Fast follower

Kinetics provides no information about the fast follow-up reactions. Any of the three may be correct. Those studying this system would endeavor to learn about the intermediates from the literature or from their own work. If the reactivity of Uv and Pu,v could be explored independently, some possibilities might be ruled out. Which reaction of Uv predominates, Eq. (6-27) or (6-29) Do PuVI and PuIV react as shown in Eq. (6-28) Do any of these reactions occur too slowly to be of consequence in the scheme ... 

BH h + HA and its reverse, both of which are fast, followed by HA- + B - BH+ + A2, which is slow. Find the rate law with HA treated as the intermediate and write the equation for the overall reaction. 

Having said all this, a recent report from a major pharmaceutical company with one of the largest reported screening collections revealed that just over 50% of their current lead optimization efforts invoke a "fast follower" approach [114]. Why is this One might speculate that as most companies work on the same targets these days chemists find it easier to "patent bust" than wait for the results of an HTS campaign which may take months to develop. Possibly, when more novel targets are identified, HTS of enhanced collections will deliver upon the promise that they hold. 

APPLICATION OF REDOX CATALYSIS TO FAST FOLLOW-UP REACTIONS... 

The preceding analysis neglects the fact that for very fast follow-up reactions, transformation of B into C may take place within the solvent cage before separation of B and P (Scheme 2.14). The ensuing systematic error is an increasing function of kc but does not exceed +30 mV for rate constants as high as 1011 M-1 s-1.21 Typical examples concern the reductive cleavage of chloro- and bromobenzenes and pyridines.22... 

FIGURE 2.31. Concentration profiles in steady-state (stirring or circulation electrolysis showing the various region of interest for a simple electron transfer reaction (top) and EC process with a fast follow-up reaction (bottom). 

The very fact that chemical catalysis involves the formation of an adduct opens up possibilities of selectivity, particularly stereoselectivity, that are absent in redox catalysis. Several examples of homogeneous chemical catalysis are described in the following section, illustrating the improvements that can be achieved when passing from redox to chemical catalysis. It remains true that redox catalysis has several useful applications that have already been discussed, such as kinetic characterization of fast follow-up reactions (Section 2.3) and determination of the redox properties of transient radicals (Section 2.6.4). 

Takeshita and colleagues299 studied the reactions of 3-bromo-l,5-azulenequinone (478) and 3-bromo-l,7-azulenequinone (484) with benzo[c]furan (479) and 1,3-diphenylbenzo [c]furan (485) by analogy with the reactions previously described by Scott and Adams300. The reaction of 478 with 479 afforded a mixture of four cycloadducts (equation 142), three stereoisomeric [2 + 4]/[6 + 4] tandem adducts (480-482) and one [2 + 4]/[2 + 4]/[6 + 4] triple adduct (483). No mono adduct was isolated, indicative of a fast follow-up cycloaddition. The [6 + 4] cycloadditions all proceeded in an exo fashion, whereas the [4 + 2] cycloaddition proceeded in an endo fashion for 480 and 483, and in an exo fashion for 481 and 482. The reaction of 478 with 485 afforded a mixture of [4 + 2] adducts and [4 + 2]/[8 + 4] tandem adducts. 

The resulting halide anion radical undergoes a fast follow-up reaction. The whole reaction sequence is as follows ... 

Quite often the resulting anionic species undergoes a fast follow-up reaction. Thus, homogeneous ET becomes a crucial step in many electrode reactions a well-known example is the cathodic reduction of organic halides. In mercury, heterogeneous ET to most halides is slow. This kinetic... 

Since formation of EGBs from amides, in all cases, is the result of direct reduction and H2 formation (and has to be done ex situ), the monomeric as well as the polymeric EGBs are recovered as the PB. Their reactions as bases have to be driven either by a thermodynamically favored proton transfer reaction or by a fast follow-up reaction of the depro-tonated substrate, which - particularly for (33) -is difficult, since (33) is a good nucleophile. 

Two types of electrogenerated carbon bases have commonly been used (1) dianions derived from activated alkenes, and (2) carbanions formed by reductive cleavage of halogen compounds or by direct reduction of weak carbon acids. In both cases, the efficiency of the proton transfer reaction relies on a thermodynamically favored proton transfer or a fast follow-up reaction of the deproto-nated substrate. 

On the extreme right-hand side of the diagram, the follow-up reaction has become so fast that it prevents the back electron transfer. Kinetic control is then by the forward electron transfer and the half-wave potential is then, once more, given by (53). It becomes more and more positive of the standard potential as the electron-transfer step (46) becomes faster and faster. Situations are thus met in which the overall process is kinetically controlled by an endergonic electron transfer due to the presence of a fast follow-up reaction. For such fast electron transfers, the reaction would have been controlled by diffusion in the absence of the follow-up reaction (upper left-hand part of Fig. 5). 

A key characteristic of square-pyramidal VO(IV) complexes is their preference to lose 0X0 ligands and become six-coordinate V(III) species upon reduction [37, 90]. This structural change is often a fast following reduction and can require only trace amounts of H+ from protic species for oxo-hgand loss as H2O to occur. A well-defined example of such a transformation is shown in Fig. 18 [91]. The starting VO(HSalamp)2 complex (Fig. 18, top left) is in equhihrium with the octahedral nonoxo complex V(Salamp)2, but the rate of interconversion is relatively slow. Following one-electron reduction of... 

This shows that for an irreversible process, the peak potential is shifted towards more negative (reduction reaction) or more positive (oxidation reaction) potentials by about 0.03 V per decade of increase in the scan rate. For a totally irreversible reaction, no return peak is observed due to the fact that the kinetics are so slow that the opposite reaction cannot occur. The activation energy, overcome by application of a potential, is so high that it is not possible to apply such a potential under experimental conditions. However, the absence of a return peak does not necessarily imply slow electron transfer, but can also be due to a fast following chemical reaction. 

The oxidation potentials 170 ——- 777 of a large number of aromatic hydrocarbons, amines, phenols,heterocycles and olefins are tabulated I0,10a>25-48 65,525-528) an(j nee(j not repeated here. Such potentials have been successfully correlated with HMO-parameters 525 530>538) ie in oxidations with the energy of the highest filled MO (HFMO).Adams 25) and Peover 65) have discussed some precaution to which attention should be paid in such correlations, e.g., shifts in potentials due to the irreversibility of the electrode process or due to fast follow-up reactions. 

For irreversible systems the peak potential of a reduction process is shifted toward more negative potentials by about 0.030 V for a decade increase in the scan rate [Eq. (3.43)]. By analogy, a peak of an anodic process is shifted toward more positive potentials. The most characteristic feature of a cyclic voltammogram of a totally irreversible system is the absence of a reverse peak. However, it does not necessarily imply an irreversible electron transfer but could be due to a fast following chemical reaction. 

Most electron transfers that involve organic compounds have rates that tend to lie in the upper range of detection by present electrochemical techniques.42 In the absence of adsorption or fast follow-up chemical reactions, the effect of the medium often can be isolated by measurement of the variation of half-wave potentials for one-electron, reversible systems. For a reduction reaction... 

A third electrochemical technique, phase selective second harmonic AC voltammetry has recently been successfully used for determining reversible redox potentials for systems where species formed undergo fast follow-up reactions (Ahlberg et al., 1978 Ahlberg and Parker, 1980 Jaun et al., 1980). 

Once the assay and assay format have been decided upon, the next step in the discovery process is to initiate compound screening for the purpose of identifying hits or lead compounds. The fundamental requirement is that the assay results identify a collection of actives or hits. The definition of hit varies between organizations, but most accept the definition that the compound shows a confirmed structure, shows a confirmed dose response, exhibits an IC50 < lOpM potency, and is a member of a chemotype that is amenable to analoging and fast follow-on synthesis. 

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