Going into my masters in organic now, we never spent too long on retro synth because the lead of the course oriented half of the course around the synthesis of peptides and biosynthesis in the 2nd and 3rd year organic courses unfortunately. So these vids are really good to understand the processes of it
That’s a shame cos it’s such a cool way to re-frame different ways of thinking about organic chemistry. It’s certainly one of my favourite topics when teaching in small groups as your discussions can go in all sorts of directions and there’s not necessarily one “correct” answer when doing stuff on paper. I’ll definitely be making these videos a core thread on my channel as it’s something I noticed there isn’t much out there on e.g. TH-cam. I’m trying to make sure each one has some new type of idea embedded in it, and I’m varying the level of the pitch to see what people like the most.
@@CasualChemistry i agree with you on that part, it’s definitely a way of collaborating and offers a better way of coming up with syntheses. It’s also good for revising and such, hearing others go over it helps to identify key reactions for when you go to do a retrosynth yourself. I know total synthesis has some similar things, not really retrosynth but explaining in a fair amount of depth the methodology of certain syntheses.
Agreed. It’s such a powerful mindset but also one that can be overlooked and often taught in a very formulaic style. To me, perhaps a bit too geekily, I can get into great discussions on the back of beermats with friends too outside of teaching that are really fun. I’m hoping that I can put something more/different out into the education space online.
@@CasualChemistry I personally couldn’t think of anything better tbh. My friends all have jobs etc. and the people in my course don’t seem to find chemistry as interesting as I do. So those discussions aren’t very common for me. My sister is doing a PhD in it, but as you could probably imagine she doesn’t tend to want to talk about Chem after work ahah. I love learning new things about chem and I’d love to be able to have discussions down at the boozer with some of my course mates lol. I think there’s a gap in the market for this sort of quality content, keep it up pal
Noted. This was my first ever video and before I’d bought a separate microphone. I think I’ve fixed the sound on most of my other videos, many of which are on retrosynthesis if you fancy checking them out 🙂
@@CasualChemistry I was watching this in metro so it made some difficulties, although the visual part was well intuitive) Thank you so much for these explanation. There was a notable lack of videos like these.
Hi! Really appreciate the inspiring video!❤ But since the NaBH4 reduction here is on a planar ketone, will that give rise to a racemic alcohol? And is it correct that steps after reduction are stereospecific? If that’s so, will we eventually yield racemic thiols?
:) Thanks - my first ever video this one. Yes, it's deliberately a racemic synthesis, so the thiol product will be racemic too. There's no opportunity for preferring one enantiomer here over another, though there are ways of doing that with more complicated reagents - such as a a "chiral version" of NaBH4 like the CBS catalyst (I have a video on that topic btw). I've got loads of other retrosynthesis videos on my channel if interested. I try to do something a bit different in each one, so they're a mixture of racemic syntheses and asymmetric syntheses, sometime using catalysis, sometimes not.
No reason why you couldn’t use it for sure in the reaction. It’s pretty toxic though so I wouldn’t want to be using a lot of it. I don’t think the reaction needs too much help though as the transformation is usually pretty easy using these conditions.
I’ll have a think about them but I usually focus on an underlying teaching topic rather than a specific molecule. On a glance it looks like Buchwald-Hartwig couplings would be useful for these.
are you sure that your amide substituted benzene will favour ortho and para substitution? Wont the N-lonepair be delocalized with the sigma * of the carbonyle and not delocalized in the benzene ring?
Not a very reliable reaction I'm afraid unless you have a very specific aldehyde - usually only really formaldehyde - and you certainly need something non-enolisable else you'll just get aldol reactions in preference.
Many thanks for the feedback :) Was finding my feet with this one as it's my first try at making a video. Do you have a timestamp for the methyl groups? Easily done by accident as usual in organic chemistry...
@@CasualChemistry Yep. I'm surprised you don't have more views. This is excellent content you're giving away for free. Are you perhaps also on #ChemTwitter? Btw. Do you happen to have a copy of Prof Roman Valiulin's "Organic Chemistry: 100 Must-Know Mechanisms"? I might have to buy one.
Hi Casual Chemistry, Sorry to comment on this video like this (I wasn't sure how else to reach you and this was the first video I saw). I just had a question I was wondering if you could help with. I am currently an undergrad and I am in the process of developing my research to write my thesis on. I am very interested in organic synthesis and compounds with antibacterial properties, and my professor worked on quinolines a fair amount in grad school, so I am focusing my research on that. Specifically, I would like to synthesize a 2,3 diubstituted quinoline with bulky groups on it (preferably a phenyl group and cyclohexane) and compare it to 2,4 disubstituted quinolines to test their antibacterial activity. However, I am having a very difficult time coming up with a synthesis for this, as most 2,3 substitutions rely on aldol condensation between o-aminobenzyl alcohol (oxidized to an aldehyde) and a secondary ketone, which means it won't really work to have a phenyl group on the ketone as I would need an alpha carbon to deprotonate, and the ring tends to stabilize compounds to be less reactive. Do you have any suggestions on how I could accomplish this synthesis? I'm sorry if this explanation was confusing and I can definitely clarify point if I did not explain it well. Thank you for your time, Kendall Doer
To be honest, I don’t have very much direct lab experience on making quinolines, but here are my initial thoughts. It might be easier to use syntheses that come from the parent aromatic amine without the ortho-CHO/CH2OH. There are two ways that might work: First, react the ArNH2 with an alpha,beta-unsaturated carbonyl with it doing Michael addition via the amine. Then use a Lewis acid to promote cyclisation-aromatisation. The alpha,beta-unsaturated ketones could be made separately by Wittig or HWE reaction, which should be pretty tolaerant of varying the groups. This would essentially be a variation on the Skraup synthesis. Alternatively, react the ArNH2 with 1,3-dicarbonyls that you’ve made separately (Coombes-type synthesis). This route has a higher risk of making regioisomers, but that would depend on exactly what you’re doing. Though if your aim is to make a library for separate biological testing, this might not be a bad thing. You could make two regioisomers from one reaction and then you could get a sample of both of them, provided that you can separate them (or even just purify a small bit of each of them). The other thing that comes to mind is perhaps using the quinolones instead first (quinolines oxidised in the 2-position) with whatever you need at the 3-poistion put in first when you build the quinoline N-containing ring. The quinolone could then be converted to the quinoline-2-chloride with e.g. POCl3. Then you could react the chloride by SNAr substitution with a Grignard reagent. You might also get away with a transition-metal mediated cross-coupling for when you’re substituting the chloride with an aromatic substituent (but probably not viable with the cyclohexyl). Hope this helps! :)
@UCxUnFxzZjb5BHpaDCHvwRnw Thanks for the reply! For the first suggestion, wouldn't it need to be an alpha beta-unsaturated aldehyde (just for the reactivity of the way the cyclization works)? Because I think the R groups need to be on carbons 2 and 3 of the aldehyde to get 2,3 substitution on the final quinoline product. Also, I haven't looked into it, but is it even possible to get cyclohexane and a phenyl group right next to each other on an alpha beta-unsaturated aldehyde via the Wittig rxn? It seems like it would be very unstable and would make the aldehyde less reactive. I will definitely take a look at the third option; I hadn't thought of doing something quite like that yet. I thought about Combes synthesis but haven't thought of a great way to get the rxn to go yet though. Thanks again for your time!
Also, would it be possible to leave the carbonyl intact in the third option and just have a phenyl group with MgBr on it to get that substitute on the 2nd carbon, or would that end up being too bulky to attack the carbonyl since the carbonyl is in the quinolone ring?
Yes you’d need the aldehyde if you’re making the 2,3 only substitution pattern, but that might be a helpful method if you need something at 4. There are lots of variants of Wittig type reactions that can deal with bulkier systems. E.g. even an HWE olefination can tolerate more substitution that a Wittig as the mechanism is essentially ionic (a fancy aldol reaction in essence). Whether or not it’s reactive enough in the cyclisation step I don’t know and you’d have to try. It would have the advantage of being intramolecular and heading to an aromatic product to drive this over just a direct nucleophile attack.
Perhaps but it’s much more common to use the chloride and SNAr type reactions as the ring might not exist in the “carbonyl” tautomer in your solution, but rather the “hydroxyl” form of the quinolone. It’s very hard to predict on paper for specific molecules what the preference is, and you might even just have a mixture of tautomers in solution in practice.
You'll definitely acylate on the nitrogen first and form the amide because that route doesn't involve breaking aromaticity - but I guess you could hydrolyse the amide off again. Just a bit messier.
Sorry - it was my first ever attempt at a video and before I’d bought a microphone. I’ve addressed that on my other video, many of which are also on retrosynthesis if you fancy checking them out
couldn't you just save 1 step by adding bromine to your aniline derivative and then doing a grignard? that would immediately give you the alkohol, and you could maybe even control the sterochemistry of the alkohol by using TADDOLe? I dont see a problem cause our the proton on the aldehyde isnt acidic enough do be deprotonated by the grignard? As long as you take into consideration that you will get an inversion of configuration after treating the alcohol with PBr3
For sure - this is an alternative route to the product depending on what you fancy doing in the lab. If you needed it to be enantioselective you could also do a CBS reduction of the ketone in the video.
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Going into my masters in organic now, we never spent too long on retro synth because the lead of the course oriented half of the course around the synthesis of peptides and biosynthesis in the 2nd and 3rd year organic courses unfortunately.
So these vids are really good to understand the processes of it
That’s a shame cos it’s such a cool way to re-frame different ways of thinking about organic chemistry. It’s certainly one of my favourite topics when teaching in small groups as your discussions can go in all sorts of directions and there’s not necessarily one “correct” answer when doing stuff on paper.
I’ll definitely be making these videos a core thread on my channel as it’s something I noticed there isn’t much out there on e.g. TH-cam. I’m trying to make sure each one has some new type of idea embedded in it, and I’m varying the level of the pitch to see what people like the most.
@@CasualChemistry i agree with you on that part, it’s definitely a way of collaborating and offers a better way of coming up with syntheses. It’s also good for revising and such, hearing others go over it helps to identify key reactions for when you go to do a retrosynth yourself.
I know total synthesis has some similar things, not really retrosynth but explaining in a fair amount of depth the methodology of certain syntheses.
Agreed. It’s such a powerful mindset but also one that can be overlooked and often taught in a very formulaic style. To me, perhaps a bit too geekily, I can get into great discussions on the back of beermats with friends too outside of teaching that are really fun. I’m hoping that I can put something more/different out into the education space online.
@@CasualChemistry I personally couldn’t think of anything better tbh. My friends all have jobs etc. and the people in my course don’t seem to find chemistry as interesting as I do. So those discussions aren’t very common for me.
My sister is doing a PhD in it, but as you could probably imagine she doesn’t tend to want to talk about Chem after work ahah. I love learning new things about chem and I’d love to be able to have discussions down at the boozer with some of my course mates lol.
I think there’s a gap in the market for this sort of quality content, keep it up pal
Well done synthesis and presentation! Thank you.
😀 Thanks. Glad you enjoyed
Thank you so much 😢😢😢i needed this in depth explanation to understand. Thank you. Thank you! Thank you!
You’re welcome 🙂 I’ve made some more videos on these topics that might also be helpful
Great effort and nice explanation. Thank you
No worries - glad you enjoyed the video 🙂
@@CasualChemistry 🙂. Yes, of course.
Wow your videos are soo good!
Thanks 😊 Glad you’ve enjoyed them so far - more on the way
The sound is too quiet. Still very helpful
Noted. This was my first ever video and before I’d bought a separate microphone. I think I’ve fixed the sound on most of my other videos, many of which are on retrosynthesis if you fancy checking them out 🙂
@@CasualChemistry I was watching this in metro so it made some difficulties, although the visual part was well intuitive) Thank you so much for these explanation. There was a notable lack of videos like these.
🙂 I also noticed the absence. I’m hoping I can help to change that over time.
Hi! Really appreciate the inspiring video!❤ But since the NaBH4 reduction here is on a planar ketone, will that give rise to a racemic alcohol? And is it correct that steps after reduction are stereospecific? If that’s so, will we eventually yield racemic thiols?
:) Thanks - my first ever video this one. Yes, it's deliberately a racemic synthesis, so the thiol product will be racemic too. There's no opportunity for preferring one enantiomer here over another, though there are ways of doing that with more complicated reagents - such as a a "chiral version" of NaBH4 like the CBS catalyst (I have a video on that topic btw).
I've got loads of other retrosynthesis videos on my channel if interested. I try to do something a bit different in each one, so they're a mixture of racemic syntheses and asymmetric syntheses, sometime using catalysis, sometimes not.
wouldnt DMAP do a better job as a nucleophilic catalyst for the first synthesis step?
No reason why you couldn’t use it for sure in the reaction. It’s pretty toxic though so I wouldn’t want to be using a lot of it. I don’t think the reaction needs too much help though as the transformation is usually pretty easy using these conditions.
Excelent video! Keep it up!
Thanks 🙂 This was my first ever one as an experiment and was still learning how to make videos. It’s turned into a nice hobby now
Can you please make vedio on retrosynthesis of aceclofenac and diclofenac
I’ll have a think about them but I usually focus on an underlying teaching topic rather than a specific molecule. On a glance it looks like Buchwald-Hartwig couplings would be useful for these.
are you sure that your amide substituted benzene will favour ortho and para substitution? Wont the N-lonepair be delocalized with the sigma * of the carbonyle and not delocalized in the benzene ring?
Yes - very sure this will direct ortho para. Although it’s delocalised into the carbonyl as well, it will be delocalised over the ring too.
I would have used butanal/AlCl3 instead to do a FC hydroxyalkylation directly to the secondary alcohol. saves a step.
Not a very reliable reaction I'm afraid unless you have a very specific aldehyde - usually only really formaldehyde - and you certainly need something non-enolisable else you'll just get aldol reactions in preference.
Nice explanations and synthesis! At the End u forgot some CH3-Groups :D
Many thanks for the feedback :) Was finding my feet with this one as it's my first try at making a video. Do you have a timestamp for the methyl groups? Easily done by accident as usual in organic chemistry...
Watching this after getting A+ in Organic Chemistry in College and working in Industry for a few years feel a little bit strange.
:) Plenty more on my channel. This was my first one when I was trying to work out what to do.
@@CasualChemistry Yep. I'm surprised you don't have more views. This is excellent content you're giving away for free. Are you perhaps also on #ChemTwitter? Btw. Do you happen to have a copy of Prof Roman Valiulin's "Organic Chemistry: 100 Must-Know Mechanisms"? I might have to buy one.
I don't have that specific book - I'll look out for it. I've put the odd thing on Twitter but perhaps not using it as effectively as I could.
Very Well 🥰
Thanks 🙂
Hi Casual Chemistry,
Sorry to comment on this video like this (I wasn't sure how else to reach you and this was the first video I saw). I just had a question I was wondering if you could help with. I am currently an undergrad and I am in the process of developing my research to write my thesis on. I am very interested in organic synthesis and compounds with antibacterial properties, and my professor worked on quinolines a fair amount in grad school, so I am focusing my research on that. Specifically, I would like to synthesize a 2,3 diubstituted quinoline with bulky groups on it (preferably a phenyl group and cyclohexane) and compare it to 2,4 disubstituted quinolines to test their antibacterial activity. However, I am having a very difficult time coming up with a synthesis for this, as most 2,3 substitutions rely on aldol condensation between o-aminobenzyl alcohol (oxidized to an aldehyde) and a secondary ketone, which means it won't really work to have a phenyl group on the ketone as I would need an alpha carbon to deprotonate, and the ring tends to stabilize compounds to be less reactive. Do you have any suggestions on how I could accomplish this synthesis?
I'm sorry if this explanation was confusing and I can definitely clarify point if I did not explain it well.
Thank you for your time,
Kendall Doer
To be honest, I don’t have very much direct lab experience on making quinolines, but here are my initial thoughts.
It might be easier to use syntheses that come from the parent aromatic amine without the ortho-CHO/CH2OH. There are two ways that might work:
First, react the ArNH2 with an alpha,beta-unsaturated carbonyl with it doing Michael addition via the amine. Then use a Lewis acid to promote cyclisation-aromatisation. The alpha,beta-unsaturated ketones could be made separately by Wittig or HWE reaction, which should be pretty tolaerant of varying the groups. This would essentially be a variation on the Skraup synthesis.
Alternatively, react the ArNH2 with 1,3-dicarbonyls that you’ve made separately (Coombes-type synthesis). This route has a higher risk of making regioisomers, but that would depend on exactly what you’re doing. Though if your aim is to make a library for separate biological testing, this might not be a bad thing. You could make two regioisomers from one reaction and then you could get a sample of both of them, provided that you can separate them (or even just purify a small bit of each of them).
The other thing that comes to mind is perhaps using the quinolones instead first (quinolines oxidised in the 2-position) with whatever you need at the 3-poistion put in first when you build the quinoline N-containing ring. The quinolone could then be converted to the quinoline-2-chloride with e.g. POCl3. Then you could react the chloride by SNAr substitution with a Grignard reagent. You might also get away with a transition-metal mediated cross-coupling for when you’re substituting the chloride with an aromatic substituent (but probably not viable with the cyclohexyl).
Hope this helps! :)
@UCxUnFxzZjb5BHpaDCHvwRnw Thanks for the reply! For the first suggestion, wouldn't it need to be an alpha beta-unsaturated aldehyde (just for the reactivity of the way the cyclization works)? Because I think the R groups need to be on carbons 2 and 3 of the aldehyde to get 2,3 substitution on the final quinoline product. Also, I haven't looked into it, but is it even possible to get cyclohexane and a phenyl group right next to each other on an alpha beta-unsaturated aldehyde via the Wittig rxn? It seems like it would be very unstable and would make the aldehyde less reactive.
I will definitely take a look at the third option; I hadn't thought of doing something quite like that yet. I thought about Combes synthesis but haven't thought of a great way to get the rxn to go yet though.
Thanks again for your time!
Also, would it be possible to leave the carbonyl intact in the third option and just have a phenyl group with MgBr on it to get that substitute on the 2nd carbon, or would that end up being too bulky to attack the carbonyl since the carbonyl is in the quinolone ring?
Yes you’d need the aldehyde if you’re making the 2,3 only substitution pattern, but that might be a helpful method if you need something at 4. There are lots of variants of Wittig type reactions that can deal with bulkier systems. E.g. even an HWE olefination can tolerate more substitution that a Wittig as the mechanism is essentially ionic (a fancy aldol reaction in essence). Whether or not it’s reactive enough in the cyclisation step I don’t know and you’d have to try. It would have the advantage of being intramolecular and heading to an aromatic product to drive this over just a direct nucleophile attack.
Perhaps but it’s much more common to use the chloride and SNAr type reactions as the ring might not exist in the “carbonyl” tautomer in your solution, but rather the “hydroxyl” form of the quinolone. It’s very hard to predict on paper for specific molecules what the preference is, and you might even just have a mixture of tautomers in solution in practice.
It’s not possible to do Friedel Craft Acylation with aniline
You'll definitely acylate on the nitrogen first and form the amide because that route doesn't involve breaking aromaticity - but I guess you could hydrolyse the amide off again. Just a bit messier.
Legend
🙂 Thanks
The video’s volume is too low
Sorry - it was my first ever attempt at a video and before I’d bought a microphone. I’ve addressed that on my other video, many of which are also on retrosynthesis if you fancy checking them out
couldn't you just save 1 step by adding bromine to your aniline derivative and then doing a grignard? that would immediately give you the alkohol, and you could maybe even control the sterochemistry of the alkohol by using TADDOLe? I dont see a problem cause our the proton on the aldehyde isnt acidic enough do be deprotonated by the grignard? As long as you take into consideration that you will get an inversion of configuration after treating the alcohol with PBr3
For sure - this is an alternative route to the product depending on what you fancy doing in the lab. If you needed it to be enantioselective you could also do a CBS reduction of the ketone in the video.
👏🏻👍🏻
Glad you enjoyed the video 🙂 Thanks for the feedback
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