Bergman enediynes

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

Of great importance for the Bergman cyclization is the distance between the triple bonds. The reaction cannot occur at moderate temperatures if the distance is too large. Optimal reactivity at physiological temperatures is obtained by fitting the enediyne element into a ten-membered ring." ... 

Recently, Tour et al. [32] described attempts to prepare PPP derivatives via a Bergman cyclization, starting from substituted enediynes, e.g. poly(2-phenyl-1,4-phenylene) (18) from l-phenyl-hex-3-en-l,5-diyne or the structurally related poly(2-phenyl-1,4-naphthalene) (19) from l-phenylethynyl-2-ethynylbenzene. 

Novel pyrimidine enediynes 104 prepared by Russell and co-workers undergo Bergman cyclization to give tricyclic products 105 . Pyrimidines 104 were also shown to cleave dsDNA under appropriate conditions. 

In these reactions, a er-bond is formed at the expense of two re-bonds and, thus, the process leads to a net loss of one chemical bond that is intrinsically unfavorable thermodynamically. Formation of the new er-bond leads to ring closure, whereas the net loss of a bond leads to the formation of two radical centers, which can be either inside (the endo pattern in Scheme 1) or outside of the newly formed cycle (the exo pattern). Note that er-radicals are formed through the endo path, while exo-closures may produce either a er-radical when a triple bond is involved or a conjugated re-radical when the new bond is formed at the central carbon of an allene. The parent version of this process is the transformation of enediyne 1 into p-benzyne diradical2 (the Bergman cyclization), shown in Scheme 2. 

Fig. 7 Internal reaction coordinate (IRC) computations for the Bergman cyclization of model enediynes.

This analysis confirms that the effect of cyclic constraints is not purely steric but also has an electronic component. Another aspect of this dichotomy is shown in Fig. 11 which illustrates the decrease in the energy gap between the frontier in-plane rc-MOs. The decrease in the C1-C6 distance destabilizes the occupied MO where the interaction between the end orbitals is antibonding and, at the same time, stabilizes the empty MO where the 7i -orbitals overlap constructively. As a result, the efficiency of the photochemical Bergman cyclization should increase and, indeed, the most efficient photo-Bergman cyclizations reported in the literature involve cyclic enediynes.43 Again, the analogy with interrupted [2 + 2] photocycloaddition is instructive. 

While in the unbound enediyne the c-d distance is 4.1 A, this distance is diminished upon metal complexation 3.3 A for Pt(II) and Pd(II), and 3.4 A for Hg(II). The Pt and Pd species cyclize in the solid state at only slightly elevated temperatures, and give Bergman products below ambient temperature in solution. While the change in reactivity was attributed to the change in distance between the alkyne termini, an accelerating influence of the metal cannot be ruled out. 

Scheme 13 Bergman cyclization of enediynes bearing ort/zo-substituents.

Fig. 12 Correlation between the calculated activation energy of the Bergman cyclization and the product of natural charges at the terminal acetylenic atoms of benzannelated enediynes. Only para substituents obey the correlation. Adapted from reference49.

Table 1 provides examples of amino enediynes which become much more reactive toward the Bergman cyclization upon protonation on nitrogen because the presence of a positively charged ammonium moiety alleviates the re-re repulsion of the in-plane re-orbitals. 

An illustrative example of how rehybridization can be used to control the Bergman cyclization is provided by substituent effects at the alkyne termini of enediynes. This effect in cycloaromatization chemistry was first studied by Schreiner and coworkers, who found dramatic acceleration of the Bergman cyclization upon... 

Fig. 17 The Bergman cyclizations of parent and fluoro-substituted enediynes with the triple bond and the incipient bond lengths and the activation energies calculated at the BS-UB3LYP/6-31G level.

In this analysis, the activation barrier for both C1-C6 and C1-C5 cyclizations of enediyne radical-anions can be described as the avoided crossing between the out-of-plane and in-plane MOs (configurations). One-electron reduction populates the out-of-plane LUMO of the enediyne moiety. At the TS (the crossing), the electron is transferred between the orthogonal re-systems to the new (in-plane) LUMO. This effect leads to the accelerated cyclization of radical-anions of benzannelated enediynes, a large sensitivity of this reaction to re-conjugative effects of remote substituents and the fact that this selectivity is inverse compared to that of the Bergman cyclization. Similar electronic effects should apply to the other reductive cyclization reactions that were mentioned in the introduction. 

In the case of the Bergman cyclization and the C1-C5 cyclization of enediynes, both the activation barrier for cyclization as well as the thermodynamics of the reaction became more favorable upon one-electron reduction compared to the thermal counterparts. The cyclization barrier drops by up to 12kcal/mol (in the C1-C5 cyclization) and the process becomes exothermic (as opposed to the endothermic cyclizations of the neutral counterparts) as illustrated in Fig. 19 and Fig. 20. 

A very interesting experimental observation of Jones et al. illustrates a different effect of strain on the efficiency of photochemical Bergman cyclizations.43d Variations in the size of the cycle which does not incorporate the whole enediyne system, but only the vinyl part of the enediyne moiety (in contrast to the previously discussed data) affect the yield of the cycloaromatized product. Initially, an increase in the ring size leads to an increase in yield (Scheme 16). 

Scheme 16 Model enediynes used in photochemical Bergman cyclization.

Enediynes amino, 127, 20, 217 antiaromatic region in, 14-15 Bergman cyclization, 3, 18, 25 C1-C5 cyclization of, 5f 25 cyclic, strain and antiaromaticity in, 11-16... 

Enediynes tend to undergo Bergman cyclizations, and the C4-C9 bond can be made in this way. The C5 and C8 radicals produced thereby can each abstract H from Cl and C12, respectively. Fragmentation of the C10-C11 bond, then radical-radical combination gives the product. 

Other researchers have reported that the cyclization step is believed to be rate determining in the cycloaromatization (Bergman) reaction of aliphatic enediynes." It has been found that the rate-limiting step is hydrogen abstraction by benzannelation. This effect should be attributable to the faster rate of retro-Bergman cyclization from the aromatic ring-condensed 1,4-didehydrobenzene diradicals and/or the slower rate of hydrogen abstraction by them. 

It is noteworthy that Jones and Darby, who pioneered the enediyne rearrangement, now known as the Bergman rearrangement, and Nicolaou, who achieved the first total synthesis of the enediyne antibiotic calicheamicin 7 / were under the joint supervision of Profs. Franz Sondheimer and Peter Garratt. It might seem that all researchers in the enediyne field have been influenced by Sondheimer and Garratt. 

Finally, just a few words dedicated to the synthesis of polyphenylenes, extremely important polymers, and in particular substituted polyphenylenes such as PPV, which exhibit superb thermal and chemical resihence, semiconduchng properties upon doping and applicahons such as OLEDs. Contrary to their linear acenes counterparts, long polyphenylenes can be obtained e.g., by Bergman s method consisting in the thermal cycloaromatization of enediynes (Lockhart et al, 1981). 

Finn et al. reported the first instance of a metal-catalyzed aromatization of enediynes via vinylidene intermediates [7]. Aromatization of unstrained enediynes is knovm as Bergman cyclization and occurs at 200-250 °C via diradical intermediates [8]. Ruthenium-vinylidene complex 7 was formed when 1,2-benzodiyne 6 was treated with RuCp(PMe3)2Cl and NH4PF6 at 100 °C, ultimately giving good naphthalene product 8 ingood yields (Scheme 6.4). This process mimics Myers-Saitocyclizationof5-allene-3-... 

Bergman cyclization of the enediyne alcohol 985 gave the tetrahydrobenzoquinazoline 986, both thermally and photochemically in isopropanol, while the analogous ketone only showed efficient thermal cyclization <20000L3761>. 

Detailed thermochemical data for the Bergman rearrangement were determined by Roth et al. from gas-phase NO trapping experiments. The activation barrier for ring opening of 28 to enediyne (Z)-16 was reported as 19.8 kcal/mol, the enthalpy of formation of (Z)-16 293 = 129.5 kcal/mol) is lower than that of p-benzyne... 

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