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2-Pyridones are a class of N,O-heterocyclic ligands capable of forming coordination complexes with a wide variety of metal centers. The inclusion of an oxygen atom adjacent to the pyridine nitrogen atom enables the ligand to adopt versatile coordination modes when bound to a metal center. The ligand can coordinate metals through either the nitrogen atom (as a typical pyridine donor), the oxygen atom, or both allowing it to bind in a monodentate or bidentate fashion. Tautomerism enables them to exist either as a neutral (L-type) hydroxypyridine or an anionic (X-type) pyridonate upon deprotonation.[1]

The tautomeric equilibrium between pyridone and hydroxypyridine strongly influences the coordination chemistry of these ligands and enables unique metal-ligand cooperativity (MLC) in various catalytic transformations.[2][3] The equilibrium can be controlled through the variation of solvent polarity and the installation of substituents on the ring, with electron withdrawing groups favoring the 2-pyridone tautomer.[4] The 2-pyridone tautomer is best described as a cyclic amide (lactam), whereas the hydroxypyridine tautomer is characterized as an aromatic pyridine ring bearing an ortho-hydroxyl substituent. The pKa of 2-pyridone is ~17 in DMSO[5] and deprotonation yields the 2-pyridonate anion, which is stabilized through resonance between the nitrogen and oxygen atoms.

Synthesis

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Substituents on the pyridone ring are commonly introduced to tune donor strengths and secondary interactions, steric properties, and tautomeric equilibria. Numerous synthetic methodologies involving cross-coupling and nucleophilic aromatic substitution reactions (SNAr) have been used for further functionalization of the ligand backbone.

The installation of a 2-oxy function is typically achieved by SNAr of a halide or deprotection of a phenolic protecting group at the 2-position.Many successful ligand designs involve covalently linking the pyridone moiety to other donor groups to form robust and versatile bidentate or tridentate ligand scaffolds.[6] Common chelating groups appended to 2-pyridones include oxazolines, pyridines, carboxylic acids or amides, and neutral amine groups.

Preparation conditions for the synthesis of metal-bound 2-pyridone complexes vary based on the oxidation state of the targeted metal and the desired binding mode of the ligand. Under basic conditions, the ligand typically deprotonates and forms the anionic pyridone complex

Coordination Chemistry and Bonding

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Binding modes of 2-pyridone ligands.

2-Pyridones are relatively weak field ligands and exhibit diverse binding modes, including monodentate κ1-N and κ1-O modes, chelation (κ2-N,O), and multiple bridging modes in multi-metallic assemblies.[3][7] The combination of hard N and O donor atoms, the electron-deficient π-system of pyridine, and the softer properties imparted by the delocalized charge in the anionic form allow for a variety of σ- and π-bonding interactions. Coordination mode is influenced by the metal’s oxidation state, ligand substituents, and solvent environment.

Chelating pyridone ligands demonstrate hemilability, which allows them to transition between bidentate (κ2-N,O) and monodentate coordination modes (κ1-N or κ1-O) by dissociating one donor atom.[8] This dynamic behavior provides vacant coordination sites and can significantly alter reactivity

Catalysis & Metal-Ligand Cooperativity

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2-pyridones can behave as a Brønsted (left) or Lewis (right) base when cooperating with a metal center.

Metal complexes containing 2-pyridone ligands demonstrate substantial catalytic versatility through MLC wherein the ligand participates in bond-breaking and bond-forming events. In these mechanisms, the ligand often acts as a Lewis or Brønsted base which assists the metal center in the activation of substrates. Nature also takes advantage of MLC, as exemplified by the 2-pyridone containing active site of [Fe] hydrogenase enzymes.[9] Outlined below are selected catalytic transformations demonstrating MLC enabled by 2-pyridone ligands:

C-H Borylation

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A 2-pyridone ligand acts as a lewis base in the iridium catalyzed meta C-H borylation of aryl silyl ethers.

Transition metal-catalyzed C–H borylation is a powerful method for preparing organoboron compounds and is especially useful when traditional synthetic approaches are difficult. The resulting organoboron products are versatile intermediates due to the abundance of methods available to transform boron into numerous other functional groups. Although several metals can catalyze this transformation, iridium complexes are most commonly employed.[10] Despite its broad utility, achieving selective remote C–H borylation remains challenging. In 2023, the Chattopadhyay group demonstrated that employing a 2-pyridone ligand, which functions as a Lewis base, can help overcome these challenges by enabling the meta-selective borylation of aryl silyl ethers.[11] Here, the pyridone ligand enables the formation of a tris(Bpin) iridium complex via an intramolecular Bpin shift initiated by nucleophilic attack by the O-atom on the ligand. This intramolecular rearrangement, combined with steric constraints from the Bpin-substituted ligand, is proposed to be responsible for the observed meta-selectivity.

Palladium Catalyzed C-H Functionalization

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2-pyridone ligands act as internal bases to facilitate CMD in the C-H hydroxylation of aryl acetic acids.

Initially popularized by the Yu group[12][6], the 2-pyridone motif has been exploited extensively in palladium catalyzed C-H activation. In these reactions, it is proposed that the deprotonated ligand acts as an internal base in the key concerted-metalation-deprotonation (CMD) step. This cyclometallation involves the concurrent cleavage of the substrate’s C–H bond and the formation of the metal–C bond. The advantage of having the base built directly into the ligand structure is two-fold: first, it eliminates the need for coordinating an additional external base, such as a carboxylate, which simplifies the assembly of the CMD-active species and lowers the entropic cost. Second, the resulting aromatization and formation of the hydroxypyridine tautomer provides additional thermodynamic driving force, making the overall process more favorable.

Hydroamination

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Pyridonate ligands encourage the formation of a titanium dimer which selectively catalyzes intramolecular HAA.

Catalytic hydroamination (HA) is the formal addition of N-H across olefins and alkynes and is a broadly useful transformation commonly employed in synthesizing pharmaceuticals and agrochemicals.[13] Hydroaminoalkylation (HAA) is a closely related reaction but instead results in C-C bond formation alpha to the amine. In practice, HA and HAA often compete, making selective promotion of one pathway over the other highly desirable. In 2013, Schafer and coworkers demonstrated that titanium complexes bearing 2-pyridonate ligands preferentially catalyze intramolecular HAA of simple olefins, significantly suppressing the competing HA reaction.[14] Studies indicated that the κ2-N,O bidentate binding mode adopted by the ligand encouraged the formation of a dimer capable of selectively catalyzing HAA over HA.

Hydrogenation

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Generalized catalytic cycle of the transfer hydrogenation of olefins and ketones by metal pyridone complexes.

Many examples of pyridone-bearing manganese catalysts enabling the transfer hydrogenation of aldehydes, ketones, imines, and carbon dioxide have been reported.[15][16][17] Broadly, in all these transformations the pyridone ligand is postulated to serve as a hydrogen reservoir by cycling between tautomers. This reactivity has been shown to not be limited to manganese-based catalysts. 2-pyridone complexes of Nickel,[18] cobalt,[19] and iron[20] have also been used for hydrogenation.

  1. ^ Cox, Richard H.; Bothner-By, Aksel A. (1969-08-01). "Proton magnetic resonance spectra of tautomeric substituted pyridines and their conjugate acids". The Journal of Physical Chemistry. 73 (8): 2465–2468. doi:10.1021/j100842a001. ISSN 0022-3654.
  2. ^ Gonçalves, Théo P.; Dutta, Indranil; Huang, Kuo-Wei (2021-03-25). "Aromaticity in catalysis: metal ligand cooperation via ligand dearomatization and rearomatization". Chemical Communications. 57 (25): 3070–3082. doi:10.1039/D1CC00528F. ISSN 1364-548X. PMID 33656025.
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  6. ^ a b Wu, Kevin; Lam, Nelson; Strassfeld, Daniel A.; Fan, Zhoulong; Qiao, Jennifer X.; Liu, Tao; Stamos, Dean; Yu, Jin-Quan (2024). "Palladium (II)-Catalyzed C−H Activation with Bifunctional Ligands: From Curiosity to Industrialization". Angewandte Chemie International Edition. 63 (19): e202400509. doi:10.1002/anie.202400509. ISSN 1521-3773. PMC 11216193. PMID 38419352.
  7. ^ Drover, Marcus W.; Love, Jennifer A.; Schafer, Laurel L. (2017-05-22). "1,3-N,O-Complexes of late transition metals. Ligands with flexible bonding modes and reaction profiles". Chemical Society Reviews. 46 (10): 2913–2940. doi:10.1039/C6CS00715E. ISSN 1460-4744. PMID 28426030.
  8. ^ Clarkson, Joseph M.; Schafer, Laurel L. (2017-05-15). "Bis(tert-butylimido)bis(N,O-chelate)tungsten(VI) Complexes: Probing Amidate and Pyridonate Hemilability". Inorganic Chemistry. 56 (10): 5553–5566. doi:10.1021/acs.inorgchem.6b02959. ISSN 0020-1669. PMID 28443662.
  9. ^ Yang, Xinzheng; Hall, Michael B. (2009-08-12). "Monoiron Hydrogenase Catalysis: Hydrogen Activation with the Formation of a Dihydrogen, Fe−Hδ−···Hδ+−O, Bond and Methenyl-H4MPT+ Triggered Hydride Transfer". Journal of the American Chemical Society. 131 (31): 10901–10908. Bibcode:2009JAChS.13110901Y. doi:10.1021/ja902689n. ISSN 0002-7863. PMID 19722671.
  10. ^ Hassan, Mirja Md Mahamudul; Guria, Saikat; Dey, Sayan; Das, Jaitri; Chattopadhyay, Buddhadeb (2023-04-21). "Transition metal–catalyzed remote C─H borylation: An emerging synthetic tool". Science Advances. 9 (16): eadg3311. Bibcode:2023SciA....9G3311H. doi:10.1126/sciadv.adg3311. PMC 10121176. PMID 37083526.
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  12. ^ Wang, Peng; Verma, Pritha; Xia, Guoqin; Shi, Jun; Qiao, Jennifer X.; Tao, Shiwei; Cheng, Peter T. W.; Poss, Michael A.; Farmer, Marcus E.; Yeung, Kap-Sun; Yu, Jin-Quan (November 2017). "Ligand-accelerated non-directed C–H functionalization of arenes". Nature. 551 (7681): 489–493. Bibcode:2017Natur.551..489W. doi:10.1038/nature24632. ISSN 1476-4687. PMC 5726549. PMID 29168802.
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  14. ^ Chong, Eugene; Schafer, Laurel L. (2013-12-06). "2-Pyridonate Titanium Complexes for Chemoselectivity. Accessing Intramolecular Hydroaminoalkylation over Hydroamination". Organic Letters. 15 (23): 6002–6005. doi:10.1021/ol402890m. ISSN 1523-7060. PMID 24224611.
  15. ^ Dubey, Abhishek; Nencini, Luca; Fayzullin, Robert R.; Nervi, Carlo; Khusnutdinova, Julia R. (2017-06-02). "Bio-Inspired Mn(I) Complexes for the Hydrogenation of CO2 to Formate and Formamide". ACS Catalysis. 7 (6): 3864–3868. doi:10.1021/acscatal.7b00943. hdl:2318/1637916.
  16. ^ Dubey, Abhishek; Rahaman, S. M. Wahidur; Fayzullin, Robert R.; Khusnutdinova, Julia R. (2019-04-02). "Transfer Hydrogenation of Carbonyl Groups, Imines andN-Heterocycles Catalyzed by Simple, Bipyridine-Based MnIComplexes". ChemCatChem. 11 (16): 3844–3852. doi:10.1002/cctc.201900358. ISSN 1867-3880.
  17. ^ Zhang, Chong; Hu, Bowen; Chen, Dafa; Xia, Haiping (2019-08-14). "Manganese(I)-Catalyzed Transfer Hydrogenation and Acceptorless Dehydrogenative Condensation: Promotional Influence of the Uncoordinated N-Heterocycle". Organometallics. 38 (16): 3218–3226. doi:10.1021/acs.organomet.9b00475. ISSN 0276-7333.
  18. ^ Chakraborty, Sumit; Piszel, Paige E.; Brennessel, William W.; Jones, William D. (2015-11-09). "A Single Nickel Catalyst for the Acceptorless Dehydrogenation of Alcohols and Hydrogenation of Carbonyl Compounds". Organometallics. 34 (21): 5203–5206. doi:10.1021/acs.organomet.5b00824. ISSN 0276-7333.
  19. ^ Zhuang, Xuewen; Chen, Jia-Yi; Yang, Zhuoyi; Jia, Mengjing; Wu, Chengjuan; Liao, Rong-Zhen; Tung, Chen-Ho; Wang, Wenguang (2019-10-14). "Sequential Transformation of Terminal Alkynes to 1,3-Dienes by a Cooperative Cobalt Pyridonate Catalyst". Organometallics. 38 (19): 3752–3759. doi:10.1021/acs.organomet.9b00486. ISSN 0276-7333.
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