A highly sensitive fluorescence method reveals the presence of palladium in a cross-coupling reaction mixture not treated with transition metals

Article abstract of DOI:10.1016/j.tetlet.2012.04.043

We previously reported a Suzuki-Miyaura coupling in dimethyl carbonate without adding additional transition metals. Here, we show an analysis of the reaction mixture that revealed the presence of palladium using a fluorogenic Tsuji-Trost reaction.

Full text of DOI:10.1016/j.tetlet.2012.04.043

Tetrahedron Letters 53 (2012) 3147–3148
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A highly sensitive fluorescence method reveals the presence of palladium
in a cross-coupling reaction mixture not treated with transition metals
a,
⇑
b
a
b,
⇑
Kiyofumi Inamoto , Laura D. Campbell , Takayuki Doi , Kazunori Koide
a
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
We previously reported a Suzuki–Miyaura coupling in dimethyl carbonate without adding additional
transition metals. Here, we show an analysis of the reaction mixture that revealed the presence of palla-
dium using a fluorogenic Tsuji–Trost reaction.
Received 21 March 2012
Revised 5 April 2012
Accepted 9 April 2012
Available online 16 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Suzuki–Miyaura coupling
Sensor
Fluorescence spectroscopy
Catalysis
Palladium-catalyzed cross-coupling reactions are widely used
in synthetic organic chemistry.1 Because it is difficult to remove
palladium from the products after palladium-catalyzed reactions,
compounds.8c,d,9 A synthetic sample prepared by a palladium-cata-
lyzed cross-coupling reaction was purified and analyzed by this
method, and the result matched those generated by ICP-MS and
inductively coupled plasma atomic emission spectrometry (ICP-
2
minimizing the stoichiometry of palladium is an important goal in
synthetic organic chemistry.3 A viable alternative approach is to
discover a metal-free system or a different metal that catalyzes
8c
AES) methods in a double-blind format. It should be noted that
rhodium can also give rise to fluorescence signals when tri(2-
furyl)phosphine is used, although the signals are far smaller than
4
the same cross-couplings. Nonetheless, even though palladium re-
8
c,d
agents were not used, palladium was present in the reactions that
those from palladium.
4a,5
The sample was prepared according to the published protocol5f:
a mixture of 4-iodobenzonitrile (60.0 mg, 0.262 mmol), phenylbo-
were typically catalyzed by this transition metal.
These exam-
ples called for more rigorous analyses of trace metals in the reac-
6
tion mixtures. Inductively coupled plasma mass spectroscopy
3 4
ronic acid (38.3 mg, 0.314 mmol), and K PO (66.7 mg, 0.314 mmol)
(
ICP-MS) has become a standard technique in this regard; however,
was heated at 135 °C for 24 h in dimethyl carbonate (2.6 mL). After
unlike other routine spectroscopic techniques such as NMR, IR, UV,
and LC–MS, ICP-MS analyses are performed mostly off site.
The Inamoto–Doi group recently reported that the cross-cou-
pling between aryl iodides and organoboron reagents could be
accomplished in dimethyl carbonate without adding a transition
the completion of the reaction, the dimethyl carbonate was evapo-
rated in vacuo. The resulting residue was treated with 10% HNO
3
(1.0 mL) for 20 min at 50 °C. After this mixture was cooled to
25 °C, ethanol (1 mL) and DMSO (0.50 mL) were added to this mix-
ture (sample A).
5
f
metal catalyst. Trace palladium, which is typically needed for such
We prepared a premixed solution for palladium detection sim-
7
9
cross-couplings, was present at a 0.42 ppb level in the mixture of
ilarly to our previous studies: A 1.23 M phosphate pH 7 buffer
5f
the reaction shown in Scheme 1a. We hypothesized that a fluores-
cence-based method for palladium detection developed by the
(95 mL) and DMSO (4.58 mL) were added to an amber glass re-
agent bottle that was rinsed with 5–10% HNO and deionized
3
water prior to use. To this solution were added a 3 mM solution
of allyl ether 1 in DMSO (0.417 mL) and tri(2-furyl)phosphine
(2.8 mg) at 25 °C. After sonicating the mixture for 5 min to dissolve
8
Koide group could also be used to quantify palladium in the reac-
tion mixture. This method has been shown to be more effective
than ICP-MS for detecting palladium in organic and inorganic
tri(2-furyl)phosphine, NaBH
The resulting solution contained allyl ether 1 at 12.5
at 10 mM, and tri(2-furyl)phosphine at 120
(1:19 v/v).
4
(38 mg) was added to the solution.
M, NaBH
M in DMSO/buffer
l
4
⇑
Corresponding authors.
E-mail addresses: inamoto@m.tohoku.ac.jp (K. Inamoto), koide@pitt.edu
l
(
K. Koide).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.043

3
148
K. Inamoto et al. / Tetrahedron Letters 53 (2012) 3147–3148
reaction solution for the conversion of allyl ether 1 to phenoxide
. The fluorescence method was performed three times (duplicate
(
a)
2
NC
I
or triplicate each time), all of which resulted in similar conclusions.
Because sample A was diluted 50-fold to perform this deallylation
reaction, the average palladium concentration in sample A (2.5 mL)
was determined to be 0.81 ppb (7.6 nM). Therefore, in the original
reaction mixture (2.6 mL) Scheme 1a), palladium was present at
K PO
3
4
+
NC
(
MeO) CO
2
(
HO) B
135 °C, 24 h
2
No addition of
0
.78 ppb (7.3 nM). The reaction mixture (Scheme 1a) used in this
transition metals
study was different from that in our previous study; therefore,
we consider this palladium level to be within a reasonable range
compared to the previous ICP-MS analysis for the same transfor-
(
b)
5
f
OH
Cl
mation. Because the conversion of allyl ether 1 to phenoxide 2
TFP = tri(2-furyl)phosphine
8d
can be catalyzed by rhodium, although to a lesser extent, we
are not able to exclude the presence of rhodium in sample A. How-
ever, since the Suzuki–Miyaura coupling reactions are typically
catalyzed by palladium, we believe that the presence of palladium
Cl
O
O
O
Pd2+, TFP
NaBH4
OH
Cl
5f
is more relevant to the previously reported reactions. If the trace
Cl
palladium is indeed the catalyst, then the turnover number would
be over ten million under the previously reported reaction condi-
tions in which the limiting agent (4-iodobenzonitrile) was at a
DMSO
pH 7 buffer
45 °C
O
O
O
5
f
1
00 mM concentration.
In summary, we demonstrated the utility of the fluorescence
O
2
Cl
Cl
fluorescent
method to analyze a reaction mixture to detect palladium although
no palladium reagents were added to the mixture. Trace palladium
O
O
OH
4
c
impurities have caused confusion in the literature. This case
study exemplifies potential applications of this user friendly10 fluo-
rescence method in other synthetic laboratories to detect palla-
dium on site.
1
nonfluorescent
Scheme 1. (a) Cross-coupling reaction without adding transition metals. The
reaction mixture was dried under a vacuum, and the resulting crude mixture was
3
treated with 10% HNO before palladium analysis. (b) Palladium(0) generated
Acknowledgments
in situ catalyzes the conversion of the nonfluorescent allyl ether 1 to the green
fluorescent phenoxide 2. The fluorescence signals were measured using a Modulus
II Microplate Multimode Reader (excitation: 490 nm, emission: 510–570 nm).
We thank Mr. Michael P. Cook (University of Pittsburgh) for
suggesting this work. This work was supported by the US National
Science Foundation (CHE-0911092) and a Grant-in-Aid for Young
Scientists (B) (No. 23790002) from Japan Society for the Promotion
of Science.
References and notes
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3
.
.
Figure 1. Standard curve based on the method in Scheme 1b.
4
4
(
2
The above pre-mixed stock solution was immediately trans-
ferred to eppendorf tubes at 25 °C (1.47 mL in each container). This
experiment was performed in duplicate, and the standard curve
was generated in triplicate. Each of these solutions was treated
5
.
with a palladium solution (0, 5, 10, or 20 ppb in 5% HNO
3
; 30 lL;
5
0-fold dilution) or sample A (30 L; 50-fold dilution) at 25 °C.
l
All of these eppendorf tubes were sealed and heated at 45 °C in
an incubator for 1 h. After cooling the reaction mixtures, the solu-
tions (200
l
L from each reaction) were transferred to a black 96-
6. Leadbeater, N. E. Nat. Chem. 2010, 2, 1007–1009.
7
8
.
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Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(a) Song, F. L.; Garner, A. L.; Koide, K. J. Am. Chem. Soc. 2007, 129, 12354–12355;
well plate for fluorescence measurement.
As Figure 1 shows, the standard curve for palladium was
y = 224,200[Pd] + 12,560 (y = fluorescence intensity in arbitrary
unit, [Pd] = palladium concentration in ppb) with the r = 0.9855.
The fluorescence intensities with sample A were 15702 and
(
b) Garner, A. L.; Koide, K. Chem. Commun. 2009, 86–88; (c) Garner, A. L.; Song,
F. L.; Koide, K. J. Am. Chem. Soc. 2009, 131, 5163–5171; (d) Song, F.; Carder, E. J.;
Kohler, C. C.; Koide, K. Chem. Eur. J. 2010, 16, 13500–13508.
Li, D.; Campbell, L. D.; Austin, B. A.; Koide, K. ChemPlusChem 2012. http://
dx.doi.org/10.1002/cplu.201200015.
2
9.
1
6665 (average = 16184). The average palladium concentration,
10. For example, first-year undergraduate students without research experience
were able to use this method after 2–3 h of training in our laboratory.
according to the equation, was determined to be 16.2 ppt in the