Complete stereocontrol in the synthesis of macrocyclic lanthanide complexes: Direct formation of enantiopure systems for circularly polarised luminescence applications

Article abstract of DOI:10.1039/c3dt52425f

Mono-C-substitution of the 1,4,7-triazacyclononane ring induces formation of single enantiomers of Eu(iii) complexes with nonadentate N₆O ₃ ligands. The absolute configuration of each complex is determined by the stereogenicity of the C-substituent, revealed by comparison of the sign and sequence of CPL transitions for a series of complexes. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3dt52425f

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Complete stereocontrol in the synthesis of macrocyclic
lanthanide complexes: direct formation of enantiopure
systems for circularly polarised luminescence
applications†
Cite this: DOI: 10.1039/c3dt52425f
Nicholas H. Evans, Rachel Carr, Martina Delbianco, Robert Pal, Dmitry S. Yufit and
David Parker*
Received 8th July 2013,
Mono-C-substitution of the 1,4,7-triazacyclononane ring induces formation of single enantiomers of
Eu(III) complexes with nonadentate N6O3 ligands. The absolute configuration of each complex is deter-
mined by the stereogenicity of the C-substituent, revealed by comparison of the sign and sequence of
CPL transitions for a series of complexes.
Accepted 9th September 2013
DOI: 10.1039/c3dt52425f
www.rsc.org/dalton
additional ligation. Six coordinate phosphinate triazacyclononane
complexes of In(III) and Ga(III) which exist as RRR/SSS enantio-
Introduction
Complexes of the most emissive lanthanides (Eu, Tb) have mers have been known for some time.8 Of particular note is
been studied extensively for luminescence applications, and control of complex configuration by the incorporation of a
now investigations into the circularly polarised luminescence single C-substitution into the ring system of a hexadentate
(CPL) of chiral lanthanide complexes are increasingly being copper-containing NOTA-derived complex.9 Nine coordinate
reported. Given the omnipresence of chirality, CPL can provide tris-carboxylate triazacyclononane complexes of Ln(III) ions
a rich source of information on local asymmetry.1
have been reported by Mazzanti and co-workers, and were
In working towards the development of well-defined chemi- shown in the solid state to exist in tri-capped trigonal pris-
cal probes that are able to signal changes in the local chiral matic coordination geometry, present as Λ-(δδδ) and Δ-(λλλ)
environment reversibly by CPL, the design and synthesis of enantiomers.10 Very recently, we reported the preparation of
highly emissive enantiopure species is key. However, the selec- the Eu and Tb complexes of trispyridylphosphinate triazacyclo-
tive formation of enantiomerically pure metal complexes has nonane [LnL1–2] (Fig. 1).11,12 These species were prepared as
been a considerable challenge to the coordination chemist. a racemate of their two enantiomers: RRR-Λ-(δδδ) and SSS-
A highly logical means of achieving this aim is by transmitting Δ-(λλλ),13 hence requiring resolution by chiral HPLC to allow for
the chiral information from one or more enantiopure ligands direct CPL analysis. In this work, we have set out to bias for-
to the metal centre.2 This approach has been explored mation of a single complex enantiomer, by the inclusion of a
in the synthesis of several lanthanide-containing systems, stereogenic centre on the triazacyclononane ring.
including helicates3 and complexes derived from the cyclen
framework.4–6
Ligands based on triazacyclononane macrocycles represent
excellent choices for the generation of thermodynamically and
kinetically stable metal complexes.7 The ring nitrogens act pri-
marily as donor atoms and are readily elaborated to allow for
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
E-mail: david.parker@dur.ac.uk; Tel: +44 (0)191 33 42033
†Electronic supplementary information (ESI) available: Synthesis of mono-
substituted macrocycles 4–6, spectral characterisation of complexes [EuL3–9],
plus details of racemisation studies and schematic figure of CPL instrumenta-
tion. CCDC 948247. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3dt52425f
Fig. 1 The stereoisomers of trispyridylphosphinate triazacyclononane com-
plexes [LnL1–2]. R = Ph, Me, where Δ and δ refer to positive NCCNpy and NCCN
(ring) torsion angles.
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Results and discussion
Synthesis and characterisation of complexes
The synthesis of the europium complexes [EuL3–9] studied is
presented in Scheme 1 (see also ESI†). The substituted 9-N3
macrocycle rings for L4–7,9 were prepared following established
methods, in which the substituted chiral centre derives from
the alkyl esters of α-amino acids.14,15 The ethyl esters of
ligands L3–7 were formed by alkylation of the 9-N3 ring with
three equivalents of the methyl phosphinate mesylate 1a or 1b.
Pyridyl bromine substituents have been included to allow for
subsequent metal catalysed C–C or C–N functionalization. In
addition, the methyl esters of the carboxylate ligands L8–9 were
prepared to allow for comparison. Basic ester hydrolysis
yielded L3–9, each of which was complexed with Eu(III).
1
Complexes [EuL3–9] were characterised by H and 31P NMR
and electrospray MS (Fig. 2 and ESI†). The non-equivalence of
the P atoms in the substituted phosphinate complexes [EuL4–7
]
is most clearly revealed by the presence of three peaks in the
31P NMR spectra (Fig. 2d).
Fig. 2 NMR spectra: (a) 1H [EuL3], (b) 1H [EuL5-S], (c) 31P [EuL3], (d) 31P
[EuL5-S] (9.4 T, CD3OD, 295 K).
Fluorescence lifetimes for [EuL3] were recorded in H2O (τ =
1.23 s) and D2O (τ = 1.52 s). Using these values, the complex
hydration state was calculated to be zero, consistent with the
ligand acting as a nonadentate donor for the Eu(III) ion.
Subsequently, single crystals of [EuL3] suitable for X-ray
crystallographic determination were grown by slow evaporation
of a MeOH solution of the racemate of the complex. The struc-
ture reveals a nine coordinate complex with C3 symmetry, in
agreement with the solution phase characterisation (Fig. 3).
The mean bond distances and NCCN and NCCNpy torsional
angles are almost identical to those previously reported for a
tris(phenyl phosphinate) complex, [EuL1] (Table 1).
series of complexes, chiral HPLC (CHIRALPAK-IC or ID,
MeOH) verified formation of a single stereoisomer indepen-
dent of substituent steric bulk, with an enantiomeric excess
>96% being observed in the case of [EuL5-R].16 The resolved
enantiomers of the methyl phosphinate complex [EuL3] race-
mised slowly when heated to 60 °C in H2O, with a half-life of
185 ( 20) h determined by observing the % ee change using
chiral HPLC (ESI†). The carboxylate complex [EuL8] racemised
in water with a half-life of 240 ( 35) h under the same con-
ditions.17 These systems are considerably more stable to race-
misation than the frequently studied tris-dipicolinate
Stereochemistry and CPL of complexes
The racemates of the unsubstituted complexes [EuL3] and complexes of the Ln(III) cations. The Eu tris-dipicolinate
[EuL8] were separated by chiral HPLC. For the C-substituted complex, [Eu(dpa)3] for example, has a half-life in water of
Scheme 1 Synthesis of [EuL3–9]. See experimental section for yields.
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Fig. 5 Views of the crystal structure of the SSS-Δ-(λλλ) enantiomer of [EuL3]
illustrating (a) the pseudo-equatorial positions of the pro-R hydrogens on the
ring, (b) the corner position of the pro-R hydrogen (filled arrow), versus the side
position of the pro-R hydrogen (dashed arrow) and (c) the ring torsional angles;
‘corner’ carbons – those that fall between two gauche bonds – are marked with
asterisks.
Fig. 3 Crystal structure of [EuL3]. SSS-Δ-(λλλ) enantiomer depicted.
to the phosphinate complexes there are significant changes in
sign of the CPL spectra, but with maximum values of gem being
of the same magnitude in the ΔJ = 1 band. As for the methyl
phosphinate series, C-substitution (e.g. for [EuL9], ESI†) had
negligible impact on the form and nature of the CPL spectra.
Rationalisation of the observed stereoselectivity in complex
formation is provided by consideration of the solid state struc-
ture of [EuL3]. The enantiomer depicted in Fig. 5 is SSS-Δ-(λλλ),
i.e. the configuration observed from complexes derived from
the unnatural R-amino acid, e.g. [EuL5-R]. Inspection reveals
that the pro-R hydrogen atom, where the ring substituent
would reside, is in one of two pseudo-equatorial positions
(Fig. 5a), the most likely of which (on steric grounds) is the
one directed away from the three pyridyl arms (Fig. 5b), con-
sistent with it occupying a corner (rather than a side) carbon
atom (Fig. 5c).
Table 1 Selected mean bond distances (Å 0.02) and torsional angles (° 1.0)
for complexes [EuL3] and [EuL1]11 a
Eu–O
Eu–N
Eu–Npy
NCCN
NCCNpy
[EuL3]
[EuL1]
2.33
2.33
2.69
2.68
2.65
2.66
−48
−47
+35.5
+33
a Signs of torsional angles are reported for the SSS-Δ-(λλλ) enantiomer.
5.1 ( 0.2) ms at 60 °C.18 Notably, the methyl substituted car-
boxylate complex [EuL9], showed no loss in enantiopurity after
heating to 60 °C in H2O for 72 h.
Emission and CPL spectra of enantiopure complexes
[EuL3–9] were recorded (see Fig. 4 and ESI†). The CPL spectra
of the two enantiomers of the [EuL3] are mirror images
(Fig. 4). The methyl phosphinate complexes derived from the
natural stereoisomer (i.e. S enantiomer) of the amino acid have
the same spectral sign as for RRR-Λ-(δδδ) enantiomer of [EuL3],
while for those derived from the unnatural stereoisomer had
the opposite sign (see ESI†).19 Large values for the emission
dissymmetry factor (gem = 2(IL − IR)/(IL + IR)) were observed in
Conclusions
In summary, complete control of the stereochemistry of triaza-
cyclononane based europium complexes has been demon-
strated by mono-substitution at a carbon atom on the 9-N3
ring. The direct and selective formation of a chiral complex
was observed with >96% isomeric purity. Such behaviour sim-
plifies the direct preparation of enantiopure emissive com-
plexes, analogues of which can be designed to act as
responsive chiral probes for application in CPL spectroscopy
and microscopy.
the ΔJ = 1 band (see ESI†), specifically gem(591.5 nm)
= 0.10 for
enantiopure samples of [EuL3–5], and generally there were no
significant differences in the appearance of the CPL spectra
for different substituents R, and whether X = Br or H.20,21
The CPL spectra of the two enantiomers of the carboxylate
complex [EuL8] were also mirror images (ESI†). In comparison
Experimental
General experimental procedures
Commercially available reagents were used as received from
suppliers. Solvents were laboratory grade and dried using an
appropriate drying agent when required. Reactions requiring
anhydrous conditions were carried out under an atmosphere
of dry argon.
1H, 13C and 31P NMR spectra were recorded on spec-
trometers operating at magnetic inductions corresponding
to 1H frequencies at 400, 600 and 700 MHz. Spectra were
recorded at 295 K in commercially available deuterated
Fig. 4 CPL spectra of Δ-[EuL3] and Λ-[EuL3] (H2O, 295 K).
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solvents. ESMS was carried out on a TQD mass spectrometer, The X-ray single crystal data for [EuL3] were collected at 120 K
and accurate masses were recorded on either a LCT Premier or on an Agilent Gemini S-Ultra diffractometer (graphite mono-
Thermo Finnigan LTQ-FT.
chromator, λMoKα, λ = 0.71073 Å) equipped with a Cryostream
Reverse phase HPLC purification was performed at 295 K (Oxford Cryosystems) open-flow nitrogen cryostat. The struc-
on either a Waters or Perkin Elmer system. The Waters system ture was solved by direct method and refined by full-matrix
consisted of a Waters 575 pump, Waters “System Fluidics least squares on F2 for all data using Olex223 and SHELXTL24
Organizer”, Waters 2545 “Binary Gradient Module”, Waters software. All non-hydrogen atoms were refined anisotropically,
2767 “Sample Manager”, Waters Fraction Collector III, Waters hydrogen atoms were placed in the calculated positions and
2998 Photodiode Array Detector and Waters 3100 Mass Detec- refined in riding mode.
tor. The Perkin Elmer system consisted of a Perkin Elmer
Crystal data for [EuL3]: C27H33Br3N6O6·2(H2O), M = 1058.23,
ˉ
Series 200 pump, Perkin Elmer Series 200 auto-sampler and triclinic, space group P1, a = 9.8356(4), b = 12.3427(5), c =
Perkin Elmer Series 200 UV/Vis detector. XBridge C18 17.2609(8) Å, α = 107.259(4), β = 97.936(4), γ = 105.863(4)°, V =
columns were used with a flow rate of 1 mL min−1 (analytical) or 1869.30(14) Å3, Z = 2, μ(Mo Kα) = 5.065 mm−1, Dcalc = 1.880 g
4.4 mL min−1 (semi-prep) or 17 mL min−1 (prep). Solvent mm−3, 21 350 reflections measured (5.12 ≤ 2Θ ≤ 60.00), 10 802
systems of H2O–CH3OH with 0.1% HCOOH (gradient elution) unique (Rint = 0.0439) were used in all calculations. The final
were used. Chiral HPLC was performed on the Perkin Elmer R1 was 0.0429 (8528 > 2σ(I)) and wR2 was 0.0918 (all data).
system described above using analytical (4.0 mm × 250 mm) and CCDC number: 948247.
semi-prep (10 mm × 250 mm) CHIRALPAK-IC or ID columns. An
isocratic solvent system of CH3OH was used in all cases.
Synthesis of complexes
The synthesis of phosphinate pyridyl mesylates 1a and 1b have
Optical spectroscopy
been reported elsewhere.11,25 1,4,7-Triazacyclononane 3 (as its
All samples were contained within quartz cuvettes with a path trihydrochloride salt) was purchased from Sigma-Aldrich.
length of 1 cm and a polished base. Measurements were Mono-substituted macrocycles 4–6 were manufactured follow-
recorded at 295 K. Absorbance spectra were measured on a ing a synthetic route presented in the ESI.† Mono-substituted
Perkin Elmer Lambda 900 UV/Vis/NIR spectrometer using FL macrocycle 7 was prepared following an adapted literature
Winlab software. Emission spectra were recorded on an ISA method.14 The unsubstituted carboxylate pyridyl mesylate 2
Jobin-Yvon Spex-Fluorolog-3 luminescence spectrometer. Life- and carboxylate ligand L8 were prepared following adapted
time measurements were carried out using a Perkin-Elmer literature procedures.10
LS55 spectrometer using FL Winlab software. The inner sphere
Tri-ethyl ester of L3. 1,4,7-Triazacyclononane trihydrochlor-
hydration number (q) for [EuL3] was obtained by measuring ide (34 mg, 0.14 mmol) and mesylate 1a (160 mg, 0.43 mmol)
the excited state lifetime in H2O and D2O. The q value was were dissolved in dry CH3CN (10 mL) and K2CO3 (119 mg,
calculated using the equation reported by Clarkson et al.22
0.86 mmol) added. The reaction mixture was heated under
CPL spectra were recorded on a custom built spectrometer reflux under Ar(g) until all the mesylate starting material had
consisting of a laser driven light source (Energetiq EQ-99 been consumed (as monitored by TLC). The reaction was then
LDLS, spectral range 170 to 2100 nm) coupled to an Acton cooled to RT and the solution decanted from excess potassium
SP2150 monochromator (600 g nm−1, 300 nm Blaze) that salts. The solvent was removed under reduced pressure and
allows excitation wavelengths to be selected with a 6 nm the crude material purified by repeated column chromato-
FWHM band-pass. The collection of the emitted light was graphy (alumina, 0–2% CH3OH–CH2Cl2) to give the title com-
facilitated (90° angle set up, 1 cm path length quartz cuvette) pound as a colourless oil (101 mg, 74%).
3
4
by a Lock-In Amplifier (Hinds Instruments Signaloc 2100)
δH (CDCl3) 8.08 (3H, dd, JH–P 5.8 Hz JH–H 1.8 Hz, ArH),
and Photoelastic Modulator (Hinds Instruments PEM-90). The 7.87 (3H, s, ArH), 3.80–4.10 (12H, m, CH2), 2.94 (12H, br s,
2
3
differentiated light was focused onto an Acton SP2150 mono- ring H), 1.74 (9H, d, JH–P 15 Hz, PCH3), 1.25 (9H, t, JH–H 7.1
chromator (1200 g nm−1, 500 nm Blaze) equipped with a high Hz, CH3). δC (CDCl3) 163.2 (para-ArC), 155.5 (d, JC–P 153 Hz,
1
2
sensitivity cooled Photo Multiplier Tube (Hamamatsu 7155-01 ortho-ArC), 134.2 (ortho-ArC), 129.2 (d, JC–P 22 Hz, meta-ArC),
red corrected). Spectra were recorded using a 5 spectral average 128.6 (meta-ArC), 63.7 (CH2), 61.3 (d, 3JC–P 6 Hz, CH2CH3), 56.0
4
1
sequence in the range of 570–720 nm with 0.5 nm spectral (ring C), 16.6 (d, JC–P 6 Hz, CH2CH3), 13.5 (d, JC–P 104 Hz,
intervals and 500 μs integration time. The recorded CPL PCH3). δP (CDCl3) 38.4. m/z (HRMS+) 955.0486 [M + H]+
spectrum than underwent a 25% Fourier transformation (C33H4979Br3N6O6P3 requires 905.0477). Rf = 0.44 (alumina,
smoothening protocol using Origin 8.0 Software (Origin Labs) CH2Cl2–CH3OH 98 : 2).
to enhance visual appearance (all calculations were carried out
using raw spectral data). A schematic figure of the CPL instru- to L3, using macrocycle 4 (13 mg, 0.090 mmol). The crude
The tri-ethyl ester of L4 was prepared in analogous manner
mentation is provided in the ESI.†
material was purified by column chromatography (alumina,
0–2% CH3OH–CH2Cl2) to give the title compound as a colour-
less oil (36 mg, 41%).
Crystal structure determination of [EuL3]
Crystals of [EuL3] suitable for single crystal structure determi-
δH (CDCl3) 8.05–8.09 (4H, m, ArH), 7.85 (1H, s, ArH), 7.79
nation were grown by slow evaporation of a CH3OH solution. (1H, s, ArH), 2.51–4.14 (23H, multiple CH2 and CH) 1.73–1.78
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(9H, m, PCH3), 1.24–1.29 (9H, m, CH2CH3), 0.95 (3H, d, 3J = 5.7 requires 1138.1926). Rf = 0.32 (silica, CH2Cl2–CH3OH–NH3(aq)
Hz, CH3). δP (CDCl3) 38.0. m/z (HRMS+) 969.0625 [M + H]+ 90 : 10 : 1).
(C34H5179Br3N6O6P3 requires 969.0633). Rf = 0.48 (alumina,
CH2Cl2–CH3OH 98 : 2).
The tri-methyl ester of L9 was prepared in analogous
manner to L3, using macrocycle 4 (50 mg, 0.35 mmol) and
The tri-ethyl ester of L5-S was prepared in analogous mesylate 2 (257 mg, 1.05 mmol). The crude material was
manner to L3, using macrocycle 5-S (29 mg, 0.16 mmol). The purified by repeated column chromatography (silica, 5–10%
crude material was purified by column chromatography CH3OH–CH2Cl2) to give the title compound as a colourless oil
(alumina, 0–2% CH3OH–CH2Cl2) to give the title compound as (27 mg, 13%).
a colourless oil (50 mg, 30%).
δH (CDCl3) 7.72–8.01 (9H, m, ArH), 3.93–4.21 (15H, m, inc.
δH (CDCl3) 8.04–8.11 (4H, m, ArH & ArH), 7.77 (2H, app s, OCH3), 2.75–3.21 (14H, m inc. CH3). m/z (HRMS+) 591.2959
ArH), 2.67–4.11 (23H, multiple CH2 and CH), 1.73–1.80 (10H, [M + H]+ (C31H39N6O6 requires 591.2931). Rf = 0.12 (silica,
m, PCH3 & CH(CH3)2), 1.24–1.29 (9H, m, CH2CH3), 0.95 (6H, CH2Cl2–CH3OH 90 : 10).
app t, CH3). δP (CDCl3) 38.1. m/z (HRMS+) 997.0955 [M + H]+
Complex [EuL3]. The tri-ethyl ester of L3 (70 mg,
(C36H55N6O6P379Br3 requires 997.0946). Rf = 0.53 (alumina, 0.073 mmol) was dissolved in CH3OH (5 mL) and a solution of
CH2Cl2–CH3OH 98 : 2). 0.1 M NaOH(aq) (5 mL) added. The mixture was heated to
The tri-ethyl ester of L5-R was prepared in analogous 60 °C. After verifying the reaction had gone to completion by
manner to L3, using macrocycle 5-R (10 mg, 0.057 mmol). Puri- 31P NMR, the solution was cooled to RT, and the pH adjusted
fication of the crude material by column chromatography to 6 using 0.1 M HBr(aq). Eu(NO3)3·5H2O (34 mg, 0.080 mmol)
(silica, 0–12% CH3OH–CH2Cl2) yielded the title compound as a was added and the mixture heated to 80 °C for 16 h. The
colourless oil (23 mg, 40%). NMR and MS data were in agree- pH was raised to 10, precipitated Eu(OH)3 was removed by
ment with the enantiomer tri-ethyl ester of L5-S
.
centrifuge. The pH was adjusted to 6 using 0.1 M HBr(aq), and
The tri-ethyl ester of L6-S-H was prepared in analogous the solvent removed under reduced pressure and the product
manner to L3, using macrocycle 6-S (94 mg, 0.68 mmol) and purified by column chromatography (silica, CH2Cl2–CH3OH–
mesylate 1b (199 mg, 0.68 mmol). The crude material was puri- NH3(aq) 80 : 20 : 1) giving the title compound as a white solid
fied by column chromatography (silica, 0–9% CH3OH–CH2Cl2) (74 mg, 98%).
to give the title compound as a yellow oil (66 mg, 35%).
δH (400 MHz, CD3OD) 8.60 (1H, s, pyH), 7.97 (1H, s,
δH (CDCl3) 6.97–8.07 (14H, br m, ArH), 2.45–4.69 (25 H, br pyCHN), 7.12 (1H, s, pyH), 4.36 (1H, s, NCH′eq), 0.54 (3H, s,
m, ring CH2, 3 × OCH2 & 4 × CH2), 1.50–1.94 (9H, br m, CH3), −0.77 (1H, s, pyCH′N), −1.37 (1H, s, NCH′ax), −2.23 (1H,
3 × PCH3), 0.97–1.35 (9H, br m, 3 × OCH2CH3). δP (CDCl3) 39.9. s, NCHeq), −5.28 (1H, s, NCHax). δP (162 MHz, CD3OD) 39.8.
m/z (HRMS+) 811.3654 [M + H]+ (C40H58N6O6P3 requires m/z (HRMS+) 1020.8512 [M + H]+ (C27H3479Br3N6O6P3151Eu
811.3631). Rf = 0.25 (silica, CH2Cl2–CH3OH 90 : 10).
requires 1020.8491). Rf = 0.31 (silica, CH2Cl2–CH3OH–NH3(aq)
The tri-ethyl ester of L6-R-H was prepared in analogous 82 : 15 : 3).
manner to L6-S-H, using macrocycle 6-R (102 mg, 0.47 mmol).
A sample of the complex racemate was separated by chiral
The crude material was purified by column chromatography HPLC using an analytical CHIRALPAK-ID column. Rt = 7.4 min
(silica, 0–25% CH3OH–CH2Cl2) to give the title compound as a & 14.3 min (4.0 mm × 250 mm, CH3OH, 1 mL min−1, 290 K).
yellow oil (91 mg, 24%). Analytical data were in agreement
with the enantiomer L6-S-H
Complex [EuL4] was prepared in an analogous manner to
[EuL3], using the tri-ethyl ester of L4 (24 mg, 0.025 mmol). The
.
The tri-ethyl ester of L6-S-Br was prepared in analogous crude material was purified by column chromatography (silica,
manner to L3, using macrocycle 6-S (36 mg, 0.16 mmol). The CH2Cl2–CH3OH–NH3(aq) 90 : 10 : 1), and then reverse phase
crude material was purified by column chromatography (silica, HPLC to obtain the title compound as a white solid (3 mg,
0–7% CH3OH–CH2Cl2) to give the title compound as a yellow oil 11%).
(65 mg, 38%).
δH (400 MHz, CD3OD) 9.57, 8.98, 8.51, 8.15, 7.69, 7.36, 7.14,
δH (CDCl3) 7.07–8.22 (11H, br m, ArH), 2.36–4.89 (25H, 6.74, 6.44, 6.04, 4.63, 2.76, 1.28, 1.12, 0.65, −0.11, −0.82,
br m, ring CH2, 3 × OCH2, 4 × CH2), 1.54–1.93 (9H, br m, −1.02, −1.50, −1.87, −2.40, −2.79, −5.13, −5.68, −5.79.
3 × PCH3), 1.12–1.43 (9H, br m, 3 × OCH2CH3). δP (CDCl3) 36.1. δP (162 MHz, CD3OD) 41.6, 40.4, 38.8. m/z (HRMS+) 1032.8668
m/z (HRMS+) 1045.0978 [M + H]+ (C40H55N6O6P379Br3 requires [M + H]+ (C28H3679Br3N6O6P3151Eu requires 1032.8658). Rf = 0.49
1045.0946). Rf = 0.27 (silica, CH2Cl2–CH3OH 95 : 5).
(silica, CH2Cl2–CH3OH–NH3(aq) 84 : 15 : 1). Due to the partial race-
The tri-ethyl ester of L7 was prepared in analogous manner misation of the chiral centre (see ESI†), a sample of the complex
to L3, using macrocycle 7 (75 mg, 0.24 mmol). The crude was submitted to chiral HPLC using an analytical CHIRALPAK-
material was purified by reverse phase HPLC to give the title ID column to separate the two enantiomers. Rt = 6.9 min
compound as a yellow oil (65 mg, 25%).
& 13.4 min (4.0 mm × 250 mm, CH3OH, 1 mL min−1, 290 K).
δH (CDCl3) 7.82–8.20 (6H, m, ArH), 6.45 (1H, br s, CONH),
Complex [EuL5-S] was prepared in an analogous manner to
3.87–4.17 (12H, m, PCH2 & NCH2), 2.59–3.23 (13H, m, ring [EuL3], using the tri-ethyl ester of L5-S (25 mg, 0.025 mmol).
CH2 & CH2CONH), 1.76–1.82 (9H, m, PCH3), 1.26–1.76 (26H, The crude material was purified by column chromatography
m, PCH2CH3, alkyl chain & cyclohexane CH2/CH). δP (CDCl3) (silica, CH2Cl2–CH3OH–NH3(aq) 90 : 10 : 1) to obtain the title
37.8. m/z (HRMS+) 1138.1914 [M + H]+ (C44H6879Br3N7O7P3 compound as a white solid (11 mg, 41%).
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δH (400 MHz, CD3OD) 11.67, 9.47, 8.41, 8.28, 7.82, 7.61,
Dalton Transactions
Complex [EuL6-S-Br]. The tri-ethyl ester of L6-S-Br (26 mg,
7.23, 7.05, 6.52, 5.14, 4.26, 2.70, 1.97, 1.66, 0.94, 0.83, 0.32, 0.025 mmol) was dissolved in CD3OD (2.4 mL) and a solution of
−0.57, −1.15, −2.24, −2.57, −2.82, −3.02, −4.64, −5.96, −6.35. 0.1 M NaOH in D2O (2.2 mL) was added. The reaction mixture
δP (162 MHz, CD3OD) 44.4, 41.3, 36.1. m/z (HRMS+) 1060.8992 was heated for 5 h at 90 °C with stirring. Subsequent removal of
[M + H]+ (C30H40N6O6P379Br3151Eu requires 1060.8971). Rf = the solvent under reduced pressure yielded the deprotected
0.10 (silica, CH2Cl2–CH3OH–NH3(aq) 90 : 9 : 1). Due to the ligand as a white solid (as verified by ESMS and 31P NMR).
partial racemisation of the chiral centre (see ESI†), a sample of
The ligand was dissolved in H2O–CH3OH (4 : 1, 1.5 mL) and
the complex was submitted to chiral HPLC using an analytical the pH of the solution adjusted to 5.5 using dilute HBr(aq)
.
CHIRALPAK-ID column to separate the two enantiomers. Rt = Eu(NO3)3·5H2O (12 mg, 0.027 mmol) was added and the reaction
7.1 min & 10.3 min (4.0 mm × 250 mm, CH3OH, 1 mL min−1
290 K).
,
mixture was heated at 80 °C for 16 h. After allowing the reac-
tion mixture to cool to RT, the pH was raised to 10.0 by the
Complex [EuL5-R] was prepared in an analogous manner to addition of dilute NaOH(aq). The resulting solution was stirred
[EuL3], using the tri-ethyl ester of L5-R (7.0 mg, 7.0 μmol). The for 1 h causing excess Eu(III) to precipitate as Eu(OH)3, which
crude material was purified by column chromatography (silica, was removed by filtration. The pH of the resulting solution was
CH2Cl2–CH3OH–NH3(aq) 90 : 10 : 1) to obtain the title compound restored to 5.5 by the addition of dilute HBr(aq) and the solvent
as a white solid (3.5 mg, 47%). NMR and MS data were in agree- lyophilised to give the crude product. The crude product was
ment with the enantiomer [EuL5-S]. Chiral HPLC (ChiralPAK-ID taken in to CH2Cl2–CH3OH (8 : 2, 2 mL) and the solution fil-
4.0 mm × 250 mm, CH3OH, 1 mL min−1, 290 K): Rt = 7.0 min.
tered to facilitate the removal of salts. Subsequent removal of
Complex [EuL6-S-H]. The tri-ethyl ester of L6-S-H (32 mg, solvent under reduced pressure yielded an off-white solid
0.04 mmol) was dissolved in CD3OD (3.5 mL) and a solution of which was further purified by column chromatography on
0.1 M NaOH in D2O (3.5 mL) was added. The reaction mixture silica gel (CH2Cl2–CH3OH–NH3(aq), 80 : 20 : 1) to give the title
was heated for 16 h at 90 °C with stirring. Subsequent removal compound as an off-white solid (21 mg, 76%).
of the solvent under reduced pressure yielded the deprotected
ligand as a white solid (as verified by ESMS).
δH (400 MHz, CD3OD) 10.87, 9.23, 8.51, 7.89, 7.16, 7.25,
7.48, 7.52, 6.16, 5.09, 4.48, 4.24, 2.85, 2.52, 1.87, 1.30, 1.47,
The ligand was dissolved in H2O–CH3OH (4 : 1, 2.5 mL) and 0.52, −0.34, −0.70, −2.23, −2.38, −2.49, −2.76, −3.11, −4.54,
the pH of the solution adjusted to 5.5 using dilute HCl(aq) −6.03, −6.46. δP (162 MHz, CD3OD) 43.9, 40.2, 33.5. m/z
EuCl3·6H2O (15.9 mg, 0.04 mmol) was added and the reaction (HRMS+) 1113.9153 [M + H]+ (C34H40N6O6P379Br3151Eu requires
mixture was heated at 80 °C for 16 h. After allowing the reac- 1113.9031). Rf 0.56 (silica, CH2Cl2–CH3OH–NH3(aq)
.
=
tion mixture to cool to room temperature, the pH was raised to 80 : 20 : 1). Chiral HPLC (ChiralPAK-ID 4.0 mm × 250 mm,
10.0 by the addition of dilute NaOH(aq). The resulting solution CH3OH, 1 mL min−1, 290 K): Rt = 11.6 min.
was stirred for 1 h causing excess Eu(III) to precipitate as
Complex [EuL7] was prepared in analogous manner to
Eu(OH)3, which was removed by filtration. The pH of the [EuL3], using the tri-ethyl ester of L7 (10 mg, 8.8 μmol). The
resulting solution was restored to 5.5 by the addition of dilute crude material was purified by column chromatography (silica,
HCl(aq) and the solvent lyophilised to give the crude product. CH2Cl2–CH3OH–NH3(aq) 90 : 10 : 1) to give the title compound as
The crude product was taken in to CH2Cl2–CH3OH (8 : 2, 2 mL) a white solid (3 mg, 30%).
and the solution filtered to facilitate the removal of salts. Sub-
δH (400 MHz, CD3OD) 10.13, 9.08, 8.57, 7.95, 7.85, 7.36,
sequent removal of solvent under reduced pressure yielded an 7.20, 6.66, 6.24, 5.69, 3.10, 2.29, 2.19, 2.03, 1.80, 1.53, 1.37,
off-white solid which was further purified by column chrom- 1.02, 0.68, −0.28, −0.60, −0.75, −1.71, −2.15, −2.38, −2.61,
atography on silica gel (CH2Cl2–CH3OH–NH3(aq), 80 : 20 : 1) to −4.91, −5.65, −6.01. δP (162 MHz, CD3OD) 43.4, 40.7, 37.5.
give the title compound as an off-white solid (17 mg, 50%).
m/z (HRMS+) 1203.9955 [M + H]+ (C38H53N7O7P379Br3151Eu
δH (400 MHz, CD3OD) 10.56, 8.50, 7.76, 7.61, 7.38, 7.28, requires 1203.9950). Rf = 0.32 (silica, CH2Cl2–CH3OH–NH3(aq)
7.17, 7.07, 6.68, 6.29, 5.33, 4.60, 4.30, 2.98, 2.17, 1.44, 1.31, 90 : 10 : 1). Chiral HPLC (ChiralPAK-ID 4.0 mm × 250 mm,
0.82, 0.42, −0.11, −0.37, −1.75, −1.88, −2.33, −2.87, −4.18, CH3OH, 1 mL min−1, 290 K): Rt = 14.5 min.
−5.82, −6.20. δP (162 MHz, CD3OD) 44.5, 40.2, 34.9. m/z
Complex [EuL8] (as a racemate) has been prepared within
(HRMS+) 875.1659 [M + H]+ (C34H43N6O6P3151Eu requires our laboratories previously.12 A sample of [EuL8] was resolved
875.1656). Rf = 0.16 (silica, CH2Cl2–CH3OH–NH3(aq) 80 : 20 : 1). using a semi-prep CHIRAL-PAK IC column. Chiral HPLC
Chiral HPLC (ChiralPAK-ID 4.0 mm × 250 mm, CH3OH, (ChiralPAK-IC 4.0 mm × 250 mm, CH3OH, 0.5 mL min−1, 290 K):
1 mL min−1, 290 K): Rt = 6.1 min.
Rt = 11.7 min & 19.8 min.
Complex [EuL6-R-H] was prepared in analogous manner
Complex [EuL9] was prepared in an analogous manner to
to [EuL6-S-H], using the tri-ethyl ester of L6-R-H (34 mg, [EuL3], using the tri-methyl ester of L9 (18 mg, 0.031 mmol).
0.04 mmol). The crude material was purified by column The crude material was purified by column chromatography
chromatography on silica gel (CH2Cl2–CH3OH–NH3, 80 : 20 : 1) (silica, CH2Cl2–CH3OH–NH3 80 : 20 : 0.1), to obtain the title
to give the title compound as an off-white solid (27 mg, 73%). compound as a white solid (16 mg, 76%).
NMR and MS data were in agreement with the enantiomer
δH (400 MHz, D2O) 7.95, 7.09, 6.79, 6.46, 5.85, 5.61, 5.44,
[EuL6-S-H]. Chiral HPLC (ChiralPAK-ID 4.0 mm × 250 mm, 5.07, 4.65, 4.34, 4.04, 2.77, 2.74, 2.57, 2.35, 1.63, 1.06, −0.53,
CH3OH, 1 mL min−1, 290 K): Rt = 10.9 min.
−0.87, −1.47, −4.58, −5.13, −5.53. m/z (HRMS+) 697.1415
Dalton Trans.
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[M + H]+ (C28H30N6O6151Eu requires 697.1425). Rf = 0.23 (silica, 13 RRR/SSS stereochemical descriptors refer to the stereo-
CH2Cl2–CH3OH–NH3 72 : 15 : 3). Due to the partial racemisa-
tion of the chiral centre (see ESI†), a sample of the complex
was submitted to chiral HPLC using a semi-prep CHIRALPAK-
IC column to separate the two enantiomers. Chiral HPLC
chemistry at P. Λ/Δ refers to the helical arrangement of the
pyridylphosphinate arms, associated with negative (Λ) or
positive NCCNpy torsional angles; similarly, δδδ/λλλ refers
to the NCCN ring torsional angle.
(ChiralPAK-IC 4.0 mm × 250 mm, CH3OH, 0.5 mL min−1
,
14 A. S. Craig, I. M. Helps, K. J. Jankowski, D. Parker,
N. R. A. Beeley, B. A. Boyce, M. A. W. Eaton, A. T. Millican,
K. Millar, A. Phipps, S. K. Rhind, A. Harrison and
C. Walker, J. Chem. Soc., Chem. Commun., 1989, 794.
15 J. P. L. Cox, A. S. Craig, I. M. Helps, K. J. Jankowski,
D. Parker, M. A. W. Eaton, A. T. Millican, K. Millar,
N. R. A. Beeley and B. A. Boyce, J. Chem. Soc., Perkin Trans.
1, 1990, 2567.
298 K): Rt = 12.3 min & 19.7 min.
Acknowledgements
This work was supported by the ERC (NHE, FCC 266804), the
EPSRC (RC) and CISbio Bioassays (MD).
16 In some samples, loss of enantiopurity was observed
leading to formation of the enantiomers in a ratio of
between 2 : 1 to 9 : 1. This was confirmed by comparison of
the sign of the CPL spectra of the separated species. Race-
misation arose during the first step of the ligand synthesis,
during reaction of ethylenediamine with the amino acid
alkyl ester at 120 °C. The use of the chiral solvating agent
R-O-acetyl mandelic acid allowed NMR analysis of the enan-
tiomeric purity of the product. See ESI† for further details.
Racemisation can be avoided by running the reaction at
lower temperature.
Notes and references
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17 In comparison, the half-life of racemisation for [YbL8] was
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.
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Dalton Trans.