Copper(ii) and zinc(ii) complexes of mono- And bis-1,2,3-triazole-substituted heterocyclic ligands

Article abstract of DOI:10.1039/d0dt01244k

Chelating 1,4-disubstituted mono- (8a-8d) and bis-1,2,3-triazole-based (9a-11a) ligands were prepared by regioselective copper(i)-catalysed 1,3-dipolar cycloaddition of terminal alkynes with aromatic azides, together with bioconjugate 13a synthesized by amide coupling of l-phenylalanine methyl ester to 11a. Cu(ii) and Zn(ii) complexes were prepared and single crystal structures were determined for complexes 8aCu, 8dCu, 9cCu and 10cCu, as well as the free ligands 10a and 10c. The in situ prepared Zn(ii) complexes were studied by NMR spectroscopy, while the stoichiometry of the Cu(ii) complexes in solution was determined by UV-Vis titrations and confirmed by the electronic structure DFT calculations at the (SMD)/M05-2X/6-31+G(d)/LanL2DZ+ECP level of theory.

Full text of DOI:10.1039/d0dt01244k

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M. Krklec, T. Novosel, B. Peric, R. Vianello, S. Rai-Mali and S. I. Kirin, Dalton Trans., 2020, DOI:
10.1039/D0DT01244K.
Volume 46
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14 March 2017
Pages 3073-3412
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DOI: 10.1039/D0DT01244K
ARTICLE
Copper(II) and Zinc(II) Complexes of Mono- and Bis-1,2,3-triazole-
substituted Heterocyclic Ligands
Received 00th January 20xx,
Accepted 00th January 20xx
Natalija Pantalon Juraj,a Marko Krklec,a,b Tiana Novosel,a,b Berislav Perić,a Robert Vianello,*,a Silvana
Raić-Malić*,b and Srećko I. Kirin*,a
DOI: 10.1039/x0xx00000x
Chelating 1,4-disubstituted mono- (8a−8d) and bis-1,2,3-triazole-based (9a−11a) ligands were prepared by regioselective
copper(I)-catalysed 1,3-dipolar cycloaddition of terminal alkynes with aromatic azides, together with bioconjugate 13a
synthesized by amide coupling of L-phenylalanine methyl ester to 11a. Cu(II) and Zn(II) complexes were prepared and
single crystal structures were determined for complexes 8aCu, 8dCu, 9cCu and 10cCu, as well as the free ligands 10a and
10c. The in situ prepared Zn(II) complexes were studied by NMR spectroscopy, while the stoichiometry of the Cu(II)
complexes in solution was determined by UV-Vis titrations and confirmed by the electronic structure DFT calculations at
the (SMD)/M05-2X/6-31+G(d)/LanL2DZ + ECP level of theory.
ligands showed preference towards forming ML2 complexes
that are trans-fac isomers,18–20 bis(2-picolyl)amine (bpa)
ligands showed versatile coordination possibilities,17,21 making
it less straightforward to obtain complexes of ML2
stoichiometry. However, when bpa ligands form ML2
complexes, they are preferentially cis-fac isomers.3,22
Introduction
The function of the 1,2,3-triazolyl moiety, derived from
copper(I)-catalysed azide−alkyne cycloaddition (CuAAC), has
recently been expanded to coordination chemistry of transition
metals.1–6 Regioselective formation of 1,4-disubstituted 1,2,3-
triazole-based mono-, bi- or multidentate chelating ligands has
received considerable attention because of its broad application
in drug development, optics, redox sensing, fluorescence and
catalysis.2,3,7–13 The large dipole moment of triazoles, around 5
D, allows easy formation of hydrogen bonds, as well as dipole-
dipole and π-interactions, which can favour their binding to
biological targets and improve their solubility.14 Moreover, 1,2,3-
triazoles are found to be versatile ligands that can coordinate to
metals through the N3, N2 and C5 donor sites, with preferential
coordination at the N3 atom.12,15 N-coordination modes offer
complexation via anionic and cationic nitrogen donors of
triazolate and triazolium ions, respectively, while CH-
deprotonation of the triazole and the triazolium affords
carbanionic and mesoionic carbene donors available for metal
coordination.16
N
N
N
N
N
N
N
N
N
N
N
N
mer
trans-fac
N
N
N
N
N
N
N
N
N
N
N
N
cis-fac
In hexacoordinated ML2 complexes of tridentate ligands,
depending on the angles between the donor atoms of the
ligand, different geometrical isomers are possible; mer, trans-fac
and Δ- or λ- cis-fac (Figure 1).17 In our previous research, similar
tridentate ligand systems and their stereochemical
preferences were described. While iminodiacetamide (imda)
Figure 1. Geometrical isomers of octahedral ML2 complexes of tridentate
ligands.
In this work, we present the synthesis of Cu(II) and Zn(II)
complexes of ML2 stoichiometry with bis-1,2,3-triazole and
mono-1,2,3-triazole-2,2′-dipyridylamine ligands, and evaluate
different effects determining the stoichiometry, geometry and
stereochemistry of the prepared complexes. In addition,
derivatives containing a methyl ester protecting group offer
the possibility of easy conjugation to a wide range of
a. Ruđer Bošković Institute, Zagreb, Croatia.
b. Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb,
Croatia.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any biomolecules, such as amino acids. Our aim was to study the
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
stereochemical preference of the bis-1,2,3-triazole ligand
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DOI: 10.1039/D0DT01244K
R
N
R =
N
N
H
N
Br
I
N
N
RN3
a
c
b
N
N
N
N
N
N
DMF, NaH
MeOH
Cu(OAc)2
S
1
8a-d
d
R'
NH
Br
O
O
2, 4, 6
N
R'
N
R'
N
R' =
N
R
NH2
K2CO3, KI
acetone
R'
N
RN3
N
S
9a-d
10a-d
11a
MeOH
Cu(OAc)2
N
N
N
3, 5, 7
2, 3, 9
4, 5, 10
6, 7, 11
R
Scheme 1. Synthesis of alkynes 1−7, mono-1,2,3-triazoles 8a−8d and bis-1,2,3-triazoles 9a−11a.
system. In literature, there are only few transition metal
complexes involving such ligands, and their stereochemical triazoles 9a
A similar two-step procedure was used to prepare bis-1,2,3-
11a. Alkynes 2 7 were prepared by propargylation
−
−
preference has not been studied so far. In the CSD database of aniline (2, 3)36, 2-aminobenzothiazole (4, 5)37 or methyl-4-
search of transition metal complexes with bis-1,2,3-triazole aminobenzoate (6, 7). In the propargylation reaction, mono-
ligands, seventeen ML and ten ML2 complexes are found. All and bis-alkynes were obtained and the bis-alkynes were reacted
reported ML2 complexes23–26 are trans-fac isomers and have further with a series of azides (a-d), forming bis-1,2,3-triazoles
weakly coordinating anions, while the majority of ML complexes 9a
−11a (Scheme 1).
are found with strongly coordinating anions, such as
In order to increase the flexibility and coordination
thiocyanate,27,28 halogenides28,29 or azides,30,31 where the anion possibilities of ligand 11a, an attempt was made to introduce an
occupies the remaining coordination sites of the metal.
additional CH2 linker. In particular, a CH2 group was added
between the central amine nitrogen and the phenyl group;
methyl-4-(aminomethyl)benzoate was used instead of methyl-4-
Results and discussion
aminobenzoate (Figure S6)
. However, the propargylation
Ligands, synthesis and solid-state characterization.32,33 Mono-
1,2,3-triazole derivatives (8a−8d) were prepared in two steps.
Starting with propargylation of 2,2′-dipyridylamine, mono-alkyne
1 was obtained and subsequently reacted with a series of azides:
azidobenzene (a), 1-azido-4-iodobenzene (b), benzyl azide (c)
and azidomethyl phenyl sulfide (d) in a regioselective copper(I)
catalysed Huisgen cycloaddition reaction, forming 1,4-
disubstituted mono-1,2,3-triazoles 8a−8d (Scheme 1). The
copper(II) salt, Cu(OAc)2, was used for in situ generation of
Cu(I).34,35
reaction gave significantly lower yields than with the aromatic
methyl-4-aminobenzoate
. A similar synthesis of N,N-di-2-
propynyl-benzenemethanamine was reported with a low yield.38
The amino acid bioconjugate 13a was prepared from ligand 11a
O
O
O
O
O
NH
N
N
N
N
(a)
(b)
N
N
N
N
N
N
11a
13a
N
N
N
N
Scheme 2. Synthesis of ligand 13a. (a) CH2Cl2/CH3OH (9:1), 1 M NaOH; (b)
TBTU, HOBt, DIPEA, H-Phe-OMe × HCl.
2 | J. Name., 2012, 00, 1-3
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Figure 2. Ortep-III diagrams for structures of ligands 10a and 10c and ML2 complexes 8aCu, 8dCu, 9cCu and 10cCu with ellipsoids of 30% probability level and labelled
heteroatoms. For 10c, only the higher occupied positions of S1 and N1 atoms are shown. The disorder is shown in Figure S9. Hydrogen atoms are omitted for
−
2−
clarity and for 8cCu only the higher occupied position of one disordered phenyl ring is shown. The anions (BF4 in 8aCu, and SiF6 in 8dCu, 9cCu and 10cCu) are
omitted for clarity, complete Ortep-III diagrams are given in ESI. In order to emphasize the position of ligands in the complexes, one ligand is shown bold and
other one, which is related by centre of symmetry in the Cu atom, is shown light. [Symmetry code (i): 1-x, 1-y, 1-z].
in a two-step procedure (Scheme 2). The methyl ester protecting bond lengths and angles are shown in Tables S3 and S4. All four
group was removed by hydrolysis in alkaline conditions39 and the metal complexes have ML2 stoichiometry in the solid state. The
−
carboxylic acid 12a was used in a standard amide coupling weakly coordinating BF4 anion was used in synthesis to avoid
reaction to obtain the ligand 13a.
The prepared ligands 8a
interaction of the anion with the metal center.40 As found in
−
−
13a were purified using column literature41,42, and in our previous publications18,21, the BF4
chromatography, and characterised by 1H, 13C NMR and IR anion can undergo decomposition, forming fluoride anions.
spectroscopy and mass spectrometry. Single crystals suitable for These F− ions can further react with the glass reaction vessel
2
−
X-ray diffraction were obtained for ligands 10a and 10c (Figure forming SiF6 anions, that were found in the crystal structures
2). Ligand 10a crystallizes in the Pbca space group, with 8 of 8dCu, 9cCu and 10cCu. Presence of the larger SiF6 anion likely
molecules in the unit cell, while ligand 10c crystallizes in the facilitates crystallization due to the large size of the cation.43,44
2−
I41/a space group, with 16 molecules in the unit cell. Ligand 10a
In complexes 8aCu and 8dCu, the two ligands are coordinated
has a bent conformation, where the distance between centroids via nitrogen atoms from the 2,2′-dipyridylamine groups forming
of the triazole rings is 3.509 Å. In the crystal structure of ligand equatorial planes of the [CuN6] or [CuN4O2] coordination
10c, the distance between centroids of the triazole rings is 6.440
Å and the conformation can be described as stretched.
N
N
N
Copper(II) complexes, synthesis and solid-state
characterization. Cu(II) complexes were prepared by mixing
boiling methanol solutions of Cu(BF4)2 x nH2O with boiling
methanol or dichloromethane solutions of the ligand, in a 2:1
ligand to metal ion ratio. The complexes were crystallized by
method of slow evaporation or vapour diffusion of diethyl-ether.
Single crystals suitable for X-ray diffraction were obtained for
metal complexes 8aCu, 8dCu, 9cCu and 10cCu (Figure 2). Selected
N
N
N
N
N
N
N
N
N
elongated
pseudo trans-fac
trans
N
N
Figure 3. Geometrical isomers observed in mono-1,2,3-triazole-2,2′-
dipyridylamine (left) and bis-1,2,3-triazole (right) ligands.
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octahedra, respectively (Figure 2). In 8aCu, the N3 triazole ligands were found. Five of the complexes have compressed
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DOI: 10.1039/D0DT01244K
nitrogen atoms of both ligands are coordinated in the apical octahedral geometry, and ten have elongated octahedral, with
positions, while for 8dCu the triazole groups are not coordinated most axial bonds around 2.4 Å, and the longest axial bond was
to the metal and the apical positions are occupied by water 2.607 Å, still significantly shorter than in 9cCu and 10cCu. Average
molecules present in the solution due to the hygroscopic nature values for Cu-N(triazole) and Cu-N(amine) bond lengths are
of Cu(BF4)2. Due to the small bite angle of the 2,2′- found to be 2.048 Å and 2.140 Å respectively, calculated as an
dipyridylamine group, only facial coordination, with both pyridyl average for the eleven Cu(II) complexes of ligands containing a
groups of one ligand bound at neighbouring sides of the bis-triazole moiety found in the CSD database.30,50–52 For
octahedron is possible, and the N(pyridyl)-M-N(pyridyl) angles complexes 9cCu and 10cCu, due to the elongated Cu-N2 distance,
found in the CSD for 2,2′-dipyridylamine complexes range from the complexes can be described as pseudo trans-fac isomers
58-99°. Therefore, complexes 8aCu and 8dCu can both be (Figure 3), with N2-M-N2 angles 180° and N3_1-M-N3_2 angles
described as trans, regarding the relative position of the triazole 93.45 and 92.33° for 9cCu and 10cCu, respectively (Table S4).
group in 8aCu (Figure 3) or the H2O molecules in 8dCu.
IR (KBr) spectra of the complexes were compared to the IR
For 8dCu, the poor quality of the data recorded at θ angles spectra of the ligands; most notably the alkene C-H stretching
higher than 35°, resulted in poor data to parameter ratio, thus (3100-3000 cm-1) peaks and the peaks of C=C and C=N bonds
the precision of geometry parameters for this structure is lower (1400-1700 cm-1) showed shifts upon complexation.
than for other structures presented in this work. However, the
Characterization in solution. The metal complexes were
structure of 8dCu was taken for comparison with 8aCu, to show studied in solution by NMR and UV-Vis spectroscopy. For the
different binding modes of mono-triazole ligands. The complex NMR measurements, Zn(II) salts were used due to the
cations of 8aCu and 8dCu are Ci symmetric and crystallize in the P- paramagnetic nature of Cu(II). Zn(II) complexes were prepared in
1 space group. Geometry parameters of the [CuN6] or [CuN4O2] situ, by dissolving a mixture of the ligand and Zn(II) salt in
coordination octahedra are given in Table S3.
deuterated solvent. The stoichiometry, anion, solvent and
A CSD search of first row transition metal ML2 complexes of temperature were varied. Upon complexation, a shift of NMR
2,2′-dipyridylamine-CH2-R ligands showed that all seven signals is observed, most notably for the triazole NH and CH2
reported complexes are hexacoordinated and have regular protons (Tables S5-S8).
8c
octahedral geometries as determined by the program FindGeo.45
To study the equilibrium in solution, an CNuMR titration was
In all the literature complexes, two 2,2′-dipyridylamine ligands performed for ligand 10c, by adding increasing equivalents of
occupy four coordination sites, while the remaining two Zn(II) (Figure 4), full titration spectra are given in Figure S18. At
coordination sites are occupied by anion or solvent molecules. each titration point, only a single set of signals was observed,
The complexes are trans isomers in regard to the coordinated indicating exchange processes faster than the NMR
anion/solvent,46,47 with the exception of one Ni(II) complex with measurement timescale.53 The largest changes were observed
cis coordination of DMF solvent molecules.48
between 0 and 0.5 equiv of added Zn(II), indicating the
Complexes of bis-triazole ligands, 9cCu and 10cCu (Figure 2) formation of ML2 complexes. The triazole and benzothiazole
are mutually similar in structure, crystallizing in the P21/c space protons showed a downfield shift, while the α-CH2 protons
group, with two molecules of Ci symmetry in the unit cell. showed an upfield shift. At higher equivalents of Zn(II), the
Octahedral geometry with an elongated z-axis is common for benzothiazole protons shifted upfield, while triazole and α-CH2
2
2 ― y
dx
Cu(II) complexes with the unpaired electron in the
protons shifted downfield. However, the shifts became smaller
orbital.49 The N3_1 and N3_2 triazole nitrogen atoms of the two for added equivalents higher than 0.5, indicating formation of
ligands are coordinated in the equatorial planes of 9cCu and ML complexes. The stability constants were too large to be
10cCu. However, the Cu-N2 distances, where N2 is the central accurately determined from these experiments.54
amine nitrogen atom, in complexes 9cCu and 10cCu are longer
For 13a and Zn(CF3SO3)2 at different ratios, a large shift of
than expected for Jahn-Teller distortion; 2.781 Å and 2.873 Å in triazole protons was observed for the 2:1 ratio compared to the
9cCu in 10cCu, respectively (Table S3). Currently there are no free ligand (0.43 ppm), while for the 1:1 ratio compared to 2:1,
published Cu(II) complexes with bis-triazole ligands of ML2 the shift is much smaller (0.03 ppm). This is similar to the NMR
stoichiometry to allow for a comparison of bond lengths. In a titration of 10c, where the shift of the triazole peak for 2:1
CSD search of CuL2 complexes with tridentate nitrogen donor compared to the free ligand was 0.29 ppm and for 1:1 compared
ligands forming 5-membered chelate rings (Table S2), complexes to 2:1, the shift was 0.04 ppm.
of bis(2-pyridylmethyl)amine (bpa) and diethylenetriamine
4 | J. Name., 2012, 00, 1-3
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Figure 4. 1H NMR (CD3CN) titration of ligand 10c with Zn(CF3SO3)2 (left) and chemical shifts of selected protons (right).
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Figure 5. UV-Vis titration of Cu(II) with ligand 13a (left) and species distribution (right) in a 1:1 CH3OH:CH2Cl2 solvent mixture.
Since the spectra show species in fast exchange, spectra of
The formation of complexes of different stoichiometry can
isolated ML or ML2 complexes could not be defined. In Figures be influenced by the coordinating ability of the counterion.21 To
S19-S21, spectra of the free ligands compared to in situ study the influence of the counterion, complexes of ligands 9c
prepared complexes in a 2 L : 1 Zn(II) ratio, that would roughly and 10c were prepared with Zn(II) salts of three counterions;
correspond to the ML2 species are shown. The large shifts of the BF4 , NO3 , Br−; ranging from weak to strong coordinating
−
−
mono-triazole protons (Δ
δ
= 0.2-0.5 ppm) are an indication that ability.40 When comparing spectra of complexes with all three
the triazole group is coordinated in all the Zn(II) complexes with anions at a 2 L to 1 Zn(II) ratio, most peaks have similar shifts,
mono-triazole ligands, since the non-coordinated triazole group however, different shifts of the triazole protons are observed
would be far away from the metal and no significant shift would (Figures S23 and S24), indicating either influence on the
be expected.
equilibrium, where the different shift is caused by a different
In hexacoordinated ML2 complexes of tridentate ligands with ratio of ML and ML2 complexes in fast exchange, and/or the
an α-CH2 group, geminal splitting of the α-CH2 protons can be difference is caused due to the different electronic effects of
indicative of the type of geometrical isomer in solution. In trans- anions coordinated to the remaining three coordination sites of
fac isomers, that would correspond to the Cu(II) crystal Zn(II) in the ML complexes. At a 1 L to 6 Zn(II) ratio, peaks are
structures, the α-CH2 protons are expected to show two shifted compared to the 2 L to 1 Zn(II) ratio, indicating a
doublets of geminal coupling, since all four α-CH2 groups are different equilibrium at different ratios (Figure S25).
equivalent in a complex of Ci symmetry. However, the spectra of
Zn(II) complexes with ligands 9a 10d showed a single α-CH2 Zn(CF3SO3)2 at a 2 L to 1 Zn(II) ratio were similar, regardless of
peak (Figures S20-S21). If a long Zn-N2 distance is assumed (see the anion.
For bioconjugate 13a, complexes with Zn(BF4)2 and
−
Computational analysis of zinc complexes), nitrogen inversion
The Cu(II) complexes were characterized by UV-Vis
would be possible and the α-CH2 protons equivalent, showing a spectroscopy (Figures S30-S38). For ligands 10c, 11a and 13a,
single sharp peak.18 Furthermore, fast ligand exchange could UV-Vis titrations were performed by adding the ligand in the
also cause the equivalence of α-CH2 protons.
solution of Cu(II) to a solution of Cu(II) of the same
1:1 CH3OH:CH2Cl2 solvent
At low temperature (
−
40°C), strengthening of the Zn-N2 concentration to avoid dilution.54
A
bond and/or slower ligand exchange could enable separation of mixture was used, due to low solubility of the ligands in polar
the α-CH2 singlet observed in complexes of ligands 9a-10d. For solvents and the metal salt in non-polar solvents. Cu(CF3SO3)2
complexes [Zn(9a)2](BF4)2 and [Zn(10a)2](BF4)2, no significant was used due to the hygroscopic nature of Cu(BF4)2 used in the
changes
were
observed
at
(−40°C),
while
for synthesis of complexes. Binding constants were determined for
[Zn(9a)(CD3CN)](BF4)2, [Zn(9c)2](BF4)2, [Zn(10c)2](BF4)2 and ML and ML2 complexes using the HypSpec2014 software55 and
[Zn(10d)2](BF4)2, peak broadening was observed, indicating their values are similar for complexes of all three ligands in the
slower ligand exchange, becoming intermediate compared to given conditions (Figure 5) and indicate somewhat greater
the NMR timescale (Figure S22). Temperatures lower than
were not possible due the melting point of CD3CN ( 45°C).
−
40°C stability of ML complexes. Furthermore, the calculated species
−
distributions (Figures S32, S35, S38) show that a mixture of ML
The only example where splitting of the α-CH2 peak was and ML2 complexes is present even at 3 equiv of added ligand.
observed, was the complex of the chiral ligand 13a, Here it should be noted that the CF3SO3− anion used in titrations
−
[Zn(13a)2](CF3SO3)2, as the chirality of the ligand lowers the has a slightly stronger coordinating ability40 than the BF4 anion
symmetry of the complex (Figure S28).
used in the synthesis of complexes, which could cause greater
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stability of the ML complexes due to possible coordination of 14a
−14d used in calculations have methyl substitVuieewnAtrsticolenOntlhinee
the CF3SO3− anion to the copper ion. triazole rings and methyl, isopropyl, phDeOnyI:l10o.1r03b9e/nDz0oDtTh0i1a2z4o4lKe
CD spectra were recorded for the addition of chiral ligand groups on the central amine nitrogen. For each complex, relative
13a to a Cu(II) solution. The spectra at different added stabilities of cis-fac, mer and trans-fac isomers were considered,
equivalents show maxima of low intensity around 650 nm, both in the gas phase and acetonitrile solution. In our previous
indicating only weak transfer of chirality from the chiral ligand to publications,17,18,21 calculations in acetonitrile consistently
the copper ion (Figure S39). This weak chirality transfer is offered a much better agreement with the experimental results,
expected due to the large distance of the chiral moieties and the so only the results in acetonitrile will be discussed here (Table
rather rigid side chains, preventing the formation of hydrogen 1). Selected bond lengths and angles of calculated structures are
bonded secondary structures.56
Computational analysis. DFT calculations at the analysed using the program FindGeo.18,45
shown in Tables S10-S12 and the coordination polyhedra were
(SMD)/M05-2X/6-31+G(d)/LanL2DZ + ECP level of theory were
For Zn(II) complexes [Zn(14)2]2+, smaller alkyl substituents on
performed for mono- and bis-triazole complexes of [ML2]2+ the central amine nitrogen favour trans-fac isomers. Larger
stoichiometry. Since the anions (BF4 or SiF62−) do not
−
coordinate to the metal, only the complex cations were
calculated; the anions were not considered due to
simplicity.18,21
R'
CH3
N
N
N
N
14a
14b
N
N
N
N
Mono-triazole ligands 8a−8d can act both as bidentate
N
N
N
N
ligands, by coordinating only with the dipyridyl group as found in
8dCu, or as tridentate ligands, by including the triazole group in
the coordination, as in 8aCu. The corresponding complexes
[Cu(8a)2]2+ and [Cu(8d)2]2+ (Figure 6) were calculated and the
structures with coordinated or non-coordinated triazole group
optimized to determine the reason for different coordination
modes observed in complexes 8aCu and 8dCu. In the later set of
systems, the remaining coordination positions around the metal
cation were occupied by two water molecules. However, we
observed no clear electronic or structural effect to which we
could attribute the mentioned coordination differences among
ligands. Still, if one considers the ligand fragments shown on
Figure 6, the atomic charge on potentially coordinating N-3 in
[Cu(8a)2]2+ in acetonitrile is –0.26 |e|, considerably more
negative than the remaining two nitrogen atoms in the triazole
M2+
[M(14)2]2+
N
N
S
N
R'
M = Cu, Zn
14c
14d
Figure 7. Structures of calculated ML2 complexes of bis-triazole ligands
14a−14d with Zn(II) and Cu(II).
aromatic groups introduce steric crowding in these positions
among ligands, thus the N-phenyl group promotes the mer
isomer. Interestingly, the N-benzothiazole moiety gives the cis-
fac isomer as the most stable and this is attributed to the
favourable π–π stacking interactions between the benzothiazole
fragment on one ligand and triazole units on the other.
ring; q(N-1) = +0.18 |e| and q(N-2) = –0.24 |e|. In [Cu(8d)2]2+
,
The size of the substituent on the amine nitrogen also affects
the coordination mode. Specifically, ligands with smaller groups
are predominantly tridentate, while when larger groups are
introduced, the ligands are mainly bidentate, as the
corresponding metal-N(amino) bonds become elongated and
ligands coordinate the metal only with the triazole nitrogen
atoms. In mer-[Zn(14c)2]2+, the octahedral geometry becomes
the charge on the analogous N-3 is reduced by 15% to –0.22
|e|, indicating that the smaller effective charge on the
coordinating nitrogen atom is likely responsible for the
bidentate coordination observed in 8dCu. The charges on the
remaining two nitrogen atoms in [Cu(8d)2]2+ are q(N-1) =
+0.09|e| and q(N-2) = –0.18 |e|.
extended with the N(amino)-Zn distances of 2.679 and 2.891 Å.
1
R
N
The same situation is observed for the cis-fac isomer, while the
ligands are classically tridentate in the trans-fac isomer, yet the
latter is the least stable among the corresponding isomers.
Ligand 14d is bidentate in all three geometrical isomers of
[Zn(14d)2]2+ with the cis-fac being the most stable, linked with
N
N
N
2 N
N
N
N
3
N
8a, q(N) = -0.26 |e|
[Cu(8)2]2+
Cu2+
large N(amino)-Zn distances of 3.136 and 3.156 Å. These results
agree with the NMR measurements, showing that large Zn-N2
distances enable nitrogen inversion leading to equivalence of α-
CH2 protons, even at −40°C.
N
N
S
N
N
N
N
N
N
N
R
8d, q(N) = -0.22 |e|
For ML2 complexes with Cu(II), trans-fac isomers are the
most stable, with the exception of [Cu(14a)2]2+ involving the
smallest methyl group substituent, where mer is most favoured.
Ligands in [Cu(14a)2]2+, [Cu(14b)2]2+ and [Cu(14c)2]2+ are
predominantly tridentate, while 14d is mainly bidentate in all
three calculated isomers of [Cu(14d)2]2+. Specifically, in the most
Figure 6. Structures of calculated ML2 complexes of mono-triazole
ligands 8a and 8d with Cu(II).
Relative stabilities of Cu(II) and Zn(II) ML2 complexes with
bis-triazole ligands 14a−14d were calculated (Figure 7). Ligands
6 | J. Name., 2012, 00, 1-3
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ARTICLE
occupied by water molecules. In complexes 9cCu aVniedw1Ar0ticclCeuO, ntlhinee
triazole groups are coordinated to Cu inDtOhIe: 10e.q10u3a9t/oDr0iaDlT0p1l2a4n4eK,
while the Cu-N2 distance is elongated and the complexes can be
considered as pseudo trans-fac isomers.
The UV-Vis titrations show formation of complexes of ML
and ML2 stoichiometry for Cu(II) complexes of ligands 10c, 11a
and 13a. NMR spectra of Zn(II) complexes also revealed
formation of complexes of ML and ML2 stoichiometry that are
in fast exchange compared to the NMR timescale. Equivalence
of the α-CH2 signal indicates nitrogen inversion of the central
amine nitrogen, due to the large Zn-N2 distance, observed also
in the calculated Zn(II) complexes.
Table 1. Relative Gibbs free energies (in kcal mol−1) and distances between the
metal and amine nitrogen atom of different structural isomers, involving the
Zn(II) or Cu(II) cation and various ligands in the 2 L to 1 M ratio. All values are
obtained by the M05-2X/6-31+G(d)/LanL2DZ + ECP model. Acetonitrile solvent
effects are modeled through the implicit SMD solvation.
N2-Zn-N2i N2-Cu-N2i
Complex
Isomer
cis-fac
mer
Zn(II) Cu(II)
(Å)
(Å)
2.394
2.357
2.272
2.289
2.282
2.282
2.603
2.441
2.316
2.320
2.425
2.425
2.614
2.613
2.679
2.891
2.467
2.465
3.136
3.156
2.876
2.876
2.877
2.570
2.494
2.164
2.116
2.097
2.405
2.406
2.207
2.760
2.436
2.437
2.621
2.624
2.724
2.278
2.523
2.522
2.670
2.561
3.059
3.188
3.289
3.200
3.066
3.206
2.0
1.7
0.0
5.1
3.1
0.0
0.9
0.0
1.9
0.0
5.3
6.7
2.3
0.0
3.5
3.8
6.8
0.0
3.1
3.5
0.0
2.3
6.3
0.0
[M(14a)2]2+
DFT calculations show that larger negative charge on the N3
atom in [Cu(8a)2]2+ compared to [Cu(8d)2]2+ could be the reason
for different coordination modes observed in crystal structures
of 8aCu and 8dCu. Calculations for ML2 complexes of bis-triazole
trans-fac
cis-fac
mer
[M(14b)2]2+
[M(14c)2]2+
[M(14d)2]2+
ligands 14a−14d showed that smaller alkyl groups on the central
nitrogen atom favour trans-fac isomers in Zn(II) complexes as
opposed to Cu(II) complexes, where trans-fac isomers are
formed predominantly for ligands with larger groups on the
central amine nitrogen. The bis-triazole ligands often prefer an
elongated octahedral geometry, with large M-N2 distances.
An interesting overall conclusion arises if the bta
complexes presented herein are compared with bpa17,21 and
imda18 complexes published recently by our group. Although
bta ligands are structurally similar to bpa, having donor atoms
as a part of heterocyclic rings, bta complexes appear to have
stereochemical preferences similar to the structurally different
imda ligands, and preferably form trans-fac isomers. The
possible cause of different preferences of bpa and bta ligands
are the different electronic properties of the donor N atoms.
trans-fac
cis-fac
mer
trans-fac
cis-fac
mer
trans-fac
i symmetry related atom
stable trans-fac isomer, the geometry of [Cu(14d)2]2+ is such that
both N(amino)-Cu distances again stretch over 3 Å and are
calculated to be 3.066 and 3.206 Å.
Lastly, the calculations clearly reveal that the most stable
isomer of complexes [Cu(14c)2]2+ and [Cu(14d)2]2+ is trans-fac,
which is in excellent agreement with the experimental
structures 9cCu and 10cCu.
Conclusions
Mono- and bis-1,2,3-triazole ligands, 8a−11a were prepared by
Cu(I) catalysed cycloaddition of azides and alkynes. Amino acid
bioconjugate 13a was obtained by standard amide coupling.
Crystal structures were determined for two ligands, 10a and 10c,
and four Cu(II) complexes, 8aCu, 8dCu, 9cCu and 10cCu. The Cu(II)
complexes were characterized in solution by UV-Vis
spectroscopy, while NMR spectroscopy was used for
characterization of diamagnetic Zn(II) complexes in solution.
Stereochemical preferences of different ligands were studied
with DFT calculations.
In the crystal structures of 8aCu and 8dCu the complexes have
ML2 stoichiometry; ligand 8a acts as a tridentate ligand, while
ligand 8d is bidentate and the remaining coordination sites are
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
(2H, m, H-4, H-4’), 4.93 (2H, d, J = 2.4 Hz, H-1’’), 3V.0ie0w A(1rtiHcle, Ot,nJlin=e
Experimental
DOI: 10.1039/D0DT01244K
2.4 Hz, H-3’’).
General remarks. Reactions were carried out in ordinary
glassware, and chemicals were used as purchased from
commercial suppliers without further purification. The
progress of all reactions was monitored by thin-layer
chromatography (TLC) on silica gel 60F-254 plates (Merck,
Darmstadt, Germany) and the spots were observed under UV
light (254 nm). Purification of compounds using column
chromatography was carried out on silica gel (0.063–0.2 mm)
13C NMR (75 MHz, DMSO) δ/ppm: 156.08, 148.36, 138.18,
118.14, 114.79, 81.75, 73.55, 37.40.
Methyl-4-(prop-2-yn-1-ylamino)benzoate (6) and methyl-4-
(di(prop-2-ynyl)amino)benzoate (7). Methyl-4-aminobenzoate
(500.0 mg, 3.30 mmol) was dissolved in 10 mL of dry acetone
and K2CO3 (2.43 g, 17.60 mmol) was added. The reaction
mixture was refluxed for 1 h. Then KI (280.0 mg, 1.65 mmol)
and propargyl bromide (0.4 mL, 6.60 mmol) were added and
the reaction refluxed for 24 h. The reaction progress was
monitored with TLC. The solvent was evaporated in a vacuum
and the crude product purified using column chromatography
(CH2Cl2). Yield: 67.0 mg (0.35 mmol, 11%) of yellow oil (6) and
323.0 mg (1.42 mmol, 43%) of white powder (7), m.p. = 72-
76°C. 1H NMR of 6 (300 MHz, DMSO-d6) δ 7.78–7.67 (2H, m, H-
3,5), 6.87 (1H, t, J = 5.9 Hz, NH), 6.74 – 6.60 (2H, m, H-2, 6),
3.98 – 3.90 (2H, m, H-1’), 3.75 (3H, s, H-8), 3.12 (1H, t, J = 2.4
Hz, H-3’). 13C NMR of 6 (75 MHz, DMSO) δ 166.31, 151.85,
130.81, 116.83, 111.69, 81.32, 73.38, 51.30, 31.58. 1H NMR of
7 (300 MHz, DMSO-d6) δ 7.90–7.77 (2H, m, H-3,5), 7.00–6.86
(2H, m, H-2, 6), 4.27 (4H, s, H-1’, H-1’’), 3.79 (3H, s, H-8), 3.20
(2H, t, J = 2.3 Hz, H-3’, H-3’’). 13C NMR of 7 (75 MHz, DMSO) δ
166.62 (C-7), 150.97 (C-1), 131.01 (C-3,5), 118.85 (C-4), 113.59
(C-2,6), 79.93 (C-2’, C-2’’), 75.57 (C-3’, C-3’’), 51.98 (C-8), 40.15
(C-1’, C-1’’).
(Fluka, Buchs, Switzerland). The H and 13C NMR spectra were
1
recorded in DMSO-d6 or acetonitrile-d3 at 298 K on a Bruker
300 or 600 MHz NMR spectrometer (Bruker Biospin,
Rheinstetten, Germany). Chemical shifts were referenced to
the signal of DMSO at δ: 2.50 ppm (1H NMR) and δ: 39.50 ppm
(13C NMR) or acetonitrile at δ: 1.94 ppm (1H NMR) and δ:
118.26 ppm (13C NMR). The melting points of novel
compounds were determined using a Kofler micro hot-stage
(Reichert, Wien, Austria) apparatus. High-resolution mass
spectra of the final compounds were recorded on
a
nanoAcquity Ultra Performance LC (Waters, Milford, MA, USA)
and a Synapt G2-Si (Waters, Milford, MA, USA) using a UPLC
column BEH130 C18 (100 µm × 100 mm, Waters, Milford, MA,
USA). IR spectra were recorded using KBr pellets with a Bruker
Alpha FT-IR spectrometer, in the 4000−350 cm−1 region. MS
spectra were recorded on
chromatography (HPLC)−MS system (Agilent Technologies
1200) coupled with 6410 Triple-Quadrupole mass
a high-performance liquid
a
spectrometer, operating in a positive ESI mode. The UV−vis
titrations were performed on a Cary 100 spectrophotometer.
General procedure for the synthesis of ligands 8a−11a. The
alkyne (1 equiv) was dissolved in methanol and the azide (1.2
or 2.4 equiv) and copper(II) acetate (0.07 equiv) were added.
The reaction mixture was stirred for 24 h at room temperature
and the reaction progress was monitored with TLC. The solvent
was evaporated in a vacuum and the crude product was
purified using column chromatography.
The CD spectra were recorded on
a
JASCO J-810
spectropolarimeter equipped with Peltier thermostat.
NMR measurements (in situ). Complexes were prepared by
dissolving the ligand (0.5, 1 or 2 equiv) and metal salt (1 equiv)
in approximately 0.6 mL CD3CN. The NMR titration was
performed by adding Zn(II) in the solution of the ligand to a
solution of the ligand of the same concentration to avoid
dilution.54
N-[(1-Phenyl-1H-1,2,3-triazol-4-yl)methyl]-2,2′-
dipyridylamine (8a). Alkyne
1 (300.0 mg, 1.41 mmol),
methanol 6 mL, azidobenzene (1.7 mL, 1.68 mmol), copper(II)
acetate (18.0 mg, 0.10 mmol). Chromatography system, CH2Cl2
: CH3OH (100 : 1). Yield: 228.4 mg (0.69 mmol, 49%) of white
powder, m.p. = 116-118°C. 1H NMR (300 MHz, DMSO-d6)
δ/ppm: 8.55 (1H, s, H-3’’), 8.33 (2H, d, J = 3.7 Hz, H-3, H-3’),
7.84 (2H, d, J = 8.0 Hz, H-5’’,9’’), 7.73 – 7.62 (2H, m, H-6’’,8’’),
7.55 (2H, t, J = 7.6 Hz, H-5, H-5’), 7.45 (1H, t, J = 7.3 Hz, H-7’’),
7.31 (2H, d, J = 8.4 Hz, H-6, H-6’), 7.03 – 6.94 (2H, m, H-4, H-4’),
5.50 (2H, s, H-1’’). 13C NMR (151 MHz, DMSO) δ/ppm: 156.63,
148.39, 146.76, 138.10, 137.04, 130.26, 128.95, 121.70,
120.39, 117.93, 115.08, 43.54. IR (KBr): ν/cm-1 3444, 3139,
3074, 3052, 3011, 2987, 2939, 1582, 1560, 1501, 1470, 1429,
1382, 1344, 1320, 1244, 1175, 1045, 978, 876, 773, 758, 667,
605, 517, 408. MALDI-HRMS (m/z): calcd 329.1515 [M+H]+,
found 329.1530.
Synthesis of alkynes. N-(Prop-2-yn-1-yl)aniline (2), N,N-
di(prop-2-yn-1-yl)aniline (3), N-(prop-2-yn-1-yl)benzothiazol-2-
amine (4) and N,N-di(prop-2-yn-1-yl)benzothiazol-2-amine (5)
were prepared according to known procedures.36,37
N-(Prop-2-yn-1-yl)-2,2′-dipyridylamine (1). 2,2′-Dipyridylamine
(500.0 mg, 2.92 mmol) was dissolved in anhydrous DMF (15
mL). Then NaH (101.4 mg, 4.23 mmol) was added, and the
reaction mixture was stirred for 1.5 h at room temperature
while bubbling with argon. Propargyl bromide (0.3 mL, 4.01
mmol) was added and the reaction was stirred for 24 h. The
reaction progress was monitored with TLC. The solvent was
evaporated in a vacuum and the crude product purified using
column chromatography (CH2Cl2 : CH3OH = 100 : 1). Yield:
1
529.3 mg (2.53 mmol, 84%) of brown oil. H NMR (300 MHz,
N-{[1-(4-Iodophenyl)-1H-1,2,3-triazol-4-yl]methyl}-2,2′-
dipyridylamine (8b). Alkyne 1 (38.0 mg, 0.18 mmol), methanol
8 mL, 1-azido-4-iodobenzene (0.43 mL, 0.22 mmol), copper(II)
DMSO-d6) δ/ppm: 8.38 – 8.30 (2H, m, H-3, H-3’), 7.74 – 7.65
(2H, m, H-5, H-5’), 7.24 (2H, d, J = 8.4 Hz, H-6, H-6’), 7.05 – 6.97
8 | J. Name., 2012, 00, 1-3
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acetate (1.82 mg, 0.01 mmol). Chromatography system, CH2Cl2 3124, 1600, 1507, 1374, 1225, 1042, 759, 74V5i,ew6A9rti0cl,e O5n0lin8e.
+
DOI: 10.1039/D0DT01244K
: CH3OH (200 : 1). Yield: 29.7 mg (0.06 mmol, 36%) of light MALDI-HRMS (m/z): calcd 408.1937 [M+H] , found 408.1929.
1
brown powder, m.p. = 125-130°C. H NMR (300 MHz, DMSO-
d6) δ/ppm: 8.59 (1H, s, H-3’’), 8.39 – 8.26 (2H, m, H-3, H-3’), N,N-Bis{[1-(4-Iodophenyl)-1H-1,2,3-triazol-4-yl]methyl}aniline
7.95 – 7.83 (2H, m, H-7’’, 9’’), 7.79 – 7.62 (4H, m, H-4,6, H- (9b). Alkyne 3 (140.0 mg, 0.82 mmol), methanol 5 mL, 1-azido-
4’,6’), 7.30 (2H, d, J = 8.4 Hz, H-6’’,10’’), 6.98 (2H, s, H-5,5’), 4-iodobenzene (4.0 mL, 1.97 mmol), copper(II) acetate (7.3
5.49 (2H, s, H-1’’). 13C NMR (75 MHz, DMSO) δ/ppm: 156.08, mg, 0.04 mmol). After 24 h at room temperature, the reaction
147.88, 146.48, 138.44, 137.60, 136.19, 121.79, 121.12, was transferred to a microwave reactor (1 h, 100°C, 300 W).
117.45, 114.53, 94.02, 43.00. IR (KBr): ν/cm-1 3433, 1673, 1583, Chromatography system, CH2Cl2 : CH3OH (200 : 1). Yield: 42.8
1
1470, 1425, 1040, 984, 821, 773, 606. MALDI-HRMS (m/z): mg (0.06 mmol, 8%) of white powder, m.p. > 250°C. H NMR
calcd 455.0481 [M+H]+, found 455.0497.
(300 MHz, DMSO-d6) δ/ppm: 8.77 (2H s, H-3’, H-3’’), 7.94 (4H,
d, J = 8.8 Hz, H6’,8’, H-6’’,8’’), 7.70 (4H, d, J = 8.8 Hz, H-5’,9’, H-
N-[1-(Benzyl-1H-1,2,3-triazol-4-yl)methyl]-2,2′-dipyridylamine 5’’,9’’), 7.15 (2H, t, J = 8.0 Hz, H-3,5), 6.94 (2H, d, J = 8.1 Hz, H-
(8c). Alkyne 1 (78.2 mg, 0.37 mmol), methanol 3 mL, benzyl 2,6), 6.66 –6.62 (1H, m, H-4), 4.79 (4H, s, H-1’, H-1’’). 13C NMR
azide (0.90 mL, 0.45 mmol), copper(II) acetate (3.6 mg, 0.02 (151 MHz, DMSO) (δ/ppm): 147.75, 145.98, 138.52, 136.27,
mmol). Chromatography system, CH2Cl2 : CH3OH (200 : 1). 128.94, 121.79, 121.19, 116.77, 112.97, 94.00, 45.65. IR (KBr):
Yield: 47.9 mg (0.14 mmol, 37%) of light-yellow powder, m.p. = ν/cm-1 3443, 3121, 2925, 1600, 1495, 1374, 1224, 1041, 987,
1
125-130°C. H NMR (600 MHz, DMSO-d6) δ/ppm: 8.31 – 8.27 820, 746, 691, 515. MALDI-HRMS (m/z): calcd 681.9689
(2H, m, H-3, H-3’), 7.91 (1H, s, H-3’’), 7.68 – 7.62 (2H, m, H-5, [M+Na]+, found 681.9681.
H-5’), 7.35 – 7.27 (3H, m, H-7’’,8’’,9’’), 7.25 (2H, d, J = 8.4 Hz,
H-6’’,10’’), 7.19 – 7.15 (2H, m, H-6, H-6’), 6.96 (2H, dd, J = 6.9, N,N-Bis[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]aniline (9c).57
5.1 Hz, H-4, H-4’), 5.50 (2H, s, H-4’’), 5.39 (2H, s, H-1’’). 13C Benzyl azide was prepared in situ: benzyl chloride (4.3 mL, 3.74
NMR (75 MHz, DMSO) δ/ppm: 156.08, 147.81, 145.15, 137.57, mmol) was dissolved in 6 mL of tert-butanol and 6 mL of
136.19, 128.62, 127.94, 127.63, 123.45, 117.38, 114.51, 52.49, water, followed by addition of sodium azide (182.7 mg, 2.81
43.12. IR (KBr): ν/cm-1 3442, 3111, 3065, 1584, 1558, 1470, mmol) and triethylamine (0.7 mL, 4.01 mmol). The reaction
1425, 1379, 1283, 1228, 1211, 775, 735, 717, 604, 456. MALDI- was stirred for 1 h at 60°C and the solvent evaporated in a
HRMS (m/z): calcd 343.1671 [M+H]+, found 343.1662.
vacuum. The prepared azide was dissolved in methanol and
used in the click reaction according to the general procedure.
N-{[1-((Phenylthio)methyl)-1H-1,2,3-triazol-4-yl]methyl}-2,2′- The click reaction mixture was stirred at 60°C for 24 h.
dipyridylamine (8d). Alkyne (100.0 mg, 0.47 mmol), Alkyne 3 (263.0 mg, 1.56 mmol), methanol 6 mL, copper(II)
1
methanol 2 mL, azidomethyl phenyl sulfide (0.08 mL, 0.56 acetate (19.9 mg, 0.11 mmol). Chromatography system, CH2Cl2
mmol), copper(II) acetate (6.0 mg, 0.03 mmol). : CH3OH (50 : 1). Yield: 318.9 mg (0.73 mmol, 46%) of white
Chromatography system, CH2Cl2 : CH3OH (200 : 1). Yield: 49.0 powder, m.p. = 161-164°C. 1H NMR (600 MHz, DMSO-d6)
1
mg (0.13 mmol, 28%) of white powder, m.p. = 205-208°C. H δ/ppm: 8.01 (2H, s, H-3’, H-3’’), 7.37 – 7.29 (6H, m, H-7’,8’,9’,
NMR (300 MHz, DMSO-d6) δ/ppm: 8.29 – 8.27 (2H, m, H-3, H- H-7’’,8’’,9’’), 7.28 – 7.21 (4H, m, H-6’,10’, H-6’’,10’’), 7.13 –
3’), 7.70 – 7.60 (3H, m, H-7’’,8’’,9’’), 7.29 – 7.15 (7H, m, H- 7.08 (2H, m, H-3,5), 6.85 (2H, d, J = 8.0 Hz, H-2,6), 6.61 (1H, t, J
4,5,6, H-4’,5’,6’, H-3’’), 7.00 – 6.93 (2H, m, H-6’’,10’’), 5.82 (2H, = 7.2 Hz, H-4), 5.53 (4H, s, H-4’, H-4’’), 4.61 (4H, s, H-1’, H-1’’).
s, H-4’’), 5.34 (2H, s, H-1’’). 13C NMR (151 MHz, DMSO) δ/ppm: 13C NMR (151 MHz, DMSO) δ/ppm: 147.65, 144.80, 136.11,
156.02, 147.82, 145.33, 137.57, 132.21, 130.96, 129.13, 128.83, 128.67, 128.00, 127.73, 123.18, 116.46, 112.79, 52.63,
127.77, 122.92, 117.40, 114.41, 51.71, 43.09. IR (KBr): ν/cm-1 45.58. IR (KBr): ν/cm-1 3442, 3117, 3068, 1599, 1504, 1455,
3442, 1584, 1561, 1471, 1438, 1380, 1228, 1042, 770, 754, 1368, 1222, 1054, 750, 726, 709, 693, 462. MALDI-HRMS
732, 601, 486. MALDI-HRMS (m/z): calcd 375.1392 [M+H]+, (m/z): calcd 436.2250 [M+H]+, found 436.2249.
found 375.1385.
N,N-Bis{[1-(phenylthio)methyl)-1H-1,2,3-triazol-4-
N,N-Bis[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]aniline (9a).57 yl]methyl}aniline (9d). Alkyne 3 (70.0 mg, 0.41 mmol),
Alkyne 3 (100.0 mg, 0.60 mmol), methanol 2 mL, azidobenzene methanol 3 mL, azidomethyl phenyl sulfide (0.14 mL, 0.99
(2.8 mL, 1.42 mmol), copper(II) acetate (8.0 mg, 0.04 mmol). mmol), copper(II) acetate (3.6 mg, 0.02 mmol). After 24 h at
After 24 h at room temperature, the reaction was heated to room temperature, the reaction was transferred to
a
60°C for 24 h. Chromatography system, CH2Cl2 : CH3OH (50 : 1). microwave reactor (1 h, 100°C, 300 W). Chromatography
Yield: 48.9 mg (0.12 mmol, 20%) of white powder, m.p. = 202- system, CH2Cl2 : CH3OH (200 : 1). Yield: 79.9 mg (0.16 mmol,
1
205°C. H NMR (300 MHz, DMSO-d6) δ/ppm: 8.75 (2H, s, H-3’, 39%) of light orange powder, m.p. = 106-110°C.
H-3’’), 7.93 – 7.82 (4H, m, H-5’,9’, H-5’’,9’’), 7.65 – 7.53 (4H, m, 1H NMR (300 MHz, DMSO) (δ/ppm): 7.85 (2H, s, H-3’, H-3’’),
H-6’,8’, H-6’’,8’’), 7.53 – 7.42 (2H, m, H-7’, H-7’’), 7.22 – 7.10 7.39 – 7.24 (10H, m, H-6’, H-7’, H-8’, H-9’, H-10’, H-6’’, H-7’’, H-
(2H, m, H-3,5), 7.01 – 6.94 (2H, m, H-2,6), 6.65 (1H, t, J = 7.2 8’’, H-9’’, H-10’’), 7.13 (2H, t, J = 7.9 Hz, H-3, H-5), 6.81 (2H, d, J
Hz, H-4), 4.81 (4H, s, H-1’, H-1’’). 13C NMR (75 MHz, DMSO) = 8.2 Hz, H-2, H-6), 6.65 (1H, t, J = 7.2 Hz, H-4), 5.86 (4H, s, H-
δ/ppm: 148.25, 146.31, 137.10, 130.33, 129.44, 129.03, 4’, H-4’’), 4.54 (4H, s, H-1’, H-1’’). 13C NMR (151 MHz, DMSO)
121.78, 120.40, 117.19, 113.43, 46.16. IR (KBr): ν/cm-1 3442, (δ/ppm): 147.61, 132.27, 131.04, 129.18, 128.81, 127.81,
This journal is © The Royal Society of Chemistry 20xx
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122.82, 116.69, 113.02, 51.91, 45.53. IR (KBr): ν/cm-1 3442,
Journal Name
View Article Online
3117, 1599, 1506, 1438, 1271, 1049, 746, 689, 491. MALDI- N,N-Bis{[1-(phenylthio)methyl)-1H-1,2,3D-tOriI:a1z0o.1l0-43-9y/Dl]0mDeTt0h12y4l}4K-
HRMS (m/z): calcd 499.1612 [M+H]+, found 499.1620.
2-aminobenzothiazole (10d). Alkyne 5 (100.0 mg, 0.44 mmol),
methanol 4 mL, azidomethyl phenyl sulfide (0.14 mL, 0.99
mmol), copper(II) acetate (5.5 mg, 0.03 mmol). After 24 h at
N,N-Bis[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-2-
aminobenzothiazole (10a). Alkyne 5 (100.0 mg, 0.44 mmol), room temperature, the reaction was heated to 60°C for 24 h.
methanol 4 mL, azidobenzene (1.1 mL, 1.06 mmol), copper(II) Chromatography system, CH2Cl2 : CH3OH (200 : 1). Yield: 69.2
1
acetate (5.8 mg, 0.03 mmol). After 24 h at room temperature, mg (0.12 mmol, 28%) of yellow oil. H NMR (600 MHz, DMSO-
the reaction was heated to 60°C for 3 h. Chromatography d6) δ/ppm: 7.97 (2H, s, H-3’, H-3’’), 7.80 – 7.75 (1H, m, H-7),
system, pure CH2Cl2. Yield: 58.2 mg (0.12 mmol, 29%) of light 7.48 (1H, d, J = 7.8 Hz, H-4), 7.38 – 7.34 (4H, m, H-6’,10’, H-
yellow powder, m.p. = 185-188°C. Crystals suitable for X-ray 6’’,10’’), 7.33 – 7.27 (2H, m, H-5,6), 7.27 – 7.20 (6H, m, H-
1
diffraction were obtained by evaporation from methanol. H 7’,8’,9’, H-7’’,8’’,9’’), 5.90 (4H, s, H-4’, H-4’’), 4.71 (4H, s, H-1’,
NMR (300 MHz, DMSO-d6) δ/ppm: 8.82 (2H, s, H-3’, H-3’’), 7.93 H-1’’). 13C NMR (151 MHz, DMSO) δ/ppm: 167.04, 152.23,
– 7.82 (4H, m, H-5’,9’, H-5’’,9’’), 7.78 (1H, d, J = 7.2 Hz, H-7), 142.66, 132.17, 130.96, 130.71, 129.17, 127.76, 125.89,
7.62 – 7.44 (7H, m, H-4, H-6’,7’, 8’, H-6’’,7’’,8’’), 7.29 (1H, s, H- 123.51, 121.27, 121.09, 118.64, 51.81, 45.18. IR (KBr): ν/cm-1
6), 7.09 (1H, s, H-5), 5.01 (4H, s, H-1’, H-1’’). 13C NMR (75 MHz, 3442, 1537, 1439, 1380, 1283, 1225, 1201, 1046, 748, 725,
DMSO) δ/ppm: 167.88, 152.83, 144.19, 137.02, 131.31, 689, 489. MALDI-HRMS (m/z): calcd 557.1364 [M+H]+, found
130.30, 129.13, 126.39, 122.41, 121.75, 121.61, 120.52, 557.1386.
119.17, 45.93. IR (KBr): ν/cm-1 3441, 3139, 1598, 1563, 1531,
1502, 1444, 1358, 1292, 1230, 1051, 760, 748, 720, 690. Methyl-4-{bis[(1-phenyl-1H-1,2,3-triazole-4-
MALDI-HRMS (m/z): calcd 465.1610 [M+H]+, found 465.1605.
yl)methyl]amino}benzoate (11a). Alkyne 7 (200.0 mg, 0.88
mmol), methanol 10 mL, azidobenzene (4.2 mL, 2.11 mmol),
copper(II) acetate (11.2 mg, 0.06 mmol). Stirred for 24 h at
N,N-Bis{[1-(4-Iodophenyl)-1H-1,2,3-triazol-4-yl]methyl}-2-
aminobenzothiazole (10b). Alkyne 5 (100.0 mg, 0.44 mmol), 60°C. Chromatography system, CH2Cl2 : CH3OH (100 : 1). Yield:
methanol 3 mL, 1-azido-4-iodobenzene (2.1 mL, 1.06 mmol), 246.3 mg (0.53 mmol, 60%) of light yellow powder, m.p. = 180-
copper(II) acetate (5.8 mg, 0.03 mmol). After 24 h at room 185°C. 1H NMR (600 MHz, DMSO-d6) δ 8.78 (2H, s, H-3’, H-3’’),
temperature, the reaction was heated to 60°C for 24 h. 7.90–7.82 (4H, m, H-5’,9’, H-5’’,9’’), 7.80–7.74 (2H, m, H-3, 5),
Chromatography system, CH2Cl2 : CH3OH (200 : 1). Yield: 262.2 7.61–7.54 (4H, m, H-6’, 8’, H-6’’, 8’’), 7.51–7.44 (2H, m, H-7’,
mg (0.37 mmol, 84%) of light yellow powder, m.p. 262-265°C. 7’’), 7.07–7.02 (2H, m, H-2, 6), 4.90 (4H, s, H-1’, 1’’), 3.74 (3H,
1H NMR (300 MHz, DMSO-d6) δ/ppm: 8.83 (2H, s, H-3’, H-3’’), s, H-8). 13C NMR (151 MHz, DMSO) δ 166.16 (C-7), 151.29 (C-
7.97 – 7.87 (4H, m, H-6’,8’, H-6’’,8’’), 7.78 (1H, d, J = 7.2 Hz, H- 1), 144.97 (C-2’, C-2’’), 136.56 (C-4’, C-4’’), 130.77 (C-3,5),
7), 7.72 – 7.65 (4H, m, H-5’,9’, H-5’’,9’’), 7.52 (1H, d, J = 7.5 Hz, 129.83 (C-6’,8’, C-6’’,8’’), 128.60 (C-7’, C-7’’), 121.44 (C-3’, C-
H- 4), 7.33 – 7.26 (1H, m, H-6), 7.12 – 7.05 (1H, m, H-5), 4.99 3’’), 119.96 (C-5’,9’, C-5’’,9’’), 116.94 (C-4), 111.80 (C-2,6),
(4H, s, H-1’, H-1’’). 13C NMR (75 MHz, DMSO) δ/ppm: 167.84, 51.32 (C-8), 45.37 (C-1’, C-1’’). IR (KBr): ν/cm-1 3441, 3129,
152.81, 144.38, 138.99, 136.64, 131.30, 126.40, 122.35, 3088, 2949, 1702, 1606, 1521, 1501, 1287, 1196, 1112, 1049,
121.77, 121.62, 119.18, 94.75, 45.92. IR (KBr): ν/cm-1 3444, 827, 762, 689, 516. MALDI-HRMS (m/z): calcd 466,1991
1531, 1495, 1454, 1356, 1236, 1048, 987, 816, 750, 507. [M+H]+, found 466,1968.
MALDI-HRMS (m/z): calcd 716.9543 [M+H]+, found 716.9530.
4-{Bis[(1-phenyl-1H-1,2,3-triazole-4-yl)methyl]amino}benzoic
N,N-Bis[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-2-
acid (12a).39 11a (150.6 mg, 0.32 mmol) was dissolved in 20 mL
aminobenzothiazole (10c). Alkyne 5 (100.0 mg, 0.44 mmol), of CH2Cl2/CH3OH (9:1) and a methanolic solution of NaOH (1
methanol 3 mL, benzyl azide (2.1 mL, 1.06 mmol), copper(II) M, 5.0 mL) was added. The reaction was stirred at 60°C for 24
acetate (5.4 mg, 0.03 mmol). Chromatography system, CH2Cl2 : h. The reaction progress was monitored with TLC and a
CH3OH (200 : 1). Yield: 119.2 mg (0.24 mmol, 55%) of white methanolic solution of NaOH (1 M, 10.0 mL) was added in
powder, m.p.
=
150-154°C. Crystals suitable for X-ray small portions. The solvent was evaporated in a vacuum, the
1
diffraction were obtained by evaporation from acetonitrile. H crude product dissolved in water and washed with diethyl-
NMR (300 MHz, DMSO) (δ/ppm): 8.15 (2H, s, H-3’, H-3’’), 7.74 ether. The aqueous layer was cooled, acidified to pH = 2 with
(1H, d, J = 0.7 Hz, H-7),7.47 (1H, d, J = 8.0 Hz, H-4), 7.42 – 7.36 HCl (5 M) and extracted with CH2Cl2. The organic layer was
(1H, m, H-5), 7.35 – 7.24 (10H, m, H-6’, H-7’, H-8’, H-9’, H-10’ evaporated in
a vacuum. No further purification was
H-6’, H-7’’, H-8’’, H-9’’, H-10’’),7.11 – 7.01 (1H, m, H-6), 5.56 (s, performed. Yield: 132.5 mg (0.29 mmol, 91%), white powder.
4H, H-4’, H-4’’), 4.81 (4H, s, H-1’, H-1’’). 13C NMR (75 MHz, 1H NMR (300 MHz, DMSO-d6) δ 12.14 (1H, s, H-8), 8.79 (2H, s,
DMSO) (δ/ppm): 167.70, 152.81, 143.14, 136.49, 131.18, H-3’, H-3’’), 7.92 – 7.83 (4H, m, H- H-5’,9’, H-5’’, 9’’), 7.75 (2H,
129.19, 128.54, 128.31, 126.37, 124.32, 121.69, 121.56, d, J = 8.9 Hz, H-3, 5), 7.63–7.53 (4H, m, H-6’,8’, H-6’’,8’’), 7.53–
119.08, 53.22, 45.84. IR (KBr): ν/cm-1 3444, 3119, 3065, 1598, 7.43 (2H, m, H-7’, 7’’), 7.02 (2H, d, J = 9.1 Hz, H-2, 6), 4.90 (4H,
1565, 1546, 1454, 1438, 1383, 1308, 1205, 1124, 1054, 753, s, H-1’, 1’’ ). 13C NMR (151 MHz, Acetonitrile-d3) δ 152.66 (C-7),
724, 709. MALDI-HRMS (m/z): calcd 493.1923 [M+H]+, found 146.34 (C-1), 132.31 (C-2’, C-2’’), 130.74 (C-4’, 4’’), 129.64 (C-3,
493.1920. ESI-MS (m/z): 493.3 (M+H+, 100%)
6’, 6’’, 7’, 7’’, 8’’, 8’’), 122.13 (C-5’, 5’’, 9’, 9’’), 121.33 (C-3’, 3’’),
10 | J. Name., 2012, 00, 1-3
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113.03 (C-2, 6), 46.92 (C-1’, C-1’’). IR (KBr): ν/cm-1 3451, 3130,
ARTICLE
View Article Online
DOI: 10.1039/D0DT01244K
3073, 1072, 1677, 1601, 1524, 1502, 1289, 1245, 1192, 1050, [Cu(9c)2](SiF6) x 0.7 H2O, 9cCu. 9c (15.7 mg, 0.04 mmol),
932, 831, 761, 690, 516. MALDI-HRMS (m/z): calcd 452.1835 Cu(BF4)2 x nH2O (4.3 mg, 0.02 mmol). Yield: 5.2 mg (0.005 mmol,
[M+H]+, found 452.1822.
24%) of brown cubic crystals suitable for X-ray diffraction. IR
(KBr): ν/cm-1 3444, 3149, 1600, 1499, 1457, 1214, 1064, 766,
752, 724, 702, 521.
Methyl-(S)-3-{4-[bis((1-phenyl-1H-1,2,3-triazol-4-
yl)methyl)amino]benzamido}-4-phenylbutanoate (13a). 12a
(120.4 mg, 0.27 mmol) was dissolved in acetonitrile (20.0 mL) [Cu(10c)2](SiF6) x 3.6 H2O, 10cCu. 10c (15.3 mg, 0.03 mmol),
and TBTU (86.7 mg, 0.27 mmol), HOBt (36.5 mg, 0.27 mmol) Cu(BF4)2 x nH2O (3.7 mg, 0.02 mmol). Yield: A small amount of
and DIPEA (0.18 mL, 1.07 mmol) were added. The reaction was pink cubic crystals suitable for X-ray diffraction were obtained by
mixed for 1 h at room temperature, followed by addition of L- slow evaporation of the solvent. IR (KBr): ν/cm-1 3444, 3135,
phenylalanine methyl ester hydrochloride (58.2 mg, 0.27 3090, 1630, 1531, 1448, 866, 760, 728, 477.
mmol). The reaction mixture was stirred for 2 days, the solvent
evaporated in a vacuum, the crude product dissolved in CH2Cl2 Calculations
and washed with saturated NaHCO3 and water. The organic All molecular geometries were optimized using a very efficient
layer was dried over anhydrous NaHCO3, filtered and DFT M05-2X/6–31+G(d)/LanL2DZ + ECP model, known to be
evaporated in a vacuum. The crude product was purified using successful in reproducing geometries, dipole moments, and
automated flash chromatography (0-5% CH3OH in CH2Cl2). homolytic bond energies in various metal complexes,58,59 and
1
Yield: 80.2 mg (0.13 mmol, 49%) of white powder. H NMR in accordance with our comparative analysis with other DFT
(600 MHz, CDCl3) (δ/ppm): 7.86 (2H, s, H-3’, H-3’’), 7.70 – 7.62 approaches on similar systems.21 We have truncated the
(5H, m, H-Ph), 7.50 – 7.46 (4H, m, H-Ph), 7.44 – 7.38 (2H, m, H- substituents on the N1 triazole atom to the methyl group in
Ph), 7.30 – 7.21 (4H, m, H-Ph), 7.14 – 7.10 (2H, m, H-Ph), 6.98 – order to simplify the calculations and place the focus on
6.94 (2H, m, H-Ph), 6.41 (1H, d, J = 7.6 Hz, H-8), 5.11 – 5.00 analysing substitution patterns on the central amine nitrogen,
(1H, m, H-9), 4.88 (4H, s, H-1’, H-1’’), 3.73 (3H, s, H-18), 3.28 – being closer to the coordinating metal, where this effect is
3.16 (2H, m, H-10). 13C NMR (151 MHz, CDCl3) (δ/ppm): much more dominant. Our previous experience with this kind
172.41, 166.59, 150.42, 145.50, 137.01, 136.15, 129.88, of calculations18 justifies this choice as such a substitution
129.46, 129.02, 128.98, 128.74, 127.26, 122.74, 120.66, distant from the metal centre typically exhibits only a marginal
120.40, 112.52, 53.49, 52.45, 46.86, 38.75, 38.18. IR (KBr): effect on the ligand coordination and complex structural
ν/cm-1 3424, 3349, 3135, 2947, 1738, 1634, 1608, 1503, 1342, preference. To account for the effect of the acetonitrile
1227, 1203, 1044, 832, 759, 700, 689, 515. MALDI-HRMS solution, during geometry optimization, we included the
(m/z): calcd 613.2676 [M+H]+, found 613.2692.
implicit SMD solvation model (ε = 35.688), being in line with
our earlier results.17,18,21 Thermal corrections were extracted
Preparation of single crystals, General procedure. Saturated from the corresponding frequency calculations, and all of the
methanol or dichloromethane solutions of the ligand (2 equiv) presented results correspond to differences in the Gibbs free
and methanol solution of the metal salt (1 equiv) were heated energies. This was followed by calculating energies of the
and boiled shortly in separate beakers until completely excited states responsible for the experimental UV/Vis spectra
dissolved. The metal salt solution was added to the ligand of three copper complexes through the TD-DFT computations
solution and the mixture was cooled to room temperature and at the same level of theory, considering 32 lowest singlet
left partially covered for slow evaporation or in a tank filled electronic excitations. The choice of this setup was prompted
with diethyl-ether until crystallization occurred. The solvent by its recent success in modelling UV/Vis spectra of organic
was decanted and the crystals washed with diethyl ether and heterocycles and their metal complexes in various
air-dried. The yields of obtained complexes were low, due to solvents.18,60,61 The calculated UV-Vis spectra are shown in the
the necessity of SiF62− formation from the glass reaction vessel Electronic Supplementary Information (Table S13). All
and due to multiple species being in equilibrium as observed in calculations were performed using the Gaussian 16 software.62
UV-Vis and NMR measurements.
Cartesian coordinates for all computed molecules are collected
in a single text file readable by the Mercury program (version
[Cu(8a)2](BF4)2, 8aCu. 8a (14.0 mg, 0.04 mmol), Cu(BF4)2 x nH2O 3.3 or later).63
(5.1 mg, 0.02 mmol). A small amount of light-blue cubic crystals
suitable for X-ray diffraction were obtained by diffusion of X-Ray Crystallography. The X-ray intensity data were collected
diethyl-ether. IR (KBr): ν/cm-1 3441, 3149, 2967, 1601, 1468, on an Oxford Diffraction Xcalibur CCD diffractometer using
1448, 1363, 1271, 1066, 802, 762, 693, 609, 545, 520, 437.
monochromatic Cu Kα (λ
= 1.54184 Å) radiation. For
temperature conditions, see Table S1. The data were
[Cu(8d)2(H2O)2](SiF6) x 4 CH3OH, 8dCu. 8d (7.2 mg, 0.02 mmol), processed with the CrysalisPro program64 (unit cell
Cu(BF4)2 x nH2O (2.3 mg, 0.01 mmol). Yield: 1.9 mg (0.002 mmol, determination and data reduction). The crystals of 8dCu
17%) of purple plate-like crystals suitable for X-ray diffraction. IR showed bad diffraction properties, only several intensities at θ
(KBr): ν/cm-1 3443, 1631, 1604, 1468, 1446, 1083, 1051, 795, angles higher than 35° were unreliably determined, therefore
744, 693.
reflections only with θ < 35° were used in structural
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Journal Name
determination. The structures were solved by direct methods
with the SHELXT program65 and refined against F2 on all data
by a full-matrix least-squares procedure with the SHELXL
program.66 Non-hydrogen atoms were refined with anisotropic
displacement parameters using rigid body restraints for
disordered parts of the structures (DELU and SIMU). Due to
the low number of reflections collected for 8dCu, the RIGU
restraint was used for all non-hydrogen atoms. All H atoms
were included at geometrically calculated positions, H atoms
from coordinated water molecule in 8dCu, were additionally
restraint to typical O-H bonds of 0.82 Å and distances toward
nearest acceptor atoms. Solvent-accessible voids of volume
252 (1 void), 35 (4 voids) and 241 Å3 (2 voids) were found in
Conflicts of interest
There are no conflicts to declare.
View Article Online
DOI: 10.1039/D0DT01244K
Corresponding Author
*E-mail:
Srecko.Kirin@irb.hr
sraic@fkit.hr
Robert.Vianello@irb.hr
ORCID
structures 8dCu, 9cCu and 10cCu, respectively. (In 10cCu there are Natalija Pantalon Juraj: 0000-0002-0357-5817
two symmetry related voids of volume 241 Å3 in the unit cell.) Marko Krklec: 0000-0003-3862-6415
Electron densities from these voids were treated by SQUEEZE Tiana Novosel: 0000-0003-4687-3723
procedure in the PLATON program67, in combination with the Berislav Perić: 0000-0002-2397-2836
SHELXL refinements. Total electron counts obtained in voids Robert Vianello: 0000-0003-1779-4524
were interpreted as 4 solvent CH3OH molecules for 8dCu, 0.7 Silvana Raić-Malić: 0000-0001-5021-8970
solvent H2O molecules for 9dCu and 3.6 solvent H2O molecules Srećko I. Kirin: 0000-0002-0500-2422
for 10cCu. These solvent molecules were taken into account for
the molecular formulas of the complexes, molecular weights,
calculated densities, F(000) values and linear absorptions
Acknowledgements
coefficients. Because the solvent electron densities were
accounted in the calculation of the structure factors by the
SQUEEZE procedure and SHELXL refinement (ABIN instruction)
their structural parameters (positions and ADPs) are not
presented in the final structural models (cif files).66–68 Disorder
of some molecular groups was detected in the structures 10c
and 9cCu. Two orientations of such groups were modelled and
occupancies of different orientations were refined: in 10c the
benzothiazole group was disordered, in 9cCu phenyl ring from
the benzyl group attached to triazole was found to occupy two
orientations. To some extent, the benzothiazole group in 10a
can also be considered as disordered, due to very elongated
displacement parameters for atoms in this group. Attempts to
model disorder of atoms in this group did not solve the
problem of elongated displacement parameters. For atoms in
these disordered groups, the additional distance restraints
were used in refinement (10a) or positions of atoms were
fitted to regular hexagon with C-C distance of 1.39 Å (9cCu).
We greatly appreciate the financial support of the Croatian
Science Foundation (grant numbers IP–2013–11–5596 and IP-
2014-09-1461)
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DOI: 10.1039/D0DT01244K
Graphical Abstract
Click chemistry is a simple way of preparing a wide scope of
ligands that can coordinate metals such as Cu(II) and Zn(II),
forming complexes of different stoichiometry, geometry and
stereochemistry.
N
N
N
N
R'
N3R
N3R
R
N
R'
N
N
N
N
N
N
R
R
N
N
N
N
R
R
N
N
N
N
· stoichiometry
· solvent
· temperature
· anion
N
N
N
N
M2+
M2+
M = Cu, Zn
N
N
N
N
N
N
R'
N
R
16 | J. Name., 2012, 00, 1-3
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