Sciencemadness Discussion Board - Preparation of amides via esters or carboxylic acids?

Preparation of amides via esters or carboxylic acids?

Rich_Insane - 6-2-2012 at 14:16

Hey everyone! So I've been thinking about how one can prepare a primary amide (is that the right terminology? I mean an amide without any N-substitution). Now I've read that a lot of people are preparing amides from ammonium salts of aliphatic carboxylic acids (ammonium acetate; ammonium propionate etc). Decomposition of this at certain temperatures would yield the amide. So my question is, can this be done with heavier carboxylic acids (say phenylpropanoic acid -- ammonium phenylpropanoate) or rather aromatic carboxylic acids (not necessarily aryl, but just possessing the ring).

A friend suggested a better idea, so I quickly looked up a mechanism (I haven't taken organic chemistry, nor am I very good at comprehending it). Basically an ester is a better leaving group that just that water coming out from the condensation. Reaction of the ester with aqueous ammonia (NH4OH, but it's mostly dissolved NH3) would allow the nucleophilic ammonia to donate an electron to the carbonyl carbon, which goes to the carbonyl oxygen (protonated) forming a tetrahedral intermediate without that double bond (so, I believe that makes the carbon sp3 hybridized?). In a snap, this intermediate is changed when the oxygen donates an electron to the leaving group, which leaves as an alcohol (ROH). What's left is an amide.

Now my friend actually did an experiment with EtOAc and 5% NH4OH, but he had a difficult time extracting the amide from the mix, because everything was miscible in everything. Does anyone have suggestions for that? It seems that neither IPA nor methanol helped that out.

GreenD - 6-2-2012 at 14:29

NH4OH is NOT mostly NH3, it is nearly all NH4OH, which is not a very good nucleophile for a carbonyl group.

I've never done an amide synthesis with an ammonium salt, I have always used N,N-dialkyl amines, they are better nucleophiles.

If you could give us your actual work up and reaction conditions perhaps we could help more. You understand the chemistry (it is very simple organic), but perhaps your procedure is incorrect. You may also need a much more concentrated sample of your ammonium salt. Vinegar probably isn't going to be such a great thing to try this with.

entropy51 - 6-2-2012 at 15:26

Quote: Originally posted by Rich_Insane

A friend suggested a better idea, so I quickly looked up a mechanism (I haven't taken organic chemistry, nor am I very good at comprehending it).

That's odd, because in other posts you have said you were taking college organic chemistry.

So which is it?

Lambda-Eyde - 6-2-2012 at 15:58

Quote: Originally posted by Rich_Insane

Now my friend actually did an experiment with EtOAc and 5% NH4OH, but he had a difficult time extracting the amide from the mix, because everything was miscible in everything. Does anyone have suggestions for that? It seems that neither IPA nor methanol helped that out.

You could either recommend this site to your friend, or you could stop SWIMing. This isn't a pool, you know. Anyways, my advice to your friend/you would be to check the literature for some actual procedures - reactions look really nice in your organic textbook, but they're something different in real life. One of the first hits upon googling "ammonia esters" uses a 50% w/w solution of ammonia in ethanol. I don't understand why people bother to screw around with the 5% solution, it's mostly good for cleaning if you ask me...

Quote: Originally posted by GreenD

NH4OH is NOT mostly NH3, it is nearly all NH4OH, which is not a very good nucleophile for a carbonyl group.

You couldn't have been more wrong.

Rich_Insane - 12-2-2012 at 21:27

Quote:

That's odd, because in other posts you have said you were taking college organic chemistry. So which is it?

You have great memory! Many years ago (actually just three our two), when I was in 8th grade, I had taken an interest in O Chem, so I audited (pretty much just sat there every morning and took a few exams/quizzes) the first two semesters of the summer session -- but I did not retain a whole lot and have forgotten some since then. At the time I thought that level of knowledge was sufficient, but I realize that I probably need a better understanding to fully comprehend these mechanisms and such!

Quote:

I did actually, but he didn't post anything and this is actually interesting to myself. It seems like a such a wonderful reaction in the textbook, but I've never really come across any methods that actually use it. I was pretty skeptic about the ester reaction, but again, I sort of doubt my intuition here so I decided to ask more informed people. I tried looking up some information on this reaction (without the use of strong nucleophiles that are not readily available). Most sources I've found come from textbooks -- such as the Carey textbook.

I also found that article that Lambda was referring to ("J. Am. Chem. Soc., 1938, 60 (1), pp 50–51"). I don't have access to the article, but I can read the first page. It seems that they ended up bubbling NH3 gas through an aqueous solution of ethanol. They did account for the hydrolysis of the ester in the solution. They claim that primary alcohols (the portion of the ester) had less hydrolysis occurring than the secondary and tertiary alcohol esters.

Utilizing this paper (thanks Lambda for giving me that search keyword -- as you can see, my Google skills are rather... terrible, I apologize). I suppose one could use an ammonium salt to generate NH3 gas versus concentrated NH4OH. This would be easier because for my friend and I, obtaining concentrated ammonia is difficult (we're minors and neither of us feel like going to a supply house and asking them for their finest concentrated NH4OH would be prudent, nor would paying hefty shipping costs for NH4OH bought online). Ammonia gas could be bubbled through a solution of ethanol-water (or methanol-water, I suppose). The paper reported creating a so-called "ammonical" solution. They used 50% EtOH in water, but only because they stated that higher MW esters separated out in more dilute solutions. I suppose that 50% is not too much to ask for anyways. I would think that 1000% excess of generated ammonia gas (relative to mols of the ester) should be sufficient.

UnintentionalChaos - 12-2-2012 at 23:38

A thorough search of this forum through google will yield a number of discussions on this subject and numerous writeups on the preparation of acetamide by aminolysis of ethyl acetate on other sites, and references in books for this conversion. You will also find reference to frogfot's website (now defunct but accessible through the wayback machine)

http://web.archive.org/web/20080424022233/http://www.frogfot...

Engager - 20-2-2012 at 07:20

Generic routes to amides.

1) Dry distillation of ammonium salt of corresponding acid (known to work fine with lower acids, bit tricky if otherwise): NH4COOCH3 => CH3-CO-NH2 + H2O.
Note: Product should be distilled over, reaction is reversible.

2) Through the acid halogen-anhydride (usually gives great yields) : RCOOH + SOCl2 => RCOCl + HCl + SO2; RCOCl + 2NH3 => RCONH2 + NH4Cl
Note: For reactive acids first step in many cases could be done without solvent with excess of SOCl2, excess removed by destillation, otherwise solvent is DMF, SOCl2/DMF mixture known to react even with CCl3COOH. Second step is simple pouring RCOCl to NH3 solution, reaction is usually vigorous, but gives excellent yields (~90%).

3) Through the carbon acid esters: RCOOH + C2H5OH = (H+, cat) => RCOOC2H5 + H2O; RCOOC2H5 + NH3 => RCONH2 + C2H5OH.
Note: Works fine with ethylacetate and aq. NH3 solution. First step is simple esterification and can be made in variety of ways. Ammonolisis is best performed in environment there amide precipitates, this gives best yields.

[Edited on 20-2-2012 by Engager]