October 04, 2022, 06:16:42 PM
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Topic: Replacing 1 M hydrochloric acid wash in the presence of N-Boc protecting groups  (Read 436 times)

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Offline Babcock_Hall

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We often work with N-Boc protected compounds, and the extraction protocols sometimes call for 1 M HCl.  Even if the next step were washing with bicarbonate, this makes me uneasy, due to possible loss of the N-Boc group.  However, I am uncertain of the best alternative and whether or not the best alternative depends on context.  Using 0.1 M HCl or using 5% NaHSO4 or KHSO4 are possible alternatives.  I occasionally see citric acid in wash steps, and I imagine its chelating abilities might be useful in certain work-ups.  This question has come up before, but I don't recall that it was resolved.
« Last Edit: August 11, 2022, 09:33:24 AM by Babcock_Hall »

Offline rolnor

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Even just 5% HOAc might be sufficient, this type of things can be tested in small scale in a test tube with a pasteaur pipette.  what are you washing out?
« Last Edit: August 12, 2022, 02:48:48 AM by rolnor »

Offline kriggy

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I used 5% HCl (95/5 water conc. HCl) or 10% citric acid and no issues so far

Offline rolnor

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Great! 1M HCl is probably old procedure.

Offline Babcock_Hall

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Wernic D. and collaborators (J. Org. Chem. 1989 54:4224) synthesized 1-tert-Butyl L-2-(t-Boc-amino)-4-oxobutanoate from the corresponding Weinreb amide using 1.5 equivalents of DIBAL-H.  “The reaction mixture was partitioned between 0.35 M NaHSO4 aqueous solution (200 mL) and ether (300 mL) and the aqueous layer was extracted with ether (3 X 100 mL). The combined ethereal solutions were washed with 1 M HCl (3 X 100 mL), 1 M NaHCO3 (3 X 100 mL), and brine (3 X 100 mL) and dried (Na2SO4).”

Zhang G. and collaborators (Org Biomol Chem 2015 13(14):4149; Supplemental DOI: 10.1039/c5ob00120j) performed an almost identical synthesis. “The reaction mixture was partitioned between 0.35 M NaHSO4 aqueous solution (20 mL) and ether (30 mL) and the aqueous layer was extracted with ether (3 X 10 mL). The combined ethereal solutions were washed with 1 M HCl (3 X 10 mL), 1M NaHCO3 (3 X 10 mL) and brine (3 X 10 mL) and dried with anhydrous Na2SO4.

Both of these examples quench the reduction with NaHSO4 prior to extraction.  Both use 1 M hydrochloric acid.  I will look for other chemistry and post when I find it.

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