Epic First Cocaine Synthesis in 25 Steps (Educational)
Vložit
- čas přidán 27. 05. 2024
- Cocaine is intertwined with the fabric of society and science in more profound ways than most realize. Join us to hear about 1) current data on cocaine use, 2) history and discovery of cocaine, 3) the first landmark total synthesis of cocaine by Richard Wilstätter, and 4) other evolutions of (bio)chemical synthesis (Robinson, Noyori). Note that we do not cover biological origins, isolation or other aspects in detail.
/ totalsynthesis
🚀 Thanks to all channel supporters!!!
/ totalsynthesis_official
👉 Follow me on Instagram for updates on random research, mechanism quizzes and interesting news!
www.total-synthesis.com
Disclaimer - This channel does not provide medical advice!
No information on this channel is intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of information on CZcams.
Key references:
- UNODC, Global report on Cocaine 2023 (United Nations publications, 2023)
- Estimating the incidence of cocaine use and mortality with music lyrics about cocaine | npj Digital Medicine 2021, 4, 100
- Cocaine: An Updated Overview on Chemistry, Detection, Biokinetics, and Pharmacotoxicological Aspects including Abuse Pattern | Toxins 2022, 14, 278
- DARK Classics in Chemical Neuroscience: Cocaine | ACS Chem Neurosci 2018, 9, 2358
- Cocaine Use Disorder (CUD): Current Clinical Perspectives | Subst Abuse Rehabil. 2022; 13: 25
- Ueber die Einwirkung des braunen Chlorschwefels auf Elaylgas | Justus Liebigs Annalen 1860, 113, 288 (not 257 like in the video, sorry!)
- Synthese des Tropidins | Ber. Dtsch. Chem. Ges. 1901, 34, 129
- Ueber die Umwandlung von Tropidin in Tropin | Ber. Dtsch. Chem. Ges 1902, 35, 1870
- Umwandlung von Tropidin in Tropin | Ber. Dtsch. Chem. Ges 1902, 35, 2295
- Synthese der activen Coniine | Ber. Dtsch. Chem. Ges 1886, 19, 2578
- Richard Willstätter and the 1915 Nobel Prize in Chemistry | Angew. Chem. Int. Ed. 2015, 54, 11910
- A synthesis of tropinone | J. Chem. Soc., Trans., 1917,111, 762
- New, general synthesis of tropane alkaloids | JACS 1974, 96, 3336
- Elucidation of tropane alkaloid biosynthesis in Erythroxylum coca using a microbial pathway discovery platform | PNAS 2022, 119, e2215372119
- Discovery and Engineering of the Cocaine Biosynthetic Pathway | JACS 2022, 144, 22000 (not 21809)
Some recommended books on organic synthesis:
- Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
- Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
- Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
- Nicolaou; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
- Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
- Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures) - Věda a technologie
How did you like it? Thanks for checking out this video, and major shoutout to my channel supporters!!
www.patreon.com/totalsynthesis; instagram.com/totalsynthesis_official/
Drug war is the problem. Quit being a puppet. ..... and do as the swiss. No drug war.
The coca plant is 11 alkaloids. Cocaine is only one. The full spectrum is incredibly special and a super “food” ?? Supplement?
6:10 mary curie?
What a joke. You mean Mercury? Mary curie. General public has no no clue
8:40 Coca leaves are 100% still used in coca cola production. Coca Cola has some sort of monopoly on coca importation in the usa. It’s bs.
10:45 What about atropine to coke ? Ok ..... coke analog
17:32 i have coniine. Likely getting rid of my collection soon. But not sure what to do with it.
19:40. I heard you just say OG.
After you a mason?
Freud wasn't an addict he safely used it 57x per day for 30 years with no sign of addiction - just ask him.
😂😂😂
Good ol' Ciggy. @user-rk8pn4xk6j
Well, considering that the euphoria is principally provided by the compounds action of inhibiting the release of Serotonin, do you really think he would be able to produce that much serotonin that many times a day?
Someone here is not telling the truth, and I bet it’s Freud. He shouldn’t even have been able to use it in a daily basis for long periods of time and produce any results. The damage to his body’s natural functions would be untold.
He wasn't addicted, he just liked the smell
Absolute mad lad. If I recall right he accidentally invented the epidural block by deciding on a whim to inject cocaine into his spine. I can only imagine what his notes were like on that one... "Experiment has failed to imbue 'spinal confidence'. Actually now I've come down a bit from this morning's more usual dosage I'm not even sure 'Spinal Confidence' makes sense as a concept. Anyway. Sure do hope this paralysis is temporary!"
CZcams just casually wants us to be on a watchlist
now this is something you should absolutely try at home
Especially the part around genetic engineering of tobacco plants
"The analytical data doesn't lie bro"
The data in question:
"beautiful off-white crystals which elevate your mind when ingested"
where's the lie
@@davidcollins6164haha true where is the lie
The first person to synthesize cocaine, discovered structure and function of Chlorophyll A. Science is wild.
Tropane
The total synthesis of morphine is really interesting too, it’s something like 13-15 steps. Completely non viable for industry, but there are some cool steps.
Yes good idea, the first synthesis and several approaches since could be interesting for a future video
I guess that depends on how you count steps? Isn't morphine to heroin two steps?
Opium to morphine?
@@stefanschleps8758 it’s making morphine from scratch that’s that many steps. It’s so complex and low yielding that we just let the poppy plants do it because it’s just a simple a/b extraction at that point. Though there are genetically modified yeasts that can produce opioids now but I haven’t heard of them being adopted for production purposes yet. Morphine to heroin is one step, that’s true. It’s just an acetylation.
@@stefanschleps8758that’s distillation not synthesis
@@stefanschleps8758 TOTAL synthesis, not extraction from organic materials
Hi watchlist buddies! Glad to see everyone here watching CZcams recommended content. 😊
When are we getting the watch ?
@@zorintoto1167I been waiting on mine for 3 years. No Rollie yet
Here before it gets taken down.
Hope it does not, it's all evidence based and just educational review of the peer-reviewed published chemistry!
@@totalsynthesisAnd such beautiful chemistry! My ochem prof promised us that we'd make him proud by quickly and efficiently making meth cuz Walter White was the worst most inefficient chemist ever 😂
"Absolutely no craving after first or even continued usage"
LOOOL
How ironic
I kind of want to download this and re-render it with NileRed’s voice narrating.
His voice fits so fucking well with this kind of stuff
The best part is that if the acetone dicarboxylic acid is a semi-ester, the second decarboxylation doesn’t occur and you get the perfectly substitute product in one step.
I had to read this a few times to comprehend 😂 good argument for a video on chair structures! Semi-ester though... I'ma be hitting the literature to see what that is.
Chair diagrams good lerd too much gin to do English or arithmetic 😢 time for calculus cuz that's way easier than arithmetic
@@SharpAssKnittingNeedles
By semi-ester I just mean one one the two carboxyl groups in acetonedicarboxylic acid is esterified and the other is free.
So, the free one undergoes decarboxylation but the esterified one remains as-is.
This helps since you don’t need to do a future re-functionalisation.
@@cezarcatalin1406
Ok now I see what you're saying! Very nice!
I've read one or two papers on it. Didn't think anyone would be brave enough to put it on CZcams. Quickly saving that video to my HDD, though.
😂😂😂
@@totalsynthesis It's not going to last. A while ago someone published a video on machining a certain device capable of accelerating projectiles in a form factor suitable to hold it in your hand.
Despite the fact that this was completely legal in his jurisdiction, he did not give exact instructions or published CAD files, and the fact that you need orders of magnitude more expensive machines, tooling and material vs what it costs to just buy that device, the video was gone in a matter of hours.
@@graealex I bet it'll stay - if someone can use this video to make cocaine I'm sure they can do it already by reading the same papers. This is not something a random person will be able to copy and attempt in their kitchen.
@@fmdj You're right that it's not an amateur guide. But that's 100% true for the video I mentioned. Even more so.
@@fmdj Btw the video in question was from "Adam the machinist". It's still up on his Patreon for free.
Really love this video. Funnily enough, my masters project was to figure out how to synthesise the core skeleton of a tropane in a structurally related tropane to cocaine through a [3+2] nitrone-alkene cycloaddition - it didn't work and I made pyrolles but man, that original synthesis via the Robinson's route is one I have in my thesis introduction. Love the chemistry videos from you, keep it up.
Thanks so much! And nice thesis haha
Atropine and scopolamine are also interesting. Their effects a lot more so even.
That's so cool, you made a pseudo cocaine
Is there a way to make cocaine longer acting, and so suitable as a replacement drug? Similar to buprenorphine
@@90klh I didn't make it, the methodology doesn't work - to form a tropane from the [3+2] approach, the major competing reaction is dehydration-aromatisation to pyrolle
@@90klh more like methadon, buprenorfinelike would be a longer acting coke with a ceiling effect because of partial agonism. (To be precise)
youtube algorithm: gives me this video
me: interesting
Bless the algo
Love your content man this is a phenomenal video, always presenting a lot of fresh information concerning history+chemistry. Very well done 👏
Thank you!!
Ayyyy noOne
I feel like I’m going awfully recollect parts of this at an after party soon.
😂
Well, that was the las thing that I expected to see in my recommendations.
When i first clicked on this video i did not think that it would be that in depth. I respect the hustle and good research! Thank you
Thank you!! Appreciate it
A US pharmaceutical advertisement for NUMBRINO (cocaine hydrochoride nasal solution) would be the best thing to happen to the internet since chicken-in-the-corn.
You forgot, it's numbrino cocaine hydrochloride 4% {40 mg/ml} NASAL spray lol that's stronger than the 1 % topical solution I've seen a picture of
That's enough to get a person all Freudian lol
Chicken in the corn😅😂
I actually bought an empty pharmaceutical bottle of Cocaine hcl 10%
Not sliced bread?
That was a wonderful and enjoyable tour through history not only of that particular compound but cehcmical history, some social history and a really detailed and engaging presentation of the chemistry. Some of that is well beyond me but certainly worth watcching. Thanks
Thank you for your comment and watching! Appreciate it
A beautiful video with history and explanation, well done!
Thanks!!
Insane to say but this video is extremely helpful in my advanced organic chem exam
Thats awesome and the hidden point of the video! 😂
No worries of being put on a list for this video, only a simple bathtubable 25 steps
😂😂😂
Actually, if I think about it:
1.) acetone dicarboxylic acid can be made from citric acid by oxidative decarboxylation in sulfuric acid below 10C
2.) methyl amine can be made from acetamide and bleach in a hoffman degradation (and acetamide is made simply from ammonium acetate)
3.) succinic dialdehyde is the tricky part… it could be made from THF by breaking the ether bond with sulfuric and water followed by CrO3/Pyridine oxidation
To make the acetone dicarboxylic acid semi-ester, it should be enough to turn it into the salt and react it with a methylating agent while keeping the dicarboxylic salt in great excess and the solutions sufficiently diluted. Then it’s just a matter of separating the semi-ester. Another way would be to dissolve the free acid it in a dry cold etheric solution and add a diluted etheric solution of sulfur trioxide which should steal water and turn it into the anhydride. Then, when nearly all is reacted, in the dry etheric solution add some methanol and warm it up. This should break the anhydride bond and form an ester and a carboxyl acid group. Separating the mono-ester shouldn’t be too hard in either case, the calcium salt of the di-carboxylic acid is water insoluble while the semi-ester calcium salt is more soluble.
Then react them all together, make the substituted tropione, reduce the ketone with sodium borohydride then add sodium benzoate and acid and do a final esterification.
@@cezarcatalin1406
Are you correct brother ?
If so big respect to your brain if it just computed that here and then 🪄
Another great video!
So, in short; it's easier to just build your own submarine and pilot it through the Caribbean.
Pretty much!
thank you for this educational video. I feel very educated on the topic of synthesizing cocaine now.
Great video, never disappoints.
Thank you!
Great work. 👍
Standing ovation for this amazing lecture ❤
Thank you!
Wild. Thank you for the lesson in history and chemistry.
CZcams now what to recommend
Great video!
Thanks!
I am disturbed by your use of purple for bromine atoms
Orange 🍊 or brown 🟤 better?
*Cries in royal purple*
@@fukpoeslaw3613For bromine, yes
Fine put me back on the watch list, I don't want to make it but I will live vicariously through you
Learning about this is pretty interesting
I can already imagine those biochemists discussing on what to do:
"alright lads we know the biosynthesis pathway of cocaine now we have to put it into another plant any suggestion?"
"Tobacco plant!"
"Brilliant idea! Nicotine and cocaine in the same cigarette! You got yourself a promotion"
"And make sure to fertilize it real good so those cigarettes are gonna be real special"
😂😂😂
Excellent work! a question. What program do you use to draw the molecules in 3D?
Good job and you my friend are a fantastic chemist! Especially if you've completed this synthesis as its quite complex. Not as complex as that of LSD but still quite complex hence the natural cocaine process is still in use today. Agreed cocaine use is on the rise but the current 50-year-old obviously failed "drug war" is to blame. More police, more courts, more prisons and yet 1,000,000 dead in American and counting. Reduce demand through comprehensive drug treatment and decades long neglected needed societal reforms such as living wage jobs, affordable housing, and education and voila you reduce the sale of drugs. Simply puy you reduce the DEMAND side, and the supply side takes care of itself.
Thanks! Agree, probably need both sides :) and for the record, I did not synthesize this or suggest people to do this!!
LSD.....complex? Uh....not really. But what do I know? 🤭
LSD is easier unless it's the denovo total synthesis.
“Hey can I film myself make cocaine and talk abt the process for education” has to be the best call a police station has ever got.😂😂😂
A truly (education) experience indeed!
I just blows my mind how people come up with synthesis methods like this, it makes physics look easy.
Wow, cool video and good educational! I can't believe that CZcams no block by drugs (community rules of our CZcamsr channels) 🎉❤
if the synthesis wasnt so difficult, we would see cool psychedelic anologues like we do with phenethylamines
The cocaine industry is wealthy enough to set up R&Ds I would think.
🤔 We should let them know.....
Do you speak Spanish ?
I doubt you could have psychedelic cocaine analogues, Amphetamine primarily targets GPCRs while cocaine is primarily an inhibitor
Back in my jam band days I would dump 100 hits of lsd on a ball or two, we called it rainblow and it was amazing and as bad as it soinfs 😂
@@sunnohh by the time you can even consume that much LSD it’s probably not working anymote
@@flipsterfloppa9065but it seems to attach itself to sigma receptors... hence the bell rings?
Good video
Dude, your videos are amazing! Please, include the degradative studies, those are very important to understanding synthesis as they are the reverse process. IF its a matter of screen time that you don't have, take less time with historical background and more with degradative and other REAL interesting chemistry content. Cheers!
Thanks for the comment! Yeah I didnt want to completely focus on chemistry as I wanted to have some topics be relevant for non chemists as well. Might include it in a future one!
10:02 shapiro reaction! Of course exactly what everyone was thinking immediately...🤣
😂😂😂 this is my version of the ancient rome meme
Doing that without modern structure analytic methods, like NMR and a lot less known chemical methods is quite a challenge.
Absolutely!
I’m definitely now on a list
Subscribed! Love your content. We about to make some moneyyyy!
Hi , I hope there’s also for Methamphetamine synthesis, for educational purpose only😊 🙏 Thank you
Cody's lab did it- look at the patents (not joking)
Im a visual learner could u pls do a diy tutorial?
😂
Ok just asking for a friend how to get precursors?????
US-2019224185-A1
2-CMT + NaHg/acid -> EME salt/ PEM salt -> base (EME freebase) -> separation from PEM/HCl salt formation -> cocaine HCl
Aside from being on a watch list have a like ol chap
Keeping up with NileRed is going to gey yall roped bro.
Cocaine for epistaxis: coming back
If you make your cocaine like this for yourself you shouldn't be arrested for it 😂
The largest users of cocaine are those that can afford it.
It seems it would be a simple process for chemists to begin by extracting specific alkaloids from Datura Stramonium (atropine, hyoscyamine, scopolamine) as they are structurally similar and it doesn't seem like it would be that complex of a reaction series to convert to the target molecule.
For sure, the point here was *total* chemical synthesis
_Sings_ I'm in love with the coco. I got it for the low low. I'm in love with the coco!
I due to lack of education cannot understand 95% of the chemistry language but still very interesting lol 🤷♂️
3:45 i've never seen someone label the norepinephrine transporter as NAT, it's always NET
You acrually see both due to norepinephrine also being called noradrenaline
@@totalsynthesis yeah like i get why they chose NAT, it's just that i've literally never seen NAT in any publication
The degradative studies seem really interesting. Would you consider making a video on that?
Wouldnt be a long one to be honest, but I could combine it with some other Wilstätter work!
@@totalsynthesis You could also cover many examples of these kinds of studies explored by many different chemists. I've always been curious about how they elucidated chemical structures in that time period before modern analytical methods. Thanks!
Only choose organic GMO-free cocaine. Ask your dealer!
No wonder it's made using the coca plant lol.
? What is?
Yup, thinking how the plants do such complex synthesis in amazing on its own.
Totally cool 😎
I'm literally on coke tn and wanted to watch an interesting vid about it and this popped up on mu CZcams
I hope you watched the part around dangers and toxicity!
@@totalsynthesislol!
Freud basically secondhand created the first speedball
Digital Footprint is crazy
😂
OMG im about to turn a new heisenberg
Lol good luck upping this synthesis to a breaking bad level.... Good on ya if you figure it out lol
ferb ya se que vamos a hacer hoy
I think the tobacco yield is like 0.2 grams per pound of tobacco at a 100% yield. That looks strictly academic, but useful for building Organic synthesis machines that can do organic reactions, you cant unlock with a chemistry set.
At 12:28, why does the amine selectively attack the anti bromide and not the syn bromide?
The need for 'backside' attack in direct SN2 substitutions comes from molecular orbital considerations. Put simply, kicking something out requires an approach right opposite to the bond between carbon and the leaving group
@@totalsynthesis It's been a while since I've studied mechanisms but this started a good review. The bromine pulls electron density toward itself and leaves a void on the carbon it's bonded to from what I understand and also leads to an inversion of stereochemistry at that site. Thanks for the reply.
Yes, also its due to the geometry of the "antibonding" carbon-bromide sigma star orbital... If that tells you something
Richard Willstätter! Albert Hofmanns nemesis!
Hi NSA agent 👋🏼
This is gonna be one of those videos CZcams sends the viewers to the feds
It would probably be cleaner at least !
I’m sat here in hospital waiting room right now, been waiting over 8 hours to get sorted, my right leg is inflamed and swelling in pain from blood clots from shooting coke, and speedballs with heroin and coke mixed, I’m in agony.
Don’t get me wrong I know the majority of coke users sniff them powder or smoke it as crack etc, but shooting it up has caught me out.
You gon make me act up
Can you do a vid on Flunitrazepam pls
2:22 - So, OT Genasis is responsible for more use. Catchy song, but I have doubts.
Its fascinating that cocaine binds to the kappa opioid receptors, and honestly i think thats why it works better for (tooth) pain, in my very VERY limited experience, than lidocaine or any of it's analogs. It's like it keeps kiling pain even after the local anesthetic effects wear off. And this eas a small dose, not even enough to cause any kind of psychoactive effects..... Hrm :/
I wonder what part of the cocaine molecule interacts with kappa opioid receptors, and could we keep that, while removing the dopaminergic reuptake inhibition, like how lidocaine is a structural analoge
Kappa opioid agonists are interesting, though its effects on the central nervous system are uncomfortable (dysphoria, hallucinations, etc). Limiting the CNS effects could make them a potential painkiller though.
....And anti-itch. There's a peripheral kappa-opioid agonist used in Japan for itching due to chronic kidney disease.
@@RestInPropofol indeed, their effects are less than fun, but that's kinda a good thing- talwin works quite well for pain, but causes absolutely no buzz, just a vague deadened feeling and a deep apathy
But that's way better than a rush of euphoria so profound you just cry (what I did my first time taking Vicodin). I think we should use our kappa agonists more in medicine.
This is a layman’s guess but when looking at the structures of opioids they all tend to have tertiary amines, and often ketones which cocaine has both. That doesn’t explain salvinorin A though
@@90klh for some cases, i agree they do have their own perks
I would just like to say hello to my fellow list-residers and the agents who moniter us
Why does the chemical structure on the thumbnail looks like its about to score a goal after doing bicycle kick?
I thought to myself " i dont need to watch it " *my monkey brain* "ooo ooo useless info ooo oo "
Google algorithm at its best. I didn't search for this.. This searched for me.
Yeah its fucken got ya
Finally, i could start my own business
Of sharing educational science information, got it
Early chemists were badass!!
Facts
I'm not a chemist, so fogive me for not knowing, but it seems to me that double bonds (especially in carbon) seem to be less flexible. Is that an accurate observation?
Yes.
You cannot turn around a double bond, (if i make sense) that's how you can get trans vs cis isomerie.
Exactly as the gentleman pointed out. They can still wiggle around a bit but there is no rotation. This means the arrangement of the double bond is "locked" (whereas single bonds can turn around like crazy)
@@fukpoeslaw3613 Thanks!
@@totalsynthesis Ah gotcha that makes so much sense, thanks!
does synthesis mean making synthetic version of or just mean doing chemistry to make something?
Both things are kinda the same?
Hey! CZcams recomended this, so no watchlists, huh!?
How do they know they have right reaction each time?
Requires a lot of 'analytical' methods to characterize your products! And back in 1901, they sometimes didnt even really know what product they had
What did it smell like?
what technique was used to determine the structure of cocaine? I think NMR didn't exist back then
Combination of various methods, but notably Hofmann degradation if you want to look that up
But for sure NMR and most other analytical methods did not exist
They should use the "Ask Ned Flanders how it made him feel" technique for all drug brand names.
How does your nose feel, Ned? "Numberino!"
Lmao
Otto Snow says tropacocaine is better:
_Tropacocaine was discovered as a trace alkaloid in Coca leaves from Java. It is longer acting and less toxic than cocaine._
Description of _THC & Tropacocaine_ by Otto Snow (2004)
As someone from Java herself, it's always funny when i remember that our colonizers used to plant coca here (our current drugs laws + societal norms could never). Not exactly the kind you'd find in South America, but still useful. Albeit the reduced content of cocaine in this species initially posed a challenge before chemists figured out how to convert the main alkaloid in this species to cocaine.
Nice Video, but neither is cycloheptatriene flat, nor is cyclooctatetraene antiaromatic (since it is not flat as well).
Yeah you are right, I think on cycloheptatriene I was fooled by software when generating the molecule so I oversaw it's present in a boat form. On COT, also agree that it's not actually antiaromatic and avoids that by going non-planar. Good callouts, thank you!
Subliminal programming cocaine use increases addiction and relapse? Interesting. Science needs to go further with new data
That numbrino would get you tweaking out. 160mg/4mL vial? Wooooo
😂😂😂