NADH model, reactions

The Zincke reaction has also been adapted for the solid phase. Dupas et al. prepared NADH-model precursors 58, immobilized on silica, by reaction of bound amino functions 57 with Zincke salt 8 (Scheme 8.4.19) for subsequent reduction to the 1,4-dihydropyridines with sodium dithionite. Earlier, Ise and co-workers utilized the Zincke reaction to prepare catalytic polyelectrolytes, starting from poly(4-vinylpyridine). Formation of Zincke salts at pyridine positions within the polymer was achieved by reaction with 2,4-dinitrochlorobenzene, and these sites were then functionalized with various amines. The resulting polymers showed catalytic activity in ester hydrolysis. ... 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

The spectral characteristics of the NADH model [20] are analogous to NADH bound to glyceraldehyde-3-phosphate dehydrogenase. The acid-catalyzed hydration (3) of [20] is affected by the micelles the reaction is... 

The catalytic effect of metal ions such as Mg2+ and Zn2+ on the reduction of carbonyl compounds has extensively been studied in connection with the involvement of metal ions in the oxidation-reduction reactions of nicotinamide coenzymes [144-149]. Acceleration effects of Mg2+ on hydride transfer from NADH model compounds to carbonyl compounds have been shown to be ascribed to the catalysis on the initial electron transfer process, which is the rate-determining step of the overall hydride transfer reactions [16,87,149]. The Mg2+ ion has also been shown to accelerate electron transfer from cis-dialkylcobalt(III) complexes to p-ben-zoquinone derivatives [150,151]. In this context, a remarkable catalytic effect of Mg2+ was also found on photoinduced electron transfer reactions from various electron donors to flavin analogs in 1984 [152], The Mg2+ (or Zn2+) ion forms complexes with a flavin analog la and 5-deazaflavins 2a-c with a 1 1 stoichiometry in dry MeCN at 298 K [153] ... 

The prepared compounds systematically differed in the distance of the dihydropyridine and the flavin recognition part. Binding between flavin and the NADH model systems was proved by potentiometric pH titrations. Redox reaction between the NADH model systems and flavin was monitored by UV - VIS spectroscopy. The intensity of the long-wave absorption of flavin at 456 nm significantly decreased during the reaction and the decrease was attributed to the reduction of flavin to the fully reduced flavohydroquinone. At the same time, the intensity of the peak around 360 nm decreased as well, because of the reduction of flavin and the concerted oxidation of the 1,4-dihydronicotinamide to the corresponding pyridinium species. Kinetics of the electron transfer was studied and two reasonable kinetic models were proposed. 

To compare these two mechanisms, an NADH model without the recognition site was synthesised. The contribution of the flavin binding to the rate constant was thus evaluated and it was shown that the proximity of flavin and NADH model influenced the electron transfer rate. Mechanistic computations helped to show that with the appropriate NADH model system, both components were optimally arranged for the electron transfer. Although the exact mechanism of the reaction is still under debate, the kinetic isotope effect experiment indicated that in this case, the hydrogen at 4-position was transferred in the rate determining step which supported the hydride mechanism. 

Reichenbach-Klinke, R., Kruppa, M., Konig, B. NADH model systems functionalized with Zn(II)-cyclen as flavin binding site - Structure dependence of the redox reaction within reversible aggregates, J. Am. Chem. Soc. 124 (2002), 12999 - 13007. 

Simulation of the reverse dehydrogenase reaction induced the use of crown ethers as NADH models [124], It is shown that hydride-ion transfer by crown ethers happens 3000 times faster than in the case of different carriers. It is believed that crown ether provides for the required... 

The catalytic activity of the immobilized flavin was determined using the oxidation of an NADH-analog, namely 1-benzyl-1,4-dihydronicotinamide (BNAH), as a model reaction (Figure 8). If a potential of +0.9 V is applied to the system, hydrogen peroxide, which is formed in the aerobic oxidation of BNAH by flavin, can be oxidized... 

Irradiation of NADH model compounds in the presence of benzyl bromide or p-cyanobenzyl bromide in acetonitrile brings about reduction of the benzyl halides to the corresponding toluene compounds114. Like the S l substitution reaction, this photoreduction also occurs via an electron-transfer chain mechanism. Unlike in that case, though, here an electron transfer from the excited state of the NADH compound is solely responsible for the initiation step. In the propagation, the benzyl radical produced by C—Br bond cleavage in the radical anion abstracts hydrogen from the NADH compound. This yields a radical intermediate, from which electron transfer to benzyl bromide occurs readily (equations 39-42). 

Another use of compound (1) involves synthesis of NADH models incorporating chiral and nonchiral l/f-pyrrolo[2,3-6]pyridine derivatives. In this latter application, the products derived from compound (1) have been useful for the study of systems that were unreactive with similar reagents. By the appropriate manipulation of reaction conditions, products derived from compound (1) selectively form either (but only one) enantiomer in reduction of a prochiral ketone. Finally, the products derived from compound (1) are useful reagents in the preparation of chiral precursors of target molecules <91T429>. 

A model reaction in which UDP-D-glucose 4-epimerase was shown20,1698 to form an inactive NADH-enzyme complex on incubation with either D-glucose or D-galactose and UMP has been shown1690 to be unrelated to the epimerization reaction. The label from D-galactose-J-t was transferred to NAD, and D-galactonic acid was isolated. Oxidation therefore occurred at C-l, which is normally involved in combination with UDP. 

The same reaction attempted on similar non-cyclic enamides gave no results. The mechanism would involve a transition state in which Mg2 + is simultaneously linked to the NADH model and the substrate, through their respective carbonyl groups. Within this ternary complex an electron migrates from the NADH model to the substrate and this migration is successively followed by a proton transfer from the NADH model radical cation to the radical anion. 

The carboxyperoxyl radical anion thus produced should be similar in reactivity to the hydroperoxyl radical, HO. The nucleophilic activity of the superoxide ion towards carbonyl groups in acid chlorides, esters and ketones is well documented The reaction between superoxide ion and the Py-Py" cation radical, which leads to destruction of the latter, would seem more likely to mitigate the long-term effects of the Py-Py rather than promote damage to components of the cell d . The occurence of Rh(bipy) -mediated photoreduction of alkenes with NADH models and... 

An autorecycling system for the specific 1,4-reduction of a,p-unsaturated ketones and aldehydes was based on 1,5-dihydro-5-deazaflavin, which can be regarded as an NADH model. The reaction occurs on heating the substrate with catalytic amounts of 5-deazaflavin in 98% formic acid, typically at 120 "C for 24 h (Scheme 80). 

The effects of Mg + on hydride transfer reactions from a typical NADH model compound, 1-benzyl-1,4-dihydronicotinamide (BNAH), to substrates are complex... 

Bronsted acid catalysis in electron transfer described in Section 1.3.1 has also been effective for redox reactions via the electron transfer step. As shown in the case of metal ion-catalyzed hydride transfer reactions (see above), hydride transfer reactions from an NADH analogue to /7-benzoquinones also proceed via Bronsted acid-catalyzed electron transfer [255, 256]. Since NADH and ordinary NADH model compounds are subjected to the acid-catalyzed hydration [98, 257, 258], an acid-stable NADH model compound, 10-methyl-9,10-dihydroacridine (AcrH2), was used as a hydride donor to / -benzoquinone (Eq. 24) ... 

Pre-steady-state kinetic studies established that the appearance of the NADH chromophore on addition of substrate was a two-step process, and these steps can now be identified as closure of the active site and hydride transfer. This study indicated that the on-enzyme equilibrium for addition of water or homocysteine to the enone was close to unity (and the value in free solution), whereas the equilibrium for oxidation of NAD by bound adenosine was 10 times more favourable than in free solution. The focusing of the catalytic power of the enzyme on the oxidation step avoids the formation of abortive complexes by hydride transfer between enone and NADH, yielding 4,5-dehydroadenosine and NAD ". This happens about 10 " times faster than productive hydride transfer at the beginning and end of the catalytic cycle, with the slow rate (close to that of model reactions) apparently arising from a conformationally modulated increase in the distance the hydride has to be transferred. 

The formal transfer of hydride is a fundamental reaction in biological catalysis. The Re formyl complex GpRe(NO)(GO)(GHO), the hydricity of which was determined by equilibrium measurements (Equation (25)), engaged in a reversible hydride transfer with an NAD/NADH model system, BzNAD /BzNADH (Equation (31)). 

Scheme 2 Proposed reaction pathways between dihydropyridine compounds (PyH2) used as NADH model compounds and quinone derivatives.

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