Lecture 08. The Chemistry of the Carboxylic Acid Family.
Nowick, James
This is the third quarter course in 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. 
 Good morning. So today I want to begin our discussion of Chapter 22. And Chapter 22 brings us back to carboxylic acids. We talked a little bit about carboxylic acids and their family in Chapter 19. And then we started to introduce some of the chemistry of the carbonyl group in general. Now of course a carbonyl group is embodied in the carboxyl group of carboxylic acids. And so we really needed this understanding to begin to proceed on. So today we're coming back to carboxylic acids. And we're going to talk about themes in carboxylic acid chemistry that involve the same type of reactivity that we saw with ketones and aldehydes. That is the ability of nucleophiles to add to the carboxyl group and to replace the carboxyl group. We're going to come back again later in a couple of more chapters where we start talking about carbon-carbon bond forming reactions and talk about clasin condensations and other additions of carbon nucleophiles that are going to be based on this other property of carbonyl compounds, the acidity of the alpha proton. But right now we're going to just talk about the carboxylic acid family and their properties, the different functions, the different members of this family and their interconversion. And today we'll conclude by discussing the chemistry of acid chlorides and acid anhydrides, the two most reactive members of the carboxylic acid family. So let me draw out the family here or at least the main members, the important players. Of course we have carboxylic acids. And then sort of as a very close relationship we have esters. We've already talked about the relationship between alcohols and water and here in the carboxylic acid you sort of have a half of a water molecule and ester you have half of an alcohol molecule. So they'll have many things in common. Amids of various flavors. I'll just draw the amids structure generically with two sort of generic R groups. They can be alcohol, they can be aromatic, they can be hydrogens and we have various flavors of amid primary, secondary and tertiary. Amid we'll talk a little bit more about them. And these then moving along in the family we have acid chlorides. Acid chlorides are very reactive. We'll be talking about their chemistry. I'm giving you the important members of the family. One could easily envision acid bromides where the bromine is replaced with the chlorine and perhaps envision very similar properties. In practice they're much less commonly encountered but very similar in their reactivity. Acid iodides even more unusual and more reactive. Acid chlorides are a little bit funny. We're not going to talk a whole lot about them. They're still quite reactive but actually a little less reactive than acid chlorides for reasons of resonance stabilization. Also in the reactive members of the family we have anhydrides or sometimes you'll hear them referred to as acid anhydrides. And finally and again of course I'm only taking a limited subset of the family we have nitriels. And if you look at the a nitrile, nitrile is sort of the odd man out in this group in the sense that you would say by comparison I guess if I'm writing everything with S I'll write carboxylic acids. By comparison it doesn't look anything like the other members of the family. It's sort of the odd cousin. And what is in common to all of these is that the oxidation state of the carbon atom is the same in all of these. In all of these family members we're in the plus three oxidation state for that carbon. So even though a carboxylic acid and ester and acid chloride and anhydride have carbonyl groups, carbon double bonded to oxygen and the nitrile obviously does not, there are many similarities in reactivity. Also when we talked about imines I said that in many ways the reactivity of a carbon nitrogen double bond is very similar to a carbon oxygen double bond. In other words, imines have a lot of the same reactivity as aldehydes and ketones. And nitriles now you have a triple bond but again you get this theme of a carbon multiply bonded in this case triply but otherwise doubly to an electronegative atom. All right, let's take a moment to talk about naming compounds and I don't want to get heavily caught up. I think it's very easy for students to obsess about nomenclature and I want you to be able to see the forest from the trees. I really want you to be able to see the anatomical features of the molecule. In other words, be able to recognize the pieces of the molecule because conceptually this is the key to understanding the molecules and it's very easy to quickly end up getting yourself confused with rules of alphabetization and so forth. So here we have an ester and an ester as I just mentioned has one component that comes from an acid and another component that comes from an alcohol and just recognizing those two key components then is key to understanding their synthesis, some of their reactivity and so forth. So let me take a specific ester and we can see how to name it. And so this ester has an acid component from butanoic acid and an alcohol component from ethyl alcohol or ethanol. So we call this ethyl, esters get a first name and a last name. We call this ethyl butanoate and it kind of makes sense on the nomenclature intuitively if you recognize that what we've done is just take the butanoic acid and replace the OIC with OATE. And so they're being able to see the components is important. I'll give us another example along the same lines. So we'd call this compound methylbenzoate. That's OATE on the end because it's derived from benzoic acid. For amides a lot of the thinking is kind of similar. We have two components and we sort of recognize that here's our amide and so we have a component that came from the acid and a component that came from an amine or ammonia. And so I'll give us a couple of examples here. In a way you can think of this as being a parent compound in the sense that this is sort of the parent of any hexanoic acid derived amide that would have a nitrogen on it whether it had substituents or not. So we would call this hexanamide. And you can just think of this as basically putting amide on the end so it's derived from hexanoic acid. So we call this a primary amide because it's derived from ammonia because there are two NHs, two hydrogens on the nitrogen. And I'll give us an example of another amide. Let's actually I'll give us an example of a couple of more amides to let them start on this blackboard over here. So I think that would work. All right, a couple more examples here. So this acid, this amide comes from acetic acid. So we would call this N-methylacetamide. This compound is a secondary amide. And if you're typing out the structure, you would italicize the N. The N means the atom nitrogen. It means that there's a methyl group on the atom nitrogen. So unlike the lower case N when I talked about say, inbutylithium which meant normal, it meant the linear chain, a capital N as I said, typeset and italics but probably just written like I've written it here, means on the nitrogen atom. Take another example here. Common amide, an amide that's often used as a solvent is N-n dimethylformamide. So we have two substituents on the nitrogen so we call this N-n dimethylformamide, all one word. It's a tertiary amide. In other words, it has two substituents on the nitrogen. And one thing to keep in mind, many, many students look at a compound like dimethylformamide and they say, oh it's an aldehyde because I'm used to the C-H-O group. Well, the nitrogen and the carbonyl function together as a pair, they work as a functional group. In other words, we see a functional group, you know, one of the driving concepts in organic chemistry is that groups of atoms closely connected also often have very specific properties. Because the nitrogen is conjugated because it's in resonance and I'll talk more about that in a moment, because it's in resonance with the carbonyl group, this behaves like an amide, not like an aldehyde in all of its reactivity. So just as methylacetamide and methylacetamide is not a ketone and N-n dimethylformamide is not an aldehyde. Is the name acetyl and borma like a proper ion? Okay, great question. Are these the proper names or are these the common names? Anyone want to answer? Common. Common, yeah. So this one would be N-methylethanamide if I wanted to write out the IAPAC name just as we had done there with hexanamide but no self-respecting chemist would call it that. The latter one would be N-n dimethylmethanamide because it's derived from methanoic acid but everyone calls it formic acid. Wait, then would it be alright if we put this instead of the IAPAC name on the test? As I said, students often obsess over nomenclature. You would be hard, no, it's okay and it's scary. It's scary because I literally can hand you a book 500 pages on how to name organic compounds and it's easy to obsess over it. The other reason it's easy to obsess over this is because when it comes down to it, this is simple. I don't mean it's simple to know all of the rules and some of them are arcane. I mean it's something that a computer can easily work through and there's very little higher thought process involved in naming a compound and so it's easy to spend time obsessing over that and not to get on to the stuff that's really conceptual. So don't worry, I won't ask you on a test. Was that the IAPAC name or the common name? Alright, now I'll give you one thing that I wouldn't expect you to obsess over but I was obsessing over just to show you one other example of where we have two different substituents here. So this is another tertiary amide and for this particular one, it actually was an example from your book. It's n-isobutyl n and I'm going to break it with the hyphen here just because I can't write it all out on one line. N-methyl and then what's our carbon chain? 1, 2, 3, 4, 5, pentanamide. I think your textbook must have had butanamide so I'm going to draw it with one fewer carbon here. Butanamide and that was an example from the problems that I asked you to work out as you go along when you're working out, working things out. Anyway, what we've done here is we've named the two halves on the nitrogen and we've alphabetized it but again, I think it's really, really easy to end up obsessing over that and don't get that obsessed. Alright, let's go on to acid chlorides and acid anhydrides. Alright, so let's go on to an acid chloride here, derived from pentanoic acid and again, we're seeing the family relationships here too. This is an acid chloride derived from pentanoic acid so we call it pentano-wheel chloride. We've taken the pentanoic of the acid from which it's derived and we've changed it to OYL. With the common names, you do it slightly differently so this compound here is acetyl chloride rather than acetoyl chloride and it's just how people name it, how it flows off the tongue. And let's do one more, I'll do an anhydride here. This is the anhydride derived from benzoic acid so we call it benzoic anhydride. Alright, last class of compounds I want to talk about in the family is nitriels. And so I'll just take the nitrile that's related to hexanoic acid, the one that has six carbons in it. You might draw it with C triple bond N, you might draw it just as CN, it's the same thing. This is called hexane nitrile so since it's a six carbon chain, it's called hexane and you just put nitrile on it. You don't have to specify the position of the nitrile because being triply bonded, there's no other place that you could put that nitrile group except on the end of it. Again, the small molecules tend to have common names. We also tend to splash the small molecules around like water in the laboratory, acetonitrile is a common solvent, this is acetonitrile, acetone is a common solvent, acetic acid is a common solvent and so you splash them around in separatory funnels and in chromatographic columns and the like. And let's see, I'll give you one more example. So one of the things that we saw when we were talking about naming carboxylic acids was we said when you have different groups, some of them will have lower priority so in general carboxylic acids have higher priority than ketones and aldehydes and nitriles have lower priority than carboxylic acid. So if you have the cyanone, if you have a nitrile group and an acid group, you end up naming it as the substituted acid. So this one is commonly called cyanowacetic acid. All right, well that gives a kind of a quick overview of how we talk about these compounds. I want to talk now about their physical and then their spectroscopic properties because I think that gets us into things that are more interesting and more important. So let's see. Your textbook sort of approaches this from the point of generalities and I decided I would approach our discussion today of the physical properties of compounds from a couple of specific examples that were kind of important compounds. So and this is maybe giving you a little bit of a flavor of my own thinking about the chemistry of the carboxylic acid family. So I decided to start our discussion today with ethyl acetate. Ethyl acetate is of course a widely used solvent. It's present in nail polish remover. You may have used it for liquid liquid extraction in the laboratory. Esters in general tend to have rather nice fruity odors and so ethyl acetate has a strong smell to it that's not unpleasant. Some of the esters like isoamyl acetate have very strong fruity odors so that's just overpoweringly banana. It's one of the components in banana. So ethyl acetate is a liquid. It has a boiling point of 77 degrees Celsius and I thought that might be a nice kickoff point to kind of contrast some of the properties to other molecules and so when I was thinking about molecules that are kind of the same size I figured well ethyl acetate has six heavy atoms, six carbon and oxygen atoms. It's about the same molecular weight as hexane. So by comparison I'd say hexane is a liquid 69 degrees as its boiling point and then if you say well we learned when we talked about Van der Waals contacts that if you have a more linear molecule you get more of Van der Waals contact and of course ethyl acetate sort of has a branch in it you might say maybe it would be a better comparison to compare it to two methyl pentane and two methyl pentane is also a liquid and it has a boiling point of 60 degrees. And so the take home message on this is not surprisingly ethyl acetate has a higher boiling point than molecules of similar size that don't have dipoles in it and it should make sense. I mean you have a molecule that has a molecular dipole in it and as a result you also see differences in solubility and all of this really can be explained by thinking about resonance structures. So I'll just add that the solubility is it's soluble in water soluble to the extent of about 8.3 grams per 100 milliliters and I always find that sort of interesting. I mean on the one hand you expect ethyl acetate to be have solubility in water. We've learned that if you have polar atoms and you have a reasonable ratio of polar atoms to carbon groups you should have some solubility in water and at the same time you may have heard the number 4 that if you have 4 carbons per oxygen or fewer you can think of something as soluble. But here we have no way we have 2 carbons per oxygen and so you think about something like ethanol and it's miscible with water it mixes with water so 2 carbons 1 oxygen. Diethyl ether 4 carbons 1 oxygen is about the same solubility in water but here we have 2 oxygens. Tetrahydrofuran 4 carbons and 1 oxygen is completely miscible with water. So in a way it surprises me it's a little less soluble than you might think. And we certainly can think of it as polar and you can think of it either as oh yeah the bond between oxygen and carbon is polarized and so you can think of it as saying delta plus delta minus or you can think of its behavior in terms of resonance structures and so just as with every carbonyl compound you can write minor resonance structures in which the carbonate a minor resonance structure in which charge is separated like so and I guess I'll be a good person in drawing my lone pairs over here. What's interesting about ethyl acetate and all other esters is you can write a second resonance form like so with a positive charge on this oxygen and so collectively the major resonance structure and the minor resonance structures, the small contributors certainly can explain the polarity of the molecule just as we saw and explained that acetone had a higher boiling point than say isobutylene and yet there's a little bit of unsatisfying why it's not more polar. The one thing that these resonance structures don't really embody is the fact that this oxygen is while it's donating electrons through resonance, it's also pulling them away in the sigma bonds. So in other words we have these two oxygens pulling in opposite directions through the sigma bonds to pull electrons away and for that reason ethyl acetate isn't as polar as you might otherwise think. In other words it's soluble in water but it's not super soluble in water and not miscible in water. It is a polar molecule that has a dipole moment to it but the dipole moment is not huge. It's not huge as say dimethyl formamide which I'll talk to you about in a moment when we talk about amids. All right I want to contrast ethyl acetate. As I said I'm coming at this from the point of view of specific molecules and their properties and sort of what they mean to me. I want to contrast ethyl acetate to a couple of familiar amids and so I'll start with acetamide and so acetamide by comparison is a solid. It's got a melting point of 82 degrees and if you heat it enough so it boils it has a boiling point of 221 degrees. So clearly acetamide even though it's a smaller molecule than ethyl acetate is much stickier and we saw this principle in carboxylic acids when we talked about their high boiling points. Acetamide has the ability to hydrogen bond and so you can form hydrogen bonded dimers and you can get further hydrogen bonding because you have the electronegative nitrogen bound to the hydrogen and so that can make these molecules stick together. Now dimethyl formamide of course doesn't have hydrogen bonding. You don't have any hydrogens on nitrogen and so dimethyl formamide can't participate in hydrogen bonding and yet it too is much higher boiling than ethyl acetate. So dimethyl formamide is a liquid. Its boiling point is 153 degrees. Decomposes to carbon monoxide and methylamine at that temperature so you can't really distill it and it's much more polar. It's got a bigger dipole moment, a bigger dielectric constant than ethyl acetate. It's miscible with water and you really in the case of dimethyl formamide can think of it getting a lot of its properties from that minor resonance structure off on the right. I'm not going to write off all of the resonance structures. I'm just going to write out the key resonance structure here and say you can explain a lot of its behavior by this type of resonance structure. Now this brings up an important point about amides. So this is still a minor resonance structure. But the point is the molecule is always, I'll get to your question in a second, the molecule is always multiple resonance structures all at the same time. These are just different pictures of the same thing. But in the case of ethyl acetate, it's just a little bit of this resonance structure. And in the case of dimethyl formamide, it's a little bit more. It's on the order of maybe 30% of that resonance structure if you needed to have a number in your head. One of the things that's very important to keep in mind about this fact is the fact that this nitrogen in dimethyl formamide and in amides in general is much closer to being sp2 in its properties, to being sp2 hybridized than sp3 hybridized. I'm going to write it as sp2 hybridized here because that really comes as the closest description. It's somewhere in between but it's more like sp2 hybridized. In other words, that nitrogen is not basic like an amine. It's much less basic than an amine because it's participating in resonance. All right. I saw a question. First. What does it say behind the table? Ah, decomposes. DEC is often the shorthand. You'll see chemists write for decomposes. Another question. Yeah. Back to the top of the board. What's the point of some kind of two pentanone? Of two pentanone. Two pentanone, let's see. It's acetone boils at I think 56 degrees. So we're talking somewhere around 80-ish. Oh wait, pentanone. So I'm thinking butanone. So pentanone, yeah, close to 100 degrees. So yeah, I mean even a bigger dipole for there. But the point is if you look at 153 versus 77, it's a big difference. So in other words, ethyl acetates a polar molecule but it's not like a super polar molecule. And by the time we come to the amides, it really is quite polar. If I wanted to make maybe a closer comparison to ethyl acetate, maybe I could also say Nn dimethylacetamide just because let's see, here we have 4, 5. I guess that's a reasonable comparison here. Other questions. All right, I want to take a look at this point at what the IR spectra tell us about the behavior of these molecules in parts so you can get used to recognizing them and in part so you can continue this theme of understanding their properties. All right, so to separate the forest from the trees, we talked before about all the carbonyl compounds. We talked, well except amide, no, I guess we talked about amides. So except acid, chlorides and anhydrides. We talked about esters and aldehydes and acids and ketones and amides and their relative carbonyl stretches. And the main point is you have a carbonyl band somewhere around 1700 wave numbers. And they differ a little bit depending on the nature of the particular carbonyl compound. So amides have their carbonyl typically around 1660, somewhere below 1700 is typical. Typically I'll sort of take a middle ground of around 1660. And so if we compare this, I always like to think of when I hold things in my head for understanding them, I always like to think around one compound. It's kind of the same that you saw in the theme of my talking about acetyl acetate or dimethyl formamide. So if I think of a typical ketone, whether it's cyclohexanone or acetone, I sort of think of a typical ketone as having about 1715 wave numbers. And so you think about this and you say, well this is saying that the nitrogen, that the carbon oxygen double bond stretch is weaker than that of a ketone. So I'd say a weaker CO. And you think about this resonance structure and this minor resonance structure really helps explain that very nicely. In other words, of course, it's not one, it's not the other, it's both and other resonance structures at the same time. But if you look at this, you say, oh yeah, I can understand. We have some single bond character mixed in here with the double bond character. So instead of vibrating at a higher frequency like a stiffer spring, it vibrates at a lower frequency, ever so slightly lower like a less stiff spring. Now if we come over to esters, typical ester, and again, these are sort of generic compounds and generic values, the typical ester is at about 1735 for the carbonyl stretch. So you don't see it very, very different from a ketone, just a little bit different. But where you really start to see things different is by the time you get to acid chlorides and acid anhydrides and this is where I think it's really telling. So you look at an acid chloride and the carbonyl stretch, now is it about 1800. And if you're looking at an IR spectrum, it's 1800s really distinctive. In other words, 1720, 1735, you'd say, okay, I can see differences, I can read the scale, but they're all sort of similar. Amid you'd say, oh 16 or 50, 1660, 1670, you'd say that's significantly different. Then at the other end you look and you'd say 1800, that really starts to look different. And one of the ways you can think about this, there are a couple of ways you can think about it. So obviously the fact that we're at 1800 means here, we have a stronger CO bond. And one way you can think of it is without resonance. You can say, well chlorine is electronegative. You can say chlorine is electronegative, it has a pulling electronegativity of 3.2 and it's basically pulling electron density down. And the big difference between chlorine and oxygen is oxygen is the same row as carbon. Oxygen can give good resonance overlap with carbon. Chlorine, instead of being second row, is third row. It's one row down. You can't get much pi bonding. You end up with very little double bond character, but a lot of that sigma electron withdrawing character, a lot of the chlorine inductively electron withdrawing. And so you can think of the chlorine as pulling electrons down from the oxygen making this bond stronger. It's pulling electron density down. You have lone pairs of electrons. They're pushing back in. I like to, in the back of my mind, I probably wouldn't write this resonance structure, say, elsewhere, but in the back of my mind, I kind of keep in mind the fact that if you take that type of thinking to its logical extreme and say, all right, there is a component of the chlorine pulling electron density away inductively, you can think about this non-bond resonance structure here. And in this non-bond resonance structure, you have some triple bond character. In other words, this is a very minor contributor, but it's basically that oxygen pushing in extra electron density, making that carbonyl bond even stronger, if it's stronger, you have it resonate at a higher frequency. And so you end up at 1800 instead of 1700 wave numbers. It's also very hot electronically. And we're going to see that acid chlorides are the most reactive member of the family with nucleophiles. Now, you have the same type of principle in acid and hydride. So just like the chlorine is pulling away electron density, you have the ASO group is pulling away electron density. And for that reason, in acid and hydrides, the carbonyl stretches also come at a higher frequency than you might expect for say a ketone. And acid and hydride show pairs. 18, 20, and 17, 60 would be typical for a pair of bands in the IR. In other words, you have two stretches, not one. And at first you might say, oh, well, that means that there are two types of carbonyl groups. It's not really that simple. When you have vibrations and they're close together, you get what are called coupled vibrations when they're close to each other in space. Kind of like splitting in the NMR spectrum. And when the vibrations couple, you have them working together. In other words, it's not one carbonyl stretching and the other carbonyl stretching, but it's both of them stretching together. And there are two types of stretches. One of them is an asymmetric stretch. And one of them is a symmetric stretch. So you end up with two bands. All right. And so I think what the IR spectra really are telling us is that acid chlorides and acid and hydride are really special in their properties. And they're special in that you have a lot of extra electrophilicity at the carbonyl. In other words, in other words, acid chlorides and acid and hydrides react with many different electrophiles because that carbonyl has the pulling away, the electron withdrawing group of the acyl group or of the chloride group. So to put it bluntly, if I take acid-teal chloride and I pour it into water, it sizzles. Spatters, it reacts violently. And the reaction gives acetic acid and HCl. Acid and hydrides also react with water not as violently, but they react. I'll just write reacts by contrast to violently. And the acetic N hydride hydrolyzes. Hydrolyzes is a fancy way of saying cleaves, lices by water. And where I really want to compare this to, to start our discussion of the chemical reactivity of the chemical properties of the carboxylic acid family, where I really want to contrast things to is to start to contrast them to say esters and amids. So if I take ethyl acetate and water, there's no reaction. We'll learn later how we can hydrolyze ethyl acetate with water, but it doesn't occur by just mixing ethyl acetate and water. I can qualify that. It can occur over a very, very, very long period, like years, or it could occur if you slowly, if you boil the ethyl acetate and water. But for all intents and purposes, there is no reaction. And that's a very good thing because esters and amids, which I'll write as the next molecule, I'll write NN dimethylacetamide, these are the molecules of biology, not ethyl acetate and NN dimethylacetamide, but of course, esters make up your lipids. The membrane in your, that covers every cell in your body is made of lipids. It's made of long chain fatty acids that are esterified to glycerol that are hooked to other fragments like acetylcholin. And what would happen if at room temperature, at 37, at body temperature, esters reacted with water, is your cells would all be, would all break apart. So it's very fortunate that esters don't automatically, don't without a catalyst or an enzyme, react with water at any appreciable rate at room temperature at 37 Celsius. Amids, it's the same thing. If I take an amid with water, there's no reaction. And again, this is very, very important because all of the proteins in your body are made up of amids. And if they were to react with water, the proteins would break down, you'd just be a pile of amino acids and fatty acids and glycerol. And you wouldn't be you. Now, amids and esters are also widely prevalent compounds, not only naturally, but synthetically. Your nylon backpack is made of a polyamid that chemists made to mimic proteins and initially the protein silk. Because stockings, as I see you're wearing, are, used to be made only available in silk. And silk is expensive and fragile. And at the time of World War II was needed for the war effort. And so having synthetic substitutes was useful. Esters, again, for a very good thing that polyamids like your backpack don't hydrolyze, when it rains your books would fall out and get wet. And polyesters, in addition to polyester fabrics, if you're wearing a polyester warm-up jacket there, are made, are used to make your water bottles. And you're plastic many of the, that's probably polystyrene in your container up front. But your water bottles that you buy, the aquafina or whatever herbal water they sell on campus here, are made of esters. And again, you'd be in a lot of trouble if they hydrolyzed on their own. Would the amide and the ester reaction go forward if we apply some acid to the amide? Would the amide, yes, and we will talk about that in tomorrow's, in our subsequent talk here. So yes, indeed, acids and strong bases can make them react. I want to finish one discussion of spectroscopic properties before moving on to chemical reactivity and focusing on acid fluorides and anhydrides. And I want to, I want to conclude maybe by talking about acetonitrile here and nitriels in general. So we talked about all the carbonyls and we said carbon-oxygen double bonds are centered around 1700 wave numbers. Triple bonds are of course stronger than double bonds. So carbon-nitrogen triple bond is centered at about 2250 wave numbers. They're usually sharp in the IR spectrum. As long as we're talking about acetonitrile, I'll add also no reaction with water. And again, that's in the absence of strong acid or strong base and we'll be talking about that later. I also want to give you a generalization. Remember we were talking about NMR before and I said I like to have a few baseline numbers in my head. The methyl group, whether it's on an acetonitrile or next to any sort of carbonyl, these methyl groups are always about 2 ppm, very close to 2 ppm in the 1H NMR, in the proton NMR. And the reason I like to keep that number in mind is then I can think okay, if we have a methylene, it's just like a methylene in an alkyl chain is a little further downfield, a few more tenths downfield than a methyl group and a methine in an alkyl chain is a little further downfield. We can go a little further downfield. So in general you can say for a hydrogen that's next to a carbonyl or next to a nitrogen, in general about let's say 2 to 3 ppm or 2 to 2.5 ppm depending on how you want to look at it. In other words, a methylene, a CH2 is going to be a few tenths further downfield, a methine will be a few tenths further downfield. I don't want to get overly caught up on the numbers here for spectra. All of, I just want to mention a few things. In the carbon 13, carbonyls in general are way downfield of the amide region, of the aromatic region. So in general you can pick out carbonyls. Carbonyls and ketones and aldehydes typically are around 200 ppm, a little bit more, 220, 190 somewhere around there. Typically for the whole carboxylic acid family, we're talking about 160 to 180 ppm in the C13 NMR. For the whole sort of carbonyl, the whole carboxylic acid family and just for the sake of completion, I'll give you nitriels. You have a carbon-carbon triple bond. It's kind of like an alkyne but you have an electronegative atom so you're talking about 115 to 120 ppm. All right. There, organic chemistry is about making stuff, at least a big part of it. And there are chemical reactions to interconvert all of the members of the carboxylic acid family. Acid chlorides, acid anhydrides, esters, carboxylic acids, amides and even nitriels can be interconverted to other members of the family, to nitriels, to esters, to carboxylic acids, to acid chlorides, to acid anhydrides. Now, if I were to say, okay, how many different, just if I figured one reaction for each of these and I think I've named six members of the family going into any other six members of the family, I basically would end up having a minimum of 15 different reactions and there are, of course, more to interconvert these members of the family. And so the first thing you might think is, oh my God, this is overwhelming. How can I possibly understand all of these reactions, all of these reagents? And the answer really becomes by thinking mechanistically, understanding the principles and understanding the general reactivity of different molecules. So I want to give you some generalization here before we dive into specifics. And so if we have some general member of the family, and nitriels are kind of the oddball, so I'm going to leave them out. We'll talk about them at the end on the next lecture. And we have some nucleophile, NU minus or NUH. Sort of a very, very generic type of species. Water, of course, was NUH. It was OHH. In general, a common theme is that the group on the carboxylic acid can under some conditions get replaced. It can get displaced by a nucleophile. And if I'm going to write a balanced equation, I would also say plus X minus or HX. And that's not meant to be a functional equation at this point. This is meant to be a generalization. And now I want to start to put structure in some specific to this. And so what I would say is this occurs with basic nucleophiles. So in other words, species like alkoxide, RO minus, hydroxide, HO minus or OH minus, and let's say amines. I'll write it as R2NH, but I'm not meaning specifically a secondary amine. I could mean a primary amine or I could mean ammonia. Or, so in other words, in general, members of the carboxylic acid family in general can react with good nucleophiles or with good electrophiles. And of course, what do I mean by good electrophiles? Well, good electrophiles are those ones that sizzle or react vigorously with nucleophiles. So specifically in this family, I'm talking about acid chlorides and acid anhydrides. So that's sort of one generalization that I'd make. And the other generalization that I would make is that weakly basic nucleophiles. And what do I mean by weakly basic nucleophiles? Well, we talked about these with ketones and with aldehydes. We're talking about things like alcohols and water. So I'll write ROH and water. And I'll say that they can react with less reactive electrophiles. And what do I mean by less reactive electrophiles? Well, I mean the members of the family that don't react with these, that don't have that electron withdrawing group, that don't have that carbonyl shifted up to 1800 or thereabouts in the IR spectrum. So we're talking esters, acids, amides, and nitriels. And they can do this if they have some help with strong acid catalysis. And what we're going to see in the next lecture is that a strong acid can protonate the carbonyl of an ester or a carboxylic acid or an amide or can protonate a nitrile group and take something that's only a weak electrophile and turn it into a strong electrophile in a mechanism that we end up going through. All right. So that generalization serves as a framework. And now I want to go on to some specifics and to talk about specific reactions of acid chloride and acid anhydrides. And so by way of a specific example, I'll take acetyl chloride. And I want to write a balanced equation here. Acetyl chloride, let's look at its reaction with a simple amine, methyl amine. Acetyl chloride can react with two molecules of methyl amine to give dimethylacetamide. And organic chemists are always bad about balancing equations, but I will balance it. And dimethylammonium chloride, dimethylamine hydrochloride, ME2NH2 plus Cl minus as a salt. What I want us to be able to do, because this is the archetype for all of our thinking about this chemistry, I want us to be able to think and understand our way through these mechanisms. And particularly to get the big picture, because sometimes the details aren't going to be that important. So here's our acetyl chloride. We know that that carbonyl is electrophilic. And we know that dimethylamine is nucleophilic. It has a lone pair of electrons. It wants, it's willing to share those electrons. We can attack very much like the theme we saw in imine formation chemistry. We can attack this extra electrophilic carbonyl. And at this point, I'll write this, I'm going to write this as irreversible. It's always a little bit of a judgment call. But if you have something where you're really, I guess I can write the first step as reversible, although honestly I'm not going to sweat about it. So I'm just going to write this one way. Okay, so at this point though, the big picture, the big idea is now just as in imine formation, at this point we formed a tetrahedral species. We formed a tetrahedral intermediate. And this and the next step really become the big idea here, the next part of the reaction. Yes. Oops, did I forget an age? No, I drew in an extra lone pair. You mean here? Ah, wait, where? Oh, okay, I was meaning to, I'm sorry, I was meaning to draw in dimethylamine. So dimethyl, let's do two molecules. We could do it with methyl amine. But let's do two molecules of dimethylamine react to form the dimethylamide and dimethylammonium chloride. And let's have our two methyls on the nitrogen with a hydrogen and a lone pair add to the carbonyl attack to give a tetrahedral intermediate. And the big point about this is our tetrahedral intermediate is going to be unstable just as we saw in imine formation where the hemiaminal is not a stable compound, it's not an isoble compound. That same theme emerges here. Question? Yeah? Why do we need two equivalents? You're going to say why do we need two equivalents? Great. All right. Just as in imine formation, your tetrahedral intermediate is unstable. I'll be a good person for one moment here. And I'm going to draw in all of my charges and all of my lone pairs of electrons. The tetrahedral intermediate can break down. It doesn't stick around. It can kick out chloride. Chloride is a good leaving group. Chloride gets expelled. But remember, this nitrogen here in an amide is not an amine nitrogen. It is not a basic nitrogen. It is not an sp3 nitrogen. It doesn't want to have a proton on it. It is very acidic and it's going to give up that proton to anything that's basic. And we have dimethylamine present. And so our dimethylamine is the strongest base in the house. And dimethylamine is going to pull off that proton to give you your dimethylacetamide plus dimethylamonium chloride. Well, I guess I've already written my chloride so I'll just balance my equation and say plus the dimethylamonium product. And if I were to not have that extra equivalent of dimethylamine around, halfway through all of my dimethylamine, the remaining dimethylamine would be protonated as the hydrochloride. Now, the reason I'm saying not to get too bent out of shape on this mechanism, the big picture, nucleophile attacks, we get a tetrahedral intermediate, the tetrahedral intermediate breaks down, protons shuffle around. Your textbook writes these two steps in reverse. Or more specifically, your textbook on closely related reactions and in the homework writes the deprotonation step at the tetrahedral intermediate. I don't think that makes as much sense on the basis of acidity. Don't get bent out of shape about it one way or another. The big picture nucleophile attacks, tetrahedral intermediate breaks down, protons shuffle around. If they shuffle around beforehand, it's not that big a deal. Other big picture item from a synthetic point of view, chemists often want to go ahead and not waste the valuable amine. Sometimes they'll add a base that's sacrificial, a tertiary amine like triethylamine or pyridine is added as a base. I'll write parenthesis pyridine here is added as a sacrificial base so you can use only one equivalent of amine. All right. This same basic principle of reactivity of acid chlorides applies with all other species whether it's strong base, whether it's basic nucleophiles like amines or weakly basic nucleophiles like alcohols and water. Acid chlorides react vigorously. So for example, if I take benzo-wheel chloride and I take ethanol, they react just like I said, acid-tyl chloride reacted to form with water. They react to form an ester ethylbenzoate. And again, if I want to balance my equation, HCl would be a byproduct. Very often in this chemistry as well, often you'll use pyridine as a base. Pyridine triethylamine can be used as well, disapropyl ethylamine as well to react with the HCl. So just for the sake of writing a balanced equation, if I take my benzo-wheel chloride, plus ethanol plus pyridine, I'm going to go ahead and get ethylbenzoate plus pyridinium hydrochloride. And on a preparative level, in the laboratory, you would probably carry out an aqueous workup in a separatory funnel in which you would extract the ethylbenzoate into the organic phase. You would wash away the pyridinium hydrochloride salt in the aqueous phase, and then you would dry your organic phase over magsulfate and filter and concentrate to get your ethylbenzoate. And you can imagine all sorts of other reactions of acid chlorides. We already saw that acetyl chloride reacted with water to give acetic acid, or you could use some sodium hydroxide in there to get ethyl acetate out of there, sodium acetate out of there. You could react sodium acetate with acetyl chloride to get acetic anhydride. And so maybe I will just very quickly sketch out these reactions, acetyl chloride plus H2O goes to acetic acid plus HCl, acetyl chloride. And you should be able to think your way through mechanistically on all of these acetyl chloride plus 2 hydroxide anion goes to acetate anion plus water H2O plus chloride anion. And I'll just write one more balanced equation, acetyl chloride plus let's say sodium acetate just to the hell of it I'll write in the counter ion here goes to acetic anhydride plus sodium chloride. All right, as disparate as all of these reactions sound, they're actually all the same basic principle. Once you get the idea of a nucleophile attacking your acid chloride to form a tetrahedral intermediate, the tetrahedral intermediate breaking down and some protons shuffling around, you end up comfortable with all of this chemistry and you see that it really, really falls into the same category. Now I wanted to mention two last points. One of these is the trends we've been talking about. We said that acetyl chloride is more reactive or in general I'll write acid chlorides are more reactive than anhydrides and those are more reactive than esters and those are more reactive than amides. And that makes sense if you consider the pKa of the conjugate acid of the leaving group. In other words, HCl is the conjugate acid of chloride as a leaving group. Its pKa is negative 7. In other words, chloride is a very good leaving group even in this or in this addition elimination chemistry. The pKa of a carboxylic acid, the conjugate base of a carboxylate leaving group in anhydrides is on the order of 4 to 5. While it's much less of a good leaving group than chloride, remember this is addition elimination chemistry, not S into displacement chemistry, it's still a good enough leaving group. By the time we come to an alcohol, the conjugate base of alkoxide leaving group, we're talking pKa 16 to 17 here. Now we're not so good and then by the time we come to an amine as our leaving group here, now we're at about, depending on which number you use from your textbook, about 38 and so now we've gone, we basically spanned five orders of magnitude here in our peak, or spanned pardon me, almost 50 orders of magnitude here, 45 orders of magnitude in our chemistry here. All right, the only sort of odd ball in this mix are carboxylic acids and the reason I haven't immediately included them is there's one special caveat. You'd say for many purposes and we'll see in fissure esterification and transesterification, esters carboxylic acids are the same, but in the case of a base, often you will have a base deprotonating a carboxylic acid to give you a carboxylate and then you end up really, since the carboxylic acid is acidic, you really have to think about O2 minus, which is just not a leaving group. So there are certain cases where you're talking about say an ester will react with an amine if you warm it, but a carboxylic acid is just going to do proton transfer with an amine, unless you heat the absolute hell out of the thing to hundreds of degrees. All right, last thing I want to do is talk about the reactivity of anhydrides and really for many, many purposes the reactivity of anhydrides is like that of chlorides, acid chlorides, except they don't sizzle with water. So they're less reactive. So if I take acetic anhydride and dimethylamine and again I'll write a balanced equation, I get dimethylacetamide and I also get plus dimethylamonium acetate. By the way, you will often see this written as acetic anhydride AC2O and sometimes you'll see it written here as an ac group, but hence I'm just writing it here as OAC. Now for this same reason and the same idea we talked about when we were talking about the chemistry of acid chlorides, because you're using a second equivalent of amine as a base in this chemistry because it's getting protonated by the acetic acid byproduct of reaction, often you will use a sacrificial base like pyridine. So I'll write a balanced equation and at this point I'll use the shorthand for acetic anhydride. So I'll write acetic anhydride plus methylamine plus pyridine. Often you would see these as reagents written above an arrow goes to ac same product here and then if I want to write a balanced equation I'm going to get pyridinium acetate as my byproduct. And all of these principles of reactivity then apply to things like alcohols as well. So if I take acetic anhydride and ethanol and again I'll just use this common shorthand for acetic anhydride plus ethanol just as we saw it reacted with water to give acetic acid, acetic anhydride reacts with ethanol to give ethyl acetate and again there are many ways you could write ethyl acetate. I'll just write it here OET plus acOH. All right so I think that gives us kind of an overview of the reactivity of the most reactive members of the family, the acid chlorides and anhydrides as well as the general properties of the family. We'll talk about the reaction of acid, catalyzed reaction with weak nucleophiles for esters and carboxylic acids as well as the effect of strong nucleophiles like bases on them next time.
 Good morning.  So today I want to begin our discussion of Chapter 22.  And Chapter 22 brings us back to carboxylic acids.  We talked a little bit about carboxylic acids  and their family in Chapter 19.  And then we started to introduce some of the chemistry  of the carbonyl group in general.  Now of course a carbonyl group is embodied  in the carboxyl group of carboxylic acids.  And so we really needed this understanding to begin  to proceed on.  So today we're coming back to carboxylic acids.  And we're going to talk about themes  in carboxylic acid chemistry that involve the same type  of reactivity that we saw with ketones and aldehydes.  That is the ability of nucleophiles to add  to the carboxyl group and to replace the carboxyl group.  We're going to come back again later in a couple  of more chapters where we start talking  about carbon-carbon bond forming reactions and talk  about clasin condensations and other additions  of carbon nucleophiles that are going to be based  on this other property of carbonyl compounds,  the acidity of the alpha proton.  But right now we're going to just talk  about the carboxylic acid family and their properties,  the different functions, the different members  of this family and their interconversion.  And today we'll conclude by discussing the chemistry  of acid chlorides and acid anhydrides,  the two most reactive members  of the carboxylic acid family.  So let me draw out the family here  or at least the main members, the important players.  Of course we have carboxylic acids.  And then sort of as a very close relationship we have esters.  We've already talked about the relationship between alcohols  and water and here in the carboxylic acid you sort  of have a half of a water molecule  and ester you have half of an alcohol molecule.  So they'll have many things in common.  Amids of various flavors.  I'll just draw the amids structure generically  with two sort of generic R groups.  They can be alcohol, they can be aromatic,  they can be hydrogens and we have various flavors  of amid primary, secondary and tertiary.  Amid we'll talk a little bit more about them.  And these then moving along in the family we have acid chlorides.  Acid chlorides are very reactive.  We'll be talking about their chemistry.  I'm giving you the important members of the family.  One could easily envision acid bromides  where the bromine is replaced with the chlorine  and perhaps envision very similar properties.  In practice they're much less commonly encountered  but very similar in their reactivity.  Acid iodides even more unusual and more reactive.  Acid chlorides are a little bit funny.  We're not going to talk a whole lot about them.  They're still quite reactive but actually a little less  reactive than acid chlorides for reasons  of resonance stabilization.  Also in the reactive members of the family we have anhydrides  or sometimes you'll hear them referred to as acid anhydrides.  And finally and again of course I'm only taking a limited subset  of the family we have nitriels.  And if you look at the a nitrile,  nitrile is sort of the odd man out in this group in the sense  that you would say by comparison I guess  if I'm writing everything with S I'll write carboxylic acids.  By comparison it doesn't look anything  like the other members of the family.  It's sort of the odd cousin.  And what is in common to all of these is  that the oxidation state of the carbon atom is the same  in all of these.  In all of these family members we're  in the plus three oxidation state for that carbon.  So even though a carboxylic acid and ester  and acid chloride and anhydride have carbonyl groups,  carbon double bonded to oxygen  and the nitrile obviously does not,  there are many similarities in reactivity.  Also when we talked about imines I said  that in many ways the reactivity  of a carbon nitrogen double bond is very similar  to a carbon oxygen double bond.  In other words, imines have a lot  of the same reactivity as aldehydes and ketones.  And nitriles now you have a triple bond but again you get  this theme of a carbon multiply bonded in this case triply  but otherwise doubly to an electronegative atom.  All right, let's take a moment to talk about naming compounds  and I don't want to get heavily caught up.  I think it's very easy for students to obsess  about nomenclature and I want you to be able to see the forest  from the trees.  I really want you to be able  to see the anatomical features of the molecule.  In other words, be able to recognize the pieces  of the molecule because conceptually this is the key  to understanding the molecules and it's very easy  to quickly end up getting yourself confused with rules  of alphabetization and so forth.  So here we have an ester and an ester  as I just mentioned has one component that comes  from an acid and another component that comes  from an alcohol and just recognizing those two key  components then is key to understanding their synthesis,  some of their reactivity and so forth.  So let me take a specific ester and we can see how to name it.  And so this ester has an acid component from butanoic acid  and an alcohol component from ethyl alcohol or ethanol.  So we call this ethyl, esters get a first name and a last name.  We call this ethyl butanoate and it kind of makes sense  on the nomenclature intuitively if you recognize  that what we've done is just take the butanoic acid  and replace the OIC with OATE.  And so they're being able  to see the components is important.  I'll give us another example along the same lines.  So we'd call this compound methylbenzoate.  That's OATE on the end because it's derived from benzoic acid.  For amides a lot of the thinking is kind of similar.  We have two components and we sort of recognize  that here's our amide and so we have a component that came  from the acid and a component that came from an amine or ammonia.  And so I'll give us a couple of examples here.  In a way you can think of this as being a parent compound  in the sense that this is sort of the parent  of any hexanoic acid derived amide  that would have a nitrogen on it whether it had substituents  or not.  So we would call this hexanamide.  And you can just think of this as basically putting amide  on the end so it's derived from hexanoic acid.  So we call this a primary amide because it's derived  from ammonia because there are two NHs,  two hydrogens on the nitrogen.  And I'll give us an example of another amide.  Let's actually I'll give us an example of a couple  of more amides to let them start  on this blackboard over here.  So I think that would work.  All right, a couple more examples here.  So this acid, this amide comes from acetic acid.  So we would call this N-methylacetamide.  This compound is a secondary amide.  And if you're typing out the structure,  you would italicize the N. The N means the atom nitrogen.  It means that there's a methyl group on the atom nitrogen.  So unlike the lower case N when I talked about say,  inbutylithium which meant normal, it meant the linear chain,  a capital N as I said, typeset and italics  but probably just written like I've written it here,  means on the nitrogen atom.  Take another example here.  Common amide, an amide that's often used  as a solvent is N-n dimethylformamide.  So we have two substituents on the nitrogen  so we call this N-n dimethylformamide, all one word.  It's a tertiary amide.  In other words, it has two substituents on the nitrogen.  And one thing to keep in mind, many, many students look  at a compound like dimethylformamide and they say,  oh it's an aldehyde because I'm used to the C-H-O group.  Well, the nitrogen and the carbonyl function together  as a pair, they work as a functional group.  In other words, we see a functional group, you know,  one of the driving concepts in organic chemistry is  that groups of atoms closely connected also often have  very specific properties.  Because the nitrogen is conjugated because it's  in resonance and I'll talk more about that in a moment,  because it's in resonance with the carbonyl group,  this behaves like an amide, not like an aldehyde  in all of its reactivity.  So just as methylacetamide and methylacetamide is not a ketone  and N-n dimethylformamide is not an aldehyde.  Is the name acetyl and borma like a proper ion?  Okay, great question.  Are these the proper names or are these the common names?  Anyone want to answer?  Common.  Common, yeah.  So this one would be N-methylethanamide if I wanted  to write out the IAPAC name just as we had done there  with hexanamide but no self-respecting chemist would  call it that.  The latter one would be N-n dimethylmethanamide  because it's derived from methanoic acid  but everyone calls it formic acid.  Wait, then would it be alright if we put this instead  of the IAPAC name on the test?  As I said, students often obsess over nomenclature.  You would be hard, no, it's okay and it's scary.  It's scary because I literally can hand you a book 500 pages  on how to name organic compounds and it's easy  to obsess over it.  The other reason it's easy to obsess over this is  because when it comes down to it, this is simple.  I don't mean it's simple to know all of the rules  and some of them are arcane.  I mean it's something that a computer can easily work  through and there's very little higher thought process  involved in naming a compound and so it's easy  to spend time obsessing over that and not to get  on to the stuff that's really conceptual.  So don't worry, I won't ask you on a test.  Was that the IAPAC name or the common name?  Alright, now I'll give you one thing  that I wouldn't expect you to obsess over but I was obsessing  over just to show you one other example  of where we have two different substituents here.  So this is another tertiary amide  and for this particular one,  it actually was an example from your book.  It's n-isobutyl n and I'm going to break it  with the hyphen here just  because I can't write it all out on one line.  N-methyl and then what's our carbon chain?  1, 2, 3, 4, 5, pentanamide.  I think your textbook must have had butanamide so I'm going  to draw it with one fewer carbon here.  Butanamide and that was an example from the problems  that I asked you to work out as you go along  when you're working out, working things out.  Anyway, what we've done here is we've named the two halves  on the nitrogen and we've alphabetized it but again,  I think it's really, really easy to end up obsessing  over that and don't get that obsessed.  Alright, let's go on to acid chlorides and acid anhydrides.  Alright, so let's go on to an acid chloride here,  derived from pentanoic acid and again,  we're seeing the family relationships here too.  This is an acid chloride derived from pentanoic acid  so we call it pentano-wheel chloride.  We've taken the pentanoic of the acid from which it's derived  and we've changed it to OYL.  With the common names, you do it slightly differently  so this compound here is acetyl chloride  rather than acetoyl chloride and it's just how people name it,  how it flows off the tongue.  And let's do one more, I'll do an anhydride here.  This is the anhydride derived from benzoic acid  so we call it benzoic anhydride.  Alright, last class of compounds I want to talk  about in the family is nitriels.  And so I'll just take the nitrile that's related  to hexanoic acid, the one that has six carbons in it.  You might draw it with C triple bond N,  you might draw it just as CN, it's the same thing.  This is called hexane nitrile so since it's a six carbon chain,  it's called hexane and you just put nitrile on it.  You don't have to specify the position of the nitrile  because being triply bonded, there's no other place  that you could put that nitrile group except on the end of it.  Again, the small molecules tend to have common names.  We also tend to splash the small molecules around like water  in the laboratory, acetonitrile is a common solvent,  this is acetonitrile, acetone is a common solvent,  acetic acid is a common solvent  and so you splash them around in separatory funnels  and in chromatographic columns and the like.  And let's see, I'll give you one more example.  So one of the things that we saw when we were talking  about naming carboxylic acids was we said  when you have different groups, some of them will have  lower priority so in general carboxylic acids have higher  priority than ketones and aldehydes  and nitriles have lower priority than carboxylic acid.  So if you have the cyanone, if you have a nitrile group  and an acid group, you end up naming it  as the substituted acid.  So this one is commonly called cyanowacetic acid.  All right, well that gives a kind of a quick overview  of how we talk about these compounds.  I want to talk now about their physical  and then their spectroscopic properties  because I think that gets us into things  that are more interesting and more important.  So let's see.  Your textbook sort of approaches this from the point  of generalities and I decided I would approach our discussion  today of the physical properties of compounds from a couple  of specific examples that were kind of important compounds.  So and this is maybe giving you a little bit of a flavor  of my own thinking about the chemistry of the carboxylic acid  family.  So I decided to start our discussion today with ethyl acetate.  Ethyl acetate is of course a widely used solvent.  It's present in nail polish remover.  You may have used it for liquid liquid extraction  in the laboratory.  Esters in general tend to have rather nice fruity odors  and so ethyl acetate has a strong smell to it  that's not unpleasant.  Some of the esters like isoamyl acetate have very strong  fruity odors so that's just overpoweringly banana.  It's one of the components in banana.  So ethyl acetate is a liquid.  It has a boiling point of 77 degrees Celsius  and I thought that might be a nice kickoff point to kind  of contrast some of the properties to other molecules  and so when I was thinking about molecules that are kind  of the same size I figured well ethyl acetate has six heavy  atoms, six carbon and oxygen atoms.  It's about the same molecular weight as hexane.  So by comparison I'd say hexane is a liquid 69 degrees  as its boiling point and then if you say well we learned  when we talked about Van der Waals contacts  that if you have a more linear molecule you get more  of Van der Waals contact and of course ethyl acetate sort  of has a branch in it you might say maybe it would be a better  comparison to compare it to two methyl pentane  and two methyl pentane is also a liquid  and it has a boiling point of 60 degrees.  And so the take home message on this is not surprisingly  ethyl acetate has a higher boiling point than molecules  of similar size that don't have dipoles in it  and it should make sense.  I mean you have a molecule that has a molecular dipole in it  and as a result you also see differences in solubility  and all of this really can be explained by thinking  about resonance structures.  So I'll just add that the solubility is it's soluble  in water soluble to the extent  of about 8.3 grams per 100 milliliters  and I always find that sort of interesting.  I mean on the one hand you expect ethyl acetate  to be have solubility in water.  We've learned that if you have polar atoms  and you have a reasonable ratio of polar atoms  to carbon groups you should have some solubility in water  and at the same time you may have heard the number 4  that if you have 4 carbons per oxygen or fewer you can think  of something as soluble.  But here we have no way we have 2 carbons per oxygen  and so you think about something like ethanol  and it's miscible with water it mixes with water  so 2 carbons 1 oxygen.  Diethyl ether 4 carbons 1 oxygen is  about the same solubility in water  but here we have 2 oxygens.  Tetrahydrofuran 4 carbons  and 1 oxygen is completely miscible with water.  So in a way it surprises me it's a little less soluble  than you might think.  And we certainly can think of it as polar and you can think  of it either as oh yeah the bond between oxygen  and carbon is polarized and so you can think of it  as saying delta plus delta minus or you can think  of its behavior in terms of resonance structures  and so just as with every carbonyl compound you can write  minor resonance structures in which the carbonate a minor  resonance structure in which charge is separated like so  and I guess I'll be a good person  in drawing my lone pairs over here.  What's interesting about ethyl acetate  and all other esters is you can write a second resonance form  like so with a positive charge on this oxygen  and so collectively the major resonance structure  and the minor resonance structures, the small contributors  certainly can explain the polarity of the molecule just  as we saw and explained that acetone had a higher boiling  point than say isobutylene and yet there's a little bit  of unsatisfying why it's not more polar.  The one thing that these resonance structures don't really  embody is the fact that this oxygen is  while it's donating electrons through resonance,  it's also pulling them away in the sigma bonds.  So in other words we have these two oxygens pulling  in opposite directions through the sigma bonds  to pull electrons away and for that reason ethyl acetate isn't  as polar as you might otherwise think.  In other words it's soluble in water  but it's not super soluble in water  and not miscible in water.  It is a polar molecule that has a dipole moment to it  but the dipole moment is not huge.  It's not huge as say dimethyl formamide which I'll talk  to you about in a moment when we talk about amids.  All right I want to contrast ethyl acetate.  As I said I'm coming at this from the point of view  of specific molecules and their properties and sort  of what they mean to me.  I want to contrast ethyl acetate to a couple  of familiar amids and so I'll start  with acetamide and so acetamide  by comparison is a solid.  It's got a melting point of 82 degrees  and if you heat it enough so it boils it has a boiling point  of 221 degrees.  So clearly acetamide even though it's a smaller molecule  than ethyl acetate is much stickier  and we saw this principle in carboxylic acids  when we talked about their high boiling points.  Acetamide has the ability to hydrogen bond  and so you can form hydrogen bonded dimers  and you can get further hydrogen bonding  because you have the electronegative nitrogen bound  to the hydrogen and so that can make these molecules stick  together.  Now dimethyl formamide of course doesn't have hydrogen  bonding.  You don't have any hydrogens on nitrogen  and so dimethyl formamide can't participate  in hydrogen bonding and yet it too is much higher boiling  than ethyl acetate.  So dimethyl formamide is a liquid.  Its boiling point is 153 degrees.  Decomposes to carbon monoxide and methylamine  at that temperature so you can't really distill it  and it's much more polar.  It's got a bigger dipole moment,  a bigger dielectric constant than ethyl acetate.  It's miscible with water and you really in the case  of dimethyl formamide can think of it getting a lot  of its properties from that minor resonance structure off  on the right.  I'm not going to write off all of the resonance structures.  I'm just going to write out the key resonance structure here  and say you can explain a lot of its behavior  by this type of resonance structure.  Now this brings up an important point about amides.  So this is still a minor resonance structure.  But the point is the molecule is always,  I'll get to your question in a second,  the molecule is always multiple resonance structures all  at the same time.  These are just different pictures of the same thing.  But in the case of ethyl acetate,  it's just a little bit of this resonance structure.  And in the case of dimethyl formamide, it's a little bit more.  It's on the order of maybe 30% of that resonance structure  if you needed to have a number in your head.  One of the things that's very important to keep in mind  about this fact is the fact that this nitrogen  in dimethyl formamide and in amides in general is much closer  to being sp2 in its properties,  to being sp2 hybridized than sp3 hybridized.  I'm going to write it as sp2 hybridized here  because that really comes  as the closest description.  It's somewhere in between but it's more like sp2 hybridized.  In other words, that nitrogen is not basic like an amine.  It's much less basic than an amine  because it's participating in resonance.  All right.  I saw a question.  First.  What does it say behind the table?  Ah, decomposes.  DEC is often the shorthand.  You'll see chemists write for decomposes.  Another question.  Yeah. Back to the top of the board.  What's the point of some kind of two pentanone?  Of two pentanone.  Two pentanone, let's see.  It's acetone boils at I think 56 degrees.  So we're talking somewhere around 80-ish.  Oh wait, pentanone.  So I'm thinking butanone.  So pentanone, yeah, close to 100 degrees.  So yeah, I mean even a bigger dipole for there.  But the point is if you look at 153 versus 77,  it's a big difference.  So in other words, ethyl acetates a polar molecule  but it's not like a super polar molecule.  And by the time we come to the amides,  it really is quite polar.  If I wanted to make maybe a closer comparison  to ethyl acetate, maybe I could also say Nn dimethylacetamide  just because let's see, here we have 4, 5.  I guess that's a reasonable comparison here.  Other questions.  All right, I want to take a look at this point  at what the IR spectra tell us about the behavior  of these molecules in parts so you can get used  to recognizing them and in part  so you can continue this theme  of understanding their properties.  All right, so to separate the forest from the trees,  we talked before about all the carbonyl compounds.  We talked, well except amide, no,  I guess we talked about amides.  So except acid, chlorides and anhydrides.  We talked about esters and aldehydes and acids  and ketones and amides and their relative carbonyl stretches.  And the main point is you have a carbonyl band somewhere  around 1700 wave numbers.  And they differ a little bit depending on the nature  of the particular carbonyl compound.  So amides have their carbonyl typically around 1660,  somewhere below 1700 is typical.  Typically I'll sort of take a middle ground of around 1660.  And so if we compare this, I always like to think  of when I hold things in my head for understanding them,  I always like to think around one compound.  It's kind of the same that you saw in the theme of my talking  about acetyl acetate or dimethyl formamide.  So if I think of a typical ketone, whether it's cyclohexanone  or acetone, I sort of think of a typical ketone as having  about 1715 wave numbers.  And so you think about this and you say, well this is saying  that the nitrogen, that the carbon oxygen double bond stretch  is weaker than that of a ketone.  So I'd say a weaker CO.  And you think about this resonance structure  and this minor resonance structure really helps explain  that very nicely.  In other words, of course, it's not one, it's not the other,  it's both and other resonance structures at the same time.  But if you look at this, you say, oh yeah, I can understand.  We have some single bond character mixed in here  with the double bond character.  So instead of vibrating at a higher frequency  like a stiffer spring, it vibrates at a lower frequency,  ever so slightly lower like a less stiff spring.  Now if we come over to esters, typical ester, and again,  these are sort of generic compounds and generic values,  the typical ester is at about 1735 for the carbonyl stretch.  So you don't see it very, very different from a ketone,  just a little bit different.  But where you really start to see things different is  by the time you get to acid chlorides and acid anhydrides  and this is where I think it's really telling.  So you look at an acid chloride and the carbonyl stretch,  now is it about 1800.  And if you're looking at an IR spectrum,  it's 1800s really distinctive.  In other words, 1720, 1735, you'd say, okay,  I can see differences, I can read the scale,  but they're all sort of similar.  Amid you'd say, oh 16 or 50, 1660, 1670,  you'd say that's significantly different.  Then at the other end you look and you'd say 1800,  that really starts to look different.  And one of the ways you can think about this,  there are a couple of ways you can think about it.  So obviously the fact that we're at 1800 means here,  we have a stronger CO bond.  And one way you can think of it is without resonance.  You can say, well chlorine is electronegative.  You can say chlorine is electronegative,  it has a pulling electronegativity of 3.2  and it's basically pulling electron density down.  And the big difference between chlorine and oxygen is oxygen  is the same row as carbon.  Oxygen can give good resonance overlap with carbon.  Chlorine, instead of being second row, is third row.  It's one row down.  You can't get much pi bonding.  You end up with very little double bond character,  but a lot of that sigma electron withdrawing character,  a lot of the chlorine inductively electron withdrawing.  And so you can think of the chlorine as pulling electrons  down from the oxygen making this bond stronger.  It's pulling electron density down.  You have lone pairs of electrons.  They're pushing back in.  I like to, in the back of my mind,  I probably wouldn't write this resonance structure,  say, elsewhere, but in the back of my mind, I kind of keep  in mind the fact that if you take that type of thinking  to its logical extreme and say, all right,  there is a component  of the chlorine pulling electron density away inductively,  you can think about this non-bond resonance structure here.  And in this non-bond resonance structure,  you have some triple bond character.  In other words, this is a very minor contributor,  but it's basically that oxygen pushing  in extra electron density, making that carbonyl bond even  stronger, if it's stronger, you have it resonate  at a higher frequency.  And so you end up at 1800 instead of 1700 wave numbers.  It's also very hot electronically.  And we're going to see that acid chlorides are the most  reactive member of the family with nucleophiles.  Now, you have the same type of principle in acid and hydride.  So just like the chlorine is pulling away electron density,  you have the ASO group is pulling away electron density.  And for that reason, in acid and hydrides,  the carbonyl stretches also come at a higher frequency  than you might expect for say a ketone.  And acid and hydride show pairs.  18, 20, and 17, 60 would be typical for a pair of bands  in the IR.  In other words, you have two stretches, not one.  And at first you might say, oh, well,  that means that there are two types of carbonyl groups.  It's not really that simple.  When you have vibrations and they're close together,  you get what are called coupled vibrations when they're close  to each other in space.  Kind of like splitting in the NMR spectrum.  And when the vibrations couple, you have them working together.  In other words, it's not one carbonyl stretching  and the other carbonyl stretching,  but it's both of them stretching together.  And there are two types of stretches.  One of them is an asymmetric stretch.  And one of them is a symmetric stretch.  So you end up with two bands.  All right.  And so I think what the IR spectra really are telling us is  that acid chlorides and acid and hydride are really  special in their properties.  And they're special in that you have a lot  of extra electrophilicity at the carbonyl.  In other words, in other words, acid chlorides  and acid and hydrides react with many different electrophiles  because that carbonyl has the pulling away, the electron  withdrawing group of the acyl group or of the chloride group.  So to put it bluntly, if I take acid-teal chloride  and I pour it into water, it sizzles.  Spatters, it reacts violently.  And the reaction gives acetic acid and HCl.  Acid and hydrides also react with water not as violently,  but they react.  I'll just write reacts by contrast to violently.  And the acetic N hydride hydrolyzes.  Hydrolyzes is a fancy way of saying cleaves, lices by water.  And where I really want to compare this to,  to start our discussion of the chemical reactivity  of the chemical properties of the carboxylic acid family,  where I really want to contrast things to is to start  to contrast them to say esters and amids.  So if I take ethyl acetate and water, there's no reaction.  We'll learn later how we can hydrolyze ethyl acetate  with water, but it doesn't occur  by just mixing ethyl acetate and water.  I can qualify that.  It can occur over a very, very, very long period, like years,  or it could occur if you slowly,  if you boil the ethyl acetate and water.  But for all intents and purposes, there is no reaction.  And that's a very good thing because esters and amids,  which I'll write as the next molecule,  I'll write NN dimethylacetamide,  these are the molecules of biology,  not ethyl acetate and NN dimethylacetamide,  but of course, esters make up your lipids.  The membrane in your, that covers every cell  in your body is made of lipids.  It's made of long chain fatty acids that are esterified  to glycerol that are hooked to other fragments  like acetylcholin.  And what would happen if at room temperature,  at 37, at body temperature, esters reacted with water,  is your cells would all be, would all break apart.  So it's very fortunate that esters don't automatically,  don't without a catalyst or an enzyme, react with water  at any appreciable rate at room temperature at 37 Celsius.  Amids, it's the same thing.  If I take an amid with water, there's no reaction.  And again, this is very, very important because all  of the proteins in your body are made up of amids.  And if they were to react with water, the proteins would  break down, you'd just be a pile of amino acids  and fatty acids and glycerol.  And you wouldn't be you.  Now, amids and esters are also widely prevalent compounds,  not only naturally, but synthetically.  Your nylon backpack is made of a polyamid that chemists made  to mimic proteins and initially the protein silk.  Because stockings, as I see you're wearing, are,  used to be made only available in silk.  And silk is expensive and fragile.  And at the time of World War II was needed for the war effort.  And so having synthetic substitutes was useful.  Esters, again, for a very good thing  that polyamids like your backpack don't hydrolyze,  when it rains your books would fall out and get wet.  And polyesters, in addition to polyester fabrics,  if you're wearing a polyester warm-up jacket there, are made,  are used to make your water bottles.  And you're plastic many of the, that's probably polystyrene  in your container up front.  But your water bottles that you buy, the aquafina  or whatever herbal water they sell on campus here,  are made of esters.  And again, you'd be in a lot of trouble  if they hydrolyzed on their own.  Would the amide and the ester reaction go forward  if we apply some acid to the amide?  Would the amide, yes, and we will talk about that in tomorrow's,  in our subsequent talk here.  So yes, indeed, acids and strong bases can make them react.  I want to finish one discussion of spectroscopic properties before moving  on to chemical reactivity and focusing on acid fluorides  and anhydrides.  And I want to, I want to conclude maybe by talking  about acetonitrile here and nitriels in general.  So we talked about all the carbonyls  and we said carbon-oxygen double bonds are centered  around 1700 wave numbers.  Triple bonds are of course stronger than double bonds.  So carbon-nitrogen triple bond is centered  at about 2250 wave numbers.  They're usually sharp in the IR spectrum.  As long as we're talking about acetonitrile,  I'll add also no reaction with water.  And again, that's in the absence of strong acid or strong base  and we'll be talking about that later.  I also want to give you a generalization.  Remember we were talking about NMR before and I said I like  to have a few baseline numbers in my head.  The methyl group, whether it's on an acetonitrile or next  to any sort of carbonyl, these methyl groups are always  about 2 ppm, very close to 2 ppm in the 1H NMR,  in the proton NMR.  And the reason I like to keep that number in mind is  then I can think okay, if we have a methylene,  it's just like a methylene in an alkyl chain is a little further  downfield, a few more tenths downfield than a methyl group  and a methine in an alkyl chain is a little further downfield.  We can go a little further downfield.  So in general you can say for a hydrogen that's next  to a carbonyl or next to a nitrogen, in general about let's  say 2 to 3 ppm or 2 to 2.5 ppm depending  on how you want to look at it.  In other words, a methylene, a CH2 is going to be a few tenths  further downfield, a methine will be a few tenths further  downfield.  I don't want to get overly caught up on the numbers here  for spectra.  All of, I just want to mention a few things.  In the carbon 13, carbonyls in general are way downfield  of the amide region, of the aromatic region.  So in general you can pick out carbonyls.  Carbonyls and ketones and aldehydes typically are  around 200 ppm, a little bit more, 220,  190 somewhere around there.  Typically for the whole carboxylic acid family,  we're talking about 160 to 180 ppm in the C13 NMR.  For the whole sort of carbonyl,  the whole carboxylic acid family and just for the sake  of completion, I'll give you nitriels.  You have a carbon-carbon triple bond.  It's kind of like an alkyne but you have an electronegative  atom so you're talking about 115 to 120 ppm.  All right.  There, organic chemistry is about making stuff,  at least a big part of it.  And there are chemical reactions to interconvert all  of the members of the carboxylic acid family.  Acid chlorides, acid anhydrides, esters,  carboxylic acids, amides and even nitriels can be  interconverted to other members of the family,  to nitriels, to esters, to carboxylic acids,  to acid chlorides, to acid anhydrides.  Now, if I were to say, okay, how many different,  just if I figured one reaction for each of these  and I think I've named six members of the family going  into any other six members of the family,  I basically would end up having a minimum  of 15 different reactions and there are, of course,  more to interconvert these members of the family.  And so the first thing you might think is, oh my God,  this is overwhelming.  How can I possibly understand all of these reactions,  all of these reagents?  And the answer really becomes by thinking mechanistically,  understanding the principles  and understanding the general reactivity  of different molecules.  So I want to give you some generalization here before we  dive into specifics.  And so if we have some general member of the family,  and nitriels are kind of the oddball, so I'm going  to leave them out.  We'll talk about them at the end on the next lecture.  And we have some nucleophile, NU minus or NUH.  Sort of a very, very generic type of species.  Water, of course, was NUH.  It was OHH.  In general, a common theme is that the group  on the carboxylic acid can under some conditions get replaced.  It can get displaced by a nucleophile.  And if I'm going to write a balanced equation,  I would also say plus X minus or HX.  And that's not meant to be a functional equation  at this point.  This is meant to be a generalization.  And now I want to start to put structure in some specific  to this.  And so what I would say is this occurs  with basic nucleophiles.  So in other words, species like alkoxide, RO minus,  hydroxide, HO minus or OH minus, and let's say amines.  I'll write it as R2NH, but I'm not meaning specifically  a secondary amine.  I could mean a primary amine or I could mean ammonia.  Or, so in other words, in general, members  of the carboxylic acid family in general can react  with good nucleophiles or with good electrophiles.  And of course, what do I mean by good electrophiles?  Well, good electrophiles are those ones  that sizzle or react vigorously with nucleophiles.  So specifically in this family, I'm talking  about acid chlorides and acid anhydrides.  So that's sort of one generalization that I'd make.  And the other generalization that I would make is  that weakly basic nucleophiles.  And what do I mean by weakly basic nucleophiles?  Well, we talked about these with ketones and with aldehydes.  We're talking about things like alcohols and water.  So I'll write ROH and water.  And I'll say that they can react  with less reactive electrophiles.  And what do I mean by less reactive electrophiles?  Well, I mean the members of the family that don't react  with these, that don't have that electron withdrawing group,  that don't have that carbonyl shifted up to 1800  or thereabouts in the IR spectrum.  So we're talking esters, acids, amides, and nitriels.  And they can do this if they have some help  with strong acid catalysis.  And what we're going to see in the next lecture is  that a strong acid can protonate the carbonyl of an ester  or a carboxylic acid or an amide  or can protonate a nitrile group and take something  that's only a weak electrophile and turn it  into a strong electrophile in a mechanism  that we end up going through.  All right.  So that generalization serves as a framework.  And now I want to go on to some specifics  and to talk about specific reactions of acid chloride  and acid anhydrides.  And so by way of a specific example,  I'll take acetyl chloride.  And I want to write a balanced equation here.  Acetyl chloride, let's look at its reaction  with a simple amine, methyl amine.  Acetyl chloride can react with two molecules  of methyl amine to give dimethylacetamide.  And organic chemists are always bad about balancing equations,  but I will balance it.  And dimethylammonium chloride, dimethylamine hydrochloride,  ME2NH2 plus Cl minus as a salt.  What I want us to be able to do, because this is the archetype  for all of our thinking about this chemistry, I want us  to be able to think and understand our way  through these mechanisms.  And particularly to get the big picture,  because sometimes the details aren't going  to be that important.  So here's our acetyl chloride.  We know that that carbonyl is electrophilic.  And we know that dimethylamine is nucleophilic.  It has a lone pair of electrons.  It wants, it's willing to share those electrons.  We can attack very much like the theme we saw  in imine formation chemistry.  We can attack this extra electrophilic carbonyl.  And at this point, I'll write this,  I'm going to write this as irreversible.  It's always a little bit of a judgment call.  But if you have something where you're really,  I guess I can write the first step as reversible,  although honestly I'm not going to sweat about it.  So I'm just going to write this one way.  Okay, so at this point though, the big picture,  the big idea is now just as in imine formation,  at this point we formed a tetrahedral species.  We formed a tetrahedral intermediate.  And this and the next step really become the big idea here,  the next part of the reaction.  Yes.  Oops, did I forget an age?  No, I drew in an extra lone pair.  You mean here?  Ah, wait, where?  Oh, okay, I was meaning to, I'm sorry,  I was meaning to draw in dimethylamine.  So dimethyl, let's do two molecules.  We could do it with methyl amine.  But let's do two molecules of dimethylamine react  to form the dimethylamide and dimethylammonium chloride.  And let's have our two methyls on the nitrogen  with a hydrogen and a lone pair add to the carbonyl attack  to give a tetrahedral intermediate.  And the big point about this is our tetrahedral intermediate is  going to be unstable just as we saw in imine formation  where the hemiaminal is not a stable compound,  it's not an isoble compound.  That same theme emerges here.  Question?  Yeah?  Why do we need two equivalents?  You're going to say why do we need two equivalents?  Great. All right.  Just as in imine formation,  your tetrahedral intermediate is unstable.  I'll be a good person for one moment here.  And I'm going to draw in all of my charges  and all of my lone pairs of electrons.  The tetrahedral intermediate can break down.  It doesn't stick around.  It can kick out chloride.  Chloride is a good leaving group.  Chloride gets expelled.  But remember, this nitrogen here in an amide is not an amine  nitrogen.  It is not a basic nitrogen.  It is not an sp3 nitrogen.  It doesn't want to have a proton on it.  It is very acidic and it's going to give up that proton  to anything that's basic.  And we have dimethylamine present.  And so our dimethylamine is the strongest base in the house.  And dimethylamine is going to pull off that proton  to give you your dimethylacetamide plus dimethylamonium chloride.  Well, I guess I've already written my chloride  so I'll just balance my equation and say plus the  dimethylamonium product.  And if I were to not have that extra equivalent  of dimethylamine around, halfway through all  of my dimethylamine, the remaining dimethylamine would  be protonated as the hydrochloride.  Now, the reason I'm saying not to get too bent out of shape  on this mechanism, the big picture,  nucleophile attacks, we get a tetrahedral intermediate,  the tetrahedral intermediate breaks  down, protons shuffle around.  Your textbook writes these two steps in reverse.  Or more specifically, your textbook  on closely related reactions and in the homework writes the  deprotonation step at the tetrahedral intermediate.  I don't think that makes as much sense on the basis  of acidity.  Don't get bent out of shape about it one way or another.  The big picture nucleophile attacks,  tetrahedral intermediate breaks down, protons shuffle  around.  If they shuffle around beforehand,  it's not that big a deal.  Other big picture item from a synthetic point of view,  chemists often want to go ahead  and not waste the valuable amine.  Sometimes they'll add a base that's sacrificial,  a tertiary amine like triethylamine  or pyridine is added as a base.  I'll write parenthesis pyridine here is added  as a sacrificial base  so you can use only one equivalent of amine.  All right.  This same basic principle of reactivity  of acid chlorides applies with all other species  whether it's strong base, whether it's basic nucleophiles  like amines or weakly basic nucleophiles  like alcohols and water.  Acid chlorides react vigorously.  So for example, if I take benzo-wheel chloride  and I take ethanol, they react just like I said,  acid-tyl chloride reacted to form with water.  They react to form an ester ethylbenzoate.  And again, if I want to balance my equation,  HCl would be a byproduct.  Very often in this chemistry as well,  often you'll use pyridine as a base.  Pyridine triethylamine can be used as well,  disapropyl ethylamine as well to react with the HCl.  So just for the sake of writing a balanced equation,  if I take my benzo-wheel chloride,  plus ethanol plus pyridine, I'm going to go ahead  and get ethylbenzoate plus pyridinium hydrochloride.  And on a preparative level, in the laboratory,  you would probably carry out an aqueous workup  in a separatory funnel in which you would extract the ethylbenzoate  into the organic phase.  You would wash away the pyridinium hydrochloride salt  in the aqueous phase, and then you would dry your organic phase  over magsulfate and filter and concentrate  to get your ethylbenzoate.  And you can imagine all sorts of other reactions  of acid chlorides.  We already saw that acetyl chloride reacted with water  to give acetic acid, or you could use some sodium hydroxide  in there to get ethyl acetate out of there,  sodium acetate out of there.  You could react sodium acetate with acetyl chloride  to get acetic anhydride.  And so maybe I will just very quickly sketch  out these reactions, acetyl chloride plus H2O goes  to acetic acid plus HCl, acetyl chloride.  And you should be able to think your way  through mechanistically on all  of these acetyl chloride plus 2 hydroxide anion goes  to acetate anion plus water H2O plus chloride anion.  And I'll just write one more balanced equation,  acetyl chloride plus let's say sodium acetate just  to the hell of it I'll write in the counter ion here goes  to acetic anhydride plus sodium chloride.  All right, as disparate as all of these reactions sound,  they're actually all the same basic principle.  Once you get the idea of a nucleophile attacking your acid  chloride to form a tetrahedral intermediate,  the tetrahedral intermediate breaking down  and some protons shuffling around, you end up comfortable  with all of this chemistry and you see  that it really, really falls into the same category.  Now I wanted to mention two last points.  One of these is the trends we've been talking about.  We said that acetyl chloride is more reactive  or in general I'll write acid chlorides are more reactive  than anhydrides and those are more reactive than esters  and those are more reactive than amides.  And that makes sense if you consider the pKa  of the conjugate acid of the leaving group.  In other words, HCl is the conjugate acid  of chloride as a leaving group.  Its pKa is negative 7.  In other words, chloride is a very good leaving group even  in this or in this addition elimination chemistry.  The pKa of a carboxylic acid, the conjugate base  of a carboxylate leaving group in anhydrides is  on the order of 4 to 5.  While it's much less of a good leaving group than chloride,  remember this is addition elimination chemistry,  not S into displacement chemistry,  it's still a good enough leaving group.  By the time we come to an alcohol, the conjugate base  of alkoxide leaving group, we're talking pKa 16 to 17 here.  Now we're not so good and then by the time we come  to an amine as our leaving group here, now we're at about,  depending on which number you use from your textbook,  about 38 and so now we've gone,  we basically spanned five orders of magnitude here  in our peak, or spanned pardon me,  almost 50 orders of magnitude here,  45 orders of magnitude in our chemistry here.  All right, the only sort of odd ball  in this mix are carboxylic acids  and the reason I haven't immediately included them is  there's one special caveat.  You'd say for many purposes and we'll see  in fissure esterification and transesterification,  esters carboxylic acids are the same,  but in the case of a base, often you will have a base  deprotonating a carboxylic acid to give you a carboxylate  and then you end up really,  since the carboxylic acid is acidic, you really have  to think about O2 minus, which is just not a leaving group.  So there are certain cases where you're talking  about say an ester will react with an amine if you warm it,  but a carboxylic acid is just going  to do proton transfer with an amine,  unless you heat the absolute hell out of the thing  to hundreds of degrees.  All right, last thing I want to do is talk  about the reactivity of anhydrides and really  for many, many purposes the reactivity of anhydrides is  like that of chlorides, acid chlorides,  except they don't sizzle with water.  So they're less reactive.  So if I take acetic anhydride and dimethylamine  and again I'll write a balanced equation,  I get dimethylacetamide and I also get  plus dimethylamonium acetate.  By the way, you will often see this written  as acetic anhydride AC2O and sometimes you'll see it written  here as an ac group, but hence I'm just writing it here  as OAC. Now for this same reason and the same idea we talked  about when we were talking  about the chemistry of acid chlorides,  because you're using a second equivalent of amine as a base  in this chemistry because it's getting protonated  by the acetic acid byproduct of reaction,  often you will use a sacrificial base like pyridine.  So I'll write a balanced equation  and at this point I'll use the shorthand for acetic anhydride.  So I'll write acetic anhydride plus methylamine plus pyridine.  Often you would see these as reagents written  above an arrow goes to ac same product here and then if I want  to write a balanced equation I'm going  to get pyridinium acetate as my byproduct.  And all of these principles of reactivity then apply  to things like alcohols as well.  So if I take acetic anhydride and ethanol and again I'll just  use this common shorthand for acetic anhydride plus ethanol  just as we saw it reacted with water to give acetic acid,  acetic anhydride reacts with ethanol to give ethyl acetate  and again there are many ways you could write ethyl acetate.  I'll just write it here OET plus acOH.  All right so I think that gives us kind of an overview  of the reactivity of the most reactive members of the family,  the acid chlorides and anhydrides as well  as the general properties of the family.  We'll talk about the reaction of acid,  catalyzed reaction with weak nucleophiles for esters  and carboxylic acids as well as the effect  of strong nucleophiles like bases on them next time.
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Good morning. So today I want to begin our discussion of Chapter 22. And Chapter 22 brings us back to carboxylic acids. We talked a little bit about carboxylic acids and their family in Chapter 19. And then we started to introduce some of the chemistry of the carbonyl group in general. Now of course a carbonyl group is embodied in the carboxyl group of carboxylic acids. And so we really needed this understanding to begin to proceed on. So today we're coming back to carboxylic acids. And we're going to talk about themes in carboxylic acid chemistry that involve the same type of reactivity that we saw with ketones and aldehydes. That is the ability of nucleophiles to add to the carboxyl group and to replace the carboxyl group. We're going to come back again later in a couple of more chapters where we start talking about carbon-carbon bond forming reactions and talk about clasin condensations and other additions of carbon nucleophiles that are going to be based on this other property of carbonyl compounds, the acidity of the alpha proton. But right now we're going to just talk about the carboxylic acid family and their properties, the different functions, the different members of this family and their interconversion. And today we'll conclude by discussing the chemistry of acid chlorides and acid anhydrides, the two most reactive members of the carboxylic acid family. So let me draw out the family here or at least the main members, the important players. Of course we have carboxylic acids. And then sort of as a very close relationship we have esters. We've already talked about the relationship between alcohols and water and here in the carboxylic acid you sort of have a half of a water molecule and ester you have half of an alcohol molecule. So they'll have many things in common. Amids of various flavors. I'll just draw the amids structure generically with two sort of generic R groups. They can be alcohol, they can be aromatic, they can be hydrogens and we have various flavors of amid primary, secondary and tertiary. Amid we'll talk a little bit more about them. And these then moving along in the family we have acid chlorides. Acid chlorides are very reactive. We'll be talking about their chemistry. I'm giving you the important members of the family. One could easily envision acid bromides where the bromine is replaced with the chlorine and perhaps envision very similar properties. In practice they're much less commonly encountered but very similar in their reactivity. Acid iodides even more unusual and more reactive. Acid chlorides are a little bit funny. We're not going to talk a whole lot about them. They're still quite reactive but actually a little less reactive than acid chlorides for reasons of resonance stabilization. Also in the reactive members of the family we have anhydrides or sometimes you'll hear them referred to as acid anhydrides. And finally and again of course I'm only taking a limited subset of the family we have nitriels. And if you look at the a nitrile, nitrile is sort of the odd man out in this group in the sense that you would say by comparison I guess if I'm writing everything with S I'll write carboxylic acids. By comparison it doesn't look anything like the other members of the family. It's sort of the odd cousin. And what is in common to all of these is that the oxidation state of the carbon atom is the same in all of these. In all of these family members we're in the plus three oxidation state for that carbon. So even though a carboxylic acid and ester and acid chloride and anhydride have carbonyl groups, carbon double bonded to oxygen and the nitrile obviously does not, there are many similarities in reactivity. Also when we talked about imines I said that in many ways the reactivity of a carbon nitrogen double bond is very similar to a carbon oxygen double bond. In other words, imines have a lot of the same reactivity as aldehydes and ketones. And nitriles now you have a triple bond but again you get this theme of a carbon multiply bonded in this case triply but otherwise doubly to an electronegative atom. All right, let's take a moment to talk about naming compounds and I don't want to get heavily caught up. I think it's very easy for students to obsess about nomenclature and I want you to be able to see the forest from the trees. I really want you to be able to see the anatomical features of the molecule. In other words, be able to recognize the pieces of the molecule because conceptually this is the key to understanding the molecules and it's very easy to quickly end up getting yourself confused with rules of alphabetization and so forth. So here we have an ester and an ester as I just mentioned has one component that comes from an acid and another component that comes from an alcohol and just recognizing those two key components then is key to understanding their synthesis, some of their reactivity and so forth. So let me take a specific ester and we can see how to name it. And so this ester has an acid component from butanoic acid and an alcohol component from ethyl alcohol or ethanol. So we call this ethyl, esters get a first name and a last name. We call this ethyl butanoate and it kind of makes sense on the nomenclature intuitively if you recognize that what we've done is just take the butanoic acid and replace the OIC with OATE. And so they're being able to see the components is important. I'll give us another example along the same lines. So we'd call this compound methylbenzoate. That's OATE on the end because it's derived from benzoic acid. For amides a lot of the thinking is kind of similar. We have two components and we sort of recognize that here's our amide and so we have a component that came from the acid and a component that came from an amine or ammonia. And so I'll give us a couple of examples here. In a way you can think of this as being a parent compound in the sense that this is sort of the parent of any hexanoic acid derived amide that would have a nitrogen on it whether it had substituents or not. So we would call this hexanamide. And you can just think of this as basically putting amide on the end so it's derived from hexanoic acid. So we call this a primary amide because it's derived from ammonia because there are two NHs, two hydrogens on the nitrogen. And I'll give us an example of another amide. Let's actually I'll give us an example of a couple of more amides to let them start on this blackboard over here. So I think that would work. All right, a couple more examples here. So this acid, this amide comes from acetic acid. So we would call this N-methylacetamide. This compound is a secondary amide. And if you're typing out the structure, you would italicize the N. The N means the atom nitrogen. It means that there's a methyl group on the atom nitrogen. So unlike the lower case N when I talked about say, inbutylithium which meant normal, it meant the linear chain, a capital N as I said, typeset and italics but probably just written like I've written it here, means on the nitrogen atom. Take another example here. Common amide, an amide that's often used as a solvent is N-n dimethylformamide. So we have two substituents on the nitrogen so we call this N-n dimethylformamide, all one word. It's a tertiary amide. In other words, it has two substituents on the nitrogen. And one thing to keep in mind, many, many students look at a compound like dimethylformamide and they say, oh it's an aldehyde because I'm used to the C-H-O group. Well, the nitrogen and the carbonyl function together as a pair, they work as a functional group. In other words, we see a functional group, you know, one of the driving concepts in organic chemistry is that groups of atoms closely connected also often have very specific properties. Because the nitrogen is conjugated because it's in resonance and I'll talk more about that in a moment, because it's in resonance with the carbonyl group, this behaves like an amide, not like an aldehyde in all of its reactivity. So just as methylacetamide and methylacetamide is not a ketone and N-n dimethylformamide is not an aldehyde. Is the name acetyl and borma like a proper ion? Okay, great question. Are these the proper names or are these the common names? Anyone want to answer? Common. Common, yeah. So this one would be N-methylethanamide if I wanted to write out the IAPAC name just as we had done there with hexanamide but no self-respecting chemist would call it that. The latter one would be N-n dimethylmethanamide because it's derived from methanoic acid but everyone calls it formic acid. Wait, then would it be alright if we put this instead of the IAPAC name on the test? As I said, students often obsess over nomenclature. You would be hard, no, it's okay and it's scary. It's scary because I literally can hand you a book 500 pages on how to name organic compounds and it's easy to obsess over it. The other reason it's easy to obsess over this is because when it comes down to it, this is simple. I don't mean it's simple to know all of the rules and some of them are arcane. I mean it's something that a computer can easily work through and there's very little higher thought process involved in naming a compound and so it's easy to spend time obsessing over that and not to get on to the stuff that's really conceptual. So don't worry, I won't ask you on a test. Was that the IAPAC name or the common name? Alright, now I'll give you one thing that I wouldn't expect you to obsess over but I was obsessing over just to show you one other example of where we have two different substituents here. So this is another tertiary amide and for this particular one, it actually was an example from your book. It's n-isobutyl n and I'm going to break it with the hyphen here just because I can't write it all out on one line. N-methyl and then what's our carbon chain? 1, 2, 3, 4, 5, pentanamide. I think your textbook must have had butanamide so I'm going to draw it with one fewer carbon here. Butanamide and that was an example from the problems that I asked you to work out as you go along when you're working out, working things out. Anyway, what we've done here is we've named the two halves on the nitrogen and we've alphabetized it but again, I think it's really, really easy to end up obsessing over that and don't get that obsessed. Alright, let's go on to acid chlorides and acid anhydrides. Alright, so let's go on to an acid chloride here, derived from pentanoic acid and again, we're seeing the family relationships here too. This is an acid chloride derived from pentanoic acid so we call it pentano-wheel chloride. We've taken the pentanoic of the acid from which it's derived and we've changed it to OYL. With the common names, you do it slightly differently so this compound here is acetyl chloride rather than acetoyl chloride and it's just how people name it, how it flows off the tongue. And let's do one more, I'll do an anhydride here. This is the anhydride derived from benzoic acid so we call it benzoic anhydride. Alright, last class of compounds I want to talk about in the family is nitriels. And so I'll just take the nitrile that's related to hexanoic acid, the one that has six carbons in it. You might draw it with C triple bond N, you might draw it just as CN, it's the same thing. This is called hexane nitrile so since it's a six carbon chain, it's called hexane and you just put nitrile on it. You don't have to specify the position of the nitrile because being triply bonded, there's no other place that you could put that nitrile group except on the end of it. Again, the small molecules tend to have common names. We also tend to splash the small molecules around like water in the laboratory, acetonitrile is a common solvent, this is acetonitrile, acetone is a common solvent, acetic acid is a common solvent and so you splash them around in separatory funnels and in chromatographic columns and the like. And let's see, I'll give you one more example. So one of the things that we saw when we were talking about naming carboxylic acids was we said when you have different groups, some of them will have lower priority so in general carboxylic acids have higher priority than ketones and aldehydes and nitriles have lower priority than carboxylic acid. So if you have the cyanone, if you have a nitrile group and an acid group, you end up naming it as the substituted acid. So this one is commonly called cyanowacetic acid. All right, well that gives a kind of a quick overview of how we talk about these compounds. I want to talk now about their physical and then their spectroscopic properties because I think that gets us into things that are more interesting and more important. So let's see. Your textbook sort of approaches this from the point of generalities and I decided I would approach our discussion today of the physical properties of compounds from a couple of specific examples that were kind of important compounds. So and this is maybe giving you a little bit of a flavor of my own thinking about the chemistry of the carboxylic acid family. So I decided to start our discussion today with ethyl acetate. Ethyl acetate is of course a widely used solvent. It's present in nail polish remover. You may have used it for liquid liquid extraction in the laboratory. Esters in general tend to have rather nice fruity odors and so ethyl acetate has a strong smell to it that's not unpleasant. Some of the esters like isoamyl acetate have very strong fruity odors so that's just overpoweringly banana. It's one of the components in banana. So ethyl acetate is a liquid. It has a boiling point of 77 degrees Celsius and I thought that might be a nice kickoff point to kind of contrast some of the properties to other molecules and so when I was thinking about molecules that are kind of the same size I figured well ethyl acetate has six heavy atoms, six carbon and oxygen atoms. It's about the same molecular weight as hexane. So by comparison I'd say hexane is a liquid 69 degrees as its boiling point and then if you say well we learned when we talked about Van der Waals contacts that if you have a more linear molecule you get more of Van der Waals contact and of course ethyl acetate sort of has a branch in it you might say maybe it would be a better comparison to compare it to two methyl pentane and two methyl pentane is also a liquid and it has a boiling point of 60 degrees. And so the take home message on this is not surprisingly ethyl acetate has a higher boiling point than molecules of similar size that don't have dipoles in it and it should make sense. I mean you have a molecule that has a molecular dipole in it and as a result you also see differences in solubility and all of this really can be explained by thinking about resonance structures. So I'll just add that the solubility is it's soluble in water soluble to the extent of about 8.3 grams per 100 milliliters and I always find that sort of interesting. I mean on the one hand you expect ethyl acetate to be have solubility in water. We've learned that if you have polar atoms and you have a reasonable ratio of polar atoms to carbon groups you should have some solubility in water and at the same time you may have heard the number 4 that if you have 4 carbons per oxygen or fewer you can think of something as soluble. But here we have no way we have 2 carbons per oxygen and so you think about something like ethanol and it's miscible with water it mixes with water so 2 carbons 1 oxygen. Diethyl ether 4 carbons 1 oxygen is about the same solubility in water but here we have 2 oxygens. Tetrahydrofuran 4 carbons and 1 oxygen is completely miscible with water. So in a way it surprises me it's a little less soluble than you might think. And we certainly can think of it as polar and you can think of it either as oh yeah the bond between oxygen and carbon is polarized and so you can think of it as saying delta plus delta minus or you can think of its behavior in terms of resonance structures and so just as with every carbonyl compound you can write minor resonance structures in which the carbonate a minor resonance structure in which charge is separated like so and I guess I'll be a good person in drawing my lone pairs over here. What's interesting about ethyl acetate and all other esters is you can write a second resonance form like so with a positive charge on this oxygen and so collectively the major resonance structure and the minor resonance structures, the small contributors certainly can explain the polarity of the molecule just as we saw and explained that acetone had a higher boiling point than say isobutylene and yet there's a little bit of unsatisfying why it's not more polar. The one thing that these resonance structures don't really embody is the fact that this oxygen is while it's donating electrons through resonance, it's also pulling them away in the sigma bonds. So in other words we have these two oxygens pulling in opposite directions through the sigma bonds to pull electrons away and for that reason ethyl acetate isn't as polar as you might otherwise think. In other words it's soluble in water but it's not super soluble in water and not miscible in water. It is a polar molecule that has a dipole moment to it but the dipole moment is not huge. It's not huge as say dimethyl formamide which I'll talk to you about in a moment when we talk about amids. All right I want to contrast ethyl acetate. As I said I'm coming at this from the point of view of specific molecules and their properties and sort of what they mean to me. I want to contrast ethyl acetate to a couple of familiar amids and so I'll start with acetamide and so acetamide by comparison is a solid. It's got a melting point of 82 degrees and if you heat it enough so it boils it has a boiling point of 221 degrees. So clearly acetamide even though it's a smaller molecule than ethyl acetate is much stickier and we saw this principle in carboxylic acids when we talked about their high boiling points. Acetamide has the ability to hydrogen bond and so you can form hydrogen bonded dimers and you can get further hydrogen bonding because you have the electronegative nitrogen bound to the hydrogen and so that can make these molecules stick together. Now dimethyl formamide of course doesn't have hydrogen bonding. You don't have any hydrogens on nitrogen and so dimethyl formamide can't participate in hydrogen bonding and yet it too is much higher boiling than ethyl acetate. So dimethyl formamide is a liquid. Its boiling point is 153 degrees. Decomposes to carbon monoxide and methylamine at that temperature so you can't really distill it and it's much more polar. It's got a bigger dipole moment, a bigger dielectric constant than ethyl acetate. It's miscible with water and you really in the case of dimethyl formamide can think of it getting a lot of its properties from that minor resonance structure off on the right. I'm not going to write off all of the resonance structures. I'm just going to write out the key resonance structure here and say you can explain a lot of its behavior by this type of resonance structure. Now this brings up an important point about amides. So this is still a minor resonance structure. But the point is the molecule is always, I'll get to your question in a second, the molecule is always multiple resonance structures all at the same time. These are just different pictures of the same thing. But in the case of ethyl acetate, it's just a little bit of this resonance structure. And in the case of dimethyl formamide, it's a little bit more. It's on the order of maybe 30% of that resonance structure if you needed to have a number in your head. One of the things that's very important to keep in mind about this fact is the fact that this nitrogen in dimethyl formamide and in amides in general is much closer to being sp2 in its properties, to being sp2 hybridized than sp3 hybridized. I'm going to write it as sp2 hybridized here because that really comes as the closest description. It's somewhere in between but it's more like sp2 hybridized. In other words, that nitrogen is not basic like an amine. It's much less basic than an amine because it's participating in resonance. All right. I saw a question. First. What does it say behind the table? Ah, decomposes. DEC is often the shorthand. You'll see chemists write for decomposes. Another question. Yeah. Back to the top of the board. What's the point of some kind of two pentanone? Of two pentanone. Two pentanone, let's see. It's acetone boils at I think 56 degrees. So we're talking somewhere around 80-ish. Oh wait, pentanone. So I'm thinking butanone. So pentanone, yeah, close to 100 degrees. So yeah, I mean even a bigger dipole for there. But the point is if you look at 153 versus 77, it's a big difference. So in other words, ethyl acetates a polar molecule but it's not like a super polar molecule. And by the time we come to the amides, it really is quite polar. If I wanted to make maybe a closer comparison to ethyl acetate, maybe I could also say Nn dimethylacetamide just because let's see, here we have 4, 5. I guess that's a reasonable comparison here. Other questions. All right, I want to take a look at this point at what the IR spectra tell us about the behavior of these molecules in parts so you can get used to recognizing them and in part so you can continue this theme of understanding their properties. All right, so to separate the forest from the trees, we talked before about all the carbonyl compounds. We talked, well except amide, no, I guess we talked about amides. So except acid, chlorides and anhydrides. We talked about esters and aldehydes and acids and ketones and amides and their relative carbonyl stretches. And the main point is you have a carbonyl band somewhere around 1700 wave numbers. And they differ a little bit depending on the nature of the particular carbonyl compound. So amides have their carbonyl typically around 1660, somewhere below 1700 is typical. Typically I'll sort of take a middle ground of around 1660. And so if we compare this, I always like to think of when I hold things in my head for understanding them, I always like to think around one compound. It's kind of the same that you saw in the theme of my talking about acetyl acetate or dimethyl formamide. So if I think of a typical ketone, whether it's cyclohexanone or acetone, I sort of think of a typical ketone as having about 1715 wave numbers. And so you think about this and you say, well this is saying that the nitrogen, that the carbon oxygen double bond stretch is weaker than that of a ketone. So I'd say a weaker CO. And you think about this resonance structure and this minor resonance structure really helps explain that very nicely. In other words, of course, it's not one, it's not the other, it's both and other resonance structures at the same time. But if you look at this, you say, oh yeah, I can understand. We have some single bond character mixed in here with the double bond character. So instead of vibrating at a higher frequency like a stiffer spring, it vibrates at a lower frequency, ever so slightly lower like a less stiff spring. Now if we come over to esters, typical ester, and again, these are sort of generic compounds and generic values, the typical ester is at about 1735 for the carbonyl stretch. So you don't see it very, very different from a ketone, just a little bit different. But where you really start to see things different is by the time you get to acid chlorides and acid anhydrides and this is where I think it's really telling. So you look at an acid chloride and the carbonyl stretch, now is it about 1800. And if you're looking at an IR spectrum, it's 1800s really distinctive. In other words, 1720, 1735, you'd say, okay, I can see differences, I can read the scale, but they're all sort of similar. Amid you'd say, oh 16 or 50, 1660, 1670, you'd say that's significantly different. Then at the other end you look and you'd say 1800, that really starts to look different. And one of the ways you can think about this, there are a couple of ways you can think about it. So obviously the fact that we're at 1800 means here, we have a stronger CO bond. And one way you can think of it is without resonance. You can say, well chlorine is electronegative. You can say chlorine is electronegative, it has a pulling electronegativity of 3.2 and it's basically pulling electron density down. And the big difference between chlorine and oxygen is oxygen is the same row as carbon. Oxygen can give good resonance overlap with carbon. Chlorine, instead of being second row, is third row. It's one row down. You can't get much pi bonding. You end up with very little double bond character, but a lot of that sigma electron withdrawing character, a lot of the chlorine inductively electron withdrawing. And so you can think of the chlorine as pulling electrons down from the oxygen making this bond stronger. It's pulling electron density down. You have lone pairs of electrons. They're pushing back in. I like to, in the back of my mind, I probably wouldn't write this resonance structure, say, elsewhere, but in the back of my mind, I kind of keep in mind the fact that if you take that type of thinking to its logical extreme and say, all right, there is a component of the chlorine pulling electron density away inductively, you can think about this non-bond resonance structure here. And in this non-bond resonance structure, you have some triple bond character. In other words, this is a very minor contributor, but it's basically that oxygen pushing in extra electron density, making that carbonyl bond even stronger, if it's stronger, you have it resonate at a higher frequency. And so you end up at 1800 instead of 1700 wave numbers. It's also very hot electronically. And we're going to see that acid chlorides are the most reactive member of the family with nucleophiles. Now, you have the same type of principle in acid and hydride. So just like the chlorine is pulling away electron density, you have the ASO group is pulling away electron density. And for that reason, in acid and hydrides, the carbonyl stretches also come at a higher frequency than you might expect for say a ketone. And acid and hydride show pairs. 18, 20, and 17, 60 would be typical for a pair of bands in the IR. In other words, you have two stretches, not one. And at first you might say, oh, well, that means that there are two types of carbonyl groups. It's not really that simple. When you have vibrations and they're close together, you get what are called coupled vibrations when they're close to each other in space. Kind of like splitting in the NMR spectrum. And when the vibrations couple, you have them working together. In other words, it's not one carbonyl stretching and the other carbonyl stretching, but it's both of them stretching together. And there are two types of stretches. One of them is an asymmetric stretch. And one of them is a symmetric stretch. So you end up with two bands. All right. And so I think what the IR spectra really are telling us is that acid chlorides and acid and hydride are really special in their properties. And they're special in that you have a lot of extra electrophilicity at the carbonyl. In other words, in other words, acid chlorides and acid and hydrides react with many different electrophiles because that carbonyl has the pulling away, the electron withdrawing group of the acyl group or of the chloride group. So to put it bluntly, if I take acid-teal chloride and I pour it into water, it sizzles. Spatters, it reacts violently. And the reaction gives acetic acid and HCl. Acid and hydrides also react with water not as violently, but they react. I'll just write reacts by contrast to violently. And the acetic N hydride hydrolyzes. Hydrolyzes is a fancy way of saying cleaves, lices by water. And where I really want to compare this to, to start our discussion of the chemical reactivity of the chemical properties of the carboxylic acid family, where I really want to contrast things to is to start to contrast them to say esters and amids. So if I take ethyl acetate and water, there's no reaction. We'll learn later how we can hydrolyze ethyl acetate with water, but it doesn't occur by just mixing ethyl acetate and water. I can qualify that. It can occur over a very, very, very long period, like years, or it could occur if you slowly, if you boil the ethyl acetate and water. But for all intents and purposes, there is no reaction. And that's a very good thing because esters and amids, which I'll write as the next molecule, I'll write NN dimethylacetamide, these are the molecules of biology, not ethyl acetate and NN dimethylacetamide, but of course, esters make up your lipids. The membrane in your, that covers every cell in your body is made of lipids. It's made of long chain fatty acids that are esterified to glycerol that are hooked to other fragments like acetylcholin. And what would happen if at room temperature, at 37, at body temperature, esters reacted with water, is your cells would all be, would all break apart. So it's very fortunate that esters don't automatically, don't without a catalyst or an enzyme, react with water at any appreciable rate at room temperature at 37 Celsius. Amids, it's the same thing. If I take an amid with water, there's no reaction. And again, this is very, very important because all of the proteins in your body are made up of amids. And if they were to react with water, the proteins would break down, you'd just be a pile of amino acids and fatty acids and glycerol. And you wouldn't be you. Now, amids and esters are also widely prevalent compounds, not only naturally, but synthetically. Your nylon backpack is made of a polyamid that chemists made to mimic proteins and initially the protein silk. Because stockings, as I see you're wearing, are, used to be made only available in silk. And silk is expensive and fragile. And at the time of World War II was needed for the war effort. And so having synthetic substitutes was useful. Esters, again, for a very good thing that polyamids like your backpack don't hydrolyze, when it rains your books would fall out and get wet. And polyesters, in addition to polyester fabrics, if you're wearing a polyester warm-up jacket there, are made, are used to make your water bottles. And you're plastic many of the, that's probably polystyrene in your container up front. But your water bottles that you buy, the aquafina or whatever herbal water they sell on campus here, are made of esters. And again, you'd be in a lot of trouble if they hydrolyzed on their own. Would the amide and the ester reaction go forward if we apply some acid to the amide? Would the amide, yes, and we will talk about that in tomorrow's, in our subsequent talk here. So yes, indeed, acids and strong bases can make them react. I want to finish one discussion of spectroscopic properties before moving on to chemical reactivity and focusing on acid fluorides and anhydrides. And I want to, I want to conclude maybe by talking about acetonitrile here and nitriels in general. So we talked about all the carbonyls and we said carbon-oxygen double bonds are centered around 1700 wave numbers. Triple bonds are of course stronger than double bonds. So carbon-nitrogen triple bond is centered at about 2250 wave numbers. They're usually sharp in the IR spectrum. As long as we're talking about acetonitrile, I'll add also no reaction with water. And again, that's in the absence of strong acid or strong base and we'll be talking about that later. I also want to give you a generalization. Remember we were talking about NMR before and I said I like to have a few baseline numbers in my head. The methyl group, whether it's on an acetonitrile or next to any sort of carbonyl, these methyl groups are always about 2 ppm, very close to 2 ppm in the 1H NMR, in the proton NMR. And the reason I like to keep that number in mind is then I can think okay, if we have a methylene, it's just like a methylene in an alkyl chain is a little further downfield, a few more tenths downfield than a methyl group and a methine in an alkyl chain is a little further downfield. We can go a little further downfield. So in general you can say for a hydrogen that's next to a carbonyl or next to a nitrogen, in general about let's say 2 to 3 ppm or 2 to 2.5 ppm depending on how you want to look at it. In other words, a methylene, a CH2 is going to be a few tenths further downfield, a methine will be a few tenths further downfield. I don't want to get overly caught up on the numbers here for spectra. All of, I just want to mention a few things. In the carbon 13, carbonyls in general are way downfield of the amide region, of the aromatic region. So in general you can pick out carbonyls. Carbonyls and ketones and aldehydes typically are around 200 ppm, a little bit more, 220, 190 somewhere around there. Typically for the whole carboxylic acid family, we're talking about 160 to 180 ppm in the C13 NMR. For the whole sort of carbonyl, the whole carboxylic acid family and just for the sake of completion, I'll give you nitriels. You have a carbon-carbon triple bond. It's kind of like an alkyne but you have an electronegative atom so you're talking about 115 to 120 ppm. All right. There, organic chemistry is about making stuff, at least a big part of it. And there are chemical reactions to interconvert all of the members of the carboxylic acid family. Acid chlorides, acid anhydrides, esters, carboxylic acids, amides and even nitriels can be interconverted to other members of the family, to nitriels, to esters, to carboxylic acids, to acid chlorides, to acid anhydrides. Now, if I were to say, okay, how many different, just if I figured one reaction for each of these and I think I've named six members of the family going into any other six members of the family, I basically would end up having a minimum of 15 different reactions and there are, of course, more to interconvert these members of the family. And so the first thing you might think is, oh my God, this is overwhelming. How can I possibly understand all of these reactions, all of these reagents? And the answer really becomes by thinking mechanistically, understanding the principles and understanding the general reactivity of different molecules. So I want to give you some generalization here before we dive into specifics. And so if we have some general member of the family, and nitriels are kind of the oddball, so I'm going to leave them out. We'll talk about them at the end on the next lecture. And we have some nucleophile, NU minus or NUH. Sort of a very, very generic type of species. Water, of course, was NUH. It was OHH. In general, a common theme is that the group on the carboxylic acid can under some conditions get replaced. It can get displaced by a nucleophile. And if I'm going to write a balanced equation, I would also say plus X minus or HX. And that's not meant to be a functional equation at this point. This is meant to be a generalization. And now I want to start to put structure in some specific to this. And so what I would say is this occurs with basic nucleophiles. So in other words, species like alkoxide, RO minus, hydroxide, HO minus or OH minus, and let's say amines. I'll write it as R2NH, but I'm not meaning specifically a secondary amine. I could mean a primary amine or I could mean ammonia. Or, so in other words, in general, members of the carboxylic acid family in general can react with good nucleophiles or with good electrophiles. And of course, what do I mean by good electrophiles? Well, good electrophiles are those ones that sizzle or react vigorously with nucleophiles. So specifically in this family, I'm talking about acid chlorides and acid anhydrides. So that's sort of one generalization that I'd make. And the other generalization that I would make is that weakly basic nucleophiles. And what do I mean by weakly basic nucleophiles? Well, we talked about these with ketones and with aldehydes. We're talking about things like alcohols and water. So I'll write ROH and water. And I'll say that they can react with less reactive electrophiles. And what do I mean by less reactive electrophiles? Well, I mean the members of the family that don't react with these, that don't have that electron withdrawing group, that don't have that carbonyl shifted up to 1800 or thereabouts in the IR spectrum. So we're talking esters, acids, amides, and nitriels. And they can do this if they have some help with strong acid catalysis. And what we're going to see in the next lecture is that a strong acid can protonate the carbonyl of an ester or a carboxylic acid or an amide or can protonate a nitrile group and take something that's only a weak electrophile and turn it into a strong electrophile in a mechanism that we end up going through. All right. So that generalization serves as a framework. And now I want to go on to some specifics and to talk about specific reactions of acid chloride and acid anhydrides. And so by way of a specific example, I'll take acetyl chloride. And I want to write a balanced equation here. Acetyl chloride, let's look at its reaction with a simple amine, methyl amine. Acetyl chloride can react with two molecules of methyl amine to give dimethylacetamide. And organic chemists are always bad about balancing equations, but I will balance it. And dimethylammonium chloride, dimethylamine hydrochloride, ME2NH2 plus Cl minus as a salt. What I want us to be able to do, because this is the archetype for all of our thinking about this chemistry, I want us to be able to think and understand our way through these mechanisms. And particularly to get the big picture, because sometimes the details aren't going to be that important. So here's our acetyl chloride. We know that that carbonyl is electrophilic. And we know that dimethylamine is nucleophilic. It has a lone pair of electrons. It wants, it's willing to share those electrons. We can attack very much like the theme we saw in imine formation chemistry. We can attack this extra electrophilic carbonyl. And at this point, I'll write this, I'm going to write this as irreversible. It's always a little bit of a judgment call. But if you have something where you're really, I guess I can write the first step as reversible, although honestly I'm not going to sweat about it. So I'm just going to write this one way. Okay, so at this point though, the big picture, the big idea is now just as in imine formation, at this point we formed a tetrahedral species. We formed a tetrahedral intermediate. And this and the next step really become the big idea here, the next part of the reaction. Yes. Oops, did I forget an age? No, I drew in an extra lone pair. You mean here? Ah, wait, where? Oh, okay, I was meaning to, I'm sorry, I was meaning to draw in dimethylamine. So dimethyl, let's do two molecules. We could do it with methyl amine. But let's do two molecules of dimethylamine react to form the dimethylamide and dimethylammonium chloride. And let's have our two methyls on the nitrogen with a hydrogen and a lone pair add to the carbonyl attack to give a tetrahedral intermediate. And the big point about this is our tetrahedral intermediate is going to be unstable just as we saw in imine formation where the hemiaminal is not a stable compound, it's not an isoble compound. That same theme emerges here. Question? Yeah? Why do we need two equivalents? You're going to say why do we need two equivalents? Great. All right. Just as in imine formation, your tetrahedral intermediate is unstable. I'll be a good person for one moment here. And I'm going to draw in all of my charges and all of my lone pairs of electrons. The tetrahedral intermediate can break down. It doesn't stick around. It can kick out chloride. Chloride is a good leaving group. Chloride gets expelled. But remember, this nitrogen here in an amide is not an amine nitrogen. It is not a basic nitrogen. It is not an sp3 nitrogen. It doesn't want to have a proton on it. It is very acidic and it's going to give up that proton to anything that's basic. And we have dimethylamine present. And so our dimethylamine is the strongest base in the house. And dimethylamine is going to pull off that proton to give you your dimethylacetamide plus dimethylamonium chloride. Well, I guess I've already written my chloride so I'll just balance my equation and say plus the dimethylamonium product. And if I were to not have that extra equivalent of dimethylamine around, halfway through all of my dimethylamine, the remaining dimethylamine would be protonated as the hydrochloride. Now, the reason I'm saying not to get too bent out of shape on this mechanism, the big picture, nucleophile attacks, we get a tetrahedral intermediate, the tetrahedral intermediate breaks down, protons shuffle around. Your textbook writes these two steps in reverse. Or more specifically, your textbook on closely related reactions and in the homework writes the deprotonation step at the tetrahedral intermediate. I don't think that makes as much sense on the basis of acidity. Don't get bent out of shape about it one way or another. The big picture nucleophile attacks, tetrahedral intermediate breaks down, protons shuffle around. If they shuffle around beforehand, it's not that big a deal. Other big picture item from a synthetic point of view, chemists often want to go ahead and not waste the valuable amine. Sometimes they'll add a base that's sacrificial, a tertiary amine like triethylamine or pyridine is added as a base. I'll write parenthesis pyridine here is added as a sacrificial base so you can use only one equivalent of amine. All right. This same basic principle of reactivity of acid chlorides applies with all other species whether it's strong base, whether it's basic nucleophiles like amines or weakly basic nucleophiles like alcohols and water. Acid chlorides react vigorously. So for example, if I take benzo-wheel chloride and I take ethanol, they react just like I said, acid-tyl chloride reacted to form with water. They react to form an ester ethylbenzoate. And again, if I want to balance my equation, HCl would be a byproduct. Very often in this chemistry as well, often you'll use pyridine as a base. Pyridine triethylamine can be used as well, disapropyl ethylamine as well to react with the HCl. So just for the sake of writing a balanced equation, if I take my benzo-wheel chloride, plus ethanol plus pyridine, I'm going to go ahead and get ethylbenzoate plus pyridinium hydrochloride. And on a preparative level, in the laboratory, you would probably carry out an aqueous workup in a separatory funnel in which you would extract the ethylbenzoate into the organic phase. You would wash away the pyridinium hydrochloride salt in the aqueous phase, and then you would dry your organic phase over magsulfate and filter and concentrate to get your ethylbenzoate. And you can imagine all sorts of other reactions of acid chlorides. We already saw that acetyl chloride reacted with water to give acetic acid, or you could use some sodium hydroxide in there to get ethyl acetate out of there, sodium acetate out of there. You could react sodium acetate with acetyl chloride to get acetic anhydride. And so maybe I will just very quickly sketch out these reactions, acetyl chloride plus H2O goes to acetic acid plus HCl, acetyl chloride. And you should be able to think your way through mechanistically on all of these acetyl chloride plus 2 hydroxide anion goes to acetate anion plus water H2O plus chloride anion. And I'll just write one more balanced equation, acetyl chloride plus let's say sodium acetate just to the hell of it I'll write in the counter ion here goes to acetic anhydride plus sodium chloride. All right, as disparate as all of these reactions sound, they're actually all the same basic principle. Once you get the idea of a nucleophile attacking your acid chloride to form a tetrahedral intermediate, the tetrahedral intermediate breaking down and some protons shuffling around, you end up comfortable with all of this chemistry and you see that it really, really falls into the same category. Now I wanted to mention two last points. One of these is the trends we've been talking about. We said that acetyl chloride is more reactive or in general I'll write acid chlorides are more reactive than anhydrides and those are more reactive than esters and those are more reactive than amides. And that makes sense if you consider the pKa of the conjugate acid of the leaving group. In other words, HCl is the conjugate acid of chloride as a leaving group. Its pKa is negative 7. In other words, chloride is a very good leaving group even in this or in this addition elimination chemistry. The pKa of a carboxylic acid, the conjugate base of a carboxylate leaving group in anhydrides is on the order of 4 to 5. While it's much less of a good leaving group than chloride, remember this is addition elimination chemistry, not S into displacement chemistry, it's still a good enough leaving group. By the time we come to an alcohol, the conjugate base of alkoxide leaving group, we're talking pKa 16 to 17 here. Now we're not so good and then by the time we come to an amine as our leaving group here, now we're at about, depending on which number you use from your textbook, about 38 and so now we've gone, we basically spanned five orders of magnitude here in our peak, or spanned pardon me, almost 50 orders of magnitude here, 45 orders of magnitude in our chemistry here. All right, the only sort of odd ball in this mix are carboxylic acids and the reason I haven't immediately included them is there's one special caveat. You'd say for many purposes and we'll see in fissure esterification and transesterification, esters carboxylic acids are the same, but in the case of a base, often you will have a base deprotonating a carboxylic acid to give you a carboxylate and then you end up really, since the carboxylic acid is acidic, you really have to think about O2 minus, which is just not a leaving group. So there are certain cases where you're talking about say an ester will react with an amine if you warm it, but a carboxylic acid is just going to do proton transfer with an amine, unless you heat the absolute hell out of the thing to hundreds of degrees. All right, last thing I want to do is talk about the reactivity of anhydrides and really for many, many purposes the reactivity of anhydrides is like that of chlorides, acid chlorides, except they don't sizzle with water. So they're less reactive. So if I take acetic anhydride and dimethylamine and again I'll write a balanced equation, I get dimethylacetamide and I also get plus dimethylamonium acetate. By the way, you will often see this written as acetic anhydride AC2O and sometimes you'll see it written here as an ac group, but hence I'm just writing it here as OAC. Now for this same reason and the same idea we talked about when we were talking about the chemistry of acid chlorides, because you're using a second equivalent of amine as a base in this chemistry because it's getting protonated by the acetic acid byproduct of reaction, often you will use a sacrificial base like pyridine. So I'll write a balanced equation and at this point I'll use the shorthand for acetic anhydride. So I'll write acetic anhydride plus methylamine plus pyridine. Often you would see these as reagents written above an arrow goes to ac same product here and then if I want to write a balanced equation I'm going to get pyridinium acetate as my byproduct. And all of these principles of reactivity then apply to things like alcohols as well. So if I take acetic anhydride and ethanol and again I'll just use this common shorthand for acetic anhydride plus ethanol just as we saw it reacted with water to give acetic acid, acetic anhydride reacts with ethanol to give ethyl acetate and again there are many ways you could write ethyl acetate. I'll just write it here OET plus acOH. All right so I think that gives us kind of an overview of the reactivity of the most reactive members of the family, the acid chlorides and anhydrides as well as the general properties of the family. We'll talk about the reaction of acid, catalyzed reaction with weak nucleophiles for esters and carboxylic acids as well as the effect of strong nucleophiles like bases on them next time.
carbon double bonded to oxygen and the nitrile concepts in organic chemistry is that groups of anhydride here. This is the anhydride derived physical and then their spectroscopic properties depending on the nature of the particular the chemical reactivity of the chemical