TACN-amino acid conjugates and their copper(II) complexes

Article abstract of DOI:10.1021/ic034598y

Triazacyclononane (TACN) was coupled to glycine (L^Gly), alanine (L^Ala), and phenylalanine (L^Phe) via standard solution phase peptide coupling techniques. Copper(II) complexes of these new ligand-amino acid conjugates, [(CuL^Gly)₂](ClO ₄)₄ (1), [(CuL^Ala)₂Cl](ClO ₄)₃ (2), and [Cu₂L^PheCl ₄] (3), were synthesized and characterized. The X-ray crystal structures of 2 and 3 were determined. Complex 2 is a dimeric species where L^Ala bridges between copper ions via its two TACN amine nitrogen atoms to one copper while the Ala terminal amine and carbonyl oxygen bind to the other copper. Complex 3 is bimetallic but only contains one L^Phe ligand that bridges between the copper ions.

Full text of DOI:10.1021/ic034598y

Inorg. Chem. 2003, 42, 5462−5464
TACN−Amino Acid Conjugates and Their Copper(II) Complexes
Arunendu Mondal, Eric L. Klein, Masood A. Khan, and Robert P. Houser*
Department of Chemistry and Biochemistry, UniVersity of Oklahoma, 620 Parrington OVal,
Norman, Oklahoma 73019
Received May 30, 2003
Scheme 1. Syntheses of Ligands LGly, LAla, and LPhe and Complexes
1-3
Triazacyclononane (TACN) was coupled to glycine (LGly), alanine
(LAla), and phenylalanine (LPhe) via standard solution phase peptide
coupling techniques. Copper(II) complexes of these new ligand−
amino acid conjugates, [(CuLGly)2](ClO ) (1), [(CuLAla)2Cl](ClO )
4 4
4 3
(2), and [Cu2LPheCl4] (3), were synthesized and characterized. The
X-ray crystal structures of 2 and 3 were determined. Complex 2
is a dimeric species where LAla bridges between copper ions via
its two TACN amine nitrogen atoms to one copper while the Ala
terminal amine and carbonyl oxygen bind to the other copper.
Complex 3 is bimetallic but only contains one LPhe ligand that
bridges between the copper ions.
Our general synthetic approach for creating ligand-peptide
Coordination chemistry in metalloproteins is dominated
by amino acids since amino acid side chains and backbone
heteroatoms entail the majority of ligands available to
coordinate to metal ions.1 Small molecule models of metal
sites in metalloproteins are an integral part of bioinorganic
chemistry, and the design of new ligands to model chal-
lenging structural and/or functional motifs plays an important
role in the development of new model complexes.2 Most
model complexes use non-amino-acid ligands that mimic
various aspects of the ligand environment found in the
protein. Our laboratory is developing a new class of ligand-
peptide conjugates where small peptides are coupled to
“standard” ligands. Here we report our initial successes in
coupling the tridentate ligand 1,4,7-triazacyclononane (TACN)
with amino acids to form ligand-amino acid conjugates.3
The synthesis and characterization of copper(II) complexes
of these new ligands are also reported.4
conjugates relies on coupling functionalized ligands to the
O-terminus of Boc-protected amino acids or oligopeptides
(Boc ) N-tert-butoxycarbonyl).5,6 The ligand-peptide con-
jugate can then be deprotected and purified. Ligands LGly
,
LAla, and LPhe were synthesized according to Scheme 1 by
coupling the secondary amine nitrogen of Boc2TACN7 to
the acid group of Boc-protected amino acids glycine (Gly),
alanine (Ala), or phenylalanine (Phe), respectively.8
Because of our interest in copper-containing metallopro-
teins,9 we set off to synthesize copper complexes of ligands
LGly, LAla, and LPhe to explore the coordination chemistry of
these new ligand-amino acid conjugates. Copper complexes
[(CuLGly)2](ClO4)4 (1), [(CuLAla)2Cl](ClO4)3 (2), and [Cu2LPhe
-
Cl4] (3) were synthesized in methanol by combining the
ligand with a copper(II) salt.10 Cupric perchlorate hexahydrate
was used to synthesize 1 and 2, whereas cupric chloride was
used to synthesize 3. Complexes 1 and 2 are dimeric with a
2:2 ligand-metal stoichiometry. The dimeric formulation for
* To whom correspondence should be addressed. E-mail: houser@ou.edu.
(1) Roat-Malone, R. M. Bioinorganic Chemistry: A Short Course; John
Wiley & Sons: Hoboken, NJ, 2002.
(4) Copper complexes with simple amino acids and oligopeptides are well-
known. See for example: Harford, C.; Sarkar, B. Acc. Chem. Res.
1997, 30, 123-130.
(5) Schmidt, B.; Ehlert, D. K. Tetrahedron Lett. 1998, 39, 3999-4002.
(6) A similar synthetic approach was used to functionalize cyclen with
amino acids: Geisser, B.; Ko¨nig, B.; Alsfasser, R. Eur. J. Inorg. Chem.
2001, 1543-1549.
(7) Kimura, S.; Bill, E.; Bothe, E.; Weyhermu¨ller, T.; Wieghardt, K. J.
Am. Chem. Soc. 2001, 123, 6025-6039.
(8) See Supporting Information.
(9) Stephens, J. C.; Khan, M. A.; Houser, R. P. Inorg. Chem. 2001, 40,
5064-5065.
(2) Karlin, K. D. Science 1993, 261, 701-708.
(3) Recent examples of ligand-amino acid conjugates: (a) Cox, C.;
Ferraris, D.; Murthy, N. N.; Lectka, T. J. Am. Chem. Soc. 1996, 118,
5332-5333. (b) Niklas, N.; Heinemann, F. W.; Hampel, F.; Alsfasser,
R. Angew. Chem. 2002, 41, 3386-3388. (c) Niklas, N.; Hampel, F.;
Liehr, G.; Zahl, A.; Alsfasser, R. Chem. Eur. J. 2001, 7, 5135-5142.
(d) Niklas, N.; Walter, O.; Alsfasser, R. Eur. J. Inorg. Chem. 2000,
1723-1731. (e) OÄ sz, K.; Va´rnagy, K.; So´va´go´, I.; Lennert, L.; Su¨li-
Vargha, H.; Danna, D.; Micera, G. New J. Chem. 2001, 25, 700-
706. (f) OÄ sz, K.; Va´rnagy, K.; Su¨li-Vargha, H.; Sanna, D.; Micera,
G.; So´va´go´, I. Inorg. Chim. Acta 2002, 339, 373-382.
5462 Inorganic Chemistry, Vol. 42, No. 18, 2003
10.1021/ic034598y CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/05/2003

COMMUNICATION
contrast to the rare examples of copper complexes with coor-
dinated tertiary amides (2.16-2.49 Å).3a-c These amide-coor-
dinated species are sensitive to C-N bond cleavage,3b-c,6
while 2 is stable in methanol. The stability of the amide C-N
bonds in 2 can be attested to the fact that the metal is not
coordinated by the amide N atom. The Ala portion of
the same ligand coordinates to the other copper atom in
2, Cu2, via the terminal amine nitrogen and the carbonyl
oxygen atom.15 The second ligand in the bimetallic complex
is related via a noncrystallographic pseudo-C2 axis to the
first ligand; thus, two LAla ligands bridge between the copper
atoms in 2.
The coordination geometry around each copper is closest
to square pyramidal, with a N3O ligand set in the equatorial
plane and a chloride ligand in the axial position (τ ) 0.16
and 0.10 for Cu1 and Cu2, respectively).16 The chloride
anions bridge between bimetallic moieties [ Cu-Cl-Cu )
158.25(5)°] to create linear chains of molecules along the
crystallographic b axis (see Figure S5). The intra- and
intermolecular Cu‚‚‚Cu distances in 2 are long (> 4.9 Å),
making any significant magnetic coupling between copper-
(II) ions unlikely, an assertion corroborated by the typical
Figure 1. Representation of the X-ray structure of 2 as 50% thermal
ellipsoids. H atoms have been omitted for clarity. Selected bond distances
(Å): Cu1-O2, 1.998(3); Cu1-N2, 1.999(3); Cu1-N1, 2.031(3); Cu1-
N8, 2.057(3); Cu1-Cl1, 2.508(1); Cu2-N6, 1.984(3); Cu1-O1, 1.999(3);
Cu2-N4, 2.007(3); Cu2-N5, 2.025(3); Cu2-Cl1A, 2.526(1).
axial EPR spectrum of 2 (g ) 2.08, g| ) 2.39, ACu
)
|
1 and 2 was determined in solution by ESI-MS. For 1 in
120 G).8
CH3CN: m/z ) 797 [M - ClO4]+, m/z ) 348 [M - CuLGly
-
(ClO4)3]+. For 2 in CH3CN: m/z ) 825 [M - Cl]+, m/z )
761 [M - ClO4]+, m/z ) 362 [M - CuLAlaCl(ClO4)2]+. The
dimeric form of 2 was verified in the solid state by X-ray
crystallography.
Unlike the dimeric 2:2 ligand-metal ratio of 1 and 2, in
the solid state 3 has a 1:2 ligand-metal stoichiometry (vide
infra). Attempts to synthesize the 1:1 or 2:2 ligand-copper
complex using LPhe were unsuccessful, with exclusive
formation of 3 even when excess LPhe was used. Attempts
to synthesize copper complexes with LPhe using cupric
perchlorate were also unsuccessful. The inability of LPhe to
form symmetrical dimers with Cu(ClO4)2, as LGly and LAla
do in 1 and 2, may be a consequence of steric interactions
of the bulkier Phe side chains.
The crystal structure of 2 confirmed that it is composed
of bimetallic species where two copper(II) ions are bridged
via two LAla ligands to form a 4+ cation (Figure 1).11,12 The
charge is balanced by one bridging chloride anion13 and three
outer sphere perchlorate anions. The chloride links molecules
of 2 in the crystal lattice by bridging between Cu1 from one
dimer and Cu2 from an adjacent dimer.
The TACN portion of the LAla ligand binds to Cu1 via
two amine nitrogens, but the amide nitrogen is not coordi-
nated.14 The Cu1‚‚‚N3 distance of 2.96 Å in 2 stands in
The crystal structure of 3 revealed a bimetallic complex
that is different than 2 (Figure 2).11,17 Here, LPhe bridges
between the two copper(II) ions in a manner similar to 2
with the TACN ring binding to Cu1 through the amine N
atoms in a bidentate fashion and the Phe portion of the ligand
binding to Cu2 through the terminal amine and the carbonyl
O atom. However, unlike the symmetric binding mode in 2,
the coordination sphere around each copper(II) ion in 3 is
completed by two chloride ligands.
(10) Analytical data for 1-3 (see Supporting Information for full details).
1: 0.18 g, 40% yield. Anal. Calcd for 1‚2H2O, C16H40Cl4Cu2N8O20:
C, 20.59; H, 4.32; N, 12.00. Found: C, 20.04; H, 4.33; N, 11.08. 2:
0.28 g, 60% yield. Anal. Calcd for 2, C18H40Cl4Cu2N8O14‚CH3NO2‚
H2O: C, 24.26; H, 4.82; N, 13.51. Found: C, 23.53; H, 4.88; N, 12.53.
3: 0.136 g, 50% yield. Anal. Calcd for 3, C15H24Cl4Cu2N4O: C, 33.04;
H, 4.44; N, 10.27. Found: C, 32.78; H, 4.91; N, 10.21.
(11) Data collection was performed on a Bruker Apex CCD diffractometer
with Mo KR radiation (0.71073 Å) at 143 K for 2 and 120 K for 3.
See Supporting Information for full details.
The coordination geometry around both copper(II) ions
is square planar,18 with an N2Cl2 ligand set around Cu1 and
(12) X-ray data for 2: C18H40Cl4Cu2N8O14‚CH3NO2‚H2O, M ) 940.52,
orthorhombic, space group P212121, a ) 9.996(1) Å, b ) 17.432(2)
Å, c ) 20.285(2) Å, V ) 3534.7(7) Å3, Z ) 4, Fcalcd ) 1.767 g/cm3.
All non-hydrogen atoms were refined with anisotropic thermal
parameters, and hydrogen atoms were included with idealized
parameters except the hydrogen atoms on N1, N2, N4, N5, N6, N8,
and O17, which were located and refined with fixed temperature
factors. Full-matrix least-squares refinement on F2 converged with R1
) 0.0505, wR2 ) 0.1334, GOF ) 1.051 for 6919 independent
reflections with I > 2σ(I) and 492 parameters.
(15) This type of chelating binding mode for amino acids is relatively
common and, in particular, has been reported for copper(II) amino
acid species. (a) Tan, X. S.; Fujii, Y.; Sato, T.; Nakano, Y.; Yashiro,
M. Chem. Commun. 1999, 881-882. (b) Castellano, E. E.; Piro, O.
E.; Casado, N. M. C.; Brondino, C. D.; Calvo, R. J. Chem. Crystallogr.
1998, 28, 61-68.
(16) Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.; Verschoor, G.
C. J. Chem. Soc., Dalton Trans. 1984, 1349-1356.
(17) X-ray data for 3: C15H24Cl4Cu2N4O, M ) 545.26, monoclinic, space
group P21, a ) 7.5158(6) Å, b ) 7.5207(6) Å, c ) 17.9669(15) Å, â
) 100.012(1)°, V ) 1000.1(1) Å3, Z ) 2, Fcalcd ) 1.811 g/cm3. All
non-hydrogen atoms were refined with anisotropic thermal parameters,
and hydrogen atoms were included with idealized parameters. Full-
matrix least-squares refinement on F2 converged with R1 ) 0.0221,
wR2 ) 0.0492, GOF ) 1.005 for 3795 independent reflections with
I > 2σ(I) and 235 parameters.
(13) The most likely origin of the chloride is either contamination in the
ligand or in the cupric perchlorate.
(14) This is not surprising in light of the poor coordinating ability of tertiary
amides. See Greenberg, A. In The Amide Linkage; Greenberg, A.,
Breneman, C. M., Liebman, J. F., Eds.; Wiley-Interscience: New York,
2000, pp 47-84.
Inorganic Chemistry, Vol. 42, No. 18, 2003 5463

COMMUNICATION
van der Waals radii [Cu2‚‚‚Cl1 ) 3.042(1) Å, intramolecular;
Cu2‚‚‚Cl2A ) 3.087(1) Å, intermolecular]. The bimetallic
complexes, loosely linked through weak intra- and intermo-
lecular axial bonds, consequently form chains along the
crystallographic b axis (see Figure S7).
Evidence of the two distinct copper coordination environ-
ments for 3 in solution was provided by EPR spectroscopy.
The EPR spectrum of a frozen solution of 3 clearly indicates
two different copper environments based on two distinct g|
signals (Cu1, g| ) 2.41, ACu| ) 119 G; Cu2, g| ) 2.24, ACu
|
) 177 G).8 Whether 3 retains its bimetallic structure or
dissociates is difficult to ascertain from EPR alone. However,
no evidence of the bimetallic species was observed by mass
spectroscopy (ESI-MS for 3 in H2O: m/z ) 410 [M -
CuCl2]+, m/z ) 374 [M - CuCl3]+), suggesting that in
solution 3 dissociates into 1:1 LPheCu monomers and solvated
Cu2+.
In summary, we have synthesized a new family of ligand-
amino acid conjugates by coupling TACN to glycine, alanine,
and phenylalanine. The copper(II) complexes of these ligands
have been synthesized and characterized. The ligands
coordinate in a bridging mode between copper ions. The
TACN amines coordinate to one copper ion whereas the
amino acid amine and carbonyl oxygen coordinate to the
other copper ion.
Figure 2. Representation of the X-ray crystal structure of 3 as 50% thermal
ellipsoids. H atoms have been omitted for clarity. Selected bond distances
(Å): Cu1-N1, 2.039(2); Cu1-N2, 2.032(2); Cu1-Cl1, 2.2729(8); Cu1-
Cl2, 2.2852(8); Cu1‚‚‚N3, 2.783(2); Cu2-O1, 2.007(2); Cu2-N4, 2.004-
(2); Cu2-Cl3, 2.2500(8); Cu2-Cl4, 2.2392(7); Cu2‚‚‚Cl1, 3.042(1).
Acknowledgment. We thank the National Science Foun-
dation (NSF CAREER Award CHE-0094079), the Herman
Frasch Foundation, the donors of the Petroleum Research
Fund, administered by the American Chemical Society, and
the University of Oklahoma for financial support. We also
thank the NSF for the purchase of a CCD equipped X-ray
diffractometer.
a NOCl2 ligand set around Cu2. However, if axial interactions
are considered, the geometry is closer to elongated octahe-
dral. The axial distances involving Cu1 are shorter than the
sum of their van der Waals radii [Cu1‚‚‚N3 ) 2.783(2) Å,
intramolecular; Cu1A‚‚‚Cl3 ) 2.818(1) Å, intermolecular],
suggesting weak Cu‚‚‚ligand interactions. Likewise, the axial
distances involving Cu2 are also shorter than the sum of their
Supporting Information Available: Experimental details and
characterization for LGly, LAla, LPhe, and 1-3 (PDF); X-ray structural
information for 2 and 3 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) The dihedral angle between the Cl1-Cu1-Cl2 plane and the N1-
Cu1-N2 plane is 14°. The dihedral angle between the Cl3-Cu2-
Cl4 plane and the O1-Cu2-N4 plane is 6°.
IC034598Y
5464 Inorganic Chemistry, Vol. 42, No. 18, 2003