On the nature of the 'heterogeneous' catalyst: Nickel-on-charcoal

Article abstract of DOI:10.1021/jo020296m

Results from aromatic aminations and Kumada couplings, together with spectroscopic analyses (TEM, EDX, ICP-AES, React-IR), reveal that catalysis using nickel-on-charcoal (Ni/C) is most likely of a homogeneous rather than heterogeneous nature. In the course of a reaction with Ni/C, nickel bleed from the support was calculated to be as high as 78%. However, the existence of an equilibrium for this homogeneous species between nickel located inside vs outside the pore system of charcoal strongly favors the former, thus leaving only traces of metal detectable in solution. This accounts for virtually complete recovery of nickel on the charcoal following filtration of a reaction mixture and allows for recycling of the catalyst. TEM and EDX data were used to explain different reactivity profiles of Ni/C, which depended upon the method of reduction used to convert Ni(II)/C to Ni(0) as well as the level of nickel loading on the support.

Full text of DOI:10.1021/jo020296m

VOLUME 68, NUMBER 4
FEBRUARY 21, 2003
© Copyright 2003 by the American Chemical Society
On th e Na tu r e of th e ‘Heter ogen eou s’ Ca ta lyst:
Nick el-on -Ch a r coa l
Bruce H. Lipshutz,*,†,‡ Stefan Tasler,† Will Chrisman,† Bernd Spliethoff,§ and Bernd Tesche*,§
Department of Chemistry & Biochemistry, University of California,
Santa Barbara, California 93106-9510 and Max-Planck-Institut fu¨r Kohlenforschung,
Elektronenmikroskopie, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim an der Ruhr, Germany
lipshutz@chem.ucsb.edu
Received April 29, 2002
Results from aromatic aminations and Kumada couplings, together with spectroscopic analyses
(TEM, EDX, ICP-AES, React-IR), reveal that catalysis using nickel-on-charcoal (Ni/C) is most likely
of a homogeneous rather than heterogeneous nature. In the course of a reaction with Ni/C, nickel
bleed from the support was calculated to be as high as 78%. However, the existence of an equilibrium
for this homogeneous species between nickel located inside vs outside the pore system of charcoal
strongly favors the former, thus leaving only traces of metal detectable in solution. This accounts
for virtually complete recovery of nickel on the charcoal following filtration of a reaction mixture
and allows for recycling of the catalyst. TEM and EDX data were used to explain different reactivity
profiles of Ni/C, which depended upon the method of reduction used to convert Ni(II)/C to Ni(0) as
well as the level of nickel loading on the support.
In tr od u ction
which is well-known to effect several types of transfor-
mations of organic substrates,4-8 was mainly used for
hydrogenation of unsaturated systems.9,10 Some recent
Following early work by Kharash et al. in the 1940s
on nickel-catalyzed C-C bond forming reactions,1 it was
not before the 1970s that the organometallic chemistry
of this metal began to accrue significant numbers of
applications to organic synthesis,2 as well as an ap-
preciable level of study on mechanistic aspects of orga-
nonickel-based transformations.3 Use of nickel catalysis
in a heterogeneous context, unlike supported palladium
(3) (a) Tolman, C. A.; Seidel, W. C.; Gerlach, D. H. J . Am. Chem.
Soc. 1972, 94, 2669. (b) Tolman, C. A.; Seidel, W. C.; Gosser, L. W. J .
Am. Chem. Soc. 1974, 96, 53. (c) Stasko, A.; Tkac, A.; Prikryl, R.; Malik,
L. J . Organomet. Chem. 1975, 92, 253. (d) Morrell, D. G.; Kochi, J . K.
J . Am. Chem. Soc. 1975, 97, 7262. (e) Fahey, D. R.; Mahan, J . E. J .
Am. Chem. Soc. 1977, 99, 2501. (f) Tsou, T. T.; Kochi, J . K. J . Am.
Chem. Soc. 1978, 100, 1634. (g) Tsou, T. T.; Kochi, J . K. J . Am. Chem.
Soc. 1979, 101, 6319. (h) Tsou, T. T.; Kochi, J . K. J . Am. Chem. Soc.
1979, 101, 7547. (i) Tsou, T. T.; Kochi, J . K. J . Org. Chem. 1980, 45,
1930. (j) Kochi, J . K. Acc. Chem. Res. 1974, 7, 351.
(4) (a) Heck reaction: Heck, R. F.; Nolley, J . P., J r. J . Org. Chem.
1972, 37, 2320. (b) Andersson, C.-M.; Hallberg, A. J . Org. Chem. 1987,
52, 3529. (c) Hydrogenation: Klenke, B.; Gilbert, I. H. J . Org. Chem.
2001, 66, 2480. (d) Savoia, D.; Trombini, C.; Umani-Ronchi, A.;
Verardo, G. J . Chem. Soc., Chem. Commun. 1981, 540. (e) Hydrode-
halogenation: J ones, J . R.; Lockley, W. J . S.; Lu, S.-Y.; Thompson, S.
P. Tetrahedron Lett. 2001, 42, 331. (f) Reductive biaryl coupling:
Mukhopadhyay, S.; Rothenberg, G.; Wiener, H.; Sasson, Y. Tetrahedron
1999, 55, 14763; and references therein. (g) Venkatraman, S.; Li, C.-
J . Org. Lett. 1999, 1, 1133. (h) Stille coupling: Roth, G. P.; Farina, V.;
Liebeskind, L. S.; Pena-Cabrera, E. Tetrahedron Lett. 1995, 36, 2191.
(i) Amidocarbonylation: Beller, M.; Moradi, W. A.; Eckert, M.; Neu-
mann, H. Tetrahedron Lett. 1999, 40, 4523. (j) Suzuki coupling: Dyer,
U. C.; Shapland, P. D.; Tiffin, P. D. Tetrahedron Lett. 2001, 42, 1765;
and references therein. (k) Varma, R. S.; Naicker, K. P. Tetrahedron
Lett. 1999, 40, 439. (l) Stereoselective hydrogenation: Farkas, G.;
Hegedus, L.; Tungler, A.; Mathe, T.; Figueiredo, J . L.; Freitas, M. J .
Mol. Catal. A 2000, 153, 215. (m) Aminations: Djakovitch, L.; Wagner,
M.; Ko¨hler, K. J . Organomet. Chem. 1999, 592, 225. (n) Allylic
substitution: Boldrini, G. P.; Savoia, D.; Tagliavini, E.; Trombini, C.;
Umani-Ronchi, A. J . Organomet. Chem. 1984, 268, 97. (o) Phosphina-
tion: Lai, C. W.; Kwong, F. Y.; Wang, Y.; Chan, K. S. Tetrahedron
Lett. 2001, 42, 4883.
† University of California, Santa Barbara.
‡ Phone: +805-893-2521. Fax: +805-893-8265.
§ Max-Planck-Institut fu¨r Kohlenforschung, Mu¨lheim an der Ruhr.
(1) (a) Kharasch, M. S.; Tawney, P. O. J . Am. Chem. Soc. 1941, 63,
2308. (b) Kharasch, M. S.; Fields, E. K. J . Am. Chem. Soc. 1941, 63,
2316. (c) Kharasch, M. S.; Lambert, F. L.; Urry, W. H. J . Org. Chem.
1945, 10, 298.
(2) (a) Corriu, R. J . P.; Masse, J . P. J . Chem. Soc., Chem. Commun.
1972, 144. (b) Cassar, L.; Giarrusso, A. Gazz. Chim. Ital. 1973, 103,
793. (c) Cramer, R.; Coulson, D. R. J . Org. Chem. 1975, 40, 2267. (d)
Felkin, H.; Swierczewski, G. Tetrahedron 1975, 31, 2735. (e) Kende,
A. S.; Liebeskind, L. S.; Braitsch, D. M. Tetrahedron Lett. 1975, 3375.
(f) Pridgen, L. N. J . Heterocycl. Chem. 1975, 12, 443. (g) Tamao, K.;
Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodama, S.-I.;
Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. J pn. 1976,
49, 1958. (h) Zembayashi, M.; Tamao, K.; Yoshida, J .-I.; Kumada, M.
Tetrahedron Lett. 1977, 4089. (i) Yamamoto, T.; Hayashi, Y.; Yama-
moto, A. Bull. Chem. Soc. J pn. 1978, 51, 2091. (j) Takagi, K.; Hayama,
N.; Okamoto, T. Chem. Lett. 1978, 191. (k) Takagi, K.; Hayama, N.;
Inokawa, S. Chem. Lett. 1979, 917. (l) Ibuki, E.; Ozasa, S.; Fujioka,
Y.; Okada, M.; Terada, K. Bull. Chem. Soc. J pn. 1980, 53, 821. (m)
Kumada, M. Pure Appl. Chem. 1980, 52, 669. (n) Semmelhack, M. F.;
Helquist, P.; J ones, L. D.; Keller, L.; Mendelson, L.; Ryono, L. S.; Smith,
J . G.; Stauffer, R. D. J . Am. Chem. Soc. 1981, 103, 6460.
10.1021/jo020296m CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/17/2002
J . Org. Chem. 2003, 68, 1177-1189
1177

Lipshutz et al.
TABLE 1. Com p a r ison of 1st a n d 2n d Gen er a tion F or m a tion of Ni/C
1st generationa
2nd generationb
impregnation
aqueous Ni(NO3)2‚6H2O
aqueous Ni(NO3)2‚6H2O
distillation of H2O (180 °C)
addition of undistilled THF
distillation of THF (100 °C)
ultrasound, 30 min
distillation of H2O (175 °C,
then 210 °C, 15 min)
washing
drying
three times with H2O
twice with undistilled THF
twice with H2O
100 °C, vacuum, 12 h
predrying at room temperature, vacuum, 2 h
100 °C, vacuum, 18 h
a
b
cf. ref 15. cf. ref 27.
exceptions outside of our work11 include hydrodehaloge-
nation reactions of aryl chlorides using ‘nickel-on-
charcoal’ (Ni/C)12,13 and Kumada couplings with nickel
mounted on a Merrifield resin.14 The potential for Ni/C
to catalyze a variety of cross-coupling reactions involving
inexpensive aryl chlorides has recently been expanded
to include Negishi-,15 Suzuki-,16 and Kumada-type cou-
plings,17 aromatic aminations,18 and hydrodehalogena-
tions.19 Whereas the pathway for heterogeneous hydro-
genation reactions using transition metal catalysts is an
example of true surface chemistry involving chemisorp-
tion of the hydrogen on a metal surface,20 the mode of
action for transformations of aryl halides is not obvious.
For Pd/C-based Suzuki couplings of aryl chlorides, a
heterogeneous mechanism involving ‘synergistic anchi-
meric and electronic effects’ was suggested to account for
the high catalytic activity; i.e., interactions of the sub-
strate with Pd atoms which are in proximity to each
other.8 Can such a scheme also explain the activities
found with Ni/C, as postulated previously for hydrode-
halogenations of aryl chlorides,13 or is a different hypoth-
esis needed in this case? Is this chemistry truly hetero-
geneous; i.e., catalyzed only by nickel atoms attached to
the support (denoted as ‘NiC’)? If so, then in addition to
such an association with the charcoal, how can nickel
accommodate both an oxidative addition and simulta-
neous coordination of (phosphine) ligands, all within the
coordination sphere of the metal? Does Ni/C, rather, serve
as a (reversible?) reservoir for nickel-in-solution (Nisol),
as previously postulated for certain Pd/C-mediated con-
versions, involving a ‘release/capture mechanism’, deter-
21,22
mined by a ‘three-phase test’
employing polymer-
bound substrates23 and by atomic absorption or emission
spectroscopy as a quantitative indicator of the transition
metal present in solution after filtration of the reaction
suspension.24-26 In this contribution, we offer physical
evidence, for the first time, on the impact of varying
methods of reduction of Ni(II)/C on the texture of the
resulting catalyst, which is correlated with catalytic
activity in organic transformations. Also addressed is the
issue of catalyst bleed from the support, and results are
presented on catalyst activity under differing reaction
conditions.
(5) Bergbreiter, D. E.; Chen, B. J . Chem. Soc., Chem. Commun.
1983, 1238.
(6) Augustine, R. L.; O’Leary, S. T. J . Mol. Catal. 1992, 72, 229.
(7) For several polymer-bound Pd catalyzed reactions, see: Berg-
breiter, D. E. Chem. Rev. 2002, 102, in press.
(8) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J . R., J r. Org.
Lett. 2001, 3, 1555; and references therein.
(9) (a) Hydrogenation: Hill, F. N.; Selwood, P. W. J . Am. Chem. Soc.
1949, 71, 2522. (b) Aika, K.-I.; Yamaguchi, T.; Onishi, T. Appl. Catal.
1986, 23, 129. (c) Medina, F.; Salagre, P.; Sueiras, J . E. Appl. Catal. A
1993, 99, 115. (d) Coq, B.; Figueras, F.; Geneste, P.; Moreau, C.;
Moreau, P.; Warawdekar, M. J . Mol. Catal. 1993, 78, 211. (e) Savoia,
D.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J . Org. Chem. 1981,
46, 5344. (f) CO/H2: Vannice, M. A. J . Catal. 1976, 44, 152. (g) Vannice,
M. A.; Garten, R. L. J . Catal. 1979, 56, 236. (h) Decomposition of
alkanes: Domingo-Garcia, M.; Fernandez-Morales, I.; Lopez-Garzon,
F. J . Appl. Catal. A 1994, 112, 75. (i) Otsuka, K.; Seino, T.; Kobayashi,
S.; Takenaka, S. Chem. Lett. 1999, 1179. (j) NO/CO: Mehandjiev, D.;
Bekyarova, E.; Khristova, M. J . Colloid Interface Sci. 1997, 192, 440.
(10) Gandia, L. M.; Montes, M. J . Catal. 1994, 145, 276.
(11) Lipshutz, B. H. Adv. Synth. Catal. 2001, 343, 313.
(12) Yakovlev, V. A.; Simagina, V. I.; Likholobov, V. A. React. Kinet.
Catal. Lett. 1998, 65, 177.
Resu lts a n d Discu ssion
P r ep a r a tion , Textu r e, a n d Activity of Ni/C. In our
original preparation of Ni/C,15 an aqueous solution of Ni-
(NO3)2‚6H2O was used to supply nickel(II) for impregnat-
ing activated charcoal by distillation of both the water
and subsequently added undistilled THF. The ‘crude’
Ni(II)/C was then washed several times with H2O and
THF and dried in vacuo at 100 °C for 12 h (Table 1). In
time, further study revealed that exposure to THF was
not crucial for catalyst activity. Far more important for
the new protocol is better control of temperature and time
of impregnation and drying, which is essential for gaining
(13) Yakovlev, V. A.; Terskikh, V. V.; Simagina, V. I.; Likholobov,
V. A. J . Mol. Catal. A 2000, 153, 231.
(14) Styring, P.; Grindon, C.; Fisher, C. M. Catal. Lett. 2001, 77,
219. For a few other polymer-immobilized Ni reactions, see ref 7, 41,
and Braca, G.; Di Girolamo, M.; Raspolli Galletti, A. M.; Sbrana, G.;
Brunelli, M.; Bertolini, G. J . Mol. Catal. 1992, 74, 421.
(15) Lipshutz, B. H.; Blomgren, P. A. J . Am. Chem. Soc. 1999, 121,
5819.
(16) Lipshutz, B. H.; Sclafani, J . A.; Blomgren, P. A. Tetrahedron
2000, 56, 2139.
(17) Lipshutz, B. H.; Tomioka, T.; Blomgren, P. A.; Sclafani, J . A.
Inorg. Chim. Acta 1999, 296, 164.
(21) (a) Rebek, J ., J r. Tetrahedron 1979, 35, 723. (b) Kagan, H. B.;
Peyronel, J . F.; Yamagishi, T. In Advances in Chemistry-Inorganic
Compounds With Unusual Properties II; King, R. B., Ed.; American
Chemical Society: Washington, DC, 1979; Vol. 173, Chapter 6, pp 50-
66.
(22) Bergbreiter, D. E.; Chen, B.; Weatherford, D. J . Mol. Catal.
1992, 74, 409.
(23) Davies, I. W.; Matty, L.; Hughes, D. L.; Reider, P. J . J . Am.
Chem. Soc. 2001, 123, 10139.
(24) J ayasree, S.; Seayad, A.; Chaudhari, R. V. J . Chem. Soc., Chem.
Commun. 1999, 1067.
(18) Lipshutz, B. H.; Ueda, H. Angew. Chem. 2000, 112, 4666;
Angew. Chem., Int. Ed. 2000, 39, 4492.
(19) Lipshutz, B. H.; Tomioka, T.; Sato, K. Synlett 2001, 970.
(20) (a) Horiuti, I.; Polanyi, M. Trans. Faraday Soc. 1934, 30, 1164.
(b) Augustine, R. L.; Yaghmaie, F.; Van Peppen, J . F. J . Org. Chem.
1984, 49, 1865. (c) Ehwald, H.; Shestov, A. A.; Muzykantov, V. S. Catal.
Lett. 1994, 25, 149. (d) Ertl, G. Chem. Rec. 2001, 1, 33. (e) Zaera, F.
Acc. Chem. Res. 2002, 35, 129.
(25) Biffis, A.; Zecca, M.; Basato, M. Eur. J . Inorg. Chem. 2001, 1131.
(26) Zhao, F.; Bhanage, B. M.; Shirai, M.; Arai, M. Chem. Eur. J .
2000, 6, 843.
1178 J . Org. Chem., Vol. 68, No. 4, 2003

Nickel-on-Charcoal
F IGURE 1. TEM analyses of Ni(0)/C formed by reduction of 1st and 2nd generation Ni(II)/C with either BuLi (top row), or H2
at 425 °C (1 atm) with lattice fringes resolved (bottom right).
a reproducible activity profile.27 Additionally, pretreat-
ment of the catalyst prior to distillation with ultrasound
was anticipated to help achieve a more homogeneous
distribution of Ni(NO3)2 within the matrix of the acti-
vated charcoal, simultaneously easing both the evolution
of gas28 out of the pore structure and the pore filling
process.
brighter grayish structures represent charcoal with only
traces of nickel, while higher nickel concentrations lead
to higher contrast and, therefore, to darker regions of the
sample in the picture. EDX data for a sample of activated
charcoal as purchased and unexposed to nickel nitrate
showed a permanent phosphorus background caused by
residual phosphates, an outgrowth of the procedure
followed for preparing activated charcoal.29 Thus, not all
of the signal due to phosphorus found in the reduced
Ni(0)/C samples can be attributed to added phosphine.
Independent of the method of impregnation, neither
Ni(II)/C nor Ni(0)/C formed via BuLi reduction display
visible nickel particles, indications that, if present to any
degree, their size is below 1 nm. The nickel atoms
associate in conglomerates, most likely with inorganic
material from the charcoal and/or the original nickel salt
and what remained of it after impregnation and drying,
which is known to cause decomposition of the nitrate and
hydrate sphere, although those processes took place at
temperatures above 110 °C and at atmospheric pres-
sure.10,27,28,30,31 The distribution of conglomerates on and
within the pore structure of charcoal was found to be
more homogeneous for second generation Ni(II)/C (not
shown) and the corresponding Ni(0)/C formed via BuLi-
reduction, as manifested by smoother transitions to
regions with darker contrast, as expected from pretreat-
ment with ultrasound. After BuLi reduction in THF, the
general distribution of nickel particles was not changed,
suggesting that nickel is not prone to migration under
these conditions, an important observation for subse-
quent experiments (vide infra). Added PPh3 is attracted
Ni/C prepared by this “second generation” protocol
displayed essentially the same catalytic activity in sev-
eral cross-couplings (Negishi-, Suzuki-, Kumada-cou-
plings, aromatic aminations, and hydrodehalogenations)
as seen with catalyst prepared via our earlier method.
These observations raised the question as to whether
impregnation using ultrasound altered in a significant
fashion the distribution pattern of nickel atoms on the
charcoal support, aside from the obvious advantage of
leading to complete and reproducible loading of Ni(NO3)2
in a simpler and faster procedure.27 Transmission elec-
tron microscopy (TEM), in combination with energy
dispersive X-ray analysis (EDX), were chosen to inves-
tigate structural features of the supported nickel cata-
lysts. TEM micrographs (Figure 1) compare samples of
Ni(0)/C prepared using our “first generation” and “second
generation” processes. Reduction of impregnated Ni(II)/C
of both generation catalysts by n-BuLi in THF in the
presence of PPh3 (room temperature, 10 min; top row) is
contrasted with reduction by heat treatment (425 °C, 4.5
h) in an atmosphere of hydrogen (atmospheric pressure)
after which PPh3 was added in THF (bottom left).
In general, TEM micrographs display a 2D image
taken of the sample mounted on a copper grid. The
(27) Lipshutz, B. H.; Tasler, S. Adv. Synth. Catal. 2001, 343, 327.
(28) Anderson, J . R. Structure of Metallic Catalysts; Academic
Press: New York, 1975, Chapter 2.12 and 4.
(29) This result was in agreement with information supplied by the
vendor of the charcoal used, concerning the impurities in their charcoal
which can include up to 1% phosphates.
J . Org. Chem, Vol. 68, No. 4, 2003 1179

Lipshutz et al.
SCHEME 1. Ar om a tic Am in a tion
SCHEME 2. Ku m a d a Cou p lin g
TABLE 2. Resu lts of Ar om a tic Am in a tion s Usin g
Ni(0)/C F or m ed u n d er Differ en t Red u cin g Con d ition s
TABLE 3. Resu lts of Ku m a d a Cou p lin gs Usin g Ni(0)/C
F or m ed via Differ en t Red u cin g Agen ts
reducing agent
for Ni(II)/C
phosphine
ligand
time
[h]
conv
[%]a
3
entry
[%]a
reducing agent
for Ni(II)/C
dppfb
dppf
PPh3
1
1
1.5
1.5
99
67
96
55
83
51
75
42
entry
R in 5 conv. [%]a
6 [%]a
7 [%]a
1
2
3
4
BuLi
H2
BuLi
H2
1
2
3
4
PhMgClb
H2
Ph
Ph
Bu
Bu
100
54
66
81
50
40
25
2.5
0.5
2.7
0.2
c
PPh3
BuMgClb
H2
a
b
By quantitative GC. 0.5 equiv relative to nickel, cf. ref 18.
c 4.0 equiv relative to nickel, cf. ref 33.
47
a
By quantitative GC; all reactions run with 2 equiv of PPh3
b
relative to nickel, reaction time 1 h. cf. ref 33.
to the newly generated Ni(0) and can be detected in high
concentrations in regions near the conglomerates (with
a ratio of 1:2-1:3 Ni:P).
hydrodehalogenation as a side reaction,13,26 which was
not observed during these reactions to any significant
degree.
A TEM picture prepared for a Ni/C sample obtained
from filtration of an incomplete Kumada coupling reac-
tion mixture revealed the nickel distribution to be es-
sentially the same as that observed prior to the reaction.
An unambiguous analysis, however, was hampered by
the presence of relatively large amounts of magnesium
salts (from the Grignard reagent).
The tendency of nickel to migrate within the charcoal
matrix, however, changes with increasing temperatures,
as noted in the literature,28,32 and is further documented
by TEM analyses on Ni(0)/C prepared by heating Ni(II)/C
to 425 °C in a hydrogen atmosphere (1 atm) over time.
Under these conditions nickel atoms sinter together10,28,32
to form almost spherical, monocrystalline particles with
sizes up to 50 nm (average particles being in the range
of 5 to 10 nm), clearly indicated by dark, sharp-edged
regions in the TEM data (Figure 1, bottom left). For these
crystallites, the lattice fringes are visible at sufficient
amplification as parallel lines (Figure 1, bottom right).
These nickel clusters are stabilized by subsequent addi-
tion of PPh3 in THF, forming a phosphine shell around
the particles (with a ratio of ca. 2.5:1 Ni:P).
While differences in metal distribution observed be-
tween the first and second generation catalyst did not
influence catalyst activity after BuLi reduction,27 ther-
mally treated catalyst showed significant differences in
activity. For example, with aromatic aminations of p-
chlorobenzonitrile (1) with morpholine (2) (Scheme 1,
Table 2), and Kumada couplings of m-chlorotoluene (4)
with phenyl and butyl Grignard 5 (Scheme 2, Table 3),
the conversion of aryl chloride after an identical time
frame reached only a level of 47% (Table 3, entry 4 vs 3)
to 67% (Table 2, entry 2 vs 1) compared to results
obtained with Ni(0)/C formed via a BuLi- or Grignard-
based reduction, respectively.18,33 Decreased reactivity of
the Ni(0)/C, formed upon initial heating of Ni(II)/C in an
hydrogen atmosphere, may be due to chemisorbed H2 still
present at the beginning of the reaction,6,28 thus blocking
active sites for oxidative addition of the aryl chloride.
Such a chemisorbed Ni-H-species should, however, cause
The structural data clearly reveal the important role
played by the impregnation procedure in determining the
final catalyst texture, but not necessarily catalyst activ-
ity, as long as significant heating to elevated tempera-
tures is avoided. Our new method for generating Ni(II)/
C,27 therefore, includes a well-defined temperature and
time regimen that reproducibly leads to active catalyst.
Heter ogen eou s vs Hom ogen eou s Ca ta lysis. For a
truly heterogeneously catalyzed process based on Ni(0)/C
and involving ‘anchimeric effects’, thermally treated
material should lead to a more effective catalyst, since
TEM data show nickel particles compared to conglomer-
ates in BuLi-reduced samples. Therefore, reaction rates
should be higher using catalyst prepared under the
former set of conditions, mitigating the effect of having
fewer metal atoms catalytically available in larger par-
ticles. However, this is not the case according to the
results shown in Tables 2 and 3. Thus, either different
mechanisms prevail for differently reduced Ni(0)/C with
catalysts which rely on anchimeric effects being slower,
or such a mechanism may be invalid for the catalysis
presented herein. The catalytic cycle may be maintained
only by nickel in solution (Nisol), resulting from bleeding
from the support, and nickel conglomerates are a better
source of atomic nickel than are nickel particles formed
via heat treatment of Ni(II)/C in the presence of hydro-
gen. Even if the larger particles were released during the
reaction, their redox potential should be higher than that
of atomic nickel,34 resulting in lower activity toward
oxidative addition. Furthermore, coordination sites within
the particles would be blocked by other nickel atoms,
(30) Bekyarova, E.; Mehandjiev, D. J . Colloid Interface Sci. 1996,
179, 509.
(31) Parkes, G. D. Mellor’s Modern Inorganic Chemistry; J ohn Wiley
& Sons Inc.: New York, 1967; p 938.
(32) Stiles, A. B. Catalyst Supports and Supported Catalysts;
Butterworth: Boston, 1987, Chapter 5.
(33) Tasler, S.; Lipshutz, B. H. J . Org. Chem. 2002, 67, 1190.
1180 J . Org. Chem., Vol. 68, No. 4, 2003

Nickel-on-Charcoal
TABLE 4. P er cen ta ge of Nick el Bleed fr om Ni/C Ba sed
on Rea ction Typ e
increased this amount to ca. 0.3%. Addition of base and/
or salts such as K3PO4 and LiBr (as used for Suzuki
couplings)16 had no influence on the detectable Nisol
concentration, whereas interaction of the aryl chloride
with Ni(0)/C at reflux increased bleed to 0.9%. The
amount of Nisol, however, proved to be independent of
ligand concentration (2, 4, and 6 equiv of PPh3 were
used), in contrast to initial speculation regarding allylic
substitutions catalyzed by Pd/C5 which, however, did not
survive scrutiny by different ‘three-phase tests’.22 Inter-
esting work by Arai et al. dealing with metal leaching
and re-deposition with different Pd/support catalysts in
Heck reactions concluded that palladium accumulates in
solution over time (for Pd(0)/C, a maximum of ca. 55%
Pdsol was detected after 1 h). Ultimately, however, it is
re-deposited almost entirely back onto the support,
especially upon consumption of the aryl iodide.26 Such a
time-dependent profile was not observed for the chem-
istry of Ni/C. Thus, at any stage of a reaction, the amount
of detectable Nisol remained essentially constant and
extremely low, in contrast to that found occasionally for
Pd/C.24-26 Interestingly, use of tetramethyldisiloxane in
tandem with Ni/C led to detectable Nisol levels as high
as 80%,19 whereas triphenylsilane released only 7% nickel
(albeit under modified reaction conditions).
cold filtration hot filtration
reaction type
Suzuki
procedure
Nisol [%]a
Nisol [%]a
b
c
d
e
d
f
0.44b
2.7c
-
1.0
Kumada
2.6-6.8
1.0-1.4
0.5
1.2
0.5
-
-
amination
2.9e
-
-
g
h
Negishi (RZnX)
hydrodehalogenation
3.0g
3.0h
a
b
d
Determined by ICP-AES. cf. ref 16. c cf. ref 17. cf. ref 33.
e cf. ref 18. f Ni(II)/C was reduced with hydrogen (1 atm) at 425
°C for 4.5 h. cf. ref 15. cf. ref 19.
g
h
raising the same mechanistic questions as with NiC.
Moreover, ligand scrambling, as oftentimes seen in
Kumada couplings, is not likely to apply directly to NiC
or nickel particles since simultaneous coordination of
phosphine and aryl chloride (via oxidative addition) at
the reaction site is required.35
To assess the level of participation by Nisol in Ni/C-
mediated conversions, filtrates of reaction mixtures were
analyzed for nickel content by atomic absorption or
emission spectroscopy. As noted by others, certain reac-
tion parameters can lead to higher concentrations of
metal in solution. Interactions between the metal and
an aryl halide,23,25 as well as reaction temperature at the
time of filtration,24 seem to play significant roles. De-
sorption of palladium from Pd/C was also postulated to
be initiated or promoted to varying degrees by the level
of added PPh3,5 or by different bases in Heck reac-
tions.25,26 For Ni/C, the Nisol content was usually deter-
mined by ICP-AES (inductively coupled plasma atomic
emission spectroscopy)36 after filtration of a cooled reac-
tion mixture, and was found to be in the range of 0.4 to
3.0% of the original nickel used as Ni/C (Table 4). When
filtrations were performed directly on hot reaction mix-
tures, the amounts of Nisol remained essentially within
the same range. No apparent trend was noted, as the
amounts of Nisol after hot filtration were higher for
Suzuki16 and Kumada couplings (of 4 with 5, Scheme 2),
but lower for aromatic aminations (of 1 with 2, Scheme
1) than for cold filtered samples. These results are in
contrast to a reported increase of metal in solution by a
factor of 15 for Pd/support-mediated carbonylation reac-
tions when switching from a cold to hot filtration of a
reaction mixture.24
From these observations new questions arose, in
particular as to whether (1) the detected amount of Nisol
is enough to account for the yields in nickel-catalyzed
reactions reported in the literature;11 (2) filtration/ICP
analyses are capable of accurately revealing the level of
Nisol; (3) there is an equilibrium between NiC and Nisol
,
or bleeding of the catalyst occurs solely just at the
beginning of the reaction; (4) the chemistry is performed
mainly by NiC or by Nisol. The latter question has been
previously addressed by filtration of the catalyst during
an ongoing reaction, and then reexposing the Ni/C-free
filtrate to the reaction conditions to see if the extent of
conversion increased.6,15,37 Generally, such tests may be
misleading, since during the filtration process substrates
and/or reagents could be re-deposited on the charcoal to
varying extents. Thus, failure of a filtered reaction
mixture to achieve additional product formation does not
guarantee that only low levels of transition metal are
present in solution during a reaction with Ni/C.
Control reactions were carried out using 5% of the
original 0.05 equiv of Ni/C in solution (relative to aryl
chloride, i.e. 0.0025 equiv of NiCl2(PPh3)2), assumed to
reflect the extent of Nisol as determined by ICP, but which
was not enough to complete Kumada couplings of chlo-
rotoluene 4 (Table 6, entry 2) or aminations of chloroben-
zonitrile 1 (Table 5, entries 2, 5) using reaction times that
normally lead to 100% conversion (cf. Table 5, entries 1,
4 and Table 6, entry 1). The observed turnover number
(TON) in the presence of only 0.0025 equiv of Ni was ca.
100, and so reactions with 0.009 equiv of Nisol (to aryl
chloride) were expected to go almost to completion, which
was found to be the case (Table 5, entries 3, 6, and Table
6, entry 3). Given these TONs, catalysis by Nisol cannot
account for the 100% conversion normally observed using
0.05 equiv of Ni/C, so these reactions appear to be due
to a combination of heterogeneous and homogeneous
Several other parameters were analyzed for their effect
on nickel bleeding from Ni/C. When the catalyst precur-
sor Ni(II)/C was stirred in dioxane at room temperature,
a metal leach of below 0.1% was observed. Heating this
mixture at reflux, however, or reduction at room tem-
perature with BuLi in the presence of four equiv of PPh3
(34) (a) Amblard, J .; Platzer, O.; Ridard, J .; Belloni, J . J . Phys. Chem.
1992, 96, 2341. (b) Khatouri, J .; Mostafavi, M.; Amblard, J .; Belloni,
J . Chem. Phys. Lett. 1992, 191, 351.
(35) (a) Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J . Org. Chem.
1995, 60, 12. (b) Goodson, F. E.; Wallow, T. I.; Novak, B. M. J . Am.
Chem. Soc. 1997, 119, 12441. (c) Grushin, V. V. Organometallics 2000,
19, 1888. (d) Kwong, F. Y.; Lai, C. W.; Tian, Y.; Chan, K. S. Tetrahedron
Lett. 2000, 41, 10285. (e) Kwong, F. Y.; Chan, K. S. Organometallics
2001, 20, 2570.
(36) Inductively Coupled Plasma Mass Spectrometry; Montaser, A.,
Ed.; Wiley-VCH: New York, 1998.
(37) For further applications of this method, see work cited in ref
25.
J . Org. Chem, Vol. 68, No. 4, 2003 1181

Lipshutz et al.
TABLE 5. Am in a tion Rea ction s of 1 w ith 2 in th e
P r esen ce of Va r yin g Am ou n ts of Nisol
the overall amount of nickel was kept constant so that
the conversions of starting material became comparable.
Both aminations were complete within 1 h, and after hot
filtration, the amount of Nisol in the presence of dry
charcoal was again only 1% of that originally used (entry
4). When the reaction was run using less NiCl2(PPh3)2
(0.025 equiv) and 0.025 equiv of Ni/C, 5% of the 0.025
equiv of NiCl2(PPh3)2 used were found in the filtrate (or
2.5% of the total nickel present; entry 5). This increase
of recovered Nisol (from 1.0 to 2.5%; cf. entries 4 and 5)
can be explained in that the amount of (dried) charcoal
involved in this latter experiment (entry 5) was about
half that involved in the reaction using only dried
charcoal (entry 4).
BuLi
conv
3
entry equiv of Nia source of Ni reductionb [%]c [%]c TONd
1
2
3
4
5
6
0.05
Ni/C
no
no
no
yes
yes
yes
100 86
23 20
98 92
100 85
18 13
100 91
20
92
109
20
72
111
0.0025
0.009
0.05
0.0025
0.009
NiCl2(PPh3)2
NiCl2(PPh3)2
Ni/C
NiCl2(PPh3)2
NiCl2(PPh3)2
a
b
Relative to aryl chloride. For procedures with and without
prior BuLi reduction of Ni(II), see ref 18 and ref 33, respectively.
c By quantitative GC; reactions run with 0.5 equiv of dppf relative
d
to nickel, 2 h. Numbers based on conversion.
TABLE 6. Ku m a d a Cou p lin gs of 4 a n d 5 in th e
P r esen ce of Va r yin g Am ou n ts of Nisol
Since the amounts of Nisol detected after readsorption
are comparable to levels obtained for the reactions listed
in Table 4, ICP data becomes unreliable as a true
indicator of nickel bleed from the support. Rather, these
observations lead to the likelihood that the actual amount
of available nickel in solution is far greater than was
originally expected, potentially even surpassing the 0.009
equiv of Nisol relative to aryl chloride (i.e., 18% bleeding
from the original 0.05 equiv of Ni/C; i.e., 0.009 equiv of
Nisol/0.05 equiv of Ni/C), which is more than enough
homogeneous catalyst to effect these aminations (Table
5, entries 3, 6) and Kumada couplings (Table 6, entry 3).
Clearly, the filtration process occurs too quickly to wash
out all the Nisol trapped within the charcoal matrix. The
nature of the interactions of Nisol with the pore structure
of the charcoal remains unknown. There might be an
equilibrium established for Nisol with only 1% nickel
outside and 99% inside the pores, with either (1) the Nisol
trapped mainly within a ‘labyrinth’; hence, a sort of
‘mechanical occlusion’,28 or (2) there might be interactions
with the support, including weak Van der Waals attrac-
tions, stronger Coulombic interactions, ion exchange,
interactions with nickel nuclei on the support, or even
formation of complexes which are akin to those formed
with graphite as a π-ligand.32,39 Whatever the inter-
action(s), the net result would be NiC as a ‘storage device’
from which Nisol could be released during a reaction. It
could not be excluded at this point that such a readsorp-
tion of nickel does not result in NiC which is performing
heterogeneous surface chemistry. Aryl halides apparently
act as a ‘shuttle’ via oxidatively adding to Ni(0),23,25
thereby transforming the metal into a species which is
more prone to exit the pores of the support (vide supra).
Silanes are somehow more effective than aryl halides at
releasing nickel from the pores, most likely also initiated
by an oxidative addition event.40
entry equiv of Nia source of Nib conv [%]c 6 [%]c 7 [%]c TONd
1
2
3
0.05
0.0025
0.009
Ni/C
NiCl2(PPh3)2
NiCl2(PPh3)2
100
29
85
81
16
67
2.5
2.0
1.6
20
116
94
e
a
b
Relative to aryl chloride. Without prior BuLi reduction of
Ni(II) and without added LiBr; run in the presence of 2 equiv of
PPh3 relative to nickel, 1 h; see ref 33. c By quantitative GC.
d
Numbers based on conversion. e Ni(0) had to be stabilized by an
additional 2 equiv of PPh3.
TABLE 7. Rea d sor p tion of Nisol on to Ch a r coa l
NiCl2(PPh3)2
[mmol]
Ni/C-loading
[mmol/g]
aryl
Nisol
entry
adsorbance
chloride [%]a
1
2
3
4
5
0.038b
0.038b
0.038b
0.038d
0.019d
dry Cc
Ni/Cc
Ni/Cc
dry Cc
Ni/Ce
-
none
none
none
1.0
0.7
1.3
0.333
0.594
-
present 1.0
0.594
present 5.0/2.5f
a
b
Determined by ICP-AES after hot filtration. Ni(II) was
reduced with BuLi. c Same amount of charcoal in the mixture.d No
prior reduction of Ni(II) with BuLi. e 0.019 mmol Ni/C added; thus,
only ca. half the amount of charcoal in this mixture. f First
percentage refers only to the amount of NiCl2(PPh3)2 used, second
to the total amount [NiCl2(PPh3)2 + Ni/C].
catalysis. Alternatively, the amounts of Nisol as measured
by ICP after filtration may not reflect the actual levels
of Nisol present during the reaction.
If the latter were true, the supporting charcoal must
retain Nisol during filtration of a hot reaction mixture.
To determine the adsorption38 capacities of the support
during this process, standard aromatic aminations were
run with and without substrate using 0.05 equiv of NiCl2-
(PPh3)2 plus an amount of dried charcoal (Table 7, entry
1 vs 4) corresponding to that normally included when
using 0.05 equiv of Ni/C. The nickel content in solution
was determined by ICP after hot filtration. Similar
experiments were then performed with additional Ni/C
of varying loadings instead of the dried charcoal (entries
2, 3) so as to evaluate the extent to which existing metal
sites on the support attract Nisol. Quite unexpectedly,
these readsorption tests in the absence of aryl chloride
(entries 1-3) showed (by ICP) uptakes as high as 99%
of the original amount of Nisol independent of preexisting
nickel loadings on the support. For the two examples
involving an aryl chloride and an amine (entries 4, 5),
Rea ction s w ith P olym er -Bou n d Liga n d s: Th e
‘Th r ee-P h a se Test’. Further evidence for potential
participation of Nisol in coupling reactions catalyzed by
Ni/C was garnered from a set of experiments based on a
‘three-phase test’,21-23 in our case using polymer-bound
PPh3 as ligand.41 Given that solid-supported PPh3 should
only interact with Nisol outside the matrix (and not with
NiC),21a other preconditions had to be established so that
(39) Vol′pin, M. E.; Novikov, Y. N.; Lapkina, N. D.; Kasatochkin, V.
I.; Struchkov, Y. T.; Kazakov, M. E.; Stukan, R. A.; Povitskij, V. A.;
Karimov, Y. S.; Zvarikina, A. V. J . Am. Chem. Soc. 1975, 97, 3366.
(40) Fontaine, F.-G.; Zargarian, D. Organometallics 2002, 21, 401.
(41) Pittman, C. U., J r.; Smith, L. R. J . Am. Chem. Soc. 1975, 97,
341.
(38) ‘Adsorption’ is used here in
a broad sense, including the
trapping of substrates within the martix.
1182 J . Org. Chem., Vol. 68, No. 4, 2003

Nickel-on-Charcoal
TABLE 8. P r elim in a r y Exp er im en ts for th e
‘Th r ee-P h a se Test’ w ith P olym er -Bou n d P P h 3
SCHEME 3. Str a tegy for ‘Th r ee-P h a se Tests’ to
Distin gu ish Nisol fr om NiC (‘en tr ies’ r efer to Ta ble
9)
conv yield
7
entry reaction type Ni source
ligand
[%]a [%]a [%]a
1
2
3
4
5
6
7
8
aminationb
aminationb
aminationb
aminationc
aminationc
aminationc
Kumadad
Ni/C
Ni/C
NiCl2
Ni/C
Ni/C
NiCl2
Ni/C
Ni/C
NiCl2
Ni/C
PPh3
-
polymer 100
PPh3
-
polymer 100
PPh3
-
polymer
polymer
100
27
78
2
52
50
3
74
77
60
47
24
-
-
-
-
-
-
5.6
25
6.8
2.4
67
22
86
100
70
Kumadad
9
10
Kumadad,e
Kumadad,e
42
a
b
By quantitative GC. Ni(II) was reduced with BuLi; total
reaction time 2 h. c No prior Ni(II) reduction with BuLi; total
d
reaction time 2 h. LiBr added according to ref 17, reaction time
1 h. e Same result after 2 h.
the derived data would be meaningful. First, with 0.05
equiv of Nisol, supplied in the form of anhydrous NiCl2
(instead of Ni/C), a coupling reaction would need to be
complete within the usual time frame in order to show
that the polymer-bound ligand is capable of mediating
the reaction as long as enough Nisol is present. Second, a
reaction in the absence of phosphine had to show no
significant product formation, otherwise any positive
result with the supported ligand could also, at least
partly, result from coupling under ligandless conditions.
As can be seen from Table 8, aromatic aminations (both
variations; Scheme 1) did qualify for such a ‘three-phase
test’; the ligandless reaction gave at most only 3% product
(entries 2, 5), while the polymer/NiCl2-catalyzed trans-
formation went to completion (entries 3, 6). However,
Kumada coupling of aryl chloride 4 and PhMgCl (5) was
not a good reaction for this test, as the ligandless version
led to 60% product along with 25% homocoupling of the
aryl chloride (entry 8) while the polymer/NiCl2-based
reaction stopped at 70% conversion (entry 9). Therefore,
amination of p-chlorobenzonitrile (1) using morpholine
(2), either with or without prior reduction of the Ni(II)/C
precursor by BuLi, was used to test different ligand
combinations to gain insight into the nature of the
effective nickel catalyst.
TABLE 9. ‘Th r ee-P h a se Test’ Accor d in g to Sch em e 3
entry
time [h]a
conv [%]b
3 [%]b
conv [%]c
3 [%]c
1
2
3
4
5
6
7
8
2
4
2
2
4
4
2
4
54
62
71
87
100
95
35
46
55
70
86
84
56
60
49
56
52
63
71
84
-
30
37
33
47
60
72
-
Our strategy (Scheme 3) is discussed on the basis of
the data obtained from aminations following BuLi reduc-
tion of Ni(II). Data from the second set of experiments
(displayed in Table 9), i.e., aminations without prior
reduction of Ni(II) with BuLi, eventually led to the same
conclusions. Initial reactions were run using four equiv
of polymer-bound PPh3, which can only complex with Nisol
derived from bleeding of Ni/C. The data after two and 4
h clearly show that Nisol loses all activity shortly after 2
h, giving a maximum of 62% conversion (entries 1, 2).
The remaining 38% of starting material which cannot
otherwise be consumed (since NiC cannot interact with
polymer-bound PPh3), might generally react further with
NiC upon subsequent addition of PPh3 (in solution) to the
reaction mixture after this 2 h period, if NiC was a
catalytically active component. The result obtained from
such an experiment (i.e., after an initial 2 h period
followed by another 2 h reaction period where PPh3 had
been added in solution), however, was similar to that
observed with polymer-bound phosphine alone after 4 h
(compare entry 3 with entry 2). Thus, either PPh3 can
71
76
64
49
a
Final reaction time at reflux, in addition to any pretreatment;
b
cf. Scheme 3. Ni(II) was reduced with BuLi; by quantitative GC.
c No prior Ni(II) reduction with BuLi; by quantitative GC.
catalyze the reaction only with Nisol, the activity of which
has already been lost during the initial couplings with
polymer-bound PPh3, or the polymer blocks the pores, e.g.
by swelling, and prevents PPh3 from reaching the still
active NiC. To check the latter explanation, another
sample was run with a preformed mixture of PPh3 and
polymer-PPh3, which now resulted in complete conversion
after the same 4 h period (entries 4, 5). Thus, this system
seems to be more active than that with just polymer-
based ligand. This could be due to either competition of
ligand types for the same Nisol, with PPh3 in solution
giving rise to higher TONs and turnover frequencies
(TOFs) compared to supported PPh3, or there is a
J . Org. Chem, Vol. 68, No. 4, 2003 1183

Lipshutz et al.
combination of reactions with both Nisol and NiC early in
the scheme, and it takes time for the polymer to block
the pores of Ni/C effectively. The latter was excluded by
experiment in which reduced Ni/C, morpholine (2), the
base, and polymer-bound PPh3, essentially all ingredients
other than the aryl chloride, were heated in toluene at
reflux for 2 h. This amount of time should have been long
enough to cause significant pore blocking, assuming this
phenomenon is actually taking place (cf. entry 3). After
this time, chlorobenzonitrile 1 and PPh3 were added and
the mixture heated for an additional 4 h. If pore blocking
had occurred, the result should be similar to that
obtained with the polymer-bound PPh3-based reaction
(entry 2). Should this hypothesis be invalid, the result
should resemble that realized from the reaction with
premixed PPh3 and polymer-bound PPh3 (entry 5). Clearly,
from this comparison (entry 6 vs entries 2, 5), pore
blocking is not a factor in these aminations. A control
experiment with only added aryl chloride (no additional
PPh3) after the first 2 h of heating, gave increased
conversions (compare entries 7, 8 with 1, 2) that were
still clearly below the 95% level already noted (entry 6).
Thus, pretreatment for 2 h is not essential for activation
of the catalytic system. The conclusion drawn from these
data is that the catalysis is done by Nisol as a homoge-
neous catalyst, while Ni/C seems to function merely as a
heterogeneous reservoir for this species. Furthermore,
the TONs and TOF using PPh3 seem to be higher than
those with polymer-bound PPh3, not surprising for a
reaction between a macroscopic substrate and a polymer-
ligated catalyst.7
Even though a related set of experiments for Kumada
couplings was inconclusive (vide supra, Table 8), a similar
assumption was reached since the analogous reaction
with Ni/C in the presence of polymer-bound PPh3 stopped
after 42% conversion (Table 8, entry 10), whereas the
ligandless variant did go to completion (Table 8, entry
8). If NiC was an active participant in the ligandless
reaction, this species should have been equally effective
in the polymer-PPh3 mediated reaction, since the latter
ligand is not likely to interact with NiC. Therefore, it is
most likely that heterogeneous nickel (NiC) plays only a
minor role, if any, as the catalytically active species.
Furthermore, from the TONs for Nisol in the presence of
polymer-bound PPh3 (indicative of a 2 h lifetime for
aminations and even less for Kumada couplings; cf. Table
8, entry 10), together with the fact that Nisol as detected
by ICP-AES does not accumulate over time (vide supra),
it can be concluded that the nickel bleeding from Ni/C is
most likely not continuous,25 but rather a one-time event
during the first minutes of the reaction.33,42
F IGURE 2. React-IR analysis: amination of chlorobenzoni-
trile 1 with morpholine (2).
usual adsorption profiles for educt and product. Progress
in the amination of 1 with 2 was followed by React-IR at
110 °C, monitoring peaks for the nitrile groups in
chloroarene 1 and in product 3 (Figure 2). A kinetic
analysis of the data was precluded due to major overlap
of IR signals. Moreover, the reaction course was altered
most likely by contact of the catalytic system with the
probe, which caused the extent of conversion to stop at
ca. 22%. From the plot of the IR maxima, 2232 cm-1 for
1 and 2221 cm-1 for 3, however, it is curious that the
concentration of the starting material in solution outside
the support remained relatively constant while the
product peak simultaneously increased. Thus, it is pos-
sible that a considerable amount of starting material is
present within the matrix, undetectable by the probe, yet
where it is converted to product.43 For reasons that are
not obvious, the product must possess some structural
or electronic features resulting in its quick diffusion out
of the pores. Another explanation is that the transforma-
tion occurs outside the pores, and the support again
serves as a storage device, in this case for 1, helping to
maintain a constant concentration of 1 outside the pores
while not retaining product 3 to any significant degree.
High er Loa d in gs of Ni/C. The effectiveness of our
newly established procedure for preparing Ni/C (i.e.,
including pretreatment with ultrasound)27 was tested
with regard to achieving higher loadings of nickel on
charcoal. Our standard level is ca. 0.59 mmol Ni per gram
catalyst, or about 3.5% Ni/catalyst by weight. For com-
Since the vast majority of active Nisol seems to be
located within the channels of the charcoal as suggested
from readsorption tests (vide supra), the question arises
as to whether the chemistry is taking place there as well.
Alternatively, the small amount of Nisol outside the pores
could be catalyzing the reaction, which is continuously
undergoing exchange with ‘fresh’ Nisol by diffusion in and
out of the pores. An experiment designed to examine the
kinetics of these aromatic aminations gave highly un-
(42) For a study concerning Pd/C-mediated Heck reactions during
which Pdsol concentrations reached a maximum after ca. 1 h reaction
time, see ref 26; in the case of Ni/C, however, a trace level of bleed
seems to occur in minutes.
(43) Macropores have average diameters of up to 500 nm (and even
higher) and contribute up to 35% of the pore volume. Even mesopores
(5-20 nm) should offer enough space for Nisol chemistry (up to 15% of
total pore volume).28,30,32
1184 J . Org. Chem., Vol. 68, No. 4, 2003

Nickel-on-Charcoal
TABLE 10. Am in a tion a n d Ku m a d a Cou p lin gs w ith
High er Loa d ed Ni/C
product formation (cf. Table 10, entries 13-15), although
this outcome is not readily understood.33
Ni/C-loading time conv yield
7
Nisol
For aminations employing BuLi-reduced Ni(II)/C, the
10%-loaded catalyst resulted in at most 44% conversion
and only 17% product 3 (Table 10, entries 2, 4). The 15%
catalyst gave slightly higher conversions but did not yield
any visible cross-coupled product 3 at all (entries 3, 5).
Instead, significant amounts of a side product were
detected by GCMS, the mass spectrum of which sug-
gested that morpholine (2) had added to the nitrile group
giving rise to an amidine-like structure. Efforts to isolate
this product failed, but the same compound was observed
by GCMS when chlorobenzonitrile (1) was treated di-
rectly with lithiated morpholine in toluene at ambient
or elevated temperatures in the absence of any nickel
catalyst. LiO-t-Bu (the base used during these aromatic
aminations), in the presence of morpholine and nitrile
1, was not sufficiently reactive by itself to significantly
deprotonate morpholine to cause formation of the adduct.
Only after addition of BuLi to this reaction mixture did
the targeted addition product become detectable. Thus,
in reactions catalyzed by 15%-loaded Ni/C, the BuLi
added for purposes of reducing Ni(II)/C may not react
completely and is ultimately ‘quenched’ in an acid/base
sense by morpholine which goes on to attack the nitrile
group. Residual BuLi might exist where higher loadings
of nickel are involved since bigger particles may be
formed during impregnation and/or pore blocking may
occur,28,32 thus excluding a certain amount of nickel from
reduction. This assumption was supported by TEM and
EDX data of a catalyst with 15% nickel loading, which
showed a high nickel distribution throughout the char-
coal, indicative of saturation of the support, with local
formation of conglomerates of nickel (including nanoc-
rystalline Ni particles; Figure 3). For the latter species,
lattice fringes are again visible (Figure 3, right micro-
graph), but they clearly differ structurally from the
particles obtained after hydrogen reduction at 425 °C (cf.
Figure 1, bottom right). Apparently, at high concentra-
tions nickel is forming colloids to some extent with a
tendency to sinter. Interestingly, the Ni:P ratio was found
to be extremely low (around a ratio of 20:1 to 100:1 Ni:P
for regions of high nickel concentration and 1:1 to 10:1
Ni:P for average nickel distributions) compared to that
from the 3.5%-loaded samples (1:2-1:3, Figure 1), despite
the fact that all Ni(0)/C samples were prepared with the
same amount of PPh3 (4 equiv relative to nickel). This
also strongly implicates pore blocking, which prevents
organic material of any type from reaching nickel par-
ticles. Further support for a limited reduction of Ni(II)
by BuLi is obtained from EDX data, which documents
considerably greater quantities of oxygen in the conglom-
erates compared to the other samples, most likely due
to nonreduced nickel.
entry reaction type
[%]
[h] [%]a [%]a [%]a [%]b
1
2
3
4
5
6
7
8
aminationc
aminationc
aminationc
aminationc
aminationc
aminatione
aminatione
aminatione
aminatione
aminatione
aminatione
aminatione
Kumadaf
3.5
10
15
10
15
3.5
10
15
10
15
15
15
3.5
10
15
10
15
15
1.5 100
87
12
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.2
0.7
-
-
0.6
3
3
4
4
2
2
2
3
3
4
8
37
45
44
51
100
66
47
100
58
70
69
d
-
17
d
-
86
55
39
83
50
60
58
83
64
40
81
51
68
9
10
11
12
13
14
15
16
17
18
-
-
1.5 100
7.2 2.6
1.9 1.5
0.4
2.4
0.7 0.9
0.8
Kumadaf
1.5
1.5
84
56
Kumadaf
-
-
Kumadaf
2.5 100
Kumadaf
2.5
4.5
68
90
Kumadaf
-
a
b
By quantitative GC. Determined by ICP-AES after hot
filtration; percentage given relative to the amount of nickel added
as Ni/C. c Ni(II)/C was reduced with BuLi; 0.5 equiv of dppf relative
d
to nickel used. Observed addition product of morpholine to the
nitrile group. e No prior Ni(II)/C reduction with BuLi; 0.5 equiv
of dppf relative to nickel used. f 4 equiv of PPh3 relative to nickel
+ LiBr added according to ref 17.
parison purposes, catalysts with 10% and 15% Ni/catalyst
were prepared, notwithstanding the already observed
drop in catalyst activity which can accompany such high
loadings.32 The protocol developed proved to be quite
efficient, as complete mounting of the Ni(NO3)2‚6H2O
occurred such that no nickel salt was recovered in the
filtrate after washing of the impregnated Ni(II)/C with
H2O (cf. Table 1). Activities of both the 10% and 15%
catalysts were next determined in Kumada couplings of
4 with PhMgCl (5) (cf. Scheme 2) and aromatic amina-
tions of 1 with 2 (cf. Scheme 1), using 0.05 equiv of nickel
relative to aryl chloride. For aminations, two different
protocols were used; one included a prior reduction of the
Ni(II)/C with two equiv of BuLi (Table 10, entries 1-5),
the other called for no formal reduction (entries 6-12).33
In all three transformations (a Kumada coupling and two
different aminations), catalyst activity decreased signifi-
cantly with increasing nickel loading, as expected from
literature precedent.32 In the case of Kumada couplings,
the extent of conversion using 10% loading decreased to
84% relative to reactions with 3.5% Ni/C (entry 13 vs 14).
The conversion dropped further to 68% when using a
15%-catalyst loading (entry 14 vs 15 and 16 vs 17).
Reactions with the 15% catalyst loading did not go to
completion even after 4.5 h (entry 18), indicating that
the active nickel was spent. This suggests that less metal
is chemically available with increased loading of Ni/C,
supported by ICP data which revealed less detectable
Consequently, aminations with higher loaded catalysts
were best performed avoiding prior BuLi reduction of Ni-
(II)/C.33 The conversion dropped to 66% in going from the
3.5%- to the 10%-loaded catalyst (Table 10, entry 6 vs
7), and to 47-58% when the loading increased further
from 10% to 15% Ni/C (entries 7 vs 8 and 9 vs 10), results
44
Nisol with increasing nickel loading on the support
(entries 13, 14 and 17).
Another interesting aspect of these reactions is the
formation of homocoupled product 3,3′-bistoluene. The
higher the loading of the catalyst, the cleaner the
conversion to the product 6 due to significantly less side-
44
consistent with decreasing concentrations of Nisol de-
tectable by ICP-AES (entries 6, 7, and 10). Intuitively,
greater levels of Nisol should be found with increased
nickel loading on the support if all nickel mounted is
(44) Recall that the amount of Nisol detectable by ICP-AES appar-
ently represents only a minor portion of available Nisol, most of which
is ‘stored’ within the support.
J . Org. Chem, Vol. 68, No. 4, 2003 1185

Lipshutz et al.
F IGURE 3. TEM analysis of Ni(0)/C with 15% nickel loading after BuLi reduction of Ni(II)/C.
TABLE 11. Am in a tion Rea ction s of 1 w ith 2 Ca ta lyzed
by Va r yin g Am ou n ts of Ni/C
TABLE 12. Resu lts of Am in a tion s a n d Ku m a d a
Cou p lin gs Ca ta lyzed by Ni/C Stor ed in Air
storage reaction
conv
[%]b
yield
[%]b
7
entry
equiv of Nia
time [h]
conv [%]b,c
3 [%]c
entry reaction type [months]a time [h]
[%]b
1
2
3
4
5
6
7
0.05
2
2
4
2
4
2
4
100
90
100
48
66
39
87
78
88
40
57
33
31
1
2
3
4
aminationc
aminationd
aminationd
Kumadae
6
5
9
6
1
2
5
1.5
33 (99) 23 (83)
56 (100) 42 (87)
80
-
-
-
0.025
0.025
0.0125
0.0125
0.005
0.005
73
76 (100) 52 (83) 10 (7.2)
a
b
Catalyst was kept on the bench for the time indicated. By
39
quantitative GC; numbers in parentheses correspond to reactions
using Ni/C stored under argon. c Ni(II)/C was reduced with BuLi,
a
b
Relative to aryl chloride. Without prior BuLi reduction of
Ni(II)/C, 0.5 equiv of dppf relative to nickel used. c By quantitative
GC.
d
0.5 equiv of dppf relative to nickel used. No prior Ni(II)/C
reduction with BuLi, 0.5 equiv of dppf relative to nickel used. e 4
equiv of PPh3 relative to nickel + LiBr added according to ref 17.
available for a reaction. The opposite trend, revealed by
ICP analysis, again indicates a certain percentage of
nickel is excluded from participation due to pore blocking
and/or the formation of bigger nickel particles.
compared to reactions run under homogeneous condi-
tions. The calculated amounts of nickel “bleeding”, 14%
vs 78%, again suggest that with higher loaded catalysts,
less nickel is actually available as Nisol due to more
extensive pore blocking. Furthermore, the calculated level
of 78% “bleeding” of Ni/C is in excellent agreement with
the ca. 80% level of nickel found by ICP-AES for hydro-
dehalogenations with tetramethyldisiloxane,19 where ap-
parently the silane is shifting the equilibrium for Nisol
to be strongly favored outside the matrix.
Stor a ge of Ni/C Ca ta lysts. J udging from the data in
Table 12, which reflect both aromatic aminations and
Kumada couplings with Ni/C which had been exposed to
air for up to nine months, it appears to be essential that
Ni(II)/C is stored in an inert atmosphere. Kumada
couplings of chlorortoluene 4 and PhMgCl (5) using
unprotected catalyst led to a significant loss of activity,
along with formation of greater amounts of homocoupling
side products.
While aminations with the 10%-loaded Ni/C can be run
to completion over extended reaction times (Table 10,
entry 9), the corresponding reaction involving a 15%
loaded catalyst ended at ca. 70% conversion (entries 10-
12). With TONs of ca. 100 for these transformations
catalyzed by Nisol (cf. Table 5), and given that (1) the
active nickel species obtained via reduction of NiCl2-
(PPh3)2 in solution and from Nisol resulting from Ni/C
bleed show comparable activities, and (2) there is no NiC
participation in the actual catalytic cycle, this leads to a
net Nisol amount of 0.007 equiv available to react with
the aryl chloride, corresponding to a 14% bleed of nickel
from the originally used 0.05 equiv of Ni/C (i.e., 0.007
equiv of Nisol/0.05 equiv of Ni/C).
The same calculation could be applied to aminations
without BuLi reduction of the Ni(II)-precursor using the
standard catalyst with 3.5% nickel loading. To determine
TONs for this catalyst, the amount of Ni/C used was
decreased stepwise and the extent of conversion analyzed
after 2 and 4 h (Table 11). A reduction from 0.05 equiv
of nickel to aryl chloride (entry 1) to 0.005 (entries 6, 7)
was needed to stop catalyst turnover prior to complete
consumption of the aryl chloride. Recalling a TON of ca.
100 for Nisol chemistry, and having established the same
preconditions as used previously, 0.0039 equiv of Nisol
were needed to reach 39% conversion, corresponding to
available Nisol from Ni/C of at least 78% (i.e., 0.0039 equiv
of Nisol/0.005 equiv of Ni/C). As already shown by ICP-
AES analyses of several reaction mixtures after filtration,
only miniscule amounts of bled metal are actually found
outside the charcoal network (vide supra), thus dramati-
cally minimizing nickel content in the final products
Con clu sion s
Nickel-on-charcoal is a versatile ‘heterogeneous’ cata-
lyst which mediates several useful organic transforma-
tions. Its removal by simple filtration usually leads to a
reaction mixture containing only traces of transition
metal, an important feature especially when potentially
applied to syntheses of pharmaceutically valuable com-
pounds. Thus, the ‘green’ nature of such catalysts should
also not go unnoticed. The revised protocol for prepara-
tion of Ni/C offers cost advantages compared to our initial
procedure; it is faster, simpler, and affords reproducible
catalyst activities. As was shown by TEM analyses,
exposure to ultrasound as part of the protocol leads to
an enhanced distribution of nickel atoms within the
1186 J . Org. Chem., Vol. 68, No. 4, 2003

Nickel-on-Charcoal
support structure, although there is no significant impact
of this feature on catalytic activity for the reactions
tested. Nonetheless, such treatment encourages complete
impregnation of nickel nitrate on the charcoal, even up
to levels as high as 15% nickel by weight. With increased
loadings, however, catalyst activities as measured by
aminations and Kumada couplings of aryl chlorides are
decreased. Reductions of the Ni(II)/C to active Ni(0)/C
using hydrogen at 425 °C, as opposed to use of BuLi at
ambient temperatures, lead to formation of large monoc-
rystalline nickel particles which, likewise, translates into
reduced catalyst activity.
The data, considered in its entirety, strongly support
homogeneous catalysis by nickel (Nisol) as the decisive
mechanism for transformations based on Ni/C. The
outstanding adsorption properties of the support, how-
ever, allow for recovery of almost all of the nickel
participating in such homogeneous catalysis by simple
filtration of reaction mixtures. Therefore, in the final
analysis, Ni/C offers all the advantages of a heteroge-
neous catalyst, while temporarily supplying the metal in
an active, mainly internal yet homogeneous state. One
noteworthy implication is that reaction times for these
homogeneous nickel-catalyzed cross-couplings under mi-
crowave conditions may be reduced substantially.45 Pre-
liminary tests along these lines already suggest that such
is indeed the case. Furthermore, the possibility of using
charcoal simply as a scavenger for homogeneous nickel
catalysis is currently under investigation. Details of this
study, along with additional methods based on Ni/C
catalyzed couplings, will be reported in due course.
ICP-AES in combination with experimental results
from cross-coupling reactions with different types and
quantities of nickel catalysts clearly implicate participa-
tion of a homogeneous nickel species in the catalytic cycle,
requiring that nickel bleeds from the solid support under
the reaction conditions. The amount of nickel in solution
detected by ICP-AES could be slightly increased by (1)
heating the reaction mixture; (2) reducing Ni(II)/C with
n-BuLi; and (3) by addition of the aryl chloride, although
these levels proved to be independent of ligand (PPh3)
concentration, or reaction time. Readsorption of 99% of
a standard amount of nickel in solution, as used for
aromatic aminations, by dry charcoal or Ni/C led to the
hypothesis that ICP-detected levels of soluble nickel are
misleading; in fact, they reflect only a minor amount of
the catalytically available Nisol which appears to be
'stored′ within the charcoal network. By means of a
‘three-phase test’, strong indications were obtained that
the catalytic cycle is supported only by nickel in solution,
i.e., little-to-no coupling occurs with nickel on the surface
on the support. Comparison of TONs of different reac-
tions under differing conditions led to an estimated
availability of nickel from Ni/C (up to 78%) far in excess
of that indicated by ICP data. The available nickel,
therefore, must be located almost entirely within the
charcoal matrix, since only small percentages can be
found at any time (by ICP) outside the support. Thus, an
equilibrium between Nisol both inside and outside the
pores is established early during the course of a reaction.
This feature allows for effective recycling of the catalyst,19
since almost no nickel is lost during filtration after
completion of the reaction, and the catalyst displays
identical activities in subsequent experiments.
Comparing TEM pictures, the activity profile of dif-
ferently reduced (BuLi vs H2 at 425 °C) or differently
loaded Ni/C catalysts can be nicely correlated with their
tendency to release nickel into solution. For Ni(0)/C (from
BuLi reduction of Ni(II)/C) prepared using either our first
or second generation process, the extent of bleed is
seemingly identical despite varying nickel distributions,
perhaps due to similar structural features of the nickel
conglomerates. Had true surface chemistry with NiC been
involved, a change in nickel distribution would be ex-
pected to bring about a corresponding change in reactivity
profile. With larger nickel particles on charcoal, formed
with either H2/heat-treated catalysts or with 15%-loaded
Ni/C, these are less prone to leach nickel into solution.
Correspondingly, their activities drop significantly. In
addition, catalysts with higher loadings of nickel suffer
from pore blocking, which contributes to reduced metal
exposure in solution, and thus for reduced participation
in the catalytic cycle.
Exp er im en ta l Section
Gen er a l. All transfers of catalyst and all reactions were
conducted under an argon atmosphere, if not stated otherwise.
Morpholine (2) and m-chlorotoluene (4) were distilled prior to
use, and PPh3 was recrystallized from hexanes. PhMgCl and
BuMgCl (1.8 M in THF) and n-BuLi (2.1 M in hexanes) were
titrated before use. All reactions were analyzed by quantitative
GC using 1,3,5-trimethoxybenzene and p-fluorotoluene as
standards for aromatic aminations and Kumada couplings,
respectively. GC response factors were determined using
commercially available compounds [3-phenyltoluene (6, R )
Ph), 3,3′-bistoluene (7)] or isolated material [N-(p-cyanophe-
nyl)morpholine (3), 3-butyltoluene (6, R ) Bu)]. Unequivocal
identification of products 6 (R ) Ph) and 7 was accomplished
by GC co-injection, GCMS analyses, and TLC comparison with
authentic materials. All spectroscopic data obtained after
product isolation were in accord with literature values.2g,33,46
GC analyses were performed using an HP-5 capillary column
(0.25 µm × 30 m; cross-linked 5% PH ME siloxane) and a time
program with 5 min at 40 °C followed by 10 °C/min ramp to
280 °C, and 20 min holding at this temp. ICP-AES analyses
were done on a Thermo J arrell Ash IRIS plasma spectrometer.
Transmission electron micrographs were taken using a Hitachi
HF 2000, at an accelerating voltage 200 kV, with a cold field
emission electron source and a point resolution of 0.23 nm.
This instrument was equipped with an EDX detector, allowing
for a beam diameter down to 1.2 nm. ReactIR analyses were
performed on an ASI ReactIR 1000 using a Sicomp probe.
P r ep a r a tion of Ni(II)/C. Activated charcoal (5.00 g) was
impregnated with Ni(NO3)2‚6H2O (727 mg, 2.50 mmol) in H2O
(75 mL) according to ref 15 (1st generation) or ref 27 (2nd
generation).
Gen er a l P r oced u r e for Ni/C-Ca ta lyzed Ar om a tic Am i-
n a tion s of p-Ch lor oben zon itr ile (1) w ith Mor p h olin e (2)
[p r ior r ed u ction of Ni(II) w ith n -Bu Li]. These reactions
were performed according to a literature protocol,18 using 0.750
mmol 1 (103 mg), 2.0 equiv of 2 (132 µL, 130.7 mg, 1.50 mmol),
and toluene (1.4 mL, total). Generally, 0.05 equiv of Ni/C (63.1
mg, 0.038 mmol, loading: 0.594 mmol/g), 0.025 equiv of dppf
33
(10.4 mg, 0.019 mmol) or 0.2 equiv of PPh3 (39.3 mg, 0.150
(45) (a) Lidstro¨m, P.; Tierney, J .; Wathey, B.; Westman, J . Tetra-
hedron 2001, 57, 9225. (b) Lew, A.; Krutzik, P. O.; Hart, M. E.;
Chamberlin, A. R. J . Comb. Chem. 2002, 4, 95.
(46) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 1264.
(b) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 6054.
(c) Takezawa, T.; Kusano, T. Nippon Kagaku Kaishi 1981, 1129; Chem.
Abstr. 1981, 95, 203442e. (d) Miki, Y.; Sugimoto, Y. Busshitsu Kogaku
Kogyo Gijutsu Kenkyusho Hokoku 1998, 6, 31; Chem. Abstr. 1998, 128,
204636h.
J . Org. Chem, Vol. 68, No. 4, 2003 1187

Lipshutz et al.
mmol), and LiO-t-Bu (72.1 mg, 0.900 mmol) were added. The
premixing period of catalyst and ligand in toluene was
shortened from 90 to 25 min and the time for reduction after
addition of BuLi (35.7 µL, 0.075 mmol, 2.1 M) was lowered
from 30 to 15 min. After each reaction (see Tables), the mixture
was cooled to room temperature and with stirring, 3 mL of
CH2Cl2 was added. The suspension was filtered through a
Bu¨chner funnel, and the cake was washed with CH2Cl2,
petroleum ether (10 mL each), and diethyl ether (25 mL). The
filtrate was refiltered, the solvent volume was reduced to ca.
1 mL, after which it was filtered through a pipet filled with
glass wool, Celite, and silica gel. The GC standard was added
to the resulting clear solution, and the extent of conversion
and percent product formed were determined by GC. Varia-
tions in reaction conditions and results for different reactions
can be found in Tables 2, 5, 8, and 12.
Gen er a l P r oced u r e for Ar om a tic Am in a tion s of p-
Ch lor oben zon itr ile (1) w ith Mor p h olin e (2) [with ou t
p r ior r ed u ction of Ni(II) w ith Bu Li]. These reactions were
performed according to a literature protocol,33 using 0.750
mmol of 1 (103 mg), 2.0 equiv of 2 (132 µL, 130.7 mg, 1.50
mmol), 0.05 equiv of Ni/C (63.1 mg, 0.038 mmol, loading: 0.594
mmol/g), 0.025 equiv of dppf (10.4 mg, 0.019 mmol) or 0.2 equiv
of PPh3 (39.3 mg, 0.150 mmol), and LiO-t-Bu (72.1 mg, 0.900
mmol) in toluene (1.4 mL). Workup and analysis of the product
mixture obtained were identical to the procedure above.
Variations of reaction conditions and results for different
reactions can be found in Tables 2, 5, 8, 11, and 12.
Ku m a d a Cou p lin gs of m -Ch lor otolu en e (4) a n d Gr ig-
n a r d Rea gen ts 5 [p r ior r ed u ction of Ni(II) w ith Bu Li].
Following a literature procedure,17 aryl chloride 4 (118 µL, 127
mg, 1.00 mmol) was treated with Grignard 5 (835 µL, 1.50
mmol, 1.8 M) at -78 °C after BuLi reduction (47.6 µL, 0.100
mmol, 2.1 M) of 0.05 equiv of Ni(II)/C catalyst precursor (84.2
mg, 0.050 mmol, loading: 0.594 mmol/g) in the presence of
0.2 equiv of PPh3 (52.5 mg, 0.200 mmol) and 1.0 equiv of LiBr
(86.9 mg, 1.00 mmol) in THF (1.5 mL), and finally heated at
reflux. After a selected reaction time (see Tables), the mixture
was cooled to room temperature and upon stirring, 3 mL of
aq NH4Cl solution were carefully added. The suspension was
filtered through a Bu¨chner funnel, and the cake was washed
with H2O, diethyl ether, petroleum ether, CH2Cl2 (each 10 mL),
and again diethyl ether (25 mL). The biphasic filtrate was
shaken, the aqueous phase was removed with a pipet, and the
organic layer was concentrated under reduced pressure. The
GC standard was added to the resulting clear solution, and
the extent of conversion and yield of product analyzed by GC.
Variations of reaction conditions and results for different
reactions can be found in Tables 8, 10, and 12.
Ku m a d a Cou p lin gs of m -Ch lor otolu en e (4) a n d Gr ig-
n a r d Rea gen ts 5 [with ou t p r ior r ed u ction of Ni(II) w ith
Bu Li]. Following a literature procedure,33 aryl chloride 4 (118
µL, 127 mg, 1.00 mmol) was treated with Grignard 5 (835 µL,
1.50 mmol, 1.8 M) at room temperature in the presence of 0.05
equiv of Ni(II)/C catalyst precursor (84.2 mg, 0.050 mmol,
loading: 0.594 mmol/g) and only 0.1 equiv of PPh3 (26.3 mg,
0.100 mmol) in THF (1.5 mL), and then heated to reflux. No
LiBr was used in this case. After a selected reaction time (see
tables), workup and analysis were preformed as described
above. Variations in reaction conditions and results for dif-
ferent reactions can be found in Tables 3 and 6.
Kumada couplings), followed by the ligand (as given in the
Tables), reagents, and the substrates. All reactions were
performed at temperatures used previously.17,18 Workup and
product analysis were as described above. Conditions and
results can be found in Tables 2 and 3.
P r ep a r a tion of TEM Sa m p les. Sa m p le A: Ni(II)/C (84.2
mg, 0.050 mmol, loading: 0.594 mmol/g) was stirred with 4
equiv of PPh3 (52.5 mg, 0.200 mmol) in THF (1.5 mL) at room
temperature for 20 min and for another 5 min after addition
of 2 equiv of n-BuLi (47.6 µL, 2.1 M). Sa m p le B: Ni(II)/C (84.2
mg, 0.050 mmol, loading: 0.594 mmol/g) was reduced under
hydrogen at 425 °C for 4.5 h as described above. THF (1.5 mL)
and 4 equiv of PPh3 (52.5 mg, 0.200 mmol) were then added.
Sa m p le C: This sample represented a standard Kumada
coupling of 4 with PhMgCl (5) for a 1 h period with prior BuLi
reduction of Ni/C as described above. Gen er a l w or k u p : All
samples were filtered through a frit under an inert atmosphere
and dried without further washing. P r ep a r a tion for m ea -
su r em en t: The samples were mounted on a Lacey carbon grid
in the dry state under argon and transported to the spectrom-
eter with a vacuum-transfer holder.
Sa m p le P r ep a r a tion for ICP -AES. Reaction mixtures
were either filtered after cooling to room temperature or
directly while hot. Use of a heated filter funnel for filtration
of a hot mixture did not result in significant differences
compared to filtration of a hot mixture through a cold funnel.
Depending on the temperature chosen for the mixture, the
filter cake was washed twice with cold or boiling solvent. The
filtrate was refiltered, and washing was performed with cold
solvent and H2O. The solvents were removed, 10 mL of 20%
HNO3 and 5 mL concentrated HCl were added, and the
mixture was heated at reflux for 5.5 h to digest as much
material into the aqueous phase as possible. Upon being cooled
and diluted with H2O (20 mL), the mixture was extracted with
hexanes (10 mL) and CH2Cl2 (2 × 7 mL), and the combined
organic layers re-extracted with H2O. The solvent was removed
from the combined aqueous phases and the ICP-AES sample
was prepared by adding 2% HCl in a way that the final
(estimated) nickel concentration was adjusted to between 1
and 35 ppm. If the solution was not completely clear at that
point, a short filtration through glass wool in a pipet was
required. Results of the following measurements are listed in
Tables 4, 7, and 10.
Rea d sor p tion Tests. With ou t su bstr a tes: NiCl2(PPh3)2
(0.038 mmol, 24.5 mg) and 0.5 equiv (relative to nickel) of dppf
(10.4 mg, 0.019 mmol) were stirred in toluene (1.4 mL) at room
temperature for 25 min, after which the Ni(II) was reduced
with 2 equiv of n-BuLi (35.7 µL, 0.075 mmol, 2.1 M) over an
additional 15 min. Then, either 56 mg dried activated charcoal
(Aldrich; drying in vacuo, 100 °C, 12 h) or ca. 62 mg Ni/C with
different nickel loadings (cf. Table 7) were added, and the
suspension was stirred at reflux for 1 h. With su bstr a tes:
The first reaction was run as a typical amination of chloroben-
zonitrile 1 with morpholine (2) with prior Ni(II) reduction by
BuLi. In this case, however, NiCl2(PPh3)2 (0.038 mmol, 24.5
mg) was used instead of Ni/C, along with 56 mg of dried
activated charcoal added together with the reaction partners.
The second reaction was performed with 0.019 mmol of both
NiCl2(PPh3)2 (12.5 mg) and Ni(II)/C (31.6 mg, loading: 0.594
mmol/g), such that the total amount of nickel theoretically
available for reaction was kept constant compared to the
former reaction. All samples were worked up as described for
the preparation of ICP-AES samples (hot filtration) and
spectroscopically analyzed.
R ed u ct ion of Ni(II)/C b y Hea t in a n At m osp h er e of
Hyd r ogen . Standard amounts of Ni(II)/C (63.1 mg, 0.038
mmol for aminations, and 84.2 mg, 0.050 mmol for Kumada
couplings; loading: 0.594 mmol/g) were placed in a Schlenck
tube which was evacuated and purged with H2, the process
being repeated three times. Under a balloon filled with H2
attached to the top of the tube, the vial was heated to 425 °C
in a sand bath for 4.5 h. Upon cooling the vial to room
temperature, the hydrogen atmosphere was replaced by evacu-
ation and purging with argon. A standard amount of solvent
was added (1.4 mL toluene for aminations; 1.5 mL THF for
Th r ee-P h a se Tests. Table 9, entries 1, 2: Reactions were
run according to the standard protocol for amination of
chlorobenzonitrile 1 with morpholine (2), each with and
without BuLi reduction of Ni(II)/C. The ligand dppf was
replaced by 4 equiv (relative to nickel) of polymer-bound PPh3
(100-200 mesh, 1.20 mmol/g). Table 9, entry 3: This reaction
was performed as with that in entry 1, and after 2 h, an
additional 4 equiv of PPh3 (not polymer-bound) was added and
1188 J . Org. Chem., Vol. 68, No. 4, 2003

Nickel-on-Charcoal
the mixture heated at reflux for an additional 2 h. Table 9,
entries 4, 5: As for that in entry 1, but with both 4 equiv of
PPh3 and 4 equiv of polymer-bound PPh3 added at the
beginning. To ensure that the outcome would not be impacted
by the increase (to 8 equiv) in phosphine ligand, the same
reaction was performed with half the amount of each ligand,
which afforded identical yields (not shown in Table 9). Table
9, entry 6: Reactions were run as with that in entry 1, but no
chlorobenzonitrile 1 was initially added. After 2 h at reflux,
the reaction mixture was cooled to room temperature and the
standard amount of 1 added, together with an additional 4
equiv of PPh3 (not polymer-bound). The mixture was then
heated for an additional 4 h at reflux. Table 9, entries 7 and
8: Run as in entry 6, but after the first 2 h of heating, only
aryl chloride 1 was added (no additional PPh3).
in an oil bath adjusted to 110 °C (rather than 130 °C as usually
used). The reaction was monitored for 7 h.
Am in a tion s w ith High er Loa d ed Ni/C. These reactions
were performed according to the standard procedures, using
0.038 mmol (aminations) or 0.050 mmol (Kumada couplings)
nickel added in the form of differently loaded Ni/C catalysts.
Catalysts used had the following nickel loadings: 0.594 mmol
nickel/g catalyst (3.5 wt %), 1.704 mmol/g (10%), and 2.556
mmol/g (15%). Results are listed in Table 10.
Ack n ow led gm en t. Financial support provided by
the NIH (GM 40287) and the DAAD (fellowship to S.
Tasler, Hochschulsonderprogramm III) is gratefully
acknowledged. Discussions with, and a preprint of a
review by, Prof. D. Bergbreiter (Texas A&M) are also
much appreciated. We are very pleased to thank Mr.
Peter M. Allen (UCSB College of Engineering) for
creating the cover artwork.
Am in a tion s Mon itor ed by Rea ctIR. A standard reaction
between chlorobenzonitrile 1 and morpholine (2) (with BuLi
reduction of Ni(II)/C) was run on a larger scale (2.00 mmol
aryl chloride 1), in 4 mL of toluene in a special Schlenck tube
allowing for connection to the ReactIR probe. To avoid vigorous
boiling around the detection window, the reaction was heated
J O020296M
J . Org. Chem, Vol. 68, No. 4, 2003 1189