The paper referenced below has always intrigued me. The fact that a simple primary amide is reported to react readily while even a simple mono methyl amide does not suggests something remarkable is going on. Could it go through a diprotonated intermediate enabled by the local concentration of protons on the acid exchange resin? How would one work out answers? It is a heterogeneous reaction?
I reproduce my original blog article below.
Carboxylic Acid Hydrazides: A Carboxylic Acid Derivative that can be Purified by Phase Switching
The core Kilomentor strategy in chemical process development is to utilize isolated intermediates that can be phase switched for purification; commonly this can be done by extraction into an aqueous phase at one pH and then taken bake into an organic phase at a second pH. Esters are a common functional group that cannot be switched in this way. Free carboxylic acids can but a free acid group can interfere with many reaction types. A carboxylic acid hydrazide is sufficiently basic (pKa ~3) http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf
to form salts with mineral acids that would be water soluble and the hydrazide would not interfere in many transformation where a free carboxylic acid would. A problem would appear to be that the final form of the intermediate you might like to have may be the ester or free carboxylic group and it is not obvious that one can smoothly convert carboxylic acid hydrazides into esters or free acids. There is however a simple procedure available for doing this.
Greenlee and Thorsett found that warming the acyl hydrazide with a fifteen fold excess by weight of Amberlyst 15 ion exchange resin under reflux in water, methanol, or ethanol gave the acid, methyl ester, or ethyl ester respectively in high yield. [William J. Greenlee , Eugene D. Thorsett J. Org. Chem., 1981, 46 (26), pp 5351–5353] This methodology also worked to convert primary amides in the same way but secondary amides, even a simple N-methylamide was inert to the treatment. It is worth noting that peptide bonds in particular were not touched.
The core Kilomentor strategy in chemical process development is to utilize isolated intermediates that can be phase switched for purification; commonly this can be done by extraction into an aqueous phase at one pH and then taken bake into an organic phase at a second pH. Esters are a common functional group that cannot be switched in this way. Free carboxylic acids can but a free acid group can interfere with many reaction types. A carboxylic acid hydrazide is sufficiently basic (pKa ~3) http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf
to form salts with mineral acids that would be water soluble and the hydrazide would not interfere in many transformation where a free carboxylic acid would. A problem would appear to be that the final form of the intermediate you might like to have may be the ester or free carboxylic group and it is not obvious that one can smoothly convert carboxylic acid hydrazides into esters or free acids. There is however a simple procedure available for doing this.
Greenlee and Thorsett found that warming the acyl hydrazide with a fifteen fold excess by weight of Amberlyst 15 ion exchange resin under reflux in water, methanol, or ethanol gave the acid, methyl ester, or ethyl ester respectively in high yield. [William J. Greenlee , Eugene D. Thorsett J. Org. Chem., 1981, 46 (26), pp 5351–5353] This methodology also worked to convert primary amides in the same way but secondary amides, even a simple N-methylamide was inert to the treatment. It is worth noting that peptide bonds in particular were not touched.
Although Amberlyst 15 acidic resin was used for most trials, other resins such as Amberlyst XN-1010 or Amberlite IR-120 were found to give even faster reactions. Powdering the resin produced no increase in rate but did cause difficulties in the filtration of the resin when the reaction was complete.
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