 All right, good morning now. Well, I feel we've now come to a very nice place in the course. You've been working extremely hard. We've just gone through what I said I felt was really the intellectual pinnacle of sophomore organic chemistry. We've been through a very rich collection of carbonyl chemistry. You've experienced it with the enolate and enol chemistry on this quiz and in this week's discussion, you'll be getting reinforced some of the things we talked about in class last week with all of these wonderful reactions, the Aldol reaction, the Claisen reaction, the Michael reaction, the Robinson annulation reaction. All this ability to recognize interrelationships in a molecule, beta hydroxy carbonyl compounds, alpha, beta unsaturated carbonyl compounds, 1, 3-dicarbonyl compounds, 1, 5-dicarbonyl compounds, and cyclohexenones. And so at this point, at least as far as the lecture part of the course, that's behind us and now you're going to be working on that and reinforcing these concepts through the discussion section and the homework problems and our last quiz. So we come into the last few chapters of the class and I think this is a fun point in the course. We've done a lot of hard work. We're still going to have a lot of nice ideas. This week, we're going to be talking about the chemistry of amines and in some ways in a course like this, this is a neither here nor there chapter of the class because you've gotten a big richness of the chemistry of amines already. You've learned about their reactions to make amides. You've learned about their chemistry as acids and as bases. You've seen some generation of amines when you studied aromatic chemistry and electrophilic aromatic substitution. So in a way, this week's chemistry is a bit of a refrain. We'll see a few new cool reactions, some cool syntheses, a few neat mechanisms. The next week, we're going to come into the chemistry of carbohydrates and carbohydrates are going to bring in some carbonyl chemistry. We'll see chemistry of acetals and their formation and their breakdown. We'll see some chemistry of enol, keto, tautomerization and some acid catalyzed reactions. We'll come way back to ideas of stereochemistry. We got a little bit of this as we talked about some of our some of our aldol chemistry and we reviewed some ideas of enantiomers and diastereomers and you'll get more of that. I'll try to bring in some of the molecular modeling that we did if things work out right. Maybe I'll ask you to bring your computers into class. I'll think about that next week but be prepared to maybe bring your laptops in next week. And then the final week of class looks like it's going to be a big thing because we've got a couple of chapters. I want to pick out a few highlights. I guess there's chapter, think if I remember the numbers, there's chapter 28 and I may have the numbers wrong but there's a chapter on amino acids, peptides and proteins and some of this is going to be redundant with your biochemistry chapters. I want to focus on one aspect of that which is another real intellectual pinnacle of organic chemistry and that is the solid phase synthesis of peptides and that'll bring in some nice reactions. You'll see amide bond formation. You'll see some concepts of aromaticity and stability of anions and you'll see a really profound idea of being able to build up molecules repetitively step after step, biologically important molecules, molecules that are all sorts of things, hormones that lead to uterine contractions in pregnancy and birth and so forth and this was one of the intellectual triumphs. And if everything works out in our timing, the last and I'll give you a selection from that chapter from the amino acids chapter selection to work on. And if everything works out right in our very last class, one of my big laments in organic chemistry is that a lot of the really modern concepts, I mean some of the chemistry you're going to see goes back more than 100 years. We've talked about some of this chemistry in some of the reactions we've discussed like the aldol reaction and the Claisen reaction. But if everything goes right in the last lecture, we'll get just a taste of organometallic chemistry, not Grignard, I mean we've already done Grignard chemistry but chemistry in which metals can act as templates to form carbon-carbon bonds. So we'll see how things go. So today I want to start by talking about amines and talking about their properties and their synthesis and amines are really cool molecules and really important biologically. They're present in so many biologically active natural products. Many of these are called alkaloids and are produced by plants and I want to draw out two of these molecules and I want you to draw along with me. They look really hairy so I'm going to draw at least the first one I'll draw slowly. It looks really, really hairy. So we're going to start by drawing a benzene ring like so and we're going to connect that to a cyclohexane ring. We'll make it a cyclohexane ring. For those of you who, well for everyone here you'll know my handwriting's no great shakes and yet a few simple tricks like being able to draw a hexagon or being able to draw a zigzag line really help. We're going to connect these two rings together by way of an ether linkage from the benzene to the cyclohexane ring and I'll show some stereochemistry over here. We'll put on a couple of hydroxy groups, one on the benzene ring and of course there's no stereochemistry on that hydroxy group and then we'll have another hydroxy group going down. In other words in the stereochemistry going down. We'll draw one more six-membered ring here. So far everything's pretty easy to visualize. Now we've got some overlapping bonds so I'm going to put a bond, a wedge, a line coming out of the blackboard to a nitrogen here and again if you're good at drawing hexagons you can do a lot of things and then fake the rest. So we'll have another bond off of the nitrogen. Going to show a bond coming out over here like so. We'll connect that over to the bond to the nitrogen so we're crossing. If you want to get fancy and people are really good can do this beforehand if they just plan their drawings. I'm not really good at drawing. You'll put a little break in there to help indicate that we're going above. So that doesn't mean a broken bond. It's sort of a way of drawing perspective. So you've got that. We'll set, I'll show you some stereochemistry over here, a hydrogen and we'll finish our molecule off by putting a methyl group on the nitrogen. Does anyone know what this molecule is? Morphene. Who said that? Good. Morphene, good for you. How do you know? What's that? I looked at the chapter. Ah, did they? Okay, so I didn't see morphene in the chapter. I saw, okay, so great, great. And this is a really important molecule in organic chemistry. And when I teach my graduate level spectroscopy course, I tell students that it took chemists 50 years to determine the structure of morphene. And now this is something that our graduate students can do in the course of an afternoon. I didn't see morphene, but I saw at least one related compound in the chapter. So morphene is part of a family of what are called alkaloids. Alkaloids are nitrogen-containing compounds produced by plants. Morphene in particular is an opioid. It's produced by the opium poppy. Incredibly important in pain relief after, you know, all of decades upon decades of pharmaceutical research when you have really bad pain, terminal cancer pain and all sorts of horrible things. Morphene is still the drug that is given. Of course, as an opioid, it's an addictive drug, but, you know, at some point if you have terminal cancer, it doesn't matter. Many of the synthetic drugs that also work on pain bind to the same receptor in the brain and it's really hard to separate pain relief from the ability to get addicted. The one I saw in the chapter, I've never taken morphene myself as a drug or in any other context, the one that I've seen in the chapter has a methoxy group over here. If you have instead of a hydroxy group, you have a methoxy group, that's another opioid. It's codeine, it's great cough medicine. I've taken that one. It's potentially abusable, potentially addictive. Morphene and opium, of course, are widely sought after, I mean, we've got tremendous trouble with drug trade from Afghanistan and so forth where poppies grow, but what really makes morphine unfortunately valuable as a street drug and highly sought is its diacetylation. In other words, if you take morphine and you treat it with acetic anhydride, you get the diacetate over here and over here, an acetoxy group. Anyone know what that drug is? Heroin, very easy to make heroin. So, as I said, morphine is an amine and it's specifically a tertiary amine to nitrogen with three groups on it. I want to draw one other alkaloid. Your textbook really goes to town talking about everything from neurotransmitters like dopamine and serotonin to nicotine, another highly addictive compound to all sorts of other molecules, spermine and spermidine. So, I'll draw one other molecule. It's based on a bicycloheptane skeleton. So, I'll draw out that skeleton. I'll show you a little trick of mine as well. So, we know how to draw a cyclohexane ring and I'm going to show you that everything else you can fake if you can draw one thing. So, the one other bicyclic structure that I like to be able to draw is norbornane. And if I can draw this, it's a cyclohexane in a boat with a bridge. If I can draw that, I can sort of fake everything else because the structure that I'm drawing now is basically norbornane with one extra methylene over here and so you can sort of fake it. And we have in the bridge position a nitrogen. It's a methylated tertiary amine group just like we have in morphine. I don't think this one's in your textbook. We'll have a methyl ester group over at this position. We'll have a benzoyl group over at this position. Anyone know what this molecule is? Cocaine. I have had that one medicinally. When I was in college, I used to get terrible nosebleeds and so to treat it, apparently the treatment involved some silver nitrate up your nose but before that, it was preceded by some cocaine up your nose. That was another one I used in my graduate level spec class. One of my colleagues is authorized to have a bottle of cocaine for research purposes. I was very happily walking around with a one gram bottle of cocaine that was to become the final exam for our graduate students. So all of these compounds and you can see how and one of the cool things about this is by this point in the course, you should be good enough with functional groups so when I go ahead and show you a big hairy molecule like morphine and I say, yeah, we treat it with acetic anhydride even though maybe your textbook examples might have included treating isopropanol with acetic anhydride to get isopropyl acetate, you can understand that these same principles of reactivity apply. You've got a basic amino group in there. The amino group is going to behave as a base. You can extract alkaloids into aqueous acid solution by protonating them and then you can go ahead and remove various impurities and then go and treat with base and extract back into organic solvents so you can recognize functional groups. We have an ester group over here. Okay, so the group there is a tertiary amine. I suppose the group is a tertiary amino group but I'm going to write tertiary amine and just write a generic structure R3N. And I'm not going to be so fussy as to go R1, R2, R3N but of course you can have three different groups. We've used tertiary amines as reagents. You've used triethylamine as a base. Tertiary amine of course has three different carbon atoms attached to the nitrogen atom and a lone pair as well on the nitrogen. A secondary amine, again I'm not going to be so fussy as to say R or R prime or R1 or R2 but you have two alkyl groups, two R groups on the nitrogen, two carbon containing groups. You've already encountered, we've used certainly again and again in our enolate chemistry. We've used this amine. We've used diisopropyl amine, the secondary amine. See primary amine, by the way you'll see people write 1-0 for primary, 2-0 for secondary, 3-0 for tertiary. That's fine too. I don't know, for primary amine of course we're talking RNH2 here so I'll give us an example of methyl amine CH3NH2. Now of course one thing to keep in mind is there's a fundamental difference between talking about amines and talking about alcohols. When we use the notation primary, secondary, tertiary for alcohols, of course we're talking, we always have NOH right? When you go ahead and have two R groups on an oxygen that's an ether, it's a different class of compounds but with alcohols you'd say okay ethanol is a primary alcohol, isopropanol is a secondary alcohol, tertbutanol is a tertiary alcohol so that's one thing that's different. All right, I want to maybe show us a couple of aryl amines so these examples here are all alcohol amines and there's some real differences in reactivity and even differences in the structure and bonding of aromatic amines and aliphatic amines so I'll just show you a couple of aryl amines. So because the chemistry of amines is so old, so many of these compounds have common names that are used in preference to maybe a more systematic name. In fact, the common names have really gotten wrapped into these systematic names so you wouldn't call that compound, no chemists would call that compound phenylamine or aminobenzene, they'd call it aniline and I guess somebody could call it aminobenzene, certainly if it's a substituent you'd call it, I'll show you that in a second but I'll just give you one other idea for substitution. I don't think we're going to be as systematic maybe in our discussion of nomenclatures we've been with some of the other compounds in part because amines people differ so much from systematic nomenclature and how they refer to them. So if we're going to refer to substituents on the nitrogen, we'll just put the capital letter n, if you're type setting it you'd set it nitallic. So this compound has two amine, two methyl groups on nitrogen so this would be nn dimethylaniline. And maybe I'll give you one more example. So if you have, remember I talked about substituents and I said okay if you have like a carboxylic acid in general things are substituent so for example if you have a hydroxy group and a carboxylic acid and a long chain alcohol group you'd call it a hydroxy acid, a beta hydroxy acid or you'd say three hydroxy propanoic acid. Similarly in terms of ranking and in terms of priority of the amino group is pretty far down the totem pole so if you have a ketone or you have an aldehyde or you have an acid in the molecule or a nitrile you're going to be naming it as an amino substituted molecule. So this molecule here we don't name as an aniline, we call this P-amino benzoic acid. So one of the things that's really defining about amines as a matter of fact is probably the first or second word that I would think about when I think about amines is their basic. And we probably also think of them as being nucleophilic. We've already seen lots of their chemistry as bases and it's a good chance to review and also to straighten some concepts in our mind. So we always think of basicity, we think of the PKA of the conjugate acid as a measure of basicity. So the PKA of the conjugate acid of an alkylamine something like triethylamine or diisopropylamine or methylamine. The PKA of the conjugate acid, I'll just write it in generic form and sort like this. The PKA is on the order of 10 to 11. There are a few numbers you should keep in your head, that's one, you can keep 10, you can keep 11, you can keep both, doesn't much matter. Now what a lot of students find confusing and I hope, I hope, I hope by this point you don't. But it's always good to have a reminder to get things in your, straight in your head is that if you have ammonia or you have a primary or secondary amine, all of these compounds are amphoteric. And it's very important to keep this straight in our head. So when we talk about diisopropylamine and we talk about making LDA, we're thinking about a completely different equilibrium. So we know diisopropylamine, when we think about making LDA, we say, oh, the PKA is about 40. And of course what we're doing and I hope, I hope, I hope by this point that you're on top of this is we're thinking about two different equilibria. One in which the amine is acting as an acid. So when you take diisopropylamine and say butyl lithium, we have an equilibrium that lies so far to the right that for all intents and purposes, I barely think of it as an equilibrium where we get diisopropylamine and butane. And here what we're saying is an acid, PKA 40, reacts with a very strong base to give a slightly less strong base and a conjugate acid of butyl lithium is butane, PKA about 50. Now, conversely, by the time you're going to do an aqueous workup on an LDA reaction, maybe you're using some aqueous acid like aqueous HCl, which I'll write as H3O plus because HCl is such a strong acid that it dissociates fully in water, you're going ahead and you're treating your diisopropylamine with H3O plus PKA 17, negative 1.7 and now you're protonating this. So now again you have this equilibrium that lies so far to the right that I'm not even bothering to write it as an equilibrium where now we're talking about say, I'll give you an exact number, it happens to be 11 in this case but again 10 or 11 doesn't matter and so that equilibrium lies way, way, way to the right. Now, one thing that's important to keep in mind in avoiding confusion is there's a huge difference between a means and a means. In a means, you have a nitrogen that's pyramidal, so this isn't a mean, it has a lone pair. If it's an alkyl amine, it has a lone pair that's in an sp3 orbital and for an alkyl amine it's not participating, the electrons are not participating in any significant resonance and so that lone pair is available to protonate. Now, where a lot of students get confused the first time around is thinking in comparison to amides and so I'll take say a generic amide but of course it could be in this case dimethylacetamide. Now, the huge difference is yes, you have a lone pair on that nitrogen but that nitrogen is tied up by resonance so it's not available. The lone pair is not available. If I had to characterize amides I'd say simply not basic. It's not exactly true. They're basic but very weakly basic, pKa sort of into the negative range, negative one for the conjugate acid but they're not basic on nitrogen, it's the lone pairs on oxygen that actually protonate. That lone pair is tied up by nitrogen by resonance and in fact because you have a good degree of double bond character for all intents and purposes your lone pair really is more like sp2 hybridized and your nitrogen is almost planar. I'll say a little tilde, approximately planar, just think of it as planar and think of it as approximately sp2 hybridized. So I want to make a comparison between amines like disapropyl amine and triethylamine and methyl amine and ammonia of course. I mean it's not an amine but it's basically the parent of the same family much as water is the same parent, is the parent to alcohol and amines that have aromatic groups in them. So when I drew aniline we also have a situation that in some ways is like our amide. You've got a nitrogen with a lone pair but that lone pair is participating in resonance. The lone pair is donating into the aromatic ring. When you learned about electrophilic aromatic substitution you learned that amino groups were ortho power directors that they were pushing electron density to the ortho and power positions of an aromatic ring and then in turn able to stabilize a positive charge that formed during the electrophilic aromatic substitution reaction. So the lone pair is tied up by resonance and it's sort of halfway between the degree to which it's tied up by resonance and an amide and the degree to which it's available in a simple aliphatic amine, a simple alkylamine. The pKa of the conjugate acid, so the pKa, so this is an aryl amine. Aryl is just a fancy word for aromatic. And the pKa of if you want to write it as AR NH3 plus, the conjugate acid of a generic aryl amine could be aniline, vary a little bit by substituents there. We're talking about five, whoops, not 55. So in other words, not as non-basic as an amide but not nearly as basic as an alkylamine. There are other nitrogen containing organic compounds. There are all sorts of nitrogen containing heterocycles and some of them you should already know from discussion of aromaticity and structure and bonding. So for example, pyridine is the nitrogen analog and I'll draw the lone pair here just to be very explicit. So this is pyridine. We've been using it as a reagent in some acylation reactions. Pyridine is the nitrogen analog of benzene. The nitrogen is participating in the aromatic ring system and instead of having a CH group, it has a lone pair of electrons. The lone pair of electrons is sp2 hybridized. And remember, when you use more S character, you hold your electrons closer to the nucleus. That makes them more stable, less willing to share. So when you use more S character, your lone pair is less available to bond to a proton. That lone pair is less basic and less nucleophilic than a regular amine. So the pKa of pyridinium, the conjugate acid of pyridine, the pyridinium ion is also about pKa of 5. I want to give you one other nitrogen-containing heterocycle and it's one that you've probably seen before in your discussion of aromaticity and this nitrogen-containing heterocycle is pyrrole. Now, pyrrole is another one I think that beginning students often find confusing. Because you look at that, you say, oh, there's a lone pair of electrons on the nitrogen. It looks like it ought to be basic. And that lone pair of electrons ends up being part of the aromatic pi system. As a result, if you protonate it, you're going to give up a ton of resonance energy. That lone pair, just like the lone pair in amides, is for all intents and purposes not basic. Pyrrole can protonate, but when it protonates, it actually ends up protonating on carbon, not on nitrogen. So thoughts or questions at this point? Yes. Why can they, if they're all, so, okay, when we're talking about basicity, this is the thing, what I was talking about with the concept of amphoteric. When you're thinking about how basic something is, you have to throw a switch in your mind and say, that means I need to think about the conjugate acid. When you're talking about how acidic something is, so we're not discussing the acidity of pyrrole, then you're thinking about, okay, what are we doing to give up a proton and form the conjugate base? So remember, in your mind's eye, when we're thinking about the basicity of pyrrole on nitrogen, you're thinking about this species here with two protons, and you're saying, oh my goodness, I've had to give up all of that resonance energy, all of that aromaticity, that's terrible, that doesn't form. Pyrrole doesn't have quite as much resonance energy as benzene, so you don't have, it's not quite as bad to protonate on the ring, and it's very reactive in electrophilic aromatic substitution. Now, okay, so as I said, to me, basicity really characterizes amines. The other thing, if I had to think about amines and sort of say what do I think about amines, I'd say, to some extent, I think of them like alcohols, but less so in everything, except basicity, and I'll show you what I mean in a series of discussions of properties in spectroscopy. So amines are kind of like alcohols, but less so. They're less polar than alcohols, they're dipole interactions or weaker, they're hydrogen bonding is weaker, so I'll say less polar than alcohols and less hydrogen bonding than alcohols. They're few compounds that's kind of worth having in your head as a reference point. Methanol or ethanol are sort of good ones. You've probably worked with them in laboratory. You should know that methanol is a liquid. If you don't know the exact boiling point, you at least would know it's a volatile liquid. It boils lower than water. It happens to have a boiling point of 65. It's toxic. It's a lower boiling point than ethanol, but not that much lower, and unlike ethanol, it causes blindness, permanent blindness, not being blind drunk. So if I compare, say, methyl amine, which you'd say, okay, it's about the same weight. It should have about the same, it's about the same size. It should have about the same Van der Waals interactions, and so then differences are going to be in hydrogen bonding and dipole-dipole interactions. So methyl amine, by contrast, is a gas. In other words, the molecules don't have enough interaction with each other to cohere into a liquid at room temperature. It's a gas until you cool it to negative 6 degrees at atmospheric pressure, or of course, if you have it at higher pressure, it's a liquid. Now, by contrast, again, the simple compounds, if you look at something about the same size, if you look at ethane, again, it's just too big, you know, two heavy atoms, two second-row atoms, and it's about the same size and the same weight, but you don't have dipole interactions, you'll have Van der Waals interactions, you don't have hydrogen bonding. And ethane, of course, is a gas. Its boiling point is negative 88 degrees, so by the time you're down to a molecule of that size, you really have to go cold. So you look at this and you'd say, well, okay, methylamine is like halfway between methanol and ethane in terms of its interactions. It doesn't hydrogen bond as much. It doesn't participate as in as many dipole-dipole interactions or as strong dipole-dipole interactions. And not surprisingly, that tracks with electronegativity because electronegativity is basically a statement of the property of elements. And so nitrogen is less electronegative than oxygen. Nitrogen, the electronegativity is 3, 3.0, and oxygen, the electronegativity is 3.4. In other words, the nitrogen pulls the electrons away from the hydrogen less, so the hydrogen bond less. You've got smaller dipoles in the molecule. And so for both reasons, that shows. And you can see this, so if you want to now separate out the hydrogen bonding component from the dipole-dipole component, I'll give you another comparison. So we'll look at trimethylamine, CH3, 3 nitrogen. So that's a gas. It's boiling point, though, is just above freezing of water. It's boiling point is 3 degrees. And if we compare it to something comparable in size to isobutane, now we have a lower boiling point, although not that much lower. So CH3, CCH is isobutane, virtually the same size and shape as trimethylamine. And the boiling point, it's also a gas. The boiling point is now negative 12 degrees. So you can look at that and say, yeah, okay, we've got dipole-dipole interactions in trimethylamine, and those raise the boiling point a little bit over isobutane that just has van der Waals interactions. But it's not a huge difference. All right, in so many ways amines are lesser versions of alcohols, and it's probably in terms of what you see in the spec part of the course you get for IR. You're not going to see it, but when we actually look at real IR spectra, you see it. So in the IR spectrum, you have an NH stretch, and the NH stretch is essentially at the same place as alcohols. It's that region above 3,000, that region kind of around 3,300 to 3,500. So the NH stretch, I'll say it's like the OH stretch. In other words, you'll typically see from your textbook you can use 33. In my graduate course, I give more detail, but you can use 3,300 to 3,500 wave numbers. But when you look at an actual spectrum, what you see is the band's a lot weaker. Now, you're not going to see this, but maybe you will if there's some spectra in the humor. But what I mean is an alcohol really stands out. It really yells at you. An amine kind of whispers at you. You can look with a small amine, and you go ahead and you say, oh yeah, I can see it. But by the time you get to a big compound with an amino group in it, it's very, very weak. If you have a primary amine, you'll actually see two bands that correspond to an asymmetric and a symmetric stretch. The other thing, and your textbook doesn't mention this, right, I always, when I read an IR spectrum, I generally look at the region from about 1,600 on up, right at the very bottom of that region. There's an NH band, and so it's right at about 1,600. And it's just below. And the thing that I'll mention to you since you may see in your lab course, or maybe you'll see it in one of your homework course, homework problems, it's just below where the carbonyl group occurs. So the carbonyl group, we said normally about 1,700, but then we said for amids, it can be about 1,650 or 1,660 or so. And this is just on the lower edge of that. So when you're reading a spectrum, you want to make sure you don't mix it up. All right, NMR spectra, again, this idea of kind of like an alcohol, but less so, comes up, or at least it's how I organize it in my own thinking. I'll show you what I mean. To me, when I'm thinking about an alcohol, I'm normally thinking about the hydrogens on the carbon next to the oxygen, and so I'm thinking, all right, that's sort of 3 to 4 ppm. That would be kind of a range if you want to keep one number in your mind. I can give you a more detailed number. But when I'm thinking about an amine, and again, I'll just sort of write a generic structure. That nitrogen's less electronegative. It's pulling electron density away from that hydrogen less, and as a result, it's not shifting it as far downfield. So generally, the hydrogens alpha to an oxygen and an alcohol are going to be kind of in the 3, 3.5 ppm range. In an amine, it's going to be in the sort of 2 to 3 range. Your textbook gives 2.3 to 3, which I think is a good sort of general assessment, but remember, those are always loose. In other words, dimethylamine is 2.3 ppm. By the time you go to a more sterically congested group or more substituted group like diisopropylamine, you're more toward 3 ppm. The NH, so when we talked about alcohols or when you talked about alcohols in spec, you said they're all over the map due to hydrogen bonding. And it's kind of the same thing about the NH group. Your textbook gives 0.5 to 5 ppm, and that's a good general start unless you're an aralamy like an aniline, in which case it's going to be a little bit further down. But the NH is often very broad and hard to see. And so for those of you who go beyond the textbook course, I'll say often broad and hard to see. And by that I mean you take an NMR spectrum and you may be looking for the NH and say, oh, this can't be an amine. I don't see an NH, and in fact, it's just that the NH is so far broadened out. In the C13 NMR and the carbon 13 NMR spectrum, again, we're sort of like an alcohol but less so. In other words, for an alcohol I think for the oxygen bound to carbon, oh, about 50 to 70 ppm. And it's pretty characteristic because by that point, you're down far enough in the carbon, you're away from everything else. For an amine, you're really not that well separated. The carbon that's bound to a nitrogen is in about the 30 to 50 ppm range, which isn't that far from other sorts of carbons that may not have electronegative substituents on them. All right. So that kind of gives the quickie view of the spectroscopy of amines and their properties. And as I said, a lot of what we're going to see particularly today is a refrain of some of the chemistry you've seen of amines before like in the aromatic chapter. So in the synthesis of amines by way of a quick review, you'll learn that nitration, that electrophilic aromatic nitration was a very common reaction in a way to substitute an aromatic group. And the nice thing is it's really, really easy to reduce the nitro group. And your textbook gives three different ways, but I can give you a hundred different ways to reduce the nitrogen, the nitro group, down to an amino group. So your textbook taught you that catalytic hydrogenation with hydrogen and palladium on carbon can reduce the nitrogen or you can use a metal, metals or reducing agents in general. Metals want to go to metal cations, they want to give up electrons. So iron and hydrochloric acid or tin and hydrochloric acid, these are three conditions from your textbook and they're all good ways to reduce the nitro group on an aromatic ring down to an amino group. Allophatic nitros are a little harder to reduce, but they can be reduced by catalytic hydrogenation as well under slightly different conditions. You've learned that lithium aluminum hydride reduces everything and anything. We saw that all the carbonyl groups got reduced down, esters go to alcohols, carboxylic acids go to alcohols, ketones and aldehydes go to alcohols. And the odd ball in the chemistry of lithium aluminum hydride was that because it's hard to kick out the nitrogen in the reduction process, you reduce, you add hydride, you get a tetrahedral intermediate, you end up forming a bond to aluminum, your nitrogen kicks out the oxygen, you add another equivalent of hydride. And so lithium aluminum hydride, LIALH4 followed by an aqueous workup reduces most amides down to amines. Lithium aluminum hydride reduces just about everything except carbon-carbon bonds in general. And so nitrials also get blasted down to amines. So if I take, say, benzonitrile and I subject it to the same conditions, I'll just write a ditto mark here, you get phenylethylamine. So immediately you can start to think about ways of making amines where you could start with a carboxylic acid, make an amide, reduce the amide to an amine, or start with an alkyl halide, do an SN2 displacement with sodium or potassium cyanide to get a nitrile and then reduce the amine to a primary, reduce the nitrile to a primary amine. All right. So one of the other analogies I like to make because nitrogen and oxygen are very similar in a lot of their structure and bonding. Nitrogen, of course, forms three val, has three valencies. Oxygen has two valencies, so there are differences. Nitrogen is less electronegative than oxygen, so compounds with bonds to nitrogen end up being less electrophilic with double bonds to nitrogen. And yet in many ways you can see similar reactivity. So in the broadest sense of abstraction, if we have some carbonyl compound, a ketone or aldehyde, and in the broadest sense of abstraction, if we envision adding a hydride nucleophile, and of course you can't go and get hydride any more than you can go ahead and get carbanion, but if we take some hydride source, I'll write this as hydride source just so you have it for your notes. Of course, you reduce after some sort of aqueous workup, you reduce, and again we're talking very broad abstractions here, you reduce your ketone to or your aldehyde to an alcohol. Now, by a similar token, if we have a carbon nitrogen double bond of an imine, an imine of a ketone or an aldehyde, and again we have some type of hydride source, H minus in quotes, you reduce your imine to an amine like so, very much by analogy. Now, this chemistry often gets put together where one can carry out the formation of an imine and the reduction, and that process is called reductive amination, and it's a nice way of making amines. And so again, in sort of very broad view from 30,000 feet abstraction, if we have some sort of carbonyl compound and some amine, some RNH2 amine, and we envision going ahead and again treating with the right hydride under the right conditions, you can both form an imine and reduce the imine often by way of the aminium ion all in the same pot. The reagent that's often used to achieve this transformation is sodium cyanoborohydride, NABH3CN. Now, we've already seen various hydride reducing agents, you've seen lithium aluminum hydride, you've seen sodium borohydride, you've I believe seen lithium tri-terbutoxy borohydride, and they all have slightly different properties. Lithium aluminum hydride has that aluminum hydrogen bond that's very polarized, you end up with a very potent hydride source. Boron is less electropositive, it's more electronegative than aluminum, less electropositive, the bond isn't as polarized, it's a milder hydride source. So sodium cyanoborohydride, here's the cyanoborohydride anion, is in many ways like sodium borohydride, but less so. The cyanobroup is electron withdrawing, it's pulling electron density away. So sodium cyanoborohydride is even less willing to donate a hydride, and that's good because it's not a good enough reducing agent to reduce a ketone, but under the reductive amination conditions, you form as an intermediate, you form an aminium ion, and the aminium ion intermediate is more electrophilic than a ketone, and so sodium cyanoborohydride can add hydride to the aminium ion in the course of the reaction. And so often in one pot, you can mix a ketone and an amine or a ketone and an ammonia and sodium cyanoborohydride, sometimes with a little bit of a mild acid like acetic acid, in order to go ahead and form an amine. So if we take benzaldehyde, and we treat it with ammonia and sodium cyanoborohydride, NABH3CN, you get benzalamine, you form the imine or rather the aminium ion forms transiently, and the cyanoborohydride adds hydride to that and reduces it to the amine. You can do the same thing with a ketone or an aldehyde, so I'll just give you one more example. If you take cyclohexanone and you take, I don't know, let's take neopentalamine as an example, tertbutylamine, not neopentalamine, tertbutylamine as an example, and subject it to the same conditions, so I'll just write ditto over here. Now you can form a secondary amine like so. Chemists, as I've emphasized all along, like to be able to build molecules. It's useful to be able to take simple stuff and make it into more complex molecules, yes, including cocaine, which one can synthesize chemically and morphine. The nitrogen atom is a beautiful lynchpin for synthesis because the nitrogen atom is nucleophilic and so it can act as a nucleophile in an SN2 displacement reaction. So it seems like it would make sense that a useful way to go ahead and build up complexity in a controlled fashion would be to alkylate that nitrogen, but it's not so simple. Usually the product of the reaction, which is also an amine or really an ammonium salt and equilibrium with an amine, usually the product of the reaction is even more nucleophilic. So if I take benzolamine and I treat it with methyl iodide, CH3I, even if I use one equivalent, you'd say, well, that should be an easy reaction. I should just get the monomethylated product. And the problem is as the monomethylated product forms by an SN2 displacement reaction, protons come on, protons go off as the reaction is proceeding. You have amine present and so now you have methylamine. So you also end up getting the dialkylated and trialkylated products as a mixture. The trialkylated is the benzol trimethylammonium ion, which is actually used as a germicide in things like eye care products. So the overall result is you get a mixture of products and so if you say, oh, I want to be smart, I know how to make methylbenzylamine, all I do would be to treat my methylbenzylamine with methyl iodide and then do a basic workup. The problem is you generally, and this isn't always true, but you generally cannot get a monoalkylated product in a controlled fashion. So the big problem is once the SN2 alkylation has occurred, the amino group, well it's protonated but protons come on and off under the reaction conditions, the amino group is still nucleophilic and still available to undergo alkylation. In fact, it's even a little more nucleophilic. So imagine for a moment that I wanted to go ahead and do an SN2 reaction. Imagine for a moment that I had hexal bromide and I wanted to treat it with ammonia and I've already said on the previous blackboard, I get a mixture of products. The solution that chemists have developed is to take away the nucleophilicity of the amine after it's done the alkylation to make it so that it's no longer nucleophilic. And the solution to this is called the Gabriel synthesis of primary amines and it's to use an ammonia surrogate. The ammonia surrogate is thalamid, P-H-T-H-A-L-I-M-I-D-E. It's an imid and imid is like an amid with two carbonyls on the nitrogen. It's the nitrogen analog of an anhydride. The proton having two carbonyls next to it is extra acidic and so a base like sodium hydroxide can pull it off. Your textbook lists the pK about 10. Other sources list the pK about 8. And so if you treat this with a base like potassium hydroxide in ethanol and then now you pull off the proton, you generate the anion. The anion is nucleophilic but it's nucleophilic in a controlled fashion. So now if you add your alkyl halide that can participate in an SN2 reaction, if you add your hexal bromide, now you go ahead, it alkylates and then what you can do, what you can do now is in another step treat with strong base or strong acid. So we'll go and treat this with sodium hydroxide. You can also use hydrazine but we can use sodium hydroxide, water and heat. And that goes ahead and it makes your amine and it also makes as the byproduct it hydrolyzes the imid and there are other sorts of synthesis using surrogates, using protected groups in order to allow the synthesis of secondary amines. There's a Fukuyama amine synthesis which I won't show you. All right, I think this is a good stopping point. We will pick up with more chemistry of amines next time.