Powerful insight into catalytic mechanisms through simultaneous monitoring of reactants, products, and intermediates

Article abstract of DOI:10.1002/anie.201102630

Keeping an eye on all the players: The combination of bulky phosphonium tags and pressurized sample infusion transforms electrospray ionization mass spectrometry into a tool capable of producing dense data on the relative concentrations of all components of a catalytic reaction, such as the palladium-catalyzed coupling of an aryl iodide with phenylacetylene (see graph).

Full text of DOI:10.1002/anie.201102630

Communications
DOI: 10.1002/anie.201102630
Reaction Mechanisms
Powerful Insight into Catalytic Mechanisms through Simultaneous
Monitoring of Reactants, Products, and Intermediates**
Krista L. Vikse, Zohrab Ahmadi, Cara C. Manning, David A. Harrington, and J. Scott McIndoe*
Electrospray ionization mass spectrometry (ESIMS) has
become a valuable tool in the mechanistic study of organo-
metallic catalytic reactions. Analysis is fast, intermediates at
low concentrations can be detected, and complex mixtures are
mediates feature.[16] The identity of palladium-containing
intermediates has been proposed on the basis of electro-
chemical or NMR spectroscopic data but not through direct
observation.
À
tractable. The family of palladium-catalyzed C C bond-
Charged tags are required for the detection of species
otherwise invisible to ESIMS,[23,24] an idea first introduced by
Adlhart and Chen;[25] we used an aryl iodide functionalized
with a phosphonium hexafluorophosphate salt, [p-IC6H4-
CH2PPh3]+[PF6]À. This tag provides very low detection limits
owing to its high surface activity, and the noncoordinating
counterion reduces ion pairing. The bulky nature of the
charged group ensures that the ionization efficiency is largely
insensitive to the remaining structure of the ion, so the
intensity of the various ions correspond very closely to their
real concentration (see the Supporting Information). ESIMS
data on reaction progress collected under typical reaction
conditions by using pressurized sample infusion (PSI)[26]
forming reactions are the most studied by ESIMS.[1–14]
Although the majority of these investigations have focused
on the structural identification of short-lived or low-concen-
tration intermediates, some recent studies have monitored the
intensities of intermediates or reactants and products over
time.[5,14] However, no one has yet shown this technique to be
capable of providing robust kinetic information for reactants,
products, by-products, and low-abundance intermediates
simultaneously and under standard reaction conditions. We
show herein how powerful this information can be in leading
reaction design.
The copper-free Sonogashira (Heck alkynylation) reac-
tion is widely used in the synthesis of natural products,
pharmaceuticals, and novel materials, but the mechanism is
not well understood.[15] Ideally, the reaction should be
observed under typical reaction conditions for meaningful
information to be obtained about the mechanism, because
under such conditions anions[16] and bases[17,18] as well as
alkynes[19] are thought to act as ligands for palladium, with
complex effects on the reaction efficiency.
1
compare well with H NMR and UV/Vis spectroscopic data
(Figure 1). The number of data points is much higher for
In most cases, a large excess of an amine base is required
to promote reaction; however, the exact role of the base is in
question.[15] Dieck and Heck[20] and Amatore et al.[21] sug-
gested a carbopalladation mechanism in which the terminal
alkyne undergoes carbopalladation and the base consumes
the H+ formed during the b-hydride elimination that forms
the product. Ljundahl et al.[22] prefer a deprotonation mech-
anism in which deprotonation of the terminal alkyne by the
Figure 1. Appearance of the product (ArC2Ph), as tracked by three
different techniques: 1H NMR spectroscopy, UV/Vis spectroscopy, and
ESIMS.
amine occurs from the cationic intermediate [Pd(Ar)(PR3)-
+
ꢀ
(NR’3)(HC CR’’)] or the neutral intermediate [Pd(Ar)-
ꢀ
(PR3)(X)(HC CR’’)], depending on the electronic nature of
the alkyne. An anionic mechanism has also been proposed in
which [Pd0(PR3)2X]À and [PdII(PR3)(X)(Ar)(CCR’’)]À inter-
ESIMS because the reaction is monitored continuously at
1 spectrum per second, whereas the other techniques require
a more conventional periodic sample–quench–concentrate–
analyze approach.
[*] K. L. Vikse, Z. Ahmadi, C. C. Manning, Dr. D. A. Harrington,
Dr. J. S. McIndoe
Department of Chemistry, University of Victoria
P.O. Box 3065, Victoria, BC, V8W 3V6 (Canada)
Fax: (+1)250-721-7147
The intensities of all tagged species observed during a
typical reaction appear in Figure 2. The relative concentra-
tions of the product (ArC2Ph), substrate (ArI), and by-
product (ArH) are depicted. At 100 ꢀ magnification, the
relative amounts of key intermediates can also be represented
on the same scale.
A key observation is the change in mechanism early in the
reaction, whereby the initial fast rate is replaced with a much
slower, zero-order process. The rate of formation of the by-
E-mail: mcindoe@uvic.ca
[**] K.L.V. thanks the University of Victoria for a Pacific Century
Fellowship. J.S.M. thanks the CFI and BCKDF for infrastructure
support; J.S.M. and D.A.H. thank the NSERC for operational
funding (Discovery).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102630.
8304
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Angew. Chem. Int. Ed. 2011, 50, 8304 –8306

Figure 3. ESIMS intensity data over time for all key species containing
p-C6H4CH2PPh3+ in a reaction mixture to which [NEt3H]I (1 equiv) has
been added. The intensity has been multiplied by 100 for the
palladium-containing intermediates.
Figure 2. ESIMS intensity data over time for all key species containing
Ar=p-C6H4CH2PPh3+. The intensity has been multiplied by 100 for the
palladium-containing intermediates.
product, ArH, through dehalogenation is essentially constant
throughout (zero order). The changeover in mechanism
corresponds to the beginning of the disappearance of
ditions throughout. [Pd(PPh3)2(Ar)(C2Ph)] is present only at
very low levels, and the concentration of [Pd(PPh3)n(Ar)(X)]
is approximately steady-state. The overall slow rate of
reaction means that the dehalogenation reaction has approx-
imately the same rate as the coupling reaction. The fact that
the dehalogenation is unaffected by the addition of protons
suggests that the rate-determining step for this side reaction
does not involve (de)protonation; a previous study on aryl
chlorides suggests that the rate-determining step is the
oxidative-addition step,[26] but that assumption is unlikely to
translate to the aryl iodide case.
For practical applications, a system in which the initial fast
rate of reaction is preserved is desirable, and given that the
presence of protons slows the reaction, a stronger base ought
to more effectively sequester the proton and allow the
reaction to continue operating in the faster regime. We
repeated the reaction with DBU (pKa = 13.9; pKa(NEt3) =
9.0). The fast first-order process dominated throughout the
reaction (Figure 4), which was complete within 90 min. The
yield was higher, and the product cleaner, because the
dehalogenation side reaction could not compete as effectively
with the desired coupling reaction. In this reaction, the
amount of [Pd(PPh3)2(Ar)(C2Ph)] is high initially and drops
off under first-order kinetics. Since the protonation step
(step 3 in reverse) has been slowed because of the use of a
stronger base, the reductive-elimination step remains rate-
determining throughout.
+
[Pd(PPh3)2(Ar)(C2Ph)] (Ar= p-C6H4CH2PPh3 ). In contrast,
[Pd(PPh3)n(Ar)(X)] (n = 1 or 2, X = halide, sum of all species)
reaches a maximum concentration at the time of the
mechanistic changeover, stays roughly constant, then dimin-
ishes to zero at the conclusion of the reaction. We suggest that
the initial fast rate has reductive elimination as its rate-
determining step, which accounts for the buildup of
[Pd(PPh3)2(Ar)(C2Ph)]. As this intermediate disappears, the
steady state of [Pd(PPh3)n(Ar)(X)] and zero-order kinetics
now suggest that the transmetalation reaction becomes rate-
determining (Scheme 1).
The buildup of either H+ or IÀ might affect the course of
the reaction by driving step 3 backwards. To test this
possibility, we added [NEt4]I to the reaction mixture in a 1:1
ratio to the catalyst. The iodide had no effect on the progress
of the reaction. [NEt3H]I was added instead, and the change
in the reaction profile was dramatic (Figure 3).
The added H+ entirely shuts down the initial fast rate of
reaction, and the reaction proceeds under zero-order con-
We performed simulations of the reactions by making
educated guesses about the relative rates of the many steps in
the catalytic cycle. Optimization of the many independent
parameters is nontrivial; however, our confidence in the cycle
was solidified by a model that could not only predict the
overall shape of all five traces in Figure 2, but that responded
appropriately to changes in the initial conditions (added acid
and stronger base) to accurately predict the behavior
observed in Figures 3 and 4 (see the Supporting Information).
A direct comparison of the appearance of the product
under the three different sets of reaction conditions (all
Scheme 1. Catalytic cycle for the copper-free Sonogashira reaction.
Only species containing Ar are visible by ESIMS; the intermediate in
the gray box is speculative, as it was not observed during the reaction.
Angew. Chem. Int. Ed. 2011, 50, 8304 –8306
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8305

Communications
become a versatile addition to the growing toolbox of
spectroscopic[28] and spectrometric[29] techniques for the
mechanistic analysis of catalytic and stoichiometric reactions.
Received: April 15, 2011
Published online: June 14, 2011
Keywords: electrospray ionization · homogeneous catalysis ·
.
mass spectrometry · reaction mechanisms ·
Sonogashira coupling
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Figure 5. ESIMS intensity data over time for the appearance of
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+
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Angew. Chem. Int. Ed. 2011, 50, 8304 –8306