Studies, mechanistic

Kinetic studies are of limited value for elucidating the mechanism of the hydroformylation reaction. This is because the empirically derived rate expressions are valid only within a narrow range of experimental conditions. For the rhodium-catalyzed reaction, in the absence of phosphine, the following rate expression has been proposed  

The value of b depends on the alkene, and both a and b under certain conditions may be less than one. The inverse dependence of rate on the concentration 

Both in situ infrared and multinuclear NMR under less severe conditions have been used to gain mechanistic insights. For the hydroformylation of 3,3-dimethyl but-l-ene, the formation and hydrogenolysis of the acylrhodium species Rh(C()R)(C())4( R=CH2CH2Bur) can be clearly seen by IR. NMR spectroscopy has also been very useful in the characterization of species that are very similar to the proposed catalytic intermediates. We have already seen (Section 2.3.3, Fig. 2.7) NMR evidence for equilibrium between a rhodium alkyl and the corresponding hydrido-alkene complex. There are many other similar examples. Conversion of 5.3 to 5.4 is therefore well precedented. In the absence of dihydrogen allowing CO and alkene to react with 5.1, CO adducts of species like 5.6 can be seen by NMR. Structures 5.11 and 5.12 are two examples where the alkenes used are 1-octene and styrene, respectively. 

The other isomer of 5.11 with one axial and one equatorial phosphine can also be seen at low temperature. Indeed at low temperature that appears to be the more stable isomer. With styrene, as shown by 5.12 the branched (Mar-kovnikov) rather than the linear (anti-Markovnikov) isomer is the major one. However, remember that the experimental conditions of an actual industrial process, and that of the NMR experiments, are different. 

Model compounds for some of the catalytic intermediates shown in Fig. 5.1 have also been synthesized and characterized. Thus fram-Rh(C2I 4H )(CO )L2 is known, which may be considered as a model of 5.4. A model for 5.7, the complex 5.13, has also been made and characterized. While there are clear differences between 5.7 and 5.13, both 5.7 and 5.13 undergo reductive elimination. For the latter, the product of reductive elimination is acetaldehyde. This reaction has been kinetically studied to gain mechanistic insights. 

This simple mechanistic picture cannot be applied to thiophene derivatives, whose HDS mechanism is still under study. Research on organometallic models 

2 Mechanistic Studies.- A number of substitution reactions of alcohols, phenols, or amines with 1,3,2-dioxaphospholans, e.g. (73), oxazaphospholans, and diazaphos-pholans have been followed by n.m.r. and shown to involve H-phosphoranes, e.g. (74). The reactions are run in toluene or without solvent, and without addition of an acidic catalyst in some systems, with 4-chlorophenol as the nucleophile, an equilibrium was established between an H-phosphorane (75) and a phosphonium salt (76), but the authors still favour (75) as the true intermediate. The equilibrium constants for a series of exchange reactions between (thio)phosphites (77) and (thio)phosphoro-dichloridites (78), and some analogous bromidites and a fluoridite, have been measured.The constants increase with increased electron donor ability of R. 

The reaction of a phosphonamidite (79) with a trifluoracetyl ester (80), to give a phosphonite (81), has been shown to be catalysed by 4-dimethylaminopyridine. In contrast to an earlier report where a similar reaction proceeded with retention of configuration at phosphorus, the present system gave an equal amount of the two diastereomers (81). A mechanism is proposed which involves attack of an alkoxide, formed by de-trifluoracetylation of (80), on an equilibrating DMAP-intermediate (82). Another unusual substitution reaction is one between an alkoxyborane (83) and a phosphite (84). The phosphite was prepared in situ from acetylacetone and diethyl phosphorochloridite, and the substitution occurred under very mild conditions and gave high yields of phosphates after oxidation. 

Arabino oligonucleotides up to a hexamer have been prepared by solid phase synthesis using (118) as the monomer the phosphoramidites (118) could be obtained rather pure without 2 -OH protection due to steric hindrance for phosphity-lation at this position. Deoxyoligonucleotides containing flexible nucleoside analogues have been synthesized using (119) or (120) as the modified monomers in both cases hybridization was greatly impeded. 

A series of 04hymidine-3 -yl thiophosphoramidites (121) have been prepared and evaluated for use to prepare dinucleoside phosphorodithioates (122). The S-cyanoethyi derivatives (121) were less prone to oxidation than the S-2,4-dichloro-benzyl analogues, and the N,M-dimethylthioamidites (121) were sufficiently reactive to 

2 Mechanistic Studies. - A kinetic study of the solvolysis of the cyclic phosphoramidite (65) in methanol at 40 °C, catalysed by different amine hydrochlorides, showed that kcat obeyed the Bronsted equation with a = 0.65. This means that a proton transfer is well advanced in the TS, which was depicted as (66). Reactions of phosphoramidites with phenols are not catalysed by amine hydrochlorides and proceed sluggishly without a solvent aromatic solvents, e.g. 

2-Dioxaphospholanes are thermodynamically most stable with the P-substituent axial due to stereoelectronic effects. The conversion of (68) to (69) with an equatorial phenoxy group has now been realised by addition of triethylamine slowly to a mixture of (68) and phenol at — 78°C. Reactions at room temperature gave (70) with an axial phenoxy group, and the conversion of 

2 Mechanistic Studies.- The kinetics and mechanism of the acid catalysed alcoholysis of phosphoramidites and aminophosphines has been studied. The rate of methanolysis in methanol 

The rate ratio for substitution of phenoxy groups by methoxide ions in (69) and (70) has been shown to be very solvent dependent. Although a high rate ratio (k(69) k(70) = 1.8x10 ) was found in methylene chloride, the ratio was only 14 in methanol. The authors propose an ion-pair stabilized phosphorane-like structure (71) for the transition state or intermediate in methylene chloride, which has a favourable axial-equatorial placement of the five-membered ring, to account for the high ratio in this solvent, and an in-line Sn2 mechanism to apply in methanol, where ion-pairing is unimportant The different stereochemical expectations (retention in methylene chloride and inversion in methanol) could not be verified because phosphites isomerize under the reaction conditions. 

A different set of questions arises from drag candidates which belong to a class that has already shown some endocrine effect, or is suspected of having endocrine-mediated effects (Harvey et al. 1999). No general recommendation can be given for the situation when specific endocrine investigations need to be performed in separate non-GLP studies. Such studies are summarised as mechanistic studies. 

The suprahypothalamic neurotransmitter level can be assessed by a determination of catecholamines in circumscribed brain areas, the technique requires preparation of frozen tissue and isolation of specific nuclei by the micropunch technique. The catecholamines and indolamines can be measured by a radio-enzymatic methods and by a high-pressure liquid chromatography (HPLC) with electrochemical detection. These mechanistic investigations are mostly initiated due to questions arising from the receptor interaction profile of the drug candidate, they may be required to prove that such receptor interactions truly change the functional state of neurotransmitters (functional expression). Mostly, however, the peripheral effects of such neurotransmitter mechanisms (for instance prolactin secretion) are sufficiently distinct. 

For the pituitary hormones, and pancreatic hormones, analytical methods are in general available with species specific reagents for the mouse, rat, dog, pig and to a limited extent for rabbit. Steroid hormones can be measured readily by an array of analytical methods. Application of gene arrays and studies on gene expression are not recommended for single-dose experiments, repeated dose exposure is required (3-7 days). 

In regulatory studies and in mechanistic studies, one may rely on changes in tissue content for hormones like corticotropin (ACTH), prolactin and growth hormone (GH), because the tissue content of these hormones changes slowly and in a characteristic direction, whereas their plasma levels may fluctuate widely both with handling stress and due to circadian rhythm. This also indicates that one condition for mechanistic studies is to select time points of investigation for which comparative laboratory data are available, or at least publications that provide evidence that circadian rhythm does not interfere during the selected time period. 

Harvey PW, Rush KC, Cockburn A (eds) (1999) Endocrine and Hormonal Toxicology. John Wiley Sons Inc., New York Heinrich-Hirsch B, Madle S, Oberemm A, Gundert-Remy U (2001) The use of toxicodynamics in risk assessment. Toxicol Lett 120 131-141 

the precatalyst 2.59 undergoes ligand dissociation to generate the coordinatively unsaturated catalytic intermediate 5.23. Second, complexes 5.24, 5.27, 5.28, 531, and 5.32 are 18-electron complexes, while the rest are 16-electron ones. Third, there are two insertion steps insertion of the alkene into the Rh-H bond and insertion of CO into the Rh-C bond. 

It is important to note that the Unear isomer of the product would be preferentially formed if 5.24 undergoes selective conversion to 5.25. In other words, high regioselectivity toward n-butyraldehyde would be observed if insertion follows the anti-Markovnikov rather than Markovnikov pathway. Finally, conversions of 5.29 and 530 to a mixture of 5.31 and 5.32 are oxidative addition reactions, while the conversion of 5.31 and 532 to 533 is reductive elimination. 

There are good kinetic, spectroscopic, and other evidences for the proposed general mechanism of the hydroformylation reaction. The oxidative addition of dihydrogen is generally the rate-determining step. The rate of hydroformylation is found to be inversely proportional to the concentration of L, which indicates ligand dissociation. 

Rh-based hydroformylation reactions, where oidy CO is present as the ligand, have also been studied. In such a situation, a rhodium carbonyl cluster such as Rh CCO), may be used as the precatalyst. Under catalytic conditions, most of the cluster is converted to HRh(CO), and the general mechanism discussed earlier operates. Similarly, other Rh-containing precursors, such as Rh(CO)2(acac), under CO and pressure are also converted to HRh(CO).  

A nucleoside methylphosphonamidite (35) derived from indole was shown to couple with a 3 -protected thymidine to give the methylphosphonite 36 in the presence of DBU. This is a rare example of base catalysis of such reactions. The reaction was shown to be stereoselective. Similar indole derived cyclic phosphor- 

How Pt alloy catalysts achieve CO tolerance has been much debated. Two mechanisms have been proposed  

Ligand effect CO adsorption is lowered by alloying, thus decreasing CO coverage and increasing sites available for H2 adsorption/ dissociation and oxidation. 

Bifunctional effect CO oxidized by the alloying element is effective at dissociating H2O and providing OH to react with CO adsorbed on Pt and thus decreasing CO coverage. 

It is likely that both mechanisms are active and dependent on potential. At low potentials ( 200 mV) on PtRu, the bifunctional mechanism is not active because Ru is unable to dissociate adsorbed H2O to produce OH. However, above 250 mV, this does occur and CO oxidation by adsorbed OH becomes the dominant reaction in achieving CO tolerance. This is strongly related to the use of PtRu as a MeOH oxidation catalyst because CO oxidation is also the rate-determining step for this reaction. 

The effect of CO2 poisoning has been well understood. Gut et al. showed that CO is produced by a Pt anode when fed with CO2/H2 mixtures, indicating that the reverse water-gas shift reaction is active at cell operating temperatures of 70°C. ° As previously observed, this has low performance over and above that expected for dilution. Gut et al.. Ball et al., and de Bruijn et al. showed that PtRu anodes were less poisoned by CO2. Using in situ IR and mass spectroscopy measurements, Smolinka et al. showed that CO2 

NMR method of analysing the spin polarization of a non-equilibrium system of coupled nuclei in CIDNP experiments. Using Fourier analysis of the variation of NMR line intensities as a function of the radio frequency excitation pulse length, they have established a relationship between the spectral components of various harmonic order and the alignment in the spin multiplet. 

CIDNP experiments can provide various kinds of information concerning the reaction mechanism. 

Goez and Sartorius have studied the effects of solvent permittivity on the radical pair reencounter probability, as reflected in CIDNP polarization patterns of reactions involving radical ion pairs. For this purpose, they used a sensitizer radical pair anion, which converts the initially formed radical ion pair into a neutral radical pair. 

4 Localization of Radical Pairs in Micelles. CIDNP can often be enhanced by the use of micelles to enhance the recombination probability of photochemi-cally produced radical pairs. Bagranskaya et al have reviewed this techique. Goez and Heun have used Monte Carlo simulations of diffusional trajectories to calculate reencounter probabilitiies of micellized radical pairs. By varying the initial locations, they found that unless at least one of the radicals starts its diffusional trajectory extremely near the micelle boundary, the reencounter probability is essentially the same as in the case of free diffusion. It was concluded 

Lebedeva et al report theoretical and experimental studies of CIDNP generated in consecutive micellised radical pairs. They measured the radical pair escape rate in the photolysis reactions of three substrates e.g., dibenzyl ketone), and compared physico-chemical aspects of the process to that occurring in biradicals, where the escape of radical pairs is inhibited by the covalent linkage. 

The differences of stereoselectivity can be explained by the corresponding transition states (TS), even if the models are amino acid and solvent dependent. ° Unlike the proline-catalysed mechanism, the ability of the C-N bond to rotate does not constrain the enamine intermediate and therefore several transition-state structures could exist. 

As a generality, amino acids alone (proline in particular) usually favour the formation of araft-adducts, whereas an organic base can be employed as cocatalyst to improve the q -selectivity.  

Product analysis revealed that the branching C-2 atom of D-hamamelose, formed on treatment with molybdic acid, was the former C-2 atom of D-ffuc-tose, while the C-1 atom of D-hamamelose was originally the C-3 atom of the ketose. Isotope tracing tracked the origin of the only minor product, D-sorbose, to a different process, as both of its topologically most significant carbon atoms, namely C-2 and C-3, remain at the same positions as in the starting D-fructose. 

If this D-sorbose had come from a process similar to the LdB-AvE reaction, then such a final reaction mixture would also have to contain other 2-ketoses and 3-ketoses. The absence of these complementary ketoses suggests that o-sorbose is formed from D-fructose by a secondary process also catalyzed with molybdic acid, similarly to D-xylose from D-arabinose and vice versa. The other direction of the interconversion by the secondary process of both 2-ketoses was shown above by the isolation of L-fructose as the only minor product [besides the main product 2-C-(hydroxymethyl)-L-lyxose] from a reaction mixture obtained on treatment of L-sorbose with molybdic acid. 

The ketohydrol form of a 2-ketose (exemplified as D-fructose) enters the ca-talytically active tetradentate dimolybdate complex 22 which stereospecifically 

Although not yet proven, some important co-functioning during the secondary process must come also from the hemiacetal carbon atom, as no configurational changes in cyclitols such as, for example, myo-inositol, are observed under the conditions of the Bflik reaction [56]. 

Using the Berzins and Delahay equation for the case in which a single substance undergoes two consecutive charge transfer reactions (diffusion-controlled electrode processes) at sufficiently different potentials [19]  

The reduction behaviour of Ti + ions in NaCl-KCl-3 wt% K2TiFg with 10 wt% KF, at Pt electrodes, was also shown by Guang-Su et al. [10] to include charge transfer and diffusion controlled mechanisms, involving Ti4+/Ti3+ and Ti +ZTi (Pt alloy) steps. 

A reoxidation plateau can be seen whose duration is equivalent to that of the reduction plateau, which suggests the formation of a metallic deposit during this second reduction step. The equivalence of the cathodic and anodic transition times for the second and first waves, respectively, was not observed c2 / Ciox 1) which once again confirmed alloy formation and/or other chemical/electrochemical complications. 

For the more noble plateau, the peak current density, ip, was proportional to K2T1F6 concentration, at scan rates from 0.1 to 1.0 V s and to the square root of scan rate, at several Ti concentrations. Therefore, the intensity of ip, could be correlated to the potentials scanning rate by the relationship  

The peak current density at the second plateau, ij, obtained at several concentrations of K2TiF and at several scan rates, was also not proportional neither to the square root of scan rate, nor to the Ti concentration for each definite temperature. The number of electrons involved in the reaction at the second plateau, estimated by means of Equation 4.7.8, was between 2.4 and 4.0 (n2 = (2.4-i-4.0)/2 = 3.2). 

The reaction mechanism and the stereochemical diversity of the addition of water to disilene has been studied at the MP2/6-311-h+G level. Two pathways are feasible leading to syn and anti-addition. The syn addition proceeds via nucleophilic attack by water oxygen with a barrier of ca. 12 kJ mol k anti-Addition proceeds via intramolecular electrophilic attack by water hydrogen in a weakly bound disilene/water complex with antarafacial approach, in accordance with the Woodward-Hoffmann rules, and leads to an activation barrier of ca. 22 kJ mol  

Tsunoyama, K. Ohshimo, Y. Yamakita, F. Misaizu and K. Ohno, Chem. Phys. Lett., 2000,316,442. 

Kwiatkowski, J. Leszczynksi and R. Venkatraman, Spectrochim. Acta, Part A, 

The rate constants ki for the dissociation of CO from the (diphosphine)-Rh( CO)2H complexes were determined by monitoring the exchange of CO for CO by exposing the CO-labeled complexes to a large excess of CO, so any dissociated CO will be replaced quantitatively by CO. Exchange of CO turned out to be about 100 times faster than hydroformylation. Thus, a fast preequilibrium with CO exists before complexation of alkene and insertion of alkene into the Rh-H bond. 

For 1-octene l/h ratios above 100 were obtained and for internal octenes average rates of above 145 mol aldehyde mol Rh h (pressure=3.6-10 bar, T=120°C, [Rh] = l mM, [aUcene] = 640-928 mM). High regio-selectivities up to 91% toward the linear product were obtained (1/1)= 10). 

Compared to other wide-bite-angle diphosphine ligands, Xantphos-type ligands can be modified easily while retaining there favorable properties, especially in hydroformylation, and as a result many derivatives have been synthesized and used in fluorous-phase hydroformylation catalysis [72], aqueous-phase catalysis [73, 74], one-phase hydroformylation and catalyst extraction [75], catalysis in ionic liquids [76, 77], hydroformylation with immobilized catalysts [78, 79], and catalysis in supercritical CO2 [80]. 

Ligands structurally related to the xanthene backbone such as generic 37 and triptycene derived 38 were shown to be just as effective as Xantphos in hydroformylation by Ahlers and coworkers [81]. Ligand 38 gave l/b ratios as high as 100 in the hydroformylation of 1-octene (100°C, 5 bar). 

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The time-dependent Schrddinger equation governs the evolution of a quantum mechanical system from an initial wavepacket. In the case of a semiclassical simulation, this wavepacket must be translated into a set of initial positions and momenta for the pseudoparticles. What the initial wavepacket is depends on the process being studied. This may either be a physically defined situation, such as a molecular beam experiment in which the paiticles are defined in particular quantum states moving relative to one another, or a theoretically defined situation suitable for a mechanistic study of the type what would happen if. .. 

In a mechanistic study, the aim is not to quantitatively reproduce an experiment. As a result it is not necessary to use the methods outlined above. The question here is what drives a reaction in a particular direction, or what would happen if the molecule is driven in different ways. The initial conditions are then at the disposal of the investigator to be chosen in a way to answer the relevant question, using a suitable spread of positions and energies. 

For the mechanistic studies made, this protocol is able to give information about how dynamical properties affect the evolution of a photochemical reaction, but is not accurate enough for quantitative results. The information obtained relates to aspects of the surface such as the relative steepness of regions on the lower slopes of the conical intersection, and the relative width of alternative channels. 

Being able to ntn direct dynamics calculations will add an extra, important, tool to help chemists understand photochemical systems. This chapter has outlined the present standpoint of the theory and practice of such calculations showing that, although much work remains to be done, they are already bringing new insight to mechanistic studies of photochemistry. 

Unfortunately, the number of mechanistic studies in this field stands in no proportion to its versatility" . Thermodynamic analysis revealed that the beneficial effect of Lewis-acids on the rate of the Diels-Alder reaction can be primarily ascribed to a reduction of the enthalpy of activation ( AAH = 30-50 kJ/mole) leaving the activation entropy essentially unchanged (TAAS = 0-10 kJ/mol)" . Solvent effects on Lewis-acid catalysed Diels-Alder reactions have received very little attention. A change in solvent affects mainly the coordination step rather than the actual Diels-Alder reaction. Donating solvents severely impede catalysis . This observation justifies the widespread use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis-acid catalysed Diels-Alder reactions. 

Mechanistic studies have tried to unravel the origin of the special effect of water. Some authors erroneously have held aggregation phenomena responsible for the observed acceleration, whereas others have hinted at effects due to the internal pressure. However, detailed studies have identified two other effects that govern the rate of Diels-Alder reactions in water. 

A large number of mechanistic studies have established the mechanism of the catalysed reactions, which is... 

Of all the work described in this thesis, this discovery is probably the most significant. Given the fact that the arene - arene interactions underlying the observed enantioselectivity of ftie Diels-Alder reactions described in Chapter 3 are also encountered in other organic reactions, we infer that, in the near future, the beneficial influence of water on enantioselectivity can also be extended to these transformations. Moreover, the fact that water can now be used as a solvent for enantioselective Lewis-add catalysed reactions facilitates mechanistic studies of these processes, because the number of equilibria that need to be considered is reduced Furthermore, knowledge and techniques from aqueous coordination chemistry can now be used directly in enantioselective catalysis. 

Dinitrogen pentoxide being the anhydride of nitric acid, is more fully treated below, as are some other systems with which mechanistic studies have been made. 

Nitration at the encounter rate and nitrosation As has been seen ( 3.3), the rate of nitration by solutions of nitric acid in nitromethane or sulpholan reaches a limit for activated compounds which is about 300 times the rate for benzene imder the same conditions. Under the conditions of first-order nitration (7-5 % aqueous sulpholan) mesitylene reacts at this limiting rate, and its nitration is not subject to catalysis by nitrous acid thus, mesitylene is nitrated by nitronium ions at the encounter rate, and under these conditions is not subject to nitration via nitrosation. The significance of nitration at the encounter rate for mechanistic studies has been discussed ( 2.5). 

The significance of establishing a limiting rate of reaction upon encounter for mechanistic studies has been pointed out ( 2.5). In studies of reactivity, as well as settii an absolute limit to the significance of reactivity in particular circumstances, the experimental observation of the limit has another dependent importance if further structural modification of the aromatic compound leads ultimately to the onset of reaction at a rate exceeding the observed encounter rate then a new electrophile must have become operative, and reactivities established above the encounter rate cannot properly be compared with those measured below it. 

Mechanistic studies show that the arylation of alkenes proceeds via the palladation of aromatic compounds to form a rr-aryl-Pd bond (261), into which insertion of alkene takes place to form 262. The final step is i3-elimina-tion to form the arylated alkenes 259 and Pd(0). 

In connection with mechanistic studies on the Wacker reaction, the transmetallation of ri-ethoxy- and /3-hydroxyethylmercury(II) chloride with PdCB has been carried out, giving ethyl vinyl ether and acetaldehyde[366]. The reaction proceeds by the formation of ri-ethoxy- and /3-hydroxyethylpalladium chlorides (401), which decompose as soon as they are formed. 

Deuterium oxide (D2O) is water in which the protons ( H) have been replaced by their heav ler isotope deuterium ( H) It is readily available and is used in a vanety of mechanistic studies in organic chemistry and biochemistry When D2O is added to an alcohol (ROH) deuterium replaces the proton of the hydroxyl group... 

Nucleophilic acyl substitutions at the ester carbonyl group are summarized m Table 20 5 on page 849 Esters are less reactive than acyl chlorides and acid anhydrides Nude ophilic acyl substitution m esters especially ester hydrolysis has been extensively mves tigated from a mechanistic perspective Indeed much of what we know concerning the general topic of nucleophilic acyl substitution comes from studies carried out on esters The following sections describe those mechanistic studies... 

Oxidation Step. A review of mechanistic studies of partial oxidation of propylene has appeared (58). The oxidation process flow sheet (Fig. 2) shows equipment and typical operating conditions. The reactors are of the fixed-bed shell-and-tube type (about 3—5 mlong and 2.5 cm in diameter) with a molten salt coolant on the shell side. The tubes are packed with catalyst, a small amount of inert material at the top serving as a preheater section for the feed gases. Vaporized propylene is mixed with steam and ak and fed to the first-stage reactor. The feed composition is typically 5—7% propylene, 10—30%... 

J. W. Hastie and C. L. McBee, Mechanistic Studies ofFriphenylphosphine Oxide-Poly(ethylene terephthalate) and FelatedFlame Fetardant Systems, Feport NBSIF 75-741, Nad. Buieau of Standards Washington, D.C., 1975. 

Synthetic and mechanistic studies of suitably substituted aryl and alkyl carbiaols to give octahydrophenanthrenes have been reported (57). 

Mechanistic studies on the formation of PPS from polymerization of copper(I) 4-bromobenzenethiolate in quinoline under inert atmosphere at 200°C have been pubUshed (91). PPS synthesized by this synthetic procedure is characterized by high molar mass at low conversions and esr signals consistent with a single-electron-transfer mechanism, the Sj l-type mechanism described earlier (22). 

The most extensive mechanistic studies of quinone Michael addition chemistry involve the arylsufinic acids, which yield reduced product (50,51). The sulfones produced in such reactions have been examined electrochemicaHy (48) and kineticaHy (52). The influence of substitutents in the quinone has... 

The first mechanistic studies of silanol polycondensation on the monomer level were performed in the 1950s (73—75). The condensation of dimethyl sil oxanediol in dioxane exhibits second-order kinetics with respect to diol and first-order kinetics with respect to acid. The proposed mechanism involves the protonation of the silanol group and subsequent nucleophilic substitution at the siHcone (eqs. 10 and 11). 

In the 1980s, advances in biotechnology had a considerable impact on steroid research. During this period, the mechanism of steroid hormone-activated gene regulation became more clearly defined. These mechanistic studies stiH receive considerable attention in the primary Hterature. 

Mechanistic studies (6,26,27,67) have shown that the acyl enzyme species is the ring opened compound (13), which can tautomerize to the transientiy inhibited amino acrylate (14), and both of these species can react further to give irreversibly inactivated enzyme. Three inactivated forms of the enzyme have been detected. Two, according to labeling studies, retain the complete clavulanate skeleton and the other retains only the carbon chain of the P-lactam ring. Stmcture (15) has been suggested as one possible inactivated form. 

Reaction between butadiene and CO2 has been extensively studied (171) since the reaction was first demonstrated (167—170). This reaction has been shown to be catalyzed by Pd (172,173), Ni (174), Ru (175), Pt (178), and Rh (172,173) catalysts. Products include gamma (5) and delta lactones (6), acids (7,8), and esters (9). Mechanistic studies have shown that butadiene initially forms a dimer (Pd, Ru, Ni) or trimer (Rh) intermediate followed by CO2 insertion (171). The fate of these intermediates depends on the metal, the ligands, and the reaction conditions. 

Because transition metals even in a finely-divided state do not readily combine with CO, various metal salts have been used to synthesize metal carbonyls. Metal salts almost always contain the metal in a higher oxidation state than the resulting carbonyl complex. Therefore, most metal carbonyls result from the reduction of the metal in the starting material. Such a process has been referred to as reductive carbonylation. Although detailed mechanistic studies ate lacking, the process probably proceeds through stepwise reduction of the metal with simultaneous coordination of CO (90). 

Kinetic Considerations. Extensive kinetic and mechanistic studies have been made on the esterification of carboxyHc acids since Berthelot and Saint-GiHes first studied the esterification of acetic acid (18). Although ester hydrolysis is catalyzed by both hydrogen and hydroxide ions (19,20), a base-catalyzed esterification is not known. A number of mechanisms for acid- and base-catalyzed esterification have been proposed (4). One possible mechanism for the bimolecular acid-catalyzed ester hydrolysis and esterification is shown in equation 2 (6). 

A novel Af-oxide (595) was prepared by the solvolysis at room temperature of (594) in 1 1 water-dioxane. A kinetic and mechanistic study of this reaction was carried out. 

A detailed mechanistic study of the hydrolysis of 2,2-dichloroazirines (260) has been carried out and shown to be compatible with the route shown (77JPS1653). 

Mechanistic studies to identify how endocrine disrupting chemicals interact with hormone systems are required. Although population effects coupled with biomarkers of exposure are strongly suggestive of endocrine disruption, the effect could be secondary to metabolic toxicity. Establishing mechanisms may avoid the need to make decisions on a weight of evidence approach alone. 

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