Lecture 15. Reduction and Oxidation, Part 3
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TonmineralDomäne <Biochemie>VancomycinValinMannoseBukett <Wein>ManganMethylmalonyl-CoA-MutaseInsulinkomabehandlungChemische StrukturOrganische ChemieRauschgiftSchmerzCytologieGenChemische VerbindungenKörpergewichtEukaryontische ZelleFettzelleProteinkinasenReaktionsmechanismusInterferon <gamma->Setzen <Verfahrenstechnik>StoffwechselwegPilleHeck-ReaktionTranskriptionsfaktorSystemische Therapie <Pharmakologie>SignaltransduktionTerminations-CodonEnergiearmes LebensmittelStickstoffatomReglersubstanzHope <Diamant>Toll-like-RezeptorenChemische ForschungFärbenProteineTankSandsteinKnoten <Chemie>Applikation <Medizin>BrandsilberPulverAktives ZentrumInduktorComputeranimation
03:59
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Transkript: Englisch(automatisch erzeugt)
00:09
Okay, welcome back to another episode of what's going on cool in the world of, in the world, I guess. Not just in the world of chemistry. Saw a news article that had something to do with drugs
00:22
that could help people lose weight or control their weight, and I'm all for that. So this had to do with a study where some investigators at the University of Michigan started screening drugs that were already approved in the market to see if they might do something about obesity.
00:40
You guys may have heard of this thing called the FEN-FEN diet pill from the 1990s, it's one of many different types of drugs where people have had high hopes that it could help people lose weight and keep weight off. Most of those kinds of drugs overwork the heart and cause heart problems, so they're still waiting to see if this particular compound that they found, which seems to be very effective,
01:01
will have those problems in humans as well. So what they showed is that this oral medication, which is actually used to treat canker sores in the mouth, it turns out that when they injected animals with this drug called Amlexinox, it made a huge difference in animal weight. And so if I could eat whatever the heck that I wanted
01:20
and then just pop, I am all for that. Get out of here and go develop some pill that I can take so that I can eat whatever I want. So let's go ahead and talk about this Amlexinox. I've never heard of that before. It's not a billion dollar pharmaceutical, but it's something that's clearly been on the market for a long time. This is the structure of Amlexinox up here.
01:44
And you can see it's a xanthone, I guess you would call it an azaxanthone because there's a nitrogen in the ring. And the target of this is this kinase here called TANK1 kinase, TBK1, and there's another kinase here.
02:01
They're not quite clear as to what the mechanism is. This was supposed to be an epsilon accordion. I just pulled this signal transduction diagram off the web. They're still trying to sort out this pathway on which Amlexinox is believed to act. And the problem is what you're seeing here is a picture that's generated by cell biologists that's an aggregate
02:20
of many different types of human cells. And so that means it's not perfectly accurate. And so the key point here is that if you have a cell that gets infected by a virus, there's something called a toll-like receptor that sends messages inside of the cell. And that message is controlled to some extent by these two protein kinases. The kinases that phosphorylate a transcription factor
02:43
which then turns on genes. And the effect of those genes depends on what type of cell it is. If it's an immune system cell, it can turn on interferons that help fight viral infections. If it's other types of cells that are simply infected, it can send a message for genes that basically say, hey, cell, don't die.
03:00
Let's keep pumping out new virus, and you'd really like a drug that inhibits that. You'd like those cells to die if they're infected by a virus. Well, those same kinds of pathways, it turns out, control adipocytes. You would like your adipocytes not to proliferate, right? You'd like them to just stay quiescent, stop proliferating, stop growing. And this drug seems to have the same effect, and Lexanot seems
03:23
to have the same effect in adipocytes as in virally infected cells. And that's cool. So hopefully, again, I'm not holding out high hopes. The general trend is usually when they find things that induce weight loss, that usually those things overwork the heart and have other problems associated with them.
03:43
But I'm sure hoping for that, for organic chemistry to come to my rescue. So we're going to finish. Let's go back to the chemistry at hand today for Chapter 12 in the Gorzynski-Smith textbook. And we just finished talking about dihydroxylation,
04:03
the addition of two hydroxyl groups across a double bond. And we talked about two different ways that you could do that. One way is you could epoxidize a double bond and then hydrolyze the epoxide open so you get an anti-disposition of hydroxyl groups. The other way that you could do it is using osmium
04:22
tetroxide and NMO, this secret co-reagent oxidant. And then it adds two hydroxyl groups on the same side of a double bond. And so you need to distinguish those two patterns where the two hydroxyl groups end up on opposite sides or where the two hydroxyl groups end up on the same side.
04:41
So now we're going to talk about a completely different type of reaction of alkenes. And one, this is the kind of money reaction that you'll be using for the rest of the Chem 51 series. On through Chem 51C, they'll be throwing this reaction at you. And it's called ozonolysis. It's a reaction where you use ozone just like the ozone up in the stratosphere that absorbs ultraviolet light.
05:02
We have little electrical ozone generators. You blow oxygen gas through a current, through a high voltage current. And it converts the oxygen gas into O3 or ozone. So you don't really need to know the structure for ozone. I'll go ahead and draw a resident structure here that looks like this. Three bonds to oxygen. You have to have a positive charge.
05:22
One bond to oxygen has to have a negative charge. So that's the structure of ozone. What we're interested in here is the reactions of ozone. So let me give you a couple of examples of what you can do with ozone. And the key phrase here is cleavage. You cleave double bonds with ozone.
05:40
And it is always a two-step sequence the way you use ozone. So here's ozone, O3. That's all you have to write, O3 as a gas. So again, in the lab, you've got this machine that generates ozone gas. You bubble it into a solution. You can either bubble it directly into your reaction solution or pre-make a dilute solution
06:01
of the ozone in solvents like methanol. So when I carry out this cleavage reaction, I need to follow it with a second step that is always some kind of reducing agent. And the book gives you two different reducing agents. And I don't know why they give you two. It's just more stuff for you to memorize. So one reducing agent is zinc metal.
06:22
It's not zinc chloride, zinc plus two. It's just zinc, ZN. And you use that as a dispersion of zinc powder in water. And so the end product of this, and I feel like it is kind of an easy reaction to see in the forward direction.
06:40
Because all you do is you sort of split that carbon-carbon double bond right down the middle. And wherever you had a CC double bond, and I'm just going to put a little squiggly line there so you can see, ozone splits that CC double bond and it leaves two carbonyls. And that's very powerful. Sometimes you want a way to generate carbonyl groups,
07:00
and this is a powerful way to do that. The reaction gets a little harder to see what's going on when you have cyclic substrates, but this is a very common application. And so if I take cyclohexene and I do my ozonolysis reaction, O3, and in this case I'll show you the second type
07:20
of workup that you'll commonly see in our textbook and the Gershinsky Smith textbook and in the Sapling online problem sets. And that is dimethyl sulfide. So I'll draw up the chemical structure like this. But I almost never draw it out like that. I write just ME2S as my common abbreviation.
07:41
That's the most common typewritten abbreviation for dimethyl sulfide. And it's also a reducing agent. It's more reliable than zinc powder. The problem is it smells bad. So I'm more interested in efficiency than in smell. So I tend to ask questions
08:02
where I use dimethyl sulfide more commonly. Okay, so now the tough part is how do I draw this out? And one of the key challenges for you is to recognize what used to be attached to the olefin. So I'm going to draw in the hydrogens that were there on the olefin, and if you draw everything that's attached
08:21
to the olefins, you'll be less likely to make a mistake. So for example, if I come over here to my top case and I remind myself that there were two hydrogens on that double bond in the beginning. There was a hydrogen up here. There was a hydrogen down there. I'll be less likely to make a mistake when I draw up my product. If I draw that there's, yep, that hydrogen is still there
08:41
and that hydrogen is still there, this is one way to help you make sure that you draw correctly draw the products. It's going to get a little bit crowded in here when I try to fit those hydrogen atoms in. But I want to be clear that these are aldehyde products, that I had two hydrogens on that alkene in the beginning. I better see those two hydrogen atoms
09:00
in the product somewhere. Okay, so when you ozonalize cyclic alkenes, the two carbonyl compounds end up attached to each other. Now, this is not a reaction that's just for,
09:21
that is just for making aldehydes. If I had a tetra substituted olefin or I had one side of the olefin had two alkyl groups on it, then you'll end up getting ketones and so here might be a way I would traditionally draw this.
09:41
And so in this case you'd get two molecules that are identical, both acetone. I'm not going to draw the other acetone molecule. You can do that on your own. In this case because it's symmetrical, you get two of the same product. All right, so ozonolysis. You know, when I used to work in the laboratory, sometimes you run reactions in the lab where instead
10:02
of getting nice clean reactions, you just get brown gunk. And we usually refer to those as hosolysis. Those are way, because it sounds like ozonolysis and that means you just got screwed in the laboratory by your reaction.
10:21
Okay, let's talk about what's going on mechanistically with this ozone gas. Ozone is very reactive. It's great when it's up in the stratosphere, but you would not want to sit around in an environment full of ozone. It does all kinds of things, but I'm going to show you what it does in the presence of an alkene.
10:41
And it involves a class of reactions called a pericyclic reaction and specifically a concerted cycloaddition. So let me draw the structure, let me try to draw an alkene. And I'm going to do my best, as I sometimes do, to emphasize the fact that alkenes have two different faces. And so I'll try to draw an alkene here that has two R groups on it.
11:01
And then in the back, I'll try to draw two H's. So you can kind of see that there's a top face to this olefin. And so the ozone has a choice, just like electrophilic reagents do, to approach from the top face or the bottom face of this double bond. So let me draw this ozone molecule. Ozone is bent. Those three atoms in the ozone molecule are bent.
11:22
And so when I draw my Lewis structure, I'm not going to draw all the lone pairs on here. I'm going to first pay attention to my charges. Three bonds to oxygen has to have a plus charge. One bond to oxygen has to leave a minus charge. And I'm going to take care to draw this one lone pair on the oxygen where I chose to draw the O minus.
11:43
There's another resonant structure that I could have drawn. And this is going to undergo a concerted cycloaddition reaction. In some sense like that osmium tetroxide where simultaneously both carbons of the alkene form bonds with the ozone. Let me draw out the arrow pushing for that.
12:00
What I'm going to do is I'm going to take this double bond, which is the nucleophile and this electrophilic oxidant, and I'm going to attack that and give the electrons to that O plus. And at the same time that I'm taking electrons away from this carbon over here on the right-hand side, I'm going to use this lone pair on the ozone to attack that.
12:21
So I'm simultaneously in this mechanism making two bonds with that alkene substrate, two oxygen carbon bonds. So that's called a cycloaddition reaction. And you're going to hear a lot about cycloaddition reactions in Chapter 16. Not this kind. We'll give you a different kind called a Diels-Alder reaction, but in Chapter 16 you'll see more paracyclic
12:43
concerted cycloadditions. You're going to get this very, very strange looking intermediate. And the book seems to make a big deal about showing you this mechanism, and I'm not entirely clear on how this helps you because you won't see anything like this ever again in this course.
13:03
This intermediate is called a mollozonide, and I could care less whether you remember the name for that. So this species right here is called the mollozonide intermediate. Whenever I see oxygen-oxygen bonds, I think gee, that's unstable. What the book does not do is it doesn't explain
13:22
to you how this cleaves the carbon-carbon bond. Ozanolysis is used to cleave C-C double bonds. At some point in this mechanism, we have to cleave this C-C double bond. And so there's a transformation that occurs that leads to a species called the ozonide intermediate.
13:41
It is also a five-membered ring. But as I draw this new intermediate out, you can tell something very fishy had to happen here. Notice how there's no more carbon-carbon bond where the alkene used to be. Now I just have carbon-oxygen bonds. So this is called the ozonide intermediate.
14:07
And this is what would be sitting around until you come along with your dimethyl sulfide or your zinc dust and sprinkle that into your reaction. Excuse me. And let me go ahead and show you the secret of what's happening here.
14:21
And you don't need to know this. The book doesn't show you this. But I'll show you what's happening here that's not shown in the book. Otherwise you'll be left wondering. What happens in order to convert the mollozonide
14:41
into the ozonide is that this undergoes a retropsycho addition. And I'll draw the mechanism so you can see what's happening. And I've already messed that up. Whoops. There we go. So I'm going to take this weak oxygen-oxygen bond here and give it, give the electrons to that oxygen.
15:03
And then I'm going to use this oxygen-oxygen bond here to swing down and make a CO double bond. And that's going to induce cleavage of the CC bond. And if you sort of follow through with my arrow pushing, I'll get this other very strange, weird intermediate
15:21
that you've never seen anything like before that looks like this. So what is that? It looks a little bit like the ozone that I started with. I've got this three atom piece here with two oxygens and a carbon. And now I think if you look here you can see
15:40
that I had an oxygen-carbon species here. And I'm now going to flip that around so that now this oxygen is down on the bottom and this R carbon is sticking over here on the side. And when I do that, I can now see how these pieces map onto the ozonide product. And this does yet another cycloaddition reaction.
16:01
And if I draw this out, it would look like this. This attacks to make an oxygen-carbon bond that breaks this CO pi bond. And now these electrons over here can attack. And that's how you get the ozonide intermediate. This mechanism is like an extravaganza of cycloaddition reactions which would be great except we've
16:23
got four more chapters before we teach you about cycloadditions. So very obscure stuff. I'm not sure why they make a big deal out of this. So I'm not going to show you the mechanism for the reduction. This is where you come along with your zinc and water
16:43
or your or dimethyl sulfide. You have to choose one or the other if I ask you how you do an ozonolysis of some alkene. And so in the end, one of these oxygens gets lost. And it's completely arbitrary there. And that's what leads to these two alkenes in your product.
17:03
Okay, so that's an ozonolysis reaction. O3 and then you follow it up with dimethyl sulfide. Yes, what's your question? Does this arrow here that I've scrawled over comes from the bond?
17:22
On this arrow? Yeah, that's coming from this O-O bond. For the, oh, you know that's a magnificent question because that's, yes, it has to come, sorry, it has to come from a pair of, you totally had that right,
17:41
it has to come from a pair of electrons on this oxygen. So let me fix that. So I hope you can see there has, yes, you're right, it has to come from this lone pair on this oxygen, not from the O-O bond. Otherwise it would have cleaved the O-O bond. So excellent point. Yeah, so, yeah, if I can't make the arrow start from this O-O bond because then there wouldn't be an O-O bond in this product.
18:01
It's coming from a lone pair on this oxygen. I probably would have been better off drawing that lone pair on the outside. Yeah, thank you for clarifying that. Okay, so ozonolysis. So you're going to be using that as a reaction, as a way to make carbonyls. And maybe that's not so important now, but that's going to be super important when you reach Chem 51C
18:21
where you're going to do a thousand different reactions where you add things to carbonyl groups, make CC bonds by adding things to carbonyl groups. So hold on to that ozonolysis reaction, practice it in this chapter and be assured that you will be using that when you reach Chem 51C ozonolysis. Okay, this is a little bit,
18:41
in fact it's substantially less common. And that is to do ozonolysis of all kinds. Most of the reactions that we showed you where you did reactions with alkenes, you also do reactions with alkynes that are in some ways analogous. So I'm going to try to take a substrate and I, all this other spinach over here
19:01
on the side is not really important. I just got tired of drawing butyne for every substrate. So if I come along with this alkyne starting material and I treat this with ozone and then I follow that up, not with a reductive workup, and this is critical. You don't want to follow this up with a reductive workup.
19:24
We'll just treat this with water. This leads to oxidative cleavage all the way to the carboxylic acid. So none of this other stuff gets, is changed in the reaction, the isopropyl, the methoxy group.
19:41
But now one of the carbons, let me draw a C right here for the two carbons and my alkyne. The carbons on one end of the alkyne gets converted to a carboxylic acid and the carbon on the other end gets converted into a carboxylic acid. And quite often you'll throw one of the pieces away. You know, you'll isolate both and then throw one of them away.
20:02
Usually just one end of your molecule is the high value end of your molecule. Don't worry about the mechanism. I'm not going to ask you anything about the mechanism for this reaction. It's just, there's nothing about that that's useful or extensible to you, by you to other chemistry
20:22
that we do this quarter or in the 51 series. Okay, so ozonolysis of alkenes gives you either aldehydes or ketones and ozonolysis of alkynes gives you carboxylic acids. Okay, finally we are moving
20:40
on to what is the most important reactions in this chapter. And these by far are the reagents that you need to know from here forward. And so I wish I had a green pen here because all of this stuff that I'm going to show you here, it'll be on every single Chem 51 exam in every section,
21:03
at every school, at every university. And that is oxidation actions. And I'm going to show you a series of chromium oxidants that are used to convert alcohols into carbonyl groups. And I'm going to show you a series of four closely related reagents. The first three are essentially identical in terms
21:23
of what they do, and then the last one is different. So let me start off by drawing out the first reagent and I'll try to use some different pen colors here so I can try to keep stuff straight. Okay, so the first reagent that I'm going to show you is potassium dichromate. And it's just this sea of elements here.
21:42
Two potassiums, two chromiums, seven oxygens, and what in the heck is going on with that? And what's worse, I think, infinitely worse, is that the book also shows you sodium dichromate. Two sodiums, two chromiums, seven, there's no functional difference between these two. There's no reason why you should ever worry about what one does.
22:01
They're identical. So I don't know why the book shows you both. Sometimes asks you one versus the other. That's totally pointless. But let's go ahead and draw out the structure of a dichromate anion. It's very similar to a diphosphate or pyrophosphate group that you might see in biology. So let me go ahead and draw out this chromate species.
22:23
Well, kind of similar here in terms of the structure. So here's the two chromiums. See, there's an oxygen bridging those two. And each of those chromiums has an oxo group, looks kind of like a carbonyl, so a double bonded O.
22:41
Each chromium has two double bonded O's. And each chromium has two O minuses. So you can see why you need two potassiums or two sodiums to balance out those charges. I'll just write the two potassiums down here. Those don't affect anything. So that's dichromate. Now when you put sodium, every case where we do it
23:02
in this book, when you put sodium dichromate or potassium dichromate in aqua sulfuric acid, it very quickly hydrolyzes one of these oxygen chromium bonds and forms a species called chromic acid. So in other words, when you use sodium dichromate and you put it in aqua sulfuric acid, the only reason you're doing
23:20
that is because you can't buy chromic acid, because you can't buy this species here. So this is called chromic acid. And I'll just write it here. It's unstable. You can't buy it. So you have to make that using sodium dichromate, chromic acid, and that's unstable.
23:41
The other way that you can make chromic acid, the other reagent that you can literally buy and mix with sulfuric acid is chromium trioxide. This is a planar molecule. It's just chromium with three oxo groups on it. And so the formula is here. It's very simple, just C or O3. I think you can see that if you add H2O to that,
24:02
you get chromic acid just by molecular formula. Okay, so there's two ways to make chromic acid. You can't buy chromic acid. You can make it from sodium dichromate or potassium dichromate, or you can make it from chromium trioxide. And the trick here in all three, in both of these cases, the trick to making chromic acid is
24:21
that you mix these things together in sulfuric acid and water. So both of these basically generate chromic acid when you put them in sulfuric acid and water. And that's really what I want you to remember. Now there's a fourth species that I want you to remember.
24:43
And I hope you'll see that it looks kind of similar to these other species. And this other species that I'm going to show you is called pyridinium chlorochromate. And you don't need to know that. You just need to know PCC.
25:00
So there's two oxo groups on the chromium. There's an O minus sticking out here, kind of like the potassium dichromate. And then sticking in back over here I've got a chlorine leaving group. So that's the chlorochromate species. The pyridinium, well, there's nothing special about pyridinium. That's the same species you get when pyridine acts as a base
25:23
in any other reaction, thionyl chloride. That's just protonated pyridine. So that's the pyridinium. That's the P. And then this other species down below is the CC. That's chlorochromate. Okay, so the most important thing about these reagents is not really the chromium.
25:41
These are all basically the same chromium species. The main thing that you need to remember with these is what solvent do you use them in. Invariably, when you use PCC, you avoid water. I can't think of any case in my life I've ever seen it used in anything other than dichloromethane.
26:01
You do everything you can to avoid water in PCC reactions. With these other species, you're using them in water, using aqueous sulfuric acid. The solvent you use for these two, for these sets of oxidizing reagents is more important than the reagent itself. In other words, if I took PCC and I put it in aqueous sulfuric acid,
26:21
it would simply generate chromic acid. You would never put PCC in water. Otherwise, why did you take the time to make PCC if you're simply going to convert it back into chromic acid? Okay, so remember the solvent for these reactions. It is super important.
26:40
It's as important as the reagent. So let's go ahead and talk about what you can do with PCC. But before I do that, I want to show you what you can't do with PCC, which may seem odd. It may seem odd that I'm going to show you what you can't do with PCC, but then it will help set us up for seeing what you can do with PCC.
27:01
You know, I can't resist. Let me go back because I have to show you what the whole point of these reagents. So I'm going to just take simple, a simple alcohol like isopropanol down here, down here, and any one of these reagents that I just showed you, sodium dichromate in aqueous sulfuric acid, chromium trioxide in aqueous sulfuric acid,
27:22
PCC in dichloromethane, and I'll just write an O in brackets here to indicate oxidation. Any one of those reagents will convert an alcohol into a ketone, and that's the main point here. And you won't be able to use this as effectively as you'd like to until you get to, until you get to Chem 51C
27:41
because in Chem 51C, we'll show you how to use ketones to make carbon-carbon bonds. So that's why it won't, this won't be super powerful until you get to that stage. Okay, so what's the limitation on this? There's a limitation, and then there's this little solvent thing that you have to remember. So let's talk about that. So here's a limitation that's, I don't know if it's
28:02
such a limitation, but it's, I feel like it's obvious that you may focus on the fact that we form carbon-oxygen double bonds with these oxidations, and that's not what I focus on. What I focus on is the fact that you remove an H. In other words, see this carbon here that I have a dot? That's called the carbon-all carbon.
28:22
You don't need to know the name carbon-all carbon. It's just a way of saying, oh, the carbon next to the OH group. That carbon-all carbon has to have an H on it. Otherwise, you can't possibly oxidize this. So if I treat this with PCC, there's no reaction, right? There's no H on here that can be removed,
28:42
and that's really what the oxidant is doing. There is no way to form a CO double bond. You'd end up with five bonds to carbon. Here's another tertiary alcohol, and here's that other recipe that I mentioned, potassium dichromate.
29:03
Look how complex that formula is. Gee, that's awful, and then you mix that in some aqueous sulfuric acid, H2O. Again, that wouldn't do anything. There's no H's on that carbon-all carbon there. It's a tertiary alcohol.
29:20
So tertiary alcohols, you cannot oxidize them to put a CO double bond. Again, you'd have some weird five bonds to carbon situation that would be crazy. So where are you going to use these chromium oxidants? You're going to use them for oxidizing secondary and primary alcohols, and secondary alcohols are easy.
29:41
Let's talk about secondary alcohols, and any one of those oxidants that I showed you. Let me step, well, I'll get to this in a moment here. So any of those oxidants that I showed you will work efficiently
30:02
for converting alcohols, secondary alcohols into ketones. So again, you may see, what you may see is the fact that there's a new CO double bond there, so it's a, but what I see is the fact that this H got removed,
30:22
and I hope that that's as plain to you before I drew that as it was to me. So let's draw one of my recipes here. Just to be different, I'll throw the chromium trioxide in, and then use sulfuric acid and water.
30:42
You know, most organic molecules aren't soluble in water, so usually people use acetone as their solvent. In that case, this is called a Jones oxidation. When you use this combination of chromium trioxide, sulfuric acid, water, and acetone as the solvent. I hope you don't get exposed.
31:02
You don't need to know that. There's no reason for you to learn that. Okay, here's another substrate where I have a tertiary alcohol, and remember what I said, that's not going to oxidize, and a secondary alcohol. And so when I treat this with any one of those reagent combinations, in this case I'll use PCC. I would encourage you every single time you write PCC
31:23
to write the solvent. If you don't remember the solvent, there is no case where an organic chemist would use water for PCC. So in theory, you don't have to write solvent for PCC. It is simply assumed to be dichloromethane. But I wish you would write dichloromethane as the solvent,
31:42
just to reinforce for yourself that, yeah, this is the one of those, the only one out of those oxidants that doesn't use an aqueous co-solvent. So the product of this reaction, the tertiary hydroxyl group doesn't get touched. That's still no H. But the secondary alcohol that had the H at the carbonyl carbon,
32:02
that now gets converted into a ketone. So tertiary alcohols, nothing happens. Secondary, any one of those oxidants would convert that efficiently into the ketone. Okay, so very powerful stuff. Let's talk about the mechanism, and then I'll talk
32:22
about what's going on with primary alcohols. Primary alcohols will give you trouble, but let's go through a mechanism for what's going on with the chromium oxidation. So this is, it's an E2 elimination. Now, what I want to emphasize is, the book shows you a mechanism
32:43
for oxidation where chromium trioxide is the active species, and I don't want you to remember that. None of these oxidants actually act through chromium trioxide. So, and there are some reagent combinations that involve chromium trioxide and other solvents,
33:00
but nothing that the book gives you is like that. And so here's the mechanism, and I want you to know this mechanism. So let's go ahead and start off by drawing our alcohol, and this is going to be a secondary alcohol, and I'm going to be super careful to draw that H on the carbon, all carbon.
33:21
I'll just explicitly draw that H, because we're going to pull that off. This is going to involve an E2 elimination to make our CO double bond. And the first step here has to do with the lone pairs on the alcohol. That's a nucleophile, and all of those chromium oxidizing reagents are electrophiles. So let me draw out our chromium oxidizing reagent,
33:41
and I'm specifically going to give you the mechanism for PCC. There's chlorochromate. There's the chromate. Here's the chloro group on the chromate. That's a minus charge, by the way, and that's R prime in case you're wondering what my, I'm just trying to distinguish those two R groups.
34:02
Okay, so here's chlorochromate. Look at all those electronegative substituents on chromium. Chromium wants to be attacked by things. Oh, look at that. Here's this oxygen lone pair. Oh, my gosh. Boop, boop, there we go. So the hydroxyl group, the lone pair on the hydroxyl group attacks the chromium atom,
34:21
and you kick the electrons, and I wish I had a thinner pen here, but you kick the electrons up from this chromium oxygen double bond and give it to one of the oxygen atoms. Okay, so let's draw this next intermediate. The only difference between this and the chromic acid is in chromic acid, where I have CL,
34:41
you would have OH. Okay, so this next intermediate is going to be kind of busy. Now I'm going to literally draw that OH bond there. Here's my two R groups on my secondary alcohol. Oh, there's now a third bond to that oxygen.
35:02
I'm going to have to put a positive charge on that now. And look at all these bonds on chromium. Oh, my God, it's so complex. How could I ever sort all of this out? It's scary. Look at this. There's two minus charges on there. Now there's a plus charge on that oxygen.
35:20
It'll sort out. Don't worry. So I just made a bond to the chlorochromate. I kicked the electrons up from this oxo group to have an O minus group. And now what I'm going to do is I'm going to kick out the chloride leaving group. Basically, we're just finding a way to do.
35:42
It's not an SN2 reaction. You don't displace chloride through SN2. So let me draw the lone pair on one of those two O minuses. And then I'll try to write more carefully with this fat pen here. Now I'll push downward to make a chromium oxygen double bond again. And I'll kick out the chloride.
36:06
And so when I do that, now I once again have two chromium oxygen double bonds. Here's my chromate.
36:22
It's starting to look a little bit simpler now. Totally simple, but I still have that positive charge on that oxygen. If you've got three bonds to oxygen, you better put a positive charge there. And the book, there's a, for the mechanism for chromium trioxide, they eventually reach this stage. It's just that they did this in one step instead
36:41
of two steps, the way I did it with PCC. The book pulls this proton off, but instead of using arrow pushing, they just write the word proton transfer. If I ask you to write an arrow pushing mechanism, I want you to show the arrow pushing mechanism for removal of the proton. So I'm going to go ahead and write a species here.
37:01
When you do these reactions with PCC, you know, there's pyridinium and stuff in there. I'm going to write B, but if you wrote A minus, I would also accept that. But something to act as a symbolic base. Either the conjugate base of an acid, A minus, or the letter B with a lone pair. Just something that, something symbolic that we can use
37:21
to pull that proton off. And so now, essentially, what we've done is we've converted this chromium atom into a leaving group. So when I draw out this next intermediate here, I'm now ready to do the equivalent of an E2 elimination that will, it looks a little bit similar
37:44
to things that you've seen before, but it's different. And I'll point out why it's different from the other types of E2 eliminations that you've seen before. So here's what's strange about the E2 elimination that's going to ensue here. What we're going to do is we're going to pull off that proton
38:02
and simultaneously push out this chromium atom. And what is weird is that the chromium is going to walk away with a pair of electrons with a lone pair. So now, there's going to be something with lone pairs in there. Either the pyridine or some sort of oxygen species that now comes along and does the equivalent
38:20
of an E2 elimination mechanism. We pull this proton off, those electrons push over, make a CO double bond, and we give the electrons in this oxygen chromium bond to chromium. That reduces, that's called, that'll end up being a reduction of the chromium.
38:41
So instead of having this orange chromate color that you have, it'll suddenly go green, which is characteristic of these chromium oxidations. Once you reduce the chromium, it turns green. It used to be the basis of these breathalyzer tests that the police would give you in the 1980s. You breathe in a bag, and if it turns green,
39:00
they know you've had too much ethanol in your breath. Okay, so let me draw this very strange-looking chromium species. You'll never see anything like this again. That's now a reduced form of chromium.
39:21
I guess that should be a minus charge on there. Okay, so this is the reduced form of the chromium, and that's the mechanism. The book mechanism on page 448 is very similar except that they do the first two steps basically in one step by adding to chromium trioxide. Okay, so it's, and this key step here is the E2 elimination
39:40
mechanism. Now, I just looked on the 51LB website. If you're taking the attendant lab, you did chemistry that was very similar to this in the lab, and I'll just highlight how that's similar. So in lab, you did an oxidation with bleach where essentially you had something like this going on. You put a chlorine leaving group.
40:02
Using bleach on your ketone, and then along came your base and pushed out chlorine. Essentially the same kind of idea. All of these oxidations of chromium, of alcohols to ketones will involve putting some leaving group
40:21
on oxygen, which is not easy to do. And so that's what makes the chromium so magic. Okay, let's talk about primary alcohols because there's something here we need to memorize. It's a distinction between primary alcohols and secondary alcohols.
40:46
So here's a primary alcohol, and the first thing I see here in my mind is there's two H's on that, and I can't resist drawing them, so you'll excuse me while I obey my irresistible urge
41:01
to draw those two H's on that primary carbon. And this is what distinguishes a primary alcohol from a secondary alcohol. And so there's two possible outcomes when we do an oxidation, and it depends on the solvent we use for our chromium oxidation. So if you use chromium trioxide or potassium dichromate, and of course you always do those
41:23
in water, and you have to write out the water. I expect you to draw this full recipe out in water. That's the important facet here of the reaction. This oxidizes the primary alcohol not to the carbonyl, just a simple aldehyde. It oxidizes it all the way down to a carboxylic acid.
41:44
Or maybe all the way up, and you have to remember that. It doesn't stop at just a simple aldehyde. If you want to stop at the aldehyde, you need to go to a non-aqueous reagent, PCC, and you don't have
42:03
to write dichloromethane here, but I wish you would write dichloromethane. Most organic, no organic chemist writes the solvent. It's simply assumed it will be a non-aqueous solvent, and specifically dichloromethane.
42:20
And so in the case of PCC, you stop at the aldehyde. So you get to choose if you have a primary alcohol, whether you want to just make the aldehyde or whether you want to burn that all the way down to a carboxylic acid. So, and it has everything to do with the solvent. It's not the reagent itself that matters here. It's the solvent. So that's why I expect you to be really picky
42:41
about this aqueous solvent business for potassium dichromate or chromium trioxide. So this is also true. I'll just write, instead of potassium dichromate, you could also use chromium trioxide. You'd get the same carboxylic acid result. Okay, why is there this distinction
43:00
between what these things are doing? Why is it that in water you get one result, whereas in an organic solvent like dichloromethane, you get a completely different result? And you're not set up to understand this, unfortunately. The book does not set you up to appreciate why this should be true. So I'll show you what's going on here.
43:24
And it has to do with the addition to carbonyls, of nucleophiles to carbonyls, and the book goes into great, immense lengths to explain this stuff to you when you get to chapter 21. What the book explains to you in chapter 21 is that when you have aldehydes, water can act as a nucleophile,
43:43
not a great one, to set up an equilibrium. Where you have this adduct called a hydrate. Where you add the elements of water, and I'm not going to draw the mechanism. It is not a one-step mechanism. It's a multi-step mechanism. But whenever you put aldehydes in water, you also have some
44:03
of this dihydroxy. This is called the hydrate. You also have some of this hydrate floating around. And typically, for most aldehydes, this ratio is about one to one in straight water. So we call this the hydrate. I'll just put a little arrow here. This is called the hydrate.
44:21
And I hope you can see that that hydrate looks kind of like an alcohol. It looks kind of like a secondary alcohol. And it's not like it's frozen in space here. This is a rapid back and forth equilibrium. And so what's happening here is when you do oxidations of primary alcohols to aldehydes is
44:43
that the aldehyde that's present in water forms a hydrate. And the hydrate undergoes an oxidation reaction. And so there's, I've just redrawn the hydrate in a slightly different way. So you notice you can see that H on the hydrate carbon.
45:02
And so this does the same oxidation business that I just showed you. And it doesn't really matter what the chromium species is here. There's some leaving group on the chromium species, whether it's an OH. You don't need to know this kind of mechanism here.
45:22
And so the point is you'll get to this same stage that we were at before. It doesn't matter that this other group is an OH. You still reach the same stage in your mechanism. You still undergo the same type of E2 elimination. And the only real difference here is
45:41
that we've got a hydroxy group sticking on the bottom. You still get to this stage where it does some sort of E2 elimination, and that's what leads to the carboxylic acid. You still give the lone pairs to chromium. So when you reach Chapter 21 in Chem 51C,
46:01
this whole hydrate business and the addition of water to the aldehyde will be completely natural to you. And at this stage, I kind of expect that to be a little bit mysterious to you. So just hold on. This stuff right here, just hold on for Chapter 21 if you'd like to read ahead and go get some more explanation
46:21
of all the things that aldehydes can do, fantastic. But that's why. You can't stop aldehydes from forming hydrates in water. And it's the hydrate that's actually undergoing oxidation to the carboxylic acid. And if you're using PCC and dichloromethane, well, there's no water in dichloromethane. So you can't form any hydrate in there.
46:41
That's why the solvent is so critical. Okay, so the last part of Chapter 12, there's a section called green chemistry in ethanol. And what they show is that you can take chromium reagents and exhort them onto solid supports. And they say that this is green chemistry
47:02
or environmentally friendly chemistry. You know, chromium 6 species are class 3 OSHA carcinogens. The Occupational Health and Safety Administration labels these as carcinogens. I don't consider that to be green chemistry. And so let me just say, you should ignore that.
47:21
That whole section is bunk. Let's move forward to the last section. There's something called the Sharpless Epoxidation. And the last time I taught this class was many years ago,
47:41
four years ago maybe. I went through this, and we ended up spending 90% of our discussion sections and office hours going through this over and over to the point where I can tell now that this reaction does not merit this much attention. This was one of the first reactions that allows you.
48:01
And so let me just clarify here. I'm not going to put this on my exam. There was a time about 25 years ago when this was basically the only reliable asymmetric reaction that you could do where you could predictably get one enantiomer versus the other. But that was 25 years ago. And we now have zillions of highly efficient reactions
48:23
that allow you to get one enantiomer or the other in a predictable fashion. And there's no reason why you should have to memorize this now dated reaction, which was historically important, but now has been complemented by such a vast number of other reactions.
48:41
Here's what the reaction does. This is called a Sharpless Epoxidation. And I'll show you the recipe, and maybe you can get a sense. Here's why I want to show you this, even though I'm not putting it on my exam. I expect you to work each and every problem in the back of the chapters. I expect you to work every single problem in order to get experience working problems you've never seen before. And unfortunately, some of the problems in the back
49:02
of the chapter involve this Sharpless Epoxidation. They really seem to work this hard. A Sharpless Epoxidation involves taking t-butyl hydroperoxide. So it's not t-butanol. There's an O-O bond. It's a hydroperoxide. So this is the oxidant in the reaction.
49:20
And the point of the Sharpless Epoxidation is that you can use it to get a single enantiomer of the epoxide. MCPBA would do exactly the same reaction and would give you a racemic mixture. And this reaction gives you just a single enantiomer of the epoxide.
49:41
And I don't feel like it's important for you to remember which enantiomer. I go through a lot of work to memorize which enantiomer you get. That does not seem useful in any way. So you use t-butyl hydroperoxide. So you can see where the oxygen atom in the epoxide is coming from. Yes, you could do the same thing with MCPBA and get a racemic mixture.
50:00
Then you need a catalyst. It's this titanium catalyst which will look super mysterious to you. So you have four isopropoxy groups. I'll just write isopropoxy here. That's the catalyst for the reaction. And then you put in this chiral additive called diethyl, excuse me, diethyl tartrate.
50:22
And I'm simply going to abbreviate that plus diethyl tartrate. It's a single enantiomer of a naturally occurring diol. There's no reason for you to memorize this recipe. If you use the opposite enantiomer of diethyl tartrate, which is also readily available, you'd get the other enantiomer of the epoxide.
50:42
And it doesn't seem fruitful to me. I'll draw a diethyl tartrate for you. This plus enantiomer of diethyl tartrate looks like this. It's an abyss ethyl ester.
51:01
And those two OH groups grip the titanium to create a chiral environment. So I encourage you to work problems in the back of Chapter 12. Some of those problems will involve this. Sharpless epoxidation, I won't put that on the exam. So when we come back on Friday, we're going to start spectroscopy.
51:21
And we're going to spend maybe somewhere between one and two weeks just talking about spectroscopy. And so, steel yourself for that.