Current methods to convert mesitylene to
2,4,6-trimethylisophthatldelhyde involve at least two steps, one of
which is a halomethylation reaction. The goal is to come up with an
economical and relatively safe method for making
2,4,6-Trimethylisophthaldehyde.  Likely, it is best to start with
mesitylene, as it is very inexpensive in bulk, and then to convert it
directly to 2,4,6-Trimethylisophthaldehyde by a means supplied in the
answer to this question.  However, it is not a requirement to use
mesitylene as a precursor.  If an alternate precursor is to be used,
it should also be a relatively low cost material.  We just want a safe
and economical method to make this material. We would like to have
enough detail in the answer to be able to test out the synthesis step
in our laboratory.   There may already be a published method to do
this, and a published method would be just fine as an answer.
Processes which use halomethylation are not considered to be
acceptable answers. By economical, we mean that the cost of the bulk
chemicals needed should be less than about $10 or less to convert a
pound of mesitylene or similar precursor.  The cost of lab grade
chemicals to try this can be expensive, as we are only interested in
larger production costs.  By safe, we mean that we do not want to work
with materials that are extremely toxic or prone to uncontrollable
reactions.   If a one step reaction is not deemed as possible, two
simple, safe and straightforward steps would be considered as an
answer, but is not preferred.

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Clarification of Question by latexbuster-ga on 04 Dec 2005 13:49 PST

muham-ga

Thank you for your comments.  I would be happy to increase the reward,
but I think that $200 is the maxium that google answers will accept. 
We would be happy to pay more for a good solution to this.

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Clarification of Question by latexbuster-ga on 07 Dec 2005 14:50 PST

I wish to open up the criteria for an acceptable answer to one that
would explain a speculative synthesis route to this material which is
not constrained by my original submission requirement of one or two
steps. I do wish to keep the constaints that the process could be
commercially viable, relatively safe and cost effective (less than
about $30 per pound of material made). Muham-ga may wish to jump back
onto this question, but it is open for all.

Quick search shows that you can use metallation/DMF quench with
dibromomesitylene - this material is commercial but pretty expensive
(about 100x more than mesitylene). And you would need to work with
Grignard or butyllithium, low temperature + moisture-free, etc.

There is also one direct bis-formylation of mesitylene in the russian
literature (not a very good source of experimentals) that does it with
Cl2CHOMe and AlCl3. Very nasty reagents. 20% yield. Lots of
monoformylated product also forms.

There is also a workaround using sequence mesitylcarboxaldehyde ->
dichloromethyl mesitylene -> formylation -> hydrolysis. Not practical.

There are routes using either the bis-hydroxymethyl or
bis-chloromethyl mesytylene which you are trying to avoid.
 
So what you are looking at is a custom synthesis process development. 
I would recommend you to go after 2 alternatives: a) direct
bis-formylation (under very forcing conditions) of mesitylene

OR

b) di-bromination of mesitylene and then Br-metal exchange with a DMF quench.

Either way, it is not going to be cheap and easy to develop and it
will not be easy-to do chemistry (you will always have nasty reagents
and strictly anhydrous conditions. Possibly low-temp, air-free).

Innocentive.com has been offering prices for problems exactly like
this - the rewards were something like $20-40 000 for developing a
practical solution for a relatively short sequence similar to yours.
So increase your reward.

1)Dibromination of mesitylene, then Br-metal exchange+DMF quench is
the way I would use to make few grams of it in the lab. (Of course, I
would probably buy the dibromomesitylene to save the time and effort.)
If you allowed $300 per pound, we would have a realistic route with
published procedures but a route that would be hard to perform in a
big reactor.

2) Direct bis-formylation of mesitylene - if it can be done at all -
is going to be nasty (you would have to find the way how to separate
mixtures, etc.) but this is the only hope for making it cheap enoug.
In this case, you would not be able to avoid
toxic/carcinogenic/lacrymatory reagents - if this is why you are
trying to replace the chloromethylation route.

3)I have grave doubts about $30 per pound (of purified product) being
possible. What makes you to put down such price - apart from wishful
thinking?

If the carcinogenity is what is your main concern about the
bischloromethylation route, perhaps you should consider
bromomethylation instead - check out this paper, they do
paraformaldehyde and HBr in acetic acid. Great yield, easy workup
(drowning in water and filtering the product). They claim that
bisbromomethylether formation is not a problem:

J. Org. Chem. 1993, 58, 1262-1263

It is going to be incredibly corrosive and irritant/lachrymatory but
you won't need a strictl moisture exclusion or cooling. There should
be no big exotherm during workup. It could be cheap too, especialy if
you make your own anh. HBr in AcOH (or could buy it cheaply).

From bis-bromomethyl-mesitylene there is a one more easy step to the
dialdehyde. (with hexamethyltetramine+AcOH or sodium methoxide in
DMSO).

I think this looks pretty reasonable for scale up - but the materials
are still unpleasant so you would need good protective measures to
avoid peoples exposure to the bis(bromomethyl)mesitylene.

muham -ga, 

Thank you again.  The low price is that we need this as an industrial
intermediate chemical, which has much value to us, but clearly not the
value of a pharma product. We also need to eventually make it by the
metric ton.  We want to avoid carginogens and we wish to avoid runaway
reactions.  We have used bischloromesitylene before, as it is readily
available to us at very low cost.  This may change your thinking about
cost and safety for our problem.  Do you think your comments apply
just as well to the bischloromesitylene as to the bisbromomesitylene. 
We will look at the literature reference which you suggest.  It would
be nice to try to avoid some of these intermediate steps, if
possible,perhaps by directly carbonylating the mestitylene.  Any ideas
in this regards would be very much welcome.

The trouble with sirect bis-formylation is that the first aldehyde (or
aldiminium) group will desactivate the ring for the second step. You
may need to use drastic conditions to push it there and solve the
problem of removing the sideproducts and the intermediate
monoaldehyde.

You can try for yourself these metods, to see how messy you get, for
bis-formylating mesitylene:

1) Vilsmeyer formylation: PCl5 or oxalyl chloride added directly to a
solution of mesitylene in DMF (lots of cooling neessary, gas evolution
with oxalyl chloride), then gradual heating up to 90-100C, then pour
onto ice with some base (sodium hydroxide). See if you get the second
formyl in.

2) CO + HCl gas mixture bubbled into a mixture of AlCl3 + mesytylene,
with gradual heating. You would need at least 3-4 equivalents of AlCl3
(a good grade)

3) Cl2CHOCH3 + AlCl3 (or TiCl4), with mesitylene, with gradual heating.

You would most likely produce a nasty mess of products that you may
try to purify by re-crystallizing(the dialdehyde is a solid). In all
cases you would end-up with lots of salt waste-products.

If you can buy bis(chloromethyl)mesitylene cheaply on a big scale,
made by somebody else, than my suggestion is to go with it - you would
skip the unpleasant first step (where the carcinogenic
bis-chloromethyether can form from HCl and paraformaldehyde). You can
specify with the manufacturer that that the bischloromethyl mesitylene
will not contain this highly carcinogenic impurity. You see, sometimes
2 easy clean steps are much better than one dirty dangerous one.

muham-ga

Thanks a lot for the insight.  Yes, we can purchase the
bis(chloromethyl)mesitylene cheaply on a big scale, made by somebody
else.  In this case, you suggest that we use one more easy step to the
dialdehyde using hexamethyltetramine+AcOH or sodium methoxide in DMSO.
 Can you elaborate on this step as to reaction conditions, etc.  Is
there a published reference on this.  Also, I would be more than happy
to pay you for this as an answer,plus a the biggest tip I am allowed
to give,  if you are able to respond as an answerer.  These two clean
steps might be good for us.

OK, I think I have found a reasonable solution of your problem:

1) Mesitylene -> bis(bromomethyl)mesitylene (using paraformaldehyde +
HBr in acetic acid)

J. Org. Chem. 1993, 58, 1262-1263

2) Bis(bromomethyl)mesitylene -> mesitylene bis-carboxaldehyde (using
2-nitropropane and sodium ethoxide or methoxide in ethanol at room
temperature)

a) Organic Syntheses, Coll. Vol. 4, p. 932 (= Vol. 30, p 99)  (get a
free download at www.orgsyn.org)
b) Alexander D., Holy P., Zavada J. et al: Collection of Czechoslovak
Chemical Communications, 61, 10 (1996), 1464-1472
http://cccc.uochb.cas.cz/Vol/61/obs9610.html (pay for download)

This is a rather uncommon oxidation method but I think it is the only
one that will work well in your case ? please look up the above Czech
journal - they claim that they were able to oxidize
tris(bromomethyl)mesitylene into mesitylene tris-carboxaldehyde in 61%
yield using very mild conditions. It is a pure coincidence ? I
happened to work in this particular lab and know that these guys are
solid.

It is not certain that this method will work for bis(chloromethyl)
mesitylene ? but you can try to add some KI (or NaI) as a catalyst or
to raise the reaction temperature. You should make and try
bis(bromomethyl)mesitylene first, because that one is supposed to work
well ? so that you can see how suitable the oxidation method actualy
is in your setting. If yes, you can then experiment with the
bis(chloromethyl)mesitylene. (It is much preferable to buy this stuff
rather than doing the bromomethylation by yourselves.)

Also, I have been proposing to try Sommelet oxidation of
bis(chloromethyl)mesitylene with hexamethylenetetramine:

Organic Syntheses, Coll. Vol. 4, p.690 (= Vol. 30, p.67) (www.orgsyn.org)

This is a typical industrial method in similar cases - but it turns
out that the method does not work at all with
bis(chloromethyl)mesitylene, probably because it likes to have at
least one unsubstituted position ortho to chloromethyl in the
substrate (and yours is too hindered).

J. Am. Chem. Soc. 72 (1950), 2992-3
Here is a review: Angyal S.J.: Organic Reactions 8 (1954) 197-217. 

Finally, heating bis-(bromomethyl)-mesitylene in dry DMSO to 100-150C
in presence of a mild base (typically used: NaHCO3 or 2,6-lutidine or
2,4,6-collidine) should give you the bis-aldehyde also.:

J. Am. Chem. Soc. 79 (1957) 6562
J. Org. Chem. 24 (1959) 1792-3
J. Am. Chem. Soc. 81 (1959) 4113-4
J. Org. Chem. 51 (1986) 1088-1094

But the DMSO oxidation is the last resort ? you would generate huge
amounts of incredibly smelly volatile sulfurous side-products - so you
would need bleach-filled gas scrubbers (few days ago some guy was
doing a Swern oxidation on gram scale in our lab ? and the stink could
make airplanes fall from the sky).

There are additional methods that should work but they use
stoechiometric amount of silver, selenium or Cr(VI) so I guess they
are out of consideration in your case.

Best luck and let me know how it went:  tvojkovsky at deletethis.gmail.andthis.com