Undergo Ligand Exchange Reactions Research Articles

Isomorphic substitution behavior of Pt on synthetic vernadite (δ-MnO2):A model reaction to elucidate the mechanism of Pt enrichment in marine ferromanganese crust

Marine ferromanganese crusts are considered to be the potential Pt deposits, and recent studies report a strong association between Pt and vernadite in these crusts. However, there are still uncertainties regarding the molecular processes involved in the enrichment of Pt by vernadite. This study investigates the adsorption behavior and molecular-scale immobilization mechanisms of Pt at water/vernadite interfaces through a combination of batch adsorption and desorption experiments, X-ray absorption fine structure (XAFS) analyses, and atomic resolution chemical imaging. Our findings suggest that the Pt enrichment on vernadite is attributed to an isomorphic substitution of Mn by Pt. The extended X-ray absorption fine structure (EXAFS) analysis reveals that Pt undergoes ligand exchange reactions during the enrichment process, and provides a comprehensive explanation of how Pt penetrates into the vernadite structure starting from the surface. Scanning transmission electron microscopy high-angle annular dark field (STEM-HAADF) observations visually confirm the infiltration of Pt atoms into the crystal structure of vernadite. Additionally, we demonstrate that the Pt enrichment in vernadite is a multi-stage chemical process. X-ray absorption near edge structure (XANES) analysis shows that Pt is initially rapidly adsorbed onto the surface of vernadite and then slowly oxidized. Our study provides a detailed understanding of the molecular-scale mechanisms involved in the adsorption of Pt onto vernadite and its subsequent structural incorporation. This knowledge is valuable for gaining insights into the Pt enrichment in marine ferromanganese crusts.

Stabilization of propene molybdenum and tungsten half-sandwich complexes by intramolecular coordination of a thioether function.

This study reports the stabilizing effect of an intramolecularly coordinated thioether function in propene complexes of the general formula [{η5:κS-C5H4(CH2)2SR}M(CO)2(η2-C2H3Me)][BF4] (M = Mo, W; R = Et, Ph). They are formed by protonation of allyl analogues [{η5-C5H4(CH2)2SR}M(CO)2(η3-C3H5)] by tetrafluoroboric acid in non-coordinating solvents. In contrast to analogues with unsubstituted Cp ligands, these propene complexes are isolable in a pure form and characterized by NMR spectroscopy. The molybdenum compounds are stable at low temperature and the propene ligand can easily be exchanged by thioethers or acetonitrile. Several representatives of the reaction products were characterized by X-ray structure analysis. The stabilization effect in tungsten complexes [{η5:κS-C5H4(CH2)2SR}W(CO)2(η2-C2H3Me)][BF4] (R = Et, Ph) was unusually high. The compounds are long-term stable at room temperature and do not undergo ligand exchange reactions even with strong chelators such as 1,10-phenanthroline. The molecular structure of the tungsten propene complex was confirmed by X-ray diffraction analysis on a single crystal.

Chirality induction in platinum-containing polyaryleneethynylenes by exchange from achiral phosphine ligands to P-chiral phosphine ligands

This study deals with chirality induction to the main chain of platinum (Pt)-containing aryleneethynylene polymers by ligand exchange reactions. The optically inactive polymers containing –(–CC–trans-Pt(PPh3)2–CC–)– moieties in the main chain undergo ligand exchange reactions with P-chiral diphosphines, (R,R)-BenzP* and (R,R)-QuinoxP* to give optically active polymers containing –(–CC–cis-Pt(P-chiral diphosphine)–CC–)– moieties. The ligand-exchanged polymers exhibit CD signals based on the conjugated main chain, indicating chirality induction to the main chain by the P-chiral ligands. The QuinoxP*-ligated polymers emit photoluminescence likely based on the transition from the QuinoxP* moieties. Quantum mechanical calculations predict reasonable CD, UV–vis absorption and photoluminescence spectra.

An all-in-one approach for synthesis and functionalization of nano colloidal gold with acetylacetone

Controllable synthesis, proper dispersion, and feasible functionalization are crucial requirements for the application of nanomaterials in many scenarios. Here, we report an all-in-one approach for the synthesis and functionalization of gold nanoparticles (AuNPs) with the simplest β-diketone, acetylacetone (AcAc). With this approach, the particle size of the resultant AuNPs was tunable by simply adjusting the light intensity or AcAc dosage. Moreover, owing to the capping role of AcAc, the resultant AuNPs could be stably dispersed in water for a year without obvious change in morphology and photochemical property. Formation of ligand to metal charge transfer complexes was found to play an important role in the redox conversion of Au with AcAc. Meanwhile, the moderate complexation ability enables the surface AcAc on the AuNPs to undergo ligand exchange reactions (LER). With the aid of Ag+, the AuNPs underwent LER with glutathione and exhibited enhanced photoluminescence (PL) with a maximum of 22-fold increase in PL intensity. The PL response was linear to the concentration of glutathione in the range of 0–500 μM. Such a LER makes the obtained AuNPs being good imaging probes. To the best of our knowledge, this is the first work on illustrating the roles of AcAc as a multifunctional ligand in fabrication of NPs, which sheds new light on the surface modulation in synthesis of nanomaterials.

Associative Ligand Exchange and Substrate Activation Reactions by a Zero-Valent Cobalt Tetraisocyanide Complex

Tetraisocyanide complex Co(CNArMes2)4 (ArMes2 = 2,6-(2,4,6-Me3C6H2)2C6H3) serves as a crystallographically characterized, thermally stable isocyano analogue of the reactive binary carbonyl Co(CO)4. The enhanced stability of Co(CNArMes2)4 allows for a systematic investigation of its reactivity profile in an operationally convenient manner, which is not possible for transient Co(CO)4. Zero-valent Co(CNArMes2)4 undergoes ligand exchange reactions with a variety of 2e– donor, L-type ligands, including triphenylphosphine, tert-butylethylene, and phenylacetylene. Kinetic studies of ligand substitution of Co(CNArMes2)4 with phenylacetylene using UV–vis spectroscopy indicates an associative reaction mechanism. This is consistent with the mechanisms proposed for other isolable 17e– transition-metal carbonyls but contrasts with studies proposing zero-valent CoL4 complexes to react via dissociative reaction pathways. Zero-valent Co(CNArMes2)4 also reacts with elemental phosphorus and sulfur and with diphenyl disulfi...

Establishing the Coordination Chemistry of Antimony(V) Cations: Systematic Assessment of Ph4 Sb(OTf) and Ph3 Sb(OTf)2 as Lewis Acceptors.

The coordination chemistry of the stiboranes Ph4 Sb(OTf) (1 a, OTf = OSO2 CF3 ) and Ph3 Sb(OTf)2 (3) with Lewis bases has been investigated. The significant steric encumbrance of the Sb center in 1 a precludes interaction with most ligands, but the relatively low steric demands of 4-methylpyridine-N-oxide (OPyrMe) and OPMe3 enabled the characterization of [Ph4 Sb(OPyrMe)][OTf] (2 a) and [Ph4 Sb(OPMe3 )][OTf] (2 b), rare examples of structurally characterized complexes of stibonium acceptors. In contrast, 3 was found to engage a variety of Lewis bases, forming stable isolable complexes of the form [Ph3 Sb(donor)2 ][OTf]2 [donor=OPMe3 (6 a), OPCy3 (6 b, Cy=cyclohexyl), OPPh3 (6 c), OPyrMe (6 d)], [Ph3 Sb(dmap)2 (OTf)][OTf] (6 e, dmap=4-(dimethylamino)pyridine) and [Ph3 Sb(donor)(OTf)][OTf] [donor=1,10-phenanthroline (7 a) or 2,2'-bipy (7 b, bipy=bipyridine)]. These compounds exhibit significant structural diversity in the solid-state, and undergo ligand exchange reactions in line with their assignment as coordination complexes. Compound 3 did not form stable complexes with phosphine donors, with reactions instead leading to redox processes yielding SbPh3 and products of phosphine oxidation.

Tri(pyridylmethyl)phosphine: The Elusive Congener of TPA Shows Surprisingly Different Coordination Behavior

Tri(pyridylmethyl)phosphine (TPPh), the remarkably elusive congener of tri(pyridylmethyl)amine (TPA), has been prepared, as well as the relative tri(N-methyl-pyridylamino)phosphine (TPAMP). The coordination properties of these new ligands have been evaluated for chromium(III), iron(II), and ruthenium(II) complexes and compared with the related TPA complexes. In all cases, a different coordination behavior has been observed whereby TPPh and TPAMP always act as tridentate ligands. A chromium(III) complex [Cr(TPPh)Cl3] has been prepared, which has shown low ethylene oligomerization activity. Octahedral low spin iron(II) complexes [Fe(TPPh)2](2+) and [Fe(TPAMP)2](2+) were obtained with two ligands bound to the metal center. Ruthenium(II) chloro complexes of TPA and TPPh undergo ligand exchange reactions in acetonitrile, and the ruthenium(II) complex [Ru(MeCN)2(TPA)](2+) can be oxidized by m-CPBA in acetonitrile to give a transient ruthenium(IV) oxo complex [Ru(O)(MeCN)(TPA)](2+). Attempts to generate high valent ruthenium(IV) oxo TPPh or TPAMP complexes could not be achieved, probably due to insufficient stabilization by these strong field ligands.

Interactions of the aquated forms of the anticancer drug AMD443 with DNA purine bases: A detailed computational approach

The mechanism of substitution reaction of chloroaqua and diaqua complexes, trans-[Pt(2-pic)(NH3)Cl(H2O)]+ and trans-[Pt(2-pic)(NH3)(H2O)2]2+, which are formed after intracellular aquation of the anticancer drug AMD443, with the DNA purine bases guanine (G) and adenine (A) were studied computationally by TST–DFT method. The aqua ligand of such complexes undergoes ligand exchange reactions with N7 atom of G or A as the preferential nucleophilic centers. The predominance of attack toward G over A has been observed. We have estimated the degree of trigonality (τ) and synchronicity (σy) for all transition states. The computed free energy of activation (ΔG‡(aq)) for chloroaqua complexes are 15.1kcal/mol and 18.5kcal/mol for guanine and adenine, respectively. The respective values for the diaqua complexes are higher. For the bifunctional adduct we observed that GG adduct with head-to-head (HH) conformation prefers over GA adduct by ≈8.5kcal/mol and over the GG head-to-tail (HT) conformation by ≈0.9kcal/mol.

Controlled tin catalyzed hydrolysis of 3-acryloxypropyltrimethoxysilane with mono- and multi-functional mercaptans

Mechanistic investigations were initiated to further our understanding of the reaction pathways for hydrolysis and condensation of organofunctional alkoxysilanes in organic media. Previous work has shown that addition of mercaptans to solutions that contain dibutyltin dilaurate (DBTDL), which functions as a catalyst, and 3-acryloxypropyltrimethoxysilane can greatly reduce the rate of silane hydrolysis and condensation. Gas chromatography/mass spectrometry (GC/MS) hydrolysis studies were carried out to understand how mercaptan structure and concentration affected the relative hydrolysis rate of the acrylate silane in solution. Detailed nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry (MS) were carried out on simple mixtures of DBTDL and select mercaptans, and with varying mercaptan concentrations, to elucidate which significant tin complexes can form. These studies showed that mercaptans readily undergo ligand exchange reactions with the labile carboxylate groups of DBTDL and that an excess of mercaptans reduced the amount of proposed active catalyst species. It was found that an excess of mercaptan functional group was necessary to prevent significant and rapid hydrolysis of the organofunctional silane in organic media. A minimum of 1:4 DBTDL carboxylate group:mercaptan functional group was required for most mercaptans examined. A tetramercaptan, pentaerythritol tetrakis(3-mercaptopropionate), was shown to be effective in deactivating the DBTDL catalyst, even at relatively low concentrations of tetramercaptan. The findings in this work provide further support for the proposed mechanism for catalyzed hydrolysis and condensation. The tin metal was determined to be predominately 4-fold coordinated in the various tin mercaptide compounds studied. Evidence for transient tin hydroxide reactive intermediates was detected using mass spectrometry, as upon the addition of water, oligomeric condensation products were observed. However, the lifetime of these reactive intermediates precluded their direct observation by either mass spectrometry or NMR. Oligomeric and cyclic tin mercaptide species were shown to form when multifunctional mercaptans were combined with DBTDL in solution.

Solid state study of sulfoxide adducts of (2-amidoethyl-C,O)trihalostannanes: Supramolecular networks constructed from hydrogen-bonds involving the amido units

The complex, (H2NCOCH2CH2-C,O)(L))SnCl3, (L = EtCONH2-O), isolated from a reaction mixture containing hydrochloric acid, tin and acrylamide in Et2O solution, undergoes ligand exchange reactions with sulfoxides (sulfoxide = dimethyl sulfoxide, tetramethylene sulfoxide, 2-phenyl-1,3-dithiane trans-1-oxide and 2-phenyl-1,3-dithiane trans-1-trans-3-dioxide) to give (H2NCOCH2CH2-C,O)(sulfoxide-O)SnCl3. The tin centres in all the complexes are hexa-coordinated with a fac-CCl3O2 donor set, in which the octahedral geometries are somewhat distorted due to variations in the Sn–halide bond lengths, exemplifying the trans effect, and the small bite angles of the chelating (2-amidoethyl-C,O) ligand. The 2-phenyl-1,3-dithiane-1,3-dioxide ligand acts only as a monodentate ligand in its complex. The supramolecular structures are dominated by intermolecular hydrogen bonds with the NH2 groups as the donor species. Halide exchange between (H2NCOCH2CH2-C,O)-(tetramethylene sulfoxide-O)SnCl3 and bromide ion was shown to give the mixed halide complex (H2NCOCH2CH2-C,O)(tetramethylene sulfoxide-O)SnCl1.5Br1.5).

Speciation analysis of the antirheumatic agent Auranofin and its thiol adducts by LC/ESI-MS and LC/ICP-MS

Auranofin is a gold(I)-based pharmaceutical for the treatment of rheumatoid arthritis. Despite the fact that it has been used since the 1970s, its mode of action is still not fully understood. Auranofin undergoes ligand exchange reactions in vivo to generate reactive metabolites. In the present study, methods are developed for the analysis of Auranofin and its adducts with endogenously available thiols. Auranofin is characterized by liquid chromatography coupled to electrospray ionization mass spectrometry (LC/ESI-MS) and inductively coupled plasma mass spectrometry (LC/ICP-MS), respectively. Obtained data indicate that monomeric Auranofin is the main compound to undergo exchange reactions with added thiol ligands. Adduct formation of the gold species with glutathione and human serum albumin is simulated successfully in vitro and analyzed by LC/ESI-MS and LC/ICP-MS. While the thiol ligand of Auranofin is displaced, the remaining triethylphosphine gold structure may covalently bind to either glutathione or human serum albumin. Moreover, oxidation of the phosphine ligand by disulfides occurs in both reaction mixtures with the phosphine oxide as the resulting product. Reactions of Auranofin with the thiols are quantitatively traced over several days by ICP-MS. Based on the obtained data, a potential reaction pathway of Auranofin with the two thiols is proposed.

Binding of Organometallic Ruthenium(II) Anticancer Compounds to Nucleobases: A Computational Study

The reaction of the anticancer compound [(eta(6)-benzene)Ru(en)(OH(2))](2+) (1) toward the nucleobases guanine, adenine, and cytosine is studied computationally using DFT/BP86 calculations. The aqua leaving group of such compounds is known to undergo ligand exchange reactions with nucleophilic centers in DNA and preferentially with the N7 atom of guanine, N7(G). Our results show that an H-bonded reactant adduct with nucleobases is formed via either the aqua ligand (cis adduct) or the en (ethylenediamine) ligand (trans adduct) of 1. All studied nucleobases favor an H-bonded cis adduct. Only guanine forms also a trans reactant adduct in the gas phase. The guanine N7 and O6 atoms in this trans adduct are situated in an ideal position to form each a strong H-bond to both amino groups of the en ligand of 1. A docking study shows that this unique recognition pattern is also plausible for the interaction with double stranded DNA. For the reaction of 1 with guanine, we identified three different reaction pathways: (i) A cis (G)N7-Ru-OH(2) transition state (TS). (ii) A direct trans reaction pathway. (iii) A 2-step trans mechanism. The activation energies for the cis pathway are smaller than for the trans pathways. The ultimately formed Ru-N7(G) product is characterized by a thermally stable H-bond between the O6(G) and a diamine-NH(2) hydrogen.

Applications of NMR spectroscopy in understanding the gold biochemistry

Gold‐based drugs have been successfully used for the treatment of rheumatoid arthritis. When administered, they undergo ligand exchange reactions in the body with biofluids, cells and proteins. NMR spectroscopy is a very useful technique for probing these ligand exchange reactions under physiological conditions. The strength of the binding ligands can be estimated by studying the chemical shift changes in 13C and 31P NMR. It is also a powerful method for investigating the kinetics and thermodynamics of the exchange reactions of gold drugs with biomolecules. The purpose of this review report is to highlight the importance of NMR spectroscopy in the study of gold biochemistry and to bridge the fairly large gap in the progress of this interesting area of bioinorganic chemistry.

Controlled Ligand Deprotonation in Lanthanide Chelates with Asymmetric Semicarbazone/Benzoylhydrazone or Semicarbazone/Thiosemicarbazone Coordination Spheres

Asymmetric, potentially pentadentate ligands (H(2)L(3)) are formed by subsequent condensation of a semicarbazide and benzoylhydrazine on 2,6-diacetylpyridine. Two equivalents of H(2)L(3) reacts with CeCl(3).7H(2)O, Ce(SO(4))(2).4H(2)O, or EuCl(3).6H(2)O under formation of [Ln(III)(HL(3))(2)](+) cations (Ln = Ce, Eu) with exclusive deprotonation of the benzoylhydrazone ligand arms. The Ce(4+) ion of the sulfate salt is reduced during the reaction and forms 10-coordinate singly charged complex cations, the structure of which is identical to the product of the reaction of cerium(III) chloride. The exact position of deprotonation in the ligands is resolved by infrared spectroscopy, bond lengths considerations, and the hydrogen bonding in the solid-state structures of the products. A similar approach allows the synthesis of mixed semicarbazone/thiosemicarbazone ligands (H(2)L(4)). The reaction of H(2)L(4) with Sm(NO(3))(3).6H(2)O leads to the first structurally characterized lanthanide complex with thiosemicarbazone coordination. The solid-state structure of the 10-coordinate complex [Sm(HL(4))(2)]NO(3).H(2)O shows exclusive deprotonation of the thiosemicarbazone arms of the ligands. All isolated complexes are air stable and do not undergo ligand exchange reactions or hydrolysis in the presence of water.

Synthesis of dialkyl, diaryl and metallacyclic complexes of Ni and Pd containing pyridine, α-diimines and other nitrogen ligands: Crystal structures of the complexes cis-NiR 2py 2 (R=benzyl, mesityl)

The alkylation of NiCl 2py 4 or PdCl 2py 2 with organomagnesium or organolithium reagents affords dialkyl complexes cis-MR 2py 2 (R=Me, CH 2SiMe 3, CH 2Ph, CH 2CMe 2Ph, 2,4,6-C 6H 2Me 3). The methyl and trimethylsilyl derivatives undergo ligand exchange reactions with chelating nitrogen ligands (α-diimines or 2-imidoylpyridines), yielding the corresponding dialkyl derivatives in good to excellent yields. A catalytic amount of PMe 3 induces the transformation of the nickel complex Ni(CH 2CMe 2Ph) 2py 2 into the metallacyclic derivative NiCH 2 CMe 2-o- C 6 H 4( py) 2 .The latter, and the related palladacycle Pd( CH 2 CMe 2-o- C 6 H 4) ( cod) , also undergo facile ligand exchange reactions.

IR spectroscopic investigations into reactions between unsaturated titanium complexes and CO or N 2 in liquid xenon or heptane

The reactions of Cp∗ 2TiR compounds with CO in liquid xenon (LXe) or heptane were studied by IR spectroscopy in special high-pressure cells. All complexes incorporate a single CO molecule to fill up their coordination sphere, forming Cp∗ 2TiR(CO) intermediates. These species undergo secondary reactions at elevated temperatures, such as disproportionation to Ti(II) and Ti(IV) complexes. The formation of the 18 VE species Cp∗ 2Ti(CO) 2 seems to be the driving force of the observed reactions. A similar behavior was found in the reaction of Cp∗ 2TiH with dinitrogen, where the adduct Cp∗ 2TiH(N 2) and its 14 15 N 2 isotopomer was identified together with Cp∗ 2Ti(N 2) 2. In addition to these orientating experiments, the stable 15 VE Cp∗FvTi (Fv = η 6C 5Me 4CH 2) and 16 VE species Cp∗AdTi (Ad = η 7C 5Me 3(CH 2) 2) show the addition of carbon monoxide to form new, reactive titanium carbonyls, which undergo ligand exchange reactions at higher temperatures and form Cp∗ 2Ti(CO) 2 as one of the final products.

Aggregation and axial ligand exchange behavior of water-soluble pyrrole-β brominated porphyrins

Synthesis of two water-soluble pyrrole-β brominated porphyrins, the tetrachloro salt of 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(N-methyl-4-pyridinio)porphyrin [tetrakis(N-methyl pyridyl)-β-octabromoporphyrin, (Br8TMpyP)H2] and the tetrasodium salt of 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(phenyl sulfonate)porphyrin [tetrakis(4-sulfonatophenyl)-β-octabromoporphyrin, (Br8TPPS)H2] and their zinc(II) derivatives have been reported. The investigated porphyrins are highly non-planar due to the presence of eight bromo substituents at the pyrrole-β positions and four aryl groups at the meso positions. At I = 0.1 M and T = 23 °C, the two sulfonated derivatives, (Br8TPPS)H2 and (Br8TPPS)Zn show a small tendency to aggregate while such behavior is almost negligible for the N-methyl pyridyl derivatives. Like the unbrominated water-soluble zinc(II) porphyrin derivatives, the pyrrole-β brominated zinc(II) porphyrins, with one or two water molecules as axial ligand(s) in aqueous solution, undergo ligand exchange reactions with nitrogeneous bases. The calculated equilibrium constant, K, for this reaction is found to be smaller in magnitude when compared to that obtained for the corresponding unbrominated zinc(II) porphyrin derivatives. The equilibrium constant values parallel the basicity of the axial ligands.

Improved Access to {[ω‐(Phosphanyl)alkyl]cyclopentadienyl}cobalt(I) Complexes: Decomplexation of the Phosphane Arm; Alkyne Complexes; Synthesis of Mononuclear Vinylidenecobalt(I) Complexes

AbstractAn improved synthesis of [(2‐phosphanylethyl)cyclopenta‐dienyl]cobalt(I) chelate complexes is presented, in which the paramagnetic chloride 3 is a precursor of the ethene complex 4. The latter readily undergoes ligand exchange reactions which in the case of bidendate reagents (1,5‐cyclooctadiene, 1,2‐bis(diisopropylphosphanyl)ethane, 2,2′‐bipyridine, nor‐bornadiene) cause a decomplexation of the phosphane arm at room temperature with formation of 7, 5, 6, 8. The ethene ligand in 4 can be replaced by alkynes under equally mild reaction conditions (formation of 9, 11 – 16). The reaction with ethyne results in the formation of vinylidene complex 10. The yields of the reactions with nonaromatic alkynes could be improved by treating 3 with the alkyne in the presence of sodium amalgam. The unsubstituted vinylidene complex 10 and its tert‐butyl derivative 17 were obtained by this route in 38 and 40% yield, respectively.

Synthesis, characterization and reactions of [Tc(NS)X 4] − complexes (XCl, Br, NCS)

The anions [Tc(NS)X 4] − (XCl, Br or NCS) can be prepared from the reaction of TcCl 6 2− and TcBr 6 2−, respectively, with trithiazyl chloride, (NSCI) 3. The equatorial ligands are kinetically labile and the complexes undergo ligand exchange reactions to form [Tc(NS)Cl n Br 4− n ] − mixed-ligand complexes ( n=1−3) or the isothiocyanate analogue [Tc(NS)(NCS) 4] −. The new compounds have been studied by EPR and the obtained parameters have been used to describe bonding properties. [Tc(NS)Cl 4] − and [Tc(NS)Br 4] − are instable in solution. Spontaneous decomposition results in nitridotechnetium(VI) complexes. The products have been characterized by EPR and X-ray diffraction.

Detection of99TcN-diethyldithiocarbamate in liver tissue by tandem mass spectrometry

The chemical form of the retention of TcN/et2dtc/2 has been investigated by mass spectrometry. The results indicate that this complex does not undergo ligand exchange reactions with plasma proteins.