Rotameric Equilibrium Research Articles

Stereocalpin B, a New Cyclic Depsipeptide from the Antarctic Lichen Ramalina terebrata.

Stereocalpin B, a new cyclic depsipeptide (1), and a new dibenzofuran derivative (3), were isolated from the Antarctic lichen, Ramalina terebrata (Ramalinaceae), along with a known cyclic depsipeptide (2). The structures of new compounds were characterized by comprehensive spectrometric analyses; high-resolution fast atom bombardment mass spectrometry (HR-FABMS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Stereocalpin B (1) existed in a rotameric equilibrium, which was confirmed using nuclear Overhauser effect spectroscopy (NOESY)/exchange spectroscopy (EXSY) spectrum. Absolute configurations of the amino acid units in 1 were assigned using the advanced Marfey’s method and subsequent NOESY analysis of the 5-hydroxy-2,4-dimethyl-3-oxo-decanoic acid residue confirmed the complete stereochemistry of 1. Compounds 1-3 exhibited moderate antimicrobial activities against E. coli, with the IC50 values ranging from 18–30 μg/mL. Compound 2 exhibited cell growth inhibition against HCT116 cell lines, with the IC50 value of 20 ± 1.20 μM, and compounds 1 and 2 also showed potent anti-inflammatory activities against lipopolysaccharide (LPS)-induced RAW264.7 macrophages with the IC50 values ranging from 5–7 μM.

Structure and Conformation of Zosteraphenols, Tetracyclic Diarylheptanoids from the Seagrass Zostera marina: An NMR and DFT Study.

Zosteraphenols, two new tetracyclic diarylheptanoids were isolated from the seagrass Zostera marina. The rotameric equilibrium of the strained tetracyclic structures, involving a diastereomeric minor rotamer with opposite axial chirality, resulted in coalescent NMR spectra. Although the elusive minor rotamer was only characterized with 1H chemical shifts, the excellent agreement between experimental and DFT-calculated chemical shifts of both rotamers unequivocally supported this analysis. Absolute configuration of zosteraphenols was determined by DFT prediction of their ECD spectra.

Combined effect of hydrogen bonding interactions and freezing of rotameric equilibrium on the enhancement of photostability.

The photophysics and photostability of 12,13-dihydro-5H-indolo[3,2-c]acridine (IA), a rigid bifunctional indole derivative with proton donor/acceptor functionalities, can be drastically changed by the environment. The formation of hydrogen bonds with alcohols leads to a significant decrease of the triplet formation efficiency and an increase of photostability. The photodegradation yield was found to be about two hundred times lower in methanol and 1-propanol than in n-hexane or acetonitrile. A similar effect has been reported for two indole-naphthyridines, molecules that can exist in syn and anti rotameric forms. We demonstrate that IA, which can exist only in the syn form, is more photostable in alcohols than similar, but non-rigid molecules. This additional photostability enhancement is due to the elimination of a slower channel of excited state deactivation in alcohol complexes, S0 ← S1 internal conversion. The dominant, faster channel of S1 depopulation is the excited state double proton transfer, manifested by the presence of low energy tautomeric fluorescence.

Solvent‐Modulated Influence of Intramolecular Hydrogen‐Bonding on the Conformational Properties of the Hydroxymethyl Group in Glucose and Galactose: A Molecular Dynamics Simulation Study

Intramolecular hydrogen‐bonding (H‐bonding) is commonly regarded as a major determinant of the conformation of (bio)molecules. However, in an aqueous environment, solvent‐exposed H‐bonds are likely to represent only a marginal (possibly adverse) conformational driving as well as steering force. For example, the hydroxymethyl rotamers of glucose and galactose permitting the formation of an intramolecular H‐bond with the adjacent hydroxyl group are not favored in water but, in the opposite, least populated. This is because the solvent‐exposed H‐bond is dielectrically screened as well as subject to intense H‐bonding competition by the water molecules. In the present study, the effect of a decrease in the solvent polarity on this rotameric equilibrium is probed using molecular dynamics simulation. This is done by considering six physical solvents (H2O, DMSO, MeOH, CHCl3, CCl4, and vacuum), along with 19 artificial water‐like solvent models for which the dielectric permittivity and H‐bonding capacity can be modulated independently via a scaling of the O–H distance and of the atomic partial charges. In the high polarity solvents, the intramolecular H‐bond is observed, but arises as an opportunistic consequence of the proximity of the H‐bonding partners in a given rotameric state. Only when the polarity of the solvent is decreased does the intramolecular H‐bond start to induce a conformational pressure on the rotameric equilibrium. The artificial solvent series also reveals that the effects of the solvent permittivity and of its H‐bonding capacity mutually enhance each other, with a slightly larger influence of the permittivity. The hydroxymethyl conformation in hexopyranoses appears to be particularly sensitive to solvent‐polarity effects because the H‐bond involving the hydroxymethyl group is only one out of up to five H‐bonds capable of forming a network around the ring.

Solvent-Modulated Ground-State Rotamerism and Tautomerism and Excited-State Proton-Transfer Processes in o-Hydroxynaphthylbenzimidazoles

The ground-state rotamerism and tautomerism and the excited-state proton-transfer processes of 2-(1'-hydroxy-2'-naphthyl)benzimidazole (1) and 2-(3'-hydroxy-2'-naphthyl)benzimidazole (2) have been investigated in various solvents by means of UV-vis absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy, and quantum-mechanical ab initio calculations. For both compounds, a solvent-modulated rotameric equilibrium, and also tautomeric for 1, was observed in the ground state. In apolar solvents, both 1 and 2 exist as planar syn normal forms, with the hydroxyl group hydrogen bonded to the benzimidazole N3. In acetonitrile and ethanol, a rotameric equilibrium is established between the syn form and its planar anti rotamer, with the phenyl ring rotated 180 degrees about the C2-C2' bond. In ethylene glycol, glycerol, and aqueous solution with 40% ethanol, a tautomeric equilibrium was detected for 1 between the syn and anti normal forms and the tautomer form, with the hydroxyl proton transferred to the benzimidazole N3. In all of the solvents studied, the syn normal form of 1 and 2 undergoes an ultrafast excited-state intramolecular proton transfer (ESIPT) to yield the excited tautomer. The anti normal forms of 1 and 2, unable to experience ESIPT, give normal form fluorescence. In addition, the anti normal conformer of 2 partly deprotonates at the hydroxyl group in aqueous solution with 40% ethanol, giving the excited anion. The monocations of 1 and 2, protonated at the benzimidazole N3, are strong photoacids that deprotonate completely in aqueous solution with 40% ethanol and to a great extent in ethanol, giving the excited tautomer.

One‐Pot Synthesis and Conformational Features of N,N′‐Disubstituted Ketene Aminals.

AbstractFor Abstract see ChemInform Abstract in Full Text.

One-pot synthesis and conformational features of n,n'-disubstituted ketene aminals.

N,N'-Disubstituted ketene aminals are bioisosteres of thioureas and are useful building blocks in many synthetic operations. A convenient one-pot synthesis of N,N'-disubstituted ketene aminals from activated methylene compounds and isothiocyanates is described. Most of these aminals exist in rotameric equilibrium around the central C=C bonds in solution, and the rotamers are stabilized by intramolecular hydrogen bonding both in solution and in solid states.

On the contribution of intramolecular H-bonding entropy to the conformational stability of alanine conformations

The experimental and theoretical rotamerization constants for the rotameric equilibrium between the two most stable conformations of the α-amino acid alanine are compared. The experimental technique of matrix-isolation Fourier transform infrared spectroscopy in combination with the density functional theory (DFT) (B3LYP) and the 6-31++G** basis set is used for this study. A large disagreement between the experimental and theoretical value of the equilibrium constant is found. A relatively strong intramolecular H-bond in conformation II is at the origin of this discrepancy. From the difference between the experimental and theoretical rotamerization constant, a Δ S° value of −6.6 J K −1 mol −1 is found for the intramolecular H-bond formation.

Rotamerism and electronic spectra of aza-derivatives of stilbene and diphenylbutadiene. A combined experimental and theoretical study

The experimental results on the rotameric equilibrium and electronic spectra of aza-derivatives of trans-stilbene and 1,4-diphenylbutadiene, have been rationalized by a theoretical study which combines simple ab initio calculations of molecular energies for the ground state with a theoretical analysis of the splitting of the conjugation band developed at CS INDO CI level. All results indicate that the stable conformer of each ortho aza-derivative is that corresponding to A species. As suggested by the 1H-NMR experiments, the ab initio geometry of ZE-2-pyridylphenylbutadiene is consistent with the presence of the N·H intramolecular hydrogen bond. As regards the Franck-Condon excited states of aza-derivatives, our theoretical results show that the first singlet excited state has (π H, π L*) character in all compounds except for E-4,4′-dipyridylethene, where S 1 has (n, π*) character in non-polar solvent. In this last compound, the theoretical study of solvatochromism indicates a crossing between the 1(n, π L*) and 1(π H, π L*) states which occurs in solvents of high polarity. The inclusion of the most important doubly- and triply-excited configurations in the CI calculations shows that the 1A g − excited state is above the spectral region analyzed.

Synthesis and conformational investigation of methyl 4a-carba-D-arabinofuranosides.

The synthesis of carbasugar analogues of methyl alpha-D-arabinofuranoside and methyl beta-D-arabinofuranoside (3 and 4) is reported. The route developed involves the conversion of D-mannose into a suitably protected diene (13), which is then cyclized via olefin metathesis. The resulting cyclopentene (14) is stereoselectively hydrogenated to provide an intermediate that can be used for the synthesis of both targets. Through the use of NMR spectroscopy, we have probed the ring conformation of 3 and 4, as well as the rotamer populations about the C(4)-C(5) and C(1)-O(1) bonds. These studies have demonstrated that there are differences in ring conformation between these carbasugars and their glycoside parents (1 and 2). However, only minor differences are seen in the rotameric equilibrium about the C(4)-C(5) bond in 3 and 4 relative to 1 and 2. In regard to the C(1)-O(1) bond, NOE data from 3 and 4 suggest that the favored position about this bond is similar to that in the glycosides; that is, the methyl group is anti to C(2). However, confirmation of this preference through measurement of (3)J(C,C) between the methyl group and C(2) or C(4a) was not successful.

Photochemistry of conjugated trienes: Vitamin D revisited

Abstract

Structural and conformational studies on sesquiterpenoids Part II: X-ray, molecular mechanics and NMR analysis of slovanolides

The crystal structures of the slovanolide 3 and of the 0(6)-monoacetate of its base-catalysed rearrangement product ( 7) are reported. These compounds differ for the closure of the γ-lactone ring (C(6)- cis versus C(8)- trans), and display a different conformation in the solid state; in both molecules the seven-membered ring assumes a twist-chair (TC) conformation, but with the approximate C 2 through C(7) in 3 and through C(5) in 7. The 1H NMR spectra indicate that these differences are also maintained in solution, where no rotameric equilibrium is present. Molecular-mechanics calculations have been carried out on several model compounds. In particular, calculations on the bis-γ-hydroxyacid 8 formed upon treatment with bases of 3 and 7, showed that the C(5)-TC conformation is more stable by about 8 kcal mol −1 and that intramolecular hydrogen bonds and, to a lesser extent, ring torsional strain, are the main cause of its stabilisation. It was also shown that lactonisation of the hydroxyacid 8 from the C(5)-TC conformation can only take place at C(8), whereas lactonisation at C(6) is only attainable from the C(7)-TC conformation. The exclusive lactonisation at C(8) reflects therefore the overwhelming preference of the bis-γ-hydroxyacid for the C(5)-TC conformation. The interconversion pathway betwewen the C(7)-and C(5)-TC conformations of the bis-γ-hydroxyacid has also been analysed. Only two minima are found, separated by a large energy barrier, corresponding to the TC conformation of lactones 3 and 7.

Rotational Barriers of 4‐Aryl‐1, 4‐dihydropyridines (Ca Antagonists)

Indications of the “pharmacologically active conformation” of the cardiotherapeutic 1 were obtained by 1H-NMR investigations on model compounds. A rapidly adjusting rotameric equilibrium apparently exists between the (preferred) synperiplanar and the antiperiplanar forms of 1. Nifedipine 1, R  CH3, X  NO2, has acquired great importance as the active component in Adalat®.

Phosphorus–phosphorus nuclear spin coupling in tetraorganobiphosphines and some of their derivatives

The signs and magnitudes of 31P–31P and 31P–H spin-coupling constants in tetraorganobiphosphines RR′PPRR′ with Me, Ph, and/or But as substituents, and in their sulphides and selenides RR′P(X)P(X)RR′(X = S or Se), have been determined by 1H-{31P} heteronuclear double resonance. Large variations in 1J(31P-31P) arise as a result of changes in the phosphorus hybridization and/or effective nuclear charge, and smaller variations as a result of changes in the position of rotameric equilibrium in the gauche conformers of the biphosphines.

Proton-coupled carbon-13 nuclear magnetic resonance spectra from individual carbon sites in a molecule: the rotameric equilibrium in menthone

Vicinal carbon-proton coupling constants have been measured for menthone by a new technique and show that the most stable rotamer is (1a) rather than (1b).

Optical rotatory dispersion studies—CXII thiosteroids ( 20) : An octant rule for the thiocyanate chromophore and its application to rotameric equilibrium studies in the steroid series

Optical rotatory dispersion and circular dichroism measurements of a number of steroidal thiocyanates have demonstrated that a low intensity absorption near 250 nm is optically active. On the assumption that this transition of thiocyanates is qualitatively similar to the n → π * transition of azides, an octant rule is proposed for thiocyanates, which leads to the prediction of the sign of the Cotton effect. Its potential utility is demonstrated by analyzing rotameric contributions of various steroidal thiocyanates.