Eric V. Patterson

Impact of Solvent Polarity on N-Heterocyclic Carbene-Catalyzed β-Protonations of Homoenolate Equivalents

N-Heterocyclic carbenes have been demonstrated to react through divergent pathways under the same conditions. Experimental and computational evidence demonstrates that the ability to favor generation of homoenolate equivalents from alpha,beta-unsaturated aldehydes versus the oxidation of aldehydes to esters is highly dependent upon the choice of solvent. The solvation environment plays an important role due to the mechanistic differences in these processes, with polar protic solvent favoring the oxidation process due to solvation of intermediates with greater charge separation.

Product-to-Parent Reversion of Trenbolone: Unrecognized Risks for Endocrine Disruption

Return of the Steroid Trace levels of organic contaminants enter aquatic ecosystems from a variety of sources, including runoff of from agricultural lands. When these compounds and their metabolites break down, it is generally assumed that they become inert and pose less ecological risk. Qu et al. (p. 347, published online 26 September) tracked the sunlight-mediated transformation of metabolites of trenbolone acetate (TBA)—a common growth-promoting steroid given to beef cattle—across a number of conditions in the laboratory and in the field. When the degradation products were exposed to dark conditions following photodegradation, they surprisingly reverted back to TBA metabolites, including analog steroidal compounds similar to TBA with unknown biological effects. Phototransformation of growth steroid metabolites is readily reversible in aquatic environments. Trenbolone acetate (TBA) is a high-value steroidal growth promoter often administered to beef cattle, whose metabolites are potent endocrine-disrupting compounds. We performed laboratory and field phototransformation experiments to assess the fate of TBA metabolites and their photoproducts. Unexpectedly, we observed that the rapid photohydration of TBA metabolites is reversible under conditions representative of those in surface waters (pH 7, 25°C). This product-to-parent reversion mechanism results in diurnal cycling and substantial regeneration of TBA metabolites at rates that are strongly temperature- and pH-dependent. Photoproducts can also react to produce structural analogs of TBA metabolites. These reactions also occur in structurally similar steroids, including human pharmaceuticals, which suggests that predictive fate models and regulatory risk assessment paradigms must account for transformation products of high-risk environmental contaminants such as endocrine-disrupting steroids.

Structure of Triplet Propynylidene (HCCCH) as Probed by IR, UV/vis, and EPR Spectroscopy of Isotopomers

Spectroscopic data for triplet isotopomers H-C-C-C-H, H-(13)C-C-C-H, and H-C-(13)C-C-H are consistent with computational predictions for a symmetric structure in which the terminal carbons are equivalent (C(2) or C(2v)) and are inconsistent with a planar (C(s)) structure in which they are not. Experimentally observed (13)C isotope shifts in the IR spectra and (13)C hyperfine coupling constants in the EPR spectra exhibit good agreement with values predicted by theory for a C(2) structure. The (13)C hyperfine coupling constants also provide an independent experimental estimate for the bond angles in the molecule. The isotope-dependence of the zero-field splitting parameters reveals the influence of molecular motion in modulating the values of these parameters. The interpretation of motional effects provides a basis for rationalizing the anomalously low E value, which had previously been interpreted in terms of an axially symmetric (D(infinity h)) structure. Computational studies involving Natural Bond Orbital and Natural Resonance Theory analyses provide insight into the spin densities and the complex electronic structure of this reactive intermediate.

MOLECULAR ORBITAL CALCULATIONS ON THE P-S BOND CLEAVAGE STEP IN THE HYDROPEROXIDOLYSIS OF NERVE AGENT VX

The P—S bond cleavage process in the hydroperoxidolysis of a model system for the nerve agent VX was studied using ab initio and semiempirical molecular orbital methods. Aqueous solvation effects were included through single-point calculations using the semiempirical SM5.2PD/A continuum solvation model and geometries optimized at the HF/MIDI! level of theory. The predominant pathway for P—S bond cleavage involves pseudorotation of a low-energy trigonal bipyramidal intermediate followed by apical ligand ejection. In aqueous solution, the free energy barriers for these processes are found to be 14.3 and 4.6 kcal mol y1 , respectively, with electronic energies calculated at the MP2/cc-pVDZ//HF/MIDI! level of theory. By comparison with another continuum model of solvation (PCM), it is concluded that the SM5.2PD/A model performs well even for hypervalent phosphorus species, in spite of not having included any such molecules in the models parameterization set.

Effects of cyano substituents on cyclobutadiene and its isomers.

The effects of cyano substitution on cyclobutadiene are explored using density functional, coupled-cluster, CASSCF, and CASPT2 calculations. An isodesmic reaction is employed to gauge the relative stabilization (DeltaH(rxn) degrees) of cyclobutadienes with varying numbers of cyano groups. Although density functional theory predicts a relatively large stabilization for the addition of four cyano substituents to cyclobutadiene (18.5 kcal/mol), coupled-cluster theory predicts a smaller stabilization (9.3 kcal/mol). The effect of the number of cyano groups on the singlet-triplet gaps is also investigated. NBO calculations lend insight into the structural trends of the triplets, and the comparison of coupled-cluster and CASSCF calculations sheds light on the multireference electronic character in these systems. The effect of tetracyano substitution on tetrahedrane and other C(4)H(4) isomers is also explored.

Atom-Centered Density Matrix Propagation Calculations on the Methyl Transfer from CH3Cl to NH3: Gas-Phase and Continuum-Solvated Trajectories.

Atom-centered density matrix propagation (ADMP) calculations have been carried out to determine gas-phase and continuum-solvated (aqueous) trajectories for the Menshutkin reaction of methyl chloride with ammonia. The gas-phase trajectories reveal an exit channel that has not been previously reported. The aqueous trajectories give the expected results, indicating that solvated ADMP trajectories may be successfully computed using implicit solvation models. The solvated trajectories demonstrate the same stability and convergence qualities as the gas-phase trajectories.

Reversible Photohydration of Trenbolone Acetate Metabolites: Mechanistic Understanding of Product-to-Parent Reversion through Complementary Experimental and Theoretical Approaches

Photolysis experiments (in H2O and D2O) and quantum chemical calculations were performed to explore the pH-dependent, reversible photohydration of trenbolone acetate (TBA) metabolites. Photohydration of 17α-trenbolone (17α-TBOH) and 17β-trenbolone (17β-TBOH) occurred readily in simulated sunlight to yield hydrated products with incorporated H(+) at C4 and OH(-) at either C5 (5-OH-TBOH) or C12 (12-OH-TBOH) in the tetracyclic steroid backbone. Although unable to be elucidated analytically, theory suggests preferred orientations of cis-12-OH-TBOH (relative to C13 methyl) and trans-5-OH-TBOH, with the former most thermodynamically stable overall. Both experiment and theory indicate limited stability of trans-5-OH-TBOH at acidic pH where it undergoes concurrent, carbocation-mediated thermal rearrangement to cis-12-OH-TBOH and dehydration to regenerate its parent structure. Experiments revealed cis-12-OH-TBOH to be more stable at acidic pH, which is the only condition where its reversion to parent TBA metabolite occurred. At basic pH cis-12-OH-TBOH decayed quickly via hydroxide/water addition, behavior that theory attributes to the formation of a stable enolate resistant to dehydration but prone to thermal hydration. In a noteworthy deviation from predicted theoretical stability, 17α-TBOH photohydration yields major trans-5-OH-TBOH and minor cis-12-OH-TBOH, a distribution also opposite that observed for 17β-TBOH. Because H(+) and OH(-) loss from adjacent carbon centers allows trans-5-OH-TBOH to dehydrate at all pH values, the presumed kinetically controlled yield of 17α-TBOH photohydrates results in a greater propensity for 17α-TBOH reversion than 17β-TBOH. Additional calculations explored minor, but potentially bioactive, trenbolone analogs that could be generated via alternative rearrangement of the acidic carbocation intermediate.

Atropselective Oxidation of 2,2',3,3',4,6'-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes: Involvement of Arene Oxide Intermediates

PCBs and their hydroxylated metabolites have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB developmental neurotoxicity; however, only limited information is available regarding the metabolism of these congeners in humans. We hypothesize that the oxidation of 2,2′,3,3′,4,6′-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) is atropselective and displays inter-individual variability. To test this hypothesis, PCB 132 (50 μM) was incubated with pooled or single donor HLMs for 10, 30 or 120 min at 37 °C, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite formed by different HLM preparations was either 2,2′,3,4,4′,6′-hexachlorobiphenyl-3′-ol (3′-140) or 2,2′,3,3′,4,6′-hexachlorobiphenyl-5′-ol (5′-132). 2,2′,3,3′,4,6′-Hexachlorobiphenyl-4′-ol (4′-132) and 2,2′,3,3′,4,6′-hexachlorobiphenyl-4′,5′-diol (4′,5′-132) were minor metabolites. The second eluting atropisomer of PCB 132 was slightly enriched in some HLM incubations. The formation of the first eluting atropisomer of 3′-140 was nearly enantiospecific (EF > 0.8). The second eluting atropisomer of 5′-132 was enriched in all microsomal preparations investigated. EF values differed slightly between single donor HLM preparations (EF = 0.84 to 0.96 for 3′-140; EF = 0.12 to 0.19 for 5′-132). These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to OH-PCBs in humans that may affect neurotoxic outcomes.

2-Amino-5-(3,4-dimethoxybenzylidene)-1-methylimidazol-4(5H)-one N,N-dimethylformamide monosolvate.

The crystal structure of the title compound, C(13)H(15)N(3)O(3) x C(3)H(7)NO, was determined as part of a larger project focusing on creatinine derivatives as potential pharmaceuticals. The molecule is essentially planar, in part because of intramolecular hydrogen bonding. Inversion-related pairs of molecules result from intermolecular hydrogen bonding. The pi systems of 2-amino-5-(3,4-dimethoxybenzylidene)-1-methylimidazol-4(5H)-one and an inversion-related molecule overlap slightly, indicating a small amount of pi-pi stacking. Bond lengths, angles and torsion angles are consistent with similar structures, except in the imidazolone ring near the doubly bonded C atom, where significant differences occur.