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Metal Ligand Cooperation[edit]

In organometallic chemistry, Metal Ligand Cooperation (MLC) is a commonly used term to describe a bond breaking or forming process in which both a metal center and a coordinated ligand are directly modified. As the name implies, this mode of reactivity relies on cooperative bond breaking or forming between a metal center and coordinated ligand. Although this type of reactivity has earlier precedence, the term was coined by Professor David Milstein. A distinguishing feature of MLC compared with classical elementary steps in organometallic chemistry is the active participation of the ligand; ligands that participate in MLC are a part of a larger group known as non-innocent ligands. However, non-innocent ligands that are only involved in electron transfer, especially those involved in biological systems are not typically considered to be part of MLC as there are no bond forming processes involved with both the metal center and ligand. However, inspiration from nature is often invoked by those designing new MLC active systems[1]. MLC can be used to activate a variety of different bonds and finds wide spread use in hydrogenation chemistry. Notable examples include the Noyori Catalysts, which led to the winning of the 2010 Nobel Prize in chemistry[2], utilize MLC to achieve higher rates. MLC that activate inert bonds typically have a large driving force of the formation of a more stable complex. Although the products of these reactions can usually be accessed through oxidative addition, MLC pathways lower the energy needed for bond activation so can predominate over more traditional mechanisms such as oxidative addition and reductive elimination. Although not all of these processes are redox neutral, bond activation typically occurs in a redox neutral fashion by converting an X-type ligand to an L-type ligand and concomitantly forming a new X-type ligand.

A classic review[3] by Milstein covers many examples of MLC both in the context of catalysis and in stoichiometric reactions. A large variety of different metals and ligands are known to participate in MLC and this is an important research topic in organometallic and coordination chemistry as well as transition metal catalysis. Catalysts that use MLC are part of important industrial processes such as in the synthesis of drugs.

Early Transition Metals[edit]

Bergman[4] and Wolczanski[5] showed that terminal amido Zr(IV) complexes were capable of activating typically inert C–H bonds including methane, hydrogen and benzene. These complexes were operative at mild conditions and were shown to be reversible upon heating. Zr(IV) is a d0 metal meaning it has no available d-electrons and therefore cannot undergo oxidative addition therefore ruling out an oxidative addition–reductive elimination pathway. In the examples by Bergman, they found that π-bonds could also be activated by MLC and form a metalocyclobutene.

Examples of inert bond activation by Zr(IV) by Wolczanski


Pyridine Dearomatization[edit]

MLC that activate inert bonds typically have a large driving force of the formation of a more stable complex. Many bidentate and tridentate ligands that posses a pyridine can be deprotonated on an sp3 carbon off of the pyridine ring. This deprotonation event places a negative charge on the ligand that causes dearomatization and changes the pyridine coordination from L-type to X-type accompanied with a loss of an X-type ligand. Notably, this sequence of events proceeds without formal change of the oxidation state of the metal. The dearomatized intermediates are sufficiently stable and have been isolated and fully characterized[6]. The dearomatized intermediates are highly reactive towards a variety of bonds and use re-aromatization as a driving force. Re-aromatization converts the pyridine nitrogen back to an L-type ligand accompanied with the formation of new X-type ligand from the molecule that was activated.

An example[7] of this process used to activate H2 and alcohols is shown in the figure. This examples uses the strong base KHMDS to deprotonate the benzylic position of the pyridine to form the dearomatized intermediate with the loss of –Br. This complex is then shown to reversibly activate the strong H–H bond. Deuterium studies show that activation of D2 gas occurs syn with the deuterium being exclusively incorporated on the ligand on the same side as the Ru–D bond that is formed. This complex as well as many other structurally related catalysts also readily active O–H bonds of primary and secondary alcohols. After beta-hydride elimination of the Ru–OR intermediate, a Ru–H and carbonyl compound are formed. Subsequent loss of H2 from this intermediate will regenerate the starting complex which renders this process catalytic.

Reversible activation of alcohols and H2 by a Ru(II)-CNN complex


Amine and Amido Ligands[edit]

Many metal complexes including Noyori catalysts utilize amine based ligands for helping the activation of H2 in the Noyori asymmetric hydrogenation. This reaction has found widespread use in various applications including those done on on industrial scale for the synthesis of FDA approved drugs and other fine chemicals[8]. These catalysts were found to react faster in the presence of base and detailed mechanistic studies[9] have shown that both the activation of H2, or alcohol in the case of transfer hydrogenation, and reduction of the carbonyl compound rely on cooperative reactivity between the metal and ligand.

Activation of H2 by Rh(I) amido species

One example[10] of this type of ligand scaffold is able to activate H2 at atmospheric pressures at extremely low temperatures (–78 °C) is shown below. This Rh complex will reversibly activate and release H2 gas under mild conditions. It was shown that no H–D mixing was found during this process suggesting a concerted process. DFT calculations for this particular complex also show that the transition state energy for activation is substantially lower for the MLC pathway (14.5 kcal/mol) vs. the oxidative addition pathway (17.9 kcal/mol).

Pyridone Ligands[edit]

2-Pyridones or 2-hydroxypyridines and their derivatives are a particularly interesting class of ligands that are known to participate in MLC because of the facile tautomerization between pyridone and pyridine form. This equilibrium can easily be controlled by modulating the pH of the solution. The tautomerization between the two different forms is particularly well suited for MLC as this motif can easily switch between X-type and L-type ligand.

pH modulated MLC of pyridone type ligands

One study[11] by Estuko Fujita and co-workers shows the use of these types of ligands can be used with iridium in the reversible hydrogenation of CO2 to formate. Compared to other ligands that participate in MLC the pka needed for deprotonation of a pyridone is much lower than those needed for other systems that typically require the use of a strong base (tert-butoxide, KHMDS, hydroxide etc.). This feature may make these systems more amenable for catalytic applications that contain functional groups that are not compatible with strong basic conditions.

These ligands are also thought to be highly effective in the field C–H activation where these ligands can undergo a concerted metalation deprotonation (CMD) mechanism[12].

Cyclopentadienyl Ligands[edit]

Cyclopentadienyl (cp) ligands and their derivates have been shown to participate in MLC. Cp metal complexes are historically some of the most important in organometallic chemistry (eg. ferrocene) and are still an important topic of research. A classical example of this type of ligand can be exemplified by Shvo's Catalyst. This complex is a ruthenium cyclopentadienone dimer that was one of the earliest known catalysts to utilize MLC.

Dehydrogenation by MLC of a Rh cp* complex

A more recent example[13] of cp type ligand used in MLC does the dehydrogenation of dimethylamine borane with an Rh(bpy)cp* complex. This example proceeds catalytically by first forming an Rhodium(III)cp*–hyrdide which reductively eliminates cp* and hydride to form a Ir(I)–cyclopentadiene. This abstracts a proton from protonated dimethylamine borane. The resulting Rh-hydride complex then evolves hydrogen gas from the hydride and a proton on cyclopentadiene to rearomatize the cyclopenadiene. Although this process was catalytic there are not necessarily any practical applications yet.

Other Examples[edit]

Although most cases of MLC involve the use of dearomatization or deprotonation of an acidic heteroatom bond, there are examples of deprotonating benzylic C–H bonds to form carbenes. These systems are more common for group 10 metals such as palladium[14] or nickel[15]. These complexes have similar reactivity to other MLC systems. Although many examples of MLC focus on the activation of H2 and alcohols, there are examples of catalytic cross coupling reactions such as those shown below for the sonogashira coupling[16].

Catalytic cycle and mechanistic experiment of PNF Pd catalyzed Sonogashira coupling


  1. ^ Hu, Xile (2018). "Natural inspirations for metal–ligand cooperative catalysis". Nature Reviews Chemistry. 2: 0099.
  2. ^ "The Nobel Prize in Chemistry 2001". NobelPrize.org. Retrieved 2019-05-22.
  3. ^ Milstein, David (2015). "Metal-Ligand Cooperation". Angewandte Chemie International Edition. 54: 12236–12273.
  4. ^ Bergman, Robert (1988). "Generation, alkyne cycloaddition, arene carbon-hydrogen activation, nitrogen-hydrogen activation and dative ligand trapping reactions of the first monomeric imidozirconocene (Cp2Zr:NR) complexes". The Journal of the American Chemical Society. 110: 8729–8731.
  5. ^ Wolczanski, Peter (1988). "Methane and benzene activation via transient (tert-Bu3SiNH)2Zr:NSi-tert-Bu3". The Journal of the American Chemical Society. 110: 8731–8733.
  6. ^ Milstein, David (2012). "Aldehyde Binding through Reversible C–C Coupling with the Pincer Ligand upon Alcohol Dehydrogenation by a PNP–Ruthenium Catalyst". The Journal of the American Chemical Society. 134: 10325–10328.
  7. ^ Song, Datong (2011). "Ester hydrogenation catalyzed by Ru-CNN pincer complexes". Chemical Communications. 47: 8349–8351.
  8. ^ Noyori, Ryoji (December 8, 2001). "Asymmetric Catalysis: Science and Opportunities" (PDF). Nobel Lecture.
  9. ^ Noyori, Ryoji (2003). "Mechanism of Asymmetric Hydrogenation of Ketones Catalyzed by BINAP/1,2-Diamine−Ruthenium(II) Complexes". The Journal of the American Chemical Society. 125: 13490–13503.
  10. ^ Grutzmacher, Hansjorg (2005). "Heterolytische Wasserstoffspaltung mit Rhodium(I)‐amiden". Angewandte Chemie. 117: 6477–6481.
  11. ^ Fujita, Etsuko (2012). "Reversible hydrogen storage using CO2 and a proton-switchable iridium catalyst in aqueous media under mild temperatures and pressures". Nature Chemistry. 4: 383–388.
  12. ^ Yu, Jinquan (2015). "Monoselective o-C–H Functionalizations of Mandelic Acid and α-Phenylglycine". The Journal of the American Chemical Society. 137: 9877–9884.
  13. ^ Nozaki, Kyoko (2018). "Dehydrogenation of dimethylamine-borane catalyzed by half-sandwich Ir and Rh complexes: Mechanism and the role of Cp* non-innocence". Organometallics. 37: 906–914.
  14. ^ Iluc, Vlad (2014). "Synthesis and Reactivity of a Nucleophilic Palladium(II) Carbene". Organometallics. 33: 6059–6064.
  15. ^ Piers, Warren (2013). "Activation of Water, Ammonia, and Other Small Molecules by PCcarbeneP Nickel Pincer Complexes". The Journal of the American Chemical Society. 135: 11776–11779.
  16. ^ Vigalok, Arkadi (2013). "Evidence for Metal–Ligand Cooperation in a Pd–PNF Pincer-Catalyzed Cross-Coupling". Journal of the American Chemical Society. 135: 967–970.
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