Halogen Exchange Reaction Research Articles

Syntheses, Structures, and Reactions of Heptacoordinate Trihalogermanes Bearing a Triarylmethyl-Type Tetradentate Ligand

Trichloro[tris(3-tert-butyl-6-methoxyphenyl)methyl]germane (3), containing a tetradentate ligand with three methoxy groups as coordinating sites, was synthesized by the reaction of the corresponding (triarylmethyl)lithium species with tetrachlorogermane. In contrast to the case for the previously reported trichlorosilane analogue, 3 slowly decomposed during column chromatography on silica gel, although it was quite stable against moisture. The corresponding trifluoro-, tribromo-, and triiodogermanes 4−6 were prepared from the trichlorogermane 3. X-ray crystallographic analyses of 3−6 showed heptacoordinate structures with interatomic distances between the oxygen atom and the central germanium atom shorter than the sum of van der Waals radii. By systematic comparisons of these intramolecular interactions based on the interatomic distances, it was found that they strongly depend on the Lewis acidity of the trihalogenated germanium atom. An Atoms-in-Molecules (AIM) analysis of the model compound 4‘, in which three tert-butyl groups of trifluorogermane 4 were omitted, showed the existence of weak and ionic bonding between oxygen and germanium atoms. Reactions of these trihalogermanes with aqueous NaOH, LiAlH4, and BX3 were also investigated. Alkaline hydrolysis of trihalogermanes resulted in the cleavage of the carbon−germanium bond. LiAlH4 also caused the same kind of bond cleavage, together with nucleophilic attack on the germanium atom, giving the trihydrogermane 8. Reaction of the trihalogermanes with trihaloboranes was found to be an efficient procedure to give other trihalogermanes through a halogen exchange reaction.

Microwave-enhanced nucleophilic fluorination in the synthesis of fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids, potential glucocorticoid receptor-mediated imaging agents

Fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids have high affinity for the glucocorticoid receptor (GR) and are highly active glucocorticoids. They are thus considered to be excellent candidates for PET imaging of GR containing tissues when labeled with fluorine-18 (t1/2=110min). Previously reported syntheses of these fluorinated glucocorticoids were accomplished by conventional thermal nucleophilic halogen exchange reactions with chloropyridyl precursors. These reactions were found to proceed at rates too slow for feasible application to radiosynthesis using [18F]fluoride. We have applied microwave-heating methods to these reactions and found that significant rate enhancements can be realized. Kinetic experiments showed an average relative rate ratio of 3/1 for microwave versus conventional heating and preparative experiments showed an average relative conversion ratio of 4.5/1 during the initial 120min, a period approximating one half-life of the isotope. The microwave method described was used to prepare previously unreported 2′-(2-fluoro-4-pyridyl)-11β,17,21-trihydroxy-16α-methyl-20-oxo-pregn-4-eno-[3,2-c]-pyrazole, which was evaluated for biological activity.

Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter

Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. (S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset. (S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT. These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.

Meso-iodo- andmeso-iodovinylporphyrins via organopalladium porphyrins and the crystal structure of 5-iodo-10,20-diphenylporphyrin

The regiospecific halogen exchange reactions of various easily accessible meso-bromoporphyrins to obtain meso-iodoporphyrins, using η1-palladioporphyrins as intermediates, have been investigated. This one-pot methodology allows the isolation of meso-iodoporphyrins in excellent yields with short reaction times. Similarly meso-(2-bromoethenyl)porphyrins can be converted to their iodoethenyl analogues. These iodoporphyrins show great potential as starting materials for various palladium catalyzed reactions. The X-ray crystal structure of 5-iodo-10,20-diphenylporphyrin has been determined.

Barriers of Hydrogen Abstraction vs Halogen Exchange: An Experimental Manifestation of Charge-Shift Bonding

This paper shows that the differences between the barriers of the halogen exchange reactions, in the H + XH systems, and the hydrogen abstraction reactions, in the X + HX systems (X = F, Cl, Br), measure the covalent-ionic resonance energies of the corresponding X-H bonds. These processes are investigated using CCSD(T) calculations as well as the breathing-orbital valence bond (BOVB) method. Thus, the VB analysis shows that (i) at the level of covalent structures the barriers are the same for the two series and (ii) the higher barriers for halogen exchange processes originate solely from the less efficient mixing of the ionic structures into the respective covalent structures. The barrier differences, in the HXH vs XHX series, which decrease as X is varied from F to I, can be estimated as one-quarter of the covalent-ionic resonance energy of the H-X bond. The largest difference (22 kcal/mol) is calculated for X = F in accord with the finding that the H-F bond possesses the largest covalent-ionic resonance energy, 87 kcal/mol, which constitutes the major part of the bonding energy. The H-F bond belongs to the class of "charge-shift" bonds (Shaik, S.; Danovich, D.; Silvi, B.; Lauvergnat, D. L.; Hiberty, P. C. Chem. Eur. J. 2005, 21, 6358), which are all typified by dominant covalent-ionic resonance energies. Since the barrier difference between the two series is an experimental measure of the resonance energy quantity, in the particular case of X = F, the unusually high barrier for the fluorine exchange reaction emerges as an experimental manifestation of charge-shift bonding.

Regioselective lithium–halogen exchange and palladium-catalyzed cross-coupling reactions of 2,4-dihaloquinolines

Lithium–halogen exchange of 2,4-dibromoquinolines proceeds regioselectively at C-4 and affords 4-substituted quinolines on quenching with electrophiles. Palladium-catalyzed cross-coupling reactions of 2-bromo-4-iodoquinoline provide 4-substituted 2-bromoquinoline derivatives.

Synthesis of 2‐[(2‐chloro‐2′‐[18F]fluoroethyl)amino]‐2H‐1,3,2‐oxazaphosphorinane‐2‐oxide (18F‐fluorocyclophosphamide), a potential tracer for breast tumor prognostic imaging with PET

AbstractA fluorine‐18 labeled analog of the widely used chemotherapeutic agent cyclophosphamide was synthesized as a tracer for prognostic imaging with positron emission tomography. 2‐[(2‐Chloro‐2′‐[18F]fluoroethyl)amino]‐2H‐1,3,2‐oxazaphosphorinane‐2‐oxide (18F‐fluorocyclophosphamide), was prepared by direct halogen exchange reaction from the parent cyclophosphamide. In small‐scale syntheses, radiochemical yields of up to 4.9% and specific activities of 960 Ci/mmol were achieved in a total synthesis time of 60–75 min. The [18F]‐labeled cyclophosphamide analog with radioactive purity >99% and chemical purity >96% was suitable for in vivo (microPET imaging) and ex vivo studies of a murine model of human breast tumors. Copyright © 2005 John Wiley & Sons, Ltd.

Radiobromination ofcloso-carboranes using palladium-catalyzed halogen exchange

This thesis describes the synthesis and radiohalogenation of compounds of potential use for tumor targeting. The first section describes the synthesis and radioiodination of DNA intercalating compounds. The compounds are derivatives of 9-aminoacridine, and the anthracyclins daunorubicin and doxorubicin. The precursor compounds were labeled with 125I (T1/2 = 60 days), which is an Auger emitting nuclide. 125I decaying in the close vicinity of DNA is known to have a much higher cell killing effect than 125I decaying in the cytoplasm and some of the labeled compounds prepared in this thesis are currently being tested for use in targeted radionuclide therapy for cancer. The second section describes the radiobromination of closo-carboranes by subjecting the corresponding iodinated compounds to palladium-catalyzed halogen exchange using [76Br]bromide. The 76Br isotope (T1/2 = 16.2 h) is a positron emitting nuclide that is suitable for PET studies. Via the halogen exchange reaction good to excellent radiochemical yields of radiobrominated closo-carboranes were obtained. The results of the present study may prove to be applicable to pharmacokinetic studies of carboranes and their derivatives. The third and final section describes the indirect radiobromination of the trastuzumab anti-HER2 monoclonal antibody and of the anti-HER2 Affibody by means of an “one-pot” procedure using N-succinimidyl-5-(tributylstannyl)-3-pyridinecarboxylate (SPC) and ((4-hydroxyphenyl)ethyl))maleimide (HPEM), respectively. It was found that SPC and HPEM can be efficiently radiobrominated and thereafter coupled to the antibody and Affibody, respectively. The labeled proteins retained their capacity to bind specifically to HER2 expressing SKOV-3 cells in vitro. Application of this method to 76Br might enable the use of PET in the detection of HER2 expression in breast, ovarian, and urinary bladder carcinomas.

Electrochemical radiofluorination. 3. Direct labeling of phenylalanine derivatives with [18F]fluoride after anodic oxidation

As an example of applying the electrochemical method in radiofluorination a new procedure was developed for preparing [18F]fluorophenylalanine by direct use of [18F]fluoride. Several protecting groups for amino and carboxylic function of phenylalanine were investigated. Best results were obtained for N-trifluoroacetylphenylalanine methyl ester (1) (10.5±2.5%) with a relative isomeric distribution of 50.5±1.5% ortho isomer, 11.5±1.5% meta isomer and 38.8±2.1% para isomer. Optimized reaction conditions were with Et3N·3HF as supporting electrolyte and temperatures between 0 and –10°C. By variation of working potential (1.5–2.0 V) and chloride concentration (added as supporting electrolyte, 0.0–0.36 M) it was demonstrated that an indirect electrolysis as reaction mechanism or a halogen exchange (halex) reaction with primary formation of a chlorinated product followed by halogen exchange are highly improbable. Copyright © 2005 John Wiley & Sons, Ltd.

Synthesis and Characterization of Heavier Dioxouranium(VI) Dihalides

The synthesis and characterization of the dioxouranium(VI) dibromide and iodide hydrates, UO(2)Br(2)x3H(2)O (1), [UO(2)Br(2)(OH(2))(2)](2) (2), and UO(2)I(2)x2H(2)Ox4Et(2)O (3), are reported. Moreover, adducts of UO(2)I(2) and UO(2)Br(2) with large, bulky OP(NMe(2))(3) and OPPh(3) ligands such as UO(2)I(2)(OP(NMe(2))(3))(2) (4), UO(2)Br(2)(OP(NMe(2))(3))(2) (5), and UO(2)I(2)(OPPh(3))(2)(6) are discussed. The structures of the following compounds were determined using single-crystal X-ray diffraction techniques: (1) monoclinic, P2(1)/c, a = 9.7376(8) A, b = 6.5471(5) A, c = 12.817(1) A, beta = 94.104(1) degrees , V = 815.0(1) A(3), Z = 4; (2) monoclinic, P2(1)/c, a = 6.0568(7) A, b = 10.5117(9) A, c = 10.362(1) A, beta = 99.62(1) degrees , V = 650.5(1) A(3), Z = 2; (4) tetragonal, P4(1)2(1)2, a = 10.6519(3) A, b = 10.6519(3) A, c = 24.0758(6) A, V = 2731.7(1) A(3), Z = 4; (5) tetragonal, P4(1)2(1)2, a = 10.4645(1) A, b = 10.4645(1) A, c = 23.7805(3) A, V = 2604.10(5) A(3), Z = 4, and (6) monoclinic, P2(1)/c, a = 9.6543(1) A, b = 18.8968(3) A, c = 10.9042(2) A, beta =115.2134(5) degrees , V = 1783.01(5) A(3), Z = 2. Whereas 1 and 2 are the first UO(2)Br(2) hydrates and the last missing members of the UO(2)X(2) hydrate (X = Cl --> I) series to be structurally characterized, 4 and 6 contain room-temperature stable U(VI)-I bonds with 4 being the first structurally characterized room temperature stable U(VI)-I compound which can be conveniently prepared on a gram scale in quantitative yield. The synthesis and characterization of 5 using an analogous halogen exchange reaction to that used for the preparation of 4 is also reported.

Conversion of halon 1211 (CBrClF 2) over supported Pd catalysts

Conversion of halon 1211 has been studied over γ-Al 2O 3 and supported 0.5% Pd catalysts (Pd/Al 2O 3, Pd/fluorinated Al 2O 3, Pd/AlF 3, Pd/Al 2O 3 pretreated with CH 4 and CHClF 2). The experiments were performed in the temperature range of 443–523 K, in a tubular alumina reactor. The temperature of the reactor was maintained uniformly by a three zone furnace. The reaction products were quantified with a micro gas chromatograph and identified with a gas chromatograph–mass spectrometer. The catalysts were characterised with XRD diffractometry and the content of halogen on the catalysts was determined with an ion chromatograph. The measurements were presented in terms of the conversion of halon 1211 and product selectivity, as functions of catalyst type, catalyst time on stream and composition of inlet gases. Transformation of Pd to Pd carbide is observed in the CH 4 treated Pd/Al 2O 3, but not in the CHClF 2 treated Pd/Al 2O 3 in which case Al 2O 3 was partially fluorinated. In the absence of hydrogen, the conversion of halon 1211 over Al 2O 3 and Pd/Al 2O 3 gives a similar product profile and the reactions follow a heterogeneous halogen exchange reaction pathway, which takes place on the positively charged aluminum ions. Introduction of hydrogen has no apparent effect on either halon 1211 conversion level or the product profile during the conversion of halon 1211 over Al 2O 3. Over supported Pd catalysts, major products are hydrogenated species which include CH 2F 2, CH 4, C 2H 6, C 3H 8, CH 3Br and CHF 3. The most striking feature of the hydrodehalogenation reactions is the increasing CH 2F 2 selectivity with time on stream, especially on Pd/Al 2O 3 and the CH 4 treated Pd/Al 2O 3. The changing selectivity during the catalytic hydrodehalogenation reactions is mainly ascribed to the interaction of support with Pd.

Synthesis, radiosynthesis and preliminary in vivo evaluation of [123I]‐(4‐fluorophenyl) {1‐[2‐(2‐iodophenyl)ethyl]piperidin‐4‐yl}methanone, a potential 5‐HT2A‐antagonist for SPECT brain imaging

AbstractMany people suffer from psychiatric illnesses like depression and anorexia. Relevant to these diseases is amongst others a malfunctioning of brain 5‐HT2A‐receptors. To allow in vivo quantification of these receptors with Single Photon Emission Computerized Tomography (SPECT), a radiolabelled ligand with high 5‐HT2A affinity is needed.This work reports the radiosynthesis of [123I]‐(4‐fluorophenyl) {1‐[2‐(2‐iodophenyl)ethyl]piperidin‐4‐yl}methanone, the synthesis of its precursor, (4‐fluorophenyl) {1‐[2‐(2‐bromophenyl)ethyl]piperidin‐4‐yl}methanone, and the preliminary in vivo evaluation of the tracer. The precursor was synthesized with a total yield of 40%. Radiolabelling was performed using a halogen exchange reaction and the yield was 70%. Radiochemical purity was >95%, and specific activity was at least 2.4 Ci/µmol. Log P was measured to be 2.52. The tracer showed uptake in mice brain (3.5% I.D./g tissue at 3 min post injection) and therefore will be evaluated further by regional brain biodistribution and displacement studies in rabbits. Copyright © 2004 John Wiley & Sons, Ltd.

Halex reactions of aromatic compounds catalysed by 2-azaallenium, carbophosphazenium, aminophosphonium and diphosphazenium salts: a comparative study

An increasing number of biologically active compounds in the pharma and agro-chemical sector contain carbon fluorine bonds. One of the most common methods to introduce fluorine into intermediates is the well-investigated halogen-exchange reaction, in which chloro- and bromoaromatics activated towards nucleophilic substitution, react with a fluoride source to yield the corresponding fluoroarenes. In general, the reaction is supported by phase-transfer catalysts. The use of a new class of very active phase-transfer catalysts gives the possibility of substituting even halogens with weak activation giving a convenient access to interesting compounds that are not available so far and opening up new synthetic routes in Halex chemistry. Our new classes of catalysts, CNC + ( 1a), PNC + ( 2a) and several different approaches presented by other groups are described and experimental results discussed.

The Metal—Halogen Exchange Reaction Between ortho‐Substituted Aryl Halides and Ph2CuLi×LiCN: Scope and Applicability for Coupling Reactions.

The Metal—Halogen Exchange Reaction Between ortho‐Substituted Aryl Halides and Ph₂CuLi×LiCN: Scope and Applicability for Coupling Reactions.

Syntheses and chemistry of hypervalent cyclo-R4Sb4, cyclo-(RSbE)n[R = 2-(Me2NCH2)C6H4, E = O, S] and precursors

The cyclostibane R(4)Sb(4)(1)(R = 2-(Me(2)NCH(2))C(6)H(4)) was synthesized by reduction of RSbCl(2) with Mg in THF or with Na in liquid NH(3). The reaction of 1 with [W(CO)(5)(THF)] gives the stibinidene complex RSb[W(CO)(5)](2)(2). RSbCl(2) and (RSbCl)(2)E [E = O (6), E = S (8)] react with KOH or Na(2)S in toluene/water to give the heterocycles (RSbE)(n)[E = O, n= 3 (3); E = S, n= 2 (4)]. The chalcogeno-bridged compounds of the type (RSbCl)(2)E [E = O (6), E = S (8)] were synthesized by reaction of RSbCl(2) with KOH or Na(2)S in toluene/water, but also by reaction of RSbCl(2) with the heterocycles (RSbE)(n). The compounds (RSbI)(2)O (7) and (RSbBr)(2)S (9) were prepared via halogen-exchange reactions between (RSbCl)(2)E and NaI (E = O) or KBr (E = S) or by reactions between RSbI(2) and KOH or RSbBr(2) and Na(2)S. The reaction of cyclo-(RSbS)(2) with W(CO)(5)(THF) in THF results in trapping of the cis isomer in cyclo-(RSbS)(2)[W(CO)(5)](5). The solution behaviour of the compounds was investigated by (1)H and (13)C NMR spectroscopy. The molecular structures of compounds 1-7 and 9 were determined by single-crystal X-ray diffraction.

Heterogeneous interaction of Br2, Cl2 and Cl2O with solid KBr and NaCl substrates: The role of adsorbed H2O and halogens

The interaction of Br2, Cl2 and Cl2O with different solid alkali halides, namely KBr and NaCl substrates, has been investigated in a low-pressure flow reactor. The observed main gaseous reaction products of the reactions of Cl2 and Cl2O with solid KBr substrates are Br2 and BrCl. The reaction of Cl2O with solid NaCl substrates leads to formation of Cl2 and small amounts of HOCl. The role of surface-adsorbed H2O (SAW) and the influence of adsorbed halogens have been investigated. Evidence for the formation of adsorbed Br2 owing to mechanical stress has been found for solid KBr. Dehydration of the substrate under vacuum leads to a better ordered, more crystalline and hence less-reactive surface and decreases the number of reactive surface sites. Adsorption of halogen compounds such as BrCl, Cl2 and Br2 leads to effective dehydration of the KBr or NaCl substrate by competing for limited amounts of SAW. In this way, the reduced degree of hydration of the substrate alkali ions leads to activation of the halogen exchange reactions or catalytic activity.

A Simple Synthesis of Brominated Analogues of 3‐Chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX).

AbstractFor Abstract see ChemInform Abstract in Full Text.

The metal–halogen exchange reaction between ortho-substituted aryl halides and Ph 2CuLi · LiCN: scope and applicability for coupling reactions

Metal–halogen exchange between Ph 2CuLi · LiCN and ortho-substituted aryl iodides or bromides may be used to conveniently afford substituted metallated aryls which can subsequently undergo reaction with electrophiles.

Versatility of KF as Selective Fluorination of Organic Compounds for Halogen Exchange Reactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

A new norepinephrine transporter imaging agent for cardiac sympathetic nervous function imaging: radioiodinated (R)- N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine

Changes of the cardiac norepinephrine transporter (NET) have been reported in several cardiac failures. (R)- N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine (MIPP), the 3-phenoxy-3-phenylpropylamine analogue iodinated at the 2-position of the phenoxy ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating the cardiac norepinephrine transporter by single photon emission computed tomography (SPECT). (R)-[ 125I]MIPP was synthesized via a halogen exchange reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (60%) and high radiochemical purity (> 98%). The binding affinity of (R)-MIPP for cardiac NET was measured in terms of the displacement of [ 3H]desipramine and (R)-[ 125I]MIPP from binding sites in rat heart membranes. The binding data revealed that the affinity of (R)-MIPP was 5 times that of nisoxetine which is a selective NET inhibitor. In biodistribution studies, (R)-[ 125I]MIPP showed a high uptake followed by rapid clearance in the heart. (R)-[ 125I]MIPP binding sites were saturable and the administration of nisoxetine and desipramine, selective NET inhibitors, decreased the cardiac accumulation of (R)-[ 125I]MIPP. These results suggested that (R)-[ 123I]MIPP may be an useful radiopharmaceutical for imaging cardiac sympathetic nervous functions.