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CC BY 4.0 · SynOpen 2025; 09(04): 302-314
DOI: 10.1055/a-2747-8835
graphical review

Functionalization and Applications of [2.2]Paracyclophanes (PCPs)

Authors

  • Chaoyu Wang‡

    a   Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian 361021, P. R. of China

  • Hong Zhang‡

    a   Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian 361021, P. R. of China

  • Lintao Chen

    a   Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian 361021, P. R. of China

  • Zehan Zhang

    a   Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian 361021, P. R. of China

  • Yadong Feng

    b   Engineering Research Center of Natural Cosmeceuticals College of Fujian Province, Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen, Fujian 361021, P. R. of China

  • Xiuling Cui  ∗

    a   Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian 361021, P. R. of China

This work was supported by Fujian Province (3502ZCQXT2021006), the 111 Project (BC2018061) and the Open Research Fund of Academy of Advanced Carbon Conversion Technology, Huaqiao University (AACCT0007).
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Graphical Abstract

Abstract

[2.2]Paracyclophane (PCP) is as a uniquely molecular scaffold, boasting substantial potential across synthetic chemistry and materials science. In this Graphical Review, recent advances in the functionalization of PCPs according to the type of transition metal employed [Rh(III), Ru(II), Ir(III), Cu(I), Co(II)], alongside their applications as chiral ligands or catalysts in stereoselective synthesis, are systematically summarized.


Key words

[2.2]paracyclophane (PCP) - transition metal - C–H activation - chiral ligand - catalyst

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Chaoyu Wang was born in Zhengzhou, Henan, China. He received his BS degree from Zhengzhou Normal University, and subsequently joined Professor Xiuling Cui’s group at Zhengzhou University in 2024 as a research assistant. In the same year, he commenced his doctoral studies at Huaqiao University under the supervision of Professor Xiuling Cui. His current research interests focus on transition-metal-catalyzed asymmetric C–H functionalization.


Hong Zhang is a senior laboratory specialist at the School of Biomedical Science at Huaqiao University. She received her BS degree in chemical engineering from Huaqiao University, and her PhD in biochemical engineering from the same institute under the guidance of Professor Xiuling Cui.


Lintao Chen was born in Ningde, Fujian Province, China. He received his BS degree from Changjiang University and is currently pursuing graduate studies at Huaqiao University under the supervision of Professor Xiuling Cui. His research focuses on transition-metal-catalyzed C–H functionalization for the synthesis of heterocyclic compounds.


Zehan Zhang was born in Xuchang, Henan, China. He received his BS degree from Henan University. In 2024, he joined Huaqiao University as a postgraduate student under the guidance of Professor Xiuling Cui. His research specializes in transition-metal-catalyzed C–H functionalization for the synthesis of heterocyclic compounds.


Yadong Feng was born in Henan, China. He obtained his PhD in 2018 under the guidance of Professor Xiuling Cui at Huaqiao University. He subsequently conducted postdoctoral research at Zhengzhou University, concentrating on photocatalytic activation of C–H bonds with the objective of developing novel and efficient photocatalytic systems. In 2023, he joined Xiamen Medical College as a lecturer and focused on the development of novel nano-photocatalysts and their applications in the research of photocatalytic degradation and organic conversion of biomass. His current research interests focus on metal-catalyzed activation of C–H bonds, with a particular emphasis on the green and efficient synthesis of heterocyclic compounds along with mechanistic studies.


Xiuling Cui is a professor at the Medical School at Huaqiao University. She studied chemistry at Zhengzhou University and received her PhD in 1999 under the guidance of Acad. Professor Yangjie Wu. Subsequently, she started her research at the Chemistry Department of Zhengzhou University as an associate professor, and was promoted to a full professor in 2008. In 2010, she joined Huagiao University as a Minjiang Scholar Shiy., and became a Distinguished Professor of Henan Province in 2015. She worked as an FCT Postdoctoral Fellow from 2000 to 2006 in the group of Professor Rita Delgado at ITQB, Universidade Nova Lisboa, Portugal. Her research interests focus on synthetic methodology and marine drugs.

Chirality is crucial for the existence of living organisms. As a unique category of chirality, planar chirality is distinguishable from others with typical central, axial, inherent, and helical chirality. [2.2]Paracyclophane (PCP) consists of two p-xylene units covalently linked by methylene bridges, forming a highly symmetric and stable tricyclic framework. Owing to their unique chemical structure, PCPs, upon losing structural symmetry, exhibit intriguing planar chirality and have thus emerged as highly interesting compounds in materials science and organic chemistry. Since the discovery of [2.2]paracyclophane by Brown and Farthing in 1949, scientists have consistently strived to develop efficient methods for its synthesis. The first synthesis of [2.2]paracyclophane was achieved in 1951 by Cram and Steinberg, primarily through intramolecular cyclization, and subsequently, other procedures were developed. Electrophilic aromatic substitution has served as a viable approach for achieving functionalization of the phenyl rings of PCP, with subsequent conversion of the installed halogen atoms being possible.

Functionalized PCPs have been widely utilized as chiral ligands, which has advanced their applications in stereochemistry considerably. In recent years, transition-metal-catalyzed C(sp2)–H activations have emerged as a transformative tool, significantly reinvigorating the functionalization of PCPs with high efficiency and regioselectivity. They have been successfully employed for various synthetically important stereocontrolled and enantioselective transformations, including arylation, acylation, esterification, alkynylation, and cyclization. Among these, Pd-catalyzed cross-coupling reactions offer a key approach for the functionalization of PCPs. This transformation often proceeds through a catalytic cycle involving oxidative addition, C–H activation, and reductive elimination. In addition, Rh/Ru/Ir-catalyzed systems also show potential in the functionalization of PCPs with the aid of directing groups. With the development of transition-metal-catalyzed C(sp2)–H functionalization, 3d metals such as Co and Cu have garnered significant attention due to their high abundance and low toxicity. These studies reveal distinct advantages, having greatly advanced the available methods for the functionalization of PCPs, whilst also providing efficient strategies for the synthesis of planar chiral PCPs.

In this graphical review, we categorize the functionalization of PCPs based on the different metal catalysts employed and summarize their applications in organic synthesis. We hope that it will provide inspiration toward the further development of asymmetric C–H functionalization reactions of PCPs and their applications in organic methodology.

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Figure 1 The development of [2.2]paracyclophane derivatives[1`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k] [l] [m] [n] [o] [p] [q] [r] [s] [t] [u] [v]
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Figure 2 Traditional monofunctionalization of [2.2]paracyclophane[1j] , [2`] [b] [c] [d] [e] [f] [g]
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Figure 3 Pd-catalyzed cross-couplings of [2.2]paracyclophanes[3`] [b] [c] [d] [e]
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Figure 4 Pd-catalyzed ortho-C–H functionalization of [2.2]paracyclophanes[4`] [b] [c] [d]
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Figure 5 Ru-, Ir- and Cu-catalyzed ortho-C–H functionalization of [2.2]paracyclophanes[5`] [b] [c]
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Figure 6 Co-catalyzed ortho-C–H functionalization of [2.2]paracyclophanes[6a] [b]
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Figure 7 Recent applications of [2.2]paracyclophane-based bifunctional catalysts[7`] [b] [c] [d] [e]
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Figure 8 Recent applications of planar chiral [2.2]paracyclophane-based bis(oxazoline) ligands[8`] [b] [c] [d] [e]
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Figure 9 Recent applications of planar chiral [2.2]paracyclophane-based bis(oxazoline) ligands and bidentate oxazoline–carbene ligands[8`] [g] [h] , [9`] [b] [c]
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Figure 10 Recent applications of functionalized planar chiral [2.2]paracyclophanes as ligands[10`] [b] [c] [d] [e]

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We wish to express our gratitude to Dr. Chao Pi and Di Hu from Zhengzhou University and Jie Chen from Huaqiao University for their constructive discussions, along with current and former members of the Cui group for their contributions.


Corresponding Author

Xiuling Cui
Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University
Xiamen, Fujian 361021
P. R. of China   

Publication History

Received: 13 October 2025

Accepted after revision: 04 November 2025

Accepted Manuscript online:
13 November 2025

Article published online:
15 December 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

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Zoom
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Figure 1 The development of [2.2]paracyclophane derivatives[1`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k] [l] [m] [n] [o] [p] [q] [r] [s] [t] [u] [v]
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Figure 2 Traditional monofunctionalization of [2.2]paracyclophane[1j] , [2`] [b] [c] [d] [e] [f] [g]
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Figure 3 Pd-catalyzed cross-couplings of [2.2]paracyclophanes[3`] [b] [c] [d] [e]
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Figure 4 Pd-catalyzed ortho-C–H functionalization of [2.2]paracyclophanes[4`] [b] [c] [d]
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Figure 5 Ru-, Ir- and Cu-catalyzed ortho-C–H functionalization of [2.2]paracyclophanes[5`] [b] [c]
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Figure 6 Co-catalyzed ortho-C–H functionalization of [2.2]paracyclophanes[6a] [b]
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Figure 7 Recent applications of [2.2]paracyclophane-based bifunctional catalysts[7`] [b] [c] [d] [e]
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Figure 8 Recent applications of planar chiral [2.2]paracyclophane-based bis(oxazoline) ligands[8`] [b] [c] [d] [e]
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Figure 9 Recent applications of planar chiral [2.2]paracyclophane-based bis(oxazoline) ligands and bidentate oxazoline–carbene ligands[8`] [g] [h] , [9`] [b] [c]
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Figure 10 Recent applications of functionalized planar chiral [2.2]paracyclophanes as ligands[10`] [b] [c] [d] [e]