Lecture 4 Notes Last time we introduced the topic of free radicals. Today we are going to spend time talking about the reactions that free radicals undergo, both on the small molecule scale and on the polymer scale. Radicals undergo two basic classes of reactions: atom transfer and addition to pi systems. An atom‐
transfer reaction is where an atom with one electron is transferred from a closed‐shell molecule to the free radical. Some examples of atom‐transfer reactions are shown below: The driving force for these reactions is usually the formation of a more stable radical or a stronger bond. The second class of reactions is the addition of free radicals to pi systems. Two examples are shown below: Here the driving force is that you are breaking a relatively weak pi‐bond and forming a new sigma bond. In general, we can also think about radical reactions as “chain reactions.” We are going to see an example of this when we talk about free‐radical polymerizations. These sorts of reactions occur when radicals react with other neutral (closed‐shell) species to generate more radicals. These chain reactions can be divided into three steps: (1) Initiation – phase of the process where free radicals are produced (2) Propagation – phase of the process in which free radicals undergo reaction to form products, including new free radicals (3) Termination – phase of the process where free radicals are removed from the system by recombination or other reactions. Real‐world example: This compound is a biradical. It was synthesized by the research group of Timothy Swager (MIT) back in 2009. The ultimate use of biradicals like this compound is for dynamic nuclear polarization (DNP) experiments‐which is a variation on NMR that provides improved signal to noise ratios. Honestly I have no idea how this works The key steps in the synthesis of this biradical are shown below: There are two key steps here – the first is the reaction of the carboxylic acid with the free amine, and the second is the formation of the biradical. We will talk about each of these steps briefly: 1. In general when you want to couple a free amine with a carboxylic acid to generate an amide bond, the overall reaction looks like this: But carboxylic acids by themselves are not reactive enough to undergo this reaction, so there are a variety of activating reagents that we use to generate intermediates known as “active esters” or “active carbonyls.” An acid chloride is substantially more reactive than the free carbonyl, and in our case we generate it using oxalacetic acid: You can also generate the acyl chloride from thionyl chloride, SOCl2: O
O
+
R
SOCl2
OH
R
Cl The second key step here is the creation of the radical using silver nitrate. You deprotonate first using potassium tert butoxide – the reason that the base goes for the proton that it does is that it is the most acidic proton. Your other choice here would be to lose the H from the nitrogen, but it doesn’t do that. Once you form the anion, silver gains an electron (and gets reduced), leading to silver metal as a byproduct. Metals in general can create radicals relatively easily. We discussed this very briefly last time when talking about iron. Let’s move on now to talk about free‐radical polymerization reactions: Free‐radical polymerization was first used in olefin polymerization reactions. This reaction, like other free‐radical reactions, involves initiation, propagation, and termination steps. Initiation: Usually people use an initiator that can form radicals under relatively mild conditions. Last time we talked about AIBN and benzoyl peroxide as two examples of initiators. Benzoyl peroxide decomposes into a radical with heat, whereas AIBN decomposes with thermal irradiation: O
O
O
heat
O
.
O
O
2. Propagation: This is where the initiator reacts with a monomer to generate a new radical. In olefin polymerization, the propagation step occurs when the radical adds to a pi bond: This new radical can add to another styrene (olefin) to continue growing the polymer chain: Theoretically this kind of chain growth can continue indefinitely. In practice, chain termination occurs when two radicals combine. This combination can occur in a few different ways: (1) Chain combination: (2) Probably the most common (for our purposes) is termination due to some impurity – like oxygen: Which is why when you are doing polymerization reactions, you have to be so careful to exclude oxygen and moisture. We are going to talk now about a few select examples of polymers formed from free‐radical polymerization: (1) poly‐olefin sulfones (POS)– We already mentioned that olefins can be polymerized by free radical polymerization. It turns out that you can form an alternating co‐polymer from an olefin and a sulfone using peroxide as an initiator: The mechanism here is a variation on free‐radical polymerization. Think about what the mechanism is, and why you get a perfectly alternating sulfone‐alkene polymer. Let’s talk now about the second topic of the day: Free‐radical cyclization reactions. Most radicals don’t live long enough in a reaction mixture to combine with other radical species. It turns out that intra‐
molecular reactions of radicals are remarkably fast (because they are in close proximity to the other part of the molecule). These intramolecular reactions most often take the form of ring‐closing/ cyclization reactions, and they are faster than the corresponding inter‐molecular reactions: These are just intra‐molecular versions of the radical addition to olefins that we talked about last time. The formation of these five‐membered rings is HIGHLY HIGHLY favored, so much so that you can perform these cyclization reactions in the presence of other functional groups (and those functional groups do not need to be protected because the radical reaction is so fast): So in general when you think about free‐radical cyclization, you should look primarily at the STERICS of the molecule, and whether it looks feasible to form a five‐membered ring. We will go through a few more examples of these cyclization reactions. Example 1: The top case undergoes a cyclization reaction, but the geometry of the bottom case prevents cyclization from occurring. Example 2: Cis‐substituted five membered rings will cyclize but trans‐substituted five membered rings will not. AIBN
Bu3Sn-H
heat or hv
H
H
H
O
I
O
H
H
O
I
O
H
AIBN
Bu3Sn-H
heat or hv
H
H
H CH3
H
Example 3: Radical reactions are also highly insensitive to electronics. So the three reactions shown below (with very different electronics) all proceed at the same rate: Example 4: Sterics of the substituted olefin affect the cyclization efficiency, so the example below gives no cyclized product and 100% of the product from the abstraction of a hydrogen atom: Finally, let’s look at three cases of the sorts of complex products that can be obtained from radical cyclization reactions: Note that this adds another option to your retrosynthetic toolbox – when you see a five membered ring, that can be disconnected back to an olefin and a halide (which forms a radical when you treat it with a radical initiator. We are going to talk next time about another class of reaction intermediates: carbenes.