A Resin-Bound Peptoid as a Recyclable Heterogeneous Catalyst for Oxidation Reactions

Article abstract of DOI:10.1002/ejoc.201901739

Reusable solid-grafted catalysts have environmental and economical advantages over soluble catalysts. Numerous catalysts, including peptides, were immobilized on solid supports to enable their recyclability. Nevertheless, the few catalytic peptoids – N-substituted glycine oligomers – reported to date were only used off-resin. The soluble peptoids BT and DI, a trimer and dimer having two catalytic side-chains, were developed as bio-inspired oxidation catalysts. BT has an additional structure-directing group, which enables intramolecular cooperativity between the two catalytic groups (“intra-peptoid” mode). Thus, it catalyzes the oxidation of primary alcohols with much higher efficiency than DI. Herein, we present resin-bound BT and DI (TG-BT and TG-DI) as the first insoluble and recyclable catalytic peptoids. We discovered that though TG-BT also operates through the intra-peptoid cooperativity mode, it is less efficient than BT, even after several cycles. On the other hand, TG-DI is far more active than DI and can be recycled several times to enable a much higher turn-over-number. Our studies revealed that TG-DI operates through an intra-resin cooperativity mode, and this enables its high activity compared with DI, BT and TG-BT.

Full text of DOI:10.1002/ejoc.201901739

DOI: 10.1002/ejoc.201901739
Full Paper
On-Resin Catalysis
A Resin-Bound Peptoid as a Recyclable Heterogeneous Catalyst
for Oxidation Reactions
Yekaterina Stamatin[a] and Galia Maayan*[a]
Abstract: Reusable solid-grafted catalysts have environmental much higher efficiency than DI. Herein, we present resin-bound
and economical advantages over soluble catalysts. Numerous BT and DI (TG-BT and TG-DI) as the first insoluble and re-
catalysts, including peptides, were immobilized on solid sup- cyclable catalytic peptoids. We discovered that though TG-BT
ports to enable their recyclability. Nevertheless, the few cata- also operates through the intra-peptoid cooperativity mode, it
lytic peptoids – N-substituted glycine oligomers – reported to is less efficient than BT, even after several cycles. On the other
date were only used off-resin. The soluble peptoids BT and DI, hand, TG-DI is far more active than DI and can be recycled
a trimer and dimer having two catalytic side-chains, were devel- several times to enable a much higher turn-over-number. Our
oped as bio-inspired oxidation catalysts. BT has an additional studies revealed that TG-DI operates through an intra-resin co-
structure-directing group, which enables intramolecular co- operativity mode, and this enables its high activity compared
operativity between the two catalytic groups (“intra-peptoid” with DI, BT and TG-BT.
mode). Thus, it catalyzes the oxidation of primary alcohols with
Introduction
were synthesized via solid-phase methods and used on-resin in
the reaction mixture.[3] The use of on-resin catalysts enable to
avoid typical work-up and purification steps that are not only
laborious but can also lead to product loss. In addition, com-
pounds immobilized on a swellable solid support are solvated
within the matrix of the resin; hence, they are expected to be
more effectively solvated than the non-bound catalyst, over-
coming the limitations of a reaction within a heterogeneous
solution.[3b,3c]
Peptoids, N-substituted glycine oligomers,[4] are an impor-
tant class of peptidomimetic foldamers,[5] with demonstrated
utilities such as metal binding[6] and solution catalysis.[7] Pep-
toids can be efficiently generated on resin by a solid-phase
method (the “submonomer method”, Figure 1)[8] from various
primary amines,[9] with high sequence specificity, and are
chemically inert towards many catalytic transformations.
Based on these features, we have recently designed and de-
veloped a unique bio-inspired oxidation catalyst, BT, which in-
corporates two catalytic side-chains, phenanthroline-copper
and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and one non-
catalytic benzyl group.[7b,7c] We showed that BT, combined with
CuI and N-methyl imidazole (NMI) in an acetonitrile solution,
The continuous financial and environmental demands, particu-
larly within the pharmaceutical industry, call for the use of
highly efficient and benign procedures suitable for large-scale
production with minimum waste. One approach for increasing
catalysts efficiencies is to attach them to a solid support and
use these in heterogeneous systems, such that the bound cata-
lyst can be separated at the end of the reaction and recycled
multiple times in subsequent catalytic reactions. In addition,
catalysts grafted on solid support, which can be easily recov-
ered and recycled, are desirable for achieving cleaner, cheaper
and environmentally friendly processes. As a result, many im-
mobilized organometallic catalysts and organocatalysts have
been developed.[1,2] Several examples of resin-supported pept-
ide catalysts were also reported; in these cases the peptides
[a] Schulich Faculty of Chemistry, Technion – Israel Institute of Technology
Technion City, Haifa 3200008, Israel
E-mail: gm92@technion.ac.il
https://gmaayanlab.net.technion.ac.il/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901739.
Galia Maayan was born in 1974 and studied Chemistry at Tel Aviv University and at The Weizmann Institute of Science, Israel. She was a
Postdoctoral research associate with Prof. Michael D. Ward and Prof. Kent Kirshenbaum, in the Molecular Design Institute at New York University
and with Prof. George Christou in the Department of Inorganic Chemistry at the University of Florida. In the spring of 2012 she joined the Schulich
Faculty of Chemistry at the Technion, Israel as an Assistant Professor. In 2019 she was promoted to Associate Prof. with tenure. The research interests
in her lab focus on bio-inspired metal complexes and on the interactions between biomimetic oligomers and metal species (ions, nanoparticles)
for applications in folding, recognition, supramolecular structures, catalysis and energy.
Yekaterina (Katia) Stamatin was born in 1995 and studied Chemistry and Material Engineering at the Technion – Israel Institute of Technology. She
graduated with honors in 2019. During her studies she joined the lab of Prof. Galia Maayan as an undergraduate researcher and studied peptoids
as chelators for metal ions and as catalysts.
Eur. J. Org. Chem. 0000, 0–0
1
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
used on-resin in two oxidation reactions; benzyl alcohol oxid-
ation and the oxidative coupling of benzyl alcohol and various
amines for the formation of imines (Figure 2B and Figure 2C).
Figure 1. The two-steps solid-phase synthesis of peptoids in the “submono-
mer” method.
performs in the oxidation of benzylic, allylic and aliphatic pri-
mary alcohols with turn-over-frequency (TON) of up to 490 (at
0.1 mol-% catalyst). This TON is 16 times higher than the TON
obtained when a mixture of the two catalytic groups, or the
peptoid dimer (DI) that is lacking the non-catalytic group were
used in the same reaction conditions. Our suggested explana-
tion for the differences in reactivity is that the non-catalytic
group constricts the spatial distance between the two catalytic
groups leading to the creation of a catalytic pocket that per-
forms via intramolecular cooperativity.[7c] We also demonstrated
the higher catalytic activity of BT in the oxidative coupling of
alcohols and amines for the production of various imines (TON
up to 980 at 0.1 mol-% catalyst),[7b] compared with the reported
catalytic system, in which the two catalytic groups were mixed
in solution (TON up to 50).[10] Following this initial success we
thought to further develop BT as a recyclable catalyst capable
of performing on-resin in a heterogeneous system, and test
whether it can perform with much higher TON in the oxidation
of primary alcohols and the oxidative coupling of alcohols and
amines.
Figure 2. (a) The sequence of the catalysts used in this study. (b) The two
reactions, benzyl alcohol oxidation and oxidative coupling of benzyl alcohol
and various amines,that were attempted to be catalyzed by on-resin pep-
toids.
In order to explore the reactivity of TG-BT as a catalyst in
the heterogeneous oxidation of primary alcohols, it was sus-
pended in acetonitrile and subjected to the same reaction con-
ditions that worked well in the homogeneous system.[7c] Thus,
it was treated with CuI and NMI and this solution was stirred
for one hour in room temperature, in order to create the Cu-
peptoid complex. Thereafter benzyl alcohol was added, the re-
action vessel was sealed under oxygen atmosphere and the
reaction mixture was stirred for 24 hours prior to its analysis by
Gas Chromatography (GC). Initially, 0.5 mol-% of TG-BT were
used, just as in the previous homogeneous reaction, but only
54 % conversion to the aldehyde were obtained (Table 1, entry
1). As the use of CuI only, even at 2 mol-%,[13] did not yield any
product, we have increased the peptoid loading to 1 mol-%
and the CuI loading to 2 mol-%, but this did not lead to an
increase in the obtained aldehyde (Table 1, entries 2–3). Only
when the temperature was increased to 40 °C, we could obtain
an increase in product formation to 88 % conversion (Table 1,
entry 4). Notably, using TG-DI and CuI in the same amounts
and reaction conditions led to full conversion. Decreasing the
amount of TG-DI to 0.5 mol-%, however, resulted in a decrease
The functionalization of copper-bipyridine (CuBipy) with
polymer resins was already reported, showing that solid-sup-
ported CuBipy can catalyze the aerobic oxidation of primary
benzylic alcohols in a heterogeneous system.[11] In this system,
however, only Bipy was supported, while the nitroxyl catalyst
operated in solution. Moreover, the supported catalysts were
used at 5 mol-% loading and therefore the TON even after
seven runs was less than 140.
Results and Discussion
Table 1. Catalyst optimization studies in the oxidation of benzyl alcohol.[a]
In our previous work, BT and DI were synthesized on a Rink-
amide resin. However, literature reports both on solid-sup-
ported CuBipy catalysts and on resin-bound peptide catalysts,
suggest that the use of TentaGel (polyethylene glycol–polysty-
rene) resin leads to the best catalytic results.[11,12] We therefore
decided to prepare the two peptoids on TentaGel resin. The
two peptoids were also prepared on rink amine resin to be used
as control catalysts. The peptoids were synthesized manually
according to the “submonomer” method and only a small sam-
ple was cleaved from the resin for analysis. The peptoids were
characterized by Reverse Phase High Performance Liquid Chro-
matography (RP-HPLC) and mass spectrometry (MS), and their
purity was determined by HPLC to be 93 % for BT and 86 % for
DI. The un-cleaved peptoids TG-BT and TG-DI (Figure 2A) were
Entry
Peptoid
mol-%
peptoid
mol-%
CuI
Conversion[b]
1[c]
2[c]
3[c]
4
5
6
TG-BT
None
0.5
–
1
1
1
0.5
1
1
0.5
2
2
2
2
2
54
< 5
54
88
> 99
46
TG-BT
TG-BT
TG-DI
TG-DI
RA-BT
RA-DI
7
8
2
2
17
5
[a] Reactions were performed in acetonitrile (1 mL) at 40 °C and under oxy-
gen atmosphere, with 3.3 μmol catalyst, 6.6 μmol CuI, 6.6 μmol NMI and
330 μmol benzyl alcohol for 24 hours. [b] Conversions were determined by
gas chromatography. [c] Reaction was done at room temperature (about
20 °C).
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
in product formation to 46 %. Moreover, the use of BT or DI on benzylamine, and TG-DP incorporating the phenanthroline
rink amine resin (RA-BT and RA-DI) led to only a small conver- group and benzylamine. Using these two peptoids for the oxid-
sion of the alcohol to the aldehyde (Table 1, entries 7–8). Over- ation of benzyl alcohol at the same reaction conditions de-
all, our results suggest that the best peptoid to catalyze this scribed in Table 1, entries 5 and 6, we discovered that each
reaction on resin is TG-DI in 1 mol-% under oxygen atmosphere peptoid alone could not catalyze this reaction. However, if the
at 40 °C. This observation is both remarkable and surprising: (a) two peptoids are used together, catalytic intermolecular coop-
because in the homogeneous system BT was shown to be a erativity is possible. Thus, by using 0.5 or 1 mol-% TG-DT to-
much better catalyst than DI and this was rationalized by the gether with 0.5 or 1 mol-% TG-DP, respectively, the conversion
intramolecular cooperativity between TEMPO and Cu-phen- from alcohol to aldehyde was 88 % and > 99 %, respectively.
anthroline (CuPhen), which was only possible within BT, and (b) The high conversions suggest that the inter-resin mode is feasi-
because in the homogeneous system we obtained only 34 % ble. An additional experiment, where different concentrations
conversion when DI was used as a catalyst (at 1 mol-%), while of TG-DI were used to catalyze benzyl alcohol oxidation, indi-
in the heterogeneous system full conversion is obtained.
According to Table 1, changing the amount of TG-BT did not
effect the conversion in the reaction, while changing the
amount of TG-DI did. This observation is consistent with our
previous results in the homogeneous system suggesting that
the cooperativity between TEMPO and CuPhen is intramolec-
ular in the case of TG-BT and intermolecular in the case of
TG-DI. Here, just like in the homogeneous system, the term
“intramolecular cooperativity” refers to the cooperativity be-
tween TEMPO and CuPhen groups that are located within the
same peptoid (“intra-peptoid”, Figure 3). Notably, this coopera-
tivity mode might be less effective when the peptoid is resin-
bound than when its unbound (steric effects). However, while
in the homogeneous system the term “intermolecular coopera-
tivity” refers to cooperativity between TEMPO and CuPhen
groups that are not located within the same peptoid but rather
within two separate peptoids in the solution (“inter-peptoid”),
here “intermolecular cooperativity” can refer to either the coop-
erativity between TEMPO and CuPhen groups that are located
within two separate peptoids bound to the same resin bead
(“intra-resin”, Figure 3) or two separate peptoids bound to two
different resin beads (“inter-resin”, Figure 3). If the reaction with
TG-DI takes place either intra-resin or both intra-resin and inter-
resin, while the reaction with TG-BT occurs only intra-peptoid,
this can explain the better conversions obtained with TG-DI
compared to the results obtained when either TG-BT or DI (that
operates in solution only via the inter-peptoid cooperativity
mode), are used as catalysts.
cates that the reaction conversion is highly dependent on the
concentration of the catalyst, supporting an inter-resin mode of
activity (Figure 4a). To test whether the intra-resin mode is also
possible when using TG-DI as a catalyst, we wished to vary to
amount of DI oligomers on the resin and see if the conversion
is changing accordingly. Therefore, we have synthesized six
batches of TG-DI such that in each batch different concentra-
tions of amines were used in the relevant synthetic steps. These
six types of TG-DI catalyst were used in the oxidation of benzyl
alcohol in the same reaction conditions as described in Table 1,
entry 5. The results show a clear dependence of the alcohol
conversion on the amount of peptoid catalyst bound to the
resin (Figure 4b), suggesting that there is an intermolecular cat-
alytic cooperativity in the intra-resin mode. The highest conver-
sion of about 97 % was obtained when 1
M amines where used
in the synthesis suggesting that these synthetic conditions pro-
duce the optimal amount of peptoids on one resin bead. At
lower concentrations, there was a decrease in the alcohol con-
version, suggesting that there are lower interactions between
peptoids on more diluted resin beads, and thus supporting the
activity of the catalyst via the intra-resin cooperativity mode. At
higher concentrations, there was also a decrease in the conver-
sion, indicating that the presence of too many peptoid oligom-
ers on one resin bead is not desirable for the activity of this
catalyst. Overall, these results suggest that TG-DI operates in
both the inter-resin and intra-resin cooperativity modes, which
can explain its higher activity, compare to TG-BT and DI.
Figure 3. The three different cooperativity modes suggested for the catalytic
activity of TG-DI (intra-resin and inter-resin) and of TG-BT (intra-peptoid).
Figure 4. (a) Conversion of benzyl alcohol to benzaldehyde as a function of
the concentration of the catalyst. (b) Conversion of benzyl alcohol to benz-
aldehyde as a function of the amounts of incorporated amines within TG-DI.
All the reactions were performed in acetonitrile (1 mL) at 40 °C and under
oxygen atmosphere, with 3.3 μmol catalyst, 6.6 μmol CuI, 6.6 μmol NMI and
330 μmol benzyl alcohol for 24 hours. Benzaldehyde conversions were deter-
mined by gas chromatography (GC).
To probe this point and to suggest a catalytic mode of opera-
tion in the heterogeneous system, we performed three experi-
ments. First, in order to check whether an inter-resin mode is
possible with TG-DI, two additional on-resin peptoid dimers
were synthesized: TG-DT, which includes the TEMPO group and
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
In order to evaluate the progress of the reaction with time
The oxidative coupling of benzyl alcohol and benzylamine,
and to determine the time needed to obtain full conversion, using 0.1 mol-% TG-DI was repeated and a sample from the
solution was analyzed by GC every several hours. The results
showed a sharp increase in imine conversion to about 80 % in
8 hours but full conversion was only achieved after 22 hours
(Figure S12). Recycling of TG-DI (0.1 mol-%) was done following
the same procedure that was used in the oxidation of alcohols
(see above). After the second cycle the conversion was 83 %,
and this was decreased further to 53 % after the third cycle.
The catalyst was recycled four more times and the conversion
decreased gradually to about 20 % in the last cycle (Figure S14).
Additional cycles yielded even lower conversions. The overall
TON after 8 cycles was therefore 2762, almost 3 times higher
and about 60 times higher than the highest TON obtained
when BT or DI, respectively, were used in the homogeneous
system.
Finally, the scope of the oxidative coupling reaction using
0.1 mol-% TG-DI, 1 equiv. of benzyl alcohol and 1.1 equiv. of
an amine (see SI for details) was evaluated. The results, depicted
in Figure 5, show that the highest conversions (> 95 %) were
obtained with benzyl-containing aromatic amines, while with
(S)-(–)-1-(1-Naphthyl)ethylamine the conversion is lower (86 %),
suggesting that the size of the aromatic group effects the reac-
tion. As expected, the conversions of the less reactive aliphatic
amines were also lower, but still comparable to these obtained
when BT was used as a homogeneous catalyst.[7b]
we have repeated the reaction from Table 1, entry 5 and ana-
lyzed by GC a sample from the solution every several hours. The
results showed a gradual and rather linear increase in alcohol
conversion, and full conversion was achieved already after 17
hours (Figure S11). Finally, we wished to explore whether the
catalyst TG-DI can be re-used, as its recyclability will enable to
obtain an overall TON higher than that achieved in one catalytic
reaction. We note here that the bound peptoid can only be
cleaved from the resin in highly acidic conditions, meaning it
cannot be cleaved from the resin in the catalytic conditions
applied during the oxidation reaction, and thus leaching of the
catalyst was not observed. In addition, as the resin is not
swelled in acetonitrile, the resin-bound catalyst is precipitated
at the end of the reaction, when the stirring is stopped. There-
fore, TG-DI could be simply separated from the solution of the
reaction mixture at the end of the reaction and re-used in a
subsequent identical oxidation reaction. Accordingly, after re-
peating the reaction described in Table 1, entry 5, the solvent
was decanted, the resin-bound catalyst was washed three times
with acetonitrile, which was decanted each time, and used
again in an identical reaction. The conversion of the alcohol in
the second cycle was about 90 % and the catalyst was sepa-
rated, washed and used again for four more consecutive cycles.
A rather constant decrease in the alcohol conversion was ob-
served in each cycle reaching a conversion of about 5 % in the
fifth cycle (Figure S13). The overall TON for the oxidation reac-
tion of benzyl alcohol using TG-DI at 1 mol-% was 296 – about
10 times higher than the TON obtained when 1 mol-% DI was
used as a catalyst in the homogeneous reaction. With these
results we have demonstrated for the first time the recycl-
ability of a peptoid catalyst in a heterogeneous catalytic
system.
Encouraged by these results we wished to test the catalytic
capability and recyclability of TG-DI in the oxidative coupling
of alcohols and amines to form imines.[7b] Initially, benzyl alco-
hol and benzylamine (in the same concentration as benzyl alco-
hol) were used as substrates and the reaction was carried out
in the same conditions described in Table 1, entry 5 (1 mol-%
catalyst), but without NMI, which is not needed in this reac-
tion.[7b] These conditions lead to > 99 % conversion. Decreasing
the catalyst loading to 0.5 mol-% or to 0.2 mol-% still yielded
> 99 % conversion. At 0.1 mol-% catalyst the conversion was
still high (96 %), but lowering it further led to lower conversion
(e.g., at 0.05 mol-% the conversion was 85 %). The highest TON
obtained in this reaction using TG-DI as a catalyst was therefore
960, similar to the TON obtained when BT was used as a catalyst
in the homogeneous system (980) but, notably, about 20 times
higher than the TON obtained when DI was used as a catalyst
in the homogeneous system (< 5 % conversion and TON < 50
in the oxidative coupling of benzyl alcohol and benzylamine at
0.1 mol-% catalyst). This result is remarkable for a heterogene-
ous system and can be explained by the observation that at
the range of 0.1–1 mol-% catalyst, the conversion to imines is
not dependent on the concentration of the catalyst, suggesting
that it operates only via the intra-resin mode.
Figure 5. Substrate scope in the oxidative coupling of benzyl alcohol with
various amines. Reactions were performed in acetonitrile (1 mL) at 40 °C with
3.3 mmol alcohol, 3.6 mmol amine, 0.1 mol-% TG-DI and 0.2 mol-% CuI under
oxygen atmosphere for 24 h. Conversions were determined by GC.
Conclusions
In this work we report an important advance in foldamers
chemistry – the finding that catalytic peptoids that are synthe-
sized on solid support (resin) can be also used on-resin. Thus,
they can perform as effective and recyclable catalysts in the
oxidation of benzyl alcohol and in the oxidative coupling of
benzyl alcohol with various amines to form imines; the later
with an overall TON of about 3000, three times higher or even
60 times (!) higher than the TON obtained using BT or DI, re-
spectively, as off-resin catalysts. We have previously demon-
strated that BT can catalyze the oxidation of primary alcohols
and the oxidative coupling of alcohols and amines with a TON
20 times higher than a mixture of the two catalytic groups, or
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
acetonitrile. After three washes, the resin was left with small
amount of solvent.
the peptoid DI in the same reaction conditions. We therefore
suggested that BT catalyzes the reactions via an intra-peptoid
cooperativity mode that enables its high efficiency. In the
present work, we have synthesized BT and DI on TentaGel resin
and tested the performance of resin-bound BT (TG-BT) and DI
(TG-DI) as heterogeneous and recyclable catalysts in the same
oxidation transformations. We discovered that although both
peptoids can be used as on-resin recyclable catalysts, TG-DI is
a much better catalyst than TG-BT. To understand this result,
we have changed the amount of peptoid on the resin or the
concentration of the catalyst in solution, and tested a mixture
of two control peptoid dimers, TG-DP and TG-DT, bearing a
benzyl group and either a phenanthroline or TEMPO group, re-
spectively. The results from these experiments showed that TG-
DI catalyzes the oxidation of benzyl alcohol in an intra-resin
cooperative mode, which we suggest that due to steric consid-
erations in the heterogeneous system, is superior to the intra-
peptoid cooperativity. Although there are several examples of
soluble catalytic peptoids, the use of on-resin peptoid catalysts
enable not only to recycle them and obtain higher TON, but
also to avoid typical work-up and purification steps that are
laborious, expensive and can lead to product loss. As such, this
work represents an important progress in the construction of
peptoids and other peptidomimetic oligomers as efficient and
recyclable on-resin catalysts towards applications in energy and
pharmaceuticals related research.
Acknowledgments
This research was funded by the Israeli Science Foundation (ISF),
grant number 395/16. The authors thank Mr. Guilin Ruan from
the Schulich Faculty of Chemistry, Technion, for performing
some of the catalytic experiments.
Keywords: Heterogeneous catalysis · Peptoids · Alcohol
oxidation · Oxidative coupling · On-resin recycling
[1] Recent books: a) Catalyst Immobilization: Methods and Applications (Eds.:
M. Benaglia, A. Puglisi), John Wiley & Sons, 2019; b) Handbook of Metath-
esis, Volume 2: Applications in Organic Synthesis (Eds.: H. Robert Grubbs,
J. O′Leary Daniel), John Wiley & Sons, 2015; c) Zinc catalysis: applications
in organic synthesis (Eds.: S. Enthaler, X. F. Wu), John Wiley & Sons, 2015;
d) Organometallics for Green Catalysis (Eds.: P. H. Dixneuf, J. F. Soulé),
Springer, 2019; e) Sustainable Catalysis in Ionic Liquids (Ed.: P. Lozano),
CRC Press, 2018.
[2] Representative reviews: a) A. F. Trindade, P. M. P. Gois, C. A. M. Afonso,
Chem. Rev. 2009, 109, 418–514; b) T. E. Kristensen, T. Hansen, Eur. J. Org.
Chem. 2010, 3179–3204; c) S. Huebner, J. G. de Vries, V. Farina, Adv. Synth.
Catal. 2016, 358, 3–25; d) P. Hu, M. Long, Appl. Catal. B 2016, 181, 103–
117; e) Y. Boyjoo, H. Sun, J. Liu, V. K. Pareek, S. Wang, Chem. Eng. J. 2017,
310, 537–559; f) T. E. Rosser, C. D. Windle, E. Reisner, Angew. Chem. Int.
Ed. 2016, 55, 7388–7392; Angew. Chem. 2016, 128, 7514.
[3] a) A. Berkessel, B. Koch, C. Toniolo, M. Rainaldi, Q. B. Broxterman, B. Kap-
tein, Biopolymers (Peptide Science) 2006, 84, 90–96; b) Y. Arakawa, M.
Wiesner, H. Wennemers, Adv. Synth. Catal. 2011, 353, 1201–1206; c) K.
Akagawa, K. Kudo, Angew. Chem. Int. Ed. 2012, 51, 12786–12789; Angew.
Chem. 2012, 124, 12958; d) L. Tuchman-Shukron, S. J. Miller, M. Portnoy,
Chem. Eur. J. 2012, 18, 2290–2296.
[4] a) N. Gangloff, J. Ulbricht, T. Lorson, H. Schlaad, R. Luxenhofer, Chem. Rev.
2016, 116, 1753–1802; b) A. S. Knight, E. Y. Zhou, M. B. Francis, R. N.
Zuckermann, Adv. Mater. 2015, 27, 5665–5691; c) C. A. Olsen, Biopolymers
2011, 96, 561–566.
Experimental Section
Catalysis Experiments: A typical heterogeneous catalytic oxidation
of benzyl alcohol was performed as following: the peptoid on differ-
ent resins (1 mol-%, 3.3 μmol) and CuI (6.6 μmol, 2 equiv.) were
placed in a dry vial, which was then capped with a septum under
nitrogen environment. Dry acetonitrile (0.3 mL) was added, and the
mixture was stirred for 2 minutes at room temperature following
by the addition of N-methylimidazole (6.6 μmol, 2 equiv.). The vial
was opened to room atmosphere and additional acetonitrile
(0.7 mL) was added. The mixture was stirred for 1 hour at room
temperature to enable peptoid-metal complex formation. After 1
hour, benzyl alcohol (330 μmol) was added, and a small oxygen
balloon at atmospheric pressure attached to a needle was inserted
via the septum. The mixture was allowed to stir at about 40 °C for
24 hr before it was cooled down and analyzed by GC. A typical
heterogeneous catalytic synthesis of imines was performed as fol-
lowing: the peptoid on Tentagel resin (0.1 mol-%, 0.33 μmol) and
CuI (0.66 μmol, 2 equiv.) were placed in a dry vial, which was then
capped with a septum under nitrogen environment. Dry acetonitrile
(0.3 mL) was added, and the mixture was stirred for 2 minutes at
room temperature before benzylamine (363 μmol) was added. The
vial was opened to room atmosphere and additional acetonitrile
(0.4 mL) was added. The solvent was stirred for 1 hour at room
temperature, to enable peptoid-metal complex formation. After 1
hour, the alcohol (330 μmol) was added, and a small oxygen balloon
at atmospheric pressure attached to a needle was inserted via the
septum. The mixture was allowed to stir at about 40 °C for 24 hr
before it was cooled down and analyzed by GC.
[5] a) I. M. Mándity, F. Fülöp, Expert Opin. Drug Delivery 2015, 10, 1163–1177;
b) G. Maayan, M. Albrecht, Metallofoldamers. Supramolecular Architectures
from Helicates to biomimetics, Wiley, Hoboken, 2013; c) G. Guichard, I.
Huc, Chem. Commun. 2011, 47, 5933–5941; d) D. Seebach, J. Gardiner,
Acc. Chem. Res. 2008, 41, 1366–1375; e) S. Hecht, I. Huc, Foldamers: struc-
ture, properties, and applications, Wiley-VCH, Weinheim, 2007; f) D. J. Hill,
M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev. 2001, 101,
3893–4012; g) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180.
[6] a) C. De Cola, S. Licen, D. Comegna, E. Cafaro, G. Bifulco, I. Izzo, P. Tecilla,
F. De Riccardis, Org. Biomol. Chem. 2009, 7, 2851–2854; b) I. Izzo, G.
Ianniello, C. De Cola, B. Nardone, L. Erra, G. Vaughan, C. Tedesco, F.
De Riccardis, Org. Lett. 2013, 15, 598–601; c) C. Tedesco, L. Erra, I. Izzo, F.
De Riccardis, CrystEngComm 2014, 16, 3667–3687; d) T. Zabrodski, M.
Baskin, J. K. Prathap, G, Maayan, Synlett 2014, 25, A–F; e) H. Tigger-Zab-
orov, G. Maayan, J. Colloid Interface Sci. 2017, 508, 56–64; f) M. Baskin,
G. Maayan, Chem. Sci. 2016, 7, 2809–2820; g) M. Baskin, L. Panz, G. Maa-
yan, Chem. Commun. 2016, 52, 10350–10353; h) G. Maayan, M. D. Ward,
K. Kirshenbaum, Chem. Commun. 2009, 56–58; i) M. Baskin, G. Maayan,
Biomolecules Pept. Sci. 2015, 104, 577–584; j) M. Baskin, H. Zhu, Z.-W. Qu,
J. H. Chill, S. Grimme, G. Maayan, Chem. Sci. 2018, 10, 620–632; k) L.
Zborovsky, A. Smolyakova, M. Baskin, G. Maayan, Chem. Eur. J. 2018, 24,
1159–1167; l) L. Zborovsky, H. Tigger-Zaborov, G. Maayan, Chem. Eur. J.
2019, 25, 9098–9107; m) T. Ghosh, N. Fridman, M. Kosa, G. Maayan,
Angew. Chem. Int. Ed. 2018, 57, 7703–7708; Angew. Chem. 2018, 130,
7829; n) H. Tigger-Zaborov, G. Maayan, J. Colloid Interface Sci. 2019, 533,
598–603; o) G. Maayan, B. Yoo, K. Kirshenbaum, Tetrahedron Lett. 2008,
49, 335–338.
Recycling Experiments: Recycling of the catalyst was done after
receiving high conversions (> 99 %). The solvent was decanted and
the resin-bound catalyst was washed three times with 2 mL of
[7] a) T. Ghosh, P. Ghosh, G. Maayan, ACS Catal. 2018, 8, 10631–10640; b) D.
Chandra Mohan, A. Sadhukha, G. Maayan, J. Catal. 2017, 355, 139–114;
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
c) P. J. Kaniraj, G. Maayan, Chem. Commun. 2015, 51, 11096–11099; d) R.
Schettini, B. Nardone, F. D. Riccardis, G. D. Sala, I. Izzo, Eur. J. Org. Chem.
2014, 7793–7797; e) G. Della Sala, B. Nardone, F. De Riccardis, I. Izzo, Org.
Biomol. Chem. 2013, 11, 726–731; f) G. Maayan, M. D. Ward, K. Kirshen-
baum, Proc. Natl. Acad. Sci. USA 2009, 106, 13679–13684.
[10] H. Tian, X. Yu, Q. Li, J. Wang, Q. Xu, Adv. Synth. Catal. 2012, 354, 2671–
2677.
[11] H. Sand, R. Weberskirch, Polym. Int. 2017, 66, 428–435.
[12] J. D. Revell, D. Gantenbein, P. Krattiger, H. Wennemers, Biopolymers (Pept-
ide Science) 2006, 84, 105–113.
[13] CuI is added as a solid and therefore we preferred to use 2 mol-% in
order to avoid the error in weighting a very small amount.
[8]
R. N. Zuckermann, J. M. Kerr, S. B. H. Kent, W. H. Moos, J. Am. Chem. Soc.
1992, 114, 10646–10647.
[9] A. S. Culf, R. J. Ouellette, Molecules 2010, 15, 5282–5335.
Received: November 26, 2019
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
On-Resin Catalysis
Catalytic peptoids that are synthesized
on solid support (resin) can be also
used on-resin. Thus, they can perform
as effective and recyclable catalysts in
the oxidation of benzyl alcohol and in
the oxidative coupling of benzyl alco-
hol with various amines to form imines
in an overall turn-over number (TON)
of up to 60 times higher than the TON
obtained when the catalyst was used
off-resin.
Y. Stamatin, G. Maayan* ................. 1–7
A Resin-Bound Peptoid as a Recycl-
able Heterogeneous Catalyst for
Oxidation Reactions
DOI: 10.1002/ejoc.201901739
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim