Diazomethane Nierenstein reaction

Nierenstein reaction. Formation of omega-chloroacetophenones by reaction of diazomethane in dry ether with aroyl chlorides. Coumaranones are obtained if an ortho-hydroxy group is present. 

This reaction was first reported by Staudinger in 1914, subsequently by Clibbens and Nierenstein in 1915, and extensively studied by Nierenstein. It is the synthesis of a -chloromethyl ketone by treatment of an aliphatic or aromatic acyl chloride with diazomethane. Therefore, it is generally known as the Nierenstein reaction." Occasionally, it is also referred to as the Clibbens-Nierenstein reaction or Nierenstein chloromethylation. ... 

Nierenstein reaction is the reaction of an acid chloride 1 with diazomethane at room temperature to yield a a-chloroketone 2. It differs from the Arndt-Eistert reaction in that the latter specifically forms diazoketone, which is used to form the higher homolog of the substrate acid chloride. 

Nierenstein reaction takes place when 1 equivalent of diazomethane is added to the acid chloride solution at 35 °C. Nierenstein reaction is now accepted to take place through the in situ generation of HCl during the formation of diazoketone 4, which reacts with it further to form the chloromethyl ketone 2. Thus diazoketone is an intermediate in the reaction. 

Benzyl chloromethyl ketone has been prepared by the reaction of diazomethane with phenylacetyl chloride. The method of Clibbens and Nierenstein, in which one equivalent of diazomethane is added to the acyl chloride and the chloromethyl ketone obtained directly, could not be duplicated by Bradley and Schwarzenbach or by the submitters. 

In 1915, Maximilian Nierenstein and Douglas Arthur Clibbens at the University of Bristol reported that when an ethereal solution of 1 equivalent of freshly diazomethane is added to an acid chloride at laboratory temperature and the mixture is stirred, the corresponding chloromethylketone 2 is obtained. The sequence of addition and the temperature appeared to be rather specific. Nierenstein proposed that this tendency of acid chlorides to form the chloroketones was analogous to the reaction of aldehydes with diazomethane to yield ketones 3 reported by Schlotterbeck. ... 

It is interesting that the conditions used by Robinson and coworkers were different from the ones described by Nierenstein, and they involved the addition of acid chloride to excess diazomethane rather than stoichiometric in the reverse order, with the reaction mixture cooled with ice and the ethereal solution of acid chloride being added to diazomethane rather than the reverse Thus, unlike Nierenstein, Robinson and co-workers had added the acid chloride to the diazomethane solution whereby the tendency for the nonformation of the chloroketone might be dominant. 

Observations from both Nierenstein and Robinson have enabled the understanding of this reaction. It is also accepted that excess diazomethane at lower temperatures leads to diazoketones because hydrogen chloride liberated gets consumed by its preferential reaction with excess diazomethane to form methyl chloride 5. This explains why hydrogen chloride gas added through an external source to a solution of diazoketone can drive the Nierenstein to completion. Further evidence to support this theory was offered by McPhee and Klingsberg in the procedure for the synthesis of benzyl chloromethyl ketone from phenylacetyl chloride, by which the diazoketone is separately treated with hydrogen chloride at 0 °C and also by Bhatt et al. in their synthesis of a-chloromethyl-3,4,5-triacetoxy acetophenone in which diazoketone is the key intermediate. ... 

One vital observation made by Nierenstein was that there was a considerable reluctance of acyl bromides to form the corresponding bromomethyl ketones. Acid bromides on reaction with diazomethane were also found to form substituted 1,4-dioxanes or specifically 3,6-dibromo-3,6-diphenyl-1,4-dioxane 8, resulting from the dimerization of adducts. The dimerization according to him could be attributed to the poor mobility of the bromide compared to the chloride group. 

In efforts to apply the reaction to total synthesis, Nierenstein reported the synthesis of fisetol 15, a product of disintegration of the flavonol fisetin. It was reported during his studies on the action of diazomethane on aromatic acyl chlorides. Some other flavonols are quercetin, datiscetin, myricetin, quercetagetin, and gosspyetin. The synthesized molecule was observed to show the same properties as that prepared by Sonn and Falkenheim by a different method, thus confirming its structure. 

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