WEBVTT 00:01.630 --> 00:07.370 Prof: So you remember Pasteur was very fond of racemic 00:07.367 --> 00:09.277 and tartaric acid. 00:09.280 --> 00:13.050 So when he'd travel around he would look for samples of 00:13.052 --> 00:14.172 tartaric acid. 00:14.170 --> 00:18.120 There are very detailed accounts that he published of 00:18.115 --> 00:19.325 these travels. 00:19.330 --> 00:22.980 I haven't found this one, so I'm not sure it's true. 00:22.980 --> 00:25.450 It may be apocryphal, but it was told to me by the 00:25.452 --> 00:27.372 guy who taught me organic chemistry. 00:27.370 --> 00:29.310 So I pass it onto you, for what it's worth, 00:29.305 --> 00:30.775 because it makes a good point. 00:30.780 --> 00:34.220 He said that Pasteur was in Alsace, 00:34.220 --> 00:37.310 the wine-producing region in northeast France, 00:37.310 --> 00:41.500 and in the town of Thann he found in a pharmacy a bottle of 00:41.495 --> 00:43.655 racemic acid that was moldy. 00:43.660 --> 00:47.200 So remember racemic acid's the 50:50 mixture. 00:47.200 --> 00:50.990 So, since he liked racemic acid -- and in fact it was becoming 00:50.985 --> 00:51.415 rare. 00:51.420 --> 00:53.480 It's a not a very common product; 00:53.480 --> 00:55.240 mostly you get the handed stuff. 00:55.240 --> 01:00.440 So he took it back and cleaned it up, got rid of the mold that 01:00.442 --> 01:02.152 was growing on it. 01:02.149 --> 01:06.129 And what he found was that after he had purified it, 01:06.132 --> 01:09.022 it was the unnatural, the left-handed, 01:09.022 --> 01:11.602 not the one you normally get. 01:11.599 --> 01:14.939 Can you see an explanation for that? 01:14.938 --> 01:19.788 Had the apothecary mislabeled it because he thought he could 01:19.793 --> 01:24.403 get a higher price for racemic than for tartaric acid? 01:24.400 --> 01:27.010 Or might he have been innocent? 01:27.010 --> 01:27.820 Zack? 01:27.819 --> 01:28.879 Student: Was it the mold by any chance? 01:28.879 --> 01:30.989 Prof: What did the mold do? 01:30.989 --> 01:32.589 Student: Might have converted one into all. 01:32.590 --> 01:34.830 Prof: Didn't convert. 01:34.830 --> 01:35.830 Student: It didn't? 01:35.830 --> 01:38.530 Prof: The mold ate the natural stuff, 01:38.534 --> 01:41.554 converted it into something completely different, 01:41.553 --> 01:43.443 leaving the unnatural one. 01:43.440 --> 01:45.310 Okay? 01:45.310 --> 01:47.620 Remember the smell of the carvones? 01:47.620 --> 01:49.360 Natural things, enzymes and so on, 01:49.358 --> 01:51.518 can distinguish between the two hands, 01:51.519 --> 01:54.739 and naturally the stuff that normally eats tartaric acid is 01:54.736 --> 01:56.786 going to eat normal tartaric acid, 01:56.790 --> 01:58.040 not the unusual one. 01:58.040 --> 01:59.670 So it left the unusual one. 01:59.670 --> 02:04.180 The penicillium glaucum had eaten the R,R. 02:04.180 --> 02:08.220 Okay, so that's one way of doing resolution, 02:08.218 --> 02:11.978 to get rid of one enantiomer from a racemic mixture, 02:11.979 --> 02:15.159 leaving the other one, because diastereomeric 02:15.157 --> 02:17.537 reactions have different rates. 02:17.538 --> 02:20.478 It's a right hand shaking a right hand versus a right hand 02:20.476 --> 02:22.026 shaking a left hand; they're just different. 02:22.030 --> 02:24.280 So one will go faster than the other. 02:24.280 --> 02:28.400 So if you react a racemate with some chiral reagent -- 02:28.400 --> 02:31.080 of course you have to use only one hand of that other thing you 02:31.084 --> 02:33.304 add in there -- but then you'll react with one 02:33.295 --> 02:34.325 more than the other. 02:34.330 --> 02:37.510 It could be even a catalyst so that it doesn't get consumed; 02:37.509 --> 02:39.269 an enzyme, for example. 02:39.270 --> 02:42.410 But that's not Nature's way, because it's very inefficient 02:42.407 --> 02:44.387 to make both and then destroy one. 02:44.389 --> 02:48.319 What nature does is prepare only one enantiomer. 02:48.318 --> 02:50.408 And you can do that, prepare only one, 02:50.414 --> 02:53.194 by starting with something that's already a single 02:53.190 --> 02:55.230 enantiomer and building on that. 02:55.229 --> 02:58.899 Or you can use a reagent, which is resolved, 02:58.900 --> 03:02.010 that will -- because diastereomeric rates are 03:02.009 --> 03:05.619 different -- will tend to produce one of the 03:05.622 --> 03:07.062 two enantiomers. 03:07.060 --> 03:10.790 So here's an example of this molecule we've been talking 03:10.788 --> 03:13.498 about, Eisai-7389, with its nineteen 03:13.498 --> 03:16.618 asymmetric centers, that's made artificially, 03:16.622 --> 03:17.522 commercially. 03:17.520 --> 03:21.070 And this is where those nineteen centers came from. 03:21.068 --> 03:24.878 Five of them came from starting materials that they bought as a 03:24.878 --> 03:25.738 single hand. 03:25.740 --> 03:27.770 But the rest were all made. 03:27.770 --> 03:30.350 One of them was done by chromatography. 03:30.348 --> 03:33.888 They have chromatography columns about this big around, 03:33.888 --> 03:36.638 and this high, with chiral stuff inside. 03:36.639 --> 03:38.499 So you pass your thing through. 03:38.500 --> 03:41.540 One hand goes through a little faster than the other, 03:41.541 --> 03:45.111 because of its diastereomeric interaction with the packing; 03:45.110 --> 03:46.510 one comes through quicker. 03:46.508 --> 03:48.928 And they actually do that for one of the centers. 03:48.930 --> 03:52.540 But the others are all done by reactions that preferentially 03:52.541 --> 03:54.991 give one center rather than the other. 03:54.990 --> 03:58.320 Three of them are ones that everybody knew which one they 03:58.324 --> 03:59.104 would give. 03:59.098 --> 04:02.268 The other ones they just had to hope, and fiddle around with 04:02.270 --> 04:05.330 different reactions until they found one that would do the 04:05.331 --> 04:05.871 trick. 04:05.870 --> 04:09.070 So anyhow, they were able to generate these nineteen 04:09.074 --> 04:10.084 stereocenters. 04:10.080 --> 04:13.350 Now we're left with a problem. 04:13.348 --> 04:17.088 That incidentally is all we're going to have for the exam on 04:17.089 --> 04:17.659 Friday. 04:17.660 --> 04:18.260 Okay? 04:18.259 --> 04:20.979 So now we're on to other stuff that will be covered on the 04:20.980 --> 04:23.750 final exam, and in particular return to this question about 04:23.750 --> 04:24.850 the tartaric acids. 04:24.850 --> 04:28.440 Remember there's d-(+) and l-(-). 04:28.439 --> 04:31.979 Could you have l-(+) and d-(-), 04:31.978 --> 04:34.068 of a different compound? 04:34.069 --> 04:36.629 Why not? 04:36.629 --> 04:40.219 What does d or l mean, in this context? 04:40.220 --> 04:44.790 Student: >. 04:44.790 --> 04:45.820 Prof: Andrew? 04:45.819 --> 04:47.679 Student: It reflects light to the left. 04:47.680 --> 04:49.600 Prof: It means which way it rotates the light. 04:49.600 --> 04:51.160 Right? 04:51.160 --> 04:53.790 And the plus means the same thing, as d. 04:53.790 --> 04:56.670 So it's redundant, this particular nomenclature. 04:56.670 --> 04:59.470 But there's a question mark because when -- Fischer just 04:59.471 --> 05:00.491 guessed, remember? 05:00.490 --> 05:02.570 And it could easily have been the opposite. 05:02.569 --> 05:04.119 So which way is it? 05:04.120 --> 05:05.130 Right? 05:05.129 --> 05:08.169 So if we knew, if we knew how optical activity 05:08.173 --> 05:12.303 worked, then by measuring the optical activity we'd know which 05:12.298 --> 05:14.528 of those structures is right. 05:14.529 --> 05:16.249 Okay? 05:16.250 --> 05:19.250 But we don't know that; at least I don't know that. 05:19.250 --> 05:23.150 Now there's a lot of knowledge about this, but it's a very, 05:23.148 --> 05:24.558 very tough problem. 05:24.560 --> 05:27.710 Fortunately there's a book by Laurence Barron called 05:27.706 --> 05:31.036 Molecular Light Scattering and Optical Activity, 05:31.036 --> 05:32.946 which goes into this stuff. 05:32.949 --> 05:35.949 And I see Professor Vaccaro -- Prof: I'm here. 05:35.949 --> 05:37.589 Prof: Oh, so we have a copy of the book. 05:37.589 --> 05:38.539 That's great. 05:38.540 --> 05:42.910 But even better than that, we have Laurence Barron. 05:42.910 --> 05:44.880 Prof: Or a copy of Laurence Barron. 05:44.879 --> 05:46.099 Prof: Or a copy of Laurence Barron. 05:46.100 --> 05:46.690 > 05:46.690 --> 05:48.440 Perhaps it's the mirror image of Laurence Barron. 05:48.440 --> 05:51.600 So he's going to tell us how this works. 05:51.600 --> 06:09.910 <> 06:09.910 --> 06:11.620 Prof: Well good morning everybody. 06:11.620 --> 06:15.860 I was both delighted and dismayed, at the same time, 06:15.858 --> 06:20.838 when Professor McBride asked me to try and -- well to address 06:20.843 --> 06:22.593 you this morning. 06:22.589 --> 06:26.069 Delighted to have the opportunity to talk science to 06:26.069 --> 06:29.889 some of America's brightest budding young scientists, 06:29.889 --> 06:33.879 but also dismayed that he asked me to try and explain the 06:33.884 --> 06:36.744 molecular origin of optical rotation, 06:36.740 --> 06:38.080 optical activity. 06:38.079 --> 06:41.029 It's a very subtle, difficult, delicate problem, 06:41.028 --> 06:44.478 that's exercised some of the finest minds in physics and 06:44.478 --> 06:47.048 chemistry for the last hundred years. 06:47.050 --> 06:49.620 But anyway, let's see how it goes. 06:49.620 --> 06:52.960 Towards the end I think I may be presenting some stuff that's 06:52.964 --> 06:56.204 sort of beyond the boundaries of your current knowledge. 06:56.199 --> 06:59.669 But anyway, it can at least pass in front of your eyes. 06:59.670 --> 07:03.820 So chirality then means, as you well know, 07:03.817 --> 07:06.647 right- or left-handedness. 07:06.649 --> 07:09.809 It pervades much of modern science; 07:09.810 --> 07:13.510 from the physics of elementary particles, through organic 07:13.514 --> 07:16.494 stereochemistry, to the structure and behavior 07:16.490 --> 07:20.820 of the molecules of life; with a lot more besides. 07:20.819 --> 07:23.689 It comes up in what's called nonlinear optics, 07:23.687 --> 07:26.707 involving intense lasers; nanotechnology; 07:26.709 --> 07:28.249 materials, electrical engineering; 07:28.250 --> 07:30.940 pharmaceuticals; astrobiology; 07:30.935 --> 07:32.875 and origin of life. 07:32.879 --> 07:38.189 So it's a very important theme in modern science. 07:38.190 --> 07:42.250 Now first of all though I'll tell you a little bit about Lord 07:42.250 --> 07:42.860 Kelvin. 07:42.860 --> 07:45.780 He was the first person to introduce the word 07:45.776 --> 07:47.896 chirality into science. 07:47.899 --> 07:52.609 He was professor of natural philosophy in Glasgow -- which 07:52.608 --> 07:57.068 is my home university -- through most of his career; 07:57.069 --> 07:58.459 well all of his career. 07:58.459 --> 08:01.909 He was one of the giants of physics of the nineteenth 08:01.906 --> 08:02.566 century. 08:02.569 --> 08:08.589 He's best known for inventing the absolute Kelvin temperature 08:08.586 --> 08:09.386 scale. 08:09.389 --> 08:13.129 Now he was originally, his original name was William 08:13.134 --> 08:17.254 Thomson, but then he became famous and became Sir William 08:17.247 --> 08:18.127 Thomson. 08:18.129 --> 08:22.209 Then he became even more famous, so they made him a Lord. 08:22.209 --> 08:25.639 And when you're made a Lord in the U.K., you choose your title 08:25.641 --> 08:28.791 from someplace that's dear to your heart, maybe your home 08:28.793 --> 08:29.303 area. 08:29.300 --> 08:32.720 He took his title from the name of the River Kelvin, 08:32.716 --> 08:36.196 which runs through the University Park in Glasgow. 08:36.200 --> 08:39.450 So whenever you use the absolute temperature scale now 08:39.450 --> 08:42.030 in the future, you can picture this idyllic 08:42.025 --> 08:42.635 scene. 08:42.639 --> 08:45.869 Anyway, so he was the first to introduce the word 08:45.868 --> 08:48.018 chirality into science. 08:48.019 --> 08:50.929 And here's his definition, which you'll be familiar with: 08:50.932 --> 08:53.692 "I call any geometrical figure or group of points 08:53.691 --> 08:56.471 chiral, and say that it has chirality 08:56.466 --> 08:59.316 if its image in a plane mirror, ideally realized, 08:59.317 --> 09:01.917 cannot be brought into coincidence with itself." 09:01.918 --> 09:04.128 That was in his Baltimore Lectures. 09:04.129 --> 09:07.739 So he's just emphasizing the non-superimposabity of the 09:07.743 --> 09:10.423 mirror image, the enantiomers of a chiral 09:10.419 --> 09:11.289 molecule. 09:11.288 --> 09:15.118 But of course the whole subject started earlier with the 09:15.115 --> 09:19.955 wonderful work of Louis Pasteur, who showed mirror-image chiral 09:19.957 --> 09:24.937 molecules show optical rotation of equal magnitude but opposite 09:24.937 --> 09:28.077 sign; which was an epoch-making 09:28.080 --> 09:29.180 discovery. 09:29.178 --> 09:32.998 So you've come across then this, the fundamental 09:32.999 --> 09:37.059 manifestation of optical activity, which is natural 09:37.062 --> 09:38.772 optical rotation. 09:38.769 --> 09:43.119 You put linearly polarized light beam into a sample -- 09:43.120 --> 09:47.840 say a sample of an isotropic collection of chiral molecules, 09:47.840 --> 09:51.000 like a sugar solution -- and it will come out the other side 09:50.998 --> 09:54.208 with the plane of polarization rotated through some angle. 09:54.210 --> 09:56.680 And if you put in the mirror image version, 09:56.681 --> 09:59.501 you'll get an equal but opposite sense of optical 09:59.504 --> 10:00.274 rotation. 10:00.269 --> 10:04.339 Now it's not to be confused with something called magnetic 10:04.336 --> 10:07.116 optical rotation, the Faraday effect. 10:07.120 --> 10:08.790 I'm just mentioning this to you. 10:08.788 --> 10:12.118 You probably haven't come across the Faraday effect yet, 10:12.120 --> 10:15.930 but you may do later on in your studies, or in your professional 10:15.934 --> 10:16.484 life. 10:16.480 --> 10:18.420 So I'll mention the Faraday effect. 10:18.418 --> 10:23.038 Faraday discovered, in 1846, that achiral samples 10:23.043 --> 10:26.963 -- no natural optical activity 10:26.955 --> 10:30.215 there -- if you apply a static magnetic 10:30.221 --> 10:32.561 field, parallel to the light beam, 10:32.562 --> 10:35.072 that will induce an optical rotation. 10:35.070 --> 10:38.750 And if you put in -- if you reverse the direction of the 10:38.754 --> 10:41.404 magnetic field, relative to the light beam, 10:41.403 --> 10:43.973 you'll get an equal and opposite sense of optical 10:43.967 --> 10:44.607 rotation. 10:44.610 --> 10:48.260 It would even work say for a sample of water, 10:48.255 --> 10:49.495 for instance. 10:49.500 --> 10:52.420 Any material will show a Faraday effect. 10:52.418 --> 10:56.638 But this has been a source of much confusion, 10:56.640 --> 10:59.040 in fact, to scientists. 10:59.038 --> 11:02.498 Now Lord Kelvin was on the ball here. 11:02.500 --> 11:03.550 He knew all about it. 11:03.549 --> 11:05.219 He made a statement here. 11:05.220 --> 11:07.760 He said, "The magnetic rotation has neither 11:07.764 --> 11:10.204 right-handed nor left-handed quality." 11:10.200 --> 11:14.340 (That is to say no chirality; it's got nothing to do with 11:14.336 --> 11:15.136 chirality.) 11:15.139 --> 11:17.759 "This was perfectly understood by Faraday and made 11:17.764 --> 11:21.044 clear in his writings, yet even to the present day we 11:21.042 --> 11:24.552 frequently find the chiral rotation and the magnetic 11:24.548 --> 11:28.398 rotation of the plane of polarization classed together in 11:28.399 --> 11:32.589 a manner against which Faraday's original description contains 11:32.592 --> 11:34.452 ample warning." 11:34.450 --> 11:37.590 Well Lord Kelvin would be turning in his grave today, 11:37.590 --> 11:40.800 100 years later, because you still see papers 11:40.796 --> 11:43.416 which involve the Faraday effect, 11:43.418 --> 11:46.278 in some way or other, and in the introduction they 11:46.278 --> 11:49.488 talk grandly of "inducing chirality with a magnetic 11:49.485 --> 11:50.415 field." 11:50.419 --> 11:52.409 That is completely wrong. 11:52.408 --> 11:58.358 Just for the record -- probably beyond your knowledge at the 11:58.360 --> 12:00.400 moment -- chiral phenomena, 12:00.399 --> 12:04.069 like natural optical rotation, they're characterized by what's 12:04.071 --> 12:07.171 called time-even pseudoscalar observables. 12:07.168 --> 12:12.078 A pseudoscalar is a number that changes sign under reflection or 12:12.075 --> 12:14.915 inversion; we'll leave it at that. 12:14.919 --> 12:16.669 So that's for the record. 12:16.668 --> 12:20.138 But well it turns out the essential symmetry 12:20.144 --> 12:24.914 characteristics of natural and magnetic optical rotation are 12:24.912 --> 12:29.032 completely different and you need different sorts of 12:29.033 --> 12:33.103 molecular quantum states, different characteristics to 12:33.100 --> 12:33.840 support them. 12:33.840 --> 12:36.110 But we won't pursue that. 12:36.110 --> 12:41.050 Right, now back to natural optical rotation. 12:41.048 --> 12:46.718 So now we bring in circularly polarized light. 12:46.720 --> 12:51.140 So in order to detect molecular chirality, you must have some 12:51.135 --> 12:52.825 sort of chiral probe. 12:52.830 --> 12:58.360 Well what we're using here is right and left-circularly 12:58.360 --> 13:00.820 polarized light beams. 13:00.820 --> 13:04.030 They are actually mirror-image chiral systems. 13:04.028 --> 13:07.248 So they can be used as chiral probes. 13:07.250 --> 13:12.070 So here's a representation of a right-circularly polarized light 13:12.065 --> 13:12.595 beam. 13:12.600 --> 13:17.740 Now you know that light involves electromagnetic 13:17.736 --> 13:22.866 oscillations in space, and usually you just think of 13:22.870 --> 13:27.010 the oscillating electric vector of a light wave, 13:27.009 --> 13:30.929 and if it's linearly polarized, it's oscillating in one plane. 13:30.928 --> 13:34.328 There's actually also an oscillating magnetic field 13:34.333 --> 13:38.083 vector that oscillates perpendicular to the electric. 13:38.080 --> 13:39.570 We'll come back to that later. 13:39.570 --> 13:42.450 We're just looking at the oscillating electric vector 13:42.452 --> 13:42.842 here. 13:42.840 --> 13:45.840 So if it's linearly polarized, or plane polarized, 13:45.844 --> 13:47.994 it's just oscillating in a plane; 13:47.990 --> 13:52.690 but circularly polarized light, as well as an oscillation in 13:52.686 --> 13:54.036 this direction. 13:54.038 --> 13:59.298 You also have an electric vector oscillating perpendicular 14:01.798 --> 14:09.088 And what happens is you get this circular polarization. 14:09.090 --> 14:11.900 Now this picture here, this represents the 14:11.899 --> 14:16.219 instantaneous electric vectors at different points in space, 14:16.220 --> 14:19.680 in the direction of propagation, along the z 14:19.678 --> 14:20.508 direction. 14:20.509 --> 14:23.989 And so here we are, that's just showing -- that's 14:23.994 --> 14:28.644 just connected the ends of the instantaneous electric vectors. 14:28.639 --> 14:31.769 And there it is for left-circularly polarized. 14:31.769 --> 14:35.819 Anyway, you can see that at the very least those are chiral, 14:35.817 --> 14:38.837 those are helical, and those are mirror-image 14:38.836 --> 14:40.136 chiral systems. 14:40.139 --> 14:43.039 Now here we go. 14:43.038 --> 14:46.788 This is some extra fancy stuff that Professor McBride added to 14:46.787 --> 14:48.447 my > 14:48.446 --> 14:49.426 presentation. 14:49.428 --> 14:52.708 He doesn't like -- it was too simple and static. 14:52.710 --> 14:55.280 Anyway, so there we are. 14:55.279 --> 15:00.689 So now if you look at the wave, if you just look at the 15:00.692 --> 15:04.502 electric vector through -- in a fixed plane, 15:04.500 --> 15:06.560 as the light wave is propagating, 15:06.558 --> 15:10.878 there's the electric vector, and it will rotate in the fixed 15:10.883 --> 15:11.473 plane. 15:11.470 --> 15:14.800 So rotating clockwise, that defines right-circularly 15:14.802 --> 15:15.982 polarized light. 15:15.980 --> 15:23.900 And here we go, rotating counter-clockwise; 15:23.899 --> 15:26.239 that's left-circularly polarized light. 15:26.240 --> 15:30.600 Okay, so we now have a chiral optical probe, 15:30.599 --> 15:33.539 circularly polarized light. 15:33.538 --> 15:37.188 Now chiral molecules respond slightly differently to right 15:37.192 --> 15:39.632 and left-circularly polarized light. 15:39.629 --> 15:45.319 I mean, an extreme example is say in the world of engineering. 15:45.320 --> 15:51.300 You can't fit a left-handed nut onto a right-handed bolt. 15:51.298 --> 15:58.018 That's an extreme example of different chiral interactions. 15:58.019 --> 16:01.519 Well it's obviously much more delicate than that here. 16:01.519 --> 16:05.239 But the point is right and left-circularly polarized light 16:05.235 --> 16:08.755 interact just slightly differently with a molecule of a 16:08.755 --> 16:10.055 given chirality. 16:10.058 --> 16:13.668 Anyway, there's a differential absorption of right and 16:13.666 --> 16:15.976 left-circularly polarized light. 16:15.980 --> 16:19.060 That corresponds to a phenomenon called circular 16:19.057 --> 16:22.527 dichroism, which is the basis of a widely used form of 16:22.527 --> 16:25.667 spectroscopy used to study chiral molecules. 16:25.668 --> 16:30.348 But now, what gives rise to optical rotation is a difference 16:30.347 --> 16:34.947 in refractive index towards -- of right and left-circularly 16:34.947 --> 16:37.007 polarized light beams. 16:37.009 --> 16:42.809 16:42.808 --> 16:46.198 Now linearly polarized light, you can describe it as a 16:46.195 --> 16:50.025 coherent superposition of right and left-circularly polarized 16:50.027 --> 16:51.877 waves of equal amplitude. 16:51.879 --> 16:54.929 Coherent means they're in-phase with each other. 16:54.928 --> 16:58.958 Rather than being random, they're oscillating in-phase 16:58.962 --> 17:01.782 with some fixed phase relationship. 17:01.778 --> 17:06.378 So, for example, now here's a linearly polarized 17:06.384 --> 17:07.664 light beam. 17:07.660 --> 17:12.900 But you can decompose it into a superposition of a left-circular 17:12.895 --> 17:15.635 and a right-circular component. 17:15.640 --> 17:19.960 You see when those are at the top they're reinforcing, 17:19.957 --> 17:24.357 and you've got the maximum linearly polarized vector up 17:24.355 --> 17:25.085 here. 17:25.088 --> 17:27.288 As they come away, left and right, 17:27.287 --> 17:31.547 they will tend to increasingly cancel, and that will decrease. 17:31.548 --> 17:35.678 And when they're this way and this way, you'll have zero 17:35.682 --> 17:39.892 electric field vector there, and as you come down it will 17:39.892 --> 17:41.322 increase again. 17:41.318 --> 17:46.938 So you can decompose a linearly polarized light into a coherent 17:46.935 --> 17:50.555 superposition of left and right waves. 17:50.558 --> 17:57.788 Now, refractive index corresponds to velocity through 17:57.789 --> 17:59.319 a medium. 17:59.318 --> 18:03.888 So if there's a difference in refractive index for right and 18:03.892 --> 18:07.072 left-circularly polarized light beams, 18:07.068 --> 18:10.088 that means there's a slight difference in the velocity of 18:10.085 --> 18:13.095 the right and left-circularly polarized light beams going 18:13.101 --> 18:14.341 through the medium. 18:14.338 --> 18:18.478 So the phase relations between the two contrarotating electric 18:18.477 --> 18:19.967 vectors will change. 18:19.970 --> 18:23.680 And you can easily see, this will give you a rotation 18:23.678 --> 18:25.888 in the plane of polarization. 18:25.890 --> 18:28.480 You see, if there's a difference in velocity, 18:28.480 --> 18:32.080 then at some instant this vector, this electric vectors of 18:32.078 --> 18:36.148 the left component will be here, and the right component here. 18:36.150 --> 18:41.140 And if you take the resultant, you see, it's no longer where 18:41.137 --> 18:41.897 it was. 18:41.900 --> 18:46.460 So this is a simple picture of how optical rotation develops, 18:46.457 --> 18:50.407 in terms of different refractive indices of the right 18:50.406 --> 18:52.226 and left components. 18:52.230 --> 18:55.980 Now there's a picture in Atkins' Physical 18:55.982 --> 18:57.382 Chemistry. 18:57.380 --> 18:59.520 He tries to illustrate this there. 18:59.519 --> 19:01.669 He's got the linearly polarized beam coming through, 19:01.670 --> 19:04.960 and you've got the -- he's broken it down into the left and 19:04.959 --> 19:06.909 right, and he's saying the two 19:06.907 --> 19:09.157 velocities are slightly different, 19:09.160 --> 19:12.000 and that gives you the resultant optical rotation. 19:12.000 --> 19:15.980 You can easily develop an expression for the angle of 19:15.978 --> 19:20.638 rotation as a function of the difference in refractive indices 19:20.644 --> 19:24.934 for left and right-circularly polarized light beams. 19:24.930 --> 19:27.290 And it's also -- it's a function of the path length. 19:27.288 --> 19:31.628 Obviously the longer the path length, the more rotation will 19:31.625 --> 19:32.355 develop. 19:32.358 --> 19:36.998 And there's the wavelength there in the denominator. 19:37.000 --> 19:39.390 In fact, I mean, this is the secret; 19:39.390 --> 19:41.860 this path length, that's the secret of how you 19:41.861 --> 19:43.401 get a measurable rotation. 19:43.400 --> 19:46.130 Because this is an incredibly tiny effect. 19:46.130 --> 19:49.120 If it was just a single molecule event you're looking 19:49.123 --> 19:52.293 at, the polarization changes, you wouldn't see anything, 19:52.288 --> 19:53.438 they're so tiny. 19:53.440 --> 19:57.620 But you can build up this rotation over long path lengths, 19:57.615 --> 19:59.735 centimeters or even meters. 19:59.740 --> 20:05.980 In fact, if you go to Google, Google Images, 20:05.980 --> 20:09.750 and just Google 'circularly polarized light,' you'll find 20:09.747 --> 20:13.377 lots of sites there which describe polarized light, 20:13.380 --> 20:16.160 and they provide beautiful simulations, 20:16.160 --> 20:20.640 animations of this effect here. 20:20.640 --> 20:24.580 I didn't want to download any and try and show them here, 20:24.582 --> 20:27.542 but I would encourage you to go to that. 20:27.538 --> 20:31.738 But go and look in particular at this site here, 20:31.737 --> 20:32.717 enzim.hu. 20:32.720 --> 20:37.250 That comes from an institute of enzymology in Budapest. 20:37.250 --> 20:41.110 They've got some beautiful simulations of this optical 20:41.105 --> 20:45.685 rotation process and other more exotic polarization effects, 20:45.690 --> 20:48.690 as light propagates through matter. 20:48.690 --> 20:54.560 Now, let's try and -- so that's just, what would you say, 20:54.559 --> 20:58.019 a phenomenological description. 20:58.019 --> 21:01.929 And in fact that's where most physical chemistry textbooks 21:01.929 --> 21:02.409 stop. 21:02.410 --> 21:05.220 And in fact Atkins' Physical Chemistry stops at that 21:05.222 --> 21:07.962 point, and then just there's just sort 21:07.959 --> 21:11.579 of hand waving saying okay, right and left-circularly 21:11.578 --> 21:14.748 polarized light interacts slightly differently with the 21:14.752 --> 21:17.322 chiral molecule; and they leave it at that. 21:17.318 --> 21:20.958 They don't attempt to try and give you a picture in molecular 21:20.962 --> 21:21.512 detail. 21:21.509 --> 21:26.179 But Professor McBride wanted me to try and attempt this. 21:26.180 --> 21:29.970 So just as a start, this is a simple picture, 21:29.971 --> 21:34.281 a simple scattering picture of optical rotation. 21:34.279 --> 21:39.079 Now a circularly polarized light wave 'bouncing' from one 21:39.075 --> 21:43.125 group to the other, as it scatters from a simple 21:43.125 --> 21:47.265 two-group chiral structure, will sample the chirality. 21:47.269 --> 21:50.919 So here we have a simple two-group chiral molecular 21:50.923 --> 21:51.803 structure. 21:51.798 --> 21:54.818 So we've got two achiral groups, held in a rigid, 21:54.824 --> 21:56.214 twisted arrangement. 21:56.210 --> 21:59.080 I think that's left-handed I've got there. 21:59.078 --> 22:02.208 And you can break down -- if you look at most chiral 22:02.212 --> 22:05.782 molecules, just look at the bonds, you can often break them 22:05.777 --> 22:06.327 down. 22:06.328 --> 22:12.078 You can see these sorts of two-group structures throughout. 22:12.078 --> 22:18.548 Anyway, so a particular model of optical rotation is that the 22:18.549 --> 22:21.639 light wave, it bounces from one group to 22:21.642 --> 22:24.442 the other, before coming off and getting 22:24.438 --> 22:28.528 involved in generating the optical rotation phenomenon. 22:28.528 --> 22:31.848 But you can see, it's sampling the chirality as 22:31.846 --> 22:34.366 it bounces from one to the other. 22:34.368 --> 22:38.048 So if the light beam is right-circularly polarized, 22:38.048 --> 22:42.988 that bouncing process will have a slightly different amplitude, 22:42.990 --> 22:46.420 as we say, from if it's left-circularly polarized. 22:46.420 --> 22:48.570 So that gives you a simple picture. 22:48.568 --> 22:52.618 It's worth mentioning that this is the basis of something called 22:52.615 --> 22:56.275 the "dynamic coupling model of optical activity" 22:56.278 --> 22:59.938 that was developed by somebody called John Kirkwood, 22:59.940 --> 23:03.590 who was chairman of this department in the 1950s. 23:03.588 --> 23:09.558 Well now we really have to > 23:09.557 --> 23:14.687 , we have to grasp the nettle at this point, 23:14.690 --> 23:20.900 because you just -- it's hopeless messing around with 23:20.895 --> 23:23.995 these simple models. 23:24.000 --> 23:25.080 > 23:25.078 --> 23:29.508 They don't get you anywhere as regards prediction; 23:29.509 --> 23:35.539 you know, relating structure to sign and magnitude of optical 23:35.542 --> 23:36.652 activity. 23:36.650 --> 23:38.770 You have to go to the quantum-mechanics. 23:38.769 --> 23:42.109 So now this was the expression for the optical rotation, 23:42.114 --> 23:45.464 in terms of the refractive index difference for left and 23:45.459 --> 23:47.709 right-circularly polarized light. 23:47.710 --> 23:51.360 Now you can develop this using something called 23:51.363 --> 23:54.703 quantum-mechanical perturbation theory, 23:54.700 --> 24:00.020 and you develop an expression for the rotation angle in terms 24:00.016 --> 24:03.646 of this incomprehensible looking stuff. 24:03.650 --> 24:09.530 But let me just try and give you a feel for what it's telling 24:09.528 --> 24:10.018 us. 24:10.019 --> 24:14.799 The heart of it is this so-called rotational strength, 24:14.798 --> 24:19.388 which involves this so-called scalar product of an electric 24:19.391 --> 24:23.271 dipole and a magnetic dipole transition moment. 24:23.269 --> 24:27.169 So what we've got here is there's the ground state of the 24:27.165 --> 24:30.085 molecule n; j is some excited 24:30.087 --> 24:33.547 electronic state; and μ is the electric 24:33.548 --> 24:36.768 dipole operator that's connecting the ground to the 24:36.772 --> 24:37.872 excited state. 24:37.868 --> 24:41.458 And the light wave is interacting, is coupling with 24:41.455 --> 24:45.035 this electric dipole operator, and it's driving the 24:45.042 --> 24:46.122 transition. 24:46.118 --> 24:49.448 And it's this -- these electric dipole transitions, 24:49.453 --> 24:52.993 like this, that's behind conventional spectroscopy. 24:52.990 --> 24:57.600 You've done probably UV and infrared spectroscopy. 24:57.598 --> 25:02.108 But now what we have in addition is the same transition, 25:02.107 --> 25:05.467 but now brought about through m; 25:05.470 --> 25:09.710 that's called a magnetic dipole operator, and that's activated 25:09.713 --> 25:13.823 by this oscillating magnetic component of the light wave. 25:13.818 --> 25:19.418 And so you have this so-called scalar product. 25:19.420 --> 25:24.660 So μ•m, that would be μ_xm_x + 25:24.660 --> 25:26.990 μ_ym_y + μ_zn_z. 25:26.990 --> 25:29.110 Some of you have probably done vectors. 25:29.109 --> 25:30.689 Maybe others haven't. 25:30.690 --> 25:31.970 But okay. 25:31.970 --> 25:33.850 So that's the heart of it. 25:33.848 --> 25:36.588 But this is a very important feature here. 25:36.588 --> 25:39.838 We're summing over all excited states, j, 25:39.837 --> 25:41.287 all excited states. 25:41.288 --> 25:45.838 So the whole plethora of excited states of a chiral 25:45.843 --> 25:49.923 molecule come in here, and some can give you -- one 25:49.915 --> 25:53.765 particular excited state can give you a positive contribution 25:53.767 --> 25:56.707 to the optical rotation; another one a negative. 25:56.710 --> 25:57.620 You know? 25:57.618 --> 26:02.548 So it's a very subtle problem, and you have to consider them 26:02.551 --> 26:03.891 all carefully. 26:03.890 --> 26:08.150 So optical activity ultimately originates in interference 26:08.145 --> 26:12.555 between electric and magnetic dipole transitions during the 26:12.555 --> 26:14.755 light scattering process. 26:14.759 --> 26:17.159 That's at the heart of it. 26:17.160 --> 26:20.510 26:20.509 --> 26:23.819 Now, let me just show you how this works out. 26:23.818 --> 26:28.048 I can now give you a chemical, an interpretation, 26:28.053 --> 26:32.993 in terms of a real and highly important system in organic 26:32.991 --> 26:36.521 chemistry: the carbonyl chromophore. 26:36.519 --> 26:39.439 I believe you have come across the carbonyl chromophore. 26:39.440 --> 26:43.270 A lot of important organic molecules contain this carbonyl 26:43.269 --> 26:44.209 chromophore. 26:44.210 --> 26:49.950 It gives rise to a transition in the near ultraviolet at about 26:49.952 --> 26:53.532 290 nanometers, and it's widely used in 26:53.530 --> 26:56.450 physical organic chemistry. 26:56.450 --> 27:02.210 It's called the n to π* transition. 27:02.210 --> 27:07.080 Now the carbonyl group itself -- here it is -- that's not 27:07.076 --> 27:10.636 chiral, that's got a plane of symmetry. 27:10.640 --> 27:14.350 So by itself it's not going -- there's going to be no optical 27:14.348 --> 27:15.398 activity there. 27:15.400 --> 27:18.550 But you see, in this particular molecule 27:18.546 --> 27:22.736 here, 3-methylcyclohexanone, that molecule overall is 27:22.741 --> 27:23.631 chiral. 27:23.630 --> 27:25.440 There's a chiral center there. 27:25.440 --> 27:29.800 So that carbonyl group is experiencing a chiral 27:29.795 --> 27:32.845 perturbation, a through space perturbation 27:32.846 --> 27:34.986 from the rest of the chiral molecule, 27:34.990 --> 27:39.640 and that induces chirality into the electronic transitions of 27:39.635 --> 27:43.695 the carbonyl group, and induces optical rotation 27:43.698 --> 27:45.718 and circular dichroism. 27:45.720 --> 27:48.840 Well let's look at this in a bit more detail, 27:48.836 --> 27:52.376 this famous n to π* transition. 27:52.380 --> 27:56.470 So here we've got the σ bonding orbital 27:56.472 --> 27:58.402 of the carbonyl group. 27:58.400 --> 28:03.750 There's the π bonding orbital, made up of two -- of 28:03.752 --> 28:07.592 the pπ on carbon and on oxygen. 28:07.588 --> 28:14.868 And here is a lone -- sorry, here is a py orbital. 28:14.869 --> 28:17.079 So those are px orbitals. 28:17.078 --> 28:20.368 That's the py orbital on the oxygen. 28:20.368 --> 28:22.948 Feed electrons in, and so you've got, 28:22.949 --> 28:25.889 in the ground state, you've got two there, 28:25.885 --> 28:26.885 two there. 28:26.890 --> 28:29.420 And you've got two electrons in the py orbital. 28:29.420 --> 28:31.380 So those are lone-pair electrons. 28:31.380 --> 28:36.030 So the lowest order, the lowest transition now is 28:36.025 --> 28:40.655 the py to π*, often called the n to 28:40.662 --> 28:41.952 π* transition. 28:41.950 --> 28:45.640 You're promoting one electron from the py orbital up to 28:45.636 --> 28:51.286 the π* orbital; and that's the origin of this 28:51.287 --> 28:52.947 transition. 28:52.950 --> 28:58.620 Well let's -- ah now. 28:58.618 --> 29:03.168 Okay, now this transition, it happens to be fully magnetic 29:03.170 --> 29:07.800 dipole-allowed but completely electric dipole-forbidden. 29:07.798 --> 29:13.568 What happens is electric dipole character is induced by mixing 29:13.570 --> 29:16.100 -- well I'm giving the example of 29:16.099 --> 29:19.899 a higher oxygen dyz_ orbital into the 29:19.898 --> 29:21.618 π* orbital. 29:21.618 --> 29:25.408 Now Professor McBride has been messing around with my 29:25.411 --> 29:26.871 presentation here. 29:26.869 --> 29:28.259 Let's see what he's done. 29:28.259 --> 29:35.429 So here's the n orbital, the py orbital of the 29:35.432 --> 29:37.502 carbonyl group. 29:37.500 --> 29:40.310 There's the π*. 29:40.309 --> 29:43.639 Ah, now here we go. 29:43.640 --> 29:49.750 So this is now -- but wait -- yeah, 29:49.750 --> 29:52.740 so here you can see, in that n to 29:52.740 --> 29:56.840 π* transition, there's a net rotation of 29:56.836 --> 29:59.266 charge, a rotation of charge. 29:59.269 --> 30:03.779 And that's the essence of the magnetic dipole-allowed 30:03.778 --> 30:04.818 character. 30:04.818 --> 30:09.188 Magnetic dipole transitions involve a rotation of charge. 30:09.190 --> 30:12.080 Prof: And the reason we messed about with them in this 30:12.083 --> 30:14.883 way is we've seen the mixing p orbitals changing the 30:14.880 --> 30:17.670 orientation, causing them to rotate that way. 30:17.670 --> 30:19.020 Prof: Right. 30:19.019 --> 30:24.319 So what's -- ah okay, now here we go again. 30:24.319 --> 30:27.229 Now here's a dyz orbital. 30:27.230 --> 30:31.380 Now one could consider a whole loads of other possible orbitals 30:31.384 --> 30:32.194 to mix in. 30:32.190 --> 30:36.140 But this is the simplest one, just to illustrate the idea 30:36.144 --> 30:36.644 here. 30:36.640 --> 30:39.030 So there's a dyz orbital. 30:39.029 --> 30:45.889 Now going from -- you see n to dyz, 30:45.890 --> 30:49.320 if you add those orbitals together, 30:49.318 --> 30:57.558 you tend to get a displacement of charge in the z 30:57.560 --> 30:59.360 direction. 30:59.358 --> 31:03.248 So now, you see, you have a combination of a 31:03.250 --> 31:07.600 rotation of charge with a displacement of charge, 31:07.595 --> 31:12.025 and rotation plus translation gives helicity. 31:12.029 --> 31:16.479 And here we go. 31:16.480 --> 31:18.000 There. 31:18.000 --> 31:23.260 So by mixing in a little bit of this dxz orbital, 31:23.256 --> 31:28.416 you get this -- which is electric dipole-allowed -- you 31:28.416 --> 31:32.236 get this helicity in the transition. 31:32.240 --> 31:35.810 31:35.808 --> 31:39.808 Now, in fact, the rotation of charge 31:39.807 --> 31:46.207 generates a magnetic dipole perpendicular to the plane of 31:46.205 --> 31:50.885 rotation, and it's pointing that way. 31:50.890 --> 31:54.020 So you'll get an m_z component, a component of the 31:54.020 --> 31:56.370 magnetic moment along the z axis. 31:56.368 --> 31:59.378 Here you can see immediately you've got a component of the 31:59.375 --> 32:01.585 electric dipole along the z axis. 32:01.588 --> 32:04.918 So that generates a μ_zm_z component, 32:04.923 --> 32:08.693 from this scalar product of μ and m, 32:08.692 --> 32:10.942 in the rotational strength. 32:10.940 --> 32:17.860 So this is sort of making a meal of it here now. 32:17.858 --> 32:20.878 So we're just putting down these so-called 32:20.882 --> 32:23.612 quantum-mechanical matrix elements. 32:23.608 --> 32:26.168 So here we've got n to π*, 32:26.171 --> 32:29.831 with a little bit of that mixed in, and that's fully magnetic 32:29.830 --> 32:30.990 dipole-allowed. 32:30.990 --> 32:33.510 Then we have n to π*, 32:33.509 --> 32:36.479 which is forbidden electric dipole, 32:36.480 --> 32:40.160 but mixing that in gives you a little bit of electric dipole 32:40.161 --> 32:40.911 character. 32:40.910 --> 32:44.810 And so you now get a non-zero contribution to the rotational 32:44.811 --> 32:45.541 strength. 32:45.538 --> 32:50.208 However, you wouldn't want to go on and actually calculate the 32:50.214 --> 32:54.974 optical rotation of the carbonyl chromophore, in some situation 32:54.967 --> 32:56.037 from this. 32:56.038 --> 32:58.868 Because, as I said, there's many other excited 32:58.865 --> 33:02.125 electronic states you could have also considered, 33:02.130 --> 33:06.400 which may be giving opposite contributions to the rotational 33:06.403 --> 33:07.203 strength. 33:07.200 --> 33:12.590 You have to sum them all, and to do that you now have to 33:12.594 --> 33:17.204 go to modern ab initio quantum-chemistry, 33:17.203 --> 33:20.543 quantum-chemical calculations. 33:20.538 --> 33:25.348 There's wonderful programs out now, from Gaussian and Dalton; 33:25.348 --> 33:29.238 you can calculate all sorts of molecular properties, 33:29.237 --> 33:33.427 with quite good -- very good accuracy, in many cases. 33:33.430 --> 33:37.350 But this now turns it all into a black box procedure. 33:37.348 --> 33:42.018 You just feed in appropriate atomic orbitals and press 33:42.015 --> 33:45.945 buttons and turn handles, whatever you do for these 33:45.953 --> 33:50.613 calculations, and out will pop some physical 33:50.612 --> 33:51.872 quantity. 33:51.868 --> 33:56.268 So you can calculate this whole thing, ab initio, 33:56.273 --> 34:00.683 and taking in however many excited states in the sum are 34:00.678 --> 34:01.798 necessary. 34:01.798 --> 34:06.148 And you can calculate the sign and magnitude of the optical 34:06.152 --> 34:09.682 rotation, for a given absolute configuration. 34:09.679 --> 34:13.569 So you would feed into the calculation whether it's the 34:13.565 --> 34:17.305 S or the R absolute stereochemistry. 34:17.309 --> 34:20.099 So you'd put that in, and that will determine the 34:20.103 --> 34:22.783 sign of the optical rotation that comes out. 34:22.780 --> 34:26.620 And so -- I mean, in this particular case, 34:26.619 --> 34:28.869 this small molecule, the S absolute 34:28.867 --> 34:31.307 configuration, goes with the plus rotation and 34:31.306 --> 34:32.956 the R goes with the minus. 34:32.960 --> 34:37.920 So from the calculation then you can relate the sign of the 34:37.923 --> 34:42.293 optical rotation to the absolute stereochemistry. 34:42.289 --> 34:45.599 But you wouldn't want to stake your life on it, 34:45.601 --> 34:48.411 because it's not completely reliable. 34:48.409 --> 34:52.239 It usually gives the right answer, for smaller molecules, 34:52.237 --> 34:53.397 but not always. 34:53.400 --> 34:57.980 And, for example, if this was -- as you know, 34:57.976 --> 35:03.176 and I think you'll hear more after my talk here. 35:03.179 --> 35:09.129 Many drugs now are chiral, and drug companies like to 35:09.130 --> 35:15.080 market now single enantiomer versions of the drug. 35:15.079 --> 35:19.049 So it's a tremendously important problem for them to 35:19.047 --> 35:21.477 know, with absolute certainty, 35:21.476 --> 35:25.536 the absolute configuration of the particular enantiomer 35:25.543 --> 35:29.123 they're marketing, because if they make a mistake 35:29.115 --> 35:33.135 and specify the wrong absolute configuration in their patent, 35:33.139 --> 35:36.109 they can literally lose billions of dollars. 35:36.110 --> 35:42.380 Anyway, there's the famous -- the importance of chirality in 35:42.375 --> 35:48.105 drugs is exemplified by the famous thalidomide case. 35:48.110 --> 35:50.420 But I won't elaborate that any more. 35:50.420 --> 35:54.260 I think Professor McBride is going to tell you some more of 35:54.255 --> 35:55.705 that in more detail. 35:55.710 --> 35:59.470 I should say that the cornerstone, the definitive 35:59.472 --> 36:03.632 method for determining absolute configuration has, 36:03.630 --> 36:06.280 for some years now, been something called the 36:06.278 --> 36:09.168 Bijvoet method of anomalous X-ray scattering, 36:09.170 --> 36:12.280 which again Professor -- have you told them about that? 36:12.280 --> 36:12.950 Prof: Yes. 36:12.949 --> 36:13.619 Prof: Yeah. 36:13.619 --> 36:14.549 Yeah, that's the definitive method. 36:14.550 --> 36:19.210 But it's sort of cheating because you're actually seeing 36:19.213 --> 36:22.693 -- you're seeing it through X-ray eyes. 36:22.690 --> 36:25.240 But even then, you can occasionally make a 36:25.237 --> 36:25.857 mistake. 36:25.860 --> 36:30.440 But I should just mention also, there are some newer optical 36:30.436 --> 36:34.856 activity techniques involving something called vibrational 36:34.860 --> 36:36.490 optical activity. 36:36.489 --> 36:39.409 Here we've been looking at optical activity in electronic 36:39.413 --> 36:41.243 transitions, using visible light. 36:41.239 --> 36:44.949 But in recent years newer methods, measuring optical 36:44.949 --> 36:48.949 activity in vibrational transitions, have come along. 36:48.949 --> 36:52.229 And these are actually comparable with X-ray, 36:52.231 --> 36:56.261 anomalous X-ray scattering, for reliability of absolute 36:56.257 --> 36:57.597 configuration. 36:57.599 --> 37:00.899 That's because these calculations are much more 37:00.898 --> 37:05.278 reliable for these vibrational optical activity phenomena than 37:05.275 --> 37:06.705 electronic ones. 37:06.710 --> 37:08.180 Well that's about it. 37:08.179 --> 37:11.109 That's all I would like to say now. 37:11.110 --> 37:12.670 So thank you for listening. 37:12.670 --> 37:22.320 > 37:22.320 --> 37:25.380 Prof: Now that you've heard from the authority, 37:25.376 --> 37:27.506 do you have any questions about it? 37:27.510 --> 37:32.970 You are unwontedly quiet, like you usually are. 37:32.969 --> 37:34.539 Any questions? 37:34.539 --> 37:38.309 Yes? 37:38.309 --> 37:42.409 Prof: I'm just wondering if the magnitude of the Faraday 37:42.407 --> 37:46.237 rotation can ever interfere with the measurement of optical 37:46.239 --> 37:48.619 rotation in the chiral material? 37:48.619 --> 37:51.309 That is to say, if one situates a polarimeter 37:51.309 --> 37:53.449 in proximity to an NMR spectrometer, 37:53.451 --> 37:54.431 for example? 37:54.429 --> 37:55.309 Prof: No. 37:55.309 --> 37:58.429 No, you wouldn't need to worry about that at all. 37:58.429 --> 37:59.029 No. 37:59.030 --> 38:03.800 You need a reasonable strength of magnetic fields just applied 38:03.802 --> 38:06.152 directly through the sample. 38:06.150 --> 38:06.560 Yeah. 38:06.559 --> 38:10.319 38:10.320 --> 38:11.280 Prof: Lucas? 38:11.280 --> 38:14.780 Student: Just if I'm understanding. 38:14.780 --> 38:20.210 The n to π* is magnetically dipole-allowed, 38:20.210 --> 38:23.890 electric dipole-forbidden, and that's why then it goes to 38:23.887 --> 38:26.617 the xz as well, in order to get the electric 38:26.617 --> 38:27.887 dipole… Prof: The electric, 38:27.885 --> 38:28.005 yeah. 38:28.010 --> 38:29.380 Student: …in there, that contribution. 38:29.380 --> 38:30.130 Prof: Yes. 38:30.130 --> 38:34.680 38:34.679 --> 38:36.449 Student: For my knowledge. 38:36.449 --> 38:38.479 > 38:38.480 --> 38:41.080 Prof: Okay, thanks again Laurence. 38:41.079 --> 38:42.049 Prof: My pleasure. 38:42.050 --> 38:43.360 Prof: Very good. 38:43.360 --> 38:52.110 > 38:52.110 --> 38:52.880 Prof: Thank you. 38:52.880 --> 38:56.710 Laurence Barron: Okay. 38:56.710 --> 39:02.680 Prof: So yeah, this is just a plug. 39:02.679 --> 39:05.969 This afternoon -- the reason Professor Barron is here is he's 39:05.969 --> 39:08.819 the Tetelman lecturer in Jonathan Edwards College. 39:08.820 --> 39:12.860 So he's giving a talk for the history majors and so on. 39:12.860 --> 39:14.570 But it'll be very interesting for anyone. 39:14.570 --> 39:17.820 And I think since we're into chirality, you would enjoy this, 39:17.824 --> 39:21.084 particularly this afternoon, in Davies Auditorium at 5:00. 39:21.079 --> 39:24.679 But there's the question, who cares? 39:24.679 --> 39:26.849 No offense. 39:26.849 --> 39:28.819 But who cares? 39:28.820 --> 39:30.530 Why do we care about chirality? 39:30.530 --> 39:32.470 Well Professor Barron hinted at it. 39:32.469 --> 39:35.229 Living things care, because they're chiral. 39:35.230 --> 39:36.300 Right? 39:36.300 --> 39:37.400 So which one they react with. 39:37.400 --> 39:38.700 Okay? 39:38.699 --> 39:41.019 The Food and Drug Administration cares, 39:41.018 --> 39:44.128 for the same reason, with respect to medications you 39:44.128 --> 39:45.348 might be taking. 39:45.349 --> 39:49.849 Drug companies care a lot, and their lawyers. 39:49.849 --> 39:52.499 And the US Patent Office cares a lot. 39:52.500 --> 39:54.150 Right? 39:54.150 --> 39:56.820 Which has generated a thing called a "chiral 39:56.815 --> 39:57.645 switch." 39:57.650 --> 40:00.490 Most drugs that used to be developed were developed as 40:00.494 --> 40:03.394 racemates, because it was difficult to separate the two 40:03.393 --> 40:03.933 hands. 40:03.929 --> 40:07.369 But if your patent runs out on the racemate, 40:07.369 --> 40:11.579 and you can resolve it and now sell just one of them, 40:11.579 --> 40:15.269 and if it's better, and the FDA will approve it, 40:15.268 --> 40:18.228 and you can convince people that that's the one they should 40:18.231 --> 40:19.981 buy, then you can go back to not 40:19.978 --> 40:22.858 having to compete with generic drug companies anymore and 40:22.860 --> 40:25.950 charge five dollars a pill instead of fifty cents a pill. 40:25.949 --> 40:27.369 Okay? 40:27.369 --> 40:30.879 So this so-called chiral switch, to go from racemic to a 40:30.882 --> 40:33.952 single enantiomer, is a big movement nowadays. 40:33.949 --> 40:36.759 For example, consider this pain reliever. 40:36.760 --> 40:38.180 Let's figure out what it is. 40:38.179 --> 40:41.429 Do you remember what that group is: four carbons, 40:41.431 --> 40:43.941 in that sort of Mercedes structure? 40:43.940 --> 40:47.630 Do you know what that group's called? 40:47.630 --> 40:51.580 This, what we're doing for the rest of the lecture here out is 40:51.583 --> 40:54.243 actually review for the exam on Friday. 40:54.239 --> 40:56.769 You're not specifically responsible for it, 40:56.773 --> 40:57.863 but it's review. 40:57.860 --> 40:59.190 So you know that group? 40:59.190 --> 41:00.700 Student: Isobutyl. 41:00.699 --> 41:01.769 Prof: Isobutyl. 41:01.768 --> 41:06.048 Okay, and what acid is that, with three carbons, 41:06.052 --> 41:07.332 do you know? 41:07.329 --> 41:10.169 The first fatty acid? 41:10.170 --> 41:11.350 Student: Propionic. 41:11.349 --> 41:12.749 Prof: Propionic acid. 41:12.750 --> 41:16.640 And in the middle we have -- Student: Phenol? 41:16.639 --> 41:18.509 Prof: Phenyl group. 41:18.510 --> 41:19.410 Okay? 41:19.409 --> 41:26.019 So what's the name of the drug? 41:26.019 --> 41:29.329 Student: Ibuprofen. 41:29.329 --> 41:30.189 Prof: Sherwin? 41:30.190 --> 41:31.810 Student: Ibuprofen. 41:31.809 --> 41:33.449 Prof: Ibu-pro-fen. 41:33.449 --> 41:34.959 Advil or Motrin. 41:34.960 --> 41:38.740 Okay, now in this case you have a chiral center there -- right? 41:38.739 --> 41:40.839 -- because there's a hydrogen on there that we don't see. 41:40.840 --> 41:43.630 And the S-form is a pain reliever; 41:43.630 --> 41:45.220 it's said to be so anyhow. 41:45.219 --> 41:46.549 And the R is inactive. 41:46.550 --> 41:47.550 Right? 41:47.550 --> 41:49.570 But it's marketed as a racemate. 41:49.570 --> 41:50.620 Right? 41:50.619 --> 41:53.929 One might try doing a chiral switch and selling only the 41:53.927 --> 41:54.587 S. 41:54.590 --> 41:58.430 But the trouble is that it very quickly racemizes inside you. 41:58.429 --> 42:00.539 So it wouldn't be doing any good, right? 42:00.539 --> 42:03.299 Because you'd do all the work of selling the S and then 42:03.297 --> 42:05.827 it would become R immediately, when you ate it. 42:05.829 --> 42:06.569 And here's another one. 42:06.570 --> 42:08.700 This is the one that Professor Barron referred to, 42:08.702 --> 42:10.962 which is a sedative; thalidomide. 42:10.960 --> 42:14.390 And there's the chiral center in that one, because there's an 42:14.387 --> 42:15.127 H on there. 42:15.130 --> 42:18.590 So the S-form is a sedative, but the R-form, 42:18.592 --> 42:20.842 at least it's said, is a teratogen; 42:20.840 --> 42:23.410 which means it makes monsters. 42:23.409 --> 42:24.859 > 42:24.860 --> 42:27.920 And it's not so funny, because it was sold as a 42:27.922 --> 42:30.922 racemate from 1957 to '62 -- never in the U.S. 42:30.920 --> 42:34.850 because the FDA didn't -- they were lucky and never approved 42:34.849 --> 42:35.449 it. 42:35.449 --> 42:38.149 But in Europe it caused 10,000 birth defects; 42:38.150 --> 42:41.520 children born without arms, legs, things like that. 42:41.519 --> 42:42.809 So it was a tragedy. 42:42.809 --> 42:47.429 But this one also undergoes in vivo racemization. 42:47.429 --> 42:48.739 Okay? 42:48.739 --> 42:51.689 You can find rate constants for these. 42:51.690 --> 42:54.190 It's curious that the rate of S going to R, 42:54.188 --> 42:56.998 and the rate of R going to S, are not the same. 42:57.000 --> 43:00.150 There's got to be more to it than that, that one has to be 43:00.150 --> 43:03.080 more stable than the other, of these mirror images; 43:03.079 --> 43:03.889 if that's true. 43:03.889 --> 43:06.049 It may be that the rates aren't exactly true. 43:06.050 --> 43:08.720 But if so, they must be bound to something that makes -- 43:08.719 --> 43:11.579 that's chiral -- that makes one of them more stable than the 43:11.583 --> 43:12.073 other. 43:12.070 --> 43:14.410 Anyhow, that's how fast they go back and forth. 43:14.409 --> 43:17.489 And this is how fast they get eliminated from the body; 43:17.489 --> 43:20.229 one gets eliminated much faster than the other. 43:20.230 --> 43:23.060 And if you put these things together, you can see how the 43:23.063 --> 43:26.203 concentration should vary with time, if it's going according to 43:26.201 --> 43:26.911 that rate. 43:26.909 --> 43:29.399 So the blue one, the one that's good for you, 43:29.398 --> 43:30.528 quickly drops off. 43:30.530 --> 43:32.360 The bad one, the teratogen, 43:32.356 --> 43:33.476 grows quickly. 43:33.480 --> 43:36.910 So you have maybe two hours of twenty-four hours where you got 43:36.905 --> 43:39.485 a lot more of the good one than the bad one. 43:39.489 --> 43:43.189 So essentially this drug is completely off-limits, 43:43.188 --> 43:46.738 especially for any women that could conceivably, 43:46.735 --> 43:49.825 under any circumstances, be pregnant. 43:49.829 --> 43:50.419 Okay? 43:50.420 --> 43:54.360 So but it's a wonderful drug for things like leprosy and so 43:54.360 --> 43:54.700 on. 43:54.699 --> 43:57.779 David here is an MD, as well as a professor of 43:57.775 --> 44:01.255 chemistry, and you probably know more about that. 44:01.260 --> 44:02.850 But it's a wonderful drug for certain things. 44:02.849 --> 44:03.559 Isn't that right? 44:03.559 --> 44:04.359 Prof: That's right, that's right. 44:04.360 --> 44:07.630 It's still actually in common usage for anxiety disorders. 44:07.630 --> 44:08.690 Prof: Yeah, but there are all sorts of 44:08.690 --> 44:10.240 warnings, in letters this big, 44:10.235 --> 44:13.305 about if you have a chance of getting pregnant, 44:13.309 --> 44:14.599 stay away from this baby. 44:14.599 --> 44:15.039 Right? 44:15.039 --> 44:17.499 Prof: In fact, if you're a male patient taking 44:17.496 --> 44:19.406 it, and your wife is pregnant or 44:19.409 --> 44:22.379 likely to become pregnant, you're encouraged not to take 44:22.384 --> 44:22.574 it. 44:22.570 --> 44:23.380 Prof: Wow. 44:23.380 --> 44:24.780 Prof: Because of possible contamination. 44:24.780 --> 44:25.750 Prof: Wow. 44:25.750 --> 44:28.760 Okay, so now here's a drug. 44:28.760 --> 44:30.060 We're going to look at the name of this one. 44:30.059 --> 44:32.409 It's a really whopper of a name, right? 44:32.409 --> 44:35.829 So let's just use this as a practice about nomenclature. 44:35.829 --> 44:39.339 Okay, so that thing there is called imidazole, 44:39.340 --> 44:43.940 and the 1H tells where -- which one has a hydrogen on 44:43.943 --> 44:44.493 it. 44:44.489 --> 44:44.939 Right? 44:44.936 --> 44:47.166 Okay, so that's position one. 44:47.170 --> 44:49.860 And that is the benzene ring; so benz. 44:49.860 --> 44:52.650 So it's benzimidazole, that group on the right. 44:52.650 --> 44:53.930 And you number it. 44:53.929 --> 44:56.589 Remember it was 1H; there's an H on the nitrogen 44:56.585 --> 44:57.145 one there. 44:57.150 --> 45:00.120 And you go around the ring and number in that conventional way. 45:00.119 --> 45:03.989 Okay, now but then you notice that there's something on the 45:03.987 --> 45:07.387 number five, and there's something on the number two 45:07.389 --> 45:08.989 carbon of that ring. 45:08.989 --> 45:12.789 On five, there's a methoxy group, which appears first among 45:12.786 --> 45:15.336 all the things in this -- named here; 45:15.340 --> 45:16.720 not the thing that's on two. 45:16.719 --> 45:19.589 Why is the methoxy group first? 45:19.590 --> 45:22.860 Do you remember what the rule is? 45:22.860 --> 45:25.680 Student: >. 45:25.679 --> 45:28.299 Prof: How do you arrange the substituent groups? 45:28.300 --> 45:30.820 Angela? 45:30.820 --> 45:32.770 Student: Alphabetically. 45:32.769 --> 45:34.939 Prof: Alphabetically; m is going to be the first one. 45:34.940 --> 45:39.230 Okay, so 5-methoxy, and then two is sulfinyl; 45:39.230 --> 45:42.130 that S with an O on it is called sulfinyl group. 45:42.130 --> 45:43.790 Okay, so it's 2-sulfinyl. 45:43.789 --> 45:46.699 But now there are all sorts of curly brackets and square 45:46.695 --> 45:49.065 brackets and so on, to tell what's attached to 45:49.074 --> 45:49.554 that. 45:49.550 --> 45:53.010 Okay, so attached to that is methyl group; 45:53.010 --> 45:54.880 the methyl is substituted. 45:54.880 --> 45:56.390 So it's methyl sulfinyl. 45:56.389 --> 45:59.839 Okay, that's the curly -- the square brackets. 45:59.840 --> 46:01.380 Okay, now what's on the methyl? 46:01.380 --> 46:04.540 There's a pyridine group; the benzene with a nitrogen, 46:04.539 --> 46:05.209 is pyridine. 46:05.210 --> 46:08.820 And it's substituted on the methyl at its own two position; 46:08.820 --> 46:11.200 the two position of the pyridine is what's attached to 46:11.195 --> 46:11.775 the methyl. 46:11.780 --> 46:16.530 So it's 2-pyridinyl, the end. 46:16.530 --> 46:18.690 But now on that, in the four position, 46:18.690 --> 46:19.450 is methoxy. 46:19.449 --> 46:22.749 And methoxy comes alphabetically before methyl; 46:22.750 --> 46:24.730 not before d, but before methyl, 46:24.733 --> 46:26.593 and you don't count the di. 46:26.590 --> 46:27.510 Right? 46:27.510 --> 46:29.010 So there's the name of that compound. 46:29.010 --> 46:30.750 And this stuff is a drug. 46:30.750 --> 46:33.100 It's a gastric proton pump inhibitor. 46:33.099 --> 46:35.849 So it treats acid reflux disease. 46:35.849 --> 46:39.529 And it's the world's largest selling drug in the Year 2000; 46:39.530 --> 46:41.080 6.2 billion dollars. 46:41.079 --> 46:44.879 And it's called omeprazole, or Prilosec. 46:44.880 --> 46:47.840 And you've seen probably, some of you at least, 46:47.838 --> 46:49.768 have seen boxes of Prilosec. 46:49.768 --> 46:52.678 I hope you don't have to take it, like I do occasionally. 46:52.679 --> 46:55.169 This is called OTC. 46:55.170 --> 46:56.840 We're going to be talking about that on Monday. 46:56.840 --> 46:59.170 Okay, so there it is. 46:59.170 --> 47:00.610 Now get your glasses up. 47:00.610 --> 47:04.380 47:04.380 --> 47:07.320 Because can you see this? 47:07.320 --> 47:12.320 Can you see any sort of three-dimensions here? 47:12.320 --> 47:14.220 What's in front, or what's behind? 47:14.219 --> 47:17.909 Can anybody tell? 47:17.909 --> 47:20.029 You have any luck in seeing it in three-dimensions? 47:20.030 --> 47:22.060 Some people can't see it, but most of you, 47:22.059 --> 47:24.139 about 95% of you, should be able to see. 47:24.139 --> 47:27.169 It's not a really high quality three-dimensions. 47:27.170 --> 47:31.570 And because the computer -- the projector doesn't do it exactly 47:31.567 --> 47:33.267 right, for the colors. 47:33.268 --> 47:35.948 So one eye sees only one and one sees only the other. 47:35.949 --> 47:37.129 Anybody see? 47:37.130 --> 47:39.760 Okay, now what is chiral here? 47:39.760 --> 47:41.650 Can you see why this thing is chiral? 47:41.650 --> 47:44.650 There's no carbon with four different things on it. 47:44.650 --> 47:46.730 But what makes it handed? 47:46.730 --> 47:49.000 Can you see? 47:49.000 --> 47:51.770 In fact, there's no group that has four different things on it. 47:51.769 --> 47:54.829 47:54.829 --> 47:56.909 Any suggestions? 47:56.909 --> 47:57.859 Lucas? 47:57.860 --> 47:58.530 Student: Sulfur. 47:58.530 --> 47:59.540 Prof: Sulfur. 47:59.539 --> 48:03.369 Sulfur has an unshared pair, an oxygen, and two different R 48:03.373 --> 48:03.973 groups. 48:03.969 --> 48:06.439 And which is pointing out toward you? 48:06.440 --> 48:08.430 Can you see it enough in three-dimensions, 48:08.429 --> 48:09.839 with the glasses, to see that, 48:09.838 --> 48:11.438 to see which is pointing out? 48:11.440 --> 48:12.660 Student: The unshared pair. 48:12.659 --> 48:14.569 Prof: Yeah, it's the unshared pair that's 48:14.570 --> 48:15.180 pointing out. 48:15.179 --> 48:18.969 So if you use your thumbs and recognize that the unshared pair 48:18.965 --> 48:21.815 has the lowest atomic number -- zero, right? 48:21.820 --> 48:22.990 -- then you can do it. 48:22.989 --> 48:25.589 And you'll find out that that particular one drawn there is 48:25.592 --> 48:26.762 the S enantiomer. 48:26.760 --> 48:28.000 Okay? 48:28.000 --> 48:33.080 So it's known -- omeprazole, Prilosec, Prilosec OTC, 48:33.077 --> 48:34.967 are the racemate. 48:34.969 --> 48:39.949 But this one that's drawn here is the S isomer, 48:39.945 --> 48:41.915 and it's called what? 48:41.916 --> 48:45.146 Esomeprazole; that's the name of it, right? 48:45.150 --> 48:47.240 Or Nexium. 48:47.239 --> 48:48.729 Right? 48:48.730 --> 48:51.210 And it's the S isomer, right? 48:51.210 --> 48:53.750 So this is the product of one of these chiral switches, 48:53.750 --> 48:57.420 where for a long time the stuff was marketed as a racemate and 48:57.420 --> 49:00.550 now they market it as a single enantiomer, Nexium. 49:00.550 --> 49:03.110 And we tried this one last time, so we're not going to 49:03.108 --> 49:04.508 spend time on it right now. 49:04.510 --> 49:07.690 That's what the class looks like when they're doing this. 49:07.690 --> 49:09.160 It's fun for me to see you. 49:09.159 --> 49:09.959 > 49:09.960 --> 49:10.980 Okay? 49:10.980 --> 49:13.230 But there are other ways of doing the stereoviewing. 49:13.230 --> 49:16.140 You can use a pair of periscopes, like this. 49:16.139 --> 49:17.399 Right? 49:17.400 --> 49:20.220 And the way that works of course -- well the point is, 49:20.215 --> 49:22.335 for each eye to see a different image. 49:22.340 --> 49:24.980 So if you want to try those and look at this after class, 49:24.983 --> 49:25.553 feel free. 49:25.550 --> 49:26.760 Or borrow them if you wish. 49:26.760 --> 49:27.510 Right? 49:27.510 --> 49:31.300 So what the eyes perceive is a superposition in the middle. 49:31.300 --> 49:31.850 It's like this. 49:31.849 --> 49:33.659 There are two pictures. 49:33.659 --> 49:36.249 But if you can do it with the glasses, you can do it probably 49:36.251 --> 49:38.931 just by looking at this picture, if you have a little while. 49:38.929 --> 49:40.299 But we don't have the little while now. 49:40.300 --> 49:43.020 The right eye will see that, the left eye will see that, 49:43.018 --> 49:44.908 and you see, in the middle -- there see, 49:44.909 --> 49:48.029 something in the same position but in slightly different 49:48.025 --> 49:48.815 projections. 49:48.820 --> 49:53.630 So the image in the middle of the three seems to be in 3-D. 49:53.630 --> 49:55.500 Okay. 49:55.500 --> 49:59.870 Now we don't have time to go -- we're going to do a lot of 49:59.867 --> 50:03.537 curved arrow stuff, about how reactions happen in 50:03.543 --> 50:06.443 making omeprazole; and then, even more 50:06.436 --> 50:09.856 interesting, in the action of omeprazole that stops the 50:09.864 --> 50:10.884 stomach acid. 50:10.880 --> 50:12.340 But we'll have to wait 'til after the exam for that. 50:12.340 --> 50:13.650 Okay? 50:13.650 --> 50:14.950 Thanks again to Professor Barron. 50:14.949 --> 50:16.699 > 50:16.699 --> 50:23.999