Competition experiments

The determination of relative reactivities of different substrates is a crucial requisite for both Hammett and KIE studies. Usually, this is done either by measuring 

Frequently, a first-order dependence regardless of the exact nature of the reacting species can be assumed and identical reaction orders in all other components, which in the context of a catalytic reaction with two substrates (A and B) competing for the active catalyst gives the following expressions ([] denotes concentration)  

This expression can be recognized as a straight line with intercept at y = 0, thus by plotting ln([A]o/[A]) versus ln([B](,/[B]) at different levels of conversion, the relative reactivity (kj lk ) can be obtained as the slope of the line. If a straight line is not obtained, the initial assumption does not hold for the system under investigation, or perhaps some of the compounds are unstable under the conditions employed. An analogous expression can be derived from the appearance of products if that is more convenient for the chemistry being studied. 

The experimental differences in reactivity are either directly compared to calculated reactivities (obtained from Eq. (8.7)), or they are converted to differences in energy (in principle, A(AG )) to avoid the exponential dependence. 

Recent DFT Developments of Relevance to Transition Metal Catalysis 

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More quantitative results are available for the nitration of alkyl-thiazoles Dou et al. (373) determined the reactivity, relative to benzene, of the nitration site of various mono- and dialkylthiazole by competition experiments (Table 1-53). 

These values represent the average of at least two competitive experiments carried out in the presence of a slight excess of nitrite with respect to 2-aminothiazole. 

These reactions occur on the benzylic hydrogens because these hydrogens are much more reactive. Competition experiments show, for example, that at 40°C a benzylic hydrogen of toluene is 3.3 times as reactive toward bromine atoms as the tertiary hydrogen of an alkane and nearly 100 million times as reactive as a hydrogen of methane. 

Tlie first suggestion of a template effect which was offered in the literature was made by Greene in 1972 °. Tlie illustration of this concept is approximately that shown in Eq. (2.2), above. Greene presented several pieces of evidence in addition to the concept itself. First, he noted that when the final concentration of 18-crown-6 in a reaction mixture (MejSO) was increased from 0.04 At to 0.09 Af, the yield of crown dropped only slightly (84% to 75%). In a competition experiment, equal amounts of 18-crown-6 and 21-crown-7 were formed when one molar equivalent each of triethylene glycol and tetra-ethylene glycol were allowed to compete for triethylene glycol ditosylate (KO-t-Bu/THF). 

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCb-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with A -bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-methylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine, only the 5-isomer (besides some side-chain bromination) is obtained in the bromination of alkylthiophenes with A -bromosuccinimide. ° However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chIoro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with thiocyanogen or chlorination with sulfuryl chloride. 2-Methyl- and 2-ethyl-thiophene give, somewhat unexpectedly, upon alkylation with t-butyl chloride in the presence of Feds, only 5-t-butyl monosubstituted and... 

Competition experiments for the partitioning of phenyl radical between a hydrocarbon and the reference compound, carbon tetrachloride, from results given in Ref. 10. The lines show that the product ratio is directly proportional to the ratio of the concentrations of the competing reagents. The plots depict data for toluene (circles.) and cyclohexane (squares). 

Competition experiments. To evaluate the relative reactivity of the pora-nitropheny 1 radical (N ) toward CHiOH and CLLCT. Boyle and Bunnett17 carried out experiments with iodobenzene as in this scheme ... 

Steady-state approximation competition experiments. The solvolysis of 2-octy lmethane-sulfonate (RX) in aqueous solutions containing azide ions yields a mixture of alcohol and azide.35 Two mechanisms should be considered ... 

The most useful of the insertion processes is the intramolecular reactions that occur with high selectivity for the formation of five-membered ring products. The electrophilic nature of the process is suggested by C-H bond reactivity in competitive experiments (3°>20 >1°) [76, 77]. Asymmetric catalysis with Rh2(MPPIM)4 has been used to prepare a wide variety of lignans that include (-)-enterolactone (3) [8], as well as (R)-(-)-baclofen (2) [7],2-deoxyxylolactone (31) [80,81],and (S)-(+)-imperanane (32) [82].Enantioselectivities are 91-96%... 

Alcohols can be selectively bound to the same host type if they are combined with an amine and vice versa, considering that a cation and an anion will be formed through a proton transfer. The so-formed alkoxide anion will bind to the boron atom, while the ammonium ion will be complexed by the crown ether (147, Fig. 39). Competition experiments involving benzyl-amine have shown enhanced selectivity for the complexation of alcohols with... 

NOTE Kj values and Hill coefficients determined by competition experiments for 0.4 nM pHJketanserin-labeled... 

Ki values and Hill coefficents determined by competition experiments for 1.0 nM [ H]LSD(+[10- M]Ketanserin)-labeled sites in rat frontal cortical homogenates. Data from Shannon et al. 1984. 

Figure 26.3 P and NMR spectra of two samples taken during the competitive experiment after 2 min and 30 min.

The following scheme represents the possible paths which can be followed during a competitive experiment. Path a refers to the hexylamine, path b to the benzophenone hydrazone. 

The relative reactivity of dienes has been estimated on the basis of competition experiments performed using two kinds of dienes (2 mmol each) and... 

In competition experiments, it is possible that the binding of the radioligand is inhibited not by competition at a common site, but by the inhibitor affecting the binding remotely through interaction with a different part of the receptor molecule (i.e., by an allosteric action). 

FIGURE 5.4 In this illustration of a competition experiment, a fixed concentration of radioligand, in the absence of inhibitor, produces specific binding of B0. The specific binding in the presence of a competitive inhibitor is denoted by Bt A constant amount of nonspecific binding is assumed to be present. The concentration of inhibitor that reduces specific binding by 50% is referred to as the IC50. 

Of course, saturation experiments are only possible when a radiolabeled form of the ligand of interest is available. Competition experiments, on the other hand, are particularly useful in allowing the determination of dissociation constants for unlabeled drugs which compete for the binding sites with a ligand that is available in a labeled form. This approach has been widely adopted by the pharmaceutical industry as a rapid means of determining the affinity of novel compounds for a particular receptor for which a well-characterized radioligand is available. 

FIGURE 5.12 Hill plots of the results of the competition experiment used for Problem 5.3. The fitted lines have been constrained to have a slope of -1. IC50 values are given by the. -intercepts and can be used to determine Kt for the binding of sotalol (see accompanying text). The IC values, as expected from Eq. (5.20), increase with radioligand concentration. 

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