Regioselective Functionalization of [2.2]Paracyclophanes: Recent Synthetic Progress and Perspectives

Abstract

[2.2]Paracyclophane (PCP) is a prevalent scaffold that is widely utilized in asymmetric synthesis, π-stacked polymers, energy materials, and functional parylene coatings that finds broad applications in bio- and materials science. In the last few years, [2.2]paracyclophane chemistry has progressed tremendously, enabling the fine-tuning of its structural and functional properties. This Minireview highlights the most important recent synthetic developments in the selective functionalization of PCP that govern distinct features of planar chirality as well as chiroptical and optoelectronic properties. Special focus is given to the function-inspired design of [2.2]paracyclophane-based π-stacked conjugated materials by transition-metal-catalyzed cross-coupling reactions. Current synthetic challenges, limitations, as well as future research directions and new avenues for advancing cyclophane chemistry are also summarized.

Keywords: [2.2]paracyclophanes; chirality; functional parylenes; regioselective synthesis; π-stacked polymers.

Figure 1

A) Structural parameters in Ångstrom [Å] determined by X‐ray crystallography. B) Representative PCP‐based ring‐fused, ring‐extended, and quadruple π‐stacked systems.

Figure 2

Common substitution patterns of mono‐ and disubstituted PCP with stereochemical description; ps=pseudo. The top view of PCP is given for clarity.

Figure 3

Aromatic substitution pattern of disubstituted [2.2]paracyclophane with the relative nomenclature.

Figure 4

Representative chiral [2.2]paracyclophane‐based N,O, P,N‐, N,N‐, and P,P‐ligands used in asymmetric catalysis.

Figure 5

Design of various PCP‐based π‐stacked systems.

Scheme 1

Monofunctionalization of [2.2]paracyclophane.

Scheme 2

Difunctionalization of [2.2]paracyclophane derivatives. DG=directing group, PIDA=phenyliododiacetate.

Scheme 3

Aromatic substitution pattern of symmetrically tetrasubstituted homo‐ and bis‐bifunctional PCPs with the relative nomenclature.

Scheme 4

Synthesis of symmetrically tetrasubstituted homo‐ and bis‐bifunctional PCPs.

Scheme 5

Overview of the performance of the directing groups in the Pd‐catalyzed ortho‐acetoxylation of [2.2]paracyclophanes.

Scheme 6

A) Oxidative cyclization. B) PIDA‐mediated para‐C−H functionalization of [2.2]paracyclophane, and oxidation to benzoquinone. Nu=nucleophile, PivOH=pivalinic acid, TIPS=triisopropylsilyl.

Scheme 7

Oxidative para‐C−H functionalization of PCP with a quinone intermediate. DCM=dichloromethane, DMAP=dimethylaminopyridine, OTf=triflate.

Scheme 8

Access to enantiopure 4‐formyl[2.2]paracyclophane (80). (R,R)‐Ts‐DPEN=https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1180813.htme.

Scheme 9

Chiral resolution of [2.2]paracyclophane sulfoxides. TMS=trimethylsilyl.

Scheme 10

Chiral resolution of di‐ (90) and tetrasubstituted (92) [2.2]paracyclophanes.

Figure 6

Overview of π‐stacked conjugated polymers with [2.2]paracyclophane scaffolds synthesized by metal‐catalyzed cross‐coupling reactions.

Figure 7

Chiral di‐ and tetrasubstituted [2.2]paracyclophane‐based helical macrocycles and PCP‐bridged bisimidazole dimer (quinoid species).

Figure 8

A) General procedure for the chemical vapor deposition (CVD) of functional [2.2]paracyclophanes and [2.2]heterophanes. B) Micropatterning by CVD. C) Templated synthesis of nanofiber arrays by CVD within anisotropic liquid‐crystalline droplets; SEM image reproduced from Ref. 93 with permission. Copyright 2018 Science, American Association for the Advancement of Science (AAAS).

Scheme 11

Supramolecular indicator displacement assay based on PCP and cucurbit[8]uril to spectroscopically determine the concentration of the Alzheimer's drug memantine in blood serum at physiologically relevant concentrations.