The 5-Hexenyl Radical

The first use of 5-hexenyl radical cyclization as a mechanistic tool was proposed in 1966 by Garst and Lamb for the study of alkyl halides reduction by naphthalene radical anion. Since then, Garst has extensively used this method in the study of the one-electron transfer reactions from aromatic radical anions to alkyl halides critical discussion of the use of the method may be 

In other examples, the fact that no cyclized products (CyS or Cy6) are observed from possible S-hexenyl intermediates has been used as proof that an Sjy2 process was more likely than a free radical or carbenium ion pathway this is the case in the solvolysis of 4-alkoxypyridinium salts.  

More familiar reactions but ones whose mechanism has been a controversial subject of interest for a long time have also been studied by this method. This is the case of the reductive demercuration of alkylmercuric halides by metal hydrides. In a careful study, Quirk was able to conclude that alkyl radicals are intermediates and that the process is a radical chain mechanism. This conclusion resulted from the knowledge that the cyclization was a relatively slow process (see Section XII.2) compared with the recombination process in the solvent cage, a conclusion recently confirmed by cidnp experiments. Furthermore, the use of metal deuterides and the measurement 

The 5-hexenyl system has been used by Garst to demonstrate that the intermolecular portion of the Wittig rearrangement of aralkyl alkyl ethers and the ketyl-alkyl iodide reaction involve free radical intermediates.  

This certainly very incomplete and fast growing list of examples was provided in order to show that the 5-hexenyl radical tool may be used in many cases. Other examples in which the 5-hexenyl cyclization also affords kinetic values will be described in Section XII.2. 

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Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization... 

Other transformations of the radicals are also possible. For example, the 5-hexenyl radical partially cyclizes in competition with coupling ... 

Other radicals undergo rearrangement in competition with bimolecular processes. An example is the 5-hexenyl radical (5). The 6-heptenoyloxy radical (4) undergoes sequential fragmentation and cyclization (Scheme 3.8).1S... 

A better-known example of a free radical clock is the 5-hexenyl radical. Timing is provided by the rearrangement reaction... 

Activation parameters. Calculate AW and AS for the cyclization of the 5-hexenyl radical, whose rate is given in Eq. (5-39). 

Eisch, Behrooz and Galle196 give compelling evidence for the intervention of radical species in the desulphonylation of certain acetylenic or aryl sulphones with metal alkyls having a lower oxidation potential at the anionic carbon. The primary evidence presented by these workers is that the reaction of 5-hexenylmagnesium chloride outlined in equation (85) gives a mixture of desulphonylation products, in accord with the known behaviour of the 5-hexenyl radical, in which the cyclopentylmethyl radical is also formed. 

These methods are usually highly regio- and stereoselective and represent a breakthrough for synthetic chemistry using radicals. Giese quotes, as an example, that the cyclisation of the 5-hexenyl radical 8 affords the primary cyclopentylmethyl... 

The one-carbon ring expansion of (17) to (18) has been accurately measured and proposed as an alternative radical clock to the 5-hexenyl radical to help determine rates in the middle regions of the kinetic scale (Scheme 8). Ab initio calculations have indicated that the isomerization of the 3-oxocyclopentylmethyl radical to the 3-oxocyclohexyl radical is energetically more favourable than the process leading to the ring-opened 5-hexenoyl radical. " ... 

As with any intermediate, a transient radical can be implicated from products formed in a reaction specific to the radical of interest. Experimentally, this is the basis of so-called mechanistic probe studies. An application of this method might employ, for example, 6-bromo-l-hexene as a probe for a radical intermediate as shown in Figure 4.3. If the 5-hexenyl radical is formed as a transient with an adequate lifetime, then cyclization of this radical to the cyclopentyhnethyl radical could eventually give the cyclic product, and detection of the cyclic product provides evidence that a radical was formed. The mechanistic probe approach is deceptively simple, however. To be useful, one must exclude other possibilities for formation of the rearranged product and demonstrate that the transient was formed in the reaction of interest and not in a side reaction. The latter is especially difficult to demonstrate, and, unfortunately, some mechanistic probe studies that seemingly provided proof of radical intermediates were later found to be complicated by radical-forming side reactions. 

As described in section 3.1, when a radical cyclization reaction involves the 5-hexenyl radical intermediate, the 6-endo-trig radical cyclization will prevail when the usually favoTed 5-exo-trig regioselectivity is suppressed by substitution at the 5-position. Such a tactic was... 

Scheme 10.28 Use of the 5-hexenyl radical clock to determine Arrec n for primary alkyl radicals by Smb in a samarium Barbier reaction (Ar = p-methoxyphenyl).

Although radicals are not nearly so prone to rearrangement as are, for example, carbocations, there are a few such rearrangements which have become identified as characteristic of carbon radicals. These include radical cyclizations, particularly the 5-hexenyl radical cyclization, and radical C-C bond cleavages, particularly the cyclopropylcarbinyl to allyl carbinyl radical rearrangement. In hydrocarbon systems, as organic synthetic chemists have learned how to control rapid chain processes, such rearrangements have become important synthetic tools [176-179]. 

The transformation of 6-bromo-l-hexene (38) into methylcyclopentane by the action of tributyltin hydride (Scheme 7) typifies the richness of the C—C bond forming chemistry in question. A knowledge of the critical rate constants (kc, ku and Br in Scheme 7) allow, through control of substrate concentration, necessary selectivity criteria to be met. Specifically the 5-hexenyl radical (39) must undergo intramolecular addition to form the cyclopentylmethyl radical (40), 40 must abstract a hydrogen atom from tributyltin hydride and the tributylstannyl radical must abstract the halogen in 38 to form 39. These processes must proceed faster than any competing side reaction. 

Interestingly, the 5-hexenyl radical, which is believed to cyclize quickly, with a rate constant on the order of k = 10 sec [73,74], had led to a high yield of cyclized product when generated in solution [75]. For example, reduction of 110 with tri-n-butyltin hydride provides 112 in 78% yield and only 7% of the straight-chain olefin 111. This contrasts with what was actually observed in formation of the Grignard reagent by reaction of 110 with magnesium, in spite of the fact that the 5-hexenyl radical is involved in both instances. 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C ir bond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so fast. The cyclization of the 5-hexenyl radical to the cyclopentylmethyl radical is very fast, occurring at a rate of about 1.0 X 105 s-1. In fact, the rate of formation of the cyclopentylmethyl radical is much faster than the rate of cyclization to the lower energy cyclohexyl radical. This stereoelectronic effect is derived from the fact that the overlap between the p orbital of the radical and the rr MO of the double bond is much better when Cl attacks C5 than when it attacks C6. The relative rates of 5-exo and 6-endo ring closures are strongly dependent on the nature of the substrate and especially on the amount of substitution on the ir bond. Cyclization of the 6-heptenyl radical in the 6-exo mode is also very favorable. 

The 5-hexenyl radical 131 rearranges in a highly regiospecific manner to give mainly the cyclopentylcarbinyl radical 132. The cyclohexyl radical 133 is formed only as a side product89). 

The data of Table 5 indicate that the conversion of the anion 145 into 146 is very much slower (by a factor of 108-1010) than the cyclization of the 5-hexenyl radical 131. However, nonnegligible quantities of product containing the cyclopentylmethyl group may still arise from cyclization of the anion 145 since the half-life for this process at temperatures above 0 °C (t1/2 = 23 min at 0 °C 5.5 min at 23 °C) is short relative to the time scale of many experiments that seek radical intermediates 103). A differentiation between radical and anion cyclization, as in the case of 134 and 138, is not available with 131 and 145. The cyclization of the anion 145 is, however, very slow at lower temperatures like —78 °C. 

When stereogenic centers are introduced on the tether, a large asymmetric induction can also be observed, especially when the product results from an initial 1,5-ring closure. The relaxed excited state of the starting enone behaves as the 5-hexenyl radicals and prefers to cyclize in a 5-exotrig process [47] according to Baldwin s rules [48]. The model used to determine the selectivity of the intramolecular addition of 5-hexenyl radicals can be applied to 66 and 68. Then the stereochemistry of the major diastereoisomers 67 and 69 can be deduced from the transition states that place the largest substiment in equatorial position, as... 

The 2 1 copolymer, first reported in 1958 (1), was assumed to have the tetrahydropyran structure, I in Scheme 1 (2K Although this structure had been widely accepted ( 3), there was no convincing evidence for it. In fact, a number of reports in the literature suggested that the kinetically controlled route leading to a tetrahydrofuran ring, II in Scheme 1, would be more likely. Thus, it was shown by ESR that the 5-hexenyl radical, formed by photolysis of 6-heptenoyl peroxide, cyclizes... 

Simple model studies show that substitution at C-l or C-3 of the 5-hexenyl radical gives mainly c/.v-disubstituted cyclopentanes, whereas substitution at C-2 or C-4 leads mainly to tran.v-disub-stituted cyclopcntanes. A variety of theoretical treatments L 2 and experimental results now aid in the planning of highly stereoselective reactions, and allow predictions according to Beckwith s guidelines. 

The following examples are ordered with respect to the position of the substituent in the 5-hexenyl radical and the complexity of the systems. 

The observation that formation of five-membered rings is favored is consistent with the findings of Beckwith125 the 5-hexenyl radical undergoes cyclization to the cyclopentylmethyl radical 75 times faster than to the cyclohexyl radical. 

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