Strain factors, conformational

Stereochemical constraints in cyclic sulfones and sulfoxides impart increased weight to strain and conformational factors in the generation of carbanions and their stability, causing distinct differences between the behavior of cyclic and open-chain systems233, due primarily to the prevention of extensive rotation about the C —S bond, which is the major way that achiral carbanions racemize. Study of the a-H/D exchange rate fce and the racemization rate ka may provide information concerning the acidity-stereochemical relationships in optically active cyclic sulfone and sulfoxide systems. 

In a similar way the potential constant method as described here allows the simultaneous vibrational analysis of systems which differ in other strain factors. Furthermore, conformations and enthalpies (and other properties see Section 6.5. for examples) may be calculated with the same force field. For instance, vibrational, conformational, and energetic properties of cyclopentane, cyclohexane and cyclodecane can be analysed simultaneously with a single common force field, despite the fact that these cycloalkanes involve different distributions of angle and torsional strain, and of nonbonded interactions 8, 17). This is not possible by means of conventional vibrational spectroscopic calculations. 

While the regiochemistry of simple electrophilic additions to double bonds is controlled by a combination of electronic (Maikovnikov rule), stereoelectronic (trans diaxial addition to cyclohexenes) and steric factors,9 the intramolecular nature of electrophilic heteroatom cyclizations introduces additional conformational, stereoelectronic and entropic factors. The combination of these factors in cyclofunctionalization reactions results in a general preference for exo cyclization over endo cyclization (Scheme 4).310 However, endo closure may predominate in cases where electronic or ring strain factors strongly favor that mode of cyclization. The observed regiochemistry may differ under conditions of kinetic control from that observed under conditions of thermodynamic control. 

The trans-selectivity observed in the above reduction is explained by the following factors. Conformer A for the iminium salt, generated from 4 under acidic conditions is favored relative to B because of A(l,2) strain between the tV-benzyl and the methyl groups at the a-position, so the hydride attacks from the preferred (3-axial direction, leading to a chairlike transition state to give rise to trans-(2,6)-piperidine selectively. 

Valuable preparative applications are rare and especially in ring-forming reactions other stereochemical factors such as ring strain and conformational effects will determine the stereochemistry. However the use of metal compounds to influence regio- and stereo-selectivity continues to excite interest. For C—C bond formation the coupling of allylic acetates with organocuprates offers broad synthetic potential as it generally seems to proceed with double bond shift. ... 

The preferred conformation will be that in which interactions between atoms on adjacent carbons are kept to a minimum. The conformations of a molecule can be analyzed in terms of three different strain factors ... 

However, steric factors are also important.74 Ruchardt and coworkers showed, for a series of acyclic alkyl derivatives, that a good correlation exists between kd and ground state strain.75,76 Additional factors are important for bicyclic and other conformationally constrained azo-compounds.49 51 77 Wolf78 has described a scheme for calculating kd based on radical stability (HOMO Jt-deloealization energies) and ground state strain (stcric parameters). 

These examples illustrate the issues that must be considered in analyzing the stereoselectivity of enolate alkylation. The major factors are the conformation of the enolate, the stereoelectronic requirement for an approximately perpendicular trajectory, the steric preference for the least hindered path of approach, and minimization of torsional strain. In cyclic systems the ring geometry and positioning of substituents are often the dominant factors. For acyclic enolates, the conformation and the degree of steric discrimination govern the stereoselectivity. 

Fig. 12.6. Conformational factors affecting syn and anti diastereoselectivity in Sharpless epoxidation. If substituent R4 > H, A1,3 strain favors the syn product. If R4 = H, the preferred transition structure leads to anti product. Reproduced from/. Org. Chem., 67, 1427 (2002), by permission of the American Chemical Society.

Further considerations. It needs to be noted that the stoichiometry of a given crown-metal complex is not only influenced by ring size a range of other factors which include the charge density on the metal, the nature of the anion, and the relative strain energies of the crown in different conformations may all make a contribution. 

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