Theoretical investigation of lone pair inversions, ring openings, and hydride shifts in O-methylated epoxides

Mechanisms associated with the isomerization of the O-methylethylene oxonium ion and its tetramethyl-substituted analogue have been explored using correlated electronic structure calculations. The minima and transition states associated with inversion at the oxygen atom, as well as those associated with opening of the epoxide ring, have been characterized. The calculated barrier to inversion at the oxygen atom for the O-methylethylene oxonium ion, 15.7 kcal/mol, agrees well with the experimentally determined value, 10+/-2 kcal/mol. Our calculations indicate that a significantly higher barrier exists for the ring-opening mechanism that leads to more thermodynamically stable structures. This work includes the first known calculations on the O-methyl-2,3-dimethyl-2-butene oxonium ion along with transition states and intermediates associated with ring opening and inversion at the oxygen atom. Results show that there is a significantly lower barrier to ring opening as compared to the O-methylethylene oxonium ion species, leading to a lower probability of isolating this species. The effects of basis sets and correlation techniques on these ions were also analyzed in this work. Our results indicate that the B3LYP/6-31G* level is reliable for obtaining molecular geometries for both minima and transition states on the C3H7O+ and C7H15O+ potential energy surfaces.     

Swelling and network parameters of crosslinked thermoreversible hydrogels of poly(N-ethylacrylamide)

Samples of Poly(N-ethylacrylamide) (PEA) have been synthesized by free radical polymerization in water using N,N′-methylene bis-acrylamide (BIS) as crosslinker. Hydrogels obtained by swelling them in water, 15 wt% KCl and 1 wt% sodium dodecyl sulphate (SDS) were examined by gravimetric, dimensional and compression-strain measurements to afford values of swelling ratio, polymer-solvent interaction parameters, elastic moduli and effective crosslinking density ν_e. Crosslinking inefficiency is evidenced by the low value (0.23) of ν_e relative to the theoretical crosslinking density ν_t based on the content of BIS in the synthesis. A small but finite extrapolated value of ν_e at ν_t = 0 is indicative of hydrophobic physical interactions. In water at 298 K increasing the content of BIS leads to a decrease in swelling and increases in values of elastic moduli and polymer-water interaction parameter. At a fixed content of BIS the values of ν_e and the elastic moduli exhibit an unusual increase with temperature, the crosslinking thus being thermally reversible. It is proposed that this results from a balance between hydrophobic interaction and breakage of hydrophilic hydrogen bonding. Although KCl in the medium decreases the swelling compared with that in water, the opposite effect occurs on incorporation of SDS, which is assumed to confer some polyelectrolyte character to the PEA chains. The finding, that these two swelling media reduce the values of ν_e and elastic moduli cf the value in water, has not been resolved satisfactorily.     

Isomolar semigrand ensemble molecular dynamics: development and application to liquid-liquid equilibria

An extended system molecular dynamics method for the isomolar semigrand ensemble (fixed number of particles, pressure, temperature, and fugacity fraction) is developed and applied to the calculation of liquid-liquid equilibria (LLE) for two Lennard-Jones mixtures. The method utilizes an extended system variable to dynamically control the fugacity fraction xi of the mixture by gradually transforming the identity of particles in the system. Two approaches are used to compute coexistence points. The first approach uses multiple-histogram reweighting techniques to determine the coexistence xi and compositions of each phase at temperatures near the upper critical solution temperature. The second approach, useful for cases in which there is no critical solution temperature, is based on principles of small system thermodynamics. In this case a coexistence point is found by running N-P-T-xi simulations at a common temperature and pressure and varying the fugacity fraction to map out the difference in chemical potential between the two species A and B (mu(A)-mu(B)) as a function of composition. Once this curve is known the equal-distance/equal-area criterion is used to determine the coexistence point. Both approaches give results that are comparable to those of previous Monte Carlo (MC) simulations. By formulating this approach in a molecular dynamics framework, it should be easier to compute the LLE of complex molecules whose intramolecular degrees of freedom are often difficult to properly sample with MC techniques.     

Nucleic acid reactivity: Challenges for next‐generation semiempirical quantum models

Semiempirical quantum models are routinely used to study mechanisms of RNA catalysis and phosphoryl transfer reactions using combined quantum mechanical (QM)/molecular mechanical methods. Herein, we provide a broad assessment of the performance of existing semiempirical quantum models to describe nucleic acid structure and reactivity to quantify their limitations and guide the development of next‐generation quantum models with improved accuracy. Neglect of diatomic differential overlap and self‐consistent density‐functional tight‐binding semiempirical models are evaluated against high‐level QM benchmark calculations for seven biologically important datasets. The datasets include: proton affinities, polarizabilities, nucleobase dimer interactions, dimethyl phosphate anion, nucleoside sugar and glycosidic torsion conformations, and RNA phosphoryl transfer model reactions. As an additional baseline, comparisons are made with several commonly used density‐functional models, including M062X and B3LYP (in some cases with dispersion corrections). The results show that, among the semiempirical models examined, the AM1/d‐PhoT model is the most robust at predicting proton affinities. AM1/d‐PhoT and DFTB3‐3ob/OPhyd reproduce the MP2 potential energy surfaces of 6 associative RNA phosphoryl transfer model reactions reasonably well. Further, a recently developed linear‐scaling “modified divide‐and‐conquer” model exhibits the most accurate results for binding energies of both hydrogen bonded and stacked nucleobase dimers. The semiempirical models considered here are shown to underestimate the isotropic polarizabilities of neutral molecules by approximately 30%. The semiempirical models also fail to adequately describe torsion profiles for the dimethyl phosphate anion, the nucleoside sugar ring puckers, and the rotations about the nucleoside glycosidic bond. The modeling of pentavalent phosphorus, particularly with thio substitutions often used experimentally as mechanistic probes, was problematic for all of the models considered. Analysis of the strengths and weakness of the models suggests that the creation of robust next‐generation models should emphasize the improvement of relative conformational energies and barriers, and nonbonded interactions. © 2015 Wiley Periodicals, Inc.     

Structural and rate studies of the 1,2-additions of lithium phenylacetylide to lithiated quinazolinones: influence of mixed aggregates on the reaction mechanism

The 1,2-addition of lithium phenylacetylide (PhCCLi) to quinazolinones was investigated using a combination of structural and rate studies. (6)Li, (13)C, and (19)F NMR spectroscopies show that deprotonation of quinazolinones and phenylacetylene in THF/pentane solutions with lithium hexamethyldisilazide affords a mixture of lithium quinazolinide/PhCCLi mixed dimer and mixed tetramer along with PhCCLi dimer. Although the mixed tetramer dominates at high mixed aggregate concentrations and low temperatures used for the structural studies, the mixed dimer is the dominant form at the low total mixed aggregate concentrations, high THF concentrations, and ambient temperatures used to investigate the 1,2-addition. Monitoring the reaction rates using (19)F NMR spectroscopy revealed a first-order dependence on mixed dimer, a zeroth-order dependence on THF, and a half-order dependence on the PhCCLi concentration. The rate law is consistent with the addition of a disolvated PhCCLi monomer to the mixed dimer. Investigation of the 1,2-addition of PhCCLi to an O-protected quinazolinone implicates reaction via trisolvated PhCCLi monomers.     

Nuclear resonance vibrational spectra of five-coordinate imidazole-ligated iron(II) porphyrinates

Nuclear resonance vibrational spectra have been obtained for six five-coordinate imidazole-ligated iron(II) porphyrinates, [Fe(Por)(L)] (Por = tetraphenylporphyrinate, octaethylporphyrinate, tetratolylporphyrinate, or protoporphyrinate IX and L = 2-methylimidazole or 1,2-dimethylimidazole). Measurements have been made on both powder and oriented crystal samples. The spectra are dominated by strong signals around 200-300 cm(-1). Although the in-plane and out-of-plane vibrations are seriously overlapped, oriented crystal spectra allow their deconvolution. Thus, oriented crystal experimental data, along with density functional theory (DFT) calculations, enable the assignment of key vibrations in the spectra. Molecular dynamics are also discussed. The nature of the Fe-N(Im) vibrations has been elaborated further than was possible from resonance Raman studies. Our study suggests that the Fe motions are coupled with the porphyrin core and peripheral groups motions. Both peripheral groups and their conformations have significant influence on the vibrational spectra (position and shape).     

Second-Generation Covalent TMP-Tag for Live Cell Imaging

Chemical tags are now viable alternatives to fluorescent proteins for labeling proteins in living cells with organic fluorophores that have improved brightness and other specialized properties. Recently, we successfully rendered our TMP-tag covalent with a proximity-induced reaction between the protein tag and the ligand-fluorophore label. This initial design, however, suffered from slow in vitro labeling kinetics and limited live cell protein labeling. Thus, here we report a second-generation covalent TMP-tag that has a fast labeling half-life and can readily label a variety of intracellular proteins in living cells. Specifically, we designed an acrylamide-trimethoprim-fluorophore (A-TMP-fluorophore v2.0) electrophile with an optimized linker for fast reaction with a cysteine (Cys) nucleophile engineered just outside the TMP-binding pocket of Escherichia coli dihydrofolate reductase (eDHFR) and developed an efficient chemical synthesis for routine production of a variety of A-TMP-probe v2.0 labels. We then screened a panel of eDHFR:Cys variants and identified eDHFR:L28C as having an 8-min half-life for reaction with A-TMP-biotin v2.0 in vitro. Finally, we demonstrated live cell imaging of various cellular protein targets with A-TMP-fluorescein, A-TMP-Dapoxyl, and A-TMP-Atto655. With its robustness, this second-generation covalent TMP-tag adds to the limited number of chemical tags that can be used to covalently label intracellular proteins efficiently in living cells. Moreover, the success of this second-generation design further validates proximity-induced reactivity and organic chemistry as tools not only for chemical tag engineering but also more broadly for synthetic biology.     

Fluence Rate-Dependent Photobleaching of Intratumorally Administered Pc 4 Does not Predict Tumor Growth Delay

We examined effects of fluence rate on the photobleaching of the photosensitizer Pc 4 during photodynamic therapy (PDT) and the relationship between photobleaching and tumor response to PDT. BALB/c mice with intradermal EMT6 tumors were given 0.03 mg kg^?1 Pc 4 by intratumor injection and irradiated at 667 nm with an irradiance of 50 or 150 mW cm^?2 to a fluence of 100 J cm^?2. While no cures were attained, significant tumor growth delay was demonstrated at both irradiances compared with drug‐only controls. There was no significant difference in tumor responses to these two irradiances (P = 0.857). Fluorescence spectroscopy was used to monitor the bleaching of Pc 4 during irradiation, with more rapid bleaching with respect to fluence shown at the higher irradiance. No significant correlation was found between fluorescence photobleaching and tumor regrowth for the data interpreted as a whole. Within each treatment group, weak associations between photobleaching and outcome were observed. In the 50 mW cm^?2 group, enhanced photobleaching was associated with prolonged growth delay (P = 0.188), while at 150 mW cm^?2 this trend was reversed (P = 0.308). Thus, it appears that Pc 4 photobleaching is not a strong predictor of individual tumor response to Pc 4‐PDT under these treatment conditions.     

Sodium periodate as a primary oxidant for water-oxidation catalysts

Sodium periodate was characterized as a primary chemical oxidant for the catalytic evolution of oxygen at neutral pH using a variety of water-oxidation catalysts. The visible spectra of solutions formed from Cp*Ir(bpy)SO(4) during oxygen-evolution catalysis were measured. NMR spectroscopy suggests that the catalyst remains molecular after several turnovers with sodium periodate. Two of our [Cp*Ir(bis-NHC)][PF(6)](2) complexes, along with other literature catalysts, such as the manganese terpyridyl dimer, Hill's cobalt polyoxometallate, and Meyer's blue dimer, were also tested for activity. Sodium periodate was found to function only for water-oxidation catalysts with low overpotentials. This specificity is attributed to the relatively low oxidizing capability of sodium periodate solutions relative to solutions of other common primary oxidants. Studying oxygen-evolution catalysis by using sodium periodate as a primary oxidant may, therefore, provide preliminary evidence that a given catalyst has a low overpotential.     

Modelling the circularly and linearly polarised spectrum of [Ni(en)3]2+

The relative intensity and band shapes of the low energy spin-allowed transitions in the linearly polarised and circular dichroism spectrum of [Ni(en)(3)](2+) have been calculated using a time-dependent density functional theory approach. The effect of the trigonal ligand-field is minimal and no splitting of the bands is predicted by the simulations or observed experimentally. The 'd-d' transitions of the [Ni(en)(3)](2+) ion are electric dipole allowed but gain much of their intensity through Herzberg-Teller vibronic coupling. Its CD spectrum is dominated by the low energy band, which gains its rotatory strength through the magnetic dipole-allowed character of the parent octahedral transition and the electric dipole character due to the trigonal field. The simulation of the spectrum incorporates the contribution from all inducing vibrational modes with significant involvement of the {NiN(6)} unit. Vibrations which are centred on the chelate rings are not important in generating intensity, reflecting the localised d-d' character of the transitions. Simulated linearly polarised and circular dichroism spectra of such an open-shell system are presented for the first time and predict the essential elements of the experimental spectra.