Synthesis and characterization of CuII complexes with amino acid substituted di(2-pyridyl)amine ligands

Article abstract of DOI:10.1002/ejic.200700273

The two-step syntheses of the substituted di(2-pyridyl)amine ligands (dpa), dpa-CH₂CO₂H (1) and dpa-PhCO₂H (2), are described. Ligands 1 and 2 are successfully coupled to the amino acid phenylalanine, yielding the derivati

Full text of DOI:10.1002/ejic.200700273

FULL PAPER
DOI: 10.1002/ejic.200700273
Synthesis and Characterization of CuII Complexes with Amino Acid
Substituted Di(2-pyridyl)amine Ligands
[a]
[a]
[a]
´
Srecko I. Kirin, Hemant P. Yennawar, and Mary Elizabeth Williams*
Keywords: Bioconjugates / Bioinorganic chemistry / Copper complexes / Di(2-pyridyl)amine
The two-step syntheses of the substituted di(2-pyridyl)-
amine ligands (dpa), dpa-CH2CO2H (1) and dpa-PhCO2H
(2), are described. Ligands 1 and 2 are successfully coupled
to the amino acid phenylalanine, yielding the derivatives 4
and 6, respectively. Four CuII(dpa)2 complexes, [Cu(dpa-
CH2CO2tBu)2(NO3)2] (3Cu), [Cu(dpa-CH2CO-PheOMe)2-
(H2O)2](NO3)2·2MeOH (4Cu), [Cu(dpa-PhCO2Me)2 (MeOH)2]-
and 4) or blue (for 5 and 6) wavelengths of the free ligands
is preserved in the corresponding Cu complexes, although
with lower intensity. X-band EPR spectra of 4Cu and 6Cu both
revealed one axial CuII signal with hyperfine and superhy-
perfine splittings. Complexes 4Cu and 6Cu are chiral inor-
ganic complexes with amino acid bioconjugates that may
serve as nucleoside analogs in modified peptide nucleic acids
(PNA).
(ClO4)2 (5Cu) and [Cu(dpa-PhCO-PheOMe)2(ClO4)2] (6Cu
)
have been prepared and characterized, including their single
crystal X-ray structures. Fluorescence emission at UV (for 3
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
variety of metal ions and oligomeric backbones (i.e. sugar
phosphate and pseudo-peptide) have also been re-
ported.[5–18]
Introduction
Inorganic nucleic acid derivatives and structural mimics
have received increased attention in recent years[1] in view
of their potential applications in biological and material sci-
ences. Electrostatic attraction has been used to coat the ex-
terior of nucleic acids with metals,[1a] and metal complexes
have been inserted into double-stranded DNA (dsDNA)
duplexes by intercalation and threading.[2] In contrast,
metal ions have been incorporated inside the core of the
nucleic acid duplex by replacing hydrogen bonds with met-
als that covalently link the nucleobases. Inclusion of metals
in this manner changes the properties of the dsDNA du-
plex. For example, Lee et al. abstracted protons from the
nucleobases of a DNA duplex at high pH, and replaced
some of these H atoms with Zn cations.[3] The resulting du-
plex had improved electrical conductivity that was attrib-
uted to the metal-linked base pairs. Analogously, two thy-
mine nucleobases have been shown to form a neutral com-
plex upon complexation of a HgII ion.[4] Using this coordi-
nation chemistry, dsDNA duplex formation by metal coor-
dination of multiple HgII ions along the oligonucleotide has
been demonstrated. Nucleobases have also been replaced by
synthetic ligands to adjust the binding affinity of metal
ions. A number of common metal binding ligands and a
Di(2-pyridyl)amine (dpa) is a well-known ligand for a
range of transition metals, and structural studies on these
complexes have been reported.[19] Metal dpa complexes
have been used as homogeneous or heterogeneous catalysts
in a number of chemical transformations including hydro-
lytic or oxidative DNA cleavage,[20] hydrolytic cleavage of
amino acid esters,[21] oxidation of alcohols,[22] ring-opening
metathesis polymerization,[23] Heck reactions,[24] and vari-
ous asymmetric reactions.[25] Dpa based luminescence has
been utilized for the development of new materials.[26]
Given these properties of metal dpa complexes, develop-
ment of methods for incorporation of the ligand into syn-
thetically modified nucleic acids, nucleobases analogs, or bi-
oconjugates will lead to broad applications in bioinorganic
systems.
We have recently described heterocyclic ligand-contain-
ing aminoethyl glycine (aeg) oligomers,[5b,14] chains that are
charge-neutral mimics of the sugar phosphate backbone of
DNA. Our aeg oligomers crosslink by coordination of tran-
sition-metal ions and are synthetic inorganic structural ana-
logs of dsDNA in which all hydrogen-bonded base pairs are
replaced by metal coordination bonds. In previous studies,
the aeg backbone has been successfully substituted with the
acetic acid derivatives of the py,[5b,14a–5e] bpy,[14a,14c,14e]
tpy,[14e] phtpy[14g] or hq[14f] ligands shown in Figure 1.
Herein we extend this chemistry by introducing the fluores-
cent dpa ligands 1 and 2 and attach the ligands to an amino
acid. Two of these ligands are crosslinked by coordination
[a] Department of Chemistry, Pennsylvania State University, 104
Chemistry Building,
University Park, PA 16802, USA
E-mail: mbw@chem.psu.edu
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
3686
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CuII Complexes with Substituted Di(2-pyridyl)amine Ligands
FULL PAPER
to one CuII ion to form the chiral inorganic building block synthesis of ester 5 included the construction of the dpa
that could be used to replace nucleosides in modified pep- framework by condensation of p-aminobenzoic acid with
tide nucleic acid (PNA).[27]
two equivalents of 2-bromopyridine, K2CO3, and co-cata-
lysts KI, Cu(SO4)2 and phenanthroline, to give the pure
compound in 52% yield. Ester 5 was deprotected in stan-
dard conditions to yield the free acid 2 (89%).
Scheme 1. Synthesis of the aliphatic side chain dpa derivatives 1, 3
and 4: (i) KOH, KI (cat.), DMSO/2 h, room temp. (47%); (ii) TFA,
TIS, DCM/10 h, room temp. (91%); (iii) HBTU, HOBt, H-Phe-
OMe·HCl, DIPEA/20 h, 0 °CǞroom temp. (51%).
Figure 1. The heterocyclic acetic acid derivatives previously used
for the synthesis of aeg-oligoligandosides[5b,14] and the dpa deriva-
tives 1 and 2 prepared in this study.
Results and Discussion
Dpa Ligands and Amino Acid Conjugates
In contrast to the other ligands shown in Figure 1, dpa
has not yet been used extensively in the synthesis of nucleo-
side analogs or bioconjugates. This is likely due to the diffi-
cult derivatization of the central amine atom. In the litera-
ture two different routes are frequently used for the synthe-
sis of the aromatic amines like 1 and 2: the Pd-catalyzed
Buchwald–Hartwig amination[28,29] and the Ullmann con-
densation,[30,31] often catalyzed by CuII salts. The Buch-
wald–Hartwig amination is strongly affected by electron-
withdrawing substituents [like the p-methoxycarbonyl
group in Scheme 2, reaction (i)],[32] while the Ullmann con-
Scheme 2. Synthesis of the aromatic side chain dpa derivatives 2, 5
and 6: (i) K2CO3, KI (cat.), Cu(SO4)2·5H2O (cat.) phen (cat.), neat/
7 h, 200 °C (52%); (ii) 1  NaOH/16 h, room temp. (89%); (iii)
HBTU, HOBt, H-Phe-OMe·HCl, DIPEA/20 h, 0 °CǞroom temp.
(56%).
The ability of the ligands 1 and 2 to react in amide con-
densation needs aggressive conditions (high temperatures densations was tested by reaction with the primary amine
and extended reaction times), to produce only moderate group of acid-protected phenylalanine according to
yields.[30]
Scheme 1 and Scheme 2. The corresponding products 4 and
The Ullmann condensation was used to prepare key in- 6 were obtained, strongly indicating the viability of 1 and
termediates 3 and 5 according to Scheme 1 and Scheme 2, 2, respectively, for the construction of dpa-substituted aeg
respectively. The ester 3 was synthesized by substitution of oligomers.
the commercially available dpa with tert-butyl bromoace-
Interestingly, the 1H NMR (CDCl3) spectra of the phen-
tate in DMSO with KOH and catalytic KI to give the puri- ylalanine conjugates 4 and 6 contain different features. The
fied ester 3 in 47% yield. Deprotection of the ester pro- amide proton in 6 is found below 7 ppm, as expected for an
ceeded smoothly to give the free acid 1 (91% yield). The amide proton not involved in H-bonding. In contrast the
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S. I. Kirin, H. P. Yennawar, M. E. Williams
FULL PAPER
amide proton in 4 is shifted above 7 ppm, which is indica- served in the Cu complexes, but are weaker in intensity than
tive of H-bonding that likely is a result of the formation of in the corresponding free ligands, as has been reported for
the cyclic conformation of 4 in Figure 2. A hydrogen bond other [Cu(dpa)2]2+ complexes.[33]
between the amide proton and the central dpa nitrogen
Table 1. Compilation of spectroscopic data.
atom causes the formation of a five-membered ring. This
cyclic conformation is not possible for the rigid conjugate
λmax/nm[a]
λabs
λex
λem
6.
3
4
5
6
228, 306
296
278
324
318
360
304
432
414
228, 303[b]
223, 311
225,[b] 311
3Cu
4Cu
5Cu
6Cu
296, 379,[c] 621[c]
296, 376,[c] 594[c]
315, 390,[c,b] 679[c,d]
309, 391,[c] 678[c,d]
280
279
324
317
305
304
434
415
Figure 2. The cyclic conformation of dpa - amino acid conjugate 4
in CDCl3 solution.
[a] The maxima (λmax) of absorption (λabs), excitation (λex) and
emission (λem) were measured in methanol. [b] Shoulder. [c] These
signals were measured in methanol/water = 1:1 solvent mixture due
to low solubility in methanol. [d] very broad peak.
Dpa Metal Complexes
The complexes 3Cu–6Cu have been obtained in moderate
to good yields (50–75%) by mixing methanolic solutions of
ligands 3 or 4 with CuII nitrate and ligands 5 or 6 with CuII
perchlorate as shown in Scheme 3. Time of flight positive
ion electrospray (TOF-ES+) mass spectra of 3Cu–6Cu con-
tain the molecular ion peaks for the [CuL2]+ complex,
where L is the corresponding ligand 3–6.
X-band EPR spectra of 4Cu and 6Cu (0.5 m in frozen
solution of a 1:1 water/methanol mixture) both show a well-
resolved axial CuII signal with large separation of gʈ and gЌ
(Figures S9 and S10 and quantitative details in the support-
ing information; for supporting information see also the
footnote on the first page of this paper). This observation is
expected for a compound containing electronically identical
CuII atoms separated by a distance of at least 6 Å[14a,34a]
and is consistent with the geometry found by X-ray crystal-
lography, see below. In addition, the EPR spectra show hy-
perfine splitting due to coupling of the unpaired electron
with the copper nucleus (I = 3/2 for 63Cu and 65Cu) and
superhyperfine splitting due to coupling with the directly
coordinated nitrogen nuclei (I = 1 for 14N and I =
1/2 15N).[34b,34c]
X-ray Crystallography
Single crystals suitable for X-ray analysis could be ob-
tained for all four complexes in this study. Precipitation
from a methanol solution was successful for 5Cu, diffusion
of diethyl ether in the methanol solution of the complex
Scheme 3. Synthesis of the [Cu(dpa)2] complexes 3Cu–6Cu: (i)
MeOH, ∆ (50–75%).
was used for 3Cu, while slow evaporation from methanol
[35]
solution was applied for 4Cu and 6Cu
.
Single crystals of
Optical absorbance and emission spectroscopy were also
used to characterize the Cu complexes. The UV/Vis ab-
sorbance and fluorescence spectroscopic data of complexes
the complexes were grown directly from the reaction mix-
3
Cu–6Cu are compared to those of the free ligands 3–6 in
Table 1. Absorption spectra of the ligands and the Cu com-
plexes contain characteristic peaks at high energy that are
due to the π–π* transition of the aryl groups (λ Ͻ 320 nm).
Additional peaks in the spectra of 3Cu–6Cu are found at
375–390 nm and above 600 nm. Both the ligands and the
metal complexes are emissive; the UV (for 3 and 4) or blue
(for 5 and 6) fluorescent emission of the free ligands is at-
tributed to π*–π relaxation in the dpa ligand.[32] The red
shift of the emission bands in the aromatic side chain li-
gands 5 and 6 is a result of the conjugation with the adja-
Figure 3. X-ray single crystal structure of 3Cu (thermal ellipsoids at
cent phenyl ring. In contrast, the emission bands are pre- 50% probability).
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CuII Complexes with Substituted Di(2-pyridyl)amine Ligands
FULL PAPER
ture at room temperature; the solved crystal structures are Table 2. Selected bond lengths [Å] and angles [°] for 3Cu-6Cu
.
shown in Figures 3, 4, 5 and 6, and the selected bond
lengths and angles are collected in Table 2.
3Cu
1.994(2) 2.011(6)
2.029
2.005(2) 2.029(6)
1.980(6)
2.467(2) 2.451(5)
2.411(6)
85.10(7) 85.3(2)
86.4(2)
96.98(6) 91.4(2)
84.8(3)
89.74(7) 93.4(3)
4Cu
5Cu
2.007(2) 2.006(7)
2.008(7)
1.982(2) 2.015(7)
2.007(6)
2.472(2) 2.452(7)
2.477(8)
85.67(9) 86.0(3)
84.7(3)
89.58(9) 93.1(2)
88.5(2)
93.43(9) 81.1(3)
6Cu
Cu(1)–N(1)
Cu(1)–N(51)
Cu(1)–N(13)
Cu(1)–N(63)
Cu(1)–O(41)
Cu(1)–O(91)
N(1)–Cu(1)–N(13)
N(51)–Cu(1)–N(63)
N(1)–Cu(1)–O(41)
N(1)–Cu(1)–O(91)
N(13)–Cu(1)–O(41)
N(13)–Cu(1)–O(91)
N(1)–C(6)–C(8)–C(13)
N(51)–C(56)–C(58)–C(63)
α [plane A/plane AЈ][a]
β [plane B/plane C][a]
χ [plane D/plane Ph][a]
–
–
–
–
–
–
–
–
–
–
–
–8.8
–
85.5(2)
3.4
–2.8
–
7.2
–
87.3(3)
5.2
2.1
43.6
38.1
–
53.4, 50.0 37.0
35.6, 36.7 39.0
–
34.8, 36.9
35.4, 41.5
87.4, 79.6
73.7
[a] See Figure 7 for explanation.
The crystal structures of 3Cu–6Cu share a number of com-
mon features that for clarity are described using 3Cu as the
example (Figure 3). The structure unambiguously confirms
Figure 4. X-ray single crystal structure of 4Cu dication (thermal el-
lipsoids at 30% probability). The nitrate counterions and methanol
solvent molecules are omitted for clarity.
Figure 5. X-ray single crystal structure of 5Cu (thermal ellipsoids at 50% probability).
Figure 6. X-ray single crystal structure of 6Cu (thermal ellipsoids at 50% probability).
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S. I. Kirin, H. P. Yennawar, M. E. Williams
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the [Cu(dpa)2] stoichiometry as well as the bidentate nature There is also weak π-stacking between the py substituent
of the dpa ligand, in which only the py nitrogen atoms coor- from one molecule with the phenyl substituent of Phe from
dinate to the Cu and the central dpa amine atom is not its neighbor. These contacts cause the formation of chains
involved in metal chelation. The N4O2 coordination polyhe- along the c axis in the crystal of 6Cu (Figure S12 in the
dron is Jahn–Teller distorted square pyramidal. Four N electronic supporting information). As a result, the Cu–Cu
atoms from the two dpa ligands coordinate to the Cu in the separation in these chains is 12.1 Å. The large separation of
equatorial plane, d(Cu–N) = 1.99 and 2.01 Å, while nitrate the copper centers in 4Cu and 6Cu is in accordance with the
counterions occupy the apical positions, d(Cu–O) = 2.47 Å. EPR spectra discussed above.
The bite angle of the dpa ligand (85.1°) indicates that there
is only minimal strain in the six-membered chelate ring. Be-
Conclusions
cause the counterions or solvent molecules occupy apical
positions, differences exist in the structures: these are ni-
trates in 3Cu, perchlorates in 6Cu, water in 4Cu, and meth-
The two new bidentate heterocyclic nitrogen ligands 3
and 5 have been prepared using the Ullmann reaction in
at least 47% yield. The ester groups in 3 and 5 have been
hydrolyzed in standard conditions to give the acids 1 and
2, respectively. Ligands 1 and 2 have a carboxylic functional
group that allows their use in conjugation with biological
molecules. To confirm this, the bioconjugates 4 and 6 with
the amino acid H-Phe-OMe have been prepared following
Scheme 1 and Scheme 2.
The Cu complexes 3Cu–6Cu have been synthesized and
fully characterized, including their X-ray single crystal
structures. In addition to confirming the 1:2 metal to ligand
stoichiometry, the X-ray structures reveal square bipyrami-
dal geometries for all four complexes in this study. Both
the free ligands and their corresponding Cu complexes are
fluorescent.
anol in 5Cu
.
Selected geometrical parameters are summarized in Fig-
ure 7. The dpa moiety in 3Cu is not planar, and the angle α
between the py rings is found to be 43.6°. In addition the
central dpa chelate ring B is not coplanar with the coordi-
nation plane C and the angle between B and C is 38.1°. The
conformation of the phenyl side chain with respect to the
dpa moiety defined by the χ angle, specific to 5Cu and 6Cu
,
is shown in Figure 7.[36] In both 5Cu and 6Cu χ is rather
large, Ͼ70°, resulting in a “twisted” conformation in these
complexes.
Conjugates of metal complexes with amino acids or pep-
tides have a number of biological applications,[37,38] includ-
ing artificial catalysts or enzymes for biochemical reac-
tions.[39] In this paper, we present complexes with an 1:2
metal/ligand stoichiometry that can serve as inorganic ana-
logs of nucleic acids.[5b,14] Our current efforts are focused
on the development of chiral inorganic nucleic acid models
based on the aeg-oligoamide chemistry.
Experimental Section
General Remarks: Chemicals were used without further purification
except where indicated. UV/Vis absorption spectra were measured
in 1-cm quartz cuvettes in a double-beam spectrophotometer (Var-
ian Cary 500). Excitation and emission spectra were recorded with
a Photon Technologies International fluorimeter. Positive-ion time
of flight electrospray mass spectrometry (TOF ES+) was performed
using a Mariner mass spectrometer (Perseptive Biosystems). For
fragments containing copper only the isotopomer of the highest
intensity was described. NMR spectra were collected with a 360-
MHz spectrometer (Bruker AV 360). Chemical shifts, δ/ppm, indi-
cate a downfield shift from tetramethylsilane, TMS, the internal
standard. Coupling constants, J, are given in Hz. X-band EPR
spectra were obtained using a 9.5-GHz Bruker eleXsys 500 spec-
trometer equipped with a liquid helium cryostat. The experiments
were performed in a frozen solution (0.5 m in methanol/water =
1:1) at 20 K, with a modulation frequency of 100 kHz and a modu-
lation amplitude of 5 G. The g factors were calculated as g =
714.484 ν/B0, were ν is the microwave frequency in GHz and B0 the
magnetic field in gauss.
Figure 7. Selected geometrical parameters in [Cu(dpa)2] complexes
are defined as α (angle between the planes A and AЈ), β (angle
between B and C), and χ (angle between the planes H and Ph).
In 3Cu and 5Cu no significant intermolecular contacts are
found, except the hydrogen bond between the coordinated
methanol and a perchlorate counterion in 5Cu. The inor-
ganic nucleoside pair analogs 4Cu and 6Cu have more inter-
esting intermolecular interactions. In 4Cu the amide oxygen
atom of the dpa ligand coordinates to the water molecule
in the apical position by hydrogen bonding. In addition,
π-stacking is found between dpa ligands from neighboring
molecules, which causes chains to form along the a crystal-
lographic axis (Figure S11 in the electronic supporting in-
formation). Dpa π-stacking allows the Cu atoms of neigh-
boring complexes to come as close as 8.2 Å. In 6Cu, short
contacts include hydrogen bonding between the coordi-
nated perchlorate counterion of one molecule and the phe-
Dpa-CH2CO2tBu (3): KOH (3.0 g, 53.6 mmol, 4.6 equiv.) was
nylalanine amide proton of the neighboring molecule. added to the solution of dpa (2.0 g, 11.7 mmol) in dimethyl sulfox-
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CuII Complexes with Substituted Di(2-pyridyl)amine Ligands
ide (DMSO, 40 mL) and the resulting suspension was stirred over-
FULL PAPER
Dpa-PhCO2Me (5): Methyl p-aminobenzoic acid (2 g, 13.23 mmol),
night at room temperature. KI (200 mg, 1.2 mmol, 0.1 equiv.) and 2-bromopyridine (2.5 mL, 26.11 mmol), potassium carbonate (2 g),
tert-butyl chloroacetate (4ϫ0.5 mL, 14.0 mmol, 1.2 equiv.) were
added. The reaction was stirred for additional 2 h and the resulting
mixture was extracted with diethyl ether (3ϫ50 mL). The organic
extracts were dried with Na2SO4, filtered and the ether removed
under reduced pressure to give a brown oil. The crude product was
purified by column chromatography (silica, hexane/ethyl acetate =
8:2). Yield: 1.56 g (47%), pale yellow oil. Mr (calcd. for
C16H19N3O2) = 285.34, MS (TOF ES+): m/z = 324.5 [M + K]+,
potassium iodide (200 mg), copper(II) sulfate pentahydrate
(200 mg) and phenanthroline (200 mg) were mixed in a 100-mL
round-bottomed flask and heated at 200 °C for 7 h. After the reac-
tion mixture was cooled down to room temperature, it was parti-
tioned between water (150 mL) and ethyl acetate (150 mL). The
water layer was further extracted with ethyl acetate (2ϫ150 mL).
The combined organic extracts were dried with sodium sulfate, fil-
tered and evaporated at reduced pressure. The crude product was
308.5 [M + Na]+, 286.5 [M + H]+, 230 [M – OtBu]+. HR MS (TOF subjected to column chromatography (Ø 2.5 cm, silica, 75 g), a hex-
ES+): exp. 286.1549 and calcd. 286.1556 for [C17H12N3O2]+. 1H
ane/ethyl acetate gradient (5:5 Ǟ 2:8) was used as eluent. Yield:
2.0 g (52%), pale yellow oil. Mr (calcd. for C18H15N3O2) = 305.33.
MS (TOF ES+): m/z = 306.1 [M + H]+. HR MS (TOF ES+): exp.
306.1261 and calcd. 306.1243 for [C18H16N3O2]+. 1H NMR
3
NMR (CDCl3): δ = 8.32 (ddd, JHH = 1.0, 2.0 and 5.0 Hz, 2 H,
H
py-6), 7.53 (ddd, 3JHH = 2.0, 7.2 and 8.4 Hz, 2 H, Hpy-4), 7.22 (dt,
3JHH = 1.0 and 8.4 Hz, 2 H, Hpy-3), 6.87 (ddd, 3JHH = 1.0, 5.0 and
7.2 Hz, 2 H, Hpy-5), 4.83 (s, 2 H, H1), 1.42 (s, 9 H, HOtBu) ppm.
13C NMR (CDCl3): δ = 175.26 (C=O), 156.75 (Cpy-2), 148.24
3
(CDCl3): δ = 8.36 (ddd, JHH = 1.0, 2.0 and 5.0 Hz, 2 H, HPy-6),
3
3
7.79 (d, JHH = 9.0 Hz, 2 H, HPh-3,5), 7.60 (ddd, JHH = 2.0, 7.5
(Cpy-6), 137.14 (Cpy-4), 117.24 (Cpy-5), 113.87 (Cpy-3), 80.93 (Cq-tBu), and 8.5 Hz, 2 H, Hpy-4), 7.16 (d, 3JHH = 9.0 Hz, 2 H, HPh-2,6), 6.99–
50.63 (C1), 28.03 (CMe) ppm.
7.04 (m, 4 H, Hpy-5 and Hpy-3), 3.89 (s, 3 H, HOMe) ppm. 13C NMR
(CDCl3): δ = 166.14 (C=O), 157.68 (Cpy-2), 149.30 (CPh-1), 148.90
(CPy-6), 137.86 (CPy-4), 130.96 (CPh-3,5), 125.83 (CPh-2,6), 124.98
(CPh-4), 119.14 (CPy-5), 117.88 (CPy-3), 52.61 (COMe) ppm.
Dpa-CH2CO2H (1): Dpa-Ac-OtBu (3, 1.5 g, 5.26 mmol) was dis-
solved in a mixture of dichloromethane (DCM, 12 mL), TIS
(0.6 mL) and TFA (12 mL), stirred at room temperature and the
reaction monitored by TLC (silica, hexane/ethyl acetate = 8:2). Af-
ter the disappearance of the starting material (10 h), the DCM was
evaporated under reduced pressure and cold ether (–20 °C) was
added to the residue. After 1 h at –20 °C, the precipitate was col-
lected by filtration. Yield: 1.10 g (91%) of an off-white solid. Mr
(calcd. for C12H11N3O2) = 229.23. MS (TOF ES+): m/z = 230.1
[M + H]+, 252.1 [M + Na]+. HR MS (TOF ES+): exp. 230.0921
Dpa-PhCO2H (2): Ligand 5 (2.0 g, 6.55 mmol) was dissolved in
methanol (20 mL), 1  NaOH (aq., 1.6 g in 20 mL) was stirred
room temperature added and monitored by TLC (silica, hexane/
ethyl acetate = 3:7). After the disappearance of the starting material
(16 h), the reaction mixture was neutralized with HCl and the sol-
vents evaporated to dryness. The residue was partitioned between
water (150 mL) and ethyl acetate (150 mL), and the aqueous layer
was further extracted with ethyl acetate (2ϫ150 mL), dried with
sodium sulfate, filtered and evaporated at reduced pressure. Yield:
1.63 g (89%), off white solid. The crude product was used without
further purification. Mr (C17H13N3O2) = 291.30. MS (TOF ES+):
and calcd. 230.0930 for [C17H12N3O2]+. H NMR ([D6]DMSO): δ
1
3
3
= 8.30 (ddd, JHH = 0.8 and 5.0 Hz, 2 H, Hpy-6), 7.72 (dq, JHH
=
3
2.0 and 8.5 Hz, 2 H, Hpy-4), 7.29 (dt, JHH = 0.8 and 8.5 Hz, 2 H,
3
H
py-3), 7.02 (dq, JHH = 0.8 and 5.0 Hz, 2 H, Hpy-5), 4.82 (s, 2 H,
H1) ppm. 13C NMR ([D6]DMSO): δ = 170.96 (C=O), 155.22
m/z = 292.1 [M + H]+, 314.1 [M + Na]+. HR MS (TOF ES+): exp.
(Cpy-2), 146.83 (Cpy-6), 137.99 (Cpy-4), 117.33 (Cpy-5), 113.70 292.1100 and calcd. 292.1086 for [C17H14N3O2]+. H NMR ([D6]-
1
3
(Cpy-3), 48.91 (C1) ppm.
DMSO): δ = 8.22 (m, 2 H, Hpy-6), 8.85 (d, JHH = 8.5 Hz, 2 H,
3
H
Ph-3,5), 7.66 (ddd, JHH = 2.0 Hz, 2 H, Hpy-4, 7.5 and 8.5), 7.03–
Dpa-CH2CO-PheOMe (4): Dpa acetic acid (1, 229 mg, 1 mmol),
was suspended in acetonitrile (30 mL) and cooled to 0 °C with an
ice bath. HBTU (379 mg, 1 mmol) and diisopropylethylamine (DI-
PEA, 875 µL, 5 mmol) were added. After the clear solution was
stirred for 1 h at 0 °C, H-Phe-OMe·HCl (216 mg, 1 mmol) was
added. The reaction mixture was allowed to reach room tempera-
ture and the stirring was continued for 20 h. After that period,
the reaction mixture was concentrated under reduced pressure. The
residue was dissolved in DCM (50 mL), washed with sodium hy-
drogen carbonate (satd. aq., 3ϫ50 mL) and the organic extract was
dried with sodium sulfate, filtered and evaporated under reduced
pressure. The crude product was subjected to column chromatog-
raphy (silica, hexane/ethyl acetate = 2:8) to yield a colorless oil
(200 mg, 51%). Mr (calcd. for C22H22N4O3) = 390.44, MS (TOF
ES+): m/z = 391.2 [M + H]+, 413.2 [M + Na]+. HR MS (TOF
ES+): exp. 391.1802 and calcd. 391.1770 for [C22H23N4O3]+. 1H
6.92 (m, 6 H, HPh-2,6, HPh-2,6 and Hpy-5) ppm. 13C NMR ([D6]-
DMSO): δ = 167.32 (C=O), 157.28 (Cpy-2), 148.61 (CPh-1), 148.41
(CPy-6), 138.23 (CPy-4), 130.58 (CPh-3,5), 127.30 (CPh-4), 124.89
(CPh-2,6), 119.19 (CPy-5), 117.63 (CPy-3) ppm.
Dpa-PhCO-Phe-OMe (6): Dpa p-benzoic acid (2, 220 mg,
0.75 mmol), was suspended in DCM (30 mL) and cooled to 0 °C
with an ice bath. HBTU (284 mg, 0.75 mmol), HOBt (125 mg,
0.75 mmol) and DIPEA (700 µL, 4 mmol) were added. After the
clear solution was stirred for 1 h at 0 °C, H-Phe-OMe·HCl (165 mg,
0.75 mmol) was added. The reaction mixture was allowed to reach
room temperature and the stirring was continued for 20 h. After
that period, the reaction mixture was washed with sodium hydro-
gen carbonate (satd. aq., 3ϫ50 mL) and the extracts was dried
with sodium sulfate, filtered and evaporated under reduced pres-
sure. The crude product was subjected to column chromatography
(silica, hexane/ethyl acetate = 2:8) to yield an off-white solid
(190 mg, 56%). Mr (calcd. for C27H24N4O3) = 452.50. MS (TOF
3
NMR (CDCl3): δ = 8.32 (ddd, JHH = 1.0, 2.0 and 5.0 Hz, 2 H,
3
3
Hpy-6), 7.85 (d, JHH = 8.0 Hz, 1 H, NHamide), 7.58 (ddd, JHH
=
2.0, 7.5 and 9.5 Hz, 2 H, Hpy-4), 7.14–7.07 (m, 5 H, 2 HPh-m, 1 ES+): m/z = 453.2 [M + H]+, 475.2 [M + Na]+. HR MS (TOF
HPh-p and 2 Hpy-3), 6.96–6.91 (m, 4 H, 2 HPh-o and 2 HPy-5), 4.90 ES+): exp. 453.1932 and calcd. 453.1940 for [C27H25N4O3]+. 1H
3
3
3
(td, JHH = 6.0 and 8.0 Hz, 1 H, HPhe-a), 4.84 (d, JHH = 16.5 Hz,
1 H, H1a), 4.71 (d, 3JHH = 16.5 Hz, 1 H, H1b), 3.63 (s, 3 H, HOMe),
3.11–2.99 (m, 2 H, HPhe-β) ppm. 13C NMR (CDCl3): δ = 171.65
NMR (CDCl3): δ = 8.33 (ddd, JHH = 1.0, 2.0 and 5.0 Hz, 2 H,
Hpy-6), 7.68 (d, 3JHH = 9.0 Hz, 2 H, HPh-3,5), 7.58 (ddd, 3JHH = 2.0,
7.5 and 9.5 Hz, 2 H, Hpy-4), 7.31–7.06 (m, 7 H, HPh-3,5, HPh-m
,
(Cester), 170.57 (Camide), 156.33 (Cpy-2), 148.32 (Cpy-6), 137.59 HPh-p and Hpy-3), 7.01–6.95 (m, 4 H, HPh-o and HPy-5), 6.49 (d, 3JHH
3
(Cph-i), 135.89 (Cpy-4), 129.22 (Cphe-m), 128.21 (Cphe-o), 126.78
(Cphe-p), 117.92 (Cpy-5), 114.42 (Cpy-3), 53.07 (C1), 52.71 (COMe),
52.09 (CPhe-α), 37.85 (CPhe-β) ppm.
= 7.5 Hz, 1 H, NHamide), 4.90 (td, JHH = 5.5 and 7.5 Hz, 1 H,
3
HPhe-α), 3.75 (s, 3 H, HOMe), 3.27 (dd, JHH = 5.5 and 14.0 Hz, 1
3
H, HPhe-β1), 3.27 (dd, JHH = 5.5 and 14.0 Hz, 1 H, HPhe-β2) ppm.
Eur. J. Inorg. Chem. 2007, 3686–3694
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
3691

S. I. Kirin, H. P. Yennawar, M. E. Williams
FULL PAPER
13C NMR (CDCl3): δ = 171.95 (Cester), 166.18 (Camide), 157.62
843.2680 for [C44H44N8O663Cu]+; X-band EPR (9.370 GHz): gʈ =
(Cpy-2), 148.76 (CPh-1), 148.23 (Cpy-6), 137.80 (CPh-i), 135.78 2.17, Aʈ = 189ϫ10–4 cm–1, gЌ = 2.05.
(Cpy-4), 129.78 (CPh-4), 129.25 (Cphe-m), 128.56 (CPh-3,5), 128.37
(Cphe-o), 127.10 (Cphe-p), 125.58 (CPh-2,6), 118.95 (Cpy-5), 117.62
(Cpy-3), 53.33 (COMe), 52.29 (CPhe-α), 37.73 (CPhe-β) ppm.
[Cu(dpa-PhCO2Me)2(MeOH)2](ClO4)2 (5Cu): Ligand 5 (33.6 mg,
0.11 mmol), Cu(ClO4)2·6H2O (18.5 mg, 0.05 mmol) and methanol
(5 + 5 mL) were used, method 1. After standing for 1 d, the product
was collected by filtration. Yield: 35 mg (75%) of dark brown crys-
tals, X-ray quality. Mr (calcd. for C36H30Cl2N6O12Cu) = 873.11; M
(TOF ES+): 306.1 [ligand 5 + H]+, 328.1 [ligand 5 + Na]+, 369.2
[M – 2 ClO4 – ligand 5], 673.2 [M – 2 ClO4]+. HR MS (TOF ES+):
exp. 673.1627 and calcd. 673.1625 for [C36H30N6O463Cu]+.
Caution: Perchlorate salts are potentially explosive and should be
handled with great care!
Cu Complexes, General Procedure: Solutions containing the corre-
sponding ligand or Cu salt were briefly heated to boiling before
adding the Cu salt solution to the ligand solution reaction mixture
was filtered hot and cooled to room temperature. If precipitation
was observed, the vial was closed and left at room temperature for
the indicated period (method 1). If no precipitation occurred, the
vial was placed in a container with diethyl ether (10 mL), closed,
and left at room temperature for the indicated period (method 2),
or the vial was left open for slow evaporation of the solvent
(method 3). In all cases the product was isolated by filtration and
dried in air.
[Cu(dpa-PhCO-PheOMe)2(ClO4)2] (6Cu): Ligand
6 (37.3 mg,
0.0825 mmol), Cu(ClO4)2·6H2O (13.9 mg, 0.0375 mmol) and meth-
anol (10 + 5 mL) were used, method 3. After standing for 7 d, the
product was collected by filtration. Yield: 27 mg (62%) of green-
brown crystals, X-ray quality. Mr (calcd. for C54H48Cl2N8O14Cu)
= 1167.46. MS (TOF ES+): m/z = 453.2 [ligand 6 + H]+, 475.2
[ligand 6 + Na]+, 967.3 [M – 2 ClO4]+. HR MS (TOF ES+): exp.
967.2982 and calcd. 967.2993 for [C54H48N8O663Cu]+; X-band EPR
(9.370 GHz): gʈ = 2.24, Aʈ = 160ϫ10–4 cm–1, gЌ = 2.07.
[Cu(dpa-CH2CO2tBu)2(NO3)2] (3Cu): Ligand
3
(62.7 mg,
X-ray Crystallographic Data Collection and Refinement: A dark
blue single crystal of 3Cu, a blue crystal of 4Cu and dark green
specimens of 5Cu and 6Cu were coated with paratone freezing oil,
picked up with nylon loops and mounted in the nitrogen cold
stream of the diffractometer. Intensity data were collected using a
Bruker AXS APEX diffractometer equipped with a Mo-target rot-
ating anode X-ray source and a graphite monochromator (Mo-Kα
radiation, λ = 0.71073 Å). Data reduction (including intensity inte-
0.22 mmol), Cu(NO3)2·2.5H2O (23 mg, 0.10 mmol) and methanol
(10 + 5 mL) were used, method 2. After standing for 7 d, the prod-
uct was collected by filtration. Yield: 38 mg (50%) of dark brown
crystals, X-ray quality. Mr (calcd. for C32H38N8O10Cu) = 758.24.
MS (TOF ES+): m/z = 286 [ligand 3 + H]+, 317 [M – 2NO3]2+
,
410 [M – NO3 – ligand 3]+, 633 [M – 2NO3]+. HR MS (TOF ES+):
m/z = exp. 633.2210 and calcd. 633.2251 for [C32H38N6O463Cu]+.
[Cu(dpa-CH2CO-PheOMe)2(H2O)2](NO3)2·2MeOH (4Cu): Ligand gration, background, Lorentz and polarization corrections) was
4 (39 mg, 0.11 mmol), Cu(NO3)2·2.5H2O (12 mg, 0.05 mmol) and
methanol (10 + 5 mL) were used, method 3. After standing for 5 d,
the product was collected by filtration. Yield: 40 mg (75%) of vi-
olet-blue crystals, X-ray quality. Mr (calcd. for C46H56N10O16Cu)
= 1068.54; M (TOF ES+): 391.2 [ligand 4 + H]+, 413.2 [ligand 4
+ Na]+, 453.1 [M – 2NO3 – ligand 4]+, 843.3 [M – 2NO3]+, 866.4
[M – 2NO3 + Na]+. HR MS (TOF ES+): exp. 843.2717 and calcd.
performed by use of the Bruker software package. The structure
was solved by direct methods (SHELXS)[40] and refined by the full-
matrix, least-squares method based on F2 against all reflections
(SHELXL).[41] All non-hydrogen atoms were refined anisotropi-
cally. Hydrogen atoms were placed geometrically and were refined
by use of the riding model. Crystallographic data of 3Cu–6Cu are
listed in Table 3.
Table 3. Crystallographic data for 3Cu–6Cu
.
3Cu
4Cu
5Cu
6Cu
Empirical formula
Formula weight
T [K]
C32H38CuN8O10
758.25
293(2)
C46H56CuN10O16
1068.54
133(2)
C38H38Cl2CuN6O14
937.19
93(2)
C54H48Cl2CuN8O14
1167.46
105(2) K
0.71073
0.09ϫ0.03ϫ0.03
monoclinic
P21
9.530(7)
27.68(2)
9.909(8)
90
λ [Å]
0.71073
0.08ϫ0.05ϫ0.01
monoclinic
C2/c
19.953(6)
10.109(3)
17.502(5)
90
102.839(5)
90
3441.9(17)
4
0.71073
0.71073
Crystal size [mm]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
0.20ϫ0.18ϫ0.07
triclinic
0.12ϫ0.11ϫ0.05
monoclinic
P21/n
11.440(5)
13.457(6)
12.735(6)
90
99.963(10)
90
1930.9(14)
2
¯
P1
8.2409(15)
11.778(2)
12.749(2)
82.676(3)
84.052(3)
81.784(3)
1210.2(4)
1
α [°]
β [°]
103.438(16)
90
2542(3)
γ [°]
V [Å3]
Z
2
ρcalcd. [gcm–3]
µMο-Kα [mm–1]
θ range [°]
1.463
0.704
1.466
0.534
1.612
0.784
1.525
0.614
2.09Յ28.34
15906
4233 [R(int) = 0.0503]
1.024
0.0455
0.1026
2.51Յ28.21
11582
9445 [R(int) = 0.0231]
1.019
0.0680
0.1632
2.21Յ28.45
15262
4804 [R(int) = 0.0593]
1.058
0.0561
0.1294
2.11Յ28.38
19198
11952 [R(int) = 0.0980]
1.093
0.1192
0.2702
Data collected
Independent data
GOF on F2[a]
Final R1 (obsd. data)[b]
Final wR2 (all data)[c]
Largest diff. p/h [eÅ–3]
0.574/–0.521
0.584/–0.450
0.452/–0.460
1.452/–1.837
2 2
[a] GOF = [Σ[w(Fo2 – Fc ) ]/(n – p)]1/2, where n = number of reflections and p = number of refined parameters. [b] R1 = Σ||Fo| – |Fc||/Σ|Fo|.
[c] wR2 = [Σ[w(Fo – Fc ) ]/Σ[w(Fo2)2]]1/2, where w = 1/σ2(Fo2) + (aP)2 + bP, P = (Fo + 2Fc )/3.
2
2 2
2
2
3692
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2007, 3686–3694

CuII Complexes with Substituted Di(2-pyridyl)amine Ligands
FULL PAPER
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[16]
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Acknowledgments
[17]
We are grateful to the David and Lucile Packard Foundation, the
Alfred P. Sloan Foundation and the NSF Chemistry Research In-
strumentation and Facilities grant CHE-0131112 for generous sup-
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Eur. J. Inorg. Chem. 2007, 3686–3694
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. I. Kirin, H. P. Yennawar, M. E. Williams
FULL PAPER
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Received: March 8, 2007
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Published Online: June 22, 2007
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Eur. J. Inorg. Chem. 2007, 3686–3694