Reports: AC4 47590-AC4: Design of New Radical Reactions: From Elusive 5-Endo-Dig Cyclization to Cascade Transformations

Igor Alabugin, Florida State University

New Radical Cyclizations: We, for the first time, offered theoretical analysis of a scarcely studied radical cyclization – the 5-endo-dig process. Although this path is apparently favorable according to the Baldwin rules, only a few isolated examples of this reaction were reported, mostly in recent years. Unfortunately, most of these reports are speculative and, in some cases, are likely to proceed through alternative reaction cascades. Moreover, the majority of literature examples are relatively inefficient for reasons that were not clear before our study. Our work elucidated stereoelectronic, thermodynamic and polar contributions to the cyclization and extended these findings to a critical analysis of available experimental work. The general factors responsible for the efficiency of such processes were clearly identified and predictions about the experimental feasibility of 5-endo-dig radical cyclizations were made (JACS, 2005, 9534).  Our experimental studies inspired by these computational predictions led to the discovery of the first efficient 5-endo-dig cyclization of a carbon-centered radical (JACS, 2008, 10984).  We found that H-bonding interaction (estimated to be. Ca. 2 kcal/mo by NBO analysis) between the relatively acidic sp-C-H bond and one of oxygens from the Ts group is not only able to selectively accelerate the 5-endo-dig cyclization but can also control competition between the 5-endo and 4-exo modes. Our subsequent studies of scope and limitations of this effect already led to the discovery of several other, synthetically useful, 5-endo-dig ring closures of carbon-centered radicals.

In the second theoretical development, we analyzed the competition between two important radical cyclization processes – 5-exo-dig and 6-endo dig cyclizations (JACS, 2005, 12583). These processes are used in organic synthesis and are implicated in the process of formation of polycyclic aromatic compounds and carbon nanostructures.  When the acetylene moiety and the radical are connected through a saturated two-atom bridge, the 5-exo process is strongly favored kinetically. However, when the bridge is unsaturated, the 6-endo products are stabilized by aromaticity. Part of the product stabilization is transferred to the decrease in the 6-endo activation barrier rendering it kinetically competitive with the 5-exo-dig path.  As a result, the 5-exo or 6-endo selectivity can be fine-tuned by seemingly subtle modifications in the structure of the starting materials. Our study determined the contributions of thermodynamic and strain effects to the 5-exo/6-endo competition, extended these findings to available experimental data and provided predictions to guide our experimental studies which led to the development of an efficient radical cascade providing polyclic systems representing the tip part of carbon nanotubes (JACS, 2008, 11535). 

Ortho-effect in the Bergman cyclization: kinetics and development of new radical cascades: We applied steric and electronic effects of ortho substituents for efficient control of thermal Bergman cyclizations of benzannelated enediynes. Theory predicts that change in ortho substituents can lead to a nearly 2000-fold difference in the cyclization rate (250-fold greater range than for para substituents). 

We confirmed these computational predictions with experiments and proved that steric and electronic effects of ortho substituents can be used for efficient control of thermal Bergman cyclizations of benzannelated enediynes.

Interception of p-benzynes by intramolecular H-abstraction increases the apparent reaction rate by rendering the cyclization step effectively irreversible. From a chemical perspective, such interception is interesting because it produces a new, more persistent diradical which is not capable of deactivation through the retro-Bergman opening. In addition, intramolecular H-abstraction in OMe-substituted p-benzynes followed by domino radical cyclizations can be used to transpose radical centers in p-benzyne and create new types of diradical species.  Interestingly, the same step is possible in natural enediyne antiobiotics of calicheamicin and esperamicin families where a OCHR substituent is similarly positioned relative to the p-benzyne intermediate. We found that such hydrogen abstraction can rationalize the so far unexplained fragmentation of esperamycin A upon its activation towards cycloaromatization. In addition, an interesting radical rearrangement which transposes oxygen and carbon atoms attached to an aromatic ring was discovered experimentally (JACS, 2010, 133, 967-979).

Anionic cyclizations of alkynes: We have also combined theory and experiment to analyze the 5-exo/6-endo selectivity in digonal cyclizations of N-nucleophiles  (J. Org. Chem. 2009, 74 , 8106–8117). We can fine-tune the regioselectivity  for nucleophilic closures via modulation of electronic properties of the alkyne moiety. Alkyl substituents at the alkyne terminus favor the 6-endo-dig closure whereas aryl groups greatly facilitate the alternative 5-exo-dig path.

Competing cyclization pathways were fully analyzed computationally. Decreased 5-exo-dig activation energies and increased stability of the 5-exo products for R = Ph confirm that the Ph group steers the cyclization selectively down the 5-exo path by providing benzylic stabilization to the anionic center in the product.  In contrast, the competition between the 5-exo and 6-endo-dig closures is close for alkyl substituted acetylenes. For R=Me, the values of cyclization barriers are within 1 kcal/mol from each other and thus, both cyclizations can proceed with comparable rates. Although the 5-exo cyclization has 0.6 kcal/mol lower barrier than the 6-endo closure in the gas phase, introduction of solvation reverses this preference. Moreover, the 5-exo-dig cyclization is predicted to be endothermic and readily reversible in the latter, whereas the 6-endo-dig closure is ~10 kcal/mole exothermic. The higher computed activation barriers for both 6-endo and 5-exo cyclizations of alkyl substituted alkynes are consistent with experimental observations.  Full potential energy surface for the competing 6-endo and 5-exo cyclizations of hydrazide anions at B3LYP/6-31+G(d,p) level of theory is given below.

These anionic cyclizations lack a significant thermodynamic driving force because the gain in stability due transformation of a weak p-bond into a stronger s-bond is offset by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. Formation of the final products is negotiated through several proton shifts, ultimately leading to the most stable tautomeric anion as a thermodynamic sink.. Such tautomerizations are likely to play the key role in driving such cyclizations to completion but may also prevent future applications of such processes as the first step in domino cyclization processes.

 
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