Design, ligands

In the last 20 years much effort has been directed to develop ligands able to increase the activity of the rhodium/iodide-based Monsanto system. In some cases, even if they do not contribute to a significant reaction improvement, they are crucial for a better understanding of the reaction mechanism and constitute basic pillars for further developments. Some representative examples are mentioned in this section. 

Chelating symmetrical and unsymmetrical ligands have been introduced in order to overcome the instability of the monophosphines under the harsh conditions of the process. The use of symmetrical diphosphines has been covered by the patent hterature [104, 105] and when using Xantphos derivatives (25-34) as 

Carraz and coworkers [106] reported the use of asymmetrically substituted 1,2-ethanediyl diphosphines 50 that are very stable under the reaction conditions, although they do not represent an improvement on the catalytic activity when compared with the Monsanto process. At the end of the reaction a mixture of diphosphine Rh(III) carbonyl complexes can be isolated and characterized, and a second run can be performed without loss of activity. 

An alternative strategy to increase the activity and stability of the systems is the use of hemilabile phosphine ligands (PX X=P, O, S). They are thought to stabilize the complex via the chelate effect and to increase the nucleophilicity of the rhodium by coordination of a hetero-donor atom. 

Trans-diphosphines in Methanol Carbonylation - Dinuclear Systems  

As discussed above, the active site of catechol oxidase comprises two copper ions, each of which surrounded by three nitrogen donor atoms from histidine residues. To model the active site of this enzyme, we have designed and synthesized new macrocyclic pyrazole-based ligands [22]py4pz (9,22-bis(2-pyridylmethyl)-l,4,9,14, 

A number of copper) I) and copper) 11) complexes with [22]py4pz and [22]pr4pz have been isolated and structurally characterized [47—49]. Their structural and catalytic properties, as well as studies on the mechanism of the catalytic oxidation of catechol performed by some of these compounds, are discussed below. 

Copper(l) and Copper(ll) Complexes with [22]py4pz Structural Properties and Mechanism of the Catalytic Reaction 

The interaction of [22]py4pz with copper) 11) and copper(I) salts led to the isolation of a dinuclear copper)11) complex of composition [Cu2( 22 py4pz)(p-OI l) (C104)3-H20, and its reduced dicopper(I) analog [Cu2([22]py4pz)](C104)2-2CH30H. The dicopper(II) complex was obtained by the reaction of copper(II) perchlorate 

The complexes obtained can be considered as structural models of two states of catechol oxidase the native met state and the reduced deoocy state. In order to investigate whether the dicopper(II) complex also possesses the functionality of the natural enzyme, for example, if it can perform the catalytic oxidation of cate- 

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Radmer, R.. 1., Kollman, P. A. Approximate free energy calculation methods and structiire based ligand design. J. Comp. Aid. Mol. Desgn (in press)... 

The synthetic accessibility of ligands designed by de novo methods. This topic typically is not considered. Some compounds with unstable or reactive function-ahties are eliminated by applying simple rules, but these rules are still insufficient. 

M A 1997. Recent Advances in Ligand Design Methods. In Lipkowitz K B and D B Boyd itors) Reviews in Computational Chemistry Volume 11. New York, VCH Publishers, pp. 1-66. 

B and W J Howe 1991. Computer Design of Bioactive Molecules - A Method for Receptor-Based Novo Ligand Design. Proteins Structure, Function and Genetics 11 314-328. i H L 1965. The Generation of a Unique Machine Description for Chemical Structures - A hnique Developed at Chemical Abstracts Service. Journal of Chemical Documentation 5 107-113. J 1995. Computer-aided Estimation of Symthetic Accessibility. PhD thesis. University of Leeds, itan R, N Bauman, J S Dixon and R Venkataraghavan 1987. Topological Torsion A New )lecular Descriptor for SAR Applications. Comparison with Other Descriptors. Journal of emical Information and Computer Science 27 82-85. 

J Apostolakis, A Caflisch. Computational ligand design. Comb Chem High Throughput Screen 2 91-104, 1999. 

In the case of ionic liquids, special ligand design is usually not necessary to obtain catalyst complexes dissolved in the ionic liquid in sufficiently high concentrations. 

Since no special ligand design is usually required to dissolve transition metal complexes in ionic liquids, the application of ionic ligands can be an extremely useful tool with which to immobilize the catalyst in the ionic medium. In applications in which the ionic catalyst layer is intensively extracted with a non-miscible solvent (i.e., under the conditions of biphasic catalysis or during product recovery by extraction) it is important to ensure that the amount of catalyst washed from the ionic liquid is extremely low. Full immobilization of the (often quite expensive) transition metal catalyst, combined with the possibility of recycling it, is usually a crucial criterion for the large-scale use of homogeneous catalysis (for more details see Section 5.3.5). 

Because of the comparatively large space requirements of a lone pair, low coordination numbers favor the expression of a stereochemically active lone pair [25]. Specific ligand design can trigger the stereochemical activity of a lone pair in complex compounds. 

Boehm H-J. Fragment-based de novo ligand design. Proceedings of the Alfred Benzon Symposium No. 39,1996. p. 402-13. 

Mnreko MA. Recent advances in ligand design methods. In Lipkowitz KB, Boyd DB, editors. Reviews in Computational Chemistry, Vol. 11. New York Wiley-VCH, 1997. p. 1-66. 

Gubernator K, Bohm HI, editors. Structure-based ligand design (Vol. 6 of Mannhold R, Kubinyi H, Timmerman H, editors. Methods and Principles in Medicinal Chemistry). Weinheim Wiley-VCH, 1998. 

Fig. 2.1 Chiral NHC ligand designs used in the Rh-catalysed enantioselective hydrogenation of...

Fig. 2.11 Chiral ligand designs in Rh catalysts for the enantioselective hydrosilylation of carbonyl compounds...

Bremner,. B., Coban, B., Griffith, R Groenewoud, K. M., Yates, B. F. Ligand design for alpha] adrenoceptor subtype selective antagonists. Bioorg. Med. Chem. 2000, 8, 201-214. 

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