Isotopic exchange reactions of bibenzyl and benzylic derivatives with deuterium (D2) and tritium (T2) gas, catalyzed by Pd/C, have been performed in solution. Catalyst pre-washed with the reacting gas showed improved H/D or H/T exchange. In aprotic solvents such as dioxane, ethyl acetate, and cyclohexane, 3.1 to 3.5 D atoms were exchanged under standard conditions in 1 h, while in benzene 1 D atom was exchanged. D atoms adsorbed on the catalyst surface were rapidly replaced by H from methanol, diluting the D2 gas phase. Compounds containing O or N atoms enhanced the rate of exchange, while S atoms inhibited the catalyst activity. The H/D exchange obeyed pseudo-first order kinetics when D2 gas was used in large excess. When T2 gas replaced D2, a substantial decrease in rate of exchange was observed, due to the slower dissociative chemisorption of T2 on the catalyst surface. The results indicated that this exchange process occurred through two simultaneous mechanisms. The breaking of the CH bond appeared to be the rate-determining step.

The synthesis of six useful auxins labelled with tritium is described. The following compounds were prepared: 3-indoleacetic acid-5-H-3 (28.9 Ci-1.07 TBq/mmol), 3-indolebutyric acid-5-H-3 (7.3 Ci-270 GBq/mmol), 1-naphthylacetic acid-4-H-3 (27.6 Ci-1.02 TBq/mmol), 2,4-dichlorophenoxyacetic acid-5-H-3 (18.5 Ci-685 GBq/mmol), 2(2,4-dichlorophenoxy-5-H-3)-propionic acid (20.7 Ci-766 GBq/mmol), 2(2,4-dichlorophenoxy)-propionic acid-3-H-3 (0.39 Ci-14.4 GBq/mmol), and 4-chlorophenoxyacetic acid-2-H-3 (13.3 ci-492 GBq/mmol).

A radioimmunoassay for clenbuterol detection in cattle has been validated and used to monitor treated cattle. The tracer used was 4-amino-3,5-dichloro-alpha(tert-butylamino-methyl) benzyl alcohol (benzyl-3H)(clenbuterol) prepared by catalytic tritiation with tritium gas of 4-amino-3,5-dibromo-alpha-(tert-butylamino)-acetophenone, followed by chlorination at positions 3 and 5 in the aromatic ring. The rabbit antiserum was raised against a diazotized clenbuterol/human serum albumin conjugate. The assay described was sensitive (7.8 pg/tube) and reproducible. The intra- and inter-assay variability, which was assessed by measuring known quantities of clenbuterol in plasma, urine and faeces, was satisfactory for RIA. When this assay was used to monitor treated cattle the concentrations of clenbuterol in plasma, urine and faeces were directly related to the administered dose. The absorption and elimination of clenbuterol in cattle was rapid. Data obtained were consistent with results obtained in other species where a rapid clearance rate was also demonstrated.

Primary, secondary and tertiary benzylamines were oxidized to aromatic aldehydes and ketones when their HX (X = Br, I) salts were heated, under anhydrous conditions, in excess of alkyl sulphoxide. Quaternary benzylammonium salts also react, to give lower yields of carbonyl compounds. Benzylamine is being oxidized in the presence of anhydrous HX formed in situ by the reaction of alkyl halide and hydrosiloxane, but not in the presence of aqueous HX.

AbstractTritiated clenbuterol was prepared starting from 4‐aminoacetophenone (I) which was selectively brominated to 4‐amino‐3,5‐dibromoacetopheno ne (II), then to 4‐amino‐α,3,5‐tribromoacetophenone (III) and reacted with tert.butylamine to 4‐amino‐3,5‐dibromo‐α‐tert.butylaminoacetoph‐none(IV). (IV) was dehalogenated and reduced with tritium gas to give 2‐(tert.butylamino)‐1‐(4‐amino‐[3,5‐3H]‐phenyl)‐[1‐3H]‐ethanol (V). This tritiated compound underwent selective aromatic chlorination to give the desired 2‐(tert.butylamino)‐1‐(4‐amino‐3,5‐dichlorophenyl)‐[1‐3H]‐ethanol, [ethanol‐1‐3H]clenbuterol, with specific activity of 13.4 Ci/mmol (496 GBq/mmol).

Abstract1,2,3‐Benzenetricarboxylic acid (hemimellitic acid) tritiated in position 5 has been labelled at a specific activity of 16.2 Ci/mmol, starting from 3‐bromo naphthalic anhydride. Attempts at direct bromination of the acid followed by tritiodebromination, or of general labelling by hydrogen‐tritium exchange gave poor results.

AbstractThe aryl bromides (I) are hydroxycarbonylated with carbon monoxide (II) in the presence of calcium formate (III) or other formic acid salts and Pd‐catalysts to give the substituted benzoic acids (IV).

Dibromochloropropane (DBCP) is an effective nematocide which has been shown to suppress spermatogenesis and cause infertility in both men and male rats. There are no similar reports concerning the effects of DBCP on female reproduction. The purpose of the present study was to attempt to interfere with the various phases of oogenesis. Proestral or pregnant rats were injected subcutaneously once with 40 mg/kg DBCP on one of each days of L12-L20 of gestation; a double dose (80 mg/kg) was injected in eight consecutive days (L11-L18). In addition, L13 fetuses were injected--directly into the amniotic sac--with 0.1 mg DBCP. Pooled data from the various days of gestation revealed that postimplantation losses were three times as high in the DBCP-treated animals as in DMSO-treated controls. Perinatal deaths were 58% higher and mean pup weights were 30% lower in the DBCP-treated rats than in controls. The reproductive performance of females exposed to DBCP while in utero was affected only to a limited degree (reduced number of ovulations and implantations) as compared with their DMSO counterparts. Doubling the dose (80 mg/kg) seriously reduced the birth weight of pups (50% of controls), all of which died within several hours post-partum. Direct injection of DBCP into embryos or to proestral rats did not have any adverse effects on their future reproductive performance. In contrast to the effect on spermatogenesis, it appears that oogenesis and ova are unaffected by DBCP.

Adult male rats were injected with [3H]dibromochloropropane dissolved in dimethylsulfoxide containing about 10 X 10(6) dpm. Blood from the tail and 24-h urine samples were collected up to 2 days post-injection. Tissue samples were further taken from the kidneys, liver, spleen, adrenals, epididymis, seminal vesicles and testes 7 h and 7 days post-injection. The results demonstrate that there is no preference in labelling of the testes compared with other organs, and the kidney and liver may have an important role in the elimination of DBCP.

The solvated ion pair [(C8H17)3NCH3]+[RhCl4]−, formed from aqueous rhodium trichloride and Aliquat®-336 in a two-phase liquid system, was shown to hydrogenate α,β-unsaturated ketones and esters selectively at the C-C double bonds. The reduction of benzylideneacetophenone was found to follow first-order kinetics in the substrate only below 0.2 M, and to approach second-order in H2; at partial pressures of < 0.12 atm. The catalysis also proved to depend on the nature of the solvent, the phase transfer catalyst and the stirring rate. The observed activation energy Ea = 12.4 kcal mol−1 suggests that the process is both chemically and diffusion controlled.

AbstractAromatische Brom‐ und Iodverbindungen (I) werden mit Polymethylhydrosiloxanen (II) in Gegenwart des Pd‐Katalysators (III) zu (IV) dehalogeniert; analog (I) werden die Halogenverbindungen (V), (VII), (IX) und (XI) beispielhaft aufgeführt.

All antipsychotics bind to the dopamine D2 receptor. An “optimal” level of D2 receptor blockade with antipsychotics is thought to ameliorate the positive symptoms of schizophrenia. However, persistent D2 receptor blockade is associated with a deteriorating clinical response in a subset of patients. Interestingly, antipsychotics with a weaker D2 receptor binding profile appear somewhat superior in this respect. This evidence challenges the hypothesis that D2 receptor blockade is the sole mechanism of antipsychotic efficacy and points to consistent inter-individual responses to antipsychotic treatment.Here, we hypothesize that clinically effective doses of antipsychotics would lead to the formation of a D2 receptor “reserve” that is likely composed of presynaptic dopamine D2 autoreceptors. The majority of the remaining postsynaptic dopamine receptors are instead occupied by antipsychotics. Endogenous dopamine would then mainly interact with this D2 autoreceptor reserve, thereby reducing the presynaptic synthesis and release of dopamine and resulting in an indirect antipsychotic effect. This new proposal reconciles conceptual and empirical gaps encountered when clinical outcomes are compared to the pharmacology of antipsychotics.

In order to label dopamine D2 receptors selectively we tritiated the potent benzamide neuroleptic, YM-09151-2 (26.7 Ci/mmol). The binding of [3H]-YM-09151-2 to canine striatal membranes was saturable and specific with a KD of 57 pmol/l and Bmax of 36 pmol/g tissue as determined by Scatchard analysis. The KD, but not the Bmax, of [3H]-YM-09151-2 increased 6-fold in the absence of sodium chloride. [3H]-YM-09151-2 labeled 40% more sites than [3H]-spiperone in the same tissue homogenate. [3H]-YM-09151-2 binding was inhibited by dopaminergic drugs in a concentration and stereoselective manner with the appropriate dopamine D2 receptor profile. Thus, dopamine agonists inhibited [3H]-YM-09151-2 binding to canine striatal membranes with the following rank order of potency: (−)-N-n-propylnorapomorphine > apomorphine > (±)-6,7-dihydroxy-2-aminotetralin > (+)-N-n-propylnorapomorphine > dopamine > (−)-noradrenaline > serotonin > (−)-isoprenaline. Dopaminergic antagonists competed for [3H]-YM-09151-2 binding with the following order of potency: spiperone > (+)-butaclamol > haloperidol > clebopride > (−)-sulpiride > SCH-23390 > (−)-butaclamol. Furthermore, dopamine agonists recognized 2 states of the receptor labeled by [3H]-YM-09151-2, D 2 high and D 2 low . The D 2 high state of the receptor could be converted to D 2 low by guanine nucleotides and sodium ions as is the case for [3H]-spiperone binding to D2 receptors. [3H]-YM-09151-2 appears to be a more selective ligand for dopamine D2 receptors than [3H]-spiperone, since YM-09151-2 displays approximately 9-fold lower affinity than spiperone for cortical serotonergic (S2) receptors. [3H]-YM-09151-2 may become a useful tool for the selective characterization of dopamine D2 receptors.

AbstractAryliodide (I) und Arylbromide (VI) reagieren mit Kohlenmonoxid (II) und dem Polymethylhydrosiloxan (III) in Gegen‐ 79 wart katalytischer Mengen des Palladiumkomplexes (IV) zu den Benzaldehyden (V) bzw. (VII).

Radioactive peaks in gas-liquid radiochromatography can be tentatively identified by predicted retention indexes on polar and apolar stationary phases. 3-Fluorotoluene reacts with tritium to give tritium labeled 3-fluorotoluene, 3-fluoromethylcyclohexane, 3-fluoro-5-methylcyclohex-1-ene, 4-fluoro-6-methylcyclohex-1-ene, 1-fluorocyclohex-1-ene and flurocyclohexane. The RI prediction method is also able to confirm the structure of cyclohexane dimer using a reference compound and the SRIR relationship observed for substituted cyclohexenes.

Abstract1‐Methyl‐[2‐13C]ethylene oxide (I) is prepared in a four‐step synthesis, starting from [1‐13C]propionic acid. A method for an efficient α‐chlorination of low carboxylic acids is developed, 2‐chloropropionyl chloride being esterified without separation to give 72% of phenyl‐2‐chloro‐[1‐13C]propionate. The ester is hydrogenated with LiAlH4 to give 95% yield of 2‐chloro‐[1‐13C]propan‐1‐ol which is then subjected to alkaline dehydrochlorination, giving 35% yield of the isolated product (I). This micro‐scale method is also suitable for syntheses of 14C‐labelled epoxides of low molecular weight.