Activation of a Metal-Halogen Bond by Halogen Bonding

Article abstract of DOI:10.1002/anie.202005214

In recent years, the non-covalent interaction of halogen bonding (XB) has found increasing application in organocatalysis. However, reports of the activation of metal-ligand bonds by XB have so far been limited to a few reactions with elemental iodine or

Full text of DOI:10.1002/anie.202005214

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Accepted Article
Title: Activation of a metal-halogen bond by halogen bonding
Authors: Julian Wolf, Florian Huber, Nikita Erochok, Flemming Heinen,
Vincent Guerin, Claude Legault, Stefan Kirsch, and Stefan
Matthias Huber
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005214
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Activation of a metal-halogen bond by halogen bonding
Julian Wolf,[a] Florian Huber,[b] Nikita Erochok,[a] Flemming Heinen,[a] Vincent Guérin,[c] Claude Y.
Legault,*[c] Stefan F. Kirsch*[b] and Stefan M. Huber*[a]
Abstract: In recent years, the non-covalent interaction of halogen
bonding (XB) has found increasing application in organocatalysis.
However, reports of the activation of metal-ligand bonds by XB have
so far been limited to a few reactions with elemental iodine or bromine.
Herein, we present the activation of metal-halogen bonds by two
classes of inert halogen bond donors and the use of the resulting
activated complexes in homogenous gold catalysis. The only recently
explored class of iodolium derivatives were shown to be effective
activators in two test reactions and their activity could be modulated
by blocking of the Lewis acidic sites. Bis(benzimidazolium)-based
halogen bonding activators provided even more rapid conversion,
while the non-iodinated reference compound showed little activity.
Figure 2. Overview of halogen bond donors and related reference compounds
applied in this study.
The role of halogen bonding in the activation of metal-halogen bonds
was further investigated by NMR experiments and DFT calculations,
which support the mode of activation occurring via halogen bonding.
In the last decade, halogen bonding has also been established in
Halogen bonding (XB)[1,2] describes the non-covalent interaction
organocatalysis, with an ever increasing number of organic
between electrophilic halogen substituents and Lewis bases.[3] Its
high directionality, tunability and complementarity to hydrogen
bonding (HB) has led to frequent use[4] of XB in the solid state,
especially with numerous applications in crystal engineering.[5],[6]
Increasingly, the use of halogen bonding has also expanded into
reactions reported which are promoted by XB donors.[10],[11] In
many of these cases, halide leaving groups were abstracted from
organohalogen compounds in order to facilitate nucleophilic
substitution reactions (Figure 1, left).
At this time, multiple classes of halogen bonding catalysts have
been established and applied to different types of organic
reactions,[11] including monodentate or multidentate neutral as
well as cationic iodine(I)-based XB donors, and also recently,
iodine(III) derivatives.[12] Lately, a first example has also been
reported in which enantioselectivity in a Mukaiyama aldol reaction
was induced by a chiral halogen bond donor devoid of any further
coordinating groups.[13]
solution chemistry, with
a multitude of reports on anion
recognition[7],[8] and the construction of supramolecular
assemblies.[9]
The application of halogen bonding in transition metal chemistry
has yet mostly been limited to halogen bonding ligands which
induce organization of the ligand sphere.[14]–[18] Halogen bonds to
halide[19]–[22] ligands as well as numerous other[23] Lewis basic
ligands in metal complexes have been observed for inorganic and
organic halogen bond donors.[24]
Figure 1. Schematic view of activation of C-X and M-X bonds by halogen
Beyond coordination of these ligands by halogen bonding, only a
handful[25]–[28] of instances exist, in which ligand exchange is
observed. In these cases, elemental iodine or bromine were used
as halide exchange reagents: even though intermediary halogen
bonding was postulated, in the progress of the reaction the I-I or
Br-Br bonds were cleaved. The transfer of the concept of C-X
activation to M-X bonds using inert XB donors has, to the best of
our knowledge, not yet been realized (Figure 1, right).
Herein, we present the first example of such, in two gold-
catalyzed reactions which are accelerated in the presence of two
separate classes of halogen bond donors via Au-Cl bond
activation. In this study, the scarcely explored class of halogen
bonding catalysts[12] based on an iodolium (cyclic diaryl iodonium)
motif, 1 and 2, are utilized (Figure 2). Additionally, the tetrakis[3,5-
bis(trifluoromethyl)-phenyl]borate (BArF4-) (4a), triflate (4b), and
the newly synthesized hexafluorophosphate (4c) salts of the
previously tested, highly preorganized[29] bis(benzimidazolium)
halogen bond donor 4[30] were investigated.
bonding.
[a]
J. Wolf, N. Erochok, F. Heinen, Prof. S. M. Huber
Fakultät für Chemie und Biochemie
Ruhr-Universität Bochum
Universitätsstraße 150, 44801 Bochum (Germany)
E-mail: stefan.m.huber@rub.de
[b]
[c]
F. Huber, Prof. S. F. Kirsch
Organic Chemistry, Bergische Universität Wuppertal
Gaussstrasse 20, 42119 Wuppertal (Germany)
E-mail: sfkirsch@uni-wuppertal.de
V. Guérin, Prof. C. Y. Legault
Department of Chemistry
Université de Sherbrooke
2500 boul. de l’Université
Sherbrooke, Québec J1K 2R1(Canada)
E-mail: claude.legault@usherbrooke.ca
Supporting information for this article is given via a link at the end of the
document.
1
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10.1002/anie.202005214
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presence of any halide-abstracting agent, the reaction shows no
background reactivity after more than 30 hours (Table 1, Entry 1).
In contrast, addition of iodolium salt 1a results in 60% conversion
after only 3 hours of reaction time (Table 1, Entry 2) and almost
quantitative conversion is reached after 12 hours (Figure 3, yellow
curve). Reference experiments showed no reaction when the
activator was added with no gold complex present. Accordingly,
doubly methylated halogen bond donor 2a showed the expected
diminished activity, with only 38% conversion after 3 hours (Table
1, Entry 4; see also Figure 3, red curve).
Gratifyingly, the doubly blocked iodolium salt 3a showed only little
activity, with less than 5% conversion after 12 hours (Table 1,
Entry 6). These results point to the mechanism of activation
occurring via halogen bonding as the blockage of electrophilic
axes results in markedly diminished activity. Initial rate
accelerations for the iodolium salts revealed that 2a results in an
acceleration of krel = 660 relative to the fully blocked compound
3a; conversely, the completely unblocked XB donor 1a provides
almost double the initial rate of 2a (Table 1, Entries 2, 4, and 6).
The analogous triflate salts 1-3b all showed poor activity, with only
slight conversion noticeable after 3 hours and comparatively poor
rate accelerations (Table 1, Entries 3, 5, and 7).
Scheme 1. Au-catalyzed cyclization of amide 6 to oxazoline 7.
As first test reaction, the gold(I)-catalyzed cyclization of
propargylic amide 6 to the oxazoline 7 was chosen (Scheme 1).
This reaction has previously been used to benchmark catalyst
activity and the effectiveness of added activators in homogenous
gold catalysis.[31]–[34] The reaction was performed with 2 mol% of
chloro(triphenylphosphine) gold and an equimolar amount of the
halide abstracting agent in deuterated chloroform as solvent.
Table 1. Cyclization of 6 in the presence of activators and reference compounds.
[c]
Entry
Activator[a]
Conversion[b] of 6 [%]
krel
This counterion-rate dependence is likely due to the need for a
weakly coordinating anion under these reaction conditions, as the
addition of the strong halide abstracting agent silver triflate only
results in 13% conversion after 12 hours. In comparison, the
analogous silver tetrafluoroborate and hexafluorophosphate salts
provided markedly increased conversions in the same time (87%
and >95%, see SI; compare also Table 1, Entries 14-16).
1
None
1a[d]
1b
≤5[d]
60
≤5
38
≤5
≤5
≤5
92
≤5
25
≤5
95
≤5
5
/
2
1100
10
3
4
2a[e]
2b
660
3
5
It is important to note, however, that rapid conversion was also
reached by the addition of NaBArF , likely due to the strong driving
6
3a
1
4
force of NaCl formation; almost complete (95%) conversion was
obtained after only 3 hours of reaction time (Table 1, Entry 12).
7
3b
/
Therefore, possible activity of the BArF anion itself was
4
8
4a
3100
18
additionally tested by the addition of TMABArF , which resulted
4
9
4b
only in trace amounts of conversion, even after 12 hours of
reaction time. This result, combined with the inactivity of 3a,
suggests that the observed activity in the cases of the iodolium
compounds stems from the unblocked electrophilic axes on the
iodine atom and thus, halogen bonding interactions.
10
11
12
13
14
15
16
17
18
4c
330
26
5a
NaBArF
3500
15
4
TMABArF
4
AgOTf
AgBF4
AgPF6
100
180
740
/
14
44
≤5
≤5
[f]
I2
[g]
I2
/
[a] Activators added in 2 mol% unless indicated otherwise. [b] Conversion
determined by 1H NMR after 3 hours of reaction time, unless indicated
otherwise. An error margin of ~5% is assumed. All experiments were
reproduced at least twice. [c] Relative initial rates after 70 minutes of reaction
time, referenced to 3a (and rounded to two valid digits). [d] 30 hours reaction
time. [e] The propargylic amide 6 was added to a preformed solution of the
activator and the gold complex. [f] Added in 1 mol%. [g] Added in 1 mol‰.
Figure 3. Kinetic plot for the reaction of amide 6 in the presence of various
activators.
Due to the subsequent slow aromatization of
7 to the
corresponding oxazole[34] (cf. Figure S1), for accuracy, only the
conversion of the starting material is considered, the extent of
which could be monitored by 1H NMR spectroscopy. Without the
With these promising results in hand, the highly preorganized
bis(benzimidazolium)-based halogen bond donor 4a was tested
2
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10.1002/anie.202005214
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and showed exceptional activity, with 92% conversion after 3
hours and almost quantitative product formation after 8 hours of
reaction time. The initial rate acceleration with 4a was almost
triple that of iodolium salt 1a (Table 1, Entry 8; see also Figure 3,
dark blue curve).
increased activity compared to the triflate salt, with 25%
conversion after 3 hours of reaction time (Figure 3). This
compound, however, suffers from poor solubility in chloroform,
which limits the direct comparison with the analogous 4a and 4b.
To probe the nature of the activation with 4a further, reference
compound 5a was synthesized; the latter is structurally analogous
to 4a, but incapable of halogen bonding (Figure 2). Expectedly,
this salt showed drastically lower activity, with almost no
conversion during the first 3 hours of reaction time (Table 1, Entry
11). It is interesting to note, however, that some activity is
observed with longer reaction times; as much as 18% conversion
is achieved after 12 hours of reaction time (Figure 3, orange
curve). The mechanism behind this activation needs to be
investigated further but is unlikely to be related to the XB
activation observed for compound 4a, especially when
considering the drastic differences in the initial rate accelerations
(Table 1, cf. Entries 8 vs 11).
Scheme 2. Au-catalyzed cyclization of malonate ester 8.
This observation agrees with previous results,[12] in which
iodolium salts were at times outperformed by a bidentate,
dicationic XB donor; this highlights again the exceptional activity
of this preorganized structural motif. The stability of 4a during the
reaction could be followed by 19F NMR: no visible decomposition
was observed after several hours of reaction time (see SI). To
exclude the effect of possible undetected decomposition of the XB
donors, molecular iodine was tested in the reaction as a possible
decomposition product. Addition of 1 mol‰ of I2 yielded no
conversion and even 1 mol% of I2, which would result from
complete decomposition of the halogen bond donor, showed no
activity. Unsurprisingly, the triflate salt 4b exhibited similar
inactivity to the iodolium salts 1-2b. (Table 1, Entry 9).
As a whole, the presented results constitute, to the best of our
knowledge, the first application of cationic XB donors as inert
activators in transition metal catalysis and show the compatibility
of these compounds with complex reaction systems.
We also tested the halogen bonding activators in the gold-
catalyzed cycloisomerization of 1,6-enyne 8 (Scheme 2). This
reaction forms a mixture of the cyclic products 9a and 9b, which
for all tested activators were obtained in a ratio of approximately
85:15 in favor of the 5-membered cyclic product 9a (see Figure
S5). Since this rearrangement is believed to proceed through
cyclopropyl gold carbene species, its efficacy underlines that
halogen bonding activation is beyond generating simple Lewis
acidity.[35-37] In this case, only negligible background reaction is
observed in the absence of any halide abstracting agent, effecting
less than 5% yield after 15 hours of reaction time (Table 2, Entry
1 and Figure 4).
Table 2. Cyclization of 8 in the presence of 1 mol% of activators and reference
compounds.
[c]
Entry
Activator[a]
Yield[b] of 9a/b [%]
krel
1
None
1a
≤5[d]
76
≤5
43
≤5
≤5
≤5
83
≤5
≤5
84
≤5
/
2
740
14
420
10
1
3
1b
2a
4
5
2b
3a
6
7
3b
4a
10
830
3
8
9
4b
5a
Figure 4. Kinetic plot for the reaction of malonate ester 8 in the presence of
various activators.
10
11
12
41
850
5
NaBArF
4
TMABArF
4
Addition of 1 mol% of iodolium salt 1a resulted in 76% combined
yield of products 9a/b after only 40 minutes of reaction time (Table
2, Entry 2). The partially hindered XB donor 2a again showed
diminished activity, with only 43% yield in comparable reaction
time (Table 2, Entry 4). The inactivity of the tetramethylated salt
3a was confirmed again; a negligible yield was observed after 5
hours of reaction time (Table 2, Entry 6). The relative rate
acceleration of 1a proved to be almost double that of 2a, with both
compounds being vastly more active than 3a (Table 2, Entries 2,
[a] Activators added in 1 mol%. [b] 1H NMR yield of 9a/b after 40 minutes of
reaction time, unless indicated otherwise. An error margin of ~5% is assumed.
All experiments were reproduced at least twice. [c] Relative initial rates after 20
minutes of reaction time, referenced to 3a (and rounded to two valid digits). [d]
15 hours reaction time.
The hexafluorophosphate salt 4c however, which could be
synthesized by simple anion exchange from 4b, showed markedly
3
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10.1002/anie.202005214
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COMMUNICATION
4, and 6), which is in line with the results observed for the
cyclization of 6.
were obtained as minima, the formation of which was predicted to
be favorable by 27 kcal/mol (in the gas phase) or 5 kcal/mol (in
chloroform). The Au-Cl bond length was elongated in both
adducts compared to the isolated complex (2.42 Å vs. 2.32 Å in
the gas phase and 2.41 Å vs. 2.37 Å in chloroform), in line with an
activation of this bond by the XB donor. The further fate of the
activated gold species will likely involve complex equilibria
(leading to (Au(PPh3)2)+, see above), the modelling of which is
outside the scope of this paper.
The strong influence of the counterion was observable in this
reaction as well, with triflate salt 1b yielding under 5% of product
after 3 hours reaction time. The same trend was observed for the
sterically hindered iodolium salts 2b and 3b: only slight activity
was observed for 2b (Table 2, Entries 3, 5, and 7).
Similarly to the previous reaction, NaBArF proved to be highly
4
active, providing 84% yield after 40 minutes, while TMABArF4 was
shown to be almost completely inactive. This supports once again
that the BArF4 anion itself is inactive and that any observed activity
is due to the corresponding cation (Table 2, Entries 11,12).
The bidentate, bis-benzimidazolium-based XB donor 4a was
found again to be the most active halogen bonding activator, with
a performance comparable to NaBArF , providing a yield of 83%
4
after 40 minutes and an initial rate acceleration of 830 compared
to 3a (Table 2, Entry 8). Reference compound 5a also showed
poor activity in this reaction, with less than 5% yield in the initial
40 minutes and only 11% yield after 3 hours of reaction time
(Table 2, Entry 10).
The parallel results obtained for two homogenous gold-catalyzed
reactions and two separate classes of XB donors thus strongly
indicate that the mode of activation occurs via halogen bonding.
Further insight into the activation of the gold chloride complex was
sought by NMR experiments. 31P NMR spectroscopy could be
utilized to track the phosphorus shift of the triphenylphosphine
ligand on the gold complex used in the catalysis experiments. For
the addition of AgOTf to (PPh3)AuCl, a shielding of the phosphine
signal has been reported.[38],[39] When NaBArF4 is added however,
a significant deshielding occurs, with a signal at 45.2 ppm being
observed (Figure 5, b). This signal has commonly been attributed
to an (Au(PPh3)2)+ species[38]–[40] and indicates significant
dissociation of the Au-Cl bond.[41]
Figure 5. Adduct between halogen bond donor 4a (with octyl groups replaced
by methyl and counteranions omitted) and (PPh3)AuCl in chloroform according
to DFT calculations (bond distances in Å, C-I--Cl angles in °). Graphics
generated by CYLview.[46]
In conclusion, two proof-of-principle reactions were presented, in
which significant activation of a metal-halogen bond was effected
by halogen bond donors. Two classes of XB donors were shown
to be efficient activators in homogenous gold catalysis, including
one of the first applications of iodolium-based XB donors. The
activities of the tested activators agreed well with previously
established trends. Different reference experiments were
conducted for both classes of XB donors, which strongly suggest
that halogen bonding is crucial to the activation observed. 31P
NMR experiments strongly suggest activation of the Au-Cl bond,
while computational results support the favorable interaction
between the gold complex and halogen bond donors.
These initial results for gold-catalyzed reactions show promise
that the activation presented in this study can be expanded to
more systems in transition metal catalysis. Halogen bond donors
could present unique and desirable reactivity profiles for this type
of activation.
Acknowledgements
Figure 5. 31P NMR shifts observed of (PPh3)AuCl (a) and its 1:1 mixtures with
NaBArF4 (b) and 4a (c) in CDCl3.
We thank Julia Jurksch for performing orientating experiments
and the European Research Council (ERC) under the European
Union´s Horizon 2020 research and innovation programme
(638337) for financial support. Funded by the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation)
under Germany´s Excellence Strategy – EXC 2033 – 390677874
– RESOLV.
When a 1:1 mixture of XB donor 4a and (PPh3)AuCl was prepared,
the same shift could be observed (Figure 5, c). This result
demonstrates again the observed activation of the Au-Cl bond,
which could be applied in the reactions demonstrated.
Finally, DFT calculations (M06-2X[42]-D3[43] def2-TZVP(D)[44] with
and without intrinsic solvation using SMD18[45] with parameters for
chloroform) were performed to obtain a first molecular picture of
the interaction of the strongest XB donor 4a with the gold complex.
In both cases, corresponding bidentate halogen bonded adducts
Keywords: supramolecular chemistry • noncovalent interactions
• halogen bonding • organocatalysis• gold
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COMMUNICATION
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10.1002/anie.202005214
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The activation of a gold-chloride complex by halogen-bonding-based Lewis acids is described as the first case of metal-ligand bond
cleavage by inert halogen bond donors. Iodine(I) and iodine(III) derivatives provided excellent performance in two proof-of-principle
reactions. Comparative experiments for both activators strongly suggest halogen bonding as the mode of activation.
6
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