Flash-vacuum pyrolysis of 1-acylbenzotriazole: Direct observation of cyclopenta-2,4-dienylidenemethaneimines by tandem mass spectrometry and low-temperature infrared spectrometry

A real-time analysis of the flash-vacuum pyrolysis products of 1-acetylbenzotriazole (1) and 1-benzoylbenzotriazole (2) was performed by tandem mass Spectrometry. In the temperature range 500-600 °C, these compounds lose nitrogen, yielding N-acetyl- and N-benzoylcyclopenta- 2,4-dienylidenemethaneimines (10 and 17, respectively). At higher pyrolysis temperatures, 1 gives 2-methylbenzoxazole, cyanocyclopentadiene, methylcyanocyclopentadiene(s), benzonitrile and ketene, which were identified by collision-activated dissociation mass Spectrometry. Low-temperature infrared experiments confirmed the pyrolytic transformation 1(2) → 10(17) at mediated temperatures.     

Tautomerization of Phenols,Part III,The Anthrone−Anthrol Equilibrium in Aqueous Solution

The equilibrium between 10H‐anthr‐9‐one and 9‐anthrol favors the ketone, which ionizes as a carbon acid in aqueous base. Rates of equilibration were measured over the pH range 1 – 13 in aqueous solution (25°, ionic strength I=0. M ). Five independent thermodynamic and kinetic parameters were determined by analysis of the pH‐rate profile: the equilibrium constant of enolization, pK_E=2.17, the ionization quotient of anthrol, pQ=7.84, and the rate constants of enolization catalyzed by acid, k=2.2⋅10⁻⁴ M ⁻¹ s⁻¹, base, k=51.0 M ⁻¹ s⁻¹, and water, k=1.21⋅10⁻⁵ s⁻¹. Structure‐reactivity relationships strongly support the view that pH‐independent enolization of anthrone in water proceeds by rate‐determining ionization of the C‐acid.     

Polymorphism - integrated approach from high-throughput screening to crystallization optimization

Crystal structure (polymorphism) as well as crystal shape (morphology) and size have a huge practical and commercial impact on active substances all the way from research to manufacture of the final product. For an optimal development process, it is important to have an integrated approach to these issues ranging from a systematic polymorphism screening to a controlled scale-up of the crystallization process. The polymorphism program has to be tailored according to the development stage. Particularly suitable for an early development stage is a high-throughput polymorphism screening, which is the basis for a more thorough investigation if the product proceeds further in development. Such a comprehensive polymorphism investigation involves further crystallization experiments and extensive physicochemical characterization of the various forms. In this article the high-throughput polymorphism screening method that we have developed is described. Using carbamazepine as an example, the power of this high-throughput polymorphism screening system is demonstrated. Not only were all published forms found, but also new forms were identified. In the second part of the article, important considerations for crystallization optimization are discussed, again using the example of carbamazepine. This revised version was published online in July 2006 with corrections to the Cover Date.