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International audience; A series of (NHC)(cod)Ir(I) complexes bearing NHC-carboxylate ligands were efficiently synthesized and fully characterized. Their solid-state structures confirmed the bidentate coordination mode of these LX-type NHC ligands. These unprecedented iridium(I) complexes demonstrated efficient catalytic activities in dehydrogenative directed C-H silylation of arenes, and allowed for excellent ortho-selectivity control with aromatic silylating agents.

The dinuclear complex [Rh(μ-Cl)(η2-coe)(IPr)]2 is an efficient catalyst for the O-selective Markovnikov-type addition of 2-pyridones to terminal alkynes. DFT calculations support a hydride-free pathway entailing intramolecular oxidative protonation of a π-alkyne by a κ1N-hydroxypyridine ligand. Subsequent O-nucleophilic attack on a metallacyclopropene species affords an O-alkenyl-2-oxypyridine chelate rhodium intermediate as the catalyst resting state. The release of the alkenyl ether is calculated as the rate-determining step., Financial support from the Spanish Ministerio de Ciencia e Innovación MCIN/AEI/10.13039/501100011033, under the Projects PID2019-103965GB-I00 and PGC2018-099383-B-I00, and the Departamento de Ciencia, Universidad y Sociedad del Conocimiento del Gobierno de Aragón (group E42_20R) is gratefully acknowledged.

This article belongs to the Collection State-of-the-Art Biochemistry in Spain., Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔGb values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme., This research was funded by MINECO, Spain, grants BFU2016-78232-P and PID2019-107293GB-I00; EU (Interreg-SUDOE), grant NEUROMED; FECYT-PRECIPITA; and Gobierno de Aragón, Spain, grants LMP30_18 and E45_20R. M.C.-G. was recipient of a predoctoral contract from Gobierno de Aragón, Spain.

This article also appears in: RSEQ-GEQO Prize Winners., A series of neutral and cationic rhodium complexes bearing IPr {IPr=1,3-bis-(2,6-diisopropylphenyl)imidazolin-2-carbene} and π-acceptor ligands are reported. Cationic species [Rh(η4-cod)(IPr)(NCCH3)]+ and [Rh(CO)(IPr)(L)2]+ (L=pyridine, CH3CN) were obtained by chlorido abstraction in suitable complexes, whereas the cod-CO derivative [Rh(η4-cod)(IPr)(CO)]+ was formed by the carbonylation of [Rh(η4-cod)(IPr)(NCCH3)]+. Alternatively, neutral derivatives of type RhCl(IPr)(L)2 {L=tBuNC or P(OMe)3} can be accessed from [Rh(μ-Cl)(η2-coe)(IPr)]2. In addition, the mononuclear species Rh(CN)(η4-cod)(IPr) was prepared by cyanide-chlorido anion exchange, which after carbonylation afforded the unusual trinuclear compound [Rh{1κC,2κN-(CN)}(CO)(IPr)]3. Divergent catalytic outcomes in the phenylacetylene-methanol transformations have been observed. Thus, enol ethers, arisen from hydroalkoxylation of the alkyne, were obtained with neutral Rh−CO catalyst precursors whereas dienol ethers were formed with cationic catalysts. Variable amounts of alkyne dimerization, cyclotrimerization or polymerization products were obtained in the absence of a strong π-acceptor ligand on the catalyst., Financial support from the Spanish Ministerio de Ciencia e Innovación (MICINN/FEDER) under the Project PID2019-103965GB−I00 and the Departamento de Ciencia, Universidad y Sociedad del Conocimiento del Gobierno de Aragón (group E42 20R) are gratefully acknowledged. A.D.G. thanks the Spanish Ministerio de Economía y Competitividad (MINECO) for the postdoctoral grant Juan de la Cierva - Incorporación2015 (IJCI-2015-27029).

The mononuclear square-planar Rh{κ2-X,N-(Xpy)}(η2-coe)(IPr) (X = O, NH, NMe, S) complexes have been synthesized from the dinuclear precursor [Rh(μ-Cl)(IPr)(η2-coe)]2 and the corresponding 2-heteroatom-pyridinate salts. The Rh-NHC-pyridinato derivatives are highly efficient catalysts for gem-specific alkyne dimerization. Particularly, the chelating N,O-pyridonato complex displays turnover frequency levels of up 17 000 h–1 at room temperature. Mechanistic investigations and density functional theory calculations suggest a pyridonato-based metal–ligand cooperative proton transfer as responsible for the enhancement of catalytic activity. The initial deprotonation of a Rh-π-alkyne complex by the oxo-functionality of a κ1-N-pyridonato moiety has been established to be the rate-limiting step, whereas the preferential protonation of the terminal position of a π-coordinated alkyne accounts for the exclusive observation of head-to-tail enynes. The catalytic cycle is closed by a very fast alkenyl–alkynyl reductive elimination., Financial support from the Spanish Ministerio de Ciencia e Innovación (MICINN/FEDER) under the Projects PID2019-103965GB-I00 and PGC2018-099383-B-I00, and the Diputación General de Aragón (FEDER 2014-2020 “Building Europe from Aragón”, group E42_20R) are gratefully acknowledged. A.D.G. thanks the Spanish Ministerio de Economía y Competitividad (MINECO) for the postdoctoral grant Juan de la Cierva - Incorporación 2015 (IJCI-2015-27029). A.U. thankfully acknowledges the Spanish MECD for a FPU fellowship (FPU 2017/05417). The authors would like to acknowledge the use of Servicio General de Apoyo a la Investigación-SAI, Universidad de Zaragoza and the computational resources provided by the Institute for Biocomputation and the Physics of Complex Systems (BIFI)–Universidad de Zaragoza.

A series of Rh(κ2‐BHetA)(η2‐coe)(IPr) complexes bearing 1,3‐bis‐hetereoatomic acidato ligands (BHetA) including carboxylato (O,O), thioacetato (O,S), amidato (O,N), thioamidato (N,S), and amidinato (N,N), have been prepared by reaction of the dinuclear precursor [Rh(μ‐Cl)(IPr)(η2‐coe)]2 with the corresponding anionic BHetA species. The RhI‐NHC‐BHetA compounds catalyze the dimerization of aryl alkynes, showing excellent selectivity for the head‐to‐tail enynes. Among them, the acetanilidato‐based catalyst has shown an outstanding catalytic performance reaching unprecedented TOF levels of 2500 h−1 with complete selectivity for the gem‐isomer. Investigation of the reaction mechanism supports a non‐oxidative pathway in which the BHetA ligand behaves as proton shuttle through intermediate κ1‐HBHetA species. However, in the presence of pyridine as additive, the identification of the common RhIIIH(C≡CPh)2(IPr)(py)2 intermediate gives support for an alternative oxidative route., Financial support from the Spanish Ministerio de Economía y Competitividad (MINECO/FEDER) under the Project CTQ2016‐75884‐P, the CSIC under the Project Proyectos Intramurales Especiales (201680I011), and the Diputación General de Aragón (DGA/FSE‐E42‐17R) are gratefully acknowledged. A.D.G. thanks the Spanish Ministerio de Economía y Competitividad (MINECO) for the postdoctoral grant Juan de la Cierva–Incorporación 2015 (IJCI‐2015‐27029).

New RhI-IPr (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-carbene) complexes bearing an N,O-pyridine-2-methanolato (N-O) bidentate ligand have been prepared. The carbonyl complex Rh(N-O)(IPr)(CO) efficiently catalyzes the hydrothiolation of a range of alkynes with high selectivity to α-vinyl sulfides. Reactivity studies and DFT calculations have revealed a new nonoxidative catalytic pathway, passing through RhI catalytic intermediates, which is driven by the interplay between the pyridine-2-methanolato and carbonyl ligands. The basic alkoxo ligand promotes the deprotonation of the thiol to generate the RhI active species, whereas the π-acceptor character of the carbonyl ligand hinders the oxidative addition process. In addition, the stereochemistry of the key thiolate-π-alkyne intermediate, which is determined by the electronic preference of the carbonyl ligand to coordinate cis to IPr, facilitates the rate-limiting alkyne thiometalation step., Financial support from the Spanish Ministerio de Economía y Competitividad (MINECO/FEDER) under the Projects CTQ2013-42532-P and CTQ2016-75884-P, the Diputación General de Aragón (E07) and CONSOLIDER INGENIO-2010, under the Project MULTICAT (CSD2009-00050) are gratefully acknowledged. A.D.G. thanks the Spanish Ministerio de Economia y Competitividad (MINECO) for the post- doctoral grant Juan de la Cierva - Incorporacion 2015 (IJCI-2015-27029).