Methylamine Methylamine HCl via Schmidt Rearrangement

This reaction is quite similar to the Hofmann Rearrangement, but it reacts a Carboxylic Acid with Hydrazoic Acid to generate the desired amine. Like the Hofmann, it has wide application and versatility, yet also has excellent yields in many cases. It will also preserve the chirality of the starting Acid/Anhydride, which is not of interest to us, but an important fact to note. The restrictions on this process are that the starting Carboxylic Acid must not adversely react with either Sulfuric Acid or Hydrazoic Acid. It would be a crime ifldidnt also mention that the Schmidt Rearrangement has much greater application than just making amines from car-boxylics, but that is well beyond the scope of this FAQ. See Organic Reactions v3 for more details.

To make Methylamine or the HCI salt using the Schmidt Rearrangement, you start off with glacial Acetic Acid. You might be saying to yourself, "Damn, why bother with the Hofmann!" since glacial Acetic Acid is so easy to get, but, there is a drawback... And that is Hydrazoic Acid, which is *not* easy to get. As well, Hydrazoic Acid is extrememly poisonous and should not be handled without a fume hood under *any* circumstances. Really. This is coming from a guy who has no problem distilling Ether solutions in his kitchen, so take it seriously. Why bother, then? Well, because you *can* generate the Hydrazoic Acid in situ using Sodium Azide and conc. Sulfuric Acid. I have not personally tried this because / don't have a powder addition funnel. Anyway, Sodium Azide is not too hard to come by through chemical supply houses and Sulfuric Acid is easy to acquire in the form of Instant Power - 265 -

Drain Opener. This reaction MUST be performed in an area of adequate upward ventilation, or at least with the air flowing away from you.

*NOTE* In the initial testing of any undesireable interaction between Sodium Azide, Acetic Acid and Sulfuric Acid, I mixed 5mL of each into a small cup underneath my "fume hood". Though I smelled *nothing*, within seconds my head felt like it was expanding, my heart started racing, and I felt more weak and confused than normal. I just barely escaped and recovered in 15 minutes, but, Needless to say, this procedure is a *tad* on the dangerous side. You have been *warned*.

Theory behind this reaction is:

R-COOH + NaN3 —HzS04—> intermediates —H20—> R-NH2 + C02

The intermediates in making amines are isocyanates (0==C==N) just like the Hofmann Rearrangement. The isocyanates are decomposed with water, just like the Hofmann. In fact, there is a lot of similarity between the Hofmann and the Schmidt reactions. Before I detail the synthesis steps, I should note that if you wish to generate the Hydrazoic Acid in the flask by adding Sodium Azide, you might need a powder addition funnel. This bit of equipment is quite pricey and it's likely you won't have one, so the first part of the synthesis details how to make the Hydrazoic Acid separately.

There are three variations on this process you may choose from:

1) Add Hydrazoic Acid to a Carboxylic Acid/Benzene or Chloroform mixture (O. React, claims this is the preferred method). 2) Add Sulfuric Acid to Carboxylic Acid/Hydrazoic Acid/Benzene or Chloroform mixture (this is my prefered method). 3) Add Carboxylic Acid/Hydrazoic Acid/Benzene or Chloroform mixture to Sulfuric Acid or Sulfuric Acid/Benzene or Chloroform mixture.

a) Preparation of Hydrazoic Acid

*CAUTION* This compound is EXTREMELY EXPLOSIVE and HIGHLY TOXIC! I am not exaggerating! Do not, under ANY circumstances, allow the acid to heat above room temperature (bp: 37C). Use latex gloves to handle, and dispose of small quantities using plenty of water followed by dilute baking soda/water.

Prepare a paste out of 65g Sodium Azide (1m NaN3) and 65mL of water in a beaker. Add 400mL of either Chloroform or Benzene to this paste (depending on what you have available, but be consistent later on) and stir well. Dump this mixture into a round bottom flask situated in an ice/salt bath, drop in a stirrer magnet, attach a Claisen adapter, addition funnel, and thermometer. Let this mixture cool to OC.

Place 49g of cold concentrated Sulfuric Acid into the addition funnel, but only after you make sure the stopcock is turned OFF. Ever so slowly add the acid to the flask, dropwise, such that the flask contents stay around 1C, and never go over5C. This might take a while, be patient. After all is added, pour the flask contents into a separatory funnel (ventilation is absolutely required here) and separate out the aqueous layer. Your HN3 is dissolved in the Chloroform/Benzene layer. If you wish to determine the exact concentration of the acid, you may titrate it, but the reaction generally goes to completion with no secondary hydrazides forming as long as you kept the temperature where I told you to. Some HN3 might have gone to the aqueous layer, but mostly the resulting Sodium Sulfate will crowd it out. The resulting concentration, then, is the moles of Hydrazoic Acid over the the total moles of HN3 and your solvent (Chloroform = 117g/m, Benzene = 78g/m).

b) Making the Amine (All Variations)

Setup your glassware for simple distillation with a claisen adapter, three way adapter, pressure-equalized addition funnel, water cooled condenser, vacuum adapter and receiver flask to catch any condensed solvent vapors.

c) Specifics for Variation 2

Drop your stirrer magnet into the flask and add 250mL of Benzene or Chloroform (take your pick), Next, add .25 moles glacial Acetic Acid (15g) then .5 moles Hydrazoic Acid with stirring. Warm this solution to about 40C using a water bath. Make sure all joints are air tight. Add 20mL concentrated Sulfuric Acid very slowly. The reaction is mildly exothermic, so take care and watch the temperature. The reaction finishes within 2 hours. The amine is in the sulfate salt form. To convert to the hydrochloride salt form, first add an equinormal amount of 10% NaOH solution and stir well. Next, extract the free amine with ether and bubble HCI gas through it to precipitate out the crystals. Filter to recover.

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