A copper(ii) complex as an intermediate of copper(i)-catalyzed C-N cross coupling of N-phenylaniline with aryl halide by in situ ESI-MS study

Article abstract of DOI:10.1039/c1cc11906k

Complexes [Cu(NPh₂)₂]^-, [Cu(NPh ₂)I]^- and K[Cu(phen)(NPh₂) (p-tolyl)] ⁺ were observed by in situ electrospray ionization mass spectrometry (ESI-MS) analysis of the copper(i)-cata

Full text of DOI:10.1039/c1cc11906k

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A copper(II) complex as an intermediate of copper(I)-catalyzed C–N
cross coupling of N-phenylaniline with aryl halide by in situ ESI-MS
studyw
Chia-Kai Tseng,ab Mei-Chun Tseng,a Chien-Chung Han*b and Shin-Guang Shyu*a
Received 4th April 2011, Accepted 19th April 2011
DOI: 10.1039/c1cc11906k
Complexes [Cu(NPh2)2]À, [Cu(NPh2)I]À and K[Cu(phen)(NPh2)
(p-tolyl)]+ were observed by in situ electrospray ionization mass
spectrometry (ESI-MS) analysis of the copper(I)-catalyzed C–N
coupling reaction under the catalytic reaction condition indicating
that they are intermediates in the reaction. A catalytic cycle
composed of a free radical path and a 2e oxidative addition path
is proposed based on these observations.
reaction. Oxidative addition intermediates [Cu(NPh2)I]À and
Na[Cu(NPh2)2(p-tolyl)]+ were observed in the spectra, and a
2e oxidative mechanism was proposed.10 Among all these
studies, the role of the ligand is still unclear, and the influence
of base is seldom addressed. We herein report a mixed base
(tBuONa/K2CO3) copper(I)-catalyzed C–N coupling reaction
which has a higher than double catalytic reactivity than that
of using only tBuONa as the base. In situ ESI-MS analysis of
the catalytic system under the catalytic reaction conditions
reveals the presence of [Cu(NPh2)2]À, [Cu(NPh2)I]À and
K[Cu(phen)(NPh2)(p-tolyl)]+ in the reaction system indicating
that they are intermediates in the reaction. Based on these
observations, a reaction mechanism composed of a free radical
path and a 2e oxidative addition path is proposed.
We followed the procedure reported in the literature11 to
investigate the copper-catalyzed C–N coupling reaction
between aryl iodide and amine (N-phenylaniline). A mixture
of N-phenylaniline (1.2 equiv.), 4-iodotoluene (1 equiv.), base
(3 equiv.), CuI (10 mol%) and phen (30 mol%) was allowed to
stir in toluene at 120 1C for 6 h. The results of the reactions are
summarized in Table 1.
Catalytic C–N coupling reactions using a Cu-catalyzed
process have been intensively studied due to its economic
attractiveness, low toxicity, and air and moisture stability.1
Copper(I)-catalyzed C–N cross coupling reaction usually
consists of a ligand, a base and a copper salt.2 In addition,
Cu complexes with various ligands were synthesized, which
served as the catalytic center in the catalytic system.3 In
general, a better yield of the reaction can be obtained when
a ligand is present, and different ligands may have different
catalytic activities.4 Thus, Cu(I) complex with the additive
ligand is generally proposed as the intermediate of the catalytic
reaction.5 During the copper-catalyzed C–N coupling reaction,
the proton of the amide may be removed by the base to
generate an amido anion, which may then replace the counter
anion of the copper source and produce a copper complex with
the amido ligand Cu(I)L(NR2).2a,b,5a Oxidative addition of the
aryl halide (ArI) to the complex produces Cu(III)LArI(NR2)
which regenerates the Cu(I)LI and the desired product ArNR2
through reductive elimination.6 Complexes with the corres-
ponding amido ligand have been prepared, and their catalytic
activities have been evaluated.7 A free radical path has also
been proposed based on the theoretical study,8 however, DFT
calculations also support the 2e oxidative addition path.9
Recently, copper(I) complex [Na(phen)3][Cu(NPh2)2] was isolated
from the catalytic system, and an in situ ESI-MS study
revealed that [Cu(NPh2)2]À is the active species for the
Accidentally, we discovered that by adding 1 equiv. of
K2CO3 into the CuI-phen-tBuONa catalytic system, the yield
and the selectivity of the reaction can be enhanced up to over
140% and 15%, respectively, as compared with the case of
using tBuONa as the sole base. This enhancement may be due
to the cation exchange between K2CO3 and tBuONa such that
tBuOK was generated in situ in the reaction system. In order
to verify this possibility, reaction using 3 equiv. of tBuOK was
carried out under similar reaction conditions. Although the
yield (product yield 75%) is better than that of the pure
tBuONa system, both the yield and selectivity (75%) are
inferior to that of the mixed base system (2 equiv. tBuONa/1
equiv. K2CO3). The differences in reactivity and selectivity
may imply that the mechanisms of the reactions in different
base systems are different. In order to evaluate this possibility,
in situ ESI-MS analyses were carried out in order to trap the
intermediates in the catalytic reaction.
a Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan,
Republic of China. E-mail: sgshyu@chem.sinica.edu.tw;
Fax: +886-2-2783-1237; Tel: +886-2-2789-8593
b Department of Chemistry, National Tsing Hua University, Hsinchu,
Taiwan, Republic of China. E-mail: cchan@mx.nthu.edu.tw;
Fax: +886-3-5711082; Tel: +886-3-5724998
Since the catalytic reactions were carried out at 120 1C,
in situ ESI-MS analyses were carried out at 120 1C in order to
detect the intermediates (Fig. 1). Similar reaction mixture in
toluene was stirred at 120 1C for 2 h. The solution was then
transferred to a GC vial in a dry box. The temperature of the
w Electronic supplementary information (ESI) available: Experimental
data, in situ ESI-MS spectra and isotope distribution of the inter-
mediates. See DOI: 10.1039/c1cc11906k
c
6686 Chem. Commun., 2011, 47, 6686–6688
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Table 1 Cu(I) catalyzed C–N coupling reaction with different base systemsa
Radical scavengerb
tBuONac
tBuONa/K2CO3
tBuONa/K2CO3
d
e
Entry
1
2
3
—
20 mol%
100 mol%
46f/38g(83%)h
50/38(76%)
53/35(66%)
95/93(98%)
88/85(97%)
80/64(80%)
17/17(100%)
23/16(70%)
42/18(43%)
a
b
1.0 mmol 4-iodotoluene, 1.2 mmol N-phenylaniline, 4 mL toluene, 0.1 mmol CuI, 0.3 mmol phen. TEMPO. 3 mmol tBuONa. tBuONa/
c
d
e
f
g
K2CO3 (2 mmol/1 mmol). Without phen. Conversion yield based on aryl iodide. GC yields based on aryl iodide. Selectivity.
h
A p-tolyl free radical [CH3C6H4]ꢀ may be formed Àby the
transformation from the radical anions [CH3C6H4I]ꢀ upon
reaction between 4-iodotoluene and the single electron donor,
sodium tert-butoxide, because metal tert-butoxide was
reported to act as a single electron donor toward alkyl
iodide.12 In addition, the presence of [Cu(phen)2]+ and
[Cu(NPh2)2]À indicates the formation of [Cu(phen)2]-
[Cu(NPh2)2] in the reaction. This Cu(I) complex may form
two equiv. of Cu(phen)(NPh2) in the reaction because it has
been reported that in polar solvent (DMF) at À25 1C,
Cu(phen)(phth) and Cu(phen)(pyrr) can form [Cu(phen)2]-
[Cu(phth)2] (phth
=
phthalimidate) and [Cu(phen)2]-
[Cu(pyrr)2] (pyrr = pyrrolidinonate) correspondingly. Thus,
the p-tolyl free radical [CH3C6H4]ꢀ reacts with the
Cu(phen)(NPh2) to form [Cu(phen)(NPh2)(p-tolyl)].7a
Based on these observations, a catalytic cycle composed of
two catalytic paths is proposed and shown in Scheme 1.
Although we did not observe the intermediate Na[Cu(NPh2)2-
(p-tolyl)]+ or [Cu(NPh2)2(p-tolyl)I]À, the presence of
[Cu(NPh2)I]À implies that the 2e oxidative addition path
may involve in the reaction mechanism.10 Complex
[Cu(NPh2)2]À was generated by the reaction among 4-iodo-
toluene, metal (sodium or potassium) tert-butoxide and CuI.
4-Iodotoluene then reacts with [Cu(NPh2)2]À to form A
through oxidative addition reaction. Reductive elimination
of 4-methyl-N,N-diphenylaniline produces [Cu(NPh2)I]À. It
À
further reacts with NPh2 to produce [Cu(NPh2)2]À and
Fig. 1 ESI(+)(À)-MS from the reaction solution taken during the
reaction of 4-iodotoluene, N-phenylaniline with tBuONa/K2CO3 in
the presence of CuI and phen in toluene at 120 1C.
completes the 2e oxidative addition catalytic cycle. During
the reaction, redistribution of phen among metal cations
occurred as indicated by the observation of [Cu(phen)2]+
and [Na(phen)2]+ in the spectra. Likewise, the ligand redis-
tribution reaction between [Cu(NPh2)2]À and [Cu(phen)2]+
produces complex Cu(phen)(NPh2), possibly in an equilibrium
fashion. Addition of the p-tolyl free radical to the complex
solution was kept at 120 1C by immersing the GC vial in a
sand bed, and ESI-MS spectra of the solution were taken. The
ESI-MS in negative-ion mode showed two peaks at m/z =
399.1 and m/z = 357.9 which are identified as [Cu(NPh2)2]À
and [Cu(NPh2)I]À correspondingly according to their isotope
distributions.w
Peaks at m/z = 423.1 and m/z = 383.1 corresponding
to [Cu(phen)2]+ and [Na(phen)2]+, respectively, were also
observed in the positive-ion mode of ESI-MS indicating that
ligand redistribution had occurred under the catalytic reaction
condition. In addition, we observed a peak at m/z = 541.1
corresponding to K[Cu(phen)(NPh2)(p-tolyl)]+, and its isotope
distribution is consistent with the assignment.w
generates a Cu(II) complex [Cu(phen)(NPh2)(p-tolyl)]. After
+
reductive elimination and reaction with the [tBuONa(phen)]ꢀ
,
4-methyl-N,N-diphenylaniline is produced, and the [Cu(I)phen]+
À
reacts with NPh2 to form Cu(phen)(NPh2) and completes the
catalytic cycle.
In order to confirm the existence of the free radical path and
to evaluate which reaction path dominates the reaction, a free
radical scavenger was applied to the reaction. When 20 mol%
of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added
to the reaction system, the yield of the reaction reduced from
93% to 85%; if 100 mol% of scavenger was added, the yield
reduced to 64% (Table 1). These observations further support
The formation of the Cu(II) complex [Cu(phen)(NPh2)-
(p-tolyl)], a portion of K[Cu(phen)(NPh2)(p-tolyl)]+, implies
that a radical path is involved in the reaction mechanism.
c
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Scheme 1 The proposed catalytic cycle.
the existence of the free radical path. In addition, the 32%
yield reduction (as compared to the yield without TEMPO)
after adding TEMPO may indicate that the free radical path
contributes one third of the whole catalytic reaction. When
TEMPO was added to the catalytic system with pure tBuONa
as the base, no yield reduction was observed for the 20 mol%
addition, and only 7% yield reduction was observed for
100 mol% TEMPO addition. This indicates that a free radical
path contributes only a very small fraction of the catalytic
reaction in the pure tBuONa system.
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We are grateful to the National Science Council, Republic of
China, and Academia Sinica for financial support of this work.
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6688 Chem. Commun., 2011, 47, 6686–6688
This journal is The Royal Society of Chemistry 2011