Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• symmetry to enable promising catalytic modes. Keywords: cavity confinement catalysis; enzyme mimicry; robust organic cages; self-assembly; supramolecular catalysis; Introduction I frequently introduce my research on organic cage enzyme mimics with the following observation. For hundreds of years

• that an underexplored cavity type, robust organic cages [38][39][40][41][42][43][44][45][46][47], are uniquely positioned to facilitate these advances. Outline and Overview The aim of this perspective is twofold: (1) to briefly review the state of the art of cavity catalysis, highlighting the catalytic

• concepts of organization and polarization, and anticipating future developments; and, (2) to introduce robust organic cages as functional enzyme mimics, and highlight how their unique features might advance cavity catalysis and provide more realistic enzyme models for studying electric field catalysis and

Unraveling aromaticity: the dual worlds of pyrazole, pyrazoline, and 3D carborane

• Zahra Noori,
• Miquel Solà,
• Clara Viñas,
• Francesc Teixidor and
• Jordi Poater

Beilstein J. Org. Chem. 2025, 21, 412–420, doi:10.3762/bjoc.21.29

• of o-carborane and pyrazole/pyrazoline. Series of reference systems for the o-carborane-fused pyrazoles under analysis. NICS (in ppm) of the boron cages (computed for the top 5-membered ring, center and bottom 5-membered ring) and the rings (center of the ring) of the systems under analysis from the

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• -driven self-assemblies like cages or containers while numerous classic organic receptors for oxalate exist. This discrepancy is astonishing because metallocontainers or metallocages have advantages over classic macrocycles or organocages like a higher modularity and good preorganization paired with a

• calcium oxalate [6][7][8]. Unsurprisingly, the detection of oxalate was studied with numerous classic organic receptors involving acyclic hosts [9][10][11][12][13][14][15][16][17][18][19][20][21], macrocycles [22][23][24][25][26][27][28][29][30][31][32][33], and cages [34][35][36][37][38][39][40][41][42

• disassembly of the host structure. Guest-driven decomplexation events can also be utilized as detection method [65][68][69][70][71][72][73] but such processes are generally not desired for containers or cages because guest binding is anticipated to take place by encapsulation while the structure of the

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• (HCPs), polymers of intrinsic microporosity (PIMs), covalent organic frameworks (COFs), extrinsic porous molecules, and porous organic cages [103] etc. Since in terms of organocatalyst immobilisation COFs are the most important, further discussion of POFs is not included in this review. Hyperbranched

Cage-like microstructures via sequential Ugi reactions in aqueous emulsions

• Rita S. Alqubelat,
• Yaroslava A. Menzorova and
• Maxim A. Mironov

Beilstein J. Org. Chem. 2024, 20, 2078–2083, doi:10.3762/bjoc.20.179

• substances [7]. A particularly interesting area is the use of colloidosomes to model processes in living cells and produce artificial protocells [8][9]. The enlargement of pores on the surface of colloidosomes leads to structures that resemble microscopic cages [10]. Obtaining such cage-like structures is

New triazinephosphonate dopants for Nafion proton exchange membranes (PEM)

• Fátima C. Teixeira,
• António P. S. Teixeira and
• C. M. Rangel

Beilstein J. Org. Chem. 2024, 20, 1623–1634, doi:10.3762/bjoc.20.145

• molecular cages [46][47] and at porous materials, as linkers in metal-organic frameworks (MOFs) [48], used in the evaluation of the cycloaddition of CO2 to epoxides [49] and CO2 uptake [50]. Taking in consideration the strategy of the incorporation of dopants to promote the proton conduction in Nafion

Synthesis of indano[60]fullerene thioketone and its application in organic solar cells

• Yong-Chang Zhai,
• Shimon Oiwa,
• Shinobu Aoyagi,
• Shohei Ohno,
• Tsubasa Mikie,
• Jun-Zhuo Wang,
• Hirofumi Amada,
• Koki Yamanaka,
• Kazuhira Miwa,
• Naoyuki Imai,
• Takeshi Igarashi,
• Itaru Osaka and
• Yutaka Matsuo

Beilstein J. Org. Chem. 2024, 20, 1270–1277, doi:10.3762/bjoc.20.109

• -butyl groups, which disrupted the π–π stacking between the fullerene cages. The slight difference in sublimation temperature between t-Bu-FIDO and t-Bu-FIDS might be due to the slightly higher electron density of the sulfur atom compared with the oxygen atom. Additionally, data on the degradation

Unveiling the regioselectivity of rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition reactions for open-cage C₇₀ production

• Cristina Castanyer,
• Anna Pla-Quintana,
• Anna Roglans,
• Albert Artigas and
• Miquel Solà

Beilstein J. Org. Chem. 2024, 20, 272–279, doi:10.3762/bjoc.20.28

• applications are still in various stages of research and development. The functionalization of fullerenes makes them versatile materials, broadening the range of potential applications [17][18]. It allows the properties of these carbon cages to be tuned, making them more soluble (especially in water for

• cages. However, in other cases, some of the bonds between the C atoms of the cage are broken and the cage is opened. The first example of an open-cage fullerene was reported in 1995 by Hummelen, Prato, and Wudl [21] through the reaction of C60 with azides followed by photooxygenation. Since then, many

Electron-beam-promoted fullerene dimerization in nanotubes: insights from DFT computations

• Laura Abella,
• Gerard Novell-Leruth,
• Josep M. Ricart,
• Josep M. Poblet and
• Antonio Rodríguez-Fortea

Beilstein J. Org. Chem. 2024, 20, 92–100, doi:10.3762/bjoc.20.10

• surface that describes the formation of irreversible C–C bonds. Molecular dynamics simulations were done in the radical C120 dimer alone; we did not consider the interaction with the CNT. After a 4 ps metadynamics, we observed the sequential formation of C–C bonds between the two C60 cages up to a number

• vertexes of each hexagon forming a hexagonal prism (HPR). Several authors have already proposed this HPR structure for the dimerization of two neutral C60 cages [13][14][15]. We characterized this structure as a minimum of the potential energy surface at 49.2 kcal mol−1 (PBE/TZP) higher than dimer 1-Cs

• CV the coordination number of ten carbon atoms of one C60 molecule (two contiguous hexagons) with respect to ten carbon atoms in the other C60, analogous to the first run. After 7 ps, we also observed the sequential formation of C–C bonds between the two cages in structures now called dimer 3B-D2h

Supramolecular approaches to mediate chemical reactivity

• Pablo Ballester,
• Qi-Qiang Wang and
• Carmine Gaeta

Beilstein J. Org. Chem. 2022, 18, 1463–1465, doi:10.3762/bjoc.18.152

• reactions by a biomimetic approach [3][4]. Very recently, many efforts have been devoted to study supramolecular catalysis processes [5][6][7][8][9][10][11][12][13][14] in which macrocyclic hosts, self-assembled capsules and metallo-cages were employed as catalysts or nanocontainers. The primary

• advantages of heteroleptic over homoleptic cages and they showed examples of nanomechanical motion influencing catalytic activity. They also discuss the regulation of the catalytic activity of heteroleptic systems by an external stimulus. We are very grateful to all colleagues who contributed to this issue

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• has led to a significant number of self-sorted cages/assemblies that have demonstrated their potential to act as functional materials [30]. Various self-sorting protocols leading to quantitative formation of heteroaggregates under thermodynamic control have recently proven their capacity. A prominent

• complexes by Chan using complementary ligand binding [39], sometimes combined with conformational regulation [40], and of Newkome/Li [41] applying mainly geometric complementarity [42]. Clever utilized shape complementarity [21] for building heteroleptic palladium(II) cages whereas Crowley developed a

• procedure to kinetically metastable cages using naked Pd2+ [43][44]. The following selected structures (Figure 1) shall give a flavor of recent achievements in making fascinating heteroleptic structures using dynamic binding motifs. The availability of powerful tools for building heteroleptic aggregates has

Using multiple self-sorting for switching functions in discrete multicomponent systems

• Amit Ghosh and
• Michael Schmittel

Beilstein J. Org. Chem. 2020, 16, 2831–2853, doi:10.3762/bjoc.16.233

• )] (Figure 4e). Equally, Schalley and Nitschke developed a guest-induced self-sorting based on two new Zn4L6 cages (Figure 5a) using the aldehyde 9 and the diamine subcomponents 7 and 8 that contained either the naphthalene diimide or zinc porphyrin moiety [51]. Both cages respond selectively to distinct

• -interlocked catenanes. When both cages were mixed without C70, the dynamic combinatorial library (DCL) of seven compositionally distinct mixed-ligand Zn4L6 cages was observed (Figure 5b). An efficient self-sorting was only observed after the addition of the guest C70. As expected, the cage [Zn4(8')6]8

• anions to amplify homoleptic cages by driving a 2-fold narcissistic self-sorting. When an excess amount of BPh4– was added, NMR and ESIMS peaks indicated only formation of the homoleptic species (Figure 6c). The amplification to homoleptic species is realized through the peripheral binding of the anion

A heterobimetallic tetrahedron from a linear platinum(II)-bis(acetylide) metalloligand

• Matthias Hardy,
• Marianne Engeser and
• Arne Lützen

Beilstein J. Org. Chem. 2020, 16, 2701–2708, doi:10.3762/bjoc.16.220

• these two design concepts – the subcomponent self-assembly strategy and the complex-as-a-ligand approach – ensured a fast and easy synthesis of large heterobimetallic coordination cages of tetrahedral shape with a diameter of more than 3 nm as a mixture of all three possible T-, S4- and C3-symmetric

• heterobimetallic structures that has recently been described in the literature, such as, e.g., helicates [27][28], cubes [29][30][31], trigonal bipyramids [21][32][33], boxes [34][35][36], prismatic cages [37], or some truly unique other shapes [38][39]. At the same time, heterobimetallic cages not only offer the

• platinum(II)-bis(acetylide) complexes [46][47] proved useful as building blocks for the construction of polymers [48], rings [49][50] and cages [36][42][51]. These neutral compounds are usually easy-to-access, rather stable and the cis- and trans-isomers can be separated efficiently. In this work we

The charge-assisted hydrogen-bonded organic framework (CAHOF) self-assembled from the conjugated acid of tetrakis(4-aminophenyl)methane and 2,6-naphthalenedisulfonate as a new class of recyclable Brønsted acid catalysts

• Svetlana A. Kuznetsova,
• Alexander S. Gak,
• Yulia V. Nelyubina,
• Vladimir A. Larionov,
• Han Li,
• Michael North,
• Vladimir P. Zhereb,
• Alexander F. Smol'yakov,
• Artem O. Dmitrienko,
• Michael G. Medvedev,
• Igor S. Gerasimov,
• Ashot S. Saghyan and
• Yuri N. Belokon

Beilstein J. Org. Chem. 2020, 16, 1124–1134, doi:10.3762/bjoc.16.99

• nondirectional forces in the crystal whilst leaving the directional hydrogen bonds still present so that the framework remained heterogeneous. Notably, simple organic cages that exhibit guest-induced “breathing” and selective gas separation have been reported [29][39][40][41]. The reversible rearrangement of the

A chiral self-sorting photoresponsive coordination cage based on overcrowded alkenes

• Constantin Stuckhardt,
• Diederik Roke,
• Wojciech Danowski,
• Edwin Otten,
• Sander J. Wezenberg and
• Ben L. Feringa

Beilstein J. Org. Chem. 2019, 15, 2767–2773, doi:10.3762/bjoc.15.268

• between the three isomers. Two of the isomers were able to form host–guest complexes opening up new prospects toward stimuli-controlled substrate binding and release. Keywords: coordination cages; molecular motors; molecular switches; overcrowded alkene; palladium; Introduction Supramolecular

• interesting strategy to form responsive coordination complexes, as they feature a large geometric change upon switching [47]. Herein, we report a photoresponsive coordination cage with ligands based on a first generation molecular motor (Figure 1). Cages with a Pd2L4 composition are formed from bidentate

• bispyridyl ligands and Pd(II) ions with a square planar geometry, which have been widely studied [6][48][49][50]. The photochromic ligands can be switched between three states, forming separate discrete cage complexes, allowing cage-to-cage transformations (Scheme 1). Interestingly, only homochiral cages are

Formation of alkyne-bridged ferrocenophanes using ring-closing alkyne metathesis on 1,1’-diacetylenic ferrocenes

• Celine Bittner,
• Dirk Bockfeld and
• Matthias Tamm

Beilstein J. Org. Chem. 2019, 15, 2534–2543, doi:10.3762/bjoc.15.246

• chemistry [28][29][30][31][32], used for instance in the preparation of aryleneethynylene macrocycles and cages through alkyne metathesis [33][34][35][36][37][38][39]. Additionally, already since the 1980s the influence of fluorinated and unfluorinated alkoxide ligands has been widely investigated [40][41

Reversible switching of arylazopyrazole within a metal–organic cage

• Anton I. Hanopolskyi,
• Soumen De,
• Michał J. Białek,
• Yael Diskin-Posner,
• Liat Avram,
• Moran Feller and
• Rafal Klajn

Beilstein J. Org. Chem. 2019, 15, 2398–2407, doi:10.3762/bjoc.15.232

• green light and resulted in the initial 1:2 cage/E-arylazopyrazole complex. This back-isomerization reaction also proceeded in the dark, with a rate significantly higher than in the absence of the cage. Keywords: arylazopyrazoles; coordination cages; inclusion complexes; molecular switches

• interfaces [1][2][3], in self-assembled cages [4][5][6][7], on DNA chains [8], and on the surfaces of inorganic nanoparticles [9][10]. Additionally, nanosized cages can induce preorganization of the encapsulated species, thus inducing unusual regioselectivities in various chemical reactions [11][12][13]. The

• limited dimensions of cage cavities can also be used for arresting the growth of polycondensates at an early stage, thereby making it possible to isolate labile species. For example, Fujita and co-workers demonstrated the stabilization of cyclic trimers of siloxanes inside small self-assembled cages [14

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• selectivity of this receptor for chloride anion is due to the cavity size (see Figure 3) [37]. 2.2. Optical anion sensing by 1,2,3-triazolium macrocycles within porphyrin cages Various porphyrin-based host supramolecules containing hydrogen-bond donor groups such as integrated amide, urea, pyrrole, ammonium

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• and background-corrected by xCellence software. Animals and cells For isolation of resident peritoneal macrophages, female Wistar rats weighing 175–185 g (VELAZ, Czech Republic) were used. They were kept in plastic cages under standard conditions, i.e., a temperature of 22 ± 2 °C, 12/12 h of light

Efficient resolution of racemic crown-shaped cyclotriveratrylene derivatives and isolation and characterization of the intermediate saddle isomer

• Sven Götz,
• Andreas Schneider and
• Arne Lützen

Beilstein J. Org. Chem. 2019, 15, 1339–1346, doi:10.3762/bjoc.15.133

• ][28]. Due to our interest in dissymmetric [29][30][31][32][33][34][35][36] and concave molecular building blocks [37] and their implementation in supramolecular architectures like (allosteric) receptors [38][39][40][41][42][43][44] or metallosupramolecular helicates and cages [45][46][47][48][49][50

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• promise for the future development of peptide pharmaceuticals. 5 Multicomponent synthesis of steroidal macrocycles and cages Since the beginning of this century, the field of macrocycle synthesis has witnessed the emergence of MCRs as effective ring closing procedures, including the cyclization of large

• have been included in previous reviews [12][13] this section will cover those reports from 2009 on, with emphasis on multicomponent macrocyclization approaches leading to steroidal cages. The first report of a MCR-derived steroidal macrocycles was described by Wessjohann et al. in 2005 as part of a

• synthesis of steroidal cages multiple multicomponent macrocyclization [73]. As shown in Scheme 20, Rivera and Wessjohann expanded the MiBs concept to the development of a threefold Ugi-4CR-based macrocyclization between cholanic tricarboxlic acid 68 and an aliphatic triisocyanide in the presence of three

Understanding the unexpected effect of frequency on the kinetics of a covalent reaction under ball-milling conditions

• Ana M. Belenguer,
• Adam A. L. Michalchuk,
• Giulio I. Lampronti and
• Jeremy K. M. Sanders

Beilstein J. Org. Chem. 2019, 15, 1226–1235, doi:10.3762/bjoc.15.120

• for a wide range of different syntheses and chemical reactions of inorganic [8][9] and organic [10][11] compounds. Even supramolecular architectures such as co-crystals and metal-organic frameworks [4][12][13][14], cages [15] and rotaxanes [16] could be formed mechanochemically. Crucially, the

Design of a double-decker coordination cage revisited to make new cages and exemplify ligand isomerism

• Sagarika Samantray,
• Sreenivasulu Bandi and
• Dillip K. Chand

Beilstein J. Org. Chem. 2019, 15, 1129–1140, doi:10.3762/bjoc.15.109

• ]. Complexation of cis-protected palladium(II), i.e., (PdL’) or bare palladium(II) with non-chelating bidentate ligands is known to afford a series of (PdL’)mLm or PdmL2m-type self-assembled coordination complexes [5]. Pd2L4-type cages are the simplest representatives among the PdmL2m-type complexes, yet most

• utilised [5][6]. The Pd2L4-type cages are well explored for the encapsulation of guests that are anionic [7][8][9][10][11], neutral [12][13][14][15][16], radical initiators [17], and drug molecules [18][19]. It is necessary to emphasize here that Pd2L4-type cages contain a cavity. McMorran and Steel

• formation of PdL2-type spiro and Pd3L4-type double-decker complexes that is reversible under appropriate conditions. Subsequently, other research groups (Chand, Clever, Crowley and Yoshizawa groups) published Pd3L4-type cages [24]. This design has been further explored by Crowley et al. for the synthesis of

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• -based macrocyclization yielded steroid-aryl hybrid macroheterocycles 151 and 152, which after ester hydrolysis, acted as trifunctional building blocks for consecutive 3-fold Ugi-4CR-based macrocyclizations with triisocyanide 153. The cross-linked igloo-shaped skeletons of cages 154 and 155 were obtained

• for the synthesis of molecular cages was described [50]. The approach was based on macromulticycle connectivities through bridgeheads. For the macrocyclization reaction, metal-template-driven and dilution conditions were used. These conditions allowed one-pot synthesis including aryl, heterocyclic

• macrocyclizations [44]. Synthesis of steroid–aryl hybrid cages by sequential 2- and 3-fold Ugi-4CR-based macrocyclizations [46]. Ugi-MiBs approach towards natural product-like macrocycles [47]. a) Bidirectional macrocyclization of peptides by double Ugi reaction. b) Ugi-4CR for the generation of exocyclic diversity

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• cages under high-speed vibration milling (HSVM) conditions. The condensation of pentaerythritol and triboronic acid at 58 Hz for 40 min led to the formation of cage structure 22 (Figure 11) with nearly 96% yield [64]. The authors also reported that the cage compounds such as 22 had high thermal

• ester cages of type 22 [64]. Mechanochemical synthesis of borasiloxane-based macrocycles. Mechanochemical synthesis of 2-dimensional aromatic polyamides. Nitschke’s tetrahedral Fe(II) cage 25. Mechanochemical one-pot synthesis of the 22-component [Fe4(AD2)6]4− 26, 11-component [Fe2(BD2)3]2− 27 and 5