Alylation of Acetic Acids

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Alylation of Acetic Acids
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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: 01:05 - Enamine Reactions 06:06 - Alkylation of Acetoacetic Ester 14:06 - Decarboxylation of Beta-Dicarbonyls 21:29 - Acetoacetic Ester Synthesis 36:54 - Alkylation of Acetic Acid: The Malonic Ester Synthesis
Umkristallisation Computer animation Chromatography Haloalkane Ketone Enol Steam distillation Enzymkinetik
Ethylgruppe Ionenbindung Reaction mechanism Activity (UML) Haloalkane Acetic acid Chloride Essigsäureethylester Cyclin-dependent kinase Methylgruppe Reactivity (chemistry) Alpha particle Electron Addition reaction Hydrolysat Data conversion Oxide Process (computing) Body weight Acyl Alkane Stickstoffatom Ketone Alkylation Veresterung Carbon (fiber) Carbonylverbindungen Chemical reaction Dimethylamin Kupplungsreaktion Iminiumsalze Nucleophilic substitution Hydrogen Gesundheitsstörung Acid Computer animation Functional group Enol Amination Chemical compound Covalent bond Base (chemistry) Bromomethane Cobaltoxide Enamine Isotopenmarkierung
Kohlenhydratchemie Resonance (chemistry) Memory-Effekt Atomic number Alpha particle Alkene Umesterung Electron Colourant Elimination reaction Derivative (chemistry) Oxide Alkylation Benzyl Tautomer Walking Veresterung Chemical reaction Animal trapping Wine tasting descriptors Electronic cigarette Acetic anhydride Acid Decarboxylation Enol Malonic acid Acetone Cobaltoxide Stop codon Starvation response Alkyne Ethylgruppe Ionenbindung Reaction mechanism Activity (UML) Carboxylate Acetic acid Hydroxyl Bromoethane Wursthülle Methylgruppe Sodium hydroxide Oxocarbonsäuren Beta sheet Active site Mixture Conjugated system Process (computing) Setzen <Verfahrenstechnik> Hydrocarboxylierung Dyeing Methyl iodide Ketone Hydrogen bond Carbon (fiber) Hydrate Water Hydrogen Sodium Computer animation Functional group Proteinkinase A Covalent bond Carbon dioxide Substrat <Chemie> Base (chemistry)
Chloride Essigsäureethylester Alpha particle Temporary work Kältemittel Derivative (chemistry) Saponification Alkylation Walking Veresterung Chemical reaction Acetylation Diethyl malonate Acetic anhydride Acid Iodide Decarboxylation Enol Chemical compound Acetone Zunderbeständigkeit Cobaltoxide Confectionery Ethylgruppe Biosynthesis Reaction mechanism Activity (UML) Carboxylate Inertgas Acetic acid Dörren Methylgruppe Diet food Solvent Hydrolysat Controller (control theory) Active site Mixture Retrosynthetic analysis Alkane Stickstoffatom Kaliumhydroxid Ketone Carbon (fiber) Protonation Kupplungsreaktion Water Hydrogen Sodium Computer animation Functional group Proteinkinase A Base (chemistry)
Ethylgruppe Biosynthesis Dicarboxylic acid Decarboxylasen Carboxylate Haloalkane Acetic acid Temporary work Hydrolysat Active site Derivative (chemistry) Retrosynthetic analysis Dyeing Saponification Walking Veresterung Carbon (fiber) Protonation Electronic cigarette Diethyl malonate Hydrogen Sodium Acid Computer animation Functional group Decarboxylation Chemical compound Base (chemistry) Carboxylierung
we left off last time talking about alternatives to using Lda to deprotonate a ketone by a followed by adding an alkyl halide because we have problems with thermodynamic kinetic enolate so we want some better alternatives that aren't going to give us mixtures because if you get products from both kinetic and thermodynamic enolates it's really really hard to separate the two by chromatography or distillation or recrystallization they're very hard to separate so we want to be able to do cleanly just form one or the other so an alternative for thermodynamic enolate is
to make an enamine yeah it's not showing thank you all right so an alternative is
to make a neat amine so let's label that we want
this is an alternative to making a kinetic enolate using LD a so LD a gives you a lot of the kinetic product it's very selective but the product that you get remember it was like 45 40 something percent not very good so what you do is you make an enamine and so here we saw an example here you make an e an amine and then you've treated with the alkyl halide now what's going to happen is the electrons on nitrogen come down boom you attack the carbon that's bonded to the leaving group and you kick off the leaving group so notice the ethyl that we just incorporated is on is on the least substituted side so this is an alternative to making a kinetic enolate using Lda all right so why is this so selective for the least substituted side and it turns out that on all of these bonds here that you see here I'm going to be making those in red are all in the same plane all those bonds are in the same plane and so you can see that it's much better including this hydrogen right here in that bond right there hysterically it's wants to be on the least substituted side if it was over on this side there's a problem with these two hydrogen's right here getting in each other's way so if there's really any substitution on that one side then it's going to be a problem making the enemy and this is why it's so selective okay so sterically not good so this is the one that you form all right so here's another example of using this we can take we can make the ena mean so again this is the most common either mean to use this not the only one you could just use dimethyl amine diethyl amine so there's not a problem here so you can see H three o plus catalyst or I might write pH 5.0 to show you that you're going to make it you know mean that's the best conditions for making an amine or an amine all right so we are going to selectively form this on the least substituted side the double bond will be here and then we can do things like we can attack acid chlorides just like this just like we've been used to see let's see what you get from that tetrahedral intermediate that has a leaving group so acyl substitution iminium ion here positively charged nitrogen electrons on oxygen come down kick off chloride so we've seen that so many times that's the reactivity that we're used to with carbonyl compounds I'm gonna have to move that arrow a little bit here okay so then HCl h2o will convert that iminium ion to a keto so notice you turn that into a met active methylene compound we've just synthesized an active methylene compound all right questions anybody okay a couple more reactions that we want to talk about the first one alkylation of Osito Osito gesture this is in a sea of acetic ester so at the the Osito for the acid teal group yep but the mechanism for hydrolysis of the immune to the ketone I'm missing a methyl group let's throw that on there now I'm gonna hurt you here everybody turning the page and the one above it also yes I am alright alright so the Osito is for the acetate group the keto group and the cdk ester is for the ester portion that has a pKa of about 11 so I'm completely deprotonated using a Sox I died on we went through that equilibrium earlier I don't remember what page that was but we went through that equilibrium earlier pKa 17 here so you can see that we get essentially complete conversion at equilibrium we have 1 Osito Osito guesser that has not been deprotonated to 10 to the 6 that has been deprotonated we call that essentially to completion ok it's always going back and forth but it is essentially to completion so it turns out that you know weights of active methylene compounds are nucleophilic and react with alkyl halides and oscillates in the typical sn2 reactions to introduce alkyl groups into the Alpha position all right so this is another alternative to making and using lda-g de protonated ketone so we'll see what that would how we do that coming up here so this is what that looks like nucleophilic carbon you get a methyl incorporated into the active methylene position pretty straightforward it's just a it's just a typical enolate reacting with an alkyl halide this process can be repeated by adding additional base and methyl bromide so we can do the same thing again the oxide comes in and deprotonates removes that second alpha hydrogen so we've probably formed a union wait again and now we can add a second equivalent of methyl bromide do another nucleophilic substitution alkylate twice
all right so pretty straightforward this is an sn2 reactions best with methyl primary primary al Lucan primary benzylic substrates by that I mean I'm referring to the alkyl halides secondary substrates e 2 competes so this is this is standard sn2 standard sn2 considerations e 2 competes but these are not as basic as unstabilized enolates so when I say unstable I seen I mean enemy you late so I'm really kind of saying double not singly stabilized enolates versus double destabilized anyways so for example if we make the enolate of a ketone PKA the conjugate acid is xx if I make the enolate of an ester pKa of the conjugate acid is 25 I'm referring to these as unstabilized they are stabilized they're just less stabilized than active methylene enolates and then if you compare that with something that I didn't leave for room for so we'll put it over here and that would be the doubly stabilized so this would be doubly stabilized and so that would be pKa of the conjugate acid is 11 so you see the big difference in PKA so it I could like I said it should be EE I'm stabilized versus singly stabilized but these these guys here are referred to as unstable isolates even though they have resonance stabilization and this is considered to be a stabilized anyway all right so less less elimination than we get if we make the enolate using LD a of either the carboxylic either the ester or the ketone we're gonna get a lot more elimination with a secondary substrate because these are stronger bases this is less basic and so a lot less elimination so just something to think about and what we're going to do is we're going to use this as an alternative to using LD a okay but first we need to talk about decarboxylation before we do that and that's on the next page any questions on this stop me right now up at the top excuse me oh did I leave off tertiary tertiary no reaction at all right did I not write that beat you only with the exclamation point yeah thank you all right let's look at decarboxylation alright loss of carbon dioxide from a carboxylic acid is called decarboxylation I'm going to circle the atoms that are missing this does not happen very readily by the way except in certain cases co2 gas which I'm putting an arrow up meaning that just bubbles away that's a decarboxylation insert carboxylic acids readily decarboxylate the first tight is type is beta keto acids this is a beta keto acid so see what that name comes from we've got a carboxylic acid here's our carboxylic acid into the beta position we have a ketone so here's alpha here's beta so beta keto acid those guys readily decarboxylate so this is a cito acetic acid in the presence of acid this happens even at room temperature you get a ketone so in this case it would be acetone plus co2 plus co2 gas which bubbles off all right how does that happen let's draw the mechanism now we're going to orient the COC to Guster's so that we're forming an intramolecular hydrogen bond here between the carbonyl of the ketone with the hydroxyl of the carboxylic acid and what we're going to do is we're going to push electrons around in a circle and so you can you can go clockwise counter clockwise you want to start with the double bond of this carbonyl and that's going to move over here to make a new bond so we're going to move electrons around and the circle kind of like diels-alder that part of the reaction is a concerted reaction and then I'm going to attempt to leave things where they are so you can see what what's happening here so I'll draw the products and then we'll take a look at how that happens if you follow the arrows here we have carbonyl right I mean we have the carbonyl here these arrows are going to go over here to make a new bond between oxygen and hydrogen so that's right here this was a double bond now it's a single bond because we need to move those two electrons over so that's a single bond this arrow here says we're breaking this bond here the Sigma bond we're moving over here to make a double bond so that's the double bond here and then we're taking this these electrons from the oxygen hydrogen's breaking and we're making a double bond here so that's where we get the co2 so um what is the name of the carb does this product right here mean all right not stable it's going to talk Tom rice you know so this is going to tautomerize to a ketone let's do the rear let's do some arrow pushing for that we've looked at that already but let's do it again just for fun two ways you can do this you can use electrons on oxygen to come down and grab the acidic hydrogen like this boom this comes in two traps this hydrogen we break the hydrogen oxygen bond that gives us a protonated ketone and then
water comes in and deprotonates this is catalyzed by acid so this is acid catalyzed tautomerization and then that gives you the ketone reversible reaction or let me do this in a different color if you if you prefer to do it the way we did it back in 51 B or a 51 B way to do the tautomerization we had an enol as a result of the hydration of an alkyne this is back in chapter 10 so if you want to go take another look at this as should ring this should jog your memory so what we did then is we h3o plus and what we did was we were in the hydration of an alkene mode right here in that chapter so we did this sort of thing and then we put the positive charge on the site that would best stabilize the positive charge mark hornik all right well this wouldn't be Americana cough this is the best best the most stable carbo cation and then we do these the electrons came down we drew the resonance structure so some students like to do this extra step here and that is perfectly fine and then you deprotonate and that will match exactly what we did back in chapter 10 so your choice questions on the tautomerization anybody all right so we're going to annecy docetic a seat acetic acid to a ketone malonic acid is also readily decarboxylate you do need a little heat this one from an acetyl acetic ester it goes at room temperature this one you need to heat so this is more of the die carboxylic acid that will give you a carboxylic acid acetic acid derivative and plus co2 the mechanism will look very much the same except you'll have a hydroxyl on one side rather than rather than a methyl okay and so what we're going to do is convert those we're going to use this to actually as an alternative to using Lda to make enolate ions because that we know that reaction doesn't work very well so here's what we're going to be doing we're gonna be taking a C to acetic ester and through a series of steps which I'm going to show you right now we're going to be going to substituted ketone derivatives we can have to our groups or one substituted acetone or derivatives so if we're if we if we go to the second product with the to our groups you can see that um this is going to give us an alternative for the thermodynamic enolate right so the previous reaction making the ena mean gave us an alternative for the connectional eight and if we introduced to our groups this gives us an alternative for the thermodynamic enolate both of those reactions using Lda are not very clean so how are we to do this we're going to alkylate the Osito Osito gesture we're going to hydrolyze the ester so we get the carboxylic acid and then we're going to decarboxylate like we just did on the previous page so let's see how that works all right sodium ethoxide ethyl bromide do we want to use sodium hydroxide for that reaction you want to use sodium ethoxide why what happened if you use sodium hydroxide it's going to saponify that Esther is hydroxide it's going to attack that ester you're going to kick off with oxide you're going to declutter and you're gonna undo protonate so you're going to get a carboxylate here in the end of reaction you're not gonna get in any alkylation here so this is very you have to very carefully and what you want to do is you want to choose your base to match the ester if this way what would happen if I use sodium ethoxide instead of sodium ethoxide what would happen I haven't heard it yeah I haven't heard the magic word transesterification right so in other words if you use methoxide here it's gonna attack this carbon eel boom or either kick electrons up on the oxygen electrons on the oxygen either to come down and some of the time it's gonna kick off at oxide so you're gonna start getting a mixture of ethyl and methyl esters here so I deliberately chose sodium ethoxide here for this reaction so what we're going to do is we're gonna essentially completely deprotonate let's go through the process here here's a thought side we're gonna remove the most acidic hydrogen which is the one here I'm going to leave electrons on I'm going to leave electrons on carbon rather than pushing them onto the oxygen so after I do that I'm going to get an enolate we'll leave the other hydrogen off then I add ethyl bromide sn2 reaction yeah maybe I should draw that out huh if I were to draw arrow pushing I need to draw that methyl group out we want to attack the carbon that's bonded to the leaving group so we attack the carbon bond to the leaving group kick off the leaving group product of that step has an ethyl incorporated into the Alpha position into the active methylene position let's do it again that was so much fun we're gonna do it again we can use ethyl we could use so do we want to change it up here want to do let's use methyl this time and a methyl iodide I'm not feeling methyl iodide right now okay so we're going to deprotonate again I'm not going to draw the arrows for that second one but we're going to deprotonate again and then we had enough lights so now we put a methyl here just like that so step one is alkylate and it we ended up actually doing it in two steps but and the first part is to alkylate the strategy here step one alkylate we can alkylate once we can alkylate twice
whatever you need to synthesize you're going to decide step two is to hydrolyze the ester we know how to hydrolyze an ester we can do that acid-catalyzed or base-catalyzed when you look at this a reaction in the literature they mostly do on base catalyzed using Koh and water probably means that it works better than acid catalyzed do you have any experience with that either one of you guys I always use Koh but it's more straightforward but you know if you did it all with acid you could do it all in one step which I'll show you coming up all right so that's gonna hydrolyze the ester that's chapter 22 right you know how to do that you get a carboxylate saponification and now you add h3o plus in a second step Ethel's still there methyl still there now we have a carboxylic acid and now that carboxylic acid can readily decarboxylate so step three is decarboxylate so we just did that mechanism for that we're going to decarboxylate we're going to form an enol and the enol is going to talk tom rise to a ketone this goes readily at room temperature so we don't even need to heat it really and so that whole entire carboxylic acid is coming off and it is replaced with a hydrogen right there so what we've we've always essentially done is we've done the same thing as if we started with a ketone we may use LD a we deprotonated and we're alkylating on the most substituted sites on making the thermodynamic enolate only this is although it's more steps it's much cleaner okay questions on that strategy anybody so the whole entire thing it's called an acid or acetic ester synthesis and basically what it can be done what it could be used for is making substituted acetone derivatives so here's retrosynthetic analysis if I give you a compound and I said so you make this can you make this compound from an Osito acetic ester synthesis so this is what you would do look for acetone and circle acetone so that's our I'm just calling this our acetone unit here and the to our groups are we're gonna put the two R groups on from the Osito acetic ester so basically this hydrogen right here comes from the decarboxylation so I'm going to cross out that hydrogen and I'm going to put a temporary ester group here so now can you see where the Osito Osito gesture is we have right here that's the acetone that that hydrogen is off that's now our ester right here so these two R groups are going to come from alkylating a CE to acetic this C docetic ester so I'm here we replace with replace hydrogen with a temporary ester group and so this these two our groups are going to come from that and that are going to come from our the our our I your choice this is going to be our prime be our it could be a chloride it could be an iodide it could be at oscillate alright so that to make this compound we're going to start with our be our our prime be our and a sea of acetic Esther and I will say use an acetyl see two guest artists synthesis to make this compound questions on how I took that apart we're going to write the synthesis on the next page that's just how I took that apart so like I said the exam would say show how you can make this using an Osito city caster synthesis so we're gonna do that means we're going to start with and Osito Osito caster it could be OE tikka Bo methyl or Wheaties probably more common step one I'm going to deprotonate na o ET I'm going to add one of the two our let's do our PR first and then I'm going to deprotonate again you want to do this stepwise and then our prime PR that does the alkylation do not write excess sodium ethoxide RB R & R prime V R then you have no control over what happens you're going to have some of them with two R's you're going to have some of them with to our primes some of them with R and R Prime different have fun have fun isolating their put the correct compound from that mixture not very easy okay so we violated twice so I need to actually draw in the alkyl groups here you were wondering if I was going to do that okay we've got the lady twice now we decarboxylate koh h2o heat and then h3o plus h2o we don't need heat but you can or if you want to make it a little shorter we can hydrolyze an ester an acid can't we we know acid catalyzed hydrolysis of an ester and we know base catalyzed or we can do this as one step we can do h3o plus h2o and heat and this will hydrolyze the ester then decarboxylate so as soon as you make that as soon as you hydrolyze that ester it will decarboxylate very readily at room temperature you're already heating it up to get the ester to hydrolyze yes instead of the third step there was an invisible second step here that I didn't tell you about yes that should be a to thank you all right okay more questions
on that you think you could do that on midterm 2 it's not that bad it really isn't trust me all right so so we're going to talk about malonic ester synthesis next which is the same idea except we start with malonic and a monic esters so ester ester rather than ester ester ketone it's the same idea so guaranteed on midterm two you will have to do either an acetyl acetic acid or synthesis or a malonic ester synthesis they're both the same I'll find some fun cool thing that you can synthesize and then then you can use that alright so this is the same idea so if you give you get the previous one you'll get this also so this is going to give us substituted acetic acids so here's our acetic acid unit here if we alkylate the active methylene compound once we get the R group here if we alkylate twice we get to our groups in the Alpha position and this is pretty cool because we really really can't deprotonate that alpha position of a carboxylic acid right because if we add base we deprotonate that gives us the carboxylate and then we're stuck so you will not find a pKa for the Alpha hydrogen of a carboxylic acid that's because if you add base the most acidic hydrogen is going to be removed so base removes proton on oxygen not carbon not on the Alpha position all right so we could alkalete the corresponding Esther and saponify so we could do LD a and then we could do our X and then we can alkylate their that way so then we have our ch2 and then our Esther and then we can hydrolyze the ester Koh h2o heat definitely need to heat that and then step to h3o plus and heat or again we can bypass that and do acid catalyzed hydrolysis or one step now I guess we don't need heat there because we're not decarboxylated so let me fix that we just need a h3o plus or or we can just do acid catalyzed hydrolysis of the ester h3o plus h2o and heat and that will give us the carboxylic carboxylic acid all right so again we can hydrolyze esters acid-catalyzed or on base-catalyzed so this is base catalyzed and this is acid catalyzed that's an alternative but it doesn't work as well for a couple different reasons it's more expensive you have to use inert atmosphere techniques you have to use dry solvents dry glassware argon or nitrogen atmosphere it's this is better for small scale reactions and then also the enol AIT's a stronger base than a stabilizing light so you get worried - so this is really not a good all not as good of an alternative all right so conceptually we have the same idea here we alkylate diethyl Melanie we hydrolyze both esters and then we decarboxylate so let's do an example here all right so step one we alkylate still an active methylene compound it's none it has a little bit higher PKA than the Osito sweetie Guster but mom still works really well and we're going to get one methyl incorporated let's just alkylate once this time just don't have to alkylate twice you can just alkylate once and then we got to diet we hydro had two highs both esters
so saponification we are going to get the die carboxylate looks like that and then in step 3 we protonate the protonate the die carboxylate then we decarboxylate only one of the carboxylates one only the one of the carboxylic acids will come off so step three we want on h3o plus h2o and heat and when we do that we get a substituted acetic acid derivative or what if or if we want to be really we want to save ourselves a little time here we can do acid catalyzed hydrolysis h3o plus h2o heat and so we're hydrolyzing the esters in acid we get the dark height dicarboxylic acid as soon as we get the dicarboxylic acid decarboxylase so this is this step here is an acid-catalyzed ester hydrolysis then decarboxylation alright so you can as you can see the same idea we could alkylate twice if we wanted to you will definitely be asked to do one of the two of those on the test if if not both probably not both just because we have so much to cover on this exam retrosynthetic analysis we want to be able to if I give you a substituted acetic acid derivative you want to be able to take it apart and see how to make it so let's do that right now all right here is our scenic acid right here circle that so we're gonna replace the hydrogen with a temporary ester and then this this is also going to become an ester right so we'll put the ET there also because we need a diaster to start with these two groups right here this is going to be from our BR and our prime be our this is our acetic acid unit so we replaced we were replaced the hydrogen with a temporary ester and then we converted this acid to an ester all right so what would we start with we would start with diethyl malonate right here our BR and our prime V R and we'll if we write out the synthesis in the forward direction then it's going to look just like the last one I said we just have a different starting material so let's show how we would use that let's outline a malonic ester synthesis of the following carboxylic acid alright so circle acetic acid try not to be thrown off by the ring this is one R alkyl halide did this is the other one we've alkylated twice let's put on our temporary ester group there's a temporary ester group and then we're gonna change this to an ester also alright so this is going to be from diethyl malonate and let's make sure we count carbons here we want one two three four five one two three four five that's going to be our alkylating agent that's our alkyl halide that's how we're going to make a ring because we've got the leading groups on both sides so let's write out the synthesis in the forward direction we've got one minute to do this start out with diethyl malonate step one na o ET I've chosen my base to match my ester step two I add this alkyl halide here I want to do this stepwise if I use two equivalents of sodium ethoxide and then I add this that we they're going to have competitions some of the thought sites gonna attack the alkyl halide and that's going to take away our starting material so you definitely want to do this stepwise that gives us this compound here and let's do the one-step thing here h3o plus h2o heat that gives us the substituted acetic acid compound and that is the end of chapter 23 we'll stop right there and we will start chapter 24
next time