Cationic Copper Iminophosphorane Complexes as CuAAC Catalysts: A Mechanistic Study

Article abstract of DOI:10.1021/acs.organomet.0c00348

We have combined Cu K-edge X-ray absorption spectroscopy with NMR spectroscopy (1H and 31P) to study the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction under operando conditions. A variety of novel, well-defined CuI iminophosphorane complexes were prepared. These ligands, based on the in situ Staudinger reduction when [Cu(PPh3)3Br] is employed, were found to be active catalysts in the CuAAC reaction. Here, we highlight recent advances in mechanistic understanding of the CuAAC reaction using spectroscopic and kinetic investigations under strict air-free and operando conditions. A mononuclear Cu triazolide intermediate is identified to be the resting state during catalysis; cyclization and protonation both have an effect on the rate of the reaction. A key finding of this study includes a novel group of highly modular CuI complexes that are active in the base-free CuAAC reaction.

Full text of DOI:10.1021/acs.organomet.0c00348

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Article
Cationic Copper Iminophosphorane Complexes as CuAAC Catalysts:
A Mechanistic Study
Bas Venderbosch, Jean-Pierre H. Oudsen, Jarl Ivar van der Vlugt, Ties J. Korstanje, and Moniek Tromp*
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sı Supporting Information
ABSTRACT: We have combined Cu K-edge X-ray absorption
1
31
spectroscopy with NMR spectroscopy ( H and P) to study the
Cu-catalyzed azide−alkyne cycloaddition (CuAAC) reaction under
I
operando conditions. A variety of novel, well-defined Cu
iminophosphorane complexes were prepared. These ligands,
based on the in situ Staudinger reduction when [Cu(PPh ) Br]
3
3
is employed, were found to be active catalysts in the CuAAC
reaction. Here, we highlight recent advances in mechanistic
understanding of the CuAAC reaction using spectroscopic and
kinetic investigations under strict air-free and operando conditions.
A mononuclear Cu triazolide intermediate is identified to be the
resting state during catalysis; cyclization and protonation both
have an effect on the rate of the reaction. A key finding of this
I
study includes a novel group of highly modular Cu complexes that are active in the base-free CuAAC reaction.
INTRODUCTION
The Cu -catalyzed azide−alkyne cycloaddition (CuAAC)
reaction is a valuable methodology to generate triazoles, a
phase. To date, limited spectroscopic studies have been
performed under operando conditions. Dinuclear intermediates
■
I
have recently been detected using electrospray ionization
1
,2
common scaffold in complex drug molecules.
The
17
(
ESI) mass spectrometry (MS) under catalytic conditions.
uncatalyzed variant of this reaction (a.k.a. Huisgen 1,3-dipolar
cycloaddition) yields a mixture of 1,4- and 1,5-regioisomers of
the targeted triazole, and the reaction requires elevated
temperature (Scheme 1a). On the contrary, the Cu-catalyzed
version yields solely the 1,4-regioisomer and is typically
performed at room temperature (Scheme 1b). Because of
the high yields, selectivity, and robustness of the CuAAC
reaction, it is a prime example of a so-called click reaction.
The CuAAC reaction was also studied by using infrared
18
spectroscopy (IR) by Wu et al., and the rate-determining
step was identified to be the cyclization of the azide and alkyne.
However, no conclusions were made regarding the exact
structure or the nuclearity of the active species.
3
4
,5
This study provides more insights into the mechanism of the
6
I
CuAAC reaction by using novel, cationic, homoleptic Cu
The active CuAAC catalyst is often generated in situ by
II
7
iminophosphorane complexes. The mechanism of the CuAAC
reduction of a Cu precursor. Alternatively, catalysis can be
I
I
performed directly with a preformed Cu complex ligated by,
reaction catalyzed by these iminophosphorane-stabilized Cu
8
9
10
for example, carbenes, amines, or phosphines.
complexes is investigated by using operando spectroscopy
Several mechanistic studies have been performed on the
CuAAC reaction. An early proposal made by Sharpless and co-
(
NMR and Cu K-edge XAS) and kinetic experiments.
I
I
Additionally, a mononuclear Cu triazolide complex is
prepared, and its relevance to the catalytic cycle is investigated.
The DFT results support protonation of the Cu triazolide to
workers suggested that catalysis proceeds via mononuclear Cu
5
intermediates. Later mechanistic studies, however, revealed a
I
11
I
second-order rate dependency on the concentration of Cu .
DFT calculations show a decrease in the activation barrier
when a second Cu atom is introduced. In addition, various
isolable polynuclear copper acetylide complexes were found to
be the rate-determining step in the catalytic cycle.
1
2
1
3−16
Received: May 18, 2020
be catalytically active in the CuAAC reaction.
Based on
these observations, catalysis is believed to proceed through
I
dinuclear Cu intermediates (Scheme 1c).
Most of these mechanistic proposals are based on either
solid-state structures, obtained through single-crystal X-ray
diffraction (XRD), or DFT calculations performed in the gas
©
XXXX American Chemical Society
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A
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1
Scheme 1. (a) Uncatalyzed Azide−Alkyne Cycloaddition
(PPh ) Br] in THF-d was monitored by using H NMR
3 3 8
23
Reaction to Yield the 1,4- and 1,5-Regioisomer of the
spectroscopy (Figure 1, left).
The conversion was
I
1
Target Triazole; (b) Cu -Catalyzed Azide−Alkyne
determined from the H spectra by comparing the amount
of benzyl azide relative to the amount of product triazole
(Supporting Information, section 1.5).
Cycloaddition Reaction to Yield Solely the 1,5-Regioisomer;
I
(
c) Recent Mechanistic Proposal for the Cu -Catalyzed
Azide−Alkyne Cycloaddition Reaction, Involving Dinuclear
After roughly 15 h a conversion of ∼75% is obtained.
Interestingly, an induction period is present, as can be seen in
the inset of Figure 1, suggestive of structural changes occurring
to the complex prior to formation of the active catalyst.
Monitoring this system in time using P NMR spectroscopy
was used to shed light on the origin of this induction period
I
a
Cu Intermediates
3
1
(
Figure 1, right). Two distinct resonances are observed over
the course of hours. First, a resonance is present at around δ =
P
−
6 ppm that decreases in time. This resonance is assigned to
PPh , either bound or free in solution. The second resonance
3
increases in time at around δ = 10 ppm.
P
The broadness of the observed resonances is indicative of
underlying dynamic processes. These processes were slowed by
cooling the reaction mixture to −60 °C; multiple novel
resonances were identified (Figure S119). One of these
resonances (δ = 6.4 ppm) is attributed to the product of
P
the Staudinger reaction between benzyl azide and PPh3,
indicating that the phosphine ligands undergo oxidation under
catalytic conditions.
Synthesis and Characterization of Cu Iminophos-
phorane Complexes. The Staudinger reaction occurring
under catalytic azide−alkyne coupling conditions in the
presence of air and moisture has already been observed with
24,25
[
Cu(PPh ) Br] and was considered an unwanted reaction.
3 3
However, our results imply that the Staudinger reaction is
relevant to generate the catalytically active species from
a
This cycle is based on the proposal made in ref 13.
[
Cu(PPh ) Br] under anhydrous and oxygen-free conditions.
3 3
These combined results suggest that iminophosphorane (IP)
ligation to copper might be of prime importance in this
activation process to enable the CuAAC reaction. Notably,
copper complexes with chelating IP-based ligands have
RESULTS AND DISCUSSION
■
Degradation of [Cu(PPh ) Br] under Catalytic Con-
3
3
ditions. Initially, [Cu(PPh ) Br] was selected for this
3
3
26,27
mechanistic study. The use of [Cu(PPh ) Br] as a potent,
previously been employed in the CuAAC reaction.
3
3
organic-soluble CuAAC catalyst was first reported by Per
́
ez-
To investigate the coordination chemistry of monodentate
IPs, we prepared a variety of IPs (Scheme 2) by mixing the
respective phosphine and benzyl azide in a suitable solvent
(either toluene or THF). For the less sterically encumbered
IPs (L1 , L2 , L3 , and L5 ) the reaction readily proceeds
1
9
Balderas et al. Later, Lal et al. increased the applicability of
the catalyst and showed that the catalyst can also operate in
20
water and under neat conditions. The catalyst has also shown
21,22
application in the field of click polymerization.
H
OMe
Cl
Me
In this study, reactions were performed under strict air-free
conditions to prevent oxygen or moisture affecting the course
of the reaction. As a model system, the reaction between
benzyl azide and phenylacetylene in the presence of [Cu-
at room temperature, indicated by rapid N2 evolution.
Formation of L4Cy required heating to 110 °C, presumably
due to steric hindrance imposed by PCy , hampering
3
elimination of N from the phosphazide intermediate. L1 ,
2
H
Figure 1. Reaction between benzyl azide (1 equiv) and phenylacetylene (1.2 equiv) in the presence of [Cu(PPh ) Br] (2.5 mol %) in THF-d . (a)
3
3
8
1
31
Conversion followed by H NMR spectroscopy. (b) Temporal evolution of the resonances observed in the P NMR spectrum. Conversion was
determined by comparing the integral of the benzyl azide and triazole moiety. In the P NMR spectrum, the first spectrum is measured after 15
3
1
min and time intervals of 15 min are employed between consecutive spectra.
B
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1
Scheme 2. Staudinger Reaction to Produce the Target
Iminophosphorane Ligands L1−L5
shift in the H NMR spectrum for the benzylic hydrogens is
observed upon coordination to copper for each complex.
Single crystals suitable for X-ray diffraction for complexes 1H
(
as the PF complex) and 2 , 3 , and 4 were obtained by
6 OMe Cl Cy
diffusion of pentane into a saturated THF solution of the
respective complex (Figure 2). Complex 5Me proved very
sensitive, with a color change (from white to yellow) of the
solid material observed inside an Ar-filled glovebox in the
course of several days, presumably hampering the isolation of
single crystals for this complex.
All four molecular structures show a linear coordination
geometry around Cu, with N−Cu−N angles close to 180°.
The largest deviation from linearity is observed for complex
4Cy (∠N−Cu−N 174.86°), presumably arising from the steric
L2OMe, L3 , and L4 were isolated as white solids, whereas
Cl
Cy
1
L5Me was obtained as a pink liquid. The H NMR spectrum of
3
each IP shows a characteristic doublet ( JP−H) for the benzylic
bulk introduced by the PCy substituents. The coordination
hydrogens. In addition, the observed 31P NMR resonance for
the respective PN moiety varied depending on the parent
phosphine employed. For L1 , L2 , and L3 a single
3
environment around the nitrogen atoms is close to trigonal
planar in each case, and the Cu−N distances vary only slightly
H
OMe
Cl
(
between 1.87 and 1.90 Å).
Catalytic Performance of the Prepared Cu Imino-
resonance was observed with a value of δ ≈ 9 ppm, while L4
P
Cy
resonates at δ = 24.3 ppm and L5 resonates at δ = 11.6
P
Me
P
phosphorane Complexes. The catalytic performance of the
complexes (1−5) in the CuAAC reaction between phenyl-
ppm.
I
Coordination of L1H to Cu was successfully achieved by
reaction of the ligand with CuBr (Supporting Information,
section 2.6). Single-crystal X-ray diffraction revealed a
homoleptic complex of the structure [Cu(L1 ) ][CuBr ].
acetylene (1.2 equiv) and benzyl azide (1 equiv) in THF-d
was monitored over the course of 15 h by using H NMR
8
1
spectroscopy (Figure 3). All complexes were found to be active
in the CuAAC reaction, but a large variation for their
performance in the CuAAC reaction is observed. A side-by-
side comparison of complexes 1 , 2OMe, and 3 may provide
H 2
2
−
The [CuBr2] anion can also participate in the CuAAC
reaction, as NBu [CuBr ] (2.5 mol % in THF-d ) showed
4
2
8
moderate activity in the CuAAC reaction (34% conversion
after 22 h). To prevent the participation of the cuprate anion
H
Cl
insight into the influence of the electronic structure of the
ligand on the catalytic activity in the CuAAC reaction (Figure
I
in the CuAAC reaction, we used [Cu(NCMe) ]BF as the Cu
4
4
3
, left). The observed activity trend is 3 > 1 > 2OMe, which
source. Through reaction of ligand L1−L5 (2.1 equiv) with
Cu(NCMe) ]BF (Scheme 3), complexes 1−5 with the
Cl H
suggests that a decrease in Lewis basicity of the ligand leads to
enhanced catalytic performance.
[
4
4
A comparison of the catalytic activity of 1 , 4 , and 5
Me
Scheme 3. Synthesis of Cu Iminophosphorane Complexes
−5
H
Cy
seems to imply that a reduction of steric bulk is beneficial for
catalysis (Figure 3, right). However, analysis of the catalytic
performance of 5Me shows an increase of its catalytic
performance with time. This may be related to the small
substituents at phosphorus, enabling the triazole product to
also ligate to the metal and have a positive influence on the rate
1
28
of the rate of the reaction (i.e., autocatalysis). This prevented
us from relating the catalytic activity to the steric bulk of the
ligand.
We also assessed the catalytic performance of 1H under
ambient conditions (Supporting Information, section 4.11).
The catalytic performance under ambient conditions is greatly
enhanced. The origin of this effect is unknown, but likely
protonation will be more facile (vide infra).
Mechanistic Study of the CuAAC Reaction Using Cu
Iminophosphorane Complexes. Because of the ease of
general structure [Cu(IP) ]BF were successfully synthesized
2
4
synthesis and good stability in solution, complex 1 was used
and were fully characterized with NMR spectroscopy, mass
spectrometry (MS), and in most cases single-crystal X-ray
diffraction.
H
for a mechanistic study. To arrive at potentially relevant
catalytic intermediates, initial synthetic attempts focused on a
Cu−acetylide species bearing ligand L1 as previously isolated
Using cold-spray ionization (CSI) MS, we detected only the
homoleptic cationic fragments, with no noticeable fragmenta-
tion of these complexes. NMR spectroscopy shows clear
H
mono- and dinuclear Cu−acetylides showed to be relevant
15
active catalytic species. Cu complexes containing an internal
base can directly react with alkynes to prepare Cu acetylides.
3
1
changes in the P NMR resonances for the corresponding
complexes compared to the free ligands (see the Experimental
Section) with Δδ of ∼24 ppm in the case of aromatic
substituents and Δδ of ∼36 ppm in the case of aliphatic
substituents on the phosphine. Interestingly, no broadening of
I
This approach has been used to prepare Cu complexes
14,29,30
containing carbene ligands.
It is likely that iminophos-
phorane ligands can also act as internal bases, given their
qualification as superbases; the closely related iminophosphor-
3
1
the P NMR resonances for any of the [Cu(IP) ]BF
ane Ph PNCy was found to have a pK
of 22.7 in
2
4
3
BH+
31
complexes was observed at room temperature. In addition, a
acetonitrile.
C
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Figure 2. ORTEP plots (50% probability level) for 1 (as PF salt, top left), 2 (top right), 3Cl (bottom left), and 4Cy (bottom right). Hydrogen
OMe
H
6
atoms and anions are omitted for clarity. Selected bond lengths [Å], angles [deg], and torsion angles [deg]: For 1 : Cu −N 1.8902(18); N −P
H
1
1
1
1
i
1
.6055(18); N −C 1.487(3); N −Cu −N 178.80(11); P −N −Cu 120.18(11); C −N −Cu 117.04(14); C −N −P 120.27(15); P −N −
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
i i
N −P 99.24. For 2 : Cu −N 1.879(5); Cu −N 1.867(5); N −P 1.600(5); N −P 1.600(5); N −C 1.464(8); N −C 1.478(8); N −Cu −
1
1
OMe
1
1
1
2
1
1
2
2
1
1
2
29
1
1
N 179.7(3); P −N −Cu 117.3(4); C −N −Cu 117.3(4); C −N −P 121.2(4); P −N −Cu 118.1(3); C −N −Cu 117.7(4); C −N −P
2
1
1
1
1
1
1
1
1
1
2
2
1
29
2
1
29
2
2
i
1
18.3(4); P −N −N −P 176.95. For 3 : Cu −N 1.865(4); N −P 1.592(4); N −C 1.474(6); N −Cu −N 180.0; P −N −Cu 121.5(2); C −
1
1
2
2
Cl
1
1
1
1
1
1
1
1
1
1
1
1
1
i
i
i
N −Cu 116.0(3); C −N −P 119.6(3); P −N −N −P 180.0; Cu −N 1.860(4); N −P 1.587(4); N −C 1.472(6); N −Cu −N 180.0; P −
1
1
1
1
1
1
1
1
1
2
2
2
2
2
26
2
2
2
2
i
i
1
N −Cu 117.5(2); C −N −Cu 121.0(3); C −N −P 119.0(3) P −N −N −P 180.0. For 4 : Cu −N 1.8796(13); Cu −N 1.8813(13) N −
2
2
26
2
2
26
2
2
1
1
1
Cy
1
1
1
2
1
P
1
1.6156(13); N −P 1.6169(13); N −C 1.477(2); N −C 1.472(2); N −Cu −N 174.84(6); P −N −Cu 121.83(8); C −N −Cu
1
2
2
1
1
2
26
1
1
2
1
1
1
1
1
1
13.18(10); C −N −P 120.54(11); P −N −Cu 119.55(7); C −N −Cu 118.07(10); C −N −P 119.24(10); P −N −N −P 144.05.
1
1
1
2
2
1
26
2
1
26
2
2
1
1
2
2
Figure 3. Conversion as a function of time for the various prepared complexes. Reactions were performed by mixing the Cu complex (2.5 mol %
with respect to Cu), with benzyl azide (1 equiv) in THF-d (1 mL), followed by the addition of phenylacetylene (1.2 equiv).
8
1
The hypothesis that IPs are capable of deprotonating alkynes
was confirmed by reacting 1H with ∼10 equiv of phenyl-
acetylene (Scheme 4a). Mixing both reagents in THF led to
immediate formation of a yellow precipitate that is insoluble in
both apolar and polar solvents. Attenuated total reflection
supernatant showed broad, uninformative resonances in the H
NMR spectrum (Figure S122), while the 31P NMR spectrum
(
Figure S123) showed unreacted 1 (δ = 33.2 ppm). Cooling
H P
to −60 °C (Figures S124 and S125) led to the detection of
L1H and an additional resonance, which was identified as
((PPh )N(H)CH Ph) , the conjugate acid of L1 (δ = 38.6
ppm) (Figure S127). These resonances remain very broad,
even at −60 °C, and are indicative of rapid exchange. No
infrared (ATR-IR) spectroscopy confirmed the presence of
+
I
both polynuclear Cu (CCPh) and unreacted 1 (Figure S118),
3
2
H
P
H
with no vibrations observed for a Cu(CCPh)(IP) species. At
1
room temperature, the H NMR spectrum of the in vacuo dried
D
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Scheme 4. Overview of (Attempted) Synthetic Procedures to Prepare Catalytically Relevant Intermediates: (a) Reaction of 1H
with Phenylacetylene; (b) Reaction of Copper Phenylacetylide with L1 ; (c) Reaction of Copper Phenylacetylide with L1H
H
and Benzyl Azide
additional resonances were observed that could be assigned to
a Cu(CCPh)(IP) species.
Other approaches that have been employed in the literature
to prepare Cu phenylacetylide complexes include the direct
reaction between polynuclear copper phenylacetylide and a
3
0
suitable ligand. However, a reaction to generate a well-
defined species by mixing polynuclear copper phenylacetylide
with L1H to prepare Cu phenylacetylide was unsuccessful
(Scheme 4b), with work-up only leading to quantitative
isolation of both starting materials (Supporting Information,
section 4.3). On the basis of the two previous unsuccessful
reactions, we propose that monodentate IPs do not provide
stable ligation to copper phenylacetylide.
During catalysis, the solution remains homogeneous, and no
precipitation of polynuclear copper phenylacetylide species is
observed. Combined with the observations made during the
previous experiments (Scheme 4a,b), it is unlikely that the
resting state during catalysis under the employed reaction
conditions is a Cu acetylide complex. Another plausible
candidate for the resting state is a Cu triazolide complex
(Scheme 1). In this regard, recent DFT studies have shown
that proton transfer from incoming acetylene substrate to a Cu
triazolide species can become the rate-determining step if the
alkyne is the only proton source present during the CuAAC
1
Figure 4. Comparison of the H NMR spectrum of L1 (top), 1H
(
H
middle), and [Cu(triaz)(L1 )] (bottom) in CD Cl .
H 2 2
3
2
reaction.
To date, only a handful of Cu triazolide complexes have
1
5,33−35
been isolated.
Common strategies to isolate such a
assigned to the benzylic hydrogens of the triazolide moiety.
Additionally, the C NMR spectrum shows two resonances
copper triazolide complex involve reaction of a ligated Cu
phenylacetylide complex with an organic azide. For our system,
this approach is not viable as no ligated Cu phenylacetylide
complexes could have been isolated. In an attempt to prepare
the targeted Cu triazolide complex, a direct reaction was
performed using Cu phenylacetylide, benzyl azide, and L1H
13
(
δC = 154.2 and 150.0 ppm) that can be attributed to the
carbons of the CC fragment present in the five-membered
ring, in correspondence with data for an earlier isolated
33
triazolide complex by Straub (δ = 154.6 and 152.2 ppm).
Finally, the P NMR spectrum shows a single resonance at δ
C
3
1
P
(Scheme 4c).
= 32.2 ppm.
After work-up, an off-white solid was obtained that was
sensitive to moisture and oxygen. The H NMR spectrum is in
line with the successful synthesis of Cu triazolide complex
Cu(PhCH N(PPh )(1-benzyl-4-phenyltriazolide)] ([Cu-
triaz)(L1 )]) (Figure 4), with a resonance at δH = 5.13
The positive mode high-resolution CSI mass spectrum
(Figure S101) shows the molecular ion peak for the
1
+
homoleptic fragment [Cu((PPh )NCH Ph) ] (expected:
3
2
2
[
(
797.228; found: 797.224). Negative mode CSI HRMS (Figur−e
S102) provides many fragments, including [Cu(triazolide)2]
(expected: 531.136; found: 531.131).
2
3
H
ppm that is not observed in L1H or 1 . This resonance is
H
E
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Figure 5. Comparison of the Cu K-edge XAS data for 1H and [Cu(triaz)(L1 )] in the absence and presence of benzyl azide (1 equiv) and
H
phenylacetylene (1.2 equiv). Under catalytic conditions, solutions were frozen after a reaction time of 10 min and 2.5 mol % of Cu was employed.
2
Both samples were measured in THF. (a) k -weighted Cu K-edge EXAFS data. (b) Fourier transform of the Cu K-edge EXAFS data. For the
Fourier transform, a k-range of 3−12 Å− was employed. (b) also shows structures of the corresponding complexes.
1
It is unclear whether the isolated complex is homoleptic or
whether ligand exchange has occurred under MS conditions
and the complex is heteroleptic. Of the few reported Cu
Table 1. Cu K-Edge EXAFS Fitting Results for 1 and
H
[Cu(triaz)(L1 )] in THF in the Absence and Presence of
H
a
Benzyl Azide and Phenylacetylene
15,33−35
triazolide complexes, none of them were homoleptic.
In
coordination
shell
d(Cu−X) (Å)
addition, [Cu(triaz)(L1 )] is highly soluble in toluene,
b
σ2 (Å−2
H
conditions
)
exptl
deeming the formation of an ionic complex unlikely.
1H
2 Cu−N
0.0037(7)
0.016(9)
0.005(2)
0.0022(6)
1.87(1)
2.90(2)
3.03(1)
1.90(1)
Furthermore, the benzylic hydrogens of [Cu(triaz)(L1 )] are
H
6
2
Cu−C
Cu−P
significantly shifted compared to the benzylic hydrogens of 1H,
indicating a different chemical environment (Figure 4). On the
1H + PhAc + BnN3 ,
cd
2 Cu−C/
basis of these findings, we propose that [Cu(triaz)(L1 )] is
H
Cu−N
indeed best formulated as a heteroleptic complex.
6
Cu−C
0.024(6)
0.003(2)
0.0029(6)
3.03(3)
3.04(2)
1.89(1)
[
Cu(triaz)(L1 )] proved to be active in the CuAAC
H
1 Cu−P
2 Cu−C/
reaction between phenylacetylene (1.2 equiv) and benzyl
azide (1 equiv) and showed similar activity compared to 1H
Cu(triaz)(L1H)
Cu−N
6
1
Cu−C
Cu−P
0.022(5)
0.003(2)
0.0028(5)
3.00(2)
3.02(2)
1.895(9)
(Figure S130). The similarity in catalytic activity of the two
complexes suggests that the [Cu(triaz)(L1 )] is indeed
H
Cu(triaz)(L1 ) + PhAc +
2 Cu−C/
formed from the 1H system under catalytic conditions.
Additional evidence for the formation of a Cu triazolide
complex under catalytic conditions was found by using VT
NMR and freeze-quench Cu K-edge EXAFS experiments. The
H
,
cd
BnN
Cu−N
3
6
1
Cu−C
Cu−P
0.021(4)
0.003(1)
3.02(2)
3.03(1)
a
3
1
These parameters were used to obtain the fits shown in Figure 5.
P NMR spectrum acquired at −50 °C shows two resonances
Fitting parameters without parentheses were kept fixed to reduce
at δ = 37.4 and 32.6 ppm (Figure S131), with the former
signal being assigned to [(PPh )N(H)CH Ph] . The latter
P
fitting parameters. Other fitting parameters are given in the
+
b
3
2
Supporting Information. 2.5 mol % of Cu was used during catalytic
31
c
signal is very similar to the P resonance as discussed
previously for the Cu triazolide complex (Figure S97).
Furthermore, Cu K-edge EXAFS analysis of 1H reveals a
Cu−N/Cu−C shell containing two atoms at a distance of
1
2
experiments. Reaction mixtures were frozen 10 min after mixing the
d
reagents. PhAc is used to denote phenylacetylene (1.2 equiv), and
BnN (1 equiv) is used to denote benzyl azide.
3
.87(1) Å, a Cu−C shell containing six atoms at a distance of
.90(2) Å, and a Cu−P shell containing two atoms at a
Having identified the resting state to be [Cu(triaz)(L1 )],
H
distance of 3.03(1) Å (Figure 5 and Table 1). The bond
distances and coordination numbers are in close agreement
with the crystal structure of 1H (Figure 2). Under catalytic
conditions, a solution containing the 1H complex shows a
reduction of the coordination number of the Cu−P shell to
one, in line with loss of one of the IP ligands. Also, the EXAFS
analysis is in very close agreement with EXAFS analysis of
we performed kinetic experiments to investigate the pathway
through which the triazole product is formed. First, the kinetic
isotope effect (KIE) for deuterium-labeled phenylacetylene-d1,
determined by reacting phenylacetylene (0.6 equiv), phenyl-
acetylene-d (0.6 equiv), and benzyl azide (1 equiv) in the
1
presence of 1H (2.5 mol %), was found to be 4.4(4)
(Supporting Information, section 4.10), which shows that the
mildly acidic C−H bond of phenylacetylene is broken in the
rate-determining step.
[
Cu(triaz)(L1 )], providing further evidence for the formation
H
of a Cu triazolide complex under catalytic conditions. Overall,
the data support formulation of [Cu(triaz)(L1 )] as the
resting state during catalytic turnover in the CuAAC reaction,
Two pathways that are in agreement with this observation
are depicted in Scheme 5. First, phenylacetylene may
coordinate to the metal center and directly protonate the
triazolide moiety to form the product and a copper−
phenylacetylide complex. Second, proton transfer from phenyl-
H
starting from 1 . On the basis of the copper complex being
H
two-coordinate, and on the absence of a Cu−Cu shell, we
propose that the Cu triazolide complex is mononuclear.
F
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Article
a
Scheme 5. Hypothesized Pathways through Which the Product Triazole Is Formed
a
Phenylacetylene can directly protonate the triazolide moiety to form the product. Alternatively, the ligand is first protonated and can then act as a
proton shuttle. In this scheme, RDS is used to denote the rate-determining step.
acetylene to the basic IP ligand may precede protonation of the
triazolide moiety, with IP acting as a proton shuttle.
phenylacetylene a broken order of 0.28(3) is observed.
These broken orders indicate that phenylacetylene and benzyl
azide are involved in a pre-equilibrium leading up to the rate-
To discern between the two pathways, we have reacted
+
36
[
Cu(triaz)(L1 )] with phenylacetylene or PhCH N(H )-
determining step(s). A broken order with respect to
H
2
(
PPh )BF for 2 h at room temperature. Both reactions lead
phenylacetylene is in line with the KIE measurements and
further confirms that coordination of phenylacetylene occurs
during the rate-determining step(s).
A broken order with respect to benzyl azide also shows that
benzyl azide coordination occurs during the rate-determining
step(s). In line with the general mechanism of the CuAAC
reaction (Scheme 1c), we propose that both the cyclization
step and protonation step contribute to the overall rate of the
reaction at low substrate loadings.
3
4
1
to the triazole product, as evidenced by the H NMR spectrum
Figure S138). If the ligand indeed does act as a proton shuttle,
it should be beneficial for the catalytic activity to have
(
+
additional [PhCH N(H )(PPh )]BF present during catalysis.
However, addition of [PhCH N(H )(PPh )]BF (1 equiv) to
2
3
4
+
2
3
4
[
Cu(triaz)(L1 )] had no effect on the catalytic performance
H
compared to the standard conditions (Figure S139). These
findings make it unlikely that catalysis occurs through proton
shuttling facilitated by the IP ligand.
Evidence for coordination of a substrate was found in the Cu
K-edge XANES region (Figure S117). Upon introduction of
benzyl azide and phenylacetylene to a THF solution of
Next, we determined the order of the reaction with respect
to copper and substrates (Table 2). A first-order dependency
[
Cu(triaz)(L1 )], a slight decrease in intensity of the pre-edge
H
Table 2. Overview of the Employed Conditions for the
Order Determination of the Various Components of the 1H
region is observed. The pre-edge region arises from 1s to 4p
transitions; distortion from linearity gives rise to a decrease in
intensity of the pre-edge region. The slight decrease in
intensity in the pre-edge region can be interpreted to arise
from a small fraction of copper centers binding substrates
(
and [Cu(triaz)(L1 )] System
37
H
a
b
component Cu (equiv) BnN (equiv) PhAc (equiv) reaction order
3
Cu
PhCCH
BnN3
PhCCH
BnN3
1−3
225
35
20−40
40
4−10
205
25−45
10
1−10
40
1.1(1)
−0.02(7)
0.00(3)
0.28(3)
0.30(6)
phenylacetylene or benzyl azide) under catalytic conditions.
Computational Study of the Cu Iminophosphorane
1
1
1
1
c
System. To verify our experimental findings, we have
performed DFT-D3 calculations at the BP86/TZ2P level of
theory on the proposed catalytic cycle (Scheme 6) with the
corresponding energies reported below the respective inter-
mediates. The Cu triazolide complex, [Cu(triaz)(L1 )] (A1),
was used as a starting for the calculations.
c
a
b
BnN is used to denote benzyl azide. PhAc is used to denote
phenylacetylene. [Cu(triaz)(L1 )] was employed due to the slow
3
c
H
kinetics.
H
Coordination of phenylacetylene to Cu triazolide A1 yields
Cu triazolide A2; this coordination step is mildly exergonic
on the Cu concentration and a zeroth-order dependency in
both substrates are observed when a large excess of both
phenylacetylene and benzyl azide is used. The former indicates
that a mononuclear Cu complex is involved in the rate-
determining step or a dinuclear complex that stays intact in all
stages of the catalytic cycle. Zeroth-order dependency on both
−
1
(
ΔG° = −0.9 kcal mol ). Protonolysis of complex A2 through
reaction with phenylacetylene proceeds with a relatively high
‡
−1
barrier (TSA1, ΔΔG = 22.5 kcal mol ) to yield the triazole
and copper phenylacetylide complex A3 (ΔΔG = 5.8 kcal
mol ). A3 is likely thermodynamically unstable, as no ligated
11
−1
substrates is indicative of saturation kinetics.
To limit saturation conditions, we reduced the amount of
substrate with respect to the metal center. At low substrate
concentrations, the formation of the Cu triazolide complex
copper phenylacetylide complex could be isolated.
A3 is incapable of directly coordinating benzyl azide.
Instead, a rather large Cu−N distance (3.33 Å) is observed
−
1
from 1 was too slow for kinetic analysis. For this reason, we
in the final geometry (A4, ΔΔG = −0.1 kcal mol ).
Subsequent cycloaddition of benzyl azide and complex A3 to
H
employed [Cu(triaz)(L1 )] as the Cu source. For benzyl
H
−
1
azide, a broken order of 0.30(6) is observed, and for
yield six-membered cupracycle A5 (ΔΔG = 7.9 kcal mol )
G
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Article
a
Scheme 6. (top) Proposed Catalytic Cycle for the CuAAC Reaction Catalyzed by Copper Iminophosphorane Complexes;
(bottom) Energy Diagram of the Proposed Catalytic Cycle with the Gibbs Free Energy Being Reported
a
DFT-D3 calculations were performed at the BP86/TZ2P level of theory. The R group denotes a phenyl substituent, and the R′ group denotes a
benzyl substituent. The ligand (L) employed in these calculations was PhCH N(PPh ).
2
3
‡
proceeds with a relatively low barrier (TSA2, ΔΔG = 11.0
relative concentration of benzyl azide and phenylacetylene are
taken into consideration (Table 2).
38
−
1
‡
−1
kcal mol ). Ring contraction (TSA3, ΔΔG = 1.4 kcal mol )
of cupracycle A5 to complete the cycle is highly exergonic
These results are in line with both our experimental findings
of a primary KIE for phenylacetylene and a broken order at low
substrate loadings for both phenylacetylene and benzyl azide,
given that both TSA1 and TSA3 likely contribute to the rate-
determining step under these conditions. The intermediates
and transition states proposed in this catalytic cycle are in close
agreement with an early DFT study performed by Fokin and
−
1
(
ΔΔG = −61.9 kcal mol ).
In line with our mechanistic studies, a rather small difference
is observed between the barrier for protonation (ΔΔG = 5.8
kcal mol , difference TSA1 and TSA3). This difference is
expected to be even smaller when (i) the polynuclearity of
copper phenylacetylide is taken into consideration and (ii) the
−
1
3
9
co-workers. The authors, however, did not perform
H
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Article
calculations for the barrier of Protonolysis. The present study
emphasizes that this barrier should also be taken into
consideration, particularly under conditions where the alkyne
is the proton source, to fully explain experimental observations.
As an alternative pathway, a mechanism proceeding through
dinuclear intermediates was considered, but attempts to
optimize dinuclear copper alkyne intermediates were ham-
pered by the steric repulsion between the two copper
complexes and a very large Cu−Cu distance (∼5.00 Å),
making a pathway proceeding via dinuclear intermediates
unlikely. Besides, Cu−Cu scattering was not observed in our
EXAFS analysis.
1098 XH Amsterdam, The Netherlands; Materials Chemistry,
Zernike Institute for Advanced Materials, University of
Groningen, 9747 AG Groningen, The Netherlands;
orcid.org/0000-0002-7653-1639; Email: moniek.tromp@
rug.nl
Authors
Bas Venderbosch − Sustainable Materials Characterization,
Van’t Hoff Institute for Molecular Sciences, University of
Amsterdam, 1098 XH Amsterdam, The Netherlands
Jean-Pierre H. Oudsen − Sustainable Materials
Characterization, Van’t Hoff Institute for Molecular Sciences,
University of Amsterdam, 1098 XH Amsterdam, The
Netherlands
Jarl Ivar van der Vlugt − Homogeneous, Supramolecular and
Bio-Inspired Catalysis, Van’t Hoff Institute for Molecular
Sciences, University of Amsterdam, 1098 XH Amsterdam, The
Netherlands
CONCLUSIONS
A mechanistic study of the CuAAC reaction, catalyzed by
cationic copper iminophosphorane complexes, has been
■
I
detailed in this work. Novel cationic, homoleptic Cu
complexes ligated by iminophosphoranes were synthesized
and fully characterized. All complexes showed to be active in
the CuAAC reaction with model substrates benzyl azide and
Ties J. Korstanje − Sustainable Materials Characterization,
Van’t Hoff Institute for Molecular Sciences, University of
Amsterdam, 1098 XH Amsterdam, The Netherlands;
orcid.org/0000-0001-8036-5963
phenylacetylene. The observed activity trend 3Cl > 1 > 2OMe
H
highlights the increased catalytic performance with increased
Lewis basicity of the ligand.
Complete contact information is available at:
Additionally, a Cu triazolide complex was prepared that was
identified as the resting state in catalysis by spectroscopic and
kinetic analysis. This Cu triazolide intermediate is proposed to
be mononuclear based on Cu K-edge EXAFS analysis, kinetic
analysis, and DFT calculations. Both protonolysis of the Cu
triazolide and cyclization of Cu phenylacetylide intermediates
contribute to the overall rate of the reaction, depending on the
relative concentration of substrates. The spectroscopic and
kinetic experiments were supplemented by DFT calculations to
support the proposed catalytic cycle. This study shows that the
use of weaker Lewis base ligands such as 3Cl catalysis is
beneficial for the rate of reaction. Most likely, the activation
barrier of protonolysis by phenylacetylene is lowered. The
strong dependency on Lewis basicity could be applied in a
more rational design of an efficient CuAAC catalyst employing,
for example, carbenes.
https://pubs.acs.org/10.1021/acs.organomet.0c00348
Author Contributions
B.V. and J.-P.H.O. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
The authors thank NWO for funding (VIDI grant 723.014.010
to M.T., B.V., and J.P.O.) and VENI grant 722.016.012 (to
T.J.K.); the staff of the beamlines SuperXAS, Swiss Light
Source (proposal numbers 20171764 and 20181154) in
Villigen, Switzerland, and B18, Diamond Light Source
(
proposal number SP22432) in Didcot, UK, for support and
access to their facilities; Josh Abbenseth for support during
synchrotron measurements; and Jan-Meine Ernsting, Andreas
Ehlers, and Ed Zuidinga for NMR spectroscopy and mass
spectrometry support.
EXPERIMENTAL SECTION
■
Experimental details are reported in the Supporting Information.
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00348.
■
*
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AUTHOR INFORMATION
Corresponding Author
Moniek Tromp − Sustainable Materials Characterization, Van’t
Hoff Institute for Molecular Sciences, University of Amsterdam,
■
I
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