Folding Patterns in a Family of Oligoamide Foldamers

A series of small, unsymmetrical pyridine‐2,6‐dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @‐type folding pattern resembled the oxyanion‐hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen‐bonding patterns and aryl–aryl interactions. In the solid state, the foldamers adopted either the globular @‐type fold or the more extended S‐type conformers, which were very similar to those foldamers obtained computationally. In some cases, the same foldamer molecule could even crystallize into two different folding patterns, thus confirming that the different folding patterns are very close in energy in spite of their completely different shapes. Finally, the best match for the observed NOE interactions in the liquid state was a conformation that matched the computationally characterized helix‐type fold.     

Phenylene Ethynylene‐Tethered Perylene Bisimide Folda‐Dimer and Folda‐Trimer: Investigations on Folding Features in Ground and Excited States

In this work, we have elucidated in detail the folding properties of two perylene bisimide (PBI) foldamers composed of two and three PBI units, respectively, attached to a phenylene ethynylene backbone. The folding behaviors of these new PBI folda‐dimer and trimer have been studied by solvent‐dependent UV/Vis absorption and 1D and 2D NMR spectroscopy, revealing facile folding of both systems in tetrahydrofuran (THF). In CHCl₃ the dimer exists in extended (unfolded) conformation, whereas partially folded conformations are observed in the trimer. Temperature‐dependent ¹H NMR spectroscopic studies in [D₈]THF revealed intramolecular dynamic processes for both PBI foldamers due to, on the one hand, hindered rotation around C?N imide bonds and, on the other hand, backbone flapping; the latter process being energetically more demanding as it was observed only at elevated temperature. The structural features of folded conformations of the dimer and trimer have been elucidated by different 2D‐NMR spectroscopy (e.g., ROESY and DOSY) in [D₈]THF. The energetics of folding processes for the PBI dimer and trimer have been assessed by calculations applying various methods, particularly the semiempirical PM6‐DH2 and the more sophisticated B97D approach, in which relevant dispersion corrections are included. These calculations corroborate the results of NMR spectroscopic studies. Folding features in the excited states of these PBI foldamers have been characterized by using time‐resolved fluorescence and transient absorption spectroscopy in THF and CHCl₃, exhibiting similar solvent‐dependent behavior as observed for the ground state. Interestingly, photoinduced electron transfer (PET) process from electron‐donating backbone to electron‐deficient PBI core for extended, but not for folded, conformations was observed, which can be explained by a fast relaxation of excited PBI stacks in the folded conformation into fluorescent excimer states.     

Oligocholate foldamers as carriers for hydrophilic molecules across lipid bilayers

Three cholate foldamers were synthesized by the click reaction between an azide-functionalized cholate trimer and different dialkynyl linkers. The foldamers were labeled with pyrene groups at the ends for their conformational study. The linkers between the two tricholate fragments were found to strongly influence the conformation of the foldamers in solution, as well as their ability to transport hydrophilic molecules across lipid bilayers. The folding of the oligocholates in mixed organic solvents was studied by fluorescence and UV/Vis spectroscopy. Although these molecules could not fold permanently in lipid bilayers, they were found to translocate carboxyfluorescein readily across by a carrier-based mechanism. The transport is proposed to happen when the oligocholates adopt transiently folded structures with a hydrophobic exterior and a hydrophilic internal cavity. The transport rate strongly depended on the structure of the oligocholates and was sensitive even to the change of a single bond in a foldamer 3000 Da in MW. Better folded oligocholates in solution gave slower transport in the membranes.     

Oligoamide Foldamers as Helical Chloride Receptors—the Influence of Electron‐Withdrawing Substituents on Anion‐Binding Interactions

The anion‐binding properties of three closely related oligoamide foldamers were studied using NMR spectroscopy, isothermal titration calorimetry and mass spectrometry, as well as DFT calculations. The ¹H NMR spectra of the foldamers in [D₆]acetone solution revealed partial preorganization by intramolecular hydrogen bonding, which creates a suitable cavity for anion binding. The limited size of the cavity, however, enabled efficient binding by the inner amide protons only for the chloride anion resulting in the formation of a thermodynamically stable 1:1 complex. All 1:1 chloride complexes displayed a significant favourable contribution of the entropy term. Most likely, this is due to the release of ordered solvent molecules solvating the free foldamer and the anion to the bulk solution upon complex formation. The introduction of electron‐withdrawing substituents in foldamers 2 and 3 had only a slight effect on the thermodynamic constants for chloride binding compared to the parent receptor. Remarkably, the binding of chloride to foldamer 3 not only produced the expected 1:1 complex but also open aggregates with 1:2 (host:anion) stoichiometry.     

锡-铟促进和微波辐射辅助下醛和炔丙基溴的炔丙基化反应

A rapid and regioselective preparation of homopropargyl alcohols was reported. In the presence of SnCl2C6HsMe3NBr and microwave irradiation, the mixture of tin-indium and propargyl bromide reacted quickly with aldehydes in aqueous media to produce the homopropargyl alcohols exclusively in high yields. For benzaldehydes bearing different substituents, electronic effect of the substituents affected the reaction, the electron-withdrawing groups promoting the reaction and the electron-donating groups impeding the reaction. The reactions of benzaldehydes bearing an ortho substituent group on the phenyl ring with propargyl bromide may yield a mixture of regioisomers （homopropargyl and homoallenyl alcohols） or a single homoallenic alcohol due to the steric effect.     

Bright,Fluorescent Dyes Based on Imidazo[1,2‐a]pyridines that are Capable of Two‐Photon Absorption

A library of imidazo[1,2‐a]pyridines was synthesized by using the Gevorgyan method and their linear and non‐linear optical properties were studied. Derivatives that contained both electron‐donating and electron‐withdrawing groups at the 2 position were comprehensively investigated. Their emission quantum yield ranged between 0.2–0.7 and it was shown to depend on the substitution pattern, most notably that on the phenyl ring. Electron‐donating substituents improved the luminescence performance of these compounds, whereas electron‐withdrawing substituents led to a more erratic behavior. Substitution on the six‐membered ring had less effect on the fluorescence properties. Extension of the delocalization increased the luminescence quantum yield. A new quadrupolar system was designed that contained two imidazo[1,2‐a]pyridine units on its periphery and a 1,4‐dicyanobenzene unit at its center. This system exhibited a large Stokes‐shifted luminescence that was affected by the polarity and rigidity of the solvent, which was ascribed to emission from an excited state with strong charge‐transfer character. This quadrupolar feature also led to an acceptable two‐photon absorption response in the NIR region.     

Conformational Control of Oligo(p‐phenyleneethynylene)s with Intrinsic Substituent Electronic Effects: Origin of the Twist in Pentiptycene‐Containing Systems

Dependence of the backbone planarity of oligo(p‐phenyleneethynylene)s (OPEs) on the intrinsic electronic character of substituents and on the nature of the solvent has been experimentally demonstrated with a series of center‐symmetrical five‐ring systems, pentiptycene‐pentiptycene‐arene‐pentiptycene‐pentiptycene, differing in the substituents on the central arene. In frozen 2‐methyltetrahydrofuran (MTHF), the adjacent pentiptycene units prefer to be in a mutually twisted orientation when the substituents are electron‐withdrawing (F and amido), resulting in a TPPT or TTTT conformation, whereas a planarized PPPP backbone is favored in the case of electron‐donating substituents (alkyl and alkoxy). The propensity to adopt the PPPP form is generally enhanced by replacing MTHF with either methylcyclohexane or mixed ethanol/methanol as solvent. These observations reveal that the twist between adjacent pentiptycene units in OPEs is a consequence of the electronic rather than steric effects of iptycenyl substituents. The electronic effect of iptycenyl substituents is manifested in decreased phenylene π polarizability as the net effect of both electron‐donating hyperconjugation and an electron‐withdrawing inductive effect. Variable‐temperature electronic absorption and emission spectroscopies are the critical tools for this work. Our findings provide important guidelines for conformational and electronic engineering of OPEs and for the design of novel iptycene‐based organic electronic materials.     

Regioselective formylation of 1,3-disubstituted benzenes through in situ lithiation

A facile method of regioselective formylation of disubstituted benzene via in situ deprotonation/metalation using n-BuLi/TMEDA/DIPA has been developed. Effect of different electron withdrawing and electron donating substituents in 1,3-interrelated aromatic system was studied; the metalation mostly occurred at the 2-position to afford the desired products in high yields.     

Folding‐Induced Modulation of Excited‐State Dynamics in an Oligophenylene–Ethynylene‐Tethered Spiral Perylene Bisimide Aggregate

The excited‐state photophysical behavior of a spiral perylene bisimide (PBI) folda‐octamer ( F8 ) tethered to an oligophenylene–ethynylene scaffold is comprehensively investigated. Solvent‐dependent UV/Vis and fluorescence studies reveal that the degree of folding in this foldamer is extremely sensitive to the solvent, thus giving rise to an extended conformation in CHCl₃ and a folded helical aggregate in methylcyclohexane (MCH). The exciton‐deactivation dynamics are largely governed by the supramolecular structure of F8 . Femtosecond transient absorption (TA) in the near‐infrared region indicates a photoinduced electron‐transfer process from the backbone to the PBI core in the extended conformation, whereas excitation power‐ and polarization‐dependent TA measurements combined with computational modeling showed that excitation energy transfer between the unit PBI chromophores is the major deactivation pathway in the folded counterpart.     

A foldamer at the liquid/graphite interface: the effect of interfacial interactions, solvent, concentration, and temperature

The unfolding process and self-assembly of a foldable oligomer (foldamer 1) at the liquid/graphite interface were investigated by scanning tunnelling microscopy. At the level of molecular conformation, we identified several molecular conformations (A(z), B, C, D, E) that represent intermediate states during unfolding, which may help to elucidate the unfolding process at the liquid/graphite interface. Adsorption at the interface traps the intermediate states of the unfolding process, and STM has proved to be a powerful technique for investigating folding and unfolding of a foldamer at the molecular level, which are not accessible by other methods. The STM observations also revealed that varying the solvent and/or concentration results in different self-assemblies of foldamer 1 as a result of variations in molecular conformations. The solvent and concentration effects were attributed to the changes in existing states (extended or folded) of foldamers in solution, which in turn affect the distribution of adsorbed molecular conformations at the interface. This mechanism is quite different from other systems in which solvent and concentration effects were also observed.     

A regioselective palladium-free protocol for accessing unsymmetrical biaryls through ring transformation of 6-aryl-α-pyrones

A regioselective synthesis of unsymmetrical biaryls with electron withdrawing or donating substituents is described and illustrated by carbanion-induced ring transformation of 6-aryl-α-pyrones with methoxyacetone in excellent yield. Our methodology is an alternative to classical organometal-catalyzed aryl-aryl coupling reactions and can be applied to the synthesis of functionally demanding naphthyl biaryls for the development of new ligands for asymmetric synthesis.     

Helical Folding Competing with Unfolded Aggregation in Phenylene Ethynylene Foldamers

The folding and aggregation behavior of a pair of oligo(phenylene ethynylene) (OPE) foldamers are investigated by means of UV/Vis absorption and circular dichroism spectroscopy. With identical OPE backbones, two foldamers, 1 with alkyl side groups and 2 with triethylene glycol side chains, manifest similar helical conformations in solutions in n‐hexane and methanol, respectively. However, disparate and competing folding and aggregation processes are observed in alternative solvents. In cyclohexane, oligomer 1 initially adopts the helical conformation, but the self‐aggregation of unfolded chains, as a minor component, gradually drives the folding–unfolding transition eventually to the unfolded aggregate state completely. In contrast, in aqueous solution (CH₃OH/H₂O) both folded and unfolded oligomer 2 appear to undergo self‐association; aggregates of the folded chains are thermodynamically more stable. In solutions with a high H₂O content, self‐aggregation among unfolded oligomers is kinetically favored; these oligomers very slowly transform into aggregates of helical structures with greater thermodynamic stability. The folded–unfolded conformational switch thus takes place with the free (nonaggregated) molecules, and the very slow folding transition is due to the low concentration of molecularly dispersed oligomers.     

Preparation of 5,5′‐pyrilidene and 5,5′‐quinolidene bis‐barbituric acid derivatives

NMR reaction following experiments were used to find optimal conditions for the barbituric acid double addition to aromatic and heteroaromatic carboxaldehydes. It was established that aromatic aldehydes with electron‐donating substituents such as hydroxy, methoxy, and dimethylamino produce only the single addition barbituric acid adduct (barbituric acid benzylidenes). If these electron‐donating substituents are transformed into electron‐withdrawing substituents by virtue of protonation (NMe₂ to NHMe₂⁺) then the double barbituric acid adduct becomes the sole product of the reaction. This is also true regardless of the reaction media if strong electron‐withdrawing substituents (such as a nitro group) are present. Considering that the reactive species for nitrogen containing aromatic heterocycles are actually the conjugated acids (electron deficient molecule) only the double barbituric acid adducts are isolated. All synthetic procedures presented are applicable to multi‐gram scale preparations of double barbituric acid adducts.     

Foldamer structuring by covalently bound macromolecules

We used fluorescence and electronic absorption spectroscopy to study the molecular weight dependence of macromolecule-induced folding in a chain-centered meta-phenylene ethynylene (mPE) oligomer. Analogous to the ability of intrinsically unstructured proteins (IUPs) to induce folding of globular proteins in cellular environments, we show that macromolecules attached to both ends of an mPE dodecamer induce the foldamer to collapse into a presumed helical conformation. The collapse is especially prominent once the macromolecule segments become larger than ca. 50 kDa. For sufficiently large macromolecules, the conformational structuring occurs even in solvents that normally denature the foldamer. Based on these findings, chain-centered foldamers might find use as models to investigate the fundamental macromolecular physics of IUPs.     

Mechanochromism,Twisted/Folded Structure Determination,and Derivatization of (N‐Phenylfluorenylidene)acridane

(N‐Phenylfluorenylidene)acridane (Ph‐FA) compounds with electron‐withdrawing and ‐donating substituents (H, MeO, Ph, NO₂, Br, F) at the para position of the phenyl group were successfully synthesized by Barton–Kellogg reactions of N‐aryl thioacridones and diazofluorene. By using the substituent on the nitrogen atom to alter the electronic properties, both the folded and twisted conformers of p‐NO₂‐C₆H₄‐FA could be crystallographically characterized, which enabled the charge transfer from the electron‐donating acridane moiety to the electron‐accepting fluorenylidene moiety to be understood. Ground‐state mechanochromism, thermochromism, vapochromism, and proton‐induced chromism were demonstrated between the folded and twisted conformations of the conformers. Protonation and chemical oxidation of Ph‐FA gave two stable acridinium compounds, namely, the fluorenylacridinium and acridinium radical cations. The present study will contribute to the development of functional dyes and organic semiconductors.     

Amphipathic helices from aromatic amino acid oligomers

Synthetic helical foldamers are of significant interest for mimicking the conformations of naturally occurring molecules while at the same time introducing new structures and properties. In particular, oligoamides of aromatic amino acids are attractive targets, as their folding is highly predictable and stable. Here the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived amino acids having either hydrophobic or cationic side chains are described. Their structures were characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR. Results of these studies suggest that an oligomer as short as a pentamer folds into a stable helical conformation in protic solvents, including MeOH and H(2)O. The introduction of polar proteinogenic side chains to these foldamers, as described here for the first time, promises to provide possibilities for the biological applications of these molecules. In particular, amphipathic helices are versatile targets to explore due to their importance in a variety of biological processes, and the unique structure and properties of the quinoline-derived oligoamides may allow new structure-activity relationships to be developed.     

Mechanochromism,Twisted/Folded Structure Determination,and Derivatization of (N‐Phenylfluorenylidene)acridane

(N‐Phenylfluorenylidene)acridane (Ph‐FA) compounds with electron‐withdrawing and ‐donating substituents (H, MeO, Ph, NO₂, Br, F) at the para position of the phenyl group were successfully synthesized by Barton–Kellogg reactions of N‐aryl thioacridones and diazofluorene. By using the substituent on the nitrogen atom to alter the electronic properties, both the folded and twisted conformers of p‐NO₂‐C₆H₄‐FA could be crystallographically characterized, which enabled the charge transfer from the electron‐donating acridane moiety to the electron‐accepting fluorenylidene moiety to be understood. Ground‐state mechanochromism, thermochromism, vapochromism, and proton‐induced chromism were demonstrated between the folded and twisted conformations of the conformers. Protonation and chemical oxidation of Ph‐FA gave two stable acridinium compounds, namely, the fluorenylacridinium and acridinium radical cations. The present study will contribute to the development of functional dyes and organic semiconductors.     

Synthesis of Phenylene Vinylene Macrocycles through Acyclic Diene Metathesis Macrocyclization and Their Aggregation Behavior

A series of phenylene vinylene macrocycles (PVMs) bearing substituents with various sizes and electronic properties have been synthesized through a one‐step acyclic diene metathesis macrocyclization approach and their aggregation behaviors have been investigated. In great contrast to the aggregation of the analogous phenylene ethynylene macrocycles, which aggregate only when substituted with electron‐withdrawing groups, these PVMs undergo exceptionally strong aggregation, regardless of the electron‐donating or ‐withdrawing characters of the substituents. The unusual aggregation behavior of the PVMs is further investigated with thermodynamic and computer modeling studies, which show a good agreement with the recently proposed direct through‐space interaction model, rather than the polar/π model. The high aggregation tendency of PVMs suggests the great potential of this novel class of shape‐persistent macrocycles in a variety of applications, such as ion channels, host–guest recognition, and catalysis.     

Development of one-pot benzylic amination reactions of azine N-oxides

An efficient one-pot synthetic methodology has been developed for the benzylic amination reactions of methyl-substituted azine N-oxides that operate under mild conditions. The reaction was found to tolerate quinoline and isoquinoline N-oxides with electron donating and withdrawing substituents as the electrophilic reaction partners as well as a broad range of nucleophilic primary, secondary and aromatic amines, affording the benzylic amination products in up to 82% yield.     

Polarity‐Dependent Isomerization of an Unsymmetrical Overcrowded Ethylene Promoted by Zwitterionic Contribution in the Twisted Isomer

The twisted form of bianthrone is known as a metastable state provided by a photo‐induced or thermal‐induced isomerization of the folded form, and thus prevents the isolation and the detailed analysis of its electronic structure. In this study, an unsymmetrical bianthrone ( 2 ), consisting of the electron‐withdrawing anthrone and electron‐donating acridane, have been synthesized and shown to exhibit a solvent‐polarity‐dependent isomerization reaction between the folded and twisted isomers. With increasing the polarity of the solvent, 2 showed an isomerization reaction from the folded form to the twisted form. The stabilization of the twisted isomer in polar solvents can be interpreted as proof of its relatively large zwitterionic character. The DMF solution of 2 displayed paramagnetically‐broadened NMR signals from the thermally populated triplet state resulting from rotation of the weakened ethylenic double bond of the twisted isomer.