Carbohydrate-Functionalized 1,2,3-Triazolylidene Complexes for Application in Base-Free Alcohol and Amine Oxidation

Article abstract of DOI:10.1021/acs.inorgchem.7b01899

Acetylglucose- and acetylgalactose-functionalized triazolylideneruthenium(II) and -iridium(III) complexes were synthesized and fully characterized. Subsequent carbohydrate deprotection yielded the first examples of glucose- and galactose-functionalized 1,2,3-triazolylideneiridium complexes. Base-free oxidation of alcohols and amines was used to probe the catalytic potential of the metal complexes and the influence of the carbohydrate wingtip group. Generally, the performance of these complexes is higher in amine oxidation than in alcohol oxidation. While the stereochemistry at the carbohydrate C4 position had no marked influence (galactose vs glucose), the ruthenium complexes typically exhibited higher substrate selectivity and product specificity compared to the analogous iridium species. Most noteworthy is the fact that the catalytic performance is significantly enhanced when the carbohydrate functionality is deprotected, suggesting an active role of the carbohydrate substituent in these transformations.

Full text of DOI:10.1021/acs.inorgchem.7b01899

Article
pubs.acs.org/IC
Carbohydrate-Functionalized 1,2,3-Triazolylidene Complexes for
Application in Base-Free Alcohol and Amine Oxidation
Rene Pretorius,†,‡ Juan Olguín,‡ and Martin Albrecht*,†,‡
́
†Departement fur Chemie und Biochemie, Universitat Bern, Freiestrasse 3, CH-3012 Bern, Switzerland
̈
̈
‡School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: Acetylglucose- and acetylgalactose-functionalized
triazolylideneruthenium(II) and -iridium(III) complexes were
synthesized and fully characterized. Subsequent carbohydrate
deprotection yielded the first examples of glucose- and galactose-
functionalized 1,2,3-triazolylideneiridium complexes. Base-free
oxidation of alcohols and amines was used to probe the catalytic
potential of the metal complexes and the influence of the
carbohydrate wingtip group. Generally, the performance of these
complexes is higher in amine oxidation than in alcohol oxidation.
While the stereochemistry at the carbohydrate C4 position had no
marked influence (galactose vs glucose), the ruthenium complexes
typically exhibited higher substrate selectivity and product
specificity compared to the analogous iridium species. Most
noteworthy is the fact that the catalytic performance is significantly enhanced when the carbohydrate functionality is deprotected,
suggesting an active role of the carbohydrate substituent in these transformations.
donors and acceptors to enhance the catalytic activity and
selectivity. Surprisingly, however, only a few NHC metal
complexes are known that are functionalized with a
carbohydrate substituent, and even fewer of these have been
applied in catalysis.4,53−67 In particular, we are aware of only
two reports that detail the synthesis and catalytic application of
protecting-group-free carbohydrate NHC metal complexes.54,60
Building on a previous study on carbohydrate-functionalized
triazolylidene complexes, which used exclusively acetyl-
protected sugar moieties,55 we have now explored new
glucose− and galactose−triazolylidene hybrid systems and
disclosed protocols for the deprotection of carbohydrates on
the metal complex. This work demonstrates that deprotection
of the carbohydrate unit considerably enhances the catalytic
activity and modifies the product selectivity, This modulation of
the catalytic performance identifies carbohydrate−triazolylidene
hybrids as attractive scaffolds for further optimization, in
particular when considering the vast variability of the
carbohydrate unit.
INTRODUCTION
■
Carbohydrates are one of the most abundant classes of
biomolecules and have unique roles in nature including cellular
recognition, structural rigidity, and a myriad of other biological
functions.1,2 A large diversity of carbohydrate molecules are
available through structural and stereochemical variations.
Moreover, the hydroxy groups on saccharides present unique
possibilities as reactive sites for modification and hydrogen
bonding.3 The use of carbohydrate-based ligands for transition-
metal catalysis is therefore a natural extension of these useful
biomolecules, in particular for imparting asymmetric induction
and substrate recognition.4−12
1,2,3-Triazolylidenes (trz’s)13−18 are a subclass of N-
heterocyclic carbenes (NHCs) that are conveniently accessible
via functional-group-tolerant copper-catalyzed click reac-
tions.17,19−23 Furthermore, these ligands have pronounced
mesoionic properties,15,16,24,25 which implies that the carbene
has an adaptive donor strength that can stabilize low as well as
high metal oxidation states.26−29 These unique characteristics
entailed the application of triazolylidenemetal complexes in a
range of catalytic transformations including cross-coupling30−36
and redox reactions such as amine and alcohol oxida-
tion,28,37−42 transfer hydrogenation,39,42−45 and water oxida-
tion.26,46−48 Current trends in NHC chemistry are focusing on
the development of functionalized ligand systems in which the
ligand is noninnocent and can act, for example, as a potential
proton shuttle during catalytic processes.49−53 Carbohydrates
are an attractive class of functional groups for such purposes
because they provide ample opportunities to serve as hydrogen
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Glucosyl- and
Galactosyltriazolylideneruthenium and -iridium Com-
plexes. Minor modifications and optimization of the literature
procedure reported by Kilpin and co-workers55 for the
synthesis of glucosyl−triazole 1a and the corresponding
Received: July 26, 2017
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of β-Pyranosyl-Functionalized Triazolylidenemetal Complexes
ruthenium complex 3a afforded the targeted carbohydrate-
functionalized ruthenium and iridium complexes 3 and 4
(Scheme 1). Galactose−triazole 1b was synthesized using
copper(I)-catalyzed [3 + 2] cycloaddition of in situ generated
β-galactosylazide and phenylacetylene (Scheme 1). Subsequent
alkylation with (Me3O)BF4 yielded the novel galactose-
functionalized triazolium salt 2b (82%). The formation of 2b
was confirmed by 1H NMR spectroscopy through the
appearance of the NCH3 resonance at 4.31 ppm and the
downfield shift of the triazolium and anomeric protons (from
δH = 8.05 and 5.90 to δH = 8.80 and 6.26, respectively).
Synthesis of the pyranosyltriazolylideneruthenium(II) and
-iridium(III) complexes 3 and 4 was accomplished through
well-established silver transmetalation procedures.15−17 Accord-
ingly, treatment of the triazolium salts 2a and 2b with Ag2O
yielded the carbene silver intermediate, which was used in situ
for transmetalation with either [RuCl2(p-cymene)]2 or
[IrCl2(Cp*)]2. Purification of the crude products by column
chromatography afforded complexes 3 and 4 in high yields
(71−86%) and high purity. In comparison to the reported
literature procedure,55 minor adjustments improved the purity
of the crude products in our hands. For example, formation of
the carbene silver species was optimized by a slight increase of
the Ag2O equivalents (from 0.5 to 0.6 mol equiv) and using
pure acetonitrile (MeCN) as the solvent for this step rather
than the CH2Cl2/MeCN mixture reported. Furthermore,
transmetalation to iridium(III) required extended reaction
times [24 h vs 2 h for ruthenium(II) complexes] to reach high
yields of 4a and 4b.
of any isomers formed.68 The low symmetry of the complex is
demonstrated by the resonances of the p-cymene ligand of the
ruthenium(II) complexes 3a and 3b, featuring, e.g., two distinct
doublets for the isopropyl CH3 groups. This ligand
desymmetrization is likely due to the large size of both triazole
substituents, which limits rotation about the Ru−Ctrz bond. No
significant differences for the carbenic C atoms were noted in
the 13C NMR spectrum upon a comparison of the glucosyl- and
galactosyl-substituted analogues. The carbenic C atoms
resonate within the range reported for related ruthenium-
(II)38,39,41,55,69,70 and iridium(III)40,47,71−73 triazolylidene com-
plexes.
Attempts to deprotect the acetylated pyranose complexes 3
and 4 initially focused on base-mediated cleavage of the acetyl
groups. However, the standard conditions (NaOMe/
MeOH)60,74−76 only yielded mixtures of compounds, as
1
evidenced by H NMR spectroscopy of the crude sample. In
contrast, exposure of complexes 4a and 4b to methanolic HCl
for 2 days cleanly afforded iridium complexes 5a and 5b.
1
Deprotection of the carbohydrate was confirmed by H NMR
spectroscopy, first by the loss of the acetate resonances in the
2.20−1.90 ppm region and second by the appearance of the
hydroxy resonances between 6.10 and 4.50 ppm (deuterated
dimethyl sulfoxide solutions). Also, deprotection induced a
1
noticeable upfield shift of the anomeric H resonance in both
5a and 5b by diagnostic values of 1.2 and 1.4 ppm, respectively.
The large coupling constant (3JHH = 9.1 0.1 Hz) indicates full
retention of the carbohydrate β-conformation.68 The free
carbohydrate-functionalized complexes 5a and 5b are soluble in
organic solvents such as CH2Cl2, methanol (MeOH), and
MeCN as well as in H2O. In contrast, the parent acetyl-
protected complexes 4a and 4b are only sparingly soluble in
H2O. The long reaction times for deprotection, together with
the high yields of complexes 5a and 5b (>80%), demonstrate
the remarkably high stability of the carbene−iridium bond
under acidic conditions. The robust nature of the iridium−
triazolylidene bond has been noted previously for related
iridium(III) complexes in water oxidation catalysis under acidic
conditions.61 Similar deprotection methodologies were attemp-
ted for the ruthenium complexes; however, a mixture of
products as well as demetalation of 3a and 3b was observed in
the crude reaction mixture, including [Ru(p-cymene)Cl2]2 and
1
The formation of complexes 3 and 4 was confirmed by H
and 13C NMR spectroscopy, mass spectrometry, and, where
possible, elemental analysis. Metalation was indicated in the 1H
NMR spectra by the disappearance of the triazolium proton
resonance, as well as a diagnostic deshielding of the anomeric
proton by 0.5−1 ppm (e.g., δH = 6.26 in 2b vs 7.23 in 3b). This
low-field shift suggests a pronounced electronic perturbation at
the anomeric position upon metal coordination of the carbene.
The β-conformation of the carbohydrate in complexes 3 and 4
was retained according to 1H NMR spectroscopy, as evidenced
by the characteristic coupling constant (3JHH = 9.1−9.7 Hz)
between the carbohydrate H-1 and H-2 protons and by the
presence of a single set of NMR resonances with no indication
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several unidentified products, suggesting a lower stability of the
Ru−Ctrz bond compared to the Ir−Ctrz bond.
Table 1. Base-Free Oxidation of Benzyl Alcohol to
Benzaldehyde
a
Inversion of the synthetic protocol toward deprotected
carbohydrate-functionalized triazolylidene complexes 5 by first
deprotection of the carbohydrate moiety of compound 2 and
subsequent metalation was unsuccessful in our hands.
Carboyhdrate deprotection under classical conditions using
NaOMe in MeOH resulted in deacylation and also in the
complete cleavage of the triazolium unit.
Crystallographic Characterization of Carbohydrate-
Functionalized Carbene Complex 5a. Single-crystal X-ray
diffraction analysis of complex 5a confirmed the bonding
pattern and, in particular, demonstrates that the β-configuration
of the carbohydrate is retained throughout the synthesis of
these complexes (Figure 1). The bonding around iridium
conv/%
entry
catalyst
5 h
24 h
1
2
3
4
5
6
3a
3b
4a
4b
5a
5b
36
32
27
23
19
29
51
53
53
57
52
69
a
General conditions: benzyl alcohol (0.25 mmol), [Ru] or [Ir] (0.012
1
mmol, 5 mol %), 1,2-DCB, 150 °C. Conversions determined by H
NMR integration (trimethoxybenzene as the internal standard),
averaged over two runs.
detrimental effect of the bulky carbohydrate wingtip group. The
presence of free versus protected carbohydrate units does not
affect the activity with the glucose derivative (cf. entries 3 and
5), while deprotected galactose wingtip groups show slightly
higher activity compared to the acyl-protected analogue (69%
vs 57% conversion after 24 h, entries 4 and 6). Possibly, the
presence of large amounts of substrate ROH groups reduces
the relevance of the ligand OH units, and, therefore, the
carbohydrate only exerts steric constraints.85
Catalytic Oxidation of Benzylamine. Acceptorless amine
oxidation through the self-condensation of amines, also referred
to as transamination, offers a relatively simple procedure for the
formation of imines and secondary and tertiary amines, with
NH3 as the only side product.86−90 As a further probe for the
catalytic potential of the carbohydrate-functionalized com-
plexes, the oxidative homocoupling of benzylamine was
investigated (Table 2 and Figure S2). In general, the complexes
were all markedly more active toward amine oxidation than
alcohol oxidation (full vs 20% conversion after 5 h). For
example, complex 5a reaches a turnover frequency of about 1
h−1 for alcohol oxidation and 16 h−1 in amine oxidation
Figure 1. ORTEP plot of one of four crystallographically independent
molecules in the unit cell of 5a (50% probability; H atoms and
cocrystallized MeOH are omitted for clarity). Selected bond lengths
(Å) and angles (deg): Ir1−C1, 2.073(7); Ir1−Cl1, 2.4522(18); Ir1−
Cl2, 2.4409(17); Ir−Cp*(centroid), 1.807; Ir1−C1−C2, 130.0(5);
Ir1−C1−N3, 127.4(5).
reveals no significant deviations compared with a related
complex containing two phenyl wingtip groups on the
triazolylidene ligand.71 Furthermore, the carbohydrate moiety
displays the expected chair conformation. Interestingly, the unit
cell contained four crystallographically independent complex
molecules, two of which had the C-6 hydroxyl substituent
facing toward the Cp* ligand, while this substituent is pointing
away from the metal center in the other two molecules. A
network of hydrogen-bonding interactions between the
independent molecules of 5a and MeOH span the unit cell.
Each molecule also displays short contacts between the
chlorido ligands and the carbohydrate hydroxy groups at
positions 2 and 3 of an adjacent molecule, although no
intramolecular hydrogen-bonding patterns were identified.
Acceptorless Oxidation of Benzyl Alcohol. Metal
complexes with trz ligands have been used in base-free catalytic
oxidation, an attractive transformation with fewer side products
in comparison to classical oxidation methodologies.28,37−42
Furthermore, pendant functional groups are known to enhance
the catalytic activity of dehydrogenative oxidations through
metal−ligand cooperativity during proton transfer.42,50,51,77−84
The ruthenium and iridium complexes 3−5 were therefore
probed as precatalysts for the base-free oxidation of benzyl
alcohol (Table 1). Catalytic experiments were performed at 5
mol % catalyst loading in 1,2-dichlorobenzene (1,2-DCB) at
150 °C in an open system.39,42 The results indicate only minute
reactivity differences between the different catalysts (entries 1−
6; Figure S1 and Table S1). Complexes 3a and 3b perform
similarly to related trz-Ru complexes but with only moderate
activity compared to the most active systems that display full
conversion within 16 h (entries 1 and 2).38,39,41,69 Complexes 4
and 5 also do not show any improved activity in comparison to
other trz-Ir systems (full conversion in 16 h),37 suggesting a
a
Table 2. Oxidative Homocoupling of Benzylamine
time
(h)
yield
b
entry
catalyst
mol %
conv (%)
6/7
(%)
1
3a
3b
4a
4b
5a
5b
5a
5b
1
5
94
100/−
100/−
83/17
78/22
86/14
83/17
81/19
80/20
100/−
−/−
61
64
2
1
5
75
3
5
1/5
1/5
1/5
1/5
5
44/94
19/86
78/> 95
71/>95
53
90
4
5
77
5
5
>95
>95
49
6
5
7
1
8
1
5
51
48
9
[Ru(cym)Cl2]2
0.5
2.5
5
62
10
[Ir(Cp*)Cl2]2
5
<5
a
General conditions: benzylamine (1.25 or 0.25 mmol), [Ru] or [Ir]
(0.012 mmol), 1,2-DCB, 150 °C. Conversions and yields were
determined by 1H NMR integration (hexamethylbenzene as the
b
internal standard), averaged over at least two runs. Spectroscopic
yields are reported at 5 h.
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(determined after 1 h of reaction; see also Table S2). In
contrast to the oxidation of benzyl alcohol, various trends in the
activity can be deduced from amine oxidation catalysis. The
activity of the ruthenium complexes 3a and 3b is markedly
higher than that of the iridium analogues 4a and 4b, and high
conversions were accomplished with only 1 mol % catalyst
loading (cf. 5 mol % for the iridium complexes; entries 1 and 2
vs entries 3 and 4). The impact of the triazolylidene ligand is
particularly pronounced in the iridium complexes because
[Ir(Cp*)Cl2]2 is essentially inactive and no products were
detected under the applied standard conditions (entry 10). This
effect is less marked in the ruthenium complexes, although we
note a considerable rate enhancement imparted by the carbene
ligand in complexes 3a and 3b in comparison to the simple
ruthenium salt [Ru(p-cymene)Cl2]2 (entries 1 and 2 vs entry
9). The beneficial role of the carbohydrate functionality is
underpinned compared with an iridium complex related to 5
yet containing a chelating pyridyl instead of a carbohydrate
substituent. With this complex and under essentially identical
conditions, amine dehydrogenation requires about twice the
time to reach completion, and the selectivity is much lower
(almost 1:1 imine vs amine).91 Likewise, related trz-Ru
complexes with nonchelating substituents (alkyl and aryl)
require substantially longer reaction times to reach high
conversion, even when used at 5 mol % catalyst loading (cf.
1 mol % here).41,69
Figure 2. Comparison of the conversion of benzylamine by
precatalysts 4 and 5. General conditions: benzylamine (0.25 mmol),
[Ir] (0.012 mmol, 5 mol %), 1,2-CB, 150 °C. Conversions were
determined by 1H NMR integration (hexamethylbenzene as the
internal standard), averaged over at least two runs.
however, rates were much slower and reached only about 50%
after 5 h, corresponding to 50 TON. The increased reactivity of
complexes 5 with deprotected rather than acetylated carbohy-
drate wingtip groups is presumably due to the ability of the
hydroxyl groups to promote substrate bonding and activation
through hydrogen bonding or even complete hydrogen
transfer.50,51,78−82,85 In any case, the increased activity suggests
a beneficial role of unprotected carbohydrates as functional sites
on NHC-containing catalysts for amine oxidation.
The product selectivity is strongly influenced by the type of
metal center. Only imine 6 was observed when the ruthenium
complexes were used as precatalysts, while the analogous
iridium complexes formed both imine 6 and the secondary
amine 7. This product selectivity implies that ruthenium
complexes directly release hydrogen gas before entering a
subsequent catalytic cycle, while iridium complexes are capable
of storing hydrogen and reusing it in a hydrogen-borrowing-
type reaction.92−94 Also, in all runs, benzaldehyde started to
appear gradually once the conversion of benzylamine was
complete. This side reaction was independent of the catalyst
used and was therefore attributed to the gradual hydrolysis of
imine 6. A comparison of complexes 3a and 4a (entries 1 and
3) with 3b and 4b (entries 2 and 4) indicates that the glucose
substituent imparts slightly higher activity than the galactose
substituent for both ruthenium- and iridium-catalyzed reac-
tions. Complexes 3a and 3b (entries 1 and 2) also reveal poor
spectroscopic yields in comparison to complexes 4 and 5
(entries 3−8). The lower yield was tentatively attributed to
overoxidation of the substrate to nitriles or hydrolysis of the
product at early stages and subsequent overoxidation to
acids.95,96 Finally, complexes 3 are slightly more active than
other trz-Ru compounds, which achieve only 72−83%
conversion under comparable conditions (albeit in toluene,
not 1,2-DCB).41,69
Notably, deprotection of the carbohydrate leads to a
considerable increase in the catalytic activity (entries 3 and 4
vs entries 5 and 6; Figure 2). The glucose-functionalized
complex 5a achieved 78% conversion in 1 h, whereas the
acetylated analogue reached only 44% (cf. entry 3 vs entry 5).
The difference is even larger for the galactose-substituted
systems, with the protected complex converting only 19% of
the substrate, while the deprotected complex is 3 times more
active (71%; entry 4 vs entry 6). The selectivity is not affected
by the deprotection and remains at an approximate 5:1 ratio of
imine versus secondary amine. Lowering the catalyst loading
and using 5a and 5b at 1 mol % led to appreciable conversions;
Mixed Catalytic Oxidation of Benzyl Alcohol and
Benzylamine. Because alcohol oxidation is about 1 order of
magnitude slower than amine oxidation, we were interested in
further investigating these reactivity differences of complexes
3−5 and therefore performed catalytic reactions using a
mixture of benzyl alcohol and benzylamine (Tables 3 and
S3). As observed in oxidation reactions with pure amines (cf.
Tables 1 and 2), ruthenium complexes 3a and 3b displayed
high selectivity for amine oxidation. Upon exposure to a
mixture of amine and alcohol substrates, dehydrogenation of
benzyl alcohol to benzaldehyde was only observed once
oxidation of the amine was complete. Furthermore, the
catalytic activity and selectivity toward the imine product was
not significantly altered in comparison to amine oxidation in
the absence of benzyl alcohol (Table 3, entries 1 and 2,
compared to Table 2, entries 1 and 2, Figure S3). This outcome
suggests a stronger bonding of the amine substrate to the Ru
center in comparison to the alcohol substrate.
In contrast, iridium complexes 4 and 5 were less selective and
converted benzylamine and benzyl alcohol simultaneously,
albeit the alcohol in a much lower rate than the amine (Table 3,
entries 3−7). Interestingly, the conversion of both substrates is
slightly enhanced when using the mixture. This effect is most
pronounced with complex 4b, which converted benzylamine
completely within 5 h when starting from the substrate mixture
(Table 3, entry 4), while the oxidation of benzylamine in the
absence of benzyl alcohol at 5 h was only 86% (Table 2, entry
4). Similarly, benzyl alcohol conversion reached 33% during the
mixed oxidation at 5 h (Table 3, entry 4), compared to 23%
conversion in the absence of benzylamine (Table 1, entry 4).
The same effect was observed for complex 4a and for
complexes 5a and 5b containing the triazolylidene with
deprotected carbohydrate groups (entries 3−7). For example,
conversion of benzyl alcohol with the deprotected carbohydrate
system 5a doubled in the presence of benzylamine (39% vs
19%). These data indicate that catalyst activation from the
iridium complexes preferably takes place from the amine,
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Table 3. Mixed Substrate Oxidation Catalysis
conv (%)
entry
catalyst
mol %
benzylamine
benzyl alcohol
6/7/8
1
2
3
4
5
6
7
3a
3b
4a
4b
5a
5a
5b
1
1
5
5
5
1
1
84
90
100/−/−
100/−/−
42/58/−
50/50/−
37/59/4
46/54/−
44/56/−
>95
>95
>95
65
43
33
39
15
15
71
a
General conditions: benzylamine (1.25 or 0.25 mmol), benzyl alcohol (1.25 or 0.25 mmol), [Ru] or [Ir] (0.012 mmol) 1,2-DCB, 150 °C.
1
Conversions were determined by H NMR integration (hexamethylbenzene as the internal standard), averaged over at least two runs.
Scheme 2. Imine Products Formed during Catalytic Homocoupling of 4-Bromobenzylamine with Benzyl Alcohol
Figure 3. Catalytic profile expressed as the mole ratio for the oxidation of benzylamine (a) with catalyst 4a (5 mol %), (b) with benzyl alcohol and
catalyst 4a (5 mol %), (c) with catalyst 5a (5 mol %), and (d) with benzyl alcohol and catalyst 5a (5 mol %). Conversion of benzyl alcohol was
omitted for clarity.
although once formed, it is active toward both amine and
alcohol oxidation. Alternatively, the amine may act as a base
and facilitate alcohol deprotonation within the metal
coordination sphere, thereby accelerating catalytic conversion.
Moreover, when using complexes 4 or 5 as catalyst precursors,
trace amounts of tribenzylamine 8 were observed at extended
reaction times when the conversion of benzylamine was
complete (ca. 6% after 7 h). Formation of the tertiary amine
8 is most likely a product of the reaction of 7 with
benzaldehyde, which is formed from the oxidation of benzyl
alcohol, a reaction that is only favorable once the more reactive
primary benzylamine is consumed.
The detection of benzaldehyde as a product of the reaction is
remarkable because Schiff base reaction with residual amine is
expected to enhance the ratio of the imine product. In an
attempt to elucidate such reaction trajectories and to further
detail the substrate specificity of the iridium complexes,
reactions were performed using 4-bromobenzyl alcohol instead
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of benzyl alcohol (Scheme 2) in mixed oxidation together with
benzylamine. In such a setup, coupling of the oxidized alcohol
with the amine will produce an unsymmetrical monobromi-
nated product 6′, while homocoupling will give the standard
unsubstituted imine 6. Likewise, hydrolysis of the imine will
produce benzaldehyde, and bromobenzaldehyde should form
predominantly from direct alcohol oxidation.
When this mixed reaction was carried out with the iridium
complex 4a, a complex product mixture was obtained,
indicative of the simultaneous oxidation of both benzylamine
and benzyl alcohol. The imine 6 and mixed imine 6′ were
observed in a 4:3 ratio after 1 h, and the amine products were
present in almost the same ratio (7/7′ was 3:2). The formation
of substantial amounts of brominated products 6′ and 7′
confirms that the alcohol and amine oxidations occur
concurrently. At extended reaction times, the formation of
both benzaldehyde and bromobenzaldehyde is observed in a
relative ratio of ca. 4:3. The quantity of benzaldehyde was
minor after 7 h and more significant after 24 h. This increasing
amount of benzaldehyde, together with the fact that the
brominated versus bromine-free aldehyde ratio is identical with
the ratio observed in the imine products, strongly suggests that
the aldehydes are formed by hydrolysis of the Schiff base 6 and
not by selective oxidation of the bromobenzyl alcohol.
A comparison of the iridium-catalyzed amine oxidation in the
presence or absence of benzyl alcohol also reveals a significant
alteration of the imine/amine product ratio. In runs with pure
amine substrate, the imine 6 was the predominant substrate (ca.
5:1 ratio of imine vs amine), whereas in runs in the presence of
benzyl alcohol, the quantities of imine and amine were
essentially equal (Table 2, entries 3−8, vs Table 3, entries 3−
7). Inspection of the reaction profiles for complexes 4a and 5a
reveals that both complexes catalyze the formation of amine 7
at faster rates in the presence of benzyl alcohol (Figure 3b,d)
than when only amine is available as the substrate (Figure 3a,c).
This change of the conversion rate is independent of the
carbohydrate system on the catalyst used and is observed
whether the carbohydrate unit is deprotected or not. The
increased formation of the saturated amine therefore suggests
that the presence of benzyl alcohol facilitates hydrogen storage
and transfer to the imine, while with only benzylamine as the
substrate, hydrogen release is predominant.
As a consequence of this model, the low conversion of benzyl
alcohol to benzaldehyde with iridium catalysts (Table 1, entries
3−6) may principally originate from efficient hydrogen storage
and, hence, a reversible reaction, involving hydrogenation of the
benzaldehyde product back to the benzyl alcohol substrate.
Such hydrogen shuffling was probed by adding acetophenone
(20 mol % relative to benzyl alcohol) to a catalytic run for the
dehydrogenation of benzyl alcohol with the iridium complex
4a. In this experiment, no hydrogenation of acetophenone was
observed. It is thus unlikely that the dehydrogenation of
aldehydes is reversible under the catalytic conditions employed.
This conclusion is also supported by the fact that the alcohol
oxidation is slow, while fast hydrogen shuttling should rapidly
reach an equilibrium situation (see the reaction profiles for
alcohol oxidation in Figure S1).
(benzylimine) and ensuing formation of the alkylated imine (6)
outside the metal coordination sphere.86−89,91 While in
ruthenium chemistry, the high selectivity toward the imine
product indicates easy dissociation of the imine from the
coordination sphere, coordination is apparently stronger in the
iridium complexes and, hence, leads to a mixture of imine and
amine products. This trend may be superimposed by the high
stability of iridium hydrides, which facilitates storage of
hydrogen in the metal coordination sphere and, hence,
increases the propensity for hydrogenation and formation of
the saturated amine. We therefore suggest that the distinct
product selectivity of iridium-catalyzed amine oxidation and its
dependence on the presence or absence of benzyl alcohol is due
to the divergent mechanisms for N-alkylation of alcohols
(amine formation) versus amine homocoupling (imine
formation).
CONCLUSIONS
■
We have used the triazole scaffold to introduce acetyl-protected
carbohydrates to a carbene ligand moiety. Deprotection under
acidic conditions was achieved on the complex, although only
the Ir−Ctrz bond is sufficiently robust to sustain the
deprotection conditions, while the Ru−Ctrz bond is cleaved
and the complexes decompose. These iridium complexes are
rare examples of carbene complexes containing unprotected
sugar units. Most significantly, the catalytic amine oxidation
activity of the Ir center is significantly enhanced when the
carbohydrate is deprotected rather than acetyl-protected.
Crossover experiments indicate that the presence of benzyl
alcohol is changing the selectivity of amine oxidation (amine vs
imine) for iridium catalysts, and this change is due to different
mechanistic pathways (homocoupling vs hydrogen-borrowing
mechanisms). The increased catalytic activity of the depro-
tected sugar complexes reveals the beneficial impact of the
hydroxy functionalities on the catalytic performance. Current
work is focusing on exploitation of the carbohydrate
functionality on these iridium complexes for other (catalytic)
applications, as well as alteration of the stereochemistry of the
carbohydrate substituent to enhance its effect.
EXPERIMENTAL SECTION
■
General Procedures. Ag2O was used after regeneration by heating
to >160 °C under vacuum. Dry degassed solvents were obtained by
filtering over columns of dried neutral aluminum oxide under a
positive pressure of argon. Compounds 1a,55 1b,100,101 2a,55 3a,55 and
102
[Ir(Cp*)Cl2]2
were synthesized using modified literature proce-
dures. All other reagents were used as received from commercial
suppliers. NMR spectra were recorded on Bruker and Varian
spectrometers operating at room temperature. Chemical shifts (δ in
ppm; coupling constants J in Hz) were referenced to residual solvent
resonances and are given downfield from SiMe4. Elemental analysis
and mass spectrometry were performed by the microanalytical services
of University College Dublin and University of Bern.
Compound 2b. This compound was prepared using a modified
literature procedure for 2a. A suspension of 1-(2,3,4,6-tetra-O-acetyl-β-
D-galactopyranosyl)-4-phenyl-1H-1,2,3-triazole (1.0 g, 2.1 mmol) and
trimethyloxonium tetrafluoroborate (0.44 g, 3.0 mmol) in dry CH2Cl2
(100 mL) was stirred for 2 days under a N2 atmosphere. MeOH (5
mL) was added and the solution evaporated to dryness under reduced
pressure. The crude product was dissolved in minimal CH2Cl2, and
diethyl ether (Et2O; 100 mL) and pentane (100 mL) were added,
followed by cold storage to induce the precipitation of a white solid.
This solid was dissolved in CH2Cl2 filtered over Celite and dried under
reduced pressure. The product was obtained as a white solid (1.0 g, 1.7
Previous mechanistic studies indicated that N-alkylation of
alcohols generally requires the aldehyde and subsequently
formed hemiaminal and imine intermediates to remain
coordinated to the Ir center for hydrogenation (formation of
the amine product 7 via hydrogen borrowing).97−99 In contrast,
homocoupling of amines involves release of the aldimine
1
mmol, 82%). H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H, CtrzH),
F
DOI: 10.1021/acs.inorgchem.7b01899
Inorg. Chem. XXXX, XXX, XXX−XXX

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7.65−7.54 (m, 5H, CArH), 6.26 (d, 3JHH = 9.1 Hz, 1H, HGal-1), 5.76 (t,
(m, 3H, HAr), 6.98 (br s, 1H, HGal-1), 6.13 (t, 3JHH = 9.7 Hz, 1H, HGal
-
3JHH = 9.5 Hz, 1H, HGal-2), 5.56 (d, J = 3.10 Hz, 1H, HGal-4), 5.34 (dd,
2), 5.55 (app. d, 1H, HGal-4), 5.22 (app. d, 1H, HGal-3), 4.39 (br s, 1H,
HGal-5), 4.29−4.20, 4.19−4.09 (2m, 1H, HGal-6), 3.84 (s, 3H, NCH3),
2.22, 2.04, 2.00, 2.00 (4s, 3H, CCOCH3), 1.38 (s, 15H, CpCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ 170.5, 170.4, 169.9 (4CO),
3JHH = 10.1 and 3.3 Hz, 1H, HGal-3), 4.48 (t, 3JHH = 6.2 Hz, 1H, HGal
-
5), 4.31 (s, 1H, NCH3), 4.27−4.12 (m, 2H, HGal-6), 2.2, 2.07, 2.05,
2.02 (4s, 3H, COCH3).13C{1H} NMR (101 MHz, CDCl3): δ 170.6,
170.2, 170.0, 169.7 (4CO), 144.1 (CtrzCAr), 132.4, 129.9, 129.7
(3CAr), 128.36 (CtrzH), 121.5 (CAr), 88.1 (CGal-1), 74.7 (CGal-5), 70.8
(CGal-3), 67.1 (CGal-2), 66.9 (CGal-4), 60.9 (CGal-6), 39.4 (NCH3),
20.8, 20.7, 20.6, 20.6 (4COOCH3). HRMS (ESI+). Calcd for
C23H28N3O9 ([M − BF4]+): m/z 490.1826. Found: m/z 490.1827
General Procedure for the Synthesis of Carbohydrate
Triazolylidene Complexes 3 and 4. A suspension of triazolium
salt 1 (1 equiv), NMe4Cl (1 equiv), and Ag2O (0.57 equiv) in MeCN
(25 mL) was stirred for 24 h under the exclusion of light. The reaction
mixture was filtered over Celite, and the volatiles were removed under
reduced pressure. The resulting brown solid was suspended in CH2Cl2
(50 mL), [RuCl2(p-cymene)]2 or [IrCl2(Cp*)]2 (0.38 equiv) was
added, and the reaction mixture was stirred under the exclusion of light
for 2 and 24 h, respectively. The reaction mixture was filtered through
Celite, and volatiles were removed under reduced pressure. The crude
product was purified by gradient column chromatography (SiO2).
Complex 3b. As per the general method, triazolium salt 2b (81.3
mg, 0.14 mmol), NMe4Cl (16 mg, 0.14 mmol), Ag2O (21 mg, 0.091
mmol), and [RuCl2(p-cymene)]2 (32.6 mg, 0.053 mmol) and
subsequent purification by column chromatography (SiO2; CH2Cl2,
then 9:1 CH2Cl2/acetone, and then 2:1 CH2Cl2/acetone) yielded
149.5, 148.8 (2Ctrz), 132.9, 130.3, 128.3, 127.2 (4CAr), 88.7 (CCp),
87.0 (CGal-1), 73.5 (CGal-5), 72.2 (CGal-3), 68.4 (CGal-2), 67.5 (CGal-4),
61.3 (CGal-6), 38.2 (NCH3), 21.3, 21.0, 20.9, 20.7 (4C(O)CH3), 8.76
(CpCH3). HRMS (ESI+). Calcd for C33H42ClIrN3O9 ([M − Cl]+): m/
z 852.2239. Found: m/z 852.2230. Anal. Calcd for C33H42Cl2IrN3O9:
C, 44.64; H, 4.77; N, 4.73. Found: C, 44.87; H, 4.32; N, 5.33.
General Procedure for Carboyhdrate Deprotection and
Formation of Complexes 5. Complex 4 (100 mg, 0.11 mmol)
was stirred in methanolic HCl (0.5 M, 2.5 mL, 1.3 mmol) for 2 days.
Precipitation was induced by the addition of Et2O (50 mL) and
pentane (50 mL), followed by cooling to −20 °C. The solvent was
decanted and the precipitate washed with pentane (100 mL) and dried
in vacuo, yielding the product as a yellow solid.
Complex 5a. The general method from 4a was used. Yield: 67.3 mg
1
(0.094 mmol, 83%). H NMR (400 MHz, (CD3)2SO): δ 7.62−7.33
(m, 5H, HAr), 6.07 (d, 3JHH = 4.4 Hz, 1H, OHGlc-2), 5.58 (d, 3JHH3 = 9.2
3
Hz, 1H, HGlc-1), 5.44 (d, JHH = 4.8 Hz, 1H, OHGlc), 5.20 (d, JHH
=
3
5.7 Hz, 1H, OHGlc), 4.53 (t, JHH = 5.4 Hz, 1H, OHGlc-6), 4.07 (td,
3JHH= 9.2 and 4.4 Hz, 1H, HGlc-2), 3.85 (s, 3H, NCH3), 3.68−3.51 (m,
3H, HGlc-6 and HGlc), 3.48−3.34 (m, 2H, HGlc), 1.60 (s, 15H,
CpCH3). 13C{1H} NMR (101 MHz, (CD3)2SO): δ 149.0 (CtrzC),
135.4 (CtrzIr), 132.1 (CtrzCAr) 129.8, 127.4, 126.9 (3CArH), 95.9
(CCp), 88.7 (CGlc-1), 78.9 (CGlc), 76.6(CGlc-3), 72.9 (CGlc-2), 69.1
(CGlc), 60.0 (CGlc-6), 38.3 (NCH3), 8.2 (CpCH3). HRMS (ESI+).
Calcd for C25H34ClIrN3O5 ([M − Cl]+): m/z 684.1811. Found: m/z
684.1811 Anal. Calcd for C25H34Cl2IrN3O5: C, 41.72; H, 4.76; N, 5.84.
Found: C, 41.23; H, 4.30; N, 6.34.
1
complex 3b as a red-brown solid (57.1 mg, 0.072 mmol, 71%) H
NMR (CDCl3, 400 MHz): δ 7.69−7.61 (m, 2H, HAr), 7.55−7.45 (m,
3
3H, HAr), 7.23 (d, JHH = 9.2 Hz, 1H, HGal-1), 6.08 (app. t, 1H, HGal
-
3
2), 5.55 (app. d, 1H, HGal-4), 5.25 (dd, JHH = 10.2 and 3.4 Hz, 1H,
HGal-3), 5.22−5.19 (m, 2H, Hcym), 4.86 (d, 3JHH = 5.9 Hz, 1H, Hcym),
3
4.83 (d, JHH = 6.2 Hz, 1H, Hcym), 4.38−4.32 (m, 1H, HGal-5), 4.28−
4.21, 4.17−4.10 (2m, 1H, HGal-6), 3.83 (s, 3H, NCH3), 2.66−2.52 (m,
Complex 5b. The general method from 4b was used. Yield: 66 mg
1H, CHMe2), 2.20, 2.05, 2.00, 1.99 (4s, 3H, C(O)CH3), 1.85 (s, 3H,
1
3
(0.092 mmol, 82%). H NMR (400 MHz, (CD3)2SO): δ 7.54−7.37
CcymCH3), 1.18, 1.14 (2d, JHH = 6.9 Hz, 3H, CHCH3). 13C{1H}
3
3
(m, 5H, HAr), 5.88 (d, JHH = 5.9 Hz, 1H, OHGal-2), 5.51 (d, JHH
=
NMR (CDCl3, 101 MHz): δ 170.4, 170.3, 169.9, 169.5 (4CO),
165.8 (Ctrz−Ru), 148.4 (CtrzC), 132.2 (CArH), 130.4 (CtrzCAr), 128.4,
128.3, (2CArH), 105.9 (CcymCH), 97.3 (CcymCH3), 87.2 (CGal-1), 86.2,
85.9, 84.0, 83.0 (4CcymH), 73.6 (CGal-5), 71.9 (CGal-3), 68.4 (CGal-2),
67.5 (CGal-4), 61.4 (CGal-6), 37.9 (NCH3), 30.7 (CHMe2), 22.9, 22.5
(2CHCH3), 21.2, 20.9, 20.9, 20.7 (4C(O)CH3), 18.4 (CcymCH3).
HRMS (ESI+). Calcd for C33H41ClN3O9Ru ([M − Cl]+): m/z
760.1575. Found: m/z 760.1576. Anal. Calcd for C33H41Cl2N3O9Ru·
H2O: C, 48.71; H, 5.33; N, 5.16. Found: C, 48.98; H, 5.12; N, 5.28.
Complex 4a. According to the general method, the reaction of 2a
(325 mg, 0.56 mmol), NMe4Cl (61 mg, 0.56 mmol), Ag2O (75 mg,
0.32 mmol), and [IrCl2(Cp*)] (170 mg, 0.21 mmol), followed by
purification by column chromatography (SiO2; CH2Cl2, then 9:1
CH2Cl2/acetone, and then 9:1 CH2Cl2/MeOH or 20:1−2:1 CH2Cl2/
acetone gradient), yielded the title product as an orange solid (0.321 g,
9.3, 1H, HGal-1), 5.21 (d, 3JHH = 5.6, 1H, OHGal-3), 4.90 (d, 3JHH = 3.9
Hz, 1H, OHGal-4), 4.63 (t, 3JHH = 5.5 Hz, 1H, OHGal-6), 4.47 (td, 3JHH
= 9.3 and 4.4 Hz, 1H, HGal-2), 3.96−3.86 (m, 1H, HGal-4), 3.84−3.80
(m, 1H, HGal-5), 3.84 (s, 3H, NCH3), 3.63−3.55 (m, 1H, HGal-6),
3.53−3.41 (m, 2H, HGal-3 and HGal-6), 1.60 (s, 15H, CpCH3).
13C{1H} NMR (101 MHz, (CD3)2SO): δ 148.8 (CtrzC), 135.1 (CtrzIr),
132.2(CtrzCAr), 129.7, 127.3, 127.0 (3CArH), 95.8 (CCp), 89.4 (CGal-1),
77.4 (CGal-5), 73.5 (CGal-3), 69.8 (CGal-2), 67.3 (CGal-4), 59.0 (CGal-6),
38.2 (NCH3), 8.2 (CpCH3). HRMS (ESI+). Calcd for
C25H34ClIrN3O5 ([M − Cl]+): m/z 684.1811. Found: m/z 684.1793.
General Considerations for Catalytic Oxidation. One-neck, 10
mL round-bottomed flasks fitted with reflux condensers were used for
all catalytic runs, and reactions were heated in an oil bath at 150 °C.
For all oxidation reactions 1,2-DCB was used as the solvent (5 mL for
runs with ruthenium complexes; 2 mL for runs with iridium
complexes). The reaction progress was monitored by dissolving
aliquots (0.1 mL) of the reaction mixture in CDCl3 (0.6 mL) and
analysis by 1H NMR spectroscopy through a comparison to the
commercial samples and literature values.103 Conversions and yields
were determined relative to the internal standard.
Procedure for the Base-Free Oxidation of Alcohols or Amines (5
mol % Catalyst Loading). A mixture of trimethoxybenzene (9.4 mg,
0.056 mmol) and benzyl alcohol (26 μL, 0.25 mmol), or
hexamethylbenzene (2 mg, 0.012 mmol) and benzylamine (27 μL,
0.25 mmol) in 1,2-DCB, with the corresponding metal complex (0.012
mmol) was heated for the time indicated.
1
0.36 mmol, 86%). H NMR (CDCl3, 400 MHz): δ 7.73 (br s, 2H,
HAr), 7.50−7.43 (m, 3H, HAr), 6.80 (br s, 1H, HGlc-1), 5.99 (t, 3JHH
=
9.5 Hz, 1H, HGlc-2), 5.40−5.22 (m, 2H, HGlc), 4.39−4.24 (m, 2H,
HGlc-6 and HGlc), 4.24−4.16 (m, 1H, HGlc-6), 3.81 (s, 3H, NCH3),
2.08, 2.05, 2.03, 1.97 (4s, 3H, C(O)CH3), 1.39 (s, 15H, CpCH3).
13C{1H} NMR (CDCl3, 101 MHz): δ 170.9, 170.2, 169.6, 168.8
(4CO), 149.5, 149.1 (2Ctrz), 132.8, 130.3, 128.3, 127.2, (4CAr), 88.8
(CCp), 86.5 (CGlc-1), 74.4 (2CGlc), 71.1 (CGlc-2), 68.1, 61.7 (2CGlc),
38.1 (NCH3), 21.1, 21.0 (2C(O)CH3), 20.8 (2C(O)CH3), 8.8
(CpCH3). HRMS (ESI+). Calcd for C33H42ClIrN3O9 ([M − Cl]+):
m/z 852.2239. Found: m/z 852.2217. Anal. Calcd for
C33H42Cl2IrN3O9: C, 44.64; H, 4.77; N, 4.73. Found: C, 44.63; H,
4.55; N, 4.59.
Procedure for the Catalytic Oxidation of Amines (1 mol %
Catalyst Loading). A mixture of hexamethylbenzene (34 mg, 0.21
mmol, for ruthenium catalysts and 10 mg, 0.062 mmol, for iridium
catalysts), 1,2-DCB, benzylamine (135 μL, 1.2 mmol), and a metal
complex (0.012 mmol) were heated for the time indicated.
Procedure for the Mixed Catalytic Oxidation of Alcohols and
Amines (5 mol % Catalyst Loading). A mixture of hexamethylben-
zene (2 mg, 0.012 mmol), benzyl alcohol (26 μL, 0.25 mmol),
Complex 4b. As per the general method, the triazolium salt 2b (325
mg, 0.56 mmol), NMe4Cl (61 mg, 0.56 mmol), Ag2O (75 mg, 0.32
mmol), and [IrCl2(Cp*)]2 (170 mg, 0.21 mmol, 86%) afforded
complex 4b, following column chromatography (SiO2; CH2Cl2, then
9:1 CH2Cl2/acetone, and then 9:1 CH2Cl2/MeOH or 20:1−2:1
CH2Cl2/acetone gradient), as an orange solid (321 mg, 0.36 mmol,
86%). 1H NMR (CDCl3, 400 MHz): δ 7.73 (br s, 2H, HAr), 7.52−7.42
G
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benzylamine (27 μL, 0.25 mmol), and a metal complex (0.012 mmol)
were heated for the time indicated.
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* Supporting Information
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AUTHOR INFORMATION
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Corresponding Author
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*E-mail: martin.albrecht@dcb.unibe.ch.
ORCID
Martin Albrecht: 0000-0001-7403-2329
Notes
The authors declare no competing financial interest.
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Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne
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ACKNOWLEDGMENTS
■
This work was financially supported by the European Research
Council (Grant CoG 615653), the Irish Research Council
through fellowships to R.P. and J.O., and the Swiss National
Science Foundation (R’equip Projects 206021_128724 and
206021_170755). We thank Dr. J. Byrne for synthetic
assistance and the group of Chemical Crystallography of the
University of Bern (P.D. Dr. P. Macchi) for the X-ray structure
solution.
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H
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