Quantitative conformational analysis

The ability of the MM method to calculate accurately potential energies and geometries of molecules is best suited for quantitative conformational analysis (44). Numerical values can readily be given to such terms as strain and stability (45). The topic is extensively covered in Allinger s review (lOd), therefore only some recent developments are mentioned. 

From a study of a range of 2-substituted tetrahydropyrans it was concluded that the effects of an electronegative substituent were to deshield C-2 by about 30 p.p.m. and C-3 to a much reduced extent (ca. 4 p.p.m.), but to cause small upheld shifts in the signals from C-4, C-5 and C-6 (740MR(6)233). The influence of a 2-substituent on the chemical shift of C-4 can be used for quantitative conformational analysis provided suitable reference compounds are available. A comparatively large shielding of the C-4 signal indicates a preference of the 2-substituent for the axial position. 

When the number of torsional degrees of freedom is increased, the intramolecular motion in gaseous molecules is increased as well. At the same time the theoretical treatment of the motion becomes more complex, and the problems that the electron-diffraction method has to face are more difficult to handle. The molecules of this category that have been subject to quantitative conformational analysis by electron diffraction so far, are limited to cases with two or a few degrees of freedom, though qualitative observations about large amplitude motion have been made also for considerably larger molecules. 

Because there are several excellent sources (Hanack, 1965 Eliel et al., 1965) which deal with steric effects and conformational analysis, we can limit our discussion to two topics related to SS, namely the qualitative and semiquantitative evaluations of steric effects and quantitative conformational analysis. In some cases, the origins of SS can be assigned unequivocally. 

Eiji Osawa, Introduction to Quantitative Conformational Analysis Use of Computer, Plirokawa, Tokyo, 1991. 

J. E. Williams, P. J. Stang, and P. v. R. Schleyer, Annu. Rev. Phys. Chem., 19, 531 (1968). Physical Organic Chemistry Quantitative Conformational Analysis Calculation Methods. 

Winstein S, Holness NJ (1955) NeighbOTing carbon and hydrogen. Xix. Tert-butylcyclohexyl derivatives. Quantitative conformational analysis. J Am Chem Soc 77 5562-5578... 

Winstein, S. Holness, N.J. Neighboring Carbon and Hydrogen. XIX. t-Butylcyclohexyl Derivatives. Quantitative Conformational Analysis . J. Am. Chem. Soc. 1955, 77, 5562-5578. 

Seeman, J. I. The Curtin-Hammett Principle and the Winstein-Holness Equation. New Definition and Recent Extensions to Classical Concepts /. Chem. Educ. 1986, 63, 42-48. Winstein, S. Holness, N. J. Neighboring Carbon and Hydrogen. XIX. rerf-Butylcyclohexyl Derivatives. Quantitative Conformational Analysis /. Awj. Chem. Soc. 1955, 77, 5562-5578. Curtin, D. Y. Stereochemical Control of Organic Reactions. Differences in Behavior of Diastereoisomers. I. Ethane Derivatives. The Cis Effect Rec. Chem. Pro ir. 1954, 15, 111-128. An alternative to the Curtin-Hammett argument presented on page 295 is that the epoxide reacts with thiophenoxide from conformation 64b such that the product is bom in the B ring boat (or twist-boat) conformation of 65b. 

Quantitative conformational analysis of frans -clerodanes (256) and 5a,10a-cw-clerodanes (378) has been conducted on X-ray diffraction results. 

Tetrakisligand nickel(0) complexes have tetrahedral stmctures. Electronic stmctures have been studied and conformational analysis performed. Quantitative equiUbria measurements of the ligands in these complexes imply a dominant role for ligand steric effects when the complexes are employed as catalysts (94). 

Applications The general applications of XRD comprise routine phase identification, quantitative analysis, compositional studies of crystalline solid compounds, texture and residual stress analysis, high-and low-temperature studies, low-angle analysis, films, etc. Single-crystal X-ray diffraction has been used for detailed structural analysis of many pure polymer additives (antioxidants, flame retardants, plasticisers, fillers, pigments and dyes, etc.) and for conformational analysis. A variety of analytical techniques are used to identify and classify different crystal polymorphs, notably XRD, microscopy, DSC, FTIR and NIRS. A comprehensive review of the analytical techniques employed for the analysis of polymorphs has been compiled [324]. The Rietveld method has been used to model a mineral-filled PPS compound [325]. 

For a quantitative description of molecular geometries (i.e. the fixing of the relative positions of the atomic nuclei) one usually has the choice between two possibilities Cartesian or internal coordinates. Within a force field, the potential energy depends on the internal coordinates in a relatively simple manner, whereas the relationship with the Cartesian nuclear coordinates is more complicated. However, in the calculations described here, Cartesian coordinates are always used, since they offer a number of computational advantages which will be commented on later (Sections 2.3. and 3.). In the following we only wish to say a few words about torsion angles, since it is these parameters that are most important for conformational analysis, a topic often forming the core of force field calculations. 

Rastelli, G., Fanelli, F., Menziani, M.C., Cocchi, M. and De Benedetti, P.G. (1991) Conformational analysis, molecular modeling and quantitative structure-activity relationships studies of 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline al-adrenergic antagonists. Journal of Molecular Structure (Theochem), 251, 307—318. 

KARMA is an interactive computer assisted drug design tool that incorporates quantitative structure-activity relationships (QSAR), conformational analysis, and three-dimensional graphics. It represents a novel approach to receptor mapping analysis when the x-ray structure of the receptor site is not known, karma utilizes real time interactive three-dimensional color computer graphics combined with numerical computations and symbolic manipulation techniques from the field of artificial intelligence. 

However, a quantitative evaluation, i.e, an exact determination of the r/0-parameter pairs for each nucleus in the solute, is not easy252. It should be determined only by the use of statistical methods to obtain reliable structural assignments, as shown for the four diastereomeric 1-cyano-2-ethylidene-3-methylcyclopropanes253. Quantitative evaluation is even more complicated if the solute is conformationally mobile, because a careful conformational analysis is the basis of any sound interpretation of LSR experiments. Moreover, the conformational equilibrium of the solute may change in the presence of LSR. 

Instruments that can be employed to measure energy barriers in acyl heterocycles should thus be able to follow these interconversion processes that occur in the energy range between 4 and 80 kJ mol". Furthermore, detection of separate conformers in equilibrium is an important intrinsic feature of experimental methods for quantitative population analysis while its sensitivity limits accuracy in measuring biased equilibria. 

Computational chemistry methodology is finding increasing application to the design of new flavoring agents. This chapter surveys several useful techniques linear free energy relationships, quantitative structure-activity relationships, conformational analysis, electronic structure calculations, and statistical methods. Applications to the study of artificial sweeteners are described. 

A general theory of quantitatively comparing molecular shapes using common overlap steric volume(33-36) and, more recently, descriptors derived from superimposed molecular potential energy fields of pairs of molecules(37) has been derived and tested. This theory allows a "marriage between Hansch analysis and conformational analysis. 

A quantitative estimation of the fraction of the 1,1 -cycles can be performed through a conformational analysis of the diepoxide molecules, i.e. determination of the number of their conformations in which the end-to-end distance is equal to the spacing between the nitrogen atoms in the corresponding diamine molecules. Such an analysis has given results qualitatively constistent with those obtained in the analysis of the molecular models by the Stewart-Brigleb method U0, n1,, I4>. 

Molecular mechanics calculations14 ) of the strain in adamantane support this interpretation. Since such calculations are based on empirically derived parameters, however, a unique set of parameters for the representation of physical reality cannot be derived. Nevertheless, all available conformational analysis calculations demonstrate that the strain in adamantane may be quantitatively accounted for in terms of angle strain, which implicitly includes strain due to... 

The following definition of computational chemistry was published in 1985 (6) quantitative modeling of chemical behavior on a computer by the formalisms of theoretical chemistry. Some quantum theoreticians naturally would like to see computational chemistry as a subset of their field (7). However, today the number of scientists employed as computational chemists well exceeds the number employed as theoreticians (8). A recent textbook author (9) views computational chemistry as encompassing not only quantum mechanics, but also molecular mechanics, [energy] minimization, simulations, conformational analysis, and other computer-based methods for understanding and predicting the behavior of molecular systems. ... 

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