Conformational Assignments Research Articles

Evaluation of polarizable continuum model for the prediction of vibrational frequencies of biomimetic molecules in solution

The prediction accuracy of density functional theory (DFT) has been investigated for the calculation of harmonic vibrational frequencies of natural, protected amino acids and dipeptides in solution within two implementations of polarizable conductor continuum model (CPCM). A training set of 20 amino acids and dipeptides has been used to establish mode-specific local scaling factors for the carboxylate stretches, the amide I and symmetric bending mode of ammonium group. With the new implementation of the PCM cavity based on a continuous apparent surface charge formalism, it has been found that these modes can be simulated with typical prediction errors of ca. 10 cm −1. This approach should thus be able to provide conformer assignments of biomimetic molecules from their infrared spectra in solution.

Spectroscopy and dynamics of methyl-4-hydroxycinnamate: the influence of isotopic substitution and water complexation

High-resolution Resonance Enhanced MultiPhoton Ionization (REMPI) and Laser Induced Fluorescence (LIF) excitation spectra of jet-cooled methyl-4-hydroxycinnamate, methyl-4-OD-cinnamate, and of their water clusters have been recorded. Whereas water complexation leads to significant linewidth narrowing, isotopic substitution does for all practical purposes not influence the excited-state dynamics. In this light, we evaluate two previously proposed decay channels of the photoexcited ππ* state involving the dissociative πσ* state (analogous to phenol) and involving the optically dark nπ* state (as concluded for para-coumaric acid). To come to an unambiguous interpretation of the REMPI studies, it has been necessary to determine ionization thresholds. For methyl-4-hydroxycinnamate and its water cluster values of 8.078 and 7.636 eV have been found. Apart from the electronic excitation studies, IR absorption studies have been performed as well. These studies provide important vibrational markers for the assignment of the various conformations that are present under molecular beam conditions, and offer a direct measure of the influence of hydrogen bonding on the properties of the hydroxyl group.

Problems with a conformation assignment of aryl-substituted resorc[4]arenes

Acid-catalyzed condensation of resorcinol with 3,5-diisopropoxybenzaldehyde and 3,5-dihydroxybenzaldehyde afforded aryl substituted resorc[4]arenes 1a and 1b, respectively. All 16 hydroxyls in 1b were acetylated providing resorc[4]arene 1c. The conformational behaviour of 1a, 1b and 1c was studied by NMR spectroscopy and quantum chemical calculations. It was found that the stabilization of their conformations is an effect of competing π-π and OH-π interactions, hydrogen bonding and steric features, respectively. As a result, C2 symmetrical boat conformations 1a, 1b and 1c with aryls in axial positions were identified in all cases. In case of 1c also the formation of C2 symmetrical conformation with aryls in equatorial positions (boat-eq) was identified. Moreover, compounds 1a and 1b being able to create hydrogen bonds, adopt also symmetrical C4 crown conformations. For 1c(boat-ax), the boat-boat conversion with energy barrier of 80 kJ/mol was observed, while the 1c(boat-eq) was found to be rigid in the whole accessible temperature range. Both conformers of 1c exhibit also second dynamic process – rotation of bridge aryl rings (ΔG‡ = 66 kJ/mol).

Overtone Spectra of 2-Mercaptoethanol and 1,2-Ethanedithiol

Vibrational spectra of vapor-phase 1,2-ethanedithiol and 2-mercaptoethanol were recorded to investigate weak intramolecular interactions. The spectra were recorded with conventional absorption spectroscopy and laser photoacoustic spectroscopy in the 2000-11,000 cm(-1) region. The room temperature spectra of each molecule are complicated by contributions from several conformers. Anharmonic oscillator local-mode calculations of the OH- and SH-stretching transitions have been performed to facilitate assignment of the different conformers in the spectra. We observe evidence of hydrogen-bond-like interactions from OH to S, but not from SH to O or S. The OH to S intramolecular interaction in 2-mercaptoethanol is weak and comparable to that found in the OH to O interaction in ethylene glycol.

ChemInform Abstract: A Convenient Synthesis of (2R)-1-Amino-1-deoxy-1-phosphinylglycerols.

2,3-O-Isopropylidene-D-glyceraldehyde reacts with dimethylphosphine oxide in the presence of triethylamine to give separable (1S,2R)-and (1R,2R)-1-dimethylphosphinylgrycerol (65 :35), from which the (1R) and (1S) title compounds are respectively derived via 1-O-mesyl and 1-azido derivatives. The corresponding 1-dimethoxyphosphinylglycerols are similarly prepared. Structural and conformational assignments of these products are made on the basis of the 1H NMR data and [α]D values.

ChemInform Abstract: Conformational Analysis and Complete Assignment of the Proton and Carbon NMR Spectra of Ouabain (Ib) and Ouabagenin (Ia).

ChemInform Abstract: Conformational Analysis and Complete Assignment of the Proton and Carbon NMR Spectra of Ouabain (Ib) and Ouabagenin (Ia).

ChemInform Abstract: Conformation and Configurational Assignment of cis and trans-3,4- Dimethyl-6-tert-butyl-5,6-dihydro-2H-thiopyran-S-oxides and S-Methyl Cations

ChemInform Abstract: Conformation and Configurational Assignment of cis and trans-3,4- Dimethyl-6-tert-butyl-5,6-dihydro-2H-thiopyran-S-oxides and S-Methyl Cations

Ethanol Monomers and Dimers Revisited: A Raman Study of Conformational Preferences and Argon Nanocoating Effects

The gauche-trans conformational distribution in ethanol can be determined from the OH stretching Raman spectrum of seeded supersonic jet expansions, which thus provides a sensitive conformational thermometer. Depending on the rare gas mixture, one, two or four ethanol dimer conformations are abundant. Their conformational assignment is facilitated by the observation of hydrogen bond acceptor modes, which have similar Raman cross sections but much inferior infrared intensities than donor modes. Ethanol monomers and dimers can be progressively Ar-coated, and the resulting spectra may be compared with those in a bulk argon matrix. The low frequency range of torsional transitions provides some evidence for conformation-changing transitions in Raman jet spectra.

Chemical shift assignment and conformational analysis of monoalkylated acylguanidines

Monoalkylated acylguanidines are important functional groups in many biologically active compounds and additionally applied in coordination chemistry. Yet a straightforward assignment of the individual NH chemical shifts and the acylguanidine conformations is still missing. Therefore, in this study, NMR spectroscopic approaches for the chemical and especially the conformational assignment of protonated monoalkylated acylguanidines are presented. While NOESY and (3)J(H, H) scalar couplings cannot be applied successfully for the assignment of acylguanidines, (4)J(H, H) scalar couplings in (1)H,(1)H COSY spectra allow for an unambiguous chemical shift and conformational assignment. It is shown that these (4)J(H, H) long-range couplings between individual acylguanidinium NH resonances are observed solely across all-trans (w) pathways. Already one cis orientation in the magnetisation transfer pathway leads to signal intensities below the actual detection limit and significantly lower than cross-peaks from (2)J(NH, NH) couplings or chemical exchange. However, it should be noted that also in the case of conformational exchange being fast on the NMR time scale, averaged cross-peaks from all-trans (4)J(H, H) scalar couplings are detected, which may lead at first glance to an incomplete or even wrong conformational analysis.

Conformations and vibrational spectroscopy of metal-ion/polylalanine complexes

The thermochemistry and structures of complexes of dialanine and trialanine with a series of singly and doubly charged metal ions have been examined by spectroscopic and computational approaches. Complexes with Li +, K +, Cs +, Ca 2+, Sr 2+ and Ba 2+ were formed by electrospray ionization, and studied by infrared multiple photon dissociation spectroscopy (IRMPD) in a Fourier-transform ion cyclotron resonance (FTICR) mass spectrometer using irradiation in the 1000–1900 cm −1 infrared (IR) region from the FELIX free electron laser. Spectra were correlated with computed thermochemistry and simulated IR spectra from density functional (DFT) calculations of likely candidate conformations to make conformational assignments and characterize the variation of characteristic normal mode frequencies as a function of metal-ion identity. All trialanine complexes were found to have the charge-solvated (CS) form of the ligand with all three carbonyl oxygens chelating the metal. Dialanine was more varied: the Ba complex had largely the salt-bridge (SB) form, the Sr and Ca complexes showed a mixture of CS and SB, the Cs complex was CS with (OO) chelation, and the K, Na and Li complexes were CS in an undetermined mixture of (OO) and (NOO) chelation. Binding of the metal ion to the carboxyl carbonyl and to the amide carbonyl(s) (Amide I band) gave a red shift of the C O stretches, and a blue shift to the Amide II band. The frequency shifts were greater for more strongly interacting metal ions (smaller size, larger charge), and were found to be linearly proportional to the metal–ligand binding energy.

Conformation of hindered piperidines: Spectroscopic evidence for contribution of boat conformations

High resolution 1H and 13C NMR resonance assignments and conformational assignments were carried out for four t(3)-benzyl-r(2),c(6)-bis(aryl)piperidin-4-ones 1–4 and their four N-nitroso-t(3)-benzyl-r(2),c(6)-bis(aryl)piperidin-4-ones 5–8. In addition to conventional 1D NMR methods, 2D shift-correlated NMR techniques (1H-1H COSY and 1H-13C COSY) were used for signal assignments. At room temperature the t(3)-benzyl-r(2),c(6)-bis(aryl)piperidin-4-ones 1–4 exist in only one isomeric form whereas their N-nitroso derivatives 5–8 exist in two isomeric forms. The preferred conformations of both the isomeric forms of nitrosamines were determined by comparison of the spectral data with those of the corresponding parent amines 1–4 and with the aid of substituent parameters. The results indicate the presence of an equilibrium mixture of boat forms B 1 and B 2 for Z isomers of 5–8. For the E isomers of 5–8, boat form B 1 is predicted to be the major conformer. The piperidin-4-ones 1–4 exist in normal chair conformations with equatorial orientations of all the substituents.

Ab Initio Structure Determination from Electron Microscopic Images of Single Molecules Coexisting in Different Functional States

We have developed methods for ab initio three-dimensional (3D) structure determination from projection images of randomly oriented single molecules coexisting in multiple functional states, to aid the study of complex samples of macromolecules and nanoparticles by electron microscopy (EM). New algorithms for the determination of relative 3D orientations and conformational state assignment of single-molecule projection images are combined with well-established techniques for alignment and statistical image analysis. We describe how the methodology arrives at homogeneous groups of images aligned in 3D and discuss application to experimental EM data sets of the Escherichia coli ribosome and yeast RNA polymerase II.

ChemInform Abstract: Bis[oxo/thioxothiazolinyl] Aromatic Compounds - Synthesis and Conformational Assignment.

A series of bis(oxo/thioxothiazolinyl) aromatic atropisomers with two chiral C(aryl)-N(heterocycle) axes was synthesized. The separation of antiparallel, parallel diastereomers was achieved by chromatography on silica. Conformational assignment for the bis-thione atropisomers 1a,b-4a,b and bis-one atropisomers 9a,b-12a,b was based on polarimetric results in analytical chiral chromatography on microcrystalline cellulose triacetate. The relationship conformation-1H NMR chemical shifts, found for the bis-thiones and bis-ones was successfully applied for the conformational assignment of thione-one atropisomers not assigned by chiral liquid chromatography.

ChemInform Abstract: Medium-Sized Cyclophanes. Part 52. Synthesis and Structures of [2.n]Metacyclophane-1,2-diones.

A series of syn- and anti-[2.n]metacyclophan-1-enes, 3, and [2.n]metacyclophane-1,2-diols, 4, were prepared in good yields by a McMurry cyclization of 1,n-bis(5-tert-butyl-3-formyl-2-methoxyphenyl)alkanes, 2. Upon increasing the length of the methylene bridge higher yields of 3 were obtained. The assignment of the syn and anti conformations has been confirmed by 1H-NMR analyses. The 1,2-diol derivatives 4 were converted to the 1,2-diones 9 by Swern oxidation. However, [2.2]metacyclophane-1,2-dione, 9a, was found to be quite labile under treatment by silica gel column chromatography and on refluxing in toluene to give the dicarboxylic acid 10 in quantitative yield. Thus, a trapping reaction of diketone 9a was attempted, in which the crude diketone 9a was treated with o-phenylenediamine in ethanol at room temperature for 24 h to afford in almost quantitative yield the desired [2.2]metacyclophane 11 having a quinoxaline skeleton. Similarly, in the case of [2.3]- and [2.4]metacyclophanes, Swern oxidation of the trans-diols trans-4b,c also afforded the desired diketones 9b,c in quantitative yields as stable yellow prisms.

Characterization of the structures of phosphodiesterase 10 binding with adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate by hybrid quantum mechanical/molecular mechanical calculations.

Quantum mechanical/molecular mechanical (QM/MM) geometry optimizations of the X-ray crystal structures of PDE10-AMP (PDB code 2OUN ) and PDE10-GMP (PDB code 2OUQ ) complexes have been performed to characterize the state of the AMP and GMP products, respectively. Results show that only one phosphate oxygen atom (O1) is protonated for both AMP and GMP product complexes. In addition, QM/MM calculations have resolved the orientation of the amide group of Gln726 in PDE10-GMP which was in conflict with the assignment of the guanine group of GMP in the X-ray crystal structure. Calculations reveal that the amide oxygen and nitrogen atom of Gln726 are rotated 180 degrees, resulting in two strong hydrogen bonds formed between the amide group of Gln726 and the guanine group of GMP. Binding free energy calculations for both QM/MM-optimized structures confirm the new conformational assignment of Gln726 in PDE10-GMP. The calculated binding free energy of the rotated structure is approximately 22 kcal/mol lower than the X-ray crystal assignment. The lower energy is mainly derived from the formation of two hydrogen bonds between the amide group of Gln726 and the guanine group of GMP. This implies that the orientation of the amide oxygen and nitrogen atoms in PDE10-AMP is different from PDE10-GMP. Finally, our results help to understand why PDE10 can hydrolyze both cAMP and cGMP.

O−H···O versus O−H···S Hydrogen Bonding. 3. IR−UV Double Resonance Study of Hydrogen Bonded Complexes ofp-Cresol with Diethyl Ether and Its Sulfur Analog

In this work the hydrogen bonded complexes of diethyl ether (DEE) and diethyl sulfide (DES) with p-cresol (p-CR) were investigated. Only one conformer of the p-CR.DEE complex and three conformers of the p-CR.DES complex were found to be present under the supersonic jet expansion conditions. The conformational assignments were done with the help of IR-UV double resonance studies and ab initio calculations. The red shifts in the OH stretching frequency for the O-H...O and O-H...S hydrogen bonded complexes were quite close to each other. In fact, one of the p-CR.DES conformers showed a slightly larger red shift in the OH stretch than that in the p-CR.DEE conformer, which suggests that in this case sulfur is not a weak hydrogen bond acceptor as noted previously in case of the p-CR.H(2)O and p-CR.H(2)S complexes (Biswal et al. J. Phys. Chem. A 2009, 113, 5633). The natural bond orbital analysis also shows that the extent of overlap between sulfur lone pair orbitals (LP) and OH antibonding orbital (sigma*(OH)) was comparable to the oxygen (LP) and sigma*(OH) overlap, consistent with the similar magnitudes of the red shifts of OH stretch in the DES and DEE complexes. The computed binding energy of the p-CR.DES complex, however, was about 80% of the p-CR.DEE complex. The electron densities at the bond critical points indicated that the O-H...S interaction was weaker than the O-H...O interaction in this particular system also. The important finding of this study was that the IR red shifts in the H-bond donor X-H stretching frequency were not quite consistent with the computed binding energies and the atoms-in-molecules analysis contrary to the general understanding. Energy decomposition analysis suggests that O-H...S hydrogen bonding interaction is dispersive in nature and the dispersion contribution decreases with the increase in the length of the alkyl chain of the "S" hydrogen bond acceptor.

Gas-phase isolation of diethyl guanosine 5′-monophosphate and its conformational assignment

We show that intact neutral molecules of guanosine 5'-monophosphate can be vaporized by laser desorption when its phosphate group is esterified. The UV and IR spectroscopic measurements of this nucleotide reveal the existence of a novel internal hydrogen-bonding conformation of the phosphate group and guanine moiety.

High-resolution cavity ringdown spectroscopy of the jet-cooled propyl peroxy radical C3H7O2

We have obtained high resolution, partially rotationally resolved, jet-cooled cavity ringdown spectra of the origin band of the A<--X electronic transition of two of the five conformers (G(1)G(2) and G(1)T(2)) of the normal propyl peroxy radical, C(3)H(7)O(2), as well as the G conformer of the iso-propyl peroxy radical isomer. This transition, located in the near infrared, was studied using a narrow band laser source (less than or approximately 250 MHz) and a supersonic slit-jet expansion coupled with an electric discharge allowing us to obtain rotational temperatures of about 15 K. All three spectra have been successfully fitted using an evolutionary algorithm approach with a Hamiltonian including rotational and spin-rotational terms. Excellent agreement with the experimental spectra was obtained by fitting seven molecular parameters in each of the ground and the first excited electronic states as well as the band origin of the electronic transition. These parameters are compared with the results from electronic structure calculations. This analysis confirms unambiguously the previous room-temperature conformer assignments that were based upon quantum chemistry calculations.

Chiral Induction from Allenes into Twisted 1,1,4,4‐Tetracyanobuta‐1,3‐dienes (TCBDs): Conformational Assignment by Circular Dichroism Spectroscopy

Conformational assignment: The mechanism of chiral induction in an optically pure 1,3-diethynylallene, from the central chiral allene moiety into directly adjacent TCBD chromophores, was confirmed and clarified. Only one low-energy conformer is found in calculations of the potential energy surface, which closely resembles the X-ray crystal structure. Simulations of the CD spectrum by time-dependent DFT showed a total agreement (see picture), in terms of position and sign, for all Cotton effects when compared to the experimental spectrum. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Absolute Conformations of the (−)‐[9](2,5)Pyridinophane Molecule

Abstract[9](2,5)Pyridinophane was first synthesized, and its enantiomers were separated, more than 40 years ago, but the molecule's absolute conformations could not be determined up to now. We show here, by the comparison of measured and computed vibrational optical activity (VOA), that the CIP descriptor (P) applies to the (−)‐enantiomer. This assignment is based on the VOA of bands from vibrations localized on the pyridine ring bent by the tense (CH2)9 chain extending from position 2 to 5. The VOA of vibrations localized on the chain is in agreement with this assignment. Its behavior differs from the VOA of the bent pyridine ring, and conclusions drawn from the chain's VOA alone would not be sufficient, because the close‐to‐enantiomorphic geometries of the chain present in some of the 14 conformers of (−)‐[9](2,5)pyridinophane lead to VOA with an opposite sign. Understanding of how VOA is generated is crucial for the unambiguous assignment of the molecule's absolute conformations.