Halide Control of N,N-Coordination versus N,C-Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) p-Cymene Phenylazobenzothiazole Complexes

Article abstract of DOI:10.1021/acs.organomet.7b00501

We report the synthesis of halido Os(II) p-cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe₂ is capable of both N,N-coordination to Os(II) and cyclometalation to form N,C-coordinated species. N,C-Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by ¹H NMR and X-ray crystallography of [Os(p-cym)(N,N-AZBTZ-NMe₂)Cl]PF₆ (1a), [Os(p-cym)(N,N-AZBTZ-NMe₂)Br]PF₆ (2a), [Os(p-cym)(N,C-AZBTZ-NMe₂)Br] (2b), and [Os(p-cym)(N,C-AZBTZ-NMe₂)I] (3b). The N,C-coordinated species is more stable and is not readily converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the p-cym and AZBTZ-NMe₂ ligands: in particular, larger monodentate halide ligands favor N,C-coordination. The complexes [Os(p-cym)(N,N-Me₂-AZBTZ-NH₂)Cl]PF₆ (4) and [Os(p-cym)(N,N-Me₂-AZBTZ-NH₂)I]PF₆ (5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry. ¹H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by ¹H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange.

Full text of DOI:10.1021/acs.organomet.7b00501

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX-XXX
Halide Control of N,N-Coordination versus N,C-Cyclometalation and
Stereospecific Phenyl Ring Deuteration of Osmium(II) p‑Cymene
Phenylazobenzothiazole Complexes
Russell J. Needham,† Abraha Habtemariam,† Nicolas P. E. Barry,†,‡ Guy Clarkson,†
and Peter J. Sadler*,†
†Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.
‡School of Chemistry and Biosciences, University of Bradford, Bradford BD7 1DP, U.K.
S
* Supporting Information
ABSTRACT: We report the synthesis of halido Os(II) p-
cymene complexes bearing bidentate chelating phenylazoben-
zothiazole (AZBTZ) ligands. Unlike the analogous phenyl-
azopyridine (AZPY) complexes, AZBTZ-NMe2 is capable of
both N,N-coordination to Os(II) and cyclometalation to form
N,C-coordinated species. N,C-Coordination occurs via an azo
nitrogen and an ortho carbon on the aniline ring, as identified
1
by H NMR and X-ray crystallography of [Os(p-cym)(N,N-
AZBTZ-NMe2)Cl]PF6 (1a), [Os(p-cym)(N,N-AZBTZ-
NMe2)Br]PF6 (2a), [Os(p-cym)(N,C-AZBTZ-NMe2)Br]
(2b), and [Os(p-cym)(N,C-AZBTZ-NMe2)I] (3b). The
N,C-coordinated species is more stable and is not readily
converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric
interactions between the p-cym and AZBTZ-NMe2 ligands: in particular, larger monodentate halide ligands favor N,C-
coordination. The complexes [Os(p-cym)(N,N-Me2-AZBTZ-NH2)Cl]PF6 (4) and [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6
(5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry.
1H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center.
Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the
1
meta position, as observed by H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions,
suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more
negatively charged, which may account for the regiospecificity of deuterium exchange.
are of great interest for medicinal applications. Numerous
organic benzothiazole compounds have been reported to have
promising anticancer activity,17−20 suggesting that Os(II)
complexes containing benzothiazole groups may possess
potential as anticancer agents. Indeed, there are studies
highlighting organometallic complexes bearing benzothiazole
groups with antiproliferative activity,21,22 and DNA binding
capabilities.23 Most notable are Os(II) and Ru(II) complexes
reported by Keppler et al. as benzothiazole and benzimidazole
pharmacophoric inhibitors of protein kinases.22
AZBTZs contain functionalities with metal coordination
affinity. In our present study we synthesized two types of
complexes (see Chart 1); charged N,N-coordinated complexes,
[Os(p-cym)(N,N-{RA}2-AZBTZ-N{RB}2)X]PF6, and neutral
C,N-coordinated complexes, [s(p-cym)(N,C-AZBTZ-NMe2)X]
where p-cym = p-cymene, RA, RB = H, Me, and X = Cl, Br, I.
We have determined their single-crystal X-ray crystal structures,
INTRODUCTION
■
There is growing interest in the chemistry of organometallic
osmium complexes, with potential applications in a range of
areas, including catalysis1−4 and anticancer activity.5−9 For
example, osmium(II) arene complexes containing N,N-
chelating phenylazopyridine (AZPY) ligands exhibit promising
anticancer properties and novel mechanisms of action.10−14
Here we explore Os(II) complexes with phenylazobenzothia-
zole (AZBTZ) ligands. Interestingly, AZBTZs have established
applications in the field of dyes and pigments owing to their
intense red coloration.15 They can also be utilized as probes for
in vivo radioimaging of neurofibrillary tangles in Alzheimer’s
diseased brains and show promising selective binding toward β-
amyloid peptides and hyper-phosphorylated τ proteins
associated with Alzheimer’s disease.16
AZBTZs are analogous to AZPY ligands, the pyridine being
substituted by a benzothiazole unit. Benzothiazole is a bicyclic
ring system consisting of a benzene ring fused to a five-
membered 1,3-thiazole ring. Because of their pronounced
biological and pharmacological activities, AZBTZ derivatives
Received: July 13, 2017
© XXXX American Chemical Society
A
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d
1H NMR, and the product was purified by silica column
chromatography.
Chart 1. Os(II) Complexes Formed from Ligands L and L*
Synthesis of Os(II) Arene AZBTZ Complexes. Os(II)
arene AZBTZ complexes were synthesized by stirring 2 mol
equiv of L with an Os(II) p-cym dimer, [Os(η6-p-cym)X2]2
(where X = Cl, Br, I), in EtOH at ambient temperature. All
three dimers reacted with L to form a positively charged N,N-
coordinated complex, A, and a neutral cyclo-metalated N,C-
coordinated complex, B, in varying ratios (Scheme 1). These
were observed in reaction mixtures via silica thin-layer
chromatography (TLC) using MeOH as eluent. Positively
charged N,N-complexes exhibit strong affinities for silica and do
not travel far from the TLC plate baseline. In contrast, neutral
N,C-complexes travel with the mobile phase with Rf values
ranging between 0.70 and 0.74.
The percentages of A (N,N) and B (N,C) complexes formed
1
were determined for each dimer from H NMR spectra of the
a
b
Product isolated and X-ray structure determined. Product isolated.
reaction mixtures after 18 h of stirring, by measuring the
integrals of aliphatic p-cym CH3 doublets (Figure S1 in the
Supporting Information). For N,N-coordinated complexes,
these doublets lie significantly closer to one another (0.09−
0.11 ppm apart), in comparison to N,C-coordinated complexes
(0.25−0.30 ppm apart). When X = Cl, Br, both the charged
complexes 1a and 2a and neutral complexes 1b and 2b were
isolated (Chart 1). However, when X = I, only the neutral
complex 3b was isolated as the major product. Complexes 1b−
3b can be easily purified via silica flash column chromatog-
raphy, which was not possible for charged complexes 1a and 2a
due to their high affinities for silica.
The reaction conditions were modified with the intention of
favoring N,N- over N,C-coordination. When the reaction
between [Os(η6-p-cym)I2]2 and L was carried out in the
aprotic and weakly coordinating solvent DCM, formation of the
N,N-coordinated species 3a was still disfavored. Furthermore,
carrying out the reaction between [Os(η6-p-cym)Br2]2 and L in
the presence of HBr did not prevent deprotonation of the
phenyl ring and hence prevent formation of the N,C-
coordinated species. Ligand L* has methyl groups situated on
the aniline ring ortho to the azo bond (RA, Chart 1), hindering
cyclometalation and formation of an N,C-coordinated species.
When [Os(η6-p-cym)I2]2 was reacted with 2 mol equiv of L*
the reaction took notably longer for the initial color change to
occur but was successful in yielding complex 5. Complex 4 was
c
Product observed in the reaction mixture by 1H NMR but not
d
isolated. Complexes 1−3 with L and complexes 4 and 5 with L*.
Complexes 1a−3a, 4, and 5 are N,N-coordinated species, and 1b−3b
are N,C-coordinated complexes.
stability in aqueous media and discovered unusual properties of
N,C-coordinated species, including stereospecific phenyl ring
deuteration.
RESULTS
■
Synthesis of AZBTZ Ligands. The bidentate phenyl-
azobenzothiazole ligand AZBTZ-NMe2 (L) was synthesized via
a diazotization coupling reaction (Scheme S1 in the Supporting
Information).15 Nitrosation of the primary amine in 2-
aminobenzothiazole occurs when the nitrosonium cation is
generated in situ from sodium nitrite and sulfuric acid, leading
to the formation of a reactive diazonium salt intermediate. On
addition of N,N-dimethylaniline, the electrophilic diazonium
salt reacts at the para position of the aniline ring to form the
highly colored ligand L. Reactivity at the ortho position of the
ring is blocked by the presence of tertiary amine methyl groups.
Similarly, a second ligand, (Me)2-AZBTZ-NH2 (L*), was
synthesized via the same reaction. When a diazonium salt was
formed from 3,5-dimethylaniline, there were no methyl groups
situated on the amine group to prevent ortho-electrophilic
addition. An ortho-substituated impurity was found at 18% by
Scheme 1. Synthetic Route to Charged N,N-Coordinated Complexes, A, and Neutral N,C-Coordinated Complexes, B
B
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1
1
Figure 1. (A) 600 MHz H NMR spectrum of 5 in chloroform-d1. (B) The corresponding H-selective NOE spectrum. The deshielded proton at
6.84 ppm, i1, was irradiated. Protons close (ca. <4 Å) are labeled. The residual solvent peak (S), residual water peak (W), and the impurity in the
chloroform-d1 solvent (*) are highlighted. The iodido monodentate ligand is pointing into the plane of the page for clarity.
Figure 2. ORTEP diagrams of complexes 1a, 2a, 2b·0.5C3H6O, and 3b·0.5CHCl3. Ellipsoids are shown at the 50% probability level, and all
hydrogens, counterions, and solvent molecules have been omitted for clarity.
also synthesized via the same reaction using [Os(η6-p-
cym)Cl2]2.
NMR spectrum of complex 3b reveals a species containing only
11 aromatic protons (Figure S3 in the Supporting Informa-
tion). We confirmed that the missing proton is from the 3-
position of the aniline ring, which is bonded to Os(II) to form a
neutral complex. This structure is characterized by a doublet of
Characterization of Complexes. The aromatic region of
1
the H NMR spectrum of 1a (Figure S2 in the Supporting
1
Information) shows 12 aromatic protons. In contrast, the H
C
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Table 1. Selected Bond Lengths (Å), Interatomic Distances (Å), and Bond/Torsion Angles (deg), Observed in the X-ray Crystal
Structures of Complexes 1, 2a, 2b·0.5C3H6O, and 3b·0.5CHCl3 (X = Cl, Br, I)
1a
2a
2b·0.5C3H6O
3b·0.5CHCl3
Bond Lengths (Å)
2.5242(3)
2.053(2)
N/A
Os1−X1
Os1−N1
Os1−N10
Os1−N11
Os1−C17
N10−N11
Os1−arene centroid
2.3784(6)
2.072(2)
N/A
2.5532(8)
N/A
2.7078(9)
N/A
2.074(5)
N/A
2.079(8)
N/A
2.079(2)
N/A
2.088(2)
N/A
2.020(7)
1.324(8)
1.722
2.050(11)
1.316(13)
1.721
1.334(3)
1.705
1.335(3)
1.706
Distances (Å)
2.380
H3···H24
H13···H22
H16···H22/H24
S1/S8···S1/S8
2.237
2.270
N/A
N/A
N/A
N/A
2.441
3.229
N/A
N/A
2.274
3.249
2.232
N/A
N/A
Bond Angles (deg)
85.74(6)
74.60(8)
85.97(6)
N/A
θX1−Os1−N1
θN1−Os1−N11
θN11−Os1−X1
θX1−Os1−N10
θN10−Os1−C17
θC17−Os1−X1
84.56(7)
75.01(9)
85.55(6)
N/A
N/A
N/A
N/A
N/A
N/A
N/A
84.87(16)
75.8(2)
86.2(2)
85.2(3)
75.8(4)
85.7(3)
N/A
N/A
N/A
N/A
Torsion Angles (deg)
0.72
θN1−C9−N10−N11
θN10−N11−C12−C17
θS1/S8−C9−N10−N11
−1.52
−17.66
N/A
N/A
1.06
0.39
N/A
0.44
14.40
N/A
−3.29
doublets assignable to proton g (J = 9.2, 2.5 Hz), which has
short-range coupling to proton h (3J = 9.2 Hz) and long-range
owing to the presence of a chiral Os(II) center. Complexes 1a
and 2a have PF6 counterions in their X-ray crystal structures,
whereas complexes 2b and 3b incorporate molecules of acetone
and chloroform in their crystal lattice, respectively, at a 2:1 ratio
of complex to solvent.
−
1
coupling to proton f (4J = 2.5 Hz). The H NMR spectrum of
complex 5 consists of 10 aromatic protons, 4 of which
correspond to the p-cym ligand. One p-cym aromatic doublet at
6.82 ppm is considerably more deshielded than the others
between 6.09 and 5.72 ppm. A selective 1H NMR NOE
experiment was conducted to identify proximate protons
(Figure 1). The deshielded arene proton i1 is close to another
aromatic p-cym proton i2, a methyl group on the arene j, and
interestingly, close to the proton at the 8-position on the
benzothiazole group, a. In comparison, the chlorido complex 4
also shows the same trend with a deshielded p-cym proton
residing at 6.90 ppm.
ESI-MS analysis of the charged N,N-coordinated complexes
1a−3a, 4, and 5 revealed m/z peaks that correspond to the
cationic species without their counteranion, [M − PF6].
Alternatively, neutral N,C-coordinated complexes 1b−3b were
observed as species with either a H+ or Na+ cation, [M + H+] or
[M + Na+].
X-ray Crystallography. The structures of complexes 1a
and 2a−3b were determined by single-crystal X-ray diffraction
(Figure 2). The crystallographic data are shown in Table S1 in
the Supporting Information, and selected bond lengths, bond
angles, torsion angles, and interatomic distances are summar-
ized in Table 1. The complexes adopt the familiar pseudo-
octahedral three-legged piano-stool geometry that is common
for Os(II) η6-arene structures, with Os(II) π-bonded to the p-
cym ligand. Osmium(II) is also coordinated to a monodentate
halide ligand and the bidentate ligand L via either N,N or N,C
atoms, which constitute the three legs of the piano stool. All
complexes exhibit a five-membered chelate ring with L: N1−
C9−N10−N11−Os1 for 1a and 2a and N10−N11−C12−
C17−Os1 for 2b and 3b. They all crystallize as racemates
The X-ray crystal structures of N,N-coordinated complexes
1a and 2a confirm that ligand L is bound to Os(II) via the N
atom of the benzothiazole group and N1 or N11 of the azo
bond. Weak π−π interactions between aniline rings (3.46 Å,
centroid to centroid) were observed for 1a (Figure S4 in the
Supporting Information). Short H···H distances were observed
between aromatic hydrogens on the p-cym ligand and bidentate
ligand L; H13···H22 and H3···H24 for complexes 1a and 2a.
The torsion angle θN1−C9−N10−N11 serves as a measure of
distortion of the chelate ring from planarity, and values of
−1.52 and 0.72° were calculated, respectively, for complexes 1a
and 2a. The torsion angle θN10−N11−C12−C17 describes the angle
between the chelate ring and the aniline ring. With values of
−17.66 and 14.40° for 1a and 2a, respectively, ligand L is not
aligned flat within the structure. In contrast, N,C-coordinated
complexes 2b and 3b exhibit fewer H···H clashes between the
p-cym ligand and ligand L (H16···H22/H24). The torsion
angle θS1/S8−C9−N10−N11, which serves as the angle between the
chelate ring and the benzothiazole moiety for complexes 2b and
3b, is small (0.39 and −3.29°, respectively). This results in a
closely planar ligand L within the crystal structures. The torsion
angles serve as a measure of distortion of the chelate ring from
planarity for 2b and 3b (θN10−N11−C12−C17), and are 1.06 and
0.44°, respectively. Also observed in 2b and 3b are
intermolecular S···S contacts, mediated through the free and
uncoordinated benzothiazole groups with outwardly pointing S
atoms (Figure S4 in the Supporting Information).
Aqueous Solubility and Stability. All synthesized
complexes were too insoluble in aqueous media for biological
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studies and stability testing in D2O by 1H NMR. The stabilities
of 1a,b in MeOH/H2O (1/1, v/v) were monitored over a 24 h
period by UV−vis spectroscopy at 25 °C. Changes in the UV−
vis absorption spectrum of 1a were monitored over 24 h, and
decreases in intensity of the bands at 653 and 716 nm were
noted (Figure S5 in the Supporting Information). The presence
of 100 mM NaCl inhibited spectral changes over 24 h. In
contrast, no decomposition of 1b was observed over 24 h in
MeOH/H2O (1/1, v/v), with two stable maxima observed at
447 and 562 nm.
disappearance of Ha (measured by integration). The reaction
exhibits first-order kinetics for deuteration of the phenyl ring
with a rate constant of 6.91 × 10−5 s−1 and a half-life of 1.00 ×
104 s (Figure S8 in the Supporting Information).
Mulliken Partial Charges. Mulliken partial charge
calculations of complex 2b are shown in Figure S9 in the
Supporting Information. Carbon C1 is significantly more
negatively charged than the other carbon atoms making up
the aniline ring. Furthermore, the aniline ring exhibits disrupted
aromaticity with only two CC bonds present, C1C2 and
C4C5, which have calculated bond lengths of 1.384 and
1.363 Å, respectively. These are consistent with the X-ray
crystal structure, which has bond lengths of 1.386(9) and
1.351(9) Å, respectively. In contrast, the bond lengths of singly
bonded C2−C3 and C5−C6 are 1.478 and 1.470 Å,
respectively, in the calculated structure and 1.434(9) and
1.433(10) Å in the crystal structure. The calculation also shows
that CH3 carbons have significantly high negative charges.
Acid Stability and Regiospecific Aniline Ring Deuter-
ation. When complex 2b was stirred with 100 mol equiv of
HBr in MeOH, no conversion to the N,N-coordinated species
1
2a was observed by H NMR (HBr was used as the acid to
avoid halide substitution on the metal). It was only after heating
under reflux for 2 days that a new set of small aliphatic p-cym
1
proton peaks began to emerge in the H NMR spectrum
(Figure S6 in the Supporting Information). TLC analysis in
MeOH revealed a small blue spot residing close to the baseline,
suggesting the presence of a charged N,N-coordinated species.
A solution of complex 2b with 3 mol equiv of HBr in methanol-
d4 was studied by 1H NMR. The peak for the aromatic
hydrogen neighboring the Os−C bond (Ha, 7.58 ppm)
disappeared almost completely after 15 h at 25 °C. Its
disappearance coincided with a loss of long-range proton
coupling to Hb (4J = 2.5 Hz, 7.26 ppm; see Figure 3). The
DISCUSSION
■
Intramolecular C−H Bond Activation and Cyclo-
metalation. Reactions between Os(II) p-cym dimers and L
were expected to yield N,N-coordinated cationic species,
analogous to AZPY complexes reported previously.10,11 To
our surprise, mixtures containing both N,N- and N,C-
coordinated complexes were obtained. Formation of the N,C-
cyclometalated complex requires C−H bond activation, a
challenging step involving deprotonation of the aniline ring at
the ortho position. There are numerous examples of ruthenium,
rhodium, osmium, and iridium complexes formed via direct
arylation of ligands such as 2-phenyl-substituted pyridines.24−28
Metalation of the phenyl ring invariably occurs at the ortho
position and results in five-membered chelate rings. Older
synthetic routes utilize a transmetalation pathway involving
ortho-mercurated species, eliminating the need for C−H
activation.29−32 However, direct metalation of 2-phenylpyridine
(2-PhPy) is also possible in the presence of bases such as
acetate and is directed by the nitrogen-containing pyridine
moiety, which initially binds to the metal center. In the reaction
between [Os(η6-p-cym)X2]2 and L, the direction may be guided
via initial coordination to the azo bond nitrogen, and C−H
activation occurs spontaneously and remarkably in the absence
́
of an additional base. Ceron-Camacho et al. have reported the
successful electrophilic cyclo-osmation of the bidentate ligands
2-PhPy and N,N-dimethylbenzylamine,33 the latter of which
was also achieved in the absence of a base. The ligand is
believed to act as both a substrate and a base for its own C−H
bond cleavage. Similar to the case for N,N-dimethylbenzyl-
amine, L possesses a basic amine group that could be
responsible for assisting C−H bond cleavage at the ortho
position of the aniline. A review of the literature suggests that a
likely mechanism may involve base-assisted SE3 electrophilic
cyclometalation.34,35 Alternatively, a mechanism involving an
agostic ortho Os(C−H) bond might be possible (see Scheme
S2 in the Supporting Information).35,36 Both mechanisms
require the nucleophilic −NMe2 group on L to play a role as a
proton acceptor during C−H bond activation. Such mecha-
nisms have been proposed for the cyclometalation of 2-PhPy
with ruthenium η6-arene complexes.
Figure 3. 400 MHz 1H NMR spectra of complex 2b (aromatic region)
with 3 mol equiv of HBr in methanol-d4. The disappearance of proton
Ha (7.58 ppm) is accompanied by loss of long-range coupling between
protons Hb and Ha (4J = 2.5 Hz).
substitution of protium at this position with deuterium occurs
only in the presence of an acid. High-resolution mass
spectrometry of the NMR sample in methanol-d4 revealed
the presence of the deuterated complex, showing exact masses
of m/z 688.0876 and 710.0696, which correspond to the
formulas [C25H26BrDN4OsS + H+] and [C25H26BrDN4OsS +
Na+], respectively (see Figure S7 in the Supporting
Selectivity toward N,C-Complex Formation over N,N-
Coordination. It was initially anticipated that ligand L may
coordinate to the metal via the S atom of the benzothiazole
group. However, to the best of our knowledge, there are no
1
Information). A kinetic H NMR study was conducted at 25
°C, and a spectrum was collected every 30 min to observe the
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literature reports of benzothiazoles coordinating to metal
centers through the S atom.37 The benzothiazole group of L
favors N-binding in our complexes, as confirmed by the X-ray
crystal structures of complexes 1a and 2a. N,C-Coordination is
preferred when X = Br, I, but for X = Cl, N,N-coordination is
preferred. From crystallographic observations, it is most likely
that the ratio of products formed is influenced by steric
considerations. Assessment of the crystal structures shows that
the N,N-coordinated species 1a and 2a exhibit more steric
hindrance in the form of H···H clashes between p-cym and L
than do N,C-coordinated species 2b and 3b. N,N-Coordinated
species also show greater torsion angles in ligand L in
comparison to N,C-coordinated species, where L is close to
planar. The ligand L in 1a and 2a appears to show aniline ring
twisting to reduce clashing with the p-cym ligand. It is most
likely that when X = Br, I, N,N-coordination is more difficult
owing to the increased halide size, hence producing greater
steric crowding around the metal center, which pushes the
organic ligands closer together. Increased steric crowding may
promote coordination via the cyclometalation route (Figure 4).
coordination, which in this case is forced due to blocking of the
ortho positions on the aniline ring, preventing cyclometalation
from occurring. N,N-Coordinated structures containing L, 1a
and 2a, do not exhibit the same trend. It is therefore likely that
hindered rotation may also play a role in the deshielding of the
observed proton. The methyl groups at positions RA in
complexes 4 and 5 (Chart 1) may play a role in hindering
rotation of the p-cym ligand.
Regiospecific Aniline Ring Deuteration of Complex
2b. Remarkably, [Os(p-cym)(N,C-AZBTZ-NMe2)Br] (2b)
undergoes deuteration of the aniline ring at a position ortho
to the Os−C bond (meta Ha), but only in the presence of acid
(HBr). On addition of 3 mol equiv of HBr, the 1H NMR signal
of Ha disappeared along with its coupling to Hb, following first-
order kinetics. The Mulliken partial charge calculation shows
that the carbon where deuteration occurs carries a greater
negative partial charge (−0.461) in comparison to the other
CH carbons making up the aniline ring (−0.264 and −0.275).
Interestingly, its exchange with deuterium occurred under
acidic conditions, suggesting an associative mechanism of
exchange (see Scheme S3 in the Supporting Information).
CONCLUSIONS
■
We report the synthesis of novel Os(II) p-cym phenyl-
azobenzothiazole complexes in which the chelated ligand can
adopt two coordination modes: N,N- or N,C-coordination. The
crystallographic data suggest that N,N-coordination leads to
steric crowding around the metal and so is formed as a minor
product when the monodentate halide ligand is large (X = I,
Br). N,C-Coordination requires C−H bond activation for
carbon metalation and occurs spontaneously in the absence of a
base, most likely owing to the presence of the basic NMe2
substituent, which assists deprotonation of the aromatic ring.
The mechanism of cyclometalation is not clear but may occur
via an SE3 mechanism. Furthermore, the N,N-coordinated
species 1a was unstable in aqueous media over 24 h but stable
over 24 h in the presence of 100 mM NaCl, indicating that the
decomposition of 1a involves loss of the monodentate ligand
and possible hydrolysis. In contrast, the N,C-coordinated
analogue 2b was stable over 24 h.
Figure 4. Diagram illustrating the possible influence of steric effects on
the ratios of products formed when [Os(η6-p-cym)X2]2 reacts with L.
N,N-Coordination results in steric clashes between p-cym and L and is
less favored when the monodentate ligand is large. N,C-Coordination
is preferred, relieves steric tension, and involves spontaneous
deprotonation of the aromatic ring.
N,N-Coordination in complexes 4 and 5 was promoted by
intentional blocking of the C−H activation sites with methyl
groups. This led to complexes with an unusually deshielded
aromatic p-cym H NMR resonance. In selective H NMR
NOE studies, the deshielded proton in 5 was observed in close
proximity to a proton on the benzothiazole group, thus
providing further evidence of steric crowding in the N,N-
coordinated complexes.
The N,C-coordinated complex 2b exhibited unusual
behavior. In the presence of acid (HBr) in methanol-d4, the
ortho H (neighboring the Os−C bond) exchanges with
deuterium with a half-life of 2.8 h at 25 °C. Calculations of
the Mulliken partial charges showed an increased partial
negative charge on the ortho C, consistent with an associative
mechanism of exchange.
Preferential binding via cyclometalation may also be
influenced by the weaker binding of benzothiazole in
comparison to pyridine. The complex FY026, [Os(p-cym)-
(AZPY-NMe2)I]PF6, synthesized previously contains an
phenylazopyridine ligand analogous to L with distinct N,N-
coordination.11 Pyridine is a stronger π-acceptor moiety than
benzothiazole. Both pyridine and benzothiazole are weak σ-
donors, but the reduced π-acceptor capability of benzothiazole
may also influence preferential N,C-coordination, as well as
steric factors.
1
1
Stability in Aqueous Media. Our UV−vis studies in
aqueous media showed that N,N-coordinated complex 1a
underwent a chemical change over a 24 h period that was
prevented in the presence of NaCl (100 mM), indicating that
loss of the chloride ligand is involved. In contrast, N,C-
coordinated complex 1b showed no sign of decomposition over
24 h and exhibited a very stable Os−Cl bond.
EXPERIMENTAL SECTION
■
Materials. OsCl3·3H2O was purchased from Sigma-Aldrich (UK)
and Heraeus (South Africa). α-Terpinene, ammonium hexafluor-
ophosphate, and hydrobromic acid were purchased from Sigma-
Aldrich (UK). N,N-Dimethylaniline, 3,5-dimethylaniline, 2-amino-
benzothiazole, sodium nitrite, sulfuric acid (>95%), and glacial acetic
acid were purchased from Fisher Scientific (UK). All organic solvents
Hindered Arene Rotation in 5. A 1H-selective NOE study
confirmed that the observed deshielded aromatic p-cym proton
in [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6 (5) is in close
proximity with an aromatic proton belonging to coordinated
L*. The steric crowding is likely to be as a result of N,N-
F
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Article
were purchased from commercial suppliers and used as received. The
dimers [Os(p-cym)X2]2, where X = Cl, Br, I, were prepared according
to literature procedures.38−40
× 5 mL), and dried overnight in a vacuum desiccator. Yield: 9.9 mg
(8%).
For 2b, the precipitate was dissolved in a minimum amount of
MeOH and purified via flash column chromatography (SiO2, MeOH,
Rf = 0.74). The selected fractions containing the product were
combined, and the solvent was removed under reduced pressure to
give a dark purple solid, which was redissolved in DCM and filtered;
the solvent was again removed, and then the product was dried
overnight in a vacuum desiccator. Yield: 20.2 mg (20%).
Syntheses. Synthesis of Ligands. The synthesis of ligands L and
L* was performed by the following procedure. 2-Aminobenzothiazole
(500.0 mg, 3.33 mmol) was mixed with glacial acetic acid (20 mL) and
cooled to 0 °C in a water/ice bath. Sulfuric acid (>95%, 7 mL) was
then added. A solution of NaNO2 (252.7 mg, 3.66 mmol) in deionized
water (10 mL) was added dropwise to the stirred mixture, and it
instantaneously turned yellow-orange. The mixture was stirred for 2 h
at 0 °C. An ice-cold solution of N,N-dimethylaniline (for L, 3.33
mmol) or 3,5-dimethylaniline (for L*, 3.33 mmol) in MeOH (34 mL)
was added dropwise, and the mixture turned dark purple. The mixture
was stirred for a further 18 h, was warmed to ambient temperature,
and then was combined with water (200 mL) and DCM (100 mL),
and the layers were separated. The aqueous layer was washed with
DCM (2 × 50 mL), and the combined DCM extracts were washed
with water (2 × 50 mL), dried over MgSO4, and filtered; the solvent
was removed under reduced pressure, yielding a dark precipitate. The
crude product was recrystallized from a minimum amount of
chloroform, giving a dark green precipitate. The product was collected
by filtration, washed with ice-cold Et2O (2 × 5 mL), and dried
overnight in a vacuum desiccator. Characterization data are shown in
the Supporting Information.
Synthesis of [Os(η6-p-cym)(N,C-AZBTZ-NMe2)I] (3b). [Os(η6-p-
cym)I2]2 (50.0 mg, 43.2 μmol) and 4-(2-benzothiazolylazo)-N,N-
dimethylaniline (24.4 mg, 86.5 μmol) were dissolved in EtOH (20
mL). The mixture was stirred at 50 °C for 2 h while the color changed
to dark blue-purple. It was then stirred for 18 h at ambient
temperature, at which point the volume was reduced under reduced
pressure to ∼2 mL. The mixture was placed in a freezer (−20 °C)
overnight, resulting in a dark brown precipitate, which was collected by
filtration and washed with ice-cold EtOH (2 × 1 mL) and Et2O (2 × 5
mL). The product was dried overnight in a vacuum desiccator. Yield:
48.6 mg (77%).
Synthesis of [Os(η6-p-cym)(N,N-AZBTZ*-NH2)Cl]PF6 (4). [Os(η6-p-
cym)Cl2]2 (30.0 mg, 37.9 μmol) was stirred in EtOH (10 mL), and a
solution of p-(2-benzothiazolylazo)-3,5-dimethylaniline (22.5 mg, 79.7
μmol) in EtOH (5 mL) was added dropwise to the stirred mixture.
The mixture was stirred for 2 h at 50 °C, and the color changed to
dark blue-purple. The mixture was then stirred for 18 h at ambient
temperature, and then NH4PF6 (61.8 mg, 0.38 mmol) was added. The
mixture was concentrated under reduced pressure and placed in a
freezer (−20 °C) overnight. The resulting dark purple precipitate was
collected by filtration and washed with ice-cold EtOH (2 × 1 mL) and
Et2O (2 × 5 mL). The product was dried overnight in a vacuum
desiccator. Yield: 41.0 mg (69%).
Synthesis of [Os(η6-p-cym)(N,N-AZBTZ-NMe2)Cl]PF6 (1a). [Os(η6-
p-cym)Cl2]2 (50.0 mg, 63.2 μmol) and 4-(2-benzothiazolylazo)-N,N-
dimethylaniline (37.5 mg, 132.8 μmol) were dissolved in EtOH (20
mL). The mixture was stirred at 50 °C for 2 h, and the color changed
to dark blue. The mixture was stirred for 18 h at ambient temperature,
and NH4PF6 (103.1 mg, 0.63 mmol) was added. The volume was
reduced under reduced pressure to ∼2 mL, and the mixture was placed
in a freezer overnight. The resulting dark blue precipitate was collected
by filtration. The precipitate was dissolved in chloroform (10 mL),
stirred for 1 h, and filtered. The filtrate was collected, and the solvent
was removed under reduced pressure. The resulting dark blue
precipitate was recrystallized from a minimum amount of EtOH and
placed in a freezer (−20 °C) overnight. The product was collected by
filtration and washed with ice-cold EtOH (2 × 1 mL) and Et2O (2 × 5
mL). The product was dried overnight in a vacuum desiccator. Yield:
44.9 mg (45%).
Synthesis of [Os(η6-p-cym)(N,N-AZBTZ*-NH2)I]PF6 (5). [Os(η6-p-
cym)I2]2 (23.1 mg, 20.0 μmol) was stirred in EtOH (10 mL), and a
solution of p-(2-benzothiazolylazo)-3,5-dimethylaniline (11.3 mg, 39.9
μmol) in EtOH (5 mL) was added dropwise to the stirred mixture.
The mixture was stirred for 2 h at 50 °C, and the color changed to
dark blue-purple. The mixture was stirred for 18 h at ambient
temperature, and then NH4PF6 (32.6 mg, 0.20 mmol) was added. The
mixture was concentrated under reduced pressure and placed in a
freezer (−20 °C) overnight. The resulting dark purple precipitate was
collected by filtration and washed with ice-cold EtOH (2 × 1 mL) and
Et2O (2 × 5 mL). The product was dried overnight in a vacuum
desiccator. Yield: 20.4 mg (58%).
Methods and Instrumentation. X-ray Crystallography. Dif-
fraction data were collected on an Oxford Diffraction Gemini four-
circle system with a Ruby CCD area detector. All structures were
refined by full-matrix least squares against F2 using SHELXL 97 and
were solved by direct methods using SHELXS(TREF) with additional
light atoms found by Fourier methods. Hydrogen atoms were added at
calculated positions and refined using a riding model. Anisotropic
displacement parameters were used for all non-H atoms; H atoms
were given an isotropic displacement parameter equal to 1.2 (or 1.5 for
methyl and NH H atoms) times the equivalent isotropic displacement
parameter of the atom to which they are attached. The data were
processed by the modeling program Mercury 1.4.1.
Synthesis of [Os(η6-p-cym)(N,C-AZBTZ-NMe2)Cl] (1b). [Os(η6-p-
cym)Cl2]2 (50.0 mg, 63.2 μmol) and 4-(2-benzothiazolylazo)-N,N-
dimethylaniline (37.5 mg, 132.8 μmol) were dissolved in EtOH (20
mL). The mixture was stirred at 50 °C for 2 h, and the color changed
to dark blue. The mixture was stirred for 18 h at ambient temperature,
and then the solvent was removed under reduced pressure. The
product was purified via flash column chromatography (SiO2, 50/1
DCM/MeOH, Rf = 0.34). The selected fractions containing the
product were combined, and the solvent was removed under reduced
pressure to give a dark purple precipitate. The precipitate was
recrystallized from a minimum amount of EtOH and placed in a
freezer (−20 °C) overnight. The product was collected by filtration,
washed with ice-cold EtOH (2 × 1 mL) and Et2O (2 × 5 mL), and
then dried in a vacuum desiccator overnight. Yield: 14.9 mg (18%).
Synthesis of [Os(η6-p-cym)(N,N-AZBTZ-NMe2)Br]PF6 (2a) and
[Os(η6-p-cym)(N,C-AZBTZ-NMe2)Br] (2b). [Os(η6-p-cym)Br2]2 (70.0
mg, 72.3 μmol) and 4-(2-benzothiazolylazo)-N,N-dimethylaniline
(40.8 mg, 144.6 μmol) were dissolved in EtOH (20 mL). The
mixture was stirred at 50 °C for 2 h, and the color changed to dark
blue-purple. The mixture was stirred for 18 h at ambient temperature,
and NH4PF6 (103.1 mg, 0.63 mmol) was added. The solvent was
removed under reduced pressure, and the dark blue residue was
redissolved in chloroform (20 mL) and stirred for 1 h. The mixture
was filtered, giving a precipitate predominantly containing 2b and a
filtrate predominantly containing 2a.
X-ray crystallographic data for complexes 1a, 2a, 2b·0.5C3H6O, and
3b·0.5CHCl3 have been deposited with the Cambridge Crystallo-
graphic Data Centre under the accession numbers CCDC 1540385−
1540388, respectively.
NMR Spectroscopy. 1H NMR and 13C NMR spectra were acquired
in 5 mm NMR tubes at 25 °C on Bruker DPX-400, HD-500, AV-600,
and AV-700 spectrometers. Data processing was carried out using
1
TOPSPIN version 2.1 (Bruker U.K. Ltd.). H NMR chemical shifts
were internally referenced to TMS via their residual solvent peaks with
acetonitrile (δ 1.94 ppm), acetone (δ 2.05 ppm), methanol (δ 3.31
ppm), chloroform (δ 7.26 ppm), and DMSO (δ 2.50 ppm), and
similarly for 13C NMR chemical shifts with acetonitrile (δ 118.26
ppm). 1H NMR spectra were recorded using standard pulse sequences,
and 13C NMR spectra were recorded using a JMOD pulse sequence.
For 2a, the filtrate was concentrated under reduced pressure to ∼1−
2 mL, combined with a small amount of Et2O (<1 mL), and placed in
a freezer (−20 °C) overnight. The resulting dark blue precipitate was
collected by filtration, washed with ice-cold EtOH (1 mL) and Et2O (2
G
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1
The 1D H sel-NOE NMR experiment was conducted using an AV-
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Corresponding Author
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ORCID
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Nicolas P. E. Barry: 0000-0002-0388-6295
Peter J. Sadler: 0000-0001-9160-1941
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We thank the ERC (Grant No. 247450), EPSRC (Grant No.
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