Disentangling the Puzzling Regiochemistry of Thiol Addition to o-Quinones.

The addition of thiol compounds to o-quinones, as exemplified by the biologically relevant conjugation of cysteine to dopaquinone, displays an anomalous 1,6-type regiochemistry compared to the usual 1,4-nucleophilic addition, for example, by amines, which has so far eluded intensive investigations. By means of an integrated experimental and computational approach, herein, we provide evidence that the addition of glutathione, cysteine, or benzenethiol to 4-methyl-o-benzoquinone, modeling dopaquinone, proceeds by a free radical chain mechanism triggered by the addition of thiyl radicals to the o-quinone. In support of this conclusion, DFT calculations consistently predicted the correct regiochemistry only for the proposed thiyl radical-quinone addition pathway. These results would prompt a revision of the commonly accepted mechanisms for thiol-o-quinone conjugation and stimulate further work aimed at assessing the impact of the free radical processes in biologically relevant thiol-quinone interactions.

High-Energy Proton-Beam-Induced Polymerization/Oxygenation of Hydroxynaphthalenes on Meteorites and Nitrogen Transfer from Urea: Modeling Insoluble Organic Matter?

Formation and structural modification of oxygenated polycyclic aromatic hydrocarbons (oxyPAHs) by UV irradiation on minerals have recently been proposed as a possible channel of PAH transformation in astrochemical and prebiotic scenarios of possible relevance for the origin of life. Herein, it is demonstrated that high-energy proton-beam irradiation in the presence of various meteorites, including stony iron, achondrite, and chondrite types, promotes the conversion of two representative oxyPAH compounds, 1-naphthol and 1,8-dihydroxynaphthalene, to complex mixtures of oxygenated and oligomeric derivatives. The main identified products include polyhydroxy derivatives, isomeric dimers encompassing benzofuran and benzopyran scaffolds, and, notably, a range of quinones and perylene derivatives. Addition of urea, a prebiotically relevant chemical precursor, expanded the range of identified species to include, among others, quinone diimines. Proton-beam irradiation of oxyPAH modulated by nitrogen-containing compounds such as urea is proposed as a possible contributory mechanism for the formation and processing of insoluble organic matter in meteorites and in prebiotic processes.

Proton-Sensitive Free-Radical Dimer Evolution Is a Critical Control Point for the Synthesis of Δ2,2'-Bibenzothiazines.

The mechanism of the acid-dependent interring dehydrogenation in the conversion of the single-bonded 3-phenyl-2H-1,4-benzothiazine dimer 2 to the Δ2,2'-bi(2H-1,4-benzothiazine) scaffold of red hair pigments is disclosed herein. Integrated chemical oxidation and oxygen consumption experiments, coupled with electron paramagnetic resonance (EPR) analyses and DFT calculations, allowed the identification of a key diprotonated free-radical intermediate, which was implicated in a remarkable oxygen-dependent chain process via peroxyl radical formation and evolution to give the Δ2,2'-bi(2H-1,4-benzothiazine) dimer 3 by interring dehydrogenation. The critical requirement for strongly acidic conditions was rationalized for the first time by the differential evolution channels of isomeric peroxyl radical intermediates at the 2- versus 3-positions. These results offer for the first time a rationale to expand the synthetic scope of the double interring dehydrogenation pathway for the preparation of novel symmetric double-bond bridged captodative heterocycles.

The phenoxyl group-modulated interplay of cation-π and σ-type interactions in the alkali metal series.

The interaction potential energy surfaces (IPESs) of four alkaline metal cations (Na+, K+, Rb+ and Cs+) complexed with phenol and catechol were explored by accurate ab initio calculations to investigate the interplay of different noncovalent interactions and their behavior along the alkali metal series and upon -OH substitution. Selected one-dimensional interaction energy curves revealed two different minimum energy configurations for all phenol- and catechol-metal complexes, characterized either by cation-π or σ-type interactions. For each investigated complex several two-dimensional IPES maps were also computed, exploiting the computational advantages of the MP2mod approach. The size of the alkali cation was found to play a similar role in modulating both kinds of complexes, as the interaction strength always decreases along the metal series, from Na+ to Cs+. Conversely, the number of hydroxyl substituents markedly affected cation-π complexes vs. σ-type ones. As a most relevant finding, in catechol-metal complexes the strength of cation-π interactions is around half that of the σ-type ones. It is argued that the combined effect of cation dimensions and hydroxyl substitution in catechol-Na+ complexes makes σ-type configurations remarkably more stable and easily accessible than cation-π ones. Besides shedding new light on the origin of biological phenomena connected with underwater adhesion, the quantum mechanical interaction energy database provided herein may offer a useful reference for tuning accurate force fields, suitable for molecular dynamics simulations, where environmental effects might be also taken into account.

Benchmarking Cation-π Interactions: Assessment of Density Functional Theory and Möller-Plesset Second-Order Perturbation Theory Calculations with Optimized Basis Sets (mp2mod) for Complexes of Benzene, Phenol, and Catechol with Na+, K+, Rb+, and Cs.

The reliability of several density functional theory (DFT) functionals and of the Möller-Plesset second-order perturbation theory calculations with modified basis sets (mp2mod) approach in describing cation-π interactions is systematically investigated by benchmarking their performances with respect to high quality reference CCSD(T) calculations of the binding energies between alkaline cations of varying radius (Na+, K+, Rb+, and Cs+) and three aromatic species (benzene, phenol, and catechol). For this class of noncovalent interaction, mp2mod delivers, on average, results in very good agreement with the reference CCSD(T) data, yet at a very small computational cost, exploiting the reduced dimensions of the modified basis set. Conversely, the tested DFT functionals show a more erratic behavior, with different performances depending on both the investigated system and the combination of the employed functional and basis set. The mp2mod computational convenience is further exploited to extensively sample two-dimensional interaction energy surfaces of all investigated cation-π systems, which allow for a deeper insight on the effect of the increasing number of hydroxyl substituents, revealing the insurgence, upon substitution, of alternative minima, evident in particular for the smaller cations. The present results strongly support for further applications of the mp2mod method to study a larger variety of aromatic/metal cation species, relevant both in biological processes and in technological applications.

A Clean and Tunable Mussel-Inspired Coating Technology by Enzymatic Deposition of Pseudo-Polydopamine (ψ-PDA) Thin Films from Tyramine.

The tyrosinase-catalyzed oxidation of tyramine, leading to the deposition of pseudo-polydopamine (ψ-PDA) thin films, is disclosed herein as a superior technology for surface functionalization and coating at a neutral pH and at a low substrate concentration, compared to the standard autoxidative PDA coating protocols. Smooth ψ-PDA thin films of variable thickness up to 87 nm were obtained from 1 mM tyramine by varying tyrosinase concentrations (5-100 U/mL). Compared to the PDA films obtained by the similar enzymatic oxidation of 1 mM dopamine with tyrosinase (T-PDA), ψ-PDA displayed slower deposition kinetics, lower water contact angles in the range of 11°-28°, denoting higher hydrophilicity but similar UV-vis absorption profiles, as well as electrochemical properties and antioxidant activity. MALDI-MS analysis indicated for ψ-PDA a well defined pattern of peaks compatible with dopamine tetrameric structures degraded to a variable extent. The exposure to a tyramine solution of tyrosinase-loaded alginate spheres, or films deposited on glass or polyethylene, resulted in a rapid gel-confined ψ-PDA formation with no leakage or darkening of the solution, allowing the complete recovery and re-utilization of the unreacted tyramine. In contrast, an abundant PDA precipitation outside the gel was observed with dopamine under the same conditions. The ψ-PDA deposition by tyrosinase-catalyzed tyramine oxidation is thus proposed as a controllable and low-waste technology for selective surface functionalization and coating or for clean eumelanin particle production.

Bioinspired Heterocyclic Partnership in a Cyanine-Type Acidichromic Chromophore.

A new red hair-inspired 1,4-benzothiazine-based scaffold is disclosed herein, built upon a modular D-π-A architecture via condensation of the easily accessible 3-phenyl-2H-1,4-benzothiazine with indole-3-carboxaldehyde. The compound was obtained in around 50% yields and was characterized by complete spectroscopic analysis. The new benzothiazine-based cyanine displayed a characteristic reversible acidichromic behavior with a marked bathochromic shift upon acidification. The chromophore resisted at least fifteen hydrochloric acid/sodium hydroxide cycles without appreciable alterations. The expedient and scalable synthetic procedure together with the pH sensitive chromophoric properties would make the new compound an attractive prototype for novel modular chromophore for pH-sensing and other applications.

Melanin Biopolymers: Tailoring Chemical Complexity for Materials Design.

Melanins, a group of dark insoluble pigments found widespread in nature, have become the focus of growing interest in materials science for various biomedical and technological applications, including opto-bioelectronics, nanomedicine and mussel-inspired surface coating. Recent progress in the understanding of melanin optical, paramagnetic redox, and conductivity properties, including photoconductivity, would point to a revision of the traditional concept of structural disorder in terms of more sophisticated and interrelated levels of chemical complexity which however have never been defined and codified. Herein, we bring to focus the various levels of structural disorder that emerged from spectral and chemical signatures over the past decade. A revised approach to structure-property relationships in terms of intermolecular interactions is also provided that may pave the way towards the rational design of next-generation melanin-based functional materials.

Deposition of Aminomalononitrile-Based Films: Kinetics, Chemistry, and Morphology.

In the last few years, the development of versatile coating chemistries has become a hot topic in surface science after the discovery that catecholamines can lead to conformal coatings upon oxidation from aqueous solutions. Recently, it was found that aminomalononitrile (AMN), a molecule implicated in the appearance of life on earth, is an excellent prototype of novel material-independent surface functionalizing agents leading to conformal and biocompatible coatings in a simple and direct chemical process from aqueous solutions. So far, very little insight has been gained regarding the mechanisms underlying coating deposition. In this paper, we show that the chemical evolution of AMN film deposition under slightly basic conditions is different in solution and on silica. Thereon, the coating proceeds via a nucleation process followed by further deposition of islands which evolve to produce nitrogen-rich superhydrophilic fibrillar structures. Additionally, we show that AMN-based material can form films at the air-solution interface from unshaken solutions. These results open new vistas into the chemistry of HCN-derived species of potential relevance in materials science.

Spontaneous wrinkle emergence in nascent eumelanin thin films.

Self-patterning processes originated by physical stimuli have been extensively documented in thin films, whereas spontaneous wrinkling phenomena due to chemical transformation processes are, to the best of our knowledge, unprecedented. Herein we report a case of spontaneous polymerization-driven surface nano-patterning (∼500 nm) that develops in smooth thin solid films of 5,6-dihydroxyindole (DHI), a major precursor of eumelanin polymers, over a time scale of 30 to 60 days in air at room temperature. The phenomenon can be observed only above a critical film thickness of ∼250 nm and it is affected by exposure to ammonia vapors causing acceleration of the oxidation process. The thickness-dependent onset of wrinkling can be attributed to non-homogeneous rates of oxidation through the film causing slow swelling/expansion of the inner layers followed by fast stiffening and cross-linking in the outer layer exposed to higher oxygen levels.

Nanoscale PDA disassembly in ionic liquids: structure-property relationships underpinning redox tuning.

Nanoscale disassembly of mussel-inspired polydopamine (PDA) in ionic liquids (ILs) was recently shown to induce an electron paramagnetic resonance (EPR)-detectable reorganization of free radical centers in the resulting nanoparticles (NPs) in an IL-controlled manner. Herein, we report electrical impedance spectroscopy (EIS) data showing that PDA NPs produced by suspending samples obtained in Tris and bicarbonate buffer (PDA-T and PDA-C) in different ILs display different redox activity as a result of structural control combined with IL-surface interactions. In particular, susceptibility to oxidation was found to correlate closely with the spin density in an ion pair-tunable fashion in ILs. Structural control over free radical properties and redox behavior of PDA NPs in ILs opens novel perspectives for the rational design of functional nanovectors of possible interest for drug delivery and theranostic applications.

Reaction-Based, Fluorescent Film Deposition from Dopamine and a Diamine-Tethered, Bis-Resorcinol Coupler.

The reaction-based deposition on various surfaces of an all-organic fluorescent coating is reported here, involving autoxidation of 2 mM dopamine in carbonate buffer at pH 9.0, in the presence of a 1 mM diamine-resorcinol coupler (Bis-Res) prepared from 2,4-dihydroxybenzaldehyde and hexamethylenediamine (HMDA). Spectral analysis of the films coupled with an LC-MS investigation of the yellow fluorescent mixture was compatible with the formation and deposition of HMDA-linked methanobenzofuroazocinone fluorophores. Both the emission properties and hydrophobicity of the film were abated in a reversible manner following exposure to acid vapors. These results provide an entry to efficient and practical fluorescent coating methodologies based on in situ generation and the deposition of wet adhesive, as well as fluorescent materials combining a strongly emitting fluorophore with the film-forming properties of long chain diamines.

Astrochemistry and Astrobiology: Materials Sciencein Wonderland?

Astrochemistry and astrobiology, the fascinating disciplines that strive to unravel the origin of life, have opened unprecedented and unpredicted vistas into exotic compounds as well as extreme or complex reaction conditions of potential relevance for a broad variety of applications. Representative, and so far little explored sources of inspiration include complex organic systems, such as polycyclic aromatic hydrocarbons (PAHs) and their derivatives; hydrogen cyanide (HCN) and formamide (HCONH2) oligomers and polymers, like aminomalononitrile (AMN)-derived species; and exotic processes, such as solid-state photoreactions on mineral surfaces, phosphorylation by minerals, cold ice irradiation and proton bombardment, and thermal transformations in fumaroles. In addition, meteorites and minerals like forsterite, which dominate dust chemistry in the interstellar medium, may open new avenues for the discovery of innovative catalytic processes and unconventional methodologies. The aim of this review was to offer concise and inspiring, rather than comprehensive, examples of astrochemistry-related materials and systems that may be of relevance in areas such as surface functionalization, nanostructures, and hybrid material design, and for innovative technological solutions. The potential of computational methods to predict new properties from spectroscopic data and to assess plausible reaction pathways on both kinetic and thermodynamic grounds has also been highlighted.

Melanin-Based Functional Materials.

Melanin biopolymers are currently the focus of growing interest for a broad range of applications at the cutting edge of biomedical research and technology. This Special Issue presents a collection of papers dealing with melanin-type materials, e.g., polydopamine, for classic and innovative applications, offering a stimulating perspective of current trends in the field. Besides basic scientists, the Special Issue is directed to researchers from industries and companies that are willing to invest in melanin research for innovative and inspiring solutions.

The maturation mechanism of γ-glutamyl transpeptidases: Insights from the crystal structure of a precursor mimic of the enzyme from Bacillus licheniformis and from site-directed mutagenesis studies.

γ-Glutamyl transpeptidases (γ-GTs) are members of N-terminal nucleophile hydrolase superfamily. They are synthetized as single-chain precursors, which are then cleaved to form mature enzymes. Basic aspects of autocatalytic processing of these pro-enzymes are still unknown. Here we describe the X-ray structure of the precursor mimic of Bacillus licheniformis γ-GT (BlGT), obtained by mutating catalytically important threonine to alanine (T399A-BlGT), and report results of autoprocessing of mutants of His401, Thr415, Thr417, Glu419 and Arg571. Data suggest that Thr417 is in a competent position to activate the catalytic threonine (Thr399) for nucleophilic attack of the scissile peptide bond and that Thr415 plays a major role in assisting the process. On the basis of these new structural results, a possible mechanism of autoprocessing is proposed. This mechanism, which guesses the existence of a six-membered transition state involving one carbonyl and two hydroxyl groups, is in agreement with all the available experimental data collected on γ-GTs from different species and with our new Ala-scanning mutagenesis data.

Modeling Fungal Melanin Buildup: Biomimetic Polymerization of 1,8-Dihydroxynaphthalene Mapped by Mass Spectrometry.

Due to the emerging biomedical relevance and technological potential of fungal melanins, and prompted by the virtual lack of information about their structural arrangement, an optimized synthetic protocol has been devised for a potential structural model of Ascomyces allomelanin through enzyme-catalyzed oxidative polymerization of 1,8-dihydroxynaphthalene (1,8-DHN). Electrospray ionization mass spectrometry (ESI-MS) measurements of freshly synthesized DHN-polymer recorded in the negative ion mode allowed detection of oligomers up to m/z 4000, separated by 158 Da, corresponding to the in-chain DHN-unit. The dominant peaks were assigned to singly-charged distribution, up to 23 repeating units, whereas a doubly charged polymer distribution was also detectable. Chemical derivatization, ultra-performance liquid chromatography (UPLC)-ESI MS, and MS/MS data confirmed that oxidative polymerization of 1,8-DHN proceeds through C-C coupling of the naphthalene rings. The new insights reported here into synthetic 1,8-DHN oligomers/polymers as a mimic of fungal melanins may guide novel interesting advances and applications in the field of biomimetic functional materials.

Multifunctional Thin Films and Coatings from Caffeic Acid and a Cross-Linking Diamine.

The exploitation of easily accessible and nontoxic natural catechol compounds for surface functionalization and coating is attracting growing interest for biomedical applications. We report herein the deposition on different substrates of chemically stable thin films by autoxidation of 1 mM caffeic acid (CA) solutions at pH 9 in the presence of equimolar amounts of hexamethylenediamine (HMDA). UV-visible, mass spectrometric, and solid state 13C and 15N NMR analysis indicated covalent incorporation of the amine during CA polymerization to produce insoluble trioxybenzacridinium scaffolds decorated with carboxyl and amine functionalities. Similar coatings are obtained by replacing CA with 4-methylcatechol (MC) in the presence of HMDA. No significant film deposition was detected in the absence of HMDA nor by replacing it with shorter chain ethylenediamine, or with monoamines. The CA/HMDA-based films resisted oxidative and reductive treatments, displayed efficient Fe(II) and Cu(II) binding capacity and organic dyes adsorption, and provided an excellent cytocompatible platform for growing embryonic stem cells. These results pointed to HMDA as an efficient cross-linking mediator of film deposition from natural catechols for surface functionalization and coatings.

Hydration-controlled anisotropic and giant permittivity in TEG-functionalized eumelanin.

Although it has long been known that the peculiar electronic-ionic conductor behavior of eumelanin is critically dependent on hydration, the detailed mechanisms by which water-polymer interactions control and affect the conduction properties have remained largely obscure. In this paper, we report a remarkable anisotropy and giant polarization effect in a synthetic eumelanin (TEGMe) chemically functionalized with hydrophilic TEG residues. FT-IR analyses of water sorption isotherms and AC measurements were consistent with a microporous structure binding or hosting mainly isolated water molecules. In contrast, similar experiments on a commercial synthetic eumelanin (AMe) used as a reference were suggestive of a bulk macroporous scaffold binding or hosting liquid water. These data disclosed for the first time the differential impact on eumelanin conductivity of vapor, liquid and ice-like forms of water adsorbed onto or embedded into the polymer layer. It is thus demonstrated, for the first time, that hydration controls the conduction properties of eumelanin in a more complex manner than is commonly believed, involving, besides the reported semiquinone comproportionation equilibria, the mode of interaction of water molecules as governed by both the chemical and morphological features of the polymer.

Deciphering Molecular Mechanisms of Interface Buildup and Stability in Porous Si/Eumelanin Hybrids.

Porous Si/eumelanin hybrids are a novel class of organic-inorganic hybrid materials that hold considerable promise for photovoltaic applications. Current progress toward device setup is, however, hindered by photocurrent stability issues, which require a detailed understanding of the mechanisms underlying the buildup and consolidation of the eumelanin-silicon interface. Herein we report an integrated experimental and computational study aimed at probing interface stability via surface modification and eumelanin manipulation, and at modeling the organic-inorganic interface via formation of a 5,6-dihydroxyindole (DHI) tetramer and its adhesion to silicon. The results indicated that mild silicon oxidation increases photocurrent stability via enhancement of the DHI-surface interaction, and that higher oxidation states in DHI oligomers create more favorable conditions for the efficient adhesion of growing eumelanin.

Replacing Nitrogen by Sulfur: From Structurally Disordered Eumelanins to Regioregular Thiomelanin Polymers.

The oxidative polymerization of 5,6-dihydroxybenzothiophene (DHBT), the sulfur analog of the key eumelanin building block 5,6-dihydroxyindole (DHI), was investigated to probe the role of nitrogen in eumelanin build-up and properties. Unlike DHI, which gives a typical black insoluble eumelanin polymer on oxidation, DHBT is converted to a grayish amorphous solid (referred to as thiomelanin) with visible absorption and electron paramagnetic resonance properties different from those of DHI melanin. Mass spectrometry experiments revealed gradational mixtures of oligomers up to the decamer level. Quite unexpectedly, nuclear magnetic resonance (NMR) analysis of the early oligomer fractions indicated linear, 4-, and 7-linked structures in marked contrast with DHI, which gives highly complex mixtures of partially degraded oligomers. Density functional theory (DFT) calculations supported the tendency of DHBT to couple via the 4- and 7-positions. These results uncover the role of nitrogen as a major determinant of the structural diversity generated by the polymerization of DHI, and point to replacement by sulfur as a viable entry to regioregular eumelanin-type materials for potential applications for surface functionalization by dip coating.