Hydride Transfer Mechanism

According to step 1 of the H-T methanol oxidation mechanism (Fig. 2b), there should be a direct hydride transfer (H17) from methanol to C5 of PQQ in concert with proton abstraction (HI6) by 014 of ASP, thus resulting in the formation of by- 

The gas-phase free energy barrier for transition state TSl to be formed is 29 and 33 kcaPmol with respect to the initial reactant complex for Models A and B respectively in gas-phase (Table 4). In presence of protein environment, the barrier is reduced by 6 kcal/mol for Model B, but still above the general kinetic requirements (15-20 kcal/mol). When water effects are added in addition to protein environment, the barrier gradually reduces to 20 kcal/mol (Table 4, Fig. 8). Water molecule W362 maintains hydrogen bonding with respect to both ASP303 and 05 of PQQ for this particular step. 

Selected Bond Lengths Corresponding to the Optimized Structures of Reactant (reactant of step 1), Transition States TSl, TS2 and TS3 for steps 1,2 and 3 Respectively, Intermediates INTI (Product of Step 1) and INT2 (Product of Step 2), and the Product (Final Product) During the Methanol H-T Oxidation Mechanism 

Bond length Reactant TSl INTI TS2 INT2 TS3 INT3 TS4 Product  

Energy Barriers (kcal/mol) Corresponding to Steps One to Four of the H-T Methanol Oxidation Mechanism Calculated at the BLPY/DNP Theory Level for Models A and B. 

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One suggested mechanism is that the reaction may take place by a conjugate hydride-transfer mechanism, analogous to what occurs during alcohol oxidations with NAD+. Electrons on the enolate ion might expel a (3 hydride ion, which could add to the doubly bonded NS nitrogen on FAD. Protonation of the intermediate at N1 would give the product. 

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. 

Noyori and coworkers reported well-defined ruthenium(II) catalyst systems of the type RuH( 76-arene)(NH2CHPhCHPhNTs) for the asymmetric transfer hydrogenation of ketones and imines [94]. These also act via an outer-sphere hydride transfer mechanism shown in Scheme 3.12. The hydride transfer from ruthenium and proton transfer from the amino group to the C=0 bond of a ketone or C=N bond of an imine produces the alcohol or amine product, respectively. The amido complex that is produced is unreactive to H2 (except at high pressures), but readily reacts with iPrOH or formate to regenerate the hydride catalyst. 

The kinetics and mechanisms of the oxidation of DNA, nucleic acid sugars, and nucleotides by [Ru(0)(tpy)(bpy)] and its derivatives have been reported. " The Ru =0 species is an efficient DNA cleavage agent it cleaves DNA by sugar oxidation at the 1 position, which is indicated by the termini formed with and without piperidine treatment and by the production of free bases and 5-methylene-2(5//)-furanone. Kinetic studies show that the I -C— activation is rate determining and a hydride transfer mechanism is proposed. The Ru =0 species also oxidizes guanine bases via an 0x0 transfer mechanism to produce piperidine-labile cleavages. 

Thymidine-specific depyrimidination of DNA by this and other Ru(lV) 0x0 complexes, e.g. electrocatalytically by [Ru(0)(py)(bpy)2] Vaq. formate buffer was studied and related to their Ru(IV)/Ru(ll) redox potentiis [664]. Oxidation of formate and of formic acid to CO by stoich. aT-[Ru(0)(py)(bpy)2] Vwater was studied kinetically, and a two-electron hydride transfer mechanism proposed [665]. 

Evidence for a hydride transfer mechanism (Scheme 29) for the PQQ-dependent enzyme methanol dehydrogenase (MDH) was obtained by a theoretical analysis combined with an improved refinement of a 1.9 A resolution crystal structure of MDH from Methylophilus methylotrophus in the presence of CH3OH <2001PNA432>. The alternative mechanism proceeding via a hemiketal intermediate was discounted when the observed tetrahedral configuration of the C-5 atom of PQQ in that crystal structure was shown to be the C-5-reduced form of the cofactor 198, a precursor to the more common reduced form of PQQ 199. 

The interconversion of aldoses and the respective 2-ketoses in alkaline solution may be somewhat more complex than originally supposed, as it has been reported that a partial transfer of hydrogen from C-2 of the aldose to C-l of the corresponding ketose occurs during the reaction.29 This observation is not inconsistent with isomerizations that involve 1,2-enediol intermediates. The transfer could occur as a result of a rapid conversion in which some of the protons originally at C-2 of the aldose molecules are retained by the solvent cage that surrounds the intermediate 1,2-enediol, and are, therefore, available for addition to C-l of the resulting ketose. It should be noted that other interpretations, such as hydride-transfer mechanisms, are also possible. 

In the case of chromous ions, wtc again looked for the composition of the hydrogen evolved from chromous solutions, again in the presence of isopropyl alcohol. This was the analytical technique used to detect hydrogen atoms. Again we were not able to produce any H—D but H2 only. This suggests a hydride transfer mechanism in the reducing of water by Cr(II). 

We don t observe oxidative deamination in the absence of oxidants. We may boil ethylenediamine with copper indefinitely without any chemical changes taking place. This observation is in addition to the lack of chloride-induced deamination, which conflicts with the hydride transfer mechanism. Moreover, if this mechanism did occur, it would imply a copper-induced exchange of hydrogen between the methylene group and water. 

Disproportionation has been observed frequently with thiopyrans and rarely with 4//-pyrans, and all cases involve a tetragonal carbon center (position 2 or 4) bearing at least one C—H bond. Some molecules of the substrate are aromatized to corresponding thiopyrylium or pyrylium ions and others reduced to dihydro or tetrahydro products. The relative abilities of pyrans and thiopyrans to disproportionate were interpreted within a proposed hydride transfer mechanism by a CNDO/2 method.45... 

A hydride-transfer mechanism involving protonation of the substrate has been postulated.360... 

The chemistry of flavins is complex, a fact that is reflected in the uncertainity that has accompanied efforts to understand mechanisms. For flavoproteins at least four mechanistic possibilities must be considered.1533 233 (a) A reasonable hydride-transfer mechanism can be written for flavoprotein dehydrogenases (Eq. 15-23). The hydride ion is donated at N-5 and a proton is accepted at N-l. The oxidation of alcohols, amines, ketones, and reduced pyridine nucleotides can all be visualized in this way. Support for such a mechanism came from study of the nonenzymatic oxidation of NADH by flavins, a reaction that occurs at moderate speed in water at room temperature. A variety of flavins and dihydropyridine derivatives have been studied, and the electronic effects observed for the reaction are compatible with the hydride ion mecha-nism.234 236... 

Hydride-Transfer Reactions. The hydride-transfer mechanism for rearrangement of sugars (20) yields a ketose anion (5) by direct transfer of the C-2 hydrogen atom with its electrons to C-l. Reversal of the process leads to epimerization at C-2 (Scheme II). 

Recently, Gleason and Barker studied the behavior of D-ribose in aqueous potassium hydroxide under aerobic and anaerobic conditions (15). They found that the D-arabinose formed from D-ribose-2-f contains a substantial amount of radioactivity at C-l and concluded that rearrangement of D-ribose occurs principally by the hydride-transfer mechanism. 

Oppenauer oxidation, using alkoxides other than aluminium, operates via a hydride transfer mechanism similar to the one depicted in the above Equation, although a complexation of the metal with the carbonyl group may not be present.22d Evidence for a radical mechanism was put forward in the case of the interaction between lithium isopropoxide and benzophenone.24... 

Some of the transient metal ions may react with water to give hydrogen. The reaction of Mn + with water produces H2 and not hydrogen atoms, implying a hydride transfer mechanism Mn(H20) + + H20— Mn(OH)(H20)n +2 + H2 + OH- (14). 

Photo-induced H-abstraction of anthraquinone from xanthene has been studied using nuclear polarization-detected EPR and the structure of the resulting short-lived radical pair determined.194 The retrodisproportionation reactions of a variety of styrenes with 9,10-diliydroanthracene (DHA), xanthene (XAN), and 9,10-dihydroacridine (DHAc) have been studied in order to determine if there was any evidence of the alternative hydride-transfer mechanism in competition with the proposed H-atom-transfer mechanism. No such evidence was found.195 The reaction between azulene and DHAC... 

A Cr(VI)-catalyst complex has been proposed as the reactive oxidizing species in the oxidation of frans-stibene with chromic acid, catalysed separately by 1,10-phenanthroline (PHEN), oxalic acid, and picolinic acid (PA). The oxidation process is believed to involve a nucleophilic attack of the olefinic bond on the Cr(VI)-catalyst complex to generate a ternary complex.31 PA- and PHEN-catalysed chromic acid oxidation of primary alcohols also is proposed to proceed through a similar ternary complex. Methanol- reacted nearly six times slower than methanol, supporting a hydride transfer mechanism in this oxidation.32 Kinetics of chromic acid oxidation of dimethyl and diethyl malonates, in the presence and absence of oxalic acid, have been obtained and the activation parameters have been calculated.33 Reactivity in the chromic acid oxidation of three alicyclic ketoximes has been rationalized on the basis of I-strain. Kinetic and activation parameters have been determined and a mechanism... 

The principle of the Lewis acid catalyzed rearrangements of hydrocarbons is well documented 4,81. Lewis acids react with a promotor deliberately added or present as an impurity in the reaction mixture to form carbonium ions which initiate intermolecular hydride transfers involving the hydrocarbon. These hydride transfers appear to be fairly unselective processes. While the expected tertiary > secondary > primary selectivity order is observed, the differences are significantly reduced relative to typical carbonium ion reactions. Possibly this is due to a hydride transfer mechanism which involves a pentaco-ordinate carbon transition state in which charge development on carbon would be minimized 38dh... 

There has been a resurgence of interest in proton-coupled redox reactions because of their importance in catalysis, molecular electronics and biological systems. For example, thin films of materials that undergo coupled electron and proton transfer reactions are attractive model systems for developing catalysts that function by hydrogen atom and hydride transfer mechanisms [4]. In the field of molecular electronics, protonation provides the possibility that electrons may be trapped in a particular redox site, thus giving rise to molecular switches [5]. In biological systems, the kinetics and thermodynamics of redox reactions are often controlled by enzyme-mediated acid-base reactions. 

Entries nos. 1 and 2 deal with a very common type of oxidant in organic chemistry, the so-called high-potential quinones (for a review, see Becker, 1974) which are normally considered to act as hydride-transfer reagents. Entry no. 1 is, however, unique in the sense that all substrates contain aromatic C—H bonds only, the strength of which precludes the operation of a hydride-transfer mechanism. Consequently, we see almost ideal electron-transfer behaviour, provided that E° (DDQH+/DDQH ) in TFA is set equal to 0.87 V. This value is entirely in line with those reported for other media (Becker, 1974). As we go to entry no. 2, where the substrate is difficult to oxidize and has at least one weak C—H bond, electron transfer is not feasible and hydride transfer takes place. The same holds for DDQ oxidation of substituted toluenes (Eberson et al., 1979). 

The nicotinamide ring of nicotinamide adenine dinucleotide can exist in both oxidized (NAD+) and reduced (NADH) forms, where the reduced form can be viewed as a double vinylogous amine, i.e. a double enamine. The hydrogen transfer from the C4 atom is widely believed to proceed by a hydride transfer mechanism, reminiscent of the mechanism of carbonyl reduction by metal hydrides. 

Numerous examples of radical formation during model reductions with 1,4-dihydropyridines are known The overall reaction would then be (e , H ). The reverse reaction, between an alcohol and NAD, would produce the equivalent of an alkoxide, as is also required in the hydride-transfer mechanism (Eq. 35). 

Three reaction mechanisms were considered a radical chain mechanism, a hydride transfer mechanism and an electron transfer reaction from Bu3SnH to the disilane followed by H transfer. The first mechanism should lead to high yields of BugSn2, but this was not observed. We thus assume the last mechanism, which is also in agreement with other investigated reactions of trialkylstaimanes [5-7]. 

Protium/deuterium/tritium kinetic isotope effects are often used to support hydride transfer mechanisms over single electron transfer mechanisms. However, sequential electron/proton/electron transfer mechanisms can easily show isotope effects as well. Even though the rate limiting step in the overall two electron reduction of flavin or NADH may be the isotope independent endergonic electron tunneling to form a radical intermediate state, once formed, this radical state can return the electron to recreate the... 

The core requirement for the carbanion mechanism to operate is that an active-site base must abstract the a-carbon hydrogen of the substrate, as a proton, forming a carbanion intermediate (Lederer, 1991). This would then require the equivalent of two electrons to be transferred to the flavin either with or without the formation of a covalent intermediate between the a-carbon and the flavin N-5 (Ghisla and Massey, 1989). With this in mind, it is intriguing to find that the crystal structure of D-amino acid oxidase reveals that there is no residue correctly located to act as the active-site base required for the carbanion mechanism (Mattevi et al., 1996 Mizu-tani et al., 1996). In fact, the crystallographic information available is far more consistent with this enzyme operating a hydride transfer mechanism (Mattevi et al., 1996). If this is correct then the earlier experiments on d-amino acid oxidase, which were claimed to be diagnostic of a carbanion mechanism, are ealled into question. It is important to note that similar experiments were used to provide support for a carbanion mechanism in the ease of flavocytochrome b2-... 

An examination of the flavocytochrome 2 active site, as defined by the crystal structure (Xia and Mathews, 1990), clearly shows that if His373 formed a hydrogen bond to the substrate hydroxyl, then the hydrogen on the a-carbon would be ideally placed for hydride transfer to flavin N-5 as shown in Figure 4a. Tyr254 would then come into play, stabilising the transition state (in which the a-carbon would have less sp and more sp character). Thus a hydride transfer mechanism is certainly consistent with recent... 

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