Free-Radical Cyclization

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Chapter: Organic Chemistry : Carbon-Carbon Bond Formation By Free-Radical Reactions

With good methods available for producing carbon-centered free radicals, the cyclization process can be examined in greater detail. Cyclization involves the intramolecular addition of a free-radical to a double bond.


With good methods available for producing carbon-centered free radicals, the cyclization process can be examined in greater detail. Cyclization involves the intramolecular addition of a free-radical to a double bond. Of course, this requires that the two reacting parts of the molecule, the free-radical center and the π bond, come within bonding distance of one another.

It is quite easy for open-chain systems to undergo intramolecular cyclization because of their many rotational degrees of freedom. More rigid systems undergo efficient cyclization only if the free-radical center and the π system are held in close proximity, as in the first example below. Where the molecular geometry is fixed in such a way as to prevent effective interaction between the free-radical center and the π system, cyclization is inefficient and reduction predominates. Cyclization in the second example is an obvious impossibility!

Other cases are not always so obvious, yet any structural or steric feature which influences the close approach of the π bond and the free-radical center will influ-ence the rate of cyclization and hence the yield of cyclized product. For example, trans-fused cyclopentyl systems are much higher in energy than cis-fused ones; thus the trans-fused cyclopentyl compound does not cyclize effectively and gives only reduction,

whereas the cis-fused cyclizes efficiently with little reduction,

The cyclization itself can produce two different ring sizes depending on which carbon of the double bond is attacked. Of the two possibilities, it is seen that one mode of cyclization gives a secondary radical while the other mode produces a primary free radical.

Since the order of free-radical stabilities falls in the order 3 > 2 > 1 , product stability would dictate that cyclization should preferentially occur to give the more stable secondary radical—a six-membered ring in reaction (9.1) (path a) and a seven-membered ring in reaction (9.2)(path a).

In contrast, is known that the rates of ring-forming free-radical cyclizations are 5 > 6 > 7. Experimentally it was found that reaction (9.1) gives the five-membered ring product (path b) exclusively, and reaction (9.2) gives the six-membered ring product (path b). Thus the regioselectivity of ring formation is controlled not by thermodynamic considerations but by kinetic control of the cyclization. It turns out that bond formation between a radical and a π system stereoelectronically requires an approach angle of about 110 between the free-radical center and the olefinic plane. (This is due to the fact that free-radical addition results from donation of the unpaired electron on the radical into the π antibonding orbital of the olefin, which coincidentally makes an angle of about 110 with the olefinic plane.)

In an intramolecular cyclization, attack on the end of the double bond closest to the radical center (an exocyclic cyclization) achieves the proper approach angle. Attack on the other olefinic carbon requires that the radical reach across the double bond to achieve the proper approach angle. This is a higher energy path and is kinetically disfavored. The same arguments hold for cyclizations which can produce six- or seven-membered rings.

A final feature of radical cyclizations is that they are mainly influenced by steric factors and are practically insensitive to inductive effects. Since free radicals are charge neutral, their reactivity is not greatly influenced by either electron-donating or electron-withdrawing groups. For instance, the following cyclizations occur with similar efficiencies even though the electronic character of the cycliz-ing radicals are vastly different:

It has also been shown that the electronic character of the olefin to which the radical adds has little influence on the efficiency of the intramolecular cyclization. Intramolecular competition between addition to an electron-rich enol ether or a simple double bond gives a 1 : 1 ratio of products, demonstrating that free-radical cyclizations have a remarkable insensitivity to inductive effects.

Resonance effects, on the other hand, can significantly affect the regiochem-istry of the cyclization. Resonance delocalization of the unpaired electron of a free radical stabilizes that radical. This is why the allyl radical is much more stable than the n-propyl radical. Thus, if a double bond is substituted with a group capable of providing resonance stabilization to a free radical, it undergoes free-radical addition much more readily than a double bond which cannot provide such resonance stabilization.

Steric effects can also influence the cyclization process markedly. Bulky sub-stituents which hinder the approach of the free radical to the π system can prevent cyclization altogether and give only reduced product.

Below are shown a few examples of the types of complex structures that can be assembled by intramolecular free-radical cyclization. Note the presence of a great many polar functional groups present in the cyclization substrates which are compatible with the process. While the examples shown do not need protecting groups, a great number of other free-radical cyclizations are known which have unprotected alcohols, carbonyl groups, and carboxylic acids in the cyclization precursor.

Free-radical cyclization reactions nicely complement the Pd(0)-catalyzed in-tramolecular Heck reaction, which also provides cyclic products from unsaturated halides. Free radicals can be generated easily at saturated carbons from saturated alkyl bromides, and the products are reduced relative to the reactants. In contrast, intramolecular Heck reactions work best for vinyl and aryl bromides (in fact they do not work for alkyl halides), and the products are at the same oxidation level as the reactants. Moreover, free radicals attack the double bond at the internal position, whereas palladium insertion causes cyclization to occur at the external carbon.

The advances made in using free radicals as synthetic intermediates in the last 10–20 years have been extraordinary due to new methods to effectively generate free radicals and new insights into their reactivity patterns which allow them to be controlled. As a consequence, the construction of ring systems has been tremendously facilitated.

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