Isotope effects steric hindrance

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). 

Challis and Rzepa (1975) observed kinetic deuterium isotope effects in the azo coupling of 2-methyl-4,6-di-tert-butylindole (12.139) and its anion. The origin of this effect must also be attributed to steric hindrance of the proton transfer step in the substitution proper, since 2-deuterated methylindole and unsubstituted indole (Binks and Ridd, 1957) do not give isotope effects. 

It is apparent from equation (16) that if k x becomes much larger than k 2, the rate will depend upon k 2 and so a kinetic isotope effect will be observed. Now kL j will become large if there is steric hindrance to formation of the intermediate, and a number of examples are now known where an electrophile which normally gives no isotope effect, does so if formation of the intermediate is hindered. 

The kinetic isotope effect will thus be observed when k 2lk 1 is small this will be occasioned by low reactivity of the reagents, and steric hindrance to reaction. 

For coupling with 2-naphthol-6,8-disulphonic-l-isotope effects (kK/kD) varied with the substituent in the benzenediazonium ion as follows 4-C1 (6.55) 3-C1 (5.48) 4-N02 (4.78), i.e. the reactivity of the ion was increased so that i correspondingly decreased. Base catalysis was observed127, 129, and there was a free energy relationship between this catalytic effect and the basicity of pyridine, 3- and 4-picoline. However, for 2-picoline and 2,6-lutidine, the catalysis was 3 times and 10 times less than expected from their basicities showing that, in this particular proton transfer, steric hindrance is important. 

A further effect of steric hindrance in the transition state was shown by comparing the isotope effects obtained in the reactions of the sulphonic acids (II-V)... 

A kinetic isotope effect, kH/kD = 1.4, has been observed in the bromination of 3-bromo-l,2,4,5-tetramethylbenzene and its 6-deuterated isomer by bromine in nitromethane at 30 °C, and this has been attributed to steric hindrance to the electrophile causing kLx to become significant relative to k 2 (see p. 8)268. A more extensive subsequent investigation304 of the isotope effects obtained for reaction in acetic acid and in nitromethane (in parentheses) revealed the following values mesitylene, 1.1 pentamethylbenzene 1.2 3-methoxy-1,2,4,5-tetramethyl-benzene 1.5 5-t-butyl-1,2,3-trimethylbenzene 1.6 (2.7) 3-bromo-1,2,4,5-tetra-methylbenzene 1.4 and for 1,3,5-tri-f-butylbenzene in acetic acid-dioxan, with silver ion catalyst, kH/kD = 3.6. All of these isotope effects are obtained with hindered compounds, and the larger the steric hindrance, the greater the isotope... 

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). 

Fig. 1 Lewis and Funderburk found that the H/D primary kinetic isotope effects (25 °C in aqueous t-butyl alcohol) for proton abstraction from 2-nitropropane by pyridine derivatives all exceed the maximum isotope effect that could have been derived from the isotopic difference in reactant-state zero-point energies alone (a value around 7). The magnitude of the isotope effect increases with the degree of steric hindrance to reaction presented by the pyridine derivative, the identical results for 2,6-lutidine and 2,4,6-collidine ruling out any role for electronic effects of the substituents. The temperature dependence shown for 2,4,6-collidine is exceedingly anomalous the pre-exponential factor Ahis expected to be near unity but is instead about 1/7, while the value of AH — AH = 3030 cal/mol would have generated an isotope effect at 25 °C of 165 if the pre-exponential factor had indeed been unity.

The effect of steric hindrance on the rates and kinetic isotope effects for reactions of l-nitro-l-(4-nitrophenyl)alkanes and their deuterated analogues with two bicyclic guanidines of comparable basicity (l,5,7-triazabicyclo[4.4.0]dec-5-ene, TBD, and its 7-methyl derivative, MTBD) in THF has been studied. The results disagree with the notion that deuterium kinetic isotope effects are enhanced by steric hindrance, since for the reactions of MTBD with various carbon acids the KIEs decrease with steric hindrance in the carbon acid but the converse is true for reactions of TBD. 

One circumstance that could affect the k2/k ratio is steric hindrance. Thus, diazonium coupling of 3 gave no isotope effect, while coupling of 5 gave a h/ d ratio of 6.55.8 For... 

An unusually large inverse secondary deuterium kinetic isotope effect (1.53-2.75, depending on the reaction conditions) has been reported for bromination of the sterically congested olefin 74. This behaviour can be rationalized by decreased steric hindrance due, in particular, to the ewrfo-placement of the deuterium atoms relative to the double bond135. 

As outlined above, the process of substitution by the nitronium ion is satisfactorily described by an SE2 mechanism in which k2 E > k v In certain circumstances the process could be changed so that this condition did not hold, and the step in which the proton is lost could become kinetically important. One such circumstance is that in which the hydrogen atom being replaced is situated between bulky substituents steric hindrance would then make it difficult for the nitro group to move from its position in the intermediate complex to that between the bulky substituents k2 would be diminished, and a kinetic isotope effect might appear. It is for this reason that 1,3,5-tri-f-butylbenzene and its derivatives are interesting (table 6.1) whilst the hydrocarbon undergoes... 

As in the reaction of imidazole, no major isotope effect has been observed 3-deuterioindole reacts at about the same rate as indole. The diazo coupling of five-membered heteroaromatic substrates therefore appears similar to that of homocyclic compounds where, in the absence of steric hindrance, slow attack of the diazonium ion is followed by a fast proton loss.165... 

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