The influence of substituents in governing the strength of the P-X bonds of substituted halophosphines R1R2P-X (X = F and Cl).

In this study, the gas-phase homolytic P-F and P-Cl bond dissociation energies (BDEs) of a set of thirty fluorophosphine (R1R2P-F) and thirty chlorophosphine-type (R1R2P-Cl) molecules have been obtained using the high-level W2 thermochemical protocol. For the R1R2P-F species, the P-F BDEs (at 298 K) differ by up to 117.0 kJ mol-1, with (H3Si)2P-F having the lowest BDE (439.5 kJ mol-1) and F2P-F having the largest BDE (556.5 kJ mol-1). In the case of the chlorophosphine-type molecules, the difference in BDEs is considerably smaller (i.e., 72.6 kJ mol-1), with (NC)2P-Cl having the lowest P-Cl BDE (299.8 kJ mol-1) and (HO)2P-Cl having the largest (372.4 kJ mol-1). We have further analyzed the effect of substituents in governing the P-F and P-Cl BDEs by considering the effect of substituents in the parent halogenated precursors (using molecule stabilization enthalpies) and the effect of substituents in the product radicals (using radical stabilization enthalpies). Finally, we have also assessed the performance of a wide range of DFT methods for their ability to compute the gas-phase P-F and P-Cl BDEs contained in this dataset. We find that, overall, the double hybrid functional DSD-PBEB95 offers the best performance for both bond types, with mean absolute deviations of just 2.1 (P-F BDEs) and 2.2 (P-Cl BDEs) kJ mol-1.

A Systematic Exploration of B-F Bond Dissociation Enthalpies of Fluoroborane-Type Molecules at the CCSD(T)/CBS Level.

Fluoroborane-type molecules (R1R2B-F) are of interest in synthetic chemistry, but to date, apart from a handful of small species (such as H2BF, HBF2, and BF3), little is known concerning the effect of substituents in governing the strength of the B-F bonds of such species toward homolytic dissociation in the gas phase. In this study, we have calculated the bond dissociation enthalpies (BDEs) of thirty unique B-F bonds at the CCSD(T)/CBS level using the high-level W1w thermochemical protocol. The B-F bonds in all species considered are very strong, ranging from 545.9 kJ mol-1 in (H2B)2B-F to 729.2 kJ mol-1 HBF2. Nevertheless, these BDEs still vary over a wide range of 183.3 kJ mol-1. The structural properties that affect the BDEs are examined in detail, and the homolytic BDEs are rationalized based on molecule stabilization enthalpies and radical stabilization enthalpies. Since polar B-F bonds may represent a challenging test case for density functional theory (DFT) methods, we proceed to examine the performance of a wide range of DFT methods across the rungs of Jacob's Ladder for their ability to compute B-F BDEs. We find that only a handful of DFT methods can reproduce the CCSD(T)/CBS BDEs with mean absolute deviations (MADs) below the threshold of chemical accuracy (i.e., with average deviations below 4.2 kJ mol-1). The only functionals capable of achieving this feat were (MADs given in parentheses): ωB97M-V (4.0), BMK (3.5), DSD-BLYP (3.8), and DSD-PBEB95 (1.8 kJ mol-1).

Intramolecular Proton-Coupled Hydride Transfers with Relatively Low Activation Barriers.

We report that bifunctional molecules containing hydroxyl and carbonyl functional groups can undergo an effective transfer hydrogenation via an intramolecular proton-coupled hydride transfer (PCHT) mechanism. In this reaction mechanism, a hydride transfer between two carbon atoms is coupled with a proton transfer between two oxygen atoms via a cyclic bond rearrangement transition structure. The coupled transfer of the two hydrogens as Hδ+ and Hδ- is supported by atomic polar tensor charges. The activation energy for the PCHT reaction is strongly dependent on the length of the alkyl chain between the hydroxyl and carbonyl functional groups but relatively weakly dependent on the functional groups attached to the hydroxyl and carbonyl carbons. We investigate the PCHT reaction mechanism using the Gaussian-4 thermochemical protocol and obtain high activation energy barriers (ΔH‡298) of 210.5-228.3 kJ mol-1 for chain lengths of one carbon atom and 160.2-163.9 kJ mol-1 for chain lengths of two carbon atoms. However, for longer chain lengths containing 3-4 carbon atoms, we obtain ΔH‡298 values as low as 101.9 kJ mol-1. Importantly, the hydride transfer between two carbon atoms proceeds without the need for a catalyst or hydride transfer activating agent. These results indicate that the intramolecular PCHT reaction provides an effective avenue for uncatalyzed, metal-free hydride transfers at ambient temperatures.

Effect of substituents on the preferred modes of one-electron reductive cleavage of N-Cl and N-Br bonds.

In this study, we investigate the effect of substituents in determining the modes of one-electron reductive cleavage of X-NRR' (X = Cl and Br) molecules. We achieve this through comparison of the calculated gas-phase electron affinities (EAs) and aqueous-phase one-electron reduction potentials (E°'s) for a range of nitrogen-centered radicals ((•)NRR') with the corresponding EA and E° values for (•)Cl and (•)Br. The gas-phase EAs have been obtained using the benchmark-quality W1w thermochemical protocol, whereas E° values have been obtained by additionally applying free energy of solvation corrections, obtained using the conductor-like polarizable continuum (CPCM) model. We find that the N-halogenated derivatives of amines and amides should generally cleave in such a way as to afford (•)NRR' and X(-). For the N-halogenated imides, on the other hand, the N-brominated derivatives are predicted to produce (•)Br in solution, whereas the N-chlorinated derivatives again would give Cl(-). Importantly, we predict that N-bromouracil is likely to afford (•)Br. This may have important implications in terms of inflammatory-related diseases, because (•)Br may damage biomolecules such as proteins and DNA. To assist in the determination of the gas-phase EAs of larger (•)NRR' radicals, not amenable to investigation using W1w, we have evaluated the performance of a wide range of lower-cost theoretical methods. Of the standard density functional theory (DFT) procedures, M06-2X, τ-HCTHh, and B3-LYP show good performance, with mean absolute deviations (MADs) from W1w of 4.8-6.8 kJ mol(-1), whereas ROB2-PLYP and B2-PLYP emerge as the best of the double-hybrid DFTs (DHDFTs), with MADs of 2.5 and 3.0 kJ mol(-1), respectively. Of the Gn-type procedures, G3X and G4 show very good performance (MADs = 2.4 and 2.6 kJ mol(-1), respectively). The G4(MP2)-6X+ procedure performs comparably, with an MAD of 2.7 kJ mol(-1), with the added advantage of significantly reduced computational expense.

Computational design of effective, bioinspired HOCl antioxidants: the role of intramolecular Cl+ and H+ shifts.

The enzyme myeloperoxidase generates significant amounts of hypochlorous acid (HOCl) at sites of inflammation to inflict oxidative damage upon invading pathogens. However, excessive production of this potent oxidant is associated with numerous inflammatory diseases. Recent kinetic measurements suggest that the endogenous antioxidant carnosine is an effective HOCl scavenger. On the basis of computational modeling, we suggest a possible mechanism for this antioxidant activity. We find that a unique structural relationship between three adjacent functional groups (imidazole, carboxylic acid, and terminal amine) enables an intramolecular chlorine transfer to occur. In particular, two sequential proton shifts are coupled with a Cl(+) shift converting the kinetically favored product (chlorinated at the imidazole nitrogen) into the thermodynamically favored product (chlorinated at the terminal amine) effectively trapping the chlorine. We proceed to design systems that share similar structural features to those of carnosine but with even greater HOCl-scavenging capabilities.

Reactivities of amino acid derivatives toward hydrogen abstraction by Cl• and OH•.

In recent computational studies of hydrogen-atom abstraction from amino acid derivatives, two distinct rationalizations have been put forward for the relative inertness of the α-C-H. Of these, the proposal that the inertness is due to a "kinetic trap" associated with particularly stable complexes is shown to be unlikely because of unfavorable entropies. On the other hand, the proposed existence of deactivating polar effects at the α-position in Cl(•) abstractions is likely also to be applicable to OH(•) abstractions, but to a lesser extent.

Assessment of theoretical procedures for calculating barrier heights for a diverse set of water-catalyzed proton-transfer reactions.

Accurate electronic barrier heights are obtained for a set of nine proton-transfer tautomerization reactions, which are either (i) uncatalyzed, (ii) catalyzed by one water molecule, or (iii) catalyzed by two water molecules. The barrier heights for reactions (i) and (ii) are obtained by means of the high-level ab initio W2.2 thermochemical protocol, while those for reaction (iii) are obtained using the W1 protocol. These three sets of benchmark barrier heights allow an assessment of the performance of more approximate theoretical procedures for the calculation of barrier heights of uncatalyzed and water-catalyzed reactions. We evaluate initially the performance of the composite G4 procedure and variants thereof (e.g., G4(MP2) and G4(MP2)-6X), as well as that of standard ab initio procedures (e.g., MP2, SCS-MP2, and MP4). We find that the performance of the G4(MP2)-type thermochemical procedures deteriorates with the number of water molecules involved in the catalysis. This behavior is linked to deficiencies in the MP2-based basis-set-correction term in the G4(MP2)-type procedures. This is remedied in the MP4-based G4 procedure, which shows good performance for both the uncatalyzed and the water-catalyzed reactions, with mean absolute deviations (MADs) from the benchmark values lying below the threshold of "chemical accuracy" (arbitrarily defined as 1 kcal mol(-1) ≈ 4.2 kJ mol(-1)). We also examine the performance of a large number of density functional theory (DFT) and double-hybrid DFT (DHDFT) procedures. We find that, with few exceptions (most notably PW6-B95 and B97-2), the performance of the DFT procedures that give good results for the uncatalyzed reactions deteriorates with the number of water molecules involved in the catalysis. The DHDFT procedures, on the other hand, show excellent performance for both the uncatalyzed and catalyzed reactions. Specifically, almost all of them afford MADs below the "chemical accuracy" threshold, with ROB2-PLYP and B2K-PLYP showing the best overall performance.

Determination of Barrier Heights for Proton Exchange in Small Water, Ammonia, and Hydrogen Fluoride Clusters with G4(MP2)-Type, MPn, and SCS-MPn Procedures-A Caveat.

Calculation of accurate water-water interaction energies is of fundamental importance in computational modeling of many biological and chemical phenomena. We have obtained benchmark barrier heights for proton-exchange reactions and complexation energies in water clusters (H2O)n (n = 1-6) by means of the high-level W1-F12 procedure. We find that lower-cost composite procedures (e.g., G4(MP2) and G4(MP2)-6X), as well as MP2 and SCS-MP2, exhibit surprisingly poor performance for the barrier heights of reactions involving multiple proton exchanges. Moreover, the performance significantly deteriorates with increasing size of the clusters. Similar observations apply to complexation energies in water clusters, and to barrier heights for proton exchange in ammonia and hydrogen fluoride clusters. We propose a modified version of G4(MP2)-6X (denoted G4(MP2)-6X+) that includes sp- and d-diffuse functions in the CCSD(T) term, which gives excellent proton-exchange barrier heights at a computational cost only slightly greater than that of standard G4(MP2). G4(MP2)-6X+ also leads to a substantial improvement over G4(MP2) and G4(MP2)-6X for the calculation of electron affinities.

Hydrogen abstraction by chlorine atom from amino acids: remarkable influence of polar effects on regioselectivity.

Quantum chemistry computations have been used to investigate hydrogen-atom abstraction by chlorine atom from protonated and N-acetylated amino acids. The results are consistent with the decreased reactivity at the backbone α-carbon and adjacent side-chain positions that is observed experimentally. The individual effects of NH(3)(+), COOH, and NHAc substituents have been examined and reveal important insights. The NH(3)(+) group in isolation is found to be deactivating at the α-position, while the acetamido group is activating. For the COOH group, polar effects lead to a contrathermodynamic deactivation of the thermodynamically most favorable α-abstraction. In the N-acetylamino acid, the α-position is deactivated by the combined inductive effect of the substituents and the presence of an early transition structure, again overriding the greater thermodynamic stability of the α-centered radical product. Deactivation of the α-, ß-, and γ-positions results in a peculiar stability for amino acids and peptides and their derivatives with respect to radical degradation.

Effect of substituents on the strength of N-X (X = H, F, and Cl) bond dissociation energies: a high-level quantum chemical study.

The effect of substituents on the strength of N-X (X = H, F, and Cl) bonds has been investigated using the high-level W2w thermochemical protocol. The substituents have been selected to be representative of the key functional groups that are likely to be of biological, synthetic, or industrial importance for these systems. We interpreted the effects through the calculation of relative N-X bond dissociation energies (BDE) or radical stabilization energies (RSE(NX)). The BDE and RSE(NX) values depend on stabilizing/destabilizing effects in both the reactant molecule and the product radical of the dissociation reactions. To assist us in the analysis of the substituent effects, a number of additional thermochemical quantities have been introduced, including molecule stabilization energies (MSE(NX)). We find that the RSE(NH) values are (a) increased by electron-donating alkyl substituents or the vinyl substituent, (b) increased in imines, and (c) decreased by electron-withdrawing substituents such as CF(3) and carbonyl moieties or through protonation. A different picture emerges when considering the RSE(NF) and RSE(NCl) values because of the electronegativities of the halogen atoms. The RSE(NX)s differ from the RSE(NH) values by an amount related to the stabilization of the N-halogenated molecules and given by MSE(NX). We find that substituents that stabilize/destabilize the radicals also tend to stabilize/destabilize the N-halogenated molecules. As a result, N-F- and N-Cl-containing molecules that include alkyl substituents or correspond to imines are generally associated with RSE(NF) and RSE(NCl) values that are less positive or more negative than the corresponding RSE(NH). In contrast, N-F- and N-Cl-containing molecules that include electron-withdrawing substituents or are protonated are generally associated with RSE(NF) and RSE(NCl) values that are more positive or less negative than the corresponding RSE(NH).

Model for the exceptional reactivity of peroxiredoxins 2 and 3 with hydrogen peroxide: a kinetic and computational study.

Peroxiredoxins (Prx) are thiol peroxidases that exhibit exceptionally high reactivity toward peroxides, but the chemical basis for this is not well understood. We present strong experimental evidence that two highly conserved arginine residues play a vital role in this activity of human Prx2 and Prx3. Point mutation of either ArgI or ArgII (in Prx3 Arg-123 and Arg-146, which are ∼3-4 Šor ∼6-7 Šaway from the active site peroxidative cysteine (C(p)), respectively) in each case resulted in a 5 orders of magnitude loss in reactivity. A further 2 orders of magnitude decrease in the second-order rate constant was observed for the double arginine mutants of both isoforms, suggesting a cooperative function for these residues. Detailed ab initio theoretical calculations carried out with the high level G4 procedure suggest strong catalytic effects of H-bond-donating functional groups to the C(p) sulfur and the reactive and leaving oxygens of the peroxide in a cooperative manner. Using a guanidinium cation in the calculations to mimic the functional group of arginine, we were able to locate two transition structures that indicate rate enhancements consistent with our experimentally observed rate constants. Our results provide strong evidence for a vital role of ArgI in activating the peroxide that also involves H-bonding to ArgII. This mechanism could explain the exceptional reactivity of peroxiredoxins toward H(2)O(2) and may have wider implications for protein thiol reactivity toward peroxides.

One-electron reduction of N-chlorinated and N-brominated species is a source of radicals and bromine atom formation.

Hypochlorous (HOCl) and hypobromous (HOBr) acids are strong bactericidal oxidants that are generated by the human immune system but are implicated in the development of many human inflammatory diseases (e.g., atherosclerosis, asthma). These oxidants react readily with sulfur- and nitrogen-containing nucleophiles, with the latter generating N-halogenated species (e.g., chloramines/bromamines (RR'NX; X = Cl, Br)) as initial products. Redox-active metal ions and superoxide radicals (O(2)(•-)) can reduce N-halogenated species to nitrogen- and carbon-centered radicals. N-Halogenated species and O(2)(•-) are generated simultaneously at sites of inflammation, but the significance of their interactions remains unclear. In the present study, rate constants for the reduction of N-halogenated amines, amides, and imides to model potential biological substrates have been determined. Hydrated electrons reduce these species with k(2) > 10(9) M(-1) s(-1), whereas O(2)(•-) reduced only N-halogenated imides with complex kinetics indicative of chain reactions. For N-bromoimides, heterolytic cleavage of the N-Br bond yielded bromine atoms (Br(•)), whereas for other substrates, N-centered radicals and Cl(-)/Br(-) were produced. High-level quantum chemical procedures have been used to calculate gas-phase electron affinities and aqueous solution reduction potentials. The effects of substituents on the electron affinities of aminyl, amidyl, and imidyl radicals are rationalized on the basis of differential effects on the stabilities of the radicals and anions. The calculated reduction potentials are consistent with the experimental observations, with Br(•) production predicted for N-bromosuccinimide, while halide ion formation is predicted in all other cases. These data suggest that interaction of N-halogenated species with O(2)(•-) may produce deleterious N-centered radicals and Br(•).

Ab initio investigation of the fragmentation of 5,5-diamino-substituted 1,4,2-oxathiazoles.

The mechanism for the fragmentation of 5,5-diamino-1,4,2-oxathiazole derivatives has been studied at the CCSD(T)/6-311+G(3df,2p)//MP2/6-31+G(2df,p) level of theory. The calculations suggest that the fragmentation occurs via a stepwise process involving the formation of polar intermediates that lie in shallow potential wells. We find a large thermodynamic driving force for fragmentation, which together with a weakening of the C-S bond through electron donation by the amino substituents provides the impetus for a low-barrier fragmentation.