Loudon Chapter 20 & 21 Review: Carboxylic Acids & Derivatives CHEM 3331, Jacquie Richardson, Fall Page 1

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1 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 1 These two chapters cover compounds which are all at the three bonds to more electronegative atoms oxidation state. They re called carboxylic acid derivatives, because they all have a carboxylic acid as the parent compound. If you want to make any of them, you often have to go through the acid form first, although there are cases where you can go directly from one derivative to another. Cl 2 Acid chloride Anhydride Carboxylic acid Ester Amide itrile Least stable/most reactive Most stable/least reactive You can rank them by stability based on the size of the delta plus at the carbon. Acyl chlorides have the biggest delta positive and nitriles have the smallest. As a side note, cyclic esters and amides are called lactones and lactams respectively. These groups do just the same chemistry as a normal ester or amide, though rings smaller than five or larger than six are often too unstable to form easily. Lactones Lactams Chapter 20 mostly just covers how to make carboxylic acids in the first place, and how to make each of the derivatives from acids. Chapter 21 gets more into reactions you can do with the derivatives. I ll mostly follow the order they use to cover the topics, but I might switch things around a bit in some places. Making carboxylic acids 1) xidation of primary alcohols and aldehydes: This normally uses something like Cr 3 and pyridine, or stronger conditions. We ve seen this in Ch. 10 and 19. Cr 3 Cr 3 pyridine pyridine 2) xidation at the benzylic position: This uses an oxidizer like Cr 3, but in vigorous conditions (usually acid and heat.) This was in Ch. 17. Cr 3 heat, 2 S 4 3) zonolysis: This is less useful because you have to break carbon-carbon bonds to do it. This is from Ch. 5. 1) 3 2) 2 2, 2 4) Grignards attacking C 2 : This is a new one in Ch. 21, but it s similar to something we saw before. Ch. 19 shows how to use a Grignard to attack a carbonyl. We can do the same thing by attacking carbon dioxide, which is kind of like a double carbonyl. Then, we just finish it off the same way, with an acid workup. C 3 + MgBr

2 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 2 ote that whatever was, we ve just added one carbon to it overall. This is a useful way of extending chains one carbon at a time. The only limitation is that has to be compatible with Grignards no alcohols or unprotected carbonyls, etc. 5) S 2 with a cyano group, followed by hydrolysis: This one doesn t show up until Ch. 22, but it s a useful complement to the Grignard/C 2 reactions shown above, and worth mentioning here. In this case, we can make a particular acid derivative by using S 2 to replace a leaving group with a C. Then, we can convert the nitrile to the parent acid compound by hydrolysis, which we ll look at the mechanism for shortly. Br ac acetone 2, heat, + or - Like the Grignard reaction above, this ends up extending the chain length by one carbon. The only requirement is that has to be S 2-capable, so primary is best. 6) Conversion from any other acid derivative: Again, this is Ch. 22 chemistry, but you can take any of the compounds shown at the beginning of this packet and convert them to the acid by hydrolysis. We ll see the mechanism later. If it s something more reactive than acid (like anhydrides and acid chlorides), you only need water. If it s less reactive, you need water, heat, and either acid or base. 2 2, heat, Cl + or , heat, + or - General idea of mechanisms Most of the reactions in Ch. 21 and 22 involve swapping out the group beside the carbonyl. Unlike S 2, you can t just attack and kick out the leaving group at the same time. You attack first and break up the carbon-oxygen double bond. This gets you to a point where the central carbon has four total groups attached the tetrahedral intermediate. Then the oxygen s lone pair comes back down and kicks out the leaving group. The general idea looks like this. X X Y Y Y Tetrahedral intermediate Depending on what you re doing and whether it s in acidic or basic conditions, there might be a few extra steps somewhere in there to account for protonation or deprotonation. But the general pattern is still the same for most of the reactions in these chapters. Making esters from acids Fischer esterification is the simplest way of making esters. You can react the carboxylic acid with the alcohol and some catalytic 2 S 4., heat 2 S 4

3 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 3 The mechanism is pretty much the same as the general pattern, but you protonate the carbonyl first since you re in acid. You also need to protonate the before it will leave. S 4 S 4 S 4 2 ote that in the middle you have the neutral tetrahedral intermediate. Another option we have is different from that general reaction pattern shown above. Instead, we keep both the oxygens that started out in the acid, and just stick an group onto one of them. This is called alkylation, and you need a good leaving group on to do it. ne way is with diazomethane, C 2 2. The leaving group here is spectacularly good, since it s nitrogen gas which leaves. Diazomethane also acts as its own base first, to deprotonated the acid. C 3 2 C 3 C ote that the oxygens stay on the molecule the entire time, just one of them gets alkylated. The other option uses a slightly less good leaving group, and you need a different mild base to deprotonated the acid in the first step. verall, these are written as: C 2 2 KC 3 3 C I C 3 C 3 I C 3 K 2 C 3 C 3 You can sometimes use different groups instead of just C 3, but they have to be very good at doing S 2. Benzylic positions are an okay choice. Usually, though, these reactions are considered the best way to make methyl esters (with an C 3 group) and not much else. Making amides from acids This is not a reaction we can do easily, because if you combine an acid and an amine they re much more likely to do acid-base chemistry first You can sort of fix this by heating them up to several hundred degrees, but there are better ways of making amides. Usually, you make them from acid chlorides instead. Making anhydrides and chlorides from acids For chlorides, we can use the same special reagent we used to turn alcohols into alkyl chlorides: SCl 2 or a similar molecule, PCl 5. We still don t cover the mechanism. SCl 2 or PCl 5 Cl

4 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 4 To make the anhydride, we have a couple of options. The name anhydride means it s had a molecule of water removed. If you take two carboxylic acid molecules, stick them together, and remove a water, you get an anhydride. You can do this by using a very powerful dehydrating reagent, P 2 5. This takes two copies of the same acid and converts them to the anhydride. P 2 5 There s another option that only works to make five- or six-membered cyclic anhydrides. If you mix it with an acyclic anhydride, they ll swap which one is the acid and which is the anhydride. + 2 ydrolysis of derivatives Any of the derivatives of carboxylic acids can be converted back into the acid by using water. If it s a more stable derivative, you also need either acid or base as a catalyst. The more stable the derivative is, the more powerful conditions you need to make it break up higher temperatures and more concentrated acid/base. The mechanism varies slightly depending on which derivative you re hydrolyzing and whether you re in acid or base. Kind of like in Ch. 19, if you re in acid you ll protonate the carbonyl first to make it more attackable. You ll also protonate the leaving group, to make it drop off more easily. The mechanism is identical for esters and amides. Acid-catalyzed ester hydrolysis: Acid-catalyzed amide hydrolysis: In base, you just go ahead and attack with -, because you can t protonate the carbonyl first. Since the product is a carboxylic acid, it immediately gets deprotonated by the base. Another name for base-catalyzed ester hydrolysis is saponification, since that s how soap is made. There is a difference here between ester and amide mechanisms: - is a much better leaving group than - 2 (the pkas are ~16 and ~35, respectively). This means that even though you re in base, you still have to protonate the 2 group with water to get it to leave. (The solutions manual gets this wrong in the answer to 21.10b). Base-catalyzed ester hydrolysis:

5 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 5 Base-catalyzed amide hydrolysis: If you re hydrolyzing a nitrile, the mechanism is longer. It breaks down into three sections: adding water to make an imidic acid, rearranging to an amide, and hydrolyzing the amide. The first part looks a lot like addition to a carbonyl, just you re attacking a triple bond to instead of a double bond to. In acid, you have to protonate the nitrogen first. The rearrangement steps going from the imidic acid to the amide look a lot like the keto-enol tautomerization. Acid-catalyzed nitrile hydrolysis: Base-catalyzed nitrile hydrolysis: (Imidic acid) (Imidic acid) (Amide) Both of these reactions finish up by hydrolyzing the amide, via the mechanism shown above (either in acid or base) 2 (Amide) The two reactive derivatives, acid chlorides and anhydrides, don t need a catalyst. They react with water on their own, within minutes. This is not something you d do on purpose, it s just a warning that you have to keep water away from them. Cl 2 Starting from here, I won t show any mechanisms if they follow the same general pattern shown above. You can figure out the exact details based on conditions. eactions with acid chlorides Being the most reactive derivative, acid chlorides will easily convert to pretty much any other derivative if you combine it with the right reagents. To make an amide, combine it with an amine. 2 + Cl (reacts with another molecule of 2 ) Cl 2 The problem is that in these reactions, you generate a molecule of Cl. This is not a problem in most cases, but if you re using amines then Cl will add to it, and make that amine incapable of doing the reaction. If you use equal amounts of acid chloride and amine, the reaction will only go halfway because half the amine gets acidified. There are two ways around this: either use twice as much amine, or throw in one equivalent of some sacrificial amine, usually pyridine, that can soak up Cl but won t make an amide itself. The overall balanced reactions that give you decent yield are: pyridine Cl 2 Cl 2 To make an ester from an acid chloride, you just need to react it with an alcohol. nly one equivalent is required, but you still need to add some weak base like pyridine to neutralize the Cl. 2

6 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 6 pyridine Cl To make an anhydride from an acid chloride, you need to react it with the deprotonated carboxylic acid, known as the carboxylate (usually with a sodium counterion). The acid itself is not strong enough to attack the chloride, but the carboxylate is. This gives acl as a byproduct, rather than Cl, so no base is required. ' a Cl ' This is a pretty useful reaction for making asymmetric anhydrides, with two different groups on them. The methods we saw before only give us symmetric anhydrides. eactions with anhydrides Again, as a reactive derivative it s easy to turn this into other, more stable derivatives. You don t even need a base like you did with acid chlorides, since you re not producing Cl as a byproduct. 2 2 eactions with Esters This is more difficult because esters are pretty stable. You can still convert them to other compounds though. If you react an ester with an amine, you can get an amide. If you react an ester with a different alcohol, you get a different ester this is called transesterification. 2 ' 2 ' eductions Like we saw in Ch. 19, you can reduce carbonyl compounds with hydrides. You can do the same with acid derivatives, and you usually end up going from the three bonds to more electronegative atoms oxidation state to the one bond to more electronegative atoms oxidation state. An important thing to point out is that ab 4 does not work for most of these derivatives it only works for aldehydes and ketones. LiAl 4 is what you want to use here. The first example shows up in Ch. 20, on the acid itself. Since it has an acidic hydrogen, that reacts first with the Al - 4. Then the remaining Al 3 reduces the acid to the aldehyde. Finally, the aldehyde gets reduced by LiAl 4 like in Ch. 19. verall it looks like this: 1) LiAl 4 2) 3 + You can do the same thing with esters. They break up the ester group entirely, so you end up with two alcohol molecules, one from each half of the ester. 1) LiAl 4 2) 3 + +

7 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 7 Amides are the odd one out in this category. ather than reducing to an alcohol, they actually choose to drop the carbonyl oxygen entirely and keep the nitrogen. The book explains this part pretty well on pg The overall reaction looks like this: 1) LiAl 4 2 2) ) - The - is necessary because otherwise you would end up with a protonated version of the product instead. You can also reduce nitriles to primary amines. Again, you need to finish up with - so the amine is neutral. 1) LiAl 4 2) ) - Another exception to this general pattern is reduction of acid chlorides. In this case, we can stop at the two bonds to more electronegative atoms oxidation state. You have to use an acid chloride and hydrogenate it with a poisoned catalyst. In fact, you can also use Lindlar catalyst here. This is called osenmund reduction. Alternatively, you can use LiAl(C(C 3 ) 3 ) 3, otherwise known as lithium tri(tert-butoxy)aluminum hydride. This is a very weak version of LiAl 4. 2 LiAl(C(C 3 ) 3 ) 3 Cl Lindlar Cl The reason you can get away with both these reactions is because unlike most of the reductions above, acid chlorides are more reactive than the aldehydes they make. A sufficiently weak reducing agent can react with the acid chloride but it can t react on the aldehyde that gets produced. eactions with rganometallics There are two useful reactions that you can do with organometallics: esters plus Grignards/organolithiums, or acid chlorides plus cuprates. Esters will react twice with organometallics. The first time looks just like a Grignard attacking an aldehyde that we saw in Ch. 19, but the biggest difference is that you can kick out a leaving group after this happens. This gives you a ketone which can react with a second equivalent of organometallic. 3 + MgBr MgBr Just as we saw in the reductions section, acid chlorides are more reactive than aldehydes or ketones. This means that if we use a weak enough organometallic, we can add just once without risking a second addition. Cl Cu Decarboxylation The general idea here is that if you have a carboxylic acid two carbons away from any type of carbonyl (ketone, aldehyde, acid, ester, etc.), then the entire C 2 unit can drop off. The that was part of the acid ends up attached where the C 2 used to be.

8 Loudon Chapter 20 & 21 eview: Carboxylic Acids & Derivatives CEM 3331, Jacquie ichardson, Fall Page 8 The mechanism for this is actually not too different from that for Diels-Alder. It helps to keep in mind that the molecule is capable of hydrogen-bonding to itself, so it normally looks a little different than what s shown up there. There s already a partial bond between the other carbonyl and the. To do this mechanism, you just show it going and picking up the fully. Everything else clicks around the ring, like in Diels-Alder. Then to finish it up, you do a keto-enol tautomerization under acidic conditions. - C 2 Keto-enol tautomerize