1,3-Diaxial interactions substituent

As is evident from the figure, the dominant van der Waals repulsion in the axial methyl conformer is between the methyl group and the axial hydrogens at C(3) and C(5). Interactions of this type are called 1,3-diaxial interactions. Substituents that are in a 1,3-diaxial orientation with respect to each other are said to be syn-axial. The... 

Conformations in which there is a 1,3-diaxial interaction between substituent groups larger than Iqidrogen are destabilized by van der Waals repulsion. Equilibration of mixtures of cis- and /ran5-l,l,3,5-tetramethylcyclohexane reveals that the cis isomer is favored by 3.7 kcal/mol. This provides a value for a 1,3-diaxial methyl interaction that is 1.9 kcal/mol higher than that for the l,3-methyl-4iydrogen interaction. 

For the kinetically controlled formation of 1,3-disubstituted tetrahydro-P-carbolines, placing both substituents in equatorial positions to reduce 1,3-diaxial interactions resulted in the cw-selectivity usually observed in these reactions." Condensation reactions carried out at or below room temperature in the presence of an acid catalyst gave the kinetic product distribution with the cw-diastereomer being the major product observed, as illustrated by the condensation of L-tryptophan methyl ester 41 with benzaldehyde. At higher reaction temperatures, the condensation reaction was reversible and a thermodynamic product distribution was observed. Cis and trans diastereomers were often obtained in nearly equal amounts suggesting that they have similar energies."... 

Chair cyclohexanes are conformationally mobile and can undergo a ring-flip, which interconverts axial and equatorial positions. Substituents on the ring are more stable in the equatorial position because axial substituents cause 1,3-diaxial interactions. The amount of 1,3-diaxial steric strain caused by an axial substituent depends on its hulk. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

The stereoselectivity is enhanced if there is an alkyl substituent at C(l). The factors operating in this case are similar to those described for 4-r-butylcyclohexanone. The tnms-decalone framework is conformationally rigid. Axial attack from the lower face leads directly to the chair conformation of the product. The 1-alkyl group enhances this stereoselectivity because a steric interaction with the solvated enolate oxygen distorts the enolate to favor the axial attack.57 The placement of an axial methyl group at C(10) in a 2(l)-decalone enolate introduces a 1,3-diaxial interaction with the approaching electrophile. The preferred alkylation product results from approach on the opposite side of the enolate. 

The stereochemistry of acyclic anionic oxy-Cope rearrangements is consistent with a chair TS having a conformation that favors equatorial placement of both alkyl and oxy substituents and minimizes the number of 1,3-diaxial interactions.214 For the reactions shown below, the double-bond configuration is correctly predicted on the basis of the most stable TS available in the first three reactions. In the fourth reaction, the TSs are of comparable energy and a 2 1 mixture of E- and Z-isomers is formed. 

In this scheme, a highly puckered metallocycle was envisioned, possessing pseudoaxial and equatorial substituents, and reaction pathways were said to be favored which minimized the following effects (a) 1,3-diaxial interactions of substituents on the two a-carbons (b) axial substituent interactions with juxtaposed ring carbons and (c) 1,2-diequatorial interactions. This scheme predicts relatively nonstereospecific metathesis of rra/j.v-olefins but highly stereospecific metathesis of ra-olefins. For example, the following pathways for reactions of m-olefins were proposed ... 

The conformational energies of monosubstituted oxanes studied to date are collected in Table I. In position 2, polar substituents (except NR2) prefer the axial position other substituents prefer the equatorial orientation, which is generally the case for groups in positions 3 and 4. Destabilizing 1,3-diaxial interactions cause the equatorial geometry to be usually favored in the 2-position, the anomeric effect stabilizes the axial conformation. A large purine moiety in position 2 of oxane, for example, prefers the equatorial position because the 1,3-diaxial interactions overcome the anomeric effect (75TL1553). 

Eliel et al. (82JA3635) examined the conformational equilibria of a number of disubstituted oxanes (Table III) by low-temperature C NMR spectroscopy (830MR94) and estimated the AG° values of 3-Me and 2-C=CH substituents (see Table I). The concentration of the axial 2-Me and 4-Me conformers, however, was so small and difficult to detect by NMR spectroscopy that they were forced to employ the use of counterpoised di-2-C=CH and ds-2-CH = CH2 groups to generate equilibria that were sufficiently balanced to measure accurately (AG° values in Table I). Eliel et al. (82JA3635) also discussed the conformational energies in terms of 1,3-diaxial interactions and the anomeric effect. 

Variable temperature studies again show the ring inversion (76T2339). They also indicate that a 2-methyl group shows equal preference for the quasi-axial or quasi-equatorial positions, presumably because there are no other axial substituents to cause 1,3-diaxial interactions. 

The following examples show how open and closed transition states may be invoked by the choice of the reaction type. For instance, aldol-type addition normally proceeds via a closed transition state because the metal ion is shifted from the enolate oxygen to the carbonyl oxygen in an ene-like mechanism ( Zimmerman-Traxler transition state 9). The crucial interactions in the Zimmerman-Traxler transition state 16 are those between the 1,3-diaxially oriented substituents around the chair-like structure. R2 adopts the location shown, thus R3 avoids the 1,3-interaction and assumes an equatorial position. Therefore, the diastereomeric ratio depends mainly on the ( )/(Z) configuration of the enolate. Whereas (Z)-enolates 13 afford syn-config-urated enantiomers, 17 and 18, the corresponding ( )-enolates 14 lead to anti-configurated adducts 19 and 20 10. 

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. 

The axial-directing effect of the C-l substituent depends on the total stereochemistry and mode of substitution and falls roughly in the order of polarity of the substituents. The axial-directing effects of the C-l substituent is augmented when acetates at the other ring positions are replaced by benzoates possibly there are attractive syn-diaxial interactions between benzoate groups. 

Closer examination of tetrahydropyrans 173 clearly reveals that two molecules of aldehyde 174 have been appended onto allylsilane 171 via a novel three-component coupling reaction. Marko et al. proposed the mechanism depicted in Scheme 13.61 [65], Formation of heterocycles 173 is described as a sequence of two processes an initial ene-type reaction [80] which leads to alcohol 177 via the chair-like transition state 176, in which both the aldehydic R-group and the OTMS substituent assume an equatorial position. The high regio- and stereoselectivity observed in this ene-reaction can be nicely explained by considering the stabilizing /(-silicon effect and the repulsive 1,3-diaxial interactions. Transition state 176 contains no 1,3-diaxial interactions and benefits fully from the stabilizing /(-silicon effect [81, 82] (for more detailed transition-state discussion see ref. [63]). 

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