Barney
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Preparation of pyroglutamic acid
Introduction
After watching a ChemPlayer video showing the preparation of succinic acid from monosodium glutamate (MSG),1 as well as discussion of the
same procedure on a thread here,2 I was inspired to research MSG as a starting material for synthesising succinimide, which in turn can be
used to synthesise the useful N-Bromosuccinimide. One seemingly simple and high yielding approach was the silver-catalysed oxidative decarboxylation
of pyroglutamic acid, which can in turn be made by simply heating glutamic acid.3 I ended up finding the workup of the second step of this
procedure troublesome, and ultimately shelved the project. However I still figured documenting the method I ended up using for preparing pyroglutamic
acid might be of some use to somebody.
The paper I was following prepared pyroglutamic acid by heating glutamic acid at 145-150°C for 45mins,3 however this method seemed tedious
and messy. The cyclisation of glutamic acid to form pyroglutamic acid goes by the mechanism in Figure 1.4 A different paper instead
described heating glutamic acid at 220°C while swirling constantly for a much shorter period of time, giving high purity and good yields with a much
more straightforward workup.5 I ended up finding that instead of specifically aiming for 220°C I could just set my hotplate to max and get
satisfactory results.
Figure 1: Mechanism for the formation of pyroglutamic acid
Reagents
Monosodium glutamate (MSG, assumed to be the monohydrate)
Concentrated hydrochloric acid
Procedure
Glutamic acid
To 187.1g of MSG (1mol) dissolved in 500mL of water (Note 1), 100mL of conc. HCl (1mol) was added in portions with strong stirring, waiting
for precipitate to appear between each addition (Note 2). By the end of this addition a large quantity of precipitate had crashed out. The
mixture was placed in an ice bath for 15min and the solid then collected by vacuum filtration, washed with a generous quantity of water (Note
3), and left to dry at the pump for 30min. This yielded 158g (107%) of wet glutamic acid as a fluffy white powder.
Pyroglutamic acid
A hotplate was set to maximum heat and left for 30min. All of the glutamic acid from the previous step was placed on the hotplate in a beaker and
stirred regularly by hand. Over the next 10-15 minutes everything slowly melted, giving a viscous white liquid which soon started to bubble. By this
point stirring was nearly constant. Over the next ~5min the liquid became less opaque and viscous, eventually giving a nearly clear liquid with much
less vigorous bubbling. The melt soon started to turn yellow and the beaker was immediately removed from heat (Note 4). It was then allowed
to cool at room temperature for 2min followed by a water bath for 2min and an ice bath for 2min. Everything was then left to crystallise at room
temperature for 1hr. The resulting solid mass was recrystallised from a minimal quantity of boiling water. The formed crystals were strongly adhered
to the beaker, so the water was decanted off and the crystals heated with a little acetone until they came loose. The product was vacuum filtered and
washed with a little acetone (Note 5), yielding 49.11g (38%) of pyroglutamic acid as nice white crystals. mp ~165°C (lit:
162-163°C)6
Notes
This solution is more dilute than that used by ChemPlayer. This was done to try and avoid crashing out the HCl salt of glutamic
acid and giving a big mess, as had been reported by some others. This improvement was suggested by Sciencemadness user steadyhand on the final page of
the referenced thread,2 and this step never gave me any problems.
After each addition there was a delay of up to around 20s before any precipitate formed
Cold water probably should have been used for washing the product but I didn't have any prepared and got lazy.
The paper I was following continued heating until bubbling had completely ceased,5 however I found I ended up with a lot of tar if I
let it run this long. This could be due to me not controlling the temperature in any way.
The addition of acetone to the crystals produced a small amount of a very fine dispersion of product which went through the glass frit when
filtering. Maybe the small amount of product dissolved in any residual water is precipitated by the addition of acetone?
Discussion
This procedure is straightforward and works well enough, but it could definitely be optimised to obtain a better yield. I think better temperature
control would probably let the reaction go further to completion without tarring up.
As for uses for this reagent, I'm not aware of anything noteworthy other than the synthesis of succinimide. I think that the synthesis of succinimide
from pyroglutamic acid is worth investigating further - my main trouble with the reaction was removing the water without raising the temperature too
much, as I found that if the temperature got too high everything tarred and foamed up. A good vacuum pump would of course make this trivial.
Ultimately I realised I could order succinimide from somewhere overseas and save myself the trouble.
References
(1) ChemPlayer. Prepare Succinic Acid from Monosodium Glutamate. Internet Archive, May 5, 2018. https://archive.org/details/ChemPlayer/Prepare+succinic+acid... (accessed 2024-07-12).
(2) Preparation of Succinic Acid. https://www.sciencemadness.org/whisper/viewthread.php?tid=69... (accessed 2024-07-12)
(3) Liu, Z.; Valente, J.; Lin, S.; Chennamsetty, N.; Qiu, D.; Bolgar, M. Cyclization of N-Terminal Glutamic Acid to Pyro-Glutamic Acid Impacts
Monoclonal Antibody Charge Heterogeneity Despite Its Appearance as a Neutral Transformation. J Pharm Sci 2019, 108 (10),
3194–3200. https://sci-hub.se/10.1016/j.xphs.2019.05.023.
(4) Liu, Y.; Goetze, A.; Bass, R.; Flynn, G. N-Terminal Glutamate to Pyroglutamate Conversion in Vivo for Human IgG2 Antibodies. _The Journal of
biological chemistry_ 2011, 286, 11211–11217. https://doi.org/10.1074/jbc.M110.185041.
(5) Barretto, F. A.; Cunha, S. Practical Synthesis of (S)-Pyroglutamic Acid. _Journal of Heterocyclic Chemistry_ 2024, 61 (6),
955–957. https://doi.org/10.1002/jhet.4813.
(6) L-Pyroglutamic Acid. The Merck Index Online. Royal Society of Chemistry. n.d. https://merckindex.rsc.org/monographs/m9383 (accessed 2024-07-12). (Monograph ID: M9383)
[Edited on 12-7-2024 by Barney]
[Edited on 12-7-2024 by Barney]
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RustyShackleford
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Well written post! I'm surprised you chose to recrystallize it from boiling water seeing as it could hydrolyze. I wonder if you could combine the
dehydration and decarboxylation into a one pot reaction.
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clearly_not_atara
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Looks awesome!
I've read some papers that say silver pyroglutamate is soluble in hot water, so I've been wondering if you could use this + H2O2 for silver
dissolution. It seems like you're on this track anyway.
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DraconicAcid
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Quote: Originally posted by RustyShackleford  | | Well written post! I'm surprised you chose to recrystallize it from boiling water seeing as it could hydrolyze. I wonder if you could combine the
dehydration and decarboxylation into a one pot reaction. |
Amides are very slow to hydrolyze.
Please remember: "Filtrate" is not a verb.
Write up your lab reports the way your instructor wants them, not the way your ex-instructor wants them.
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Barney
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Just realised I fucked up the references but can no longer edit this post. The third reference should instead be:
(3) Deng, J.; Zhang, Q.-G.; Pan, T.; Xu, Q.; Guo, Q.-X.; Fu, Y. Synthesis of Biobased Succinimide from Glutamic Acid via Silver-Catalyzed
Decarboxylation. RSC Adv. 2014, 4 (52), 27541–27544. https://sci-hub.se/https://doi.org/10.1039/C4RA04567J.
The link on the fourth reference is also wrong. The following should work:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064176/
| Quote: Originally posted by RustyShackleford | | Well written post! I'm surprised you chose to recrystallize it from boiling water seeing as it could hydrolyze. I wonder if you could combine the
dehydration and decarboxylation into a one pot reaction. |
The reason I ended up using water was that the solubility of pyroglutamic acid in it seemed to be much better than the other solvents I tried
(acetone, isopropanol). And as already pointed out the hydrolysis of pyroglutamic acid is slow enough that it shouldn't be significant. Doing both
steps in a one pot reaction is an interesting thought. Maybe it's possible.
| Quote: Originally posted by clearly_not_atara | Looks awesome!
I've read some papers that say silver pyroglutamate is soluble in hot water, so I've been wondering if you could use this + H2O2 for silver
dissolution. It seems like you're on this track anyway. |
That sounds interesting - do you have those papers on hand?
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