Substitution Reactions of Carbonyl Compounds at the α-Carbon

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Substitution Reactions of Carbonyl Compounds at the α-Carbon
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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: 00:21 - Irreversible Addition Reactions of Type 2 Carbonyl Compounds 17:31 - Acidity of Alpha Hydrogens 19:50 - Why is the Alpha Hydrogen of a Carbonyl Acidic? 34:02 - Enolization of Carbonyl Compounds 40:33 - What Determines the Percentage of Enol at Equilibrium?
Biosynthesis Reaction mechanism Carboxylate Aluminium Amine Set (abstract data type) Methoxygruppe Methylgruppe Ammonium Electron Data conversion Common land Film grain Transformation <Genetik> Lithium Aluminium hydride Stickstoffatom Ketone Walking Hydrierung Hydrogen bond Carbon (fiber) Carbonylverbindungen Protonation Chemical reaction Iminiumsalze Water Lone pair Acid Computer animation Functional group Etomidate Nitrile Amination By-product Grignard-Reaktion Carboxylierung Cobaltoxide Ammonia
Ester Species Reaction mechanism Aluminium Amine Organische Verbindungen Dreifachbindung Klinisches Experiment Electron Transformation <Genetik> Aluminium hydride Dyeing Hydride Stickstoffatom Elektronenpaar Walking Aldehyde Addition reaction Chemical reaction CHARGE syndrome Water Lone pair Acid Computer animation Functional group Aluminium oxide Nitrile Salt
Alkyne Ester Carboxylate Sunscreen Resonance (chemistry) Substitutionsreaktion Wursthülle Alpha particle Electron Acid dissociation constant Beta sheet Conjugated system Atom Chemical element Induktiver Effekt Ketone Hydrierung Carbon (fiber) Carbonylverbindungen Aldehyde Electronegativity Alcohol Food additive Acid Computer animation Functional group Enol Cobaltoxide Base (chemistry) Stereoselectivity
Ester Chain (unit) Species Carboxylate Haloalkane Resonance (chemistry) Methylgruppe Alpha particle Nitroverbindungen Electron Acid dissociation constant Conjugated system Compliance (medicine) Dye Stickstoffatom Ketone Hydrierung Carbon (fiber) Aldehyde Protonation River source CHARGE syndrome Electronic cigarette Lone pair Acid Computer animation Nitrile Chemical compound Cobaltoxide Base (chemistry)
Alkyne Ester Activity (UML) Resonance (chemistry) Wursthülle Aromaticity Ether Methylgruppe Alpha particle Nitroverbindungen Solvent Electron Acid dissociation constant Beta sheet Hexane Conjugated system Diketone Dyeing Stickstoffatom Ketone Hydrogen bond Tautomer Hydrierung Carbon (fiber) Alkoxide Carbonylverbindungen Aldehyde Gleichgewichtskonstante CHARGE syndrome Alcohol Food additive Acid Computer animation Cyanidion Functional group Enol Nitrile Covalent bond Chemical compound Acetone Chemical structure Cobaltoxide Base (chemistry) Bottling line Thermoforming
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okay so we talked last time about
reaction of it means with and you need to see that don't you alright we talked
about reactions of amines with grignard I mean nitriles with grain yards so the grignard adds once and then we get this deep deep protonated amine and then once we add acid we form the amine and most of the time an amine is less stable than a ketone so it's going to be converted it's going to go backwards we know how to go from forward direction for the ketone to an amine now we're going to go back and and do the reverse reaction and so that's going to happen automatically so notice the overall transformation we go from a nitrile to a ketone may be a useful transformation that you might need in synthesis so you want to get in the habit of looking at the overall transformation we go from a nitrile to a ketone so that's a good good thing to be able to do there's other ways to do that but that's a pretty fast way to do that alright so we were gonna we're going to do the mechanism for converting than amine to the ketone let's do that right now so let's start with the Emmy all right so there's our Emmy and no big surprise here we're going to protonate the Emmy to make an iminium ion and of course once we protonate that I mean just the same thing that happens when we protonate a carbon eel we make the carbon eel more electrophilic when we protonate an amine to make an iminium ion we're also making it more electrophilic so that a weak nucleophile can attack the weak nucleophile that's going to attack his water all right so the argos be alert the water's going to attack so it's just the attacks is going to look just the same as it does when you have a protonated carbonyl we're going to attack push electrons up on to nitrogen alright so the water that just attacked that's going to stay so the groups that stay we're going to deprotonate and then that that water that just attacked that oxygen is going to become the carbonyl okay so we need to lose ammonia but in an acid catalyzed mechanism we're always going to protonate the leaving group before it leaves so that's what we'll do first want to make sure you don't combine two steps into one so the deprotonation of the water that just came on the deprotonation of the oxygen and the protonation of the nitrogen you don't want that taking place at the same time okay so now we just made hydronium in that last step let's use the hydronium to protonate nitrogen and of course once we protonate hydrogen it's going to be ready to leave we're gonna have the electrons on oxygen come down and help kick off the leaving group ammonia as a leaving group and that will leave us with their protonated ketone and what I really hope is that all these mechanisms are starting to look really similar because they are and that ammonia that just kicked off we can come and have that deprotonate we could have water deprotonate also but we also could have ammonia to protonate I'll do I'll draw both of them you can use either but even if you have ammonia to protonate I mean even if you have water to protonate the wad the h3o plus that you make is going to react with the ammonia so that you will get ammonium ion as your side product and that's something you want to keep in mind when you're doing the sapling problems so NH 4 plus would be your side product we don't normally what you that worried about the side product with some of the questions in sapling asks you to worry about the side products all right questions on that mechanism anybody going from an amine to a ketone so possible mechanism for midterm two so this whole thing right here attack of the grignard and then conversion of the amine to a ketone I had that on last year's midterm 2 it's possible I could put that again on there okay so I'm not saying I will but I'm just saying that was on there okay anybody have questions before we move on all right let's do another let's predict another new reaction we'll let the aluminum hydride plus a nitrile and we certainly have done a lot of lithium aluminum hydride reactions probably be able to figure out what's going to happen here so let's just kind of take it one step at a time we have AOH four and we have the so there should come from the aluminum hydrogen bond we're going to attack the carbon and we're going to kick it up on to nitrogen so on nitrile is electrophilic certainly not as electrophilic as carbonyls but they are electrophilic and lithium aluminum hydride is a very powerful nucleophile so it has no trouble attacking so we've got the negatively charged nitrogen with two loans two sets of lone pairs and we have the Al a ch3 that we just formed in the last step and so we have a really very strong nitrogen nucleophile and that's going to attack the al a ch3 so this has a lot of features in common with Luthi aluminum hydride plus the carboxylic acid or plus the amide all right and then what's going to happen is the lithium aluminum hydride is going to tack again so that alh 3 remember when we did this so with lithium aluminum hydride plus a carboxylic acid we had oh la la ch3 and that kind of behaved like a methoxy group and so this is going to this is going to behave kind of like a methyl group attached to nitrogen okay so so same idea so that's going to attack twice
and then when we add water in the second step we're going to protonate everything and so as you can see the overall transformation is that we have converted and a nitrile into an amine all right so that's an that's so so so so look at again look at the overall transformation we've gone from the night trials they're basically or what we're doing is we're adding two equivalents of h2 across that triple bond 1 1 equivalent here and then we do it one more time and so we end up getting and it means so if you see a CH 2 and H 2 added on to something you know maybe you start with something R and then you see a CH 2 NH 2 added onto it you might want to think I could do that with a nitrile okay not directly but I could certainly do that with a nitrile yes well we get it well we just would prove we could protonate the nitrogen and the dal the water's also been attacked the aluminum and so it's it's kind of involved I don't think we need to go to that extent I usually don't but it's just like if you have grignard salts in there and you add water those come off also so the nitrogen certainly can attack directly with the water and then the aluminum is also going to have water attack the aluminum I don't want to get involved in the whole nitty-gritty of that because you don't really need to worry about it just kind of suffice to say everything's going to be protonated okay all right I did it one time because I do get some students asking me that question and everyone in the whole class was just like oh god we need to know this you know it's it gets involved with all the things happening with the aluminum so we're just not going to worry about it okay all right okay so that's the idea let's does the mechanism we want to use for this you don't want to use the book mechanism I don't know just some of you may still have the second edition I don't want you to use the book mechanism for this in the second addition they did something like this the first step was the same you could probably buy the second addition for 10 so our 10 or 20 so I'm sure some maybe some people have it they did that and then they added it again just straight so this is what it looked like and they added one more time to make into - I don't want you to do that so like I said back in 51 a we don't want to ever have a doubly charged anything in this class so n/2 - is not good so that - - charge is a bad idea so in the third edition they changed it they must have gotten complaints I don't know so they did something similar to what we've done first step looks the same and their second step looks the same so there's always a question when you're teaching you know the first year organic chemistry how much do we really want to show you and you always have to make a decision on how much to show how much not to show because things are oftentimes more complicated than we're showing so it looks like that and then they did this sort of thing al like this and then they had this coming in up here they have this coming and this is I believe in the third and the fourth edition full and they have a sort of a and I'll do red arrows for this this coming in and that going here like that in the new edition so what would be wrong with that one something else I told you that we don't want to do in this class well we have three species coming together simultaneously right termolecular reaction so that's that that's the problem with that so you're basically you're asking for three things to come together in the right orientation to colliding in the right orientation with the correct energy all happening at the same fraction of a second not likely so we don't want to certainly propose that for a mechanism alright questions anybody so one more reaction with nitriles and that's die ball if you want to stop at one addition you can use die ball and we know that dipole behaves a little differently it's aluminum species with only three groups so it only has six six electrons in its valence shell so it's looking for lone pairs to donate electrons to grab electrons from and so the nitrogen is going to donate its electron pair and so here we have the aluminum die I Sub util aluminum hydride so there's two isobutyl groups and we have a hydride right here that's ready to be transferred intramolecularly boom just like this okay and that is going to stay that intermediate is going to stay until you add acid so once you add water h2o and acid this is going to be protonated again we're not going to get involved with the nitty-gritty there but that nitrogen is going to be protonated aluminum is going to come off Luna is going to become the water is going to be attacking the aluminum so you're going to get a lot of aluminum oxide species we're not going to worry about that but you do get on you get do get an amine and certainly the amine is going to go to the that particular amine is going to go to an aldehyde and we just did the mechanism for that right see page 76 for mechanism so I don't know how well that reaction works I don't know if that works as advertised uncertainly die ball with esters doesn't work very well how about this one nobody knows nobody does it's done it okay yeah question well it's a little bit different because we're not doing a we when we had the five to six membered ring deprotonation this is a little bit different because it's not a deprotonation and that you know the dive ball can also come in from the outside also but it tends to go intramolecularly okay alright and that is chapter 22 are ready to move on to chapter 23 everybody good so far I can say if it's safe
all right so we're going to be talking about substitution reactions of carbonyl compounds out of the alpha carbon I think we need to put those the podcasts up for the nomenclature no one's been emailing me about that no one's real anxious to do nomenclature so but that will happen this week alright so when you read the nomenclature you'll see that you have your carbonyl i'm adjacent to anything adjacent to the carbonyl we don't want that anything adjacent to the carbonyl is alpha and then the next carbon is beta so we have alpha right next door and then we have beta and it turns out that the alpha hydrogen on some but not all carbonyls certainly aldehydes ketones or esters and some other select carbonyl compounds is acidic so the Alpha hydrogen has a PKA for a ketone is that it's about a ketone or ester I mean a ketone or aldehyde is about 20 so we're gonna add that to our PKA chart rounded to the nearest 5 aldehydes and ketones are about 20 and so significantly more acidic than the beta hydrogen this beta hydrogen right here is has more of the pKa of what we would normally expect for a hydrogen bonded to carbon of beta hydrogen is not acidic PKA is about 40 to 50 so there's a tremendous advancement of a tremendous enhancement of acidity on that alpha hydrogen so if you compare acidities here we have alcohols and hydrogen's about 15 aldehydes and ketones are about 20 esters we're going to talk about those coming up those are about 25 and terminal alkynes also about 25 so ester is about the same as terminal alkynes aldehydes and ketones a little bit more acidic alright so the first thing we want to answer is why is that alpha hydrogen so much works acidic thing we would expect there's two reasons number one the carbonyl is strongly electron withdrawing all right so let's have generic base come in remove that acidic hydrogen and take a look at the conjugate base and we know that a carbonyl is an electron withdrawing group we saw that back in chapter 18 so it's going to be pulling electron density towards it just like that all right so electron withdrawing the inductive effect of the carbonyl makes on the carbon less negative right less charge less negative less negative which equals more stable we can also think of it by the fact that that carbon is sp3 high sp2 hybridized sp2 hybridized carbons more electronegative so it's pulling electron density towards itself you can think of it that way let's add that in case you were thinking that way instead carbonyl carbon is sp2 hybridized and therefore more electronegative and therefore this makes also makes the carbon less negative therefore makes the alpha carbon less negative so two ways to think about the same thing so that's reason number one reason number two is the loss of the alpha hydrogen gives a residence stabilize M anion we're actually have three reasons this is probably what you would have thought of if I asked you with the reason why this is so much more acidic if we remove that alpha hydrogen we get a resonance stabilized carvanha and we can move electrons up onto oxygen to make a really nice resonance structure which one of those is major first one of the second one second one's major because we have the negative charge on oxygen so we have minor major this one is the major resonant structure this is the minor but together those make our resonance stabilized and we call this an enolate ion so that's a new term for you if you remember but where does that come from if you remember back in 51 B when we learned about enol whoops I drew that wrong let's fix that remember enols from chapter 10 that's an enol and if you deprotonate an enol that you get an enol eight so that eight means we did we've deprotonated that oxygen so it's just kind of like a carboxy group you do protonate a carboxy group you get a carboxylate so that would that's where that name comes from and so that one's the second one is major because the negative charge is on the more electronegative atom all right there's a third reason that's not very obvious negative charge of the ena lights delocalized onto oxygen electronegative element okay well we know that we picked that as the better resonance structure but how big of a factor is that the fact that we can move that uncharged onto oxygen and so a good way to do that is to compare so we can let's do this here let's compare
something where we do the same thing except we're moving electrons onto carbon rather than oxygen and let's compare and see just how valuable that is all right so if we do that so did everybody see the parallel there so now we have carbon instead of oxygen both of them are resonance stabilized and then we can go boom boom move charges onto carbon we can create the second resonance structure all right two resonance structures we can also do two resonance structures for the second example let's do the same thing so we're going to move electrons around here over onto oxygen so throw some lone pairs on oxygen now we had the negative charge on oxygen so both residents stabilized but here that the negative charge is delocalized onto oxygen so negative charge do you localized on to more electronegative oxygen this one also residents stabilized but the negative charges on carbon rather than oxygen so what's the difference in PKA for these guys this one here on PKA about 20 as we said in previous page this one here PKA 42 okay so it's not just 22 times more acidic it's ten to the twenty twenty second times more acidic to take that negative charge and push it onto oxygen so that's very valuable here all right so all of those for all of those reasons here nitro back to alkanes nitriles and n and dye substituted Amex also have unusually acidic alpha hydrogen so here's some other examples here this one here pKa 26 PKA 8.6 and over here PKA 30 so I'm not super good but also with the city hydrogen's why does it have to be a and and I substitute here why do we have to have two methyls here for that proton to be acidic before you if I just replaced that with and if I just put NH 2 there could we remove that alpha hydrogen no because that of that hydrogen on nitrogen is going to be more acidic right okay and then once you remove the I the hydrogen on nitrogen that changes everything so so for a carboxylic acid the alpha hydrogen is not acidic right because when you add base what's going to happen you're gonna remove the proton on nitrogen and likewise for and ammon so it has to be an end I substituted and so through all of those can be deprotonated and you can see that the conjugate bases for the conjugate bases for these guys I'm not going to draw all the resonance structures but you can kind of get an idea what we're doing here here we're moving electrons on to nitrogen for that conjugate base then here's a nitro group and we can move electrons up on to oxygen here and this one's actually significantly more acidic even better than a ketone or aldehyde and an end I substituted compound here we can move electrons onto oxygen and we can also do that with an ester okay so here a negative charge delocalized on two nitrogen in here the negative charge is delocalized on two oxygen which is better and then here also negative charge delocalized on to oxygen okay and we want to think about that kind of in the back your head why the amat is so much less acidic than these other two examples okay and so as you can see at the bottom of the page if I could scroll nicely here we can't remove the acidic proton on a carboxylic acid or a regular anima that's not an end I substituted because this has a pKa of five if we add a base we're certainly going to remove the more acidic proton on oxygen rather than the proton on carbon and likewise here when we if we have a regular AM adhere that has a pKa of about 15 and so if we add base there we're going to remove the acidic hydrogen on nitrogen we're not going to remove this one over here that only has a pKa of 30 right so that's not going to happen questions so far okay why is this really valuable we're actually most of the time we've been using carbon it's been electrophilic carbon in chapter 7 when we had alkyl halides it was electrophilic carbon right and all of the chapters we've done so far this quarter it's been electrophilic carbon we had nucleophiles attacking carbon when we removed the alpha hydrogen we turned that species into a nucleophile and that's really very valuable when we have nucleophilic carbon and so we're going to be doing a lot with that yes mm-hm more carpets on the chain is is okay
but it's still not going to be as valuable as having that negative charge on oxygen even so it's that negative charge on oxygen that's that's making them having the big effect here so if your if this was even more conjugated yeah we'd be more acidic but not as acidic as having that oxygen there okay all right more questions anybody somebody else okay let's talk about utilization of carbonyl compounds we've already talked about anoles now we're going to talk about it in a more formal way so back in chapter 10 when we talked about hydration of alkynes you made an enol as an intermediate and what did it do touched on rise to a ketone or a ketone right remember that remember all that business so these guys are in equilibrium all you need is a trace of acid or base so that acetone bottle that you use in the lab there's a little bit of enol in there tiny bit and it's going back and forth and back and forth at equilibrium for this particular ketone we have in 99.98% keto form at what we said back in chapter 10 was that most of the time the keto form is favored there are some exceptions and here's where we're going to talk about some exceptions here's the enol form here 0.02 percent and the equilibrium constant for this one here 4 times 4.0 times 10 to the minus fifth 4.0 times 10 to the minus fifth so as you can see the equilibrium strongly favors the keto form here's some other examples here you know keto tautomer ization and some numbers for you all that you don't need to memorize these numbers but just to know that most of the time we have the long arrow towards the keto form there's a few exceptions that we're going to talk about the one here is - the scroll bar is really touchy here's a good example at equilibrium we have less than 0.01% here and 99.99% why is that why is the enol form favored there it's the anal forms aromatic right so this is a really big exceptional exception so enol form is aromatic and therefore extremely stable so that's one exception there's another class of compounds that for the enol form is can be favored and a lot of its going to depend on what solvent that you're in so this is a 1/3 die carbonyl or a beta die carbonyl so here's alpha beta if we start counting from the left and in the beta position we have another carbon eel so it's a beta die carbonyl and for this at equilibrium in hexane we get 8% keto and 92% you know all right so why would we why would we stay why would we favored eknoll here what do you think yeah this double bond when they're there this way they're not conjugated here this is conjugated um and you can actually you can get a hydrogen bond between thus oxygen and this hydrogen here a hydrogen bond in the six membered ring that's really valuable and so when you're in hexane which is a non-polar solvent this form actually becomes predominant if we put this same beta diketone in ether that can actually hydrogen bond you'd get less but in hexane which can't really help out with hydrogen bonding the enol form is actually more favored and so conjugation is the big deal and also the intramolecular hydrogen bond so let's draw the resonance structures here for the enol form so we can move here these electrons can go right here negative charge goes in between the two carbonyls and then we can move that over on to the other oxygen and so that's the resident stabilization that's happening through that conjugated form and you can see that even this third resonance structure here is also conjugated so resonance stabilized enol and again that intermolecular hydrogen ball which is going to become very important in hexane let's look at that let's draw that out so here's the hydrogen bond right here so that's why I have a dotted line there intramolecular hydrogen bond especially important in nonpolar solvents such as hexane all right so what determines the percentage savino form president equilibrium the percentage enol equilibrium depends on the structure of the carbonyl compound which determines the acidity of the Alpha hydrogen's and so the more residents stabilization the greater the present of enol at equilibrium and we can actually correlate acidity with PKA city their pKa can be correlated to the extent of enol keto-enol tautomerization at equilibrium that's on the next page huh move it up a little down or up move it up you're still writing that other thing okay how about that all right so we're gonna look at some carbonyl compounds I'm going to be giving you pk's and we're gonna be having a trends question on midterm two on these pk's so I'm gonna scroll down I have to because I have to otherwise I
can't get to this it's not scrolling right okay so PK is over to the left do not memorize these PKS but this one is about 24 Kieffer and I bowled it in the hydrogen that the hydrogen that is city hydrogen that we're talking about 25 for an ester may want to think about why an ester is less acidic than it a ketone something to think about PKA for a methyl that's a-- bonded to a nitro group is nine way more acidic might want to think about why that's the case hydrogen on on a honesty to nitrile is 25 so about the same as an ester and then we move into what we call the the die keto the beta died ketones or the beta die carbonyls we also call them active methylene compounds and let's look at what happens to the pKa 9 for this one we have a ketone on one side a ketone on the other ester on one side ketone on the other is 11 ester on one side ester on the other is 13 so are you seeing a pattern here ester on one side nitro on the other is 6 what if like how to a nitro on one side and a ketone on the other would it be lower than 6 or higher than 6 lower right so you guys are already seeing what I'm talking about here nitrile nitrile boom-boom on either side that's 12 which is about the same as ester ester right they're almost the same all right so what we can saying is that number one lower PKA equals greater percentage of enol at equilibrium and number two some groups are better at stabilizing an adjacent negative charge than others so what we mean is that if you don't the conjugate base for any of these compounds some of these groups are better at stabilizing charge what's the what group is the best at stabilizing an adjacent charge nitros the best of all okay so we're gonna let's let's list gosh okay so we have nitro group is the best followed by what just looking at the pka's ketone aldehyde are going to be about the same and then nitrile and ester about the same and that leads us to active methylene groups that's an active methylene group that is alpha to two carbonyl to nitro or cyano groups is called an active methylene the hydrogens of an active methylene group are easily removed by basis such as alkoxide because the resulting conjugate base is highly stabilized so let's indicate and I swear I'm just moving this like a fraction of any thing here these guys right here are active methylene compounds and these are so much more acidic because they have double stabilization we can push the electrons over onto one side then we can push them over onto the other side so so doubly stabilized active methylene oh all right so let's come here I'm gonna compare a ketone with an active methylene compound let's change this to a two and let's do some arrow pushing here here's our enolate ion and we can take those electrons that we can push them onto oxygen and as we saw that's very very valuable in stabilizing this conjugate base let's look at the direction of equilibrium here we have a pKa of about 20 for the first compound and for an alcohol what's that pKa rounded to the nearest five about 15 right those things come in handy so as you can see at equilibrium the ketone is favored and the ratio at equilibrium you take the difference in PKA it's about 10 to the fifth to 1 and what we'll do next time is draw the resonance structures for the second one you'll see the equilibrium is favored in the opposite direction we'll
do that on Friday