Synthesis and Characterization of the Most Active Copper ATRP Catalyst Based on Tris[(4-dimethylaminopyridyl)methyl]amine

Article abstract of DOI:10.1021/jacs.7b12180

The tris[(4-dimethylaminopyridyl)methyl]amine (TPMA^NMe2) as a ligand for copper-catalyzed atom transfer radical polymerization (ATRP) is reported. In solution, the [Cu^I(TPMA^NMe2)Br] complex shows fluxionality by variable-temperature NMR, indicating rapid ligand exchange. In the solid state, the [Cu^II(TPMA^NMe2)Br][Br] complex exhibits a slightly distorted trigonal bipyramidal geometry (τ = 0.89). The UV-vis spectrum of [Cu^II(TPMA^NMe2)Br]⁺ salts is similar to those of other pyridine-based ATRP catalysts. Electrochemical studies of [Cu(TPMA^NMe2)]²⁺ and [Cu(TPMA^NMe2)Br]⁺ showed highly negative redox potentials (E_1/2 = -302 and -554 mV vs SCE, respectively), suggesting unprecedented ATRP catalytic activity. Cyclic voltammetry (CV) in the presence of methyl 2-bromopropionate (MBrP; acrylate mimic) was used to determine activation rate constant k_a = 1.1 × 10⁶ M^-1 s^-1, confirming the extremely high catalyst reactivity. In the presence of the more active ethyl α-bromoisobutyrate (EBiB; methacrylate mimic), total catalysis was observed and an activation rate constant k_a = 7.2 × 10⁶ M^-1 s^-1 was calculated with values of K_ATRP ≈ 1. ATRP of methyl acrylate showed a well-controlled polymerization using as little as 10 ppm of catalyst relative to monomer, while side reactions such as Cu^I-catalyzed radical termination (CRT) could be suppressed due to the low concentration of L/Cu^I at a steady state.

Full text of DOI:10.1021/jacs.7b12180

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Article
Synthesis and Characterization of the Most Active Copper ATRP
Catalyst Based on Tris[(4-dimethylaminopyridyl)methyl]amine
Thomas G. Ribelli, Marco Fantin, Jean-Claude Daran, Kyle
F. Augustine, Rinaldo Poli, and Krzysztof Matyjaszewski
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12180 • Publication Date (Web): 10 Jan 2018
Downloaded from http://pubs.acs.org on January 10, 2018
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Synthesis and Characterization of the Most Active Copper
ATRP Catalyst Based on Tris[(4-
dimethylaminopyridyl)methyl]amine
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Thomas G. Ribelli,a◊ Marco Fantin,a◊ Jean-Claude Daran,b Kyle F. Augustine,a
Rinaldo Polib,c and Krzysztof Matyjaszewski*a
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aDepartment of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA
15213, United States
bCNRS, LCC (Laboratoire de Chimie de Coordination), Université de Toulouse, UPS, INPT, 205
Route de Narbonne, BP 44099, F-31077, Toulouse Cedex 4, France
cInstitut Universitaire de France, 1, rue Descartes, 75231 Paris Cedex 05, France
ABSTRACT
The synthesis and characterization of tris[(4-dimethylaminopyridyl)methyl]amine
(TPMANMe2) as a ligand for copper catalyzed atom transfer radical polymerization (ATRP) is
reported. In solution, the [CuI(TPMANMe2)Br] complex shows fluxionality by variable
temperature NMR, indicating rapid ligand exchange. In the solid-state, the
[CuII(TPMANMe2)Br][Br] complex exhibits a slightly distorted trigonal bipyramidal geometry (τ =
0.89). The UV-Vis spectrum of [CuII(TPMANMe2)Br]+ salts is similar to those of other pyridine-
based ATRP catalysts. Electrochemical studies of [Cu(TPMANMe2)]2+ and [Cu(TPMANMe2)Br]+
showed highly negative redox potentials (E1/2 = -302 mV and -554 mV vs. SCE, respectively),
suggesting unprecedented ATRP catalytic activity. Cyclic voltammetry (CV) in the presence of
methyl 2-bromopropionate (MBrP; acrylate mimic) was used to determine activation rate
constant ka = 1.1 x106 M-1s-1, confirming the extremely high catalyst reactivity. In the presence
of the more active ethyl α-bromoisobutyrate (EBiB; methacrylate mimic), total catalysis was
observed and an activation rate constant ka = 7.2 x 106 M-1s-1 was calculated with values of KATRP
≈ 1. ATRP of methyl acrylate showed a well-controlled polymerization using as little as 10 ppm
of catalyst relative to monomer while side reactions such as CuI catalyzed radical termination
(CRT) could be suppressed due to the low concentration of L/CuI at a steady-state.
INTRODUCTION
Atom transfer radical polymerization (ATRP) has gained widespread use due to its easy
setup, tolerance to functional groups, mild conditions and wide range of applications.1-4 Since
its inception in 1995, when stoichiometric amounts of air-sensitive CuI relative to alkyl halide
initiator were used,5 many advances have been made to improve the efficiency of this
polymerization system.6 The development of new operating techniques such as initiators for
continuous activator regeneration (ICAR) ATRP7-8, activators regenerated by electron transfer
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(ARGET) ATRP9-11, supplemental activators and reducing agents (SARA) ATRP12 as well as
photoATRP13-17, eATRP18 and most recently mechanoATRP19-20 have allowed polymerizations to
be conducted using ppm levels of catalyst relative to monomer.
As shown in Scheme 1, the control in ATRP is achieved via a reversible redox equilibrium
between a L/CuI/II couple where L signifies a multidentate nitrogen-based ligand. L/CuI activates
a (macro)alkyl halide chain end, resulting in the L/CuII-X deactivator and a carbon-based
radical,21 which propagates by adding to monomer before being trapped by the L/CuII-X
deactivator, regenerating the L/CuI species and the dormant polymer chain.4 To control the
polymerization,22 this equilibrium (KATRP) should lie on the dormant side to diminish the
concentration of radicals and retain chain-end functionality (CEF). KATRP can be expressed as the
ratio of activation (ka) to deactivation (kd) rate constants and can be tuned over 8-orders of
magnitude23 based on temperature, pressure, solvent,24-25 polymer chain-end,26 and choice of
catalyst.23 In order to reach even lower catalyst loadings or to polymerize less active monomers
such as vinyl acetate (VAc),27 higher values of KATRP must be achieved.
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Scheme 1 Mechanism of ATRP (boxed) and equilibria involving association of ligand (βm) and
halide (βm ) to either the CuI (m = I) or CuII (m = II) ion.
x
One simple way to tune ATRP is by changing the coordination sphere of copper. Over
the years, rational ligand design has allowed for the understanding of how the catalyst
structure affects reactivity. The activity of the catalyst in ATRP correlates with ligand denticity,
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nature of the N-donor atom and electron donating ability through the coordinating nitrogen
atom(s).28 Indeed, a linear correlation between the redox potential (E1/2) and ln(KATRP) has been
29
7
established where a more negative E1/2 results in a larger value of KATRP
.
This strong
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correlation allows for the prediction of new catalysts’ activity based solely on their redox
potential. The activity of a catalyst can also be further assessed by comparing the stability
constants (binding constants), β, of the L/CuI and L/CuII complexes since KATRP scales with the
βII/βI ratio, as shown in Scheme 1. While both βII and βI should be large, βII > βI in order to
provide a thermodynamic driving force for alkyl halide activation.29 Indeed, βI values are rather
constant but βI values change significantly with the ligand structures.30
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To date, the most active ATRP catalyst has used the ligand tris[((4-methoxy-2,5-
dimethyl)-2-pyridyl)methyl]amine (TPMA*3) which has three electron donating groups on each
pyridine ring.31-32 This led to a catalyst that is 5 million times more active than the seminal
catalytic system employing the 2,2’-bipyridine (bpy) ligand and 1000 times more active than the
commonly used tris(pyridylmethyl)amine (TPMA) ligand (Scheme 2).
According to Hammett parameters, using the even more electron donating dimethyl
amino (–NMe2) group should further increase the catalyst activity as already observed for bpy
derivatives.33 Therefore, we have considered using tris[(4-dimethylamino-2-
pyridyl)methyl]amine (TPMANMe2) ligand as shown in Scheme S1.34-36 This ligand was previously
reported by Karlin et al where the [CuI(TPMANMe2)]+ complex was used as an oxygen activation
catalyst to mimic various copper containing enzymes37-38 such as amine oxdiases,39 multicopper
oxidases40 (MCOs) and tyrosinases41 as well as to study this complex’s interactions with carbon
monoxide.42 This new Cu-based ATRP catalyst with TPMANMe2, in both relevant oxidation states,
has been characterized in solution and the solid state and utilized in ATRP systems with low
catalyst loadings (down to 10 ppm) and was shown to exhibit unprecedented reactivity with
alkyl halides.
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Scheme 2 Structure of the ligands used in this study.
RESULTS AND DISCUSSION
TPMANMe2 was prepared by a procedure slightly modified from that used by Karlin et al34
(Scheme S1). The synthesis of 2-hydroxymethyl-4-dimethylaminopyridine (2; Scheme S1) was
conducted as previously published by Comba et al.35 The synthesis of 2-phthalimidomethyl-4-
chloropyridine (5; Scheme S1) was conducted as previously published by our group.31 2-
Aminomethyl-4-dimethylpyridine (6; Scheme S1) was synthesized directly from a basic workup
of 2-phthalimidomethyl-4-dimethylaminopyridine. It should be noted that it is very important
to use chemical resistant O-Ring (ACE glass # 7855-813) for reactions using high pressure tubes.
The ligand has been characterized by 1H/13C NMR and ESI-MS which confirmed the predicted
structure.
Variable Temperature NMR of CuI complexes
It has been previously shown that L/CuI complexes with multidentate pyridine-based
ligands can undergo fast ligand exchange in the presence of excess ligand relative to CuI.43 The
solution prepared by addition of TPMANMe2 to CuBr was studied by variable temperature NMR,
as shown in Figure 1.
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Figure 1 Variable temperature 1H NMR of the aromatic region of the free TPMANMe2 ligand and
its CuBr complex at the molar ratio [CuBr]0:[TPMANMe2]0 = 1:3 in d6-acetone.
Upon reacting equimolar amounts of TPMANMe2 and CuBr in d6-acetone, the reaction
initially turned to a pale-yellow color, common for CuI complexes coordinated by pyridinic
ligands. However, upon stirring, the reaction mixture turned green along with a dark
precipitate indicative that the [CuI(TPMANMe2)Br] complex underwent disproportionation to
[CuII(TPMANMe2)Br][Br] and Cu0 + TPMANMe2. Typically, unsubstituted TPMA shows little to no
disproportionation. The position of the disproportionation equilibrium, KDisp,LCu, depends on the
relative stability of LCuII compared LCuI. Since TPMANMe2 stabilizes CuII much more than TPMA,
disproportionation is possible. This is especially true in a disproportionating solvent such as
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acetone, which is polar and coordinates weakly to CuI.29 To suppress disproportionation and
reform the [CuI(TPMANMe2)Br] complex, 2 additional equivalents of TPMANMe2 were added.44
Indeed, upon further stirring for 30 minutes, the reaction regained its yellow color and the Cu0
particles were no longer visible.
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The 1H NMR spectrum shows significant broadening of the aromatic peaks upon
complexation, which has been previously been shown for other CuI complexes.45-47 This
broadening indicates a fast exchange between free and coordinated ligand. Upon decreasing
the temperature to 240 K, the peaks attributed to coordinated and uncoordinated ligand began
to resolve due to the slower rate of exchange. At 180 K, two distinct peaks were observed at
8.05 and 8.5 ppm, attributed to free and coordinated ligand, respectively.43, 48-51 The peaks
became narrower at lower temperature but were broader than those of previously published
TPMA-based CuI complexes at 180 K. This could be due to the presence of small amounts of
paramagnetic CuII formed from disproportionation and plausible self-exchange between the CuII
and CuI complexes. This cannot be avoided due to the disproportionating nature of acetone
and the highly reactive [CuI(TPMANMe2)]+ complex. Although the variable temperature NMR
spectra indicate a significant amount of ligand exchange, the total amount of uncoordinated Cu
is extremely low due to the large stability constants, βI, as has been previously observed for
substituted TPMA ligands.43
Structural Studies of CuII Deactivator Complex The [CuII(TPMANMe2)Br]+ complex was
synthesized and crystallized as reported in the Supporting Information. The resulting molecular
structure is presented in Figure 2 with selected bond distances and angles summarized in Table
1.
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Figure 2 Molecular structure of [CuII(TPMANMe2)Br][Br] shown (left) with 50% probability
displacement ellipsoids. H atoms, counter Br- anion and solvent molecules have been omitted
for clarity.
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The [CuII(TPMANMe2)Br]+ cation is in a slightly distorted trigonal bipyramidal geometry,
indicated by a structural parameter τ = 0.89 (τ = 1.00 for trigonal bipyramidal). Coordination of
the tetradentate ligand occurs through three substituted pyridinic nitrogen atoms in the
equatorial plane (Neq) and a central anchoring aliphatic nitrogen in the axial plane (Nax). The Nax-
Cu-Neq bond angles are all slightly smaller than 90° which is consistent with a previously
reported cupric aqua adduct,36 [CuII(TPMANMe2)(H2O)]2+. The similar Nax-Cu-Neq angles between
the two complexes, although with differently sized axial ligands (Br- vs. H2O), suggests these
deviations from 90° are most likely due to the natural bite of the ligand as opposed to steric
repulsion from the axial ligand. The previously reported42 cuprous carbonyl adduct,
[CuI(TPMANMe2)(CO)]+, showed a CuI-Nax bond distance of 2.446 Å which is significantly
elongated compared to the CuII-Nax bond distance of 2.05 Å presented in this study. Although
the two complexes cannot be directly compared due to the difference in axial ligand, Cu-Nax
bond elongation upon reduction of CuII to CuI has been observed in other TPMA-based
complexes.52 This is attributed to CuII preferring a 5-coordinate environment while the reduced
CuI ion prefers 4-coordinate geometries.53 Thus, the CuI-Nax bond is elongated to a non-
bonding distance forming a distorted tetrahedral geometry. Furthermore, as shown in Figure
S5, the crystal structure is stabilized by π−π stacking interactions between substituted pyridine
rings as well as weak C-H---Br (2.84 Å) interactions.
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Table 1 Selected Bond Distances and Angles of Relevance for L/CuII-Br Deactivator Speciesa
[CuII(TPMA)Br][Br]b [CuII(TPMA*3)Br][Br]c [CuII(TPMANMe2)Br][Br]d
Cu-N1ax
Cu-N2eq
Cu-N3eq
Cu-N4eq
Cu-Br1
2.040(3)
2.073(15)
2.073(15)
2.073(15)
2.384(6)
80.86(5)
80.86(5)
2.028(3)
2.059(3)
2.149(3)
2.044(3)
2.3740(5)
81.07(12)
82.81(12)
2.047(3)
2.051(2)
2.108(3)
2.046(3)
2.3898(6)
80.59(10)
80.60(10)
N1-Cu-N2
N1-Cu-N3
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N1-Cu-N4
N2-Cu-N3
N2-Cu-N4
N3-Cu-N4
N1-Cu-Br1
N2-Cu-Br1
N3-Cu-Br1
N4-Cu-Br1
τe
80.86(5)
79.82(11)
132.39(12)
115.63(12)
104.99(12)
178.33(9)
100.99(8)
98.35(8)
81.42(10)
126.78(10)
116.34(10)
109.40(10)
179.89(9)
98.59(8)
99.49(7)
99.32(7)
0.89
117.53(3)
117.53(3)
117.53(3)
180.00(5)
99.14(5)
99.14(5)
99.14(5)
1.0
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97.27(8)
0.77
aBond lengths are given in angstroms (Å) and angles in degrees (°). From Ref 51. cFrom Ref 42.
dThis work. eτ parameter is calculated as τ = (φ1 − φ2)/60, where φ1 and φ2 are the largest (N1-
Cu-Br1) and second largest (N2-Cu-N3) bond angles, τ = 1 (trigonal bipyramidal geometry), and τ
= 0 (square pyramidal geometry).
b
Solution Studies of CuII Complexes The UV-Vis-NIR spectra were obtained using CuBr2 to form
[CuII(TPMANMe2)Br]+ and also Cu(OTf)2 to form [CuII(TPMANMe2)(MeCN)]2+, since the OTf- anion
coordinates very weakly to the CuII center in solution. As shown in Figure 3A, two dꢀd
transitions are observed in the NIR and visible region at 1038 and 776 nm for the
[CuII(TPMANMe2)Br]+ and 980 and 725 nm for the [CuII(TPMANMe2)(MeCN)]2+ complex,
respectively. These two transitions are typical of d9 CuII possessing trigonal bipyramidal
geometry and are attributed to dxz ≈ dyz ꢀ dz2 and to dx2-y2 ≈ dxy ꢀ dz2.54-55 A ligand to metal
charge transfer (LMCT) band is apparent in both complexes, centered around 425 and 395 nm
for [CuII(TPMANMe2)Br]+ and [CuII(TPMANMe2)(MeCN)]2+, respectively. The absorption spectra of
these two complexes are consistent with previously published results for many ATRP
deactivator complexes presenting trigonal bipyramidal geometry.43, 56
A sample of [CuII(TPMANMe2)Br][Br] crystals was also investigated, after dissolution into a
dichloromethane (DCM)/toluene mixture, by X-Band EPR spectroscopy at 120 K as shown in
Figure 3B. The spectrum revealed a pattern and g/A parameters rather close to those of the
related [CuII(TPMA)Br]+ complex.57 On the other hand, a rather uninformative cubit tensor at g
= 2.123 and a linewidth of ca. 110 G without observable copper hyperfine coupling was
observed in pure MeCN or pure DCM as shown in Figure S4.
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(A)
[CuII(TPMANMe2)Br][Br]
(B)
[CuII(TPMANMe)Br]+
[CuII(TPMANMe)(MeCN)]2+
4
2
0
Sim.
Exp.
0.3
0.2
0.1
0.0
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×
500 700 900 1100
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Field (G)
wavelegnth (nm)
Figure 3 A) Absorption spectra of the [CuII(TPMANMe2)Br]+ deactivator complex (red) and
[CuII(TPMANMe2)(MeCN)]2+ complex (blue) in MeCN. [CuX2]0 = 1 mM (X = Br- or OTf-) and B)
Experimental (red) and simulated (green) X-band EPR spectra of the [CuII(TPMANMe2)Br][Br]
complex in a 1:1 mixture of DCM:toluene recorded at 120K (g1 = 2.173, A1 = 255.3 MHz, g2 =
2.198, A2 = 336.5 MHz, g3 = 1.95, A3 = 260.1 MHz).
Thermodynamic Parameters As noted above, one method to determine catalyst activity in
ATRP is by measuring the stability constants, βI and βII, for the L/CuI and L/CuII complexes.43 The
redox potential of the [Cu(L)]2+ complex gives the βII/βI ratio as shown in Eq 1, where
ꢀꢁ°ꢂ
and ꢀ°
represent the standard redox potential of solvated Cu and the ligated
ꢆ
ꢅꢁꢂ /ꢅꢁꢂ
ꢃꢄ
ꢄ
ꢆꢆ
/ꢁꢂ
Cu species, respectively.58 Furthermore, according to Eq 2, it is also possible to obtain the ratio
βꢇꢊꢊ,ꢈꢉꢉ/βꢊꢇ,ꢈꢉꢉ electrochemically, where βꢇꢊꢊ,ꢈꢉꢉ and βꢊꢇ,ꢈꢉꢉ are the apparent equilibrium
constants of halide association to ligated copper, L/CuII–X or L/CuI–X, respectively.43
considers that addition of X- do not change the original βI and βII values. For efficient
β
ꢊꢊ
ꢇ,ꢈꢉꢉ
deactivation, βꢊꢇꢊ values must be high. Values of βꢊꢇ should be low, since the [CuI(L)Br] is an
inefficient activator in ATRP.59
βI
F
ln
ln
=
(
ECou2+
− ELoCuII
)
(Eq. 1)
(Eq. 2)
/Cu+
/LCuI
βII RT
II
β
F
X,app
=
(
ELoCuII
− ELoCu
)
/LCuI
II −X/LCuI −X
βIX,app RT
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As shown in Figure 4, both the [Cu(TPMANMe2)(MeCN)]2+ and [Cu(TPMANMe2)Br]+
complexes exhibit a reversible redox wave at E1/2 = -302 mV and -554 mV vs. SCE, respectively,
representing the most reducing ATRP catalysts to date. Separation between the anodic and
cathodic peaks is ca. 60 mV at a scan rate of 0.2 V s-1, indicating good reversibility. Increasing
the scan rate results in the expected increase in current; peak separation also increases,
revealing a quasi-reversible nature of the electron transfer. This shows that the TPMANMe2
ligand is able to sufficiently stabilize the electrochemically generated CuI, and indicates that
these complexes have small rearrangement energies between the CuI/II oxidation states. Using
Eq 1, the βII/βI ratio was calculated as 1.1 x 1023 (Table 2) which is 1500 times larger than the
previously reported value for the tris(2-dimethylaminoethyl)amine (Me6TREN) complex in
MeCN.58 This large increase may be either due to a more stabilized CuII or a destabilized CuI.
However, it was previously shown43 that stability constants for CuI were similar using variously
substituted pyridine-based ligands in DMF.30
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Upon introduction of coordinating bromide anions, the complex [Cu(TPMANMe2)Br]+ is
formed, and the redox potential shifts by -252 mV to give E1/2 = -554 mV vs. SCE. KATRP increases
roughly one order of magnitude for every 59 mV shift of redox potential,26 indicating KATRP
should be approximately 140,000 times greater relative to the unsubstituted TPMA-based
catalyst, which has E1/2 = -240 mV vs. SCE,46 and >109 times greater than the original bpy
catalyst, which has E1/2 = +30 mV vs. SCE.60 Furthermore, using Eq. 2, the β
/βꢊꢇ,ꢈꢉꢉ ratio
ꢊꢊ
ꢇ,ꢈꢉꢉ
was calculated to be 1.8 x 104, similar to that of other TPMA-based ligands in MeCN.43
(A)
(B)
[Cu(TPMANMe)(MeCN)]2+
[Cu(TPMANMe2)Br]+
100
50
0
50
0
Scan Rate (mV/s)
Scan Rate (mV/s)
50
-50
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-50
-100
-150
-100
-0.6
-0.4
-0.2
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-0.8 -0.6 -0.4 -0.2 0.0 0.2
Potential (V) vs. SCE
Potential (V) vs. SCE
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Figure 4 Cyclic voltammograms of (A) 1 mM [Cu(TPMANMe2)(MeCN)]2+ and (B) 1 mM
[Cu(TPMANMe2)Br]+ + 20 mM Et4NBr in dry MeCN at different scan rates using Et4NBF4 as a
supporting electrolyte and glassy carbon working electrode; [L/CuII]0 = 1 mM.
6
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8
9
II
[LCu ] [L]
eq
eq
ꢋꢌꢍꢎꢉ,ꢅꢁꢂ
βII
=
(Eq. 3)
(Eq. 4)
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2
I
[LCu ]
eq
Kdisp,LCu
(βI )2 Kdisp,Cu
=
Since cyclic voltammetry can only provide the βII/βI ratio, further analysis was carried
out to estimate the individual β values. We previously reported43 on the disproportionation
equilibrium allowing for the calculation of βII/(βI)2, as shown in Eq’s 3 & 4, where Kdisp,LCu and
K
disp,Cu are the equilibrium constants of disproportionation for ligated and solvated copper,
respectively.43 The determination of the disproportionation equilibrium, when coupled with
electrochemical measurements, allows for the calculation of individual stability constants.
Analysis of Kdisp,LCu is difficult in MeCN due to the highly comproportionating nature of
this solvent, i.e. very small values of Kdisp,. In fact, values of Kdisp,Cu for the solvated CuI complex
in acetonitrile have previously been estimated on the order of 10-21.61 Therefore, it was only
possible to estimate a limit of Kdisp,LCu < 1.0 x 10-4. Nonetheless, using this value the lower limits
of βII and βI as 3.5 x 1029 and 1.9 x 106 were estimated, respectively. These values, although
likely underestimated due to uncertainty of Kdisp,LCu, are in good agreement with previously
reported values for other ATRP catalysts.43, 58 All thermodynamic parameters obtained in this
study, as well as for TPMA and TPMA*3-based complexes, are summarized in Table 2. It should
be noted that values of βI are significantly limited by unattainable values of Kdisp,LCu in MeCN.
Table 2 Thermodynamic Properties of the [Cu(L)(MeCN)]2+ and [Cu(L)Br]+ Complexes in MeCN
(L = TPMA, TPMA*3, TPMANMe2
)
TPMANMe2
1.06
TPMA
1.06
-0.030c
-0.240
1.090
TPMA*3
1.06
-0.177b
-0.420
1.237
aE1/2,Cu
E1/2,LCu
-0.302
-0.554
1.362
E1/2,LCuBr
E1/2,Cu-E1/2,LCu
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0.210
0.243
E1/2,LCu-E1/2,LCuBr
dKDisp,Cu
eKDisp,LCu
βII/βI
0.252
1.0 x 10-21
<1.0 x 10-4
2.7 x 1018
<1.0x 1017
>7.1 x 1019
>2.7 x 101
1.0 x 10-21
<1.0 x 10-4
8.1 x 1020
<1.0 x 1017
>6.6 x 1024
>8.1 x 103
1.3 x 104
1.0 x 10-21
<1.0 x 10-4
1.1 x 1023
<1.0 x 1017
>1.1 x 1029
>1.1 x 106
5.3 x 103
βII/(βI)2
βII
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βI
ꢊꢊ
β
/βꢊꢇ,ꢈꢉꢉ
5.3 x 103
ꢇ,ꢈꢉꢉ
≈10-3
≈10-1
fKATRP
≈10-5
8.4 x 103 h
1.1 x 106
ka (MBrP)
2.2 x 102g
Redox potentials in V vs. SCE; ka in M-1s-1. aTaken from literature62. bTaken from Ref43, cTaken from Ref46
using the conversion factor Eo(Fc+/Fc) = 0.390 V vs. SCE. From Ref61 eExperimental limiting value of
d
KDisp,LCu. Estimated for acrylates based on value of E1/2,LCuBr and the trend of E1/2 vs. KATRP43 gFrom Ref63
f
hFrom Ref31.
Assessment of ATRP Activity
The ability of L/CuI complexes to activate (macro)alkyl halide bonds is paramount to the
success of an ATRP system. The bond dissociation free energy (BDFE) of a C-X (X = Cl or Br) has
been correlated to values of KATRP via DFT.21, 27 Generally, the activation reaction is faster
(larger values of ka) if the resulting radical is more stabilized either through steric or resonance
effects.
Electrochemistry is a useful tool in determining kinetic parameters in ATRP. The use of a
rotating disk electrode allowed for measurement of ka and KATRP for systems with moderately
high activity (ka < 104). For more active processes such as in aqueous media64 and systems
involving highly active catalysts65, cyclic voltammetry of copper complexes under catalytic
conditions (in the presence of RX) can be used to obtain ka.65-67 ka is obtained from the current
enhancement or degree of catalysis defined as Ip/Ip,0, where Ip and Ip,0 stand for the cathodic
peak current of the catalyst measured in the presence and absence of initiator, respectively
(Figure 5B). The procedure is described in the supporting information.
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(A)
(B)
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0.0
Ip,0
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-0.1
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-0.2
-0.3
-0.4
50
Ip
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[MBrP]
0 mM
100
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500
1000
5 mM
10 mM
Ip
-1.0 -0.8 -0.6 -0.4 -0.2 0.0
Potential (V) vs. SCE
-0.8
-0.6
-0.4
-0.2
Potential (V) vs. SCE
Figure 5 Cyclic voltammograms of [Cu(TPMANMe2)Br]+ in the presence of methyl 2-
bromopropionate (MBrP; acrylate mimic) at (A) varying scan rates and (B) different [MBrP]0 in
MeCN at scan rate 0.2 V s-1 at room temperature. In (A) current was normalized by dividing by
square root of the scan rate. [MBrP]0:[TPMANMe2]0:[CuBr2]0:[TEMPO]0 = 0-10:1:1:10; [CuBr2]0 = 1
mM.
As shown in Figure 5A, cyclic voltammetry of the [Cu(TPMANMe2)Br]+ complex was
conducted in the presence of methyl 2-bromopropionate (MBrP) and TEMPO. Here, MBrP
acted as a small molecule model of acrylate chain-end, while TEMPO was used as a radical trap
to prevent the deactivation reaction. The dramatic increase in Ip/Ip,0, as the scan rate decreased,
is consistent with previous reports.65, 68 The absence of an oxidation peak indicates that the
electrochemically generated CuI was completely consumed in the activation of MBrP, showing
the high activity of this catalyst in the activation of acrylates. As shown in Figure S7, cyclic
voltammetry under catalytic conditions gave a rate coefficient of activation, ka, of (1.1 ± 0.4) x
106 M-1 s-1, which is the largest value reported for this initiator with copper-based ATRP
catalysts. As will be shown later, values of kd were calculated to be 5 x 107 M-1s-1. Thus, KATRP
was estimated on the order of 10-1. This value is consistent with that estimated from the redox
potential (Table 2, KATRP = 1.0 x 10-1). This also indicates that deactivation for so active and
reducing complexes is still very efficient. These preliminary studies further indicate that this
new complex is the most active copper-based ATRP catalyst to date.
Figure 6A shows cyclic voltammetry of [Cu(TPMANMe2)Br]+ in the presence of more
active ethyl α-bromoisobutyrate (EBiB; methacrylate mimic). With [EBiB]0 >>
[CuII(TPMANMe2)Br]0 a large increase of the cathodic current and complete disappearance of the
anodic peak was observed, similar to the voltammograms in the presence of the less active
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MBrP. Cyclic voltammetry under catalytic conditions gave ka = (7.2 ± 2.0) x 106 M-1s-1 indicating
that KATRP approaches unity. However, at a ratio of [CuII(TPMANMe2)Br]0:[EBiB]0 = 1, an
interesting cyclic voltammogram was observed where the cathodic wave splits into two peaks
(Figure 6B). This particular phenomenon is attributed to “total catalysis”, which is usually found
for extremely efficient catalysts with rate constants for bimolecular reactions > 106 M-1 s-1.69
Indeed, in this case, only an infinitesimal amount of L/CuI is required for the complete reduction
of RBr, giving a first irreversible peak at E > E1/2,LCuBr due to the very fast catalytic reduction of
EBiB. On the other hand, the electrochemical reduction of [Cu(TPMANMe2)Br]+ is still reversible
since the majority of the catalyst is not involved in the electrocatalytic process. Overall, these
results show the extreme reactivity of [Cu(TPMANMe2)Br]+, which can be used in ATRP with
unprecedentedly low ppm concentrations.
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(A)
(B)
0
-10
-20
-30
Scan Rate (mV/s)
Scan Rate (mV/s)
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5000
-0.8
-0.6
-0.4
-0.2
-0.8 -0.6 -0.4 -0.2 0.0
Potential (V) vs. SCE
E (V vs SCE)
Figure 6. Cyclic voltammograms of 1 mM [Cu(TPMANMe2)Br]+ in the presence of ethyl α-
bromoisobutyrate (EBiB; methacrylate mimic) at (A) 5 mM (B) 1 mM concentration in MeCN at
at room temperature. In (A) current was normalized by dividing by square root of the scan rate.
[EBiB]0:[TPMANMe2]0:[CuBr2]0:[TEMPO]0 = 1-5:1:1:10.
Low ppm ATRP of Acrylates
To assess the efficiency of the [Cu(TPMANMe2)Br]+ catalyst, various forms of ATRP with activator
regeneration were conducted. First, ICAR ATRP was conducted at catalyst loadings ranging from
10 to 100 ppm relative to monomer with 2,2′-azobis(2-isobutyronitrile) (AIBN) as radical
initiator.70 As shown in Figure 7, linear semi-logarithmic plots vs. time were observed at all
catalyst loadings. This is consistent with previously established ICAR kinetics with bimolecular
termination for which the amount of catalyst does not change the rate of polymerization as
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shown in Eq 5, where f is initiator efficiency of AIBN, kazo is the decomposition rate coefficient
and kt is the rate coefficient of radical-radical termination.71-72
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9
f kazo[AIBN]
[R• ] =
[R• ] =
(Eq. 5)
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kt
f kazo[AIBN]
(Eq. 6)
app
CRT
k
[CuI ]
After 4 hours, >90% conversion was achieved for all reactions with a linear increase of
molecular weights with conversion, typical of a well-controlled polymerization. While the rate
of polymerization was unaffected by the initial amount of catalyst, molecular weight
distributions gradually broadened upon decreasing catalyst concentration (Figure S9). This is
attributed to decreased rate of deactivation relative to propagation. Although the initial
amount of catalyst does not affect the rate of polymerization, at lower catalyst loadings there is
less deactivator complex to reversibly trap radicals. This causes more monomer additions per
activation cycle and thus a broadening of the molecular weight distribution. (cf. Eq. 7)
(A)
(B)
3.0
2.5
2.0
1.5
1.0
0.5
0.0
25
20
15
10
5
2.5
2.0
1.5
1.0
100 ppm
25 ppm
50 ppm
10 ppm
Mn,theor
100 ppm
50 ppm
25 ppm
10 ppm
0
0.0
0
1
2
3
4
5
0.2
0.4
0.6
0.8
1.0
time (h)
conversion
Figure 7 A) Semi-logarithmic plots and B) Mn and Ð vs. conversion for the ICAR ATRP of n-butyl
acrylate (BA) at different [CuII(TPMANMe2)Br][Br] loadings under the initial conditions
[BA]0:[EBiB]0:[L/CuBr2]0:[TPMANMe2]0:[AIBN]0 = 160:1:0.016-0.0016:0.2 in anisole at 60 °C;
catalyst loadings in ppm vs. monomer; [BA]0 = 4.5 M.
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An interesting point to note is that, according to the kinetic plots presented in Figure 7A and
PREDICI simulations provided in the SI, bimolecular radical termination (RT) should dominate
catalytic radical termination (CRT), contrary to previous studies with other ATRP catalysts.13 If
CRT would significantly contribute to overall termination, the polymerization kinetics would
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app
CRT
depend on catalyst concentration (Eq. 6), where
k
is the apparent CRT rate coefficient.73
This is because, as shown in Scheme 3, CRT requires the coordination of a propagating radical
(Pn ) to the L/CuI complex to form a L/CuII-Pn organometallic species.73
•
Scheme 3 Interplay between conventional bimolecular radical termination (RT) and catalytic
radical termination via the reactive L/CuII-Pn intermediate in ATRP of acrylates.
Since the L/CuI concentration in ICAR ATRP is governed by the dynamic ATRP
equilibrium74 (Scheme 1), and considering the very high values of KATRP ≈ 10-1 for this system,
the amount of TPMANMe2/CuI present in solution is calculated to be 9.6 x 10-10 at equilibrium
(See Supporting Information for calculation).74 In other words, a radical will kinetically
terminate with a second radical faster than with the trace amounts of TPMANMe2/CuI. This
should still happen, even if addition of a radical to TPMANMe2/CuI occurs at diffusion controlled
rates (kadd = 108 M-1s-1). This is not the case of less active catalysts such as TPMA-based systems
(KATRP ≈ 10-5)63 where CRT dominates because of a relatively higher concentration of TPMA/CuI
of 1.8 x 10-6 M. As shown in Figure S10, these findings are supported by PREDICI simulations:
the much more active TPMANMe2-based system kinetically suppressed CRT because only a small
fraction of TPMANMe2/CuI is present in solution, resulting in a relatively larger fraction of living
chains compared to less active systems.
Then, Ag0 ATRP, a form of ARGET ATRP, was conducted to further test the scope of the
newly synthesized catalyst. Ag0 ATRP employs silver wire to heterogeneously reduce L/CuII to
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L/CuI, with oxidation of Ag0 to AgIBr.11 As shown in Figure 8, the TPMANMe2 catalyst successfully
polymerized MA via Ag0 ARGET ATRP using as little as 10 ppm of catalyst relative to monomer.
However, at 5 ppm, the polymerization was no longer living as confirmed by the molecular
weights decreasing with conversion and high Ð values (>1.5). Since the rate of Ag0 ARGET ATRP
depends on the rate of CuI generation, the linear semi-logarithmic kinetic plots showed that CuII
was still reduced but unable to efficiently deactivate radicals. This is because, at such low
catalyst concentrations, the rate of propagation and termination are competing with the rate of
deactivation. Thus, it is likely that 10 ppm is around the lowest possible limits to achieve a well-
controlled polymerization in copper catalyzed ATRP of acrylates. Nevertheless, unprecedented
control was achieved using as little as 10 ppm of catalyst for the polymerization of acrylates.
The nearly colorless nature of the polymerization solution at 10 ppm can be seen in Figure 8C.
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(B)
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0
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5
2.5
2.0
1.5
1.0
100 ppm
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5 ppm
50 ppm
10 ppm
Mn,theory
100 ppm
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25 ppm
10 ppm
5 ppm
0
0.0 0.2 0.4 0.6 0.8 1.0
conversion
0
5
10
15
20
25
time (h)
Figure 8 A) Semi-logarithmic plots and B) Mn and Ð vs. conversion for the Ag0 ATRP of methyl
acrylate (MA) at different loadings of [CuII(TPMANMe2)Br][Br] under the initial conditions
[MA]0:[EBiB]0:[CuII(TPMANMe2)Br][Br]0 = 200:1:0.02-0.002 with 10 cm Ag0 wire (SA/V) = 0.53 cm-1
in DMF at 50 °C; catalyst loadings in ppm vs. monomer; [MA]0 = 5.75M and C) pictures of
polymerization solution at decreasing catalyst loadings of [CuII(TPMANMe2)Br][Br].
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Using the results from the two polymerization systems shown in Figures 6 & 7, one can
estimate the rate coefficient of deactivation, kd, according to Eq 7 where DP is the degree of
polymerization, kp is the propagation rate constant,75 and p is monomer conversion.4
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kp[RX]




1
2







Mw / Mn =1+
+
−1
(Eq. 7)
II

DP
kd[LCu − X]
p




Due to the negligible amount of termination, it has been assumed that [RX] = [RX]0.
Furthermore, since the KATRP is so large, it can be assumed that essentially all copper is in the
form of L/CuII-X and therefore [L/CuII-X] = [L/CuII-X]0. Using the final dispersity data of the
polymerizations in Figures 6 & 8, kd = (5.4 ± 1.7) x 107 M-1s-1 was obtained which gives an
estimated value of KATRP = 2.2 x 10-2 for acrylate systems. This indicates that the degree of
substitution and redox potential of pyridinic-based catalysts have very little effect on kd.
Instead, only the total amount of CuII-X deactivator, which is regulated by [CuII]0 and KATRP, will
define the level of control in a particular ATRP system with activator regeneration.
Comparison of TPMANMe2 to Other Ligands in ATRP
As shown in Figure 8, the redox potential scales linearly with log(KATRP) for EBiB in MeCN
at room temperature for a variety of ligands (Figure S11 for structures of ligands). Based on
E
1/2 values, the newly synthesized TPMANMe2-based catalyst (E1/2 = -554 mV) is almost 10 billion
times more active than seminal bpy-based catalyst (E1/2 = +30 mV). Even looking at catalysts
which are widely used for low ppm ATRP, the TPMANMe2-based system is ≈300,000 and 30,000
times more active than the TPMA (E1/2 = -240 mV) and Me6TREN (E1/2 = -300 mV) based
catalysts, respectively. Unfortunately, with such a highly active catalyst as [Cu(TPMANMe2)]+,
activation of alkyl halides approaches diffusion controlled limits (ka >106 M-1s-1), and with
already diffusion controlled deactivation rates (kd = >107 M-1s-1), values of KATRP begin to
approach unity. This would mean that for commonly used monomers such as acrylates and
methacrylates, this catalytic system may be the upper limit of activity since the only way to
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further increase KATRP would be to decrease kd. This is not best since the control achieved in
ATRP is due to fast rates of deactivation. Encouragingly, the high ATRP activity provided by the
TPMANMe2-based catalyst can open the possibility to polymerize less active monomers such as
vinyl acetate and N-vinylpyrrolidone which have historically fallen victim to too low values of
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KATRP
.
TPMANMe2
TPMA*3
0
-2
TPMA*2
Me6TREN
BPMA*Pr
PMDETA
-4
TPMA
-6
dNbpy
-8
bpy
-10
0
-200
-400
-600
E1/2 vs. SCE (mV)
Figure 9 Redox potential (E1/2) vs. log(KATRP) for various ATRP catalysts complexed by
multidentate nitrogen-based ligands. Values for E1/2 have previously been determined
experimentally vs. an SCE electrode in MeCN at room temperature. Values of KATRP are for ethyl
α-bromoisobutyrate (EBiB; methacrylate mimic) in MeCN at room temperature. Structures of
all ligands are shown in Figure S11.
Conclusions
The synthesis of a new ATRP catalyst employing the p-dimethylamino substituted TPMA
ligand, tris[(4-dimethylaminiopyridyl)methyl]amine (TPMANMe2), is reported. Variable
temperature NMR showed a fluxional CuI complex with rapid ligand exchange. In the solid
state, the [CuII(TPMANMe2)Br]+ complex exhibited nearly perfect trigonal bipyramidal geometry.
UV-Vis and EPR confirmed that this geometry was retained in solution. Electrochemical
measurements showed a quasi-reversible TPMANMe2CuI/II couple indicating small geometric
rearrangement throughout the redox cycle. Stability constants for CuI and CuII were
comparable to other copper ATRP catalysts in MeCN. Electrochemistry was also utilized to
assess the activation of methyl 2-bromopropionate (MBrP; acrylate mimic) and ethyl α-
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bromoisobutyrate, for which a rate coefficient of activation was measured as ka = 1.1 x 106 M-1s-
1 and 7.2 x 106 M-1s-1, respectively. This leads to an estimation of KATRP = 2.2 x10-2 and 7.2 x10-1,
respectively which indicated this is the most active ATRP catalyst to date. A large value of kd >
107 M-1 s-1 was calculated and indicated that the catalyst is also a good deactivator. Both ICAR
and Ag0 ATRP of acrylates were well-controlled using as little as 10 ppm of catalyst relative to
monomer. Encouragingly, due to the high values of KATRP and low [TPMANMe2/CuI], unwanted
side reactions involving CuI such as catalytic radical termination (CRT) are suppressed leading to
higher chain-end functionality. Furthermore, this catalyst can potentially allow for the
successful ATRP of less active monomers. Investigations in this direction are currently ongoing
in our laboratories.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, X-ray diffraction details, discussion of electrochemical
methods, GPC traces, example calculations of L/CuI at steady-state, kinetic simulations and
structures of common ligands employed in ATRP.
AUTHOR INFORMATION
Corresponding Author:
*(K.M.) Email: km3b@andrew.cmu.edu
◊T.R. and M.F. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Support from the NSF (CHE 1707490) is acknowledged. We thank the Centre National de la
Recherche Scientifique (CNRS) for support through the PICS06782 grant and through the
Laboratoire International Associé (LIA) “Laboratory of Coordination Chemistry for Controlled
Radical Polymerization”. We are also grateful to the French Embassy in Washington D.C. for a
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Chateaubriand Fellowship to T.R. We would like to acknowledge Mateusz Olszewski for
designing the graphical abstract for this manuscript.
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