On the hydrolysis mechanism of the second-generation anticancer drug carboplatin

The hydrolysis reaction mechanisms of carboplatin, a second-generation anticancer drug, have been explored by combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The decomposition of carboplatin in water is expected to take place through a biphasic mechanism with a ring-opening process followed by the loss of the malonato ligand. We have investigated this reaction in water and acid conditions and established that the number of protons present in the malonato ligand has a direct effect on the energetics of this system. Close observation of the optimised structures revealed a necessary systematic water molecule in the vicinity of the amino groups of carboplatin. For this reason we have also investigated this reaction with an explicit water molecule. From the computed potential-energy surfaces it is established that the water hydrolysis takes place with an activation barrier of 30 kcal mol(-1), confirming the very slow reaction observed experimentally. The decomposition of carboplatin upon acidification was also investigated and we have computed a 21 kcal mol(-1) barrier to be overcome (experimental value 23 kcal mol(-1)). We have also established that the rate-limiting process is the first hydration, and ascertained the importance of a water molecule close to the two amine groups in lowering the activation barriers for the ring-opening reaction.     

Reaction HFCO + 2H2O — Calculated Mechanisms

Three possible reaction mechanisms of methanoyl fluoride with 2H₂O include a concerted and a stepwise hydrolysis of HFCO into HCOOH + HF, and a pure catalytic decomposition of HFCO into HF + CO. Among these, the two H₂O molecules acting as catalyst to decompose HFCO has the lowest calculated barrier, 25.1 kcal/mol with respect to the reactant‐adduct complex, whereas the barriers for the concerted and stepwise hydrolytic reactions in which one H₂O acts as a reactant and the other H₂O as catalyst are similar, 30.8 kcal/mol for concerted and 29.9 kcal/mol for stepwise. The formation of transoid HCOOH in the hydrolysis of HFCO is more favorable than cisoid HCOOH.     

Modeling the catalysis of anti-cocaine catalytic antibody: competing reaction pathways and free energy barriers

The competing reaction pathways and the corresponding free energy barriers for cocaine hydrolysis catalyzed by an anti-cocaine catalytic antibody, mAb15A10, were studied by using a novel computational strategy based on the binding free energy calculations on the antibody binding with cocaine and transition states. The calculated binding free energies were used to evaluate the free energy barrier shift from the cocaine hydrolysis in water to the antibody-catalyzed cocaine hydrolysis for each reaction pathway. The free energy barriers for the antibody-catalyzed cocaine hydrolysis were predicted to be the corresponding free energy barriers for the cocaine hydrolysis in water plus the calculated free energy barrier shifts. The calculated free energy barrier shift of -6.87 kcal/mol from the dominant reaction pathway of the cocaine benzoyl ester hydrolysis in water to the dominant reaction pathway of the antibody-catalyzed cocaine hydrolysis is in good agreement with the experimentally derived free energy barrier shift of -5.93 kcal/mol. The calculated mutation-caused shifts of the free energy barrier are also reasonably close to the available experimental activity data. The good agreement suggests that the protocol for calculating the free energy barrier shift from the cocaine hydrolysis in water to the antibody-catalyzed cocaine hydrolysis may be used in future rational design of possible high-activity mutants of the antibody as anti-cocaine therapeutics. The general strategy of the free energy barrier shift calculation may also be valuable in studying a variety of chemical reactions catalyzed by other antibodies or proteins through noncovalent bonding interactions with the substrates.     

Role of the somersault rearrangement in the oxidation step for flavin monooxygenases (FMO). A comparison between FMO and conventional xenobiotic oxidation with hydroperoxides

Model quantum mechanical calculations presented for C-4a-flavin hydroperoxide (FlHOOH) at the B3LYP/6-311+G(d,p) level suggest a new mechanism for flavoprotein monooxygenase (FMO) oxidation involving a concerted homolytic O-O bond cleavage in concert with hydroxyl radical transfer from the flavin hydroperoxide rather than an S(N)2-like displacement by the substrate on the C-4a-hydroperoxide OOH group. Homolytic O-O bond cleavage in a somersault-like rearrangement of hydroperoxide C-4a-flavinhydroperoxide (1) (FLHO-OH → FLHO···HO) produces an internally hydrogen-bonded HO(?) radical intermediate with a classical activation barrier of 27.0 kcal/mol. Model hydroperoxide 1 is used to describe the transition state for the key oxidation step in the paradigm aromatic hydroxylase, p-hydroxybenzoate hydroxylase (PHBH). A comparison of the electron distribution in the transition structures for the PHBH hydroxylation of p-hydroxybenzoic acid (ΔE(?) = 23.0 kcal/mol) with that of oxidation of trimethylamine (ΔE(?) = 22.3 kcal/mol) and dimethyl sulfide (ΔE? = 14.1 kcal/mol) also suggests a mechanism involving a somersault mechanism in concert with transfer of an HO(?) radical to the nucleophilic heteroatom center with a hydrogen transfer back to the FLH-O residue after the barrier is crossed to produce the final product, FLH-OH. In each case the hydroxylation barrier was less than that of the O-O rearrangement barrier in the absence of a substrate supporting an overall concerted process. All three transition structures bear a resemblance to the TS for the comparable hydroxylation of isobutane (ΔE(?) = 29.2 kcal/mol) and for simple Fenton oxidation by aqueous iron(III) hydroperoxides. To our surprise the oxidation of N- and S-nucleophiles with conventional oxidants such as alkyl hydroperoxides and peracids also proceeds by HO(?) radical transfer in a manner quite similar to that for tricyclic hydroperoxide 1. Stabilization of the developing oxyradical produced by somersault rearrangement for concerted enzymatic oxidation with tricyclic hydroperoxide 1 results in a reduced overall activation barrier.     

An Unsual Cys-Glu-Lys Catalytic Triad is Responsible for the Catalytic Mechanism of the Nitrilase Superfamily: A QM/MM Study on Nit2

Nitrilase 2 (Nit2) is a representative member of the nitrilase superfamily that catalyzes the hydrolysis of α-ketosuccinamate into oxaloacetate. It has been associated with the metabolism of rapidly dividing cells like cancer cells. The catalytic mechanism of Nit2 employs a catalytic triad formed by Cys191, Glu81 and Lys150. The Cys191 and Glu81 play an active role during the catalytic process while the Lys150 is shown to play only a secondary role. The results demonstrate that the catalytic mechanism of Nit2 involves four steps. The nucleophilic attack of Cys191 to the α-ketosuccinamate, the formation of two tetrahedral enzyme adducts and the hydrolysis of a thioacyl-enzyme intermediate, from which results the formation of oxaloacetate and enzymatic turnover. The rate limiting step of the catalytic process is the formation of the first tetrahedral intermediate with a calculated activation free energy of 18.4 kcal/mol, which agrees very well with the experimental k_cat (17.67 kcal/mol).     

A new intramolecular transformation of aromatic nitroso oxides

The possibility of intramolecular interaction of a nitroso oxide group with an aromatic ring is investigated at the UB3LYP/6-311+G(d,p) and G3MP2B3 levels of theory for a wide series of aromatic nitroso oxides. It is found that this reaction leads to the formation of a dioxazole cycle, its subsequent decay resulting in opening of the benzene ring and formation of nitriloxide and carbonyl functional groups. The activation enthalpy of the transformation of phenylnitroso oxide is 75.1 kJ/mol. It is shown that various sub-stituents at ortho-position (with respect to the nitroso oxide fragment) considerably lower the activation barrier of the investigated transformation, particularly in case of o,p-dimethoxyphenylnitroso oxide ΔH ^≠ = 43.7 kJ/mol. It is concluded that in the case of polyaromatic nitroso oxides, for which intramolecular cyclization is more typical (ΔH ^≠ ∼ 50 kJ/mol), a factor favoring the attack on the ortho-carbon atom is the stabilization of the product’s diene group due to its inclusion in the polyaromatic system. It is established that sum of these effects leads to a low activation barrier for the transformation of nitroso oxide that forms during the photooxidizing of 2-azido-1-methoxyphenazine, ΔH ^≠ = 19 kJ/mol. It is proposed that due to the low activation energy of some nitroso oxides, their intramolecular cyclization may be the primary channel of their unimolecular decay.     

Tautomeric and conformational equilibrium of 2-nitrosophenol and 9,10-phenanthrenequinonemonooxime: ab initio and NMR study

The tautomeric and conformational equilibrium of 2-nitrosophenol and 9,10-phenanthrenequinonemonooxime was studied by ab initio methods. The geometry optimizations of the structures investigated were done without any geometrical restrictions at HF/6-31G** and MP2/6-31G** levels of theory. The transition structures for tautomeric and rotameric conversions were located. To correct for electron correlation, single-point calculations were carried out up to MP4/6-311G*//MP2/6-31G* level of theory.

Ab initio calculations for 2-nitrosophenol in agreement with the available experimental data define the nitroso form as more stable. It was found that the influence of the correlation energy on the relative stabilities is smaller for the rotamers of the nitroso tautomer but substantially (4–6 kcal/mol) for the oxime forms. It was found that the barrier height of tautomerization reaction is 10.24 kcal/mol.

The structure of the 9,10-phenanthrenequinonemonooxime was studied by solid and liquid state NMR spectroscopy. Ab initio calculations in agreement with our experimental data predict that the compound exists as oxime tautomer and the syn-oxime is most stable. It was found that the solvent influence on the relative stabilities of both isomers: syn- and anti-oxime. While in chloroform solution the syn-oxime is preferred but in DMSO anti-oxime is more stable in energy.

At the MP4/6-311G*//MP2/6-31G**+ZPE level of theory the barrier of tautomerization was predicted to be 10.96 kcal/mol and the rotational barrier around the single C–O bond in the syn-oxime was found to be 7.57 kcal/mol. The rotation is facile and this explains the absence of nitroso tautomers in solution.     

Ab initio study of the S(N)2 and E2 mechanisms in the reaction between the cyanide ion and ethyl chloride in dimethyl sulfoxide solution

[reaction: see text] Reliable theoretical calculations predict a free energy barrier for nitrile formation from the reaction between the cyanide ion and ethyl chloride in DMSO solvent of 24.1 kcal/mol, close to the experimental value of 22.6 kcal/mol. We have also predicted that the isonitrile formation is less favorable by 4.7 kcal/mol, while the elimination mechanism is less favorable by more than 10 kcal/mol. These results indicate that isonitrile formation and bimolecular elimination are not significant side reactions for primary alkyl chloride reactions.     

The catalytic mechanism of mouse renin studied with QM/MM calculations

Hypertension is a chronic condition that affects nearly 25% of adults worldwide. As the Renin-Angiotensin-Aldosterone System is implicated in the control of blood pressure and body fluid homeostasis, its combined blockage is an attractive therapeutic strategy currently in use for the treatment of several cardiovascular conditions. We have performed QM/MM calculations to study the mouse renin catalytic mechanism in atomistic detail, using the N-terminal His6-Asn14 segment of angiotensinogen as substrate. The enzymatic reaction (hydrolysis of the peptidic bond between residues in the 10th and 11th positions) occurs through a general acid/base mechanism and, surprisingly, it is characterized by three mechanistic steps: it begins with the creation of a first very stable tetrahedral gem-diol intermediate, followed by protonation of the peptidic bond nitrogen, giving rise to a second intermediate. In a final step the peptidic bond is completely cleaved and both gem-diol hydroxyl protons are transferred to the catalytic dyad (Asp32 and Asp215). The final reaction products are two separate peptides with carboxylic acid and amine extremities. The activation energy for the formation of the gem-diol intermediate was calculated as 23.68 kcal mol(-1), whereas for the other steps the values were 15.51 kcal mol(-1) and 14.40 kcal mol(-1), respectively. The rate limiting states were the reactants and the first transition state. The associated barrier (23.68 kcal mol(-1)) is close to the experimental values for the angiotensinogen substrate (19.6 kcal mol(-1)). We have also tested the influence of the density functional on the activation and reaction energies. All eight density functionals tested (B3LYP, B3LYP-D3, X3LYP, M06, B1B95, BMK, mPWB1K and B2PLYP) gave very similar results.     

Catalytic mechanism of dopamine beta-monooxygenase mediated by Cu(III)-oxo

Mechanisms of dopamine hydroxylation by the Cu(II)-superoxo species and the Cu(III)-oxo species of dopamine beta-monooxygenase (DBM) are discussed using QM/MM calculations for a whole-enzyme model of 4700 atoms. A calculated activation barrier for the hydrogen-atom abstraction by the Cu(II)-superoxo species is 23.1 kcal/mol, while that of the Cu(III)-oxo, which can be viewed as Cu(II)-O*, is 5.4 kcal/mol. Energies of the optimized radical intermediate in the superoxo- and oxo-mediated pathways are 18.4 and -14.2 kcal/mol, relative to the corresponding reactant complexes, respectively. These results demonstrate that the Cu(III)-oxo species can better mediate dopamine hydroxylation in the protein environment of DBM. The side chains of three amino acid residues (His415, His417, and Met490) coordinate to the Cu(B) atom, one of the copper sites in the catalytic core that plays a role for the catalytic function. The hydrogen-bonding network between dopamine and the three amino acid residues (Glu268, Glu369, and Tyr494) plays an essential role in substrate binding and the stereospecific hydroxylation of dopamine to norepinephrine. The dopamine hydroxylation by the Cu(III)-oxo species is a downhill and lower-barrier process toward the product direction with the aid of the protein environment of DBM. This enzyme is likely to use the high reactivity of the Cu(III)-oxo species to activate the benzylic C-H bond of dopamine; the enzymatic reaction can be explained by the so-called oxygen rebound mechanism.     

Theoretical study on the reaction pathways of HFCO + H2O

For the reaction of methanoyl fluoride with water, both optimized structures and vibrational wavenumbers of reaction intermediates, transition structures and product complexes were calculated and characterized with theory at the MP2/6-311++G(d,p) level. Including a catalytic path and concerted and stepwise hydrolysis paths, possible reaction mechanisms were also investigated. The catalytic reaction of HFCO yielding HF and CO has the smallest activation barrier, 29.6 kcal/mol, whereas for the concerted hydrolysis 33.0 kcal/mol is required to overcome the barrier to form transoid HCOOH + HF, which is less than for the stepwise counterpart, 42.0 kcal/mol.     

The "somersault" mechanism for the p-450 hydroxylation of hydrocarbons. The intervention of transient inverted metastable hydroperoxides

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.     

Influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine. A theoretical study

The influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine has been studied using density functional theory (DFT) methods. For the neutral system, two different pathways (with retention and inversion of configuration at the C1' anomeric carbon) have been found, both of them consisting of two steps and involving the formation of a dihydrofurane-like intermediate. The Gibbs free energy barrier for the first step is very high in both cases (53 and 46 kcal/mol for the process with inversion and with retention, respectively). However, the N7-protonated system shows a very different mechanism which consists of two steps. The first one leads to the formation of an oxacarbenium ion intermediate, with a Gibbs free energy barrier of 27 kcal/mol, and the second one corresponds to the nucleophilic attack of the water molecule to the oxacarbenium ion and takes place with a barrier of 1.3 kcal/mol. Thus, these results agree with a stepwise SN1 mechanism (DN*AN), with a discrete intermediate formed between the leaving group and the nucleophile approach, and show that N7 protonation strongly catalyzes the hydrolysis of the N-glycosidic bond, making the guanine a better leaving group. Finally, kinetic isotope effects have been calculated for the protonated system, and the results obtained are in very good agreement with experimental data for analogous systems.     

Investigation of the mechanism of the cell wall DD-carboxypeptidase reaction of penicillin-binding protein 5 of Escherichia coli by quantum mechanics/molecular mechanics calculations

Penicillin-binding protein 5 (PBP 5) of Escherichia coli hydrolyzes the terminal D-Ala-D-Ala peptide bond of the stem peptides of the cell wall peptidoglycan. The mechanism of PBP 5 catalysis of amide bond hydrolysis is initial acylation of an active site serine by the peptide substrate, followed by hydrolytic deacylation of this acyl-enzyme intermediate to complete the turnover. The microscopic events of both the acylation and deacylation half-reactions have not been studied. This absence is addressed here by the use of explicit-solvent molecular dynamics simulations and ONIOM quantum mechanics/molecular mechanics (QM/MM) calculations. The potential-energy surface for the acylation reaction, based on MP2/6-31+G(d) calculations, reveals that Lys47 acts as the general base for proton abstraction from Ser44 in the serine acylation step. A discrete potential-energy minimum for the tetrahedral species is not found. The absence of such a minimum implies a conformational change in the transition state, concomitant with serine addition to the amide carbonyl, so as to enable the nitrogen atom of the scissile bond to accept the proton that is necessary for progression to the acyl-enzyme intermediate. Molecular dynamics simulations indicate that transiently protonated Lys47 is the proton donor in tetrahedral intermediate collapse to the acyl-enzyme species. Two pathways for this proton transfer are observed. One is the direct migration of a proton from Lys47. The second pathway is proton transfer via an intermediary water molecule. Although the energy barriers for the two pathways are similar, more conformers sample the latter pathway. The same water molecule that mediates the Lys47 proton transfer to the nitrogen of the departing D-Ala is well positioned, with respect to the Lys47 amine, to act as the hydrolytic water in the deacylation step. Deacylation occurs with the formation of a tetrahedral intermediate over a 24 kcal x mol(-1) barrier. This barrier is approximately 2 kcal x mol(-1) greater than the barrier (22 kcal x mol(-1)) for the formation of the tetrahedral species in acylation. The potential-energy surface for the collapse of the deacylation tetrahedral species gives a 24 kcal x mol(-1) higher energy species for the product, signifying that the complex would readily reorganize and pave the way for the expulsion of the product of the reaction from the active site and the regeneration of the catalyst. These computational data dovetail with the knowledge on the reaction from experimental approaches.     

Theoretical study of cisplatin binding to DNA: the importance of initial complex stabilization

The first and second substitution reactions between activated (hydrolyzed) cisplatin, Pt(NH3)2(H2O)2(2+), and purine bases guanine and adenine are explored using the B3LYP hybrid functional, IEF-PCM solvation models, and large basis sets. The computed free energy barrier for the first substitution is 19.5 kcal/mol for guanine (exptl value = 18.3 kcal/mol) and 24.0 kcal/mol for adenine. The observed predominance toward guanine in the first substitution is explained in terms of significantly larger stabilization energy for the initially formed complex, compared with adenine, in combination with favored kinetics, and represents a revised view of the proposed mechanism for cisplatin binding to DNA. For the second substitution, the computed barrier for Pt(NH3)2G2(2+) head-to-head formation is 22.5 kcal/mol, in very good agreement with experimental data for adduct closure (23.4 kcal/mol). Again, a higher stability in complexation with G over A is ascribed as the main contributing factor favoring G over A substitution. The calculations provide a first explanation for the predominance of 1,2-d(GpG) over 1,2-d(ApG) intrastrand didentate adducts, and the origin of the 5'-3' direction specificity of the 1,2-d(ApG) adducts.     

193-nm photodissociation of acryloyl chloride to probe the unimolecular dissociation of CH2CHCO radicals and CH2CCO

The work presented here uses photofragment translational spectroscopy to investigate the primary and secondary dissociation channels of acryloyl chloride (CH2==CHCOCl) excited at 193 nm. Three primary channels were observed. Two C-Cl fission channels occur, one producing fragments with high kinetic recoil energies and the other producing fragments with low translational energies. These channels produced nascent CH2CHCO radicals with internal energies ranging from 23 to 66 kcal/mol for the high-translational-energy channel and from 50 to 68 kcal/mol for the low-translational-energy channel. We found that all nascent CH2CHCO radicals were unstable to CH2CH + CO formation, in agreement with the G3//B3LYP barrier height of 22.4 kcal/mol to within experimental and computational uncertainties. The third primary channel is HCl elimination. All of the nascent CH2CCO coproducts were found to have enough internal energy to dissociate, producing CH2C: + CO, in qualitative agreement with the G3//B3LYP barrier of 39.5 kcal/mol. We derive from the experimental results an upper limit of 23 +/- 3 kcal/mol for the zero-point-corrected barrier to the unimolecular dissociation of the CH2CHCO radical to form CH2CH + CO.     

A theoretical study of the mechanisms and regiochemistry of the reactions of 5-alkoxyoxazole with thioaldehydes,nitroso compounds,and aldehydes

A theoretical study based on B3LYP/6-31G calculations has been applied to the mechanisms and regiochemistry of reactions of 5-alkoxyoxazole with thioaldehydes, nitroso compounds, and aldehydes. All three reactions adopt similar mechanisms, which start with Diels-Alder (DA) reactions, followed by either a novel, concerted ring-opening-ring-closing (RORC) step to transfer the DA adduct to 2-alkoxycarbonyl-3-thiazoline and 2-alkoxycarbonyl-3-oxazoline for thioaldehydes and aldehydes, respectively, or stepwise ring-opening and ring-closing steps to generate 1,2,4-oxadiazoline for nitroso compounds. The reactions of 5-alkoxyoxazole with thioaldehydes and nitroso compounds can be conducted under thermal reaction conditions due to the 10 kcal/mol activation barriers for their rate-determining DA reactions. By contrast, the reaction of 5-alkoxyoxazole with aldehydes cannot take place under thermal conditions, since this bimolecular reaction has the rate-determining RORC transition state higher than the reactants by 30.5 kcal/mol.     

Mechanism of the hydration of carbon dioxide: direct participation of H2O versus microsolvation

Thermochemical parameters of carbonic acid and the stationary points on the neutral hydration pathways of carbon dioxide, CO 2 + nH 2O --> H 2CO 3 + ( n - 1)H 2O, with n = 1, 2, 3, and 4, were calculated using geometries optimized at the MP2/aug-cc-pVTZ level. Coupled-cluster theory (CCSD(T)) energies were extrapolated to the complete basis set limit in most cases and then used to evaluate heats of formation. A high energy barrier of approximately 50 kcal/mol was predicted for the addition of one water molecule to CO 2 ( n = 1). This barrier is lowered in cyclic H-bonded systems of CO 2 with water dimer and water trimer in which preassociation complexes are formed with binding energies of approximately 7 and 15 kcal/mol, respectively. For n = 2, a trimeric six-member cyclic transition state has an energy barrier of approximately 33 (gas phase) and a free energy barrier of approximately 31 (in a continuum solvent model of water at 298 K) kcal/mol, relative to the precomplex. For n = 3, two reactive pathways are possible with the first having all three water molecules involved in hydrogen transfer via an eight-member cycle, and in the second, the third water molecule is not directly involved in the hydrogen transfer but solvates the n = 2 transition state. In the gas phase, the two transition states have comparable energies of approximately 15 kcal/mol relative to separated reactants. The first path is favored over in aqueous solution by approximately 5 kcal/mol in free energy due to the formation of a structure resembling a (HCO 3 (-)/H 3OH 2O (+)) ion pair. Bulk solvation reduces the free energy barrier of the first path by approximately 10 kcal/mol for a free energy barrier of approximately 22 kcal/mol for the (CO 2 + 3H 2O) aq reaction. For n = 4, the transition state, in which a three-water chain takes part in the hydrogen transfer while the fourth water microsolvates the cluster, is energetically more favored than transition states incorporating two or four active water molecules. An energy barrier of approximately 20 (gas phase) and a free energy barrier of approximately 19 (in water) kcal/mol were derived for the CO 2 + 4H 2O reaction, and again formation of an ion pair is important. The calculated results confirm the crucial role of direct participation of three water molecules ( n = 3) in the eight-member cyclic TS for the CO 2 hydration reaction. Carbonic acid and its water complexes are consistently higher in energy (by approximately 6-7 kcal/mol) than the corresponding CO 2 complexes and can undergo more facile water-assisted dehydration processes.     

Substitution of hydrogen by deuterium changes the regioselectivity of ethylbenzene hydroxylation by an oxo-iron-porphyrin catalyst

Heme oxo-iron complexes are powerful oxygenation catalysts of environmentally benign hydroxylation processes. We have performed density functional theoretic calculations on a model system, that is, an oxo-iron-porphyrin (Por) complex [(Fe=O)Cl(Por)], and studied its reactivity toward a realistic substrate, namely, ethylbenzene. The calculations showed that the dominant reaction process in the gas phase is benzyl hydroxylation leading to 1-phenylethanol, with an energetic barrier of 9.1 kcal mol(-1), while the competing para-phenyl hydroxylation has a barrier 3.0 kcal mol(-1) higher in energy. This benzyl hydroxylation barrier is the lowest C-H hydroxylation barrier we have obtained so far for oxo-iron-porphyrin complexes. Due to electronic differences between the intermediates in the phenyl and benzyl hydroxylation processes, the phenyl hydroxylation process is considerably stabilised over the benzyl hydroxylation mechanism in environments with a large dielectric constant. In addition, we calculated kinetic isotope effects of the substitution of one or more hydrogen atoms of ethylbenzene by deuterium atoms and studied its effect on the reaction barriers. Thus, in a medium with a large dielectric constant, a regioselectivity change occurs between [H(10)]ethylbenzene and [D(10)]ethylbenzene whereby the deuterated species gives phenol products whereas the hydrogenated species gives mainly 1-phenylethanol products. This remarkable metabolic switching was analysed and found to occur due to 1) differences in strength between a C-H versus a C-D bond and 2) stabilisation of cationic intermediates in a medium with a large dielectric constant. We have compared our calculations with experimental work on synthetic oxo-iron-porphyrin catalysts as well as with enzyme-reactivity studies.     

Thermochemical properties and group values for nitrogen-containing molecules

Gas-phase thermochemical group additivity values were derived from CBS-QB3 computational chemistry calculations for 105 noncyclic C/H/O/N molecules. The molecules contain nitrile, nitro, nitroso, nitrite, nitrate, amine, imino, and azo functional groups. The enthalpy of formation, entropy, and heat capacity values for 49 atom-centered groups were derived. The effect of hindered internal rotations was included via rotor potential energy scans and solution of the one-dimensional Schrodinger equation. The average 95% confidence intervals across all derived groups are 1.4 kcal mol(-1) for the enthalpy, 1.3 cal mol(-1) K(-1) for the entropy, and 1.0 cal/mol K for the heat capacity. The presented group values will be useful when employing automatic reaction mechanism generation tools to examine the role of fuel-bound or molecular nitrogen in energy-related or atmospheric processes.