I made a problem based on this article. Ferricyanide doesn't form nitriles from sulfonates (or with at least an order of magnitude smaller yield). Thank you for the video and bringing up this topic. But, I would suggest you pay closer attention to drawing formulae, there are several mistakes
@@rojaslab Your video almost verbatim repeats the article 10.1021/ja01437a023. I haven't seen a single procedure employing iron complexes for introducing the nitrile moiety, only neat cyanides
Very interesting pathway. I was thinking more about something less selective but more brute force: 1.) Taking succinic acid and turning it into its acyl chloride 2.) Friedel-Crafts double dropwise acylation in dilute solution (high bp solvent) with a slight excess of naphthalene at >100C which is mainly expected to occur at the least crowded positions on the aromatic rings. Dilute and with slight excess because although the double carbonyl group is deactivating towards the aromatic system you still don’t want a double-substitution that makes a fused 4 ring system and you don’t want two naphthalene groups bridged by the succinic bit. 3.) Reduction of the carbonyl to alcohol with NaBH4 4.) Turning the diol into dibromide 5.) Reacting the dibromide with KOH in methanol to eliminate Br and H and form two alkene bonds, thus creating the new aromatic ring.
3 methods I did : 1. Using diels alder reaction with butadiene creates anthracene skeleton but adding further double bond might be tough which can be done by Pt(300°C) . However diene may attach anywhere in the whole naphtalene. 2. Malonic acid, using SOCl2 , gets acid chloride then Friedel craft acylation and reduction using NaBH4 followed by conc H2SO4(dehydrate) . This also gives some more products like phenanthrene etc. 3. Using 1-iodo, 2-(a good leaving grp like OTs) butane first performs anchimeric assistance, then naphthalene double bond attacks as nucleophile(maybe) followed by friedel craft alkylation, after which reduction again with Pt 300°C.
Oh those are really great ideas. I really like those. I know for sure that the route in this video has been published but I wonder if anyone has ever tried any of your routes!
For the next problem I would use 1,3 cyclohexandione which has a pretty acidic a carbon as a nucleophile (actually it is very interesting why it is even more acidic than a linear 1,3 diketone - the conjugated system of the enolate is locked and the lack of rotation alines the π* orbital of the π bond with the lone pair when the a carbon in the middle gets deprotonated, the same reason explains the high acidity of Meldrum's acid), then a b addition occurs because the enolate is a soft nucleophile from the a carbon and the beta carbon of acrolein is a soft electrophile. Then the real fun begins because we should chemoselectively completely reduce the aldehyde and not the ketone FGs. I would use a thioacetal protection with ethanedithiol ideally at a low temperature, with low dithiol excess and for a short amount of time to ensure the thioacetal is formed selectively at the aldehyde since aldehydes are more reactive. Then an acetal protection at the 2 carbonyls and finally a catalytic hydrogenolysis with Raney Nickel of the thioacetal which reduces a thioacetal to an alkane. Deprotection of the 2 acetals using pTsOH with acetone will transacetalise the acetal protection of the 2 carbonyls of the substrate to acetone giving us the final product. Otherwise since the thioacetal protection is not a very common reaction and it is typically not used because of the extremely disturbing smell of the chemical, a Wolff-Kischner or a Clemmensen reduction would also completely reduce a carbonyl FG but I highly doubt that the process will be chemoselective.
Oh that's an interesting proposal for the next one! I was actually thinking of addition to the carbonyl carbon using nbuLi, re-oxidizing and then move toward a dieckman cyclization. Yours is pretty cool though!
@@rojaslab yes and I would really think that making a video about the hard-soft acid base theory and MO theory and their applications in organic chemistry would be a great video topic for you. Many chemistry students might know the reactions and the mechanism behind them but don't really understand in a molecular stucture and orbital level why reactions happen. It is also something that TH-cam organic chemistry, as far as I have researched, lacks and as a pharmacy undergrad it took me lots of time studying to deeply understand these topics. Because I see that you are a great educator I think you can make it happen!
That's a great idea and a few people have suggested that as well. I don't think napthalene would act as an effective dienophile, especially without putting the 3rd ring in a different placement, keeping it from being that symmetrical fused cyclic system.
I wonder if there is a way you can use the Bergman cyclisation? Perhaps you chlorinate the 2-position, then react with BuLi (Cl is an ortho directing group) and iodine to make 2-chloro-3-iodo naphthalene (and probably some 2-chloro-1-iodo naphthalene), then sonagshira with trimethylsilyl acetylene, cleavage of the silyl, then bergman cyclisation.
Oh that's an awesome idea! What's funny is that even though my training is in organometallic chemistry, I often try to avoid using it in my multistep synthesis problems because I think most people will think it's cheating haha. But that's just transition metals allow for way cooler chemistry, IMO!
Really nice procedure, and interesting last step! I ended up looking up methods for lateral expansion of aromatic rings, and I found in literature that acylation with succinic anhydride and reduction of the aryl ketone leads to a 4-aryl butyric acid intermediate, that can be ring closed with another acylation leading to an intermediate that is now the one ring expanded arene with the new ring still being aliphatic with the 1-carbon being a carbonyl group, which then can be dehyrated and thus aromatized with strong base (tBuOK) in DMAC and heating (150 C). Although maybe high heat in DMAC and strong base combo woud warrrant the use of a blast shield lol. Anyways it was an interesting synthetic excercise.
Oh that's a really cool prep! Do you remember where you found that procedure for the lateral expansion of aromatic rings? That sounds really cool! Thanks so much for this comment.
Spectacular question! It will, and actually that's the kinetic product. In contrast to many other electrophilic aromatic substitution reactions, aromatic sulfonation is reversible, in other words it is an equilibrium. If you use a large excess of SO3 you push the reaction to the sulfonation side; if you heat the sulfonated product in the absence of SO3 it will de-sulfonate. This makes sulfonation a nice method to 1) control where a second substituent will be introduced or 2) serve as a protecting group (block second substituent introduction) - and then when you are done, you simply de-sulfonate. Now to your question, If we look at the intermediates leading to the 2 isomers we see that we can draw 2 resonance structures that preserve aromaticity in one ring for the transition state leading to naphthalene-1-sulfonic acid, but only one resonance structure where the other aromatic ring remains intact for the 2-isomer (draw the resonance structures to convince yourself). Therefore the transition state leading to the 1-isomer will be lower in energy and naphthalene-1-sulfonic acid will be formed fastest - it is the kinetically favored product. However, naphthalene-2-sulfonic acid is a few kcal/mol more stable than its 1-isomer. This is due to an adverse 1,8 steric interaction present in the 1-isomer. Because the sulfonation reaction is reversible, if we run it long enough at high temperature (favoring reversibility), eventually we will wind up with the thermodynamically preferred (more stable) product, the 2-isomer.
Great question! The counterion isn't really important to the transformation as it doesn't participate anyway but there probably would be a difference in the reactivity based on the oxidation state of iron!
Good question! Birch reduction is really just the name of the reaction used to reduce aromatic rings. The specific conditions can vary, depending on the specific substrates being used. Sodium and lithium are the most common alkali metals used for this process and even an amalgam like Na/Hg, as in this case, may be necessary. For the purposes of this exercise, it’s not super important, but these were the real conditions used in the published synthesis.
Amazing video for that anthracene synthesis, i usually forget about nitriles and their versatility. For the next transformation, I have thought in a kind of Robinson annulation, while trying to avoid the final elimination. In this reaction, 2-hexanone would be the Michael donor for acrolein, deprotonating the methyl group for the kinetic enolate, which attacks acrolein. After the reaction, the formed alcoxide (which tends to eliminate to form the enone) could be oxidized to a ketone, giving the product. Given this is a multistep exercise, let's assume we get the enone. We could oxidize that double bond to form the previously mentioned alcohol (I just dont remember how) and then convert it into a ketone. Another way to obtain the product would be with a Diels-Alder reaction with a Danishefsky-like diene, which would contain the propyl chain. Then, the aldehyde from acrolein would be degraded in a decarbonylaton reaction (e.g. the Tsuji-Wilkinson reaction). Finally, the 2 ketone groups be revealed, trying not to form the enone.
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I made a problem based on this article. Ferricyanide doesn't form nitriles from sulfonates (or with at least an order of magnitude smaller yield). Thank you for the video and bringing up this topic. But, I would suggest you pay closer attention to drawing formulae, there are several mistakes
I appreciate the feedback! I’ll keep an eye on it - where did you find the ferric cyanide article?! Love to read about this stuff!
@@rojaslab Your video almost verbatim repeats the article 10.1021/ja01437a023. I haven't seen a single procedure employing iron complexes for introducing the nitrile moiety, only neat cyanides
@@dimaminiailo3723 1921!!!! Wiiiiiild.
@@rojaslab The eldest article I've read is dated 1865 IIRC. Atoms haven't changed much since then
Very interesting pathway.
I was thinking more about something less selective but more brute force:
1.) Taking succinic acid and turning it into its acyl chloride
2.) Friedel-Crafts double dropwise acylation in dilute solution (high bp solvent) with a slight excess of naphthalene at >100C which is mainly expected to occur at the least crowded positions on the aromatic rings. Dilute and with slight excess because although the double carbonyl group is deactivating towards the aromatic system you still don’t want a double-substitution that makes a fused 4 ring system and you don’t want two naphthalene groups bridged by the succinic bit.
3.) Reduction of the carbonyl to alcohol with NaBH4
4.) Turning the diol into dibromide
5.) Reacting the dibromide with KOH in methanol to eliminate Br and H and form two alkene bonds, thus creating the new aromatic ring.
3 methods I did :
1. Using diels alder reaction with butadiene creates anthracene skeleton but adding further double bond might be tough which can be done by Pt(300°C) . However diene may attach anywhere in the whole naphtalene.
2. Malonic acid, using SOCl2 , gets acid chloride then Friedel craft acylation and reduction using NaBH4 followed by conc H2SO4(dehydrate) . This also gives some more products like phenanthrene etc.
3. Using 1-iodo, 2-(a good leaving grp like OTs) butane first performs anchimeric assistance, then naphthalene double bond attacks as nucleophile(maybe) followed by friedel craft alkylation, after which reduction again with Pt 300°C.
Oh those are really great ideas. I really like those. I know for sure that the route in this video has been published but I wonder if anyone has ever tried any of your routes!
For the next problem I would use 1,3 cyclohexandione which has a pretty acidic a carbon as a nucleophile (actually it is very interesting why it is even more acidic than a linear 1,3 diketone - the conjugated system of the enolate is locked and the lack of rotation alines the π* orbital of the π bond with the lone pair when the a carbon in the middle gets deprotonated, the same reason explains the high acidity of Meldrum's acid), then a b addition occurs because the enolate is a soft nucleophile from the a carbon and the beta carbon of acrolein is a soft electrophile. Then the real fun begins because we should chemoselectively completely reduce the aldehyde and not the ketone FGs. I would use a thioacetal protection with ethanedithiol ideally at a low temperature, with low dithiol excess and for a short amount of time to ensure the thioacetal is formed selectively at the aldehyde since aldehydes are more reactive. Then an acetal protection at the 2 carbonyls and finally a catalytic hydrogenolysis with Raney Nickel of the thioacetal which reduces a thioacetal to an alkane. Deprotection of the 2 acetals using pTsOH with acetone will transacetalise the acetal protection of the 2 carbonyls of the substrate to acetone giving us the final product. Otherwise since the thioacetal protection is not a very common reaction and it is typically not used because of the extremely disturbing smell of the chemical, a Wolff-Kischner or a Clemmensen reduction would also completely reduce a carbonyl FG but I highly doubt that the process will be chemoselective.
Oh that's an interesting proposal for the next one! I was actually thinking of addition to the carbonyl carbon using nbuLi, re-oxidizing and then move toward a dieckman cyclization. Yours is pretty cool though!
@@rojaslab yes and I would really think that making a video about the hard-soft acid base theory and MO theory and their applications in organic chemistry would be a great video topic for you. Many chemistry students might know the reactions and the mechanism behind them but don't really understand in a molecular stucture and orbital level why reactions happen. It is also something that TH-cam organic chemistry, as far as I have researched, lacks and as a pharmacy undergrad it took me lots of time studying to deeply understand these topics. Because I see that you are a great educator I think you can make it happen!
@@Nikosmentis That's a really great idea! Thanks for the tip!
Could you do a birch reduction of the naphthalene, a Diels-Alder with 1,3-butadiene, and use an oxidizing agent like DDQ to rearomatize it?
That's a great idea and a few people have suggested that as well. I don't think napthalene would act as an effective dienophile, especially without putting the 3rd ring in a different placement, keeping it from being that symmetrical fused cyclic system.
Keep going 🎉😊
I appreciate you!
I wonder if there is a way you can use the Bergman cyclisation? Perhaps you chlorinate the 2-position, then react with BuLi (Cl is an ortho directing group) and iodine to make 2-chloro-3-iodo naphthalene (and probably some 2-chloro-1-iodo naphthalene), then sonagshira with trimethylsilyl acetylene, cleavage of the silyl, then bergman cyclisation.
Oh that's an awesome idea! What's funny is that even though my training is in organometallic chemistry, I often try to avoid using it in my multistep synthesis problems because I think most people will think it's cheating haha. But that's just transition metals allow for way cooler chemistry, IMO!
Great Video! Very excited for the new Format :)
Ahh I’m so glad to hear that! I appreciate you giving it a chance!
Really nice procedure, and interesting last step! I ended up looking up methods for lateral expansion of aromatic rings, and I found in literature that acylation with succinic anhydride and reduction of the aryl ketone leads to a 4-aryl butyric acid intermediate, that can be ring closed with another acylation leading to an intermediate that is now the one ring expanded arene with the new ring still being aliphatic with the 1-carbon being a carbonyl group, which then can be dehyrated and thus aromatized with strong base (tBuOK) in DMAC and heating (150 C). Although maybe high heat in DMAC and strong base combo woud warrrant the use of a blast shield lol. Anyways it was an interesting synthetic excercise.
Oh that's a really cool prep! Do you remember where you found that procedure for the lateral expansion of aromatic rings? That sounds really cool! Thanks so much for this comment.
@@warlokyx I believe that the main product of this reaction with naphthalene would be phenanthrene
Nice synthesis, I learned some new reactions !
Glad to hear that! So what ya got for the next one?!
Cool synthesis! Does it work with other educts, too, e.g., with benzene, toluene, phenol, etc., instead of naphthalene?
what is stopping the sulfonate from adding to carbon number 1 of naphthalene in the first step?
Spectacular question! It will, and actually that's the kinetic product. In contrast to many other electrophilic aromatic substitution reactions, aromatic sulfonation is reversible, in other words it is an equilibrium. If you use a large excess of SO3 you push the reaction to the sulfonation side; if you heat the sulfonated product in the absence of SO3 it will de-sulfonate. This makes sulfonation a nice method to 1) control where a second substituent will be introduced or 2) serve as a protecting group (block second substituent introduction) - and then when you are done, you simply de-sulfonate. Now to your question, If we look at the intermediates leading to the 2 isomers we see that we can draw 2 resonance structures that preserve aromaticity in one ring for the transition state leading to naphthalene-1-sulfonic acid, but only one resonance structure where the other aromatic ring remains intact for the 2-isomer (draw the resonance structures to convince yourself). Therefore the transition state leading to the 1-isomer will be lower in energy and naphthalene-1-sulfonic acid will be formed fastest - it is the kinetically favored product. However, naphthalene-2-sulfonic acid is a few kcal/mol more stable than its 1-isomer. This is due to an adverse 1,8 steric interaction present in the 1-isomer. Because the sulfonation reaction is reversible, if we run it long enough at high temperature (favoring reversibility), eventually we will wind up with the thermodynamically preferred (more stable) product, the 2-isomer.
What’s a Fe(CN)6, did you mean K2[Fe(CN)6] or K3[Fe(CN)6]?
Great question! The counterion isn't really important to the transformation as it doesn't participate anyway but there probably would be a difference in the reactivity based on the oxidation state of iron!
*fewer than five carbons.
🤣🤣
burch reaction isnt Na/NH3?
Good question! Birch reduction is really just the name of the reaction used to reduce aromatic rings. The specific conditions can vary, depending on the specific substrates being used. Sodium and lithium are the most common alkali metals used for this process and even an amalgam like Na/Hg, as in this case, may be necessary. For the purposes of this exercise, it’s not super important, but these were the real conditions used in the published synthesis.
@ thanks for answering!!!
Amazing video for that anthracene synthesis, i usually forget about nitriles and their versatility.
For the next transformation, I have thought in a kind of Robinson annulation, while trying to avoid the final elimination. In this reaction, 2-hexanone would be the Michael donor for acrolein, deprotonating the methyl group for the kinetic enolate, which attacks acrolein. After the reaction, the formed alcoxide (which tends to eliminate to form the enone) could be oxidized to a ketone, giving the product.
Given this is a multistep exercise, let's assume we get the enone. We could oxidize that double bond to form the previously mentioned alcohol (I just dont remember how) and then convert it into a ketone.
Another way to obtain the product would be with a Diels-Alder reaction with a Danishefsky-like diene, which would contain the propyl chain. Then, the aldehyde from acrolein would be degraded in a decarbonylaton reaction (e.g. the Tsuji-Wilkinson reaction). Finally, the 2 ketone groups be revealed, trying not to form the enone.
Oh this is an awesome proposal. I love using the Danishefsky diene. I haven't thought about those since my first year of graduate school haha.