Structural and NMR investigations of the ternary adducts of twenty α-amino acids and selected dipeptides with a chiral, diaqua-ytterbium complex

Article abstract of DOI:10.1039/b311791j

A detailed investigation of the nature of the binding of each of the 20 common α-amino acids and various selected dipeptides to a chiral, diaqua-ytterbium complex in aqueous solution has been carried out. Analysis of the dipolar ¹ NMR paramagnetic shifts suggests that the α-amino acids form a common chelated structure within a nine-coordinate mono-capped square antiprismatic coordination environment, with the amine N axially disposed. Crystal structures of nine chelated YbL¹-amino acid adducts (Gly, Ala, Ser, Thr, Met) confirm this. The ternary complexes with dipeptides (e.g. Gly-Ala, Gly-Ser, Gly-Met, Gly-Asp, Gly-Asn, Gly-His, Ser-Met, Asp-Phe, His-Gly) also favour the terminal amine as the axial donor with the proximate amide group binding to generate a five-ring chelate. Evidence for chelation through side-chain functionality was found only in the case of N-terminal Asp. The chiral environment about the ytterbium ion upon amino acid binding has also been probed using near-IR circular dichroism spectroscopy.

Full text of DOI:10.1039/b311791j

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Structural and NMR investigations of the ternary adducts of
twenty ꢀ-amino acids and selected dipeptides with a chiral,
diaqua–ytterbium complex
a
a
a
a
Rachel S. Dickins,* Andrei S. Batsanov, Judith A. K. Howard, David Parker,
a
a,b
Horst Puschmann and Stefania Salamano
Department of Chemistry, University of Durham, South Road, Durham, UK DH1 3LE.
a
E-mail: r.s.dickins@durhan.ac.uk
b
Dipartmento di Chimica IFM, Via P. Giuria, Universita degli Studi di Torino, 10125 Torino,
Italy
Received 24th September 2003, Accepted 31st October 2003
First published as an Advance Article on the web 27th November 2003
A detailed investigation of the nature of the binding of each of the 20 common α-amino acids and various selected
dipeptides to a chiral, diaqua–ytterbium complex in aqueous solution has been carried out. Analysis of the
1
dipolar H NMR paramagnetic shifts suggests that the α-amino acids form a common chelated structure within a
nine-coordinate mono-capped square antiprismatic coordination environment, with the amine N axially disposed.
1
Crystal structures of nine chelated YbL –amino acid adducts (Gly, Ala, Ser, Thr, Met) confirm this. The ternary
complexes with dipeptides (e.g. Gly-Ala, Gly-Ser, Gly-Met, Gly-Asp, Gly-Asn, Gly-His, Ser-Met, Asp-Phe, His-Gly)
also favour the terminal amine as the axial donor with the proximate amide group binding to generate a five-ring
chelate. Evidence for chelation through side-chain functionality was found only in the case of N-terminal Asp.
The chiral environment about the ytterbium ion upon amino acid binding has also been probed using near-IR
circular dichroism spectroscopy.
Introduction
or two labile water molecules from well-defined, chiral lan-
13,14
thanide complexes.
Following crystallographic studies and
Amino acids are the fundamental building blocks of a number
of important biomolecules such as peptides, proteins and
molecular messengers. Recognition of the common amino
analyses of the dipolar NMR paramagnetic shifts (Yb, Eu), we
have recently reported that glycine and serine bind to such lan-
thanide complexes at physiological pH and favour a chelated
structure in which the amine nitrogen is axially disposed and
1
acids is therefore an important target for supramolecular
chemists and many abiotic receptors and carriers have been
one carboxylate oxygen occupies the remaining equatorial
2,3
reported. Such recognition systems have relied heavily on the
zwitterionic nature and side-chain functionality of the amino
acids and have either incorporated multiple binding sites to
14,15
site.
Herein, we report extended investigations of the revers-
ible binding of each of the common α-amino acids with a
1 3ϩ
cationic, heptadentate Yb complex, [YbL ] , in aqueous solu-
3
accommodate a variety of host–guest interactions or have
relied upon interaction with either the charged ammonium or
carboxylate moieties of the amino acid.
tion. The cationic nature of the complex and the high charge
density of the Yb ion compared to the earlier lanthanides serve
to enhance the affinity towards amino acid binding. The amino
acid ternary complexes have been structurally characterised
through crystallographic and solution NMR studies. The large
induced paramagnetic shifts observed, which, for Yb are prim-
arily due to a dipolar contribution and are determined to a
4
Despite the vast current interest in biological aspects of
lanthanide coordination chemistry, relatively few investigations
have been carried out with the simple amino acids. Lan-
thanide() ions are hard acceptors which prefer to bind to hard
σ-donors in solution and therefore coordinate strongly with the
unprotonated carboxylate oxygen of amino acids. Their cap-
ability to coordinate to the unprotonated amine group in aque-
ous solution has been the subject of controversy notwithstand-
15
considerable extent by the polarisability of the axial donor,
5,6
1
allow for relative ease of interpretation of the H NMR spectra.
The binding of the amino acids has also been signalled using
2
2
near-IR circular dichroism: the F – F optical transition of
3ϩ
7/2
5/2
ing the numerous examples that have been reported of N–Ln
16
Yb is the most CD-sensitive of all the lanthanides. Finally, we
coordination with polydentate chelates containing oxygen
donors. The underlying problem stems from the small stability
constants of the complexes studied and as the pH is raised to
allow amine chelation, lanthanide hydrolysis becomes an over-
have studied the binding mode of some selected peptides with
1 3ϩ
[
YbL ] . As with the simple amino acids, previous studies have
suggested that peptides and proteins primarily bind to various
5,6
riding factor. Hence, lanthanide complexation at ambient pH
with amino acids is generally regarded as occurring between the
lanthanide ion and the zwitterionic form of the amino acid with
7
the amine group unbound. Indeed, crystallographic analyses
of Ln–amino acid complexes in near neutral (physiological)
solution reveal primarily the formation of oligomeric, carb-
oxylate or hydroxy bridged complexes, with the amine remain-
8
ing uncoordinated. However, a limited number of reports have
revealed the formation of oligomeric Ln clusters involving
9
N-chelation and lanthanide binding to side-chain function-
10
11
12
ality such as hydroxyl, carboxylate and amine groups have
also been suggested by NMR studies with Ln complexes of low
charge demand.
We have been involved in studying the selective recognition
of bioactive anions in aqueous solution by displacement of one
7
0
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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lanthanide complexes of moderate charge demand through the
C-terminal carboxylate or the side-chain acidic (e.g. Glu, Asp)
17
and basic groups (e.g. His).
Crystallographic studies
1
a 3ϩ
1b 3ϩ
The diaqua complexes (RRR)-[YbL ] and (SSS)-[YbL ]
were isolated as their trifluoromethanesulfonate salts following
13b
previously reported procedures.
Crystals of the solvated
complex, (RRR)-[YbL (H O) ] , suitable for X-ray analysis
1a
3ϩ
2
2
were isolated by slow evaporation from 5% methanol–water
solution. In the presence of >20 equivalents of amino acid,
several ternary amino-acid complexes were also isolated from
5
% methanol–water or aqueous solution. Crystallographic data
relating to the coordination environment of the Yb ion are
given in Table 1.
Invariably, the Yb() ion is in a nine-coordinate polyhedron
of a monocapped square antiprism, in which one base com-
prises four N atoms of the macrocycle and the other base con-
tains three O atoms of the pendent arms. The amino acid anion
completes the latter base by one of the carboxy O atoms and
simultaneously caps this base by the N atom. Remarkably,
different amino acids can be accommodated within a broadly
similar (pseudo-isomorphous) crystal structure. Thus, (RRR)-
1a 2ϩ
1a 2ϩ
[
(S)-Ala–YbL ] (3) and (RRR)-[(S)-Thr–YbL ] (4) (Fig. 1)
are pseudo-isomorphous with the previously reported (RRR)-
1
a 2ϩ
1a 2ϩ
[
Gly–YbL ] (2) and (RRR)-[(S)-Ser–YbL ] (7) derivatives
14
of Yb, as well as (S)-lactato-O,O derivatives of Yb (8) and
Ho (9). Each crystallises in the space group P1, the unit cell
= asymmetric unit) containing one cation, two triflate anions,
13a
(
two water and one methanol molecules of crystallisation, each
linked through a three-dimensional network of hydrogen
bonds. Interestingly, the coordinated amino or hydroxyl (in lac-
tate) groups do not participate in hydrogen bonding. Further-
1a 3ϩ
more, the diaqua (RRR)-[YbL ] complex without amino acid
also gave pseudo-isomorphous product (Fig. 2). In fact, crystal-
lisation from aqueous methanol gave crystals of similar oblique
habits (peculiar also for the amino-acid complexes of (RRR)-
1a 3ϩ
[
YbL ] with (S)-Ala (3), (S)-Thr (4), Gly (6) and (S)-Ser (7))
with either sharp (1) or blunted (1Ј) edges. Small but significant
differences of unit cell parameters of 1 and 1Ј encouraged us to
carry out full X-ray studies of each. It appeared that in 1 both
additional sites (in the O base and capping it) are occupied by
4
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0
71

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aqua ligands, the third triflate anion occupies roughly the site of
the methanol molecule in 3, 4, 6–9, and the additional water
molecule of crystallisation – that of the amino-acid substituent
including 6 which contains the same cation. Unlike the latter, 2
contains a non-stoichiometric amount of partially disordered
crystallisation water (estimated as 3.8 molecules per complex
cation) and no methanol.
(
or lactato methyl). In 1Ј the apical (capping) site is shared
between aqua and methanol ligands, probably in a 1 : 1 ratio,
judging by the electron density and by the difference (ca. 9 Å )
between unit cell volumes of 1 and 1Ј. The methyl group is
disordered between two positions, differing by a rotation
around the Yb–O bond.
In each of the complexes discussed so far, the three pendent
side chains adopt equatorial orientations, resembling the
3
2
conformations of the tetra-amide complexes (RRRR)-[LnL -
18–20
1
2
(H O)](CF SO ) .
In each of the L and L complexes
2
3
3 3
discussed so far, an R configuration of the ligand stereogenic
2
On the other hand, the crystal structure of (RRR)-[Gly–
carbon centres C(12), C(22), C(32) and (in L ) C(42) results in
1a 2ϩ
21
YbL ] (2) is entirely different from those mentioned above,
a Λ-(δδδδ) conformation.
A different conformation, however, is adopted by methionine
complexes 5, where the three pendent phenyl groups are dir-
ected axially, encapsulating the methionine side-chain between
them, which extends in the same (axial) direction (Figs. 3 and 4).
Probably because of this, the absolute configuration of the
methionine does not affect the crystal packing. Hence, com-
1a 2ϩ
plexes (RRR)-[(S)-Met–YbL ] (5a) and (RRR)-[(R)-Met–
1
a 2ϩ
1a
YbL ] (5b) containing the same (RRR)-YbL ligand but
enantiomeric methionines, are isomorphous and have the same
absolute structure (chirality of the crystal packing), while the
1b
two (SSS)-YbL complexes (5c and 5d) are also isomorphous
and their crystal packings are enantiomeric to the former. This
was confirmed by full structure determination of 5c and the
unit cell determination of 5d. Note that here the ligand system
adopts conformations of opposite chirality, compared to 1–4
1a
and 6–9, namely ∆-(λλλλ) for (RRR)-YbL and Λ-(δδδδ) for
SSS)-YbL .
1b
(
The asymmetric unit in each isomer of 5 contains one cation,
1a 2ϩ
Fig. 1 Cation (RRR)-[(S)-Thr-YbL ] in the structure of 4, viewed
down the axial Yb–N(5) bond. Hydrogen atoms bonded to carbon are
omitted for clarity. The same atom numbering scheme is used for other
complexes.
two triflate anions (one of them disordered) and 1.5 molecules
of crystallisation water, disordered between three partially
occupied positions. In 5a, the methionine sulfur atom is also
disordered. As in other amino-acid complexes, the amino
groups in 5 form no hydrogen bonds, being masked by the side-
1
chains of L .
1
a 2ϩ
The structure of (RRR)-[(R)-Ala–YbL ] (10) is entirely
1a 2ϩ
different from that of (RRR)-[(S)-Ala–YbL ] (3) (Fig. 5). It
contains two independent cations with significantly different
conformations of the alanine moiety, and six crystallo-
graphically non-equivalent triflate anions. Two anions occupy
general positions and one of them is disordered. The other four
lie on twofold axes and display different modes of disorder (see
ESI). The asymmetric unit also contains three water molecules
ordered, one disordered (equally between two positions), and
one having a 50% site occupancy, the disorder being correlated
with that of triflate anions.
The cations of 10, like those of 5 but unlike 3, have axial
orientations of the amide pendent groups, and ∆-(λλλλ) con-
formations for the (RRR)-YbL.
1
a
3ϩ
1a
Fig. 2 Cation (RRR)-[YbL (H O) ] in the crystal structure of 1.
2
2
1
a
2ϩ
1a 2ϩ
Fig. 3 (a) Cations (RRR)-[(S)-Met–YbL ] (left, showing the disorder of the methionine S atom) and (RRR)-[(R)-Met–YbL ] (right) in the
1
b 2ϩ
structures of 5a and 5b, respectively. (b) Space-filling representation of the (SSS)-[(S)-Met–YbL ] cation of 5c. The methionine side chain is
enclosed in a tight hydrophobic pocket formed by the axial arrangement of the pendent arms.
7
2
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0

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1
a
2ϩ
1b 2ϩ
Fig. 4 Cations (RRR)-[(R)-Met–YbL ] (left) and (SSS)-[(S)-Met–YbL ] (right) in the structures of 5b and 5c.
1
a
2ϩ
1a 2ϩ
Fig. 5 Cations (RRR)-[(S)-Ala–YbL ] (left) and (RRR)-[(R)-Ala–YbL ] (right) in the structures of 3 and 10, respectively. Note the equatorial
and axial conformations of the pendent side chains, respectively, and the opposite chirality of the macrocyclic ring and pendent arm configuration.
1
Solution NMR studies
Table 2 Effect of the axial donor on the H NMR spectral range
1a 3ϩ
observed for [YbL ] in D O (295 K, 200 MHz)
2
1
1a
The H NMR spectrum of (RRR)-[YbL (D O) ](CF SO )
2
2
3
3
3
a
(
10 mmol, D O, pD 7, 200 MHz, 295 K) revealed the presence
Anion
Axial donor
Shift range/ppm
Mean shift Hax
2
of a single major species in solution (Fig. 6). The eight distinct
resonances to high frequency (ϩ112 to ϩ23 ppm) were attri-
buted to the four most shifted axial and equatorial ring protons,
assigned through a H– H COSY experiment, and the assign-
ment of the ring NH was established at Ϫ83 ppm by deuterium
Phosphate
Water
H O
ϩ124 to Ϫ98
ϩ110 to Ϫ82
ϩ96 to Ϫ74
ϩ96 to Ϫ100
ϩ98 to Ϫ108
ϩ57 to Ϫ55
ϩ55 to Ϫ41
ϩ45 to Ϫ40
100
75
71
68
73
39
37
27
2
H O
2
1
1
Lactate
Acetate
Succinate
ROH
δϪ
CO
b
δϪ
CO
exchange. However, variable temperature (295–193 K, CD OD)
Ϫ
Ϫ
Ϫ
3
Malonate
Oxalate
Carbonate
CO
CO
CO
NMR revealed the presence of a minor isomer in solution
which was first observed at 253 K (ratio ∼6 : 1) and became
more apparent as the temperature was reduced further (193 K,
ratio ∼2 : 1).
a
Mean chemical shift (ppm) of the four most-shifted axial protons of
b 1
the 12-N ring; additional data is taken from refs. 14 and 15. H NMR
4
The isomerism exhibited by such chiral lanthanide complexes
titration and ESMS analysis give no evidence for a succinate bridged
2 : 1 complex.
21
is well documented and understood. They display two
independent elements of chirality: the pendent arms can be
rotated clockwise (∆) or anticlockwise (Λ) (NCCO torsion
angle positive = ∆; negative = Λ) and the ring can adopt two
conformations (NCCN torsion angle positive = δδδδ; negative
renders each of the isomers diastereomeric. Square anti-
prismatic (SAP) isomers of such Yb complexes with amide
donors usually display a spectral width of around ϩ120 to
=
λλλλ), giving rise to four possible isomers as depicted in
Ϫ80 ppm (in D O) whereas the twisted square-antiprismatic
2
Chart 1. The remote chiral centre at the amide functionality
(
TSAP) isomer has a much reduced spectral width ranging from
15,22
around ϩ60 to Ϫ40 ppm.
The resonances of the two
1a 3ϩ
isomers of (RRR)-[YbL ] observed through the VT experi-
ments were typical of the SAP structures consistent with the
formation of Λδδδδ and ∆λλλλ diastereoisomers.
We have recently reported the effect of adding two amino
1
3ϩ
acids (Ser, Gly) and a range of oxy-anions to [YbL ] and
1
ascertained that the observed H NMR chemical shifts are
critically dependent on the nature of the donor atom located in
15
the axial position. Hard, uncharged donors such as water give
rise to the largest shifts (Table 2) whereas more polarisable
donors (e.g. carbonate, serine) give much smaller shifts. Indeed,
1
1a
Fig. 6 Partial H NMR spectrum of diaqua-(RRR)-[YbL ] (D O, 295
2
it was shown that it is the polarisability of the axial donor that
K, pD 7), showing the four axial ring protons in the range ϩ48 to ϩ110
2
o
ppm.
ranks the second order crystal field coefficient B
and hence
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0
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1
1a 3ϩ
Table 3 H NMR data for (RRR)-[YbL ] in the presence of α-amino acids (200 MHz, 295 K, pD 7.4 ± 0.4, >20 fold excess of amino acid)
a
No. of species
Most shifted Hax
(major isomer)/ppm
Most shifted Hax
(minor isomer)/ppm
b
α-Amino acid
(ratio major : minor)
Shift range /ppm
Gly
Ala
Val
Leu
Ile
2 (2 : 1)
2 (3 : 1)
2 (5 : 1)
2 (4 : 1)
2 (3 : 1)
1
ϩ68 to Ϫ56
ϩ64 to Ϫ55
ϩ67 to Ϫ59
ϩ67 to Ϫ60
ϩ67 to Ϫ58
ϩ62 to Ϫ50
ϩ65 to Ϫ50
ϩ68 to Ϫ53
ϩ70 to Ϫ60
ϩ60 to Ϫ36
ϩ70 to Ϫ52
ϩ65 to Ϫ59
ϩ71 to Ϫ59
ϩ68 to Ϫ58
ϩ79 to Ϫ56
ϩ74 to Ϫ52
ϩ68 to Ϫ53
ϩ84 to Ϫ66
ϩ60 to Ϫ38
ϩ55 to Ϫ45
64
63
64
66
64
62
65
64
64
60
65
62
67
64
62
61
58
84
60
55
68
64
67
67
67
–
c
Ser
Thr
Cys
Met
Asp
Glu
Asn
Gln
Lys
Arg
Phe
Tyr
Pro
His
Trp
1
–
2 (6 : 1)
2 (2 : 1)
1
68
70
–
2 (6 : 1)
2 (9 : 1)
2 (5 : 1)
2 (2 : 1)
2 (2 : 1)
2 (4 : 1)
2 (7 : 1)
2 (10 : 1)
1
70
65
71
68
79
74
68
–
–
–
1
a
b
One species denotes >19 : 1 ratio. Signals from excess free amino acid occurred in the 0–10 ppm range and are in slow exchange with those of the
c
bound adduct. Addition of just 1 equivalent of amino acid gave rise to an identical spectrum for the bound ternary adduct to that following the
addition of 20 equivalents of amino acid. An excess of amino acid was generally used to ensure formation of the fully-bound ternary adduct.
1a 3ϩ
Chart 1 Possible constitutional isomers and stereoisomerism associated with (RRR)-[YbL ] ternary amino acid complexes.
1
4,15
determines the magnitude of the observed dipolar shift.
Furthermore, whilst this was first demonstrated for C -
the C-terminal carboxylate oxygens then a shift range similar to
that of acetate would be expected (ϩ96 to Ϫ100 ppm, Table 2).
The observed chemical shift range also rules out any chelation
possible through side-chain functionality such as in Ser or Thr
(cf. lactate in Table 2) or the acidic amino acids Asp and Glu
(cf. succinate in Table 2). Proline, however, exhibits a larger
chemical shift range (ϩ88 to Ϫ66 ppm) consistent with binding
4
15
symmetric complexes, the validity of the approach has been
shown to apply to related complexes formally lacking a C axis
such as those described herein. Such an assumption has
13
n
14
–
often been used in related analyses of dipolar NMR shifts.
A
thorough investigation of the nature of the ternary complexes
formed upon binding of each of the common amino acids and
selected peptides to (RRR)-[YbL ] in solution was therefore
23
through a secondary amine.
1a 3ϩ
For 15 of the amino acid complexes there are two species
present in solution in varying ratio (Table 3 and Fig. 7(a)). As
depicted in Chart 1, there are eight diastereoisomers possible
in solution upon amino acid chelation; not only the four
1
undertaken using H NMR.
1
The H NMR spectra were recorded in D O (or 10% MeOD,
2
1
a
D O) at pD 7.5 (±0.4) (200 MHz, 295 K) for (RRR)-[YbL ] in
2
the presence of an excess of (S)-amino acid (>20 equivalents to
ensure formation of the fully-bound ternary adduct). At pD<6
the amino acids did not bind strongly and only an exchange
broadened spectrum corresponding to the diaqua complex was
observed. [At pD>10 carbonate binding may become competi-
tive]. Representative NMR data for each of the (S)-amino
diastereomers associated with the 12-N ring conformation and
4
the helicity of arm rotation, but also constitutional isomerism
associated with the amino acid mode of chelation. The NO
chelate may adopt two possible modes of binding, with the
amine axially disposed and the carboxylate in the equatorial
position or vice versa (Chart 2). The predicted chemical shifts of
the two isomers could be similar. It has been reported that
groups on the chelating anion that lie within the ‘McConnell
1a
acids with (RRR)-[YbL ](CF SO ) is collated in Table 3. The
3
3 3
observed chemical shift range (av. ϩ68 to Ϫ56 ppm) is similar
for each amino acid and is consistent with a common binding
mode. This was hypothesised to involve chelation with the more
polarisable amine nitrogen and one of the carboxylate oxygens
binding to form a favourable five-membered chelate ring. If
binding were to occur through bidentate chelation of each of
2
Ϫ3
cone’ ((3cos θ Ϫ 1)r dependence) will also exhibit a large
13a
paramagnetic shift. If the two observed isomers are associ-
ated with the two possible modes of binding of the amino acid
then a large paramagnetic shift of the resonance for the amino
acid CH at the chiral centre (and possibly side chain) would
7
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the Yb complex where they may undergo stabilizing H-bond
interactions with solvent or counter ions. Indeed, comparison
with the structures observed in the solid state, in which both Ser
and Thr complexes adopt a more open structure with the
phenyl groups orientated away from the amino acids, reveals
that the side-chain OH can undergo H-bonding interactions
with a proximate triflate counter ion.
The remaining amino acids exist as two isomers in solution.
1a 3ϩ
In each case for (RRR)-[YbL ] in the presence of (S)-amino
acid, the resonance of the most shifted Hax for the major isomer
occurs to slightly lower frequency of the minor isomer and is
consistent with data observed for the amino acids with one
isomer alone. Presumably, the major isomer adopts a more
open conformation with the phenyl rings equatorially orien-
tated, away from the principal axis and may tentatively be
assigned as the Λδδδδ isomer, by comparison with the observ-
ations in the solid state structures. The minor isomer is likely to
be the ∆λλλλ isomer, in which the phenyl groups prefer to align
axially alongside the amino acid side chain creating a cavity for
potential hydrophobic interactions, as revealed in the crystal
structure of methionine (Figs. 3 and 4). The ∆λλλλ isomer
becomes more prevalent for complexes of the amino acids with
less sterically demanding side-chain groups. For example, com-
paring Gly and Val the ratio changes from 2 : 1 to 5 : 1 respect-
ively. Similarly, the longer alkyl chain of Met compared to Cys
allows the large sulfur atom to extend out of the phenyl cavity,
reducing any unfavourable steric interactions. This effect is
exemplified in the change in the ratio of isomers; 6 : 1 for Cys
and 2 : 1 for Met. The amide group on Asn (ratio = 9 : 1) can
only undergo H-bonding in the open form. Hence, mainly one
isomer is observed, whereas the longer chain of Gln (ratio =
1
1a 3ϩ
Fig. 7 Partial H NMR spectrum of (RRR)-[YbL ] (D O, 295 K,
2
pD 7.5 ± 0.4) in the presence of (a) Gly, (b) (S)-Asp, (c) (R)-Asp, (d)
S)-Ser-(S)-Met peptide.
(
5
: 1) allows the amide group to extend out of the phenyl-lined
cavity allowing stabilizing H-bond interactions with either
isomer.
Solution NMR studies of selected peptides
1
1a
Further H NMR studies with (RRR)-[YbL ](CF SO ) (10
3
3 3
mmol, D O, pD 7.5 ± 0.4) in the presence of an excess of
2
selected di- or tri-peptides of varying steric demand and charge
(
>20 equivalents) were undertaken and representative data are
1
3ϩ
Chart 2 Possible modes of amino acid chelation to [YbL ] depicting
collated in Table 4. There are several possible modes of binding
to consider for the peptides, which are depicted in Chart 3. Con-
trol experiments were performed in parallel to rule out various
alternative binding modes (Table 4). In each of the dipeptide
ternary complexes of (RRR)-[YbL ], the chemical shift range
is similar, on average varying between ϩ73 and Ϫ50 ppm
arrangement of atoms within the McConnell cone.
only be observed when the amine is axial, as the substituents
would lie well within the ‘McConnell cone’ (Chart 2). On close
inspection of the spectra, two resonances corresponding to the
amino acid CH and two resonances corresponding to the
amino acid side chain, where appropriate, were apparent at a
higher, shifted frequency. Hence, the binding mode of the
amino acid in both isomers is identical, with the amine axially
disposed and the carboxylate occupying the equatorial pos-
ition. The two observed isomers are therefore stereoisomers and
not constitutional isomers. The nature and the similarity of the
observed chemical shifts suggests the isomers are both of the
SAP forms, S -N -RRR-Λδδδδ and S -Naxial-RRR-∆λλλλ
1a
(
Fig. 7(d)). This immediately rules out bidentate chelation of
the C-terminal carboxylate group (11) by comparison to the
observed shift for acetate (ϩ100 to Ϫ100 ppm) and by com-
parison to succinate (ϩ100 to Ϫ110 ppm). Succinate appears to
aa
axial
aa
(
A and G, respectively, in Chart 1). This is also consistent with
the X-ray crystallographic studies discussed above. The amino
acid amine was found to be axially disposed in every case and
examples of both the Λδδδδ and ∆λλλλ isomers were defined
with different amino acids.
The five amino acids, Ser, Thr, Asp, His and Trp exhibit only
one isomer in solution (Fig. 7(b)) and Pro and Asn also give rise
to mainly one (ratio 9 : 1). His, Trp and Pro each possess a
relatively sterically demanding side chain. Each may preferen-
tially bind to Yb in a more open structure of the complex, in
which the bulky phenyl rings are orientated away from the
principal axis, reducing any potential steric interactions. Ser,
Thr, Asp and Asn contain H-bond acceptors/donors close to
(
<3 bonds) the chiral carbon of the amino acid. Similarly, these
1 3ϩ
Chart 3 Possible modes of binding of peptides to [YbL ] ; the
preferred mode is amine–amide (15).
four amino acids may also prefer to bind to a more open face of
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0
75

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1
1a 3ϩ
Table 4 H NMR data for (RRR)-[YbL ] in the presence of selected peptides (200 MHz, 295 K, pD 7.4 ± 0.4, 20 fold excess of anion, amino acid
or peptide)
a
No. of species
Four most shifted Hax
resonances of major isomer/ppm
Mean value for Hax
of major isomer/ppm
b
Anion
(ratio major : minor)
Shift range /ppm
Acetate
Succinate
Glycine
N-Acetyl-(S)-ala
N-Acetyl-gly
N-Acetylglycinamide
1
1
ϩ100 to Ϫ100
ϩ98 to Ϫ108
ϩ68 to Ϫ56
ϩ63 to Ϫ54
ϩ64 to Ϫ52
ϩ88 to Ϫ60
ϩ67 to Ϫ67
ϩ65 to Ϫ59
ϩ68 to Ϫ58
ϩ68 to Ϫ50
ϩ68 to Ϫ60
ϩ68 to Ϫ60
ϩ68 to Ϫ64
ϩ69 to Ϫ63
ϩ68 to Ϫ61
ϩ61 to Ϫ61
ϩ61 to Ϫ52
ϩ64 to Ϫ64
ϩ73 to Ϫ64
ϩ77 to Ϫ77
ϩ61 to Ϫ60
ϩ72 to Ϫ60
100, 80, 58, 40
98, 88, 61, 35
64, 38, 37, 32
62, 45, 36, 33
64, 45, 28, 26
69.5
70.5
42.8
44.0
40.8
2 (2 : 1)
2 (3 : 1)
1
c
1
(
S)-Alaninamide
2 (3 : 1)
1
62, 59, 46, 30
65, 56, 48, 32
64, 54, 50, 33
66, 58, 51, 35
66, 58, 52, 34
65, 56, 51, 34
68, 60, 54, 34
67, 58, 52, 34
68, 59, 51, 34
61, 59, 44, 30
61, 52, 48, 26
58, 57, 44, 28
64, 60, 51, 28
62, 55, 52, 31
61, 54, 54, 30
70, 56, 53, 39
49.2
50.2
50.2
52.5
52.5
51.5
54.0
52.8
53.0
48.5
46.7
46.7
50.7
50.0
49.8
54.5
Gly-Ala
Gly-Leu
Gly-Ser
2 (2 : 1)
2 (3 : 1)
2 (1 : 1.2)
2 (2 : 1)
2 (2 : 1)
2 (2 : 1)
2 (3 : 1)
1
Gly-(R)-Thr
Gly-Met
Gly-Asp
Gly-Asn
Gly-His
Ala-Ala
Ser-Met
Met-Leu
Met-Met
1
2 (2 : 1)
2 (6 : 1)
3 (9 : 5 : 1)
1
d
Asp-Phe
His-Gly
Gly-Gly-Ala
2 (2 : 1)
a
b
One species denotes >19 : 1 ratio. Signals from excess free peptide occurred in the 0–10 ppm range and are in slow exchange with those of the
c
d
bound adduct. Only weak binding was observed and the spectrum resembled that of the exchange broadened di-aqua complex. An additional set
of resonances was apparent, indicating competitive chelation of the N-terminal side-chain carboxylate oxygen.
bind very similarly to acetate, suggesting that bidentate chel-
ation involving each oxygen of one of the terminal carboxylates
is favoured over formation of a seven-membered chelate
ring. Such observations rule out the carboxylate–carboxylate
chelation mode (12).
isomer by comparison of Hax shifts. N-terminal Ser peptides,
however, gave exclusively the Λδδδδ isomer, presumably
favoured by stabilizing H-bond interactions involving the side-
chain hydroxyl, which may only occur in the open form. Inter-
estingly, Asp-Phe gave rise to three isomers in a ratio 9 : 5 : 1,
the major and minor species corresponding to the expected
amino–amide chelation and the additional isomer indicative of
competitive chelation of the carboxylate side-chain functional-
ity. Such side-chain participation only appears to be present for
N-terminal Asp peptides, which are able to form an additional
six-membered chelate ring using a favourable, hard carboxylate
oxygen donor atom. Side-chain participation with N-terminal
Glu peptides is not expected. Formation of such a seven-
membered chelate ring was not observed with succinate or
indeed in the possible binding modes for dipeptides depicted in
Chart 3. Similarly, no evidence for side-chain chelation was
apparent for Gly-Asp, Gly-Asn, Gly-Ser, Gly-Thr, Ser-Met or
His-Gly.
The relative shift positions of the four most shifted axial pro-
tons (H ) is indicative of the mode of binding. In each of the
ax
1a 3ϩ
spectra for the (RRR)-[YbL ] -dipeptide complex, as exam-
ined, there are three axial protons above ϩ44 ppm and one
below ϩ35 ppm (Table 4). Comparing the Hax resonances for
the simple amino acids (amide-acid bound), one Hax comes
above ϩ55 ppm and three Hax come below ϩ40 ppm in every
case. Considering this difference in relative Hax frequencies and
the requirement for a seven-membered chelate ring to be
formed for amino–carboxylate binding (13), it is highly unlikely
to be the mode of binding for the dipeptides. Similarly, chel-
ation through amide–carboxylate (14) can also be ruled out: in
the control experiments amide–carboxylate chelation (N-Ac-
Ala and N-Ac-Gly) resulted in a distinctive and different shift
pattern with two Hax resonances above ϩ45 ppm and two below
ϩ36 ppm. It appears that the binding of each dipeptide occurs
via chelation involving the terminal amine and the proximate
amide group, giving rise to the formation of a five-membered
chelate (15). Comparison of the relative Hax shifts of each of
the dipeptide chelates screened to those of a control, (S)-alanin-
amide, revealed an identical shift pattern, with three Hax above
ϩ44 ppm and one below ϩ35 ppm (Table 4). Tripeptides also
bind in an identical manner (e.g. Gly-Gly-Ala) and no evidence
Enantioselectivity
Binding to each of the unnatural (R)-amino acids (R ) to
aa
1a 3ϩ
1
(RRR)-[YbL ] has also been examined by H NMR. The
ternary complexes formed behave similarly to those of
(S)-amino acids (S ); two isomers were observed with NMR
aa
shifts consistent with bidentate chelation. However, the most
shifted Hax for the major isomer now resonates at a higher
frequency than that for the minor (Fig. 7(c)). This apparent
reversal in chemical shift is not surprising since the complexes
24
for an amide–amide binding mode was apparent (16).
1
3ϩ
1a 3ϩ
1a 3ϩ
As with the simple amino acids the [YbL ] –peptide ternary
complexes may exist as two isomers in solution, one favouring
a more open structure and one a closed structure (Fig. 5) as
discussed above. The chelating N-terminal amino acid must
determine the relative ratio of the isomers observed as sub-
sequent amino acids in the peptide chain will extend outwards
S -(RRR)-[YbL ] and R -(RRR)-[YbL ] are after all,
a
a
a
a
diastereomeric. The magnitude of the shift difference between
diastereomers (∆∆δ values) observed for the H ring protons
ax
1a 3ϩ
1a 3ϩ
for R -(RRR)-[YbL ] and S -(RRR)-[YbL ] is of the
aa
aa
order of 3–5 ppm. This is an improvement over spectral
resolution observed using reported aqueous lanthanide shift
1
3ϩ
21
away from any interaction with [YbL ] . Indeed several
reagents which are generally of the order of 0.1 ppm. Such
1a 3ϩ
(
RRR)-[YbL ] -peptide ternary complexes were examined
well-defined Yb complexes were therefore considered as
25
with glycine as the N-terminal amino acid and in each case both
the Λδδδδ and ∆λλλλ isomers were observed in a ratio of
around 2 : 1. More sterically demanding N-terminal Ala, Met
or His peptides gave rise to mainly the more open Λδδδδ,
aqueous NMR chiral derivatising agents.
Following the addition of an excess (>20 equivalents) of a
1a 3ϩ
racemic mixture of amino acid to (RRR)-[YbL ] preferential
binding of the S-amino acid was observed. The degree of
7
6
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0

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1
Table 5 Enantioselectivity, determined by H NMR (295 K, D O; pD
indicative of the axial ligation of 1Њ vs. 2Њ amine group, respect-
15
2
1a 3ϩ
7
.5 ± 0.4), exhibited by (RRR)-[YbL ] towards racemic α-amino
ively. On addition of amino acids a reduction and shift
∼5 nm) to shorter wavelength was observed for the band
acids (20 fold excess)
(
1
a
1a
centred around 994 nm. The reduction appeared more signifi-
cant with complexes of (S)-amino acids (Table 6), possibly
highlighting differences in complimentarity of the helicity of
the bound amino acid five-membered chelate ring compared to
the chiral environment of Yb. The band centred around 964 nm
shifted to slightly longer wavelength (∼5 nm) upon binding. The
relative intensity of the band only appeared to drop signifi-
cantly (∼60%) upon binding of those amino acids that give rise
to two isomers in solution. The two diastereomers present in
solution, RRR-Λδδδδ and RRR-∆λλλλ, are enantiomeric with
respect to macrocyclic ring and pendent arm layout. These
elements of chirality are located close to the Yb centre and will
have a large influence on the Yb CD and may give rise to a
cancellation of the observed circular dichroism to some
extent. The remote chiral centre on the amide arm of the
diastereoisomers is located far away from the Yb centre and
therefore is not expected to contribute significantly to the Yb
CD. Therefore, it appears that the intensity of the CD band at
Amino acid
S -(RRR)-YbL : R -(RRR)-YbL
aa
aa
Ala
Ser
Thr
Asp
Asn
His
1 : 1
4 : 1
4 : 1
2 : 1
3 : 1
2 : 1
enantioselectivity is dependent upon the nature of the amino
acid side chain (Table 5). No enantioselectivity in complex
formation was observed with Ala, but for Asp, His (2 : 1) and
Ser, Thr (4 : 1) preferential complexation of the S-amino acid
was observed. Such observations preclude the use of (RRR)-
YbL ] as a broad spectrum chiral derivatising agent for
direct NMR analysis of the enantiomeric purity of simple
amino-acids. However, the precise chemical shift of the shifted
amino acid adduct allows the absolute configuration of the
substrate to be assigned unequivocally.
la 3ϩ
[
9
64 nm could tentatively be associated with the relative propor-
tions of the two isomers in solution. Ternary complexes with a
large proportion of the minor isomer may be expected to
exhibit a reduced CD band at 964 nm due to partial cancelling
out of the CD arising from the RRR-Λδδδδ isomer by the
RRR-∆λλλλ, isomer.
Circular dichroism
The local coordination environment around the Yb centre may
also be probed through near-IR CD. Yb exhibits sensitive CD
bands centred around 980 nm associated with the magnetic-
2
2
26
dipole allowed F7/2 F5/2 transitions. However, spectral
analysis is not straightforward owing to the large number of
sub-levels present. Furthermore, the chirality exhibited by the
Conclusions
Diaqua complexes of [YbL ]
1 3ϩ
form well-defined ternary
1
3ϩ
ternary-[YbL ] complexes (pendent arm, macrocyclic ring,
remote chiral centre and amino acid chiral centre) provides an
added complication in relating the observed CD to specific
structural characteristics of the complexes.
adducts with the α-amino acids in aqueous solution at ambient
pH. The α-amino acids bind in a bidentate manner displacing
both of the water molecules with the amine nitrogen axially
disposed and the carboxylate oxygen occupying the remaining
equatorial position. Peptides behave in an analogous manner,
with formation of a five-ring chelate involving the terminal
amine N (axial) and the proximate amide oxygen (equatorial).
Competitive chelation through amino acid side-chain function-
ality (Glu, Asp, Asn, His) is only apparent for N-terminal Asp
peptides and not observed for the simple amino acids or other
peptides studied in this system. Thus, the simple cationic Yb
complex may be considered as an NMR probe for the N-ter-
minus of peptides, affording opportunities to explore more
complex systems in which the N-terminus is accessible.
1
a 3ϩ
Near-IR CD spectra of (RRR)-[YbL ] (10 mmol in Hepes
buffer, pH 7.4) were recorded in the presence of an excess of
amino acid (>20 fold) (Fig. 8). The overall form of the spectra
obtained was very similar for each amino acid, apart from Pro,
The relative proportion of the ‘open’ Λ-(δδδδ) and the more
‘pocket like’ ∆-(λλλλ) diastereoisomeric complexes with
amino-acids is independent of amino-acid configuration, and is
a function of the nature of the α-substituent. Substituents
which may serve as a hydrogen bond donor/acceptor to solvent,
favour the more open structure (e.g. Ser, Asp, Asn) while those
substitutents that offer opportunities for hydrophobic inter-
actions or closer van der Waals contacts with the ligand tend to
1a 3ϩ
Fig. 8 Near-IR CD spectra of (RRR)-[YbL ] as diaqua, (S)-Ala
and (S)-Thr adducts (295 K, 10 mmol, Hepes, pH 7.4)
1a 3ϩ
Table 6 Variation of the intensity of the near-IR CD bands of (RRR)-[YbL ] at 960 and 990 nm upon chelation with α-amino acids (aa)
(
10 mmol Yb complex, 200 mmol amino acid in Hepes buffer, pH 7.4, 295 K)
1
a
3ϩ
1a
3ϩ
Imax[YbL (H O) ] /Imax
-
Imax[YbL (H O) ] /Imax-
2 2
1a 2ϩ
2
2
a
1a 2ϩ
α-Amino acid
Isomer(s)
Ratio
[aa–YbL ] (∼990 nm)
[aa–YbL ] (∼990 nm)
(R)-Ala
(S)-Ala
(R)-Ser
(S)-Ser
(R)-Thr
(S)-Thr
(S)-Met
(R)-His
(S)-His
Λδδδδ/∆λλλλ
Λδδδδ/∆λλλλ
Λδδδδ
Λδδδδ
Λδδδδ
Λδδδδ
Λδδδδ/∆λλλλ
Λδδδδ
Λδδδδ
2 : 1
3 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
2 : 1
0.54
0.51
0.80
1.05
0.97
1.05
0.56
0.86
0.86
0.60
0.55
0.71
0.60
0.78
0.67
0.55
0.59
0.54
>19 : 1
>19 : 1
a
1
This was assessed independently by H NMR analysis in D O and is expressed as the ratio of the Λδδδδ/∆λλλλ isomers.
2
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0
77

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stabilise the other diastereoisomeric complex. This is particu-
larly evident in the structures with methionine and alanine, and
is reminiscent of the enhancement of binding at an enzymic
active site when a hydrophobic binding pocket is occupied by an
27
apolar side chain.
Experimental
General procedures and characterization techniques
Reactions requiring anhydrous or inert conditions were carried
out using Schlenk-line techniques under an atmosphere of dry
argon. Anhydrous solvents when required were freshly distilled
over the appropriate drying agent. Water was purified by the
‘PuriteSTILLplus’ system.
Thin layer chromatography was carried out on neutral
alumina plates (Merck Art 5550) and detection was made by
irradiation at 254 nm or by staining with iodine.
Melting points were measured with a Köfler block and are
uncorrected. Infrared spectra were recorded on a Graseby-
Specac ‘Golden Gate’ Diamond ATR accessory spectro-
meter.
The NMR spectra were recorded using a Varian Mercury 200
1
13
1
operating at 199.975 and 50.3 MHz for H and C-{ H} at
2
1
95 K. H NMR spectra of the paramagnetic complexes were
referenced internally relative to tert-butyl alcohol (1 drop, δ 0)
H
or the residual protio-solvent resonances which are reported
relative to SiMe . Two-dimensional and variable-temperature
4
spectra were recorded on a Varian Mercury 200 and a Varian
VXR400 operating at 199.975 and 400 MHz, respectively for
1
1
H. H NMR spectra for the amino-acid and peptide bound
ternary complexes were obtained by adding an excess (>20
equiv.) of the solid α-amino acid or dipeptide to a solution of
the complex (10 mmol in D O). The pD was carefully adjusted
2
28
to 7.5 (±0.4) using sodium deuteroxide.
Electrospray mass spectra were recorded on a VG platform II
Fisons instruments) operating in positive or negative ion mode
(
as stated. Accurate mass spectra were recorded at the EPSRC
Mass Spectrometry Service at Swansea.
Near-IR CD spectra were recorded in four successive scans
using a Jasco J-810 spectropolarimeter at 295 K using a 1 cm
pathlength and slits of 160 µm. To the complex solution
(
10 mmol in Hepes buffer) was added an excess (>20 equiv.) of
the amino acid as a solid. Spectra were recorded immediately
and showed no change in form 24 h later.
Ligand and complex synthesis
(
RRR)-1,4,7-Tris[1-(1-phenyl)ethylcarbamoylmethyl]-1,4,7,
1a
1
0-tetraazacyclododecane, L . 2-Chloro-N-[(R)-methylbenzyl]-
ethanamide (2 g, 10.3 mmol) in ethanol (25 cm ) was added
portionwise, over 8 h, to a stirred solution of 1,4,7,10-tetraaza-
cyclododecane (0.58 g, 3.4 mmol) and triethylamine (1.4 cm ,
0.3 mmol) in ethanol (125 cm ) at 40 ЊC. The solution was
3
3
3
1
heated for a further 48 h at 80 ЊC. The solvent was removed
in vacuo and the resulting solid dissolved in dichloromethane
3
3
(
100 cm ) and washed quickly with purite water (2 × 75 cm ) to
remove any mono- or dialkylated side-product. The trialkylated
product was then extracted into the aqueous phase by exhaust-
3
ive washing with purite water (6 × 75 cm ) and the combined
aqueous fractions lyophilized to give a white solid (1.45 g,
6
5%), mp 63–65 ЊC; R (Al O ; 10% MeOH–CH Cl ; I and
f 2 3 2 2 2
Ϫ1
UV-detection) 0.5 (br); νmax (thin film)/cm 3363 (N–H), 1643
(
C᎐O); δ (199.975 MHz; CDCl ) 7.30 (3 H, s, NHCO), 7.29–
᎐
H
3
7
.21 (15 H, m, Ar), 5.12 (3 H, m, CH), 2.97 (4 H, br s, CH CO),
2
2
.93 (2 H, br s, CH CO), 2.58 (16 H, br m, ring-CH ), 1.8 (1H,
2
2
3
3
br s, ring-NH) 1.48 (6 H, d, J 7.1, CH ), 1.45 (3 H, d, J 7.6,
3
CH ); δ (50.3 MHz; CDCl ) 170.8 (2 C, CO), 170.6 (CO), 143.7
3
C
3
(
q-Ar), 129.1 (m-Ar), 127.8 (p-Ar), 127.0 (o-Ar), 59.9 (2 C,
CH CO) 58.0 (CH CO), 54.5 (ring-CH ), 48.9 (2 C, CHN), 48.6
2
2
2
(
CHN), 47.6 (ring-CH ), 22.1 (2 C, CH ), 21.9 (CH ); m/z
2
3
3
7
8
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0

View Article Online
ϩ
(
ESϩ) 656 (100%, MH ) (Found: 656.4287. C H N O
3
4 (a) M. T. Reetz, in Comprehensive Supramolecular Chemistry,
38
54
7
ϩ
ed. F. Voegtle, Oxford, 1996, vol. 2, p. 553; (b) T. Mizutani, K. Wada
and S. Kitagawa, J. Am. Chem. Soc., 1996, 11425; (c) J. W. Canary,
O. Santos and A. R. Lajmi, Tetrahedron Lett., 1997, 38, 4383;
requires MH , 656.4288).
1b
An analogous procedure was adopted for L and identical
spectra were obtained.
(
d ) H. Tsukube, H. Fukui and S. Shinoda, Tetrahedron Lett., 2001,
4
2, 7583; (e) S. Sansone, S. Barbosos, A. Casnato, D. Scrotto and
1a
1a
R. Ungaro, Tetrahedron Lett., 1999, 40, 4741.
[
YbL ](CF SO ) . A solution of the ligand L (1.0 g, 1.5
3 3 3
5
6
C. H. Evans, Biochemistry of the Lanthanides, Plenum Press,
New York, 1990, vol. 8, p. 85.
H. B. Silber and S. J. Parquette, Metals Ions In Biological Systems,
ed. A. Sigel and H. Sigel, Marcel Dekker, New York, 2003, vol. 40,
p. 69.
mmol) and ytterbium triflate (0.95 g, 1.5 mmol) was heated
3
under reflux in dry acetonitrile (5 cm ) for 18 h. The volume was
3
reduced to ca. 1 cm and the solution was added to stirring,
3
dry diethyl ether (80 cm ). The resulting precipitate was
7
(a) H. B. Silber, T. Parker and N. Nguyen, J. Alloys Compd., 1992,
collected by centrifugation and filtration, redissolved in the
minimum amount of acetonitrile and the precipitation pro-
1
4
80, 369; (b) G. A. Elgavish and J. Reuben, J. Magn. Reson., 1981,
2, 242; (c) R. M. Smith, R. J. Motekaitis and A. E. Martell,
cedure repeated twice more. A white solid resulted (1.6 g,
Inorg. Chim. Acta., 1985, 103, 83; (d ) H. B. Silber, T. Chang and
E. Mendoza, J. Alloys Compd., 2001, 190, 323; (e) L. I. Katzin,
Inorg. Chem., 1969, 8, 1649; ( f ) H. G. Brittain, Coord. Chem. Rev.,
1983, 48, 243.
Ϫ1
8
5%), mp 164 ЊC; νmax (solid)/cm 3264 (N–H), 1623 (C᎐O);
partial δ (199.975 MHz, D O) 112 (1H, s, ring-H ), 80 (1H, s,
H
2
ax
ring-H ), 65 (1H, s, ring-H ), 50 (1H, s, ring-H ), 47 (1H, s,
ax
ax
ax
8
9
(a) Z. Zheung, Chem. Commun., 2001, 2521; (b) K. Aparna, S. S.
Krishnamurthy, M. Nethaji and P. Balaram, Polyhedron, 1997, 16,
ring-H ), 32 (1H, s, ring-H ), 28 (1H, s, ring-H ), 23 (1H, s,
eq
eq
eq
ring-H ), 10 (1H), 8 (1H), Ϫ8 (3H), Ϫ12 (1H), Ϫ17 (1H), Ϫ26
eq
5
05; (c) P. P. Gawryszewska, L. Jerzyhiewicz, P. Sobota and
(
1H), Ϫ27 (1H), Ϫ32 (1H), Ϫ35 (1H), Ϫ38 (1H), Ϫ47 (1H),
J. Legendziewicz, J. Alloys Compd., 2000, 300, 275.
(a) R. Wang, H. D. Selby, H. Liu, M. D. Carducci, T. Jin, Z. Zheung,
J. W. Anthuis and R. J. Staples, Inorg. Chem., 2002, 41, 278;
(b) Z. Zheung, R. Wang, T. Jin and R. J. Staples, Angew. Chem.,
Int. Ed., 1999, 38, 1813.
Ϫ48 (1H), Ϫ72 (1H), Ϫ82 (1H, ring-NH); m/z (ESϩ) 489
3
ϩ
Ϫ 2ϩ
2ϩ
(
100%, [M ϩ CF SO ] ), 414 (55%, M ), 1126 (20%,
3 3
3ϩ Ϫ ϩ
[M
ϩ 2CF SO ] ).
3 3
An analogous procedure was adopted for YbL and identi-
1b
1
1
0 R. Prados, L. G. Stadtherr, H. Donato and R. B. Martin, J. Inorg.
Nucl. Chem., 1974, 36, 689.
cal spectra were obtained.
1 (a) B.-Q. Ma, D.-S. Yhang, S. Gao, T.-Z. Jin and G.-X. Xu, Angew.
Chem., Int. Ed., 2000, 39, 3644; (b) B.-Q. Ma, D.-S. Yhang, S. Gao
and T.-Z. Jin, New J. Chem., 2000, 24, 251; (c) S. Aime,
N. D’Amelio, M. Fragai, Y. M. Lee, C. Luchinat, E. Terreno and
G. Valensin, J. Biol. Inorg. Chem., 2002, 7, 617.
Crystallographic studies
X-Ray diffraction experiments (see Table 7) were carried out on
SMART 3-circle diffractometers with a 1K (2, 5a, 5c), APEX
1
2 A. D. Sherry, C. Yoshida, E. R. Birnbaum and D. W. Darnall, J. Am.
Chem. Soc., 1973, 95, 3011.
1
(
10) or 6K CCD area detectors. Graphite-monochromated
¯
Mo-K radiation (λ= 0.71073 Å) from a 60 W Mo-target micro-
α
3 (a) R. S. Dickins, C. S. Love and H. Puschmann, Chem. Commun.,
focus Bede Microsource® X-ray generator with glass poly-
capillary X-ray optics (for 10) or a sealed tube was used. Low
temperature (120 K) of the crystals was maintained with a
2
001, 7, 5160; (b) J. I. Bruce, R. S. Dickins, L. J. Govenlock,
T. Gunnlaugsson, S. Lopinski, M. P. Lowe, D. Parker, R. D.
Peacock, J. J. B. Perry, S. Aime and M. Botta, J. Am. Chem. Soc.,
2
000, 122, 9674; (c) R. S. Dickins, T. Gunnlaugsson, D. Parker and
Cryostream open-flow N cryostat (Oxford Cryosystems). Full
2
R. D. Peacock, Chem. Commun., 1998, 1643.
sphere of reciprocal space was covered by several sets of narrow
1
4 S. Aime, A. S. Batsanov, A. Beeby, M. Botta, J. I. Bruce, R. S.
Dickins, J. A. K. Howard, C. S. Love, D. Parker, R. D. Peacock and
H. Puschmann, J. Am. Chem. Soc., 2002, 124, 12697.
(
0.3Њ) ω scans, each set with different φ and/or 2θ angles. The
intensities for 1, 2, 3, 4, 5b and 5c were corrected for absorption
by numerical integration based on real crystal shape, for 5a, by
15 J. I. Bruce, R. S. Dickins, D. Parker and D. J. Tozer, Dalton Trans.,
29
semi-empirical method based on Laue equivalents. The struc-
tures of 3, 5a and 10 were solved by a combination of Patterson
and direct methods, the rest by analogy with isomorphous
complexes, and all were refined by full-matrix least squares
2003, 1264.
1
1
6 F. S. Richardson, Inorg. Chem., 1980, 19, 2806.
7 (a) J. B. Vaughn, R. L. Stephens, R. E. Lenkinski, G. A. Heavner,
G. Goldstein and N. R. Krishna, Arch. Biochem. Biophys., 1982, 217,
4
1
68; (b) R. E. Lenkinski and R. L. Stephens, J. Inorg. Biochem.,
983, 18, 175; (c) M. Asso, G. Granier, J. Van Rietschoten and
2
30
against F of all data, using SHELXTL software. The abso-
lute structures for all compounds were confirmed from anom-
D. Benlian, Int. J. Pept. Protein Res., 1985, 26, 10; (d ) C. F. G. C.
Geraldes, C. Luchinat, Metals Ions In Biological Systems, ed. A.
Sigel and H. Sigel, Marcel Dekker, New York, 2003, vol. 40, p. 562;
A. D. Sherry, C. Yoshida, E. R. Birnbaum and D. W. Darnall, J. Am.
Chem. Soc., 1973, 95, 3011.
31
alous dispersion, using Flack method.
CCDC reference numbers 213967–213975.
See http://www.rsc.org/suppdata/dt/b3/b311791j/ for crystal-
lographic data in CIF or other electronic format.
1
8 A. S. Batsanov, A. Beeby, J. I. Bruce, J. A. K. Howard, A. M.
Kenwright and D. Parker, Chem. Commun., 1999, 1011.
1
9 (a) R. S. Dickins, J. A. K. Howard, C. W. Lehmann, J. Moloney,
D. Parker and R. D. Peacock, Angew. Chem., Int. Ed., 1997, 36, 521;
Acknowledgements
(
b) R. S. Dickins, J. A. K. Howard, C. L. Maupin, J. M. Moloney,
D. Parker, J. P. Riehl, G. Siligardi and J. A. G. Williams, Chem.
Eur. J., 1999, 5, 1095.
0 S. Aime, A. Barge, A. S. Batsanov, M. Botta, D. D. Castelli,
F. Fedeli, A. Mortillaro, D. Parker and H. Puschmann, Chem.
Commun., 2002, 1120.
We thank EPSRC and the Royal Society for a Dorothy
Hodgkin Fellowship (R. S. D.) for support.
2
2
1 D. Parker, R. S. Dickins, H. Puschmann, C. Crossland and J. A. K.
Howard, Chem. Rev., 2002, 102, 1977.
References
1
(a) D. Voet and J. G. Voet, Biochemistry, Wiley, New York, 2nd edn.,
995; (b) Excitatory Amino Acid Receptors, ed. P. Krogsgaard-
22 (a) S. Aime, A. Barge, J. I. Bruce, M. Botta, J. A. K. Howard, J. M.
Moloney, D. Parker, A. De Sousa and M. Woods, J. Am. Chem. Soc.,
1999, 121, 5672; (b) S. Amin, J. R. Morrow, C. H. Lake and M. R.
Churchill, Angew. Chem., Int. Ed., 1994, 33, 773; (c) L. L. Chappell,
D. A. Voss, W. de W. Horrocks and J. R. Morrow, Inorg. Chem.,
1998, 37, 3989; (d ) L. Alderighi, A. Bianchi, L. Calabi, P. Dapporto,
C. Giorgi, P. Losi, L. Pateari, P. Paoli, P. Rossi, B. Valtancoli and
M. Virtuani, Eur. J. Chem., 1998, 1581.
1
Larsen and J. J. Hansen, Ellis Horwood,Chichester, 1992.
(a) C. Seel, A. Galan and J. de Mendoza, Top. Curr. Chem., 1995,
2
1
75, 101; (b) A. Metzger, K. Gloe, H. Stephan and F. P.
Schmidtchen, J. Org. Chem., 1996, 61, 2051; (c) H. Miyake,
T. Yamashita, Y. Kojima and T. Tsukube, Tetrahedron Lett., 1995,
3
6, 7669; (d ) M. Takakashi, N. Shiraiski, K. Tanabe and H. Ogoshi,
2
3ϩ
J. Am. Chem. Soc., 1995, 117, 10950, and references therein; (e) R. J.
Pieters and F. Diederich, Chem. Commun., 1996, 2255.
23 In the corresponding tetraamide Yb complex, [YbL ]
, the
chemical shift of the most shifted axial ring proton increased along
1
5
3
(a) J. L. Sessler and A. Andrievsky, Chem. Eur. J., 1998, 4, 159, and
references therein; (b) I. Suzuki, K. Obata, J. Anzai, H. Ikeda and
A. Ueno, J. Chem. Soc., Perkin Trans. 2, 2000, 1705.
the amine series 1Њ < 2Њ < 3Њ.
24 Amide–amide binding appears to be relatively weak. DMF does not
1a 3ϩ
bind significantly to the diaqua complex [YbL ] (in D O or DMF)
2
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0
79

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1
and H spectra for amide–amide controls (e.g. N-acetyl glycinamide)
27 For a recent example exploring the use of an apolar thiobenzyl
were exchanged broadened (200 MHz, 298 K, 20 fold-excess,
pD 7.4).
5 Indeed in (R)- and (S)-lactate complexes of (RRR)-[YbL ] a shift
substituent, see: E. A. Meyer, R. Brenk, R. K. Castellano,
M. Furber, G. Klebe and F. Diederich, Chem. Biochem., 2002, 2,
250.
1a 3ϩ
2
2
non-equivalence of >10 ppm has been observed for the lactate CH
28 P. K. Glascoe and F. A. Long, J. Phys. Chem., 1960, 64,
1
3a
and CH resonance.
188.
3
6 (a) F. S. Richardson, Inorg. Chem., 1980, 19, 2806; (b) L. Di Bari,
G. Pintacuda, P. Salvadori, R. S. Dickins and D. Parker, J. Am.
Chem. Soc., 2000, 122, 9257; (c) M. Asano-Scmeda and Y. Kaizu,
J. Photochem. Photobiol. A, 2001, 139, 161; (d ) A. I. Voloshin,
N. M. Shavaleev and V. P. Kozakov, J. Lumin., 2001, 93, 115.
29 SADABS, version 2.03, Bruker AXS, Madison, WI, USA,
2001.
30 SHELXTL, version 5.1, Bruker AXS, Madison, WI, USA,
1997.
31 H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876.
8
0
D a l t o n T r a n s . , 2 0 0 4 , 7 0 – 8 0