Steric, and Stereoelectronic Effects

Many molecules exhibit strain caused by nonideal geometry. Any molecule will adopt a minimum-energy conformation at equilibrium, but the structural adjustments may not compensate entirely for nonideal bonding arrangements. Strain energy is the excess energy relative to an unstrained reference molecule. This chapter will 

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Steric and stereoelectronic effects control the direction of approach of an electrophile to the enolate. Electrophiles approach from the least hindered side of the enolate. Numerous examples of such effects have been observed. In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a slight... 

The 5-methyI-2-cycloheptenones generated the Irani-product in both systems. Again, steric and stereoelectronic effects work in the same direction27. 

Acyclic Ketones. The stereochemistry of the reduction of acyclic aldehydes and ketones is a function of the substitution on the adjacent carbon atom and can be predicted on the basis of the Felkin conformational model of the TS,63 which is based on a combination of steric and stereoelectronic effects. 

There have been many applications of conjugate additions in synthesis. Some representative reactions are shown in Scheme 8.2. Entries 1 and 2 are examples of addition of lithium dimethylcuprate to cyclic enones. The stereoselectivity exhibited in Entry 2 is the result of both steric and stereoelectronic effects that favor the approach syn to the methyl substituent. In particular, the axial hydrogen at C(6) hinders the a approach. 

Reactions through chelated TS Reactions of a- or (3-oxy-substituted aldehydes often show chelation-controlled stereoselectivity with Lewis acids that can accommodate five or six ligands. Chelation with substituents in the allylic reactant can also occur. The overall stereoselectivity depends on steric and stereoelectronic effects in the chelated TS. 

This model is rationalized by a combination of steric and stereoelectronic effects. From a purely steric standpoint, an approach from the direction of the smallest substituent, involving minimal steric interaction with the groups L and M, is favorable. The stereoelectronic effect involves the interaction between the approaching hydride ion and the LUMO of the carbonyl group. This orbital, which accepts the electrons of the mcommg... 

Molecular models show that isomers 21 and 21 can exist In three different conformations each whereas four different conformations are possible for isomer 2Z- Analysis of the steric and stereoelectronic effects of these different conformations indicated that isomer 21 should exist in only one conformation (15A, 0 kcal/mol), isomer 16 should also exist in only one... 

It has however been suggested by Cieplak (9) that the stereochemistry of nucleophilic addition to cyclohexanone is determined by a combination of steric and stereoelectronic effects. According to this interesting model, steric hindrance favors the equatorial approach while electron donation favors the axial approach. The stereoelectronic effect favors the axial approach because the axial C —H bonds next to the carbonyl group (C — Ha and Cn-Ha) are better electron donors than the Cn-C-j and Cc-Cfi a bonds (cf 7A 7 and 7A-8). J... 

Gilbert BC, Lindsay Smith JR, Taylor P, Ward S, Withwood AC (1999) The interplay of electronic, steric and stereoelectronic effects in hydrogen-atom abstraction reactions of S04, revealed by EPR spectroscopy. J Chem Soc Perkin Trans 2 1631-1637 Flasegawa K, Neta P (1978) Rate constants and mechanisms of reaction of Cl2 radicals. J Phys Chem 82 856-859... 

Table 10.1 shows analogous additions of methylmagnesium bromide to the same tert-butylcyclohexanone. As can be seen from the complete absence of diastereoselectivity in this addition, the mentioned steric and stereoelectronic effects on diastereocontrol cancel each other out. 

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