JP2002241388A - Method for producing array - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for the synthesis, screening and characterization of an organic metal compound and a catalyst (for example, a homogeneous catalyst). SOLUTION: A method for producing an array of a carried metal ligand compound, which enables the measurement of at least one change of a ligand core, the identity of the substituent of the ligand core, the electric charge of a metal ion, a counter ion, an activating substance, reaction conditions, a solvent, additives, and a linker, comprises disposing the first metal ligand compound and the second metal ligand compound different from the first metal ligand compound, carried on a carrier different from the substrate, thus forming the combinatorial array of the metal ligand compounds carried at a space.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates in particular to a method for the synthesis, screening and characterization of organometallic compounds and catalysts. The method of the present invention provides for the combined synthesis of libraries of supported and unsupported organometallic compounds and catalysts.
binatorial synthesis), screening, and characterization. The method of the present invention can be applied in preparing and screening a large number of organometallic compounds that can be used not only as catalysts (eg, homogeneous catalysts) but also as additives and therapeutic agents.

[0002]

BACKGROUND OF THE INVENTION The present invention relates to U.S. patent application Ser. No. 60 / 028,106 (filed on Oct. 9, 1996), which is a continuation-in-part of U.S. Patent Application No. 60 / 016,102 (filed on July 23, 1996). No. 60 / 035,366 (filed on Jan. 10, 1997), which is a continuation-in-part of US Patent Application No. 60 / 029,255 (filed on Oct. 25, 1996). This is a continuation-in-part of US Patent Application No. 60 / 048,987 (filed on June 9, 1997), which is a continuation-in-part application. The teachings of these patent applications are incorporated herein by reference.

[0003] Metal complexes stabilized by ancillary ligands (ie organometallic compounds)
Are catalysts, additives, stoichiometric reagents (stoichiometric
reagents), monomers, solid precursors, therapeutics, drugs. The ancillary ligand system contains organic substituents, which are bound to the metal center and remain associated with the metal center, and therefore the shape, electronic and chemical properties of the active metal center of the organometallic compound Gives the opportunity to modify.

Certain organometallic compounds are oxidized, reduced,
Hydrogenation, hydrosylation, hydrocyanation, hydroformylation, polymerization, carbonylation, isomerization, metathesis, carbon-hydrogen activation, cross-coupling, Friedel-Crafts reaction and alkylation, hydration, It is a catalyst for performing reactions such as dimerization, trimerization, and Diels-Alder reaction. The organometallic compound can be prepared by combining the auxiliary ligand precursor with a suitable metal precursor in a suitable solvent at a suitable temperature. The activity and selectivity obtained from the desired organometallic compound include the shape of the auxiliary ligand, the choice of metal precursor, the reaction conditions (eg, solvent, temperature, time, etc.) and the stability of the desired product. It depends on various factors. In some cases, the resulting organometallic compound is catalytically inactive until "activated" by a third component or cocatalyst. In many cases, a third component, a "modifier", is added to the active catalyst to improve performance. The effectiveness of cocatalysts, the type and amount of modifiers, auxiliary ligands, metal precursors and the adequacy of the reaction conditions to form effective catalyst species in high yields cannot be predicted from their principles alone. Can not. Given many variables involved,
It is not surprising that the lack of theoretical feasibility makes finding and optimizing catalysts cumbersome and inefficient.

One important example is the single-sited olefin polymerization catalyze.
sis). The active site is usually a ligand-unsaturated transition metal alkyl complex (a
ncillary ligand-stabilizedcoordinately unsaturated
transition metal alkyl complex). Such catalysts are often prepared by reacting two components. The first component is a transition metal complex stabilized by an auxiliary ligand and having a relatively low coordination number (typically 3 or 4). The second component, known as an activator or cocatalyst, is an alkylating agent, a Lewis acid capable of abstracting a negatively charged leaving group ligand from the first component, Either an ion exchange reactant containing a non-coordinating anion, or a combination thereof. Although various organometallic catalysts have been discovered over the past 15 years, these discoveries have involved the time and effort of individually synthesizing potential catalytic materials and then screening them for catalytic activity. Work has been required. Developing a more efficient, economical, and systematic approach to synthesizing new organometallic catalysts and screening the resulting catalysts for useful properties would significantly advance the state of the art. There will be. A particularly promising method to simplify the discovery task is to create a library of combinatorial ligands and catalysts and use efficient parallel or rapid sequential detection methods to determine the catalytic activity in the library. And screening methods for the compounds.

[0006] Combinatorial methods of synthesizing libraries of organic compounds are well known. For example, Pirrun
g) Others include, for example, light-directed, spatially-addressable synthesis
techniques have been developed to produce arrays of peptides and other molecules (US Pat. No. 5,143,854 and PCT WO 90/15070). In addition, Fodor
r) Others have developed automated methods for performing light-dependent spatially addressable synthetic methods, photolabile protecting groups, masking methods, and methods for collecting fluorescence intensity data (Fodor
And PCT Publication No. WO92 / 10092). In addition, recently, Ellman et al. Reported that three therapeutically important groups of organic compounds, benzodiazepines,
Prostaglandins, β-turn mime
(combinatorial synthesis) and screening methods have been developed (see US Pat. No. 5,288,514).

[0007] Using these various combinatorial synthetic methods, arrays containing thousands and millions of different organic elements can be formed (US Patent Application No. 805,727, filed December 6, 1991). ). The solid-phase synthesis methods currently used to prepare such libraries include a step-wise process (ie, a method of sequentially coupling building blocks to form a compound of interest). For example, in the method of Pilrung et al., Photoremovable groups are attached to the surface of a substrate, and selected areas on the substrate are exposed to activate those areas so that the amino acid monomer having the photoremovable group is removed. A polypeptide array is synthesized on a substrate by binding to the active region and repeating this activation and binding process until a polypeptide having the desired length and sequence is synthesized. This Pilgung other method is binding,
It is a sequential and step-by-step process using masking, protection release, bonding, etc. Biological polymers, biological organic substances
(biological organic molecules) and libraries of small organic molecules.
Such techniques have been used to screen for the ability to bind and block gical rfeceptors (ie, proteins, DNA, etc.). Such a solid-phase synthesis method, which involves the sequential addition of building blocks (ie, monomers, amino acids) to form the desired compound, is used immediately to prepare a large number of inorganic and organic compounds. It is not possible. These methods are based on the “Very Large Scale Immobilized Polymer Synthesis Method” because of the semiconductor manufacturing method.
Synthesis) or "VLSIPS" technology.

Schultz et al. First applied the method of combinatorial chemistry to the field of materials science (PCT WO / 961187).
8; the teachings of which are incorporated herein by reference). In particular, Schultz et al. Disclose a method and apparatus for manufacturing and preparing substrates having arrays of various materials in each predetermined area. Typically, an array of suitable substances is made by supplying a component of the substance to each predetermined area on the substrate while simultaneously reacting the reactants to form various substances. The use of this method by Schultz et al. Makes it possible to combine a large number of substances, including, for example, inorganic substances, intermetallic substances, alloys, and ceramic materials.
ally) can be manufactured. Once adjusted, these materials can be screened for various useful properties. Liu and Ellman (J. Org. Chem. 199) active in the field of asymmetric catalysis.
5, 60: 7) has developed a solid-phase synthesis strategy for synthesizing 2-pyrrolidine methanol ligands, and has developed a rapid parallel method (rap
id parallel mdethod) or serial screening method (ser
It was shown that these ligands can be directly evaluated for the enantioselective addition of the diethylzinc reactant to the aldehyde substrate using conventional analytical methods, rather than the ail screening method).

[0009]

From the above, it is apparent that it is necessary to synthesize a library of organometallic materials and to develop a method for screening this library for catalytic properties. These methods will greatly accelerate the speed of discovering and optimizing the catalytic process. Quite surprisingly, the present invention provides such a method.

[0010]

SUMMARY OF THE INVENTION The present invention relates to a method for performing library synthesis and characterization of arrays, ie, catalysts and organometallic compounds. More specifically, the method of the present invention provides for the combined synthesis, screening and characterization of a large array or library of various supported and unsupported ligands, catalysts and organometallic compounds.

Accordingly, the present invention, in one aspect, is a method of making and screening an array of metal-ligand compounds, comprising: (a) synthesizing an array of spatially separated ligands; (B) providing an appropriate metal precursor to each element of the ligand array to produce an array of metal-ligand compounds; and (c) arraying the metal-ligand compound with an appropriate cocatalyst. Selectively activating, (d) modifying the array of metal-ligand compounds with a third component, (e) optical imaging, optical spectroscopy, mass spectrometry, chromatography,
Using a parallel or rapid serial screening method selected from the group consisting of acoustic imaging, acoustic spectroscopy, infrared imaging and infrared spectroscopy,
A method comprising screening an array of ligand compounds for useful properties is provided.

[0012] In another aspect, the present invention relates to 10 to 10 ⁶
Consisting of an array of different metal-ligand compounds at known locations on a substrate. In one embodiment, the array comprises
There are over 50 different metal-ligand compounds at each known position on the substrate. In another embodiment, the array will consist of 100 or more or 500 or more different metal-ligand compounds. In yet another embodiment,
The array has at least 1,000, at least 10,000, or at least 10 ⁶ different metal-ligand compounds at known locations on the substrate.

[0013] Other features, objects, and advantages of the invention and preferred embodiments of the invention will be apparent from the following detailed description.

[0014]

DESCRIPTION OF THE PREFERRED EMBODIMENTS (Table of Contents) Words: Abbreviations and definitions II. Assembly of Combination Library A. Overview B. Carrier and substrate for synthesis Ligand D. Linker E. Metal F. Immobilized reactants G. Non-coordinating anions (NCA) Design and synthesis of diimine catalyst library III. Screening of combinatorial libraries IV. Example

I. Vocabulary: Abbreviations and Definitions As used herein, abbreviations and generalized chemical formulas have the following meanings.

Embedded image Dienyl; MAO, methylaluminoxane; [Q] ⁺ [NC
A] ^- , reactive cation / non-coordinating anion compound; ED
G, electron donating group; EWG, electron-withdrawing group (electron-with
drawing group); DME, dimethoxyethane; PEG,
Poly (ethylene glycol); DEAD, diethyl azodicarboxylate; COD, cyclooctadiene; D
BU, 1,8-diazabicyclo [5.4.0] undec-7-ene;
FMOC, 9-fluorenylmethoxycarbonyl; HO
BT, 1-hydroxybenzotriazole; BTU, O
-Benzotriazole-N, N, N ', N'-tetramethyl-uronium-hexafluorophosphate; D
IAD, diisopropyl azodicarboxylate. Other abbreviations and formulas used herein have the meaning commonly given by those skilled in the art.

Catalyst : As used herein, the term "catalyst" refers to a compound that speeds up or causes a chemical reaction. The catalyst of the present invention is formally an organometallic compound. Some of the organometallic compounds of the present invention become catalytically active only after being "activated". Other organometallic compounds of the present invention include:
It is a "catalyst that does not require an activating substance" and has catalytic activity even without activation.

Ligand : An organometallic compound is formulated as consisting of a central atom or ion surrounded by and bound to other atoms, ions or small molecules, conventionally known as "ligands". Has been transformed. The ligand may be organic (eg, η ¹ -aryl, alkenyl, alkynyl, cyclopentadienyl, CO, alkylidene, carbene) or inorganic (eg, Br ⁻ , Cl ⁻ , OH ⁻ , NO
^2- etc.), Either charged or neutral. The number of inorganic or organic moieties present as ligands in a metal compound is usually indicated by the prefix di, tri, tetra, etc. When a plurality of complex organic ligands exist, they are indicated by prefixes such as bis, tris, and tetrakis.

As used herein, the term "ancillary ligand" is different from "leaving group ligand". An ancillary ligand is one that remains associated with the metal center as an integral component catalyst or organic compound. An ancillary ligand is defined by the number of coordination sites it occupies and the formal charge. A leaving group is a ligand that is displaced in a ligand displacement reaction. The leaving group ligand may be replaced by a component of the auxiliary ligand or activator.

In most cases, the format for assigning charge to a ligand and assigning the number of coordination sites occupied by the ligand is straightforward and straightforward. As with many forms of chemistry, there are instances where these assignments become symmetrical for interpretation and discussion. This ligand is based on the η5 cyclopentadienyl (Cp) ligand, which is believed to occupy three or one coordination site on the metal, depending on the overall symmetry about the metal center. Examples are such examples. If the symmetry of the metal compound is best described as being octahedral, Cp
Ligands are assigned to occupy three ligand loci (on the face of the octahedron). However, if the symmetry of the metal compound is best described as tetrahedral, planar square or triangular, the Cp ligand is considered to occupy one ligand locus. For the purposes of the present invention, a Cp ligand will be formally considered to occupy one coordination site on a metal compound.

Activator : Activators are commonly used in the synthesis of various catalysts. The activator activates the metal center as a catalyst, e.g., activating the metal center and, in some embodiments, directing from a source to a catalyst precursor located at a predetermined area on the substrate. Chemical or energy source. In embodiments where the activator is a chemical reactant that converts a metal compound to an olefin polymerization catalyst, the activator is typically
There are two broad classes of substances: (1) alkylating agents and (2) ionizing agents.

As used herein, “alkylating agent” refers to a non-reactive ligand such as, for example, a halide or alkoxide, for example, a reactive σ bond such as a methyl or ethyl group. A reactant that functions by exchanging for an alkyl group. Examples of this type of activation are:
Cp ₂ ^* ScCl is converted to Cp ₂ ^* Sc using methyllithium.
It is explained by conversion to Me (where Cp ^* = η ₅ -C ₅ Me ₅ ). In general, activation by alkylation means that the metal center of the catalyst precursor is highly unsaturated in coordination,
The activation mode is not limited to such a metal center, although it is performed in a system where the coordination number does not need to be further reduced to function as a catalyst.

An "ionizing agent" functions as an activator that reduces the coordination number of the transition metal precursor by at least one coordination site to form an ionic product. There are two types of ionizing agents: (1) Lewis acids and (2)
There are ion exchange activators.

The "Lewis acid" functions by abstracting a leaving group from the metal center and comprises a compatible non-coordinating anion ("NCA" consisting of a leaving group ligand and a Lewis acid);
Form coordinatively unsaturated active transition metal cations.
An "ion exchange activator" supplies a preformed compatible non-coordinating anion to a catalyst precursor and receives a coordinating anion (such as a methyl or halide group) from the catalyst precursor. The ion exchange activating substance has the general formula Q ⁺ NC
A ^- has, where Q ⁺ is a reactive cation, NCA
^- is a compatible noncoordinating anion. The Lewis acid and the ion exchange activating substance used in the present invention include both a soluble and supportable (for example, silica resin-bound) Lewis acid and an ion exchange activating substance.

In some cases, the activation can be effected by means of a Lewis acid or an ion exchange material.
For example, the catalyst [Cp ₂ ZrCH ₃ ] ⁺ [B (C ₆ F ₅ ) ₃ CH
₃ ] ^- (where [B (C ₆ F ₅ ) ₃ CH ₃ ] is a “compatible non-coordinating anion” or “counter ion”)
Consider two chemical pathways. When using the Lewis acid pathway, the catalyst precursor is [Cp ₂ Zr (CH ₃ ) ₂ ] and the activator is [B (C ₆ F ₅ ) ₃ ]. When using the “ion exchange” route, the catalyst precursor is [Cp
₂ Zr (CH ₃ ) ₂ ], and the activating substance is [Ph ₃ C] ⁺ [B
(C ₆ F ₅ ) ₃ CH ₃ ] ^- . These examples show that all or part of the activator can be a “compatible non-coordinating anion” or “counter ion”.

Compatible non-coordinating anions : Compatible non-coordinating anions are non-coordinating or weakly coordinating to metal cations and are converted to neutral Lewis acid groups or during the catalytic cycle. An anion that is adapted to retain sufficient activity to be displaced by a molecule. The term "compatible non-coordinating anion" refers to the transfer of an anionic fragment to a metal cation to form an inert neutral product when acting as a stabilizing anion in the catalyst system of the present invention. It specifically refers to an anion that does not exist.

Organometallic compounds : Classically, compounds having a bond between one or more metal atoms and one or more carbon atoms of an organic group are defined as "organometallic compounds". . For purposes of this application, "organometallic compounds"
Is defined as encompassing all metal compounds stabilized by ancillary ligands, with or without metal-carbon bonds. As used herein, "organometallic compounds" are distinguished from catalysts by lack of useful levels of catalytic activity in an initial screen. However, this definition was initially specified as having no catalytic activity with respect to a particular class of reaction (eg, alkene polymerization), but later having a catalytic activity to effect another class of reaction (eg, alkyne polymerization). It does not exclude metal compounds.

Metallocenes : organometallic compounds in which a transition metal such as, for example, zirconium, cobalt or nickel is bound to at least one substituted or unsubstituted η5-cyclopentadienyl group.

Substrate : A material having a rigid or semi-rigid surface. In some embodiments, at least one surface of the substrate is substantially flat. In another embodiment, the substrate will be divided into physically spaced composite regions. Dividing the substrate into physically separated composite regions can be achieved, for example, with recesses, wells, protrusions, etched grooves, and the like. In yet another embodiment, small beads or pellets may be placed on the surface of the substrate, for example, by placing beads in recesses or wells on the surface of the substrate or inside or on other regions of the substrate. Place.
Alternatively, the small beads or pellets themselves may be the substrate. Suitable substrates can be made of any material compatible with the process that is to occur thereon. Such materials include organic and inorganic polymers, quartz,
Examples include, but are not limited to, glass and silica. It will be apparent to those skilled in the art that an appropriate substrate can be selected for a given condition.

Carrier for synthesis : A material such as silica, alumina, resin or controlled pore glass (CPG), such that the ligand or the components of the ligand can be reversibly or irreversibly bound. Those that functionalize into Examples of synthesis supports include Merrifield resin and functionalized silica gel. The carrier for synthesis can be held within or on the "substrate". Here, "synthesis carrier",
"Carrier", "beads" and "resin" are used interchangeably.

Prescribed area : A pre-defined area is a localized, addressable area on a substrate that can be used to form a selection material, otherwise a "known" area, a "reactive" area, a "selected area". Area ", or simply" area ". This predetermined area can have any convenient shape, for example, a shape such as a circle, rectangle, oval, wedge, and the like. In addition, the predetermined area may be beads or pellets coated with the reactant components of interest. In this embodiment, the bead or pellet is a tag, such as an etched binary barcode, which can be used to indicate the history of the bead or pellet (ie, identify which components have been deposited on the bead or pellet). Can be identified by Generally, the predetermined area is from about 25 cm ² to about 10 μm ² . In a preferred embodiment, the predetermined area, ie,
The area where each individual material is synthesized is less than about 10 cm ² . In another preferred embodiment, the predetermined area is less than 5 cm ² , and in yet another preferred embodiment, the predetermined area is less than 1 cm ² . In still yet another preferred embodiment, the area of the predetermined area is less than 1 mm ² . In still yet another preferred embodiment, the area is less than about 10,000 μm ² . In yet a further preferred embodiment, the area is less than 10 μm ² in size.

Linker : As used herein,
The term “linker” or “linker arm” refers to a moiety interposed between a substrate and a ligand, catalyst or organometallic compound. A linker is cleavable or non-cleavable.

Metal ion : as used herein:
The term “metal ion” is used, for example, as a simple salt (eg,
AlCl ₃ , NiCl ₂ etc.), organic ligands and inorganic ligands

Embedded image It refers to ions derived from a compound (for example, Gd (NTA) ₂ , CuEDTA, etc.). The metal ions used in practicing the present invention include, for example, main group metal ions (m
ain group metal ions), transition metal ions, lanthanide ions, and the like. For example, 0 such as Ni (COD) ₂
Valent metal precursors are also included in this definition.

(II. Assembly of Combinatorial Libraries) (A. Overview) The present invention relates to supported and unsupported organometallic compounds and auxiliary ligand stable catalysts (ie, homogeneous and heterogeneous catalysts). And methods, compositions and devices used for combinatorial synthesis, screening and characterization of those libraries.
Desirably, the synthesis and screening of such libraries is performed in a spatially selective, simultaneous parallel or rapid serial manner. In embodiments where library synthesis is performed in parallel, it is preferred to use a parallel reactor. Illustrated here is a first method for preparing and screening a combinatorial library of an organometallic compound and a catalyst.

The method of the present invention provides for the assembly of a library of organometallic compounds and catalysts. The catalyst of the present invention is of a type that requires activation by an activating substance or does not require an activating substance. The present invention also provides
Methods for synthesizing both supported and unsupported organometallic compounds and catalysts are provided. When compounds of the library are supported, they may be bound to a substrate or, as needed, bound to an intermediate synthetic support on or within the substrate. Either. The supported library compound may be directly attached to the substrate or the support for synthesis via a functional group attached to the ligand core, or may itself be the ligand core or the side of the ligand core. Either linked through a linker arm that is a chain. If the library consists of a catalyst, it can be assembled such that the catalyst is a homogeneous catalyst, a heterogeneous catalyst, or a mixture thereof.

Accordingly, the present invention, in one aspect, provides a method for producing an array of metal-ligand compounds having the following structure: (a) a first metal binding ligand and a second metal binding. (B) supplying a first metal ion to the first metal binding ligand, and synthesizing a second metal ion to the first metal binding ligand. Supply to the bimetallic ligand,
A first metal-ligand compound and a second metal-ligand compound are formed.

In this embodiment, the ligand is assembled on a substrate by providing the steps of the ligand fragments and the reactants necessary to couple these fragments. Once the ligands are synthesized, the ligands are reacted with metal ions to form a metal-ligand compound.

The present invention, in another aspect, provides a method of immobilizing an intact ligand to a substrate by attaching the ligand to a reactive group on the surface of the substrate. That is,
In this aspect, the present invention is directed to producing an array of metal-ligand compounds having the following configuration: (a) a first metal-binding ligand and a second metal-binding ligand; (B) supplying the first and second regions of the substrate to the first region and the second region;
Supplying a metal ion to the first metal binding ligand and a second metal ion to the second metal binding ligand to form a first metal-ligand compound and a second metal ligand compound; .

In another embodiment, the metal-ligand compound thus synthesized is reacted with an activator. Suitable _{activators, B (C 6 F 5)} 3 and as well as Lewis acids such as _{MAO [H (OEt) 2]} + [BAr 4] - and [H (OE
^{_{t) 2] + [B (}} C 6 F 5) 4] - , such as [Q] ⁺ [NCA] ^-
However, the present invention is not limited thereto. In yet another preferred embodiment, the activator is independently selected for each compound in the library. In another preferred embodiment, the activated metal-ligand compound is an olefin polymerization catalyst. In yet another preferred embodiment, the catalyst is a catalyst that does not require an activating substance.

In yet another aspect, the invention is a method of preparing and screening an array of metal-ligand compounds having the following structure: (a) providing an array of spatially separated ligands; Synthesize and
(B) providing an appropriate metal precursor to each element of the ligand array to produce a metal-ligand compound array;
(C) optionally, activating the array of organometallic compounds with an activating substance (eg, a suitable cocatalyst);
(D) if necessary, modifying the metal-ligand compound array with a third component, and (e) parallel or rapid serial optical imaging and / or spectroscopy, mass spectrometry, chromatography, acoustics Using imaging / spectroscopy, infrared imaging / spectroscopy, arrays of the above metal-ligand compounds are screened for useful properties.

Various types of ligands are used in practicing the present invention (see FIGS. 1-16). In a preferred embodiment, the ligand is a neutral bidentate ligand (neutral biden
tateligants). In another preferred embodiment, the ligand is a monoanionic bidentate ligand. In yet another preferred embodiment, the ligand is a chelating diimine ligand (che
lating diimine ligands). In yet another preferred embodiment, the ligand is a salen ligand. Preferred ligands have a coordination number independently selected from the group consisting of 1, 2, 3, and 4. These preferred ligands have a charge independently selected from the group consisting of 0, -1, -2, -3 and -4. Some of the preferred ligands have a charge greater than the coordination number.

The ligand is bound directly or via a linker group to the substrate or carrier for synthesis, and is present separately in solution. In one preferred embodiment, the ligand is directly attached to the synthesis support. In another alternative preferred embodiment, the ligand is attached to the synthesis support via a linker group. In yet another preferred embodiment, the ligand is attached to the substrate, directly or via a linker group.

Either the ligand or linker functional group or the ligand or linker component can be protected to prevent interference with the coupling reaction. This protection can be achieved by standard methods or variants thereof. Numerous protection schemes for very well-known functional groups are known to and used by those skilled in the art. For example, Green (T) other "PROTECTIVE G
ROUPS IN ORGANIC SYNTHESIS "(Protecting Groups in Organic Synthesis), Second Edition, John Wiley a
nd Sons), New York, 1991.
The teachings of this are incorporated herein by reference.

The step of chemical synthesis can be carried out by a solid phase synthesis method, a solution phase synthesis method or a combination of a solid phase synthesis method and a liquid phase synthesis method. The ligand, metal, activator, counterion, substrate, support for synthesis, linker and additives to the substrate or support for synthesis can be varied as part of the library. The various elements of the library are usually prepared, for example, by supplying reactants in parallel to each spatially addressable site, or by a known "split-and-
Can be changed by the "pool" combination method. Other methods of assembling combinatorial libraries will be apparent to those skilled in the art. For example, Thompson
on, LA) Other, "Synthesis and Applications of Sma
ll Molecule Libraries "(Synthesis and Use of Libraries of Small Molecules), Chem. Rev., 1996, 96: 555-6.
See 00. The teaching contents are incorporated herein by reference.

In the present invention, any number of wide ranges of metal ions are suitable for use. In one preferred embodiment, the metal ion is a transition metal ion. In another preferred embodiment,
Metal ions are Pd, Ni, Pt, Ir, Rh, Co,
Cr, Mo and W ions. When the metal ion is a transition metal ion, in one preferred embodiment, the metal binding ligand is a neutral bidentate ligand and the transition metal ion is replaced by a displaceable Lewis base in the metal precursor. It has been stabilized. In another preferred embodiment, the ligand is a monoanionic bidentate ligand and the transition metal center is stabilized by a displaceable anionic leaving group ligand in the metal precursor. In yet another preferred embodiment, the ligand is
In the [2,2] or [2,1] ligand, each ligand comes into contact with the main group metal alkyl complex to bring the ligand into a monoprotic or diprotic form. Particularly preferred metal alkyl complexes are trialkylaluminum complexes. In one particularly preferred embodiment, the resulting metal-ligand compound is
For example, a stereoselective coupling reaction (stereoselective
It is useful for organic transformations that require a Lewis acid moiety, such as coupling reactions, olefin oligomer formation reactions, and olefin polymerization reactions. In yet another preferred embodiment, the aluminum-ligand compound is further modified with an ion exchange activator to produce a ligand-stable cationic aluminum compound. Suitable ion exchange activators are [PhNMe ₂ H] [B (C
₆ F ₅₎ is _four.

Catalysts prepared using the process of the present invention include oxidation, reduction, hydrogenation, hydrosylation, hydrocyanation, polymerization (eg, olefins and acetylenes), water gas shift reactions, oxo reactions, Carboalkoxylation, carbonylation reaction (for example, acetylene,
It is useful for catalyzing a wide range of reactions including carbonylation reaction of alcohols and the like, decarbonylation and the like.
The reaction is not limited to these.

As described in detail below, following the synthesis of the library, the compounds of the library are screened for useful properties. In one preferred embodiment,
Useful properties are properties relating to the polymerization reaction. In another preferred embodiment, the useful property is a mechanical, optical, physical or morphological property. In certain preferred embodiments, useful properties include, for example, the lifetime of metal-ligand compounds, the stability of these compounds under certain reaction conditions,
A chemical property, such as the selectivity of a compound of a library in a particular reaction, the conversion efficiency of a compound in a library in a particular reaction, or the activity of a compound in a library in a particular reaction. The library uses a wide range of methods to
Compounds having useful properties can be screened. Thus, in one preferred embodiment, screening comprises scanning mass spectrometry, chromatography, ultraviolet imaging, visible imaging, infrared imaging, electromagnetic imaging, ultraviolet spectroscopy, visible spectroscopy, infrared spectroscopy, electromagnetic spectroscopy, acoustic methods. Performed using a method selected from the group consisting of:

In general, the analysis of catalysts and organometallic compounds requires that each component can be quickly identified (characterized) to identify compounds having particular desired properties. One example of the use of the present invention is to discover and optimize new catalysts. In one preferred embodiment of synthesizing the catalyst, the components of the combinatorial library are active (ie, turnover), selective in converting the reactants to the desired product, over a wide range of substrate concentrations and reaction conditions. Analyzed by using high-throughput methods to determine properties such as stability during operation.
Examples of spatially selective characterization methods include (i) identification and characterization of volatile components of gas phase products and aggregated phase products, (ii) identification and characterization of aggregated phase products, (iii) Includes methods by which measurements of the physical properties of the catalytic elements of the library can be made. Similar high-throughput methods can be used to measure non-catalytic properties (eg, target binding, solubility, hydrophilicity, etc.) of both organometallic and catalyst libraries.

In yet another aspect, the present invention provides a method for forming a substrate on a substrate.
10 to 10 located at each position of knowledge ⁶Seed different metals
-Consists of an array composed of ligand compounds. A certain fruit
In an embodiment, the array is located at each known location on the substrate.
Consisting of more than 0 different metal-ligand compounds
Would. In another embodiment, the array is more than 100 species,
Or from more than 500 different metal-ligand compounds
Will be. In yet another embodiment, the array comprises a substrate
More than 1,000 species at each of the above known locations, 10,000
More than 00 species, or 10⁶Different metals beyond seed
Will consist of a ligand compound.

Assembling a combinatorial library of organometallic compounds and catalysts allows the rapid assessment of the effects of numerous changes in the properties of the compounds themselves, the reactions used to prepare the compounds, and the reactions involving the compounds. Becomes possible. Examples of properties and properties that can be mutated (herein collectively referred to as “parameters”) are the identity of the ligand core itself and the substituents of the ligand core, the charge of the metal ion and / or It includes, but is not limited to, counterions, activators, reaction conditions, solvents, additives, carriers, substrates, and linkers. Other parameters of interest that can be examined for their effects by using the method of the present invention will be apparent to those skilled in the art.

In one preferred embodiment of the invention, only one parameter is mutated for each addressable location.
In another preferred embodiment, the synthetic compound is a catalyst, and variations in various parameters are used to identify optimal species and conditions for performing the catalytic reaction or desired reaction or group of reactions.

The combinatorial library synthesizes both the organometallic compound and the catalyst to obtain the optimum metal ion, the charge of the metal ion,
It can be used to specify the geometry and / or coordination number. Similarly, libraries can be used to determine the effects of changing counterions, activators, reaction conditions, solvents and additives. The properties of the components of the library of interest include, for example, catalytic parameters, solubility, conductivity, hydrophilicity, mechanical properties, and general pharmacologic parameters (eg, target binding, pharmacokinetics). Characteristic, distribution volume, clearance, etc.).

Specific examples of the types of compounds that can be synthesized and analyzed in a combinatorial format are the diimines Ni and P found by Brookhart.
d complex. This family of catalysts comprises 4-coordinated Ni
Consists of a 1,2 diimine ligand moiety attached to a ²⁺ or Pd ²⁺ center. These precursors are then converted to Lewis acids,
For example, a Lewis acid such as MAO, and [H (OEt)
_2] ⁺ [BAr _4] ^- and ^{_{[H (OEt 2)] +}} [B (C
^{_{6 F 5) 4] - [}} Q] + [NCA] , such as ^- activated by the form of the ion-exchange reactants to form a polymerization catalyst. The properties of the catalyst (eg, the molecular weight range of the polymer, the statistical properties of polymer branching, etc.) depend on what is selected as a component of the catalyst. The use of combinatorial libraries makes it possible to optimize the properties of these components.

Combinatorial libraries can also be used to identify the optimal means of coupling an organometallic compound or catalyst to a substrate or carrier (silicate, aluminate, polystyrene, etc.). The catalyst or organometallic compound can be directly bound to the substrate or the synthesis support via a functional group on the ligand, or can be bound via a linker arm. Linker arm parameters that can be varied throughout the library include, for example, length, charge, solubility, conformational labili
ty), including chemical composition. The substituents on these linkers can vary, so for a particular combination of catalyst, linker, support for synthesis, metal, polymerization conditions, etc.
It can be evaluated directly using a two- or three-dimensional array format or a bead carrier.

For example, the optimization of the components of the compound such as metal ions, counter ions, the type and concentration of the activating substance, etc. can be performed by changing the type and concentration of the components whose effects on the produced compound are being investigated. Achieved. In particular, the parameters can be varied throughout the array of addressable locations making up the library. In addition to the above components, the nature of the substrate can also be varied using a combinatorial strategy.

The effects of altering the properties of each component of the combinatorial library can be analyzed directly or indirectly. Thus, in one embodiment, the structure or properties of the library compounds themselves are examined. In another embodiment, the effect of compounds in the library on other molecules or systems is determined. For example, when synthesizing a library of polymerization catalysts, the effect of component changes throughout the library should be assessed by analyzing polymer products made using the species components of the catalyst library. Can be. By doing this analysis,
To determine catalytic properties, including, for example, molecular weight range, copolymerizability, lifetime, comonomer compatibility, chemical stability, ability to form polymers of various topologies, molecular weight distribution, and / or microstructure Can be. Other means of analyzing combinatorial libraries will be apparent to those skilled in the art.

Libraries can be synthesized on different substrates, made of different materials or having different topological properties, and the effect of the nature of the carrier on the compound can be examined as described above. In some embodiments, the substrate may also be a carrier for synthesis.

B. Synthesis Supports and Substrates In one preferred embodiment, the library consists of an array of supported metal-ligand compounds. Generally, when synthesizing a supported organometallic compound or catalyst, the metal ligand compound is directly bound to a library of organometallic compounds or a substrate for a catalyst or a support for synthesis. In another embodiment, the metal-ligand compound is attached to the substrate or synthesis support via a linker arm.

The structure, shape and functional properties of the substrate are limited only by the nature and scale of the reaction performed using the substrate. In some embodiments, the substrate is a porous material. In another embodiment, the substrate is a non-porous material. The substrate may be substantially flat, or may include wells and protrusions. Substrates include, for example, holes, needles, valves,
It may have an integral means for the liquid transfer means, such as a pipette or a combination thereof. The substrate may also have means for performing the reaction under an inert or controlled atmosphere. Thus, in one embodiment, the substrate further comprises a cover, the cover having means for replacing the substrate and its contents with a specific atmosphere. In another embodiment,
The substrate comprises means for heating or irradiating a substance on or within the substrate with light, sound or ionizing radiation. In yet another embodiment, the substrate comprises means for agitating the substance in or on the substrate.

In one preferred embodiment, the substrate has a substantially flat upper surface having a plurality of recesses or wells,
These recesses or wells have a depth sufficient to allow a large volume of the synthesis support to be accommodated in the recesses or wells with one or more conversion reactants during the reaction.

The substrate is composed of any material that can be formed into a shape that allows for the synthesis and screening of the libraries of the present invention. The only limitation on the materials useful for constructing the substrate is that the substrate must be able to adapt to the reaction conditions to which it will be exposed. Thus, useful substrates when useful in performing the methods of the present invention include organic and inorganic polymers, metal oxides (eg, silica, alumina), mixed metal oxides, metal halides (eg, magnesium chloride), Including, but not limited to, minerals, quartz, zeolites, Teflon, polyethylene (crosslinked, uncrosslinked, or dentrimeric), polypropylene, copolymers, polypropylene, polystyrene, and ceramics. Other shapes for the substrate and materials for making the substrate will be apparent to those skilled in the art. Soluble catalysts can be adsorbed on inorganic or organic substrates to form useful heterogeneous catalysts.

In an example of a two-dimensional combinatorial library of a supported organometallic compound or a catalyst using a carrier for synthesis, the shape of the carrier for synthesis on the following substrate is possible. i) a porous carrier is disposed in the well, and reactants flow through the carrier by flowing out of the top of the well through holes in the bottom of the well (which may be in the opposite direction of flow); ii) the porous carrier is disposed in the well, and the reactant flows in / out only into or out of the top of the well; iii) the non-porous carrier is disposed in the well, and the reactant Flows around the substrate from the top of the well through the holes in the bottom of the well (the flow may be in the opposite direction); iv) the non-porous carrier is disposed within the well and the reactants are transferred from the top to the bottom of the well. Flow into or out of the well top or only from the top of the well without passing through; or v) the non-porous or porous carrier is not located in the well and the reactants are spatially addressed It is deposited directly on the surface of the substrate with the ability manner.

In embodiments where a ligand or synthesis support is attached to the substrate, the substrate is functionalized to allow this attachment. In embodiments in which the ligands are synthesized by bringing together each fragment of the ligand on a substrate, the substrate is functionalized so that the first ligand fragment can bind. In embodiments where no ligand or synthesis support is attached to the substrate, the substrate may or may not be functionalized.

Substrates that can be functionalized are known in the art. For example, a glass plate can be functionalized to allow binding of oligonucleotides (see, for example, Southern, Chem. Abstr. 1990, 113: 152979r). Another method of functionalizing glass is to use polar silanes containing hydroxyl or amino groups.
s) consisting of using Brennan (TM)
(U.S. Patent No. 5,474,796, the teachings of which are incorporated herein by reference.) Organic polymers can also be functionalized, e.g., polypropylene can be e.g. It can be surface-derivatized by oxidation and subsequently converted to a hydroxymethylated or aminomethylated surface with ligands, ligand fragments or anchors for synthetic supports. Polymers include, for example, highly crosslinked polystyrene-divinylbenzene, which can be surface derivatized by chloromethylation and subsequent functional group modification.
The surface of nylon can also be derivatized to give an initial surface of hexylamino groups.

As with the substrate, the carrier for synthesis can be an organic polymer material or an inorganic material such as alumina, silica, quartz glass, zeolite, Teflon (registered trademark), etc., but is not limited thereto. is not. Depending on the material comprising the carrier for synthesis, the carrier can be porous, woven or solid, and can be flat or in the form of beads or any other geometric shape It may be. Synthetic supports are known in the art, for example, consisting of functionalized polystyrene, polyacrylamide, controlled pore glass. Jones, J., "Amino Ac
"id and Peptide Synthesis", "Synthesis of Amino Acids and Peptides," Oxford Science Publications, Oxford, 1992; Ed. Narang, S., Ed.
See Thesis and Application of DNA and RNA, "Synthesis and Application of DNA and RNA," Academic Press, Inc., New York, 1987. Note that these teachings are incorporated herein by reference. In addition, any suitable method for functionalizing the substrate is suitable for functionalizing the intended material to be used as a support for synthesis. Once the substrate or synthesis support is functionalized, the ligand or ligand component is bound to the substrate or synthesis support.

(C. Ligands ) The method of the present invention is widely applicable to all ligands capable of binding metal ions. Ligand combinatorial mutations can be achieved by solid or solution phase reactions or multiple reactions. Alternatively, a sequence consisting of a solid phase reaction and a solution phase reaction can be used to synthesize an array of metal binding ligands.
The properties of ligands that can be mutated using the method of the invention include the number of coordination sites that can be occupied by the ligand on the metal, the charge and electronic effects of the ligand, the coordination Includes, but is not limited to, the geometry imparted to the metal by the element, the geometry imparted to the ligand by the metal, and the like. Numerous metal binding ligands are known in the art, and other ligands and ligand parameters that can be mutated using the methods of the invention will be apparent to those skilled in the art. For example, Colman (JP) and others, "Principl
es and Applications of Organotransition Metal Chem
istry "" Principles and Applications of Organic Transition Metal Chemistry ", University Science Books
ks), California, 1987. The teaching contents are incorporated herein by reference.

In one preferred embodiment, the generic approach is as follows: 1) metal coordination complexes of low coordination number (eg, 3 to 5) can be combined in various geometries (eg, triangular, tetrahedral, Synthesizing ligands (eg, ancillary ligands) that can be stabilized in square quadrangles, square pyramids, pentagons, double pyramids) to form these libraries; Forming a metal compound; 3) reacting the metal compound library with various activators and / or modifiers, if necessary; 4) subjecting the resulting metal compound library to various properties and properties (eg, Olefin polymerization activity, polymerization performance characteristics). In other embodiments, the activated metal catalyst can be immobilized on a library of supports and / or linkers, and then various properties (eg, olefin polymerization activity, polymerization performance properties) examined. In a particularly preferred embodiment, the metal ion is a transition metal ion.

In one preferred embodiment, the auxiliary ligand binds to the metal center and stabilizes the metal center with a low ligand and does not directly participate in catalytic chemistry. In general, it is preferred that the number of coordination loci be small, but this does not preclude embodiments using larger coordination loci. If the number of coordination loci is 3 or more, the metal-ligand compound may have more than one geometric shape.

In another preferred embodiment, the coordination site of the ancillary ligand is 1, 2, 3 or 4, and the charge of the ligand is 0,-.
1, -2, -3 or -4. Other ancillary ligands are those that are more charged than the number of coordination loci occupied by the ligand. Depending on the structural properties of some ligands, they can take on more than one coordination number and / or more than one charge. For example, the charge and / or coordination number of the ligand can be different when bound to different metals, such as early transition metal ions and late transition metal ions. Further examples include strongly basic conditions (strongly ba
For example, a ligand deprotonated with n-butyllithium and contacted with a metal ion may have a different ligand than the same ligand would have when reacted with a metal ion under milder conditions. It may have an order and / or charge.

Examples of ligands, metal-ligand complexes and catalysts that can be used in the method of the present invention include, but are not limited to: ^{(1) Cp * MR2 + NCA} - ( wherein, M is a metal, R represents an alkyl, NCA is a non-coordinating an anion) and one coordination site monoanionic ancillary ligands such as Mechiruarumo Mono-Cp system in combination with Xan (MAO).

(2) For example, a bi-coordinated dianionic auxiliary ligand containing a bis-Cp system (US Pat. No. 4,752,597)
No. 5,470,927, the teachings of which are incorporated herein by reference), mono-Cp systems in which a heteroatomic auxiliary ligand occupies a second coordination site (US Pat. No. 5,064,802, the teachings of which are incorporated herein by reference), non-Cp bis-amide systems (US Pat. Nos. 5,318,935 and 5,495,055).
No. 36 is mentioned. The teachings of which are incorporated herein by reference), and bridging bis-amide ligands and ligand stabilized Group IV catalysts (Organometallics 1995, 14: 3154-3156 and J. Am. Ch
em. Soc. 1996, 118: 10008-10009, the teachings of which are incorporated herein by reference).

(3) Bidentate monoanionic auxiliary ligands including, for example, Cp (L) CoR ⁺ X ^- and related systems. (Reference is made to WO 96/13529, the teachings of which are incorporated herein by reference). (4) Neutral auxiliary ligands in two-coordinates, such as, for example, the Ni ²⁺ and Pd ²⁺ systems. For example, Johnson (Johnson) et al.
J. Am. Chem. Soc. 1995, 117: 6414-6415 and WO 96/230
See 10. The teachings are incorporated herein by reference.

(5) Neutral auxiliary ligand in the three-coordinated position. (6) A monoanionic auxiliary ligand having three coordination sites. (7) Three-coordinate dianionic auxiliary ligand. (8) Trianionic trianionic auxiliary ligand. (9) Four-coordinated, neutral, monoanionic and dianionic auxiliary ligands. (10) Auxiliary ligands whose charge is greater than the number of coordination sites occupied by the ligand. (See, for example, US Pat. No. 5,504,049, the teachings of which are incorporated herein by reference.)

One application of the present invention is to prepare and screen a large number of ligands that are components of organometallic compounds or catalysts. The ligand used in practicing the present invention is a structural motif of the ligand.
groups) as part of the binding domain, e.g., alkyl, carbene, carbine, cyanide, olefin, ketone, acetylene, allyl, nitrosyl, diazo, dioxo, disulfur, diseleno, sulfur monoxide, sulfur dioxide , Aryl, heterocycle (heterocycle), acyl, carbonyl, nitrogen, oxygen, sulfur, phosphine, phosphide, hydride and the like. Other sources and groups consisting of metal binding domains are known in the art and are useful in practicing the present invention. For example, Colman (JP) and others, "PRINCIPLES AND APPLCATIO
See NS OF ORGANOTRANSITION METAL CHEMISTRY, "Principles and Applications of Organic Transition Metal Chemistry", University Science Books, California, 1987, the teachings of which are incorporated herein by reference.

As described above, the library of ancillary ligands is made using a combinatorial chemistry format. Within the library, a wide range of ligand properties can be mutated. Properties that can be mutated across libraries include, for example, ligand bulk, electronic properties, hydrophobic / hydrophilicity, geometry, chirality, ligand occupancy, and metal occupancy, There is a charge on both the ligand core and its substituents, the geometry that the ligand imparts to the metal.

Bidentate, tridentate and tetradentate ligand systems useful in combinatorial synthesis can be constructed, for example, from ligand fragments listed below according to charge.

The synthesis of these ligand libraries can be performed by a combination method (parallel method or split pool method) using various already established organic synthesis methods. The neutral ligand fragment is an amine (R ₃
N), phosphine (R ₃ P), arsine (R ₃ As), stilbine (R ₃ Sb), ether (R ₂ O), thioether (R ₂ S), selenoether (R ₂ Se), telluroether (R ₂ Te), ketones (R ₂ C = 0), a thioketone,
Imine (R ₂ C = NR), phosphinimine (R ₃ = N
R, RP = NR, R ₂ C = PR), pyridine, pyrazole, imidazole, furan, oxazole, oxazoline, thiophene, thiazole, isoxazole, isotrazol, arene, nitrile (RC-N), isocyanide (RN-) C), acetylene, and olefins, but are not limited thereto.

The monoanionic ligand fragment is an amide (N
R ₂ ), phosphide (PR ₂ ), silyl (SiR ₃ ), alcide (AsR ₂ ), SbR ₂ , alkoxy (OR), thiol (SR), selenol (SeR), terol (TeR), siloxy (OSiR ₃ ) , Cyclopentadienyl (C ₅ R ₅ ), boratbenzene (C ₃ BR ₆ ), pyrazoyl borate, carboxylate (RCO ₂ ⁻ ), acyl (RCO), amidate, alkyl, aryl, triflate (R ₃ CSO) ₃ ^-), thiocarboxylate (RC
S ₂ ⁻ ), halides, nitrates and the like, but are not limited thereto.

The dianionic ligand fragments include cyclooctatetrenyl (R ₈ C ₈ ²⁻ ), alkylidene (R ₂ C), boronide (C ₄ BR ₅ ), imide (RN), phosphide (R
P), carboxides, oxides, sulfides, sulfates, carbonates and the like, but are not limited thereto.

[0079] trianionic ligand fragments, alkylidyne (R-C≡), - P 3- ( phosphido), - Ar (Arushido), including phosphites, but is not limited thereto.

Polydentate ligands can generally be constructed by cross-linking a plurality of ligand fragments via one or more pendent R-groups. Specific examples of bidentate neutral ligands [2,0] that can be constructed from the above list of ligand fragments include diimine (derived from two imine fragments), and diimine (derived from pyridine and imine fragments). Pyridyl imine (derived), diamine (derived from two amine fragments), imine amine (derived from imine and amine), imine thioether (derived from imine and thioether), derived from imine and ether ) Imine ether, imine phosphine (derived from imine and phosphine), bisoxazoline (derived from two oxazolines), diether (derived from two ethers), bis (derived from two phosphinimines) Phosphinimine, diphosphine (derived from two phosphines), derived from phosphine and amine It has been) including phosphine amine, but is not limited thereto. Other bidentate neutral ligand systems,
It can be similarly constructed from the list of neutral ligand fragments described above.

The bidentate monoanionic ligand [2,1] is
Neutral ligand fragments can be constructed by crosslinking with monoanionic ligand fragments from the above list. Examples include salen and other alkoxyimine ligands (derived from imine and alkoxy ligand fragments), amidoamines (derived from amides and amines), and amide ethers (derived from amides and ethers). ), But is not limited thereto. Other bidentate monoanionic ligand systems can be constructed in a similar manner.

The bidentate dianionic ligand [2,2] has 2
It can be constructed by combining two monoanionic or dianionic ligand fragments with a neutral ligand fragment. Specific examples include dicyclopentadienyl ligands (derived from two cyclopentadienyl ligand fragments), cyclopentadienylamide ligands (cyclopentadienyl ligand fragments and amide ligands). Ligand fragment), imidothioether ligand (derived from imide ligand fragment and thioether ligand fragment), imidophosphine ligand (derived from imide ligand fragment and phosphine ligand fragment) Derived), and alkoxyamide ligands (derived from alkoxide and amide ligand fragments), but are not limited thereto. Other bidentate dianionic ligand systems can be constructed in a similar manner.

A bidentate ligand having a charge greater than -2 may be obtained by combining a monoanionic ligand fragment with a dianionic or trianionic ligand fragment or by combining two dianionic ligand fragments. Can be built by Examples include the bisimide ligand (2
Derived from two imide ligands) and a carbine ether ligand (derived from a carbine ligand fragment and an ether ligand fragment).

The tridentate neutral ligand [3,0] can be constructed by combining three neutral ligand fragments from the above list. Examples include 2,5 diiminopyridyl ligands (derived from two imine ligand fragments and one pyridyl ligand fragment), triimidazoyl phozphines (3 immobilized at the central phosphorus atom). One imidazole ligand fragment), a trispirazoyl alkane (derived from three pyrazole ligands attached to a central carbon atom), but is not limited thereto. Other tridentate neutral ligands (eg [3,1], [3,2], [3,3])
Can be similarly constructed.

In a preferred embodiment, the coordination numbers (CN) of the auxiliary ligands are each independently 1, 2, 3 or 4, and the charges on the ligands are each independently 0, -1, -2, -3 or -4. The ancillary ligand or ligand fragment need not be negatively charged, for example, tropylium (C ₇ H ₇ ⁺ )
Positively charged ligands such as are also utilized in practicing the present invention.

Currently preferred "families" of coordination numbers and charges include (i) CN = 2, charge = -2; (ii) CN =
2, charge = -1; (iii) CN = 1, charge = -1; (iv) C
N = 2, charge = neutral; (v) CN = 3, charge = −1; (vi)
(Vii) CN = 3, charge = −2; (v
iii) CN = 2, charge = −3; (ix) CN = 3, charge = −
3; (x) CN = 3, charge = 0; (xi) CN = 4, charge =
0; (xii) CN = 4, charge = −1; (xiii) CN = 4, charge = −2. In another preferred embodiment, the auxiliary ligand has a charge greater than the number of coordination sites occupied by the ligand on the metal ion.

Other preferred embodiments of the ligand family described herein that are useful in combinatorial synthetic strategies include (1) CN
= 2, charge = neutral carrier-carrying auxiliary ligand (denoted as [2,0]); (2) CN = 2, charge = -1 carrier-carrying auxiliary ligand (denoted as [2,1] ); (3) CN = 2, charge = −2
, An auxiliary ligand of a metal compound supported on a carrier (denoted as [2, 2]); (4) an auxiliary ligand not expressed as [2, 1] with CN = 2 and a charge of −1 (denoted as [2, 1]) (5) CN = 2, charge = -2
A carrier-unsupported auxiliary ligand (denoted as [2, 2]);
(6) Auxiliary ligand having CN = 2, charge = −2, not carrying a carrier, and having a functional linker (described as [2, 2]); (7)
Ancillary ligand with CN = 2, charge = −2, unsupported carrier and “non-functional” linker (denoted as [2,2]); (8) CN
= 3, charge = -3, and a carrier-unsupported auxiliary ligand ([3,
3]).

FIGS. 4 and 5 illustrate another route that may be used in synthesizing a catalyst precursor using the combinatorial synthesis approach of the present invention. In general, libraries of other ligand cores could be envisioned that can be made by using similar combinatorial chemistry formats. Examples are the ligand cores shown in FIGS.

In one important embodiment of the invention, an acidic functional group is located at the R group substituent in the library. Acidic functional groups have a significant effect on the catalytic performance of polymerization catalyst systems, including improving the ability of the catalyst to rapidly incorporate polar functional comonomers. Late transition metal catalysts, such as Brookhart's catalyst, allow the use of certain polar functional comonomers, but the coordination of the polar functional group to the metal center in the molecule significantly reduces the rate of polymerization. (See FIG. 15). As shown in FIG. 16, when the acidic moiety is properly positioned on the ancillary ligand, the acidic moiety competes with the metal center for coordination of the polar functional group, creating an empty coordination site at the metal center. Accelerates the rate of polymerization. Suitable acidic functional groups include, but are not limited to, trivalent boron groups, trivalent aluminum groups, carboxylic acids, and sulfuric acid. Introducing an acidic functional group into the R group of the auxiliary ligand system is a general concept applicable to all ligand / metal compounds of the present invention.

The ligands of the present invention, especially the diimine ligands,
It may be symmetric or asymmetric. Symmetric ligands have two parts, each derived from the same imine. In contrast, asymmetric ligands have two moieties each derived from an unequal amine. Numerous synthetic routes can be used to obtain asymmetric ligands. For example, protecting one carbonyl group of a diketone and reacting the other carbonyl group with an amine. The protected group is deprotected and the second carbonyl group is reacted with a second amine. In another useful reaction route, a nearly stoichiometric amount of a primary amine is added, followed by a similar amount of a secondary amine. Other synthetic routes for contrasting and asymmetric ligands will be apparent to those skilled in the art.

The R group, which is a side group of the auxiliary ligand core, is selected based on the properties imparted to the organometallic compound by the R group. The R group affects the reactivity and stability of the catalyst and the organometallic compound, but does not bind directly and irreversibly to the metal center. By changing the size and electronic properties of the R group, the bulk around the metal center and the electronic properties of the ligand-metal compound can be changed. An R group that is chiral can impart chirality to the ligand-metal compound. In addition, the R group can be used to adjust the hydrophobicity / hydrophilicity of the ligand-metal compound.

The R groups on the ligand are each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, halogen, amino, cyano, nitro, hydroxy,
Alkoxy, alkylamino, acylamino, silyl,
Germyl, stannyl, siloxy, phosphino, aryloxy, aryloxyalkyl, substituted aryloxyalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle,
Substituted heterocyclic, heterocyclic alkyl, substituted heterocyclic alkyl S-
It is selected from the group consisting of aryl and S-alkyl mercaptans.

As used herein, the term "independently selected" indicates that the R groups, eg, R1, R2, R3, can be the same or different (eg, R1, R2 and R3 may all be substituted alkyl, or R1 and R2 may be substituted alkyl, R3 may be aryl, etc.). Adjacent R groups may combine to form a cyclic structure.

The group named R group usually has the structure recognized in the art as corresponding to the R group having that name. For purposes of illustration, representative of the R groups shown above are defined below. These definitions are intended to augment and illustrate those known to those skilled in the art, but not to exclude them.

As used herein, the term “alkyl” refers to a branched or unbranched, saturated or unsaturated, monovalent hydrocarbon group. Alkyl group is
If it has 1-6 carbon atoms, the alkyl is said to be "lower alkyl". Suitable alkyl groups include, for example, methyl, ethyl, n-propyl, i-propyl, 2-propyl (or allyl), n-butyl, t-
Butyl, i-butyl (or 2-methylpropyl) and the like. As used herein, the term also includes "substituted alkyl."

“Substituted alkyl” refers to one or more of the functional groups just described and is a lower alkyl, aryl, acyl, halogen (ie, alkylhalo, such as C
F ₃ ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, mercapto, saturated and unsaturated cyclic hydrocarbons, heterocycles and the like. These groups may be attached to any carbon of the alkyl moiety.

The term “aryl” is used herein to refer to an aromatic substituent, wherein the aromatic substituent is
It may be a single aromatic ring or a plurality of aromatic rings fused to each other, covalently linked, or linked to a common group (eg, a methylene or ethylene moiety). The common linking group may be a carbonyl as in benzophenone. Aromatic rings include substituted or unsubstituted phenyl, naphthyl, biphenyl, diphenylmethyl and benzophenone.

"Substituted aryl" is used herein to refer to one or more functional groups that include lower alkyl, acyl, halogen, alkylhalo (eg, C
F ₃ ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto, saturated and covalently bonded to an aromatic ring or linked to a common group (eg, a methylene or ethylene moiety); And unsaturated cyclic hydrocarbons. The linking group may be a carbonyl, as in cyclohexyl phenyl ketone.

The term “acyl” refers to a ketone substituent
It is used to refer to -C (O) R, where R is alkyl or substituted alkyl, aryl or substituted aryl as defined herein.

As used herein, the term “amino” refers to the group —NRR ′, where R and R ′ are each independently hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl or Acyl). If the amino group is attached to the metal via a nitrogen atom, the group is said to be an "amide" ligand.

The term "alkoxy" is used to refer to the group --OR, where R is alkyl, substituted lower alkyl, aryl, substituted aryl, and substituted alkyl, aryl and substituted aryl groups are It is as described here. Suitable alkoxy groups include, for example, methoxy, ethoxy, phenoxy, substituted phenoxy, benzyloxy, phenethyloxy, t-butoxy, and the like.

[0102] As used herein, the term "mercapto" refers to the general group in which R and R 'are the same or different and are alkyl, aryl, or heterocyclic, as described herein. Defines the portion of the structure RSR.

The term "saturated cyclic hydrocarbon" refers to groups such as cyclopropyl, cyclobutyl, cyclopentyl, and the like, and the like as substitutes for these structures.

The term "unsaturated cyclic hydrocarbon" is used to refer to a monovalent non-aromatic group having at least one double bond, such as cyclopentene, cyclohexene, and the like, and equivalents thereof. You.

The term "heteroaryl" as used herein refers to an aromatic ring in which one or more carbon atoms of the aromatic ring have been replaced by a heteroatom such as nitrogen, oxygen or sulfur. Heteroaryl refers to a structure that may be a single aromatic ring, multiple aromatic rings, or one or more aromatic rings attached to one or more non-aromatic rings. In structures having multiple rings, the rings can be fused to each other, covalently linked, or linked to a common group such as a methylene or ethylene moiety. The common linking group may be carbonyl, as in phenylpyridyl ketone.

As used herein, the term “heteroaryl” refers to a ring such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan, or the like, or a benzo condensate and homolog of such a ring. Define.

"Heteroarylalkyl" refers to a portion of "alkyl" wherein a heteroaryl group is attached through an alkyl group, as defined herein.

"Substituted heteroaryl" is heteroaryl as defined above, wherein the heteroaryl nucleus is lower alkyl,
Refers to those substituted by one or more substituents such as acyl, halogen, alkylhalo (eg CF ₃ ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto and the like.

Accordingly, heteroaromatic rings, such as thiophene, pyridine, isoxazole, phthalimide, pyrazole, indole, furan and the like, or a homolog of a benzo condensate of these rings are defined by the term “substituted heteroaryl”. Is done.

"Substituted heteroarylalkyl" is "substituted alkyl" as described above, wherein an alkyl group links the heteroaryl group to the nucleus, as defined herein.

The term “heterocycle” is used herein for 1-1.
Monovalent saturated or unsaturated monocyclic or multiple condensed rings from two carbon atoms and from one to four heteroatoms in the ring selected from nitrogen, phosphorus sulfide or oxygen in the ring. Used to describe saturated non-aromatic groups. Such heterocycles are, for example, tetrahydrofuran, morpholine, piperidine, pyrrolidine and the like.

The term "substituted heterocycle" as used herein means that the nucleus of the heterocycle is alkyl, acyl, halogen, alkylhalo (eg CF ₃ ), hydroxy, amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto Refers to a portion of a “heterocycle” that is substituted by one or more functional groups, such as

The term "heterocyclic alkyl" refers to a portion of "alkyl" in which an alkyl group, as defined herein, connects the heterocyclic group to the nucleus.

The term "substituted heterocyclealkyl" defines that the heterocyclic nucleus is part of one or more functional groups such as amino, alkoxy, alkylamino, acylamino, acyloxy, mercapto and the like.

In a preferred embodiment, an array of ligand moieties is synthesized on a substrate. The array is a combinatorial array of surrate- or synthetic carrier ligand portions spatially separated from one another. Although any of the types of ligands described above can be used in this synthesis strategy, in a preferred embodiment, the array of ligand moieties comprises a neutral bidentate or chelating diimine ligand.
Following its synthesis, the array of ligand moieties can be bound to metal ions (eg, transition element ions, main group metal ions, lanthanide ions).

In another embodiment of the invention, the metal-ligand array or library is adjusted so that each element of the ligand array contacts the metal ion precursor in the presence of a suitable solvent. Wherein the metal ligand is a neutral bidentate moiety and the metal precursor is stabilized by at least one displaceable neutral Lewis base. Transition metal ion precursors are particularly preferred. In another preferred embodiment, the ligand moiety is a diimine ligand and the transition metal precursor is selected from a Group 10 transition metal.

In yet another embodiment, the ligand is a monoanionic bidentate moiety and the transition metal precursor is stabilized by at least one displaceable anionic leaving group ligand. .

In one preferred embodiment of the present invention, the ligand library described herein can be reacted with a main group metal precursor to make a catalyst library.
Such catalytic libraries can be used for a variety of organic transformations requiring Lewis acid sites, including stereoselective coupling reactions (here, chiral Lewis acids are required), olefin oligomer formation reactions, and olefin polymerization reactions. used. An example of such a reaction is
[2,2] or [2,1] of trialkylaluminum
There is a reaction with the ligand library, in which each element of the ligand library is in a di- or monoprotic form, respectively. This reaction produces an organometallic library consisting of a bidentate ligand attached to a mono or dialkyl aluminum center. Such a library comprises [PhNMe ₂ H] ⁺ [B (C
₆ F _{5) 4]} ^- reaction further modified by the an using an ion-exchange activator as, a ligand capable of acting as catalysts for organic coupling reactions, olefin oligomers produced reactions and olefin polymerization - A stabilized cationic aluminum reactant can be produced. like this,
An example of a [2,2] or [2,1] reaction is shown in Scheme 1 below.
It is shown below.

Embedded image Scheme 1

These compounds are useful, for example, as catalysts for polymerizing organic monomers. Organic monomers are ethylene, propylene, butene, isobutylene, hexene, methyl acrylate, methyl vinyl ether,
Including, but not limited to, dienes.
The reaction can be carried out in the gas phase or in solution, on a substrate or synthesis support, or separately. Since the catalytic properties of the metal-ligand compound on the substrate or the carrier for synthesis can be examined, a library of catalysts bound to various substrates or carriers for synthesis (eg, polystyrene, silica, alumina, etc.) can be prepared. It can be manufactured.

In another preferred embodiment of the present invention, the polymer blend is prepared such that two or more elements of the metal-ligand library are contacted with at least one cocatalyst and at least one monomer. To manufacture. In yet another preferred embodiment of the present invention, an olefin, such that at least two elements of the metal-ligand library are contacted with at least one cocatalyst and at least one monomer.
Polymerizes diolefin and acetylene unsaturated monomers.

Another example of the library comprises a diimine ligand of the following general formula (I): These libraries can be synthesized by solution or solid phase methods or a combination thereof.

Embedded image

The substituents R ¹ , R ² , R ³ and R ⁴ can be selected from the wide range of organic fragments mentioned above. The role of the R group substituent is based on the steric properties, stereochemical properties,
To modify solubility and electronic properties. The R groups can be polar or non-polar and can consist of neutral, acidic or basic functional groups. Suitable R groups include those mentioned above and organic metalloid groups such as, for example, silyl or germyl groups. The molecular weight of the R group substituent generally ranges from 1 to 1
It is in the range of 0,000 daltons. Molecular weight 10,000
Polymeric or oligomeric R groups greater than 0 can also be made.

The diimine ligand library described above can be contacted with a number of metal precursors to form an organometallic library. In one method, the ligand library is contacted with a coordinating unsaturated metal precursor or a metal precursor complexed with a weakly bound leaving group ligand as shown in Scheme 2 below.

Embedded image Scheme 2

Note that L in the formula is a neutral Lewis acid base, n
Is an integer greater than or equal to 0; Z is an integer greater than or equal to 0; "a" represents the number of L groups transferred, a + z = n; M is a metal; X is an anionic ligand such as halide, hydrocarbyl or hydride M represents the number of X ligands and is an integer of 0 or more.

Metal catalysts comprising non-coordinating anions can be synthesized by contacting a protonated form of a ligand library with a low valent metal precursor. For example, a transition metal catalyst stabilized with diimine
Two steps: 1) reacting the diimine library with the Bronsted acid of a non-coordinating anion to form an iminium salt library; 2) converting the iminium salt library to a suitable low valent metal It can be adjusted by a method comprising a step of contacting with a precursor. One example of such a method is shown in Scheme 3 below.

Embedded image Scheme 3

In some embodiments, the ligand of the invention is
Although made as pure stereo or regio conformational isomers, the ligands can alternatively be a mixture of isomers. Metals suitable for use in the present invention include:
Cr, Mo, W, Pd, Ni, Pt, Ir, Rh, Co
Etc., but is not limited thereto. Activators suitable for use in the method of the invention include MAO,
^{_{[H (OHt) 2] +}} [BAr 4] - including such as but not limited thereto. Solvents suitable for use in the method of the present invention include hexane, CH ₂ Cl ₂ , toluene, CH
Including, but not limited to, Cl _{3 and the} like.

The above-mentioned method is more than 3, more than 10, 2
Over 0, over 50, over 100, over 200,
It can be used to synthesize more than 500, more than 1,000, more than 10,000 or more than 100,000 different compounds.

The step of chemical synthesis can be carried out by combining a solid phase step and a solution phase step on a substrate or a carrier for synthesis such as pins or beads or in a well. The method of mutating the ligand can be performed by dispensing the reactants in parallel to spatially addressable sites, or by a known “split and pool” combination method.

The method of the present invention also includes embodiments in which the length and / or chemical composition of the binding moiety between the ligand and the substrate or carrier for synthesis are varied.

(D. Linker ) The combinatorial library is prepared by using an organometallic catalyst on a substrate or a solid support (for example,
(Silica, alumina, polystyrene, etc.). In another embodiment of the invention, a linker group is interposed between the substrate and the ligand and / or between the support for synthesis and the ligand and / or between the substrate and the support for synthesis. A wide range of cleavable and non-cleavable linker groups are known to and used by those skilled in the chemical arts, and are used in the present invention to construct libraries of ligands and organometallics. be able to. Linker length and structure are potential variables that can affect catalyst performance and can be factors in library design. Examples of various linkers suitable for use in the methods of the present invention are described in more detail in PCT US94 / 05597, the teachings of which are incorporated herein by reference.

(E. Metal ) Once formed, the ligand library of the present invention can be contacted with metal ions to produce organometallic compounds. These compounds are
Usually a catalyst. Metal ions are in the form of simple salts, mixed salts or organometallic compounds.

When the process of the present invention is used to find active catalysts, any class of metal ions can be used. The broad classes of metal ions used in practicing the present invention include, but are not limited to, transition metal ions, lanthanide ions, main group metals and actinide ions.

F. Immobilized Reactants In practicing the present invention to produce combinatorial (combinatorial) solution libraries, one or more immobilized reactants that serve different roles are used. It is useful. Therefore,
For example, immobilized base, acid, proton sponge, oxidizing agent,
The use of reducing agents, acylation and alkylation catalysts and the like is included in the present invention. Many such immobilized reactants are
It is known to and used by those skilled in the art.

(G. Non-coordinating anion (NCA) ) If an anion not coordinating at the metal center or a weakly coordinating anion is present in the catalyst, the reactivity of the catalyst will be such that the anion is located at the metal center. It is known in the art that it is higher compared to the catalyst being placed. (For example, US Pat. No. 5,198,401,
Nos. 5,278,119, 5,502,017 and 5,447,895
Reference is made to these issues, the complete disclosures of which are incorporated herein by reference. )

Anions that are bulky, highly stable, non-coordinating to cationic metal centers, and that exhibit strong Lewis acidity and high reactivity are particularly useful in the practice of the present invention. In a preferred embodiment, the non-coordinating anion is a boron-containing structure. In another preferred embodiment, the non-coordinating anion is an organometallic or catalytic system wherein the four aryl structures are replaced by one or more electron-withdrawing substituents (eg, fluorine) and at least one bulky R group. A tetraarylboron structure that increases solubility and thermal stability. Representative R groups are as described above for the ligand. In a preferred embodiment, R groups, C ₁ -C ₂₀ alkyl or C ₁ -C ₂₀
Group 14 metalloids substituted with alkyl (eg, silicon, germanium or tin). Other non-coordinating ions used in practicing the present invention will be apparent to those skilled in the art.

(H. Design of Diimine Catalyst Library
(Synthesis ) The principle and method of synthesizing and synthesizing an array of a ligand and an organometallic compound have been outlined. Further, a method of designing and synthesizing a solution phase and a solid phase library of a diimine ligand and an organometallic compound will be described. .

FIG. 17 shows the design of a 96-well ligand and ligand-metal solid phase library using Merrifield resin and the chemical methods described in the Examples section. This library consists of 48 diimine ligands derived from diketone precursors and 48 substituted anilines linked by Merrifield resin.
The diketone precursor bound by Merrifield resin is added to each of the 96 wells in a microtiter plate. An excess of each aniline is added to two wells of a microtiter plate and the reaction is allowed to proceed using the protocol described in the Examples section. Ni was added to each of the obtained resin-bonded diimines.
And the Pd metal ion precursor to produce the desired catalyst precursor. The catalyst precursor can be activated using a suitable activator and screened for activity and performance using the methods described in the present invention.

The method of the present invention can also be used to prepare solution phase diimine ligands and catalyst libraries. The use of solid phase reactants, which catalyze the reaction, provide the reactants, and adsorb by-products and / or unreacted starting materials, greatly exploits solution phase combinatorial chemistry. A general approach for the parallel synthesis of diimine ligands and the corresponding metal compounds is shown in FIG.
This is described in section 1. Mutations in the ligand backbone substituents (ie, R ₁ and R ₂ ) are based on the various commercially available 1,1 species illustrated in FIG.
This can be achieved by utilizing a 2-diketone. The condensation of the imine in the solution phase can be catalyzed, for example, by various Lewis acid catalysts / dehydrants immobilized on the solid phase (FIG. 20). Examples include: _{[PS] -CH 2 -O-TiCl} 3; [PS] -CH 2 -O-AlCl 2; [PS] -SO 2 -O-TiCl 3; [PS] -SO 2 -O-AlCl 2; [PS _{-PEG] -TiCl 4; [PS-} PEG] -AlCl 3; [SiO 2] - (O) 4-n -TiCl n; and _{[SiO 2] - (O)} 3-n -AlCl n one embodiment , these catalysts, the solid-phase proton scavenger, [PS] -CH ₂ - used with piperidine.

The selective capture of excess aniline in the presence of diimine can be achieved using various solid phase reactants. Examples include: [PS] -C (O) Cl + [PS] -CH 2 - _{piperidine; [PS] -SO 2 Cl +} [PS] -CH 2 - piperidine; [PS] -NCO; and [PS] -NCS

(III. Combinatorial Library
Screening ) The success or failure of combinatorial chemistry depends on, first, whether an assembly (library) of molecular compounds (elements) each having a unique elemental composition can be synthesized, and Depends on the ability to rapidly characterize a compound having certain desired properties. Thus, in one preferred embodiment, an array of substances is synthesized on a single substrate. By synthesizing an array of substances on a single substrate, screening of the array for substances having useful properties can be more easily performed.

Thus, following library synthesis, libraries of compounds are screened for useful properties. Properties that can be screened include, for example, electrical properties, thermomechanical properties, morphological properties, optical properties, magnetic properties, chemical properties, and the like. In one preferred embodiment, useful properties are those involved in the polymerization reaction. In another preferred embodiment, the useful property is a mechanical, optical, physical or morphological property.
In certain preferred embodiments, useful properties include, for example, the lifetime of metal-ligand compounds, the stability of these compounds under particular reaction conditions, the selectivity of library compounds for particular reactions, the library A chemical property such as the conversion efficiency of a compound in a particular reaction or the activity of a library compound in a particular reaction. Other properties that can be screened are shown in Table 1 below. Any substance found to have useful properties can then be manufactured on a large scale. For simplicity, the analytical methods of the present invention are comprehensively illustrated by describing their use in a library of catalytic compounds. The use of such a library of catalyst compounds does not limit the scope of analytical methods applicable to the analysis of libraries of organometallic compounds.

[Table 1]

The properties listed in Table 1 can be screened using a wide range of methods and equipment known to and used by those skilled in the art. Such methods include scanning mass spectrometry, chromatography, ultraviolet imaging, visible imaging, infrared imaging, electromagnetic imaging, ultraviolet spectroscopy, visible spectroscopy, infrared spectroscopy, electromagnetic spectroscopy, acoustic methods, However, the present invention is not limited to this. In addition, scanning systems that can be used to screen the properties listed in Table 1 include scanning Raman spectroscopy; scanning NMR spectroscopy; eg, surface potentiometry, tunneling current, nuclear power, acoustic microscopy, shear stress microscopy. Analysis, ultrafast photoexcitation, electrostatic force microscopy analysis, tunnel-induced photoemission microscopy analysis, magnetic force microscopy analysis,
Scanning probe spectroscopy, such as microwave field guided surface harmonic generation microscopy, non-linear AC tunneling microscopy, near-field scanning optical microscopy, inelastic electron tunneling spectroscopy, etc .; optical microscopy at different wavelengths; Scanning optical ellipsometry (to measure the modulus and thickness of the multi-phase film); scanning eddy current microscopy; electron (diffraction) microscopy; and the like.

In the currently preferred embodiment, a scanning detection system is used. In one embodiment, a substrate having an array of substances thereon is immobilized and the detector performs XY motion. In this embodiment, the base is provided in the closed chamber close to the detection device. Detector (for example, RF resonator, SKU
ID detection device, etc.), scanning range up to 1 inch and 2 μm
And mounted at room temperature on a rigid bar of low thermal conductivity coupled to an XY positioning table. The position of the sensing device is controlled using a stepper motor (or servomotor) coupled to a computer controlled positioning device. In another embodiment, the substrate on which the sensing device is immobilized and has the substance array thereon is the R-
Perform θ movement. In this embodiment, the substrate is placed on a rotating stage (eg, a spur gear) driven by a gear rack coupled to a micrometer and a stepper motor. In each embodiment, the temperature of the sensing device and the substrate can be reduced by, for example, a helium exchange gas.
The scanning system can be operated at temperatures ranging from 600 K to 4.2 K below (when immersed in liquid helium).

The use of combinatorial chemistry to discover and optimize new catalysts involves activity (ie, turnover), selectivity in converting reactants to desired products, a wide range of substrate concentrations and It is further enhanced by using high-throughput methods in measuring properties such as stability during operation under reaction conditions). Spatially selective characterization methods include, for example, (i) identification and characterization of volatile components of gas phase products and aggregated phase products, (ii) identification and characterization of aggregated phase products, and (iii) Methods that allow the measurement of the physical properties of various catalytic elements of the library.

The method described here with high throughput (0.1 to over 1000 library elements per second) and position sensitivity (0.01 to 10 mm resolution)
It includes several fundamentally different approaches, including scanning mass spectrometry and chromatography, electromagnetic imaging and spectroscopy such as ultraviolet, visible, infrared, etc., and acoustics. Methods for measuring the activity and specificity of the catalyst include, for example,
Includes a method for directly measuring the product concentration or a method for indirectly measuring the heat of reaction. Parallel screening methods have a common approach of integrating position sensitive photon detectors into the measurement system, while serial screening methods involve controlled scanning of libraries or detectors / sources relative to each other. Relying on

The activity of each compound in the array is measured using one or more of several optical, thermal, and mass spectral methods. In one example, infrared imaging techniques monitor such temperature changes, taking advantage of the fact that the exothermic or endothermic nature of the reaction localizes the temperature difference in regions adjacent to the compound. Thereby, the active sites in the compound array are specified in parallel. Similar techniques can be used to quantify the stability of each catalyst with a compound array in parallel. For each site in the array, the lifetime of the catalyst can also be quantified by measuring the decrease in activity over time.

The determination of the selectivity of a catalyst in a combinatorial array is performed by using ultraviolet / visible / infrared imaging and / or spectroscopy, chromatography or mass spectroscopy. One of the most common methods of the present invention is to use scanning mass spectrometry to locally measure the relative concentrations of reactants and products adjacent to a catalytic compound in a library. is there. Such measurement systems use laser desorption to vaporize liquids, binding reactants and / or binding products in a spatially localized manner, and facilitate the incorporation of chemicals into the scanning mass spectrometer. And can be made even more powerful.

Optical methods are used for active and selective characterization. Infrared spectroscopy or infrared spectroscopy imaging monitors the relative concentrations of end groups and monomers of the saturated backbone along the polymer chains on the polymer. In this way, the average molecular weight of the library element and the average composition of the copolymer can be estimated. ultraviolet/
Visible spectroscopy techniques are used, for example, in analyzing reactions involving compounds having suitable chromophores (eg, aromatic and unsaturated compounds). Another example is
Partial oxidation of benzene to phenol may produce different electronic absorption spectra for different products.
In this case, benzene is clearly distinguished from phenol as a spectroscopic fingerprint, thus making it possible to determine the relative amounts of each compound using UV / visible spectroscopy.

Rapid chromatographic analysis of reactants and products as separate substances or mixtures can be used to determine product conversion, product identification, isomer purity, etc. in parallel. Also, when performing a polymerization reaction, the velocity of the product polymer solution through the vertical tube is used to measure the viscosity of the polymer and, therefore, the molecular weight of the polymer. In addition, mass spectrometry can be used for gas phase characterization.

Those skilled in the art will readily appreciate that numerous methods and apparatus in addition to the ones described above may be used to screen libraries of compounds for useful properties. Such methods and devices are also included within the scope of the present invention.

The present invention relates to the synthesis of supported and unsupported ligand molecules and the subsequent conversion of the ligand molecules to organometallic compounds and catalyst compounds. In the following examples, the synthesis of two representative compounds, diimines and pyridyl imines, is described in detail using the method of the present invention.
Representative examples using both solution and solid phase methods are shown. The use of these two broad groups of ligands to further illustrate the invention is exemplary and can be assembled by using the scope of the invention or the method of the invention. It does not define or limit the scope of ligands, organometallic compounds or catalysts.

(IV. Embodiments) The following embodiments explain various embodiments of the present invention. Example 1 describes the synthesis of a bis-imine ligand in the solution phase. Example 2 describes the concept of combinatorial synthesis (combinatorial synthesis) of diimine ligands in the solid phase. Example 3
The application of the method of the present invention to the solid-phase synthesis of diimine ligands in which the synthesis of diimine is performed on a carrier will be described.
Example 4 illustrates the utility of the catalyst of the present invention in the synthesis of olefins. Both the supported and unsupported catalysts of the present invention were evaluated for their ability to polymerize ethylene into poly (ethylene). The polymerization of higher olefins such as hexene was also investigated. Example 5 details the preparation of a pyridylimine ligand and its nickel complex. This catalyst was used to polymerize both hexene and ethylene. Example 6 describes a reaction scheme that can be used to prepare various [2,0], [2,1] and [2,2] ligand libraries. Such [2,0],
[2,1] and [2,2] ligand libraries can be prepared from a salen-based skeleton using solution or solid phase methods.

Example 1 Example 1 details the solution phase synthesis of the bis-imine ligand component of a combinatorial ligand library. A comprehensive strategy was undertaken for arylbis-imines having both electron donating and electron withdrawing groups on the aryl moiety.

(1.1 via solution phase method [(2,4,
6Me ₃ PH) Synthesis of _{DABMe 2] NiBr 7) (a} . Resin-bound Lewis acid catalyst PS-CH ₂ -O-TiC
l ₃ Synthesis) 10 g of hydroxymethyl polystyrene swelled in the anhydrous of CH ₂ Cl ₂ 100mL (OH1.1
To 2 mmol / g of resin) was added 4.24 g (2.24 mmol) of TiCl ₄ and the suspension was heated to reflux under N ₂ with gentle stirring for 1 hour. The resin was filtered under N ₂ and washed with 5 × 50 mL of anhydrous CH ₂ Cl ₂ , then
Dry under high vacuum for 24 hours. Chlorine analysis value (chlor
ide analysis) (9.98%) gave a loading of 0.94 mmol TiCl ₃ / g resin.

(B. Synthesis of aniline scavenger PS-SO ₂ Cl) 10 g of PO ₂ S in 50 mL of anhydrous CH ₂ Cl ₂
O ₂ -OH (washed with MeOH, and vacuum dried Amberlyst 15 (Amberlyst 15; about 5 mmoles of OH /
To 1 g of resin) was added 3 g (25 mmol) of SOCl ₂ . The mixture under N ₂ and heated to reflux for 18 hours. The resin was filtered under N ₂ and 5 × 50 mL of anhydrous CH ₂ C
washed with l _2, and dried under high vacuum for 24 h. From the chlorine analysis value (16.05%), 4.53 mmol of SO ₂ C
A loading of 1 / g of resin was obtained.

(C. Synthesis of ligand) 250 mg (0.2
PS-CH ₂ -O-TiCl ₃ of 4 mmol) and 93mg
(0.25 mmol) of PS-CH ₂ -piperidine 5
To a suspension in anhydrous CHCl ₂ (mL) was added 676 mg (0.
5 mmol) of 2,4,6-trimethylaniline, followed by 8.6 mg (0.1 mmol) of 2,3-butanedione. The mixture was shaken at room temperature (RT) for 24 hours, then filtered and washed with ₂ × 1 mL of anhydrous CH ₂ Cl ₂ . When analyzed by gas chromatography,
4,6-trimethylaniline and the product (2,4,
6-Me ₃ Ph) DABMe ₂ was shown in a ratio of about 3: 1.

(D. Capture of excess aniline) 2,4,6
-Trimethylaniline and (2,4,6-Me ₃ Ph) D
ABME ₂ of 3: To a mixture of 1, 111 mg of PS-S
O ₂ Cl and 185mg of PS-CH ₂ - piperidine was added and the mixture was shaken for 12 hours at room temperature. Filter the resin,
Washed with ₂ × 0.5 mL anhydrous CH ₂ Cl ₂ . The filtrate was evaporated and 285 mg (89%) of (2,4,6-Me
₃ PH) DABMe ₂ was obtained as yellow crystals.

(E. [(2,4,6-Me ₃ Ph) DA
Synthesis of BMe ₂ ] NiBr ₂ complex) 285 mg (0.89
Mmol) of (2,4,6-Me ₃ Ph) DABMe ₂ and 274 mg (0.89 mmol) of (DME) NiBr ₂
In 5 mL of CH ₂ Cl ₂ was shaken in a sonication bath at room temperature for 24 hours. The resulting solid was collected by filtration, washed with ₃ × 1 mL of anhydrous CH ₂ Cl ₂ and 456
mg (95%) of [(2,4,6-Me ₃ Ph) DAB
[Me ₂ ] to obtain Br ₂ as a red powder.

(1.2 (2,4,6-Me) ₂ DAB
(Me) Production of EtPh nickel (II) dibromide )

Embedded image Scheme 4

(2,4,6-Me) ₂ DAB (Me) E
tPh (0.50 g, 1.17 mmol) and (DME)
8 mL of NiBr ₂ (0.36 g, 1.17 mmol)
In dry CH ₂ Cl ₂ under nitrogen and stirred at room temperature for 8 hours. The resulting reddish-brown solution was concentrated and the residue was washed with CH ₂
Recrystallisation from Cl ₂ / hexane gave 0.40 g of (2,4,6-Me) ₂ DAB (Me) EtPh nickel (II) dibromide in 53% yield as reddish brown crystals. C ₃₀ H ₃₆ N ₂ NiBr ₂ requires: C 55.88; H 5.6
2 _; N 4.34. Found: C, 55.08; H, 5.55; N, 4.21.

(1.3 Synthesis in Solution Phase (Spectral Analysis Model
Compound) ) A compound having all the structural features of the immobilized compound was prepared in parallel with the immobilized compound. With this model compound, appropriate spectroscopic parameters could be determined for similar immobilized compounds. In addition, these compounds have catalytic activity similar to that represented by similar immobilized metal-ligand compounds.

(1.3 (a) Using benzyl bromide
Alkyl of (2,4,6-Me) ₂ DAB (Me) Et
Conversion )

Embedded image Scheme 5

(2,4,6-Me) ₂ DAB (Me) E
t (2.00 g, 5.99 mmol) in dry THF 15
to a cooled solution (0 ° C.) under nitrogen and LDA (4.
40 ml, 6.59 mmol, 1.5 M in THF) was added. After stirring at 0 ° C. for 2 hours, benzyl bromide (0.
86 ml, 7.19 mmol) was added and the resulting solution was stirred at 0 ° C. for 3 hours at room temperature for 10 hours. The reaction mixture was concentrated on a rotovap and 50 ml of an oily residue
In Et ₂ O and washed with H ₂ O ( ₂ × 50 ml). The Et ₂ O layer was dried over MgSO ₄ , filtered and concentrated. The crude material was passed through a plug of silica gel with CH ₂ Cl ₂ and concentrated again to give 2.54 g of the desired product in 95% yield as a yellow oil. ¹ H
NMR 300 MHz, (CDCl ₃ ) δ7.23-7.28 (m, 3H), 7.19
(D, 2H, J = 6.9 Hz), 6.98 (s, 2H), 6.94 (s, 2
H), 2.87 (br s, 4H), 2.64 (q, 2H, J = 7.6 Hz),
2.37 (s, 3H), 2.35 (s, 3H), 2.14 (s, 6H), 2.06
(S, 6H), 1.12 (t, 3H, J = 7.6 Hz); ^13C NMR 75M
Hz, (CDCl ₃ ) θ 171.97, 169.97, 145.85, 145.56, 141.1
5, 132.28, 132.20, 128.66, 128.28, 128.15, 125.9
7, 124.37, 32.76, 31.28, 22.24, 20.67, 18.22, 18.0
6, 11.24; IR (C = N) @ 1635 cm ^-1 .

(1.3 (b) benzyl (2,4,6-M
e) Hydrolysis of ₂ DAB (Me) Et (methyl) )

Embedded image Scheme 6

10 ml of THF / H ₂ O (5: 1 v /
benzyl (2,4,6-Me) ₂ DAB within v)
(Me) A stirred solution of Et (0.20 g, 0.47 mmol) and oxalic acid (0.20 g, 2.35 mmol) was added to 7
Heat at 0 ° C. for 8 hours. Cool to room temperature and add 30 ml of E
After dilution with t ₂ O, the organic layer was washed with H ₂ Cl ₂ ( ₂ × 10 m
1), dried over MgSO ₄ , filtered and concentrated. Gas chromatography / mass spectrometry (GC / MS)
As a result, the detectable species in the crude reaction mixture was 1
-Phenyl-3,4-hexanedione and 2,4,6-
It was only trimethylaniline. The crude mixture was passed through a silica gel plug to give pure 1-phenyl-3,4-hexanedione (89 mg)> 95.
% Yield as a colorless oil. ¹ H NMR 300 MHz,
(CDCl ₃ ) δ 7.20-7.31 (m, 5H), 3.14 (t, 2H, J = 7.6
Hz) 3.01 (t, 2H, J = 7.4 Hz), 2.75 (q, 2H, J = 6.
7 Hz), 1.07 (t, 3H, J = 6.6 Hz); ¹³ C NMR 75 MHz,
(CDCl ₃ ) δ 199.44, 198.25, 140.19, 128.20, 128.06, 1
25.94, 37.34, 29.10, 28.67, 6.53; IR (C = O) @ 1712cm
^-1 .

(1.3 (c) (2,4,6-Me) ₂ D
AB (Me) Et of 1- (bromomethyl) -2-methoxy
Alkylation with cyetane )

Embedded image Scheme 7

(2,4,6-Me) ₂ DAB (Me) Et (0.50) in 15 ml of dry THF under nitrogen
g, 1.48 mmol) in a cooled solution (0 ° C.).
(1.09 ml, 1.65 mmol, 1.5 in THF
M) was added. After stirring at 0 ° C. for 4 hours, 1- (bromoethyl-2-methoxyethane (0.24 ml, 0.1 mL) was added.
1.79 mmol)) in Bu ₄ NI (0.27 ml g,
(0.75 mmol) and the reaction mixture was heated to 50 ° C. and stirred for 10 hours. After cooling to room temperature, the reaction mixture was diluted with 30 ml of Et ₂ O and H ₂ O (3 × 15
ml), dried over MgSO ₄ , filtered and concentrated on a rotovap. The crude material was chromatographed with 20% Et ₂ O / hexane (R _f = 0.45) to give 0.93 g of the desired product as a yellow oil in 45% yield. . ¹ H NMR 300 MHz, (CDCl ₃ )
δ6.81 (s, 2H), 3.33 (s, 4H), 3.25-3.32 (m, 2
H), 3.23 (s, 3H), 2.41-2.47 (m, 4H), 2.20 (s, 6
H), 1.94 (s, 12H), 1.54-1.69 (m, 2H), 0.94 (t,
3H, J = 7.5 Hz). ¹³ C NMR 75 MHz (CDCl ₃ ) δ 171.97,
170.35, 145.65, 145.52, 132.15, 128.56, 128.53, 12
4.36, 71.72, 70.95, 69.48, 58.89, 27.33, 25.51, 2
2.19, 20.61, 18.06, 11.11

(1.3 (d) (2,4,6-Me) ₂ D
AB (1 methoxyethoxyethyl) Et nickel (II)
Preparation of dibromide )

Embedded image Scheme 8

(2,4,6-Me) ₂ DAB (1-methoxyethoxypropoxy) ethane (0.29 g, 0.1 g).
67 mmol) and (DME) NiBr ₂ (0.21 g,
(0.67 mmol) was dissolved in 6 ml of dry CH ₂ H ₂ under nitrogen and stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and concentrated to give crude (2,4,6-Me)
₂ DAB (1 methoxyethoxypropyl) ethylnickel (II) dibromide is obtained, which is purified by recrystallization from CH ₂ Cl ₂ / hexane to give 0.35 g of pure product in 80% yield. Obtained as red-brown crystals. C
_{28 H 40 N 2 O 2 NiBr} 2 of theory: C 51.33; H 6.15; N 4.27. Found: C, 52.01; H, 6.26; N, 3.91.

(1.3 (e) (2,4,6-Me) ₂ D
AB (Me) EtPh palladium (II) (Me) Cl
Preparation )

Embedded image Scheme 9

(2,4,6-Me) ₂ DAB (Me) E
tPh (0.23 g, 0.65 mmol) and (COD)
PdMeCl (0.17 g, 0.65 mmol) was dissolved in 8 ml of dry CH ₂ Cl ₂ under nitrogen and 8
Stirred for hours. The resulting orange-red solution was concentrated and the residue was recrystallized from CH ₂ Cl ₂ / hexane to give 0.30 g
Of (2,4,6-Me) ₂ DAB (Me) EtPh palladium (II) (Me) Cl was obtained as an orange solid in 80% yield. C ₃₁ H ₃₉ N ₂ PdCl requires C 64.02;
H 6.76; N 4.81 found: C 63.47; H 6.70; N 4.62.

(1.4 Combinatorial solution in solution phase
Formation of bis-imines using synthesis ) catalysts generally works well for aniline derivatives containing an electron donating group (X = EDG). However, anilines containing an electron withdrawing group (X = EWG) are much less nucleophilic and no bis-imine formation is observed under standard conditions (Experiment 1 of Table 1). Therefore, a typical electron-deficient aniline derivative (X =
3.5-CF ₃₎ with bis - looked for conditions to initiate the formation of the imine. The overall scheme is shown in Scheme 10. Table 2 shows the results.

Embedded image Scheme 10

Table 2 Experiment A B Catalyst Conditions C number (equivalent) (equivalent) (equivalent) Yield (GC / MS) 11 20 HCO ₂ H (10) CH ₂ CL ₂ / MeOH 0% room temperature, 12 hours 21 _{20 H 2 SO 4 (10)} CH 2 CL 2 / MeOH 20% at room temperature, 12 hours _{3 1 20 (CO 2 H)} 2 (10) CH 2 CL 2 / MeOH 65% at room temperature, 12 hours 4 1 10 (CO ₂ H) ₂ (10) (CH ₈ O) CH 0% 70 ° C., 12 hours 5 120 (CO ₂ H) ₂ (10) Si (OEt) ₄ 60% room temperature, 12 hours 61 13 TiCl ₄ (2) CH ₂ CL ₂ 80% at room temperature, 12 hours _{7 1 15 TiCl 4 (5)} CH 2 CL 2 95% at room temperature, 12 hours

Example 2 Example 2 shows the concept of combination synthesis of a diimine ligand in a solid phase. The alkylation of the diimine ligand with 1% cross-linked (bromomethyl) polystyrene is performed by the approach described below. The supported diimine is hydrolyzed to form the corresponding resin-bound diketone used as a starting material for the synthesis of a wide variety of chemically diverse bis-imine ligands. A similar solution phase reaction was also performed in parallel, and the solution phase reaction was fully characterized by spectroscopy to provide spectroscopic handles.
( ¹ H and ¹³ C NMR, FTIR, Raman IR) and help to enable the characterization of the desired resin-bound compound.

(2.1 Combination Strategy on Solid Phase (Con
Binatorial strategy) ) This approach involves the parallel synthesis of an organometallic library immobilized on a polymer support. Advantages of this approach include exposing a significant excess of reactants to the immobilized substrate to efficiently complete the reaction. The excess reactants and / or by-products are then removed from the desired immobilized substrate by subsequent filtration and thorough washing.

(2.2 (bromomethyl) polystyrene
Preparation )

Embedded image Scheme 11

(Hydroxymethyl) polystyrene (2.
50 g, 2.84 mmol, 0.80 mmol / g) and triphenylphosphine dibromide (2.40 g, 5.
68 mmol) under nitrogen and 20 ml of dry TH
F was added. After stirring at room temperature for 24 hours, the resin was filtered and THF (3 × 20 ml), DMF (3 × 20 m
1), washed vigorously with CH ₂ Cl ₂ (3 × 20 ml) and dried under high vacuum to give 2.75 g of (bromomethyl) polystyrene as a light brown resin. 0.58 mmol / mol based on bromide analysis (4.65% Br)
g loading was calculated.

(2.3 (bromomethyl) polystyrene
Of (2,4,6-Me) ₂ DAB (Me) Et
Ruquilization )

Embedded image Scheme 12

(2) in 15 ml of dry THF under nitrogen
4,6-Me) ₂ DAB (Me) Et (0.50 g,
LAD (0.49 mmol) in a cold solution (0 ° C).
19 ml, 1.49 mmol, 1.5 M in THF) were added. After stirring at 0 ° C. for 2 hours, (bromomethyl) polystyrene (1.06 g, 0.75 mmol) was added,
The resulting suspension was stirred at 0 ° C. for 3 hours and at room temperature for 10 hours. The resin is filtered and THF (2x20ml),
H ₂ O ( ₂ × 20 ml), CH ₂ Cl ₂ ( ₂ × ₂₀ ml)
And dried under high vacuum to give 0.60 g of the desired light yellow resin. The amount of the resin carried was calculated to be 0.38 mmol / g based on the analysis value of nitrogen (1.07% N). By single bead FTIR, 16
Strong absorption was observed at 35 cm ^-1 (C = N).

(2.4 (2,4,6-Me) ₂ DAB
(Me) Hydrolysis of Et (methyl) polystyrene

Embedded image Scheme 13

17 ml of THF / H ₂ O (5: 1 v / v
(2,4,6-Me) ₂ DAB (Me) Et in v)
A stirred suspension of (methyl) polystyrene (1.0 g, 0.38 mmol) and oxalic acid (340 g, 3.80 mmol) was heated at 70 ° C. for 12 hours. Cool to room temperature 3
After dilution with Et ₂ O to the 0 ml, the resin was filtered and the filtrate was washed with H ₂ O (2x10 ml), dried over MgSO _4, filtered, and concentrated to gas chromatography / mass spectrometry and ¹ 24 mg,> 99% pure by HNR analysis
Of 2,4,6-trimethylaniline was obtained in a yield of 98%. The beads were dried under high vacuum and 850 mg of (2,
(3-Butandionemethyl) polystyrene was obtained. Strong absorption was observed at 1712 cm ^-1 (C = O) by single bead FTIR.

(2.5 (bromo) PEG polystyrene
Of (2,4,6-Me) ₂ DAB (Me) Et
Ruquilization )

Embedded image Scheme 14

(2,4,6-Me) ₂ DAB (Me) Et (0.7) in 15 ml of dry THF under nitrogen
g, 2.09 mmol) in a cold solution (0 ° C.).
(1.63 ml, 2.44 mmol, 1.5 in THF
M) was added. After stirring at 0 ° C. for 4 hours, (bromo) P
EG polystyrene (2.33 g, 0.70 mmol,
0.30 mmol / g) and Bu ₄ NI (0.77 g,
2.09 mmol) was added and the reaction mixture was heated to 50 ° C. and stirred for a further 8 hours. Then, the resin is filtered,
THF (3 × 20 ml), H ₂ O (3 × 20 ml), M
Washed vigorously with MeOH (3 × 20 ml). After drying under high vacuum, 2.37 g of (2,4,6-Me) ₂ DA
B (Me) Et (bromo) PEG polystyrene was obtained as a yellow resin. Based on the nitrogen analysis (0.71% N), a loading of 0.25 mmol / g was calculated. Magic Angle Spin (MAS) ¹ H NMR 400 MHz,
(CDCll ₃ ) δ 6.87 (br s, 2H), 3.51 (br s, 2H), 2.76
(Br s, 2H), 2.51 (d, 2H, J = 7.6 Hz), 2.28 (s,
6H), 2.01 (s, 12H), 1.74 (brs, 2H). 1.03
(T, 3H, J = 6.8 Hz). 2.6 (2,4,6-M
e) Hydrolysis of ₂ DAB (Me) EtPEG polystyrene
Solution

Embedded image Scheme 15

(2,4,6-Me) ₂ DAB (Me) E
tPEG polystyrene (0.50 g, 0.12 mmol, 0.25 mmol / g) and oxalic acid (0.10 g,
1.12 mmol) in 20 ml of THF / H ₂ O (5:
1, v / v) and 7 with gentle stirring for 8 hours
Heated at 0 ° C. After cooling to room temperature and diluting with 25 ml Et ₂ O, the resin was filtered and the filtrate was washed with H ₂ O ( ₂ × 10 m
1), dried over MgSO ₄ , filtered and concentrated to give a quantitative yield of 16 mg of 2,4,6-trimethylaniline. The 2,4,6-trimethylaniline had a purity of> 99% by gas chromatography / mass spectrometry and ¹ NMR analysis. The beads were dried under high vacuum to give 450 mg of a beige 2,3-butanedinone PEG resin. Magic Angle Spin (MAS) ¹ H 400 MHz, (CDCl ₃ ) δ 2.80 (m, 2H), 1.90
(M, 2H), 1.08 (t, 3H, J = 6.8 Hz).

(2.7 (2,4,6-Me) ₂ DAB
(Me) Et nickel (II) dibromide PEG polystyrene
Preparation of Len )

Embedded image Scheme 16

(2,4,6-Me) ₂ DAB (Me) E
t PEG polystyrene (0.40 g, 0.10 mmol, 0.25 mmol / g) and (DMe) NiBr
₂ (0.15 g, 0.50 mmol) under nitrogen for 10 m
Dissolved in 1 liter of dry CH ₂ Cl ₂ and stirred at room temperature for 12 hours. The resin was then washed vigorously with CH ₂ Cl ₂ and anhydrous acetone to give 0.42 g of (2,4,6-Me) ₂ DAB
(Me) Et nickel (II) dibromide PEG polystyrene was obtained as a dark reddish brown resin. The amount of the resin supported was calculated to be 0.54 mmol / g from the analytical value of nickel (3.40% Ni), and the analytical value of bromine (8.6).
0.57 mmol / g based on (7% Br), indicating that some residual nickel (II) dibromide was coordinated to the PEG polystyrene backbone.

(2.8 (2,4,6-Me) ₂ DAB
(Me) Et palladium (II) (Me) Cl PEG
Preparation of polystyrene )

Embedded image Scheme 17

(2,4,6-Me) ₂ DAB (Me) E
t PEG polystyrene (0.50 g, 0.12 mmol, 0.25 mmol / g) and (COD) PdMeCl
(0.16 g, 0.63 mmol) was dissolved in 7 ml of dry CH ₂ Cl ₂ under nitrogen and stirred at room temperature for 12 hours. The resin is then washed extensively with CH ₂ Cl ₂ to give 0.5
1 g of (2,4,6-Me) ₂ DAB (Me) Et Pd
(II) (Me) ClPEG polystyrene was obtained as a red-orange resin. Magic Angle Spin (MAS) ¹ H
NMR 400 MHz, (CDCl ₃ ) δ 6.97 (br s, 2H), 6.92 (br
s, 2H), 2.75 (br s, 2H), 2.45 (br s, 2H)), 2.
32 (s, 3H), 2.30 (s, 3H), 2.24 (s, 6H), 2.21 (b
rs, 6H), 1.62 (br s, 2H), 1.03 (br s, 3H), 0.
36 (s, 3H).

(2.9 (2,4,6-Me) ₂ DAB
(Me) Et palladium (II) (Me) Cl PEG
Preparation of polystyrene )

Embedded image Scheme 18

(2,4,6-Me) ₂ DAB (Me) E
t polystyrene (0.30 g, 0.11 mmol,
0.38 mmol / g) and (COD) PdMeCl
(0.15 g, 0.57 mmol) under nitrogen,
Dissolved in 8 ml of dry CH ₂ Cl ₂ . After stirring for 10 hours, the resin was washed vigorously with CH ₂ Cl ₂ , dried under high vacuum and dried with 0.32 g of (2,4,6-Me) ₂ DAB (M
e) Et palladium (II) (Me) Cl polystyrene was obtained as a red-orange resin. Based on the analysis value of palladium (4.15% Pd), the supported amount of this resin was 0.32 mmol / g and the analysis value of chlorine (3.39%
It was calculated to be 0.39 mmol / g based on Cl).

Example 2 shows the synthesis of a representative diimine ligand using the solid phase combination method (solid phase combinatorial method) of the present invention. The diimine of Example 2 was synthesized on a support other than on the support, and then bound to the support for further modification. Subsequent to the hydrolysis of the diimine attached to the support, the diketone used to produce further diimine is produced.

Example 3 Example 3 shows an example in which the method of the present invention is applied to solid-phase synthesis of a diimine ligand synthesized on a carrier.

(3.1 Formation of Bis-imine on Solid Phase)

Embedded image Scheme 19

To a suspension of 2,3 butanedione (methyl) polystyrene (0.10 g, 0.08 mmol) in dry CH ₂ Cl ₂ in 5 ml was added 3,5-bis (trifluoromethyl) aniline (0. .25 ml, 1.60 mmol) and TiCl ₄ (0.80 ml, 0.80 mmol,
(1.0 M in CH ₂ Cl ₂ ) was added. Mix the mixture at room temperature for 2 hours.
Stir for 4 hours, filter the resin, CH ₂ Cl ₂ (3 × 10
ml), MeOH (3 × 10 ml), H ₂ O (3 × 10
ml) and dried under high vacuum to give 0.11 g of the desired resin. The supported amount of the resin was 0.43 mmol / mol based on the analytical value of nitrogen (0.43% N).
g. Example 3 illustrates that diimines can be formed directly on resins functionalized with diketones.

Example 4 Example 4 shows that the catalyst of the present invention can be used for olefin polymerization. It has been investigated that both the supported and unsupported catalysts of the present invention can polymerize ethylene into poly (ethylene).
The polymerization of higher olefins such as hexene was also considered.

4.1 Polymerization of ethylene

Embedded image Scheme 20

The above resin-bound nickel (II) dibromide complex (0.16 g, 0.03 mmol) was suspended in 10 ml of dry toluene, and MAO was added thereto (2.0%).
0 ml, 300.0 mmol, 10% by weight in toluene). The resin immediately turned dark blue. After stirring for 1 hour, ethylene gas was bubbled through the suspension for 1 minute, and the reaction vessel was sealed at 5 PSI. An internal thermocouple measured 29 ° C. exotherm for 20 minutes. After stirring for an additional 1.5 hours, the temperature gradually returned to room temperature, the viscous solution was filtered, and the beads were washed with toluene (3 × 10 ml). Concentrate the filtrate, then
Upon quenching with MeOH, a white rubbery (poly) ethylene was immediately formed. This material is filtered, dried and
1.60 g of (poly) ethylene were obtained. The beads were dried under high vacuum to yield 1.60 g of material, corresponding to a 10-fold weight gain of polystyrene beads.

The catalyst activated with MAO was treated with toluene (3
x10 ml), but the same procedure as above was followed. After filtering off the excess MAO, it is dissolved in 10 ml of toluene before introducing ethylene. The same product as in the above procedure was obtained. When this washed resin was dissolved in 10 ml of hexane instead of toluene, the amount of (poly) ethylene weighed 0.1% on the beads as well as in the filtrate.
It was only 26 g.

The above examples show that the supported catalysts of the present invention can catalyze the polymerization of olefins.

(4.2 [2-Ph) PMI (2,6-
(Pr) ₂ Ph] of ethylene using NiBr ₂ / MAO
Polymerization ) 6 mg (0.01 mmol) of [2-Ph) PMI (2,6- (Pr) ₂ P in anhydrous degassed toluene
h)] To a suspension of NiBr _2, 3.3 mL in toluene
(5 mmol) of 10% MAO was added and the resulting green solution was stirred at room temperature for 1 hour. The solution was then flushed with ethylene and stirred under 10 psi of ethylene for 2 hours. The reaction mixture was added to 4M HCl (5
0 mL) and Et ₂ O (100 mL) were added, the layers were separated, and the organic layer was dried over MgSO ₄ . Removal of volatile components on a rotary evaporator yielded 1.3 g of polymer material.

(4.3 (2,4,6-Me) ₂ DAB
(1-methoxyethoxypropyl) Et nickel (II)
Polymerization of ethylene using dibromide )

Embedded image Scheme 21

(2,4,6-Me) ₂ DAB (1-methoxyethoxypropyl) ethylnickel (II) dibromide (0.02 g, 0.03 mmol) was suspended in 15 ml of dry toluene, and MAO was added. (2.00 ml, 3
00.0 mmol, 10% by weight in toluene). The solution turned dark blue over 1 hour. After stirring for 1 hour, ethylene gas was bubbled through the suspension for 1 minute, then the reaction vessel was sealed at 5 psi. The internal thermocouple was measured to generate a 23 ° C. exotherm for 45 minutes. After stirring for another 1.5 hours, the temperature gradually returned to room temperature and the solution was washed with MeOH followed by 5N HCl.
And quenched. The precipitated polyethylene was collected by filtration and dried under high vacuum, yielding 1.38 g of polyethylene.

(4.4 (2,4,6-Me) ₂ DAB
(Me) EtPh using nickel (II) dibromide
Polymerization of styrene )

Embedded image Scheme 22

(2,4,6-Me) ₂ DAB (Me) E
tPh nickel (II) dibromide (0.02 g, 0.0
3 mmol) in 15 ml of dry toluene
O was added (2.00 ml, 9.33 mmol, 10% by weight in toluene). The solution turned dark blue over 1 hour. After stirring for 1 hour, ethylene gas was bubbled through the suspension for 1 minute, and the reaction vessel was sealed at 5 psi. An internal thermocouple measured 19 ° C. exotherm for 45 minutes. After stirring for another 1.5 hours, the temperature gradually returned to room temperature and the solution was washed with MeOH.
Subsequently, it was quenched with 5N HCl. When the precipitated polyethylene was collected by filtration, dried under high vacuum,
2.10 g of polyethylene were obtained.

The above examples show that the supported and unsupported catalysts of the present invention can be used in olefin polymerization reactions.

(4.5 (2,4,6-Me) ₂ DAB
(Me) Et nickel (II) dibromide PEG polystyrene
Polymerization of ethylene using len )

Embedded image Scheme 23

The above resin-bound nickel (II) dibromide resin (0.20 g, 0.02 mmol, 0.10 mmol / g) was suspended in 20 ml of dry toluene, and MAO was added (2.00 ml, 300.0%). Mmol, 10% by weight in toluene). The resin immediately turned dark blue. 1
After stirring for an hour, the suspension was bubbled with ethylene gas for 1 minute and the reaction vessel was sealed at 5 psi. An internal thermocouple measured a 3 ° C. exotherm for 45 minutes. After stirring for a further 1.5 hours, the temperature gradually returned to room temperature, the solution was filtered and the beads were washed with toluene (3 × 10 ml). The beads are dried under high vacuum and have a 0.6 mass equivalent to a 3 fold increase in mass of polystyrene beads.
7 g of material were obtained. No polyethylene was obtained from the filtrate.

(4.6 (2,4,6-Me) ₂ DAB
(Me) Et palladium (II) (Me) ClPEG poly
Polymerization of ethylene using styrene )

Embedded image Scheme 24

The above resin-bound palladium (II) (Me)
Cl resin (0.20 g, 0.02 mmol, 0.10 mmol / g) was suspended in 20 ml of dry CH ₂ Cl ₂ ,
aB (Ar ') was added ₄ F (18mg, 0.02 mmol). The resin turned brown-red for 1 hour and ethylene gas was bubbled through the suspension for 1 minute. The reaction vessel was sealed at 5 psi. No exotherm was observed throughout the course of the reaction. After stirring for an additional 1.5 hours, the solution was filtered and the beads were washed with toluene (3 × 10 ml). Dry the beads under high vacuum and remove 20% of the polystyrene beads.
0.25 g of material corresponding to the weight gain was obtained. No polyethylene was obtained from the filtrate.

(4.7 (2,4,6-Me) ₂ DAB
(Me) Et palladium (II) (Me) Cl polystyrene
Of ethylene using ethylene )

Embedded image Scheme 25

The above resin-bound palladium (II) (Me)
Cl resin (0.10 g, 0.03 mmol, 0.32 mmol / g) was suspended in 25 ml of dry CH ₂ Cl ₂ ,
aB (Ar ') ₄ F was added (30 mg, 0.03 mmol). The resin turned brown-red for 1 hour and ethylene gas was bubbled through the suspension for 1 minute. The reaction vessel was sealed at 5 psi. Throughout the course of the reaction, a temperature of 23
° C. was observed. After stirring for another 1.5 hours,
The solution was filtered and the beads were washed with toluene (3 × 10 ml). The beads were dried under high vacuum to give 0.25 g of material, corresponding to a 100% weight gain of the polystyrene beads. From the filtrate, 2.28 g of polyethylene was obtained as a colorless rubber. Gel filtration chromatography (toluene, 23 ° C, polystyrene standard): Mn = 18,5
_{18; Mw = 31,811; M w} / M n = 1.72.

(4.8 (2,4,6-Me) ₂ DAB
(Me) Et using palladium (II) (Me) Cl
Polymerization of styrene )

Embedded image Scheme 26

(2,4,6-Me) ₂ DAB (Me) E
t palladium (II) (Me) Cl (0.02 g, 0.0
3 mmol) were suspended in 25 ml of dry CH ₂ Cl ₂ ,
aB (Ar ') ₄ F was added (30 mg, 0.03 mmol). The solution turned brown-red over 1 hour and ethylene gas was bubbled through the suspension for 1 minute. Reaction vessel 5ps
Closed to i. An exotherm of 28 ° C. was observed throughout the course of the reaction. After stirring for an additional 2.5 hours, the solution was filtered through celite. From the filtrate, 3.50 g of polyethylene was obtained as a colorless rubber. Gel filtration chromatography (toluene, 23 ° C., polystyrene standards): W _n
= 21,016; _Mw = 31,471; _Mw / _Mn = 1.50.

(4.9[2-Ph) PMI (2,6-
(Pr) ₂ Ph] Hexene using NiBr ₂ / MAO
polymerization) 6 mg of [2-P in 1 mL of anhydrous degassed toluene
h) PMI (2,6- (Pr) _TwoPh)] NiBr
_Two(0.01 mmol) of suspension into 3.3 mL (5 ml)
(Mol) in a 10% toluene solution of MAO.
The green solution was stirred at room temperature for 1 hour. Then, the solution
8.4 g (100 mmol) of hexene was added to the solution and dissolved.
Liquid to N_TwoStirred under for 24 hours. Add 4
M HCl (50 mL) and Et_TwoO (100 mL)
The layers are separated and the organic layer is_FourDried on.
Volatile components were removed on a rotary evaporator, 3.9 g (46%)
Of the polymer material was obtained.

Example 5 Example 5 details the preparation of a pyridylimine ligand and its nickel complex. This catalyst was used for the polymerization of both hexene and ethylene. Scheme 27 shows the synthesis route of the pyridylimine nickel complex.

Embedded image Scheme 27

(5.1 2-acetyl-6-bromopyri)
To a solution of Jin preparation) 20 mL of anhydrous Et ₂ O in the 2,6-dibromopyridine 3.00 g (12.7 mmol) (-78 ℃), n- B of 1.6M in cyclohexane
8.0 mL (12.8 mmol) of uLi was added dropwise over 30 minutes. After stirring at −78 ° C. for 3 hours, 8.2 mL (88 mmol) of N, N-dimethylacetamide was added dropwise and the solution was stirred at −78 ° C. for 1 hour. Upon heating to room temperature, Et ₂ O (100 mL) and saturated aqueous NH ₄ Cl (50 mL) were added and the layers were separated. The organic layer was dried over Na ₂ SO _4, the volatiles were removed on a rotary evaporator. The resulting yellow solid was recrystallized from hexane and 1.8 g (71%) of 2-acetyl-6.
-Bromopyridine was obtained as colorless crystals. ¹ H NMR
(CDCl ₃ ): δ 2.81 (s, 3H); 7.67-7.77 (m, 2 H);
8.22 (dd, J = 6.8, 1.6 Hz, 1H). Mass spectrometry value: m / e 2
00.

(5.2 2-acetyl-6-phenylpy
Preparation of lysine ) 200 m in 10 mL of degassed toluene
g (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph ₃ P) ₄ P
Degassed H2O / M was placed in the Schlenk tube filled with the solution
A solution of 150 mg (1.2 mmol) of phenylboronic acid and 270 mg (2.5 mmol) of Na ₂ CO _{3 in} 8 mL of MeOH (4: 1) was added. The biphasic mixture was heated to 80 ° C. for 1 hour with vigorous stirring. Upon cooling to room temperature, Et ₂ O (50 mL) was added and the phases were separated. The organic layer was dried over Na ₂ SO _4, the volatiles were removed on a rotary evaporator. The oil obtained is 10-50% C
Chromatography on silica with H ₂ Cl ₂ / hexane gave 176 mg (89%) of 2-acetyl-6.
-Phenylpyridine was obtained as a white powder. ¹ H NMR
(CDCl ₃ ): δ 2.84 (s, 3H); 7.43-7.62 (m, 3H); 7.
91-8.08 (m, 3H); 8.18 (d, J = 6.6 Hz, 2H). Mass spec: m / e 197.

(5.3 2-acetyl-6-phenylpy
Lysine 2,6-di (isopropyl) phenylimine
Key of [(2-Ph) PMI (2,6- (Pr) ₂ Ph]]
Ltd.) in anhydrous MeOH in 5 mL, 2-acetyl-6-phenylpyridine of 197 mg (mmol) and 266m
g (1.5 mmol) of a solution of 2,6-diisopropylaniline and 0.1 M H ₂ SO _{4 in} MeOH at 50 ° C.
For 12 hours. The volatile components were removed on a rotary evaporator and the crude was chromatographed on silica with 5% EtOAc / hexane eluent to give 287m
g (80%) of (2-Ph) PMI (2,6- (Pr)
₂ Ph) was obtained as a yellow solid. ¹ H NMR (CDC
_{l 3): δ1.17 (ddd,} J = 4.6,1.7,0.7 Hz, 12H); 2.
23 (d. J = 2.5 Hz, 3H); 2.73 (dq, J = 6.8, 2.5 H
z); 7.10-7.25 (m, 3H); 7.60-7.75 (m, 2H); 7.90-
8.06 (m, 2H); 8.33-8.40 (m, 1H). Mass spectrometry value: m /
e 356.

(5.4 [(2-Ph) PMI (2,6
-(Pr) ₂ Ph)] Preparation of NiBr ₂ ) Anhydrous CH ₂ Cl ₂
Within, 71 mg (0.2 mmol) of (2-Ph) PM
I (2,6 (Pr) ₂ Ph) and 62mg (0.2 mmol) a suspension of (dimethoxyethane) nickel (II) bromide, stirred at room temperature for 48 hours under N _2. The volatile components were removed on a rotary evaporator and the solid was washed several times with hexane to give 101 mg (88%) of 1 [(2-Ph) P
MI (2,6- (Pr) ₂ Ph)] NiBr ₂ was obtained as an orange powder.

The above examples show that pyridyl imines can be prepared by the process of the present invention and that these imines can be used in the polymerization of olefins. An analog of the catalyst solid phase described above is prepared using the starting materials shown in Scheme 13 (insert) above.

(Embodiment 6) In this embodiment, various [2,
1 shows a reaction scheme that can be used to prepare a library of [0], [2,1], [2,2] ligands. Such [2,0], [2,1], [2,2] ligand libraries are summarized in Scheme 14 where R ¹ and R ² are defined in the Dimine Library section above. It can be adjusted from the basic salen system using solution or solid phase methods using some synthetic methods.

Embedded image Scheme 28

Scheme 28 describes the chemistry involved in both the solution and solid phase methods. When this chemistry is performed via solid phase chemistry, the scaffold is attached to solid particles, shown as spheres in the figure above.

[2,0] Ligand libraries can be converted to organometallic libraries by using the substitution or oxidative addition methods described above for the diimine system. [2,1] Ligand libraries can be converted to organometallic libraries using oxidative addition or metathesis reactions. Oxidative addition of a heteroatom-proton to a low-valent metal precursor to form a hydride or hydrocarbyl ligand-metal compound is an effective method of making a reactive organometallic library. Metathesis reactions are also useful for making organometallic libraries from [2,1] ligand libraries. The Bronsted acid library described in the above figure is based on a metal reactant (such as trimethylaluminum) containing a leaving group ligand capable of abstracting acidic protons on the [2,1] ligand. (Including main alkyl groups) can be used directly in metathesis reactions. Alternatively, the [2,1] ligand library can be deprotonated and further reacted with a metal compound to form a metal salt library that can undergo a metathesis reaction. Other metathesis reactions that result in loss of tin or silyl by-products are also contemplated.

A diamide-based organometallic library can be prepared from a diamino ligand library using oxidative addition or metathesis reactions similar to those described above. The diamino ligand library can be prepared using the synthetic methods described in FIGS. 3, 9, and 13.

The tetradentate [4,0] ligand is synthesized according to Scheme 15
Can be produced by combining two [2,0] ligands. An example of such a combination is shown in the figure below. The [4,0] ligand-metal library converts [4,0] ligand to [2,0] bis-
It can be made by contacting a suitable transition metal precursor in a manner similar to that described for making the imine library.

Embedded image Scheme 29

It is to be understood that the above description is illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. Accordingly, the scope of the invention should not be determined by reference to the above description, but instead should be determined with reference to the appended claims, for all equivalents to such claims. It is. The disclosures of all articles and references, including patent applications and publications, are hereby incorporated by reference for all purposes.

[Brief description of the drawings]

1A and 1B show examples of transition metal-based metallocene catalysts and subsequent transition metal, eg, zirconium and nickel-based catalysts, respectively.

FIG. 2 shows a solid phase reaction that can be used to achieve a combination variant of a series of combinatorially mutated diimine ligants and / or diamine ligants. Shows the sequence.

FIG. 3 shows a solid phase reaction that can be used to achieve a combination variant of a series of combinatorially mutated diimine ligants and / or diamine ligants. Show the sequence.

FIG. 4 shows various combination routes for synthesizing various ligands.

FIG. 5 shows various combination routes for synthesizing various ligands.

6A-6G show examples of ligand cores that can be made using a combinatorial chemistry format.

FIG. 7 shows an example of synthesizing an auxiliary ligand having CN = 1 or 2 and charge = 0 or −1 on a carrier.

FIG. 8 shows an example of synthesizing an auxiliary ligand having CN = 1, 2 or 3, and charge = 0, −1 or −2 on a carrier.

FIG. 9 shows CN = 2, charge = −2, [2,
2] shows an example in which the auxiliary ligand represented by 2) is synthesized on a carrier together with a metal complex.

FIG. 10 shows that CN = 2, charge = 0, −1, or −2.
The following shows examples of the synthesis of two types of auxiliary ligands not supporting a carrier.

FIG. 11 shows CN = 2, charge = −1,
An example of the synthesis of a carrier-unsupported auxiliary ligand represented by [2, 1] will be described.

FIG. 12 shows an example of the synthesis of a carrier-unsupported auxiliary ligand having CN = 2, charge = 0, −1, −2 or −3, and having a functional linker.

FIG. 13 shows that CN = 2, charge = 0, −1 or −2.
And shows an example of the synthesis of a carrier-unsupported auxiliary ligand having a “non-functional” linker.

FIG. 14 shows that CN = 2 or 3, charge = 0, −1,
A synthesis example of a carrier-unsupported auxiliary ligand of -2, -3, or -4 is shown.

FIG. 15 shows an example of a synthetic scheme useful for conferring acidic functionality on R group substituents in an array or library.

FIG. 16 shows an example of a synthetic scheme useful for imparting acidic functionality to R group substituents in an array or library.

FIG. 17 illustrates the synthesis of a library consisting of 48 diimine ligands, which is later converted to a library of 96 diimine-metal compounds.

FIG. 18 shows a generalized solution phase synthesis of diimine using a fixed catalyst, a proton sponge, and a reactant-adsorbing reactant.

FIG. 19 shows an array of commercially available diketones used in practicing the present invention.

FIG. 20 shows examples of immobilized Lewis acid catalysts and dehydrating reactants.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 251/16 C07C 251/16 C07F 15/00 C07F 15/00 C // C07B 61/00 300 C07B 61 / 00 300 C07D 213/53 C07D 213/53 C07M 1:00 C07M 1:00 (31) Priority claim number 60/035366 (32) Priority date January 10, 1997 (1.10.10) (33) Priority Country United States (US) (72) Inventor McFarland, Eric United States of America, California 95112, San Jose, 607 North Third Street (72) Inventor Goldwasser, Icy United States of America, 94025, California, Menlo Park, 435 Encina Le Avenue, Apartment She (72) Inventor Bussy, Thomas United States, 94025, California, Menlo Park, 462 Ravenswood (72) Inventor Turner, Howard United States, California 95008, Campbell, 2948 Massy Court (72) Inventor Van Van Beek, Johannes A.M., United States, 94043, California, Mountaineer View, 75 Tirrera Court (72) Inventor Murphy, Vince, United States, 95014, California, Cupertino, 20800 Homestead Road # 11 F. (72) Invention Powers, Timothy 94595, California, United States, Walnut Creek, 111 Adams Ranch Road F-term (reference) 4C055 AA01 BA03 BA06 BA08 BA30 BB04 CA01 DA01 GA02 4G069 AA08 BA27A BA27B BC68B BC72B BE13B BE33B BE37B BE43A FA01 4006 A02 AC59 BA10 BA45 BA51 4H039 CA71 CD40 CL25 4H050 AA02 AB40 WB14 WB17 WB21

Claims (13)

[Claims] A first metal ligand compound and a second metal ligand compound different from the first metal ligand compound supported on a carrier different from the substrate in a predetermined region of the substrate; Form a combinatorial array of spatially separated supported metal ligand compounds, the ligand core, the identity of the substituents of the ligand core, the charge of the metal ion, the counter ion, the activator,
A method for producing an array of supported metal ligand compounds, wherein the result of changing at least one of a reaction condition, a solvent, an additive, and a linker can be measured. 2. The method according to claim 1, wherein the first metal ligand compound is supported on a first carrier, and the second metal ligand compound is supported on a second carrier. 3. The method according to claim 1, wherein the first metal ligand compound and the second metal ligand compound are synthesized on the first carrier and the second carrier. 4. The method according to claim 1, wherein the metal of the second metal ligand compound is different from the metal of the first metal ligand compound. 5. The substrate according to claim 1, wherein the first metal ligand compound is supported on a first region of the substrate, and the second metal ligand compound is supported on a second region of the substrate. 2. The method according to item 1. 6. The method according to claim 1, wherein the metal of the first ligand compound is selected from the group consisting of main group metal ions and transition metal ions. 7. The method according to claim 1, wherein the ligand has a coordination number (CN) independently selected from the group consisting of 1, 2, and 3. 8. The method according to claim 1, wherein the ligands are 0, -1, -2, -3 and -4.
The method according to any one of claims 1 to 7, having a charge independently selected from the group consisting of: 9. The ligand is (i) CN = 2, charge = −2,
(Ii) CN = 2, charge = −1, (iii) CN = 1,
Charge = -1, (iv) CN = 2, charge = neutral, (v) C
N = 3, charge = −1, (vi) CN = 1, charge = −2,
(Vii) CN = 3, charge = −2, (viii) CN =
9. The method according to claim 1, having a coordination number (CN) and a charge independently selected from the group consisting of 2, charge = -3, (ix) CN = 3, charge = -3. the method of. 10. A metal compound represented by the general formula L _n MX _m (L is a neutral Lewis acid base, n is an integer of 0 or more, M is a metal, X is an anionic ligand, and m is an integer of 0 or more). 10. The method according to any one of the preceding claims, wherein a metal is provided. 11. The method according to claim 1, wherein the ligand is an auxiliary ligand. 12. The method of claim 1, further comprising the step of screening said array for useful properties.
The method according to any one of claims 1 to 4. 13. The useful properties include: polymerization properties, mechanical properties, optical properties, physical properties, morphological properties, lifetime of the metal ligand compound during catalysis, specific reaction conditions. Stability of the metal ligand compound of, selectivity of the metal ligand compound under a catalytic reaction, selected from the group consisting of conversion efficiency and reactivity of the metal ligand compound in a catalytic reaction, The method according to claim 12.