Heterogeneous catalysis with nickel-on-graphite (Ni/Cg)

Article abstract of DOI:10.1039/b714600k

Impregnation of nickel(ii) onto graphite, upon reduction in situ, leads to a reagent that catalyzes both C-H and C-C bond formations between aryl halides, or aryl pseudo-halides, and various organometallics. Cross-couplings, most notably with tosylates, can lead to either reduced aromatics, biaryls, or styrenes as products under the influence of Ni/C_g. The catalyst is inexpensive, non-pyrophoric, and reusable. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b714600k

www.rsc.org/obc
Volume 6 | Number 1 | 7 January 2008 | Pages 1–204
ISSN 1477-0520
EMERGING AREA
Tom A. Butler, Elizabeth C. Swift
and Bruce H. Lipshutz
PERSPECTIVE
John E. Baldwin and Phyllis A. Leber
Molecular rearrangements through
thermal [1,3] carbon shifts
Heterogeneous catalysis with nickel-
on-graphite (Ni/Cg)

EMERGING AREA
www.rsc.org/obc | Organic & Biomolecular Chemistry
Heterogeneous catalysis with nickel-on-graphite (Ni/Cg)
Tom A. Butler, Elizabeth C. Swift and Bruce H. Lipshutz*
Received 21st September 2007, Accepted 24th September 2007
First published as an Advance Article on the web 5th November 2007
DOI: 10.1039/b714600k
Impregnation of nickel(II) onto graphite, upon reduction in situ, leads to a reagent that catalyzes both
C–H and C–C bond formations between aryl halides, or aryl pseudo-halides, and various
organometallics. Cross-couplings, most notably with tosylates, can lead to either reduced aromatics,
biaryls, or styrenes as products under the influence of Ni/Cg. The catalyst is inexpensive,
non-pyrophoric, and reusable.
three in the lab? Even a single improvement in a process could
Introduction
make a huge difference in the lifetime of a compound making
its way to market. One approach that may have merit, given the
extraordinary popularity of organopalladium chemistry, involves
finding suitable alternatives to this precious group 10 metal for
highly valued cross-couplings. The ‘base’ metal among the group
10 trio (Ni, Pd, Pt) is nickel, and while most organonickel-
catalyzed cross-couplings (as with Pd) are done in solution, there
“Make it cheaper, faster, and better.” We hear it all the time.
What industrial process chemist doesn’t look for ways to get all
Department of Chemistry & Biochemistry, University of California, Santa
Barbara, 93106, USA. E-mail: lipshutz@chem.ucsb.edu; Fax: +1 805-893-
8265
Tom Butler received his B.S. degree at Cal State, Chico under the direction of Prof. David B. Ball. He arrived at UCSB in late 2004 and
joined the research group of Prof. Bruce Lipshutz, where early work on nickel-on-graphite had begun. After completing this study on its use for
heterogeneous reductions of aryl sulfonates, he spent considerable time and effort developing new technology for controlling regiochemistry
in Negishi carboaluminations, and a process for applying this chemistry towards the industrial production of coenzyme Q10. Most recently,
he has completed his studies on Ni/Cg as a catalyst for carbon–carbon bond formations and is employed at Gilead.
Liz Swift is in her senior year at UCSB, working towards her bachelor’s degree in organic chemistry. As a member of the Lipshutz group
since the summer of 2006, she has been involved with various projects in organometallic chemistry looking forward to graduate school in
organic chemistry.
Bruce Lipshutz has been at UC Santa Barbara since beginning his professorial career in 1979, after extensive training by three phenomenal
instructors: Howard Alper (B.A.; SUNY Binghamton); Harry Wasserman (Ph.D.; Yale), and postdoctoral mentor E. J. Corey (Harvard).
Much of his career has been devoted to developing reagents of general use for the synthetic community (e.g., SEM-Cl, “Higher Order
Cuprates”, “Cuprate-in-a-Bottle”, DCAD, “Copper Hydride-in-a-Bottle”, Ni/C, etc.). The group’s efforts have now turned to a mix of
heterogeneous catalysis, including development of metal-supported cross-coupling reagents, and homogeneous catalysis, including several
‘name’ reactions in water. A number of projects in total synthesis involving axially chiral biaryls and chemistry associated with coenzyme Q10
are also well underway.
Tom Butler
Elizabeth Swift
Bruce Lipshutz
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are other options. Initially considered was activated charcoal.
The reagent derived from the combination of inexpensive nickel
and charcoal (Aldrich; new catalog # 675326), namely nickel-
in-charcoal (Ni/C), is easily prepared and has been shown to
mediate several common ‘name’ reactions.1 Oftentimes, these
heterogeneous events can be greatly accelerated by the convenient
use of microwave heating.2 Although the extent of impregnation
of metals (such as Ni) within a charcoal matrix benefits from
ultrasonication of Ni(NO3)2 admixed with 100 mesh charcoal
in water,3 the loading phenomenon can be dependent upon the
intricacies of charcoal itself. That is, there are many “flavors”
of charcoal; indeed, books with titles such as Active Carbon
contain an enormous reservoir of science on this allotrope.4
The variety of natural sources from which activated charcoal is
prepared is interesting, including as examples wood, coconut,
coal, nutshells, lignite, lignin, sawdust, fruit stones, and peat.
Processing (or “carbonization”) can determine pore structure and
surface area, and hence catalytic activity. Although an empirically-
derived “formulation” leads reproducibly to useful heterogeneous
catalysts such as Ni/C5 and more recently Cu/C,6 switching to
graphite (from graphein, Greek, to write) was expected to offer
some advantages: (1) it is less costly than activated charcoals;
(2) its thermal conductivity is far greater than that of charcoal,
potentially important when used under microwave conditions;
(3) it is free-flowing and thus easier to handle and control;
and (4) its structural differences (Scheme 1) relative to charcoal
might lead to different reactivity patterns in their corresponding
metal-impregnated catalysts. While charcoal has its irregular,
random pore structure brought about by cracking of carbon
sheets during carbonization,7 graphite retains its ordered state
˚
in which the distance between sheets is constant (ca. 3.3 A).
Thus, charcoal can have micropores (diameters, d < 2 nm),
mesopores (d = 2–50 nm), and macropores (d > 50 nm)
in which cross-couplings can take place. On the other hand,
graphite can accommodate metals between the sheets but the
desired catalysis must occur on the surface (and hence, nickel-on-
graphite).
Catalyst preparation: Ni/Cg
It’s easy . . . at least in hindsight.8 Grams of graphite (Aldrich;
catalog # 28,286–3) from a 1 kilo jug are mixed in water at
room temperature with hydrated nickel nitrate [Ni(NO3)2·6H2O],
also sold in multi-gram bottles (Aldrich; catalog # 24,407–4).
Impregnation of nickel is best accomplished by ultrasonication of
the heterogeneous mixture for ca. 1 hour in a standard laboratory
ultrasonic bath (Scheme 2). Subsequent distillation of water
presumably serves to convert the nickel present, by removal of
(NO)x, to nickel(II) oxide, in which state the reagent is stored.
Transmission electron microscopy (TEM) shows both the sheets of
graphite and the distribution of nickel nanoparticles (dark blobs;
Scheme 3). The procedure below, carried out on a convenient
scale, produces Ni/Cg in sufficient quantities for several trials as
a group 10 metal catalyst. Activation by reduction to Ni(0)/Cg is
done either immediately before use, or in situ, depending upon the
intended chemistry (vide infra).
Scheme 2 Impregnation of nickel(II) onto graphite.
Scheme 1 Comparison: charcoal vs. graphite.
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Scheme 3 Bright field TEM of Ni/Cg nm size blobs.
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applicable to both tosylates and mesylates, however, based on
inexpensive nickel should be competitive. Preformed Ni(0)/Cg
(prepared in THF as above) and then used in dry(!) DMF under
conventional conditions of heating at 120 ◦C (Scheme 5), catalyzes
the reduction of aryl tosylates in the presence of the potassium salt
of commercially available dimethylamine-borane, Me2NH·BH3
(Acros; catalog # 177310250). The combination of K2CO3 with
this Lewis acid–Lewis base complex, forming a white solid of
somewhat limited shelf-life, provides a highly chemoselective
source of hydride for the presumed Ni(II) intermediate following
oxidative addition. The caesium salt, generated using Cs2CO3 in
place of K2CO3, provides a more quickly formed, more soluble
(but far more expensive) alternative that works equally well.
Usually, ca. 5% Ni/Cg is used relative to substrate, not to be
confused with the percent loading of Ni on the solid support
(which can be far different). The amount of catalyst is actually
not crucial, since the metal is being used on the support, although
too much catalyst may prevent stirring and hence slow the rate.
Thus, there is a balance that needs be achieved, and at the loading
indicated in the procedure provided (ca. 3–4%), a 5% level of
catalyst allows for essentially complete conversion. Noteworthy is
the overall tolerance to several functional groups, including aryl
esters, amides, and ketones. Moreover, since the amide–borane
is pre-formed prior to introduction of the substrate, the reaction
conditions are not highly basic. Thus, peptidic educts (e.g., 1,
Scheme 6) survive the time needed for full conversion, which is on
the order of a day (although most substrates took 3–12 hours).
The Ni(II)/Cg as prepared above is best stored under argon in
a dessicator or glove box. This precaution is mainly to extend
lifetime, which is on the order of months, rather than due to any
safety issues that, in all likelihood, would have been observed
by now after years of use in our group. Thus, unlike other metals
impregnated onto graphite (e.g., K/Cg,9 Cu/Cg10), Ni/Cg prepared
in this fashion appears to have no pyrophoric nature. The same
is true for the activated catalyst, Ni(0)/Cg, which is conveniently
generated in dry THF at room temperature using n-BuLi (2 equiv.
vs. Ni) for ca. 15 minutes (Scheme 4).
Scheme 5 Ni/Cg-catalyzed reduction of aryl tosylates.
To add potential value to reductions with Ni/Cg, two additional
features needed attention: (1) reaction times should be shortened,
and (2) the catalyst should be recyclable. Thus, while conventional
heating led to clean reactions, reducing the timeframe from
several hours to minutes seemed like a worthwhile goal. By car-
rying out these reductions in a microwave instrument at elevated
temperatures (ca. 200 ◦C) under otherwise identical conditions,
reaction times were dramatically lowered (e.g., 1 to 2: conventional
29 h, lW 45 min; Scheme 6). A similar pattern of susceptibility
to Ni/Cg-mediated reduction was observed for mesylates. Using
tosylated quinoline 3 to arrive at product 4 as a test case for
recycling of the catalyst, virtually identical results were obtained
after a second use (Scheme 7). Also, particularly intriguing was
the unexpected result with substrate 3 using Ni/C, realized under
otherwise identical conventional conditions (DMF, 120 ◦C) but
Scheme 4 Reduction of Ni(II)/Cg to active Ni(0)/Cg.
Ni/Cg-catalyzed reductions of aryl sulfonates. . .
. . .No, not triflates, or even nonaflates; the cheaper ones: tosylates
and mesylates, compliments of nickel. In hindsight, it was not
obvious that such reductions represented the ideal starting point
for developing the chemistry of this reagent. Nonetheless, the
methodology for effecting such transformations at the time was
quite limited11 and this observation provided the incentive. More
recently, several new procedures have appeared that offer both
homogeneous alternatives, such as cat. Pd–HCOOH–Et3N–cat.
run overnight: no reaction. A hint that Ni/C
ꢀ= Ni/Cg (vide infra).
Cross-couplings catalyzed by Ni/Cg
Suzuki couplings
Prior success using Ni/C15 suggested that Ni/Cg should also
mediate biaryl bond formation between ArB(OH)2 and aryl
halides (including chlorides). In light of the reductions of tosylates
PPF-P(t-Bu)2 and cat. Ni–NaBH4–Cy3P,13 and heterogeneous
12
options, including Pd/C as catalyst.14 A heterogeneous method
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Scheme 6 Microwave-assisted reduction of a tyrosine tosylate.
Scheme 8 Ni/Cg vs. Ni/C as catalysts in Suzuki couplings.
and/or KF) can be used, allowing for more efficient stirring.
Employing these modified conditions, the graphite-based catalyst
led to a better yield, e.g., of biaryl 12 from precursors 6 and 11
(Scheme 9), although only ca. half the time was needed for reaction
relative to that using Ni/C. An additional representative example
involving tosylate 13 is illustrated in Scheme 10, highlighting the
deactivated nature of the boronic acid 14 en route to 15.
Scheme 7 Recycling of Ni/Cg; comparison with Ni/C.
and mesylates catalyzed by Ni/Cg (vide supra),8 perhaps these
pseudo-halides are viable alternatives? If both halides (especially
chlorides) and tosylates are useful in such couplings, then several
aspects of the chemistry look economically attractive: substrates
(Ar–Cl/OTs), catalyst (heterogeneous Ni), ligand (Ph3P), solvent
(dioxane), reaction times (shortened by microwave assistance?).
Halides were tested first to gauge the relative catalytic properties
of nickel-in-charcoal versus nickel-on-graphite. Ni(0)/Cg was
formed in the usual way, by prior reduction of Ni(II)/Cg with
n-BuLi. Under conventional heating conditions, the trend was
clear: in all cases Ni/Cg gave either similar or better results
(meaning cleaner, higher yielding reactions) relative to nickel-in-
charcoal. Thus, for deactivated p-chloroanisole 5, coupling with
boronic acid 6 gave rise to 7 in roughly the same yields and
reaction times, although Ni/Cg was slightly favored with respect
to both parameters (Scheme 8). The o-chloro-analog 8, however,
revealed a greater difference, with none of the corresponding biaryl
being observed in the Ni/C-catalyzed reaction with phenylboronic
acid 9, while Ni/Cg led to a good yield of product 10.
Scheme 9 Suzuki couplings using lW assistance: effect of temperature.
Aryl tosylates were studied next. Apparently, biaryl bond
formations involving tosylates that rely on heterogeneous nickel
of any form are unprecedented. Nonetheless, a variety of this
substrate type along with boronic acid partners (2 equivalents
vs. sulfonate) could be coupled in good yields. Reactions under
conventional conditions of heating were run in refluxing dioxane
at ca. 0.2 M in tosylate using excess K3PO4 as the base, with the
Ni/Cg pre-reduced with n-BuLi. Done in this fashion, however,
reactions can take several hours or even days to reach completion.
On the other hand, increasing the temperature, conveniently done
in a microwave instrument at 180–200 ◦C, greatly accelerates the
process leading to completion in 1.5–5 hours. Under microwave
irradiation, lower molecular weight bases/additives (e.g., LiOH
Scheme 10 Another example of Ni/Cg-catalyzed coupling of an aryl
tosylate.
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hydrozirconation–cross-couplings, THF can be used for both steps
◦
and the catalysis is complete within 15 minutes at 200 C. As is
oftentimes the case in hydrozirconation chemistry, the quality of
the Schwartz reagent and handling of the derived intermediate
zirconocenes can be crucial in subsequent group 10 metal-
catalyzed C–C bond formation. Care should be taken to exclude
moisture, not only given the sensitivity of C–Zr bonds but also to
avoid hydrolysis of the starting tosylates back to the corresponding
phenols, which has been observed if the solvent (THF) is wet. The
conclusion here is that there is no obvious benefit to graphite over
charcoal, other than the fundamental differences noted earlier.
Noteworthy is the finding that homocoupling is minimal in
these reactions. Curiously, these couplings are also considerably
less sensitive to hydrolysis of the sulfonate back to phenols by
adventitious water (perhaps more readily retained within the
charcoal matrix). Although roughly twice the more commonly
used amount of Ni/Cg (ca. 8% relative to substrate) is required
for net tosylate displacement, the virtues of this heterogeneous
catalyst should far outweigh the usual goal of achieving high
turnover numbers. Thus, given a recyclable, heterogeneous nickel
catalyst, this is a case where “more is better than less”: who
cares whether a reaction takes 8% Ni or 4% Ni under such
circumstances?
Negishi couplings of vinylzirconocenes17
Another comparison between Ni/Cg and Ni/C came in the form
of cross-couplings between vinylic zirconocenes, derived from
terminal alkynes, and aryl halides. Previously, it had been shown
that such intermediates, in fact, are unexpectedly robust upon
heating to 200 ◦C under microwave irradiation in the presence
of an aryl halide and Ni/C, leading to stereodefined styrenes in
good yields.15 Perhaps not unexpectedly, pre-activated Ni(0)/Cg,
likewise, produced clean E-b-substituted styrenes, typified by
the conversion of octyne 16 to product 19, R = n-C6H13 upon
exposure to bromide 18 (83%; Scheme 11). By way of comparison,
related acetylene 17 led to 19 (R = (CH2)4OTIPS) in comparable
yield under identical conditions using Ni/C. In these sequential
Carboalumination-coupling
Vinylalanes are viable coupling partners with various sp2-based
substrates, using Pd(0) catalysis. On the other hand, use of catalytic
Scheme 11 Hydrozirconation–Ni-catalyzed couplings.
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as opposed to an earlier solution using the bridged Brintzinger
zirconocene (ebi)ZrCl2 (ebi = ethylene bis-indenyl).19 Transfer
of the vinylalane intermediate 20, upon consumption of the
acetylene, to a microwave vial containing Ni/Cg and an aryl
tosylate (e.g., 11) was followed by heating at 200 ◦C for one hour.
Filtration of the mixture through a Buchner funnel and workup led
to an 83% isolated yield of the desired E-trisubstituted styrene 21.
Reaction variables & processing
There are several other reaction parameters associated with the
use of Ni/Cg not addressed as yet in these latest cross-coupling
reactions, including: (1) ligand used; (2) reaction work-up; and (3)
recycling of Ni/Cg, all of which can be considered in terms of the
potential impact insofar as the overall economics of the chemistry
are concerned. Fortunately, all three work to the advantage of
this heterogeneous catalysis. That is, screening of ligands (e.g.,
PCy3, S-Phos) led to the conclusion that Ph3P is the most effective,
and least expensive. In cases where biaryl products were close in
polarity to Ph3P, addition of CuCl to the crude worked-up reaction
mixtures cleanly and quickly removed the phosphine and allowed
for the smooth isolation of products (Scheme 13).20 Recycling of
Ni/Cg, as with Ni/C, is possible, and here the greater ease of
handling of graphite over charcoal allows for more facile recovery
and reuse. As illustrated in Scheme 14, an initial Suzuki coupling
Scheme 12 Carboalumination–cross-coupling: vinylalane + aryl tosylate.
Ni(0) to effect the equivalent process is not common and, to the
best of our knowledge, cross-couplings of vinylalanes with aryl
tosylates have not been described, let alone with a heterogeneous
source of Ni(0). While admittedly only a single example has been
demonstrated to date, a modified carboalumination of 1-octyne
16 was initially carried out in toluene (Scheme 12).18 Then, in the
presence of a mixed Al–Zr catalyst generated from excess Me3Al
and 5% Cp2ZrCl2, addition of commercial isobutylaluminoxane
(IBAO), exchange of isobutyl residues into a mixed metal complex
presumably occurs. This approach takes advantage of our recently
discovered method for controlling the regiochemistry in Negishi
carboaluminations18 using the inexpensive zirconocene Cp2ZrCl2,
Scheme 13 Use of CuCl to remove phosphines from reaction mixtures.
Scheme 14 Recycling the Ni/Cg catalyst.
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under microwave conditions between boronic acid 6 and halide
18 led to biaryl 22 (84%). The Ni/Cg could be easily recovered
by simple filtration in air, and then reused following activation in
the standard fashion (i.e., using n-BuLi in THF; vide supra). Re-
exposure of the catalyst to the same reaction conditions, albeit
involving completely different coupling partners (13 and 14),
afforded product 15 in similar yield (83%; cf. Scheme 10).
chemistry, and Dr Louise Weaver (University of New Brunswick)
for TEM analyses.
References
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Outlook
3 B. H. Lipshutz and S. Tasler, Adv. Synth. Catal., 2001, 343, 327–
Nickel-on-graphite has some attractive features, including ele-
ments of “green” chemistry,21 and if these are highly competitive
with those of the catalyst impregnated into charcoal, it could find
broader use. Nonetheless, it’s the unexpected differences between
reagents that may offer the biggest ‘bonus’; in particular, with
respect to chemoselectivities that lead to options otherwise not
possible under more commonly used homogeneous conditions.
For example, Ni/C catalyzes aminations of aryl chlorides15 easily
under microwave irradiation conditions22 especially when using
an activated case such as chlorobenzonitrile (23, Scheme 15).
Remarkably, all attempts to effect this standard coupling with
morpholine and 23 under identical conditions with nickel-on-
graphite have met with total failure.23 But in this case, failure might
be a good thing! When considered in light of the above discussion
on selected Suzuki couplings (8 + 9 → 10), where Ni/Cg catalyzes
the intended chemistry while Ni/C does not (cf. Scheme 8), it’s
clear that there is much to be learned about the properties of these
materials. With progress, there are likely to be other surprises
ahead with Ni, as well as other inexpensive metals (e.g., Fe),
impregnated into graphite. Perhaps these contributions will find
utility within the synthetic community; after all, when starting with
base metal salts and graphite, two trivial ingredients approaching
earth, wind, and fire, the eventual catalysis is almost for free.
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Scheme 15 Unexpected chemoselectivity between catalysts.
Acknowledgements
We warmly thank the NIH (GM 40287) for its support of our
program in biaryl synthesis involving Ni-catalyzed cross-coupling
23 B. H. Lipshutz, V. Kogan, B. A. Freiman and T. Butler, unpublished
work.
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