Stability of chair conformations

Glucose is an equilibrium mixture of cyclic forms (hemiacetals containing a tetrahydropyran), and a small concentration of acyclic polyhydroxyaldehyde, which is responsible for many of the observed chemical reactions. This illustrates the inherent stability of chair conformers of saturated six-membered systems. The propensity for cyclisation is a general one 5-hydroxy-aldehydes, -ketones and -acids all easily form six-membered oxygen-containing rings - lactols and lactones respectively. 

Let s compare the stability of chair conformations once again, this time for compounds that bear more than one substituent. Consider the following example ... 

Exercise 20-4 Draw the chair conformation of /3-D-glucose with all of the substituent groups axial. Explain how hydrogen bonding may complicate the usual considerations of steric hindrance in assessing the stability of this conformation relative to the form with all substituent groups equatorial. 

Condensation of hydroxylamine rac-10 with 1,4-cyclohexanedione monoethylene acetal provided nitrone rac-9, which was treated with ethyl acrylate to give 74% of a 8-9 1 mixture of isoxazolidine rac-8 and its diastereomer. Reduction of this mixture with hydrogen afforded 8-9 1 of a mixture of lactam rac-1 and its diastereomer (Scheme 7). After crystallization, X-ray analysis of the major product confirmed that its stereochemistry is the one required for carrying out the synthesis of FR901483. The excellent stereoselectivity observed in the 1,3-dipolar cycloaddition of nitrone rac-9 was attributed to the substitution pattern in the stereogenic center adjacent to the nitrogen atom. These substituents stabilize one chair conformer relative to the other and thus allow a good... 

FIGURE 3.4 Conformations of ring structures, (a) Boat and chair conformation, (b) Stability of chair form of D-glucose... 

Draw both chair conformations of CK-l,3-dimethoxycyclohexane. Which is the more stable Draw analogous structures for ds-l,3-dihydroxycyclohexane. Would you expect the relative stability of the conformers to be the same Give your reasoning. 

According to this concept, the aldol condensation normally occurs through a chairlike transition state. It is further assumed that the stmcture of this transition state is sufficiently similar to that of chair cyclohexane to allow the conformational concepts developed for cyclohexane derivatives to be applied. Thus, in the example above, the reacting aldehyde is shown with R rather than H in the equatorial-like position. The differences in stability of the various transition states, and therefore the product ratios, are governed by the steric interactions between substituents. 

The six-membered rings 8.12a and 8.12b adopt chair conformations with all three halogen atoms in axial positions. This arrangement is stabilized by the delocalization of the nitrogen lone pair into an S-X a bond (the anomeric effect) All the S-N distances are equal within experimental error [ld(S-N)l = 1.60 (8.12a)/ 1.59 A (8.12b) ]. 

The vibrational spectrum of 1,4-dioxin was studied at the MP2 and B3-LYP levels in combination with the 6-3IG basis set [98JST265]. The DPT results tend to be more accurate than those obtained by the perturbational approach. The half-chair conformation of 4//-1,3-dioxin 164 was found to be more stable than the corresponding conformations of 3,4-dihydro-1,2-dioxin 165,3,6-dihydro-1,2-dioxin 166, and of 2,3-dihydro-1,4-dioxin 167 (Scheme 114) [98JCC1064, 00JST145]. The calculations indicate that hyperconjugative orbital interactions contribute to its stability. 

Trioxane 210 has been used as a model system by Gu and coworkers to study the antimalarial drug artemisinin 211 (Scheme 137) [97CPL234, 99JST103]. It is the boat/twist form rather than the chair conformer of 210 that describes the subunit in 211. Moreover, geometric parameters and vibrational frequencies can only reliably be computed at the DFT level and by post-Hartree-Fock methods. B3-LYP/6-31G calculations on the conformers of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane show that the chair conformer is stabilized with respect to the twisted conformer by about -2.8 kcal/mol [00JST85]. No corresponding boat conformer was found. 

Optimization of the valence and dihedral angles yields planar cyclic structures for the 3- to 5-ring intermediates in contrast to a chair conformation for that of the 6-ring. In the cases of n = 4, 5, 6 the oxygen atom is placed almost in the plane of the three C-atoms directly bonded to it. Therefore, an intramolecular solvation of the cationic chain end by methoxy groups which are bonded to the polymer backbone is preferred in the gas phase. The calculations show that for a non-polar solvent such as CH2C12 a decrease in stability of the cyclic intermediates exists. But this decrease does not result in a total break of the intramolecular solvation (Table 13). An equilibrium between open chain and cyclic intermediates must only be taken into account in more polar solvents, due to the competition of intra- and intermolecular solvation. 

Because of the greater stability of the chair, more than 99% of the molecules are estimated to be in a chair conformation at any given moment. 

A comparison of the structures of products and initial 1,3,5-diazapho-sphorinane reactants reveals a correlation between the number of added borane molecules and the predominant conformation of the initial compounds. l,3-Dibenzyl-5-phenyl-l,3,5-diazaphosphorinane (45) adopts a chair conformation. The substituents at the phosphorus atom and at one of the nitrogen atoms are equatorial, and another nitrogen possesses an axial substituent. In other 1,3,5-diazaphosphorinanes, all the substituents are equatorial. The number of borane molecules added is likely to be determined by the same factors as their conformational stability. There is steric hindrance when the three BH3 groups are axial. 

Fig. 35. Dominant stabilizing orbital interactions in the boat and chair conformers of...

The antibodies can also act like entropy traps by stabilizing a particular conformation of a substrate that is favorable to the formation of the TS. It is the case of the antibody 1F7 catalyzing the transformation of chorismate into prephenate," which stabilizes, thanks to several hydrogen bonds and an ionic bond between an arginine (Arg H95) and a carboxylate substituent of the substrate, the conformation of the chorismate which will give rise to the TS in a chair conformation for this reaction (Figure 11). 

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