Rational Tuning of the Reactivity of Three-Membered Heterocycle Ring Openings via SN2 Reactions

The development of small-molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the “electrophilic trap” that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. Here we investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with a nitrogen (aziridine), phosphorus (phosphirane), oxygen (epoxide) or sulfur atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring opening of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C₆H₁₀Y with Y=NH, PH, O, S). It was revealed that the activation energy of the ring opening does not necessarily follow the trend that is expected from C−Y leaving-group bond strength, but steeply decreases from Y=NH, to PH, to O, to S. We illustrate that the HOMO_Nu–LUMO_Substrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.     

Adamantyl Side Chains as Anti-Aggregating Moieties in Dyes for Dye-Sensitized Solar Cells

Designing and evaluating novel dye concepts is crucial for the development of the field of dye-sensitized solar cells (DSSCs). In our recent report, the novel concept of tethering the anti-aggregation additive chenodeoxycholic acid (CDCA) to dyes for DSSC was introduced. Based on the performance improvements seen for this modification, the aim of this study is to see if a simplified anti-aggregation unit could achieve similar results. The following study reports the synthesis and photovoltaic characterization of two novel dyes decorated with the steric ethyladamantyl moiety on the π-spacer, and on the triarylamine donor. This modification is demonstrated to be successful in increasing the photovoltages in devices employing copper-based electrolytes compared to the non-modified reference dye. The best photovoltaic performance is achieved by a device prepared with the adamantyl decorated donor dye and CDCA, this device achieves a power conversion efficiency of 6.1 % (Short-circuit current=8.3 mA cm⁻², Open-circuit voltage=1054 mV, Fill factor=0.69). The improved photovoltaic performance seen for the adamantyl decorated donor demonstrate the potential of ethyladamantyl side chains as a tool to ensure surface protection of TiO₂.     

Flow birefringence of polymer melts: Application to the investigation of time dependent rheological properties

Summary Transient stresses including normal stresses, which are developed in a polymer melt by a suddenly imposed constant rate of shear, are investigated by mechanical measurement and, indirectly, with the aid of the flow birefringence technique. For the latter purpose use is made of the so-called stress-optical law, which is carefully checked.It appears that the essentially linear model of the rubberlike liquid, as proposed byLodge, is capable of describing the behaviour of polymer melts rather well, if the applied total shear does not exceed unity. In order to describe also steady state values of the stresses successfully, one should extend measurements to extremely low shear rates.These statements are verified with the aid of a method which was originally designed bySchwarzl andStruik for the practical calculation of interrelations between linear viscoelastic functions. In the present paper dynamic shear moduli are used as reference functions.

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Zusammenfassung Mit der Zeit anwachsende Spannungen, darunter auch Normalspannungen, wie sie sich nach dem plötzlichen Anlegen einer konstanten Schergeschwindigkeit in einer Polymerschmelze entwickeln, werden mit Hilfe mechanischer Messungen und indirekt mit Hilfe der Strömungsdoppelbrechung untersucht. Für den letzteren Zweck wird das sogenannte spannungsoptische Gesetz herangezogen, dessen Gültigkeit sorgfältig überprüft wird.Es ergibt sich, daß das im Wesen lineare Modell der gummiartigen Flüssigkeit, wie es vonLodge vorgeschlagen wurde, sich recht gut zur Beschreibung des Verhaltens von Polymerschmelzen eignet, solange der im ganzen angelegte Schub den Wert Eins nicht überschreitet. Um auch stationäre Werte der Spannungen in die Beschreibung erfolgreich einzubeziehen, sollte man die Messungen bis zu extrem niedrigen Schergeschwindigkeiten ausdehnen.Die gemachten Feststellungen werden mit Hilfe einer Methode verifiziert, die vonSchwarzl undStruik ursprünglich für die praktische Berechnung von Beziehungen zwischen Zustandsfunktionen entwickelt wurde, die dem linear viskoelastischen Verhalten entsprechen. In der vorliegenden Veröffentlichung dienen die dynamischen Schubmoduln als Bezugsfunktionen.

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a _T shift factor - B _ij Finger deformation tensor - C stress-optical coefficient, (m²/N) - f (p _jl ) undetermined scalar function - G shear modulus, (N/m²) - G(t) time dependent shear modulus, (N/m²) - G() shear storage modulus, (N/m²) - G() shear loss modulus, (N/m²) - G _r reduced shear storage modulus, (N/m²) - G _r reduced shear loss modulus, (N/m²) - H() shear relaxation time spectrum, (N/m²) - k Boltzmann constant, (Nm/°K) - n _ik refractive index tensor - p undetermined hydrostatic pressure, (N/m²) - p _ij ,p _ik stress tensor, (N/m²) - p ₂₁ shear stress, (N/m²) - p ₁₁ –p ₂₂ first normal stress difference, (N/m²) - p ₂₂ –p ₃₃ second normal stress difference, (N/m²) - q shear rate, (s^–1) - t, t time, (s) - T absolute temperature, (°K) - T ₀ reference temperature, (°K) - x the ratiot/ - x position vector of a material point after deformation, (m) - x position vector of a material point before deformation, (m) - ₀, ₁ constants in eq. [37] - ₀, ₁ constants in eq. [37] - shear deformation - (t, t) time dependent shear deformation - _ij unity tensor - n flow birefringence in the 1–2 plane - (q) non-Newtonian shear viscosity, (N s/m²) - ^* () complex dynamic viscosity, (N s/m²) - | ^* ()| absolute value of complex dynamic viscosity, (N s/m²) - () real part of complex dynamic viscosity, (N s/m²) - () imaginary part of complex dynamic viscosity, (N s/m²) - (t — t) memory function, (N/m² · s) - v number of effective chains per unit of volume, (m^–3) - temperature dependent density, (kg/m³) - ₀ density at reference temperatureT ₀, (kg/m³) - relaxation time, (s) - integration variable, (s) - (x) approximate intensity function - ₁ (x) error function - extinction angle - _m orientation angle of the stress ellipsoid - circular frequency, (s^–1) - 1 direction of flow - 2 direction of the velocity gradient - 3 indifferent direction - t time dependence The present investigation has been carried out under the auspices of the Netherlands Organization for the Advancement of Pure Research (Z. W. O.).North Atlantic Treaty Organization Science Post Doctoral Fellow.Research Fellow, Delft University of Technology.With 11 figures and 2 tables     

Real-Space Renormalization Estimates for Two-Phase Flow in Porous Media

We present a spatial renormalization group algorithm to handle immiscibletwo-phase flow in heterogeneous porous media. We call this algorithmFRACTAM-R, where FRACTAM is an acronym for Fast Renormalization Algorithmfor Correlated Transport in Anisotropic Media, and the R stands for relativepermeability. Originally, FRACTAM was an approximate iterative process thatreplaces the L × L lattice of grid blocks, representing the reservoir,by a (L/2) × (L/2) one. In fact, FRACTAM replaces the original L× L lattice by a hierarchical (fractal) lattice, in such a way thatfinding the solution of the two-phase flow equations becomes trivial. Thistriviality translates in practice into computer efficiency. For N=L ×L grid blocks we find that the computer time necessary to calculatefractional flow F(t) and pressure P(t) as a function of time scales as N^1.7 for FRACTAM-R. This should be contrasted with thecomputational time of a conventional grid simulator N^2.3. The solution we find in this way is an accurateapproximation to the direct solution of the original problem.     

Numerical solution of integro-differential and singular integral equations for plate bending problems

Two integral equation formulations for the determination of the vertical displacement and the bending moment around holes in an elastic plate are presented. Each formulation consists of two equations, the first one an integral equation and an integro-differential equation and the second one two singular integral equations. The equations are solved using B-splines as approximations to the unknowns and the method is applied to the case of one elliptic hole in a twisted plate.

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Zusammenfassung Zwei verschiedene Integralgleichungssysteme für die Bestimmung von die Durchbiegung und die Biegemoment in einer gelochten elastischen Platte werden entwickelt. Die eine Systeme besteht von einer Integralgleichung und einer Integro-Differentialgleichung und die andere von zwei singulären Integralgleichungen von Cauchy'schen Typus. Bei der Auflösung der Systeme werden die unbekannten mit Hilfe B-splines ausgedrückt. Beide Systeme werden benutzt in dem Fall von einer elliptischen Loch in einer uendlichen, tordierten Platte.

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An abbreviated version of this paper was included in a paper Integral equation solutions to mechanical problems. A review and an application to plate theory which will appear in the Proceedings from second national congress of theoretical and applied mechanics, Druzba, Bulgaria, 1973.     

Metastable flow in capillary tubes: An experimental evaluation

This work presents the results of an experimental study with pure refrigerants R-134a and R-600a and refrigerant–oil mixtures flowing through capillary tubes in order to analyse the metastable flow. A large number of experiments were carried out to verify the influence of several variables on the underpressure of vaporization, mainly the inlet subcooling, internal diameter and inlet pressure. Capillary tubes with internal diameter of 0.69 mm and 0.82 mm were tested for condensation temperatures between 40 °C and 50 °C and subcooling degrees between 3 °C and 12 °C. Measurements for oil concentrations of 1% and 3% were conducted and compared with those for pure refrigerant R-134a. The oil influence on the metastable flow was tested and the effect on the underpressure of vaporization is addressed for lower oil concentrations.     

Rotating Navier-Stokes Equations in $${\mathbb R}^{3}_{+}$$ with Initial Data Nondecreasing at Infinity: The Ekman Boundary Layer Problem

We prove time local existence and uniqueness of solutions to a boundary layer problem in a rotating frame around the stationary solution called the Ekman spiral. We choose initial data in the vector-valued homogeneous Besov space for 2 <  p <  ∞. Here the L ^p -integrability is imposed in the normal direction, while we may have no decay in tangential components, since the Besov space contains nondecaying functions such as almost periodic functions. A crucial ingredient is theory for vector-valued homogeneous Besov spaces. For instance we provide and apply an operator-valued bounded H ^∞-calculus for the Laplacian in for a general Banach space .     

Fragmentation Reactions of Methionine-Containing Protonated Octapeptides and Fragment Ions Therefrom: An Energy-Resolved Study

The fragmentation reactions of the MH⁺ ions as well as the b₇, a₇, and a₇* ions derived therefrom have been studied in detail for the octapeptides MAAAAAAA, AAMAAAAA, AAAAMAAA, and AAAAAAMA. Ionization was by electrospray using a QqToF mass spectrometer, which allowed a study of the evolution of the fragmentation channels as a function of the collision energy. Not surprisingly, the product ion mass spectra for the b₇ ions are independent of the original precursor sequence, indicating macrocyclization and reopening to the same mixture of protonated oxazolones prior to fragmentation. The results show that this sequence scrambling results in a distinct preference to place the Met residue in the C-terminal position of the protonated oxazolones. The a₇ and a₇* ions also produce product ion mass spectra independent of the original peptide sequence. The results for the a₇ ions indicate that fragmentation occurs primarily from an amide structure analogous to that observed for a₄ ions (Bythell et al. in J Am Chem Soc 132:14766–14779, 2010). Clearly, the rearrangement reaction they have proposed applies equally well to a_n ions as large as a₇. The major fragmentation modes of the MH⁺ ions at low collision energies produce b₇, b_6, and b₅ ions. As the collision energy is increased further fragmentation of these primary products produces, in part, non-direct sequence ions, which become prominent at lower m/z values, particularly for the peptides with the Met residue near the N-terminus.

Non-Direct Sequence Ions in the Tandem Mass Spectrometry of Protonated Peptide Amides—an Energy-Resolved Study

The fragmentation reactions of the MH⁺ ions of Leu-enkephalin amide and a variety of heptapeptide amides have been studied in detail as a function of collision energy using a QqToF beam type mass spectrometer. The initial fragmentation of the protonated amides involves primarily formation of b_n ions, including significant loss of NH₃ from the MH⁺ ions. Further fragmentation of these b_n ions occurs following macrocyclization/ring opening leading in many cases to b_n ions with permuted sequences and, thus, to formation of non-direct sequence ions. The importance of these non-direct sequence ions increases markedly with increasing collision energy, making peptide sequence determination difficult, if not impossible, at higher collision energies.