The strength of the O−O bond is of fundamental importance in a variety of chemical processes. Traditionally, a value of 34 kcal/mol has been ascribed to a generic O−O bond dissociation energy. The present, high-level ab initio calculations indicate that the average O−O bond energy is significantly higher, ca. 45 kcal/mol, and that the bond energy is sensitive to the bonding environment. Calculations at the G2 level of theory give bond dissociation enthalpies at 298 K of 50 kcal/mol for HOOH, 45 kcal/mol for CH3OOH, 39 kcal/mol for CH3OOCH3, and 48 kcal/mol for HC(O)OOH and CH3C(O)OOH. The G2(MP2) results are similar and, additionally, give bond dissociation enthalpies of 38 kcal/mol for diacetyl peroxide, 49 kcal/mol for trifluoroperoxyacetic acid, 23 kcal/mol for isopropenyl hydroperoxide, and 22 kcal/mol for peroxynitrous acid.

A model C-(4a)-flavinhydroperoxide (FlHOOH) is described that contains the tricyclic isoalloxazine moiety, the C-4a-hydroperoxide functionality, and a beta-hydroxyethyl group to model the effect of the 2'-OH group of the ribityl side chain of native FADHOOH. The electronic structures of this reduced flavin (H(3)()Fl(red)()), its N1 anion (H(2)()Fl(red)()(-)()), oxidized flavin (HFl(ox)()), and FlHOOH have been fully optimized at the B3LYP/ 6-31+G(d,p) level of theory. This model C-4a-flavinhydroperoxide is used to describe the transition state for the key step in the paradigm aromatic hydroxylase, p-hydroxybenzoate hydroxylase (PHBH): the oxidation of p-hydroxybenzoate (p-OHB). The Tyrosine-201 residue in PHBH is modeled by phenol, and Arginine-214 is modeled by guanidine. Electrophilic aromatic substitution proceeds by an S(N)2-like attack of the aromatic sextet of p-OHB phenolate anion on the distal oxygen of FlHOOH 3. The transition structure for oxygen atom transfer is fully optimized [B3LYP/6-31+G(d,p)] and has a classical activation barrier of 24.9 kcal/mol. These data suggest that the role of the Tyr-201 is to orient the p-OHB substrate and to properly align it for the oxygen transfer step. Although the negatively charged phenolate oxygen does activate the C-3 carbon of p-OHB phenolate anion toward oxidation relative to ortho oxidation of the carboxylate anion, it appears that H-bonding the Tyr-201 residue to this phenolic oxygen stabilizes both the ground state (GS) and the transition state (TS) approximately equally and therefore plays only a minor role, if any, in lowering the activation barrier. Complexation of p-OHB with guanidine has only a modest effect upon the oxidation barriers. When the complex is in the form of a salt-bridge (10a), the barrier is only slightly reduced. When the TSs are placed in THF solvent (COSMO) with full geometry optimization, salt-bridge TS-A is slightly favored (DeltaDeltaE() = 2.3 kcal/mol).

A series of model theoretical calculations are described that suggest a new mechanism for the oxidation step in enzymatic cytochrome P450 hydroxylation of saturated hydrocarbons. A new class of metastable metal hydroperoxides is described that involves the rearrangement of the ground-state metal hydroperoxide to its inverted isomeric form with a hydroxyl radical hydrogen bonded to the metal oxide (MO-OH --> MO....HO). The activation energy for this somersault motion of the FeO-OH group is 20.3 kcal/mol for the P450 model porphyrin iron(III) hydroperoxide [Por(SH)Fe(III)-OOH(-)] to produce the isomeric ferryl oxygen hydrogen bonded to an *OH radical [Por(SH)Fe(III)-O....HO(-)]. This isomeric metastable hydroperoxide, the proposed primary oxidant in the P450 hydroxylation reaction, is calculated to be 17.8 kcal/mol higher in energy than the ground-state iron(III) hydroperoxide Cpd 0. The first step of the proposed mechanism for isobutane oxidation is abstraction of a hydrogen atom from the C-H bond of isobutane by the hydrogen-bonded hydroxyl radical to produce a water molecule strongly hydrogen bonded to anionic Cpd II. The hydroxylation step involves a concerted but nonsynchronous transfer of a hydrogen atom from this newly formed, bound, water molecule to the ferryl oxygen with a concomitant rebound of the incipient *OH radical to the carbon radical of isobutane to produce the C-O bond of the final product, tert-butyl alcohol. The TS for the oxygen rebound step is 2 kcal/mol lower in energy than the hydrogen abstraction TS (DeltaE() = 19.5 kcal/mol). The overall proposed new mechanism is consistent with a lot of the ancillary experimental data for this enzymatic hydroxylation reaction.

High-level ab initio molecular orbital calculations at the G2(+) level of theory have been carried out on the identity front-side nucleophilic substitution reactions with retention of configuration, X -+ CH 3 X, for X ) F, Cl, Br, and I. Overall gas-phase barrier heights do not show a strong variation with halogen atom and are calculated to be 184.5 (X ) F), 193.8 (X ) Cl), 178.9 (X ) Br), and 171.4 kJ mol -1 (X ) I), substantially higher than the corresponding barriers for back-side attack (-8.0 for X ) F, 11.5 for X ) Cl, 5.8 for X ) Br, and 6.5 kJ mol -1 for X ) I). The difference between the overall barrier for back-side attack and front-side attack is smallest for X ) I (164.9 kJ mol -1 ). Central barrier heights for front-side attack decrease in the following order: 241.0 (X ) F), 237.8 (X ) Cl), 220.0 (X ) Br), and 207.4 kJ mol -1 (X ) I). The minimum energy pathways for both back-side and front-side S N 2 reactions are found to involve the same ion-molecule complex (X -‚‚‚H 3 CX), with the front-side pathway becoming feasible at higher energies. Indeed, our results suggest that the chloride exchange in CH 3 Cl, which has been found in gas-phase experiments at high energies, may be the first example of a front-side S N 2 reaction with retention of configuration at saturated carbon. Analysis of our computational data in terms of frontier orbital theory suggests that elongation of the bond between the central atom and X could be a significant factor in decreasing the unfavorable nature of the front-side S N 2 reaction with retention of configuration in going from X ) F to X ) I. Ion-molecule complexes CH 3 -X‚‚‚X -, which may be pre-reaction complexes in direct collinear halophilic attack, were found for X ) Br and I but not for X ) F and Cl. The calculated complexation energies (∆H comp ) for halophilic complexes are considerably smaller (7.3 and 19.4 kJ mol -1 for X ) Br and I, respectively) than those for the corresponding pre-reaction complexes for S N 2 attack at carbon (41.1 and 36.0 kJ mol -1 for X ) Br and I, respectively). Nucleophilic substitution reactions at the halogen atom in CH 3 X (X ) F-I) (halophilic reactions) are highly endothermic and appear to represent an unlikely mechanistic pathway for identity halide exchange.