We provide the first in situ and real-time study of the effect of milling frequency on the course of a mechanochemical organic reaction conducted using a vibratory shaker (mixer) ball mill. The use of in situ Raman spectroscopy for real-time monitoring of the mechanochemical synthesis of a 2,3-diphenylquinoxaline derivative revealed a pronounced dependence of chemical reactivity on small variations in milling frequency. In particular, in situ measurements revealed the establishment of two different regimes of reaction kinetics at different frequencies, providing tentative insight into processes of mechanical activation in organic mechanochemical synthesis.
We demonstrate catalytic organic synthesis by Resonant Acoustic Mixing (RAM): a mechanochemical methodology that does not require bulk solvent or milling media. Using as model reactions rutheniumcatalyzed ring-closing metathesis and copper-catalyzed sulfonamide-isocyanate coupling, RAM mechanosynthesis is shown to be faster, operationally simpler than conventional ball-milling, while also providing the first example of a mechanochemical strategy for rutheniumcatalyzed ene-yne metathesis. Reactions by RAM are readily and directly scaled-up without any significant changes in reaction conditions, as shown by the straightforward 200-fold scaling-up of the synthesis of the antidiabetic drug Tolbutamide, from hundreds of milligrams directly to 30 grams.
The Reformatsky reaction of 2-bromo esters and carbonyl compounds
in the presence of zinc can
be carried out in concentrated aqueous salt solutions without any
cosolvent. The reaction of
bromoacetates is greatly enhanced by catalytic amounts of benzoyl
peroxide or peracids and gives
satisfactory yields with aromatic aldehydes. Preparative yields
comparable to those of the
traditional procedure are obtained with ethyl 2-bromoisobutyrate.
This ester needs no catalyst
and reacts even with saturated aldehydes and aromatic ketones, although
in low yields. A radical
chain mechanism, initiated by electron abstraction from the
organometallic Reformatsky reagent,
is proposed. Two nonchain pathways, involving radicals directly
produced on the metal surface,
may compete, especially in the case of secondary and tertiary
halides.
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