Mechanistic probe

From a historical perspective it is interesting to note that the Nozaki experiment was, in fact, a mechanistic probe to establish the intermediacy of a copper carbe-noid complex rather than an attempt to make enantiopure compounds for synthetic purposes. To achieve synthetically useful selectivities would require an extensive exploration of metals, ligands and reaction conditions along with a deeper understanding of the reaction mechanism. Modern methods for asymmetric cyclopropanation now encompass the use of countless metal complexes [2], but for the most part, the importance of diazoacetates as the carbenoid precursors still dominates the design of new catalytic systems. Highly effective catalysts developed in... 

Adam and Lohray122 have used thianthrene 5-oxide (88) as a mechanistic probe in oxidations with transition metal peroxides. They oxidized 88 with various diperoxo complexes of chromium, molybdenum and tungsten and formulated a plausible mechanism on the basis of the products formed, 89 and 90. 

The structurally simplest silicon reagent that has been used to reduce sulphoxides is the carbene analog, dimethylsilylene (Me2Si )29. This molecule was used as a mechanistic probe and did not appear to be useful synthetically. Other silanes that have been used to reduce sulphoxides include iodotrimethylsilane, which is selective but unstable, and chlorotrimethylsilane in the presence of sodium iodide, which is easy to use, but is unselective since it cleaves esters, lactones and ethers it also converts alcohols into iodides. To circumvent these complications, Olah30 has developed the use of methyltrichlorosilane, again in the presence of sodium iodide, in dry acetonitrile (equation 8). A standard range of sulphoxides was reduced under mild conditions, with yields between 80 and 95% and with a simple workup process. The mechanism for the reaction is probably very similar to that given in equation (6), if the tricoordinate boron atoms in this reaction scheme are replaced... 

Watts AG, Withers SG (2004) The synthesis of some mechanistic probes for sialic add processing enzymes and the labeling of a sialidase from Trypanosoma rangeli. Can J Chem 82 1581-1588 Watts AG, Oppezzo P, Withers SG, Alzari PM, Buschiazzo A (2006) Structural and kinetic analysis of two covalent sialosyl-enzyme intermediates on Trypanosoma rangeli sialidase. J Biol Chem 281 4149-4155... 

Trager, W.F. (1988). Isotope effects as mechanistic probes of cytochrome P450-catalysed reactions. In Synthesis and Application of Isotopically Labelled Compounds Proceedings of the Third International Symposium T.A. Baillie and J.R. Jones (Eds.) Amsterdam Elsevier 333-340. 

The reduction ofsec-, and /-butyl bromide, of tnins-1,2-dibromocyclohexane and other vicinal dibromides by low oxidation state iron porphyrins has been used as a mechanistic probe for investigating specific details of electron transfer I .v. 5n2 mechanisms, redox catalysis v.v chemical catalysis and inner sphere v.v outer sphere electron transfer processes7 The reaction of reduced iron porphyrins with alkyl-containing supporting electrolytes used in electrochemistry has also been observed, in which the electrolyte (tetraalkyl ammonium ions) can act as the source of the R group in electrogenerated Fe(Por)R. ... 

Cunningham AF Jr (1994) Sequential Friedel-Crafts diacetylation of ferrocene interannular proton transfers as a mechanistic probe. Organometallics 13 2480-2485... 

Totten LA, U Jans, AL Roberts (2001) Alkyl bromides as mechanistic probes of reductive dehalogenation reactions of vicinal stereoisomers with zerovalent metals. Environ Sci Technol 35 2268-2274. 

I,eung LWH, Chang SC, WeaverMJ. 1989. Real-time FTTR spectroscopy as an electrochemical mechanistic probe—Electrooxidation of ethanol and related species on well-defined Pt(l 11) surfaces. J Electroanal Chem 266 317-336. 

In addition to clusterification, ligand substitution also occurs for Fe(CO)5, and in fact for most metal carbonyls. This has proved useful as a mechanistic probe of the reactive species formed during cavitation. Sonica-tion of Fe(CO)5 in the presence of phosphines or phosphites produces Fe(CO)5 L (n = 1,2, and 3). The ratio of these products is independent of length of sonication the multiply substituted products increase with increasing initial [L] Fe(CO)4L is not sonochemically converted to Fe(CO)3L2 on the timescale of its production from Fe(CO)5. These observations are consistent with the same primary sonochemical event... 

Considerable interest in the subject of C-H bond activation at transition-metal centers has developed in the past several years (2), stimulated by the observation that even saturated hydrocarbons can react with little or no activation energy under appropriate conditions. Interestingly, gas phase studies of the reactions of saturated hydrocarbons at transition-metal centers were reported as early as 1973 (3). More recently, ion cyclotron resonance and ion beam experiments have provided many examples of the activation of both C-H and C-C bonds of alkanes by transition-metal ions in the gas phase (4). These gas phase studies have provided a plethora of highly speculative reaction mechanisms. Conventional mechanistic probes, such as isotopic labeling, have served mainly to indicate the complexity of "simple" processes such as the dehydrogenation of alkanes (5). More sophisticated techniques, such as multiphoton infrared laser activation (6) and the determination of kinetic energy release distributions (7), have revealed important features of the potential energy surfaces associated with the reactions of small molecules at transition metal centers. 

Scheme 9.8 Radical clock-based mechanistic probe...

Scheme 39.9 Deuterium labeling as a mechanistic probe for hydrogenation pathways in scC02.

D. B., Ballas, S. K., King, S. B., Hydroxyurea analogues as kinetic and mechanistic probes of the nitric oxide producing reactions of hydroxyurea and oxyhemoglobin,/. Med. Chem. 46... 

J. F. Brennecke, J. E Chateauneuf, Homogeneous Organic Reactions as Mechanistic Probes in Supercritical Fluids , Chem. Rev. 1999, 99, 433-452, and references cited therein. 

Williams, D.H. Hvistendahl, G. Kinetic Energy Release As a Mechanistic Probe. The Role of Orbital Symmetry. J. Am. Chem. Soc. 1974, 96, 6755-6757. 

Structure and Function of Peptidyl Carrier Protein Domains Structure and Function of Adenylation Domains Structure and Function of Condensation Domains Structure and Function of Thioesterase Domains Multidomain NRPS Structural Information PCP-C didomain structure PCP-TE didomain structure Structure of a C-A-PCP-TE termination module Pathways to Nonproteinogenic Amino Acids Incorporated into NRP Natural Nonproteinogenic Amino Acids Present as Cellular Metabolites Modification of Proteinogenic Amino Acids Nonproteinogenic Amino Acids Derived from Multistep Pathways Tailoring Enzymology in NRP Natural Products Chemical Approaches Toward Mechanistic Probes and Inhibitors of NRPS... 

Chemical Approaches Toward Mechanistic Probes and inhibitors of NRPS Enzymes... 

Pinene hydroperoxide (PHP) when compared with r-butyl hydroperoxide has been proposed as an excellent mechanistic probe in metal-catalysed oxidations. " If inter-molecular oxygen transfer from a peroxometal species to the substrate is rate limiting, the bulky PHP is unreactive, but for reaction of an oxometal species as the rate-limiting step, little or no difference is observed and only small differences in reactivity are observed when re-oxidation of the catalyst by ROOH to an active oxometal species is the rate-limiting step. 

The enzyme chemistry of cyclopropylmethanols has been studied both as inhibitors and mechanistic probes [4, 47]. Thus, a series of alkylcyclopropyl-methanol derivatives have been proved as being inhibitors of horse liver alcohol dehydrogenase. There are two sites in the cyclopropylmethanol inhibitors able of reacting with nucleophiles ... 

A metal-nucleotide complex that exhibits low rates of ligand exchange as a result of substituting higher oxidation state metal ions with ionic radii nearly equal to the naturally bound metal ion. Such compounds can be prepared with chromium(III), cobalt(III), and rhodi-um(III) in place of magnesium or calcium ion. Because these exchange-inert complexes can be resolved into their various optically active isomers, they have proven to be powerful mechanistic probes, particularly for kinases, NTPases, and nucleotidyl transferases. In the case of Cr(III) coordination complexes with the two phosphates of ATP or ADP, the second phosphate becomes chiral, and the screw sense must be specified to describe the three-dimensional configuration of atoms. 

The ratio of the turnover number (i.e., Emax/[Etotai]) to the Xn, value of a substrate in a particular enzyme-catalyzed reaction. When kcat and are the true steady-state parameters, this ratio (or the ratio Emax/T m) is an excellent gauge of the specificity of the enzyme for that substrate. The larger the ratio, the more effective that substrate is used by the enzyme under study. In addition, the effects of a number of mechanistic probes of enzyme action on this ratio (for example, pH effects, isotope effects, temperature effects, the influence of various modifiers, etc.) can provide much information on the catalytic and binding mechanism. See... 

Proton/deuterium isotope effects on reaction rates are useful mechanistic probes. In the zirconocene-catalyzed alkene polymerization, the observed values of k .iH/feo(.2H determined by NMR fall in the range of 1.2-1.3 and support a transition state in which there is an a-agostic interaction (see 88) [132]. 

J. D. McCarter, M. J. Adam, and S. G. Withers, Binding energy and catalysis. Fluorinated and deoxygen-ated glycosides as mechanistic probes of Escherichia coli (lac Z) p-galactosidase, Biochem. J., 286 (1992) 721-727. 

---