Symmetry in chemistry from the hydrogen atom to proteins

The last 2 decades have seen discoveries in highly excited states of atoms and molecules of phenomena that are qualitatively different from the “planetary” model of the atom, and the near-rigid model of molecules, characteristic of these systems in their low-energy states. A unified view is emerging in terms of approximate dynamical symmetry principles. Highly excited states of two-electron atoms display “molecular” behavior of a nonrigid linear structure undergoing collective rotation and vibration. Highly excited states of molecules described in the “standard molecular model” display normal mode couplings, which induce bifurcations on the route to molecular chaos. New approaches such as rigid–nonrigid correlation, vibrons, and quantum groups suggest a unified view of collective electronic motion in atoms and nuclear motion in molecules.

On the electronic nature of low-barrier hydrogen bonds in enzymatic reactions

The electronic nature of low-barrier hydrogen bonds (LBHBs) in enzymatic reactions is discussed based on combined low temperature neutron and x-ray diffraction experiments and on high level ab initio calculations by using the model substrate benzoylacetone. This molecule has a LBHB, as the intramolecular hydrogen bond is described by a double-well potential with a small barrier for hydrogen transfer. From an “atoms in molecules” analysis of the electron density, it is found that the hydrogen atom is stabilized by covalent bonds to both oxygens. Large atomic partial charges on the hydrogen-bonded atoms are found experimentally and theoretically. Therefore, the hydrogen bond gains stabilization from both covalency and from the normal electrostatic interactions found for long, weak hydrogen bonds. Based on comparisons with other systems having short-strong hydrogen bonds or LBHBs, it is proposed that all short-strong and LBHB systems possess similar electronic features of the hydrogen-bonded region, namely polar covalent bonds between the hydrogen atom and both heteroatoms in question.

Comparison of structures and energies of CH52+• with CH4+• and their possible role in superacidic methane activation

Contrary to previous theoretical studies at the UHF/6-31G* level, the methonium radical dication CH52+ is not a Cs symmetrical structure with a 2e—3c bond but a C2v symmetrical structure 1 with two 2e—3c bonds (at the UHF/6-31G**, UMP2/6-31G**, and UQCISD(T)/6-311G** levels). The Cs symmetrical structure is not even a minimum at the higher level of calculations. The four hydrogen atoms in 1 are bonded to the carbon atom by two 2e—3c bonds and the fifth hydrogen atom by a 2e—2c bond. The unpaired electron of 1 is located in a formal p-orbital (of the sp2-hybridized carbon atom) perpendicular to the plane of the molecule. Hydrogen scrambling in 1 is however extremely facile, as is in other C1 cations. It is found that the protonation of methane to CH5+ decreases the energy for subsequent homolytic cleavage resulting in the exothermic (24.1 kcal/mol) formation of CH4+•. Subsequent reaction with neutral methane while reforming CH5+ gives the methyl radical enabling reaction with excess methane to ethane and H2. The overall reaction is endothermic by 11.4 kcal/mol, but offers under conditions of oxidative removal of H2 an alternative to the more energetic carbocationic conversion of methane.

Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes.

A computational model is presented that can be used as a tool in the design of safer chemicals. This model predicts the rate of hydrogen-atom abstraction by cytochrome P450 enzymes. Excellent correlations between biotransformation rates and the calculated activation energies (delta Hact) of the cytochrome P450-mediated hydrogen-atom abstractions were obtained for the in vitro biotransformation of six halogenated alkanes (1-fluoro-1,1,2,2-tetrachloroethane, 1,1-difluoro-1,2,2-trichloroethane, 1,1,1-trifluro-2,2-dichloroethane, 1,1,1,2-tetrafluoro-2-chloroethane, 1,1,1,2,2,-pentafluoroethane, and 2-bromo-2-chloro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: In(rate, rat liver microsomes) = 44.99 - 1.79(delta Hact), r2 = 0.86; In(rate, human CYP2E1) = 46.99 - 1.77(delta Hact), r2 = 0.97 (rates are in nmol of product per min per nmol of cytochrome P450 and energies are in kcal/mol). Correlations were also obtained for five inhalation anesthetics (enflurane, sevoflurane, desflurane, methoxyflurane, and isoflurane) for both in vivo and in vitro metabolism by humans: In[F(-)]peak plasma = 42.87 - 1.57(delta Hact), r2 = 0.86. To our knowledge, these are the first in vivo human metabolic rates to be quantitatively predicted. Furthermore, this is one of the first examples where computational predictions and in vivo and in vitro data have been shown to agree in any species. The model presented herein provides an archetype for the methodology that may be used in the future design of safer chemicals, particularly hydrochlorofluorocarbons and inhalation anesthetics.

The change in hydrogen bond strength accompanying charge rearrangement: Implications for enzymatic catalysis

The equilibrium for formation of the intramolecular hydrogen bond (KHB) in a series of substituted salicylate monoanions was investigated as a function of ΔpKa, the difference between the pKa values of the hydrogen bond donor and acceptor, in both water and dimethyl sulfoxide. The dependence of log KHB upon ΔpKa is linear in both solvents, but is steeper in dimethyl sulfoxide (slope = 0.73) than in water (slope = 0.05). Thus, hydrogen bond strength can undergo substantially larger increases in nonaqueous media than aqueous solutions as the charge density on the donor or acceptor atom increases. These results support a general mechanism for enzymatic catalysis, in which hydrogen bonding to a substrate is strengthened as charge rearranges in going from the ground state to the transition state; the strengthening of the hydrogen bond would be greater in a nonaqueous enzymatic active site than in water, thus providing a rate enhancement for an enzymatic reaction relative to the solution reaction. We suggest that binding energy of an enzyme is used to fix the substrate in the low-dielectric active site, where the strengthening of the hydrogen bond in the course of a reaction is increased.