Pre-transmetalation intermediates in the Suzuki-Miyaura reaction revealed: The missing link

Article abstract of DOI:10.1126/science.aad6981

Despite the widespread application of Suzuki-Miyaura cross-coupling to forge carbon-carbon bonds, the structure of the reactive intermediates underlying the key transmetalation step from the boron reagent to the palladium catalyst remains uncertain. Here we report the use of low-temperature rapid injection nuclear magnetic resonance spectroscopy and kinetic studies to generate, observe, and characterize these previously elusive complexes. Specifically, this work establishes the identity of three different species containing palladium-oxygen-boron linkages, a tricoordinate boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and 1:1 stoichiometry with respect to palladium. All of these species transfer their boron-bearing aryl groups to a coordinatively unsaturated palladium center in the critical transmetalation event.

Full text of DOI:10.1126/science.aad6981

RESEARCH
| REPORTS
power, given by the Curzon-Ahlborn (26) formula
28. B. Lin, J. Chen, Phys. Rev. E 68, 056117 (2003).
29. S. An et al., Nat. Phys. 11, 193–199 (2014).
30. N. Linden, S. Popescu, P. Skrzypczyk, Phys. Rev. Lett. 105,
130401 (2010).
31. R. Kosloff, A. Levy, Annu. Rev. Phys. Chem. 65, 365–393
(2014).
32. M. O. Scully, M. S. Zubairy, G. S. Agarwal, H. Walther, Science
299, 862–864 (2003).
33. R. Dillenschneider, E. Lutz, Europhys. Lett. 88, 50003 (2009).
34. F. G. Brandão, M. Horodecki, J. Oppenheim, J. M. Renes,
R. W. Spekkens, Phys. Rev. Lett. 111, 250404 (2013).
35. M. Horodecki, J. Oppenheim, Nat. Commun. 4, 2059 (2013).
ACKNOWLEDGMENTS
pffiffiffiffiffiffiffiffiffiffiffiffiffi
hCA ¼ 1 − T1=T2 = 1.9%, reflects that the cur-
rent trap parameters do not correspond to the
optimal point (14). The performance of future
single-ion heat engines could be improved by re-
designing the geometry of the trap to have cycles
with a higher range of frequencies wr (see Fig.
4B). This could be achieved by increasing either
the angle of the taper or the absolute radial trap
frequencies.
We thank Princeton Instruments for the loan of the ICCD camera
and S. Deffner for fruitful discussions. Supported by the German
Research Foundation (grant “Einzelionenwärmekraftmaschine”),
the Volkswagen Foundation (grant “Atomic Nano-Assembler”),
European Union (EU) COST action MP1209, and the EU
Collaborative Project TherMiQ (grant agreement 618074). The data
presented in this report are available upon request to K.S.
14 October 2015; accepted 4 March 2016
10.1126/science.aad6320
We have demonstrated a realization of a heat
engine whose working agent is a single atom. This
classical device offers a broad platform for future
experiments investigating, for instance, machines
coupled to nonthermal reservoirs (27) or single-
ion refrigerators and pumps (28). Moreover, the
quantum regime (kBT ≈ ħwr) could be reached by
replacing Doppler cooling by electromagnetically
induced transparency cooling or side-band cool-
ing (10), as in the recent verification of the quantum
Jarzynski equality (29). In the quantum domain,
dark-state thermometry could be replaced by side-
band spectroscopy, again allowing for the determi-
nation of the cycle of the engine and thus its power
and efficiency. Such a system would permit the
study of the performance of small quantum ma-
chines (30, 31) and the exploration of genuine
quantum effects in thermodynamics, such as quan-
tum coherences (32) and correlations (33), as well
as the testing of predictions of quantum resource
theory (34, 35).
ORGANOMETALLICS
Pre-transmetalation intermediates in
the Suzuki-Miyaura reaction
revealed: The missing link
Andy A. Thomas and Scott E. Denmark*
Despite the widespread application of Suzuki-Miyaura cross-coupling to forge
carbon-carbon bonds, the structure of the reactive intermediates underlying the key
transmetalation step from the boron reagent to the palladium catalyst remains
uncertain. Here we report the use of low-temperature rapid injection nuclear magnetic
resonance spectroscopy and kinetic studies to generate, observe, and characterize
these previously elusive complexes. Specifically, this work establishes the identity
of three different species containing palladium-oxygen-boron linkages, a tricoordinate
boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and
1:1 stoichiometry with respect to palladium. All of these species transfer their
boron-bearing aryl groups to a coordinatively unsaturated palladium center in the
critical transmetalation event.
REFERENCES AND NOTES
1. Y. A. Çengel, M. A. Boles, M. Kanoğlu, Thermodynamics:
An Engineering Approach (McGraw-Hill, ed. 8, 2014).
2. S. Whalen, M. Thompson, D. Bahr, C. Richards, R. Richards,
Sens. Actuators A 104, 290–298 (2003).
3. P. Steeneken et al., Nat. Phys. 7, 354–359 (2011).
4. J.-P. Brantut et al., Science 342, 713–715 (2013).
5. V. Blickle, C. Bechinger, Nat. Phys. 8, 143–146 (2012).
6. I. A. Martínez et al., Nat. Phys. 12, 67–70 (2016).
7. T. Hugel et al., Science 296, 1103–1106 (2002).
8. R. P. Feynman, Eng. Sci. 23, 22 (1960).
9. J. Roßnagel, K. N. Tolazzi, F. Schmidt-Kaler, K. Singer, New J.
Phys. 17, 045004 (2015).
10. D. Leibfried, R. Blatt, C. Monroe, D. Wineland, Rev. Mod. Phys.
75, 281–324 (2003).
11. R. Blatt, D. Wineland, Nature 453, 1008–1015 (2008).
12. J. F. Poyatos, J. I. Cirac, P. Zoller, Phys. Rev. Lett. 77,
4728–4731 (1996).
13. C. J. Myatt et al., Nature 403, 269–273 (2000).
14. O. Abah et al., Phys. Rev. Lett. 109, 203006 (2012).
15. H. J. Metcalf, P. van der Straten, Laser Cooling and Trapping
(Springer, 1999).
16. J. I. Cirac, R. Blatt, P. Zoller, W. D. Phillips, Phys. Rev. A 46,
2668–2681 (1992).
17. J. I. Cirac, M. Lewenstein, P. Zoller, Phys. Rev. Lett. 72,
2977–2980 (1994).
18. H. C. Nägerl, D. Leibfried, F. Schmidt-Kaler, J. Eschner, R. Blatt,
Opt. Express 3, 89–96 (1998).
19. B. Lin, J. Chen, Phys. Rev. E 67, 046105 (2003).
20. T. Peters, B. Wittrock, F. Blatt, T. Halfmann, L. P. Yatsenko,
Phys. Rev. A 85, 063416 (2012).
21. S. Knünz et al., Phys. Rev. A 85, 023427 (2012).
22. G. S. Agarwal, S. Chaturvedi, Phys. Rev. E 88, 012130
(2013).
23. K. Brandner, K. Saito, U. Seifert, Phys. Rev. X 5, 031019
(2015).
24. J. R. Taylor, Classical Mechanics (University Science, Sausalito,
CA, 2005).
25. L. D. Landau, E. M. Lifschitz, Statistical Physics (Elsevier,
1980).
26. F. Curzon, B. Ahlborn, Am. J. Phys. 43, 22 (1975).
27. J. Roßnagel, O. Abah, F. Schmidt-Kaler, K. Singer, E. Lutz, Phys.
Rev. Lett. 112, 030602 (2014).
alladium-catalyzed cross-coupling reactions
have fundamentally changed the practice
of organic synthesis. These reactions forge
carbon-carbon bonds through the migra-
tion of a carbon-based substituent from a
plays in initiating the transmetalation event.
Path A proceeds through the combination of a
negatively charged aryltrihydroxyboronate (com-
pound 1) and a palladium halide complex (2),
which form a hypothetical intermediate con-
taining a Pd-O-B unit (3). The alternative path B
proceeds through the combination of a neutral
arylboronic acid (4) and a palladium hydroxide
complex (formed through the displacement of the
organopalladium halide by hydroxide; 5), ultimately
converging to the same intermediate 3, which is
then poised to transfer the aryl group to pal-
ladium in an intramolecular b-aryl elimination
step, followed by reductive elimination (Fig. 1).
Species such as 3 represent the missing link be-
tween the starting organoboron reagents and the
diorganopalladium intermediates that are known
to afford cross-coupling products.
The role of the base in the Suzuki-Miyaura re-
action was investigated initially by the Soderquist
laboratory (12) and, more recently, by the labo-
ratories of Hartwig (13), Amatore and Jutand
(14–16), and Schmidt (17, 18). The kinetic analysis
in (13) established that path B is favored over
path A by more than four orders of magnitude,
a conclusion that is reinforced by the extensive
kinetic studies in (14–16), which clearly identi-
fied multiple antagonistic roles for the hydrox-
ide ion. Although nuclear magnetic resonance
(NMR) spectroscopic and kinetic studies have
P
main group element to palladium, as exemplified
by the Kumada-Tamao-Corriu (Mg) (1), Suzuki-
Miyaura (B) (2), Stille-Migita-Kosugi (Sn) (3),
Negishi (Zn) (4), and Hiyama-Denmark (Si) (5) re-
actions. The Nobel Prize–sharing Suzuki-Miyaura
reaction (6) is currently the premier cross-coupling
process and has been widely applied in organic
(7), medicinal (8), and materials (9) chemistry. It
is also frequently used in the industrial syntheses
of fine chemicals (10) and pharmaceuticals (11)
because of its demonstrated reliability, its func-
tional group compatibility, and the low cost and
ease of handling of a wide variety of commer-
cially available boron-based reagents.
Despite the preeminent status of the Suzuki-
Miyaura reaction, a fundamental understanding
of the critical migratory transmetalation event
from boron to palladium has thus far been lack-
ing (12–18). For decades, chemists have consid-
ered two pathways (path A and path B in Fig. 1)
that differ in the role that the hydroxide ion
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, IL 61801, USA.
*Corresponding author. E-mail: sdenmark@illinois.edu
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well within the chemical shift regime for 6-B-3
boron compounds (29). Related 6-B-3 complexes
of arylboronic and diarylborinic acids with Pt and
Rh have been synthesized and exhibit 11B NMR
resonances similar to that of 11 (30, 31).
To provide additional evidence for the struc-
ture of 11, an independent synthesis was carried
out (route 2). This synthesis involved combin-
ing trans-(i-Pr3P)2(4-FC6H4)Pd(I) (8) with 3.0
equivalents of thallium 4-fluorophenylboronate
(10) in the presence of dibenzo-22-crown-6 (32),
together with 1.0 equivalent of i-Pr3P in THF, at
−78°C; this was followed by warming to −30°C in
the NMR spectrometer (Fig. 2). A small amount
of conversion (~10%) to complex 11 was observed,
together with cross-coupling product 13 (~30%),
by 31P and 19F NMR spectroscopy, demonstrat-
ing that intermediate 11 can be formed without
the intermediacy of arylpalladium hydroxide
complexes (33).
To support the assertion that the boron atom
in 11 is tricoordinate (6-B-3), a second independent
synthesis of 11 was undertaken (route 3). A solu-
tion of arylpalladium hydroxide complex 6 and
4-fluorophenylboroxine 12 (0.33 equivalents) in
THF-d8 was combined with 2.0 equivalents of
i-Pr3P at −78°C in an NMR tube, which was quickly
inserted into the NMR spectrometer that had been
pre-cooled to −60°C, whereupon complex 11 was
observed (Fig. 2, route 3). A ~50% conversion to
11 was observed at −60°C over 36 hours, along
with cross-coupling product 13. The similarity of
the spectroscopic data (including the NOE spec-
troscopy cross peaks and the 11B NMR chemical
shifts; figs. S13 to S21) for the species generated
from the three independent syntheses provides
compelling support for the structural assignment
of 11 as a 6-B-3 palladium(II) complex containing
a Pd-O-B linkage.
Fig. 1. Palladium-catalyzed cross-coupling reactions and proposed transmetalation pathways
in the Suzuki-Miyaura process. R indicates an organic group. Compound numbers are shown in bold
in the lower panel.
provided independent evidence for these path-
ways, the actual composition and structure of
the transmetalation precursors have not been
unambiguously defined, despite being widely as-
sumed. Because of the transient nature of these
intermediates, traditional methods (e.g., electro-
spray mass spectrometry and traditional NMR
spectroscopy) have proven incapable of charac-
terizing highly reactive intermediates such as 3
(19, 20). Although the intermediacy of a species
containing a Pd-O-B linkage has been proposed,
its observation and characterization have eluded
chemists for over 30 years (21). A recent review
by Lennox and Lloyd-Jones (22) states that “[t]he
barrier of this process was predicted computa-
tionally to be low (14–22 kcal mol−1), suggesting
specialist techniques will need to be applied to
detect and confirm the identity of [3] experimen-
tally.” One such technique that has proven valua-
ble for providing structural and kinetic data in
similar mechanistic studies is rapid injection
NMR (RI-NMR) (23).
Aided by the RI-NMR apparatus developed in
our laboratories (24), we have undertaken the
generation and structural and kinetic character-
ization of these elusive intermediates. We hypoth-
esized that combining stoichiometric amounts of
arylpalladium complex trans-(i-Pr3P)2(4-FC6H4)
Pd(OH) (6) with 4-fluorophenylboronic acid (7)
(Fig. 2, route 1), ortrans-(i-Pr3P)2(4-FC6H4)Pd(I) (8)
with thallium 4-fluorophenylboronate (10) (Fig.
2, route 2), should converge on a species whose
structure and kinetic competence can be exam-
ined. The choice of triisopropylphosphine (i-Pr3P)
was critical to allow the preparation of discrete,
stable precursors and also to facilitate structural
assignments (25, 26).
−60°C, warming the solution to −30°C resulted in
the quantitative conversion of compounds 6
and 7 to a new species. The combination of one-
and two-dimensional NMR spectroscopic tech-
niques executed at −30°C led to the structural
elucidation of the newly formed species as com-
plex 11, containing a Pd-O-B linkage (supplemen-
tary materials, figs. S1 to S10).
The coordination geometry was assigned to a
trans-bisphosphino square planar palladium com-
plex. This assignment was based on the obser-
vation of the 13C NMR signal (PCH) at 25.38 parts
per million (ppm) as an apparent triplet (JP-C
=
10 Hz; J is the coupling constant between the
phosphorus and carbon atoms) attributable to vir-
tual coupling (27) and the 31P NMR signal at 29.98
ppm (a solitary singlet), which is shifted slightly
upfield compared with the corresponding reso-
nance of 6 at 33.00 ppm (figs. S2 and S4).
The formation of 6-B-3 complex 11 must pro-
ceed via an 8-B-4 complex (such as 3; Fig. 1) that
is formed initially which then suffers by the rapid
loss of a molecule of water. We attempted to shift
the equilibrium toward such a complex by gen-
erating 11 in mixtures of THF and H2O (99:1),
The bonding connectivity of complex 11 was
established by the observation of strong through-
space interactions [nuclear Overhauser effect
(NOE) spectroscopy] of both Hb and Hd (hydrogens
in the b and d positions) with the methyl hydro-
gens on the i-Pr3P group (Fig. 2, blue arrows, and fig.
S10). In addition, cross peaks between the B-OH
group and the ipso-carbon [C(1)]–bearing boron
(3JBOH-C(1)) were observed in the heteronuclear
multiple-bond correlation (HMBC) spectrum (Fig.
2, red bonds, and fig. S9). The resonances for Ha
and Hb (Fig. 2, blue aryl) and Hc and Hd (green
aryl) are shifted slightly downfield (+0.07 to
+0.16 ppm) in complex 11, compared with sub-
strates 6 and 7 (table S1). The resonances for the
fluorine atoms in 11 [Fa (blue aryl) and Fb (green
aryl)] are both shifted upfield relative to those
associated with 6 and 7, but the change was much
more pronounced for Fb (–4.54 to –0.91 ppm),
which facilitated their identification.
but we observed no change in the 31P, 19F, or 11
B
NMR spectra. We considered exploring more
strongly coordinating hydroxide sources that are
often used in Suzuki-Miyaura reactions, but the
addition of inorganic bases to THF-H2O blends is
known to form biphasic mixtures (13). Fortu-
nately, CsOH•H2O dissolves readily at −30°C in
mixtures of THF and CH3OH (12:1). A freshly gen-
erated sample of 6-B-3 complex 11 (from 6 and 7;
vide supra) at 0.034 M in THF was cooled to −78°C;
this was followed by the addition of 50 ml of a 2 M
solution (5.0 equivalents) of CsOH•H2O in meth-
anol. The sample was monitored by NMR spec-
troscopy at −30°C, but again, no change in the
19F, 31P, or 11B NMR spectra was observed.
The resistance of the boron atom in complex
11 to adopt a tetracoordinate geometry is prob-
ably caused by the steric hindrance that results
from the presence of two i-Pr3P ligands on the
palladium atom (F- and B-strain) (34). Thus, to
enable saturation of the boron valences would re-
quire a decrease in steric congestion, achieved by
The synthesis in route 1 involved the addition
of a tetrahydrofuran-d8 (THF-d8) solution of
4-fluorophenylboronic acid (7) to a THF-d8 so-
lution of trans-(i-Pr3P)2(4-FC6H4)Pd(OH) (6), to-
gether with 2.0 equivalents of i-Pr3P, at −78°C (Fig.
2). Although no new species were observed at
Most importantly, the boron atom in complex
11 was assigned to a tricoordinate geometry [6-
B-3 (28)] on the basis of the 11B NMR signal, which
appeared as a broad singlet at 29 ppm (table S1)—
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(from 17 and 7; vide supra), which resulted in
the quantitative formation of a new species (20)
(Fig. 3). The presence of a Pd-O-B linkage in 20
was established by the observation of NOE cross
peaks between the methyl hydrogens on the
i-Pr3P and both Hb and Hd (Fig. 3, blue arrows,
and fig. S57). The 11B NMR chemical shift of 20
at 9 ppm is well within the characteristic chem-
ical shift regime of tetracoordinate (8-B-4) com-
plexes (12, 13, 39). The proposed Pd-O-B-O core
can be found in an analogous bridging arylpal-
ladium acetate complex (40, 41).
The ability to generate intermediate species
containing Pd-O-B linkages provided a singular
opportunity to examine the kinetic aspects of the
transmetalation event in the Suzuki-Miyaura cross-
coupling reaction. The transfer of the aryl group
from boron to palladium was investigated by using
NMR spectroscopy to follow the decay of com-
plex 20 and the concomitant formation of cross-
coupling product 13.
Fig. 2. Formation of a 6-B-3 complex containing a Pd-O-B linkage. The crossing lines for com-
pound 12 signify a cyclic trimer. In the middle panel, the red bonds indicate HMBC cross peaks.
Throughout, h indicates hours; equiv, equivalents; conv., conversion; quantitative, 100% conv.
removing a i-Pr3P ligand from arylpalladium
hydroxide complex 6. This hypothesis led to the
investigation of monoligated arylpalladium hy-
droxy complex, [(i-Pr3P)(4-FC6H4)Pd(OH)]2 (17),
which exists in dimeric form in both solution
and solid states (35).
tributed to the thermochemical preference for
Pd-(m-OH)-Pd moieties, which is observed in
other bridged mixed-hydroxide complexes (38).
The connectivity of the Pd-O-B linkage in 18
was confirmed by the observation of NOEs be-
tween Hb, Hd, and the bridging OH group with
the methyl hydrogens on the i-Pr3P group. The
observation of NOE cross peaks, along with HMBC
(3JBOH-C(1)) cross peaks between the BOH and the
ipso-carbon–bearing boron (red bonds), indicates
that the arylboronic acid and arylpalladium hy-
droxide are connected. The 11B NMR chemical
shift of 18 was too broad to determine accurately.
The broadening of the 11B NMR signal in complex
18 is probably attributable to the chemical ex-
change between 7 and 18.
To further aid in the structure determination of
18, we combined 3.0 equivalents of thallium aryl-
boronate 10 with [(i-Pr3P)(4-FC6H4)Pd(I)]2 (19) in
THF-d8 at −78°C and then warmed the sample to
−50°C(Fig. 3, route5). Coolingthemixtureto−100°C
resulted in the observation of complex 18 (~50%)
by 1H NMR spectroscopy. The ability to forge the
Pd-O-B linkage in 18 by two routes provides com-
pelling support for the structural assignment.
In an attempt to arrive at a different stoichiom-
etry (1B:1Pd), 60 ml of CH3OH was injected into
a THF-d8 solution of 18 with 1.0 equivalent of 7
The addition of CH3OH into a THF solution
of 18 and 7 at −55°C led to the generation of
20. The subsequent formation of cross-coupling
product 13 was monitored by 19F NMR spectros-
copy at −30°C (to expedite data collection). First-
order plots of [20] and [13] versus time (figs. S62
to S64) were fitted by using the functions [A] =
[A]0e−kt and [P] = [A]0(1 − e−kt), respectively,
where [A] is the concentration of 20, [A]0 is the
initial concentration of 20, [P] is the concentra-
tion of 13, k is the rate constant, and t is time.
These functions provided accurate values for kobs
(the observed kinetic constant) for the decay of
20 [(1.41 0.02) × 10−3 s−1] and the formation of
13 [(1.55 0.09) × 10−3 s−1; Fig. 4A].
A similar kinetic analysis was performed in pure
THF by combining a THF solution of 7 (2.0 equiv-
alents) with a THF solution of 17 (1.0 equivalent) at
−78°C, followed by warming the sample to −30°C.
First-order decay of arylpalladium complex 18 and
the formation of 13 were observed with kobs values
of (7.59 0.58) × 10−4 s−1 and (5.78 0.13) × 10−4 s−1,
respectively (figs. S65 to S67), indicating that the
decay of 18 and the formation of 13 coincide. The
correspondence of these rate constants and the
clean first-order behavior suggests that at –30°C,
18 is largely converted to 20 (sufficient 7 is present
to allow this) (42). Moreover, the similarity of
the rate constants in THF and
The addition of a THF-d8 solution of 7 (2.0 equiv-
alents) to a THF-d8 solution of 17 (1.0 equivalent) at
−78°C, followed by warming to −60°C, produced
no new complexes. However, upon cooling the solu-
tion to −100°C, a new species emerged, with complete
consumption of 17 and with 50% of 7 remaining
(Fig. 3, route 4). The structure of this species
could be assigned as the bridged bis-arylpalladium
arylboronate complex (18), which is reminiscent
of other palladium acetate and carbonate com-
plexes (36, 37). The stoichiometry of complex 18
was determined by adding a THF-d8 solution of
7 (1.0 equivalent) to a THF-d8 solution of 17 (1.0
equivalent) at −60°C, followed by cooling to
−100°C, where a quantitative conversion was ob-
served. This dinuclear complex did not incorporate
another molecule of 7, even in the presence of 3
additional equivalents of 7 at −100°C. However,
exchange spectroscopy showed cross peaks be-
tween 18 and unbound 7 at −100°C, demonstrat-
ing that the system was in equilibrium even at this
temperature. This stoichiometry (1B:2Pd) is at-
the THF-CH3OH mixture further
supports the conclusion that 18
is converted to 20 before trans-
metalation (Fig. 4A) (43).
The generation of 6-B-3 complex
11, with its Pd-O-B linkage, raised
the question of whether this com-
plex is a competent intermediate in
the Suzuki-Miyaura reaction. Com-
plex 11 was thermally stable at
−30°C in the presence of an excess
of i-Pr3P for over 24 hours, indicat-
ing that added phosphine attenuates
the rate of the transmetalation
process. A THF solution of this
complex was warmed from −30°C
in 10°C intervals, whereupon a
Fig. 3. Formation of 8-B-4 complexes containing Pd-O-B linkages.
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Fig. 4. Kinetic data. (A) Formation of 13 from 8-B-4 complexes 18 and 20 (negative signs indicate consumption of starting material). (B) Inverse order
dependence on [i-Pr3P] for the formation of 13 from 6-B-3 complex 11.
considerable amount of cross-coupling product 13
was observed by means of 19F NMR spectroscopy
at 20°C over the course of 3 to 12 hours. A plot of
[11] versus time displayed s-shaped curves (figs.
S68 to S91), signifying that the kobs increases during
the course of the reaction (which is indicative of
autocatalysis) (44).
form for further investigations of the venerable
Suzuki-Miyaura cross-coupling process.
30. K. Osakada, H. Onodera, Y. Nishihara, Organometallics 24,
3815–3817 (2005).
31. P. Zhao, C. D. Incarvito, J. F. Hartwig, J. Am. Chem. Soc. 129,
1876–1877 (2007).
32. E. Weber, K. Skobridis, M. Ouchi, T. Hakushi, Y. Inoue, Bull.
Chem. Soc. Jpn. 63, 3670–3677 (1990).
REFERENCES AND NOTES
1. F. Chemla, F. Ferriera, A. Perez-Luna, L. Micouin, O. Jackowski,
in Metal-Catalyzed Cross-Coupling Reactions and More,
A. de Meijere, S. Bräse, M. Oestreich, Eds. (Wiley-VCH, ed. 3,
vol. 1, 2014), chap. 5, pp. 365–422.
2. J. C. H. Lee, D. G. Hall, in Metal-Catalyzed Cross-Coupling
Reactions and More, A. de Meijere, S. Bräse, M. Oesteich,
Eds. (Wiley-VCH, ed. 3, vol. 1, 2014), chap. 2,
33. We cannot unambiguously exclude the possibility that thallium
hydroxide dissociates to a minor extent, forming the palladium
hydroxide complex 6. These results do not contradict the
conclusions of the studies led by Hartwig (13) and Amatore
and Jutand (14–16). The kinetic incompetence of sodium or
potassium boronates in aqueous-organic solutions need not
carry over to organic-only solutions of thallium boronates.
34. H. C. Brown, J. Am. Chem. Soc. 67, 374–378 (1945).
35. V. V. Grushin, H. Alper, Organometallics 15, 5242–5245 (1996).
36. T. A. Stephenson, S. M. Morehouse, A. R. Powell, J. P. Heffer,
G. Wilkinson, J. Chem. Soc. 3632–3640 (1965).
37. C. S. Wei et al., Angew. Chem. Int. Ed. 52, 5822–5826 (2013).
38. M. S. Driver, J. F. Hartwig, Organometallics 16, 5706–5715 (1997).
39. H. Nöth, B. Wrackmeyer, in Nuclear Magnetic Resonance
Spectroscopy of Boron Compounds, P. Diehl, E. Fluck,
R. Kosfeld, Eds., vol. 14 of NMR Basic Principles and Progress
(Springer-Verlag, 1978), chap. 7, pp. 74–100.
To confirm the kinetic requirement for phos-
phine dissociation in the cross-coupling of 11, the
kinetic order in phosphine was determined by
adding a THF solution of 7 to a solution of 6
with increasing amounts of i-Pr3P, ranging from
97 to 294 mM, at 20°C (Fig. 4B). The s-shaped
kinetic profiles were fitted, and a vmax (maximum
rate) was extracted from the data (45). A plot of
log[vmax] versus log[i-Pr3P] gave a slope of −1.05
0.05 (fig. S92), which is consistent with an in-
verse dependence on phosphine, indicating that
dissociation of a phosphine is a pre-equilibrium
process that leads to the hypothetical 14-electron
palladium complex 15. Because 15 is formed in
such a low-equilibrium concentration, it is not
possible to determine whether transmetala-
tion occurs directly from this 6-B-3 species or
whether it requires the coordination of another
group on boron to form species related to 20.
Although very low levels of halide and water are
present, the coordination state of boron in the
transmetalation event cannot be unambiguously
established.
Through the combination of three methods of
investigation (spectroscopic analyses, independent
syntheses, and kinetic measurements), we have
unambiguously identified and characterized three
pre-transmetalation species containing Pd-O-B
linkages that undergo the Suzuki-Miyaura cross-
coupling reaction. Despite the long-held assump-
tion that these types of intermediates are involved
in the transmetalation event, our study provides
the first definitive evidence for their involvement.
We have demonstrated that both tetracoordinate
(18 and 20) and tricoordinate (11) boron com-
plexes containing the critical Pd-O-B moieties
are able to transfer their B-aryl groups to pal-
ladium. Moreover, our investigations establish
that an empty coordination site on the palladium
atom is needed for the transmetalation event to
take place from all three Pd-O-B–containing spe-
cies. We foresee these results serving as a plat-
pp. 65–132.
3. B. Martín-Matute, K. J. Szabó, T. N. Mitchell, in Metal-Catalyzed
Cross-Coupling Reactions and More, A. de Meijere, S. Bräse,
M. Oestreich, Eds. (Wiley-VCH, Weinheim, ed. 3, vol. 1, 2014),
chap. 6, pp. 423–465.
4. S. Xu, H. Kamada, E. H. Kim, A. Oda, E. Negishi,
in Metal-Catalyzed Cross-Coupling Reactions and More,
A. de Meijere, S. Bräse, M. Oestreich, Eds. (Wiley-VCH,
Weinheim, ed. 3, vol. 1, 2014), chap. 3, pp. 133–278.
5. W. T. T. Chang et al., Org. React. 75, 213–746 (2011).
6. A. Suzuki, Angew. Chem. Int. Ed. 50, 6722–6737 (2011).
7. A. Suzuki, J. Organomet. Chem. 576, 147–168 (1999).
8. C. Valente, M. Organ, in Boronic Acids: Preparation and
Applications in Organic Synthesis and Medicine, D. G. Hall,
Ed. (Wiley-VCH, vol. 2, 2005), chap. 4, pp. 213–262.
9. J. Liu, J. J. Lavigne, in Boronic Acids: Preparation and
Applications in Organic Synthesis and Medicine, D. G. Hall,
Ed. (Wiley-VCH, vol. 2, 2005), chap. 14, pp. 612–676.
10. B. Matthias, H. U. Blaser, Eds., Organometallics
as Catalysts in the Fine Chemical Industry, vol. 42 of
Topics in Organometallic Chemistry (Springer-Berlin, 2013).
11. J. Magano, J. R. Dunetz, Chem. Rev. 111, 2177–2250 (2011).
12. K. Matos, J. A. Soderquist, J. Org. Chem. 63, 461–470 (1998).
13. B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 133, 2116–2119 (2011).
14. C. Amatore et al., Chemistry 17, 2492–2503 (2011).
15. C. Amatore et al., Chemistry 18, 6616–6625 (2012).
16. C. Amatore et al., Chemistry 19, 10082–10093 (2013).
17. A. F. Schmidt et al., Russ. J. Gen. Chem. 81, 1573 (2011).
18. A. F. Schmidt, A. A. Kurokhtina, Kinet. Catal. 53, 714–730 (2012).
19. A. O. Aliprantis, J. W. Canary, J. Am. Chem. Soc. 116,
6985–6986 (1994).
20. C. Sicre et al., Tetrahedron 64, 7437–7443 (2008).
21. N. Miyaura, A. Suzuki, J. Chem. Soc. Chem. Commun. 1979,
866–867 (1979).
22. A. J. J. Lennox, G. C. Lloyd-Jones, Angew. Chem. Int. Ed. 52,
7362–7370 (2013).
23. J. F. McGarrity, J. Prodolliet, J. Org. Chem. 49, 4465–4470 (1984).
24. S. E. Denmark, B. J. Williams, B. M. Eklov, S. M. Pham,
G. L. Beutner, J. Org. Chem. 75, 5558–5572 (2010).
25. Although i-Pr3P is not commonly used in Suzuki-Miyaura
reactions, it is structurally similar to c-Hex3P (c-Hex,
cyclohexyl), which has widespread application (2, 26).
26. G. C. Fu, Acc. Chem. Res. 41, 1555–1564 (2008).
27. Y. Nishihara, H. Onodera, K. Osakada, Chem. Commun. (Camb.)
2004, 192–193 (2004).
40. Y. Tan, F. Barrios-Landeros, J. F. Hartwig, J. Am. Chem. Soc.
134, 3683–3686 (2012).
41. We cannot unambiguously exclude the possibility that
methanol has incorporated into complex 20.
42. Although 18 and 7 are both observed at –100°C, at –30°C,
these species converge, thus preventing a definitive
assignment of whether 18 or 20 is the actual species
undergoing decay in the kinetic analysis.
43. M. Wakioka, Y. Nakamura, Q. Wang, F. Ozawa, Organometallics
31, 4810–4816 (2012).
44. The identity of the species that is inducing autocatalysis has
not been determined at this time.
45. R. Schmid, V. N. Sapunov, Non-Formal Kinetics: In Search for
Chemical Reaction Pathways, vol. 14 of Monographs in Modern
Chemistry, H. F. Ebel, Ed. (Verlag Chemie, 1982).
ACKNOWLEDGMENTS
We are grateful for generous financial support from the NSF
(CHE-1012663 and CHE-1151566). A.A.T. is grateful to the University
of Illinois for graduate fellowships. We thank L. Zhu for helpful
suggestions regarding NMR spectroscopy. Some of the data
presented here were collected in the Core Facilities of the
Carl R. Woese Institute for Genomic Biology on a 600-MHz NMR
instrument (funded by NIH grant S10-RR028833) or at the Integrated
Molecular Structure Education and Research Center at Northwestern
University. Full experimental procedures, characterization and kinetic
data, and copies of the 1H, 13C, 31P, 19F, 11B, NOE, and exchange spectra
can be found in the supplementary materials.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/352/6283/329/suppl/DC1
Materials and Methods
Figs. S1 to S118
Tables S1 to S26
References (46–51)
28. This nomenclature designates an N-X-L species, where N is the
number of formally valence-shell electrons around atom X that
are involved in bonding L ligands to X (29).
28 October 2015; accepted 23 February 2016
10.1126/science.aad6981
29. C. W. Perkins et al., J. Am. Chem. Soc. 102, 7753–7759 (1980).
332 15 APRIL 2016 • VOL 352 ISSUE 6283
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