Simultaneous determination of losartan and hydrochlorothiazide in combined dosage forms by first-derivative spectroscopy and high-performance thin-layer chromatography.

Losartan (LST) is the first orally active nonpeptide angiotensin-II receptor antagonist with an improved safety and tolerability profile. It is prescribed alone or in combination with hydrochlorothiazide (HCTZ) for the treatment of moderate-to-severe hypertension. This paper describes the development of 2 methods that use different techniques, first-derivative spectroscopy and high-performance thin-layer chromatography (HPTLC), to determine LST and HCTZ in the presence of each other. LST and HCTZ in combined preparations were quantitated by using the first-derivative responses at 271.6 nm for LST and 335.0 nm for HCTZ in spectra of their solutions in water. The linearity ranges are 30-70 microg/mL for LST and 7.5-17.5 microg/mL for HCTZ with correlation coefficients of 0.9998 and 0.9997, respectively. In the HPTLC method, a mobile phase of chloroform-methanol-acetone-formic acid (7.5 + 1.5 + 0.5 + 0.03, v/v) and a prewashed Silica Gel G60 F254 TLC plate as the stationary phase were used to resolve LST and HCTZ in a mixture. Two well-separated and sharp peaks for LST and HCTZ were obtained at Rf values of 0.61+/-0.02 and 0.41+/-0.02, respectively. LST and HCTZ were quantitated at 254.0 nm. The linearity ranges obtained for the HPTLC method are 400-1200 and 100-300 ng/spot with corresponding correlation coefficients of 0.9944 and 0.9979, for LST and HCTZ, respectively. Both methods were validated, and the results were compared statistically. They were found to be accurate, specific, and reproducible. The methods were successfully applied to the estimation of LST and HCTZ in combined tablet formulations.     

Determination of nebivolol hydrochloride and hydrochlorothiazide in tablets by first-order derivative spectrophotometry and liquid chromatography

Two simple and accurate methods for analysis of nebivolol hydrochloride (NEB) and hydrochlorothiazide (HCTZ) in their combined dosage forms were developed using first-order derivative spectrophotometry and reversed-phase liquid chromatography (LC). NEB and HCTZ in their combined dosage forms (tablets) were quantified using first-derivative responses at 294.6 and 334.6 nm in the spectra of their solutions in methanol. The calibration curves were linear in the concentration range of 8-40 microg/mL for NEB and 10-60 microg/mL for HCTZ. LC analysis was performed on a Phenomenex Gemini C18 column (250 x 4.6 mm id, 5 microm particle size) in the isocratic mode with 0.05 M potassium dihydrogen phosphate-acetonitrile-methanol (30 + 20 + 50, v/v/v; pH 4) mobile phase at a flow rate of 1 mL/min. Detection was made at 220 nm. Both of the drugs and the internal standard (ezetimibe) were well resolved with retention times of 5.1 min for NEB, 2.9 min for HCTZ, and 8.2 min for ezetimibe. The calibration curves were linear in the concentration range of 1-14 microg/mL for NEB and 0.3-28 microg/mL for HCTZ. Both methods were validated and found to be accurate, precise, and specific, and results were compared statistically. Developed methods were successfully applied for the estimation of NEB and HCTZ in their combined dosage forms.     

HPLC�CDAD Analysis of Hydrochlorothiazide and Irbesartan in Hypertensive Patients on Fixed-Dose Combination Therapy

Hydrochlorothiazide (HCTZ) and the angiotensin II type 1 receptor antagonist (ARB) irbesartan (IRBE) are well-known antihypertensive drugs, frequently administered as a low-dose combination in a single pill. In this work, a simple, sensitive, and selective high-performance liquid chromatographic (HPLC) method with diode-array detection was developed for simultaneous determination of HCTZ and IRBE levels in the plasma of hypertensive patients given a fixed combination of 12.5 mg HCTZ and 300 mg IRBE. Compounds were extracted from acidified plasma samples with 3 mL ethyl acetate, and eluted at 6 and 19 min from a C₄ column by elution with an acetonitrile?Cphosphate buffer (pH 3.6) mobile-phase gradient at a flow rate of 1 mL min^?1. The assay was linear over the ranges 2.5?C500 and 20?C4,000 ng mL^?1 for HCTZ and IRBE, respectively. Overall intra-assay and inter-assay variation were within acceptance limits. Limits of quantification were 2.5 and 20 ng mL^?1 for HCTZ and IRBE, respectively. Plasma samples remained stable for 12 h at room temperature, through three thaw?Cfreeze cycles, and for 2 and 7 months at ?20 °C. In hypertensive patients, residual concentrations were 22.3 ± 6.0 and 241.8 ± 39.0 ng mL^?1 for HCTZ and IRBE, respectively. There was no interference from other co-administered drugs. Despite the different physicochemical properties of HCTZ and IRBE, our method enables accurate measurement of both drugs for assessment of compliance by patients treated by fixed-dose combination therapy with HCTZ?CIRBE.     

Evaluation of the Potentialities of a Carbon Nanotubes/Silicone Rubber Composite Electrode in the Determination of Hydrochlorothiazide

A multiwall carbon nanotube/silicone rubber (MWCNT/SR) composite electrode has been used for the determination of hydrochlorothiazide (HCTZ) in pharmaceutical formulations by differential pulse voltammetry (DPV). The electro-oxidation process was evaluated by cyclic voltammetry, from which it was observed that HCTZ presents an irreversible oxidation peak at 0.82 V vs. saturated calomel electrode (SCE) in the potential range from 0.5 to 1.1 V, in Britton-Robinson buffer pH 7.0 at MWCNT/SR. HCTZ was determined by DPV using a MWCNT/SR 70% (MWCNT, m/m) composite electrode after the optimization of the experimental parameters. The linear range was from 5.0 to 70.0 µ mol L^?1, with a limit of detection (LOD) of 2.6 µ mol L^?1. The HCTZ was determined in pharmaceutical formulations using the proposed composite electrode and the results agreed with those from the official high performance liquid chromatography (HPLC) method within 95% confidence level, according to the t-Student test.     

Stability-indicating method for simultaneous estimation of olmesartan medoxomile, amlodipine besylate and hydrochlorothiazide by RP-HPLC in tablet dosage form

A simple, specific, accurate and precise stability-indicating reversed-phase high-performance liquid chromatographic method was developed for simultaneous estimation of olmesartan medoxomile (OLME), amlodipine besylate (AMLO) and hydrochlorothiazide (HCTZ) in tablet dosage form. The method was developed using an RP C18 base deactivated silica column (250 × 4.6 mm, 5 μm) with a mobile phase consisting of triethylamine (pH 3.0) adjusted with orthophosphoric acid (A) and acetonitrile (B), with a timed gradient program of T/%B: 0/30, 7/70, 8/30, 10/30 with a flow rate of 1.4 mL/min. Ultraviolet detection was used at 236 nm. The retention times for OLME, AMLO and HCTZ were found to be 6.72, 4.28 and 2.30, respectively. The proposed method was validated for precision, accuracy, linearity, range, robustness, ruggedness and force degradation study. The calibration curves of OLME, AMLO and HCTZ were linear over the range of 50-150, 12.5-37.5 and 31-93 μg/mL, respectively. The method was found to be sensitive. The limits of detection of OLME, AMLO and HCTZ were determined 0.19, 0.16 and 0.22 μg/mL and limits of quantification of OLME, AMLO and HCTZ were determined 0.57, 0.49 and 0.66, respectively. Forced degradation study was performed according to International Conference on Harmonization guidelines.     

Simultaneous LC–MS–MS Analysis of Valsartan and Hydrochlorothiazide in Human Plasma

A rapid and specific liquid chromatographic–tandem mass spectrometric method is described for simultaneous analysis of valsartan (VAL) and hydrochlorothiazide (HCTZ) in human plasma. VAL and HCTZ were chromatographed on a C₈ column with 75:15:10 (v/v) acetonitrile–methanol–0.001% aqueous ammonia as mobile phase. VAL and HCTZ were eluted at 0.69 min and 1.22 min, respectively, and, after electrospray ionization (ESI), detected in selected-reaction-monitoring mode. The precursor to product-ion transitions m/z 434.32 → 179.22 and m/z 295.85 → 204.86 were used to quantify VAL and HCTZ, respectively. Recovery by solid-phase extraction was >90% for both analytes and the internal standard. The method was suitable for application to a pharmacokinetic study after oral administration of tablet containing 160 mg VAL and 25 mg HCTZ to 18 healthy volunteers.     

In vitro study of the interaction of cysteine with a thiazide diuretic (hydrochlorothiazide) at different ph by voltammetric and spectroscopic techniques

The interaction of cysteine (RSH) with a thiazide diuretic, hydrochlorothiazide (HCTZ) was characterized by UV-Vis absorption spectroscopy and square-wave voltammetry in Britton-Robinson (B-R) buffer solution (with pH 5, 7 and 9). On the square-wave voltamogram of cysteine, the reduction peak current of mercurous cysteine thiolate (Hg₂(RS)₂) decreased and its peak potential shifted to more positive values with the addition of HCTZ. This results showed that the RSH interacted with HCTZ. The stoichiometry of HCTZ-RSH molecular complex was determined by voltammetric data with the result of 1: 1. By using linear regression analysis of the voltammetric data at pH 5, 7 and 9, the apparent formation constants of HCTZ-RSH complex were calculated to be 9.54 × 10³, 2.80 × 10⁴ and 2.55 × 10⁴ M^?1, respectively. At the same time, this interaction was also supported by UV-Vis spectroscopic measurements. According to the voltammetric and spectroscopic results, it was suggested that the interaction mode between RSH and HCTZ molecules might be a combination of hydrophobic interactions and hydrogen bonds.     

Simultaneous Determination of Hydrochlorothiazide, Cilazapril and Its Active Metabolite Cilazaprilat in Urine by Gradient RP-LC

A rapid and simple liquid chromatographic method with UV detection has been developed for the determination of hydrochlorothiazide (HCTZ), cilazapril (CL) and its active metabolite cilazaprilat (CLT) in urine. Sample preparation for urine consisted of solid-phase extraction using styrene-divinylbenzene (SDB-2) cartridges. The chromatographic system was a Zorbax Eclipse XDB-C₁₈ column with a mixture of methanol and 10 mM phosphate buffer, pH 2.3 with gradient (20 to 60% of methanol) as mobile phase at a flow rate of 1.0 mL min^?1. The detection was performed at the wavelength of 206 nm. Enalapril maleat was used as an internal standard. The detector response was linear in the range of 2.4–30.0, 1.6–15.0 and 1.8–20.0 μg mL^?1 for HCTZ, CL and CLT, respectively. LOQ was determined to be 2.4, 1.6 and 1.8 μg mL^?1 for HCTZ, CL and CLT, respectively. Both intra- and inter-day precision were within acceptable limits. The method has been applied to urine samples obtained from three hypertensive patients after intake of HCTZ and CL therapeutic dose.     

Simultaneous determination of aliskiren and hydrochlorothiazide from their pharmaceutical preparations using a validated stability‐indicating MEKC method

A stability‐indicating MEKC method was developed and validated for the simultaneous determination of aliskiren (ALI) and hydrochlorothiazide (HCTZ) in pharmaceutical formulations using ranitidine as an internal standard (IS). Optimal conditions for the separation of ALI, HCTZ and its major impurity chlorothiazide (CTZ), IS and degradation products were investigated. The method employed 47 mM Tris buffer and 47 mM anionic detergent SDS solution at pH 10.2 as the background electrolyte. MEKC method was performed on a fused‐silica capillary (40 cm) at 28°C. Applied voltage was 26 kV (positive polarity) and photodiode array (PDA) detector was set at 217 nm. The method was validated in accordance with the ICH requirements. The method was linear over the concentration range of 5–100 and 60–1200 μg/mL for HCTZ and ALI, respectively (r²>0.9997). The stability‐indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using the PDA detection. Precision and accuracy evaluated by RSD were lower than 2%. The method proved to be robust by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of ALI and HCTZ both individually and in a combined dosage tablet formulation to support the quality control.     

Simultaneous determination of losartan,EXP-3174 and hydrochlorothiazide in plasma via fully automated 96-well-format-based solid-phase extraction and liquid chromatography–negative electrospray tandem mass spectrometry

An automated, sensitive and high-throughput liquid chromatographic/electrospray tandem mass spectrometric (LC–MS/MS) assay was developed for the simultaneous determination of losartan (LOS), its major circulating metabolite EXP-3174 and hydrochlorothiazide (HCTZ) in human plasma. LOS and HCTZ coexist in the same drug formulation, and this is the first method that enables the simultaneous determination of both drugs along with the active metabolite of LOS. Since these drugs have different physicochemical properties, the employment of a liquid–liquid extraction (LLE) protocol was precluded. A fully automated solid-phase extraction (SPE) protocol, based on 96-well format plates, was used to isolate these compounds and furosemide (internal standard, IS) from plasma. Washing and elution steps were amended accordingly in order to minimize any matrix effect from components of the plasma without reducing the elution of the molecules of interest. The compounds were eluted from a C18 column and detected with an API 3000 triple-quadrupole mass spectrometer using negative electrospray ionization and multiple reaction monitoring (MRM). The assay was linear over the range 1.00–400 ng/mL for LOS and EXP-3174 and 0.500–200 ng/mL for HCTZ, respectively, when 200 μl of plasma was used in the extraction. The overall intra- and interassay variations were within acceptance limits. The analysis time for each sample was 4 min, and more than 300 samples could be analyzed in one day by running the system overnight. The assay was simple, highly sensitive, selective, precise, fast, and it enables the reliable determination of LOS, EXP-3174 and HCTZ in pharmacokinetic or bioequivalence studies after per os administration of a single tablet containing both drugs.     

The Performance of Boron‐Doped Diamond Electrode for the Determination of Ramipril and its Association with Hydrochlorothiazide

The voltammetric behavior of ramipril (RMP), an angiotensin‐converting enzyme inhibitor, was investigated for the first time in the literature on a boron‐doped diamond electrode (BDDE) using cyclic (CV) and square‐wave voltammetry (SWV). Its behavior was also considered in the presence of a thiazide diuretic, hydrochlorothiazide (HCTZ), for the simultaneous determination. The performance of BDDE and glassy carbon electrode (GCE) was compared, since RMP provides a high oxidation potential. It was observed that the anodic peak potentials for HCTZ and RMP at the BDDE were 1.23 and 1.67 V (vs . Ag/AgCl (3.0 mol L^‐1 KCl)) by CV in BR buffer solution (pH 2.0), respectively. The influence of supporting electrolyte, pH and scan rate in the current response of these both drugs was examined to select optimum experimental conditions. By this way, the determination of RMP and its association with HCTZ using SWV and a BDDE was successfully applied in real samples (single and combined dosage forms), with results in close agreement at 95% confidence level with those obtained using high‐performance liquid chromatography.     

Simultaneous densitometric analysis of amlodipine,hydrochlorothiazide, lisinopril,and valsartan by HPTLC in pharmaceutical formulations and human plasma

A simple, accurate, and precise high-performance thin layer chromatographic (HPTLC) method has been developed and validated for the simultaneous quantification of antihypertensive drugs, amlodipine (AML), hydrochlorothiazide (HCTZ), lisinopril (LIS), and valsartan (VAL) in their pharmaceutical formulations and human plasma. Separation of the drugs was performed on aluminum-backed layer of silica gel 60?F₂₅₄ using a mixture of methanol–dichloromethane–glacial acetic acid (9.0:1.0:0.1, v/v/v) as the mobile phase. Densitometric determination of the separated spots was done at 215?nm. The retention factors (R_f) obtained under the optimized conditions were 0.56, 0.75, 0.29, and 0.67 for AML, HCTZ, LIS, and VAL, respectively. Linearity of the method was established in the range of 200–1,500?ng/band for AML, 300–1,500?ng/band for HCTZ, 400–2,000?ng/band for LIS, and 1,000–7,000?ng/band for VAL. The limit of detection/limit of quantitation of the method found were 54.21/164.28, 77.27/234.15, 83.45/252.87, and 156.48/474.19?ng/band for AML, HCTZ, LIS, and VAL, respectively. To determine the drugs in spiked plasma samples, solid phase extraction was performed, which provided highly consistent and quantitative recovery for all four drugs. The method was satisfactorily applied for the analysis of different tablet formulations and proved to be specific and accurate for the quality control of these drugs.     

Inflammation Due to Voriconazole‐induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa‐knockout Mice

Voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide (HCTZ ) on the enhancement of UV ‐induced inflammatory responses and UV ‐induced tumorigenesis, we utilized Xpa ‐knockout mice, which is DNA repair‐deficient and more susceptible to UV ‐induced inflammation and tumor development than wild‐type mice. Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle‐ or HCTZ ‐administered groups. Voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa ‐knockout mice. Furthermore, the investigation of UVB ‐induced DNA damage using embryonic fibroblasts of Xpa ‐knockout mice revealed a significantly higher 8‐oxo‐7,8‐dihydroguanine level in cells treated with voriconazole N‐oxide, a voriconazole‐metabolite during UV exposure. The data suggest that voriconazole plus UVB ‐induced inflammatory response may be related to voriconazole‐induced skin phototumorigenesis.     

Increase in intrinsic anion conductance upon inhibition of the electroneutral Cl(-)/HCO(3)(-) exchanger: effect of CO(2)/HCO(3)(-).

The electroneutral Cl(-)/HCO(3)(-) exchange, present at the apical membrane of rabbit gallbladder epithelium, apparently is converted into a stilbene- and dipyridamole-sensitive, nonrectifying, approximately 5-pS anion channel after the exchange is directly inhibited (inhibitors tested: hydrochlorothiazide (HCTZ), phlorizin, phenylglyoxal and diphenylamine-2-carboxylic acid (DPC)). In intact tissue, in the absence of CO(2)/HCO(3)(-) in the media, the opening of these channels causes an approximately 7-mV depolarization of the apical membrane. This has been shown to be a constant index of the total Cl(-) conductance (G(Cl)) activated. The effect of exogenous and endogenous CO(2)/HCO(3)(-) on the depolarization has now been investigated in the intact tissue by conventional microelectrodes. The anion exchange has been measured radiochemically. The presence of exogenous or endogenous CO(2)/HCO(3)(-) reduces the depolarization induced by HCTZ, phlorizin and DPC from approximately 7 to 3 mV, but 10(-4) mol/l acetazolamide restores the full depolarization. Response time, S(0.5) and Hill number are unchanged in each case. The way of bicarbonate replacement is irrelevant. The depolarization generated by phenylglyoxal, which covalently binds to the transport site of the exchanger and prevents HCO(3)(-) binding, is unaffected by CO(2)/HCO(3)(-) presence. HCO(3)(-) binding to the transport site is suggested to partially hinder the conversion of the exchanger into the channel.     

A tantalum electrode coated with graphene nanowalls for simultaneous voltammetric determination of dopamine,uric acid,L-tyrosine,and hydrochlorothiazide

The authors describe a voltammetric sensor for simultaneous determination of dopamine (DA), uric acid (UA), L-tyrosine (Tyr), and the diuretic drug hydrochlorothiazide (HCTZ). The assay is based on the use of graphene nanowalls deposited on a tantalum substrate. The nanowalls are characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, electrochemical impedance spectroscopy, and cyclic voltammetry. The nanowalls are vertically grown on the substrate by direct-current arc plasma jet chemical vapor deposition. The modified electrode is shown to enable simultaneous differential pulse voltammetric determination of DA, UA, Tyr, and HCTZ. The graphene nanowalls display a large specific surface, high conductivity, and a large number of catalytically active sites for oxidation of analytes. Simultaneous detection is performed best at a pH value of 7.0 and at peak potentials of 0.124 V (vs. SCE) for DA, 0.256 V for UA, 0.536 V for Tyr and 0.708 V for HCTZ. The respective detection limits are 0.04 μM, 0.1 μM, 0.6 μM and 0.4 μM. The results show that this graphene wall modified electrode is a promising tool for the design of sensitive, selective, and stable sensors.

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Graphical abstract The graphene-based differential pulse voltammetric sensor for simultaneous determination of dopamine, uric acid, L-tyrosine, and hydrochlorothiazide exhibits high selectivity, sensitivity, and stability.

     

RP-HPLC Method for the Simultaneous Estimation of Eight Cardiovascular Drugs

The present study describes a convenient method for the separation and simultaneous determination of eight drugs used in cardiovascular diseases, viz., atenolol (ATN), lisinopril (LISI), hydrochlorothiazide (HCTZ), enalapril maleate (ENA), amlodipine besylate (AMLO), losartan potassium (LOSA), valsartan (VAL) and atorvastatin calcium (ATOR) in pharmaceutical formulations. A ZORBAX Rx-C8 column (250 × 4.6 mm, 5 μm particle size) was used with mobile phase consisting of acetonitrile, 10 mM dipotassium hydrogen phosphate buffer (pH 2.2 adjusted with orthophosphoric acid) using a gradient program and quantitative evaluation was performed at 210 nm with a flow rate of 1.0 mL min^?1. Suitability of this method for the quantitative determination of the drugs was proved by validation in accordance with International Conference on Harmonization guidelines. The method is selective, precise, robust, accurate and can be used for routine analysis of 15 combination pharmaceutical formulations in quality control.     

Development and Validation of a Stability-Indicating LC Method to Quantify Hydrochlorothiazide in Oral Suspension for Pediatric Use

A stability-indicating reversed-phase high-performance liquid chromatography (LC) method was developed and validated for the determination of hydrochlorothiazide in an oral suspension. Isocratic chromatography was performed on a C₁₈ column with 0.1 M sodium phosphate buffer pH 3.0/acetonitrile (70:30 v/v) as mobile phase, at a flow rate of 1.3 mL min⁻¹, and UV detection at 254 nm. The method was linear (r ² = 0.9998), accurate (mean recovery = 100.3%), and precise (RSD <2%). It was also validated for specificity and robustness. The method was successfully applied for the quality control analysis of a new pharmaceutical formulation of HCTZ for pediatric use.     

Dual separation mode for simultaneous determination of antihypertensive drug combinations by high-performance liquid chromatography

A simple, reproducible and efficient dual separation mode high performance liquid chromatographic (HPLC) method was developed for simultaneous determination of antihypertensive drug combinations including; hydrochlorothiazide (HCTZ), valsartan (VAL), amiloride (AML) and captopril (CAP). The newly developed Platinum™ column, which provides a dual-mode separation with its polar and non-polar sites, was used for rapid separation of these co-administered drugs. Good resolution was obtained when Platinum™ column was used compared with C₁₈ column. Additionally, simple isocratic mode with mobile phase containing methanol and 0.02 mole L⁻¹ phosphate buffer adjusted to pH 3.0 (45:55, v/v) was used for separation. The flow rate was 0.5 mL min⁻¹ and effluent was monitored at 270 nm. All the investigated drugs were completely separated within less than 6 min. The linearity range obtained for the developed HPLC method was 0.5-100 μg mL⁻¹ with detection limits of 0.13-1.2 μg mL⁻¹ for all the studied drugs. The method was validated in accordance with the requirements of ICH guidelines and shown to be suitable for intended applications. The method was successfully used for determination of the studied drugs in pure form and pharmaceutical dosage forms without prior need for separation. The method is valuable for quality control laboratories for simultaneous determination of these co-administered antihypertensive drugs in binary, ternary and quaternary mixtures.     

Electronic structure of thiazides studied by 35Cl‐NQR spectroscopy and DFT calculations

NQR frequencies were determined for the ³⁵Cl isotope in a few benzodithiazine derivatives, chlorothiazide (CTZ), hydrochlorothiazide (HCTZ), althiazide (ATZ), trichloromethiazide (TCTZ), benzthiazide (BTZ) and furosemide (FSE), at liquid nitrogen and room temperatures. It was found that changes of the substituent at C‐3 are transferred through a system of coupled rings on to the chlorine atom at C‐6. The substituents occurring in thiazides can be ordered according to increasing electron‐acceptor properties as —CH₂SCH₂Ph < —CH₂SCH₂CH?CH₂ <—CHCl₂. At the liquid nitrogen temperature —CH₂SCH₂Ph and —CH₂SCH₂CH?CH₂ are electron donors, and CHCl₂ is an electron acceptor, whereas at room temperature —CH₂SCH₂Ph is an electron donor and —CH₂SCH₂CH?CH₂ and —CHCl₂ are electron acceptors. The character of the substituent properties is preserved irrespective of whether the system is aromatic or aliphatic. The NQR frequencies and substituents properties are well reproduced by the DFT B3LYP/6–311+G(2d,p) method. The topological properties of the Laplacian of the electron density were analysed within the AIM (atoms in molecules) approach. The changes in the electron density at C‐3 are correlated with the biological activity of the compounds studied. Copyright © 2003 John Wiley & Sons, Ltd.     

Sigma-borane complexes of iridium: synthesis and structural characterization

Reaction of NaBH4 with (tBuPOCOP)IrHCl affords the previously reported complex (tBuPOCOP)IrH2(BH3) (1) (tBuPOCOP = kappa(3)-C6H3-1,3-[OP(tBu)2]2). The structure of 1 determined from neutron diffraction data contains a B-H sigma-bond to iridium with an elongated B-H bond distance of 1.45(5) A. Compound 1 crystallizes in the space group P1 (Z = 2) with a = 8.262 (5) A, b = 12.264 (5) A, c = 13.394 (4) A, and V = 1256.2 (1) A(3) (30 K). Complex 1 can also be prepared by reaction of BH3 x THF with (tBuPOCOP)IrH2. Reaction of (tBuPOCOP)IrH2 with pinacol borane gave initially complex 2, which is assigned a structure analogous to that of 1 based on spectroscopic measurements. Complex 2 evolves H2 at room temperature leading to the borane complex 3, which is formed cleanly when 2 is subjected to dynamic vacuum. The structure of 3 has been determined by X-ray diffraction and consists of the (tBuPOCOP)Ir core with a sigma-bound pinacol borane ligand in an approximately square planar complex. Compound 3 crystallizes in the space group C2/c (Z = 4) with a = 41.2238 (2) A, b = 11.1233 (2) A, c = 14.6122 (3) A, and V = 6700.21 (19) A(3) (130 K). Reaction of (tBuPOCOP)IrH2 with 9-borobicyclononane (9-BBN) affords complex 4. Complex 4 displays (1)H NMR resonances analogous to 1 and exists in equilibrium with (tBuPOCOP)IrH2 in THF solutions.