One-electron oxidation of a hydrogen-bonded phenol occurs by concerted proton-coupled electron transfer

The hydrogen-bonded phenol 2-(aminodiphenylmethyl)-4,6-di-tert-butylphenol (HOAr-NH2) was prepared and oxidized in MeCN by a series of one-electron oxidants. The product is the phenoxyl radical in which the phenolic proton has transferred to the amine, *OAr-NH3+. The reaction of HOAr-NH2 and tris(p-tolyl)aminium ([N(tol)3]*+) to give *OAr-NH3+ + N(tol)3 has Keq = 2.0 +/- 0.5, follows second-order kinetics with k = (1.1 +/- 0.2) x 105 M-1 s-1 (DeltaG = 11 kcal mol-1), and has a primary isotope effect kH/kD = 2.4 +/- 0.4. Oxidation of HOAr-NH2 with [N(C6H4Br)3]*+ is faster, with k congruent with 4 x 107 M-1 s-1. The isotope effect, thermochemical arguments, and the dependence of the rate on driving force (DeltaDeltaG/DeltaDeltaG degrees = 0.53) all indicate that electron transfer from HOAr-NH2 must occur concerted with intramolecular proton transfer from the phenol to the amine (proton-coupled electron transfer, PCET). The data rule out stepwise paths that involve initial electron transfer to form the phenol radical cation *+HOAr-NH2 or that involve initial proton transfer to give the zwitterion -OAr-NH3+. The dependence of the electron-transfer rate constants on driving force can be fit with the adiabatic Marcus equation, yielding a large intrinsic barrier: lambda = 34 kcal mol-1 for reactions of HOAr-NH2 with NAr3*+.     

High affinity, paralog-specific recognition of the Mena EVH1 domain by a miniature protein

Many protein domains involved in cell signaling contain or interact with proline-rich sequences, and the design of molecules that perturb signaling pathways represents a foremost goal of chemical biology. Previously we described a protein design strategy in which the well-folded alpha-helix in avian pancreatic polypeptide (aPP) presents short alpha-helical recognition epitopes. The miniature proteins designed in this way recognize even shallow protein clefts with high affinity and specificity. Here we show that the well-folded type-II polyproline helix in aPP can present the short PPII-helical recognition epitope within the ActA protein of Listeria monocytogenes. Like miniature proteins that use an alpha-helix for protein recognition, the miniature protein designed in this way displays high affinity for a natural ActA target, the EVH1 domain Mena1-112, and achieves the elusive goal of paralog specificity, discriminating well between EVH1 domains Mena1-112, VASP1-115, and Evl1-112. Most importantly, the miniature protein competed with ActA in Xenopus laevis egg cytoplasmic extracts, decreasing actin-dependent motility of L. monocytogenes and causing extreme speed variations and discontinuous tail formation. Our results suggest that miniature proteins based on aPP may represent an excellent framework for the design of ligands that differentiate the roles of EVH1 domains in vitro and in vivo.     

Selective anion encapsulation by a metalated cryptophane with a pi-acidic interior

Metalation of the exterior arene faces of the molecular capsule (+/-)-cryptophane-E with [Cp*Ru]+ moieties results in a pi-acidic cavity capable of encapsulating anions. The [CF3SO3]- and [SbF6]- salts have been crystallographically characterized and demonstrate the encapsulation of these anions by the metalated cryptophane. 1H and 19F NMR spectroscopy establish the binding of anions in NO2CD3 solution and reveal the relative affinity of the cavity for different anions (KX-/KOTf-): [BF4]- approximately 0, [PF6]- = 1.18, [CF3SO3]- identical with 1, [SbF6]- = 0.30. Variable temperature rate studies reveal the activation barrier for triflate encapsulation to be DeltaG298K = 18.0(8) kcal.mol-1 (DeltaH = 17.5(4) kcal.mol-1 and DeltaS = 2(1) cal.mol-1.K-1).     

Miniature homeodomains: high specificity without an N-terminal arm

Recently, we described a strategy for the design of miniature proteins that bind DNA and protein surfaces with high affinity and selectivity. This strategy involves identifying the functional epitope required for macromolecular recognition by a natural protein and presenting it on a small, stable protein scaffold. In previous work, high-affinity DNA recognition was achieved only when the miniature protein contained the complete functional epitope. Here we report a miniature homeodomain that recognizes its 6-bp target site in the nanomolar concentration range at 25 degrees C, despite the absence of DNA contact residues located along the homeodomain N-terminal arm. We conclude that miniature proteins can achieve high affinity and selectivity for DNA by design even when the functional epitope is incomplete by using pre-organization to effectively compensate for lost protein-DNA contacts. In this case it has been possible to miniaturize both the recognition surface and the structural framework of a globular protein fold.     

Molecular recognition of protein surfaces: high affinity ligands for the CBP KIX domain

Potent and specific inhibitors of protein.protein interactions have potential both as therapeutic compounds and biological tools, yet discovery of such molecules remains a challenge. Our laboratory has recently described a strategy, called protein grafting, for the identification of miniature proteins that bind protein surfaces with high affinity and specificity and inhibit the formation of protein.protein complexes. In protein grafting, those residues that comprise a functional alpha-helical binding epitope are stabilized on the solvent-exposed alpha-helical face of the small yet stable protein avian pancreatic polypeptide (aPP). Here we use protein grafting in combination with molecular evolution by phage display to identify phosphorylated peptide ligands that recognize the shallow surface of CBP KIX with high nanomolar to low micromolar affinity. Furthermore, we show that grafting of the CBP KIX-binding epitope of CREB KID onto the aPP scaffold yields molecules capable of high affinity recognition of CBP KIX even in the absence of phosphorylation. Importantly, both classes of designed ligands exhibit high specificity for the target CBP KIX domain over carbonic anhydrase and calmodulin, two unrelated proteins that bind hydrophobic or alpha-helical molecules that might be encountered in vivo.     

Cycloalkane and cycloalkene C-H bond dissociation energies

Both C-H bond dissociation energies for cyclobutene were measured in the gas phase (BDE = 91.2 +/- 2.3 (allyl) and 112.5 +/- 2.5 (vinyl) kcal mol-1) via a thermodynamic cycle by carrying out proton affinity and electron-binding energy measurements on 1- and 3-cyclobutenyl anions. The results were compared to those for an acyclic model compound, cis-2-butene, and provide the needed information to experimentally establish the heat of formation of cyclobutadiene. Chemically accurate G3 and W1 calculations also were carried out on cycloalkanes, cycloalkenes, and selected reference compounds. It appears that commonly cited bond energies for cyclopropane, cyclobutane, and cyclohexane are 3 to 4 kcal mol-1 too small and their pi bond strengths, as given by BDE1 - BDE2, are in error by up to 8 kcal mol-1.     

Discovery of novel inhibitors of anti-apoptotic Bcl-2 proteins derived from Bim BH3 domain

The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2 family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5 (K_D=9.48 nmol/L for Bcl-2) and SM-6 (K_D=0.08 nmol/L for Bcl-x_L), which exhibited improved binding affinity compared with the lead Bim (K_D=16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-x_L, respectively). These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.     

Ab initio conformational space study of model compounds of O-glycosides of serine diamide

Relative stabilities of rotamers of the N-acetyl-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyl)-L-seryl-N'-methyl amide (1) and eleven analogous molecules containing beta-galactose, alpha- and beta-mannose, alpha- and beta-glucose, and L-threonine were calculated to learn whether they could explain the natural preference for 1 in linkages between the carbohydrate and protein in glycoproteins. The lowest energy rotamers of four O-glycoside models of serine diamide were identified with a Monte Carlo search coupled with molecular mechanics (MM2*). These rotamers were further optimized with an ab initio level of theory (HF/6-31G(d)). Subsequently, B3LYP/6-31 + G(d) single point energies were calculated for the most stable HF structures. The most favorable interactions are present in 1 and its glucose analogue. The monosaccharide for the carbohydrate antenna is anchored to the serine residue with an AcNH...O=C-NHMe hydrogen bond in the most stable rotamers. The mannose analogue and the beta-anomers are considerably less stable according to the MM2* and especially to the ab inito energy values. The three analogues have HF/6-31 G(d) energies which are 4-6 kcal mol-1 higher; the single point B3LYP/6-31 + G(d)//HF/6-31 G(d) calculations yield preferences of 3-5 kcal mol-1 for 1. The most stable L-threonine analogues show a behaviour very similarly to the corresponding serine analogues. The ZPE and thermal correction components of the calculated delta H298 and delta G298 values are relatively small (< 0.4 kcal mol-1). However, the T delta S298 term can be as large as 2.6 kcal mol-1. The entropy terms stabilize the alpha-anomers relative to beta-anomers, and ManNAc relative to GalNAc. The largest stabilization effect is observed for one of the rotamers of the alpha-anomer of ManNAc.     

Thermochemistry of methyl and ethyl nitro, RNO2, and nitrite, RONO, organic compounds

Computational quantum theory is employed to determine the thermochemical properties of n-alkyl nitro and nitrite compounds: methyl and ethyl nitrites, CH3ONO and C2H5ONO, plus nitromethane and nitroethane, CH3NO2 and C2H5NO2, at 298.15 K using multilevel G3, CBS-QB3, and CBS-APNO composite methods employing both atomization and isodesmic reaction analysis. Structures and enthalpies of the corresponding aci-tautomers are also determined. The enthalpies of formation for the most stable conformers of methyl and ethyl nitrites at 298 K are determined to be -15.64 +/- 0.10 kcal mol-1 (-65.44 +/- 0.42 kJ mol-1) and -23.58 +/- 0.12 kcal mol-1 (-98.32 +/- 0.58 kJ mol-1), respectively. DeltafHo(298 K) of nitroalkanes are correspondingly evaluated at -17.67 +/- 0.27 kcal mol-1 (-74.1 +/- 1.12 kJ mol-1) and -25.06 +/- 0.07 kcal mol-1 (-121.2 +/- 0.29 kJ mol-1) for CH3NO2 and C2H5NO2. Enthalpies of formation for the aci-tautomers are calculated as -3.45 +/- 0.44 kcal mol-1 (-14.43 +/- 0.11 kJ mol-1) for aci-nitromethane and -14.25 +/- 0.44 kcal mol-1 (-59.95 +/- 1.84 kJ mol-1) for the aci-nitroethane isomers, respectively. Data are evaluated against experimental and computational values in the literature with recommendations. A set of thermal correction parameters to atomic (H, C, N, O) enthalpies at 0 K is developed, to enable a direct calculation of species enthalpy of formation at 298.15 K, using atomization reaction and computation outputs.     

A free energy calculation study of the effect of H-->F substitution on binding affinity in ligand-antibody interactions

Changes in binding affinity to catalytic antibody 6D9 of chloramphenicol phosphonate derivatives (CPDs) containing H or F were investigated by performing free energy calculations based on molecular dynamics simulations. We calculated the binding free energy, enthalpy, and entropy changes (DeltaDeltaG, DeltaDeltaH, and -TDeltaDeltaS) attributable to H-->F substitution by comparing results for CPDs containing a trifluoroacetylamino group (CPD-F) or an acetylamino group (CPD-H). The calculated DeltaDeltaG, DeltaDeltaH, and -TDeltaDeltaS values were -2.9, -6.3, and 3.5 kcal mol(-1) and close to experimental values observed for a series of similar ligands, chloramphenicol phosphonates with F and H (-1.4, -3.5, and 2.1 kcal mol(-1)). Therefore, CPD-F binds more strongly to 6D9 than does CPD-H. To clarify the origin of the large difference in DeltaDeltaG, we apportioned the calculated values of DeltaDeltaG and DeltaG for the associated and dissociated states into contributions from various atomic interactions. We found that the H-->F substitution increased the binding affinity mainly by decreasing the hydration free energy and not by increasing favorable interactions with the antibody. The decreased hydration free energy of the ligand was mainly due to unfavorable coulombic interactions between the trifluoroacetylamino group and solvent waters, which increased the free energy of the dissociated state (by about 3.7 kcal mol(-1)). Also, the trifluoroacetylamino group slightly increased the free energy level of the associated state (about 0.8 kcal mol(-1)) because favorable van der Waals interactions compensated for unfavorable coulombic interactions with antibody atoms. In addition, the enthalpy and entropy changes, DeltaDeltaH and -TDeltaDeltaS (computationally -6.3 and 3.5 kcal mol(-1)), originated mainly from a decrease in hydration free energy in the dissociated state. The CPD-F and CPD-H ligands had substantially different structures in the dissociated and complexed states.     

Large ground-state entropy changes for hydrogen atom transfer reactions of iron complexes

Reported herein are the hydrogen atom transfer (HAT) reactions of two closely related dicationic iron tris(alpha-diimine) complexes. FeII(H2bip) (iron(II) tris[2,2'-bi-1,4,5,6-tetrahydropyrimidine]diperchlorate) and FeII(H2bim) (iron(II) tris[2,2'-bi-2-imidazoline]diperchlorate) both transfer H* to TEMPO (2,2,6,6-tetramethyl-1-piperidinoxyl) to yield the hydroxylamine, TEMPO-H, and the respective deprotonated iron(III) species, FeIII(Hbip) or FeIII(Hbim). The ground-state thermodynamic parameters in MeCN were determined for both systems using both static and kinetic measurements. For FeII(H2bip) + TEMPO, DeltaG degrees = -0.3 +/- 0.2 kcal mol-1, DeltaH degrees = -9.4 +/- 0.6 kcal mol-1, and DeltaS degrees = -30 +/- 2 cal mol-1 K-1. For FeII(H2bim) + TEMPO, DeltaG degrees = 5.0 +/- 0.2 kcal mol-1, DeltaH degrees = -4.1 +/- 0.9 kcal mol-1, and DeltaS degrees = -30 +/- 3 cal mol-1 K-1. The large entropy changes for these reactions, |TDeltaS degrees | = 9 kcal mol-1 at 298 K, are exceptions to the traditional assumption that DeltaS degrees approximately 0 for simple HAT reactions. Various studies indicate that hydrogen bonding, solvent effects, ion pairing, and iron spin equilibria do not make major contributions to the observed DeltaS degrees HAT. Instead, this effect arises primarily from changes in vibrational entropy upon oxidation of the iron center. Measurement of the electron-transfer half-reaction entropy, |DeltaS degrees Fe(H2bim)/ET| = 29 +/- 3 cal mol-1 K-1, is consistent with a vibrational origin. This conclusion is supported by UHF/6-31G* calculations on the simplified reaction [FeII(H2N=CHCH=NH2)2(H2bim)]2+...ONH2 left arrow over right arrow [FeII(H2N=CHCH=NH2)2(Hbim)]2+...HONH2. The discovery that DeltaS degrees HAT can deviate significantly from zero has important implications on the study of HAT and proton-coupled electron-transfer (PCET) reactions. For instance, these results indicate that free energies, rather than enthalpies, should be used to estimate the driving force for HAT when transition-metal centers are involved.     

Reactivities of methylenetriangulanes and spirocyclopropanated bicyclopropylidenes toward bromine. Relative stabilities of spirocyclopropanated versus methyl-substituted bromonium ions

The bromine additions to methylenecyclopropane (1), bicyclopropylidene (2), and spirocyclopropanated methylenecyclopropanes and bicyclopropylidenes 3-6 in methanol at 25 degrees C proceed essentially with the same rate as those to the corresponding oligomethyl-substituted ethylenes. An increasing number of spiroannelated three-membered rings enhances the rate of bromination and stabilizes the intermediate cyclopropyl bromonium cations against ring opening in the course of bromine addition. Calculations at the B3LYP/6-311G(d,p) level show that unsymmetrical bromonium ions are the intermediates, and that they are stabilized by the spiroannelation with cyclopropane rings. The bromonium ion derived from 1 is less stable by 6.3 kcal mol-1 than that from isobutene. One or two spirocyclopropane rings as in 3 and 4 stabilize the corresponding bromonium ion by 9.6 and 16.4 kcal mol-1, respectively, while one or two alpha-cyclopropyl substituents as in ethenylcyclopropane (7) and 1,1-dicyclopropylethene (8) stabilize the corresponding bromonium ions by 13 and 29 kcal mol-1, respectively. The experimental bromination rates of all the studied alkenes correlate reasonably well (r2 = 0.93) with calculated relative energies of the corresponding bromonium ions. The correlation is even better within the series of methylenecyclopropanes 1, 3, and 4 (r2 = 0.974) and bicyclopropylidenes 2, 5, and 6 (r2 = 0.999). The experimental bromination rates also correlate fairly well with the first ionization energies of the corresponding alkenes 1-12 (with r2 = 0.963) and 13-19 (with r2 = 0.991). The calculated preferred nucleophilic attack of a water molecule at both the C1' and C1 atoms of representative bromonium ions conforms well to the experimentally observed product distribution.     

Remote substituent effects on allylic and benzylic bond dissociation energies. Effects on stabilization of parent molecules and radicals

The effect of remote substituents on bond dissociation energies (BDE) is examined by investigating allylic C-F and C-H BDE, as influenced by Y substituents in trans-YCH=CHCH2-F and trans-YCH=CHCH2-H. Theoretical calculations at the full G3 level model chemistry are reported. The interplay of stabilization energies of the parent molecules (MSE) and of the radicals formed by homolytic bond cleavage (RSE) and their effect on BDE are established. MSE values of allyl fluorides yield an excellent linear free energy relationship with the electron-donating or -withdrawing ability of Y and decrease by 4.2 kcal mol-1 from Y = (CH3)2N to O2N. RSE values do not follow a consistent pattern and are of the order of 1-2 kcal mol-1. A decrease of 4.1 kcal mol-1 is found in BDE[C-F] from Y = CH3O to NC. BDE[YCH=CHCH2-H] generally increases with decreasing electron-donating ability of Y for electron-donating groups and does not follow a consistent pattern with electron-withdrawing groups, the largest change being an increase of 3.6 kcal mol-1 from Y = (CH3)2N to CF3. The G3 results are an indicator of benzylic BDE in p-YC6H4CH2-F and p-YC6H4CH2-H, via the principle of vinylogy, demonstrated by correlating MSE of the allylic compounds with physical properties of their benzylic analogues.     

The structure of arachno-[B6H11]-, at -25 degrees C in (CD3)2O,is resolved via the ab initio/IGLO-GIAO/NMR procedure

The arachno-[B6H11]- solution structure at -25 degrees C was clarified as fluxional compound 2 by applying the ab initio/IGLO/NMR method. The anion 2 can be derived from arachno-B6H12, 1, by the removal of the B2/B3 bridging hydrogen (2). No minimum on the potential energy surface could be found for an asymmetric complex, a, between [B5H8]- and BH3, which had been proposed originally. A Cs-symmetric [mu-(BH3)B5H8]- complex, A, only 3.2 kcal mol-1 higher in energy than 2, is the intermediate in the fluxional rearrangement observed on the NMR time scale. The transition structure [D] connecting 2 (Erel = 0.0) and A (Erel = 3.2) has a relative energy of 9.7 kcal mol-1. The elimination of both a and A as "most stable structure" candidates of arachno-[B6H11]- reinforces the early geometrical bonding systematics for boranes and carboranes.     

Cu^2＋诱导甘氨酸质子迁移机理的理论研究

采用CCSD/6-31＋＋G＊＊//B3LYP/6-31＋＋G＊＊方法研究了Cu2＋诱导甘氨酸质子迁移的机理.优化得到了7个中性配合物和1个两性配合物,其中两性配合物最稳定,结合能为215.93 kcal mol-1.中性构型间通过分子内单键的旋转相互转化,C-N、C-C和C-O键旋转的能垒范围分别为1.62～2.49、0.27～7.80和2.27～16.97 kcal mol-1;中性构型N6经质子迁移变为两性构型,能垒为33.82 kcal mol-1.Cu2＋作用于甘氨酸,使甘氨酸N5原子负电荷减少超过0.5,降低了N5对H6原子的库仑吸引,钝化了共价键B（O3–H6）,动力学上不利于H6质子迁移;但是H6质子迁移后,形成的两性构型Z1却是热力学最稳定体系.     

Bimetallo-radical carbon-hydrogen bond activation of methanol and methane

Carbon-hydrogen bond cleavage reactions of CH3OH and CH4 by a dirhodium(II) diporphyrin complex with a m-xylyl tether (.Rh(m-xylyl)Rh.(1)) are reported. Kinetic-mechanistic studies show that the substrate reactions are bimolecular and occur through the use of two Rh(II) centers in the molecular unit of 1. Second-order rate constants (T = 296 K) for the reactions of 1 with methanol (k(CH3OH) = 1.45 x 10-2 M-1 s-1) and methane (k(CH4) = 0.105 M-1 s-1) show a clear kinetic preference for the methane activation process. The methanol and methane reactions with 1 have large kinetic isotope effects (k(CH3OH)/k(CD3OD) = 9.7 +/- 0.8, k(CH4)/k(CD4) = 10.8 +/- 1.0, T = 296 K), consistent with a rate-limiting step of C-H bond homolysis through a linear transition state. Activation parameters for reaction of 1 with methanol (DeltaH = 15.6 +/- 1.0 kcal mol-1; DeltaS = -14 +/- 5 cal K-1 mol-1) and methane (DeltaH = 9.8 +/- 0.5 kcal mol-1; DeltaS = -30 +/- 3 cal K-1 mol-1) are reported.     

Very large changes in bond length and bond angle in a heavy group 14 element alkyne analogue by modification of a remote ligand substituent

The synthesis and characterization of the compound Me3Si-4-Ar'SnSnAr'-4-SiMe3 (Ar'-4-SiMe3 = C6H2-2,6-(C6H3-2,6-i-Pr2)2-4-SiMe3) shows that it has a Sn-Sn bond length = 3.066(1) A and a Sn-Sn-C bending angle of 99.25(14) degrees . These parameters differ by about 0.4 A and about 26 degrees from those previously reported for the closely related Ar'SnSnAr' (Ar' = C6H3-2,6-(C6H3-2,6-i-Pr2)2). The results show that, in accordance with the theoretical predictions by Nagase and Takagi, very small amounts of energy (ca. 5 kcal mol-1) separate structural isomers of distannynes that have large differences in their bonding parameters.     

Transesterification and amide cis-trans isomerization in Zn and Cd complexes of the chelating amino acid ligand Boc-Asp(Dpa)-OBzl

The amino acid derivative Boc-Asp-OBzl (Boc=N-butyloxycarbonyl; Asp=aspartic acid; Bzl=benzyl) was functionalized by coupling its carboxylate side chain to dipicolylamine. This yielded the tridentate nitrogen donor ligand Boc-Asp(Dpa)-OBzl (-OBzl). The compound -OBzl contains three different carbonyl groups: a tertiary amide linkage between Asp and Dpa, a C-terminal benzyl ester function, and an N-terminal urethane protecting group. NMR spectra were used to compare the reactivity of these moieties. The Boc protecting group gives rise to two isomers, (E, 9%) and (Z, 91%). Coordination of Cd(NO3)2 and Zn(NO3)2 yielded the complexes and. These compounds have significantly reduced barriers to rotation about the tertiary amide C-N bond compared with the free ligand (-OBzl:18.5 kcal mol-1 in CDBr3;: 12.9 kcal mol-1 in (CD3)2CO;: 13.8 kcal mol-1 in (CD3)2CO). Both complexes readily undergo transesterification in methanol or CD3OD. Experimental pseudo-first order rate constants were determined in CD3OD and (CD3)2CO:CD3OD (3:1;). It was found that the zinc complex (k=(2.28+/-0.02)x10(-4) s-1) is significantly more reactive than the cadmium complex (k=(1.41+/-0.03)x10(-6) s-1). In order to study their tertiary amide cis-trans isomerization, the cadmium complex [(-OCH3)Cd(NO3)2] was synthesized, and the zinc complex [(-OCD3)Zn(NO3)2] was generated in situ in (CD3)2CO:CD3OD (3:1). The barriers to rotation were determined (:14.1 kcal mol-1 in CD3OD;: 13.4 kcal mol-1 in (CD3)2CO:CD3OD (3:1)). Our results show that the stronger Lewis-acid zinc(II) is significantly more active than cadmium(II) in the acceleration of the transesterification. This is in marked contrast to the tertiary amide bond rotation which is comparably fast with both metal ions.     

Theoretical study of radical and neutral intermediates of artemisinin decomposition

Four artemisinin reductive decomposition routes A, B1, B2, and B3 with 13 species (QHS, 1/2, 3, 4, 5, 5a, 6, 7, 18, 18a, 19, 20, and 21) were studied at the B3LYP/6-31G** level. Structures of the species were analyzed in terms of geometrical parameters, L?wdin bond orders, partial atomic charges and spin densities, electronic and free energies, and entropy. Searches in the Cambridge Structural Database for high-level quality artemisinin-related structures were also performed. Principal Component and Hierarchical Cluster analyses were performed on selected electronic and structural variables to rationalize relationships between the routes. The A and B1 routes are possibly interconnected. Structural and electronic features of all species show that there are two clusters: A-B1 and B2-B3. The latter cluster is thermodynamically more favorable (DeltaDeltaG is -64 to -88 kcal mol(-1)) than the former (DeltaDeltaG is -58 to -59 kcal mol(-1)), but kinetical preference may be the opposite. Along the artemisinin decomposition routes, especially B2 and B3, larger structural changes including formation of branched structures and CO2 release are related to increased exothermicity of the conversions, weakened attractive oxygen-oxygen interactions, and increased entropy of the formed species. The intermediate 4 definitely belongs to some minor artemisinin decomposition route.     

Pressure dependence of peroxynitrite reactions. Support for a radical mechanism

Activation volumes (delta V++) have been determined for several reactions of peroxynitrite using the stopped-flow technique. Spontaneous decomposition of ONOOH to NO3- in 0.15 M phosphate, pH 4.5, gave delta V++ = 6.0 +/- 0.7 and 14 +/- 1.0 cm3 mol-1 in the presence of 53 microM and 5 mM nitrite ion, respectively. One-electron oxidations of Mo(CN)8(4-) and Fe(CN)6(4-), which are first order in peroxynitrite and zero order in metal complex, gave delta V++ = 10 +/- 1 and 11 +/- 1 cm3 mol-1, respectively, at pH 7.2. The limiting yields of oxidized metal complex were found to decrease from 61 to 30% of the initially added peroxynitrite for Mo(CN)8(3-) and from 78 to 47% for Fe(CN)6(3-) when the pressure was increased from 0.1 to 140 MPa. The bimolecular reaction between CO2 and ONOO- was determined by monitoring the oxidation of Fe(CN)6(4-) by peroxynitrite in bicarbonate-containing 0.15 M phosphate, pH 7.2, for which delta V++ = -22 +/- 4 cm3 mol-1. The Fe(CN)6(3-) yield decreased by approximately 20% upon increasing the pressure from atmospheric to 80 MPa. Oxidation of Ni(cyclam)2+ by peroxynitrite, which is first order in each reactant, was characterized by delta V++ = -7.1 +/- 2 cm3 mol-1, and the thermal activation parameters delta H++ = 4.2 +/- 0.1 kcal mol-1 and delta S++ = -24 +/- 1 cal mol-1 K-1 in 0.15 M phosphate, pH 7.2. These results are discussed within the context of the radical cage hypothesis for peroxynitrite reactivity.