N-methylation of glycine

ID: 181803  |  No.: 631  |  Institut für Chemieinformation

Category: Evidence

DOI: https://doi.org/10.5281/zenodo.22928398

3 Glycine (C2H5NO2 _(s)) + 2 Trioxane (C3H6O3 _(s)) + 6 Oxalic acid (C2O4H2 _(s)) → 3 dimethylglycine (C₄H₉NO₂ _(s)) + 12 carbon dioxide (CO₂ _(g)) + 6 water (H₂O _(l))

Reaction mechanism:

1 Formation of the aminol, 2 Protonation of the aminol, 3/4 Dehydration to form the iminium, 5/6 Reduction of the imine to sarcosine (secondary amine). Repetition of the reaction sequence at a higher reaction rate until dimethylglycine (tertiary amine) is formed.

1. Prepare the mixture (trituration): In a mortar, carefully and thoroughly triturate 225 mg of glycine (3.0 mmol), 810 mg of 1,3,5-trioxane (9.0 mmol) and 756 mg of oxalic acid dihydrate (6.0 mmol) in a mortar until a homogeneous powder mixture is obtained. 
2. Transfer to the reaction vessel: Transfer the solid mixture quantitatively into a test tube (TT) using a solid-feed funnel (if necessary, use a spatula to transfer any remaining material; dislodge any adhering residues by tapping gently).
3. Set-up: Seal the test tube with a perforated stopper and insert it into a rising tube acting as an air-cooled reflux condenser.
4. Heating / Reaction: The test tube is carefully heated in a hot-air stream at 150°C (or using another similarly controlled heat source) until visible condensate forms in the rising tube (approx. 10 min).
5. Switch off the heating and allow the reaction mixture to cool to approx. 50°C. Caution: Prolonged heating leads to a dark brown colour, which indicates the formation of decomposition products.
6. Add 10 ml of water to the cooled reaction mixture. A clear, orange-coloured solution forms.
7. Half of the mixture is transferred to a test tube and 1 ml of Dragendorff’s reagent is added. An orange-red precipitate forms immediately. => Detection of a tertiary amine!
8. Optional: Approx. 0.5 ml of the reaction mixture is placed in the centre of a watch glass (on an overhead projector). A drop of Dragendorff’s reagent is placed at the edge of the watch glass. 
   Using a glass rod, the Dragendorff’s reagent is mixed with the reaction mixture. The formation of the precipitate can be observed in the projection. 
9. Optional – TLC: 200 µl of the reaction mixture and, for comparison, a glycine solution are applied to a DC plate and chromatographed using a mobile phase of acetone (5 ml) : isopropanol (5 ml) : acetic essence (25%; 4 ml).
   After drying (with a hairdryer), the plate is first sprayed evenly with ninhydrin spray reagent solution. When dried with a hair dryer, only a violet spot develops on the glycine track => primary amine
   . Any slightly yellowish spot that may appear on the reaction mixture would indicate the intermediate monomethylglycine (sarcosin) => secondary amine.
10. The plate is then sprayed evenly with Dragendorff’s reagent. In the reaction mixture, an orange-red spot just above the starting line indicates dimethylglycine => tertiary amine

Observations during heating (for process control):

• After approx. 2 mins, the mixture begins to sinter and shortly afterwards a clear solution forms, accompanied by the formation of bubbles (CO₂) and condensation on the RG wall.
• The solution slowly turns yellowish and is orange-red after approx. 5 mins.
• Heating is continued until, after a total time of approx. 10 min, condensate accumulates in the rising tube. The reaction mixture (temperature approx. 105°C) is now dark red.

HPLC on silica gel (2.5 × 7.5 cm); mobile phase: 5 mL acetone, 5 mL isopropanol, 4 mL acetic acid solution (25%):  Rf: dimethylglycine 0.14, glycine 0.47 (sarcosin 0.21)

• Safety goggles must be worn.
  German original

  Eine Gestellschutzbrille ist zu tragen.
• Disposable nitrile gloves are used as splash protection.
  German original

  Als Spritzschutz dienen Nitril-Einmalhandschuhe.

N,N-Dimethylglycin.png

N,N-dimethylglycine

https://upload.wikimedia.org/wikipedia/commons/thumb/9/9d/N%2CN-Dimethyl_glycine_Structural_Formula_V1.svg/250px-N%2CN-Dimethyl_glycine_Structural_Formula_V1.svg.png

Substitution of paraformaldehyde: Proske W. and Klemeyer H., unpublished communication

Substitution of formic acid: Rosenau T. et al. SYNTHETIC COMMUNICATIONS, 32(3), 457–465 (2002) A SOLVENT-FREE AND FORMALIN-FREE ESCHWEILER-CLARKE METHYLATION FOR AMINES; https://sl1nk.com/jxnxnwc (Substitution of formic acid)

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