The Steric Hypothesis

The first attempt at rationalization was made by Lamb, who proposed that the 5-hexenyl radical (A ) is in the form of an intramolecular complex between the free radical site and the double bond, and that transfer of hydrogen from the solvent to this complex would be sterically easier if it were to give the (CyS) product rather than the Cy6. The possibility of such a complex, or at least of a coiled conformation in which the terminal unsaturated linkage lies over the radical center, was later confirmed by esr. Nevertheless, this proposal does not seem to have been used extensively and is not in accord with more recent ideas (Section III.l.B). 

A second, and rather more widely discussed, steric proposal was that 

This hypothesis has been discussed in the review cited and it is supported by substituent eflfects (Section IV). 

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Egli M (2012) The steric hypothesis for DNA replication and fluorine hydrogen bonding revisited in hght of strucmral data. Acc Chem Res 45 1237... 

This extension in the laboratory can be seen as the fantastic hypothesis testing application of molecular modeling. It is rare to find a chemical problem where there are not at least a few theories of the molecular mechanism involved. How many times has each of us heard steric affect or hydrogen bonding invoked as the explanation of a variety of experimental observations made at the bench level How useful would it be to be able to actually build accurate, quantitative models to investigate such ideas ... 

If the above hypothesis is correct, the basic assumption of the extrather-modynamic treatment, namely, that there is exact cancellation of chemical contributions in the quantity 8AH, no longer holds. Reduction of the contribution to the activation enthalpy from steric compression (AH sc) should be accounted for by introducing an appropriate 0A//+sc-term besides a0AH° into (62), giving (68). Now, if we make the reasonable assumptions that the... 

The hypothesis that 128 is twisted in solution and that the transition state to E-Z isomerization has perpendicular fluorene groups was supported by a study of 2,3,2, 3 -dibenzo-annelated 128 (159). In this, the steric situation around the double bond is similar to that in 128a, but an improved stabilization of the diradical perpendicular transition state should lead to a lower barrier to E-Z isomerization, as is found (AG 53 = 23.5 kcal/mol). A close approach of the 1 and 1 (8 and 8 ) positions in 128 is indicated by a through-space H- F coupling of 7 Hz in ( )-l, 1 -difluoro-128 (160). In this compound the barrier to E-Z exchange is >25.6 kcal, because of the small contribution of the fluorine atoms to the ground state strain. 

N - Benzyl- N -p icolinoylpiperazine (EGYT-475, 4.88), a compound with potential antidepressant activity, underwent similar hydrolysis. After intravenous administration, picolinic acid (4.89) was one of its major urinary metabolites in rats the other product, A-benzylpiperazine (4.90) was also detected, but at much lower levels, since it was further transformed by A-de-benzylation [55], Since the products of direct hydrolysis of these cyclic tertiary amides (i.e., the corresponding secondary amines) were found at substantial levels, it appears that oxidative A-monodealkylation is not an essential step for hydrolysis in these compounds, in contrast to the findings for A,A-diethylbenzamide. This contradicts the hypothesis [52] (see above) that the steric bulk of the tertiary amide group impedes direct hydrolysis. Here, although the degree of steric bulk is at least comparable, direct hydrolysis clearly takes place. 

On the basis of the observed stereoinduction trend, the addition of HCN took place over the diaminocyclohexane portion of the catalyst away from the amino acid and amide unit. The last hypothesis led to the prediction that a more sterically demanding amino acid or amide unit (Figure 6.14) could additionally favor the cyanide attack compared to the less bulky diaminocyclohexane unit and thus making the Schiff base catalyst more enantioselective in Strecker reactions of aldimines and ketimines. To evaluate this perspechve, the authors performed a model-(mechanism-) driven systematic structure optimizations by stepwise modification of the amide, the amino acid, and the (thio)urea unit of catalyst 42 and examined these derivatives of 42 (lmol% loading ) in the model Strecker reaction (toluene ... 

However, Felkin s hypothesis may be advantageously replaced by the assumption of non perpendicular attack. It is clear that the steric hindrance encountered by the nucleophile is much more serious in 13 than in 12. Furthermore non-perpendicular attack increases the Nu-R interaction at the expense of the Nu-0 interaction, thus accounting for the predominance of R over O. Finally, as R becomes bigger, the nucleophile is pushed toward the chiral carbon and can feel better the difference between S (in 12) and M (in 13), which should lead to an increased selectivity. 

As shown in Scheme 9, when anti-syn-30 was subjected to the usual acetonide formation condition, the corresponding 5- and 6-membered acetonides, anti-syn-31 and anti-syn-32, respectively, were obtained in a ratio of 91 3 in spite of the steric congestion in the major product by the syn relationship of the two substituents, which would be a clear reflection of the above hypothesis. Anti-syn-31,... 

Discussions to this point rely on the hypothesis that the ligands of oxo(salen)manganese(V) complexes have planar structures by analogy to metalloporphyrin complexes and Mn(III)-salen complexes 11 and 12, the structures of which were determined by the X-ray crystallographic analysis [29a,47]. However, the assumption that the ligand of the oxo-Mn-salen species is planar failed to give a satisfactory explanation for the following stereochemistry observed in the recent study. Trans-cis selectivity in the epoxidation of 1-alkylindenes usually improves as the steric bulk of the catalyst increases. However, the epoxidation of 1-methylindene with the smallest... 

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