WEBVTT 00:01.067 --> 00:04.527 J. MICHAEL MCBRIDE: So we were talking about green chemistry. 00:04.533 --> 00:07.603 Today we'll talk about one aspect, the Mitsunobu 00:07.600 --> 00:11.330 reaction, and then get on to acids and acid derivatives. 00:11.333 --> 00:15.103 And then we'll do that again next lecture, more about acid 00:15.100 --> 00:17.530 derivatives, condensations, and some stuff about 00:17.533 --> 00:23.003 carbohydrates, and then the last two lectures. 00:23.000 --> 00:24.870 Now, remember when we were talking about green chemistry, 00:24.867 --> 00:27.097 there were some new processes that were desired. 00:27.100 --> 00:30.400 There were old processes that need improvement, and new 00:30.400 --> 00:36.170 processes that need to be developed, according to the 00:36.167 --> 00:40.127 wishes of the pharmaceutical industry. 00:40.133 --> 00:44.403 Remember, there were six votes for aromatic cross-coupling I 00:44.400 --> 00:45.700 mentioned right at the end last time. 00:45.700 --> 00:49.430 That's how to put two benzene rings or other aromatic rings 00:49.433 --> 00:52.373 together, without using haloaromatics. 00:52.367 --> 00:57.397 We haven't talked about those reactions, but that's their 00:57.400 --> 00:58.870 top desire. 00:58.867 --> 01:04.327 Then how to use aldehydes or ketones plus ammonia and 01:04.333 --> 01:06.673 reduction to give a chiral amine. 01:06.667 --> 01:10.927 Now, notice how many of these things have to do with getting 01:10.933 --> 01:13.973 a single enantiomer, because that's so important in drugs, 01:13.967 --> 01:15.697 to have a single enantiomer. 01:15.700 --> 01:17.900 And this, notice what they want here is to 01:17.900 --> 01:19.030 do what nature does. 01:19.033 --> 01:22.903 We talked before about making glutamic acid by what's called 01:22.900 --> 01:26.900 reductive amination, where you have a reducing agent, NADH. 01:26.900 --> 01:29.400 You make the imine and then reduce it. 01:29.400 --> 01:33.830 So four of the six pharmaceutical companies said 01:33.833 --> 01:36.703 that was something they would really like to be able to do. 01:36.700 --> 01:39.970 Or asymmetric hydrogenation of olefins 01:39.967 --> 01:41.627 and enamines or imines. 01:41.633 --> 01:44.073 And notice, this is hydrogenation of an imine, 01:44.067 --> 01:45.667 this very reaction here. 01:45.667 --> 01:47.527 But what they want is asymmetric. 01:47.533 --> 01:51.073 That is, the ability to make a single enantiomer so you don't 01:51.067 --> 01:55.467 have to throw half the stuff away and do a separation. 01:55.467 --> 01:58.567 Four voted for a greener fluorination method. 01:58.567 --> 02:02.527 A lot of drugs have fluorine in them, and the reagents that 02:02.533 --> 02:06.673 put those in are often pretty vigorous ones. 02:06.667 --> 02:10.367 Nitrogen chemistry, avoiding azides, and three, avoiding 02:10.367 --> 02:13.527 hydrazine, which is very poisonous. 02:13.533 --> 02:15.373 Asymmetric hydramination. 02:15.367 --> 02:17.227 Again, asymmetric. 02:17.233 --> 02:19.333 Greener electrophilic nitration. 02:19.333 --> 02:21.733 We talked about electrophilic aromatic 02:21.733 --> 02:24.033 substitution, nitration. 02:24.033 --> 02:26.833 But what they want is a greener way to do it. 02:26.833 --> 02:30.773 And the final one is asymmetric addition of HCN. 02:30.767 --> 02:34.297 Notice, incidentally, that four of these eight-- half of 02:34.300 --> 02:37.770 them-- have to do with asymmetric synthesis, making 02:37.767 --> 02:38.897 chiral things. 02:38.900 --> 02:43.470 And notice that six of them, six of the eight, have to do 02:43.467 --> 02:44.727 with nitrogen. 02:46.633 --> 02:50.803 Now at the end last time, we were talking about the other 02:50.800 --> 02:53.700 table, the one of processes that need improving. 02:53.700 --> 02:56.600 And in particular, something that seems surprising to many 02:56.600 --> 03:00.430 chemists is O activation for nucleophilic substitution. 03:00.433 --> 03:03.933 We've talked about that so long, getting a halogen or a 03:03.933 --> 03:09.373 tosylate that can be substituted, but they want 03:09.367 --> 03:10.967 something that's better than that. 03:10.967 --> 03:13.927 And noticed that three voted for a safer and more 03:13.933 --> 03:16.233 environmental Mitsunobu reaction. 03:16.233 --> 03:19.073 So let's see what the Mitsunobu reaction is. 03:19.067 --> 03:23.897 And you'll see that it is a type of that second case, 03:23.900 --> 03:27.170 activation of OH for nucleophilic substitution. 03:27.167 --> 03:29.897 So there's a picture of Mitsunobu. 03:29.900 --> 03:34.200 And in the 1960s, he invented this reaction with a great 03:34.200 --> 03:35.530 leaving group. 03:35.533 --> 03:39.433 The OP plus Ph1-3 leaving group. 03:39.433 --> 03:42.803 And so if you bring in a nucleophile, bingo! 03:42.800 --> 03:46.730 It's a very clean substitution reaction, that is clean in the 03:46.733 --> 03:50.473 sense that it gives a high yield. 03:50.467 --> 03:53.567 And it's very general. 03:53.567 --> 03:57.767 Any nucleophile will work, it seems, if it has a pKa, if 03:57.767 --> 04:00.167 it's more acidic, than 15. 04:00.167 --> 04:04.067 For example, a carboxylate can get an R put on it, or the 04:04.067 --> 04:10.527 phosphoric acid, or the imide, or N3 minus, or most 04:10.533 --> 04:13.633 significantly, active methylene compounds. 04:13.633 --> 04:18.803 So let's see what that means, active methylene compound. 04:18.800 --> 04:23.130 So here's a specific example taken from Mitsunobu's paper 04:23.133 --> 04:25.333 in the journal Synthesis to make 04:25.333 --> 04:27.803 (S)-(-)-methylsuccinic acid. 04:27.800 --> 04:30.930 So it's an asymmetric synthesis to make it, and it 04:30.933 --> 04:34.133 starts with a chiral starting material, 04:34.133 --> 04:36.633 (S)-(-)-ethyl lactate. 04:36.633 --> 04:40.503 So the idea is to make the OH into a leaving group, so let's 04:40.500 --> 04:42.830 read through his thing and see how he does it. 04:42.833 --> 04:46.273 He uses the reagents 1 and 2. 04:46.267 --> 04:50.397 Now, 1 is triphenylphosphine, and 2 is a compound whose 04:50.400 --> 04:55.070 acronym is DEAD, and we'll see later what-- it's diethyl 04:55.067 --> 04:57.067 azodicarboxylate. 04:57.067 --> 04:58.397 So we'll see how that works. 04:58.400 --> 05:00.930 But at any rate-- those two in the next slide-- 05:00.933 --> 05:04.633 but for now, let's just take that that makes that leaving 05:04.633 --> 05:09.533 group, puts the triphenyl phosphorus on the oxygen, with 05:09.533 --> 05:10.803 a plus charge. 05:10.800 --> 05:12.870 So now we've got a good leaving group, and we want a 05:12.867 --> 05:15.197 nucleophile to displace it. 05:15.200 --> 05:18.600 And the nucleophile they use in this example is ethyl 05:18.600 --> 05:20.430 cyanoacetate. 05:20.433 --> 05:26.603 So it's the ethyl ester of acetic acid, but the carbon 05:26.600 --> 05:28.400 has a cyano on it. 05:28.400 --> 05:33.430 And that makes it an active methylene compound. 05:33.433 --> 05:36.233 And the reason is it has a pKa of 13. 05:36.233 --> 05:39.103 It's pretty acidic for a CH bond. 05:39.100 --> 05:41.730 Now the reason, of course, is what you get, is an enolate, 05:41.733 --> 05:43.973 because there's an alpha carbonyl. 05:43.967 --> 05:47.497 It's alpha to a carbonyl, but it's also alpha to the CN 05:47.500 --> 05:48.270 triple bond. 05:48.267 --> 05:52.927 So it's doubly activated by low LUMOs next door. 05:52.933 --> 05:55.733 So it easily makes that anion. 05:55.733 --> 05:59.303 So this then can be a nucleophile that will displace 05:59.300 --> 06:00.500 on the carbon. 06:00.500 --> 06:06.030 So it's going to come across and invert the carbon and make 06:06.033 --> 06:06.733 the new bond. 06:06.733 --> 06:09.703 And that's the first product they want: diethyl 06:09.700 --> 06:14.200 2-cyano-3-methyl succinate. 06:14.200 --> 06:16.730 Now, notice they say the yield is pretty good, 06:16.733 --> 06:19.533 61%, right? 06:19.533 --> 06:23.333 And notice especially that the conditions are very mild. 06:23.333 --> 06:26.703 These reactions started at minus 20 degrees and then just 06:26.700 --> 06:27.830 warmed to room temperature. 06:27.833 --> 06:30.233 It's not something that needs a lot of heating. 06:30.233 --> 06:33.673 On the other hand, they had to isolate it by preparative 06:33.667 --> 06:35.567 layer chromatography. 06:35.567 --> 06:40.927 So that's not an easy thing to do on a large-ish scale. 06:40.933 --> 06:45.403 So that's certainly a painful thing to do, to try to get-- 06:45.400 --> 06:48.600 it tends to be insoluble so you can filter it off. 06:48.600 --> 06:51.930 But to get the last bits of it out, you have to do this layer 06:51.933 --> 06:53.133 chromatography. 06:53.133 --> 06:54.733 So that's certainly not so great. 06:57.833 --> 07:01.333 Notice that it says, ultimately the optical purity 07:01.333 --> 07:04.603 is greater than 99%. 07:04.600 --> 07:08.630 Now, this reaction is indeed very, very clean inversion. 07:08.633 --> 07:11.873 So that's one of the hallmarks of the Mitsunobu reaction. 07:11.867 --> 07:16.827 But, in fact, it's not proved by that 99% purity, because 07:16.833 --> 07:20.273 you notice, at the end it was recrystallized. 07:20.267 --> 07:22.497 The product is recrystallized. 07:22.500 --> 07:26.000 So even if there was a little bit of the wrong enantiomer in 07:26.000 --> 07:28.630 there, when you crystallize it, you'd get only the right 07:28.633 --> 07:31.903 enantiomer, in purifying it that way. 07:31.900 --> 07:34.570 So this doesn't prove it, but it's true that it gives very, 07:34.567 --> 07:36.827 very clean inversion, and that's one of its main 07:36.833 --> 07:38.273 advantages. 07:38.267 --> 07:38.527 OK. 07:38.533 --> 07:40.903 But notice, incidentally, that this isn't the 07:40.900 --> 07:41.970 product they wanted. 07:41.967 --> 07:44.767 This is an intermediate. 07:44.767 --> 07:48.927 And notice that there are two chiral centers. 07:48.933 --> 07:54.233 This one, which was 99% inverted, and this one, which 07:54.233 --> 07:58.003 came from the anion that did the attacking, the active 07:58.000 --> 07:59.430 methylene compound. 07:59.433 --> 08:01.003 And there's no reason that that should 08:01.000 --> 08:02.930 be only one, right? 08:02.933 --> 08:06.273 It could have inverted at this stage of the anion. 08:06.267 --> 08:09.397 That is, the anion would have been planar because of the 08:09.400 --> 08:15.070 conjugation with the double bonds next door. 08:15.067 --> 08:17.927 So wouldn't that lower the yield? 08:17.933 --> 08:21.033 No, because of the product they're finally going to. 08:21.033 --> 08:22.333 And you'll see how that is. 08:22.333 --> 08:25.703 They hydrolyze this intermediate to (S)-(-)-methylsuccinic 08:25.700 --> 08:28.500 acid, which you notice is what it is they're 08:28.500 --> 08:30.270 trying to make up at the top. 08:30.267 --> 08:34.267 So they were able to convert the ester to an acid, the 08:34.267 --> 08:36.997 other ester to an acid. 08:37.000 --> 08:39.330 That's the reverse of a Fischer 08:39.333 --> 08:41.773 esterification, acid and water. 08:41.767 --> 08:46.297 And the CN triple bond also hydrolyzes to an acid, 08:46.300 --> 08:47.770 although it takes more work. 08:47.767 --> 08:51.727 It was heated under reflux for 16 hours, but that converted 08:51.733 --> 08:55.533 that one to an acid. And now you notice this carbon isn't 08:55.533 --> 08:58.773 chiral anymore, because it's got two acid groups. 08:58.767 --> 09:02.267 And even more than that, it turns out that when you have a 09:02.267 --> 09:05.167 situation like that, it decarboxylates. 09:05.167 --> 09:09.067 It loses the CO2, and the H comes on here. 09:09.067 --> 09:10.897 So again, it's not a chiral carbon. 09:10.900 --> 09:13.700 So this is the product, and the ultimate 09:13.700 --> 09:17.900 yield was 29% overall. 09:17.900 --> 09:22.870 So that's not 100% reaction, but it's very, very clean, in 09:22.867 --> 09:28.497 terms of the product being stereochemically pure. 09:28.500 --> 09:32.170 And the purity, the stereochemical purity, the 09:32.167 --> 09:35.727 inversion, is sometimes used by synthetic chemists when 09:35.733 --> 09:38.833 they design a complicated synthesis and they make an 09:38.833 --> 09:41.433 alcohol, but it turns out not to be the 09:41.433 --> 09:43.073 one they want, right? 09:43.067 --> 09:44.867 It's the wrong enantiomer. 09:44.867 --> 09:47.497 So then they use a version of this reaction called the 09:47.500 --> 09:49.300 Mitsunobu Inversion. 09:49.300 --> 09:52.970 So for example, suppose they made this (S)-configured 09:52.967 --> 09:56.997 alcohol, but what they really wanted was the ()R. So what you 09:57.000 --> 10:01.030 need to do is make that OH into a leaving group and bring 10:01.033 --> 10:04.203 an oxygen in from the backside to make the other one. 10:04.200 --> 10:09.530 So they can do this, to correct the synthetic “mistake”, by 10:09.533 --> 10:15.603 using these reagents triphenylphosphine and DEAD 10:15.600 --> 10:16.670 and acetic acids. 10:16.667 --> 10:20.027 So the acetic acid is something that's more acidic 10:20.033 --> 10:23.973 than pKa 15. 10:23.967 --> 10:26.627 It's got pKa 5, so it'll do the trick. 10:26.633 --> 10:29.303 So you mix these things together, do the reaction, and 10:29.300 --> 10:31.170 it makes the acetate in the back. 10:31.167 --> 10:33.827 And now that's the ester of the alcohol you want, so all 10:33.833 --> 10:36.433 you have to do is treat it with acid[correction: base] and get 10:36.433 --> 10:38.833 the inverted alcohol. 10:38.833 --> 10:41.133 Now, how does this activation work? 10:41.133 --> 10:44.873 How do you do this in order to get the great leaving group? 10:44.867 --> 10:47.627 Well, you react triphenylphosphine 10:47.633 --> 10:49.473 with HOR to do that. 10:49.467 --> 10:51.467 But they won't interact directly. 10:51.467 --> 10:54.567 That's, notice, -3, and in the 10:54.567 --> 10:56.167 product it's -1, 10:56.167 --> 10:58.697 so you're going to need an oxidizing agent 10:58.700 --> 10:59.570 in order to go there. 10:59.567 --> 11:03.467 And that oxidizing agent is this compound 11:03.467 --> 11:04.827 number 1 up here. 11:04.833 --> 11:06.003 Diethyl-- 11:06.000 --> 11:08.570 so it's an ethyl ester on both ends, notice it's 11:08.567 --> 11:09.497 symmetrical-- 11:09.500 --> 11:14.400 azodicarboxylate, DEAD. 11:14.400 --> 11:18.130 Now, this is sort of a complicated scheme. 11:18.133 --> 11:23.603 And it's balanced just right so the correct nucleophile 11:23.600 --> 11:25.430 will attack at each step. 11:25.433 --> 11:28.173 There are three nucleophiles that are involved. 11:28.167 --> 11:32.197 There's the phosphorus unshared pair. 11:32.200 --> 11:36.430 There's the unshared pair on an oxygen of the alcohol. 11:36.433 --> 11:40.773 And there's X minus that was formed from the acid that you 11:40.767 --> 11:43.067 put in, which is ultimately the thing that's going to do 11:43.067 --> 11:43.967 the displacing. 11:43.967 --> 11:46.167 That's the nucleophile that comes in. 11:46.167 --> 11:49.467 So you don't want the wrong nucleophile to be operating at 11:49.467 --> 11:51.297 any given time. 11:51.300 --> 11:51.600 OK. 11:51.600 --> 11:55.170 So first, the unshared pair on phosphorus attacks the double 11:55.167 --> 11:58.927 bond on nitrogen, which will put a charge on this nitrogen 11:58.933 --> 12:01.233 here when these electrons go on there. 12:01.233 --> 12:03.833 What's good about having the charge on that nitrogen? 12:06.400 --> 12:10.100 Why would that be better than adding to any old 12:10.100 --> 12:11.600 N=N? 12:11.600 --> 12:16.670 STUDENT: Resonance? 12:16.667 --> 12:20.127 PROFESSOR: Yeah. It's got the resonance with the carbonyl, so 12:20.133 --> 12:24.033 it's going to make this allylic system here. 12:24.033 --> 12:24.403 OK. 12:24.400 --> 12:27.230 So that comes in. 12:27.233 --> 12:31.833 And now this HX is one of these things that has a pKa 12:31.833 --> 12:33.533 less than 15. 12:33.533 --> 12:40.233 So it's able, then, to protonate this-- 12:40.233 --> 12:43.803 Remember, this is a fairly stable anion, but it's not as 12:43.800 --> 12:45.070 stable as X minus. 12:45.067 --> 12:48.067 It doesn't have that low a pKa. 12:48.067 --> 12:51.367 So this one's able to protonate here. 12:51.367 --> 12:56.767 Now, notice, if X attacked-- 12:56.767 --> 13:01.167 X is the anion of a pretty good acid. 13:01.167 --> 13:04.167 You could imagine that attacking the phosphorus to 13:04.167 --> 13:06.597 make a fifth bond to phosphorus. 13:06.600 --> 13:06.870 Right? 13:06.867 --> 13:09.067 Phosphorus has vacant d-orbitals. 13:09.067 --> 13:12.567 But if it did, it would come off again, because it's a much 13:12.567 --> 13:17.267 better anion than the anion formed if you broke the 13:17.267 --> 13:19.127 phosphorus-nitrogen bond. 13:19.133 --> 13:22.773 So this is an example of it being tuned just right. 13:22.767 --> 13:26.897 So if the X came on it, would just come off again. 13:26.900 --> 13:33.000 But if the unshared pair of oxygen goes on, then you would 13:33.000 --> 13:37.230 get the bond formed like this. 13:37.233 --> 13:41.333 And now that would come off again. 13:41.333 --> 13:45.203 The protonated oxygen is a stronger acid 13:45.200 --> 13:47.030 than this would be. 13:47.033 --> 13:54.433 But if it loses the proton, then this one is now a better 13:54.433 --> 13:58.473 leaving group, especially if it gets protonated. 13:58.467 --> 14:03.797 So now we've made this thing here. 14:03.800 --> 14:06.930 We've made the oxygen into a leaving group. 14:06.933 --> 14:11.203 And notice, at the same time, the nitrogen-nitrogen, which 14:11.200 --> 14:15.200 originally was a double bond, now has two hydrogens on it. 14:15.200 --> 14:17.500 So it got reduced, right? 14:17.500 --> 14:21.130 That is, it was the oxidizing agent that 14:21.133 --> 14:23.833 allowed this to happen. 14:23.833 --> 14:27.303 And now X minus is able to do the nucleophilic substitution, 14:27.300 --> 14:32.430 and that's how the Mitsunobu activation happens. 14:32.433 --> 14:36.433 And notice that this last one here, then, is irreversible. 14:36.433 --> 14:39.533 Once you put the X on, this is not a good nucleophile. 14:39.533 --> 14:40.773 It's not going to come back on. 14:40.767 --> 14:45.227 So this is a high yield process, when you do that one. 14:48.000 --> 14:51.600 But the problem is that complete separation required 14:51.600 --> 14:52.470 chromatography. 14:52.467 --> 14:53.497 That was bad about it. 14:53.500 --> 14:56.670 And at least this aspect of it has been improved. 14:56.667 --> 14:59.097 And it's an interesting way in which it's been improved. 14:59.100 --> 15:03.130 Instead of using triphenyl phosphine, the benzene rings 15:03.133 --> 15:06.573 of the triphenyl phosphine, some of them, are attached to 15:06.567 --> 15:09.727 a polymer, right, like that. 15:09.733 --> 15:12.903 So that means if you have a polymer bead that holds this 15:12.900 --> 15:16.770 reagent, at the end, you don't have to do the chromatography 15:16.767 --> 15:19.727 in order to separate your product from the triphenyl 15:19.733 --> 15:21.173 phosphine oxide. 15:21.167 --> 15:23.597 You just have to filter it, because it's attached to a 15:23.600 --> 15:24.870 solid polymer. 15:27.300 --> 15:31.730 But what disturbs the green chemists about this otherwise 15:31.733 --> 15:37.233 handy reaction is that your goal is to eliminate water 15:37.233 --> 15:41.073 between HX and ROH. 15:41.067 --> 15:47.997 But in order to do that, you generate byproducts that have 15:48.000 --> 15:50.300 a molecular weight of 450. 15:50.300 --> 15:52.500 So this is what's called atom inefficient. 15:52.500 --> 15:56.600 You generate lots of waste for the way to the 15:56.600 --> 15:59.500 molecule you generate. 15:59.500 --> 16:02.930 Now, we're going to be talking about oxidation of aldehydes 16:02.933 --> 16:03.573 and alcohols. 16:03.567 --> 16:05.797 We have talked about some of them already. 16:05.800 --> 16:08.630 But it's nice to do those in a green way, too. 16:08.633 --> 16:11.273 And in fact, we already talked about such a 16:11.267 --> 16:12.667 reaction last semester. 16:12.667 --> 16:18.527 It was one of the first oxidations of an aldehyde that 16:18.533 --> 16:21.133 was studied, which was the oil of bitter almonds. 16:21.133 --> 16:22.803 You remember what was special about this sample? 16:25.933 --> 16:28.833 When you turned it over, it turned out that this aldehyde 16:28.833 --> 16:30.573 was in fact mostly solid. 16:30.567 --> 16:36.467 It had converted spontaneously to benzoic acid without adding 16:36.467 --> 16:40.727 any chromium, manganese, or anything like that. 16:40.733 --> 16:44.973 You got benzoic acid just by reacting it with oxygen. 16:44.967 --> 16:51.497 So there could hardly be a cleaner, greener process. 16:51.500 --> 16:55.730 So the air oxidation of benzaldehyde is a process that 16:55.733 --> 16:57.373 I think we've mentioned before, but I'll 16:57.367 --> 16:59.027 talk about it again. 16:59.033 --> 17:02.303 So it's a free-radical chain reaction. 17:02.300 --> 17:05.670 You have some radical which pulls the hydrogen away from 17:05.667 --> 17:10.427 the aldehyde, which generates this acyl radical. 17:10.433 --> 17:14.373 But the acyl radical can now attack oxygen to form a new 17:14.367 --> 17:18.327 bond, and a single bond to oxygen, which itself is now a 17:18.333 --> 17:24.003 radical, which is the X. So X comes back and takes the 17:24.000 --> 17:27.630 hydrogen from the other, and the product, then, is not 17:27.633 --> 17:32.973 benzoic acid, but peroxybenzoic acid. 17:32.967 --> 17:36.767 So that's what you would expect to get at first. 17:36.767 --> 17:42.027 But in fact, it might be fun for you just to review free 17:42.033 --> 17:46.033 radical chain reactions by writing this thing in one of 17:46.033 --> 17:49.303 those cyclic diagrams as to what comes in, where the 17:49.300 --> 17:50.770 radicals are, what comes out. 17:50.767 --> 17:53.767 That would be a good exercise. 17:53.767 --> 17:56.127 So this is the initial product. 17:56.133 --> 17:58.933 But this itself as an oxidizing agent. 17:58.933 --> 18:02.503 It's got this weak oxygen-oxygen bond, a low 18:02.500 --> 18:07.670 LUMO, which is a little bit like using a 18:07.667 --> 18:09.567 halogen-halogen bond. 18:09.567 --> 18:11.897 So it also is like an alcohol. 18:11.900 --> 18:16.800 So it can form a hemiketal by attacking the carbonyl. 18:16.800 --> 18:19.830 So here's the group that attacked, here's the new bond, 18:19.833 --> 18:20.803 and we have OH. 18:20.800 --> 18:24.270 So it's like a hemiketal, except it's peroxy. 18:24.267 --> 18:29.567 And now notice that it's converted what would have been 18:29.567 --> 18:32.927 an OH into an O with a leaving group. 18:32.933 --> 18:36.303 If this had just been a regular old hydrate of the 18:36.300 --> 18:37.930 aldehyde, there would be OH here. 18:37.933 --> 18:39.933 But now we have O with a leaving group. 18:39.933 --> 18:43.703 So a base can pull off the proton, the electrons come in 18:43.700 --> 18:46.670 to make a double bond, these leave, and now you have 18:46.667 --> 18:51.367 benzoic acid and benzoate, which is a base that can do 18:51.367 --> 18:53.997 that reaction next time. 18:54.000 --> 18:56.300 So what could be a more efficient reaction? 18:56.300 --> 18:59.870 All you do is expose benzaldehyde to oxygen, and it 18:59.867 --> 19:01.867 becomes benzoic acid. 19:01.867 --> 19:06.427 So there's a very green oxidation reaction. 19:06.433 --> 19:10.803 You can see Section 18.12, which talks about this. 19:10.800 --> 19:14.070 But last year when I was talking about this subject, we 19:14.067 --> 19:18.167 had a seminar from a professor at Weizmann Institute, David 19:18.167 --> 19:22.467 Milstein, who talked about devising catalysts for greener 19:22.467 --> 19:23.267 operations. 19:23.267 --> 19:25.727 And I thought this one was a very interesting one. 19:25.733 --> 19:29.233 So this is a ruthenium catalyst, and it has on it 19:29.233 --> 19:33.903 carbon monoxide and hydrogen, and then this funny ligand. 19:33.900 --> 19:38.500 It's a pyridine, benzene with the nitrogen in it, with 19:38.500 --> 19:43.800 two groups, CH2 here, CH2, and it has a nitrogen, diethylamine, 19:43.800 --> 19:47.100 on this end, and di-t-butylphosphine 19:47.100 --> 19:48.270 on the other end. 19:48.267 --> 19:51.667 So it has three things with unshared pairs, phosphorus, 19:51.667 --> 19:55.797 nitrogen, and nitrogen, that can mix with the orbitals of 19:55.800 --> 19:58.700 the ruthenium to make this complex. 19:58.700 --> 20:04.200 Now, I've colored two of the hydrogens here green, because 20:04.200 --> 20:05.500 they can come off. 20:05.500 --> 20:10.230 You could lose H2, having lost those two hydrogens, notice, 20:10.233 --> 20:14.473 or you can add H2 and come back again. 20:14.467 --> 20:17.527 Now, how does that happen? 20:17.533 --> 20:21.933 Well, notice that this stuff here, the nitrogen plus charge 20:21.933 --> 20:26.403 with an extra bond here, going to this kind of ring, is a 20:26.400 --> 20:30.230 little bit reminiscent of what we saw before with 20:30.233 --> 20:32.733 NAD plus and NADH. 20:32.733 --> 20:36.633 That this is a nucleophilic aromatic substitution, the 20:36.633 --> 20:37.333 start of it. 20:37.333 --> 20:39.973 So the H minus adds here. 20:39.967 --> 20:41.967 These go on to the nitrogen. 20:41.967 --> 20:45.267 So you have a ring like that one, and H attached. 20:45.267 --> 20:47.967 But the H minus can come off again, and be given to 20:47.967 --> 20:48.967 something else. 20:48.967 --> 20:52.197 So this is closely balanced, right? 20:52.200 --> 20:55.200 This one has the advantage of being aromatic. 20:55.200 --> 20:57.930 This one has the advantage of having a new bond, and not 20:57.933 --> 20:59.833 being charged. 20:59.833 --> 21:02.533 So being closely balanced, it can go back and forth. 21:02.533 --> 21:06.303 So the same way that NADH in nature can function as both an 21:06.300 --> 21:08.970 oxidizing and a reducing agent, going one way or 21:08.967 --> 21:11.627 another, you could imagine that a thing like this can go 21:11.633 --> 21:12.973 back and forth. 21:12.967 --> 21:17.127 So lose the H plus and go back, as far as the stability 21:17.133 --> 21:18.173 in this part of it goes. 21:18.167 --> 21:19.867 But there's a problem. 21:19.867 --> 21:22.697 The H could be thought of as H minus, because 21:22.700 --> 21:25.230 it's bonded to a metal. 21:25.233 --> 21:27.973 So the electrons are mostly on the more 21:27.967 --> 21:29.927 electronegative hydrogen. 21:29.933 --> 21:34.433 But it can't reach to that position, so you can't do that 21:34.433 --> 21:36.933 kind of thing. 21:36.933 --> 21:40.503 But what it can reach is the hydrogen here, if we change 21:40.500 --> 21:43.930 the conformation of the thing a little bit. 21:43.933 --> 21:48.503 So you can imagine that the hydride attacks this hydrogen, 21:48.500 --> 21:53.130 which loses these electrons to make that bond. 21:53.133 --> 21:56.403 And that's helped by the fact that these electrons then get 21:56.400 --> 21:59.870 stabilized by moving on to the positive nitrogen. 21:59.867 --> 22:00.497 Right? 22:00.500 --> 22:05.130 So this type of effect is what allows this to go back and 22:05.133 --> 22:06.633 forth in either direction. 22:06.633 --> 22:09.833 But we're most interested in the direction going up. 22:09.833 --> 22:14.773 So let's redraw that thing and look at what happens if 22:14.767 --> 22:15.767 there's an alcohol. 22:15.767 --> 22:19.797 So an alcohol comes in, and its unshared pair makes a bond 22:19.800 --> 22:24.570 to the ruthenium, and now it's O plus. 22:24.567 --> 22:29.097 Now we can have the hydride-- 22:29.100 --> 22:31.630 notice it's H-- 22:31.633 --> 22:33.673 Wait a second, have I done the right thing here? 22:33.667 --> 22:34.667 Oh no. 22:34.667 --> 22:37.227 What we're doing is using the unshared pair of nitrogen. 22:37.233 --> 22:38.703 This is not like hydride. 22:38.700 --> 22:39.870 I said the wrong thing. 22:39.867 --> 22:40.927 This is a proton. 22:40.933 --> 22:43.473 The electrons are going away from this hydrogen. 22:43.467 --> 22:47.567 So the proton is able to go on here, to 22:47.567 --> 22:49.267 generate the N plus again. 22:52.100 --> 22:55.930 And now notice, at the same time, that that alcohol that 22:55.933 --> 23:00.103 came on had two H's that I drew explicitly. 23:00.100 --> 23:03.130 The one down here is the one I'm interested in, because 23:03.133 --> 23:06.273 it's near the ruthenium. 23:06.267 --> 23:10.467 And now if this were O minus-- 23:10.467 --> 23:13.827 and notice, in a sense, it is O minus, because it's bonded 23:13.833 --> 23:15.703 to a metal-- 23:15.700 --> 23:19.000 then the electrons of the O minus, these electrons, can 23:19.000 --> 23:23.700 make a double bond here, giving hydride. 23:23.700 --> 23:25.330 A hydride can attack the ruthenium. 23:28.200 --> 23:29.270 Like that. 23:29.267 --> 23:32.227 So notice what the product of this is, then. 23:32.233 --> 23:37.473 At the top, we get a carbonyl group, and the thing we have 23:37.467 --> 23:42.497 at the bottom is this, which can start the whole process 23:42.500 --> 23:45.400 over again by giving off H2. 23:45.400 --> 23:50.030 So what has this whole catalytic cycle accomplished? 23:50.033 --> 23:54.403 You've brought in an alcohol, and you removed from it these 23:54.400 --> 23:56.330 two hydrogens as H2. 23:59.700 --> 24:05.830 So it's an oxidation of the alcohol, not by bringing in 24:05.833 --> 24:09.133 oxygen and making water, but by giving off H2. 24:11.933 --> 24:16.203 So now in this particular reaction, there's another 24:16.200 --> 24:20.830 oxidation removing H2 from a different alcohol. 24:20.833 --> 24:24.303 Notice the product is an aldehyde, but in water it will 24:24.300 --> 24:25.700 form a diol. 24:25.700 --> 24:28.270 So it could be the alcohol that comes in, and you remove 24:28.267 --> 24:36.127 another H2 from it, which gives then a carboxylic acid. 24:36.133 --> 24:43.673 Plus you're oxidizing another alcohol, and have CO coupling, 24:43.667 --> 24:45.767 and you get-- 24:45.767 --> 24:46.997 Have I done this right? 24:50.500 --> 24:52.830 I think I counted wrong here. 24:52.833 --> 24:55.373 I think I wrote this wrong. 24:55.367 --> 24:57.197 I don't think you oxidize that alcohol. 24:57.200 --> 24:59.470 But at any rate, it couples to give the ester. 24:59.467 --> 25:02.627 I think that should be two H2s there. 25:02.633 --> 25:05.933 I'll correct that. 25:05.933 --> 25:08.533 But this happens in the presence of this catalyst with 25:08.533 --> 25:10.833 no other activation. 25:10.833 --> 25:14.433 So what comes in is the alcohol, what comes out is two 25:14.433 --> 25:17.233 moles of hydrogen and the ester. 25:17.233 --> 25:17.533 Right? 25:17.533 --> 25:20.933 A very clean process. 25:20.933 --> 25:26.173 So here's a table taken from Milstein's paper, and you can 25:26.167 --> 25:30.427 see, with several different alcohols, he was able to get 25:30.433 --> 25:34.973 high conversions, higher than 90, up to 99%, very high 25:34.967 --> 25:37.627 yields of the ester, and only a little bit of the aldehyde. 25:37.633 --> 25:38.873 Most of it got oxidized. 25:41.533 --> 25:43.573 Let's look at the thermochemistry of this. 25:43.567 --> 25:46.427 And again, I think that should be two H2s. 25:46.433 --> 25:50.533 So if you look at the heat of formation of ethanol and the 25:50.533 --> 25:54.803 heat of formation of the ester that's the product from that, 25:54.800 --> 25:59.870 and hydrogen has a free energy of zero, so the two hydrogens 25:59.867 --> 26:00.897 don't count. 26:00.900 --> 26:05.570 But if we add it together, this reaction is endothermic 26:05.567 --> 26:08.227 by seventeen kilocalories per mole. 26:08.233 --> 26:09.503 So it's way uphill. 26:09.500 --> 26:11.830 You'd think the equilibrium constant would be very 26:11.833 --> 26:13.233 unfavorable. 26:13.233 --> 26:17.673 What makes it possible for this to happen catalytically? 26:17.667 --> 26:20.927 We're not putting in something that's a strong reagent that 26:20.933 --> 26:23.503 makes one of these very reactive, and then it can 26:23.500 --> 26:25.000 react with the other things. 26:25.000 --> 26:27.170 We're just putting the alcohol in. 26:27.167 --> 26:30.327 And to have the alcohol come in, and ester come out, and 26:30.333 --> 26:35.033 everything stay the same otherwise with the catalyst, 26:35.033 --> 26:38.273 you have to go uphill in energy by 17 kilocalories per 26:38.267 --> 26:39.967 mole, which sounds very tough. 26:39.967 --> 26:44.427 But there are two things that make this good. 26:50.367 --> 26:55.427 You start with two molecules, and you form three molecules. 26:55.433 --> 26:57.373 Two H2 and the ester. 26:57.367 --> 27:00.467 Again, I counted wrong here. 27:00.467 --> 27:03.067 So by making more molecules, you make 27:03.067 --> 27:05.127 more entropy available. 27:05.133 --> 27:08.203 And furthermore, this is especially helped because you 27:08.200 --> 27:12.830 make those two hydrogen gas molecules, and you can remove 27:12.833 --> 27:14.333 those from the solution. 27:14.333 --> 27:16.603 So notice how this was done. 27:16.600 --> 27:20.470 It was done, in one case, under a flow of argon to sweep 27:20.467 --> 27:22.227 the hydrogen gas out. 27:22.233 --> 27:26.203 And in the other case, the toluene solution was refluxed, 27:26.200 --> 27:30.000 which again, the solvent pushes the other gas out. 27:30.000 --> 27:34.900 So at low pressure of hydrogen, it's possible to do 27:34.900 --> 27:36.130 this spontaneously. 27:36.133 --> 27:41.033 So that's an important type of analysis to do on a catalytic 27:41.033 --> 27:45.303 cycle that you've proposed, as to whether, in fact, it could 27:45.300 --> 27:48.070 be thermodynamically allowed. 27:48.067 --> 27:51.697 They also were able to make amines that way, starting with 27:51.700 --> 27:57.070 alcohols make an imine by reacting with ammonia. 27:57.067 --> 28:00.097 So alcohol plus ammonia gives an amine. 28:00.100 --> 28:03.030 And also, incidentally, an imine. 28:03.033 --> 28:05.333 So probably, it's the same kind of thing as before. 28:05.333 --> 28:09.103 The alcohol gets oxidized to an aldehyde, but in the 28:09.100 --> 28:12.430 presence of the nitrogen, it forms the imine, the CN double 28:12.433 --> 28:18.273 bond, and then that gets reduced by the hydrogen that's 28:18.267 --> 28:21.127 there in order to give the amine. 28:21.133 --> 28:24.473 But again, these are very high yield reactions. 28:30.533 --> 28:34.133 When you look at a synthetic paper and a table in it, it's 28:34.133 --> 28:37.373 important to look at two different kinds of yields. 28:37.367 --> 28:40.527 The normal yields given here are an analyzed by gas 28:40.533 --> 28:43.503 chromatography to figure out how much was in there. 28:43.500 --> 28:45.830 But what you're really interested in is what you can 28:45.833 --> 28:48.503 put in a bottle as a pure form, right? 28:48.500 --> 28:51.270 So the yields in parentheses are isolated products. 28:51.267 --> 28:57.297 So sometimes they're very good, compared to the gas 28:57.300 --> 28:58.500 chromatography yield. 28:58.500 --> 29:01.330 But in this particular case, it's hard to separate, and you 29:01.333 --> 29:04.933 only get half as much out to sell to your neighbor as you 29:04.933 --> 29:08.873 had analyzed by GC. 29:08.867 --> 29:11.827 So you can also make imines and amides and so on with 29:11.833 --> 29:12.573 these catalysts. 29:12.567 --> 29:15.567 So that's an interesting development which seems to 29:15.567 --> 29:18.527 address, if not to solve perhaps, some of these 29:18.533 --> 29:21.403 problems that the pharmaceutical industry 29:21.400 --> 29:23.970 identified. 29:23.967 --> 29:26.867 Now, we've been talking in these last examples of green 29:26.867 --> 29:29.767 chemistry about acids and acid derivatives. 29:29.767 --> 29:33.267 So let's talk about them a little more systematically. 29:33.267 --> 29:38.267 First, the acidity of our CO2H, of a carboxylic acid. 29:38.267 --> 29:42.527 You remember that the pKa of a normal carboxylic acid is 29:42.533 --> 29:46.833 between 4 and 5, like butyric acid is 4.8. 29:46.833 --> 29:48.433 Now let's look at the effect of putting 29:48.433 --> 29:50.073 a chlorine in there. 29:50.067 --> 29:53.467 So if you put the chlorine in on the terminal carbon, it 29:53.467 --> 29:57.097 hardly changes the pKa at all, just by 0.3 units. 29:57.100 --> 29:59.930 If you move it a little bit closer to the carboxylic acid, 29:59.933 --> 30:03.673 it's 4.1, and if you move it as close as possible to the 30:03.667 --> 30:06.427 carboxylic acid, now it makes a real difference. 30:06.433 --> 30:07.933 2.8. 30:07.933 --> 30:10.873 What is it that the chlorine is doing? 30:14.933 --> 30:16.273 STUDENT: It's electron withdrawing? 30:16.267 --> 30:17.467 PROFESSOR: So it's electron withdrawing. 30:17.467 --> 30:19.327 And how does that help? 30:19.333 --> 30:21.173 STUDENT: It makes the H come off. 30:21.167 --> 30:25.097 PROFESSOR: And how does it make the H come off? 30:25.100 --> 30:27.470 STUDENT: By reducing the bond strength. 30:27.467 --> 30:29.067 PROFESSOR: Why does it reduce the bond strength? 30:32.100 --> 30:34.730 You know, actually, I bet that's not true. 30:34.733 --> 30:37.303 I bet it doesn't reduce the bond strength. 30:37.300 --> 30:39.600 The bond strength is the kind of thing that Professor 30:39.600 --> 30:41.330 Ellison talked about last time. 30:41.333 --> 30:44.033 Breaking a bond to give two-- 30:44.033 --> 30:45.203 people laugh already. 30:45.200 --> 30:48.430 I just mentioned his name, and they laugh. 30:48.433 --> 30:48.873 OK? 30:48.867 --> 30:51.267 You break the body and you get two free-radicals. 30:51.267 --> 30:54.367 I don't know the results, but my strong suspicion is that 30:54.367 --> 30:57.267 chlorine hardly affects that at all. 30:57.267 --> 31:01.127 What it affects is dissociation as an acid. 31:01.133 --> 31:02.833 So what is it that the chlorine is stabilizing? 31:06.067 --> 31:07.297 STUDENT: The LUMO? 31:09.367 --> 31:11.627 PROFESSOR: It affects the anion, right? 31:11.633 --> 31:16.033 So the electron withdrawal by the chlorine makes the 31:16.033 --> 31:19.473 nearby region of the molecule a better place to put more 31:19.467 --> 31:22.297 electrons, as in the anion rather 31:22.300 --> 31:23.900 than the neutral molecule. 31:23.900 --> 31:27.500 So this inductive effect of the chlorine works, but only 31:27.500 --> 31:28.970 in the vicinity of the chlorine. 31:28.967 --> 31:30.727 It dies away as you get further and 31:30.733 --> 31:32.373 further from the chlorine. 31:32.367 --> 31:35.797 So this is so-called inductive effect. 31:35.800 --> 31:38.030 And it's not very big if you're far away, but if you 31:38.033 --> 31:41.473 get pretty close, it can be big. 31:41.467 --> 31:46.167 Now let's just see this inductive effect, if it could 31:46.167 --> 31:49.427 be quantitatively reasonable. 31:49.433 --> 31:53.773 If the withdrawal by the chlorine stabilizes the 31:53.767 --> 31:58.967 negative charge by a certain amount of energy, then the 31:58.967 --> 32:06.027 equilibrium becomes easier by that amount of energy, and 32:06.033 --> 32:11.533 that energy difference would appear in the exponent for the 32:11.533 --> 32:12.473 equilibrium constant. 32:12.467 --> 32:15.267 Remember, 10 to the 2/3 delta H. 32:15.267 --> 32:20.627 So it would make a certain energy effect in the exponent, 32:20.633 --> 32:24.473 and if you put two of them in, you'd make twice that change 32:24.467 --> 32:27.867 in the exponent, if it were simple. 32:27.867 --> 32:31.227 And that means results would be multiplicative, because 32:31.233 --> 32:34.173 when you add things in an exponent, that means you 32:34.167 --> 32:35.397 multiply the numbers. 32:37.600 --> 32:37.900 OK. 32:37.900 --> 32:43.900 So let's look at acetic acid, chloroacetic acid, dichloro 32:43.900 --> 32:47.770 and trichloroacetic acid, and see whether this inductive 32:47.767 --> 32:53.497 effect of the chlorine is additive in energy, therefore 32:53.500 --> 32:57.770 multiplicative in equilibrium constant. 32:57.767 --> 33:01.927 Or if you do the log of the equilibrium constant, then it 33:01.933 --> 33:05.133 would be additive, because it's up in the exponent. 33:05.133 --> 33:07.833 So notice, here it's 4.8. 33:07.833 --> 33:09.373 Same as here. 33:09.367 --> 33:12.197 Here it's 2.9, same as here. 33:12.200 --> 33:13.430 So it's the same kind of effect. 33:16.133 --> 33:19.833 But let's look at the values here, not at the values 33:19.833 --> 33:21.373 themselves, but at the difference. 33:21.367 --> 33:24.167 How much difference did that first chlorine make? 33:24.167 --> 33:28.197 It made a difference of 1.9 pKa units. 33:28.200 --> 33:31.930 Now, if the second one had the same effect on the energy of 33:31.933 --> 33:34.933 an anion, that would also be 1.9. 33:34.933 --> 33:36.503 It's actually 1.6. 33:36.500 --> 33:37.770 Not quite as big. 33:37.767 --> 33:41.567 And the third one hardly makes any difference at all. 33:41.567 --> 33:42.927 It's only 0.6. 33:42.933 --> 33:47.473 I mean, it's substantial, but it's not anything like the 33:47.467 --> 33:48.627 first ones. 33:48.633 --> 33:52.073 And the reason is that once the anion is already 33:52.067 --> 33:55.397 stabilized, it gets harder and harder to 33:55.400 --> 33:57.270 withdraw subsequent electrons. 33:57.267 --> 34:00.567 One chlorine withdraws a certain amount. 34:00.567 --> 34:03.497 The next chlorine doesn't have as much to withdraw, so it 34:03.500 --> 34:04.730 can't do quite as good a job. 34:04.733 --> 34:08.733 The third one does a much poorer job. 34:08.733 --> 34:12.633 But fluorine is better than chlorine, and trifluoroacetic 34:12.633 --> 34:14.303 acid is quite a strong acid. 34:14.300 --> 34:17.300 It's got a negative pKa. 34:17.300 --> 34:19.730 So that's the inductive effect. 34:19.733 --> 34:23.533 And now we might wonder, what is it that makes the 34:23.533 --> 34:27.803 carboxylic acid acidic altogether, ignoring these 34:27.800 --> 34:30.500 additional inductive effects? 34:30.500 --> 34:36.530 So Paul Rablen from Swarthmore College published a paper in 34:36.533 --> 34:38.973 the Journal of the American Chemical Society in 2000 that 34:38.967 --> 34:41.227 had an interesting analysis of this. 34:41.233 --> 34:47.673 And I put it on because Professor Ellison is such a 34:47.667 --> 34:50.967 big advocate of resonance structures, as you saw last 34:50.967 --> 34:53.827 time, rather than molecular orbital theory. 34:53.833 --> 34:56.473 So this is an interesting analysis, in terms of 34:56.467 --> 34:58.127 resonance structures. 34:58.133 --> 35:03.473 Now, what he did is do very good calculations, but 35:03.467 --> 35:08.067 calculations in the gas phase, not in a solvent, of what the 35:08.067 --> 35:10.727 equilibrium constant should be, or what the energy 35:10.733 --> 35:13.473 involved should be in transferring a proton from an 35:13.467 --> 35:18.327 alcohol to a carboxylic acid. 35:18.333 --> 35:20.873 So you get the anion of the alcohol, and the protonated 35:20.867 --> 35:22.467 carboxylic acid. 35:22.467 --> 35:26.827 And now, the carboxylic acids are called acids because they 35:26.833 --> 35:28.733 give their protons to bases. 35:28.733 --> 35:31.103 So this reaction lies to the left. 35:31.100 --> 35:33.800 And to go to the right is uphill by almost 28 35:33.800 --> 35:36.000 kilocalories per mole in the gas phase. 35:39.433 --> 35:42.403 Now, the difference in pKa, the pKa of an 35:42.400 --> 35:43.830 alcohol is about 16. 35:43.833 --> 35:47.603 The pKa of a carboxylic acid is about 5. 35:47.600 --> 35:51.970 So the difference in pKa is about 11. 35:51.967 --> 35:54.427 Therefore, you would expect the equilibrium constant at 35:54.433 --> 35:57.973 room temperature to be about 4/3 of that. 35:57.967 --> 36:02.197 So it should be about 15 kilocalories per mole. 36:02.200 --> 36:07.100 But notice that pKas are defined in water, so it must 36:07.100 --> 36:11.330 be that the solvent makes an enormous effect, right? 36:11.333 --> 36:16.703 It reduces this to about half of its value, from close to 30 36:16.700 --> 36:20.930 to 15, by making it easier to go to the right. 36:20.933 --> 36:23.703 Only 15 kilocalories uphill, instead of 30 36:23.700 --> 36:25.300 kilocalories uphill. 36:25.300 --> 36:26.100 Why? 36:26.100 --> 36:29.330 It could be because this one has a much more concentrated 36:29.333 --> 36:33.273 negative charge, so it gets more effectively solvated by 36:33.267 --> 36:36.167 the water, compared to this one, which helps drive the 36:36.167 --> 36:37.497 reaction on the left. 36:37.500 --> 36:42.030 But anyhow, that's a secondary consideration, because we're 36:42.033 --> 36:43.933 just looking, as Rablen did, at the 36:43.933 --> 36:46.433 molecules in the gas phase. 36:46.433 --> 36:46.773 OK. 36:46.767 --> 36:51.127 So it's 28 kilocalories uphill to do that. 36:51.133 --> 36:52.573 Now, what's the reason? 36:52.567 --> 36:54.397 Why does it want to go that way? 36:54.400 --> 36:58.270 Well, we're tempted to say resonance. 36:58.267 --> 37:01.067 That's certainly what Ellison would have said. 37:01.067 --> 37:04.167 You have two resonance structures of this anion, and 37:04.167 --> 37:06.527 only one resonance structure that's 37:06.533 --> 37:09.673 reasonable on the right. 37:09.667 --> 37:13.727 Can you think of any other reason that it might be good 37:13.733 --> 37:16.503 to go to the left? 37:16.500 --> 37:21.430 Anything else that makes that a better anion, compared to 37:21.433 --> 37:23.203 this anion other than resonance? 37:26.333 --> 37:27.033 Any idea? 37:27.033 --> 37:28.103 These are Hs's. 37:28.100 --> 37:28.700 Incidentally. 37:28.700 --> 37:31.000 CH3. 37:31.000 --> 37:35.230 And here's HCOO minus. 37:35.233 --> 37:37.773 If resonance weren't a factor, would you expect 37:37.767 --> 37:39.627 these to be the same? 37:39.633 --> 37:40.903 Would you expect the equilibrium 37:40.900 --> 37:42.130 constant to be one? 37:45.767 --> 37:46.667 Amy? 37:46.667 --> 37:52.627 STUDENT: Well, no, because the pi* is helping out. 37:52.633 --> 37:52.973 PROFESSOR: Yeah. 37:52.967 --> 37:56.927 The pi-star helping out is the molecular orbital way of 37:56.933 --> 37:58.973 saying there's resonance. 37:58.967 --> 38:00.127 That's how they do it. 38:00.133 --> 38:02.203 So that, in fact, is the same thing. 38:02.200 --> 38:04.600 But is there anything else that would tend to 38:04.600 --> 38:07.670 make it go that way? 38:07.667 --> 38:09.667 STUDENT: Having the other oxygen up there? 38:09.667 --> 38:11.797 PROFESSOR: And how would the oxygen help? 38:11.800 --> 38:12.630 STUDENT: Inductive effect? 38:12.633 --> 38:13.933 PROFESSOR: So it could be an inductive effect. 38:13.933 --> 38:17.933 But notice this oxygen is closer than the chlorine that 38:17.933 --> 38:19.873 was making the difference before. 38:19.867 --> 38:23.027 The chlorine was out on the next carbon. 38:23.033 --> 38:25.133 So you could also have an inductive 38:25.133 --> 38:27.073 effect due to the oxygen. 38:27.067 --> 38:30.627 Now, notice that it's a double bond. 38:30.633 --> 38:33.303 So it's an interesting question whether you count the 38:33.300 --> 38:35.070 oxygen once or count it twice. 38:38.533 --> 38:43.503 So for purposes of this paper, Rablen hypothesized that you 38:43.500 --> 38:46.770 count the oxygen twice. 38:46.767 --> 38:50.797 So now we have resonance and inductive effects, and we can 38:50.800 --> 38:55.230 do some numerology about these, about how important 38:55.233 --> 38:57.133 resonance structures are. 38:57.133 --> 38:57.503 OK. 38:57.500 --> 39:02.130 So notice that this 27.0 kilocalories is due to loss of 39:02.133 --> 39:07.033 resonance and to loss of two inductive effects for oxygen, 39:07.033 --> 39:09.973 if you're supposed to count it twice with the double bond. 39:09.967 --> 39:13.697 Now, let's look at this one, where instead of using 39:13.700 --> 39:16.170 alcohol, we used the ketone and a 39:16.167 --> 39:17.967 protonated acid here. 39:17.967 --> 39:21.267 So instead of the anion, it's protonated now. 39:21.267 --> 39:24.697 And now we transfer the proton from here to the ketone-- 39:24.700 --> 39:26.030 or it's the aldehyde, actually. 39:26.033 --> 39:28.133 these are hydrogens. 39:28.133 --> 39:29.903 So we make the protonated ketone and 39:29.900 --> 39:32.000 the carboxylic acid. 39:32.000 --> 39:37.930 Now, here the reaction lies to the right. 39:37.933 --> 39:41.103 It's exothermic by 6.2 kilocalories per 39:41.100 --> 39:42.570 mole in the gas phase. 39:42.567 --> 39:44.897 Now, which side would resonance favor? 39:49.233 --> 39:50.473 Debbie, can you help us out? 39:53.700 --> 39:57.300 Would you draw resonance structures of this? 39:57.300 --> 39:57.330 STUDENT: You could. 39:57.333 --> 39:58.103 PROFESSOR: You could. 39:58.100 --> 40:01.300 You could use the unshared pair on the OH, and it would 40:01.300 --> 40:03.070 be stabilized by the pi*, 40:03.067 --> 40:06.067 but that would require separation of charge, and 40:06.067 --> 40:09.627 Ellison told us we don't want to do that. 40:09.633 --> 40:10.603 How about on the left? 40:10.600 --> 40:13.970 Any resonance structures there? 40:13.967 --> 40:15.227 STUDENT: Yes. 40:17.400 --> 40:18.370 Because of the positive charge? 40:18.367 --> 40:19.567 PROFESSOR: Speak up. 40:19.567 --> 40:22.267 STUDENT: Because of the positive charge. 40:22.267 --> 40:24.127 PROFESSOR: Now you could draw a double bond here 40:24.133 --> 40:26.333 and a single bond there and put the charge on the bottom. 40:26.333 --> 40:27.733 And you're not separating charge, you're 40:27.733 --> 40:29.073 just moving the charge. 40:29.067 --> 40:31.197 So here you have good resonance. 40:31.200 --> 40:36.970 Here on the right you don't have reasonable resonance. 40:36.967 --> 40:39.397 On this one you had resonance on the left 40:39.400 --> 40:40.700 and not on the right. 40:40.700 --> 40:43.430 So now-- 40:43.433 --> 40:44.073 or no, pardon. 40:44.067 --> 40:46.497 In both cases, we had resonance on the left. 40:46.500 --> 40:46.770 OK. 40:46.767 --> 40:51.767 So resonance is going to favor the left and cause you to go 40:51.767 --> 40:53.427 uphill, in either case. 40:56.100 --> 41:00.400 Now, how about the inductive effect? 41:00.400 --> 41:01.670 How about the oxygen? 41:01.667 --> 41:03.997 Let's try somebody else here. 41:04.000 --> 41:08.370 Chris, which side is favored by the inductive effect? 41:08.367 --> 41:12.297 In the top, the inductive effect favored the left, 41:12.300 --> 41:16.530 because we had two bonds to oxygen withdrawing electrons, 41:16.533 --> 41:19.503 stabilizing in the anion, right? 41:19.500 --> 41:22.670 Now how about in this case, when we have two bonds here? 41:22.667 --> 41:23.897 STUDENT: Favors the right. 41:26.600 --> 41:29.300 PROFESSOR: If it stabilizes the anion, the 41:29.300 --> 41:32.700 argument is, it destabilizes the cation. 41:32.700 --> 41:34.430 So it's the same deal. 41:34.433 --> 41:41.003 Except now... the same resonance that would cause it to go 41:41.000 --> 41:44.600 uphill to the right, but the oxygen now makes it 41:44.600 --> 41:46.000 go down[correction: up] to the left. 41:48.533 --> 41:52.173 Now, how many oxygens did we have? 41:52.167 --> 41:55.167 This time the difference between this and this 41:55.167 --> 41:56.397 is just this bond. 41:59.000 --> 42:01.300 So it's not a question of counting one or two. 42:01.300 --> 42:02.930 There's only one bond there. 42:02.933 --> 42:06.873 So that's one inductive effect of oxygen. 42:06.867 --> 42:11.327 Now we have two equations and two unknowns. 42:11.333 --> 42:14.103 We have the resonance effect, which is the same direction in 42:14.100 --> 42:18.930 both cases, and the inductive effect, which is in opposite 42:18.933 --> 42:22.403 directions and twice as strong, in one case. 42:22.400 --> 42:27.700 So if we take the difference of these two, minus this one, 42:27.700 --> 42:33.700 we get plus 34.1 is three of the oxygen inductive effect. 42:33.700 --> 42:38.630 So the oxygen inductive effect is 11.4 kilocalories per mole. 42:38.633 --> 42:41.833 And once we have that, we can plug back in to see how big 42:41.833 --> 42:44.673 the resonance effect is. 42:44.667 --> 42:45.897 It's 4.8. 42:48.300 --> 42:53.670 And now, from this point of view, if we look in the top 42:53.667 --> 42:59.167 case of that 30 kilocalories per mole going uphill, only 5 42:59.167 --> 43:01.727 of it was due to resonance. 43:01.733 --> 43:04.633 By far and away, the dominant effect is 43:04.633 --> 43:06.673 the inductive effect. 43:06.667 --> 43:10.267 Only 20% of the special acidity of the carboxylic acid 43:10.267 --> 43:14.927 is due to resonance from this viewpoint. 43:14.933 --> 43:16.703 Now, you may buy this resonance 43:16.700 --> 43:18.470 argument, and you may not. 43:18.467 --> 43:20.627 I'm personally skeptical. 43:20.633 --> 43:24.533 But one way or the other, it would be good to check it. 43:24.533 --> 43:27.473 So Rablen checked it. 43:27.467 --> 43:31.227 He did this one with carbonic acid, the 43:31.233 --> 43:33.373 anion of carbonic acid. 43:33.367 --> 43:36.867 And now that's plus 37.3. 43:36.867 --> 43:38.367 Now, what does it involve? 43:38.367 --> 43:42.767 Here's the anion, which is stabilized by resonance, as 43:42.767 --> 43:45.597 this one was. 43:45.600 --> 43:47.900 And there's no resonance involved in this one, because 43:47.900 --> 43:49.170 it has the hydrogen on it. 43:53.033 --> 43:55.373 So it has resonance, the same as the others. 43:55.367 --> 43:56.727 How about inductive effect? 43:59.333 --> 44:03.773 Compared to this, how many oxygens are 44:03.767 --> 44:06.627 stabilizg in this O minus? 44:06.633 --> 44:08.003 Matt? 44:08.000 --> 44:09.430 STUDENT: I can count three. 44:09.433 --> 44:09.933 PROFESSOR: Count three. 44:09.933 --> 44:12.633 If you count double bond twice, which is the rules he 44:12.633 --> 44:15.273 set, then you have three. 44:15.267 --> 44:19.227 So that's O inductive times three. 44:19.233 --> 44:20.833 Now let's put that together. 44:20.833 --> 44:23.203 So we have O inductive times 3. 44:23.200 --> 44:26.700 That's 34.2. 44:26.700 --> 44:32.730 And the resonance is 4.8, is 39. 44:32.733 --> 44:34.933 Not bad. 44:34.933 --> 44:37.273 So we can try another one. 44:37.267 --> 44:41.927 Here we do the analog of what we did here, put a proton on. 44:41.933 --> 44:47.673 And now we have no resonance on the right. 44:47.667 --> 44:50.027 We have resonance on the left. 44:50.033 --> 44:54.633 How many resonance structures in addition to 44:54.633 --> 44:55.933 the original structure? 44:55.933 --> 45:04.873 STUDENT: Two? 45:04.867 --> 45:06.867 PROFESSOR: Chris? You can draw the double bond here. 45:06.867 --> 45:08.597 That's what we did in that case. 45:08.600 --> 45:12.970 But you can also draw the double bond over here. 45:12.967 --> 45:16.667 So there should be resonance times two. 45:16.667 --> 45:21.827 And that should favor the left, make it uphill. 45:21.833 --> 45:25.433 But also, you're going to have oxygens destabilizing this 45:25.433 --> 45:30.233 cation, two oxygens destabilizing that cation. 45:30.233 --> 45:32.773 And if you put those together, it's minus 13.2, 45:32.767 --> 45:37.027 and observed is 11. 45:37.033 --> 45:41.773 So there are people who think this, right? 45:41.767 --> 45:45.197 I personally don't like this kind of argument so much, 45:45.200 --> 45:47.130 because I don't think it comes down to really the 45:47.133 --> 45:47.973 physics of the thing. 45:47.967 --> 45:51.467 It comes to whether you count a double bond as two bonds and 45:51.467 --> 45:52.467 things like that. 45:52.467 --> 45:55.067 Which, it works out. 45:55.067 --> 45:57.367 So there are people who talk about this thing. 45:57.367 --> 46:00.697 And from that point of view, resonance isn't as important 46:00.700 --> 46:05.500 to making acids acidic as inductive effect is. 46:05.500 --> 46:08.230 So the inductive effect is certainly important. 46:08.233 --> 46:11.133 Now, making acids by oxidation and reduction. 46:11.133 --> 46:13.573 And we've talked about these things. 46:13.567 --> 46:16.827 Oxidizing an alcohol with chromium, oxidizing-- 46:16.833 --> 46:19.673 and remember, on the way, you get an aldehyde, so you can 46:19.667 --> 46:21.027 also oxidize aldehydes. 46:21.033 --> 46:22.533 And you can do it with chromium. 46:22.533 --> 46:25.403 I put potassium permanganate in here. 46:25.400 --> 46:28.570 We also talked about oxidizing double bonds with ozone and 46:28.567 --> 46:32.197 then hydrogen peroxide to get carboxylic acids. 46:32.200 --> 46:35.700 There's one different type of oxidation that we haven't 46:35.700 --> 46:38.900 talked about yet which is mentioned in the Jones 46:38.900 --> 46:44.670 textbook here, which is alkyl groups attached to a benzene 46:44.667 --> 46:48.897 ring can be oxidized by permanganate at 100 degrees to 46:48.900 --> 46:52.370 make carboxylic acids, as well. 46:52.367 --> 46:58.327 Now, you can also make carboxylic acids by reduction. 46:58.333 --> 47:02.833 Of course, the carbon in a carboxylic acid is pretty much 47:02.833 --> 47:04.703 oxidized, right? 47:04.700 --> 47:10.700 But there are more oxidized things, like CO2. 47:10.700 --> 47:14.870 So if you had CO2, what would you react it with in order to 47:14.867 --> 47:18.867 form a carbon-carbon bond to make a carboxylic acid? 47:22.667 --> 47:25.027 What kind of reagent? 47:25.033 --> 47:28.503 What would attack the carbon of CO2? 47:28.500 --> 47:29.770 High HOMO or low LUMO? 47:33.233 --> 47:36.303 What would make CO2 double bond double bond? 47:36.300 --> 47:37.530 What would make it reactive? 47:40.700 --> 47:42.400 Suppose it were just a single double bond. 47:42.400 --> 47:45.530 What makes it reactive? 47:45.533 --> 47:46.973 The pi*, right? 47:46.967 --> 47:48.027 The low LUMO. 47:48.033 --> 47:50.173 So you want a high HOMO. 47:50.167 --> 47:52.867 It's like the things we talked about with alcohols, right, 47:52.867 --> 47:57.227 where you could have a ketone, react it with R minus, react 47:57.233 --> 48:00.873 it with H minus, to go on, and in this case that would be a 48:00.867 --> 48:04.067 reduction of the central carbon, and would form a 48:04.067 --> 48:05.527 carboxylic acid. 48:05.533 --> 48:09.133 So you can do that kind of thing, too. 48:09.133 --> 48:14.303 You can also react carboxylic acids with alkyl lithium, or 48:14.300 --> 48:16.100 hydride compounds. 48:16.100 --> 48:19.630 So for example, you could react a generic carboxylic 48:19.633 --> 48:21.533 acid here with alkyl lithium. 48:21.533 --> 48:23.033 What do you think the product is? 48:28.667 --> 48:30.727 Alkyl lithium is like R minus, right? 48:30.733 --> 48:35.433 It's a high HOMO on the R, the R lithium bond. 48:35.433 --> 48:37.373 So what will it attack? 48:40.533 --> 48:41.633 Mary? 48:41.633 --> 48:44.573 STUDENT: Is it addition at the carbon? 48:44.567 --> 48:45.667 PROFESSOR: Addition to what? 48:45.667 --> 48:47.227 STUDENT: To the carbony pi*. 48:47.233 --> 48:48.373 PROFESSOR: To the cabonyl right. 48:48.367 --> 48:51.867 That's what I was trying to trick you into saying. 48:51.867 --> 48:57.997 In fact it reacts in another way. What else does a high HOMO 48:58.000 --> 49:03.130 do, besides make something a nucleophile? 49:03.133 --> 49:06.903 It makes it a base. And here we have and acid. 49:06.900 --> 49:10.800 So in fact the easy thing to react with is the proton. 49:10.800 --> 49:13.470 That's easier to access than the carbonyl 49:13.467 --> 49:17.467 Oops! I'm sorry I've talked too long. 49:17.467 --> 49:20.467 Thanks for your patience.