# Kinetic and High-Pressure Mechanistic Investigation of the Aqua Substitution in theTrans-Aquaoxotetracyano Complexes of Re(V) and Tc(V): Some Implications for Nuclear Medicine

Authors: J. Mattheus Botha; Andreas Roodt
Journal: Metal-Based Drugs
 (2008)

---

## Abstract

A kinetic study of the aqua substitution in the[
TcO
(
OH
2
)
(
CN
)
4
]
− complex by different thiourea ligands (TU = thiourea, NMTU = N-methyl thiourea, NNDMTU = N, N
′-dimethylthiourea)  yielded second-order formation rate constants (
25
∘
C
) as follows [NNDMTU, NMTU, TU, respectively]: k
f
= 11.5 ± 0.1, 11.38 ± 0.04, and 7.4 ± 0.1 M
−
1
s
−
1, with activation parameters:
Δ
H
k
f
#
:
55
±
2,   42
±
3, 35
±
5 kJ mol
−
1;
Δ
S
k
f
#
:
−
40
±
8,
−
84
±
11,
−
110
±
17 J K
−
1
mol
−
1. A subsequent high-pressure investigation of the aqua substitution in the [
ReO
(
OH
2
)
(
CN
)
4
]
− and [
TcO
(
OH
2
)
(
CN
4
)
]
− complexes by selected entering ligands yielded Δ
V
k
f
# values as follows: Re(V): −
1.7
±
0.3
(
NCS
−
), −
22.1
±
0.9 (TU) and for Tc(V): −
3.5
±
0.3
(
NCS
−
), −
14
±
1 (NNDMTU), and−
6.0
±
0.5 (TU) cm
3
mol
−
1, respectively. These results point to an interchange associative mechanism for the negative NCS
− as entering group but even a pure associative mechanism for the neutral thiourea ligands.


---

## Body

## 1. Introduction

Technetium-99m
is widely used in over 90% of all current diagnostic nuclear medicinal applications [1–5]
due to its favourable nuclear properties (t
1
/
2
=
6.02 hours,
y
=
140 keV 100%) and availability from a generator.
It is routinely used for brain, heart, liver, kidney, and bone imaging. Technetium’s third-row
congener and 5
d analog, rhenium, also
has applications in nuclear medicine since its two radioactive isotopes, Re-186
and Re-188, have nuclear properties suitable for radiotherapeutic applications
[6–8].The development
of technetium myocardial imaging agents commenced with work by Deutsch [9–12], who investigated the [Tc
99
mCl2(dmpe)2]+ [dmpe = bis(1,2-dim  ethylphosphino)ethane] and [Tc
99
mX2(diars)2]+ complexes (diars = o-phenylenebis(dimethylarsine),
X = Cl, Br) [12].  Studies on
animal models indicated that the reduction of Tc
III is biologically
accessible for the cationic [Tc
III
99
m - Cl2(dmpe)2]+ complex, yielding neutral [Tc
II
99
mCl2(dm- pe)2]. The latter then washes from the heart and
becomes trapped in the liver. The
reduction of Re
III
⁡ to Re
II
⁡ [186
Re
III
⁡-  Cl2(dmpe)2]+ is 0.2 V more negative compared to the anal-  ogous Tc complex and is thus
retained in the heart [10].  Kinetic,
electrochemical, and structural work on the [Re/  Tc
IICl2(dmpe)2]
complexes has been published and illustrates its importance as initial models [13–18].Currently,
however, other monocationic complexes of technetium-99m
are of significant interest because of their extensive use asTc
99
m
myocardial imaging agents [19, 20] with examples including Cardiolite or [Tc
99
m(MIBI)6]+ (MIBI = 2-methoxy-2-methylpropylisocyanide) [21, 22]
and Myoview [Tc
99
mO2(Tetrofosmin)2]+. While the monoca  tionic
complexes are traditionally based on the [O=Tc
V=O]+, [Cl–Tc
III–Cl]+, and Tc
I cores, a new
class of myocardial im-  aging agents feature the [
Tc
V
99
m
≡
N
]
2
+ core, an exam-  ple being the
Tc–N–NOET complex (bis(N-methoxy-N-  methyldithiocarbamato)nitridotechnetium(V)).Two technetium
complexes, containing specificallyphosphine ligands, currently used for
myocardial imaging are the above-mentioned Myoview and TechneScan
Q12/TechneCard ([Tc
99
m(PR3)2(L
′)]+)
[23]. In [Tc
99
mO2(Tetrofosmin)2]+ the technetium is in a high-oxidation state {
Tc
(
V
)
} and shows
substantial myocardial uptake [24].
It is interesting to note that [Tc
99
mO2(dmpe)2]+,
which has methyl groups on the phosphine rather than the ether groups as in the
tetrofosmin ligand, is not retained in the myocardium [25].With the ongoing
development of new Tc and Re agents, it is essential that their basic coordination chemistry is understood. Nonradioactive rhenium is widely
utilized to imitate technetium chemistry on a macroscale
and has been extensively pursued for the past two decades or more, describing
changes in coordination modes. We reported structural effects induced by
different Re-cores while maintaining an equatorial ligand set, utilizing two
dmpe ligands, while varying the axial core, to investigate the impact this
change induces on the solid-state structure of the coordinated
polyhedron and on the bidentate tertiary phosphine ligand, dmpe [26]. Similarly, the effect of different
conformers/isomers and energies associated therewith has been described [27].  More recent extensive work by Alberto showed
that the fac-[(CO)3M(H2O)3]+
{M = Re⁡
(
I
)
,
Tc
(
I
)
} core provides excellent access to numbers of model
radiopharmaceuticals [28–35].The “lanthanide contraction” results in similar physical characteristics for analogous Re and
Tc complexes (i.e., size or lipophilicity) [1, 6]. Thus, when rhenium is used as the nonradioactive surrogate for the
development of Tc chemistry because it is nonradioactive,
their similar physical characteristics make it very difficult for biological
systems to distinguish between analogous Tc and Re [6] complexes based on properties such as size, shape, and charge. However, firstly, they differ significantly in
their redox properties, which can result in different in vivo handling of
analogous complexes. Rhenium complexes are more stable in higher-oxidation states and thus are more
difficult to reduce (by ca.
200 mV) than their Tc analogs [36].
Thus, Re is more readily reoxidized
to perrhenate (Re
⁡
O
4
−) than Tc is to pertechnetate (
TcO
4
−
) in
vivo, and perrhenate requires the use of stronger
reducing agents for the synthesis of Re radiopharmaceuticals.A second difference is the larger ligand field
splitting for Re complexes, which results in slower-ligand substitution onto Re than Tc.  We have previously investigated
different aspects of thetrans-dioxo complexes, with the
general structure of trans-[
MO
2
(
L
4
)
]
n
−,
M = Mo(IV), W(IV), Tc(V), Re(V), Os(VI), and related systems, evaluating
structural and reactivity correlations for a range of ligands L. It was shown
that a twelve-order of magnitude in reactivity in these systems exists, ranging
from the very rapid proton exchange, to the slower hydroxo and aqua
substitution and the extremely slow-equatorial ligand substitution [37–41].Subsequent kinetic studies on the [ReO(OH2)(TU)4]3+ complex, showed that the trans-substitution reactions of the aqua
ligand most likely proceed via an interchange
dissociative mechanism (I
d) [42]. This outlined a discrepancy in the
proposed mechanism for trans-substitution reactions on the [ReO(OH2)(CN)4)− complex as concluded earlier in the literature [43, 44].
The substitution rate for the [ReO(OH2)(TU)4]3+ complex with NCS−  was in the order of ca. 450
⁢
000 times faster than for the [ReO(OH2)(CN)4]− complex. Furthermore, the reactions
involving [ReO(OH2)(TU)4]3+ and higher
concentrations of the entering ligand showed typical limiting kinetics, while
in the [ReO(OH2)(CN)4]− complex, no tendency
of limiting kinetics was observed.We have previously
correlated different in vivo reactivities with
in
vitro behaviour
[41] and attempted to link certain sites with biodistribution and bioactivity, but
was, and still is, unable to do more detailed comparisons. Thus, since detailed
mechanistic studies and data on substitution processes are fairly limited, it
prompted us to reinvestigate  the type of mechanism obeyed for the [ReO(OH2)(CN)4]− complex when reacted with different entering ligands and extending it to the Tc
V complex, by specifically utilizing advanced
high-pressure
kinetics.  This high-pressure study of the [MO(OH2)(CN)4]− complex (M = Re and Tc), with different entering ligands, is therefore reported here.


## 2. Material and Methods

All reagents and chemicals were of analytical reagent grade, and double-distilled water was used
in all experiments. All pH measurements
were done with an Orion 701 pH meter and a combined glass/calomel electrode
using standard buffer solutions and standardized hydrochloric acid
solutions for calibration. The ionic
strength was constant(
μ
=
1
⁢
M
) in all the experiments, maintained
with NaNO3 as noncoordinating electrolyte. In all calculations, pH = −log [H+].  Na3[ReO2(CN)4]
and Na3[TcO2(CN)4] were prepared as previously
described [37]. Caution: Technetium-99, although a low-energetic radio-active β-emitter (230 KeV, t
1
/
2
=
2.1
×
10
5
y), should always be handled with care and under approved conditions.Kinetic measurements were done on modified Durrum-Gibson Model D110 and
Applied Photophysics SX.18 MV (control experiments; coupled with a J&M
Tidas-16 diode array) stopped flow spectrophotometers equipped with
constant temperature syringe and cell holder systems (accurate within 0.1°C). These were coupled to
a personal computer or Acorn Risc workstation capable of performing
least-squares analyses on the absorption values versus time
data obtained from the kinetic runs.  The
SCIENTIST [45]
program was used to fit the data to selected functions.  High-pressure studies were done on a GBC 916
spectrophotometer in a high-pressure vessel with pill box cells of path length ≈15 mm or in a stopped flow high-pressure vessel [46]. All kinetic runs were performed under pseudo-first-order
conditions with the ligand in large excess.
The solid lines in the figures represent computer least-squares fits of
data, while the experimentally determined values are given as points. The [MO(L)(CN)4
]
n
+  complexes from the reactions between [MO(OH2)(CN)4]− and different entering ligands were characterised as previously described [43, 44].


## 3. Results and Discussion

It was previously shown that the complete reaction scheme  governing
the substitution reactions on the protonated forms  of thetrans-[MO2(CN)4
]
(
n
+
2
)
− complexes is limited to the aqua species, trans-[MO(OH2)(CN)4
]
n
− and with small con  tributions, under selected conditions from trans-[MO(OH)-  (CN)4
]
(
n
+
1
)
− [37]. Assumptions made and approximations have all been
reported previously.Thep
K
a
1 value (of the [TcO(OH2)(CN)4]− complex, Scheme 1)
was previously determined from the reaction between [TcO(OH2)(CN)4]− and NCS− ions as 2.90(5) by Roodt et al. [44]. To further verify this by another ligand
system, an independent kinetic p
K
a determination was carried out for the reaction between [TcO(OH2)(CN)4]− and NNDMTU and is illustrated in Figure 1. NNDMTU was selected since these
reactions showed the largest absorbance changes.Figure 1
Plot ofk
obsd
versus pH for the reaction between
[TcO(OH2)(CN)4]− and NNDMTU at 24.8°C, μ
=
1.0
M (NaNO3), [NNDMTU] = 0.3 M, and [M] = 5
×
10
−
5 M, λ
=
420 nm.Scheme 1
Illustration of an associative (A; k
1
/
k
2) or associative interchange (B; k
3
/
k
4). Activation for the aqua substitution
in [MO(OH2)(CN)4]−[M = Re(V), Tc(V)]; RDS = rate
determining step.The general expression for the observed pseudo-first-order rate constant{
[
L
]
≫
[
M
]
} shown in (1),
as obtained  previously, describes the acid-base behaviour
of the trans-[MO(OH2)(CN)4
]
n
− complexes, where k
f and k
r represent the forward and
reverse rate constants, that is,
the anation/ligation and acid hydrolysis, respectively.(1)
k
obsd
=
k
f
[
L
]
1
+
K
a
1
/
[
H
+
]
=
k
r
.
The data in Figure 1 was fitted to (1), and a p
K
a
1 value as
reported in Table 1 was obtained. The acid dissociation constant thus
determined from the reaction between [TcO(OH2)(CN)4]− and NNDMTU {
2.99
±
0.19
} is in good agreement with the p
K
a value reported for the reaction between the metal
complex and NCS− ions (2.90
⁢
±
0.05) [44].Table 1
Kinetic data for the reaction between [TcO(OH2)(CN)4]− and the different thiourea entering ligands; μ
=
1.0 M (NaNO3), pH = 0.6. (a)L.S. fits to (2); (b)since small-negative intercepts were obtained
in some cases, the value was fixed (= 0.00). The standard deviations reported are those
from the first fits; (c)L.S. fits to (1).
Parameter
T (°C)
NNDMTU
T (°C)
NMTU
T (°C)
TU
k
f(M-1s-1
)
(
a
)
9.3
3.13(6)
5.7
3.26(7)
6.8
2.68(8)
16.5
6.1(1)
15.9
5.95(6)
15.8
5.0(1)
25.1
11.5(1)
25.1
11.38(4)
25.5
7.4(1)
k
r(s-1
)
(
a), (b
)
9.3
0.00(1)
5.7
0.00(3)
6.8
0.00(2)
16.5
0.00(4)
15.9
0.00(5)
15.8
0.00(3)
25.1
0.00(3)
25.1
0.00(2)
25.5
0.06(2)
p
K
a
1
(
c
)
24.8
2.99(19)
—
—
—
—
Δ
S
#
k
f(J K-1 mol-1)
—
−
40(8)
—
−
84(11)
—
−
110(17)
Δ
H
#
k
f(kJ mol-1)
—
55(2)
—
42(3)
—
35(5)It is
therefore evident that if the reaction between [TcO(OH2)(CN)4]− and the different entering ligands (TU, NMTU, NNDMTU) is investigated at a pH
value of 0.6 [p
K
a
1
>
2.9, see Table 1], the trans-oxo aqua species
of the metal complex is more than 99% present in solution. At these high-acidic
conditions where K
a
1
≪
[
H
+
], (1)
simplifies to the well-known simple expression in (2),
assuming negligible reverse or concurrent reactions (k
r
⁢ca. 0). The k
obsd versus [L] data obtained from these runs was fitted
to (2), and
values for k
f  and k
r were consequently obtained
(Table 1):(2)
k
obsd
=
k
f
[
L
]
+
k
r
≈
k
f
[
L
]
.
The ligand
concentration and temperature dependence study for
each of the different thiourea entering ligands (TU, NMTU, and NNDMTU) were therefore completed for the [TcO(OH2)(CN)4]−,
with the data for NMTU as entering ligand shown in Figure 2.Figure 2
Effect ofk
obsd versus [NMTU] for the reaction between
[TcO(OH2)(CN)4]− and NMTU at different
temperatures, μ
=
1.0 M (NaNO3), λ
=
420 nm, pH = 0.6, and [M] = 5
×
10
−
5 M.Thesek
f versus temperature data sets were used in the Eyring equation [43] to calculate the
activation parameters governing the k
f step (Table 1). The intercepts (k
r) in all these runs were
zero within standard deviations, thus confirming a large K
f value (
K
f
=
k
f
/
k
r
) for each of the different nucleophiles.The activation
entropies (Table1) for all the reactions studied suggest increased order in
the transition state, indicative of association being important.Following similar arguments used by Grundler et al. [35], and by our group [47], different pathways for the substitution process were therefore
considered.Firstly, for anassociative mechanism
(Scheme 1,
A, k
1 and  k
2 pathway), the rate of
the reaction is given by
(3)
Rate
=
k
2
[
MO
(
OH
2
)
(
L
)
(
CN
)
4
n
−
]
−
k
−
2
[
MO
(
L
)
(
CN
)
4
m
−
]
.
If it is assumed that the [MO(OH2)(L)(CN)4
]
n complex is formed under steady-state conditions, its formation and
decomposition would be equal yielding
(4)
[
MO
(
OH
2
)
(
L
)
(
CN
)
4
n
−
]



=
k
1

[
MO
(

OH
2

)
(
CN
)
4
−
]
[

L

]
+
k
−
2
[

MO
(
L
)
(
CN
)
4
m
−

]
k
−
1
+
k
2
.
Upon
incorporation of the definition of K
a
1 (= [MO(OH)  (
CN
)
4
2
−][H+]/[MO(OH2)(
CN
4
−
)]),
[
M
]
tot (= [MO(OH2)  (
CN
)
4
−] +
[MO(OH)(
CN
)
4
2
−]) and substituting (4) into (3), integration of the rate law {{
[
L]
≫
[
M
]
},  by assuming a fast k
2 step (Scheme 1), 5 {
with
⁢
k
2
′
=
k
1
k
2
/
(
k
−
1
+
k
2
)
}, and defining the pseudo-first-order rate constant, is obtained:
(5)
k
obsd
=
k
2
′
[
L
]
1
+
K
a
1
/
[
H
+
]
+
k
−
2
.
Similar
arguments may be used, considering an interchange pathway (Scheme 1, k
3 and k
4),  incorporating the definition of K
a
1 (= [MO(OH)(
CN
)
4
2
−][H+]/[MO(OH2)(
CN
)
4
−]),
[
M
]
tot (= [MO(OH2)(
CN
)
4
−] +
[MO(OH)(
CN
)
4
2
−] +  [MO(OH2)(L)(
CN
)
4
n
−]), K
3 (= [MO(OH2)(L)(
CN
)
4
n
−]/  [MO(OH2)(
CN
)
4
−][L];
([L] ≫
[
M
]
tot), yielding an expression for the pseudo-first-order
rate constant as given in (6), and assuming K
3[L] ≪ 1,
(6)
k
obsd
=
k
4
K
3
[L]
K
a
1
/
[
H
+
]
+
1
+
k
−
4
.
It is clear that (5)
and (6) are similar and both adequately describe the experimental results {associative mechanism (5): k
f
=
k
2
′  and k
r
=
k
−
2; interchange mechanism
(6): k
f
=
k
4
K
3 and k
r
=
k
−
4 and K
3
=
k
3
/
k
−
3
},
and both simplify to (1) and (2), respectively.The pressure
dependence for the substitution process as studied here, at different pressuresa and b, is given by [47]
(7)
ln
(
k
a
/
k
b
)
=
−
Δ
V
#
expt.
(
P
a
−
P
b
)
/
RT
.
Since the
contribution by the reverse step is negligible in all cases in this study as
concluded above, this implies that  Δ
V
#
expt.
≈
Δ
V
#
k
f.  The data obtained for the trans-[TcO  (OH2)(CN)4]− are shown in Figure 3, where (7) was utilized to obtain Δ
V
#
expt.,
and the results are reported in Table 1.Figure 3
The effect of pressure on the second-order
formation rate constant for the reaction between [TcO(OH2)(CN)4]− and NCS−, NNDMTU, and TU at 25°C, pH = 0.6, [M] = 5
×
10
−
5 M, λ
=
420 nm, a refers to left axis, b refers to the right axis.  [NCS−] = 0.2 M, [NNDMTU] = [TU] =
0.05 M, μ =
1.0 M (NaNO3).In order to compare the type of mechanism
obeyed fortrans-aqua
substitution in the [ReO(OH2)(CN)4]− complex,
a high pressure study with NCS− ions and TU was also performed.  Since the reaction between [ReO(OH2)(CN)4]− and L (L = NCS− and TU) shows equilibrium constants of 87
±
7 and
7.0
±
0.4 M-1, respectively [48, 49], similar arguments to the Tc(V) as
mentioned above could be used to determine the activation volume, Δ
V
#
expt.,
for which the values are reported in Table 2.Table 2
Comparative table for the kinetic
data and activation parameters for the ligation
reactions of [ReO(OH2)(CN)4]− and [TcO(OH2)(CN)4]− at 25°C. (a)Refrences [37, 48], (b)this work.
Parameter
Metal
NCS−
NNDMTU
NMTU
TU
HN3
k
f (M-1 s-1)
Re(a)
0.00348(4)
0.059(2)
0.067(2)
0.0399(9)
0.0064(2)
Tc(b)
22.2(3)(a)
11.5(4)
11.38(4)
7.4(1)
—
k
fTc/k
fRe
—
6321
195
170
185
—
Δ
S
#
k
f (J K-1 mol-1)
Re(a)
−
11
(
6
)
−
119(40)
−
125(10)
−
95(3)
−
87(6)
Tc(b)
−
9(12)
−
40(8)
−
84(11)
−
110(17)
—
Δ
H
#
k
f (kJ mol-1)
Re(a)
17.4(1.9)
45(11)
42(3)
52(1)
60(2)
Tc(b)
62(4)
55(2)
42(3)
35(5)
—
Δ
V
#
k
f (cm3 mol-1)
Re(b)
−
1.7(3)
—
—
−
22.1(9)
—
Tc(b)
−
3.5(3)
−
14(1)
—
−
6.0(5)
—This high pressure kinetic study on the reaction between [TcO(OH2)(CN)4]− and NCS− ions, NNDMTU and TU [Figure 3], yields Δ
V
#
expt. values of −
3.5
±
0.3,  −
14
±
1 and −
6.0
±
0.5 cm3/mol, respectively. Similarly, the data for the Re(V), as
represented in Figure 4 gave Δ
V
#
expt. values of −
1.7
±
0.3 and −
22.1
±
0.9 cm3/mol for NCS− ions
and TU respectively. It is clear that all these indicate small to large
negative values, contrary to the experiments on Alberto's Re
I
⁡ and Tc
I complexes  [35].Figure 4
The effect of pressure on the second-order
formation rate for the reaction between [ReO(OH2)(CN)4]− and NCS− ions and TU at 25°C, pH = 0.3, [M] = 1.5
×
10
−
3 M, a refers to left axis, b
refers to right axis.  [NCS−]
=0.6 M, λ
NCS
−
=
420 nm; [TU] =
1.0 M, λ
TU
=
350 nm, μ =
1.0 M (NaNO3).We previously concluded that with regard to the mechanism, due to
the large distortion (metal displaced out of the plane formed by the fourcis ligands bonded to the metal, away from the trans-oxo) observed for the
[MO(L)(CN)4]n- complexes of Mo
IV, W
IV,
Re
⁡
V, and Tc
⁡
V, a dissociative acti-  vation would be favoured
during trans-aqua
substitution reactions [44, 47].  A positive
volume of activation (+10.6
±
0.5 cm3/mol) was observed for the
reaction between the corresponding isostructural [WO(OH2)(CN)4]2- complex and N
3
−, forming an important basis of the
mechanistic assignment.However, the current high-pressure study on the [ReO(OH2)(CN)4]− and [TcO(OH2)(CN)4]− complexes clearly indicates
a negative volume of activation for all these reactions (Table 2), ranging
from slightly negative for the anionic NCS− as entering ligand, to
substantially negative for the neutral thiourea ligands.  This yields important evidence, along with
the large negative Δ
S
# values, that an associative (A) mechanism or an associative
interchange (I
a) mechanism
is operative for the activation step during these trans-aqua substitution reactions on the
M(V) metals. In principle, this is actually quite acceptable,
since the [MO(OH2)(CN)4
]
n
− complexes of Mo
IV, W
IV,
Re
⁡
V and Tc
⁡
V are all classic
16  electron species. Clearly, the M(IV) metal centres are softer than the
corresponding Re
V
⁡ and Tc
V, allowing easier dissociation
of the aqua ligand in the rate determining step. This is confirmed by the solid
state structures of the [MO(NCS)(CN)4]2- complexes, wherein
both of the NCS− ligands where nitrogen bound. [43, 44].The formation of
the [MO(L)(CN)4
]
m
− complex in Scheme 1 in an A mechanism yields an activation volume Δ
V
#
expt.
=
Δ
V
#
k
f
=
Δ
V
#
k
2
′, which
is expected to be large negative, and holds true for the reactions between both
[ReO(OH2)(CN)4]− and TU (Δ
V
#
k
2
′
=
−
22.1(9)  cm3 mol-1)
and [TcO(OH2)(CN)4]− and NNDMTU (Δ
V
#
k
f
=
−
14
(
1
) cm3 mol-1) and to a
lesser extend for [TcO  (OH2)(CN)4]− and TU (Δ
V
#
k
f
=
−
6.0
±
0.5 cm3 mol-1).
It is therefore realistic that the neutral ligands will associate more
easily with the [MO(OH2)(CN)4]− species,
compared to association between two negative species {[MO(OH2)(CN)4]− and the NCS− ligand}, supporting the assumption of an associative
process.  Furthermore, the reaction
between [MO(OH2)(CN)4]− and NCS− yielded activation values of −
1.7
±
0.3 and −
3.5
±
0.3 cm3 mol-1 for Re
V
⁡ and Tc
V, respectively.  These are considered too small negative
values to support a pure associative activation, although electrostriction
between the negatively charged complex and entering NCS− ligand
might affect the total value of Δ
V
#
expt
..For anI
a mechanism, the volume of
activation can be expressed as the sum of the individual contributions for each
step in Scheme 1(8), where k
f
=
k
4
K
3 and  Δ
V
K
3 = reaction volume for the equilibrium reaction
defined by K
3:
(8)
Δ
V
#
expt.
=
Δ
V
K
3
+
Δ
V
#
k
4
.
The k
4 step is associated with a
simultaneous bond breaking/formation process, and therefore Δ
V
#
k
4 is expected to be slightly negative in an
interchange associative process.
Furthermore, Δ
V
K
3 can be expressed in terms of its individual
components (9):
(9)
Δ
V
K
3
=
Δ
V
#
k
3
−
Δ
V
#
k
−
3
.
Since Δ
V
#
k
−
3 is expected to be positive (associated with
bond breaking), and Δ
V
#
k
3 in turn is slightly negative, Δ
V
K
3 is expected to be either small positive or
slightly negative.  It is thus clear from (9), that depending on the relative
magnitude of the volume change associated with K
3 and k
4,
that either an I
d or I
a mechanism is
possible.   However, since an overall
negative tendency for Δ
V
#
expt. was obtained, an associative interchange mechanism is considered more likely
for the NCS− reaction, since there should be significant
electrostriction between the NCS− and [M]− species.  For the neutral thiourea ligands, an even
larger-negative
activation volume is observed, and a pure associative mode of activation could well be operative.Upon comparison
of thetrans-substitution
reactions on the [ReO(OH2)(CN)4]− and [TcO(OH2)(CN)4]− complexes (Table 2), a few other interesting observations are also made.Firstly, for the [ReO(OH2)(CN)4]− complex, the order of reactivity for the ligands are: NMTU >
NNDMTU > TU > NCS−> HN3 and for the
[TcO(OH2)(CN)4]− complex: NCS−>
NNDMTU > NMTU > TU.  It is clear
that the NCS− ligand shows the fastest reaction with the Tc centre (ca.
6300 times faster), but the slowest reaction with the Re centre [see relative
ratio’s of k
fTc/k
fRe in Table 2]. A
comprehensive explanation of this rate difference is not yet possible.  It is, however, known that the Tc
V centre
can more readily accept electron density than does the Re
V
⁡ [50, 51]
and to some extend favour, in spite of the negative charge on
the NCS− as entering ligand, association with the Tc
V centre.  This is, however, not manifested in the activation
volumes.  The rate constants of the thiourea
ligands are more comparable, showing a great deal of consistency for both metal
centres, although a slight dependence on steric bulk/electron density of the
TU ligands is apparent, but cannot currently be convincingly explained, see
below.Secondly, since
it is known that methyl substituents on a ligand can increase thep
K
a value and therefore the
electron donating ability thereof (see examples in Table 3 [52]), it is expected in an associative
mechanism that the methyl substituted thiourea will react slightly faster than
TU, as was concluded from this work on the Re
V
⁡ system.Table 3
Comparison betweenp
K
a values of methyl substituted
and unsubstituted compounds [52].
Compound
p
K
a
1
Compound
p
K
a
1
Cinnamic acid
4.44
P-Methylcinnamic acid
4.56
Malonic acid
2.83
Methylmalonic
acid
3.07
Acetic acid
4.75
Trimethylacetic
acid
5.03
Pyridine
5.25
2,4-Dimethylpyridine
6.57
Methylamine
10.66
Dimethylamine
10.73Thirdly, the
[MO(OH2)(CN)4
]
n
− compounds of    Tc
V and
Re
V
⁡ react both according to an associative mechanism or partly
associative, while the Mo
IV and W
IV compounds react via
a dissociative mechanism.  From this, it is clear that the work done on
the Mo
IV and W
IV centres, although all iso-structural d
2 species,
cannot be applied directly to the Tc
V and Re
V
⁡ centres, as
assumed previously [13].  It also
implies that the higher-oxidation
state of the Tc
V and Re
V
⁡ centres favour
the more associative activation, while the Mo
IV and W
IV could
favour a dissociative activation mode.However, even more detailed high-pressure studies, to enable
construction of complete volume profiles, are required in future.These results, along with the fact that the Tc(V) centre is much
more reactive than the Re(V), is of particular relevance to nuclear
medicine.  In the preparation ofTc
99
m
radiopharmaceuticals or in the labelling of antibodies with Tc
99
m,
“transfer” ligands are often used to stabilize the required oxidation state,
and then the actual labelling is accomplished by simple ligand substitution
onto the “transfer complex” [53].  From this work, the best way of optimizing
labelling conditions would be to use a S-donor transfer ligand instead of a C-
or N-donor transfer ligand so that the exchange process would be dissociative
in nature.  This would imply that the
transfer ligand, rather than the concentration of the antibody or chelating
moiety attached to the antibody, would influence the reaction rate and yield a much “cleaner” reaction mixture
(concentration of unlabeled antibody in solution would be low).  Furthermore, the greater reactivity of Tc
compared to Re must be taken into account when developing therapeutic radio-rhenium
analogues to known diagnostic Tc
99
m radiopharmaceuticals.  For example, more drastic conditions are required in the preparation of Re
⁡
186
diphosphonates (for bone imaging) than in the preparation of Tc
99
m
diphosphonates [54].  These differences in reactivities between Tc
V and Re
V
⁡ centres needs to be taken into account before procedures that are available for certain
technetium complexes are applied to the preparation of the rhenium analogues.



---

*Source: 745989-2008-04-17.xml*