Macrocyclic receptor for pertechnetate and perrhenate anions

Article abstract of DOI:10.1039/c1ob05873h

The design and synthesis of a neutral macrocyclic host that is capable of perrhenate and pertechnetate recognition is described. The anion affinities and underlying coordination modes were estimated by several experimental and theoretical methods includin

Full text of DOI:10.1039/c1ob05873h

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PAPER
Macrocyclic receptor for pertechnetate and perrhenate anions†
Grigory V. Kolesnikov,a,b Konstantin E. German,c Gayane Kirakosyan,c Ivan G. Tananaev,c Yuri A. Ustynyuk,a
Victor N. Khrustalevb and Evgeny A. Katayev*d
Received 1st June 2011, Accepted 5th August 2011
DOI: 10.1039/c1ob05873h
The design and synthesis of a neutral macrocyclic host that is capable of perrhenate and pertechnetate
recognition is described. The anion affinities and underlying coordination modes were estimated by
several experimental and theoretical methods including a new technique—reverse 99Tc NMR titration.
here a new technique, namely a 99Tc NMR21 reverse titration
protocol, that facilitates estimation of the pertechnetate anion
The design of anion receptors of analytical and biochemical utility
affinities.
Introduction
is a recognized challenge within the supramolecular community.1–4
-
-
Perrhenate (ReO4 ) and pertechnetate (TcO4 ) are among the
anions that are the most “difficult to catch” due to their relatively
large size and low charge density.5 However, these anions are
readily available from 99Mo/99mTc and 188W/188Re generators and
are of great interest in nuclear medicine for both diagnostic and
therapeutic applications.6 The most significant source of 99Tc by far
is from the nuclear fuel cycle, and it is considered as one of the most
hazardous pollutants due to its long half-life and high mobility in
the environment. The design and synthesis of receptors capable of
achieving the selective recognition of Re(Tc)O4- is of great interest
because the resulting species could lead to the development of
sensors7,8 and materials9–11 allowing for the detection and capture
of these anions. Appropriate receptors might also permit new
approaches for the radiolabeling of organic compounds without
the need for the classic reduction steps involving conversion of
Re(VII) and Tc(VII) to easier-to-manipulate oxidations states.12,13
To date, positively charged receptors have proved to be the
most efficient for perrhenate and pertechnetate recognition.7,14–19
However, neutral receptors are promising in the sense that
they may display higher binding selectivities for the targeted
anions.15,20
Results and discussion
Synthesis and structure of receptors
In our previous work22,23 we showed that an anion-induced
combinatorial selection of macrocyclic hosts from dialdehyde
and diamine building blocks via reversible acid-catalyzed imine
condensation is a convenient method for host design.24 On the
˚
basis of the O–O distance (2.8 A) in perrhenate we suggested that
compounds 1 and 2 are promising building blocks with which to
construct receptors for Re(Tc)O4- (Fig. 1). The dialdehyde 1, with
˚
an Npyrrole–Npyrrole distance known to vary from 2.5 to 4.3 A, is
particularly attractive since it can provide two different binding
sites.25 Once incorporated in a macrocycle, we propose that a third
binding site, located at least 5.8–7.2 A from other binding sites, is
advantageous.20
˚
We used HClO4, HReO4, H2SO4, HNO3, HCl and H3PO4, as
templates in the synthesis of the receptor. HReO4, HClO4 and
HCl gave only the [1 + 1] product of the condensation (according
to MALDI-TOF spectra) and highest isolated yields of L1·(acid)2
(45%). The free-base ligand was prepared by neutralization of the
salt using triethylamine. An understanding as to why different
In this work we describe the synthesis of a neutral macro-
-
cyclic host that is capable of Re(Tc)O4 recognition. The an-
-
-
anions (Cl- vs. ReO4 or ClO4 ) gave rise to different products
came from an analysis of the X-ray structures of the corresponding
ligand salts (Fig. 2a,b)
ion affinities of this system have been estimated on the ba-
sis of several known analytical methods. We also introduce
According to the X-ray analysis, one perrhenate anion in
L1·2HReO4 interacts via H-bonds with both dipyrromethane and
diamidopyridine binding units, while in L1·2HCl two chloride
anions are found in completely isolated binding sites. The two
perrhenate anions are coordinated to the receptor from both
sides in different modes (Fig. 2), forming strong H-bonds with
pyrrole NH’s, and weak H-bonds with amide NH’s and benzene
CH’s. Interestingly, the fact that only three oxygen atoms of
the perrhenate anion are involved in H-bonding is in agreement
with the H-bond network found by one of us in the structure of
guanidinium perrhenate.26
aDepartment of Chemistry, M.V. Lomonosov Moscow State University,
Leninskie gory 1/3, 119992, Moscow, Russian Federation
bA.N. Nesmeyanov Institute of Organoelement Compounds Russian Academy
of Sciences, Vavilov st., 28, 119991, Moscow, Russian Federation
cA.N. Frumkin Institute of Physical Chemistry and Electrochemistry Russian
Academy of Sciences, Leninskiy pr. 31, 119991, Moscow, Russian Federation
dInstitut fu¨r Organische Chemie, Universita¨t Regensburg, Universita¨tsstr.
31, 93040 Regensburg, Germany. E-mail: evgeny.katayev@chemie.uni-
regensburg.de; Tel: +49 941 9434628
† Electronic supplementary information (ESI) available. CCDC reference
numbers 818214. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob05873h
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The slower kinetics of L1·2HCl complex formation in compar-
ison with the corresponding perrhenate complex allowed us to
determine the half-life of the template-mediated reaction using 1H
NMR spectroscopy; this value was found to be ca. 800 s. Addition
of one equivalent of HCl to a mixture of 1 + 2 led to mono-
protonation of the diamine (green signals, Fig. 3). During the
reaction, the diamine loses the proton and the signal disappears
but not completely. This is rationalized in terms of the fact that for
full transformation to the macrocycle, two equivalents of the acid
are needed. Fig. 3 shows the course of the spectral changes as a
function of time as the reaction is allowed to run its course. Signals
corresponding to the product (red signals) are already visible after
1
1 min. In order to assign all the signals we conducted H NMR
titrations of diamine 2 with HCl and HReO4 (cf. ESI†).
Anion binding studies
Binding affinities of the free-base receptor were determined using
-
-
UV-vis titrations. Both anions ReO4 and TcO4 have low charge
densities and thus produce small changes in the electronic spec-
trum of the receptor upon interaction. The maximal changes were
observed in 1,2-dichloroethane (Table 1, cf. ESI†). Interestingly,
the first binding event for all anions is 2 : 1 ligand-to-anion. This
stoichiometry was additionally supported by Job’s plot and ESI(-)
mass spectrometry, where the peak with m/z 1625.6 was detected,
which corresponds to 2L1·ReO4 (cf. ESI†).
-
Because the anion in complex L1·2HReO4 is coordinated
to the protonated receptor, we cannot directly compare this
binding mode with that of the free-base receptor. In order to
Fig. 1 Synthesis and structures of receptors considered in this study. The
distances in A between binding sites shown in this figure were estimated
from DFT calculations.
˚
Fig. 2 Structures of L1·2HReO4 (a) and L1·2HCl (b) according to X-ray analysis. In (b) one of the chloride atoms is disordered. Most of the hydrogen
atoms and solvent molecules are omitted for clarity.
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Fig. 3 Changes in the 1H NMR spectrum of an equimolar mixture 1 + 2 in CD3OD after addition of one equiv. of HCl (26% aqueous solution). The
first spectrum represents the spectrum of dialdehyde 1. Green signals belong to diamine 2, violet signals belong to dialdehyde 1 and red signals belong to
complex L1·2HCl.
Table 1 Affinity constants (logb/M-1) of receptors for anions as deter-
provided by two molecules of the receptor, which are oriented
mined from UV-vis titrations carried out in two solvents at 25 ◦C (DCE—
almost perpendicular to each other. According to the calculations
1,2-dichloroethane, DMSO—dimethylsulfoxide). Binding stoichiometries
other than 1 : 1 are indicated
the formation of a 2 : 1 complex (DE = -46 kcal mol-1) is more
energetically favorable than the formation of a 1 : 1 complex (DE =
L1 DCE
L1 DMSO
L2 DCE
4.85(1)
L2 DMSO
4.32(1)
-26 kcal mol-1).
Support for the conclusion that the benzene CH’s of L1 are
involved in hydrogen bonding interactions with the perrhenate
anion was obtained from 1H NMR titrations carried out in CDCl3.
Maximal proton shifts were observed for pyrrole NH- (+0.92
ppm) and benzene CH-protons H1 (+0.04 ppm, Fig. 5). Other
aromatic CH- and amide NH-protons move to lower field but
with smaller shifts. Fitting the titration data allowed us to estimate
-
H2PO4
10.54(5) 2 : 1
5.21(1) 1 : 1
11.34(8) 2 : 1
5.00(10) 1 : 1
12.72(14) 2 : 1
5.35(9) 1 : 1
4.65(9)a
10.83(12) 2 : 1
5.49(9) 1 : 1
9.72(12) 2 : 1b
3.18(10) 1 : 1
8.73(12) 2 : 1
3.70(8) 1 : 1
9.65(8) 2 : 1
4.46(5) 1 : 1
8.60(8) 2 : 1
4.29(6) 1 : 1
8.73(8) 2 : 1
4.38(6) 1 : 1
4.42(1)
-
HSO4
4.91(2)
5.16(5)a
4.64(4)
OAc-
Cl-
3.52(2)
6.30(15)a
3.60(2)
2.99(14)
5.50(2)a
4.72(2)
4.28(2)
4.71(4)
-
NO3
the stepwise binding constants as logK21 = 5.15(10) and logK11
=
I-
5.26(15)b
4.60(10)
4.61 (5)
4.40(2)b
5.01(1)
5.55(4)b
4.10(3)
4.95(6)b
4.60(6)b
3.12(10), respectively.
As for UV-vis titrations, addition of (Bu4N+)(ReO4 ) to the
receptor induces only small changes in the spectrum of the ligand.
Analysis of the data included in Table 1 reveals that L1 has
almost the same affinity for most anions included in this study, with
a small preference for the two hydrophilic anions CH3COO- and
-
-
ClO4
-
ReO4
4.55(10)b
4.22(30)b
-
TcO4
5.00(30)b
-
HSO4 . However, the solvation energies of the more hydrophobic
a Average binding constant for all events was calculated. b Values were
calculated taking into consideration the anion absorption.
-
-
-
anions, e.g., ReO4 , TcO4 , ClO4 , are much less than those of these
two more hydrophilic anions.27 Hence, increasing the polarity of
the solvent should reverse the selectivity of the host and favor
its interaction with the more hydrophobic anions, simply because
hydrophilic anions require more energy to be desolvated in polar
environments.5 Indeed, measurement of binding constants in a
mixture of DCE–MeOH and DMSO revealed that the selectivity
is reversed and that the greatest effect is observed in DMSO (Table
1). Interestingly, in the more polar solvents little evidence of 2 : 1
binding was seen, presumably due to the competition between the
solvent and the ligand for coordination of the second anion.
To establish the reliability of UV-Vis titrations we conducted
the competition experiment, namely the titration of complex
L1·HSO4- with ReO4- in both solvents. Changes in the absorbance
upon dilution of L1·HSO4- with more than 5–10 equiv. of L1 should
follow Lambert–Beer behavior, because the receptor will be in a
estimate the geometry of the host–guest complexes formed
in 1,2-dichloroethane, we carried out DFT calculations of 1 : 1
and 2 : 1 receptor–perrhenate complexes (Fig. 4a, b). To establish
the reliability of these calculations, we compared the optimized
structures and those obtained from the X-ray analysis. On the
basis of a bond length comparison, the average difference between
the experimental (X-ray, solid state) and optimized (DFT, gas
˚
phase) value was found to be 0.13 0.06 A, which is 10% of
the length of the C–C bond with a confidence interval of 95%
(cf. ESI†). According to the calculations carried out for complex
-
L1·ReO4 , the coordination of the anion takes place due to two
pairs of hydrogen bonds provided by the dipyrromethane NH’s,
the benzene CH’s and the amide NH’s. A conformational and
geometrical search for the global minimum of the 2 : 1 structure
resulted in the structure shown in Fig. 4b. In this case, all
oxygen atoms of the anion are involved in an H-bonding network
-
-
large excess. However, if ReO4 can replace HSO4 (the receptor
has large affinity for the perrhenate anion), then the changes upon
dilution of L1·HSO4 with a mixture of L1 and ReO4 should
-
-
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Fig. 4 The structures of complexes L1·ReO4- (a), 2L1·ReO4- (b) and L2·ReO4- (c) are optimized using DFT calculations. In (b) “Tol” stands for the tolyl
group which is partially removed for clarity; however, the resting carbon atom shows the direction of the tolyl group in space. Most of the hydrogen atoms
were removed for clarity as well.
is in agreement with the observed selectivities (Table 1). Fitting
of the data allowed us to obtain a competition binding constant
-
-
logK(HSO4 /ReO4 ) = 3.60(2).
We thought that increasing the number of hydrogen bonding
-
donor sites could increase the selectivity for ReO4 . Accordingly, a
new polyamide receptor, L2, was synthesized. The H-bond network
of L2 is similar to that of [L1H2]2+ (compare Fig. 2a and Fig. 4c).
However, the results of screening the anion binding affinities in
different solvents did not agree with our expectations (Table 1).
Thus, we concluded that by increasing the number of NH sites on
the receptor in both polar and non-polar media the effect of anion
solvation becomes negligible in defining the selectivity of the host.
In point of fact, receptor L1 appears to possess a better number
and arrangement of H-bond donor sites; certainly, it has allowed
us to achieve almost one order of magnitude selectivity for the
-
-
ReO4 anion over HSO4 , Cl- and CH3COO-.
Reverse 99Tc NMR titrations
Additional evidence of binding of pertechnetate to the receptors
was provided by reverse 99Tc NMR titrations carried out in CDCl3
solution. This method appears to be more reliable in comparison
1
with H NMR titration, because the shift of the 99Tc signal is
close to 1 ppm when the binding is present. In this experiment
the stock solution of tetrabutylammonium pertechnetate was
titrated with the ligand and the technetium signal was followed
until a 1 : 5 anion–receptor ratio was reached. The technetium
peak shifted upfield from 21.30 to 20.88 ppm in the case of
L1 (logK = 3.24(10)) and from 21.30 to 20.54 ppm in the case
of L2 (logK = 1.96(10)). The binding affinities are almost two
orders of magnitude lower than those obtained from UV-vis
titrations; however, this is in agreement with general correlation
between NMR and UV-vis methods observed for similar host–
guest complexes.28,29 The difference of binding affinities arises from
the difference in the concentrations used in NMR (ca. 10-3 mol
L-1) and UV-vis (ca. 10-5 mol L-1) methods. At a concentration
of host higher than 10-4 mol L-1, the absorbance did not follow
Lambert–Beer behavior, indicating that aggregations of the host
Fig. 5 99Tc NMR titration of (Bu4N+)(TcO4-) with L1 (a) and 1H NMR
titration of L1 with (Bu4N+)(ReO4-) (b) in CDCl3 at 25 ◦C.
not be linear. In this experiment, we observed non-linear changes
only in DMSO solution (cf . ESI, Fig. S27 and S28†). This fact
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are present. Carrying out the reverse titration, a receptor can self-
associate and this will compete with the anion binding process.
Because in the reverse 99Tc NMR method the chemical shifts are
not large, the obtained binding affinities represent a presumably
average value which include both 2 : 1 and 1 : 1 events.
Macrocycle L1 (R = Pr). Diamine 2 43.0 mg (0.12 mmol) and
dialdehyde 1 50.0 mg (0.12 mmol) were dissolved in 1.0 ml of
MeOH and stirred for 10 min. Then 2.5 eq. of a template acid
was added to the solution (HClconc (33%), HClO4 conc (70%) or
HReO4 conc (70%)). The mixture was allowed to react for the next
10 h at r.t. The red colored precipitate formed was filtered off
yielding the macrocyclic product as a salt of the corresponding
acid. The solid was dissolved in 95 : 5 (v/v) DCM–MeOH solution
and layered with hexane. The resulting crystals were dissolved in
95 : 5 (v/v) DCM–MeOH and treated with 3.3 ml (2.4 mmol) of
triethylamine and evaporated. The product was passed through
an alumina plug (eluent 95 : 5 (v/v) DCM-MeOH) yielding the
free base as a yellow-red powder. Overall yield - 38 mg (45%).
1H NMR ([D6]DMSO): d (ppm) 1.12 (6H, t, CH3), 1.60 (4H,
m, CH2),2.24(3H, s, CH3), 2.67 (4H, m, CH2), 5.69 (1H, s, CH),
6.90 (2H, d, CH-benzene), 7.07 (2H, d, CH-benzene), 7.16 (2H,
d, CH-benzene), 7.43 (4H, m, CH-benzene), 8.27 (2H, m, CH-
pyridine), 8.32 (1H, m, CH-pyridine), 8.42 (2H, s, CH N), 11.15
(2H, bs, NH-amide), 11.71 (2H, bs, NH-pyrrole). 13C NMR
([D6]DMSO): d (ppm) 161.5, 154.12, 147.22, 139.86, 136.04,
133.32, 131.61, 131.50, 129.72, 129.55, 128.82, 128.13, 127.14,
126.43, 116.86, 116.54, 116.33, 116.20, 113.64, 47.95, 26.16, 25.02,
21.06, 14.00, 9.13. MALDI-TOF (matrix – DHB), m/z: calcd [M +
H] 716.4, found 716.4. Anal. calcd for C45H45N7O2: C, 75.50; H,
6.34; N, 13.70. Found: C, 75.31; H, 6.54; N, 13.87. UV-vis (1,2-
dichloroethane): lmax = 342(42630)
Conclusions
We have prepared for the first time what is, to our knowledge,
a viable neutral receptor for the perrhenate and pertechnetate
anions. The structural and binding data collected in the context
of this study provide support for this conclusion. They are also
expected to increase our understanding of how these important
anions interact with organic hosts. Currently, we are working
to generalize these findings by extending the present studies to
include receptors that can bind the perrhenate anion in water.
Experimental
All solvents were purchased commercially and were of reagent
grade quality. Starting materials were purchased from Aldrich
Chemical Co. or Acros Organics and used without further purifi-
cation. NMR spectra used in the characterization of products were
recorded on a Bruker Avance 600 spectrometer. The NMR spectra
were referenced to the solvent and the spectroscopic solvents were
purchased from Cambridge Isotope Laboratories. All MALDI-
TOF mass spectra were recorded on a Reflex 3 Bruker instrument.
Elemental analyses were performed by INEOS Analytical Lab
and are reported as percentages. TLC analyses were carried out
using Baker-flex Silica gel IB-F sheets. Column chromatography
5,5¢-(Propane-2,2-diyl)bis(N-(3-aminophenyl)-4-methyl-3-phen-
yl-1H-pyrrole-2-carboxamide) (3). 5,5¢-(Propane-2,2-diyl)bis(4-
methyl-3-phenyl-1H-pyrrole-2-carboxylic
acid)
440
mg
(1.0 mmol) was suspended in 25 ml DCM, oxalyl chloride
2.8 ml (32 mmol) in 25 ml DCM was added followed by addition
of 20 ml of dry DMF. The reaction mixture was allowed to stir
for 4 h at room temperature then◦evaporated to dryness under
vacuum on a water bath at 40–45 C, and dried in high vacuum
for 1 h. The green colored residue was dissolved in 50 ml THF and
was added slowly to a mixture of N-Boc-m-phenylenediamine
416 mg (2.0 mmol), pyridine 1.6 ml (20.0 mmol) and DMAP
30 mg (0.24 mmol) in 50 ml of THF. The reaction mixture was
left stirring for the next 12 h. The reaction mixture was then
evaporated to dryness, dissolved in MeOH : DCM = 1 : 20 and
filtered through a plug of silica gel. The resulting solution was
evaporated to dryness, dissolved in 15 ml DCM, and 5 ml of
trifluoroacetic acid was added. The reaction mixture was stirred
at room temperature for the next 3 h and poured into cold 10%
NaOH in water, and extracted with DCM 50 ml twice. The organic
fractions were combined and washed with brine 100 ml, and
dried with Na2SO4. The crude product was recrystallized from
EtOAc : Hex. Overall yield was 441 mg (67%). M.p. 359–260◦ C.
1H NMR ([D6]DMSO): d (ppm) 1.43 (6H, s, CH3), 1.82 (6H, s,
CH3), 5.02 (4H, s, NH2), 6.20 (2H, d, J = 8.0 Hz, CH-benzene),
6.31 (2H, d, J = 8.0 Hz, CH-benzene), 6.70 (2H, s, CH-benzene),
6.84 (2H, t, J = 8.0 Hz, CH-benzene), 7.25–7.44 (10H, m,
CH-benzene), 8.15 (2H, s, NH-amide), 10.62 (2H, s, NH-pyrrole).
13C NMR ([D6]DMSO): d (ppm) 158.3, 149.0, 139.32, 137.0,
135.4, 130.4, 128.9, 128.8, 128.2, 126.9, 119.5, 114.8, 109.1, 106.8,
104.7, 36.2, 27.8, 9.5. ESI(+) m/z: calcd [M + H] 623.7, found.
623.8. Anal. calcd for C39H38N6O2: C, 75.22; H, 6.15; N, 13.49.
Found: C, 75.47; H, 6.30; N, 13.55.
˚
was performed on Acros silica gel 60 A (230–400 mesh). 2,2¢-(5-
Formyl-3-methyl-4-propyl-pyrrolyl)(p-tolyl)methane (1) was pre-
pared according to a literature procedure.1
Synthesis
Bis(3-aminophenyl)pyridine-2,6-dicarboxamide (2). N-Boc-m-
phenylenediamine 0.50 g (2.40 mmol), TEA 0.37 ml (2.64 mmol)
and DMAP 0.03 g (0.24 mmol) were dissolved in 25 ml of DCM
and stirred for 30 min. The solution of 0.29 g (1.44 mmol)
of pyridine-2,6-diacid dichloride in 10 ml of DCM was added
dropwise and the reaction mixture was left stirring for the next 10
h. The reaction mixture was evaporated to dryness and dissolved
in MeOH. The precipitate was filtered off, dried under vacuum,
redissolved in a dichloromethane–trifluoroacetic acid (15 : 5 ml)
mixture and stirred at rt. After 3 h an aqueous 10% NaOH
solution was added until a white slurry precipitate was formed.
The precipitate was filtered off, washed with water twice, and
dried under high vacu◦um for 4 h at 50 ◦C. Overall yield – 0.28
g (68%). M.p. 247–248 C. 1H NMR ([D6]DMSO): d (ppm) 5.18
(4H, bs, NH2), 6.41 (2H, d, J = 7.8 Hz, CH-benzene), 7.00 (2H, d,
J = 7.9 Hz, CH-benzene), 7.06 (2H, t, J = 7.9 Hz, CH-benzene),
7.21 (2H, s, CH-benzene), 8.28 (1H, t, J = 7.6 Hz, CH-pyridine),
8.36 (2H, d, J = 7.7 Hz, CH-pyridine), 10.79 (2H, s, C(O)NH).
13C NMR ([D6]DMSO): d (ppm) 164.85, 148.86, 140.19, 135.68,
130.20, 128.71, 128.22, 126.88, 109.65, 108.52, 106.21. ESI(+) m/z:
calcd [M + H] 348.4, found 348.4. Anal. calcd. for C19H17N5O2: C,
65.69; H, 4.93; N, 20.16. Found: C, 65.47; H, 5.12; N, 20.25.
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Macrocycle L2. 62 mg (0.1 mmol) of 3 was dissolved in 150 ml
of THF, 140 ml (1 mmol) of Et3N and DMAP 3 mg (0.02 mmol)
was added. The solution of 31 mg (0.15 mmol) pyridine-2,6-diacid
dichloride (4) in 50.0 ml of THF was added slowly to the former
solution. The reaction mixture was left stirring for the next 12 h.
The reaction mixture was then evaporated to dryness, dissolved
in MeOH : DCM = 1 : 20 and filtered through a plug of silica gel.
The product was purified by flash chromatography on silica gel,
and eluted with EtOAc–Hex 1 : 2 mixture. Additional purification
steps were carried out by suspending the product in Et2O and
filtering through a glass filter. Overall yield was 35 mg (46%). 1H
NMR ([D6]DMSO): d (ppm) 1.93 (6H, s, CH3), 2.09 (6H, s, CH3),
6.20 (2H, d, CH-benzene) 7.14–7.24 (4H, CH-benzene), 7.42–7.60
(10H, CH-benzene), 7.72 (1H, s, CH-benzene), 8.07 (1H, t, J =
7.8 Hz, CH-pyridine), 8.30 (2H, d, J = 8.2 Hz, CH-benzene),
8.49 (2H, d, J = 7.8 Hz, CH-pyridine), 9.05 (2H, s, NH-amide),
9.44 (2H, s, NH-amide). 13C NMR ([D6]DMSO): d (ppm) 160.1,
158.2, 148.0, 138.1, 136.9, 136.5, 135.9, 133.4, 129.6, 128.5, 128.2,
127.4, 125.0, 118.6, 115.8, 115.4, 115.3, 112.6, 28.7, 27.2, 10.4.
ESI(+), m/z: calcd [M + H] 754.8, found 754.8. Anal. calcd for
C46H39N7O4: C, 73.29; H, 5.21; N, 13.01. Found: C, 73.17; H, 5.33;
N, 12.95. UV-Vis (1,2-dichloroethane) lmax = 300(32000)
for the 99Tc NMR binding studies involved making sequential
additions of titrant (e.g. receptor 3) using Hamilton syringes to
a 0.5 mL aliquot of the host (anion) stock solution in the NMR
tube. The data were combined to produce plots that showed the
changes in anion chemical shift (ppm) as a function of changes in
the concentration of receptor 3. The experimental data were fitted
by HYPERNMR 2006 computer program.30
Combinatorial experiments for imine macrocycle L1. Diamine
2 4.6 mg (0.08 mmol) and dialdehyde 1 5.0 mg (0.08 mmol)
were dissolved in 0.6 ml of methanol and stirred for 10 min.
Then 2.5 eq. of template acid were added (H3PO4 conc (98%),
H2SO4 conc (98%), HClconc (26%), HNO3 conc (73%), HClO4 conc (70%),
HReO4 conc (76%)). The mixture was allowed to react for the
next 12 h under ambient conditions. The yellow-green colored
precipitate formed was filtered off then washed with Et2O, yielding
the macrocyclic product as a salt of the corresponding acid. The
resulting solid was analyzed by MALDI-TOF spectra (matrix
DHB-2,5-dihydroxybenzoic acid).
NMR kinetics measurements of macrocyclization. Diamine 2
4.6 mg (0.08 mmol) and dialdehyde 1 5.0 mg (0.08 mmol) were
placed in a 5 mm NMR tube and 0.6 ml of CD3OD was added.
Then, 1.0 equiv. of the template acid were added (HClconc (26%),
HReO4conc (76%)). The NMR tube was immediately placed into
the spectrometer and the spectra were recorded.
UV-Vis titration technique. Stock solutions of the host
molecule being studied were made up in DMSO with the final
concentrations being between 1.295 ¥ 10-5 M and 2.200 ¥ 10-5 M.
For instance, 2.33 mg of receptor L1 were dissolved in 25.0 mL
of DMSO (spectrophotometric grade) yielding a 1.303 ¥ 10-4
M stock solution. This first stock solution was then diluted 10
times to give the titration stock solution with a concentration of
1.303 ¥ 10-5 M. Stock solutions of the guest were prepared by
dissolving 10–100 equivalents of tetrabutylammonium salts of the
anions used in this study in 1.5–2.5 ml of stock solution of the
host, prepared as described above. Making up the anion source
solutions in this way allowed the binding studies to be carried out
without having to make mathematical corrections to account for
changes in host concentration as the result of dilution effects. The
general procedure for the UV-Vis binding studies involved making
Crystal structure of L1·2HCl. Crystal data for C44H45Cl4N7O2,
CCDC 818214 M = 845.67 g mol-1, monoclinic, P21/c, a = 16.89(4)
◦
A,◦b = 15.29(4) A, c = 16.64(4) A, a = 90 , b = 110.63(3)◦◦, g =
˚
˚
˚
3
˚
90 , V = 4023(16) A , Z = 4, 33694 reflections measured, 7016
independent (Rint = 0.1104), which were used in all calculations.
The final wR2 was 0.2213 (all data). Data were collected on
a Bruker SMART APEX II CCD diffractometer l(Mo-Ka)-
˚
radiation (0.71073 A), graphite monochromator, w and j scan
mode) and corrected for absorption using the SADABS program.31
One of the two chloride anions is disordered over two sites with
the occupancies of 0.6 : 0.4. The independent part of the unit
cell of L1·2(HCl) contains a dichloromethane solvate molecule.
The hydrogen atoms were placed in calculated positions and
refined within the riding model with fixed isotropic displacement
parameters (Uiso(H) = 1.5Ueq(C) for the CH3 groups and Uiso(H) =
1.2Ueq(N or C) for the other groups). All calculations were carried
out using the SHELXTL program.32
R
sequential additions of titrant (anionic guest), using Hamiltonꢀ
syringes, to a 2 mL aliquot of the host stock solution in the
spectrometric cell. The data were then collated and combined to
produce plots that showed the changes in host spectral features
as a function of changes in the concentration of the guest. The
experimental data were fitted by HYPERQUAD 2006 computer
program.30
Acknowledgements
Reverse 99Tc NMR titrations technique. Caution! Titrations
were performed with 99Tc isotope, a low energy (0.292 MeV)
b2-particle emitter with a half-life of 2.12 ¥ 105 years. When
handled in milligram quantities (the concentration range 10-3–10-5
M), 99Tc does not present a serious health hazard since common
laboratory materials provide adequate shielding. Bremsstrahlung
is not a significant problem due to the low energy of the b2-particle
emission, but normal radiation safety procedures must be used at
all times to prevent contamination.
We gratefully acknowledge Prof. Burkhard Ko¨nig for support,
Dr D. Laikov for the program “PRIRODA” for structure opti-
mization and Russian Academy of Sciences program “Chemistry
and Physico-Chemistry of Supramolecular Systems and Atomic
Clusters”.
Notes and references
Stock solutions of the tetrabutylammonium pertechnetate were
prepared in CDCl3 with the final concentration of 1.016 ¥ 10-3
M. Stock solution of the titrant was prepared by dissolving 10
equivalents of the receptor in 1.0 mL of titration stock solution
of the anion, prepared as described above. The general procedure
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7364 | Org. Biomol. Chem., 2011, 9, 7358–7364
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