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Development of new technetium cores containing technetium—nitrogen multiple bonds. Synthesis and characterization of some diazenido-, hydrazido- and imido- complexes of technetium
Polyhedron Vol. 9, No. 12, PP. Prim&cn”uretrrbifdilo
1497-1502, 1990
0277-5387/90 s3.lw+.oLl ?=c~Rmon~.dlc
COMMUNICATION DEVELOPMENT OF NEW TECHNETIUM CORES CONTAINING TECHNETIUM-NITROGEN MULTIPLE BONDS. SYNTHESIS AND CHARACTERIZATION OF SOME DIAZENIDO-, HYDRAZIDO- AND IMIDO- COMPLEXES OF TECHNETIUM C. M. ARCHER,
J. R. DILWORTH,”
P. JOBANPUTRA
and R. M. THOMPSON
Department of Chemistry and Biological Chemistry, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K. and M. McPARTLIN School of Chemistry, Polytechnic of North London, Holloway Road, London N7 8DB, U.K. and D. C. POVEY and G. W. SMITH Department of Chemistry, University of Surrey, Guildford, Surrey GU2 5XH, U.K. and J. D. KELLY Amersham International plc, White Lion Road, Amersham, Buckinghamshire HP7 9LL, U.K. (Received 29 March 1990 ; accepted 26 April 1990)
Abstract-The syntheses of several novel diazenido-, hydrazido- and imido- complexes of technetium are described. These precursors which contain technetium-nitrogen multiple bonds are derived directly from the appropriate organohydrazine or amine in good yield. Some of the chemistry has been extended to the metastable isotope g9mT~(y, t 1,2= 6 h) in highly dilute aqueous media to give single species in high radiochemical purity. These, preparations are applicable to the synthesis of new technetium radiopharmaceuticals and should provide for the development of a whole new range of technetium-based diagnostic agents in nuclear medicine.
Tte abvelopmenr’ or’rtie da& cooralinauon cnemistry of the synthetic radioactive element technetium has undergone a revolution in recent years * Author to whom correspondence should be addressed. Abbreviations : dppe, 1,2-bis(diphenylphosphino) &LLWC;&zq?&, I ~~~~~~~~~~~~~~~~~~~~~~~~~~~ &qE, L,.Z-bisJdieth;ulphospEnojethane; Ar, generalized a@ subsfifuent.
owmg ro tis expanaliig apptlcaribn in rtle ai8_eno& imaging of internal organs by y-scintillation detection. ‘,2The combination of reasonable cost, extensive availability and optimal nuclear properties makes technetium-99m the radionuclide of choice for many applications in nuclear medicine.‘~2 Typi&Z%! Zequi~~& fQT c!c&&%&UZ?.Z CQZZZ@&GS tQ b.2
clinicalry useful radiopnarmaceuticals are ease of preparation (to give a single radio&em&&~-pure
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product), stability (under biological conditions), controllable overall charge (oxidation state) and redox properties, and useful biodis~bution prop erties.3 The biological targeting ability of such yemitting technetium species depends largely on the physical or metabolic properties of its coordinated ligands, which cause the complex to locate in a particular organ after intravenous injection. l-4 The development of new technetium chemistry and subsequently the design of new or improved radiopharmaceutical reagents therefore depends crucially on the availability of both new ligand systems and new technetium central core moieties. The chemistry of technetium in its higher and intermediate oxidation states is dominated by its tendency to form oxo-species. Indeed, several of the currently used clinical reagents are coordination compounds of the mono-oxo- [TcV=O13’ and dioxo- [O=Tc”=O]+ cores, and these are used to image all the major organs including kidney, liver, heart and brain. Potential alternative cores for technetium are the nitrosyl moiety [TcNO14 and trun~-[Tc?Cl~]+,~ but these are not currently utilized in any commercial radiopharmaceuticals. Baldas and Bonnyman ’ have reported the facile synthesis of the robust nitridomoiety [TEN, and demonstrated its ability to undergo various ligand substitution reactions. However, there have been few reports of derivatives of this core of potential use as imaging agents. We report here the synthesis of several novel “Tc precursors containing Tc-N multiple bonds (Fig. 1). These include mono- and bis-diazenido-, hydrazido(2-)- and imido- species. Some of this chemistry has been successfully extended to the metastable isotope 9gmTc(y emitter = 140 keV, tljz = 6 h) in highly dilute (ca 10e8 M) aqueous media to give single compounds in high radiochemical purity. These novel technetium cores with their chemically robust metal-nitrogen bonds in combinatiqn with appropriate ancillary ligands to control biological targeting characteristics offer a whole new range of possibilities for the development of technetium-based diagnostic agents.
TECHNETIUM
DIAZENIDO-
Monosubstituted organodi~enido ligands, MN=NR, may adopt several different bonding modes in transition metal complexes (Fig. 2).6 The singly bent geometry (I) is the most common structure found. The doubly bent geometry (II) and bridging mode (III) are much less common. We have previously reported the synthesis and characteristics of the rhenium bis(diazenido)- complexes, [ReC1(N,Ar),(PPh3)2].7 These rhenium(II1) bis(di~enido)complexes are easily protonated or alkylated at the P-nitrogen of one of the coordinated diazenido- ligands to give the rhenium(V) diazenidehydrazido- complexes, [ReCl, (NNAr)(~HAr)(PPh3)~], in quantitative yield. The complex with Ar = C6H,-- was structurally characterized and shown to contain a linear (three-electron donor) diazenido- ligand and a bent (two-electron donor) hydrazido(2 -)- ligand. 7 Reaction of [~-Bu4~[TcO~14] with excess arylhydrazine and PPh3 in alcohol gives air-stable, orange, crystalline [TcCl(N2Ar)2(PPh3)2] complexes in 70-80% yield. These are entirely analogous to the rhenium complexes, [ReCl(N,Ar)* (PPh&],7 and HPLC analysis indicates that these technetium species form in > 95% yield in solution. They are diamagnetic five-coordinate technetium(II1) d4 compounds. The 3‘P NMR spectrum exhibits a singlet consistent with a ague-arrangement of PPh3 groups. A trigonal bipyramidal structure with cis-diazenido ligands in the equatorial plane is proposed by analogy with the known rhenium structure.8 This has very recently been verified by the independent structural characterization of ~ccl(~c6H4Br)*(PPh~)~].’ These workers also investigated the facile protonation at N, of these species,’ which we demonstrated earlier for the [ReCl(N,Ar),(PPh,)J complexes.’ We have now shown that the chloride and phosphine ligands may be displaced by a range
ONiR Tc-N=N\
II N, M”
Tc =N-NRz R
diazenido -
hydrazido (2-l -
ON//
SINGLY
Tc-N-R
Fig.
2.
Q/R II H/N\
II BENT
3-electron donor
Imido -
7 NQ
h
I
Fig. 1. New core moieties for technetium radiopharmaceuticals.
COMPLEXES
DOUBLY I-
III BENT
BRIDGING
eteckon donor
Formal bonding modes for transition organodiazenido-
complexes.
metal
Communication of other ligands to give new technetium(II1) monoand bis-diazenido- complexes. Indeed, subsequent reaction of ~~l~~Ar)~(PPh~)~] with P-P (P-P = dppe, dmpe) under reflux in alcohol gives orange-yellow fTcC1(N2Ar)(P-P)$ in high (70%) yield with loss of one -N2Ar ligand. HPLC analysis indicates that these species comprise > 95% of the reaction product in solution. These synthetic reactions can also be carried out directly from TcO;- in high yield and this chemistry has been extended to the ggmTc level. The monodi~enidocomplex with Ar = C6H5- and P-P = dppe has been structurally characterized (Fig. 3) as its PF,-salt.* This complex cation has slightly distorted trans-octahedral coordination geometry. Equatorial sites are occupied by phosphorus donor atoms of the two bidentate dppe iigands. The phenyldiazenidoand chloridoligands occupy the trans-axial sites. The diazenidoligand is described as singly bent with an intermediate Tc-N,-_NB angle of 162(2>0 and is thus formally a three-electron donor. 6 The Tc-N bond length of 1.917( 19) 8, is much longer than that normally found for diazenido- complexes,6 and may reflect the repulsive interaction with the four equatorial phosphorus atoms. This complex has the same overall structure as the isoelectronic technetium nitrosyl cation, [TcCl(NO)(depe),]+. lo This behaviour of jTcCl(N,Ar),(PPh,),1 contrasts sharply with that of ~ReCl(N*Ar)*(PPh~) j which reacts under similar conditions with bidentate phosphines to give the formally 20-electron rhenium(II1) species [Re(N,Ar),(P-P),]+. The presence of two truns-diazenido-singly bent (formally three-electron donor) ligands bound to rhenium has been verified by the structural determination of the complex with Ar = CH,C6Hh-and P-P = dppe.” TECHNETIUM HYDRAZIDO(Z-)COMPLEXES
Fig. 3. Structural representation of the complex cation [TcClcNNC,H,)(dppe)d’.
many examples of essentially isostructural metal0x0 and metal-hydrazido(2 - )- complexes. ’ 4 The addition of l,l-disubstituted hydrazines to [n-Bu,Nj[TcOClJ in dry methanol gives a deep red solution which contains a single t~hneti~-containing species (HPLC, p-detection). This species is tentatively presumed to be [Tc(NNR2)C14]-. It is not easily characterized, but can be routinely generated in situ and further derivatized to give desired t~hnetium hydr~do(2 - )- products. Thus reaction of [n-Bu,Nj[TcOCl,] with MePhNNH* in refluxing methanol with PPh, gives the technetium(V) species [TcCl,(NNMePh)(PPh&]. Use of less bulky phosphines such as PMe,Ph leads to the formation of the cationic species [TcCl~~NMe
l,l-Disubstituted organohydrazines (R,NNH;) may give rise to te~inally bound hydr~ido(2-)iigands, M = NNR2 (Fig. 4). These may also arise from the protonation or alkylation of N, of organodiazenido- ligands. 6,12Hydrazido(2 -)- complexes are also proven intermediates in the protonation of coordinated dinitrogen to give ammonia. I3 The linear bonding mode (IV) M=IU-NR2 is formally isoelectronic with the metal-oxo core, and there are
*Preliminary representations of all of the structures are given and full details will be reported at a later date.
LINEAR
BENT
4-electron donor
P-electron donor
Fig. 4. Formal bonding modes of the terminally-bound hydrazido(2 -)- moiety.
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Fig. 5. Structural representation of the complex cation [TcCl(NNMe,>(dppe),l’.
[TcCl(N,)(dppe)J, v(NJ 1980 cm-‘, which is not formed under argon. However, use of MePhNNH, and dppe in methanol under reflux yields trunsl?c~NWm?e)21+~ which has the new oxo-imidotechnetium(V) core moiety [O=Tc”=NH]+. This has also been confirmed by an X-ray structural analysis (Fig. 6). Although the structural data was better refined as a bis(imido)- complex fTc(=NH)J* , the marked asymmetry in the bonding of the two axial ligands and elemental analysis suggests that they should be assigned as oxo- and imido-, respectively. TECHNETIUM
Ph)(PMePh) J’ in moderate yield. Excess hydrazine gives access to bis(hydrazido)- complexes believed to be analogous to the known rhenium complex [ReCl~~NR*)*(PPh~)]~. I5 Reaction of [n-I3u,Nj FcOCl,] with Me2NNH2 and dppe in methanol at room temperature gives good yields of the technetium(IV) cation [TcCl(NNMe,)(dppe)J+. This has been st~ct~ally characterized as its PFBsalt (Fig. 5). The synthetic chemistry is again easily extrapolated to 99mTc in high overall radiochemical purity. Reactions of organohydrazines are notoriously dependent on reaction conditions,‘,” and some unexpected products due to cleavage or loss of the hydrazido(2-)moiety have been isolated. Thus, reaction of [n-Bu4Nj[TcOC14] with Me,NNH, and dppe in methanol under reflux gives lower yields of the cationic ~cCl(~Me~)(dppe)~]+ together with a yellow neutral product, we believe to be
IMIDO-
COMPLEXES
The terminal imido(2-)- ligand is formally isoelectronic with the more common terminal 0x0(2-)- group.16 However, the imido- ligand is much more resistant to protic attack and rarely bridges between transition metal ions. The ligand may function formally as either a linear four-electron donor (VI) or as a bent two-electron donor (VII) where the M-N-C framework is generally about 140” and two electrons reside on the nitrogen (Fig. 7).16 The R group is easily varied and derivatives with alkyl” and aryl’* -COPh” and -SOZPh” are known. In the special case where R = NR2’ a dialkylamide, the ligand is more commonly named hydrazido(2 - )-. Reaction of ~~-Bu~~~cOX~] (X = Cl, Br) with excess ArNCO in refluxing dry toluene under nitrogen gives [Tc(NAr)X,]- as diamagnetic blue-black solids in virtually quantitative yield. These anionic technetium(V) complexes are quite sensitive to adventitious moisture but are useful starting materials for the preparation of a whole range of technetium(V) imido- species. The [Tc(NAr)X,]complexes contain the new core moiety [Tc”= NAr] 3+, making [Tc(NAr)X,]a 16-electron species in which the imido- ligand functions as a linear four-electron donor. In efforts to derive preparative routes more applicable for radiopharmaceutical synthesis, [PIBu*~[TcOCl~] was reacted with aromatic amines
MeN-R
0
M=N
\ ‘R VI LINEAR
Fig. 6. Structural representation of the complex cation trans-[TcO(NH)(dppe),]+.
VII BENT
4-electron
Z-electron
donor
donor
Fig. 7. Bonding modes of the imido(2 -)- ligand
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CONCLUSION
Fig. 8. Structural representation
of [TcCl,(Ntol)(PPh,)&
and PPh3 in alcohols to give the neutral greenbrown [TcCl,(NAr)(PPh,),] complexes which are directly analogous to the known rhenium complexes [ReCl,(NAr)(PPh,),]. ’ 9 These air-stable technetium(V) compounds are diamagnetic solids which exhibit a singlet in the 3‘P NMR spectrum indicating two trans-PPh, groups. They are more stable than the [Tc(NAr)XJ species and consequently are superior starting materials for the preparation of a range of technetium imido- complexes. The derivative with Ar = CH3C6H4- has been structurally characterized (Fig. S), and is pseudooctahedral with two trans-PPh, groups. The tolylimido- ligand is essentially linear with a Tc-N-C angle of 168” and a Tc-N distance of 1.7 A, characteristic of a metal-nitrogen multiple bond. The imido- ligand is therefore functioning as a fourelectron donor giving the technetium complex an overall 1g-electron valence configuration. The analogous technetium oxo- complex is not known due to facile oxygen atom abstraction and reduction in the presence of monodentate tertiary phosphines. Reaction of [n-Bu4~J1[TcOC14] with aromatic amines and dppe in refluxing alcohols gives cationic, purple technetium(IV) complexes, [TcCl (NAr)(dppe) d+, in good yield. These air-stable complexes exhibit no v(NH) and show broadened NMR spectra characteristic of paramagnetic metal centres. They are formally analogous to the structurally characterized technetium(IV) hydrazido (2-)- complex [TcCl(NNMe,)(dppe),]+ (Fig. 5). Related technetium alkyl imido- complexes may be synthesized using phosphinimines, ’ 7 alkylamines” and symmetrically substituted dialkyl hydrazines, ’ ’ and these investigations will be reported at a later date.
We have described the synthesis and characterization of some novel technetium diazenido-, hydrazido- and imido- complexes derived directly from the appropriate organohydrazine or amine in good yield, and successfully extrapolatd the chemistry to the 99mT~level in some cases. These preparations are extremely applicable to the synthesis of new technetium radiopharmaceuticals. Unlike previous core moieties these multiplybonded nitrogenous ligands may carry a wide variety of different substituents attached to the nitrogen. This allows the coordination properties of these geometrically versatile ligands to be very effectively varied and also permits the complexes to be easily functionalized for suitable attachment to biological materials. We have as yet only directed the synthetic work of the new technetium cores to the generation of cationic species for possible use as potential myocardial imaging agents. However, the further substitution chemistry of these new cores will be reported at a later date. This work has been the subject of a recent patent application.” are indebted to Amersham International plc for financial support of this work and for provision of laboratory facilities for 99mT~chemistry and biodistribution studies. We thank the SERC for provision of a CASE Award (to P.J.). Acknowledgements-We
REFERENCES 1. E. Deutsch, K. Libson, S. Jurisson and L. F. Lindoy, Prog. Znorg. Chem. 1983,30,75.
2. E. Deutsch and K. Libson, Comm. Znorg. Chem. 1984,3, 83.
3. M. J. Clarke and L. Podbielski, Coord. Chem. Rev. 1987, 78, 253 ; C. J. Jones, Comprehensive Coordination Chemistry (Edited by G. Wilkinson, R. D. Gillard and J. A. McCleverty), p. 881. Pergamon Press, Oxford (1988). 4. J. D. Eakins, D. G. Humphreys and C. E. Mellish, J. Chem. Sot. 1963, 6012; L. J. Radnovich and J. L. Hoard, J. Phys. Chem. 1984, 88, 6713; R. A. Armstrong and H. Taube, Znorg. Chem. 1976, 15, 1904. 5. J. Baldas and J. Bonnyman, Znt. J. Appl. Radiat. Zsot. 1985, 36, 133.
6. B. F. G. Johnson, B. L. Haymore and J. R. Dilworth, Comprehensive Coordination Chemistry (Edited by G. Wilkinson, R. D. Gillard and J. A. McCleverty), Ch. 13.3, pp. 99-159. Pergamon Press, Oxford (1988). 7. J. R. Dilworth, S. A. Harrison, D. R. M. Walton and E. Schweda, Znorg. Chem. 1985,24,2594. 8. T. Nicholson, P. Lombardi and J. Zubieta, Polyhedron 1987,6, 1577.
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9. T. Nicholson, N. de Vries, A. Davison and A. G. Jones, Znorg. Chem. 1989,28,3813. 10. I. A. Latham, J. R. Thornback and J. E. Newman, Eur. Patent 0291281-Al (1988). 11. C. M. Archer, J. R. Dilworth, P. Jobanputra, R. M. Thompson, J. Strahle and S. S&mid, unpublished work. 12. W. A. Nugent and B. L. Haymore, Coord. Chem. Rev. 1980, 31, 123. 13. J. R. Dilworth and R. L. Richards, Comprehensive OrganometaNic Chemistry (Edited by G. Wilkinson, F. G. A. Stone and E. W. Abel), p. 1017. Pergamon Press, Oxford (1982); J. Chatt, J. R. Dilworth and R. L. Richards, Chem. Rev. 1978, 78, 589; R. A. Henderson, G. J. Leigh and C. J. Pickett, Ado. Znorg. Chem. Radiochem. 1983,27,197. 14. R. Cotton, I. B. Tomkins and P. W. Wilson, Aust. J. Chem. 1964,17,496 ; F. W. Moore and M. L. Larson, Znorg. Chem. 1967,6,988 ; J. Chatt, B. A. Crichton, J. R. Dilworth, P. Dahlstrom, R. Gutkoska and J. Zubieta, Znorg. Chem. 1982,21,2383 ; J. R. Dilworth and S. Morton, Transition Met. Chem. 1987, 12,41.
15. J. R. Dilworth, P. Jobanputra, S. J. Parrott and R. M. Thompson, unpublished work. 16. M. H. Chisholm and I. P. Rothwell, Comprehensive Coordination Chemistry (Edited by G. Wilkinson, R. D. Gillard and J. A. McCleverty). Pergamon Press, Oxford (1988). 17. J. Chatt and J. R. Dilworth, Chem. Commun. 1972, 519. 18. M. W. Bishop, J. Chatt, J. R. Dilworth, M. B. Hursthouse and M. Motevalli, J. Less-Common Met. 1977,54,487. 19. D. Bright and J. A. Ibers, Znorg. Chem. 1968, 7, 1099; D. Bright and J. A. Ibers, Znorg. Chem. 1969, 8, 703 ; G. V. Goeden and B. L. Haymore, Znorg. Chem. 1983,22,157. 20. J. Chatt, J. D. Garforth, N. P. Johnson and G. A. Rowe, J. Chem. Sot. 1964, 1012. 21. J. Chatt, J. R. Dilworth and G. J. Leigh, J. Chem. Sot. A 1970,2239. 22. C. M. Archer, J. R. Dilworth, I. A. Latham and R. M. Thompson, Brit. Pat. Applic. 8919488.0 (filed 29 August 1989).
1497-1502, 1990
0277-5387/90 s3.lw+.oLl ?=c~Rmon~.dlc
COMMUNICATION DEVELOPMENT OF NEW TECHNETIUM CORES CONTAINING TECHNETIUM-NITROGEN MULTIPLE BONDS. SYNTHESIS AND CHARACTERIZATION OF SOME DIAZENIDO-, HYDRAZIDO- AND IMIDO- COMPLEXES OF TECHNETIUM C. M. ARCHER,
J. R. DILWORTH,”
P. JOBANPUTRA
and R. M. THOMPSON
Department of Chemistry and Biological Chemistry, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K. and M. McPARTLIN School of Chemistry, Polytechnic of North London, Holloway Road, London N7 8DB, U.K. and D. C. POVEY and G. W. SMITH Department of Chemistry, University of Surrey, Guildford, Surrey GU2 5XH, U.K. and J. D. KELLY Amersham International plc, White Lion Road, Amersham, Buckinghamshire HP7 9LL, U.K. (Received 29 March 1990 ; accepted 26 April 1990)
Abstract-The syntheses of several novel diazenido-, hydrazido- and imido- complexes of technetium are described. These precursors which contain technetium-nitrogen multiple bonds are derived directly from the appropriate organohydrazine or amine in good yield. Some of the chemistry has been extended to the metastable isotope g9mT~(y, t 1,2= 6 h) in highly dilute aqueous media to give single species in high radiochemical purity. These, preparations are applicable to the synthesis of new technetium radiopharmaceuticals and should provide for the development of a whole new range of technetium-based diagnostic agents in nuclear medicine.
Tte abvelopmenr’ or’rtie da& cooralinauon cnemistry of the synthetic radioactive element technetium has undergone a revolution in recent years * Author to whom correspondence should be addressed. Abbreviations : dppe, 1,2-bis(diphenylphosphino) &LLWC;&zq?&, I ~~~~~~~~~~~~~~~~~~~~~~~~~~~ &qE, L,.Z-bisJdieth;ulphospEnojethane; Ar, generalized a@ subsfifuent.
owmg ro tis expanaliig apptlcaribn in rtle ai8_eno& imaging of internal organs by y-scintillation detection. ‘,2The combination of reasonable cost, extensive availability and optimal nuclear properties makes technetium-99m the radionuclide of choice for many applications in nuclear medicine.‘~2 Typi&Z%! Zequi~~& fQT c!c&&%&UZ?.Z CQZZZ@&GS tQ b.2
clinicalry useful radiopnarmaceuticals are ease of preparation (to give a single radio&em&&~-pure
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product), stability (under biological conditions), controllable overall charge (oxidation state) and redox properties, and useful biodis~bution prop erties.3 The biological targeting ability of such yemitting technetium species depends largely on the physical or metabolic properties of its coordinated ligands, which cause the complex to locate in a particular organ after intravenous injection. l-4 The development of new technetium chemistry and subsequently the design of new or improved radiopharmaceutical reagents therefore depends crucially on the availability of both new ligand systems and new technetium central core moieties. The chemistry of technetium in its higher and intermediate oxidation states is dominated by its tendency to form oxo-species. Indeed, several of the currently used clinical reagents are coordination compounds of the mono-oxo- [TcV=O13’ and dioxo- [O=Tc”=O]+ cores, and these are used to image all the major organs including kidney, liver, heart and brain. Potential alternative cores for technetium are the nitrosyl moiety [TcNO14 and trun~-[Tc?Cl~]+,~ but these are not currently utilized in any commercial radiopharmaceuticals. Baldas and Bonnyman ’ have reported the facile synthesis of the robust nitridomoiety [TEN, and demonstrated its ability to undergo various ligand substitution reactions. However, there have been few reports of derivatives of this core of potential use as imaging agents. We report here the synthesis of several novel “Tc precursors containing Tc-N multiple bonds (Fig. 1). These include mono- and bis-diazenido-, hydrazido(2-)- and imido- species. Some of this chemistry has been successfully extended to the metastable isotope 9gmTc(y emitter = 140 keV, tljz = 6 h) in highly dilute (ca 10e8 M) aqueous media to give single compounds in high radiochemical purity. These novel technetium cores with their chemically robust metal-nitrogen bonds in combinatiqn with appropriate ancillary ligands to control biological targeting characteristics offer a whole new range of possibilities for the development of technetium-based diagnostic agents.
TECHNETIUM
DIAZENIDO-
Monosubstituted organodi~enido ligands, MN=NR, may adopt several different bonding modes in transition metal complexes (Fig. 2).6 The singly bent geometry (I) is the most common structure found. The doubly bent geometry (II) and bridging mode (III) are much less common. We have previously reported the synthesis and characteristics of the rhenium bis(diazenido)- complexes, [ReC1(N,Ar),(PPh3)2].7 These rhenium(II1) bis(di~enido)complexes are easily protonated or alkylated at the P-nitrogen of one of the coordinated diazenido- ligands to give the rhenium(V) diazenidehydrazido- complexes, [ReCl, (NNAr)(~HAr)(PPh3)~], in quantitative yield. The complex with Ar = C6H,-- was structurally characterized and shown to contain a linear (three-electron donor) diazenido- ligand and a bent (two-electron donor) hydrazido(2 -)- ligand. 7 Reaction of [~-Bu4~[TcO~14] with excess arylhydrazine and PPh3 in alcohol gives air-stable, orange, crystalline [TcCl(N2Ar)2(PPh3)2] complexes in 70-80% yield. These are entirely analogous to the rhenium complexes, [ReCl(N,Ar)* (PPh&],7 and HPLC analysis indicates that these technetium species form in > 95% yield in solution. They are diamagnetic five-coordinate technetium(II1) d4 compounds. The 3‘P NMR spectrum exhibits a singlet consistent with a ague-arrangement of PPh3 groups. A trigonal bipyramidal structure with cis-diazenido ligands in the equatorial plane is proposed by analogy with the known rhenium structure.8 This has very recently been verified by the independent structural characterization of ~ccl(~c6H4Br)*(PPh~)~].’ These workers also investigated the facile protonation at N, of these species,’ which we demonstrated earlier for the [ReCl(N,Ar),(PPh,)J complexes.’ We have now shown that the chloride and phosphine ligands may be displaced by a range
ONiR Tc-N=N\
II N, M”
Tc =N-NRz R
diazenido -
hydrazido (2-l -
ON//
SINGLY
Tc-N-R
Fig.
2.
Q/R II H/N\
II BENT
3-electron donor
Imido -
7 NQ
h
I
Fig. 1. New core moieties for technetium radiopharmaceuticals.
COMPLEXES
DOUBLY I-
III BENT
BRIDGING
eteckon donor
Formal bonding modes for transition organodiazenido-
complexes.
metal
Communication of other ligands to give new technetium(II1) monoand bis-diazenido- complexes. Indeed, subsequent reaction of ~~l~~Ar)~(PPh~)~] with P-P (P-P = dppe, dmpe) under reflux in alcohol gives orange-yellow fTcC1(N2Ar)(P-P)$ in high (70%) yield with loss of one -N2Ar ligand. HPLC analysis indicates that these species comprise > 95% of the reaction product in solution. These synthetic reactions can also be carried out directly from TcO;- in high yield and this chemistry has been extended to the ggmTc level. The monodi~enidocomplex with Ar = C6H5- and P-P = dppe has been structurally characterized (Fig. 3) as its PF,-salt.* This complex cation has slightly distorted trans-octahedral coordination geometry. Equatorial sites are occupied by phosphorus donor atoms of the two bidentate dppe iigands. The phenyldiazenidoand chloridoligands occupy the trans-axial sites. The diazenidoligand is described as singly bent with an intermediate Tc-N,-_NB angle of 162(2>0 and is thus formally a three-electron donor. 6 The Tc-N bond length of 1.917( 19) 8, is much longer than that normally found for diazenido- complexes,6 and may reflect the repulsive interaction with the four equatorial phosphorus atoms. This complex has the same overall structure as the isoelectronic technetium nitrosyl cation, [TcCl(NO)(depe),]+. lo This behaviour of jTcCl(N,Ar),(PPh,),1 contrasts sharply with that of ~ReCl(N*Ar)*(PPh~) j which reacts under similar conditions with bidentate phosphines to give the formally 20-electron rhenium(II1) species [Re(N,Ar),(P-P),]+. The presence of two truns-diazenido-singly bent (formally three-electron donor) ligands bound to rhenium has been verified by the structural determination of the complex with Ar = CH,C6Hh-and P-P = dppe.” TECHNETIUM HYDRAZIDO(Z-)COMPLEXES
Fig. 3. Structural representation of the complex cation [TcClcNNC,H,)(dppe)d’.
many examples of essentially isostructural metal0x0 and metal-hydrazido(2 - )- complexes. ’ 4 The addition of l,l-disubstituted hydrazines to [n-Bu,Nj[TcOClJ in dry methanol gives a deep red solution which contains a single t~hneti~-containing species (HPLC, p-detection). This species is tentatively presumed to be [Tc(NNR2)C14]-. It is not easily characterized, but can be routinely generated in situ and further derivatized to give desired t~hnetium hydr~do(2 - )- products. Thus reaction of [n-Bu,Nj[TcOCl,] with MePhNNH* in refluxing methanol with PPh, gives the technetium(V) species [TcCl,(NNMePh)(PPh&]. Use of less bulky phosphines such as PMe,Ph leads to the formation of the cationic species [TcCl~~NMe
l,l-Disubstituted organohydrazines (R,NNH;) may give rise to te~inally bound hydr~ido(2-)iigands, M = NNR2 (Fig. 4). These may also arise from the protonation or alkylation of N, of organodiazenido- ligands. 6,12Hydrazido(2 -)- complexes are also proven intermediates in the protonation of coordinated dinitrogen to give ammonia. I3 The linear bonding mode (IV) M=IU-NR2 is formally isoelectronic with the metal-oxo core, and there are
*Preliminary representations of all of the structures are given and full details will be reported at a later date.
LINEAR
BENT
4-electron donor
P-electron donor
Fig. 4. Formal bonding modes of the terminally-bound hydrazido(2 -)- moiety.
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Fig. 5. Structural representation of the complex cation [TcCl(NNMe,>(dppe),l’.
[TcCl(N,)(dppe)J, v(NJ 1980 cm-‘, which is not formed under argon. However, use of MePhNNH, and dppe in methanol under reflux yields trunsl?c~NWm?e)21+~ which has the new oxo-imidotechnetium(V) core moiety [O=Tc”=NH]+. This has also been confirmed by an X-ray structural analysis (Fig. 6). Although the structural data was better refined as a bis(imido)- complex fTc(=NH)J* , the marked asymmetry in the bonding of the two axial ligands and elemental analysis suggests that they should be assigned as oxo- and imido-, respectively. TECHNETIUM
Ph)(PMePh) J’ in moderate yield. Excess hydrazine gives access to bis(hydrazido)- complexes believed to be analogous to the known rhenium complex [ReCl~~NR*)*(PPh~)]~. I5 Reaction of [n-I3u,Nj FcOCl,] with Me2NNH2 and dppe in methanol at room temperature gives good yields of the technetium(IV) cation [TcCl(NNMe,)(dppe)J+. This has been st~ct~ally characterized as its PFBsalt (Fig. 5). The synthetic chemistry is again easily extrapolated to 99mTc in high overall radiochemical purity. Reactions of organohydrazines are notoriously dependent on reaction conditions,‘,” and some unexpected products due to cleavage or loss of the hydrazido(2-)moiety have been isolated. Thus, reaction of [n-Bu4Nj[TcOC14] with Me,NNH, and dppe in methanol under reflux gives lower yields of the cationic ~cCl(~Me~)(dppe)~]+ together with a yellow neutral product, we believe to be
IMIDO-
COMPLEXES
The terminal imido(2-)- ligand is formally isoelectronic with the more common terminal 0x0(2-)- group.16 However, the imido- ligand is much more resistant to protic attack and rarely bridges between transition metal ions. The ligand may function formally as either a linear four-electron donor (VI) or as a bent two-electron donor (VII) where the M-N-C framework is generally about 140” and two electrons reside on the nitrogen (Fig. 7).16 The R group is easily varied and derivatives with alkyl” and aryl’* -COPh” and -SOZPh” are known. In the special case where R = NR2’ a dialkylamide, the ligand is more commonly named hydrazido(2 - )-. Reaction of ~~-Bu~~~cOX~] (X = Cl, Br) with excess ArNCO in refluxing dry toluene under nitrogen gives [Tc(NAr)X,]- as diamagnetic blue-black solids in virtually quantitative yield. These anionic technetium(V) complexes are quite sensitive to adventitious moisture but are useful starting materials for the preparation of a whole range of technetium(V) imido- species. The [Tc(NAr)X,]complexes contain the new core moiety [Tc”= NAr] 3+, making [Tc(NAr)X,]a 16-electron species in which the imido- ligand functions as a linear four-electron donor. In efforts to derive preparative routes more applicable for radiopharmaceutical synthesis, [PIBu*~[TcOCl~] was reacted with aromatic amines
MeN-R
0
M=N
\ ‘R VI LINEAR
Fig. 6. Structural representation of the complex cation trans-[TcO(NH)(dppe),]+.
VII BENT
4-electron
Z-electron
donor
donor
Fig. 7. Bonding modes of the imido(2 -)- ligand
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Fig. 8. Structural representation
of [TcCl,(Ntol)(PPh,)&
and PPh3 in alcohols to give the neutral greenbrown [TcCl,(NAr)(PPh,),] complexes which are directly analogous to the known rhenium complexes [ReCl,(NAr)(PPh,),]. ’ 9 These air-stable technetium(V) compounds are diamagnetic solids which exhibit a singlet in the 3‘P NMR spectrum indicating two trans-PPh, groups. They are more stable than the [Tc(NAr)XJ species and consequently are superior starting materials for the preparation of a range of technetium imido- complexes. The derivative with Ar = CH3C6H4- has been structurally characterized (Fig. S), and is pseudooctahedral with two trans-PPh, groups. The tolylimido- ligand is essentially linear with a Tc-N-C angle of 168” and a Tc-N distance of 1.7 A, characteristic of a metal-nitrogen multiple bond. The imido- ligand is therefore functioning as a fourelectron donor giving the technetium complex an overall 1g-electron valence configuration. The analogous technetium oxo- complex is not known due to facile oxygen atom abstraction and reduction in the presence of monodentate tertiary phosphines. Reaction of [n-Bu4~J1[TcOC14] with aromatic amines and dppe in refluxing alcohols gives cationic, purple technetium(IV) complexes, [TcCl (NAr)(dppe) d+, in good yield. These air-stable complexes exhibit no v(NH) and show broadened NMR spectra characteristic of paramagnetic metal centres. They are formally analogous to the structurally characterized technetium(IV) hydrazido (2-)- complex [TcCl(NNMe,)(dppe),]+ (Fig. 5). Related technetium alkyl imido- complexes may be synthesized using phosphinimines, ’ 7 alkylamines” and symmetrically substituted dialkyl hydrazines, ’ ’ and these investigations will be reported at a later date.
We have described the synthesis and characterization of some novel technetium diazenido-, hydrazido- and imido- complexes derived directly from the appropriate organohydrazine or amine in good yield, and successfully extrapolatd the chemistry to the 99mT~level in some cases. These preparations are extremely applicable to the synthesis of new technetium radiopharmaceuticals. Unlike previous core moieties these multiplybonded nitrogenous ligands may carry a wide variety of different substituents attached to the nitrogen. This allows the coordination properties of these geometrically versatile ligands to be very effectively varied and also permits the complexes to be easily functionalized for suitable attachment to biological materials. We have as yet only directed the synthetic work of the new technetium cores to the generation of cationic species for possible use as potential myocardial imaging agents. However, the further substitution chemistry of these new cores will be reported at a later date. This work has been the subject of a recent patent application.” are indebted to Amersham International plc for financial support of this work and for provision of laboratory facilities for 99mT~chemistry and biodistribution studies. We thank the SERC for provision of a CASE Award (to P.J.). Acknowledgements-We
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