An isocyanide ligand for the rapid quenching and efficient removal of copper residues after Cu/TEMPO-catalyzed aerobic alcohol oxidation and atom transfer radical polymerization

Article abstract of DOI:10.1039/d0sc00623h

Transition metal catalysts play a prominent role in modern organic and polymer chemistry, enabling many transformations of academic and industrial significance. However, the use of organometallic catalysts often requires the removal of their residues from reaction products, which is particularly important in the pharmaceutical industry. Therefore, the development of efficient and economical methods for the removal of metal contamination is of critical importance. Herein, we demonstrate that commercially available 1,4-bis(3-isocyanopropyl)piperazine can be used as a highly efficient quenching agent (QA) and copper scavenger in Cu/TEMPO alcohol aerobic oxidation (Stahl oxidation) and atom transfer radical polymerization (ATRP). The addition ofQAimmediately terminates Cu-mediated reactions under various conditions, forming a copper complex that can be easily separated from both small molecules and macromolecules. The purification protocol for aldehydes is based on the addition of a small amount of silica gel followed byQAand filtration. The use ofQA?SiO₂synthesizedin situresults in products with Cu content usually below 5 ppm. Purification of polymers involves only the addition ofQAin THF followed by filtration, leading to polymers with very low Cu content, even after ATRP with high catalyst loading. Furthermore, the addition ofQAcompletely prevents oxidative alkyne-alkyne (Glaser) coupling. Although isocyanideQAshows moderate toxicity, it can be easily converted into a non-toxic compound by acid hydrolysis.

Full text of DOI:10.1039/d0sc00623h

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An isocyanide ligand for the rapid quenching and
efficient removal of copper residues after Cu/
TEMPO-catalyzed aerobic alcohol oxidation and
atom transfer radical polymerization†
Cite this: DOI: 10.1039/d0sc00623h
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Grzegorz Szczepaniak,b *ab Jakub Pi a˛ tkowski, ‡ Wojciech Nogas,
a
a
‡
´
c
b
Francesca Lorandi, ‡ Saigopalakrishna S. Yerneni, Marco Fantin,
a
d
a
Karol Grela *a
Anna Ruszczynska,
Alan E. Enciso, Ewa Bulska,
´
b
and Krzysztof Matyjaszewski
*
Transition metal catalysts play a prominent role in modern organic and polymer chemistry, enabling many
transformations of academic and industrial significance. However, the use of organometallic catalysts often
requires the removal of their residues from reaction products, which is particularly important in the
pharmaceutical industry. Therefore, the development of efficient and economical methods for the
removal of metal contamination is of critical importance. Herein, we demonstrate that commercially
available 1,4-bis(3-isocyanopropyl)piperazine can be used as a highly efficient quenching agent (QA) and
copper scavenger in Cu/TEMPO alcohol aerobic oxidation (Stahl oxidation) and atom transfer radical
polymerization (ATRP). The addition of QA immediately terminates Cu-mediated reactions under various
conditions, forming a copper complex that can be easily separated from both small molecules and
macromolecules. The purification protocol for aldehydes is based on the addition of a small amount of
2
silica gel followed by QA and filtration. The use of QA@SiO synthesized in situ results in products with
Cu content usually below 5 ppm. Purification of polymers involves only the addition of QA in THF
followed by filtration, leading to polymers with very low Cu content, even after ATRP with high catalyst
loading. Furthermore, the addition of QA completely prevents oxidative alkyne–alkyne (Glaser) coupling.
Although isocyanide QA shows moderate toxicity, it can be easily converted into a non-toxic compound
by acid hydrolysis.
Received 31st January 2020
Accepted 25th March 2020
DOI: 10.1039/d0sc00623h
rsc.li/chemical-science
7,8
compromise the performance of advanced materials. Addi-
tionally, transition metal-catalyzed reactions are used in the
Introduction
The goal of synthetic chemistry is to efficiently produce diverse large scale synthesis of modern active pharmaceutical ingredi-
9
–11
compounds of high purity. Since many important synthetic ents (API).
transformations require the use of transition metal catalysts,
Therefore, this issue is crucial in the pharma-
1
–6
ceutical industry, which is subject to stringent limits on the
the problem of purifying the products from metal residues is of allowed concentration of heavy metals in the nal API, typically
considerable practical importance. A metal impurity can less than 10 ppm. Traditional separation methods, such as
promote the decomposition of the desired product or chromatography or crystallization, oen fail to give products
with acceptably low metal content, especially when applied to
compounds with functional groups that can bind to transition
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, metals.
12
a
Z˙ wirki i Wigury 101, 02-089 Warsaw, Poland. E-mail: szczepaniak.grzegorz@gmail.
In recent years, more attention has been given to tackling the
problem of metal contamination as early as possible in the
com; prof.grela@gmail.com
b
Department of Chemistry, Carnegie Mellon University, 4400 Fih Avenue, Pittsburgh,
13
synthetic pipeline. Possible approaches include heteroge-
Pennsylvania 15213, USA. E-mail: km3b@andrew.cmu.edu
neous catalysis, self-scavenging catalysts, and the use of metal
c
Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh,
1
4,15
scavengers.
In 2015, inspired by the work of Diver and co-
Pennsylvania, USA
d
16
workers, we reported a new, stable, odorless, bidentate iso-
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston,
Illinois 60208, USA
cyanide scavenger and quenching agent QA (1,4-bis(3-iso-
†
1
‡
Electronic supplementary information (ESI) available. See DOI: cyanopropyl)piperazine),17 which was used to remove
0.1039/d0sc00623h
ruthenium impurities from olen metathesis products and
These authors contributed equally.
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palladium residues from cross-coupling products by straight-
17–19
forward purication protocols.
Copper-based catalysts are used in many transformations of
critical importance to both laboratory and industrial applica-
2
0
tions,
CuAAC), atom transfer radical polymerization (ATRP), Ull-
including azide–alkyne Huisgen cycloaddition
21
22
(
23
24
mann coupling, and aerobic oxidation reactions. Since iso-
cyanide ligands can coordinate to late 4d and 5d transition
25
metals due to their s-donor and p-acceptor properties, we
hypothesized that QA could be used as a copper scavenger in the
purication of Cu/TEMPO alcohol aerobic oxidation (Stahl
oxidation) products and also for polymers made by Cu-catalyzed
ATRP. The results presented in this study validate this hypoth-
esis and show that QA could be used to purify both small
molecules and macromolecules from copper impurities. In
addition, QA immediately stops copper-mediated reactions,
facilitating kinetic studies, and reaction design. Finally, we
demonstrated that QA could be used to prevent side reactions,
such as Glaser coupling, that can occur during polymers
workup.
Alcohol oxidation is one of the most widely used oxidation
reactions in the synthesis of complex organic molecules. In
recent years, aerobic oxidation reactions have been the focus of
26,27
considerable attention.
Compared to traditional reagents
and methods, these transformations are attractive due to the
use of molecular oxygen as an inexpensive oxidant. Further-
more, aerobic oxidation is an environmentally benign method
characterized by lower process mass intensity (PMI) compared
2
8
to traditional alcohol oxidation protocols such us Swern,
29
Parikh–Doering oxidation and TEMPO/NaOCl (TEMPO ¼
30,31
2
,2,6,6-tetramethylpiperidine N-oxyl) based methods.
The Stahl group developed a highly practical, selective, mild
and efficient aerobic alcohol oxidation mediated by the Cu/
Scheme 1 (A) Mechanism of Cu/TEMPO alcohol aerobic oxidation
32–34
TEMPO system,
which exhibits high functional group
(Stahl oxidation). (B) Mechanism of Cu-catalyzed normal ATRP and
tolerance and has found many applications in organic low-ppm ATRP in the presence of excess reducing agents.
26,35–37
synthesis.
However, to the best of our knowledge, there
has been no study on the removal of copper residues for this
type of transformation.
The control over radical propagation in ATRP is provided via
I
II
The catalytic cycle for Cu/TEMPO-catalyzed aerobic alcohol an atom transfer equilibrium between a Cu /L and a X–Cu /L
I
oxidation involves oxidation of Cu /L complex by molecular complex, where L represents a multidentate nitrogen-based
II
I
oxygen to a peroxo-bridged binuclear Cu intermediate (Scheme ligand and X is a halogen (Scheme 1B). The Cu /L complex
II
3
1
A). The [Cu /L] O species oxidize the hydroxylamine (TEM- activates the C(sp )–X polymer chain end, resulting in the
2 2
POH ¼ 2,2,6,6-tetramethylpiperidin-1-ol) to TEMPO, leading to formation of a propagating carbon-based radical and the
II
I
II
II
the formation of a HOO–Cu /L and a Cu /L complex. Then, the deactivator form (X–Cu /L) of the catalyst. Then, the X–Cu /L
II
II
HOO–Cu /L intermediate reacts with water to afford a HO–Cu / reacts with the propagating radical in a reverse reaction,
L and hydrogen peroxide. Finally, the OH–Cu /L and TEMPO regenerating the active catalyst Cu /L and the dormant polymer
II
I
3
22
mediate the oxidation of alcohol via a six-membered transition chain end C(sp )–X.
state, resulting in aldehyde formation and regeneration of Cu /L
I
Standard ATRP requires a large amount of an oxygen sensitive
Cu /L catalyst (>10 000 ppm with respect to the monomer),
I
43,44
38
complex.
the
Atom transfer radical polymerization (ATRP) is now consid- residues of which are difficult to remove from the polymer
ered one of the stock transformations in the toolbox of modern (Scheme 1B). Recently, several new ATRP techniques were
22,39–41
polymer chemistry.
Due to its compatibility with a wide developed to overcome this (Scheme 1B). They are based on the
variety of functional groups, easy setup, and mild conditions, it regeneration of the active form of the catalyst using various
is used in a wide range of applications. ATRP is based on external stimuli, which allows reducing the catalyst loading to
a reversible redox reaction catalyzed by transition metal less than 100 ppm. These methods include: activators generated
45
complexes in their lower oxidation state. The most common by electron transfer (AGET), activators regenerated by electron
42
46
ATRP catalysts are Cu complexes.
transfer (ARGET),
initiators for continuous activator
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regeneration (ICAR), supplemental activators and reducing
Chemical Science
47
48
49
agent (SARA), electrochemically mediated ATRP (eATRP),
50
photoinduced ATRP (pATRP), and mechanically/ultrasound
51,52
induced ATRP (mechano/sonoATRP).
The ideal approach to overcoming copper contamination in
traditional ATRP systems is the recently developed metal-free
53–56
ATRP, catalyzed by an organic photoredox catalyst.
However, the narrow monomer scope is a major limitation of
this technique. Moreover, it creates a new challenge – the
product can be contaminated with the organocatalyst.
Despite signicant progress in the development of ATRP
techniques, many modern applications that give access to
complex macromolecular architectures still require the use of
57
high loadings of copper catalysts. Moreover, in biomedical
applications, copper residues in polymers can induce cellular
58
oxidative damage. For these reasons, the development of
economical and practical methods for the removal of copper
impurities aer ATRP is highly desirable.
The problem of copper contamination in polymers can be
solved by precipitation, dialysis, extraction, or ltration through
a silica gel or aluminum oxide. Unfortunately, standard polymer
purication protocols are oen insufficient to bring the copper
content below 10 ppm, in particular when polymers exhibit high
59
affinity towards copper. To address this issue, many advanced
6
0,61
methods of purication have been developed,
including
62–64
65–67
heterogeneous catalysis,
self-scavenging catalysts,
scavengers, switchable systems, ion-exchange resins, elec-
metal
70
68
69
5
9,71
trolysis of copper residues
and other related electrochemical
72
methods to reduce copper. However, most of these purica-
tion protocols suffer from at least one critical aw, such as
complexity and limited availability, the need of specialized
equipment, long purication time, issues with end-group

delity or inability to decrease the copper content below
0 ppm.
Herein, we demonstrate that the introduction of the
1
quenching agent QA rapidly stops ATRP under various condi-
tions, forming a copper complex that precipitates, allowing for
facile removal by ltration. Aer this treatment, the residual
Fig. 1 (A) Quenching of Stahl oxidation by QA. (B) Evaluation of the
copper contamination of the polymers was <2 ppm, even when performance of QA as a quenching agent in Stahl oxidation of nerol
a high initial catalyst loading was used. Similarly, the addition (1a), reaction conditions: 1a (1 mmol), bpy (5 mol%), DMAP (10 mol%),
CuI (5 mol%), TEMPO (5 mol%).
of QA to Stahl oxidation products decreased the copper content
below 5 ppm.
Next, we evaluated the performance of QA as a quenching
Results and discussion
agent in the Cu-catalyzed oxidation of 1a. The kinetic study was
Quenching of Stahl oxidation by isocyanide QA
performed at room temperature in a reaction vessel open to the
air, using CuI/bpy/TEMPO/DMAP catalytic system (Fig. 1B).
Aliquots of the reaction mixture (0.2 mL) were added to a solu-
We started our investigation by examining QA as a quenching
agent of Stahl oxidation (Fig. 1A). Our hypothesis assumed that
QA might form a stable complex with copper(I) that does not
oxidize further. Aerobic oxidation of nerol (1a) was performed in
MeCN at room temperature, in a reaction vessel open to the air,
ꢀ
1
tion of QA in DCM (1.0 mL, 1 mg mL ) at selected time and
then analyzed with gas chromatography (GC).
Aer 5 min, a sample was taken from the reaction mixture.
Half of it was added to a solution of scavenger QA in DCM, and
the remainder was added to pure DCM (Fig. 1B). Even though
the reaction mixture was signicantly diluted and the access to
air was limited (vial with screw cap), the oxidation of alcohol 1a
was still proceeding (blue curve). In the vial containing QA, the
conversion did not change over time (red curve).
0
with CuI/bpy/TEMPO/DMAP (bpy ¼ 2,2 -bipyridine, DMAP ¼ 4-
(dimethylamino)pyridine) as the catalytic system. Aer 24 h, in
the presence of QA, the conversion of alcohol 1a was 0%
Fig. 1A), while in the control experiment without the addition
(
of QA, it was >99%. These experiments showed that isocyanide
QA is binding to copper, inhibiting the oxidation reaction.
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Then, we examined the activity of various copper catalytic process. Herein, we applied this protocol to the removal of
systems utilizing QA (Fig. 1S†). This study demonstrated that copper residues aer Cu-mediated oxidation of alcohols.
QA could be used as a fast-acting quenching agent to facilitate
For the evaluation of QA performance in the removal of
the kinetic studies of Cu-mediated oxidation of alcohols by copper impurities aer Stahl oxidation, we selected aliphatic and
halting the reaction progress at a specic point in time and aromatic alcohols with different functional groups (Table 1). All
using an offline analytic method, such as GC, to analyze the reactions used 1.0 mmol of the alcohol and were performed in
73
samples. To the best of our knowledge, no quenching agent MeCN at room temperature with ambient air as the source of
for this transformation has yet been described in the literature. oxidant, using a CuI/bpy/TEMPO/DMAP catalytic system. Aer
To determine the conversion as a function of time by GC, it was 2 h, the conversions for all tested substrates were >99%.
necessary to conduct an independent experiment for every time
To minimize the risk of leaching the copper-containing
74
interval and terminate it by ltration through silica gel. The contaminants from the silica gel, MeCN was evaporated before
proposed quenching method is fast and easy to carry out. removing the copper, and then DCM was added. The solvent
Encouraged by these promising results, we evaluated QA as switch can be avoided. However, the best results were obtained
a metal scavenger in the removal of copper residues.
when MeCN was removed before the purication (ESI Table S1†).
The addition of silica gel, followed by the isocyanide treatment,
allowed for isolating aldehydes with very low copper content,
below 5 ppm. Meanwhile, a control experiment with furfural (4b),
in which no QA was added, yielded a product that remained
contaminated with copper at a very high level, 800 ppm. In
Removal of copper residues aer Stahl Oxidation
Recently, we reported
a semi-heterogeneous purication
protocol for the removal of ruthenium impurities aer olen
19
metathesis reaction. It is based on the noncovalent immobi-
lization of QA on unmodied silica gel during the purication
a
Table 1 Removal of Cu residues after Stahl oxidation
a
Fig. 2 (A) Stahl oxidation of the rosuvastatin precursor (7a) on a gram
starting material). Cu content was scale. (B) Removal of Cu residues from 7b. (C) H NMR spectrum of 7b
after purification. (D) Rosuvastatin structure.
Conversions were determined by GC analysis and are based on the
1
ratio of product/(product
determined by ICP-MS.
+
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II
addition, since most of the catalytic system components bind whether QA could form a complex with Cu in the presence of
strongly to silica gel aer simple ltration through a syringe strong s-donor ligands.
II

lter, followed by evaporation of the solvent, the isolated prod-
To test the performance of QA, its reaction with [Cu (TPMA)
Br] (TPMA ¼ tris(2-pyridylmethyl)amine) was performed in
1
+
ucts were pure, based on H NMR spectroscopic analysis.
Cu/TEMPO catalyst systems show reduced reactivity with DMSO under ambient atmosphere (Fig. 3). The progress of the
aliphatic and sterically hindered alcohols. Stahl and co-workers reaction was monitored by UV-vis spectroscopy. Aer the addi-
II
+
demonstrated that replacement of TEMPO with the less steri- tion of QA (4 equiv.) to [Cu (TPMA)Br] , no ligand exchange
cally hindered ABNO (ABNO ¼ 9-azabicyclo[3.3.1]nonane N- occurred in the coordination sphere of copper (Fig. 3B). For
oxyl) diminishes the steric and electronic constraints of the Cu/ Me
6
TREN (Me
6
TREN ¼ tris[2-(dimethylamino)ethyl]amine) and
75
0
00 00
TEMPO. The aerobic oxidation of the sterically hindered PMDETA (PMDETA ¼ N,N,N ,N ,N -pentamethyldiethylenetri-
alcohol 7a in a gram scale (4 mmol, 1.41 g) was performed using amine) ligand, the results were similar (ESI Fig. S2 and S3†).
the highly active CuI/bpy/ABNO/DMAP catalytic system (Fig. 2). However, the addition of ascorbic acid (AA) in excess (10 equiv.)
The new purication protocol proved to be scalable. Aer resulted in the immediate replacement of TPMA with QA. The
II
+
purication, the copper content in the isolated aldehyde 7b, absorption band of [Cu (TPMA)Br] immediately disappeared
a key intermediate in the synthesis of cardiovascular disease in the UV-vis spectrum (Fig. 3C). Conversely, the addition of AA
76
drug rosuvastatin, was only 3.6 ppm.
alone did not cause any changes in the spectrum (ESI Fig. S4B†).
II
I
Ascorbic acid reduces Cu to Cu , which results in a swi
reaction between the [Cu (TPMA)] complex and the isocyanide
I
+
Reactivity of QA toward ATRP catalysts
QA, even though atmospheric oxygen is present in the system
(
Fig. 4C). In the absence of QA, the atmospheric oxygen
The promising results on the removal of copper residues aer
Stahl oxidation prompted us to utilize QA in ATRP. First, we
examined QA reactivity towards benchmark ATRP Cu -catalysts.
I
+
immediately oxidizes [Cu (TPMA)] . Therefore, the UV-vis
spectrum does not show any changes aer the addition of AA
(
weak p-acidity, isocyanides preferentially bind to transition
metals in a low oxidation state. As expected, the compound QA
has very high affinity to Cu /L and does not react with Cu /L
with electron-rich ligands that strongly bind to Cu .
II
ESI Fig. S4B†). Due to their strong s-donor properties and their
Nitrogen-based polydentate ligands commonly used in Cu-
77
mediated ATRP have strong s-donor properties, which
ensure effective coordination of the ligand to copper in both
oxidation states. However, for ATRP ligands, the stability
25
I
II
II
II
II
I
constant b (binding constant for Cu ) is much higher than b
I
Similar conclusions can be drawn from the experiment
(
binding constant for Cu ), providing a thermodynamic driving
force for the activation of C(sp )–X bonds. b values ranging
from 10 to 10
have been reported for conventional ATRP catalysts in
organic solvents. The rst question we had to answer was
II
+
3
II
where the complex [Cu (TPMA)Br] was reduced by compro-
portionation with Cu(0) in the presence of excess QA under
anaerobic conditions in DMSO (Fig. 4). In the presence of QA,
a white solid precipitated as the copper comproportionation
1
8
27
ꢀ1
I
7
M
and corresponding b between 10 and
1
3
ꢀ1
10
M
78
II
+
II
ꢁ
Fig. 3 QA reactivity towards the [Cu (TPMA)Br] . (A) UV-vis spectra of [Cu Br
2
] ¼ 2.5 mM; [TPMA] ¼ 2.5 mM in DMSO at 22 C in air. (B) UV-vis
spectra of copper complex after addition of QA (4 equiv.). (C) UV-vis spectra of copper complex after addition of QA (4 equiv.) and AA (10 equiv.).
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II
Fig. 4 Comproportionation of [Cu Br
2
] ¼ 2.5 mM with [TPMA] ¼ 5.25 mM in the presence of [QA] ¼ 10.0 mM and 4 cm Cu(0) wire (d ¼ 1 mm, S ¼
2
ꢁ
1
.27 cm ); in DMSO at 22 C.
II
+
proceeded. Aer 18 hours, the reaction mixture was exposed to potentials compared to the cathodic peak of [Cu (TPMA)Br] .
air and ltered through a syringe lter. The UV-vis spectrum While the latter gradually decreased in intensity, a more
II
showed the complete disappearance of the Cu /L complex (ESI pronounced decrease was observed in the intensity of the anodic
I
Fig. S5A†). The same result was recorded aer 19 hours of air peak, corresponding to the re-oxidation of [Cu (TPMA)Br] to
I
II
+
exposure, indicating that the Cu bound to QA ligand was not re- [Cu (TPMA)Br] . A new broad oxidation peak appeared at more
II
oxidized to Cu (ESI Fig. S5B†). In the control experiment in positive potentials. When the concentration of QA was increased,
which no QA was added, [Cu (TPMA)] was oxidized (ESI only the cathodic peak at more positive potentials was detected.
Fig. S6†). These experiments have shown that QA can quanti- Its intensity slightly decreased when the amount of QA was
I
+
I
tatively bind to the Cu generated by the action of a reducing increased. No oxidation peak could be recorded when $1 equiv.
agent, even in the presence of strong s-donor ligands, to form of QA was present. The described behavior is consistent with the
air-stable, polar copper(I) complexes with QA.
occurrence of a fast and irreversible chemical reaction following
80
These results were conrmed by electrochemical analysis. the electron transfer process, which results in the shi of the
Cyclic voltammetry (CV) is commonly used to investigate the voltammetric signal to more positive potential values. In our
7
9
I
reactivity of ATRP catalysts, which typically exhibit a quasi- experiment, QA reacted with the Cu species that was generated
reversible voltammetric behavior (e.g., Fig. 5, black line). There- in the vicinity of the electrode during the potential scan. This
II
+
II
+
fore CV was used to analyze the effect of QA on [Cu (TPMA)Br] in reaction rendered the reduction of [Cu (TPMA)Br] to
DMSO. When a relatively small amount of QA was present (<0.5 [Cu (TPMA)Br] more favorable, thus shiing its potential to more
I
equiv.), a new cathodic peak appeared, shied at more positive positive values. Moreover, QA formed a stable species with the
copper(I) complex (at least in the timescale of CV), and therefore
the cathodic peak corresponding to the re-oxidation of
I
[
Cu (TPMA)Br] decreased in intensity and then disappeared for
relatively high amounts of QA. The fact that no other peaks ware
detected in the explored potential range supports the formation
of a non-electroactive complex between Cu(I) and QA (i.e. that
cannot be oxidized), which is therefore unable to catalyze Stahl
oxidation or ATRP reactions.
The CV experiment supported the ability of QA to strongly bind
I
to Cu species. However, one can expect a similar voltammetric
I
response both when QA binds to Cu /L and when it displaces the
I
ligand and binds to “naked” Cu . One possibility to discriminate
between these two scenarios is to look at a more positive potential
range in a similar CV experiment. When the amount of QA
increased, several anodic signals appeared or increased in inten-
sity at E > 0.8 V vs. SCE, which could be ascribed to the oxidation of
free Br anions and TPMA (ESI Fig. S7†). This suggested that
TPMA was at least partially displaced by QA.
II
+
Fig. 5 Cyclic voltammetry of 2 mM [Cu (TPMA)Br] in DMSO + 0.1 M
ꢀ
Et
4
NBF
4
, in the absence and in the presence of QA. Scan rate ¼ 0.2 V
ꢀ
1
ꢁ
s
, T ¼ 25 C.
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Quenching of ATRP by QA
On a lab scale, typical ATRP quenching involves opening the post-
reaction mixture to air, which provides oxidative conditions to
II
form the deactivator Cu species. However, the amount of oxygen
needed depends on the reaction volume, and thus, it cannot be
scaled to industrial settings. Moreover, exposing a reaction
mixture containing catalyst residues to oxidative conditions may
82,83
cause undesired side products to form.
Therefore, anaerobic
methods of ATRP quenching are strongly desirable.
The performance of QA as a quenching agent was evaluated
in SARA ATRP. Methyl 2-bromopropionate (MBP) was used as an
initiator with CuBr
reaction was carried out in DMSO with [MA]/[MBP]/[Cu Br
TPMA]/[QA] molar ratios of 200/1/0.02/0.12/0.08 in the pres-
ence of copper wire, under anaerobic conditions (Fig. 7). Aer
2
/TPMA/Cu(0) as the catalytic system. The
II
2
]/
[
Fig. 6 Decay of limiting current vs. time for the reaction between
I
+
0
.7 mM [Cu (TPMA)] and 2.8 mM QA in DMSO + 0.1 M Et
4
NBF
4
,
ꢁ
recorded at Eapp ¼ 0.29 V vs. SCE on a RDE, l ¼ 4000 rpm, T ¼ 25 C. 90 min at room temperature, the conversion of methyl acrylate
1
(
MA) measured by H NMR was 0%, while in the corresponding
A rotating disk electrode (RDE) was used to directly observe
I
+
the effect of QA on [Cu (TPMA)] in DMSO. Chronoamperometry
under hydrodynamic conditions was used to monitor the
I
+
concentration of [Cu (TPMA)] by applying a potential of 0.29 V
I
+
vs. SCE (Fig. 6). Initially, only [Cu (TPMA)] was present in the
solution and a slowly decreasing limiting current was recorded
due to the slow disproportionation of the complex. When 4
equiv. of QA were added, the current immediately dropped to
I
+
zero, indicating that no [Cu (TPMA)] remained in the solution.
If only a stoichiometric amount of QA was added, the current
81
did not drop to zero but to a small value (ESI Fig. S8A†),
indicating that an excess of QA was needed to effectively bind to
I
all Cu species. Nevertheless, the current drop was instanta-
I
+
I
neous, both for [Cu (TPMA)] and for a Cu complex with 3
orders of magnitude higher ATRP activity (ESI Fig. S8B†), sug-
gesting that QA can be used for the removal of Cu even when
ATRP is performed with highly active catalysts.
Fig. 8 (A) Kinetics of temporal control in ARGET ATRP using QA,
II
reaction conditions: [MA]/[EBiB]/[Cu Br
2
]/[Me
6
ꢁ
TREN]/[AA] ¼ 200/1/
Fig. 7 Quenching of SARA ATRP by QA, reaction conditions: [MA]/ 0.05/0.15/0.25 in DMSO ([MA] ¼ 7.4 M) at 22 C, in the presence of
II
0
[
4
MBP]/[Cu Br
2
]/[TPMA]/[QA] ¼ 200/1/0.02/0.12/0.08, Cu wire (l ¼ limited amounts of air (without degassing of DMSO and MA). (B) SEC
2
ꢁ
II
cm, S ¼ 1.27 cm ); in DMSO ([MA] ¼ 7.4 M) at 22 C, under anaerobic traces after addition of QA (2 equiv. with respect to Cu Br
2
) and
II
conditions.
2 6
[Cu Br ]/[Me TREN] (with a molar ratio of 0.05/0.05 respect to EBiB).
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polymerization without the addition of QA it was 81% (Fig. 7). toward higher MWs (M
Furthermore, the addition of QA to the reaction mixture aer ATRP, verifying a well-controlled polymerization (Fig. 8B).
n
¼ 12 000, Đ ¼ 1.10) aer restarting the
40 min of polymerization resulted in an immediate quenching
of ATRP (Fig. 7).
Removal of copper residues aer ATRP
Temporal control was successfully demonstrated in ARGET
ATRP of MA using QA. Ethyl a-bromoisobutyrate (EBiB) was used
The purication of the polymers consisted of the addition of
a solution of QA (4 equiv.) in THF once the reaction was
complete, followed by ltration using a syringe lter (0.2 mm).
QA proved to be highly effective at removing metal residues
aer ATRP, usually reducing the copper content to a level below
as an initiator with CuBr
2
/Me
6
TREN/AA as the catalytic system.
ꢁ
The polymerization was performed in DMSO at 22 C with [MA]/
II
[
EBiB]/[Cu Br
2 6
]/[Me TREN]/[AA] molar ratios of 200/1/0.05/0.15/
0.25 (Fig. 8A). Aer 10 min, the conversion of MA was 48%.
2
ppm (Table 2). In control experiments without QA, metal
Size exclusion chromatography (SEC) analysis showed that the
contamination remained above 10 ppm. In extreme cases, it was
over 50 times higher, up to 525 ppm (Table 2, entry 3). Addi-
tionally, the new purication protocol proved to be compatible
with various monomers and ATRP techniques, including
ARGET, SARA, and pATRP. The use of QA did not affect the
molecular weight or dispersity of the puried polymers.
polymer had a low dispersity (Đ ¼ 1.10), and a molecular weight
(
(
MW) matching theoretical value (Mn,th ¼ 8300, M ¼ 9100)
n
II
2
Fig. 8B). The addition of QA (2 equiv. with respect to Cu Br )
immediately stopped the ATRP. No increase in monomer
conversion was observed during the 20 min period aer adding
QA. Then the polymerization was switched on by adding a second
II
batch of [Cu Br ]/[Me TREN] (with a molar ratio of 0.05/0.05
2
6
Preventing post-ATRP glaser coupling using QA
respect to [EBiB]). Aer a 20 min period, the monomer conver-
sion reached 68%, conrming the retention of chain-end func- Azide–alkyne Huisgen cycloaddition (CuAAC) in combination
tionality in the presence of QA. SEC traces showed a clear shi with ATRP allows the synthesis of strictly dened, tailored
84–88
polymers with various architectures,
especially macrocyclic
a
Table 2 Removal of Cu residues after ATRP
a
b
c
d
d
e
f
No.
Monomer
ATRP
Time (h)
a (%)
M
n,th
M
n,GPC
Đ
QA (equiv.)
Cu (ppm)
g
1
MA
MA
MA
MA
MA
MA
MA
nBA
nBA
tBA
MMA
ARGET
ARGET
SARA
3
3
3
3
3
3
5
24
5
5
68
68
90
85
80
79
77
86
65
81
90
11 900
11 900
15 700
14 800
14 000
13 800
13 500
22 200
16 900
21 000
18 100
12 400
13 800
15 400
14 400
13 100
13 600
15 400
21 600
14 200
18 500
17 100
1.05
1.03
1.05
1.07
1.05
1.04
1.08
1.05
1.04
1.18
1.24
—
4
—
4
—
4
4
4
4
4
26.7
1.38
525
g
2
h
3
h
4
SARA
0.97
51.6
0.91
0.80
2.20
1.41
0.71
1.07
i
5
pATRP
pATRP
pATRP
ARGET
pATRP
pATRP
ARGET
i
6
j
7
g
8
j
9
j
1
1
0
1
g
10
4
a
II
Reaction conditions: [monomer]/[EBiB]/[Cu Br
2
]/[Me
6
TREN] ¼ 200/1/0.05/0.25 in MeCN, ([MA] ¼ 7.4 M, [nBA] ¼ 4.7 M, [tBA] ¼ 4.6 M, [MMA] ¼ 6.2
1 c
ꢁ
b
M) at 22 C. Monomer conversion was determined by using H NMR spectroscopy. Theoretical molecular weight was calculated using the
equation Mn,th ¼ [M] ꢂ MW ꢂ a + MWEBiB, where [M], MW , a, and MWEBiB correspond to initial monomer concentration, molar mass of
monomer, conversion, and molar mass of EBiB initiator, respectively. Molecular weight and dispersity (Đ) were determined by GPC analysis
M
M
d
e
II
f
(THF as eluent) calibrated to poly(methyl methacrylate) standards. Equivalents of QA with respect to Cu Br
2
.
Copper content was determined
g
II
h
by ICP-MS. ARGET ATRP: ascorbic acid (5 equiv. with respect to Cu Br
2
), under anaerobic conditions. SARA ATRP: 4 cm Cu(0) wire (d ¼ 1
2
i
j
mm, S ¼ 1.27 cm ), under anaerobic conditions. pATRP: UV irradiation (l ¼ 365 nm), under anaerobic conditions. pATRP: UV irradiation (l
¼
365 nm), in the presence of limited amounts of air (without degassing of MeCN and monomer).
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89
polymers that are difficult to prepare by other methods. This protection/deprotection sequence, which has a low atom and
synthetic route involves the preparation of a linear precursor time economy. In addition, the deprotection step requires the
with a terminal alkyne group by ATRP, followed by the nucleo- use of reagents that can cause the degradation of the synthe-
philic displacement of the bromide chain end with azide and sized polymer.

nally CuAAC-mediated macrocyclization reaction at high
Recently, in an inspiring work, Koberstein and co-workers
dilution. However, during these transformations, side reactions showed two methods for preventing post-ATRP alkyne–alkyne
82
can occur that compromise the delity of the chain end, such as coupling. First, Glaser coupling can be completely prevented
ꢁ
(
i) radical termination at high monomer conversions and (ii) by cooling the post-reaction mixture below ꢀ28 C before
Glaser coupling of the alkyne moiety under oxidative condi- exposing it to air and then maintaining a low temperature
tions. Both side reactions jeopardize the subsequent CuAAC- during the polymer workup. Second, the coupling is suppressed
mediated macrocyclization. by the use of an excess of reducing agents, such as tin(II) 2-
90
While the conventional radical termination can be mini- ethylhexanoate or (+)-sodium L-ascorbate. Moreover, it was
mized by decreasing the rate of polymerization and by termi- found that high-denticity ligands can reduce Glaser coupling
nating the reaction at lower monomer conversion, suppression rates. However, the proposed approaches are difficult to scale
82,91,92
of the Glaser coupling remains a challenge.
One of the up because of the necessity of using aluminum oxide during the
methods of preventing the Glaser coupling is the protection of purication process. For this reason, the development of
the alkyne group with a trimethylsilyl or triisopropylsilyl economical and simple methods of preventing oxidative
93
group.
However, this approach requires an additional alkyne–alkyne coupling is desirable.
I
Fig. 9 (A) Preventing post-ATRP Glaser coupling using QA. Normal ATRP of styrene, reaction conditions: [styrene]/[PgBiB]/[Cu Br]/[dNbpy] ¼ 1/
ꢁ
I
1
/2/230 in bulk at 110 C. (B) Exposure to air post-ATRP mixture after the addition of QA (4 equiv. with respect to Cu Br). (C) Exposure to air post-
ATRP mixture without the addition of QA.
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The linear polystyrene (a-alkyne,u-Br-PS) was prepared using Cytotoxicity study of QA
standard ATRP. 3-Butynyl 2-bromoisobutyrate (PgBiB) was used
Finally, we investigated the cytotoxicity of QA and its acidic
hydrolysis product HQA (N,N -(piperazine-1,4-diylbis(propane-
0
0
as initiator with CuBr/dNbpy (dNbpy ¼ 4,4 -dinonyl-2,2 -bipyr-
0
idine) as the catalyst system. The reaction was carried out in
3,1-diyl))diformamide). HQA was obtained by adding 4 equiv.
ꢁ
I
bulk at 110 C with [styrene]/[PgBiB]/[Cu Br]/[dNbpy] molar
ratios of 230/1/1/2. Aer 1.5 h, two samples of 4.5 mL each were
taken from the reaction mixture and puried using method A or
B (Fig. 9A).
of HCl to QA dissolved in water and stirring for 2 hours. The
resulting solution was diluted in buffer to the desired concen-
tration without isolating HQA (Fig. 10). To ensure that hydro-
lysis was quantitative, the same procedure was performed in
I
The addition of QA (4 equiv. with respect to Cu Br) to the
1
D O and monitored by H NMR spectroscopy. Aer 2 hours, no
2
post-ATRP reaction mixture not only completely prevented the
Glaser coupling (i.e., the average molecular weight of the poly-
mer did not change over time when the mixture was exposed to
air) but also caused the quantitative precipitation of the cop-
per(I) complex with the QA ligand (Fig. 9B). The complex was
easily removed by simple ltration, giving a colorless polymer
with copper content below 1 ppm and low Đ (1.08). In the
control experiment in which QA was not added, the average
molecular weight and Đ of the resulting polymer increased over
time (Fig. 9C), and the obtained polymer had an intense color
and a very high copper content of 2305 ppm.
peaks from QA were visible in the spectrum.
The toxicity study was performed using two different cell
lines: HEK293 (human embryonic kidney cells) and NIH3T3
(mouse broblast cells). QA and HQA were tested at ve
different concentrations (Fig. 10). The cells were tolerant to 0.01
mM of either of the compounds up to 72 hours. However, at
concentrations above 0.01 mM, QA started exhibiting cytotox-
icity in a time-dependent manner (ESI Fig. S9†) in both cell
lines. The highest level of cytotoxicity of QA was observed at 72
hours, with approximately 50% of cells remaining viable aer
treatment with 10 mM QA compared to the control (no treat-
ment) group. On the other hand, HQA was not cytotoxic even at
10 mM, suggesting that acidic hydrolysis of QA is an effective way
to neutralize its toxicity.
Conclusions
In this study, we have shown that QA is a rapid quenching agent
for Stahl oxidation and ATRP, as well as a highly efficient Cu
scavenger. The use of a small amount of silica gel in combina-
tion with a small excess of QA reduced the Cu content in alde-
hydes below 5 ppm. This purication protocol was effective on
a gram scale in the synthesis of the cardiovascular disease drug
precursor (rosuvastatin), leading to a product containing only
3.6 ppm Cu.
Spectroscopic and electrochemical studies provided insights
into the reactivity of QA toward Cu complexes used as ATRP
I
catalysts and showed that QA is highly reactive against Cu /L,
1
3
even for ligands with very high copper binding constants (10
M
ꢀ1
II
). At the same time, QA proved to be inert towards Cu /L
complexes with strong s-donor ligands. However, the use of
a reducing agent allowed QA to bind copper quantitatively.
QA very efficiently removed Cu aer ATRP without compro-
mising the molecular weight and dispersity of the puried
polymers. The addition of QA followed by simple ltration using
a syringe lter proved to be highly effective in removing Cu
contamination, affording polymers with Cu content below
2
ppm. This protocol was of great signicance for normal ATRP,
leading to polystyrene with less than 1 ppm Cu. Treatment with
QA not only facilitated the removal of Cu, but also completely
prevented the Glaser coupling under oxidative conditions.
Finally, we examined the cytotoxicity of QA. The isocyanide
showed moderate cytotoxicity, with approximately 50% of cells
remaining viable aer 72 hours of treatment with 10 mM of the
compound. However, it could be easily hydrolyzed by adding
a small excess of HCl. The hydrolysis product showed no cyto-
toxicity even at relatively high concentrations.
Fig. 10 The cytotoxicity assay performed using HEK293 (black) and
NIH3T3 cells (orange). Cells were treated with five concentrations of
QA or HQA for 72 hours and compared to control group (no treat-
ment). Bars indicate the mean percent viability ꢃ SEM (n ¼ 3), ns: no
significant difference, *p < 0.5, **p < 0.01, ***p < 0.001 (vs. control
group).
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In summary, we presented the applicability of QA in two 13 P. Wheeler, J. H. Phillips and R. L. Pederson, Org. Process Res.
fundamental reactions catalyzed by copper complexes. We Dev., 2016, 20, 1182–1190.
expect this straightforward approach to nd application in 14 G. Szczepaniak, K. Kosi n´ ski and K. Grela, Green Chem., 2014,
other signicant transformations catalyzed by transition metal
16, 4474–4492.
complexes.
15 G. C. Vougioukalakis, Chem.–Eur. J., 2012, 18, 8868–8880.
16 B. R. Galan, K. P. Kalbarczyk, S. Szczepankiewicz, J. B. Keister
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Conflicts of interest
1
7 G. Szczepaniak, K. Urbaniak, C. Wierzbicka, K. Kosi n´ ski,
K. Skowerski and K. Grela, ChemSusChem, 2015, 8, 4139–
There are no conicts to declare.
4148.
1
8 G. Szczepaniak, A. Ruszczy n´ ska, K. Kosi n´ ski, E. Bulska and
K. Grela, Green Chem., 2018, 20, 1280–1289.
Acknowledgements
G. S. wishes to thank the National Science Centre (“Etiuda” 19 G. Szczepaniak, W. Noga ´s , J. Pi ˛a tkowski, A. Ruszczy n´ ska,
fellowship) and the Foundation for Polish Science (“Ventures”
Program) for nancial support. The project “Ventures/2013-11/
E. Bulska and K. Grela, Org. Process Res. Dev., 2019, 23,
836–844.
8
” is funded by the “Ventures” program of the Foundation for 20 A. J. Hickman and M. S. Sanford, Nature, 2012, 484, 177–185.
Polish Science, co-nanced from the European Union Regional 21 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
Development Fund. J. P., W. N., and K. G. are grateful to the
Ed., 2001, 40, 2004–2021.
Catalysis for the Twenty-First Century Chemical Industry 22 K. Matyjaszewski, Macromolecules, 2012, 45, 4015–4039.
Project carried out within the TEAM-TECH Programme of the 23 C. Sambiagio, S. P. Marsden, A. J. Blacker and
Foundation for Polish Science co-nanced by the European
Union from the European Regional Development under the 24 S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and
Operational Programme Smart Growth. The study was partially M. C. Kozlowski, Chem. Rev., 2013, 113, 6234–6458.
carried out at the Biological and Chemical Research Centre, 25 V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin and
University of Warsaw, established within a project co-nanced V. Y. Kukushkin, Chem. Rev., 2015, 115, 2698–2779.
by the European Union from the European Regional Develop- 26 B. L. Ryland and S. S. Stahl, Angew. Chem., Int. Ed., 2014, 53,
ment Fund under the Operational Programme “Innovative
8824–8838.
P. C. McGowan, Chem. Soc. Rev., 2014, 43, 3525–3550.
Economy”, 2007–2013. The support from the National Science 27 C. Parmeggiani and F. Cardona, Green Chem., 2012, 14, 547.
Foundation (CHE 1707490) is also acknowledged. The authors 28 A. J. Mancuso and D. Swern, Synthesis, 1981, 1981, 165–185.
thank Krzysztof Kosi n´ ski and Emilee Tkacik for fruitful 29 J. R. Parikh and W. v. E. Doering, J. Am. Chem. Soc., 1967, 89,
discussions and proofreading.
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3
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0 S. Wertz and A. Studer, Green Chem., 2013, 15, 3116.
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