Removable Water-Soluble Olefin Metathesis Catalyst via Host-Guest Interaction

Article abstract of DOI:10.1021/acs.orglett.7b03871

A highly removable N-heterocyclic carbene ligand for a transition-metal catalyst in aqueous media via host-guest interactions has been developed. Water-soluble adamantyl tethered ethylene glycol in the ligand leads a hydrophobic inclusion into the cavity of β-cyclodextrin. Ruthenium (Ru) olefin metathesis catalyst with this ligand demonstrated excellent performance in various metathesis reactions in water as well as in CH₂Cl₂, and removal of residual Ru was performed via filtration utilizing a host-guest interaction and extraction.

Full text of DOI:10.1021/acs.orglett.7b03871

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Removable Water-Soluble Olefin Metathesis Catalyst via Host−Guest
Interaction
Cheoljae Kim, Brian A. Ondrusek, and Hoyong Chung*
Department of Chemical and Biomedical Engineering, Florida State University, 2525 Pottsdamer Street, Building A, Suite A131,
Tallahassee, Florida 32310, United States
S
* Supporting Information
ABSTRACT: A highly removable N-heterocyclic carbene
ligand for a transition-metal catalyst in aqueous media via
host−guest interactions has been developed. Water-soluble
adamantyl tethered ethylene glycol in the ligand leads a
hydrophobic inclusion into the cavity of β-cyclodextrin.
Ruthenium (Ru) olefin metathesis catalyst with this ligand
demonstrated excellent performance in various metathesis
reactions in water as well as in CH2Cl2, and removal of residual
Ru was performed via filtration utilizing a host−guest
interaction and extraction.
omplete removal of homogeneous organometallic catalysts
is an important issue in modern chemistry.1−3 There are
catalysis,11 biomedical applications,8b,9c analytical chemistry,12
and many other areas due to its advantages in noncovalent
interaction, reversibility, bio and environmental compatibility,
and stimuli response. Adamantane (guest) and β-CD (host, 7-
membered cyclic polysaccharide) is known to demonstrate very
high association constant, Ka (log Ka = 5.04)13 which will enable
very efficient catalyst removal on a stationary solid according to
the principle illustrated in Figure 1.
C
two major removal methods of well-defined organometallic
catalysts: (1) solid-supported heterogeneous systems and (2)
homogeneous methods utilizing modified catalyst ligands.4
Homogeneous catalysts typically display many advantages over
heterogeneous catalysts such as rapid reaction rate, facile
characterization, higher reactivity, and chemoselectivity.5 In
spite of those general advantages, the homogeneous catalyst
cannot be easily removed by the simple methods available for
heterogeneous catalysts, such as filtration or decantation. Thus,
the combination of the homogeneous reactivity and heteroge-
neous removal represent ideal design principles for highly
reactive and removable organometallic catalysts as depicted in
Figure 1. In addition, catalysts bearing thermomorphic character-
Among many possible catalyst designs that can be used to
introduce our principle of host−guest catalyst removal, Ru-based
olefin metathesis catalysts are suitable catalyst systems due to
their practical utility in wide areas and high stability of the
resulting precatalysts toward air and moisture. Olefin metathesis
itself represents a ubiquitous chemical transformation for the
formation of carbon−carbon double bonds in the presence of a
transition-metal catalyst.14,15 In particular, Ru-based olefin
metathesis catalysts have garnered a strong following mainly
due to the low oxophilicity of Ru and their tolerance toward polar
functional groups, impurities, and solvents, including water. The
most frequently used Ru-based olefin metathesis catalyst is the
Hoveyda−Grubbs second-generation catalyst, which possesses
metal alkylidene and N-heterocyclic carbene (NHC) ligands.15,16
In spite of the importance of Ru-based olefin metathesis
catalysts, the complete removal of Ru residue from the resulting
products still represents a major challenge for their practical
application because the metal residue causes undesirable
electronic properties, colorization, and toxicity of pharmaceutical
products.4 Specifically, the maximum amount of Ru permissible
in pharmaceutical products is less than 10 ppm.17,18 Herein, we
Figure 1. Working principle for heterogeneous catalyst removal of a
homogeneous catalyst via host−guest interaction.
istics are well-established for their ability to be separated from
reaction solution. This can be achieved by utilizing a fluorous
biphasic system, thermoregulated phase-transfer catalyst, or
soluble polymer-based catalyst.6
Host−guest chemistry is a widely studied topic in supra-
molecular chemistry describing noncovalent molecular recog-
nition events between host molecules and guest molecules.7−9
Host−guest chemistry, in particular using cyclodextrin (CD)
hosts, has been extensively studied in polymer science,10
Received: December 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03871
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
report a new NHC ligand and the resulting Ru-based olefin
metathesis catalyst designed for the removal of Ru catalyst
residues via host−guest interactions and phase selective
solubilities of the new catalyst. One defining trait of the designed
catalyst is its complete solubility in water, allowing for high
performance in both aqueous and organic conditions. To the best
of our knowledge, the present report is the first example of an
almost complete removal of Ru-based olefin metathesis catalyst
in aqueous media after olefin metathesis and ring-opening
metathesis polymerization (ROMP).
fluoroborate yielded imidazolium salt 8. In situ generation of the
carbene of 8 with potassium bis(trimethylsilyl)amide, followed
by the addition of Hoveyda−Grubbs first-generation catalyst 9,
generated the desired precatalyst 3.
Figure 3 describes a Ru-catalyzed metathesis and catalyst
removal in aqueous media via host−guest interactions. After
Figure 2 displays three catalyst structures that utilize host−
guest interactions for the removal of organometallic catalysts.
Figure 3. Illustration of a typical olefin metathesis and host−guest
removal process in aqueous media.
Figure 2. Examples of catalysts which engage in host−guest interactions
with β-cyclodextrin, including our catalyst 3.
completion of the homogeneous metathesis reaction in water, as
soon as a host compound was added to the reaction mixture, the
heterogeneous host−guest complex was generated spontane-
ously between β-CD grafted silica and the adamantyl moiety on
the catalyst. Finally, the resulting heterogeneous solution was
filtered through a cotton plug to isolate the host−guest complex
containing the catalyst. The efficiency of removal was analyzed by
inductively coupled plasma mass spectrometry (ICP-MS) of the
filtered product. Herein, β-CD grafted silica was prepared
separately prior to the host−guest removal process by previously
reported methods.20
With the water-soluble catalyst 3, we explored a scope of ring-
closing metathesis (RCM) reactions of commonly used
substrates in aqueous media (Table 1). Overall, 3 demonstrated
high-efficiency on par with previously reported water-soluble Ru-
based olefin metathesis catalysts.21,22 Residual Ru levels were
measured by ICP-MS with fully converted examples. In entry 1,
quaternary ammonium salt 10 was fully converted into 17 with
only 53 ppm of residual Ru (calculated Ru level in the crude
product without any purification ∼5600 ppm). In order to
examine the affinity of catalyst 3 to unmodified silica without β-
CD, the product treated with unmodified silica showed
significant 1H NMR signals corresponding to the ethylene glycol
moiety of the NHC ligand. This result implies that the removal of
Ru from solution occurs effectively via host−guest interactions.
In addition, the Grubbs first-generation catalyst demonstrated
1912 ppm residual Ru after careful silica gel column
chromatography in CH2Cl2 according to previous studies.17,23
RCM of primary ammonium salt 12 showed 90% conversion
with 1 mol % catalyst after 48 h. Then 3 mol % catalyst loading
yielded full conversion (entry 2). The residual Ru level in this
Catalyst 1 contains an adamantyl tether for the recovery of Pd
catalyst following Suzuki−Miyaura coupling.19 Catalyst 2 is the
first example from our group of showing high removal of Ru-
based olefin metathesis catalyst in organic solvent using host−
guest interactions.20 The present work is concerned with catalyst
3, which is highly reactive in aqueous solution with excellent
removal rates of catalysts (0.14 ppm Ru residue in CH2Cl2 and 53
ppm in water).
In order to prepare water-soluble catalyst 3, we began with
readily available tetraethylene glycol (Scheme 1). Tetraethylene
glycol was converted into the adamantyl-tethered extended
ethylene glycol 4 via multiple iterative steps (see the Supporting
Information (SI) for details). The number of ethylene glycol
repeating units was increased sequentially through iterative
substitution reactions between tosylated ethylene glycol and
alcohols of another ethylene glycol compound. We were
concerned that a large number of oxygens from extended
ethylene glycols would increase the likelihood of coordination to
the central metal, thereby decreasing the catalytic activity. To
avoid this deactivation, we sought to find the minimum length of
ethylene glycol units to satisfy water solubility of the catalyst with
8, 16, 24, and 32 repeating units. Finally, 32 repeating units were
determined to be the minimal number. The 32 ethylene glycol
repeating unit containing methanesulfonate 5 was generated
from compound 4 with methanesulfonyl chloride and triethyl-
amine. Diamine compound 7 was synthesized using a
substitution reaction between compound 5 and N,N′-dimesi-
tyl-2,3-diamino-1-propanol 6. The reaction of the resulting
diamine 7 with triethyl orthoformate and ammonium tetra-
Scheme 1. Preparation of Catalyst 3
B
DOI: 10.1021/acs.orglett.7b03871
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Organic Letters
Letter
Table 1. RCM in Aqueous Media and Catalyst Removal via
Host−Guest Interaction
Scheme 2. ROMP in Aqueous Media with Use of Catalyst 3
a
water, and polymer 22 was obtained in quantitative yield. For the
removal of Ru catalyst with using the developed host−guest
interaction, we quenched the reaction with 0.1 mL of ethyl vinyl
ether. After removal of Ru catalyst by host−guest interaction
from polymer 22, the final Ru content was 269 ppm which
represents a 97.7% removal of Ru from solution (calculated Ru
level in crude polymer product ∼11500 ppm).
In addition, because the catalyst 3 is also homogeneously
soluble in organic solvents, we studied the scope of several olefin
metathesis substrates in CH2Cl2 (Table 3).24 The evaluated
Table 3. RCM in CH2Cl2 Solvent and Catalyst Removal via
Phase Selectivity
a
Reactions were carried out at 45 °C in D2O for 24 h. Conversions
a
b
1
were determined by H NMR spectroscopy. Analyzed by ICP-MS.
Fully converted products 11 and 13 were characterized to measure the
c
d
residual ruthenium levels. Isolated yield. Reactions were carried out
for 48 h.
case was 284 ppm, which means that 98.7% of the total Ru was
removed by the host−guest interaction (theoretical Ru level in
crude product ∼22000 ppm). Presumably, the reason is that
while the nitrogen of the tetraalkyl ammonium salt was highly
shielded having no association to Ru metal due to alkyls, nitrogen
of the primary ammonium may coordinate to the metal center
after ionization in water. RCM of hydrochloric acid salts (14, 16)
were tested (entries 3 and 4). Although they were moderately
active compared to carbocyclic substrates, the six-membered N-
heterocycle 15 was more favorably formed by RCM than five-
membered product 17 due to the low reactivity of catalyst as a
result of the formation of Ru hydride decomposition products
according to previous literature reports.21,22b
Isomerization and cross-metathesis (CM) of two different
olefins were successfully performed in aqueous media with
catalyst 3 as shown in Table 2. The first substrate cis-2-butene-
Table 2. Isomerization and Cross-Metathesis Reactions in
a
Aqueous Media
a
Reactions were carried out at 40 °C with 1 mol % of catalyst 3 in
CH2Cl2 for 1 h. Conversions were determined by 1H NMR
spectroscopy. The detailed catalyst removal procedure is described
in the SI. Analyzed by ICP-MS. Reactions were carried out at room
temperature. Isolated yield. The diluted crude product was washed
with water 5 times. The extracted crude product was filtered through a
b
c
d
e
f
silica plugged column.
a
Reactions were carried out at room temperature with 5 mol % of
catalyst 3 in D2O for 24 h. Conversions were determined by 1H NMR
spectroscopy. 6% of cis isomer remains due to thermodynamic
equilibrium. E/Z ∼ 8.5:1.
b
olefins 23, 25, 29, 31, and 33 demonstrated full conversion under
the optimized conditions, 1 mol % of 3 at 40 °C for 1 h.
Unsubstituted cyclopentenes (24, 30) were obtained at room
temperature. Hindered olefin substrate 27 showed very low
conversion due to steric congestion. The results in Table 3
suggest that the new catalyst 3 can be universally used in both
aqueous media and organic solvent with high catalytic efficiency
over a broad range of olefin substrates. The catalyst 3 is easily
soluble in water as well as in common organic solvents for olefin
metathesis such as CH2Cl2 and toluene. However, 3 is not
soluble in diethyl ether due to the presence of ethylene glycol
c
1,4-diol 18 was converted to its corresponding trans isomer 19 in
94%, while the remaining 6% resulting from thermodynamic E/Z
equilibrium (Table 2, entry 1). A cross-metathesis reaction of
allyl alcohol 20 yielded 94% of the desired metathesis product
with 8.5:1 E/Z ratio (Table 2, entry 2).
As shown in Scheme 2, the catalyst 3 was also utilized to
perform ROMP of water-soluble norbornene monomer 21 in
C
DOI: 10.1021/acs.orglett.7b03871
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Organic Letters
Letter
segment.24c By leveraging this observed phase-selective solubility
of catalyst 3, the catalyst was extracted into the aqueous phase
from the diethyl ether layer (see SI for detailed removal
procedure). This phase-selective method yielded excellent
removal efficiency, displaying 0.14−5.9 ppm of Ru residues
according to ICP-MS results. Although phase-selective removal
is not the key motivation of the present work, this removal
method presents an alternative option for catalyst removal when
organic solvents are preferred.
We have developed a highly removable NHC ligand which
relies upon host−guest interactions in aqueous media. The
described NHC-containing Ru-based olefin metathesis catalyst
demonstrated excellent catalytic efficiency for RCM, CM, and
ROMP in both aqueous and organic solvents. After reaction, the
Ru catalyst was successfully removed (53 ppm Ru residue
99.1% removalfrom RCM in water via host−guest interaction,
269 ppm Ru residue97.7% removalfrom ROMP in water via
host−guest interaction, 0.14 ppm from RCM in CH2Cl2 via
extraction). The new NHC ligand possessing ethylene glycol
segment-tethered adamantyl moieties demonstrates a crucial role
for high-yield catalyst removal via host−guest interactions and
catalyst reactivity. The described NHC ligand and resulting
catalyst demonstrates potential for application in many areas of
organic synthesis, materials science, and green chemistry, not just
those related to olefin metathesis. Further detailed studies of
host−guest interactions of NHCs and organometallic catalysts
are underway in our group.
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ASSOCIATED CONTENT
* Supporting Information
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■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03871.
1
Experimental procedures, characterization data, and H,
13C NMR spectra for catalysts and new compounds (PDF)
(17) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 6786.
(18) Committee for medicinal products for human use (CHMP).
Guidelines on the specification limits for residues of metal catalysts or metal
reagents; Doc. Ref. EMEA/CHMP/SWP/4446/2000; European
Medicines Agency: London, Feb 2008; pp 1−34.
(19) Qi, M.; Chew, B. K. J.; Yee, K. G.; Zhang, Z.-X.; Young, D. J.; Hor,
T. S. A. RSC Adv. 2016, 6, 23686.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hchung@fsu.edu.
ORCID
(20) Ondrusek, B. A.; Chung, H. ACS Omega 2017, 2, 3951.
(21) Tomasek, J.; Schatz, J. Green Chem. 2013, 15, 2317.
(22) For selected examples of olefin metathesis in aqueous media, see:
(a) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996, 15,
4317−4325. (b) Gallivan, J. P.; Jordan, J. P.; Grubbs, R. H. Tetrahedron
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Gulajski, L.; Bieniek, M.; Grela, K. Catal. Sci. Technol. 2012, 2, 2424.
(e) Skowerski, K.; Wierzbicka, C.; Szczepaniak, G.; Gulajski, L.; Bieniek,
M.; Grela, K. Green Chem. 2012, 14, 3264.
Cheoljae Kim: 0000-0002-4771-8656
Hoyong Chung: 0000-0003-0370-230X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Florida State University Energy
and Materials Hiring initiative and the FSU Department of
Chemical and Biomedical Engineering. We acknowledge Dr.
Banghao Chen for support of the NMR facilities and Dr. Umesh
Goli for the mass spectroscopy at Florida State University. We
also thank Evandro Barbosa da Silva at University of Florida for
the ICP-MS analysis.
(23) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531.
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DOI: 10.1021/acs.orglett.7b03871
Org. Lett. XXXX, XXX, XXX−XXX