The Robinson Annulation & Amines

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The Robinson Annulation & Amines
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This is the third (and final) quarter of the organic chemistry series. Topics covered include: Fundamental concepts relating to carbon compounds with emphasis on structural theory and the nature of chemical bonding, stereochemistry, reaction mechanisms, and spectroscopic, physical, and chemical properties of the principal classes of carbon compounds. Index of Topics: 00:45 - The Robinson Annulation: Michael Reaction Followed by Aldol 04:57 - The Robinson Annulation: Retrosynthetic Analysis 17:19 - More Organic Synthesis: Looking for Disguised Key Structural Units 37:01 - Famous Amines
Perfumer Meeting/Interview
Ionenbindung Chain (unit) Reaction mechanism Oxygenierung Activity (UML) Electron donor Hydroxyl Alpha particle Electron Hydroxybuttersäure <gamma-> Shear strength Alkoxy group Addition reaction Ballistic trauma Beta sheet Elimination reaction Conjugated system Retrosynthetic analysis Process (computing) Hydrocarboxylierung Annulation Aldol Walking Carbon (fiber) Multiprotein complex Michael-Addition Chemical reaction Solution Alcohol Hydroxide Lone pair Acid Computer animation Functional group Valence (chemistry) Materials science Enol Proteinkinase A Covalent bond Dehydration reaction Base (chemistry) Cobaltoxide Thermoforming Condensation
Ionenbindung Nitrogen fixation Oxygenierung Complication (medicine) Hydroxyl Wursthülle Alpha particle Molecule Ethanol Sodium hydroxide Chemische Synthese Shear strength Addition reaction Beta sheet Lithium Sodium borohydride Acetaldehyde Aluminium hydride Biochemistry Hydrocarboxylierung Dyeing Annulation Ketone Aldol Walking Carbon (fiber) Aldehyde Sodium oxide Chemical reaction Michael-Addition Aldol reaction Alcohol Iminiumsalze Water Acid Gesundheitsstörung Computer animation Materials science Enol Chemical compound Amination Separator (milk) Base (chemistry) Enamine
Digestate Activity (UML) Cyclische Verbindungen Meat Hydroxyl Chloride Essigsäureethylester Chemistry Alpha particle Umesterung Chemische Synthese Sodium hydroxide Halogenation Beta sheet Derivative (chemistry) Lithium Sodium borohydride Claisen-Umlagerung Aluminium hydride Pyridine Hydrocarboxylierung Saponification Hydride Bromide Precursor (chemistry) Aldol Ketone Alkylation Walking Veresterung Carbon (fiber) Chemical reaction Iodide Computer animation Functional group Propylgruppe Decarboxylation Enol Chemical compound Amination Acetone Claisen-Kondensation Condensation
Ethylgruppe Chemical property Recreational drug use Activity (UML) Phenyl group Methylphenidate Chemical plant Hydroxyl Organische Verbindungen Wursthülle Aromaticity Methylgruppe Alkaloid Alpha particle Norepinephrine Diet food Crystallographic defect Common land Beta sheet Storage tank Epinephrine Substituent Setzen <Verfahrenstechnik> Methamphetamine Asset Ephedrine Designer drug Hydrogen Combine harvester Ingredient Computer animation Functional group Dopamine Amination Chemical compound Salt Acetone Methanol
good afternoon we're going to get started any questions I did open up the sapling Qin chapter 24 assignment it's due on Wednesday we don't want to do on Thursday night because so you're going to perfume in nature right you're going to procrastinate and then you're gonna be more stressed down on Friday don't you think who thinks we should do things we should have a due date of Wednesday night okay see and Thursday okay you'll be glad all right so here's how I know you
guys are burned out and ready for summer to start because nobody emailed me to say oh by the way the chapter 24 assignments not up nobody emailed me so and where ever finished in chapter 24 today so I can tell all right so we left off we're going to finish this today we're going to start chapter 25 two more chapters left and you're done all right so we left off last time talking about the Michael followed by the aldol also known as the Robinson annulation so we went through the Michael edition so this is two mechanisms so if I ask you a Robinson annulation mechanism on the test it's actually like me asking you to mechanisms a Robinson Michael and an aldol alright so we do the michael addition and we said without you you can stop at this Michael on product here so I will always add he to let you know that you're going to keep going so then we want show we're showing the aldol condensation we kind of left off in the middle of that mechanism so this is exactly the same as the less complex alcohol general Khan you know mechanism that we showed already so we're forming the enolate and then we attacking the carbonyl it's an intramolecular aldol but that's no problem and so what we need to do is we need to protonate this alkoxy group so we're going to protonate and then we're going to do a two-step elimination so because we're adding Heat we're going to go all the way to the alcohol condensation product or the alpha beta unsaturated carbonyl remember that is a two-step process what are the two steps the two steps are we going to make the enolate and then we're going to kick off the hydroxyl in the second step if you just directly kick off the hydroxyl you're going to miss on some points on there test if you do that as it is not one step it is two steps so I'm going to make the enolate by pushing like pushing
the electrons all the way up on to the oxygen and so I definitely going to need my lone pairs here on oxygen and then so that's our enolate so again 2-step elimination we make an enolate first you can make the enolate by pushing electrons onto oxygen or you can make the enolate by pushing electrons onto carbon just as long as you make the enolate first you're in good shape these electrons are going to come down we're going to move the electrons over and kick off hydroxide so notice I'm throwing lone pairs on the oxygen at the last minute and there's your final product alpha beta unsaturated carbonyl all right so that's the Robinson annulation if I give you a compound and say how were two starting materials would you use to make this by a robinson annulation we're going to take this apart and see what we would do your book shows you a little bit different way to do this that some students find easier so by all means if you can use the book way to do that that's absolutely fine so I'm going to do the since the Robinson is a Michael followed by an aldol I'm going to when I do retrosynthesis I'm going to take apart the aldol first and then the Michael alright so retro aldol same steps as we talked about before alpha beta we're going to break the alpha beta bond we're going to put a carbonyl in the beta position so here's my carbonyl in the beta position and enolate goes in the Alpha position okay and a good idea to count carbons here 1 2 3 4 5 6 it's a six membered ring so we should have 6 carbons there so that's the year retro aldol and then the next thing we want to do is the retro Michel and when we did the regular Michel Michel we took it apart two different ways when we're doing retro Robinson yes are we talking about this right here okay and that that would be that would be what you would do if it was acid catalyzed dehydration but if you look at the pKa of a protonated alcohol it's about negative 5 or negative 6 you're not going to be forming that in a basic solution okay it certainly would make a better leaving group but even if you formed it what's the hydroxide going to do in a shots going to deprotonate that you know what saying so you can't form it and even if you did it would instantly be deprotonated before it could lead alright so that would be what you would do for an acid catalyzed dehydration so for the retro Michael we want to only take it apart one way when we're doing retro Robinson so for retro Robinson always on break at the bond hanging off the ring so we're not going to take it apart two ways we're going to take it apart one way and so how you always break at the bond hanging off the ring is that you on start counting from the chain hanging off the ring all right so that's how we're going to do that so this guy is well we're going to go this way Alpha Beta Gamma okay we're going to we're going to break the Beta Gamma bond we're going to put a double bond in the gamma position in the Alpha position so there's the double bond right there and the negative charge goes in the gamma position so this is going to be a negative charge and and we're going to we're not going to show this deprotonated here so this is what our two starting materials would be that and this I forgot to take away the negative charge from the retro aldol but we would certainly do that also so those would be a those would be our two starting materials is that going to work well so we can take it apart but is that actually going to work well in this reaction what do we know about Michael reactions and the Michael donor what do we want there do we want us do we want to do we want to stabilize the enolate that's not a stabilized and Elaine so that's not going to work very well okay so not a stabilized being late therefore it won't work well in the Robinson annulation and is what we're going to look well in the Robinson annulation because the Michael reaction part of the step is not going to work well so we talked about that last time but let's talk about it again why won't unstabilized enolate work and that's because the Robinson annulation involves a micro reaction the micro reaction does not work well with unstabilized anyways because unstabilized enolates are going to do a lot of one two addition we've talked about that last time so let's do it again and I believe this is page 32 of the notes maybe I don't know you can look 31 or 32 I think that number might be off remember the stronger the nucleophile the more one two addition so if we compare this pKa of the conjugate acid is about 20 and PKA for active methylene compounds if we round to the nearest five is about 10 so if we have an unstable I zeolite it's 10 to the tenth times more acidic so this here is a stronger base therefore and it's a stronger nucleophile how do we know it's a stronger nucleophile well we do know some trends from 51 a and 51 B here's the trend that would tell us that and that is C n o F and we're going across and I won't even go out bother to go down but if we're going across this way increasing base strength increasing base strength that direction and we also will have increasing nucleophile strength in the same direction increasing nucleophile strength in the same row of the periodic table as the base strength increases the
nucleophile strength increases increases so stronger base therefore stronger nucleophile the stronger the nucleophile the more one two addition and that's why it's not going to work very well in the michael reaction because we're going to get competition a lot more competition from one to addition all right so and that's where I should have drawn this down here where I had more room that's what we're talking about here base strength correlates with nucleophile strength and so conditions for this robinson annulation that we just do I'm drew we just took this thing apart and saw what we would use to make it and realize that it wasn't going to work very well not only do we get competition with 1/2 or 1/4 addition we also have on to enolates that are can competitively for all right so we've got what do we have here we have enolate can form here it could also form on the other side that would give you the same you know late but we also have this one here enol a can form here also right so when you mix the two together with nao et I'm putting some I'm drawing this in the wrong spot I don't know why I'm doing that NaOH h2o and water okay when you do that you're going to get 1 2 & 1 4 addition in addition to two different enol aids I'm drawing everything in the wrong section here I'll fix that in just a minute here in addition to two analytes forming all right so that's going to be a big mess so really what we really want to do is when we're doing a Michael we use a stabilized enol 8 and so we can use a stabilized analyte or we can use a stork in what's called the stork enamine synthesis so instead of making the enol 8 here we can use an enamine and we talked about that before in a different in a different context but that also works really well here so this guy is supposed to be here and now I'm going to get on the right page here in the right column so stork enamine synthesis will make this reaction work a lot better so it's a great alternative so we make the eight amine and the ena mean works really well so it's much more well behaved than an enol a tie on it's going to do one for addition alright so there that would be that would be one for addition we add h3o plus and water we're going to hydrolyze that iminium ion to a ketone we're going to protonate the enolate ion to make a ketone also and then we can do intermit intramolecular aldol could be out that you could keep it in acid it could be acid catalyzed or it can be base catalyzed so if we just keep it in acid and heat it up we can go all the way to the good product a single product here cleanly if we try if we did it without making any to mean it's not going to be as clean all right so that's the Robinson annulation any questions on that anybody so as much as possible we want to use the stabilized enol aid if we can if we can't then this is a good alternative the stork enamine synthesis all right let's do some a little bit more organic synthesis before we move on to chapter 24 in this chapter we've learned to synthesize beta hydroxy carbonyl is alpha beta unsaturated carbonyl is beta keto carbonyls and 1 5 dicarbonyl so when a target molecule you're asked to synthesize a target molecule has these key structural features you should be able to recognize those features and know how to make it but what if we went what if we had those key structural features and maybe we reduced and so those carbonyls would be alcohols would it be able to is easily recognize those structural features so we want to be able to be ready to look for that so it's not only going to be a 1 5 dicarbonyl if we reduce that 1 5 dicarbonyl with lithium aluminum hydride we'd have a 1:5 die all so not obvious that you would make that bio Michael but if you remember that you know that that one 5 die all could come from a 1 5 dicarbonyl then you're going to be in good shape so you got to get your you got to get yourself trained to look for these structural features all right so here's an example right here this is a beta hydroxy ketone so here's alpha here's beta so how do we make a beta hydroxy ketone what reaction what we actually gives us a beta hydroxy keto aldol addition so that we can recognize or we'll be able to recognize by the test on Friday next Friday okay but what if we if we did sodium borohydride here and we reduced that alcohol now no longer looks recognizable so no longer has one of these recognizable features so you have to be ready you have to be ready for this you have to be ready to look for things that are if you want to call it one degree of separation from the the patterns that we recognize you have to be able to look for that so let's say for example I asked you to synthesize this compound and so you're thinking okay well I just saw this example I could make that by an aldol and then followed by sodium borohydride so that would mean I could make this from one of these two compounds here this to match the one above or but but assuming I had the seen what I started with here or I could do it the other way right have one of those okay so either one of those if I reduced it with sodium borohydride would give me that target molecule let's call this first one a and then let's call the second one B and we're going to see which one actually ends up working better so I'm going to make this target molecule by doing an aldol reaction followed by sodium borohydride to reduce it but we want to make sure let's take these guys apart using the retro aldol and see which one's going to be more feasible so that was we'll do that on
the next page let's do a first all right so we can start counting from the ketone alpha beta break the alpha beta bond beta position gets the carbonyl alpha position gets the negative charge so it's that enol eight and this would be an aldehyde so beta position gets the ketone and so that's what my two starting materials would be all right let's draw the other one and then we'll take a look and see which we think what is going to be better so if V was my strategy all right now we're going to queue now we have the opposite direction so this is alpha this is beta we're going to break right here so beta position gets the carbonyl so this would be acetaldehyde and alpha position is the enolate all right so let's look at these I don't have my laser pointer today so we'll have to do the best we can so let's look at the first one are we going to be able to make that enolate well we've got more than one enol eight that can form this only has one enol eight right if we mix the two of these only one enolate that can form but this we could also form the enolate on the second carbon here so in other words we would have to use directed aldol here can also formulate here therefore we need to raft it out all so remember directed aldol we form the enolate completely using Lda and then we add our second compound let's look at the second one and see if this is going to work better we have an aldehyde here we can form the enolate oh this is not going to go well here so enolate here enolate here enol eight here we have three different analytes that can form so what we really want to do is we we definitely want to make we want to make this enolate here so we could use Lda THF you know minus 78 to form the kinetic enolate and then you would also need directed aldol here but we expect to see some contamination with the thermodynamic enolate here because that's got two different ones that can form so I would also need directed aldol the good news is if we use the directed aldol in either one of these cases it's going to add selectively to the aldehyde so that part of it will be clean it's just a matter of how many analytes we can form this one here because it's symmetrical on there's only one ena like that can form we're going to form the enolate first and then we add the aldehyde it seems to me like a is better don't you think just because of the complication with this guy right here that guy right there is is going to be more complicated so I think that a is the best strategy this one's best all right so let's draw out the synthesis LD a THF - 78 degrees centigrade completely form the enolate ion and then step 1 we add our aldehyde step 2 acid or water here definitely water if we use acid we're going to tend to get the alpha beta unsaturated carbonyl and that's not what we want to synthesize okay so then that will give us what did I just did I say something would I do I said oh oh my gosh awesome okay all right h2o okay so we're in good shape now almost there we have to do our we have to do a sodium borohydride in ethanol and that will give us our the product we're trying to synthesize okay kind of an elaborate thing here alright
so another crazy synthesis here on the last one on this in this part again we're going to we're try to do these provided synthesis of the following compound from a cyclic precursors so we're thinking about doing intramolecular aldol zorse any sort of cyclization intramolecular is going to help us make this compound here alright so what I'm thinking is if I replace that bromine with a hydroxyl I could use this strategy what are you thinking here what does this look like I what are you thinking of a strategy now that you see it like that does it seem like you can see something now if you look here we've got this is a substituted acetone right substituted
ketone so maybe think Osito acetic ester synthesis all right so if I'd made that by a/c to acetic ester synthesis then I would do here I would go here and then I would have this group on here I would do alkylation to get this group on here see that propyl group on there and then I could take this apart further and that would be this so and each time we do this for thinking of ways to make these compounds if I did this and then I had propyl bromide propyl iodide propyl chloride your choice are you seeing another recognizable structural structural feature there in the carbonyl containing compound what does that remind you of how can we how can you make that compound that's right there we've made that already one three one three dicarbonyl or beta keto ester right what is that beta keto Esther this is a product of a claisen condensation got to know that and so then had that's how we're going to take this apart by a cyclic precursors actually what was an intramolecular claisen called a dieckmann condensation right I don't know if it's one N or two ns D that's close enough actually a deccan condensation intramolecular claisen is a dieckmann condensation all right so that means that this is from will keep going here and remember how we take a part of claisen start counting from the ester so let's lime going to label that start counting from an ester if you don't start counting from the ester you're going to get you're not going to get a cyclic precursors so classic claisen you start counting from the ester this is alpha beta we put a foxy group in the beta position alpha position becomes the enolate so let's take this apart further right there and so in the Alpha position gets the negative charge so that would be what we would cycle eyes with let's double check that we have not made a mistake in counting carbons here this would be 1 2 3 4 5 and yes we have we have 1 2 3 4 5 we have a 5 membered ring here so that's our a cyclic precursor all right so what ours well when our synthesis look like writing our synthesis out in the forward direction we start off with our a cyclic precursor our digester we choose our bass to match our Esther so we don't get any transesterification we certainly would not use sodium hydroxide because we're going to get saponification we want to do the claisen condensation so remember what drives the equilibrium in a claisen condensation is forming the deprotonated active methylene compound so that's what we're going to form we don't need to protonate because we actually need to alkylate so we're going to put this on there here sn2 reaction to alkylate that position so it looks like that at that point and with our group here now we want to get rid of that ester group we're going to hydrolyze in decarboxylate h3o plus h2o heat which is going to hydrolyze the ester then we're going to decarboxylate that gives us the substituted acetone derivative and then we're going to reduce you could do lithium aluminum hydride or you could do sodium borohydride I'm going to use looking a little hydride this time and then pbr3 pyridine in our last step and that will take us to their target compound so you can get very complicated very fast but on all the reactions in this chapter allow us to build up carbon skeletons quickly and easily questions on chapter 24 that's carbonyl chemistry we're going to change gears and we're going to start on amines so very briefly start on them today and so recommendation to you is that when we get into the meat of this chapter where we're doing a lot of synthesis you're going to review chapter 18 right I know you're not going to do it now because we have a test coming up but after the test you're going to want to review chapter 18 any questions before we get started on chapter 25 anybody up at the top really loud
you're going to have to show me because I want now that it's closed I'm not going to be able to continue come up afterwards and show me okay all right pretty exciting you guys only have two more chapters and you're going to be done with ochem kind of bittersweet huh
I do have a lot of students that come up to me afterwards and they say that next year you know you got some of you might call to me and say I miss ochem so much you know it's cool all right okay so it means super important many plants that can synthesize complex and means called alkaloids and some which have medicinal or poisonous property and a lot of amines are very bioactive in the brain I have a book that's called drugs in the brain and there's only one compound in that entire book that doesn't have an amine in it so they're very active in the brain I'm going to give you some examples here and we're going to look for structural features in common with all these compounds on this first compound here anybody know the name of it that's good that you don't know the name because that means you're not making drugs on the side which is awesome this is methamphetamine okay I had a student one time like when I took we used to have the I do the honors lab now but we used to have the honors lecture and there was a guy in the back and I made a mistake on one of these compounds and he corrected me on that you know you never ended up passing the class he just kind of disappeared so anyway I don't know I'm just saying this is um this is amphetamine so you see the difference between methamphetamine and amphetamine so it changes the addictive potential dramatically when you just simply take that hydrogen from an FET Amina replace it with a methyl this is amphetamine this is also the active ingredient in adderall just in case you were wondering this is dopamine this is dopamine this is a ephedrine also known as adrenaline this is nor ephedrine or I'm sorry norepinephrine um this is Ritalin whoops and what do we have here sudafed sudafed reen used to be over-the-counter now you have to go to the pharmacy and show your driver's license to get this compound here which that was pretty recent that that happened so this is sudafed and some people when they take sudafed they have to take it in the morning it's for deacon Jett it's a decongestant but when they take it they have to take in the morning because it gets you kind of wired and so you can see the relationship here are you starting to see some things in common here this is of ecstasy let's stop right here and look at what these all have in common these are all beta Fenella means let me start with it tell you what that means beta fen I spelled that wrong doggone it beta F&F Allah means so all our beta phonetical means here's the structural skeleton of a beta Fenella mean we have an aromatic ring so that's the fan for the phenyl and then we have an ethyl group and then we have an amine and that could be a night that could be hydrogen's or our groups so there's the fennel for the fin of the fennel and here's the Ethel right here and here's the amine so you can see that in all of these here's your Ethel here's your amine there's your ethyl group here's your amine so there can be other substituents but these all have that same thing in common there's your Ethel there's your amine and we can go through and do that and there's two types there's the type that have no hydroxyl in the Alpha position so this is alpha this is beta there's Sun no hydroxyl in the Alpha position or a hydroxyl in the Alpha position so everybody knows why you can't get sudafed right without showing your license does everybody know why that is okay you can take sudafed and convert it into methamphetamine by getting rid of that hydroxyl right that's also why you have to go when you get assets when you get nail polish remover you have to show your driver's license now isn't that crazy because people take the acetone and they use it as a solvent to take sudafed and convert it into into meth so that's why you have to show your license okay so guys are so funny so so this guy here I think this is gone now but there's designer drugs out there people are like okay I'm going to make something that looks a lot like this but it'll be slightly different and this this came out this is MIFF ed rone so what they did is they oxidize that hydroxyl in the Alpha position we have some others substituents here on this was a designer drug that was in bath salts it was sold in stores if you heard about that it was called bath salts and people got really really bad bad on this they had guys they talked about this guy that was arrested and he just makes you big makes people extremely angry and he like with his teeth he pulled off the knob on the in the cop car just like ah you know like that it's crazy and they would these people would come to the emergency room and they couldn't sedate them they had to just tie them down because they were so whatever anyway two more to show you this is Fenn flora mean and this is phentermine this was a combination that was used for a diet egg fan fan and they had to pull it off the market because it caused heart valve defects so now I think it was the fan forming that was causing the heart valve defects now you can buy phentermine by itself and this of course is fentanyl these are all beta hydroxy amines and we'll talk more about those on Monday