[PoetryInMotion]

Problem. What is the mechanism for this reaction:
http://en.wikipedia.org/wiki/Rhodamine_B#Synthesis


My thoughts. I hade this far identified electrophilic aromatic acylation as a likely (first?) step. Also, I have an idea about an second S_EAr reaction and an esterfication reaction. See picture below. Am I on the right track?

The (last?) step seems to be some kind of etherfication. How does that happen? Usually, etherficaton of simple alcoholes in acid goes through protonation by the hydroxyl group followed by an S_N1 displacement. I doubt that my case is that simple since a) phenol is quite a poor base and b) a benzene-like carbocation ("aryl cation"?) wouldn't be very favorable. Any ideas?

I made a (very quick) sketch here:


Summarized.
1) Are the two S_EAr likely to be a part of the mechanism (despite the unconventional electrophile and steric hindrance)?
2) Is it an ordinary esterfication that creates the lactone ring?
3) How is the diaryl ether formed?
4) What can be said about the order of the different steps?

[C-hemCards]

A hint: One rule of thumb in drawing mechanisms is that if you can make a 5-membered ring, do it. In your first product (the diaryl ketone), that carboxylic acid is suitably place to form a 5-membered ring with the ketone, to make a lactone/hemi-acetal.

You end up at the same place that you did, but it's just more technically sound.

[Dan]

1) Are the two S_EAr likely to be a part of the mechanism (despite the unconventional electrophile and steric hindrance)?
2) Is it an ordinary esterfication that creates the lactone ring?
3) How is the diaryl ether formed?

1. Yes, you have a very electron rich arene
2. Define "ordinary" - do you mean A_AC2? If so, I would argue no. I think it's debatable whether the lactone even opens the first place, but if it does I would not expect an A_AC2-type closure. What other mechanisms for esterification do you know? Can you draw a mechanism for the reaction that doesn't involve a free carboxylic acid?
3. Draw the mechanism for the second S_EAr stepwise - The Wheland intermediate is also an α,β-unsaturated iminium ion.

[AlphaScent]

Not to change the subject, but where can I read on the mechanistic notation of S_EAR and A_AC2??

Is there a good source??

[Dan]

Not to change the subject, but where can I read on the mechanistic notation of S_EAR and A_AC2??

They should be covered in any organic chemistry textbook.

S_EAr = Electrophilic aromatic substitution
A_AC2 is the acid catalysed, acyl attack, bimolecular, mechanism of ester hydrolysis (which is fully reversible and so also applies to acid esterification as well). There are theoretically 8 possible mechanisms of ester hydrolysis. I know that Peter Sykes's book covers them well, but I should think it's in any general organic textbook.

[AlphaScent]

Dan,

I have looked in both books that I own.  Is Peter Sykes book A Guide Book to Mechanism in Organic Chemistry ?

[Dan]

I have looked in both books that I own.  Is Peter Sykes book A Guide Book to Mechanism in Organic Chemistry ?

It is yes, but actually the description is better in March's Advanced Organic Chemistry.

I also found this page which will be of interest.

[PoetryInMotion]

2. Define "ordinary" - do you mean A_AC2? If so, I would argue no. I think it's debatable whether the lactone even opens the first place, but if it does I would not expect an A_AC2-type closure. What other mechanisms for esterification do you know? Can you draw a mechanism for the reaction that doesn't involve a free carboxylic acid?
3. Draw the mechanism for the second S_EAr stepwise - The Wheland intermediate is also an α,β-unsaturated iminium ion.

2. I actually meant A_AC2, but I now realize this seems to be something SN1 based. A_AL1 or maybe A_AC1. Bot the tertiary/benzylic carbocation formed in A_AL1 and the acyl cation formed in  A_AC1 look pretty good to me, and the strong acid seems to be favourable to both mechanisms.

What will the reaction look like if the ring is kept closed? I made a quick sketch of the best I could come up with (part a of the image below). Does it look okay? What worries me a bit is that we i) seem to have more steric hindrance in both the S_EAr steps if we keep the ring closed and ii) don't seem to have any resonance stabilization from the oxygen in the same way as we had above. But maybe the carbocation still is stable enough?

3. Ah! I guess that's an especially stable resonance form? Is it stable enough to make the route below (part b of the image) available?

[orgopete]

2. I think it's debatable whether the lactone even opens the first place, but if it does I would not expect an A_AC2-type closure. What other mechanisms for esterification do you know? Can you draw a mechanism for the reaction that doesn't involve a free carboxylic acid?
3. Draw the mechanism for the second S_EAr stepwise - The Wheland intermediate is also an α,β-unsaturated iminium ion.

I don't know that I agree with the lactone advice. This reaction is being heated. The notion that a ketal will not open can make the mechanism more difficult to write. Wikipedia shows the structure of Rhodamine B as the acid even though it could as easily be written as the lactone also.

This mechanism isn't necessarily easy to figure out. When I try to write what I think is the best mechanism for a problem like this, I sometimes write several mechanism so that I can compare different possible steps. Two reactions that come to mind are the Mannich and an acid catalyzed enamine formation. These reactions contain basic amines and an acid. I had to think carefully as to what species was an acid and the protonation steps.

Dehydration of a phenol is quite unlikely. I'd consider two options. Phenols may also be written as ketones tautomers, or as suggested by Dan, the nitrogen can be written as an iminium ion in one or more intermediates (product?).

[Dan]

2. I actually meant A_AC2, but I now realize this seems to be something SN1 based. A_AL1 or maybe A_AC1. Bot the tertiary/benzylic carbocation formed in A_AL1 and the acyl cation formed in  A_AC1 look pretty good to me, and the strong acid seems to be favourable to both mechanisms.

Right idea. Which of those two carboctaions is more stable? Consider the effect that conjugation to heteroatom lone pairs, inductive effects and hybridisation have on of carbocation stability. One looks substantially more stable than the other to me.

What will the reaction look like if the ring is kept closed? I made a quick sketch of the best I could come up with (part a of the image below). Does it look okay? What worries me a bit is that we i) seem to have more steric hindrance in both the S_EAr steps if we keep the ring closed and ii) don't seem to have any resonance stabilization from the oxygen in the same way as we had above. But maybe the carbocation still is stable enough?

Yes, your sketch is what I had in mind. Re: i) - a fair point, but it is still planar so I don't think it is such an issue. Re: ii) You can still use the lone pair of the lactone's endocyclic O to delocalise the charge (albeit less effectively), and you still have resonance stabilisation by the phenol and the aniline.

I fully concede that this could be wrong (see orgopete's post), but here is my reasoning: The two potential carbocations will be in equilibrium, it is a question of which is more likely to react with the aminophenol. I would predict that the lifetime of the ring-open carbocation is very short. Not because it is inherently unstable, but because the reverse reaction (intramolecular trapping with a pendant carboxylic acid nucleophile to form a 5-membered ring) will be very fast due to the permanent proximity of the carboxylic acid to the carbocation. On formation of the cyclic carbocation, the reverse reaction would be attack of water - water can diffuse away from the carboction, giving the arene nucleophile a higher probablility of colliding with it. I do think both mechanisms are plausible though.

3. Ah! I guess that's an especially stable resonance form? Is it stable enough to make the route below (part b of the image) available?

No, you're still jumping the gun here. That aryl carbocation is not resonance stabilised as the empty p orbital is orthogonal to the pi system (there is no overlap).

Draw the S_EAr stepwise (you have not shown the mechanism in this step so far). When you get to the Wheland intermediate, deprotonation is normally the final step. Consider other possible avenues of reactivity for this intermediate.

[PoetryInMotion]

Right idea. Which of those two carboctaions is more stable? Consider the effect that conjugation to heteroatom lone pairs, inductive effects and hybridisation have on of carbocation stability. One looks substantially more stable than the other to me.

The one formed in A_AL1 is stabilized by resonance from three different aryl groups. It will be sp² hybridized.
The one formed in A_AC1 is stabilized by resonance from one aryl group and from the oxygen. Resonance from oxygen probably isn't good enough to match even one case of benzylic resonance stabilization and definitely not two of them. Especially not in an acidic medium where the oxygen might get protonated (and thus positively charged and thus less willing to donate electrons to the positive carbon). Also, this carbocation is sp hybridized, which is less favorable than sp².

I guess this means that A_AL1 is the most probable mechanism for the lactone re-formation (if it is even opened in the first place).

No, you're still jumping the gun here. That aryl carbocation is not resonance stabilised as the empty p orbital is orthogonal to the pi system (there is no overlap).

Draw the S_EAr stepwise (you have not shown the mechanism in this step so far). When you get to the Wheland intermediate, deprotonation is normally the final step. Consider other possible avenues of reactivity for this intermediate.

Good point there (but isn't it an sp² orbital that is the empty one?)

So, the only time we seem to have an electrophilic carbon at the right position, is during the S_EAr, when we have the Wheland intermediate. But is the intermediate stable enough undergo a nucleophilic attack from the hydroxyl group before it is derotonated? I'm not sure, since the more immediate deprotonation could be expected to be rather fast.

[PoetryInMotion]

Dehydration of a phenol is quite unlikely. I'd consider two options. Phenols may also be written as ketones tautomers, or as suggested by Dan, the nitrogen can be written as an iminium ion in one or more intermediates (product?).

As for the keton tautomer option, what about this suggestion?



(The formation of the other possible keton tautomer of this molecule would be less favorable since its formation would mean going from sp2 to sp3 at a carbon with a very bulky substituent.)

[Dan]

Good point there (but isn't it an sp² orbital that is the empty one?)

Yes, sorry, empty sp²

So, the only time we seem to have an electrophilic carbon at the right position, is during the S_EAr, when we have the Wheland intermediate. But is the intermediate stable enough undergo a nucleophilic attack from the hydroxyl group before it is derotonated? I'm not sure, since the more immediate deprotonation could be expected to be rather fast.

I like this mechanism, it makes sense to me (it's what I came up with on paper). That is not a good reason to assume it's correct though.

You can draw the same mechanism with the open-chain form instead of he lactone as well.

In terms of whether the Wheland intermediate is intercepted before rearomatisation by deprotonation - I'm not sure. You could regenerate the Wheland intermediate by protonation, or actually maybe something like this is more likely:

[PoetryInMotion]

Thanks for all the answers this far

What can be said about the mechanism of the last elimination? Will it be concerted or more E1-like? Or is it too hard to tell? I would guess the latter, since we have acidic conditions, which gives us H2O as (an excellent) LG and since we can form a good resonance-stabilized carbocation.

[orgopete]

Now several mechanisms have been written. They contain several proton transfer reactions. They are usually fast reactions and it can be difficult to declare a single route as the correct one or given so many possible steps, that more than one might operate to give the expected product. I don't have any insight. I did think it peculiar that Wikipedia showed the synthesis to the lactone while showing the chloride salt as the carboxylic acid. I would not have anticipated they should differ.