ADMET kinetic

Wagener ADMET kinetics (2a) and (4a) Reaction rates using (4a) were much more temperature dependant than those using (2a). Indicating that phosphine dissociation is an energy barrier for (4a) processes. 

Shorter chain dienes have an increased propensity to form stable five-, six-, and seven-membered rings. This thermodynamically controlled phenomenon is known as the Thorpe-Ingold effect.15 Since ADMET polymerization is performed over extended time periods under equilibrium conditions, it is ultimately thermodynamics rather than kinetics that determine the choice between a selected diene monomer undergoing either polycondensation or cyclization. 

Methyl-l,10-undecadiene, ADMET polymerization of, 442 Michaelis-Menten enzymatic kinetics, 84 Microbial hydrolysis, 43 Microcellular elastomers, 204-205 Microphase-separated block copolymers, 6-7... 

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. 

While the effects of various functionalities and their spatial location on ADMET chemistry are now evident, only recently has the dramatic influence of the functional group on the kinetics of the reaction depending upon the organometallic... 

Representative data illustrating the influence of Lewis base functional groups in the ADMET reaction are shown in Table 1. When molybdenum catalysts are used to polymerize ether or thioether dienes, little change in reaction rate is observed as compared with the standard, 1,9-decadiene, which possesses no heteroatoms in its structure. When a sulfur atom is three carbons atoms away from the alkene site, the reaction rate is reduced approximately one order of magnitude otherwise, the kinetics are all essentially unaffected [20a]. 

The next section describes the utilization of //PLC for different applications of interest in the pharmaceutical industry. The part discusses the instrumentation employed for these applications, followed by the results of detailed characterization studies. The next part focuses on particular applications, highlighting results from the high-throughput characterization of ADMET and physicochemical properties (e.g., solubility, purity, log P, drug release, etc.), separation-based assays (assay development and optimization, real-time enzyme kinetics, evaluation of substrate specificity, etc.), and sample preparation (e.g., high-throughput clean-up of complex samples prior to MS (FIA) analysis). 

The introduction and use of primary cells for ADMET assays may make a valuable contribution to the level and quality of information obtained from the tests. Absorption, distribution, metabolism, and excretion (ADME) encompass the disposition of a pharmaceutical compound within an organism. These four criteria influence the levels and kinetics of drug exposure to tissues and hence influence the performance and pharmacological activity of a compound as a drug. 

Wagener, K.B. Brzezinska, K. Anderson, J.D. Younkin, T.R. Steppe, K. DeBoer, W. Kinetics of Acyclic Diene Metathesis (ADMET) Polymerization Influence of the Negative Neighboring Group Effect. Macromolecules 1997,30,7363-7369. 

This chapter will present some of the history of ADMET and olefin metathesis in general, although the emphasis will be on the mechanism and kinetics of ADMET polymerization. The general mechanism for olefin metathesis will be presented before any of the specific catalyst structures are introduced or discussed in order to provide the reader with a firm basis upon which to compare the various popularly used catalysts for ADMET polymerization. In addition, procedural information will be given at the end of the chapter to give the reader an idea of what is specifically involved in a typical ADMET polymerization. 

Olefin metathesis has been extensively written on in both books and journals [1-10]. This chapter will focus on ADMET. Of particular interest are the issues of catalysis, mainly functional group tolerance, kinetics, and mechanistic details. The development of late-transition metal catalysts has enormously expanded the scope of ADMET, so particular attention will be given to the well-defined ruthenium-based olefin metathesis catalysts. Pertinent information pertaining to catalysts of Group VI metals will also be provided. Important procedural aspects of ADMET will be presented in conclusion. 

ADMET has been shown to be a step-growth polycondensation reaction [31[. The kinetics of step-growth polymerization and consequences thereof are completely different than those of chain polymerizations. Since ROMP and many other single-site transition metal-catalyzed polymerizations discussed in this book proceed... 

This has been referred to as the negative neighboring group effecf and has been proposed to be responsible for the slower kinetics of ADMET of ether dienes compared to hydrocarbon dienes [35]. Three carbons between the olefin and a carbon bearing coordinating functionahty are usually sufficient to allow polymerization, although there are exceptions to this trend [33]. Intense catalyst development efforts are producing catalysts that are more and more tolerant to functionality closer to the olefin. 

The preferences of the various pathways are dependent on the catalyst used, specifically the electronic and steric factors involved. The electronic contribution is based on the preference of the metallacycle to have the electron-donating alkyl groups at either the a or the carbon of ftie metallacycle [23]. The steric factors involved in the approach of the olefin to the metal carbene also determine the re-giochemistry of the metallacyclobutane formed. These factors include both steric repulsion of the olefin and carbene substituents from each other and from the ancillary ligands of the metal complex. Paths (b), (c), and (e) in Scheme 6.10 are important to productive ADMET. The relative rates of pathways (c) and (e) will determine the kinetic amount of cis and trans double bonds in the polymer chain. Flowever, in some cases a more thermodynamic ratio of cis to trans olefin isomers is attained after long reaction times, presumably by a trans-metathesis olefin equilibration mechanism [31] (Scheme 6.11). 

The kinetics of ADMET with complex 6 were compared to those of complex 2 by measuring the volume of ethylene liberated from ADMET reactions over time [35], Obtaining an approximate second order rate constant from the DP versus time curves, it was found that molybdenum complex 2 polymerizes 1,9-decadiene 24 times faster than ruthenium complex 6 (Tab. 6.1). 

The kinetics of polymerization of 1,9-decadiene by complex 6 and complex 10 were compared by measuring the volume of ethylene liberated over time. It was found that complex 10 catalyzed ADMET up to six times faster than complex 6 at temperatures of 45 to 75 °C, but complex 6 was the faster catalyst at 30°C. Additionally, complex 10 displayed a very conspicuous induction period that was not present for catalyst 6. It was also apparent that complex 10 is stable over at least a period of hours at 75 °C in the presence of dienes, whereas complex 6 rapidly decomposes at this temperature [100]. 

The effects of fhis kinetic situation were clearly demonstrated in the context of ADMET, In DP versus time curves (Fig. 6.4) for the ADMET of 1,9-decadiene with complexes 6 and 10 a conspicuous induction period is witnessed for 10 that is absent for 6. 

It should be mentioned that although the methylidene displays anomalous kinetic behavior, complex 10 is active for ADMET and produces higher molecular weight polymers than 6, in many cases. In other cases, the two complexes produce polymers of similar molecular weights. This observation was recently reported for the ADMET of phosphazene-containing monomers, which could be due to the relative inactivity of the methylidene [104]. 

If a volatile monomer is used in an ADMET polymerization, a condenser should be used to return monomer vapor to the reaction mixture. The kinetics of step-growth polymerization dictate that the concentration of monomer falls very quickly to produce dimer, trimer, and so forth. Nevertheless, monomer will be present for some time after the start of the polymerization. If the monomer is particularly volatile, a dry ice-isopropanol condenser is useful. This can be constructed in any glass shop by attaching a cup-shaped cooling reservoir to a vacuum valve or other cylindrical glass tube with the required joints and valve. If the monomer is only slightly volatile, or the carrier gas method is used, a water-cooled condenser is sufficient to retain monomer in the flask, while allowing ethylene to escape. 

Overall, PBPK models can provide insight into the several aspects associated with the kinetics of a drug within the human body, collectively termed as ADMET, for absorption, distribution, metabohsm, elimination, and toxicity. An application of the PBPK models at the early stage of drug development can be useful to rapidly screen candidate drugs based on their PK properties via in silico approaches (3,4). Due to the rapid increases in the computational power, and the parallel advances in the PBPK area, the role of PBPK models in pharmacometrics is likely to substantially increase. 

Substituted unsaturated pyrans prepared by RCM using 18 as catalyst can be immediately submitted to zirconium-catalyzed kinetic resolution of the racemic product at 70°C. This provides a new route to medicinally important agents containing 6-membered cyclic ethers. A one-pot synthesis can give 63% conversion with >99% enantiomeric purity (Morken 1994). Dienes of the type CH2=CH(CH2)30(CH2(H20) CH2)3CH=CH2 (m = 2-4) readily undergo ADMET polymerization in the presence of catalyst 8 (Qiao 1995). 

The polymer 17, prepared by the ADMET polymerization of neat diallyldi-phenylsilane using Mo(=CHCMe2Ph)(=NAr)[OCMe(CF3)2]2 (Anhaus 1991), can be degraded by diluting the living polymer solution with sufficient toluene. This gives a 30% yield of the tt cyclic dimer 18, which separates as a white precipitate. When this is isolated and placed in contact with further initiator, an equilibrium is established between the cyclic monomer 19 and the three cyclic dimers (cc ct ft = 73 21 6), eqn. (3) (Anhaus 1993). The formation of the tt cyclic dimer in the initial degradation of 17 is thus kinetically favoured. 

The kinetics of the ADMET reaction is not amenable to study by many traditional means, as these polymerizations are mostly conducted in bulk. The most effective way to measure the kinetics of the polymerization is to monitor the volume of evolved ethylene. This technique has been used to probe the difference in activity between [Mo] 2 and [Ru]l for ADMET polymerization of 1,9-decadiene [37]. At 26 °C in bulk monomer, [Mo] 2 promotes ADMET polymerization of 1,9-decadiene at a rate approximately 24 times that of [Ru]l. Additionally, [Mo] 2 polymerizes 1,5-hexadiene 1.7 times faster than 1,9-decadiene, while [Ru]l only cyclodimerizes 1,5-hexadiene to 1,5-cyclooctadiene. Monomers with coordinating functionality, specifically ethers and sulfides, were also investigated. Predictably, these monomers did not undergo polymerization as rapidly as hydrocarbon monomers however, this difference was dramatically more pronounced with [Ru]l than with [Mo]2. In fact, the dialkenyl sulfide monomers that were studied completely shut down the polymerization with [Ru]l, whereas the catalytic activity of [Mo]2 was only slightly lowered. This reduction in polymerization rate is most likely due to coordination of the heteroatom to the vacant coordination site of [Ru] 1, following phosphine dissociation. This reversible coordination of heteroatoms to the ruthenium complex likely occurs both intramolecularly and intermolecularly. Conversely, the steric bulk of the ligands in [Mo] 2 makes it less likely to intramolecularly form a coordinate complex, despite molybdenum being far more electrophilic than ruthenium. 

Nonetheless, ADMET is a versatile technique that allows the incorporation of a wide variety of functional groups into the resultant polymers. Scheme 1.9 shows the catalytic cycle of ADMET, controlled by the metathesis catalyst, which can be either ruthenium- [76, 77] or molybdenum-based [78, 79]. While the kinetics are controlled by the catalyst (there is no reaction in its absence), it still follows the kinetic picture described in Section 1.3.2. This is because the catalyst is removed from the chain end after each successful alkene metathesis reaction (i.e., coupling) and the olefin with which it subsequently reacts is statistically random. 

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