Lecture 09. Reactions of Carboxylic Acids, Esters, Amides, & Nitriles.
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. 
 Today we're really in the heart of the chemistry of the carboxylic acid family. Last time after talking in sort of generalities about their chemistry we introduced the most reactive members of the carboxylic acid family. We introduced acid anhydrides and we introduced acid chlorides and we talked about their chemistry. Today we're going to focus on all of the remaining members of the family. We'll talk about some of the chemistry of carboxylic acids that we haven't seen before. We'll talk about the chemistry of esters and we'll talk about amids and nitrials. And these are all less reactive than acid chlorides and anhydrides. So if I wanted to make some generalization here's a generic ester structure. Here's a generic carboxylic acid structure. And what I would say is in general these structures are less reactive. These functional groups are less reactive to nucleophiles than acids and acid chlorides. And acid chlorides and anhydrides let's say. And so let me maybe start with an example that shows a similar type of reactivity but it's a much less great degree of reactivity. Let's look at the reaction of a simple ester and I think for today for all of our examples I'm going to be giving very small and simple compounds just because we're going to be writing out a lot of structures. So let's take a look at the simplest typical ester methyl acetate. The reason I say typical ester is formates are a little different formic acid although it's a carboxylic acid is a little more reactive but acetates and propionates and various other acids all are kind of the same. And let's take ammonia. Now when we were talking about nucleophiles before we talked about species like ammonia and hydroxide as basic nucleophiles. These aren't super basic nucleophiles like Grignard reagents and hydride reagents but they're not things that are base only in name. And ammonia is a good enough nucleophile that it will react with esters and so we undergo a reaction to get acetamide and the other product of the reaction is methanol. So we call this reaction an ammonolysis meaning a lysosacleavage by ammonia. We've already mentioned the term hydrolysis cleavage by water. Now what I really wanted to be I've been trying to keep everything simple up here what I really wanted to draw up here was an aminolysis. These names don't matter a whole heck of a lot. An aminolysis would be within a mean like R with say a general structure of R and H2 or even a secondary amine although they're much less reactive so there's a primary amine. But I'll show you since I'm trying to keep all of our drawings simple today I'll show you an ammonolysis instead of an aminolysis. And the mechanism for this I'm not going to write it out in gory detail because you've seen all of the principles with acid chlorides and anhydrides. The ammonia is a nucleophile it has a lone pair of electrons on it. It can attack the carbonyl even though the carbonyl of an ester is not nearly as electrophilic as the carbonyl of an anhydride or a chloride that has a good electron withdrawing group pulling away electron density. It can attack. We excel methoxide we transfer a proton if you want more detail you can see your textbook for a mechanism for this reaction. But the general gist is that the carbonyl of an ester group is sufficiently electrophilic to react with a basic nucleophile like ammonia or later on I'll show you hydroxide. Now for all intents and purposes the electrophilicity of the carbonyl group of an acid is really very similar to an ester but there's one big, big difference. A carboxylic acid has an acidic proton so whereas the first thing that happens when you mix an ester with ammonia is that the ammonia attacks the carbonyl it's not a fast reaction it'll occur over hours of time. This is the reaction of Windex when you clean fingerprints off of the window because grease the oils in your skin are esters of glycerol they're triesters you've heard of triglycerides. Windex has ammonia and that ammonia is cleaving the ester groups to break them down to smaller pieces fatty acid, amides and glycerol so that's ammonalysis. Now if by comparison I take acetic acid and I mix it with ammonia you might think well it's going to be very similar but acetic acid has one thing that's very different than methyl acetate it's got an acidic proton so if I mix acetic acid and ammonia you get a salt you get ammonium acetate and for the most part you don't get nabbed. Now I say for the most part because under the right conditions if you heat the crud out of ammonium acetate if you heat the crud out of acetic acid and ammonia at high temperature you will eventually get some acetamide out of there. This is not a what I would say useful reaction a reaction that synthetic chemists would typically use to make an amide but you will get some but the first thing that will happen and the thing that would happen under typical conditions would be salt formation not amide formation. Can you make the alcohol group a good leaving group by protonating it? Can you? Ah you're getting ahead of me. Can I make the alcohol group a good leaving group by protonating it? The answer is yes and sit tight in your seat. Alright so we already talked about the concept of pKa and we talked about the concept of pKa specifically of the conjugate acid. We said that the pKa of the conjugate acid of ammonia or the conjugate acid of an amine was about 10 or 11 and that's a typical sort of moderately basic compound kind of the same pKa as hydrosyanic acid. Cyanides another species that as you just encountered on the quiz is a reasonably good nucleophile. Now by contrast if you go to something like water then you have something that's much less basic much less nucleophilic. The pKa of the hydronium ion of the conjugate acid of water is negative 1.7. Water is very weakly basic. It is basic but sort of in name only. So as I mentioned in our previous discussion of esters if I just mix an ester and water you have no reaction and I also mentioned that that's fortunate for you because all of the lipids in your body all of your cell membranes are made up of esters and so if they cleaved at 37 degrees Celsius if they underwent hydrolysis at any appreciable rate you'd be in trouble. Now by similar token and again I'm using methyl acetate I'll use it a lot today just because it's a nice example and then I'll use acetic acid sort of in acetamide sort of as counter points but of course these could be any esters and any acids. So by very similar token if I mix methanol and acetic acid again the carbonyl is moderately electrophilic for an ester it's moderately electrophilic for an acid but water and alcohols are very weak bases and very weak nucleophiles. And remember when we're scanning over pKa's and I'm tossing out numbers like negative 2 or negative 3 for the pKa of the conjugate acid of an alcohol or negative 1.7 for water and positive 10 we're on a log scale. In other words we're scanning over 12 orders of magnitude what is that 10 to the third is a thousand million billion trillion orders of difference in basicity a trillion orders of magnitude or a trillion times different in reactivity to a first order approximation as nucleophilicity tracks with basicity. If a reaction of ammonia and methyl acetate takes a minute roughly then you know ball park it you're going to say a trillion minutes for the reaction of water and methyl acetate or a trillion minutes for the reaction of methanol and acetic acid. I don't know about you I know for me I don't expect to be around here a trillion minutes from now so they're not going to react. All right so no reaction. All right so chemists love to make stuff happen they love to make what they want to have happen happen. And so if you want acetic acid to react with methanol as was alluded earlier you do something that can protonate the carbonyl group. That's going to make the carbonyl group like a trillion times more electrophilic. In other words you protonate it in the presence of a very strong acid. So I could write that if I take acetic acid and I mix it with methanol in the presence of sulfuric acid I get methyl acetate and I get a molecule of water. So then chemists as I keep repeating are very bad at balancing equations but it's really important to keep this in mind because this reaction is an equilibrium. And so if I go ahead and just mix them and don't have a lot of methanol just a little bit of methanol I'm going to have an equilibrium in the middle. Sulfuric acid and methanol for all intents and purposes is similar. I got to have a lot of methanol or I've got to do something to soak up the water. And sulfuric acid actually really likes water so that's one of the ways to make it hang on to drive the reaction is just to use more than a little pinch of sulfuric acid. Question? The H2SO4 is indeed a catalyst and technically you don't need to use a whole mole equivalent. In practice sulfuric acid often is used in a reasonable quantity for exactly the reason I said because it tends to bind to the water it helps drive the reaction as well but it's not consumed by the reaction. So in fact chemists when they write a reaction like this will often show solvent and reagents with an arrow and so you'll often see this written as sulfuric acid sometimes you'll see it written as a catalyst you know with parenthesis cat and often you'll see methanol just indicated it's the solvent. Now with acetic acid I might use as little as possible but if I have a valuable carboxylic acid I'm probably going to use a whole big splash of methanol a whole pot of methanol a whole flask full of methanol for a couple of grams of acid. And so here's our product of the reaction. Now this reaction's been known for a long time it was discovered or invented by Fisher and so it's called a Fischer esterification. Sometimes people will use sulfuric acid for the reaction sometimes they'll use another strong mineral acid like hydrochloric acid. Ironically in the laboratory if I want dry hydrochloric acid in methanol not in water so I don't want to go to a bottle in the laboratory in the stock room and get HCl with water in it one of the ways I'll do that one of the ways I'll get anhydrous HCl in methanol is to throw some acetyl chloride into my methanol it'll react to give HCl in methanol and methyl acetate and those all will be just the methyl acetate I might not pay attention to and then I might use this as a reaction to take a big valuable carboxylic acid and make a methyl ester out of it so this is often how we roll in the laboratory. Alright let's take a look at the mechanism of the reaction. So in acid protons go on and off all different lone pairs any lone pair that's weakly basic is going to get protonated it's an equilibrium. If I throw sulfuric acid a strong acid into methanol it dissociates it protonates the methanol so my strongest acid in methanol is protonated methanol it's the leveling effect you learned about in general chemistry. So protons go on protons come off when the carbonyl gets protonated the carbonyl goes from being moderately electrophilic to being very electrophilic. We show the flow of electrons by drawing a curved arrow from the electrons to the hydrogen representing the formation of a new bond electrons flow back on to the oxygen atom we have an equilibrium we generate protonated acetic acid plus methanol I'll put my electrons I'm not always good about writing my lone pairs but I'll put my lone pair of electrons back on to the oxygen where they belong. Now this process the protonation of the carbonyl has made it into a good electrophile now it's ready to react even with a relatively weak nucleophile like methanol. Electrons flow from the lone pair on methanol to the carbonyl carbon atom we start to form a bond but concurrently because we can't have 10 electrons around the carbon concurrently electrons flow up on to the oxygen atom so we get an OH group here and we get a methoxy group with a proton and a positive charge on it and another OH group and I will try to be as good as I can about keeping track of all of my lone pairs of electrons so we form the tetrahedral intermediate and in strong acid protons go on protons come off protons go on and off every lone pair of electrons and so you can think of it as a proton being directly transferred among there I probably think of this more as being mediated by solvent I'd say that's a better way to think about the process and so in our equilibrium we have lots and lots of methanol around protons flow on protons flow off I will draw a curved arrow representing the flow of electrons back to the methanol doesn't matter which side I write the proton on which side I write the lone pair of electrons on I'm representing a tetrahedral oxygen atom and oxygen atom with four substituents equally disposed about it I guess you'd call it trigonal parameter for the geometry of the oxygen. Alright so that sort of takes us to an uncharged tetrahedral intermediate and this looks a heck of a lot like a geminal diol if you think about it and the common theme in all of this chemistry that we've talked about is these types of tetrahedral intermediates these types of geminal diols are not generally stable. The end of last lecture at the end when we were talking about acetals or in the previous lecture Hemiacetals I mentioned glucose a cyclic example that was stable we'll see a tetrahedral intermediate that's stable on the discussion section where you actually have it as a low energy species but in general tetrahedral intermediates are not stable they're not something that you can isolate or put in a bottle they're just a high energy species a stable stable enough that it's in an energy well stable enough that it can sit around for a microsecond but not stable enough that you could put it in a bottle and so our reaction continues in strong acid protons come on protons go off you put a proton back on the methoxy group we're just on the backwards pathway and so I'm going to continue forward protons come on and off every lone pair of electrons and so now we've protonated one of our OH groups it doesn't matter which one gets protonated they're both equivalent remember we're just tetrahedral about this oxygen now just as we had the attack we can have a breakdown now with the expulsion of water electrons flow down from the oxygen we can't stop at that point because that would force us to have 10 electrons around carbon carbon can't accommodate 10 electrons and so we're going to break down actually I am going to good person and write this mechanism on different lines so give me a moment here I'm just going to continue to balance here and so I will write the breakdown of this tetrahedral intermediate in the next step all right so as I was saying electrons flow down from the oxygen they flow back onto the oxygen this gives us a molecule of the protonated methyl ester and we have expelled a molecule of water and our final step is the very reverse of the first step of the reaction in the first step we put a proton onto a carbonyl in the last step we take a proton off of a protonated carbonyl we're in this vast sea of methanol remember this is an equilibrium reaction if we don't have a lot of excess methanol you're going to get only partial conversion to the ester so we have a ton of methanol floating around our methanol which in protonated form served as the catalyst is now going to accept a proton our protonated methanol at the very first step of the reaction was consumed our acid catalyst was consumed in the very last step it is regenerated and so those six steps constitute the mechanism for our fissure esterification they constitute the mechanism for ester formation thoughts or questions? so your question is why does it protonate this oxygen? why is this oxygen protonated? why is this protonated? because when we push electrons down over here it ends up with a positive charge on the oxygen now remember in the back of your mind when you see this structure as we just saw in the quiz there are multiple contributing resonance forms so that is one resonance form think in your mind for a second about two other resonance forms you can picture another resonance form in which the positive charge is on this carbon and a third resonance form in which we have a double bond to this oxygen single bond to this oxygen and a positive charge on this oxygen and collectively all three of those resonance structures make up a picture of the actual species just as in your oxo-carbenium ion I asked you to draw one structure although it was fine if you drew two resonance structures or it was fine as a matter of fact if you draw any of the three resonance structures any of the two resonance structures so we are just thinking about one of the different pictures that are present in part because if you look at this it is already a long mechanism and so you are sort of holding in the back of your head all of this relevant stuff all right any other questions that I want to talk about the reverse reaction the hydrolysis of esters remember fissure esterification is an equilibrium so if I take and again I am keeping my whole lecture really really simple with simple small molecules if I take methyl acetate and I treat it now with water and sulfuric acid I am going to hydrolyze it to acid acid plus methanol just the reverse of the reaction I could write it like this I could write it like this saying I am treating it with sulfuric acid in water it is all the same thing and since this is so identical to what we just saw at this point you should be able to write a mechanism for acid catalyzed ester hydrolysis I will leave that to you it is identical to the mechanism that I just wrote up but in reverse and you can figure that out all right I want to move on to a little bit of other chemistry of esters carboxylic acids and then talk about amides and nitriels and again I will keep our keep things kind of simple and general esters as I said are moderately electrophilic they react with strong nucleophiles if I treat an ester with sodium hydroxide potassium hydroxide for most intents and purposes these are equivalent in water I get the carboxylate salt I get the alcohol you call this reaction saponification it is a reaction that mankind has been doing for hundreds of years before we had organic chemistry it is the making of soap when you take a fat which is a triester of glycerol 1, 2, 3 propane triol with 3 long chain carboxylic acids esterified on and you stir it with sodium hydroxide that's Lai Drano the sodium hydroxide hydrolysis saponifies the glycerol esters to get the sodium salts of the carboxylic acids that have greasy tails and polar head groups and like both water and grease which is very good for getting clean in the shower makes my cells so reaction here same same principle as we saw in the aminolysis I kind of wanted to when I was talking about this and thinking about where to present it I kind of wanted to present it after we did the water the acid promoted hydrolysis but mechanistically it's right up there with the aminolysis and aminolysis we talked about in other words here's our ester group hydroxide is a strong is a good base a moderately strong base relatively strong base it's a good enough nucleophile it attacks our carbonyl I'll give you a little bit of an abbreviated mechanism here only showing relevant lone pairs we get our tetrahedral intermediate our tetrahedral intermediate is going to break down it kicks out the OR group and again I'm just skipping a few lone pairs here this gives rise to the carboxylic acid plus the alkoxide and the alkoxide is basic and so the alkoxide reacts to form the carboxylate and again I'm not going to write out every curved arrow and every step in painful detail but the carboxylate reacts to give you the alkoxide salt and the to give you the the alkoxide reacts to give you the carboxylate salt and the alcohol and in a preparative sense if I carry out this reaction in the laboratory and I want to isolate my carboxylic acid a very common laboratory procedure to saponify an ester with sodium hydroxide then wash the aqueous layer that contains the carboxylate salt to remove the alcohol and any unreacted ester to extract it with ether to wash it with ether and then very commonly in the laboratory you will acidify with some strong acid in water like HCl or H2SO4 and isolate from there the carboxylic acid sometimes in the laboratory it will precipitate out alright so that gives us a little bit of an overview of carboxylic acids and of esters and now I want to move on to the last members the last main members there are plenty of other members in the carboxylic acid family but I want to move on to the last main members of the family on to amids and nitriels amids I'll write them in general form with two R groups here that could be two hydrogens in which case we have a primary amid a hydrogen and an R group which case we have a secondary amid or two R groups in which case we have a tertiary amid nitriels look very different and yet in some ways are very similar both of these compounds are generally less reactive toward nucleophiles than esters and I think it's kind of easy at least to compare an amid to an ester we already saw this in the IR the stretching frequency for the amid carbonyl is lower there's less double bond character the nitrogen of the amid is less electronegative than the oxygen of the ester the nitrogen of the amid is better able to donate in electrons by resonance to the carbonyl making it less electrophilic and so a general principle is that amids and nitriels generally react less quickly and so if I tried to try to epitomize this with a reaction and again I'm going to write very simple compounds so I will write a set of my but again this could be any amid if I imagine treating it with sodium hydroxide in water like we did with our ester in saponification how would I epitomize this I'd say long time or heat to make it react so let's say delta or long time would be how I'd describe this and again we get hydrolysis we get cleavage by the sodium hydroxide to the carboxylate salt and in this case since we have a primary amid to ammonia now what do I mean by long time well actually the drain oh is which I mentioned for ester cleavage is a good example when hair hair you know you get your drain clogged up with hair is made up of protein which are polyamids when I throw drain oh down the drain it doesn't clog the unclog the drain instantly the drain oh sits with the hair and the grease that are down the drain for a number of hours before it unclogs it in the laboratory if you want to speed this reaction along you could boil your sodium hydroxide with an amid but unlike my comment about trillions of seconds for the water promoted hydrolysis of an ester the reaction occurs even at room temperature at a reasonable rate on the laboratory time scale and again nitrials maybe a hair less reactive than amids I know that that problem comes up on your sapling and but honestly I don't think of them personally as being very different so I can say sort of ditto if I take acetonitrile and treat it under these conditions with sodium hydroxide in water maybe with heat or a long time you know a few hours I'll get again sodium acetate plus ammonia all right by by now you should be reasonably strong in your mechanistic understanding of carboxyl compounds and maybe I'll just give you a quick quick abbreviated tour of some of the mechanisms here your textbook has them in more detail if you want but all of the principles that you can think about are similar hydroxides a reasonably good nucleophile it's it's basic it can attack we can kick up form a tetrahedral intermediate and in part in part here I really don't want to lose the forest from the trees this is the gist of this mechanism your textbook writes the next step in the mechanism as kicking out NH2 minus I think it's okay to think about that the realities maybe a little bit more complicated in some cases one can see died deprotonation occurring but I think I think in terms of your thinking right now it's fine to think about this anyway so that gives us our carboxylic acid and our amide anion the amide anion is very basic you can think of it as pulling off a proton on the carboxylic acid to give you the carboxylate plus ammonia remove the Click it 그 And for nitriels, again, I don't want to get fantastically into a whole lot of mechanism here. And so maybe I'll just sort of start us out here on the mechanism. There's a lot of proton shuffling that's going on. But the gist, remember the theme that I talked about in carbon nitrogen double bonds is basically in very many ways they're like carbon oxygen double bonds. And in a similar way, carbon nitrogen triple bond is very much like a carbon yield or a carbon nitrogen double bond. And so if you look at acetonitrile, you can think of it. So now we're looking at the hydrolysis of nitriels. You can think of this as being very similar. In other words, hydroxide adds, we kick in electrons. You get a negative charge on nitrogen. We're going to shuffle some protons around. I'll say minus H plus, in other words, you can think of this or I guess first we're going to put on a proton here. So I'll say plus H plus. Of course, that's not plus H plus. That's water going ahead and protonating. You can think of this as minus H plus as the next step. Again, we've got sort of a lot of tedious proton shuffling in the mechanism at this point. And I'm abbreviating things a little bit. One thing to keep in mind, again, this theme that I mentioned where carboxylate, where nitrogen, oxygen, nitrogen carbon double bonds are very similar to carbon oxygen double bonds. And so this structure here is really just like the analog of a carboxylate. In other words, there are two resonance structures here. And again, I'm kind of abbreviating this. And so we have two equivalent resonance structures. And then the last step you can think of is just that we're going to pick up a proton. And I'll draw this explicitly. It's nice to be able to pick and choose the resonance structure that you want when you're writing a mechanism. And so I'll just say our last step here is going to be protonation. In some cases you can stop your nitrile hydrolysis at the primary amide. In other cases the amide is going to go on further all the way to the carboxylate. All right, just as esters can be hydrolyzed by aqueous acid, amides can be hydrolyzed by aqueous acid, nitriles can be hydrolyzed by aqueous acid. If I take some amide, I'll write this as RCO NR2 prime. And I cook it up with acid H3O plus in water. Maybe heat that a little bit. And again, of course you can't go to the stock room and get a bottle of H3O plus. It's going to be sulfuric acid in water or HCl in water. You'll get the carboxylic acid and the corresponding ammonium salt. So if I took acetamide as just an example, since I was using acetamide in the previous panel and I talked about trying to stick to small molecules, and let's say I cook that up with sulfuric acid and water, maybe a little bit of heat boiled it up, you get the ammonium salt, the ammonium in this case, bisulfate HSO4 minus and the carboxylic acid. And this is a reaction that's done in the laboratory with proteins. If you want to break down a protein into individual amino acids, for example, if you want to extract the amino acid proline from hair clippings, and this is a procedure in organic syntheses, you can take 6 molar hydrochloric acid, that's about half the strength in the bottle, boil your hair or boil your protein with it for a number of hours and it will break down to the individual amino acids. So it's a very standard way to hydrolyze amides. And again, I've just given acetamide as an example to keep the structure small here. Do the same thing just for comparison with acetonitrile for the sake of simplicity, I'll just write ditto marks here and you get the exact same products, you get the corresponding acetic acid and the ammonium bisulfate salt. And maybe since all of this is really, really, really analogous to ester chemistry, all the things we covered, maybe I'll say write as an exercise on your own, write a mechanism for let's say the acid-promoted nitrile hydrolysis. Okay. Quick question. Yeah, so for the blackboard on the left, can the OH group just perform a nucleophilic attack on the carbonyl? Yes, yes, yes, and I was only starting us out on the nitrile hydrolysis. So in the cleavage of the nitrile bisodium hydroxide to the corresponding amide, yes indeed, you first, to the carboxylic acid, the first step is the hydrolysis to the amide and then it continues on. Oh, okay. So, and sometimes if you're careful, you can control it and stop it at the amide stage. All right. The last couple of minutes that I would like to take here, I want to talk about a few sort of synthetically useful reactions and kind of wrap up our carboxylic acid chemistry. So, we haven't really talked about where acid chlorides come from and basically acid chlorides are high in energy and so you make them from other highly reactive species. Acid chlorides, indeed, remember when I started out, I said every member of the carboxylic acid family can be interconverted by some chemistry or another and so I'm only giving you a little bit of a smattering here but making an acid chloride is a very useful reaction. Treating a carboxylic acid with thionyl chloride is a great way to do it. There are a few other species that are also used for this but thionyl chloride, SOCl2, is particularly popular and the products of the reaction are the carboxylic acid chloride plus if we're going to write a balanced equation, sulfur dioxide and HCl hydrogen chloride gas which generally bubble out. So, I don't want to go into full detail on the mechanism and again I'll leave it to your textbook to do this but I do want to bring out a theme that highlights this chemistry. Thionyl chloride is kind of a sulfur acid chloride. It's kind of a double acid chloride of sulfur. Indeed, this is very similar to another species, phosgene which has a carbon here which also does this reaction. It's a very reactive molecule. It's extremely electrophilic. You've got two chlorines pulling electron density away from sulfur. Through the same types of chemistry that we saw for acid chloride reactions, carboxylic acids can react with thionyl chloride to give an intermediate that looks like a funny anhydride. And this is a theme that you should pick up on in seeing the forest from the trees in this chemistry. And that is that all of these species where you have a carbonyl with an ester linkage, where you have a carbonyl with an ester like linkage to another electrophilic species, the carbonyl becomes super electrophilic. And nucleophiles can attack, even not very good nucleophiles, can attack at there. And this theme, forget the details now, look at the theme. We've kicked out chloride already. That's one of the byproducts. Chloride can come in, form a funny looking tetrahedral intermediate, and that intermediate can fall apart, kicking back, kicking out sulfur dioxide so we get our acid chloride, sulfur dioxide, and chloride anion. And when you write a balanced equation since a proton was lost at the very beginning, you get HCl. All right. That same theme reemerges in other carboxylic acid chemistry. Remember, this is the theme of the anhydride. This is the theme that when you have something electron withdrawing on the carbonyl, it makes it into a good electrophile. And so your textbook gives you another reagent, which in various forms and variations is quite popular for forming esters and amids. We will see it again in the very last lecture when we talk about the chemistry of amino acids, peptides, and that reagent is DCC. And the general idea is acid chlorides and acid anhydrides are generally species on the way to somewhere. They're generally things that you're making to use. Esters and amids are widely valuable, important compounds. They're stable enough to be in drugs. They're the proteins and peptides in your body. And they're molecules that are a lot of interest. And so being able to take a carboxylic acid and an alcohol and make an ester is an extremely valuable operation. Being able to take a carboxylic acid and an amine, I'll write it as a primary amine, although it could be a secondary amine or ammonia for that matter, and make an amide. That is an extremely valuable operation. And a reagent that often gets used for this is called DCC. They're variants of it. But what this reagent is is dicyclohexyl carbodiimid. The carbodiimid functionality is another member of the carbon dioxide family of molecules. And carbonic acid and carbon dioxide are essentially like a double acid, a double acid, carboxylic acid. Carbon's in the plus 4 oxidation state here. The carbon nitrogen bond is electrophilic. And the carboxylic acid in the above case can add to the carbon nitrogen bond. And here's where this theme comes in. So here's our cyclohexane ring. The CC is cyclohexyl carbodiimid. So we have a cyclohexane ring. And here's the big picture. Here's the big idea. The carbodiimid reacts in exactly the same way. We see thionyl chloride. It reacts to make something that looks a heck of a lot like an anhydride. Because remember, the carbon nitrogen double bond is very similar to the carbon oxygen double bond. And a nucleophile can come in just as we have seen time and time again with all of the chemistry we've been seeing today. A nucleophile can come in. And I'm just going to abbreviate CY for cyclohexane. Our nucleophile can come in. And we can kick back and kick out. And eventually, basically, end up giving rise to our acyl nucleophile. Our acylated nucleophile above and dicyclohexyl urea, which is a byproduct of this reaction. So DCC is a very useful reagent for making esters and amides. All right. The last thing I want to do, your book, your textbook has nicely kind of picked and chosen a few additional key reactions. And I'd like to remind you of these, although I know that you also will be able to learn about them from the readings. And these reactions basically fit in the broad theme that we've seen. Lithium aluminum hydride is a super, super good hydride nucleophile. It can push hydride into practically any double or triple bond between carbon and any sort of electronegative atom. It can push it into a carbonyl group. It can push it into an imine. It can push it into a nitrile. Lithium aluminum hydride generally reacts completely to reduce things down. And so your textbook has chosen as a couple of examples to show you in the chemistry of nitriles that lithium aluminum hydride can react with a nitrile to give a primary amine adding in two equivalents of hydride temporarily going through an intermediate where you have aluminum on the nitrogen. Your textbook has chosen to remind you. And this is again just a smattering of the rich chemistry of the carboxylic acid family, much of which you're going to be guided not by having, and this is where people always make a mistake in learning chemistry, organic chemistry, not by memory because there's way too much of it. But by broad principles, all the principles we've seen today, you can apply to all the members of the carboxylic acid family and basically intuit lots and lots of different reactions. So your textbook has also pointed out and reminded you that nitriles can be reduced selectively. And we saw this in esters. We said lithium aluminum hydride blasts the heck of an ester all the way down to an alcohol. Di-Bal is a more mild reducing agent. It can stop and only add one equivalent of hydride. And so your textbook chooses to give you an example of a di-Bal reduction of a nitrile with water as a workup where you can use H3O plus as a workup. Remember, you're going to get an imine initially, but as was aptly asked early on, I think the gentleman in the third row there about primary imines, primary imines generally aren't stable and break down to the corresponding aldehyde in water conditions. And I'll give you two more examples from your textbook while we're talking about the chemistry of nitriles. And again, I could show you many other examples. So Grignard reagents and organolithium reagents, I'll call it R prime MGX or R prime LI followed by an aqueous workup H2O or H3O plus can add to give you ketones like so. And again, this is the same general idea that we've seen before, the idea that these nucleophiles can add in the case of the nitrile group, you often can stop at one addition, which is something you generally can't do with esters. Anyway, I think that basically wraps it up for the chapter. We will be picking up with chapter 23 next time. Thank you.
 Today we're really in the heart of the chemistry of the carboxylic acid family.  Last time after talking in sort of generalities about their chemistry we introduced the most  reactive members of the carboxylic acid family.  We introduced acid anhydrides and we introduced acid chlorides and we talked about their chemistry.  Today we're going to focus on all of the remaining members of the family.  We'll talk about some of the chemistry of carboxylic acids that we haven't seen before.  We'll talk about the chemistry of esters and we'll talk about amids and nitrials.  And these are all less reactive than acid chlorides and anhydrides.  So if I wanted to make some generalization here's a generic ester structure.  Here's a generic carboxylic acid structure.  And what I would say is in general these structures are less reactive.  These functional groups are less reactive to nucleophiles than acids and acid chlorides.  And acid chlorides and anhydrides let's say.  And so let me maybe start with an example that shows a similar type of reactivity but  it's a much less great degree of reactivity.  Let's look at the reaction of a simple ester and I think for today for all of our examples  I'm going to be giving very small and simple compounds just because we're going to be writing  out a lot of structures.  So let's take a look at the simplest typical ester methyl acetate.  The reason I say typical ester is formates are a little different formic acid although  it's a carboxylic acid is a little more reactive but acetates and propionates and various other  acids all are kind of the same.  And let's take ammonia.  Now when we were talking about nucleophiles before we talked about species like ammonia  and hydroxide as basic nucleophiles.  These aren't super basic nucleophiles like Grignard reagents and hydride reagents but  they're not things that are base only in name.  And ammonia is a good enough nucleophile that it will react with esters and so we undergo  a reaction to get acetamide and the other product of the reaction is methanol.  So we call this reaction an ammonolysis meaning a lysosacleavage by ammonia.  We've already mentioned the term hydrolysis cleavage by water.  Now what I really wanted to be I've been trying to keep everything simple up here what I really  wanted to draw up here was an aminolysis.  These names don't matter a whole heck of a lot.  An aminolysis would be within a mean like R with say a general structure of R and H2  or even a secondary amine although they're much less reactive so there's a primary amine.  But I'll show you since I'm trying to keep all of our drawings simple today I'll show  you an ammonolysis instead of an aminolysis.  And the mechanism for this I'm not going to write it out in gory detail because you've  seen all of the principles with acid chlorides and anhydrides.  The ammonia is a nucleophile it has a lone pair of electrons on it.  It can attack the carbonyl even though the carbonyl of an ester is not nearly as electrophilic  as the carbonyl of an anhydride or a chloride that has a good electron withdrawing group  pulling away electron density.  It can attack.  We excel methoxide we transfer a proton if you want more detail you can see your textbook  for a mechanism for this reaction.  But the general gist is that the carbonyl of an ester group is sufficiently electrophilic  to react with a basic nucleophile like ammonia or later on I'll show you hydroxide.  Now for all intents and purposes the electrophilicity of the carbonyl group of an acid is really  very similar to an ester but there's one big, big difference.  A carboxylic acid has an acidic proton so whereas the first thing that happens when  you mix an ester with ammonia is that the ammonia attacks the carbonyl it's not a fast  reaction it'll occur over hours of time.  This is the reaction of Windex when you clean fingerprints off of the window because grease  the oils in your skin are esters of glycerol they're triesters you've heard of triglycerides.  Windex has ammonia and that ammonia is cleaving the ester groups to break them down to smaller  pieces fatty acid, amides and glycerol so that's ammonalysis.  Now if by comparison I take acetic acid and I mix it with ammonia you might think well  it's going to be very similar but acetic acid has one thing that's very different than  methyl acetate it's got an acidic proton so if I mix acetic acid and ammonia you get  a salt you get ammonium acetate  and for the most part you don't get nabbed.  Now I say for the most part because under the right conditions if you heat the crud out  of ammonium acetate if you heat the crud out of acetic acid and ammonia at high temperature  you will eventually get some acetamide out of there.  This is not a what I would say useful reaction a reaction that synthetic chemists would typically  use to make an amide but you will get some but the first thing that will happen and the  thing that would happen under typical conditions would be salt formation not amide formation.  Can you make the alcohol group a good leaving group by protonating it?  Can you?  Ah you're getting ahead of me.  Can I make the alcohol group a good leaving group by protonating it?  The answer is yes and sit tight in your seat.  Alright so we already talked about the concept of pKa and we talked about the concept of  pKa specifically of the conjugate acid.  We said that the pKa of the conjugate acid of ammonia or the conjugate acid of an amine  was about 10 or 11 and that's a typical sort of moderately basic compound kind of the  same pKa as hydrosyanic acid.  Cyanides another species that as you just encountered on the quiz is a reasonably good  nucleophile.  Now by contrast if you go to something like water then you have something that's much  less basic much less nucleophilic.  The pKa of the hydronium ion of the conjugate acid of water is negative 1.7.  Water is very weakly basic.  It is basic but sort of in name only.  So as I mentioned in our previous discussion of esters if I just mix an ester and water  you have no reaction and I also mentioned that that's fortunate for you because all  of the lipids in your body all of your cell membranes are made up of esters and so if  they cleaved at 37 degrees Celsius if they underwent hydrolysis at any appreciable rate  you'd be in trouble.  Now by similar token and again I'm using methyl acetate I'll use it a lot today just  because it's a nice example and then I'll use acetic acid sort of in acetamide sort  of as counter points but of course these could be any esters and any acids.  So by very similar token if I mix methanol and acetic acid again the carbonyl is moderately  electrophilic for an ester it's moderately electrophilic for an acid but water and alcohols  are very weak bases and very weak nucleophiles.  And remember when we're scanning over pKa's and I'm tossing out numbers like negative  2 or negative 3 for the pKa of the conjugate acid of an alcohol or negative 1.7 for water  and positive 10 we're on a log scale.  In other words we're scanning over 12 orders of magnitude what is that 10 to the third  is a thousand million billion trillion orders of difference in basicity a trillion orders  of magnitude or a trillion times different in reactivity to a first order approximation  as nucleophilicity tracks with basicity.  If a reaction of ammonia and methyl acetate takes a minute roughly then you know ball  park it you're going to say a trillion minutes for the reaction of water and methyl acetate  or a trillion minutes for the reaction of methanol and acetic acid.  I don't know about you I know for me I don't expect to be around here a trillion minutes  from now so they're not going to react.  All right so no reaction.  All right so chemists love to make stuff happen they love to make what they want to have happen  happen.  And so if you want acetic acid to react with methanol as was alluded earlier you do something  that can protonate the carbonyl group.  That's going to make the carbonyl group like a trillion times more electrophilic.  In other words you protonate it in the presence of a very strong acid.  So I could write that if I take acetic acid and I mix it with methanol in the presence  of sulfuric acid I get methyl acetate and I get a molecule of water.  So then chemists as I keep repeating are very bad at balancing equations but it's really  important to keep this in mind because this reaction is an equilibrium.  And so if I go ahead and just mix them and don't have a lot of methanol just a little  bit of methanol I'm going to have an equilibrium in the middle.  Sulfuric acid and methanol for all intents and purposes is similar.  I got to have a lot of methanol or I've got to do something to soak up the water.  And sulfuric acid actually really likes water so that's one of the ways to make it hang  on to drive the reaction is just to use more than a little pinch of sulfuric acid.  Question?  The H2SO4 is indeed a catalyst and technically you don't need to use a whole mole equivalent.  In practice sulfuric acid often is used in a reasonable quantity for exactly the reason  I said because it tends to bind to the water it helps drive the reaction as well but it's  not consumed by the reaction.  So in fact chemists when they write a reaction like this will often show solvent and reagents  with an arrow and so you'll often see this written as sulfuric acid sometimes you'll  see it written as a catalyst you know with parenthesis cat and often you'll see methanol  just indicated it's the solvent.  Now with acetic acid I might use as little as possible but if I have a valuable carboxylic  acid I'm probably going to use a whole big splash of methanol a whole pot of methanol  a whole flask full of methanol for a couple of grams of acid.  And so here's our product of the reaction.  Now this reaction's been known for a long time it was discovered or invented by Fisher  and so it's called a Fischer esterification.  Sometimes people will use sulfuric acid for the reaction sometimes they'll use another  strong mineral acid like hydrochloric acid.  Ironically in the laboratory if I want dry hydrochloric acid in methanol not in water  so I don't want to go to a bottle in the laboratory in the stock room and get HCl with water in  it one of the ways I'll do that one of the ways I'll get anhydrous HCl in methanol is  to throw some acetyl chloride into my methanol it'll react to give HCl in methanol and methyl  acetate and those all will be just the methyl acetate I might not pay attention to and  then I might use this as a reaction to take a big valuable carboxylic acid and make a  methyl ester out of it so this is often how we roll in the laboratory.  Alright let's take a look at the mechanism of the reaction.  So in acid protons go on and off all different lone pairs any lone pair that's weakly basic  is going to get protonated it's an equilibrium.  If I throw sulfuric acid a strong acid into methanol it dissociates it protonates the  methanol so my strongest acid in methanol is protonated methanol it's the leveling  effect you learned about in general chemistry.  So protons go on protons come off when the carbonyl gets protonated the carbonyl goes  from being moderately electrophilic to being very electrophilic.  We show the flow of electrons by drawing a curved arrow from the electrons to the hydrogen  representing the formation of a new bond electrons flow back on to the oxygen atom we have an  equilibrium we generate protonated acetic acid plus methanol I'll put my electrons I'm  not always good about writing my lone pairs but I'll put my lone pair of electrons back  on to the oxygen where they belong.  Now this process the protonation of the carbonyl has made it into a good electrophile now it's  ready to react even with a relatively weak nucleophile like methanol.  Electrons flow from the lone pair on methanol to the carbonyl carbon atom we start to form  a bond but concurrently because we can't have 10 electrons around the carbon concurrently  electrons flow up on to the oxygen atom so we get an OH group here and we get a methoxy  group with a proton and a positive charge on it and another OH group and I will try to  be as good as I can about keeping track of all of my lone pairs of electrons so we form  the tetrahedral intermediate and in strong acid protons go on protons come off protons  go on and off every lone pair of electrons and so you can think of it as a proton being  directly transferred among there I probably think of this more as being mediated by solvent  I'd say that's a better way to think about the process and so in our equilibrium we have  lots and lots of methanol around protons flow on protons flow off I will draw a curved  arrow representing the flow of electrons back to the methanol doesn't matter which side  I write the proton on which side I write the lone pair of electrons on I'm representing  a tetrahedral oxygen atom and oxygen atom with four substituents equally disposed about  it I guess you'd call it trigonal parameter for the geometry of the oxygen.  Alright so that sort of takes us to an uncharged tetrahedral intermediate and this looks a  heck of a lot like a geminal diol if you think about it and the common theme in all of this  chemistry that we've talked about is these types of tetrahedral intermediates these types  of geminal diols are not generally stable.  The end of last lecture at the end when we were talking about acetals or in the previous  lecture Hemiacetals I mentioned glucose a cyclic example that was stable we'll see a  tetrahedral intermediate that's stable on the discussion section where you actually  have it as a low energy species but in general tetrahedral intermediates are not stable they're  not something that you can isolate or put in a bottle they're just a high energy species  a stable stable enough that it's in an energy well stable enough that it can sit around  for a microsecond but not stable enough that you could put it in a bottle and so our reaction  continues in strong acid protons come on protons go off  you put a proton back on the methoxy group we're just on the backwards pathway and so  I'm going to continue forward protons come on and off every lone pair of electrons  and so now we've protonated one of our OH groups  it doesn't matter which one gets protonated they're both equivalent remember we're just  tetrahedral about this oxygen now just as we had the attack we can have a breakdown  now with the expulsion of water electrons flow down from the oxygen we can't stop at  that point because that would force us to have 10 electrons around carbon carbon can't  accommodate 10 electrons and so we're going to break down actually I am going to good  person and write this mechanism on different lines so give me a moment here I'm just going  to continue to balance here and so I will write the breakdown of this tetrahedral intermediate  in the next step  all right so as I was saying electrons flow down from the oxygen they flow back onto the  oxygen this gives us a molecule of the protonated methyl ester and we have expelled a molecule  of water and our final step is the very reverse of the first step of the reaction in the first  step we put a proton onto a carbonyl in the last step we take a proton off of a protonated  carbonyl we're in this vast sea of methanol remember this is an equilibrium reaction if  we don't have a lot of excess methanol you're going to get only partial conversion to the  ester so we have a ton of methanol floating around our methanol which in protonated form  served as the catalyst is now going to accept a proton our protonated methanol at the very  first step of the reaction was consumed our acid catalyst was consumed in the very last  step it is regenerated  and so those six steps constitute the mechanism for our fissure esterification they constitute  the mechanism for ester formation thoughts or questions?  so your question is why does it protonate this oxygen?  why is this oxygen protonated?  why is this protonated? because when we push electrons down over here it ends up with a  positive charge on the oxygen now remember in the back of your mind when you see this  structure as we just saw in the quiz there are multiple contributing resonance forms  so that is one resonance form think in your mind for a second about two other resonance  forms you can picture another resonance form in which the positive charge is on this carbon  and a third resonance form in which we have a double bond to this oxygen single bond to  this oxygen and a positive charge on this oxygen and collectively all three of those  resonance structures make up a picture of the actual species just as in your oxo-carbenium  ion I asked you to draw one structure although it was fine if you drew two resonance structures  or it was fine as a matter of fact if you draw any of the three resonance structures  any of the two resonance structures so we are just thinking about one of the different  pictures that are present in part because if you look at this it is already a long mechanism  and so you are sort of holding in the back of your head all of this relevant stuff  all right any other questions that I want to talk about the reverse reaction the hydrolysis  of esters remember fissure esterification is an equilibrium so if I take and again I am  keeping my whole lecture really really simple with simple small molecules if I take methyl  acetate and I treat it now with water and sulfuric acid I am going to hydrolyze it to  acid acid plus methanol just the reverse of the reaction I could write it like this I  could write it like this saying I am treating it with sulfuric acid in water it is all the  same thing and since this is so identical to what we just saw at this point you should  be able to write a mechanism for acid catalyzed ester hydrolysis I will leave that to you  it is identical to the mechanism that I just wrote up but in reverse and you can figure  that out all right I want to move on to a little bit of other chemistry of esters carboxylic  acids and then talk about amides and nitriels and again I will keep our keep things kind  of simple and general esters as I said are moderately electrophilic they react with strong  nucleophiles if I treat an ester with sodium hydroxide potassium hydroxide for most intents  and purposes these are equivalent in water I get the carboxylate salt I get the alcohol  you call this reaction saponification it is a reaction that mankind has been doing for  hundreds of years before we had organic chemistry it is the making of soap when you take a fat  which is a triester of glycerol 1, 2, 3 propane triol with 3 long chain carboxylic acids esterified  on and you stir it with sodium hydroxide that's Lai Drano the sodium hydroxide hydrolysis  saponifies the glycerol esters to get the sodium salts of the carboxylic acids that  have greasy tails and polar head groups and like both water and grease which is very good  for getting clean in the shower makes my cells so reaction here same same principle as we  saw in the aminolysis I kind of wanted to when I was talking about this and thinking  about where to present it I kind of wanted to present it after we did the water the acid  promoted hydrolysis but mechanistically it's right up there with the aminolysis and aminolysis  we talked about in other words here's our ester group hydroxide is a strong is a good  base a moderately strong base relatively strong base it's a good enough nucleophile it attacks  our carbonyl I'll give you a little bit of an abbreviated mechanism here only showing  relevant lone pairs we get our tetrahedral intermediate  our tetrahedral intermediate is going to break down it kicks out the OR group and again I'm  just skipping a few lone pairs here this gives rise to the carboxylic acid plus the alkoxide  and the alkoxide is basic and so the alkoxide reacts to form the carboxylate and again I'm  not going to write out every curved arrow and every step in painful detail but the carboxylate  reacts to give you the alkoxide salt and the to give you the the alkoxide reacts to give  you the carboxylate salt and the alcohol and in a preparative sense if I carry out this  reaction in the laboratory and I want to isolate my carboxylic acid a very common laboratory  procedure to saponify an ester with sodium hydroxide then wash the aqueous layer that  contains the carboxylate salt to remove the alcohol and any unreacted ester to extract  it with ether to wash it with ether and then very commonly in the laboratory you will acidify  with some strong acid in water like HCl or H2SO4 and isolate from there the carboxylic  acid sometimes in the laboratory it will precipitate out alright so that gives us a  little bit of an overview of carboxylic acids and of esters and now I want to move on to  the last members the last main members there are plenty of other members in the carboxylic  acid family but I want to move on to the last main members of the family on to amids and  nitriels amids I'll write them in general form with two R groups here that could be  two hydrogens in which case we have a primary amid a hydrogen and an R group which case  we have a secondary amid or two R groups in which case we have a tertiary amid nitriels  look very different and yet in some ways are very similar both of these compounds are generally  less reactive toward nucleophiles than esters  and I think it's kind of easy at least to compare an amid to an ester we already saw  this in the IR the stretching frequency for the amid carbonyl is lower there's less double  bond character the nitrogen of the amid is less electronegative than the oxygen of the  ester the nitrogen of the amid is better able to donate in electrons by resonance to the  carbonyl making it less electrophilic and so a general principle is that amids and nitriels  generally react less quickly and so if I tried to try to epitomize this with a reaction and  again I'm going to write very simple compounds so I will write a set of my but again this  could be any amid if I imagine treating it with sodium hydroxide in water like we did  with our ester in saponification how would I epitomize this I'd say long time or heat  to make it react so let's say delta or long time would be how I'd describe this and again  we get hydrolysis we get cleavage by the sodium hydroxide to the carboxylate salt and in this  case since we have a primary amid to ammonia now what do I mean by long time well actually  the drain oh is which I mentioned for ester cleavage is a good example when hair hair  you know you get your drain clogged up with hair is made up of protein which are polyamids  when I throw drain oh down the drain it doesn't clog the unclog the drain instantly the drain  oh sits with the hair and the grease that are down the drain for a number of hours before  it unclogs it in the laboratory if you want to speed this reaction along you could boil  your sodium hydroxide with an amid but unlike my comment about trillions of seconds for  the water promoted hydrolysis of an ester the reaction occurs even at room temperature  at a reasonable rate on the laboratory time scale and again nitrials maybe a hair less  reactive than amids I know that that problem comes up on your sapling and but honestly  I don't think of them personally as being very different so I can say sort of ditto  if I take acetonitrile and treat it under these conditions with sodium hydroxide in  water maybe with heat or a long time you know a few hours I'll get again sodium acetate  plus ammonia  all right by by now you should be reasonably strong in your mechanistic understanding of  carboxyl compounds and maybe I'll just give you a quick quick abbreviated tour of some  of the mechanisms here your textbook has them in more detail if you want but all of the  principles that you can think about are similar hydroxides a reasonably good nucleophile it's  it's basic it can attack we can kick up form a tetrahedral intermediate  and in part in part here I really don't want to lose the forest from the trees this is  the gist of this mechanism your textbook writes the next step in the mechanism as kicking  out NH2 minus I think it's okay to think about that the realities maybe a little bit more  complicated in some cases one can see died deprotonation occurring but I think I think  in terms of your thinking right now it's fine to think about this anyway so that gives us  our carboxylic acid and our amide anion the amide anion is very basic you can think of  it as pulling off a proton on the carboxylic acid to give you the carboxylate plus ammonia  remove the Click it 그  And for nitriels, again, I don't want to get fantastically  into a whole lot of mechanism here.  And so maybe I'll just sort of start us out here  on the mechanism.  There's a lot of proton shuffling that's going on.  But the gist, remember the theme that I talked about in carbon  nitrogen double bonds is basically in very many ways  they're like carbon oxygen double bonds.  And in a similar way, carbon nitrogen triple bond is very much  like a carbon yield or a carbon nitrogen double bond.  And so if you look at acetonitrile, you can think of it.  So now we're looking at the hydrolysis of nitriels.  You can think of this as being very similar.  In other words, hydroxide adds, we kick in electrons.  You get a negative charge on nitrogen.  We're going to shuffle some protons around.  I'll say minus H plus, in other words, you can think  of this or I guess first we're going to put on a proton here.  So I'll say plus H plus.  Of course, that's not plus H plus.  That's water going ahead and protonating.  You can think of this as minus H plus as the next step.  Again, we've got sort of a lot of tedious proton shuffling  in the mechanism at this point.  And I'm abbreviating things a little bit.  One thing to keep in mind, again, this theme  that I mentioned where carboxylate, where nitrogen,  oxygen, nitrogen carbon double bonds are very similar  to carbon oxygen double bonds.  And so this structure here is really just  like the analog of a carboxylate.  In other words, there are two resonance structures here.  And again, I'm kind of abbreviating this.  And so we have two equivalent resonance structures.  And then the last step you can think of is just  that we're going to pick up a proton.  And I'll draw this explicitly.  It's nice to be able to pick  and choose the resonance structure that you want  when you're writing a mechanism.  And so I'll just say our last step here is going  to be protonation.  In some cases you can stop your nitrile hydrolysis  at the primary amide.  In other cases the amide is going to go on further all  the way to the carboxylate.  All right, just as esters can be hydrolyzed  by aqueous acid, amides can be hydrolyzed by aqueous acid,  nitriles can be hydrolyzed by aqueous acid.  If I take some amide, I'll write this as RCO NR2 prime.  And I cook it up with acid H3O plus in water.  Maybe heat that a little bit.  And again, of course you can't go to the stock room  and get a bottle of H3O plus.  It's going to be sulfuric acid in water or HCl in water.  You'll get the carboxylic acid  and the corresponding ammonium salt.  So if I took acetamide as just an example,  since I was using acetamide in the previous panel  and I talked about trying to stick to small molecules,  and let's say I cook that up with sulfuric acid and water,  maybe a little bit of heat boiled it up,  you get the ammonium salt, the ammonium in this case,  bisulfate HSO4 minus and the carboxylic acid.  And this is a reaction that's done in the laboratory  with proteins.  If you want to break down a protein  into individual amino acids, for example,  if you want to extract the amino acid proline from hair  clippings, and this is a procedure in organic syntheses,  you can take 6 molar hydrochloric acid,  that's about half the strength in the bottle,  boil your hair or boil your protein with it for a number  of hours and it will break down to the individual amino acids.  So it's a very standard way to hydrolyze amides.  And again, I've just given acetamide as an example  to keep the structure small here.  Do the same thing just for comparison with acetonitrile  for the sake of simplicity, I'll just write ditto marks here  and you get the exact same products,  you get the corresponding acetic acid  and the ammonium bisulfate salt.  And maybe since all of this is really, really, really analogous  to ester chemistry, all the things we covered,  maybe I'll say write as an exercise on your own,  write a mechanism for let's say the acid-promoted  nitrile hydrolysis.  Okay.  Quick question.  Yeah, so for the blackboard on the left,  can the OH group just perform a nucleophilic attack  on the carbonyl?  Yes, yes, yes, and I was only starting us out  on the nitrile hydrolysis.  So in the cleavage of the nitrile bisodium hydroxide  to the corresponding amide, yes indeed,  you first, to the carboxylic acid, the first step is the  hydrolysis to the amide and then it continues on.  Oh, okay.  So, and sometimes if you're careful, you can control it  and stop it at the amide stage.  All right.  The last couple of minutes that I would like to take here,  I want to talk about a few sort  of synthetically useful reactions and kind  of wrap up our carboxylic acid chemistry.  So, we haven't really talked  about where acid chlorides come from and basically acid  chlorides are high in energy and so you make them  from other highly reactive species.  Acid chlorides, indeed, remember when I started out,  I said every member of the carboxylic acid family can be  interconverted by some chemistry or another  and so I'm only giving you a little bit of a smattering here  but making an acid chloride is a very useful reaction.  Treating a carboxylic acid  with thionyl chloride is a great way to do it.  There are a few other species that are also used for this  but thionyl chloride, SOCl2, is particularly popular  and the products of the reaction are the carboxylic acid  chloride plus if we're going to write a balanced equation,  sulfur dioxide and HCl hydrogen chloride gas  which generally bubble out.  So, I don't want to go into full detail on the mechanism  and again I'll leave it to your textbook to do this  but I do want to bring out a theme  that highlights this chemistry.  Thionyl chloride is kind of a sulfur acid chloride.  It's kind of a double acid chloride of sulfur.  Indeed, this is very similar to another species,  phosgene which has a carbon here  which also does this reaction.  It's a very reactive molecule.  It's extremely electrophilic.  You've got two chlorines pulling electron density away  from sulfur.  Through the same types of chemistry that we saw  for acid chloride reactions, carboxylic acids can react  with thionyl chloride to give an intermediate  that looks like a funny anhydride.  And this is a theme that you should pick up on in seeing the  forest from the trees in this chemistry.  And that is that all of these species where you have a carbonyl  with an ester linkage, where you have a carbonyl  with an ester like linkage to another electrophilic species,  the carbonyl becomes super electrophilic.  And nucleophiles can attack, even not very good nucleophiles,  can attack at there.  And this theme, forget the details now, look at the theme.  We've kicked out chloride already.  That's one of the byproducts.  Chloride can come in, form a funny looking tetrahedral  intermediate, and that intermediate can fall apart,  kicking back, kicking out sulfur dioxide  so we get our acid chloride, sulfur dioxide,  and chloride anion.  And when you write a balanced equation since a proton was  lost at the very beginning, you get HCl.  All right.  That same theme reemerges  in other carboxylic acid chemistry.  Remember, this is the theme of the anhydride.  This is the theme that when you have something electron withdrawing  on the carbonyl, it makes it into a good electrophile.  And so your textbook gives you another reagent,  which in various forms and variations is quite popular  for forming esters and amids.  We will see it again in the very last lecture when we talk  about the chemistry of amino acids, peptides,  and that reagent is DCC.  And the general idea is acid chlorides  and acid anhydrides are generally species  on the way to somewhere.  They're generally things that you're making to use.  Esters and amids are widely valuable, important compounds.  They're stable enough to be in drugs.  They're the proteins and peptides in your body.  And they're molecules that are a lot of interest.  And so being able to take a carboxylic acid and an alcohol  and make an ester is an extremely valuable operation.  Being able to take a carboxylic acid and an amine,  I'll write it as a primary amine,  although it could be a secondary amine or ammonia  for that matter, and make an amide.  That is an extremely valuable operation.  And a reagent that often gets used for this is called DCC.  They're variants of it.  But what this reagent is is dicyclohexyl carbodiimid.  The carbodiimid functionality is another member  of the carbon dioxide family of molecules.  And carbonic acid and carbon dioxide are essentially  like a double acid, a double acid, carboxylic acid.  Carbon's in the plus 4 oxidation state here.  The carbon nitrogen bond is electrophilic.  And the carboxylic acid in the above case can add  to the carbon nitrogen bond.  And here's where this theme comes in.  So here's our cyclohexane ring.  The CC is cyclohexyl carbodiimid.  So we have a cyclohexane ring.  And here's the big picture.  Here's the big idea.  The carbodiimid reacts in exactly the same way.  We see thionyl chloride.  It reacts to make something that looks a heck of a lot  like an anhydride.  Because remember, the carbon nitrogen double bond is very  similar to the carbon oxygen double bond.  And a nucleophile can come in just as we have seen time  and time again with all of the chemistry  we've been seeing today.  A nucleophile can come in.  And I'm just going to abbreviate CY for cyclohexane.  Our nucleophile can come in.  And we can kick back and kick out.  And eventually, basically, end up giving rise  to our acyl nucleophile.  Our acylated nucleophile above and dicyclohexyl urea,  which is a byproduct of this reaction.  So DCC is a very useful reagent for making esters and amides.  All right.  The last thing I want to do, your book,  your textbook has nicely kind of picked  and chosen a few additional key reactions.  And I'd like to remind you of these, although I know  that you also will be able to learn about them  from the readings.  And these reactions basically fit  in the broad theme that we've seen.  Lithium aluminum hydride is a super, super good hydride  nucleophile.  It can push hydride into practically any double  or triple bond between carbon  and any sort of electronegative atom.  It can push it into a carbonyl group.  It can push it into an imine.  It can push it into a nitrile.  Lithium aluminum hydride generally reacts completely  to reduce things down.  And so your textbook has chosen as a couple of examples  to show you in the chemistry of nitriles  that lithium aluminum hydride can react with a nitrile  to give a primary amine adding in two equivalents  of hydride temporarily going through an intermediate  where you have aluminum on the nitrogen.  Your textbook has chosen to remind you.  And this is again just a smattering of the rich chemistry  of the carboxylic acid family,  much of which you're going to be guided not by having,  and this is where people always make a mistake  in learning chemistry, organic chemistry, not by memory  because there's way too much of it.  But by broad principles, all the principles we've seen today,  you can apply to all the members  of the carboxylic acid family and basically intuit lots  and lots of different reactions.  So your textbook has also pointed out and reminded you  that nitriles can be reduced selectively.  And we saw this in esters.  We said lithium aluminum hydride blasts the heck  of an ester all the way down to an alcohol.  Di-Bal is a more mild reducing agent.  It can stop and only add one equivalent of hydride.  And so your textbook chooses to give you an example  of a di-Bal reduction of a nitrile with water as a workup  where you can use H3O plus as a workup.  Remember, you're going to get an imine initially,  but as was aptly asked early on, I think the gentleman  in the third row there about primary imines,  primary imines generally aren't stable and break down  to the corresponding aldehyde in water conditions.  And I'll give you two more examples from your textbook  while we're talking about the chemistry of nitriles.  And again, I could show you many other examples.  So Grignard reagents and organolithium reagents,  I'll call it R prime MGX or R prime LI followed  by an aqueous workup H2O or H3O plus can add  to give you ketones like so.  And again, this is the same general idea  that we've seen before, the idea that these nucleophiles can add  in the case of the nitrile group, you often can stop  at one addition, which is something you generally can't do  with esters.  Anyway, I think that basically wraps it up for the chapter.  We will be picking up with chapter 23 next time.  Thank you.
Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__0_4031.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__4032_8723.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__8724_17927.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__17928_18311.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__18312_18995.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__18996_21335.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__21336_21671.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__21672_25655.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__25656_27527.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__27528_29939.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__29940_32207.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__32208_32303.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__32304_33263.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__33264_52079.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__52080_52691.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__52692_53375.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__53376_56231.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__56232_56759.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__56760_56927.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__56928_58847.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__58848_59651.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__59652_68135.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__68136_69431.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__69432_72095.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__72096_78779.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__78780_81263.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__81264_82247.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__82248_83363.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__83364_85007.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__85008_87767.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__87768_88079.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__88080_93095.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__93096_93227.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__93228_97955.png Organic_Chemistry_51C__Lecture_09__Reactions_of_Carboxylic_Acids__Esters__Amides____Nitriles__97956_98318.png
Today we're really in the heart of the chemistry of the carboxylic acid family. Last time after talking in sort of generalities about their chemistry we introduced the most reactive members of the carboxylic acid family. We introduced acid anhydrides and we introduced acid chlorides and we talked about their chemistry. Today we're going to focus on all of the remaining members of the family. We'll talk about some of the chemistry of carboxylic acids that we haven't seen before. We'll talk about the chemistry of esters and we'll talk about amids and nitrials. And these are all less reactive than acid chlorides and anhydrides. So if I wanted to make some generalization here's a generic ester structure. Here's a generic carboxylic acid structure. And what I would say is in general these structures are less reactive. These functional groups are less reactive to nucleophiles than acids and acid chlorides. And acid chlorides and anhydrides let's say. And so let me maybe start with an example that shows a similar type of reactivity but it's a much less great degree of reactivity. Let's look at the reaction of a simple ester and I think for today for all of our examples I'm going to be giving very small and simple compounds just because we're going to be writing out a lot of structures. So let's take a look at the simplest typical ester methyl acetate. The reason I say typical ester is formates are a little different formic acid although it's a carboxylic acid is a little more reactive but acetates and propionates and various other acids all are kind of the same. And let's take ammonia. Now when we were talking about nucleophiles before we talked about species like ammonia and hydroxide as basic nucleophiles. These aren't super basic nucleophiles like Grignard reagents and hydride reagents but they're not things that are base only in name. And ammonia is a good enough nucleophile that it will react with esters and so we undergo a reaction to get acetamide and the other product of the reaction is methanol. So we call this reaction an ammonolysis meaning a lysosacleavage by ammonia. We've already mentioned the term hydrolysis cleavage by water. Now what I really wanted to be I've been trying to keep everything simple up here what I really wanted to draw up here was an aminolysis. These names don't matter a whole heck of a lot. An aminolysis would be within a mean like R with say a general structure of R and H2 or even a secondary amine although they're much less reactive so there's a primary amine. But I'll show you since I'm trying to keep all of our drawings simple today I'll show you an ammonolysis instead of an aminolysis. And the mechanism for this I'm not going to write it out in gory detail because you've seen all of the principles with acid chlorides and anhydrides. The ammonia is a nucleophile it has a lone pair of electrons on it. It can attack the carbonyl even though the carbonyl of an ester is not nearly as electrophilic as the carbonyl of an anhydride or a chloride that has a good electron withdrawing group pulling away electron density. It can attack. We excel methoxide we transfer a proton if you want more detail you can see your textbook for a mechanism for this reaction. But the general gist is that the carbonyl of an ester group is sufficiently electrophilic to react with a basic nucleophile like ammonia or later on I'll show you hydroxide. Now for all intents and purposes the electrophilicity of the carbonyl group of an acid is really very similar to an ester but there's one big, big difference. A carboxylic acid has an acidic proton so whereas the first thing that happens when you mix an ester with ammonia is that the ammonia attacks the carbonyl it's not a fast reaction it'll occur over hours of time. This is the reaction of Windex when you clean fingerprints off of the window because grease the oils in your skin are esters of glycerol they're triesters you've heard of triglycerides. Windex has ammonia and that ammonia is cleaving the ester groups to break them down to smaller pieces fatty acid, amides and glycerol so that's ammonalysis. Now if by comparison I take acetic acid and I mix it with ammonia you might think well it's going to be very similar but acetic acid has one thing that's very different than methyl acetate it's got an acidic proton so if I mix acetic acid and ammonia you get a salt you get ammonium acetate and for the most part you don't get nabbed. Now I say for the most part because under the right conditions if you heat the crud out of ammonium acetate if you heat the crud out of acetic acid and ammonia at high temperature you will eventually get some acetamide out of there. This is not a what I would say useful reaction a reaction that synthetic chemists would typically use to make an amide but you will get some but the first thing that will happen and the thing that would happen under typical conditions would be salt formation not amide formation. Can you make the alcohol group a good leaving group by protonating it? Can you? Ah you're getting ahead of me. Can I make the alcohol group a good leaving group by protonating it? The answer is yes and sit tight in your seat. Alright so we already talked about the concept of pKa and we talked about the concept of pKa specifically of the conjugate acid. We said that the pKa of the conjugate acid of ammonia or the conjugate acid of an amine was about 10 or 11 and that's a typical sort of moderately basic compound kind of the same pKa as hydrosyanic acid. Cyanides another species that as you just encountered on the quiz is a reasonably good nucleophile. Now by contrast if you go to something like water then you have something that's much less basic much less nucleophilic. The pKa of the hydronium ion of the conjugate acid of water is negative 1.7. Water is very weakly basic. It is basic but sort of in name only. So as I mentioned in our previous discussion of esters if I just mix an ester and water you have no reaction and I also mentioned that that's fortunate for you because all of the lipids in your body all of your cell membranes are made up of esters and so if they cleaved at 37 degrees Celsius if they underwent hydrolysis at any appreciable rate you'd be in trouble. Now by similar token and again I'm using methyl acetate I'll use it a lot today just because it's a nice example and then I'll use acetic acid sort of in acetamide sort of as counter points but of course these could be any esters and any acids. So by very similar token if I mix methanol and acetic acid again the carbonyl is moderately electrophilic for an ester it's moderately electrophilic for an acid but water and alcohols are very weak bases and very weak nucleophiles. And remember when we're scanning over pKa's and I'm tossing out numbers like negative 2 or negative 3 for the pKa of the conjugate acid of an alcohol or negative 1.7 for water and positive 10 we're on a log scale. In other words we're scanning over 12 orders of magnitude what is that 10 to the third is a thousand million billion trillion orders of difference in basicity a trillion orders of magnitude or a trillion times different in reactivity to a first order approximation as nucleophilicity tracks with basicity. If a reaction of ammonia and methyl acetate takes a minute roughly then you know ball park it you're going to say a trillion minutes for the reaction of water and methyl acetate or a trillion minutes for the reaction of methanol and acetic acid. I don't know about you I know for me I don't expect to be around here a trillion minutes from now so they're not going to react. All right so no reaction. All right so chemists love to make stuff happen they love to make what they want to have happen happen. And so if you want acetic acid to react with methanol as was alluded earlier you do something that can protonate the carbonyl group. That's going to make the carbonyl group like a trillion times more electrophilic. In other words you protonate it in the presence of a very strong acid. So I could write that if I take acetic acid and I mix it with methanol in the presence of sulfuric acid I get methyl acetate and I get a molecule of water. So then chemists as I keep repeating are very bad at balancing equations but it's really important to keep this in mind because this reaction is an equilibrium. And so if I go ahead and just mix them and don't have a lot of methanol just a little bit of methanol I'm going to have an equilibrium in the middle. Sulfuric acid and methanol for all intents and purposes is similar. I got to have a lot of methanol or I've got to do something to soak up the water. And sulfuric acid actually really likes water so that's one of the ways to make it hang on to drive the reaction is just to use more than a little pinch of sulfuric acid. Question? The H2SO4 is indeed a catalyst and technically you don't need to use a whole mole equivalent. In practice sulfuric acid often is used in a reasonable quantity for exactly the reason I said because it tends to bind to the water it helps drive the reaction as well but it's not consumed by the reaction. So in fact chemists when they write a reaction like this will often show solvent and reagents with an arrow and so you'll often see this written as sulfuric acid sometimes you'll see it written as a catalyst you know with parenthesis cat and often you'll see methanol just indicated it's the solvent. Now with acetic acid I might use as little as possible but if I have a valuable carboxylic acid I'm probably going to use a whole big splash of methanol a whole pot of methanol a whole flask full of methanol for a couple of grams of acid. And so here's our product of the reaction. Now this reaction's been known for a long time it was discovered or invented by Fisher and so it's called a Fischer esterification. Sometimes people will use sulfuric acid for the reaction sometimes they'll use another strong mineral acid like hydrochloric acid. Ironically in the laboratory if I want dry hydrochloric acid in methanol not in water so I don't want to go to a bottle in the laboratory in the stock room and get HCl with water in it one of the ways I'll do that one of the ways I'll get anhydrous HCl in methanol is to throw some acetyl chloride into my methanol it'll react to give HCl in methanol and methyl acetate and those all will be just the methyl acetate I might not pay attention to and then I might use this as a reaction to take a big valuable carboxylic acid and make a methyl ester out of it so this is often how we roll in the laboratory. Alright let's take a look at the mechanism of the reaction. So in acid protons go on and off all different lone pairs any lone pair that's weakly basic is going to get protonated it's an equilibrium. If I throw sulfuric acid a strong acid into methanol it dissociates it protonates the methanol so my strongest acid in methanol is protonated methanol it's the leveling effect you learned about in general chemistry. So protons go on protons come off when the carbonyl gets protonated the carbonyl goes from being moderately electrophilic to being very electrophilic. We show the flow of electrons by drawing a curved arrow from the electrons to the hydrogen representing the formation of a new bond electrons flow back on to the oxygen atom we have an equilibrium we generate protonated acetic acid plus methanol I'll put my electrons I'm not always good about writing my lone pairs but I'll put my lone pair of electrons back on to the oxygen where they belong. Now this process the protonation of the carbonyl has made it into a good electrophile now it's ready to react even with a relatively weak nucleophile like methanol. Electrons flow from the lone pair on methanol to the carbonyl carbon atom we start to form a bond but concurrently because we can't have 10 electrons around the carbon concurrently electrons flow up on to the oxygen atom so we get an OH group here and we get a methoxy group with a proton and a positive charge on it and another OH group and I will try to be as good as I can about keeping track of all of my lone pairs of electrons so we form the tetrahedral intermediate and in strong acid protons go on protons come off protons go on and off every lone pair of electrons and so you can think of it as a proton being directly transferred among there I probably think of this more as being mediated by solvent I'd say that's a better way to think about the process and so in our equilibrium we have lots and lots of methanol around protons flow on protons flow off I will draw a curved arrow representing the flow of electrons back to the methanol doesn't matter which side I write the proton on which side I write the lone pair of electrons on I'm representing a tetrahedral oxygen atom and oxygen atom with four substituents equally disposed about it I guess you'd call it trigonal parameter for the geometry of the oxygen. Alright so that sort of takes us to an uncharged tetrahedral intermediate and this looks a heck of a lot like a geminal diol if you think about it and the common theme in all of this chemistry that we've talked about is these types of tetrahedral intermediates these types of geminal diols are not generally stable. The end of last lecture at the end when we were talking about acetals or in the previous lecture Hemiacetals I mentioned glucose a cyclic example that was stable we'll see a tetrahedral intermediate that's stable on the discussion section where you actually have it as a low energy species but in general tetrahedral intermediates are not stable they're not something that you can isolate or put in a bottle they're just a high energy species a stable stable enough that it's in an energy well stable enough that it can sit around for a microsecond but not stable enough that you could put it in a bottle and so our reaction continues in strong acid protons come on protons go off you put a proton back on the methoxy group we're just on the backwards pathway and so I'm going to continue forward protons come on and off every lone pair of electrons and so now we've protonated one of our OH groups it doesn't matter which one gets protonated they're both equivalent remember we're just tetrahedral about this oxygen now just as we had the attack we can have a breakdown now with the expulsion of water electrons flow down from the oxygen we can't stop at that point because that would force us to have 10 electrons around carbon carbon can't accommodate 10 electrons and so we're going to break down actually I am going to good person and write this mechanism on different lines so give me a moment here I'm just going to continue to balance here and so I will write the breakdown of this tetrahedral intermediate in the next step all right so as I was saying electrons flow down from the oxygen they flow back onto the oxygen this gives us a molecule of the protonated methyl ester and we have expelled a molecule of water and our final step is the very reverse of the first step of the reaction in the first step we put a proton onto a carbonyl in the last step we take a proton off of a protonated carbonyl we're in this vast sea of methanol remember this is an equilibrium reaction if we don't have a lot of excess methanol you're going to get only partial conversion to the ester so we have a ton of methanol floating around our methanol which in protonated form served as the catalyst is now going to accept a proton our protonated methanol at the very first step of the reaction was consumed our acid catalyst was consumed in the very last step it is regenerated and so those six steps constitute the mechanism for our fissure esterification they constitute the mechanism for ester formation thoughts or questions? so your question is why does it protonate this oxygen? why is this oxygen protonated? why is this protonated? because when we push electrons down over here it ends up with a positive charge on the oxygen now remember in the back of your mind when you see this structure as we just saw in the quiz there are multiple contributing resonance forms so that is one resonance form think in your mind for a second about two other resonance forms you can picture another resonance form in which the positive charge is on this carbon and a third resonance form in which we have a double bond to this oxygen single bond to this oxygen and a positive charge on this oxygen and collectively all three of those resonance structures make up a picture of the actual species just as in your oxo-carbenium ion I asked you to draw one structure although it was fine if you drew two resonance structures or it was fine as a matter of fact if you draw any of the three resonance structures any of the two resonance structures so we are just thinking about one of the different pictures that are present in part because if you look at this it is already a long mechanism and so you are sort of holding in the back of your head all of this relevant stuff all right any other questions that I want to talk about the reverse reaction the hydrolysis of esters remember fissure esterification is an equilibrium so if I take and again I am keeping my whole lecture really really simple with simple small molecules if I take methyl acetate and I treat it now with water and sulfuric acid I am going to hydrolyze it to acid acid plus methanol just the reverse of the reaction I could write it like this I could write it like this saying I am treating it with sulfuric acid in water it is all the same thing and since this is so identical to what we just saw at this point you should be able to write a mechanism for acid catalyzed ester hydrolysis I will leave that to you it is identical to the mechanism that I just wrote up but in reverse and you can figure that out all right I want to move on to a little bit of other chemistry of esters carboxylic acids and then talk about amides and nitriels and again I will keep our keep things kind of simple and general esters as I said are moderately electrophilic they react with strong nucleophiles if I treat an ester with sodium hydroxide potassium hydroxide for most intents and purposes these are equivalent in water I get the carboxylate salt I get the alcohol you call this reaction saponification it is a reaction that mankind has been doing for hundreds of years before we had organic chemistry it is the making of soap when you take a fat which is a triester of glycerol 1, 2, 3 propane triol with 3 long chain carboxylic acids esterified on and you stir it with sodium hydroxide that's Lai Drano the sodium hydroxide hydrolysis saponifies the glycerol esters to get the sodium salts of the carboxylic acids that have greasy tails and polar head groups and like both water and grease which is very good for getting clean in the shower makes my cells so reaction here same same principle as we saw in the aminolysis I kind of wanted to when I was talking about this and thinking about where to present it I kind of wanted to present it after we did the water the acid promoted hydrolysis but mechanistically it's right up there with the aminolysis and aminolysis we talked about in other words here's our ester group hydroxide is a strong is a good base a moderately strong base relatively strong base it's a good enough nucleophile it attacks our carbonyl I'll give you a little bit of an abbreviated mechanism here only showing relevant lone pairs we get our tetrahedral intermediate our tetrahedral intermediate is going to break down it kicks out the OR group and again I'm just skipping a few lone pairs here this gives rise to the carboxylic acid plus the alkoxide and the alkoxide is basic and so the alkoxide reacts to form the carboxylate and again I'm not going to write out every curved arrow and every step in painful detail but the carboxylate reacts to give you the alkoxide salt and the to give you the the alkoxide reacts to give you the carboxylate salt and the alcohol and in a preparative sense if I carry out this reaction in the laboratory and I want to isolate my carboxylic acid a very common laboratory procedure to saponify an ester with sodium hydroxide then wash the aqueous layer that contains the carboxylate salt to remove the alcohol and any unreacted ester to extract it with ether to wash it with ether and then very commonly in the laboratory you will acidify with some strong acid in water like HCl or H2SO4 and isolate from there the carboxylic acid sometimes in the laboratory it will precipitate out alright so that gives us a little bit of an overview of carboxylic acids and of esters and now I want to move on to the last members the last main members there are plenty of other members in the carboxylic acid family but I want to move on to the last main members of the family on to amids and nitriels amids I'll write them in general form with two R groups here that could be two hydrogens in which case we have a primary amid a hydrogen and an R group which case we have a secondary amid or two R groups in which case we have a tertiary amid nitriels look very different and yet in some ways are very similar both of these compounds are generally less reactive toward nucleophiles than esters and I think it's kind of easy at least to compare an amid to an ester we already saw this in the IR the stretching frequency for the amid carbonyl is lower there's less double bond character the nitrogen of the amid is less electronegative than the oxygen of the ester the nitrogen of the amid is better able to donate in electrons by resonance to the carbonyl making it less electrophilic and so a general principle is that amids and nitriels generally react less quickly and so if I tried to try to epitomize this with a reaction and again I'm going to write very simple compounds so I will write a set of my but again this could be any amid if I imagine treating it with sodium hydroxide in water like we did with our ester in saponification how would I epitomize this I'd say long time or heat to make it react so let's say delta or long time would be how I'd describe this and again we get hydrolysis we get cleavage by the sodium hydroxide to the carboxylate salt and in this case since we have a primary amid to ammonia now what do I mean by long time well actually the drain oh is which I mentioned for ester cleavage is a good example when hair hair you know you get your drain clogged up with hair is made up of protein which are polyamids when I throw drain oh down the drain it doesn't clog the unclog the drain instantly the drain oh sits with the hair and the grease that are down the drain for a number of hours before it unclogs it in the laboratory if you want to speed this reaction along you could boil your sodium hydroxide with an amid but unlike my comment about trillions of seconds for the water promoted hydrolysis of an ester the reaction occurs even at room temperature at a reasonable rate on the laboratory time scale and again nitrials maybe a hair less reactive than amids I know that that problem comes up on your sapling and but honestly I don't think of them personally as being very different so I can say sort of ditto if I take acetonitrile and treat it under these conditions with sodium hydroxide in water maybe with heat or a long time you know a few hours I'll get again sodium acetate plus ammonia all right by by now you should be reasonably strong in your mechanistic understanding of carboxyl compounds and maybe I'll just give you a quick quick abbreviated tour of some of the mechanisms here your textbook has them in more detail if you want but all of the principles that you can think about are similar hydroxides a reasonably good nucleophile it's it's basic it can attack we can kick up form a tetrahedral intermediate and in part in part here I really don't want to lose the forest from the trees this is the gist of this mechanism your textbook writes the next step in the mechanism as kicking out NH2 minus I think it's okay to think about that the realities maybe a little bit more complicated in some cases one can see died deprotonation occurring but I think I think in terms of your thinking right now it's fine to think about this anyway so that gives us our carboxylic acid and our amide anion the amide anion is very basic you can think of it as pulling off a proton on the carboxylic acid to give you the carboxylate plus ammonia remove the Click it 그 And for nitriels, again, I don't want to get fantastically into a whole lot of mechanism here. And so maybe I'll just sort of start us out here on the mechanism. There's a lot of proton shuffling that's going on. But the gist, remember the theme that I talked about in carbon nitrogen double bonds is basically in very many ways they're like carbon oxygen double bonds. And in a similar way, carbon nitrogen triple bond is very much like a carbon yield or a carbon nitrogen double bond. And so if you look at acetonitrile, you can think of it. So now we're looking at the hydrolysis of nitriels. You can think of this as being very similar. In other words, hydroxide adds, we kick in electrons. You get a negative charge on nitrogen. We're going to shuffle some protons around. I'll say minus H plus, in other words, you can think of this or I guess first we're going to put on a proton here. So I'll say plus H plus. Of course, that's not plus H plus. That's water going ahead and protonating. You can think of this as minus H plus as the next step. Again, we've got sort of a lot of tedious proton shuffling in the mechanism at this point. And I'm abbreviating things a little bit. One thing to keep in mind, again, this theme that I mentioned where carboxylate, where nitrogen, oxygen, nitrogen carbon double bonds are very similar to carbon oxygen double bonds. And so this structure here is really just like the analog of a carboxylate. In other words, there are two resonance structures here. And again, I'm kind of abbreviating this. And so we have two equivalent resonance structures. And then the last step you can think of is just that we're going to pick up a proton. And I'll draw this explicitly. It's nice to be able to pick and choose the resonance structure that you want when you're writing a mechanism. And so I'll just say our last step here is going to be protonation. In some cases you can stop your nitrile hydrolysis at the primary amide. In other cases the amide is going to go on further all the way to the carboxylate. All right, just as esters can be hydrolyzed by aqueous acid, amides can be hydrolyzed by aqueous acid, nitriles can be hydrolyzed by aqueous acid. If I take some amide, I'll write this as RCO NR2 prime. And I cook it up with acid H3O plus in water. Maybe heat that a little bit. And again, of course you can't go to the stock room and get a bottle of H3O plus. It's going to be sulfuric acid in water or HCl in water. You'll get the carboxylic acid and the corresponding ammonium salt. So if I took acetamide as just an example, since I was using acetamide in the previous panel and I talked about trying to stick to small molecules, and let's say I cook that up with sulfuric acid and water, maybe a little bit of heat boiled it up, you get the ammonium salt, the ammonium in this case, bisulfate HSO4 minus and the carboxylic acid. And this is a reaction that's done in the laboratory with proteins. If you want to break down a protein into individual amino acids, for example, if you want to extract the amino acid proline from hair clippings, and this is a procedure in organic syntheses, you can take 6 molar hydrochloric acid, that's about half the strength in the bottle, boil your hair or boil your protein with it for a number of hours and it will break down to the individual amino acids. So it's a very standard way to hydrolyze amides. And again, I've just given acetamide as an example to keep the structure small here. Do the same thing just for comparison with acetonitrile for the sake of simplicity, I'll just write ditto marks here and you get the exact same products, you get the corresponding acetic acid and the ammonium bisulfate salt. And maybe since all of this is really, really, really analogous to ester chemistry, all the things we covered, maybe I'll say write as an exercise on your own, write a mechanism for let's say the acid-promoted nitrile hydrolysis. Okay. Quick question. Yeah, so for the blackboard on the left, can the OH group just perform a nucleophilic attack on the carbonyl? Yes, yes, yes, and I was only starting us out on the nitrile hydrolysis. So in the cleavage of the nitrile bisodium hydroxide to the corresponding amide, yes indeed, you first, to the carboxylic acid, the first step is the hydrolysis to the amide and then it continues on. Oh, okay. So, and sometimes if you're careful, you can control it and stop it at the amide stage. All right. The last couple of minutes that I would like to take here, I want to talk about a few sort of synthetically useful reactions and kind of wrap up our carboxylic acid chemistry. So, we haven't really talked about where acid chlorides come from and basically acid chlorides are high in energy and so you make them from other highly reactive species. Acid chlorides, indeed, remember when I started out, I said every member of the carboxylic acid family can be interconverted by some chemistry or another and so I'm only giving you a little bit of a smattering here but making an acid chloride is a very useful reaction. Treating a carboxylic acid with thionyl chloride is a great way to do it. There are a few other species that are also used for this but thionyl chloride, SOCl2, is particularly popular and the products of the reaction are the carboxylic acid chloride plus if we're going to write a balanced equation, sulfur dioxide and HCl hydrogen chloride gas which generally bubble out. So, I don't want to go into full detail on the mechanism and again I'll leave it to your textbook to do this but I do want to bring out a theme that highlights this chemistry. Thionyl chloride is kind of a sulfur acid chloride. It's kind of a double acid chloride of sulfur. Indeed, this is very similar to another species, phosgene which has a carbon here which also does this reaction. It's a very reactive molecule. It's extremely electrophilic. You've got two chlorines pulling electron density away from sulfur. Through the same types of chemistry that we saw for acid chloride reactions, carboxylic acids can react with thionyl chloride to give an intermediate that looks like a funny anhydride. And this is a theme that you should pick up on in seeing the forest from the trees in this chemistry. And that is that all of these species where you have a carbonyl with an ester linkage, where you have a carbonyl with an ester like linkage to another electrophilic species, the carbonyl becomes super electrophilic. And nucleophiles can attack, even not very good nucleophiles, can attack at there. And this theme, forget the details now, look at the theme. We've kicked out chloride already. That's one of the byproducts. Chloride can come in, form a funny looking tetrahedral intermediate, and that intermediate can fall apart, kicking back, kicking out sulfur dioxide so we get our acid chloride, sulfur dioxide, and chloride anion. And when you write a balanced equation since a proton was lost at the very beginning, you get HCl. All right. That same theme reemerges in other carboxylic acid chemistry. Remember, this is the theme of the anhydride. This is the theme that when you have something electron withdrawing on the carbonyl, it makes it into a good electrophile. And so your textbook gives you another reagent, which in various forms and variations is quite popular for forming esters and amids. We will see it again in the very last lecture when we talk about the chemistry of amino acids, peptides, and that reagent is DCC. And the general idea is acid chlorides and acid anhydrides are generally species on the way to somewhere. They're generally things that you're making to use. Esters and amids are widely valuable, important compounds. They're stable enough to be in drugs. They're the proteins and peptides in your body. And they're molecules that are a lot of interest. And so being able to take a carboxylic acid and an alcohol and make an ester is an extremely valuable operation. Being able to take a carboxylic acid and an amine, I'll write it as a primary amine, although it could be a secondary amine or ammonia for that matter, and make an amide. That is an extremely valuable operation. And a reagent that often gets used for this is called DCC. They're variants of it. But what this reagent is is dicyclohexyl carbodiimid. The carbodiimid functionality is another member of the carbon dioxide family of molecules. And carbonic acid and carbon dioxide are essentially like a double acid, a double acid, carboxylic acid. Carbon's in the plus 4 oxidation state here. The carbon nitrogen bond is electrophilic. And the carboxylic acid in the above case can add to the carbon nitrogen bond. And here's where this theme comes in. So here's our cyclohexane ring. The CC is cyclohexyl carbodiimid. So we have a cyclohexane ring. And here's the big picture. Here's the big idea. The carbodiimid reacts in exactly the same way. We see thionyl chloride. It reacts to make something that looks a heck of a lot like an anhydride. Because remember, the carbon nitrogen double bond is very similar to the carbon oxygen double bond. And a nucleophile can come in just as we have seen time and time again with all of the chemistry we've been seeing today. A nucleophile can come in. And I'm just going to abbreviate CY for cyclohexane. Our nucleophile can come in. And we can kick back and kick out. And eventually, basically, end up giving rise to our acyl nucleophile. Our acylated nucleophile above and dicyclohexyl urea, which is a byproduct of this reaction. So DCC is a very useful reagent for making esters and amides. All right. The last thing I want to do, your book, your textbook has nicely kind of picked and chosen a few additional key reactions. And I'd like to remind you of these, although I know that you also will be able to learn about them from the readings. And these reactions basically fit in the broad theme that we've seen. Lithium aluminum hydride is a super, super good hydride nucleophile. It can push hydride into practically any double or triple bond between carbon and any sort of electronegative atom. It can push it into a carbonyl group. It can push it into an imine. It can push it into a nitrile. Lithium aluminum hydride generally reacts completely to reduce things down. And so your textbook has chosen as a couple of examples to show you in the chemistry of nitriles that lithium aluminum hydride can react with a nitrile to give a primary amine adding in two equivalents of hydride temporarily going through an intermediate where you have aluminum on the nitrogen. Your textbook has chosen to remind you. And this is again just a smattering of the rich chemistry of the carboxylic acid family, much of which you're going to be guided not by having, and this is where people always make a mistake in learning chemistry, organic chemistry, not by memory because there's way too much of it. But by broad principles, all the principles we've seen today, you can apply to all the members of the carboxylic acid family and basically intuit lots and lots of different reactions. So your textbook has also pointed out and reminded you that nitriles can be reduced selectively. And we saw this in esters. We said lithium aluminum hydride blasts the heck of an ester all the way down to an alcohol. Di-Bal is a more mild reducing agent. It can stop and only add one equivalent of hydride. And so your textbook chooses to give you an example of a di-Bal reduction of a nitrile with water as a workup where you can use H3O plus as a workup. Remember, you're going to get an imine initially, but as was aptly asked early on, I think the gentleman in the third row there about primary imines, primary imines generally aren't stable and break down to the corresponding aldehyde in water conditions. And I'll give you two more examples from your textbook while we're talking about the chemistry of nitriles. And again, I could show you many other examples. So Grignard reagents and organolithium reagents, I'll call it R prime MGX or R prime LI followed by an aqueous workup H2O or H3O plus can add to give you ketones like so. And again, this is the same general idea that we've seen before, the idea that these nucleophiles can add in the case of the nitrile group, you often can stop at one addition, which is something you generally can't do with esters. Anyway, I think that basically wraps it up for the chapter. We will be picking up with chapter 23 next time. Thank you.
reaction to get acetamide and the other product laboratory in the stock room and get HCl with the positive charge is on this carbon and a third theme of the anhydride. This is the theme that chemistry, organic chemistry, not by memory