Au-iClick mirrors the mechanism of copper catalyzed azide-alkyne cycloaddition (CuAAC)

Article abstract of DOI:10.1039/c5dt02405f

This report outlines the investigation of the iClick mechanism between gold(i)-azides and gold(i)-acetylides to yield digold triazolates. Isolation of digold triazolate complexes offer compelling support for the role of two copper(i) ions in CuAAC. In add

Full text of DOI:10.1039/c5dt02405f

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Au-iClick mirrors the mechanism of copper catalyzed azide-alkyne
cycloaddition (CuAAC).
Received 00th January 20xx,
Accepted 00th January 20xx
A. R. Powers,a I. Ghiviriga,a K. A. Abboud,a and A. S. Veige*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
This report outlines the investigation of the iClick mechanism between gold(I)-azides and gold(I)-acetylides to yield digold
triazolates. Isolation of digold triazolates complexes offers compelling support for the role of two copper(I) ions in CuAAC.
In addition, a kinetic investigation reveals the reaction is first order in both Au(I)-N3 and Au(I)-C≡C-R, thus second order
overall. A Hammett plot with a ρ = 1.02(5) signifies electron-withdrawing groups accelerate the cycloaddition by
facilitating the coordination of the second gold ion in
triphenylphosphine to the reaction indicates that ligand dissociation is a prerequisite for the reaction. The mechanistic
conclusions mirror those proposed for the CuAAC reaction.
a π-complex. Rate inhibition by the addition of free
cycloaddition. In fact, we found that a gold-acetylide is a
prerequisite partner for a successful cycloaddition with metal-
azides. For example, PPh3Au-C≡C-C6H4-p-NO2 will undergo
cycloaddition with (PPh3)2Pt(N3)2;27 however, (PPh3)2Pt-(C≡C-
Ph-NO2)2 will not add PPh3AuN3.
Introduction
The cycloaddition of a metal-azide with a metal-acetylide to
form bimetallic triazolates was introduced in 20111 and
termed inorganic click (iClick) to acknowledge the participation
In an effort to expand iClick beyond gold and across the
transition metals it was imperative to first, understand why
the gold-acetylide was a critical ingredient, and second, to
elucidate the mechanism. Scheme 1 summarizes the currently
accepted mechanism28 for CuAAC.2-4 We offer, in a somewhat
unusual format, essentially the conclusions of this paper in
Scheme 1. That is, the data to follow offers compelling support
for the proposed mechanism that mirrors CuAAC.
of the metal ions in the reaction (Figure 1: A). Essentially, iClick
replaces the R-group on the azide and the proton of a terminal
alkyne with a metal ion in well-established copper catalyzed
azide-alkyne cycloadditions (CuAAC; Figure 1: B
).2-4 Others5-7
extended iClick to include the already prevalent8-9
cycloaddition of an organic substrate to either a metal-azide or
metal-acetylide.7,
10-21
Important to this work, Gray et al.22
demonstrated that gold-acetylides and gold-azides will
undergo cycloaddition to their organic counterparts.
R1
[Cu]
H
N
N
N
R2
[Cu]
[Cu]
R1
R1
H
H
H+
MLn
H+
N
N
+
N
N
N
MLn
N
iClick
N
N
N
A
N
R2
[Cu]
M'Ln
N
Au PPh3
N
R1
R1
M'Ln
R1
R1
[Cu]
R
Au PPh3
[Cu]
Au
PPh3
R2
R2
R2
N3 R2
N
N
N
N
N
N
N
N
R2
[Cu]
[Cu]
N
N
R1
[Cu]
N
CuAAC
N
[Cu]
+
B
R1
H
H
R1
Ph3P Au N3
[Cu]
Au
Au PPh3
R1
PPh3
N
N
Figure 1. Generic iClick (A) and copper-catalyzed azide-alkyne cycloaddition (CuAAC; B).
N
N
PPh3
N
Au
N
R
R
Au
PPh3
Despite the fact that several transition metals other than
Cu(I) catalyze the azide-alkyne cycloaddition, including
ruthenium, silver, and iridium,23-26 it became apparent that not
all metal-acetylide/azide species will participate in the iClick
Scheme 1. CuAAC mechanism overlaid with the proposed iClick mechanism.
In step one of CuAAC a copper ion forms a π-complex with
the alkyne that serves to reduce the pKa of the proton; a
second copper ion then replaces the proton to generate a
copper acetylide. Mirroring this step, our kinetic studies
indicate loss of PR3 precedes Au-azide π-complexation with the
acetylide. Fokin et al.28 firmly establish, using isotopically
enriched Cu sources, the need for exogenous copper to
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ARTICLE
catalyze the cycloaddition, i.e. two CuI ions are prerequisite.
Journal Name
Also, De Angelis et al. recently detected dicopper
a
intermediate via electrospray ionization mass spectrometry.29
However, the isolation of a dicopper intermediate still remains
elusive.30 Not only do our kinetic results agree, as both the Au-
azide and Au-acetylide are first-order participants in the
cycloaddition, but also the product of the reactions, by default,
are digold triazolates. In addition, we present a Hammett-plot
study that clearly indicates the rate of reaction accelerates
with electron-withdrawing groups (EWG) in the para-position
of the acetylide. The EWG serves to lower the CC π* orbital
thus facilitating the recruitment of the second gold ion.
Finally, in the Au/Au cycloaddition, the triazolate produced
matches the exclusive 1,4 selectivity in the copper-catalyzed
reaction (with Au-PR3 retained in the C5 position; Scheme 1).
The following text communicates the results and data that
support the Au/Au cycloaddition mechanistic claims presented
in Scheme 1.
Figure 2. Molecular structure of 3-NO2 with ellipsoids drawn at the 50% probability
level. Two lattice molecules of chloroform, disordered atoms, and hydrogen atoms are
removed for clarity.
In the CuAAC mechanism the second Cu(I), of unknown
coordination number and geometry, binds to the acetylide.
Presumably, the Cu(I) ion is a low-coordinate species. In
support of this contention, and according to Scheme 1, loss of
Results and Discussion
Ph3P Au N3
Ph3PAu
AuPPh3
PR3 is a requirement in the reaction between
1 and 2-R.
1
CHCl3
N
Adding free PPh3 to the reaction between 1 with 2-R depresses
+
N
Ph3P Au
R
the rate. Figure 3 depicts kobs as a function of [PPh3] and the
data indicate the inhibition is first-order.
N
R
R = H, NO2, F, OMe
2-R
3-R
Scheme 2. iClick reaction between Au(I)-azide (1) and Au(I)-acetylides (2-R).
0.12
0.1
The following mechanistic studies center on the general
reaction depicted in Scheme 2. Treating PPh3-Au-N3 ) with
(
1
0.08
0.06
0.04
Ph3P-Au-C≡C-Ph-R (2-R) provides the digold triazolates 3-R
(where, R = H, NO2, F, and OMe). The electronic supporting
information contains multinuclear NMR data, 2D-NMR spectra,
and combustion analysis for all new bimetallic complexes. An
X-ray diffraction experiment, performed on a single crystal
grown via pentane diffusion into a chloroform solution of 3-
NO2, provides unambiguous solid-state characterization for the
R² = 0.986
0.02
0
0
0.01
0.02
0.03
0.04
[PPh3] (M)
Figure 3. Rate inhibition by addition of free PPh3 to the reaction between 1 and 2-NO2.
bimetallic triazolate. Figure 2 depicts the solid-state structure
31
of 3-NO2
.
Complex 3-NO2 is Cs-symmetric and crystallizes in
Further confirming the need for a k low coordinate
intermediate, NHC ligands shut-down the cycloaddition. 1,3-
Diisopropylbenzimidazolin-2-ylidene (Bimz),32 an NHC ligand of
intermediate basicity, and comparable size33-34 to PPh3 was
chosen. No cycloaddition products form upon treating
the Pī space group with two lattice molecules of chloroform.
The geometry of each Au(I) ion is nearly linear (P1-Au1-C1 =
174.44(8)
°
and P2-Au2-N1 = 172.64(7)°). The nitro-phenyl ring
with the triazolate, perhaps
is nearly coplanar (~12.5
°)
providing stabilization through electron delocalization across
the two aromatic systems.
35
36
(Bimz)AuN3
(
4
)
with (Bimz)Au-C
≡
C-Ph
(
5)
at ambient
temperature or 65 °C (Scheme 3). Unable to dissociate,37 the
gold ion cannot access a lower coordination state, thus no
cycloaddition occurs. NHC-supported gold(I)-acetylides and -
azides are competent in cycloadditions,38-39 but the reactions
always include one organic counterpart (either the azide or
alkyne) or are facilitated with a copper(I) catalyst.
2 | J. Name., 2012, 00, 1-3
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ꢀ5
ꢀ5.5
ꢀ6
N
[Azide] = 0.033 M
[Azide] = 0.046 M
[Azide] = 0.053 M
[Azide] = 0.063 M
[Azide] = 0.073 M
Au
N
N
N
ꢀ6.5
4
CHCl3
ꢀ7
N
no reaction
+
ꢀ7.5
ꢀ8
N
N
ꢀ8.5
ꢀ9
Au
5
ꢀ9.5
ꢀ10
Scheme 3. No reaction is observed when NHC ligands replace PR3 in Au(I)-
acetylide/azide cycloadditions.
0
5000
10000
15000
time (s)
Figure 5. Plot of ln[2-H] versus time at five different ten-fold excess concentrations of 1.
Fokin et al.28 convincingly demonstrate that exogenous CuI
participates in CuAAC. Mirroring this requirement, the iClick
reaction exhibits first-order dependence in both the gold-azide
0.0006
0.0005
0.0004
0.0003
0.0002
(1) and gold-acetylide (2-NO2). Integration of a downfield
1
doublet (3JHH = 8.5 Hz) resonance at 8.59 ppm in the H NMR
spectrum of the product 3-NO2 relative to
hexamethyldisiloxane as an internal standard, provides
quantitative concentration versus time data for the
progression of the reaction between
depicts a ln[ ] versus time plot under pseudo-first-order
conditions in 2-H The linear plot signifies first-order
dependence in . Confirming a first order dependence in gold-
acetylide, Figure 5 depicts linear plots of ln[2-H] versus time
under five different pseudo-first-order concentrations of
1 and 2-R. Figure 4
R² = 0.986
0.0001
1
.
0
0
0.02
0.04
0.06
0.08
1
[1] (M)
Figure 6. Plot of kobs versus [1], slope, k = 7.6(5) x 10-3 M-1s-1
.
1.
Again, the linear plots for each concentration signifies the
reaction is first-order in 2-H. These results are significant
because we are able to control both the concentration of the
Au-azide and Au-acetylide independently. Exploiting this even
The kinetic data clearly point to a digold intermediate, but
not the identity of the transition state. However, there is
precedence for σ- and π-interactions between Au(I) ions and
alkynes that look conspicuously similar to the dicopper
intermediate proposed in Scheme 1. Depicted in Figure 7 are
σ-π-digold acetylide complexes isolated by Himmelspach et
al.40 Aiding the formation of the complexes is an aurophilic
interaction between the Au(I) centers. It is reasonable to
expect that similar interactions occur during the reaction
further, plotting kobs as a function of [1] in Figure 6 provides
the rate constant k = 7.6(5) x 10-3 M-1s-1 for the cycloaddition
from the slope.
ꢀ5
ꢀ5.5
ꢀ6
between
1
and 2-R, and in CuAAC.
ꢀ6.5
C
R² = 0.995
ꢀ7
ꢀ7.5
ꢀ8
= closoꢀ1ꢀCB11H11
C
R3PAu
i
R = Me, Et, Pr, tBu
ꢀ8.5
ꢀ9
AuPR3
Figure 7. Literature precedence40 for Au(I) bound to an acetylide in both a σ– and π–
fashion, analogous to what is proposed for copper.
0
5000
10000
15000
time (s)
Figure 4. Plot of ln[1] versus time under ten-fold excess concentrations of 2-H.
In addition to the σ– and π-interactions, precedence exists
for an azido-bridged digold complex.41-42 Figure 8 depicts the
isolable azide bridging digold complex {[PPh3](μ-N3)}+.
ClO4ꢀ
N
N
N
Ph
Ph
Au
Au
Ph
Ph
P
P
Ph
Ph
Figure 8. Literature precedent for a bridging azide between two Au(I) centers.42
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Fokin et al. propose a nucleophilic attack of acetylide on
azide in CuAAC;28 iClick offers an opportunity to probe this
Conclusions
The goal of this work was to understand the mechanism of
gold iClick reactions and why Au-acetylides are prerequisites. It
is clear now that the Au(I)-acetylide plays the same role as the
Cu(I)acetylide in CuAAC. In addition, our kinetic studies
complement the CuAAC mechanism and offer additional
support for the presence of exogenous Cu(I). By employing
Au(I)-acetylides and -azides we are able to exert exquisite
control over the reaction conditions enabling conclusive
evidence for the participation of two gold ions in the
mechanism. Loss of PPh3 is a prerequisite for the reaction
suggesting the second gold ion is low-coordinate and likely to
bind to the alkyne triple bond. Hammett plot data point to a
stabilization of electron density as the second gold ion binds to
the acetylide π-bond. Taken together these conclusions reflect
the proposed mechanism for CuAAC.28
proposal. Figure 9 depicts a Hammett plot for the reaction of
with 2-R The reactions all proceed with quantitative
conversion (NMR) to their respective dinuclear triazolate
products 3-R). Electron withdrawing groups significantly
accelerate the reaction. Plotting the log(kR/kH) versus
published substituent constants for the different
σ 43
functional groups, provides = 1.02(5). The positive value for
indicates that a negative charge develops on 2-R in the rate
1
.
(
(
)
ρ
ρ
determining step. Stabilization of the negative charge build-up
with an EWG is consistent with the recruitment of the
electron-rich gold ion as a π-complex, according to Scheme 1.
Also, Fokin proposes an oxidation state change from
Cu(I)ꢀCu(II) as the first C-N bond forms. For Au(I) on oxidation
state change is unlikely, but also unnecessary, since Au(I)
already has the Au(I)-N bond preformed as the “R-group”
substituent on the azide.
EXPERIMENTAL
Glassware was oven dried before use. Pentane, toluene,
and methylene chloride were sparged with ultra-high purity
1
argon, and dried using
a GlassContours drying column.
0.8
ρ = 1.02(5)
Methanol was degassed, dried over copper sulfate and
distilled prior to use. Chloroform-d (Cambridge Isotopes) was
dried over calcium hydride, distilled, and stored over 4 Å
molecular sieves. Me2S-Au-Cl, TMS-N3, 1-ethynyl-4-
NO2
0.6
0.4
R² = 0.995
0.2
F
fluorobenzene,
1-ethynyl-4-nitrobenzene,
1-ethynyl-4-
0
ꢀ0.4
ꢀ0.2
0
0.2
0.4
0.6
0.8
1
methoxybenzene, triphenylphosphine, were purchased from
commercial sources, and used without further purification.
Commercially available phenylacetylene was distilled from
H
ꢀ0.2
ꢀ0.4
OMe
σ
calcium hydride before use.
22
Ph3PAuN3
was prepared according to literature
Figure 9. Hammett plot depicting substituent effects for the reaction between 1 and 2-
R (R = OMe, H, F, NO2).
procedures using freshly synthesized Ph3PAuCl.45 PPh3Au–
CPh, and PPh3Au–C
CPh-R (R = OMe, F, NO2)46 were
synthesized according to the literature with slight
C
≡
≡
a
Finally, measuring the rate constant for the cycloaddition
modification; a fresh batch of NaOMe in MeOH was made by
dissolving sodium metal in dry methanol directly before each
between
1 and 2-NO2 within the temperature range of 20 °C –
60
°
C enables the construction of an Eyring44 plot (Figure 10).
synthesis. (Bimz),32 (Bimz)AuN3,35 and (Bimz)Au-C
synthesized according to literature procedures.
≡
C-Ph36 were
From the plot in Figure 10, the activation parameters ΔH‡ =
15.5(5) kcal/mol and ΔS‡ = -12(2) cal/molK, are determined.
The large and negative entropy of activation is significant.
Mirroring the proposed multinuclear transition state in CuAAC,
NMR spectra were obtained with either Varian Mercury or
Varian Inova instruments, operating at 300 MHz or 500 MHz
for proton, respectively. Chemical shifts are in ppm on the TMS
scale and were referenced to the residual signal of the
chloroform solvent (7.26 ppm for proton and 77.4 ppm for
carbon), and 31P{1H} NMR chemical shifts were referenced to
an external standard of 85% H3PO4 in D2O. Elemental analyses
were performed at Complete Analysis Laboratory Inc.,
Parsippany, New Jersey. Kinetic experiments were performed
on a Varian Inova 500 MHz spectrometer.
the cycloaddition between
1 and 2-NO2 must also proceed
through a highly ordered transition state.
ꢀ3.0
ꢀ4.0
∆H‡ = 15.5(5) kcal/mol
∆S‡ = ꢀ12(2) cal/molK
ꢀ5.0
ꢀ6.0
ꢀ7.0
ꢀ8.0
The general procedure followed for the iClick reaction
R² = 0.9964
between PPh3Au-N3 (
1
) and PPh3Au-C
≡
F, OMe) to yield 3-R is as follows. Complex
C-Ph-R (2-R, R = H, NO2,
was taken up in
ꢀ9.0
1
ꢀ10.0
0
0.001
0.002
0.003
0.004
CDCl3 (0.3 mL) and added to a solution of 2-R also in CDCl3 (0.3
1/T (Kꢀ1)
mL). The reaction mixture was transferred to a sealable NMR
1
tube and the reaction progress was monitored via 31P and H
Figure 10. Eyring plot for the reaction between 1 and 2-NO2 (20 – 60 °C).
NMR. The reactions all proceed quantitatively by NMR and the
products can be isolated by removing all the volatiles in vacuo
and then triturating with pentane.
4 | J. Name., 2012, 00, 1-3
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Synthesis of 3-NO2
Acknowledgements
General synthetic scheme followed. 94% Yield (41 mg,
3
ASV thanks the donors of the Petroleum Research Fund
(51715-ND3) for financial support to initiate this project. The
completion of this work was supported by the US Department
of Energy, Materials Sciences Division, under Award No. DE-
0.037 mmol). 1H NMR (300 MHz, CDCl3): δ 8.59 (d, JHH = 8.5
3
Hz, 2H, C4-H), 8.11 (d, JHH = 8.5 Hz, 2H, C5-H), 7.47 (m, 18H,
aromatic), 7.30 (m, 12H, aromatic). 13C NMR Shifts (indirect
detection through H-13C gHMBC and H-13C gHSQC (500 MHz,
CDCl3)): δ 149.7 (C2), 145.3 (C6), 143.5 (C3), 134.2 (C7, C8,
C11, C12), 131.7 (C10), 131.6 (C14), 129.1 (C9, C13), 125.9
(C4), 123.7 (C5) (Note: C1 is not observed). 31P{1H} NMR (121.4
MHz, CDCl3): δ 44.39 (s, P1). 32.08 (s, P2). Anal. Calcd for
C44H34Au2P2N4O2: C, 47.75; H, 3.10; N, 5.06. Found: C, 47.91;
H, 3.26; N, 5.16.
1
1
SC0010510. KAA thanks UF and the NSF CHE-0821346 for
funding the purchase of X-ray equipment.
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2
3
4
5
6
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General synthetic scheme followed. 89% Yield (38 mg, 0.035
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=6.1 Hz 2H, C4-H), 7.45 (m, 18H, aromatic), 7.30 (m, 12H,
aromatic), 6.95 (dd, JHF = 8.6 Hz, JHH = 8.6 Hz, 2H, C5-H). 13C
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3
8
9
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Hz, 2H, C4-H), 7.46 (m, 18H, aromatic), 7.30 (m, 12H,
3
aromatic), 6.84 (d, JHH = 8.2 Hz, 2H, C5-H), 3.81 (s, 3H, OCH3).
13C NMR Shifts (indirect detection through H-13C gHMBC and
1H-13C gHSQC (500 MHz, CDCl3)): δ 157.8 (C6), 151.2 (C2),
134.2 (C7, C8, C11, C12), 131.6 (C10, C14), 129.6 (C3), 129.1
(C9, C13), 127.6 (C4), 113.4 (C5), 55.3 (OCH3), (Note: C1 is not
observed). 31P{1H} NMR (121.4 MHz, CDCl3): δ 44.58 (s, P1),
31.81 (s, P2). Anal. Calcd for C45H37Au2P2N3O: C, 49.51; H,
3.42; N, 3.85. Found: C, 49.79; H, 3.25; N, 3.65.
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General Guidelines for Kinetic Experiments
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solutions spiked with hexamethyldisiloxane (HMDSO) as an
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integrations could be referenced. For each set of experiments,
a fresh stock solution of azide and acetylide was created. In
order minimize the time a sample was mixed before spectra
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began to be collected,
a NMR tube charged with a
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A lock was already established on the NMR
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spectrum. If a third stock solution needed to be added to the
tube (triphenylphosphine), it was mixed with the azide
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Isolated digold-triazolate products and first-order kinetic profiles for Au-acetylide/azide reactants in
iClick provide compelling support for two copper ions in CuAAC.