Igor V. Alabugin

Concerted Reactions That Produce Diradicals and Zwitterions: Electronic, Steric, Conformational, and Kinetic Control of Cycloaromatization Processes

ion (H in reactions with 1,4-CHD and Cl in reactions Figure 50. Free energy diagram of the electrophilic 5-exo and 6-endo-dig cyclizations of the p-OMe-substituted alkyne diazonium salt calculated at the B3LYP/6-31G(d,p) level with CPCM (water) correction (kcal/mol). Dashed lines correspond to the deprotected substrate where the acyl group is removed. The 6-endo product in the latter case opens to the starting material upon optimization. Scheme 21. Cationic Version of the Myers−Saito Cyclization Isopropanol acts as both a nucleophile and a proton source. Figure 51. Interaction of p-benzyne with halide anions illustrates that zwitterionic cycloaromatization of enediynes is feasible. Scheme 22. Radical Reactivity in Myers−Saito Cyclization of Enyne Allenes in Nonpolar Solvents Chemical Reviews Review dx.doi.org/10.1021/cr4000682 | Chem. Rev. XXXX, XXX, XXX−XXX U with CCl4) proceeds at the σ-center, whereas the delocalized πradical is stabilized and reacts much slower. The pattern of reactivity changes in methanol where benzyl methyl ether is formed as the major product (38%), as expected for a polar pathway. Products expected from the radical pathways (2-phenyl ethanol, 10%, and 1,2-diphenyl ethane, 2%) are formed in small amounts. These experimental observations excluded pathways including slowly equilibrating or nonequilibrating intermediates from the possible mechanistic scenarios. The data suggested that products from both polar and free radical reaction pathways arise either from a single reactive intermediate or from a pair of rapidly equilibrating species. Interestingly, reaction in CD3OH (0.003 M of enyne allene, 100 °C) leads to a complete shift into the ionic mode; methyl-d3 benzyl ether is formed as the only detectable product in 70% yield (Figure 52). To understand this complex mechanistic scenario, Carpenter et al. analyzed the possible roles of diradical, zwitterionic, and cyclic allene forms of α,3-didehydrotoluene in a thorough mechanistic study. The authors pointed out that, due to the absence of direct orbital overlap between the σand π-radical centers, the contribution of zwitterionic resonance to the diradical wave function should be severely diminished. Their computational analysis suggested that the first excited state is zwitterionic but lies 30−40 kcal/mol (with ∼10 kcal/mol possible energy lowering due to the solvent polarity) above the diradical ground state. Because the reaction has zeroth order in methanol, methanol cannot be involved in the rate-limiting step (e.g., in a nucleophile-assisted cyclization). The key kinetic experiment found that ratio of these products changed linearly in response to changes in 1,4-CHD concentration. This result shows that the two methanol-derived products are not formed from a single intermediate. The lack of solvent polarity effects on the observed rates for the disappearance of enyne allene suggests that the partitioning between the diradical and zwitterionic pathways occurs after the rate-determining TS. Because the two paths have to diverge before the system arrives to p-benzyne to explain the above [CHD] effect, the authors interpreted this combination of experimental and computational data in favor of the unusual electronically nonadiabatic reaction in Figure 53. It involves a post-transition state bifurcation between the two alternative paths: one to the ground-state diradical, and the other to the excited-state zwitterion. Thermal reactions that form products in their excited states are rare and usually include reactants that contain either strained systems or weak bonds or both, for example, dioxetanes responsible for the firefly bioluminescence. Direct formation of excited states from a strain-free all-carbon reactant is a remarkable and unusual finding, which deserves a more extensive study. Further evidence for the generality of zwitterionic intermediates in the Myers−Saito reaction was presented by Shibuya and co-workers who reported that such products often dominate under polar conditions. Deuterium-labeling studies confirmed the presence of zwitterionic species in cycloaromatization of enyne allenes with push−pull disubstitution at the terminal carbon. Decarboxylative cycloaromatization of the analogous Arsubstituted enediyne also proceeds via initial base-catalyzed isomerization into enyne allene (Scheme 23). The allene cyclizes in methanol within ∼6 h at 37 °C to give exclusively the ionic products. Reaction in benzene follows the radical routes, which involve either intramolecular (without 1,4-CHD) or intermolecular trapping (with 1,4-CHD) via H-atom transfer. The ketone product can form either via a radical or via an ionic path, but its yield increases in the presence of molecular oxygen at the expense of the classic Myers−Saito product. An example of a zwitterionic product in cycloaromatization of “skipped” (aza)enediynes was reported by Kerwin and coworkers. These compounds rearrange to (aza)enyne allenes Figure 52. Solvent-mediated switch to ionic reactivity in Myers−Saito cyclization of enyne allenes in methanol. Blue and red structures correspond to the ionic and diradical pathways, respectively. Figure 53. Top panel: Diradical/zwitterion resonance in α,3didehydrotoluene would require mixing of states of different symmetry. Bottom panel: The nonadiabatic transition from the ground state PES (S0) of Myers−Saito reaction to the zwitterionic excited state (S1) suggested by Carpenter. Scheme 23. Products Derived from Aryl-Substituted α,3Didehydrotoluenes via Radical (Blue) or Ionic (Red) Pathways Chemical Reviews Review dx.doi.org/10.1021/cr4000682 | Chem. Rev. XXXX, XXX, XXX−XXX V that subsequently cyclized when stored in methanol. Only the products derived from the zwitterionic reaction pathway were detected (Figure 54). This difference from the all-carbon system is either due to the lower H-atom abstracting ability of the N-substituted diradical or due to the an alternative path initiated by methanol addition to the (aza)enyne allene. The significance of the diradical/zwitterion dichotomy expands beyond purely mechanistic aspects. The relatively high polarity of many biological settings often facilitates ionic reactivity. Polar mechanisms were suggested for the formation of products not consistent with simple radical chemistry in natural enediynes. An ionic mechanism was suggested to explain the formation of formal 1:1:1 adduct of thiol, NCS chromophore, and water from holo-NCS (complex of NCS chromophore and its carrier protein).Subsequently, Myers and co-workers revised the product’s structure and suggested an alternative mechanism via the rearrangement of an α,3dehydrotoluene diradical to an α,2-dehydrotoluene diradical (Figure 55). They suggested that nucleophilic epoxide opening in holo-NCS is disfavored by the lack of stabilization from the resulting oxyanion in the hydrophobic pocket of the protein. Instead, the intermolecular nucleophilic attack of the thiol leads to a protonation-assisted nucleophilic ring closure. The α,3-dehydrotoluene product of this transformation undergoes an epoxy “radical clock” ring-opening to give the α,2dehydrotoluene species where the zwitterionic form is stabilized by resonance with the adjacent oxygen. Substitution patterns that stabilize either positive or negative charges (or both) favor the zwitterionic products. In particular, the presence of electronegative elements assists in accommodating the negative charge, thus facilitating the zwitterionic path. There is increasing evidence that in enyne heteroallene, cyclizations proceed via a variety of pathways (diradical, zwitterionic, carbine, as shown in Figure 56). In particular, zwitterionic C2−C7 cyclizations are promoted by acceptors at the exocyclic carbon. For example, the Moore cyclization of enyne ketenes proceeds through a cyclic intermediate, which can often behave as zwitterion because the exocyclic oxygen atom can efficiently accommodate the negative charge (Figure 57). The zwitterions formed in the thermal “C2−C7” cyclization of enyne-isocyanates benefit from delocalization of the negative charge between the exocyclic oxygen and endocyclic nitrogen. However, breaking the relatively strong isocyanate C O bond requires considerably higher temperatures than breaking of the respective CC and CNR bonds in the cyclizations of analogous allenes and keteneimines/carbodiimides. Only in the presence of excess of H-atom donor at 230 °C was the product of formal H-abstraction, 3-phenyl-2(1H)quinoline, produced in 47% along with a small amount of chlorinated compound (Scheme 24). Change from Ph to 2-MeOPh at the alkyne terminus led to benzofuro[3,2-c]quinolin-6(5H)-one in 11% yield and the Nmethylated adduct in 9% yield. The yield of the major product improved to 53% in the presence of 1.1 equiv of dimethylphenylsilyl chloride, which can intercept the oxyanion. Both the Me-group transfer and the dramatic effect of the Figure 54. The zwitterionic cyclization product of aza-enyne allenes is stabilized by endocyclic hyperconjugation and exocyclic π-conjugation. Figure 55. Revised mechanism for formation of formal thiol/water addition product after the holo-NCS activation by a thiol. Figure 56. A variety of cyclization pathways are available to enyne heteroallene due to the effects of incorporated heteroatom. Figure 57. Top: The zwitterionic resonance in the Moore C2−C7 cyclization product. Bottom: Selected products derived from trapping the zwitterionic Moore product formed from substituted enyne ketenes. Scheme 24. “C2−C7” Cyclization of Enyne-isocyanates Proceeds at Relatively High Temperatures Chemical Reviews Review dx.doi.org/10.1021/cr4000682 | Chem. Rev. XXXX, XXX, XXX−XXX W oxyanion trap additive strongly suggest the intermediacy of zwitterionic species (Scheme 25). In a similar way, the formation of pyrrolo quinolones from dimethylamino substituted enyne carbodiimides reported by Wang and co-workers also stems from a polar pathway.

Radical cascade transformations of tris(o-aryleneethynylenes) into substituted benzo[a]indeno[2,1-c]fluorenes.

Oligomeric o-aryleneethynylenes with three triple bonds undergo cascade radical transformations in reaction with a Bu 3SnH/AIBN system. These cascades involve three consecutive cycle closures with the formation of substituted benzo[ a]indeno[2,1- c]fluorene or benzo[1,2]fluoreno[4,3- b]silole derivatives. The success of this sequence depends on regioselectivity of the initial attack of the Bu 3Sn radical at the central triple bond of the o-aryleneethynylene moiety. The cascade is propagated through the sequence of 5-exo-dig and 6-exo-dig cyclizations which is followed by either a radical attack at the terminal Ar substituent or radical transposition which involves H-abstraction from the terminal TMS group and 5-endo-trig cyclization. Overall, the transformation has potential to be developed into an approach to a new type of graphite ribbons.

Photoinduced phase transfer of luminescent quantum dots to polar and aqueous media.

We report a new strategy for the photomediated phase transfer of luminescent quantum dots, QDs, and potentially other inorganic nanocrystals, from hydrophobic to polar and hydrophilic media. In particular, we demonstrate that UV-irradiation (λ < 400 nm) promotes the in situ ligand exchange on hydrophobic CdSe QDs with lipoic acid (LA)-based ligands and their facile QD transfer to polar solvents and to buffer media. This convenient method obviates the need to use highly reactive agents for chemical reduction of the dithiolane groups on the ligands. It maintains the optical and spectroscopic properties of the QDs, while providing high photoluminescence yield and robust colloidal stability in various biologically relevant conditions. Furthermore, development of this technique significantly simplifies the preparation and purification of QDs with sensitive functionalities. Application of these QDs to imaging the brain of live mice provides detailed information about the brain vasculature over the period of a few hours. This straightforward approach offers exciting possibilities for expanded functional compatibilities and reaction orthogonality on the surface of inorganic nanocrystals.

Polyaromatic ribbon/benzofuran fusion via consecutive endo cyclizations of enediynes.

The Sonogashira/5-endo-dig/6-endo-dig cascade fuses a polycyclic aromatic backbone to the electron-rich furan subunit. The transformation proceeds in modest yields as a one-pot reaction. Efficiency of the full cascade is increased by removal of base prior to the addition of gold catalyst. Under these conditions, conversion to the full cascade products is achieved in nearly quantitative yields without purification of the intermediate products. Extension of the cascade toward triynes opens access to benzofuran-fused chrysene derivatives.

Polyaromatic Ribbons from Oligo-Alkynes via Selective Radical Cascade: Stitching Aromatic Rings with Polyacetylene Bridges

Selective radical generation in conjugated oligomeric o-aryleneethynylenes initiates an intramolecular cascade which involves five fast radical cyclizations followed by aromatization via a 1,5-H shift with a >93% yield per step. This radical cascade transformation opens a new avenue for the systematic and controlled preparation of functionalized graphene nanoribbons where, potentially, each of the peripheral aromatic rings can be different.

C-lysine conjugates: pH-controlled light-activated reagents for efficient double-stranded DNA cleavage with implications for cancer therapy

Double-stranded DNA cleavage of light-activated lysine conjugates is strongly enhanced at the slightly acidic pH (<7) suitable for selective targeting of cancer cells. This enhancement stems from the presence of two amino groups of different basicities. The first amino group plays an auxiliary role by enhancing solubility and affinity to DNA, whereas the second amino group, which is positioned next to the light-activated DNA cleaver, undergoes protonation at the desired pH threshold. This protonation results in two synergetic effects which account for the increased DNA-cleaving ability at the lower pH. First, lysine conjugates show tighter binding to DNA at the lower pH, which is consistent with the anticipated higher degree of interaction between two positively charged ammonium groups with the negatively charged phosphate backbone of DNA. Second, the unproductive pathway which quenches the excited state of the photocleaver through intramolecular electron transfer is eliminated once the donor amino group next to the chromophore is protonated. Experiments in the presence of traps for diffusing radicals show that reactive oxygen species do not contribute significantly to the mechanism of DNA cleavage at the lower pH, which is indicative of tighter binding to DNA under these conditions. This feature is valuable not only because many solid tumors are hypoxic but also because cleavage which does not depend on diffusing species is more localized and efficient. Sequence-selectivity experiments suggest combination of PET and base alkylation as the chemical basis for the observed DNA damage. The utility of these molecules for phototherapy of cancer is confirmed by the drastic increase in toxicity of five conjugates against cancer cell lines upon photoactivation.

Rehybridization as a general mechanism for maximizing chemical and supramolecular bonding and a driving force for chemical reactions

Dynamic variations in hybridization patterns (rehybridization) were analyzed at B3LYP/6–31G** and MP2/6–31+G* levels. Computations clearly illustrate the generality of rehybridization in a variety of chemical phenomena, which involve structural reorganization in hydrogen‐bonded complexes, nonhyperconjugative stereoelectronic effects in saturated heterocycles, Mills‐Nixon effect, and contrasting substituent effects in cycloaromatization reactions.

Lysine–enediyne conjugates as photochemically triggered DNA double-strand cleavage agents

Statistical analysis of DNA-photocleavage by two types of lysine-enediyne conjugates confirms that more double-strand breaks are produced than can be accounted for by coincident single-strand breaks.

Alkenes as alkyne equivalents in radical cascades terminated by fragmentations: overcoming stereoelectronic restrictions on ring expansions for the preparation of expanded polyaromatics.

Chemoselective interaction of aromatic enynes with Bu3Sn radicals can be harnessed for selective cascade transformations, yielding either Sn-substituted naphthalenes or Sn-indenes. Depending on the substitution at the alkene terminus, the initial regioselective 5-exo-trig cyclizations can be intercepted at the 5-exo stage via either hydrogen atom abstraction or C-S bond scission or allowed to proceed further to the formal 6-endo products via homoallylic ring expansion. Aromatization of the latter occurs via β-C-C bond scission, which is facilitated by 2c,3e through-bond interactions, a new stereoelectronic effect in radical chemistry. The combination of formal 6-endo-trig cyclization with stereoelectronically optimized fragmentation allows the use of alkenes as synthetic equivalents of alkynes and opens a convenient route to α-Sn-substituted naphthalenes, a unique launching platform for the preparation of extended polyaromatics.

In Search of Efficient 5-Endo-dig Cyclization of a Carbon-Centered Radical: 40 Years from a Prediction to Another Success for the Baldwin Rules

Despite being predicted to be stereoelectronically favorable by the Baldwin rules, efficient formation of a C-C bond through a 5-endo-dig radical cyclization remained unknown for more than 40 years. This work reports a remarkable increase in the efficiency of this process upon beta-Ts substitution, which led to the development of an expedient approach to densely functionalized cyclic 1,3-dienes. Good qualitative agreement between the increased efficiency and stereoselectivity for the 5-endo-dig cyclization of Ts-substituted vinyl radicals and the results of density functional theory analysis further confirms the utility of computational methods in the design of new radical processes. Although reactions of Br atoms generated through photochemical Ts-Br bond homolysis lead to the formation of cyclic dibromide side products, the yields of target bromosulfones in the photochemically induced reactions can be increased by recycling the dibromide byproduct into the target bromosulfones through a sequence of addition/elimination reactions at the exocyclic double bond. Discovery of a relatively efficient radical 5-endo-dig closure, accompanied by a C-C bond formation, provides further support to stereoelectronic considerations at the heart of the Baldwin rules and fills one of the last remaining gaps in the arsenal of radical cyclizations.