Mechanistic Consideration

Mechanistic studies have played a particrdarly important role in the development of new mthenium-carbene catalysts for olefm metathesis. The most critical aspects of their chemistry include (i) the formation of the catalytically active species from the starting mthenium-carbene complex (ii) the propagation of this species in the catalytic cycle and (iii) the ultimate decomposition of the active species. A range of mechanistic studies have revealed that the profiles of Ru-2 and Ru-4 differ significantly with respect to these points. 

NMR and UV-visible kinetics, and mass spectrometry [8], Consistent with a dissociative mechanism, catalytic turnover is inhibited by the addition of free phosphine, and enhanced by the addition of phosphine scavengers [8], 

The overall metathesis activity of this class of ruthenium-carbene catalysts is determined by the relative magnitudes of several rate constants (i) the rate constant of phosphine dissociation (fej), which dictates the rate at which the precatalyst complex enters the catalytic cycle (ii) the ratio of k i/k2. which dictates the rate of catalyst deactivation (by re-coordination of phosphine) versus catalytic turnover (by coordination of olefmic substrate and subsequent steps) and (iii) the rate constant of metallacyclobutane formation (k ), which dictates the rate of carbon-carbon bond formation. 

Catalyst Ru-4 exhibits overall superior activity and improved substrate scope relative to catalyst Ru-2. For example, Ru-4 completes simple metathesis reactions, such as the RCM of diethyl diallylmalonate or the ROMP of cyclooctadiene, at rates several orders of magnitude greater than with Ru-2. In addition, whereas catalyst Ru-2 is unreactive toward sterically congested or electronically deactivated substrates, Ru-4 successfully mediates the formation of tetra-substituted olefins in five- and six-mem-bered rings systems [9], as well as CM to form tri-substituted olefins and products containing electron-withdrawing substituents [10]. 

Case Study Developing a Ruthenium-Carbene Catalyst for Acrylonitrile Metathesis 

In the area of C—E bond construction (E = C, O, N) that proceeds via a direct C—H bond functionalization process, Rh catalysts are particularly outstanding for their high efficiency, excellent selectivity, functional group tolerance, and wide range of synthetic utility. Over the course of the past decade, considerable efforts on Rh-catalyzed C—H bond functionalization reactions have 

Pioneered by the seminal work of Lim and Kang on the alkylation of C—H bond using a rhodium catalyst, the chelation-assisted Rh-catalyzed C—H bond functionalization reactions for new C—C bond construction have witnessed significant improvements. Various aromatic, vinylic, and even allylic C—H bonds were found possible to be cleaved by a chiral Rh catalyst. The formed C—Rh species can readily react with common unsaturated functionalities such as alkenes, alkynes, allenes, and even ketones and imines. 

Notably, the reaction of vinyl ether substrate (X = O) could be conducted at room temperature. In addition, the indole-based substrate could also cyclize rapidly and gave the tricyclic product 108, the core of the protein kinase C (PKC) inhibitor, in 90% yield and 70% ee. 

Notably, this stereoselective catalytic transformation provides facile access to a wide range of chiral dihydrobenzofurans 115 with diverse substitution patterns which are frequently found as the core structure of biologically active compounds. 

Despite these notable advances in the Rh-catalyzed enantioselective C(sp )—H bond alkylation reactions, the enantioselective C(sp )—H bond 

Since fluorine is less than 1 % dissociated at room temperature, the concentration of fluorine atoms may not be sufficient to initiate a radical chain process. An alternative initiation step lb (Table 1), originally suggested by Miller [31-33], probably occurs but conclusive evidence for this pathway has not been established. 

Due to the highly exothermic nature of the process, the replacement of primary, secondary and tertiary hydrogens upon reaction with electrophilic fluorine atoms is not as selective as for other radicals. For example, early work by Tedder [30,34], showed that the order of selectivity follows the usual pattern, i. e. tert sec prim, but the relative selectivity of fluorine atoms is less than chlorine atoms (Table 2). 

Indeed, it has recently been shown by Rozen [13] that tertiary carbon-hydrogen bonds can be selectively replaced by carbon-fluorine bonds when the reaction is carried out in a polar solvent at low temperature,but it was suggested that an electrophilic process involving a carbocationic transition state is occuring in these instances (see 3.1.1.1). 

Further fluorination of hydrofluorocarbons becomes increasingly difficult as a perfluorination reaction proceeds, for a number of reasons. The deactivating effect of a fluorine substituent in a hydrocarbon can be seen in the retardation of the rate of fluorination of 1-fluorobutane as compared to -butane (Table 3) and, furthermore, the relative selectivity values obtained upon fluorination of 

1-fluorobutane (Table 3) [35] show that fluorination of the CH2F group is more difficult than both CH2 and CH3 groups. 

Given the structural similarity of intermediates A and E, and also of B and D, it seems obvious that each reaction step in the cycle is potentially reversible. The equilibrium is shifted, however, into the desired direction by the steric shielding of the sacrificial hydrogen acceptor, which makes the reductive elimination of TBA an essentially irreversible process. 

Kinetic analyses and deuterium-labeling experiments have demonstrated that, remarkably, the reductive elimination of TEA and the formation of intermediate C is the rate-determining step in the (de)hydrogenation cycle. Accordingly, hydrogenation of the acceptor appears to be slower than dehydrogenation of the alkane substrate. This contrasts with the fact that catalytic olefin hydrogenation is well-established in transition-metal-mediated chemistry [10]. 

The existence of the coordinatively unsaturated complex C also rationalizes the sensitivity of the catalyst towards weakly coordinating species such as N2 and heterocycles, as well as towards substrates containing more labile C—H bonds, such 

Tliouglt OUT knowledge about catalyst surfaces has increased significantly in recent years due to the introduction and application of new analytical methods, it remains difficult to decide w hich mechanism is operative. The different proposals will be discussed briefly io point out the state of present understanding (11,12, 152-1551. 

As mentioned above, many transition metals catalyze the cyclooligomerization of 1,3-dienes. The nickel-catalyzed cyclooligomerization of BD, however, is probably one of the best-understood reactions in the field of homogeneous catalysis. In the 40 years since its discovery a mass of evidence has been collected, indicating that these oligomerizations are the result of a multistep addition-elimination mechanism at a nickel atom template, which constantly flips between two oxidation states. The following strategies played an important role isolation of key intermediates, simulation of the catalytic cycle in a stoichiometric manner, product analysis, and study of model compounds. Detailed analysis of the intellectual development of the mechanism is not included here as this can be followed from excellent reviews [6]. 

Some typical examples of cyclooligomerization catalysts other than nickel are listed in Table 5 and 6. Examination of these reactions indicates that the mechanisms are closely related to each other. They all seem to proceed via allylic intermediates in a stepwise oxidative insertion (addition)/reductive coupling (elimination) fashion while the metal center undergoes changes in the formal oxidation state (viz. Fe -Fe Ti -Ti Cr -Cr Co -Co Mn -Mn Mo -Mo Ni°-Ni [6b]. 

Higher cyclooligomers of BD with ring sizes between 16 and 28 can be synthesized as a mixture using a two-component nickel catalyst [Ni2(7/ -allyl)3Cl] [52], Fourteen membered rings can easily be obtained from two molecules of BD and one molecule of 1,3,5-hexatriene on ligand-free nickel catalysts, which are typical trimerization catalysts (eqs. (19) and (20)) [53]. 

Epoxy resins may be cured in the manner of polyadditions, i. e., homogeneously catalyzed by multifunctional amines and isocyanates, or cyclic anhydride, dicyan-diamide, or biguanide derivatives. On the other hand epoxy resins are also subject to homopolymerization. The catalysts represent Lewis bases, preferably tertiary amines, imidazoles, or ureas (the latter exclusively for the dicyandiamide curing) 

A purely cationic curing can be induced by Lewis acids such as AICI3, BF3, ZnCl2, TiCU, or FeBr3. The cationic polymerization of the epoxy resins has received little attention and is mentioned only in connection with photo- or radiation chemistry initiation. 

In general, aldehydes are more easily reduced than carboxylic acids. A high yield of aldehyde over this catalyst is a result of, as mentioned above, the reaction equilibrium between benzaldehyde and benzyl alcohol is on the side of benzaldehyde. Strong interaction of benzoic acid with the catalyst surface is believed to suppress consecutive reaction of benzaldehyde, resulting in high aldehyde selectivity. There might also be an equilibrium between benzoic acid and benzaldehyde. The reverse reaction between benzaldehyde and water over Z1O2 forms 

Pqa the partial pressures of hydrogen and carboxylic acid, and a, f), and y are reaction orders. Eq. (4) suggests that the rate-determining step is activation of a hydrogen molecule via dissociative adsorption, p is negligibly small and a and y are nearly 1 and 2, respectively [19]. 

Onishi et al. [20] reported that molecular hydrogenation is activated on Zr02 by dissociative adsorption. This may show the validity of the current study. 

Domen et al. reported that the surface carboxylate is formed by adsorption of acid via interaction of the acid group with Zr02 and Cr -modified Zr02 

We wish to thank all our collaborators who are involved in the work reported here  

Herlihy, B. A. Ley, S. J. Lippard, K. E. Liu, S. G. Lloyd, L. Mangravite, S. E. Parkin, A. S. Pereira, N. Ravi, P. Riggs-Gelasco, W. Small, J. Stubbe, E. C. Theil, P. Tavares, W. H. Tong, A. M. Valentine, A. Vicol, and D. Wang. Research from our laboratory reported in this chapter has been supported by an NIH grant GM47295. 

Frank Rusnak, Pamela Mertz, Tiffany Reiter and Lian Yu 

Despite their limited set of functional groups, ribozymes can accelerate complex organic transformations like Diels-Alder reactions between small molecules in a way similar to protein enzymes or supramolecular catalysts featuring multiple turnover, substrate specificity and stereoselectivity. The three-dimensional sbucture shows striking similarities with proteins evolved for similar reactions, and the catalytic strategies used appear to be similar as well. 

Cochrane, S. A. Strobel, Catalytic strategies of self-cleaving ribozymes, Acc. Chem. Res., 2008, 41, 1027-1035. 

The Genetic Code The Molecular Basis for Genetic Expression, Harper Row, New York, 1967. 

Klussmann (Ed.) The Aptamer Handbook - Functional Oligonucleotides and Their Applications, Wiley VCH, Weinheim, 2006. 

Cholesterol esterase activity by in vitro selection of RNA against a phospate transition-state analogue, J. Am. Chem. Soc., 1999, 121, 10844-10845. 

Although a seemingly simple transformation, the mechanism for the proline-catalysed aldol reaction and for other related addition reactions has been the source of much scientific debate and discussion over the last decade. Some issues of contention have included understanding the complex equilibria governing intermediate formations, the stereochemical 

Nature eontinues to excel at facile synthesis of asymmetric molecules under mild eonditions, and has constantly served as a wellspring of knowledge and strategies. Aldolase enzymes are merely another example of Nature s prowess, in their ability to perform asymmetric aldol reactions with unactivated and unprotected highly functionalised carbonyl groups under mild eonditions with impressive efficieneies and ehemoselectivities. In light of sueh enzymatie reactions, the mechanism for the Hajos-Parrish-Eder-Sauer-Wieehert reaction was postulated to oeeur via a similar pathway to elass I aldolase-eatalysed reactions. 

Another issue of contention was whether the proline-catalysed aldol condensation occurred via a one-proline or two-proline model. Agami proposed a two-enamine model where the first proline molecular formed the enamine intermediate, while the second proline exploited its bifunctional 

In terms of stereochemical considerations, proline-catalysed aldol reactions are proposed to occur via a metal-free Zimmerman-Traxler transition state, which has been supported by computational studies indicating that this is the most energetically favourable and consistent in predicting stereochemical outcomes.  

In general, proline-catalysed reactions and aminocatalysis continue to offer new mechanistic insights. As further experimental and computational 

Within this sequence reactivity towards a particular silylating reagent will also be influenced by steric hindrance hence the ease of reactivity for alcohols follows the order  

The trans effect of the halide anion favors dissociation of one phosphorus 

In the early days of industrial aromatic chemistry, reaction mechanisms were completely unknown. Their elucidation, especially in the 1930 s and 1940 s together with considerable improvements in analytical techniques for identifying intermediates and by-products, was enormously important for the industrial aromatic chemistry. It is hardly possible to design and equip modem processes without in-depth knowledge of the reaction mechanisms. 

Ethyl acrylate, the hydroformylation of which has been studied many times, is an interesting case. Tanaka et al. [66] found that the ratio of l b could be varied from 100 0 (80 °C and 1 bar) to 1 99 (40 °C and 30 bar) by using a rhodium catalyst and triphenyl phosphite as the ligand. Electronic arguments lead to the same result as for trifluoropropene because the frontier orbitals on ethyl acrylate are the same. Thus, high pressures lead to the expected result. 

In a broad range of conditions the rate laws for the rate of formation of the linear and the branched product are different, which explains the enormous influence tiiat tiiese have on the product distribution. At low CO pressures the enolate-rhodium species may be the resting state of the catalyst. Species of this type often undergo hydrogenation instead of hydro formy lation. 

For styrene the reactivity pattern is less obvious. The assumption that there is an early transition state does not lead to a simple conclusion, because the coefficients of both the LUMO and the HOMO of styrene are higher on the terminal carbon atom. If the interaction of the HOMO on the Rh-H 

Insertion of styrene does not always lead to branched alkyl species. Insertion of styrene into a cationic palladium hydride species may give purely linear alkyl species, but perhaps not for steric reasons [67]. An early transition state for this process may involve the interaction of the LUMO for PdH, which has the highest coefficient on palladium, with the HOMO of styrene, which has the highest coefficient on the terminal carbon atom. 

Hydroformylation Using the Reversed Water Gas Shift (RWGS) or Methyl Formate 

An intrinsic problem that has to be overcome in the future is posed by the low partial concentration of CO. This leads to low reaction rates of hydroformylation. 

Virtually all diastereoselective and enantioselective reactions are based on a kinetic phenomenon if the rate constant of the reaction 

The enantiomeric or diastereomeric ratio is simply the ratio of the rate constants. 

The Arrhenius equation gives the relationship between the rate constant and the activation energy. 

It is important to note the dependence of the selectivity achieved on the reaction temperature. For a given value of AE, lowering the temperature will lead to increased selectivity (but also to a slower rate). Many asymmetric reactions are carried out well below room temperature, in some cases as low as -120°C, in order to achieve the maximum selectivity. 

Let us now consider in more detail the nature of this difference in activation energy. The transition states leading to the/ and Sproducts are diastereomeric, and therefore non-equivalent, and of different energies. In most of the stereodifferentiating reactions described in this book the key step involves preferential addition from the/ e or 5/ face to a trigonal carbon, which is usually unsaturated. 

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It can be concluded, as already stated above, that the diminution in intermolecular selectivity observed in these nitrations with nitronium salts in organic solvents does not of itself require any special mechanistic considerations as regards the process of substitution. 

A rational classification of reactions based on mechanistic considerations is essential for the better understanding of such a broad research field as that of the organic chemistry of Pd. Therefore, as was done in my previous book, the organic reactions of Pd are classified into stoichiometric and catalytic reactions. It is essential to form a Pd—C cr-bond for a synthetic reaction. The Pd— C (T-bond is formed in two ways depending on the substrates. ir-Bond formation from "unoxidized forms [1] of alkenes and arenes (simple alkenes and arenes) leads to stoichiometric reactions, and that from oxidized forms of alkenes and arenes (typically halides) leads to catalytic reactions. We first consider how these two reactions differ. 

Another method for the hydrogenoiysis of aryl bromides and iodides is to use MeONa[696], The removal of chlorine and bromine from benzene rings is possible with MeOH under basic conditions by use of dippp as a ligand[697]. The reduction is explained by the formation of the phenylpalladium methoxide 812, which undergoes elimination of /i-hydrogen to form benzene, and MeOH is oxidized to formaldehyde. Based on this mechanistic consideration, reaction of alcohols with aryl halides has another application. For example, cyclohex-anol (813) is oxidized smoothly to cyclohexanone with bromobenzene under basic conditions[698]. 

It is possible to balance all of these thermodynamic, kinetic, and mechanistic considerations and to prepare well-defined PTHF. Living oxonium ion polymerizations, ie, polymerizations that are free from transfer and termination reactions, are possible. PTHF of any desired molecular weight and with controlled end groups can be prepared. 

Numerous other penicillin sulfones have been reported to be P-lactamase inhibitors, as illustrated in Table 5. The effect of C-6 substituents has been extensively explored starting with 6-APA sulfone (25, R = NH2, R = H, R" = R " = CH ), which has modest activity. Mechanistic considerations led to preparation of sulfones of poor substrates, compounds such as methicillin, cloxaciUin, nafaciUin, and quinaciUin sulfone (25,... 

Equation 1 is referred to as the selective reaction, equation 2 is called the nonselective reaction, and equation 3 is termed the consecutive reaction and is considered to proceed via isomerization of ethylene oxide to acetaldehyde, which undergoes rapid total combustion under the conditions present in the reactor. Only silver has been found to effect the selective partial oxidation of ethylene to ethylene oxide. The maximum selectivity for this reaction is considered to be 85.7%, based on mechanistic considerations. The best catalysts used in ethylene oxide production achieve 80—84% selectivity at commercially useful ethylene—oxygen conversion levels (68,69). 

The P configuration at C-6 is based on mechanistic considerations and analysis of optical rotatory dispersion curves. 

The benzidine rearrangement is of interest for mechanistic considerations. The preparative applicability may be limited because of the many side products, together with low yields. Furthermore benzidine is a carcinogenic compound. ... 

Juba, M. R., A Review of Mechanistic Considerations and Process Design Parameters for Precipitation Polymerization, in Polymerization Reactions and Processes, ACS Symposium Series No. 104, Washington D.C., 1979, pp. 267-279. 

The ultimate purpose of mechanistic considerations is the understanding of the detailed reaction pathway. In this connection it is important to know the structure of the active catalyst and, closely connected with this, the function of the cocatalyst. Two possibilities for the action of the cocatalyst will be taken into consideration, namely, the change in the oxidation state of the transition metal and the creation of vacant sites. In the following, a few catalyst systems will be considered in more detail. 

The preferred kinetic model for the metathesis of acyclic alkenes is a Langmuir type model, with a rate-determining reaction between two adsorbed (complexed) molecules. For the metathesis of cycloalkenes, the kinetic model of Calderon as depicted in Fig. 4 agrees well with the experimental results. A scheme involving carbene complexes (Fig. 5) is less likely, which is consistent with the conclusion drawn from mechanistic considerations (Section III). However, Calderon s model might also fit the experimental data in the case of acyclic alkenes. If, for instance, the concentration of the dialkene complex is independent of the concentration of free alkene, the reaction will be first order with respect to the alkene. This has in fact been observed (Section IV.C.2) but, within certain limits, a first-order relationship can also be obtained from many hyperbolic models. Moreover, it seems unreasonable to assume that one single kinetic model could represent the experimental results of all systems under consideration. Clearly, further experimental work is needed to arrive at more definite conclusions. Especially, it is necessary to investigate whether conclusions derived for a particular system are valid for all catalyst systems. 

Particularly interesting examples of mechanistic considerations can be found in the work of Graham [124-126], Schubert [127,128] and Crabtree [129]. Cophotolysis of hexamethylbenzenechrom- (or tungsten) tricarbonyl or Cp Mn(CO)3 with diphenylsilane yields, after cleavage of CO, a side-on coordinated silane with a M(H)Si 3c2e bond 30 [130, 131],... 

Simple mechanistic considerations easily explain why heterolytic dissociation of the C — N bond in a diazonium ion is likely to occur, as a nitrogen molecule is already preformed in a diazonium ion. On the other hand, homolytic dissociation of the C —N bond is very unlikely from an energetic point of view. In heterolysis N2, a very stable product, is formed in addition to the aryl cation (8.1), which is a metastable intermediate, whereas in homolysis two metastable primary products, the aryl radical (8.2) and the dinitrogen radical cation (8.3) would be formed. This event is unlikely indeed, and as discussed in Section 8.6, homolytic dediazoniation does not proceed by simple homolysis of a diazonium ion. 

A Review of Mechanistic Considerations and Process Design Parameters for Precipitation Polymerization... 

Safe, S. (1990). PCBs, PCDDs, PCDFs and related compounds Environmental and mechanistic considerations which support the development of toxic equivalency figures. CRC Critical Reviews in Toxicology 24, 1-63. 

Under these conditions, although nitrosamine formation appears to occur to some extent, formation of an unknown product (or set of products) is also observed. On the basis of mechanistic considerations we believe this product to be primarily a nitroso-hydrazine. Upon photolysis, this compound may give rise to an N-nitrohydrazine, or, when O3 is present, to the nitrosamine. 

Thus, decarboxylase of disubstituted malonic acid could be easily converted to racemase of the corresponding monobasic acid, in spite of the fact that decarboxylation and racemization are quite different from each other. The key for the success is the mechanistic consideration focusing on the fact that the intermediate of both reactions is the same type of enolate of monobasic carboxylic acid. 

Stevenson DE, JN Wright, M Akhtar (1988) Mechanistic consideration of P-450 dependent enzyme reactions studies on oestriol biosynthesis. J Chem Soc Perkin Trans I 2043-2052. 

Burch, R., Sullivan, J.A. and Watling, T.C. (1998) Mechanistic considerations for the reduction of NOx over Pt/A1203 and A1203 catalysts under lean-burn conditions. Catal. Today, 42, 13. 

There are distinct advantages of these solvent-free procedures in instances where catalytic amounts of reagents or supported agents are used since they provide reduction or elimination of solvents, thus preventing pollution at source . Although not delineated completely, the reaction rate enhancements achieved in these methods may be ascribable to nonthermal effects. The rationalization of microwave effects and mechanistic considerations are discussed in detail elsewhere in this book [25, 193]. A dramatic increase in the number of publications [23c], patents [194—203], a growing interest from pharmaceutical industry, with special emphasis on combinatorial chemistry, and development of newer microwave systems bodes well for micro-wave-enhanced chemical syntheses. 

House, J. E. (1993). "Mechanistic Considerations for Anation Reactions in the Solid State." Coord. Chem. Rev. 128, 175-191. 

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