Synthesis, characterization, and reactivity of new copper(II) complexes of 2-methylthio-N-(2-pyridylmethyl)acetamide

Article abstract of DOI:10.1021/ic049136e

Copper(II) complexes were prepared with the new N₂S(thioether) ligand 2-methylthio-N-(2-pyridylmethyl)acetamide (2-HL^N2S). [Cu(2-L^N2S)Cl(MeOH)], which formed in the presence of excess triethylamine, is a distorted square pyramidal complex containing the ligand with the amide nitrogen deprotonated. The structurally analogous complex, [Cu(2-HL^N2S)Cl₂], which formed in the absence of triethylamine, contains 2-HL^N2S in the tautomeric imidic acid form. Neutral copper(II) N₂S(thioether)S(thiolate) species were generated by addition of alkyl or aromatic thiolates to [Cu(2-L^N2S)Cl(MeOH)] and an unusual decomposition pathway was discovered.

Full text of DOI:10.1021/ic049136e

Inorg. Chem. 2004, 43, 7272−7274
Synthesis, Characterization, and Reactivity of New Copper(II) Complexes
of 2-Methylthio-N-(2-pyridylmethyl)acetamide
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 July 1, 2004
Copper(II) complexes were prepared with the new N2S(thioether)
ligand 2-methylthio-N-(2-pyridylmethyl)acetamide (2-HLN2S). [Cu(2-
LN2S)Cl(MeOH)], which formed in the presence of excess triethyl-
amine, is a distorted square pyramidal complex containing the
ligand with the amide nitrogen deprotonated. The structurally
analogous complex, [Cu(2-HLN2S)Cl2], which formed in the absence
of triethylamine, contains 2-HLN2S in the tautomeric imidic acid form.
Neutral copper(II) N2S(thioether)S(thiolate) species were generated
by addition of alkyl or aromatic thiolates to [Cu(2-LN2S)Cl(MeOH)]
and an unusual decomposition pathway was discovered.
two copper ions bridged by two cysteine thiolates.6 Copper
metallothioneins contain copper(I) ions coordinated exclu-
sively by cysteine thiolate ligands.7 A methionine thioether
sulfur atom and two histidines coordinate to the copper ion
in CuB from the peptidylglycine R-hydroxylating monooxy-
genase (PHM) domain of peptidylglycine R-amidating
monooxygenase (PAM).8 And finally, inorganic sulfide is
found in the unprecedented catalytic CuZ site from N2OR.9
The diverse and plentiful copper-sulfur chemistry in these
systems has inspired us to investigate the chemistry of copper
complexes of a new thioether-containing ligand. Herein we
report preliminary results of an investigation into the syn-
thesis and characterization of mixed thiolate/thioether copper-
(II) complexes with pyridyl/amide/thioether supporting ligands.
We have synthesized new N2S(thioether) ligands and their
copper(II) complexes, probed their thiolate reactivity, and
discovered an unusual redox decomposition pathway.
The coordination chemistry of copper with sulfur-contain-
ing ligands has attracted considerable interest because of its
relevance to bioinorganic chemistry. Copper thiolate and
thioether complexes are of particular interest because of their
key roles in a number of ubiquitous metalloproteins such
as the type 1 copper electron transfer sites found in
cupredoxins.1 Type 1 copper centers contain a copper ion
coordinated by a distorted tetrahedral arrangement of His2-
CysMet (e.g., plastocyanin2), an axially elongated trigonal
bipyramidal array of His2CysMetGly (e.g., azurin3), or a
distorted trigonal planar array of His2Cys (e.g., azurin
mutants3). In each case, the cysteine residue donates a thiolate
sulfur atom to copper, and in the first two cases methionine
donates a thioether sulfur atom. In what can be described as
a binuclear version of the type 1 copper center, the CuA
electron transfer site, found in both cytochrome c oxidase
(CcO)4 and nitrous oxide reductase (N2OR),5 contains
The new ligand 2-methylthio-N-(2-pyridylmethyl)aceta-
mide (2-HLN2S) was synthesized by DCC-mediated coupling
of methylthioacetic acid to 2-picolylamine.10-12 Ligand
2-HLN2S, which is reminiscent of the N3S(thioether) tetra-
(6) Farrar, J. A.; Neese, F.; Lappalainen, P.; Kroneck, P. M. H.; Saraste,
M.; Zumft, W. G.; Thomson, A. J. J. Am. Chem. Soc. 1996, 118,
11501-11514.
(7) Henkel, G.; Krebs, B. Chem. ReV. 2004, 104, 801-824.
(8) Prigge, S. T.; Eipper, B. A.; Mains, R. E.; Amzel, L. M. Science 2004,
304, 864-867.
(9) (a) Alvarez, M. L.; Ai, J. Y.; Zumft, W.; Sanders-Loehr, J.; Dooley,
D. M. J. Am. Chem. Soc. 2001, 123, 576-587. (b) Ghosh, S.; Gorelsky,
S. I.; Chen, P.; Cabrito, I.; Moura, J. J. G.; Moura, I.; Solomon, E. I.
J. Am. Chem. Soc. 2003, 125, 15708-15709.
(10) DCC ) 1,3-dicyclohexylcarbodiimide. DCC-mediated coupling of
amines with carboxylic acids was used previously in our laboratory
to synthesize ligand-peptide conjugates. Mondal, A.; Klein, E. L.;
Khan, M. A.; Houser, R. P. Inorg. Chem. 2003, 42, 5462-5464.
(11) See Supporting Information for synthetic details and characterization.
(12) The 3- and 4-substituted isomers, 2-methylthio-N-(3-pyridylmethyl)-
acetamide (3-HLN2S) and 2-methylthio-N-(4-pyridylmethyl)acetamide
(4-HLN2S), have also been synthesized. Their syntheses, characteriza-
tion, and coordination chemistry will be reported elsewhere.
* To whom correspondence should be addressed. E-mail: houser@ou.edu.
(1) Solomon, E. I.; Szilagyi, R. K.; George, S. D.; Basumallick, L. Chem.
ReV. 2004, 104, 419-458.
(2) Freeman, H. C.; Guss, J. M. In Handbook of Metalloproteins;
Wieghardt, K., Ed.; Wiley: Chichester, 2001; Vol. 2, pp 1153-1169.
(3) Kolczak, U.; Dennison, C.; Messerschmidt, A.; Canters, G. W. In
Handbook of Metalloproteins; Messerschmidt, A., Huber, R., Poulos,
T., Wieghardt, K., Eds.; Wiley: Chichester, 2001; Vol. 2, pp 1170-
1194.
(4) Tsukihara, T.; Aoyama, H.; Yamashita, E.; Tomizaki, T.; Yamaguchi,
H.; Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yoshikawa, S.
Science 1995, 269, 1069-1074.
(5) Brown, K.; Tegoni, M.; Prudeˆncio, M.; Pereira, A. S.; Besson, S.;
Moura, J.; Moura, I.; Cambillau, C. Nat. Struct. Biol. 2000, 7, 191-
195.
7272 Inorganic Chemistry, Vol. 43, No. 23, 2004
10.1021/ic049136e CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/19/2004

COMMUNICATION
deprotonated to [2-LN2S]- and [Cu(2-LN2S)Cl(MeOH)] (2) is
obtained.11 The structure of 2 (Figure 1, right)15 is similar
to that of 1 in that the ligand coordinates to copper(II) in
the three basal plane positions of the distorted square-
pyramidal complex via its N(py), N(amidate), and S(thio-
ether) donors, but while 2-HLN2S is neutral in 1, the amide
group in 2 is deprotonated and [2-LN2S -
is anionic.
]
Consequently, only one chloride, located trans to N2, is found
coordinated in 2, while the axial coordination site is occupied
by MeOH. With the exception of the axial ligands, the bond
distances and angles around the copper atoms in 1 and 2 are
remarkably similar (see Table 1). The axial Cu1-O1 bond
distance in 2 is more than 0.3 Å shorter than the Cu1-Cl2
distance in 1. This shorter axial bond length in 2 is
accompanied by a shifting of the copper atom out of the
basal plane, giving rise to a larger τ value of 0.21.16 The
tautomeric relationship of the ligands in 1 and 2 is illustrated
quantitatively by the C-N and C-O bond distances high-
lighted in Table 1, which support the assignment of the imidic
acid form of the ligand in 1 and the amidate form of the
ligand in 2. It is noteworthy that 2 is structurally and
spectroscopically similar to [Cu(pyge)Br].13c With the excep-
tion of the axial Cu(II)-ligand bond and the Cu(II)-halide
bonds, the solid state structural parameters for 2 and
[Cu(pyge)Br] are nearly identical. However, while the
structure of 2 is a slightly distorted square pyramid (τ )
0.21), [Cu(pyge)Br] has a τ value of 0.01,13c making it a
nearly ideal square pyramid.
Figure 1. X-ray crystal structure of 1 (left) and 2 (right) as 50% thermal
ellipsoids. Only the imidic acid H1 (1, left) and the methanol H1 (2, right)
hydrogen atoms are shown for clarity.
Table 1. Bond Lengths (Å) for 1 and 2
1
2
Cu1-N1
2.015(3)
1.950(3)
2.3670(9)
2.2369(9)
2.6479(10)
2.0194(12)
1.9316(11)
2.3322(4)
2.2382(4)
Cu1-N2
Cu1-S1
Cu1-Cl1
Cu1-Cl2a
Cu1-O1b
C7-O1a/C7-O2b
C7-N2
2.3293(10)
1.2519(16)
1.3176(17)
1.318(4)
1.277(4)
a Complex 1 only. b Complex 2 only.
dentate ligand N-(2-pyridylmethyl)-2-((2-aminoethyl)thio)-
acetamide (pygeH),13 contains pyridyl and thioether func-
tional groups connected by an amide linkage, providing up
to four potential ligand donor atoms: N(py), N(amide),
O(amide), and S(thioether). Indeed, in the case of copper
complexes of the closely related N-(2-pyridylmethyl)acet-
amide (2-HLN2), the ligand coordinates through all three
potential donor atoms, N(py), N(amide), and O.14
The similarity of the N2S(thioether) ligand set in 2 to the
His2Met ligands of the type 1 copper site in azurin prompted
us to attempt the synthesis of thiolate complexes of 2.
Methanol solutions of 2 were treated at -80 °C with thiols
2,6-dimethylthiophenol (HSAr) or triphenylmethylmercaptan
(HSCPh3), in the presence of triethylamine to deprotonate
the thiols in situ. Alternatively, 2 was treated with the sodium
thiolate salts of HSAr and HSCPh3, producing the same
products. The reactions occur spontaneously and are ac-
companied by dramatic color changes of scarlet red for
2(SAr) and intense green for 2(SCPh3). While solutions of
both 2(SAr) and 2(SCPh3) are stable at -80 °C, they
decompose rapidly at room temperature (vide infra), thwart-
ing recrystallization attempts.
The reaction of 2-HLN2S with CuCl2‚2H2O in methanol
resulted in tautomerization of the ligand amide bond to its
corresponding imidic acid form upon coordination to copper-
(II), generating deep blue [Cu(2-HLN2S)Cl2] (1).11 The X-ray
crystal structure of 1 (Figure 1, left)15 reveals that the copper
ion is coordinated by 2-HLN2S via its N(py), N(amide), and
S(thioether) donors in three basal plane positions of the
square pyramidal complex (τ ) 0.02),16 while the fourth basal
position and one axial position are occupied by chloride
ligands. The imidic acid form of 2-HLN2S is evident in the
C7-N2 and C7-O1 bond distances (Table 1), as well as in
the presence of the hydrogen atom H1 bonded to O1.
When the reaction of 2-HLN2S with CuCl2‚2H2O is carried
out in the presence of excess of triethylamine, 2-HLN2S is
The spectroscopic properties of 2(SAr) and 2(SCPh3)
support their formulation as copper(II) thiolate species. The
EPR spectra of both 2(SAr) and 2(SCPh3) differ considerably
from the EPR of 2 alone,11 suggesting significant geometric
and electronic changes in the coordination sphere around the
copper ion. Furthermore, the UV-vis spectra of 2(SAr) and
2(SCPh3) are dominated by strong absorptions at 496 and
428 nm, respectively [see Supporting Information for 2(SAr)
and Figure 2 for 2(SCPh3)]. These absorptions have been
tentatively assigned as S(thiolate) f Cu(II) LMCT transi-
tions. Additionally, the copper(II) d-d transition is shifted
upon thiolate coordination from 642 nm for 2 to 555 nm for
2(SCPh3) along with an increase in intensity (ꢀ ) 500 M-1
cm-1).
(13) (a) Toscano, P. J.; Marzilli, L. G. Inorg. Chem. 1983, 22, 3342-
3350. (b) Toscano, P. J.; Belsky, K. A.; Engelhardt, L. M.; Fordon,
K. J.; White, A. H. Inorg. Chem. 1990, 29, 1357-1359. (c) Toscano,
P. J.; Fordon, K. J.; Macherone, D.; Liu, S.; Zubieta, J. Polyhedron
1990, 9, 2375-2383.
(14) Mondal, A.; Li, Y.; Khan, M. A.; Ross, J. H., Jr.; Houser, R. P. Inorg.
Chem., in press.
(15) X-ray data collection was performed on a Bruker Apex CCD
diffractometer with Mo KR radiation (0.71073 Å) at 153 K for 1 and
120 K for 2. X-ray data for 1: C9H12Cl2CuN2OS, M ) 330.71, trigonal,
space group P31, a ) 6.9560(8) Å, c ) 21.791(5) Å, V ) 913.1(3)
Å3, Z ) 3, Fcalcd ) 1.804 g/cm3, R1 ) 0.025, wR2 ) 0.062, GOF )
1.023. X-ray data for 2: C10H15ClCuN2O2S, M ) 326.29, triclinic,
space group P1h, a ) 7.3002(3) Å, b ) 8.2461(4) Å, c ) 10.8430(5)
Å, a ) 78.0590(10)°, b ) 80.3540(10)°, c ) 84.5680(10)°, V )
628.36(5) Å3, Z ) 2, Fcalcd ) 1.725 g/cm3, R1 ) 0.020, wR2 ) 0.051,
GOF ) 1.051.
(16) τ ) (â - R)/60. Addison, A. W.; Rao, T. N.; Reedijk, J.; van Rijn, J.;
Verschoor, G. C. J. Chem. Soc., Dalton Trans. 1984, 1349-1356.
Inorganic Chemistry, Vol. 43, No. 23, 2004 7273

COMMUNICATION
and quantified gravimetrically, accounting for 50% of the
copper ions and half of the HSCPh3.20 A mixture of organic
products, including the other half of the HSCPh3 in the form
of disulfide and ligand products, was isolated from the
decomposition solution by flash column chromatography.21
From these observations, it is apparent that only half of
the copper(II) is reduced, leaving the remainder unchanged
as 2. Furthermore, only half of the thiolate is oxidized to
disulfide. When 2 equiv of thiolate is added to 2, all of the
Cu(II) is reduced, as indicated by the complete bleaching of
the solution and formation of [Cu(SCPh3)].20 The absence
of any observable features in the UV-vis or EPR of this
decomposition solution confirms the absence of any detect-
able quantities of Cu(II). These data are consistent with the
reactions illustrated in eqs 1 and 2, where the slow redox
formation of Cu(I) is followed by a fast step where the Cu(I)
sequesters the thiolate from the remaining CuII(2-LN2S)(SR)
species, producing CuI(SR) and CuII(2-LN2S). Thus, 2 equiv
of thiolate are required to reduce the copper(II) since 1 equiv
of thiolate is sequestered by CuI(SR).
Figure 2. Decomposition of 2(SCPh3) in THF at room temperature. Scans
were collected every 10 min.
With the notable exceptions of several stable copper(II)17
and mixed valence thiolate complexes,18 copper(II) thiolates
are readily reduced to copper(I) with concomitant oxidation
of thiolate to disulfide.19 However, our preliminary experi-
ments suggest that the decompositions of 2(SAr) and
2(SCPh3) proceed by way of an alternate pathway. When
solutions of 2(SCPh3) or 2(SAr) are allowed to equilibrate
at room temperature, their color surprisingly changes back
to the blue color of the starting material, 2. The decomposi-
tion of 2(SCPh3) was followed by UV-vis spectroscopy in
THF (Figure 2) and was observed to proceed cleanly as per
the isosbestic point at 338 nm. While the S(thiolate) f Cu(II)
LMCT band at 428 nm completely diminishes, the 555 nm
d-d band undergoes a red shift of about 50 nm, with the
final spectrum corresponding to the spectrum of 2 in the
same solvent. The amount of 2 was quantified by UV-vis
spectrometry, corresponding to exactly half of the original
amount of 2. Furthermore, the identity of the blue species
was verified by X-ray crystallographic analysis of 2 recrys-
tallized from the decomposition solution. A white precipitate
with the empirical formula [Cu(SCPh3)] was also isolated
CuII(2-LN2S)(SR) slow8 CuI + RSSR + 2-HLN2S (1)
fast
CuI + CuII(2-LN2S)(SR) 8 CuI(SR) + CuII(2-LN2S) (2)
In summary, we have synthesized a new ligand, 2-HLN2S
,
that was used to synthesize copper(II) complexes. Thiolate
species were identified spectroscopically and decompose by
an unusual pathway. We are currently investigating this
reaction as well as the coordination chemistry of the related
ligands 3- and 4-HLN2S 12
.
Acknowledgment. We thank the National Science Foun-
dation (NSF-CAREER Award CHE-0094079), and the
Herman Frasch Foundation for financial support. We also
thank the NSF for the purchase of a CCD equipped X-ray
diffractometer at the University of Oklahoma (CHE-
0130835).
Supporting Information Available: X-ray structural informa-
tion for 1 and 2 (CIF). Full experimental details for 2-HLN2S, 1,
and 2. UV-vis and EPR spectra for 1, 2, 2(SAr), and 2(SCPh3)
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) John, E.; Bharadwaj, P. K.; Potenza, J. A.; Schugar, H. J. Inorg.
Chem. 1986, 25, 3065-3069. (b) Kitajima, N.; Fujisawa, K.; Tanaka,
M.; Moro-oka, Y. J. Am. Chem. Soc. 1992, 114, 9232-9233. (c)
Houser, R. P.; Halfen, J. A.; Young, V. G., Jr.; Blackburn, N. J.;
Tolman, W. B. J. Am. Chem. Soc. 1995, 117, 10745-10746. (d)
Holland, P. L.; Tolman, W. B. J. Am. Chem. Soc. 1999, 121, 7270-
7271. (e) Holland, P. L.; Tolman, W. B. J. Am. Chem. Soc. 2000,
122, 6331-6332.
(18) Houser, R. P.; Young, V. G.; Tolman, W. B. J. Am. Chem. Soc. 1996,
118, 2101-2102.
(19) Downes, J. M.; Whelan, J.; Bosnich, B. Inorg. Chem. 1981, 20, 1081-
1086.
IC049136E
(20) The white precipitate, [Cu(SCPh3)], was characterized in THF-d8 by
1H and 13C NMR and by elemental analysis. Anal. Calcd for C19H15-
CuS: C, 67.33; H, 4.46; N, 0.00; S, 9.46. Found: C, 67.58; H, 4.85;
N, 0.17; S, 9.43.
(21) Organic products were separated from the inorganic products and
analyzed by GC/MS.
7274 Inorganic Chemistry, Vol. 43, No. 23, 2004