Macrocyclic Amides Research Articles

Mechanical insulation of aza-Pechmann dyes within [2]rotaxanes.

Aza-Pechmann derivatives have emerged as interesting building blocks for the preparation of organic electronic devices. The development of methodologies aimed to enhance their chemical stability and modulate their physical and chemical properties constitutes an interesting goal. Here we report the synthesis of mechanically interlocked aza-Pechmann dyes with benzylic amide macrocycles, along with the study of how the mechanical bond impacts their stability, photophysical and redox properties. Rotaxanes composed of Pechmann dilactams as threads exhibit one of the highest energy barriers for macrocyclic ring rotation, highlighting the strength of the attractive interactions ring-thread within the interlocked structure. Their enhanced thermal stability, compared to the non-interlocked counterparts, evidences the protective role of the macrocycle. Computational and electrochemical analyses indicate that the benzylic amide macrocycle improves the stability of the HOMO and LUMO orbitals of the interlocked dyes. Finally, spectroscopic and electrochemical data reveal that the macrocycle subtly modulates the optoelectronic and redox behaviour of the Pechmann dilactams.

Synthesis and spontaneous self-assembly of non-planar aromatic amide macrocycles

We report here the self-assembly behavior of a series of nonplanar phenanthroline-based macrocycles bearing polyaromatic bridges. Even without any directional noncovalent interaction, they undergo spontaneous self-assembly and produce well-defined nanostructures....

Ring-to-Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams.

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

Ring‐to‐Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

Hydrogen-bonded aromatic amide macrocycles: synthesis, properties and functions.

As a classic example of nearly planar cyclic compounds, hydrogen-bonded aromatic amide (H-bonded aramide) macrocycles, consisting of consecutive intramolecular hydrogen bonds and aromatic residues, receive considerable research attention due to their rich host-guest chemistry. This review provides a detailed summary of the synthesis, properties and functions of H-bonded aramide macrocycles and their derivatives. Herein, the constitutional patterns of these macrocycles are divided into two subcategories: interior hydrogen bonding motifs and exterior hydrogen bonding motifs. Based on these two motifs, we summarize the facile synthesis, self-assembly, host-guest interaction complexation of H-bonded aramide macrocycles and the resulting applications such as molecular recognition, artificial ion channels, soft materials, supramolecular catalysis, and artificial molecular machines. The development of H-bonded aramide macrocycles is still in its infancy, although a considerable number of examples have been reported. We hope that this review will provide useful information and unlock new opportunities in this field.

Chiroptical Sensing of Amino Acid Derivatives by Host-Guest Complexation with Cyclo[6]aramide.

A hydrogen-bonded (H-bonded) amide macrocycle was found to serve as an effective component in the host–guest assembly for a supramolecular chirality transfer process. Circular dichroism (CD) spectroscopy studies showed that the near-planar macrocycle could produce a CD response when combined with three of the twelve L-α-amino acid esters (all cryptochiral molecules) tested as possible guests. The host–guest complexation between the macrocycle and cationic guests was explored using NMR, revealing the presence of a strong affinity involving the multi-point recognition of guests. This was further corroborated by density functional theory (DFT) calculations. The present work proposes a new strategy for amplifying the CD signals of cryptochiral molecules by means of H-bonded macrocycle-based host–guest association, and is expected to be useful in designing supramolecular chiroptical sensing materials.

Effective Encapsulation of C60 by Metal-Organic Frameworks with Polyamide Macrocyclic Linkers.

A flexible benzylic amide macrocycle, functionalized with two carboxylic acid groups, was employed as the organic ligand for the preparation of robust copper(II)- and zinc(II)-based metal-organic frameworks. These polymers crystallized in the C2/m space group of the monoclinic crystal system, creating non-interpenetrated channels in one direction with an extraordinary solvent-accessible volume of 46 %. Unlike metal-organic rotaxane frameworks having benzylic amide macrocycles as linkers, the absence of the thread in these novel reticular materials causes a decrease of dimensionality and an improvement of pore size and dynamic guest adaptability. We studied the incorporation of fullerene C60 inside the adjustable pocket generated between two macrocycles connected to the same dinuclear clusters, occupying a remarkable 98 % of the cavities inside the network. The use of these materials as hosts for the selective recognition of different fullerenes was evaluated, mainly encapsulating the smaller size fullerene derivative in several mixtures of C60 and C70 .

Effective Encapsulation of C60 by Metal–Organic Frameworks with Polyamide Macrocyclic Linkers

AbstractA flexible benzylic amide macrocycle, functionalized with two carboxylic acid groups, was employed as the organic ligand for the preparation of robust copper(II)‐ and zinc(II)‐based metal–organic frameworks. These polymers crystallized in the C2/m space group of the monoclinic crystal system, creating non‐interpenetrated channels in one direction with an extraordinary solvent‐accessible volume of 46 %. Unlike metal–organic rotaxane frameworks having benzylic amide macrocycles as linkers, the absence of the thread in these novel reticular materials causes a decrease of dimensionality and an improvement of pore size and dynamic guest adaptability. We studied the incorporation of fullerene C60 inside the adjustable pocket generated between two macrocycles connected to the same dinuclear clusters, occupying a remarkable 98 % of the cavities inside the network. The use of these materials as hosts for the selective recognition of different fullerenes was evaluated, mainly encapsulating the smaller size fullerene derivative in several mixtures of C60 and C70.

Real-Time Fluctuations in Single-Molecule Rotaxane Experiments Reveal an Intermediate Weak Binding State during Shuttling.

We report on the use of atomic force microscopy (AFM) to identify and characterize an intermediate state in macrocycle shuttling in a hydrogen bonded amide-based molecular shuttle. The [2]rotaxane consists of a benzylic amide macrocycle mechanically locked onto a thread that bears both fumaramide and succinic amide-ester sites, each of which can bind to the macrocycle through up to four intercomponent hydrogen bonds. Using AFM-based single-molecule force spectroscopy, we mechanically triggered the translocation of the ring between the two principal binding sites ("stations") on the axle. Equilibrium fluctuations reveal another interacting site involving the two oxygen atoms in the middle of the thread. We characterized the ring occupancy distribution over time, which confirms the intermediate in both shuttling directions. The study provides evidence of weak hydrogen bonds that are difficult to detect using other methods and shows how the composition of the thread can significantly influence the shuttling dynamics by slowing down the ring motion between the principal binding sites. More generally, the study illustrates the utility that single-molecule experiments, such as force spectroscopy, can offer for elucidating the structure and dynamics of synthetic molecular machines.

Switchable supramolecular ensemble for anion binding with ditopic hydrogen-bonded macrocycles

A novel supramolecular strategy has been proposed by using a ditopic H-bonded amide macrocycle that is capable of controlling the binding process in response to external stimulus due to its assembly-and-disassembly-induced anion binding.

The Effects of the Solvents on the Macrocyclic Structures: From Rigid Pillararene to Flexible Crown Ether

The differences in the macrocyclic structures lead to different flexibilities, and yet the effect of solvents on the conformations is not clear so far. In this work, the conformations of four representational macrocyclic molecules (pillar[5]arene, p-tert-butyl calix[6]arene, benzylic amide macrocycle and dibenzo-18-crown-6) in three solvents with distinct polarity have been studied by all-atom molecular dynamics simulations. The structural features of the macrocycles in the solvents indicate that the conformations are related to the polarity of the solvents and the formation of hydrogen bonds. For the pillar[5]arene, the benzylic amide macrocycle and the dibenzo-18-crown-6, that cannot form intramolecular hydrogen bonds, the polarity of solvents is the major contributing factor in the conformations. The formation of intramolecular hydrogen bonds, in contrast, determinates the conformations of the calix[6]arene. Furthermore, the slight fluctuations of the structures will result in tremendous change of the intramolecular hydrogen bonds of the macrocycles and the intermolecular hydrogen bonds between the macrocycles and the solvents. The current theoretical studies that serve as a basis for the macrocyclic chemistry are valuable for the efficient structural design of the macrocyclic molecules.

The influence of high pressure on static combinatorial libraries of chiral BINOL-based macrocyclic amides

In this work we presented two-, three-, and four-substrate static combinatorial libraries (SCLs) obtained via macrocyclization of BINOL-based dimethyl ester and five α,ω-diaminoethers of varying lengths. We investigated the distribution of macrocyclic products and measured the conversion of ester, comparing the results under atmospheric pressure to those obtained under high pressure conditions. Overall, we found that pressurization had a great impact on the proportions between macrocyclic products, promoting diamides with smaller macrocyclic cavities, i.e. those formed with shorter diaminoethers. Furthermore, static combinatorial chemistry (SCC) approach allow us to receive various potential macrocyclic receptors in single experiment.

A Novel Cyclic Mobile Transporter Can Induce Apoptosis by Facilitating Chloride Anion Transport into Cells.

We report here the preparation of an aminoxy amide-based pseudopeptide-derived building block using furanoid sugar molecules. Through the cyclo-oligomerization reaction, we generate a hybrid triazole/aminoxy amide macrocycle using the as-prepared building block. The novel conformation of the macrocycle has been characterized using NMR and molecular modeling studies, which show a strong resemblance of our synthesized compound to d-,l-α-aminoxy acid-based cyclic peptides that contain uniform backbone chirality. We observe that the macrocycle can efficiently and selectively bind Cl– ion and transport Cl– ion across a lipid bilayer. 1H NMR anion binding studies suggest a coherent relationship between the acidity of aminoxy amide N–H and triazole C–H proton binding strength. Using time-based fluorescence assay, we show that the macrocycle acts as a mobile transporter and follows an antiport mechanism. Our synthesized macrocycle imposes cancer cell death by disrupting ionic homeostasis through Cl– ion transport. The macrocycle induced cytochrome c leakage and changes in mitochondrial membrane potential along with activation of family of caspases, suggesting that the cellular apoptosis occurs through a caspase-dependent intrinsic pathway. The present results suggest the possibility of using the macrocycle as a biological tool of high therapeutic value.

A Versatile Approach to Dynamic Amide Bond Formation with Imine Nucleophiles.

Dynamic covalent chemistry has rapidly become an important approach to access supramolecular structures. While the products generated in these reactions are held together by covalent bonds, the reversible nature of the transformations can limit the utility of many these systems in creating robust materials. We describe herein a method to form stable and commonly employed amide bonds by exploiting the reversible coupling of imines and acyl chlorides. The reaction employs easily accessible reagents, is dynamic under ambient conditions, without catalysts, and can be trapped with simple hydrolysis. This offers an approach to create broad families of amide products under thermodynamic control, including the selective formation of amide macrocycles or polymers.

Synthesis, antimicrobial activity, and ion transportation investigation of four new [1 + 1] condensed furan and thiophene‐based cycloheterophane amides

AbstractFour new macrocyclic compounds with thiophene (L1 and L2) and furan (L3 and L4) rings were synthesized and characterized by IR, 1H NMR, 13C NMR, and Q‐TOF spectral data. Macrocyclic amides (L1, L2, L3, and L4) were tested for ion transportation with Na+ and K+ ions, and also, antimicrobial activities were investigated against the Gram‐negative Escherichia coli ATCC 25922, Gram‐positive Staphylococcus aureus ATCC 25923, Gram‐negative Listeria monocytogenes ATCC 19115, Gram‐negative Salmonella typhimurium ATCC 14028, Bacillus cereus bacteria, and Candida albicans ATCC 10231 for all amides.

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

Light-controlled switchable complexation by a non-photoresponsive hydrogen-bonded amide macrocycle

A light controlled switchable host–guest system based on a non-photoresponsive H-bonded macrocycle and pyridinium salts was developed using a photoacid.

Efficient Straightforward Synthesis of Amidopiperazinophanes as Versatile Novel Supramolecular Scaffolds

A simple one-pot synthesis of amidopiperazinophanes with a combination of electron-deficient amide groups and electron-rich alkyne and piperazine functionalities has been achieved by using multicomponent reaction (MCR) methodology with the Mannich reaction. Herein, we demonstrate the synthesis of macrocyclic amide structures in good yields. These macrocycles, with electron donor/acceptor sites, are versatile molecules for host–guest and binding.

Dynamic Control of Chiral Space Through Local Symmetry Breaking in a Rotaxane Organocatalyst.

We report on a switchable rotaxane molecular shuttle that features a pseudo-meso 2,5-disubstituted pyrrolidine catalytic unit on the axle whose local symmetry is broken according to the position of a threaded benzylic amide macrocycle. The macrocycle can be selectively switched (with light in one direction; with catalytic acid in the other) with high fidelity between binding sites located to either side of the pyrrolidine unit. The position of the macrocycle dictates the facial bias of the rotaxane-catalyzed conjugate addition of aldehydes to vinyl sulfones. The pseudo-meso non-interlocked thread does not afford significant selectivity as a catalyst (2-14 % ee), whereas the rotaxane affords selectivities of up to 40 % ee with switching of the position of the macrocycle changing the handedness of the product formed (up to 60 % Δee).

Dynamic Control of Chiral Space Through Local Symmetry Breaking in a Rotaxane Organocatalyst

AbstractWe report on a switchable rotaxane molecular shuttle that features a pseudo‐meso 2,5‐disubstituted pyrrolidine catalytic unit on the axle whose local symmetry is broken according to the position of a threaded benzylic amide macrocycle. The macrocycle can be selectively switched (with light in one direction; with catalytic acid in the other) with high fidelity between binding sites located to either side of the pyrrolidine unit. The position of the macrocycle dictates the facial bias of the rotaxane‐catalyzed conjugate addition of aldehydes to vinyl sulfones. The pseudo‐meso non‐interlocked thread does not afford significant selectivity as a catalyst (2–14 % ee), whereas the rotaxane affords selectivities of up to 40 % ee with switching of the position of the macrocycle changing the handedness of the product formed (up to 60 % Δee).