Ozonelabs
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Vilsmeier–Haack reaction
Hiya,
Considering the recent posts regarding the preparation of 2,5-Dimethoxybenzaldehyde, we considered perfoming a Vilsmeier–Haack formylation on
1,4-Diethoxybenzene.
The reagent was prepared with POCl3 and DMF in an ice bath, it was then dripped over the course of 90 minutes into a solution of 0.35 Moles
p-Diethoxybenzene in 75ml. DMF at 115 C. It was then allowed to react for 2 hours. Bubbling was observed however no HCl gas was observed.
The flask was then taken off the heat and allowed to cool, afterwhich a large mass of crystals formed. The contents were crashed into mildly basic
water and vacuum filtered. However, once a melting point check was made on the final product it was the same as the starting compound (Analytical
sample from EtOH- 69 C, as opposed to lit. 59-63 C.) (Checked on Stuart SMP3 melting point apparatus).
We are a little stumped as to why this is the case and would very much appreciate any input.
The following are pictures from the reaction-
Pictures of the chemicals
Preparation of the Vilsmeier complex
Addition of the Vilsmeier complex
Final crystal yield
Thanks for any and all help.
Regards,
The Ozonelabs Team
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chemrox
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You say bubbling but no HCl gas formed. What gas was it then? Did you catch an odor you could characterize?
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Ozonelabs
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At the time we tested the top of the air condenser with damp pH paper and it remained neutral. This led us to believe that the bubbling could well
have been boiling, perhaps of the Phosphoryl chloride (106 C). There was no discernable odour.
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behemoth
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Vilsmeyer on 1,4-dimethoxybenzene doesn't work (I remember a post somewhere saying he got a 14% yield). I don't think it's gonna work for
diethoxybenzene either. Try a different route.
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Barium
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Try to generate the bisufite adduct to see if you have a carbonyl group present at all.
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chemrox
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I'm puzzled. I would think dialkoxy would make for an electron rich environment all around the ring. Maybe that's the problem. The activation is
unfocused so to speak. With one MeO you'd get 34% para and 4% ortho. With dimethoxy maybe there's a slightly more active ring but no activated
sites.
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solo
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Related Reference of the type .......
The vilsmeier-haack formylation of 1,2,3-trimethylindole
Carlo Bastianelli, Antonio Cipiciani, Sergio Clementi, Gianfranco Giulietti
Journal of Heterocyclic Chemistry Volume 18 Issue 6, Pages 1275 - 1276, 2009
Attachment: The vilsmeier-haack formylation of 1,2,3 trimethylindole.pdf (196kB)
This file has been downloaded 1333 times
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entropy51
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Ozonelabs, I'm not sure that pictures of reagent bottles and ordinary glassware add that much to your presentation. They aren't found in journal
articles. And they seem to cause the text to run off the window in my browser. Maybe smaller images would not be so distracting from your nice
writeups.
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chemrox
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Thanks you Solo; I requested this one in refs.
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behemoth
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Quote: Originally posted by chemrox  | | I'm puzzled. I would think dialkoxy would make for an electron rich environment all around the ring. Maybe that's the problem. The activation is
unfocused so to speak. With one MeO you'd get 34% para and 4% ortho. With dimethoxy maybe there's a slightly more active ring but no activated
sites. |
If the methoxy groups are 1,2 or 1,3, the Vilsmeyer gives good results. The 1,4 for some reason wouldnt react.
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smuv
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The issue is sterics. The ethoxyhomologue is even more hindered than the methoxy.
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chemrox
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That must be it. I looked up some dimethoxyphenyl V-H reax and found some that worked. Would a Gatterman work in these conditions for the required
product?
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Klute
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I like the pictures of the reagents. It's always interesting for thoses that don't have acces to most chemicals. Always appreciate a little chemporn
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Ozonelabs
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Steric Hindrance was the first thing that came to mind, and also the fact that none of the ring sites are 'active' as such, at least, one is no more
susceptible to attack than another.
It would appear as though an alternate synthesis is necessary- such as a Gatterman formylation on 4-alkoxyphenol followed by alkylation- more on this
soon.
Is there an interest in the preparation of 2,5-Dimethoxybenzaldehyde? If so, we can make it a priority.
Regards,
The Ozonelabs Team
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Nicodem
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| Quote: Originally posted by Ozonelabs | | Steric Hindrance was the first thing that came to mind, and also the fact that none of the ring sites are 'active' as such, at least, one is no more
susceptible to attack than another. |
The sterics play a role, but it mostly about electronic effects. The deactivating -I inductive effect acts on all positions from both MeO groups, but
the activating +M mesomeric effect only acts from each MeO group toward its ortho positions, but not also on its meta positions.
This is apparently why 1,4-dimethoxybenzene is less reactive than anisole in aromatic electrophilic substitutions.
| Quote: | | It would appear as though an alternate synthesis is necessary- such as a Gatterman formylation on 4-alkoxyphenol followed by alkylation- more on this
soon. |
It is known that 1,4-dimethoxybenzene can not be formylated with DMF/POCl3 (there were experiments reported at The Hive forum confirming this is the
case). The formylation of this substrate with N-methylformanilide/POCl3 gives a 16% yield (see JACS (1952) 5546). Therefore, I would
expect the same results with 1,4-diethoxybenzene as well, and your result confirms this.
1,4-Diethoxybenzene can be formylated using the modified Duff formylation in CH3COOH/CF3COOH (9:3) but the yield was only 34% (see ARKIVOC (2000) 240-251 discussed also in this thread). Maybe the authors did not optimize the reaction conditions for this substrate and by prolonging the reaction time one would get
better yields. If you have no trifluoroacetic acid you can consider the modification using CH3COOH/H2SO4 developed by our member Ullmann.
| Quote: | | Is there an interest in the preparation of 2,5-Dimethoxybenzaldehyde? If so, we can make it a priority. |
Judging from the posts from this and other forums most people simply acquire it given that it is commercially available. However, buying it is not as
rewarding as preparing it. As far as I know there is little one step or one-pot alternatives for preparing 2,5-dimethoxybenzaldehyde from
1,4-dimethoxybenzene. The simplest is direct lithiation with n-BuLi followed by addition of DMF, but BuLi is not something just any amateur
has access to. Therefore, I would say there is no overly strong interest but there is some. But more importantly, it would be a nice contribution from
the organic synthesis viewpoint.
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Klute
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I would rather do a Mg-mediated formylation on 4-ethoxyphenol followed by alkylation of the phenol than a Gatterman.. Yields are ovcer 80%, several
members have tried out the procedure and found it too work, and the conditions are much less drastic than a Gatterman.. I would keep the gatterman
for more delicate formylation where the Mg-mediated formylation can't be employed, when there no free phenol for example.
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donlaszlow
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Make sure,that the DMF is water free, distill with adding pure benzene to it before use (water and benzene will be the first to distill). Use the
fresh DMF as soon as possible, and don't allow it to acquire any moisture whatsoever.
Wait until the Vilsmayer agent becomes paste-like (it's harder to stir) and has a red or pink color. And keep it cool as possible, use ice and salt
(NaCl). After that add the p-diethoxybenzene slowly. After you added the whole quantity necessary remove the ice, and continue as before. And use as
little solvent as possible.
The method mentioned above, with BuLi gives the highest yields, but this can be pretty good too, if you don't have any BuLi.
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Nicodem
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Do you care to provide a reference or experimental details that confirm 1,4-diethoxybenzene can be formylated with Vilsmeier–Haack using DMF/POCl3?
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flyingbanana
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There definitely is something fishy about the 1,4 position.
Two attempts were made at this reaction using 4-methoxyphenol, which should supposedly be more activated, but only starting material could be
recovered.
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devongrrl
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If 2,5 dimethoxy benzaldehyde was your target molecule, could you not do a Riemer Tiemann formylation using 4-MeO phenol and get
2-hydroxy-5-methoxybenzaldehyde and then go from there ?
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DJF90
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I dont like it when people start talking about substituted benzaldehydes, especially 2,5-dimethoxy and other closely related isomers... but Riemer
Tiemann reaction is pretty shit tbh, Klutes work on magnesium mediated ortho formylation on the same substrate you suggest would be much more
appropriate and high yeilding I suspect...
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flyingbanana
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I'm aware of alternate preparations of substituted benzaldehydes, I was only hoping to further the discussion on sterics vs. electronics of the topic
reaction.
Judging from the mechanism of the Vilsmeier, I don't see why the reaction shouldn't go better than 1,4-dimethoxybenzene. I won't be looking further
into this for various reasons, but the results are what they are.
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flyingbanana
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I'd just like to retract my previous statement on Vilsmeier failing for 4-methoxyphenol. Turns out my POCl3 was bad/old. I haven't had time to repeat
the experiment with the good POCl3, but I believe it would work. Apologies-
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elifyldz
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hi,
I will synthesize 4-formyl-3-phenylsydnone according to this procedure .
http://rapidshare.com/files/3218933014/formylsydnone%20schmd...
I used freshly distilled dmf and phosphoryl chloride but precipitate doesn't occur.
the amount of dmf wasn't writted. I used 50 ml, 20 ml, 2 ml of dmf. however, the precipitate doesn't occur. What is the wrong? please help me 
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