The Fascinating Flexibility and Coordination Modes of a Pentamethylene Connected Macrocyclic CNC Pincer Ligand
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ABSTRACT:
SUBMITTER: Jordan R
PROVIDER: S-EPMC8002578 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bidentate and tridentate coordination of a 2,4-di-tert-butyl-substituted bridging amine bis-(phenolate) ligand to a palladium(II) center are observed within the same crystal structure, namely di-chlorido-({6,6'-[(ethane-1,2-diylbis(methyl-aza-nedi-yl)]bis-(methyl-ene)}bis-(2,4-di-tert-butyl-phenol))palladium(II) chlorido-(2,4-di-tert-butyl-6-{[(2-{[(3,5-di-tert-butyl-2-hy-droxy-phen-yl)meth-yl](meth-yl)amino}-eth-yl)(meth-yl)amino]-meth-yl}phenolato)palladium(II) methanol 1.685-solvate 0.315-hydrate, [PdCl2(C34H56N2O2)][PdCl(C34H55N2O2)]·1.685CH3OH·0.315H2O. Both complexes exhibit a square-planar geometry, with unbound phenol moieties participating in inter-molecular hydrogen bonding with co-crystallized water and methanol. The presence of both ?2 and ?3 coordination modes arising from the same solution suggest a dynamic process in which phenol donors may coordinate or dissociate from the metal center, and offers insight into catalyst speciation throughout Pd-mediated processes. The unit cell contains di-chlorido-({6,6'-[(ethane-1,2-diylbis(methyl-aza-nedi-yl)]bis-(methyl-ene)}bis-(2,4-di-tert-butyl-phenol))palladium(II), {(L 2)PdCl2}, and chlorido-(2,4-di-tert-butyl-6-{[(2-{[(3,5-di-tert-butyl-2-hy-droxy-phen-yl)meth-yl](methyl)amino}eth-yl)(meth-yl)amino]-meth-yl}phenolato)palladium(II), {(L 2 X)PdCl}, mol-ecules as well as fractional water and methanol solvent mol-ecules.
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Project description:Large and flexible ligands gain increasing interest in the development of bioactive agents. They challenge the applicability of computational ligand optimization strategies originally developed for small molecules. Free energy perturbation (FEP) is often used for predicting binding affinities of small molecule ligands, however, its use for more complex ligands remains limited. Herein, we report the structure-based design of peptide macrocycles targeting the protein binding site of human adaptor protein 14-3-3. We observe a surprisingly strong dependency of binding affinities on relatively small variations in substituent size. FEP was performed to rationalize observed trends. To account for insufficient convergence of FEP, restrained calculations were performed and complemented with extensive REST MD simulations of the free ligands. These calculations revealed that changes in affinity originate both from altered direct interactions and conformational changes of the free ligand. In addition, MD simulations provided the basis to rationalize unexpected trends in ligand lipophilicity. We also verified the anticipated interaction site and binding mode for one of the high affinity ligands by X-ray crystallography. The introduced fully-atomistic simulation protocol can be used to rationalize the development of structurally complex ligands which will support future ligand maturation efforts.
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Project description:The mechanism for the borylation of an aromatic substrate by a cobalt pincer complex was investigated by density functional theory calculations. Experimental observations identified trans-(iPrPNP)CoH2(BPin) as the resting state in the borylation of five-membered heteroarenes, and 4-BPin-(iPrPNP)Co(N2)BPin as the resting state in the catalytic borylation of arene substrates. The active species, 4-R-(iPrPNP)CoBPin (R=H, BPin), were generated by reductive elimination of H2 in the former, through Berry pseudorotation to the cis isomer, and N2 loss in the latter. The catalytic mechanism of the resulting Co(I) complex was computed to involve three main steps: C-H oxidative addition of the aromatic substrate (C6H6), reductive elimination of PhBPin, and regeneration of the active complex. The oxidative addition product formed through the most favorable pathway, where the breaking C-H bond of C6H6 is parallel to a line between the two phosphine atoms, leaves the complex with a distorted PNP ligand, which rearranges to a more stable complex via dissociation and re-association of HBPin. Alternative pathways, ?-bond metathesis and the oxidative addition in which the breaking C-H bond is parallel to the Co-B bond, are predicted to be unlikely for this Co(I) complex. The thermodynamically favorable formation of the product PhBPin via reductive elimination drives the reaction forward. The active species regenerates through the oxidative addition of B2Pin2 and reductive elimination of HBPin. In the overall reaction, the flipping (refolding) of the five-membered phosphine rings, which connects the species with two phosphine rings folded in the same direction and that with them folded in different directions, is found to play an important role in the catalytic process, as it relieves steric crowding within the PNP ligand and opens Co coordination space. Metal-ligand cooperation based on the ligand's aromatization/dearomatization, a common mechanism for heavy-metal pincer complexes, and the dissociation of one phosphine ligand, do not apply in this system. This study provides guidance for understanding important features of pincer ligands with first-transition-row metals that differ from those in heavier metal complexes.
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Project description:This report describes a synthetic protocols and the crystal structures involving a novel pincer-type H3[NNN] ligand, namely di-?-bromido-?-{2-(2,2-di-methylpropanimido-yl)-N-[2-(2,2-di-methyl-propanimido-yl)-4-methyl-phen-yl]-4-methylaniline}-bis-[(diethyl ether)lithium], [Li2Br2(C24H33N3)(C4H10O)2] (1) and a dinuclear metal complex, namely di-?-bromido-2:3?4Br:Br-bis-{2-(2,2-di-methylpropanimido-yl)-N-[2-(2,2-di-methyl-propanimido-yl)-4-methyl-phen-yl]-4-methylaniline}-1?3N,N',N'';4?3N,N',N''-tetra-?-iso-propano-lato-1:2?4O:O;3:4?4O:O-diiso-propano-lato-1?O,4?O-2,3-dilithium-1,4-dititanium, [Li2Ti2Br2(C24H32N3)2(C3H7O)6] or {[NHNNH]Ti(O i Pr)3(LiBr)2}2 (2). Complex 1, which sits on a twofold rotation axis, is a rare example of a pincer-type ligand which bears ketimine side arms. A unique feature of complex 1 is that the ketimine N atoms have an LiBr(Et2O) fragment bonded to them, with the Li atom adopting a distorted tetra-hedral geometry. This particular fragment creates an LiBr bridge between the two ketimine sidearms, which leads to a cage-type appearance of the ligand. Complex 2 consists of the previously described ligand and a TiIV metal atom in an octa-hedral environment, and is located on an inversion center. Complex 2 crystallizes as a dinuclear species with the metal atoms being bridged by an LiBr entity [the Br atoms are disordered and refined in two positions with their site occupation factors refining to 0.674?(12)/0.372?(12)], and the Li cation being bonded to the isopropoxide O atoms (Li having a tetra-hedral coordination as in 1). The organic ligand of compound 2 exhibits disorder in its periphery groups; isopropyl and tert-butyl groups (occupation factors fixed at 0.6/0.4). The novel [NNN]H3 pincer-type ligand was characterized by multinuclear and multidimensional NMR, HRMS and X-ray crystallography. The dinuclear metal complex 2 was characterized by X-ray crystallography. Although each structure exhibits donor N-H groups, no hydrogen bonding is found in either one, perhaps due to the bulky groups around them. One of the ethyl groups of the ether ligand of 1 is disordered and refined in two parts with site-occupation factors of 0.812?(8) and 0.188?(8). One and a half toluene solvent mol-ecules are also present in the asymmetric unit of 2. The toluene mol-ecules were significantly disordered and could not be modeled properly, thus SQUEEZE [Spek (2015 ?). Acta Cryst. C71, 9-18] was used to remove their contributions to the overall intensity data.
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