Hydride Transfer Reaction Pathway

Structure Distance [ in A] C4N... H41N Hartree Energy Relative Energy  

2 Protein-Substrate Interactions During the Hydride Transfer Reaction 

The free energy associated with the hydride ion transfer from C4 of the nicotinamide ring to C6 of the pteridine ring was computed in a manner 

It is important to note that during these simulations, the solvent molecules do not access either the N5 position or the 04 position of the substrate. This fact supports the conclusion that the ternary complex in which the proton is bound to Asp27 is a kinetically productive complex. 

Structure Ab Initio energy (Hartree Units) Relative Energy (kcal/mol) Distance N5-H2 (A) 

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SEQUENTIAL ELECTRON TRANSFER AND PROTON TRANSFER PATHWAYS IN HYDRIDE TRANSFER REACTIONS... 

The same mechanistic dichotomy for HAT reactions, one-step (concerted) HAT versus sequential (stepwise) electron and proton transfer (Scheme 2.1), is applied to hydride transfer reactions, one-step (concerted) hydride transfer versus sequential (stepwise) ET followed by proton-electron (or hydrogen) transfer.13,40 64 68 Such one-step versus multistep pathways have been discussed extensively in hydride transfer reactions of dihydronicotinamide coenzyme (NADH) and analogues, particularly including the effect of metal cations and acids, 69-79 because of the essential role of acid catalysis in the enzymatic reduction of carbonyl compounds by NADH.80 In contrast to the one-step hydride transfer pathway that proceeds without an intermediate, the ET pathway would produce radical cation hydride donors as the reaction intermediates, which have rarely been observed. The ET pathway may become possible if the ET process is thermodynamically feasible. 

Linear correlations between hydride transfer reactions of NADH analogues with (L)FeIV(0)]2 f and CI4Q in Figure 2.14 imply that the hydride transfer mechanism of (L)FeIV(0)]2+ is virtually the same as that of C14Q." Although there is still debate on the mechanism(s) of hydride transfer from NADH analogues to hydride acceptors in terms of an ET pathway versus a one-step hydride transfer pathway, the ET pathway is now well accepted for hydride transfer from NADH analogues to hydride acceptors... 

As demonstrated in this chapter, there have always been the fundamental mechanistic questions in oxidation of C-H bonds whether the rate-determining step is ET, PCET, one-step HAT, or one-step hydride transfer. When the ET step is thermodynamically feasible, ET occurs first, followed by proton transfer for the overall HAT reactions, and the HAT step is followed by subsequent rapid ET for the overall hydride transfer reactions. In such a case, ET products, that is, radical cations of electron donors and radical anions of electron acceptors, can be detected as the intermediates in the overall HAT and hydride transfer reactions. The ET process can be coupled by proton transfer and also by hydrogen bonding or by binding of metal ions to the radical anions produced by ET to control the ET process. The borderline between a sequential PCET pathway and a one-step HAT pathway has been related to the borderline between the outer-sphere and inner-sphere ET pathways. In HAT reactions, the proton is provided by radical cations of electron donors because the acidity is significantly enhanced by the one-electron oxidation of electron donors. An electron and a proton are transferred by a one-step pathway or a sequential pathway depending on the types of electron donors and acceptors. When proton is provided externally, ET from an electron donor that has no proton to be transferred to an electron acceptor (A) is coupled with protonation of A -, when the one-electron reduction and protonation of A occur simultaneously. The mechanistic discussion described in this chapter will provide useful guide to control oxidation of C-H bonds. 

Hydride-transfer reactions suffer from the several shortcomings. First, a conventional optical resolution must usually be performed to obtain an optically active carbinol, which is then converted to the halide when the Grignard method is to be used. The actual reduction is generally not the only reaction pathway hence carbinol by-product is produced. More undesirable, however, is the fact that the asymmetric center of the organometallic reagent is sacrificed when the new chiral center is created. Unless the reaction is stereospecific, which is rarely the case, a net overall decrease in chirality results. 

ReductioiMrearrangements. The reaction of the carbinol (1) and related CiiCiuO alcohols with -pentane (hydride donor) in 957 H2SO4 leads to formation of 4-homoisotwistane (2) in high yield. Dilferent products, (3) and (4), are formed when phosphoric acid serves as the acid catalyst. The paper suggests several pathways for these hydride-transfer reactions. ... 

The LST pathway is only a crude approximation to the presumed intrinsic reaction coordinate (IRC, minimum-energy pathway) that crosses through the true transition state (TS) saddle point. If possible with your ESS, find the true TS and IRC for hydride transfer reaction 1 —> 3 (Problem 4.2), and compare the optimal NLS description, charge distribution, NHO angle deviations, or other features of interest with the corresponding LST-TS features found previously. 

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack [rapid and reversible—step (1)] is by an anion—this time eCN—on the carbonyl carbon atom of one molecule, the donor (125) but instead of hydride transfer (cf. Cannizzaro, p. 216) it is now carbanion addition by (127) to the carbonyl carbon atom of the second molecule of ArCHO, the acceptor (128), that occurs. This, in common with cyanohydrin formation (p. 212) was one of the earliest reactions to have its pathway established— correctly —in 1903. The rate law commonly observed is, as might be expected,... 

Under similar conditions, reactions between pyrrolidine derivatives 632 and MTAD proceed much more slowly and less cleanly with formation of a polymeric material. When the reaction is stopped before 50% conversion is reached, starting compound 632 is isolated as the main component (c. 40%) and compound 637 as a minor product (10-14%). Mechanistically, the most difficult problem lies in the fact that a reduction step has to be involved and no particular reduction agent is present. A proposed mechanism is shown in Scheme 103. The pathway includes a Cannizzaro-type hydride transfer between dipole 633 and product 634 (keto tautomer), resulting in the formation of the iminium derivative 635, which might be responsible for the polymeric material, and hydroxy derivative 636, the direct precursor of the final products 637. The low experimental yield of 637 could be explained by this mechanism <2003EJ01438>. 

The pyridine-catalysed lead tetraacetate oxidation of benzyl alcohols shows a first-order dependence in Pb(OAc)4, pyridine and benzyl alcohol concentration. An even larger primary hydrogen kinetic isotope effect of 5.26 and a Hammett p value of —1.7 led Baneijee and Shanker187 to propose that benzaldehyde is formed by the two concurrent pathways shown in Schemes 40 and 41. Scheme 40 describes the hydride transfer mechanism consistent with the negative p value. In the slow step of the reaction, labilization of the Pb—O bond resulting from the coordination of pyridine occurs as the Ca—H bond is broken. The loss of Pb(OAc)2 completes the reaction with transfer of +OAc to an anion. 

Since the first use of catalyzed hydrogen transfer, speculations about, and studies on, the mechanism(s) involved have been extensively published. Especially in recent years, several investigations have been conducted to elucidate the reaction pathways, and with better analytical methods and computational chemistry the catalytic cycles of many systems have now been clarified. The mechanism of transfer hydrogenations depends on the metal used and on the substrate. Here, attention is focused on the mechanisms of hydrogen transfer reactions with the most frequently used catalysts. Two main mechanisms can be distinguished (i) a direct transfer mechanism by which a hydride is transferred directly from the donor to the acceptor molecule and (ii) an indirect mechanism by which the hydride is transferred from the donor to the acceptor molecule via a metal hydride intermediate (Scheme 20.3). 

In the direct transfer mechanism, the metal ion coordinates both reactants enabling an intramolecular reaction, and activates them via polarization. Consequently, strong Lewis acids including Alln and the Lnln ions are the most suitable catalysts in this type of reactions. In the hydride mechanism, a hydride is transferred from a donor molecule to the metal of the catalyst, hence forming a metal hydride. Subsequently, the hydride is transferred from the metal to the acceptor molecule. Metals that have a high affinity for hydrides, such as Ru, Rh and Ir, are therefore the catalysts of choice. The Lewis acidity of these metals is too weak to catalyze a direct hydride transfer and, vice versa, the affinity of Alm and Lnm to hydride-ions is too low to catalyze the indirect hydrogen transfer. Two distinct pathways are possible for the hydride mechanism one in which the catalyst takes up two hydrides from the donor molecule and another in which the catalyst facilitates the transfer of a single hydride. 

Of particular interest is the dinuclear Ru complex 34, the so-called Shvo catalyst [55, 56]. It has been established that, under the reaction conditions, this complex is in equilibrium with two monometal complexes (35 and 36) [57-59]. Both of these resemble catalytic intermediates in the concerted proton-hydride transfer pathway (Scheme 20.13), and will react in a similar way (Scheme 20.15) involving the six-membered transition state 37 and the reduction of the substrate via 38. 

Butene as the feed alkene would thus—after hydride transfer—give 2,2,3-TMP as the primary product. However, with nearly all the examined acids, this isomer has been observed only in very small amounts. Usually the main components of the TMP-fraction are 2,3,3-, 2,3,4-, and 2,2,4-TMP, with the selectivity depending on the catalyst and reaction conditions. Consequently, a fast isomerization of the primary TMP-cation has to occur. Isomerization through hydride- and methyl-shifts is a facile reaction. Although the equilibrium composition is not reached, long residence times favor these rearrangements (47). The isomerization pathways for the TMP isomers are shown schematically in Fig. 3. 

Several reaction pathways for the cracking reaction are discussed in the literature. The commonly accepted mechanisms involve carbocations as intermediates. Reactions probably occur in catalytic cracking are visualized in Figure 4.14 [17,18], In a first step, carbocations are formed by interaction with acid sites in the zeolite. Carbenium ions may form by interaction of a paraffin molecule with a Lewis acid site abstracting a hydride ion from the alkane molecule (1), while carbo-nium ions form by direct protonation of paraffin molecules on Bronsted acid sites (2). A carbonium ion then either may eliminate a H2 molecule (3) or it cracks, releases a short-chain alkane and remains as a carbenium ion (4). The carbenium ion then gets either deprotonated and released as an olefin (5,9) or it isomerizes via a hydride (6) or methyl shift (7) to form more stable isomers. A hydride transfer from a second alkane molecule may then result in a branched alkane chain (8). The... 

The mechanism for the iridium-catalyzed hydrogen transfer reaction between alcohols and ketones has been investigated, and there are three main reaction pathways that have been proposed (Scheme 4). Pathway (a) involves a direct hydrogen transfer where hydride transfer takes place between the alkoxide and ketone, which is simultaneously coordinated to the iridium center. Computational studies have given support to this mechanism for some iridium catalysts [18]. 

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