bottleneck (Hive Bee)
02-25-03 20:32
No 411507
      Notes on ergolines from tryptophan  Bookmark   

These are just some preliminary notes on tryptophan.

Speculations (
02-25-03 21:34
No 411533
      Good work! Why don't you post it here.  Bookmark   

Good work! Why don't you post it here. Especially the 2,3-bisulfite / 1-ester protection seems promising. The protonated indolium species is only available in equilibrium (= trace) amounts and can't serve as a 'protected' species.
(Chief Bee)
02-26-03 03:24
No 411716
      bisulfite protection  Bookmark   

More info dealing with bisulfite/acetyl amide protection (not ester, Lili) can be found in this writeup (../rhodium/chemistry /5-br-indole.html) from a trial based on an article from Chem. Ber. 95, 2205-2211 (1962) (../rhodium/djvu /indole-2-bisulfite.djvu)
02-26-03 10:34
No 411874
      nitrogen protection  Bookmark   

To protect the nitrogen after bisulfite addition you have to esterify it... smile
(Hive Bee)
02-26-03 11:13
No 411884
      acylation  Bookmark   

isn't that an acylation as opposed to an esterification?
02-26-03 13:08
No 411908
      :-o sure  Bookmark   

blush sure
(Hive Bee)
02-27-03 02:24
No 412107
      Thanks. I should have known to check ...  Bookmark   

Thanks. I should have known to check before thiking about heading for the library.

About not posting, I guess I found it a bit clumsy with the reaction-diagrams.

This protective scheme is a very enticing thing, if it could be made to work.

In Patent GB795184, adrenochrome forms a bisulfite adduct at the 2-position, losing its hydroxyl group in the 3-position (the patent says the sulfonate goes on the 3-position, but according to the Merck Index, this is incorrect). Adrenochrome is obviously not an indoline or an indole, but this elimination of the 3-radical doesn't sound terribly reassuring.

Still, once it is in there, treatment with dilute hydrochloric acid just yields the free sulfonic acid. If this stability to acids is shared by indoline-2-sulfonic acids, it seems less unlikely that some sort of Friedel-Crafts catalyst might be compatible. Stability to conc. phosphoric acid would be ideal, as the chlorination with noxious SOCl2 could presumably be skipped.

(Hive Bee)
02-28-03 20:34
No 412601
      L-tryptophan, 2.3 g NaHSO3, 4 g Water, 20 mL...  Bookmark   

L-tryptophan, 2.3 g
NaHSO3, 4 g
Water, 20 mL
Methanol, 5 mL

This is a suspension and it's appearance does not change even after six hors of stirring at room-temperature.

The reaction-mixture still gives a van Urk-reaction. If it were the indolinesulfonate, it should not give a positive reaction.

I shall try to form sodium indoline-2-sulfonate as described in the link for 5-bromoindole and see if this too gives a van Urk rxn. That smell really sticks with you.

Does anybody have any more references to the application or theory of this reaction? It would be great to know if it had worked with other 3-substituted indoles. Can't somebody with literature database-searching capability search for "sodium 3-methylindoline-2-sulfonate", "3-methylindoline-2-sulfonic acid" or something like that?
(Chief Bee)
03-01-03 03:03
No 412678
      I searched CASreact on STN for sulfonated...  Bookmark   

I searched CASreact on STN for sulfonated tryptamines or tryptophans and found nothing else of use except the article I'm advertising for in Novel discourse.
(Hive Bee)
03-01-03 13:41
No 412762
      Thanks for the help! What is that reference...  Bookmark   

Thanks for the help!

What is that reference you mention? I cannot find any mention of it in the "wanted references" thread.

Sodium indoline-2-sulfonate is indeed a light beige solid after stirring overnight. The solvent had been absorbed by the mixture, so a little additional water and some EtOH was required for stirring.

The tryptophan/NaHSO3 suspension has an unchanged appearance after 24 hours of stirring. I will test with DMAB later.

I have been reading a bit about adrenochrome, and most places it is listed as an indoline. I suppose there is no reason to expect a 3-substituted indole to lose the 3-radical then as a result of addition of sodium bisulfite, but it would be nice to know if such materials have been manufactured.

The simple cyclization I hoped for using polyphosphoric acid probably will not occur, at least under normal circumstances. I had forgotten that Kornfeld/Woodward had already tried that on N-benzoyl-protected 3-indolinepropionic acid and reported "very small conversion", cf. the article hosted by pHarmacist.

The aniline sub-structure strongly activates the paraposition, the 5-indolic one, and deactivates the metaposition. In the article, it can be seen that the position is deactivated to such an extent that when the reaction of the acid chloride is carried out in benzene as solvent, acylation happens exclusively on the benzene.

Strange to note, then, that the strongly activated 5-position of the indoline does not render this reaction completely impossible under normal circumstances.
(Chief Bee)
03-01-03 21:27
No 412842
      bisulfite  Bookmark   

The article in question was Org Prep Proced Int 17(6), 391 (1985) but it is on its way to me from moo, who has already retrieved it.
(Hive Bee)
03-01-03 21:50
No 412850
      Okay, thank you.  Bookmark   

Okay, thank you.
(Hive Bee)
03-02-03 17:24
No 413068
      Indole 2.7 g NaHSO3 5.4 g Water 15 mL MeOH 5...  Bookmark   

Indole 2.7 g
NaHSO3 5.4 g
Water 15 mL
MeOH 5 mL
+Some added water and EtOH after 12 hours for stirring.

After standing overnight, the sodium indoline-2-sulfonate reaction mixture was filtered and washed with ether. The ether wash was moderately strongly salmon-coloured, indicating some unreacted indole, but the product retains a significant odour of indole after much washing. Sulfur dioxide is also detectable by scent, indicating the decomposition of sodium bisulfite.

The product is an amorphous mass, nearly chalk-white with a pinkish-tinge. It retains significant wetness of feel, probably from some sort of absorption of water.

Van Urk-magenta seems visible after a while, but strong yellowing is immediately visible, maybe somewhat different from when testing pure sodium bisulfite.

The product is still in the process of drying, but I fully expect a mass of more than 100% of the indole used, given the chemical similarity of sodium alkyl sulfonates and sodium bisulfite. Does anyone have any ideas on how to separate remaining sodium bisulfite?

Still, a van Urk reaction is odd. In the Chem. Ber. article, don't they say that the sulfonate moiety survives conditions of 50% nitrating acid (H2SO4/HNO3), and is only cleaved when neutralising with NaOH?

Addendum to "Speculations on tryptophan...": A number of mistakes appear in my notes on tryptophan, a serious one being that I make the mistake of saying that indole can be nitrated directly in the 5-position, giving a reference to . Obviously this is not correct, as I have missed the presence of a full methyl group in the 2-position.

About polyphosphoric acid: I find it curious, this report of "very small conversion" in the Kornfeld/Woodward article. What does that mean, surely one must wonder? Does it mean that most of the precursor stayed intact, with only a small yield of the cyclized product, or did most of the precursor yield biproducts?

Given a case of the former, one might feel intrigued to experiment with PPA using other conditions. For example, water would appear to be a biproduct of acylation with carboxylic acids. In newer articles, I have seen mention of continuous removal of reaction-water using a Dean-Stark trap, but this does not appear to have been in much use in the time of the Kornfeld article.

Edit: Yield, after a bit of microwave-drying to speed things up: 7.2 g. Molecular weight is 221.21, so yield calculated on indole is 141%. Obviously a lot of bisulfite must be present, even allowing considerable moisture-content.


In DMAB/HCl, the particles of indoline-SO3Na immediately turn a strong yellow like ferric chloride hexahydrate. The color gradually turns red, then brown.

This does not seem the standard van Urk reaction, but indole is known to give either a "yellow or magenta coloring, depending on conditions" (Dibbern & Rochelmeyer, Arzneimittel-Forschung 13, 7-16 (1963). Pure tryptophan slowly turns magenta, and then some hours later, deep blue like ink.

In HCl, particles immediately turn red. Color seems to significantly lessen with time.

Experiments to try:

Basify sodium indoline-2-sulfonate. Does this give indole?

Acidify to redness, then basify. Does this give indole?
What is the yield?

Van Urk-test pure indole in the presence of sodium bisulfite. Does this also give the strong yellowing reaction?

Does the tryptophan+bisulfite reaction-mixture give the preliminary yellowing reaction?

Estimate solubilities of the reaction dyes in different solvents.

Borrow an NMR-scanner from the grocery-store.
(Hive Bee)
03-05-03 15:57
No 414049
      This article which Rhodium mentions is good.  Bookmark   

This article which Rhodium mentions is good.

Guess I am not the only one having troubles understand exactly what is going on. "Although this should be the beginning of a powerful new approach to the 5-substituted indoles, the low reported yields, lack of definitive characterization of the intermediates and the paucity of reported examples (the only subsequent reported use was a failure), led us to a detailed examination[...]"

Still, to answer a main question concerning tryptophan: "To our knowledge there have been no reports of the bisulfite reaction with indoles substituted at the 1, 2 and/or 3 positions and these poentially significant reactions are currently under investigation in our laboratory."

Guess one might do worse than to try to find later articles by the authors. Geez, I need some sleep.

(Chief Bee)
03-06-03 03:29
No 414154
      Indole bisulfite adduct  Bookmark   

Here is the article I promised you in Post 412842 (Rhodium: "bisulfite", Tryptamine Chemistry):

Org Prep Proced Int 17(6), 391 (1985) (../rhodium/chemistry /indole-2-bisulfite.html)
(Hive Bee)
03-06-03 19:10
No 414341
      > if you could reduce the bisulfite to...  Bookmark   

> if you could reduce the bisulfite to dithionite then you'ld be cooking. maybe microwaving bisulfite over activated carbon?

I don't know about that. As you can now see in the article, "the compound was unstable toward heat or water and reverted to indole..."

In the article, using the acetamide, they "dissolve" in acetic acid and nitrate with fuming nitric acid. Apparently leaving the sulfonate moiety intact. Any sodium bisulfite should decompose to sulfur dioxide under these acidic conditions. But surely the indoline sulfonate compound would yield the free sulfonic acid.

If tryptophan and sodium bisulfite truly were to prove to yield the sodium indoline-2-sulfonate analogue, maybe the easiest thing would be to just dump the whole reaction-mixture into PPA and start boiling.

It would be nice to know whether alkyl sulfonic acids or alkali sulfonates are inert to Lewis acids though, so one could use AlCl3.
(Hive Bee)
03-08-03 01:13
No 414693
      Oh, okay. I get it. Concerning this line of...  Bookmark   

Oh, okay. I get it.

Concerning this line of work in Org. Prep. Proc. Int., no subsequent work has been published. It was tried with methyl groups in the indolic 1-, 2-, or 3- positions, but no product was obtained. I have no further information.