Ring inversions

High temperature searches of conformational space (see Quenched Dynamics" on page 78), can produce unwanted conformational changes, such as cis-tmnx peptide flips, ring inversions, and other changes that you cannot reverse easily by geometry optimization. You can use restraints to prevent these changes. 

Terms in the energy expression that describe a single aspect of the molecular shape, such as bond stretching, angle bending, ring inversion, or torsional motion, are called valence terms. All force fields have at least one valence term and most have three or more. 

We have seen that alkanes are not locked into a single conformation Rotation around the central carbon-carbon bond m butane occurs rapidly mterconvertmg anti and gauche conformations Cyclohexane too is conformationally mobile Through a process known as ring inversion, chair-chair mterconversion, or more simply ring flipping, one chair conformation is converted to another chair... 

The activation energy for cyclohexane ring inversion is 45 kJ/mol (10 8 kcal/mol) It IS a very rapid process with a half life of about 10 s at 25°C... 

A potential energy diagram for nng inversion m cyclohexane is shown m Figure 3 18 In the first step the chair conformation is converted to a skew boat which then proceeds to the inverted chair m the second step The skew boat conformation is an inter mediate in the process of ring inversion Unlike a transition state an intermediate is not a potential energy maximum but is a local minimum on the potential energy profile... 

A more detailed discussion of cyclohexane ring inversion can be found in the July 1997 issue of the Journal of Chemical Education pp 813-814... 

The most important result of ring inversion is that any substituent that is axial in the original chair conformation becomes equatorial in the ring flipped form and vice versa... 

Ring inversion in methylcyclohexane differs from that of cyclohexane m that the two chair conformations are not equivalent In one chair the methyl group is axial m the other It IS equatorial At room temperature approximately 95% of the molecules of methylcyclohexane are m the chair conformation that has an equatorial methyl group whereas only 5% of the molecules have an axial methyl group... 

Ring inversion (Section 3 9) Process by which a chair conforma tion of cyclohexane is converted to a mirror image chair All of the equatonal substituents become axial and vice versa Also called ring flipping or chair-chair interconversion... 

Bond angles ( ) Pucker angle Ring inversion Section... 

H-Azepine, 2-allyloxytetrahydro-Claisen rearrangement, 7, 508 3H-Azepine, 2-amino-acylation, 7, 511 effect of acidification, 7, 510 nucleophilic displacement reactions, 7, 514 synthesis, 7, 533, 535 3H-Azepine, 2-amino-7-bromo-synthesis, 7, 529 3H-Azepine, 2-anilino-ring inversion, 7, 495-499 structure, 7, 533... 

H-Azepine, 2,6,7-tri(methoxycarbonyl)-ring inversion, 7, 499 Azepine-1-carboxylic acid tricarbonylruthenium complexes, 7, 523 1 H-Azepine-2,3-dicarboxylic acid, 4,7-dihydro-6-phenyl-diethyl ester synthesis, 7, 539-540 1 H-Azepine-3,6-dicarboxylic acid... 

The free enthalpy of activation, aG, of the ring inversion at 253 K is calculated from the logarithmic form of the Eyring equation ... 

Substitution on a cyclohexane ring does not greatly affect the rate of conformational inversion but does change the equilibrium distribution between alternative chair forms. All substituents that are axial in one chair conformation become equatorial on ring inversion, and vice versa. For methylcyclohexane, AG for the equilibrium... 

Fig. 3.4. Energy diagram for ring inversion of cyclohexane. [For a rigorous analysis of ring inversion in cyclohexane, see H. M. Pickett and H. L. Strauss, J Am. Chem. Soc. 92 7281 (1979).]...

Energy differences between conformations of substituted cyclohexanes can be measured by several physical methods, as can the kinetics of the ring inversion processes. NMR spectroscopy has been especially valuable for both thermodynamic and kinetic studies. In NMR terminology, the transformation of an equatorial substituent to axial and vice versa is called a site exchange process. Depending on the rate of the process, the difference between the chemical shifts of the nucleus at the two sites, and the field strength... 

The effect of introducing -hybridized atoms into open-chain molecules was discussed earlier, and it was noted that torsional barriers in 1-alkenes and aldehydes are somewhat smaller than in alkanes. Similar effects are noted when sp centers are incorporated into six-membered rings. Whereas the fiee-energy barrier for ring inversion in cyclohexane is 10.3 kcal/mol, it is reduced to 7.7 kcal/mol in methylenecyclohexane and to 4.9 kcal/mol in cyclohexanone. ... 

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