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Topic: Decarboxylation to hydroxyindole mechanism  (Read 8443 times)

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Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #15 on: July 22, 2016, 10:59:22 PM »
Hi Fireredburn1,

Good, you seem to be working hard on this problem! Keep it up!

You're answer is essentially backwards... Your system is almost exactly the same as the one in the MCAT example you showed, which involves the decarboxylation of a beta-ketoacid, but in your system there is an added double bond between the keto and carboxylate groups. So your arrows should go in exactly the same direction as in that example. The way that you have CO2 being pushed off in your mechanism is really not how CO2 is lost in decarboxylation reactions: overall, you need to reverse the direction of the arrows.

No, his mechanism is correct.

Offline Fireredburn1

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #16 on: July 23, 2016, 01:09:36 AM »
Hi Fireredburn1,

Good, you seem to be working hard on this problem! Keep it up!

You're answer is essentially backwards... Your system is almost exactly the same as the one in the MCAT example you showed, which involves the decarboxylation of a beta-ketoacid, but in your system there is an added double bond between the keto and carboxylate groups. So your arrows should go in exactly the same direction as in that example. The way that you have CO2 being pushed off in your mechanism is really not how CO2 is lost in decarboxylation reactions: overall, you need to reverse the direction of the arrows.

I agree that this may be an unusual way of doing decarboxylation.

I drew two other mechanisms based on your feedback, one that involves the lone pair of nitrogen in the mechanism



and the other one without.





Offline lb2

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #17 on: July 23, 2016, 01:26:27 AM »
@orthoformate,

Well, I'm not tying to be confrontational, I'm just trying to help the OP. That being said, I cannot think of any other example where the decarboxylation would happen in such a counter-intuitive way. Do you know of any other example?

I'm sure you've seen that in his two paper(s) Padwa shows it, but does not explain it, in this weird way that I don't like. If it's any valuable counterpoint, between me and my two organic chemistry university professor colleagues we have more than 60 years experience teaching o-chem and we separately found a mechanism much more similar to the new one shown by the OP. I'll let you decide for yourself what the best answer is.


@Fireredburn1

Something like that would be my best guess, whether it is in one or multiple steps (I would personally favor the protonation of the top C=O to lead to the formation of an intermediate carboxylic acid). By the way, your two mechanisms are the exact same mechanism and are just related by the fact that the two intermediate structures are two resonance structures of the same compound (so one of your reaction arrows needs to be replaced by a resonance arrow)

Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #18 on: July 23, 2016, 10:33:23 AM »
I apologize, there is nothing wrong with this other mechanism either.

Offline critzz

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #19 on: July 27, 2016, 12:10:37 PM »
Lets carry out a kinetic isotope effect experiment to see who is right, haha.

Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #20 on: July 27, 2016, 03:01:38 PM »

Something like that would be my best guess, whether it is in one or multiple steps (I would personally favor the protonation of the top C=O to lead to the formation of an intermediate carboxylic acid).

Perhaps this could be explained further. Is this an elimination of HCO2(+)? The proton being eliminated seems quite basic. How would protonation make this mechanism probable? In the other mechanism, it seems to satisfy a plausible flow of electrons and allows for a plausible alternative for aromatization.
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Offline lb2

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #21 on: July 27, 2016, 04:13:19 PM »
Hi orgopete,

What "other" mechanism are you referring to in your question? Also, did you really mean "basic"?

Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #22 on: July 28, 2016, 07:09:00 AM »
Posts #12 and #16 contain different mechanisms. The first uses the non-bonded electrons of a nitrogen to initiate a decarboxylation while the second uses water to remove a proton from an inactivated CH2 to initiate the reaction. The first uses an acid to create an electron sink to accept electrons donated in the decarboxylation. While the second uses this same electron sink, this seems unnecessary as the deprotonation-decarboxylation would generate a vinylogous enolate. My question is if the reaction is initiated by a deprotonation by water of an unactivated CH2, how or why does an acid initiate the reaction?

One might ask a similar question about the mechanism in post #12. I normally expect a nitrogen to be protonated before an sp2-oxygen. However, one can find instances in which one seemingly must protonate the less basic oxygen in a reaction, e.g., acid catalyzed enamine formation.
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Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #23 on: July 28, 2016, 09:42:34 AM »
In my opinion, both of these mechanisms occur, but I believe that Post #12's mechanism predominates because it is faster.

My reasoning is this: Once the ketone becomes protonated, decarboxylation can occur intramolecularly (at least, there are no problems on paper  :D), so it will occur.

I can't find a reference for this reaction, I think it's a fictional reaction made for instructional purposes. Can anyone find anything on this?

Offline lb2

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #24 on: July 28, 2016, 01:09:42 PM »
@orthoformate (great name by the way!)

As I mentioned in my previous reply to you, this chemistry has been described in two papers by the great Al Padwa. The refs are: J. Org. Chem. 2006, 7391 and Org. Lett. 2006, 601.

Let me know if you don't have access to these journals but would like to look at these articles.

As to your argument that "Posts #12's mechanism predominates because it is faster"... Think about it: Since you have no experimental clue about the correctness, or indeed the relative rates, of the two mechanisms, as stated your argument is just circular reasoning and I could rephrase it with "I think it's the fastest because I think it's the fastest".  ;)


@orgopete

Thanks for clarifying your question. First, let me reiterate that I favor something similar to what's in post #16, but I haven't completely disregarded the one from post #12. If only, as I mentioned before, because Padwa himself included the mechanism from post #12 in his papers, I'm willing to not completely eliminate this mechanism.

That being said, there is, in my opinion, plenty wrong with the mechanism in #12. My main points though are that it doesn't make much sense in terms of electron-pushing and that there are very few (any?) precedent for this kind of decarboxylative process. By comparison, the mechanism in #16 has a very intuitive electron flow and has solid background in the decarboxylation of beta-keto acids (here a vinylogous variant.)

By the way, I'm just trying to entertain this fun discussion here: I know you are very knowledgeable so please don't be insulted if any of this sounds like I'm lecturing. I'm just trying to make it as clear as possible for anyone who may be reading.

As a note, if you look at the experimental section of the article, the reaction is conducted in refluxing DCM for 4 hours, with a huge excess of the very strong TfOH. Yeah, it's very strongly acidic! That being said, as you mention it doesn't matter in a mechanism what the most basic site in a molecule is. Whether the O or the N is more basic is irrelevant: if you can protonate it even to a tiny extent, it may be enough to funnel everything toward product. That's how most acid-catalyzed carbonyl condensation chemistry works: a tiny amount of the C=O compound gets protonated, and that's enough to get things going. But to come back to the problem at hand: the nitrogen is really not basic as it's part of an enamine and it's very unlikely to get protonated.

Why do I say that the mechanism in #12 has weird electron flow? Because of microscopic reversibility arguments, a mechanism has to make sense in both directions. If you look at the reverse of #12, it involves the quite cringe-inducing nucleophilic attack of an enol on the oxygen of CO2 (!), together with the carbon of CO2 acting as a nucleophile (!) and attacking an iminium ion.

The reverse of mechanism in #16 is completely well precedented and involves attack of an enol on the C of CO2, followed by an alkene addition reaction under strong acidic conditions. Also, if the alignment is ok and if there is a carbocylic acid intermediate, you could potentially invoke a vinylogous ene reaction to form the acid (i.e., the decarboxylation of a beta-keto acid is a retro-ene reaction.)

For the mechanism in #16: If it is, as pictured in #16, a concerted process, then the incipient aromatization should increase the acidity of that hydrogen just as it does in #12. By the way, it could very well be concerted. If you look at the molecule in 3D (I just minimized its structure in ChemBio3D Ultra), you can see that everything is really well aligned.
If it's not a concerted process and you first form a carboxylic acid: Protonating the top oxygen makes the carboxylic acid a very good leaving group. Then everything is perfectly aligned (H and O are stuck in a perfectly antiperiplanar conformation) for an anti elimination with one of the H's of the methylene group. Furthermore, this elimination relieves the tension forced in by the bicyclo system. To say it differently: I would not expect this elimination to be very difficult, especially with an excess of TfOH in boiling DCM!

This is a fun mechanistic problem. Let me know what you think!

Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #25 on: July 28, 2016, 03:01:39 PM »
@lb2

As you know the paper you referenced (J. Org. Chem. 2006, 7391) contains the mechanism described in Post #12 (attached).

Assuming that the decarboxylation can occur faster intramolecularly is not circular reasoning.

Generally intramolecular reactions occur faster than intermolecular reactions. The mechanism in Post #16 is an intermolecular reaction (involving water) and would naturally occur at a slower rate. The sluggish rate of the Post #16 mechanism is exacerbated by the fact that there is very little water in the reaction, the only water in the system is the water ejected from the Pictet–Spengler reaction.

Why would the molecule wait around for water to show up when it could just react on its own. My thought is that it wouldn't, and that is why I support the Post #12 mechanism.

Offline lb2

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #26 on: July 28, 2016, 05:32:14 PM »
Hi orthoformate,

I understand what you mean. But I think you are not being careful enough in your statement, which in my opinion leads you to a false interpretation.

As written, this broad statement

"Generally intramolecular reactions occur faster than intermolecular reactions."

is 100% wrong.

There is absolutely no data supporting this statement. Take a random sample of 1000 reactions, half intramolecular and half intermolecular, and you'll get a statistical distribution of rates, with statistically as many intermolecular reactions that are faster or slower than the mean intramolecular reaction. Never mind the fact that they will have different molecularity and different concentration dependencies. In fact, it is a safe assumption that in your favored mechanism from post #12, the intermolecular protonation of the carbonyl group is much much much faster than the intramolecular loss of CO2.

A more correct statement is something like the following:

"For two identical reactions with identical electron movement and under exactly the same reaction conditions, but one being intramolecular and the other intermolecular, the rate of the intramolecular reaction is expected to be higher."

For the comparison to be relevant, the two reactions have to be exactly the same, with the same electron movement but one inter- and the other intramolecular. This is clearly not the case with the two mechanisms at hand. And the fact that they form the same product is entirely irrelevant to this intra vs. intermolecular argument. Since there is no information (experimental or calculated) about the relative rate constants of the different steps in each mechanism (never mind that they don't all have the same order), there is no way to discuss the relative rates of these two imaginary mechanisms in terms of one being inter- and the other being intramolecular.

Again, I'm totally ok with someone saying that they prefer the mechanism in post #12. I prefer the one in #16 for reasons that I've explained in my previous answer to orgopete. But, with all respect, the argument that you brought up about inter- vs, intramolecular is, in my humble opinion, not valid.

Cheers!
« Last Edit: July 28, 2016, 05:56:56 PM by lb2 »

Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #27 on: July 29, 2016, 11:17:59 AM »

@orgopete

Thanks for clarifying your question. First, let me reiterate that I favor something similar to what's in post #16, but I haven't completely disregarded the one from post #12. If only, as I mentioned before, because Padwa himself included the mechanism from post #12 in his papers, I'm willing to not completely eliminate this mechanism.

That being said, there is, in my opinion, plenty wrong with the mechanism in #12. My main points though are that it doesn't make much sense in terms of electron-pushing and that there are very few (any?) precedent for this kind of decarboxylative process. By comparison, the mechanism in #16 has a very intuitive electron flow and has solid background in the decarboxylation of beta-keto acids (here a vinylogous variant.)

As a note, if you look at the experimental section of the article, the reaction is conducted in refluxing DCM for 4 hours, with a huge excess of the very strong TfOH. Yeah, it's very strongly acidic! That being said, as you mention it doesn't matter in a mechanism what the most basic site in a molecule is. Whether the O or the N is more basic is irrelevant: if you can protonate it even to a tiny extent, it may be enough to funnel everything toward product. That's how most acid-catalyzed carbonyl condensation chemistry works: a tiny amount of the C=O compound gets protonated, and that's enough to get things going. But to come back to the problem at hand: the nitrogen is really not basic as it's part of an enamine and it's very unlikely to get protonated.

Why do I say that the mechanism in #12 has weird electron flow? Because of microscopic reversibility arguments, a mechanism has to make sense in both directions. If you look at the reverse of #12, it involves the quite cringe-inducing nucleophilic attack of an enol on the oxygen of CO2 (!), together with the carbon of CO2 acting as a nucleophile (!) and attacking an iminium ion.

The reverse of mechanism in #16 is completely well precedented and involves attack of an enol on the C of CO2, followed by an alkene addition reaction under strong acidic conditions. Also, if the alignment is ok and if there is a carbocylic acid intermediate, you could potentially invoke a vinylogous ene reaction to form the acid (i.e., the decarboxylation of a beta-keto acid is a retro-ene reaction.)

For the mechanism in #16: If it is, as pictured in #16, a concerted process, then the incipient aromatization should increase the acidity of that hydrogen just as it does in #12. By the way, it could very well be concerted. If you look at the molecule in 3D (I just minimized its structure in ChemBio3D Ultra), you can see that everything is really well aligned.
If it's not a concerted process and you first form a carboxylic acid: Protonating the top oxygen makes the carboxylic acid a very good leaving group. Then everything is perfectly aligned (H and O are stuck in a perfectly antiperiplanar conformation) for an anti elimination with one of the H's of the methylene group. Furthermore, this elimination relieves the tension forced in by the bicyclo system. To say it differently: I would not expect this elimination to be very difficult, especially with an excess of TfOH in boiling DCM!

This is a fun mechanistic problem. Let me know what you think!


Triflic acid in dichloromethane seems counter intuitive for a base catalyzed reaction. If you are not going to use the acid to initiate the reaction, then why not use DBU or triethylamine to catalyze the reaction? If you are going to use water, then hydrolyze the lactone. The decarboxylation is a vinylogous beta-keto acid. The result of this is a dihydrobenzene with an eliminatable alcohol. I'd agree with that. If it were to go by that route, then it might be better to add a saponification step and decarboxylate the acid.

It is the base catalyzed elimination in mechanism #16 that I am troubled by. Perhaps you could cite an example of an acid catalyzed E2 elimination. Let me follow your reasoning. If you took an acetate of an alpha-keto secondary alcohol, you could treat it with triflic acid in refluxing dichloromethane and get acetic acid and an enone. You are saying protonation of the acetate increases the acidity of the beta-hydrogen enough for water to remove it. I'll have to check my textbook for this reaction. I'm presuming a similar concerted reaction is known, though without the triflic acid. Just heat.

If one did a Diels-Alder reaction with a pyrone and an acetylene, the intermediate can decarboxylate to give a benzene ring. As a concerted reaction, one could (not must) write the elimination with the arrows going in the wrong direction.

I understand that it is unusual for an oxygen lose its electrons or to be an electron donor, but I can think of other examples. In a hypochlorite oxidation of an alcohol, oxygen donates its electrons to a chloride (the electron sink). If one tries to write the reverse of this reaction, it may seem implausible. Does that render the reaction incorrect? I grant that it is unusual for an oxygen to donate electrons to a carbon sink (and I cannot think of a single example), mechanistically the conditions are consistent with a protonated ketone to accept an electron pair.

R2CHOCl  :rarrow: R2C=O + HCl

On the donation side, the enamine seems like a plausible donor. Again, I'm thinking this is an acid catalyzed reaction, that is, it is the protonation of the carbonyl group that provides the impetus for the electron donation. I don't expect a gamma-carboxyl enamine to decarboxylate.

Since I also agree with seeking similar electron movements in other reactions. I don't like to have a one-off reaction. If you try to do a Friedel-Crafts reactions with a phthalimide of an alpha-amino acid chloride, the reaction will fail. The Lewis acid will pull the chloride away and the nitrogen will donate its electrons to give a decarbonylation reaction. Although this is not specifically identical, I feel it retains the electronic movements of this reaction. I suspect others can give additional examples, especially of decarbonylation reactions.
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Offline lb2

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #28 on: July 29, 2016, 01:52:39 PM »
Hi orgopete,

Thanks for the detailed and well tought-out reply. I know that these can take quite a bit of time to write and I really appreciate you taking the time to do it.

Unfortunately, I'm on the road and will be with very little access to internet for the next two weeks. I'll hopefully be able to look more into your answer and reply then.

Thanks again, and to orthoformate, for entertaining such a fun discussion!

Cheers!

Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #29 on: July 31, 2016, 03:55:56 PM »

... I don't expect a gamma-carboxyl enamine to decarboxylate.


Wrong? That is an imino-beta-carboxylate. It may decarboxylate similar to an beta-keto acid, just not the same intramolecular reaction. The product would be a decarboxylated enamine and CO2.
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