Solvent-dependent conformational analysis

The first method based on an ensemble of conformers was developed by Hopfinger and Battershell in 1976. Using the solvent-dependent conformational analysis procedure (SCAP), which identifies the preferred conformations of a solute in different solvents (water, methanol, ethanol, -octanol), the free energy of the solute at 300 K can be calculated, whereupon the partition coefficients can be obtained by means of Eq. [35] ... 

Hopfinger and Battershell developed a semiempirical program, CAMSEQ, with the aim of attempting to make a solvent-dependent conformational analysis and calculating logP values on a whole-molecule basis. For simplicity of calculation, methanol was chosen as a model solvent, and it... 

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

A lanthanide-induced shift analysis of tetrahydrothiopyran 1-oxide based on calculated geometrical parameters indicated that the equilibrium mixture contained ca. 45% of the equatorial conformer in CDCI3 solution. However, the conformational equilibrium is solvent dependent, with the equatorial conformer predicted to be favored by polar solvents. The calculated dipole moments for the equatorial and axial conformers are 4.39 and 4.17 D respectively, which compare favorably with the experimental value of 4.19 D <1994J(P2)2329>. 

There are three NMR-based approaches suitable to propose the bioactive conformation of ligands in the absence of the coordinates of the whole complex 1. conformation analysis of free ligand in solution has a high chance to find with some population the bound conformation, although it may be solvent dependent (refer to Sect. 2.2.2) 2. determination of bound ligand conformation by means of transferred NMR methods if the dissociation constant is not smaller than approximately 50 pM (refer to Sects. 2.1 and 2.3) 3. solid-state NMR of the complex if the ligand can be obtained with 13C labels (Sect. 2.2.3). 

The earliest studies on the IR spectra of crown ethers and their complexes were carried out by Pederson (B-78MI52101). Since then IR spectroscopy has been applied a number of times to solve structural problems in crown ether chemistry including ion pair interactions and conformational analysis (B-79MI52103). A low frequency vibration of the cation within the macrocycle has been identified which is dependent on the cation but not on the solvent (214 cm for Na -dibenzo[18]crown-6 in both DMSO and pyridine). This is in contrast to the frequency of cation vibration within a solvent cage, which for Na is 202 cm in... 

An analysis of the solvent dependence of the A>c and /hh couplings combined with an analysis of the changes in the IR first overtone carbonyl bond intensities and theoretical calculations allowed Abraham and co-workers to determine directly the conformational equilibria in 2-bromocyclo-hexanone, a model compound, by the use of which the authors illustrated an improved method of conformational analysis of substituted cyclohexanones. 

Isoaromatization of dienone macrocycles afforded Horning-crown macro-cycles - flexible macrocycles bearing structural elements reminiscent of those found in both calixarenes and crown ethers. In some cases the Horning-crown macrocycles exhibited solvent-dependent and switchable conformations. For macrocycles with the same short linker, self-complementarity was observed, and dimers tended to crystallize as solvates or inclusion compounds. This tendency was suppressed with longer linkers and in some Horning-crowns derived from trapezoidal macrocycles. These properties suggest potential applications in analysis, separation and detection (Figure 6.8). ... 

Studies of Equilibria, Configuration and Conformation. - Conformational analysis of trihalo- triphospholanes (29) by low-temperature P NMR spectroscopy revealed the presence of two conformers. The ylidyl substituent of the chlorophosphine (94) exerts a strong influence on the P-Cl bond. The ylidyl chlorophosphines (94 R = R2N) are covalent in benzene but become more or less ionic in dichloromethane solution. The solvent dependent dissociation equilibrium can be followed by P NMR spectroscopy. In the case of an enamine-derived ylidyl chlorophosphine, the equilibrium shifts almost completely from the covalent to the ionic side within a rather narrow range of solvent composition, from 20 to 70% (vol) of dichloromethane. ... 

A large number of studies employing different NMR techniques have been devoted to the investigation of the temperature dependence of the ring inversion of cyclohexane. This is not surprising in view of the fact that the problem of cyclohexane inversion represents the seminal problem in conformational analysis. What is surprising, however, that all previous studies have used a single solvent - carbon disulfide, and, that only a limited pressure study (up to 2 kbar) of cyclohexane in quaternary mixture has been performed by Liidemann et al. ( 7)... 

Tormena et al studied conformational analysis of fluoroacetoxime using the solvent dependence of the IH, and 15N NMR spectra of (E)-fluoroacetoxime... 

Batchelor JG (1976) Conformational analysis of cyclic amines using carbon-13 chemical shift measurements dependence of conformation upon ionization state and solvent. J Chem Soc Perkin Trans 2 1585-1590... 

The detection of both monomeric and dimeric structures in the solid state, depending on the polarity of the solvent from which the crystals were grown, and the consistency of these results with the solution structures as provided by spectroscopic methods nicely demonstrates that crystallographic data can be sensitive even to solvent influences. Moreover, the crystal structure of the intermediate complex shows the importance of solid-state conformational analysis for the elucidation of complex formation mechanisms or, more generally speaking, for molecular dynamics. 

The halogenated polymers are slightly less tractable, but they are are in any case known to give shifts that depend somewhat upon solvent, especially in the methylene region. However, the spectrum of poly(methylmethacrylate) (PMMA) cannot be predicted by any reasonable conformational analysis [34]. In this case the shift of the methyl carbon in the M-trans chain should be insensitive to the stereochemistry at its neighbouring centres, for the PMMA chain is known from other measurements to have this predominantly a -trans stereochemistry. Yet the shifts of its carbons show a very large dependence upon tacticity, in both the solution and crystalline states. 

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