Engineering Amino Acid and Peptide Supramolecular Architectures through Fluorination.

Fluorinated non-natural amino acids are attracting considerable research interest, especially in the biomedical field and in materials science, thanks to their ability to self-assemble into peculiar supramolecular structures. The conformational changes induced by the presence of fluorine atoms obviously affect their functions, as well as the biological activity of the deriving peptides and proteins. Here, we will briefly describe the main effects of fluorination on the aggregation behavior of such building blocks, focusing in particular on their improved tendency to form fibrils, and gels therefrom. Our aim is to underline the promising potential of fluorination as a tool to affect the self-assembly features of amino acids, both when used alone and when inserted into polypeptide sequences. The ability of fluorine to influence physical, chemical, and structural properties of these substrates offers the possibility to engineer bioinspired materials with specific and tunable functions.

Acid⋠⋠⋠Amide Supramolecular Synthon for Tuning Amino Acid-Based Hydrogels' Properties.

Invited for the cover of this issue is the Laboratory of Supramolecular and Bio-Nanomaterials, coordinated by Pierangelo Metrangolo, at the Politecnico di Milano, Italy. The image depicts the co-crystal formed by N-Fmoc-pentafluorophenylalanine and benzamide, which is also involved in the formation of their mixed hydrogels. Read the full text of the article at 10.1002/chem.202301743.

Acid⋠⋠⋠Amide Supramolecular Synthon for Tuning Amino Acid-Based Hydrogels' Properties.

Supramolecular hydrogels formed by the self-assembly of N-Fmoc-l-phenylalanine derivatives are gaining relevance for several applications in the materials and biomedical fields. In the challenging attempt to predict or tune their properties, we selected Fmoc-pentafluorophenylalanine (1) as a model efficient gelator, and studied its self-assembly in the presence of benzamide (2), a non-gelator able to form strong hydrogen bonds with the amino acid carboxylic group. Equimolar mixtures of 1 and 2 in organic solvents afforded a 1 : 1 co-crystal thanks to the formation of an acid⋅⋅⋅amide heterodimeric supramolecular synthon. The same synthon occurred in the transparent gels formed by mixing the two components in 1 : 1 ratio in aqueous media, as revealed by structural, spectroscopic, and thermal characterizations performed on both the co-crystal powder and the lyophilized hydrogel. These findings revealed the possibility of modulating the properties of amino acid-based hydrogels by involving the gelator in the formation of a co-crystal. Such a crystal engineering-based approach is shown also to be useful for the time-delayed release of suitable bioactive molecules, when involved as hydrogel coformers.

Photoluminescent nanocluster-based probes for bioimaging applications.

In the continuous search for versatile and better performing probes for optical bioimaging and biosensing applications, many research efforts have focused on the design and optimization of photoluminescent metal nanoclusters. They consist of a metal core composed by a small number of atoms (diameter < 2-3 nm), usually coated by a shell of stabilizing ligands of different nature, and are characterized by molecule-like quantization of electronic states, resulting in discrete and tunable optical transitions in the UV-Vis and NIR spectral regions. Recent advances in their size-selective synthesis and tailored surface functionalization have allowed the effective combination of nanoclusters and biologically relevant molecules into hybrid platforms, that hold a large potential for bioimaging purposes, as well as for the detection and tracking of specific markers of biological processes or diseases. Here, we will present an overview of the latest combined imaging or sensing nanocluster-based systems reported in the literature, classified according to the different families of coating ligands (namely, peptides, proteins, nucleic acids, and biocompatible polymers), highlighting for each of them the possible applications in the biomedical field.

BODIPY Dyes Bearing Multibranched Fluorinated Chains: Synthesis, Structural, and Spectroscopic Studies.

A small series of boron-dipyrromethene (BODIPY) dyes, characterized by the presence of multibranched fluorinated residues, were designed and synthesized. The dyes differ in both the position (para-perfluoroalkoxy-substituted phenyl ring or boron functionalization) and number of magnetically equivalent fluorine atoms (27 or 54 fluorine atoms per molecule). Photophysical and crystallographic characterization of the synthesized BODIPYs was carried out to evaluate the effect of the presence of highly fluorinated moieties on the optical and morphological properties of such compounds.

On the molecular optical nonlinearity of halogen-bond-forming azobenzenes.

We study hyper-Rayleigh scattering and computed molecular hyperpolarizability in a series of azobenzene chromophores in chloroform and dimethylformamide as solvents. The chromophores form halogen or hydrogen bonds of varying strength with dimethylformamide molecules, differently from what is expected for chloroform. We show that hyperpolarizability is unaffected or sligthly lower with the azobenzene forming the strongest halogen bond. Solid supramolecular polymers with the same chromophores have previously demonstrated clearly higher second-order nonlinear responses when a halogen-bond-accepting polymer is used, the larger increase being associated with the stronger halogen bond. The present study proves that the higher optical nonlinearity in polymers lies in the better ordering of the chromophores instead of changes in molecular hyperpolarizability, highlighting the unique properties of halogen bonding in supramolecular chemistry.

Crystallographic insights into the self-assembly of KLVFF amyloid-beta peptides.

Amyloidogenic peptide fragment KLVFF (H2 N-Lys-Leu-Val-Phe-Phe-COOH, Aß16-20 ), the core-sequence of the polypeptide Aß40, is a well-studied model for amyloid formation. However, due to its low crystallinity, detailed atomic information of KLVFF structure is lacking. Here we report the high-resolution single-crystal X-ray structure of two monohalogenated KLVFF derivatives, KLVFF(I) and KLVFF(Br). The obtained results highlight how halogenation is a good strategy to promote crystallization and facilitate the phase determination of KLVFF(I) and KLVFF(Br) fragments. Detailed structural studies on the packing features of both monohalogenated derivatives reveal the role of the halogen atoms showing that when they are positioned on the Phe aromatic moiety at the C-terminus they do not form halogen bonds and thus do not produce any extra stabilization of the ß-sheet in the self-assembly process. The structural evidences gained from these studies corroborate the various polymorphic nanostructures of the halogenated variants of KLVFF and confirm the possibility to use halogenation as innovative strategy to tune the morphology of this pentapeptide.

Photoresponsive ionic liquid crystals assembled via halogen bond: en route towards light-controllable ion transporters.

We demonstrate that halogen bonding (XB) can offer a novel approach for the construction of photoresponsive ionic liquid crystals. In particular, we assembled two new supramolecular complexes based on 1-ethyl-3-methylimidazolium iodides and azobenzene derivatives containing an iodotetrafluoro-benzene ring as XB donor, where the iodide anion acted as an XB acceptor. DSC and X-ray diffraction analyses revealed that the preferred stoichiometry between the XB donors and acceptors is 2 : 1, and that the iodide anions act as bidentate XB-acceptors, binding two azobenzene derivatives. Due to the high directionality of the XB, calamitic superanions are obtained, while the segregation occurring between the charged and uncharged parts of the molecules gives rise to a layered structure in the crystal lattice. Despite the fact that the starting materials are non-mesomorphic, the halogen-bonded supramolecular complexes exhibited monotropic lamellar liquid-crystalline phases over broad temperature ranges, as confirmed with polarized optical microscopy. Due to the presence of the azobenzene moieties, the LCs were photoresponsive, and a LC-to-isotropic phase transition could be obtained by irradiation with UV light. We envisage that the light-induced phase transition, in combination with the ionic nature of the LC, provides a route towards light-induced control over ion transport and conductance in these supramolecular complexes.

Surface-Relief Gratings in Halogen-Bonded Polymer-Azobenzene Complexes: A Concentration-Dependence Study.

In recent years, supramolecular complexes comprising a poly(4-vinylpyridine) backbone and azobenzene-based halogen bond donors have emerged as a promising class of materials for the inscription of light-induced surface-relief gratings (SRGs). The studies up to date have focused on building supramolecular hierarchies, i.e., optimizing the polymer-azobenzene noncovalent interaction for efficient surface patterning. They have been conducted using systems with relatively low azobenzene content, and little is known about the concentration dependence of SRG formation in halogen-bonded polymer-azobenzene complexes. Herein, we bridge this gap, and study the concentration dependence of SRG formation using two halogen-bond-donating azobenzene derivatives, one functionalized with a tetrafluoroiodophenyl and the other with an iodoethynylphenyl group. Both have been previously identified as efficient molecules in driving the SRG formation. We cover a broad concentration range, starting from 10 mol % azobenzene content and going all the way up to equimolar degree of complexation. The complexes are studied as spin-coated thin films, and analyzed by optical microscopy, atomic force microscopy, and optical diffraction arising during the SRG formation. We obtained diffraction efficiencies as high as 35%, and modulation depths close to 400 nm, which are significantly higher than the values previously reported for halogen-bonded polymer-azobenzene complexes.

Synthesis and Linker-Controlled Self-Assembly of Dendritic Amphiphiles with Branched Fluorinated Tails.

Amphiphiles containing fluorinated segments tend to aggregate in the aqueous solution into structure of lower curvature than their hydrocarbon analogs due to their larger diameter. A benefit of supramolecular structures incorporating fluorine moieties is their high electron density, which can be viewed in cryo-TEM with better contrast than their hydrogenated forms. A modular approach has been developed for the synthesis of a new family of nonionic branched amphiphiles consisting of oligoglycerol units (G2) as the hydrophilic part and a branched fluorinated (F27) hydrophobic part. The design of this hydrophobic moiety allows to achieve a higher fluorine density than the previously used straight-chain perfluoroalkanes. Two different chemical approaches, amide, and triazole, are used to link the hydrophilic and hydrophobic segments. In addition, the aggregation behavior is investigated by dynamic light scattering (DLS) and cryo-TEM. The measurements prove the formation of multivesicular (MVVs) and multilamellar (MLVs) vesicles as well as smaller unilamellar vesicles. Further, the cell viability test proves the low cell toxicity of these nanoarchitectures for potential biomedical applications.

High-resolution crystal structure of a 20 kDa superfluorinated gold nanocluster.

Crystallization of atomically precise nanoclusters is gaining increasing attention, due to the opportunity of elucidating both intracluster and intercluster packing modes, and exploiting the functionality of the resulting highly pure crystallized materials. Herein, we report the design and single-crystal X-ray structure of a superfluorinated 20 kDa gold nanocluster, with an Au25 core coated by a shell of multi-branched highly fluorinated thiols (SF27) resulting in almost 500 fluorine atoms, i.e., ([Au25(SF27)18]0). The cluster shows a switchable solubility in the fluorous phase. X-ray analysis and computational studies reveal the key role of both intracluster and intercluster F···F contacts in driving [Au25(SF27)18]0 crystal packing and stabilization, highlighting the ability of multi-branched fluorinated thiols to endow atomically precise nanoclusters with remarkable crystallogenic behavior.

Cationic and radical intermediates in the acid photorelease from aryl sulfonates and phosphates.

The irradiation of a series of phenyl sulfonates and phosphates leads to the quantitative release of acidity with a reasonable quantum yield (≈0.2). Products characterization, ion chromatography analysis and potentiometric titration are consistent with the intervening of two different paths in this reaction, viz. cationic with phosphates and (mainly) radical with sulfonates.

Waterproof-breathable films from multi-branched fluorinated cellulose esters.

Cellulose ester films were prepared by esterification of cellulose with a multibranched fluorinated carboxylic acid, "BRFA" (BRanched Fluorinated Acid), at different anhydroglucose unit:BRFA molar ratios (i.e., 1:0, 10:1, 5:1, and 1:1). Morphological and optical analyses showed that cellulose-BRFA materials at molar ratios 10:1 and 5:1 formed flat and transparent films, while the one at 1:1 M ratio formed rough and translucent films. Degrees of substitution (DS) of 0.06, 0.09, and 0.23 were calculated by NMR for the samples at molar ratios 10:1, 5:1, and 1:1, respectively. ATR-FTIR spectroscopy confirmed the esterification. DSC thermograms showed a single glass transition, typical of amorphous polymers, at -11 °C. The presence of BRFA groups shifted the mechanical behavior from rigid to ductile and soft with increasing DS. Wettability was similar to standard fluoropolymers such as PTFE and PVDF. Finally, breathability and water uptake were characterized and found comparable to materials typically used in textiles.

Solarylations via 4-aminophenyl cations.

The application of the photo-S(N)1 reaction on some 4-chloroanilines was explored under solar irradiation in view of obtaining a convenient metal-free arylation method. Several reactions previously carried out by UV irradiation, as well as some new ones, where either a new trap (alpha-methylstyrene) or a new halide (N,N-dimethyl-4-fluoroaniline) were adopted, were studied under these conditions and found to occur conveniently. Furthermore, at least in some cases the halide starting concentration could be raised up to 0.2 M, the excess trapping agent reduced from 20:1 to 2.5:1, and the solvent replaced by more environmentally friendly (co)solvents including water. Under these improved conditions, the photoarylation was carried out in a gram scale by merely exposing the solution to solar irradiation. This process has a low impact on the environment and can be considered a serious competitor of metal-catalyzed arylations.

Confined space design by nanoparticle self-assembly.

Nanoparticle (NP) self-assembly has led to the fabrication of an array of functional nanoscale systems, having diverse architectures and functionalities. In this perspective, we discuss the design and application of NP suprastructures (SPs) characterized by nanoconfined compartments in their self-assembled framework, providing an overview about SP synthetic strategies reported to date and the role of their confined nanocavities in applications in several high-end fields. We also set to give our contribution towards the formation of more advanced nanocompartmentalized SPs able to work in dynamic manners, discussing the opportunities of further advances in NP self-assembly and SP research.

The diiodomethyl-sulfonyl moiety: an unexplored halogen bond-donor motif.

Herein, we report the crystal structures of the antimicrobial agent diiodomethyl-p-tolylsulfone and of three halogen bonded co-crystals demonstrating that the bioactive moiety -SO2CHI2 can function as a quite effective halogen bond based motif in the solid state and in solution, namely demonstrating that α-iodosulfones may become a new entry in the quite small group of alkyl-iodides functioning as reliable halogen bond-donors.

Halogen bond-assisted self-assembly of gold nanoparticles in solution and on a planar surface.

Halogen bonding (XB) has been shown to be a powerful tool for promoting molecular self-assembly in different fields. The use of XB for noncovalent assembly of inorganic nanoparticles (NP) is, instead, quite limited, considering how extensively other interactions (i.e., electrostatic forces, hydrophobic effect, hydrogen bonding, etc.) have been exploited to modulate and program NP self-assembly. Here, we designed and synthesized XB-capable organic ligands that were efficiently used to functionalize the surface of gold NPs (AuNPs). XB-assisted AuNP self-assembly was attained in solution mixing AuNPs bearing XB-donor ligands with ditopic XB-acceptor molecules and AuNPs functionalized with XB-acceptor moieties. Likewise, a preliminary study of XB-driven adsorption of these AuNPs on surface was performed via Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D), used as an in situ tool for measuring mass changes upon XB-driven self-assembly.

The beta effect of silicon in phenyl cations.

Irradiation of chloroanisoles, phenols, and N,N-dimethylanilines bearing a trimethylsilyl (TMS) group in the ortho position with respect to the chlorine atom caused photoheterolysis of the Ar-Cl bond and formation of the corresponding ortho-trimethylsilylphenyl cations in the triplet state. The beta effect of silicon on these intermediates has been studied by comparing the resulting chemistry in alcoholic solvents with that of the silicon-free analogues and by computational analysis (at the UB3LYP/6-311+G(2d,p) level in MeOH). TMS groups little affect the photophysics and the photocleavage of the starting phenyl chlorides, while stabilizing the phenyl cations, both in the triplet (ca. 4 kcal/mol per group) and, dramatically, in the singlet state (9 kcal/mol). As a result, although triplet phenyl cations are the first formed species, intersystem crossing to the more stable singlets is favored with chloroanisoles and phenols. Indeed, with these compounds, solvent addition to give aryl ethers (from the singlet) competed efficiently with reduction or arylation (from the triplet). In the case of the silylated 4-chloro-N,N-dimethylaniline, the triplet cation remained in the ground state and trapping by pi nucleophiles remained efficient, though slowed by the steric bulk of the TMS group. In alcohols, the silyl group was eliminated via a photoinduced protiodesilylation during the irradiation. Thus, the silyl group could be considered as a directing, photoremovable group that allowed shifting to the singlet phenyl cation chemistry and was smoothly eliminated in the same one-pot procedure.