Steric effects, hydrogen isotopes

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

There are several possible sequences for the addition, cyclization and dehydration steps involved in the overall transformation. A study of the effect of the size of 3,4-substituents in 2,5-hexanediones showed that rates decreased in the order Me > Et > Ph > Me2CH. Both dl and meso isomers were compared and the dl isomers reacted more rapidly in each case <86JOC62l>. The fact that the stereoisomers do not interconvert under the cyclization conditions and the absence of a primary isotope effect for 3,4-hydrogen atoms have been taken to indicate that the cyclization of the hemiaminal is the rate-determining step <9lJOC6924>. This proposal is consistent with the observed steric effect, since the meso diketones result in cw-stereochemistry in the cyclization step (Scheme 68). 

The steric effect of the eclipsing interaction between the an//-position at the methylene carbon and the two adjacent vinylic hydrogens conhnes C—H(D) vibrations in this position more than in the 5> M-position. Deuterium is therefore preferred in the anti-position and hydrogen in the syn-position. The reported values for the isotope effect are AT = 1.41-1.10 with AG° = —11 to —30 cal mol " between — 168°C and — 114°C H°= -142 30calmol" andAS = -0.7 0.3calmol" K" . 

In conclusion, purely steric effects due to the replacement of hydrogen by deuterium inside the protein seem not to be relevant to the isotopic effect on the thermal denaturation of met-hemoglobin. 

Both sets of results may also be discussed in terms of inductive differences between hydrogen and deuterium (see Halevi, 1963). Brown et al. (1966) jDoint out that both the inductive and steric explanations qualitatively predict isotope effects in the same direction, but that an inductive effect would be expected to operate from the 3 and 4 positions nearly as effectively as from the 2 position . Furthermore, there is no observable isotope effect on the heat of reaction of 2,6-(dimethyl-de)-pyridine with the relatively small molecule diborane A AH = —20 18 cal mol ), but a significant effect is obtained with the larger molecule boron trifluoride AAH = 230 + 150 cal mol ). 

It may have been the dramatic 1964 publication of E.S. Lewis and L. Funderburk that forced the question of hydrogen tunneling in complex solution reactions near room temperature into the consciousness of a larger scientific public, particularly in physical-organic chemistry. This article presented isotope effects for proton abstraction from 2-nitropropane by a series of substituted pyridines, and the values rose sharply as the degree of steric hindrance to the reaction increased (Fig. 1). AU the observed H/D isotope effects, from 9.6 to 24, were larger than expected from the simplest version of the so-called semiclassical theory of isotope effects (Fig. 2). 

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