Conformational equilibria, solvent effects

A prototype of such phenomena can be seen in even the simplest carboxylic acid, acetic acid (CH3CHOOH). Acidity is determined by the energy or free energy difference between the dissociated and nondissociated forms, whose energetics usually depend significantly on their conformation, e.g., the syn/anti conformational change of the carboxyl-ate group in the compound substantially affects the acid-base equilibrium. The coupled conformation and solvent effects on acidity is treated in Ref. 20. 

Most of these results have been obtained in methanol but some of them can be extrapolated to other solvents, if the following solvent effects are considered. Bromine bridging has been shown to be hardly solvent-dependent.2 Therefore, the selectivities related to this feature of bromination intermediates do not significantly depend on the solvent. When the intermediates are carbocations, the stereoselectivity can vary (ref. 23) widely with the solvent (ref. 24), insofar as the conformational equilibrium of these cations is solvent-dependent. Nevertheless, this equilibration can be locked in a nucleophilic solvent when it nucleophilically assists the formation of the intermediate. Therefore, as exemplified in methylstyrene bromination, a carbocation can react 100 % stereoselectivity. 

Conformational Equilibria. The solvent effect on the conformational equilibria represents a typical problem studied using the DFT/SCRF methods. The presence of the environment may affect the free energy of a given conformer, its equilibrium conformation or even destabilize a particular conformation. The DFT/SCRF calculations have been applied to study such effects using various KS methods as well as different techniques for calculating [Pg.112]

The several theoretical and/or simulation methods developed for modelling the solvation phenomena can be applied to the treatment of solvent effects on chemical reactivity. A variety of systems - ranging from small molecules to very large ones, such as biomolecules [236-238], biological membranes [239] and polymers [240] -and problems - mechanism of organic reactions [25, 79, 223, 241-247], chemical reactions in supercritical fluids [216, 248-250], ultrafast spectroscopy [251-255], electrochemical processes [256, 257], proton transfer [74, 75, 231], electron transfer [76, 77, 104, 258-261], charge transfer reactions and complexes [262-264], molecular and ionic spectra and excited states [24, 265-268], solvent-induced polarizability [221, 269], reaction dynamics [28, 78, 270-276], isomerization [110, 277-279], tautomeric equilibrium [280-282], conformational changes [283], dissociation reactions [199, 200, 227], stability [284] - have been treated by these techniques. Some of these... 

In the case of 2-hydroxytetrahydropyran, the axial conformer 22 is calculated to be more stable than its equatorial conformer 23 in vacuum (Fig. 12). Solvent effects change the equilibrium constant and the equatorial form 23 is favored in aqueous solution, in agreement with data. The magnitude of the conformational endo-anomeric effect in 22 is estimated to 2.0 kcal/mol (gas phase stereoelectronic effects overwhelming the steric... 

The influence of the solvent on chiroptical properties of synthetic polymers is dramatically illustrated in the case of poly (propylene oxide). Price and Osgan had already shown, in their first article, that this polymer presents optical activity of opposite sign when dissolved in CHCI3 or in benzene (78). The hypothesis of a conformational transition similar to the helix-coil transition of polypeptides was rejected because the optical activity varies linearly with the content of the two components in the mixture of solvents. Chiellini observed that the ORD curves in several solvents show a maximum around 235 nm, which should not be attributed to a Cotton effect and which was interpreted by a two-term Drude equation. He emphasized the influence of solvation on the position of the conformational equilibrium (383). In turn, Furakawa, as the result of an investigation in 35 different solvents, focused on the polarizability change of methyl and methylene groups in the polymer due to the formation of a contact complex with aromatic solvents (384). 

NMR is an especially sensitive tool for detecting non-equivalence and for studying the underlying phenomena (steric hindrance, solvent effects, etc.) and a number of examples were cited in the previous section. Thus, it was noted from work of Rudolph and Newmark<1969,31) that conformational equilibrium exists in F2PSPF2 (in which sulphur acts as a rather loose link) but not in F2PPF2 or F2P(NCH3)PF2 (see Sections... 

Assuming there are no solvent effects, which isomer is likely to predominate in an equilibrium between the conformers A and B ... 

Since there is only a small energy difference between the different conformational states depending upon the presence or absence of a Pro, Gly or N-alkylated amino acid residue, and upon the chirality of the constituent amino acid residues and also to a lesser extent upon the side-chain functionalities, it is not possible to unambiguously predict the conformation of a cyclic pentapeptide. These molecules have often been studied in different solvents and solvent effects were neglected, and/or the methodology to handle such conformational equilibrium was not available. It is only recently that modem NMR techniques and computational procedures have become available to treat this complex problem of fast exchanging conformational equilibria. 36,269,270 ... 

An anomeric effect is observed in 3,4-dihydro-2H- pyrans. For example, a 2-alkoxy group preferentially occupies an axial position (71DOKd96)367>. Indeed, a study of the NMR spectra of some 2-alkoxy-3,4-dihydro-2//-pyrans and their 4-methyl derivatives established that the anomeric effect was more important in the unsaturated heterocycles than in the corresponding tetrahydropyrans (72BSF1077). The axial preference of an alkoxy group is even more accentuated when the double bond is associated with a fused benzenoid ring, as in the 2-alkoxychromans. It is also of interest to note that the role of the polarity of the solvent on the conformational equilibrium is less important than for the saturated analogues. 

The purpose of this research was to compare the effect on the conformational equilibrium for the hydroxylated compounds listed in Table II of changing the solvent from dimethyl sulfoxide, which is expected to minimize intramolecular hydrogen bonding, to 1,2-dichloroethane which should promote such bonds. These solvation effects on conformational equilibria were then to be compared with those of water which can serve as a hydrogen donor and hydrogen acceptor in hydrogen bond formation. As will be seen, the conformational equilibria generally appear similar for water and dimethyl sulfoxide but often different from those in 1,2-dichloroethane. 

Another question concerns the effect of solvent polarity on the conformational equilibrium. The results in Table XIII show for / -D-xylo-pyranose tetrabenzoate (which is approximately a 1 1 mixture of chair conformers in chloroform) that changes in the solvent polarity over a... 

Solvent polarity has a negligible effect on conformational equilibrium in the aldopentopyranose tetrabenzoates, but a regular effect is observed for methyl glycoside derivatives. 

The preferred conformation of related 2-substituted /ra j--l,3-dithia-5,6-benzocycloheptene 1-oxides 43 depends on the substitution pattern. Compounds 43b-f (R = phenyl, methyl, ethyl, isopropyl) exist in CDC13 at — 60 °C as an equilibrium of chair and boat conformations with the substituents in the equatorial position. Unsubstituted 43a (R = H) possesses a boat form with an axial sulfinyl group whereas, for the butyl derivative the conformational equilibrium is completely shifted to the boat structure. The proton-proton distances for the chair conformer of 2-phenyl-l,3-dithia-5,6-benzocycloheptene 1-oxide 43b were determined by 2D NOESY experiments in CD2CI2 and CS2-CDCI3. It has been shown that solvent effects influence the thermodynamic parameters of the conformational equilibrium <2001JGU1266>. 

The SM2/AM1 model was used to examine anomeric and reverse anomeric effects and allowed to state that aqueous solvation tends to reduce anomeric stabilization [58]. Moreover, SM2/AM1 and SM3/PM3 models were accounted for in calculations of the aqueous solvation effects on the anomeric and conformational equilibria of D-glucopy-ranose. The solvation models put the relative ordering of the hydroxymethyl conformers in line with the experimentally determined ordering of populations. The calculations indicated that the anomeric equilibrium is controlled primarily by effects that the gauche/trans 0-C6-C5-0 hydroxymethyl conformational equilibrium is dominated by favorable solute-solvent hydrogen bonding interactions, and that the rotameric equilibria were controlled mainly by dielectric polarization of the solvent [59]. On the other hand, Monte Carlo results for the effects of solvation on the anomeric equilibrium for 2-methoxy-tetrahydropyran indicated that the AM1/SM2 method tends to underestimate the hydration effects for this compound [60]. 

In the above equation T is the native protein and is in equilibrium with the metal complex, TM, which is resistant. Ti to Tn are the conformations which are susceptible to the particular condition which is impressed upon the protein. The various forms of T would be susceptible, in different degree to changes caused by heat, solvent effects, enzymolysis, etc., to give the products denatured forms (D), proteolytic fragments (P), and chemically modified forms (C). Possible combinations of these also could exist, such as C could rapidly undergo denaturation. There also is the possibility that different molecular forms of the metal complexes exist. These forms might have different susceptibilities, but the susceptibilities would not be the same as those of the metal-free proteins. 

Gas-phase NMR spectroscopy has been used to obtain equilibrium constants and rate constants for many low-energy molecular processes. These data have been used to address questions regarding the relative stability of conformers and tautomers in the gas phase, the kinetics of exchange processes in the gas phase, and the direction and magnitude of solvent effects on these equilibria and processes. Most of the studies have appeared in the last 10 years. Continued progress in NMR instrumentation and techniques as well as considerable recent developments in kinetic theory ensure that the next 10 years will see many novel applications of gas-phase NMR spectroscopy. 

H. E. Alper, Solvent Effect on a Conformational Degree of Freedom The Effect of Water on the Conformational Equilibrium of n-Butane, Ph.D. Dissertation, Columbia University, New York, 1987. 

Calculation of the effect of the solvent on the abundance of the 2- oxan-2-yloxy)oxane conformers revealed that the solution behavior of the a, a) form is markedly different from that of other saccharides where laige differences in the solvent effect of aqueous and nonaqueous solution on the equilibrium around the glycosidic linkage have been found. The calculated population of the most stable conformer is 96.5%, in both the isolated molecule and in solution. The equilibrium composition of con-formers in the other two forms, (a, e) and e, e), depends on the solvent, and the solvent-solute electrostatic interactions (Eq. 7) are mainly responsible for the shift of equilibrium in solution. ... 

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