Modeling novel radiopharmaceuticals: Mono-C6-substituted PnAO ligands (PnAO = 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime)

Article abstract of DOI:10.1021/ic0497634

The solid-state behavior of six novel 6-substituted PnAO (propylene amine oxime) complexes (6-11) involving Tc(V), Co(III), and Cu(II) salts is reported. Each of the Tc complexes 6-8 has the C6-substituent located equatorially in a six-membered chelate ring involving a Tc=O unit which has the expected boat geometry. The C6-substituent therefore has little effect on the conformational behavior of the PnAO complex and thus provides an attractive site for further modification. The Co(III) complex 9 has the expected octahedral geometry, while the Cu(II) complexes 10 and 11 form square-based pyramids capped by water molecules. One Cu(II) system (10) contains two unique complexes in the asymmetric unit which are associated via multiple hydrogen bonds to a BF ₄ anion, the remaining BF₄ anion being loosely hydrogen bonded to a coordinating water molecule. The cobalt and copper complexes 9-11 each exhibit a chair conformation for the six-membered chelate ring.

Full text of DOI:10.1021/ic0497634

Inorg. Chem. 2004, 43, 4145−4153
Modeling Novel Radiopharmaceuticals: Mono-C6-Substituted PnAO
Ligands (PnAO ) 3,3,9,9-Tetramethyl-4,8-diazaundecane-2,10-dione
Dioxime)
Paul S. Walker, Paul M. Bergin, Martin C. Grossel,* and Peter N. Horton
School of Chemistry, UniVersity of Southampton, Highfield, Southampton SO17 1BJ, England
Received February 23, 2004
The solid-state behavior of six novel 6-substituted PnAO (propylene amine oxime) complexes (6−11) in-
volving Tc(V), Co(III), and Cu(II) salts is reported. Each of the Tc complexes 6−8 has the C6-substituent lo-
cated equatorially in a six-membered chelate ring involving a TcdO unit which has the expected boat geom-
etry. The C6-substituent therefore has little effect on the conformational behavior of the PnAO complex and thus
provides an attractive site for further modification. The Co(III) complex 9 has the expected octahedral geom-
etry, while the Cu(II) complexes 10 and 11 form square-based pyramids capped by water molecules. One Cu(II)
system (10) contains two unique complexes in the asymmetric unit which are associated via multiple hydro-
gen bonds to a BF anion, the remaining BF anion being loosely hydrogen bonded to a coordinating water mole-
4
4
cule. The cobalt and copper complexes 9−11 each exhibit a chair conformation for the six-membered chelate
ring.
Introduction
As a result of a combination of its favorable nuclear prop-
erties (γ, Eγ ) 140 keV, t1/2 ) 6.02 h) and its ready
availability from an on-site generator, the metastable isotope
99mTc is used in approximately 90% of all diagnostic nuclear
medical scans performed annually.1 However, as a metal ion,
this radionuclide must be bound by an appropriate ligand
into a complex which is suitable for administration to the
patient. For the current generation of radiopharmaceuticals
localization in vivo tends to result from the physiological
properties of the complex as a whole rather than any specific
receptor-binding interactions.1 To improve control over the
distribution of radiopharmaceuticals in the body, investiga-
tions have been made into the attachment of suitable
technetium-binding ligands to biologically active molecules.2
In such cases the chelation of the radionuclide must not
interfere with biological receptor interaction.
with oxotechnetium(V), [TcO3+]3-5 and charged complexes
with nitridotechnetium(IV), [TcN2+].6 These complexes are
neutral as a result of the deprotonation of both amine groups
and of one of the oxime hydroxyl groups. The former process
is indicative of the acid-inducing effect of the high-valent
Tc(V) species which causes the deprotonation of the amine
ligands. The resulting amides may then further stabilize the
metal center by π-donation. The latter facilitates the forma-
tion of an intramolecular hydrogen bond to give a pseudomac-
rocyclic complex. Since the development of the commercial
cerebral perfusion agent Ceretec7,8 (2), attention has turned
3,3,9,9-Tetramethyl-4,8-diazaundecane-2,10-dione dioxime
(1), known as PnAO (from propylene amine oxime), and
related ligands form stable, lipophilic complexes such as 2
(3) Fair, C. K.; Troutner, D. E.; Schlemper, O. E.; Murmann, R. K.; Hoppe,
M. L. Acta Crystallogr. 1984, C40, 1544-1546.
(4) Jurisson, S.; Schlemper, O. E.; Troutner, D. E.; Canning, L. R.;
Nowotnik, D. P.; Neirinckx, R. D. Inorg. Chem. 1986, 25, 543-549.
(5) Cyr, J. E.; Nowotnik, D. P.; Pan, Y.; Gougoutas, J. Z.; Malley, M. F.;
Di Marco, J.; Nunn, A. D.; Linder, K. E. Inorg. Chem. 2001, 40,
3555-3561.
(6) Kani, Y.; Takayama, T.; Inomata, S.; Sekine, T.; Kudo, H. Chem.
Lett. 1995, 11, 1059-1060.
* Author to whom correspondence should be addressed. E-mail:
mcg1@soton.ac.uk.
(1) Jurisson, S.; Berning, D.; Wei Jia; Dangshe Ma. Chem. ReV. 1993,
93, 1137-1156.
(2) Hom, R. K.; Katzenellenbogen, J. A. Nucl. Med. Biol. 1997, 24, 485-
498.
10.1021/ic0497634 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/09/2004
Inorganic Chemistry, Vol. 43, No. 14, 2004 4145

Walker et al.
to the further modification of the PnAO skeleton to fine-
tune the properties of its complexes. The effect of two
identical substituents at the 6-position4,9 and that of the
attachment of a bioactive targeting group at the 1-position10
have been investigated, and synthetic routes to mono-6-
substituted ligands have been described.11 However, there
has as yet been no systematic study of the behavior of mono-
6-substituted ligands or the structural characterization of their
corresponding metal ion complexes.12 Nonetheless, for
reasons of synthetic ease and minimal interference with the
complexation process, the 6-position would appear to be the
most logical choice for the point of attachment of a targeting
group. Furthermore, elaboration at this position would avoid
stereochemical complexity arising from the formation of
racemic products upon complexation in addition to any
stereoisomerism present in the C6-substituent.
All isotopes of technetium are radioactive, and as such
the study of all of its complexes is necessarily limited.
However, there is a wealth of information regarding the
complexation behavior of PnAO and related ligands with
more easily accessible metal ions such as Co(III),13,14
Cu(II),15-20 Cu(III),19 Pd(II),21 Ni(II),18,22 and Rh(III).23 The
results of these crystallographic studies indicate that it would
be possible for nonspecialists to investigate the effect of
6-substitution upon the complexing behavior of the PnAO
ligand and ultimately on complex stability.
complexes have provided an insight into the effect of such
ligand modification on the nature of the resulting complexes.
Experimental Section
General Procedures. All solvents were purified and dried using
standard techniques. All other chemicals were of reagent grade and
used without further purification. Melting points were recorded
using open-ended capillary tubes on an electrothermal melting point
apparatus and are uncorrected. Elemental analyses were performed
by Microanalytical Service, Department of Chemistry, Imperial
College of Science, Technology and Medicine, London. Low-
resolution electrospray mass spectrometry was performed on a
Micromass Platform quadrupole mass analyzer (capillary 3.50 kV,
HV lens 0.5 kV, cone voltage 20 V, source temperature 110 °C,
100% acetonitrile eluent). High-resolution electrospray mass spec-
trometry was performed on a Bruker Apex III FT-ICR-MS high-
resolution electrospray mass spectrometer (ES eluent 50:50 MeOH/
water). Infrared spectrometry was performed on a Perkin-Elmer
1600 series FTIR spectrometer. 1H and 13C NMR data were acquired
at room temperature on a Bruker AC300 spectrometer (1H, 300.135
MHz; 13C, 75.469 MHz) with the chemical shifts referenced to the
peak for the deuterated solvent.
Radiation Protection. 99Tc is a low-energy (292 keV) â-particle
emitter with a half-life of 2.12 × 105 years. When handled on the
milligram scale, 99Tc does not present any significant health hazards
and bremsstrahlung is avoided as a result of the low energy of the
â-particle emission. However, routine radiological practices were
observed at all times to prevent contamination. This requirement
extended to the characterization of the 99Tc-containing complexes,
which were therefore characterized by single-crystal X-ray diffrac-
tion alone.
Ligand Synthesis. The general synthetic route is outlined in
Scheme 1. Elaboration at the 6-position of the PnAO backbone (1)
was achieved by the suitable modification of an established
pathway.24 Alkylation was achieved by substitution at the central
carbon of diethyl 1,3-propanedioate followed by conversion of the
diester to the corresponding 2-substituted 1,3-diamine. The oxime
functionality was then added by substitution of an R-haloketone
followed by conversion to the dioxime. The synthesis of the parent
PnAO ligand 3a has been reported elsewhere.25
Synthesis of 2-Benzyl-1,3-propanediamine (5a). 2-Benzyl-1,3-
propanediamide26 (7.28 g, 38.0 mmol) was slowly added in portions
to a solution of borane in THF (1 mol dm-3, 288 mL, 290.0 mmol).
The mixture was refluxed for 24 h, carefully acidified at 0 °C with
concentrated HCl to pH 1, and then concentrated by evaporation
at reduced pressure. The residue was repeatedly coevaporated with
methanol (5 × 100 mL) to remove borane residues as the trimethyl
borate ester and then neutralized with 10% NaOH. The aqueous
solution was then saturated with NaCl and extracted into DCM.
The combined organic phases were dried over Na2SO4, and the
solvents were evaporated at reduced pressure. The crude oil was
In the work reported here a series of ligands (3a-d)
bearing simple model groups in the 6-position have been
synthesized to investigate the effect of such substitution upon
their coordination behavior with TcO3+, Cu(II), and Co(III).
Single-crystal X-ray diffraction studies of the resulting
(7) Leonard, J. P.; Nowotnik, D. P.; Neirinckx, R. D. J. Nucl. Med. 1986,
27, 1819-1823.
(8) Neirinckx, R. D.; Canning, L. R.; Piper, I. M.; Nowotnik, D. P.; Pickett,
R. D.; Holmes, R. A.; Volkert, W. A.; Forster, A. M.; Weisner, P. S.;
Marriot, J. A.; Chaplin, S. B. J. Nucl. Med. 1987, 28, 191-202.
(9) Tsai, C. S.; Lu, T. H.; Duh, J. Y.; Yeh, S. J. Acta Crystallogr. 1996,
C52, 838-840.
(10) Linder, K. E.; Chan, Y. W.; Cyr, J. E.; Malley, M. F.; Nowotnik, D.
P.; Nunn, A. D. J. Med. Chem. 1994, 37, 9-17.
(11) Pillai, M. R. A.; Kilcoin, T.; Kothari, K.; Ramamoorthy, N.; Lal, R.;
Jurisson, S. S.; Schlemper, E. O. J. Labelled Compd. Radiopharm.
1999, 42, 1161-1173.
(12) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. (The United Kingdom
Chemical Database Service). J. Chem. Inf. Comput. Sci. 1996, 36,
746-749.
(13) Engelhardt, L. M.; Harrowfield, J. M.; McNiven, S. J.; Skelton, B.
W.; White, A. H. Aust. J. Chem. 1990, 43, 1803-1816.
(14) Murmann, R. K.; Schlemper, E. O. Inorg. Chem. 1973, 12, 2625-
2631.
(15) Liss, I. B.; Schlemper, O. E. Inorg. Chem. 1975, 14, 3035-3039.
(16) Schlemper, O. E.; Hussain, M. S.; Murmann, R. K. Acta Crystallogr.
1981, B37, 234-237.
(17) Lee, T. J.; Chang, Y.; Chung, C. S.; Wang, Y. M. Acta Crystallogr.
1990, 46, 2360-2363.
(18) Duda, A. M.; Karaczyn, A.; Kozlowski, H.; Fritsky, I. O.; Glowiak,
T.; Prisyazhnaya, E. V.; Sliva, T. Y.; Swiatek-Kozlowska, J. J. Chem.
Soc., Dalton Trans. 1997, 3853-3859.
(19) Hanss, J.; Beckmann, A.; Kruger, H. J. Eur. J. Inorg. Chem. 1999,
163-172.
(20) Fritsky, I. O.; Swiatek-Kozlowska, J.; Kapshuk, A. A.; Kozlowski,
H.; Sliva, T. Y.; Gumienna-Kontecka, E.; Prisyazhnaya, E. V.;
Iskenderov, T. S. Z. Naturforsch. 2000, 55, 966-970.
(21) Hussain, M. S.; Schlemper, O. E. Inorg. Chem. 1979, 18, 1116-
1121.
(24) Nanjappan, P.; Raju, N.; Ramalingam, K.; Nowotnik, D. P. Tetrahe-
dron 1994, 50, 8617-8632.
(25) Kilcoin, T. Ph.D. Thesis, University of MissourisColumbia, 1993.
(26) Russel, P. J. Am. Chem. Soc. 1950, 72, 1853-1854.
(22) Hussain, M. S.; Schlemper, O. E. Inorg. Chem. 1979, 18, 2275-2282.
(23) Siripaisarnpipat, S.; Schlemper, O. E. Inorg. Chem. 1984, 23, 330-
334.
4146 Inorganic Chemistry, Vol. 43, No. 14, 2004

Modeling NoWel Radiopharmaceuticals
Scheme 1. General Synthetic Route to 6-Derivitized PnAO Ligandsa
to neutralize the solution (moist litmus paper). Water was care-
fully added to neutralize any remaining NaH, and then the or-
ganic phase was washed with water (3 × 100 mL), dried (MgSO4),
and evaporated at reduced pressure. The residue was distilled at
reduced pressure to provide the intermediate substituted diester as
a colorless oil. Yield: 11.59 g (82%). Bp: 215-220 °C at 18
mmHg. IR (film; cm-1): 1749, 1600, 1588, 1494. 1H NMR
(CDCl3): δ 1.25 (t, J ) 7.4 Hz, 6 H, CH2), 1.62 (quin, J ) 7.7
Hz, 2 H, CH2), 1.94 (q, J ) 7.6 Hz, 2 H, CH2), 2.64 (t, J ) 7.4
Hz, 2 H, CH2), 3.37 (t, J ) 7.4 Hz, 1 H, CH), 3.80 (s, 3 H, OCH3),
4.18 (q, J ) 7.1, 4 H, CH2), 6.81-6.89 (m, 2 H, ring), 7.10-7.19
(m, 2 H, ring). 13C{1H} NMR (CDCl3): δ 14.2 (q, CH3CH2),
27.7 (t, CH2), 28.7 (t, CH2), 29.9 (t, CH2), 52.1 (d, CH), 55.3 (q,
OCH3), 61.4 (t, CH3CH2), 110.3 (d, ring), 120.5 (d, ring), 127.3
(d, ring), 130.0 (d, ring), 130.3 (s, ring), 157.6 (s, ring), 169.7 (s,
CdO).
Diethyl 2-(3-(2-methoxyphenyl)-1-propyl)-1,3-propanedioate (4.05
g, 16.3 mmol) was dissolved in 2-propanol/toluene (1:1, 50 mL)
and saturated with ammonia gas at 0 °C. The mixture was left
overnight at room temperature, again saturated with ammonia gas,
and then placed in a freezer for 48 h. The precipitated solid was
filtered, and the filtrate was concentrated to yield more solid. The
combined solids were recrystallized from hot toluene/60-80
petroleum ether to provide the intermediate diamide as a colorless
crystalline solid. Yield: 1.38 g (32%). Mp: 159-169 °C. Anal.
Calcd: C, 62.4; H, 7.3; N, 11.2. Found: C, 62.5; H, 7.0; N, 11.0.
ES-MS: m/z 251 (M + H+). IR (Nujol mull, cm-1): 3394, 3184,
1674. 1H NMR (DMSO-d6): δ 1.48 (m, 2 H, CH2), 1.67 (m, 2 H,
CH2), 2.53 (q, J ) 7.7 Hz, 2 H, CH2), 2.98 (t, J ) 7.4 Hz, 1 H,
CH), 3.76 (s, 3 H, OCH3), 6.85 (t, J ) 7.4 Hz, 1 H, ring), 6.95 (d,
J ) 8.1 Hz, 1 H, ring), 7.04 (br s, 2 H, NH2), 7.09-7.19 (m, 2 H,
ring), 7.27 (br s, 2 H, NH2). 13C{1H} NMR (DMSO-d6): δ 29.3 (t,
CH2), 30.0 (t, CH2), 30.6 (t, CH2), 52.9 (d, CH), 55.1 (q, OCH3),
110.5 (s, ring), 120.1 (d, ring), 127.1 (d, ring), 129.5 (d, ring), 129.7
(d, ring), 157.0 (s, ring), 171.8 (s, CdO).
2-(3-(2-Methoxyphenyl)-1-propyl)-1,3-propanediamide (1.37 g,
5.47 mmol) was slowly added in portions to a solution of borane
in THF (1 mol dm-3, 43.8 mL, 43.8 mmol). Otherwise the method
for the synthesis of 5a was followed to provide the product diamine
5c as a colorless oil. Yield: 1.05 g (86%). ES-MS: m/z 223 (M +
H+). IR (film, cm-1): 3370, 3290, 1600, 1587. 1H NMR (CDCl3):
δ 1.34 (m, 2 H, CH2), 1.44 (m, 5 H, NH2, CH), 1.60 (m, 2 H,
CH2), 2.60 (t, J ) 7.4 Hz, 2 H, CH2), 2.67 (dd, J ) 5.9 Hz, J )
16.9 Hz, 2 H, CH2), 2.71 (dd, J ) 5.9 Hz, J ) 16.9 Hz, 2 H, CH2),
3.80 (s, 3 H, OCH3), 6.81-6.89 (m, 2 H, ring), 7.10-7.19 (m, 2
H, ring). 13C{1H} NMR (CDCl3): δ 27.0 (t, CH2CH2CH), 29.5 (t,
CH2CH2CH), 30.4 (t, ArCH2CH2), 43.5 (d, CH), 43.7 (t, CH2NH2),
55.1 (q, OCH3), 110.0 (d, ring), 120.2 (d, ring), 126.8 (d, ring),
129.6 (d, ring), 130.7 (s, ring), 157.2 (s, ring).
a Reagents and conditions: (i) NH3, MeOH, MeONa; (ii) B2H6, THF;
(iii) H2O, H+; (iv) 3-bromo-3-methyl-2-butanone, DMF, K2CO3; (v)
NH2OH, MeOH.
distilled on a Kugelrohr apparatus at reduced pressure to provide
the product diamine 5a as a colorless oil. Yield: 4.13 g (66%). IR
(film, cm-1): 3371, 3289, 1974, 1878, 1811, 1602. 1H NMR
(CDCl3): δ 1.58 (s, 4 H, NH2), 1.73 (sep, J ) 6.2 Hz, 1 H, CH),
2.61 (d, J ) 7.4 Hz, 2 H, CH2), 2.69 (dd, J ) 6.1 Hz, J ) 12.7 Hz,
2 H, CH2), 2.74 (dd, J ) 5.5 Hz, J ) 12.5 Hz, 2 H, CH2), 7.17-
7.31 (m, 5 H, ring). 13C{1H} NMR (CDCl3): δ 36.8 (t, CH2CH),
43.6 (t, CH2NH2), 46.1 (d, CH), 126.0 (d, ring), 128.4 (d, ring),
129.1 (d, ring), 140.7 (s, ring).
Synthesis of 2-(2-(4-Methoxyphenyl)ethyl)-1,3-propanedi-
amine (5b). 2-(2-(4-Methoxyphenyl)ethyl)-1,3-propanediamide27
(3.00 g, 13.0 mmol) was slowly added in portions to a solution of
borane in THF (1 mol dm-3, 100 mL, 100.0 mmol). Otherwise the
method for the synthesis of 5a was followed to provide the product
diamine 5b as a colorless oil. Yield: 1.95 g (72%). ES-MS: m/z
209 (M + H+). IR (film, cm-1): 3371, 3292, 1611, 1583, 1512.
1H NMR (CDCl3): δ 1.24 (br s, 4 H, NH2), 1.44 (sep, J ) 5.9 Hz,
1 H, CH), 1.59 (dt, J ) 7.6 Hz, J ) 7.6 Hz, 2 H, CH2), 2.59 (t, J
) 7.6 Hz, 2 H, CH2), 2.73 (dd, J ) 5.5 Hz, J ) 15.8 Hz, 2 H,
CH2), 2.78 (dd, J ) 5.9 Hz, J ) 16.2 Hz, 2 H, CH2), 3.78 (s, 3 H,
OCH3), 6.82 (d, J ) 8.1 Hz, 2 H, ring), 7.11 (d, J ) 8.8 Hz, 2 H,
ring). 13C{1H} NMR (CDCl3): δ 32.1 (t, CH2CH2CH), 32.6 (t,
CH2CH2CH), 43.6 (d, CH), 43.9 (t, CH2NH2), 55.4 (q, OCH3), 114.0
(d, ring), 129.3 (d, ring), 134.7 (s, ring), 157.9 (s, ring).
Synthesis of 2-(2-(2-Pyridinyl)ethyl)-1,3-propanediamine (5d).
Diethyl 2-(2-(2-pyridinyl)ethyl)-1,3-propanedioate29 (11.00 g, 41.0
mmol) was dissolved in methanol (50 mL), treated with sodium
methoxide (0.01 g, 0.255 mmol), and saturated with ammonia gas
at 0 °C. The mixture was left overnight at room temperature, again
saturated with ammonia gas, and then placed in a freezer for 48 h.
The precipitated solid was filtered, and the filtrate was concentrated
to yield more solid. The combined solids were recrystallized from
hot ethanol to provide the intermediate diamide as colorless needles.
Yield: 6.54 g (76%). Mp: 215-216 °C. Anal. Calcd: C, 58.0; H,
Synthesis of 2-(3-(2-Methoxyphenyl)-1-propyl)-1,3-propanedi-
amine (5c). Diethyl 1,3-propanedioate (8.06 g, 5.0 mmol) was
carefully added dropwise to a suspension of NaH (1.83 g, 4.60
mmol) in THF (100 mL), and the mixture was stirred for 1 h. 3-(2-
Methoxyphenyl)-1-propyl 4-methylbenzenesulfonate28 (14.66 g,
4.60 mmol) in THF (100 mL) was added dropwise, and the mixture
was stirred for a further 1 h and then refluxed for a sufficient time
(28) Knipe, J. O.; Vasquez, P. J.; Coward, J. K. J. Am. Chem. Soc. 1982,
104, 3202-3209.
(27) Aroyan, A. A.; Kaldrikyan, M. A.; Melik-Ogandzhanyan, R. G. Arm.
Khim. Zh. 1967, 20, 61-67.
(29) Shapiro, S. L.; Bandurco, V.; Freedman, L. J. Org. Chem. 1962, 27,
174-178.
Inorganic Chemistry, Vol. 43, No. 14, 2004 4147

Walker et al.
6.3; N, 20.3. Found: C, 58.3; H, 6.1; N, 20.4. ES-MS: m/z 207
(3.86 g, 23.0 mmol). Otherwise the method for the synthesis of 3a
was followed. Yield: 2.07 g (59%). ES-MS: m/z 377 (M + H+).
1
(M + H+). IR (Nujol mull, cm-1): 3383, 3168, 1671. H NMR
1
(DMSO-d6): δ 2.06 (q(app), J ) 7.8 Hz, 2 H, CH2), 2.66 (t(app),
J ) 7.7 Hz, 2 H, CH2), 3.03 (t, J ) 7.7 Hz, 1 H, CH), 7.10 (br s,
2 H, NH2), 7.20 (m, 2 H, ring), 7.30 (br s, 2 H, NH2), 7.70 (dd, J
) 7.4 Hz, J ) 7.7 Hz, 1 H, ring), 8.48 (d, J ) 5.1 Hz, 1 H, ring).
13C{1H} NMR (DMSO-d6): δ 29.5 (t, CH2), 35.2 (t, CH2), 52.5
(d, CH), 121.2 (d, ring), 122.7 (d, ring), 136.4 (d, ring), 148.9 (d,
ring), 160.7 (s, ring), 171.3 (s, CdO).
2-(2-(2-Pyridinyl)ethyl)-1,3-propanediamide (3.00 g, 14.0 mmol)
was slowly added in portions to a solution of borane in THF (1
mol dm-3, 100 mL, 100.0 mmol). Otherwise the method for the
synthesis of 5a was followed to provide the product diamine 5d as
a yellow oil. Yield: 1.35 g (52%). ES-MS: m/z 179 (M + H+). IR
(film, cm-1): 3364, 3282, 1591, 1568. 1H NMR (CDCl3): δ 1.50
(sep(app), J ) 6.1 Hz, 1 H, CH), 1.64 (br s, 4 H, NH2), 1.75 (m,
2 H, CH2), 2.80 (m, 6 H, CH2), 7.11 (dd, J ) 5.5 Hz, J ) 7.0 Hz,
1 H, ring), 7.17 (d, J ) 8.1 Hz, 1 H, ring), 7.59 (dd, J ) 7.4 Hz,
J ) 7.7 Hz, 1 H, ring), 8.52 (d, J ) 4.0 Hz, 1 H, ring). 13C{1H}
NMR (CDCl3): δ 29.9 (t, CH2CH2CH), 35.7 (t, CH2CH2CH), 43.3
(d, CH), 43.7 (t, CH2NH2), 121.1 (d, ring), 122.7 (d, ring), 136.4
(d, ring), 149.2 (d, ring), 162.0 (s, ring).
Synthesis of 3,3,9,9-Tetramethyl-4,8-diaza-6-benzyl-2,10-un-
decanedione Dioxime (3a). To a suspension of K2CO3 (8.71 g,
63.0 mmol) in dry DMF (32 mL) were added diamine 5a (4.13 g,
25.0 mmol) and 3-bromo-3-methyl-2-butanone30 (10.40 g, 63.0
mmol). The mixture was stirred for 18 h at 45 °C, after which time
DCM (50 mL) was added. The mixture was filtered, and the solvent
was removed under reduced pressure. The residue was chromato-
graphed (silica column, 5% methanol in DCM) to provide the
intermediate diketone as a slightly impure pale yellow wax which
was used directly in the next reaction step. Yield: 5.86 g (71%).
IR (film; cm-1): 3321, 2961, 1708s. 1H NMR (CDCl3): δ 1.22 (s,
12 H, CH3), 1.91 (m, 1 H, CH), 2.12 (s, 6 H, CH3), 2.31 (br s, 2
H, NH), 2.38 (dd, J ) 7.0 Hz, J ) 11.4 Hz, 2 H, CH2), 2.47 (dd,
J ) 4.4 Hz, J ) 11.0 Hz, 2 H, CH2), 2.60 (d, J ) 7.4 Hz, 2 H,
CH2), 7.14-7.29 (m, 5 H, ring). 13C{1H} NMR (CDCl3): δ 24.5
(q, CH3), 24.8 (q, CH3CO), 38.0 (t, CH2CH), 41.8 (d, CH), 46.6 (t,
CH2NH2), 63.1 (s, C), 126.1 (d, ring), 128.4 (d, ring), 129.1 (d,
ring), 140.5 (s, ring), 213.6 (s, CdO).
IR (film, cm-1): 3323, 1706s, 1675, 1612, 1584, 1513. H NMR
(CDCl3): δ 1.25 (s, 12 H, CH3), 1.58 (m, 3 H, CH, CH2), 1.97 (br
s, 2 H, NH), 2.18 (s, 6 H, CH3), 2.40 (m, 2 H, CH2), 2.53 (m, 4 H,
CH2NH), 3.78 (s, 3 H, OCH3), 6.82 (d, J ) 8.8 Hz, 2 H, ring),
7.08 (d, J ) 8.1 Hz, 2 H, ring). 13C{1H} NMR (CDCl3): δ 24.3
(q, CH3), 24.5 (q, CH3), 24.8 (q, CH3CO), 32.5 (t, CH2), 33.4 (t,
CH2), 39.2 (d, CH), 46.9 (t, CH2NH2), 55.2 (q, OCH3), 62.9 (s, C),
113.8 (d, ring), 129.2 (d, ring), 134.4 (s, ring), 157.7 (s, ring), 213.4
(s, CdO).
Hydroxylamine hydrochloride (2.87 g, 41.2 mmol) was added
to NaOH (1.54 g, 38.5 mmol) in methanol (40 mL), and the
resulting solution was stirred for 2 h at 0 °C. Otherwise the method
for the synthesis of 3a was followed with recrystallization from
hot ethanol to provide the product 3b as very fine, colorless needles.
Yield: 0.89 g (40%). Mp: 200-201 °C. ES-MS: m/z 407 (M +
H+). HR-ES-MS: C22H39N4O3, calcd m/z 407.3017, found m/z
407.3013 (M + H+). IR (Nujol mull, cm-1): 3356, 3300, 3194,
1
1612, 1585, 1513. H NMR (DMSO-d6): δ 1.33 (s, 12 H, CH3),
1.53 (br s, 3 H, CH, CH2), 1.82 (s, 6 H, CH3), 2.42-2.67 (m, 6 H,
CH2), 3.72 (s, 3 H, OCH3), 5.95 (br s, 2 H, NH), 6.84 (d, J ) 8.1
Hz, 2 H, ring), 7.15 (d, J ) 8.1 Hz, 2 H, ring), 10.94 (s, 2 H,
NOH). 13C{1H} NMR (DMSO-d6): δ 9.7 (q, CH3), 23.9 (q, CH3),
31.5 (t, CH2), 32.7 (t, CH2), 46.0 (t, CH2NH2), 55.0 (q, OCH3),
59.3 (s, C), 113.7 (d, ring), 129.2 (d, ring), 133.8 (s, ring), 157.4
(s, ring).
Synthesis of 3,3,9,9-Tetramethyl-4,8-diaza-6-(3-(2-methoxy-
phenyl)-1-propyl)-2,10-undecanedione Dioxime (3c). To a sus-
pension of K2CO3 (1.66 g, 12.2 mmol) in dry DMF (10 mL) were
added diamine 5c (1.05 g, 4.72 mmol) and 3-bromo-3-methyl-2-
butanone30 (1.94 g, 12.0 mmol). Otherwise the method for the
synthesis of 3a was followed. Yield: 0.93 g (50%). ES-MS: m/z
391 (M + H+). IR (film, cm-1): 3400, 3318, 1706s, 1674, 1600,
1
1588. H NMR (CDCl3): δ 1.26 (m, 12 H, CH3), 1.33 (m, 2 H,
CHCH2CH2), 1.56 (m, 2 H, CHCH2CH2), 1.64 (m, 1 H, CH), 2.17
(s, 6 H, CH3), 2.47-2.60 (m, 6 H, CH2, CH2NH), 3.81 (s, 3 H,
OCH3), 6.82-6.89 (m, 2 H, ring), 7.09-7.19 (m, 2 H, ring).
13C{1H} NMR (CDCl3): δ 24.3 (q, CH3), 24.5 (q, CH3), 24.9 (q,
CH3CO), 27.4 (t, CH2), 30.6 (t, CH2), 31.4 (t, CH2), 39.4 (d, CH),
47.3 (t, CH2NH2), 55.3 (q, OCH3), 63.2 (s, C), 110.3 (d, ring), 120.5
(d, ring), 127.1 (d, ring), 130.0 (d, ring), 130.9 (s, ring), 157.5 (s,
ring), 213.5 (s, CdO).
Hydroxylamine hydrochloride (7.82 g, 113.0 mmol) was added
to NaOH (4.20 g, 105.0 mmol) in methanol (115 mL), and the
resulting solution was stirred for 2 h at 0 °C. The solution was
filtered directly onto 3,3,9,9-tetramethyl-4,8-diaza-6-benzyl-2,10-
undecanedione (4.96 g, 15.0 mmol), and the resulting solution was
stirred at room temperature for 18 h. After removal of the solvent
under reduced pressure the residue was triturated with water and
recrystallized from hot ethyl ethanoate/ethanol to provide the
product 3a as fine, colorless needles. Yield: 1.77 g (33%). Mp:
176-177°C. ESMS: m/z363(M+H+). HR-ES-MS: C20H35N4O2,
m/z calcd 363.2755, found m/z 363.2753 (M + H+). IR (Nujol mull,
Hydroxylamine hydrochloride (21.65 g, 23.8 mmol) was added
to NaOH (0.89 g, 22.2 mmol) in methanol (15 mL), and the
resulting solution was stirred for 2 h at 0 °C. Otherwise the method
for the synthesis of 3a was followed with recrystallization from
hot ethanol to provide the product 3c as shiny, colorless needles.
Yield: 0.39 g (39%). Mp: 198 °C. ES-MS: m/z 421 (M + H+).
HR-ES-MS: C23H41N4O3, calcd m/z 421.3173, found m/z 421.3176
1
(M + H+). IR (Nujol mull, cm-1): 3317, 3194, 1588, 1492. H
1
cm-1): 3316, 3173, 1636, 1600, 1495. H NMR (DMSO-d6): δ
NMR (DMSO-d6): δ 1.31 (s, 12 H, CH3), 1.49 (br s, 3 H, CH,
CH2), 1.80 (s, 6 H, CH3), 2.56-2.61 (m, 6 H, CH2), 3.78 (s, 3 H,
OCH3), 4.48 (br s, 2 H, NH), 6.84-6.96 (m, 2 H, ring), 7.12-7.21
(m, 2 H, ring), 10.87 (s, 2 H, NOH). 13C{1H} NMR (DMSO-d6):
δ 10.2 (q, CH3), 24.4 (q, CH3), 27.1 (t, CH2), 30.2 (t, CH2), 30.8
(t, CH2), 46.8 (t, CH2NH2), 55.7 (q, OCH3), 59.7 (s, C), 111.1 (d,
ring), 120.7 (d, ring), 127.6 (d, ring), 130.1 (d, ring), 130.3 (s, ring),
157.5 (s, ring).
Synthesis of 3,3,9,9-Tetramethyl-4,8-diaza-6-(2-(2-pyridinyl)-
ethyl)-2,10-undecanedione Dioxime (3d). To a suspension of
K2CO3 (2.50 g, 19.0 mmol) in dry DMF (10 mL) were added
diamine 5d (1.35 g, 7.53 mmol) and 3-bromo-3-methyl-2-butanone30
1.33 (s, 12 H, CH3), 1.79 (s, 6 H, CH3), 2.22 (m, 1 H, CH), 2.59
(m, 8 H, CH2, NH), 7.21-7.35 (m, 5 H, ring), 10.88 (s, 2 H, NOH).
13C{1H} NMR (DMSO-d6): δ 10.9 (q, CH3), 25.1 (q, CH3), 37.8
(t, CH2CH), 38.6 (d, CH), 46.8 (t, CH2NH2), 60.5 (s, C), 127.4 (d,
ring), 129.6 (d, ring), 130.2 (d, ring), 140.6 (s, ring).
Synthesis of 3,3,9,9-Tetramethyl-4,8-diaza-6-(2-(4-methoxy-
phenyl)ethyl)-2,10-undecanedione Dioxime (3b). To a suspension
of K2CO3 (3.23 g, 23.0 mmol) in dry DMF (10 mL) were added
diamine 5b (1.95 g, 9.36 mmol) and 3-bromo-3-methyl-2-butanone30
(30) Pfleiderer, W.; Zondle, H. Chem. Ber. 1966, 99, 3008-3021.
4148 Inorganic Chemistry, Vol. 43, No. 14, 2004

Modeling NoWel Radiopharmaceuticals
(3.10 g, 19.0 mmol). Otherwise the method for the synthesis of 3a
was followed. Yield: 1.03 g (39%). ES-MS: m/z 347 (M + H+).
IR (film, cm-1): 3304, 1705s, 1668, 1592, 1568. 1H NMR
(CDCl3): δ 1.32 (s, 12 H, CH3), 1.70 (m, 2 H, CH2), 1.83 (m, 1 H,
CH), 2.20 (s, 6 H, CH3), 2.46 (dd, J ) 8.1 Hz, J ) 11.0 Hz, 2 H,
CH2), 2.65 (dd, J ) 3.7 Hz, J ) 11.0 Hz, 2 H, CH2), 2.80 (m, 2 H,
CH2), 3.17 (br s, 2 H, NH), 7.11 (dd, J ) 5.5 Hz, J ) 7.0 Hz, 1 H,
ring), 7.16 (d, J ) 8.1 Hz, 1 H, ring), 7.59 (dd, J ) 7.7 Hz, J )
7.7 Hz, 1 H, ring), 8.50 (d, J ) 3.7 Hz, 1 H, ring). 13C{1H} NMR
(CDCl3): δ 23.8 (q, CH3), 24.2 (q, CH3), 24.7 (q, CH3CO), 31.5
(t, CH2), 35.7 (t, CH2), 38.2 (d, CH), 47.3 (t, CH2NH2), 63.3 (s,
C), 121.1 (d, ring), 122.9 (d, ring), 136.5 (d, ring), 138.6 (d, ring),
149.2 (d, ring).
Synthesis of (6-Benzyl-3,3,9,9-tetramethyl-4,8-diazaundecane-
2,10-dione dioximato(1-)-N,N′,N′′,N′′′)cobalt(III) Dinitrite (9).
Preparation of the intermediate dichloride complex and subsequent
anion substitution to provide the required dinitrite complex was
carried out by adaptation of a previously described method.31 3a
was dissolved in hot ethanol and filtered. To this was added an
excess of CoCl2, resulting in a purple solution. On cooling, the
solution turned green, and after 1 h a light green microcrystalline
solid had deposited which was separated by filtration and dried
under vacuum. This precursor salt was not purified further but was
used directly to prepare the product. The cobalt dichloride complex
of 3a (1.0 g) was dissolved in water (50 mL) by the addition of
dilute KOH solution. KNO2 (1.0 g) was added with stirring, and
the solution was brought to pH 5 with dilute HCl. The solution
was warmed for 30 min at 50 °C, during which time it turned orange
and precipitated a brown solid. The brown solid was separated by
filtration and recrystallized from an excess of hot water to provide
crystalline orange plates. Mp: 215 °C. ES-MS: m/z 420 (M+). HR-
ES-MS: C20H33N4O2Co, calcd m/z 420.1930, found m/z 420.1931
(M+). 1H NMR (CD3CN): δ 1.02 (d, J ) 4.5 Hz, 6 H, CH3), 1.52
(d, J ) 4.5 Hz, 6 H, CH3), 2.10 (s, 4 H, CH2), 2.12 (s, 1 H, CH),
2.17 (s, 6 H, CH3), 2.64 (m, 2 H, NH), 2.84 (d, J ) 6.8 Hz, 2 H,
CH2), 7.24-7.38 (m, 5 H, ring). 13C NMR (CD3CN): δ 13.2 (q,
CH3), 19.9 (q, CH3), 24.7 (q, CH3), 38.3 (t, CH2), 40.3 (d, CH),
45.8 (t, CH2), 67.6 (s, C), 126.49 (d, ring), 128.8 (d, ring), 129.8
(d, ring), 139.0 (s, ring), 160.0 (s, CtN).
Synthesis of (6-Benzyl-3,3,9,9-tetramethyl-4,8-diazaundecane-
2,10-dione dioximato(1-)-N,N′,N′′,N′′′)copper(II) Hydrate Tet-
rafluorborate (10). The following procedure was based on the
preparation of a similar perchlorate salt.17 3a (20.0 mg) and
Cu(BF4)2 (10.0 mg) were separately dissolved in hot methanol (2
mL) and filtered. The solutions were mixed and allowed to cool,
resulting in the precipitation of a dark purple microcrystalline
solid. The solid was separated and recrystallized from water by
slow evaporation to provide crystalline dark purple blocks. Mp:
185-185 °C. ES-MS: m/z 424 (M+). HR-ES-MS: C20H33N4O2-
Cu, calcd m/z 424.1894, found m/z 424.1895 (M+). NMR gave poor
results due to the paramagnetic nature of Cu(II).
Synthesis of (6-(2-(4-Methoxyphenyl)ethyl)-3,3,9,9-tetra-
methyl-4,8-diazaundecane-2,10-dione dioximato(1-)-N,N′,N′′,N′′′)-
copper(II) Hydrate Tetrafluoroborate (11). The following pro-
cedure was based on the preparation of a similar perchlorate salt.17
3b (20.0 mg) and Cu(BF4)2 (12.0 mg) were separately dissolved in
hot methanol (2 mL) and filtered. The solutions were mixed and
allowed to cool. Slow evaporation provided crystalline dark purple
needles. Mp: 170-173 °C. ES-MS: m/z 468 (M+). HR-ES-MS:
C22H37N4O3Cu, calcd m/z 468.2156, found m/z 468.2157 (M+).
NMR gave poor results because of the paramagnetic nature of
Cu(II).
Synthesis of (6-(2-(2-Pyridinyl)ethyl)-3,3,9,9-tetramethyl-4,8-
diazaundecane-2,10-dione dioximato(1-)-N,N′,N′′,N′′′)copper-
(II) Hydrate Tetrafluoroborate (12). 3c (20.0 mg) and Cu(BF4)2
(10.0 mg) were separately dissolved in hot methanol (2 mL) and
filtered. The solutions were mixed and allowed to cool, resulting
in the formation of a brown solid. The solid was separated and
recrystallized from water in the presence of excess Cu(BF4)2 by
slow evaporation to provide crystalline orange-brown fine plates.
Very little material was recovered with which to attempt charac-
terization other than by single-crystal X-ray crystallography.
Single X-ray Crystallographic Studies. Details of the crystal
data and a summary of the intensity data collection parameters for
Hydroxylamine hydrochloride (1.54 g, 22.2 mmol) was added
to NaOH (0.83 g, 20.7 mmol) in methanol (22 mL), and the
resulting solution was stirred for 2 h at 0 °C. Otherwise the method
for the synthesis of 3a was followed with recrystallization from
ethyl ethanoate to provide the product 3d as a sticky, low-melting-
point, yellow solid. Yield: 0.30 g (27%). Mp: 49 °C. ES-MS: m/z
378 (M + H+). HR-ES-MS: C20H36N5O2, calcd m/z 378.2864,
found m/z 378.2862 (M + H+). IR (film, cm-1): 3168, 1644, 1594,
1
1569. H NMR (CDCl3): δ 1.21 (s, 12 H, CH3), 1.56 (m, 1 H,
CH), 1.68 (m, 2 H, CH2), 1.77 (s, 6 H, CH3), 2.38 (br s, 4 H, CH2),
2.72 (m, 2 H, CH2), 3.72 (br s, 2 H, NH), 7.21 (dd, J ) 5.1 Hz, J
) 6.6 Hz, 1 H, ring), 7.28 (d, J ) 8.1 Hz, 1 H, ring), 7.72 (dd, J
) 7.4 Hz, J ) 8.1 Hz, 1 H, ring), 8.49 (d, J ) 3.7 Hz, 1 H, ring),
10.59 (br s, 2 H, NOH). 13C{1H} NMR (DMSO-d6): δ 9.3 (q, CH3),
25.1 (q, CH3), 30.5 (t, CH2), 34.9 (t, CH2), 39.7 (d, CH), 45.6 (t,
CH2NH2), 121.1 (d, ring), 122.6 (d, ring), 136.4 (d, ring), 148.8
(d, ring), 161.7 (s, ring).
Synthesis of Oxo(6-benzyl-3,3,9,9-tetramethyl-4,8-diazaun-
decane-2,10-dione dioximato(3-)-N,N′,N′′,N′′′)technetium(V)
(6). Preparation of the Tc complex was carried out by adaptation
of a previously described method.4 3a (20.0 mg, 55.2 µmol) was
dissolved in 0.9% saline (5 mL) and 5 M HCl (1 drop). NH4TcO4
(4.98 mg, 27.6 µmol), 1 M sodium hydrogen carbonate solution (3
mL), and ether (20 mL) were added with stirring. Tartaric acid
(9.06 mg, 60 µmol) in 0.9% saline (1 mL) was added followed by
SnIICl2‚2H2O (13.5 mg, 60 µmol) in 0.9% saline (1 mL), whereupon
the aqueous phase changed from colorless to yellow. The mixture
was stirred at room temperature for 20 min, during which time the
yellow color moved into the organic phase. The layers were
separated, and the aqueous phase was extracted with ether (10 mL
aliquots) until no further yellow color was observed in the extract.
The organic layers were combined, dried (Na2SO4), and then
concentrated to 2 mL under reduced pressure. The resulting orange
organic solution was chromatographed (5 g silica column, 10 mL
of ether to wash, methanol to elute orange product). Fractions
containing the orange product were pooled and evaporated under
reduced pressure. The orange solid was dissolved in the minimum
volume of ether at room temperature and crystallized at -20 °C
(24 h). Characterization of this radioactive product was by single-
crystal X-ray diffraction alone.
Synthesis of Oxo(6-(3-(2-methoxyphenyl)propyl)-3,3,9,9-tet-
ramethyl-4,8-diazaundecane-2,10-dione dioximato(3-)-N,N′,-
N′′,N′′′)technetium(V) (7) and Oxo(6-(2-(2-pyridyl)ethyl)-3,3,-
9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioximato(3-)-
N,N′,N′′,N′′′)technetium(V) (8). X-ray-quality crystals of com-
plexes 7 and 8 were prepared using a procedure identical with that
used for complex 6 except for the period allowed for crystallization
(14 and 3 days, respectively) and, in the case of 8, the solvent
(methanol/ether). Characterization of these radioactive products was
by single-crystal X-ray diffraction alone.
(31) Goff, H.; Kidwell, S.; Lauher, J.; Murmann, R. K. Inorg. Chem. 1973,
12, 2631-2640.
Inorganic Chemistry, Vol. 43, No. 14, 2004 4149

Walker et al.
Table 1. Crystal Data, Intensity Measurements, and Structure Refinements for 6-11
6
7
8
9
10
11
empical formula
fw
C20H31N4O3Tc
473.49
293
0.2 × 0.05 × 0.05
monoclinic
P21/c
7.957(2)
11.979(2)
22.914(5)
C23H37N4O4Tc
531.57
293
0.5 × 0.15 0.1
Monoclinic
P21/n
12.963(3)
7.577(2)
C20H32N5O3Tc
488.51
293
C20H33CoN6O6
512.45
293
C20H35BCuF4 N4O3 C22H39BCuF4N4O4
529.87
150
573.92
150
temp (K)
cryst dimens (mm)
cryst syst
space group
a (Å)
0.25 × 0.15 × 0.05 0.5 × 0.2 × 0.07
0.75 × 0.35 × 0.30 0.65 × 0.15 × 0.15
Triclinic
P1h
triclinic
P1h
monoclinic
P21/c
monoclinic
C2/c
10.678(2)
10.852(2)
11.052(2)
92.05(3)
113.21(3)
109.55(3)
1088.2(3)
2
10.867(2)
12.248(2)
9.617(2)
103.64(3)
93.66(3)
71.47(3)
1179.3(4)
2
14.336(3)
18.443(4)
18.931(4)
22.067(4)
19.047(4)
12.928(3)
b (Å)
c (Å)
25.431(5)
R (deg)
â (deg)
91.00(3)
91.89(3)
99.52(3)
104.04(3)
γ (deg)
V (Å3)
2183.8(8)
4
6.86
1.440
984
2496.5(10)
4
6.11
1.414
1112
4936.4(18)
8
5271.4(19)
8
Z
µ (cm-1
)
6.92
1.491
508
7.76
1.443
540
9.43
8.92
d(calcd) (g cm-3
F(000)
)
1.426
1.446
2216
2408
θ range (deg)
1.92-27.57
2θ-θ
32236
5025
0.1728
0.985
0.0610
0.1383
2.92-30.00
2θ-θ
14941
6036
0.0672
1.037
3.15-30.56
2.18-25.00
2.64-25.04
2θ-θ
9226
8662
0.0423
1.068
2.69-25.00
scan type
2θ-θ
2θ-θ
2θ-θ
no. of reflns collected
no. of indep reflns
R(int)
12741
5467
0.0419
1.051
0.0367
0.0790
4484
4149
0.0361
0.965
0.0388
0.0880
4877
4646
0.0235
0.970
0.0355
0.0817
0.346 and -0.410
GOF on F2
R1a [I > 2σ(I)]
0.0462
0.1026
0.0575
0.1560
wR2b [I > 2σ(I)]
largest difference peak 1.1012 and -1.684 0.834 and -1.022 1.037 and -0.906
0.323 and -0.443 1.175 and -1.127
and hole (e Å-3
)
2
2
2
2
2
a R1 ) ∑||Fo| - |Fc||/∑|Fo|. b wR2 ) {∑[w(|Fo| - |Fc| )2]/∑[w(|Fo| )2]}1/2, where w ) 1/[σ2(|Fo| ) + (0.0717P)2 + (1.4086P)] for 6, w ) 1/[σ2(|Fo| )
+ (0.0557P)2] for 7, w ) 1/[σ2(|Fo| ) + (0.0422P)2] for 8, w ) 1/[σ2(|Fo| ) + (0.0488P)2] for 9, w ) 1/[σ2(|Fo| ) + (0.0971P)2 + (13.4682P)] for 10, and
2
2
2
w ) 1/[σ2(|Fo| ) + (0.0403P)2] for 11; P ) (|Fo|2 + 2|Fc|2)/3.
2
6-11 are given in Table 1. Data for 6-8 were collected on an
Enraf-Nonius FR591 rotating anode diffractometer, and those for
9-11 on a Rigaku AFC7S diffractometer. Both machines used
graphite-monochromated Mo KR radiation (λ ) 0.71073 Å). The
structures were solved by direct methods and refined by full-matrix
least squares on F2 using SHELX9732 through the WinGX
interface.33 All non-hydrogen atoms were refined with anisotropic
thermal parameters in the latter stages of refinement. In the case
of 9 and 11 all hydrogen atoms were located by difference Fourier
maps and refined isotropically. In the case of 6-8 and 10 all non-
methyl hydrogen atoms were located and refined as described above
whereas methyl hydrogen atoms were placed in idealized positions
and refined using general isotropic temperature factors. Final values
of the atomic positional parameters for 6-11 are available as
Supporting Information. Although 12 appeared to provide good-
quality diffraction data, attempts to solve its structure by numerous
methods failed, there being consistently high disorder in the majority
of non-hydrogen atoms.
dine under the basic reaction conditions. However, 2-vi-
nylpyridine itself (4d) was found to react efficiently with
the malonate anion. Use of sodium metal in ethanol was
favored for the alkylations involving benzyl bromide and
2-vinylpyridine, whereas sodium hydride in THF was
preferred for the methoxyphenyl derivatives. Each diester
was then converted to its corresponding diamine 5a-d before
alkylation to the corresponding PnAO analogue 3a-d. Metal
complexes 6-11 with Tc,3,4 Co,31 and Cu17 were then
Results and Discussion
Synthesis of Ligands 3a-d. The 6-substituted PnAO
ligands 3a-d were prepared as outlined in Scheme 1
following established literature methodology.24 While benzyl
bromide (4a) was used in the preparation of 3a, the simple
purification of tosylates 4b and 4c favored their use as the
malonate alkylating agents for the preparation of methox-
yphenyl derivatives 3b and 3c. Initial attempts to add the
pyridylethyl ligand using 2-(2-chloroethyl)pyridine were
hampered by in situ conversion of the latter to 2-vinylpyri-
prepared by suitable modifications of established literature
procedures. The technetium complexes were formed via the
in situ reduction of pertechnetate using Sn(II); the Co and
Cu complexes were formed directly from the easily acces-
sible salts CoCl2 and CuBF4. Oxidation to Co(III) occurred
during the heating required for anion substitution with KNO2.
(32) SHELX97 SuitesPrograms for Crystal Structure Analysis (Release
97-2): Sheldrick, G. M., Institu¨t fu¨r Anorganische Chemie der
Universita¨t, Tammanstrasse 4, D-3400 Go¨ttingen, Germany, 1998.
(33) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.
4150 Inorganic Chemistry, Vol. 43, No. 14, 2004

Modeling NoWel Radiopharmaceuticals
Figure 1. ORTEP representation of 8.
Figure 2. Boat (A) and chair (B) conformations of 134 (with ring
conformations highlighted in the insets).
Table 2. Comparison of Selected Bond Lengths and Distances (Å)
6
7
8
2a
structures. Further evidence for this comes from the exami-
nation of the tables of inter- and intramolecular close contacts
for each structure.
Tc(1)-O(4t)
Tc(1)-N(1)
Tc(1)-N(2)
Tc(1)-N(3)
Tc(1)-N(4)
Tc(1)-N4 plane
1.679(3)
2.084(4)
1.905(4)
1.911(4)
2.081(4)
0.667(22)
1.6758(13)
2.0672(15)
1.9190(14)
1.9121(13)
2.0770(15)
0.667(9)
1.6722(17)
2.0848(19)
1.910(2)
1.9213(19)
2.079(2)
1.679(3)
2.086(3)
1.917(3)
1.908(3)
2.093(4)
0.678(1)
Technetium complexes 6-8 clearly illustrate that the
TcO-PnAO complex is a robust pseudocrown which is
insensitive to the nature of the C6-substituent. In particular,
since the TcO-PnAO complex can be regarded as an 18-
electron species featuring a strong multiple bond, the absence
of coordination from the additional pyridyl group in complex
8 is not surprising. Such a coordination would also require
some distortion of the geometry of the complex since the
pyridine ring is tethered to the PnAO skeleton by a short
ethyl chain.
Conformation of the Six-Membered Chelate Ring. In
each of the TcO complexes reported here the six-membered
chelate ring adopts the pseudoboat conformation common
to the majority of TcO-PnAO complexes. A survey of the
Cambridge Crystallographic Database12 reveals that the only
exception is displayed by complex 13,4 where the asymmetric
unit contains one molecule of the complex in a boat
conformation (Figure 2A) and, uniquely, a second indepen-
dent molecule in a chair conformation (Figure 2B).
0.664(20)
a Reference 3.
Technetium Complexes. In each technetium complex
6-8 (e.g., Figure 1) the observed structure is analogous to
that of the known parent TcO-PnAO complex (23) as
summarized in Table 2. Each adopts a square-pyramidal
geometry in which the base is defined by the plane of the
four nitrogen donors with the oxo ligand occupying the apical
position. The technetium ion sits approximately 0.67 Å above
the plane of the nitrogen atoms. The ligand is deprotonated
at both amine groups and at one of the oxime hydroxyl
groups, thereby affording a neutral complex of oxotechne-
tium(V) [TcO3+]. The shorter N(amide)-Tc bond lengths
(ca. 1.91 Å) compared with the N(oxime)-Tc distance (ca.
2.08 Å) reflect the multiple bond character of the former
caused by π-donation stabilizing the high formal charge of
the oxotechnetium core. Such high bond character from the
ligand leads to a slight weakening and hence lengthening of
the TcdO bond (ca. 1.68 Å), a value which lies at the upper
end of the range observed for oxotechnetium(V) complexes
(1.610-1.672 Å),3 in common with the complexes previously
observed with this ligand class.4 In each complex the C6-
substituent occupies a pseudoequatorial position which places
it at the greatest distance from the metal-binding site. Such
a conformation is desirable for the application of a PnAO
ligand as a radioactive-metal-chelating agent attached to a
bioactive targeting group via a functionalized side arm.
In each of the structures 6-8 the non-methyl hydrogen
atoms were located from a difference map including the
proton of the O‚‚‚H-O hydrogen bond, which has previously
proved somewhat difficult to detect in similar complexes.3,4
The disorder of the methyl hydrogen atoms suggests that
intra- or intermolecular hydrogen-bonding of the type
CH‚‚‚X involving the methyl groups is unimportant in these
Complex 13 appears to be the only example in which the
relative energies of the two conformations are close enough
for the chair conformation to compete with the boat, leading
to the presence of both conformers. One possible explanation
for this behavior centers around the conformation of the
methyl substituents at C3 and C9; in most other examples
of this ligand class at least one of these groups occupies the
lower face of the complex anti to the TcO core. The con-
sequent steric bulk may force the lower face C6-substituent
Inorganic Chemistry, Vol. 43, No. 14, 2004 4151

Walker et al.
Table 3. Six-Membered Chelate Ring Conformational Data (R, â, and
d Being Defined in Figure 3)
complex
R
R′
R/deg
â/deg
d/Å
1a
14b
13c
6
7
8
-H
-H
158.61 121.48 3.134
165.78 123.48 3.249
-(CH2)3-
-Me
-CH2Ph
-Me 168.90 128.01 3.341
-H
159.64 123.87 3.179
158.68 123.44 3.171
159.53 123.52 3.169
-(CH2)3-o-C6H4OMe -H
-(CH2)2-o-C5H4N
-H
a Reference 3. b Reference 9. c Reference 4.
Figure 4. ORTEP representation of 9.
oxo ligand and upper face pseudoaxial C6-substituent. The
corresponding values for the cyclobutane derivative 14 lie
Figure 3. Definitions of R, â, and d.
to adopt a pseudoequatorial position which pushes the
propylene bridge up toward the oxo ligand and hence a boat
conformation. However, in 13 both methyl groups are syn
to the core (Figure 2B), leaving the lower face relatively
unhindered. This may permit the lower face C6-substituent
to reside in a pseudoaxial position and consequently the
chelate ring to adopt the chair conformation.
between these extremes as might be predicted for smaller
methylene substituents which are further constrained by their
restricted cyclic conformation. Clearly the steric overlap in
14 is not sufficient to force the adoption, partial or otherwise,
of the less favorable chair conformer. Since 14, like 13, has
no lower face substituents but does not exhibit a chair
conformer, it can be concluded that the initially observed
boat-chair dependence upon C3- and C9-substitution is a
more fundamental rather than specific contributor to the
conformation of the chelate ring. This is further confirmed
by analysis of the data for the complexes presented here
bearing a single substituent at C6. The values for the distance
d and the angles R and â are very close to those found in
the complex unsubstituted at C6 (i.e., R = R′ ) H, 1) as
would be expected for ligands which also bear the same small
hydrogen atom in the key, sterically unfavorable pseudoaxial
position.
Non-technetium Complexes. We have also prepared the
cobalt and copper complexes 9-11. Once again these form
pseudomacrocycles via the deprotonation of one oxime
hydroxyl group. However, in keeping with all other reported
PnAO complexes involving metals other than technetium,
the amine functions remain protonated in each case. This
leads to a number of important changes in the overall prop-
erties of the complexes when compared to their technetium
analogues.
The TcO-PnAO complexes presented here adopt the boat
conformation exclusively with the C6-substituents residing
in pseudoequatorial positions. Since each complex exhibits
C3- and C9-substituents on the lower face of the complex,
such a conformation might therefore have been predicted.
The alternative chair conformation was not observed. This
may indicate that the methyl groups at C3 and C9 have
sufficient steric bulk to encourage the adoption of the boat
conformer alone, even though the chair conformer would
require only that the sterically unfavorable pseudoaxial
position were occupied by a hydrogen atom.
In support of this theory a closer examination of the precise
geometry of the six-membered chelate ring in complexes
6-8 and in representative examples of technetium-PnAO
complexes reported previously was also undertaken. This
revealed that the conformational sensitivity may be more
dependent upon a steric clash between the oxo ligand and
the upper face C6-substituent regardless of the substitution
at C3 and C9. It appears that flattening of the boat
conformation can be quantified (Table 3) by measurement
of the distance d and the angles of fold R and â (Figure 3).
The shortest distance d is observed with R ) R′ ) H (1),
while the introduction of bulkier methyl groups, R ) R′ )
Me (13), produces the greatest flattening of the ring with d
increasing by ca. 0.2 Å, a significant increase in the distance
between the technetium and C6. If the boat conformation is
energetically more favorable because of the fundamental
nature of the TcO-PnAO complex, then the partial popula-
tion of the less favorable chair conformer in 13 can be
explained by the need to reduce the steric overlap of the
The cobalt complex 9 (Figure 4) displays the expected
Co(III) octahedral geometry comprising the four approxi-
mately planar nitrogen atoms from the PnAO skeleton with
two nitrite ligands occupying the remaining vertexes. The
nitrite ligands are mutually orthogonal, an arrangement that
4152 Inorganic Chemistry, Vol. 43, No. 14, 2004

Modeling NoWel Radiopharmaceuticals
conformation. Our review of the metal complexes of PnAO
derivatives reported in the Cambridge Crystallographic
Database12 indicates that all non-technetium complexes exist
exclusively in pseudochair conformations.
The cobalt and copper complexes discussed here behave
in a typical and predictable fashion. When compared to the
corresponding complex with simple PnAO 1, monoalkylation
at the 6-position has effectively substituted the existing
pseudoequatorial hydrogen, leaving the ligand-metal con-
formation unchanged. The cobalt and copper complexes share
the expected preference for a pseudoequatorial C6-substituent
as seen in the Tc complexes, and its presence did not affect
the established binding motif.
Figure 5. ORTEP representation of 11.
Interestingly our searches did not reveal any instance of
the use of rhenium as a model for technetium in the context
of PnAO ligands. Being a congener of technetium and similar
in size due to lanthanide contraction, it might be expected
to be the perfect, nonradioactive analogue of technetium.
-
However, it is present in the form of perrhenate (ReO4 ) as
a Cu(II)-PnAO complex counterion,15 suggesting that
unsuccessful attempts may have been made to prepare an
oxorhenium(V) [ReO3+]-PnAO complex. Further attempts
to utilize rhenium in this way may be beneficial in permitting
the wider study of TcO-PnAO complex behavior.
Conclusions
We have shown that the attachment of a single substituent
in the C6-position does not significantly perturb the com-
plexation behavior of PnAO ligands with technetium. It is
likely therefore that oxotechnetium(V) complexes of 6-sub-
stituted PnAO ligands will retain similar overall in vivo
stability. This result is of particular relevance to the use of
PnAO ligands as technetium binding units attached to large
functional pendant groups.
We have also shown that typical, easily accessible metal
complexes remain similarly unperturbed upon substitution
at the C6-position, further evidence of the suitability of this
site for elaboration.
Figure 6. Intermolecular close contacts within the asymmetric unit of
10.
permits one ligand to loosely hydrogen bond to the amine
hydrogens on one face of the PnAO while the other is aligned
to minimize steric clash with the methyl substituents at C3
and C9. Steric clash is further reduced by this nitrite group
leaning away from the methyl groups on C3 and C9 by
approximately 5° from its ideal octahedral position.
The copper complexes 10 and 11 (Figure 5) both exhibit
square-based pyramidal geometry comprising the PnAO
nitrogen donors and a capping water molecule. In each case
the water molecule lies anti to the amine hydrogens. The
unit cell of 10 contains two similar complexes in the
asymmetric unit which are associated via multiple hydrogen
Acknowledgment. Thanks are due to EPSRC for CASE
studentships for P.S.W. and P.M.B. in collaboration with
Amersham International PLC and for their gift of 99Tc, to
The Wellcome Trust for Project Grant Funding in the area
of radiopharmaceutical diagnosis, and to the EPSRC National
Crystallographic Service and Professor Mike Hursthouse
(University of Southampton) for access to their facilities and
helpful advice.
-
bonds to one of the noncoordinating BF4 anions (Figure
6), the remaining anion being loosely hydrogen bonded to a
coordinating water molecule.
Since complexes 9-11 do not require a high formal charge
to be neutralized at the core, the amine donors remain
protonated, giving rise to charged species, 2+ overall for
the Co(III) complex and 1+ for the Cu(II) complexes.
Further, the cobalt and copper atoms also lie within the plane
of the PnAO donor ring and adopt a pseudochair conforma-
tion of the C6 chelate ring. This contradicts a previous study4
which reported that the chair conformation of 13 was the
only example of a metal-PnAO complex exhibiting this
Supporting Information Available: Details of the X-ray
structure determinations, in CIF format, of the structures of 6-11
and Ortep figures of structures 6, 7, and 10 including the numbering
schemes used for crystallographic data in PDF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
IC0497634
Inorganic Chemistry, Vol. 43, No. 14, 2004 4153