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JJay
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That looks like it might actually work! Pure genius....
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Hexavalent
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Quote: Originally posted by CuReUS  | | Quote: Originally posted by JJay | | This is the first time I have heard of the Fries rearrangement... interesting. Why doesn't the chloro acetylchloride react with pyridine ?
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because it can react more easily with the exposed,protruding OH rather than try to react with the flat,boxed in N.Also the lone pair of N is in
resonance making it less juicy
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Chloroacetyl chloride will react with pyridine, indeed much faster than with a hydroxyl group. The pyridine is a nucleophilic catalyst. It is both a
good nucleophile, increases the electrophilic character of the intermediate (acyl pyridinium salt is positively charged) and a good leaving group
(large and uncharged) and so it facilitates the acylation reaction which would otherwise be much more difficult.
Finally, the lone pair on the nitrogen atom in pyridine is most definitely not conjugated to the pi system. The nitrogen has an
sp2 orbital which completes the aromatic sextet. The lone pair resides in a p orbital orthogonal to the plane of the ring. There is zero
overlap between the aromatic system and this orbital and so it cannot be delocalised (the overlap integral is zero).
[Edited on 27-10-2017 by Hexavalent]
"Success is going from failure to failure without loss of enthusiasm." Winston Churchill
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SWIM
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I thought the lone pair occupied the spare sp2 orbital and the Pi orbital completed the aromatic sextet.
Getting a third sp2 bond to contribute to that ring sounds like a stressful situation for the bonds.
The Pi orbitals (I thought) can just flop over either way like the wobbly bits they are.
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Hexavalent
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My apologies, you're absolutely right, I wrote them the wrong way round. The unhybridised p-orbital completes the aromatic sextet, while the lone pair
sits in an sp2 orbital orthogonal to this.
I'm not sure what you mean by saying the "pi orbitals can flop over". In short, assuming you mean p-orbitals, this is not possible since they must
maintain matching phase/symmetry to the others.
For a better understanding, have a look at a molecular orbital diagram for a benzenoid system; the p-orbitals which constitute the aromatic system
indeed appear symmetric but they are seen as having two lobes of opposite phase. The lowest-energy molecular orbital is achieved when all of these
phases are aligned, such as to avoid creating nodal planes which interrupt resonance. The next-highest energy configuration contains one nodal plane.
There are two ways of arranging this and so there are two degenerate molecular orbitals. These are the HOMOs. Flipping more p-orbitals results in an
antibonding MO which is clearly disfavourable.
[Edited on 27-10-2017 by Hexavalent]
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SWIM
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Sorry for confusing Pi with p in my reply.
What I meant by the inexact term flop-over was that they can bond either to one side or the other along the ring and therefore resonate between the
two effectively making 1/2 bond in either direction.
I believe this is also sometimes visualized as a de-localized ring of electrons around the aromatic structure.
Your references to opposite phases, nodal planes, HOMOs &etc is, I am afraid, all just clicks and whistles to me as I have no clear Idea what any
of them mean.
I am aware that various less favorable resonant forms are contributory to the overall shape in any molecule, but your terminology is not something I
have any familiarity with.
I suspect part of the problem is that we are speaking different languages in terms of terminology.
When 2 p orbitals form a Pi bond they do something which I am referring to as 'flopping over' If you can visual these orbitals and the bond they form
you perhaps can see what I mean.
When they are part of a cyclic structure satisfying Huckle's rule they do something I am describing as 'flopping over both ways'. Again, this may be
some thing you can visualize.
[grousing deleted]
[Edited on 28-10-2017 by SWIM]
[Edited on 28-10-2017 by SWIM]
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Hexavalent
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The p-orbitals do not flop/bend to one side and then alternate. Resonance is not “flipping between two different structures” (the name is
unfortunate); the true structure is the superposition of all canonicals, some of which contribute more strongly than others. Your argument about the
p-orbitals bending is correct for an isolated alkene (giving the “banana-shaped” MOs) but not for an aromatic system.
Regardless, the main point I was trying to make previously is that the nitrogen lone pair is not delocalised across the pi system in pyridine. This is
true for pyrrole, where it completes the aromatic sextet, but not for pyridine. It is localised and therefore allows for reactivity as a base and as a
nucleophile.
[Edited on 28-10-2017 by Hexavalent]
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CuReUS
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| Quote: Originally posted by Hexavalent | | pyridine is a nucleophilic catalyst. It is both a good nucleophile, increases the electrophilic character of the intermediate (acyl pyridinium salt
is positively charged) and a good leaving group (large and uncharged) and so it facilitates the acylation reaction which would otherwise be much more
difficult. |
the only catalyst in an FC reaction is the lewis acid.Pyridine just acts like a base and mops up any HCl formed,pushing the equilibrium to the right
http://www.mhhe.com/physsci/chemistry/carey/student/olc/grap...
BTW,I found an even better reaction than fries - the nencki reaction http://onlinelibrary.wiley.com/doi/10.1002/9780470638859.con... (procedure given for resorcinol)
http://onlinelibrary.wiley.com/doi/10.1002/prac.18810230111/...
[Edited on 28-10-2017 by CuReUS]
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Hexavalent
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The acylation you're talking about is not a Friedel-Crafts reaction since it does not substitute on the ring. It is a pyridine-catalysed
O-acylation to give the chloroacylcatechol. Pyridine will indeed also mop up the HCl produced (unless the hydroxyl group on the catechol is
first deprotonated by pyridine before attacking the carbonyl).
The Fries rearrangement requires you to have pre-formed the chloroacylcatechol. AlCl3 is the catalyst for this to re-arrange.
(Side note - AlCl3 isn't truly catalytic for the Friedel-Crafts acylation anyway since it is sequestered during the reaction (and therefore
unable to provide further catalysis) by coordination to the acyl oxygen.)
This article regarding the Nencki reaction on cresols:
https://link.springer.com/content/pdf/10.1007%2FBF03172188.p...
seems to indicate a problem with obtaining para-selectivity and indeed getting good overall yield for any regiochemistry. The ratio of ortho/para
substitution depends on the size of the acid used, and given that they had little success with up to butyric acid, I can't see it working well in this
case. Additionally, they specifically mention that a Fries rearrangement is superior to the Nencki chemistry they describe in terms of
yield/selectivity.
[Edited on 28-10-2017 by Hexavalent]
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CuReUS
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| Quote: Originally posted by Hexavalent | | The acylation you're talking about is not a Friedel-Crafts reaction, it is a pyridine-catalysed O-acylation to give the chloroacylcatechol.
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you got me there
| Quote: | This article regarding the Nencki reaction on cresols:
seems to indicate a problem with obtaining para-selectivity and indeed getting good overall yield for any regiochemistry. The ratio of ortho/para
substitution depends on the size of the acid used, and given that they had little success with up to butyric acid, I can't see it working well in this
case. |
in the resorcinol paper I linked,they used propanoic acid and got 73% yield.We are going to use glycine,so I don't see the size problem here | Quote: | | Additionally, they specifically mention that a Fries rearrangement is superior to the Nencki chemistry they describe in terms of yield/selectivity.
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It might be superior but can it beat the simplicity of the nencki ?
Also melgar mentioned on pg 1 that he didn't like working with pyridine
| Quote: Originally posted by Melgar |
The vanillin demethylation method that was mentioned earlier seems to be legitimate, although the pyridine part could be a sticking point.
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Melgar
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Pyridine is a sticking point only because it's not OTC. Neither is chloroacetyl chloride, for that matter. I'd rather like to have the opportunity
to work with pyridine, actually, but it's unavailable in all but the smallest quantities OTC, and on eBay it seems to cost about $1/gram, which is
extortion. However, I've since learned that triethylamine can also be used, and is available at a price that isn't nearly so ridiculous. The yields are a bit lower, but so what? I'm interested in developing a way to make anhydrous AlCl3 OTC anyway,
because it seems like it should be possible somehow, and it's also quite useful.
If it were up to me, somebody would answer my question about whether ethylvanillin is easier to dealkylate than regular vanillin, and if so, how,
rather than continue to discuss rearrangements that require chloroacetyl chloride, which is MUCH less OTC than pyridine. I don't mind reading this
stuff, but the discussion is getting pretty far out into the weeds as far as speculation, and since catechol is somewhat toxic, I think, I might
prefer to start with vanillin or ethylvanillin, which are both considerably safer and considerably more OTC.
[Edited on 10/28/17 by Melgar]
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JJay
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YouTube videos demonstrate decarboxylation of niacin to make pyridine with basic copper carbonate or copper chromite catalyst: https://www.youtube.com/watch?v=FNsqYwzm40M
Is there a reason that can't be done in bulk?
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Crowfjord
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I don't see why not. Members here have made pyridine, also. Magpie has a nice writeup in prepublication on the subject.
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Corrosive Joeseph
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What is the general consensus on vanillin demethylation with AlI3.............?
/CJ
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clearly_not_atara
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JJay: the biggest objection I've heard to pyridine is the smell
CJ: waste of iodine, no practical advantage over HBr or AlCl3/pyridine
[Edited on 28-10-2017 by clearly_not_atara]
[Edited on 04-20-1969 by clearly_not_atara]
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Corrosive Joeseph
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@ clearly - Thank you. All I know is aluminum and iodine are much more OTC for me than AlCl3........
/CJ
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CuReUS
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| Quote: Originally posted by Melgar | | Pyridine is a sticking point only because it's not OTC. Neither is chloroacetyl chloride, for that matter. |
chloroacetyl chloride isn't directly OTC,but it can be easily made from OTC chemicals like glycolic acid or even glycine.Once you have chloroacetic
acid,you don't need to convert it to the acyl chloride since you can esterify it with phenol in the presence of TCT.
But if you do the nencki,there is no need for chloroacetyl chloride.Glycine can be directly used.Coupled that with the ease of making catechol from
aspirin via the one pot method I proposed,i feel that would be a much simpler,shorter and higher yielding route.
one pot aspirin to catechol -http://www.sciencemadness.org/talk/viewthread.php?tid=77708#...
amen to that
[Edited on 29-10-2017 by CuReUS]
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Melgar
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I believe dealkylation can occur with lithium iodide, which forms the lithium phenol salt and an alkyl iodide. You pretty much have to make lithium
iodide by combining the elements though, and it'll catch fire if you accidentally use too much lithium, which is extremely easy to do.
I tried dealkylating ethylvanillin with hydrobromic acid. It didn't do much, so I heated it. It turned a really vivid pink and purple color. No
idea what that's all about.
I have a lot of aluminum that's alloyed with gallium and other metals, and is attacked very easily. I've used it to make aluminum triiodide by adding
iodine to a nonpolar solution with this aluminum alloy in it. Is that something I could do with HCl gas, to get anhydrous AlCl3? Only one way to
find out, I guess.
[some time later]
Okay, well the only solvent that seemed to work was diethyl ether. Bubbled HCl into that, with a chunk of activated aluminum, and it bubbled quite a
lot, then formed a film on the glass, and the index of refraction of the solution went up noticeably. Interesting...
[Edited on 10/29/17 by Melgar]
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JJay
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I'm going to give this a try starting with 325 mg aspirin x 200 and see how far I get.
I have the materials and equipment on hand to make aluminum bromide, but I don't have much vanillin.
The Duff reaction looks like the easiest, least toxic, and most OTC formylation reaction I'm seeing.
Edit: deleted garish aspirin photo
[Edited on 30-10-2017 by JJay]
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Melgar
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I was thinking the Duff reaction looked safest too, but alas, it appears to only ortho-formylate.
The first step in the process of learning something is admitting that you don't know it already.
I'm givin' the spam shields max power at full warp, but they just dinna have the power! We're gonna have to evacuate to new forum software!
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JJay
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I'm certainly no expert on the Duff reaction, but I've read that it para-formylates when the ortho position is occupied. (Like here: http://www.orgsyn.org/demo.aspx?prep=cv4p0866)
I wouldn't expect high yields, but what leads you to believe that the Duff reaction won't result in the desired product?
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DJF90
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What leads you to believe that catechol will behave like the substrate in that OrgSyn paper? You even say that when the ortho-position is occupied
then para-formylation occurs. Can you not count the two(!) unoccupied ortho-positions in catechol?
I'll be honest here guys, I'm shocked by some of the nonsense I've seen in this thread.
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JJay
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@DJF90: The mechanism and selectivity of the Duff reaction is a subject of current research, much of which I find nearly incomprehensible since I
don't know how to calculate bond angles from first principles.
But here you go: http://pubs.rsc.org/en/Content/ArticleLanding/1932/JR/JR9320...
And actually, I might just skip catechol....
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clearly_not_atara
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Dealkylation with lithium chloride in refluxing DMF has also been reported, actually. The iodide may not be necessary. As with other situations I
think the bromide might be a good compromise.
I'm sorry you weren't successful with HBr. Maybe Bronsted acid catalyzed Friedel-Crafts hydroxyalkylation is the culprit?
[Edited on 29-10-2017 by clearly_not_atara]
[Edited on 04-20-1969 by clearly_not_atara]
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DJF90
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I have no idea what your remark about calculating bond angles is about. If thats what is hindering you though, download the MarvinBeans suite (free
software) and let it do the calculations on your behalf (thats what any sane organic chemist would do anyway, albeit with whatever software is
licensed to them).
As for the paper you link to, it shows that the reaction is low yielding and unselective when using salicylic acid as substrate. What was you trying
to illustrate?
As for skipping catechol, thats kind of outside of the scope of this thread (as the title suggests) and even if it were permissible by the OP, that
sort of leaves guaiacol, vanillin, isovanillin, bourbonal and veratraldehyde as viable starting materials, each of which have their own
problems/difficulties en route to dopamine.
[Edited on 29-10-2017 by DJF90]
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JJay
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@DJF90: The point was that the Duff reaction doesn't only ortho-formylate. I had mentioned that I didn't expect high yields. I'm still not 100% sure
that the Duff reaction will formylate in the right position to make dopamine from catechol, but I suspect it will since one of the ortho positions is
occupied relative to the starting phenol group in catechol, no matter which phenol group you start with. The OP wanted multiple routes by which to
make dopamine in order to verify the composition of the final product, and I think it is actually possible to prepare dopamine from salcylic acid
without ever preparing catechol (although it would likely require protecting an aldehyde).
There's current research on methods for getting high yields and high selectivity from the Duff reaction. Comprehending this research seems to require
extensive and detailed knowledge on the geometry of intermediates that I'm certainly not going to memorize for this project, but if I could derive it
from first principles, I think I could make more sense of it.
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