Representative publications of Prof Eiichi Nakamura
A. Base metal catalysis and mechanism
*Accounts: Mechanisms of Nucleophilic Organocopper(I) Reactions, N. Yoshikai, E. Nakamura, Chem. Rev., 112, 2339-2372 (2012); Iron-Catalyzed Cross-Coupling Reactions, Eiichi Nakamura, Takuji Hatakeyama, Shingo Ito, Kentaro Ishizuka, Laurean Ilies, and Masaharu Nakamura, Organic Reactions, 83, 1–209 (2014). Iron-Catalyzed C-H Bond Activation, R. Shang, L. Ilies, E. Nakamura, Chem. Rev., 117, 9086–9139 (2017).
1. Reaction Pathway of Conjugate Addition of Lithium Organocuprate Clusters to Acrolein, E. Nakamura, S. Mori, and K. Morokuma, J. Am. Chem. Soc., 119, 4900-4910 (1997).
2. Theoretical Studies on the Addition of Polymetallic Lithium Organocuprate Clusters to Acetylene. Cooperative Effects of Metals in A Trap-and-Bite Reaction Pathway, E. Nakamura, S. Mori, M. Nakamura, and K. Morokuma, J. Am. Chem. Soc., 119, 4887-4899 (1997).
These studies combined experiment and theory to clarify how lithium organocuprate clusters react with unsaturated substrates. For both acrolein and acetylene, a trap-and-bite mechanism was established in which multiple lithium and copper centers act cooperatively to stabilize intermediates and control selectivity, providing a general framework for understanding polymetallic organocuprate reactivity.
3. Iron-Catalyzed Cross-Coupling of Primary and Secondary Alkyl Halides with Aryl Grignard Reagents, M. Nakamura K. Matsuo S. Ito and E. Nakamura, J. Am. Chem. Soc., 126, 3686–3687 (2004). Cited 602 times.
This publication represents a clear message on the value of iron catalysis in organic chemistry. Seeing that the iron-catalyzed reaction works so well, many people started to shift their research focus from precious metals to iron and other base metals.
4. Iron-Catalyzed Direct Arylation through Directed C-H Bond Activation, J. Norinder, A. Matsumoto, N. Yoshikai, and E. Nakamura, J. Am. Chem. Soc., 130, 5858-5859 (2008). Cited 384 times.
This paper reports the first example of C–H bond activation for organic synthesis using iron catalysis. An iron complex promotes nitrogen-directed C–H activation of heteroaromatics with arylzinc reagents at 0 °C, achieving direct arylation in high to near-quantitative yields.
5. Synthesis of Anthranilic Acid Derivatives through Iron-Catalyzed Ortho Amination of Aromatic Carboxamides with N-Chloroamines, T. Matsubara, S. Asako, L. Ilies, E. Nakamura, J. Am. Chem. Soc., 136, 646–649 (2014). Cited 274 times.
This highly cited communication reported the first example of iron-catalyzed conversion of C–H bond to C–N bond, providing a venue for the synthesis of pharmaceutically important aryl amines.
6. Homocoupling-free Iron-catalysed Twofold C–H Activation/Cross-couplings of Aromatics via Transient Connection of Reactants, T. Doba, T. Matsubara, L. Ilies, R. Shang, E. Nakamura, Nat. Catal. 2, 400-406 (2019). Cited 78 times.
This work reports a homocoupling-free iron-catalyzed two-fold C–H activation/cross-coupling of arenes, enabled by introducing an ionic handle on one coupling partner to enforce a defined sequence of C–H activations and prevent self-coupling side reactions. Transient “connection” between reactants under the iron catalysis orchestrates selective cross-coupling without homocoupled byproducts.
7. Iron-Catalysed Regioselective Thienyl C–H/C–H Coupling, T. Doba, L. Ilies, W. Sato, R. Shang, E. Nakamura, Nat. Catal., 4, 631–638 (2021). Cited 37 times.
This publication reports polymerization by C–H/C–H coupling via C–H bond activation. Analogous palladium-catalyzed polymerization suffers from low efficiency because of a high Pd(II)/Pd(0) redox potential of ~1 V. On the other hand, the Fe(III)/Fe(I) redox potential is only ~0.5 V, and the reaction tolerates a wide variety of functional groups in the polymer to be exploited in organoelectronics applications.
8. Iron-catalyzed C–H Activation for Heterocoupling and Copolymerization of Thiophenes with Enamines, T. Doba, R. Shang, E. Nakamura, J. Am. Chem. Soc., 144, 6823–6828 (2022). Cited 22 times.
Iron-catalyzed C–H/C–H heterocoupling between enamines and thiophenes is achieved using a trisphosphine-ligated iron catalyst, enabling direct formation of C–C bonds without prefunctionalization. This method extends to copolymerization of bis-enamine and bis-thiophene monomers, yielding enamine–thiophene hybrid π-conjugated polymers via a mechanism involving σ-bond metathesis at thiophene and subsequent enamine C–H cleavage at the Fe center.
9. Iron-catalysed C(sp²)–H activation for aza-annulation with alkynes on extended π-conjugated systems. Y. Zhang, S. Fukuma, R. Shang, E. Nakamura, Nat. Synth., 3, 1349–1359 (2024). Cited 11 times.
An iron-catalysed aza-annulation π-extension (AAPE) strategy enables direct C(sp²)–H activation on π-extended conjugated ketones using oxime ethers as both directing group and nitrogen source. The reaction yielded new N-doped π-conjugated chromophores with narrow emission bands and high regiocontrol.
10. Deep-red Emitting Copper(I) Indenediyltrisphosphine Complexes with Minimized Skeletal Vibrations and Configurational Disorder, S. Fukuma, J. Fu, T. Nakamuro, R. Shang, E. Nakamura, Angew. Chem. Int. Ed., 63, e202416583 (2025). Cited 2 times.
In this work, new copper(I) complexes based on an indenediyl–trisphosphine (ITP) ligand framework emit genuine deep-red light (λₑₘ ~ 616–677 nm) with a remarkably narrow spectral width (FWHM = 56 nm), achieving color coordinates close to pure red. A quantitative correlation was established between emission broadening and the entropy of disorder in the crystal lattice, revealing that mechanical stress raises configurational entropy and thus degrades color purity.
B. Synthetic carbon materials chemistry
Accounts: Functionalized Fullerenes in Water. The First Ten Years of Their Chemistry, Biology and Nanoscience, E. Nakamura and H. Isobe, Acc. Chem. Res., 36, 807-815 (2003); Selective Multiaddition of Organocopper Reagents to Fullerenes, Y. Matsuo and E. Nakamura, Chem. Rev., 108, 3016-3028 (2008); Carbon-Bridged Oligo(phenylene vinylene)s: A de Novo Designed, Flat, Rigid, and Stable π-Conjugated System, H. Tsuji, E. Nakamura, Acc. Chem. Res., 52, 2939−2949 (2019); Interfacial Chemistry of Conical Fullerene Amphiphiles in Water, K. Harano, E. Nakamura, Acc. Chem. Res., 52, 2090−2100 (2019).
1. Photo-induced Biochemical Activity of Fullerene Carboxylic Acid, H. Tokuyama, S. Yamago, E. Nakamura, T. Shiraki, and Y. Sugiura, J. Am. Chem. Soc., 115, 7918–7919 (1993). Cited 862 times.
The work reported a water-soluble fullerene (later also a 14C-labeled version) and discovered a significant level of the biological activities of water-soluble nanocarbon materials as illustrated by photo-induced DNA cleavage, enzyme inhibition, and relatively low cytotoxicity.
2. Stacking of Conical Molecules with a Fullerene Apex into Polar Columns in Crystals and Liquid Crystals, M. Sawamura, K. Kawai, Y. Matsuo, K. Kanie, T. Kato, and E. Nakamura, Nature, 419, 702–705 (2002). Cited 450 times.
Through a suitable structure modification, the pentahapto fullerene molecules look like badminton shuttlecocks and were found to stack together linearly to generate a columnar liquid crystalline phase made of conical molecules.
3. Columnar Structure in Bulk Heterojunction in Solution-Processable Three-Layered p-i-n Organic Photovoltaic Devices Using Tetrabenzoporphyrin Precursor and Silylmethyl[60]fullerene, Y. Matsuo, Y. Sato, T. Niinomi, I. Soga, H. Tanaka, E. Nakamura, J. Am. Chem. Soc., 131, 16048–16050 (2009). Cited 561 times.
By designing and using his own fullerene molecule called SIMEF, Prof Nakamura demonstrated the feasibility of organic solar cells made of only small molecules in place of polymer materials. This publication reminded people of the advantages of small molecules over polymers because of the more flexible structural design and higher purity.
4. Electron transfer through rigid organic molecular wires enhanced by electronic and electron–vibration coupling, J. Sukegawa, C. Schubert, X. Zhu, H. Tsuji, D. M. Guldi, E. Nakamura, Nat. Chem., 6, 899–905 (2014). Cited 216 times.
Prof Nakamura’s profound contribution to physical organic chemistry is illustrated here for the design and mechanistic study of the electron-tunneling achieved for the first time for organic electronic wire.
5. A Cyclic Phosphate-based Battery Electrolyte for High-voltage and Safe Operation, Q. Zheng, Y. Yamada, R. Shang, S. Ko, Y.-Y. Lee, K. Kim, E. Nakamura, A. Yamada, Nat. Energy, 5, 291-298 (2020). Cited 411 times.
A fluorinated cyclic phosphate solvent, 2-(2,2,2-trifluoroethoxy)-1,3,2-dioxaphospholane 2-oxide (TFEP), is developed to replace conventional carbonate electrolytes, enabling nonflammable operation compatible with both graphite anodes and high-voltage cathodes. This electrolyte supports stable cycling at voltages up to ~ 4.6 V (vs Li/Li⁺), suppresses side reactions, and improves safety without sacrificing performance.
6. De Novo Synthesis of Free-Standing Flexible 2D Intercalated Nanofilm Uniform over Tens of cm2, P. Ravat, H. Uchida, R. Sekine, K. Kamei, A. Yamamoto, O. Konovalov, M. Tanaka, T. Yamada, K. Harano, E. Nakamura, Adv. Mater. 2146465 (2021). Cited 7 times.
A 3-nm thick, free-standing 2D nanofilm was synthesized de novo at the air/water interface by intercalating a hydrogen-bonded network between two layers of fullerene-based amphiphiles, producing a uniform film over tens of cm² that can be transferred to various substrates.
7. Doubly spiro-conjugated chiral carbocycles exhibiting SOMO-HOMO inversion in persistent radical cations. T. Sakamaki, Y. Zhang, S. Fukuma, C. M. Cruz, A. Cardenas, A. G. Campana, J. Casado, R. Shang, E. Nakamura, J. Am. Chem. Soc., 146, 12712–12722 (2024). Cited 11 times.
The work reports chiral, doubly spiro-conjugated carbocycles whose radical cations display a non-Aufbau electron configuration: the SOMO lies energetically below HOMO. These molecules are highly stable (half-life ~ 570 h under ambient conditions), emit circularly polarized luminescence with high quantum yield, and achieve configurational stability through spiro-conjugative stabilization.
C. SMART-EM: From Molecular Imaging to Statistical Mechanics
*Accounts: Atomic-Resolution Transmission Electron Microscopic Movies for Study of Organic Molecules, Assemblies, and Reactions: The First 10 Years of Development, E. Nakamura, Acc. Chem. Res., 50, 1281–1292 (2017); Cinematographic study of stochastic chemical events at atomic resolution, K. Harano, T. Nakamuro, E. Nakamura, Microscopy, 73, 101-116 (2024).
1. Imaging Single Molecules in Motion, M. Koshino, T. Tanaka, N. Solin, K. Suenaga, H. Isobe, and E. Nakamura, Science, 316, 853 (2007). Cited 274 times.
In this seminal paper on “Single-Molecule Atomic-Resolution Time-resolved Electron Microscopy (SMART-EM) Technique”, The work demonstrated for the first time that humans could see in situ conformational changes of individual organic molecules at atomic resolution.
2. Direct Microscopic Analysis of Individual C60 Dimerization Events: Kinetics and Mechanisms, S. Okada, S. Kowashi, L. Schweighauser, K. Yamanouchi, K. Harano, E. Nakamura, J. Am. Chem. Soc., 139, 18281–18287 (2017). Cited 48 times.
This work demonstrated the feasibility of a statistical kinetic study of [2+2] cycloaddition reaction by taking a close look at individual reaction events under variable temperature conditions. The work for the first time that we can determine the activation energy and the frequency factor of a chemical without recourse to ensemble average measurements.
3. Atomistic structures and dynamics of prenucleation clusters in MOF-2 and MOF-5 syntheses, J. Xing, L. Schweighauser, S. Okada, K. Harano, and E. Nakamura, Nat. Commun., 10, 3608 (2019). Cited 103 times.
The visual identification of an intermediate in the MOF formation process attracted the interest of lay people, and the video was viewed over 16k times. Prof Nakamura suggested a future direction of SMART-EM research—in situ capture, structure determination, and statistical analysis of minute transient intermediates of chemical reactions by the use of “chemical fishhooks.”
4. Capturing the Moment of Emergence of Crystal Nucleus from Disorder, T. Nakamuro, M. Sakakibara, H. Nada, K. Harano, and E. Nakamura, J. Am. Chem. Soc., 143, 1763-1767 (2021). Cited 124 times.
This groundbreaking paper reports a video on NaCl crystal growth at the atomic level, representing a 1/10,000,000 scale version of an elementary school crystal growth experiment, and has attracted the interest of people worldwide. This paper in JACS has been viewed 36k times (the Most Read in 12 months), and the video was viewed over 30k times within three weeks after publication. In addition, the paper has recorded an Altmetric value of over 936, which is the highest among all JACS publications since the Altmetric metric was developed.
5. Rim Binding of Cyclodextrins in Size-Sensitive Guest Recognition, H. Hanayama, J. Yamada, I. Tomotsuka, K. Harano, and E. Nakamura, J. Am. Chem. Soc., 143, 5786–5792 (2021). Cited 21 times.
The “cavity” binding of cyclodextrin was the first prototype of molecular recognition reported in the 1940s. The work has proved that there is a significant contribution of “rim” binding through statistical analysis of the binding modes visualized by the SMART-EM technique.
6. Ionization and electron excitation of fullerene molecules in a carbon nanotube. A variable temperature/voltage transmission electron microscopic study, D. Liu, S. Kowashi, T. Nakamuro, D. Lungerich, K. Yamanouchi, K. Harano, and E. Nakamura, Proc. Natl. Acad. Sci. USA., 119, e2200290119 (2022). Cited 17 times.
Prof Nakamura carried out single-molecule kinetic studies by counting individual reaction events. It was done under variable voltage conditions to control the energy given to the molecules and hence to choose between singlet and triplet states. He demonstrated experimentally that individual chemical reaction events follow the quantum transition state theory (RRKM theory) rule.
7. Time-resolved Imaging of Stochastic Cascade Reactions over a Submillisecond to Second Time Range at the Angstrom Level, T. Shimizu, D. Lungerich, K. Harano, and E. Nakamura, J. Am. Chem. Soc., 144, 9797-9805 (2022). Cited 24 times.
Chemical reactions often occur through a series of transient intermediates that appear and disappear stochastically over an extended period ranging between picoseconds and hours. Because of the overlapping signals of each intermediate, the time course of the reaction of individual intermediates is challenging to monitor. Prof Nakamura observed individual van der Waals dimer of C60 in carbon nanotube and identified previously unknown intermediates of lifetimes between <3 milliseconds and minutes.
8. Time-resolved Atomistic Imaging and Statistical Analysis of Daptomycin Oligomers with and without Calcium Ion, T. Nakamuro, K. Kamei, K. Sun, J. W. Bode, K. Harano, and E. Nakamura, J. Am. Chem. Soc., 144, 13612-13622 (2022). Cited 22 times.
Daptomycin acts in oligomeric form, and Prof. Nakamura revealed its dynamic monomer-to-tetramer transitions. SMART-EM showed the cyclic tetramer is the largest aggregate, while the face-to-face dimer is most abundant, providing key insight into its biological activity.
9. Wavy Graphene-Like Network Forming during Pyrolysis of Polyacrylonitrile into Carbon Fiber, T. Ishikawa, F. Tanaka, K. Kurushima, A. Yasuhara, R. Sagawa, T. Fujita, R. Yonesaki, K. Iseki, T. Nakamuro, K. Harano, E. Nakamura, J. Am. Chem. Soc., 145, 12244–12454 (2023). Cited 22 times
Toray Co. produces the main frame of Boeing 787 under optimized thermal conditions, not knowing why they can achieve high tensile strength and high tensile modulus simultaneously. Prof Nakamura has solved this problem by combined use of SMART-EM and Raman spectroscopy.
10. Melting entropy of crystals determined by electron-beam-induced configurational disordering. D. Liu, J. Fu, O. Elishav, M. Sakakibara, K. Yamanouchi, B. Hirshberg, T. Nakamuro, E. Nakamura, Science, 384, 1212-1219 (2024). Cited 2 times.
This work linked Clausius’ entropy (S = Q/T) with Boltzmann’s formula (S = Rln W) by visualizing disorder in organic crystals under electron irradiation, showing unexpected molecular robustness. The method enables experimental determination of molecular degrees of freedom, revealing soluble proteins possess 10–50 times more microstates than membrane proteins.
11.Atomic-resolution imaging as a mechanistic tool for studying single-site heterogeneous catalysis. Y. Kratish, Y. Liu, J. Li, A. Das, L. O. Jones, A. Agarwal, Q. Ma, M. J. Bedzyk, G. C. Schatz, T. Nakamuro, E. Nakamura, T. J. Marks, Chem, 11, 102541 (2025). Cited 2 times.
Using single-molecule SMART-EM, the work directly visualized key intermediates in a MoO₂ single-site heterogeneous catalyst during alcohol dehydrogenation, revealing a reaction pathway involving alkoxide/hemiacetal equilibration and acetal oligomerization.
12. Non-deterministic Dynamics in η-to-θ Phase Transition of Alumina Nanoparticles. M. Sakakibara, M. Hanaya, T. Nakamuro, E. Nakamura, Science, 387 522-527 (2025). Cited 11 times.
In nanoparticles supported on bulk Al(OH)₃, the η → θ phase transition of alumina proceeds via a nondeterministic, ergodic intermediate state in which the original lattice orientation is lost — in contrast to the unidirectional, orientation-preserving transition in bulk alumina. Monitoring a single particle for a long time (cf. ergodicity) provided activation parameters, DG‡, DH‡, and DS‡ without recourse to ensemble averages.
13. Rapid, low-temperature nanodiamond formation by electron-beam activation of adamantane C–H bonds. J. Fu, T. Nakamuro, E. Nakamura, Science, 389, 1024, (2025).
This work established a rapid electron-beam route to transform adamantane crystals into defect-free cubic nanodiamonds at low temperature, with hydrogen evolution. Time-resolved TEM showed oligomeric intermediates reorganizing into the diamond lattice, and a strong isotope effect identified C–H bond cleavage as the rate-determining step.