The rate of oxidation of ClO2- by HOCl is first order in each reactant and is general-acid catalyzed. In the initial steps of the proposed mechanism, a steady-state intermediate, HOClOClO-, forms (k1 = 1.6 M-1 s-1) and undergoes general-acid (HA)-catalyzed reactions (k2HA) to generate a metastable intermediate, ClOClO. Values of k2HA/k-1 are 1.6 x 10(4) M-1 (H3O+), 20 M-1 (HOAc), and 8.5 M-1 (H2PO4-). Subsequent competitive reactions of ClOClO with ClO2- (k3) to give 2ClO2 and with OH- (k4OH) and other bases (k5B) to give ClO3- are very rapid. The relative yields of these products give k4OH/k3 = 1.3 x 10(5), k5HPO4/k3 = 0.20, and k5OAc/k3 = 0.06. At low pH and low buffer concentrations, the apparent yield of ClO2, based on 2ClO2 per initial HOCl, reaches 140%. This anomaly is attributed to the induced disproportionation of ClO2- by ClOClO to give ClO3- and additional HOCl. A highly reactive intermediate, ClOCl(O)OClO-, is proposed that can undergo Cl-O bond cleavage to give 2ClO2 + Cl- via one path and ClO3- + 2HOCl via another path. The additional HOCl recycles in the presence of excess ClO2- to give more ClO2. Ab initio calculations show feasible structures for the proposed reaction intermediates. Acetic acid has a second catalytic role through the formation of acetyl hypochlorite, which is much more reactive than HOCl in the transfer of Cl+ to ClO2- to form ClOClO.
A fast screening method for the determination of the dissociation constants (pKa) of acidic, basic, and multivalent compounds was developed by using pressure-assisted capillary electrophoresis (PACE). External air pressure was applied to shorten the analysis time. The separation efficiency decreases as air pressure increases. However, it was found that air pressure does not affect the measurement of electrophoretic mobility and pKa significantly when it is less than 2 psi. The method was evaluated in terms of accuracy, precision, and ruggedness by using a set of 48 compounds with literature pKa values ranging from 2 to 10. The difference between the measured pKa values and literature values is less than 0.2 units. The throughput is approximately 20 compounds per day with a 12-point measurement ranging from pH 2.5 to 11. It was demonstrated that this method is applicable for pKa screening of pharmaceuticals with diverse chemical structures.
Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [ 3 H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26°C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal ⅐ mol Ϫ1 ), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (⌬H O ) and entropy (ϪT⌬S O )contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% ⌬G O ) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.Inhibitors of the serotonin transporter (SERT) have long been in clinical use for treatment of depression and anxiety, predating even the molecular identification of the target (Blakely et al., 1991). As such, SERT is the target of a large number of clinically proven drugs from diverse chemotypes (Fig. 1) that act by blocking transit of 5-hydroytryptamine (serotonin) (5-HT) through the transporter. Many reports describe the equilibrium binding properties of members of this class of drugs with SERT as well as potency for inhibition of 5-HT reuptake (Blakely et al., 1994;Tatsumi et al., 1997;Nemeroff and Owens, 2003;Rothman and Baumann, 2003). Although the three-dimensional structure of SERT has not yet been elucidated, crystal structures have been determined for other members of the 12 transmembrane domain major facilitator superfamily. Of these, the most homologous transporter to SERT is the bacterial leucine transporter LeuT (Yamashita et al., 2005). A three-dimensional model of SERT based on the published crystal structure of LeuT places several key amino acid residues that interact with SERT inhibitors along the proposed substrate permeation path (Ravna et al., 2006a).Recently, crystal structures of LeuT in complex with highaffinity SERT inhibitors wer...
A fast screening method for the determination of the dissociation constants (pKa) of acidic, basic, and multivalent compounds was developed by using pressure-assisted capillary electrophoresis (PACE). External air pressure was applied to shorten the analysis time. The separation efficiency decreases as air pressure increases. However, it was found that air pressure does not affect the measurement of electrophoretic mobility and pKa significantly when it is less than 2 psi. The method was evaluated in terms of accuracy, precision, and ruggedness by using a set of 48 compounds with literature pKa values ranging from 2 to 10. The difference between the measured pKa values and literature values is less than 0.2 units. The throughput is approximately 20 compounds per day with a 12-point measurement ranging from pH 2.5 to 11. It was demonstrated that this method is applicable for pKa screening of pharmaceuticals with diverse chemical structures.
Very rapid oxidations of N2H5+ by Br2, Cl2, and BrCl are measured by stopped-flow and pulsed-accelerated-flow methods in acidic solutions with excess N2H5+. Second-order rate constants (M-1 s-1) at 25.0 degrees C, mu = 1.0 M are 1.49 x 10(7), 1.01 x 10(8), and 5.6 x 10(8) for the reactions with Br2, Cl2, and BrCl, respectively. The reactions are postulated to proceed by nucleophilic reaction of N2H5+ with XY electrophiles (XY = Br2, Cl2, BrCl) to form XN2H4+ with Y- and H+ release in the rate-determining step. In the subsequent reactions, we propose that XN2H4+ eliminates X- and H+ rapidly to form N2H3+ and diazine, N2H2, which is oxidized by a second Br2, Cl2, or BrCl to form N2 in fast steps. The stoichiometries are measured and confirmed to be 1:2 for the Cl2 and BrCl reactions. The relative reactivities for the oxidation of N2H5+ by halogens and interhalogens (BrCl > Cl2 > Br2 > ICl >> IBr >> I2) are used to establish an electrophilicity scale (EXY) for this type of reaction in aqueous solution.
The kinetics of N2H5 + oxidation by ICl and IBr in 0.1−1.0 M [H+] is investigated by following the formation of I2Cl- and I2Br- with excess ICl2 - and IBr2 -, respectively, when total hydrazine is the limiting reactant. Highly acidic solutions are needed to suppress the rates of N2H4 reactions and to avoid hydrolysis of the interhalogens. Protonation constants of N2H5 +, K P2 = [N2H6 2+]/[N2H5 +][H+], measured spectrophotometrically at 25.0 °C with picric acid as an indicator, are 1.61 M-1 (μ = 0.50 M) and 1.72 M-1 (μ = 1.00 M). In the proposed mechanisms, ICl and IBr react by an I+ transfer process to N2H5 + with loss of H+ (k 1) to form a steady-state species, IN2H4 +, that eliminates I- and H+ to give N2H3 + (k 2). Subsequent reactions consume a second interhalogen, as diazine (N2H2) is rapidly oxidized to N2. Rate constants (25.0 °C, μ = 1.00 M) for the ICl/N2H5 + reaction are k 1 = 4.12 × 106 M-1 s-1, k - 1/k 2 = 1.9 M-2 and for the IBr/N2H5 + reaction are k 1 = 7.6 × 104 M-1 s-1, k - 1/k 2 = 28 M-2. The relative rates of oxidation of N2H5 + are ICl ≫ IBr ≫ I2.
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