Density function theory calculations reveal that the GrubbsHoveyda olefin metathesis pre-catalyst is activated by the formation of a complex in which the incoming alkene substrate and outgoing alkoxy ligand are both clearly associated with the ruthenium centre. The computed energies for reaction are in good agreement with the experimental values, reported here.
Regulatory requests that marketing authorization holders for chemically
synthesized active substances risk assess their medicines for the
potential presence of N-nitrosamines have led to
a renewed interest in amine nitrosation. We have used published mechanistic
and kinetic studies of amine nitrosation to assess the risk that traces
of nitrite in the water used during active pharmaceutical ingredient
(API) manufacturing could give rise to significant levels of N-nitrosamines. We conclude that the levels of nitrite typically
found in water used for API manufacture are very low (<0.01 mg/L)
and will not give rise to significant levels of N-nitrosamines through reaction with basic secondary amines (pK
a > 9.5) in the majority of cases. The use of
less basic amines, elevated processing temperatures, or low pH conditions
in combination with elevated levels of nitrite have the potential
to generate levels of N-nitrosamines that could lead
to significant quantities being present in the isolated API if the
downstream processing does not provide an adequate purge. The kinetic
models described may be used to risk assess specific situations or
processes. For example, the addition of traces of dimethylamine to
a nitrosation reaction is predicted to lead to the rapid, quantitative
formation of N-nitroso dimethylamine. Simple tertiary
alkylamines can nitrosate via a dealkylative process, which is significantly
slower than secondary amine nitrosation. Therefore, they do not represent
a risk of N-nitrosamine formation under conditions
where there is no significant risk of secondary amine nitrosation.
Gold nanoparticles with diameters of ca. 13 nm were synthesised by UV irradiation of a supramolecular organogel into which HAuCl4 and tetraoctylammonium bromide had been diffused-the gel network plays an essential role in nanoparticle stabilisation.
The potential energy surfaces for the activation of Grubbs−Hoveyda-type precatalysts with the substrates ethene, propene, 1-hexene, and ethyl vinyl ether (EVE) have been probed at the density functional theory (DFT) (M06-L) level. The energetically favored pathway of the reaction leading to a 14e Fischer carbene and styrene starts with an initiation step in which the incoming substrate and outgoing alkene ligand are both clearly associated with the ruthenium center. For these substrates, with the exception of ethene, the rate determining step is predicted to be the formation of the metallocyclobutane (MCB). We have taken the initial reactant to be a weak van der Waals complex between substrate and precatalyst. This model yields good agreement between the computed activation parameters for both the parent Grubbs−Hoveyda and Grela complex with EVE substrate, and the experimental values, reported here. The alternative model which takes the initial reactant to be two isolated molecules requires an estimate of the entropy loss on formation of the initial complex in solution which is difficult to evaluate. Our estimate of this quantity yields a barrier for the rate determining step for the interchange mechanism which is close to the value we find for the alternative mechanism in which the rate determining step is the initial dissociation of the precatalyst. The relative energetics of these two mechanisms involving different initiation steps but with similar activation barriers, could well be dependent upon the precatalyst and substrate in line with the recent experimental findings of Plenio and co-workers.
This paper describes the gelation of symmetric dendrimers based on building blocks constructed from L-lysine. These dendrimers form gel-phase materials in nonpolar organic solvents. The thermal properties and concentration dependence of the gelation were investigated, and it was found that there was a clear dendritic effect on the behavior of the soft materials formed, with higher generation dendrimers giving rise to more thermally stable gels. Variable temperature 1H NMR studies indicated that this behavior was probably a consequence of more extensive interdendrimer hydrogen bonding occurring between the peptidic groups in the higher generation dendrimers. The supramolecular aggregates were found to have a fibrillar structure, with the dimensions and alignment of the fibers being dependent on dendritic generation. Circular dichroism measurements confirmed that these fibers possessed chiral organization of the peptidic groups on the supramolecular (nano) scale, assigned as helicity. This paper indicates that dendritic functionalization provides a useful way of tuning gel-phase materials properties, with clear dendritic effects on gel formation being quantified for the first time, hence illustrating the way dendritic functionalization can play a positive role in the formation of highly functional organic materials with desirable properties.
Although Grubbs metathesis catalysts have enabled syntheses of a range of molecules, alkene isomerization, a known and problematic side reaction, is poorly understood. Several mechanisms which have been advanced to account for isomerization were studied by using electronic structure calculations. The pathway catalyzed by a ruthenium hydride emerged as the most facile process by a significant margin. For the first time, we have obtained experimental evidence for the presence of this species in a metathesis‐active system.
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