Lecture 10. October 18, We are going to spend the first part of today s class going over the test.

Transcription

1 Lecture 10 We are going to spend the first part of today s class going over the test. ctober 18, 2011 In the second half of the class we will talk about LEFIN METATHESIS, mostly because it is a fairly important transformation, and I am not sure how much you have already learned about this topic. A general depiction of olefin metathesis is shown below, where you have two olefins that literally switch partners: The first metathesis reaction came from Ziegler and Natta, who found that 2-pentene could be treated with tungsten hexachloride and ethylaluminum dichloride to give a mixture of alkene isomers: This is an equilibrium mixture, because the olefins keep switching partners with each other. Subsequently, two researchers developed highly active catalysts for this metathesis reaction: These researchers (as well as a third guy) won the Nobel Prize in chemistry in 2005 for this work. The active catalytic species in the metathesis reaction is a metallocarbene complex with a carbon-metal double bond, which is formed from the two catalysts: After that, there is a 2+2 cycloaddition between the carbene and the alkene. The alkene can be oriented in one of two ways to generate two different 4-membered rings: Now the four-membered rings undergo retro-2+2 cycloadditions: The top ring regenerates the starting materials:

2 Cl n CH 3 W Me Et Me Et + Cl n W CHCH 3 The bottom ring, however, gives the dimethyl-substituted olefin and a new carbene: This new carbene undergoes a new round of metathesis to generate the diethyl-substituted alkene: Now we have accounted for all of the alkenes formed by the Ziegler-Natta reaction. In practice, olefin metathesis has become remarkably useful in the context of organic synthesis. There are actually several different categories of olefin metathesis: 1. Ring closing metathesis (RCM) two terminal olefins react to give a closed ring system: This is still a case of switching partners just that the unseen partner is ethene: Also note that the net effect on the ring is that it loses two carbon atoms. 2. Ring opening metathesis here you open a ring that contains an alkene and form two new alkenes in the process. The general scheme is shown below:. 3. Cross-metathesis You start with two alkenes that switch partners to form two new alkenes: Also note here that the two substituents on the SAME side of the double bond stick together i.e. A and B are never separated, nor are C and D just the pairs of substituents swap. There are two competing reactions here the first is ring-closing metathesis to generate the desired product. The second possible reaction is intermolecular metathesis, which will give long chain polymers.

3 You can bias the reaction towards forming the desired closed ring by keeping the reactant concentration low. Why does this work? Well the ring closure is a unimolecular process, so even if the reaction is very dilute, the ring-closure will proceed. The intermolecular metathesis, in contrast, requires two molecules to come together, and that process will become increasingly disfavored under highly dilute conditions. Another way to accomplish high dilution experimentally is to use slow addition that is, you add slowly add a solution of diene to a solution of the catalyst. As you add the diene, it reacts with the catalyst, so that the concentration of unreacted diene hanging around in your reaction vessel is minimal. Ring-closing metathesis examples: Example 1: Terminal olefin with Grubbs catalyst. Note that the Grubbs catalyst is the reagent of choice (because it is so much more stable than the Mo complexes), and that the original Grubbs catalyst works best with terminal olefins. Example 2: Medium-sized ring formation using Grubbs catalyst: The first reaction works great because five-membered rings are so highly favored. The reason why the third reaction works well whereas the second reaction doesn t work at all has to do with the conformation of the molecule. Medium-sized rings have a large entropic penalty to overcome in order to cyclize meaning they tend to be large and flexible, and only one conformation (of many, many possible ones) will be the right one for cyclization to occur, so it becomes difficult for them to cyclize. This explains why the second reaction doesn t work. The third reaction, however, has a benzene ring that pre-organizes things and removes some degree of the flexibility here. Example 3: Another illustration of the importance of reactant conformation:

4 Grubbs catalyst 45 o C,1hour Li + no additive: 39% yield LiCl4(5 equivalents): >95% yield Li + Here the lithium cation coordinates to the oxygens and pre-organizes the substrate for cyclization. Example 4: You can also form large rings using Grubbs catalyst if you carefully control conditions (like using slow addition and/or organizing the substrates): You often get a mixture of olefin isomers (cis and trans), especially for the larger rings. But, more often than not, the next step is to hydrogenate the olefin, so then the double bond isomer mixture is largely inconsequential. Let s do one final example where they use olefin metathesis in the context of total synthesis in this case the total synthesis of zampanolide. The target structure is shown below:

5 If I told you to do a retrosynthesis of this compound using olefin metathesis, you could probably disconnect it at any of the double bonds, and that would be a valid answer. However, if you look closer you will see that there are two double bonds that are also part of a,b-unsaturated ketones: It turns out that it is not so easy to do a ring closing metathesis on those types of olefins, which means that we have one olefin left to disconnect. If you do that disconnection, it brings you back to this immediate precursor: In the forward direction, if you tried to do this reaction it would give you a big mess. You have three terminal olefins that will react within the same molecule as well as with other molecules (to give you oligomers and polymers). Also any of the internal olefins can also react via cross-metathesis to give you a big mess. But in practice, Grubbs catalyst is much more reactive with terminal olefins compared to internal ones, so it is usually a safe bet to say that terminal olefins will react first/ exclusively. No class on Thursday because of the Jewish holiday. Next week we will move on to a new and very interesting topic: chirality.