Different behavior of nitrenes and carbenes on photolysis and thermolysis: Formation of azirine, ylidic cumulene, and cyclic ketenimine and the rearrangement of 6-phenanthridylcarbene to 9-phenanthrylnitrene

Flash vacuum thermolysis (FVT) of 9-azidophenanthrene 8, 6-(5-tetrazolyl)phenanthridine 18, and [1,2,3]triazolo[1,5-f]phenanthridine 19 yields 9-cyanofluorene 12 as the principal product and 4-cyanofluorene as a minor product. In all cases, when the product is condensed at or below 77 K, the seven-membered ring ketenimine 24 is detectable by IR spectroscopy (1932 cm(-1)) up to 200 K. Photolysis of Ar matrix isolated 8 at lambda = 308 or 313 nm generates at first the azirine 26, rapidly followed by the ylidic cumulene 27. The latter reverts to azirine 26 at lambda > 405 nm, and the azirine reverts to the ylidic cumulene at 313 nm. Nitrene 9 is observed by ESR spectroscopy following FVT of either azide 8, tetrazole 18, or triazole 19 with Ar matrix isolation of the products. Nitrene 9 and carbene 21 are observed by ESR spectroscopy in the Ar matrix photolyses of azide 8 and triazole 19, respectively.

Imidoylketene-alpha-oxoketenimine and alpha-oxoketene-alpha-oxoketene rearrangements. 1,3-Shifts of substituted phenyl groups

1,3-Phenyl shifts interconvert imidoylketenes 1 and alpha-oxoketenimines 2 and, likewise, alpha-oxoketenes 3 automerize by this 1,3-shift. These rearrangements usually take place in the gas phase under conditions of. ash vacuum thermolysis. Energy profiles calculated at the B3LYP/6-31G(d, p) and B3LYP/6311 + G(3df,2p)//B3LYP/6-31G(d,p) levels demonstrate that electron donating substituents ( D) in the migrating phenyl group and electron withdrawing ones ( W) in the non-migrating phenyl group, can stabilise the transition states TS1 and TS2 to the extent that activation barriers of ca. 100 kJ mol(-1) or less are obtained; i.e. enough to make these reactions potentially observable in solution at ordinary temperatures. The calculated transition state energies Delta G(TS1) show an excellent correlation with the Hammett constants sigma(p)(W) and sigma(p) +(D).

Design strategies for controlling the molecular weight and rate using reversible addition-fragmentation chain transfer mediated living radical polymerization

Living radical polymerization has allowed complex polymer architectures to be synthesized in bulk, solution, and water. The most versatile of these techniques is reversible addition-fragmentation chain transfer (RAFT), which allows a wide range of functional and nonfunctional polymers to be made with predictable molecular weight distributions (MWDs), ranging from very narrow to quite broad. The great complexity of the RAFT mechanism and how the kinetic parameters affect the rate of polymerization and MWD are not obvious. Therefore, the aim of this article is to provide useful insights into the important kinetic parameters that control the rate of polymerization and the evolution of the MWD with conversion. We discuss how a change in the chain-transfer constant can affect the evolution of the MWD. It is shown how we can, in principle, use only one RAFT agent to obtain a poly-mer with any MWD. Retardation and inhibition are discussed in terms of (1) the leaving R group reactivity and (2) the intermediate radical termination model versus the slow fragmentation model. (c) 2005 Wiley Periodicals, Inc.

Mesoionic 1,3-oxazinium olates. Rearrangement to acylketenes and 3-azabicyclo[3.1.1]heptanetriones

Metastable but isolable mesoionic 1,3-oxazinium 4-olates 9d-f undergo ring opening to acylketenes 10 at or near room temperature. The ketenes undergo intramolecular criss-cross [2 + 2] cycloaddition to afford 3-azabicyclo[3.1.1]heptanetriones 12. The structure of 12d was established by X-ray crystallography.

Energy profiles for ketene cyclizations. interconversion of 1,3-oxazin-6-ones, mesoionic 1,3-oxazinium olates and acylketenes, imidoylketenes, oxoketenimines, and cyclization products

The energy surface connecting oxazinium olates 9, several possible conformers of ketenes 10 and 11, and the final cyclization products 12, 13 and 14, as well as the isomeric 1,3-oxazine-6-ones 15, ring opening of the latter to N-acylimidoylketenes 16, and subsequent rearrangement of 16 to oxoketenimines 17, azetinones 18, and the cyclization products 19 and 20 are evaluated computationally at the B3LYP/6-31G* and B3LYP/6-311+G*//B3LYP/6-31G* levels. The cyclizations of ketenes to oxazinium olates 9 and oxazines 15 have the characteristics of pseudopericyclic reactions. Plots of the energy vs internal reaction coordinate for the cyclization of transoid acylketenes such as 10 to 9 (via TS1) and 16 to 15 (via TS7) feature two inflection points and indicate that the part of the energy surface above the lower inflection points describe internal rotation of the acyl function in the ketene moiety, and the part below this point describes the cyclization of the cisoid ketene to the planar mesoionic oxazinium olate 9 or oxazinone 15. The 1,3-shifts of the OR group that interconvert ketenes 16 and ketenimines 17 via four-membered cyclic transition states TS8 behave similarly, the first portion (from the ketenimine side) of the activation barrier being due largely to internal rotation of substituents, and the top part being due to the 1,3-shift proper.

A cyclopropabenzenylidenethenone (Propadienone) via a new route to alkylidenecycloproparenes

Reaction of 1,1-dichloro-2,5-diphenylcyclopropabenzene 6 with Meldrum's acid 8 in the presence of pyridine leads to coupling of the cycloproparenyl cation 7 with the stabilized diketo anion 9. Subsequent, spontaneous, base-induced dehydrochlorination gives the alkylidenecyclopropabenzene 11 in a one-pot reaction. Flash vacuum thermolysis of 11 at 650 degreesC ejects acetone and carbon dioxide, giving cyclopropabenzenylldenethenone 12 that is isolated in an Ar matrix at 20 K and characterized by a strong ketene band at 2107 cm(-1) in the IR spectrum.

Leading coordinate analysis of reaction pathways in proton chain transfer: Application to a two-proton transfer model for the green fluorescent protein

The ‘leading coordinate’ approach to computing an approximate reaction pathway, with subsequent determination of the true minimum energy profile, is applied to a two-proton chain transfer model based on the chromophore and its surrounding moieties within the green fluorescent protein (GFP). Using an ab initio quantum chemical method, a number of different relaxed energy profiles are found for several plausible guesses at leading coordinates. The results obtained for different trial leading coordinates are rationalized through the calculation of a two-dimensional relaxed potential energy surface (PES) for the system. Analysis of the 2-D relaxed PES reveals that two of the trial pathways are entirely spurious, while two others contain useful information and can be used to furnish starting points for successful saddle-point searches. Implications for selection of trial leading coordinates in this class of proton chain transfer reactions are discussed, and a simple diagnostic function is proposed for revealing whether or not a relaxed pathway based on a trial leading coordinate is likely to furnish useful information.

Mimicking the action of GroEL in molecular dynamics simulations: Application to the refinement of protein structures

Bacterial chaperonin, GroEL, together with its co-chaperonin, GroES, facilitates the folding of a variety of polypeptides. Experiments suggest that GroEL stimulates protein folding by multiple cycles of binding and release. Misfolded proteins first bind to an exposed hydrophobic surface on GroEL. GroES then encapsulates the substrate and triggers its release into the central cavity of the GroEL/ES complex for folding. In this work, we investigate the possibility to facilitate protein folding in molecular dynamics simulations by mimicking the effects of GroEL/ES namely, repeated binding and release, together with spatial confinement. During the binding stage, the (metastable) partially folded proteins are allowed to attach spontaneously to a hydrophobic surface within the simulation box. This destabilizes the structures, which are then transferred into a spatially confined cavity for folding. The approach has been tested by attempting to refine protein structural models generated using the ROSETTA procedure for ab initio structure prediction. Dramatic improvements in regard to the deviation of protein models from the corresponding experimental structures were observed. The results suggest that the primary effects of the GroEL/ES system can be mimicked in a simple coarse-grained manner and be used to facilitate protein folding in molecular dynamics simulations. Furthermore, the results Sur port the assumption that the spatial confinement in GroEL/ES assists the folding of encapsulated proteins.

Strong electronic correlations in superconducting organic charge transfer salts

We review the role of strong electronic correlations in quasi-two-dimensional organic charge transfer salts such as (BEDT-TTF)(2)X, (BETS)(2)Y, and beta'-[Pd(dmit)(2)](2)Z. We begin by defining minimal models for these materials. It is necessary to identify two classes of material: the first class is strongly dimerized and is described by a half-filled Hubbard model; the second class is not strongly dimerized and is described by a quarter-filled extended Hubbard model. We argue that these models capture the essential physics of these materials. We explore the phase diagram of the half-filled quasi-two-dimensional organic charge transfer salts, focusing on the metallic and superconducting phases. We review work showing that the metallic phase, which has both Fermi liquid and 'bad metal' regimes, is described both quantitatively and qualitatively by dynamical mean field theory (DMFT). The phenomenology of the superconducting state is still a matter of contention. We critically review the experimental situation, focusing on the key experimental results that may distinguish between rival theories of superconductivity, particularly probes of the pairing symmetry and measurements of the superfluid stiffness. We then discuss some strongly correlated theories of superconductivity, in particular the resonating valence bond (RVB) theory of superconductivity. We conclude by discussing some of the major challenges currently facing the field. These include parameterizing minimal models, the evidence for a pseudogap from nuclear magnetic resonance (NMR) experiments, superconductors with low critical temperatures and extremely small superfluid stiffnesses, the possible spin- liquid states in kappa-(ET)(2)Cu-2(CN)(3) and beta'-[Pd(dmit)(2)](2)Z, and the need for high quality large single crystals.

Mechanism and kinetics of dithiobenzoate-mediated RAFT polymerization. I. The current situation

Investigations into the kinetics and mechanism of dithiobenzoate-mediated Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerizations, which exhibit nonideal kinetic behavior, such as induction periods and rate retardation, are comprehensively reviewed. The appreciable uncertainty in the rate coefficients associated with the RAFT equilibrium is discussed and methods for obtaining RAFT-specific rate coefficients are detailed. In addition, mechanistic studies are presented, which target the elucidation of the fundamental cause of rate retarding effects. The experimental and theoretical data existing in the literature are critically evaluated and apparent discrepancies between the results of different studies into the kinetics of RAFT polymerizations are discussed. Finally, recommendations for further work are given. (c) 2006 Wiley Periodicals, Inc.

Characterization of the structure of RAMP1 by mutagenesis and molecular modeling

Receptor activity modifying proteins (RAMPs) are a family of single-pass transmembrane proteins that dimerize with G-protein-coupled receptors. They may alter the ligand recognition properties of the receptors (particularly for the calcitonin receptor-like receptor, CLR). Very little structural information is available about RAMPs. Here, an ab initio model has been generated for the extracellular domain of RAMP1. The disulfide bond arrangement (Cys 27-Cys82, Cys40-Cys72, and Cys 57-Cys104) was determined by site-directed mutagenesis. The secondary structure (a-helices from residues 29-51, 60-80, and 87-100) was established from a consensus of predictive routines. Using these constraints, an assemblage of 25,000 structures was constructed and these were ranked using an all-atom statistical potential. The best 1000 conformations were energy minimized. The lowest scoring model was refined by molecular dynamics simulation. To validate our strategy, the same methods were applied to three proteins of known structure; PDB:1HP8, PDB:1V54 chain H (residues 21-85), and PDB:1T0P. When compared to the crystal structures, the models had root mean-square deviations of 3.8 Å, 4.1 Å, and 4.0 Å, respectively. The model of RAMP1 suggested that Phe93, Tyr 100, and Phe101 form a binding interface for CLR, whereas Trp74 and Phe92 may interact with ligands that bind to the CLR/RAMP1 heterodimer. © 2006 by the Biophysical Society.

Hydrotalcite intercalated siRNA:computational characterization of the interlayer environment

Using molecular dynamics (MD) simulations, we explore the structural and dynamical properties of siRNA within the intercalated environment of a Mg:Al 2:1 Layered Double Hydroxide (LDH) nanoparticle. An ab initio force field (Condensed-phase Optimized Molecular Potentials for Atomistic Simulation Studies: COMPASS) is used for the MD simulations of the hybrid organic-inorganic systems. The structure, arrangement, mobility, close contacts and hydrogen bonds associated with the intercalated RNA are examined and contrasted with those of the isolated RNA. Computed powder X-ray diffraction patterns are also compared with related LDH-DNA experiments. As a method of probing whether the intercalated environment approximates the crystalline or rather the aqueous state, we explore the stability of the principle parameters (e.g., the major groove width) that differentiate both A- and A'- crystalline forms of siRNA and contrast this with recent findings for the same siRNA simulated in water. We find the crystalline forms remain structurally distinct when intercalated, whereas this is not the case in water. Implications for the stability of hybrid LDH-RNA systems are discussed.

Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents

A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.

Exotic meson decay widths using lattice quantum chromodynamics

Most experiments in particle physics are scattering experiments, the analysis of which leads to masses, scattering phases, decay widths and other properties of one or multi-particle systems. Until the advent of Lattice Quantum Chromodynamics (LQCD) it was difficult to compare experimental results on low energy hadron-hadron scattering processes to the predictions of QCD, the current theory of strong interactions. The reason being, at low energies the QCD coupling constant becomes large and the perturbation expansion for scattering; amplitudes does not converge. To overcome this, one puts the theory onto a lattice, imposes a momentum cutoff, and computes the integral numerically. For particle masses, predictions of LQCD agree with experiment, but the area of decay widths is largely unexplored. ^ LQCD provides ab initio access to unusual hadrons like exotic mesons that are predicted to contain real gluonic structure. To study decays of these type resonances the energy spectra of a two-particle decay state in a finite volume of dimension L can be related to the associated scattering phase shift δ(k) at momentum k through exact formulae derived by Lüscher. Because the spectra can be computed using numerical Monte Carlo techniques, the scattering phases can thus be determined using Lüscher's formulae, and the corresponding decay widths can be found by fitting Breit-Wigner functions. ^ Results of such a decay width calculation for an exotic hybrid( h) meson (JPC = 1-+) are presented for the decay channel h → πa 1. This calculation employed Lüscher's formulae and an approximation of LQCD called the quenched approximation. Energy spectra for the h and πa1 systems were extracted using eigenvalues of a correlation matrix, and the corresponding scattering phase shifts were determined for a discrete set of πa1 momenta. Although the number of phase shift data points was sparse, fits to a Breit-Wigner model were made, resulting in a decay width of about 60 MeV. ^