Copper complexes of anionic nitrogen ligands in the amidation and imidation of aryl halides

Article abstract of DOI:10.1021/ja076668w

Copper(I) imidate and amidate complexes of chelating N,N-donor ligands, which are proposed intermediates in copper-catalyzed amidations of aryl halides, have been synthesized and characterized by X-ray diffraction and detailed solution-phase methods. In some cases, the complexes adopt neutral, three-coordinate trigonal planar structures in the solid state, but in other cases they adopt an ionic form consisting of an L₂Cu⁺ cation and a CuX₂^- anion. A tetraalkylammonium salt of the CuX₂^- anion in which X = phthalimidate was also isolated. Conductivity measurements and ¹H NMR spectra of mixtures of two complexes all indicate that the complexes exist predominantly in the ionic form in DMSO and DMF solutions. One complex was sufficiently soluble for conductance measurements in less polar solvents and was shown to adopt some degree of the ionic form in THF and predominantly the neutral form in benzene. The complexes containing dative nitrogen ligands reacted with iodoarenes and bromoarenes to form products from C-N coupling, but the ammonium salt of [Cu(phth) ₂]^- did not. Similar selectivities for stoichiometric and catalytic reactions with two different iodoarenes and faster rates for the stoichiometric reactions implied that the isolated amidate and imidate complexes are intermediates in the reactions of amides and imides with haloarenes catalyzed by copper complexes containing dative N,N ligands. These amidates and imidates reacted much more slowly with chloroarenes, including chloroarenes that possess more favorable reduction potentials than some bromoarenes and that are known to undergo fast dissociation of chloride from the chloroarene radical anion. The reaction of o-(allyloxy)iodobenzene with [(phen)₂Cu] [Cu(pyrr)₂] results in formation of the C-N coupled product in high yield and no detectable amount of the 3-methyl-2,3-dihydrobenzofuran or 3-methylene-2,3-dihydrobenzofuran products that would be expected from a reaction that generated free radicals. These data and computed reaction barriers argue against mechanisms in which the haloarene reacts with a two-coordinate anionic copper species and mechanisms that start with electron transfer to generate a free iodoarene radical anion. Instead, these data are more consistent with mechanisms involving cleavage of the carbon-halogen bond within the coordination sphere of the metal.

Full text of DOI:10.1021/ja076668w

Published on Web 07/03/2008
Copper Complexes of Anionic Nitrogen Ligands in the
Amidation and Imidation of Aryl Halides
Jesse W. Tye, Zhiqiang Weng, Adam M. Johns, Christopher D. Incarvito, and
John F. Hartwig*
Departments of Chemistry, UniVersity of Illinois, 600 South Matthews AVenue, Urbana, Illinois
61801, and Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received September 4, 2007; Revised Manuscript Received May 6, 2008; E-mail: jhartwig@uiuc.edu
Abstract: Copper(I) imidate and amidate complexes of chelating N,N-donor ligands, which are proposed
intermediates in copper-catalyzed amidations of aryl halides, have been synthesized and characterized by
X-ray diffraction and detailed solution-phase methods. In some cases, the complexes adopt neutral, three-
coordinate trigonal planar structures in the solid state, but in other cases they adopt an ionic form consisting
-
-
of an L2Cu+ cation and a CuX2 anion. A tetraalkylammonium salt of the CuX2 anion in which X )
phthalimidate was also isolated. Conductivity measurements and 1H NMR spectra of mixtures of two
complexes all indicate that the complexes exist predominantly in the ionic form in DMSO and DMF solutions.
One complex was sufficiently soluble for conductance measurements in less polar solvents and was shown
to adopt some degree of the ionic form in THF and predominantly the neutral form in benzene. The
complexes containing dative nitrogen ligands reacted with iodoarenes and bromoarenes to form products
from C-N coupling, but the ammonium salt of [Cu(phth)2]- did not. Similar selectivities for stoichiometric
and catalytic reactions with two different iodoarenes and faster rates for the stoichiometric reactions implied
that the isolated amidate and imidate complexes are intermediates in the reactions of amides and imides
with haloarenes catalyzed by copper complexes containing dative N,N ligands. These amidates and imidates
reacted much more slowly with chloroarenes, including chloroarenes that possess more favorable reduction
potentials than some bromoarenes and that are known to undergo fast dissociation of chloride from the
chloroarene radical anion. The reaction of o-(allyloxy)iodobenzene with [(phen)2Cu][Cu(pyrr)2] results in
formation of the C-N coupled product in high yield and no detectable amount of the 3-methyl-2,3-
dihydrobenzofuran or 3-methylene-2,3-dihydrobenzofuran products that would be expected from a reaction
that generated free radicals. These data and computed reaction barriers argue against mechanisms in
which the haloarene reacts with a two-coordinate anionic copper species and mechanisms that start with
electron transfer to generate a free iodoarene radical anion. Instead, these data are more consistent with
mechanisms involving cleavage of the carbon-halogen bond within the coordination sphere of the metal.
bipyridines and phenanthrolines,7–10 1,2-diamines,11,12 R-amino
Introduction
acids,13 bis-pyridylimines,14 1,3-diketones,15,16 and others.17–19
The catalytic amidation of aryl halides has become an
important synthetic process.1 Much of this chemistry has been
developed with palladium catalysts,2,3 but the oldest examples
of this process were reported with copper catalysts.4 Much effort
has been spent recently by many groups to improve upon the
original copper catalysts for the coupling of aryl halides with
nitrogen nucleophiles by conducting the reactions with added
ligands (eq 1).5,6 Ligands used for this chemistry have included
(7) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001,
42, 4791.
(8) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3,
4315.
(9) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670.
(10) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999,
40, 2657.
(11) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(12) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684.
(1) Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. In Chemistry
of Anilines; Rappoport, Z. Ed.; Wiley-Interscience: New York, 2007;
Vol. 1, p 455.
(2) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2000.
(3) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling
Reactions; De Meijere, A., Diederich, F. Eds.; Wiley-VCH: Weinheim,
2004; Vol. 2, p 699.
(13) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998,
120, 12459.
(14) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.-
Eur. J. 2004, 10, 5607.
(15) de Lange, B.; Lambers-Verstappen, M. H.; Schmieder-van de Vond-
ervoort, L.; Sereinig, N.; de Rijk, R.; de Vries, A. H. M.; de Vries,
J. G. Synlett 2006, 3105.
(16) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(17) Chen, Y. J.; Chen, H. H. Org. Lett. 2006, 8, 5609.
(18) Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333.
(19) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043.
(4) Goldberg, I. Chem. Ber. 1906, 39, 1691.
(5) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(6) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248,
2337.
9
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 9971–9983 9971

A R T I C L E S
Tye et al.
Scheme 1
Although much progress has been made toward improving
the reaction scope and developing milder reaction conditions,
a mechanistic foundation that explains the relative reactivities
of different catalysts for various C-N, C-O, and C-S coupling
processes has not been established. The effect of the dative and
ancillary ligand on the identity and facility of the turnover-
limiting step of the catalytic process and the effect of these
ligands on the rates of the C-N bond-forming process have
not been evaluated.
Studies to reveal the oxidation state of the starting copper
were published many years ago,20 but an understanding of the
relationships between reactivity and ligand structure requires
the synthesis and characterization of copper amide, amidate,
and imidate complexes containing a series of ancillary ligands.
To date, few such complexes have been isolated in pure form
and evaluated for their reactions with haloarenes. Examples of
copper amidate and imidate complexes ligated by triphenylphos-
phine were reported by Yamamoto et al.21 However, most
copper complexes with anionic nitrogen ligands that have been
characterized22-25 have lacked dative ligands. Thus, the body
of literature on the synthesis, isolation, and structures of ligated
copper amide, amidate, and imidate complexes has been too
limited to understand the relationships between the identity of
the ligands and the patterns of reactivity.
catalyzed coupling processes. We report the synthesis of copper
amidate and imidate complexes containing nitrogen and phos-
phorus ancillary ligands, the structure determinations of these
species in the solid state and solution phase, the reactions of
these species with a series of haloarenes, comparisons of the
selectivities and rates of stoichiometric and catalytic reactions,
quantitative kinetic data on the stoichiometric reactions of these
species with haloarenes, the use of probes for aryl radical
intermediates, and calculations of the free energies of activation
for nonradical pathways by DFT methods. These studies provide
rare data on the effect of ancillary and reactive ligands on the
individual steps of this type of coupling, as well as mechanistic
data that begin to distinguish between a series of proposed
pathways for the reactions of haloarenes with ligated copper
complexes containing anionic nitrogen ligands.
In addition, few studies on the reactions of isolated, ligated
copper amide, amidate, or imidate complexes with iodoarenes
have been reported. In one of the few cases of such a study,
PPh3-ligated amidates and imidates were shown to react slowly
and in only modest yield with haloarenes.21 More recently,
Strieter et al. generated a copper amidate from a 1:1:1 ratio of
mesityl copper, pyrrolidinone, and N,N′-dimethylcyclohexanedi-
amine.26 Although they were unable to isolate this complex in
pure form, they showed the species generated in situ reacted
with 3,5-dimethylphenyl iodide to form an N-arylpyrrolidinone
with a rate that was faster than the rate of the related copper-
catalyzed coupling. Finally, a computational study of the C-N
bond-forming step of the coupling between acetamide and
bromobenzene, catalyzed by ethylenediamine-ligated copper,
was published recently, but experimental mechanistic data to
compare and validate this computational work are limited.27
To begin to define the relationships between the structures
and reactivity of proposed intermediates in the copper catalyzed
coupling of aryl halides, we have sought to isolate, fully
characterize, and study the reactivity of copper complexes
containing anionic nitrogen ligands and the types of dative
ligands that have been used to generate catalysts for copper-
Results and Discussion
1. Synthesis of Ligated Amidate and Imidate Complexes. A
series of copper amidate and imidate complexes ligated by
phenanthroline, bipyridine, diamine, and diphosphine ligands
were prepared by the methods shown in Scheme 1. The reaction
of copper tert-butoxide28,29 with the dative ligand, followed by
addition of phthalimide (phth-H), led to the formation of
complexes 1a-d containing 1,10-phenanthroline (phen), 4,4′-
di-tert-butylbipyridine (dtbpy), N,N′-dimethylethylenediamine
(dmeda), and 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene
(Xantphos) as the ancillary dative ligand and phthalimidate as
the anionic nitrogen ligand. Reaction of [Cu(OtBu)]4 with 1,10-
phenanthroline or N,N′-dimethylethylenediamine and pyrroli-
dinone (pyrr-H) led to complexes 2a or 2b containing phen or
dmeda as the dative ligand and pyrrolidinonate as the anionic
ligand. A stable two-coordinate, anionic copper imidate lacking
dative ligands was also prepared. This complex, [N(n-
Bu)4]+[Cu(phth)2]- (3), was prepared by combining [N(n-
Bu)4][phth], [Cu(OtBu)]4, and phthalimide in THF (eq 2).
Complexes 1a-d and 2a were isolated in 84-98% yield by
precipitation of the product or evaporation of solvent, followed
by recrystallization. Attempts to isolate 2b led to decomposition.
Therefore, studies on 2b were always conducted on material
that was freshly generated in situ from a 1:1:1 mixture of
[Cu(OtBu)]4, pyrrolidinone, and dmeda.30 Complex 3 precipi-
tated from the reaction solution over the course of 15 min and
was isolated in 85% yield. This material was judged to be pure
(20) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496.
(21) Yamamoto, T.; Ehara, Y.; Kubota, M.; Yamamoto, A. Bull. Chem.
Soc. Jpn. 1980, 53, 1299.
(22) Gambarotta, S.; Bracci, M.; Floriani, C.; Chiesivilla, A.; Guastini, C.
Dalton Trans. 1987, 1883.
(23) Hope, H.; Power, P. P. Inorg. Chem. 1984, 23, 936.
(24) Tsuda, T.; Watanabe, K.; Miyata, K.; Yamamoto, H.; Saegusa, T.
Inorg. Chem. 1981, 20, 2728.
1
by H NMR spectroscopy but required recrystallization from
(25) Tsuda, T.; Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T. J. Org.
Chem. 1981, 46, 192.
(28) Lemmen, T. H.; Goeden, G. V.; Huffman, J. C.; Geerts, R. L.; Caulton,
K. G. Inorg. Chem. 1990, 29, 3680.
(26) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4120.
(29) Tsuda, T.; Hashimoto, T.; Saegusa, T. J. Am. Chem. Soc. 1972, 94,
658.
(27) Zhang, S. L.; Liu, L.; Fu, Y.; Guo, Q. X. Organometallics 2007, 26,
4546.
(30) For a related synthesis, see ref 26.
9
9972 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Cu-Catalyzed Amidation and Imidation of Aryl Halides
A R T I C L E S
Figure 1. Crystal structures of 1a (a), 1b (b), 1d (c), and 2a (d) with 50% ellipsoids. The tert-butyl groups of the dtbpy ligand of 1b have been omitted
for clarity.
CH2Cl2 to yield material suitable for elemental analysis.
Crystalline samples of these complexes displayed a range
of colors. Complexes 1a and 1b were isolated as orange-red
crystalline solids, and complex 1d as a light-yellow powder.
Complex 1c was obtained as a green oil at room temperature
that solidified when cooled to -35 °C. Complex 2a was isolated
as an orange-red crystalline solid, while complex 3 was
colorless. Solutions of complexes 1a-d and 2a,b decomposed
in air within hours, but a solution of complex 3 was stable in
air for days to weeks.
and 2a determined by X-ray diffraction. The structure of 1c
was also determined by X-ray diffraction. The connectivity of
1c was clearly defined, but disorder in the backbone of the
dmeda ligand prevented a high-resolution structure in this case.
The solid-state structures of complexes 1a and 1d consist of
three-coordinate, trigonal planar geometries in which the cop-
per(I) center is bound by one neutral bidentate ligand and one
anionic imidate ligand. In contrast, the structures of 1b, 1c, and
2a consisted of ionic species containing one cationic tetrahedral
copper center ligated by two of the dative N,N-donor ligands
and one anionic, two-coordinate linear copper center ligated by
two anionic nitrogen ligands. Such ionic structures have rarely
been included in previous mechanistic proposals for reactions
of ligated copper complexes, even though such ionic forms have
been observed for copper halides. For example, Ouali et al.
recently showed that the tetradentate bis-pyridylimine used in
catalytic couplings forms dimeric complexes of the form
[L2Cu2]X2 upon reaction with CuI or [Cu(CH3CN)4]PF6 in
acetonitrile.31 Related structures of Cu(I) halides can be found
2. Structures of the Amidate and Imidate Complexes. The
identities of the imidate and amidate products were not
straightforward to determine. A variety of methods were
necessary, and the structures depended on the phase and the
1
solvent. The H NMR spectra of each complex revealed a 1:1
ratio of the dative ligand to the imidate or amidate ligand.
Moreover, all analytical data were consistent with this 1:1 ratio.
However, the solid-phase structures of only complexes 1a and
1d reflected a simple LCu(imidate) structure, and solution data
of 1a-d and 2a implied that the identity of these complexes
depends on the solvent.
2.1. Solid-State Structures of the Amidate and Imidate
Complexes. Figure 1 shows the solid-state structures of 1a,b,d
(31) Ouali, A.; Taillefer, M.; Spindler, J. F.; Jutand, A. Organometallics
2007, 26, 65.
9
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A R T I C L E S
Tye et al.
in the Cambridge Crystallographic Database.32–35 For example,
the reaction of copper(I) halides and various substituted phenan-
throlines in a 1:1 ratio has formed monomeric copper complexes
of the form (phen′)CuX, ionic complexes of the form
[(phen′)2Cu][CuX2], and halide-bridged dimeric complexes of
the form [(phen′)CuX]2, in which X ) Cl, Br, or I and phen′ is
either a substituted or unsubstituted 1,10-phenanthroline.
Phen-ligated and Xantphos-ligated imidates 1a and 1d are
both three-coordinate monomers in which the copper center is
trigonal planar. In 1a, the C-N distances to the dative ligand
(2.01 and 2.07 Å) are longer than that to the formally anionic
phthalimidate (phth) ligand (1.88 Å). The phth ligand is bound
symmetrically between the two nitrogens of the dative ligand
in complex 1a, giving nearly perfect C2V symmetry. The Cu-N
distance to the phth ligand in 1d is longer (1.95 Å) than that in
1a, and, in contrast to that in 1a, the imidate ligand of 1d is
canted toward one of the phosphorus donors, making one
P-Cu-N angle larger than the other.
unconventional due to the small values and the resulting need
for highly concentrated samples to obtain substantial readings,
along with the lack of solubility of most ionic species in these
media. Nevertheless, we were able to compare the conductivity
of complex 1b with that of [(n-octyl)4N][Br] in THF and
benzene. The conductivity of a 65.5 mM concentration of 1b
in THF was 22.1 µΩ cm-1 (0.34 Ω-1 cm2 mol-1). For
comparison, the conductivity of the same concentration of a
THF solution of [(n-octyl)4N][Br] was 65.1 µΩ cm-1 (0.99 Ω-1
cm2 mol-1), and the value for a 65.5 mM solution of ferrocene
was 0.0 µΩ cm-1 (0.0 Ω-1 cm2 mol-1). Thus, complex 1b
appears to adopt at least some of the ionic structure in THF.
However, the conductivity of a 65.5 mM solution of 1b in
benzene was <0.1 µΩ cm-1 (<0.002 Ω cm2 mol-1), whereas
the value for the same concentration of [(n-octyl)4N][Br] was
1.2 µΩ cm-1 (0.018 Ω-1 cm2 mol-1), and the value for a 65.5
mM solution of ferrocene was 0.0 µΩ cm-1 (0.0 Ω-1 cm2
mol-1). These data imply that complex 1b exists as the neutral,
three-coordinate structure in an arene solvent.
The X-ray data for complexes 1b, 1c, and 2a revealed an
ionic structure of the general formula [L2Cu]+[CuX2]- (L )
dtbpy, dmeda, or phen, X ) phth or pyrr). The Cu-N distances
in these species are similar to those in the neutral compound,
despite the different coordination number and charge. The
Cu-N distance in the [(dtbipy)2Cu]+ portion of 1b is 2.01 Å,
which is similar to the Cu-N distances in neutral 1a. The Cu-N
distance in the anionic [Cu(phth)2]- portion of 1b is 1.86 Å,
which is also similar to the C-N(phth) distance in neutral 1a.
Even the [Cu(pyrr)2]- portion of 2a has the same Cu-N
distance of 1.86 Å. The anionic portions of 1b and 2a are linear.
The N-Cu-N angle in 1a is 179.3°, while that in 2a is a
rigorously linear 180.0° because the copper lies on a crystal-
lographic inversion center.
To gain further data on the identity of these species in polar
solvents, we compared the 1H and 15N spectral data for
complexes 1a-c to those of [N(n-Bu)4][Cu(phthalimidate)2] (3).
1
The H NMR resonances of the phthalimidate ligand in 3 and
1a-c in DMSO-d6 were indistinguishable. The 1H NMR
spectrum of all four complexes contained a multiplet or broad
singlet at ∼7.6 ppm. Although one might think that the 15N
chemical shifts of 15N-labeled 1a-c (-196.9 ppm vs neat
MeNO2) would be more diagnostic, the signals were broad. The
15N chemical shifts of 15N-labeled 1a-c were identical to that
of 15N-labeled 3. Although these values are distinct from those
measured for H-phth (-152.6 ppm) and K-phth (-221.7 ppm),
the 15N NMR spectra of a THF solution of 15N-enriched 1c
contained a single resonance at -196 ppm, and the spectrum
of labeled 1c in toluene consisted of a single resonance at -195
ppm with a linewidth of 400 Hz. Thus, all the copper complexes
in all media that we examined have relatively similar 15N NMR
chemical shifts.
More informative were some of the 1H NMR spectra of
mixtures of two complexes containing the same dative ligand
but a different anionic ligand. These studies proved most
informative for phen complexes 1a and 2a. If complexes 1a
and 2a are simple neutral monomers, then the 1H NMR spectrum
of the mixture of the two complexes would contain one set of
1H NMR resonances for each of the anionic ligands and two
sets of resonances for the dative ligand. However, if they are
ionic species, then this spectrum would contain two sets of
resonances for the anionic ligands (one set for the homoleptic
anion and one set for the mixed anion) and one set for the dative
ligand.
2.2. Solution-Phase Structures of the Amidate and
Imidate Complexes. To determine which structure was present
in solution, techniques other than simple 1H NMR spectroscopy
were required. A simple 1H NMR spectrum does not distinguish
the neutral form from the ionic form because both contain a
1:1 ratio of dative to anionic nitrogen ligands. Instead, conduc-
tivity of solutions containing the complexes and spectra of
mixtures of compounds were used to clarify the relationship
between the solid-state and solution structures.
The conductivities of solutions of complexes 1a-d, 2a, and
3 in DMSO solvent were measured.36 The values of 1.0 mM
solutions of these complexes in DMSO were 15.9 Ω-1 cm2
mol-1 for 1a, 14.5 Ω-1 cm2 mol-1 for 1b, 18.4 Ω-1 cm2 mol-1
for 1c, 23.1 Ω-1 cm2 mol-1 for 1d, 20.1 Ω-1 cm2 mol-1 for
2a, and 44.5 Ω-1 cm2 mol-1 for 3. The size and thus mobility
of ions in solution affects the conductivity of the solution
containing these ions.36 Thus, it is difficult to use these values
to quantify the concentrations of ions in solution. Nevertheless,
a comparison of these values to the 0.3 Ω-1 cm2 mol-1 value
for ferrocene and the 23.5 Ω-1 cm2 mol-1 value for
[NBu4][BPh4] implies that all the complexes contain substantial,
if not exclusive, amounts of the ionic form in polar solvents.
Measurements of conductivity in much less polar solvents is
To obtain data for this analysis, the phen-ligated phthal-
imidate complex 1a was mixed with the phen-ligated amidate
complex 2a in DMF-d7 solvent. Consistent with each complex
1
existing largely in the ionic form in polar solvents, the H
NMR spectrum of 1a and 2a at -25 °C in DMF-d7 contained
1
two sets of resonances for the pyrrolidinone ligand. The H
NMR resonances of the phth and phen ligands overlapped
with each other, but the pyrr resonances were resolved. This
(32) Healy, P. C.; Pakawatchai, C.; White, A. H. Dalton Trans. 1985, 2531.
(33) Klemens, F. K.; Palmer, C. E. A.; Rolland, S. M.; Fanwick, P. E.;
McMillin, D. R.; Sauvage, J. P. New J. Chem. 1990, 14, 129.
(34) Pallenberg, A. J.; Koenig, K. S.; Barnhart, D. M. Inorg. Chem. 1995,
34, 2833.
1
mixture of 1a and 2a at -25 °C contained two distinct H
NMR resonances at 3.25 and 3.18 ppm, corresponding to
the methylene protons of the pyrr ligands alpha to the
carbonyl group.37 Unfortunately, the 1H NMR spectra of
dmeda-ligated phthalimidate complex 1c and dmeda-ligated
pyrrolidinonate complex 2b in toluene were temperature
(35) tom Dieck, H.; Stamp, L. Z. Naturforsch., B: Chem. Sci. 1990, 45,
1369.
(36) Geary, W. J. Coord. Chem. ReV. 1971, 7, 81.
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Cu-Catalyzed Amidation and Imidation of Aryl Halides
A R T I C L E S
dependent, and a temperature at which signals due to both
compounds were sharp could not be obtained.
3. Reactivity of the Amidate and Imidate Complexes with
Haloarenes. 3.1. Reactions of Complexes Containing Dative
Ligands. Having established the solution structures of 1a-c and
2a, we sought to determine the effect of dative ligand, anionic
ligand, and solvent on the rates of the reaction of these
complexes with haloarenes. Qualitative data on the relative
reactivity of these complexes was obtained by heating them with
iodoarene or bromoarene in DMSO, THF, or toluene in sealed
than the amidate complex 2a ligated by phen. Reaction of 2b
with p-iodotoluene in toluene for 1 h at -10 °C formed N-(p-
tolyl)pyrrolidinone in 93% yield. Reaction of 2b with p-
iodotoluene in a 1:1 mixture of toluene and DMF was only
slightly faster than that in pure toluene (vide infra). Thus, the
reactions of the pyrrolidinonate complexes were less affected
by solvent polarity than were the reactions of the phthalimidate
complexes. It is possible that this difference in solvent effect
results from a change in rate-determining step due to the
different electronic properties of these two anionic nitrogen
ligands.
1
NMR sample tubes. Yields of product were determined by H
NMR spectroscopy with an internal standard.
The reactions of phthalimidates 1a-c with iodoarenes are
summarized in eq 3. The reaction of phen-ligated 1a with 25
equiv of p-tolyl iodide in DMSO formed the coupled product
in 98% yield after 3 h at 120 °C, and the reaction of dtbpy-
ligated 1b occurred in 93% yield after 1.5 h. (Reactions for
these times at lower temperatures occurred to lower conver-
sions.) In contrast, reactions of these complexes with 25 equiv
Bromoarenes reacted much more slowly than iodoarenes. The
reaction of diamine-ligated imidate 1c with p-tolyl bromide in
toluene required 5 h at 25 °C to produce p-tolylphthalimide in
50% yield, whereas the reaction of 1c with p-tolyl iodide in
toluene produced p-tolylphthalimide in 95% yield in 2 h at 25
°C. In contrast to the reaction of 1c with p-tolyl iodide and
bromide, no reaction occurred between 1c and p-tolyl chloride
or p-tolyl triflate (DMSO, 120 °C, 18 h). Amidate complexes
2a and 2b were also less reactive toward bromoarenes than
iodoarenes. In contrast to the high yield of N-aryl pyrrolidinone
from reaction of phen-ligated 2a with 4-iodotoluene, heating
of 2a with p-bromotoluene in DMSO solvent at 110 °C for 3 h
led to 59% conversion of 2a, but no N-(p-tolyl)pyrrolidinone
was formed; in contrast to the reaction of dmeda-ligated 2b with
4-iodotoluene at room temperature, the reaction of 2b with
p-bromotoluene required 6.5 h at 110 °C to form the N-tolyl
product in 94% yield.
of p-tolyl iodide in the less polar THF and benzene solvents
occurred with half-lives of about 3 h at 120 °C. Complex 1c
containing the diamine ligand was more reactive but showed a
similar effect of the rate on the polarity of the solvent. The
reaction of this species with 5 equiv of p-tolyl iodide in DMSO
formed N-(p-tolyl)phthalimide in 95% yield after 2 h at 25 °C,
but the same reaction in THF at 70 °C (in a sealed NMR tube)
for 2 h formed N-(p-tolyl)phthalimide in 78% yield and for 4 h
formed this product in 99% yield. Little reaction occurred over
2 h at 25 °C. Although the yields in THF solvent were lower
than those in DMSO, neither biaryl nor hydrodehalogenated
byproducts were observed in substantial amounts. For example,
reaction of 4-iodo-tert-butylbenzene with 1c in THF formed
75% of the N-arylphthalimide and <2% tert-butylbenzene by
reduction of the halogen, as determined by GC and GC/MS.
Complex 1d containing a diphosphine ligand was much less
reactive than any of the complexes containing dative nitrogen
ligands; its reaction with 4-iodotoluene proceeded to only 50%
conversion in DMSO after 17.5 h at 120 °C and formed no
coupled product.
The reactions of amidates 2a and 2b with iodoarenes are
summarized in eq 4. The reaction of phen-ligated 2a with 5
equiv of p-tolyl iodide in DMSO occurred in 98% yield after
3.3 h at 80 °C or 99% yield after only 20 min at 120 °C. This
reaction is much faster than that of p-tolyl iodide with phen-
ligated 1a containing a phthalimidate, which required 3 h at
120 °C in DMSO to form the coupled product in 98% yield.
The amidate complex 2b ligated by dmeda was more reactive
3.2. Reactions of a Ligandless, Anionic Cu(I) Phthalimidate. One
might expect that the anionic portions of the ionic complexes
containing the nitrogen ligands would be the species that react
with the haloarene because they are unsaturated and electron
rich. Many conflicting conclusions have been drawn on the
relative reactivity of ligandless anionic and neutral copper
alkoxides in the copper-catalyzed coupling of phenoxides and
alkoxides with haloarenes (see section 11 for more details on
these previous studies). To help resolve the issue of the relative
reactivity of anionic and neutral copper(I) complexes with
haloarenes, and to address whether the iodoarene reacts with
-
the anionic CuX2 portions of the ionic complexes containing
the nitrogen ligands or with the neutral LCuX complexes
resulting from comproportionation of the ions, we studied reactions
of p-iodotoluene with the tetraalkylammonium salt of the anionic
copper bis-imidate 3 lacking any dative nitrogen ligand. In contrast
to complexes 1a-c and 2a,b, this ligandless anion did not react
with haloarenes. Despite the unsaturation and anionic charge on
complex 3, this complex by itself was stable toward 25 equiv of
p-iodotoluene in DMSO after 23 h at 120 °C (eq 5).
(37) The 1H NMR spectrum of the phen- and pyrr-ligated 2a alone in DMF-
d7 at-25 °C contained resonances at 3.19 and 1.84 ppm in a 2:4 ratio
for the six protons of the pyrr ligand.
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9975

A R T I C L E S
Tye et al.
Scheme 2
We probed for potential cooperative effects between Lewis
acidic cations and cuprate anions38 to cleave the carbon-halogen
bond in the iodoarene by conducting reactions of anionic 3 with
25 equiv of iodotoluene in the presence and in the absence of alkali
metal cations. The reaction of anionic complex 3 with p-iodotoluene
in DMSO at 120 °C in the presence of added LiBF4 slowly formed
N-(p-tolyl)phthalimide, but this reaction (t1/2 > 5.5 h) was much
slower than the reaction of any of the ligated complexes with this
iodoarene. Likewise, addition of KOTf to the reaction of complex
3 with p-iodotoluene in DMSO at 120 °C led to formation of the
N-arylphthalimide with t1/2 > 9 h. Although the reactions were
faster in the presence of alkali metal cations than in the absence of
the cations, these reactions were much slower than reactions of
the ligated complexes, which occurred with half-lives of minutes
at 120 °C for bpy and phen complexes 1a,b or room temperature
for dmeda complex 1c. As a side note, the rate and yield of the
reactions of the phen-ligated phthalimidate 1a with iodotoluene
were indistinguishable in the presence and in the absence of added
LiBF4.
4. Identity of the Copper Products from Reactions with
Haloarenes. The copper product of the reaction of 1c with p-tolyl
iodide was determined by X-ray diffraction (see Supporting
Information) and independent synthesis. From the reaction of
p-tolyl iodide with 1c, the copper(II) species [Cu(dmeda)2]I2
(4) was formed in 43% isolated yield. The addition of 1 equiv
of the dmeda ligand to this reaction had no effect on the identity
and yield of this complex. We presume that disproportionation
of [Cu(dmeda)I] to form [Cu(dmeda)2]I2 and Cu(0) accounts
for the roughly 50% yield of the Cu(II) species from this
reaction. Clearly, the efficiency of the recycling of the copper
product to Cu(I) imidate and amidate can impact the amount
of copper lying within the catalytic cycle and the observed
kinetic behavior of the catalytic system.
Scheme 3
5. Comparison of Selectivities of Stoichiometric and
Catalytic Reactions. To evaluate the relevance of these isolated
complexes to the amidation and imidation of aryl halides
catalyzed by copper complexes, we compared the relative rates
and selectivities of the catalytic and stoichiometric reactions.
More specifically, we compared the relative reactivity of two
iodoarenes toward the isolated copper complexes to the relative
reactivity of two iodoarenes in catalytic processes. We compared
these relative reactivities to those of pyrrolidinone catalyzed
by CuI alone and the combination of CuI and dmeda or phen
ligands. Most diagnostic were reactions with two sterically
distinct iodoarenes, p-tolyl iodide and o-tolyl iodide.
The relative amounts of the two N-aryl products for three
catalytic systems are shown in Scheme 2. These data show that
the product ratios are distinct for reactions catalyzed by CuI
and for reactions catalyzed by complexes of the two dative
nitrogen ligands. In the absence of added dative ligand, the
reaction conducted with 10 mol % CuI occurred at 80 °C to
yield an approximately 1:1 ratio of N-(p-tolyl)pyrrolidinone and
N-(o-tolyl)pyrrolidinone. The same product ratio was observed
after 1 h and after 5 h. The coupling of pyrrolidinone with p-tolyl
iodide and o-tolyl iodide at 80 °C in DMSO catalyzed by 5
mol % [(phen)2Cu][Cu(pyrr)2] (10 mol % copper) formed N-(p-
tolyl)pyrrolidinone and N-(o-tolyl)pyrrolidinone in an 84:16 ratio
in an overall yield <90% after 5 h. The same reaction catalyzed
by 10 mol % CuI and 20 mol % dmeda gave a 83:17 ratio of
the two products in <80% overall yield. Data obtained after
1 h clearly showed that the reaction catalyzed by CuI without
added ligand was slower than the two reactions conducted with
added ligand.
Data on reactions of the isolated complexes 2a and 2b with
the two haloarenes are shown in Scheme 3. The reaction of
complex 2a at 80 °C with a mixture of p-tolyl iodide and o-tolyl
iodide with 1 equiv of added phen gave N-(p-tolyl)pyrrolidinone
and N-(o-tolyl)pyrrolidinone in a 79:21 ratio and roughly 90%
total yield after 45 min. The 84:16 product ratio observed for
the reactions catalyzed by 5 mol % [(phen)2Cu][Cu(pyrr)2] does
not match precisely the 79:21 ratio observed for the stoichio-
metric reaction, but it is close to this ratio and is far from the
1:1 ratio of products obtained from the reaction catalyzed by
CuI alone.39
The reaction of in situ-generated complex 2b with a mixture
of p-tolyl iodide and o-tolyl iodide at 80 °C formed N-(p-
(39) Reactions with other reagents that would be present in the catalytic
reaction were also investigated. The addition of 9 equiv of pyrroli-
dinone or 19 equiv of K3PO4 formed the two products in ratios of
72:28 and 77:23, respectively.
(40) Enemaerke, R. J.; Christensen, T. B.; Jensen, H.; Daasbjerg, K.
J. Chem. Soc., Perkin Trans. 2 2001, 1620.
(41) Andrieux, C. P.; Saveant, J. M.; Zann, D. New J. Chem. 1984, 8, 107.
(42) Jutand, A.; Negri, S. Eur. J. Org. Chem. 1998, 1811.
(38) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3751.
9
9976 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Cu-Catalyzed Amidation and Imidation of Aryl Halides
A R T I C L E S
Table 1. νCO Values for Nickel Carbonyl Complexes with Ligands
temperatures, and free energies of activation. Reactions of 1a
and 1b were conducted with 5-25 equiv of p-iodotoluene in
DMSO in flame-sealed NMR tubes heated at 120 °C. 1H NMR
spectra were obtained at various time points during the course
of the reaction. Reactions of the copper imidate 1c and copper
amidates 2a,b were conducted with 5 equiv of p-iodotoluene
and p-bromotoluene in both toluene and DMSO solvents.
Complex 2b was freshly generated in situ for each experiment.
The rate constants for reactions of 1c, 2a, and 2b with these
haloarenes at -20 to 85 °C were measured in the NMR
spectrometer probe.
Related to Those in This Work
complex
νCO
ref
(PPh3)2Ni(CO)2
(phen)Ni(CO)2
2,4-Me2bipyNi(CO)2
4,4′-Me2bipyNi(CO)2
1990-2010, 1925-1955
1977-1980, 1897-1915
1982, 1883
a, b, c
a, d
e
1973, 1893
d
a Plankey, B. J.; Rund, J. V. Inorg. Chem. 1979, 18, 957.
b Meriwether, L. S.; Fiene, M. L. J. Am. Chem. Soc. 1959, 81, 4200.
c Tolman, C. A. J. Am. Chem. Soc. 1970, 92, 2956. d Christensen, P. A.;
Hamnett, A.; Higgins, S. J.; Timney, J. A. J. Electroanal. Chem. 1995,
395, 195. e Sieler, J.; Than, N.-N.; Benedix, R.; Dinjus, E.; Walther, D.
Z. Anorg. Allg. Chem. 1985, 522, 131.
All reactions occurred with a smooth first-order exponential
appearance of the organic product. Because this product is
directly related by stoichiometry to the copper reagent in the
presence of excess haloarene, these data indicate that the
reactions are first-order in the starting copper complexes. Similar
first-order rate constants from reactions initiated with much
different concentrations of copper confirmed this first-order
behavior. The order in iodoarene was measured for the reactions
of 1a-c by conducting reactions with varied excess of iodo-
arene. Each reaction was first-order in the iodoarene. This order
in the two reagents might seem unremarkable; however, the first-
order behavior in copper was observed regardless of whether
the reaction was initiated with a complex that was ionic or
neutral in the solid state and whether the reaction was conducted
in a polar solvent in which the complexes contain a large degree
of the ionic structure or in a nonpolar solvent in which the
complexes contain a larger degree of the neutral structure.
The rate laws for reactions of the ionic compounds through
the neutral species initiated as tight ion pairs and as solvent-
separated ions are shown in Schemes 4 and 5, respectively. In
both cases, the reaction is assumed to occur from the neutral
three-coordinate structure because of the lack of reactivity of
[N(n-Bu)4][Cu(phth)2] with iodoarenes. Derivations of these
expressions are provided as Supporting Information. One might
expect that the first-order behavior for reactions starting with
the ionic species in polar solvents requires that the irreversible
step involve the ionic form of the complexes. However, these
rate equations show that the reaction will be first-order in copper
when the two ions are separate species and related in a 1:1
fashion by stoichiometry. Reactions in which a starting tight
ion pair generates two neutral species give rise to a rate equation
that is half-order in copper. Thus, the observation of first-order
behavior in copper implies that the reactions in DMSO, after
dissolution of the added copper species, start from solvent-
separated ion pairs and generate small equilibrium amounts of
the reactive neutral complex.
tolyl)pyrrolidinone and N-(o-anisyl)pyrrolidinone in 60.9 and
15.4% yields after 10 min (ratio of N-(p-tolyl)pyrrolidinone to
N-(o-tolyl)pyrrolidinone is 80:20) (Scheme 3). This value
matches well with the 83:17 selectivity observed for the catalytic
reaction employing 10 mol % CuI and 20 mol % dmeda.
Several sets of conclusions can be drawn from these experi-
ments. First, the rates of the stoichiometric reactions are greater
than those of the catalytic reactions. These data demonstrate
the kinetic competence of each of the isolated species to be
intermediates in the corresponding catalytic process. Second,
the selectivities of the stoichiometric reactions are similar to
those of the catalytic processes. The congruence of these
selectivities provides additional evidence that the copper
complexes characterized in solution are intermediates or lead
to intermediates in the catalytic process. Third, the steric
properties of the phen and dmeda ligands lead to a greater
discrimination of the steric properties of the aryl iodide than
was observed from reactions catalyzed by CuI alone.
6. Effect of Ligand Properties on Reaction Rates. Compari-
sons of the relative rates of reactions of 1a-d and 2a,b allow
one to draw some initial conclusions about the effect of ligand
electronic properties on the rates of the reactions of these
complexes with haloarenes. For reference, Table 1 provides νCO
values for nickel carbonyl complexes containing phen, bpy, and
two PPh3 ligands. These data imply that phenanthroline and bpy
ligands are stronger electron donors than triarylphosphines.
Although (diamine)Ni(CO)2 complexes are not known, we
presume that the alkylamine ligand is a stronger electron donor
than the phen and bpy ligands.
Among the imidate complexes 1a-d, the complexes contain-
ing more-electron-donating dative ligands reacted faster than
those containing less-electron-donating dative ligands. Consis-
tent with the higher νCO values of the PPh3 complex and the
previous slow rates for reactions of PPh3-ligated imidates,21 no
reaction of the copper amidate 1d containing the Xantphos
ligand was observed up to 120 °C for 17.5 h. In addition, a
comparison of the reactivity of complexes 1a and 2a, which
contain the same dative phenanthroline ligand but different
anionic ligands, shows that the complex containing the more-
electron-donating anionic ligand reacts faster.
8. Comparative Reactivities To Probe an Electron-Transfer
Mechanism. The mechanism of carbon-heteroatom bond forma-
tion from copper alkoxides and amides has been proposed in
some cases to occur by radical20,44–46 and in other cases by
nonradical27,47–53 pathways.5,54 The proposed radical mechanism
is triggered by electron transfer from copper to the aryl halide
7. Quantitative Kinetic Studies. Kinetic studies of the stoi-
chiometric reaction of haloarenes with the copper imidates and
amidates were conducted by H NMR spectroscopy to help
determine the identity of the species that reacts with the
haloarene and to provide free energies of activation that can be
compared to the values determined by DFT methods (vide infra).
Table 2 summarizes the observed rate constants, reaction
(44) Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra,
O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565.
(45) Couture, C.; Paine, A. J. Can. J. Chem. 1985, 63, 111.
(46) Arai, S.; Hida, M.; Yamagishi, T. Bull. Chem. Soc. Jpn. 1978, 51,
277.
1
(47) Bethell, D.; Jenkins, I. L.; Quan, P. M. J. Chem. Soc., Perkin Trans.
2 1985, 1789.
(48) Weingarten, H. J. Org. Chem. 1964, 29, 3624.
(49) Cohen, T.; Cristea, I. J. Org. Chem. 1975, 40, 3649.
(50) Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748.
(51) Cohen, T.; Tirpak, J. G. Tetrahedron Lett. 1975, 143.
(52) Cohen, T.; Wood, J.; Dietz, A. G., Jr. Tetrahedron Lett. 1974, 3555.
(43) Takeda, N.; Poliakov, P. V.; Cook, A. R.; Miller, J. R. J. Am. Chem.
Soc. 2004, 126, 4301.
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9977

A R T I C L E S
Tye et al.
Table 2. Rate Constants and Free Energies of Activation for the Reactions of L2CuNRR′ Complexes with 4-Iodotoluene and 4-Bromotoluene
entry
complex
L
NRR′
X in p-TolX
kobs (s-1
)
∆Gq(exp) (kcal/mol)
T (°C)
∆Gq(calc) (kcal/mol)a
solvent
1
2
3
4
5
6
7
8
1a
1b
1c
1c
2a
2b
2b
2b
phen
phth
phth
phth
phth
pyrr
pyrr
pyrr
pyrr
HNAc
iodide
iodide
iodide
bromide
iodide
iodide
iodide
bromide
bromide
iodide
5.4 × 10-4
7.4 × 10-4
5.8 × 10-4
4.1 × 10-4
6.2 × 10-4
1.3 × 10-3
2.8 × 10-3
1.6 × 10-4
29
29
21
26
26
18
18
29
120
120
25
80
85
-20
-20
120
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
1:1 DMF:tol
toluene
toluene (calc)
toluene (calc)
toluene (calc)
toluene (calc)
dtbpy
dmeda
dmeda
phen
dmeda
dmeda
dmeda
eda
25
38
9
29c
45
10
11
12
[Cu(phth)2]-
b
b
120
[Cu(pyrr)2]-
iodide
bromide
42
[Cu(HNAc)2]-
44c
a Computed values for the reaction of respective three coordinate copper complex and phenyl iodide or bromide and incorporate solvent effects using
the CPCM method. b No reaction was observed when [Bu4N][Cu(phth)2] was heated to 120 °C for 24 h in DMSO solvent. c Reference 27.
Scheme 4
Table 3. Reduction Potentials (E0) of Four Haloarenes and
1-Naphthyl Triflate and Rates for Halide Dissociation (kdissoc) from
the Corresponding Radical Anions
Scheme 5
two haloarenes to react with similar rates by an inner sphere
electron-transfer process that forms a free aryl halide radical
anion, particularly if the haloarene interacts through the arene
π-system. Computational studies described later in this paper
imply that coordination of the haloarene to the metal through
the halide and that through the π-system are nearly isoenergetic.
The chloroarene and bromoarenes chosen for this study are
4-chlorobenzonitrile and 1- and 2-bromonaphthalene. The
reduction potentials and rates for halide dissociation of the
corresponding haloarene radical anions, along with values for
bromobenzene as comparison, are shown in Table 3. This table
also shows the potential for reduction of 1-naphthyl triflate,
which forms aryl oxide upon reduction by S-O bond cleavage.42
The rate constants for halide dissociation have been measured
several times,40,41,43 and a range of values are provided in the
table. However, the rate constants measured for chloride
dissociation from the radical anion of 4-chlorobenzonitrile and
for bromide dissociation from 1- and 2-bromonaphthalene are
within a factor of 3 of each other when measured by the same
method.40,41,57
to form a haloarene radical anion, which eliminates the halide
to form a neutral aryl radical. This aryl radical could then
combine with the amidate or imidate ligand to form the organic
product.
To probe for this radical pathway, we conducted experiments
with two aryl halides possessing different electronic properties
and with aryl halides containing radical clocks. In the first set
of experiments, we conducted reactions of copper complexes
with a chloroarene and two bromoarenes chosen to have relative
reduction potentials and reactivities such that the chloroarene
is easier to reduce than the two bromoarenes and has a rate of
dissociation of halide from the radical anion that is similar to
that for dissociation of halide from the two bromoarene radical
anions. If the reactions are initiated by an outer-sphere electron
transfer, then one would expect this chloroarene to react with
similar or faster rates than the bromoarene because of the larger
driving force for reduction of the chloroarene and the connection
between driving force and rates of outer-sphere electron
transfer.55,56 Although less rigorous, one could also expect these
Reactions of 4-chlorobenzonitrile, 1-naphthyl triflate, and the
two bromonaphthalenes with complexes 2a and 2b in DMSO
and toluene, respectively, are shown in Scheme 6. Despite the
more favorable reduction potential of 4-chlorobenzonitrile and
1-naphthyl triflate and the known fast chloride dissociation from
(55) Douglas, B. E.; McDaniel, D. H.; Alexander, J. J. Concepts and Models
in Inorganic Chemistry, 3rd ed.; Wiley: New York, 1993.
(56) Marcus, R. A.; Eyring, H. Annu. ReV. Phys. Chem. 1964, 15, 155.
(57) More recent measurements of the bromide dissociation from bro-
monaphthalene radical anions by pulse radiolysis showed the absolute
rate constants to be larger than those reported in previous studies (see
ref 43). However, the value for dissociation of chloride was not
remeasured, and it is likely to also increase in value because the
assessment of smaller values resulted from technique, not the chemistry
of these haloarene radical anions.
(53) Lewin, A. H.; Zovko, M. J.; Rosewater, W. H.; Cohen, T. Chem.
Commun. 1967, 80.
(54) Lindley, J. Tetrahedron 1984, 40, 1433.
9
9978 J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008

Cu-Catalyzed Amidation and Imidation of Aryl Halides
A R T I C L E S
Scheme 6
with 1 equiv of o-(allyloxy)iodobenzene in DMSO-d6. After
31 h at 110 °C, the product from C-N coupling at the aryl
group formed in 95.5% yield (eq 6). GC and GC/MS analysis
of the reaction mixture revealed a 1.9% yield of phenyl allyl
ether by hydrodehalogenation of the iodoarene. Comparison of
the GC and GC/MS of authentic samples of phenyl allyl ether
and 3-methyl-2,3-dihydrobenzofuran confirmed that no 3-meth-
yl-2,3-dihydrobenzofuran product was formed. The reaction of
pyrrolidinone with o-(allyloxy)iodobenzene, catalyzed by 10 mol
% CuI and 20 mol % dmeda or 20 mol % phen, was also
conducted in DMSO solvent at 110 °C (eq 7). These reactions
formed the product from C-N coupling at the aryl group in
>90% yield and phenyl allyl ether by hydrodeiodination in <2%
yield. Again, no products from cyclization were detected. Thus,
neither the stoichiometric or catalytic reactions yielded the
products that one would expect from reaction through a free
aryl radical. The absence of this product with detection limits
of >100:1 implies that the rate constant for recombination of
the aryl radical with the amidate or imidate ligand from within
the solvent cage would have to be >1012 s-1
.
the reduced chloroarene, these reagents reacted with 2a and 2b
much more slowly than did 1- or 2-bromonaphthalene. Heating
of these complexes with the chloroarene or 1-naphthyl triflate
at 110 °C for 2 h led to decomposition identical to that seen in
the absence of the haloarene; no observable N-arylpyrrolidinone
was formed. No naphthol was detected from the reaction of in
situ-generated 2b with the aryl triflate. In contrast, the bro-
monaphthalenes reacted with these complexes in each case
tested. Phen-ligated 2a reacted with 1-bromonaphthalene in
DMSO at 110 °C after 2 h to form the N-aryl product in 34%
yield.58 The dmeda-ligated 2b reacted with 1-bromonaphthalene
in toluene at 110 °C after 2 h to form the N-aryl product in
97% yield and with 2-bromonaphthalene under the same
conditions to form the N-aryl product in 65% yield. These data
argue against a reaction mechanism that would be initiated by
outer-sphere electron transfer.
In a second set of experiments, the intermediacy of an aryl
radical was probed by conducting reactions with an aryl halide
linked to an olefin that serves as a radical clock. The aryl radical
that would be generated from o-(allyloxy)iodobenzene is known
to undergo cyclization to yield the 2,3-dihydrobenzofuranyl-
methyl radical with a rate constant of 9.6 × 109 s-1 in DMSO
and 7.87 × 107 s-1 in hexane.59,60 The resulting methyl radical
can then abstract hydrogen from the solvent, can dimerize, or
could combine with the amidate or imidate ligand to form a
C-N bond.
9. Computed Barriers for Oxidative Addition of
Iodobenzene and Bromobenzene to 1c and 2b. The free energies
of activation for the oxidative addition of bromobenzene and
iodobenzene to a series of neutral, three-coordinate and monoan-
ionic, two-coordinate copper complexes by two-electron pro-
cesses have been computed, and these results are summarized
in Table 2. We have employed the B3LYP functional as
implemented in Gaussian 0361 and the conductor-like polarizable
contiuum model (CPCM) to model the toluene solvent. The free
energies of activation are determined from the free energy of
the geometry-optimized transition-state structure for C-X
cleavage versus the sum of the free energies of the starting
copper complex and haloarene, as shown in Figure 2. For
computational efficiency, the p-tolyl group of the haloarene was
abbreviated to a phenyl group. We computed the barriers for
addition of iodobenzene to the neutral, ligated [(dmeda)Cu(pyrr)]
for which we have kinetic data, the [Cu(phth)2]- anion that did
not react with iodotoluene, and the analogous bis-pyrrolidinonate
complex ([Cu(pyrr)2])-. Zhang et al. recently reported calcula-
tions of the free energy barriers for the reaction of [(eda)Cu-
(NHAc)] (eda ) ethylenediamine) and [Cu(NHAc)2]- with
bromobenzene by DFT methods.27
To use this substrate to probe for aryl radicals in the copper-
catalyzed couplings, [(phen)2Cu][Cu(pyrr)2] was allowed to react
(59) Abeywickrema, A. N.; Beckwith, A. L. J. Chem. Commun. 1986, 464.
(60) Annunziata, A.; Galli, C.; Marinelli, M.; Pau, T. Eur. J. Org. Chem.
2001, 1323.
(58) It was difficult to monitor the conversion of the copper complex due
to the accumulation of paramagnetic materials during the reaction.
However, this reaction formed 38% of the N-aryl product after 7 h.
Thus, the yield after 2 h reflects nearly full conversion of the copper.
(61) All calculations were carried out with the Gaussian 03 program: Frisch,
M. J.; et al. Gaussian 03, revision C.02; Gaussian Inc.: Wallingford,
CT, 2004 See Supporting Information for the full reference.
9
J. AM. CHEM. SOC. VOL. 130, NO. 30, 2008 9979

A R T I C L E S
Tye et al.
well with our calculations, although the modeled system is
somewhat different from the actual system for which free energy
barriers have been measured experimentally. The reaction of
(eda)Cu(NHAc) (eda ) ethlyenediamine) with PhBr to yield
(eda)Cu(NHAc)(Ph)(Br) was calculated to have a free energy
barrier of 29 kcal/mol (with free energy difference of 23 kcal/
mol between the reactants and five-coordinate neutral product)
at 25 °C, and the reaction of (dmeda)Cu(NHAc) with PhBr to
yield (dmeda)Cu(NHAc)(Ph)(Br) was calculated to have a free
energy barrier of 30 kcal/mol in toluene at 25 °C. This barrier
is essentially identical to the free energy of activation we
calculate for the reaction of bromobenzene with [(dmeda)Cu-
(pyrr)], which is the same compound studied experimentally,
at 25 °C using our computed activation parameters.
10. Mechanism of the C-N Bond Formation. Three classes
of potential mechanisms for the reactions of these copper
amidate and imidate complexes with iodoarenes are shown in
Scheme 7. In pathway A, the ionic complex reacts directly with
the haloarene to form a four-coordinate, anionic oxidative
addition product. This pathway was proposed for reactions of
haloarenes with copper alkoxides,44,48 and it draws analogies
to the proposed pathway for oxidative addition of haloarenes
to anionic Pd(0).63,64
Pathways B and C involve reaction of the haloarene with
the three-coordinate, neutral Cu(I) species. Path B involves
initial electron transfer, followed by extrusion of halide. In the
sequence shown, recombination of the resulting aryl radical with
the Cu(II) center occurs to generate a cationic arylcopper(III)
imidate or amidate complex that eliminates coupled product.
Comproportionation of the copper(II) species [LCuI(NR2)] with
copper(0) could then generate an LCuI product and regenerate
one of the two equivalents of the LCu(NR2) reactant.65
Pathway C involves coordination of the haloarene to the
copper amidate or imidate complex, followed by oxidative
addition to form a Cu(III) intermediate. This oxidative addition
could occur by several pathways, including direct expulsion of
the halide to generate a four-coordinate cationic species, inner-
sphere electron transfer followed by collapse of the resulting
intermediate to form a neutral, five-coordinate Cu(III) species
without dissociation of an aryl radical, or concerted insertion
of copper into the carbon-halogen bond.
Figure 2. DFT-computed free energies in toluene solvent using the CPCM
solvent model. Energies are relative to separate copper complex and
halobenzene and are given in kcal/mol.
The computed barriers for reactions of iodobenzene with
[Cu(phth)2]- (anionic portion of 3) are much higher than the
barriers for reaction with the three-coordinate neutral species
(vide infra). The computed free energy barrier for the oxidative
addition of PhI to [Cu(phth)2]- to give [Cu(phth)2(Ph)(I)]- in
toluene solvent was 45 kcal/mol. Much of the high barrier is
due to the unfavorable thermodynamics for binding of the arene
to the anionic, two-coordinate species and for addition of the
iodoarene to form the anionic four-coordinate intermediate. For
example, an η2-arene complex is computed to lie 41 kcal/mol
uphill, and the initial, four-coordinate, anionic addition product
[Cu(phth)2(Ph)(I)]- is computed to lie 44 kcal/mol uphill in free
energy compared to the separate reactants. Zhang et al.
computed a free energy barrier of 44 kcal/mol for oxidative
addition of PhBr to [Cu(NHAc)2]- to give [Cu(NHAc)2-
(Ph)(Br)]- in toluene solvent.27 In this case, the oxidative
addition product [Cu(NHAc)2(Ph)(Br)]- was calculated to be
37 kcal/mol less stable than the separate reactants.
Calculations of the energies for oxidative addition of bro-
mobenzene and iodobenzene to the neutral forms of the isolated
copper complexes provide insight into the potential intermediacy
of arylcopper(III) intermediates. The enthalpy for oxidative
addition of iodobenzene to [(dmeda)Cu(pyrr)], a reaction we
studied experimentally, was calculated to be only 2 kcal/mol,
and the free energy for oxidative addition was calculated to be
15 kcal/mol. The analogous values for oxidative addition of
bromobenzene were calculated to be 10 and 28 kcal/mol. These
data imply that the Cu(III) intermediates lie uphill of the Cu(I)
complex and free aryl halide, but that the Cu(III) species lie at
energies that are accessible under mild conditions.
The absence of any reactivity of iodotoluene with the isolated
anionic copper bis-imidate complex [N(n-Bu)4][Cu(phth)2]
(described in section 3.1) and the high computed barrier for
addition of iodobenzene to these two-coordinate, anionic copper
amidates argue against reaction by pathway A. If the reaction
occurred by pathway A, then one would expect [N(n-
Bu)4][Cu(phth)2] to react with the haloarene under mild condi-
tions. Instead, this anionic complex was stable toward an excess
of p-iodotoluene in DMSO, even after hours at 120 °C (eq 5).
We also calculated the barriers for these two oxidative
addition processes. The enthalpy of activation for oxidative
addition of iodobenzene to [(dmeda)Cu(pyrr)] was calculated
to be 6 kcal/mol, and the free energy of activation was calculated
to be 25 kcal/mol at 25 °C. The activation energies for the
analogous reaction of [(dmeda)Cu(pyrr)] with bromobenzene
in toluene were calculated to be 9 and 38 kcal/mol at the 120
°C temperature of the experiment. Although these barriers are
7-9 kcal/mol higher than the 18 and 29 and kcal/mol barriers
determined from the experimental kinetic data, these values
agree reasonably when considering the uncertainties of the
continuum solvent models and computed entropies.62
(62) Alternatively, a lower energy pathway to the Cu(III) species could
involve an intimate electron-transfer process prior to formation of the
Cu(III) species without generation of a free aryl halide radical anion
or aryl radical. Calculations of mechanisms involving diradical
intermediates are challenging, and we have not been able to optimize
either singlet or triplet structures in which an unpaired electron is
located on the iodoarene.
(63) Goossen, L. J.; Koley, D.; Hermann, H. L.; Thiel, W. Organometallics
2005, 24, 2398.
(64) Senn, H. M.; Ziegler, T. Organometallics 2004, 23, 2980.
(65) As noted by one reviewer, there are many possible pathways related
to this one, such as the reaction of a second copper(I) amidate complex
with the aryl radical to generate a copper(II) complex of the form
(L)CuII(NR2)(Ar) that reductively eliminates ArNR2 to generate
copper(0).
The barriers calculated by Zhang et al.27 for oxidative addition
of bromobenzene using PCM to model the toluene solvent fit
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Cu-Catalyzed Amidation and Imidation of Aryl Halides
A R T I C L E S
Scheme 7
Consistent with this observation, the barrier we computed for
reaction of this anion with iodobenzene was 39 kcal/mol in the
gas phase and 45-47 kcal/mol in toluene or DMSO solvent.
Apparently, the linear, two-coordinate anion alone is not
capable of reacting with the haloarene, even though it is
unsaturated and electron rich. This observation is counterintui-
tive, but it is consistent with several pieces of prior data. One
set of results showed that the coupling of potassium phthalimide
with iodoarenes or bromoarenes, catalyzed by CuBr, occurred
faster when a 1:1 ratio of potassium phthalimide to copper was
used, although the actual copper species in these systems were
not identified.66 More recently, Karlin has shown that three-
coordinate Cu(I) complexes undergo air oxidation much faster
than linear two-coordinate Cu(I) complexes.67
Computational studies on the reactions of dialkyl cuprates
with alkyl halides have suggested that alkali metal cations
capable of binding halide lower the reaction barrier for
carbon-halogen bond cleavage.68 These studies could imply
that the absence of a Lewis acidic cation in [Bu4N][Cu(phth)2]
creates the high barrier for reactions of this species with aryl
halides. However, such a proposal is not consistent with relative
rate data for reactions of haloarenes with the isolated ligated
species and with the anion 3 in the presence of added alkali
metal cations, and it is not consistent with the high computed
energy of binding of a haloarene to the anionic Cu(phth)2-. First,
we showed that the reactions of the ligated complexes were
faster than those of the Bu4N+ salt of cuprate 3 in the presence
of added alkali metal cation, even though the saturated L2Cu+
cation (L ) bpy, phen, dmeda) is less likely than an alkali metal
cation to bind halide. Second, we showed that added LiBF4 does
not affect the reaction of iodotoluene with 1a. Third, the
computed energy for binding of the aryl halide to the anionic
species that would precede C-X bond cleavage is higher than
the overall barrier for the reaction of the ligated species 1a-d
and 2a,b measured experimentally. Thus, mechanisms for
cleavage of the aryl halide by cooperative reactivity of the anion
and cation of the ionic form of the ligated complexes should
be considered but are not consistent with our current data.
Several lines of kinetic data argue against reaction by the
family of steps initiated by electron transfer and followed by
dissociation of halide from the haloarene radical anion (pathway
B). First, the absence of biaryl products or substantial amounts
of arenes from hydrodehalogenation formed in solvents pos-
sessing relatively weak C-H bonds argues against the inter-
mediacy of free or caged phenyl radicals. The strengths of the
weakest C-H bonds of the toluene, DMSO, and THF solvents
used in these studies are between 88 and 94 kcal/mol,69 and
the rate of hydrogen atom abstraction of aryl radicals from
DMSO is on the order of 106-107 s-1 70
.
Second, an aryl chloride and an aryl triflate possessing a more
positive reduction potential and a fast rate for chloride dissocia-
tion or X-O bond cleavage from the radical anion were shown
to react with the copper amidate and imidate complexes much
more slowly than bromoarenes possessing more negative
reduction potentials and similar rates for halide dissociation.
Third, a substrate containing an ortho allyloxy group did not
undergo cyclization, and the lack of cyclized products indicates
that any aryl radical must combine with a copper amide with a
rate constant of >1012 s-1. In other words, the recombination
must occur with a half-life close to the time scale of a vibration,
and this fast rate seems unlikely to occur in a system requiring
such reorganization. Altogether, these data argue strongly against
the intermediacy of free aryl radical intermediates. Thus, we
conclude that the carbon-halogen bond is cleaved within the
coordination sphere of the metal.
11. Comparison of the Mechanistic Data and Conclusions
to Those of Previous Studies. The data and conclusions from
this work can be compared and contrasted to those of several
previous studies of the mechanism of copper-mediated coupling
processes. Much of this early work led to different mechanistic
(66) Bacon, R. G. R.; Karim, A. J. Chem. Soc., Perkin Trans. 1 1973,
272.
(67) Himes, R. A.; Park, G. Y.; Barry, A. N.; Blackburn, N. J.; Karlin,
K. D. J. Am. Chem. Soc. 2007, 129, 5352.
(68) (a) Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000,
122, 7294. (b) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem.
Soc. 1998, 120, 8273.
(70) (a) M’Halla, F.; Pinson, J.; Saveant, J. M. J. Am. Chem. Soc. 1980,
102, 4120. (b) Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. J.
Org. Chem. 1987, 52, 4072. (c) Branchi, B.; Galli, C.; Gentili, P. Eur.
J. Org. Chem. 2002, 2844.
(69) Luo, Y. R. Handbook of Dissociation Energies in Organic Compounds;
CRC Press: Boca Raton, FL, 2003.
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A R T I C L E S
Tye et al.
proposals about the coordination number and charge of the
copper species that reacts with the haloarene, the presence or
absence of an arylcopper intermediate, the oxidation state of
an arylcopper intermediate, the potential intermediacy of aryl
radicals during the C-X activation step, and the possibility that
electron transfer initiates the C-X bond cleavage.54 The
relationship between our data and previous data on these issues
is discussed in this section.
The coordination number and charge of the reactive species
in ligandless copper-catalyzed reactions have been ambiguous.
Several studies have drawn different conclusions about the active
species in couplings to form the C-O bond in aryl ethers.
Weingarten proposed that the reaction of bromobenzene with
sodium phenoxide occurred through the two-coordinate, anionic
[Cu(OPh)2]-.48 A few years later, van Koten and co-workers
proposed that the reaction of copper(I) alkoxides with PhBr
occurred through a similar [Cu(OMe)2]- intermediate.44 How-
ever, Whitesides and co-workers generated a series of copper(I)
alkoxides that were shown by protonolysis to contain a 1:1 ratio
of copper to alkoxide, and these species reacted under mild
conditions with haloarenes to yield C-O coupled products.71
Thus, it is unclear from these studies if the active species in
these reactions contain a Cu:OR ratio of 1:1 or 1:2.
Fewer data were available on the relative reactivity of
haloarenes with anionic versus neutral copper complexes
containing anionic nitrogen ligands. Most recently, a mechanism
in which the haloarene reacts through a diamine-ligated copper
amidate complex containing a Cu:NR2 ratio of 1:1 was deduced
from kinetic data,26 but isolated compounds were not studied,
and the anionic species was not generated independently.
Moreover, Yamamoto’s isolated neutral, PPh3-ligated copper
amidate and imidate complexes reacted only at high tempera-
tures.21 During studies of related ligandless copper-catalyzed
imidation of bromoarenes, Bacon and Karim showed that a 1:1
ratio of copper iodide to phthalimide led to the fastest formation
of N-arylphthalimide product, but no copper complexes in this
reaction were identified.66 We have now shown clearly by
experiments with fully characterized compounds that two-
coordinate imidates alone react with haloarenes more slowly
than neutral, three-coordinate imidates.
Other proposals involve formation of π-bound aryl halide
radical anions. In the mid 1980s, Paine reported mechanistic
data on C-N coupling reactions catalyzed by “ligandless”
copper(I).20,45 This author suggested that the C-X cleavage of
aryl halides by copper(I) catalysts proceeds by binding of Cu
to the π system of the haloarene to form an η2-arene complex,
followed by electron transfer to the arene and dissociation of
iodide. Van Koten and co-workers also proposed that the
reaction of potassium methoxide with bromoarenes occurs
through a π-bound aryl radical. They concluded that this reaction
proceeds by binding of the halide atom of the aryl halide to
[Cu(OMe)2]-, followed by transfer of electron density to the
haloarene to form an aryl halide radical anion that remains
directly bound to the copper center.
Others have proposed the intermediacy of Cu(III) complexes.
Cohen and co-workers have many times proposed mechanisms
forcopper-catalyzedcouplingthrougharylcopper(III)complexes.49–53
Most recently, alkylcopper(III) species have been observed
directly during the reactions of cuprates with alkyl iodides.72
We have provided strong evidence against the intermediacy
of free aryl radicals during reaction of haloarenes with the
copper amidate and imidate complexes of this study. The
absence of significant quantities of biaryl or arene products from
reactions of the copper amidate and imidate complexes in
solvents that can act as hydrogen atom donors provides some
evidence against the intermediacy of aryl radicals. The relative
rates for reactions of different haloarenes further argued against
mechanisms involving outer-sphere electron transfer to form
haloarene radical anions, and the clean formation of aromatic
C-N bonds by reactions of o-(allyloxy)iodobenzene provided
particularly strong evidence against the generation of free aryl
radicals.
It is challenging to rigorously distinguish between direct
oxidative addition without formation of copper(II) intermediates
and stepwise oxidative addition initiated by intimate electron
transfer. However, the greater dependence of the reaction rates
on the identity of the halogen than on the reduction potential
of the haloarene provides some evidence against a mechanism
initiated by electron transfer to the type of π-arene complex
proposed in previous work.20,45
Some of the studies that take into consideration the presence
or absence of radical intermediates are summarized in a recent
review on copper-catalyzed couplings.5 Van Koten and co-
workers stated that addition of the radical scavenger 1,3-
dinitrobenzene completely inhibited CuBr-catalyzed C-O bond
formation between NaOMe and bromobenzene.44 Moreover,
Arai et al. observed a stable quinone radical from reaction of
2-aminoethanol with 1-bromoanthraquinone, catalyzed by CuBr,
and used these data to support reaction by an electron-transfer
pathway.46 However, the reduction potentials of dinitrobenzene
and of a haloquinone are much less negative than those of the
more electron-rich arenes in our study, and the stability of the
aryl radical resulting from reduction of the haloquinone is much
greater than that of the more electron-rich haloarenes. Thus,
the data of van Koten and Arai are not directly relevant to the
mechanism of the reactions reported here. Moreover, Bethell
et al. more recently did not observe radical intermediates in the
reaction of primary alkyl amines, benzyl amine, and aniline with
1-halogenoanthraquinones, and they observed little hydrodeha-
logenated product.47
Summary
In summary, we have isolated copper imidate and amidate
complexes that are kinetically and chemically competent to be
intermediates in the copper-catalyzed amidation and imidation
of aryl halides and that appear to exist in an unexpected ionic
form in solvents more polar than hydrocarbons. A set of
complexes with varied dative and neutral ligands has allowed
us to probe the effect of the reactive and ancillary ligands on
the rates of these reactions. The complexes with the more
electron-rich anionic and dative ligands react faster. Reactions
conducted in different media show that the rate of formation of
the C-N coupled product from the phthalimidate complexes is
much faster in more polar solvents, while the rate of formation
of the C-N coupled product from the pyrrolidinonate complexes
is only slightly faster in more polar solvents. Studies on the
effect of the electronic properties of the haloarene, in particular
the contrast between the lack of reaction of electron-poor
chloroarenes and the high-yield reactions of more electron-rich
bromoarenes, argue against pathways that involve electron
(71) Whitesides, G. M.; Sadowski, J. S.; Lilburn, J. J. Am. Chem. Soc.
1974, 96, 2829.
(72) Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor, B. J. J. Am.
Chem. Soc. 2007, 129, 7208.
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A R T I C L E S
transfer and halide dissociation from the resulting radical anion,
and reactions of aryl iodides containing a radical clock argue
against the generation of free aryl radicals. Arylcopper(III)
intermediates containing dative nitrogen ligands are calculated
to be kinetically accessible under mild conditions, and such
species could be formed by a concerted oxidative addition or
by internal electron transfer and formation of an arylcopper
species within the coordination sphere of the metal. Overall,
the isolation and full characterization of the solid-state and
solution-phase structures of ligated copper amidates and imi-
dates, in combination with quantitative studies on the reactivity
of these species with a variety of haloarenes, has begun to
provide kinetic benchmarks and structural data that should help
to clarify some of the mechanistic questions on the reactions
of aromatic electrophiles with copper compounds containing
anionic nitrogen and oxygen ligands.
Acknowledgment. We thank the NIH NIGMS (GM-55382) for
support of this work.
Supporting Information Available: Experimental procedures,
characterization of products, computational details, and full
citation for the Gaussian 03 program (ref 61). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA076668W
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