Sciencemadness Discussion Board

Starting from benzene...

Ex Nihilo - 27-6-2018 at 05:44

Good day!
Can you help me understand the attached synthesis circuit?
Will all the described reactions proceed, which way to go is better and why?


schemat1.jpg - 134kB

JnPS - 27-6-2018 at 05:52

Is this a school assignment or a synthetic scheme you wish to carry out? Cause I don't see why you wouldn't just start from toluene to skip the first step, which, if I'm not mistaken, is hard to limit to only a mono-alkylation since alkyl groups are activating in EAS.

There are some other steps I don't believe at the moment but they're certainly interesting reactions and I may have just never seen them before, it could just be my inexperience *shrug*

EDIT: Also the third transformation I'm fairly sure won't work. Are you thinking of it as a friedel-crafts alkylation? Cause I was taught those won't proceed with vinyl or *aryl* halides since their cations are too stable.

[Edited on 27-6-2018 by JnPS]

CuReUS - 27-6-2018 at 08:23

1.like JnPS said,in the first step there will be overalkylation and the yield of toluene will be very bad (1.5%)-http://www.umich.edu/~chemh215/CHEM216/HonorsCup/HC%20220-II...

2.You can make thiols from H2S -https://pubs.acs.org/doi/pdf/10.1021/jo00403a014,but the safer and less stinkier way is to use thiourea.

3.For showing oxidation,you write [O] instead of [O2],unless you want to do the oxidation with O2-https://www.organic-chemistry.org/abstracts/lit4/114.shtm

overall the synthesis is correct theoretically, but practically its wrong since its too long and your final yield would be in single digits.The same product can be made in 2 steps starting from benzhydrol,or in 1 step from modafinil :D

are you trying to do something similar to nurdrage's daraprim synthesis,by making a drug from scratch using OTC reagents ?Because there are better OTC starting compounds than benzene
Quote: Originally posted by JnPS  
Cause I was taught those won't proceed with vinyl or *aryl* halides since their cations are too stable.
You mean their cations are too "unstable".But this is a benzyl halide.

[Edited on 27-6-2018 by CuReUS]

zed - 27-6-2018 at 15:45

It would be a lot easier to make Benzyl Chloride starting with Benzyl Alcohol and HCl.

The Grignard reaction of BromoBenzene with Magnesium, and then with Benzaldehyde, might be better still. Produces an alcohol. Reaction of the resulting Alcohol with HCl, takes you pretty far along.

Then perhaps, Sodium Hydrogen Sulfide, could be reacted with the Halogen. to produce your Organosulfide.

From a practical standpoint, you must optimize yields, and minimize reaction steps. Otherwise, a tractor trailer load of reagents, might produce only a thimble full of product. After six steps, at so-so yield, there ain't much beef left.
And, in my rough estimation, there are actually more than 6 steps involved.

50%x50%x50%x50%x50%x50%= .5 to the 6th power=.015625=1.5625% over-all yield.

Now, it's pretty noisy around me right now, and I may be miscalculating, but the principle is still present. Minimize reaction steps, and Maximize yields.
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OK, I checked the WEB. Some kind of prescription alertness enhancer.

I don't always catch on, right away. But, depending upon your location, synthesis may be proscribed by local laws.

As luck would have it, its synthesis was discussed at length, back in the Hive/Rhodium era. Reagents that I wasn't sure existed, do exist, and reasonable synthetic pathways have been well mapped out.

https://erowid.org/archive/rhodium/chemistry/adrafinil.modaf...



[Edited on 28-6-2018 by zed]

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clearly_not_atara - 27-6-2018 at 17:27

Quote: Originally posted by Ex Nihilo  
Good day!
Can you help me understand the attached synthesis circuit?
Will all the described reactions proceed, which way to go is better and why?
Where did you get that? Is it for a class? No amateur chemistry is performed "starting from benzene", as purchases of benzene are restricted to professionals because of its carcinogenicity.

If you wrote it yourself, my advice is: you're not ready to attempt the synthesis of modafinil.

However, for the purposes of our amusement, I'm pretty sure that the "just stir it" method of making acetamide from ethyl acetate could also be applied to make thioglycolamide from ethyl thioglycolate. If you can esterify thioglycolic acid with ethanol, stirring this ester with aqueous ammonia should produce thioglycolamide. This then reacts with benzhydryl chloride or bromide to give the desired compound, short an oxygen atom. This 2-step procedure should be much easier (and safer) than trying to produce thioglycolamide by heating ammonium thioglycolate, as thiol-containing carboxylates sometimes decompose to release H2S

Metacelsus - 27-6-2018 at 20:10

Quote: Originally posted by clearly_not_atara  


If you wrote it yourself, my advice is: you're not ready to attempt the synthesis of modafinil.


And that's not even modafinil that's drawn. OP drew the N-methyl derivative.

Benzhydrol would be a much better starting point than benzene.

[Edited on 6-28-2018 by Metacelsus]

DraconicAcid - 28-6-2018 at 09:49

The first few steps could be replaced by the FC rxn of benzene and dichloromethane.

Ex Nihilo - 28-6-2018 at 10:57

Quote: Originally posted by CuReUS  

are you trying to do something similar to nurdrage's daraprim synthesis,by making a drug from scratch using OTC reagents ?Because there are better OTC starting compounds than benzene


Actually, yes! I want to attempt the synthesis of N-methyl-modafinil from the scratch similar to nurdrage's daraprim synthesis in educational purpose. I really like to think about different syntheses from the scratch - starting from very basic components or even OTC reagents. So my goal is not a viable amount of the end product but to do all the steps in the lab, starting from this theoretical issue I made on my own mention and ending with positive NMR results which will confirm a success of the overall process.
One of the most important deeds in my wish-list - to synthesise the toluene from benzene using F-C alkylation.
The reason why I use CH3I instead of CH3Cl - because of its easiest handling (liquid instead of gas) and as I think more easiest synthesis. The AlBr3 seems for me more simple in making instead AlCl3 or even other Lewis acids (if anyone knows a better reagent just give me know).
So, if you have any idea on how to make toluene from the scratch I would appreciate your help. Maybe it will not be in one step, maybe it took more than two or three but if get overall yield about 10% or higher it will be ok!
Quote: Originally posted by DraconicAcid  
The first few steps could be replaced by the FC rxn of benzene and dichloromethane.

I was thought about that.
Starting from methyl ketone ( R(C=O)CH3 , R= CH3, C2H5, etc ) via Haloform reaction making chloroform and then reducing chloroform with hydrochloric acid and zinc metal in ethanol to obtain dichloromethane.
But I did not have any synthesis references on that so if anyone has one - I will be grateful!
Quote: Originally posted by clearly_not_atara  

However, for the purposes of our amusement, I'm pretty sure that the "just stir it" method of making acetamide from ethyl acetate could also be applied to make thioglycolamide from ethyl thioglycolate. If you can esterify thioglycolic acid with ethanol, stirring this ester with aqueous ammonia should produce thioglycolamide. This then reacts with benzhydryl chloride or bromide to give the desired compound, short an oxygen atom. This 2-step procedure should be much easier (and safer) than trying to produce thioglycolamide by heating ammonium thioglycolate, as thiol-containing carboxylates sometimes decompose to release H2S


Thank you very much!
I will study this information in some detail.

[Edited on 28-6-2018 by Ex Nihilo]

CuReUS - 29-6-2018 at 02:26

Quote: Originally posted by zed  
The Grignard reaction of BromoBenzene with Magnesium, and then with Benzaldehyde

or with formate ester to give benzhydrol directly :)
Quote:
Then perhaps, Sodium Hydrogen Sulfide, could be reacted with the Halogen. to produce your Organosulfide.

hydrosulfides tend to give disulfides rather than thiols.
Quote: Originally posted by clearly_not_atara  
If you can esterify thioglycolic acid with ethanol, stirring this ester with aqueous ammonia should produce thioglycolamide.
Can you do it in one step using TCT ?-https://www.sciencedirect.com/science/article/pii/S004040390...
Quote: Originally posted by Ex Nihilo  

Quote: Originally posted by DraconicAcid  
The first few steps could be replaced by the FC rxn of benzene and dichloromethane.

I was thought about that.
Starting from methyl ketone ( R(C=O)CH3 , R= CH3, C2H5, etc ) via Haloform reaction making chloroform and then reducing chloroform with hydrochloric acid and zinc metal in ethanol to obtain dichloromethane.
DCM is OTC :P
your craze for trying to synthesize compounds "ex nihilo" is really getting to me :D

[Edited on 29-6-2018 by CuReUS]