Steven Feldgus

Absolute pKa Determinations for Substituted Phenols

The CBS-QB3 method was used to calculate the gas-phase free energy difference between 20 phenols and their respective anions, and the CPCM continuum solvation method was applied to calculate the free energy differences of solvation for the phenols and their anions. The CPCM solvation calculations were performed on both gas-phase and solvent-phase optimized structures. Absolute pK(a) calculations with solvated phase optimized structures for the CPCM calculations yielded standard deviations and root-mean-square errors of less than 0.4 pK(a) unit. This study is the most accurate absolute determination of the pK(a) values of phenols, and is among the most accurate of any such calculations for any group of compounds. The ability to make accurate predictions of pK(a) values using a coherent, well-defined approach, without external approximations or fitting to experimental data, is of general importance to the chemical community. The solvated phase optimized structures of the anions are absolutely critical to obtain this level of accuracy, and yield a more realistic charge separation between the negatively charged oxygen and the ring system of the phenoxide anions.

Efficient and Accurate Characterization of the Bergman Cyclization for Several Enediynes Including an Expanded Substructure of Esperamicin A1

Incorporation of enediynes into anticancer drugs remains an intriguing yet elusive strategy for the design of therapeutically active agents. Density functional theory was used to locate reactants, products, and transition states along the Bergman cyclization pathways connecting enediynes to reactive para-biradicals. Sum method correction to low-level calculations confirmed B3LYP/6-31G(d,p) as the method of choice in investigating enediynes. Herein described as MI:Sum, calculated reaction enthalpies differed from experiment by an average of 2.1 kcal x mol(-1) (mean unsigned error). A combination of strain energy released across the reaction coordinate and the critical intramolecular distance between reacting diynes explains reactivity differences. Where experimental and calculated barrier heights are in disagreement, higher level multireference treatment of the enediynes confirms lower level estimates. Previous work concerning the chemically reactive fragment of esperamcin, MTC, is expanded to our model system MTC2.

An ONIOM study of the Bergman reaction: a computationally efficient and accurate method for modeling the enediyne anticancer antibiotics

The Bergman cyclization of large polycyclic enediyne systems that mimic the cores of the enediyne anticancer antibiotics was studied using the ONIOM hybrid method. Tests on small enediynes show that ONIOM can accurately match experimental data. The effect of the triggering reaction in the natural products is investigated, and we support the argument that it is strain effects that lower the cyclization barrier. The barrier for the triggered molecule is very low, leading to a reasonable half-life at biological temperatures. No evidence is found that would suggest a concerted cyclization/H-atom abstraction mechanism is necessary for DNA cleavage.

Catalytic Enantioselective Hydrogenation of Alkenes

Computations utilizing the ONIOM scheme have been used to model key features of the the Rh(chiral bisphosphine)-catalyzed enantioselective hydrogenation of prochiral enamides. Extensive computations and comparison with detailed mechanistic studies demonstrate that major features of the catalytic mechanism are reproduced by computation. These features include (1) relative stabilities of diastereomeric catalyst-enamide adducts (2) the anti “lock-and-key” motif, in which the majority of catalytic flux is carried by the less stable catalyst-enamide adduct (3) reversal of the sense of enantioselection when the enamide substrate bears a bulky, electron-donating group in the α-position. Based on the computational results, simple models demonstrate how specific steric effects of the chiral ligand environment co-mingle with orbital interactions between the catalyst and substrate to result in distinctive, and often surprising, mechanistic features of enantioselective hydrogenation reactions.

Hindered internal rotation in S1 meta-chlorotoluene and D0 meta-chlorotoluene+

Abstract Resonant two-photon ionization and pulsed field ionization (PFI) were used to measure the S1-S0 and D0-S1 spectra of internally cold meta-chlorotoluene. Here D0 denotes the (doublet) ground electronic state of the cation. We report the adiabatic ionization potential of meta-chlorotoluene as 71333 ± 5 cm−1 ± 8.8442 ± 0.0006 eV. Low lying torsional levels in both S1 (A1a1) meta-chlorotoluene and D0 (X2A1) meta-chlorotoluene+ are assigned. In both S1 and D0, we extract parameters for a one-dimensional hindered rotor model. In S1 these parameters are F′ = 5.0 ± 0.3 cm−1, V3′ = 110 ± 5 cm−1, and V6′ = - 20 ± 3 cm−1. The parameters in D0 are F+ 5.4 ± 0.2 cm−1, V3+ = − 285 ± 5 cm−1, and V6+ = − 20 ± 3 cm−1. Ab initio calculations from earlier work permit unambiguous assignment of the minimum energy conformation in D0 as pseudo-cis, having one CH bond of the rotor in the plane of the ring on the same side as the chlorine substituent. The PFI intensity patterns then fix the minimum in S1 as pseudo-trans, with one CH bond on the opposite side from chlorine. The strong effects of π* ← π electronic excitation and of π ionization on conformation and barrier height are very similar to those observed earlier in meta-fluorotoluene by Ito and co-workers. The cation conformation can be understood simply in terms of ionization from a particular Huckel π molecular orbital which is oriented to have pseudo-C2v symmetry with respect to the axis bisecting the methyl and halogen substituents. This places the methyl rotor between two ring CC bonds of unequal bond order, which in turn causes the strong conformational preference in D0, analogous to that in 2-methylpropene. Evidently fluorine and chlorine act equivalently as weak π donors for purposes of orienting the Huckel orbitals of the cation.