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The invention relates to 1 ,10-phenanthrolιne derivatives substituted at the 3-, 8- positions


Self-assembling supramolecular systems capable of photo-induced electron and energy transfer, and molecular arrays displaying non-linear optical (NLO) properties, exemplify key design targets in materials chemistry For leading references discussing supramolecular chemistry, see (a) Lehn, J -M Angew Chem Int Ed Engl 1990, 29, 1304-1319 (b) Balzani, V , Scandola, F Supramolecular Photochemistry Ellis Horwood, New York, 1991 (c) Schneider, H -J , Durr, H (Eds) Frontiers in Supramolecular Organic Chemistry and Photochemistry, VCH, Weinheim, 1991 For a leading reference discussing assemblies with optical non-linearities, see Marks, T J , Ratner, M A Angew Chem Int Ed Engl 1995, 34, 155-173, and references cited therein The incorporation of transition metal ions into polymers provides unique opportunities to control the electrical, magnetic and optical properties of the metals The major approaches taken to date involve incorporating metal ions as side groups attached to the backbone (e g polyvinylferrocene), or as part of the polymer mam chain (e g metallynes) These approaches do not provide full control of the physical properties of the resulting materials and in most cases are not amendable for the synthesis of conducting polymers, as the metal containing polymers are non conjugated

Ruthenium coordination compounds play a central role in these systems, for example, ruthenium complexes of polypyπdine ligands are potential building blocks for luminescent and redox active assemblies as well as for "molecular wires" For an excellent review of the photophysics and photochemistry of Ru(ll) polypyπdine complexes, see Juris, A , Balzani, V , Baπgelletti, F ,
Campagna, S , Belser, P , Von Zelewsky, A Coord Chem Rev 1988, 84, 85-277 For some selected examples for the construction of multinuclear ruthenium complexes, see (a) Grosshenny, V , Ziessel, R J Organometallic Chem 1993, 453, C19-C22 (b) Romero, F M , Ziessel, R Tetrahedron Lett 1994, 35, 9203-9206 (c) Masschelem, A , Kirsch-De Mesmaeker, A , Verhoeven, C ,
Nasielski-Hinkens, R Inorg Chim Acta 1987, 129, L13-L16 (d) Baπgelletti, F , Flamigm, L , Balzani V , Collin, J -P , Sauvage, J -P , Sour, A , Constable, E C , Cargill Thompson, A M W J Am Chem Soc , 1994, 116, 7692-7699 (e) Benniston, A C , Goulle, V , Harnman, A , Lehn, J -M , Marczinke, B J Phys Chem 1994, 98, 7798-7804

Tuning the electronic properties of the ligands can induce desirable changes in the physical properties of the resulting complexes In particular, tπs(2,2'-bιpyrιdyl)ruthenιum(ll) exhibits NLO effects, (see Zyss, J et al , Chem Phys Lett 1993, 206, 409-414, see for a review that summarizes the application of organometallic compounds for non-linear optics Long, N J Angew Chem Int Ed Engl 1995, 34, 21-38) however, trιs([4,4'-dιbutylamιnostyryl]-2,2'-bιpyrιdyl)-ruthenιum(ll) shows much larger optical non-linearities (Dhenaut, C et al , Nature 1995, 374, 339-342)

The rigid framework of 1 ,10-phenanthrolιne ligands is an attractive feature for the construction of functional molecular assemblies Yet, despite their advantageous metal binding properties,
1 ,10-phenanthrolιne ligands have rarely been employed for these purposes (Sammes, P G et al , Chem Soc Rev 1994, 23, 327-334, Dietnch-Buchecker, et al , Angew Chem Int Ed Engl 1987, 26, 661-663,Chambron, J -C et al, J Chem Soc , Chem Comm 1993, 801-804, Chambron et al , Pure & Appl Chem 1995, 67, 233-240, Vogtle, et al , Angew Chem Int Ed Engl 1991 , 30, 1333-1336, Goodman et al , Tetrahedron Lett 1994, 35, 8943-8946) This is largely due to the lack of synthetically accessible building blocks In general, 1 ,10-phenanthrolιne ligands substituted at the 2,9 and 4,7 positions are available, while derivatives substituted along the strategic long axis of the molecule, (/ e , at the 3-, 8- positions), have been traditionally difficult to synthesize, requiring low-yield multi-step Skraup reactions sequences which utilize carcinogens like bromoacrolein and produce arsenic rich waste streams, see Case, J Org Chem 16 941-945 (1951) Since the most intense electronic transitions of the phenanthroline ring are polarized along this axis, (Bosnich, B Ace Chem Res 1969, 2, 266-273) a need existed for the facile synthesis of 1 ,10-phenanthrolιne derivatives functionalized at the 3 and/or 8 positions

Accordingly, it is an object of the invention to provide methods for the bromination of 1 , 10-phenanthroline at the 3- and/or 8- positions It is a further object of the invention to provide conjugated derivatives, such as acetylene derivatives, of 1 ,10-phenanthrolιne at the 3 and/or 8 position It is an additional object to provide dendritic derivatives of 1 ,10-phenanthrolιne It is a further object to provide 1 ,10-phenanthrolιne covalently attached to a variety of biomolecules such as proteins and nucleic acids via flexible or rigid linkers such as acetylene linkages at the 3 and/or 8 position SUMMARY OF THE INVENTION

In accordance with the objects outlined above, the present invention provides methods for making derivatives of phenathrohnes comprising reacting a 3,8 brominated phenanthroline with an acetylene to form an acetylene derivative of phenanthroline The invention further provides methods of hydrogenating the acetylenes to form alkene and alkane derivatives of phenanthrohnes

In an additional aspect, the invention provides compounds having the formula comprising

A and B are selected from carbon or nitrogen such that Y is a bond selected from the group consisting of acetylene, alkene, alkane, azo or imine, and
Z is alkyl, substituted alkyl, aromatic or substituted aromatic group

In a further aspect, the invention provides compounds having the formula comprising

D is a linker and
Z is alkyl, substituted alkyl, aromatic or substituted aromatic group

In an additional aspect, the invention provides compounds which are polymers having the formula


The invention provides compounds comprising derivatives of 1 ,10-ρhenanthrolιne, and methods useful in their synthesis The 3-, 8- positions of 1,10-phenanthroline have special properties It is very difficult to modify 1,10-phenanthroline at these positions However, the novel methods disclosed herein allow the facile bromination of 1 , 10-phenanthrolιne at one or both of these positions The brominated 1 ,10-phenanthroline is then useful in a wide variety of reactions, most particularly in reactions with aromatic and aliphatic acetylenes, acetenes and azo derivatives, to form a wide variety of compounds In particular, compounds containing the 3- and/or 8-modιfιed 1 ,10-phenanthroline are used to chelate a vaπety of metals such as transition metals The resulting metal complexes are useful in a wide variety of applications, including novel dendritic materials and for the addition of such transition metal complexes to nucleic acids and other biological compounds

In one embodiment, the compounds of the invention are modified at at least one of the 3-, 8- positions, and thus have the formula comprising Structure 1
Structure 1

In this embodiment, A and B are each independently either carbon or nitrogen, and Y is preferably a conjugated bond, that is, a bond that contains a sigma (σ) bond and at least one pi (π) bond
Preferred embodiments utilize carbon as both the A and B atoms, thus forming either acetylene (ethynyl, one sigma and two pi bonds, Structure 2) or acetene (ethylene, one sigma and one pi bond, Structure 3), or both nitrogens, thus forming azo bonds (Structure 4), although imine bonds may also be used in some embodiments In an additional embodiment, A and B are both carbons and Y is an alkyl bond (ethane, sigma bond, see Structure 3A) When the A-B bond is unsaturated, there may be either hydrogen atoms or substitutent groups attached to the A and B atoms For example, when Y is an alkene or double bond, either or both of the carbon atoms may contain hydrogen or an alternative substitutent group Similarly, when Y is an alkane bond, there may be two groups on each carbon atom, independently selected from hydrogen and substitutent groups as defined herein Preferably, hydrogens are used Z is an aromatic or alkyl group, as defined below
Structure 2

Structure 3

Structure 3A

Structure 4

Acetylene linkages are preferred, and the remainder of the disclosure and structures herein will be directed primary to the invention utilizing acetylene linkages It will be appreciated by those in the art that acetene, alkyl, azo or imine linkages may be substituted for one or more of the acetylene linkages in any of the structures

In an additional embodiment, linkers containing more or less than the A and B atoms, with attached moieties, may be used, as is generally depicted in Structure 4A below
Structure 4A

In this embodiment, D is a linker moiety As will be appreciated by those in the art, a wide variety of linkers can be used The composition and length of the linker may vary widely In one embodiment, a single atom, with attached hydrogens or substituent groups is used, for example, a -CH2- group (or -CHR- or -CR2- group) or an ammo group (-NH- or -NR-) may be used Linkers utilizing two atoms such as acetylene, alkene, alkyl and azo bonds, are described above Alternatively, linkers with more than two atoms are used in the linkage, that is, longer linkers may be utilized to connect the phenathroline derivative and the Z moiety This may be preferred to avoid steric or metal ion disruption of the biological function of the Z moiety, for example, when Z is a nucleic acid base, in some embodiments it may be desirable to have the metal ion at a distance from the duplex Preferred linkers include, but are not limited to, alkyl including substituted alkyl linkers, acetylene, alkene and substituted alkene, all of which are generally from 2 to 10 atoms long, although longer linkers may be used For example, saturated alkyl linkers include -(CR^Jn-, wherein R, and R2 are independently selected from hydrogen and other substitutent groups as defined herein Structure 4B depicts a non-substituted butyl linker Alternatively, suitable linkers include multiple acetylene linkages, as is generally depicted in Structure 4C with a butynyl linker As will be appreciated by those in the art, linkers utilizing mixtures of different bonds, such as acetylene and alkyl bonds, may also be used Similarly, linkers utilizing heteroatoms may also be used
Structure 4B

Structure 4C

In one embodiment, the compounds of the invention are modified at both the 3- and 8- positions, and thus have the formula depicted in Structure 5, with acetylene linkages
Structure 5

In a preferred embodiment, the compounds of the invention serve as metal chelates, preferably transition metal chelates, and thus the compounds further include a metal ion or atom That is, the nitrogens of the 1 ,10-phenanthroline serve as coordination atoms, preferably in conjunction with other ligands, for the chelation of a transition metal atom or ion, as is generally depicted in Structure 6
Structure 6

X n

In this embodiment, M is a metal atom, with transition metals being preferred Suitable transition metals for use in the invention include, but are not limited to, Cadmium (Cd), Copper (Cu), Cobalt (Co), Zinc (Zn), Iron (Fe), Ruthenium (Ru), Rhodium (Rh), Osmium (Os) and Rhenium (Re), with
Ruthenium, Rhenium and Osmium being preferred and Ruthenιum(ll) being particularly preferred

X is a co-ligand, that provides at least one coordination atom for the chelation of the metal ion As will be appreciated by those in the art, the number and nature of the co-ligand will depend on the coordination number of the metal ion Mono-, di- or polydentate co-hgands may be used Thus, for example, when the metal has a coordination number of six, two coordination atoms are provided by the nitrogens of the 1 , 10-phenanthroline, and four coordination atoms are provided by the co-ligands Thus, n = 4, when all the co-ligands are monodentate, n = 2, when the co-ligands are bidentate, or n = 3, for two monodentate co-ligands and a bidentate co-ligand Thus generally, n will be from 1 to 10, depending on the coordination number of the metal ion

In a preferred embodiment, as is generally depicted herein, the metal ion has a coordination number of six and two bidentate co-ligands are used (X and X,), as is depicted in Structure 7 (corresponding to Structure 2) and Structure 8 (corresponding to Structure 5)
Structure 7

Structure 8

As will be appreciated in the art, the co-ligands can be the same or different, or only one may be present Suitable ligands are well known in the art and include, but are not limited to, amines, pyridine, pyrazine, isonicotinamide, imidazole, bipyridine (abbreviated bpy) and substituted derivatives of bipyridine such as tetramethylbipyndyl (Me4bpy), phenanthrolines, particularly 1,10-phenanthroline (abbreviated pheπ) and substituted derivatives of phenanthrolines such as 4,7-dιmethylphenanthrolιne and the compounds disclosed herein, dipyndophenazine, 1 ,4,5,8, 9, 12-hexaazatrιphenylene
(abbreviated hat), 9,10-phenanthrenequιnone dιιmιne (abbreviated phi), 1 ,4,5,8-tetraazaphenanthrene (abbreviated tap), 1 ,4,8, 11-tetra-azacyclotetradecane (abbreviated cyclam) In some embodiments, porphyrins and substituted derivatives of the porphyπn family may be used

Thus, in one embodiment, a single transition metal ion utilizes one, two or three phenathroline derivatives as the ligands

In a preferred embodiment, as is outlined below, enatiomeπcally pure ligands may be used, to form diastereomeπcally pure metal containing complexes, for example, metal containing nucleosides In the structures depicted herein, Z is an aromatic, substituted aromatic, alkyl or substituted alkyl group or a Silicon (Si) or Tin (Sn) moiety By "aromatic" or "aromatic group" herein is meant aromatic and polynuclear aromatic rings including aryl groups such as phenyl, benzyl, and naphthyl, naphthalene, anthracene, phenanthroline, heterocyclic aromatic rings such as pyridine, furan, thiophene, pyrrole, indole, pyrimidine and puπne, and heterocyclic rings with nitrogen, oxygen, sulfur or phosphorus Preferred aromatic groups include phenyl groups, pyridine, puπne, pyrimidine and phenathroline groups

By "substituted aromatic group" herein is meant that the aromatic moiety to which the 1,10-phenanthroline is attached contains further substitution moieties That is, in addition to the phenanthroline derivative, the aromatic group may be further substituted by any number of substitution moieties The substitution moiety may be chosen from a wide variety of chemical groups, or biological groups including ammo acids, proteins, nucleosides, nucleotides, nucleic acids, carbohydrates, or lipids That is, any group which contains an aromatic group may serve as the substituted aromatic group Suitable chemical substitution moieties (sometimes referred to herein as "R" groups) include, but are not limited to, alkyl, aryl and aromatic groups and their substituted derivatives, ammo, nitro, phosphorus and sulfur containing moieties, ethers, esters, and halogens In some embodiments, as is more fully described below, the substitution moiety of the aromatic group is acetylene linked 1 ,10-phenanthrohne of Structure 2, i e two or more 1 ,10-phenanthrolιnes share a single Z group, creating multimers and polymers (including dendπmers) of Structure 2

By "alkyl group" or grammatical equivalents herein is meant a straight or branched chain alkyl group, with straight chain alkyl groups being preferred If branched, it may be branched at one or more positions, and unless specified, at any position The alkyl group may range from about 1 to 20 carbon atoms (C1 - C20), with a preferred embodiment utilizing from about 1 to about 15 carbon atoms (C1 -C15), with about C1 through about C10 being preferred, although in some embodiments the alkyl group may be much larger Also included within the definition of an alkyl group are heteroalkyl groups, which include heteroatoms such as nitrogen, oxygen, sulfur and phosphorus Further included are cycioalkyl groups such as C5 and C6 rings, and heterocyclic rings with nitrogen, oxygen, sulfur or phosphorus In the broadest embodiments, alkyl includes alkynyl, alkenyl, and alkanyl, and mixtures thereof

By "substituted alkyl group" herein is meant an alkyl group further comprising one or more substitution moieties, as defined above

By "silicon moiety" herein is meant an alkylsilyl group, with tnalkylsilyl being preferred and tπmethylsilyl (TMS) being particularly preferred By "tin moiety" herein is meant an alkylstannyl group

In a preferred embodiment, the phenanthroline is linked to an aromatic or alkyl group containing a substitution moiety such that the phenanthroline is conjugated with the substitution moiety In the case of a substituted alkyl or substituted aromatic containing an alkyl moiety, this may require that the alkyl group itself be unsaturated so as to facilitate conjugation

In a preferred embodiment, for example when the compounds of the invention include a transition metal ion, the Z group comprises a biological moiety such as a nucleotide or a nucleic acid In such an embodiment, the preferred attachment is through the nucleoside base, i e an acetylene group is attached to the base for example as depicted below in Structure 9, although as outlined herein the attachment may be through other bonds including alkene, alkyl and azo bonds That is, the aromatic heterocyclic base is an aromatic group, and the remainder of the nucleotide or nucleic acid comprises the substitution moiety of the aromatic group By "nucleoside" herein is meant a puπne or pyrimidine nitrogen base bonded to a carbohydrate such as a nbose, i e adenosine, guanosine, thymidine, cytidme, and undine By "nucleotide" herein is meant a nucleoside further containing a phosphate group Specifically included within the definition of nucleotide is the phosphoramidite form of a nucleotide, as is depicted in Structure 11 By "nucleic acid" herein is meant at least two nucleotides covalently linked together A nucleic acid of the present invention will generally contain
phosphodiester bonds, although in some cases, as outlined below, a nucleic acid may have an analogous backbone, comprising, for example, phosphoramide (Beaucage et al , Tetrahedron 49(10) 1925 (1993) and references therein, Letsinger, J Org Chem 35 3800 (1970)),
phosphorothioate, phosphorodithioate, O-methylphophoroamidite linkages (see Eckstein,
Oligonucleotides and Analogues A Practical Approach, Oxford University Press), or peptide nucleic acid linkages (see Egholm, J Am Chem Soc 114 1895 (1992), Meier et al , Chem Int Ed Engl 31 1008 (1992), Nielsen, Nature, 365 566 (1993)) The nucleic acids may be single stranded or double stranded, as specified The nucleic acid may be DNA, RNA or a hybrid, where the nucleic acid contains any combination of deoxyπbo- and nbo-nucleotides, and any combination of uracil, adenine, thymine, cytosme and guanine, or other bases such as inosine, xathanme and hypoxathanine, etc Included within the definition of nucleic acid are single nucleosides and nucleotides, and the phosphoramidite form of nucleotides, as is described herein

Structures 9, 10, and 11 depict a 3-acetylene-phenanthrolιne modified undine nucleoside, nucleotide, and phosphoramidite nucleotide respectively, and Structure 12 depicts a undine attached to a peptide nucleic acid backbone subunit, all attached to the 1,10-phenanthroline via the acetylene linkage described herein, in the absence of metal ions and co-ligands Structures 9, 10, 11 and 12 depict the attachment via the 5 position of the uracil base, although attachment at the 6 position are also possible. R can be either H (deoxyribose) or OH (ribose).
Structure 9

Structure 10

Structure 11

Structure 12

These structures, as for all the structures depicted herein, may also include the transition metal ion and co-ligands, as will be appreciated in the art, or alternative linkages such as alkene and alkyl linkages and their substituted derivatives, azo and imine bonds, and D linkers, as defined herein The protecting group depicted in Structure 11 may be any number of known protecting groups, such as 5 dimethoxytπtyl (DMT), see generally Greene, Protecting Groups in Organic Synthesis, J Wiley &
Sons, 1991

Similarly, linkages such as acetylene linkages may also be made to the bases of the other nucleic acids, including cytosme, thymine, adenine, and guanine For cytosme, the linkage is preferably via

10 the 5 or 6 positions For thymine, the linkage is preferably via the 5 and 6 positions For adenine, the linkage is preferably via the 8 position For guanine, the linkage is preferably via the 8 position In some embodiments, the synthesis of the compounds may require the use of protecting groups for moieties of the compound, such as the base or sugar, such as a protecting group for the exocyclic ammo group of cytosme, etc Protecting groups are known in the art, see Greene, supra
As will be appreciated by those in the art, the phenanthroline compounds of the present invention may also be attached to ammo acids and proteins (including polypeptides and peptides) Thus, for
example, covalent attachment may be done through the ammo acid side chains

20 In a preferred embodiment, the Z group contains one or more acetylene-linked 1 ,10-phenanthrolιnes as the substitution group Thus, as will be appreciated by those in the art, multimers and polymers or dendnmers of the basic compound of Structure 1 can be made By "multimers" herein is meant two or more 1,10-phenanthrolιnes linked via a single Z group That is, a single Z group has two or more phenanthroline groups attached For example, the Z group may be substituted by one or more

25 acetylene-linked 1 ,10-phenanthrolιnes, as is depicted in Structure 13 (with an acetylene linkage and in the absence of a transition metal) or Structure 14 (with an acetylene linkage in the presence of metal ions and two co-ligands, although other numbers of ligands may be used) for two 1,10- phenanthrolmes, or Structure 15 (with acetylene linkages in the presence of metal ions and two co- ligands) for three 1,10-phenanthrolιnes Structure 15 utilizes phenyl as an aromatic Z group, but as

30 will be appreciated in the art, other Z groups may be utilized, as well as other linkages
Structure 13

Structure 14

Structure 15

When the multimers are further extended, that is, the 1 , 10-phenanthrolιne is substituted, for example to form acetylene linkages at both the 3- and the 8- position, polymers may be formed. The polymers of the invention have the general structure shown below, depicted below with the metal ion and co-ligands, and using acetylene linkages, although as described herein other linkages may be used.
Structure 16

As will be appreciated by those in the art, n can range from quite small, such as n = 2, to very large, from greater than about 100, 1 ,000, 10,000 or 100,000 or more In this embodiment, various metal ions and Z groups (substituted or unsubstituted) may be used That is, the polymer may comprise more than one type of metal ion and more than one type of Z group In addition, as outlined below, the 1 ,10-phenanthroline may be additionally substituted, and thus substituted and unsubstituted 1 ,10-phenanthroline may be used In a preferred embodiment, substitution positions are chosen for linear molecules, such that the molecules are fully conjugated Alternatively, such as depicted in Structures 15 and 17, the molecules are non-linear In this embodiment, Z groups may be used that contain three or more acetylene-linked 1 , 10-phenanthroline groups, thus forming "cross-linking" structures, or dendπmers

Thus, in a preferred embodiment, the 1 ,10-pheπanthrolιnes depicted in Structure 15 have additional Z groups at the 8- position, as is depicted below in Structure 17 (with acetylene linkages in the presence of metal ion and two co-ligands)
Structure 17

In this embodiment, the Z groups are preferably aromatic groups, with phenyl being preferred

In addition, the 1 ,10-phenanthroline may be substituted at other positions in addition to the 3-,8-position, as defined above, as depicted in Structure 18 in the absence of the metal ion and co-ligands R may be a wide variety of R substitution groups, as defined above In some embodiments, adjacent R groups form cyclic, preferably aromatic groups, conjugated to the phenanthroline If the R groups are added prior to bromination, the R groups preferably do not interfere with the bromination at the 3 and/or 8 positions Structure 18

As will be appreciated by those in the art, the compounds of the invention generally are charged, due to the metal ion

The invention further provides methods for the synthesis of the compounds depicted herein

The invention provides methods for the bromination of 1 ,10-phenanthroline at the 3 and/or 8 positions The method comprises reacting an acid salt of 1,10-phenanthroline with bromine in the presence of a solvent such as nitrobenzene, bromobenzene, or chlorobenzene By "acid salt" herein is meant a compound derived from the acids and bases in which only a part of the hydrogen of the acid is replaced by a basic radical Preferred acid salts include the monohydrochloπde monohydrate of 1 ,10-phenanthroline (1 in Scheme I) In some embodiments, the acid salt form is generated in situ and thus is not required as a starting material The solvent used may be nitrobenzene, bromobenzene, or chlorobenzene The method is schematically depicted in Scheme I
Scheme I

Scheme I generally results in a mixture of 3-bromo-phenanthrolιne and 3,8-bromo-phenanthrolιne, which are separated using a variety of techniques known in the art, such as silica gel purification and flash column chromatography The 3- or 3,8 brominated 1 ,10-phenanthroline is then used in a variety of reactions to form the compounds of the invention

In a preferred embodiment, palladium-mediated cross coupling as is known in the art is used to react the brominated 1 ,10-phenanthroline with a Z group such as an aromatic acetylene to form the compounds of the invention, as is generally depicted in Scheme II Alternatively, the brominated 1 ,10-phenanthroline is reacted with an acetylene, to form a 3- or 3,8-acetylene-phenanthrolιne, which then may be reacted with a halogenated aromatic Z group to form the compounds, as is depicted in Scheme III
Scheme II

(Ph3P)2PdCl2, Cul,


Scheme II and III are depicted with a single bromine on the 1 ,10-phenanthroiιne The use of the doubly brominated 1 , 10-phenanthrolιne permits the incorporation of two Z groups at the 3- and 8-positions coupled by acetylene linkages As is discussed below, the polymers of the invention can be generated using such 3,8-bιfunctιonal phenanthrolines Suitable palladium-mediated cross coupling conditions are well known in the art See for example, K Sonogashira et al , Tetrahedron Lett 1975, 4467, L S Hegedus, in Transition Metals in the Synthesis of Complex Organic Molecules, University Science Books, Mill Valley, CA 1994, pp 65-127, R Rossi et al , Org Prep Proc Int 1995, 27, 127, K C Nicolaou et al , Chem Eur J 1995, 1, 318, M D Shair et al , J Org Chem 1994, 59, 3755, Z Xu et al , J Am Chem Soc , 1994, 116, 4537, D L Pearson et al , Macromolecules, 1994, 27, 2348, DiMagno et al , J Org Chem Soc 58 5983 (1993), S Prathapan et al , J Am Chem Soc 1993, 115, 7519, R W Wagner et al, J Org Chem 1995, 60, 5266, J Seth etal J Am Chem Soc 1994, 116, 10578, V S -Y Lin et al , Science 1994, 264, 1105, and H L Anderson et al , Angew Chem Int Ed Engl 1990, 29, 1400, all of which are hereby expressly incorporated by reference Alkenyl (vinyl) linkages may be generated using dissolving metal reduction (e g Na/NH3), and hydrogenation can result in the acetene derivatives Alternatively, other cross-coupling methodologies may be used, as is known in the art, for example using borane reactions, see Rossi et al , Org Prep and Proc 27 127-160 (1995), hereby expressly incorporated by reference Similarly, alkane linkages may be derived from the alkynyl linkages by various
hydrogenation methods

Once the compounds are generated, transition metal ions and co-ligands can then be added, using techniques well known in the art As will be appreciated by those in the art, the reaction conditions may vary slightly with different metals, for example, ruthenium has a faster rate of ligand exchange than osmium

In a preferred embodiment, the palladium-mediated cross coupling reaction is done with the compounds already containing the transition metal ions and co-ligands As discussed above, this has the advantage of allowing the synthesis of diastereomeπcally pure metal containing Z compounds Thus for example, ethynyl-contaming nucleosides may be reacted with functionalized coordination complexes containing resolved ligands, to form diastereomeπcally pure metal containing nucleosides Without being bound by theory, it appears that the electron withdrawing properties of the transition metal ion facilitates the addition reaction, allowing a simple single step synthesis, as is depicted in Scheme IV (3-bromιnated 1 ,10-phenanthroline and aromatic acetylene) and Scheme V (3-acetylene-phenanthroline and aromatic bromine)


The aromatic acetylenes may be made using techniques well known in the art See for example, Nguyen et al , Synlett 1994, 299-301 , expressly incorporated herein by reference Many aromatic acetylenes are commercially available, such as phenylacetylene, 4-ethynyltoluene, or are easily generated from brominated precursors, for example, 1 ,3,5 tnbromobenzene is commercially available

In a preferred embodiment, the compounds of the invention are attached to nucleosides, nucleotides, and nucleic acids Generally, halogenated nucleosides are commercially available For example, undine iodinated at the 5- position may be used in either Scheme III or Scheme V Similarly, the phosphoramidite derivative of the nucleotides may be made as is known in the art, and generally depicted below in Scheme VA for undine and Scheme VB for cytosme
Scheme VA

a) (Ph3P)PdCI2, Cul, DMF, Et3N, 3-bromo-1 ,10-phenathrolιne, b) DMT-CI, pyr, Et3N, d)
(ιPr2N)2POCH2CH2CN, 1 H-tetrazole

Scheme VA may also be modified to include the protection of the 5'-hydroxyl as the DMT derivative before the cross-coupling with 3-bromo-1 ,10-phenanthroiιne, which renders the compounds more soluble in organic solvents but does not significantly affect their reactivity In addition, as for all the schemes herein, other protecting groups may be used to protect reactive moieties on the compounds, such as on the base or sugar

Scheme VB

a) (i) TMS-CI, pyr, (n) PhCOCI, (in) 2 M NH40H, b) (i) (Ph3P)PdCI2, Cul, DMF, Et3N, Ne3SιC=CH, (n) K2C03, NeOH, c) (Ph3P)PdCI2, Cul, DMF, Et3N, 3-bromo-1 ,10-phenanthrolιne, d) (i) DMT-CL, pyr, Et3N, (n) (ιPr2N)2POCH2CH2CN, 1H-tetrazole

In addition, the nucleosides can be coupled to solid supports such as controlled pore glass (CPG) using techniques well known in the art, to synthesis metal-containing oligonucleotides with the modification at the 3' end Thus, in a preferred embodiment, the invention further provides methods of generating nucleic acids comprising the compounds of the invention The method comprises incorporating a phosphoramidite nucleotide containing the acetylene-linked 1 ,10-phenanthroline into a synthetic nucleic acid, using techniques well known in the art The compounds of the invention may be incorporated into a nucleic acid at any position, e g 3', 5', or at an internal position

The compounds may also be incorporated into proteins, using for example attachment to ammo acid side chains, including phenylalanine, trptophan, tyrosine, and histidine, using techniques similar to those outlined herein, as will be appreciated by those in the art

As outlined herein, a preferred embodiment utilizes polymers or dendnmers of the compounds of the invention Polymers can be generated by using 3,8 halogenated 1 ,10-phenanthroline, and any number of Z groups

In a preferred embodiment, the polymers are generated using a single type of Z group, preferably an aromatic group A preferred embodiment utilizes 1 ,3,5-trιethynylbenzene as an aromatic acetylene Alternative embodiments utilize other Z groups

In an alternate embodiment, the polymers are generated using more than one type of Z group, thus forming co-polymers As will be appreciated by those in the art, any number of different Z groups may be used

The compounds of the invention are purified if necessary, using techniques known in the art

Once made, the compounds of the invention find use in a number of applications The phenanthroline compounds of the invention are fluoroscent, and in a preferred embodiment, may be used as labels Thus, for example, nucleic acids or proteins may be labelled with the phenanthroline compounds of the invention as described herein In a preferred embodiment, nucleic acid probes may be made and labelled with the compounds of the invention, for the detection of target sequences, for example for diagnostic purposes In a preferred embodiment, the fluoroscent properties of the compounds may be used as the basis of a hybridization assay, as it is expected that the fluoroscent properties of the phenanthroline deπvatives might change upon the hybridization of a target sequence to a probe sequence

In an additional embodiment, the compounds are used to attach metal ions to biological moieties such as nucleic acids and proteins for energy and electron transfer purposes In a preferred embodiment, the compounds of the invention are used to make multimetallic assemblies for the study of energy and electron transfer, and find application in the area of non-linear optics, liquid crystals, electrochromic display devices, photonic and electrochemical sensing devices, energy conversion systems, information recording and "molecular wires"

The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes All references cited herein are incorporated by reference


Example 1
Bromination of 1 , 10-phenanthrolιne

Method A Nitrobenzene as solvent
Phenanthroline substituted in either the 3 or the 3 and 8 positions have been traditionally difficult to functionalize, requiring low-yield multi-step Skraup reaction sequences (see Case, supra)
Conventional wisdom advises that simple bromination of 1,10-phenanthroline is poor and unselective See Katntzky et al , Electrophilic Substitution of Heterocycles Quantitative Aspects (Vol 47 of Adv Heterocycl Chem ), Academic Press San Diego, 1990, Graham, in the Chemistry of Heterocyclic Compounds, Allen, Ed Intersαence Publishers, Ine New York 1958, pp386-456 A direct bromination reaction gives low yields of di-, tn- and tetrabrommated 1,10-phenanthroline and traces of the 3- and 5- bromo derivatives has been reported, see Denes et al , J Prukd Chem 320 172-175 (1978)

However, starting with the commercially available 1 ,10-phenanthroline monohydrochloπde
monohydrate, the reaction with bromine using nitrobenzene as the solvent gives 3-bromo-phenanthroline and 3,8-bromo-phenanthrolιne as major products In a typical procedure, a solution of the 1, 10-phenanthroline monohydrochloπde monohydrate(10 g, 43 mmol) in nitrobenzene (20 ml) was heated to 130-140 °C in a 250 ml 3-neck flask Bromine (3 3 ml, 64 mmol in 9 3 ml nitrobenzene) was added dropwise over a period of 1 hr Upon the addition of bromine, the 1 , 10-phenanthrolιne went into solution After stirring for 3 hr at the same temperature, the reaction mixture was cooled to room temperature, treated with concentrated ammonium hydroxide (100 ml) and extracted with
dichloromethane (3X50 ml) The combined organic layers were washed with water (3X50 ml) and dried (MgS04) Concentration in vacuum afforded a suspension of the products in nitrobenzene The nitrobenzene was removed by dissolving the suspension in dichloromethane (10 ml) and filtering it through silica gel (300 ml) using dichloromethane as the eluent After the nitrobenzene eluted out, the products were recovered by gradually increasing the polarity of the eluent up to 10% MeOH in CH2CI2 Flash column chromatography (0 6% MeOH in CH2CI2) afforded 3-bromo-phenanthrolιne (3 6 g, 33% yield, m p 164-167°C) and the 3,8-bromo-phenanthrolιne (2 4 g, 17% yield, m p 270-273°C) as white powders Higher solvent polarity (10% MeOH in CH2CI2) elutes unreacted 1 ,10-phenanthroline (ca 4 g) that can be recycled

Variations of the amount of bromine, reaction time, or temperature influence the outcome of the reaction Attempts to push the reaction to completion usually resulted in higher yields of the 3,8-bromo-phenanthrohne but at the same time led to the generation of various other brominated derivatives Under the present conditions, ca 90% of crude 1 ,10-phenanthrolιne containing products can be accounted for as unsubstituted 1 ,10-phenanthroline, the 3-bromo product and the 3,8-bromo product The remaining 10% contains several other brominated by-products (5-bromo-, 3,5,8-tnbromo- and 3,5,6,8-tetrabromo-phenanthrolιne) that can be removed by column chromatography

Method B Bromobenzene as solvent
3 01 g, 1 eq, 0 128 moles of 1 ,10-phenanthroline monohydrochloπde monohydrate was placed in a round bottom flask (2 neck) with a stir bar 200 ml of bromobenzene was added and the mixture was sonicated for 20 minutes After heating the mixture to 135°C with reflux and stirnng, 1 drop of bromine mixture (2 ml of bromine and 100 mis of bromobenzene) was added per minute The reaction was monitored by TLC (aluminum oxide, 3% methanol/methylene chloride) Reflux was continued for 30 minutes after addition was complete The reaction was then quenched with aqeuous ammonia with sonication for 20 minutes The aqueous phase was removed, and washed with methylene chloride (X2) The organic phase was washed three times with saturated NaCl solution, and the organic phases combined, and dried with anhydrous magnesium sulfate, filtered, and the bromobenzene evaporated under reduced pressure The separation of the two forms was done by flash
chromatography (silica gel, 0 3% methanol/methylene chloride under dibromopheπanthroline eluted, 1% methanol/methylene chloride until monobromophenanthroline eluted The solvent was evaporated under reduced pressure

Example 2
Synthesis of 3,8-bιs(aromatιcethynyl)-phenanthrolιne in the
absence of transition metal ions

The following scheme was used Scheme VI

The new ligands are synthesized by cross-coupling reactions between
3,8-dιbromo-1, 10-phenanthrolιne (1) as described in Example 1 and substituted phenylacetylenes (2) in the presence of (Ph3P)2PdCI2 and Cul under sonication at room temperature (Scheme) In a typical reaction, a degassed solution of phenylacetylene (0 26 ml, 2 5 mmol) in triethylamine (8 ml) and methanol (4 ml) was added under argon to a reaction flask containing 1 (0 1 g, 0 3 mmol),
(Ph3P)2PdCI2 (16 mg, 0 03 mmol) and Cul (10 mg, 0 05 mmol) The mixture was sonicated at room temperature under argon for 2-4 hr The reaction mixture was dissolved in dichloromethane (50 ml), washed with aqueous KCN and water Drying (MgS04) and evaporation afforded the crude product Flash chromatography (1% methanol/dichloromethane) followed by recrystallization from chloroform afforded 3a Η NMR (CDCI3) d 9 31 (d, J=1 9 Hz, 2H, H2,9), 8 41 (d, J=Λ 9 Hz, 2H, H4,7), 7 83 (s, 2H, H5,6), 7 65 (m, 4H, phenyl-H2), 7 36 (m, 6H, phenyl-H3,4), 13C NMR (CDCI3) d 152 4, 144 3, 138 0, 131 9, 129 0, 128 5, 128 0, 126 8, 122 3, 119 8, 94 0, 86 3 Reactions performed at room temperature without sonication proceed much slower The effect of sonication was not thoroughly investigated, although it is possible that sonication promotes the reaction by facilitating the solubilization of 1 in the reaction medium Although reactions at elevated temperatures yielded the desired products, they were accompanied by the formation of undesired by products Table 1 summarizes selected data for the new ligands
Table 1. Preparation and selected spectral data for 3.
Ligand R Yield" MS^ UV^
1 1,,1100--pphh** -- -- -- 230(5.1),264(3 0),280(1 2)
3a H 90% 380.1302(380.1313) 284(5 3),340(5 1),354(4 1)
3b CH3 87% 408.1607(408.1626) 286(4.2),346(5.1),560^ 6)
3c OCH3 89% 440.1516(440.1524) 290(4.0),' 352(5.5),368(4 9)
3d CF, 43% 516.1060(516.1061 ) 286(5.4),338(6.4),i52f5 5;

"Isolated yields of chromatographically pure products based on 1 "Observed
and (in parenthesis) calculated El high resolution mass spectrum CUV spectra
of 1x1 Cr5 M solutions in acetonitrile The absorption maxima are given in nm and
104e (in parenthesis) is given in M1cm 1 Prominent shoulders are italicized
The data for 1 ,10-phenanthrolιne is given for comparison βA broad absorption
between 268-290 nm is observed

Comparing the ultraviolet spectra of the new ligands 3 to that of the parent 1 ,10-phenanthrolιne shows a substantial red-shift of the p-p* transitions and a change in the relative intensity of the two major bands (Table 1) The higher energy transition in 3a is shifted by 54 nm compared to that of phenanthroline, while the lower energy transition is shifted by 76 nm The two major bands in the UV spectrum of phenanthroline have been assigned to the long-axis polarized β (230 nm) and β' (264 nm) transitions, see Bray, R G et al , Aust J Chem 1969, 22, 2091-2103 The major transitions of the new ligands are only tentatively assigned here A careful study of the absorption and fluorescence spectra of the conjugated ligands under various conditions is required for a full analysis Similar effects have been observed in other phenylacetylene conjugated aromatic systems, for example, the major absorption band of 9,10-bιs(phenylethynyl)-anthracene is red-shifted by 73 nm compared to anthracene See Mauldmg et al , J Org Chem 34 134-136 (1969) This is indicative of a substantial electron delocahzation through the ethynyl groups The lower energy absorption maximum of the methoxyphenyl derivative 3c is 6 nm red-shifted compared to the toluyl derivative 3b which is red-shifted by 6 nm compared to the phenyl derivative 3a Clearly, the absorption maxima are affected by the remote ring substituents which support an extended conjugation
In a typical reaction, the ligand 3a (0 1 g, 0 26 mmol) in degassed DMF (10 ml) was treated under argon with a solution of K2RuCI5 (33 mg, 0 08 mmol) in water (4 ml) containing 1 drop of 6N HCI The solution was refluxed for 1 h Sodium hypophosphite (38 mg, 0 44 mmol) in water (1 ml) was added, and reflux was continued for 1 h After cooling to 60CC, the reaction mixture was treated with potassium hexafluorophosphate (48 mg, 0 26 mmol) as a 10% aqueous solution, cooled to RT and concentrated in vacuo Silica-gel chromatography using 1 % aqueous 0 5 M KN03 in acetonitrile as eluent afforded Ru(3a)3 Η NMR (CD3CN) d 8 75 (d, J=1 3 Hz, 2H H2,9), 8 27 (s, 2H, H5,6), 8 18 (d, J=1 3 Hz, 2H, H4,7), 7 45 (m, 10H, phenyl)

Upon complex formation, the electronic transitions of 1 ,10-phenanthroline remain largely unmodified except for a small hypsochromic effect of the two major transitions (Table 2) In contrast, the Ru(ll) complexes of ligands 3 show a different behavior (Table 2) Although the higher energy transitions around 280 nm are blue-shifted upon Ru(ll) complexatton, the lower energy transitions at ca 340 nm are red-shifted (compare Tables 1 and 2) The latter seem to be more sensitive to the nature of the substituent on the phenyl rings with the methoxy derivative Ru(3c)3 suffering the largest shift of more than 25 nm The visible metal to ligand charge transfer (MLCT) bands, while red-shifted by ca 30 nm in Ru(3)3 compared to Ru(1 ,10-phen)3, appear at the same wavelength for all derivatives MCLT bands in Ru(ll) complexes of other substituted phenanthrolines have been shown not to be very sensitive to the nature of the substituents See for example Lin etal , J Am Chem Soc 98 6536-6544 (1976)

Table 2. Preparation and selected spectral data for Ru(ll) complexes of ligands
Complex R Yield" MS" UV-vis'
Ru(l ,10-Ph), - 77% - 224(7.2), 262(9.6), 290(2 0),
Ru(3a)3 H 60% 1242(NT) 280(6.3),294 (5 8), 356(6.5),
376(5 0), 474(0.72)
Ru(3b)3 CH3 86% 1325(M2*-H*) 276(8.7), 296(7 4), 364(9.8),
1471 (M2*+PF6) 382(82), 474(0.97)
RU(3c)3 OCH3 94% 1442(M') 274(9.3), 300(5 7), 378(8.2),
394(7 7). 472(0.97)
"Isolated yields of chromatographically pure complexes (based on 3) as their
PF6- salts "Positive FAB mass spectrum. cUV-vιs spectra were taken in
acetonitrile Absorption maxima are given in nm and 1 CPe (in parenthesis) is
given in M"1cm \ The major bands are boided and prominent shoulders are

Example 3
Synthesis of 3,8-bιs(aromatιcethynyl)-phenanthrolιne in the presence of transition metal ions

The complex [(bpy)2Ru(3-bromo-1 ,10-phenanthrolιne)]2+(PF6-)2 (1) is an attractive building block for the synthesis of multimetallic Ru(ll) arrays using cross-coupling methodology The 1 , 10-phenanthrolιne ligand is substituted at the 3-posιtιon which is sterically and geometrically favored and provides electronic conjugation Tzalis et al , Tetrahedron Lett 36.6017 (1995) The Ru(ll) complexed 3-bromo-1,10-phenanthrolιne is expected to be relatively electron-deficient and to therefore undergo facile oxidative-addition reactions Furthermore, the phenanthroline's nitrogens are "masked", and complications due to complexation of the transition-metal catalysts are prevented Suffert et al , Tetrahedron Lett 32 757 (1991 ) Treating a DMF solution of 4 (shown below) with 4-ethynyltoluene at room temperature for 1 hour in the presence of (Ph3P)2PdCI2, Cul and Et3N proceeds smoothly to afford 6 in excellent yield (Table 3)

Table 3. Preparation and selected spectral data for Ru11 complexes
Complex Yιeld(%) MS" UV-VISς
4 68 819.3(rvT) 236(4.2), 272(6 6), 286(6.5), 448(1 5)
5 68 763(M0 238(4.2), 276(6.3). 286(6.1), 450(1 2)
6 91 853.5(M<) 244(4.2), 286(7.6), 346(3.0), 452(1.3)
7 86 327(M**) 238(8.2), 286(15.3), 362(8 1), 440(2.9)
88 7733 334477((MM44**)) 238(7.6), 286(13.8) 368(8 4), 440(2.6)

"Isolated yields of recrystallized complexes as their Pζ- salts The yields
reported for complexes 6 through 9 represent the reaction yields of 1 with the
corresponding acetylene (see text) "Electrospray Ionization Mass Spectrum
The observed peaks correspond to [M-nPFj-]"* CUV-VIS spectra were taken in
acetonitrile Absorption maxima are given in nm and 1 QV (m parenthesis) is
given in dm3 mol 1 cm 1

A representative procedure for the palladium-mediated cross-coupling reactions between 4 and aromatic acetylenes is as follows A mixture of 4 (50 mg, 0 052 mmol), (Ph3P)2PdCI2 (4 mg, 0 0057 mmol) and Cul (0 5 mg, 0 0026 mmol) was treated with a degassed solution of 4-ethynyltoluene (11 μl, 0 11 mmol) in DMF (5 ml) and triethylamme (3 ml) for 1 hour at room temperature under Argon The crude reaction mixture was evaporated to dryness and the product 6 was obtained in 91% yield as an orange-red powder after successive crystallizations from dichloromethane-ethanol Selected data for 3 1H NMR (500 MHz, CD3CN) d 8 72 (d, 1H, H2Phβn), 8 62 (d, 1 H, H9Phβn), 8 56-8 49 (m, 4H, Ha bpy), 8 27 (d, 1H, H5Phβn), 8 22 (d, 1 H, H6Phβn), 8 19 (d, 1H, H4Phβn), 8 12-8 07 (m, 3H, H7Phβn, 2H9 bpy), 8 04-7 99 (m, 2H, Hg bpy), 7 86 (d. 1 H. Ha bpy), 7 81 (d, 1H, Hβ bpy), 7 74 (dd, 1 H, H8Phβn), 7 65 (d, 1 H, Ha „„), 7 52 (d, 1H, Ha bpy), 7 48-745 (m, 4H, 2Hb bpy, 2Hphβnyl), 7 28-7 23 (m, 4H, Hb bpy, 2Hphβnyl), 2 24 (s, 3H, CH3) IR (film, NaCl) nmax 2215 cm 1 (CJC)

All Ru(ll) complexes were synthesized as their PF6- salts and showed spectroscopic data (UV-VIS, IR, NMR and MS) consistent with the assigned structure Electrospray Ionization Mass Spectrometry has been found particularly useful in analyzing these complexes due to the characteristic formation of multiply charged species with typical isotopic distribution Note that the binuclear and tπnuclear complexes are formed as a mixture of stereoisomers No attempt has been made to resolve these complexes at this point

Similarly, reacting 4 with 1 ,4-dιethynylbenzene, or 4, 4'-dιethyny 1-1 ,1 '-biphenyl affords the bimetallic complexes 7 and 8, respectively, in good yields The same mild reaction conditions are applied for the coupling of 1,3,5-trιethynylbenzene with 3 equivalents of 4 to afford the tπnuclear complex 9 in 70% yield Cross-coupling reactions of the Ru(ll) complex containing the alkyne functionality with aromatic electrophiles have been found to proceed efficiently as well Thus, treating [(bpy)2Ru(3-ethynyl-1 , 10 -phenanthrolιne)]2+(PF6-)2 (5) with 1 ,4-dιιodobenzene or 4,4'-dιιodobιphenyl under the same reaction conditions, affords the bmuclear Ru(ll) complexes 7, and 8, in 43% and 56% yield, respectively In general, the reactions of 5 with aromatic iodides proceed slower than the reactions of 4 with aromatic acetylenes

The compounds synthesized represent a novel family of multi Ru(ll) complexes of various structures and spectral properties (Table 3) The parent complex 4 exhibits two mam absorption bands at 272 and 286 nm due to the overlapping π-π* transitions of the bpy and phenanthroline ligands Although the major band of the bpy appears to remain largely unchanged, extending the conjugation of the phenanthroline ligand results in the appearance of a lower energy band above 330 nm (Table 3) For example, in addition to a strong absorption at 286 nm, 6 shows a new band at 346 nm This lower energy n-n* transition is further red-shifted with increasing conjugation as is evidenced when comparing the spectrum of 6 to that of 7 (362 nm) The bmuclear complex 8 shows similar behavior to that of 7, indicating a substantial electronic conjugation between the two phenanthroline ligands through the biphenyl ring In contrast, the lower energy π-π* transition of the phenanthroline ring in the tnnuclear complex 9 appears at a much shorter wavelength (338 nm) as compared to 7 (362 nm) and 8 (368 nm), and is almost overlapping with that of the mononuclear complex 6 (346 nm) This indicates that each of the metal centers in 9 is electronically isolated and is not involved in
π-conjugation The visible metal to ligand charge transfer (MLCT) bands appear around 440 nm for all derivatives This somewhat unexpected behavior has been observed in other mono- and bmuclear Ru(ll) complexes (see Bolger et al , J Chem Soc Chem Commun 1799 (1995) and Tzahs et al , supra) Nevertheless, the different nucleanty of the complexes 6, 7 (8) and 9 is beautifully evident from the approximate 1 2 3 ratio of the extinction coefficients of the major n-n* as well as the MLCT bands Structures of example 3