The NAD+/NADH Redox Couple—Insights from the Perspective of Electrochemical Energy Transformation and Biomimetic Chemistry


  • Ronald L. Reyes Organometallic Chemistry Laboratory, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810
  • Koji Tanaka Institute for Integrated Cell-Material Sciences, Kyoto University, Advanced Chemical Technology Center in Kyoto (ACT Kyoto), Jibucho 105, Fushimiku, Kyoto 612-8374



NAD /NADH redox couple, redox, ruthenium, biomimetic chemistry


The constructions of various photochemical systems and catalysts have become a common theme in the realm of metal-catalyzed energy transformation. The biologically important redox couple β-nicotinamide adenine dinucleotide (NAD+)/1,4,β-dihydronicotinamide adenine dinucleotide (NADH) provides a reversible prototype system for the conversion of electrical to chemical energy via the reversible formation of a C–H bond centered on the nicotinamide ring representing an efficient system for numerous biological hydrogen-transfer reactions. In this short review, the first part emphasizes the need to construct operational system for the catalytic transformation of energy from viable sources due to the globally increasing demand in energy consumption. This is followed by a discussion on the redox chemistry of the NAD+/NADH reversible redox process centered on the nicotinamide ring as a representative chemical system enabling the efficient transformation of energy. Next, pioneering examples of NAD+/NADH mimics providing model systems that can perform non-enzymatic reactions based on the hydrogen (hydride) transfer ability of the model compounds are outlined. And lastly, several examples of ruthenium polypyridyl complexes having NAD+/NADH analogous ligands exhibiting excellent photo- and electrochemical properties similar to the NAD+/NADH redox couple are given. This is to demonstrate the importance of biomimetic chemistry in realizing novel strategies in the development of catalytic systems that can provide solutions in the alleviation or eradication of the world’s energy problems.


Ali MM, Sato H, Haga M-A, Tanaka K, Yoshimura A, Ohno T. Two-Electron Reduction of [{(bpy)2Ru(dmbbbpy)}3Ru]8+ from (BNA)2 via Photoinduced Electron Transfer [dmbbbpy = 2,2'-Bis(N-methylbenzimidazole-2-yl)-4,4'-bipyridine]. Inorg Chem. 1998;37(24).

Bardea A, Katz E, Bückmann AF, Willner I. NAD+-Dependent Enzyme Electrodes: Electrical Contact of Cofactor-Dependent Enzymes and Electrodes. J Am Chem Soc. 1997 Oct;119(39):9114–9.

Birrell JA, Hirst J. Investigation of NADH Binding, Hydride Transfer, and NAD+ Dissociation during NADH Oxidation by Mitochondrial Complex I Using Modified Nicotinamide Nucleotides. Biochemistry. 2013 Jun 11;52(23):4048–55.

Bresnahan W, Elving P. Spectrophotometric investigation of products formed following the initial one-electron electrochemical reduction of nicotinamide adenine dinucleotide (NAD+). Biochim Biophys Acta - Gen Subj. 1981 Dec 4;678(2):151–6.

Bresnahan WT, Elving PJ. The role of adsorption in the initial one-electron electrochemical reduction of nicotinamide adenine dinucleotide (NAD+). J Am Chem Soc. 1981 May;103(9):2379–86.

Brubach J-B, Mermet A, Filabozzi A, Gerschel A, Roy P. Signatures of the hydrogen bonding in the infrared bands of water. J Chem Phys. 2005 May 8;122(18):184509.

Burgess VA, Davies SG, Skerlj RT. NADH mimics for the stereoselective reduction of benzoylformates to the corresponding mandelates. Tetrahedron: Asymmetry. 1991 Jan;2(5):299–328.

Burgess VA, Davies SG, Skerlj RT. Chiral organometallic NADH mimics: stereoselective reduction of ethyl benzoylformate utilising the homochiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)] at C-3 and a chiral β-hydroxy-carboxamide derived from valinol at C-5. J Chem Soc, Chem Commun. 1990;(24):1759–62.

De Kok PMT, Bastiaansen LAM, Van Lier PM, Vekemans JAJM, Buck HM. Highly reactive and stereoselective (R)- and (S)-3-(N,N-dimethylcarbamoyl)-1,2,4-trimethyl-1,4-dihydropyridines for NADH-NAD+ mimicry. J Org Chem. 1989 Mar;54(6):1313–20.

De Kok PMT, Bastiaansen LAM, Van Lier PM, Vekemans JAJM, Buck HM. Highly reactive and stereoselective (R)- and (S)-3-(N,N-dimethylcarbamoyl)-1,2,4-trimethyl-1,4-dihydropyridines for NADH-NAD+ mimicry. J Org Chem. 1989 Mar;54(6):1313–20.

De VJG, Kellogg RM. Asymmetric reductions with a chiral 1,4-dihydropyridine crown ether. J Am Chem Soc. 1979;101(10):2759–61.

Dryhurst G. Electrochemistry of Biological Molecules. New York: Academic Press; 1977.

Elving PJ. No Title. In: Milazzo G, editor. Topics in Bioelectrochemistry and Bioenergetics. New York: Wiley-Interscience; 1976. p. 278.

Elving PJ, Bresnahan WT, Moiroux J, Samec Z. NAD/NADH as a model redox system: Mechanism, mediation, modification by the environment. J Electroanal Chem Interfacial Electrochem. 1982 Jul;141(3):365–78.

Fulton RL, Perhacs P. Sharing Analysis of the Behavior of Electrons in Some Simple Molecules. J Phys Chem A. 1998 Nov;102(45):8988–9000.

Htet Y, Tennyson AG. NAD+ as a Hydride Donor and Reductant. J Am Chem Soc. 2016 Dec 14;138(49):15833–6.

Huang J, Antonietti M, Liu J. Bio-inspired carbon nitride mesoporous spheres for artificial photosynthesis: photocatalytic cofactor regeneration for sustainable enzymatic synthesis. J Mater Chem A. 2014;2(21):7686.

Imanishi T, Hamano Y, Yoshikawa H, Iwata C. 1-Substituted (S)-3-(p-tolyl)sulphinyl-1,4-dihydropyridines: novel NADH model compounds. J Chem Soc Chem Commun. 1988;(7):473.

Khenkin AM, Efremenko I, Weiner L, Martin JML, Neumann R. Photochemical Reduction of Carbon Dioxide Catalyzed by a Ruthenium-Substituted Polyoxometalate. Chem - A Eur J. 2010 Jan 25;16(4):1356–64.

Kobayashi K, Ohtsu H, Nozaki K, Kitagawa S, Tanaka K. Photochemical Properties and Reactivity of a Ru Compound Containing an NAD/NADH-Functionalized 1,10-Phenanthroline Ligand. Inorg Chem. 2016 Mar 7;55(5):2076–84.

Koizumi TA, Tanaka K. Reversible hydride generation and release from the ligand of [Ru(pbn)(bpy)2](PF6)2 driven by a pbn-localized redox reaction. Angew Chemie - Int Ed. 2005;44(36):5891–4.

Li H, Worley KE, Calabrese Barton S. Quantitative Analysis of Bioactive NAD+ Regenerated by NADH Electro-oxidation. ACS Catal. 2012 Dec 7;2(12):2572–6.

Limoges B, Marchal D, Mavré F, Savéant J-M. Electrochemistry of Immobilized Redox Enzymes: Kinetic Characteristics of NADH Oxidation Catalysis at Diaphorase Monolayers Affinity Immobilized on Electrodes. J Am Chem Soc. 2006 Feb;128(6):2084–92.

Ma Y, Jin Z, Peng B, Ding J, Wang N, Zhou M. Investigation of Direct Electrooxidation Behavior of NADH at a Chemically Modified Glassy Carbon Electrode. J Electrochem Soc. 2015 Feb 24;162(6):H317–20.

Meyers AI, Oppenlaender T. Efficient chirality transfer between a chiral 4-methyl-1,4-dihydropyridine and benzoylformic ester. An example of a pure intermolecular self-immolative process. J Am Chem Soc. 1986 Apr;108(8):1989–96.

Mitrasinovic PM. Sharing analysis of the behavior of electrons in some simple ylides. Chem Phys. 2003 Jan;286(1):1–13.

Molnar SM, Nallas G, Bridgewater JS, Brewer KJ. Photoinitiated Electron Collection in a Mixed-Metal Trimetallic Complex of the Form {[(bpy)2Ru(dpb)]2IrCl2}(PF6)5 (bpy = 2,2’-Bipyridine and dpb = 2,3-Bis(2-pyridyl)benzoquinoxaline). J Am Chem Soc. 1994 Jun;116(12):5206–10.

Nakajima H, Tanaka K. Novel Reversible Metallacyclization in [Ru(bpy) 2 ( η 1 -napy)(CO)] 2+ (bpy = 2,2-bipyridine, napy = 1,8-naphthyridine) by Intramolecular Attack of Non-Bonded Nitrogen of napy to Carbonyl Carbon. Chem Lett. 1995 Oct;24(10):891–2.

Ohnishi Y, Kagami M, Ohno A. Reduction by a model of NAD(P)H. Effect of metal ion and stereochemistry on the reduction of .alpha.-keto esters by 1,4-dihydronicotinamide derivatives. J Am Chem Soc. 1975 Aug;97(16):4766–8.

Ohno A, Ikeguchi M, Kimura T, Oka S. Reduction by a model of NAD(P)H. 25. A chiral model which induces high asymmetry. J Am Chem Soc. 1979 Nov;101(23):7036–40.

Ohno A, Ikeguchi M, Kimura T, Oka S. Asymmetric reduction of methyl benzoylformate with a chiral NAD(P)H-model compound. J Chem Soc Chem Commun. 1978;(7):328.

Ohtsu H, Tsuge K, Tanaka K. Remarkable accelerating and decelerating effects of the bases on CO2 reduction using a ruthenium NADH model complex. J Photochem Photobiol A Chem. 2015 Dec;313:163–7.

Polyansky DE, Cabelli D, Muckerman JT, Fukushima T, Tanaka K, Fujita E. Mechanism of Hydride Donor Generation Using a Ru(II) Complex Containing an NAD + Model Ligand: Pulse and Steady-State Radiolysis Studies. Inorg Chem. 2008 May;47(10):3958–68.

Radoi A, Compagnone D. Recent advances in NADH electrochemical sensing design. Bioelectrochemistry. 2009 Sep;76(1–2):126–34.

Santhanam KS V., Elving PJ. Electrochemical redox pattern for nicotinamide species in nonaqueous media. J Am Chem Soc. 1973 Aug;95(17):5482–90.

Scipioni R, Pumera M, Boero M, Miyahara Y, Ohno T. Investigation of the Mechanism of Adsorption of β-Nicotinamide Adenine Dinucleotide on Single-Walled Carbon Nanotubes. J Phys Chem Lett. 2010 Jan 7;1(1):122–5.

Seki M, Baba N, Oda J, Inouye Y. High enantioselectivity in reductions with a chiral bis(NADH) model compound. J Am Chem Soc. 1981 Jul;103(15):4613–5.

Seki M, Baba N, Oda J, Inouye Y. High enantioselectivity in reductions with a chiral polymethylene-bridged bis(NADH) model compound. J Org Chem. 1983 Apr;48(8):1370–3.

Takeda H, Koike K, Inoue H, Ishitani O. Development of an Efficient Photocatalytic System for CO 2 Reduction Using Rhenium(I) Complexes Based on Mechanistic Studies. J Am Chem Soc. 2008 Feb;130(6):2023–31.

Tannai H, Koizumi T, Wada T, Tanaka K. Electrochemical and Photochemical Behavior of a Ruthenium(II) Complex Bearing Two Redox Sites as a Model for the NAD+/NADH Redox Couple. Angew Chemie Int Ed. 2007 Sep 17;46(37):7112–5.

Tomon T, Koizumi T, Tanaka K. Electrochemical Hydrogenation of [Ru(bpy)2(napy-κN)(CO)]2+: Inhibition of Reductive RuCO Bond Cleavage by a Ruthenacycle. Angew Chemie Int Ed. 2005 Apr 8;44(15):2229–32.

Vidugiriene J, Leippe D, Sobol M, Vidugiris G, Zhou W, Meisenheimer P, et al. Bioluminescent Cell-Based NAD(P)/NAD(P)H Assays for Rapid Dinucleotide Measurement and Inhibitor Screening. Assay Drug Dev Technol. 2014 Dec;12(9–10):514–26.

White H. Evolution of Coenzymes and the Origin of Pyridine Nucleotides. New York: Academic Press; 1982. 4-11 p.

Wouters KL, de Tacconi NR, Konduri R, Lezna RO, MacDonnell FM. Driving Multi-electron Reactions with Photons: Dinuclear Ruthenium Complexes Capable of Stepwise and Concerted Multi-electron Reduction. Photosynth Res. 2006 Jan 19;87(1):41–55.

Zhao J, Wang N-X, Wang W-W, Liu Y-H, Li L, Wang G-X, et al. A New Type of NADH Model Compound: Synthesis and Enantioselective Reduction of Benzoylformates to the Corresponding Mandelates. Molecules. 2007 May 11;12(5):979–87.




How to Cite

Reyes, R. L., & Tanaka, K. (2017). The NAD+/NADH Redox Couple—Insights from the Perspective of Electrochemical Energy Transformation and Biomimetic Chemistry. KIMIKA, 28(1), 32–43.



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