Synthesis of propanamide

I have made several attempts to synthesize propanamide. Unfortunately, all amides tends to be solids, with the exception of methanamide (formamide) which is a liquid, their melting points are:
- methanamide: 2.49°C (275.64K)
- ethanamide: 80.16°C (353.31K)
- propanamide: 84.3°C (354.45K)[
- i-propanamide: 129°C (402.15K)
- butanamide: 114.8°C (387.95K)

I said "unfortunately" because you can't distill a solid over, unless if you use a hot liquid of e.a. 90°C in your Liebig condenser...

Method 1: reaction between ammonia and esters FAILED

Because esters are really stable it is difficult to do a reaction with these. Also, because of the fact that ammonia is a weaker nucleophile than hydroxide ions which is a stronger nucleophile, the reaction simply doesn't work. On heating you get hydrolysis.

I tried the reaction between methyl propanoate and 12%(v/v) ammonia. The result: methanol and propionic acid as end products.


Without making esters it seems even more impossible. Direct reaction between a carboxylic acid and NH3 renders the corresponding ammonium salt of the carboxylic acid. Maybe dehydration of this salt with the right amount of phosphorus(V)oxide in a dry and suited solvent is feasible (not any alcohol, since P4O10 react with it!). Some people claim that P4O10 reacts further with amides to give nitriles!

Another issue is "How do you isolate the ammonium salt of the carboxylic acid in this ammonia containing mixture?" Heating it is no option since ammonia will come over first and then the carboxylic acid comes over without getting a solid in the destillation flask! So, how do I isolate this salt with this nasty ammonia, if you don't have a garden?


Method 2: Heating ammonium chloride with sodium propionate

Dry distillation of ammonium chloride with sodium propionate is a very slow reaction. But it certainly works! See picture. The under layer consists of ammonia, but when cooling a white solid was visible. This is propanamide, but in a too small amount. When the temperature rises up to 140°C the distillation apparatus was fully filled with smoke but a yellow liquid came over! It has a density of around 0.9 g/mL and don't give NH3 gas when heating it up with NaOH. Instead, the yellow oil was becoming even more darker,so no idea what it could be...

Method 3: Reaction of propanoyl bromide with excess ammonia

At first, I will create propanoyl bromide by the reaction of propionic acid with PBr3 in my dark red DCM solution. The smoke is produced as a result of the quick reaction with the water in the air.

Because this reaction produces HBr gas as side product just use 2 molecules of ammonia to react with propanoyl bromide, so you get NH4Br. Yes, I know: H2O does also react with propanoyl bromide but if you don't heat it up I think that the main product is propanamide since NH3 is a much stronger nucleophile and the amount of hydroxide ions are very small if you keep the mixture cold.

Method 4: reaction between propionic acid and urea

I have read that this is an alternative way to prepare primairy amides since no water has to be used. However, the reaction mechanism is unclear to me.
Is there formation of an ammonium carbamate?
Does it act as base and form a salt which then decomposes?
Or is the nitrogen acting as a nucleophile and attacking the carbonyl group on the -COOH?

I have also read that 2 molecules of urea are needed to react with one mole of the carboxylic acid.


...And if this is a decomposion reaction, why not using dry ammonium carbonate which is added immediately to the carboxylic acid and heating it up until CO2 escapes?

SUMMARY
1) How to explain the low mp of formamide compared to the very high mp of ethanamide?
2) Is the -CONH2 group electron withdrawing?
3) What solvent do I need to do a liquid-liquid extraction of the aqueous solution of propanamide?
4) Why I don't find propanoyl bromide in the "Handbook of chemistry and physics 2010-2011" while propanoyl chloride is just listed?
5) How to explain the reaction mechanism between urea and carboxylic acids?
6) What is the most preferred method when making a primairy amide in complex organic molecules (like medicines,...) and what is the best way to prepare amides?
7) What is the yellow oil on the picture? Is it propionic anhydride?

[Edited on 29-7-2011 by Bitburger]

Quote: Originally posted by Bitburger

SUMMARY 1) How to explain the low mp of formamide compared to the very high mp of ethanamide? 2) Is the -CONH2 group electron withdrawing? 3) What solvent do I need to do a liquid-liquid extraction of the aqueous solution of propanamide? 4) Why I don't find propanoyl bromide in the "Handbook of chemistry and physics 2010-2011" while propanoyl chloride is just listed? 5) How to explain the reaction mechanism between urea and carboxylic acids? 6) What is the most preferred method when making a primairy amide in complex organic molecules (like medicines,...) and what is the best way to prepare amides? 7) What is the yellow oil on the picture? Is it propionic anhydride?

Damn it aliced25, first time I was going to be useful here and you said it before me
I had studyied this reaction this semester, reacting the NH3 with a Carboxylic acid, and then heating to make the salt rearrange itself and then finally give the amide as a product.
Actually it was the reaction of NH3 with an anhydride, that resulted in a carboxylic acid in one extreme that then reacted with the NH3, but the idea is the same..

Quote: Originally posted by Bitburger

I tried the reaction between methyl propanoate and 12%(v/v) ammonia. The result: methanol and propionic acid as end products.

Quote: Originally posted by Bitburger

Method 1: reaction between ammonia and esters FAILED Because esters are really stable it is difficult to do a reaction with these. Also, because of the fact that ammonia is a weaker nucleophile than hydroxide ions which is a stronger nucleophile, the reaction simply doesn't work. On heating you get hydrolysis. I tried the reaction between methyl propanoate and 12%(v/v) ammonia. The result: methanol and propionic acid as end products.

Alright, this weekend I did some more experiments with other more exotic substrates. This was my homework as Bitburger:

I did contact the editor-in-chief of the CRC and got a answer. The entire organic section is reviewed and took the researchers 3 full months and plenty of work. The latest version have the right data, over 1/3 of all the major organic molecules are listed, based on plenty of huge datebases (like Merck,...).

The major problem is that the insertion of one single molecule (like propanoyl bromide) in the CRC is due technical problems as the "structures" are often displayed on the other page after editing. This cause too much problems with editing. This is not the original text, just to explain my initial question 4.

Propanoyl anhydride is fairly stable and hard to break that bond with anhydrous ammonia in a hobby lab and not recommended. Hydroxide anions are way stronger as nucleophile and thus this recommendation can not be used.
That's the second method which yields propanoyl anhydride.

Only method 4 with urea seems to work in this topic to create primairy amides.
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Metaboric acid will be formed at temperatures about 180°C, I did repeat this procedure with phenylpropionic acid and the same molar ratio's are used as discussed in this experimental topic (see source). I did add boiling water after 2,5 hours and did kept the temperature at 175°C during the dry reaction. The water turned to a brown liquid, after adding toluene this brown unknown substance did dissolved in toluene. However, no crystals where observed. A off-white fine powder was visible at the bottom of the aquous layer. This might be the corresponding amide.

Is there a test method for primairy amides ?

All the feedback is really appreaciated about the extraction or identification of the products that where formed.Not sure what the entire mechanism is and what the role is of boric acid as the yields are way higher with H₃BO₃. Any idea's ?

I wasn't aware that benzylacetamide is soluble in water (7,2 g/L) and that was a big mistake.btw: I try the other methods to find out what my favorite procedure is.

Sources:
The synthesis of benzamide (recommended)

chemspider - benzylacetamide

Other relevant literature or methods are appreciated about this topic. The (NH₄)₂S method can't convince me as there was a topic about acetophenone and this reagent.

Quote: Originally posted by MeshPL

Why don't you try dry distillation of ammonium propionate? I remember that method works for ammonium formate and acetate to make formamide or acetamide, so why not propanamide?