WEBVTT 00:02.500 --> 00:04.170 J. MICHAEL MCBRIDE: We're talking about nucleophilic 00:04.167 --> 00:07.167 substitution reactions. 00:07.167 --> 00:10.227 And today we're going to talk, in the next lecture as well, 00:10.233 --> 00:11.903 about mechanistic tools. 00:11.900 --> 00:14.330 How you find out what the mechanism is. 00:14.333 --> 00:17.773 You can talk about plausible mechanism, but whether that's 00:17.767 --> 00:21.167 really it or not, and almost always there are several, 00:21.167 --> 00:22.867 requires experimentation. 00:22.867 --> 00:26.597 So we're going to look at experimental tools you can use 00:26.600 --> 00:30.430 to decide what the mechanism of the reaction is. 00:30.433 --> 00:33.073 So last time we saw a whole bunch of examples of 00:33.067 --> 00:36.827 nucleophilic substitution reactions, where a nucleophile 00:36.833 --> 00:42.103 approaches a compound that has a low LUMO, the substrate. 00:42.100 --> 00:45.800 It reacts in a particular solvent to give the product in 00:45.800 --> 00:49.900 which the nucleophile has replaced the leaving group. 00:49.900 --> 00:53.870 So now we're interested in what the mechanism of that is. 00:53.867 --> 00:57.097 We talked last semester about the possibility of attacking 00:57.100 --> 01:00.630 on the carbon of the sigma-star, and the leaving 01:00.633 --> 01:03.903 group leaving with the electrons that were formerly 01:03.900 --> 01:05.330 in the R-L bond. 01:05.333 --> 01:07.333 That's certainly plausible, the question is 01:07.333 --> 01:09.303 whether it's true. 01:09.300 --> 01:10.470 Because as you'll see, there are other 01:10.467 --> 01:13.297 possibilities as well. 01:13.300 --> 01:15.730 So there are many different mechanisms. In fact they're 01:15.733 --> 01:17.233 not all the same. 01:17.233 --> 01:20.733 But many of them fall in the same two 01:20.733 --> 01:22.773 classes as you'll see. 01:22.767 --> 01:25.197 And the one we're going to talk about first is called 01:25.200 --> 01:28.400 nucleophilic substitution, SN. 01:28.400 --> 01:32.270 Substitution, nucleophilic 2 means second order in 01:32.267 --> 01:34.027 kinetics, and you'll see what that means. 01:34.033 --> 01:37.103 So SN2, nucleophilic substitution. 01:37.100 --> 01:41.670 And we're interested, as I said in the pragmatic logic of 01:41.667 --> 01:44.667 proving a mechanism with experiment and theory. 01:44.667 --> 01:47.827 Now this kind of logic isn't like the logic they teach you 01:47.833 --> 01:50.503 in philosophy or mathematics. 01:50.500 --> 01:54.000 Things are rarely 100% proven. 01:54.000 --> 01:58.130 But there's a practical use to know how these things work, 01:58.133 --> 02:02.203 because they can help you in designing new reactions, or 02:02.200 --> 02:05.470 changing the conditions to make a reaction work better. 02:05.467 --> 02:07.727 So you'll see what it means to prove a 02:07.733 --> 02:10.373 mechanism in organic chemistry. 02:10.367 --> 02:14.397 And actually, mostly it involves disproving all the 02:14.400 --> 02:18.070 alternative mechanisms. You remember Sherlock Holmes in 02:18.067 --> 02:21.327 The Adventure of the Beryl Coronet, said "It's an old 02:21.333 --> 02:24.803 maxim of mine, that when you have excluded the impossible, 02:24.800 --> 02:27.500 whatever remains, however improbable, must be the 02:27.500 --> 02:30.900 truth." That's generally the logic of how you prove things 02:30.900 --> 02:34.370 in chemistry. 02:34.367 --> 02:38.597 But the problem is you have to disprove "all the alternative 02:38.600 --> 02:41.500 mechanisms, which means you have to imagine all the 02:41.500 --> 02:43.900 alternative mechanisms in disprovement. 02:43.900 --> 02:46.530 Of course it's always a possibility that there's one 02:46.533 --> 02:52.103 you haven't thought of that's the real McCoy. 02:52.100 --> 02:53.870 Now let's just look at what has to happen. 02:53.867 --> 02:57.297 You have to break the R-L bond, leaving group has to 02:57.300 --> 03:00.430 leave, and you have to make the new bond. 03:00.433 --> 03:02.873 So there has to be a dissociation and there has to 03:02.867 --> 03:04.497 be an association. 03:04.500 --> 03:08.900 And you could classify the possible mechanisms in the 03:08.900 --> 03:12.000 sequence that's involved in these two processes. 03:12.000 --> 03:14.570 You could first have dissociation, and then 03:14.567 --> 03:15.927 association. 03:15.933 --> 03:18.073 And we'll see that actually happens-- 03:18.067 --> 03:20.767 that's called the SN1 reaction. 03:20.767 --> 03:24.927 You can have association followed by dissociation, 03:24.933 --> 03:28.773 which happens, but not with carbon. 03:28.767 --> 03:32.327 And you'll see also the possibility of a simultaneous 03:32.333 --> 03:35.303 or a concerted reaction as you call it, where you make the 03:35.300 --> 03:38.400 new bond at the same time you break the old one, so that 03:38.400 --> 03:40.830 they come at the same time. 03:40.833 --> 03:44.433 That seems to pretty much cover the territory of 03:44.433 --> 03:46.603 how you can do it. 03:46.600 --> 03:48.700 So you can have concerted, where they both happen at the 03:48.700 --> 03:51.670 same time, association/dissociation, or 03:51.667 --> 03:54.297 dissociation followed by association. 03:54.300 --> 03:57.100 And we can imagine reaction-coordinate diagrams 03:57.100 --> 03:59.370 for these, and geometries. 03:59.367 --> 04:02.367 So in the concerted, the nucleophile is coming in and 04:02.367 --> 04:05.127 attacking the carbon at the same time the leaving group is 04:05.133 --> 04:08.373 leaving, and that's a transition state. 04:08.367 --> 04:11.367 You can have a pentavalent carbon intermediate. 04:11.367 --> 04:14.697 So you first make the new bond, and only subsequently do 04:14.700 --> 04:16.270 you break the old bond. 04:16.267 --> 04:19.597 Or you could break the old bond, and get a trivalent 04:19.600 --> 04:21.500 intermediate, and then subsequently 04:21.500 --> 04:24.000 make the new bond. 04:24.000 --> 04:26.530 So if we look at the reaction coordinate diagram, the first 04:26.533 --> 04:29.703 one just has a transition state, but the other two have 04:29.700 --> 04:32.000 intermediates. 04:32.000 --> 04:35.400 Either a pentavalent intermediate of pentavalent 04:35.400 --> 04:39.970 carbon, or a trivalent carbon intermediate. 04:39.967 --> 04:42.927 As I've drawn it there, the first step is rate limiting. 04:42.933 --> 04:47.303 We talked about the complex reaction of two steps, where 04:47.300 --> 04:50.230 either the first or the second step would be rate limiting. 04:50.233 --> 04:52.773 It would be possible to imagine the second step to be 04:52.767 --> 04:54.967 rate limiting as well. 04:54.967 --> 04:58.127 However, that might not be so common. 04:58.133 --> 05:02.803 We will ask what's normally the case in a reaction. 05:02.800 --> 05:07.300 These ones where the second step has a higher barrier are 05:07.300 --> 05:11.300 not so common if you have an exothermic process because 05:11.300 --> 05:15.470 it's against the Hammond postulate. 05:15.467 --> 05:18.367 Not that it couldn't be, because you have the 05:18.367 --> 05:22.467 intermediate, and you can go either to the product or back 05:22.467 --> 05:24.697 to the starting material. 05:24.700 --> 05:28.600 But if the second step is rate limiting, it implies that you 05:28.600 --> 05:32.430 have a higher barrier going to the lower energy product, 05:32.433 --> 05:35.503 which could be, but it's not so likely. 05:35.500 --> 05:38.230 So it's much more likely to have these up at the top in a 05:38.233 --> 05:39.973 reaction that's exothermic. 05:39.967 --> 05:44.197 Of course the same reaction run backwards would retrace 05:44.200 --> 05:47.300 the same path, and running this backwards would have the 05:47.300 --> 05:48.870 second step rate limiting. 05:48.867 --> 05:50.997 But generally we're going to talk about cases where the 05:51.000 --> 05:53.270 first step is rate limiting, because we're interested in 05:53.267 --> 05:56.327 reactions that go to give a product, not the ones that 05:56.333 --> 05:59.833 come back from the product and the starting material so much. 05:59.833 --> 06:04.633 Now if you have three different other substituents 06:04.633 --> 06:07.373 on the carbon that's being attacked, other than the 06:07.367 --> 06:11.567 leaving group that's leaving, then you have the possibility 06:11.567 --> 06:13.167 of chirality. 06:13.167 --> 06:16.767 So that the first transition state and the pentavalent 06:16.767 --> 06:18.297 intermediate are chiral. 06:18.300 --> 06:21.800 But the trivalent intermediate, if it's planar, 06:21.800 --> 06:23.670 is achiral. 06:23.667 --> 06:28.227 And that means that there are stereochemical implications. 06:28.233 --> 06:32.433 Because in the first two cases the nucleophile comes on the 06:32.433 --> 06:36.003 opposite face from where the leaving group is leaving. 06:36.000 --> 06:38.370 But in the third case when you have the trivalent 06:38.367 --> 06:41.927 intermediate it could do that, but it could also come in from 06:41.933 --> 06:43.403 the other side. 06:43.400 --> 06:45.900 So you would get two enantiomers. 06:45.900 --> 06:48.700 So the stereochemical consequences, the 06:48.700 --> 06:51.930 stereochemistry of the product, whether it's inverted 06:51.933 --> 06:57.203 from the starting material, or whether it's racemic, you 06:57.200 --> 06:59.200 attack both sides, will tell you 06:59.200 --> 07:00.570 something about the mechanism. 07:00.567 --> 07:04.667 I suppose if we want to be complete in our thinking about 07:04.667 --> 07:06.967 this, we could also imagine that there would be a 07:06.967 --> 07:10.527 frontside attack where the nucleophile would come in on 07:10.533 --> 07:15.733 the same face that the leaving group is leaving, either in a 07:15.733 --> 07:20.503 concerted process, or in a process with a pentavalent 07:20.500 --> 07:23.070 intermediate, where nucleophile and leaving group 07:23.067 --> 07:24.527 are on the same side. 07:24.533 --> 07:27.833 That's a possibility, which isn't shown here. 07:27.833 --> 07:31.673 But whichever it is, whether it's the same side or the 07:31.667 --> 07:34.097 opposite side, the first two cases are going to give a 07:34.100 --> 07:37.270 single chirality to the product, where the trivalent 07:37.267 --> 07:41.097 intermediate will give both. 07:41.100 --> 07:44.470 There are tools for testing, that is for excluding 07:44.467 --> 07:49.197 mechanisms. They can involve stereochemistry, rate law, 07:49.200 --> 07:53.800 rate constant, and structure (X-ray work and quantum 07:53.800 --> 07:55.370 mechanics). 07:55.367 --> 07:59.127 In the particular book that you might be using, the Jones 07:59.133 --> 08:01.703 book, these are in the sections indicated there, and 08:01.700 --> 08:03.570 I'll indicate those as we go along. 08:03.567 --> 08:06.297 But these things will be covered in all the texts, so 08:06.300 --> 08:09.830 you'll see a good treatment almost anywhere. 08:09.833 --> 08:12.303 We're first going to look at stereochemistry, what we were 08:12.300 --> 08:14.000 just talking about. 08:14.000 --> 08:16.500 So when you have nucleophilic substitution, where the 08:16.500 --> 08:20.930 nucleophile comes in place of the leaving group, it could 08:20.933 --> 08:22.873 either do exactly that-- 08:22.867 --> 08:28.697 it could REplace the leaving group, so the nucleophile is 08:28.700 --> 08:31.570 on the right in the product, the same way that the leaving 08:31.567 --> 08:34.227 group was on the right in the starting material, so they 08:34.233 --> 08:36.573 just change positions. 08:36.567 --> 08:41.627 Or it could be a DISplacement, where the nucleophile comes in 08:41.633 --> 08:44.833 on the opposite side, and the things that make 08:44.833 --> 08:47.303 it chiral are inverted. 08:47.300 --> 08:50.230 You could imagine either way. 08:50.233 --> 08:53.573 If you were naive and in the nineteenth century, which do 08:53.567 --> 08:55.897 you think you would think more likely? 08:55.900 --> 09:00.300 That it would actually replace the thing that it was 09:00.300 --> 09:03.700 exchanging with, or that it would come in and invert 09:03.700 --> 09:04.430 everything? 09:04.433 --> 09:07.773 Which do you think you would have thought was more likely? 09:07.767 --> 09:09.727 How many would think it more likely if you're going to 09:09.733 --> 09:12.533 replace something, you replace it? 09:12.533 --> 09:15.373 How many think it would displace it? 09:15.367 --> 09:18.297 That's exactly what they thought in the 19th century, 09:18.300 --> 09:22.000 that it should be replacement not displacement. 09:22.000 --> 09:26.530 So when it was found in 1898 that there was an example, 09:26.533 --> 09:31.233 where it inverted the configuration, Emil Fischer, 09:31.233 --> 09:34.373 the guy who invented the Fischer projection after all, 09:34.367 --> 09:37.827 who was a big expert on stereochemistry at the turn of 09:37.833 --> 09:42.003 the century, said this was "the most astounding discovery in 09:42.000 --> 09:45.430 stereochemistry since the groundbreaking work of van 't 09:45.433 --> 09:49.433 Hoff." which was a quarter century earlier. 09:49.433 --> 09:52.603 So it was really astounding to these people that it could 09:52.600 --> 09:54.300 invert the stereochemistry. 09:54.300 --> 09:58.300 They thought this weird case that showed that, was just 09:58.300 --> 09:59.330 that-- a weird case. 09:59.333 --> 10:02.173 But the normal case must be replacement. 10:02.167 --> 10:05.967 So the goal then was to find out which one was normal. 10:08.833 --> 10:12.203 The first really good evidence on this, and a beautiful 10:12.200 --> 10:14.900 experiment, was done in England by Kenyon 10:14.900 --> 10:17.600 and Phillips in 1923. 10:17.600 --> 10:21.570 And it involved this alcohol, and they resolved it, and got 10:21.567 --> 10:25.427 a single enantiomer which rotated light 33 degrees plus, 10:25.433 --> 10:27.803 to the right. 10:27.800 --> 10:30.970 Now they want to do a substitution reaction, replace 10:30.967 --> 10:36.597 the OH by something else, and see whether the configuration 10:36.600 --> 10:40.330 is the same or whether it's been inverted. 10:40.333 --> 10:45.273 Notice incidentally that if in doing the process you do two 10:45.267 --> 10:48.897 steps you'll get the same ultimate product, whether it's 10:48.900 --> 10:53.200 two inversions, or two retentions of configuration. 10:53.200 --> 10:56.400 They'll both give the same product. 10:56.400 --> 11:00.100 So you have to have just one step that involves the 11:00.100 --> 11:02.870 nucleophilic substitution reaction. 11:02.867 --> 11:06.027 So now in the first place, OH minus, as we'll see later in 11:06.033 --> 11:07.803 the lecture is a crummy leaving group. 11:07.800 --> 11:10.300 You can't undergo the replacement 11:10.300 --> 11:13.400 reaction easily with OH. 11:13.400 --> 11:15.900 So what they did first, was to react it with this 11:15.900 --> 11:18.700 chlorosulfonic acid. 11:18.700 --> 11:21.700 And this is indeed a nucleophilic substitution, 11:21.700 --> 11:26.230 where O attacks sulfur this time, not carbon, 11:26.233 --> 11:28.133 and chloride leaves. 11:28.133 --> 11:31.303 So now you have a product where the group attached to 11:31.300 --> 11:36.730 the chiral carbon, is not OH but O with sulfur on it. 11:36.733 --> 11:40.403 Notice incidentally that nothing happened to the chiral 11:40.400 --> 11:41.770 carbon at this stage. 11:41.767 --> 11:43.627 The reaction was at the oxygen. 11:43.633 --> 11:46.073 So whatever configuration of the carbon you had in the 11:46.067 --> 11:47.927 starting material, you have in the product. 11:47.933 --> 11:52.103 This is not an interesting reaction stereochemically. 11:52.100 --> 11:56.270 It's just the way to get there to be a group that'll leave. 11:56.267 --> 12:00.797 And notice that this mechanism is A/D. It's first 12:00.800 --> 12:06.170 association, attack the sulfur, and then dissociation, 12:06.167 --> 12:07.597 lose the chloride. 12:07.600 --> 12:09.700 And the reason you could do that is that there's a vacant 12:09.700 --> 12:11.100 d orbital on the sulfur. 12:11.100 --> 12:14.630 So there's a way that you can form a new bond without 12:14.633 --> 12:15.603 breaking the old one. 12:15.600 --> 12:18.100 You don't have to attack sigma-star. 12:18.100 --> 12:21.000 And once you have this product, that now is a good 12:21.000 --> 12:24.970 leaving group, because if you break the bond between carbon 12:24.967 --> 12:29.467 and oxygen, now the anion you get is not OH minus, but an 12:29.467 --> 12:36.627 anion analogous to the anion of sulfuric acid, OSO2 Now 12:36.633 --> 12:40.473 that has a rotation of +31 degrees, and the starting 12:40.467 --> 12:44.397 material was +33 degrees, so that confirms what we were 12:44.400 --> 12:47.370 saying, that the configuration hasn't changed 12:47.367 --> 12:48.797 at the chiral carbon. 12:48.800 --> 12:50.070 Am I right? 12:50.067 --> 12:51.297 Is that a good inference? 12:53.833 --> 12:56.903 That it's + at the product and + at the starting material? 12:56.900 --> 12:59.470 Does that prove that the carbon didn't turn inside out? 13:02.633 --> 13:06.533 How many think it proved it, or at least supported it? 13:06.533 --> 13:09.073 How many think it had nothing to do with it? 13:09.067 --> 13:09.467 Right. 13:09.467 --> 13:11.897 Because they're different compounds and who knows how 13:11.900 --> 13:13.630 they're going to rotate light, so that 13:13.633 --> 13:15.473 doesn't prove anything. 13:15.467 --> 13:17.867 Now we're going to do the nucleophilic substitution 13:17.867 --> 13:21.897 reaction where the anion is acetate. 13:21.900 --> 13:25.100 And it's going to attack the carbon, and break the bond 13:25.100 --> 13:27.300 from carbon. So the nucleophile attacks, the 13:27.300 --> 13:28.630 leaving group leaves. 13:28.633 --> 13:30.773 This is the reaction we're interested in, whether it 13:30.767 --> 13:32.597 inverts the configuration. 13:32.600 --> 13:36.400 And we find out that we get that product, and that's the 13:36.400 --> 13:39.570 nucleophilic substitution at saturated carbon. 13:39.567 --> 13:43.167 And the rotation of that product is -7 degrees. 13:43.167 --> 13:45.467 So it was an inversion right? 13:45.467 --> 13:48.127 It shows that the carbon turned inside out, because 13:48.133 --> 13:51.733 it's opposite the starting material, right? 13:51.733 --> 13:54.203 I hear you say-- 13:54.200 --> 13:55.870 wrong! 13:55.867 --> 13:56.997 Because it has nothing to do with it. 13:57.000 --> 13:58.270 Same as the first step. 13:58.267 --> 13:59.327 So we don't really know. 13:59.333 --> 14:01.573 That proves nothing. 14:01.567 --> 14:06.297 The only way we're going to prove is to get a product 14:06.300 --> 14:10.130 that's exactly the same as the starting material, except for 14:10.133 --> 14:12.333 the possibility of configuration. 14:12.333 --> 14:14.703 Then we'll know if it's the mirror image, but we can't use 14:14.700 --> 14:17.100 any derivative. 14:17.100 --> 14:23.800 So what we needed to do is change that OCOCH3 into OH. 14:23.800 --> 14:25.170 And you can do that. 14:25.167 --> 14:28.697 You can bring in hydroxide, attack the carbonyl carbon, 14:28.700 --> 14:35.600 which generates this intermediate, and then that 14:35.600 --> 14:39.130 can do this reaction, breaking the CO bond and 14:39.133 --> 14:41.103 generate that anion. 14:41.100 --> 14:42.800 Now there's another product, of course. 14:42.800 --> 14:47.800 The top right of the molecule is this. 14:47.800 --> 14:52.270 It's got OHCCH3, and then that becomes a double bond. 14:52.267 --> 14:55.097 So it's acetic acid. 14:55.100 --> 14:58.170 Incidentally, notice this is a substitution reaction too. 14:58.167 --> 15:01.267 The reaction across the top was a substitution. 15:01.267 --> 15:03.597 The reaction coming down was a substitution. 15:03.600 --> 15:07.770 The reaction going at the bottom is a substitution. 15:07.767 --> 15:11.197 But the top was a substitution at sulfur. 15:11.200 --> 15:13.330 The coming down was the one we're interested in, 15:13.333 --> 15:15.603 substitution at a saturated carbon. 15:15.600 --> 15:18.000 The one going across is substitution 15:18.000 --> 15:20.470 at a carbonyl carbon. 15:20.467 --> 15:21.567 That one. 15:21.567 --> 15:26.427 So OH minus comes in, and this anion comes off. 15:26.433 --> 15:30.873 But again it's possible to do that by association first, and 15:30.867 --> 15:34.467 then dissociation, because there's that vacant pi-star 15:34.467 --> 15:36.127 orbital that you can go in without 15:36.133 --> 15:38.973 breaking anything away. 15:38.967 --> 15:41.327 So we're not interested in the one on the top and the one on 15:41.333 --> 15:43.373 the bottom, we're interested in that one that 15:43.367 --> 15:44.727 comes down the side. 15:44.733 --> 15:46.573 That's the reaction were interested in. 15:46.567 --> 15:51.367 Nucleophilic substitution at saturated carbon. 15:51.367 --> 15:53.797 Now notice the product. 15:53.800 --> 15:56.500 Remember that was an acid and this was an anion. 15:56.500 --> 15:59.700 But of course this is a stronger acid than hydroxide, 15:59.700 --> 16:02.130 so the proton will be transferred in this direction. 16:02.133 --> 16:05.003 And now we have a product which is the same as the 16:05.000 --> 16:08.270 starting material, except possibly for its 16:08.267 --> 16:11.167 configuration. 16:11.167 --> 16:14.227 So the question is, "Is it the same as the starting material?" 16:14.233 --> 16:19.573 Is the normal course of the reaction a replacement or a 16:19.567 --> 16:21.927 displacement? 16:21.933 --> 16:26.833 And the rotation is -32, where it was +33 before. 16:26.833 --> 16:29.503 That's experimental error in the difference. 16:29.500 --> 16:31.630 So it's a displacement. 16:31.633 --> 16:33.773 It inverted the configuration. 16:33.767 --> 16:37.697 And so we know that in this kind of reaction, backside 16:37.700 --> 16:42.500 attack on the carbon, the kind we anticipated, although 16:42.500 --> 16:46.170 nobody could have thought about it in 1923, on the basis 16:46.167 --> 16:50.427 of a sigma-star orbital being attacked where it's big. 16:50.433 --> 16:53.033 So backside attack in nucleophilic substitution at 16:53.033 --> 16:54.273 saturated carbon. 16:54.267 --> 16:57.667 And notice in this scheme that's the only case where you 16:57.667 --> 16:59.227 broke a bond to that carbon. 16:59.233 --> 17:01.873 That's the beauty and the design of this scheme. 17:01.867 --> 17:03.967 Now there's another nice feature in the 17:03.967 --> 17:04.767 design of this scheme. 17:04.767 --> 17:07.367 It looks a little clunky, actually to have to do all 17:07.367 --> 17:08.497 those things. 17:08.500 --> 17:12.230 And you might wonder. "Why not avoid all that stuff going 17:12.233 --> 17:17.803 around the bottom by just doing hydroxide attacking this 17:17.800 --> 17:19.700 sulfonate ester?" 17:19.700 --> 17:23.230 Because if you brought hydroxide in there you'd get 17:23.233 --> 17:27.433 this product, and you'd do it without all this stuff. 17:27.433 --> 17:29.303 But there was a reason in the experimental 17:29.300 --> 17:30.770 design they did that. 17:30.767 --> 17:35.027 Because if you use hydroxide, a much stronger base than 17:35.033 --> 17:39.403 acetate is, then it turns out it attacks that hydrogen, and 17:39.400 --> 17:42.430 pulls it off, when the leaving group leaves. 17:42.433 --> 17:45.273 So you generate a double bond there. 17:45.267 --> 17:46.927 So you don't get the product. 17:46.933 --> 17:49.073 And of course that stuff is achiral, not 17:49.067 --> 17:51.427 that you really care. 17:51.433 --> 17:54.303 But you don't do the reaction if you use hydroxide, so they 17:54.300 --> 17:55.730 had to use acetate. 17:55.733 --> 17:58.303 So this was a very clever experimental design, and 17:58.300 --> 18:03.600 proved that inversion is the normal course, backside attack 18:03.600 --> 18:06.300 on the carbon. 18:06.300 --> 18:07.530 So inversion. 18:09.967 --> 18:13.297 The trivalent intermediate could have been attacked from 18:13.300 --> 18:16.630 either face, and would have given racemic product. 18:16.633 --> 18:19.073 So we can be confident that in this case 18:19.067 --> 18:21.467 that's not the mechanism. 18:21.467 --> 18:23.327 That doesn't mean there couldn't be a case where it's 18:23.333 --> 18:26.133 the mechanism, but it's not the mechanism in this kind of 18:26.133 --> 18:29.933 case, and things that are related to it. 18:29.933 --> 18:33.003 So stereochemistry is a good tool, and it shows inversion. 18:35.867 --> 18:42.967 Which means that it's not a concerted frontside attack, 18:42.967 --> 18:46.197 not a pentavalent intermediate where the nucleophile came in 18:46.200 --> 18:48.930 on the same side the leaving group was leaving. 18:48.933 --> 18:51.403 And it also means that you can't have had the trivalent 18:51.400 --> 18:53.330 intermediate. 18:53.333 --> 18:55.733 Now let's look at the rate law, and what it can tell us. 18:55.733 --> 18:58.333 How the rate depends on concentration. 18:58.333 --> 19:03.333 So this reaction I'm showing here is ethoxide anion attacking 19:03.333 --> 19:04.333 ethyl bromide. 19:04.333 --> 19:07.533 So the ethoxide replaces bromide as the leaving group. 19:07.533 --> 19:10.373 And we're looking at the rate of forming the product or 19:10.367 --> 19:14.697 losing the starting material as a function of how much the 19:14.700 --> 19:16.970 concentration of ethoxide is. 19:16.967 --> 19:18.067 And we're going to fix the 19:18.067 --> 19:20.097 concentration of ethyl bromide. 19:20.100 --> 19:23.070 It's assumed that ethyl bromide, which is the subject 19:23.067 --> 19:24.997 of this whole thing, that rate's going to be 19:25.000 --> 19:26.370 proportional to it. 19:26.367 --> 19:29.827 The question is, is the rate proportional to ethoxide? 19:29.833 --> 19:33.003 So you plot the rate as a function of ethoxide, and you 19:33.000 --> 19:35.370 get a line that looks like that. 19:35.367 --> 19:37.267 So it's a second order rate law. 19:37.267 --> 19:40.097 It's proportional to how much ethyl bromide you have, and 19:40.100 --> 19:43.300 it's proportional how much ethoxide you have. So both of 19:43.300 --> 19:44.730 those things must be in the rate 19:44.733 --> 19:46.473 determining transition state. 19:46.467 --> 19:49.627 Both the ethoxide and the ethyl bromide. 19:49.633 --> 19:53.873 Now there's something funny about this plot. 19:53.867 --> 19:55.097 Do you see what it is? 19:58.900 --> 20:02.930 It's nice and linear, so it's first order in ethoxide. 20:02.933 --> 20:05.033 But what else? 20:05.033 --> 20:05.303 Ayesha? 20:05.300 --> 20:06.570 STUDENT: It doesn't start from zero. 20:06.567 --> 20:09.167 PROFESSOR: It doesn't start at zero. 20:09.167 --> 20:10.027 If you don't have any 20:10.033 --> 20:13.673 ethoxide, you get the reaction. 20:13.667 --> 20:16.927 How can that be? 20:16.933 --> 20:20.473 It's because, although it's second order-- 20:23.000 --> 20:23.300 Wait a second. 20:23.300 --> 20:24.000 What just happened? 20:24.000 --> 20:26.670 Did I press the wrong button? 20:26.667 --> 20:28.767 This was just to say about the second order. 20:28.767 --> 20:31.097 Sorry I got out of whack here. 20:31.100 --> 20:33.900 So the initial rate-limiting dissociation in the 20:33.900 --> 20:37.800 dissocation/association would give a rate independent of 20:37.800 --> 20:39.030 nucleophile, this one. 20:39.033 --> 20:42.733 Because the first step doesn't involve the nucleophile. 20:42.733 --> 20:44.533 Only the second step. 20:44.533 --> 20:47.933 So if the rate-limiting step depends on nucleophile, it 20:47.933 --> 20:49.233 can't be this mechanism. 20:49.233 --> 20:52.033 So we could exclude it on this basis, as well as on the 20:52.033 --> 20:53.303 stereochemistry. 20:56.867 --> 20:59.297 Back to this, we have the problem that 20:59.300 --> 21:00.530 Ayesha brought up. 21:00.533 --> 21:03.473 How can you get the product if there's no ethoxide? 21:07.467 --> 21:10.427 So there must be a reaction that's going on all the time, 21:10.433 --> 21:12.573 whether you have ethoxide or not. 21:12.567 --> 21:15.627 And then another reaction that depends on ethoxide. 21:15.633 --> 21:16.873 What's that first reaction? 21:19.533 --> 21:22.603 It doesn't depend on the concentration of ethoxide, so 21:22.600 --> 21:25.100 it seems to be a first order process. 21:25.100 --> 21:26.330 It's constant. 21:29.300 --> 21:31.730 First order could be dissociation followed by 21:31.733 --> 21:34.973 association, so there could be some of that 21:34.967 --> 21:36.997 going on all the time. 21:37.000 --> 21:40.200 And then a little bit of this where the ethoxide attacks, 21:40.200 --> 21:42.000 getting more and more as you have a higher 21:42.000 --> 21:43.900 concentration of ethoxide. 21:43.900 --> 21:47.100 But that's not what it is. 21:47.100 --> 21:49.930 This is done in ethanol solvent. 21:49.933 --> 21:53.133 So the unshared pair on the oxygen of the solvent can 21:53.133 --> 21:57.133 attack, the same way the unshared pair on ethoxide can. 21:57.133 --> 22:00.773 Of course the ethoxide has a much higher HOMO because of 22:00.767 --> 22:04.297 its negative charge, so it will react faster. 22:04.300 --> 22:07.130 But there's a lot of the ethanol there compared to how 22:07.133 --> 22:09.873 much ethoxide, especially here at the beginning when you 22:09.867 --> 22:13.267 don't have any ethoxide at all. 22:13.267 --> 22:17.567 So actually that second process is a pseudo first 22:17.567 --> 22:18.927 order reaction. 22:18.933 --> 22:21.673 It depends on the concentration of ethanol. 22:21.667 --> 22:26.067 But ethanol solvent's concentration is constant. 22:26.067 --> 22:29.167 So it appears to be first order. 22:29.167 --> 22:34.327 But it's actually a pseudo first order process where the 22:34.333 --> 22:38.333 first order rate constant is k-pseudo times the 22:38.333 --> 22:43.233 concentration of ethanol, which is not changing. 22:43.233 --> 22:46.503 So now we have these two possible reactions, ethoxide 22:46.500 --> 22:50.530 or ethanol, unshared pair, attacking the sigma-star of 22:50.533 --> 22:51.773 ethyl bromide. 22:53.567 --> 22:59.027 We can tell at this point here, when it's half and half, 22:59.033 --> 23:02.933 half the mechanism is pseudo first order, half the rate is 23:02.933 --> 23:04.403 the second order. 23:04.400 --> 23:08.100 Then we know that whatever the difference in these rate 23:08.100 --> 23:11.470 constants is, is made up by the difference in 23:11.467 --> 23:15.527 concentration, so that they have the same rate. 23:15.533 --> 23:18.673 That is, there's enough ethoxide, a small amount of 23:18.667 --> 23:22.127 ethoxide with a much higher rate constant, so it has the 23:22.133 --> 23:24.933 same overall rate as the pseudo first order rate 23:24.933 --> 23:26.003 constant does. 23:26.000 --> 23:29.530 And from that you can figure out that the second order rate 23:29.533 --> 23:32.803 constant is 20,000 times faster than 23:32.800 --> 23:34.500 first order rate constant. 23:34.500 --> 23:37.830 So this is 20,000 times faster than that. 23:37.833 --> 23:40.533 Now does that make sense to you? 23:40.533 --> 23:41.433 Yeah, it does. 23:41.433 --> 23:46.233 Because you'd expect the much higher HOMO of the anion to 23:46.233 --> 23:47.833 attack more rapidly. 23:47.833 --> 23:49.673 How much more rapidly? 23:49.667 --> 23:53.067 Do you have any way of measuring how reactive these 23:53.067 --> 23:55.427 two things should be? 23:55.433 --> 23:56.903 These two HOMOs? 23:56.900 --> 24:00.300 Any way of measuring how high the relative height of those 24:00.300 --> 24:06.330 two HOMOs, and their ability to form a bond. 24:09.000 --> 24:10.270 Hint it's what we talked about in the last lecture. 24:12.600 --> 24:13.600 Debby? 24:13.600 --> 24:14.570 STUDENT: pKa. 24:14.567 --> 24:15.597 PROFESSOR: pKa. 24:15.600 --> 24:18.830 How different are they in attacking a proton. 24:21.667 --> 24:26.397 So, the analogy to that is attacking protons. 24:26.400 --> 24:29.170 And that's an equilibrium that's easy to measure by the 24:29.167 --> 24:30.497 way we did last time. 24:30.500 --> 24:39.900 We find out that their pKa's differ by 17.5 powers of ten. 24:39.900 --> 24:41.900 Here they differ by only a little more 24:41.900 --> 24:44.170 than 4 powers of ten. 24:44.167 --> 24:49.227 So you might expect it to be even bigger, the difference. 24:49.233 --> 24:53.403 But in fact this is measured in equilibrium. 24:53.400 --> 24:56.670 When you've completely formed the bond. 24:56.667 --> 25:00.127 Whereas in the nucleophilic substitution, we're only at a 25:00.133 --> 25:01.233 transition state. 25:01.233 --> 25:03.903 We haven't completely formed the bond. 25:03.900 --> 25:07.470 So you don't expect it to be as big a difference by the 25:07.467 --> 25:08.927 Hammond postulate kind of thing. 25:08.933 --> 25:10.503 You're only part of the way across. 25:10.500 --> 25:11.500 Not all the way. 25:11.500 --> 25:18.000 So it's maybe not surprising that seems a plausible rate 25:18.000 --> 25:20.630 constant ratio. 25:20.633 --> 25:21.773 So that makes sense. 25:21.767 --> 25:26.567 So the rate law then, shows that it can't be dissociation 25:26.567 --> 25:30.767 first, because that wouldn't depend on how much nucleophile 25:30.767 --> 25:31.697 you have there. 25:31.700 --> 25:36.500 Nor can it be frontside attack, either concerted or 25:36.500 --> 25:38.870 pentavalent intermediate and then lose the leaving group. 25:38.867 --> 25:44.197 It has to be from the backside. 25:44.200 --> 25:47.230 Another thing you can test, is not just how it depends on 25:47.233 --> 25:51.403 concentration, but what the rate constant is. 25:51.400 --> 25:54.300 In fact we just looked in the last slide at whether these 25:54.300 --> 25:57.100 rate constants were plausible for a higher 25:57.100 --> 26:00.800 HOMO and a lower HOMO. 26:00.800 --> 26:04.300 So the rate constant will depend, certainly on what the 26:04.300 --> 26:08.070 nucleophile is, ethoxide versus ethanol. 26:08.067 --> 26:10.897 But it will also depend on what R is, what the leaving 26:10.900 --> 26:14.700 group is, what the solvent is. 26:14.700 --> 26:17.200 It also may be on the nature of the product. 26:17.200 --> 26:21.270 For example whether the product is charged or not. 26:21.267 --> 26:25.127 So all of these things will influence the rate constant, 26:25.133 --> 26:28.433 and we're going to look at the whole set of them, one at a 26:28.433 --> 26:32.433 time, and see whether these tell us something about the 26:32.433 --> 26:34.133 mechanism of the reaction. 26:34.133 --> 26:37.303 First let's look at the substrate, the R group. 26:37.300 --> 26:42.730 Here are different R's, and the relative rate constant for 26:42.733 --> 26:51.503 how fast they get attacked by iodide in acetone solvent at 26:51.500 --> 26:54.870 room temperature, when bromide is the leaving group. 26:54.867 --> 27:01.067 So this is how the relative rates as we change R. We'll 27:01.067 --> 27:04.767 call ethyl 1. 27:04.767 --> 27:06.727 Then, methyl is much faster. 27:10.400 --> 27:15.800 But propyl is about the same rate. 27:15.800 --> 27:18.370 Isopropyl is ever so much slower. 27:21.633 --> 27:26.673 The isobutyl is faster again. 27:26.667 --> 27:29.367 t-butyl is very slow. 27:29.367 --> 27:32.327 In fact, you don't know how slow it is. 27:32.333 --> 27:34.333 It's got to be slower than that. 27:34.333 --> 27:37.473 Because something else happens other than the reaction we're 27:37.467 --> 27:37.797 talking about. 27:37.800 --> 27:42.670 So all you know is it can't be any faster than that. 27:42.667 --> 27:48.167 And neopentyl is really, really slow. 27:48.167 --> 27:51.997 Now, do these make sense? 27:52.000 --> 27:53.970 Let's look at it in two ways. 27:53.967 --> 27:57.027 First we could have substituents on the alpha 27:57.033 --> 28:00.073 carbon, the carbon that has the leaving group on it. 28:00.067 --> 28:04.297 And notice here we add one methyl group to that carbon. 28:04.300 --> 28:06.430 Here we've added two methyl groups to that carbon. 28:06.433 --> 28:08.973 Here we've added three methyl groups to that carbon. 28:08.967 --> 28:11.427 So we can have alpha-substitution. 28:11.433 --> 28:13.673 But we can also have beta-substitution. 28:13.667 --> 28:15.727 We can add methyls to this carbon. 28:15.733 --> 28:17.773 Here we put one methyl on that carbon. 28:17.767 --> 28:20.467 Here we put two methyls on that second carbon. 28:20.467 --> 28:23.227 Here we put three methyls on that second carbon. 28:23.233 --> 28:26.733 So we can try to classify it as we put extra methyls on a 28:26.733 --> 28:28.403 particular carbon. 28:28.400 --> 28:30.630 So those are the beta-substituents, for 28:30.633 --> 28:33.773 example, one, two, or three methyl groups on that 28:33.767 --> 28:34.997 beta-carbon. 28:36.633 --> 28:41.403 Now notice that as we put a methyl group on the 28:41.400 --> 28:45.500 alpha-carbon, the first carbon, we add a methyl group 28:45.500 --> 28:46.770 to it in place of hydrogen. 28:49.733 --> 28:54.973 As we add it, it decreases the rate by 145 times. 28:54.967 --> 28:57.527 So there's a higher activation energy, enough to 28:57.533 --> 29:01.233 slow it by 145 fold. 29:01.233 --> 29:03.503 Now let's put a second one on. 29:03.500 --> 29:06.570 That slows it down by 128. 29:06.567 --> 29:08.527 Another factor of 128. 29:08.533 --> 29:09.633 About the same. 29:09.633 --> 29:13.433 So the influence of the first methyl group in slowing it 29:13.433 --> 29:16.203 down is about the same as the influence of the 29:16.200 --> 29:17.470 second methyl group. 29:17.467 --> 29:19.227 How about the third methyl group? 29:19.233 --> 29:20.503 Do you see what it does? 29:23.667 --> 29:27.627 So that means it's raising the activation energy by about the 29:27.633 --> 29:30.073 same amount each time you do that. 29:30.067 --> 29:32.427 So you might think that the third one would do it by that 29:32.433 --> 29:39.233 amount, but in fact all you know is that it's 29:39.233 --> 29:41.273 greater than 15 times. 29:41.267 --> 29:43.567 You can't really measure it because 29:43.567 --> 29:45.567 something else happens. 29:45.567 --> 29:47.597 Now let's look at the same thing with respect to the 29:47.600 --> 29:49.200 beta-hydrogen. 29:49.200 --> 29:53.000 The first one slows it down almost not at all. 29:53.000 --> 29:54.370 From 1 to 0.82. 29:54.367 --> 29:56.667 Only by a factor of 1.2. 29:56.667 --> 30:00.367 The second one slows it down by a factor of twenty three. 30:00.367 --> 30:03.197 But how about the third one? 30:03.200 --> 30:06.370 Slows it by 3,000 fold! 30:06.367 --> 30:10.197 Why does the third one make so much difference, where the 30:10.200 --> 30:12.730 first two don't make much difference of adding those 30:12.733 --> 30:14.773 methyl groups? 30:14.767 --> 30:19.197 Well here's the case in methyl with bromide ready to leave, 30:19.200 --> 30:21.370 and we have to attack the backside. 30:21.367 --> 30:23.797 Or let us suppose we're attacking the backside, which 30:23.800 --> 30:27.570 seems plausible on the basis of the stereochemistry and the 30:27.567 --> 30:29.297 rate constant. 30:29.300 --> 30:32.530 That means we're attacking that LUMO. 30:32.533 --> 30:35.673 Now let's look at that same thing in the case of the 30:35.667 --> 30:37.527 alpha-substitution. 30:37.533 --> 30:41.003 There's that-- between the red and the second blue is the 30:41.000 --> 30:44.570 anti-bonding node that's going to break. 30:44.567 --> 30:47.767 Here's the surface potential. 30:47.767 --> 30:51.027 The blue area is a good place to put an anion, 30:51.033 --> 30:53.233 so that makes sense. 30:53.233 --> 30:58.773 So we have methyl, ethyl, isopropyl, and t-butyl. 30:58.767 --> 31:01.397 Let's look at the total electron densities. 31:01.400 --> 31:04.270 Notice methyl, the arrow, gets there OK. 31:04.267 --> 31:05.627 Ethyl gets there OK. 31:05.633 --> 31:08.103 Although it's bumping into this thing at the back a 31:08.100 --> 31:11.100 little bit, but it could lean forward just a little bit to 31:11.100 --> 31:12.370 avoid that. 31:12.367 --> 31:15.227 Here it's getting in trouble. 31:15.233 --> 31:19.903 That slows it down by a factor of 23. 31:19.900 --> 31:20.430 Oh. 31:20.433 --> 31:20.773 Let's see. 31:20.767 --> 31:22.067 I've got the wrong one. 31:22.067 --> 31:25.027 This was 100, that's another factor of a hundred-- 31:25.033 --> 31:29.373 But this one is a much bigger factor because you just can't 31:29.367 --> 31:30.827 get there now when you have three. 31:30.833 --> 31:34.773 So the third one is what really stops it. 31:34.767 --> 31:36.697 And this is called steric hindrance. 31:36.700 --> 31:40.030 The space gets in the way. 31:40.033 --> 31:42.803 So that's the effect of alpha-methylation. 31:42.800 --> 31:44.370 Let's look at the LUMO. 31:44.367 --> 31:47.267 It looks pretty complicated. 31:47.267 --> 31:49.827 The reason I put it up is not to look at that, but to look 31:49.833 --> 31:53.203 at that one orbital in the context of the total 31:53.200 --> 31:54.900 electronic density. 31:54.900 --> 31:57.570 So there it is at 0.06 contour. 31:57.567 --> 32:00.567 And now I'll put the total electron density there, and 32:00.567 --> 32:03.897 look through that to see how much we can see of that LUMO 32:03.900 --> 32:05.600 that we need to attack. 32:05.600 --> 32:07.800 So you see, you can really see it here. 32:07.800 --> 32:10.170 You could see it a little bit here, and a little bit here, 32:10.167 --> 32:14.027 but you can't see it at all from the backside here. 32:14.033 --> 32:16.233 So this one is going to be shut down. 32:18.733 --> 32:22.373 And there's the surface potential, and you see even 32:22.367 --> 32:25.297 the surface potential isn't as good here as it is in the 32:25.300 --> 32:28.630 other ones for the anion to come in and attack. 32:28.633 --> 32:31.973 Now let's look at the beta-methylation, where we 32:31.967 --> 32:39.097 have this carbon, and we start putting one, two or 32:39.100 --> 32:41.800 three on that one. 32:41.800 --> 32:42.900 And here are the rates remember. 32:42.900 --> 32:48.970 One, 0.82, 0.036, and then 0.000012. 32:48.967 --> 32:50.497 Why is the third one so bad? 32:53.200 --> 32:55.370 Well you see this one can get in there. 32:55.367 --> 32:57.667 That one can get in there just as well, because this methyl 32:57.667 --> 33:00.697 group, the substituent is out of the way. 33:00.700 --> 33:04.170 You can put two of them out of the way, but the third one you 33:04.167 --> 33:05.267 can't get out of the way. 33:05.267 --> 33:07.767 Once you have three, there's no way to avoid it. 33:07.767 --> 33:10.627 So that one gets slowed way down. 33:10.633 --> 33:13.873 No way to avoid the third beta-methyl group. 33:13.867 --> 33:17.167 There you can see that you can't get any place near the 33:17.167 --> 33:20.367 really good blue areas. 33:20.367 --> 33:25.627 So this is consistent with the idea that you have a 33:25.633 --> 33:29.103 transition state that involves backside attack. 33:29.100 --> 33:32.000 Not the planar intermediate. 33:32.000 --> 33:34.230 Now there's a question. 33:34.233 --> 33:37.273 Might it be possible to have frontside attack. 33:37.267 --> 33:41.327 Might it be just easier to do backside, but you could do 33:41.333 --> 33:45.503 frontside attack if the other one weren't faster? 33:45.500 --> 33:49.730 How hard is it to do frontside attack? 33:49.733 --> 33:52.673 So is this possible? 33:52.667 --> 33:59.797 Or is it possible to form a cation that's not planar? 33:59.800 --> 34:03.330 So could you have it bent, and not planar, so that the 34:03.333 --> 34:05.633 stereochemical consequences would not 34:05.633 --> 34:08.433 necessarily be inversion. 34:08.433 --> 34:11.803 Might it be possible to have a non-planar cation as an 34:11.800 --> 34:12.470 intermediate? 34:12.467 --> 34:16.367 But remember that BH3, which has the same 34:16.367 --> 34:20.967 electrons that CH3+ does. 34:20.967 --> 34:23.827 Remember we talked last semester about XH3, that when 34:23.833 --> 34:28.333 that's a cation, or in BH3, you expect it to be planar, 34:28.333 --> 34:33.573 but still might not be too bad to have bent. 34:33.567 --> 34:38.597 This was the subject of a second really classic 34:38.600 --> 34:40.870 experiment in the twentieth century. 34:40.867 --> 34:43.227 The first one I talked about, which I really love, is that 34:43.233 --> 34:45.103 Kenyon and Phillips that proves that 34:45.100 --> 34:46.530 it must be an inversion. 34:46.533 --> 34:49.433 But there's another one that shows that it's not possible 34:49.433 --> 34:50.673 to have frontside attack. 34:50.667 --> 34:53.527 At least it's very, very hard. 34:53.533 --> 34:56.403 And it's not possible to have a non-planar cation. 34:56.400 --> 34:59.070 At least it's very, very hard. 34:59.067 --> 35:03.427 That was in this paper published in 1939, 35:03.433 --> 35:06.073 which if you click there you can download a copy of the 35:06.067 --> 35:08.427 paper, by Bartlett and Knox. 35:08.433 --> 35:13.233 So this is your chemical grandfather, P.D. Bartlett, 35:13.233 --> 35:15.073 who was a young man at that time. 35:15.067 --> 35:19.597 He was 32-years-old, and Knox, who was his graduate student, 35:19.600 --> 35:23.230 who was almost the same age, because he was an African 35:23.233 --> 35:25.973 American, one of the first African Americans to get a 35:25.967 --> 35:30.327 Ph.D. in chemistry. 35:30.333 --> 35:35.303 And if you click on that asterisk, you can download an 35:35.300 --> 35:37.500 account of his life, which is fascinating. 35:37.500 --> 35:40.570 He's the grandson of a slave, and he has a lot of trouble. 35:40.567 --> 35:43.967 And that's why he was old at the time he got his Ph.D. But 35:43.967 --> 35:46.167 you can read about it there if you want to. 35:46.167 --> 35:51.397 At any rate, they specifically designed and prepared this 35:51.400 --> 35:54.830 molecule to test the mechanistic questions. 35:54.833 --> 35:58.033 This is rather different than just taking things, reacting 35:58.033 --> 36:01.203 them, messing around, observing what happens, and 36:01.200 --> 36:02.730 then trying to interpret it. 36:02.733 --> 36:06.903 They specifically designed a molecule that would test these 36:06.900 --> 36:10.570 questions about whether you could have frontside attack, 36:10.567 --> 36:13.367 whether you could have a nonplanar cation. 36:13.367 --> 36:16.727 And one that wouldn't be complicated by other problems. 36:16.733 --> 36:18.903 So they thought through very carefully to design it. 36:18.900 --> 36:24.200 And then Knox had to prepare it and study it. 36:24.200 --> 36:27.270 Now this is a comment about that paper. 36:27.267 --> 36:30.467 "In 1939 Bartlett and Knox published the account of their 36:30.467 --> 36:33.127 work on the bridge-head chloride, apocamphyl 36:33.133 --> 36:35.973 chloride." That's where X equals Cl. 36:35.967 --> 36:39.167 "I believed then, and I believe now, that this was a 36:39.167 --> 36:41.797 fantastically influential paper. 36:41.800 --> 36:45.200 For thirty years afterwards, no one really accepted any 36:45.200 --> 36:47.800 mechanism unless it had been tested out on 36:47.800 --> 36:50.030 a bridgehead case. 36:50.033 --> 36:53.773 Indeed, the Bartlett-Knox paper shaped the interests and 36:53.767 --> 36:56.467 viewpoint of many chemists about the kind of physical 36:56.467 --> 36:58.167 organic they wanted to do. " 36:58.167 --> 37:00.467 And that's a quote from John D. Roberts, who is an 37:00.467 --> 37:04.027 Institute Professor at Caltech, and one of the real 37:04.033 --> 37:07.773 leaders of organic chemistry through the twentieth century. 37:07.767 --> 37:09.227 And he's still living now. 37:09.233 --> 37:13.033 He said that in 1975. 37:13.033 --> 37:15.933 This is the structure of that molecule 37:15.933 --> 37:17.603 with balls and sticks. 37:17.600 --> 37:23.800 And it became so important, this kind of structure, that 37:23.800 --> 37:26.800 people who are in the field know how to draw it quickly. 37:26.800 --> 37:29.700 And I'll show you how to draw it. 37:29.700 --> 37:32.130 It has that stick structure. 37:32.133 --> 37:33.333 And here's how you draw it. 37:33.333 --> 37:36.733 You first form, or I do any how, different people draw it 37:36.733 --> 37:37.333 different ways. 37:37.333 --> 37:41.773 But you draw this sort of a distorted W. And then you 37:41.767 --> 37:44.267 start at the nearest carbon, and draw up and 37:44.267 --> 37:46.427 down, and to the right. 37:46.433 --> 37:50.373 And then you draw the last bond, and you draw it last, 37:50.367 --> 37:52.097 because it goes behind that one. 37:52.100 --> 37:54.270 So you make it broken, so it has a sort of a 37:54.267 --> 37:57.467 3D aspect to it. 37:57.467 --> 38:00.067 That's this case. 38:00.067 --> 38:01.067 And notice what it is. 38:01.067 --> 38:02.297 It's a boat cyclohexane. 38:04.967 --> 38:07.797 It has a bridge across the top. 38:07.800 --> 38:09.730 So it's a bridged compound. 38:09.733 --> 38:13.173 And formally it's called a bicycloheptane. 38:13.167 --> 38:16.727 It's got seven carbons, the six of the cyclohexane plus 38:16.733 --> 38:18.703 the bridge. 38:18.700 --> 38:21.930 And you give numbers in brackets in the middle of 38:21.933 --> 38:24.973 bicyclo to say how many carbons 38:24.967 --> 38:26.527 there are in each bridge. 38:26.533 --> 38:30.903 So there's a two carbon bridge, between these two, and 38:30.900 --> 38:33.170 a one carbon bridge. 38:33.167 --> 38:37.567 And those two positions are called bridgeheads. 38:37.567 --> 38:40.097 So this is a bridgehead chloride that we have in the 38:40.100 --> 38:45.230 molecule of the apocamphyl chloride that they designed 38:45.233 --> 38:48.003 and then prepared to study. 38:48.000 --> 38:51.300 Now here's a space filling model of it, and there's where 38:51.300 --> 38:54.000 you would have to attack to get in the backside of 38:54.000 --> 38:55.270 sigma-star. 38:55.267 --> 38:57.727 So that's obviously out of the question, that you 38:57.733 --> 38:58.773 could get in there. 38:58.767 --> 39:02.097 So the molecule was designed so you can't do backside 39:02.100 --> 39:02.800 displacement. 39:02.800 --> 39:05.600 The question is if you can't do backside, can you do 39:05.600 --> 39:08.670 frontside displacement? 39:08.667 --> 39:11.127 So the attack would have to be frontside. 39:11.133 --> 39:14.503 Now notice something else about this structure. 39:14.500 --> 39:17.530 That if you were to flatten that carbon, if you were to 39:17.533 --> 39:22.503 lose the chloride without attacking it, and generate a 39:22.500 --> 39:26.670 flat cation, that would require generating really 39:26.667 --> 39:30.127 strongly-strained angles here, and here, and here. 39:30.133 --> 39:32.803 And it was estimated by Bartlett and Knox that that 39:32.800 --> 39:36.130 would cost more than 23 kilocalories per mole. 39:36.133 --> 39:38.673 Which 3/4 of that is 16. 39:38.667 --> 39:42.567 So it would be 10^-16 factor in rate. 39:42.567 --> 39:44.867 Forget that. 39:44.867 --> 39:47.167 So they've designed the molecule so it can't undergo 39:47.167 --> 39:51.397 backside displacement, and it can't give the cation either, 39:51.400 --> 39:55.070 lose the chloride to generate the cation. 39:55.067 --> 39:58.497 If you were to get a cation, it would have to not be 39:58.500 --> 40:03.730 planar, otherwise it would be slowed down by 10^16 fold. 40:03.733 --> 40:07.833 So they set up to answer those two questions. 40:07.833 --> 40:10.203 But there's another possible competition. 40:10.200 --> 40:13.200 Remember in Kenyon and Phillips, they couldn't use 40:13.200 --> 40:16.270 hydroxide, they had to use acetate, because the reaction 40:16.267 --> 40:18.997 would go otherwise if they used the 40:19.000 --> 40:21.230 strong base, hydroxide. 40:21.233 --> 40:25.233 So might competition from loss of HCl to generate a double 40:25.233 --> 40:27.503 bond be a problem here? 40:27.500 --> 40:31.130 Well, although there are hydrogens on the carbon 40:31.133 --> 40:34.433 adjacent to the carbon bearing the chloride, there are 40:34.433 --> 40:35.833 beta-hydrogens. 40:35.833 --> 40:38.473 But they're not in the position you would need in 40:38.467 --> 40:40.397 order to get elimination. 40:40.400 --> 40:43.000 Notice that if you had hydrogens here, here, and 40:43.000 --> 40:46.070 here, then you could do the elimination. 40:46.067 --> 40:49.127 This is anti to the leaving group, so you to do that, and 40:49.133 --> 40:50.833 make a double bond there. 40:50.833 --> 40:56.833 But there are not hydrogens here, or here, or here. 40:56.833 --> 40:59.603 So you can't do the elimination. 40:59.600 --> 41:02.600 Those are gauche, not anti to the chloride 41:02.600 --> 41:05.500 that going to be leaving. 41:05.500 --> 41:09.200 And even if you could break off H and Cl, this would be 41:09.200 --> 41:11.970 the double bond you would generate. 41:11.967 --> 41:15.427 Now think about that double bond. 41:15.433 --> 41:18.333 Here's the p orbital on the carbon that used to have the 41:18.333 --> 41:21.573 chlorine in it. 41:21.567 --> 41:24.497 But here's the p orbital on the carbon that now has only 41:24.500 --> 41:25.730 one hydrogen. 41:25.733 --> 41:28.803 What's wrong? 41:28.800 --> 41:31.630 They don't overlap. 41:31.633 --> 41:33.333 There's horrid overlap. 41:33.333 --> 41:37.933 So in fact, there's a rule called Bredt's rule that 41:37.933 --> 41:40.973 a carbon-carbon double bond cannot originate from such a 41:40.967 --> 41:42.527 bridgehead. 41:42.533 --> 41:45.703 Incidently, I looked up Bredt's paper yesterday, and 41:45.700 --> 41:49.830 it's interesting that Bredt himself calls it Bredt's rule. 41:49.833 --> 41:52.973 Usually somebody else names it in honor of the inventor, but 41:52.967 --> 41:54.397 Bredt didn't wait around. 41:56.933 --> 41:59.803 Would competition from loss of HCl make it hard to do? 41:59.800 --> 42:00.530 No. 42:00.533 --> 42:03.573 So here's the beauty of the design of this molecule. 42:03.567 --> 42:06.027 It can't do backside displacement. 42:06.033 --> 42:09.973 If it forms a cation, it has to be a non-planar cation, and 42:09.967 --> 42:13.097 it can't do elimination, so how reactive is it? 42:13.100 --> 42:15.700 Well here's the part of the paper that discusses that. 42:15.700 --> 42:20.500 It says "all attempts to replace the chlorine failed." 42:20.500 --> 42:23.900 You can't do displacement on this bridgehead chloride. 42:23.900 --> 42:27.000 They refluxed it "for twenty-one hours with 30% 42:27.000 --> 42:30.800 potassium hydroxide in 80% ethanol." And they didn't get 42:30.800 --> 42:32.170 any reaction. 42:32.167 --> 42:35.767 Notice they said it was a little hard to do because 42:35.767 --> 42:39.697 these vigorous conditions attacked the glass, but they 42:39.700 --> 42:41.030 didn't attack this molecule. 42:44.333 --> 42:48.073 So that frontside attack, where you can't come at the 42:48.067 --> 42:51.167 backside, you have to come in from the front, must be at 42:51.167 --> 42:54.167 least a million times slower than the 42:54.167 --> 42:55.627 typical backside attacks. 42:55.633 --> 42:59.733 So probably much, much slower than that. 42:59.733 --> 43:03.273 Now how about the possibility of forming the cation. 43:03.267 --> 43:06.097 They said they refluxed it with silver nitrate in aqueous 43:06.100 --> 43:09.200 ethanol solution for two days. 43:09.200 --> 43:11.300 What's the idea of the silver? 43:11.300 --> 43:15.600 Because silver can attack the unshared pair on chlorine, and 43:15.600 --> 43:21.100 form a bond, and break the bond from the R, to leave a 43:21.100 --> 43:25.300 cation of R. So instead of pushing by attacking the 43:25.300 --> 43:27.800 backside, you pull the chloride 43:27.800 --> 43:31.300 off leaving the cation. 43:31.300 --> 43:36.400 So that's a good way to generate cations, except in 43:36.400 --> 43:37.830 this case it didn't work. 43:37.833 --> 43:40.703 There was no opalescence. 43:40.700 --> 43:42.370 The solution remained clear. 43:42.367 --> 43:44.067 Why opalescence? 43:44.067 --> 43:47.367 Because if you get this reaction, the sodium chloride, 43:47.367 --> 43:48.667 makes a precipitate. 43:48.667 --> 43:51.427 If you get just a little bit of it, you can see a little 43:51.433 --> 43:52.903 bit of cloudiness there. 43:52.900 --> 43:56.000 But they saw none, and in fact as you can read here, "the 43:56.000 --> 43:59.930 reaction of silver nitrate with 1-chloroapocamphane is 43:59.933 --> 44:05.873 least 2 x 10^-10 at about 85 degrees." 44:05.867 --> 44:14.397 Now the reaction in this compound, so it's carbon that 44:14.400 --> 44:19.070 has two methyls and an ethyl on it. 44:19.067 --> 44:21.967 This one here is at least a billion 44:21.967 --> 44:23.727 times slower than that. 44:23.733 --> 44:26.703 And when this one was measured, it was done 60 44:26.700 --> 44:31.200 degrees cooler, and without the silver pulling on it. 44:31.200 --> 44:37.070 So it's many, many, many powers of 10 more difficult to 44:37.067 --> 44:39.267 form this cation when it's bent. 44:39.267 --> 44:43.867 So it's very hard to form bent cations. 44:43.867 --> 44:47.467 And it's very hard to do frontside attack. 44:47.467 --> 44:52.027 So this was a beautiful experiment where they 44:52.033 --> 44:53.903 specifically designed a molecule to 44:53.900 --> 44:55.300 answer these questions. 44:55.300 --> 44:58.800 And it succeeded, and it became the model for many 44:58.800 --> 45:01.700 kinds of mechanistic studies that were done over the next 45:01.700 --> 45:03.770 thirty years. 45:03.767 --> 45:07.467 Now there are also interesting cases when the R 45:07.467 --> 45:09.127 group is in a ring. 45:09.133 --> 45:12.903 So here's no ring at all, just two methyl groups, then three, 45:12.900 --> 45:14.830 four, five, and six membered rings. 45:14.833 --> 45:18.573 And we're going to displace the bromide. 45:18.567 --> 45:22.027 Now cyclopentyl bromide is almost exactly the same rate 45:22.033 --> 45:25.303 as isopropyl bromide, which we're taking to be 1 for 45:25.300 --> 45:27.330 relative purposes. 45:27.333 --> 45:35.303 But cyclobutyl is very much slower, 200 times slower. 45:35.300 --> 45:40.670 And cyclopropyl is very, very much slower than that. 45:40.667 --> 45:44.827 Now any ideas about why there's no problem with 45:44.833 --> 45:48.303 cyclopentane, but cyclobutyl and cyclopropyl are bad. 45:52.000 --> 45:55.600 What do you think about when you compare those rings? 45:55.600 --> 45:56.070 Chris? 45:56.067 --> 45:56.997 STUDENT: Strain. 45:57.000 --> 45:57.730 PROFESSOR: Strain. 45:57.733 --> 45:59.473 Right, exactly. 45:59.467 --> 46:02.567 That one has 109 degree bond angle, and so does 46:02.567 --> 46:06.227 cyclopentane, but the others have very small bond angles. 46:06.233 --> 46:08.003 Now wait a second. 46:08.000 --> 46:11.570 This strain is in the starting material. 46:11.567 --> 46:15.197 If you destabilize the starting material, you should 46:15.200 --> 46:17.230 make a reaction faster, not slower. 46:19.767 --> 46:23.127 So that in itself seems to be backwards. 46:26.533 --> 46:29.433 What the heck is going on? 46:29.433 --> 46:31.073 Let's think about the transition 46:31.067 --> 46:32.127 state for the reaction. 46:32.133 --> 46:34.573 How hard does it get from the starting material to the 46:34.567 --> 46:35.567 transition state? 46:35.567 --> 46:38.167 That's what determines the rate. 46:38.167 --> 46:41.097 So the transition state looks like this. 46:41.100 --> 46:45.100 And it wants-- it's sp2 hybridized to make those bonds 46:45.100 --> 46:47.770 to the original substituents. 46:47.767 --> 46:51.067 So it wants to have 120 degree bond angle. 46:51.067 --> 46:54.367 Beforehand, it wanted to have 109 degree bond angle. 46:54.367 --> 46:58.327 Now it wants the bond angle to be even bigger. 46:58.333 --> 47:00.733 So if you have a 60 degree bond angle and it wants to be 47:00.733 --> 47:05.873 120, that's worse than having 60 when it wants to be 109. 47:05.867 --> 47:09.697 So indeed the starting material is strained. 47:09.700 --> 47:13.000 But the transition state is even more strained. 47:13.000 --> 47:15.230 So you always have to compare the starting material and the 47:15.233 --> 47:17.573 transition state in a situation like this. 47:17.567 --> 47:20.927 So the increased strain in the transition state is 47:20.933 --> 47:22.333 what slows it down. 47:22.333 --> 47:24.273 Now how about cyclohexane? 47:24.267 --> 47:30.427 It has 109 degree bond angle here, but it's slowed down. 47:30.433 --> 47:31.803 It can't be this kind of thing. 47:31.800 --> 47:34.230 It could go to 120 no problem. 47:34.233 --> 47:38.503 No problem with making 120 degree bond angle here. 47:38.500 --> 47:42.430 Can you see what the problem is in the six member ring? 47:42.433 --> 47:46.303 Why is it slower than five? 47:46.300 --> 47:48.770 Remember the shape of the five member ring? 47:48.767 --> 47:49.797 It's almost flat. 47:49.800 --> 47:51.870 A little bit puckered. 47:51.867 --> 47:57.827 But cyclohexane is the chair, which means that chloride is 47:57.833 --> 48:03.273 running into these two CH2 groups right here. 48:03.267 --> 48:05.497 In cyclopentane, those other groups would be out 48:05.500 --> 48:09.530 here, not up here. 48:09.533 --> 48:13.373 And you notice that it's strained because the line 48:13.367 --> 48:16.727 between the leaving group and the nucleophile is bent here. 48:16.733 --> 48:19.333 This thing is being pushed back. 48:19.333 --> 48:22.503 So there's a different kind of strain in this case that slows 48:22.500 --> 48:27.900 it down by a factor of 200, compared to that one. 48:27.900 --> 48:35.970 So we've seen the rate constant dependence on R. Now 48:35.967 --> 48:37.827 we're going to look at it just really quickly on the 48:37.833 --> 48:39.833 nucleophile. 48:39.833 --> 48:42.403 So here are a bunch of nucleophiles, and they get 48:42.400 --> 48:45.600 faster, and faster, and faster. 48:45.600 --> 48:48.130 Now, is it the same with the proton? 48:48.133 --> 48:51.233 How about the pKa's? 48:51.233 --> 48:54.833 If we look at this, water as a 48:54.833 --> 48:56.373 leaving group[correction; as a nucleophile],flouride, and 48:56.367 --> 49:05.297 hydroxide, you see that indeed, as it gets to be a 49:05.300 --> 49:10.930 stronger acid, it's slow. 49:10.933 --> 49:11.603 Is that right? 49:11.600 --> 49:14.930 A weak acid is fast. Is that 49:14.933 --> 49:16.803 reasonable, or is that backwards? 49:16.800 --> 49:18.500 STUDENT: It seems like it would be backwards. 49:18.500 --> 49:20.130 PROFESSOR: A weak acid means it holds 49:20.133 --> 49:21.403 on to a proton tightly. 49:24.367 --> 49:26.827 But it also is holding onto-- 49:26.833 --> 49:28.973 attacking a carbon well. 49:28.967 --> 49:31.097 So that makes sense. 49:31.100 --> 49:33.170 That makes a lot of sense. 49:33.167 --> 49:36.527 So for first row elements, the nucleophilicty attack on 49:36.533 --> 49:40.173 sigma-star, parallels basicity attack on H+. 49:40.167 --> 49:42.467 Both require a higher HOMO, which'll 49:42.467 --> 49:43.827 make it more reactive. 49:43.833 --> 49:45.403 So far, so good. 49:45.400 --> 49:47.200 Now let's look at the halides. 49:47.200 --> 49:50.270 Fluoride, chloride, bromide, iodide. 49:50.267 --> 49:56.967 Notice that as the acid get stronger, it speeds up. 49:56.967 --> 49:59.327 Now it's backwards. 49:59.333 --> 50:01.473 The halides are going backwards. 50:01.467 --> 50:06.297 The better they are at attacking a proton, the worse 50:06.300 --> 50:07.770 they are at attacking carbon. 50:07.767 --> 50:09.667 That doesn't make sense. 50:09.667 --> 50:13.527 And we see the same thing here for oxygen and sulfur. 50:13.533 --> 50:18.533 Sulfur is a stronger acid, but it's better 50:18.533 --> 50:20.873 at attacking carbon. 50:20.867 --> 50:22.097 This seems nuts. 50:25.300 --> 50:29.430 Now this is actually tied into the effect of solvent. 50:29.433 --> 50:33.533 Because if you look at the relative rates in water for 50:33.533 --> 50:36.833 attacking methyl iodide with these different nucleophiles, 50:36.833 --> 50:40.273 you see this which is essentially what we see here. 50:40.267 --> 50:43.727 This is 14 times faster, here's 10,000. 50:43.733 --> 50:47.603 This is 160 times faster, here it's 80 times faster. 50:47.600 --> 50:50.630 These are generic numbers, and these are specific ones for a 50:50.633 --> 50:52.833 particular case. 50:52.833 --> 50:54.773 But look what happens if you do it in acetone. 50:57.267 --> 50:59.727 It turns around. 50:59.733 --> 51:02.933 So it's what you expect in acetone, but it's 51:02.933 --> 51:04.573 backwards in water. 51:04.567 --> 51:08.067 What's special about water? 51:08.067 --> 51:10.197 Why are things backwards in water? 51:10.200 --> 51:11.770 What's different about water and acetone? 51:11.767 --> 51:13.597 STUDENT: Water is polar. 51:13.600 --> 51:16.630 PROFESSOR: Water forms hydrogen bonds. 51:16.633 --> 51:21.103 And when you form hydrogen bond to an anion, you 51:21.100 --> 51:22.030 deactivate it. 51:22.033 --> 51:24.903 You have to break the hydrogen bond in order for it to attack 51:24.900 --> 51:27.870 something else. 51:27.867 --> 51:32.127 So you can see that this is sensible in acetone, but it's 51:32.133 --> 51:35.903 backwards in water, because it's harder to break hydrogen 51:35.900 --> 51:38.730 bonds to the smaller ions. 51:38.733 --> 51:42.973 So as the ions get big, like iodide, then they're not very 51:42.967 --> 51:45.497 much hydrogen bonded, and even though they're not so good at 51:45.500 --> 51:48.500 attacking protons, they're in fact better at attacking 51:48.500 --> 51:51.830 carbons because you don't have to break the water away. 51:51.833 --> 51:54.203 OK, will continue with this stuff next time. 51:54.200 --> 51:55.470 Thanks.