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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Babcock_Hall on August 29, 2017, 11:32:09 AM
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We plan to synthesize Pyrdinium-CH2C(O)CO2X (where X could be a proton or a pyridinium ion) by the method of Arthur Green and Raymond Delaby ("Pyridinium and thiazolium salts with multifunctional propyl side chain" Bull Soc Chim France 1955, pp. 697-699). My student translated this article. It seems straightforward (solvent is diethyl ether), except for one problem. The mass of bromopyruvic acid (MW 166.96) is 16.7 g, and the mass of pyridine (MW 79.1) is 1.7 g). This works out to 100 mmols of bromopyruvic cid, and 21.5 mols of pyridine. In other words, the bromopyruvic acid is almost 5-fold in excess, which strikes me as odd.
One possibility is that the mass of pyridine is a typo, and there should be 17 grams of pyridine, which would provide just over a twofold excess of pyridine. A second equivalent of pyridine might be expected to deprotonate the carboxylic acid, which might facilitate the reaction. Any suggestions on the best way to proceed?
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a). Probably, it is a typing error because for the preparation of Girards T and P reagents, equimolar amounts of tertiary amine and haloacetate ester are used.
1). Helvetica Chimica Acta, 19(1), 1095-1107, (1936)
http://onlinelibrary.wiley.com/doi/10.1002/hlca.193601901148/full
2). Organic Syntheses, Coll. Vol. 2, 85, (1943)
http://orgsyn.org/demo.aspx?prep=cv2p0085
b). Pay attention to translation from French to English (if not already done) because French use a different numeration system for decimals.
Seven thousand = 7.000 in French
One and a half = 1,5 in French.
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For both numbers the authors use commas. The masses are given for bromopyruvic acid and pyridine are 16,7 g and 1,7 g, respectively.
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Actualy I´ve never seen anyone in europe writing 7 thousand as "7.000 its always 7000).
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I think that they must have meant 17 grams, not 1.7 grams. This would allow for a second equivalent to neutralize the carboxylic acid.
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Officially, they do so in France, Belgium and in other French speaking countries, as well as in Greece.
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What they isolated had a single nitrogen by elemental analysis. Therefore, if they used two equivalents of pyridine (corresponding to 17 grams), one equivalent was discarded in the synthesis.
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Then obviously, it was a typing error. But the obtained results indicate that the reaction occurs via preliminary formation of the carboxylate salt, followed by formation of the tertiary amine salt and not through direct betaine formation that would need only one equivalent of pyridine.
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Should not the product be a quaternary amine?
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Yes, right!
....the obtained results indicate that the reaction occurs via preliminary formation of the carboxylate salt, followed by formation of the "quaternary" amine salt and not through direct betaine formation that would need only one equivalent of pyridine.
Thanks Rolnor and very sorry for that serious mistake.
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This is my attempt to type out the original (which I believe was a scanned image in the form of a pdf file. I left out the accents and such. I may have made some typos:
Bromure de N-(-carboxy –cetoethyl)pyridinium (II.7).
L’acide bromopyruvique (16,7 g) est dissous dans 100 cm3 d’ether absolu. La solution etheree est traitee par du noir Norit et le filtrate est fortement refroidi. Par ailleurs, 1,7 g de pyridine seche est dissous dans 100 cm3 d’ether anhydreet cette solution est egalement refroidie dans la glace. Lorsque la temperature des solutions etherees est de 0 °, la solution contenant la pyridine est verse dans l’autre: aussitot un precipite huileux se depose. Peu apres, il se recrystallize dans l’acide acetique et seche ensuite sous vide sur P2O5; il est recristiallise dan l’alcool butylique. Le produit est conserve au sec. Obtenu: 15 g.
Analyses pour C8H8O3NBr:
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The pKa of pyruvic acid itself is 2.50, and the pKa is 5.17 for the conjugate acid of pyridine (both values from Williams). This is our translation of the passage in my previous message:
N-(β-carboxy-β-oxoethyl)pyridinium bromide (II.7)
Bromopyruvic acid (16.7 g) was dissolved in 100 mL absolute ether. The ether solution was treated with Norit® activated carbon and the filtrate was significantly cooled. In addition, 1.7 g dry pyridine was dissolved in 100 mL anhydrous ether and this solution was also cooled in ice. Once the temperature of the ether solutions is 0°, the solution containing the pyridine was poured into the other: immediately, an oily precipitate settled. Shortly after, it forms a white crystalline mass. The compound was rotary evaporated; recrystallized from acetic acid and then dried under vacuum with P2O5; it is recrystallized from butyl alcohol. The product is kept dry. Obtained: 15 g.
Analysis for C8H8O3NBr
Calculated: C % 39.02 H % 3.25 N % 5.69 Br % 32.52
Found: 41.2 3.59 5.98 35.6
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It an obvious typing error, as being concluded from your experimental results, as well from the preparation protocols of Girard’s reagents and various betains.
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I agree that 1.7 grams is a typing error. It is less clear to me what the correct value should be, with 17.0 and 8.5 grams being the best contenders. The reactant in the reference from Organic Syntheses is an ester, as opposed to a free acid. If only one equivalent of pyridine is added, the reaction may be sluggish, because some of the pyridine will exist as a pyridinium salt with the carboxylate group.
That is why I think that the authors intended 17.0 grams (two equivalents). My best guess is that after the reaction is over (during rotary evaporation or high vacuum), the second pyridinium ion donates its proton back to the carboxylate group, and the now-neutral pyridine leaves under reduced pressure. This would return the carboxylate group back into its neutral acid form. Something like this must happen when excess triethylammonium bicarbonate is removed from a product. TEAB is sometimes used in the gradient ion-exchange purification of nucleotides. In its removal, the triethylammonium ion must give its proton back to bicarbonate, so that both will be volatile.
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The example in the "Organic Syntheses" is indicative to the necessity of one equivalent of tertiary amine per one halogen substituent. In your case, another equivalent of tertiary amine is also required for neutralization of the carboxylic group, in order to avoid the inhibition the formation of the quaternary salt.
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After the end of the reaction the compound is recrystallized in acetic acid. Thus, the second equivalent of pyridine is removed as acetate salt. Concerning the selective salt formation, it’s not only a question of pka but is also a question of concentrations; acetic acid is in high excess, during recrystallization.
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I had not thought about the acidity during the recrystallization; thank you.
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My students tried a recrystallization from acetic acid, but no crystals came out. I told them to remove some solvent, and still nothing happened. Recalling that we intended to remove one equivalent of pyridine at some point (so that we make the carboxylic acid form of our product--see upthread), I suggested pulling a vacuum and hoping that both acetic acid and pyridine would leave. It might be possible to use NMR integrations to decide whether or not the second pyridine is present. Such an event would mean that our product would still in the crude form, as a bromide salt. The original procedure called for a second recrystallization, this one using 1-butanol; therefore, this step might remove the brown color that we see.
Should we keep plugging away at the acetic acid step or should we try a high vacuum in the hopes of removing the excess pyridine that way?
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1). According to the publication, the temperature must be ≈ 0oC (or possibly, slightly higher) during recrystallization in the acetic acid, followed by recrystallization in butanol. Did the students work so?
2). Pyridine cannot easily be removed from a pyridinium salt by vacuum distillation, even if being a salt of a weak acid that is supposed to be in equilibrium with the non-ionic form.
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I believe that they did the synthetic steps (the ones involving diethyl ether) using ice, and they did get the solid initially. The recrystallization did not specify an amount of solvent or a temperature, unless I am mistaken. I was worried that if they cooled acetic acid below room temperature, that they would get crystals of acetic acid. However with the crude product present, perhaps it is possible to go lower in temperature with respect to the recrystallization.
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Indeed, the article does not specify the amount of acetic acid, needed and whether glacial acetic acid or not. On the other hand, acetic acid crystals might possibly cause a co-crystallization of the desired product.
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I know it's deviating off paper, but have you considered copper sulfate extraction to remove pyridine? Or maybe add a little water to help that recrystallization.
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I used copper sulfate to remove lutidine or collidine a long time ago, but I had not thought about employing it here. It might not work, in that the product may be too water-soluble. As far as having water in the recrystallization, can you explain your rationale? This is a very old paper, and I have found one error so far (the amount of pyridine); therefore, I am not opposed to deviating from the protocol. I am not entirely sure how I would.
One trick that has worked for me in the past is ion-exchange chromatography using a gradient of triethylammonium bicarbonate. I am thinking it might be time to dust off that trick again.
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If your stuff doesn't crystallize out of acetic acid easily, just add more of a bad solvent to it. Water might not be the right choice, it could be cyclo hexane or something organicky. I'm advocating trying like 10-50% of something that is an even worse solvent for the product than acetic acid is.
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As pgk pointed out to us, the acetic acid might be instrumental in removing the second equivalent of pyridine, the one that is ion-paired to the carboxylate group. However, at this point I would be happy for a relatively pure product in any form.
I recently rediscovered a description of the ethyl ester of our desired compound, which is compound (19) in this paper: Lubbers et al. "Design, synthesis, and structure–activity relationship studies of new phenolic DNA gyrase inhibitors" Bioorg Med Chem Letters (2007) 17:4708-14. I have not looked up one of the papers in reference 10 in this paper yet, which might be the actual description of how it was made. One advantage is that the ethyl ester of bromopyruvate is not as expensive a starting material as the free acid. One disadvantage (besides having to start over) is that we would need to work out a hydrolysis of the product that does not harm the pyridinium ketone functional group.
EDT
I looked up one paper in reference 10 within Lubbers' paper, the one from Tetrahedron (2004) 60:2937, by Wang et al. They make the ethyl ester of pyridinium pyruvate, but they move on, apparently without isolating it.
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You could try alkaline hydrolysis of the betaine ester with NaOH in DCM/MeOH (1) or K2CO3 in DCM (2) that are very fast operations and work at room temperature. Aldol/Claisen condensation and/or rupture of the quaternary salt do not seem possible during that short time and under these mild alkaline conditions.
1). A simple method for the alkaline hydrolysis of esters, Tetrahedron Letters, (2007), 48(46), 8230-8233
Indian Journal of Chemistry-Section B, (2006), 45B(09), 1729-1733
http://www.sciencedirect.com/science/article/pii/S0040403907018539
2). Isomerization of the Baylis-Hillman adducts using amberlyst-15 as a heterogeneous reusable catalyst: a simple and efficient stereoselective synthesis of (E)-cinnamyl alcohol derivatives, Indian Journal of Chemistry-Section B, (2006), 45B(09), 1729-1733
http://nopr.niscair.res.in/bitstream/123456789/6587/1/IJCB%2045B%287%29%201729-1733.pdf
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We are confused by the H-1 NMR of our putative product, which is pyridinium pyruvate. The aromatic region looks reasonable, but the only candidate for the N-CH2-C(O)R protons is at 5.0 ppm. In our case R is a carboxylic acid; in the case of the pyridinium ketones I have found so far, R is an aromatic ring of some kind. When R is aromatic, the chemical shift of this methylene group is often near 6.6 with some variation. 5.0 is slightly downfield of what I would expect if the -CH2- group were next to a simple alkyl chain, not a ketone. Thoughts?
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Methylene 1H-NMR shift at δ = 5 ppm, seems reasonable because there is an additive effect from α-pyrdinium, α-carbonyl and β-carboxyl groups (Curphy-Morrison Shift Additivity Rules).
Nevertheless, the final determination of the structure can be concluded only by correlation of 1H-NMR, 13C-NMR and IR spectra.
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For the compound PyrNCH2C(O)Ph, the chemical shift is 6.60. For the compound 4CNPyrNCH2C(O)Ph, the chemical shift is 6.67 ppm (Szafran and coworkers, J Molecular Structure 2004 708:87-95). For the compound 4-CNPyrN-CH2C(O)-Me, the chemical shift is 6.13 ppm (Szafran and coworkers, J Molecular Structure 2002 643:55-68).
I checked on page 222 of the 4th edition of Silverstein. For groups that are β with respect to a CH2 group, the downfield shift change of a phenyl ring is 0.35 ppm, relative to a β-methylene group. The downfield shift change of a β-carboxlate ester is 0.5 ppm, relative to a β-CH2. In other words both the phenyl group and the carboxylate ester group should shift downfield in the general vicinity of 0.3-0.5 ppm. IMO 5.0 ppm is too upfield for the proposed structure. We will attempt to acquire more data, however.
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1). How many protons correspond to the integration of the peak at 5 ppm?
2). Is your product a pyridiniumpyruvic acid derivative or is pyridiniumpyruvic acid, which is a zwitterionic betaine (pyridiniumpyruvate)?
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Taking one of the aromatic protons as 1.0, the peak at 5.00 ppm has an integral of 0.8. The material did not bind to the C-25 sephadex column that we tried, and for that reason I am not sure about its form. Given that the pH was about 8, I am presuming that it is a zwitterion.
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Then, what you see in the 1H-NMR spectrum, is obviously the enol form of pyridiniumpyruvate zwitterion. Thus, it’s not a bad idea to repeat the 1H-NMR spectrum up to 15 ppm and see if any other peak appears beyond 10 ppm and if it disappears by exchanging with a deuterated solvent; as well as observing carefully the base line between 5 ppm and the aromatic zone and look for a possibly very small peak (whose integration could permit a rough estimation of the keto/enol equilibrium, though integral of 0.8/1 proton usually means one proton).
Please note that the enol form of pyridiniumpyruvate zwitterion, is obviously more thermodynamically stable as having a more extended conjugation than the keto form.
Furthermore, please also note that neighboring with a carboxylate anion, leads to upfield shift change.
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We synthesized this molecule in the hope that it would enolize easily, but I did not consider the possibility that the enol form might predominate. We will continue collecting data.
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Why not trap the enol with TMS and see what happens to that peak?.
P.S. I've always wondered if TBDMS would work just as well too for that reaction, just in terms of ease of handling. x10000 more hydrolytically stable. I've never had to do that silyl enol ether chemistry and check it.
Edit: Yes, and using pretty ordinary conditions (imidazole) http://reag.paperplane.io/00000479.htm