A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.

Mitosis inhibitor (R)-litronesib (LY2523355) is a 1,3,4-thiadiazoline-bearing phenyl and N-(2-ethylamino)ethanesulfonamido-methyl substituents on tetrahedral C5. Chiral instability has been observed at pH 6 and above with the rate of racemization increasing with pH. A positively charged trigonal intermediate is inferred from the fact that p-methoxy substituent on the phenyl accelerated racemization, whereas a p-trifluoromethyl substituent had the opposite effect. Racemization is proposed to occur through a relay mechanism involving intramolecular deprotonation of the sulfonamide by the side chain amino group and attack of the sulfonamide anion on C5, cleaving the C5S bond, to form an aziridine; heterolytic dissociation of the aziridine yields an ylide. This pathway is supported by (1) a crystal structure providing evidence for a hydrogen bond between the sulfonamide NH and the amino group, (2) effects of substituents on the rate of racemization, and (3) computational studies. This racemization mechanism results from neighboring group effects in this densely functionalized molecule. Of particular novelty is the involvement of the side-chain secondary amino group, which overcomes the weak acidity of the sulfonamide by anchimeric assistance.

The delamination of glass contact surfaces because of hydrolytic instability has been well documented. However, the lack of glass surface integrity can also lead to other undesirable outcomes prior to visible glass delamination. This work shows how the early stages of delamination, namely, glass corrosion, can influence the chemical stability of active pharmaceutical ingredient (API) solutions contained within a glass container, even prior to the observation of visible delamination. Multiple containers, all constructed of glass classified as USP Type I, were evaluated for hydrolytic stability and how they influence the chemical stability of the API in question. The glass composition of these analytical consumables, the vendor source, and presumably manufacturing process were examined. The implications of glass container durability on product development decisions, the influence on analytical results, and the practice of like-for-like glass container interchangeability are considered.

Oxidative susceptibility testing was performed on a drug substance containing a methoxy-naphthalene moiety. 2,2'-azobisisobutyronitrile (AIBN) was employed to initiate peroxy radical oxidation to mimic autoxidation processes. In acetonitrile (ACN)-water solvents, three major degradation products are formed. However, addition of small amounts of methanol to the solvent system completely eliminated the observed degradation products. To understand this effect, the structures of the three degradants have been elucidated using nuclear magnetic resonance, liquid chromatography-tandem mass spectrometry, and accurate mass Fourier transform ion cyclotron resonance mass spectrometry. One degradant structure definitively proves the degradation resulted from alkoxy radicals (2-cyano-2 propoxy radical) arising from the disproportionation of the tertiary AIBN-derived peroxy radicals, rather than from the intended action of the AIBN peroxy radicals themselves. The reaction occurs over a wide range of AIBN and drug substance concentrations. This "protective effect" of several percent methanol by volume is rationalized by known methanol H atom donation rates to similar tert-butoxy and cumyloxy radicals (ca. 10 M(-1) s(-1) ) and the high methanol concentration relative to the dilute substrate being investigated. This work confirms recent proposals for addition of at least about 10% methanol to the standard ACN-water AIBN stress testing diluent to insure that only the desired peroxy radical activity is present during the oxidative stress test.

The reactivity of two metallated nitrenium ions toward various substrates was examined in the gas phase. The nitrenium ions were generated by a reaction of benzoyl azide with laser-ablated Mg+ or Cu+ in a Fourier transform ion cyclotron resonance mass spectrometer. The two nitrenium ions show drastically different reactivity. While the Mg-nitrenium ion reacts by radical mechanisms (e.g., H atom abstraction), the Cu-nitrenium ion follows non-radical pathways (e.g., metal ion transfer). (C) 2009 Elsevier B.V. All rights reserved.

A mass spectrometric method has been developed for the identification of functional groups in unknown bifunctional oxygen-containing compounds and for the identification and counting of the hydroxyl groups in polyols. This method utilizes gas-phase ion–molecule reactions of protonated analytes with neutral trimethylborate (TMB) in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The diagnostic reaction sequence involves proton abstraction from the protonated analyte by TMB, followed by the addition of the analyte to TMB and elimination of methanol. The functional groups in bifunctional oxygen-containing compounds are identified based on the total number of TMB molecules that have added to the protonated analyte and/or the number of methanol molecules lost, or by sustained off-resonance irradiation collision-activated dissociation (SORI-CAD) of the reaction products. The number of hydroxyl groups in polyols is revealed by the number of methanol molecules lost during their reactions with TMB. Reactions of protonated carboxylic acids with TMB also lead to elimination of a methanol molecule. However, carboxylic acids can be differentiated from the isomeric hydroxyketones based on the loss of HO-B(OCH3)2 upon SORI-CAD of the reaction product. Reactions of protonated amides with TMB also lead to elimination of a methanol molecule. However, amides can be differentiated from bifunctional oxygen-containing compounds based on the loss of OBR from the reaction product upon SORI-CAD. Protonated amines do not react with TMB.

A mass spectrometric method was developed for the screening of the amido functionality in monofunctional protonated analytes. This method is based on selective gas-phase derivatization of protonated analytes by (N,N-diethylamino)dimethylborane in a Fourier transform ion cyclotron resonance (FT-ICR) and triple quadrupole mass spectrometer. Examination of a series of protonated analytes demonstrated that only the compounds containing the amido functionality react with the aminoborane by the derivatization reaction. The mechanism involves proton transfer from the protonated analyte to the borane, followed by addition of the amide to the boron center, which leads to the elimination of neutral diethylamine. The derivatized analytes are readily identified on the basis of a shift of 40 m/z units relative to the m/z value of the protonated analyte and characteristic boron isotope patterns. Collision-activated dissociation was used to provide support for the structures assigned to the derivatized analytes. The structural information gained from this gas-phase derivatization method will aid in the functional group identification of unknown compounds and their mixtures.

Dichlorocarbene radical cation reacts with benzaldehyde in the gas phase by oxygen radical anion abstraction, generating a new carbene radical cation population. The ion population consists of two isomeric carbene radical cations. Molecular orbital calculations, diagnostic ion-molecule reactions, and examination of ion-molecule reactions’ kinetics and thermochemistry were utilized to elucidate the structures (phenylcarbene radical cation and dehydrotropylium cation), provide the relative abundances (20% and 80%, respectively) and propose a likely mechanism for the formation of the two isomeric carbene radical cations. A single potential energy surface was found to explain the formation of both carbene radical cations. Oxygen radical anion abstraction followed by prompt dissociation of the collision complex leads to the formation of the phenylcarbene radical cation. However, in a longer-lived collision complex, the phenylcarbene radical cation can rearrange to a more stable isomer, the dehydrotropylium cation.

We report here the first application of laser desorption (LD) in transmission geometry (backside irradiation of the sample through a transparent support) inside a Fourier-transform ion cyclotron resonance mass spectrometer (FT-ICR). A probe-mounted fiber optic assembly was used to simplify the implementation of this LD technique. This setup requires little or no instrument modifications, has minimum maintenance requirements, and is relatively inexpensive to build. The performance of the probe was tested by determining the molecular weight of a commercial polystyrene standard from its matrix-assisted laser desorption/ionization (MALDI) spectrum. The measured average molecular weight is comparable to that obtained for the same sample by MALDI in the conventional top-illumination arrangement (reflection geometry) and by the manufacturer of the sample by gel permeation chromatography. The average velocities measured for ions evaporated by transmission mode LD of several neat samples are about half the velocity of those obtained by using the reflection geometry. Therefore, transmission mode irradiation of the sample holds promise to desorb ions that are easier to trap in an ICR cell. An oscillating capillary nebulizer was adapted for the deposition of analytes to improve sampling reproducibility.

Sexual maturity in the bald eagle (Haliaeetus leucoce- phalus) is commonly thought to occur after the bird attains a completely white head and tail, typically at age 4 yr (Clark and Wheeler 1987). Various factors probably in- fluence initial reproductive attempts by individual eagles, so plumage is not always a reliable indicator of age or reproductive readiness (McCollough 1989). In 1993, a pair of bald eagles in subadult plumage nested in eastern Kansas. The nesting pair consisted of a 4-yr-old male and 3-yr-old female, and they successfully fledged one eaglet. OBSERVATIONS