WEBVTT 00:02.133 --> 00:02.503 J. MICHAEL MCBRIDE: OK. 00:02.500 --> 00:05.130 I realize it's reading period, so we're supposed 00:05.133 --> 00:07.633 to be having fun. 00:07.633 --> 00:11.273 So the structure of glucose is really fun. 00:14.000 --> 00:17.800 I originally had this lecture mostly about the synthesis of 00:17.800 --> 00:19.230 two unnatural products. 00:19.233 --> 00:22.973 These last two lectures were going to be about synthesis. 00:22.967 --> 00:24.827 One about unnatural products and one 00:24.833 --> 00:28.133 about natural products. 00:28.133 --> 00:31.173 But glucose is such a great story that I couldn't miss 00:31.167 --> 00:31.627 telling it. 00:31.633 --> 00:34.203 So we might not get to the synthesis of two unnatural 00:34.200 --> 00:36.970 products, or I might just mention it at the end. 00:36.967 --> 00:39.667 It's also Nobel Prize work, but so is the 00:39.667 --> 00:41.127 structure of glucose. 00:41.133 --> 00:44.133 And there are Nobel Prizes and Nobel Prizes, but the 00:44.133 --> 00:46.833 structure of glucose is a really great Nobel Prize. 00:49.533 --> 00:53.033 So we saw last time that there are carbohydrates, and I found 00:53.033 --> 00:54.703 who used the word first. It was a guy 00:54.700 --> 00:56.830 named Schmidt in 1844. 00:56.833 --> 00:59.773 He said, "I may be allowed to denote compounds [with] carbon 00:59.767 --> 01:03.267 plus hydrogen and oxygen in the same ratio that obtains in 01:03.267 --> 01:06.627 water...as carbohydrates." That is, it doesn't have to be one 01:06.633 --> 01:08.803 to one, one carbon to one water. 01:08.800 --> 01:11.800 So there were examples known. 01:11.800 --> 01:15.730 Like grape sugar was isolated pure in 1792. 01:15.733 --> 01:19.333 And it was given by Dumas the name glucose, which comes from 01:19.333 --> 01:23.003 the Greek word gleukos, which means sweetness. 01:23.000 --> 01:24.570 So that's where glucose came from. 01:24.567 --> 01:28.567 But even more important, the -ose ending, which is just 01:28.567 --> 01:33.167 part of the word glucose, came to be the generic ending for 01:33.167 --> 01:34.227 all sugars. 01:34.233 --> 01:36.233 So when you see something -ose, is means it's one of 01:36.233 --> 01:38.973 these carbohydrates. 01:38.967 --> 01:41.967 And we remember that Couper, as soon as structure became 01:41.967 --> 01:44.367 something that you could talk about, because of the 01:44.367 --> 01:46.697 tetravalence of carbon, he proposed that there was 01:46.700 --> 01:49.670 another water added to give the hydrate of glucose, which 01:49.667 --> 01:50.397 is just fine. 01:50.400 --> 01:52.270 That would still be a carbohydrate. 01:52.267 --> 01:55.297 And he was right. 01:55.300 --> 02:01.870 So you can have aldoses like glucose where you take two 02:01.867 --> 02:04.567 hydrogens from the top carbon, put them on either end so you 02:04.567 --> 02:05.827 have an aldehyde. 02:05.833 --> 02:08.273 Or you can do the next carbon or the next carbon and 02:08.267 --> 02:11.197 ketones, so you can have ketoses. 02:11.200 --> 02:13.470 For example, fructose is a ketose, and 02:13.467 --> 02:16.197 glucose is an aldose. 02:16.200 --> 02:18.830 Now, how do you know this? 02:18.833 --> 02:21.233 Of course, nowadays we know the structure of things by 02:21.233 --> 02:22.803 spectroscopy. 02:22.800 --> 02:25.070 For example, here's the IR spectrum of 02:25.067 --> 02:26.927 glucose, this aldehyde. 02:26.933 --> 02:30.103 What do you notice specially about this spectrum? 02:30.100 --> 02:30.900 Anything? 02:30.900 --> 02:35.530 What would you look for if you were looking for a sugar? 02:35.533 --> 02:37.673 You'd look for OH groups-- 02:37.667 --> 02:39.967 sure enough, big O-H peak. 02:39.967 --> 02:41.497 And you'd look for what other group? 02:44.600 --> 02:46.130 Antonia? 02:46.133 --> 02:47.033 STUDENT: The aldehyde? 02:47.033 --> 02:48.203 PROFESSOR: The aldehyde carbonyl. 02:48.200 --> 02:50.330 And where would you look for it, do you remember? 02:50.333 --> 02:51.603 STUDENT: The C=O stretch 02:54.300 --> 02:56.530 PROFESSOR: You look for it around 1,700, 02:56.533 --> 02:58.833 and it's not there. 02:58.833 --> 03:02.833 Or you could do the NMR. So here's the proton NMR of 03:02.833 --> 03:03.603 crystalline glucose. 03:03.600 --> 03:06.930 You dissolve it in D2O, so now you don't have 03:06.933 --> 03:10.773 the OH protons there. 03:10.767 --> 03:12.597 And there's the proton NMR spectrum. 03:12.600 --> 03:15.770 And again, there's no way downfield peak. 03:15.767 --> 03:17.427 No aldehyde. 03:17.433 --> 03:20.833 Or if you look at the carbon NMR spectrum, no downfield 03:20.833 --> 03:23.803 peak for aldehyde, or ketone, either. 03:23.800 --> 03:25.970 They would both come down there in the carbon spectrum. 03:25.967 --> 03:28.927 Of course, there wouldn't be a hydrogen on the ketone. 03:32.900 --> 03:36.530 So let me draw it, to try to explain this, draw it in a 03:36.533 --> 03:37.803 funny conformation. 03:40.433 --> 03:44.003 Which could be in equilibrium with a hemiketal. 03:44.000 --> 03:44.400 Remember? 03:44.400 --> 03:48.630 With either acid or base catalysis in water, here 03:48.633 --> 03:52.733 deuterated water, you could make a hemiketal down here at 03:52.733 --> 03:54.833 the bottom right. 03:54.833 --> 03:59.133 So all the Os are ODs, but here you have Hs. 03:59.133 --> 04:01.833 Now let's blow up that part of the NMR spectrum 04:01.833 --> 04:05.033 that you can see there. 04:05.033 --> 04:08.233 What peak stands out? 04:08.233 --> 04:10.233 One far downfield. 04:10.233 --> 04:13.603 What's it due to? 04:13.600 --> 04:16.570 Which of the hydrogens in this compound should come the 04:16.567 --> 04:17.827 furthest downfield? 04:24.700 --> 04:25.170 Leen? 04:25.167 --> 04:29.767 STUDENT: The one that's attached to oxygen 04:29.767 --> 04:31.027 PROFESSOR: That's attached to what? 04:31.033 --> 04:33.433 STUDENT: Attach the carbons to O. 04:33.433 --> 04:34.273 PROFESSOR: They all have an O. 04:34.267 --> 04:40.927 STUDENT: Well yeah, but attached to one without the alcohol? 04:40.933 --> 04:42.503 PROFESSOR: The one here, you mean. 04:42.500 --> 04:43.500 STUDENT: Yeah, over there. 04:43.500 --> 04:45.500 PROFESSOR: Now, that one is on a carbon that has 04:45.500 --> 04:49.070 two carbons attached to it and an oxygen, 04:49.067 --> 04:52.627 and oxygens withdraw, tend to shift things downfield. 04:52.633 --> 04:53.873 Can you do better than that? 04:57.067 --> 04:59.597 There's one oxygen to withdraw from that carbon, right? 05:05.000 --> 05:06.070 Megan? 05:06.067 --> 05:07.797 STUDENT: The equatorial hydrogen 05:07.800 --> 05:08.800 PROFESSOR: The equatorial one. 05:08.800 --> 05:13.500 The one at the far right has two oxygens pulling on it, the 05:13.500 --> 05:15.770 one that's on a hemiketal. 05:15.767 --> 05:17.797 So it's way downfield. 05:17.800 --> 05:20.200 Now notice that there's a little peak 05:20.200 --> 05:22.200 here, a little doublet. 05:22.200 --> 05:23.170 What's that due to? 05:23.167 --> 05:26.927 Well, it could be just impurity, but it's not. 05:26.933 --> 05:30.373 Because if you let it sit a day, it grows, and the other 05:30.367 --> 05:31.597 one shrinks. 05:33.733 --> 05:38.733 It's also downfield, so it looks like it's got more 05:38.733 --> 05:39.933 oxygens on it. 05:39.933 --> 05:41.203 Anybody got an idea? 05:45.133 --> 05:47.133 What did you call this one, Megan? 05:47.133 --> 05:48.303 STUDENT: Equatorial 05:48.300 --> 05:49.570 PROFESSOR: Suppose it had been axial. 05:52.533 --> 05:57.203 Then if you had a ring current, as in benzine-- 05:57.200 --> 05:58.570 you don't here-- 05:58.567 --> 06:02.297 this one would be downfield, and the one where it was axial 06:02.300 --> 06:03.570 would be upfield. 06:03.567 --> 06:06.367 More over the top of the ring. 06:06.367 --> 06:07.897 Can you get it there? 06:07.900 --> 06:10.630 Yeah, you can go back here and attack the carbonyl from the 06:10.633 --> 06:15.073 other side, and get that one. 06:15.067 --> 06:17.327 Now, how do you know which is which? 06:17.333 --> 06:19.503 How do you know which one was axial and which one was 06:19.500 --> 06:20.470 equitorial? 06:20.467 --> 06:22.927 Well, you might use this argument about ring currents. 06:22.933 --> 06:24.073 People talk about that. 06:24.067 --> 06:25.997 I'm not sure whether it means anything. 06:26.000 --> 06:27.870 There are other kinds of arguments you could make that 06:27.867 --> 06:29.567 might have to do with that, too. 06:29.567 --> 06:32.627 But one thing that's clear in the spectrum is that there's a 06:32.633 --> 06:35.503 doublet splitting here which is about 8 Hz, and a 06:35.500 --> 06:38.670 doublet splitting here which isn't even half as big. 06:38.667 --> 06:42.197 So one is a big splitting, and one is a small splitting. 06:42.200 --> 06:44.470 Now, what is it that's splitting this hydrogen? 06:47.500 --> 06:49.500 Karl? 06:49.500 --> 06:52.700 STUDENT: Sometimes that D is replaced with an H? 06:52.700 --> 06:54.270 PROFESSOR: So there has to be another H on the 06:54.267 --> 06:57.497 adjacent carbon that's splitting that one, right? 06:57.500 --> 06:59.270 So this H here. 06:59.267 --> 07:04.127 And in this case, this H here would be doing it. 07:04.133 --> 07:06.603 But one of them is a big splitting, and the other is a 07:06.600 --> 07:08.700 small splitting. 07:08.700 --> 07:09.970 Sebastian, you got an idea? 07:13.733 --> 07:16.073 STUDENT: In the top one there, anti. 07:16.067 --> 07:16.827 PROFESSOR: Right. 07:16.833 --> 07:19.933 The top one is anti, and the other one is a gauche. 07:19.933 --> 07:23.533 So there's much better overlap, anti than gauche. 07:23.533 --> 07:25.573 So this one is the one that's anti. 07:25.567 --> 07:27.567 That's the one with axial hydrogen. 07:27.567 --> 07:29.897 And this is the one that came from the crystal. 07:29.900 --> 07:31.970 So the crystal was all the same. 07:31.967 --> 07:35.397 You dissolve it and it begins to equilibrate, and ultimately 07:35.400 --> 07:42.570 has more of the equatorial OD than of the axial OD. 07:42.567 --> 07:44.927 And in fact, if you look at the original material, just 07:44.933 --> 07:48.073 after you dissolve it, it has a rotation of 112 degrees, 07:48.067 --> 07:50.127 optically active. 07:50.133 --> 07:54.903 But after a day in D2O, it's only 53 degrees, because the 07:54.900 --> 07:56.800 other isomer is 19 degrees. 07:56.800 --> 08:00.130 So people used that, before there was spectroscopy, to try 08:00.133 --> 08:04.773 to figure out what the ratio of the two was at equilibrium. 08:04.767 --> 08:07.167 Or if you really want to do it, you do it by X-ray 08:07.167 --> 08:10.097 diffraction, and you get Cartesian coordinates for all 08:10.100 --> 08:13.430 the atoms. That's what you do nowadays. 08:13.433 --> 08:15.803 But the interesting thing, and what got a Nobel 08:15.800 --> 08:17.470 Prize, was not this. 08:17.467 --> 08:18.967 It was, how did they know? 08:18.967 --> 08:24.167 How could they figure out what the structure of glucose was? 08:24.167 --> 08:27.427 Well, a lot of sugars were known in the last half of the 08:27.433 --> 08:28.373 19th century. 08:28.367 --> 08:31.997 When van 't Hoff wrote the German version of his book in 08:32.000 --> 08:38.800 1877, he mentioned a lot of sugars as optically active, 08:38.800 --> 08:41.900 for example, here, he cites glucose. 08:41.900 --> 08:44.730 He also cites levulose. 08:44.733 --> 08:48.573 And in fact, those both come from sucrose. 08:48.567 --> 08:51.297 So sucrose is a more complex sugar. 08:51.300 --> 08:54.230 It's a ketale that has two of them together. 08:54.233 --> 08:58.933 But if you take them apart, one of them is glucose and the 08:58.933 --> 09:01.633 other is levulose, which is also called fructose. 09:01.633 --> 09:03.903 Do you know why it's called levulose? 09:03.900 --> 09:05.170 What does levo mean? 09:08.333 --> 09:10.773 Actually, the English word has the same root. 09:10.767 --> 09:12.797 Left. 09:12.800 --> 09:16.900 Levo is left, dextro is right in Latin. 09:16.900 --> 09:20.400 So this rotates white to the left. 09:20.400 --> 09:24.200 This rotates light to the right, and is called dextrose, 09:24.200 --> 09:27.270 also, or dextrine down here. 09:27.267 --> 09:28.997 He also mentioned lactose. 09:29.000 --> 09:32.930 And it was found in 1876 that lactose treated with acid 09:32.933 --> 09:37.073 gives also glucose, but another one called galactose, 09:37.067 --> 09:38.997 which comes from the Greek word for milk. 09:39.000 --> 09:41.500 So it's called milk sugar in German. 09:41.500 --> 09:43.670 So lactose, obviously, came from milk. 09:43.667 --> 09:48.667 5% of milk, I think, by weight is lactose sugar. 09:48.667 --> 09:50.127 Or there's stuff called mannitol, 09:50.133 --> 09:52.333 which came from manna. 09:52.333 --> 09:58.073 They would slash the bark of flowering ash trees around the 09:58.067 --> 10:00.927 Mediterranean and this stuff would ooze out which they 10:00.933 --> 10:02.103 called manna. 10:02.100 --> 10:04.670 And from that, they got mannitol. 10:04.667 --> 10:08.667 And mannitol turns out to have these kind of CHOH groups that 10:08.667 --> 10:10.267 van 't Hoff was interested in because 10:10.267 --> 10:11.597 they made things chiral. 10:11.600 --> 10:15.830 But notice in mannitol, the two ends are both OHs. 10:15.833 --> 10:20.133 The aldehyde on the end has been reduced, in this case. 10:20.133 --> 10:26.773 Or both ends can be oxided as in what's called sugar acid. 10:26.767 --> 10:30.097 So you could have both ends be an acid. 10:30.100 --> 10:36.800 Or you can have arabinose, which was isolated in 1873 10:36.800 --> 10:38.900 from gum arabic. 10:38.900 --> 10:40.800 A gum that came from Arabia. 10:40.800 --> 10:43.570 You know, if you're an actor, you put your mustache on with 10:43.567 --> 10:44.227 gum arabic. 10:44.233 --> 10:45.303 I think you used to, anyhow. 10:45.300 --> 10:46.530 I don't know. 10:48.700 --> 10:54.070 And in fact, it was possible to take mannitol and oxidize 10:54.067 --> 10:55.467 it back to an aldehyde. 10:55.467 --> 10:59.227 That must have been a tough thing to do, because aldehydes 10:59.233 --> 11:01.133 are-- very hard to stop an aldehyde. 11:01.133 --> 11:06.133 But somehow, in 1888, they were able to get mannose, maybe 11:06.133 --> 11:09.503 just a teeny, teeny bit of mannose, doing that. 11:09.500 --> 11:12.000 So aldehyde. 11:12.000 --> 11:14.400 So there were lots and lots of these known, and people 11:14.400 --> 11:16.570 fiddled around with them, and found out what you'd get if 11:16.567 --> 11:20.497 you oxidized, what you'd get if you reduced, and so on. 11:20.500 --> 11:26.000 And on comes Heinrich Kiliani, the hydrogen cyanide man. 11:28.533 --> 11:31.673 Because in this paper in 1855, 11:31.667 --> 11:34.867 which, fortunately, I've translated here, 11:34.867 --> 11:37.827 he says, "While a large number of compounds are very easily 11:37.833 --> 11:40.503 formed upon oxidation of dextrose"-- 11:40.500 --> 11:42.800 remember, dextrose is glucose, it rotates 11:42.800 --> 11:44.300 light to the right-- 11:44.300 --> 11:48.000 "by dilute nitric acid or by halogens, these molecules 11:48.000 --> 11:52.200 retain six carbons bound together in a chain. 11:52.200 --> 11:53.830 Under the same conditions, levulose"-- 11:53.833 --> 11:59.733 The other one that came from sucrose-- 11:59.733 --> 12:03.173 "yields substances containing chains with a smaller number of 12:03.167 --> 12:09.167 carbons, (like glycolic acid, or inactive tartaric acid.)"-- 12:09.167 --> 12:11.267 That's meso-tartaric acid, OK? 12:11.267 --> 12:13.467 "Here oxidation causes immediate 12:13.467 --> 12:14.867 splitting of the molecule."-- 12:14.867 --> 12:18.667 it breaks the carbon chain--," a fact which means that levulose 12:18.667 --> 12:20.797 is a ketone." 12:20.800 --> 12:26.170 So that glucose, or dextrose, has an aldehyde at the end of 12:26.167 --> 12:28.197 the chain, you oxidize that to an acid. 12:28.200 --> 12:30.330 But if you have a ketone in the middle of the chain and 12:30.333 --> 12:34.603 you oxidize it, you break the chain. 12:34.600 --> 12:36.900 So it must be a ketose of some sort. 12:36.900 --> 12:39.430 "Bearing in mind further the fact that levulose is 12:39.433 --> 12:43.203 transformed into mannitol by nascent hydrogen"-- 12:43.200 --> 12:45.800 nascent means at the time it's being born. 12:45.800 --> 12:48.830 They had this interesting idea in those days that when they 12:48.833 --> 12:55.703 dissolved sodium in alcohol, it generated hydrogen, 12:55.700 --> 12:59.170 but this hydrogen was more reactive than most hydrogen, 12:59.167 --> 13:01.567 and could reduce things that normal hydrogen 13:01.567 --> 13:02.797 gas couldn't do. 13:02.800 --> 13:05.400 So they said it was nascent hydrogen that could do things. 13:05.400 --> 13:09.100 In fact, of course, it was the metal actually transferring 13:09.100 --> 13:12.430 the electrons to the compound to be reduced. 13:12.433 --> 13:14.403 But anyhow, he said, if you do that with 13:14.400 --> 13:16.270 levulose, you get mannitol. 13:16.267 --> 13:18.427 Which, remember, was the thing that has OH on 13:18.433 --> 13:20.503 both ends of the chain. 13:20.500 --> 13:24.400 So if it was a ketose, a ketone in the middle chain, it 13:24.400 --> 13:26.430 already had alcohols on the end. 13:26.433 --> 13:28.773 But if you reduce the ketone to an alcohol, then you got 13:28.767 --> 13:31.867 alcohols all the way, much like mannitol, which 13:31.867 --> 13:32.997 they got from that. 13:33.000 --> 13:37.170 So one comes to the conclusion that levulose must be adjudged 13:37.167 --> 13:40.597 to have one of the following two constitutional formulae. 13:40.600 --> 13:41.770 Either CO-- 13:41.767 --> 13:42.927 they can't be the first carbon. 13:42.933 --> 13:43.803 That's the aldehyde. 13:43.800 --> 13:46.870 That's the one where you reduce it or oxidize it, it 13:46.867 --> 13:47.797 doesn't break the chain. 13:47.800 --> 13:49.630 You just get an acid there. 13:49.633 --> 13:52.473 If it's a ketone here, you break the chain. 13:52.467 --> 13:54.667 If it's a ketone here, you break the chain. 13:54.667 --> 13:56.997 What if it's a ketone on the next carbon down? 14:00.233 --> 14:01.573 Why didn't he consider that? 14:07.033 --> 14:07.903 Matt? 14:07.900 --> 14:08.830 STUDENT: It's the same as that one. 14:08.833 --> 14:10.233 PROFESSOR:It's the same as the one above, right? 14:10.233 --> 14:11.703 There are only two. 14:11.700 --> 14:13.500 OK. 14:13.500 --> 14:16.300 So is it I, or is it II? 14:16.300 --> 14:18.800 So he goes on in the paper to say, "One could hope to 14:18.800 --> 14:21.270 distinguish definitively between one and the other 14:21.267 --> 14:25.967 formula by succeeding in, adding HCN to the ketone 14:25.967 --> 14:31.227 radical of that levulose and transforming the cyanhydrine 14:31.233 --> 14:33.773 into the corresponding carboxylic acid." 14:33.767 --> 14:37.167 So you add CN, hydrolyze it so it's COOH. 14:37.167 --> 14:39.027 It adds to the carbonyl carbon. 14:39.033 --> 14:41.333 So from compound one, you would get this. 14:41.333 --> 14:44.473 Add in CN here and turn it into carboxylic acid. 14:44.467 --> 14:47.767 From compound II, the ketone on the next position down, 14:47.767 --> 14:52.197 you'd add here and get that carboxylic acid. 14:52.200 --> 14:59.330 So the question is, if it has this structure, then you add 14:59.333 --> 15:00.403 HCN and HCl. 15:00.400 --> 15:01.600 You get this-- 15:01.600 --> 15:04.570 and it's very concentrated HCl he used, incidentally-- 15:04.567 --> 15:08.997 or if it's the next one down, you get this. 15:09.000 --> 15:09.330 OK. 15:09.333 --> 15:10.903 So you do it and decide. 15:10.900 --> 15:13.370 All you have to know is which product you get. 15:13.367 --> 15:15.497 Get it pure, see what it is. 15:15.500 --> 15:19.500 The problem is, these things, as almost all things are in 15:19.500 --> 15:22.170 sugar chemistry, are syrups. 15:22.167 --> 15:24.767 It's very, very, very difficult to get 15:24.767 --> 15:26.167 crystals from them. 15:26.167 --> 15:28.897 So it was really hard, in those days, to purify things. 15:28.900 --> 15:31.070 Nowadays you to do chromatography, maybe, or 15:31.067 --> 15:31.867 something like that. 15:31.867 --> 15:34.397 But then it was essentially impossible. 15:34.400 --> 15:38.100 So they had to try to make things simpler so that they 15:38.100 --> 15:40.600 had a chance of crystallization. 15:40.600 --> 15:43.130 He says, "It must, upon exhaustive reduction by 15:43.133 --> 15:48.733 concentrated HI, yield methyl butyl acetic acid."-- 15:48.733 --> 15:49.803 so this one-- 15:49.800 --> 15:50.970 the one on the top-- 15:50.967 --> 15:56.397 would give methyl butyl acetic acid, reduced with HI and 15:56.400 --> 15:57.970 phosphorus.--" 15:57.967 --> 16:00.727 and on the contrary, the carboxylic acid from compound II 16:00.733 --> 16:04.833 would give ethyl propyl acetic acid. 16:04.833 --> 16:08.533 So all you have to do is know which of these you've got. 16:08.533 --> 16:11.103 And he said, this is fine. 16:11.100 --> 16:14.600 But when he did the reaction and got the product, which 16:14.600 --> 16:18.600 should be either this or this, he says, "[It] does not agree 16:18.600 --> 16:21.730 with the description that Hecht gives of the Ca 16:21.733 --> 16:24.203 salt of methylbutyl acetic acid." 16:24.200 --> 16:26.800 So Hecht, he said, had done a lot of good work on this 16:26.800 --> 16:29.630 compound, including making the calcium salt. 16:29.633 --> 16:31.903 He was able to crystallize the calcium salt of 16:31.900 --> 16:33.170 the product he got. 16:33.167 --> 16:36.227 And it didn't agree with Hecht. 16:36.233 --> 16:43.973 So he says, "which means that my heptanoic acid is identical 16:43.967 --> 16:46.427 with ethylpropylacetic acid." 16:46.433 --> 16:48.233 So this is the one he's got. 16:48.233 --> 16:50.603 But that compound wasn't known, so he couldn't 16:50.600 --> 16:53.030 be sure about it. 16:53.033 --> 16:55.633 But anyhow, he concluded that it must be this, since it's 16:55.633 --> 16:58.173 not Hecht's compound. 16:58.167 --> 17:09.027 Now the next year, in 1886, he reacted ethyl acetoacetate. 17:09.033 --> 17:13.533 So this is acetyl group on acetic ester. 17:13.533 --> 17:14.833 What's special about those hydrogens? 17:18.233 --> 17:20.533 Active methylene adjacent to two carbonyls. 17:20.533 --> 17:23.603 You make the anion, you can put an R group on. 17:23.600 --> 17:27.430 You can make the anion again, put another R group on. 17:27.433 --> 17:32.173 So he put on ethyl. 17:32.167 --> 17:34.767 Put on propyl. 17:34.767 --> 17:37.897 And then, what I told you last time is that when you 17:37.900 --> 17:41.870 hydrolyze this, you get the acid, and then it 17:41.867 --> 17:43.497 decarboxylates. 17:43.500 --> 17:48.700 So from the acetoacetic ester synthesis, you lose CO2 and 17:48.700 --> 17:49.870 get a ketone. 17:49.867 --> 17:52.527 But he did it differently in those days. 17:52.533 --> 17:56.633 He used really, really strong KOH, which 17:56.633 --> 17:58.403 doesn't give a ketone. 17:58.400 --> 18:00.870 It gives acetate. 18:00.867 --> 18:04.597 That is, the hydroxide attacks here. 18:04.600 --> 18:08.170 Acetic acid comes off, generating that anion, which 18:08.167 --> 18:10.627 then picks up a proton from the acetic acid. 18:10.633 --> 18:16.773 So you have acetate and an acid anion. 18:16.767 --> 18:19.567 Which you then put a proton on, and you've got this. 18:22.400 --> 18:27.200 So he made authentic stuff, but it didn't agree with what 18:27.200 --> 18:29.370 he got from levulose. 18:29.367 --> 18:33.297 So now from Hecht, he knows it wasn't this, and from his own 18:33.300 --> 18:36.700 work, he knows it's not that. 18:36.700 --> 18:39.170 So now he began to wonder about Hecht and just 18:39.167 --> 18:42.727 how good Hecht was. 18:42.733 --> 18:45.803 So he went on and did the same thing, putting on methyl and 18:45.800 --> 18:49.330 butyl, to make this. 18:49.333 --> 18:52.873 And he compared it with the product from this, and found 18:52.867 --> 18:55.997 that the calcium, barium, strontium, and lead salts all 18:56.000 --> 18:57.900 agreed in their properties. 18:57.900 --> 18:59.530 So Hecht was wrong. 18:59.533 --> 19:02.073 He said at the end of the paper that Hecht is going to 19:02.067 --> 19:04.367 go back and look at this a little more. 19:04.367 --> 19:08.897 But at any rate, he was then able to prove that levulose or 19:08.900 --> 19:10.800 fructose has that structure. 19:10.800 --> 19:13.200 The carbonyl is in the second position. 19:13.200 --> 19:15.800 So he now knows the constitution of fructose. 19:20.100 --> 19:25.270 This paper from 1887 is on the composition and constitution 19:25.267 --> 19:28.197 of arabaric acid and arabinose. 19:28.200 --> 19:31.200 So now he's going to look at a different sugar. 19:31.200 --> 19:35.470 And what he says is, "In a report dated 27 November 1886, 19:35.467 --> 19:39.097 I showed, on the one hand, that arabaric acid, formed by 19:39.100 --> 19:43.700 oxidation of arabinose, has the formula shown there, but 19:43.700 --> 19:46.930 on the other hand, described several derivatives of 19:46.933 --> 19:51.373 arabinose carboxylic acid with the formula C7." 19:51.367 --> 19:59.297 So it was uncertain whether arabinose was a five carbon 19:59.300 --> 20:02.270 sugar or a six carbon sugar. 20:02.267 --> 20:05.267 If it was a five carbon sugar and he oxidized it, he'd get 20:05.267 --> 20:05.997 five carbons. 20:06.000 --> 20:10.830 If it was a six carbon sugar, and he added HCN to add 20:10.833 --> 20:13.503 another carbon, he would get C7. 20:13.500 --> 20:16.330 So here says, he admits that he had said 20:16.333 --> 20:17.533 contradictory things. 20:17.533 --> 20:20.403 One that implied that it was C5, another that 20:20.400 --> 20:22.300 implied it was C6. 20:22.300 --> 20:25.900 "Since at that time I had no basis in truth to dispute the 20:25.900 --> 20:28.700 generally accepted formula for arabinose, which is that it's 20:28.700 --> 20:30.270 C6." 20:30.267 --> 20:33.897 The analyses are very similar to one another, whether it's 20:33.900 --> 20:34.970 one or the other. 20:34.967 --> 20:37.697 "and my analytical results did not contradict either 20:37.700 --> 20:38.200 assumption." 20:38.200 --> 20:41.500 So he couldn't be sure whether arabinose, the stuff that came 20:41.500 --> 20:48.300 from gum arabic, was C5 or C6. 20:48.300 --> 20:50.070 So he took arabinose. 20:50.067 --> 20:54.967 He added HCN He made the arabinose carboxylic acid, the 20:54.967 --> 20:58.097 stuff that he talked about up there, 20:58.100 --> 20:59.930 but he said then it was C7. 20:59.933 --> 21:02.603 Here he made it with one, two, three, four, five, six. 21:02.600 --> 21:03.800 Here he made the six-- 21:03.800 --> 21:07.300 assuming that it starts with five, right? 21:07.300 --> 21:12.470 And he was able to reduce that with sodium with mercury to 21:12.467 --> 21:17.327 get mannitol, which was known to be C6. 21:17.333 --> 21:20.903 So it was clear that arabinose wasn't a C6 sugar. 21:20.900 --> 21:22.270 It was a C5 sugar. 21:22.267 --> 21:25.397 So he had resolved this. 21:25.400 --> 21:29.100 But it was pointed out that-- One of the reasons it was 21:29.100 --> 21:31.200 difficult to work with this was this original 21:31.200 --> 21:33.870 compound was a mixture. 21:33.867 --> 21:36.267 Why would it be a mixture? 21:36.267 --> 21:41.297 Because the cyanide could add to either face of this carbon 21:41.300 --> 21:45.230 to make right- or left-handed carbon. 21:45.233 --> 21:48.333 And these other carbons are, of course, chiral, too. 21:48.333 --> 21:51.073 So you get diastereomers, depending on which 21:51.067 --> 21:52.697 side you add from. 21:52.700 --> 21:55.530 This was pointed out by someone who was very sensitive 21:55.533 --> 21:59.603 to not just the constitution, the sequence of bonds, but to 21:59.600 --> 22:02.770 the configuration of these sugars, which is going to make 22:02.767 --> 22:03.767 a lot of difference. 22:03.767 --> 22:05.667 With so many chiral centers, there are going 22:05.667 --> 22:07.397 to be lots of isomers. 22:07.400 --> 22:10.630 So the person who pointed that out was an Emil Fischer, who 22:10.633 --> 22:16.033 was three years older than Kiliani, and died much sooner, 22:16.033 --> 22:18.703 for reasons you'll see. 22:18.700 --> 22:23.730 So one thing he did with Kiliani's acid-- 22:23.733 --> 22:28.003 this is the acid you get by adding CN to the five-carbon 22:28.000 --> 22:31.270 sugar, and then hydrolyzing it. 22:31.267 --> 22:34.167 So Kiliani treated it with sodium and 22:34.167 --> 22:37.027 mercury, and got mannitol. 22:37.033 --> 22:39.433 But Fischer did something different. 22:39.433 --> 22:41.003 Bear in mind, this is a reduction. 22:41.000 --> 22:43.900 So you take the acid all the way to the alcohol. 22:43.900 --> 22:46.500 It's very difficult to stop at the aldehyde. 22:46.500 --> 22:49.930 But Fischer found a way to stop at the aldehyde, which 22:49.933 --> 22:54.773 was to first heat it to make this lactone, a cyclic ester, 22:54.767 --> 22:58.427 and then reduce that with sodium and mercury, and now he 22:58.433 --> 23:00.603 got the aldehyde here. 23:00.600 --> 23:02.700 Now, why was that handy? 23:02.700 --> 23:05.870 Because it gave a way to convert one sugar 23:05.867 --> 23:07.527 into another sugar. 23:07.533 --> 23:11.703 Now you could make new sugars synthetically, because it was 23:11.700 --> 23:14.570 possible to stop at the aldehyde. 23:14.567 --> 23:17.397 So a Kiliani-Fischer synthesis on 23:17.400 --> 23:22.470 arabinose gave this compound. 23:22.467 --> 23:26.027 So Kiliani-Fischer synthesis elongates an aldose, makes it 23:26.033 --> 23:28.333 one carbon longer. 23:28.333 --> 23:28.703 OK. 23:28.700 --> 23:34.200 Now, that wasn't the reason Fischer got the Nobel Prize. 23:34.200 --> 23:36.600 A contributing factor was phenylhydrazine. 23:36.600 --> 23:40.070 When he was a graduate student, he synthesized 23:40.067 --> 23:43.827 phenylhydrazine, and he loved to make derivatives with it. 23:43.833 --> 23:46.133 Remember, we talked about how you could make derivatives of 23:46.133 --> 23:52.133 carbonyl compounds with N-N things to make imine bonds, 23:52.133 --> 23:54.033 and they're very strong, if you have two Ns 23:54.033 --> 23:55.473 together like that. 23:55.467 --> 24:00.227 So he could do it with sugars. 24:00.233 --> 24:04.903 You could react with a sugar, and make an imine. 24:04.900 --> 24:07.470 It's called a hydrazone, right? 24:07.467 --> 24:12.027 Now, this hydrogen here is allylic, so it could shift up 24:12.033 --> 24:14.473 to here and make the double bond here. 24:14.467 --> 24:17.467 But now this hydrogen is allylic, and it could shift to 24:17.467 --> 24:19.627 there, so you can get this. 24:19.633 --> 24:22.133 Now you've got another ketone. 24:22.133 --> 24:23.403 So what's going to happen? 24:25.900 --> 24:27.600 You can make another hydrazone. 24:31.533 --> 24:36.803 So now you've used the second mole of phenylhydrazine. 24:36.800 --> 24:38.630 So now that one's allylic. 24:38.633 --> 24:40.003 You can shift it over here. 24:44.267 --> 24:46.927 Here we do a cyclic rearrangement. 24:46.933 --> 24:49.073 This hydrogen goes to that nitrogen. 24:49.067 --> 24:50.997 This bond breaks. 24:51.000 --> 24:54.130 These electrons go here to make a double bond, becomes a 24:54.133 --> 24:56.233 single, double. 24:56.233 --> 24:58.533 So it breaks apart into two molecules, 24:58.533 --> 25:01.433 one of which leaves. 25:01.433 --> 25:04.733 And now we have a C=N double bond, which is very like a C=O 25:04.733 --> 25:06.433 double bond, so you can get a 25:06.433 --> 25:07.903 third molecule of phenylhydrazine 25:07.900 --> 25:12.470 to react and make a new C=N double bond, losing 25:12.467 --> 25:15.667 ammonia, and you get this compound, that has two of his 25:15.667 --> 25:18.327 favorite molecules stitched in there. 25:18.333 --> 25:20.633 It's called an osazone. 25:20.633 --> 25:24.503 It's a hydrazone that's made from an ose, from a sugar. 25:30.800 --> 25:33.530 By treating this with his favorite compound, 25:33.533 --> 25:34.773 you could make this. 25:34.767 --> 25:38.097 Now, it was his favorite compound, but 25:38.100 --> 25:39.970 it's also deadly poisonous. 25:39.967 --> 25:42.897 And he poisoned himself very badly for almost a decade 25:42.900 --> 25:45.100 he was in very bad health because of poisoning 25:45.100 --> 25:46.030 himself with this. 25:46.033 --> 25:50.273 And in fact, in 1919, he committed suicide. 25:50.267 --> 25:53.667 He had cancer at the time, and who knows whether it had to do 25:53.667 --> 25:57.697 with exposure to his favorite molecule. 25:57.700 --> 26:00.170 But if what was so dangerous, and he knew he was being 26:00.167 --> 26:03.097 poisoned, why did he like it so much? 26:03.100 --> 26:06.330 It was because ozasones are crystalline. 26:06.333 --> 26:08.773 Remember, these sugars are always syrups, and you can't 26:08.767 --> 26:09.927 do anything with them. 26:09.933 --> 26:13.603 But with crystals, you could purify and tell what things 26:13.600 --> 26:15.300 were, tell if one thing is the same as 26:15.300 --> 26:16.870 something else or different. 26:16.867 --> 26:20.167 So that was the beauty, for him, of phenylhydrazine. 26:20.167 --> 26:23.027 That you could make an osazone and identify 26:23.033 --> 26:25.433 things in sugar chemistry. 26:28.833 --> 26:35.503 So he was interested in identifying the structures of 26:35.500 --> 26:36.470 these things. 26:36.467 --> 26:41.597 So let's try to be systematic about seeing what the 26:41.600 --> 26:45.200 configurations could be of different sugars. 26:45.200 --> 26:47.130 Let's look at the hexoses. 26:47.133 --> 26:50.933 We all we already have erythrose, 26:50.933 --> 26:53.473 arabinose, and xylose. 26:53.467 --> 26:55.767 Arabinose came from gum arabic, 26:55.767 --> 26:57.697 xylose came from wood. 26:57.700 --> 27:01.700 Erythrose comes from a lichen. 27:01.700 --> 27:06.400 Eryth means red in Greek, so erythrose was because it came 27:06.400 --> 27:09.170 from this red plant. 27:09.167 --> 27:13.327 But there were also hexoses glucose, mannose, galactose, 27:13.333 --> 27:15.003 and gulose. 27:15.000 --> 27:20.900 And all these were identified by Kiliani as being aldoses. 27:20.900 --> 27:22.570 Aldehydes, not ketones. 27:22.567 --> 27:25.967 We showed how he could tell the difference there. 27:25.967 --> 27:31.197 So these must differ in their configuration. 27:31.200 --> 27:32.000 Right? 27:32.000 --> 27:34.830 Now, how many should there be? 27:34.833 --> 27:37.373 If you have six carbons in a chain that ends in an 27:37.367 --> 27:40.697 aldehyde, how many should there be? 27:40.700 --> 27:42.700 Well, for this purpose, we could write them 27:42.700 --> 27:44.200 all out like this. 27:44.200 --> 27:49.630 This is a particular one, using what projection? 27:49.633 --> 27:50.333 STUDENT: Fischer projection. 27:50.333 --> 27:51.833 PROFESSOR: The Fischer projection. 27:51.833 --> 27:55.103 And one of the most amazing things about Fischer is that 27:55.100 --> 27:58.270 he figured this all out without having the Fischer 27:58.267 --> 27:59.397 projection. 27:59.400 --> 28:03.330 It's easy for us to trace his thought now using the Fischer 28:03.333 --> 28:06.473 projection, but he used van 't Hoff's notation, which was 28:06.467 --> 28:08.067 very, very complicated. 28:08.067 --> 28:11.297 And I have never figured it out. 28:11.300 --> 28:13.970 So that's one of the real triumphs of Fischer, was to be 28:13.967 --> 28:16.797 able to think through this stuff without Fischer 28:16.800 --> 28:20.100 projections, which he published the next year. 28:20.100 --> 28:23.770 But we could abbreviate that Fischer projection by writing 28:23.767 --> 28:24.467 it that way. 28:24.467 --> 28:26.497 Whoops, I wrote it wrong here. 28:26.500 --> 28:29.430 These lines show which way the OH points. 28:29.433 --> 28:32.733 So the bottom, you don't care, it's not chiral. 28:32.733 --> 28:35.333 The next one, the OH to right, OH to the right, that one 28:35.333 --> 28:38.133 should be OH to the left, OH to the right. 28:38.133 --> 28:40.073 So the code is clear. 28:40.067 --> 28:44.197 Now we can just write out all the possibilities. 28:44.200 --> 28:54.600 So there are four chiral carbons, so there are going to 28:54.600 --> 28:58.200 be 16 possible isomers. 28:58.200 --> 29:01.670 But if we're looking only at the D-sugars, those are the 29:01.667 --> 29:04.927 ones that are all to the right on the bottom. 29:04.933 --> 29:07.673 We could draw the mirror image, too, the L-sugars. 29:07.667 --> 29:10.197 But let's keep it simple just by showing the D sugars, 29:10.200 --> 29:14.000 because as Fischer well knew, he had no way of telling D 29:14.000 --> 29:18.070 from L. You could measure the rotation, but not the absolute 29:18.067 --> 29:19.067 configuration. 29:19.067 --> 29:22.397 So let's just assume that a given compound 29:22.400 --> 29:25.200 is D in the D series. 29:25.200 --> 29:26.870 Now, how can you draw them all out? 29:26.867 --> 29:30.167 You can draw right, right, right, right, left, left, 29:30.167 --> 29:31.897 left, left. 29:31.900 --> 29:35.530 Then you can go right, right, left, left, right, right, 29:35.533 --> 29:39.933 left, left and finally right, left, right, left, right, 29:39.933 --> 29:41.303 left, right, left. 29:41.300 --> 29:46.270 So you've got eight isomers, and four of them must be 29:46.267 --> 29:48.997 glucose, mannose, galactose, and gulose. 29:49.000 --> 29:52.800 But not arabinose and xylose, because as we just saw, 29:52.800 --> 29:56.270 Kiliani showed that arabinose was a five-carbon sugar, not a 29:56.267 --> 29:57.397 six-carbon sugar. 29:57.400 --> 29:58.470 It's a pentose. 29:58.467 --> 30:01.927 An erythrose is a tetrose, a four-carbon sugar. 30:01.933 --> 30:04.933 And finally, at the top, you have glyceraldehyde, the one 30:04.933 --> 30:10.003 that Fischer chose as the reference for what's D. 30:10.000 --> 30:14.370 So the question only is which is which? 30:14.367 --> 30:17.497 And at first glance, that looks impossible, until you 30:17.500 --> 30:20.900 come along with X-ray or NMR, maybe, or something 30:20.900 --> 30:22.070 to figure it out. 30:22.067 --> 30:23.627 But Fischer figured it out. 30:26.200 --> 30:29.100 So here was the evidence he used. 30:29.100 --> 30:32.170 You can look online on the website and see the 30:32.167 --> 30:34.967 translation of his paper, how he actually did it. 30:34.967 --> 30:42.567 Almost all textbooks nod and cover this a little bit, 30:42.567 --> 30:45.427 because it's realized what a great contribution it was. 30:45.433 --> 30:47.673 I mean, it's like Shakespeare or something like that. 30:47.667 --> 30:48.967 But they all mess it up. 30:48.967 --> 30:51.827 They use modern reagents, they say it should have worked this 30:51.833 --> 30:52.603 way, or something. 30:52.600 --> 30:55.870 This is what Fischer actually did, so you can read about it. 30:55.867 --> 30:58.127 But anyhow, this is the evidence he used. 30:58.133 --> 31:02.773 He found that glucose could be oxidized by nitric acid to 31:02.767 --> 31:04.697 make the compound that is an acid on 31:04.700 --> 31:06.300 both ends of the chain. 31:06.300 --> 31:09.700 So it's symmetrical with respect to acid. 31:09.700 --> 31:12.900 Not just the aldehyde, but also the primary alcohol got 31:12.900 --> 31:14.600 oxidized to an acid. 31:14.600 --> 31:18.770 And then he did his heating to make a lactone reduce it with 31:18.767 --> 31:24.827 sodium, which made it back into a sugar again. 31:24.833 --> 31:29.333 And the sugar he got he called gulose. 31:29.333 --> 31:31.573 It's different from what he started with. 31:31.567 --> 31:35.467 You'd think if you oxidize and then reduce back again, you 31:35.467 --> 31:37.767 got the same thing you started with. 31:37.767 --> 31:42.797 But he could get a different sugar this way, Why? 31:42.800 --> 31:46.300 How could it be different? 31:46.300 --> 31:51.900 It could be the aldehyde was on the top, made two acids, 31:51.900 --> 31:56.070 reduced the top to an alcohol and the bottom to an aldehyde. 31:56.067 --> 31:59.967 So now it's upside down, so you'd have to rotate it. 31:59.967 --> 32:02.667 So it could be a different one of these sugars that we drew 32:02.667 --> 32:05.397 on the last slide. 32:05.400 --> 32:07.470 And he decided to call it gulose. 32:07.467 --> 32:08.697 Why? 32:15.600 --> 32:17.070 It's a sort of an anagram. 32:17.067 --> 32:21.197 It reverses the U and the L. Glucose, gulose. 32:21.200 --> 32:23.230 Because he went end for end. 32:23.233 --> 32:28.833 So, you know, chemists sometimes have sort of geeky 32:28.833 --> 32:31.333 senses of humor, right? 32:31.333 --> 32:33.833 So gulose. 32:33.833 --> 32:35.773 So that was the first evidence. 32:35.767 --> 32:41.127 And then subsidiary evidence for that is that the diacid he 32:41.133 --> 32:44.773 got on the way is chiral, and both 32:44.767 --> 32:48.367 enantiomers of it were known. 32:48.367 --> 32:50.397 That's the first line of evidence. 32:50.400 --> 32:53.930 The second line of evidence is that glucose and mannose give 32:53.933 --> 32:55.603 the same osazone. 32:55.600 --> 32:58.430 Remember, he made osazones to make crystals, but glucose and 32:58.433 --> 33:00.103 mannose gave the same one. 33:00.100 --> 33:04.230 Also, arabinose, if you do a Kiliani reaction, gives two 33:04.233 --> 33:05.173 different acids. 33:05.167 --> 33:06.997 Gluconic and mannonic acid. 33:07.000 --> 33:10.630 We talked about that before, that it could add either side. 33:10.633 --> 33:14.103 And fructose, when it's reduced to give alcohols all 33:14.100 --> 33:16.830 along the chain, gives two different alcohols, glucitol 33:16.833 --> 33:17.833 and mannitol. 33:17.833 --> 33:21.203 And notice all of these are glucose-related and 33:21.200 --> 33:22.600 mannose-related. 33:22.600 --> 33:25.230 So there's some special relationship between glucose 33:25.233 --> 33:29.473 in mannose, that all three of these things do that. 33:29.467 --> 33:31.667 The second line of evidence is mannitol and 33:31.667 --> 33:34.627 mannonic acid are chiral. 33:34.633 --> 33:39.633 So if you have OHs on both it ends or acids on both ends, 33:39.633 --> 33:40.903 it's chiral. 33:42.833 --> 33:45.833 Bear in mind that people were just fiddling around, seeing 33:45.833 --> 33:47.303 what they could make from what. 33:47.300 --> 33:52.300 But Fischer collected the key items of evidence that could 33:52.300 --> 33:56.100 be used to make a real logical argument. 33:56.100 --> 33:59.230 So third, arabinose, when he did a Kiliani-Fischer 33:59.233 --> 34:01.473 synthesis, gave glucose. 34:01.467 --> 34:03.227 But also, it gave mannose. 34:03.233 --> 34:03.533 Right? 34:03.533 --> 34:07.203 Now we see this relationship between gluc- and man-. 34:07.200 --> 34:11.730 And xylose, which came from wood-- 34:11.733 --> 34:14.303 that's the, like, xylophone, right?-- 34:14.300 --> 34:19.030 xylose, wood sugar, by the Kiliani-Fischer synthesis, 34:19.033 --> 34:21.603 added a carbon and made gulose. 34:21.600 --> 34:23.470 Remember, this one up here. 34:23.467 --> 34:26.527 And also another compound which I think is one 34:26.533 --> 34:28.973 called idose now. 34:28.967 --> 34:32.767 But these aren't really relevant. 34:32.767 --> 34:35.027 But then 3a, arabinose. 34:35.033 --> 34:39.903 If you make two OHs, or two carboxylic acids on each end, 34:39.900 --> 34:41.500 is optically active. 34:41.500 --> 34:45.530 But xylose gives inactive compounds with OH on both 34:45.533 --> 34:47.233 ends, or acid on both ends. 34:47.233 --> 34:48.733 In fact, that was tough. 34:48.733 --> 34:51.533 Because arabitol has no rotation. 34:51.533 --> 34:54.603 You put it in, you think it's not chiral. 34:54.600 --> 35:01.200 But if you add boric acid, then it rotates light. 35:01.200 --> 35:03.500 Remember, it's hard to know what causes rotation. 35:03.500 --> 35:08.900 And it just happens that arabitol has no rotation, or 35:08.900 --> 35:10.930 unmeasurably small rotation. 35:10.933 --> 35:13.133 But if you make a derivative of it, then you can see-- 35:13.133 --> 35:14.733 and the acid is rotating. 35:14.733 --> 35:17.803 So it required a lot of work to know these things for sure. 35:17.800 --> 35:20.970 So that's the evidence, and therefore, he knows what 35:20.967 --> 35:25.597 glucose is and what all the others are. 35:25.600 --> 35:29.200 That's pretty much of an accomplishment, right? 35:29.200 --> 35:33.300 Just to conceive that on the basis of this evidence you 35:33.300 --> 35:35.070 could figure it out is amazing. 35:35.067 --> 35:39.297 And this is only fifteen years after van 't Hoff proposed the 35:39.300 --> 35:41.270 tetrahedral carbon, and a lot of people still 35:41.267 --> 35:44.527 didn't believe in it. 35:44.533 --> 35:49.403 So here are the hexoses and pentoses. 35:49.400 --> 35:52.230 And we're going to go through his lines of evidence and see 35:52.233 --> 35:55.073 how his logic worked. 35:55.067 --> 36:00.467 Evidence 1 was that glucose gives a diacid, and on heating 36:00.467 --> 36:02.597 and reducing, it gives gulose. 36:02.600 --> 36:08.270 So when you turn it end for end, then you've got a 36:08.267 --> 36:09.527 different compound. 36:12.033 --> 36:13.733 So let's go across and see. 36:13.733 --> 36:15.733 Would that be true of this? 36:15.733 --> 36:18.033 If you turned it end for end, would it 36:18.033 --> 36:19.273 be a different compound? 36:21.367 --> 36:23.827 Remember, with a Fischer projection, the idea is things 36:23.833 --> 36:25.203 turn out at you. 36:25.200 --> 36:27.870 So can't rotate 90 degrees, but you 36:27.867 --> 36:30.027 can rotate 180 degrees. 36:30.033 --> 36:33.403 So if we rotate this one 180 degrees, do we get the same 36:33.400 --> 36:35.670 thing again? 36:35.667 --> 36:41.097 That is, what you do here with this is make a dot on the 36:41.100 --> 36:44.100 bottom and not on the top, so then you have to rotate it to 36:44.100 --> 36:46.800 bring it back into this series that we've drawn here. 36:46.800 --> 36:47.400 Right? 36:47.400 --> 36:49.470 Obviously, those would all point to the left. 36:49.467 --> 36:52.597 It would be the mirror image of the one we started with. 36:52.600 --> 36:56.970 So we'll put that on the back burner for a second. 36:59.867 --> 37:01.027 How about the next one? 37:01.033 --> 37:03.403 If you turn that end for end, does it look the same, if you 37:03.400 --> 37:05.770 put the dot on the bottom and rotate it? 37:05.767 --> 37:07.797 Obviously different. 37:07.800 --> 37:09.900 Is everybody with me on its being different? 37:09.900 --> 37:11.700 That one will be different. 37:11.700 --> 37:15.000 This one, however, will be the same. 37:15.000 --> 37:18.400 If you rotate it 180 degrees, it's going to be left, left, 37:18.400 --> 37:20.200 right, right again. 37:20.200 --> 37:22.900 If you change top to bottom and rotate. 37:22.900 --> 37:30.470 So that one is not glucose, nor is it gulose, because if 37:30.467 --> 37:31.827 you rotate end for end it's different. 37:31.833 --> 37:32.633 How about the next one? 37:32.633 --> 37:34.933 Will that be different? 37:34.933 --> 37:36.203 Should we take it out? 37:36.200 --> 37:37.670 That'll be different. 37:37.667 --> 37:39.227 Will that be different? 37:39.233 --> 37:41.203 Ah, that's going to be the same. 37:41.200 --> 37:42.630 Not different. 37:42.633 --> 37:44.373 So we can take that one out. 37:44.367 --> 37:45.267 How about the next one? 37:45.267 --> 37:47.767 Will that be different? 37:47.767 --> 37:49.927 That's going to be like the first one, where everything 37:49.933 --> 37:51.603 that's right is going to be left, everything that's left 37:51.600 --> 37:52.600 is going to be right. 37:52.600 --> 37:55.100 So we'll put that in abeyance for a while. 37:55.100 --> 37:56.800 And the last one also is different. 37:56.800 --> 37:59.770 So from Item 1, we know for sure that it's not that and 37:59.767 --> 38:01.827 not that glucose. 38:01.833 --> 38:04.633 Now, item 1a-- 38:04.633 --> 38:07.673 and we're not so confident about that, because it changes 38:07.667 --> 38:09.167 the hand in this only. 38:09.167 --> 38:12.267 But the diacid is chiral. 38:12.267 --> 38:14.197 Both the enantiomers are known when the two 38:14.200 --> 38:17.300 ends are the same. 38:17.300 --> 38:19.630 So with this one, if the two ends were the 38:19.633 --> 38:22.603 same, would it be chiral? 38:22.600 --> 38:22.730 No. 38:22.733 --> 38:24.203 It would have a horizontal plane of 38:24.200 --> 38:25.700 symmetry through the middle. 38:25.700 --> 38:28.300 So it can't be that one. 38:28.300 --> 38:30.700 This one, would that have a plane of symmetry? 38:30.700 --> 38:32.600 No, No. 38:32.600 --> 38:34.100 That one's out already. 38:34.100 --> 38:35.300 How about that one? 38:35.300 --> 38:36.570 No. 38:36.567 --> 38:37.627 How about that one? 38:37.633 --> 38:38.303 Ah. 38:38.300 --> 38:39.200 That one's out. 38:39.200 --> 38:40.900 That wouldn't be chiral. 38:40.900 --> 38:42.070 The last one would be chiral. 38:42.067 --> 38:42.367 OK. 38:42.367 --> 38:45.797 So from 1a, we confirm that it's not that 38:45.800 --> 38:47.600 and it's not that. 38:47.600 --> 38:49.200 So we're down to four candidates for 38:49.200 --> 38:50.970 what could be glucose. 38:50.967 --> 38:52.797 Now we go to Item 2. 38:52.800 --> 38:55.300 Glucose and mannose give the same osazone. 38:55.300 --> 38:57.000 Remember what the osazone did? 38:57.000 --> 39:00.670 It made a double bond at the top carbon and a double bond 39:00.667 --> 39:01.967 at the next carbon. 39:01.967 --> 39:06.367 So that means this next carbon here isn't chiral anymore. 39:06.367 --> 39:07.297 Right? 39:07.300 --> 39:11.200 And if you take arabinose, start with that being the 39:11.200 --> 39:14.430 carbonyl and add CN, it can add to either side. 39:14.433 --> 39:18.073 One would give that, one would give that. 39:18.067 --> 39:21.097 Depending on what arabinose is, one would give this, this, 39:21.100 --> 39:23.570 one would give that, that, one would give that, that. 39:23.567 --> 39:26.797 So again, it says they differ only at this second carbon. 39:26.800 --> 39:30.700 And fructose, which has a ketone at the second carbon, 39:30.700 --> 39:34.070 as Kiliani showed, gives two alcohols. 39:34.067 --> 39:37.027 So it could give this alcohol and that alcohol, this 39:37.033 --> 39:38.973 alcohol, that alcohol, and so on. 39:38.967 --> 39:43.397 So anyhow, what that means is you disregard that. 39:43.400 --> 39:49.630 So this Item 2 shows that glucose and mannose differ only 39:49.633 --> 39:50.903 in this carbon. 39:50.900 --> 39:55.530 So now, when we look at Evidence 2, we know that if 39:55.533 --> 39:59.003 this is glucose, this is mannose. 39:59.000 --> 40:02.300 They differ only at that carbon, which this shows is not 40:02.300 --> 40:03.430 relevant here. 40:03.433 --> 40:03.903 OK. 40:03.900 --> 40:05.770 So if this is glucose, this is mannose. 40:05.767 --> 40:09.027 If this is glucose, what's mannose? 40:09.033 --> 40:11.103 This one, right? 40:11.100 --> 40:15.300 If this is glucose, this is mannose. 40:15.300 --> 40:19.170 And if this is glucose, this is mannose. 40:19.167 --> 40:22.297 That's what Evidence 2 shows. 40:22.300 --> 40:25.970 Now, Evidence 2a is that mannitol, 40:25.967 --> 40:28.997 OH on both ends, or acid on both ends, 40:29.000 --> 40:31.900 those molecules are chiral. 40:31.900 --> 40:35.730 So can this be mannose if the two ends are the same? 40:35.733 --> 40:37.133 Is it handed? 40:37.133 --> 40:38.373 No. 40:38.367 --> 40:42.897 So this can't be glucose. 40:42.900 --> 40:44.470 How about this? 40:44.467 --> 40:46.797 Could this be mannose? 40:46.800 --> 40:48.770 If the two ends are the same, will it be chiral? 40:51.700 --> 40:51.930 No. 40:51.933 --> 40:53.473 It doesn't have a mirror in the middle. 40:58.600 --> 41:00.730 It's a propeller. 41:00.733 --> 41:02.233 It's not a chiral. 41:02.233 --> 41:05.503 The one that's right at the top and left at the bottom is 41:05.500 --> 41:06.430 the mirror image of this. 41:06.433 --> 41:08.573 Not identical to it. 41:08.567 --> 41:11.367 So it could be could still be that. 41:11.367 --> 41:13.497 Could this be mannose? 41:13.500 --> 41:14.500 Yes. 41:14.500 --> 41:16.770 That means this could be glucose. 41:16.767 --> 41:20.027 Could this be mannose? 41:20.033 --> 41:22.473 No, because now it has a mirror in the middle. 41:22.467 --> 41:23.797 So that can't be glucose. 41:26.433 --> 41:29.173 So from 2a, then, we can exclude this, and we can 41:29.167 --> 41:32.027 exclude that. 41:32.033 --> 41:36.503 So one of these must be glucose, and the other one is 41:36.500 --> 41:41.670 gulose, the one that's turned end for end, top to bottom. 41:41.667 --> 41:44.797 So how we going to decide that, or how did Fischer 41:44.800 --> 41:45.270 decide that? 41:45.267 --> 41:46.967 He went to Evidence 3. 41:46.967 --> 41:51.267 Which is, arabinose, in the Kiliani-Fischer synthesis, 41:51.267 --> 41:55.697 gives glucose, and xylose gives gulose. 41:55.700 --> 41:59.900 So one of them gives one of these, and the other one gives 41:59.900 --> 42:03.070 the other one of those. 42:03.067 --> 42:06.967 So we know something now about arabinose and xylose. 42:06.967 --> 42:09.697 They can't be this, and they can't be this, because that, 42:09.700 --> 42:11.770 on a Kiliani-Fischer synthesis, couldn't give 42:11.767 --> 42:15.767 either of these, and this couldn't give either of those. 42:15.767 --> 42:17.067 So those are out. 42:17.067 --> 42:21.427 That one's out and that one's out for arabinose and xylose. 42:21.433 --> 42:27.003 But what we know from Evidence 3 is that if this is glucose, 42:27.000 --> 42:30.370 that one had to be arabinose, the thing that you add another 42:30.367 --> 42:33.727 carbon here and make that. 42:33.733 --> 42:36.003 And if this was glucose, that would be arabinose. 42:39.033 --> 42:39.903 And vice versa. 42:39.900 --> 42:41.130 If it's arabinose, it's glucose. 42:45.267 --> 42:48.197 So if we know arabinose, which is arabinose and which is 42:48.200 --> 42:52.130 xylose, then we know which is glucose and which is gulose, 42:52.133 --> 42:53.403 because of those connections. 42:55.700 --> 43:00.630 So Evidence 3a is arabinose gives optically active 43:00.633 --> 43:03.203 arabitol and arabaric acid. 43:03.200 --> 43:06.430 When the two ends are the same, it's chiral. 43:06.433 --> 43:10.403 But xylose is not chiral when the two ends are the same. 43:10.400 --> 43:11.630 OK. 43:11.633 --> 43:13.733 Could this one be arabinose? 43:13.733 --> 43:17.073 Would it be chiral if the two ends are the same? 43:17.067 --> 43:18.967 How about that one? 43:18.967 --> 43:20.597 No. 43:20.600 --> 43:24.100 So that one's got to be arabinose, and that one's got 43:24.100 --> 43:25.370 to be xylose. 43:29.600 --> 43:32.200 So we know that glucose can't be this, because 43:32.200 --> 43:33.270 it comes from arabinose. 43:33.267 --> 43:36.727 So that one is glucose. 43:36.733 --> 43:38.003 So he proved it! 43:45.433 --> 43:50.973 So all these known compounds were then assigned. 43:50.967 --> 43:53.797 If you knew this was glucose, then you know that was gulose. 43:53.800 --> 43:55.770 You know that glucose and mannose differ 43:55.767 --> 43:56.797 only at this carbon. 43:56.800 --> 43:59.170 So you know which mannose is, you know which arabinose is, 43:59.167 --> 44:00.497 which xylose is. 44:00.500 --> 44:03.700 You also can figure out which one it erythrose is, by making 44:03.700 --> 44:05.970 arabinose from it. 44:05.967 --> 44:07.297 So all these things now work. 44:07.300 --> 44:09.570 It's like the end of a solitaire game, when 44:09.567 --> 44:12.367 everything begins to work, right? 44:12.367 --> 44:13.927 So you now you get all the other sugars. 44:13.933 --> 44:17.603 In fact, of these sixteen sugars, the right- and left- 44:17.600 --> 44:21.000 handed ones in the bottom row, the hexose, of the sixteen 44:21.000 --> 44:23.870 Fischer made, thirteen of them himself. 44:23.867 --> 44:26.997 And he made fifty artificial sugars overall 44:27.000 --> 44:31.270 in the 1880s and 1890s. 44:31.267 --> 44:32.397 So he got others. 44:32.400 --> 44:36.270 Like he also got threose. 44:36.267 --> 44:37.527 So this was a new compound. 44:37.533 --> 44:39.703 How did he name it? 44:39.700 --> 44:42.170 Where did the name threose come from? 44:42.167 --> 44:44.097 It's erythrose turned around, right? 44:44.100 --> 44:45.530 Sort of turned around. 44:45.533 --> 44:48.103 Or he got ribose. 44:48.100 --> 44:51.900 Like ribonucleic acid, deoxyribonucleic acid. 44:51.900 --> 44:54.100 Where does the name ribose come from? 44:54.100 --> 44:54.470 STUDENT: Arabinose. 44:54.467 --> 44:56.297 PROFESSOR: From arabinose. 44:56.300 --> 44:57.700 From gum arabic. 44:57.700 --> 44:59.770 Or he got lyxose. 44:59.767 --> 45:01.367 That's pretty obvious. 45:01.367 --> 45:06.867 Or you got talose from galactose. 45:06.867 --> 45:08.527 T A L, OK? 45:08.533 --> 45:10.503 Or he got altrose. 45:10.500 --> 45:13.570 He was beginning to run out, so this just means "another 45:13.567 --> 45:15.567 one." Alter, right? 45:15.567 --> 45:18.067 Or he got idose. 45:18.067 --> 45:21.767 That's idem, you know, the same as the one above in a 45:21.767 --> 45:23.227 list is idem. 45:23.233 --> 45:25.433 So it's another one, right? 45:25.433 --> 45:28.273 Or alose, which is the Greek version of altrose. 45:31.033 --> 45:33.933 So he got all these, and he got the Nobel Prize. 45:33.933 --> 45:36.503 And he got the second Nobel Prize. 45:36.500 --> 45:39.500 The first Nobel Prize went to van 't Hoff. 45:39.500 --> 45:45.030 Not for chirality, but for his work in physical chemistry. 45:45.033 --> 45:48.533 But the second Nobel Prize went to chirality via Fischer, 45:48.533 --> 45:51.433 because everybody realized what a great contribution-- 45:51.433 --> 45:53.773 you know, it's not just doing it. 45:53.767 --> 45:57.097 but doing it without Fischer projections is a lot tougher. 45:57.100 --> 46:00.200 It's to conceive that you can do it, that the evidence is 46:00.200 --> 46:03.730 there, that you apply this new theory that van 't Hoff came 46:03.733 --> 46:07.533 up with not so long ago, and follow it through with 46:07.533 --> 46:09.473 rigorous logic, and you've got it. 46:09.467 --> 46:12.397 Rather just fiddling around, making this, making this, 46:12.400 --> 46:15.100 making this, making this, he puts it all together. 46:15.100 --> 46:17.230 He finds the crucial bits of evidence and puts them 46:17.233 --> 46:19.373 together to do this really beautiful proof. 46:19.367 --> 46:21.897 So I thought you would want to know about that. 46:21.900 --> 46:27.170 Now, if you want to remember it, the guy 46:27.167 --> 46:28.227 who taught me Organic-- 46:28.233 --> 46:30.373 I took Organic Chemistry the way you are, 50 46:30.367 --> 46:32.997 years ago this year. 46:33.000 --> 46:35.030 And the guy that I took it from, Louis 46:35.033 --> 46:36.933 Fieser, made up this. 46:36.933 --> 46:43.303 "All altruists gladly make gum in gallon tanks." And I 46:43.300 --> 46:45.300 remembered that for fifty years. 46:45.300 --> 46:48.170 So I have no trouble doing alose, altrose, glucose, 46:48.167 --> 46:53.097 mannose, gulose, idose, galactose, and tolose. 46:53.100 --> 46:56.670 It's not a very fundamental contribution to science, but 46:56.667 --> 47:00.427 it's very handy, if you want to teach about hexoses. 47:00.433 --> 47:03.573 And if you want to do this one, it's raxl. 47:03.567 --> 47:10.897 R A X L. And erythrose and threose, you just remember. 47:10.900 --> 47:11.330 OK. 47:11.333 --> 47:16.303 So hooray for Emil Fischer. 47:16.300 --> 47:19.400 Now we've got two minutes just to show you-- 47:19.400 --> 47:21.870 I'm not going to show you how this happened. 47:21.867 --> 47:23.797 It's going to be a stream of consciousness thing. 47:23.800 --> 47:25.930 You're not responsible for it on the exam. 47:25.933 --> 47:28.833 But I've got all the slides here, so what the hell, right? 47:28.833 --> 47:32.173 And it is a neat thing. 47:32.167 --> 47:32.997 OK. 47:33.000 --> 47:35.230 So we talked about cyclobutadiene. 47:35.233 --> 47:37.403 Is it antiaromatic? 47:37.400 --> 47:39.670 Make it and see what its properties are. 47:39.667 --> 47:41.427 The problem is, 47:41.433 --> 47:43.103 So you can make it by this. 47:43.100 --> 47:44.300 Shine light on it. 47:44.300 --> 47:49.070 It closes up in in a disrotatory process. 47:49.067 --> 47:54.067 And then with light, it loses CO2, and you get it. 47:54.067 --> 47:55.767 So study its properties. 47:55.767 --> 48:00.367 The problem is that it undergoes a really quick 48:00.367 --> 48:01.927 reaction with itself. 48:01.933 --> 48:05.533 A Diels-Alder reaction, which gives this. 48:05.533 --> 48:09.803 And then that opens up, because it's very strained, of 48:09.800 --> 48:14.570 course, and gives cyclooctatetraene. 48:14.567 --> 48:19.097 So you get cyclooctatetraene, which is sort of evidence that 48:19.100 --> 48:21.800 you had cyclobutadiene, but it's not like knowing its 48:21.800 --> 48:24.000 properties. 48:24.000 --> 48:28.330 So the problem is that it reacts with itself. 48:28.333 --> 48:31.433 So it's presumptive evidence of existence. 48:31.433 --> 48:33.973 Could you do spectroscopy? 48:33.967 --> 48:36.227 So you have to make it, somehow, under conditions that 48:36.233 --> 48:38.103 it won't react with itself. 48:38.100 --> 48:41.230 So if you made it inside a cage, like a big clam shell, 48:41.233 --> 48:44.573 so only one molecule was in there, then it couldn't react 48:44.567 --> 48:46.927 with itself. 48:46.933 --> 48:51.273 So they made this compound with a guest inside. 48:51.267 --> 48:53.327 So it's two big, like a clam shell. 48:53.333 --> 48:56.103 It holds the precursor inside. 48:56.100 --> 48:59.200 There's a mouth that you can put things in and out from. 48:59.200 --> 49:02.630 And it was done by Donald Cram, who got the Nobel Prize, 49:02.633 --> 49:07.133 and Martin Tanner, the son of Dennis Tanner, who burned his 49:07.133 --> 49:10.303 eyebrows off with a Fourth of July demonstration? 49:10.300 --> 49:12.230 They grew back again, you know, he was 49:12.233 --> 49:15.003 not permanently marred. 49:15.000 --> 49:17.930 Thomas, I don't know. 49:17.933 --> 49:21.673 So these R groups were big things to make it soluble. And 49:21.667 --> 49:26.097 it was that, and you can make that by thinking backwards 49:26.100 --> 49:28.770 with an aldol reaction. 49:28.767 --> 49:32.097 So first, they make the bottom half of the thing, and how to 49:32.100 --> 49:36.600 form this big ring with sixteen carbons in it. 49:36.600 --> 49:38.800 You take resorcinol and 49:38.800 --> 49:44.530 hydrocinnamaldehyde, and then-- 49:44.533 --> 49:49.773 This is very active for electrophilic substituition. 49:49.767 --> 49:52.767 So you protonate that, you have an electrophile, it forms 49:52.767 --> 49:56.367 a bond, ortho-para, you've got the first bond made. 49:56.367 --> 50:00.967 Put that in, dehydrate, you can react it was another one, 50:00.967 --> 50:02.327 so you've got another one. 50:02.333 --> 50:04.103 Now you just keep doing it to make all 50:04.100 --> 50:05.100 those all the way around. 50:05.100 --> 50:06.970 But you could imagine lots and lots of different 50:06.967 --> 50:08.327 ways of doing it. 50:08.333 --> 50:11.003 And it turns out that the electrophilic aromatic 50:11.000 --> 50:14.370 substitution is reversible, and ultimately, this compound, 50:14.367 --> 50:17.727 the one they wanted to make this, precipitates from the 50:17.733 --> 50:21.403 equilibrated mixture in a 69% yield. 50:21.400 --> 50:24.200 That is luck. 50:24.200 --> 50:28.900 So the fish jumped into this particular boat, right? 50:28.900 --> 50:31.300 But now they need these bonds across the top of 50:31.300 --> 50:32.230 that bottom, too. 50:32.233 --> 50:35.273 The teeth for the clam. 50:35.267 --> 50:37.867 So what they did is they put bromine on. 50:41.600 --> 50:47.730 Then they made anions here with base, and reacted with CH2 50:47.733 --> 50:49.203 with two leaving groups. 50:49.200 --> 50:51.930 So one leaving group, the other leaving group. 50:51.933 --> 50:54.933 And now do it on all the others, and you've got those 50:54.933 --> 50:57.773 carbons put in. 50:57.767 --> 51:03.197 Now you have to join the top half to the bottom half. 51:03.200 --> 51:04.700 Oh, they got this, incidentally. 51:04.700 --> 51:06.370 They didn't get a 69% yield. 51:06.367 --> 51:08.997 That was 5% from the tetramer. 51:09.000 --> 51:12.100 And they had to isolate it by chromatography. 51:12.100 --> 51:15.870 So now they had to join the two hemispheres, which they 51:15.867 --> 51:20.427 put a lithium on in place of the bromine. 51:20.433 --> 51:26.973 And then they put boron on, and then hydrogen peroxide, 51:26.967 --> 51:30.667 which we've seen before, to make those into alcohols. 51:33.933 --> 51:36.003 We've seen that before. 51:36.000 --> 51:39.900 So you see, this was really to be review of stuff we've done. 51:39.900 --> 51:41.600 So now you've got alcohols all the way up. 51:41.600 --> 51:44.830 So you've got the Os that are going to do the bridging. 51:44.833 --> 51:50.733 And now you just do that same thing you did before, to put a 51:50.733 --> 51:53.933 carbon in, this carbon the same way you did that one by 51:53.933 --> 51:58.833 having a carbon with two halogens, 51:58.833 --> 52:00.233 so two leaving groups. 52:00.233 --> 52:02.573 And now again, when those two things come together, if you 52:02.567 --> 52:06.097 have three things that can react here and three things 52:06.100 --> 52:07.800 that can react here that can go like that, 52:07.800 --> 52:08.800 which is what you want. 52:08.800 --> 52:11.430 It could go like that, it could go like that, it could 52:11.433 --> 52:12.633 go like that. 52:12.633 --> 52:15.503 There are lots of different ways. 52:15.500 --> 52:18.970 But it turned out that they got 40% of it. 52:18.967 --> 52:21.367 40% of this stuff went into that. 52:21.367 --> 52:25.197 Overall, from the stuff they started, and it's a 1% yield. 52:25.200 --> 52:27.070 But they started with a lot of stuff. 52:27.067 --> 52:30.167 So they had the clam shell. 52:30.167 --> 52:32.997 And now it turned out they could get the guest out. 52:33.000 --> 52:37.100 This is a crystal structure, so this stuff at the top is 52:37.100 --> 52:41.400 chloroform, and this is solvent. 52:41.400 --> 52:42.800 There are two different solvents in there. 52:42.800 --> 52:46.470 But in the middle of the cage is DMF. 52:46.467 --> 52:48.497 This is that clam shell here. 52:48.500 --> 52:51.230 And these things are just put on to make it soluble, so you 52:51.233 --> 52:52.773 can work with it. 52:52.767 --> 52:53.027 OK. 52:53.033 --> 52:55.633 So they could get that stuff out, and they could 52:55.633 --> 52:58.373 replace it with this. 52:58.367 --> 53:02.227 So here's that stuff on the cover of Angewandte Chemie 53:02.233 --> 53:04.173 inside that compound. 53:04.167 --> 53:05.697 And this is the NMR spectrum. 53:05.700 --> 53:09.930 So most of the peaks come from these hydrogens in the shell. 53:09.933 --> 53:13.903 But the ones marked in red, and one that's under here, are 53:13.900 --> 53:18.030 these four hydrogens on the starting material. 53:18.033 --> 53:21.103 And then they photolyzed it, and they got the purple peaks. 53:21.100 --> 53:22.700 It changed. 53:22.700 --> 53:26.170 And then they photolyzed it again, and they 53:26.167 --> 53:28.127 got just one peak. 53:28.133 --> 53:31.833 That's the peak of cyclobutadiene. 53:31.833 --> 53:33.803 And it can't react with any others, because there are no 53:33.800 --> 53:35.500 others around. 53:35.500 --> 53:38.300 And then if you get it out again, then it will react to 53:38.300 --> 53:40.200 give cyclooctatetraene. 53:40.200 --> 53:45.830 So this is way upfield, antiaromatic. 53:45.833 --> 53:48.773 As we talked about before. 53:48.767 --> 53:51.267 Now, is that what causes the upfield shift? 53:51.267 --> 53:53.497 Because you'll notice something else. 53:53.500 --> 53:59.630 If you put benzene inside, its normal position would be here. 53:59.633 --> 54:03.803 But benzene inside that clam shell is there. 54:03.800 --> 54:05.500 It shifted way upfield. 54:05.500 --> 54:07.230 Why? 54:07.233 --> 54:12.103 Because it's above all sorts of other benzene rings. 54:12.100 --> 54:14.930 Remember, when you have something above but a benzene 54:14.933 --> 54:16.603 ring, it's shifted upfield. 54:16.600 --> 54:19.170 If it's out beside it, it's shifted downfield. 54:19.167 --> 54:21.327 But this, the one that's in the middle is above all. 54:21.333 --> 54:24.373 So some of that shift must be due to the same effect that 54:24.367 --> 54:26.327 makes benzene go up. 54:26.333 --> 54:29.333 So most of the shift comes from the other rings. 54:29.333 --> 54:32.603 Still, it's about one and a half ppb above 54:32.600 --> 54:35.070 benzene, so it is shifted upfield and it is 54:35.067 --> 54:36.397 antiaromatic. 54:36.400 --> 54:38.500 So I think that's what I wanted to show you. 54:38.500 --> 54:40.300 That's the end. 54:40.300 --> 54:44.800 But the big lesson is how Fischer did glucose. 54:44.800 --> 54:46.030 Thanks.