Biomedical subjects

Erich Kleinpeter

Publications and source records attributed to Erich Kleinpeter.

At least 19 recordsLinked to original sources

PubMed2006

Stereodynamics of 1-(methylsulfonyl)-3,5-bis(trifluoromethylsulfonyl)-1,3,5-triazinane: experimental and theoretical analysis.

Dynamic NMR of 1-(methylsulfonyl)-3,5-bis(trifluoromethylsulfonyl)-1,3,5-triazinane reveals the existence of three conformers and two dynamic processes: ring inversion and rotation about the N-S bond, both processes having DeltaG(++) = 13.5 kcal/mol. An unprecedented large reverse Perlin effect (J(CHax) > J(CHeq)) was found experimentally and calculated theoretically.

Journal Article↗

PubMed2006

Hyperconjugation and the increasing bulk of OCOCX3 substituents in trans-1,4-disubstituted cyclohexanes destabilize the diequatorial conformer.

The trans diesters of 1,4-cyclohexanediol with a number of acetic acid analogues, CX3COOH, of varying steric hindrance and polarity (CX3 = Me, Et, iso-Pr, tert-Bu, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, CBr3) were synthesized, and the axial,axial/equatorial,equatorial conformational equilibria were studied by low-temperature 1H NMR spectroscopy in CD2Cl2. The structures and relative energies of the axial,axial and equatorial,equatorial conformers were calculated at both the MP2/6-311G* and the MP2/6-311+G* levels of theory, and it was only by including diffuse functions that a good correlation of deltaG(o)calcd vs deltaG(o)exptl could be obtained. Both the structures and the energy differences of the axial,axial and equatorial,equatorial conformers are discussed with respect to the established models of conformational analysis, viz., steric 1,3-diaxial and hyperconjugative interactions. Interestingly, the hyperconjugative interactions sigma(C-C)/sigma(C-H) --> sigma*(C-O), together with a steric effect which also destabilizes the equatorial,equatorial conformers on increasing bulk of the substituents, proved to dominate the position of the conformational equilibria. In addition, the preference of the axial,axial conformers with respect to their equatorial,equatorial analogues was greater than expected from the conformational energies of the corresponding substituents in the monosubstituted cyclohexyl esters. The reason for this very interesting and unexpected result is also discussed.

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PubMed2006

Quantification of the push-pull effect in tolanes and a revaluation of the factors affecting the 13C chemical shifts of the carbon atoms of the CC triple bond.

Variously substituted tolanes were employed to show that the push-pull effect is also active in CC triple bonds by the successful correlation of the occupation quotient pi/pi of the pi orbital in resonance with the substituted phenyl moieties of tolanes versus the bond length of the CC triple bond. In addition, the influences of the ortho phenyl ring substituents on the 13C chemical shifts of the triple bond carbon atoms, which were estimated by Rubin et al.(4) to be "inapplicable for describing triple bond polarization", were re-evaluated, leading to the conclusion that, while anisotropic effects of ortho substituents are negligible, the steric ortho-substituent effects do in fact dominate the deviations obtained. A detailed theoretical NBO/NCS study has been employed to illuminate the facts of this case.

Journal Article↗

PubMed2005

Propagation of polar substituent effects in 1-(substituted phenyl)-6,7-dimethoxy-3,4-dihydro- and -1,2,3,4-tetrahydroisoquinolines as explained by resonance polarization concept.

[structures: see text] Propagation of inductive and resonance effects of phenyl substituents within 1-(substituted phenyl)-6,7-dimethoxy-3,4-dihydro- and -1,2,3,4-tetrahydroisoquinolines were studied with the aid of 13C and 15N NMR chemical shifts and ab initio calculations. The substituent-induced changes in the chemical shift (SCS) were correlated with a dual substituent parameter equation. The contributions of conjugative (rhoR) and nonconjugative effects (rhoF) were analyzed, and mapping of the substituent-induced changes is given over the entire isoquinoline moiety for both series. The experimental results can be rationalized with the aid of the resonance polarization concept. This means the consideration of the substituent-sensitive balance of different resonance structures, i.e., electron delocalization, and the effect of the aromatic ring substituents on their relative contributions. With tetrahydroisoquinolines, the delocalization of the nitrogen lone pair (stereoelectronic effect) particularly contributes. Correlation analysis of the Mulliken atomic charges for the dihydroisoquinoline derivatives was also performed. The results support the concept of the substituent-sensitive polarization of the isoquinoline moiety even if the polarization pattern achieved via the NMR approach is not quite the same as that predicted by the computational charges. Previously the concepts of localized pi-polarization and extended polarization have been used to explain polar substituent effects within aromatic side-chain derivatives. We consider that the resonance polarization model effectively contributes to the understanding of the polar substituent effects.

Journal Article↗

PubMed2005

The interplay of thio(seleno)amide/vinylogous thio(seleno)amide "resonance" and the anisotropic effect of thiocarbonyl and selenocarbonyl functional groups.

Amino-substituted thio(seleno)acrylamides 1-4 were synthesized and their 1H and 13C NMR spectra assigned. Both the NMR data and the results of theoretical calculations at the ab initio level of theory were employed to elucidate the adopted structures of the compounds in terms of E/Z isomerism and s-cis/s-trans configuration. In the case of the asymmetrically N(Me)Ph-substituted compounds, ab initio GIAO-calculated ring current effects of the N-phenyl group were applied to successfully determine the preferred conformer bias. The restricted rotations about the two C-N partial double bonds were studied by DNMR and the barriers to rotation (DeltaG(c)++) determined at the coalescence temperatures, and these were discussed with respect to the structural differences between the compounds. The barriers to rotation were also calculated at the ab initio level of theory where the best results (R(2) = 0.8746) were obtained only with inclusion of the solvent at the SCIPCM-HF/6-31G* level of theory. The calculations also provided means of assessing structural influences which were not available due to inaccessible rotation barriers. By means of natural bond orbital (NBO) analysis of 1-4, the occupation numbers of nitrogen lone pairs and bonding/antibonding pi/pi orbitals were shown to quantitatively describe thio(seleno)amide/vinylogous thio(seleno)amide "resonance". Finally, the thio(seleno)carbonyl anisotropic effect was quantitatively calculated by the GIAO method and visualized by isochemical shielding surfaces (ICSS). Only marginal differences between the two anisotropic effects were calculated and are therefore of questionable utility for previous and future applications with respect to stereochemical assignments.

Journal Article↗

PubMed2005

Ab initio study of the substituent effects on the relative stability of the E and Z conformers of phenyl esters. Stereoelectronic effects on the reactivity of the carbonyl group.

Equilibria between the Z (tau1= 0 degrees) and E (tau1= 180 degrees) conformers of p-substituted phenyl acetates 4 and trifluoroacetates 5 (X = OMe, Me, H, Cl, CN, NO2) were studied by ab initio calculations at the HF/6-31G* and MP2/6-31G* levels of theory. The preference for the Z conformer, DeltaE(HF), was calculated to be 5.36 kcal mol(-1) and 7.50 kcal mol(-1) for phenyl acetate and phenyl trifluoroacetate (i.e., with X = H), respectively. The increasing electron-withdrawing ability of the phenyl substituent X increases the preference of the Z conformer. An excellent correlation with a negative slope was observed for both series between DeltaE of the E-Z equilibrium and the Hammett sigma constant. By using an appropriate isodesmic reaction, it was shown that electron-withdrawing substituents decrease the stability of both conformers, but the effect is higher with the E conformer. Electron-withdrawing phenyl substituents decrease the delocalization of the lone pair of the ether oxygen to the C=O antibonding orbital (nO--> pi*C=O) in both the E and Z forms and in both series studied; this effect is higher in the E conformer than in the Z conformer. The nO --> pi*C=O electron donation has a minimum value with tau1= 90 degrees and a maximum value with tau1= 0 degrees (the Z conformer), the value with tau1= 180 degrees (the E conformer) being between these two values, obviously due to steric hindrance. The effects of the phenyl substituents on the reactivity of the esters studied are discussed in terms of molecular orbital interactions. ED/EW substituents adjust the availability of the pi*C=O antibonding orbital to interact with the lone pair orbital of the attacking nucleophile and therefore affect the reactivity: EW substituents increase and ED substituents decrease it. Excellent correlations were observed between the rate coefficients of nucleophilic acyl substitutions and pi*C=O occupancies of the ester series 4 and 5.

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PubMed2005

Pulsed field gradient NMR study of anomalous diffusion in a lecithin-based microemulsion.

Self-diffusion measurements in microemulsion systems composed of a naturally occurring soybean lecithin mixture, an aqueous phase, either water or a 1% aqueous PDADMAC solution, and isooctane were accomplished by pulsed field gradient (PFG) 1H NMR spectroscopy at oil dilution lines of low and intermediate water/lecithin ratios. The concentration-dependent diffusion data reveal water-in-oil (W/O) reverse micellar aggregates with dimensions on the nanometer scale being slightly smaller at low water content. With increasing micellar volume fractions, both hydrodynamic as well as direct interactions between particles significantly slow aggregate diffusion. The surfactant mean square displacements (msd's) in dilute and concentrated polymer-free systems studied as a function of diffusion time (20-1000 ms) are characterized by a crossover from Gaussian diffusion, due to slow aggregate motion, to anomalously enhanced diffusion, due to fast surface-bulk surfactant exchange at intermediate times revealing weak, barrier-controlled adsorption behavior. Upon addition of the polycation PDADMAC, the diffusion characteristics change to exclusively superdiffusive behavior with surfactant msd scaling with time as t(3/2) over the entire time range studied. This is caused by surfactant molecules performing Levy walks along the surface of reverse micelles mediated by the dilute bulk. The bulk-mediated surface diffusion is a consequence of the diffusion-controlled micelle-bulk exchange dynamics induced by interactions of PDADMAC with surfactant headgroups.

Colloids↗

PubMed2005

Synthesis, characterisation and theoretical calculations of 2,6-diaminopurine etheno derivatives.

Four derivatives of 2,6-diaminopurine (1) were synthesised and characterised. When 1 was reacted with chloroacetaldehyde, 5-aminoimidazo[2,1-i]purine (2), 9-aminoimidazo[2,1-b]purine (3), 9-aminoimidazo[1,2-a]purine (4) and diimidazo[2,1-b:2',1'-i]purine (5) were formed. The purified products (3-5) were fully characterised by MS, complete NMR assignments as well as fluorescence and UV spectroscopy. The purified, isolated yields of these products (3-5) varied from 2.5 to 30%. The relative stability of different tautomers was investigated by theoretical calculations. Fluorescence characteristics are also discussed and compared to the starting material 1 and a reference molecule 2-aminopurine.

2-Aminopurine↗

PubMed2005

Synthesis of mono- and disubstituted porphyrins: A- and 5,10-A2-type systems.

General syntheses have been developed for meso-substituted porphyrins with one or two substituents in the 5,10-positions and no beta substituents. 5-Substituted porphyrins with only one meso substituent are easily prepared by an acid-catalyzed condensation of dipyrromethane, pyrrole-2-carbaldehyde, and an appropriate aldehyde using a "[2+1+1]" approach. Similarly, 5,10-disubstituted porphyrins are accessible by simple condensation of unsubstituted tripyrrane with pyrrole and various aldehydes using a "[3+1]" approach. The yields for these reactions are low to moderate and additional formation of either di- or monosubstituted porphyrins due to scrambling of the intermediates is observed. However, the reactions can be performed quite easily and the desired target compounds are easily removed due to large differences in solubility. A complementary and more selective synthesis involves the use of organolithium reagents for S(N)Ar reactions. Reaction of in situ generated porphyrin (porphine) with 1.1-8 equivalents of RLi gave the monosubstituted porphyrins, while reaction with 3-6 equivalents of RLi gave the 5,10-disubstituted porphyrins in yields ranging from 43 to 90 %. These hitherto almost inaccessible compounds complete the series of different homologues of A-, 5,15-A(2)-, 5,10-A(2)-, A(3)-, and A(4)-type porphyrins and allow an investigation of the gradual influence of type, number, and regiochemical arrangement of substituents on the properties of meso-substituted porphyrins. They also present important starting materials for the synthesis of ABCD porphyrins and are potential synthons for supramolecular materials requiring specific substituent orientations.

Journal Article↗

PubMed2005

Interpretation of conformational effects on 2-endo-norborneol by natural chemical shielding analysis.

This paper represents an extension of our work on the (1)H and (13)C NMR chemical shifts of norbornane and 2-endo-norborneol. NCS-NBO analysis was employed to probe contributions of bond orbitals and orbitals of lone pairs to nuclear shielding in conformers of the alcohol generated by rotation of the C-O bond. Variations in (1)H and (13)C chemical shifts with the dihedral angle are discussed in terms of Lewis and non-Lewis partitioning and their respective importance is evaluated. In addition to hyperconjugation of the lone pair in a p orbital of oxygen that was previously reported, a sizable participation of the lone pair which is in an sp orbital is also observed and their combined effect dominates the carbon chemical shifts of the C(1)-C(2)-OH and C(3)-C(2)-OH fragments. Both lone pairs on oxygen also contribute to localized, though-space effects on nuclei in the vicinity, these effects answering for the largest deviations in hydrogen chemical shifts on rotation around the C-O bond. On the other hand, for conformers in which nonbonded repulsions lead to distortions in the molecular framework, variations in chemical shifts may be attributed to angular effects.

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PubMed2005

Configuration and E/Z interconversion mechanism of O(S)-allyl-S(O)-methyl-N-(acridin-9-yl) iminothiocarbonate.

The configuration and dynamic behavior of O-allyl-S-methyl-N-(acridin-9-yl)iminothiocarbonate (1) and its S-allyl-O-methyl regioisomer (2) were studied using quantum chemical calculations and by applying a novel graphical method to scatter maps obtained from MD simulations for evaluation of an NOE-weighted internuclear distance (r(NOE)). Energy calculations indicated that the Z configuration was predominant for each compound and, further, this was supported both by the calculated chemical shifts and the r(NOE). Both N-inversion- and rotation-type transition-state structures were also calculated for the E/Z isomerization process, the results indicating that the preferred interconversion mechanism for 1 is N-inversion, but contrastingly, interconversion via rotation is equally as probable as N-inversion for 2. This supports the notion that one or the other or both pathways can be active and each system needs to be assessed on a case-by-case basis.

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PubMed2004

Electronic state of push-pull alkenes: an experimental dynamic NMR and theoretical ab initio MO study.

The (1)H and (13)C NMR spectra of a number of push-pull alkenes were recorded and the (13)C chemical shifts calculated employing the GIAO perturbation method. Of the various levels of theory tried, MP2 calculations with a triple-zeta-valence basis set were found to be the most effective for providing reliable results. The effect of the solvent was also considered but only by single-point calculations. Generally, the agreement between the experimental and theoretically calculated (13)C chemical shifts was good with only the carbons of the carbonyl, thiocarbonyl, and cyano groups deviating significantly. The substituents on the different sides of the central C=C partial double bond were classified qualitatively with respect to their donor (S,S < S,N < N,N) and acceptor properties (C identical with N < C=O < C=S) and according to the ring size on the donor side (6 < 7 < 5). The geometries of both the ground (GS) and transition states (TS) of the restricted rotation about the central C=C partial double bond were also calculated at the HF and MP2 levels of theory and the free energy differences compared with the barriers to rotation determined experimentally by dynamic NMR spectroscopy. Structural differences between the various push-pull alkenes were reproduced well, but the barriers to rotation were generally overestimated theoretically. Nevertheless, by correlating the barriers to rotation and the length of the central C=C partial double bonds, the push-pull alkenes could be classified with respect to the amount of hydrogen bonding present, the extent of donor-acceptor interactions (the push-pull effect), and the level of steric hindrance within the molecules. Finally, by means of NBO analysis of a set of model push-pull alkenes (acceptors: -C identical with N, -CH=O, and -CH=S; donors: S, O, and NH), the occupation numbers of the bonding pi orbitals of the central C=C partial double bond were shown to quantitatively describe the acceptor powers of the substituents and the corresponding occupation numbers of the antibonding pi orbital the donor powers of the substituents. Thus, for the first time an estimation of both the acceptor and the donor properties of the substituents attached to the push-pull double bond have been separately quantified. Furthermore, both the balance between strong donor/weak acceptor substituents (and vice versa) and the additional influences on the barriers to rotation (hydrogen bonding and steric hindrance in the GSs and TSs) could be differentiated.

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PubMed2004

Stereoelectronic effects in ring-chain tautomerism of 1,3-diarylnaphth[1,2-e][1,3]oxazines and 3-alkyl-1-arylnaphth[1,2-e][1,3]oxazines.

The disubstitution effects of X and Y in 1-(Y-phenyl)-3-(X-phenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines on the ring-chain tautomerism, the delocalization of the nitrogen lone pair (anomeric effect), and the (13)C NMR chemical shifts were analyzed by using multiple linear regression analysis. Study of the three-component equilibrium B<==>A<==>C revealed that the chain<==>trans (A<==>B) equilibrium constants are significantly influenced by the inductive effect (sigma(F)) of substituent Y on the 1-phenyl ring. In contrast, no significant substituent dependence on Y was observed for the chain<==>cis (A<==>C) equilibrium. There was an analogous dependence for the epimerization (C<==>B) constants of 1-(Y-phenyl)-3-alkyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines. With these model compounds, significant overlapping energies of the nitrogen lone pair was observed by NBO analysis in the trans forms B (to sigma*(C1-C1'), sigma*(C1-C10b), and sigma*(C3-O4)) and in the cis forms C (to sigma*(C1-H), sigma*(C1-C10b), and sigma*(C3-O4)). The effects of disubstitution revealed some characteristic differences between the cis and trans isomers. However, the results do not suggest that the anomeric effect predominates in the preponderance of the trans over the cis isomer. When the (13)C chemical shift changes induced by substituents X and Y (SCS) were subjected to multiple linear regression analysis, negative rho(F)(Y) and rho(F)(X) values were observed at C-1 and C-3 for both the cis and trans isomers. In contrast, the positive rho(R)(Y) values at C-1 and the negative rho(R)(X) values at C-3 observed indicated the contribution of resonance structures f (rho(R) > 0) and g (rho(R) < 0), respectively. The classical double bond-no-bond resonance structures proved useful in explaining the substituent sensitivities of the donation energies and the behavior of the SCS values.

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PubMed2004

Conformational analysis of mixed oxathia crown ethers and their complexational ability towards Ag(I) and Pd(II)-an experimental solution NMR and theoretical molecular modelling study.

Both the conformation and flexibility of four mixed oxathia crown ethers and their Ag(I) and Pd(II) complexes were studied by (1)H NMR (delta, J, NOE, T(1)), (13)C NMR, dynamic (1)H NMR spectroscopy and molecular modelling. The stoichiometry and stability constants of the complexes were determined from corresponding Job's plots in the case of Ag(I) complexes as the interchange between free and complexed states was fast on the NMR timescale; interchange for the Pd(II) complexes was sufficiently slow such that distinct sub-spectra were observable for the free and complexed states. In all cases where complexation was observed, 1 : 1 complexes were formed. Global minima structures determined from the modelling studies were analysed with respect to the barriers to ring interconversion, the flexibility of the species in solution and the preferred complexation of Ag(I) and Pd(II) to the sulfur atoms of the crown ethers.

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PubMed2004

Separation of anisotropic and steric substituent effects-nuclear chemical shielding analysis of H-4 and C-4 in phenanthrene and 11-ethynylphenanthrene.

The anisotropic effect of a proximally introduced ethynyl group on the chemical shifts of H-4 and C-4 of the phenanthrene skeleton was calculated using GIAO-HF/NICS methodology. The anisotropic effect, long considered to be the source of the considerable downfield shift of H-4 in 11-ethynylphenanthrene in comparison to the chemical shift value of the corresponding proton in phenanthrene, was determined to be only negligible in magnitude on the basis of these calculations. Partitioning of the natural chemical shieldings of H-4 and C-4 by the NCS-NBO method into various contributions from the C-C and C-H bonds present in each molecule revealed that steric compression was able to account for the large downfield shifts of both H-4 and C-4 in 11-ethynylphenanthrene relative to phenanthrene. Thus, the substituent effect is almost totally permeated by this latter interaction and not by the aforementioned process, which was previously presumed to be the sole underlying cause.

Journal Article↗

PubMed2004

Solution structure of the palladium(II) complex of 1,4,7,10-tetrathiacyclododec-2-ene-2,3-dicarbonitrile.

The solution structure of the Pd(II) complex of mn-12-S4 was studied in detail by NMR spectroscopy. The stoichiometry of the complex was determined by 1H NMR titration experiments. 3J(H,H) coupling constants were extracted from the 2D J-resolved NMR spectrum of the complex providing information concerning the S-C-C-S torsional angles. Further conclusions about the conformation of [Pd(mn-12-S4)](BF4)2 were drawn from experimental NOEs. The results of the NMR study were corroborated by molecular modelling.

Algorithms↗

PubMed2004

Electronic influences on 3J(C,H) coupling constants via -S-, -S(O)- and -SO2-: their determination, calculation and comparison of detection methods.

3J(C,H) coupling constants via a sulfur atom in two series of compounds, both including a sulfide, a sulfoxide and a sulfone, were detected experimentally and calculated by quantum mechanical methods. In the first series (1-3) the coupling between a hydrogen, bonded to an sp3 carbon, and an sp2 carbon is treated; the second series (4-6) deals with the coupling between a hydrogen, bonded to an sp3 carbon, and an sp3 carbon. Different pulse sequences (broadband HMBC, SelJres, 1D HSQMBC, J-HMBC-2, selective J-resolved long-range experiment and IMPEACH-MBC) proved to be useful in determining the long-range 3J(C,H) coupling constants. However, the dynamic behaviour of two of the compounds (4 and 6) led to weighted averages of the two coupling constants expected (concerning equatorial and axial positions of the corresponding hydrogens). DFT calculations proved to be useful to calculate not only the 3J(C,H) coupling constants but also the different contributions of FC, PSO, DSO and SD terms; the calculation of the Fermi contact term (FC) was found to be sufficient for the correct estimation of 3J(C,H) coupling constants.

Journal Article↗

PubMed2003

Solution- and bound-state conformational study of N,N',N"-triacetyl chitotriose and other analogous potential inhibitors of hevamine: application of trNOESY and STD NMR spectroscopy.

The solution-state conformations of N,N',N"-triacetyl chitotriose (1) and other potential chitinase inhibitors 2-4 were studied using a combination of NMR spectroscopy (NOESY) and molecular mechanics calculations. Determination solely of the global energy minimum conformation was found to be insufficient for an agreement with the NMR results. An appropriate consistency between the NMR experimental data and theoretical calculations was only reached by assessing the structures as population-weighted average conformers based on Boltzmann distributions derived from the calculated relative energies. Analogies, but also particular differences, between the synthetic compounds 2-4 and the naturally-occurring N,N',N"-triacetyl chitotriose were found. Furthermore, the conformation of compounds 1 and 2 when bound to hevamine was also studied using transferred NOESY experiments and the binding process was found to impart a level of conformational restriction on the ligands. The preferred conformation as determined for 1 in the bound state to hevamine belonged to one of the conformational families found for the compound when free in solution, although full characterisation of the bound-state conformations was impeded due to severe signal overlap. Saturation transfer difference NMR experiments were also employed to analyse the binding epitopes of the bound compounds. We thus determined that it is mainly the acetyl amido groups of the trisaccharide and the heterocyclic moiety which are in close contact with hevamine.

Carbohydrate Sequence↗