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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