I'm looking for a plausible synthesis for 2,5 (alkyl)phenol.  Having
trouble with a question in an organic chemistry textbook I'm studying.
 hydoxyl groups appear to be ortho-para directing, so the first
addition would result in an even mix of ortho and para alkyl phenol,
and the second addition would result in a mix of ortho-para and the
desired ortho-ortho product, with yeild of the ortho-ortho form being
very low.  I'm looking for a synthesis that results mostly in the
formation of the ortho-ortho form.  Consider other initial reactants
than phenol, and the addition of other groups besides alkyl as
reaction intermediates.  The question hints that the sequence of
reactants is important.  I'm not sure I'm using the proper
nomenclature for the location, so to clarify, I wish a phenol molecule
with two alkyl groups, one on either side of the hydroxyl on the
benzene ring.  It shouldn't be neccesary to provide details of the
specific reactions neccesary to attach the alkyl or other groups, but
names of the reactions would be helpful, as in "attach the alkyl group
by freidel-krafts alkylation", or "chlorinate with FeCl3 and Cl2".

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Clarification of Question by khordas-ga on 25 Jun 2002 20:49 PDT

Apparently I miscounted.  the designation WOULD be 2,6 (alkyl)phenol. 
Lots of good comments so far.  I'm still going to give a researcher a
chance to earn some money.  Websites that explain the WHY as well as
the sequence would be helpful, as I'm struggling to learn.  In this
case, I picked up a textbook for the first time in two decades.  it
made sense to me once..............

Khordas

Ok, I will give it a shot, if you are not happy then feel free to
resubmit. I am not an organic chemistry major and in fact have not
done any chemistry since, well a long time ago. I am not really sure
what you are trying to make but with the help of our ever favorite
Google search engine I came up with a few sites that might answer your
question or at least point you in the right direction.


This page is called the Index for Organic Chemistry Online and it
includes practice questions:
http://www.cem.msu.edu/~reusch/OrgPage/VirtualText/intro1b.htm


Dr. David Woodcock at the Okanagan University College has this page
with a lot of good stuff:
http://people.ouc.bc.ca/woodcock/molecule/molecule.html


Then there is 11th hour Organic Chemistry I&II:
http://www.blackwellscience.com/11thhour/book6/oc2ch3.html


Again I am not entirely sure of what exactly you are looking for but
these at least looked like a good place to start. By using complex
search terms, sometimes you can tease out a website with just exactly
what you want. In this case the terms I used were:

organic chemistry phenols
Organic Chemistry 2,6 (alkyl)phenol

Approx. 2800 hits so I am sure that one of those will get you what you
need.

thanks for the prompt answer.  Sorry it took so long to get a rating
posted.  The sites you posted for me have been helpful, and while I
haven't been able to work out a definitive synthesis, I'm closer.

Forty-year-rusty organic chemistry....Could you start with meta
xylene?? creating the phenol from it?? Sulfonate the meta xylene then
use alkali fusion rather than trying to alkylalate the phenol??

seedy

Hello
 I think the product you are looking for is 2,6-di alkyl phenol.A well
known product from this group is
2,6-ditertiary butyl phenol .These type of products are usually
synthesised from phenol and C4
(isobutylene).The catalyst used is Sulfuric acid or some other acid
catalyst.The alkylated phenols
find use as resin intermediates and antioxidants for polymers.You
could look up the process details
in Foerst's volumes or Olah's books on Friedel Craft's synthesis.The
reactions are not very difficult to conduct
Best Luck

Hi There,

An interesting alternative synthetic strategy for 2,6-dialkyphenols
would be to use a directed ortho metallation strategy.  Whilst phenol
is a general ortho/para director for electrophillic substitution,
O-alkylphenols (in particular O-methyl) are excellent substrates for
ortho metallation/electophile quench.  Thus treatment of phenol with
NaH then MeI will give methyl phenyl ether (anisole);  treatment of
this with a strong base at low temp. (e.g. tert-butyl lithium at -78
C) followed by an electrophile quench (e.g. MeI EtI D2O etc.)  will
give an ortho substituted anisole.  Subsequent re-treatment of this
with strong base and an electrophile would then give a
2,6-disubstituted anisole (steric considerations aside).  The O-methyl
group could then be cleaved with an acid (e.g. boron tribromide) to
give the 2,6-disubstituted phenol.

Given that the question hints at the sequence that the reactants are
used in, you could accomplish the synthesis of 2,6-dimethylphenol
using only phenol, methyl iodide and a stong base - all in the correct
order of course.

That said, you would only really consider this route for asymmetric
disubstituted phenols.

Have fun.

Although I have not been able to find a specific reaction mechanism to
create a significant quantity of 2,6 alkyl phenol, I have found a
significant supplier of 2,6 xylenol which I have suggested as a
possible precurser to your final product.  You may wish to contact
their research department to determine if anyone there can assist you
in turning the 2,6 xylenol into a phenol.

From Chemical Week, 11/1/2000, Vol. 162 Issue 41, p39, 1/2p

" Schenectady's O-Cresol

Schenectady International (Schenectady, NY) will bring onstream 20,000
m.t./year of ortho-cresol and 2,6-xylenol capacity at its Freeport, TX
site late next year. A debottlenecking of the methylation unit at the
site will make possible the o-cresol and 2,6-xylenol production that
will supply Schenectady's requirements and growing external market
demand. O-cresol is used in solvents, disinfectants, and cleaners. "

They do make a meta alkyl phenol    2,6 DI-tert-BUTYLPHENOL

Hope this information helps in your quest.

seedy

Sorry, I left off the URL for Schenectady International

   http://www.siigroup.com/products/ProductLine.asp?LineID=8

seedy

If you are trying to make 2,6 dialkyl phenol you are looking to make,
here is how I would go about doing it (of course this implies that
your alkyl groups are the same in both positions):

Since the hydroxyl group is ortho/para directing, and phenol is cheap,
add a meta directing blocking group such as NO2 to the para position. 
Depending on possible shifts in your alkyl group use either a
friedel-crafts alkylation or acylation (followed by either the
clemmenson or wolff-kischner reduction for the acylation), then reduce
off the NO2 first with SnCl2 to turn it into the amine and then
removal  via a diazonium salt (treatment with nitrous acid at low
temperatures, then clavage with aqueous phosphoric acid).

Sure it's not elegant, but short of construction of an aromatic ring
using lots of nasty reagents it's probably the easiest way to go about
doing it.

Enjoy

Thanks to jlchem-ga.  That was the step by step sort of process I was
looking for.  It looks like it should work, and it follows the form of
lots of earlier answers to similar questions in the text.  Should have
been able to work that out for myself....  I DID consider the nitrate,
but in my notes, it looks like I wrote down an incorrect set of
directing proporties for it.  Thanks again.

Khordas

One thing to add - you should be able to separate the ortho/para
isomers after you nitrate the ring by distillation - the ortho will
distill off first.  Isolate the para-nitrophenol (and keep in mind it
is related to picric acid so may be explosive) and go to town.

Enjoy.

Sorry, one more forgotten thing - be sure when nitrating the ring to
use a stoichiometric amount of nitric acid so you *don't* make
trinitrophenol (picric acid)!

I would expect that mononitration of phenol would result mostly in
mononitrophenol, a scant amount of dinitrophenol, and a very small
amount of picric acid.  My texts suggest that phenol is very easy to
nitrate, so this is a plausable step.  It DOES look like mononitration
of phenol would lead to a mixture of ortho and para nitrated phenol,
of which only the para isomer is of use for the final product.  Like
you said, not neccesarily the elegant way, but it sounds like it
should work.  I'd expect to see melting point differences in the
isomers, so the separation should be pretty straightforward if I ever
try the reactions.  (should go back and take a few college courses
over.  wonder if the local uni would let an old grad do an independent
study in organic synthesis)

Khordas

I recently had to separate similar ortho and para isomers, and a good
rule of thumb is that the ortho isomers will distill off long before
the para isomers because the  hydrogen bonding in ortho isomers is
intramolecular, whereas in para isomers it is intermolecular.  Since
the ortho isomers are not sticking to each other as strongly as the
para isomers they will distill first.

Enjoy

Also, you are correct: the nitro group is electron withdrawing from
the ring, so the addition of multiple nitro groups is less favored. 
What I meant was to not use a massive excess of nitric acid, so you
make it even less favored.