Di-iron aza diphosphido complexes: mimics for the active site of Fe-only hydrogenase, and effects of changing the coordinating atoms of the bridging ligand in [Fe2[mu-(ECH2)2NR](CO)6

The bis(phosphido)-bridged complex [Fe(2)(mu-PPhH)(2)(CO)(6)] (1) undergoes double deprotonation to give the phosphorus-centered dianionic derivative [Fe(2)(mu-PPh)(2)(CO)(6)](2)(-) (2) which in turn reacts with the tertiary base RN(CH(2)Cl)(2) to give [Fe(2)[(PPhCH(2))(2)NR](CO)(6)] (3) in moderate yield. Treatment of 3 with HBF(4).Et(2)O affords the N-protonated species [Fe(2)[(PPhCH(2))(2)NHR](CO)(6)] BF(4) (4). The structural changes to the heavy atom skeleton of 3 arising from protonation are slight, the most obvious being a ca. 0.03 Alengthening of the N-C bonds.     

Protonation, electrochemical properties and molecular structures of halogen-functionalized diiron azadithiolate complexes related to the active site of iron-only hydrogenases

Diiron complexes [{(micro-SCH2)2NCH2C6H4X}{Fe(CO)2L}2] (L = CO, X = 2-Br, 1; 2-F, 2; 3-Br, 3; L = PMe(3), X = 2-Br, 4) were prepared as biomimetic models of the iron-only hydrogenase active site. The N-protonated species [(NH)]+ClO(4)(-), [(NH)](+)ClO(4)(-) and the micro-hydride diiron complex [4(FeHFe)]+PF(6)(-) were obtained in the presence of proton acids and well characterized. The protonation process of 4 was studied by in-situ IR and NMR spectroscopy, which suggests the formation of the diprotonated species [4(NH)(FeHFe)](2+) in the presence of an excess of proton acid. The molecular structures of 1, [(NH)]+ClO(4)(-), 4 and [4(FeHFe)]+PF(6)(-) were determined by X-ray crystallography. The single-crystal X-ray analysis reveals that an intramolecular H...Br contact (2.82 A) in the crystalline state of [1(NH)]+ClO(4)(-). In the presence of 1-6 equiv of the stronger acid HOTf, complex 1 is readily protonated on the bridged-N atom and can electrochemically catalyze the proton reduction at a relatively mild potential (ca.-1.0 V). Complex 4 is also electrocatalytic active at -1.4 V in the presence of HOTf with formation of the micro-hydride diiron species.     

Infrared multiphoton dissociation spectroscopy study of protonated p-aminobenzoic acid: does electrospray ionization afford the amino- or carboxy-protonated ion?

Infrared multiphoton dissociation spectra of protonated p-aminobenzoic acid generated by electrospray ionization (ESI) from aqueous methanol and acetonitrile solutions were recorded in the gas phase from 2800-4000 cm(-1). The O-protonated ion is more stable than the N-protonated structure in the gas phase, whereas the opposite is true in both solutions. When CH(3)OH/H(2)O was used as the ESI solvent, only the O-protonated ion was observed. In contrast, a 70:30 mixture of the O- and N-protonated species were produced from CH(3)CN/H(2)O. These structural assignments are based on an assortment of experimental data (action spectra, photofragments, photofragmentation kinetics, and H/D exchange) and are fully supported by extensive computations. This work shows that ESI can lead to isomerization and that the ionization site may be varied by changing the solvent from which the substrate is analyzed.     

Reactive N-protonated isocyanate species stabilized by bis(μ-hydroxo)divanadium(IV)-substituted polyoxometalate

O- or N-protonated? The bis(μ-hydroxo)divanadium(IV)-substituted γ-Keggin-type polyoxometalate (see picture, left) (TBA)(4)[γ-SiV(IV)(2)W(10)O(36)(μ-OH)(4)] (TBA = tetra(n-butyl)ammonium) was synthesized and characterized by X-ray crystallography. Its reaction with phenyl isocyanate gave (TBA)(4)[γ-SiV(IV)(2)W(10)O(38)(μ-OH)(2)(PhNHCO)(2)], which contains two N-protonated phenyl isocyanate species and catalyzes the cyclotrimerization of phenyl isocyanate.     

1-Azabicyclo[3.3.1]nonan-2-one: nitrogen versus oxygen protonation

Protonation of typical unstrained amides and lactams is heavily favored at oxygen. In contrast, protonation of the highly distorted lactam 1-azabicyclo[2.2.2]octan-2-one is heavily favored at nitrogen. What structures occupy "crossover boundaries" where N- and O-protonation are nearly equienergetic? Density function theory calculations at the B3LYP/6-31G* level, as well as QCISD(T)/6-31G* calculations, predict that 1-azabicyclo[3.3.1]nonan-2-one favors N-protonation at nitrogen only very slightly (<2.0 kcal/mol; "gas phase") over O-protonation. (1)H and (13)C NMR as well as ultraviolet (UV) studies of this lactam, in its combination with sulfuric acid, confirm predominant protonation at nitrogen. Although the calculations very slightly favor the N-protonated chair-chair conformation, experimental spectra clearly support the N-protonated boat-chair. Broadened resonances in the (13)C NMR spectrum suggest an exchange phenomenon. Variable-temperature studies of the (13)C NMR spectra support dynamic exchange between the major tautomer (N-protonated) and the minor tautomer (O-protonated) in a roughly 4:1 mixture. The findings also support the published prediction that a twisted bridgehead lactam with the nitrogen lone pair (n(N)) as HOMO will protonate at nitrogen.     

Conformers of gaseous protonated glycine

Ab initio geometry optimizations were performed on gaseous protonated glycine using the second-order Møller–Plesset perturbation theory with the 6-31G*, 6-31G**, 6-31+G**, and 6-311+G** basis sets. Eight energy minima and 12 saddle points in the low-energy region of the electronic potential energy surface were characterized. The global minimum was an amino N-protonated conformer containing an ionic H bond between the (SINGLE BOND)NH₃⁺ and O(DOUBLE BOND)C(DIAGONAL BOND)(DIAGONAL BOND) groups. The lowest energy O-protonated conformer was stabilized by a conjugative attraction between the nitrogen lone-pair electrons and the positively charged planar fragment (SINGLE BOND)C(OH)₂⁺. Relative electronic energies of the nine N- and 11 O-protonated species fall in the ranges of 0–10 and 30–40 kcal mol⁻¹. At room temperature the equilibrium distribution contained the most stable N-protonated conformer almost exclusively. Additional subjects for investigation include the effects of basis set and electron correlation on the predicted structures, nonbonded interactions that influence the relative stability of protonated conformers, conformational interconversions based on intrinsic reaction coordinate calculations, and kinetic pathways for protonation and associated changes in Gibbs free energy. The work provides geometric, energetic, and thermodynamic data pertinent to the study of gas-phase ion chemistry of amino acids and peptides. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1862–1876, 1998     

Theoretical study of the acid-promoted hydrolysis of oxazolin-5-one: a microhydration model

The acid-promoted hydrolysis of 2,4,4-trimethyloxazolin-5-one (TMO) is studied employing the density functional theory (B3LYP) method in conjunction with the 6-31++G(d,p) basis set. Two types of reaction mechanism, N-protonated and O-protonated, are considered, involving protonation at the nitrogen and carbonyl oxygen of TMO to activate the C2 and C5 atoms, respectively, in favor of attack by water molecules. In the N-protonated pathway, the nucleophilic water molecule attacks the activated C2 atom, with a proton transfer from the water molecule to the oxygen atom attached to C2 and the fission of the C2-O bond, leading to a cis ring-opening product (N-acyl-alpha-amino isobutyric acid). While, in the O-protonated pathway, the nucleophilic water molecule attacks the activated carbonyl C5 atom, accompanied by a proton transfer from the water molecule toward the nitrogen atom of oxazole ring and the cleavage of C5-O bond; as a result, a corresponding trans product is generated. The water-assisted hydrolysis reactions are also examined together. A local microhydration model, in which an extra water molecule was added to obtain a continuous H-bond network around the reaction centers, was adopted to mimic the system for the two types of reaction processes. In addition, bulk solvent effect is introduced by use of the conductor-like polarizable continuum model (CPCM). Our computational results in kinetics and thermodynamics clearly manifest that the O-protonated pathway with the nucleophilic attack at the carbonyl C5 atom is more favorable than the N-protonated one, in nice agreement with the available experimental conclusion.     

Density functional theory studies of N-protonation of the free base phthalocyanine

The structures and relative energies of twenty-two N-protonated species of the free base phthalocyanine (H₂Pc) have been systematically studied with the density functional theory at the B3LYP/6-31G(d) level of theory. The calculations demonstrated that the N-protonation tends to increase the N–C bonds and the C–N–C angles on the protonation sites. The inner protonation at the isoindole-nitrogen atoms causes significant out-of-plane deformation of the macrocycle, ascribed to the steric hindrance of the central cavity. The relative energies of various protonated species were calculated and compared to deduce the preferred sites for protonation. It was revealed that the outer protonation at the meso-nitrogen atoms is energetically more favorable than the inner protonation at the isoindole-nitrogen atoms. Among the studied twenty-two protonated species, the most stable one is H₆Pc⁴⁺(IS1), for which all the outer meso-nitrogen atoms are protonated. TDDFT calculations have been performed for selected species, and the results were used to analysis the UV–visible spectrum of the concentrated sulfuric acid solution of the free base phthalocyanine.     

Theoretical studies on the mechanism of acid-promoted hydrolysis of N-formylaziridine in comparison with formamide

[reaction: see text] We present an ab initio study of the acid-promoted hydrolysis reaction mechanism of N-formylaziridine in comparison with formamide. Since the rate of amide hydrolysis reactions depends on the formation of the tetrahedral intermediate, we focused our attention mainly on the reactant complex, the tetrahedral intermediate, and the transition state connecting these two stationary points. Geometries were optimized using the density functional theory, and the energetics were refined using ab initio theory including electron correlation. Solvent effects were investigated by using polarizable continuum method calculations. The proton-transfer reaction between the O-protonated and N-protonated amides was investigated. In acidic media, despite that the N-protonated species is more stable than the O-protonated one, it is predicted that both N-protonated and O-protonated pathways compete in the hydrolysis reaction of N-formylaziridine.     

N- vs O-protonation and the transannular substituent interaction in 8-(Dimethylamino)-1-acetonaphthone

Dynamic NMR measurements of 8-(dimethylamino)-1-acetonaphthone 1 in neutral solutions reveal a solvent dependency of the barrier to NMe group interchange similar to that reported for N,N-dimethylacetamide. Titrating 1 with TFA in solvents of varying donicities gives rise to equilibrium mixtures of N-protonated aminoketone 2 and the O-protonated transannular addition product 3, the interconversion rate of which is slow on the NMR time scale at ambient temperature. The preference for O- or N-protonation is medium-dependent, the amount of N-protonated 2 increasing with a decrease in the nucleophilicity of the solvent. The set of equilibria which govern the interconversion of 2 and 3 in the titration mixtures are identified and their equilibrium constants evaluated from the NMR data. X-ray analysis of the crystalline trifluoroacetate salt of O-protonated 3 indicates that the transannular N.CO bond of 3 is formed to an extent of only 80%. The equilibrium distribution of 2 and 3, paired with the tetrafluoroborate anion, depends on both the nucleophilicity and the polarity of the solvent. In PhNO(2) the enthalpy change 3 --> 2 amounts to 2.6 kcal/mol.     

Hydrolysis of N-alkyl sulfamates and the catalytic efficiency of an S-N cleaving sulfamidase

The final step in the degradation of heparin sulfate involves the enzymatic hydrolysis of its 2-sulfamido groups. To evaluate the power of the corresponding sulfamidases as catalysts, we examined the reaction of N-neopentyl sulfamate at elevated temperatures and found it to undergo specific acid catalyzed hydrolysis even at alkaline pH. A rate constant of 10(-16) s(-1) was calculated using the Eyring equation for water attack on the N-protonated species at pH 7, 25 °C. As a model for the pH neutral reaction, a rate constant for hydroxide attack on (CH(3))(3)CCH(2)N(+)H(2)SO(3)(-) at pH 7, 25 °C was calculated to be 10(-19) s(-1). The corresponding rate enhancement (k(cat)/k(non)) produced by the N-sulfamidase of F. heparinum is approximately 10(16)-fold, which is somewhat larger than those generated by most hydrolytic enzymes but considerably smaller than those generated by S-O cleaving sulfatases.     

QM/MM modeling of benzene hydroxylation in human cytochrome P450 2C9

The mechanism of benzene hydroxylation was investigated in the realistic enzyme environment of the human CYP 2C9 by using quantum mechanical/molecular mechanical (QM/MM) calculations of the whole reaction profile using the B3LYP method to describe the QM region. The calculated QM/MM barriers for addition of the active species Compound I to benzene are consistent with experimental rate constants for benzene metabolism in CYP 2E1. In contrast to gas-phase model calculations, our results suggest that competing side-on and face-on geometries of arene addition may both occur in the case of aromatic ring oxidation in cytochrome P450s. QM/MM profiles for three different rearrangement pathways of the initially formed sigma-adduct, leading to formation of epoxide, ketone, and an N-protonated porphyrin species, were calculated. Our results suggest that epoxide and ketone products form with comparable ease in the face-on pathway, whereas epoxide formation is preferred in the side-on pathway. Additionally, rearrangement to the N-protonated porphyrin species was found to be competitive with side-on epoxide formation. This suggests that overall, the competition between formation of epoxide and phenol final products in P450 oxidation of aromatic substrates is quite finely balanced.     

Quantum chemical studies of azoles 4. A novel elimination–addition mechanism of tetrazole and 1,2,4-triazole electrophilic substitution

Thermodynamic parameters of the addition–elimination and elimination–addition electrophilic substitution reactions of 1H-tetrazole and 1,2,4-1H-triazole obtained from DFT B3LYP/ 6-31G(d,p) quantum chemical calculations with proton as model electrophile are compared. According to calculations, the elimination–addition reactions can proceed without preliminary formation of N-protonated azolium salts.     

Decomposition of protonated noradrenaline and normetanephrine assisted by NH2 migration studied by electrospray tandem mass spectrometry and molecular orbital calculations

As part of a research program on neurotransmitters in a biological fluid, the fragmentations characterising catecholamines protonated under electrospray ionisation (ESI) conditions, under low collision energy in a triple-quadrupole mass spectrometer, were investigated. The decompositions of protonated noradrenaline (VH) and normetanephrine (VIH) were studied. Both precursor ions eliminate first H2O at very low collision energy, and the fragmentations of [MH-H2O]+ occur at higher collision energy. The breakdown graphs of [MH-H2O]+ ions, with collision energy varying from 0-40 eV in the laboratory frame, are presented. [VIH-H2O]+ ions lose competitively NH3 and CH3OH. For [VH-H2O]+ the loss of NH3 is dominant while H2O is eliminated at very low abundance at all collision energies. All of these secondary fragmentations are followed at higher collision energies by elimination of CO. These fragmentations are interpreted by means of ab initio calculations up to the B3LYP/6-311+G(2d,2p) level of theory. The elimination of H2O requires first the isomerisation of N-protonated forms, chosen as energy references, to O-protonated forms. The isomerisation barriers are calculated to be lower than 81 kJ/mol above the N-protonated forms. The elimination of NH3 from [MH-H2O]+ requires first the migration, via a cyclisation, of the amine function from the linear chain to the aromatic ring in order to prevent the formation of unstable disubstituted carbocations in the ring. The barriers associated with the loss of NH3 are located 220 and 233 kJ/mol above VH and 219 kJ/mol above VIH. The energy barrier for the loss of ROH is located 236 and 228 kJ/mol above VH and VIH, respectively. The absence of ions corresponding to [VH-2H2O]+ is due to a parasitic mechanism with an activation barrier lower than 236 kJ/mol that leads to a stable species unable to fragment, thus preventing the second loss of H2O. Losses of CO following the secondary fragmentations involve activation barriers higher than 330 kJ/mol.     

Experimental and theoretical prediction of the redox potentials of noradrenaline and its supramolecular complex with glycine

The redox reaction of N-protonated noradrenalin (NA) is a two-proton-two-electron reaction in aqueous solution. NA can be oxidated to N-protonated noradrenalin quinone (NAquinone). The standard electrode potential (E⁰) value of NA/NAquinone couples is obtained experimentally with cyclic voltammetry (CV) and theoretically with two methods at B3LYP/6-311++G(d, p) level. The theoretical E⁰ value of NA/NAquinone couples is in good agreement with experimental ones and close to each other. Glycine (Gly) can form hydrogen bonds with NA in physiological environment. The E⁰ values of NA–Gly/NAquinone–Gly couples are predicted experimentally and theoretically. Hydrogen bond interaction weakens the electrondonation abilities of NA.     

N-PtIV-H/N-H...PtII intramolecular redox equilibrium in a product of H-C(sp2) cleavage and unusual alkane/arene C-H bond selectivity of ([2.1.1]pyridinophane)PtII(CH3)+

T-shaped 14 valence electron (eta2-L)PtMe+ (based on DFT geometry optimization, L = [2.1.1]-2,6-pyridinophane) reacts with benzene to give (eta3-L) PtIV(Ph)2H+ and methane; the latter cation is in thermal equilibrium with the N-protonated PtII tautomer (eta2-L-H)Pt(Ph)2+, and these complexes react with ethane or cyclopentane to produce benzene and (L)PtH(olefin)+.     

On the applicability of resonance forms in pyrimidinic bases. II. QTAIM interpretation of the sequence of protonation affinities

The atomic properties of neutral and protonated forms of uracil and some model compounds, computed from B3LYP/6-31++G//B3LYP/6-31G charge densities with the QTAIM theory, indicate that sigma electron reorganization plays a significant role in the protonation processes. This reorganization is substantially different for O=C-C=C and O=C-C-X (X = N, O) units, involving transfers of electron population between all atoms in the first case but not across the C-X bond in the second unit. O-Protonation is basically favored over the N-protonation because of the lower electron population transferred to the proton. The stability sequence of N-protonated forms can be rationalized in terms of the closer position of the proton, when attached to N3, to regions of larger electron population (carbonyl groups).     

Superelectrophilic protio methyl- and protio dimethylmethyleniminium dications

Electronic structures and energies of superelectrophilic dications derived by protonation of methyl- and dimethylmethyleniminium (R'R' 'C=N+R'R' '; R', R' ' = CH3 or H) ions were calculated at the ab initio MP2/6-311+G level. The calculations identified the N-protonated isopropyleniminium dication 14 as a minimum structure. On the basis of computed energies, deprotonation energies of the global minimum structures were also calculated. The 13C NMR chemical shifts of the intriguing dication 14 were calculated using the GIAO-MP2 method. The 13C NMR chemical shifts of the isoelectronic analogue tert-butyl cation were also calculated at the same level in order to explore the effect of an additional charge in dications 14.     

Isopentenyl diphosphate isomerase catalyzed reactions in D2O: product release limits the rate of this sluggish enzyme-catalyzed reaction

The E. coli isopentenyl diphosphate isomerase (IDI) catalyzed reaction of isopentenyl diphosphate (IPP) in D(2)O gives a 66% yield of dimethylallyl diphosphate labeled with deuterium at the (E)-methyl group (d-DMAPP) and a 34% yield of IPP labeled with 1 mol of deuterium at C-2 (d-IPP). This shows that the release to D(2)O of the initial product of the IDI-catalyzed reaction (d-DMAPP) is slower than its conversion to d-IPP. Product dissociation is therefore rate determining for isomerization of IPP with a rate constant k(dis) ≈ k(cat) = 0.08 s(-1). The data provide an estimated rate constant of k(as) = 6 × 10(3) M(-1) s(-1) for binding of DMAPP to E. coli IDI that is similar to rate constants determined for the binding of N-protonated 2-amino ethyl diphosphate intermediate analogs to IDI from yeast [Reardon, J. E.; Abeles, R. H. Biochemistry1986, 25, 5609-5616]. We propose that ligand binding to IDI is relatively slow because there is a significant kinetic barrier to reorganization of the initial encounter complex between enzyme, substrate, and an essential Mg(2+) to form the Michaelis complex where the metal cation bridges the protein and the substrate diphosphate group.     

Two new "onium" fluorosilicates, the products of interaction of fluorosilicic acid with 12-membered macrocycles: structures and spectroscopic properties

Two novel compounds, (L(1)H)(2)[SiF(6)] x 2H(2)O (1) and (L(2)H)(2)[SiF(5)(H(2)O)](2) x 3H(2)O (2), resulting from the reactions of H(2)SiF(6) with 4'-aminobenzo-12-crown-4 (L(1)) and monoaza-12-crown-4 (L(2)), respectively, were studied by X-ray diffraction and characterised by IR and (19)F NMR spectroscopic methods. Both complexes have ionic structures due to the proton transfer from the fluorosilicic acid to the primary amine group in L(1) and secondary amine group incorporated into the macrocycle L(2). The structure of 1 is composed of [SiF(6)](2-) centrosymmetric anions, N-protonated cations (L(1)H)(+), and two water molecules, all components being bound in the layer through a system of NH[...]F, NH[...]O and OH[...]F hydrogen bonds. The [SiF(6)](2-) anions and water molecules are assembled into inorganic negatively-charged layers via OH[dot dot dot]F hydrogen bonds. The structure of 2 is a rare example of stabilisation of the complex anion [SiF(5)(H(2)O)](-), the labile product of hydrolytic transformations of the [SiF(6)](2-) anion in an aqueous solution. The components of 2, i.e., [SiF(5)(H(2)O)](-), (L(2)H)(+), and water molecules, are linked by a system of NH[...]F, NH[...]O, OH[...]F, OH[dot dot dot]O hydrogen bonds. In a way similar to 1, the [SiF(5)(H(2)O)](-) anions and water molecules in 2 are combined into an inorganic negatively-charged layer through OH[...]F and OH[...]O interactions.