Conformational isomerization of <Emphasis Type="Italic">N</Emphasis>-(naphthalen-1-yl)-<Emphasis Type="Italic">N</Emphasis>-(phenyl(quinolin-3-yl)methyl)amide derivatives

A series of N-(naphthalen-1-yl)-N-(phenyl(quinolin-3-yl)methyl)amide derivatives were designed and synthesized as anti-Mycobacterium tuberculosis drugs. NMR spectra showed that two conformational isomers of these compounds exist in solution, which is not due to cis-trans isomerization of amide bond. We proposed that the spatial interactions between three large aromatic groups caused the conformational isomerization, which was supported by molecular modeling and X-ray diffraction.     

Conformational mobility of thianthrene-5-oxide

[reaction: see text] Data on the apparent dipole moment of thianthrene-5-oxide (1) and (1)H NMR spectra in different solvents support the conformational mobility of 1, which flaps between two limit boat conformations with the sulfinyl group in pseudoequatorial and pseudoaxial positions, respectively. The conformational equilibrium of 1 occurs too fast for the (1)H NMR (500 MHz) time-scale even at -130 degrees C, and the equilibrium constant has not been determined. The apparent dipole moments of 1 in n-hexane and 1,4-dioxane and the (1)H NMR spectra of 1 and the model compounds cis- and trans-thianthrene-5,10-dioxides (2) and thianthrene (5) in different solvents and at various temperatures confirm that the relative position of the conformational equilibrium of 1 is solvent-dependent, and more polar solvents favor the conformation with the sulfoxide group in the pseudoaxial position (1(')(ax)). Variable-temperature (1)H NMR spectra have established the interconversion barrier of trans-2 and confirmed that the conformational equilibrium of cis-2 is strongly displaced toward the conformation with both sulfinyl groups in the pseudoequatorial position. The (1)H NMR data support the transannular interaction of the functional groups in 1 and trans-2.     

Synthesis and conformational analysis of 6-C-methyl-substituted 2-acetamido-2-deoxy-beta-D-glucopyranosyl mono- and disaccharides

Several 6-C-substituted 2-acetamido-2-deoxy-beta-D-glucopyranosides (beta-D-GlcNAc monosaccharides 1a-3a and 1,4-linked disaccharides 1b-3b) were studied by solution NMR spectroscopy. Conformational analysis of the (6S)- and (6R)-C-methyl-substituted beta-d-GlcNAc monosaccharides indicates that the stereodefined methyl groups impose predictable conformational biases on the exocyclic C-5-C-6 bond, as determined by (1)H-(1)H and (13)C-(1)H coupling constants. Variable-temperature NMR experiments in methanol-d(4) were performed to determine DeltaDeltaH and DeltaDeltaS values derived from the two lowest energy conformers. These indicate that while the influence of 6-C-methyl substitution on conformational enthalpy is in accord with the classic principles of steric interactions, conformational preference in solution can also be strongly affected by other factors such as solvent-solute interactions and solvent reorganization.     

The assignment of the absolute configuration of diethyl hydroxy- and aminophosphonates by 1H and 31P NMR using naproxen as a reliable chiral derivatizing agent

The assignment of the absolute configuration of hydroxy- and aminophosphonates by their double derivatization with commercially available naproxen is presented. The correlation between the spatial arrangement around the stereogenic carbon center and the signs of the DeltadeltaRS allows determination of the absolute configuration of hydroxy- and aminophosphonates by simple comparison of the 1H and 31P NMR spectra of the (R)- and (S)-naproxen ester or amide derivatives. Extensive conformational analysis (theoretical calculations, low-temperature experiments) supported by the NMR studies of structurally diverse naproxen esters and amides of hydroxy- and aminophosphonates proved that a simplified model can be successfully used.     

Determination of the Absolute Configuration of Amines and alpha-Amino Acids by (1)H NMR of (R)-O-Aryllactic Acid Amides

(R)-O-Aryllactic acid (ROAL) amides derived from alpha-chiral primary amines and alpha-amino acid esters show different chemical shifts in (1)H NMR spectroscopy (300 MHz) depending on their configuration. Molecular mechanics, semiempirical calculations, and (1)H NMR studies suggest that, in solution, these amides prefer an ap-Z conformation with the C(alpha)OAr and C=O groups close to anti-periplanar as in the case of mandelic acid amides. The proposed conformational preference is different from that of the ROAL esters (C(alpha)H and C=O groups in a syn-periplanar conformation). The conformational model for ROAL amides allows the absolute configuration assignment of primary amines and alpha-amino acid esters according to the relative position of the aryl group and the substituents on the amine moiety, and also their enantiomeric composition.     

Physico-chemical characterization of MCM-41 silica spheres made by the pseudomorphic route and grafted with octadecyl chains

This work reports on the first comprehensive characterization of octadecyl (C(18)) modified MCM-41 silica spheres, prepared via the pseudomorphic route, followed by grafting with mono- or trifunctional octadecyl (C(18)) alkyl chains and endcapping with hexamethyldisilazane. Small angle X-ray scattering (SAXS), nitrogen adsorption-desorption and scanning electron microscopy (SEM) measurements were performed to obtain information about the MCM-41 pore structure, surface properties and morphological features. The degree of grafting and cross-linking of the silanes were determined by (29)Si magic angle spinning NMR spectroscopy, while FTIR and (13)C NMR were employed to study the conformational behavior of the surface-immobilized alkyl chains. The SAXS pattern proved the existence of a hexagonal mesopore arrangement for both the ungrafted and the grafted MCM-41 silica spheres. In addition, there is evidence of some long-range distortion in the pore structure. SEM measurements revealed the same morphological features for the parent silica and the MCM-41 silica spheres before and after C(18) grafting. The achieved surface loading for the MCM-41 material is rather low. It was also shown that a substantial amount of the accessible surface silanol groups is endcapped by trimethylsilane which in turn results in a very low surface coverage due to the octadecyl chains. The nitrogen sorption studies provided values for the surface area, total pore volume and pore diameter which are very typical for mesoporous materials. The reduction in surface area and total pore volume upon surface grafting is related to the binding of trimethylsilane in the interior of the pores, while due to the spatial restrictions octadecyl chains are primarily attached near the pore entrance. The experimental FTIR and (13)C NMR data point to a very low conformational order of the C(18) chains which is in accordance with the observed low surface coverage and the resulting spatial freedom for these surface-immobilized alkyl chains.     

A Robust and Cost-Efficient Scheme for Accurate Conformational Energies of Organic Molecules

Several standard semiempirical methods as well as the MMFF94 force field approximation have been tested in reproducing 8 DLPNO-CCSD(T)/cc-pVTZ level conformational energies and spatial structures for 37 organic molecules representing pharmaceuticals, drugs, catalysts, synthetic precursors, industry-related chemicals (37conf8 database). All contemporary semiempirical methods surpass their standard counterparts resulting in more reliable conformational energies and spatial structures, even though at significantly higher computational costs. However, even these methods show unexpected failures in reproducing energy differences between several conformers of the crown ether 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6). Inexpensive force field MMFF94 approximation groups with contemporary semiempirical methods in reproducing the correct order of conformational energies and spatial structures, although the performance in predicting absolute conformational energies compares to standard semiempirical methods. Based on these findings, we suggest a two-step strategy for reliable yet feasible conformational search and sampling in realistic-size flexible organic molecules: i) geometry optimization/preselection of relevant conformers using the MMFF94 force field; ii) single-point energy evaluations using a contemporary semiempirical method. We expect that developed database 37conf8 is going to be useful for development of semiempirical methods.     

Conformational analysis of polymethine dyes derived from the 2-azaazulene

A systematic investigation of the conformational structure was performed for the series of symmetrical and unsymmetrical mono-, tri-, pentamethine cyanines, and styryl dyes bearing 2-azaazulenium terminal group. The rotation energy barriers of terminal groups were determined via the dynamic variable temperature NMR experiments. The conformational transformation energy was calculated by quantum chemical methods (B3LYP and M05-2X) both for the cases of considering the solvent influence and not tacking it into account. Based on the comparison of theoretical and experimental data, relative electron-donating abilities and geometrical features of the heterocyclic terminal groups in 2-azaazulenium dyes were estimated. The arrangement of certain heterocyclic nuclei in order of basicity by considering the results of the dynamic NMR investigations was proposed. Influence of the conjugated chain length and the solvent nature on the conformational lability of the investigated dye molecules was discussed.     

Enantiodiscrimination in deuterium NMR spectra of flexible chiral molecules with average axial symmetry dissolved in chiral liquid crystals: the case of tridioxyethylenetriphenylene

Flexible chiral molecules undergoing fast interconversion (on the NMR time scale) between different conformational enantiomers may yield "average" axial species with enantiotopically related sites. Contrary to the situation observed for rigid axial molecules, signals from these enantiotopic sites in NMR spectra recorded in chiral liquid-crystalline solvents can be resolved. In the present work, we studied the deuterium NMR spectra of tridioxyethylenetriphenylene (compound 4) statistically deuterated to 10% in the flexible side chains and dissolved in chiral and achiral lyotropic liquid crystals based on poly(gamma-benzylglutamate). The fast chair-chair flipping of the side chains in 4 on average renders the molecule axially symmetric ( D 3 h ) with pairs of enantiotopic ethylene deuterons. These deuterons exhibit unusually large enantiodiscrimination. To explain this observation, we first describe how the average symmetry of flexible molecules can be derived from the symmetry of the "frozen" conformers and the nature of the averaging process. The procedure is then applied to 4 and used to analyze the NMR results. It is shown that the large enantiodiscrimination in the present case reflects a large difference in the orientational ordering of the conformational enantiomers participating in the interconversion processes as well as a large geometrical factor due to the special shape of the dioxyethylene side groups. (1)H and (13)C NMR spectra of 4 in the same lyotropic liquid crystalline solvent are analyzed to determine its ordering characteristics. Several related cases are also discussed.     

NMR Conformational Analysis and Theoretical Calculations for 2‐Aryl‐ 1,3‐dihydroxy‐4,4,5,5‐tetramethylimidazolidines

Conformational studies of 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐1‐yl)imidazolidine ( 1a ) and 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐3‐yl)imidazolidine ( 1b ), carried out by using 1D ¹H‐ and ¹³C‐NMR and 2D HMQC, HMBC, and NOESY experiments and with the aid of theoretical calculations, indicate that the OH groups are trans to the pyridinyl substituent. Because the two ¹H‐NMR signals of the Me groups are distinguishable and do not change between 290 and 380 K, it is proposed that 1a and 1b have each only one conformation in this temperature range. This behavior was not found with 1,3‐dihydroxy‐4,4,5,5‐tetramethyl‐2‐(pyridin‐2‐yl)imidazolidine ( 1c ) because its Me ¹H‐NMR signals cross over at 300 K. Hence, more than one conformation must be present, beyond those produced by simple inversions. Theoretical calculations including temperature and solvent effects were performed to provide further information on the conformational analysis and to help to assign the NMR data. The combination of NMR measurements and quantum‐chemical calculations is shown to be a very promising strategy for conformational analysis studies in solution.     

Characterizing Active Site Conformational Heterogeneity along the Trajectory of an Enzymatic Phosphoryl Transfer Reaction

States along the phosphoryl transfer reaction catalyzed by the nucleoside monophosphate kinase UmpK were captured and changes in the conformational heterogeneity of conserved active site arginine side‐chains were quantified by NMR spin‐relaxation methods. In addition to apo and ligand‐bound UmpK, a transition state analog (TSA) complex was utilized to evaluate the extent to which active site conformational entropy contributes to the transition state free energy. The catalytically essential arginine side‐chain guanidino groups were found to be remarkably rigid in the TSA complex, indicating that the enzyme has evolved to restrict the conformational freedom along its reaction path over the energy landscape, which in turn allows the phosphoryl transfer to occur selectively by avoiding side reactions.     

Conformational study of 9-dehydro-9-trifluoromethyl cinchona alkaloids via 19F NMR spectroscopy: emergence of trifluoromethyl moiety as a conformational stabilizer and a probe

The trifluoromethyl substituent has been incorporated into quinidine as a conformational stabilizer and a probe to provide straightforward insight into the conformational behavior of cinchona alkaloids. By significantly decreasing the rotation rate of the quinoline-carbinol bond, the relatively bulky CF(3) group enables the NMR signals of the syn and anti conformers to be differentiated at room temperature. In addition to the stabilizing effect, the introduction of the fluorinated moiety also facilitates the application of (19)F NMR spectroscopy, thereby allowing conformational studies under various conditions without the use of deuterated solvents.     

The conformation of cyclo(-D-Pro-Ala4-) as a model for cyclic pentapeptides of the DL4 type

The conformation of the cyclic pentapeptide cyclo(-D-Pro-Ala(4)-) in solution and in the solid state was reinvestigated using modern NMR techniques. To allow unequivocal characterization of hydrogen bonds, relaxation behavior, and intramolecular distances, differently labeled isotopomers were synthesized. The NMR results, supported by extensive MD simulations, demonstrate unambiguously that the preferred conformation previously described by us, but recently questioned, is indeed correct. The validation of the conformational preferences of this cyclic peptide is important given that this system is a template for several bioactive compounds and for controlled "spatial screening" for the search of bioactive conformations.     

An NMR investigation of the importance of intramolecular hydrogen bonding in determining the conformational equilibrium of ethylene glycol in solution

Although conformational analysis by NMR of ethylene glycol indicates generally strong preferences for the gauche conformation in solvents ranging from water to chloroform, the bulk of the NMR evidence indicates that intramolecular hydrogen bonding between the hydroxyl groups is unlikely to be a significant factor in determining that preference, except possibly in fairly non-polar solvents. The 'gauche effect' is clearly very important, especially in aqueous solution.     

Analog of dolastatin 3 synthesis, 1h nmr studies and spatial conformation

The total synthesis of the peptide cyclo [Pro-Leu-Val-(gly)Thz-(gly)Thz] a simplified analog of dolastatin 3 is reported here. Analysis of the 350 MHz ¹H NMR spectrum permits the design of a spatial molecular model. This conformational feature is of interest in the tentatives to assign the real structure of dolastatin 3 in the knowledge of intramolecular interaction of this drug with biological receptors.     

NMR and rotational angles in solution conformation of polypeptides

Professor San-Ichiro Mizushima and Professor Yonezo Morino's classical contributions provided unique means and firm basis for understanding of conformational states and internal rotation in polypeptide molecules. Now the NMR spectroscopy is the best choice to study molecular conformation, mechanism of action and structure-functional relationships of peptide and proteins in solution under conditions approaching those of their physiological environments. Crucial details of spatial structure and interactions of these molecules in solution are revealed by using proton-proton and carbon-proton vicinal coupling constants, proton nuclear Overhauser effect and spectral perturbation techniques. The results of NMR conformational analysis are presented for valinomycin “bracelet”, gramicidin A double helices, honey-bee neurotoxin apamin, scorpion insectotoxins and snake neurotoxins of long and short types.     

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.     

Conformational communication between the Ar-CO and Ar-N axes in 2,2'-disubstituted benzanilides and their derivatives

Benzanilides containing two or more potentially stereogenic amide axes exist in solution as mixtures of conformers which are detectable by NMR. For simple tertiary benzanilides carrying an ortho substituent on each ring, conformational control can be high (up to about 10:1) providing the substituents are large, indicating that the two axes are in conformational communication with one another. For more complex diamides, conformational communication breaks down, and mixtures of conformers are evident by NMR.     

Driving the Active Site Incorporation in Zeolitic Materials via the Organic Structure-Directing Agent Through Development of H-Bonds with Hydroxyl Groups

(1S,2S)-N-methyl-pseudoephedrine (MPS) was used as organic structure-directing agent (OSDA) for the synthesis of Mg-doped nanoporous aluminophosphates. This molecule displays a particular conformational behavior, where the presence of H-bond donor and acceptor groups provide a rigid conformational space with one asymmetric conformation preferentially occurring. MPS drives the crystallization of Mg-containing AFI materials. Characterization of these materials shows that the OSDA incorporate as protonated species, arranged as head-to-tail monomers. Combination of three-dimensional electron diffraction with high-resolution synchrotron powder X-ray diffraction allowed to locate both the Mg and the organic species. Interestingly, results showed that the spatial incorporation of Mg is driven by the hydroxyl groups of the organic cation through the development of H-bonds with negatively-charged MgO₄ tetrahedra. This work demonstrates that H-bond forming groups can be used to drive the spatial incorporation of low-valent dopants within zeolitic frameworks, a highly desired aim in order to control their catalytic activity and selectivity.