Copper(II) complexes of the tetraazamacrocyclic tertiary amide ligand alanyl-cyclam

Article abstract of DOI:10.1002/ejic.200600055

Hydrogen bonding to the electrically neutral tertiary carboxamide nitrogen atom of peptidyl-prolyl groups is known to facilitate the C-N bond rotation during peptide and protein folding. Since metal complexes with nitrogen-coordinated tertiary amide ligan

Full text of DOI:10.1002/ejic.200600055

FULL PAPER
DOI: 10.1002/ejic.200600055
Copper(II) Complexes of the Tetraazamacrocyclic Tertiary Amide Ligand
Alanyl-Cyclam
Christian Schickaneder,[a] Frank W. Heinemann,[a] and Ralf Alsfasser*[b]
Keywords: Copper / Cyclam / Bioinorganic chemistry / Electrophilic activation / Winkler–Dunitz parameters
Hydrogen bonding to the electrically neutral tertiary carbox-
amide nitrogen atom of peptidyl-prolyl groups is known to
facilitate the C–N bond rotation during peptide and protein
folding. Since metal complexes with nitrogen-coordinated
tertiary amide ligands are formally analogous, they may be
used to model this so-called electrophilic activation. In this
paper we report on the synthesis of a monoacylated cyclam
complex, [(Boc-Ala-cyclam)Cu](CF3SO3)2 (8; Boc: tert-butyl-
oxycarbonyl, Ala: alanine, cyclam: 1,4,8,11-tetraazacyclo-
tetradecane). It contains a fully sp3-hybridized metal-bound
amide nitrogen atom. The resonance is completely cancelled
and the observed C–N distance of 147 pm is consistent with
a single bond. These features are exceptional among Wer-
ner-type complexes and define the maximal possible electro-
philic distortion of an amide bond.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
The activation of tertiary carboxamides towards hydro-
lytic cleavage and C–N bond rotation is a topic of consider-
able interest. Two catchwords are the hydrolysis of β-lactam
antibiotics[1] and the cis-trans isomerization about peptidyl–
prolyl bonds in proteins.[2] The latter is often the slow step
during protein folding and supposed to play an important
role as a functional switch in different processes such as
enzymatic substrate recognition[3] or neurodegenerative
protein aggregation.[4] Isomerases, PPIases, are known to
facilitate the amide rotation. How exactly they operate is
not known, although different means to lower the rota-
tional barrier have been discussed.[5] Particularly interesting
for coordination chemists is a motif observed in the cata-
lytic centre of cyclophilines,[6] and in histidyl peptides:[7] hy-
drogen bonding to the amide nitrogen atom is proposed
to stabilize the pyramidal transition state structure at the
nitrogen atom. This is formally analogous to the coordina-
tion of a metal ion as it has been proposed to explain the
effect of siver() ions on the rotational barrier of dimethyl-
acetamide.[8] An illustration of an arginine hydrogen bond
in comparison with a coordinated metal center is shown in
Scheme 1.
Scheme 1. Electrophilic activation of a tertiary amide group; hydro-
gen bonding in peptides and proteins (left), or metal coordination
(right).
Based on this analogy, Lectka and colleagues have sug-
gested that metal complexes could be developed into syn-
thetic catalysts to trigger biological proline switches.[9] This
perspective is highly interesting but suffers from the lack of
information on coordination complexes containing nitro-
gen-bound tertiary carboxamide ligands. We have therefore
started a systematic study of these unusual compounds.[10]
Here we describe the synthesis and structural properties of
copper() complexes with macrocyclic alanyl-cyclam li-
gands. Our aim was to place a metal ion in close proximity
to an amide nitrogen atom in order to achieve full pyrami-
dalization and complete cancellation of resonance. This li-
miting case is an important missing piece required for a
quanitative understanding of the electrophilic amide acti-
vation.
[a] Institut für Anorganische Chemie, Universität Erlangen-
Nürnberg,
Egerlandstr. 1, 91058 Erlangen, Germany
[b] Institut für Anorganische Chemie, Universität Freiburg,
Albertstr. 21, 79104 Freiburg, Germany
Fax: +49-761-2036012
E-mail: ralf.alsfasser@ac.uni-freiburg.de
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C. Schickaneder, F. W. Heinemann, R. Alsfasser
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Results and Discussion
Synthesis
trum shows a shift of the carbonyl band from 1625 cm–1 to
1592 cm–1. This clearly indicates that the metal ion does not
bind to the amide nitrogen atom which would cause a high
energy shift due to the reduced amide resonance.[14] We pro-
pose the structure 6 shown in Scheme 3 with a bidentate
ethylenediammine part of the cyclam ligand and two chlo-
ride ions coordinated to the copper() ion. This is based on
the analogy to observations in related acylated triazacyclo-
nonane complexes by Houser et al.[15] and supported by
C,H,N,S elemental analysis data. The shift of the carbonyl
IR band indicates that the amide oxygen atom may also
coordinate.
We concluded from the results summarized in Scheme 3
that complete removal of HCl from the ligand 5 is a pre-
requisite for the coordination of the tertiary amide nitrogen
atom in copper complexes. Since this required a strong base,
NaOH in dichloromethane was applied to prepare the acid-
free ligand. Subsequent reaction with Cu(CF3SO3)2 in ace-
tonitrile and layering with diethyl ether yielded a violet ma-
terial with elemental analysis data indicating the consti-
tution [(Ala-cyclam)(H2O)Cu](CF3SO3)2·0.25Et2O. There is
no evidence for the presence of chloride in the sample and
an IR band at 1756 cm–1 is consistent with a nitrogen-
bound amide ligand. However, a second IR band at
1592 cm–1 with a shoulder at 1649 cm–1 indicates that a
mixture of N- and O-coordinated tertiary amide complexes
is present and we were not able to separate these species. It
is not yet clear whether trace impurities of chloride or an
unknown coordination mode involving the free amine func-
tion of the amino acid moiety is responsible for this behav-
iour.
Our first aim was to prepare a cyclam ligand in which
one of the amine functions is converted into a tertiary
amide. Prior to monoacylation, three of the cyclam nitrogen
atoms had to be protected. Scheme 2 shows the synthesis
of triple-protected cyclam. We have synthesized the tris(tert-
butoxycarbonyl) (Boc) and tris(benzoxycarbonyl) (Cbz) de-
rivatives 1 and 2 according to a slightly modified route re-
ported by Brandes et al.[11] The yields of 35–50% after flash
column chromatography on silica gel were moderate in both
cases. Coupling with N-tert-butoxycarbonyl-(S)-alanine
[Boc-(S)-Ala-OH] was achieved by the well-established
DCC/HOBt (DCC = dicyclohexylcarbodiimide, HOBt = N-
hydroxybenzotriazole) method.[12] We have applied this
method earlier to the synthesis of ruthenium-modified
1,4,7,10-tetraazacyclodecane (cyclen) ligands.[13] The iso-
lated yields were moderate in the case of Boc-(S)-Ala-cy-
clam-Boc3 (3, 70%) and low in the case of Boc-(S)-Ala-
cyclam-Cbz3 (4, 26%). The structures and the synthesis of
both compounds are shown in Scheme 2.
Acid deprotection of Boc-(S)-Ala-cyclam-Boc3 was
achieved with aqueous HCl in dioxane.[13] Scheme 3 shows
the structure of the tris(hydrochloride) salt 5 which was
characterized by an X-ray structure analysis (Figure 1). In
order to facilitate binding of a copper() ion inside the
macrocyclic ring and to enhance the solubility of the ligand
in organic aprotic solvents, we attempted to remove most
of the HCl. An interesting and revealing result was ob-
tained with a ligand sample obtained by passing an NH3
Our failure to obtain well-defined N-coordinated amide
stream through a suspension of 5 in chloroform. The solu- complexes from the protonated ligand 5 reflects the diffi-
ble product was isolated and reacted with copper() triflate culties involved in the synthesis of such compounds. Even
in acetonitrile. Unfortunately, we were not able to obtain though the cyclam framework should strongly favour coor-
single crystals of the complex formed. However, its IR spec- dination of a copper() ion within the ring, the system avo-
Scheme 2. Synthesis of the Boc- and Cbz-protected Boc-(S)-alanylcyclam derivatives Boc-(S)-Ala-cyclam-Boc3 (3) and Boc-(S)-Ala-cy-
clam-Cbz3 (4).
Scheme 3. Acid deprotection of Boc-(S)-Ala-cyclam-Boc3 (3) and the reaction of Ala-cyclam·3HCl (5) with copper() triflate.
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Copper() Complexes of the Tetraazamacrocyclic Tertiary Amide Ligand Alanyl-Cyclam
FULL PAPER
Scheme 4. Hydrogenation of the Cbz-protected compound 4 to the free ligand 7 and synthesis of the copper complex [{Boc-(S)-Ala-
–
cyclam}Cu](CF3SO3 )2 (8).
ids coordination of the weak amide donor. It is therefore than in related dipicolylamide derivatives[10b] although not
not surprising that amide nitrogen coordination was un- unusual for carboxamides. Large deviations from planarity
known before the 1990s and has been categorically ruled are possible because the energy barrier for out-of-plane
out in several important older articles on amide com- wagging is rather low.[19] An examination of amide struc-
plexes.[16] We reasoned that in our case a protecting group tures by Gilli et al. reveals that χN can reach values of over
would be preferable which can be removed without proton- 20° without a significant elongation of the C–N bond.[20]
ation of the ligand. The Cbz function turned out to be a Much effort of organic chemists focused on the effects of
good choice.[17] It is cleaved off by hydrogenation in the distortion on non-planar amides which model different
presence of a palladium catalyst in methanol. This and stages during the C–N-bond rotation.[21] It was shown that
the following reaction of Boc-(S)-Ala-cyclam (7) with geometric strain can enforce significant twisting and pyram-
Cu(CF3SO3)2 is shown in Scheme 4. The copper complex idalization. However, the effects on the C–N bond lengths
[{Boc-(S)-Ala-cyclam}Cu](CF3SO3)2 (8) was obtained with are generally rather small and the variety of different com-
a yield of 74%. Its composition was confirmed by C,H,N,S pounds having the amide group as a part of an acyclic,
elemental analysis and FAB mass spectrometry. The IR cyclic, or polycyclic structure make quantitative corre-
spectrum shows two bands at 1742 cm–1 for the amide func- lations difficult. An examination of different structures
tion and 1658 cm–1 for the Boc protecting group. The blue leads to the conclusion that the amide C–N bond is only
shift of the amide band is in excellent agreement with our affected when χN reaches values of ca. 30°. This has not
data on a Cu(CF3SO3)2 of dipicolyl-N-boc-glycylamide[10a] been specifically addressed by other authors but it is inter-
and confirms amide nitrogen coordination in the bulk sam- esting in the context of our observations on metal com-
ple. An X-ray structure analysis of the complex is discussed plexes. We will show below that the latter provide a better
below.
basis for quantitative structure correlations since their
amide groups are not forced into a rigid structure which
may obscure changes in the C–N bond length. A key com-
pound in our studies is the copper complex 8 which con-
tains a fully pyramidalized amide nitrogen atom.
X-ray Structure Analyses
Single crystals were obtained from the ligand tris(hydro-
chloride) salt 5 and the copper complex 8. An ORTEP
plot representing the structure of the cation in 5 is shown in
Figure 1. All hydrogen atoms were localized in the electron
density map. The alanyl nitrogen atom N5 and the two cy-
clam atoms N2 and N4 are positively charged. Hydrogen
bonds between those ammonium functions and the chloride
ions loosely connect individual molecules in a three-dimen-
sional network. Most important for our study is the geome-
try of the tertiary amide function. Deviations from planar-
ity are most conveniently described by two quantitative pa-
rameters defined by Winkler and Dunitz.[18] One is the twist
angle τ between the C1–C10 and the C12–O1 axes which
ranges from 0° to 90°. The second is the pyramidalization
χN at the nitrogen atom. It varies between 0° for a planar
environment and ca. 60° for a fully pyramidal geometry. We
will later discuss how the binding of metal ions deplanarize
an amide group and how this activation affects the C–N
bond length. In this context, ligand structures are useful for
comparison. The C11–N1 bond length in 5 of 135.7 pm and
Figure 1. ORTEP plot at 50% probability of the cation Ala-
cyclam·3H+ (5) (hydrogen atoms except for NH are omitted for
clarity); selected bond lengths [pm], angles [°], τ [°], and χN [°]:
C11–N1 135.7(2), C11–O1 123.3(2); C1–N1–C10 118.1(2), C1–N1–
C11 124.3(2), C10–N1–C11 115.3(2); τ = 9.3; χN = 17.7.
Compound 8 crystallizes in the acentric space group P21
the small twist angle τ = 9.3° are typical for an undistorted with two independent complexes A and B in the asymmetric
amide function. Interestingly, a significant pyramidalization unit. They are depicted in Figure 2. In complex 8A the cop-
at the nitrogen atom of χN = 17.7° is observed. This is larger per ion is bound in the center of the cyclam ligand which
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C. Schickaneder, F. W. Heinemann, R. Alsfasser
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coordinates in the typical trans-III mode[22] with one five- Cu–N(amide) distances (8A: 212.7 pm; 8B: 214.7) are not
membered chelate ring in the δ, one in the λ, and both six- much longer than the contacts between the copper ion and
membered rings in the chair configuration. The Boc pro- the secondary amine group which have typical values of
tecting group is weakly bound at a distance Cu1–O2 of 200–203 pm. A comparison with the few known copper()
248.8 pm and a triflate ion is positioned in the apical posi- complexes with N-coordinated tertiary amide ligands shows
tion of a distorted octahedron with a long contact of Cu1– that the Cu–N(amide) bond in 8 is unusually short. A re-
O63 of 278.9 pm. The second complex 8B also has a trans- cently published diisopropyl-triazacyclononane acetamide
III type cyclam ligand but one of the six-membered chelate copper() chloride complex by Watkinson et al. has a Cu–
rings is in the rare boat form.[23] As a consequence, the pro- N distance of 251.1 pm[24] and a paper by Schröder et al.
ton H20b of the central methylene group is only 270.5 pm reports on a related triazacyclononane derivative with a dis-
away from the copper centre and there is no room for an tance of 261.1 pm.[25] The closest contact observed in a di-
apical triflate ion. The coordinated Boc group compensates picolylamide derivative is 216.4 pm in a copper() triflate
for the lack of σ-donation and binds at a distance of Cu2– complex from our group.[10c] The short Cu–N(amide) dis-
O5 of 230.5 pm, which is 13.3 pm shorter than the corre- tance in 8 corresponds to a fully pyramidalized nitrogen
sponding contact in 8A. However, the coordinated tertiary atom as is evident from the pyramidalization parameter χN
amide function is not much affected by these differences.
of almost 60° (8A: 58.5°; 8B: 56.9°). Again, these values are
exceptional in that they are the highest observed in Werner-
type complexes to date.
In accord with this finding the C–N distance of 146 pm
is typical for a single bond (147 pm[26]) and indicates that
the amide resonance[27] is completely cancelled. It is inter-
esting to compare this result with the situation in Schröder’s
complex with its long Cu–N(amide) distance of 261.1 pm
which is significantly larger than the sum of the ionic radii
of a six-coordinate Cu2+ ion (87 pm) and the van der Waals
radius of a nitrogen atom (160 pm).[26] This weak electro-
static interaction suffices to induce a significant pyrami-
dalization at the nitrogen atom (χN = 30°), whereas the C–
N distance of 135.7 pm is typical for an undistorted organic
carboxamide. Further support for this interpretation is pro-
vided by Schindler et al.[28] who described the pyramidaliz-
ation of a secondary amide group located 282.7 pm above
the copper() ion the apical position of a square-pyramidal
complex. These data are very important and confirm that
with our new complex 8 Werner-type nitrogen-coordinated
tertiary carboxamide complexes now span the whole range
of electrophilic amide activation.
Figure 2. ORTEP plots at 50% probability of the two complexes A
and
B
observed in the structure of [{Boc-(S)-Ala-
cyclam}Cu](CF3SO3)2 (8) (hydrogen atoms except for those located
at C20 in complex B, and the three non-coordinating triflate ions
are omitted for clarity); selected distances [pm], angles [°], τ [°], and
χN [°] of A: Cu1–N1 212.7(3), Cu1–N2 201.2(3), Cu1–N3 202.1(3),
Cu1–N4 200.5(3), Cu1–O2 248.8(2), Cu1–O63 278.9, C11–N1
146.9(4), C11–O1 120.2(4); N1–Cu1–N2 95.3(2), N1–Cu1–N3
175.7(2), N1–Cu1–N4 86.7(2), N1–Cu1–O2 92.4(2), N2–Cu1–N3
86.7(2), N2–Cu1–N4 170.3(2), N2–Cu1–O2 92.7(2), N3–Cu1–N4
90.7(2), N3–Cu1–O2 91.4(2), N4–Cu1–O2 96.7(2), Cu1–N1–C1
112.4(2), Cu1–N1–C10 100.6(2), Cu1–N1–C11 112.8(2), C1–N1–
C10 109.8(3), C1–N1–C11 112.8(2), C10–N1–C11 109.3(2); τ =
35.8; χN = 58.5; selected distances [pm], angles [°], τ [°], and χN [°]
of B: Cu2–N6 214.7(3), Cu2–N7 203.1(3), Cu2–N8 200.9(3), Cu2–
N9 202.1(3), Cu2–O5 230.5(2), Cu2–H20b 270.5, C29–N6 146.2(5),
C29–O4 119.9(5); N6–Cu2–N7 96.3(2), N6–Cu2–N8 172.02(2),
N6–Cu2–N9 85.3(2), N6–Cu2–O5 92.2(2), N7–Cu2–N8 85.5(2),
N7–Cu2–N9 165.7(2), N7–Cu2–O5 97.3(2), N8–Cu2–N9 91.1(2),
N8–Cu2–O5 93.3.4(2), N9–Cu–O5 96.8(2), Cu2–N6–C19 112.5(2),
Cu2–N6–C28 102.6(2), Cu2–N6–C29 109.2(2), C19–N6–C28
110.4(3), C19–N6–C29 110.9(3), C28–N6–C29 111.1(2); τ = 30.6;
χN = 56.9.
Conclusions
With the crystallographic characterization of 8, we have
shown that forcing a metal center into a macrocyclic cyclam
ring with a neutral amide N-donor produces a completely
non-resonant tertiary carboxamide. The complex defines an
upper limit for nitrogen pyramidalization and C–N bond
elongation achievable by purely electrophilic activation
without geometric strain. In this respect, it complements
the generation of a purely organic amino ketone in Kirby’s
most twisted amide, 3,5,7-trimethyl-1-azaadamantan-2-
one.[29]
The stereochemistry of the amino acid part is in both
cases (S) at the stereogenic α-carbon atom and (Rp) with
respect to the chiral plane defined by the amide function.
This implies that the methyl group is exo with respect to
the seven-membered chelate ring formed by the coordinat-
ing Boc group and is analogous to the situation in a cad-
Experimental Section
General Methods: Spectra were recorded with the following instru-
ments: IR: Mattson Polaris FT IR. UV/Vis: Varian Cary 1G spec-
trophotomer. 1H and 13C NMR: Bruker Avance DPX 300. All
mium() complex of dipicolyl-Boc-alanylamide.[10a] The chemical shifts are referenced to TMS (CDCl3) or TSP (D2O) as
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Copper() Complexes of the Tetraazamacrocyclic Tertiary Amide Ligand Alanyl-Cyclam
FULL PAPER
internal standards, with high frequency shifts recorded as positive.
MS: Varian MAT 212 (FD, FAB) and Micromass ZabSpec (FAB)
mass spectrometer. Elemental analysis: Carlo Erba Elemental Ana-
lyser 1106 (C,H,N), and Carlo Erba Elemental Analyser 1108
(C,H,N,S). All reactions except for the syntheses of cyclam-Boc3
(1) and cyclam-Cbz3 (2) were carried out in absolute solvents under
dry nitrogen. The subsequent workup was performed under ambi-
ent laboratory conditions unless stated otherwise. The synthesis of
cylam-Boc3 is a slight modification of a literature procedure.[11] Ab-
solute solvents (CH2Cl2, Et2O, CH3CN) were purchased from
Fluka, stored under nitrogen and used without further purification.
All other chemicals and deuterated solvents were obtained from
Aldrich.
(q, 1 H, αCH) ppm. IR (KBr): ν = 3178 (NH +), 1646 (amide)
˜
3
cm–1.
[(Boc-Ala-cyclamH2)CuCl2](CF3SO3)2 (6): Tris(hydrochloride) salt
5 (2.51 g, 6.02 mmol) was suspended in 100 mL of CHCl3 and the
solution cooled to 0 °C. A slow stream of NH3 gas was passed
through the reaction mixture. After 1.5 h, the mixture was warmed
to room temperature. Precipitated ammonium chloride was filtered
off, the filtrate concentrated to dryness and the residue treated with
50 mL of CH2Cl2. Insoluble material was removed by filtration and
all solvent by rotary evaporation. Drying under vacuum afforded
a colourless resin (1.62 g). This compound (1.31 g) was dissolved
in 200 mL of CH3CN. A solution of Cu(CF3SO3)2 in 150 mL of
CH3CN was added dropwise with stirring over a period of 1 h. The
reaction mixture turned deep blue. Stirring was continued at room
temperature for 12 h. The solution was concentrated to dryness and
the residue re-dissolved in a minimum amount of CH3CN. Layer-
ing with diethyl ether and storage at –18 °C overnight afforded the
product 6 as a blue precipitate which was isolated by filtration and
dried under vacuum [2.46 g, 3.49 mmol, 72.2% based on
Cu(CF3SO3)2]. C15H31Cl2CuF6N5O7S2 (706.01): calcd. C 25.52, H
4.43, N 9.92, S 9.08; found C 25.42, H 4.34, N 9.63, S 8.92. IR
Syntheses
Cyclam-Boc3 (1): A solution of di-tert-butyl pyrocarbonate (Boc2O,
2.72 g, 12.5 mmol) in 150 mL of CH2Cl2 was added dropwise at
room temperature over a period of 6 h to a stirred solution of cy-
clam (1.00 g, 5.00 mmol) in 300 mL of CH2Cl2. Stirring was contin-
ued for 12 h and the solvent stripped by rotary evaporation. The
oily residue was dissolved in a minimum amount of diethyl ether.
Rapid stripping of all solvent and drying under vacuum yielded a
pale-yellow foam which was re-dissolved in CH2Cl2/CH3OH (95:5)
and purified by flash column chromatography on silica; using the
solvent as the eluent yielded 1.08 g (2.13 mmol, 51.1%) of cyclam-
(KBr): ν = 3244 (R–NH +), 1592 (amide) cm–1. UV/Vis (CH3CN):
˜
3
λmax (lgε) = 619 (2.17 –1cm–1) nm. FAB-MS (nitrobenzyl alcohol):
m/z = 483 [M–2 HCl–CF3SO3]+.
[(Ala-cyclam)(H2O)Cu](CF3SO3)2·0.25Et2O:
A
mixture of
5
Boc3 as
a colourless, hygroscopic solid. FD-MS [CHCl3;
(450 mg, 1.08 mmol) and excess NaOH(s) was suspended in ca.
50 mL of CH2Cl2 at room temperature. The suspension was stirred
for 24 h. Insoluble material was removed by filtration and the clear
filtrate concentrated to dryness. Drying under vacuum afforded the
free base as a colourless oily residue. It was dissolved in 50 mL of
CH3CN and Cu(CF3SO3)2 (340 mg, 0.94 mmol) was added in small
portions to the stirred solution. Stirring was continued for 12 h.
The mixture was filtered and the clear blue filtrate layered with
Et2O. Upon storage at –18 °C the product precipitated as a
violet oily residue. Separation and drying under vacuum afforded
C25H48N4O6 (500.68)]: m/z = 501 [M+]. 1H NMR (CDCl3): δ =
1.45 (s, 27 H, Boc), 1.70 (m, 2 H, cyclam), 1.92 (m, 2 H, cyclam),
2.61 (t, 2 H, cyclam), 2.78 (t, 2 H, cyclam), 3.27–3.39 (m, 12 H,
cyclam) ppm.
Boc-(S)-Ala-cyclam-Boc3 (3): Boc-Ala-OH (1.02 g, 5.40 mmol), 1
(2.45 g, 4.90 mmol), N-hydroxybenzotriazole (0.71 g, 5.22 mmol),
and NEt3 (1.41 mL, 9.98 mmol) were dissolved in 300 mL of
CH2Cl2 and the mixture was stirred with cooling at 0 °C. Dicyclo-
hexylcarbodiimide (1.76 g, 8.47 mmol) in 20 mL of CH2Cl2 was
added in one portion. The solution was warmed slowly to room
temperature after which stirring was continued for 12 h. The re-
sulting mixture was filtered and the volume of the filtrate was re-
duced to 1/2 by rotary evaporation. Filtration was repeated after
storage at –18 °C overnight. The filtrate was washed 3 times with
aqueous 5% NaHCO3 and 3 times with saturated aqueous NaCl,
dried with solid MgSO4 and filtered. All solvent was removed by
rotary evaporation and the residue purified by flash column
chromatography on silica gel using CH2Cl2/CH3OH (95:5) as the
eluent. All solvent was removed by rotary evaporation and the solid
residue dissolved in a minimum amount of diethyl ether. Rapid
stripping of the solvent and drying under vacuum yielded 2.42 g
the product (446 mg, 0.73 mmol, 77.7%) as
FD-MS (CH3CN): m/z 484 [MH
a
–
violet solid.
=
CF3SO3]+.
C15H29CuF6N5O7S2·1H2O·0.25Et2O (651.10+18.53): calcd.
C
28.70, H 5.04, N 10.46; found C 28.60, H 4.78, N 10.17. IR (KBr):
ν = 3342, 3226 (NH +), 1756, 1649 (shoulder), 1592 cm–1.
˜
3
cyclam-Cbz3 (2): A solution of dibenzyl pyrocarbonate (Cbz2O,
7.20 g, 25.00 mmol) in 500 mL of CH2Cl2 was added dropwise at
room temperature over a period of 6 h to a stirred solution of cy-
clam (2.00 g, 10.00 mmol) in 200 mL of CH2Cl2. Stirring was con-
tinued for 12 h and the solvent stripped by rotary evaporation. The
oily residue was dissolved in a minimum amount of dichlorometh-
ane and the pale yellow solution was filtered through silica gel.
The filtrate which contained benzyl alcohol was discarded and the
compound was eluted with methanol. All solvent was removed by
rotary evaporation and drying under vacuum. The residue was re-
dissolved in a minimum amount of CH2Cl2/CH3OH (98:2) and
purified by flash column chromatography on silica using the sol-
vent as the eluent. The colourless, oily compound was repeatedly
treated with small quantities of diethyl ether which was stripped
under vacuum until formation of a foam; 1.80 g (2.99 mmol,
35.9%) of the product 2 was obtained as a highly hygroscopic,
colourless resin. FD-MS [CHCl3; C34H42N4O6 (602.72)]: m/z = 603
(3.60 mmol, 73.5%) of
3 as a colourless hygroscopic solid.
C33H61N5O9·0.33H2O (671.87+6.00): calcd. C 58.47, H 9.17, N
10.33; found C 58.65, H 10.59, N 10.33. FD-MS (CHCl3): m/z =
1
β
672 [M+]. H NMR (CDCl3): δ = 1.31 (t, 3 H, CH3), 1.45 (m, 36
H, Boc), 1.74 (m, 4 H, cyclam), 3.14–3.69 (m, 16 H, cyclam), 4.56
α
(m, 1 H, CH), 5.19–5.50 (m, 1 H, NH) ppm.
(S)-Ala-cyclam·3HCl (5): Compound 3 (2.42 g, 3.60 mmol) was
treated with 15 mL of a cold 4  HCl/dioxane solution with stirring
at 0 °C. Stirring was continued without further cooling for 12 h.
The product Boc-Ala-cyclam·3HCl·4H2O formed 1.36 g
(3.00 mmol, 83.4%) of a colourless precipitate which was collected
on a glass filter funnel, washed with hot ethanol (3×50 mL) and
diethyl ether (3×20 mL), and dried under vacuum.
C13H29N5O·3HCl·4H2O (452.79): calcd. C 34.45, H 8.83, N 15.46;
found C 34.39, H 9.15, N 15.29. 1H NMR (D2O): δ = 1.46 (d, 3
1
[M+]. H NMR (CDCl3): δ = 1.64 (m, 2 H, cyclam), 1.93 (m, 2 H,
cyclam), 2.55 (m, 2 H, cyclam), 2.76 (m, 2 H, cyclam), 3.10–3.52
(m, 12 H, cyclam), 5.03 (s, 2 H, Ph-CH2), 5.12 (s, 4 H, Ph-CH2),
7.33 (m, 15 H, C6H5) ppm.
Boc-Ala-cyclam-Z3 (4): Boc-Ala-OH (0.62 g, 3.28 mmol), 2 (1.79 g,
H, βCH3), 2.22 (m, 4 H, cyclam), 2.92–4.00 (m, 16 H, cyclam), 4.40 2.97 mmol), N-hydroxybenzotriazole (0.43 mg, 3.17 mmol), and
Eur. J. Inorg. Chem. 2006, 2357–2363
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
2361

C. Schickaneder, F. W. Heinemann, R. Alsfasser
FULL PAPER
NEt3 (0.85 mL, 6.06 mmol) were dissolved in 150 mL of CH2Cl2
and the mixture stirred with cooling at 0 °C. Dicyclohexylcarbodi-
imide (1.07 g, 5.14 mmol) in 10 mL of CH2Cl2 was added in one
portion. The solution was warmed slowly to room temperature af-
ter which stirring was continued for 12 h. The resulting mixture
was filtered and the volume of the filtrate was reduced to 1/2 by
rotary evaporation. Filtration was repeated after storage at –18 °C
overnight. The filtrate was washed 3 times with aqueous 5%
NaHCO3 and 3 times with saturated aqueous NaCl, dried with
solid MgSO4 and filtered. All solvent was removed by rotary evapo-
ration and the residue purified by flash column chromatography
on silica gel using CH2Cl2/CH3OH (95:5) as eluent. All solvent was
removed by rotary evaporation and the solid residue dissolved in
a minimum diethyl ether. Drying under vacuum yielded 595 mg
was applied for 5 and 432 s per frame for 8·1/8H2O. Lorentz and
polarization corrections were applied. Semi-empirical absorption
corrections based on equivalent reflections were made using the
program SADABS.[30] All structures were solved by direct methods
and refined using full-matrix least-squares procedures on F2 using
the program package SHELXTL NT 6.12.[31] All non-hydrogen
atoms were refined anisotropically. One of the triflate ions in 8·
1/8H2O was disordered. Two positions with occupation factors of
0.75 and 0.25 were refined. All hydrogen atoms in 5 were located in
the difference Fourier map and refined with isotropic displacement
parameters being 1.2 or 1.5 times U(eq) of the corresponding C or
N atom. All hydrogen atoms in 8·1/8H2O (except for those of the
water which were located in the difference Fourier map and not
refined) were geometrically positioned with isotropic displacement
parameters being 1.2 or 1.5 times U(eq) of the corresponding C, N
or O atom. CCDC-262792 (5) and -262793 (8·1/8H2O) contain the
supplementary crystallographic data for this paper. These data can
(0.77 mmol, 25.9%) of
4 as a colourless hygroscopic solid.
C42H55N5O9·0.5Et2O (773.91+37.06): calcd. C 65.16, H 7.46, N
8.64; found C 65.46, H 8.27, N 8.90. FD-MS (CHCl3): m/z = 774
1
β
[M+]. H NMR (CDCl3): δ = 1.26 (m, 3 H, CH3), 1.43 (2 s, 9 H, be obtained free of charge from The Cambridge Crystallographic
Boc), 1.71 (m, 4 H, cyclam), 3.05–3.75 (m, 16 H, cyclam), 4.45 (m,
1 H, αCH), 4.86–5.19 (m, 7 H, Ph-CH2 + NH), 7.13–7.45 (m, 15
H, C6H5) ppm.
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Table 1. Details of the crystal structure analyses.
Compound
5
8·1/8H2O
Boc-Ala-cyclam (7): A solution of 2 (315 mg, 0.41 mmol) in abso-
lute methanol was transferred to a flask containing catalytic
amounts of Pd/C and equipped with a hydrogen inlet, a reflux con-
denser, a magnetic stir bar, and a mineral oil bubbler. Nitrogen was
passed over the suspension for 15 min. The mixture was heated to
45 °C in an oil bath and a slow stream of H2 was applied for 2 h.
The flask was then flushed with N2 and the suspension filtered
through Celite at room temperature. Rotary evaporation of the sol-
vent and drying under vacuum yielded 116 mg (0.31 mmol, 76.0%)
of 4 as a hygroscopic resin. It was characterized by 1H NMR spec-
troscopy and used without further purification. 1H NMR (CDCl3):
δ = 1.29 (m, 3 H, βCH3), 1.42 (s, 9 H, Boc), 1.59–2.00 (m, 6 H,
cyclam), 2.45–3.12 (m, 10 H, cyclam), 3.19–3.80 (m, 4 H, cyclam),
Empirical formula
Formula mass
Temperature [K]
Wavelength [Å]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
α [°]
β [°]
γ [°]
Volume [Å3]
Z
Calculated density [Mg/m3]
Absorption coefficient [mm–1
F(000)
Crystal size[mm]
θ range [°]
Index ranges
C13H32Cl3N5O C20H37.25CuF6N5O9.125S2
380.79
100(2)
0.71073
orthorhombic
P212121
11.491(2)
12.262(2)
13.605(1)
90
90
90
1901.3(5)
4
1.330
735.46
100(2)
0.71073
monoclinic
P21
11.762(2)
13.274(1)
19.890(2)
90
103.380(6)
90
3021.1(6)
4
α
4.59 (m, 1 H, CH ), 5.41 (m, 1 H, NH) ppm.
1.617
0.953
1521
[(Boc-Ala-cyclam)Cu](CF3SO3)2 (8): Boc-Ala-cyclam (116 mg,
0.31 mmol) was dissolved in 25 mL of absolute acetonitrile and a
solution of anhydrous Cu(CF3SO3)2 (112 mg, 0.31 mmol) in 25 mL
of absolute acetonitrile was added dropwise with stirring over a
period of 30 min. The blue solution gradually turned deep purple.
Stirring was continued at room temperature overnight and all sol-
vent removed by evaporation under vacuum. The crude product
was re-dissolved in CH2Cl2 and insoluble materials were removed
by filtration. Drying of the filtrate under vacuum yielded the prod-
uct as a deep purple solid; yield 209 mg (0.29 mmol, 92.0%).
C20H37CuF6N5O9S2·2CH2Cl2 (903.11): calcd. C 29.26, H 4.58, N
]
0.491
816
0.24×0.23×0.14 0.23×0.15×0.05
3.43–28.28
3.42–27.10
–15 Յ h Յ 15
–16 Յ k Յ 15
–18 Յ l Յ 18
28742/4702
based on F2
4702/0/295
–14 Յ h Յ 14
–17 Յ k Յ 16
–25 Յ l Յ 25
56796/12866
based on F2
12866/1/830
0.925
R1 = 0.0430
wR2 = 0.0773
R1 = 0.0799
wR2 = 0.0874
0.601/–0.514
Reflections collected/unique
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
1.069
Final R indices [I Ͼ 2σ(I)]
R1 = 0.0318
wR2 = 0.0635
R1 = 0.0428
wR2 = 0.0668
0.251/–0.289
7.76; found C 29.34, H 4.60, N 8.05. IR (KBr): ν = 1742 (amide);
˜
1658 (Boc) cm–1. UV/Vis (CH3CN): λmax (lgε)
= 540.4
R indices (all data)
(1.89 –1cm–1) nm. FAB-MS (nitrobenzyl alcohol): m/z = 583 [M –
Largest diff. peak/hole [e·Å–3
]
CF3SO3]+.
X-ray Structure Analyses: Colorless blocks of Ala-Cyclam·3HCl (5)
were obtained by precipitation from diethyl ether/ethanol and
recrystallization of the solid from D2O upon slow evaporation of Acknowledgments
the solvent at room temperature. The copper complex salt 8·
1/8H2O crystallized upon slow concentration of a dichlorometh-
ane/acetonitrile solution. Details of the X-ray structure analyses
are summarized in Table 1. Suitable single crystals were embedded
in protective perfluoropolyether oil and data were collected at
100 K with a Bruker-Nonius KappaCCD diffractometer using Mo-
Kα radiation (λ = 0.71073 Å, graphite monochromator). Images
were taken using φ- and ω-rotations with a rotation angle of 2.0°
for 5 and 1.8° for 8·1/8H2O. An irradiation time of 80 s per frame
Financial support from the Bayerischer Forschungsverbund
Prionen is greatfully acknowledged.
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Eur. J. Inorg. Chem. 2006, 2357–2363

Copper() Complexes of the Tetraazamacrocyclic Tertiary Amide Ligand Alanyl-Cyclam
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Received: January 19, 2006
Published Online: April 18, 2006
Eur. J. Inorg. Chem. 2006, 2357–2363
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2363