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Author: Subject: Preparation of pyrrolidine via decarboxylation of l-proline
Scr0t
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[*] posted on 24-12-2015 at 15:17
Preparation of pyrrolidine via decarboxylation of l-proline


Several different methods of decarboxylation were applied to the amino-acid l-proline in attempts to obtain the cyclic secondary amine pyrrolidine. Pyrrolidine can substitute piperidine in many applications.


Copper catalysed decarboxylation

50.0g l-proline mixed with 5.0g basic copper carbonate Cu2(OH)2CO3 [1] and heated directly over an electric hotplate (~1.5kW).
When plate temperature was ~320°C a small amount of product came across (going by smell but had obvious water contamination) but was very slow. It was not until plate temperature was ~420°C when collection rate picked-up (~1 drop every 1-2s), the collected product was a pale yellow colour and smelled 'charred', collection was continued at 420-450°C for about 3hrs when it slowed considerably yet the contents in the distilling flask was still significant [2].

The collected material was dried over a few grams of solid NaOH and then distilled, the material collected between 85-89°C weighed 3.1g Yield of pyrrolidine 10%.
A clear higher boiling point residue was left behind (bp >90°C, ~15ml) in the distilling and was not examined further.


Overall the reaction was very low yielding, required a higher temperature and was sluggish compared to the decarboxylation of niacin to pyridine with the same catalyst loading.

Copper carbonate is not an effective catalyst for decarboxylation of this substrate and the results are probably no better than simply heating the proline on its own.

[1] If the mixture is allowed to stand at room temperature for ~24hrs it darkens to a deep blue colour.
[2] Proline reportedly decomposes at its melting point ~200°C, decarboxylation is evidently only a minor component of this.

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Acetophenone catalysed decarboxylation

20.00g l-proline in 80ml acetophenone was set for reflux and heated in an oil bath to 150°C
At ~130°C evolution of CO2 commenced, generation of some water and a mild smell of pyrrolidine from the top of the condenser was noticed.
Over the course of the reaction the solids dissolved and the reaction progressed to a deep orange colour, CO2 evolution rapidly abated at around 40mins and at 50mins it was removed from the heat.

30ml 36% HCl made up to 100ml was added to the cooled mixture and stirred for 30mins (white mist formed on addition due to the presence of freebase vapour), the lower aqueous phase was separated and the acetophenone layer washed with 50ml H2O containing a few grams of NaCl to aid with phase separation, the combined aqueous portions were washed with 2x20ml DCM.
The aqueous phase was cautiously treated with 20g NaOH in 30ml H2O whereupon a separate upper phase formed however this was not primarily pyrrolidine.

The mixture was distilled with stirring to collect the product and some water (<=92°C), the upper phase that formed earlier remained in the distillation flask as a few millilitres of a brown viscous oil/goo when cool.
The distillate was treated with a couple of grams of solid NaOH and the upper phase separated and distilled (bp 87°C) to yield 10.85g pyrrolidine (85%).

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Carvone catalysed decarboxylation

Into a 1L RBF 50.0g l-proline, 500ml turpentine and 2.0g spearmint oil was added and with stirring it was refluxed in an oil bath (~180°C). The mixture was heated to a rapid reflux (145-160°C).
At 20hrs there was still a few small lumps of what appeared to be unreacted proline in suspension [1] but the reaction was removed from the heat and allowed to cool. The mixture was treated with 60ml 36% HCl made up to 200ml with H2O and stirred for ~15min.
The mixture was separated (small amount of brown gummy material at the interface), washed with DCM, treated with 40g NaOH in 100ml H2O and then the whole distilled to collect the product and water. The distillate was treated with a few grams of solid NaOH [2], separated and distilled to yield 25.2g (82%) pyrrolidine.

The spearmint oil used was the same as that used for successful decarboxylation of tryptophan, the slow reaction is possibly due to a low solubility of proline in this solvent. Inclusion of some DMSO may improve reaction time.

[1] These lumps turned out to be quite gooey, possibly some proline surrounded by a side-product precipitate.
[2] The two-phase mixture of aqueous NaOH and distillate turned to a pink colour on standing in air.
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[*] posted on 24-12-2015 at 15:35


Excellent work! I would strongly consider moving the latter two preps to Prepub (maybe with a few pics?)! Pyrrolidine is now a readily accessible secondary amine for the amateur chemist. I have looked into making morpholine (via diethanolamine) or piperidine (via sodium reduction of pyridine, see orgsyn) for a Mannich reaction but this is so much easier sounding.

Pyrrolidine readily forms enamines from enolizable ketones and aldehydes which has significant synthetic utility and may have been the source of separation troubles in the acetophenone prep.

Copper seems to require pyridine-like ligands to function as a decarboxylation catalyst (and I have mostly seem it applied to aromatic carboxylic acid groups), so I am not sure if it could ever be made to work here.

[Edited on 24-12-2015 by UC235]
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[*] posted on 24-12-2015 at 18:06


Piperidine via piperidinecarboxaldhyde , aka formylpiperidine. Non-regulated.
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[*] posted on 24-12-2015 at 20:21


Nice piece of work. I have been meaning to try the proline-acetophenone reaction for a while. Now to the lab!

I have made piperidine from the hydrolysis of N- formylpiperidine. It's easy and fast.

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[*] posted on 25-12-2015 at 06:55


Scr0t, I like your report and I hope you don't mind me moving it to Prepublication.
I particularly liked your comparison of the three different methods.




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[*] posted on 25-12-2015 at 08:20


I have read articles of glucose catalyzing the formation of cyclic amines from amino acids . I never tried it. I did try thermal decarboxylation of lysine to form cadaverine, and then to piperidine witch is the same procedure for pyrrolidine from proline and piperazine from ethylene diamine. I was unsuccessful in my attemps and just moved on and bought the compounds. It was interesting and fun but not really practical because of time.
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[*] posted on 25-12-2015 at 19:32


The importance of Schiff base (imine) formation in these decarboxylation reactions cannot be overstated. Some time ago I ran across a post by Nicodem alluding to this fact but I do no recall any references cited for this. Here are two which address the importance of imine formation (and imine hydolysis). The first also has data on the transamination side reaction.

1. AF Al-Sayyeb and A Lawson, J. Chem. Soc. (C), 1968, 406
2. Patent application: US2014/0275569 A1 (Sept. 18, 2014)

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[*] posted on 1-1-2016 at 14:58
Other Amino Acids?


Decarboxylating tryptophan can be use to make tryptamine
Proline can be used to make pyrrolidine

That got me wondering if there are any other similar useful preparations from amino acids.

It looks like histidine would give histamine (?), and phenylalanine would give phenylethylamine, both easily available and not too interesting.

How about the non-cyclic amino acids? Do these decarboxylations work?

If they did alanine would give methylamine (lack of references to this when I Google makes me pretty sure this does not work), valine would give isobutylAMINE (corrected - I mistyped, thanks), and so forth.

[Edited on 5-1-2016 by careysub]
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[*] posted on 4-1-2016 at 18:22


Quote: Originally posted by careysub  
Decarboxylating tryptophan can be use to make tryptamine
Proline can be used to make pyrrolidine

That got me wondering if there are any other similar useful preparations from amino acids.

It looks like histidine would give histamine (?), and phenylalanine would give phenylethylamine, both easily available and not too interesting.

How about the non-cyclic amino acids? Do these decarboxylations work?

Cyclic amines are not a requirement. If it can form an imine/enamine with the ketone catalyst then it should work.
Note, it's not the indolyic nitrogen that plays a part in the decarboxylation of tryptophan.

You wont get isobutylene as that is missing a nitrogen atom.

[Edited on 5-1-2016 by Scr0t]
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[*] posted on 6-1-2016 at 12:15


Would be nice to comparatively test also 2-cyclohexen-1-one since it is known catalyst of amino acid decarboxylation and its structural parenthood is present in acetophenone and in carvone (see C=C-C=O sequence).



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[*] posted on 24-8-2016 at 23:20


I just want to make sure I have the mechanism correct.

A lot of papers that I've been reading (a couple threads here too for that matter) state that attempting thermodecarboxylation without ketone results in poor yields or polymerization. It sounds like heat is definitely the driving factor behind the actual decarboxylation itself, with the ketone "protecting" the amino function by forming an enamine. The water formed hydrolizes the enamine and regenerates the original ketone catalyst and the newly created amine. Am I on the right track?

If so, what are the chances are that L-proline could be used as a direct substitute for pyrrolidine, specfically for enamine formation with ketones/aldehydes? I was hesitant to try, as I've read there is a tendency to favor the formation of unwanted oxazolidinones, but Scr0ts yields seem to indicate this wasn't a problem. Then again the enamine is being hydrolyzed back to the amine and not stabilized so perhaps they cannot form?

Also Scr0t, your workup mentions "the whole [aqueous layer] distilled to collect the product and water." As an acid/base reaction, could a fractional, vaccuum distillation be utilized after the first basification to yield the pyrrolidine freebase? It wouldn't seem that pyrrolidine and water would form an azeotrope, but then I was also reading that water is hard to separate from pyrrolidine..

-J

[Edited on 25-8-2016 by paraguay]

Attachment: Schiff Bases. Part 1. Thermal Decarboxylation of a-Amino-acids in the Presence of Ketones.pdf (642kB)
This file has been downloaded 142 times

Attachment: Analytical characterisation - thermolytic decarboxylation from tryptophan to tryptamine.pdf (596kB)
This file has been downloaded 130 times

Attachment: The Proline-Enamine Formation Pathway Revisited in DMSO.pdf (1007kB)
This file has been downloaded 120 times

Attachment: The Increased Reactivity of the Proline Carboxylate Derived Enamine.pdf (109kB)
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[Edited on 25-8-2016 by paraguay]
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