Flexible ring systems

This isomer was also formed with larger rings containing both cis- and trani-alkenes. In these cases with more flexible ring systems, the diastereochemical outcome is explained... 

Most small molecules in pharmaceutical research have at least a few rotatable bonds or even flexible ring systems. Seventy percent of drug-like... 

Discussion of the conformation and relative stabilities of bicyclic diacetals with cis ring junctions requires consideration of the possibilities of H-inside and 0-inside conformations of the flexible ring system (XVIII and XIX) as well as of axial and equatorial positions of residues. One possibility that may be excluded is an inside axial position for a substituent of the type XVII shown for cis-decalin, as this would be extremely unstable compared to other conformations. 

A rare example of entropy control is afforded by the equilibration of bi-cyclo[2.2.2]octane, bicyclo[3.2.1]octane, and cis -bicyclo[3.3.0]octane (15). At 298 K the order of stability (AAG ) is bicyclo[3.2.1]octane > m-bicy-clo[3.3.0]octane > bicyclo[2.2.2]octane. The enthalpy difference measured (15) between bi( clo[2.2.2]octane and bicyclo[3.2.1]octane is indistinguishable from zero the greater stability of bicyclo[3.2.1 ]octane over bicyclo[2.2.2]octane is due entirely to more favorable entropy. Both bicyclo[2.2.2]octane and bicy-clo[3.2.1]octane are less strained than m-bicyclo[3.3.0]octane (AAH measured = 1.9 kcal mole" ) but this is counterbalanced by the high entropy of c/s-bicyclo[3.3.0]octane. Above 378 K ciJ-bicyclo[3.3.0Joctane is the most stable of the three isomers. The high entropy of the 3.3.0 system is due to its more flexible ring system. The entropy difference between the more rigid 3.2.1 and 2.2.2 systems is due primarily to symmetry. The symmetry number ( r) of bicyclo[2.2.2]octane is 6, whereas relative contribution to the entropy is / In 6 — /fin 1 = 3.6 eu, which equals (TAS ) 1.1 kcal mole" the AA(7 298 measured (15) is 1.69 kcal mole". ... 

These 3D models describe a fixed conformation. The only permissible motions of this model are 3D translations and rotations of the molecule as a whole. The relative mobility of parts of an individual molecule can also be described on the basis of its 3D coordinates (see Three-dimensional Structure Generation Automation). It requires the specification of so-called rotatable bonds to record permissible or feasible changes of the conformation. Conformational analysis programs use such a model as their internal problem representation. Partially flexible ring systems require additional sophistication to be modeled adequately using this approach. 

On hydogenation, the now-flexible ring system could fold into the spiro ketal. With the primary and secondary alcohols bridged by the linking silyl ether, only one anomeric form, 2, of the spiro ketal was energetically accessible. 

In the next step, the molecule is fragmented into ring systems and acyclic parts. Ring systems are then separated into small and medium-sized rings with up to nine atoms and into large and flexible systems. 

A more deviating stoichiometry is found in the case of the inclusion compound of / with /-propanol 77 >. Here the assistance of two independent host molecules is required and results in a 2 1 stoichiometry. Nevertheless, even this unusual host guest ratio gives rise to a similar H-bond pattern (Fig. 18a and type lib in Fig. 19) as found for the inclusions of 1 with simpler alcohols (cf. Fig. 17a), namely the 12-membered ring system. Now, another interesting fact arises, signalling the flexibility of host 1 in its inclusion behavior. This is the formation of host dimers through H-bonds to ensure clathration. 

Another cis-diol (XV) derived from BP was obtained by the action of osmium tetroxide on 4,5-dihydroxybenzo[a]pyrene (86). The hydroxyl group at C5a is axial and that at C6 is equatorial, illustrating the relative rigidity of the BP ring system and the flexibility at C6 of the ring bearing the diol groups. 

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