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

• across many fields of selective catalysis under the term confinement [3], a term borrowed from heterogeneous catalysis. Polarization can be understood as the catalyst providing an electrostatic environment that works to stabilize electron redistribution. Since all reactions redistribute electrons, and

• catalytically active sites but can promote chemical transformations has received significant attention, but it remains a synthetic challenge [27].” The vague term “confinement” is sometimes used as a catch-all explanation for the property changes that arise within a cavity environment, often in the context of

Oxidation of [3]naphthylenes to cations and dications converts local paratropicity into global diatropicity

• Abel Cárdenas,
• Zexin Jin,
• Yong Ni,
• Jishan Wu,
• Yan Xia,
• Francisco Javier Ramírez and
• Juan Casado

Beilstein J. Org. Chem. 2025, 21, 277–285, doi:10.3762/bjoc.21.20

• angular dication preserves the aromatic–antiaromatic confinement of the neutral and radical cation species. This is an unusual case scarcely described in 1D π-conjugated polycyclic molecules, where the stability of the linear dication is attributed to the formation of a global ring current. Experimental

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

• esterification reactions (Scheme 1). By adjusting the pore size of the support, the catalyst selectivity can be influenced. To counteract the decrease in selectivity caused by catalyst immobilisation, the concept of “confinement” was introduced [62], which involves forcing the catalytic moieties into confined

• spaces. The confinement of the heterogeneous version of cinchona amine and thiourea catalysts was reported, leading to improved enantioselectivity values in the Michael addition of nitromethane (5) to chalcone (6) through modification of the pore size of mesoporous silica 8 or 9 (Scheme 2) [63]. Thus

• area, morphology and pore size of the solid support have a strong influence on the catalytic properties. Innovative approaches such as confinement effects and advanced material designs such as MOFs, COFs and hyperbranched systems offer promising solutions to enhance catalyst efficiency and selectivity

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

• and reversible process named phase 1. We find that the barriers for the radical cation mechanism are significantly lower than those found for the neutral pathway. The peapod is mainly providing one-dimensional confinement for the reaction to take place in a more efficient way. Car–Parrinello

• confinement for the reaction to proceed. The barriers for the reversible phase 1 are found to be easily surmountable at ambient temperature for both the forward and the inverse processes, especially for the dimerization of radical cation fullerenes. For the initial steps of irreversible phase 2, up to six C–C

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface

• Kendra Drayton-White,
• Siyue Liu,
• Yu-Chia Chang,
• Sakashi Uppal and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2022, 18, 1488–1498, doi:10.3762/bjoc.18.156

• Cu(II). Confinement of the Cu(I) catalyst to the selected electrodes was accomplished with the use of oxygen in solution. The oxygen oxidized any Cu(I) before it could migrate to a non-selected electrode. The electrodes selected for the reduction were cycled on an off with each cycle turning the

• electrode on for 90 s and then off for 180 s. This was done to tune the rate of Cu(I) generation to match the rate of Cu(I) oxidation in solution and in so doing optimize confinement of the Cu(I) catalyst to the selected electrodes. Longer "on-times" would lead to more reagent generation making it harder

• for the confinement strategy to keep up. The result is a loss in confinement. It is important to point out that the reaction shown in Scheme 1 is not a typical electrosynthetic reaction. The cross-coupling reaction shown is a Cu(I)-catalyzed transformation that requires no recycling of a reagent

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• processes [5] (Figure 1d): The heterogeneous catalyst remains located in a specific part of the reactor through which the reaction mixture is pumped, which reduces material damage through attrition and the confinement of the catalysts in the packed bed lifts the need for solid separation. If the catalyst is

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• ], cucurbiturils [24][25], and cavitands [26][27] have been widely applied. While these conventional macrocycles can usually enable a confinement effect or serve as a supporting scaffold, they do not contain definite catalytic sites in their cyclic skeletons. When required, an additional catalytic functional group

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• ]. Several examples of supramolecular catalysts [5][6][7] have been introduced in the recent years [3][8] where the catalytic host is designed to bind substrates, accelerate reactions, and steer product [9][10][11][12] and substrate [13][14] selectivities thanks to confinement effects [15][16][17]. Many host

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• environment inside the container. The containers include supramolecular structures self-assembled through metal/ligand interactions or hydrogen bonding and open-ended covalent structures such as cyclodextrins and cavitands. Challenges and prospects for the future are also provided. Keywords: confinement

• reactions occur under confinement in the host. When using a rigidified host F, the secondary alkyl dibromide 22 was transformed to the monoreduced product 23 with high site-selectivity, which benefited from the high KA value (≈1.5 × 105 M−1) (Figure 6c). This work represented the first example of

• monoamine product 47 further underwent intramolecular cyclization facilitated by the confinement of the cavitand and produced cyclized urea product 48. In a following work (Figure 13c) [78], the binding dibromide 49 showed rapid tumbling conformation in the cavity of the cavitand host E on the NMR timescale

Diametric calix[6]arene-based phosphine gold(I) cavitands

• Gabriele Giovanardi,
• Andrea Secchi,
• Arturo Arduini and
• Gianpiero Cera

Beilstein J. Org. Chem. 2022, 18, 190–196, doi:10.3762/bjoc.18.21

• ]. This occurs via strong steric interactions, often outside the macrocycle (Figure 1a) [11], that affect the first coordination sphere of the metal or by creating a spatial confinement around the metal that is thus directed towards the inner cavity (Figure 1b) [26][27]. Contrarily, calix[6]arene

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

Insight into functionalized-macrocycles-guided supramolecular photocatalysis

• Minzan Zuo,
• Krishnasamy Velmurugan,
• Kaiya Wang,
• Xueqi Tian and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2021, 17, 139–155, doi:10.3762/bjoc.17.15

• ]. Republished with permission of The Royal Society of Chemistry from [47] (“Supramolecular photocatalysis by confinement—photodimerization of coumarins within cucurbit[8]urils” by B. C. Pemberton et al., Chem. Commun. vol. 46, © 2010); permission conveyed through Copyright Clearing Center, Inc. Formation of a

Control over size, shape, and photonics of self-assembled organic nanocrystals

• Chen Shahar,
• Yaron Tidhar,
• Yunmin Jung,
• Haim Weissman,
• Sidney R. Cohen,
• Ronit Bitton,
• Iddo Pinkas,
• Gilad Haran and
• Boris Rybtchinski

Beilstein J. Org. Chem. 2021, 17, 42–51, doi:10.3762/bjoc.17.5

• - and morphology-dependent properties arising from confinement effects and strong interactions between neighboring atoms [1][2][3]. The correlation between nanoparticle size and the related electronic and optical properties has extensively been studied, leading to applications in novel technologies and

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• problematic for photovoltaics and photocatalysts but a useful property for OLEDs where the radiative decay of the charge recombination is desired [112][114]. Charge carriers are normally localised to only a few atoms and cause large distortions in the local electronic structure. This small spatial confinement

Probing of local polarity in poly(methyl methacrylate) with the charge transfer transition in Nile red

• Aydan Yadigarli,
• Qimeng Song,
• Sergey I. Druzhinin and
• Holger Schönherr

Beilstein J. Org. Chem. 2019, 15, 2552–2562, doi:10.3762/bjoc.15.248

• polymers possess an enormous impact on the properties of polymers and polymer thin films. For ultrathin films, in which the film thickness is in the order of the radius of gyration, special effects of confinement have been observed. Prominent examples are the properties of substrate-supported ultrathin

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

• ; photochromism; Introduction The importance of confinement for chemical reactivity is becoming increasingly appreciated. Confining reactive species to small volumes can greatly increase their effective molarity and consequently, promote chemical reactions. Such reaction acceleration has been demonstrated at

• ] and, using larger cages, the synthesis of 4 nm silica nanoparticles, which would be difficult to obtain otherwise [15]. One class of organic compounds that exhibit various intriguing properties under confinement is photochromic molecules. In a seminal contribution, unusual switching patterns have been

• affected by their confinement to the surfaces of inorganic nanoparticles. Among other examples, the isomerization kinetics of azobenzene could be tuned by a factor of >5000 by the molecules with which it was co-adsorbed on gold nanoparticles [23], and donor–acceptor Stenhouse adduct (DASA) switches were

Fluorescent phosphorus dendrimers excited by two photons: synthesis, two-photon absorption properties and biological uses

• Anne-Marie Caminade,
• Artem Zibarov,
• Eduardo Cueto Diaz,
• Aurélien Hameau,
• Maxime Klausen,
• Kathleen Moineau-Chane Ching,
• Jean-Pierre Majoral,
• Jean-Baptiste Verlhac,
• Olivier Mongin and
• Mireille Blanchard-Desce

Beilstein J. Org. Chem. 2019, 15, 2287–2303, doi:10.3762/bjoc.15.221

• structure organic fluorophores especially engineered to demonstrate TPA properties and maintain fluorescence upon confinement within the dendrimeric backbone. The presentation will be organized depending on the location of the fluorophores, either as terminal functions, at the core, in the branches, or at

• confinement in the double layer dendrimer has a detrimental influence on the TPA properties [63]. Biological properties of dendrimers having TPA properties Most of the water-soluble fluorescent dendrimers shown in the previous paragraphs have been synthesized for diverse biological purposes. The first type of

Complexation of a guanidinium-modified calixarene with diverse dyes and investigation of the corresponding photophysical response

• Yu-Ying Wang,
• Yong Kong,
• Zhe Zheng,
• Wen-Chao Geng,
• Zi-Yi Zhao,
• Hongwei Sun and
• Dong-Sheng Guo

Beilstein J. Org. Chem. 2019, 15, 1394–1406, doi:10.3762/bjoc.15.139

• complexation of p-sulfonatocalix[n]arenes (SCnAs, n = 4, 5, 6, 8) with ammonium-modified TPE derivatives reported previously by us [54][55]. We assume that the geometrical confinement of P-TPE within GC5A restricts rotational freedom and thus hampers disfavorable non-radiative decay pathways. The inflection

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• for continuous processing. The main issue that has to be solved in such set-up is the tolerability of the catalyst to water (its solubility, its activity, etc.) [55]. A strategy to overcome this problem is the inclusion and confinement of the homogeneous catalysts into a host nano-architecture [56

• of catalysts in a nanoreactor facilitates one-pot tandem reactions that, in most cases, require two or more incompatible catalysts [22][57]. Catalyst confinement leads to a high local concentration of the substrate at the active site, which results in higher reaction rates and better conversion [9

• -assembled nanoreactors are macromolecular architectures that are non-covalently assembled from their constituent building units [58][59]. Such nanoreactors allow for physical confinement of catalysts, shielding them from their surroundings [60]. Compartmentalization of catalysts in supramolecular

Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs)

• Thanh-Tuân Bui,
• Fabrice Goubard,
• Malika Ibrahim-Ouali,
• Didier Gigmes and
• Frédéric Dumur

Beilstein J. Org. Chem. 2018, 14, 282–308, doi:10.3762/bjoc.14.18

• , optimization of the device stacking, an appropriate choice of the host as well as the materials in the adjacent layers, an adequate dopant concentration, and the efficient confinement of excitons within the emissive layer are primordial parameters to elaborate high performance OLEDs while maintaining the color

• ° between the donor unit and the nearby phenylene linker for T29 and T30 was confirmed by quantum chemical calculations. Resulting from the almost perfect orthogonality, a good confinement of the electronic density of the two orbitals was obtained with a HOMO level predominantly located on the donor and a

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

• Carmen Moreno-Marrodan,
• Francesca Liguori and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• , selective liquid phase flow processes for the fine-chemicals synthesis, including partial hydrogenations, usually requires a more intimate contact with the heterogeneous catalyst to be efficient. One example is the so-called "confinement effect" found in mesoporous catalytic materials [77][78]. Catalytic

Interactions between photoacidic 3-hydroxynaphtho[1,2-b]quinolizinium and cucurbit[7]uril: Influence on acidity in the ground and excited state

• Jonas Becher,
• Daria V. Berdnikova,
• Darinka Dzubiel,
• Heiko Ihmels and
• Phil M. Pithan

Beilstein J. Org. Chem. 2017, 13, 203–212, doi:10.3762/bjoc.13.23

• restrictions of the molecular movement of the guest ligand provided by confinement of the latter inside the host cavity. Nevertheless, the titrations show that the binding process depends on the pH of the solution (Figure 7), indicating the interference of the prototropic equilibrium (see below) with the host

Diels–Alder reactions in confined spaces: the influence of catalyst structure and the nature of active sites for the retro-Diels–Alder reaction

• Ángel Cantín,
• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2016, 12, 2181–2188, doi:10.3762/bjoc.12.208

• and selectivity is the special confinement of the reactants and the presence of catalytic active sites, [15][16] by use of microporous materials doped with metals. While pore dimensions and topology of the microporous materials can affect the selectivity of the reaction, their activity can be strongly

• framework and extra framework composition of mesoporous materials and zeolite could be used to control the selectivity of the DAR of cyclopentadiene and p-benzoquinone. In the present work, a series of large pore, pure silica zeolites (in which rate enhancement can only occur by spatial confinement) and the

• . The effect of confinement of the reactant within the pores of the catalyst can decrease the entropy of the activated complex [17][18][19][20][21][22][23][24][25][26][29][30] producing not only an increase of the reaction rate but also a modification of the selectivity. To study this effect, we have

Ru complexes of Hoveyda–Grubbs type immobilized on lamellar zeolites: activity in olefin metathesis reactions

• Hynek Balcar,
• Naděžda Žilková,
• Martin Kubů,
• Michal Mazur,
• Zdeněk Bastl and
• Jiří Čejka

Beilstein J. Org. Chem. 2015, 11, 2087–2096, doi:10.3762/bjoc.11.225

• restrictions in coordination of bulky molecules; we can speculate about some confinement in the coordination sphere of Ru in HGIIN+Cl−/MCM-22 (partial immersion of HGIIN+Cl− into support cavities and/or other deformation of the coordination sphere as a result of immobilization). When the initiation passed with

Anomalous diffusion of Ibuprofen in cyclodextrin nanosponge hydrogels: an HRMAS NMR study

• Monica Ferro,
• Franca Castiglione,
• Carlo Punta,
• Lucio Melone,
• Walter Panzeri,
• Barbara Rossi,
• Francesco Trotta and
• Andrea Mele

Beilstein J. Org. Chem. 2014, 10, 2715–2723, doi:10.3762/bjoc.10.286

• dynamic regimes is triggered by the polymer structure. CDNSEDTA 1:4 is characterized by a nanoporous structure able to induce confinement effects on IP, thus causing subdiffusive random motion. CDNSEDTA 1:8 is characterized not only by nanopores, but also by dangling EDTA groups ending with ionized COO

• )2 to achieve sufficient contrast. The picture clearly illustrates the porous morphology of the material and the structural heterogeneities in the pore size distribution. Confinement effects are expected to drive the diffusion process from normal to subdiffusive behaviour and interaction with the

• observed on IP in CDNSEDTA 1:8 can be rationalized as a complex balance of the confinement effects and the electrostatic acceleration, with the latter dominating on the former. As a final remark, we mention that the pH variations occurring during the preparative steps affording the drug-loaded hydrogels