Substituent

About: Substituent is a research topic. Over the lifetime, 42877 publications have been published within this topic receiving 516716 citations. The topic is also known as: side chain & side group.

Peptidyl (acyloxy)methyl ketones and the quiescent affinity label concept: the departing group as a variable structural element in the design of inactivators of cysteine proteinases

Abstract: (Acyloxy)methyl ketones, of general structure Z-[AA2]-[AA1]-CH2OCOAr, are potent inactivators of the cysteine proteinase cathepsin B. These reagents have been designed as affinity labels in which the dipeptidyl moiety serves as an affinity group (complementary to the S1 and S2 sites of the enzyme), while the (acyloxy)methyl ketone unit (-COCH2OCOR), containing a weak leaving group in the form of a carboxylate nucleofuge, functions as the potentially reactive entity that labels the enzyme. The inhibition is time dependent, active site directed, and irreversible. The apparent second-order rate constant kinact/Kinact, which characterizes the inhibition of cathepsin B by this series, spans several orders of magnitude and in certain cases exceeds 10(6) M-1 s-1. The activity of this series of inhibitors was found to be exquisitely sensitive to the nature of the carboxylate leaving group as well as the affinity group. A strong dependence of second-order inactivation rate on leaving group pKa was uncovered for Z-Phe-Ala (acyloxy)methyl ketones [log(k/K) = 1.1 (+/- 0.1) X pKa + 7.2 (+/- 0.4); r2 = 0.82, n = 26]. Heretofore in constructing affinity labels the choice of leaving group was quite restricted. The aryl carboxylate group thus offers considerable variation as a design element in that both its binding affinity and reactivity can be controlled by substituent effects. Specific peptidyl (acyloxy)methyl ketones thus represent prime examples of highly potent, chemically stable enzyme inhibitors with variable structural elements in both the affinity and departing groups.

Chiral Induction Effects in Ruthenium(II) Amino Alcohol Catalysed Asymmetric Transfer Hydrogenation of Ketones: An Experimental and Theoretical Approach

Abstract: The enantioselective outcome of transfer hydrogenation reactions that are catalysed by ruthenium(II) amino alcohol complexes was studied by means of a systematically varied series of ligands. It was found that both the substituent at the 1-position in the 2-amino-1-alcohol ligand and the substituent at the amine functionality influence the enantioselectivity of the reaction to a large extent: enantioselectivities (ee values) of up to 95 % were obtained for the reduction of acetophenone. The catalytic cycle of ruthenium(II) amino alcohol catalysed transfer hydrogenation was examined at the density functional theory level. The formation of a hydrogen bond between the carbonyl functionality of the substrate and the amine proton of the ligand, as well as the formation of an intramolecular H⋅⋅⋅H bond and a planar H-Ru-NH moiety are crucially important for the reaction mechanism. The enantioselective outcome of the reaction can be illustrated with the aid of molecular modelling by the visualisation of the steric interactions between the ketone and the ligand backbone in the ruthenium(II) catalysts.

Remote Substituents Controlling Catalytic Polymerization by Very Active and Robust Neutral Nickel(II) Complexes

Abstract: More than 70 million tons of polyethylene and polypropylene are produced annually. The majority is prepared by catalytic polymerization employing Ziegler or Phillips catalysts based on early transition metals. More recently, olefin polymerization by complexes of late transition metals has also received increasing attention. A major motivation is their higher tolerance towards polar reagents due to a reduced oxophilicity by comparison to early transition-metal catalysts. Thus, ethylene and 1-olefins can be copolymerized with acrylates in a random fashion, and ethylene homoand copolymerizations can be carried out in aqueous emulsion to afford polymer latexes (i.e., aqueous dispersions of polymer particles of about 50–1000 nm size). The discovery by Brookhart and co-workers of the unique catalytic properties of cationic nickel and palladium diimine catalysts in olefin polymerization has given a strong impulse to the field. As a result, polymerization with neutral Ni complexes has received renewed interest, as these catalysts are expected to be more functional-group tolerant than their cationic Ni counterparts. However, catalyst activity and stability over time and the capability to form polymers with higher molecular weights at the same time are critical issues, particularly if the effort for catalyst synthesis is also considered. By analogy with the influence of bulky alkyl or aryl groups in cationic diimine complexes, in neutral Ni kN,O salicylaldiminato complexes bulky isopropyl groups on theN-aryl moiety retard chain transfer, which is supported by computational studies by Ziegler and co-workers. Introduction of electron-withdrawing substituents in the ortho or para position of the O donor in neutral nickel(ii) complexes has been reported to increase catalytic activities substantially, again in accordance with theoretical calculations. Most specifically for this class of catalysts, Grubbs and co-workers have shown that bulky groups in the C3 position of the Ocoordinating phenolate moiety of salicylaldimine ligands substantially increase polymerization activity. While these ligands afford highly active catalysts, their syntheses require multistep procedures with very low yields. Our particular interest in the design of novel Ni salicylaldiminato complexes stems from the recent finding that the known isopropyl-substituted complexes enable the synthesis of latexes of high-molecular-weight polyethylene, which are, to date, inaccessible by other techniques. Such polyolefin latexes can provide environmentally friendly and economically attractive coatings, which, for example, can be stable towards UV light and hydrolysis at the same time in contrast to current commodity coatings. In view of applications, a very active catalyst based on conveniently accessible ligands, and that is suited to polymerization in emulsion to higher-molecular-weight polyethylene is a prerequisite. Such a system is equally attractive for fundamental studies of catalytic polymerization in emulsion, in which well-defined catalyst precursors are also desirable. Our investigations subject to this report were initiated by the reasoning that an aryl substituent with strongly electron-withdrawing groups could provide steric bulk and electron withdrawing properties at the same time. Suzuki coupling provided a convenient synthetic method for the introduction of electron-withdrawing substituted aryl groups in the C2 and C6 position of the aniline aryl ring (Scheme 1). A series of salicylaldimine ligands with systematically varied electronic properties, 1a–e, resulted from the condensation of the corresponding substituted anilines with 3,5-diiodo-salicylaldehyde. The C NMR resonances of the compounds were fully assigned by H–H COSY, heteronuclear H-C 2D NMR and H–C 2D longrange-coupling NMR spectroscopy. The chemical shifts of the carbon atom para to the imine function in 1a–e (atom labeled p in Scheme 1) are d= 126.90, 126.96, 126.55, 126.48, and 126.56 ppm, respectively, and for the imine carbon atom, C= N, d= 168.42, 168.05, 166.99, 166.23, and 166.26 ppm were observed. Although the differences in chemical shifts are moderate, this trend follows the electron withdrawing/donating character of the R group and indicates that the electronic character of the substituents R in 1 indeed affects the electronic properties of the neighboring aryl ring and the imine function. Reaction of 1a–e in diethylether with [(tmeda)Ni(CH3)2] [12] (tmeda=N,N,N’,N’-tetramethylethylenediamine) in the presence of excess pyridine afforded the neutral methylnickel(ii) complexes 2a–e in high yield (Scheme 1). The molecular structure of 2a and 2c was determined by single-crystal X-ray crystallography (Figure 1). 14] To our knowledge, these are the first examples of structurally characterized neutral methylnickel complexes, which are precursors to very active olefin polymerization catalysts. Such methyl complexes are of particular interest, in comparison to the more frequent phenyl complexes [*] Dr. M. A. Zuideveld, Dipl. Chem. P. Wehrmann, Priv.-Doz. Dr. S. Mecking Institut f$r Makromolekulare Chemie und Freiburger Materialforschungszentrum der Albert-Ludwigs-Universit*t Freiburg Stefan-Meier-Strasse 31, 79104 Freiburg (Germany) Fax: (+49)761-203-6319 E-mail: stefan.mecking@makro.uni-freiburg.de