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I am forming 2,2-dimethoxyacetic acid from its methyl ester, and below is the experimental protocol I am following (from Tetrahedron 2016, 72 (3), 420–430):

2,2-Dimethoxy Acetic Acid Formation

  1. Add lithium hydroxide monohydrate ($\pu{89.5 mmol}$, $\pu{3.75 g}$, $\pu{1.2 equiv}$) to a solution of methyl dimethoxyacetate ($\pu{74.6 mmol}$, $\pu{10 g}$, $\pu{1 equiv}$) in dioxane ($\pu{45 mL}$) and water ($\pu{45 mL}$) at $\pu{0 ^{\circ}C}$.
  2. Stir the mixture for $\pu{1 h}$ at $\pu{0 ^{\circ}C}$ and one additional hour at room temperature.
  3. Add sodium hydroxide ($\pu{1M}$ aq soln, $\pu{75 mL}$) to the mixture.
  4. Extract the mixture with diethyl ether ($\pu{375 mL}$).
  5. Acidify the recovered aqueous layer with hydrogen chloride ($\pu{6N}$ aq soln) until a pH of 1-2.
  6. Extract the organics with diethyl ether ($\pu{375 mL}$).
  7. Dry the combined organic layers with magnesium sulfate and filter.
  8. Evaporate the solvent slowly under reduced pressure to obtain 2,2-dimethoxyacetic acid.

I repeated this reaction many times but every time I check the $\mathrm{^{13}C}$-NMR, I only see a single peak at $\delta \: \pu{67.12 ppm}$. I believe this corresponds to C-OMe. By theory (and by literature) I should see 3 peaks. $\mathrm{^{1}H}$-NMR does show 6:1 ratio of singlets at $\delta \: \pu{3.704 ppm}$ (6H) and $\delta \: \pu{3.458 ppm}$ (1H) but it is not well aligned with literature; By theory, a single hydrogen atom adjacent to $\ce{C=O}$ group should be more deshielded than $\delta \: \pu{3.458 ppm}$ (i.e. be placed at higher ppm). I thought through what I have done and I still can't figure out which step has gone wrong. Any thoughts and ideas? Would appreciate any advice.

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    $\begingroup$ What weight of material do you get after concentrating the ether extract? I can't access the paper but I see it comes from a reputable group. Are you required to reproduce this procedure exactly or can you change it? $\endgroup$ – Waylander May 6 at 15:02
  • $\begingroup$ @ Waylander: OP has followed exactly what experimental section given in the paper. Only change is the volume of ether extracts. Paper recorded 99% yield of colorless liquid as a product: $\mathrm{^1H}$-NMR are reported as $\delta$ 3.44 (s, 6H), 4.85 (s, 1H), and 10.32 (broad s, 1H). $\mathrm{^{13}C}$-NMR are reported as $\delta$ 54.1 ($\ce{2CH3}$), 98.6 ($\ce{CH}$), and 170.7 ($\ce{C_q}$). $\endgroup$ – Mathew Mahindaratne May 6 at 17:26
  • $\begingroup$ I assume you have mixed up your ether extracts and had an NMR made of the cleaved methanol. A single peak in 13C !?! $\endgroup$ – Karl May 6 at 17:58
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    $\begingroup$ The step that draws my suspicion is the acidification with 6N HCl to pH 1-2. It would be easy to add a bit too much acid, leave the mixture too long, or let it get a bit too warm and hydrolyse the dimethyl acetal. The resulting glyoxalic acid, if formed, would not easily extract from aqueous. $\endgroup$ – Waylander May 6 at 18:07
  • $\begingroup$ Ok, the CS doesn't fit, and of course also the 1H spectrum you report. $\endgroup$ – Karl May 6 at 18:08
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The answer from @Mathew Mahindaratne in my opinion correctly identifies what the OP has isolated. It remains to suggest how to get the required product. It may be a matter of salting out the aq phase, but there are other possibilities. Some observers may feel that given a literature prep from a respected group there is no need to alter it, however the OP has not been able to replicate it. Accordingly I offer this procedure.

Dissolve the methyl dimethoxy acetate in a mixture of 9:1 THF/water at rt. Add 1.1eq of LiOH monohydrate. Leave to stir at rt overnight. Concentrate under reduced pressure. Dissolve the residue in a minimum amount of water, cool in ice bath. Wash with Et2O. Acidify using a slight excess of 2N HCl (pH really doesn't need to go below 3.0 as pKa of product is probably around 3.7). Extract x3 with Et2O. Dry the combined organic extract, filter and concentrate. This should minimise any change of hydrolysing the acetal.

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  • $\begingroup$ Should I add 2N HCl in an ice bath? Would adding an acid at r.t. increase the chance of hydrolysis of dimethyl acetal? $\endgroup$ – chemrese May 7 at 7:59
  • $\begingroup$ You said In only should use a 'minimum amount' of water- is it to reduce the chance of hydrolysis of acetal? $\endgroup$ – chemrese May 7 at 8:02
  • $\begingroup$ Minimum amount of water as the product appears to have a significant water solubility, you may need to salt it. Keep the aq phase cold as you add the acid as this is exothermic, swirl it too so that you don't get a locally high concentration of acid. This is to minimise the chances of the acetal hydrolysing. $\endgroup$ – Waylander May 7 at 8:17
  • $\begingroup$ so I add NaCl to the aq. layer to salt my product out? $\endgroup$ – chemrese May 7 at 8:25
  • $\begingroup$ Correct. This increases the ionic concentration and forces less water soluble species out of solution. $\endgroup$ – Waylander May 7 at 8:35
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If your reaction has worked and you get the expected product, you should see following NMR data as the sought literature reported:

$\mathrm{^{1}H}$-NMR: $\delta$ 3.44 (s, $\ce{6H}$), 4.85 (s, $\ce{1H}$), and 10.32 (broad s, $\ce{1H}$).

$\mathrm{^{13}C}$-NMR: $\delta$ 54.1 ($\ce{2CH3}$), 98.6 ($\ce{CH}$), and 170.7 ($\ce{C_q}$).

Instead, you got two peaks, $\delta$ 3.704 (s, $\ce{6H}$) and $\delta$ 3.458 (s, $\ce{1H}$), in your $\mathrm{^{1}H}$-NMR. And, you got only one peak at $\delta$ 67.12 in your $\mathrm{^{13}C}$-NMR. All this data telling me is your reaction has not worked as expected. What you have is 1,4-dioxane during the ether extract, $\mathrm{^{1}H}$-NMR of which gives only a singlet at $\delta$ 3.71 when $\ce{CDCl3}$ is the solvent. It also gives one peak at $\delta$ 67.14 in $\mathrm{^{13}C}$-NMR under same solvent (Ref.1).

I believe your compound may still be in the aqueous phase. You may need to saturate the aqueous phase with salt ($\ce{NaCl}$) before extract the product to organic phase. Note that acetic acid is very soluble in water. Therefore, I expect 2,2-dimethoxyacetic acid to be highly soluble in water as well (a $\ce{C4(H2O)4}$ compound like a monosaccharide).

References:

  1. H. E. Gottlieb, V. Kotlyar, A. Nudelman, “NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities,” J. Org. Chem. 1997, 62(21), 7512–7515 (DOI: 10.1021/jo971176v).
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    $\begingroup$ And maybe not add the NaOH soln. I don't see why that was done, you're just increasing the volume of the aq phase. $\endgroup$ – Waylander May 6 at 18:49
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    $\begingroup$ Dioxane, of course! And a spot of water, which probably comes from the CDCl3 bottle. $\endgroup$ – Karl May 6 at 18:53
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    $\begingroup$ @Waylander It lowers the dioxane content in the aqueous phase, helping to get a better phase separation for the extraction of methanol and residual ester. $\endgroup$ – Karl May 6 at 19:14
  • $\begingroup$ Not working is it $\endgroup$ – Waylander May 6 at 19:25

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