Intramolecular radical reactions are more efficient than intermolecular ones

All of the reactions you have met so far involve radical attack of one molecule on another. We’ve pointed out some of the drawbacks when C–C bonds are made in this way: the radical trap has to be activated (that is, electrophilic to capture nucleophilic radicals) and must often be present in excess, and the radical starting material must contain very weak C–X bonds (such as C–Br, C–I). The requirements are much less stringent, however, if the radical reaction is intramolecular. For example, this reaction works:

Notice that the double bond is not activated: in fact, it is nucleophilic, and the reaction still works even though the radical is also substituted with an electron-donating group. The C–S bond that is broken is also relatively strong, yet nonetheless a high yield of product is obtained. Why should this be so? What difference does it make that the reactions are intramolecular?

The key is that the intramolecular cyclization of the radical is now enormously favoured over other possible courses of action for the radical. Remember that when we were carrying out radical reactions intermolecularly, addition to the radical trap was encouraged by increasing the concentration of radical trap and decreasing the concentration of Bu3SnH to avoid radical reduction. For intramolecular reactions, the double bond that acts as the radical trap is always held close to the radical, and cyclization takes place extremely rapidly, even on to unactivated double bonds. The hydride donor (Bu3SnH) doesn’t get a look in, and can be pre sent in higher concentrations than would otherwise be possible. Moreover, as there is only one equivalent of radical trap, and the trap need not be highly reactive, there is little danger of high concentrations of Bu3Sn• reacting with it, so the concentration of Bu3Sn• can build up to levels where the rate of abstraction of groups like Cl, SPh, and SePh is acceptable, despite their stronger C–X bonds.

For all these reasons, intramolecular radical reactions are very powerful, and are often used to make five-membered rings.

It is possible to make other ring sizes also, but the range is rather limited. Because of ring strain, three- and four-membered rings cannot be formed by radical reactions. Otherwise, smaller rings form faster than larger ones: look at these selectivities.

The preference for formation of a smaller ring is a very powerful one: in this reaction, the five-membered ring forms and not the six-membered one, even though cyclization to give a six-membered ring would also give a more stabilized radical.

We said earlier that the toxicity of tin poses some problems, so it is useful that the borane oxygen method works well for initiating radical cyclizations too. It is not necessary to incorporate boron into the starting material, since a combination of Et₃B, O₂, and hypophos phorous acid, H₃PO₂, can generate a radical from a halide which will cyclize in the same way as the tin-promoted examples you have just seen. Once again, a five-membered ring is pre ferred to the alternative six-membered ring.

Notice that the ethyl groups from Et₃B are not incorporated into the product. The displace ment of Et• from Et₃B initiates the chain reaction by abstracting the iodine atom from the starting material. The radical cyclizes to give a five-membered ring, as expected. A cis ring junction is inevitable because of the acetal ‘tether’.

The product radical has to collect a hydrogen from somewhere, and this is the role of the hyphosphorous acid. Abstraction of H gives a radical that can be drawn either as P-centred or O-centred.

The chain is finally completed by a hydrogen abstraction from H₃PO₂, which gives a radical that attacks the borane, just like oxygen did in the initiation step. A new ethyl radical is generated, which starts the cycle again.

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مواضيع ذات صلة

Attack of carbenes on lone pairs

Nitrenes are the nitrogen analogues of carbenes

Rearrangement reactions

Insertion into C–H bondsInsertion into C–H bonds

Making cyclopropanes

Carbenes react with alkenes to give cyclopropanes

The structure of carbenes depends on how they are made

Carbenes can be divided into two types

اكتشاف العناصر

العناصر

Diazomethane makes methyl esters from carboxylic acids

Alkyl radicals from boranes and oxygen