WEBVTT 00:01.233 --> 00:01.703 J. MICHAEL MCBRIDE: OK. 00:01.700 --> 00:04.330 So we're going to finish up on nucleophilic substitution, 00:04.333 --> 00:07.573 SN2, where we're spending so much time looking at how you 00:07.567 --> 00:08.727 prove a mechanism. 00:08.733 --> 00:12.703 And then look at the elimination, that's second 00:12.700 --> 00:15.270 order, and then the substitution and elimination 00:15.267 --> 00:16.967 that are first order kinetically. 00:19.533 --> 00:23.333 We've looked at proving mechanisms, that is disproving 00:23.333 --> 00:27.933 mechanisms by stereochemistry, by rate law, by rate constant, 00:27.933 --> 00:30.873 varying all the different components of the reaction. 00:30.867 --> 00:34.067 And finally there's another way, which is to look at 00:34.067 --> 00:37.897 structure, which you can do either with quantum mechanics 00:37.900 --> 00:39.630 or by X-ray. 00:44.033 --> 00:47.773 The problem, remember, is this really subtle distinction, one 00:47.767 --> 00:49.927 that probably doesn't make much difference. 00:49.933 --> 00:52.733 But if you're really looking carefully at mechanism and 00:52.733 --> 00:55.233 want to understand them it's an interesting question, which 00:55.233 --> 00:58.303 is, is there an energy minimum at the top? 00:58.300 --> 01:03.330 Is there an intermediate in the concerted SN2 reaction, or 01:03.333 --> 01:05.173 is it just a transition state? 01:05.167 --> 01:09.867 And of course they blend into one another as the stability 01:09.867 --> 01:12.227 of the pentavalent intermediate, if there were 01:12.233 --> 01:17.003 one, gets less and less. 01:17.000 --> 01:19.930 The interesting thing is when you have the nucleophile, a 01:19.933 --> 01:23.403 leaving group and a carbon in the middle, trivalent carbon, 01:23.400 --> 01:25.800 is it actually a pentavalent carbon? 01:25.800 --> 01:28.900 Is there some stability associated with that? 01:28.900 --> 01:32.030 You could imagine arranging groups like oxygens, so there 01:32.033 --> 01:35.273 are unshared pairs are on the left and right, and a planar 01:35.267 --> 01:38.097 carbon cation in the middle and see whether 01:38.100 --> 01:39.870 there's a bond there. 01:39.867 --> 01:42.427 How are you going to get them? 01:42.433 --> 01:46.273 Remember the non-bonded distances between atoms, when 01:46.267 --> 01:49.467 they're in contact, is about twice as big as bonded 01:49.467 --> 01:51.527 distances, right? 01:51.533 --> 01:56.103 So if the thing is only marginally stable, what's going 01:56.100 --> 01:57.530 to keep it from flying apart? 01:57.533 --> 02:00.473 How will that last long enough for you to look at it? 02:00.467 --> 02:03.627 Well, you can put other things in a molecule that hold those 02:03.633 --> 02:08.233 pieces in place, like this set of three aromatic rings of the 02:08.233 --> 02:10.503 anthracene system. 02:10.500 --> 02:13.400 Now we've got the groups up there on top where we want and 02:13.400 --> 02:16.100 the question is going to be-- 02:16.100 --> 02:17.970 Well first, how do we get them there? 02:17.967 --> 02:21.627 The thing in the middle started as an ester, right? 02:21.633 --> 02:24.233 But we want it to be a cation with a vacant p 02:24.233 --> 02:26.003 orbital in the middle. 02:26.000 --> 02:28.800 So what you do is react it with a molecule we've talked 02:28.800 --> 02:32.430 about before, Meerwein's reagent, which is a way of 02:32.433 --> 02:33.633 giving methyl groups. 02:33.633 --> 02:35.503 It's got a great leaving group on it. 02:35.500 --> 02:38.500 A dimethyl ether is the leaving group. 02:38.500 --> 02:42.470 We can have a substitution reaction and put a methyl 02:42.467 --> 02:45.227 group on and now the carbon has a positive charge. 02:45.233 --> 02:48.103 Although if you want to be careful about it, not all the 02:48.100 --> 02:52.230 positive charge is on carbon because the unshared pairs on 02:52.233 --> 02:54.733 the adjacent oxygens, of course, are mixing with that 02:54.733 --> 02:57.433 vacant orbital. 02:57.433 --> 03:01.703 We've got our trivalent carbon cation in the middle. 03:01.700 --> 03:04.170 There we see it. 03:04.167 --> 03:08.497 There should be this anion that was left from the 03:08.500 --> 03:10.170 original Meerwein salt. 03:10.167 --> 03:12.997 And the people who did the X-ray work we're surprised to 03:13.000 --> 03:18.730 find that it was not BF4 minus, but B2F7 minus. 03:18.733 --> 03:21.673 It had gotten together with another BF3. 03:21.667 --> 03:24.097 That's neither here nor there, but it's what was 03:24.100 --> 03:27.000 there in the crystal. 03:27.000 --> 03:30.400 They have the oxygens next to the central carbon. 03:30.400 --> 03:34.870 And remember, calculated when you had a cation with waters 03:34.867 --> 03:39.967 on both sides of a trivalent carbon, was that at the 03:39.967 --> 03:44.797 symmetrical pentavalent, quote, "geometry," it was a 03:44.800 --> 03:46.330 transition state. 03:46.333 --> 03:47.903 OK? 03:47.900 --> 03:51.200 If you believed in the theory, you wouldn't expect there to 03:51.200 --> 03:52.630 be stability here now. 03:52.633 --> 03:54.633 How do you know if there's stability? 03:54.633 --> 03:57.403 How do you know if there are bonds there? 03:57.400 --> 04:00.100 Well, you can look in the paper that's cited down there 04:00.100 --> 04:02.770 on the bottom right, and it shows a picture and you can 04:02.767 --> 04:05.867 see that indeed there are bonds there. 04:05.867 --> 04:07.797 Right? 04:07.800 --> 04:09.830 That's supposed to engender a laugh. 04:09.833 --> 04:11.503 I see Chris smiling. 04:11.500 --> 04:13.030 Why do you smile? 04:13.033 --> 04:14.003 STUDENT: They just drew the bonds. 04:14.000 --> 04:15.770 PROFESSOR: They just drew the bonds, right? 04:15.767 --> 04:17.967 How do you know there are bonds there? 04:17.967 --> 04:19.467 Well there's one interesting thing. 04:19.467 --> 04:23.127 This structure is symmetrical, as drawn. 04:23.133 --> 04:26.433 And, you notice these funny shapes the atoms have. What 04:26.433 --> 04:31.433 they are, are ellipses with an octant cut out of them to show 04:31.433 --> 04:33.433 the size of the axes. 04:33.433 --> 04:36.273 And one thing you measure in X-ray is how 04:36.267 --> 04:40.227 much the atoms vibrate. 04:40.233 --> 04:42.733 Those show how much it vibrates in the three 04:42.733 --> 04:46.203 principal directions for vibration. 04:46.200 --> 04:50.200 If we look at that C19, the central carbon there, notice 04:50.200 --> 04:51.430 it's not elongated. 04:54.033 --> 04:58.203 It would be elongated if it vibrated with great amplitude 04:58.200 --> 05:00.570 back and forth. 05:00.567 --> 05:03.127 It would move a lot in that direction. 05:03.133 --> 05:06.303 So it could be-- remember in X-ray, what you see is the 05:06.300 --> 05:09.030 average structure over many molecules-- 05:09.033 --> 05:11.833 it could have been that one of them is like this another one 05:11.833 --> 05:13.873 is like this, another one was like this, 05:13.867 --> 05:15.127 another is like this. 05:15.133 --> 05:18.403 And the average would appear to be in the middle. 05:18.400 --> 05:21.400 But it would have a long displacement, on the 05:21.400 --> 05:22.800 average, you see. 05:22.800 --> 05:24.370 But that's not what you see there. 05:24.367 --> 05:27.167 It could be like this bell clapper or sometimes there, 05:27.167 --> 05:29.797 sometimes there, but on average in the middle. 05:29.800 --> 05:34.230 But it's not because it's not stretched out that way. 05:34.233 --> 05:36.333 That still didn't answer the question, whether they're 05:36.333 --> 05:37.073 bonds there. 05:37.067 --> 05:41.097 It could be in the middle, but no bonds. 05:41.100 --> 05:45.730 So let's look right edge-on at the central carbon. 05:45.733 --> 05:50.133 And ask the question, how far apart are those two oxygens? 05:50.133 --> 05:55.203 If the interaction is repulsive then they should 05:55.200 --> 05:56.270 move apart. 05:56.267 --> 05:59.297 If it's attractive they should move together. 05:59.300 --> 06:00.970 Compared to what? 06:00.967 --> 06:03.897 Well, the authors compared it with the two carbons they were 06:03.900 --> 06:08.830 attached to, which are 5.02 angstroms apart. 06:08.833 --> 06:12.403 And the white is 4.86. 06:12.400 --> 06:14.270 So, they've been drawn together. 06:14.267 --> 06:18.197 The distance is shortened by 0.16 angstoms, as if they're 06:18.200 --> 06:21.700 being sucked in. 06:21.700 --> 06:24.170 That looks like there's a pentavalent carbon that's 06:24.167 --> 06:27.127 actually attracting those adjacent oxygens. 06:27.133 --> 06:29.273 This was published in a distinguished journal, the 06:29.267 --> 06:31.627 Journal of the American Chemical Society. 06:31.633 --> 06:35.033 And notice that it's not only that distance but you can see 06:35.033 --> 06:38.333 also that the angles are distorted. 06:38.333 --> 06:41.603 Instead of those being 120 degree angles out on the left 06:41.600 --> 06:44.270 there, one of them is larger and one of them 06:44.267 --> 06:45.727 is 7 degrees smaller. 06:45.733 --> 06:49.173 It's bent in, as if it's being sucked by the central carbon, 06:49.167 --> 06:50.697 so that there's a bond there. 06:50.700 --> 06:54.400 So pentavalence seemed to be a safe inference, and that was 06:54.400 --> 06:57.300 the subject of this paper. 06:57.300 --> 07:02.170 But, if they did compared to what, and just had hydrogen in 07:02.167 --> 07:05.897 the middle instead of that positive carbon, it turned out 07:05.900 --> 07:08.800 they were sucked in even further. 07:08.800 --> 07:14.870 So instead of being 4.84, whatever it is, it's 4.75 07:14.867 --> 07:19.667 angstroms. So much for that proof, that these groups are 07:19.667 --> 07:21.227 being sucked in. 07:21.233 --> 07:23.473 With nothing in the middle, just the hydrogen, 07:23.467 --> 07:25.667 they're sucked in? 07:28.667 --> 07:32.527 Now, notice that there wasn't just that 07:32.533 --> 07:33.633 positive carbon there. 07:33.633 --> 07:35.973 There were these other things, the oxygens, and the methyls. 07:35.967 --> 07:38.227 There was some space to that which could have 07:38.233 --> 07:41.133 pushed things apart. 07:41.133 --> 07:46.333 Now lacking that push apart, they come together closer. 07:46.333 --> 07:49.273 From one point of view, that's reasonable, but why should they 07:49.267 --> 07:50.367 come together? 07:50.367 --> 07:53.327 It's not a pull to the central carbon. 07:53.333 --> 07:55.433 It seems to be a push. 07:55.433 --> 07:57.133 Where is the push coming from? 07:57.133 --> 07:58.403 Can anybody see? 08:04.200 --> 08:07.970 What pushes those methoxy groups, the oxygens, toward 08:07.967 --> 08:10.397 the center? 08:10.400 --> 08:11.770 Helen? 08:11.767 --> 08:12.627 STUDENT: Maybe it's the steric hinderance or the strain of 08:12.633 --> 08:13.873 the two methyls. 08:17.233 --> 08:21.203 PROFESSOR: What are the methyls being pushed by? 08:21.200 --> 08:22.430 STUDENT: ... 08:24.933 --> 08:30.273 PROFESSOR: It must be some push to bend those angles in. 08:30.267 --> 08:32.067 Anybody got an idea? 08:32.067 --> 08:32.397 Chris? 08:32.400 --> 08:33.800 STUDENT: Is it with the hydrogens? 08:33.800 --> 08:35.630 PROFESSOR: Ah, the hydrogens. 08:35.633 --> 08:36.673 Right? 08:36.667 --> 08:37.767 They're eclipsed. 08:37.767 --> 08:42.197 And there's repulsion there that causes them to bend in. 08:42.200 --> 08:46.530 Now, you can put instead of a positive carbon, you can put 08:46.533 --> 08:49.873 oxygen in the middle with this extra group on it. 08:49.867 --> 08:53.667 And that, you see, does push them further apart. 08:53.667 --> 08:57.167 But still they're bent in a little bit as 08:57.167 --> 08:59.097 compared to the carbon. 08:59.100 --> 09:03.270 But the central oxygen is only slightly repulsive, compared 09:03.267 --> 09:03.927 to the carbon. 09:03.933 --> 09:06.333 So the carbon's not pulling things in at all. 09:06.333 --> 09:09.903 It's pushing them out trying to fight against that hydrogen 09:09.900 --> 09:13.970 pushing into the methyl out on the side. 09:13.967 --> 09:17.767 If you have BF3 in the middle, which clearly has the vacant 09:17.767 --> 09:21.667 orbital on boron, has very small other things on the 09:21.667 --> 09:24.127 boron, so they're not pushing apart. 09:24.133 --> 09:27.633 And those other things are fluorine, so not only are they 09:27.633 --> 09:30.503 small, but they're withdrawing electrons and making that B 09:30.500 --> 09:33.170 orbital especially low in energy. 09:33.167 --> 09:38.567 Then you can see them genuinely being sucked in, 09:38.567 --> 09:43.697 further than in any of the other cases, as compared there 09:43.700 --> 09:46.970 to the positive carbon in the middle. 09:46.967 --> 09:51.367 Now, if you try to make the things on the outside more 09:51.367 --> 09:54.167 willing to give up their electrons, that is higher 09:54.167 --> 09:57.997 HOMOs to make stronger bonds, and make it O 09:58.000 --> 10:01.570 minus rather than CH3O. 10:01.567 --> 10:04.927 So we have the minus charge raising those HOMOs. 10:04.933 --> 10:08.503 Then indeed, it forms a bond, but not two bonds. 10:08.500 --> 10:09.770 It's unsymmetrical. 10:12.533 --> 10:15.073 One of them is a reasonable bond. 10:15.067 --> 10:19.067 The other one is just a non-bonded interaction. 10:19.067 --> 10:21.997 In fact it turns out that this is a salt. 10:22.000 --> 10:23.700 It's an anion. 10:23.700 --> 10:28.470 So there's a positive cation nearby, a potassium, which 10:28.467 --> 10:30.097 makes it a little bit unsymmetrical. 10:30.100 --> 10:33.030 So it's better to have the minus charge on the right near 10:33.033 --> 10:35.773 the potassium cation than on the left. 10:35.767 --> 10:39.097 That also helps distort it. 10:39.100 --> 10:42.730 Now remember that as compared to the anion that was 10:42.733 --> 10:46.833 calculated, which again, was said to be by calculation a 10:46.833 --> 10:48.103 transition state. 10:50.933 --> 10:53.273 Here are a whole bunch of things they studied, and I 10:53.267 --> 10:54.827 don't want to spend the time going through 10:54.833 --> 10:56.133 this in great detail. 10:56.133 --> 10:57.673 But compared to what? 10:57.667 --> 11:01.197 Compared to just having a hydrogen in the middle-- to see 11:01.200 --> 11:03.030 what these distances are. 11:03.033 --> 11:06.133 Then in the case where C+ was in the middle-- 11:06.133 --> 11:11.033 they made the C+ that way-- but it's not such a great C+ 11:11.033 --> 11:15.733 because of the vacant orbital on the carbon being mixed with 11:15.733 --> 11:19.103 the unshared pairs on the adjacent oxygens. 11:19.100 --> 11:20.370 But if you have-- 11:23.733 --> 11:27.603 if the central atom is bonded to oxygen or sulfur, which has 11:27.600 --> 11:30.470 these extra electrons, that seems to use 11:30.467 --> 11:32.227 up the vacant orbital. 11:32.233 --> 11:34.233 So it's not so good at bonding and therefore 11:34.233 --> 11:36.003 sucking things in. 11:36.000 --> 11:40.870 If you have fluorine on boron then, as we said, the electron 11:40.867 --> 11:44.127 withdrawal lowers the energy and indeed it does seem to 11:44.133 --> 11:45.433 suck it in to give a 11:45.433 --> 11:47.503 pentavalent atom in the middle. 11:47.500 --> 11:52.830 But if you have higher HOMOs on the neighbor of the boron, 11:52.833 --> 11:56.733 giving their electrons to the boron, then that's a better 11:56.733 --> 11:59.203 source of electrons for the boron than the 11:59.200 --> 12:00.830 neighboring atoms are. 12:00.833 --> 12:03.503 And you can see in these cases. 12:03.500 --> 12:06.170 If you look at this whole bunch of things plotted in 12:06.167 --> 12:10.197 this particular way, you can see, for example, there's 12:10.200 --> 12:14.000 boron with two chlorines in the middle and methoxides on 12:14.000 --> 12:15.630 both sides. 12:15.633 --> 12:19.503 The bar then shows the two different bond distances. 12:19.500 --> 12:20.730 So it's unsymmetrical. 12:20.733 --> 12:22.233 One is short, one is long. 12:22.233 --> 12:25.133 It's not a pentavalent carbon. 12:25.133 --> 12:27.403 There's some that are like that on the right, very 12:27.400 --> 12:29.300 different and unsymmetrical. 12:29.300 --> 12:32.430 Then there's some on the left that are about equal bond 12:32.433 --> 12:36.833 distances, right and left or symmetrical. 12:36.833 --> 12:40.803 There's our reference with hydrogen in the middle. 12:40.800 --> 12:45.670 And it's pressed in to give somewhat short distances by 12:45.667 --> 12:48.427 the hydrogen pushing on the methyl as 12:48.433 --> 12:50.203 we spoke about before. 12:50.200 --> 12:52.700 If you have boron in the middle it's not 12:52.700 --> 12:55.370 sucked in very much. 12:55.367 --> 12:59.767 Unless you have that case with fluorine on the boron, and then 12:59.767 --> 13:02.697 it attracts enough that you could make a pentavalent atom 13:02.700 --> 13:05.000 in the middle. 13:05.000 --> 13:08.930 But most of the borons are tetracoordinate, that is 13:08.933 --> 13:15.103 unsymmetrical not a single minimum but a double minimum. 13:15.100 --> 13:18.930 If you look at the two cases of carbon, the one with 13:18.933 --> 13:24.373 oxygens on each side there on the left, is 13:24.367 --> 13:27.427 symmetrical but not short. 13:27.433 --> 13:32.073 And the one on the right is short, one of them is short, 13:32.067 --> 13:33.127 but the other is long. 13:33.133 --> 13:34.573 It's not symmetrical. 13:34.567 --> 13:39.927 There's no sign from this exercise for a pentavalent 13:39.933 --> 13:43.303 intermediate of the SN2 sort being stable. 13:43.300 --> 13:47.970 It seems genuinely to be just a maximum on the way across. 13:50.967 --> 13:53.567 So it's a transition state as calculated by quantum 13:53.567 --> 13:56.867 mechanics, so that should give us a little more confidence, 13:56.867 --> 14:00.127 perhaps, in the reliability of quantum mechanics, which of 14:00.133 --> 14:03.373 course, can't take into account all the neighbors 14:03.367 --> 14:04.627 around the molecule. 14:07.833 --> 14:10.203 That's as far as we're going to go looking at the mechanism 14:10.200 --> 14:11.500 of the SN2. 14:11.500 --> 14:14.900 Now we're going to look at alternative paths of reaction, 14:14.900 --> 14:17.500 the elimination reaction, which we already mentioned 14:17.500 --> 14:21.600 last semester and also first order nucleophilic 14:21.600 --> 14:23.600 substitution and elimination. 14:23.600 --> 14:27.470 First E2, or beta-elimination. 14:27.467 --> 14:30.167 Now, this is from last semester. 14:30.167 --> 14:33.697 You remember, you can attack here with a high HOMO, 14:33.700 --> 14:35.330 antibonding here, antibonding here. 14:35.333 --> 14:36.503 You break off flouride. 14:36.500 --> 14:39.600 You break off hydrogen, and form the carbon-carbon bond, 14:39.600 --> 14:41.470 as shown by the curved arrows here. 14:41.467 --> 14:43.467 We said last semester that that's the 14:43.467 --> 14:45.027 E2 elimination mechanism. 14:47.667 --> 14:50.167 What influences the rate? 14:50.167 --> 14:53.297 The rate is influenced by the base. 14:53.300 --> 14:55.230 That's what makes it second order. 14:55.233 --> 14:57.703 It depends not only on the concentration of this 14:57.700 --> 15:02.270 substrate but also on the concentration of hydroxide. 15:02.267 --> 15:05.297 The two must be getting together in the rate-limiting 15:05.300 --> 15:08.470 step, or before the rate-limiting step in a 15:08.467 --> 15:11.697 preliminary equilibrium that gets drawn off. 15:11.700 --> 15:15.530 That's the same thinking as we had on the SN2, that both 15:15.533 --> 15:18.603 things are involved in the rate-limiting, or before, the 15:18.600 --> 15:20.300 rate-limiting step. 15:20.300 --> 15:22.470 It depends on the nature of the leaving group. 15:22.467 --> 15:24.997 A better leaving group reacts faster. 15:25.000 --> 15:28.730 So that means that the fluoride is leaving in the 15:28.733 --> 15:33.233 rate-limiting step, or before the rate-limiting step in a 15:33.233 --> 15:35.273 pre-equilibrium. 15:35.267 --> 15:39.527 There's a hydrogen isotope effect, called a kinetic 15:39.533 --> 15:40.573 isotope effect. 15:40.567 --> 15:44.827 If you change hydrogen for deuterium, you change the rate, 15:44.833 --> 15:47.633 and this has special implication, 15:47.633 --> 15:48.933 as you can see here. 15:48.933 --> 15:52.433 These others only meant it was at the transition state, or 15:52.433 --> 15:55.873 before the transition state, that something was happening. 15:55.867 --> 15:59.327 But if this makes a difference it shows that bond is being 15:59.333 --> 16:03.803 broken during the transition state. 16:03.800 --> 16:05.630 We know the leaving group is leaving, 16:05.633 --> 16:09.773 we know the base is coming in, those 16:09.767 --> 16:11.427 two things either before or at the 16:11.433 --> 16:14.773 transition state, and now we know the hydrogen is leaving 16:14.767 --> 16:19.267 at the transition state, and let's see how that works. 16:19.267 --> 16:22.627 We saw in "Erwin Meets Goldilocks that you have a 16:22.633 --> 16:25.433 vibrational potential surface. 16:25.433 --> 16:28.973 And you'd have also a vibrational potential surface 16:28.967 --> 16:31.267 for the hydrogen that's being transferred after it's 16:31.267 --> 16:31.867 transferred. 16:31.867 --> 16:34.797 It's stuck first place to the carbon, in the second place to 16:34.800 --> 16:37.100 the oxygen. 16:37.100 --> 16:40.600 But halfway across, when the bond is being broken, it's 16:40.600 --> 16:43.870 between the two so it's not being bound to either. 16:43.867 --> 16:45.597 It's very low-- 16:45.600 --> 16:47.500 It's easy to move back and forth when 16:47.500 --> 16:50.100 it's halfway between. 16:50.100 --> 16:54.600 What implication does this have for the kinetic energy of 16:54.600 --> 16:56.230 that hydrogen? 16:56.233 --> 16:58.903 Remember, there's a lowest possible kinetic energy, the 16:58.900 --> 17:04.870 one that gives no nodes in the wave. It'll be here in that 17:04.867 --> 17:09.197 case, here in the oxygen case, but when it's very easy to 17:09.200 --> 17:13.470 move you can stretch the wave way out, very little 17:13.467 --> 17:16.467 curvature, very little kinetic energy. 17:16.467 --> 17:20.427 So you can have much lower minimum kinetic energy when 17:20.433 --> 17:23.703 the hydrogen bond is being broken than when it's either 17:23.700 --> 17:28.530 attached to the carbon or attached to the oxygen. 17:28.533 --> 17:30.573 What's the implication of that? 17:30.567 --> 17:33.167 When you do the reaction you have to get to the transition 17:33.167 --> 17:35.327 state so you have to put in that much energy. 17:38.067 --> 17:40.597 What's the implication if we change 17:40.600 --> 17:41.830 from hydrogen to deuterium? 17:46.600 --> 17:50.770 You remember what happens when you change the mass in "Erwin 17:50.767 --> 17:53.767 Meets Goldilocks to the lowest energy? 17:58.800 --> 18:02.600 If you make them into deuteriums, then you have a 18:02.600 --> 18:07.100 wave that looks like this, but the bigger mass means it has 18:07.100 --> 18:08.330 lower energy. 18:12.400 --> 18:16.030 So, we have lower energy here, lower energy here, and lower 18:16.033 --> 18:19.833 energy here, but it can't be lower than the minimum. 18:19.833 --> 18:22.503 There's hardly any change in the energy here, when you go 18:22.500 --> 18:25.730 from hydrogen to deuterium, but there's a substantial change 18:25.733 --> 18:27.573 here and a substantial change here. 18:30.600 --> 18:32.730 If you look at the energy that's required for the 18:32.733 --> 18:36.133 reaction, more energy is required for the deuterium, 18:36.133 --> 18:38.473 because it started lower. 18:38.467 --> 18:41.527 If you were talking about an equilibrium between here and 18:41.533 --> 18:45.273 here, then that difference would cancel out. 18:45.267 --> 18:48.667 It's only in that transition stage, which has the very low 18:48.667 --> 18:52.967 potential, that means that there's something special 18:52.967 --> 18:55.727 about the deuterium, or perhaps you should say 18:55.733 --> 18:58.773 something NOT special about the deuterium. 18:58.767 --> 19:01.867 When it's bonded, it's unusually low in energy, but 19:01.867 --> 19:03.797 when it's not tightly bonded, then it has the 19:03.800 --> 19:05.070 same energy as hydrogen. 19:07.367 --> 19:11.027 Because you have more of a barrier for deuterium, the 19:11.033 --> 19:13.603 reaction should be slower. 19:13.600 --> 19:17.770 Hydrogen is faster than deuterium if that is the 19:17.767 --> 19:19.667 rate-limiting step. 19:19.667 --> 19:22.127 If that's not the rate-limiting step, if it 19:22.133 --> 19:28.203 happens before this or after this, then you don't have the 19:28.200 --> 19:30.430 difference between hydrogen and deuterium. 19:30.433 --> 19:35.133 It's only when the hydrogen is being broken away during the 19:35.133 --> 19:38.533 transition state, during the rate-determining step, that 19:38.533 --> 19:40.073 you can see it. 19:40.067 --> 19:43.697 You get that difference in rates, that so-called kinetic 19:43.700 --> 19:47.470 isotope effect, only if bond is being weakened in the 19:47.467 --> 19:51.097 rate-determining transition state. 19:51.100 --> 19:54.600 There's another interesting implication as there was in 19:54.600 --> 19:58.700 SN2, which is stereochemistry. 19:58.700 --> 20:01.200 So we have a hydrogen and a leaving group that are going 20:01.200 --> 20:02.770 to come off. 20:02.767 --> 20:04.767 And if we look at that from the end with the Newman 20:04.767 --> 20:07.427 projection, we see them anti to one another. 20:07.433 --> 20:10.833 We can imagine pulling the two off and forming a bond by 20:10.833 --> 20:12.033 what's left. 20:12.033 --> 20:14.803 They could've been syn to one another in an eclipsed 20:14.800 --> 20:16.370 conformation. 20:16.367 --> 20:17.997 Which should be better? 20:18.000 --> 20:21.070 Should we pull them off anti to one another 20:21.067 --> 20:23.797 or syn to one another? 20:23.800 --> 20:26.830 Well of course, the top conformation 20:26.833 --> 20:31.133 would involve eclipsing. 20:31.133 --> 20:34.233 So that would be higher in energy than the anti. 20:34.233 --> 20:37.403 And furthermore it turns out, although we don't have time to 20:37.400 --> 20:42.100 talk about it right now, that anti orbitals overlap with one 20:42.100 --> 20:45.330 another better than syn orbitals. 20:45.333 --> 20:47.333 To me, that seems counterintuitive. 20:47.333 --> 20:49.433 You'd think when they're like this, they'd overlap better 20:49.433 --> 20:51.003 than when they're like that. 20:51.000 --> 20:53.870 But in fact they overlap better when they're anti. 20:53.867 --> 20:58.667 By both accounts, one would expect the anti to be the 20:58.667 --> 21:02.267 preferred mode for elimination. 21:02.267 --> 21:03.597 But is it true? 21:03.600 --> 21:06.200 How could you test it experimentally? 21:06.200 --> 21:09.100 How could you tell whether they had been pulled off, or 21:09.100 --> 21:12.230 were being pulled off, from the same side or 21:12.233 --> 21:13.503 from opposite sides? 21:17.100 --> 21:19.130 Well, if you look at the title of the slide you use 21:19.133 --> 21:20.403 stereochemistry. 21:25.833 --> 21:39.233 Notice then, that if we put R groups on here, then when we 21:39.233 --> 21:43.433 lose H and L here these two R's will be on the same side. 21:43.433 --> 21:46.003 But if it's rotated into this form, then they'll be on 21:46.000 --> 21:48.770 opposite sides of the new double bond that's being made 21:48.767 --> 21:51.427 across the middle. 21:51.433 --> 21:54.573 We can start, for syn elimination of this particular 21:54.567 --> 21:58.967 compound, where notice this configuration is S and that 21:58.967 --> 22:03.667 one also is S. It's rotated into a conformation where the 22:03.667 --> 22:07.097 leaving groups are syn to one another. 22:07.100 --> 22:08.800 Of course it could rotate, and they could 22:08.800 --> 22:10.830 be anti to one another. 22:10.833 --> 22:15.503 And the question is, which one really happens? 22:15.500 --> 22:19.430 We can look at the product and find that the two methyls are 22:19.433 --> 22:22.373 on the same side of the double bond as they are 22:22.367 --> 22:23.697 here, both in back. 22:23.700 --> 22:27.870 Where as here, one's in front, the other's in back. 22:27.867 --> 22:31.397 This suggests then that the fact that one gets the E 22:31.400 --> 22:36.930 isomer of the alkene that it was the anti form that gave 22:36.933 --> 22:38.033 rise to it. 22:38.033 --> 22:40.773 Stereochemistry showed that it's anti 22:40.767 --> 22:42.997 elimination in this case. 22:43.000 --> 22:45.170 Of course there could have been another reason for anti 22:45.167 --> 22:46.527 elimination. 22:46.533 --> 22:50.133 It could've been that this product is more stable than 22:50.133 --> 22:52.433 the one where the phenyl group is near the methyl. 22:55.233 --> 22:58.833 How can we discriminate whether it's just that it's 22:58.833 --> 23:02.533 the preferred conformation and anti is good for the reason 23:02.533 --> 23:05.673 shown here, or whether the only reason you get that one 23:05.667 --> 23:07.467 is because it's more stable? 23:07.467 --> 23:09.367 Can anybody see how you can test that? 23:15.300 --> 23:17.700 You could use a different stereochemistry on the 23:17.700 --> 23:23.030 starting material and see if it still gives that one. 23:23.033 --> 23:28.473 So maybe E is just more stable than the Z isomer. 23:28.467 --> 23:31.197 Here we can change the configuration on the right to 23:31.200 --> 23:35.030 make it R. The methyl is now in back and the hydrogen in 23:35.033 --> 23:37.533 front here. 23:37.533 --> 23:40.003 So now the syn is the one that should give 23:40.000 --> 23:42.670 the E isomer, and the anti 23:42.667 --> 23:49.597 should give the Z. In fact, you see it is Z. So no matter 23:49.600 --> 23:51.070 which way-- 23:51.067 --> 23:54.697 it can't be just because this one is more stable, because if 23:54.700 --> 23:57.870 you change it you get that one. 23:57.867 --> 24:02.667 It has to be that it favors the anti conformation for the 24:02.667 --> 24:03.927 elimination. 24:05.800 --> 24:11.530 There's anti stereochemistry but nature is not dogmatic 24:11.533 --> 24:12.533 about this. 24:12.533 --> 24:19.003 If you can't do the anti, then the syn is still OK. 24:19.000 --> 24:25.300 And here's an example of that taken from the Jones textbook. 24:25.300 --> 24:29.230 Notice that in this case, the treatment with base to 24:29.233 --> 24:31.973 eliminate hydrogen or deuterium from this side and 24:31.967 --> 24:36.097 tosylate from that side, removes the deuterium, leaving 24:36.100 --> 24:37.730 two hydrogens. 24:37.733 --> 24:43.503 It gives that a 98% yield even though those two are required 24:43.500 --> 24:47.170 to be syn to one another because, again, this bicyclic 24:47.167 --> 24:50.897 framework, the same one used by Bartlett and Knox, that idea 24:50.900 --> 24:56.370 of holding things in place that way, doesn't allow 24:56.367 --> 24:58.427 conformational change around here. 24:58.433 --> 25:01.973 So these have to be syn to one another. 25:01.967 --> 25:07.827 It loses DOTs not HOTs despite the kinetic isotope effect. 25:07.833 --> 25:10.633 Remember hydrogen is eliminated in preference to 25:10.633 --> 25:14.073 deuterium, other things being equal. 25:14.067 --> 25:16.427 Other things aren't equal as you can look here. 25:16.433 --> 25:19.603 If you do a sort of semi-Newman projection along 25:19.600 --> 25:24.400 this bond you can see the D and OTs, their bonds are in 25:24.400 --> 25:25.830 the same plane. 25:25.833 --> 25:30.303 So in this rigid, eclipsed case the overlap of sigma-star 25:30.300 --> 25:34.300 here, which is losing its electrons 25:34.300 --> 25:36.800 that is, as the OTs minus leaves 25:36.800 --> 25:40.200 this vacant orbital is able to overlap well and stabilize the 25:40.200 --> 25:43.930 sigma orbitals in this bond, so it takes away those 25:43.933 --> 25:46.133 electrons and D+ leaves. 25:46.133 --> 25:51.803 So, the eclipsed D is better than H which would be better 25:51.800 --> 25:53.330 if it could be anti. 25:53.333 --> 25:55.903 But this framework doesn't allow it to be anti. 25:55.900 --> 25:58.900 There's not good overlap between the H and the OTs. 25:58.900 --> 26:00.200 It's anticlinal. 26:02.067 --> 26:04.997 Notice in this case you don't have to pay a penalty for 26:05.000 --> 26:07.200 having the starting material for the 26:07.200 --> 26:09.430 syn elimination eclipsed. 26:09.433 --> 26:13.203 It's required to be eclipsed by the nature of the linkage 26:13.200 --> 26:14.430 among the carbons. 26:16.967 --> 26:20.267 That's a question of stereochemistry, whether you 26:20.267 --> 26:23.697 get E or Z isomer. 26:23.700 --> 26:26.730 There's also a question of what's called regiochemistry. 26:26.733 --> 26:29.333 Where does the double bond appear? 26:29.333 --> 26:32.033 If the leaving group is here on the second carbon, and you 26:32.033 --> 26:36.403 treat it with base to remove H and L, then you can get the 26:36.400 --> 26:40.200 double bond either in this position, or in this position. 26:40.200 --> 26:42.730 And that can be both cis and trans. 26:42.733 --> 26:47.073 I draw only the trans isomer. 26:47.067 --> 26:50.767 You could remove a blue hydrogen or a red hydrogen. 26:50.767 --> 26:53.697 And this is the kind of thing, where before people knew 26:53.700 --> 26:57.500 anything about mechanism, people tried to figure out how 26:57.500 --> 27:02.400 you can get a certain product and different pathways. 27:02.400 --> 27:04.070 This was just lore: 27:04.067 --> 27:05.027 this would do this: 27:05.033 --> 27:06.473 this would do this. 27:06.467 --> 27:08.467 There were two kinds of rules. 27:08.467 --> 27:10.967 One was the rule due the Hofmann. 27:10.967 --> 27:14.567 The other was the rule due to Saytzeff. 27:14.567 --> 27:18.467 So there was the Saytzeff rule, which said you should take off 27:18.467 --> 27:20.097 the blue hydrogen. 27:20.100 --> 27:23.230 And there was the Hofmann rule that you should take off the 27:23.233 --> 27:25.633 red hydrogen. 27:25.633 --> 27:28.973 Some cases did one, and some cases did the other. 27:28.967 --> 27:32.097 And it was your business if you were a synthetic chemist 27:32.100 --> 27:35.300 to know which ones did which, so you would know what kind of 27:35.300 --> 27:40.500 leaving group to choose or what kind of base to choose to 27:40.500 --> 27:44.300 get the particular products you were desirous of. 27:44.300 --> 27:46.970 If you have the leaving group of the halogens, iodine, 27:46.967 --> 27:49.427 bromine, chlorine, you see they're Saytzeff. 27:49.433 --> 27:54.333 The dominant isomer you get is in the second position not the 27:54.333 --> 27:56.503 terminal position. 27:56.500 --> 27:59.600 But notice as we go iodine, bromine, chlorine it gets less 27:59.600 --> 28:01.600 and less Saytzeff. 28:01.600 --> 28:05.100 In fact if you go to fluoride it turns around and it becomes 28:05.100 --> 28:08.500 Hofmann in its orientation. 28:08.500 --> 28:12.330 The same is true for the leaving group being 28:12.333 --> 28:13.833 trimethylamine. 28:13.833 --> 28:20.303 The trimethyl ammonium starting material loses this 28:20.300 --> 28:26.470 trimethylamine and this proton, so it's 98% of Hofmann 28:26.467 --> 28:27.627 orientation. 28:29.567 --> 28:32.467 This big group seems to be Hofmann. 28:32.467 --> 28:35.667 Iodide seems to be Saytzeff. 28:35.667 --> 28:37.997 Let's look a little bit about the energetics that are 28:38.000 --> 28:40.230 involved here. 28:40.233 --> 28:42.333 This is a ratio of about 4:1. 28:42.333 --> 28:44.573 This is about 1:50. 28:44.567 --> 28:48.067 The whole range, which is very important, what you're 28:48.067 --> 28:52.367 going to be getting, is only a factor of 200 28:52.367 --> 28:54.867 between 4:1 and 1:50. 28:54.867 --> 29:00.297 So 400 means a factor of 10^2.3, which means that it's 29:00.300 --> 29:04.130 about three kilocalories change in energy that makes it 29:04.133 --> 29:08.903 from going 4:1 one way, to 50:1 the other way. 29:08.900 --> 29:11.400 A change of just three kilocalories. 29:11.400 --> 29:12.630 Remember that a hydrogen bond-- 29:14.900 --> 29:17.730 not a particularly strong hydrogen bond--is worth three 29:17.733 --> 29:18.733 kilocalories. 29:18.733 --> 29:20.873 So you can see that subtle things are going 29:20.867 --> 29:23.327 to enter into this. 29:23.333 --> 29:27.933 It's not surprising that there are not hard and fast rules, 29:27.933 --> 29:33.203 that sometimes it's Saytzeff and sometimes it's Hofmann. 29:33.200 --> 29:34.400 This is a very subtle thing. 29:34.400 --> 29:39.630 It's important for synthesis, but it's not a big factor that 29:39.633 --> 29:41.803 you could be confident, that you could put your finger on 29:41.800 --> 29:44.000 it and say that's the reason it went that way. 29:47.200 --> 29:50.270 You can have E2 versus SN2. 29:50.267 --> 29:53.397 You could have the high HOMO come in, either attack a 29:53.400 --> 29:55.430 carbon or take a hydrogen. 29:55.433 --> 29:59.803 How well do we understand what does that? 29:59.800 --> 30:01.030 Suppose we take t-butyl. 30:03.967 --> 30:07.267 To do an SN2 reaction you'd have to attack there, but 30:07.267 --> 30:09.327 we've seen this picture before and you know 30:09.333 --> 30:10.733 that's sterically hindered. 30:10.733 --> 30:12.333 You can't get in there. 30:12.333 --> 30:19.103 Steric hindrance tends to disfavor SN2 processes. 30:19.100 --> 30:23.800 But it's much easier to get to the neighboring hydrogen and 30:23.800 --> 30:24.530 pull it off. 30:24.533 --> 30:26.773 It's on the surface of the molecule. 30:26.767 --> 30:31.097 Steric hindrance favors E2 over SN2. 30:31.100 --> 30:34.000 It does it by disfavoring SN2. 30:34.000 --> 30:36.470 If you have a very hindered center, you tend to get 30:36.467 --> 30:39.467 elimination, not substitution. 30:39.467 --> 30:41.467 That makes perfect sense. 30:41.467 --> 30:46.727 Furthermore, remember when we looked at nucleophilicity, how 30:46.733 --> 30:50.273 good things are at attacking carbon, we tried to see 30:50.267 --> 30:53.397 whether it would be the same as attacking hydrogen. 30:53.400 --> 30:57.170 There wasn't such good parallelism. Some things were 30:57.167 --> 31:01.697 more dramatic in their pKa in attacking hydrogen than they 31:01.700 --> 31:04.830 were in attacking carbon. 31:04.833 --> 31:07.873 That obviously means that if you take something that's a 31:07.867 --> 31:12.867 fairly weak nucleophile, compared to how basic it is, 31:12.867 --> 31:17.097 the pKa, if you look at those which are grossly out of whack, 31:17.100 --> 31:20.500 then they could be ones that would prefer 31:20.500 --> 31:22.070 attacking the hydrogen. 31:22.067 --> 31:24.727 For example, hydroxide is of that case. 31:24.733 --> 31:28.403 It's a strong base but not as good a nucleophile as you 31:28.400 --> 31:30.430 would expect for such a strong base. 31:30.433 --> 31:34.703 So hydroxide, or alkoxide, tends to do elimination rather 31:34.700 --> 31:36.300 than substitution. 31:36.300 --> 31:39.370 But always these are a balancing act and it could depend on 31:39.367 --> 31:40.697 other factors as well. 31:46.433 --> 31:51.533 I've given the title of these next things Synthesis Games 31:51.533 --> 31:57.103 because synthesis is for many people the real goal of 31:57.100 --> 32:01.300 organic chemistry is how to make new molecules, or make 32:01.300 --> 32:02.970 old molecules in better ways. 32:08.633 --> 32:12.933 One of the best ways is to follow lore. 32:12.933 --> 32:15.003 But it's also guided by understanding. 32:15.000 --> 32:20.000 There has been lots of progress made in the last 32:20.000 --> 32:23.970 fifty years because of people having studied mechanism. 32:23.967 --> 32:26.867 If something isn't going right you have some idea what you 32:26.867 --> 32:30.927 might change in order to make it, not just looking up in the 32:30.933 --> 32:34.203 literature to see what people did before, although that 32:34.200 --> 32:37.030 remains a very important procedure. 32:37.033 --> 32:40.533 We saw all these different nucleophilic substitution 32:40.533 --> 32:43.403 reactions, and the question then if you're trying to apply 32:43.400 --> 32:47.330 somebody else's work to yours, is how general they are. 32:47.333 --> 32:49.673 For example, the Williamson ether synthesis, 32:49.667 --> 32:51.467 how general is it? 32:51.467 --> 32:54.267 For example here's the compound, MTBE. 32:54.267 --> 32:56.197 Have you ever heard of that? 32:56.200 --> 32:59.730 I bet you've seen the word. 32:59.733 --> 33:01.573 Or the acronym. 33:01.567 --> 33:04.327 It's methyl t-butyl ether. 33:04.333 --> 33:07.533 Have you ever seen MTBE? 33:07.533 --> 33:10.173 Where did you see it? 33:10.167 --> 33:10.367 STUDENTS: Lab. 33:10.367 --> 33:11.597 PROFESSOR: On the gasoline pump. 33:11.600 --> 33:15.200 This is an additive to gasoline. 33:15.200 --> 33:19.070 So it's made in enormous quantities. 33:19.067 --> 33:21.797 Here, you want to make this ether. 33:21.800 --> 33:22.730 Here's a way to do it. 33:22.733 --> 33:27.573 You can start with methanol, treat it with sodium hydride. 33:27.567 --> 33:31.667 There is a high HOMO which can attack the proton and take it 33:31.667 --> 33:35.327 away as H2, leaving the sodium salt of methoxide. 33:35.333 --> 33:37.333 We have a nucleophile. 33:37.333 --> 33:40.333 Now if we want to make this bond here, the one between the 33:40.333 --> 33:43.533 oxygen and the tertiary carbon, then we would react it 33:43.533 --> 33:46.373 with t-butyl bromide. 33:46.367 --> 33:49.367 Are you going to get rich in the petroleum industry, making 33:49.367 --> 33:51.727 MTBE that way? 33:51.733 --> 33:52.973 Are there any problems? 34:05.000 --> 34:08.870 What have we just been talking about? 34:08.867 --> 34:14.067 The competition between substitution and elimination. 34:14.067 --> 34:19.167 And what are the factors that favor E2 over SN2? 34:19.167 --> 34:19.597 Amy? 34:19.600 --> 34:20.430 STUDENT: Steric hindrance. 34:20.433 --> 34:22.373 PROFESSOR: Steric hindrance. 34:22.367 --> 34:22.797 Right? 34:22.800 --> 34:23.870 Crowded here. 34:23.867 --> 34:26.567 It's hard for this oxygen to get at the carbon. 34:26.567 --> 34:29.297 And what else? 34:29.300 --> 34:33.470 If you have an anion, a nucleophile, that's even 34:33.467 --> 34:36.367 better as a base, taking hydrogen. 34:36.367 --> 34:38.627 Here we have the worst of all possible worlds. 34:38.633 --> 34:41.473 We have something that wants to take hydrogen, and something 34:41.467 --> 34:45.227 that doesn't want to be attacked at the carbon. 34:45.233 --> 34:46.503 So you get elimination. 34:46.500 --> 34:50.930 It's too hindered for SN2, and the strong base favors E2. 34:50.933 --> 34:55.873 All you get is the double bond compound. 34:55.867 --> 34:58.827 You don't get methyl t-butyl ether. 34:58.833 --> 35:02.573 Does the Williamson synthesis then not work? 35:02.567 --> 35:04.127 Do you just throw up your hands, if 35:04.133 --> 35:05.373 you're a synthetic chemist? 35:08.400 --> 35:10.670 We said we wanted to make MTBE. 35:10.667 --> 35:14.297 We wanted to make that oxygen-carbon bond. 35:14.300 --> 35:15.530 Can you see any alternative? 35:18.867 --> 35:20.127 To make this ether? 35:24.400 --> 35:28.900 You can make that oxygen-carbon bond. 35:28.900 --> 35:33.630 There's more than one way to skin this kind of cat. 35:33.633 --> 35:35.933 That one won't work. 35:35.933 --> 35:40.473 But if we do it the other way around and make this anion, 35:40.467 --> 35:43.727 which again would prefer to eliminate rather than 35:43.733 --> 35:46.203 substitute. 35:46.200 --> 35:49.930 But you attack methyl bromide which can't eliminate because 35:49.933 --> 35:52.533 it doesn't have a hydrogen on the other carbon because it 35:52.533 --> 35:55.673 doesn't have another carbon. 35:55.667 --> 35:59.467 Now you've got the MTBE in high yield although nobody 35:59.467 --> 36:00.727 makes it that way. 36:00.733 --> 36:03.803 The stuff that's made for petroleum is made a different 36:03.800 --> 36:06.830 way, and we'll talk about that a little later on. 36:06.833 --> 36:10.373 Anyhow, this illustrates that often there are different ways 36:10.367 --> 36:13.167 of choosing putting the reagents together. 36:13.167 --> 36:16.027 One will work and one won't work for reasons that you can 36:16.033 --> 36:18.873 understand mechanistically. 36:18.867 --> 36:22.767 Here's another interesting synthetic intermediate which 36:22.767 --> 36:26.367 is, if you start with a compound that has OH and 36:26.367 --> 36:31.327 chlorine on adjacent atoms and notice it has one in the front 36:31.333 --> 36:34.403 and one in the back. 36:34.400 --> 36:37.100 You treat this with base. 36:37.100 --> 36:40.470 It gives this funny ether, an ether that's a 36:40.467 --> 36:42.967 three-membered ring. 36:42.967 --> 36:45.627 It does so in pretty good yield. 36:45.633 --> 36:47.033 How does it do it? 36:47.033 --> 36:52.133 Well, hydroxide takes off this proton and can you see what 36:52.133 --> 36:53.403 happens next? 37:01.433 --> 37:03.433 It's a reaction that's familiar to you. 37:07.033 --> 37:10.003 We want to make this bond. 37:10.000 --> 37:14.570 How do we make that second bond, the new bond, in the 37:14.567 --> 37:15.827 three-membered ring? 37:18.033 --> 37:21.503 It's an SN2 reaction. 37:21.500 --> 37:28.230 This HOMO attacks sigma-star backside, so it's an 37:28.233 --> 37:32.273 intramolecular SN2 reaction. 37:32.267 --> 37:35.297 And chloride leaves to generate this 37:35.300 --> 37:36.500 three-membered ring. 37:36.500 --> 37:40.800 The three-membered ether is called sometimes epoxide, 37:40.800 --> 37:43.070 sometimes oxirane. 37:43.067 --> 37:47.097 Some people call it one, some call it the other. 37:47.100 --> 37:53.500 In fact, epoxides are very useful synthetic intermediates, 37:53.500 --> 38:02.930 because, although R-O minus is a crummy leaving group, in 38:02.933 --> 38:06.033 this case it's helped by losing the ring strain. 38:06.033 --> 38:10.903 So it's spring-loaded to open up. 38:10.900 --> 38:15.200 You can attack here with some nucleophile, break the bond, 38:15.200 --> 38:19.870 the O minus comes away, and this gives a way of adding 38:19.867 --> 38:22.797 C-C-O to a nucleophile. 38:22.800 --> 38:26.800 You bring some nucleophile in, and it adds to the nucleophile 38:26.800 --> 38:29.470 two carbons and then an oxygen. 38:29.467 --> 38:33.497 Synthetic chemists often think, what is it? 38:33.500 --> 38:39.400 If I want to get this product, that's something plus C-C-O. 38:39.400 --> 38:41.400 How could I do that? 38:41.400 --> 38:43.130 Ethylene oxide. 38:43.133 --> 38:46.003 That epoxide can do it. 38:46.000 --> 38:48.900 In fact we're going to talk more about that as a synthetic 38:48.900 --> 38:50.470 intermediate later. 38:50.467 --> 38:54.027 For example, that's the stuff from which you make crown 38:54.033 --> 38:58.803 ethers because it has, remember, C-C-O, C-C-O, C-C-O, 38:58.800 --> 39:03.370 but we'll talk about that in a few lectures further on. 39:03.367 --> 39:06.727 For synthetic purposes a particularly useful set of 39:06.733 --> 39:11.533 nucleophiles is cyanide, acetylide, the thing you get 39:11.533 --> 39:15.703 by losing a proton from acetylene, and this other type 39:15.700 --> 39:20.200 of anion, which has an alpha-anion. 39:20.200 --> 39:23.000 It's lost a proton adjacent to carbonyls. 39:23.000 --> 39:25.200 We talked about that one before. 39:25.200 --> 39:28.130 The reason these are interesting is because they 39:28.133 --> 39:32.003 are nucleophiles that form carbon-carbon bonds. 39:32.000 --> 39:37.100 Most of the things we've talked about replace one 39:37.100 --> 39:38.530 functional group by another. 39:38.533 --> 39:40.103 A leaving group goes away. 39:40.100 --> 39:41.500 The new one comes in. 39:41.500 --> 39:43.930 The new one is typically something 39:43.933 --> 39:46.533 like oxygen or nitrogen. 39:46.533 --> 39:51.373 But these anions have carbon coming in and that means you 39:51.367 --> 39:53.397 make a new carbon skeleton. 39:53.400 --> 39:56.900 That's something that's very important in putting together 39:56.900 --> 39:58.900 organic molecules. 39:58.900 --> 40:03.830 Notice that these two both have a pKa of 9. 40:03.833 --> 40:05.703 You put the starting material-- 40:05.700 --> 40:08.900 that is, the protonated forms have a pKa of 9-- 40:08.900 --> 40:10.970 put them in with base and you get the anion 40:10.967 --> 40:13.627 and it does its trick. 40:13.633 --> 40:14.433 Acetylide 40:14.433 --> 40:17.033 is pKa of 25. 40:17.033 --> 40:18.773 You can't use that in water. 40:18.767 --> 40:21.927 It would immediately take the proton away from water. 40:21.933 --> 40:26.073 So it's a base, and it actually tends to do elimination 40:26.067 --> 40:29.527 sometimes rather than substitution. 40:29.533 --> 40:32.533 So you need a stronger base if you want to pull off a proton 40:32.533 --> 40:34.003 and do that. 40:34.000 --> 40:38.430 You can do it with sodium amide notice that this is the 40:38.433 --> 40:41.873 anion coming from NH3 as the acid. 40:41.867 --> 40:44.127 And NH3 then is the product after it's 40:44.133 --> 40:45.573 pulled off this proton. 40:45.567 --> 40:49.667 And it is a much, much stronger base, a much weaker 40:49.667 --> 40:53.497 acid by nine powers of 10 than the acetylide is. 40:53.500 --> 40:55.130 You could make it that way. 40:55.133 --> 40:57.033 These could be important in synthesis. 40:57.033 --> 41:00.373 We'll see later on in the course how very important 41:00.367 --> 41:02.467 nucleophiles that are carbon are in 41:02.467 --> 41:05.897 putting molecules together. 41:05.900 --> 41:09.000 Now if we look at the rate of the reaction of sodium 41:09.000 --> 41:11.770 hydroxide with an alkyl bromide, 41:11.767 --> 41:12.997 for different R groups. 41:16.367 --> 41:19.297 We're going to look at a log scale so we can cover five 41:19.300 --> 41:21.270 powers of 10 in the rate. 41:21.267 --> 41:28.727 And it's how much of R-Br gets converted to HO-R per minute. 41:28.733 --> 41:29.733 We're going to do it in 41:29.733 --> 41:34.433 ethanol/water, 4:1 at 55 degrees. 41:34.433 --> 41:44.933 We see 1% about 10^-2, of methyl bromide is converted to 41:44.933 --> 41:46.173 this ether-- 41:46.167 --> 41:50.927 or pardon me, to the alcohol-- per minute, 1% per minute. 41:50.933 --> 41:57.533 If we make it ethyl bromide, it's only a tenth of a percent 41:57.533 --> 41:59.933 per minute. 41:59.933 --> 42:01.273 What would you expect for isopropyl? 42:03.733 --> 42:05.033 Looks good. 42:05.033 --> 42:06.303 What do you expect for t-butyl? 42:11.867 --> 42:12.927 So there's something funny. 42:12.933 --> 42:15.703 Something has changed when we went from methyl, ethyl, 42:15.700 --> 42:16.970 isopropyl, and t-butyl. 42:21.800 --> 42:25.630 This was done with 0.01 molar sodium hydroxide 42:25.633 --> 42:27.273 getting these rates. 42:27.267 --> 42:30.397 It turns out that the rate of these depends on how much 42:30.400 --> 42:31.670 hydroxide there is. 42:31.667 --> 42:34.067 That doesn't surprise you, it's SN2. 42:34.067 --> 42:38.497 Depends on how much of the nucleophile there is. 42:38.500 --> 42:42.730 In fact, if you looked at the second-order rate constant, 42:42.733 --> 42:46.903 which takes into account the concentration of base, then 42:46.900 --> 42:50.870 you see these fall on a nice curve and it's slowed down by 42:50.867 --> 42:54.227 crowding, the steric hindrance that we talked about before. 42:54.233 --> 42:57.533 But you'd expect t-butyl to be down here someplace. 42:57.533 --> 43:00.773 In fact, it's up there. 43:00.767 --> 43:05.897 That's because that one is not dependent on hydroxide. 43:05.900 --> 43:07.970 It's not SN2. 43:07.967 --> 43:10.097 The rate doesn't depend both on the 43:10.100 --> 43:12.530 halide and the hydroxide. 43:12.533 --> 43:16.303 It depends only on the halide. 43:16.300 --> 43:18.930 At the rate-determining step, the base hasn't gotten 43:18.933 --> 43:20.173 involved yet. 43:23.033 --> 43:25.703 Notice that it's accelerated by crowding. 43:25.700 --> 43:28.200 When you get to the most crowded one, that mechanism 43:28.200 --> 43:37.170 goes really fast. It can happen because the cation is 43:37.167 --> 43:40.297 more stable when it's more substituted. 43:40.300 --> 43:43.470 It's also accelerated by a polar solvent. 43:43.467 --> 43:46.327 If you try a solvent that's not polar, it's harder to make 43:46.333 --> 43:48.603 ions in it. 43:48.600 --> 43:54.330 But the ethanol and water is a reasonably polar solvent. 43:54.333 --> 43:59.333 "This is the SN1 reaction, as opposed to SN2. 43:59.333 --> 44:05.433 This categorization was formulated, SN1, SN2, in 44:05.433 --> 44:11.673 England, in London, in the 1930s by Hughes and Ingold. 44:11.667 --> 44:14.997 That rate actually wasn't measured at that temperature. 44:15.000 --> 44:17.170 They measured at a lower temperature and figured out 44:17.167 --> 44:20.397 what it would be at this temperature. 44:20.400 --> 44:24.230 This is how much is converted to HO-R but some of the 44:24.233 --> 44:27.903 starting material is not converted to HO-R. Some of it 44:27.900 --> 44:30.330 undergoes elimination. 44:30.333 --> 44:36.273 At this stage 19%, about one-fifth of the product, is 44:36.267 --> 44:39.997 in fact the elimination product, E2. 44:40.000 --> 44:43.300 The base attacks the adjacent hydrogen rather than waiting 44:43.300 --> 44:45.100 for it to ionize. 44:45.100 --> 44:49.400 And we know it's E2 because the amount you get depends on 44:49.400 --> 44:52.230 how much hydroxide you put in there. 44:52.233 --> 44:55.603 The rate of forming the alcohol, the rate of the 44:55.600 --> 44:59.630 substitution, doesn't depend on the hydroxide. 44:59.633 --> 45:01.773 But the rate of forming the alkene does 45:01.767 --> 45:03.627 depend on the hydroxide. 45:03.633 --> 45:06.733 You change the ratio of the products by changing the 45:06.733 --> 45:09.533 hydroxide concentration. 45:09.533 --> 45:14.703 Now you can have SN1 and E1 as well. 45:14.700 --> 45:18.200 In that case we just talked about, if you put more 45:18.200 --> 45:21.430 hydroxide in, the starting material goes away more 45:21.433 --> 45:25.533 rapidly because the elimination is 45:25.533 --> 45:27.233 dependent on hydroxide. 45:27.233 --> 45:30.873 But in the case here where it's cyanide, that's the high 45:30.867 --> 45:33.827 HOMO, that's doing the attacking, you find that you 45:33.833 --> 45:37.633 get not only the cyanide substitution but you also get 45:37.633 --> 45:38.903 substitution by water. 45:43.267 --> 45:47.267 The product ratio depends on how much cyanide you put in. 45:47.267 --> 45:48.267 That doesn't surprise you. 45:48.267 --> 45:50.697 You put in more cyanide, the formation of 45:50.700 --> 45:53.270 this product is faster. 45:53.267 --> 45:54.927 But the rate doesn't change. 45:58.267 --> 46:01.127 The rate of destroying the starting material doesn't 46:01.133 --> 46:03.703 change when you do this. 46:03.700 --> 46:06.100 Can anybody see how that could be? 46:06.100 --> 46:09.130 How could you change the products but 46:09.133 --> 46:10.403 not change the rate? 46:15.667 --> 46:16.097 Matt? 46:16.100 --> 46:17.330 STUDENT: Because even though you have a different ratio, it 46:17.333 --> 46:18.603 could be doing a different mechanism, possibly. 46:25.367 --> 46:27.027 PROFESSOR: Let's try it here. 46:27.033 --> 46:30.003 We have this starting material and these two products. 46:30.000 --> 46:32.930 We're going to draw a reaction coordinate diagram to get from 46:32.933 --> 46:35.333 the starting material to the products. 46:35.333 --> 46:40.803 Here we formed, as in SN1, an intermediate cation. 46:40.800 --> 46:43.870 And then it goes on, if there's cyanide around, to 46:43.867 --> 46:48.267 give that product or with water to give that product. 46:48.267 --> 46:50.967 What determines the rate of the process? 46:50.967 --> 46:53.927 What's the rate-determining step? 46:53.933 --> 46:56.333 The red one, right? 46:56.333 --> 47:00.133 That happens before you decide which product you get. 47:00.133 --> 47:02.933 If you have more cyanide in there, more of it 47:02.933 --> 47:05.503 will go this way. 47:05.500 --> 47:10.600 You can change the products without changing the rate, if 47:10.600 --> 47:12.700 you have this cation intermediate. 47:12.700 --> 47:15.600 So if the product is determined after the rate, by 47:15.600 --> 47:20.100 competition for the short lived cation, that's evidence 47:20.100 --> 47:22.530 that you have a cation intermediate in this 47:22.533 --> 47:25.203 substitution. 47:25.200 --> 47:29.230 Here's silver nitrate helping to pull off the 47:29.233 --> 47:31.573 leaving group, iodide. 47:31.567 --> 47:34.527 Notice what's funny in this case. 47:34.533 --> 47:37.773 Whoops, what's funny is I've talked my head off here. 47:40.533 --> 47:42.633 There are a few more slides that I think it would be 47:42.633 --> 47:49.233 helpful to have to make the exam coherent. 47:49.233 --> 47:51.373 Since the exam's going to be on Friday, why don't we put a 47:51.367 --> 47:55.327 few more of them onto the next and I apologize. 47:55.333 --> 47:56.433 I'll let you go now. 47:56.433 --> 48:00.803 We'll do a few more slides next time for the exam. 48:00.800 --> 48:03.070 And there will be a review session on Wednesday.