Conformational behaviour

When two substituents, heavier than hydrogen, take up positions as far from one another as possible, their relative conformation is called staggered (formerly, trans , which is confusing because of its use in geometrical isomerism). When these two groups move opposite one another, their relative conformation is called eclipsed gauche is intermediate). These conformations are illustrated here by 1-chloropropane in 12.34) and (12.35). 

This conformational analysis can be extended to alicyclic rings, both with respect to substituents and ring-shape. As regards the latter, cyclohexane (12.2) can exist in three conformations chair (12.36), boat or tub (12.37), and twist or half-chair (12.38). 

The two principal conformations into which substituents fall are classified as equatorial (i.e. in the general plane of the ring) and axial (i.e. perpendicular to this 

Many other formulae embodying conformational information have been used in earlier chapters of this book, e.g. atropine (7.75), nicotine (7.25), morphine 7.35), permethrin 6.54), and penicillin 13.4), and other formulae of this kind will be used later in this chapter. 

In thyroxine 11.14) and the more biologically active tri-iodothyronine, the iodine atoms in the 3- and 4-positions force the two rings into a conformation in which they are perpendicular to one another. Further work, with analogues, indicates that this arrangement is essential for thyroid function (Dietrich etal., 1977). See Section 2.4 for other stereochemical data on how thyroid hormones fit their receptor. 

Even when a bond is perfectly free to rotate, as every single-bond is, an infrared spectrum often reveals that the atoms of the molecule assume 

Emetine and cycloheximide are two molecules that look quite dissimilar at first glance, but have conformationally similar areas which cause both of them to inhibit protein synthesis in the ribosomes of most living cells (Section 4.1, p. 127). 

At this stage we would do well to pause and ask ourselves Which conformation of a drug is of the most importance for its action Is it the form assumed in aqueous solution, in lipid solution, or in the solid state, particularly that solvent-free and hence virtually solid state in which many 

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Conformational behaviour of reduced pyridopyrimidines does not appear to have been systematically investigated. 

The stereochemistry and conformational behaviour of 2,3-dimethyl-l,2,3,4-tetrahy-dropyrido[2,3-f ]pyrazine and some related compounds have been studied, as have the corresponding pyrido[3,4-f ]pyrazine derivatives (67JOC1378, 60JA3762). 

Before analyzing in detail the conformational behaviour of y9-peptides, it is instructive to look back into the origins and the context of this discovery. The possi-bihty that a peptide chain consisting exclusively of y9-amino acid residues may adopt a defined secondary structure was raised in a long series of studies which began some 40 years ago, on y9-amino acid homopolymers (nylon-3 type polymers), such as poly(/9-alanine) 3 [14, 15], poly(y9-aminobutanoic acid) 4 [16-18], poly(a-dialkyl-/9-aminopropanoic acid) 5 ]19], poly(y9-L-aspartic acid) 6 ]20, 21], and poly-(a-alkyl-/9-L-aspartate) 7 [22-36] (Fig. 2.1). 

From conformational analysis it appears that there is no signifiant influence of the methoxyl group on the conformational behaviour [31,32] only the role of the carboxylic group on the long range electrostatic interaction must be important... 

The conformational behaviour in solution of a dermatan-derived tetra-saccharide has been explored by means of NMR spectroscopy, especially by NOE-based conformational analysis. RDCs were also measured for the tetrasaccharide in a phage solution and interpreted in combination with restrained MD simulations. The RDC-derived data substantially confirmed the validity of the conformer distribution resulting from the NOE-derived simulations, but allowed an improved definition of the conformational behaviour of the oligosaccharides in solution, which show a moderate flexibility at the central glycosidic linkage. Differences in the shapes of the different species with the IdoA in skew and in chair conformations and in the distribution of the sulphate groups were also highlighted.28... 

Combining 2D-NOESY and 2D-ROESY NMR experiments with molecular modelling protocols, Kuhn and Kunz32 have been able to study the saccharide-induced peptide conformational behaviour of the recognition region of Ll-Cadherin. The detailed conformational analysis of this key biomolecule not only proves that the saccharide side chain exerts a marked influence on the conformation of the peptide chain, but also that the size and type of the saccharide indeed strongly affects the conformation of the main chain. 

A very important question in the context of dendrimers and their utility as host molecules relates to the existence of cavities within these macromolecules. The presence of internal voids in dendrimers is closely related to their conformational behaviour and to the degree of back-folding of the terminal branches into the interior of the dendrimer. The issue of back folding was already briefly touched upon in section 16.2.1. Next to the purely theoretical calculations mentioned there, several calculations have been performed on specific dendrimer types. 

Figure 16.11 The pH-dependent conformational behaviour of polypropylene imine) dendrimers. At low pH (left) the occurrence of a soft-core, dense-shell dendrimer, whereas at high pH (right) severe back-folding occurs leading to a dense-core structure [57]...

The development of predictive transition state models for the interpretation of selectivity data pertaining to the use of cinchona alkaloid derivatives in all the processes described above is challenging due to the complex conformational behaviour of these natural scaffolds (for example, it is well known that 0-acylated quinidines undergo major conformational changes upon protonation) [223]. Consequently, hypotheses regarding the details of chirality transfer in these systems are notably absent. 

The maximum adsorption (deposition) of three proteins on rhombohedral hematite (SA = 19 m g ) ranged from 5 to 20 mg m (Johnson and Matijevic, 1992 a), and, for ovalbumin and y-globuline occurred near their iep 4.7 and 6.8, respectively. For lysozyme, however, the highest adsorption occurred at pH 9, much below its iep (11.0) and was probably due to strong intermolecular association of the protein (minimum solubility) at this pH. Protein uptake may depend on the number and kind of amino acids in the protein as well was on their association and conformational behaviour. 

It is a trivial statement that properties such as molecular weight and volume are additive. At the other extreme, conformational freedom (defined as the number of discrete allowed conformations) is not an additive property. Indeed, this number increases exponentially with the number of residues, while the conformational possibilities of the monomers decrease when they lose their individuality to become bound as residues. Thus, additivity is found to break down when conformational behaviour is considered. In... 

In formulating the terms of the partition function, it is convenient to group them according to the maximum number of residues permitted in a strand, which is denoted by/. The ultimate interest is in the limiting conformational behaviour as / approaches n. 

Opschoor, A., and W. Prins Thermoelasticity and conformational behaviour of polyethylene and ethylene-propylene copolymers. J. Polymer Sci., Pt. C16, 1095 (1967). 

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