Edyta M. Greer

Computational Evidence for Heavy-Atom Tunneling in the Bergman Cyclization of a 10-Membered-Ring Enediyne

DFT and CASSCF calculations for the cyclization of (3Z)-cyclodec-3-en-1,5-diyne were carried out to investigate heavy-atom tunneling. At 37 °C, tunneling was computed to enhance the rate by 38-40% over the transition-state theory rate. Intramolecular (12)C/(13)C kinetic isotope effects were predicted to be substantial, with a steep temperature dependence. These results are discussed in relation to recent experimental findings that show heavy-atom tunneling at moderate temperatures. The calculations point to the possibility of a simple computational test for the likelihood of heavy-atom tunneling using standard quantum-chemical information.

NMR Spectroscopic and Computational Study of Conformational Isomerism in Substituted 2-Aryl-3H-1-benzazepines: Toward Isolable Atropisomeric Benzazepine Enantiomers

Certain 2-aryl-3H-1-benzazepines are conformationally mobile on the NMR time scale. Variable-temperature NMR experiments bolstered by calculations indicate that alkylation of the azepine ring will slow the interconversion of conformational enantiomers markedly. DFT studies show that, while the substitution patterns of the aryl groups at C2 and C4 do not exert large effects on the rate of enantiomerization, alkylation at C5 slows it appreciably. Alkylation at C3 slows enantiomerization even more, possibly to the extent that isolation of atropisomers might be attempted.

Reaction mechanisms: pericyclic reactions

This review summarizes a number of articles published in 2011 describing mechanisms of pericyclic reactions. The types of reactions studied were of the cycloaddition sort (e.g., [2+1], [2+2], [3+2], [4+2], etc.), as well as sigmatropic (e.g., [1,2], [1,3], [3,3] shifts, etc.), group transfer (e.g., ene), and electrocyclic types. Interestingly, the literature on pericyclic cascade reactions was quite rich in 2011.

Theoretical Study of the Bergman Cyclization of 2,3-Diethynyl-1-nitrotropylium Ion: Formation of a Nitroxide Radical Amenable to EPR Detection for Biological Applications.

We report a DFT study of a Bergman cyclization producing a stable triplet nitroxide diradical and monoradical (after H abstraction from an external source). The monoradical is predicted to be amenable to detection by EPR methods to potentially probe the structure and dynamics of enediyne molecules for drug interactions.

Metalla-cope rearrangements: bridging organic and inorganic chemistry.

Density functional theory calculations are performed to explore both concerted chairlike and boatlike as well as stepwise mechanisms of the Cope rearrangement of two hypothetical metalladienes. An osma-1,5-hexadiene is designed by substituting CH(2) in 1,5-hexadiene by its isolobal analogue, 16-electron Os(PH(3))(4). The energy of activation corresponding to the rearrangement of osma-1,5-hexadiene involving the chairlike saddle point is computed as 37.4 kcal/mol, 3.9 kcal/mol above the energy barrier of the parent 1,5-hexadiene calculated with the same method and basis set, and is 4.5 kcal/mol below that of the boatlike pathway. In another isolobal replacement, the CH in 1,5-hexadiene is substituted by a 15-electron Re(PH(3))(3) fragment. Now the chairlike rearrangement of the rhenia-1,5-hexadiene has an E(a) value of 23.0 kcal/mol, 10.8 kcal/mol less than the energy barrier of the parent 1,5-hexadiene calculated at the same level of theory. The ring inversion of the chair and osma-chair diradical intermediates of the stepwise reaction pathway is also examined and is found in both cases to proceed through a very flat potential energy surface involving twist intermediates.

Experimental and DFT Computational Insight into Nitrosamine Photochemistry—Oxygen Matters

A nitrosamine photooxidation reaction is shown to generate a peroxy intermediate by experimental physical-organic methods. The irradiation of phenyl and methyl-substituted nitrosamines in the presence of isotopically labeled 18-oxygen revealed that an O atom was trapped from a peroxy intermediate to trimethylphosphite or triphenylphosphine, or by nitrosamine itself, forming two moles of nitramine. The unstable peroxy intermediate can be trapped at low temperature in postphotolyzed solution in the dark. Chemiluminescence was also observed upon thermal decomposition of the peroxy intermediate, that is, when a postphotolysis low-temperature solution is brought up to room temperature. A DFT study provides tentative information for cyclic nitrogen peroxide species on the reaction surface.

Interplay of Nitrogen-Atom Inversion and Conformational Inversion in Enantiomerization of 1H-1-Benzazepines

A series of 2,4-disubstituted 1H-1-benzazepines, 2a-d, 4, and 6, were studied, varying both the substituents at C2 and C4 and at the nitrogen atom. The conformational inversion (ring-flip) and nitrogen-atom inversion (N-inversion) energetics were studied by variable-temperature NMR spectroscopy and computations. The steric bulk of the nitrogen-atom substituent was found to affect both the conformation of the azepine ring and the geometry around the nitrogen atom. Also affected were the Gibbs free energy barriers for the ring-flip and the N-inversion. When the nitrogen-atom substituent was alkyl, as in 2a-c, the geometry of the nitrogen atom was nearly planar and the azepine ring was highly puckered; the result was a relatively high-energy barrier to ring-flip and a low barrier to N-inversion. Conversely, when the nitrogen-atom substituent was a hydrogen atom, as in 2d, 4, and 6, the nitrogen atom was significantly pyramidalized and the azepine ring was less puckered; the result here was a relatively high energy barrier to N-inversion and a low barrier to ring-flip. In these N-unsubstituted compounds, it was found computationally that the lowest-energy stereodynamic process was ring-flip coupled with N-inversion, as N-inversion alone had a much higher energy barrier.

S,S-Chiral Linker Induced U Shape with a Syn-facial Sensitizer and Photocleavable Ethene Group

There is a major need for light‐activated materials for the release of sensitizers and drugs. Considering the success of chiral columns for the separation of enantiomer drugs, we synthesized an S,S‐chiral linker system covalently attached to silica with a sensitizer ethene near the silica surface. First, the silica surface was modified to be aromatic rich, by replacing 70% of the surface groups with (3‐phenoxypropyl)silane. We then synthesized a 3‐component conjugate [chlorin sensitizer, S,S‐chiral cyclohexane and ethene building blocks] in 5 steps with a 13% yield, and covalently bound the conjugate to the (3‐phenoxypropyl)silane‐coated silica surface. We hypothesized that the chiral linker would increase exposure of the ethene site for enhanced 1O2‐based sensitizer release. However, the chiral linker caused the sensitizer conjugate to adopt a U shape due to favored 1,2‐diaxial substituent orientation; resulting in a reduced efficiency of surface loading. Further accentuating the U shape was π–π stacking between the (3‐phenoxypropyl)silane and sensitizer. Semiempirical calculations and singlet oxygen luminescence data provided deeper insight into the sensitizers orientation and release. This study has lead to insight on modifications of surfaces for drug photorelease and can help lead to the development of miniaturized photodynamic devices.

Density Functional Theory and ab Initio Computational Evidence for Nitrosamine Photoperoxides: Hammett Substituent Effects in the Photogeneration of the Nitrooxide Intermediate

Little attention has been focused on diradical and zwitterionic photoperoxides formed from nitrosamine compounds. Here, an attempt is made to probe the electronic character of the nitrooxide intermediate formed in photochemical reactions with triplet oxygen (3O2). Theoretical studies have been conducted to screen para‐substituted phenyl nitrosamines. In particular, we find that electron‐withdrawing substituents produce low‐lying triplet nitrooxide diradicals. A clear electronic dependence in the S0 – T1 and S0 – S1 energy gaps of nitrooxides was found using Hammett plots. Computed geometries show a twisted diradical triplet nitrooxide moiety, which contrasts to the nearly flat singlet zwitterionic ground state nitrooxide moiety; analyses of charges (natural bond order), molecular orbitals (HOMO/LUMO) and spin densities enable these assignments. Calculations predict the former triplet species is photogenerated initially from nitrosamine with O2. The conversion of the triplet nitrooxide diradical to the singlet ground state is an example where longer‐lived zwitterionic nitrooxide structures become possible. The reaction mechanism is consistent with a zwitterionic ground state nitrooxide playing an important role in the bimolecular oxygen‐transfer reaction with phosphine and phosphite trapping agents as has been observed experimentally.

Kinetic Control in the Regioselective Alkylation of Pterin Sensitizers: A Synthetic, Photochemical, and Theoretical Study

Alkylation patterns and excited‐state properties of pterins were examined both experimentally and theoretically. 2D NMR spectroscopy was used to characterize the pterin derivatives, revealing undoubtedly that the decyl chains were coupled to either the O4 or N3 sites on the pterin. At a temperature of 70°C, the pterin alkylation regioselectively favored the O4 over the N3. The O4 was also favored when using solvents, in which the reactants had increased solubility, namely N,N‐dimethylformamide and N,N‐dimethylacetamide, rather than solvents in which the reactants had very low solubility (tetrahydrofuran and dichloromethane). Density functional theory (DFT) computed enthalpies correlate to regioselectivity being kinetically driven because the less stable O‐isomer forms in higher yield than the more stable N‐isomer. Once formed these compounds did not interconvert thermally or undergo a unimolecular “walk” rearrangement. Mechanistic rationale for the factors underlying the regioselective alkylation of pterins is suggested, where kinetic rather than thermodynamic factors are key in the higher yield of the O‐isomer. Computations also predicted greater solubility and reduced triplet state energetics thereby improving the properties of the alkylated pterins as 1O2 sensitizers. Insight on thermal and photostability of the alkylated pterins is also provided.