A simple, multidimensional approach to high-throughput discovery of catalytic reactions

Article abstract of DOI:10.1126/science.1207922

Transition metal complexes catalyze many important reactions that are employed in medicine, materials science, and energy production. Although high-throughput methods for the discovery of catalysts that would mirror related approaches for the discovery of medicinally active compounds have been the focus of much attention, these methods have not been sufficiently general or accessible to typical synthetic laboratories to be adopted widely. We report a method to evaluate a broad range of catalysts for potential coupling reactions with the use of simple laboratory equipment. Specifically, we screen an array of catalysts and ligands with a diverse mixture of substrates and then use mass spectrometry to identify reaction products that, by design, exceed the mass of any single substrate. With this method, we discovered a copper-catalyzed alkyne hydroamination and two nickel-catalyzed hydroarylation reactions, each of which displays excellent functional-group tolerance.

Full text of DOI:10.1126/science.1207922

A Simple, Multidimensional Approach to High-Throughput Discovery
of Catalytic Reactions
Daniel W. Robbins and John F. Hartwig
Science 333, 1423 (2011);
DOI: 10.1126/science.1207922
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Society, Palaeontological Scientific Trust, Andrew W.
Mellon Foundation, Ford Foundation, U.S. Diplomatic
Mission to South Africa, French Embassy of South Africa,
Oppenheimer and Ackerman families, and Sir Richard
Branson. Thanks also to the University of the Witwatersrand’s
Schools of Geosciences and Anatomical Sciences, Bernard
Price Institute for Palaeontology; Gauteng Government,
Gauteng Department of Agriculture, Conservation and
Environment, Cradle of Humankind Management Authority;
E. Mbua, P. Kiura, and V. Iminjili at the National Museums
of Kenya for access to comparative specimens; and the
University of Zurich 2010 Field School. For the fossil
preparation, we thank C. Dube, C. Kemp, M. Kgasi,
M. Languza, J. Malaza, G. Mokoma, P. Mukanela,
T. Nemvhundi, M. Ngcamphalala, S. Jirah, S. Tshabalala,
and C. Yates. Others who have given significant support
are B. de Klerk, W. Lawrence, C. Steininger, B. Kuhn,
L. Pollarolo, J. Kretzen, D. Conforti, C. Dlamini, H. Visser,
B. Nkosi, B. Louw, L. Backwell, F. Thackeray, M. Peltier,
and M. Klinkmüller. Further acknowledgements are given
to Texas A&M University (The Ray A. Rothrock ’77
Fellowship, the Program to Enhance Scholarly and
Creative Activities, and the International Research Travel
Assistance Grant of Texas A&M University), Swiss National
Research Foundation (PBBEP2-126195), Australian
Research Council (DP0877603), University of Melbourne
(McKenzie Fellowship), Liverpool University Geomagnetism
Laboratory staff, AfricaArray, James Cook University, and
the BHPBilliton Geosciences staff development program.
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Acknowledgments: We thank the South African Heritage
Resources and the Nash family. Funding was received
from the South African Department of Science and
Technology, South African National Research Foundation,
Institute for Human Evolution, University of the
Witwatersrand, University of the Witwatersrand’s Vice
Chancellor’s Discretionary Fund, National Geographic
Supporting Online Material
www.sciencemag.org/cgi/content/full/333/6048/1421/DC1
SOM Text S1 to S4
Figs. S1 to S8
Tables S1 to S3
References (23–73)
1 February 2011; accepted 2 August 2011
10.1126/science.1203697
though the experimental designs that have been
reported all have merit, few have been used by
laboratories beyond those disclosing the original
studies. Many of these approaches require cat-
ionic intermediates (11, 12, 15, 16), acidic products
(18), substrates with colorimetric tags, serial op-
timization of portions of modular ligands (19–21),
the attachment of reactants to DNA fragments
and polymerase chain reaction amplification to
identify the product, or robotic equipment with
a cost that is prohibitory to most laboratories.
A Simple, Multidimensional Approach
to High-Throughput Discovery of
Catalytic Reactions
Daniel W. Robbins and John F. Hartwig*
Transition metal complexes catalyze many important reactions that are employed in medicine,
materials science, and energy production. Although high-throughput methods for the discovery of Thus, to apply combinatorial methods to catalyst
catalysts that would mirror related approaches for the discovery of medicinally active compounds discovery in a general fashion, new methods that
have been the focus of much attention, these methods have not been sufficiently general or
accessible to typical synthetic laboratories to be adopted widely. We report a method to evaluate a
require equipment commonly available in a syn-
thetic laboratory or obtainable at a comparable
broad range of catalysts for potential coupling reactions with the use of simple laboratory equipment. cost are needed.
Specifically, we screen an array of catalysts and ligands with a diverse mixture of substrates and then
use mass spectrometry to identify reaction products that, by design, exceed the mass of any single
substrate. With this method, we discovered a copper-catalyzed alkyne hydroamination and two
Most published methods for the high-
throughput discovery of catalysts evaluate one
of the two catalyst-reactant dimensions. In other
nickel-catalyzed hydroarylation reactions, each of which displays excellent functional-group tolerance. words, these methods have been used to exam-
ine either many catalysts for a single class of
echanistic data often provide the foun- ery of new drug candidates and new enzymes reaction or a single catalyst for many reactions.
dation for catalyst development and for organic synthesis has raised the prospect of
M
optimization. However, many reactions applying analogous high-throughput experimen-
were discovered serendipitously while seeking tal methods to the discovery of catalytic transfor-
a different synthetic transformation (1, 2). The mations. Many studies on this topic have been
advent of combinatorial methods for the discov- published over the past two decades (3–17). Al- jhartwig@illinois.edu
Department of Chemistry, University of Illinois, Urbana-
Champaign, Urbana, IL 61801, USA.
*To whom correspondence should be addressed. E-mail:
Fig. 1. Contents of a single well in the multidimensional ex-
periments for reaction discovery. The combination of 17 sub-
strates was placed into each reaction well. Twelve ligands were
dispensed, one into each well of a column, and eight metal cat-
alyst precursors were dispensed, one into each well of a row. The
plate was sealed and heated at 100°C for 18 hours. After this
time, the contents of the wells in the plate were analyzed by
mass spectrometry. The number of substrates is arbitrary; the
17 substrates contain a representative set, not a comprehensive
set, of typical organic functional groups. A group of catalysts de-
rived from Mn, Fe, Cr, Co, Cu, Ni, and W was chosen because of
its abundance and low cost. In addition, we examined catalysts
derived from Ru and Mo because these are inexpensive relative
to the more precious metals, Yb as a representative f-block metal, and Au be-
cause of its wide range of reactivity that has recently been uncovered. The ligands
we combined with these metals included common phosphines and amines, as
well as less explored phosphine oxides, phosphine sulfides, and amidinates
(table S1). Excess of the metal complexes were used in this system to alleviate
poisoning all of the potential catalysts by one substrate. Reactions discovered
in such a system would be rendered catalytic after initial identification of the
transformation and metal-ligand combination that induces the transformation.
The 17 substrates, in combination with catalysts derived from 15 metal centers
and 23 ligands or the absence of a ligand, correspond to more than 50,000
reactions. These reactions were conducted in a few days, after developing our
protocol. Bu, butyl; tBu, tert-butyl; Me, methyl; Ph, phenyl.
www.sciencemag.org SCIENCE VOL 333 9 SEPTEMBER 2011
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A two-dimensional approach in which many fore, the reaction partners) would be difficult cursor (15 total plus 1 negative control containing
catalysts for many possible catalytic reactions to determine from the mass spectrum alone. no metal) and one ligand (23 ligands plus 1 neg-
are tested simultaneously would create a more Therefore, we devised an additional protocol to ative control containing no ligand). In this experi-
efficient discovery platform if the reactants and identify the product within a particular well by ment, we included the substrates, metal-catalyst
products from such a system could be identi- running a small set of additional experiments precursors, and ligands for three known reactions
fied. Here, we disclose a method to discover cat- (see below).
as positive controls. These reactions were the
alytic reactions by conducting experiments in We implemented our design by conducting Ni-catalyzed carbocyanation of an alkyne (25),
an xy array on pools of substrates that have sim- experiments in which the 17 reagents were com- the Cu-catalyzed oxidative coupling of an aro-
ilar masses and analyzing combinations of these bined in each of 384 wells (of a 16-by-24 array), matic amine and an aryl boronic acid (26), and
pools by mass spectroscopy. This format allows with all but one well containing one metal pre- the Ru-catalyzed alkylation of a sulfonamide
us to evaluate thousands of reactions at one
time and to pinpoint, with just a few mass spec-
tral measurements, the coordinates of the metal
and ligand that effect a reaction between two or
more substrates.
For the study described here, we conducted
the core experiment with a set of 17 organic re-
actants, each of which contains 10 to 13 heavy
atoms (C, N, O, F, S) and possesses a single
functional group (Fig. 1) (22). A reaction between
two of these substrates would produce a product
with a mass outside of the range of masses of
the reactants. We obtained mass spectral data
by a combination of gas chromatography–mass
spectrometry (GC-MS) to measure the masses
of nonpolar products and electrospray ionization
mass spectrometry (ESI-MS) to measure the
masses of polar products (23). The mass of po-
tential products from joining two substrates is
easily calculated from the masses of the reactants,
including the masses of potential products formed
with concomitant loss of common small mole-
cules, such as H2O, NH3, H2, and HCN or common
leaving groups, such as halides (24).
We chose the catalyst components for the
initial implementation of this strategy to identify
Earth-abundant metals that catalyze reactions
previously induced by precious metal complexes.
Although progress has been made toward the
goal of catalyzing reactions with first-row tran-
sition metals, the smaller body of mechanistic
information on reactions catalyzed by such sys-
tems makes high-throughput discovery methods
particularly appealing. The exact metals and lig-
ands that we used in these experiments are de-
picted in table S1. The reactions identified in this
format would necessarily have the high degree
of functional-group tolerance most often needed
to prepare natural products and medicinally im-
portant compounds (22), because they were
formed in a medium containing a wide range of
additional functional groups.
Fig. 2. GC–mass spectrum of the combination of reactions in the row containing Cu(OAc)2 as a metal
To minimize the number of mass spectra, in
catalyst precursor. The product from Cu-catalyzed oxidative coupling was observed. The peak at 17.9 min
anticipation of conducting such studies on a large
corresponds to material with an m/z value of 281, which is the mass of the amination product. MW,
molecular weight.
format, we analyzed reaction products by creat-
ing 8 samples containing a portion of the contents
of each row and 12 samples containing a portion
of the contents of each column of a 96-well plate.
By this method, only 20 mass spectra on each
96-well plate are needed to identify the xy co-
ordinates of the metal-ligand combination that
gives rise to a reaction product. These coordi-
nates correspond to the pooled samples of the
row and column containing the same reaction
product. In some cases, the product (and, there- Fig. 3. Cu-catalyzed alkyne hydroamination with 4-nBu-aniline. THF, tetrahydrofuran.
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REPORTS
with an alcohol (Fig. 2 and figs. S1 and S2) (27).
Table 1. Selected copper-catalyzed alkyne hydroaminations with aromatic amines.
We observed the product from each of these three
reactions among the more than 50,000 possible
catalytic reactions [(17·16/2 cross-combinations
of substrates plus 17 homo-coupling of substrates)
by 15 metal catalyst precursors by 24 ligands].
The GC-MS trace from the row containing
Ni(cod)2 (cod, 1,5-cyclooctadiene) revealed the
product from carbocyanation of 5-decyne with
2-cyanonaphthalene, which eluted at 18.1 min
and showed a molecular ion with a mass/charge
ratio (m/z) of 291 (fig. S1). The GC-MS trace from
the row containing Cu(OAc)2 (OAc, an acetoxy
group) revealed the diarylamine obtained from
oxidative coupling of 4-tert-butylphenylboronic
acid with 4-butylaniline, which eluted at 17.9 min
and showed a molecular ion with an m/z val-
ue of 281 (Fig. 2). Finally, the ESI-MS for the
row containing [Ru( p-cymene)Cl2]2 [cymene,
1-methyl-4-(1-methylethyl)benzene] had peaks
corresponding to the mono- and dialkylation of
p-toluenesulfonamide with 1-dodecanol (fig. S2)
with m/z = 339 and m/z = 507, respectively. These
positive-control experiments showed that discrete
transition metal–catalyzed reactions can be iden-
tified from a pool of substrates that could undergo
thousands of possible binary reactions.
In addition to the products of these positive-
control reactions, we observed the products from
a reaction catalyzed by a first-row metal complex
without ligands and a reaction catalyzed by a
first-row metal complex containing a phosphine
ligand. The GC–mass spectra of the solutions
in the two rows containing CuCl and Cu(OAc)2
consisted of a peak corresponding to a molecular
ion with m/z = 315 (fig. S3). This product cor-
responds to that from the coupling of 1-dodecyne
with 4-butylaniline. This peak also appeared in the
GC–mass spectra of the contents of the rows cor-
responding to reactions containing PBu3 (C), the
b-diketiminate ligand (L), and tri-p-tolylphosphite
(S), as well as the row corresponding to reactions
containing no ligand (T), indicating that the re-
action occurs with the copper precursors alone
and with the combination of the precursors and
two of the phosphine ligands or the b-diketiminate
ligand.
Separate experiments with the amine, alkyne,
and catalyst components alone demonstrated that
the reaction of the aromatic amine with the al-
kyne catalyzed by CuCl and Cu(OAc)2 leads to
the Markovnikov addition of the amine to the
alkyne, followed by tautomerization to the cor-
responding imine (Fig. 3) (28, 29–31). The product
of this reaction was isolated as the secondary
amine after reduction with NaBH3CN. Reactions
catalyzed by CuCl occurred in higher yield than
those catalyzed by Cu(OAc)2 (32). Although this
reaction occurs in the presence of three of the
ligands identified in the combinatorial format, the
reaction also proceeded rapidly in the absence of
a ligand. This copper-catalyzed reaction repre-
sents a rare hydroamination of an alkyne catalyzed
by a first-row metal (33–35). As shown by data
in Table 1, this process occurs under conditions
Fig. 4. Deconvolution strategy to identify coupling partners for products observed in high-throughput
reaction discovery.
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REPORTS
triarylalkene product. A similar strategy showed
that an additional product in the wells containing
Ni(cod)2 and P(nBu)3 that eluted at 16.6 min with
a molecular ion of m/z = 292 (fig. S5) corre-
sponded to a triarylalkene product from hydro-
arylation of diphenylacetylene with the haloarene
4-bromo-1,2-difluorobenzene. Examination of
the combinations of Ni(cod)2 and NiCl2-dme
with the ligands identified from the initial catalyst
screening showed that Ni(cod)2 and PPh3 cat-
alyzed the hydroarylation of diphenylacetylene
with phenylboronic acid to give triphenylethylene
in good yield (Fig. 5). The reaction catalyzed by
Ni(cod)2 without an added ligand formed just
15% yield of triphenylethylene. When the hydro-
arylation of diphenylacetylene was conducted with
bromobenzene and the combination of Ni(cod)2
and P(nBu)3 as the catalyst, triphenylethylene
was formed in less than 10% yield, but the same
reaction with triethylsilane as a third component
to act as a reducing agent furnished triphenyl-
ethylene in 71% yield (Fig. 5). This transfor-
mation of arylboronic acids has been reported
most commonly with rhodium (36) and palla-
dium (37) catalysts (38), which contain costly
precious metals.
Fig. 5. Ni-catalyzed hydroarylation of diphenylacetylene with phenylboronic acid and bromobenzene.
Fig. 6. Nickel-catalyzed al-
kyne hydroarylation with aryl
and heteroaryl boronic acids.
The ratio given is cis/trans
(Z/E) olefin geometry.
The synthesis of stereochemically defined
trisubstituted alkenes is a challenging problem
(39, 40). Such products are often prepared by
stereocontrolled additions to alkynes, but fewer
reactions yield anti-addition products than syn-
addition products, and hydroarylations that give
anti-addition products are unknown. In con-
trast to this precedent, the major products of the
two types of nickel-catalyzed hydroarylation
discovered here result from anti-addition to the
alkyne in most cases (41). For example, the
hydroarylation of diphenylacetylene with 4-tert-
butylphenylboronic acid gave the addition product
Fig. 7. Nickel-catalyzed al-
kyne hydroarylation with aryl
and heteroaryl bromides. The
ratio given is Z:E olefin ge-
ometry. Et, ethyl.
with 25 mole percent of the inexpensive CuCl in pools in the presence of the metal catalyst pre- with an 8.7/1 ratio when the catalyst contained
good yield. Moreover, this reaction tolerates an cursor and ligand that had been shown to form PPh3. Likewise, the products from nickel cata-
array of potentially reactive functional groups, the unidentified product. These binary combina- lyzed hydroarylation of an alkyne with the aryl
such as nitriles, esters, ketones with enolizable tions of the four sets of substrates corresponded halide and silane gave predominantly the anti-
hydrogens, and unprotected alcohols, vindicating to just six reactions. In addition, to assess whether addition product. Moreover, the ligand affects the
a core hypothesis of our experimental design.
the coupling of two of the reactants requires a E/Z ratio from reaction of the arylboronic acid.
The GC-MS analysis from our experiment third component that could act as a ligand or Reactions conducted with the catalyst generated
also revealed a reaction product eluting at promoter, three of the substrate sets were also from PCy3 (Cy, cyclohexyl) gave the addition
18.6 min with an apparent molecular ion having allowed, in parallel, to react in a similar manner, product in a 1/3.8 ratio favoring the stereoisomer
an m/z value of 312. This peak was observed for a total of 10 reactions. This set of 10 reactions from syn addition. These stereochemical out-
in the traces of the wells containing the com- identified the two sets that contained the reactants comes were unexpected and show the ability
bination of Ni(cod)2 or NiCl2-dme (dme, 1,2- that formed the unknown product. We then di- to use the discovery platform to identify reactions
dimethoxyethane) and several phosphine ligands vided the components of these two sets into four that occur with different selectivities, presum-
and an N-heterocyclic carbene (fig. S4). Because sets, each containing two substrates. In a similar ably, from mechanisms not followed by earlier
the identity of this product was not obvious from manner, we conducted 10 reactions in parallel catalysts.
the mass spectrum, we devised a deconvolution with the metal catalyst precursor and ligand and
strategy to determine the reactants from which identified the two sets that yielded the desired arylation of alkynes with various boronic acids
it formed. product. We then allowed the four individual com- (Fig. 6) showed that, like the hydroamination
A survey of this nickel-catalyzed hydro-
For this strategy, we first divided the potential ponents of these sets to react with each other in that we identified, this reaction tolerates a broad
reactants (in this case, 17) into a small number binary and ternary combinations. From these range of functional groups. The nickel-catalyzed
of subsets (in this case, three sets of 4 potential reactions, we identified the two reactants that hydroarylation of alkynes with aromatic boronic
reactants and one set of 5 potential reactants) formed the unknown product.
acids containing esters, nitriles, ketones with
(Fig. 4 and figs. S15 to S18) And then combined This short series of 3 by 10 reactions showed enolizable hydrogens, aryl chlorides, and alde-
the reactants in each of these sets to create four that the unknown product with m/z = 312 corre- hydes formed trisubstituted alkenes in good yield
reactant pools. The pool of reactants in one set sponded to the hydroarylation of diphenylacetylene with generally good selectivity for the Z over
was then allowed to react with the three other with 4-tert-butylphenylboronic acid to yield a E alkene geometry. 2-heteroaryl boronic acids,
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Acknowledgments: We thank the NIH (grant GM-55382) and
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for financial support and the Univ. of Illinois and the
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support (D.W.R.). We also thank P. Hergenrother
(Univ. of Illinois), M. Burke (Univ. of Illinois), and
S. Herzon (Yale Univ.) for helpful discussions.
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Materials and Methods
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28. Intermolecular hydroamination of an alkyne has been
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compatibility, and it has been catalyzed by complexes of
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References (46–50)
4 May 2011; accepted 6 July 2011
10.1126/science.1207922
tures (1). Until now, however, the vast extent of
East Antarctica, which comprises 77% of the
continent, has been devoid of quality data; only
a few floating ice shelves have been mapped,
and comprehensive velocity mapping has been
limited to the lower reaches of key outlet gla-
ciers (2).
Balance velocity calculated from ice thick-
ness, surface slope, and snow accumulation data
provides insights about the potential flow pat-
tern of the ice sheet (3), but the technique as-
sumes an ice sheet in mass equilibrium, which
is not correct everywhere, and that ice flows
perpendicular to surface contours, which is a
Ice Flow of the Antarctic Ice Sheet
E. Rignot,1,2* J. Mouginot,1 B. Scheuchl1
We present a reference, comprehensive, high-resolution, digital mosaic of ice motion in Antarctica
assembled from multiple satellite interferometric synthetic-aperture radar data acquired during
the International Polar Year 2007 to 2009. The data reveal widespread, patterned, enhanced
flow with tributary glaciers reaching hundreds to thousands of kilometers inland over the entire
continent. This view of ice sheet motion emphasizes the importance of basal-slip–dominated
tributary flow over deformation-dominated ice sheet flow, redefines our understanding of ice
sheet dynamics, and has far-reaching implications for the reconstruction and prediction of ice
sheet evolution.
ce velocity is a fundamental characteristic of ground-based stations are limited relative to the
glaciers and ice sheets that measures the rate size of the continent, leading to an incomplete
at which ice is transported from the interior picture of Antarctica. Satellite radar interferom-
1Department of Earth System Science, University of California
Irvine, Irvine, CA 92697, USA. 2Jet Propulsion Laboratory, Cal-
ifornia Institute of Technology, Pasadena, CA 91109, USA.
I
regions toward the ocean, the location of pre- etry, or InSAR, has been successfully used to
ferred channels of ice transport, and how ice mass map glacier flow independent of cloud cover,
evolves with time. Traditional measurements from solar illumination, or the presence of surface fea- erignot@uci.edu
*To whom correspondence should be addressed. E-mail:
www.sciencemag.org SCIENCE VOL 333 9 SEPTEMBER 2011
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