N -Heterocyclic carbene (NHC) gold(I) complexes offer great prospects in medicinal chemistry as antiproliferative, anticancer, and antibacterial agents. However, further development requires a thorough understanding of their reaction behavior in aqueous media. Herein, we report the conversion of the bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I) ((NHC)Au I Br, 1 ) complex in acetonitrile/water mixtures to the bis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(I) ([(NHC) 2 Au I ] + , 7 ), which is subsequently oxidized to the dibromidobis[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propylimidazol-2-ylidene]gold(III) ([(NHC) 2 Au III Br 2 ] + , 9 ). By combining experimental data from HPLC, NMR, and (LC-)/HR-MS with computational results from DFT calculations, we outline a detailed ligand scrambling reaction mechanism. The key step is the formation of the stacked ((NHC)Au I Br) 2 dimer ( 2 ) that rearranges to the T-shaped intermediate Br(NHC) 2 Au I –Au I Br ( 3 ). The dissociation of Br – from 3 and recombination lead to (NHC) 2 Au I –Au I Br 2 ( 5 ) followed by the separation into [(NHC) 2 Au I ] + ( 7 ) and [Au I Br 2 ] − ( 8 ). [Au I Br 2 ] − is not stable in an aqueous environment and degrades in an internal redox reaction to Au 0 and Br 2 . The latter in turn oxidizes 7 to the gold(III) species 9 . The reported ligand rearrangement of the (NHC)Au I Br complex differs from that found for related silver(I) analogous. A detailed understanding of this scrambling mechanism is of utmost importance for the interpretation of their biological activity and will help to further optimize them for biomedical and other applications.
Development of CÀ N coupling methodologies based on Earthabundant metals is a promising strategy in homogeneous catalysis for sustainable processes. However, such systems suffer from deactivation and low catalytic activity. We here report that encapsulation of Cu(I) within the phenanthroyl-containing calix [8]arene derivative 1,5-(2,9-dimethyl-1,10-phenanthroyl)-2,3,4,6,7,8-hexamethyl-p-tert-butylcalix[8]arene (C 8 PhenMe 6 ) significantly enhances CÀ N coupling activity up to 92 % yield in the reaction of aryl halides and aryl amines, with low catalyst loadings (2.5 % mol). A tailored multiscale computational protocol based on Molecular Dynamics simulations and DFT investigations revealed an oxidative addition/reductive elimination process of the supramolecular catalyst [Cu(C 8 PhenMe 6 )I].The computational investigations uncovered the origins of the enhanced catalytic activity over its molecular analogues: Catalyst deactivation through dimerization is prevented, and product release facilitated. Capturing the dynamic profile of the macrocycle and the impact of non-covalent interactions on reactivity allows for the rationalization of the behavior of the flexible supramolecular catalysts employed.
Functionalization of the phenolic rim of p-tert-butylcalix [8]arene with phenanthroline to create a cavity leads to formation of two regioisomers. Substitution of positions 1 and 5 produces the known C 2v -symmetric regioisomer 1,5-(2,9-dimethyl-1,10phenanthroyl)-p-tert-butylcalix[8]arene (L 1,5 ), while substitution of positions 1 and 4 produces the C s -symmetric regioisomer 1,4-(2,9-dimethyl-1,10-phenanthroyl)-p-tert-butylcalix[8]arene (L 1,4 ) described herein. [Cu(L 1,4 )I] was synthesized from L 1,4 and CuI in good yield and characterized spectroscopically. To evaluate the effect of its cavity on catalysis, Ullmann-type CÀ S coupling was chosen as proof-of-concept. Selected aryl halides were used, and the results compared with the previously reported Cu(I)/L 1,5 system. Only highly activated aryl halides generate the CÀ S coupling product in moderate yields with the Cu(I)/L 1,4 system. To shed light on these observations, detailed computational investigations were carried out, revealing the influence of the calix[8]arene macrocyclic morphology on the accessible conformations. The L 1,4 regioisomer undergoes a deformation that does not occur with L 1,5 , resulting in an exposed catalytic center, presumably the cause of the low activity of the former system. The 1,4-connectivity was confirmed in the solid-state structure of the byproduct [Cu(L 1,4 À H)(CH 3 CN) 2 ] that features Cu(I) coordinated inside a cleft defined by the macrocyclic framework.
The synthesis of imines denotes a cornerstone in organic chemistry. The use of alcohols as renewable substituents for carbonyl-functionality represents an attractive opportunity. Consequently, carbonyl moieties can be in situ generated from alcohols upon transition-metal catalysis under inert atmosphere. Alternatively, bases can be utilized under aerobic conditions. In this context, we report the synthesis of imines from benzyl alcohols and anilines, promoted by KO t Bu under aerobic conditions at room temperature, in the absence of any transition-metal catalyst. A detailed investigation of the radical mechanism of the underlying reaction is presented. This reveals a complex reaction network fully supporting the experimental findings.
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