WEBVTT 00:01.320 --> 00:05.000 Prof: So you remember this slide from several lectures 00:05.001 --> 00:05.371 ago. 00:05.370 --> 00:07.340 What are they trying to make? 00:07.340 --> 00:12.840 Remember what the point of this synthesis was, 00:12.840 --> 00:16.140 this particular reaction? 00:16.140 --> 00:21.010 The idea was to do a catalytic reaction with something that was 00:21.008 --> 00:25.658 chiral as the catalyst, to do an oxidation on sulfur, 00:25.660 --> 00:29.530 to make a single enantiomer of omeprazole. 00:29.530 --> 00:32.730 And remember the idea was that the product, 00:32.729 --> 00:35.969 after you've gone through these three steps that we showed you 00:35.969 --> 00:38.369 before, that the product then comes 00:38.372 --> 00:42.182 back and is the catalyst again, and you can do another cycle. 00:42.180 --> 00:44.370 So, in fact, there's this thing called a 00:44.369 --> 00:45.379 catalytic cycle. 00:45.380 --> 00:49.560 So what comes in is a peroxide and a sulfide, 00:49.563 --> 00:54.603 and what comes out is an alkoxide and the product that 00:54.602 --> 00:59.822 you want, the oxidized product; where an oxygen has been added 00:59.821 --> 01:02.281 to that unshared pair, that high HOMO. 01:02.280 --> 01:06.840 And so the idea of the chiral oxidizing agent was so you'd get 01:06.841 --> 01:09.611 a single enantiomer of the product. 01:09.610 --> 01:11.690 But do you remember what happened? 01:11.689 --> 01:11.979 Student: It was racemic. 01:11.980 --> 01:14.550 Prof: Right, it gave racemic material. 01:14.549 --> 01:15.659 So what did they do? 01:15.659 --> 01:17.659 Do you remember? 01:17.659 --> 01:19.949 Pardon me? 01:19.950 --> 01:21.620 Student: >. 01:21.620 --> 01:24.640 Prof: Yeah, ethyldiisopropylamine they 01:24.640 --> 01:28.410 added; these researchers added, 01:28.411 --> 01:29.621 in 2000. 01:29.620 --> 01:34.060 And they found out that that gave a 94% enantiomer excess, 01:34.059 --> 01:36.239 but for no obvious reason. 01:36.239 --> 01:40.989 Now it would be great if we knew what the reason for this 01:40.989 --> 01:41.499 was. 01:41.500 --> 01:45.980 And it turned out that, in fact, this kind of oxidative 01:45.983 --> 01:48.973 catalytic reaction, to be stereospecific, 01:48.974 --> 01:52.554 to give a single enantiomer, was the source of the Nobel 01:52.549 --> 01:53.609 Prize in 2001. 01:53.610 --> 02:02.250 And if we click on this thing here, we can see -- should see 02:02.251 --> 02:05.621 -- yeah, there we go. 02:05.620 --> 02:09.650 So this is the Nobel website, and you can see that K. Barry 02:09.653 --> 02:13.623 Sharpless here got the Nobel Prize in 2001 for his work on 02:13.619 --> 02:16.749 chirally catalyzed oxidation reactions; 02:16.750 --> 02:17.940 so exactly this reaction. 02:17.938 --> 02:23.728 So if anyone can tell us how ethyldiisopropylamine does its 02:23.733 --> 02:26.333 trick, who should it be? 02:26.330 --> 02:29.890 Barry Sharpless, right? 02:29.889 --> 02:32.229 > 02:32.229 --> 02:41.139 > 02:41.139 --> 02:53.329 <> 02:53.330 --> 02:54.730 Prof: There, we're all set. 02:54.729 --> 02:55.849 Prof: Thanks Mike. 02:55.848 --> 02:59.128 Well I'd do anything for my friend Mike, because he saved me 02:59.133 --> 03:01.753 from publishing errors in JACS at least once. 03:01.750 --> 03:05.120 And he's saved a lot of us, who were willing to listen to 03:05.117 --> 03:07.287 him, because he's got a genius for 03:07.293 --> 03:10.743 seeing flaws in the beautiful stories that people tell, 03:10.740 --> 03:13.320 and then they realize that their beautiful stories are 03:13.316 --> 03:14.916 going to be too slick, usually; 03:14.919 --> 03:17.569 and Nature doesn't like things to be too slick. 03:17.568 --> 03:23.148 Well I'm going to just use -- I think the next slide should be 03:23.151 --> 03:30.071 -- < 03:37.684 adjustments>> 03:37.680 --> 03:40.950 Prof: Well this is something which we all possibly 03:40.947 --> 03:42.637 manipulate in-utero. 03:42.639 --> 03:46.049 It's interesting, because many things in our 03:46.045 --> 03:47.915 body, like a part can be on the left 03:47.923 --> 03:50.353 or right, and a mirror image -- I assume 03:50.353 --> 03:53.383 that means they're mirror-image related then. 03:53.378 --> 03:57.298 But this is a vein and two arteries that has a sheath on 03:57.300 --> 04:00.580 it, and it's the umbilical cord of a mammal. 04:00.580 --> 04:05.390 And it's got a nice screw axis; you know how we like to pull 04:05.389 --> 04:07.539 our hand down a screw axis. 04:07.538 --> 04:09.718 And then I have other reasons why I think I handled it. 04:09.718 --> 04:12.218 And then they take it away from you at birth; 04:12.218 --> 04:14.108 they cut it and they take it away. 04:14.110 --> 04:16.600 It becomes a narcissistically cathected object. 04:16.600 --> 04:19.870 And that means you're in trouble because you can't ever 04:19.870 --> 04:20.960 heal that wound. 04:20.959 --> 04:23.359 You want to get it back, but you can't heal it. 04:23.360 --> 04:25.430 You needed that mirror, that umbilical cord, 04:25.428 --> 04:26.968 back there when you were born. 04:26.970 --> 04:29.290 Anyway, that's why I went crazy trying to do asymmetric 04:29.285 --> 04:29.795 synthesis. 04:29.800 --> 04:37.520 And now, if you're a chemist, unless you're in deep space -- 04:37.519 --> 04:39.509 I don't know if they have any carbon atoms out there, 04:39.509 --> 04:42.209 but you got to be in a very high vacuum to get them. 04:42.209 --> 04:44.869 But this is the way we make organic compounds, 04:44.867 --> 04:45.337 right? 04:45.339 --> 04:48.249 But we don't really do it this way because we have to live on a 04:48.252 --> 04:49.712 condensed phase of the earth. 04:49.709 --> 04:51.979 So these are two -- but you put them together. 04:51.980 --> 04:53.030 This is a point. 04:53.029 --> 04:54.719 Then you get a line. 04:54.720 --> 04:56.590 It's polyacetylene really. 04:56.589 --> 05:00.309 But let me -- give me poetic license of just having it be a 05:00.310 --> 05:00.760 line. 05:00.759 --> 05:04.689 And I'll take one unit out, and now if I add things across 05:04.687 --> 05:08.677 that line, I get into the plane, A and B, or I can add them 05:08.682 --> 05:10.822 cis or trans. 05:10.819 --> 05:13.149 And essentially you can make anything this way, 05:13.149 --> 05:16.289 almost, if you could do it by just surgically adding things. 05:16.290 --> 05:17.390 Now we're in the plane. 05:17.389 --> 05:22.769 And now the job in the plane -- and I've actually drawn a 05:22.769 --> 05:26.419 trans-disubstituted 2-butene. 05:26.420 --> 05:31.350 And it has a shape like this, right? 05:31.350 --> 05:34.090 It has a methyl group here, a methyl group here, 05:34.093 --> 05:35.323 and then hydrogens. 05:35.319 --> 05:37.599 So there's open space in these quadrants. 05:37.600 --> 05:40.910 And if you look at me coming at you this way, 05:40.910 --> 05:45.590 and if I turn around, you see it's going to be -- 05:45.589 --> 05:48.579 well you'll see it's going to be a mirror image situation. 05:48.579 --> 05:49.879 But I'm flat. 05:49.879 --> 05:52.989 So I have no chirality, as a starting point. 05:52.990 --> 05:56.450 I'm in the plane of flat. 05:56.449 --> 05:59.569 So then if I add hydrogen to it, I get nothing interesting. 05:59.569 --> 06:02.439 But if I add an atom, like oxygen, 06:02.435 --> 06:06.515 to it, like here, then I've pyramidalized it. 06:06.519 --> 06:10.009 And so I can either add the oxygen from my front, 06:10.009 --> 06:12.189 and go like that -- epoxide. 06:12.189 --> 06:14.759 Or I can add it from my back, and I go like that. 06:14.759 --> 06:17.039 And that's the other mirror-image compound. 06:17.040 --> 06:20.120 That's a really cool way. 06:20.120 --> 06:20.910 And it works. 06:20.910 --> 06:22.340 You can make epoxides that way. 06:22.339 --> 06:25.519 And we have reagents today where you can recognize the 06:25.519 --> 06:29.059 front and the back of a flat object, that has pro-chirality, 06:29.060 --> 06:29.900 like this. 06:29.899 --> 06:35.159 06:35.160 --> 06:39.790 And back in the early, in the mid -- early seventies, 06:39.788 --> 06:44.058 we saw this industrial reaction that was nice. 06:44.060 --> 06:46.050 You could take vanadium and molybdenum, 06:46.050 --> 06:50.010 and you could epoxidize olefins with these things called -- 06:50.009 --> 06:53.989 well I don't have the darn structure unfortunately -- 06:53.990 --> 06:55.680 but it's t-butylhydroperoxide. 06:55.680 --> 07:03.030 It's the alcohol group here, with a peroxide bond. 07:03.028 --> 07:06.298 And I think you've already learned that peroxide bonds are 07:06.302 --> 07:07.052 weak bonds. 07:07.050 --> 07:12.370 They have a low lying σ* orbital, 07:12.370 --> 07:16.080 and you can attack them on the back side and transfer atoms to 07:16.084 --> 07:20.334 make transfer to carbons, like a HOMO of an olefin. 07:20.329 --> 07:24.709 So what we noticed -- I noticed in one case that allylic 07:24.709 --> 07:28.689 alcohols were very much -- seemed to be special. 07:28.689 --> 07:31.929 It was just noticed by English chemists in the thirties that 07:31.927 --> 07:34.997 they seemed to react better than just normal alcohols. 07:35.000 --> 07:42.150 And so, but nobody had taken any really -- action on that. 07:42.149 --> 07:45.709 Prof: We're not as fast as some people at getting to 07:45.711 --> 07:46.511 this stuff. 07:46.509 --> 07:50.209 So we should say that an allylic alcohol group is one 07:50.209 --> 07:54.409 that has an oxygen on the carbon next to the double bond. 07:54.410 --> 07:55.550 Prof: Oh, oh yeah. 07:55.550 --> 07:57.850 Prof: The OH is -- Prof: Oh right. I forget. 07:57.850 --> 08:01.510 The allylic alcohol -- allylic means -- allylic, 08:01.507 --> 08:05.007 you're alpha, one atom away from an olefin. 08:05.009 --> 08:07.169 So you could have anything there; 08:07.170 --> 08:08.420 nitrogen and oxygen. 08:08.420 --> 08:10.780 So you could have an OH, like in ethanol; 08:10.779 --> 08:12.229 that's an allylic alcohol. 08:12.230 --> 08:17.120 This is an allylic alcohol right -- where is it? 08:17.120 --> 08:19.580 I don't -- see, I'm sorry, I don't have the 08:19.577 --> 08:20.687 right structures. 08:20.689 --> 08:21.889 This is the allylic alcohol. 08:21.889 --> 08:25.069 It would be, if I go back one; I'll show you, 08:25.071 --> 08:26.991 not by going forward. 08:26.990 --> 08:28.970 Prof: There's the allylic alcohol actually. 08:28.970 --> 08:30.980 Prof: Yeah, but I got one -- like here, 08:30.976 --> 08:32.446 this is a carbon, that's a carbon, 08:32.447 --> 08:33.337 that's a carbon. 08:33.340 --> 08:37.340 By putting an OH group there, that's allylic alcohol. 08:37.340 --> 08:39.830 If I have another carbon, it's homoallylic. 08:39.830 --> 08:44.540 But it has a handle now, and that handle allows it to 08:44.542 --> 08:47.082 grab hold of the vanadium. 08:47.080 --> 08:49.750 The vanadium has all these alcohol -- these are esters. 08:49.750 --> 08:51.270 Imagine that's phosphorous. 08:51.269 --> 08:53.539 It is like phosphorous actually. 08:53.538 --> 08:59.538 But it's a yellowish liquid, and it exchanges its ligands 08:59.544 --> 09:02.874 like the wind, with alcohols. 09:02.870 --> 09:03.950 So they come in, they go out. 09:03.950 --> 09:04.930 It's a real dance. 09:04.929 --> 09:05.759 It's fast. 09:05.759 --> 09:07.309 You don't have to worry about that happening. 09:07.308 --> 09:09.158 Phosphates, we'd all be dead if that happened; 09:09.159 --> 09:11.459 we'd melt. 09:11.460 --> 09:13.750 But this is a transition metal. 09:13.750 --> 09:14.910 It goes to here. 09:14.908 --> 09:19.468 Now, and when I'm the metal, and I have oxygen here, 09:19.474 --> 09:22.074 and then I say have an arm. 09:22.070 --> 09:25.960 You can imagine my arm being a double bond, with π 09:25.961 --> 09:27.151 going like this. 09:27.149 --> 09:31.769 And here, on my belly, I'm going to have an atom -- 09:31.773 --> 09:36.123 and this is an atom like -- it should be red. 09:36.120 --> 09:37.450 Oxygen's red. 09:37.450 --> 09:39.000 But he knows why. I don't. 09:39.000 --> 09:40.300 Except for blood. 09:40.298 --> 09:45.598 So you come like this and you grab it, and it pops off me -- 09:45.595 --> 09:50.615 I'm the activated thing on the metal -- and it goes on to 09:50.621 --> 09:51.521 there. 09:51.519 --> 09:53.639 That's an epoxide; a three-membered ring. 09:53.639 --> 09:57.679 And if I attack it with a backhand, I would get the 09:57.684 --> 10:00.764 opposite result, in terms of attack. 10:00.759 --> 10:04.609 And that doesn't happen, because the geometry of the 10:04.605 --> 10:08.825 transition states and the projections of the center -- 10:08.830 --> 10:11.760 you can't get as close to a center shot on this thing, 10:11.759 --> 10:12.829 with a backhand. 10:12.830 --> 10:15.510 So that's my way of starting to explain. 10:15.509 --> 10:16.829 We're going to explain a little bit more. 10:16.830 --> 10:20.210 Mike's going to do some acting later, and you'll see it a 10:20.208 --> 10:23.828 little bit more clearly -- the topology of this situation. 10:23.830 --> 10:28.610 But here it's cool because you get this template. 10:28.610 --> 10:29.690 It's like a mandrel. 10:29.690 --> 10:33.260 You grab hold of this oxygen atom, which is proto-oxygen. 10:33.259 --> 10:36.159 The metal has lots of empty orbitals. 10:36.159 --> 10:37.539 It's a d^0 metal. 10:37.538 --> 10:40.458 It activates the thing this way, and then the olefin 10:40.464 --> 10:42.824 lone-pair, the HOMO, attacks the backside, 10:42.816 --> 10:45.106 and all this funny business goes on. 10:45.110 --> 10:47.330 But there's no mechanism. 10:47.330 --> 10:48.990 It's a no-mechanism transfer. 10:48.990 --> 10:52.630 It's one of these -- like you draw a bunch of arrows and 10:52.629 --> 10:55.609 everything happens sort of in a smooth way; 10:55.610 --> 10:59.520 no ions involved, unlike SN_2 chemistry. 10:59.519 --> 11:04.259 Okay, slow step is then this step. 11:04.259 --> 11:07.219 And then it comes off and more stuff goes on and it goes 11:07.216 --> 11:07.696 around. 11:07.700 --> 11:10.470 So that's the trick we played here. 11:10.470 --> 11:16.270 The first idea was take advantage of fixing the thing. 11:16.269 --> 11:20.549 So once you've fixed this flat system that you want to make go 11:20.554 --> 11:23.344 pop up this way, or that way, 11:23.335 --> 11:27.665 now you have a chance of doing it, 11:27.668 --> 11:31.178 because the thing you're transferring from can recognize 11:31.179 --> 11:33.789 this kind of situation, from that one, 11:33.791 --> 11:37.191 by -- it's part of the same molecule temporarily. 11:37.190 --> 11:40.000 In fact, it's a covalent bond, right there, 11:39.999 --> 11:41.069 at this point. 11:41.070 --> 11:42.730 Too much, I always say too much. 11:42.730 --> 11:43.810 Okay, let's keep going. 11:43.808 --> 11:48.318 Then came a great man from Japan. 11:48.320 --> 11:51.340 He's now a head professor at Kyoto, Oshima. 11:51.340 --> 11:55.430 He was a fantastic boiler room producer in titanium, 11:55.428 --> 11:57.018 osmium; you name it. 11:57.019 --> 12:00.969 I think that was where all the work was done for the Nobel 12:00.974 --> 12:02.824 Prize; it was done at MIT. 12:02.820 --> 12:05.410 But it happened at Stanford; just because I was there for a 12:05.408 --> 12:05.838 few years. 12:05.840 --> 12:08.340 But you know those early years in your career, 12:08.342 --> 12:11.512 when you do your work in the boiler room, are what produce 12:11.514 --> 12:11.964 you. 12:11.960 --> 12:15.120 Like your personality doesn't change after you're four years 12:15.116 --> 12:15.916 old -- right? 12:15.919 --> 12:19.979 -- or three years old; you're pretty much locked in, 12:19.975 --> 12:22.575 unfortunately, in some ways. 12:22.580 --> 12:26.190 This is vanadium system, and we put on this chiral 12:26.186 --> 12:29.126 machinery here, and it gave us 80% ee; 12:29.129 --> 12:34.469 that means enantiomeric excess was -- it was 90% one isomer -- 12:34.474 --> 12:39.034 enantiomer, the right hand say, and 10% the other. 12:39.029 --> 12:40.829 And this looks good. 12:40.830 --> 12:45.470 But it only works for that one substrate, and all the other 12:45.466 --> 12:49.296 types with it -- you can have like methyls there, 12:49.302 --> 12:52.742 or a methyl there, and you get nothing. 12:52.740 --> 12:54.930 So you have to get everything customized. 12:54.928 --> 12:56.578 This ligand, you got to get the right 12:56.581 --> 12:59.151 ligand, the -- and that's what you expect with Nature. 12:59.149 --> 13:02.279 We're taught by Emil Fisher -- the lock and key. 13:02.278 --> 13:06.798 Nature is supposed to be very, very touchy about changing her 13:06.803 --> 13:07.863 preferences. 13:07.860 --> 13:09.290 And that was what we expected. 13:09.289 --> 13:10.419 Well I didn't expect that. 13:10.418 --> 13:13.928 I expected that this type of olefin and this type, 13:13.927 --> 13:16.927 with something, that all these would need a 13:16.932 --> 13:18.582 class of catalysts. 13:18.580 --> 13:20.370 There are about six shapes of olefins. 13:20.370 --> 13:23.550 So that's what my dream was, to get maybe six catalysts. 13:23.548 --> 13:26.398 Because we didn't have the paraphernalia that nature has 13:26.404 --> 13:27.084 all around. 13:27.080 --> 13:30.040 Well for years we tried. 13:30.038 --> 13:31.678 Ten years we didn't get anything. 13:31.678 --> 13:36.518 It was always this game of like almost no reliability. 13:36.519 --> 13:39.639 And then when we came to titanium -- we'd been working 13:39.635 --> 13:41.455 with vanadium and molybdenum. 13:41.460 --> 13:46.170 We came over to titanium, and we put in tartaric acid 13:46.169 --> 13:47.619 ester one day. 13:47.620 --> 13:49.380 This wasn't me, it was Katsuki. 13:49.379 --> 13:51.899 He should've gotten the Nobel Prize with me, 13:51.899 --> 13:55.219 because this means half of this -- I picked the right metal, 13:55.220 --> 13:57.370 at that time, and the right system, 13:57.370 --> 13:59.250 but he's the one who picked the right ligand. 13:59.250 --> 14:02.670 And let's go on to the next thing. 14:02.668 --> 14:04.718 You'll see, this is tartaric acid. 14:04.720 --> 14:06.010 This is so-called natural. 14:06.009 --> 14:07.449 It comes from grapes. 14:07.450 --> 14:08.880 It's the cream of tartar. 14:08.879 --> 14:11.429 When you protonate it, it becomes tartaric acid. 14:11.429 --> 14:12.939 Over here is the unnatural. 14:12.940 --> 14:16.530 But there's a plant in Africa, Bauhinia reticulata, 14:16.530 --> 14:20.060 that has about -- it's a huge area, around the Sahara. 14:20.058 --> 14:23.398 So there's maybe more of that so-called unnatural than there 14:23.404 --> 14:24.544 is of the natural. 14:24.538 --> 14:28.568 You know the story about tartaric acid. 14:28.570 --> 14:31.620 And it goes way back to Louis Pasteur, with the discovery of 14:31.623 --> 14:35.343 tetrahedral carbon; I mean then the precursor to it. 14:35.340 --> 14:37.920 Grapes, very sexy looking things. 14:37.918 --> 14:40.938 We always like -- humans seem to like to drink them, 14:40.942 --> 14:42.902 and eat them, and look at them. 14:42.899 --> 14:47.969 This is the famous recipe. 14:47.970 --> 14:51.940 So that day, Katsuki took a tartrate and put 14:51.940 --> 14:57.850 it together with -- oh I think I forgot to say something here. 14:57.850 --> 15:01.230 Yeah, just quickly. 15:01.230 --> 15:02.660 Maybe I don't have it. 15:02.659 --> 15:04.069 No, it comes later. Okay. 15:04.070 --> 15:08.900 TBHP was the kind of oxygen we'd always been using. 15:08.899 --> 15:11.679 There's the titanium, which comes from titanium 15:11.682 --> 15:13.862 dioxide or titanium tetrachloride. 15:13.860 --> 15:17.330 Everything that's white in this world, all these -- that's 15:17.331 --> 15:18.491 titanium dioxide. 15:18.490 --> 15:22.530 It's the only white pigment anybody ever uses. 15:22.529 --> 15:25.149 And so that's titanium dioxide. 15:25.149 --> 15:25.989 It's very insoluble. 15:25.990 --> 15:29.470 But you can make it into this soluble derivative, 15:29.470 --> 15:31.790 if you do the right chemistry. 15:31.789 --> 15:33.669 And this is the wine acid. 15:33.668 --> 15:36.048 We put in diisopropyl tartrate as an ester, 15:36.048 --> 15:40.208 and we kept getting 90%, 100%, 95 -- 15:40.210 --> 15:43.460 every olefin we put in that was an allylic alcohol, 15:43.460 --> 15:47.910 that had this handle on it, gave Katsuki -- 15:47.908 --> 15:50.058 about a week of this, and we were just about dying. 15:50.058 --> 15:53.408 I was looking at him; he was looking at me. 15:53.409 --> 15:55.599 We didn't believe it, you know. 15:55.600 --> 15:57.490 So we had to try to kill this. 15:57.490 --> 15:57.970 But it was right. 15:57.970 --> 16:01.810 And so it meant that here we had some new principle. 16:01.808 --> 16:05.268 We could actually just take one catalyst and get them all; 16:05.269 --> 16:06.749 almost get them all. 16:06.750 --> 16:08.090 But they had to be allylic alcohols. 16:08.090 --> 16:14.550 So this is the famous recipe discovered I think on an October 16:14.549 --> 16:17.349 day in 1980 at Stanford. 16:17.350 --> 16:19.290 I'd already decided to go back to MIT. 16:19.288 --> 16:22.288 I might not have decided to do that, if this had happened 16:22.288 --> 16:22.768 sooner. 16:22.769 --> 16:24.639 We get depressed when our research isn't working; 16:24.639 --> 16:26.899 I mean, whether we don't show it or not. 16:26.899 --> 16:30.649 It's the only thing that matters really to a real killer 16:30.645 --> 16:34.255 research guy who wants to understand what makes nature 16:34.255 --> 16:34.865 tick. 16:34.870 --> 16:38.980 And whatever else -- if that's going well, life is good. 16:38.980 --> 16:40.750 Otherwise nothing's good. 16:40.750 --> 16:44.080 So I went back to MIT, which I wouldn't have if I'd 16:44.076 --> 16:47.466 gotten this about three months earlier, probably. 16:47.470 --> 16:49.080 And here we are. 16:49.080 --> 16:52.860 There's Katsuki-san drinking tartaric aqueous -- it's about 16:52.855 --> 16:56.235 5% aqueous tartaric acid -- in wine and champagne. 16:56.240 --> 16:58.920 And this was on the porch at the Mudd Building, 16:58.916 --> 17:01.356 which was where our lab was, on the top. 17:01.360 --> 17:05.580 And what I'm going to show here is why Katsuki was so important, 17:05.577 --> 17:06.647 in a nutshell. 17:06.650 --> 17:08.770 This is really a nice little substrate. 17:08.769 --> 17:13.549 It has this type of alcohol; it's trisubstituted. 17:13.549 --> 17:14.969 But you see the OH here? 17:14.970 --> 17:16.740 There's no OH over here. 17:16.740 --> 17:20.790 This is a more reactive olefin for the transfer of the oxygen, 17:20.788 --> 17:22.978 but it doesn't have the handle. 17:22.980 --> 17:26.260 So this one ends up winning by a factor of 200, 17:26.256 --> 17:30.096 in this system where the epoxidation requires the thing 17:30.102 --> 17:32.882 to bind and go in intramolecularly. 17:32.880 --> 17:36.150 And that's nice in its own right, but to get -- we got 17:36.150 --> 17:39.300 racemate all the time, of course, because we have no 17:39.297 --> 17:40.467 face selection. 17:40.470 --> 17:46.300 And titanium goes about ten times faster with tartrate. 17:46.298 --> 17:48.888 When you add it, this does something to make -- 17:48.890 --> 17:52.190 every other metal, years before Oshima had taken 17:52.185 --> 17:55.655 vanadium and molybdenum, which were the best for 17:55.663 --> 17:57.253 isolated double bonds. 17:57.250 --> 17:59.840 But you put tartrate in, it kills them. 17:59.838 --> 18:03.398 So my instinct would not have been to put tartrate in again. 18:03.400 --> 18:06.520 This is the kind of thing -- everything in science, 18:06.515 --> 18:08.505 the rules change all the time. 18:08.509 --> 18:11.209 You wake up in the morning -- you should iterate your favorite 18:11.211 --> 18:12.231 desire every morning. 18:12.230 --> 18:13.960 It's going to look different to you in the shower. 18:13.960 --> 18:19.850 And you can never -- the atomic bomb was made by theoretical 18:19.851 --> 18:20.951 geniuses. 18:20.950 --> 18:23.740 But the guys who did it, actually they had aluminum foil 18:23.744 --> 18:25.934 on the source, and they kept it on there for 18:25.930 --> 18:27.150 about a year or two. 18:27.150 --> 18:28.640 Some guy said, "No, I don't think we need 18:28.637 --> 18:28.867 this. 18:28.868 --> 18:30.008 What about if we take it off?" 18:30.009 --> 18:31.369 That was the answer. 18:31.369 --> 18:32.899 I mean, these guys are like us. 18:32.900 --> 18:34.940 They just try this, try that, in the lab. 18:34.941 --> 18:35.351 Right? 18:35.348 --> 18:38.698 That's what gets really things done in this world. 18:38.700 --> 18:40.790 The theories are important. 18:40.788 --> 18:43.308 Nobody would even think about trying it without the theory. 18:43.308 --> 18:45.938 But -- okay, "A man in California just 18:45.941 --> 18:49.201 won a Nobel Prize for mixing paint and wine!" 18:49.200 --> 18:52.860 That's what they said, in the LA Times. 18:52.859 --> 18:53.759 It's sort of true. 18:53.759 --> 18:55.919 Titanium dioxide and tartaric acid. 18:55.920 --> 18:59.950 And there's the -- I like my students to know where Mother 18:59.951 --> 19:00.731 Earth is. 19:00.730 --> 19:02.890 And I like things to be cheap. 19:02.890 --> 19:07.070 I don't like to be far away from a river that's strong, 19:07.070 --> 19:09.670 or a power source; or in this case, 19:09.673 --> 19:11.193 this is tartaric acid. 19:11.190 --> 19:12.560 It comes in 100-pound bags. 19:12.558 --> 19:15.328 This is Spanish tartar, and this is Victor Martin, 19:15.328 --> 19:18.548 who's one of the heroes of this chemistry, from the Canary 19:18.550 --> 19:19.230 Islands. 19:19.230 --> 19:20.710 This comes to Pfizer. 19:20.710 --> 19:22.380 They make things out of it. 19:22.380 --> 19:25.050 But it comes in ships in 100-pound bags. 19:25.048 --> 19:28.088 And we still have that in our stockroom somewhere. 19:28.088 --> 19:33.058 There's my daughter celebrating the synthesis of the unnatural 19:33.064 --> 19:35.594 sugars > 19:35.592 --> 19:37.062 by this method. 19:37.058 --> 19:40.128 And oh I got the wrong one, didn't I? 19:40.130 --> 19:42.890 I threw out the wrong -- yeah, anyway, you're going to have to 19:42.894 --> 19:43.444 interpret. 19:43.440 --> 19:45.980 This is the mirror-image of the picture that was taken, 19:45.979 --> 19:48.049 I guess; because you see the name over 19:48.050 --> 19:49.100 here is backwards. 19:49.098 --> 19:51.428 But she's looking at the l-sugars. 19:51.430 --> 19:52.670 These are the ones we don't make. 19:52.670 --> 19:54.270 There's eight of those, the hexoses. 19:54.269 --> 19:57.609 And these are the ones Emil Fisher made, in his famous work; 19:57.608 --> 20:00.168 about the best chemist who ever lived, 20:00.170 --> 20:02.200 except for van't Hoff, who was even better, 20:02.200 --> 20:04.900 because he did organic stereochemistry and physical 20:04.897 --> 20:06.907 chemistry, and I think he was the greatest 20:06.913 --> 20:09.503 chemist who ever lived; van't Hoff was. 20:09.500 --> 20:13.270 But anyway, Fisher was better than anybody who lived in this 20:13.271 --> 20:16.531 century, in terms of understanding and arguments and 20:16.532 --> 20:18.262 rationale of synthesis. 20:18.259 --> 20:21.289 And he made a lot of these sugars over here. 20:21.289 --> 20:24.249 But this is Tito Simboli. 20:24.250 --> 20:26.410 She's a photographer, my wife's friend. 20:26.410 --> 20:28.700 This is taken in 1983. 20:28.700 --> 20:30.330 It was on the cover of Chemistry in Britain. 20:30.329 --> 20:32.899 And Hannah was seven. 20:32.900 --> 20:36.320 And anyway, Tito was a friend. 20:36.319 --> 20:37.519 So she took the picture. 20:37.519 --> 20:39.739 And this book though, is a huge book, 20:39.744 --> 20:43.214 which was gotten by Nancy Schrock, who's in charge of the 20:43.207 --> 20:45.677 MIT Archives and is a book restorer. 20:45.680 --> 20:48.560 And Nancy -- so here we got Nancy Schrock, 20:48.557 --> 20:52.277 we got Tito Simboli, whose husband is Dan McFadden; 20:52.279 --> 20:55.379 won the Nobel Prize in economics ten years later, 20:55.382 --> 20:58.612 and Dick won the Nobel Prize a couple of years ago, 20:58.614 --> 21:00.234 and I won it in 2001. 21:00.230 --> 21:02.150 So the picture is kind of connected. 21:02.150 --> 21:05.180 And there's Lewis Carroll, of course, looking-glass milk. 21:05.180 --> 21:06.910 And Emil Fisher. 21:06.910 --> 21:08.910 It's a heavy duty picture; for me anyway. 21:08.912 --> 21:10.282 > 21:10.278 --> 21:13.678 There's Nexium, and maybe we're getting -- I 21:13.675 --> 21:16.515 went too far into the other stuff. 21:16.519 --> 21:18.299 But here's the atom, the red atom, 21:18.301 --> 21:21.491 that's going to end up being transferred onto the sulfur. 21:21.490 --> 21:30.230 And well Mike showed -- told you that the diisopropylamine -- 21:30.228 --> 21:33.868 what would its role be? 21:33.868 --> 21:36.368 I hope I can go to the board now and show you a few things. 21:36.368 --> 21:39.168 But this catalyst is exactly the recipe. 21:39.170 --> 21:41.410 And it makes billions of dollars a year, 21:41.413 --> 21:42.163 this product. 21:42.162 --> 21:42.682 Right? 21:42.680 --> 21:46.200 But the patent is -- the Stanford patent is no longer 21:46.198 --> 21:46.738 valid. 21:46.740 --> 21:49.580 It's run out; even though it hadn't run out 21:49.583 --> 21:50.513 when they started. 21:50.509 --> 21:53.489 But they didn't believe that it might. 21:53.490 --> 21:56.150 This was an infringing of that patent actually in the 21:56.154 --> 21:56.774 beginning. 21:56.769 --> 21:59.069 But nobody in universities sues companies. 21:59.069 --> 22:00.019 They can't afford to. 22:00.019 --> 22:01.769 Stanford couldn't afford to. 22:01.769 --> 22:02.759 Prof: Do you want to go to the board now? 22:02.759 --> 22:04.549 Prof: Should I? Yeah. 22:04.548 --> 22:36.418 <> 22:36.420 --> 22:38.900 Prof: Do you remember the vanadium picture? 22:38.900 --> 22:41.170 I'll make it titanium now. 22:41.170 --> 22:44.690 But there's this alcohol group and -- 22:44.690 --> 22:51.370 <> 22:51.368 --> 22:56.088 Prof: And on this we have this peroxide group that's 22:56.086 --> 22:59.256 bound, and it's bound datively there. 22:59.259 --> 23:01.469 It's got this tertiary-butyl group here. 23:01.470 --> 23:11.350 And then the alcohol is bound here, and well it goes sort of 23:11.347 --> 23:12.517 down. 23:12.519 --> 23:17.329 I'll just try to show some of the stereochemistry. 23:17.328 --> 23:23.258 And then underneath it's coming -- yeah, it's coming folded like 23:23.260 --> 23:25.050 this, underneath. 23:25.048 --> 23:28.378 I can't draw very well, but this is supposed to be 23:28.375 --> 23:31.765 coming with its lone pairs, it's π bonds, 23:31.769 --> 23:34.009 on the backside of this bond. 23:34.009 --> 23:38.549 So we're going to do an attack on there, and we'll break this 23:38.548 --> 23:43.538 bond, we'll bring the lone pair here in, and we get the epoxide. 23:43.538 --> 23:46.898 Now, but the thing about this is patent lawyers can be very 23:46.896 --> 23:49.046 creative -- like every field has creative 23:49.046 --> 23:51.986 people, and Yale is connected to this 23:51.990 --> 23:53.610 fellow, Bert Rowland. 23:53.608 --> 23:57.078 And he was in Palo Alto at the time, at a company, 23:57.079 --> 24:00.549 and he had just gotten famous, or almost infamous, 24:00.550 --> 24:03.810 because that patent was really aggressive; 24:03.809 --> 24:06.169 this Boyer-Cohen Patent. 24:06.170 --> 24:07.290 He wrote the Boyer-Cohen Patent. 24:07.288 --> 24:09.958 He's related to Mike, because he got his Ph.D. 24:09.960 --> 24:11.970 with Bartlett at Harvard, like Mike did. 24:11.970 --> 24:14.040 So that's a long time ago. 24:14.038 --> 24:16.138 That's a great-something relationship. 24:16.140 --> 24:20.270 And then comes Wiberg, who's here at Yale. 24:20.269 --> 24:23.169 He was at Seattle then, and he took a post-doc. 24:23.170 --> 24:25.300 He decided he liked chemistry in principle. 24:25.299 --> 24:27.669 He was smart; a physical-organic chemist. 24:27.670 --> 24:29.890 But he didn't like the lab; he wasn't any good in the lab 24:29.888 --> 24:30.968 and he didn't like to be there. 24:30.970 --> 24:33.810 So he became a patent attorney, and did very well. 24:33.809 --> 24:36.409 And he writes great patents. 24:36.410 --> 24:39.650 And so he read our paper, our first paper. 24:39.650 --> 24:40.920 We gave him the little communication. 24:40.920 --> 24:45.670 And then he got Katsuki and me over to his office, 24:45.674 --> 24:50.144 and he interviewed us for about ten minutes. 24:50.140 --> 24:51.920 The next day we got a patent. 24:51.920 --> 24:53.370 He never changed a word of it. 24:53.368 --> 24:55.808 And I'll tell you why it's creative, I think. 24:55.808 --> 24:59.418 We're getting ready for the Nexium. 24:59.420 --> 25:01.150 But I could tell you about that. 25:01.150 --> 25:03.890 If we don't make it, it won't matter that much. 25:03.890 --> 25:07.780 But here's the main -- so this is going to be the oxygen; 25:07.778 --> 25:10.528 and they should be red but we have pink here. 25:10.529 --> 25:11.689 So does this one. 25:11.690 --> 25:13.020 But that one doesn't transfer. 25:13.019 --> 25:14.089 This is the one that transfers. 25:14.088 --> 25:20.078 So what Rowland said is you got a metal, which can grab things. 25:20.078 --> 25:22.878 Now the things it grabs, it could be X, 25:22.876 --> 25:26.556 it could be sulfur, or an amine group that it could 25:26.557 --> 25:27.217 grab. 25:27.220 --> 25:30.130 And then he just drew -- I think he drew a carbon with no 25:30.133 --> 25:31.593 -- it could be any carbon. 25:31.588 --> 25:34.798 It didn't have to have to have just CH_2. 25:34.799 --> 25:38.869 And then he drew this, G. 25:38.868 --> 25:42.678 And then he drew -- yeah, he did draw an oxygen atom 25:42.680 --> 25:45.520 here, I guess, but it was activated. 25:45.519 --> 25:48.769 And so this oxygen, he didn't have a generality 25:48.773 --> 25:49.343 there. 25:49.339 --> 25:50.369 That was specific. 25:50.368 --> 25:52.088 That was the only thing that was specific, 25:52.092 --> 25:52.892 these two things. 25:52.890 --> 25:55.360 So this could be any kind of lone pair. 25:55.359 --> 25:56.649 An olefin is a lone pair. 25:56.650 --> 25:58.150 Sulfur has a lone pair. 25:58.150 --> 25:59.330 Phosphorous has a lone pair. 25:59.329 --> 26:00.429 Nitrogen has a lone pair. 26:00.430 --> 26:02.420 And sure enough, when I read that, 26:02.416 --> 26:05.426 I said, "My God, this gives us ideas." 26:05.430 --> 26:07.800 So we started doing amino alcohols. 26:07.799 --> 26:08.969 All these things work. 26:08.970 --> 26:09.780 You know? 26:09.778 --> 26:12.178 So this is from Bert Rowland, the patent attorney. 26:12.180 --> 26:16.000 He was a co-inventor of those other reactions. 26:16.000 --> 26:18.040 We never wrote any more patents. 26:18.039 --> 26:19.389 It's a good thing. 26:19.390 --> 26:20.660 Don't waste your time on patents. 26:20.660 --> 26:22.320 They'll just not use them until they expire. 26:22.318 --> 26:25.028 And we never -- we made enough to go on a vacation once a year, 26:25.028 --> 26:26.208 in a car, not too far away. 26:26.209 --> 26:27.389 > 26:27.390 --> 26:31.440 Katsuki and I, we got -- people think we got 26:31.440 --> 26:32.100 rich. 26:32.098 --> 26:35.088 We got the most -- one year we got $20,000 each, 26:35.094 --> 26:36.054 or something. 26:36.048 --> 26:39.488 That was a really sharp maximum, from the bag-a-bug 26:39.487 --> 26:42.097 gypsy moth traps – Disparlure. 26:42.098 --> 26:47.108 But okay, to show the transfer, I think maybe it would be nice 26:47.112 --> 26:51.062 for us, Mike and I, to show what features have to 26:51.056 --> 26:53.846 be over here in these ligands. 26:53.848 --> 26:56.968 You see, the tartrate has this feature. 26:56.970 --> 27:01.400 It grabs the titanium, like out front. 27:01.400 --> 27:02.730 Let's kind of put it out front here. 27:02.730 --> 27:04.910 So the titanium is out here. 27:04.910 --> 27:08.290 And down in the back here you have this ester group, 27:08.286 --> 27:11.396 and up in the back, over here, you have an ester 27:11.396 --> 27:12.056 group. 27:12.058 --> 27:14.458 And I can't remember if that's what we planned to do. 27:14.460 --> 27:15.850 But out here, on the front, 27:15.846 --> 27:18.086 it's coming -- the alcohol -- this G-group, 27:18.087 --> 27:20.327 and there's an oxygen that's hot over here, 27:20.328 --> 27:21.928 that can be transferred. 27:21.930 --> 27:27.020 So Mike's going to put that -- I'm going to put that on and -- 27:27.019 --> 27:28.149 Prof: I'm the olefin. 27:28.150 --> 27:29.670 Prof: Yeah, you're the -- is that okay if 27:29.665 --> 27:30.895 you're the ole-- Prof: It's okay. 27:30.900 --> 27:32.970 Prof: Maybe it's better if I'm the olefin. 27:32.974 --> 27:34.104 > 27:34.098 --> 27:35.538 Prof: No, okay. 27:35.540 --> 27:37.120 I'll be the titanium. 27:37.118 --> 27:38.008 Prof: Yeah, you're the titanium. 27:38.009 --> 27:40.709 Prof: So see, I've got this oxygen that wants 27:40.708 --> 27:42.718 to go off, because it's a weak bond. 27:42.720 --> 27:46.380 And I've got to get it over to him. 27:46.380 --> 27:48.060 He's the allylic alcohol. 27:48.058 --> 27:50.268 But we're going to pretend he doesn't have to bind to me. 27:50.269 --> 27:52.319 We're just going to do this straight-out attack here. 27:52.319 --> 27:57.999 And yeah, it's like that. Right? 27:58.000 --> 27:59.720 So I'm blocked here, but I'm open in these 27:59.724 --> 28:00.234 quadrants. 28:00.230 --> 28:02.430 Prof: So you're natural tartaric acid. 28:02.430 --> 28:03.280 Prof: Is that right? 28:03.276 --> 28:03.836 Boy you're quick. 28:03.838 --> 28:05.388 I don't -- okay, so I'm natural? 28:05.390 --> 28:06.690 > 28:06.690 --> 28:08.310 Prof: Okay, well wait a minute. 28:08.308 --> 28:10.728 And also, but I'm not like this, I'm like that. 28:10.730 --> 28:13.100 You see, I'm in a three-dimensional world, 28:13.099 --> 28:14.719 because I'm tartaric acid. 28:14.720 --> 28:15.970 So I'm sticking out here. 28:15.970 --> 28:17.360 So I'm a chiral object now. 28:17.358 --> 28:19.548 My mirror-image won't superimpose. 28:19.549 --> 28:22.049 But he's, yeah he's that way. 28:22.049 --> 28:24.369 He's a trans-olefin. 28:24.368 --> 28:26.218 > 28:26.221 --> 28:29.851 And he looks like an Egyptian, like -- anyway. 28:29.848 --> 28:31.478 Prof: I have a double bond here, right? 28:31.480 --> 28:32.200 Prof: Yeah. 28:32.200 --> 28:34.180 Prof: The question is whether you're going to come on 28:34.182 --> 28:34.892 here or on my back. 28:34.890 --> 28:36.400 Prof: Actually the double -- we don't have this 28:36.403 --> 28:36.753 quite right. 28:36.746 --> 28:37.656 Can you get an arm down here? 28:37.660 --> 28:39.290 Because the double bonds is here. 28:39.288 --> 28:40.418 Prof: No, no, the double bond is going 28:40.424 --> 28:40.714 this way. 28:40.710 --> 28:41.300 Prof: Okay. 28:41.295 --> 28:42.265 You've got it going that way. 28:42.269 --> 28:43.929 Prof: So here, right now. 28:43.930 --> 28:46.030 Prof: Okay, so yeah double bond's going 28:46.034 --> 28:46.454 that way. 28:46.454 --> 28:46.834 Okay. 28:46.828 --> 28:47.058 Prof: Thank you. 28:47.058 --> 28:48.398 So you -- Prof: Yeah, that's good. 28:48.400 --> 28:49.330 Prof: Get your tartrate on. 28:49.328 --> 28:52.338 Prof: Okay, because I could go like -- I 28:52.337 --> 28:54.887 may not -- it's like this, I'm sorry. 28:54.890 --> 28:56.300 Yeah, I got to go like that. 28:56.299 --> 28:57.429 I could go like that. 28:57.430 --> 28:58.360 That's the mirror-image. 28:58.358 --> 29:00.178 Okay, now I'm coming towards him. 29:00.180 --> 29:02.270 Prof: But I want to go on my back. 29:02.269 --> 29:03.949 Prof: Okay, you want it on your back? 29:03.950 --> 29:04.810 Oh my gosh. 29:04.809 --> 29:08.599 Oh I can't do it. See? 29:08.598 --> 29:11.308 But that's the other -- you need the other mirror-image for 29:11.306 --> 29:11.816 that one. 29:11.818 --> 29:15.648 So I come this way, and I can -- it says 29:15.653 --> 29:18.113 "Think Safety". 29:18.109 --> 29:18.699 Oh. 29:18.700 --> 29:23.120 So now you have to -- yeah, if he was a good yoga person, 29:23.115 --> 29:26.265 he could pyramidalize it a little better. 29:26.270 --> 29:28.480 > 29:28.480 --> 29:31.760 Yet now when you put him that way, he's one enantiomer, 29:31.760 --> 29:34.920 and if you put him on the other way, that's the other 29:34.922 --> 29:35.592 enantiomer. 29:35.589 --> 29:36.319 Simple. 29:36.319 --> 29:37.219 It's real simple, isn't it? 29:37.220 --> 29:39.250 Thanks Mike. 29:39.250 --> 29:43.040 Yeah, we just organized that ten seconds before we came over, 29:43.044 --> 29:44.124 as you can see. 29:44.118 --> 29:46.938 We didn't have any red ping pong balls. 29:46.940 --> 29:48.140 It's good with Velcro. 29:48.140 --> 29:49.230 You can do it with Velcro. 29:49.230 --> 29:51.150 We did it once with Velcro red balls. 29:51.150 --> 29:55.100 Okay now. 29:55.099 --> 29:59.729 Prof: Back to the screen. 29:59.730 --> 30:01.880 Prof: Yeah, I think we're -- oh no, 30:01.884 --> 30:03.414 I'm not back to the screen. 30:03.410 --> 30:04.580 Let's leave it alone. 30:04.579 --> 30:09.869 This is going to be a little -- < 30:13.191 adjustments>> 30:13.190 --> 30:19.070 Prof: Now if you look at the structure of the omeprazole. 30:19.068 --> 30:21.668 I won't put all the bells and whistles on it. 30:21.670 --> 30:25.700 It's an imidazole structure, benzimidazole, 30:25.700 --> 30:29.730 which has a benzene ring, two nitrogens. 30:29.730 --> 30:34.200 It's a five-membered aromatic heterocycle. 30:34.200 --> 30:39.910 And so you have a double bond and one H. 30:39.910 --> 30:43.360 And I can't remember what's on the sulfur. 30:43.358 --> 30:46.018 Is it an aromatic ring, or is it a benzyl? 30:46.019 --> 30:49.179 It's an aromatic benzyl thing, I think. 30:49.180 --> 30:51.960 And you might look at this and say, "This doesn't look 30:51.960 --> 30:54.310 anything like Bert Rowland's thing there." 30:54.308 --> 30:58.808 Because where are the anchor points that we need, 30:58.813 --> 31:01.913 the group that binds the metal? 31:01.910 --> 31:04.080 We have the lone pairs all right; 31:04.078 --> 31:07.978 you know, two lone pairs, rabbit ears. 31:07.980 --> 31:14.310 And there, if you put oxygen on one side, it's the same story as 31:14.306 --> 31:15.206 before. 31:15.210 --> 31:17.110 This isn't flat to start with. 31:17.109 --> 31:19.429 But now we have these pairs. 31:19.430 --> 31:21.590 If you put something here, you get one enantiomer. 31:21.588 --> 31:23.288 You put something there, you get the other. 31:23.288 --> 31:28.528 So the idea was to try to get -- and Kagan had done this. 31:28.528 --> 31:30.838 He's a fellow that could've won the Nobel Prize, 31:30.838 --> 31:31.918 I thought should of. 31:31.920 --> 31:33.160 But he's in France. 31:33.160 --> 31:37.360 And he had done a lot of great work in asymmetric chemistry. 31:37.358 --> 31:42.128 And he took the titanium tartrate catalyst of Katsuki, 31:42.130 --> 31:44.050 and he found if you put a little water in it, 31:44.048 --> 31:47.008 and you did the right things, and wished -- 31:47.009 --> 31:49.799 it wasn't as general, but he got very good asymmetric 31:49.798 --> 31:50.388 addition. 31:50.390 --> 31:53.610 So titanium was already known to do this. 31:53.608 --> 31:58.518 But the feature that's important here is the pKa of 31:58.519 --> 32:03.529 this benzimidazole is probably -- I looked it up; 32:03.528 --> 32:05.678 I think it's below that of an alcohol. 32:05.680 --> 32:10.310 So that means it can go on the titanium, reversibly. 32:10.308 --> 32:13.868 So you see the titanium has alcohols on it, 32:13.865 --> 32:18.265 or ligands like this, or -- and this can exchange. 32:18.269 --> 32:22.929 So we can have that come off, and this N go on, 32:22.928 --> 32:27.788 for this heterocycle, and the benzene ring's down 32:27.788 --> 32:28.698 here. 32:28.700 --> 32:33.460 And now we have something like that, a covalent bond. 32:33.460 --> 32:41.460 And we've got the sulfur here, and we also have the alcohol. 32:41.460 --> 32:43.970 So there's an equilibrium where you could invoke that. 32:43.970 --> 32:48.800 But this is not as easy to probably do as an alcohol. 32:48.798 --> 32:51.438 It's more encumbered, and it's probably -- kinetics 32:51.443 --> 32:53.453 are slower for this, and off of oxygen, 32:53.453 --> 32:55.943 for the hydrogen transfers that are needed. 32:55.940 --> 33:00.460 So I hypothesize here that what the diisopropyl -- what the 33:02.642 --> 33:05.372 diisopropylethylamine is doing. 33:05.368 --> 33:09.958 This is such a hindered amine that it can't react with 33:09.957 --> 33:13.937 anything, but it's good for getting protons. 33:13.940 --> 33:15.760 So it can't itself get at the oxygen; 33:15.759 --> 33:17.179 which you would worry about. 33:17.180 --> 33:18.560 It would make an N-oxide. 33:18.558 --> 33:21.218 And it can't bind to the titanium anyway. 33:21.220 --> 33:23.550 Titanium hates nitrogen. 33:23.548 --> 33:27.718 If you have an oxygen around, it'll spit it out so fast it'll 33:27.720 --> 33:29.250 make your head spin. 33:29.250 --> 33:32.700 I mean, this thing is amazing hating nitrogen -- titanium, 33:32.703 --> 33:35.313 and silicon too, but especially titanium. 33:35.308 --> 33:38.168 So it's never going to get involved with titanium. 33:38.170 --> 33:39.360 So what's it going to do? 33:39.358 --> 33:44.258 Well remember when you try to get chemistry going in a system 33:44.256 --> 33:49.556 like this, this amine has enough pKa power to pull this proton. 33:49.558 --> 33:53.128 And usually you could write a concerted mechanism. 33:53.130 --> 33:56.260 Like let me erase some of this and have some room here. 33:56.259 --> 33:59.839 Well I shouldn't erase that. 33:59.839 --> 34:00.469 I'll go over here. 34:00.470 --> 34:08.360 34:08.360 --> 34:13.250 You got this benzimidazole, with a sulfur here, 34:13.251 --> 34:17.931 and I'm going to put the hydrogen up here. 34:17.929 --> 34:22.649 Whenever you engage compounds in reaction, acid-base 34:22.653 --> 34:27.563 reactions, you look for the basic sites and the acidic 34:27.563 --> 34:28.493 sites. 34:28.489 --> 34:29.689 There's the acidic site. 34:29.690 --> 34:32.840 You might think that's where the titanium goes. 34:32.840 --> 34:36.390 But usually the mechanism for these reactions involves a 34:36.385 --> 34:39.735 simultaneous loss of this proton, and attack here. 34:39.739 --> 34:41.519 This is the place you can attack. 34:41.518 --> 34:44.108 So you'll be attacking the titanium here, 34:44.110 --> 34:48.750 and you're going to get some help from -- 34:48.750 --> 34:51.550 you're going to get a lot of help from this amine, 34:51.550 --> 34:53.280 because you can put it someplace; 34:53.280 --> 34:55.280 just take it right off. 34:55.280 --> 34:58.310 But you'll have some of that ammonium salt around too, 34:58.309 --> 34:59.909 a little bit, transiently. 34:59.909 --> 35:07.019 And this will help you, because you need to move things 35:07.023 --> 35:08.213 around. 35:08.210 --> 35:12.200 That's why this reaction was not good without that amine. 35:12.199 --> 35:15.349 You need to scramble the system and keep it rolling, 35:15.353 --> 35:17.583 so that the things get on and off. 35:17.579 --> 35:21.619 Catalysis often has this -- like there's six, 35:21.615 --> 35:22.345 maybe. 35:22.349 --> 35:24.819 There's always a loop, and if you look at any 35:24.815 --> 35:27.275 catalytic cycle, there'll be usually one step 35:27.280 --> 35:30.140 that's really bad news, until you get it fixed. 35:30.139 --> 35:33.649 And that step is where it controls the rate. 35:33.650 --> 35:37.590 If you get steady state, the slowest step -- this is a 35:37.594 --> 35:39.684 real democracy, catalysis. 35:39.679 --> 35:43.329 There's no step that's more important than any other. 35:43.329 --> 35:44.729 The catalyst goes from each step. 35:44.730 --> 35:46.980 The titanium is moving through those cycles. 35:46.980 --> 35:50.490 If there's a slow step, there's 99.9% of the titaniums 35:50.485 --> 35:53.455 that you need, stuck before this one mountain, 35:53.463 --> 35:56.113 that goes way up like Mount Everest. 35:56.110 --> 35:57.850 You got to drop that one down. 35:57.849 --> 36:00.109 If you get that one down, the rate goes way up. 36:00.110 --> 36:02.360 And if you get them all the same height, you're really 36:02.356 --> 36:02.776 rolling. 36:02.780 --> 36:05.190 And that's a sacred rule. 36:05.190 --> 36:09.490 The turnover-limiting step is everything, in catalysis. 36:09.489 --> 36:11.829 And a lot of times the turnover-ruling step is so high, 36:11.829 --> 36:13.649 they don't even know there is catalysis. 36:13.650 --> 36:16.280 If you can break that, you'll find a world of 36:16.284 --> 36:18.504 catalysis that didn't exist before. 36:18.500 --> 36:21.200 So that's what I think is exciting about catalysis; 36:21.199 --> 36:22.339 it's alive. 36:22.340 --> 36:25.500 As long as you have some energy to dissipate you're -- it's life 36:25.498 --> 36:25.948 itself. 36:25.949 --> 36:31.219 Then I'll finish this quickly off, without any details. 36:31.219 --> 36:32.669 You can see what I'm going to do here. 36:32.670 --> 36:37.230 It's just that that hot oxygen atom, that's activated to 36:37.228 --> 36:38.138 transfer. 36:38.139 --> 36:42.239 This is the handle that would be the allylic alcohol. 36:42.239 --> 36:46.179 And so it's a dead ringer for the Katsuki -- for the Bert 36:46.181 --> 36:47.871 Rowland Patent, right? 36:47.869 --> 36:49.059 That's what I think. 36:49.059 --> 36:52.919 And the amine, yeah, the amine makes sense 36:52.922 --> 36:53.962 here too. 36:53.960 --> 36:57.760 And I guess that's -- Prof: So did that patent 36:57.760 --> 36:58.460 apply to this process? 36:58.460 --> 37:00.170 Prof: Well Stanford made a little -- 37:00.170 --> 37:04.340 they brought over ten people, from research, 37:04.340 --> 37:07.760 and they brought over three lawyers from AstraZeneca; 37:07.760 --> 37:10.880 because Stanford thought maybe they should get something out of 37:10.876 --> 37:11.226 this. 37:11.230 --> 37:15.130 And I told the story like this, and they didn't -- they 37:15.130 --> 37:18.090 pretended it didn't make any sense at all. 37:18.090 --> 37:19.030 You know? 37:19.030 --> 37:21.660 And it was pretty unsatisfying. 37:21.659 --> 37:22.429 Bert Rowland was there. 37:22.429 --> 37:23.539 I don't know if he's still alive. 37:23.539 --> 37:24.539 He had cancer then. 37:24.539 --> 37:27.349 But so we didn't -- but they'd already made six billion 37:27.349 --> 37:29.449 dollars; because the catalyst patent was 37:29.452 --> 37:30.682 the only extant patent. 37:30.679 --> 37:32.899 But it did have this feature in it. 37:32.900 --> 37:37.000 And so they were right in the -- I think they're right in the 37:37.003 --> 37:38.443 face of the patent. 37:38.440 --> 37:39.650 But they didn't like that. 37:39.650 --> 37:43.320 And we didn't -- Stanford wasn't going to pursue it. 37:43.320 --> 37:48.380 Another thing we -- I'd like to mention -- is they invited me 37:48.378 --> 37:48.968 over. 37:48.969 --> 37:53.829 This is before this meeting about the patent. 37:53.829 --> 37:56.749 I guess I started to notice the old titanium chemistry, 37:56.750 --> 37:59.560 and Katsuki and I talked, and we agreed that maybe we 37:59.563 --> 38:00.973 should raise our hand. 38:00.969 --> 38:03.829 But before that, what happened was I got invited 38:03.829 --> 38:06.629 to go to a hotel in Munich, the fanciest hotel, 38:06.630 --> 38:09.430 and they put me in this big room upstairs. 38:09.429 --> 38:11.909 They wanted me to say something about right- and left-handed 38:11.905 --> 38:12.405 medicines. 38:12.409 --> 38:16.839 And I had a little 15-minute spot -- 1000 or 1200 38:16.835 --> 38:20.705 gastroenterologists, from Germany alone. 38:20.710 --> 38:24.170 And they were doing a story about how important drugs have 38:24.172 --> 38:25.572 to be optically pure. 38:25.570 --> 38:29.070 And that story doesn't wash too well here. 38:29.070 --> 38:31.510 And I didn't realize it, when it was going. 38:31.510 --> 38:34.120 But I went and I did my part. 38:34.119 --> 38:38.329 And it is true that many drugs are toxic in one form and good 38:38.327 --> 38:39.377 in the other. 38:39.380 --> 38:42.630 And I was able to make those points. 38:42.630 --> 38:47.110 But what happens here is -- oh, and also they gave me this 38:47.110 --> 38:50.180 suite on the top, that had like a spiral 38:50.177 --> 38:53.477 staircase to the bed, at the very top; 38:53.480 --> 38:55.460 and Madonna had stayed there the week before. 38:55.460 --> 38:56.610 > 38:56.610 --> 38:58.700 That's okay for her. 38:58.699 --> 39:00.239 She doesn't have a prostate problem. 39:00.239 --> 39:01.319 > 39:01.320 --> 39:02.220 I hated that place. 39:02.219 --> 39:04.639 I had to go -- they should've had a fire pole so I could get 39:04.637 --> 39:05.577 down to the bathroom. 39:05.579 --> 39:06.409 Anyway. 39:06.409 --> 39:10.289 What happens is, as Mike told you, 39:10.291 --> 39:15.471 you just look at the facts in that system. 39:15.469 --> 39:17.869 And I noticed them just the day I was sitting there in the 39:17.865 --> 39:19.795 audience, and the press was interviewing us. 39:19.800 --> 39:22.170 And I whispered to the guy next to me, and he looked at me and 39:22.170 --> 39:22.560 frowned. 39:22.559 --> 39:24.059 It was about the weights. 39:24.059 --> 39:24.839 All right? 39:24.840 --> 39:28.530 I mean, the racemate 20 mgs, and optically pure. 39:28.530 --> 39:31.420 And I think the optically pure is substantially more reactive, 39:31.420 --> 39:33.410 in this case, because it gets in better. 39:33.409 --> 39:35.309 It's, of course, just a pro-drug, 39:35.309 --> 39:36.259 for the thing. 39:36.260 --> 39:40.550 But the thing that was missing from the experiments is the 39:40.550 --> 39:44.390 forty milligrams of racemate, which would give them 39:44.387 --> 39:47.847 equivalence against the one enantiomer of the twenty 39:47.853 --> 39:49.353 milligrams of pure. 39:49.349 --> 39:52.319 And that was missing, and they doubled the -- and it 39:52.317 --> 39:54.467 was just a sore thumb there for me. 39:54.469 --> 39:58.209 But I didn't say anything; nobody asked me, fortunately. 39:58.210 --> 40:00.970 Because if they had, I would've said something about 40:00.965 --> 40:01.825 it, I imagine. 40:01.829 --> 40:03.269 It's the way we are. 40:03.271 --> 40:04.211 Right, Mike? 40:04.210 --> 40:09.140 Mike doesn't -- he smiles, but he gets the hard evidence. 40:09.139 --> 40:12.989 In the middle of your talk sometimes he does this. 40:12.989 --> 40:15.459 But for me it's the best thing you can get. 40:15.460 --> 40:16.010 Prof: > 40:16.010 --> 40:18.100 Prof: If you can get killed by a friend, 40:18.099 --> 40:19.509 it's the best way to get killed. 40:19.507 --> 40:20.777 > 40:20.780 --> 40:23.620 Prof: Anyway, I'm finished. 40:23.617 --> 40:24.647 That's it. 40:24.650 --> 40:25.390 Prof: Great. 40:25.389 --> 40:29.019 > 40:29.019 --> 40:29.989 Prof: Great. 40:29.989 --> 40:30.769 Thanks again. 40:30.768 --> 40:34.188 Prof: Yeah, you're welcome. 40:34.190 --> 40:37.180 Prof: We maybe have time for one question or so, 40:37.181 --> 40:39.621 before we get back to our normal business. 40:39.619 --> 40:41.669 Anybody got a question for Professor Sharpless? 40:41.670 --> 40:44.700 40:44.699 --> 40:45.919 No. Well thanks again. 40:45.920 --> 40:46.240 Prof: You're welcome. 40:46.239 --> 40:47.759 Prof: Have a good trip back. 40:47.760 --> 40:54.300 < 40:57.692 Professor Sharpless>> 40:57.690 --> 40:58.870 Prof: Okay thanks. 40:58.867 --> 40:59.237 So long. 40:59.244 --> 40:59.814 Good luck. 40:59.809 --> 41:06.489 * Prof: Okay, 41:06.485 --> 41:08.825 back to our routine now. 41:08.829 --> 41:18.129 < 41:22.936 Professor Sharpless>> 41:22.940 --> 41:25.620 Prof: Oh, he forgot to show this picture. 41:25.619 --> 41:28.659 41:28.659 --> 41:34.699 There he is with the royalty of Sweden, and his wife, 41:34.701 --> 41:39.931 and the other Nobel Laureates in Chemistry. 41:39.929 --> 41:46.739 Okay, and he was going to talk about carvone too. 41:46.739 --> 41:47.869 He wanted you to smell it. 41:47.869 --> 41:49.289 I told him you'd smelled it. 41:49.289 --> 41:52.039 But he had an idea for a novel based on carvone, 41:52.038 --> 41:54.258 which he didn't have time to get to. 41:54.260 --> 42:01.540 Okay, so we were talking about the conformation of rings. 42:01.539 --> 42:04.629 And we talked last time a lot about cyclohexane, 42:04.630 --> 42:08.660 and how it distorted -- remember, that it's not really 42:08.664 --> 42:10.984 ideal, with the axial bonds parallel 42:10.978 --> 42:11.708 to the axis. 42:11.710 --> 42:12.860 They spread out a little bit. 42:12.860 --> 42:15.760 The ring flattens a little bit to minimize the energy, 42:15.757 --> 42:17.887 as calculated by molecular mechanics. 42:17.889 --> 42:20.219 Now how about in a four-membered ring, 42:20.215 --> 42:22.285 instead of a six-membered ring? 42:22.289 --> 42:25.199 Well if we look at the, what molecular mechanics says 42:25.195 --> 42:27.705 about the source of strain in this system, 42:27.710 --> 42:32.220 you can see that the big contributors are bend -- 42:32.219 --> 42:37.469 that's what Baeyer had already talked about, 42:39.320 --> 42:45.010 angles is not going to be good; so that's costing 13.5 kcal/mol 42:45.014 --> 42:47.014 -- and torsion. 42:47.010 --> 42:50.930 Because why is there such high torsional energy; 42:50.929 --> 42:52.339 15 kcal/mol, almost? 42:52.340 --> 42:55.030 What's the source of that? 42:55.030 --> 42:56.700 Anybody see? 42:56.699 --> 43:03.119 As you go around the ring, everything is exactly eclipsed. 43:03.119 --> 43:05.259 Everybody see that? 43:05.260 --> 43:08.520 Every carbon-carbon bond is eclipsed. 43:08.516 --> 43:09.236 Right? 43:09.239 --> 43:12.619 So that, in molecular mechanics, sums up to almost 15 43:12.623 --> 43:13.343 kcal/mol. 43:13.340 --> 43:16.940 Now, if you were -- how would you try to minimize the energy? 43:16.940 --> 43:21.350 Is this probably the lowest energy form, or can you think of 43:21.349 --> 43:24.189 changing it, so that it'll be lower? 43:24.190 --> 43:29.010 43:29.010 --> 43:32.130 Any ideas? Kevin? 43:32.130 --> 43:35.650 Student: Make it so the bond, in cyclobutane, 43:35.648 --> 43:38.488 aren't exactly parallel to the new bond. 43:38.489 --> 43:40.669 Prof: Yeah, if you make it not exactly 43:40.666 --> 43:42.716 eclipsed, if you make it a little bit 43:42.722 --> 43:44.732 towards scatter- towards staggered, 43:44.730 --> 43:49.470 by twisting about the bonds, that'll lower that 15 kcal/mol. 43:49.469 --> 43:55.019 But, can you see what happens, if you begin to twist around 43:55.021 --> 43:56.171 the bonds? 44:01.768 --> 44:05.828 So here's what happens when you do it. 44:05.829 --> 44:10.579 The bending energy goes up, by 2.5 kilocalories per mole. 44:10.581 --> 44:11.261 Right? 44:11.260 --> 44:17.110 But the torsional energy goes down, by 3.5 kilocalories per 44:17.106 --> 44:18.716 mole -- right? 44:18.719 --> 44:20.429 -- if you don't bend it too far. 44:20.429 --> 44:24.129 Okay, and the other things stay pretty much the same. 44:24.130 --> 44:28.190 So this is a competition between torsion energy and 44:28.188 --> 44:31.738 bending energy, and the minimum is reached with 44:31.742 --> 44:35.252 a little bit of bending, in order to relieve some of 44:35.251 --> 44:36.161 that torsion. 44:36.159 --> 44:39.359 Now how about if you had a five-membered ring? 44:39.360 --> 44:44.220 Now you notice you have -- notice the bending energy isn't 44:44.222 --> 44:47.302 bad, because as Baeyer pointed out, 44:47.302 --> 44:49.842 a pentagon, a regular pentagon, 44:53.297 --> 44:53.987 Right? 44:53.989 --> 44:55.339 So there's hardly any bending. 44:55.340 --> 44:58.040 But there's still a lot of torsion, from the eclipsing of 44:58.043 --> 44:58.723 the carbons. 44:58.719 --> 45:02.589 So what you do, if you run the molecular 45:02.594 --> 45:07.274 mechanics program, is to cause bending energy to 45:07.266 --> 45:10.076 occur; that is, sharpen the angles a 45:10.077 --> 45:11.267 little bit, right? 45:11.268 --> 45:14.658 But you get rid of a lot of torsional energy by doing that. 45:14.659 --> 45:17.579 And this particular conformation -- which you can 45:17.579 --> 45:20.569 see how it's bent down; the black carbon, 45:20.572 --> 45:25.262 eight there -- is sometimes referred to as the envelope 45:25.255 --> 45:28.025 conformation of cyclopentane. 45:28.030 --> 45:32.510 See how it looks like the fold of the envelope bent down? 45:32.510 --> 45:36.440 Okay, so there again is a competition between bending and 45:36.438 --> 45:37.138 torsion. 45:37.139 --> 45:41.499 Now, like plastic models, molecular mechanics is 45:41.498 --> 45:47.068 satisfying because it says not only what the structure should 45:47.065 --> 45:48.545 be, but why. 45:48.550 --> 45:50.950 What is it that makes the energy the way it is? 45:50.949 --> 45:54.389 Okay, so you remember last time we passed around the 45:54.387 --> 45:55.397 cyclohexanes. 45:55.400 --> 45:58.660 Remember how they clicked, to go from one form to another? 45:58.659 --> 46:00.079 So what's happening? 46:00.079 --> 46:02.179 The question is, what's the source of the 46:02.181 --> 46:04.231 barrier to the cyclohexane ring flip? 46:04.230 --> 46:06.800 So here's the chair cyclohexane, and when the ring 46:06.802 --> 46:08.762 starts to flip -- remember first you go toward a 46:08.764 --> 46:10.634 boat, by bending one of those carbons 46:10.626 --> 46:12.076 up, like that. 46:12.079 --> 46:15.299 Now what do you think the source of the energy is, 46:15.295 --> 46:17.195 that makes this hard to do? 46:17.199 --> 46:19.659 Why do you go to a maximum energy, as you do this, 46:19.664 --> 46:21.884 and then it clicks and it goes down again? 46:21.880 --> 46:25.670 Sherwin? 46:25.670 --> 46:27.540 Student: Torsion. 46:27.539 --> 46:28.629 Prof: Torsion. 46:28.630 --> 46:29.980 Now, that's a good point. 46:29.980 --> 46:34.210 There are, in fact, two bonds, two butanes, 46:34.208 --> 46:36.318 that become eclipsed. 46:36.322 --> 46:37.232 Right? 46:37.230 --> 46:38.370 Both of the ones on the right. 46:38.369 --> 46:43.019 This one is eclipsed, but also this one is eclipsed; 46:43.016 --> 46:44.016 those four. 46:44.018 --> 46:44.838 Right? 46:44.840 --> 46:49.170 And indeed, that's worth about 7 kcal/mol of going uphill. 46:49.170 --> 46:51.160 But there's an interesting point. 46:51.159 --> 46:52.969 You did this with the models -- right? 46:52.969 --> 46:54.009 -- and you felt it click. 46:54.010 --> 46:58.680 How do those models, those plastic models, 46:58.677 --> 47:01.977 know from torsional energy? 47:01.980 --> 47:03.570 Do you see what I mean? 47:03.570 --> 47:06.840 If you take ethane in those models, and spin it, 47:06.835 --> 47:08.845 it spins completely freely. 47:08.849 --> 47:10.029 There's nothing in the model. 47:10.030 --> 47:13.000 You could make it -- you could make the thing that goes into 47:12.996 --> 47:14.386 the tube, and the tube, 47:14.389 --> 47:17.609 a little bit triangular, so that as you tried to twist, 47:17.610 --> 47:20.020 it would go up in energy and then down again. 47:20.016 --> 47:20.506 Right? 47:20.510 --> 47:21.920 Do you see how you could do that in a model? 47:21.920 --> 47:23.100 But that's not the way those are made. 47:23.099 --> 47:24.489 They're cylinders, they rotate freely. 47:24.489 --> 47:27.689 So why did the model click? 47:27.690 --> 47:29.700 Pardon me? 47:29.699 --> 47:30.309 Student: Bending. 47:30.309 --> 47:31.349 Prof: Bending? 47:31.349 --> 47:32.379 Of what? 47:32.380 --> 47:33.210 Student: The bonds. 47:33.210 --> 47:34.710 Prof: Right, exactly. 47:34.713 --> 47:35.553 Look at this. 47:35.550 --> 47:37.840 Why does the plastic model click? 47:37.840 --> 47:40.150 Because when you're halfway across, 47:40.150 --> 47:44.030 it's becoming -- if it were flat, if the whole ring were 47:44.034 --> 47:45.304 flat, what would the 47:45.297 --> 47:49.437 carbon-carbon-carbon angles be, if the ring were flat? 47:49.440 --> 47:50.610 Sam? 47:50.610 --> 47:51.500 Student: I don't know. 47:51.500 --> 47:58.740 Prof: In a regular hexagon, what's the angle? 47:58.739 --> 48:00.159 Dana? 48:00.159 --> 48:03.369 You got to be careful holding your hand up, 48:03.367 --> 48:06.497 even if it's just to scratch your face. 48:06.500 --> 48:10.170 What's the angle in a regular hexagon? 48:10.170 --> 48:11.590 Students: 120. 48:12.920 --> 48:14.130 It wants to be 109. 48:14.130 --> 48:16.380 So it has to stretch out, if it becomes flat. 48:16.380 --> 48:19.190 And even when it becomes only partly flat -- right? 48:19.190 --> 48:22.330 -- this part of it is flat; this one's out of the plane. 48:22.329 --> 48:26.239 But that means in order to have this one in there, 48:26.237 --> 48:28.307 this bond gets compressed. 48:28.311 --> 48:29.031 Right? 48:29.030 --> 48:31.750 Because if these angles want to be 109, instead of 120, 48:31.751 --> 48:33.771 everything -- these are going to move; 48:33.768 --> 48:36.098 this one and this one will move closer together. 48:36.099 --> 48:41.029 So these are -- in this form, when it's half planar, 48:41.030 --> 48:46.350 these angles are bent out, and that angle is bent in. 48:46.349 --> 48:49.549 So it's the angle bending which in fact does it, 48:49.547 --> 48:53.017 does stress those plastic models, which causes it to 48:53.018 --> 48:53.698 click. 48:53.699 --> 48:57.349 So it's interesting to be able to look at models, 48:57.351 --> 49:01.001 or at these calculations of molecules as springs, 49:01.003 --> 49:03.823 and see why various things occur. 49:03.820 --> 49:07.740 So are molecular mechanics programs useful? 49:07.739 --> 49:10.249 Yes, definitely they're useful. 49:10.250 --> 49:11.580 Are they true? 49:11.579 --> 49:13.799 No. 49:13.800 --> 49:16.380 Okay, so we'll go on from there next time. 49:16.380 --> 49:22.000