Rapid ‘on-column’ preparation of hydrogen [11C]cyanide from [11C]methyl iodide via [11C]formaldehyde

Hydrogen [¹¹C]cyanide ([¹¹C]HCN) is a versatile ¹¹C-labelling agent for the production of ¹¹C-labelled compounds used for positron emission tomography (PET). However, the traditional method for [¹¹C]HCN production requires a dedicated infrastructure, limiting accessibility to [¹¹C]HCN. Herein, we report a simple and efficient [¹¹C]HCN production method that can be easily implemented in ¹¹C production facilities. The immediate production of [¹¹C]HCN was achieved by passing gaseous [¹¹C]methyl iodide ([¹¹C]CH₃I) through a small two-layered reaction column. The first layer contained an N-oxide and a sulfoxide for conversion of [¹¹C]CH₃I to [¹¹C]formaldehyde ([¹¹C]CH₂O). The [¹¹C]CH₂O produced was subsequently converted to [¹¹C]HCN in a second layer containing hydroxylamine-O-sulfonic acid. The yield of [¹¹C]HCN produced by the current method was comparable to that of [¹¹C]HCN produced by the traditional method. The use of oxymatrine and diphenyl sulfoxide for [¹¹C]CH₂O production prevented deterioration of the molar activity of [¹¹C]HCN. Using this method, compounds labelled with [¹¹C]HCN are now made easily accessible for PET synthesis applications using readily available labware, without the need for the ‘traditional’ dedicated cyanide synthesis infrastructure.

In a reaction column, gaseous [¹¹C]methyl iodide was converted to [¹¹C]formaldehyde in a first layer containing N-oxide and then transformed into hydrogen [¹¹C]cyanide in a second layer containing hydroxylamine-O-sulfonic acid within 2 minutes.     

Quantitative evaluation of the biosynthetic pathways leading to δ-aminolevulinic acid from the Shemin precursor glycine via the C5 pathway in Arthrobacter hyalinus by analysis of 13C-labeled coproporphyrinogen III biosynthesized from [2-13C]glycine, [1-13C]acetate, and [2-13C]acetate using 13C NMR spectroscopy

The biosynthetic pathways leading to δ-aminolevulinic acid (ALA) from the Shemin precursor glycine via the C5 pathway in Arthrobacter hyalinus were quantitatively evaluated by means of feeding experiments with [2-¹³C]glycine, sodium [1-¹³C]acetate, and sodium [2-¹³C]acetate, followed by analysis of the labeling patterns of coproporphyrinogen III (Copro’gen III) (biosynthesized from ALA) using ¹³C NMR spectroscopy. Two biosynthetic pathways leading to ALA from glycine via the C5 pathway were identified: i.e., transformation of glycine to l-serine catalyzed by glycine hydroxymethyltransferase, and glycine synthase-catalyzed catabolism of glycine to N ⁵,N ¹⁰-methylene-tetrahydrofolic acid (THF), which reacts with another molecule of glycine to afford l-serine. l-Serine is transformed to acetyl-CoA via pyruvic acid. Acetyl-CoA enters the tricarboxylic acid cycle, affording 2-oxoglutaric acid, which in turn is transformed to l-glutamic acid. The l-glutamic acid enters the C5 pathway, affording ALA in A. hyalinus. A ¹³C NMR spectroscopic comparison of the labeling patterns of Copro’gen III obtained after feeding of [2-¹³C]glycine, sodium [1-¹³C]acetate, and sodium [2-¹³C]acetate showed that [2-¹³C]glycine transformation and [2-¹³C]glycine catabolism in A. hyalinus proceed in the ratio of 52 and 48 %. The reaction of [2-¹³C]glycine and N ⁵,N ¹⁰-methylene-THF, that of glycine and N ⁵,N ¹⁰-[methylene-¹³C]methylene-THF generated from the [2-¹³C]glycine catabolism, and that of [2-¹³C]glycine and N ⁵,N ¹⁰-[methylene-¹³C]methylene-THF transformed the fed [2-¹³C]glycine to [1-¹³C]acetyl-CoA, [2-¹³C]acetyl-CoA, and [1,2-¹³C₂]acetyl-CoA in the ratios of 42, 37, and 21 %, respectively. These labeled acetyl-CoAs were then incorporated into ALA. Our results provide a quantitative picture of the pathways of biosynthetic transformation to ALA from glycine in A. hyalinus.     

Synthesis of [carbonyl-C]acetophenone via the Stille cross-coupling reaction of [1-C]acetyl chloride with tributylphenylstannane mediated by Pd2(dba)3/P(MeNCH2CH2)3N·HCl

The Stille cross-coupling reaction of [1-¹¹C]acetyl chloride with tributylphenylstannane leading to [carbonyl-¹¹C]acetophenone was studied with the goal of developing a new ¹¹C-labeling method for positron emission tomography tracer synthesis. The coupled product [carbonyl-¹¹C]acetophenone was synthesized using the Pd₂(dba)₃/P(MeNCH₂CH₂)₃N·HCl system with a 60-61% radiochemical conversion from [1-¹¹C]acetyl chloride (decay-corrected, n = 3).     

An Efficient Synthesis of Optically Active [4-13C] Labelled Quorum Sensing Signal Autoinducer-2

A new synthetic route for the quorum sensing signal Autoinducer-2 (AI-2) is described and used for the preparation of [4-¹³C]-AI-2 starting from [1-¹³C]-bromoacetic acid. The key step in this process was the enantioselective reduction of an intermediate ketone. This synthesis provides, selectively, both enantiomers of the labelled or unlabelled parent compound, (R) or (S)-4,5-dihydroxypentane-2,3-dione (DPD) and was used for an improved synthesis of [1-¹³C]-AI-2.     

A new convenient method for the synthesis of [2-C]thymine utilizing [C]phosgene

β-(N-Benzoylamino)methacrylamide, a key intermediate for the preparation of [2-¹¹C]thymine, was synthesized in three steps from ethyl α-formylpropionate and NH₃. Reaction of the alkali metal salts of β-(N-benzoylamino)methacrylamide with [¹¹C]phosgene gave [2-¹¹C]thymine. The yield of [2-¹¹C]thymine was 362 ± 53 MBq at EOS (n = 3) (18 MeV proton beam; 10 μA, 10 min). The total synthesis was accomplished in just 16 min from the end of bombardment.     

Simple NMR method for assigning relative stereochemistry of bridged bicyclo[3.n.1]-2-enes and tricyclo[7.n.1.0]-2-enes

The stereochemistry of syn and anti-forms of bridged bicyclo[3.n.1]-2-ene, tricyclo[7.n.1.0]-2-ene (n=1-3) and bicyclo[4.3.1]dec-7-ene derivatives can be assigned from the ¹³C chemical shift difference of the double bond. Both syn-9-R-bicyclo[3.3.1]non-2-enes and syn-13-R-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes have a large shielding difference between sp² carbons, while the corresponding anti-forms have a smaller one. In contrast, 8-R-bicyclo[3.2.1]oct-2-enes and 12-R-tricyclo[7.2.1.0^2,7]dodec-2(7)-enes have an inverse correlation. The reason of this specificity is the influence of the γ-gauche effect on the chemical shift of C(2) atom. The GIAO theory has been applied to investigate the ¹³C chemical shifts. The conformational equilibrium in the formamide group of 13-formylamino-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes has been studied.     

Chemoenzymatic synthesis of [3,9-C]-labeled NeuAc and KDN

The chemoenzymatic synthesis of ¹³C-labeled sialic acid (NeuAc) and 3-deoxy-d-glycero-d-galacto-2-nonulosonic acid (KDN) as useful molecular probes for studying the conformation of sialyl or KDN oligosaccharides attached to proteins was performed by using [6-¹³C]-ManNAc, [6-¹³C]-Man and [3-¹³C]-pyruvic acid sodium salt. In the synthesis of the compounds, 5,6-anhydro intermediates were found to easily provide not only 6-¹³C-labeled but also 5-, and 6-modified NeuAc and KDN analogs. Furthermore, it was demonstrated that identical results are obtained by NMR for both [3,9-¹³C]-NeuAc and 1:1 mixtures of [3-¹³C]- and [9-¹³C]-NeuAc.     

Biosynthetic studies of marine lipids—3 : Experimental demonstration of the course of side chain extension in marine sterols

The Pacific sponge Aplysina fistularis was fed cholesterol-[4-¹⁴C],(24R)-methyl-25-dehydrocholesterol-[26-¹⁴C] (epicodisterol[26-¹⁴C]), (24S)-methyl-25-dehydrocholesterol-[26-¹⁴C] (codisterol-[26-¹⁴C]), and 24-methylenecholesterol-[28-¹⁴C]. Only epicodisterol, which has the same stereochemistry at C-24 as (24R,25S)-24,26-dimethylcholesterol (aplysterol), was converted with high efficiency into (24R)-24,27-dimethyl-25-dehydrocholesterol (25-dehydroaplysterol). Further side chain extension [to E-(24R)-24,26,27-trimethyl-25-dehydrocholesterol (verongulasterol)] could also be demonstrated.     

Stability constants of cesium complexes with 18-crown-6 in ionic liquids

The stability constants of the complex[Cs(18C6)]⁺ (18C6 is 18-crown-6 (L)) in N-butylpyridinium methyl sulfate (I) and of the complex [Cs(18C6)₂]⁺ in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide (II) were measured by using ¹³³Cs NMR spectroscopy at 23°C. It was found that logK(Cs + L) in solvent I is 1.20±0.13 and logK(CsL + L) in solvent IIis 1.18±0.05. For the complex [Cs(18C6)₂]⁺, the dependence of its stability constant on the temperature in the 23–50°C range was obtained and the enthalpy change in the complexation was determined: ΔH(CsL + L)= ?47 kJ/mol. It was demonstrated that the enthalpy change is favorable for the formation of [Cs(18C6)₂]⁺, while the entropy change hinders the complexation.     

Cyclization of substituted 3,4-diaminopyridines into 1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxide derivatives during the nitration process

The nitration of pyridine-3,4-diamine, its N,N′-diacetyl derivative, and N ⁴-alkylpyridine-3,4-diamines with excess nitric acid in concentrated sulfuric acid at 60°C was accompanied by cyclization with formation of the corresponding 1-substituted 4-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxides. 4-Chloro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxide derivatives were obtained under analogous conditions from 2-chloropyridine-3,4-diamine, its N,N′-diacetyl derivative, and 2-chloro-N ⁴-methylpyridine-3,4-diamine. The nitration of these compounds at 80–90°C gave 4-chloro-7-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxides.     

Assignment of C NMR spectrum for blepharismin C based on biosynthetic studies

Blepharismins, toxic pigments of the ciliate Blepharisma japonicum, are polycyclic ring-condensed compounds. Assignment of ¹³C NMR signals for blepharismin C, a major constituent of blepharismins, was achieved by analyses of the HMQC, HMBC, and INADEQUATE spectra of ¹³C-enriched samples obtained by feeding experiments using sodium [1-¹³C], [2-¹³C], and [1,2-¹³C₂]acetates.     

Second crystal modification of 1,10-diazonia-18-crown-6 dichloride

The second crystal modification (II) of 1,10-diazonia-18-crown-6 dichloride [H₂DA18C6]²⁺·2Cl^?, where [H₂DA18C6]²⁺ is the 1,10-diaza-18-crown-6 dication (DA18C6) with two protonated nitrogen atoms, was investigated by XRD. The monoclinic modification (II) (space group P2₁/n, a = 9.600 Å, b = 5.689 Å, c = 15.749 Å, β = 91.03°, Z = 2) was solved by direct methods and refined by full-matrix least squares analysis in an anisotropic approximation to R = 0.032 for all 2494 independent reflections collected (CAD-4 automatic diffractometer, λMoK _α). In modification II, the conformation of the DA18C6 dication and the ion packing differ from those in triclinic modification I investigated previously.     

The synthesis of a new cardiac sympathetic nerve imaging agent N-[11C]CH3-dopamine and biodistribution study

In this study, we synthesized and characterized N-[¹¹C]methyl-dopamine ([¹¹C]MDA) for cardiac sympathetic nerve imaging. [¹¹C]MDA was synthesized by direct N-methylation of dopamine with [¹¹C]methyl iodide and purified by semi-preparation reverse high pressure liquid chromatography (HPLC). The total synthesis time was 45 min including HPLC purification. The radiochemical yields of [¹¹C]MDA was 20 ± 3 %, without decay correction. The radiochemical purity was >98 % and the specific activity was about 50 GBq/mmol. The biological properties of [¹¹C]MDA were evaluated by biodistribution study in normal mice. PET imaging was performed in healthy Chinese mini-swines. Biodistribution study showed that [¹¹C]MDA had high myocardium uptake. PET/CT imaging showed [¹¹C]MDA had clear and symmetrical myocardium uptake, which was blocked obviously by injecting imipramine hydrochloride. [¹¹C]MDA would be a promising candidate of radiotracer for cardiac sympathetic nervous system imaging.     

The mechanism of acetoacetate coupling in the biosynthesis of hygrine

Sodium[3-¹⁴C]- and [4-¹⁴C]-acetoacetate were wick fed to 3-month-old Nicandra physaloides plants. The hygrine was isolated and by degradation it was shown that acetoacetate is a precursor. It was also shown that the C(2) carbon is the reactive site in its condensation with the N-methyl-Δ′-pyrrolinium cation.     

Spectroscopic and electrochemical properties of mixed-ligand cyclopalladinized complexes of deprotonated forms of 2-(2-thienyl)pyridine and 2-phenylpyridine with 1,10-phenantroline and its 1,4-diazine derivatives

A comparative study of [Pd(N?C)(N?N)]⁺ complexes {(N?C)^? are deprotonated forms of 2-phenylpyridine and 2-(2-thienyl)pyridine and (N^N) is 1,10-phenantroline, dipyrido[f,h]quinoxaline, dipyrido[a,c]phenazine or 6,7-dicyanodibenzo[f,h]quinoxaline} was carried out by the methods of ¹H NMR, electronic absorption and emission spectroscopy, and cyclic voltammetry. Optical and electrochemical properties of dipyrido-substituted 1,4-diazines are conditioned by the electron transfer involving π* orbitals localized on weakly interacting phenantroline (π*_phen) and diazne (π*_diaz) components.     

Skew-trapezoidal bipyramidal diorganotin(IV) bischelates. Crystal structure of dimethylbis(2-pyridinethiolato-N-oxide)tin(IV)

Dimethylbis(2-pyridinethiolato-N-oxide)tin(IV), Me₂Sn(2-SPyO)₂, crystallizes in space group P2₁/c with a 9.877(3), b 11.980(4), c 13.577(3) Å, β 109.1(2)° and Z = 4. The structure was refined to R_F = 0.036 for 2263 Mo-K_α observed reflections. The coordination geometry at tin is a skew-trapezoidal bipyramid, with the oxygen [SnO 2.356(3), 2.410(4) Å] and sulfur [SnS 2.536(1), 2.566(1) Å] atoms of the chelating groups occupying the trapezoidal plane and the methyl groups [SnC 2.106(6), 2.128(7) Å] occupying the apical positions. The methyl-tin-methyl skeleton is bent [CSnC 138.9(2)°]. The SSnS angle is 77.8(1)°, but the OSnO angle is opened to 136.7(1)° to accommodate the intruding methyl groups. The carbontincarbon angles predicted from quadrupole splitting (^119mSn Mössbauer) and one-bond ¹¹⁹Sn¹³C coupling constant (solution ¹³C NMR) data agree closely with the experimental value.     

Effect of solvation on the thermodynamics of formation for 18-crown-6 ether complexes with glycine and triglycine in water-ethanol solutions at 298 K

Using data from calorimetric titration, standard thermodynamic parameters logK ^○, Δ_r G ^○, Δ_r H ^○, and TΔ_r S ^○ of the formation of 18-crown-6 ether (18C6) molecular complex with triglycine (3Gly), [3Gly18C6] in H₂O-EtOH solvents with contents of ethanol x ranging between 0.0 and 0.5 mole fractions are calculated. Increasing the concentration of EtOH in the solvent is found to raise the reaction’s exothermicity from ?5.9 to ?21.0 kJ mol^?1 and logK ^○ [3Gly18C6] from 1.10 to 2.53. A comparative analysis of the effect the composition of H₂O-EtOH solvent has on the reactions of [3Gly18C6] and [Gly18C6] formation is performed. As in case of [Gly18C6] formation, the changes in the complex’s enthalpy of solvation Δ_tr H ^○([3Gly18C6]) are close to the Δ_tr H ^○(18C6) parameter and differ considerably from the Δ_tr H ^○(3Gly) value, testifying to the crucial role 18C6 plays in changing the [3Gly18C6] state of solvation. The ratio between solvation contributions from reagents to Δ_tr G ^○ of [3Gly18C6] formation is found to differ from that the one between the corresponding contributions to Δ_tr H _r ^o : in transferring from water to H₂O-EtOH mixtures, the increase in the positive Δ_tr G ^○(18C6) values is slight and therefore negligible when compared to Δ_tr G ^○(3Gly).     

N-phosphonio formamidine derivatives: Synthesis,characterization, X-ray crystal structures,and deprotonation reactions

A simple and efficient method for the preparation of N-phosphonio formamidine derivatives of the general formula [R”₂N?C(H)=N?P(R’)R₂]⁺X^? is described. The data recorded in solution and the single crystal X-ray studies revealed that these compounds are best described by the combination of the two mesomeric N-phosphonio formamidine [R”₂N?C(H)=N?P(R’)R₂]⁺ and iminium phosphazene [R”₂N=C(H)?N=P(R’)R₂]⁺ forms. Formamidine phosphorus ylides ⁱPr₂N?C(H)=N?P(CH₂)R₂ were prepared after addition of ^tBuLi at –78 °C from the corresponding N-phosphonio compounds. [(PhCN)₂Pd(Cl)₂] was reacted with ⁱPr₂N?C(H)=N?P(CH₂)ⁱPr₂ to form the dimeric complex [(ⁱPr₂N?C(H)=N?P(CH₂)ⁱPr₂)Pd(Cl)(μ-Cl)]₂ which was structurally characterized by X-ray analysis. The deprotonation reactions conducted on [ⁱPr₂N?C(H)=N?PPh₃]⁺X^? occurred via an intramolecular rearrangement to give the cyanamide compound ⁱPr₂N?C≡N and PPh₃; transient formation of the amino-phosphazene-carbene ⁱPr₂N?C?N=PPh₃ was not observed.     

Complexation of sodium and silver ions by the cryptand 4,7,13-trioxa-1,10-diazabicyclo[8.5.5]eicosane in a range of solvents

The apparent stability constants (K) of the cryptates [AgβC21C₅]⁺ and [Na·C21C₅]⁺ (C21C₅ = 4,7,13-trioxa-1,10-diazabicyclo[8.5.5]eicosane) have been determined in a range of solvents. For [Na·C21C₅]⁺ log (K/dm³ mol⁻¹) = 2.87, 3.72, 3.76, 3.98, 5.08 and 5.12 at 298.2 K in dimethylformamide, pyridine, methanol, acetone, acetonitrile and propylene carbonate, respectively, in the presence of 0.05 mol dm⁻³ tetraethylammonium perchlorate supporting electrolyte. These values are substantially lower than those observed for [Na·C211]⁺ (C211 = 4,7,13,18-tetraoxa-1,10-diazabicyclo[8.5.5]eicosane) and this is attributed to the presence of one less oxygen atom in C21C₅ than in C211. A similar relationship is observed for [Ag·C211]⁺ and [Ag·C21C₅]⁺, where, for the latter cryptate, log (K/dm³ mol⁻¹) = 5.19, <2, 7.62, 8.58 and 4.55 at 298.2 K in dimethylformamide, pyridine, methanol, acetone and acetonitrile, respectively.     

H and C NMR assignments of the three dicyclopenta-fused pyrene congeners

Complete ¹H and ¹³C NMR assignments of the (di-)cyclopenta-fused pyrene congeners, cyclopenta[cd]- (2), dicyclopenta[cd,fg]- (3), dicyclopenta[cd,jk]- (4) and dicyclopenta[cd,mn]pyrene (5), respectively, are achieved using two-dimensional (2D) NMR spectroscopy. The experimental ¹³C chemical shift assignments are compared with computed ab initio CTOCD-PZ2/6-31G^∗∗13C chemical shifts; a satisfactory agreement is found. Substituent-induced chemical shifts in the pyrene core induced by annelation of cyclopenta moieties are discussed. Effects of dicyclopenta topology on electronic structure are illustrated for 3-5.