Pincer ligands based on α-amino acids: III. New ligands based on 4-substituted phenols and their copper complexes. Enantioselective recognition of tyrosine

Article abstract of DOI:10.1134/S107042800903004X

Reactions of L-methionine, L-serine, and L-valine with 5-substituted-2- hydroxybenzene-1,3-dicarbaldehydes gave a series of chiral Schiff base pincer ligands which were reduced to the corresponding diamines. The new Schiff base ligands reacted with copper

Full text of DOI:10.1134/S107042800903004X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 3, pp. 365–373. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © N.E. Borisova, V.A. Knizhnikov, T.G. Gulevich, M.Yu. Seliverstov, E.A. Borisov, M.D. Reshetova, 2009, published in Zhurnal Or-
ganicheskoi Khimii, 2009, Vol. 45, No. 3, pp. 377–385.
Pincer Ligands Based on α-Amino Acids: III.* New Ligands
Based on 4-Substituted Phenols and Their Copper Complexes.
Enantioselective Recognition of Tyrosine
N. E. Borisovaa, V. A. Knizhnikovb, T. G. Gulevichb, M. Yu. Seliverstova,
E. A. Borisova, and M. D. Reshetovaa
a Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: Borisova.Nataliya@gmail.com
b Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
Received February 18, 2008
Abstract—Reactions of L-methionine, L-serine, and L-valine with 5-substituted-2-hydroxybenzene-1,3-di-
carbaldehydes gave a series of chiral Schiff base pincer ligands which were reduced to the corresponding
diamines. The new Schiff base ligands reacted with copper(II) chloride to form dinuclear copper complexes
which were found to be capable of recognizing tyrosine enantiomers in aqueous solution. The structure of the
complexes was determined on the basis of their spectral parameters.
DOI: 10.1134/S107042800903004X
Design of synthetic receptors for selective binding
and separation of enantiomeric chiral substrates, as
well as of enantioselective sensors for analytical deter-
mination of optical purity of chiral compounds, consti-
tutes an important problem in modern chemistry. Syn-
thetic receptors for biomolecules such as α-amino
acids and peptides (that are the most important chiral
substrates) attract specific interest. Studies on enantio-
selective recognition of these substrates have been ini-
tiated long ago; nevertheless, interest in this topic con-
tinuously increases, as follows from analysis of data
published during the past decade. Up to now, various
receptors and sensors based on chiral multidentate
macromolecules have been proposed for recognition of
chiral amino acids. Most studies were performed in
nonpolar organic solvents, whereas receptors working
in aqueous medium were studied to a lesser extent.
fragments were proposed as fluorescent sensors for
α-amino acid tetrabutylammonium salts [5, 6]. Well
developed anion recognition techniques (e.g., introduc-
tion of guanidinium fragments into receptor molecule)
were applied to recognize neutral amino acids that
exist as zwitterions. Effective combination of calix-
arene and crown ether scaffolds with guanidinium
recognizing groups located in the vicinity of chiral
centers made it possible to construct receptors capable
of binding amino acids in aqueous medium [7, 8].
Among other types of receptors for enantioselective
recognition of amino acids, chiral macrocycles derived
from pyridine-2,6-dicarboxamide [9] and 2,6-diamino-
pyridine-based amides [10] and having chiral amino
acid fragments in the macroring should be noted. Such
systems were effective in recognizing stereoisomeric
amino acid methyl esters and peptides. Liu et al. [11]
described receptors for chiral recognition of amino
acids in buffer solution (pH 7.2), which were synthe-
sized on the basis of chiral β-cyclodextrins modified
by substituted benzeneselenols.
Among the examined classes of compounds, macro-
cycles on the basis of crown ethers and calixarenes
should primarily be noted. Cross host–guest interaction
between chiral crown ethers and α-amino acid methyl
ester hydrochlorides was studied by spectrophotomet-
ric titration [2, 3] and mass spectrometry (FAB) [4].
Calix[4]arenes having side-chain chiral amino acid
The use of chiral metal complexes capable of
coordinating molecules with donor groups seems to be
a quite promising method for recognition of optical
isomers. Belokon’ and co-workers [12, 13] tried to
* For communication II, see [1].
365

BORISOVA et al.
366
Scheme 1.
R'
R'
R
O
NH2
EtONa/EtOH
+
R
O
N
OH
N
R
O
OCH
CHO
OH
OH
ONa
NaO
Ia–Ie
R = MeS(CH2)2, R′ = t-Bu (a), Me (b); R = HOCH2, R′ = t-Bu (c), Me (d); R = Me2CH, R′ = t-Bu (e).
create enantiomeric receptors for chiral recognition of
amino acids on the basis of mononuclear copper com-
plexes with macrocyclic Schiff bases. However, the
proposed systems showed no selectivity for enantio-
meric amino acids [12]. Acyclic mononuclear systems
based on optically active copper complexes with
2,6-bis(oxazol-2-yl)pyridines turned out to be capable
of recognizing enantiomeric amino acids in 50% aque-
ous methanol at a submillimolar level; for example, the
dissociation constants for the complexes with phenyl-
alanine were Kd(L-Phe) = 1.95×10–4 and Kd(D-Phe) =
1.10×10–4, but the enantioselectivity was poor [14].
atom in the amino group [17]. Just that factor was
responsible for the failure [16] to obtain analogous
Schiff base from 2-hydroxy-5-methylbenzene-1,3-di-
carbaldehyde and L-alanine. The use of the corre-
sponding sodium salt instead of free amino acid elimi-
nates limitations related to the substrate nature. Schiff
base disodium salts Ia–Ie were yellow hygroscopic
crystalline powders, which were poorly soluble in
organic solvents and unstable on exposure to moisture.
1
Their structure was determined by H and 13C NMR
spectroscopy. The difference in the frequencies of
symmetric and antisymmetric vibrations of the carbox-
ylate ion indicated that the carboxy group acts as a uni-
dentate ligand [18]. The NMR spectra were recorded
from solutions in methanol, for both deuterated di-
methyl sulfoxide and the more so D2O [16] promoted
hydrolysis of Schiff bases Ia–Ie. The presence of 2–
4% of water in commercial methanol-d4 did not induce
hydrolysis of the ligands and did not interfere with
signal resolution. The chemical shifts of the aromatic
carbon atom linked to the phenolic hydroxy group
were about δC 150 ppm; this value is typical of neutral
phenols. In the spectrum of Ia, the corresponding
signal was displaced downfield (δC 165.5 ppm), in-
dicating deprotonation of the phenolic hydroxy group.
We presumed that the use of dinuclear metal com-
plexes could not only proportionally enhance binding
of an amino acid substrate to metal ion but also in-
crease the selectivity due to rigid fixation of amino
acid molecule via coordination at two centers. It is
known that tetranuclear copper complexes with Schiff
bases derived from vanillin can be used as active com-
ponents of ion-selective membrane electrodes [15].
The present work was aimed at synthesizing di-
nuclear copper complexes with chiral acyclic Schiff
bases Ia–Ie and studying their interaction with optical-
ly active amino acids. Initial chiral Schiff bases were
synthesized by reaction of 5-alkyl-2-hydroxybenzene-
1,3-dicarbaldehydes with L-valine, L-serine, and
L-methionine sodium salts in anhydrous ethanol and
were isolated as the corresponding disodium salts Ia–
Ie in 80–95% yield (Scheme 1). Illán-Cabeza et al.
[16] previously reported on the reaction of L-histidine
with 2-hydroxy-5-methylbenzene-1,3-dicarbaldehyde
in boiling methanol at pH 6.5, which gave the corre-
sponding Schiff base. However, this procedure cannot
be extended to other amino acids, for histidine mole-
cule possesses an additional basic center (imidazole
nitrogen atom) which is protonated in the zwitterionic
form of the amino acid; other amino acids in neutral
medium exist as zwitterions with protonated nitrogen
The reduction of Schiff bases Ia–Id with 3 equiv
of sodium tetrahydridoborate in anhydrous methanol,
followed by treatment of the reaction mixture with
3 equiv of ethanolic hydrogen chloride, gave sodium
salts IIa–IId, which were isolated as individual sub-
stances (Scheme 2). By treatment of the reaction mix-
ture with excess HCl (5 equiv) in ethanol we obtained
free diacids IIIa–IIId in 75–85% yield. Pincer amino
acid salts IIa–IId were yellow powders readly soluble
in water and methanol and insoluble in other solvents.
Unlike their sodium salts, free acids IIIa–IIId were
isolated as white powders moderately soluble in alco-
hols and water.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

PINCER LIGANDS BASED ON α-AMINO ACIDS: III.
367
Scheme 2.
R'
R'
(1) NaBH4 (3 equiv), MeOH
(2) HCl (3 equiv), EtOH
(1) NaBH4 (3 equiv), MeOH
(2) HCl (5 equiv), EtOH
Ia–Id
R
O
NH
OH HN
NaO
R
O
R
O
NH
OH
OH HN
HO
R
O
ONa
IIa–IId
IIIa–IIId
R = MeS(CH2)2, R′ = t-Bu (a), Me (b); R = HOCH2, R′ = t-Bu (c), Me (d).
spectra of IIIa–IIId, the corresponding difference is
much smaller or equal to zero. The C–OH signal in the
13C NMR spectra shifts upfiled by 3–4 ppm in going
from salts IIa–IId to acids IIIa–IIId, indicating weak
coordination of sodium ion at the oxygen atom in the
phenolic hydroxy group.
According to the IR data, the structure of salts IIa–
IId is analogous to their precursors Ia–Id. The sodium
ions are linked to the carboxy groups, as follows from
the difference νas – νs between the vibration frequen-
cies of the carboxylate ion. The carboxy groups in
free acids IIIa–IIId give rise to absorption at 1730–
1750 cm–1. Signals from the phenolic carbon atom
(C–OH) in IIa–IId are located in the 13C NMR spectra
at about δC 155 ppm, i.e., in the region typical of un-
dissociated hydroxy group in substituted phenols. Salts
We also made an attempt to synthesize chiral Schiff
bases from amino acid methyl esters. The products
were expected to be better soluble in organic solvents
than the corresponding derivatives of free amino acids.
As model substrate we used L-methionine methyl ester.
Its reaction with 2-hydroxy-5-methylbenzene-1,3-di-
carbaldehyde gave methyl ester IV (Scheme 3) as
a yellow oily substance readily soluble in most organic
solvents, poorly soluble in saturated hydrocarbons, and
readily hydrolyzable with water. Ester IV was charac-
terized by spectral and analytical data. By reduction of
IV with sodium tetrahydridoborate in anhydrous meth-
1
IIa–IId characteristically showed in the H NMR
spectra a large difference in the chemical shifts of
diastereotopic protons in the NHCH2 group, and this
difference did not depend on the temperature. This
pattern originates from the specific steric structure of
molecules II and III, where one hydrogen atom in the
CH2NH group appears in the vicinity of the carbox-
ylato (IIa–IId) or carboxy group (IIIa–IIId). In the
Scheme 3.
Me
Me
S
NH2
Me
MeOH
+
MeS
N
OH
N
SMe
OCH
CHO
O
OMe
OH
O
OMe
MeO
O
IV
Me
NaBH4, MeOH
MeS
NH
OH HN
SMe
O
OMe
MeO
O
V
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

BORISOVA et al.
368
Scheme 4.
R'
R'
O
H2O
N
CuCl2 ·2H2O, MeOH
R
O
N
OH
N
R
O
R
O
N
O
R
O
Cu
Cu
ONa
NaO
O
O
H
OH2
Ib, Id, Ie
VIb, VId, VIe
R′ = Me, R = MeS(CH2)2 (b), HOCH2 (d); R′ = t-Bu; R = Me2CH (e).
anol we obtained pincer amino ester V in high yield.
Compound V is readily soluble in polar organic sol-
vents, insoluble in nonpolar hydrocarbons, and stable
to hydrolysis.
and VIe we observed an absorption band correspond-
ing to the C=N bond involved in coordination to cop-
per ion (~1610 cm–1) and bands due to antisymmetric
and symmetric stretching vibrations of the carboxylate
ions at 1640 and 1360 cm–1, respectively. Appreciably
increased difference between the symmetric and anti-
symmetric vibration frequencies, as compared to the
corresponding sodium salts, indicates a considerable
covalent character of the bond between the copper ion
and carboxylate oxygen atom [16, 18]. Simultaneously,
the stretching vibration frequency of the phenolic C–O
bond increases from 1220 cm–1 in the spectra of so-
dium salts Ib, Id, and Ie to 1320 cm–1 in the spectra of
copper complexes VIb, VId, and VIe. The observed
change is typical of coordination of metal ions to
Schiff bases derived from salicylaldehyde [18]. These
findings suggest that the copper coordination entity
consists of the C=N nitrogen atom and three oxygen
atoms. Among the latter, one oxygen atom belongs to
the carboxylate group, and the two other, phenolic and
hydroxy oxygen atoms, form bridges between two
copper ions. The configuration of the copper ions is
supplemented to tetragonal–pyramidal via apical coor-
dination of a water molecule as extra ligand. In fact,
an absorption band at 3400 cm–1 is present in the IR
spectra due to OH stretching vibrations. The structure
of the coordination polyhedron is determined mainly
by the structure of the 2-hydroxy-5-methylbenzene-
1,3-dicarbaldehyde moiety. It is known [19] that 2-hy-
droxy-5-methylbenzene-1,3-dicarbaldehyde is the key
building block for the synthesis of dinuclear com-
plexes with two bridging oxygen atoms.
Contrary to the expectation, both MALDI-TOF and
ESI mass spectra of the synthesized Schiff bases and
their reduction products turned out to be low informa-
tive. As a rule, no molecular ion peak was observed.
Exception were negative ion mass spectra of Schiff
base Id (m/z 339, Irel 20%), acid IIIa (m/z 471,
Irel 10%), and diester IV (m/z 453, Irel 100%). The
spectra showed the presence of large amounts of oligo-
mers (di- and even trimers), and their fragment ion
peaks strongly complicated identification of the target
products. The main fragmentation pathway of the
Schiff bases derived from methionine and serine
involves elimination of one amino acid fragment
[MeS(CH2)2CHCO2H or HOCH2CHCO2H] as a result
of cleavage of the C–H bond. The fragmentation of
serine derivatives was also characterized by elimina-
tion of the entire amino acid residue and loss of CO2
molecule.
Dimethyl ester IV reacted with copper salts to give
a copper complex which we failed to isolate as individ-
ual substance. As a result of hydrolysis, copper com-
plex with methionine methyl ester was isolated. Unlike
diester IV, disodium salts Ib, Id, and Ie readily under-
went transmetalation upon treatment with a concentrat-
ed solution of copper(II) chloride dihydrate in metha-
nol, and the corresponding complexes VIb, VId, and
VIe were isolated in high yields (Scheme 4).
Complexes VIb, VId, and VIe are green powders;
they are soluble in methanol and water and poorly
soluble in organic solvents. Their structure was proved
by the IR spectra and elemental analyses. The com-
plexes had similar structures, regardless of the amino
acid nature. In the IR spectra of complexes VIb, VId,
We examined cross interaction between dinuclear
complex VIe and tyrosine enantiomers in aqueous
solution using the equimolar series technique. It was
found that complex VIe is capable of binding enantio-
meric D- and L-tyrosine to form 1:2 and 1:1 adducts,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

PINCER LIGANDS BASED ON α-AMINO ACIDS: III.
369
A
respectively. According to the spectrophotometric titra-
tion data, the main absorption maxima of the adducts
almost coincided with those of the initial complex (see
figure). In the course of titration, the long-wave part of
the absorption band of complex VIe increased in in-
tensity, while the intensity of the short-wave compo-
nent slightly decreased. Thus we observe absorption of
both initial complex VIe and its adduct with the amino
acid at any wavelength during spectrophotometric ti-
tration. In addition, the isosbestic point is located near
the absorption maximum of VIe. To calculate the bind-
ing constant it was necessary to find a point (wave-
length) at which the difference in the absorbances of
the initial complex and its adduct with the amino acid
be maximal. Full shape analysis of the absorption band
of the complex with D-tyrosine revealed two more
long-wave bands with their maxima at λ 394.2 and
411.1 nm. The maximal difference in the absorbances
was observed at λ 411 nm. Analogous procedure for
the complex with L-tyrosine revealed one additional
band with its maximum at λ 404 nm. The binding
constants for the different tyrosine enantiomers were
determined at λ 411 and 404 nm for the D- and
L-isomers, respectively. The equilibrium constant for
L-tyrosine was estimated at β1 = KB(1:1) = 97(5) mol–1
(r2 = 0.980), while only the constant β2 = KB(1:1)×
KB(1:2) = 4.4(4)×104 mol–1 (r2 = 0.990) was reliably
determined for D-tyrosine.
1.2
0.6
0.0
360
390
420
450
480
λ, nm
Variation of the electronic absorption spectrum of complex
VIe upon addition of D-tyrosine.
of band shapes, absorption curves were approximated
by Gauss functions. The parameters of the Gauss func-
tion for the initial complex (λmax 382.6 nm) were deter-
mined by approximation of the absorption band of the
pure complex at the same concentration. The purity
in the determination of wavelength corresponding to
maximum difference in the absorbances of the copper
complex and its associate with tyrosine was ±3 nm for
the D-stereoisomer and ±1 nm for the L-isomer. The
mean-square deviation for the resultant function was
0.0028 (r2 = 0.993) for D-tyrosine and 0.0021 (r2 =
0.995) for L-tyrosine. The initial amino acid methyl
esters were synthesized according to the procedures
described in [21], and 2-hydroxy-5-alkylbenzene-1,3-
dicarbaldehydes were prepared as reported in [22].
Methanol was distilled over calcium hydride under
argon before use. The other reagents and solvents were
used without additional purification.
To conclude, we have synthesized acyclic pincer
Schiff base and amine ligands and examined their
complex formation with copper ions. The complex
with the Schiff base derived from L-valine showed
analytical response toward tyrosine enantiomers. The
proposed approach, which implies binding of amino
acids by several metal ions with formation of rigid
structure, seems to be promising from the viewpoint of
design of enantioselective sensor systems.
Disodium salts Ia–Ie (general procedure). L-Val-
ine, L-serine, or L-methionine, 10 mmol, was added at
room temperature to a solution of sodium ethoxide pre-
pared from 0.23 g (10 mmol) of metallic sodium and
100 ml of anhydrous ethanol. The mixture was stirred
for 1 h at room temperature, 5 mmol of the corre-
sponding 5-alkyl-2-hydroxybenzene-1,3-dicarbalde-
hyde and 4 g of 3-Å molecular sieves were added, and
the mixture was stirred for 10 h and filtered. The
filtrate was concentrated under reduced pressure and
cooled to –30°C, and the yellow precipitate (powder)
was filtered off, washed with diethyl ether, and dried
under reduced pressure.
EXPERIMENTAL
The IR spectra were recorded in KBr on a Nicolet
Protégé-460 spectrometer with Fourier transform. The
1H and 13C NMR spectra were measured at 20°C on
a Bruker Avance-400 spectrometer; the chemical shifts
were determined relative to tetramethylsilane. Spectro-
photometric titration was performed on a Helios &
Thermo Scientific spectrophotometer in aqueous solu-
tions with a zero ionic strength. The binding constants
were determined in distilled water. Stoichiometric co-
efficients for extra ligand exchange were determined
using the equimolar series method [20]. In the analysis
Compound Ia was synthesized from 1.49 g of
L-methionine and 2.06 g of 5-tert-butyl-2-hydroxyben-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

BORISOVA et al.
370
zene-1,3-dicarbaldehyde. Yield 2.05 g (80%). IR spec-
trum, ν, cm–1: 3426.2, 2956.3, 2916.5, 1648.6, 1629.7,
1584.8, 1510.3, 1393.3, 1359.4, 1336.7, 1224.9,
Compound Ie was synthesized from 1.17 g of
L-valine and 2.06 g of 5-tert-butyl-2-hydroxybenzene-
1,3-dicarbaldehyde. Yield 2.13 g (95%). IR spectrum,
ν, cm–1: 1646.9, 1631.5, 1598.7, 1521.6, 1390.4,
1
1041.0. H NMR spectrum (methanol-d4), δ, ppm:
1
1363.4, 1226.5. H NMR spectrum (methanol-d4), δ,
1.33 s (9H, t-Bu), 2.09 s (6H, SCH3), 2.15 m (2H,
CHN), 2.25 m (2H, CHN), 2.55 m (4H, CH2), 4.06 t
(2H, CH, J = 4.7 Hz), 7.63 s (2H, CH), 8.42 s (2H,
CH=N). 13C NMR spectrum (methanol-d4), δC, ppm:
13.8, 29.9, 30.2, 33.5, 33.7, 71.6, 117.3, 128.0, 137.4,
163.4, 165.5, 174.4.
ppm: 0.98 d (6H, CH3, J = 6.61 Hz), 1.03 d (6H, CH3,
J = 6.36 Hz), 1.33 s (9H, t-Bu), 2.30 d.t (2H, CH, J =
6.61, 6.36 Hz), 3.65 br.s (2H, CH), 7.57 s (2H, CH),
8.30 s (2H, CH=N). 13C NMR spectrum (methanol-d4),
δC, ppm: 17.3, 18.6, 30.1, 31.9, 33.1, 79.3, 121.5,
135.2, 136.4, 148.4, 163.1, 176.7.
Compound Ib was synthesized from 1.49 g of
L-methionine and 1.64 g of 2-hydroxy-5-methylben-
zene-1,3-dicarbaldehyde. Yield 2.00 g (85%). IR spec-
trum, ν, cm–1: 3422.9, 2916.4, 1711.5, 1629.0, 1600.6,
Disodium salts IIa–IId (general procedure). A so-
lution of 5 mmol of Schiff base Ia–Id in 100 ml of
anhydrous methanol was cooled to –30°C, 0.57 g
(15 mmol) of sodium tetrahydridoborate was added,
and the mixture was stirred for 1 h at –30°C and was
allowed to warm up to room temperature. A 2 N solu-
tion of hydrogen chloride in ethanol, 7.5 ml, was
slowly added dropwise, and the mixture was stirred for
1 h and evaporated under reduced pressure. The resi-
due was extracted with anhydrous ethanol, the extract
was filtered and evaporated, and the residue was
treated with diethyl ether. The precipitate was filtered
off, washed with diethyl ether, and dried under reduced
pressure.
1
1522.6, 1393.8, 1206.3, 1158.7, 552.8. H NMR spec-
trum (methanol-d4), δ, ppm: 2.02 m (4H, CH2), 2.08 s
(6H, SCH3), 2.27 s (3H, CH3), 2.59 t (4H, CH2, J =
8.3 Hz), 4.03 d.d (2H, CH, J = 4.6, 3.7 Hz), 7.38 s (2H,
CH), 8.36 s (2H, CH=N). 13C NMR spectrum (metha-
nol-d4), δC, ppm: 13.7, 30.1, 31.5, 34.3, 72.2, 124.0,
137.5, 137.8, 155.7, 162.9, 179.8. Found, %: C 48.32;
H 5.29; N 5.65. C19H24N2Na2O5S2. Calculated, %:
C 48.50; H 5.14; N 5.95.
Compound Ic was synthesized from 1.05 g of
L-serine and 2.06 g of 5-tert-butyl-2-hydroxybenzene-
1,3-dicarbaldehyde. Yield 1.84 g (87%). IR spectrum,
ν, cm–1: 1633.2, 1520.2, 1391.9, 1359.8, 1224.3,
Compound IIa was synthesized from 2.56 g of
Schiff base disodium salt Ia. Yield 1.96 g (76%). IR
spectrum, ν, cm–1: 3425.9, 2960.2, 2918.6, 2863.9,
1602.8, 1485.8, 1395.1, 1362.8, 1274.5, 1218.3, 881.6.
1H NMR spectrum (methanol-d4), δ, ppm: 1.29 s
(t-Bu), 2.10 s (6H, SCH3), 2.15 m (4H, CH2), 2.66 t
(4H, CH2, J = 7.09 Hz), 3.53 t (2H, CH, J = 5.1 Hz),
4.02 d and 4.18 d (2H each, CH2N, J = –16.4 Hz),
7.23 s (2H, CH). 13C NMR spectrum (D2O), δC, ppm:
14.0, 29.8, 30.9, 32.4, 33.2, 47.3, 62.6, 118.3, 123.9,
126.8, 156.1, 181.8. MALDI-TOF mass spectrum, m/z
(Irel, %): 635 (80) [2M – C16H24NO3S]+, 324 (100)
[M – Met]+, 105 (40) [C4H8NO2 + 3H]+, 72 (52)
[C3H7S – 3H]+.
1
1041.6, 627.1. H NMR spectrum (methanol-d4), δ,
ppm: 1.32 s (9H, t-Bu), 3.86 t (2H, CH, J = 11.3 Hz),
4.03 d (4H, CH2OH, J = 11.3 Hz), 7.55 s (2H, CH),
8.33 s (2H, CH=N). 13C NMR spectrum (methanol-d4),
δC, ppm: 30.2, 33.2, 63.8, 73.5, 117.9, 131.1, 151.7,
166.0, 178.8.
Compound Id was synthesized from 1.05 g of
L-serine and 1.64 g of 2-hydroxy-5-methylbenzene-
1,3-dicarbaldehyde. Yield 1.72 g (90%). IR spectrum,
ν, cm–1: 3405.7, 2922.9, 2854.6, 1628.5, 1527.8,
1
1394.7, 1218.3, 1033.3, 563.6. H NMR spectrum
Compound IIb was synthesized from 2.35 g of
Schiff base disodium salt Ib. Yield 1.97 g (83%). IR
spectrum, ν, cm–1: 3423.8, 2960.8, 2916.9, 2853.9,
(methanol-d4), δ, ppm: 2.26 s (3H, CH3), 3.89 t (2H,
CH, J = 5.4 Hz), 4.00 d (4H, CH2OH, J = 5.4 Hz),
7.35 s (2H, CH), 8.30 s (2H, CH=N). Mass spectrum,
m/z (Irel, %): MALDI-TOF, positive ions: 89 (100)
[HOCH2CHCO2H]+, 105 (28) [Ser + H]+, 449 (30)
[M + Ser + 6H]+; MALDI-TOF, negative ions: 185
(100), 213 (60) [M – HOCH2CHCO2H – CH2OH]–,
265 (100) [M – CH2OH – CO2]–, 339 (20) [M]–; elec-
trospray ionization: 333 (84) [M – 5H]+, 275 (100)
[M – CO2H – OH]+, 234 (50) [M – Ser – H]+. Found,
%: C 47.45; H 4.41; N 7.77. C15H16N2Na2O7. Calcu-
lated, %: C 47.13; H 4.22; N 7.33.
1
1608.6, 1483.3, 1402.8, 1342.7, 1241.8. H NMR
spectrum (D2O), δ, ppm: 2.02 s (6H, SCH3), 2.06 m
(4H, CH2), 2.17 s (3H, CH3), 2.62 t (4H, CH2, J =
7.6 Hz), 3.59 t (2H, CH, J = 6.1 Hz), 4.02 d and 4.15 d
(2H each, CH2N, J = –13.5 Hz), 7.07 s (2H, CH).
13C NMR spectrum (D2O), δC, ppm: 14.0, 19.3, 29.1,
47.5, 53.9, 60.5, 119.7, 128.9, 132.5, 155.1, 174.5.
Compound IIc was synthesized from 2.12 g of
Schiff base disodium salt Ic. Yield 1.67 g (78%). IR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

PINCER LIGANDS BASED ON α-AMINO ACIDS: III.
371
spectrum, ν, cm–1: 1601.8, 1488.9, 1451.4, 1409.5,
1364.2, 1203.1, 1132.5, 1086.3, 1048.7. 1H NMR spec-
trum (D2O), δ, ppm: 1.32 s (9H, t-Bu), 3.74 t (2H, CH,
J = 3.7 Hz), 4.01 m and 4.06 d.d (4H, CH2, J = 3.7,
–12.47 Hz), 4.35 d and 4.38 d (2H each, CH2N, J =
6.1 Hz), 7.47 s (2H, CH). 13C NMR spectrum (D2O),
δC, ppm: 30.6, 34.3, 47.2, 59.8, 62.6, 119.3, 128.7,
129.7, 154.7, 171.3.
N,N′-(2-Hydroxy-5-methylbenzene-1,3-diyldi-
methylidene)bis[(2S)-2-amino-4-methylsulfanyl-
butanoic acid] (IIIb) was synthesized from 2.35 g of
Schiff base Ib. Yield 1.68 g (78%). IR spectrum, ν,
cm–1: 1737.3, 1490.0, 1435.7, 1201.7, 1180.9, 1134.9,
1
720.6. H NMR spectrum (methanol-d4), δ, ppm:
2.12 s (6H, SCH3), 2.20 m (4H, CH2), 2.12 s (3H,
CH3), 2.68 t (4H, CH2, J = 8.6 Hz), 3.68 t (2H, CH,
J = 5.1 Hz), 4.16 d and 4.23 d (2H each, CH2N, J =
–12.9 Hz), 7.17 s (2H, CH). 13C NMR spectrum (D2O),
δC, ppm: 13.9, 19.2, 28.9, 29.0, 46.3, 60.2, 119.4,
131.7, 134.1, 151.0, 172.8. Found, %: C 49.32; H 6.20;
N 5.79. C19H26N2O5S2·2H2O. Calculated, %: C 49.33;
H 6.54; N 6.06.
Compound IId was synthesized from 1.91 g of
Schiff base disodium salt Id. Yield 1.64 g (85%). IR
spectrum, ν, cm–1: 1603.8, 1579.3, 1434.7, 1397.5,
1
1349.3, 1237.2, 1200.4, 1072.3, 1043.4. H NMR
spectrum (D2O), δ, ppm: 2.35 s (3H, CH3), 3.87 t
(2H, CH, J = 5.6 Hz), 4.02 d and 4.06 d (2H each,
CHN, J = –2.2 Hz), 4.33 d (4H, CH2, J = 5.6 Hz),
7.28 s (2H, CH).
N,N′-(5-tert-Butyl-2-hydroxybenzene-1,3-diyldi-
methylidene)bis[(2S)-2-amino-3-hydroxypropanoic
acid] (IIIc) was synthesized from 2.12 g of Schiff base
Ic. Yield 1.54 g (80%). IR spectrum, ν, cm–1: 1739.4,
Pincer amino acids IIIa–IIId (general procedure).
A solution of 5 mmol of Schiff base Ia–Id in 100 ml of
anhydrous methanol was cooled to –30°C, 0.57 g
(15 mmol) of sodium tetrahydridoborate was added,
and the mixture was stirred for 1 h at –30°C and was
allowed to warm up to room temperature. A 2 N solu-
tion of hydrogen chloride, 12.5 ml, was slowly added
dropwise, and the mixture was stirred for 1 h and evap-
orated under reduced pressure. The residue was ex-
tracted with anhydrous ethanol, the extract was filtered
and evaporated, and the residue was treated with di-
ethyl ether. The precipitate was filtered off, washed
with diethyl ether, and dried under reduced pressure.
1
1494.6, 1215.8, 1078.4, 1044.1, 826.3. H NMR spec-
trum (D2O), δ, ppm: 1.28 s (9H, t-Bu), 4.08 m (6H,
CH, CH2), 4.43 br.s (4H, CH2OH), 7.54 s (2H, CH).
Found, %: C 51.62; H 7.63; N 6.47. C18H28N2O7 ·
2H2O. Calculated, %: C 51.42; H 7.67; N 6.66.
N,N′-(2-Hydroxy-5-methylbenzene-1,3-diyldi-
methylidene)bis[(2S)-2-amino-3-hydroxypropanoic
acid] (IIId). A solution of 1.91 g (5 mmol) of Schiff
base disodium salt Id in 100 ml of methanol was
cooled to –30°C, 0.57 g (15 mmol) of sodium tetra-
hydridoborate was added, and the mixture was stirred
for 1 h at –30°C and was allowed to warm up to
room temperature. Trifluoroacetic acid, 25 mmol, was
slowly added dropwise to the resulting solution, and
the precipitate was filtered off, washed in succession
with acetone and diethyl ether, and dried under
reduced pressure. Yield 1.45 g (85%). IR spectrum, ν,
cm–1: 1736.8, 1492.6, 1203.3, 1199.5, 1072.2, 1045.2.
1H NMR spectrum (D2O), δ, ppm: 2.18 s (3H, CH3),
3.72 d.d (2H, CH, J = 3.7, 5.6 Hz), 3.87 d.d (2H, CHN,
J = 5.6, –12.5 Hz), 3.94 d.d (2H, CHN, J = 3.7,
–12.5 Hz), 4.23 s (4H, CH2), 7.17 s (2H, CH).
13C NMR spectrum (D2O), δC, ppm: 19.2, 46.1, 59.3,
62.5, 119.4, 131.6, 133.9, 149.8, 171.1. Found, %:
C 49.43; H 5.98; N 7.30. C15H18N2O7·H2O·MeOH.
Calculated, %: C 49.48; H 6.23; N 7.21. Mass spec-
trum (ESI), m/z (Irel, %): 715 (74) [2M + MeO]+, 282
(100) [M – CO2 – O]+, 265 (96) [282 – O]+.
N,N′-(5-tert-Butyl-2-hydroxybenzene-1,3-diyldi-
methylidene)bis[(2S)-2-amino-4-methylsulfanyl-
butanoic acid] (IIIa) was synthesized from 2.56 g of
Schiff base Ia. Yield 1.77 g (75%). IR spectrum, ν,
cm–1: 3419.5, 2964.2, 2921.3, 2868.0, 1742.9, 1492.4,
1
1437.6, 1218.3, 1031.9, 885.3. H NMR spectrum
(methanol-d4), δ, ppm: 1.34 s (9H, t-Bu), 2.12 s (6H,
SCH3), 2.24 d.t (4H, CH2, J = 6.6, 7.8 Hz), 2.68 t (4H,
CH2, J = 7.8 Hz), 3.96 t (2H, CH, J = 6.6 Hz), 4.31 d
and 4.35 d (2H each, CH2N, J = –13.2 Hz), 7.51 s (2H,
CH). 13C NMR spectrum (methanol-d4), δC, ppm: 13.8,
29.2, 29.3, 30.4, 33.8, 46.3, 58.9, 119.3, 130.7, 144.0,
152.9, 170.7. Mass spectrum, m/z (Irel, %): MALDI-
TOF, positive ions: 368 (70) [M + Na – MeS(CH2)2-
CHCO2 + 5H]+, 346 (100); MALDI-TOF, negative
ions: 471 (10) [M – H]–, 148 (30) [Met – H]–, 113
(100) [MeS(CH2)2CHCO – 3H]–; electrospray ioniza-
tion: 1210 (68) [3M – Met – CO2H – MeS(CH2)2]+,
904 (96) [2M – CO2 + 3H]+, 596 (100) [2M –
C18H24N2O3S]+, 340 (60) [M – MeS(CH2)2CHCO2H]+.
Found, %: C 53.76; H 7.63; N 5.68. C22H36N2O5S2·
H2O. Calculated, %: C 53.85; H 7.81; N 5.71.
Dimethyl N,N′-(2-hydroxy-5-methylbenzene-1,3-
diyldimethylidene)bis[(2S)-2-amino-4-methylsul-
fanylbutanoate] (IV). 2-Hydroxy-5-methylbenzene-
1,3-dicarbaldehyde, 1.23 g (10 mmol), was dissolved
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

BORISOVA et al.
372
in 100 ml of anhydrous methanol, 3.26 g (20 mmol) of
freshly prepared L-methionine methyl ester, 2 g of
magnesium sulfate, and 2 g of 3-Å molecular sieves
were added, the mixture was stirred for 7 h and
filtered, and the filtrate was evaporated under reduced
pressure. The residue was extracted with diethyl ether,
the extract was filtered and concentrated under reduced
pressure, 100 ml of hexane was added, and the oily
material was separated from the hexane solution,
washed with hexane, and dried under reduced pressure
at 40°C. Yield 3.41 g (75%). IR spectrum, ν, cm–1:
1736.8, 1630.3, 1599.5, 1461.9, 1434.6, 1265.7,
water (3 ×1 ml), and dried first in air and then in
a vacuum desiccator over phosphoric anhydride.
Complex VIb was obtained from 0.94 g of diso-
dium salt Ib. Yield 0.55 g (45%). IR spectrum, ν, cm–1:
3405.7, 3239.8, 2917.8, 2856.1, 1641.1, 1608.0,
1554.3, 1450.2, 1359.6, 1332.6, 1240, 1182.2, 1083.8.
Found, %: C 37.82; H 4.70; N 4.61. C19H24Cu2N2O6S2·
2H2O. Calculated, %: C 37.80; H 4.68; N 4.64.
Complex VId was obtained from 0.94 g of diso-
dium salt Id. Yield 0.75 g (73%). IR spectrum, ν, cm–1:
3399.9, 3299.6, 3243.7, 3156.9, 2967.9, 2935.1,
2888.8, 1639.2, 1606.4, 1561.5, 1452.1, 1398.1,
1353.8, 1315.2, 1101.2, 1052.9. Found, %: C 35.12;
H 4.07; N 5.31. C15H16Cu2N2O8·2H2O. Calculated, %:
C 34.95; H 3.91; N 5.44.
1
1223.6, 1164.1, 1091.5, 980.1, 867.8, 570.9. H NMR
spectrum (CDCl3), δ, ppm: 2.04 s (6H, SCH3), 2.1–
2.7 m (8H, CH2), 3.70 s (6H, OCH3), 4.11 t (2H, CH,
J = 6.4 Hz), 7.50 s (2H, CH), 8.06 s (2H, HC=N).
MALDI-TOF mass spectrum, m/z (Irel, %): positive
ions: 908 (69) [2M – H]+, 762 (100) [2M – MeS-
(CH2)2CHCO2Me]+; negative ions: 453 (100) [M – H]–,
307 (43) [M – MeS(CH2)2CHCO2Me]–.
Complex VIe was obtained from 0.90 g of diso-
dium salt Ie. Yield 0.66 g (57%). IR spectrum, ν, cm–1:
3432.7, 2962.1, 2931.3, 2873.4, 1648.8, 1613.7,
1554.3, 1468.6, 1454.1, 1392.4, 1365.4, 1322.9,
1278.6, 1232.3, 1072.2. Found, %: C 45.18; H 5.68;
N 4.98. C22H30Cu2N2O6·2H2O. Calculated, %: C 45.43;
H 5.89; N 4.82.
Dimethyl N,N′-(2-hydroxy-5-methylbenzene-1,3-
diyldimethyl)bis[(2S)-2-amino-4-methylsulfanyl-
butanoate] (V). A solution of 2.27 g (5 mmol) of
Schiff base IV in 75 ml of methanol was cooled to
–30°C, 0.57 g (15 mmol) of sodium tetrahydridoborate
was added, and the mixture was stirred for 1 h at
–30°C and for 1 h at room temperature. A solution of
0.9 g (15 mmol) of acetic acid in 10 ml of methanol
was then slowly added dropwise, the mixture was
stirred for 1 h, and the solvent was removed on a rotary
evaporator. The residue was extracted with diethyl
ether, the extract was filtered and concentrated under
reduced pressure, 100 ml of hexane was added, and the
oily material was separated from the hexane solution,
washed with hexane, and dried under reduced pressure
at 45°C. Yield 1.61 g (70%), light yellow oily sub-
This study was performed under financial support
by the Byelorussian Foundation for Basic Research
(project no. № Kh08R-051), by the Russian Founda-
tion for Basic Research (project no. 08-03-90025), and
partly by the President of the Russian Federation
(project no. MK-3588.2008.3). The authors thank
Prof. Yu.A. Ustynyuk for setting the task and helpful
discussions.
REFERENCES
1. Cherevin, M.S., Gulevich, T.G., Borisova, N.E., Zubrei-
chuk, Z.P., Kolesnikov, G.V., Reshetova, M.D., and
Knizhnikov, V.A., Russ. J. Org. Chem., 2007, vol. 43,
p. 1567.
1
stance. IR spectrum: ν 1733 cm–1 (C=O). H NMR
spectrum (CDCl3), δ, ppm: 1.98 s (6H, SCH3), 2.10–
2.35 m (8H, CH2), 2.33 s (3H, CH3), 3.73 t (2H, CH,
J = 6.6 Hz), 3.80 s (6H, OCH3), 4.26 s (4H, CH2N),
7.24 s (2H, CH). MALDI-TOF mass spectrum: m/z
1229 (Irel = 100%) [3M – MeS(CH2)2CHCO2Me + 4H]+.
2. Lee, Ch.-S., Teng, P.-F., Wong, W.-L., Kwong, H.-L., and
Chan, A.S.C., Tetrahedron, 2005, vol. 61, p. 7924.
3. Turgut, Y., Demirel, N., and Hosgoren, H., J. Inclusion
Phenom. Macrocycl. Chem., 2006, vol. 54, p. 29.
4. Sawada, M., Okumura, Y., Yamada, H., Takai, Y., Taka-
hashi, Sh., Kaneda, T., Hirose, K., and Misumi, S., Org.
Mass Spectrom., 1993, vol. 28, p. 1525.
5. Liu, Sh.-Y., He, Y.-B., Qing, G.-Y., Xu, K.-X., and
Qin, H.-J., Tetrahedron: Asymmetry, 2005, vol. 16,
p. 1527.
Copper complexes VIb, VId, and VIe (general
procedure). A solution of 0.68 g (4 mmol) of cop-
per(II) chloride dihydrate in 35 ml of methanol was
added to a solution of 2 mmol of disodium salt Ib, Id,
or Ie in 35 ml of anhydrous methanol. The mixture
was stirred for about 1 h at room temperature, evap-
orated by half, and mixed with 15 ml of toluene. The
green precipitate was filtered off, washed with ice
6. Qing, G.-Y., He, Y.-B., Zhao, Y., Hu, Ch.-G., Liu, Sh.-Y.,
and Yang, X., Eur. J. Org. Chem., 2006, p. 1574.
7. Lu, G., Liu, F., Song, W., He, W., Prados, P., and de
Mendoza, J., Mater. Sci. Eng. C, 1999, vol. 10, p. 29.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009

PINCER LIGANDS BASED ON α-AMINO ACIDS: III.
373
8. Liu, F., Lu, G.-Y., He, W.-J., Liu, M.-H., and Zhu, L.-G.,
16. Illán-Cabeza, N.A., Moreno-Carretero, M.N., and
Costa Pessoa, J., Inorg. Chim. Acta, 2005, vol. 358,
p. 2246.
Thin Solid Films, 2004, vol. 468, p. 244.
9. Du, C.-P., You, J.-S., Yu, X.-Q., Liu, Ch.-L., Lana, J.-B.,
and Xie, R.-G., Tetrahedron: Asymmetry, 2003, vol. 14,
p. 3651.
17. Jakubke, H.-D. and Jeschkeit, H., Amino Acids,
Peptides, and Proteins: An Introduction, New York:
Wiley, 1977. Translated under the title Aminokisloty.
Peptidy. Belki, Moscow: Mir, 1985, p. 33.
10. Dowden, J., Edwards, P.D., Flack, S.S., and Kil-
burn, J.D., Chem. Eur. J., 1999, vol. 5, p. 79.
18. Nakamoto, K., Morimoto, Y., and Martell, A.E., J. Am.
Chem. Soc., 1961, vol. 83, p. 4528.
11. Liu, Y., You, Ch.-Ch., Zhang, H.-Y., and Zhao, Y.-L.,
Eur. J. Org. Chem., 2003, p. 1415.
19. Sorrell, T.N., Jameson, D.L., and O’Connor, Ch.J.,
Inorg. Chem., 1984, vol. 23, p. 190.
20. Analytical Methods in Supramolecular Chemistry,
12. Belokon’, Y.N., Pritula, L.K., Tatarov, V.I., Bakhmu-
tov, V.I., Gusev, D.G., Saporovskaya, M.B., and Beli-
kov, V.M., J. Chem. Soc., Dalton Trans., 1990, p. 1873.
Schalley, Ch.A., Weinheim: Wiley, 2007, p. 484.
13. Belokon’, Yu.N., Pure Appl. Chem., 1992, vol. 64,
p. 1917.
14. Kim, H.-J., Asif, R., Chung, D.S., and Hong, J.-I., Tetra-
hedron Lett., 2003, vol. 44, p. 4335.
21. Gershkovich, A.A. and Kibirev, V.K., Sintez peptidov.
Reagenty i metody (Synthesis of Peptides. Reagents and
Methods), Kiev: Naukova Dumka, 1987, 264.
15. Ye, G., Chai, Y.R., Zhou, L., Li, Y., and Zhang, L., Anal.
Sci., 2007, vol. 23, p. 171.
22. Lindoy, L.F., Meehan, G.V., and Svenstrup, N.,
Synthesis, 1998, p. 1029.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 3 2009