We have previously alkylated cysteine with bromoacetylpyridinium bromide and two equivalents of base (this alkylation apparently takes several days at room temperature). A typical protocol in our laboratory is to run the reaction in water at a concentration of about 80 mM in each reactant and to follow the reaction by means of the DTNB assay (Ellman's reagent). I had to set this reaction up again this weekend, and so I thought I would try to alkylate cysteine with 2-Chloro-3′,4′-dihydroxyacetophenone (chloroacetylcatechol) and one equivalent with base, at the same time. The reaction started showing precipitation in less than 30 minutes.
I have not done an exhaustive search of the literature, but there is a 1958 paper from B. R. Baker's laboratory on the alkylation of cysteine with chloroacetophenone (Goodman et al, JOC 23, 1251) "A suspension of 1.0 g. (6.35 mmoles) of L-cysteine hydrochloride and 0.97 g. (6.35 mmoles) of a-chloroacetophenone in a mixture of 4ml. of water and 2 ml. of 95% ethanol was prepared. To the well- stirred mixture was added, dropwise, a solution of 0.84 g. (12.7 mmoles) of potassium hydroxide in 5 ml. of water. Upon complete addition of the base, 1.07 g. (68% yield) of compound II precipitated as a crystalline, slightly yellow compound. It could be recrystallized in poor yield from water on a small scale but decomposed rapidly on prolonged heating in water. Purification of the material wm carried out by washing thoroughly with cold water and acetone. The material melted at 90-95' (dec.) and was homogeneous on paper using the t-butyl alcohol/formic acid/water system. Compound II gave a faint yellow color with ninhydrin."
I am surprised that our reaction showed precipitation. Could the precipitate be some other compound entirely? The chemistry of alkylating cysteine is not without its surprises, in my experience. For example, attempts to alkylate cysteine with chloroacetone (which sounds pretty straightforward) gives a reddish substance of unknown composition. Even given the results above and assuming that the precipitate is the desired product, our reaction was performed at a lower concentration that the one from the Baker laboratory, and I would have expected our compound (a catechol) to be more soluble with the two hydroxyl groups than without.
We often purify amino acid derivatives with ion-exchange chromatography, but solubility may be an issue if we attempt that here. However, I suppose we can cross that bridge when we come to it.
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Topic: unexpected precipitate in the alkylation of cysteine (Read 5385 times)