Preferred pathway mechanism, initial

The kinetics with all the substrates and isotope exchange studies are consistent with the preferred pathway mechanism described in Section II,B,4. With secondary alcohols, hydride transfer is slow, the steady-state concentration of the reactant ternary complex is large, and leak of NAD from this complex occurs thus, < a = Ak- /kki (Table I) and is different for different alcohols. With primary alcohols as substrates, hydride transfer and aldehyde dissociation are much faster than NADH dissociation. Under initial rate conditions, therefore, the ternary complex is not present in significant steady-state concentration, and dissociation of NAD from it does not occur to an appreciable extent thus, 4> = 1/ki, and like < o is the same for all primary alcohols. 

The conclusion that even with the best substrate, ethanol, dissociation of NAD occurs from the active ternary complex is consistent with the evidence-from isotope exchange experiments 32), mentioned previously, that the dissociation of coenzyme is not greatly suppressed in the ternary complex compared with the binary complex, in contrast to liver alcohol dehydrogenase. This is also indicated by the initial rate data in another way 4>a/4>o for the preferred pathway mechanism approximates to the dissociation constant for NAD from the ternary complex (Table I), and is reasonably constant for the three primary alcohols and approximately equal to the dissociation constant of E-NAD, determined independently 40). 

MMM [68] have also studied the reaction mechanism for RhCl(PH3)2 -f C2H4 -I- BH3 -> RhCl(PH3)2 -I- C2H5BH2 catalytic reaction without dissociation of phosphine ligands and have found that (i) the mechanism involving olefin insertion into the Rh-B bond is a few kilocalories per mole more favorable than that for insertion into Rh-H bond and (ii) in the preferable pathway, BH3 reacts with the catalyst before olefin does. Thus, for this reaction occurring without dissociation of a PH3 group the initial formation of a C-B bond is more favorable than initial formation of a C-H bond. DS [69] have studied the mechanism of this reaction with dissociation of one of PH3 ligands upon coordination of olefin and have shown that the insertion of olefin into the Rh-H bond is a few kilocalories per mole more favorable than that into the Rh-B bond. 

Lewis et al.106 calculated four possible decomposition pathways of the ot-HMX polymorph N-N02 bond dissociation, HONO elimination, C-N bond scission, and concerted ring fission. Based on energetics, it was determined that N-N02 dissociation was the initial mechanism of decomposition in the gas phase, whereas they proposed HONO elimination and C-N bond scission to be favorable in the condensed phase. The more recent study of Chakraborty et al.42 using density functional theory (DFT), reported detailed decomposition pathways of p-HMX, which is the stable polymorph at room temperature. It was concluded that consecutive HONO elimination (4 HONO) and subsequent decomposition into HCN, OH, and NO are the most energetically favorable pathways in the gas phase. The results also showed that the formation of CH20 and N20 could occur preferably from secondary decomposition of methylenenitramine. 

The first steps involve coordination and cycloaddition to the metal. Insertion of a third molecule of ethene leads to a more instable intermediate, a seven-membered ring, that eliminates the product, 1-hexene. This last reaction can be a (3-hydrogen elimination giving chromium hydride and alkene, followed by a reductive elimination. Alternatively, one alkyl anion can abstract a (3-hydrogen from the other alkyl-chromium bond, giving 1-hexene in one step. We prefer the latter pathway as this offers no possibilities to initiate a classic chain growth mechanism, as was also proposed for titanium [8]. The byproduct observed is a mixture of decenes ( ) and not octenes. The latter would be expected if one more molecule of ethene would insert into the metallocycloheptane intermediate. Decene is formed via insertion of the product hexene into the metallo-cyclopentane intermediate followed by elimination. 

Unlike ATM, which strongly prefers DSBs, ATR is a broad-spectrum signal initiator. Various types of replication interference, such as those induced by UV irradiation or ribonucleotide reductase inhibitor Hydroxyurea (HU), strongly elicit the ATR pathway. This versatility and the pivotal role of ATR in cell viability and genomic stability has prompted an intensive investigation into the mechanism(s) by which ATR senses different types of DNA damage and activates the checkpoint. 

This example also illustrates one of the pitfalls of attempting to elucidate a mechanistic pathway. The use of alkyl groups, such as methyl and ethyl, to label certain carbon atoms changes their character from, say, primary to secondary, and this may have an effect on the mechanism that is being studied. The use of deuterium labels may be preferred, but requires the initial stereoselective synthesis of such compounds, and this might be difficult. Furthermore, it must be possible to distinguish between the various isotopic products, otherwise no useful information will be gained. 

Another, related type of reaction is the halodifluoromethylation of nucleophiles by dihalodifluoromethanes (e.g. CF2Br2) [9]. This reaction is always initiated by a single electron transfer from the nucleophile to the CF2XY species (X and Y denote halogens other than fluorine). The subsequent fate of the resulting radical ion pair depends on the ability of the nucleophile to form a stabilized radical, and also on the choice of solvent [10]. For phenoxides [4a, 5, 11] and thiophenoxides [4c, Ila] a reaction pathway via difluorocarbene is usually preferred whereas enamines and ynamines are halodifluoromethylated by a radical chain mechanism (see also Section 2.2.1) [12] (Scheme 2.169). 

As in the uncatalyzed reactions with enamines (vide supra), there is potentially more than one point where stereochemical differentiation can occur (Scheme 59). Selectivity can occur if the initial addition of the enol ether to the Lewis acid complex of the a,/J-unsaturated acceptor (step A) is the product-determining step. Reversion of the initial adduct 59.1 to the neutral starting acceptor and the silyl enol ether is possible, at least in some cases. If the Michael-retro-Michael manifold is rapid, then selectivity in the product generation would be determined by the relative rates of the decomposition of the diastereomers of the dipolar intermediate (59.1). For example, preferential loss of the silyl cation (or rm-butyl cation for tert-butyl esters step B) from one of the isomers could lead to selectivity in product construction. Alternatively, intramolecular transfer of the silyl cation from the donor to the acceptor (step D) could be preferred for one of the diastereomeric intermediates. If the Michael-retro-Michael addition pathway is rapid and an alternative mechanism (silyl transfer) is product-determining, then the stereochemistry of the adducts formed should show little dependence on the configuration of the starting materials employed, as is observed. 

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