Second-coordination sphere effects on the reactivities of Hoveyda-Grubbs-type catalysts: A ligand exchange study using phenolic moiety-functionalized ligands

Article abstract of DOI:10.1039/d0dt02353a

The Hoveyda-Grubbs (HG) second-generation catalyst (HG-II), a Ru complex with a 2-isopropoxybenzylidene ligand, is extensively used for olefin metathesis, the rearrangement of carbon-carbon double bonds. A well-known strategy to control its complex reactivity is to modify the phenyl ring in the ligand, thereby directly influencing the coordination of the phenolic oxygen to the metal center. We, herein, report that a functional group attached to the phenolic moiety in the 2-alkoxybenzylidene ligand can indirectly affect the reactivities of HG-type complexes. In this work, the ligand exchange reactions between HG-II and phenolic moiety-modified 2-alkoxybenzylidene ligands are useful for evaluating the structural effects of the ligands. Specifically, an ethylene amide or an ester group at the terminal phenolic moiety in the benzylidene ligand was found to influence the relative stabilities of HG-type complexes compared to that of the HG-II complex. The structural analyses proved that the observed effects of the functional groups on the complex stabilities originate from the interactions with a chlorido ligand in HG-type complexes without changes in coordination fashions at the metal centers. It was found that the outer-sphere interactions also influence the catalytic activities of HG-type complexes, namely, the properties of HG-type complexes can be controlled by outer-sphere structural factors toward the metal center (i.e., "the second-coordination sphere effect"). In the design of functionalized HG-type complexes, the outer-sphere structural effects need to be considered in addition to the optimization of the metal coordination site.

Full text of DOI:10.1039/d0dt02353a

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DOI: 10.1039/D0DT02353A
Second-coordination sphere effects on reactivities of Hoveyda–
Grubbs-type catalysts: A ligand exchange study using phenolic
moiety-functionalized ligands
Received 00th January 20xx,
Accepted 00th January 20xx
Catur Jatmika, Kenta Goshima, Kazumo Wakabayashi, Naoki Akiyama, Shun Hirota and Takashi
Matsuo*
DOI: 10.1039/x0xx00000x
The Hoveyda–Grubbs (HG) second-generation catalyst (HG-II), a Ru complex with 2-isopropoxybenzylidene ligand, is
extensively used for olefin metathesis, the rearrangement of carbon–carbon double bonds. A well-known strategy to control
its complex reactivity is to modify the phenyl ring in the ligand, thereby directly influencing the coordination of the phenolic
oxygen to the metal center. We, herein, report that a functional group attached to phenolic moiety in 2-alkoxybenzylidene
ligand can indirectly affect the reactivities of HG-type complexes. In this work, the ligand exchange reactions between HG-II
and the phenolic moiety-modified 2-alkoxybenzylidene ligands are useful for evaluating the structural effects of the ligands.
Specifically, an ethylene amide or an ester group at the terminal phenolic moiety in the benzylidene ligand was found to
influence the relative stabilities of HG-type complexes to HG-II complex. The structural analyses proved that the observed
effects of the functional groups on the complex staibilities originate from the interactions with a chlorido ligand in HG-type
complexes without changes in coordination fashions at the metal centers. It was found that the outer-sphere interactions
also influence the catalytic activities of HG-type complexes. Namely, the properties of HG-type complexes can be controlled
by outer-sphere structural factors toward the metal center (i.e., “second-coordination sphere effect”). In the design of
functionalized HG-type complexes, the outer-sphere structural effects are to be considered in addition to the optimization
of the metal coordination site.
contribute to the suitability of their stabilities but also enable
introducing various structural modifications in these ligands.6-8
Introduction
Both in the laboratory-level syntheses and industrial production
of fine chemicals, olefin metathesis, the rearrangement of
carbon–carbon double bonds, has gained increased
methodological importance for forming the skeletons of natural
products and pharmaceuticals in the presence of various
functional groups in the starting compounds.1, 2 Ru complexes,
with Grubbs catalysts3 as representative examples, are
extensively used metal catalysts for olefin metathesis, because
the metal complexes typically have high catalytic reactivities
with appropriate stabilities. The high affinity of a Ru center
toward olefins is also highly advantageous to regioselective
syntheses.4, 5 Particularly, the Hoveyda–Grubbs (HG) second-
generation catalyst (HG-II (1), see Fig. 1(a)) has frequently been
a research objective to investigate the structure-reactivity
relationship. This is because the N-heterocyclic carbene (NHC)
and 2-alkoxybenzylidene ligands in HG-type complexes not only
Fig. 1. (a) Chemical structures of the Hoveyda–Grubbs second-generation complex (1)
and its derivatives with a modified phenolic part (2–4’); (b) interaction mode between
the Ru center and the carbonyl oxygen in 4 or 4’; (c) cross-over reaction of HG-II (1) with
a 13C-labelled 2-isopropoxybenzilidene ligand.
Division of Materials Science, Graduate School of Science and Technology, Nara
Institute of Science and Technology (NAIST), Ikoma, Nara 630-0192, Japan. E-mail:
tmatsuo@ms.naist.jp
†Electronic Supplementary Information (ESI) available: [Experimental details,
crystallographic data, NMR spectral analyses for evaluation of complex stabilities,
NMR spectral changes in ligand exchange reactions, crystal structure of HG-II(1), IR
spectra in the entire measurement range, time-courses and NMR spectral change
for metathesis reactions, photographs of reaction solutions, and NMR spectra of
synthesized ligands and complexes]. See DOI: 10.1039/x0xx00000x
Motivated by the usability of HG-type complexes, several
research groups have developed various HG-type catalysts with
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functionalized ligands for application in syntheses in aqueous exchange with HG-II (1) (5-amide–11-ester). The selection of
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media as well as conventional syntheses in organic solvents.9-11 amide and ester groups was based on the frequent use of these
DOI: 10.1039/D0DT02353A
Furthermore, the applications of HG-type complexes have been functional groups as tethering groups to introduce additional
extended to the biochemical research field involving chemical building blocks and extend the linker. Based on of our ligand
13
modification of biomacromolecules12,
and development of exchange study using several 2-alkoxybenzylidene compounds,
biocatalysts with olefin metathesis activity.14-16
we found that the structure composed of a functional group and
One of the well-known strategies for optimizing the catalytic an ethylene linker at the ligand phenolic part determines the
reactivities of HG-type catalysts is through the modification of stabilities and reactivities in HG-type complexes through the
the phenyl ring in the 2-alkoxybenzylidene ligand. The second-coordination effect. This is a different method to control
introduction of electron-withdrawing groups, such as nitro and the properties of HG-type complexes from those reported until
ammonium groups, into the phenyl ring can directly regulate the now.
coordination of the ether oxygen to the Ru center, accelerating
the initial stage of the catalytic cycle.17,18 In this case, most of the
HG-type catalysts have an isopropoxy phenolic part, because the
bulkiness of the isopropyl group is believed to appropriately
regulate the coordination of the ether oxygen to the Ru center.
The above concept is supported by the fact that the replacement
of the isopropoxy phenolic part by an adamantyloxy group (2),
cyclopentoxy group (3) or other alkyl/alkoxy groups influences
the catalytic activity.19-21 Furthermore, some HG-type
complexes with a phenolic-moiety modified ligand control their
catalytic activities by direct interactions between the metal center
and a functional group attached to the phenolic moiety (the so-
23
called first-coordination sphere effect).22,
For example, an
acetate moiety at the phenolic moiety (4 and 4’) weakly
coordinates to the Ru center (Fig. 1(b)) to increase the ring-
closing metathesis (RCM) activity.22 In this case, the second
interaction of the ester carbonyl oxygen to the metal center in
addition to the coordination of the ether oxygen enhances both
the stabilities and reactivities of the catalysts. To decrease metal
contamination in products, N, O-dimethylhydroxylamide
(Weinreb amide) with high affinity toward silica gel in place of
acetate moiety was introduced into the phenolic moiety.24 As
presented above, the structural design for the alkoxy part in the
ligand will also increase the divergence in HG-type catalyst
derivatives. To evaluate the stabilities and metathesis reactivities
of HG-type complexes with the designed ligands, a suitable
platform reaction system is required. With this in mind, we
focused on a previous finding of the occurrence of a cross-over
Scheme 1. Ligand exchange between HG-II (1) and phenolic part-modified ligands.
Results and discussion
Syntheses of ligands and complexes
The synthetic routes of amide-type ligands (5-amide–8-
amide), ester-type ligands (9-ester–11-ester), and Ru
complexes with these ligands ([Ru]5-amide–[Ru]11-ester) are
presented in Schemes 2–4, respectively.
reaction
between
13C-labelled
and
unlabeled
2-
isopropoxybenzylidene ligands in HG-II (1) (see Fig. 1(c)).25
This reaction indicates that a ligand exchange can occur between
the 2-isopropoxybenzylidene ligand in HG-II (1) and a designed
benzylidene ligand. Motivated by this, we established a ligand
exchange study between functionalized 2-alkoxybenzylidene
compounds and HG-II (1) in a 1:1 mixture. Alkoxybenzylidene
ligands affording more stable HG-type complexes can be
expected to present high conversions in ligand exchange
reactions. The relative stabilities of the different complexes were
compared to that of HG-II (1).
In this study, we built a ligand library composed of 2-
alkoxybenzylidene ligands with a modified phenolic part
(Scheme 1), to reveal the structural determinants of the stabilities
and catalytic activities of HG-II derivatives possessing these
ligands. Particularly, we focused on the effects of amide and
ester bonds in the terminal phenolic group in 2-
alkoxybenzylidene compounds on the efficiencies of the ligand
Scheme 2. Synthesis of amide-type ligands.
To obtain the secondary amide ligands (5-amide–7-amide), the
Boc group in compound 15a or 15b was deprotected, followed
by acylation using acetic anhydride (for 5-amide and 6-amide)
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or pivaloyl chloride (for 7-amide). For the synthesis of the N- that the prepared complexes are stable in solutions under the
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DOI: 10.1039/D0DT02353A
methyl amide ligand (8-amide), the nitrogen atom in compound conditions over 24 h.
15a was methylated under a basic condition, followed by
removal of the Boc group. Finally, the secondary amine group
was acylated with acetic anhydride to afford compound 8-amide
as a mixture of cis/trans isomers in the N-methyl amide moiety22 Initially, we monitored the 1H-NMR spectral changes caused by
Ligand exchange reactions between HG-II complex and
modified 2-alkoxybenzylidene ligands
(1:2 ratio at 20 ˚C, see ESI for the NMR spectra).
the reaction of the HG-II complex (1) with ligand 5-amide to
The ester-type ligands (9-ester–11-ester) were synthesized confirm the occurrence of ligand exchange (see Fig.2 for the
from three halogenoalkyl acetate precursors (compounds 19– magnified spectra and Fig. S8(a) for the entire range of the
21). Sequentially, these compounds were subjected to spectra). For the determination of ligand exchange efficiency,
Williamson syntheses and Wittig reactions.
hexamethyldisiloxane (HMDSO, 4 mM) was contained in the
reaction solution as an internal standard.
On mixing the HG-II complex and 5-amide in a 1:1 ratio, the
benzylidene proton peak of HG-II (1) at 16.560 ppm (peak a)
gradually decreased along with the appearance of a new peak at
16.640 ppm (peak A). We assigned this new peak as the
benzylidene proton of the [Ru]5-amide complex, based on the
spectrum of [Ru]5-amide. The ligand moiety in [Ru]5-amide was
observed (featured by peaks D, E, and F). Another product, free
2-isopropoxybenzylidene ligand (iPr-L), was also detected by
the NMR signals at 1.36 ppm (peak B) and 4.54 ppm (peak C)).
At completion of the reaction after 24 h, we determined the
1
ratio of the two complexes using the intensities of H-NMR
peaks that are characteristic of each complex (See Fig. S8(b) for
relative integration values against HMDSO). From the signal
intensities of benzylidene protons (peaks a and A), the ratio of
HG-II(1) and [Ru]5-amide was evaluated to be 18:82. As a double-
check, we also determined the complex ratio on the basis of
signal intensities of the isopropyl-Me proton in HG-II(1) (peak
b) and acetamide methyl protons at the terminal of ligand in
[Ru]5-amide (peak D). A similar value was obtained (20:80). More
amount of [Ru]5-amide than HG-II(1) indicates that [Ru]5-amide is
more stable than HG-II(1). Some peaks with small intensities
near peaks B and D (peaks with asterisks in Fig. 2(c)) may derive
from the cross-metathesis products. A tiny signal at 5.4 ppm
(ethylene protons27) was also observed at 24 h. From the
calculated total amount of the two complexes (40–42 mM), the
percentage of metathesis products was estimated to be <5%;
namely, the observed spectral change is mainly associated with
the conversion from HG-II(1) into [Ru]5-amide. On the addition of
Scheme 3. Synthesis of ester-type ligands.
i
excess Pr-L (20 eq.) to the reaction mixture after 24 h, the
Scheme 4. Synthesis of Ru complexes.
intensity of peak A tended to decrease, in turn, peak a relatively
increased over the further 24 h (Fig. S9). During this period, the
isopropyl-CH proton in HG-II(1) (peak c) and free 5-amide
(featured by peaks d and e) recovered. The spectral change
displayed the back reaction from [Ru]5-amide to HG-II(1),
indicating that the spectral changes shown above reflects a
reversible process (i.e. equilibrium).
Next, we examined other 2-alkoxybenzylidene ligands for a
ligand exchange study to reveal the effects of the functional
groups in these ligands on the efficiency of the ligand exchange
reaction. Table 1 summarizes the ratio of HG-II(1) and
complexes produced by ligand exchange at 24 h. The time-
courses of the ratios of HG-II(1) between the complexes
produced by the ligand exchange) are illustrated in Fig. 3 (see
spectral changes in Figs. S10–S15).
The Ru complexes ([Ru]5-amide–[Ru]11-ester) were obtained from
the Grubbs second-generation catalyst (24) in the presence of
CuCl (Scheme 4).26 All the Ru complexes were isolable as green
complexes and stable in air. The moderate yields (45–52%,
except for that observed in [Ru]7-amide) were due to the
requirement of removal of unreacted ligands in purification
procedures. [Ru]8-amide was obtained as a mixture of cis/trans
isomers similar to the precursor ligand. The 1H-NMR spectrum
of the compound displayed two benzylidene proton peaks at
16.49 ppm and 16.51 ppm (ratio = 2:3; see ESI).
To evaluate the stabilities of these complexes in solutions,
1
we monitored H-NMR spectral changes for the complexes in
CDCl3 at 25 ˚C over 24 h (Fig. S1–S7) under a N2 atmosphere.
No appearance of new signals nor decrease in signal intensities
(with respect to an internal standard) were observed, indicating
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DOI: 10.1039/D0DT02353A
Fig. 2. Ligand exchange between HG-II (1) and ligand 5-amide ([HG-II (1)] = [5-amide] = 42 mM in CDCl3, 25 °C under N2). (a) Reaction scheme, (b) 400-MHz 1H-NMR spectral change
(downfield region), and (c) 400-MHz 1H-NMR spectral change (upfield region). The spectral changes in the entire region are presented in Fig. S8(a). The spectra of HG-II (1), [Ru]5-
i
amide, Pr-L, and 5-amide were collected separately as authentic samples for the comparison of the chemical shift. The signals with an asterisk (*) are ascribed to cross-metathesis
products (< 5%).
Table 1. Ratio of HG-II(1) and complexes produced by ligand exchange (HG-II(1) : product
complex at 24 h)a,b
5-amide
7-amide
6-amide
11-ester
Ratio value
determined from
10-ester
determined
iPr-Me protons in HG-II(1)
8-amide
Ligand
n
R1
R2
from
benzylidene
protons
and
Me (or tBu) protons in
product complexc
20 : 80
9-ester
5-amide
6-amide
7-amide
8-amide
9-ester
2
3
2
2
2
3
4
Me
Me
tBu
H
H
H
18 : 82
39 : 61
n.d.e
38 : 62d
23 : 77
Me Me
69 : 31
69 : 31
81 : 19
59 : 41
49 : 51
Me
Me
Me
H
H
H
n.d e
time /h
10-ester
11-ester
n.d e
52 : 48
Fig. 3. Time-courses of the complex ratio (HG-II (1) : complex produced by ligand
exchange); red: amide ligands; blue: ester ligands. Errors bars are drawn at 4%. Reaction
conditions: [HG-II (1)]/[ligand] = 1/1 (42 mM) in CDCl3 (sealed in a J-young NMR tube) at
25 °C under a N2 atmosphere in the presence of HDMSO (internal standard, 4 mM).
a[HG-II(1)]/[ligand] = 1/1 (42 mM) in CDCl3 (sealed in a J-young NMR tube) at 25 ˚C
under an N2 atmosphere in the presence of an internal standard
(hexamethyldisioxane (HMDSO, 4 mM). bDetermined from the relative integration
values based on the peak intensity of HMDSO (0.066 ppm). c To determine the
amount of product complexes, the peak intensities of methyl or tBu protons
at the terminal of a ligand in product complexes were employed. dThe peak of
terminal Me protons overlaps with that of methylene linker; Thereby, the peak
intensity was calculated as five protons (3H+2H). eNot determined due to overlap
of signals in HG-II(1) and product complexes.
In the reactions with the secondary amide-type ligands (i.e.,
RC(=O)NH-), 5-amide, 6-amide, and 7-amide, the percentages
of the complexes with these ligands among all the complexes in
the reaction system (corresponding to the ligand exchange
conversion) exceeded 50%. In contrast, all the ester ligands had
comparatively lower ratios. The final ratios of the formed
complexes reflect their relative stabilities compared to HG-II (1):
the ratio of >50% indicate that these complexes produced by the
ligand exchange reactions are more stable than HG-II (1). The
above finding indicates that a secondary amide group in the
phenolic moiety in HG-type ligands is essential for stabilizing
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their complexes, whereas an ester group will reduce their distances among HG-type complexes.19-21 However, in [Ru]6-
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DOI: 10.1039/D0DT02353A
and [Ru]10-ester (i.e., complexes with an n = 3 linker), the
stabilities. Focusing on the effects of the linker length (i.e., the
amide
distance between the phenolic oxygen atom and the amide (or Ru(1)–O(1) distances tend to be close to that in HG-II (1). The
ester) group) on the ligand exchange, we found that 5-amide (n observed tendency indicates that the long Ru(1)–O(1) bonds in
= 2) presented the highest ligand exchange efficiency among the [Ru]5-amide and [Ru]9-ester (n = 2) may be caused by any structural
ligands tested in this study; in contrast, 9-ester (n = 2) resulted factors at other places than their metal coordination site (for
in the lowest conversion. Thus, [Ru]5-amide and [Ru]9-ester are the example, the amide or ester moiety in the ethylene linker part).
most and least stable complexes, respectively, among the The dihedral angles of O(1)–C(8)–C(9)–N(1) (or O(2)) of [Ru]5-
complexes produced by ligand exchange reactions although the
and [Ru]9-ester are –64.38° and +77.95°, respectively, with
amide
respective linkers have the same length (n = 2). Another finding typical synclinal conformations (Figs 4(a) and 4(b)). The long
was that the ligand exchange conversions tended to be closer to linker length in [Ru]6-amide and [Ru]10-ester results in the increase
50% with long linker lengths (conversions at the final state: 5- in the dihedral angles. Particularly, [Ru]10-ester displays an anti-
amide (n = 2) ~ 7-amide (n = 2) > 6-amide (n = 3) |50%| 11- periplanar conformation, an ideally relaxed conformation.
ester (n = 4) > 10-ester (n = 3) > 9-ester (n = 2)). Concurrently,
Table 2. Selected structural information of Ru Complex crystalsa
the effect of the amide (or ester) group on the ligand exchange
efficiency diminished. Specifically, the length of the ethylene
Ru(1)-O(1)
distance /Å
Ru(1)-C(1)
distance /Å
Ru(1)-
carbene
carbon
Dihedral
angle along
C(8)–C(9)b
linker (n = 2) is a structural factor for reflecting the functional
group effect on the ligand exchange efficiency. Although their
linker lengths are identical (n = 2), 5-amide achieved a more
rapid ligand exchange than 7-amide, which is attributed to the
steric hindrance caused by the terminal function group in these
ligands (Me versus tBu group).
As an exception among the amide ligands, 8-amide, a tertiary
amide ligand (N-methyl amide), displayed a low ligand exchange
efficiency (~30%). Based on this finding, we assumed that an
amide proton (N–H) is essential for stabilizing the complexes.
An amide proton may form a hydrogen bond to interact with
another part in the complex, where the ethylene linker (n = 2) has
the ideal length for interacting effectively with an amide proton.
The corresponding structural investigation is described in detail
subsequently.
Ru
complex
distance /Å
–64.4(2)˚
(O(1)–C(8)–
C(9)–N(1))
[Ru]5-amide
(n = 2)
2.278(1)
2.277(1)
2.256(2)
2.245(2)
1.830(2)
1.831(2)
1.832(2)
1.830(2)
1.978(2)
1.978(2)
1.976(3)
1.981(2)
+77.9(2)˚
(O(1)–C(8)–
C(9)–O(2))
[Ru]9-ester
(n = 2)
+70.0(3)˚
(O(1)–C(8)–
C(9)–C(10))
[Ru]6-amide
(n = 3)
+179.5(2)˚
(O(1)–C(8)–
C(9)–C(10))
[Ru]10-ester
(n = 3)
2.233(2)
2.261(3)c
1.832(2)
1.828(5)c
1.975(2)
1.981(5)c
X-ray crystallographic analysis: Structural effect of amide group
on complex stability
HG-II(1)
–
To clarify the effects of an ethylene amide/ester moiety on ligand
exchange efficiency (i.e. the stabilities of the above-mentioned
complexes) we, firstly, conducted single crystal structural
analyses for [Ru]5-amide (n = 2; amide), [Ru]9-ester (n = 2; ester),
[Ru]6-amide (n = 3; amide), and [Ru]10-ester (n = 3; ester), (Fig. 4).
Detailed crystallographic parameters and structure refinements
are summarized in Table S1. For structural comparison, we also
analyzed the structure of HG-II (1) under the same crystallization
solvent system and diffraction collection temperature as those
used for the crystallization of the above-mentioned four
complexes (Fig. S16 and Table S1). Selected structural
information (distances between the Ru center and the atoms
coordinating to it and the dihedral angles along C(8)–C(9) axis)
is provided in Table 2.
The overall coordination geometries around the metal centers
in the four Ru complexes are similar to that in HG-II (1) (see the
Ru(1)–C(1) and Ru(1)–carbene carbon distances). Against HG-
II(1), [Ru]5-amide and [Ru]9-ester have the opposite relative
stabilities. However, these two complexes have similar Ru(1)–
O(1) distances (see Table 3) with the larger distance observed in
HG-II (1). The similar bond distances in these complexes are not
unusual because several previous works reported that the Ru(1)–
O(1) strengths do not always correlate with the Ru(1)–O(1) bond
aCrystals were obtained by vapor diffusion of hexane into a CHCl3 solution at 5 ˚C.
X-ray diffraction was collected at 125 ± 0.1 K. bSign (+ or –) was defined along the
axis direction from C8 to C9, where “+” and “–” were defined in the counter
clockwise and clockwise directions, respectively. cRef.26; Diffraction was collected
at 273 K.
Focusing on the amide moiety in [Ru]5-amide (see Fig. 4(b)),
we found that the spatial distance between N(1) and Cl(1) is
3.233 Å, corresponding to the sum of the van der Waals radii of
nitrogen and chlorine atoms (N: 1.50 Å; Cl: 1.75 Å). The small
distance between the two atoms indicates the occurrence of any
interaction between these atoms. On the basis of the geometry
around N(1) atom, the amide hydrogen (N–H) is assumed to turn
to Cl(1) (not exactly determined by the X-ray crystallography).
Therefore, one possible interaction occurred at this site is the N–
H•••Cl hydrogen bonding. Several reports have presented the
stabilization of metal complexes through intramolecular N–
H•••Cl hydrogen bonding,28, 29 where N–Cl distances are 3.1–3.4
Å and estimated N–H–Cl angles are in the range from 135˚ to
170˚. The estimated N–H–C angle of [Ru]5-amide (150.96˚) is
within this range (see magnified figure around the amide moiety
in [Ru]5-amide in Fig. S17).
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most of type-I XB units have |1–2| values of < 20º. The
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Cl
a)
Ru1
calculated values of |1–2| and |1–2’| DfoOrI: [1R0.u10]359-a/mDi0deDTa0r2e35to3oA
large as a type-I XB geometry. Furthermore, if XB occurred
between Cl(1) and N(1), 8-amide with an N-Me amide moiety
(more electron-donating characteristic) would also form XB with
Cl(1). However, the ligand exchange data (Table 1 and Fig. 3)
presented above do not indicate the interaction with Cl(1) atom.
The possibility of Cl(1)•••N(1) XB cannot be completely ruled
out; however, the N–H•••Cl hydrogen is more likely as an
interaction between the amide moiety in [Ru]5-amide. The
interaction may cause the amide nitrogen to adopt a position with
a small O(1)–C(8)–C(9)–N(1) dihedral angle (close to the
Gauche form).
Cl1
H
O1
N1
H
H
C
H
H
O
C(12)
Ru(1)
Cl(1)
C(1)
3.233 Å
Cl(2)
N(1)
O(1)
C(10)
C(9)
C(8)
b)
Cl
Ru1
Cl1
O1
O2
H
H
C
O
H
H
In contrast, the ester oxygen atom (O(2)) in [Ru]9-ester was
found to turn away from the direction of Cl(1) so as to avoid the
electrostatic repulsion with the chlorido ligand. The synclinal
conformation observed in [Ru]9-ester is a result of the avoidance
of the steric hindrance between the ester carbonyl group and the
NHC phenyl ring in the periplanar conformation.
C(12)
Ru(1)
C(1)
Cl(1)
Cl(2)
C(9)
O(2)
O(1)
C(8)
Investigation of N–H ••• Cl hydrogen bonding in solution
Cl1
c)
Ru1
O1
Cl2
To confirm that N–H•••Cl hydrogen in [Ru]5-amide also occurs in
solutions (i.e., it is not caused by the crystal packing factor), we
investigated the N–H/D exchange velocity in 5-amide and [Ru]5-
C10
H
H
H
H
C(13)
Cl(1)
Cl(2)
by 1H-NMR spectral monitoring. The NMR spectral
amide
Ru(1)
C(1)
changes in the presence of D2O are depicted in Fig. 5.
C(10)
C(9)
O(1)
C(8)
H
N(1)
*
b)
*
a)
H
H
[Ru]
O
H
O
O
O
N
N
H
H
*
*
d)
Cl1
Ru1
O1
Cl2
20 h
4 h
H
H
H
80 min
30 min
H
C10
C(13)
Ru(1)
1 h
0 h
Cl(1)
7 min
0 min
Cl(2)
C(1)
C(9)
*
*
C(10)
*
*
O(1)
C(8)
O(2)
chemical shift /ppm
chemical shift /ppm
c)
Fig. 4. ORTEP figures of (a) [Ru]5-amide, (b) [Ru]9-ester, (c) [Ru]6-amide, and (d)
[Ru]10-ester. The structures on the right of each figure show the local structures
around the Ru centers. Thermal ellipsoids are drawn at 50% probability level.
In the magnified structure of figure (a), the amide hydrogen was assumed
according to the geometry around atom N(1).
[Ru]5-amide
Another possibility of an interaction at the amide moiety is
N–Cl halogen bonding (denoted as XB).30 In general, XB is
classified into two types according to geometries of an XB donor
and acceptor; type-I (cis/trans) and type-II.31 Assuming the
occurrence of XB at this site, we can raise two possibilities of
XB on the basis of the local geometry around the site: cis-type-I
XB (Ru(1)–Cl(1)•••N(1)–C(9)) and trans-type-I XB (Ru(1)–
Cl(1)•••N(1)–C(10)). The Ru(1)–Cl(1)–N(1) dihedral angle (=
1) is 79.83º. The Cl(1)–N(1)–C(9) and Cl(1)–N(1)–C(10)
dihedral angles (defined as 2 and 2’, respectively) are 109.31º
and 124.59º, respectively (see Fig. S17). Namely, |1–2| = 29.5º
and |1–2’| = 44.8º. According to several examples of XBs,32
Ligand 5-amide
time /min
Fig. 5. 400-MHz 1H-NMR spectral changes (in CDCl3, 600 L) involving the H/D exchange
on the addition of D2O (1% (v/v)) at 25 °C under N2 atmospheres: (a) ligand 5-amide (0.02
M) and (b) complex [Ru]5-amide (0.02 M). (c) Time-courses of the relative intensities of the
N–H proton signals (marked in red or blue asterisk in (a) and (b)) to the peak intensities
of an unexchangeable proton (marked in black asterisk in (a) and (b)).
The amide proton peaks in 5-amide and [Ru]5-amide appear at
5.78 ppm and 7.21 ppm, respectively. The above comparatively
6 | J. Name., 2012, 00, 1-3
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higher chemical shifts observed for [Ru]5-amide suggest that its amide vibration analyses presented above proveVitehwaAtrticthleeOnNlin–e
amide proton participates in a strong hydrogen bonding. The H•••Cl hydrogen bonding occurs both in tDhOeIc: 1ry0.s1t0a3l9a/Dn0dDsTo0l2u3t5io3An
time-courses of the H/D exchange reactions were monitored states. The N–H•••Cl hydrogen bonding in [Ru]5-amide
using the peak intensity ratio of the amide proton in each contributes to complex stabilization. The stabilization effect
compound and a non-exchangeable proton (an olefin proton in decreases with increase in the linker length. The electrostatic
5-amide observed at 5.26 ppm; the benzylidene proton in [Ru]5- repulsion in [Ru]9-ester is a main factor that the decrease in the
at 16.64 ppm). The half-time values of the H/D exchange relative stability of this complex toward HG-II(1). The
amide
observed for 5-amide and [Ru]5-amide are 12 min and 63 min, enhancement of the ligand exchange efficiency with increasing
respectively. The deaccelerated N–H/D exchange in [Ru]5-amide linker length in the series of ester-type Ru complexes is
is indicative of a hydrogen bonding involving the amide proton. attributed to the diminishment of this electrostatic repulsion
The chemical shifts of the amide protons in the amide-type between the ester oxygen and the chlorido ligand that
Ru complexes are ranked as [Ru]5-amide (7.21 ppm) > [Ru]8-amide coordinates to the Ru center.
(7.12 ppm) > [Ru]7-amide (6.53 ppm), consistent with the order of
the ligand exchange efficiency. In addition, this finding proves
that the N–H••• Cl hydrogen bonding also occurs in solution.
Effects of ethylene amide/ester moiety in ligand on catalytic
activities.
Complexes [Ru]5-amide and [Ru]9-ester commonly have an
Amide-I
ethylene linker at their benzylidene ligand moieties and exhibit
similar Ru-O distances. However, the complexes showed a
distinctly opposite tendency in the relative stability against HG-
II(1), which is caused by the structural factors that are seen apart
from the Ru center. In this view, our next concerns will be the
effects of these structural factors on their catalytic activities.
Accordingly, we conducted some metathesis reactions to
compare the reactivities of these complexes with that of HG-II(1)
to explore effects of the amide or ester group in [Ru]5-amide (the
most stable complex) and [Ru]9-ester (the least stable complex) on
their catalytic activities, (Table 3).

(N-H)
Amide-II
1669
1662
3452
3317
1520
1545
5-amide
20%(T)
[Ru]5-amide
HG-II(1)
We, at first, carried out the ring-closing metathesis (RCM) of
compound 25 to coumarin 26 at 5 mol% catalyst loading because
the moderate rate of this reaction enables us to readily conduct
the comparison of the reactivities between the complexes.33 The
time-courses of the RCM products and the NMR spectral
changes observed in the [Ru]5-amide-catalyzed reaction are
displayed in Fig. S19, as a representative example of the
monitored RCM reactions. All the three Ru complexes exhibited
the RCM cyclization activity for compound 25 with final yields
of >94% at 5 mol% catalyst load (Entries 1–3 in Table 3). The
reaction velocities follow the order, [Ru]9-ester > HG-II(1) >
wavenumber /cm1
Fig. 6. FT-IR spectra of 5-amide, [Ru]5-amide, and HG-II (1) in CHCl3 (resolution of 0.5 cm–1
,
L = 0.5 mm, CaF2 window, accumulation number: 256). Each spectrum is obtained by
subtracting the background spectrum of chloroform from the corresponding collected
spectrum of the ligand or complex.
We also investigated the N–H•••Cl hydrogen bonding in
terms of the bond characteristics of the amide moiety via Fourier
transform infrared (FT-IR) spectroscopy. Fig. 6 depicts the FT-
IR spectra of 5-amide, [Ru]5-amide, and HG-II (1) (see the spectra
over the entire measurement range in Fig. S18). In the low-
wavenumber range, the bands at 1660–1670 cm–1 and 1520–
1550 cm–1 observed in 5-amide and [Ru]5-amide are assigned as
amide-I ((C=O)) and amide-II (coupling of (C–N) and (N–
H)), respectively. This assignment is confirmable by comparing
their spectra to that of HG-II (1) (without an amide bond in the
structure). Complex [Ru]5-amide presents a decrease in frequency
of the C=O vibration with an increase in the frequency of the C–
N vibration coupled with N–H bending. This indicates that the
N–H•••Cl hydrogen bonding enhances the contribution of the
C=N bonding character in the amide bond. The perturbation of
the N–H bonding is remarkably reflected in the high-
wavenumber region, where the amide N–H stretching ((N–H))
of [Ru]5-amide appears at 3317 cm–1, whereas the (N–H) of
ligand 5-amide is 3452 cm–1. The complete red-shift of  (N-H)
observed in [Ru]5-amide suggests that there is significant N–
H•••Cl hydrogen bonding in the solution structure. The series of
crystallographic investigation, H/D exchange kinetics, and
[Ru]5-amide
.
The slower velocity in the [Ru]5-amide-mediated reaction,
compared to other two catalysts, was also observed in the
reaction of N-tosyldiallylamide 27 (Entries 4–6 in Table 2). One
possible reason of the slow [Ru]5-amide-catalyzed reactions is that
the N–H•••Cl hydrogen bonding in [Ru]5-amide deaccelerates the
exchange between the 2-alkoxybenzilidene ligand and a
substrate molecule. However, the existence of several pathways
at the initiation step in HG-type catalyst-mediated reactions has
been known (denoted as dissociative and associative/interchange
pathways).34-36 The contribution of these pathways depends on
substrate concentrations (i.e. the relative ratio of catalyst to
substrate). To investigate this matter, we conducted the RCM
reaction at low catalyst load (0.1 mol%; Entries 7–9 in Table 3;
see the time-courses of the [Ru]5-amide-catalyzed reaction in Fig.
S20). All the complexes showed the final yields of >90%. The
order of reaction velocity (evaluated by the yield the initial
phase) was [Ru]9-ester > HG-II(1) > [Ru]5-amide, which is the same
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Journal Name
tendency as that seen in the reaction of compound 25 with 5
View Article Online
DOI: 10.1039/D0DT02353A
mol% catalyst load (Entries 1–3 in Table 3).
Table 3. RCM activities of [Ru]5-amide, [Ru]9-ester, and HG-II(1)a,b
Entry
1
Substrate
Product
Catalyst
[Ru]5-amide
Reaction conditions
5 mol%; 25 ˚C
Yield(%)c
15 (2 h); 94 (54 h)
83 (2h); 95 (24 h)
53 (2 h); 99 (24 h)
30 (0.5 h); >99 (7 h)d
>99 (0.5 h)d
O
O
2
[Ru]9-ester
HG-II(1)
5 mol%; 25 ˚C
5 mol%; 25 ˚C
5 mol%; 25 ˚C
5 mol%; 25 ˚C
5 mol%; 25 ˚C
0.1 mol%; 25 ˚C
0.1 mol%; 25 ˚C
0.1 mol%; 25 ˚C
5 mol%; 45 ˚C
5 mol%; 45 ˚C
5 mol%; 45 ˚C
1 mol%; 25 ˚C
O
O
26
3
25
4
[Ru]5-amide
[Ru]9-ester
HG-II(1)
Ts
N
5
Ts
N
6
>99 (0.5 h)d
27
28
7
[Ru]5-amide
[Ru]9-ester
HG-II(1)
11 (0.5 h); 91 (24 h)
85 (0.5 h); >99 (24 h)d
63 (0.5 h); >99 (24 h)d
>99 (0.5 h)d
8
9
10
11
12
13
[Ru]5-amide
[Ru]9-ester
HG-II(1)
>99 (0.5 h)d
>99 (0.5 h)d
O
O
O
O
[Ru]5-amide
31e: 19 (2 h); 37 (24 h)
32e: < 5 (2 h); 5 (24 h)
O
O
O
O
31
30
29
14
15
[Ru]9-ester
HG-II(1)
1 mol%; 25 ˚C
1 mol%; 25 ˚C
31e: 54 (2 h); 61 (24 h)
32e: 7 (2 h); 8 (24 h)
O
(29 : 30 = 1 : 2)
O
31e: 48 (2 h); 74 (24 h)
32e: 5 (24 h); 6 (24 h)
2
32
a[substrate] = 42 mM in CDCl3 in the dark at a N2 atmosphere. bReaction was conducted in a J-young tube (Entries 1–10) or in a Schlenk tube (Entries 11–12). cDetermined by 1H NMR
measurements for a reaction mixture that contains an internal standard (Entries 1–3 and 13–15: HMDSO (4 mM, H 0.066 ppm), Entries 4–12: toluene (42 mM, H 2.356 ppm)).
dStarting material cannot be precisely quantified because of tiny peaks on 1H NMR spectra. eE/Z > 20/1.
Considering the intrinsically higher stability of [Ru]5-amide reactions mediated by the other two complexes. Eventually, the
than the other two complexes, the most possible mechanism to product yield in the [Ru]9-ester-catalyed reaction was lower than
explain the results of catalytic activity measurements is that the that mediated by HG-II(1) reaction.
slow velocities of [Ru]5-amide-mediated reactions are
At first glance, [Ru]5-amide seems to have a drawback in terms
predominantly caused by the slow dissociation of the of the reaction velocity. However, during the reaction of
benzylidene ligand in [Ru]5-amide at the initial phase. The slow compound of 27 at 45 ˚C, we found that the reaction mixture with
initiation of catalytic reaction is led by the interaction between [Ru]5-amide after the complete of the reaction still kept green in
the amide moiety and a chloride ligand. The interaction will color (a characteristic in HG-type complexes), whereas the
decrease at higher temperatures. In fact, [Ru]5-amide also showed solution with [Ru]9-ester had turned to brown (indicative of
a comparable reactivity to the other two complexes at 45 ˚C, degradation) (Fig. S22). The relative stability of [Ru]5-amide at
where the reaction completed at 0.5 h (cf. Entries 4 and 10). At room temperature is higher than HG-II(1). Although we need to
the temperature, the exchange of the benzylidene ligand with a investigate in detail, our finding regarding the color change
substrate molecule can be facilitated. On the other hand, [Ru]9- would suggest the potential of [Ru]5-amide as a durable catalyst
ester showed the faster initial velocities than HG-II(1) in all cases that can be thermally activated.
of RCM reactions (cf. Entries 2 and 3; Entries 8 and 9; Figs. S19
and S20). As described above, the ester oxygen atom (O(2))
adopts the positioning to turn away from the metal center (see
Regulation of HG-type complex properties through second-
coordination sphere effects
Fig. 4(d)). The acceleration observed in [Ru]9-ester may also be Previous studies on HG-type complex-mediated olefin
explained by the electrostatic repulsion between the oxygen atom metathesis reactions have mainly focused on the coordination
and a chlorido ligand. The conformation will promote the properties at the Ru center to discuss the reactivities of the
dissociation of the benzylidene ligand moiety, leading to the complexes. However, the stability and catalytic activities of
facilitation of initial phase in catalytic reactions.
[Ru]5-amide and [Ru]9-ester are determined by the interactions at
The slow initial reaction for [Ru]5-amide was also observed in rather far from the reaction site, which is a different mechanism
cross-metathesis (CM) reaction between compound 29 and 30 from that reported in previous studies.
(Entries 13–15). In the [Ru]9-ester-catalyed CM reaction, the
The N–H•••Cl hydrogen bonding in [Ru]5-amide and the
initial CM production (compounds 31/32) was higher than that electronic repulsion between the ester moiety and a chlorido
mediated by HG-II(1). However, we observed that the change in ligand in [Ru]9-ester affect the stabilities and reactivities of these
solution color (green to brown) was significant compared to the complexes, where these structural factors indirectly influence the
8 | J. Name., 2012, 00, 1-3
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reactivities of their Ru centers. The structural effect is known as KAKENHI Grant Number JP19H05395) and a Grant-in-Aid for
View Article Online
“second-coordination sphere effect”, and the above-presented Scientific Research (C) (JSPS KAKENDOHII: 10G.10ra39n/tD0DNTu0m23b53eAr
findings indicate that the properties of metathesis catalysts can JP17K01947). C. J. acknowledge Faculty of Pharmacy, University
be affected by second-coordination sphere effects as well as the of Indonesia for granting permission to him to study in NAIST,
characteristics of ligands that directly coordinates to the mental Japan. The authors acknowledge Yoshiko Nishikawa for support
center. The attachment of a functional group to the phenolic of mass analyses and Shohei Katao for X-ray crystallographic
moieties in HG-type complexes enables tuning its effects on their analyses.
metal center reactivities, with the linker length between the
phenolic oxygen atom and the introduced functional group being
crucial. The importance of the linker length emerged as a
Notes and references
mechanistic difference between [Ru]5-amide/[Ru]9-ester and
compounds 4/4’ (comparison of the structural influences
displayed in Figs.1(b) and 4). Thus, a change in the linker length
may switch the mechanism for controlling the reactivities of HG-
type complexes (i.e., between first- and second-coordination
sphere effects).
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Conclusion
In Hoveyda-Grubbs-type complexes with a modified 2-
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manner of coordination around the metal center. This fact is a
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In this study, the ligand exchange reaction between the HG-
II complex and a designed 2-alkoxybenzylidene ligand was
found to be useful for evaluating the stability of the complex with
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the ethylene linker extending from the phenolic oxygen
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on the metal center are due to structural factors at the outer
sphere (i.e. second-coordination sphere effects). The catalytic
activities were also influenced by the functional group at the
terminal of the phenolic moiety in the ligand. Therefore, in
functionalization of metathesis-mediating catalysts, second-
coordination sphere effects should be taken into consideration as
one important factor to determine the reactivities of catalysts,
along with traditionally discussed factors such as the
coordination fashion to the metal center.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by a Grant-in Aid for Scientific
Research on Innovative Areas “Molecular Engine” (JSPS
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Dalton Transactions
View Article Online
DOI: 10.1039/D0DT02353A
TOC one sentence
The reactivities of Hoveyda-Grubbs-type complexes are modulable through second-
coordination sphere effects caused by a functional group in the ligand.