Esko Pohjala

Bisphosphonic compounds. Part 3. Preparation and identification of tetraalkyl methylene- and (α-halomethylene)bisphosphonates by mass spectrometry, NMR spectroscopy and X-ray crystallography

The preparation and identification of tetraalkyl methylenebisphosphonates {XYC[P(O)(OR)2]2; X = Y = H, Cl or Br and R = alkyl} have been studied. Detailed procedures are given for the synthesis of XYC[P(O)(OR)2]2(X = Y = H; R = hexyl; X = Y = Cl or Br and R = Me). 1H, 13C and 31P NMR data are reported including 1JCH, 2JCP, 3JCP and 2JPP coupling constants. The fragmentation of 19 XYC[P(O)(OR)2]2 has been studied in the gas phase. The solid state structures are given for two compounds (X = Y = Cl, R = Pri and X = Y = Br, R = Me).

BISPHOSPHONIC COMPOUNDS. IV.1 PREPARATION AND IDENTIFICATION OF MIXED TETRAALKYL METHYLENE- AND (DICHLOROMETHYLENE)-BISPHOSPHONATES BY NMR SPECTROSCOPIC, MASS SPECTROMETRIC AND X-RAY CRYSTALLOGRAPHIC STUDIES

Abstract The chemistry of 28 mixed tetraalkyl methylene- and (dichloromethylene)bisphosphonates, (R1O)(R2O)P(O)CX2P(O)(OR3)(OR4), where R1=Et, Allyl, CH=CHMe, Pri, Bu, But, Hex, Ph, Bn or octadecyl, R2=Me, Et, Pri, Bu, But, Hex, Ph or Bn, R3=R4=Me, Et, Pri or Ph and X=H or Cl, have been studied. 1H, 13C, 31P NMR data are reported, including 1JCH, 3JCP, 3JCP and 2JPP coupling constants. The fragmentation of some representative compounds were studied in the gas phase. The solid state structure is given for (PhO)2P(O)CH2P(O)(OMe)2.

Timolol derivatives. I: X-ray, NMR and theoretical studies of the crystallization of (S)-timolol O,O-diacetyl-L-tartaric acid monoester

Abstract The absolute configurations of (S)-timolol hemihydrate and (S)-timolol O,O-diacetyl-(R,R)-tartaric acid monoester were determined by single crystal X-ray diffraction. An NMR analysis based on the temperature dependence of vicinal coupling constants was carried out to characterize the conformational behaviour of the S,R,R- and R,R,R-forms in solution. The same conformation as in crystalline state was also found in solution, although with a rather low preference over some other conformations. Results of theoretical calculations using MNDO and AMBER force field methods are reported. An infinite chain of hydrogen bonds, along with other favourable inter- and intramolecular forces that are present in the crystal framework of the (S)-timolol-(R,R)-tartrate but not possible for (R)-timolol-(R,R)-tartrate, explain the astonishingly dominating crystallization of the S,R,R-form. Racemic timolol is accordingly easily resolved.

A 31P CP/MAS NMR study on dehydration of disodium clodronate tetrahydrate

AbstractPurpose. 31P CP/MAS NMR is used to characterize stability and changes in solid state properties of disodium clodronate tetrahydrate upon variable temperature and slow dehydration.nMethods. Variable temperature 31P CP/MAS NMR spectroscopy.nResults. A fast rise in temperature leads to loss of lattice waters and produces an averaged structure characterized by a single 31P NMR resonance at 398 K. Slow room temperature dehydration converts the crystalline form to an anhydrous structure with two non-equivalent phosphorus atoms. The molecular skeleton of clodronate is stable within the temperature range 296 K-398 K of experiments. Rehydration of the anhydrous samples at room temperature restores the crystalline tetrahydrate form verified by a 3IP CP/MAS NMR spectrum similar to that of a virginal sample.nConclusions. Solid state NMR is a method which can offer both molecular and crystal scale information, when either bulk or dosage forms of a drug can be altered by temperature or by loss of lattice waters or solvents. The experiments are easy to perform, though time consuming, especially when low abundant nuclei are examined.

Ab initio studies on organophosphorus compounds. Part 2. Monoanionic methyl methylphosphonate and methyl methylphosphinate and their sulfur analogues

The molecular properties of nine monoanionic methyl methylphosphonate and methyl methylphosphinate and their sulfur analogues have been studied by ab initio molecular orbital methods. Molecular structures, dipole moments, stability, charge distributions and torsional barriers have been reported. The effects of sulfur and oxygen substitution have been compared. Energetics for model and hydrolysis reactions have been calculated for all the compounds up to the MP2/6-31G*//6-31G* level. Phosphonate compounds with –OCH3 group were found to adopt an extended molecular backbone while –SCH3 systems preferred bent conformations. Inclusion of the correlation corrections with 6-31 G* basis set, instead of 3-21G(*) level, was found to have an effect on the calculated energetics of model reactions.

Ab initio studies on organophosphorus compounds. Part 4. Intramolecular hydrogen bonding and water interactions of bisphosphonates

Molecular properties of two clodronate-type bisphosphonates have been studied in the gas-phase by ab initio molecular orbital methods. Both compounds have P–C–P backbone structure and divalent localized negative charge on oxygen atoms. Molecular structures, charge distributions and energetics of the molecules were calculated with the 3-21G(*) basis set. Internal hydrogen bonds were found between the monophosphonic acid ends of the bisphosphonate molecules. A gas-phase ab initio study has also been made of complexes of the bisphosphonate molecule with one to six explicit water molecules. Interactions between the bisphosphonate and water molecules took place through intermolecular hydrogen bonding. Finally, a self-consistent reaction field (SCRF) model was applied to the interaction models to complement the explicit study. The results of the study provide a quantum chemical reference for future experimental and theoretical studies of bisphosphonate compounds.

Ab initio studies on organophosphorus compounds. Part 3. Cationic calcium binding to phosphonate and phosphinate monoanions and their sulfur analogues

Interactions between cationic calcium and 18 organophosphorus compounds, containing different numbers of oxygen and sulfur atoms, have been studied systematically. All the molecular backbones studied were of the phosphonate or phosphinate type. Molecular structures and calcium orientations through space were calculated by ab initio molecular orbital methods with the 3-21G (*) basis set. Different calcium binding sites were found for each molecule. The energetics of the calcium orientations were compared. The results give a quantum chemical reference for experimental studies of many phosphorus-containing biological systems inside living organisms, in which calcium(II) regulates cell functions. Examples of such systems are the bisphosphonate–osteoclast interactions in osteolytic bone diseases.

Ab initio studies on organophosphorus compounds. Part 1 : Monoanionic methylphosphonate and methylphosphinate and their nitrogen and sulfur analogues

The effects of sulfur and nitrogen substituents on the properties of 23 different analogues of monoanionic methylphosphonates and methylphosphinates have been investigated by an ab initio method with 3-21G(*) and 6-31G* basis sets. Conformational analyses were performed on all compounds with rotational bonds and the relative energies of conformers were studied. The effects of nitrogen and sulfur substituents were compared in terms of geometries, charge distributions and torsional barriers. In addition, the total energy changes of model reactions between the analogues were investigated. On the basis of the model reactions the most stable compounds were methylphosphonte (1), methylphosphonamidate (7) and methylphosphindithioate (20).

Structural studies on beta-blockers Part I. Structural similarities of pronethalol and propranolol

Abstract Conformations of phenylethanolamine and aryloxpyropanolamine type beta-adrenergic blockers, pronethalol ( 1 ) and propranolol ( 2 ), has been examined theoretically with the van der Waals method together with molecular mechanics. Conformations were compared using molecular graphics. A common conformation of a low total energy ( 1a for pronethalol and 2c for propranolol), capable of forming intermolecular hydrogen bonds, has been found and thus considered as the most probable structure through which beta-adrenergic agents exert their effects on the beta-receptors.

Pyrolysis of three acetates of methylbicyclo[2.2.1]heptan-2-ols and the parent alcohols

The acetates of exo-2-methyl-endo-bicyclo[2.2.1]heptan-2-ol, endo-2-methyl-exo-bicyclo-[2.2.1]heptan-2-ol, and 1-methyl-exo-bicyclo[2.2.1]heptan-2-ol together the parent alcohols have been pyrolysed at several temperatures and the product distribution determined. The mechanism and direction of elimination in relation to structure are discussed qualitatively. The formation of the principal products is consistent with a concerted elimination involving a six-membered cyclic transition state. Wagner–Meerwein rearrangement occurs as a competing reaction in cases where the formation of a tertiary structure is possible at the expense of a secondary one. In the case studied a two-step reaction is considerably faster than direct pyrolysis of the secondary structure.