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Author: Subject: Revisit to Zealot's total synthesis of Ketamine
mardyart
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[*] posted on 6-10-2013 at 18:52
Revisit to Zealot's total synthesis of Ketamine


For years I've read through ZTSK on erowid. At first I really didn't understand what I was reading. But I started researching every chemical and every step of each process. And now I feel like I know enough to ask about some of the things I still don't understand.

1. In the first synthesis of o-Chlorobenzoic Acid, it's stated that the o-Bromobenzoic Acid analog can be obtained substituting CuCl for CuBr. But then in the second synthesis of o-Chlorobenzonitrile, the o-Bromobenzonitrile analog requires 50g o-Bromobenzamide. I'm not an expert but aren't o-Bromobenzoic Acid and o-Bromobenzamide two different compunds? If this is the case, why do we need to synth o-Bromobenzoic Acid? Or is there an omitted synthesis for the benzamide from the benzoic acid?

2. In the synthesis of o-Chlorobenzonitrile it states to mix sodium hydroxide, the benzoic acid and zinc sulphate. In this step, what is the name for the reaction product? I have been researching and I think it's a Zinc Carboxylate, but you tell me.

It then states to mix the precipitate with lead(ii) thiocyanate and to heat until gas is evolved and distilled. I've been reading about thiocyanates and found that most give off toxic fumes when heated to decomposition. If one were to follow this process, wouldn't it just create a deadly gas?

3. It states that the methylamine freebase can be obtained by dripping a saturated solution of the hydrochloride over sodium hydroxide and then dried through NaOH. Can anyone be more detailed on this process?

4. Carbon Tetrachloride and Undecane are unavailable now. What are acceptable substitutions?

I feel that the whole thing is very void of critical information and I would benefit from some clarification. Thanks for your time, I look forward to reading your responses.
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Rich_Insane
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[*] posted on 6-10-2013 at 19:57


Please provide a source/reference.


Quote:

I'm not an expert but aren't o-Bromobenzoic Acid and o-Bromobenzamide two different compunds? If this is the case, why do we need to synth o-Bromobenzoic Acid? Or is there an omitted synthesis for the benzamide from the benzoic acid?


They are different compounds, but the carboxamide can be prepared from the carboxylic acid.



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Nicodem
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6-10-2013 at 22:36
mardyart
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[*] posted on 12-10-2013 at 18:09


Here is the link to the procedure:

http://www.erowid.org/archive/rhodium/chemistry/ketamine2.ht...

Thanks for the reply. Maybe you can elaborate more when you've read through the procedures?

Thanks again
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Rich_Insane
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[*] posted on 14-10-2013 at 21:32


1/2. The benzamide is synthesized from the carboxylic acid. The first reaction involves diazonium salt (Sandenmeyer) to the o-bromo compound. The carboxylic acid is reacted to form the Zn(2+) salt. I don't know the mechanism of this, but the salt is then converted to nitrile in the high-heat conditions.

There are other ways to convert amides into nitriles (search literature), but this method seems to allow direct access from the -COOH.

3. THF and the equivalent mass of methylamine hydrochloride might work. You just need a base to deprotonate the hydrochloride.

4. Undecane is a high boiling aliphatic solvent. As such it is relatively inert. Diglyme doesn't have as high a BP, but it might work.

Same goes with CCl4; It's an inert. It will not mess with the bromination. Any other solvent that is inert to bromination will work. Perhaps benzene?

Disclaimer: I'm not a chemist and I do not know organic chemistry as well as other people on this forum.

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bbartlog
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[*] posted on 15-10-2013 at 11:47


Diglyme has a bp something like 30 degrees lower; since the reaction takes 3-4 hours in undecane I'm skeptical that it can be completed in a reasonable time using diglyme. Possibly you could fractionate diesel fuel as an improvised way of obtaining an alkane solvent with a similar boiling point, though such a process would likely be pretty smelly.




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mardyart
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[*] posted on 18-10-2013 at 12:17


Thanks Rich_Insane those are interesting answers. I will review as much literature possible with the information you have provided.

bbartlog, thank you. But I would not want to fill the lab with nasty smelling diesel fumes. Although your opinion about reasonable reaction time is very intriguing. Perhaps there are other opinions to support your skepticism.

Shame this thread got moved, I really feel it belongs in the Organic Synthesis category. I have the feeling that Beginnings doesn't get much press.

But don't stop there guys, as well as the questions I've asked, I welcome more open discussion about this topic from everyone. It's a legendary synth and has been around for years. However, there is little discussion throughout the web and I feel it deserves more.

Perhaps someone can suggest the reaction mechanism that Rich_Insane previously elaborated on, for example.

I would also like to read some opinions about the thiocyanate I mentioned.

I look forward to reading more of this community's thoughts, let's really get this thread flowing!
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Rich_Insane
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[*] posted on 18-10-2013 at 21:09


Would there be any reason why something like dry ethylene glycol would be undesirable?

Also, try decalin. It's got a boiling point around 190oC. It's aliphatic as well, just not extremely OTC.

I think it's overkill to synthesize cyclopentanol manually, and I'm sure there are better routes to the compound. If you wan to go the adipic acid route to cyclopentanone, perhaps it might be easier to reduce using NaBH4 or a similar reducing agent.

To convert carboxylic acids into amides via acid chlorides using cyanuric chloride see "Tet. Lett., No. 32, 3037-3040 (1979)." There was another route using P(Ph)3 and TCCA somewhere (though triphenylphosphine isn't OTC, there are several suppliers on certain auction sites that I can think of). That reference is hidden in my library somewhere.

Cyanuric chloride in DMF can be used to convert the amide into a nitrile ("Chakrabarti, J. K.; Hotten, T. J. Chem. Soc., Chem. Commun., 1972, 1226").

Good luck.

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mardyart
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[*] posted on 28-10-2013 at 22:07


Are there any opinions about the validity of this synthesis? E.g. whether there is missing information? Are there any easier routes to the final product?
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[*] posted on 8-11-2013 at 12:35


why would anyone want to make such a weird cmpd? Anyway someone over at DEA thought it should be added to the big no-no list so best to leave it where it is: An interesting rundown on erowid. Actually you're making the best possible use of the article, going through step by step and asking questions. I should have said second best. It would be best to try and look up most the questions you asked. For example you could have looked up benzoic acid and benzamide. I believe a simple search engine quest would have answered the questions you had.



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hyfalcon
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[*] posted on 8-11-2013 at 13:40


Ketamine=Date rape drug. I would be very careful accessing information on this compound. LEO is watching for it.
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mardyart
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[*] posted on 19-1-2014 at 21:10


Why is it whenever anyone talks about drugs they think the authorities are gonna kick the door down?
For a start off Ketamine is a very useful and widely used Anesthetic not just a drug some people may use for illicit activities, not just for animals either. It doesn't matter who's watching whatever anyone posts anywhere. You can't be arrested or charged for talking, hell we'd all be in jail.
I don't have to worry bout DEA I live in the UK. But even if British authorities are watching this exact thread, there is nothing they can do about it. Even if they wanted to search my property, which they can't without probable cause, they wouldn't find a thing because I don't own lab equipment or chemicals. I am simply interested in the chemistry. That's the whole reason I started this thread.

So can we all stop whining about our opinions of law and morality and continue with some constructive narrative?

@chemrox I did in fact do a search for Benzoic Acid and Benzamide. But what I am confused about is can the 'o-chloro' species be used in exactly the same way?

Thanks for your replies, keep them coming.

Are there any thoughts about step 5 of the synthesis, Cyclopentanol? It calls for: 'The ppt inside the flask is carefully decomposed with 50% H2SO4 until acidic and saturated with NaCl.'

If you add NaCl(aq) to the acidic solution will it generate HCL gas?
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