Gerhard Hägele

Perspectives in high-resolution solid-state nuclear magnetic resonance, with emphasis on combined rotation and multiple-pulse spectroscopy

Recent trends of general interest in high-resolution NMR of solids are mentioned, and some examples briefly discussed. Stress is laid on the use of the multiple-pulse technique, particularly when combined with magic-angle spinning to give CRAMPS. Two studies of proton CRAMPS are described, one concerning hydrogen bonding in carboxylic acids and the other involving phosphonic acid derivatives. The relationship between proton isotropic chemical shifts and hydrogen-bond distances is explored in some detail. A clear correlation is found.

Enzyme catalysed resolution of aminophosphonic acids - I - serin and isoserin analogues

Abstract Lipase PS (Pseudomonas- Amano) was proved to to be the catalyst of choice for the transesterification reaction of N-benzyloxycarbonyl derivatives of the phosphonic analogues of isoserin and serin. A very high enantiomeric excess was obtained for the former while the lipase showed a very poor selectivity for the latter.

SYNTHESIS, NMR INVESTIGATION AND FAB-MS CHARACTERIZATION OF 1-AMINO-2-ARYLMETHYL-DIPHOSPHONATE ESTERS

Abstract Variously substituted amino aryl-methyl-diphosphonate ethyl esters have been prepared in good yields by adding diethyl phosphonate to the corresponding Schiff bases. All compounds were characterized by NMR and MS-FAB techniques, which reveal the presence of peaks or fragmentation patterns very useful and diagnostic for constitutional assignment. Evidences for a stereospecific addition of diethyl phosphonate to the two—CH·N—sites in diaryl diimines have been observed. The presence of heteroaromatic rings such as pyridine or azo-groups renders such compounds also very attractive for complexation studies towards metals; thus, these molecules are for potential uses in agrochemistry and biodiagnostic medicine.

NMR-controlled titrations: characterizing aminophosphonates and related structures

Aminophosphonic acids, aminophosphinic acids, and aminophosphonous acids give rise to interesting protonation and metal complex formation equilibria, which can be monitored by potentiometric and NMR spectroscopic methods. A hyphenated technique referred to as NMR-controlled titrations or titration-dependent NMR spectroscopy has been introduced. Vicinal and geminal bisphosphonic acids have also been characterized by this method. Gradients (titration shifts) in chemical shifts and coupling constants were used to elucidate the structures of the protolytic species. Microscopic dissociation equilibria have also been studied by NMR-controlled titrations for glufosinate and 4-aminophenylphosphonic acid. Some comments are made on the UV-vis-controlled titration of the latter compound. Novel, advanced algorithms were used to estimate the error of analytical and NMR parameters, such as pK values, molar fractions, and ion-specific chemical shifts, describing the aminophosphonate ligands in each protonation form.

Solid‐state NMR of bisphosphonates adsorbed on hydroxyapatite

Solid‐state 31P and 13C magic angle spinning (MAS) NMR spectra were used to characterize pure bisphosphonates and also bisphosphonates adsorbed on hydroxyapatite. Four geminal bisphosphonates, including the clinically used compounds ethane‐1‐hydroxy‐1,1‐diphosphonic acid, 3‐amino‐1‐hydroxypropane‐1,1‐diphosphonic acid and 4‐amino‐1‐hydroxybutane‐1,1‐diphosphonic acid, five α,ω‐bisphosphonates and phosphonoacetic acid were investigated. NMR spectra of pure and adsorbed bisphosphonates differ in the observed linewidths and in the isotropic chemical shifts. The broad lines reflect mainly the poor crystallinity of the adsorbed compounds. Shifts of δiso in both directions do not reveal a correlation with the molecular structures. The molar ratio of phosphonates adsorbed on hydroxyapatite determined by 31P spectra without cross‐polarization (CP) is approximately two times larger for geminal bisphosphonates than for α,ω‐bisphosphonates and phosphonoacetic acid. 13C CP/MAS spectra of pure and adsorbed bisphosphonates recorded in two cases for identification of adsorbed compounds give additional information about the state of adsorbed compounds. Disodium α,ω‐dihydroxypolymethylene‐α,ω‐bisphosphonates in the solid state show characteristic 13C chemical shifts which are indicative of either odd or even numbers of CH2 groups. Copyright

Synthesis and preclinical pharmacology of 2-(2-aminopyrimidinio) ethylidene-1,1-bisphosphonic acid betaine (ISA-13-1)-a novel bisphosphonate.

AbstractPurpose. To validate our hypothesis that a bisphosphonate (BP) having a nitrogen-containing heterocyclic ring on the side chain, and with no hydroxyl on the geminal carbon would possess increased activity, and better oral bioavailability due to enhanced solubility of its calcium complexes/salts and weaker Ca chelating properties. Methods. A novel BP, 2-(2-aminopyrimidinio)ethylidene-l,l-bisphosphonic acid betaine (ISA-13-1) was synthesized. The physicochemical properties and permeability were studied in vitro. The effects on macrophages, bone resorption (young growing rat model), and tumor-induced osteolysis (Walker carcinosarcoma) were studied in comparison to clinically used BPs. Results. The solubility of the Ca salt of ISA-13-1 was higher, and the log βCa: BP stability constant and the affinity to hydroxyapatite were lower than those of alendronate and pamidronate. ISA-13-1 exhibited effects similar to those of alendronate on bone volume, on bone osteolysis, and on macrophages, following delivery by liposomes. ISA-13-1 was shown to have 1.5−1.7 times better oral absorption than the other BPs with no deleterious effects on the tight junctions of intestinal tissue. Conclusions. The similar potency to clinically used BPs, the increased oral absorption as well as the lack of effect on tissue tight junction of ISA-13-1 warrant its further consideration as a potential drug for bone diseases.

Direct chiral HPLC separation of the enantiomers of fluorinated N-arylamino-1-arylmethylphosphonate esters. Substituent effects on the enantioselectivity

Abstract Racemic N-arylamino-1-arylmethylphosphonic acid diethyl esters with various fluorinated substituents in one or both aryl rings have been resolved in their enantiomers by a direct HPLC method, using chiral stationary phases. The chiral separation on Chiralcel OD strongly depends on the substitution pattern in the N-aryl and/or in the C-aryl moieties and it improves markedly with the polarity of the fhiorinated substitnent. A new Pirkles chiral stationary phase (R)-α-Burke 1 is more efficient and in some cases more enantioselective than other Pirkles phases. A chiral recognition model between this phase and the enantiomers of an analyte afforded to propose the absolute configuration of the optical isomers and to relate it to the chiroptical behaviour.

THE PREPARATION AND CHARACTERIZATION OF SOME FLUORINATED α-AMINOARYLMETHANEPHOSPHONIC ACIDS

Abstract α-Aminoarylmethanephosphonic acids have been prepared with a range of fluoro, fluoroalkyl, or fluoroalkoxy substituents in the benzene ring (4-F, 3-F, 2-F, 3,4-F2, F5, 4-CF3, 3-CF3, 4-CF3O, and 3-CF3O). These compounds have relatively low aqueous solubility and their NMR spectra (1H, 13C, 31P and 19F) were therefore recorded in D2O in the presence of an excess of alkali. Under these conditions, the ring substituents appear to have little effect on δH (15–18 ppm), or on the 1H and 13C parameters for the benzylic group (α-CH), which are mainly in the ranges observed for other types of α-aminoarylmethanephosphonic acids under alkaline conditions (δH, 3.8–4.0 ppm, 2 J PH 15.3–16.5 Hz; δc 57–58 ppm, 1 J PC 128–132 Hz). For those examples with fluorine in the ortho position (i.e., the 2-fluoro and pentafluoro derivatives) a slightly higher field chemical shift was observed for the benzylic carbon atom (δc 50–51 ppm). In the fast-atom bombardment mass spectra, pseudo-molecular ions, MH+, and ions result...

Silicium-verbindungen mit starken intramolekularen sterischen wechselwirkungen : II. Präparative und kernresonanzspektroskopische untersuchungen an isopropylsilanen☆

Abstract Several isopropylsilanes including tetraisopropylsilane have been obtained by the reaction of chloro- or fluoro-silanes with isopropyllithium. Their AB 6 proton NMR spectra have been recorded and analyzed. The reaction between triisopropylfluorosilane and isopropyllithium in ether gives triisopropyl(3-methylbutyl)silane as the main product. In petroleum ether as solvent, however, tetraisopropylsilane together with triisopropylsilane is formed.

SYNTHESE VON FLUORIERTEN N-ARYLAMINO-ARYLMETHANPHOSPHONSÄUREDIALKYLESTERN

Abstract Fluorinated α-C-and N-arylsubstituted aminomethanephosphonic acid diethylesters 5 are prepared in high yields by a „two-step“ procedure: mixing equimolar amounts of fluorinated benzaldehydes 1 and anilines 2 to benzaldehyde-(N-aryl-)imines 3. Subsequently N-arylamino-arylmethanephosphonic acid diethylesters 5 are obtained by addition of diethyl phosphite 4 to the imines 3. All compounds are characterized by 31 P {1 H}, 1H and 19F NMR spectroscopical investigations. External biological studies involving the 27 new aminophosphonic acid esters 5 show insecticidal activity of N-4-trifluoromethoxy-phenylamino-phenylmethanephosphonic acid diethylester 5h towards harmful and parasitic insects.