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Author: Subject: The credibility of syntheses around?
Refinery
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[*] posted on 1-5-2020 at 05:29
The credibility of syntheses around?


How much of the syntheses floating around the internet and classic media are credible? I've found out that many process descriptions are either misinterpreted or outright false, or they produce significantly lower yields or totally other compounds than prescribed. There are also a plethora of concept reactions which are highly unproved.

(Of course, not speaking of operator errors including impure/false reagents which in reality can be a much bigger factor)

Have you faced with this issue, and are there legitimate sources that are highly credible? The issue not only wastes time and reagents, but it can be outright dangerous to perform these reactions.

Apparently, highly professional and institutional chemists have better capability of dealing with good practices and they have resources to study even the most intrigue reactions, and therefore this is more of a matter for us amateurs that must many times rely on second hand processes.
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mackolol
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[*] posted on 1-5-2020 at 05:49


Most of theoretical syntheses, that are not tested are not credible. Usually, when you perform such synthesis, you come to the point when you have to change something and you must figure it out by yourself or by looking into literature.

Typical example of such synthesis is the one from erowid, which carries MPV reduction of cyclopentanone, which isn't even enough diluted, and then neutralises all stuff with 50% H2SO4...

I don't know how this synthesis were written, I assume that on some drugs, but in the most popular book that talks about MPV reduction it's clearly said, that particular cyclopentanone is very delicate and if one carries this reduction with it must dilute it extremely and even though the yields will be pretty low....

So if it's not clearly marked, that synthesis has been performed in reality, you'll probably end up with few times work than you predicted and even then its not guaranteed that you will even make it. Ideally if synthesis has some photos in it, but that's not always the case..
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Sigmatropic
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[*] posted on 1-5-2020 at 08:21


I'd consider orgsyn.org to have some of the more credible syntheses floating around on the internet. Presumably due to the fact that they have two independent labs carry out the synthesis before publication. Should become a standard practice imo.

So many scientific papers cannot be reproduced, it's a shame.

Impure reagents are a thing of all time and can be for the better and worse. I would recommend reading about the dispute about the first quinine total synthesis, hint Impure reagents make the reaction chooch). I surely wouldn't call that operator mistake, and it happens all too often to professional chemists.
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mackolol
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[*] posted on 1-5-2020 at 09:46


Oh yes and speaking about websites that are credible I can also recommend prepchem.com
Also youtube or any videos are very good as they show the whole process of synthesis, the ones that are specially noteworthy:
chemplayer, nilered, nurdrage, extractions&ire, cody's lab...
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Texium (zts16)
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[*] posted on 1-5-2020 at 09:49


Oddly enough I actually encountered more problems with literature procedures in the university research lab I worked in than I ever did at home. This is likely because the reactions I ran at work were usually more sensitive and complicated than anything I’d do at home, but it still goes to show that even with optimal conditions, replicating what should be working procedures will not go as smoothly as expected.

Three years ago, I unsuccessfully tried to run a reaction several times based on a reputable journal article that claimed nearly quantitative yield for it, and I had no idea what was going on. I tried emailing the authors of the paper looking for some insight, and never got a reply. My PI and an old friend of his who worked in the lab at the time, both experienced veterans of synthetic chemistry, also attempted the reaction after me, and failed as well. The fact that we couldn’t get that reaction to work resulted in us having to scrap plans for making several analogs of the drug we were studying.




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morganbw
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[*] posted on 1-5-2020 at 14:26


I have come across a couple of synthesis that I could not replicate. I usually conclude that there was a step or reagent that was not mentioned in the paper.
I am also highly aware that my skill might not be up to par on some reactions.

I am pretty sure that some papers are worthless but I lack the confidence to state so definitely.
I have royally screwed up simple/basic stuff so it is hard for me to critique a serious synthesis.

Just because I cannot or you cannot make it work does not mean that it cannot happen/work.
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Heptylene
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[*] posted on 1-5-2020 at 15:02


I have struggled myself with syntheses that provided insufficient information to be reproduced. In fact, a lot of the synthesis papers I read nowadays seem to lack some experimental information and it infuriates me :mad:. I wish people would write a detailled procedure everytime, as in orgsyn papers, instead of the usual non-descript bullshit like:
"1 (0.01 mmol) in THF (1 ml) was added to 2 (0.02 mmol) in THF (1 ml) and stirred overnight at RT. The product was isolated by filtration in quantitative yield."

Sometimes I use Reaxys (organic reactions database) and it's filled with 99+% yields. That's a major red flag to me regarding credibility. Maybe I just suck at workups, or my reactions don't work, but a 99% yield sounds like their product is either not dry, not pure, or they are just lying.

While I'm at it, what's up with using novel, facile, serendipitous, mechanistic insight and other shitty buzzwords in every damn paper title?
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karlos³
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[*] posted on 1-5-2020 at 15:15


Quote: Originally posted by Heptylene  
99+% yields. That's a major red flag to me regarding credibility. Maybe I just suck at workups, or my reactions don't work, but a 99% yield sounds like their product is either not dry, not pure, or they are just lying.

It is likely they don't mean isolated yield, and simply have analytically measured a 99% yield.
Either this, or they are exaggerating, I would agree on that.
It does take quite much attention and good lab techniques to isolate a quantity corresponding to a yield of 90%, of course likewise to make.
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Refinery
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[*] posted on 1-5-2020 at 23:27


And then there are these outright foolish and even life-threatening synthesis, where "just simple add 2.5kg of this and 7.5kg of that, quickly place a bucket over the vessel and wait for the explosive reaction of cyanidious nitroglycerol to dissipate and reflux for few hours".

Like, a child could conclude that by slowly mixing the reagents could result in a safer, cleaner and better yield with much less losses.
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mackolol
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[*] posted on 2-5-2020 at 00:48


Quote: Originally posted by Heptylene  
I wish people would write a detailled procedure everytime, as in orgsyn papers, instead of the usual non-descript bullshit like:
"1 (0.01 mmol) in THF (1 ml) was added to 2 (0.02 mmol) in THF (1 ml) and stirred overnight at RT. The product was isolated by filtration in quantitative yield."

Sometimes I use Reaxys (organic reactions database) and it's filled with 99+% yields. That's a major red flag to me regarding credibility. Maybe I just suck at workups, or my reactions don't work, but a 99% yield sounds like their product is either not dry, not pure, or they are just lying.

Quote: Originally posted by karlos³  

It is likely they don't mean isolated yield, and simply have analytically measured a 99% yield.

Quote: Originally posted by Refinery  
And then there are these outright foolish and even life-threatening synthesis, where "just simple add 2.5kg of this and 7.5kg of that, quickly place a bucket over the vessel and wait for the explosive reaction of cyanidious nitroglycerol to dissipate and reflux for few hours".


It's typical for patents. They just give incomplete information, workup at super big scale, often using some very fancy lab equipment. Usually they don't even bother to isolate the product and give the yield basing on chromatography or whatever of mother liquor contents.

What's even worse about patents is that they give very good and interesting routes to hard to reach compounds, but you must be very lucky or experiment a lot to get what you want by following the patent. Usually it just turns you that they don't work or you don't know what to do at some point and end up pissed out.
And they don't even bother if the chemical is nasty or sensitive. Just pure theory and theory is totally different thing than practice in chemistry.

[Edited on 2-5-2020 by mackolol]
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karlos³
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[*] posted on 2-5-2020 at 07:33


A patent has to be that way, I mean it is also meant for protection, they can't give absolutely clear instructions.
Especially when some nations don't really care about patent law at all, then the vagueness of it are the only form to protect the ownership.
But we can be lucky with the patents nowadays, have you had a look at pre-WWII patents?
And for that matter, maybe ever seen a japanese patent out of that time?
Those are all rather vague, obviously obfusciated, not unusual you end up with more questions than you had before.
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Sigmatropic
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[*] posted on 2-5-2020 at 10:07


Pre ww2 patents from Germany are actually pretty good, maybe some pretty hardcore chemistry involved but it sure as hell worked.
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Sigmatropic
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[*] posted on 2-5-2020 at 10:16


Quote: Originally posted by mackolol  
Oh yes and speaking about websites that are credible I can also recommend prepchem.com
Also youtube or any videos are very good as they show the whole process of synthesis, the ones that are specially noteworthy:
chemplayer, nilered, nurdrage, extractions&ire, cody's lab...


Prepchem is some sort of unreferenced compendium similar to Vogels, most of it works but not everything should be taken at face value.

YouTube videos show the process but all too often fail to follow up on product characterization (and also isolation and purification). I seem to remember a dispute about one of Chem players videos of making succinic acid from glutamate, so even there it's not always crystal clear( http://www.sciencemadness.org/talk/viewthread.php?tid=69635&... )
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mackolol
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[*] posted on 2-5-2020 at 13:22


Quote: Originally posted by karlos³  
nd for that matter, maybe ever seen a japanese patent out of that time?
Those are all rather vague, obviously obfusciated, not unusual you end up with more questions than you had before.


Lately, I have performed deethylation of ethylvanillin to protocatechualdehyde following japanese patent. It was quite brief and understandable, but the thing that pissed me off was, that they ended the synthesis at the state of post reaction mixture and stated that yield is quantitative taking in mind chromatography of mother liquor.
And they didn't mention single way of purification or extration. I had to take that knowledge from another english patent. Even though it turned out that this particular aldehyde has much poorer solubility in Ethyl acetate than expected

(strange thing because the first extraction with EA was very abundant in color, but following extractions were light in color and I couldn't extract the water layer in such way that it became decolorised. After evaporation of solvent it turned out that the product is in 50% yield, which would mean that another half is left in mother liquor). Anyways, when I'll figure it out better I can share results.
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AvBaeyer
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[*] posted on 2-5-2020 at 19:30


There appears to be general misunderstanding here about experimental procedures in patents. First off, patents are not scientific papers. A patent only has to teach a person "skilled in the art" how to reproduce what is in the claims. For example, if a product yield for a reaction is not a part of any claim, it is not considered a critical piece of information. It assumed that enough information is provided that a "skilled practitioner" will know how to make the reaction product even if not every detail is provided. Depending on the "skill" of the practitioner, a reported yield may or may not be achieved.

I was an expert witness for several years for lawyers challenging or defending chemistry patents in court. In the case of chemical procedures, all the patent owner had to show was that the reaction product could be "found" irrespective of any reported yield. Typically, this was demonstrated by both parties in the case agreeing to have a person "skilled in the art" run the disputed reaction and determine the product(s) formed.

A bigger problem is the irreproducability of procedures in published papers. I was a reviewer/referee for several journals years ago. Many times experimental sections were sloppily written and had to be sent back for rewriting and clarification. More often, experimental procedures in papers describe only a single run of the experiment so there can be no information about yield ranges or side products. There is not much that can be done about these problems unless paper authors learn to take some pride in providing well written experimental sections and referees pay real attention to experiment descriptions (that is a tedious exercise.)

Just my nickels worth.

AvB
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mackolol
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[*] posted on 3-5-2020 at 02:47


Quote: Originally posted by AvBaeyer  
There appears to be general misunderstanding here about experimental procedures in patents. First off, patents are not scientific papers. A patent only has to teach a person "skilled in the art" how to reproduce what is in the claims. For example, if a product yield for a reaction is not a part of any claim, it is not considered a critical piece of information. It assumed that enough information is provided that a "skilled practitioner" will know how to make the reaction product even if not every detail is provided. Depending on the "skill" of the practitioner, a reported yield may or may not be achieved.


Okay, maybe I said it in wrong words, patents are credible, but they aren't the easiest and most practical source of knowledge for amateur chemist.
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