Dear all,
I am planning to prepare a hydroxamic acid by the condensation of NH2OH·HCl with carboxylic acid in the presence of base(mostly NaOH). However, my substrate bears a diaryl ketone moiety, which is likely to undergo condensation with NH2OH to afford ketoxime. So, is it possible for me to get desired hydroxamic acid without protection and deprotection? There do exist a few literatures that achieved this goal, but why the others didn't ? what should be the decisive factor? Any suggestion is welcome~
The presence of NaOH is to get rid of HCl in order to obtain NH2OH alone. Hydroxyamine will target the carbonyl group in aldehydes & ketones in a condensation reaction converting the C=O into C=N while your aim is solely to transform –COOH into - C(O)NHOH "which is an unstable moiety, as you know". Eventually, the CO2 gas separates & amino –NH2 group is formed.
A ketoxime will be present & your product will have a terminal amino group. So the research project requires a different approach.
Activation of carboxyl group may be useful. It could be synthesis via standart acylchloride or methods developed in peptide chemistry. It mostly depends on substrate (carbonyl group reactivity, other reactive groups presence).
For examples, see review 10.1002/9780470741962.ch6
And first representative example which I've found by google:
A solution of hydroxylamine hydrochloride (4.90 g, 71 mmol) dissolved in 2 N NaOH (35.5 mL, 71 mmol) was slowly added to a stirred solution of 4-(2,2-dimethyl-1-oxopropyl)benzoyl chloride (8.00 g, 35.6 mmol) in ether (50 mL) at 0 °C. The mixture was poured into 2 N HCl (30 mL) and extracted twice with ether. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was recrystallized (hexane/ether, 4:1) to yield 6.5 g (82%) of 4-(2,2-dimethyl-1-oxopropyl)-N-hydroxybenzamide (12) as white crystals: mp 125-126 °C. (from 10.1021/JM980438Y)
Thanks for suggestions from Abdul and Anton, their approaches are worth trying. Besides, I 've also found that using DBU as base under a carefully controlled reaction duration could achieve hydroxamic acid as the major product from according methyl esters. see reference:
Beillard, Audrey; Bhurruth-Alcor, Yushma; Bouix-Peter, Claire; Bouquet, Karinne; Chambon, Sandrine; Clary, Laurence et al. (2016): A facile and rapid preparation of hydroxamic acids by hydroxylaminolysis using DBU as base. In Tetrahedron Letters 57 (20), pp. 2165–2170. DOI: 10.1016/j.tetlet.2016.04.003.
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