Search

Methylene-selective C-H functionalization is a significant hurdle that remains to be addressed in the field of Pd(II) catalysis. We report a Pd(II)-catalyzed synthesis of benzocyclobutenes by methylene-selective C(sp3)-H arylation of ketones. The reaction utilizes glycine as a transient directing group and a 2-pyridone ligand, which may govern the methylene selectivity by making intimate molecular associations with the substrate during concerted metalation-deprotonation. This reaction is shown to be highly selective for intramolecular methylene C(sp3)-H arylation, thus enabling sequential C(sp3)-H functionalization.

Pressure-induced changes in the solid-state structures and transport properties of three oxobenzene-bridged bisdithiazolyl radicals 2 (R = H, F, Ph) over the range 0–15 GPa are described. All three materials experience compression of their π-stacked architecture, be it (i) 1D ABABAB π-stack (R = Ph), (ii) quasi-1D slipped π-stack (R = H), or (iii) 2D brick-wall π-stack (R = F). While R = H undergoes two structural phase transitions, neither of R = F, Ph display any phase change. All three radicals order as spin-canted antiferromagnets, but spin-canted ordering is lost at pressures

Host-defense peptides (HDPs) are produced by eukaryotes to defend against bacterial infection, and diverse synthetic polymers have recently been explored as mimics of these natural peptides. HDPs are rich in both hydrophobic and cationic amino acid residues, and most HDP-mimetic polymers have therefore contained binary combinations of hydrophobic and cationic subunits. However, HDP-mimetic polymers rarely duplicate the hydrophobic surface and cationic charge density found among HDPs ( Hu , K. ; et al. Macromolecules 2013 , 46 , 1908 ); the charge and hydrophobicity are generally higher among the polymers. Statistical analysis of HDP sequences ( Wang , G. ; et al. Nucleic Acids Res. 2009 , 37 , D933 ) has revealed that serine (polar but uncharged) is a very common HDP constituent and that glycine is more prevalent among HDPs than among proteins in general. These observations prompted us to prepare and evaluate ternary nylon-3 copolymers that contain a modestly polar but uncharged subunit, either serine-like or glycine-like, along with a hydrophobic subunit and a cationic subunit. Starting from binary hydrophobic-cationic copolymers that were previously shown to be highly active against bacteria but also highly hemolytic, we found that replacing a small proportion of the hydrophobic subunit with either of the polar, uncharged subunits can diminish the hemolytic activity with minimal impact on the antibacterial activity. These results indicate that the incorporation of polar, uncharged subunits may be generally useful for optimizing the biological activity profiles of antimicrobial polymers. In the context of HDP evolution, our findings suggest that there is a selective advantage to retaining polar, uncharged residues in natural antimicrobial peptides.

The heterocyclic bisdithiazolyl radical 1b (R1 = Me, R2 = F) crystallizes in two phases. The α-phase, space group P2₁/n, contains two radicals in the asymmetric unit, both of which adopt slipped π-stack structures. The β-phase, space group P2₁/c, consists of cross-braced π-stacked arrays of dimers in which the radicals are linked laterally by hypervalent 4-center 6-electron S···S-S···S σ-bonds. Variable-temperature magnetic susceptibility measurements on α-1b indicate Curie-Weiss behavior (with Θ = -14.9 K), while the dimer phase β-1b is diamagnetic, showing no indication of thermal dissociation below 400 K. High-pressure crystallographic measurements indicate that the cross-braced π-stacked arrays of dimers undergo a wine-rack compression, but the dimer remains intact up to 8 GPa (at ambient temperature). The resistance of β-1b to dissociate under pressure, also observed in its conductivity versus pressure profile, is in marked contrast to the behavior of the related dimer β-1a (R1 = Et, R2 = F), which readily dissociates into a pair of radicals at 0.8 GPa. The different response of the two dimers to pressure has been rationalized in terms of differences in their linear compressibilities occasioned by changes in the degree of cross-bracing of the π-stacks. Dissociation of both dimers can be effected by irradiation with visible (λ = 650 nm) light; the transformation has been monitored by optical spectroscopy, magnetic susceptibility measurements, and single crystal X-ray diffraction. The photoinduced radical pairs persist up to temperatures of 150 K (β-1b) and 242 K (β-1a) before reverting to the dimer state. Variable-temperature optical measurements on β-1b and β-1a have afforded Arrhenius activation energies of 8.3 and 19.6 kcal mol(-1), respectively, for the radical-to-dimer reconversion. DFT and CAS-SCF calculations have been used to probe the ground and excited electronic state structures of the dimer and radical pair. The results support the interpretation that the ground-state interconversion of the dimer and radical forms of β-1a and β-1b is symmetry forbidden, while the photochemical transformation is symmetry allowed.

A critical feature of the electronic structure of oxobenzene-bridged bisdithiazolyl radicals 2 is the presence of a low-lying LUMO which, in the solid state, improves charge transport by providing additional degrees of freedom for electron transfer. The magnitude of this multiorbital effect can be fine-tuned by variations in the π-electron releasing/accepting nature of the basal ligand. Here we demonstrate that incorporation of a nitro group significantly stabilizes the LUMO, and hence lowers Ueff, the effective Coulombic barrier to charge transfer. The effect is echoed, at the molecular level, in the observed trend in Ecell, the electrochemical cell potential for 2 with R = F, H and NO2. The crystal structures of the MeCN and EtCN solvates of 2 with R = NO2 have been determined. In the EtCN solvate the radicals are dimerized, but in the MeCN solvate the radicals form superimposed and evenly spaced π-stacked arrays. This highly 1D material displays Pauli-like temperature independent paramagnetic behavior,...

We investigate the physical origin of peptide-induced membrane curvature by contrasting differences between H-bonding interactions of prototypical cationic amino acids, arginine (Arg) and lysine (Lys), with phosphate groups of phospholipid heads using quantum mechanical (QM) calculations of a minimum model and test the results via synthetic oxaorbornene-based transporter sequences without the geometric constraints of polypeptide backbones. QM calculations suggest that although individual Lys can in principle coordinate two phosphates, they are not able to do so at small inter-Lys distances without drastic energetic penalties. In contrast, Arg can coordinate two phosphates down to less than 5 Å, where guanidinium groups can stack "face to face". In agreement with these observations, poly-Lys cannot generate the nanoscale positive curvature necessary for inducing negative Gaussian membrane curvature, in contrast to poly-Arg. Also consistent with QM calculations, polyguanidine-oxanorbornene homopolymers (PGONs) showed that curvature generation is exquisitely sensitive to the guanidinium group spacing when the phosphate groups are near close packing. Addition of phenyl or butyl hydrophobic groups into guanidine-oxanorbornene polymers increased the amount of induced saddle-splay membrane curvature and broadened the range of lipid compositions where saddle-splay curvature was induced. The enhancement of saddle-splay curvature generation and relaxation of lipid composition requirements via addition of hydrophobicity is consistent with membrane activity profiles. While PGON polymers displayed selective antimicrobial activity against prototypical (Gram positive and negative) bacteria, polymers with phenyl and butyl groups were also active against red blood cells. Our results suggest that it is possible to achieve deterministic molecular design of pore-forming peptides.

Antimicrobial peptides (AMPs) are cationic amphiphiles that comprise a key component of innate immunity. Synthetic analogues of AMPs, such as the family of phenylene ethynylene antimicrobial oligomers (AMOs), recently demonstrated broad-spectrum antimicrobial activity, but the underlying molecular mechanism is unknown. Homologues in this family can be inactive, specifically active against bacteria, or nonspecifically active against bacteria and eukaryotic cells. Using synchrotron small-angle X-ray scattering (SAXS), we show that observed antibacterial activity correlates with an AMO-induced topological transition of small unilamellar vesicles into an inverted hexagonal phase, in which hexagonal arrays of 3.4-nm water channels defined by lipid tubes are formed. Polarized and fluorescence microscopy show that AMO-treated giant unilamellar vesicles remain intact, instead of reconstructing into a bulk 3D phase, but are selectively permeable to encapsulated macromolecules that are smaller than 3.4 nm. Moreover, AMOs with different activity profiles require different minimum threshold concentrations of phosphoethanolamine (PE) lipids to reconstruct the membrane. Using ternary membrane vesicles composed of DOPG:DOPE:DOPC with a charge density fixed at typical bacterial values, we find that the inactive AMO cannot generate the inverted hexagonal phase even when DOPE completely replaces DOPC. The specifically active AMO requires a threshold ratio of DOPE:DOPC = 4:1, and the nonspecifically active AMO requires a drastically lower threshold ratio of DOPE:DOPC = 1.5:1. Since most gram-negative bacterial membranes have more PE lipids than do eukaryotic membranes, our results imply that there is a relationship between negative-curvature lipids such as PE and antimicrobial hydrophobicity that contributes to selective antimicrobial activity.

The alternating ABABAB π-stacked architecture of the EtCN solvate of the iodo-substituted, oxobenzene-bridged bisdithiazolyl radical IBBO (space group Pnma) gives rise to strong ferromagnetic exchange along the π-stacks, and the material orders as a spin-canted antiferromagnet with T(N) = 35 K, with a spontaneous (canted) moment M(spont) = 1.4 × 10(-3) μB and a coercive field H(c) = 1060 Oe (at 2 K). The observation of spin-canting can only be understood in terms of multiorbital contributions to both isotropic and anisotropic exchange interactions, the magnitude of which are enhanced by spin-orbit effects arising from the heavy-atom iodine substituent. Pseudodipolar interactions lead to a net canted moment along the c-axis, while the sublattice magnetization is predicted to possess an easy a-axis.

Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.

The crystal structure and charge transport properties of the prototypal oxobenzene-bridged 1,2,3-bisdithiazolyl radical conductor 3a are strongly dependent on pressure. Compression of the as-crystallized α-phase, space group Fdd2, to 3-4 GPa leads to its conversion into a second or β-phase, in which F-centering is lost. The space group symmetry is lowered to Pbn2₁, and there is concomitant halving of the a and b axes. A third or γ-phase, also space group Pbn2₁, is generated by further compression to 8 GPa. The changes in packing that accompany both phase transitions are associated with an "ironing out" of the ruffled ribbon-like architecture of the α-phase, so that consecutive radicals along the ribbons are rendered more nearly coplanar. In the β-phase the planar ribbons are propagated along the b-glides, while in the γ-phase they follow the n-glides. At ambient pressure 3a is a Mott insulator, displaying high but activated conductivity, with σ(300 K) = 6 × 10(-3) S cm(-1) and E(act) = 0.16 eV. With compression beyond 4 GPa, its conductivity is increased by 3 orders of magnitude, and the thermal activation energy is reduced to zero, heralding the formation of a metallic state. High pressure infrared absorption and reflectivity measurements are consistent with closure of the Mott-Hubbard gap near 4-5 GPa. The results are discussed in the light of DFT calculations on the molecular and band electronic structure of 3a. The presence of a low-lying LUMO in 3a gives rise to high electron affinity which, in turn, creates an electronically much softer radical with a low onsite Coulomb potential U. In addition, considerable crystal orbital (SOMO/LUMO) mixing occurs upon pressurization, so that a metallic state is readily achieved at relatively low applied pressure.

The diffusion temperature of molecular 'walkers', molecules that are capable of moving unidirectionally across a substrate violating its symmetry, can be tuned over a wide range utilizing extension of their aromatic backbone, insertion of a second set of substrate linkers (converting bipedal into quadrupedal species), and substitution on the ring. Density functional theory simulation of the molecular dynamics identifies the motion of the quadrupedal species as pacing (as opposed to trotting or gliding). Knowledge about the diffusion mode allows us to draw conclusions on the relevance of tunneling to the surface diffusion of polyatomic organic molecules.

One member of a prototypical class of antimicrobial oligomers was used to study pore formation in cardiolipin rich membranes. Using both vesicle dye-leakage assays and small angle x-ray scattering, bilayer remodeling was studied. The results indicate that the presence of negative intrinsic curvature (NIC) lipids is essential for pore formation by this class of molecules: In Gram-positive bacteria, cardiolipin and divalent metal cations like Ca2+ and Mg2+ are needed. This is completely consistent with the role of phosphatidylethanolamine (PE) lipid in Gram-negative bacteria, where antimicrobial activity is dependent on the negative intrinsic curvature of PE, rather than a specific interaction with PE.

It is empirically known that anionic polyelectrolytes present in cystic fibrosis (CF) airways due to bacterial infection significantly decrease the activity of cationic antimicrobials via electrostatic binding. In this work, we use synchrotron small-angle X-ray scattering to investigate the interaction between tobramycin, an aminoglycoside antibiotic commonly administered to CF patients via inhalation, with DNA, which is found in high concentrations in the CF airway. We find that interactions between DNA and tobramycin are significantly modified by the presence of mixtures of amphiphilic molecules. We measure a hierarchy of self-assembled structures formed between tobramycin, DNA, and the amphiphile mixtures and show how interactions between these components can be controlled. Results indicate that mixtures of cationic and negative curvature amphiphiles optimized for DNA binding via charge matching and curvature matching can competitively displace bound tobramycin from DNA and thereby drastically suppress tobramycin-DNA binding and resultant antimicrobial inactivation. Growth inhibition assays confirm the increased activity of tobramycin in the presence of DNA with the addition of the amphiphiles. These results suggest that optimized cationic amphiphile solutions have the potential to enhance antimicrobial function in highly infected environments that contain increased concentrations of anionic inflammatory polymers.

9,10-Dithioanthracene adsorbed on Cu(111) diffuses exclusively along the high-symmetry axis of the molecule−substrate system. Further reduction of the symmetry of the system by asymmetric methylation does not reduce the symmetry of the motion although it has a substantial effect on the diffusion rate (100-fold reduction) and renders the diffusion barrier asymmetric. This is in contrast to the behavior expected of a classical particle, and it provides a direct single-molecule-scale vista on the validity of The Principle of Microscopic Reversibility first formulated by Tolman in 1924, which despite its fundamental role has attracted little visualization.

Complexes of anionic DNA and cationic liposomes self-assemble into a multilamellar structure where two-dimensional lipid sheets confine a periodic one-dimensional lattice of parallel DNA chains, between which Cd(2+) ions can condense, and be subsequently reacted with H(2)S to form CdS nanorods. In this work, we identify the synergistic roles of the anionic and cationic components within the DNA-membrane template; DNA is highly anionic and condenses the Cd(2+) ions, while the cationic membrane modulates the concentration of condensed Cd(2+) ions to control the final CdS nanorod dimensions. Due to the strong electrostatic interactions between the DNA sugar-phosphate backbone and the Cd(2+) ions, crystallographic control of CdS nanostructures is possible using these simple DNA-membrane templates, which we demonstrate using nanobeam electron diffraction experiments on individual templated CdS nanorods.

The strength of hydrogen bridge bonds in rows of anthraquinone (AQ) and 9,10-dithioanthracene (DTA) molecules adsorbed at a Cu(111) surface is investigated by means of scanning tunneling microscopy. The temperature-dependent rate of abstraction of molecules from the molecular rows was measured. Evaluation of the results similar to molecular diffusion data indicates an abstraction barrier of 0.13 and 0.16 eV for AQ and DTA, respectively. Given known diffusion barriers, this offers an estimated energy of the O···H−C and S···H−C hydrogen bond of 0.05 and 0.02 eV for AQ and DTA, respectively.

Incomplete coverages of p-fluorothiophenol, p-chlorothiophenol, and p-bromothiophenol form ordered islands on a Cu(111) surface even at low temperatures. The complexity of the molecular patterns increases from a simple (3 x 4) superlattice to a honeycomb (8 x 8)R19 degrees structure with increasing substituent electronegativity. We propose a model based on quadrupolar intermolecular interactions to account for this observation.

A wide range of biomineralization and templating methods exist for organizing inorganic materials at a wide range of length-scales. Here, we show that crystallographic control of the inorganic nanostructures is possible using synthetic biomolecular templates comprised of anionic DNA and cationic membranes, which self-assemble into a multilamellar structure where a periodic one-dimensional (1D) lattice of parallel DNA chains is confined between stacked two-dimensional (2D) lipid sheets. We have organized Cd2+ ions within the interhelical pores between DNA strands and subsequently reacted them with H2S to form CdS nanorods of controllable widths and crystallographic orientation. The strong electrostatic interactions align the templated CdS (002) polar planes parallel to the negatively charged sugar-phosphate DNA backbone, which indicates that molecular details of the DNA molecule are imprinted onto the inorganic crystal structure. The resultant nanorods have (002) planes tilted by 60 degrees with respect to the rod axis, in contrast to all known II-VI semiconductor nanorods.

The kinetics of homolytic methylation of the model purine compound caffeine at carbon-8 were determined as a function of several reaction variables. The methyl radical was generated from tert-butyl peracetate (BPA) either thermally (65 to 95/sup 0/C) or photochemically (greater than 300 nm, 25/sup 0/C). The thermal reaction k (25/sup 0/C) was found to be 3.09 x 10/sup -8/ s/sup -1/ from the linear log k (pseudo-first-order) vs. l/T plot. The light reactions using the 450- and 1200-W mercury lamps proceeded with k (25/sup 0/C) 450- and 2160-fold greater, respectively. The derived activation energies are consistent with an S/sub E/Ar reaction. Increasing the concentration of caffeine from 0.25 M to 1.67 M in the presence of 3 molar equiv of BPA did not cause any side reaction. The pH-rate profile can be predicted by rate equations, which are derived on the basis of an electrophilic substitution occurring on the free base and conjugate acid of a heteroaromatic system. A competition study using tetrahydrofuran reveals the presence of a radical sigma complex IIIa and a charge transfer complex IIIb as intermediates for methylation under neutral and acidic conditions, respectively. Their rate-determining nature was indicated by the small positive kinetic isotope effectmore » and the inverse solvent isotope effects: k/sub H/sub 3/O/sup +///k/sub D/sub 3/O/sup +// = 0.87 and k/sub H/sub 2/O//k/sub D/sub 2/O/ = 0.32. Thus, in acidic medium, a preequilibrium proton transfer to form the caffeine conjugate acid precedes the rate-controlling formation of IIIb. In neutral solution, the rate-determining step appears to be the protonation of the radical nitrogen in IIIa converting it to III. The acid-catalyzed caffeine-BPA reaction was shown to be general for other purines such as adenine, adenosine, guanine, guanosine, hypoxanthine, and inosine.« less