Substituents in axial position

The steric interference between substituents in axial positions is particularly severe when there are large groups on two carbon atoms that bear a 1,3-diaxial relationship (cis on Cl and C3, or Cl and C5), as in the two chair conformations of cis-l,3-dimethyl-cyclohexane shown here. The less stable conformation has both methyl groups in axial positions. The more stable conformation has both methyl groups in equatorial positions. Note the strongly unfavorable 1,3-diaxial interaction between the two methyl groups in the diaxial conformation. The molecule can relieve this 1,3-diaxial interference by flipping to the diequatorial conformation. Use your models to compare the diaxial and diequatorial forms of cis-1,3-dimelhylcyclohexane. 

Exceptions to these generalizations occur if the system is constrained to cyclize via transition states with substituents in axial positions. Two examples appear in Figure 31. The IMDA cyclization of (115)... 

A tendency toward stabilization of the a form is usually quite pronounced in the acetyl and benzoyl derivatives of D-xylopyranosyl halides (see Fig. 7a) which, in solution, exist mainly or completely in the Ci conformation, with all substituents in axial positions. This was first pointed out for... 

In contrast to dihydropyran rearrangements, the rearrangement of 1,4-dioxins is believed to proceed via a chairlike transition state with the substituents in axial positions. Dihydro-1,4-dioxins 10 and 11, obtained by acid-catalyzed double-bond isomerization of 9. on heating in a sealed tube, undergo a sigmatropic shift to give dihydropyrans 12 and 13322 323. 

The chair conformer with both substituents in axial positions has four 1,3-diaxial interactions, causing it to be about 4 X 0.9kcal/mol = 3.6kcalmol (15.1 kJ/mol) less stable than the chair conformer with both methyl groups in equatorial positions. We can, therefore, predict that trans-l,4-dimethylcyclohexane will exist almost entirely in the more stable diequatorial conformation. 

What accounts for the much faster reaction of the trans-substituted compound In this reaction, the thio substituent is an intramolecular nucleophilic catalyst. It displaces the chloro substituent by attacking the back side of the carbon to which the chloro substituent is attached. Back-side attack requires both substituents to be in axial positions, and only the trans isomer can have both of its substituents in axial positions (Section 2.14). Subsequent attack by water or ethanol on the sulfonium ion is rapid because the positively charged sulfur is an excellent leaving group and breaking the three-membered ring releases strain. 

The structure of penta-O-acetyl-catechin is an interesting example of problems encountered in definition of the conformation of these compounds. In the crystal state, the heterocyclic ring is in a reverse half-chair conformation with both the 5-ring and 3-acetoxy substituents in axial positions (120). However, the heterocyclic ring proton coupling constants 2,3 = h,4a - and... 

Compounds in which conformational, rather than configurational, equilibria are influenced by the anomeric effect are depicted in entries 4—6. Single-crystal X-ray dilfiaction studies have unambiguously established that all the chlorine atoms of trans, cis, ira j-2,3,5,6-tetrachloro-l,4-dioxane occupy axial sites in the crystal. Each chlorine in die molecule is bonded to an anomeric carbon and is subject to the anomeric effect. Equally striking is the observation that all the substituents of the tri-0-acetyl-/ -D-xylopyranosyl chloride shown in entry 5 are in the axial orientation in solution. Here, no special crystal packing forces can be invoked to rationalize the preferred conformation. The anomeric effect of a single chlorine is sufficient to drive the equilibrium in favor of the conformation that puts the three acetoxy groups in axial positions. 

As one would expect, the tri-substituted eis-trans-2,4-diaryl-3-dimethylaminothietanes (187c,d) were shown by NMR to have all three substituents in pseudoequatorial positions with the remaining hydrogens in axial positions202. 

Conformational analysis in connection with determinations of ffee-energy differences (AG°) between axial and equatorial conformers is still attracting interest. Schneider and Hoppen (114) discussed A values ( —AG°) and preferred orientations of axial substituents with lone pairs at heteroatoms directly attached to C (e.g., -OR, -NR2, and -N3), as well as of some other nonspherical substituents (X = -NC, -NCS, -CN, -C CH). Phenyl and vinyl groups were investigated by Eliel and Manoharan (277), who found A values of 2.87 0.09 kcal/mol for phenyl and 1.68 0.06 kcal/mol for vinyl. The latter value was essentially confirmed by Buchanan (196) the formyl group A = 0.84 0.08 kcal/mol) in axial position adopts a predominant (93%) conformation (305) with the plane of the axial CHO group nearly perpendicular to the plane of symmetry of the cyclohexyl residue (Scheme 71) (196). 

Also for 1,2,4-trioxane, from MM3 calculations, a structure close to a chair with the protons and substituents in axial and equatorial positions, respectively, was suggested [92JCS(CC)1689]. The substituted derivatives 63 (Scheme 25) have substituents R [Me, iPr, CH2HgBr, CH(HgBr)Me] in an equatorial position (all in agreement with standard conformational principles), and only in 64-66 were axial methyl substituents reported, based on NOE measurements and 7c-h coupling constants [92JCS(CC)1689]. 

As an example of spectra of molecules containing the CH2CH2C H chiral fragment, the spectra of (—)-menthone and (-t-)-isomenthone are shown in Figure 5. (—)-Menthone has two bulky substituents and the favored chair conformation is 16, which corresponds to 14 with both substituents in equatorial positions. The observed (-1— +) VCD pattern is that predicted for this fragment geometry. For isomenthone both chair conformations 18 and 19 are populated since, in each, one alkyl substituent is axial and one equatorial. However, the... 

Simple calculations (MM2 and HF/6-31G ), supported by a low-temperature NMR study, reveal that 2-NMc2-l,3-dioxane and the 5,5-dimethyl derivative exist exclusively in the conformation with the dimethylamino group in axial position <2001ARK(xii)58>, and DFT calculations at the B3LYP/6-31G(d,p) level of theory show that the anomeric effect of 2-Cl in 1,3-dioxane is of stereoelectronic origin while 2-F, 2-OMe, and 2-NH2 substituents on the same molecule are not <2000MI42>. 

When all 12 substituents are hydrogen atoms, there is no steric strain. The presence of any groups larger than H changes the stability by increasing the steric strain, especially if these groups are present in axial positions. When axial, diaxial interaction can cause steric strain. In the equatorial case, there is more room and less steric strain. Bulky groups always preferably occupy equatorial positions. 

As a last example, the epimerization of corynantheidol (58) is examined. Refluxing 58 in AcOH resulted in a mixture of C-3 epimers 58 and 59 in a ratio of 27 73, Fig. (14) [41]. Both compounds possess one equatorial and one axial substituent and they are in conformation a, as can be verified by l3C NMR data. The question arises as to which is the lesser evil an axial ethyl group or an axial hydroxyethyl group. The empiric result shows that the latter is preferred. A plausible explanation is that, in axial position, hydrogen bonding may exist between Nb and the alcohol proton. 

An anti and coplanar arrangement allowing E2 elimination of two adjacent substituents on a cyclohexane ring. The substituents must be trans to each other, and both must be in axial positions on the ring. (p. 307)... 

The anomers of glucose. The hydroxyl group on the anomeric (hemiacetal) carbon is down (axial) in the a anomer and up (equatorial) in the /3 anomer. The /3 anomer of glucose has all its substituents in equatorial positions. 

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