[NickDC]

Does anyone have any clue how 2-methyl-3-nitrophenol could possibly be synthesized?

Often when you attempt to purchase this chemical, you get nitrocresol instead, which is 2-hydroxy-6-nitrotoluene and very similar, but the methyl and nitro groups are in the wrong positions. In fact, when you look up 2-methyl-3-nitrophenol they say a synonym for it is 2-hydroxy-6-nitrotoluene (nitrocresol).

Here is what 2-methyl-nitrophenol looks like:

        OH
         | CH3
        /\/
       |  |
        \/\
            NO2

And here is what phenol looks like:

        OH
         |
        /\
       |  |
        \/

Just a benzene ring with a hydroxyl group.

So it seems like all you would need to do is add the methyl group and nitro group by some method. But to get them at just the right spot is tricky I'm guessing. They need to be at the 2 and 3 positions.


Then there is nitrotoluene which looks like this:

         
            CH3
        /\/
       |  |
        \/\
            NO2
       
It's only missing the hydroxyl group, but attaching the hydroxyl group at that position is nearly impossible I think.


This chemical, 2-methyl-3-nitrophenol is used as the building block for making tryptamines like seritonin, melotonin, DMT, psilocin, 4-AcO-DMT, LSD, and many new designer drugs, etc. But also is used to make many other indoles besides tryptamines.

I have no intention to make any illegal drugs; I'm simply unwilling to pay $60 to $70 for a single gram of 2-methyl-3-nitrophenol.

I'm convinced it can be made from phenol which is found in "soar throat" spray bottles because its a local anesthetic. I know when purified, phenol is an extremely corrosive and harsh chemical to work with, but it's readily available and very cheap. Phenol could even be made from benzene, and benzene itself can be made from scratch.

That gives me an idea: Whatever process is used to convert benzene to phenol by adding that hydoxyl group might be usable on nitrotoluene to convert it to 2-methyl-3-nitrophenol.

[nj_bartel]

Honestly, that looks pretty sticky to make.  I can't think of anything where your desired would be the major product.

[azmanam]

In fact, when you look up 2-methyl-3-nitrophenol they say a synonym for it is 2-hydroxy-6-nitrotoluene (nitrocresol).

That's because they're the same compound.  Just numbered differently.

[Fridushka]

Well i know few..but i would like to help..
from phenol i don't think that you will get what you want..
if you start with toluene, you can make o-cresol since OH is ortho or para director, where here our interst lies on ortho..after this you have to add NO₂ which is meta director..
well to get o-cresol don't remember the mechanism..but to add the NO₂ you have to add HNO₃ in the presence of H₂SO₄
but there is another problem which i have forgotten, which one will be the leader, i mean which of OH or CH₃, will decide the position of the NO₂? Maybe there was such a rule and maybe not ...i don't remember..sorry..
hope it helps..

[nj_bartel]

They hydroxyl is the stronger activator and thus the primary director.  However, due to sterics, you're going to get primarily para substitution.  To get the cresol from toluene, you'd need to sandmeyer.  Here, you're also likely to get mostly para substitution.

[sjb]

How about (depending on where you want to start) benzene  toluene  o-nitrotoluene  2,6-dinitrotoluene, then reduce with Na₂S₂ (which I think will chemoselectively give you an nitroaniline, then Sandemeyer and water work-up.

Of course, there are still regioselectivity issues here, but I think you can also go ArNH₂  ArH via H₃PO₂, so you can potentially recycle a bit that way...

[NickDC]

Thanks for all the feedback people! I see a couple good ideas on where to start with this synthesis.

I guess the best method, and seemingly only logical method, would be to start with toluene because its a popular solvent, and its also needed later in the process when building the indole/tryptamine molecules.

I think I can manage to find a synthesis of 2-hydroxy-6-nitrotoluene but I doubt it's actually the same exact thing as 2-methyl-3-nitrophenol because it's actually missing the methyl group. Here is what some websites which sell the chemical show as 2-hydroxy-6-nitrotoluene:


        NO2
   OH  |
      \ /\
       |  |
        \/\


As you can see, there is nothing attached where the methyl group would be, and also all 3 groups (hydroxy, nitro, methyl) are in the wrong positions.

It's crucial they be in this position:

       OH
         | CH3
        /\/
       |  |
        \/\
            NO2


And all attempts at finding a synthesis for this chemical have been futile. It could in fact be a trade secret which only a few chemical companies know how to make, or it could be a chemical formed by the cracking of coal or petroleum products.

Messing with the nitration of toluene can be a dangerous thing as Wikipedia warns: "It undergoes nitration to give ortho and para nitrotoluene isomers, but if heated it can give dinitrotoluene and ultimately the explosive trinitrotoluene (TNT)."

But its now obvious this is the only route and my hypothesis that it could be produced from phenol was but the fevered dream of a mad man.

It would be so much easier to just purchase 2-methyl-3-nitrotoluene but like I said, the price is outrageous, especially since there will be considerable loss of this starting chemical during the development stage of my research. Until I'm successful at making the complex chemicals I want from this starting chemical, most of it will be lost as the synthesis continuously goes wrong. It's simply too expensive to experiment with a chemical that costs $70 per gram.

[NickDC]

How about (depending on where you want to start) benzene  toluene  o-nitrotoluene  2,6-dinitrotoluene, then reduce with Na₂S₂ (which I think will chemoselectively give you an nitroaniline, then Sandemeyer and water work-up.

Let me see if  I'm understanding the logic here. If you converted nitrotoluene to 2,6 dinitrotoluene you get this:

       CH3
 NO2  |  NO2
       \/\/
       |  |
        \/
         
Then I'm guessing by reduction with Sodium Sulfide (Na2S2) you would be able to replace the nitro group in the 6 position with NH2? But wouldn't it also rip off the methyl? And this would be a sort of nitroanaline looking like this?
 
       CH3?       
 NH2   |  NO2
       \/\/
       |  |
        \/


Then a Sandmeyer reaction using water instead of copper salts, you would be able to replace the NH2 with a hydroxyl group and have this:

 
       CH3       
   OH  |  NO2
       \/\/
       |  |
        \/

Which is hopefully the equivalent of this:

       OH       
         |  CH3
        /\/
       |  |
        \/\
           NO2

2-methyl-3-nitrophenol



Correct? I know the Sandmeyer reaction is used to produce phenols when water is used in place of copper salts for the reaction. So in this case, we would be adding the hydroxy group to the nitroanaline.

[nj_bartel]

I think you generally reduce aromatic nitro groups with an acidified reducing metal, like tin in dilute HCl, or some such.  Wiki actually says iron in refluxing acetic acid.  You might have some complications given that you have two nitro groups.  However, using one molar equiv of reducing agent, you might get fair yield.  Intuitively, it seems like it would pretty selectively tend to reduce one nitro group per compound, as the electron density would increase around the other nitro group following the first reduction.

And yes, those last two compounds are the same.  The variance in your chemistry knowledge confuses me

What's your desired final product, out of curiosity?

[sjb]

Thanks for all the feedback people! I see a couple good ideas on where to start with this synthesis.

I guess the best method, and seemingly only logical method, would be to start with toluene because its a popular solvent, and its also needed later in the process when building the indole/tryptamine molecules.

I think I can manage to find a synthesis of 2-hydroxy-6-nitrotoluene but I doubt it's actually the same exact thing as 2-methyl-3-nitrophenol because it's actually missing the methyl group. Here is what some websites which sell the chemical show as 2-hydroxy-6-nitrotoluene:


        NO2
   OH  |
      \ /\
       |  |
        \/\

Are you sure you're looking at the right images - can you show us some links where this is described as 2-hydroxy-6-nitrotoluene?

As you can see, there is nothing attached where the methyl group would be, and also all 3 groups (hydroxy, nitro, methyl) are in the wrong positions.

It's crucial they be in this position:

       OH
         | CH3
        /\/
       |  |
        \/\
            NO2


And all attempts at finding a synthesis for this chemical have been futile. It could in fact be a trade secret which only a few chemical companies know how to make, or it could be a chemical formed by the cracking of coal or petroleum products.

Messing with the nitration of toluene can be a dangerous thing as Wikipedia warns: "It undergoes nitration to give ortho and para nitrotoluene isomers, but if heated it can give dinitrotoluene and ultimately the explosive trinitrotoluene (TNT)."

But its now obvious this is the only route and my hypothesis that it could be produced from phenol was but the fevered dream of a mad man.

It would be so much easier to just purchase 2-methyl-3-nitrotoluene but like I said, the price is outrageous, especially since there will be considerable loss of this starting chemical during the development stage of my research. Until I'm successful at making the complex chemicals I want from this starting chemical, most of it will be lost as the synthesis continuously goes wrong. It's simply too expensive to experiment with a chemical that costs $70 per gram.

2-methyl-3-nitrotoluene would potentially be even worse, as I see no real way to convert a methyl to a OH that cleanly, let alone with the regio and chemoselectivity this would need.

How about (depending on where you want to start) benzene  toluene  o-nitrotoluene  2,6-dinitrotoluene, then reduce with Na₂S₂ (which I think will chemoselectively give you an nitroaniline, then Sandemeyer and water work-up.

Let me see if  I'm understanding the logic here. If you converted nitrotoluene to 2,6 dinitrotoluene you get this:

       CH3
 NO2  |  NO2
       \/\/
       |  |
        \/
         
Then I'm guessing by reduction with Sodium Sulfide (Na2S2) you would be able to replace the nitro group in the 6 position with NH2? But wouldn't it also rip off the methyl? And this would be a sort of nitroanaline looking like this?

Or in the 2-position, but that's the same beast, due to the symmetry. I don't think that will affect the methyl, but don't know for sure.

Then a Sandmeyer reaction using water instead of copper salts, you would be able to replace the NH2 with a hydroxyl group and have this:

 
       CH3       
   OH  |  NO2
       \/\/
       |  |
        \/

Which is hopefully the equivalent of this:

       OH       
         |  CH3
        /\/
       |  |
        \/\
           NO2

2-methyl-3-nitrophenol

Yes, it's the same, just move your benzene ring 60 degrees to the right. You do know that the double bonds in benzene aren't really localised, a la Kekule, don't you?

Correct? I know the Sandmeyer reaction is used to produce phenols when water is used in place of copper salts for the reaction. So in this case, we would be adding the hydroxy group to the nitroanaline.

Well, replacing the amine with OH, but yes.

I think you generally reduce aromatic nitro groups with an acidified reducing metal, like tin in dilute HCl, or some such.  Wiki actually says iron in refluxing acetic acid.  You might have some complications given that you have two nitro groups.  However, using one molar equiv of reducing agent, you might get fair yield.  Intuitively, it seems like it would pretty selectively tend to reduce one nitro group per compound, as the electron density would increase around the other nitro group following the first reduction.

Sure, I have reduced mononitro compounds down to the aniline this way, but never a dinitrocompound. Perhaps see http://books.google.co.uk/books?id=x77djyQHX8UC&pg=PR11&lpg=PR11&dq=m-nitroaniline+synthesis+from+dinitro&source=bl&ots=WJ7h3R4m4O&sig=36DfxXi65_7JCGvDuJlS8XZ5q2g&hl=en&ei=J3iqSri0At_TjAfNwIzhBw&sa=X&oi=book_result&ct=result&resnum=8#v=onepage&q=&f=false - p657 (or http://preview.tinyurl.com/dinitro  , if you prefer, and this wraps)


S

[NickDC]

The reason my chemistry knowledge varies so much, and I seem like I really know what I’m talking about with some things, and then will have questions about other extremely basic things is because I’ve never taken a single chemistry class. I taught myself everything I know. I’m not even fortunate enough to have any friends who know about chemistry, so I learn everything from people like you guys on forums.

I’m really quite impressed with how much I was able to understand about our discussion here with the synthesis of 2-methyl-3-nitrotoluene since I’m not a professional chemist, just a hobbyist. And other than my notes, I’ve never discussed this synthesis yet with anyone. Even before I came back to read the responses on my theory of making this chemical from phenol as the starting point, I realized how impossible it would be and then knew toluene would be the only way.

The only reason I consider myself a chemist at all is because I’m smart enough to not only follow a written synthesis and successfully make the end product, but also able to figure out how the chemical reaction is taking place and why it does what it does, so I can understand when I’m doing something wrong and correct my mistakes as I make them. When I read a synthesis now, it’s so easy to understand how to construct the equipment I will need even though most syntheses don’t explain even the least little bit about how to go about actually performing the process. They just tell you what you need to do, and your prior chemistry training and experience/knowledge learned in class is what would enable you to follow and know *how* to do what is described.

As for my amateur question about those two molecules being the same, just one is rotated 60 degrees, I was well aware the way it’s orientated is irrelevant, but I know about the double-bonds in the benzene ring, even though I didn’t include them in my illustrations because it’s too hard using text characters, and I always *assumed* they were localized and that’s why I asked, because if they weren’t in the right spot, then the two molecules wouldn’t actually be the same exact chemical. When I’m drawing my illustrations of molecules that include a benzene ring, I’m always careful to make sure I put the double bonds in the right place, but apparently this is irrelevant?

[NickDC]

Well now I’ve found a place that sells 2-hydroxy-6-nitrotoluene for less than 8 bucks a gram. This really convinces me that 2-methyl-3-nitrophenol simply can’t be the same chemical, because when it’s labeled as that, the price is at least $60 per gram, even though it still has 2-hydroxy-6-nitrotoluene and nitrocresol listed as synonyms. I can’t remember which chemical supplier’s website it was that illustrated 2-hydroxy-6-nitrotoluene being so different from 2-methy-3-nitrophenol.

But I usually don’t write down the URL’s of where I obtained my molecule illustrations, so I don’t know where the  2-hydroxy-6-nitrotoluene drawing came from, but I do know it was correct because it upset me to find out that it was a completely different chemical apparently.

I buy blank hardcover books and fill them with my notes. Each book is for synthesizing a different chemical. By the time I’m done filling up the book with all my notes on all the various routes to synthesizing the chemical, I have a thorough understanding of the chemistry involved, and I review the notebook many times over before attempting to start the work. Each time I review the notes and imagine myself doing the work, it seems easier and easier. Then when I actually do start, I feel like I’ve already done it many times before, so it’s nice and easy.
Now for instance, the conversion of 2-methyl-3-nitrophenol to 4-benzyoxyindole is a simple 3 step a,b,c process by the Batcho and Leimgruber literature. But when I first read it, I was a bit overwhelmed, and it seemed like a long hard road.

Unfortunately the final step of converting 4-benzyoxyindole into the wonderful chemical I'm seeking would require Ac2O which is cheap and readily available to professional researchers who work for certified companies, but not available for citizens to purchase, and virtually impossible to make yourself. So far I think only one synthesis of this chemical has been published because that's all I can find, and of course the 1st synthesis to be published for any drug always uses Ac2O because it’s usually a one step process and produces high yield.

But as we all well know, there are many ways to work around the use of Ac2O and get the job done with other more common chemicals, but it involves more steps and usually produces a much lower yield. We always have to wait for a true genius in the community to invent those new methods. Usually it happens from people on message boards just like this one, after enough people have become aware of the new chemical and get interested in making it themselves.

This one I'm talking about is on a fine line of legality. Technically even seritonin and melatonin are illegal by the analogue act because they are structurally so similar to illegal schedule I drugs like DMT.

So I doubt this is the right message board to discuss the final step of converting the 4-benzyloxyindole into the end product.

I figured the discussion of 2-methyl-3-nitrophenol would be a good topic though since it's 100% perfectly legal and used for a wide variety of things.

But if it is indeed the exact same chemical as  2-hydroxy-6-nitrotoluene, then there's no need to synthesize it because I can buy it so cheap at only $750 for a kilo. That's plenty enough to experiment with and make plenty of mistakes, but perhaps too much? Might draw unwanted attention? 

[Borek]

When I’m drawing my illustrations of molecules that include a benzene ring, I’m always careful to make sure I put the double bonds in the right place, but apparently this is irrelevant?

Yes, they are delocalized - there are no single nor double bonds in the benzene ring.

http://en.wikipedia.org/wiki/Aromaticity

[Borek]

So I doubt this is the right message board to discuss the final step of converting the 4-benzyloxyindole into the end product.

If you have doubts you are most likely right.

[billnotgatez]

I should have posted this earlier NickDC, so please answer if you can.

I am curious, do you have a final use for this synthesis?
Do you have a MSDS link I could look at?
I would like to follow along with what you are doing but organic compounds are hard to look up.