Impact of normal-phase gradient elution in chiral chromatography: a novel,robust, efficient and rapid chiral screening procedure

Novel normal-phase gradient systems have been employed for fast high-throughput chiral analyses of Discovery compounds in our research laboratories in Eli Lilly and Company. In this report, we describe an automated screening approach based on gradient elution, in order to achieve accurate enantiomeric excess determinations, and chiral separations when needed, in the shortest possible timeframe. Baseline resolution of enantiomers has been obtained for over 85% of the samples so tested. For the remaining cases, complete enantioseparation by isocratic optimisation is generally achieved in a single shot. This technique has been proven to be robust and is now standard operating procedure at our analytical research laboratories.     

Radical-driven dissociation of odd-electron peptide radical ions produced in 157 nm photodissociation

Odd-electron a+1 radical ions generated in the 157 nm photodissociation of peptide ions were investigated in an ion trap mass spectrometer. To localize the radical, peptide backbone amide hydrogens were replaced with deuterium. When the resulting radical ions underwent hydrogen elimination, no H/D scrambling was obvious, suggesting that without collisional activation, the radical resides on the terminal α-carbon. Upon collisional excitation, odd-electron radical ions dissociate through two favored pathways: the production of a-type ions at aromatic amino acids via homolytic cleavage of backbone C_α-C(O) bonds and side-chain losses at nonaromatic amino acids. When aromatic residues are not present, nonaromatic residues can also lead to a-type ions. In addition to a-type ions, serine and threonine yield c _n−1 and a _n−1+1 ions where n denotes the position of the serine or threonine. All of these fragments appear to be directed by the radical and they strongly depend on the amino acid side-chain structure. In addition, thermal fragments are also occasionally observed following cleavage of labile Xxx-Pro bonds and their formation appears to be kinetically competitive with radical migration.     

Time-resolved observation of product ions generated by 157 nm photodissociation of singly protonated phosphopeptides

Vacuum UV photodissociation tandem mass spectra of singly charged arginine-terminated phosphopeptides were recorded at times ranging from 300 ns to ms after photoexcitation, to investigate when the phosphate group falls off from the precursor and product ions and whether loss of phosphate can be eliminated in tandem mass spectra. For peptide ions containing phosphoserine and phosphothreonine, little loss of 98 Da from the product ions was observed up to 1 μs after photoexcitation. However, neutral losses from the precursor ions were considerable just 300 ns after photoactivation. Loss of 98 Da from product ions first appears about 1 μs after laser irradiation and becomes more common 13 μs after photoexcitation. Consistent with previous reports, phosphotyrosine was more stable than either phosphoserine or phosphothreonine.     

An optimization design method for chemically amplified resistprocess control

A novel optimization method called chemically-amplified resist process optimization design (CARPOD) applicable to the chemically amplified resist (CAR) process development is described. The method finds the optimal process conditions and the design center (maximum process tolerance space) of a CAR process with minimum experimental runs. First a modified response surface method is used to form the numerical response surface of a CAR, and its most sensitive point, which is the minimum requirement of X-ray dose, is located as an optimal process condition by an optimization method called POSM under the constraint of the contrast of the photoresist. Second, the design center is found to maximize the process tolerance space around the optimal process condition. Third, verifications are made on the optimal design as well as the design center. The process optimization of AZ PF-514 has been used as an example to show that the CARPOD method can identify the optimal process condition as well as the maximum tolerable parameter space with minimum experimental runs     

Tunable and switchable dual wavelength lasers using optical fibreBragg grating external cavities

Two novel external cavity lasers are demonstrated experimentally. The first utilises a Bragg grating fabricated in highly birefringent optical fibre and offers the ability to switch between modes that are separated in polarisation and wavelength. The second utilises two spatially separate Bragg gratings fabricated in mono-mode fibre. Both can be used for tunable beat frequency generation     

Theory of internal upconversion and frequency doubling in optical parametric oscillators

A uniform plane-wave theory of the type previously employed for the optical parametric oscillator (OPO) is extended to include internal upconversion and frequency doubling. All the experimental configurations for internal upconversion and doubling in the three basic OPO types are treated. Generated intensities are calculated for representative system parameters, and both design parameters and quantum upconversion and doubling efficiencies are obtained for optimum operation in each configuration. The position of the upconverter in the OPO cavity relative to the oscillator crystal and input-pump direction is shown to affect efficiency and output characteristics drastically. The detrimental effects of internal up-conversion on threshold are shown to be an important design consideration. Applicability of the results to pulsed OPO internal upconversion and frequency doubling is determined, and design criteria for selecting the best mode of operation are discussed.     

The absorption of hydrogen by binary vanadium-chromium alloys

The thermodynamic parameters of the solution of hydrogen in binary vanadium-chromium alloys (to 20 at. % Cr) have been determined. The partial molar enthalpy at infinite dilution increases with increasing Cr content (values range from ?7615 cal/H in pure vanadium to ?5891 cal/H in V/19.96 at. % Cr). The partial molar entropy of solution is unaffected by the presence of Cr. It is suggested that this behavior indicates that Cr atoms do not block potentially available interstitial sites for occupation by hydrogen. The apparent H-H interaction is diminished by the presence of Cr. The stability of the dihydride is decreased by Cr additions, to the point that V/19.96 at. % Cr does not form a dihydride (?78°C, 68 atm). X-ray data indicate that the structural characteristics of the alloy hydrides are similar to those observed in vanadium/hydrogen.