 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. Release 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 a 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 a 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 fluorides 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 nitrials 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 an 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 and so we'd call this compound methyl benzoate that's OATE on the end because it's derived from benzoic acid. For amids a lot of the thinking is kind of similar. We have two components and we sort of recognize that here's our amid 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 amid that would have a nitrogen on it whether it had substituents or not so we would call this hexanamid and you can just think of this as basically putting amid on the end so it's derived from hexanoic acid. So we call this a primary amid 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 amid. Let's actually I'll give us an example of a couple of more amids so let me start on this blackboard over here. A couple more examples here. So this acid, this amid comes from acetic acid so we would call this N-methylacetamide. This compound is a secondary amid and if you're typing out the structure you would, I talusize 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 N-butylythium 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 amid, an amid 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 amid, 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 amid not like an aldehyde in all of its reactivity so just as methylacetamide N-methylacetamide is not a ketone N-n-dimethylformamide is not an aldehyde. Okay great question, are these the proper names or are these the common names? Anyone want to answer? 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 chemists 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. IAPAC name on the test. As I said, students often obsess over nomenclature. You would be heart, 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? All right. 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 them but again, I think it's really, really easy to end up obsessing over that and don't get that obsessed. All right, let's go on to acid chlorides and acid anhydrides. 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 O-Y-L. With the common names, you do it slightly differently so this compound here is acetyl chloride rather than aceto-wheel 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. Last class of compounds I want to talk about in the family is nitrials 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 and 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 cyan, 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. It 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. Your textbook sort of approaches this from the point of generalities and I decided I would approach, 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 2 methyl pentane and 2 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 that's 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 with 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 carbonyl a minor resonance structure in which charge is separated like so and I guess I'll be a good person and draw in 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 unsatisfying why it's not more polar so 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 not miscible in water it has 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 it's boiling point is 153 degrees decomposes to carbon monoxide and methyl amine 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 like 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 decomposes DEC as often the shorthand you'll see chemists write for decomposes. Another question of 2 pentanone. 2 pentanone let's see it's acetone boils at I think 56 degrees so we're talking somewhere around 80ish 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 you know quite polar if I wanted to make maybe a closer comparison to ethyl to ethyl acetate maybe I could also say NN dimethyl acetamide just because let's see here we have 4 or 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 part so you can get used to recognizing them and in part so you can continue this theme of understanding their properties. 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 ethyl acetate or dimethyl formimid 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'd 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 at 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 1650, 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 appalling 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 anhydride so just like the chlorine is pulling away electron density you have the AESO group is pulling away electron density and for that reason in acid anhydrides the carbonyl stretches also come at a higher frequency than you might expect for say a ketone and acid anhydrides 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 and so I think what the IR spectra really are telling us is that acid chlorides and acid anhydrides 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 acid chlorides and acid anhydrides 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 to chloride and I pour it into water it sizzles spatters it reacts violently and the reaction gives acetic acid and HCl acid anhydrides also react with water not as violently but they react I'll just write reacts by contrast to violently and acetic anhydride 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 acetyl colon 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 and 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 your plastic many of the it'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 amid yes and we will talk about that in tomorrow's in next 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 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 1 H NMR and 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 and 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. 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 basic nucleophiles or with good electrophiles. 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 and hydrides. 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 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 electro 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. 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 chlorides 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 and 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. Oops, did I forget an H? 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 dim, let's do two molecules, we couldn't do it with methylamine 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 isolable compound, that same theme emerges here. You're going to see, 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 dimethylesetamide plus dimethylamonium, 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. 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 benzoyl chloride and I take ethanol they react just like I said acetyl chloride reacted to form with water, they react to form an ester ethyl benzoate 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 benzoyl chloride plus ethanol plus pyridine I'm going to go ahead and get ethyl benzoate 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 ethyl benzoate 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 ethyl benzoate. 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 for 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. And 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, 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 have and 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. 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 dimethylammonium 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 methyl amine 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 of these principles of reactivity then applied 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 AC OH. 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.