ADMET mechanism

Referring to the ADMET mechanism discussed previously in this chapter, it is evident that both intramolecular complexation as well as intermolecular re-bond formation can occur with respect to the metal carbene present on the monomer unit. If intramolecular complexation is favored, then a chelated complex, 12, can be formed that serves as a thermodynamic well in this reaction process. If this complex is sufficiently stable, then no further reaction occurs, and ADMET polymer condensation chemistry is obviated. If in fact the chelate complex is present in equilibrium with re complexation leading to a polycondensation route, then the net result is a reduction in the rate of polymerization as will be discussed later in this chapter. Finally, if 12 is not kinetically favored because of the distant nature of the metathesizing olefin bond, then its effect is minimal, and condensation polymerization proceeds efficiently. Keeping this in perspective, it becomes evident that a wide variety of functionalized polyolefins can be synthesized by using controlled monomer design, some of which are illustrated in Fig. 2. 

Scheme 6.27 Revised ADMET mechanism for Grubbs catalysts [100],...

These data in total have led to the revising of the ADMET mechanism with ruthenium-based catalysts to include the very important aspect of phosphine dissociation (Scheme 6.27). In this mechanism k, k4, ky, and kg are assumed to be very fast, such that the dissociative olefin-phosphine exchange is die rate-determining process [100]. 

PA can also be obtained via the thiol-ene click reaction from a,ro-diene monomers bearing amide groups in the main backbone or as side moieties via the Ugi four-component reaction [36, 37]. In one such study [38], the authors used 10-undecenoic acid as carboxylic acid, 10-undecen-l-al as an aldehyde, and different primary amines and isonitriles to synthesise a,C0-diene monomers, and then applied them to polymerisation reactions. The main focus of this specific work was the ADMET mechanism, though thiol-ene photopolymerisation was also implemented to prepare linear aliphatic PA with Mn values of 3-9 kDa and Tg values of 1-10 °C. 

At this point it is appropriate to discuss the mechanism for ADMET, because ADMET polymerization is more involved than its chain polymerization counterpart— ROMP. Figure 8.6 illustrates the accepted mechanistic pathway which leads to productive metathesis polymerization, as first described by Wagener et al.14a A general model reaction between an a,o>-diene with a metal alkylidene... 

The ADMET cycle involves the formation of two metallacyclobutane intermediates [D, F], whereas the ROMP mechanism contains only one. 

We have synthesized such a material, which is called perfectly imperfect polyethylene, where each branch is a methyl group and its frequency along the backbone is controlled by the nature of the symmetrical diene used in the ADMET polycondensation reaction [37]. Equation 12 illustrates the chemistry used to produce polyethylene by a step polycondensation route rather than a chain propagation mechanism. 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

The ADMET polymerization of sugar-based monomers is much less explored than the ROMP approach, and only a few examples have been reported to date. Bui and Hudlicky prepared a,oo-dienes derived from a biocatalytically synthesized diene diol, from which chiral polymers (up to 20 kDa) with D-c/uro-inositol units were prepared via ADMET in the presence of 1 mol% of C4 [169]. Furthermore, several ot,co-dienes containing D-mannitol, D-ribose, D-isomannide, and D-isosorbide have been synthesized by Enholm and Mondal [170]. Also in this study, C4 was used to catalyze the ADMET polymerizations at 1 mol% catalyst loading. As pointed out by the authors, the viscosity increased as the reactions progressed and vacuum had to be applied to efficiently remove the released ethylene. Unfortunately, the polymers obtained were not further analyzed. As already mentioned above, Fokou and Meier have also reported the ADMET polymerization of a fatty acid-/D-isosorbide-based a,co-diene [126]. Furthermore, Krausz et al. have synthesized plastic films with good mechanical properties by cross-linking fatty esters of cellulose in the presence of C3 [171-173]. 

Chiral polymers have been applied in many areas of research, including chiral separation of organic molecules, asymmetric induction in organic synthesis, and wave guiding in non-linear optics [ 146,147]. Two distinct classes of polymers represent these optically active materials those with induced chirality based on the catalyst and polymerization mechanism and those produced from chiral monomers. Achiral monomers like propylene have been polymerized stereoselectively using chiral initiators or catalysts yielding isotactic, helical polymers [148-150]. On the other hand, polymerization of chiral monomers such as diepoxides, dimethacrylates, diisocyanides, and vinyl ethers yields chiral polymers by incorporation of chirality into the main chain of the polymer or as a pedant side group [151-155]. A number of chiral metathesis catalysts have been made, and they have proven useful in asymmetric ROM as well as in stereospecific polymerization of norbornene and norbornadiene [ 156-159]. This section of the review will focus on the ADMET polymerization of chiral monomers as a method of chiral polymer synthesis. 

ADMET polymerization has been used to integrate silicon into linear and network hydrocarbon polymers in an attempt to produce novel materials with enhanced thermal and mechanical stability. While ADMET has been used to produce copolymeric architectures unattainable through conventional methods, application of this polymerization to synthesis is feasible only if the silicon-based functionality does not inhibit metathesis. This research, initiated in the early 1990s by Wagener and colleagues, has shown that the silane and siloxane... 

The Step Polymerization Mechanism in ADMET Chemistry and Catalyst Selection... 

The mechanism of ADMET polymerization (Scheme 5) contains intermediates similar to those found in ROMP chemistry in that both polymerizations contain, inclusively, various metallacyclobutane/carbene species." Although ROMP propagates exclusively via trisubstituted metallacycles, whereas ADMET requires disubstituted metallacycles, the major difference is that ADMET step chemistry is an equilibrium process driven by condensation and ROMP chain chemistry propagates irreversibly owing to the high reactivity of the carbene with strained cycloalkenes. Therefore ROMP is much faster than ADMET simply because competing equihbria, absent during ROMP, decrease the net productive rate in ADMET chemistry. 

Polybutadiene containing an unprecedented high trans stereochemistry can be synthesized via the ADMET polymerization of 1,5-hexadiene. " The extension to other purely hydrocarbon-based homopolymers has shown that (aside from steric factors that influence the formation of the metallacycle in the mechanism) the polymerization method is both trivial and broad in scope. 

ADMET Properties of Drugs Cytochrome P450 Monooxygenases, Chemistry of Drug Metabolizing Enzymes, Chemistry of Enzyme Inhibition, Chemistry and Mechanisms of Polymorphisms, Detection of... 

Terminal dienes (also called a,w-diolefins) are useful in ADMET polymerization. The scheme below shows a number of processes that were patented by Shell Oil Company and were designed to produce terminal dienes. The name FEAST (Further Exploitation of Advanced Shell Technology) was coined to describe these reactions, most of which involve metathesis. Assume that the catalyst is a generic carbene complex, L M=CRR. Propose mechanisms for the transformations indicated by an asterisk near the reaction arrow. 

---