Radical cyclopentylmethyl

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. 

A more recent example is found in the work of Schmid and Ingold (1978), who used the rate of rearrangement (17) of 5-hexenyl radicals into cyclopentylmethyl radicals (R- and R - in Scheme 5) to time the spin trapping of primary alkyl radicals. In this system, both R and R are primary alkyl, and their spin adducts with several traps therefore have virtually indistinguishable spectra. This difficulty was circumvented by labelling C-l in the hex-5-enyl radical with 13C the unrearranged radical then gives spin... 

Radical cyclization reactions provide a good example of the situation where kinetic and thermodynamic products appear to differ. Cyclization of hex-5-enyl radical can either yield cyclopentylmethyl radical or cyclohexyl radical. 

While cyclohexyl radical would be expected to be thermodynamically more stable than cyclopentylmethyl radical (six-membered rings are less strained than five-membered rings and 2° radicals are favored over 1° radicals), products formed from the latter dominate, e.g. 

We will see in Chapter 19 that calculations show cyclohexyl radical to be about 8 kcal/mol more stable than cyclopentylmethyl radical. Were the reaction under strict thermodynamic control, products derived from cyclopentylmethyl radical should not be observed at all. However, the transition state corresponding to radical attack on the internal double bond carbon (leading to cyclopentylmethyl radical) is about 3 kcal/mol lower in energy than that corresponding to radical attract on the external double bond carbon (leading to cyclohexyl radical). This translates into roughly a 99 1 ratio of major minor products (favoring products derived from cyclopentylmethyl radical) in accord to what is actually observed. The reaction is apparently under kinetic control. 

Organic chemists have a keen eye for what is stable and what is not. For example, they will easily recognize that cyclohexyl radical is more stable than methylcyclopentyl radical, because they know that "6-membered rings are better than 5-membered rings", and (more importantly) that "2° radicals are better than 1° radicals". However, much important chemistry is not controlled by what is most stable (thermodynamics) but rather by what forms most readily (kinetics). For example, loss of bromine from 6-bromohexene leading initially to hex-5-enyl radical, results primarily in product from cyclopentylmethyl radical. ... 

The calculated difference in transition-state energies in 2.3 kcal/ mol in favor of ring closure to the cyclopentylmethyl radical. Inclusion of entropy increases this difference to around 2.7 kcal/ mol. Methylcyclopentane is in fact the kinetic product and only about 1 - 2% ofthe total product mixture should be cyclohexane. This is what is observed, suggesting that the radical mechanism is not at fault but that the reaction is under kinetic control. 

The reaction (equation 76) of the hexenyl radical 47 forming cyclopentyl-methyl radical was discovered independently in several laboratories and has been of pervasive utility in both synthetic and mechanistic studyThe competition between formation of cyclopentylcarbinyl and cyclohexyl radicals favors the former even though the latter is more stable, and this kinetic preference is explained by more favourable transition state interaction. The effects of substituents on the double bond, heteroatoms in the chain, and many other factors on the partitioning between these two paths have been examined. In the gas phase above 300°C, methylcyclopentane has been observed to form cyclohexane via isomerization of cyclopentylmethyl radicals into the more stable cyclohexyl radicals. ... 

Scheme 10.11 shows a PRE-mediated 5-exo-trig radical cyclisation in which the controlled thermal formation of active radicals from the dormant alkoxyamine 2 is facilitated by steric compression of the alkoxyamine C—O bond by the bulky N-alkyl and O-alkyl groups [8]. Intramolecular H-bonding between a —CH2—OH and the nitroxyl oxygen of the incipient nitroxide in a six-membered cyclic transition structure further facilitated the dissociation of 2. After cyclisation, the resultant primary cyclopentylmethyl radical was trapped by the free nitroxide to form the new dormant isomerised alkoxyamine 3, which is more stable than 2 since the O-alkyl is now primary. The same reaction using TEMPO as the nitroxide component did not work presumably because the C—O bond in the alkoxyamine precursor is much stronger. 

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. 

A typical cyclization reaction example is the cyclization of the 5-hexen-l-yl radical, which cyclizes to give a cyclopentylmethyl radical (primary alkyl radical) and a cyclohexyl radical (secondary alkyl radical), as shown in eq. 1.2. Generally, the radical cyclization proceeds via a kinetically controlled pathway, so the less stable cyclopentylmethyl radical is formed predominantly. 

Thus, it is called exo , when the cyclization occurs on the inside of the unsaturated carbon-carbon bond, and it is called endo , when the cyclization occurs on the outside of the unsaturated carbon-carbon bond. Moreover, it is tet (tetrahedral 109.5°), when the carbon-carbon bond at the reaction site is sp3 hybridization it is trig (trigonal, 120°), when the unsaturated carbon-carbon bond at the reaction site is sp2 hybridization and it is dig (digonal, 180°), when the unsaturated carbon-carbon bond at the reaction site is sp hybridization. For example, there are two types of cyclization manner in 5-hexen-l-yl radical, exo-trig and endo-trig, based on the above classification. Since a 5-membered cyclopentylmethyl radical is formed through exo-trig cyclization, it is finally... 

Hexenyl bromide 22 can be activated similarly to 5-hexenyl radical 22A, which cyclizes to cyclopentylmethyl radical 22B with a rate constant of 2.3 x 105 s 1 [91]. For this slower reaction, a competition between direct trapping of 22A to 24 and 5-exo cyclization to 22B followed by coupling to 23 is often found. These unimolcular reaction steps are in comparison to bimolecular transition metal-centered transformations faster or at least as fast. 

We have studied the same rearrangement directly by preparing the radical from 6-bromo-hex-l-ene in a suitable matrix, and observing the e.s.r. spectrum of the product radical. The cyclopentylmethyl radical (6) is formed predominantly in matrices of camphane, adamantane or dicyclopentadiene dimer (BCPD). 

Hexenyl radicals cyclize to cyclopentylmethyl radicals (see Volume 4, Chapter 4.2). Thus radical decarboxylation of 6-heptenoic acids, by whatever means, usually results in die formation of five-mem-v beied rings. Although this fact had been appreciated previously it is only recendy, widi the advent of the 0-acyl thiohydroxamates, that it has been exploited from a syndietic point of view. An example is provided by the synthesis of bicyclo[4.3.0]proline derivatives from aspartic acid carried out by the Barton group (equation 51). It will be noted that activation of die C—C double bond acting as a radical trap is not necessary in these intramolecular reactions. 

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 most favourable approach for attack by a radical appears to be along the line on which the new bond is being formed (Figure 6.7). For the intramolecular addition of the hex-5-enyl radical 49, this results in the formation of the less stable primary cyclopentylmethyl radical 50 by reaction (6.37) rather than the more stable secondary cyclohexyl radical 51 by reaction (6.38). 

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. 

With 6-alkenoic acids 21, the intermediate radical 22 partially cyclizes to a cyclopentylmethyl radical 23 in a 5-exo-trig cyclization (Eq. 4) (see also Section... 

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