fstque
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Protocatechualdehyde from p-hydroxybenzaldehyde
Hi all. I wanna know is this possible to synthesize 3,4-dihydroxybenzaldehyde from 4-hydroxybenzaldehyde following this route:
4-OH-BA + I2+KI --> 3-Iodo-4-OH-BA
3-I-4-OH-BA --NaOH,CuSO4,reflux--> 3,4-diOH-BA
What yields I should expect from these rxn's?
Help pls 
p.s. sorry for my english
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fluorescence
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So I checked your reaction with Reaxys here is what they think how you could do it ( I'll leave out the ones that require chemicals which you probably
don't have).
- TCCA, Iodine in DCM (RT) -> 98% yield
- Ammoniumpersulfate, Potassium Iodide in Methanol/Water -> 80%
- Ammoniumhydroxide, Iodine, Potassium Iodide in Water (6h) -> 72%
- Iodine, Dimethylamine, Potassium Iodide (3h) -> 50%
There are more but I thought those where the easier ones.
Usually Iodine isn't reactive enough to really get it into reaction.
You'd use Sandmeyer or Finkelstein to Substitute it.
And I looked up your desired product, too.
It can be made from your Iodine-Compound but they usually use
the Bromo-Version. The yield should be 100% there since you just convert it. So the maximum yield is probably what you get from your halogenation
minus some loss due to cleaning.
For the Bromo Version it would be:
- Bromine in Chloroform but you can probably use DCM, too (2h). They say 100% yield but I doubt it. I guess you could add a second Bromine, too. So
don't leave it for too long. Especially at elevated temperatures the yield seems to decrease. At 40°C you'll only get about 75% of it.
And in all the other syntheses the Dibromo-Compound is formed, too. So there will be some loss if you use the Bromo-Version. For the Iodine Version I
can't really tell. We never had any example where you could add Iodine directely so I don't anything about Doubleiodations. If you need the Paper for
any of the mentioned procedures, tell me. I don't want to copy and paste them all in here now. But before you do anything you'll have to checked it in
literature whether it's correct or Reaxys just messed up something, again.
[Edited on 20-9-2015 by fluorescence]
Edit: I just saw I forgot to mention the second reaction.
After you have the halogen Compound it says here:
For the Bromo-Version:
- Sodium Hydroxide (150-200°C)
- Sodium Hydroxide, Copper, Water
- Sodium Hydroxide, Copper(I)Bromide, Water
- Sodium Hydroxide, Copper Salts, Water (Pressure)
So your idea would probably work here although I have never heard of that method using copper salts before.
[Edited on 20-9-2015 by fluorescence]
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fstque
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I just thought it will take much more time to hydrolyze bromo-compound (about 24h reflux? according to erowid with 5-bromovanillin) unlike with iodo-
(about 5h?). Or am I wrong?
I cant really find TCCA in my country. Same for methanol (only tanks with tons of it). So I would probably use NH4OH+I2+KI in water. But I'm not sure.
If there's any method to hydrolyze bromo-compound faster than 24h I'd prefer to use bromo-version.
[Edited on 21-9-2015 by fstque]
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zed
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Yeah, the Lucky 8 Ball, sez.... methinks not!
Expect di-substitution. The industrial process for Trimethoxy Benzaldehyde begins with Bromination of P-hydroxy toluene. Expect the same result.
Some of the guys have produced protocatechualdehyde from Vanillin. Ethyl Vanillin is reputed to be a better starting material.
[Edited on 22-9-2015 by zed]
[Edited on 22-9-2015 by zed]
[Edited on 22-9-2015 by zed]
[Edited on 22-9-2015 by zed]
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clearly_not_atara
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| Quote: | | The industrial process for Trimethoxy Benzaldehyde begins with Bromination of P-hydroxy toluene. Expect the same result. |
p-hydroxybenzaldehyde is less reactive than p-hydroxytoluene due to the presence of the formyl EWG. Monosubstitution is possible and in fact
preferred.
There is a faster method to hydrolyse the bromo-compound; if you use NaOEt/EtOH/CuBr the 2-bromo-4-formylphenol rapidly reacts to produce
ethylvanillin. However, you then must cleave the ether with HBr. Ethylvanillin is easier to cleave than vanillin because the intermediate carbocation
is more stable (due to the greater electron-donating effect of ethyl resp. methyl) which is why it is generally considered to be a better starting
material.
Iodine is probably easier if you want to produce a small amount of protocatechualdehyde. For larger amounts, the two-step procedure NaOEt //>>
HBr might be preferable.
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byko3y
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Vanilline is a nightmare to cleave. Meta-hydroxy group is activated comparing to ortho-para. When the ring draws electrons from the oxygen, PO- anion
becomes stable and easily gives away whatever is hanging on it. When the electron is completely on oxygen, the oxygen becomes less reactive and
prefers to stick to whatever ligand is on it, thus it is something slightly more reactive than alcohol and water (pka=11 for phenol vs pka=14 for
water and alcohol). Cleaving activated phenols is similar to cleaving ethers. The problem is that HCl/HBr/HI are not soluble in organic solvents and
they react too slowly - something like autoclave is required and the yield is moderate.
AlCl3-thiourea, AlBr3/AlI3, Pyridine-HCl, NaSR, and some other reagents can successfully perform the operation.
Most likely there's no difference in procedures for cleaving ethyl and methyl ethers, one thing I can tell for sure - thiols won't work for ethyl
ether. The former 3 methods are based on halide attack happening while aluminium halides withdraw electrons from oxygen (remember what I've told about
electrons withdrawing?), so the only reaquirement for alkyl group to be cleaved is to be a good Sn2 target (methyl, ethyl, propyl, allyl, benzyl,
etc). Chloride reagents require soft base (thiourea, pyridine, triethylamine) to perform the reaction at acceptable conditions (without autoclave).
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clearly_not_atara
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HBr is soluble in all sorts of organic solvents (CHCl3, AcOH, DMSO, others); whose textbook are you reading? All the yields I found were bad
though (apparently there are ring-brominated side-products). There's an old report from the Hive using AlBr3, which is relatively easy to make, but
not trivial, and requires loads of bromine (twice as much Br2 as vanillin).
Apparently the hydrolysis yield gets much better using phenanthroline as ligand:
http://onlinelibrary.wiley.com/doi/10.1002/anie.200903923/ab...
Phenanthroline isn't too hard to make (o-phenylenediamine, glycerol, nitrobenzene, H2SO4) but perhaps another ligand would be easier... it is worth
pointing out that in the time we've spent arguing the author could have carried out several 24h hydrolysis attempts. You could probably get some
effect from pyridine or thiocyanate.
[Edited on 28-9-2015 by clearly_not_atara]
[Edited on 28-9-2015 by clearly_not_atara]
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byko3y
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I don't think anything you've mentioned can dissolve inorganic acid to appreciable amount, while protic solvents can't be used, because they
inactivate the chloride. There's a patent about cleavage of vanillin with HCl, they used an autoclave and high temperature to perform the reaction.
You've posted a completely different reaction (aromatic halogen substitution) compared to ether cleavage. There's ether synthesis in fact.
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clearly_not_atara
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I posted about the original topic reaction, which is protocatechualdehyde from p-hydroxyphenol via bromination/hydrolysis. Pay attention, silly. If
vanillin is too hard then OP should do something else.
While there are plenty of available resources discussing the indeed significant solubility of HBr in chloroform; that is not the primary topic at
issue.
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zed
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Huh? I'm under the impression that EthylVanillin can be cleaved via H2SO4. I'll check the search engine.
Well, OK. Not easy to find here.
But, on the Vespiary, some one has translated this from a Japanese Patent.
0013 Example of Execution 1
Inside an Argon gas stream, at room temperature, 96% by weight sulfuric acid
(60.20mmol) was placed into a 25ml flask; after reducing the temperature
to 5 degrees C, this temperature of 3-ethoxy-4-hydroxybenzaldehyde
(6.02mmol) was added, all the while stirring. Next, the temperature was
raised to 65-70 degrees C; after an additional 2 hours of stirring heated at
the same temperature, the reaction liquid was cooled to room temperature.
Then, to the thus obtained reaction liquid was added, with stirring, ice
water (20ml) and the reaction liquid stirred for 1 hour. After, when the
aqueous solution was analyzed by high speed liquid chromatography, it was
established that the conversion ratio of 3-ethoxy-4-hydroxybenzaldehyde was
97%, yield of protocatechualdehyde was 91%. Also, the entire procedure
described above was done under normal pressure.
0014 Example of Execution 2
Same, except the amount of 96% by weight sulfuric acid was changed to
116.19mmol, and the reaction time was changed to 1 hour. Procedure was
performed in the same manner as Example of Execution 1. The result was
conversion ratio of 3-ethoxy-4-hydroxybenzaldehyde 99%, yield of
protocatechualdehyde 96%.
0015 Example of Execution 3
Same, except the amount of 96% by weight sulfuric acid was changed to
30.15mmol, and the reaction time was changed to 11 hours. Procedure was
performed in the same manner as Example of Execution 1. The result was
conversion ratio of 3-ethoxy-4-hydroxybenzaldehyde 91%, yield of
protocatechualdehyde 84%. Results of the Examples of Execution are shown
in Table 1.
0016
[Table 1]
+----------------------+---------------+---------------+---------------------+
|Example of Execution | Sulfuric Acid | Reaction Time | Protocatechualdehyde|
| | mmol | hr | yield % |
+----------------------+---------------+---------------+---------------------+
|Example of Execution 1| 60.20 | 2 | 91 |
+----------------------+---------------+---------------+---------------------+
|Example of Execution 2| 116.19 | 1 | 96 |
+----------------------+---------------+---------------+---------------------+
|Example of Execution 3| 30.15 | 11 | 84 |
+----------------------+---------------+---------------+---------------------+
[Edited on 28-9-2015 by zed]
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byko3y
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Thanks, zed, I can finally remember the difference between demethylation of ethylvanillin and a regular vanillin, and the difference is - you can
cleave any ether with sulfuric acid, except methyl. Well, you can try to cleave it, but in the end you will get a lot of charbon and small amount of
protocatechuic aldehyde. Here's the original discussion on hive Demethylation of Vanillin
I agree that bromination/hydroxylation might be a good way to prepare the 3,4-diHO-benzaldehyde, go ahead and try this procedure Simple and efficient CuI/PEG-400 system for hydroxylation of aryl halides with potassium hydroxide
or maybe this Iron-catalyzed conversion of unactivated aryl halides to phenols in water
[Edited on 28-9-2015 by byko3y]
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solo
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Reference Information
Simple and efficient CuI/PEG-400 system for hydroxylation of aryl halides with potassium hydroxide
Junmin Chen ⁎, Tangjun Yuan
Catalysis Communications
12 (2011) 1463–1465
Abstract
This work reports a simple and efficient CuI/PEG-400 system for hydroxylation of aryl halides with potassium hydroxide. This protocol offers a direct
transformation of aryl iodides or bromides to substituted phenols in great diversity. A very wide variety of functional groups are tolerated on aryl
halides partners such as carboxyl, aldehyde and hydroxyl group.
--------------------------------------------------------------------
Iron-catalyzed conversion of unactivated aryl halides to phenols in water
Yunlai Ren, Lin Cheng, Xinzhe Tian
Tetrahedron Letters
51 (2010) 43–45
Abstract
lthough iron is low-cost and environmentally friendly, there is no report about iron-catalyzed conver-sion of unactivated aryl halides to phenols. In
this Letter, a new method for the present conversion wasdeveloped with iron compounds as the catalyst and water as the solvent. The suggested method
alloweda series of unactivated aryl bromides and aryl iodides to be converted into the corresponding substituted phenols in moderate to high yields.
------------------------------------------------------------------------
Synthesis of Phenol, Aromatic Ether, and Benzofuran Derivatives by Copper-Catalyzed Hydroxylation of Aryl Halides
Dongbing Zhao, Ningjie Wu
Angew.Chem.Int.Ed.
2009 ,48, 8729 –8732
Attachment: phpVWtbQp (142kB)
This file has been downloaded 608 times
Attachment: Iron-catalyzed conversion of unactivated aryl halides to phenols in water.pdf (94kB)
This file has been downloaded 575 times
[Edited on 29-9-2015 by solo]
Attachment: Synthesis of Phenol, Aromatic Ether, and Benzofuran Derivatives by Copper-Catalyzed Hydroxylation of Aryl Halides.pdf (342kB)
This file has been downloaded 529 times
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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clearly_not_atara
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FeCl3/ethylenediamine in H2O sounds like a winner if you can get the latter. Unfortunately the synthesis of ethylenediamine is not easy.
CuI/L-proline in H2O/DMSO seems okay, too. Unfortunately it apparently doesn't work in other solvents (even H2O/DMF), but you might get away with
propylene carbonate. However, the scope of the reaction may actually be expanded with amino acids resp. phenanthroline:
http://pubs.rsc.org/en/content/articlelanding/2010/cc/c0cc00...
I would try CuI/proline in H2O with NaOH, based on this. TBAF may be unnecessary since the brominated intermediate is water soluble (unlike most
substrates tested in these papers). I'm not sure if Li+ is actually necessary for the latter reaction to proceed -- maybe LiF precipitates leaving
tetrabutylammonium pipecolinate? In any case, thanks to the likely solubility of the intermediate, PTC should be much less important.
[Edited on 29-9-2015 by clearly_not_atara]
[Edited on 29-9-2015 by clearly_not_atara]
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chemrox
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I'm thinking Shulgin might have done this conversion but I'll be damned if I can recall which PHiKAL entry was involved. He started from
protocatechualdehyde a few times..I'll try yo look it up in ACS and the Shulgin Index vol. 1. Think Clearly-not-.. is right about vanillin. They ethyl
group is too much trouble and cost to deal with.
[Edited on 30-9-2015 by chemrox]
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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