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

• [329][330][331], superbases [332][333][334][335][336], or non-specific arrays of hydrogen-bond donors [337]/acceptors [338]. Advances in post-assembly modifications [339] have recently allowed stable organic cages featuring endohedral (internally directed) functionality [340][341], or metals [342][343

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• (CF2H); fluorine; hydrogen bond donors; hydrogen bond strength; Introduction Hydrogen bonding interactions are ubiquitous non-covalent forces in chemistry and biology [1][2][3][4]. In canonical hydrogen bond (HB) donor–acceptor pairs, the donor typically comprises an electronegative heteroatom, such as

• oxygen, nitrogen, or sulfur, and a positively charged hydrogen atom, which interacts with a lone pair on the acceptor. Apart from these common heteroatom-containing hydrogen bond donors, certain carbon–hydrogen moieties can also act in this way, although in a substantially weaker capacity [5][6][7][8][9

• weak inverse association was observed between ΔGexp and ΔδDMSO–CDCl3 values for neutral hydrogen bond donors (Figure 6D). This result suggests that the CF2H···O interactions are likely to be a predominant contributor to the binding between HB donating and accepting molecules but other weak

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• nitrogen atom which is prone to interacting with hydrogen-bond donors or Brønsted acids decreasing the LUMO energy of the diene. This review article aims to give an overview of the non-covalent organocatalyzed cyclization reactions involving α,β-unsaturated imines. Although most of the cyclization

• covered in this review are hydrogen-bond donors such as thioureas and squaramides, Brønsted bases such as tertiary amines, and Brønsted acids such as chiral phosphoric acids. As depicted in Figure 4, a bifunctional squaramide is able to activate both an α,β-unsaturated imine through hydrogen bonding with

• reviews [17][18]. Review Hydrogen bond donors: bifunctional thioureas and squaramides The use of bifunctional catalysts is commonplace in organocatalyzed transformations [19][20][21][22][23]. These catalysts are able to activate an electrophile and a nucleophile simultaneously and in IEDADA reactions they

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• that function as hydrogen-bond donors and acceptors. Additionally, the nitrogen atoms in the pyrrole units of the porphyrin structure can also act as Lewis bases, capable of donating electron pairs. These properties enable tetrapyrrolic macrocycles to act as effective binding sites or catalytically

• addition of furan-based silyloxydiene synthons to a variety of achiral aldehydes using four different calix[4]pyrrole macrocycles (3, 4, 11, and 12) as organocatalysts (Figure 3) [38]. These calixpyrrole macrocycles acted as hydrogen-bond donors, activating substrate aldehydes through hydrogen-bonding

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• guanidine motif in AA-3 compared to simple AA-1. Alterations in the thiol structure within thiomalonates significantly impact their stability and reactivity, thereby influencing both reaction efficiency and stereochemical outcome, as demonstrated in the case of catalysis employing bifunctional hydrogen bond

• donors [29]. In the context of imine catalysis using acid, the catalyst AQ-1's ability to abstract protons from bisthiomalonate, thereby activating the nucleophile may be at least restricted. Consequently, we chose to investigate the impact of the thioester group on the outcome, including stereochemical

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• expands the considerable reaction space in organocatalysis. The discussed principle of mechanistic transferability has also been employed outside of CPA catalysis, with a focus on amine-based hydrogen-bond donors, for example imidodiphosphorimidate-type catalysts for the construction of THF and THP rings

• [107] (Figure 11B). Werth and Sigman [127] investigated multiple nucleophilic additions to nitroalkenes, catalysed by bifunctional hydrogen bond donors, observing good correlations to new bi-functional donors, new nucleophiles, new electrophiles and even similar cascade-type reactions. In the authors

• complement and augment experimental chemistry. In addition to these methods, Corminboeuf and co-workers [134] proposed a genetic algorithm for the de novo design of general catalysts (Figure 14). Considering the Pictet–Spengler cyclization of tryptamine derivatives catalysed by hydrogen-bond donors, the

Novel truxene-based dipyrromethanes (DPMs): synthesis, spectroscopic characterization and photophysical properties

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2024, 20, 2163–2170, doi:10.3762/bjoc.20.186

• of a variety of biologically important anions due to the presence of two pyrrolic NH hydrogen bond donors [38][39][40][41][42][43]. Notably, in the past few decades, the chemistry of DPMs have attested to be imperative in the existing chemical research because of their easy syntheses, good stability

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• combination with an ML model to predict a variety of properties. These properties encompass the site of metabolism [31][33], the strengths of hydrogen bond donors and acceptors [34][35][36], and the regioselectivity of electrophilic aromatic substitution reactions [14]. Building on the methodology from

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• Figure 3). The blue shift is more pronounced for those zwitterions not bearing any hydrogen-bond-donating functional groups. Accordingly, it is plausible to explain the blue-shifted absorption maxima of 2b and 2h in chloroform by a more polar environment of the chromophore caused by the hydrogen-bond

• donors attached to the alkyl substituent of the phosphonium center (Figure 3). This hypothesis is further supported by the observation of two very different chemical shifts for the two amide protons in the 1H NMR spectrum of 2b in CDCl3 giving resonance at 5.21 and 8.58 ppm. Kinetic studies In the next

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• amines 52 with 2,5-DMTHF (2) under a L-(+)-tartaric acid-choline chloride based deep eutectic solvent as green medium (Scheme 25a). Deep eutectic solvents (DESs) are mainly synthesized by mixing quaternary ammonium salts and hydrogen-bond donors. In this study, various combinations of salts and hydrogen

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• -unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov

• isolated in 54% yield (Table 1, entry 8). The exchange of chloride with the non-coordinating BF4− anion, driven by the precipitation of NaCl, is proposed to be responsible for this positive result. Next, we turned our attention to the use of hydrogen-bond donors as anion-binding catalysts [57][58]. To this

• amount to promote the aza-Nazarov reactions investigated in this study, the results discussed above showcase the potential of strong hydrogen-bond donors as effective anion binding catalysts for this transformation. Finally, it should be noted that all aza-Nazarov products that are presented in Table 1

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• coupling, or deprotonation followed by the functionalization of α- and β-positions of the starting aldehyde. NHC-catalyzed photochemical processes [64] and oxidative cyclizations with heterocycle formation [65] were reviewed previously. Acidic molecules or hydrogen-bond donors are used as organocatalysts

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• transformations using chiral Brønsted acids, Brønsted base, and hydrogen bond donors. Recently noncovalent activation continues to expand into other types of weak attractive interactions such as halogen and chalcogen bonds. Not surprisingly, all activation modes allow further expansion and diversification via a

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• bifunctional hydrogen-bonding catalyst would activate both CPD via a tertiary amino group of a quinuclidine moiety acting as a base via anion-binding, and an oxindole through the squaramide or thiourea moieties of the catalyst as hydrogen bond donors (Figure 1) [29][30][31][32]. Therefore, squaramide and

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• inversion of the local electronic environment, or the precise deletion of hydrogen-bond donors, respectively, with minimal steric variation [7]. The latter aspect is a crucial determinant in enabling fluorinated materials to adopt intriguing conformations which are a manifest representation of stabilising

Anion-driven encapsulation of cationic guests inside pyridine[4]arene dimers

• Anniina Kiesilä,
• Jani O. Moilanen,
• Anneli Kruve,
• Christoph A. Schalley,
• Perdita Barran and
• Elina Kalenius

Beilstein J. Org. Chem. 2019, 15, 2486–2492, doi:10.3762/bjoc.15.241

• + formed complexes with 1 and 12, neither using electrospray ionization (ESI) in the positive nor the negative mode. Pr4N+ is certainly too large to fit inside the dimeric capsule, whereas the other non-complexing cations are protic and – as rather strong hydrogen-bond donors – may interfere with

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

• chemistry. Different hydrogen bond donors such as pyrrole N–H and benzene C–H along with the triazolium C5–H have been successfully incorporated within a single macrocyclic framework. The complex formation of anions with the hydrogen bond donors varied according to the polarity of the solvent. It was found

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

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

• . In 2008, they have established a [2 + 2] photodimerization through solid-state grinding either in neat or liquid-assisted conditions [93]. To achieve 100% stereospecific products they considered resorcinol derivatives as hydrogen-bond donors for the photodimerization of 1,2-di(pyridin-4-yl)ethylene

• reaction through solid-state grinding. Hydrogen-bond donors are a) resorcinol and b) 1,8-dipyridylnaphthalene, respectively. Formation of the cage and encapsulation of [2.2]paracyclophane guest molecule in the cage was done simultaneously under mechanochemical conditions. Formation of the 1:1 complex C60

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• both catalysts gave the Michael adduct in excellent yields, high ees were obtained only when 54b was used as organocatalyst (up to 94% ee, Scheme 16). During the last decade, squaramide catalysts have become a powerful alternative to the urea/thiourea and guanidine catalysts as multiple hydrogen bond

• donors in order to design novel bifunctional catalytic scaffolds [54][55]. Hybrid calixarene hosts bearing bis-squaramide moieties at the endo (or lower) and exo (or upper) rims and their recognition properties toward anionic guests have been already reported [56][57]. Therefore, it would be interesting

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• C–F activation of benzylic fluorides for nucleophilic substitutions and Friedel–Crafts reactions, using a range of hydrogen bond donors such as water, triols or hexafluoroisopropanol (HFIP) as the activators. This study examines the stereointegrity of the C–F activation reaction through the use of

• ]. Protocols using water/isopropanol [3], optimally coordinated triols [4][5], and hexafluoroisopropanol (HFIP) [6][7] as the corresponding hydrogen bond donors have shown considerable success. This mode of activation has been demonstrated for amination [3][4][5] and Friedel–Crafts reactions [6][7] on benzylic

• also occurs via an associated ion pair, rather than the fully solvated carbocation. Conclusion In summary, we have analyzed the stereochemical outcomes of substitution and Friedel–Crafts reactions of 7-[2H1]-(R)-benzyl fluoride ((R)-1), mediated by C–F activation using hydrogen-bond donors. When strong

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• of organocatalysis. While traditional hydrogen bond donors containing N–H and O–H moieties have been effectively used for electrophile activation, activation based on other types of non-covalent interactions is less common. This mini review highlights recent progress in developing and exploring new

• these efforts. The use of synthetic hydrogen bond donors for the activation of neutral or ionic electrophiles has been one of the major focuses of these research efforts in the past two decades (Figure 1) [1]. Many privileged hydrogen bond donor scaffolds capable of forming single or double hydrogen

• and energy, and is often invoked to rationalize the outcome of various transformations [21][22][23][24][25][26][27]. However, until recently C–H hydrogen bond-based interactions have not been employed in rational organic catalyst design, and more traditional A–H hydrogen bond donors such as I–IX

Creating molecular macrocycles for anion recognition

• Amar H. Flood

Beilstein J. Org. Chem. 2016, 12, 611–627, doi:10.3762/bjoc.12.60

• ). The motivation for this new work was to generalize the idea of activating CH hydrogen bond donors using electron-withdrawing groups. In cyanostilbene, Lee recognized the cyano group could polarize the CH bond. Following some molecular modeling, he settled on a five-fold symmetric target that demanded

• using click chemistry and to prepare another potent binding pocket for anions composed solely of CH hydrogen bond donors. Now just a little larger than cyanostars at 4.8 Å, their affinities showed peak affinity for slightly larger anions (Figure 16b). The tricarb structure is highly planar and this is

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• (Figure 1). Some examples of these properties are rigidity, disposition of the two stereogenic centers, ability of the hydroxy and amino groups to coordinate to some metals or to act as hydrogen-bond donors/acceptors, the different catalytic activity of these chemical groups and their possible

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• ; urea and thiourea moieties have also been proposed to interact with nucleophiles. Besides the fact that hydrogen bond donors increase the electrophilicity of the substrates, they mostly coordinate the transition state of the reaction, controlling this way the stereoselectivity of the products. It has

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors

• Ming-Liang Zhang,
• Deng-Feng Yue,
• Zhen-Hua Wang,
• Yuan Luo,
• Xiao-Ying Xu,
• Xiao-Mei Zhang and
• Wei-Cheng Yuan

Beilstein J. Org. Chem. 2016, 12, 295–300, doi:10.3762/bjoc.12.31

• 100049, China 10.3762/bjoc.12.31 Abstract For the first time, a catalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones was achieved with a chiral bifunctional amine-thiourea as a catalyst possessing multiple hydrogen-bond donors. With this developed method, a range of 3-hydroxy-3-nitromethyl-1H

• sites, have captured tremendous attention in particular due to their unique ability of the simultaneous activation of the nucleophile and the electrophile in the same transition state [7][8][9][10][11]. Among them, chiral bifunctional thioureas bearing multiple hydrogen-bond donors have been

• -pyrrole-2,3-diones with a chiral bifunctional amine-thiourea possessing multiple hydrogen-bond donors as the catalyst. With the developed protocol, a range of 3-hydroxy-3-nitromethyl-1H-pyrrol-2(3H)-ones bearing quaternary stereocenters were obtained in good yield (up to 75%) and with moderate to good