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Fluorine atoms play an important role in all branches of chemistry and accordingly, it is very important to study their unique and varied effects systematically, in particular, the structure-physicochemical properties relationship. The present study describes exceptional physicochemical effects resulting from a H/F exchange at the methylene bridge of gem-difunctional compounds. The Δlog P(CF2-CH2) values, that is, the change in lipophilicity, observed for the CH2 /CF2 replacement in various α,α-phenoxy- and thiophenoxy-esters/amides, diketones, benzodioxoles and more, fall in the range of 0.6-1.4â units, which for most cases, is far above the values expected for such a replacement. Moreover, for compounds holding more than one such gem-difunctional moiety, the effect is nearly additive, so one can switch from a hydrophilic compound to a lipophilic one in a limited number of H/F exchanges. DFT studies of some of these systems revealed that polarity, conformational preference as well as charge distributions are strongly affected by such hydrogen to fluorine atom substitution. The pronounced effects described, are a result of the interplay between changes in polarity, H-bond basicity and molecular volume, which were obtained with a very low 'cost' in terms of molecular weight or steric effects and may have a great potential for implementation in various fields of chemical sciences.
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Amino acid and peptide couplings are widely used in fields related to pharma and materials. Still, current peptide synthesis continues to rely on the use of expensive, water sensitive, and waste-generating coupling reagents, which are often prepared in multi-step sequences and used in excess. Herein is described a peptide coupling reaction design that relies mechanistically on sun-light activation of a 4-dimethylamino-pyridine-alkyl halide charge-transfer complex to generate a novel coupling reagent in situ. The resulting coupling method is rapid, does not require dry solvents or inert atmosphere, and is compatible with all the most common amino acids and protecting groups. Peptide couplings can be run on gram-scale, without the use of special equipment. This method has a significantly reduced environmental and financial footprint compared to standard peptide coupling reactions. Experimental and computational studies support the proposed mechanism.
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Inverse melting α-cyclodextrin·4-methylpyridine·H2O ternary mixtures were studied via solution, high-resolution magic-angle-spinning and 2D-NOESY NMR spectroscopy with the aim of unveiling the supramolecular driving force for the unusual inverse-melting phase transition. The role of solvent-solvent interactions as well as solvent-solute interactions in the emergence of the inverse-melting phenomenon is revealed. A surprising re-entrant solvent-solvent interaction is found in the system and in the 4-methylpyridine·water solvent system, supporting the non-coincidental relationship between inverse melting and re-entrant phase transitions, at least in the present system.
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The first steps in the gas-phase decomposition mechanism of N3,N6-bis (1 H-tetrazol-5-yl)-1,2,4,5-tetrazine-3,6-diamine, BTATz, anions and the kinetic isotope effects in these processes were studied using combined multistage mass spectrometry (MS/MS) and computational techniques. Two major fragmentation processes, the exergonic loss of nitrogen molecules and the endergonic loss of hydrazoic acid, were identified. The observation of a primary isotope effect supported by calculations suggests that the loss of a nitrogen molecule from the tetrazole ring involves proton migration, either to or within the terazole ring, as a rate-determining step. The fragmentation of a hydrazoic acid occurs through an asymmetrical retro-pericyclic reaction. Calculations show the relevance of these mechanisms to neutral BTATz. Our findings may contribute to the understanding of decomposition routes in these nitrogen-rich energetic materials and allow tailoring their reactivity and decomposition pathways for better control of performance.
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2-(2-Diphenylphosphanylethyl)benzo[de]isoquinoline-1,3-dione is a poorly luminescent, photoinduced-electron-transfer (PET) dyad, NI-(Ph)2 P:, in which the luminescence of its naphthaleneimide (NI) part is quenched by the lone-pair electrons of the phosphorus atom of the (Ph)2 P: group. Photoinduced oxidation of (Ph)2 P: to (Ph)2 P=O by molecular oxygen regenerates the luminescence of the NI group, because the oxidized form (Ph)2 P=O does not serve as a quencher to the NI system. The oxidation of (Ph)2 P: is thermally inaccessible. The NI-(Ph)2 P: system was applied to monitoring the cumulative exposure of oxidation-sensitive goods to molecular oxygen. The major advantage of this new PET system is that it reacts with oxygen only via the photoinduced channel, which offers the flexibility of monitoring the cumulative exposure to oxygen in different time periods, simply by varying the sampling frequency. Electronic-energy calculations and optical spectroscopic data revealed that the luminescence turn-on upon reaction with molecular oxygen relies on a PET mechanism.
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A systematic study of trends in the lipophilicity of prominent representatives of the opioid family, including natural, semisynthetic, synthetic, and endogenous neuropeptide opioids, is described. This was enabled by a straightforward 1H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous logD determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact ΔlogD values of matched pairs is required. Interpretation of the experimental ΔlogD7.4 values of selected matched pairs, focusing inter alia on the 3-OMe and 14-OMe motifs in morphinan opioids, is suggested with the aid of DFT calculations and may be useful for the discovery of new opioid therapeutics.
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Analgésicos Opioides , Analgésicos Opioides/química , Espectroscopía de Protones por Resonancia Magnética , Interacciones Hidrofóbicas e Hidrofílicas , Teoría Funcional de la Densidad , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.
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Plasticulture, the practice of using plastic materials in agricultural applications, consumes about 6.7 million tons of plastics every year, which is about 2% of the overall global annual plastics production. For different reasons, plastic material used for agriculture is difficult to recycle. Therefore, most of it is either buried in fertile soils, thereby significantly causing deterioration of their properties, or, at best case, end in landfills where its half-life is measured in decades and even centuries. Hence, developing biodegradable plastic materials that are suitable for agricultural applications is a vital and inevitable need for the global human society. In our labs, two types of potentially biodegradable plastic polymer films were prepared and characterized imidazolium in terms of their bio-degradability. In the first approach, polymers made of ionic liquid monomers were prepared using photo radical induced polymerization. The second approach relies on formation of polyethylene-like n-alkane disulfide polymers from 1,ω-di-thiols through thermally activated air oxidation. These two families of materials were tested for their biodegradability in soils by using a simulation system that combines a controlled environment chamber equipped with a respirometer and a proton-transfer-reaction time of flight mass spectrometer (PTR-TOF-MS) system. This system provides a time-dependent and comprehensive fingerprint of volatiles emitted in the degradation process. The results obtained thus far indicate that whereas the ionic-liquid based polymer does not show significant bio-degradability under the test conditions, the building block monomer, 1,10-n-decane dithiol, as well as its disulfide-based polymer, are bio-degradable. The latter reaching, under basic soil conditions and in room temperature, â¼20% degradation within three months. These results suggest that by introduction of disulfide groups into the polyethylene backbone one may be able to render it biodegradable, thus considerably shortening its half-life in soils. Principal component analysis, PCA, of the data about the total volatiles produced during the degradation in soil indicates a distinctive volatile "fingerprint" of the disulfide-based bio-degradable products which comes from the volatile organic compounds portfolio as recorded by the PTR-TOF-MS. The biodegradation volatile fingerprint of this kind of film was different from the "fingerprint" of the soil background which served as a control. These results can help us to better understand and design biodegradable films for agricultural mulching practices.
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Systematically studying the lipophilicity of phosphorus compounds is of great importance for many chemical and biological fields and particularly for medicinal chemistry. Here, we report on the study of trends in the lipophilicity of a wide set of phosphorus compounds relevant to drug design including phosphates, thiophosphates, phosphonates, thiophosphonates, bis-phosphonates, and phosphine chalcogenides. This was enabled by the development of a straightforward log P determination method for phosphorus compounds based on 31P-NMR spectroscopy. The log P values measured ranged between -3.2 and 3.6, and the trends observed were interpreted using a DFT study of the dipole moments and by H-bond basicity (pKHB) measurements of selected compounds. Clear signal separation in 31P-NMR spectroscopy grants the method high tolerability to impurities. Moreover, the wide range of chemical shifts for the phosphorus nucleus (250 to -250 ppm) enables a direct simultaneous log P determination of phosphorus compound mixtures in a single shake-flask experiment and 31P-NMR analysis.
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Organofosfonatos , Compuestos de Fósforo , Espectroscopía de Resonancia Magnética/métodos , Fósforo/químicaRESUMEN
Modulation of the H-bond basicity (pKHB) of various functional groups (FGs) by attaching fluorine functions and its impact on lipophilicity and bioisosterism considerations are described. In general, H/F replacement at the α-position to H-bond acceptors leads to a decrease of the pKHB value, resulting, in many cases, in a dramatic increase in the compounds' lipophilicity (logâ¯Po/w). In the case of α-CF2H, we found that these properties may also be affected by intramolecular H-bonds between CF2H and the FG. A computational study of ketone and sulfone series revealed that α-fluorination can significantly affect overall polarity, charge distribution, and conformational preference. The unique case of α-di- and trifluoromethyl ketones, which exist in octanol/water phases as ketone, hemiketal, and gem-diol forms, in equilibrium, prevents direct logâ¯Po/w determination by conventional methods, and therefore, the specific logâ¯Po/w values of these species were determined directly, for the first time, using Linclau's 19F NMR-based method.
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Flúor/química , Cetonas/química , Teoría Funcional de la Densidad , Halogenación , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Isomerismo , Cetonas/síntesis química , Cinética , Espectroscopía de Resonancia Magnética , Piridinas/síntesis química , Piridinas/química , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
Solutions of cyclohexakis-(1â4)-α-d-glucopyranosyl, α-cyclodextrin, αCD, in R-(+)-1-phenylethylamine, αCD/R-PEA, and S-(-)-1-phenylethylamine, αCD/S-PEA, display abnormal phase transitions that strongly depend on supramolecular diastereomeric interactions. While αCD/R-PEA mixtures show one sol-gel inverse-melting phase transition, αCD/S-PEA mixtures show temperature dependent gel-sol-gel re-entrant behavior. NMR, Raman spectroscopy, microscopy and X-ray scattering measurements reveal that hydrogen bond weakening in solution, as well as changes in crystal composition are responsible for entropy increase and gel formation upon heating.
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Alkylating agents are simple and reactive molecules that are commonly used in many and diverse fields such as organic synthesis, medicine, and agriculture. Some highly reactive alkylating species are also being used as blister chemical-warfare agents. The detection and identification of alkylating agents is not a trivial issue because of their high reactivity and simple structure. Herein, we report on a new multispot luminescence-based approach to the detection and identification of alkylating agents. In order to demonstrate the potential of the approach, seven pi-conjugated oligomers and polymers bearing nucleophilic pyridine groups, 1-7, were adsorbed onto a solid support and exposed to vapors of alkylators 8-15. The alkylation-induced color-shift patterns of the seven-spot array allow clear discrimination of the different alkylators. The spots are sensitive to minute concentrations of alkylators and, because the detection is based on the formation of new covalent bonds, these spots saturate at about 50 ppb.
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Alquilantes/síntesis química , Modelos Moleculares , Alquilantes/química , Alquilación , Estructura MolecularRESUMEN
Aqueous methylcellulose is an "abnormal" inverse-freezing fluid, which gelates when heated. We ventured to stimulate this phase-transition by mechanical impact, whose resulting shockwaves and local heat could be uptaken by the endothermic gelation. High-speed photography was used to observe this transition in microsecond timescales. This phenomenon enables attenuation of shockwaves.
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Uniform bimetallic nanowires, tunable in size, have been grown on artificial DNA templates via a two-step metallization process. Alkyne-modified cytosines were incorporated into 900-base-pair polymerase-chain-reaction fragments. The alkyne modifications serve as addressable metal-binding sites after conversion to a sugar triazole derivative via click chemistry. Reaction of the Tollens reagent with these sugar-coated DNA duplexes generates Ag0 metallization centers around the sugar modification sites of the DNA. After a subsequent enhancement step using gold, nanowires < or = 10 nm in diameter with a homogeneous surface profile were obtained. Furthermore, the advantage of this two-step procedure lies in the high selectivity of the process, due to the exact spatial control of modified DNA base incorporation and hence the confinement of metallization centers at addressable sites. Besides experiments on a membrane as a proof for the selectivity of the method, atomic force microscopy (AFM) studies of the wires produced on Si-SiO2 surfaces are discussed. Furthermore, we demonstrate time-dependent metallization experiments, monitored by AFM.
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Materiales Biomiméticos/química , ADN/química , Oro/química , Nanocables/química , Ácidos Nucleicos Heterodúplex/química , Plata/química , Emparejamiento Base , Carbohidratos/química , Microscopía de Fuerza Atómica , Ácidos Nucleicos Heterodúplex/síntesis química , Ácidos Nucleicos Heterodúplex/aislamiento & purificación , Ácidos Nucleicos Heterodúplex/ultraestructura , Saccharomyces cerevisiae , Factores de TiempoRESUMEN
We report on the use of charge-transfer complexes between amines and carbon tetrachloride, as a novel way to activate the amine for photochemical reactions. This principle is demonstrated in a mild, transition metal free, visible light assisted, dealkylative amide formation from feedstock carboxylic acids and amines. The low absorption coefficient of the complex allows deep light penetration and thus scale up to a gram scale.
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Trihalogenated compounds act as effective and selective templates in the template-assisted synthesis of meso-hexaphenyl-calix[6]pyrrole.
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Sustancias Macromoleculares , Pirroles/síntesis química , Calixarenos , Ligandos , Estructura Molecular , Pirroles/química , Ácido Tricloroacético/químicaRESUMEN
meso-hexamethyl-meso-hexaphenyl calix[6]pyrrole assembles into well-defined dimeric capsules in the crystalline state; the preorganized capsule serves as an efficient host for different organic guests as well as for solvent molecules.
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A 1,3,5-alternate conformation of the pyrrole rings is adopted by the calix[6]pyrrole 1 in the crystal (see picture). Compound 1 was synthesized in a two-step process and although it crystallizes in the form of the adduct 1â 3CH3 COCH3 â H2 Oâ CHCl3 , there are no solvent molecules in the cavity (cross section ca. 60Å2 ) of this macrocycle which possesses alternating dimethyl and diphenyl substitutents at the meso positions.
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Cyclo[2]benzimidazole is a new host for anions that turns on its luminescence up to 150 fold upon binding. Photoexcited cyclo[2]benzimidazole undergoes an efficient non-radiative deactivation through an excited-state intramolecular proton-transfer (ESIPT) mechanism. Upon binding an anion, the ESIPT pathway is blocked, resulting in an increase in the luminescence efficiency.
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Tripyrrolemethane- and bistripyrrolemethane-containing systems were recently reported to be efficient and selective hosts for anions. Nevertheless, the basic intrinsic properties of tripyrrolemethane as a ligand for anions have not yet been explored. Here we report the study of the anion-binding properties of the tripyrrolemethane group. We applied a combined experimental and theoretical approach to determine the affinity of the tripyrrolemethane system for different anions in the gas phase, in solution and in the crystalline state. In the crystal, the tripyrrolemethane group forms a number of different complexes with the bromide ion, some involving the participation of more than one ligand species. Despite the very similar basicity of fluoride and dihydrogen phosphate, the tripyrrolemethane ligand exhibits a clear preference for the fluoride anion in solution, which indicates an anion-binding system and not merely deprotonation. Although the affinity of the tripyrrolemethane ligand for other ions was negligible in solution, gas-phase studies show that complexation with larger halide ions is favoured over complexation with fluoride.