Thanks for the feedback - very much appreciated 🙂 I’m using the preferred IUPAC description in the video - to count electrons not atoms and use square brackets. I think I’ve been bashed into doing this by default by physical chemists I know because I definitely used to use the atom counting convention. The electron one makes more sense in lots of ways to map the same reactivity/symmetry more consistently. Link is here to The Gold Book: goldbook.iupac.org/terms/view/C01496
Thanks 🙂 thought I’d try something a bit different. I dabbled in this area for a few years on a methodology project. You get some really cool coloured products with these systems.
Did you get the Nobel prize news early? Posted 10 days ago on a hot topic!! I work at a click chemistry reagent company and it's great seeing our day to day blow up like this .
Ah - actually I think I have mis-spoken there and haven’t noticed this before. Good spot! Should really say minimise alternative substitution reaction (ie using a non nucleophilic base)
Your channel really helps me understand organic synthesis a lot more, so keep going! Btw something to the part of making the 4-N,N-Dimethylamino-acetanilide: Wouldn’t be it much easier to use methanol and sulfuric acid instead of methyliodide? That especially might be safer because of the toxicity of methyliodide
Thanks for the feedback - very much appreciated :) The methanol/H+ route would probably be fine but I'd be worried about its efficiency. I've no doubt you'd get the product too in some yield but you are fighting against the amine just being protonated more often than not, and so the lone pair not being able to do substitution as easily. My experience with MeI in the lab hasn't been so bad as it's a pretty well-behaved liquid in practice (e.g. not so reactive with air), and so transferring it around in syringes isn't so much of a problem. Admittedly I'd want to find something else as an alkylating agent if I was on big scale. Although at that point you might just want to take a formaldehyde based route using an atmosphere of H2 in the presence of a metal catalyst (Ni or Pd) and do a double reductive amination.
@@CasualChemistry Eschweiler-Clarke reaction would probably be perfect for this step! Although with the off-gassing of CO2 during the process it may not be the preferred route for large scale (plant) production.
Thank you very much for your channel. It is totally useful for me. About the dimethylation of 4-aminoacetanilide, I would go for Eschweiler-Clarke reaction (methylation) to avoid formation of quartery ammonium salt which is very probable with methyliodide.
Yes - I totally agree, particularly on scale. I was trying to make sure the video was emphasising other points so wasn’t elaborating too much on that synthesis.
Very nice chemistry and explanations. Will try to use some bits with my students. At 18´38 you said that tBuOK was good to prevent some elimination? Elimination or prevent SN on the HexBr being a non nucleophilic base?
🙂 Thanks for the feedback - very much appreciated! Ah - very good spot! Yes, that’s a slip of the tongue from me there. I meant to prevent SN of the alkoxide on the hexBr. I must’ve missed that in editing, but I guess people will understand what I meant in that particular context.
Thanks :) Patreon maybe some day when I've got fewer real life things to juggle. Also need to have a think about what would be the best sort of thing I could provide for people in that model - ideas welcome!
I did a samdmeyer type reaction to add an azide on a calixarene before. No catalyst required, just an aromatic amine, NaNO2 and acid plus NaN3. I even dissolved the NaN3 in water and added it into the reaction as such, just keep it cool and it works with greater than 75% yield. Seems strange to kick off N2 to add N3 though, but diazo transfer is a pain in the ass. My brain feels so broken seeing the fluorene after having a nightcap of whiskey + milk until I realised it has axial chirality. Not sure if you cared for forming both enanteomers or is my whiskey affecting my judgement? 🤔
Definitely another route for sure - that slight wasn’t exhaustive - I guess I was trying to emphasise copper more to make a particular point. Agreed that swapping a diazo for an aside is intuitively very weird. There’s no axial chirality here between the aryl rings - the carbon with the gem dimethyls holds the biphenyl coplanar. It needs to be there to allow the pi conjugation across all of the rings for its use as a chromophore.
@@CasualChemistry LOL I still didn't trust you about the chirality until I drew it out...Shaking my head at myself. No more commenting allowed after whiskey for me XD...also I think the R substituents (n-hexyl in your case) at the 9 positions of the fluorene are there to prevent deprotonation which would give an aromatic cyclopentadiene type anion. That's the part that tripped me up for some reason. Even If they were different, I would still have been wrong about the axial chirality though XD
No worries! I’ve often had some great ideas for research projects after too many beers and only to realise I’d missed a carbon or something. That central carbon is certainly a point for diversification for making device libraries. You often see other elements in there too, but yes I agree for the C version some sort of substitution is required to remove the acidic protons from interfering with other stuff.
Love this one! The bit about the pyrimidine was very fascinating. Actually, that aminotetrazole is comparatively stable, as the amino group donates electron density to the ring. I don't think it's sensitive to any reasonable amount of shock or friction, but it probably is able to burn well. 16:50 Are you sure LiAlH4 is a good choice in this case? Wouldn't it just reduce the amide to an secondary amine? I would have picked aqueous acid (dilute sulfuric acid maybe) to hydrolyse that amide off.
🙂 Thanks for the feedback. It seemed like a good discussion point when I was doing some background checks on thing. An yes you’re totally right that should be a hydrolysis not a reduction - that’s a slip of the tongue/pen there. I must’ve been tired when doing the proof check! I’ll put a pinned comment on or something if I can’t edit it directly.
So luckily I think I've managed to be able to snip out a second of my voice and blur the reagent out and it still makes sense in context. It'll just take a bit of time for UA-cam to process the change. Annoyingly careless of me - but now I've learnt a new thing about editing on the platform.
Great video! Just a thought, could you not make the 4-azido-N,N-dimethylaniline from the 4-amino derivative via the Sandmeyer reaction? That's how I've made aryl azides in the past; I've never used it on a dialkyl phenylenediamine derivative before but I can't see there being issues aside from just needing extra acid to protonate the extra amine?
Thanks! 🙂 Glad you enjoyed the video. A Sandmeyer reaction is definitely possible here in my opinion when you have the required amine. I guess that slide isn't fully exhaustive - I was aiming for highlighting a few specific issues before getting back to the final product synthesis. Plus I was running out of drawing space 😂
Absolutely not at all - definitely always up for discussing the chemistry 🙂 I've got a series of videos on retrosynthesis precisely because I think it's cool to plan out and weigh up the pros and cons of things in synthesis when there's not only one well-defined "answer". It's definitely my favourite topic to teach when doing tutorials in-person.
The reaction is certain part of a sub-class of pericyclic reactions called 1,3-diplomat cycloadditions, but there are many other reactions in that class, e.g. in an ozonolysis mechanism, and also there are other 1,3-diplomat cycloadditions that tend to fall under the umbrella of “Click Chemistry”, e.g. nitrone-alkyne cycloadditions. So you often hear the azide-alkyne phrasing around the place to be more specific when talking about Click Chemistry
No. Metal-catalysed AACs such as the CuAAC have stepwise mechanisms, so the language of pericyclic chemistry is no longer strictly accurate. Uncatalysed AACs are 1,3-dipolar cycloadditions but - except for in strained systems - nobody does these reactions; this is because they require long reaction times and high temperatures (not good with azides) and lack the predictable regiocontrol of the CuAAC and RuAAC. So, on a fundamental mechanistic level and in terms of practical use, they are different reactions.
Ah yes - I see what you mean. The metal assisted reactions definitely have more elementary steps to the mechanisms - not least the pre coordination to get the regioselectivity
technically this molecule would fall under the drug isomer act (dont know the exact translation from my country) basically, it has a phenethylamine backbone, its illegal. quite strange. altho very good video
Glad you enjoyed the video 🙂 I figure the research teams making these things for real will be working under special licence for controlled substances for research progress.
Could you accomplish the aborted nitration of the NMe2 bearing aromatic ring using acetyl nitrate perhaps? Isn't this generally an acid-free way of nitrating aromatic rings for this sort of thing.
Do you have a reference for this? I would worry that you'd have to have a strong acid in there too to help form the NO2+ in the reaction, else you might need to heat that up a lot perhaps to the point of it being not so practical. It's certainly not an option that you see around the place so often.
I see what you're saying and I certainly used to use the atom counting notation. What I think I've learnt (actually from this comment in fact as I hadn't noticed myself!) is that after a number of years of poking, I've used the new "preferred" IUPAC convention of counting electrons instead for cycloadditions. goldbook.iupac.org/terms/view/C01496 That must be what happens working closely with physical organic chemists and also someone who works with IUPAC has done some effective behavioural nudging on me 😅 I'm not sure how I feel about that (!)
CORRECTION: At 16:45, in the bottom-left corner of the screen: This should be a hydrolysis using NaOH on the arrow, not LiAlH4. Whoops!
At 3:42 it should also say [3+2] cycloaddition not [4+2]. Great videos, thank you very much!
Thanks for the feedback - very much appreciated 🙂
I’m using the preferred IUPAC description in the video - to count electrons not atoms and use square brackets. I think I’ve been bashed into doing this by default by physical chemists I know because I definitely used to use the atom counting convention. The electron one makes more sense in lots of ways to map the same reactivity/symmetry more consistently. Link is here to The Gold Book:
goldbook.iupac.org/terms/view/C01496
Very cool! I like that you brought in molecules with applications beyond just pharmaceuticals.
Thanks 🙂 thought I’d try something a bit different. I dabbled in this area for a few years on a methodology project. You get some really cool coloured products with these systems.
Did you get the Nobel prize news early? Posted 10 days ago on a hot topic!! I work at a click chemistry reagent company and it's great seeing our day to day blow up like this .
🤣 lol no, but I was hedging my bets in case of this eventuality and moved this video up in my production schedule
At 18:35, how would tert-butoxide reduce the risk of elimination on the bromohexane?
Ah - actually I think I have mis-spoken there and haven’t noticed this before. Good spot! Should really say minimise alternative substitution reaction (ie using a non nucleophilic base)
Your channel really helps me understand organic synthesis a lot more, so keep going!
Btw something to the part of making the 4-N,N-Dimethylamino-acetanilide: Wouldn’t be it much easier to use methanol and sulfuric acid instead of methyliodide? That especially might be safer because of the toxicity of methyliodide
Thanks for the feedback - very much appreciated :)
The methanol/H+ route would probably be fine but I'd be worried about its efficiency. I've no doubt you'd get the product too in some yield but you are fighting against the amine just being protonated more often than not, and so the lone pair not being able to do substitution as easily. My experience with MeI in the lab hasn't been so bad as it's a pretty well-behaved liquid in practice (e.g. not so reactive with air), and so transferring it around in syringes isn't so much of a problem. Admittedly I'd want to find something else as an alkylating agent if I was on big scale. Although at that point you might just want to take a formaldehyde based route using an atmosphere of H2 in the presence of a metal catalyst (Ni or Pd) and do a double reductive amination.
@@CasualChemistry I mean, you are still the expert; But yeah, now I learned another thing :)
@@CasualChemistry Eschweiler-Clarke reaction would probably be perfect for this step! Although with the off-gassing of CO2 during the process it may not be the preferred route for large scale (plant) production.
Genuinely enjoyed the video, you made a very complicated topic easy to digest and enjoy, love the content looking out for the next video !
Thanks for the feedback 🙂 Very much appreciated and glad you enjoyed the video. More on the way for sure when I can squeeze in the recording time.
Thank you very much for your channel. It is totally useful for me. About the dimethylation of 4-aminoacetanilide, I would go for Eschweiler-Clarke reaction (methylation) to avoid formation of quartery ammonium salt which is very probable with methyliodide.
Yes - I totally agree, particularly on scale. I was trying to make sure the video was emphasising other points so wasn’t elaborating too much on that synthesis.
Very nice chemistry and explanations. Will try to use some bits with my students. At 18´38 you said that tBuOK was good to prevent some elimination? Elimination or prevent SN on the HexBr being a non nucleophilic base?
🙂 Thanks for the feedback - very much appreciated!
Ah - very good spot! Yes, that’s a slip of the tongue from me there. I meant to prevent SN of the alkoxide on the hexBr. I must’ve missed that in editing, but I guess people will understand what I meant in that particular context.
I wish i have seen this video few week back. I jus did my PhD candidacy Orals yesterday on Aliphatic cycopolymers using Click chemistry
Hope the viva went well!
excellent course, I obtain enormous of useful knowledge from this video, as a synthesis engineer respecting author
Thanks 🙂 I liked making this video because I wanted to highlight non-biological connected synthesis
One of the best chemistry videos ever . Bravo
- start a patreon??
Thanks :) Patreon maybe some day when I've got fewer real life things to juggle. Also need to have a think about what would be the best sort of thing I could provide for people in that model - ideas welcome!
I did a samdmeyer type reaction to add an azide on a calixarene before. No catalyst required, just an aromatic amine, NaNO2 and acid plus NaN3. I even dissolved the NaN3 in water and added it into the reaction as such, just keep it cool and it works with greater than 75% yield. Seems strange to kick off N2 to add N3 though, but diazo transfer is a pain in the ass. My brain feels so broken seeing the fluorene after having a nightcap of whiskey + milk until I realised it has axial chirality. Not sure if you cared for forming both enanteomers or is my whiskey affecting my judgement? 🤔
Definitely another route for sure - that slight wasn’t exhaustive - I guess I was trying to emphasise copper more to make a particular point. Agreed that swapping a diazo for an aside is intuitively very weird.
There’s no axial chirality here between the aryl rings - the carbon with the gem dimethyls holds the biphenyl coplanar. It needs to be there to allow the pi conjugation across all of the rings for its use as a chromophore.
@@CasualChemistry LOL I still didn't trust you about the chirality until I drew it out...Shaking my head at myself. No more commenting allowed after whiskey for me XD...also I think the R substituents (n-hexyl in your case) at the 9 positions of the fluorene are there to prevent deprotonation which would give an aromatic cyclopentadiene type anion. That's the part that tripped me up for some reason. Even If they were different, I would still have been wrong about the axial chirality though XD
No worries! I’ve often had some great ideas for research projects after too many beers and only to realise I’d missed a carbon or something. That central carbon is certainly a point for diversification for making device libraries. You often see other elements in there too, but yes I agree for the C version some sort of substitution is required to remove the acidic protons from interfering with other stuff.
Love this one! The bit about the pyrimidine was very fascinating. Actually, that aminotetrazole is comparatively stable, as the amino group donates electron density to the ring. I don't think it's sensitive to any reasonable amount of shock or friction, but it probably is able to burn well.
16:50 Are you sure LiAlH4 is a good choice in this case? Wouldn't it just reduce the amide to an secondary amine? I would have picked aqueous acid (dilute sulfuric acid maybe) to hydrolyse that amide off.
🙂 Thanks for the feedback. It seemed like a good discussion point when I was doing some background checks on thing. An yes you’re totally right that should be a hydrolysis not a reduction - that’s a slip of the tongue/pen there. I must’ve been tired when doing the proof check! I’ll put a pinned comment on or something if I can’t edit it directly.
@@CasualChemistry No worries, that happens!
So luckily I think I've managed to be able to snip out a second of my voice and blur the reagent out and it still makes sense in context. It'll just take a bit of time for UA-cam to process the change. Annoyingly careless of me - but now I've learnt a new thing about editing on the platform.
Subscribed! I found about this video and channel via That Chemist.
Cool 🙂 his channel is great and we’ve been sharing experience on making chemistry videos recently
@@CasualChemistry
That's good to hear! Wishing your channel the very best 😃
Absolute great Video and very helpful :)
Thanks 🙂 glad the video was helpful. It means a lot to me to get the feedback
Great video! Just a thought, could you not make the 4-azido-N,N-dimethylaniline from the 4-amino derivative via the Sandmeyer reaction? That's how I've made aryl azides in the past; I've never used it on a dialkyl phenylenediamine derivative before but I can't see there being issues aside from just needing extra acid to protonate the extra amine?
Thanks! 🙂 Glad you enjoyed the video. A Sandmeyer reaction is definitely possible here in my opinion when you have the required amine. I guess that slide isn't fully exhaustive - I was aiming for highlighting a few specific issues before getting back to the final product synthesis. Plus I was running out of drawing space 😂
@@CasualChemistry of course, I hope it didn't look like I was nitpicking!
Absolutely not at all - definitely always up for discussing the chemistry 🙂 I've got a series of videos on retrosynthesis precisely because I think it's cool to plan out and weigh up the pros and cons of things in synthesis when there's not only one well-defined "answer". It's definitely my favourite topic to teach when doing tutorials in-person.
Thank you!
🙂 No worries
Out of interest: Isn't the azide-alkyne coupling better described as 1,3-dipolar cycloaddition?
Regarding the differences to a classic [4+2] CA like the Diels-Alder reaction in substrate scope and reaction mechanism.
The reaction is certain part of a sub-class of pericyclic reactions called 1,3-diplomat cycloadditions, but there are many other reactions in that class, e.g. in an ozonolysis mechanism, and also there are other 1,3-diplomat cycloadditions that tend to fall under the umbrella of “Click Chemistry”, e.g. nitrone-alkyne cycloadditions.
So you often hear the azide-alkyne phrasing around the place to be more specific when talking about Click Chemistry
No. Metal-catalysed AACs such as the CuAAC have stepwise mechanisms, so the language of pericyclic chemistry is no longer strictly accurate. Uncatalysed AACs are 1,3-dipolar cycloadditions but - except for in strained systems - nobody does these reactions; this is because they require long reaction times and high temperatures (not good with azides) and lack the predictable regiocontrol of the CuAAC and RuAAC. So, on a fundamental mechanistic level and in terms of practical use, they are different reactions.
Ah yes - I see what you mean. The metal assisted reactions definitely have more elementary steps to the mechanisms - not least the pre coordination to get the regioselectivity
technically this molecule would fall under the drug isomer act (dont know the exact translation from my country) basically, it has a phenethylamine backbone, its illegal.
quite strange. altho very good video
Glad you enjoyed the video 🙂 I figure the research teams making these things for real will be working under special licence for controlled substances for research progress.
Could you accomplish the aborted nitration of the NMe2 bearing aromatic ring using acetyl nitrate perhaps? Isn't this generally an acid-free way of nitrating aromatic rings for this sort of thing.
Do you have a reference for this? I would worry that you'd have to have a strong acid in there too to help form the NO2+ in the reaction, else you might need to heat that up a lot perhaps to the point of it being not so practical. It's certainly not an option that you see around the place so often.
Nice, but its a [3+2] not a [4+2] cycloaddition as stated
I see what you're saying and I certainly used to use the atom counting notation. What I think I've learnt (actually from this comment in fact as I hadn't noticed myself!) is that after a number of years of poking, I've used the new "preferred" IUPAC convention of counting electrons instead for cycloadditions.
goldbook.iupac.org/terms/view/C01496
That must be what happens working closely with physical organic chemists and also someone who works with IUPAC has done some effective behavioural nudging on me 😅 I'm not sure how I feel about that (!)
Woww...It’s really amazing ❤️
🙂 Thanks for the feedback. Glad you enjoyed the video!
Click bait :p
😂 I did tweak the title card last week when the prize was announced.