PainKilla
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Questions about various substitution reactions
I am trying to synthesize a compound with the general formula of Ar1-X-Ar2, but am unsure of which of these reactions will actually work to achieve
this goal. X can be O or N, and Ar2 is a plain aromatic ring.
I would be starting from:
From here to get to the target compound, I can go directly through diazotization (if possible), or “phenylate” the amine (if possible), or to a
halide/phenol and then perform the appropriate Williamson ether synthesis, or Ullmann reaction. My questions are thus as follows:
1) Diazotization is a reaction that I know the general mechanism and such for, but none of the books I have, or literature I’ve found, addresses the
issue of whether or not phenols/phenolates can be directly used in the substitution of the diazo salts.
IE, (R-N2Cl + H/K-OC6H5 --> R-O-Ph.)
a. What are the conditions of diazo substitution needed to introduce nucleophiles other than the “standard” Sandmeyer nucleophiles?
i. If this is possible, as far as performing the reaction directly, would isolating the diazo (danger?!) salt and performing reaction in an
appropriate solvent be a suitable method? (The ethyl ester of the starting compound would likely have to used for this)
2. Using diazo substitution to form the phenol/halide, and then doing the corresponding ether synthesis:
a. I would picture the 3-iodobenzoic acid (would be the better halide, since phenol would be a less sterically hindered nucleophile…
i. How much of a role would steric effects play in this substitution?
ii. How does one gauge relatively acidity/basicity based on the substituents on an aromatic ring?
3. “Phenylating” the amine, using iodobenzene or something along those lines. I am unsure of this entire reaction, so I have no questions other
than is this at all possible?
4. Ullmann reaction, for which I have pretty much the same questions as for the ether synthesis.
[Edited on 26-9-2007 by PainKilla]
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Nicodem
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| Quote: | Originally posted by PainKilla
From here to get to the target compound, I can go directly through diazotization (if possible), |
Aryl diazonium salts couple with phenols on the ortho/para ring positions to give diazo compounds. See the many examples for the synthesis of various
diazo dyes. Therefore, phenols can not be used as nuclephiles in the Sandmeyer reaction. Equally goes for alcohols which get oxidized by diazo salts
rather than O-arylated. This has to do with the mechanism of the Sandmeyer, which is said to be SN1 for nucleophiles that can not form stabile enough
radical intermediates trough Cu catalyzed SET mechanisms (like fluorides, hydroxides and alkoxydes).
| Quote: | | or “phenylate” the amine (if possible), |
This is an Ullman/Goldberg type of reaction, so the last answer in my reply is applicable.
| Quote: | | or to a halide/phenol and then perform the appropriate Williamson ether synthesis, |
You can not use the Williamson ether synthesis on aryl halides or other halides on sp2 carbons. "Normal" nucleophilic substitution on aromatic halides
only work where the addition/elimination mechanism is made possible. This happens if you have at least one NO2, CN, COOMe or other such –M groups on
the positions para or ortho to the halide (or a halide on positions 2 or 4 in pyridines and such). This is not the case with your substrate.
| Quote: | | or Ullmann reaction. |
The Ullman or Goldberg reaction (depends on how you see it) requires you to have a Cu coordinating site ortho to the halide. This is generally a -COOH
or -OH group, but several others can work more or less well. The EtO group in your case is not a particularly useful coordination site. In the absence
of the coordination site, you need to have a ligand for Cu present in catalytic amounts. There are numerous publications on using all kinds of
ligands, mainly amino acids like proline and such. Sometimes it works just as well if the solvent or the nucleophile is able to coordinate with Cu,
but only bidentate ligands work well, which however is not the case with your phenol.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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PainKilla
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Thanks for your help.
It seems then that the only route(s) I have left to consider is the Ullmann then, assuming I can find a somewhat relevant procedure.
I did stumble across this journal however, which seems like it could make the diaryl synthesis via phenol/halide viable. If it works.
Microwave-Assisted Synthesis of Diaryl Ethers without Catalyst
ORGANIC LETTERS (2003) Vol. 5, No. 12 2169-2171
Attachment: Microwave-Assisted Synthesis of Diaryl Ethers Without Catalysts.pdf (60kB)
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Nicodem
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That is unfortunately a nucleophilic aromatic substitution (addition followed by elimination) which is not applicable to your substrate. I don't know
why they mention "without catalyst" when this reaction never requires catalysts, probably just to get it published in Organic letters, just like the
obsolete premiss of using the MW which where the latest fad in that period.
You should try the Ullmann/Goldberg reaction in DMF or NMP, with K2CO3 as a base, 10mol% CuI catalyst and 10mol% of a ligand (proline, glycine, etc.).
Run the reaction at 150°C and follow with TLC (remember to add 1% AcOH in the mobile phase since your reagent and product are carboxylic acids and
will not move otherwise). If you get no new spots after 1h, try NMP as solvent and heat to 200°C. This should get it going. You can also try without
a ligand for Cu as chances are that it will work as well with NMP or DMF as solvents.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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