Multitechnique approach to reveal the mechanism of copper(II)-catalyzed arylation reactions

Article abstract of DOI:10.1021/om9010643

Multipleinsitu and time-resolved spectroscopic techniques (EDXAFS,UV-vis, EPR,and NMR), with a focus on simultaneously acquired EDXAFS and time-resolved UV-vis, are described to reveal detailed structural and electronic information on reaction intermediates of an important Cu(II)-catalyzed N-arylation of imidazole. The N-arylation of imidazole was performed in a NMP/H₂O solvent mixture, at ambient temperature and atmosphere, using the commercially available Cu catalyst [Cu(OH)(TMEDA)]₂Cl₂ (I). The spectroscopic study resulted in the characterization of most reaction intermediates, and a novel mechanism for the Cu(II)-catalyzed arylation reaction is proposed. The first and selectivity-determining step is the reaction of the dimeric Cu(II) starting complex with imidazole, forming a mononuclear Cu(II)(imidazole) intermediate, II. After subsequent addition of phenylboronic acid, we propose the formation of a Cu(III)(imidazolate)(phenyl) intermediate, III, which after reductive elimination forms the phenylimidazole product, and a known Cu(I) monomeric species, IV, is identified. Finally, this Cu species is reoxidized, forming back an equilibrium mixture of Cu(II) mononuclear and dinuclear complexes. Inhibition of the reaction by imidazole and phenylimidazole is observed. The phenylboronic acid is, in combination with H₂O, involved in the oxidation and reoxidation steps in the described catalytic cycle.

Full text of DOI:10.1021/om9010643

Organometallics 2010, 29, 3085–3097 3085
DOI: 10.1021/om9010643
Multitechnique Approach to Reveal the Mechanism of
Copper(II)-Catalyzed Arylation Reactions
Moniek Tromp,*,† Gino P. F. van Strijdonck,‡ Sander S. van Berkel,‡
Adri van den Hoogenband,§ Martinus C. Feiters,^ Bas de Bruin,4 Steven G. Fiddy,"
Ad M. J. van der Eerden,† Jeroen A. van Bokhoven,† Piet W. N. M. van Leeuwen,‡ and
Diederik C. Koningsberger†
†Debye Institute, Department of Inorganic Chemistry and Catalysis, Utrecht, The Netherlands,
‡Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands,
§Solvay Pharmaceuticals, Weesp, The Netherlands, ^IMM, Department of Organic Chemistry, Faculty of
Science, University of Nijmegen, Nijmegen, The Netherlands, 4IMM, Department of Inorganic Chemistry,
Faculty of Science, University of Nijmegen, Nijmegen, The Netherlands, and "ESRF, Grenoble, France
Received December 11, 2009
Multiple in situ and time-resolved spectroscopic techniques (EDXAFS, UV-vis, EPR, and NMR),
with a focus on simultaneously acquired EDXAFS and time-resolved UV-vis, are described to
reveal detailed structural and electronic information on reaction intermediates of an important
Cu(II)-catalyzed N-arylation of imidazole. The N-arylation of imidazole was performed in a NMP/
H2O solvent mixture, at ambient temperature and atmosphere, using the commercially available Cu
catalyst [Cu(OH)(TMEDA)]2Cl2 (I). The spectroscopic study resulted in the characterization of most
reaction intermediates, and a novel mechanism for the Cu(II)-catalyzed arylation reaction is pro-
posed. The first and selectivity-determining step is the reaction of the dimeric Cu(II) starting complex
with imidazole, forming a mononuclear Cu(II)(imidazole) intermediate, II. After subsequent addi-
tion of phenylboronic acid, we propose the formation of a Cu(III)(imidazolate)(phenyl) intermediate, III,
which after reductive elimination forms the phenylimidazole product, and a known Cu(I) monomeric
species, IV, is identified. Finally, this Cu species is reoxidized, forming back an equilibrium mixture of
Cu(II) mononuclear and dinuclear complexes. Inhibition of the reaction by imidazole and phenyl-
imidazole is observed. The phenylboronic acid is, in combination with H2O, involved in the oxidation
and reoxidation steps in the described catalytic cycle.
Introduction
lower costs of copper compared to palladium, the use of
copper is preferred over palladium for industrial processes.3
Due to the more general use of palladium catalysts for
coupling reactions, much research2a,4 has been dedicated
toward understanding the reaction mechanism of these cata-
lysts, and only a few studies concerning the copper-catalyzed
mechanism have appeared. The mechanisms proposed for Cu-
catalyzed reactions are as yet reasonable guesses, because none
of the intermediates have been isolated or characterized.5-7
In this paper, Cu(II)-catalyzed Caryl-N and Caryl-Caryl coup-
ling reactions are investigated in detail using several spectros-
copic techniques. The coupling of imidazole with phenylboronic
acid in the presence of the binuclear tetramethylenediamine
bis-μ-hydroxy copper(II) complex [Cu(OH)(TMEDA)]2Cl2
The formation of aryl-aryl bonds and aryl-heteroatom
bonds are among the most important reactions in organic
synthesis. Caryl-N-containing structures are important in
biological systems and are common moieties in pharma-
ceuticals. Copper is the most ancient transition metal used
for the synthesis of biaryls.1,2 Since palladium complexes are
by far the most used, they are the more studied catalysts for
these reactions. In many cases, palladium catalysts are more
active and selective under milder conditions compared to
copper. Some reactions such as the arylation of imidazole,
however, only proceed with copper catalysts. Because of the
*To whom correspondence should be addressed. E-mail: M.Tromp@
soton.ac.uk. Tel: þ44 (0) 2380 596877. Fax: þ44 (0) 2380 593781.
Current address: School of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ, U.K.
(4) (a) Rosner, T.; Le Bars, J.; Pfatlz, A.; Blackmond, D. G. J. Am.
Chem. Soc. 2001, 123, 1848. (b) Guari, Y.; van Strijdonck, G. P. F.; Boele,
M. D. K.; Kamer, P. J. C.; van Leeuwen, P. W. N. M. Chem.;Eur. J. 2001, 7,
275.
(1) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
(2) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. ; Angew.
Chem. 1998, 110, 2154. (b) Hartwig, J. F. Synlett 1997, 329–340.
(c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res.
1998, 31, 805. (d) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125. (e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(3) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(5) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937.
(6) (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2 (9), 1233.
(b) Collman, J. P.; Zhong, M.; Zhang, C.; Constanzo, S. J. Org. Chem.
2001, 66, 7892.
(7) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P.
Tetrahedron Lett. 2003, 44, 1691.
r
2010 American Chemical Society
Published on Web 06/22/2010
pubs.acs.org/Organometallics

3086 Organometallics, Vol. 29, No. 14, 2010
Tromp et al.
Table 1. Influence of Radical Scavengers and Initiators
on the Reaction of Imidazole and Phenylboronic Acid
Using the [Cu(OH)(TMEDA)]2Cl2 Catalyst
(C-N Coupling Yield Is Reported Here)
Scheme 1. Copper-Catalyzed Coupling Reaction of Imidazole
with Phenylboronic Acid
additive
time (h)
GC yielda
none
20
72
56
99
(I) inNMP/H2O (1:1 v/v %) at ambient conditions (Scheme 1)8
is studied as a model arylation reaction (TMEDA=tetramethyl-
enediamine, NMP = N-methylpyrrolidone). We have already
shown that the presence of water was essential for this reac-
tion, whereas a base was not required.8 Moreover, the reac-
tion proceeds under anaerobic conditions; that is, it does not
need O2 as an oxidant.8 To identify reaction intermediates
and thus further elucidate the mechanism of this reaction,
we describe here the application of a combination of time-
resolved and in situ spectroscopic techniques. We have used a
combined spectroscopic setup that enables the simultaneous
acquisition of time-resolved in situ X-ray absorption fine
structure spectroscopy (XAFS) and UV-vis on homogeneous
catalytic systems.9
XAFS spectroscopy is a powerful technique to determine
the local structure of metal complexes, such as the type and
number of neighboring atoms, distances, and electronic
properties. XAFS can be applied in situ, e.g., in solution in
which the reaction is taking place. Using an energy dispersive
data acquisition setup (ED), spectra can be obtained in the
subsecond range during reaction.10 Moreover, the use of a
combination of techniques gives complementary information
on the system under investigation.9,11 With the use of UV-
vis spectroscopy, the electronic absorption by molecules can
be detected both in situ and time-resolved. We have deve-
loped a setup that enables the simultaneous acquisition of time-
resolved in situ XAFS and UV-vis data on homogeneous
catalytic systems,9 thus allowing detailed characterization of
the reaction intermediates in situ and time-resolved and making
it a powerful tool in revealing reaction mechanisms.
Scavengers
2,6-di-tert-butylphenol
20
72
20
72
20
72
5
23
0
0
0
hydroquinone
tetrachlorohydroquinone
0
Initiators
H2O2 (35% in H2O)
20
72
20
72
20
72
2
37
0
0
3
19
benzoylperoxide
AIBN
a Reaction conditions: 5 mol % Cu catalyst, 1:1 mmol imidazole/
PhB(OH)2 in NMP/H2O (1:1), ambient conditions. The yield was deter-
mined by GC.
Scheme 2. Overview of the Reactions Studied
Extensive nuclear magnetic resonance (NMR) and elec-
tron paramagnetic resonance (EPR) studies are performed to
gain more insights into the diamagnetic and paramagnetic
species present in the reaction mixture. Based on these spec-
troscopic studies, in combination with catalytic results, a
catalytic reaction cycle is proposed.
that the reaction can be performed in a NMP/H2O mixture,
at ambient temperature and atmosphere, using catalytic
amounts of a cheap and commercially available Cu catalyst,
[Cu(OH)(TMEDA)]2Cl2 (I). The use of an NMP/H2O mix-
ture as a solvent, instead of either H2O or NMP only,
increased the yield considerably. Surprisingly, H2O is neces-
sary for the reaction to proceed, whereas the addition of base
and dioxygen is not required.
Results and Discussion
Catalysis. Recently, we have established a modified proto-
col8 for the N-arylation of imidazole that works under milder
conditions than previous ones.6,7,12,13 It was demonstrated
(8) van Berkel, S. S.; van den Hoogenband, A.; Terpstra, J. W.;
Tromp, M.; van Leeuwen, P. W. N. M.; van Strijdonck, G. P. F.
Tetrahedron Lett. 2004, 45 (41), 7659.
(9) (a) Tromp, M.; Sietsma, J. R. A.; van Bokhoven, J. A.; van
Strijdonck, G. P. F.; van Haaren, R. J.; van der Eerder, A. M. J.; van
Leeuwen, P. W. N. M.; Koningsberger, D. C. Chem. Commun. 2003, 128.
(b) Tromp, M. Developments of Time-Resolved XAFS Techniques: Applica-
tions in Homogeneous Catalysis. Ph.D. Thesis, Utrecht, The Netherlands,
2004, pp 20-23.
(10) For example, overview: Newton, M. A.; Dent, A. J.; Evans, J.
Chem. Soc. Rev. 2002, 31, 83.
(11) For example, overview: (a) Weckhuysen, B. M. Phys. Chem.
Chem. Phys. 2003, 5 (20), 4351. (b) Newton, M. A.; Dent, A. J.; Diaz-
Moreno, S.; Fiddy, S. G.; Evans, J. Angew. Chem., Int. Ed. 2002, 41 (14),
2584.
(12) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 13 (3), 2077.
(13) Lan, J.-B.; Chem, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G. Chem.
Commun. 2004, 188.
The absence of dioxygen as an oxidant for this catalytic
reaction implies the involvement of an oxidant other than
dioxygen.8 To investigate the possible involvement of radical
steps in the reaction mechanism and to gain more insights in
the nature of the oxidizing species in this system, the reaction
was performed in the presence of both radical scavengers and
radical initiators. As can be observed in Table 1, the use of
scavengers resulted in a considerable decrease in the C-N
coupling yield or even a complete inhibition of the reaction.
This might be indicative of the involvement of radical inter-
mediates; however, it is known that redox reactions or com-
plexation of the scavengers (some scavengers can act as Cu
ligands) with the catalyst can also result in reaction inhibition.
Radical initiators on the other hand also caused a decrease in

Article
Organometallics, Vol. 29, No. 14, 2010 3087
Scheme 3. Proposed Productive Pathway of the Catalytic Cycle for the Cu(II)-Catalysed Arylation of Imidazole and Phenylboronic Acid
activity, showing that the reaction does not require a radi-
cal initiator and that probably catalytic intermediates are
“derailed” by radicals.
1s f 3d Cu(II) and 1s f 4p Cu(II) transitions and char-
acteristic for the presence of a Cu(II) species.14 The UV-vis
absorption spectrum exhibits a ligand-to-metal charge transfer
(LMCT) band of the bridging O(H) to Cu(II) at ∼355 nm.15
Additional CT bands up to ∼300 nm and d-d transitions at
∼620 nm are observed.
The use of only phenylboronic acid as a reactant results in
the fast formation of C-C homocoupled biphenyl. A sto-
ichiometric reaction of the Cu(II) dimer with phenylboronic
acid, followed by the addition of imidazole, does not result in
C-N product formation, while the reverse addition seq-
uence (first imidazole and then phenylboronic acid) resulted
in a selective formation of the C-N coupled product. We
therefore concluded that during catalysis a Cu complex
reacts fast with imidazole in the selectivity-determining step,
followed by reaction with the boronic acid.8 Experiments
with increasing amounts of imidazole or phenylimidazole
product added to the reaction mixture result in a decrease of
the reaction rate. This suggests inhibition of the reaction by
excess imidazole and/or phenylimidazole.
The raw EXAFS data are shown in the Supporting Infor-
mation, Figure S1. EXAFS data analysis of the [Cu(OH)-
(TMEDA)]2Cl2 (I) complex in NMP/H2O was performed.
The Fourier transforms of the raw EXAFS data and the obta-
ined EXAFS fit for these data are shown in Figure 2. These
figures show a good agreement between the raw EXAFS
data and fit, which is confirmed by the low variances in fit
found for both the imaginary and absolute part (Table 2).
The obtained EXAFS fitting parameters show four C/N/
˚
O atoms at a short distance of 2.02 A and one Cu at a longer
˚
distance of 2.96 A. In the EXAFS analysis we cannot dis-
Spectroscopic Studies. The Cu(II)-catalyzed reaction of
imidazole with phenylboronic acid (Scheme 1) was further
investigated using multiple spectroscopic techniques. Sto-
ichiometric reactions were performed to decrease the number
of reaction intermediates. Single-step reactions were perfor-
med to mimic possible subsequent individual steps of the
catalytic reaction cycle. An overview of the reactions perfor-
med is given in Scheme 2.
Throughout the paper, different reaction intermediates in
the catalytic cycle will be identified, and a catalytic cycle can
be proposed. As a guide to the reader, the proposed produc-
tive pathway of the cycle is presented here, in Scheme 3.
[Cu(OH)(TMEDA)]2Cl2 (I). First, the dimeric structure of
the starting [Cu(OH)(TMEDA)]2Cl2 (I) complex in NMP/
H2O solution is confirmed. The results obtained with the
combined EDXAFS/UV-vis setup are shown in Figure 1a,b.
The XANES spectrum (Figure 1a) clearly displays two pre-
edge features, at ∼8977 and 8985 eV, assigned to respectively
tinguish between C, N, and O, because they are neighboring
atoms in the periodic table and thus have similar back-
scattering amplitudes.16 Fitting the first contribution in EXAFS
using the three different calibrated Cu-C, Cu-N, and Cu-O
references results only in slightly different E0 values. A Cu-
Cu contribution is fitted for this complex. As explained in
detail in ref 28, Cu-Cu contributions in organometallic
complexes can be very difficult to identify and reliably fit.
A reasonable fit, especially with the somewhat lower quality
EXAFS data for these experiments, can also be obtained
with two CuC shells albeit with higher variances. However,
the EXAFS analyses in this work are never used as a proof of
intermediate on their own, and the other techniques confirm
the presence of a Cu dimer in this solution (and in fact guide
the EXAFS analyses).
The Cu-Cu contribution detected and the short distance
of the four C, N, or O atoms to the Cu suggest that the dimeric
(15) Karlin, K. D.; Hayes, J. C.; Gultneh, Y.; Cruse, R. W.;
McKown, J. W.; Hutchonson, J. P.; Zubieta, J. J. Am. Chem. Soc.
1984, 106, 2121.
(16) Koningsberger, D. C.; Mojet, B. L.; van Dorssen, G. E.; Ramaker,
D. E. Top. Catal. 2000, 10, 143.
(14) (a)Kau,L.-S.;Spira-Solomon,D.-J.;Penner-Hahn,J.E.;Hodgson,
K. O.; Solomon, E. I. J. Am. Chem. Soc. 1987, 109, 6433. (b) DuBois, J. L.;
Mukherjee, P.; Stack, T. D. P.; Hedman, B.; Solomon, E. I.; Hodgson, K. O.
J. Am. Chem. Soc. 2000, 122, 5775.

3088 Organometallics, Vol. 29, No. 14, 2010
Tromp et al.
Figure 1. (a) XANES and (b) UV-vis spectra of [Cu(OH)-
(TMEDA)]2Cl2 in NMP/H2O.
Figure 2. Fourier transform of the EXAFS data of [Cu(OH)-
(TMEDA)]2Cl2 in NMP/H2O (room temperature), raw (solid
line) and fit (dotted line); (a) k0-weighted, (b) k2-weighted.
structure in NMP/H2O solution is intact. The first shell
around Cu then consists of the two N atoms of the TMEDA
ligand and two O atoms of the two bridging OH groups.
The EPR spectrum of a frozen solution (∼20 K) of dimer I
(in NMP/H2O) is shown in Figure 3 (dotted line). A very weak
signal with Cu hyperfine structure is observed. This signal
possibly originates from a Cu(II) monomeric species formed
by dissociation of a small part of the dimer. But as expected for a
Cu(II) dimer with an antiferromagnetically coupled ground
state (S = 0), this compound is EPR silent. The integrity of
the dimeric Cu(II) structure is also confirmed by 1H NMR,
showing two broad signals at 70-100 ppm. This broadening
of the signals indicates that the antiferromagnetic coupling is
relatively weak and that the excited paramagnetic state (S=1)
is accessible at the temperature of the NMR experiment.17
Thus, the dimeric Cu(II) structure of the [Cu(OH)(TME-
DA)]2Cl2 (I) complex in NMP/H2O solution is confirmed by
all characterization techniques presented here in the wide
concentrations range used for the different techniques.
Reaction A: [Cu(OH)(TMEDA)]2Cl2 þ Imidazole. From
stoichiometric reaction results it was concluded that imidazole
reacts with the catalyst prior to reaction with the phenylboronic
acid.8 The addition of imidazole to a solution of [Cu(OH)-
(TMEDA)]2Cl2 is therefore performed in an attempt to char-
acterize and isolate the resulting reaction intermediate.
deprotonated ligands has been suggested.18 A crystal struc-
ture of a similar compound has appeared in literature.19 The
trimeric [L3Cu3(imidazolate)3]ClO4 (with L = 1,4,7-trimethyl-
1,4,7-triazacyclononane) crystal structure has been reported in
which the Cu centers are connected via imidazolate anions.
Moreover, a crystal structure of a monomeric [(TMEDA)-
Cu(II)(imidazolate)2] complex obtained from reaction with an
excess of imidazole and base has been described.18
a. Isolation in Methanol/Ether. The reaction of one equi-
valent of imidazole (per mole of Cu) to a solution of [Cu-
(OH)(TMEDA)]2Cl2 in methanol and subsequent crystal-
lization from methanol diethyl ether afforded blue crystals.20
IR results on this isolated complex do not display an N-H
stretching mode in the region 3200-3500 cm-1, suggesting
the deprotonation of the imidazole.18
EXAFS analysis of the (with methanol/ether) isolated Cu
complex dissolved in NMP/H2O solution, presented in Table 3,
shows the presence of three N atoms and one chloride. A Cu-
Cu contribution was not observed; either it is not present, or it is
not observed due to its long distance. The presence of only three
instead of four N atoms in close proximity to the Cu, as observed
(18) Okawa, H.; Mikuriya, M.; Kida, S. Bull. Chem. Soc. Jpn. 1983,
56 (7), 2142.
(19) Chaudhuri, P.; Karpenstein, I.; Winter, M.; Butzlaff, C.; Trautwein,
A. X.; Florke, U.; Haupt, H.-J. J. Chem. Soc., Chem. Commun. 1992, 321.
(20) Preliminary results on single-crystal X-ray analysis suggest a
trinuclear Cu(II) complex, [Cu(Cl)(Imidazolate)(TMEDA)]3, in corres-
pondence to ref 19. This trimer thus breaks up into Cu(II) monomers
upon dissolving in NMP/H2O: Lutz, M.; Tromp, M.; van Strijdonck,
G. P. F.; Spek, A. L., in preparation.
On the basis of cryomagnetic measurements in DMF
the formation of a trinuclear Cu(II) compound bridged by
(17) Marthy, N. N.; Karlin, K. D.; Bertini, I.; Luchinat, C. J. Am.
Chem. Soc. 1997, 119, 2156.

Article
Organometallics, Vol. 29, No. 14, 2010 3089
Table 2. EXAFS Data Analysis Results of [Cu(μ-OH)(TMEDA)]2Cl2 in NMP/H2O (room temperature) and the
Complexes Present after the Different Reactionsb
c
2
-2
˚
Abs-Sca
Nc
[Cu(OH)(TMEDA)]2Cl2 in NMP/H2O
[R-space fit, 2.4 < k < 7.8, 0.8 < R < 3.0]
R (A)
σ (A
)
E0 (eV)
V.I.a
V.A.a
˚
Cu-N (C/O)
Cu-Cu
3.8
0.9
2.02
2.96
0.003
0.003
-2.3
6.0
k0-weighted:
0.10
0.07
0.27
k2-weighted:
0.56
A. [Cu(OH)(TMEDA)]2Cl2 þ Imidazole in NMP/H2O
[R-space fit, 2.35 < k < 7.8, 1.0 < R < 3.0]
Cu-N (C/O)
Cu-C (N/O)
4.2
3.9
2.01
2.94
0.001
0.003
-0.3
-4.6
k0-weighted:
0.24
0.13
0.05
k2-weighted:
0.07
B. [Cu(OH)(TMEDA)]2Cl2 þ PhB(OH)2 in NMP/H2O
[R-space fit, 2.0 < k < 7.7, 1 < k < 3.7]
Cu-N (C/O)
Cu-C (N/O)
Cu-C (N/O)
5.7
1.4
3.7
1.96
2.77
3.92
0.002
0.003
0.003
-5.3
-1.1
-0.3
k0-weighted:
0.03
0.03
k2-weighted:
0.007
0.004
C. [Cu(OH)(TMEDA)]2Cl2 þ Phenylimidazole in NMP/H2O
[R-space fit, 2.4 < k < 8, 0.8 < k < 3.8]
Cu-N (C/O)
Cu-C (N/O)
Cu-C (N/O)
4.2
2.4
5.1
1.97
2.98
3.86
0.004
0.001
0.001
-1.0
-8.6
-0.7
k0-weighted:
0.80
0.53
0.19
k2-weighted:
0.34
a Abbreviations: Abs = absorber, Sc = scatterer, V.I. = variance in imaginary part, V.A. = variance in absolute part. b The raw EXAFS data are
shown in the Supporting Information, Figure S1a. The k0-weighted and k2-weighted Fourier transforms of the raw EXAFS and fitted EXAFS data are
shown in the Supporting Information in Figures S2-S4. c Estimated errors in coordination number N and distance R are 15-20% and 0.01-0.03 A,
˚
respectively. S02 was fixed at 0.92 (based on references).
The small N superhyperfine coupling and its multiplicity
suggest the presence of three N ligand donor atoms, i.e., two
of the TMEDA ligands and one of an (coordinated) imida-
zol(at)e. 1H NMR displays neither distinct characteristic
peaks in the range of diamagnetic species nor the peaks at
70-100 ppm characteristic of the weakly antiferromagnetic
coupled dinuclear species.
The IR results and the mentioned [(TMEDA)Cu(II)-
(imidazolate)2] crystal structure18 suggest that the hydroxy
ligand of the starting copper dimer has deprotonated the
imidazole and coordination of the imidazolate to the Cu(II)-
(TMEDA) takes place, which is also in correspondence to
the trinuclear Cu structure as reported.19 EXAFS results
show that a chlorine atom acts as a coordinating ligand. The
spectroscopic results thus characterize [(TMEDA)Cu(imida-
zolate)]Cl (II0) as the intermediate isolated after the reaction
Figure 3. X-band EPR spectra of [Cu(OH)(TMEDA)]2Cl2 in
NMP/H2O (dotted black line), after addition of imidazole (solid
of Cu(II) dimer and imidazole (Cu:imidazole = 1:1) from a
gray line), and after subsequent addition of phenylboronic acid
methanol/ether solution. The monomeric structure in NMP/
(solid black line) [T=∼20 K].
H2O is in contrast to the proposed trimer described in ref 18,
in which the trimeric structure remains intact in DMF solu-
in the starting Cu(II) dimer, corresponds to a monomeric Cu-
(TMEDA)(imidazole) species. The XAFS results thus suggest a
Cu(Cl)(imidazole)(TMEDA) (II0) structure in solution.
In EPR the blue solution of the isolated Cu complex in
NMP/H2O displays a strong Cu(II) signal, with a small N hyper-
fine coupling, confirming a mononuclear Cu(II) structure.
tion. Moreover, in the presence of only one equivalent of
imidazole per mole of Cu, only one imidazolate coordinates
to the (TMEDA)Cu(II) fragment, whereas in an excess of imida-
zole a [(TMEDA)Cu(imidazolate)2] structure was formed.18
b. In NMP/H2O (reaction conditions). Monitoring the sto-
ichiometric reaction of the Cu(II) catalyst (I) and imidazole in

3090 Organometallics, Vol. 29, No. 14, 2010
Table 3. EXAFS Data Analysis Results of Isolated Cu Complexesb
Tromp et al.
2
-2
˚
Abs-Sca
N
σ (A )
E0 (eV)
V.I.a
V.A.a
˚
R (A)
[Cu(imidazolate)(TMEDA)]Cl (II0) in NMP/H2O
[R-space fit, 2.7 < k < 7.95, 1.0 < R < 3.0]
Cu-N (O/C)
Cu-Cl
3.2
1.0
1.94
2.62
0.005
0.005
-1.3
-7.4
k0-weighted:
0.90
0.20
0.17
k2-weighted:
0.60
[Cu(OH)(phenylimidazole)(TMEDA)]Cl in NMP/H2O
-1
˚
[R-space fit, 2.70 < k < 7.95 A , 0.8 < R < 2.8 A]
˚
Cu-N (C/O)
Cu-C (N/O)
5.0
5.6
1.97
2.97
0.005
0.005
-5.8
-4.4
k0-weighted:
0.34
0.28
0.29
k2-weighted:
0.54
a Abbreviations: Abs = absorber, Sc = scatterer, V.I. = variance in imaginary part, V.A. = variance in absolute part. b The raw EXAFS data are
shown in the Supporting Information, Figure S1b. The k0-weighted and k2-weighted Fourier transforms of the raw EXAFS and fitted EXAFS data are
shown in the Supporting Information in Figures S5 and S6.
NMP/H2O with EDXAFS/UV-vis (Figure 4) shows only
small changes in the Cu(II) XANES region in time, which are
difficult to address further or analyze in detail in a reliable manner
due to the poor data quality. This is the case for all time-resolved
XANES presented in this paper. For these time-resolved experi-
ments there is a clear trade-off between data quality and time
resolution (which is true for XANES and EXAFS especially
since they are obtained in one shot only). The quality of data
does not allow us to performed further XANES analyses or
simulation rather than observing the large significant changes
like pre-edge features and edge shifts.
The EXAFS data analysis of the resulting reaction mixture
(when no further changes are observed) is given in Table 2
and indicates the disappearance of the Cu-Cu contribution
(analysis was refined starting from the dimer and subseq-
uently supported by results from other techniques). Addi-
˚
tionally four C/N/O atoms are detected at an average of 2.94 A,
which are second-shell contributions from the coordinating
moiety and/or ligand. In contrast to the dissolved species II0,
the reaction mixture of dimer I with imidazole does not show
˚
the presence of chlorine atoms at a distance less than 3 A from
the Cu absorber atom.
Time-resolved UV-vis spectra simultaneously taken with
the EDXAFS spectra display the dissociation of the dimeric
structure by the disappearance of the LMCT band (Figure 4b,
355 nm). The d-d band slightly shifts while retaining its
intensity, indicating only small changes in Cu(II) surround-
ings. 1H NMR confirms the dissociation of the Cu dimers by
the disappearance of the lower field peaks at 70-100 ppm.
Upon addition of imidazole to the copper dimer (I) solu-
tion, an intense EPR signal characteristic of a mononuclear
Cu(II) species appears (Figure 3). Simulation of the axial spec-
trum yielded the following g-values: g = 2.265, g^= 2.060.
The g signal reveals strong Cu hyperfine splitting (ACu
=
Figure 4. (a) ED-XAFS and (b) UV-vis spectra of reaction A:
[Cu(OH)(TMEDA)]2Cl2 in NMP/H2O þ imidazole (first spec-
trum after about 1 s reaction time; see Experimental Section; one
spectrum every 3 s displayed).
514 MHz). The hyperfine coupling pattern for the g^ signal
was satisfactorily simulated by assuming superhyperfine coup-
ling with two pairs of equivalent nitrogen nuclei (AN1
=
^
77 MHz and AN2^=48 MHz) and an additional small hyper-
fine contribution from copper (ACu^=11 MHz, unresolved).
Contributions from the N-donors are not resolved in the
g direction. EPR thus suggests that addition of excess imida-
zole to I results in mononuclear Cu(II) species II with four
coordinated N-donors from two distinct pairs of equiva-
lent ligands. These most likely consist of the TMEDA
(weaker N-donor; AN2) and two additional imidazole ligands

Article
Organometallics, Vol. 29, No. 14, 2010 3091
Figure 6. X-band EPR spectra of [Cu(OH)(TMEDA)]2Cl2 in
NMP/H2O solution (dotted black line), after addition of phe-
nylboronic acid (solid black line), in time (solid gray line) and
after subsequent addition of imidazole [T = ∼20 K].
detected by EXAFS. See the EXAFS parameters of the for-
med Cu(I) complex in Table 2. We now observe three shells
˚
around the Cu atom with the first shell at 1.96 A consisting of
more than five N/C/O atoms. Besides the two N atoms of the
TMEDA ligand, additional neighbors are present that can
originate from H2O, coordinated phenyl group(s), or coordi-
nated boronic species. In UV-vis, the LMCT and d-d band
completely disappear, indicating respectively the breakup of
the dimeric structure and the consumption of Cu(II) species.
In the EPR, Figure 6, this reaction results in small signals
indicating a marginal rise of the concentration of at least two
closely related monomeric Cu(II) species of probably axial
symmetry (g^∼2.23-2.26 and g ∼2.05). Hyperfine splitting
Cu
Figure 5. (a) EDXAFS and (b) UV-vis spectra of reaction B:
[Cu(OH)(TMEDA)]2Cl2 in NMP/H2O þ PhB(OH)2 (first spec-
trum after ∼1 s reaction time; see Experimental Section; one spec-
trum every 3 s displayed).
is observed at both the signals along B^ and B (A^ ∼80-
Cu
120 MHz, g ∼500-560 MHz). After a short reaction time
at room temperature (the mixture is again frozen for mea-
surement), the Cu signal weakens and probably EPR-silent
species are formed, i.e., Cu(I) and/or re-formation of coupled
Cu(II) dimers. 1H NMR confirms the initial dissociation of
the dimeric structure (I) by the disappearance of the lower
field 70-100 ppm peaks, followed by the re-formation of dimers.
As was observed in catalysis, the reaction of phenylboro-
nic acid and Cu dimer I results in the exclusive formation of
biphenyl. Spectroscopic results shown here suggest that this
reaction proceeds with the formation of a Cu(I) species.
Reaction C: [Cu(OH)(TMEDA)]2Cl2 þ Phenylimidazole.
Since catalytic studies showed that product inhibition takes
place, the Cu(II) dimer (I) in the presence of the phenylimi-
dazole product was studied. EDXAFS/UV-vis measure-
ments of this mixture, Figure 7a,b, show results similar to
reaction A. No clear changes can be observed in the Cu(II)
XANES region, whereas in UV-vis the LMCT is disappear-
ing and only small changes in position of the d-d band are
observed. The EXAFS results in Table 2 display only three
large Cu-C/N/O contributions. The broad peak assigned to
phenylimidazole in 1H NMR shifts from ∼7.3 ppm to 66 ppm
after coordination to the Cu complex, and the lower field
signals (70 and 100 ppm) have disappeared. These results
indicate the formation of a monomeric Cu(II) species, similar
to that observed in reaction A. Phenylimidazole is now co-
ordinated to Cu(II), forming a Cu(II) monomeric species.
Dimer I and excess phenylimidazole were reacted in metha-
nol, and after precipitation with ether, a blue solid was isolated.
(stronger N-donor; AN1); see Figure S7 in the Supporting
Information for a simulation. The axial symmetry of the
spectrum and the equivalence of the TMEDA and imidazole
nitrogen nuclei suggest that II is either the square-planar
[(TMEDA)(imidazole)2CuII] or the square-pyramidal (with
the N-donors in the basal plane) [(TMEDA)(imidazole)2-
CuII(L)] (L=OH-, Cl-, H2O, or imidazole) complex similar
to the reported crystal structure.18
Reaction B: [Cu(OH)(TMEDA)]2Cl2 þ Ph(BOH)2. The
addition of phenylboronic acid to the dimeric Cu(II) com-
plex resulted in the homocoupled biphenyl product. The
stoichiometric addition of phenylboronic acid (per mole of
Cu) to the starting complex was studied with combined
EDXAFS and UV-vis, and the results are shown in Figure 5.
The signal-to-noise ratio of these XANES spectra is clearly
lower than for most of the other experiments due to the pro-
blems with beamline setup and alignment during this beam-
time period (this experiment was performed at a different
beamtime period, six months apart from the other experi-
ments). It just affects the data quality, not the data or inter-
pretation itself.
The XANES spectrum shows the fast appearance of a
large pre-edge around 8982 eV, which is assigned to a 1s f 4p
Cu(I) transition14 and thus indicates the formation of a large
amount of Cu(I) species. No Cu-Cu contribution was

3092 Organometallics, Vol. 29, No. 14, 2010
Tromp et al.
Figure 8. (a) ED-XAFS and (b) UV-vis spectra of reaction D:
[Cu(OH)(TMEDA)]2Cl2 þ imidazole þ PhB(OH)2. Maximum
after ∼30 s (arrow 1), after which the features decrease again
(arrow 2).
Figure 7. (a) EDXAFS and (b) UV-vis spectra of reaction E:
[Cu(OH)(TMEDA)]2Cl2 in NMP/H2O þ phenylimidazole (first
spectrum after about 1 s reaction time; see Experimental Section;
one spectrum every 3 s displayed).
[(TMEDA)Cu(imidazole)2X] complex II. The EPR Cu hyper-
fine signal slightly increases in intensity (Figure 3, solid black
line), the signal along B slightly shifts from g = 2.265 to g =
2.275 and slightly broadens, and A Cu has increased from 514 to
522 MHz. The signal parameters along B^ are hardly affected,
but remarkably the N super hyperfine splitting becomes more
pronounced. See Supporting Information, Figure S7, for the
experimental and simulated EPR spectrum. Probably, a slightly
different Cu species is formed, possibly by substitution of X in
[(TMEDA)Cu(imidazole)2X] by (a fragment of) phenylboronic
acid.
After warming the sample to ∼60 ꢀC, allowing it to react
for a ∼10 min, and cooling again to ∼20 K, the Cu(II) EPR
signal had decreased (Figure 3) and the color of the solution
changed from blue to colorless, indicating the formation of
a Cu(I) species. After subsequent addition of extra phenyl-
boronic acid, both the blue color of the solution and the
intensity of the EPR signal are fully regained. This strongly
suggests that phenylboronic acid is involved in the reoxida-
tion of Cu(I) to Cu(II) species.
The EXAFS results of this complex in NMP/H2O solution
are presented in Table 3 and show the presence of two large
˚
˚
N/C/O shells at respectively short (1.97 A) and longer (2.97 A)
distance to copper. According to XANES and UV-vis a mono-
meric Cu(II) species is present. The EPR spectrum of the pre-
cipitate, redissolved in NMP/H2O solution, displays a Cu(II)
signal nearly identical to that of II, although broader, resul-
ting in less resolved hyperfine splitting. In 1H NMR no char-
acteristic peaks are observed. From these results we conclude
that the reaction of phenylimidazole with Cu dimer I results
in the formation of [(TMEDA((phenylimidazole)2Cu(II)(X)],
V, with X probably being OH-.
According to these measurements, the imidazole reagent
and the phenylimidazole product have a similar affinity for
Cu(II). This is in good agreement with the observed inhibi-
tion in catalysis.
Reaction D: [Cu(OH)(TMEDA)]2Cl2 þ Imidazole þ PhB-
(OH)2. a. [Cu(Cl)(Imidazolate)(TMEDA)] (II0) þ PhB(OH)2
in NMP/H2O. Addition of phenylboronic acid to the iso-
lated[Cu(Cl)(Imidazolate)(TMEDA)] (II0) inNMP/H2Oresults
in N-phenylimidazole product formation. A Cu-coordinated
phenylimidazole signal in the 1H NMR, obtained after tens
of minutes, at ∼66 ppm indicates the coordination of phenyl-
imidazole to Cu, i.e., intermediate V.
Addition of imidazole to the mixture of Cu dimer I and
phenylboronic acid (reaction B, Figure 6) results in a strong
signal in the EPR spectrum (gray striped line), similar to the
spectrum of [(TMEDA)(imidazole)2Cu(X)], II. From EPR
measurements we cannot distinguish between the coordination
of imidazole or phenylimidazole moieties to the (TMEDA)Cu
complex. Stoichiometric experiments with first the addition
b. Subsequent Addition of Imidazole and PhB(OH)2. Phenyl-
boronic acid is added to the mixture of Cu dimer Iand imidazole
(reaction A); that is, phenylboronic acid is added to the putative

Article
Organometallics, Vol. 29, No. 14, 2010 3093
Figure 9. Time-resolved 11B NMR spectra of reaction D: [Cu(OH)TMEDA]2Cl2 in NMP/H2O þ imidazole þ phenylboronic acid
(one spectrum is taken every 20 s). The top spectrum is a reference spectrum of boric acid, B(OH)3.
of phenylboronic acid to the Cu complex I and subsequent
addition of imidazole results in a fast and selective homo-
coupling. This suggests that in the EPR solution mixture all
the phenylboronic acid has reacted prior to the addition of
imidazole (confirming the fast CC coupling) and that imida-
zole coordinates to the Cu(II), forming intermediate II identi-
cal to reaction B.
acid, H-B(OH)2.21,22 Finally, this boron hydride reacts to a
boric acid B(OH)3, which is observed by the chemical shift at
20 ppm.
With EDXAFS and UV-vis we observe that, after for-
mation of the Cu(I) species and phenylimidazole product,
the intensity of the 8982 eV pre-edge decreases again and the
Cu(II) pre-edge at 8985 eV is increasing, forming back Cu(II)
species (Figure 8a, 2). Simultaneously, in the UV-vis the
LMCT band is partly regaining intensity, while the intensity
of the d-d band is almost fully regained (Figure 8b, 2). These
results indicate the re-formation of Cu(II) species, both in
monomeric and in dimeric form.
The extensive spectroscopic study as described here has
also been performed using exclusively NMP or H2O as a sol-
vent. For the reactions in NMP, no changes in Cu coordina-
tion or oxidation state are observed, in line with the observa-
tion that the arylation reaction does not proceed. Reaction in
H2O resulted in the fast and irreversible formation of large
amounts of Cu(I) species. Although H2O is necessary for the
reaction to proceed, an excess of H2O results in a lowering of
the catalytic activity. Probably hydrolysis of the boronic
acid6 limits the efficiency of the reaction.
Spectroscopically monitoring the reaction of Cu(II) cata-
lysts with other bidentate dinitrogen ligands like phenan-
throline (in NMP/H2O, NMP, or H2O solvent) displays only
a change in reaction rates (i.e., faster in comparison to the
TMEDA); all other results (oxidation state, coordination of
the Cu) remain the same, suggesting that a similar mechanism is
followed.
Catalytic Cycle. From the different complementary spec-
troscopic results described above, we propose the formation
of the [Cu(imidazole)2(TMEDA)] intermediate II from the
reaction of imidazole with the starting [Cu(OH)(TMEDA)]2
complex I (Scheme 3). On the basis of the spectroscopic
results of the proposed isolated monomer II0 and the descrip-
tion of a monomeric Cu(imidazolate)2 complex19 we assume
the deprotonation of imidazole, forming Cu(II)(imidazolate).
Since only one OH group per Cu is present in our starting
c. Simultaneous Addition of Imidazole and PhB(OH)2. The
ED-XAFS and time-resolved UV-vis spectra of the sto-
ichiometric arylation reaction D are shown in Figure 8a,b.
All reactants are injected simultaneously in the observation
cuvette. During the reaction, a pre-edge at ∼8982 eV is for-
med in the XANES (Figure 8a, 1), indicating the formation
of a Cu(I) species. The Cu(II) species disappears, which is
concluded from the decrease of the pre-edge peak at 8985 eV
(the changes in the peak at 8979 eV are obscured in this
experiment). In the UV-vis spectra (Figure 8b, 1) the LMCT
band of the starting dimer at ∼355 nm disappears; that is,
the copper dimers dissociate. Simultaneously, the d-d band
decreases by ∼40%, indicating that this amount is most
likely converted into Cu(I) species. The small shift in d-d
band corresponds to only small changes in the Cu(II) coordi-
nation during reaction. The XANES and UV-vis results
suggest the formation of a monomeric Cu(I) species, which is
confirmed by the decrease of the Cu(II) signal in the EPR.
The stoichiometric reaction D is also monitored with 11B
NMR to investigate the role and fate of the boron atom/
boronic species during this arylation reaction (Figure 9).
Initially, the starting phenylboronic acid is clearly observed
by the chemical shift at 30 ppm. Progressing, this signal
disappears and the formation of a doublet signal at 26.4 ppm
(J = 96.8 Hz) is observed. Since these values are similar to
bis-pinacol-borane (chemical shift of 31 ppm), we assign this
to a boron hydride intermediate, H-BX2, most likely boronic
(21) Watanabe, H.; Nagasawa, K. Inorg. Chem. 1967, 6, 1068–1070.
(22) La Monica, G.; Ardizzoia, G. A.; Cariati, F.; Cenini, S.; Pizzotti,
M. Inorg. Chem. 1985, 24, 3920.

3094 Organometallics, Vol. 29, No. 14, 2010
Scheme 4. Disproportionation Mechanism
Tromp et al.
dimeric complex I and the addition of base is not necessary
for the reaction to proceed, probably one imidazole per Cu is
deprotonated; additional imidazole is only coordinated to
the Cu. This implies that reaction intermediate II can be des-
cribed as a [Cu(imidazolate)(imidazole)(TMEDA)] complex.
Since imidazole is reversibly coordinated to the Cu center, we
believe that the imidazole dissociates from the complex, lea-
ving an empty coordination place. A similar process takes
place with phenylimidazole, explaining the observed inhibi-
tion of the reaction with addition of these compounds.
In addition to the starting Cu dimer I and intermediate II,
two other reaction intermediates were characterized. The
reaction of II with phenylboronic acid forms the phenylimi-
dazole product and the known Cu(I) intermediate IV. Re-
oxidation of the Cu(I) intermediates is shown to result in
Cu(II) monomeric species with either phenylimidazole or
imidazole coordinated, respectively V or II (“resting” state),
or the starting dimeric Cu(II) species I. Additionally, the
oxidative character of phenylboronic acid is shown with
EPR. From catalytic studies we established that O2 is not
necessary for the reaction to proceed, whereas the presence
of water is essential.8 Thus both phenylboronic acid and H2O
are likely to be involved in the oxidation steps. The 11B NMR
study has shown the formation of a H-B(OH)2, which, in the
presence of water, readily reacts to boronic acid.
techniques used. Upon reductive elimination of the product
from the transient Cu(III) species, the Cu(I) species IV is
formed.
Addition of a phenyl radical to intermediate II could occur
via a homolytic splitting of the phenylboronic acid. Similar
boron radicals have been described in the literature.23 In the
presence of water the boronic radical then reacts to the
boronic hydride and a (high-energy) hydroxyl radical, which
can oxidize the Cu(I) species and form boric acid. The 11B
NMR study and the use of radical scavengers support this
radical mechanism. The formation of the proposed radicals,
however, is highly endergonic and thus not an easy process.
EPR experiments with the addition of radical scavengers would
give more details about this proposed homolytic pathway.
Alternatively, the disproportionation of the Cu(II) inter-
mediate II to a Cu(III) species and Cu(I) species is shown
in Scheme 4. Phenylboronic acid is converted to a [phenyl-
B(OH)3]- anion, an intermediate often proposed to be invol-
ved in transmetalation processes.24 This “activated” boric
acid reacts with the Cu(III)(imidazolate) species to form a
Cu(III)(phenyl)(imidazolate) intermediate III (similar to the
“homolytic mechanism”) and B(OH)3. The disproportiona-
tion is likely to be the rate-determining step, whereas the
addition of phenyl and the reductive elimination are very
fast. This allows us to monitor only the increasing amount of
Cu(I) species, whereas the lifetime of the Cu(III) species is too
short to detect this species. Reoxidation of Cu(I) complex V is
observed to occur with phenylboronic acid. Moreover, the
proton Hþ formed during the activation of phenylboronic
The organic product phenylimidazole could be formed
from electrophilic attack of a phenylboron species on the
nucleophilic imidazole. Alternatively, it could be produced
via reductive elimination from a Cu(III)(aryl)(imidazolate)
species. This pathway implies either the addition of a phenyl
radical to the Cu(II)(imidazolate) intermediate (II) or the
disproportionation of the Cu(II) intermediate in Cu(I) and
Cu(III) species. Since a Cu(III) intermediate will be rather
reactive, it most likely cannot be detected by any of the
(23) Li, C.-J. Angew. Chem., Int. Ed. 2003, 42, 4856.
(24) (a) Miyaura, N. In Advances in Metal-Organic Chemistry, Vol. 6;
Diederich, F, Stang, J. P, Eds.; JAI Press Inc., 1998; pp 187-243.
(b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Ed.; Wiley-VCH: Weinheim, 1997.

Article
Organometallics, Vol. 29, No. 14, 2010 3095
acid might be involved here. This disproportionation mecha-
nism cannot be ruled out, on the basis of the studies presen-
ted here. This mechanism, however, does not account for the
formation of a HBX2 species as observed in the 11B NMR
unless it is formed in the reoxidation step of Cu(I) to Cu(II)
with PhB(OH)2. Additional 11B NMR experiments with diffe-
rent concentration and ratios of Cu and phenylboronic acid,
as well as electrochemical data, and extensive kinetic studies
are required to validate this disproportionation mechanism.
Alternative mechanisms involving a transmetalation-type
phenyl transfer can be considered, such as a concerted path-
way. In this pathway, both the imidazole and phenylboronic
acid coordinate to the Cu(II)(TMEDA) complex, forming a
cyclic Cu-N-Ph-B transition. Simultaneously the product
and a Cu(II)(TMEDA)-B(OH)2 species are formed, the
latter reacting in the presence of H2O to form HB(OH)2
and finally boronic acid. In this mechanism the Cu oxida-
tion state remains 2þ throughout the entire cycle. On the
basis of our results, a transmetalation mechanism seems
unlikely but cannot completely be ruled out since the pro-
posed Cu(II)-B species could react with water to form a Cu(I)
intermediate.
The productive part of the catalytic cycle is established
by the characterization of the reaction intermediates as
given in Scheme 3 and is in good correspondence with all
spectroscopic results obtained. Further research including
quantitative EPR and NMR, electron spray MS, IR, and
kinetic studies is required to elucidate the mechanism in
further detail. More detailed XANES studies, including
FEFF and DFT calculations, will provide more informa-
tion on the structure and geometry of the different Cu
intermediates.14,25
distilled from CaH2 under nitrogen. Reactions in the absence
of dioxygen were carried out using standard Schlenk techniques.
Gas chromatographic analyses were run on an Interscience HR
GC Mega 2 apparatus (split/splitless injector, J&W Scientific,
DB-1 J&W 30 m column, film thickness 3.0 μm, carrier gas
70 kPa He, FID detector) equipped with a Hewlett-Packard
data system (Chrom-Card). Gas chromatographic mass spectra
were run on an Agilent Technologies 6890/5973 GC-MS com-
bined with an Agilent mass selective detector. Column type:
HP5MS, length 30 m, film thickness 0.25 μm, cross-linked 5%
PhMe-siloxane.
Synthesis of Bis-μ-hydroxycopper(II) (TMEDA) Complex.
This complex has been prepared according to the literature.26
Elemental Analysis Results. [Cu(OH)(TMEDA)]2 (I) was pre-
pared according to the literature.26 Anal. Found: 30.66% C, 7.39%
H, 11.70% N. Theory: 31.03% C, 7.37% H, 12.06% N.
[Cu(Cl)(imidazolate)(TMEDA)] (II0) was isolated as descri-
bed in the text. Anal. Found: 31.89% C, 8.46% H, 16.63% N.
Theory: 38.20% C, 6.78% H, 19.85% N.
[Cu(OH)(phenylimidazole)(TMEDA)]Cl was isolated as des-
cribed in the text. Anal. Found: 49.35% C, 4.78% H, 11.79% N.
Theory: 52.42% C, 6.11% H, 13.59% N.
Combined Time-Resolved in Situ ED-XAFS and UV-Vis. a.
Setup. The combined ED-XAFS UV-vis setup9 is schemati-
cally shown in Figure 10. Using the energy dispersive setup,10
a curved crystal reflects and focuses the total synchrotron
white beam on the sample. All energies can be measured at
once using a position-sensitive detector, thereby enabling the
acquisition of EXAFS spectra in the millisecond-second
range. Combining this setup in a perpendicular manner with
an optical fiber UV-vis apparatus, both techniques can be
applied simultaneously.
A Biologic SFM-400 stopped-flow module with four syringes
as schematically shown in Figure 11a is used to perform the
homogeneous reactions. The four syringes (S1-S4) can be filled
with 10 mL of reaction solution or solvent. The system is com-
puter controlled and allows injection of precise volumes with
controlled injection rates (and thus injections times). The solu-
tions are injected using stepper motors from the syringes (S1-S4)
via the delay lines (D1 and D2) and mixers (M1-M3) into the
observation cuvette and finally, after measurement, through
the cuvette into a waste flask. Each time, a total volume is
injected large enough to refresh all delay lines, mixers, and the
total cuvette content. The stopped-flow system has a dead
time of ∼4 ms, the time for the solutions to mix and reach the
observation cuvette. This means that for all experiments the
first recorded spectrum can only start after a reaction time of
about ∼4 ms, to which an additional 1 s data acquisition per
spectrum should be added (vide infra, i.e., average of 15 spec-
tra of 50 ms). Spectra at t=0 thus cannot be obtained as such,
and one should refer to Figure 1 for that in which the starting
solution, before any reaction, is measured.
On the basis of the spectroscopic results described in this
paper, the C-C coupling reaction as observed in reaction B
seems to proceed via a reaction mechanism similar to the
C-N coupling. In this case, the first step in the reaction
mechanism will be the transmetalation of phenylboronic
acid to the Cu dimer (I).
Conclusions
In this study we show that the application of a wide range
of spectroscopic techniques gives detailed insights into reac-
tion intermediates involved in the Cu(II)-catalyzed arylation
reaction. Five out of six reaction intermediates have been
characterized (Scheme 3), and the time-resolved in situ
techniques allow the monitoring of changing oxidation states
and characteristic transitions during reaction. In combina-
tion with catalytic results a catalytic cycle for the important
Cu(II)-catalyzed arylation reactions has been proposed. The
productive part of this catalytic cycle is established and is
in correspondence with all spectroscopic results obtained.
More experiments are necessary to give more insight into the
oxidation steps involved.
Special quartz cuvettes have been designed in which the
X-rays and UV-vis light traverse perpendicular to one another
(Figure 11b). Cuts in different directions through the capillary
are shown. Due to the different sensitivity of the two techniques
for different (metal) systems, different path lengths are required
(A=XAFS pathway, B=UV-vis pathway) to allow simulta-
neous measurements on the same reaction mixture. For the Cu
systems described in this paper, A is 5 mm and B is 1 mm. The
quartz windows have a thickness of 100 μm.
Experimental Section
b. Reactions. The reactions described in this study have been
performed stoichiometrically with 10 mM of [Cu(OH)(TM-
EDA)]2Cl2 (I) (20 mM Cu) in the observation cuvette after
Catalytic Experiments. Unless stated otherwise, all reactions
were carried out in an air atmosphere using 20 cm glass tubes.
THF, hexane, and diethyl ether were distilled from sodium
benzophenone ketyl, and NMP (N-methylpyrrolidone) was
(26) (a) McWhinnie, W. R. J. Chem. Soc. 1964, 2959. (b) Ferraro, J. R.;
Walker, W. R. Inorg. Chem. 1965, 4, 1382. (c) Collman, J. P.; Zhong, M.;
Zeng, L.; Costanzo, M. J. Org. Chem. 2001, 66, 1528. (d) General procedure:
1 equiv of CuCl and 1 equiv of bidentate ligand are added to a solution of
EtOH/H2O (95:5 v/v %) and stirred in an air atmosphere for 20 h.
(25) Tromp, M.; van Bokhoven, J. A.; van Strijdonck, G. P. F.; van
Leeuwen, P. W. N. M.; Koningsberger, D. C.; Ramaker, D. E. J. Am.
Chem. Soc. 2005, 127 (2), 777–789.

3096 Organometallics, Vol. 29, No. 14, 2010
Tromp et al.
well as beamline setup differences in different runs (some experi-
ments were taken 6 months apart in time). Static XAFS spec-
tra were measured before and after the reactions, by averaging
50 ꢀ 15 spectra of 100 ms, to enable a reliable EXAFS ana-
lysis of the complexes in solution. The data quality of the time-
resolved spectra (1 s acquisition time) was often not good
enough to perform full EXAFS analyses. Moreover, a large
mixture of species is present, which complicates the analyses
even more.
Simultaneous ED-XAFS at the Cu K-edge and time-resolved
UV-vis experiments were performed at ID24 of the ESRF
(European Synchrotron Radiation Facility), Grenoble Cedex,
France, project CH-1275. Data were acquired using a Bragg
monochromator.27 The energy calibration was carried out using
a copper foil. Data are collected using a masked Peltier cooled
Princeton CCD camera. In our combined setup a commercially
available Biologic stopped-flow module SFM-400 (MMS-UV1/
500-1 high-speed diode array spectrometer with fiber optics) was
used to perform the homogeneous reactions.
Figure 10. Schematic representation of the combined ED-XAFS/
UV-vis setup.
EXAFS Data Analysis. Calibrated references generated as
described in ref 28 were used for the analysis of the Cu-N,
Cu-Cu, and Cu-C coordinations. In a similar way a theore-
tical reference for Cu-O generated using the code FEFF829
was calibrated and optimized using EXAFS data of a CuO
reference compound. The EXAFS data were analyzed using
the commercially available program XDAP.30 During R-
space fitting, the difference file technique was used to be able
to conclude a good analysis for all contributions in all weight-
ings.28 To allow refinement of the coordination numbers
for the different contributions, the S02 as determined for the
Cu-N and Cu-C references was assumed to be accurate for
the samples under investigation here and implemented as a
fixed parameter, S02 = 0.92.
1H and 11B NMR Measurements. The 1H and 11B NMR
spectra were obtained from a Bruker DRX 300 MHz spectro-
meter. D2O was used as solvent if not further specified. Solu-
tions of 0.2 M imidazole and PhB(OH)2 were used. A solution of
0.01 M [Cu(OH)TMEDA]2Cl2 was used. All reactions were
performed at ambient conditions. 11B NMR spectra were
obtained time-resolved, i.e., every 20 s.
EPR Measurements. Experimental X-band EPR spectra were
recorded on a ca. 9.30 GHz Bruker ER-220 spectrometer, equip-
ped with an ESR-9 variable-temperature cryostat (Oxford In-
struments). Reactions were started at room temperature and
subsequently frozen to ∼20 K and measured.
Figure 11. (a) Schematic drawing of the stopped-flow module,
equipped with four syringes (S1, S2, S3, and S4). The solutions
(with reagents) are injected via the mixers (M1, M2, and M3) and
delay lines (D1 and D2) into the cuvette. (b) Schematic drawing of
the specially designed cuvette. In two directions, a cut through the
capillary is shown. Two different path lengths allow simultaneous
measurements on the same reaction mixture.
The spectra were simulated by iteration of the anisotropic
g-values, (hyper)hyperfine coupling constants, and line widths.
Acknowledgment. P. van de Belt (UU), H. Heeze (UU),
S. Pasternak (ESRF), T. Mairs (ESRF), F. Perrin (ESRF),
and S. Pascarelli (ESRF) are gratefully acknowledged
for discussions, help in building the setup, and perfor-
ming the EDXAFS/UV-vis measurements, S. Diaz-
Moreno (ESRF) for initial help with the stopped-flow
design and experiments, and M. Lutz and A. L. Spek
(UU) for the preliminary X-ray diffraction experiments.
We thank Prof. Dr. F. Neese (Bonn, Germany) for a copy
of his EPR simulation program, the ESRF for provision
of synchrotron radiation facilities, project CH-1275, and
mixing. Higher concentrations would be preferable to increase
the quality of the obtained XAFS data; however, we are limited
to the solubility of complex I. For the Cu system described in this
paper, with this setup it is possible to measure EXAFS spectra
with a minimum time resolution of 10 ms and UV-vis spectra
with a minimum time resolution of 0.3 ms.
ED-XAFS measurements at the Cu K-edge and time-resolved
UV-vis measurements were performed simultaneously to study
the mechanism of the Cu(II)-catalyzed arylation reaction of
phenylboronic acid and imidazole to form N-phenylimidazole at
ambient conditions. ED-XAFS measurements were taken with
a time resolution of ∼1 s; every ED-XAFS spectrum is an
average of 15 spectra with an acquisition time of 50 ms each.
Figures presented in this paper show a spectrum every 3 s for
clarity reasons. UV-vis spectra were recorded every 30 ms.
Again, figures display a spectrum every 3 s (to match XAS) for
clarity reasons. EDXAS data quality is clearly different between
different experiments, which is due to beam stability problems as
(27) Hagelstein, M.; Ferraro, C.; Hatje, U.; Ressler, T.; Metz, W.
J. Synchrotron Radiat. 1995, 2, 174.
(28) Tromp, M.; van Bokhoven, J. A.; Arink, A. M.; Bitter, J. H.;
van Koten, G.; Koningberger, D. C. Chem.;Eur. J. 2002, 8, 5667.
(29) Ankudinov, A. L.; Ravel, B.; Rehr, J. J.; Conradson, S. D. Phys.
Rev. B 1998, 7565.
(30) Vaarkamp, M.; Linders, J. C.; Koningsberger, D. C. Physica B
1995, 208 & 209, 159.

Article
Organometallics, Vol. 29, No. 14, 2010 3097
The National Research School Combination Catalysis for
the financial support of M.T.
k0- and k2-weighted Fourier transforms of the raw and fitted
EXAFS data after reactions A, B, and C, and of raw and fitted
EXAFS data of isolated intermediates, and experimental and
simulated EPR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: Raw EXAFS data reac-
tion intermediates and isolated Cu complexes in NMP/H2O,