Ruthenium Removal Using Silica-Supported Aromatic Isocyanides

Article abstract of DOI:10.1016/j.jorganchem.2021.121800

New silica gel scavengers containing aromatic isocyanides have been synthesized and evaluated for Ru removal. A thiol-ene click reaction was used to attach the isocyanide precursor to a thiol-containing siloxane. Conventional methods for grafting to silica gel at elevated temperature resulted in significant hydrolysis of the isocyanide. A novel cleavage reaction was developed to quantitate the amount of surface-loaded isocyanide. Binding by the new materials was comparatively evaluated for a variety or Ru carbene catalysts. The optimal conditions were extended to two ring-closing metatheses (RCM). The residual Ru was determined by inductively coupled plasma mass spectrometry (ICP-MS). For facile RCM reactions, the UV data agreed with the ICP-MS results. However, more difficult RCM did not correlate well with the UV data. This was interpreted in terms of varying extent of catalyst decomposition. In all cases, isocyanide scavenger reagents were found to be superior to commonly used, silica gel-based metal scavengers.

Full text of DOI:10.1016/j.jorganchem.2021.121800

Journal of Organometallic Chemistry 944 (2021) 121800
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Ruthenium Removal Using Silica-Supported Aromatic Isocyanides
∗
Zackary R. Gregg, Elise Glickert, Ruoshui Xu, Steven T. Diver
Department of Chemistry, University at Buffalo, the State University of New York
a r t i c l e i n f o
a b s t r a c t
Article history:
New silica gel scavengers containing aromatic isocyanides have been synthesized and evaluated for Ru re-
moval. A thiol-ene click reaction was used to attach the isocyanide precursor to a thiol-containing silox-
ane. Conventional methods for grafting to silica gel at elevated temperature resulted in significant hy-
drolysis of the isocyanide. A novel cleavage reaction was developed to quantitate the amount of surface-
loaded isocyanide. Binding by the new materials was comparatively evaluated for a variety or Ru carbene
catalysts. The optimal conditions were extended to two ring-closing metatheses (RCM). The residual Ru
was determined by inductively coupled plasma mass spectrometry (ICP-MS). For facile RCM reactions, the
UV data agreed with the ICP-MS results. However, more difficult RCM did not correlate well with the UV
data. This was interpreted in terms of varying extent of catalyst decomposition. In all cases, isocyanide
scavenger reagents were found to be superior to commonly used, silica gel-based metal scavengers.
Received 2 March 2021
Revised 23 March 2021
Accepted 26 March 2021
Available online 1 April 2021
Keywords:
Metal scavenger
Grubbs complexes
isocyanide
Ru removal
thiol-ene reaction
©
2021 Elsevier B.V. All rights reserved.
1
. Introduction
the removal of Pd in cross couplings. Both Ru [1a] and Pd [1b]
could be removed to ppm levels, usually with only a filtration
step (Scheme 1a). Subsequently, Grela and co-workers developed
soluble isocyanides for similar purposes (Scheme 1b) [3]. These
tertiary amine-containing isocyanides were shown to react with
a variety of Grubbs catalysts to form highly polar isocyanide-Ru
complexes. The most studied tertiary amine-containing scavenger,
C, was shown to effectively remove Ru to ppm levels from a
ring-closing metathesis (RCM). [3a] Though soluble isocyanides are
effective, the need exists for improved solid-supported reagents,
since simple bed filtration is a validated and scalable process that
is used in industry. Simple filtration is an attractive purification
step for any metal-catalyzed reaction.
From a sustainability and cost perspective, removal and recov-
ery of metal catalysts from crude reactions is significant for the
recycling of precious metal catalysts. For the organic or medicinal
chemist, recovery of the metal also facilitates purification of the or-
ganic products which may need to be completely metal free for bi-
ological studies. Even within families of catalysts like Ru carbenes
(
Grubbs catalysts) and Pd-phosphine complexes, variation of lig-
ands can dramatically alter reactivity with organic substrates and
scavenger materials. Not surprisingly, a wide range of scavenger
agents have emerged to address this problem. In particular, silica
gel-supported reagents are desirable due to their low cost, robust-
ness and ease of retrieval. At the end of a reaction, the starting
metal catalyst ends up as several different species, so an effective
scavenger must capture all of these. Effective scavengers can also
be used as quenching agents in the best cases by rapidly arresting
a chemical reaction to facilitate the analysis of reaction mixtures
and for kinetic studies. Understanding the rate of scavenger bind-
ing helps with the selection of the appropriate metal scavenger.
We recently developed isocyanides as scavengers for late tran-
sition metals such as Pd and Ru [1]. Isocyanides are strongly bind-
ing ligands which are isoelectronic to CO. We found that these pi-
acid ligands arrested metathesis reactions instantly and caused a
Buchner reaction in Ru carbene complexes [2]. The silica-supported
reagent, B, containing an alkyl isocyanide, proved effective for
Previously reported kinetic analysis of a Buchner reaction found
that aryl isocyanides reacted faster than alkyl isocyanides [4]. Aryl
isocyanides have optimal σ donor / π acceptor properties which
allow rapid binding to the Ru and result in a fast Buchner reaction.
Since a diverse array of Grubbs catalysts are used for catalytic
olefin metathesis applications, the ideal metal scavenger must
work effectively for them all, or it must be delineated which com-
binations of catalyst and scavenger are best. The Hoveyda-Grubbs
type precatalysts (Ru1-6), indenylidene-containing catalysts, (Ru2,
Ru8-10) and the Grubbs catalyst (Ru7) were studied to determine
how structural effects impacted the effectiveness of Ru removal us-
ing silica-supported aromatic isocyanides (Scheme 2).
In this work, new silica gel scavengers containing aromatic iso-
cyanides were evaluated for Ru removal from a range of commonly
used Grubbs metathesis catalysts. A motivation of this work was
to develop a faster screening assay to find optimum combination
∗
Corresponding author
E-mail address: diver@buffalo.edu (S.T. Diver).
https://doi.org/10.1016/j.jorganchem.2021.121800
0
022-328X/© 2021 Elsevier B.V. All rights reserved.

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
a) Soluble (A) and silica-supported (B) isocyanides
R
H
R
(
our previous work)
H
N
N
H
(
a)
H
A and B ppm Pd
O
Pd catalysts
Ru catalysts
O
Initial:
After:
25300
<1
O
O
R
NC
n
O
R
KO
n
A
S
Si(OEt)3
2
a-c
3a-c
(b)
A
ppm Pd
1552
1.2
O
Si
O
O
NC
Initial:
After:
B
R
R
NC
Silica-supported
NC
R
(
c)
B
Initial:
After:
108
5.7
O
R
O
A - chromatography; B - filtration
n
O
n
b) Soluble tertiary amine isocyanides
S
Si
O
S
Si(OEt)3
(
C-E, Grela and coworkers)
O
1
a-c
4a-c
NC
N
a: R = H, n = 1;
b: R = CH , n = 1; 1b: 90% isocyanide, 0.20 mmol/g isocyanide
c: R = H, n = 9;
1c: 96% isocyanide, 0.26 mmol/g isocyanide
1a: 93% isocyanide, 0.22 mmol/g isocyanide
N
3
C
ppm Pd
4938
CN
C
Ru catalysts Initial:
O
After silica plug: 82
CN
CN
Conditions: (a) 3-mercaptopropyltriethoxysilane, Irgacure 651 (2 mol%),
rt; (b) POCl , Et N, THF, -78 ˚C to 0 ˚C; (c) silica, Et N, benzene, rt
N
D
C-E
Initial:
ppm Pd
334
3
3
3
NC
NC
After silica plug: <1
Scheme 3. Synthetic scheme and intermediates for silica-supported aryl iso-
N
cyanides.
E
c) New silica-supported aromatic isocyanides (this work)
R
then used for Ru removal from two catalytic ring-closing metathe-
sis reactions (RCMs), which were quantitated by inductively cou-
pled plasma-mass spectrometry (ICP-MS). Overall, we found that
the new isocyanide materials were highly effective scavengers and
the developed UV assays were useful for reaction optimization and
for the comparison of materials, but these assays alone could not
quantitatively predict the effectiveness of Ru removal.
NC
O
O
Si
S
O
R
O
n
1
a R = H, n = 1; 1b R = CH , n = 1; 1c R = H, n = 9
3
Scheme 1. Soluble, supported and new isocyanide-based scavengers for Ru removal
from catalytic reactions such as ring-closing metathesis (RCM).
2. Results and Discussion
2
.1. Synthesis of materials
of scavenger and metal catalyst. In the grafting process, hydrolysis
was found under standard grafting conditions. This required a new
procedure to quantitate isocyanide and with this, grafting condi-
tions were optimized. Ultimately, the results from the UV assay al-
lowed for the selection of the best scavenger materials which were
Silica-supported
isocyanides
were
synthesized
by
a
scalable thiol-ene reaction (Scheme 3). In all cases, 3-
mercaptopropyltriethoxysilane served as the thiol, which could be
grafted to the silica surface. Aryl formamides 2a-c bearing pendant
N
N
N
N
N
N
N
N
N
Cl
Ru
Cl
Ru
Cl
Ru
Cl
Ru
Cl
N
Ph
Cl
Ru
Cl
PCy3
Ru2
Cl
Cl
Cl
O
O
H
O
H
O
t-Bu
t-Bu
Ru1
Ru3
Ru4
Ru5
N
N
Cl
Ru
Cl
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Cl
Ru
Cl
Cl
Ru
Cl
PPh3
Ru9
Cl
Ru
i-PrO) P
O
Ru
t-Bu
Cl
Ph
Cl
(
3
H
PCy3
PPh3
Ru8
Cl
Ru10
Ru6
Ru7
Scheme 2. Ru carbenes analysed by UV and ICP-MS assays.
2

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
Table 1
Stability of Ru carbenes on silica gel.
R
X
R
Entry
RuX
Percent bound(a)
X
R
(
b)
1
2
3
4
5
6
7
8
9
Ru1
Ru2
Ru3
Ru4
Ru5
Ru6
Ru7
Ru8
Ru9
Ru10
8 ± 3
O
R
O
(a)
n
3
O
-1
4
n
S
Si
O
Y
2
1
a-c
O
Solution-phase products
analyzed by H NMR
1
1
70 (76)(c)
38
71 (94)(c)
X = NC or NCHO; Y = SCN or Br
1
0
93
Conditions: (a) 1) crushed 4 Å mol. sieves, CD CN, rt, overnight;
3
2
) BrCN, CD CN, 60 ˚C, 2 h
3
the relative binding kinetics of soluble isocyanides 4a and 4b with
Ru1 and Ru2 [10]. Consumption of the ν(C≡NAr) absorbance at
Scheme 4. Cyanogen bromide cleavage of thioethers.
−1
2
120 cm resulted in the formation of a new Ru-C≡N isocyanide
−1
alkenes were the partners for the click reaction. Following the
procedure of Garrell and co-workers, [5] the thiol and alkene were
coupled to give quantitative yields of thioethers 3a-c. A subse-
quent dehydration step provided isocyanides 4a-c in good yields
after chromatography. Last, grafting siloxane monomers onto silica,
followed by extensive washing, gave the silica-supported materials
stretch between 2098-2109 cm
(Fig. S5). Treating 3 equiv iso-
cyanides with Ru carbenes then monitoring the formation of Ru-
isocyanide complex provided insight into relative reactivity rates
(Fig. 2 and Fig. S6). For Ru2, a modest difference in rate was seen
in the first 15 min at 0 ˚C, and no difference was seen at room
temperature. Although 4a and 4b are sterically unique, there was
only a minor difference in reactivity between these isocyanides.
1a-c.
2
.2. Determination of isocyanide loading
2
.4. UV Binding studies and comparisons of new materials
Pure isocyanides 4a-c were grafted onto silica gel, however the
Following kinetic analysis by in situ FT-IR, we developed a UV
silica-supported materials 1a-c were found to contain a mixture
of isocyanide and formamide. Diffuse Reflectance Infrared Fourier
Transform spectroscopy (DRIFT IR) provided a qualitative assess-
ment of isocyanide purity (Fig. 1). Analysis of silica gel materials
by DRIFT-IR showed the presence of the isocyanide and formamide
assay to monitor the reaction of silica-supported isocyanides. Fig.
S8 shows the time course of Ru1 removal up to 2 h using iso-
cyanide 1a as determined by UV. To rapidly analyze binding, we
treated a measured amount of silica-supported material with a 2
mM stock solution of RuX at room temperature for 30 min. Re-
actions were subsequently filtered and the solids were washed
extensively to verify that all changes in precatalyst concentration
were due to ligation and not due to adsorption onto silica gel. An
appropriate dilution was performed and samples were analysed by
UV to determine the difference of precatalyst concentrations in a
treated and non-treated sample. By measuring solution concentra-
tions of the remaining unbound metal complex we can indirectly
arrive to the percent bound by the difference from the initial and
final solution concentration of the metal complex.
−
1
−1
functional groups at 2125 cm and 1678 cm , respectively. Com-
parison of isocyanide 1a grafted at 25 °C (Fig. 1a), 80 °C (Fig. 1b),
and formamide 5a (Fig. 1c) showed an increasing formamide sig-
nal with increased grafting temperature. The recovered (ungrafted)
isocyanides 4a-c were found to be pure with no hydrolysis to the
formamide. The undesired surface-bound formamide was formed
by silica-catalyzed hydrolysis of pure isocyanides with more hy-
drolysis occurring at higher temperatures. Improved isocyanide pu-
rity was obtained by grafting at room temperature.
The standard literature method for quantification of solid-
supported isocyanides is through elemental analysis for nitrogen
Control studies showed that untreated silica gel accounted for
removal of some Ru complexes. Of the ten RuX tested, we found
Ru1-6 were stable to silica and Ru7-10 were unstable (Table 1).
To our knowledge, the role of untreated silica gel in Ru removal
has not been previously documented. Stable Ru complexes (Ru1-6)
were chosen for further analysis so background binding by silica
would not obscure metal removal by the isocyanide.
[
6]. This assumes that all nitrogen is present as one functional
group, which is not accurate when hydrolysis occurs since %N rep-
resents a composite of isocyanide and formamide. No satisfactory
method exists in the literature to solve this problem.
To determine the isocyanide loading, isocyanides 1a-c were
cleaved from silica using cyanogen bromide. Cyanogen bromide
cleavage of thioethers is known as the von Braun reaction [7].
Thioether activation by cyanogen and subsequent S-C bond cleav-
age by the bromide nucleophile resulted in monomer detachment,
thereby allowing quantitative analysis of the soluble products by
1H NMR; see Scheme 4 and Figures S1 and S2 [8]. Combination of
N elemental analysis with the measured isocyanide and formamide
ratio enabled calculation of the isocyanide loading. Triplicate anal-
ysis of a freshly prepared batch of 1a found 93 ± 4% isocyanide
and 0.32 mmol/g N loading; therefore, the isocyanide loading was
calculated to be 0.30 ± 0.01 mmol/g [9].
The general procedure for UV assays was performed with 25 mg
silica gel.a) Percent bound was calculated as [1-(concentration RuX
in sample / concentration RuX in non-treated sample)] x 100%,
where concentrations were determined through a standard curve.
b)
Average and standard deviation of three trials using different
stock solutions. c) Results from two absorbance values.
Initially, UV analyses of Ru1-2, commercially-available scav-
engers 7-10, formamide 5a, and isocyanides 1a-c were performed
(
Fig. 3). Ru1 and Ru2 were chosen because they are widely used
and are the least and most sterically encumbered ruthenium car-
benes used in this study, respectively. Analysis of Ru carbene bind-
ing efficacy was performed using 1, 2, and 4 equiv of scavenger for
30 min treatments.
2
.3. Rate of binding by aromatic isocyanides
Overall, the isocyanides were highly effective at Ru binding
relative to commercially-available scavengers. Treatment of Ru1
(Fig. 3a) with 4 equiv of commercial scavengers 7-10 did not result
in complete binding, but the same condition afforded at least 94%
To determine the optimal time for Ru binding by isocyanides,
we monitored the reactions of two commercially-available Ru car-
benes with soluble isocyanides. In situ FT-IR was used to compare
3

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
Fig. 1. DRIFT IR of silica gel material 1a produced by grafting at (a) 25 ˚C, 94% isocyanide, (b) 80 ˚C, 45% isocyanide, and (c) silica-supported formamide, 5a.
7
6
5
4
3
2
1
0
1
bulkier Ru2 (Fig. 3b) with 4 equiv of the commercial scavengers
7-10 resulted in less than 8% binding for all scavengers, whereas
at least 76% of Ru2 was bound using isocyanides 1a-c. Treatment
with 1 equiv isocyanides 1a-c resulted in greater than 15% bind-
ing; therefore 1 equiv isocyanide is more effective than 4 equiv of
standard scavengers 7-10 in all cases. The 2,6-dimethyl substituted
isocyanide 1b was slightly less effective than the unsubstituted aryl
isocyanide 1a. By contrast, the longer linker length of 1c resulted
in slightly improved metal binding.
Ru2
a
b
c
d
-
5
5
15
25
35
45
55
-
Time (min)
Fig. 2. In situ FTIR analysis of Ru carbene binding by solution-phase isocyanides.
Entries a, b, c, and d correspond to reactions of 4a at 23.5 °C, 4b at 23.5 °C, 4a at
Comparison of Ru carbene binding by isocyanides 1a-c is pro-
vided in Fig. 4. All isocyanide materials were highly effective for
the removal of Ru carbene complexes from solution [11].
0
°C, and 4b at 0 °C.
Binding efficacy among new aryl isocyanide materials was com-
pared at 2 equiv isocyanide relative to Ru complex (center horizon-
tal lanes in Fig. 4a-c). Since treatment of Ru1 and Ru3-6 with 4
equiv of isocyanides 1a-c resulted in >92% binding, we examined
lower loading to tease out structure-activity relationships. The 2,6-
dimethyl substituted aryl isocyanide 1b showed little reactivity dif-
ference compared to 1a; see Fig. 4a (2 equiv) and Fig. 4b (2 equiv).
Isocyanide 1c was generally less effective, but for Ru2 the longer
linker resulted in superior performance (Fig. 3b). This could be due
to better multivalent binding possible with longer or more flexible
linkers. Overall isocyanides 1a and 1b had generally similar reac-
metal binding for all isocyanides 1a-c. New isocyanide silica gels
were able to bind more Ru1 with 2 equiv scavenger than the com-
mercial scavengers bound with 4 equiv scavenger. The formamide,
5a, did bind 17% of Ru1 when 4 equiv were used, which may be
due to the presence of the thioether. The steric environment on
the aryl isocyanide and linker length had minimal effect on rela-
tive binding for 1a-1c.
The different profiles between Fig. 3a and 3b show the effect
of Ru ligand environment on isocyanide-Ru bonding. Treatment of
Fig. 3. UV analysis of Ru carbene binding by silica-supported materials. Panels a and b are results with Ru1 and Ru2, respectively.
4

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
to formation of a strained, 2,2,3,3-tetrasubstituted ruthenacyclobu-
tane intermediate, and since it requires forcing conditions, signifi-
cant Ru carbene decomposition was expected [13]. When decom-
position has occurred, the scavenger must remove Ru in its various
forms. Contrastingly, the UV studies above were conducted on the
Ru precatalyst alone with no decomposition products present.
The mild RCM of DEDAM (11) gives crude product 12 which
was assayed for Ru impurity. Treatment of the crude reaction mix-
ture with 4 and 8 equiv metal scavengers 1a and 9 resulted in
excellent and modest Ru removal, respectively (Table 2). Equiva-
lents of scavenger is based on the Ru catalyst loading; e.g. 4 equiv
corresponds to 4 mol % for 1 mol % catalyst loading. One mol
%
of Ru catalyst corresponds to 15422 ppm Ru in the crude or-
ganic sample after evaporation of solvent. The best result was the
treatment of the crude metathesis performed with Ru1 by 8 equiv
isocyanide 1a, where only 2 ppm Ru of the initial 15244 ppm
Ru remained (Table 2, entries 1 and 3). Using the same condi-
tions, thiourea 9 left 10091 ppm, which corresponds to 34% Ru
removed (Table 2, entry 5). A similar trend was seen with Ru4,
where treatment with 8 equiv 1a and 9 achieved final Ru concen-
trations of 39 ppm and 6456 ppm, respectively (Table 2, entries 8
and 10).
The more difficult RCM of DEDMAM (13) gave cyclopentene 14
after a 24 h reaction time. Treatment of crude 14 with 4 and 8
equiv metal scavengers 1a and 9 resulted in good to excellent Ru
removal in all cases (Table 3) [14]. The best result for Ru removal
from crude 14 was with 8 equiv isocyanide 1a, where Ru6 was re-
moved to 28 ppm from an initial 9832 ppm (Table 3, entries 6 and
8
). Similarly, treatment of Ru1 with 8 equiv 1a removed Ru to 36
ppm from 11024 ppm (Table 3, entries 1 and 3). Treatment of Ru1
and Ru6 with 8 equiv thiourea 9 was less effective and resulted in
final Ru concentrations of 1141 and 580 ppm, respectively (Table 3,
entries 5 and 10).
The two unique RCM reactions were performed under different
conditions and resulted in different final distributions of Ru com-
plexes and their decomposition products. The RCM performed un-
der mild conditions (11 to 12) presumably had minimal decompo-
sition products. Conversely, the more challenging RCM using forc-
ing conditions (13 to 14) was expected to contain mostly decom-
posed Ru, with minimal to no precatalyst remaining at the end.
The different Ru species present help explain the differences be-
tween the ICP-MS data and the UV experiments which used pure
Ru precatalysts.
Fig. 4. UV analysis of Ru carbene binding by silica-supported isocyanides. Panels a,
b, and c are results of Ru1-6 with isocyanides 1a, 1b, and 1c, respectively.
tivity and higher efficacy than 1c, but 1c was more effective for
binding Ru2.
Treatment of the most sterically unique Ru carbenes studied
(
Ru1 and Ru2) with metal scavengers demonstrated that more
hindered Ru atoms can have reduced scavenger binding. Steric
bulk impacted the effectiveness of commercial scavengers 7-10
more than isocyanides 1a-c; see Fig. 3 above. Differences in NHC
steric demand, H IMes (Ru1) versus H DIPP (Ru3), had little effect
The metatheses of DEDAM (11) were performed under mild
conditions so most Ru complexes were expected to be Ru carbenes.
Since the UV binding assays were performed with only Ru car-
benes, there was good correlation between the UV and ICP-MS ex-
periments for the RCM of 11; see Table 2 entries 2, 5, 7, 9, and
10.
2
2
on the isocyanide efficacy. For the H DIPP series, the equatorial
2
(
Ru5) and axial (Ru6) cyclohexane-containing Ru carbenes showed
slightly improved binding for the faster-initiating precatalyst Ru6
Fig. 4c). DRIFT IR of a reacted isocyanide suggests the presence of
multiple isocyanide species (Fig. S9).
(
The metatheses of DEDMAM (13) were performed using ex-
tended heating which can lead to Ru carbene decomposition. A
greater fraction of decomposition products can explain the poorer
correlation between the UV and ICP-MS experiments. Interestingly,
the isocyanide 1a removed residual Ru with similar effectiveness
for both ring-closing metathesis; see Table 3 entries 2 and 7. Con-
versely, the thiourea 9 performed better in the RCM reactions than
in precatalyst binding. Decomposition of the Ru carbene may ex-
pose the Ru by loss of ligands, affording improved thiourea scav-
enging performance.
2
.5. Correlation of binding results with performance in ring-closing
metathesis reactions
To correlate the results of our UV binding assays with actual
metal removal, we performed two different ring-closing metathe-
ses with various Grubbs complexes and scavengers, and analyzed
the resulting crude product by ICP-MS. Since isocyanides 1a and
1
b had similar reactivity profiles, only 1a was used to examine Ru
We have demonstrated that the UV binding assay developed
is a useful tool for rapid determination of relative scavenger effi-
cacy and reaction condition optimization. Most importantly, from
UV we determined that at least 4 equiv of isocyanide 1a was re-
quired for >99% precatalyst binding. Upon treatment of crude RCM
reactions with 4 and 8 equiv 1a we observed >95% metal removal,
so the UV and ICP-MS results are in agreement even though the
removal for the new materials. Thiourea 9 was chosen for compar-
ison.
The RCMs of diethyl diallylmalonate (DEDAM, 11) and diethyl
di(2-methyl)allylmalonate (DEDMAM, 13) were examined [12]. The
RCM of 11 afforded quantitative conversion within 30 min un-
der mild conditions. Conversely, the RCM of 13 is challenging due
5

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
Table 2
Ru removal from crude 12.
Entry
RuX
Scavenger(a) (equiv)
[Ru] [ppm](b)
% Removal(c)
% Bound(d)
1
2
3
4
5
6
7
8
9
Ru1
Ru1
Ru1
Ru1
Ru1
Ru4
Ru4
Ru4
Ru4
Ru4
none
1a (4)
1a (8)
9 (4)
9 (8)
none
1a (4)
1a (8)
9 (4)
9 (8)
15244
423
97
99
2
>99
13
13239
10091
18670
708
40
42
34
96
98
39
>99
37
11725
6456
43
71
1
0
65
(a)
Equivalents of scavenger is relative to Ru. (b) Concentration of Ru was calculated as μg Ru per g
crude material after solvent evaporation. (c) Determined by ICP-MS. (d) Determined by UV.
Table 3
Ru removal from crude 14.
Entry
RuX
Scavenger(a) (equiv)
[Ru] [ppm](b)
% Removal(c)
% Bound(d)
99
1
2
3
4
5
6
7
8
9
Ru1
Ru1
Ru1
Ru1
Ru1
Ru6
Ru6
Ru6
Ru6
Ru6
none
1a (4)
1a (8)
9 (4)
9 (8)
none
1a (4)
1a (8)
9 (4)
9 (8)
11024
434
96
36
>99
78
2445
1141
9832
45
40
42
90
>99
>99
89
99
28
1129
580
3
5
1
0
94
(a)
Equivalents of scavenger is relative to Ru. (b) Concentration of Ru was calculated as μg Ru per g crude
material. (c) Determined by ICP-MS. (d) Determined by UV.
Ru complexes being scavenged may vary between assays (Table 2
and Table 3, entries 2, 3, 7, and 8).
trations in the crude organic products. ICP-MS analysis was per-
formed on these products treated with isocyanides followed by a
simple filtration. In the RCM examples, 8 equiv of silica-supported
isocyanide 1a can effectively remove Ru to below 40 ppm in all
cases and down to 2 ppm in the best example. This was signif-
icantly better than commercial scavengers and an improvement
from our previous silica-supported alkyl isocyanide which required
3. Conclusions
New silica-supported aromatic isocyanides were prepared and
found to effectively remove Ru from two metathesis reactions
using different Grubbs catalysts. By studying a wide variety of
Grubbs’ metathesis catalysts, the interplay between catalyst struc-
ture and aromatic isocyanide structure was comparatively evalu-
ated. During typical grafting conditions, isocyanides were found
to undergo partial hydrolysis, so a new method for quantifying
isocyanide was developed. With this technique, grafting condi-
tions could be optimized where minimal isocyanide hydrolysis was
found. The UV binding assay allowed visualization of reaction rate,
optimization of treatment conditions and allowed comparisons of
scavenger efficacy. Control reactions with silica gel showed that the
Ru complexes examined did not decompose or get removed by sil-
ica gel alone. Isocyanides were highly effective at removing Ru pre-
catalysts from solution. Aromatic isocyanide containing materials
performed significantly better than commercially-available scav-
engers and only small differences were found between isocyanide
structures. Two RCM reactions were investigated which required
drastically different reaction conditions and have high Ru concen-
6
0 equiv for comparable Ru removal. The contrasting ability of
scavengers to remove Ru in the two RCMs compared to the UV as-
says using Ru precatalysts alone was attributed to differing degrees
of decomposition.
4. Experimental
General. Unless otherwise stated, all reactions were performed
using standard Schlenk line technique under nitrogen with oven
or flame-dried glassware. Solvents used in reactions were ob-
tained from an anhydrous column purification system. Grubbs car-
benes were obtained from Umicore or Materia and used as re-
ceived. Commercially-available reagents were used as received un-
less otherwise noted. Triethylamine was distilled before use. Cop-
per(I) chloride was recrystallized from concentrated hydrochloric
acid, washed with deionized water and dried in vacuo. Crushed
˚
4 A molecular sieves were activated and stored at >150 °C in
6

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
a drying oven. Flash chromatography was carried out on un-
treated silica gel 60 from Sorbtech Technologies Inc. (230 – 400
mesh) under air pressure. Thin layer chromatography (TLC) was
performed on glass-backed silica plates (F254, 250 micron thick-
ness, EMD Millipore), visualized with UV light, phosphomolybdic
acid, iodine, or potassium permanganate. 1H NMR spectra were
recorded at 300, 400, or 500 MHz; proton-decoupled 13C NMR
spectra were recorded at 75, 100 or 125 MHz using Varian Mer-
as: percent bound = [1-(concentration RuX in sample / concentra-
tion RuX in non-treated sample)] x 100%.
General procedure for in situ FT-IR isocyanide-binding
time-course analysis (using 4a and Ru2 as an example)
A stock solution of isocyanide 4a (232.8 mg, 0.59 mmol, 23.6
mM) in PhCH3 (25.00 mL) was prepared in a 25 mL volumetric
flask. A stock solution of Ru carbene Ru2 (265.1 mg, 0.28 mmol,
56.0 mM) in PhCH3 (5.00 mL) was prepared in a 5 mL volumet-
ric flask. An oven-dried 50 mL ReactIR reaction vessel containing a
magnetic stirring bar was cooled to room temperature under the
flow of nitrogen. Isocyanide stock solution (3.7 mL, 0.09 mmol, 3
equiv) was added to the reaction vessel and monitored by in situ
IR as the temperature and solution equilibrated. If the reaction was
performed at 0 °C – as in this example – the reaction was temper-
ature controlled by an ice-water bath, otherwise the temperature
was controlled with a recirculating water bath set to 23.5 °C. Ru
carbene stock solution (500 μL, 0.03 mmol, 1 equiv) was injected
directly into the isocyanide solution, then the reaction was moni-
tored to observe a new stretching frequency corresponding to the
Ru-C≡NAr isocyanide stretch at 2103 cm−1.
cury 300, Inova 400, Inova 500 instruments; proton decoupled 1
H
NMR chemical shifts are reported in ppm relative to the solvent
used (chloroform-d 1H: 7.26 ppm, 13C: 77 ppm, DMSO-d6 1H: 2.50,
13C: 39, acetonitrile-d3
1H: 1.94, 13C: 118). Infrared spectra were
recorded using a Perkin Elmer Spectrum Two FTIR-ATR. Mass anal-
ysis was performed on a Bruker SolariX 12T FTMS using electro-
spray ionization with acetonitrile or dichloromethane as solvent.
DRIFT-IR were recorded using a Perkin Elmer Spectrum Two FTIR
spectrometer. UV spectroscopy was performed using an Agilent
8
453 UV-visible spectrophotometer. UV assays and solutions were
performed open to air, stock solutions were prepared in volumet-
ric flasks, and appropriately-sized gas-tight Hamilton syringes were
used to transfer measured solutions. All glassware except for dis-
posable pipets used in ICP-MS analyses were pretreated by wash-
ing with nitric acid (≥2%) and deionized water, then allowed to
dry. Ultrapure water was obtained from a Milli-Q gradient A10
purifier system equipped with a Q-Gard 1 pack and a APS Ultra
FP1001 purification pack. In situ infrared spectroscopy was per-
formed with Mettler Toledo ReactIR ic10 and data was acquired in
General procedure for ring-closing metathesis of diethyl diallyl
malonate and treatment with silica-supported metal scavengers
All manipulations of stock solutions and metatheses were per-
formed in the glovebox. A stock solution of diethyl diallyl malonate
5
second intervals.
(
290 μL, 1.2 mmol) in PhCH3 (3.00 mL) was prepared in a 3 mL
volumetric flask. A stock solution of RuX (10 μmol) in PhCH3 (5.00
mL) was prepared in a 5 mL volumetric flask. A 20 mL scintillation
vial containing a magnetic stir bar was charged with diethyl diallyl
malonate stock solution (500 μL, 0.2 mmol, 1.0 equiv), PhCH3 (2.50
mL), and RuX stock solution (1000 μL, 0.002 mmol, 0.01 equiv).
The reaction was loosely capped and allowed to mix at ambient
temperature (29 °C) for 30 min. The vial was sealed, removed from
the glovebox, and an appropriate amount of silica-supported metal
scavenger was added. The mixture was allowed to stir at ambient
temperature for 30 min, then the reaction was filtered through a
glass fiber pipet plug and eluted with PhCH3 (0.5 mL six times)
into a tared 20 mL scintillation vial. The sample was concentrated
General procedure for cyanogen bromide induced thioether
cleavage (using 1a as an example)
A 2 dram vial containing a magnetic stir bar was charged with
˚
1a (71.6 mg, 17.2 μmol, 1 equiv), activated, crushed, 4 A molecu-
lar sieves (51.0 mg), and acetonitrile-D3 (0.3 mL), then the mix-
ture was allowed to stir gently at room temperature for 16.2 h.
Cyanogen bromide (18.6 mg, 175.6 μmol, 10.2 equiv) dissolved in
acetonitrile-d3 (0.2 mL) was added to the reaction mixture, then
the reaction was sealed with a Teflon-lined cap, transferred to a
preheated 60 °C oil bath, and allowed to react for 2 h. The reac-
tion was filtered through a glass fiber pipet plug and eluted with
acetonitrile-d3 (0.1 mL four times then 0.2 mL two times). The elu-
ent was allowed to slowly evaporate in the hood over the course
of several hours, then the solution was analyzed by 1H NMR by
comparing the ratio of isocyanide and formamide cleavage prod-
ucts according to Table S1 (see Supporting Information). It should
be noted that evaporating the eluent in vacuo resulted in loss of
cleavage products due to their volatility.
in vacuo, dissolved in 0.7 mL CDCl , and an 1H NMR was taken to
3
determine percent conversion. Percent conversion was calculated
from the allylic protons for diethyl diallyl malonate (2.64 ppm,
d, 3J = 7.5 Hz, 4 H) and diethyl cyclopent-3-ene-1,1-dicarboxylate
(
2.99 ppm, s, 4 H). The solution was transferred into the tared vial,
rinsing once with CH Cl2 (1.5 mL), then concentrated in vacuo. The
2
mass was recorded, then the crude sample was prepared for ICP-
MS analysis.
General procedure for UV metal binding assays
General procedure for ring-closing metathesis of diethyl
di(2-methyl)allyl malonate and treatment with silica-supported
metal scavengers
A 1 dram vial was charged with the measured amount of silica-
supported scavenger and a magnetic stir bar. An aliquot of RuX in
PhCH3 (1000 μL, 2 mM, 2 μmol) was added to the vial and the
mixture was stirred at room temperature for 30 min. The time-
course analyses were performed at the denoted time intervals. Care
was taken such that the stirring was not so rapid that significant
amounts of solids deposited out of the solution. The mixture was
filtered through a glass fiber pipet plug and eluted with PhCH3
All manipulations of stock solutions and metatheses were
performed in the glovebox.
A stock solution of diethyl di(2-
methyl)allyl malonate (363.6 mg, 1500 μmol) in PhCH3 (3.00 mL)
was prepared in a 3 mL volumetric flask. A stock solution of RuX
(60 μmol) in PhCH3 (10.00 mL) was prepared in a 10 mL volumet-
ric flask. A 1 dram scintillation vial containing a magnetic stir bar
was charged with diethyl di(2-methyl)allyl malonate stock solution
(250 μL, 125 μmol, 1.0 equiv) and RuX stock solution (1000 μL,
6.0 μmol, 0.05 equiv). The reaction was loosely capped and trans-
ferred to a preheated 60 °C aluminum block and allowed to re-
act for 24 h. The reaction was sealed, removed from the glove-
box, and the appropriate amount of silica-supported metal scav-
(
0.5 mL six times) into a 5 or 10 mL volumetric flask. The vol-
ume of eluent was adjusted to the mark with PhCH , then an
3
appropriate dilution was performed. If the RuX used was Ru1-6,
then the dilution was performed according to Table S2. UV spectra
were obtained, then the concentration of solution was calculated
through the standard curve for RuX. Percent bound was calculated
7

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
+
enger was added. The mixture stirred for 30 min at rt, was filtered
through a glass fiber pipet plug, and washed with PhCH3 (0.5 mL
six times) into a tared 20 mL scintillation vial. The solution was
olution MS (EI , m/z): molecular ion calculated for C10H11 NNaO2
+
[M+Na ] 200.0682, found 200.0685, error -1.4 ppm.
concentrated in vacuo, dissolved in 0.7 mL CDCl , then analyzed
N-(4-(Allyloxy)-2,6-dimethylphenyl)formamide (2b)
3
by 1H NMR to determine percent conversion. Percent conversion
was calculated from the allylic protons for diethyl di(2-methyl)allyl
malonate(2.73 ppm, s, 4 H) and diethyl 3,4-dimethylcyclopent-3-
ene-1,1-dicarboxylate (2.91 ppm, s, 4 H) . The solution was trans-
ferred to the tared scintillation vial, rinsing once with CH Cl (1.5
Reaction adapted from the literature [15]. In an oven dried
250 mL round bottom flask
a solution of N-(4-hydoxy-2,6-
dimethylphenyl)formamide (6.22 g, 37.7 mmol, 1.0 equiv) in DMF
(100 mL), potassium carbonate (5.7 g, 41.5 mmol, 1.1 equiv) and
allyl bromide (2.55 g, 41.5 mmol, 1.1 equiv) were added. The re-
action was monitored by TLC, and upon completion, most of the
DMF was removed in vacuo. To the residue was added water (50
mL) and the solution filtered through a Buchner funnel. The re-
2
2
mL), then concentrated in vacuo. The mass was recorded, then the
crude sample was prepared for ICP-MS analysis.
Preparation of crude samples for ICP-MS analysis
maining light brown crystals were dissolved in CH Cl2 and purified
2
through flash chromatography (50% EtOAc/hexane) to afford prod-
Once the mass of crude material from metatheses was recorded,
nitric acid (1.00 mL, 70%, for trace metals analysis) was added to
the 20 mL scintillation vial containing the crude material. The vial
was capped with a piece of Kimwipe secured with a rubber band,
then the organic material was allowed to digest overnight at room
temperature. The nitric acid solution was quantitatively transferred
to a 25 mL volumetric flask and diluted to 25.00 mL with ultrapure
water. The resulting solution was diluted appropriately, then the
sample was filtered through a PTFE syringe filter (25 mm, 0.45 μm
membrane) and analyzed by ICP-MS.
uct 2b (2.0 g, 9.74 mmol, 26%) as a white solid. Melting point 144
-
146 °C. Rf 0.20 (50% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3,
ppm, major rotamer reported): δ 8.38 (s, 1H), 6.71 (br s, 1 H), 6.66
(
s, 2 H) 6.03 (m, 1H) 5.38 (dt, 3J = 17.3 Hz, J = 2.5 Hz, 1 H), 5.28
3
3
3
(
td, 3J = 10.0 Hz, J = 2.5 Hz), 4.49 (d, J = 5.3 Hz, 2 H), 2.26 (s,
1
3
1
6
H) C{ H} NMR (75 MHz, CDCl , ppm): δ 165.51, 160.06, 157.52,
3
1
37.19, 136.63, 133.24, 133.01, 126.18, 125.48, 117.74, 117.54, 114.47,
−
1
14.44, 114.18, 68.79, 18.97, 18.75. FT-IR (ATR, cm 1): 3260, 3087,
2
916, 2893, 2865, 1654, 1608, 1593, 1507, 1458, 1424, 1380, 1325,
1281, 1253, 1223, 1172, 1133, 1054, 1005, 964, 931, 883, 852, 736,
+
7
00, 652, 618, 579, 527. High resolution MS (EI , m/z): molecular
+
Preparation of scavenger materials
ion calculated for C12H15NO2 [M ] 205.1103, found 205.1101, error
-1.3 ppm.
N-(4-(Allyloxy)phenyl)formamide (2a)
N-(4-(Undec-10-en-1-yloxy)phenyl)formamide (2c)
An oven-dried 250 mL round bottom flask was charged with N-
(
4-hydroxyphenyl)formamide (7.01 g, 51.1 mmol, 1.0 equiv), oven-
An oven-dried 250 mL round-bottomed flask with a magnetic
stir bar was charged with N-(4-hydroxyphenyl)formamide (1.37 g,
10 mmol, 1.0 equiv), potassium carbonate (2.77 g, 20 mmol, 2.0
equiv), acetonitrile (50 mL), and 11-bromo-1-undecene (3.3 mL, 15
mmol, 1.5 equiv). A reflux condenser was attached and the mixture
was gently refluxed at 85 °C for 24 h. The reaction mixture was
filtered through celite and concentrated in vacuo. The crude mix-
ture was purified by column chromatography (50% EtOAc/hexanes)
to afford the desired product 2c (5.27 g, 7.50 mmol, 75% yield)
as a light-yellow solid. Melting point 66-67 °C. Rf 0.38 (50%
dried potassium carbonate (8.16 g, 59.0 mmol, 1.2 equiv), and a
magnetic stir bar. The solids were suspended in acetonitrile (45
mL), then the flask was equipped with a reflux condenser. To
the stirring solution allyl bromide (5.0 mL, 57.9 mmol, 1.1 equiv)
was added dropwise over the course of 15 min and the reaction
gradually became yellow. The reaction was transferred to a pre-
heated 60 °C oil bath. After 93 h the reaction was cooled to room
1
temperature and a 0.1 mL aliquot was taken for H NMR anal-
ysis to reveal 68% conversion of N-(4-hydroxyphenyl)formamide
to N-(4-(allyloxy)phenyl)formamide had occurred. Additional allyl
bromide (2.0 mL, 23.1 mmol, 0.45 equiv) was added dropwise,
the reaction was transferred to a preheated 60 °C oil bath, and
the reaction turned orange-red upon heating. After 24 h a sec-
ond 0.1 mL aliquot was analyzed by 1H NMR to show no ad-
ditional conversion from N-(4-hydroxyphenyl)formamide to N-(4-
EtOAc/hexanes). 1H NMR (400 MHz, CDCl , ppm, major rotamer
3
reported): δ 8.48 (d, 3J = 11.5 Hz, 1 H), 7.41 (d, J = 9.0 Hz, 2
3
H), 7.00 (d, 3J = 9.0 Hz, 2 H), 5.80 (ddt, J = 17.0 Hz, J = 10.2 Hz,
3
3
3
3
3
J = 6.7 Hz, 1 H), 4.98 (d, J = 17.0 Hz, 1 H), 4.92 (d, J = 10.2
Hz, 1 H), 3.92 (t, 3J = 6.6 Hz, 2 H), 2.05-2.0 (m, 2 H), 1.78-1.73
(m, 2 H), 1.44-1.29 (m, 12 H). 13C{ H} NMR (100 MHz, CDCl , ppm,
1
3
(allyloxy)phenyl)formamide. The solution was decanted and the
major rotamer reported): δ 162.8, 158.7, 139.2, 121.8, 115.5, 114.9,
solids were subsequently rinsed and decanted three times with
CH Cl , filtered with filter paper, and the filter cake was washed
114.1, 66.3, 33.8, 29.5, 29.4, 29.3, 29.2, 29.2, 29.1, 28.9, 26.0. FT-IR
(ATR, cm 1): 3112.77, 3078.03, 2920.05, 2850.42, 2753.84, 1742.42,
−
2
2
five times with CH Cl (25 mL). The filter cake was dissolved in
1643.24, 1515.40, 1472.09, 1248.16. High resolution MS (ESI): m/z
2
2
+
deionized H O and extracted three times with CH Cl . The organic
calculated for [C18 H27NO +Na] 312.1939, found 312.1933, error: -
2
2
2
2
phase was concentrated in vacuo to obtain 8.94 g of a dark red oil.
The crude material was purified by flash chromatography (20-100%
EtOAc/hexanes) to collect 2a (5.85 g, 33.0 mmol, 65%) as a light
1.9 ppm.
N-(4-(3-((3-Triethoxysilyl)propyl)thio)propoxy)phenyl)formamide (3a)
tan solid. Melting point 51-52 °C. R 0.45 (70% EtOAc/hexanes), 1H
f
NMR (400 MHz, CDCl , ppm, minor rotamer reported): δ 8.52 (d,
Reaction was adapted from the literature [5]. An oven-dried
20 mL scintillation vial was charged with 2a (2.54 g, 14.3 mmol,
1 equiv), 3-mercaptopropyltriethoxysilane (3.45 mL, 14.3 mmol, 1
equiv), Irgacure 651 (54.6 mg, 0.21 mmol, 0.02 equiv), and a mag-
netic stir bar. The sample was heated gently to promote solvation
of Irgacure-651, and then the reaction was cooled to room temper-
ature and irradiated at 365 nm for 3.5 h. The solution became or-
ange and an aliquot was analyzed by 1H NMR to show formamide
3
3
3
J = 11.6 Hz, 1 H), 8.10 (br s, 1 H), 7.43 (d, J = 9.2 Hz, 2 H),
6
3
.89 (t, 3J = 9.2 Hz, 2 H), 6.03 (m, 1 H), 5.4 (ddd, J =17.2 Hz,
3
2
3
2
J = 2.0 Hz, J = 2.0 Hz), 5.29 (td, J = 10.0 Hz, J = 1.2 Hz, 1
H), 4.52 (td, 3J = 4.4 Hz, J = 2.0 Hz, 2 H). C{ H} NMR (75 MHz,
4
13
1
CDCl , ppm): δ 163.14, 159.01, 156.50, 155.6, 133.07, 132.91, 130.08,
3
1
29.70, 121.70, 121.41, 117.84, 117.71, 115.72, 115.05, 69.08, 69.02.
FT-IR (ATR, cm 1): 3262, 3129, 3065, 2868, 2075, 1875, 1677, 1601,
536, 1508, 1456, 1409, 1362, 1291, 1233, 1176, 1150, 1112, 1021,
98, 926, 889, 826, 741, 655, 640, 616, 601, 572, 562, 528. High res-
−
1
3a (quantitative yield). R 0.49 (70% EtOAc/hexanes). 1H NMR (400
f
9
MHz, CDCl , ppm): δ 8.50 (d, 3J = 11.6 Hz, 0.5 H), 8.33 (s, 0.5 H),
3
8

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
3
7
.43 (d, 3J = 8.8 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 6.87 (app t,
triethylamine (7.5 mL, 54 mmol, 5.0 equiv) were dissolved in THF
(13.4 mL) then cooled to -78 °C via dry ice/acetone. A solution of
phosphorus(V) oxychloride (1.22 mL, 13 mmol, 1.2 equiv) in THF
(5.6 mL) was added dropwise to the stirring formamide-containing
solution. The reaction was allowed to mix at -78 °C for 5 min,
then the flask was transferred to a 0 °C ice-water bath and al-
lowed to react for 2 h. The reaction was stored at -20 °C in a
freezer overnight. The reaction was warmed to 0 °C, then ice cold
deionized water (13 mL) was added slowly. The reaction was ex-
tracted four times with Et2O, washed once with brine, then dried
over sodium sulfate. The crude product was concentrated in vacuo,
then purified by column chromatography (5-20% EtOAc/hexanes) to
obtain 5a (2.94 g, 7.4 mmol, 69% yield) as a colorless oil with a dis-
agreeable odor. Rf 0.24 (10% EtOAc/hexanes). 1H NMR (300 MHz,
CDCl3, ppm): δ 7.30 (d, 3J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H),
3
3
J = 9.2 Hz, 2 H), 4.10-3.97 (m, 2 H), 3.81 (q, J = 7.2 Hz, 6 H), 2.68
3
3
3
(
td, J = 2.0 Hz, J = 6.8 Hz, 2 H), 2.55 (t, J = 7.6 Hz, 2 H), 2.12-
3
3
1
.97 (m, 2 H), 1.71 (p, J = 8.0 Hz, 2 H), 1.22 (t, J = 7.2 Hz, 9 H),
1
0
.81-0.65 (m, 2 H). 13C{ H} NMR (100 MHz, CDCl , ppm): δ 163.10,
3
1
59.12, 156.60, 155.69, 130.09, 129.61, 121.56, 121.17, 115.28, 114.70,
1
14.59, 66.42, 66.36, 58.20, 34.92, 29.12, 29.04, 28.14, 28.10, 22.96,
8.28, 18.09, 9.65, 9.63. FT-IR (ATR, cm 1): 2974, 2926, 1682, 1603,
−
1
1
511, 1471, 1413, 1391, 1294, 1236, 1166, 1100, 1073, 957, 913, 828,
+
7
79, 730, 646, 528, 479. High resolution MS (EI , m/z): molecu-
+
lar ion calculated for C19 H34NO SSi [M ] 416.1921, found 416.1922,
5
error -0.2 ppm.
N-(2,6-Dimethyl-4-(3-((3-(triethoxysilyl)propyl)
thio)propoxy)phenyl)formamide (3b)
3
3
3
4
.06 (t, 3J = 6.3 Hz, 2 H), 3.82 (q, J = 6.9 Hz, 6 H), 2.71 (t, J = 6.9
Hz, 2 H), 2.55 (t, 3J = 7.5 Hz, 2 H), 2.06 (p, J = 6.9 Hz, 2 H), 1.71
3
To
a stirred solution of 2b (0.765 g, 5.35 mmol, 1.0
(p, 3J = 7.2 Hz, 2 H), 1.22 (t, J = 6.9 Hz, 9 H), 0.78-0.68 (m, 2 H).
3
equiv) and CDCl3 (1.5 mL) in a one-dram vial was added 3-
mercaptopropyltriethoxysilane (1.37 mL, 5.35 mmol, 1.0 equiv) and
Irgacure 651 (27.4 mg, 0.107 mmol, 0.02 equiv). The solution was
flushed with argon then irradiated at 365 nm for 24 h. The
crude solution was purified through flash chromatography (50%
EtOAc/hexanes) to afford product 3b (1.0 g, 2.3 mmol, 50% yield) as
13
1
C{ H} NMR (75 MHz, CDCl3, ppm): δ 156.47, 58.06, 57.95, 39.94,
39.85, 39.78, 38.23, 34.71, 33.53, 28.62, 27.98, 23.15, 22.90, 22.32,
18.45, 18.00, 9.51. FT-IR (ATR, cm 1): 2973, 2925, 2883, 2122, 1606,
−
1584, 1505, 1468, 1440, 1389, 1297, 1250, 1193, 1164, 1100, 1075,
+
1029, 958, 833, 781, 523. High resolution MS (EI , m/z): molec-
yellow oil. R 0.20 (50% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3,
+
ular ion calculated for C19 H31NNaO4SSi [M+Na ] 420.1635, found
f
ppm, major rotamer reported): δ 8.39 (s, 1 H), 6.81 (br s, 1 H),
420.1645, error -2.4 ppm.
3
6
.64 (s, 2 H), 4.02 (t, 3J = 6.0 Hz, 2 H), 3.82 (q, J = 7.0 Hz, 6
H), 2.68 (t, 3J = 7.0 Hz, 2 H), 2.55 (t, J = 7.1 Hz, 2 H), 2.24 (s,
3
Triethoxy(3-((3-(4-isocyano-3,5-dimethylphenoxy)propyl)
thio)propyl)silane (4b)
3
6
H), 2.03 (p, 3J = 7.0 Hz, 2 H), 1.73 (p, J = 7.5 Hz, 2 H), 1.24
3
13
1
(
t, 3J = 7.0 Hz, 9 H), 0.75 (t, J = 8.0 Hz, 2 H). C{ H} NMR (75
MHz, CDCl , ppm): δ 165.43, 159.95, 157.85, 137.22, 136.65, 126.00,
Reaction was adapted from the literature. [1a] To an oven-dried
5 mL round bottom flask 3b (379 mg, 0.85 mmol, 1.0 equiv) and
triethylamine (0.595 mL, 4.27 mmol, 5.0 equiv) were added to THF
(1.0 mL) and cooled to -78 °C. A solution of POCl3 (0.096 mL, 1.03
mmol, 1.2 equiv) in THF (0.500 mL) was added dropwise to the
formamide solution. After 1 h the reaction was placed in an ice
bath and allowed to stir for 1 h then the solution was quenched
with ice-water (3.0 mL). The reaction was then extracted with di-
ethyl ether (three time with 3.0 mL) and the organic layer dried
over Na2SO4. The reaction was concentrated in vacuo to afford
crude yellow oil, which was purified through a silica pipette (20%
Et2O/hexanes) to give product 4b (0.118 g, 2.78 mmol, 33% yield)
as a yellow oil. Rf 0.30 (20% Et2O/hexanes). 1H NMR (300 MHz,
3
1
25.31, 114.19, 113.98, 66.27, 58.38, 35.14, 29.29, 28.36, 23.17, 18.96,
8.75, 18.29, 9.87. FT-IR (ATR, cm 1): 3244, 2972, 2923, 2882, 1666,
−
1
1
596, 1488, 1439, 1387, 1326, 1277, 1249, 1167, 1100, 1074, 958,
+
52, 834, 780, 701, 629. High resolution MS (EI , m/z): molecu-
8
+
+
lar ion calculated for C21H37NNaO SSi [M Na ] 466.2059, found
5
4
66.2053, error -0.1 ppm.
N-(4-((11-((3-(Triethoxysilyl)propyl)thio)undecyl)oxy)phenyl)
formamide (3c)
To an oven-dried 20-mL scintillation vial with a magnetic
stir bar was charged with 2c (2.17 g, 7.5 mmol, 1.0 equiv), 3-
mercaptopropyltriethoxysilane (1.81 mL, 7.5 mmol, 1.0 equiv), and
Irgacure 651 (38.4 mg, 0.15 mmol, 0.02 equiv). To dissolve the
solid, chloroform (3 mL, purified by passing through a short alu-
mina column before use) was added. The solution was irradiated
at 365 nm for 24 h then concentrated in vacuo. The crude prod-
uct was purified by column chromatography (25% EtOAc/hexanes)
to afford 3c (3.7 g, 7.12 mmol, 95% yield) as a brown oil. Rf 0.15
3
CDCl3, ppm): δ 6.59 (s, 2 H), 4.03 (t, J = 6.1 Hz, 2 H), 3.81 (q,
3
3
3
J = 7.0 Hz, 6 H), 2.67 (t, J = 7.1 Hz, 2 H), 2.55 (t, J = 7.2 Hz, 2
H), 2.38 (s, 6 H), 2.03 (p, 3J = 6.6 Hz, 2 H), 1.71 (p, J = 8.0 Hz, 2
3
H), 1.22 (t, 3J = 7.0 Hz, 9 H), 0.73 (t, J = 8.0 Hz, 2 H). C{ H} NMR
3
13
1
(75 MHz, CDCl3, ppm): δ 158.45, 136.43, 113.51, 66.37, 58.37, 35.15,
29.10, 28.26, 23.17, 22.61, 19.14, 18.28, 9.89, 9.43 FT-IR (ATR, cm 1):
2973, 2925, 2884, 2113, 1605, 1594, 1481, 1466, 1441, 1389, 1329,
1292, 1249, 1192, 1154, 1141, 1100, 1075, 997, 958, 914, 858, 838,
−
(
25% EtOAc/hexanes). 1H NMR (400 MHz, CDCl , ppm, major ro-
3
tamer reported): δ 8.49 (d, 3J = 11.6 Hz, 1 H), 7.42 (d, J = 8.9 Hz,
3
+
781, 733, 713, 647, 629, 557. High resolution MS (EI , m/z): molec-
H), 7.01 (d, 3J = 8.9 Hz, 2 H), 3.93 (t, J = 6.4 Hz, 2 H), 3.81 (q,
3
+
+
2
3
ular ion calculated for C21H35NNaO4SSi [M Na ] 448.1954, found
448.1948, error -1.0 ppm
3
3
J = 7.0 Hz, 6 H), 2.53 (t, J = 7.5 Hz, 2 H), 2.49 (t, J = 7.5 Hz,
2
H), 1.75-1.59 (m, 4 H), 1.57-1.46 (m, 2 H), 1.38-1.23 (m, 14 H),
13
1
1
.22 (t, 3J = 7.0 Hz, 9 H), 0.76-0.72 (m, 2 H); C{ H} NMR (100
Triethoxy(3-((11-(4-isocyanophenoxy)undecyl)thio)propyl)silane (4c)
MHz, CDCl , ppm, major rotamer reported): δ 162.9, 158.7, 141.3,
3
1
21.8, 115.5, 68.4, 58.4, 35.2, 32.0, 29.8, 29.5, 29.5, 29.3, 29.2, 29.2,
An oven-dried round-bottomed flask with a magnetic stir bar
was charged with formamide 3c (1.06 g, 2 mmol, 1.0 equiv), tri-
ethylamine (1.4 mL, 10 mmol, 5 equiv) and THF (20 mL). The re-
action was cooled to -78 °C by dry ice/acetone bath. Phospho-
rous oxychloride (0.22 mL, 2.4 mmol, 1.2 equiv) dissolved into THF
9.2, 28.9, 26.0, 23.2, 18.3, 9.9. FT-IR (ATR, cm 1): 3112, 3077, 2919,
−
2
2
850, 2754, 1746, 1516, 1473, 1249. High resolution MS (ESI): m/z
calculated for [C27H49NO SSi+Na]+ 550.2998, found 550.2998, er-
5
ror: 0 ppm.
(
12 mL), was then slowly added to the reaction flask. The dry
Triethoxy(3-((3-(4-isocyanophenoxy)propyl)thio)propyl)silane (4a)
ice/acetone bath was replaced by an ice-water bath to warm the
reaction flask to 0 °C. After 2 hours at 0 °C, water (10 mL) was
added slowly to quench the reaction. The mixture was then ex-
Reaction was adapted from the literature [1a]. In an oven-dried
5
0 mL round bottom flask 3a (4.46 g, 10.7 mmol, 1 equiv) and
tracted with Et O (three times with 10 mL), washed with brine
2
9

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
(
three times with 10 mL), and dried over Na SO . Solvent was
mg, 0.87 mmol, 73% recovery) was recovered by concentrating the
combined filtrate in vacuo. The solids were dried in vacuum oven
at 50 °C for 24 h to give silica-bound scavenger 1c (690 mg). Ele-
mental analysis: (%N = 0.38; 0.27 mmol/g N). FT-IR (DRIFT IR, KBr,
2
4
removed in vacuo, and the crude product was purified by col-
umn chromatography (25% EtOAc/hexanes with 1% Et N) to give
3
4
c (610 mg, 1.20 mmol, 60% yield) as a light yellow oil. Rf 0.45
25% EtOAc/hexanes). 1H NMR (300 MHz, CDCl , ppm): δ 7.21 (d,
cm ) 2149, 2125.
−1
(
3
3
3
3
J = 7.5 Hz, 2 H), 6.84 (d, J = 7.5 Hz, 2 H), 6.78 (t, J = 6.6 Hz,
H), 3.88 (q, 3J = 7.2 Hz, 6 H), 2.47 (t, J = 7.5 Hz, 2 H), 2.43 (t,
3
2
3
Silica-bound N-(4-(3-((3-triethoxysilyl)propyl)thio)propoxy)phenyl)
formamide (5a)
J = 7.5 Hz, 2 H), 1.75-1.59 (m, 4 H), 1.57-1.46 (m, 2 H), 1.38-1.23
m, 14 H), 1.17 (t, 3J = 7.2 Hz, 9 H). 0.71-0.66 (m, 2 H). C{ H}
13
1
(
NMR (75 MHz, CDCl , ppm): δ 162.7, 159.4, 139.0, 127.6, 115.0,
1
An oven dried 25 mL round-bottom flask was charged with sil-
ica gel (1.01 g, F60 40-63 μm, 60 A˚ ), PhH (3.4 mL), and triethy-
3
14.1, 68.3, 58.3, 35.1, 33.7, 31.9, 29.7, 29.4, 29.3, 29.3, 29.2, 29.0,
8.9, 25.9, 23.2, 18.3, 9.8. FT-IR (ATR, cm 1): 2973, 2924, 2894,
−
2
lamine (0.19 mL, 0.03 mmol, 0.02 equiv). Formamide 3a (778.4 mg,
1.87 mmol, 1.0 equiv) was added and the reaction was allowed to
mix at room temperature for 18 h. Solids were filtered through a
medium porosity fritted glass funnel then washed with anhydrous
2
121, 1606, 1504, 1251, 1076.12; High resolution MS (ESI): m/z cal-
culated for [C27H47NO SSi+Na]+ 532.2893, found 532.2903, error:
4
1
.9 ppm.
Et O (approx. 75 mL) then anhydrous CH Cl (approx. 75 mL). The
2
2
2
Silica-bound triethoxy(3-((3-(4-isocyanophenoxy)thio)propyl)silane
1a)
solids were dried under vacuum, then dried at 40 °C, 25 in Hg
for 11.5 h. Silica bound formamide 5a (1.09 g) was collected as a
white powder. Elemental analysis: (%N = 0.36; 0.26 mmol/g N). FT-
(
−
1
An oven-dried 50 mL round-bottom flask containing a magnetic
IR (DRIFT IR, KBr, cm ) 1678.
˚
stir bar was charged with silica gel (3.23 g, F60, 40-63 μm, 60 A),
PhH (9.0 mL), and triethylamine (0.6 mL, 4.3 mmol, 0.7 equiv). Iso-
cyanide 4a (2.39 g, 6.03 mmol, 1.0 equiv.) was dissolved in PhH (1.5
mL) and added slowly to the stirring suspension. The reaction was
allowed to mix at room temperature for 17 h. The solids were col-
lected by filtration on a medium porosity sintered glass funnel and
Funding
This work was supported by the National Science Foundation
(
CHE-1566162) and the Holm Catalyst Fund (University at Buffalo).
washed with anhydrous Et O four times then anhydrous CH Cl
2
2
2
Declaration of Competing Interest
four times. The solids were allowed to dry under vacuum. The elu-
ent was concentrated in vacuo to recover isocyanide 4a (1.98 g,
One of the authors (S.T.D.) has filed a provisional patent with
the University at Buffalo using isocyanides for the removal of met-
als from reactions.
5
.0 mmol, 83% recovery). A 50 mg aliquot of the solid was taken,
shaken with 0.7 mL CDCl , filtered, and the eluent was analyzed
3
by 1H NMR to verify that no residual triethylamine was present.
Solids were transferred to a vacuum oven and dried at 40 °C, 25
in Hg for 6 h. Silica-bound scavenger 1a (3.284 g) was collected as
an off-white powder. Elemental analysis: (%N = 0.34; 0.24 mmol/g
Acknowledgements
We thank Materia/Umicore for supplying Ru catalysts used in
this work. We gratefully acknowledge Dr. Valerie Frierichs (Direc-
tor, University at Buffalo Instrumentation Center) for assistance
with ICP-MS analysis and Professor Luis Colón’s group (University
at Buffalo) for access to their DRIFT IR spectrometer.
−1
N). FT-IR (DRIFT IR, KBr, cm ) 2151, 2125.
Silica bound triethoxy(3-((3-(4-isocyano-3,5-dimethylphenoxy)
propyl)thio)propyl)silane (1b)
˚
To a suspension of silica (1.17 g, F60, 40-63 μm, 60 A) and PhH
Supplementary materials
(
3.84 mL) was added isocyanide 4b (0.935 g, 2.19 mmol, 1.0 equiv)
and triethylamine (0.214 mL, 1.53 mmol, 0.7 equiv). The reaction
was stirred for 20 h at room temperature. The solids were col-
lected by filtration on a medium porosity sintered glass funnel and
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2021.
121800.
washed with anhydrous Et O four times then anhydrous CH Cl
2
2
2
four times. The solids were dried under vaccuum and the eluent
References
was concentrated in vacuo to recover 4b (0.407 g, 0.956 mmol,
4
4% recovery). A 50 mg aliquot of the solid was shaken with 0.7
[
1] (a) J.M. French, C.A. Caras, S.T. Diver, Removal of Ruthenium Using a Silica Gel
Supported Reagent, Org. Lett. 15 (2013) 5416–5419; (b) J.M. French, J.R. Grif-
fiths, S.T. Diver, Removal of Palladium from Cross-Coupling Reactions Using
Isocyanide Reagents, Adv. Synth. Catal. 357 (2015) 361–365; (c) B.R. Galan,
K.P. Kalbarczyk, S. Szczepankiewicz, J.B. Keister, S.T. Diver, A Rapid and Simple
Cleanup Procedure for Metathesis Reactions, Org. Lett. 9 (2007) 1203–1206.
2] (a) B.R. Galan, M. Gembicky, P.M. Dominiak, J.B. Keister, S.T. Diver, Carbon
Monoxide-Promoted Carbene Insertion into the Aryl Substituent of an N-Hete-
rocyclic Carbene Ligand: Buchner Reaction in a Ruthenium Carbene Complex,
J. Am. Chem. Soc. 127 (2005) 15702–15703; (b) B.R. Galan, M. Pitak, M. Gem-
bicky, J.B. Keister, S.T. Diver, Ligand-Promoted Carbene Insertion into the Aryl
Substituent of an N-Heterocyclic Carbene Ligand in Ruthenium-Based Metathe-
sis Catalysts, J. Am. Chem. Soc. 131 (2009) 6822–6832.
mL CDCl , filtered, and the eluent analyzed by 1H NMR to verify
3
no residual triethylamine was present. The solids were transfered
to a vaccuum oven and dried at 40 °C, 25 in Hg for 6 h. Silica
bound scavenger 2b (1.20 g) was collected as an off white powder.
Elemental analysis: (%N = 0.22; 0.18 mmol/g N). FT-IR (DRIFT IR,
[
−1
KBr, cm ) 2117, 2140.
Silica-bound triethoxy(3-((11-(4-isocyanophenoxy)undecyl)thio)
propyl)silane (1c)
[
3] (a) G. Szczepaniak, W. Noga s´ , J. Pia˛tkowski, A. Ruszczy n´ ska, E. Bulska, K. Grela,
Semiheterogeneous Purification Protocol for the Removal of Ruthenium Impu-
rities from Olefin Metathesis Reaction Products Using an Isocyanide Scavenger,
Org. Proc. Res. Dev. 23 (2019) 836–844; (b) G. Szczepaniak, A. Ruszczy n´ ska,
K. Kosi n´ ski, E. Bulska, K. Grela, Highly efficient and time economical purifi-
cation of olefin metathesis products from metal residues using an isocyanide
scavenger, Green Chemistry 20 (2018) 1280–1289; (c) G. Szczepaniak, K. Ur-
baniak, C. Wierzbicka, K. Kosi n´ ski, K. Skowerski, K. Grela, High-Performance
Isocyanide Scavengers for Use in Low-Waste Purification of Olefin Metathesis
Products, ChemSusChem 8 (2015) 4139–4148.
In an oven-dried 25 mL round-bottomed flask containing a stir
˚
bar, silica gel (640 mg, F60, 40-63μ μm, 60 A), PhH (5 mL), triethy-
lamine (0.12 mL, 0.85 mmol, 0.7 equiv) and 4c (610 mg, 1.2 mmol,
1
.0 equiv) were mixed for 24 h at room temperature. The mixture
was filtered, and the solids collected from filtration were washed
with anhydrous THF (three times with 10 mL) followed by anhy-
drous diethyl ether (three times with 10 mL). Isocyanide 4c (439
10

Z.R. Gregg, E. Glickert, R. Xu et al.
Journal of Organometallic Chemistry 944 (2021) 121800
[
4] J.R. Griffiths, E.J. Hofman, J.B. Keister, S.T. Diver, Kinetics and Mechanism
of Isocyanide-Promoted Carbene Insertion into the Aryl Substituent of an
N-Heterocyclic Carbene Ligand in Ruthenium-Based Metathesis Catalysts,
Organometallics 36 (2017) 3043–3052.
[12] T. Ritter, A. Hejl, A.G. Wenzel, T.W. Funk, R.H. Grubbs, A Standard System
of Characterization for Olefin Metathesis Catalysts, Organometallics 25 (2006)
5740–5745.
[13] (a) D. Amoroso, G.P.A. Yap, D.E. Fogg, Deactivation of Ruthenium Metathe-
sis Catalysts via Facile Formation of Face-Bridged Dimers, Organometallics
21 (2002) 3335–3343; (b) G.A. Bailey, M. Foscato, C.S. Higman, C.S. Day,
V.R. Jensen, D.E. Fogg, Bimolecular Coupling as a Vector for Decomposition
of Fast-Initiating Olefin Metathesis Catalysts, J. Am. Chem. Soc. 140 (2018)
6931–6944; (c) S.H. Hong, M.W. Day, R.H. Grubbs, Decomposition of a Key In-
termediate in Ruthenium-Catalyzed Olefin Metathesis Reactions, J. Am. Chem.
Soc. 126 (2004) 7414–7415; (d) S.H. Hong, A.G. Wenzel, T.T. Salguero, M.W. Day,
R.H. Grubbs, Decomposition of Ruthenium Olefin Metathesis Catalysts, J. Am.
Chem. Soc. 129 (2007) 7961–7968; (e) W. Janse van Rensburg, P.J. Steynberg,
W.H. Meyer, M.M. Kirk, G.S. Forman, DFT Prediction and Experimental Obser-
vation of Substrate-Induced Catalyst Decomposition in Ruthenium-Catalyzed
Olefin Metathesis, J. Am. Chem. Soc. 126 (2004) 14332–14333; (f) W.L. Mc-
Clennan, S.A. Rufh, J.A.M. Lummiss, D.E. Fogg, A General Decomposition Path-
way for Phosphine-Stabilized Metathesis Catalysts: Lewis Donors Accelerate
Methylidene Abstraction, J. Am. Chem. Soc. 138 (2016) 14668–14677.
[14] (a) Although DEDAM RCMs all reached 100% conversion, the DEDMAM RCMs
did not; (b) Ru6 was the most effective catalyst; see Table S3.
[
[
5] A.K. Tucker-Schwartz, R.A. Farrell, R.L. Garrell, Thiol–ene Click Reaction as a
General Route to Functional Trialkoxysilanes for Surface Coating Applications,
J. Am. Chem. Soc. 133 (2011) 11026–11029.
6] M. Berry, R.K. Champaneria, J.A.S. Howell, The preparation and catalytic activity
of Rhodium(I) complexes of isonitrile functionalized silica gel, J. Mol. Cat. 37
(1986) 243–252.
[
7] J. von Braun, W. May, R. Michaelis, Haftfestigkeit organischer Reste. (VIII. Mit-
teilung), Liebigs Ann. 490 (1931) 189–200.
8] We assumed this cleavage was equally efficient for silica-supported isocyanide
and formamide, as these functional groups were remote from the thioether
cleavage site.
[
[
9] Since good precision was observed, single analyses of 1a, 1b, and 1c batches
used in the following metal binding experiments were performed to find >90%
isocyanide and 0.20-0.26 mmol/g isocyanide loading for all materials as shown
in Scheme 3.
[
10] Isocyanide 4c was not investigated since the steric variation of 1c is due to the
distance of the isocyanide to the silica surface which is not present in solution
phase experiments.
[15] M. Hu, L. Li, H. Wu, Y. Su, P.-Y. Yang, M. Uttamchandani, Q.-H. Xu, S.Q. Yao,
Multicolor, One- and Two-Photon Imaging of Enzymatic Activities in Live Cells
with Fluorescently Quenched Activity-Based Probes (qABPs, J. Am. Chem. Soc.
133 (2011) 12009–12020.
[
11] It should be noted that although isocyanide binding of Ru2 may not have
reached completion within 30 min, all other Ru carbenes show >90% conver-
sion after this time period using 4 equiv 1a-1c. This suggests that these Ru
carbenes may have similar binding rates to Ru1.
11