Organic Chemistry Frontiers Blog

Carbon–phosphorus (C–P) bond cleavage reactions are one of the most important transformations because organophosphorus compounds are widely utilized as pharmaceuticals, phosphine ligands, organocatalysts, and functional materials. Therefore, C–P bond cleavage reactions have been developed using various approaches such as radicals produced using photolysis or peroxides, reduction using transition metal catalysts and alkali metals, and via P(V) intermediates (Scheme 1A). However, these synthetic methodologies require relatively harsh conditions, leading to low functional group tolerance. In addition, they require the use of precious transition metals and the formation of highly polarized C–P bonds in activated species.

Recently, the group of Prof. Shinobu Takizawa and Mohamed S. H. Salem as a collaborator from SANKEN, Osaka University have developed a metal-free C(aryl)–P bond cleavage reaction starting via the reaction of triarylphosphines and alkynyl esters using water as a nucleophile and electrophile to yield propanoic acid/phosphine oxide derivatives (Scheme 1B), which have applications in pharmaceuticals and catalysis.

Scheme 1: Methods of C(aryl)–P bond cleavage.

The reaction proceeded under mild and neutral conditions (10 °C, 24 h, H₂O as a nucleophile) without using any metal catalyst, which is consistent with the concepts of green chemistry. In addition, they have carried out the full optimization of the reaction system to obtain high yields (up to 98%). The scopes of phosphine reagents and activated alkynes were investigated under the optimal conditions to disclose a broad spectrum with high yields in most of the cases.

Takizawa, Salem and coworkers have complemented their experimental work with computational calculations to understand and verify their proposed reaction mechanism. DFT calculations and some control experiments using (allenic esters, or vinyl ketone instead of propiolate esters), and (D₂O, or H₂¹⁸O instead of water) indicated that the rapid formation of hydroxy-λ⁵-phosphane as a key intermediate plays a crucial role in smooth C(aryl)–P bond cleavage (Scheme 2).

Scheme 2: The proposed reaction mechanism of rapid C(aryl)–P bond cleavage and 1,2-aryl migration to the Michael acceptor via a hydroxyl-λ5-phosphane intermediate.

The development of this new synthetic method using metal-free conditions is crucial for the development of greener chemical practices. Further, the understanding of the mechanism of these synthetic reactions has a key value in expanding their applications, as well as the synthesis of industrially important phosphorus-containing molecules.

Author:

Mohamed S. H. SALEM
Osaka University

Mohamed Salem is a Ph.D. student in the SANKEN at Osaka University (Japan). He received his M.Sc. in Medicinal Chemistry at the Faculty of Pharmacy, Suez Canal University in 2017. Subsequently, he received a Japanese Government Scholarship (MEXT) to study for a Ph.D. in 2019 with Professor Hiroaki SASAI and Shinobu TAKIZAWA. The research field of Mohamed Salem is asymmetric catalysis using first-row organometallic complexes such as Cobalt and Vanadium and the study and development of new green and cutting edge electrochemical transformations.

https://orcid.org/0000-0002-8919-095X
https://www.researchgate.net/profile/Mohamed-Salem-39

Corresponding Author:

Shinobu TAKIZAWA 滝澤　忍
Osaka University

Shinobu TAKIZAWA is an associate professor in the Institute of Scientific and Industrial Research (SANKEN) and AI Research Center at Osaka University (Japan). He received his Ph.D. in chemistry at the Graduate School of Pharmaceutical Science, Osaka University in 2000. From 2006 to 2008 he did postdoctoral studies at The Scripps Research Institute (USA) with Professor Dale L. Boger. The research field of Professor Shinobu TAKIZAWA is asymmetric catalysis using either organo-or organometallic catalysts and the study and development of new green and cutting edge chemical transformations either electrochemically or photochemically guided by AI and ML. He is the author of more than 118 articles indexed by SCI and cited more than 4000 times with an index H = 38.

https://orcid.org/0000-0002-9668-1888

Moving from single molecules to dynamic molecular systems and responsive materials requires control of molecules that can induce motion and enable machine-like functions. Light-driven rotary molecular motors are compounds that can undergo unidirectional rotational motion, using light as a power source. Their 360° rotation cycle is driven by the successive interconversion of four unique isomers of the motor, undergoing two energetically uphill photochemical E-Z isomerisation (PEZ) steps and two downhill thermal helix inversion (THI) steps. Thanks to this unidirectional rotational behaviour, molecular motors can be used to produce useful physical work on the nanoscale – finding a multitude of applications in fields of catalysis, smart materials, and nanotechnology. 

The physical characteristics governing the rotational motion of molecular motors include their rotational speed, the wavelength of light which the motors can consume to power their motion, and their photochemical efficiency (or quantum yield). Investigating these characteristics will allow us to understand the dynamic behaviour of molecular motors – and ultimately how to tune this behaviour – will allow molecular motors to be used as tuneable actuators and  molecular machines. 

Figure 1: A) Oxindole-based molecular motors functionalised on the upper half or lower half of the motor scaffold, with either cyano or methoxy groups; B) Unidirectional rotation cycle of the molecular motors, consisting of two photochemical E-Z isomersations (PEZ) and two thermal helix inversions (THI).

Molecular motors containing the heterocyclic oxindole moiety were discovered in 2019 and it was found that they have desirable rotational properties – they can be driven with benign visible light, and they can be synthesised easily and quickly, relative to traditional hydrocarbon-based molecular motors. Due to these advantages, more research into the functionalisation of oxindole-based motors could help to further improve these promising motors.

Recently, researchers in the group of Ben Feringa have carried out a systematic benchmark study on oxindole-based molecular motors; through functionalisation with cyano or methoxy groups at three different positions along the motor backbone, the rotational properties of oxindole-based molecular motors can be fine-tuned (Figure 1).

By functionalising the motors at these positions (Figure 1, R¹, R² and R³), the wavelength of light used to power the molecular motors can be further red-shifted into the visible region of the electromagnetic spectrum, which is a lower energy source of light. In some cases, the use of longer wavelengths even improved the photochemical efficiency of the motors. In addition, the photochemical quantum yields of the motors could be tuned, with electron withdrawing cyano groups improving the quantum yields of the photochemical isomerisation steps of the motor rotation cycle.

The favourable properties fulfilled by the oxindole-based molecular motors investigated in this work show the great potential of these molecules to be used as viable visible light-driven actuators, which can be fine-tuned to accurately control nanoscale motion in light responsive systems.

Corresponding author:

Professor Ben Feringa

Ben Feringa obtained his PhD degree in 1978 at the University of Groningen in the Netherlands under the guidance of Prof. Hans Wynberg. After working as a research scientist at Shell he was appointed full professor at the University of Groningen in 1988 and named the distinguished Jacobus H. van’t Hoff Professor of Molecular Sciences in 2004. He was elected foreign member of the American Academy of Arts and Sciences, and the Royal Society and is member of the Royal Netherlands Academy of Sciences. His research interests include stereochemistry, organic synthesis, asymmetric catalysis, molecular switches and motors, photopharmacology, self-assembly and nanosystems.