Nitrobenzene/phenol/aspirin synthesis

[espen180]

I have been thinking about attempting a synthesis of nitrobenzene compounds, with a long-term prospect of synthesizing aspirin.

I have some questions regarding the synthesis.

During the addition of the nitro group to benzene, I only want molecules with a single nitro group. How do I minimize the yield of multinitrobenzene compounds? During the addition, the reaction container is to be kept below 55 degrees celcius. Is this the temperature multinitrobenzene compounds start forming?

Once I have the nitrobenzene, I plan on doing a series of reactions to make phenol. I then need to add a second hydroxy group.
1. How high yield can I hope for when making phenol from benzene using this method?
2. When adding the nitro group to the phenol, I need it in the orto-position. I'm suspecting about 66% of the compounds will satisfy this, so what is the best way of separating the ortonitrophenol from the paranitrophenol?

Any feedback is appreciated.

 

[DDTea]

Have you ever toyed around making trinitrated aromatic compounds? Basically, it's easy to get the first nitro group on there. The second and third nitrations are more difficult, to the point that they require heating and longer reaction times, because nitro is an electron withdrawing group which decreases reactivity of the benzene ring toward electrophilic aromatic substitution reactions.

Also, the hydroxyl group on phenol is ortho/para directing. So if you nitrate phenol, you can expect a 66:33 ratio of ortho/para product.

Could you describe your proposed acetyl salicylic acid synthesis, because I'm not sure I follow. Specifically, I don't understand why you need nitrobenzene to get to acetyl salicylic acid.

 

[espen180]

The nitrobenzene is a precursor of phenol. The diazonium salt method was the simplest method I could find for adding a hydroxy group to benzene.

It turns out the nitration of phenol was a mistake. What I need to do is, I think, to preform an addition of 2-Bromoethane or 2-Chloroethane to the phenol, then separate out the orto product. Still, something bothers me. When I try to oxidize the benzyl hydroxy group, is it possible that the ring hydroxy group is oxidized as well, removing the aromacity of the ring?

 

[DDTea]

So basically you're proposing the following:

Benzene -(H₂SO₄/HNO₃)--> Nitrobenzene
Nitrobenzene --(suitable catalyst/H₂)--> Aniline
Aniline --(sandmeyer reaction/nucleophilic aromatic substitution)--> Phenol
Phenol --(Friedel Crafts alkylation using 2-chloroethane)--> 2-ethyl phenolI would suggest a different synthesis, quite honestly. You're making this entirely too difficult and you've got quite a few toxic chemicals along the way (benzene, nitrobenzene, haloalkanes)! Also, aromatic nitrations can be hairy if you don't know what you're doing. Temperature control is imperative. I hope this is just a thought experiment.

If I were you, I'd start with phenol. From there, I'd perform a Friedel Crafts alkylation using methyl chloride (carcinogenic, but tolerable to work with). This would give you 66/33 ortho/para cresol (o-methyl phenol). The next step would be to form o-cresyl acetate by reaction with either acetyl chloride or acetic anhydride. Personally, I'd use acetyl chloride: the reaction is fast, easy, and occurs at room temperature. HCl bubbles off from the reaction vessel and everything is very clean. It gives good yields, too! Finally, I would oxidize that methyl group to form your carboxylic acid using potassium permanganate (KMnO₄).

Remember: the more reactions you perform, the more purifications you will also have to form, and the more product you will lose. Keep things simple!

 

[espen180]

Thank you very much for your reply! I like your suggested method much better.

If I am not mistaken, your synthesis is

[PLAIN]http://img261.imageshack.us/img261/8104/synthesisaspirin.png

Reaction 1. needs to be performed in an anhydrous environment. How should this be done? Would using diethyl ether or acetone as a solvent alone do the job, or is additional water absorbing compounds needed?

Also, what method should I use to separate the products?

I assume reaction 3. is exothermic and should be performed in a cold water bath or icebath?

As for your remark about whether or not it is a thought experiment, it is not. I intend to cary out the synthesis, but I was put off by the heavy use of dangerous chemicals, which is why I like your suggestion much better.

 

[DDTea]

Yep, you got it. Now I have a question for you: what kind of scale are you thinking of? How much aspirin are you aiming to synthesize? If I were you, I would keep it below 1g if possible. It's a lot easier, cleaner, and safer to do things on a small scale--especially if you're learning something new.

Anhydrous environments are easy to achieve. First of all, you have to ensure your equipment is dry: so put it on a hot plate, flame dry it, use a laboratory blow dryer (I know that's not the technical name for it), etc. You may want to add a desiccant, such as Magnesium Sulfate, to your methyl chloride. For AlCl₃ or FeCl₃, you can dry them in a crucible. I'm not sure what kind of solvent is needed for Friedel Crafts alkylations. For that, I'd recommend some literature searching.

You can separate o-cresol (bp 191 C) from p-cresol (bp 202 C) by distillation. You may want to use a vacuum to avoid the higher temperatures (it's best to do laboratory-scale syntheses under gentle conditions whenever possible).

The reaction with acetyl chloride is beautifully simple. I've only done it once when I was making methyl chloroacetate (I don't do much O. Chem work these days). It is exothermic, but on a small scale it shouldn't be a problem. It's pretty much mix, stir, and let HCl fume off. Since the HCl is leaving solution, the reaction goes to completion by LeChatelier's principle. You don't really need a cold water bath.

Lastly, when you do your aromatic sidechain oxidation, it would probably be better to use Jones Reagent than KMnO₄ (sorry, I misled you a bit, hah). With the permanganate oxidation, you will have to do an acid workup (again, more steps) because it will form the potassium salt.

Further reading: A laboratory exercise on aromatic sidechain oxidations: http://www.miracosta.edu/home/dlr/211exp6.htm

Jones reagent: http://www.organic-chemistry.org/chemicals/oxidations/jones-reagent.shtm As always, be careful working with Cr(VI) compounds. Don't spill it on your clothes or you'll never get the stain out! :)

Definitely search literature for specific reaction conditions, though. That's the way all ideas are done in science: literature search <---> write method ---> experiment <---> revise method

 

[chemisttree]

Thank you very much for your reply! I like your suggested method much better.

If I am not mistaken, your synthesis is

[PLAIN]http://img261.imageshack.us/img261/8104/synthesisaspirin.png

Reaction 1. needs to be performed in an anhydrous environment. How should this be done? Would using diethyl ether or acetone as a solvent alone do the job, or is additional water absorbing compounds needed?

Also, what method should I use to separate the products?

I assume reaction 3. is exothermic and should be performed in a cold water bath or icebath?

As for your remark about whether or not it is a thought experiment, it is not. I intend to cary out the synthesis, but I was put off by the heavy use of dangerous chemicals, which is why I like your suggestion much better.

No way the acetyl ester of o-cresol will survive KMnO4 oxidation. Keep working on it!

 

[DDTea]

No way the acetyl ester of o-cresol will survive KMnO4 oxidation. Keep working on it!

Yep. That's why I'm now in favor of the Jones Reagent route. It should leave the ester unaffected. If it does become a problem, you can always adjust the amount of sulfuric acid used in the preparation.

EDIT: wait, I just realized that it would be easiest if you did the acetylation as your final step. So revision!

phenol -(F-C alkylation)-> o-cresol/p-cresol, separate your o-cresol by distillation
o-cresol --(Jones Reagent oxidation)--> salicylic acid
salicylic acid --(acetyl chloride)--> acetyl salicylic acid

There! I'm quite comfortable with that now. I was concerned that the acetyl chloride would reaction with the carboxyl group to form an anhydride bond. However, that won't happen under acidic conditions, as would be created by a Jones Reagent oxidation.

espen, if you're interested, the industrial synthesis for Aspirin is a two step process:
-Kolbe-Schmitt carboxylation: Sodium Phenoxide reacts with CO₂ at 100 atm and 125 C, followed by acid workup. The product is salicylic acid.
-Acetylation of salicylic acid: Industrially, this is done using acetic anhydride.

Of course, lab scale is very different from industrial scale and the considerations are also different! You probably don't want to work with 100 atm pressures, for example. Also, as I mentioned, acetyl chloride is a lot cleaner to work with than acetic anhydride.

More reading for you:
http://en.wikipedia.org/wiki/Kolbe–Schmitt_reaction

 

[espen180]

Thanks a lot! I will read more about the spesific reaction conditions. According to the aricle on Jones' reagent, acetone should be a suitable solvent, and could be used throughout the synthsis, correct?

 

[sjb-2812]

So basically you're proposing the following:...

If I were you, I'd start with phenol. From there, I'd perform a Friedel Crafts alkylation using methyl chloride (carcinogenic, but tolerable to work with). This would give you 66/33 ortho/para cresol (o-methyl phenol).

Bear in mind that the ratio is unlikely to be the statistical 2:1 o/p, due to things like sterics etc.

 

[espen180]

Yeah, but I don't think hydroxy groups or halomethane are steric enough to make a significant shift (am I wrong?)

Also, I spoke to another student at my university who studies organic chemistry, and he reccomended I use the same Lewis catalyst, AlCl₃ or FeCl₃, in the final acetylation reaction. (Salicyclic acid ---(acetyl chloride)---> aspirin). Any somebody comment on this? He also suggested that the first alkanation reaction would need a bit of temperature to proceed. He said I should leave the reaction mixture boiling a few hours to ensure that the reaction proceeds completely, but I will be using acetone as a solvent, so I'm not sure.

 

[DDTea]

The hydroxy group is going to activate the ring toward electrophilic aromatic substitution as it is, the F-C alkylation is going to be quite favorable. If you add more energy to the system, as by heating, you may promote multiple alkylations on the ring. Remember: the methyl group that you are adding is *also* activating toward electrophilic aromatic substitution. For these reasons, heating could complicate things. Also, you may want to use an excess of phenol.

I would not use any lewis acid catalyst in the final acetylation either. That would encourage Friedel-Crafts acylation on the aromatic ring because the intermediate formed between AlCl₃ and acetyl chloride, H₃C-C(triple bond)O⁺ is the necessary intermediate in F-C acylation. The intermediate required to do the acylation reaction on the hydroxy group is a tetrahedral intermediate formed by nucleophilic addition of the -OH group to the carbonyl group of acetyl chloride. If anything, the final acylation should be done under *basic* conditions, to form something like -O^-Na⁺, which would be a better nucleophile than the -OH itself. Again, though, this should not be necessary. Also, avoid water in this step, because that will also react with the acetyl chloride to form acetic acid, which would be a waste.

As far as specific choices of solvents and temperature, your best bet is going to be doing literature searches. Another good option would be to read the lab manuals for organic laboratory courses at different universities. Many are available online. Surely *someone* has done a F-C alkylation in their course at some university!