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Author: Subject: Synthesis of propanamide
Bitburger
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[*] posted on 29-7-2011 at 09:14
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...

propanamide2011.jpg - 48kB


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.
PBr3-DCM.JPG - 37kB
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]




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[*] posted on 29-7-2011 at 10:23


A method for making propanamide that I have been wanting to try is through acetone ammonia and sulfur. a willgerodt kindler reaction.

http://www.organic-chemistry.org/namedreactions/willgerodt-k...

also I believe the mechanism for the urea involves the formation of the cyanate which then is hydrolyzed and decarboxylated.
The mechanism half way down the page on here
http://www.sciencemadness.org/talk/viewthread.php?tid=4201&a...
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[*] posted on 29-7-2011 at 10:27




http://www.chemguide.co.uk/organicprops/amides/preparation.h...


http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=v81...


There is a least one thread on this site regarding amides using urea.
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[*] posted on 29-7-2011 at 11:38


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?

1) Formamide has a lower MW.
2) Yes. It has -I and -M electronic properties.
3) Propanamide has a calculated logP of -0.7, so it can not be efficiently extracted with any solvent unless continuous extraction is used.
4) Ask the authors.
5) Was already answered: A mechanism proposal published in a Molecules article was posted in the thread you were already pointed to. Personally, I don't find a certain step in in that mechanism convincing enough, but can live with it until someone publishes a more thorough study with a convincing experimental support.
6) The prefered lab method for making primary amides in complex molecules is by partial hydrolysis of nitriles, by activation of carboxy group and reaction with ammonia (e.g., via acid chlorides, or using CDI or a more chemoselective reagent), debenzylation of N-benzylamides, or ammonolysis of esters. There are numerous other methods as well, but there is no general answer, as the choice of strategy and method depends on the substrate.
7) It is not possible to analyze compounds online via pictures.




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[*] posted on 29-7-2011 at 11:55


I really think that the yellow liquid is propionic anhydride. After the reaction with solid NaOH and cooling it down, the product that formed was a waxy solid, I suppose sodium propanoate.. But what is the reason of the yellow colour, conjugation?

I forgot another method. If you have 1-propanol you can selective oxidize it (chromyl chloride should work pretty well) and so get propional, reaction with ammonia delivers maybe the molecule with both a amine group and a alcohol at the terminal carbon. Just oxidize the -OH and you get ...propanamide.

However, I believe that the first link in the above reply (chemguide) is the easiest way to prepare. It will depend on the amount of heat whether this is suited for larger molecules..

So if amides are electron withdrawing...than you could make 1-iodo acetamide, like this could be achieved with acetic acid and iodine?

You are awesome Nicodem, thanks for this intellectual challenge!

[Edited on 29-7-2011 by Bitburger]

[Edited on 30-7-2011 by Bitburger]




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[*] posted on 21-4-2013 at 20:10


Quick tip - ammonia is a base, propionic acid is an acid surprisingly enough. It can be used to neutralize the base forming ammonium propionate. Thermal dehydration of an ammonium acid salt will give an amide of the acid. Wasting PBr3 on it is, well, criminal from the viewpoint of people who have no access to PBr3 to use let alone waste.



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[*] posted on 22-4-2013 at 18:46


Damn it aliced25, first time I was going to be useful here and you said it before me :D
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..
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[*] posted on 23-4-2013 at 08:38


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.


What were your reaction conditions, ie, time, temperature, and concentrations?

I have made acetamide this way, and yes, you do have to be careful during the distillation.

[Edited on 23-4-2013 by Magpie]

[Edited on 23-4-2013 by Magpie]




The single most important condition for a successful synthesis is good mixing - Nicodem
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[*] posted on 23-4-2013 at 10:08


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.


I have used methyl esters and NON-AQUEOUS ammonia solutions to produce primary amides a few times. Sometimes the reaction requires heat and or pressure, but this works well in many cases. The key is getting ammonia into a solvent other than water, like methanol, dioxane, THF or other somewhat polar solvent. It should be possible to produce these solutions by simple distilling some ammonia from 12% into a cooled flask of methanol or perhaps reacting NH4Cl with NaOH in methanol, or a few other ways. Then put your ester in that, maybe in a small sealed tube or a flask with a very cold condenser and heat. I like to use lab microwave vials for these reaction, as they are designed for some pressure, but microwave heating is not required. NOTE: Use shields and caution with pressurized vessels.
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[*] posted on 23-4-2013 at 12:59


I made acetamide from 50mL ethyl acetate and 70mL con ammonium hydroxide, per Brewster (1960). This mixture was stoppered in an Erlenmeyer flask then left to stand at room temperature for at least 48hrs, with occasional shaking.

The reaction mix was then distilled, first with a water condenser to 180°C, then with an air condenser. Two fractions were collected: 150-210°C; 210-225°C. The second fraction was mainly acetamide; the first fraction can be redistilled to collect more acetamide. If the condenser clogs it must be warmed to melt the acetamide. I insulated the glassware. My yield was 85%; mp = 78-80°C (lit=82.3°C). I didn't bother to redistill the first fraction.




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[*] posted on 23-4-2013 at 16:27


BTW there are previously posted pdfs for esters and NH4OH (not what was done in the first post I assume) such as
http://dx.doi.org/10.2475/ajs.s4-24.140.173
http://dx.doi.org/10.2475/ajs.s4-24.143.429

Can it be a quick tip after 21 months? There's explicit known ways for that too, such as:
http://www.erowid.org/archive/rhodium/chemistry/amide.prepar...

[Edited on 24-4-2013 by S.C. Wack]




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[*] posted on 18-4-2016 at 09:45


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.
___________________________________________________________________________________________________________________________________

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. ;)
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[*] posted on 18-4-2016 at 11:23


Phenyl propionate can bee had as described here:

http://www.sciencemadness.org/talk/files.php?pid=304709&...

This is a pretty good starting point; it should react with ammonia or urea under the right conditions.

[Edited on 18-4-2016 by clearly_not_atara]
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[*] posted on 18-4-2016 at 15:09


For method number 3 I would have bubbled dry ammonia into the propanoyl bromide from an ammonia generator after being dried through a CaCl2 tube. I would imagine you would have better yields under dry conditions.
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[*] posted on 19-4-2016 at 03:36


TCT can be used for amidation of carboxylic acids
Quote:
Development of a Process for Triazine-Promoted Amidation of Carboxylic Acids

http://chemistry.mdma.ch/hiveboard/novel/000372508.html

[Edited on 19-4-2016 by CuReUS]
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[*] posted on 20-4-2016 at 07:02


Interesting!

Quite recently I did read a very interesting article, according to the literature 2 mole of urea is heated with 1 mole of the aromatic carboxylic acid. first 1 mole of the carboxylic acid was reacted with 1 mole imidazole and 90 s later... 90% yield of the corresponding amide.

In this case EW groups on the aromatic ring provides even better yields and vice versa.

Imidazole is hard to get, the only what comes up in my mind is the amino acid histidine which slowly decompose to histamine. To destroy the amino group, I suppose that a reaction with HONO is a good intake. Then this alcohol can be easily converted to e.a. ester or ether functions.

The carboxylic salt of the imidazole can absorb more MW energy to speed up the reaction.

Source:
http://www.cs.gordon.edu/~ijl/_lead_papers/Direct%20amidatio...
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[*] posted on 20-4-2016 at 22:34


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?
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[*] posted on 21-4-2016 at 12:10


http://www.orgsyn.org/demo.aspx?prep=cv1p0003

Distillation of acids with ammonium carbonate works! Baker's ammonia can still be bought (it is quite useful, like baking soda on steroids) but making your own ammonium carbonate is also very possible.

http://www.google.com/patents/US4335088

[Edited on 21-4-2016 by clearly_not_atara]
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[*] posted on 10-5-2016 at 09:58


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?


1) It does work with formic acid, acetamide... but for propionic acid you need a strong EW group on the other end of the chain. It depends what substrate that is used. The same for the esterification mentioned in the first post of the TS.

2) The reaction of the aromatic anhydride with dry ammonia don't take place in your hobby lab. You need to perform that reaction in solution.

3) Seems that urea is soluble in water as well as benzylacetamide. How do you think to separate urea from benzylacetamide if both are present ?

The solubility of benzylacetamide in tol is slightly soluble, the solubility of urea is slightly soluble in toluene.

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[*] posted on 10-5-2016 at 11:29


Bitburguer,

Questions number 5 and 6: the reaction between urea and carboxilic acid affords amides and carbamates. I think this method was the better and quickly way to get your propanamide. From propanoic acid and urea. See the attachment paper about acetamide from acetic acid and urea below.

However urea method is easy to apply at the lab, the most part of the pharmaceutical sinthesys i have seen uses estherification of the carboxilic acid, followed by ammonolisys.

Amides also can be achieved by tratament of nitriles with H2O2 in basic enviroment. See the attachment below.

Question number 3: The better way to separate an amide from an aqueous solution is adding hot Xilene, which dissolves amides readly, cristalizing it when the solution is cold.

Attachment: Acetamide-From-Urea-Fertiliser.pdf (3.3MB)
This file has been downloaded 248 times

Attachment: Acetamide-From-Ethyl Acetate and amonea.pdf (49kB)
This file has been downloaded 209 times

Attachment: aldehydes to nitriles and amides - NH2OH + DMSO + H2O2.pdf (167kB)
This file has been downloaded 283 times
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[*] posted on 10-5-2016 at 23:20


There is a video from Doug on Youtbe demonstrating the synthesis of acetamide from acetic acid and urea.
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[*] posted on 3-6-2016 at 04:51


Another way to make it is via a willgerodt reaction on acetone
http://pubs.acs.org/doi/abs/10.1021/ja01211a083
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