly aliphatic secondary amines, which always have relatively strong basicity, and the pKa values of their protonated species are in the range of 9–11. However, the secondary amines on MPAs have a much wider pKa range. Generally, the first protonation steps of MPAs are much easier (pKa 9–11, similar to common secondary amines) than the last protonation steps (pKa 1–3, low basicity). This behavior might be attributable to charge-repulsion effects [1] due to the higher positive charge density on the cycle compared with open-chain polyamines. Some typical aliphatic MPAs with their pKa values for each amine are listed below; for detailed data, the reader may refer to the review by Izatt and coworkers [2]. The positive charge of MPAs under neutral conditions facilitates their interaction with negatively charged biomolecules such as nucleic acids and some proteins. MPA derivatives may bind to nucleic acids through electrostatic interaction, protect the nucleic acid cargo from degradation, and deliver the cargo to target cells or tissues (Chapter 4). Moreover, the wider pKa range of amines may afford the vector materials special pH buffering capability in the intracellular environment, leading to enhanced endosomal escape.
Macrocyclic structures are extremely favorable for metal complexation. Similar to crown ethers, the nitrogens on MPAs may coordinate to metal ions of appropriate size. They show a pronounced ability to bind a wide variety of metals and, in many cases, undergo marked conformational changes during binding [3]. The increased stability of a metal coordination complex of a tetra-amine macrocyclic ligand over that of similar noncyclic tetra-amine ligands has been called the macrocyclic effect. 1,4,7-Triazacyclononane (TACN) has a smaller cavity, and the binding ability is weaker than that of cyclen or compound 1-11. Cyclen may coordinate well to first-row transition elements such as Cu2+ and Zn2+, and the resultant metal complexes are widely used as artificial nucleases (Chapter 3), chemical sensors (Chapter 6), ionophores (Chapter 7), or chemical catalysts. MPA 1-11 has a larger cycle, which facilitates its binding with larger metal ions such as Cd2+ and Hg2+. In addition, MPAs with a cavity larger than that of 1-11 may also coordinate with more than one first-row transition metal ion [2]. The analogs of 1-12 with 7–9 nitrogens can form dinuclear complexes, whereas those with 11 or 12 nitrogens can form even trinuclear complexes. In addition, pendant coordinating groups can also be attached to the nitrogens on the macrocycle, resulting in more extensive metal coordination properties and applications [4]. For example, some MPA derivatives with carboxylic groups on the arms may act as chelating agents to coordinate with lanthanide metal ions. For example, the Gd-complexes of cyclen derivatives are used intensively in the field of bio-imaging, as described in detail in Chapter 5.
Although most applications involving MPAs employ their metal complexes, the polyamine itself may also serve as a bioactive species. Certain MPAs might act as promising cytotoxic agents by depleting the ATP level of tumor cells [5]. Combinatorial chemistry studies have also found that polyazapyridinophanes possess potent antimicrobial activities [6]. These findings are not included in this book.
As mentioned earlier, most MPA applications employ their metal complexes, which have been used (i) as enzyme mimics, especially artificial nucleases for the cleavage of nucleic acids, (ii) as magnetic resonance imaging (MRI) contrast agents for advanced diagnosis, (iii) as carrier molecules in studies of the selective uptake and transport of metal ions in biological systems, (iv) as gene carriers, (v) as chemical sensors or receptors for metal ions or bioactive molecules, and (vi) in metal recovery that depends on selective extraction. In addition, non-metal chelating MPAs have been used as nucleic acid carriers due to their positive charge in aqueous solution.
The main application areas are reviewed in detail in this book. Chapter 3 presents recent progress on metal or metal-free chemical nucleases based on MPAs, which cleave nucleic acids through a hydrolytic or oxidative mechanism; Chapter 4 introduces non-viral nucleic acid vectors, including cationic lipids and polymers, based on the MPA structure; Chapter 5 presents the use of MPA derivatives as contrast agents in bio-imaging studies; Chapter 6 focuses on the design and synthesis of fluorescent chemosensors for metal ions and bioactive molecules; and Chapter 7 introduces other applications, such as the use of MPA derivatives as ionophores or electrophoretic separation agents.