Discovery and synthesis of a new bis(thiourea)-Pd pincer guided by ESI-MS/MS

Full text of DOI:10.1002/jms.1354

JOURNAL OF MASS SPECTROMETRY
J. Mass Spectrom. 2008; 43: 542–546
Published online 14 December 2007 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/jms.1354
JMS Letters
Dear Sir,
pressure of 100 psi and the flow rate was 40 arbitrary units. Helium
was used as the buffer gas. The ESI interface and mass spectrometer
parameters were optimized to obtain maximum sensitivity. The ion
isolation width was set at 2.0 Th and the collision energies ranged
from 30 to 40%.
Discovery and synthesis of a new bis(thiourea)-Pd pincer guided
by ESI-MS/MS
The Palladium-catalyzed cross-coupling reactions are very versatile
protocols for C–C bond formation in organic synthesis.1 The
Yang and Chen group have demonstrated that bulky thiourea–Pd
complexes are active catalysts for Heck and Suzuki reactions, which
are generally air- and moisture-stabled.2–5 Although thioureas and
their corresponding Pd complexes are very useful, there are few
articles concerned with the exploration of their fission mechanism.
In the present study, the research of fission mechanisms of them
under electrospray ionization (ESI) conditions was conducted by
our group. From the research, the abnormal [M ꢀ H]C parent ion
was observed in the (C)electrospray ionization-mass spectrometry
(ESI-MS) experiment of bis(thiourea)–Pd0 complex. With tandem
mass experiments, the structure of the new bis(thiourea)–Pd pincer
was assumed. Then, a new Pd pincer was synthesized and its
catalytic activity in Suzuki reactions was compared with the bis
(thiourea)–Pd0 complex.
In the following experiments, we found that the ligand 2 was
ionized as the protonated ion at m/z 515 under positive full scan ESI
mode, then in the tandem mass experiment, the fragment ions were
detected at m/z 513, 481, 451, 295 and others with high intensities
(Fig. 2). The ion at m/z 513 can be rationalized by loss of a molecule
of H2 from the thiourea ring, which would stablize the thiourea
ring because of the extended conjugate system. This would enable
it to fragment further to produce the ion at m/z 481 by loss of a
sulfur atom. At the same time, the carbene group, together with its
aryl substituent, would be eliminated to produce the most abundant
ion at m/z 295 (diagnostic fission). The ion at m/z 451 should be
ascribed to loss of two sulfur atoms from the parent ion. The fission
mechanism was depicted in Scheme 1.
However, the fission mechanism of deprotoned 1 is different
from that of ligand 2. First of all, few fragment ions were detected
(Fig. 3) in MS/MS spetra of deprotoned 1. The most important fact is
that an ion of m/z 555 corresponding to loss of two sulfur atoms was
observed, indicating that Pd was bound to the middle aryl group.
Otherwise, in the CID condition, the Pd atom would be eliminated
together with the two sulfur atoms. To bond to the aryl group, Pd0
must be oxidized to Pd2C. So, we assumed that the Pd0 was oxidized
to Pd2C in the ion source with spray voltage at 4.5 kV and a Cl
anion was added to the Pd2C ion. Finally, through the intrusion and
oxidation of Pd2C to the C–H bond of the middle aryl group, the
bis(thiourea) Pd pincer7–18 was formed, accompanied by the loss of
a molecule of HCl to give rise to the precursor ion 3. Next in the
ion trap (IT), collision with helium occurred and the precursor ion
m/z 619 [M ꢀ H]C fragmented to produce the fragment ions at m/z
604, 585, 572 and 555. Just like ligand 2, the ion (m/z 585) derived
from loss of a molecule of H2 together with one sulfur atom from
the parent ion was observed, but there is no similar fragment ion
8 (m/z 399) corresponding to successive loss of the carbene group
as m/z 295 from ligand 2, which indicated that the carbene group
coordinated to the Pd atom to give rise to the hybrid (thiourea and
carbene) Pd pincer 5. In a similar fashion, the pincer 7 was formed
by the loss of two sulfur atoms followed by the coordination of the
two newly formed carbenes to the Pd atom. The ion at m/z 604 can
be rationalized by the loss of the peripheral methyl group. This was
In Chen’s manuscript,6 bis(thiourea)–Pd0 catalysts were syn-
thesized, which possessed high thermal stability and good cat-
alytic activity for aryl iodides and bromides in Heck and Suzuki
coupling reactions. According to the isotopic distribution of the
bis(thiourea)–Pd0 complex
1 (Fig. 1), the actual mass of the
bis(thiourea)–Pd0 complex is m/z 619, which should correspond
to the form of [M ꢀ H]C. To further explore the structure of the
deprotonated parent ion, ESI-MS/MS experiments of 1 and the
corresponding bis(thiourea) ligand 2 were carried out in this paper.
All MS and tandem MS experiments were performed on a
Finnigan LCQDECA ion trap mass spectrometer (San Jose, CA, USA)
equipped with an ESI source and capable of analyzing ions up to
m/z 2000. The samples were introduced via a syringe pump at a
flow rate of 10 µl/min maintained by a syringe pump. The spray
voltage was set to 4.5 kV in positive mode. The capillary voltage
°
was fixed at 15.0 V and the temperature at 350 C. The ion gauge
pressure was 2.4 ð 10ꢀ5 torr. Nitrogen was used as a sheath gas at a
ŁCorrespondence to: Chen Lijuan, State Key Laboratory of
Biotherapy, West China Hospital, Sichuan University, Chengdu 610
041, China. E-mail: chenlijuan125@163.com
LIUNAIO1PD0 #11-20 RT: 0.15-0.27 AV: 10 NL: 1.98E5
T: + c Full ms [ 50.00-700.00]
619.32
100
95
90
85
80
621.30
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
618.36
N
N
N
N
623.35
S
S
620.33
Pd
617.35
622.39
1
Chemical Formula: C30H34N4PdS2
Molecular Weight: 620Da
624.35
625.36
626.30
627.26
615.31
613.56
614
616.06
0
616
618
620
622
624
626
628
m/z
Figure 1. Experimental isotopic distribution of 1.
Copyright  2007 John Wiley & Sons, Ltd.

JMS letters 543
LIUNIA1 #24-38 RT: 0.43-0.65 AV:15 NL: 3.56E5
T: + c Full ms2 515.00@40.00 [140.00-730.00]
295.3
100
95
90
85
80
75
70
+H+
65
60
55
50
45
40
35
30
25
20
15
10
5
N
N
+
+H+
S
423.4
N
N
N
N
327.3
338.3
296.3
304.3
515.4
513.4
424.4
481.3
451.3
516.3
516.9
380.2
381.2
339.3
453.4
467.3
482.4
484.2
450.4
265.5
250
363.3
204.2
200
218.3
0
300
350
400
450
500
550
m/z
Figure 2. The (C)ESI-MS/MS spectrum of bis(thiourea) ligand 2.
+H+
+H+
N
N
−2S
N
N
N
N
N
N
2
S
S
m/z 515
m/z 451
−H2
+H+
+H+
−S
N
N
N
N
N
N
N
N
S
S
S
m/z 481
m/z 513
+H+
N
N
S
m/z 295
Scheme 1. The fission mechanism of bis(thiourea) ligand under positive ESI-MS/MS condition.
Pd2C and C–H bond is very favorable (about 0.214 nm obtained
by optimization of PdCl2 ligand complex with PM3 method). On
the basis of our hypothesis, we added PdCl2ꢀCH3CNꢁ2 (0.1 mmol)
to a solution of bis(thiourea) ligand 2 (0.1 mmol) in DCM (2 ml)
at room temperature and stirred overnight. Then the solvent was
removed under vacuum and ether (3 ml) was added. The precipitates
were washed with water and ethanol to give mahogany powder
(40mg, 62%). The 13C, 1H NMR experiments and X-ray experiment
(Fig. 4) of the mahogany powder indicated that Pd was attatched
followed by loss of a sulfur atom to form the other hybrid Pd pincer
6 at m/z 572. (Scheme 2)
Through the above analysis, we can conclude that Pd2C can
easily oxidize and insert the C–H bond of the middle aryl group
due to the following reasons. First, the electron density on the
C–H bond is increased by the electron donor effect of its vicinal
amide groups, which make the C–H bond more vulnerable to the
oxidation. Second, the oxidation product is very stable due to the
two newly formed 6-membered rings. Finally, the distance between
Copyright  2007 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 542–546
DOI: 10.1002/jms

544
JMS letters
Figure 3. The (C)ESI-MS/MS spectrum of bis(thiourea)–Pd0 complex 1.
+4500V
N
N
N
N
N
N
N
N
1
CH3OH
Cl-
-HCl
capillary
H
S
S
S
S
Pd2+
Pd
3
Cl-
m/z 619
MS/MS
N
N
-H2
N
N
-S
N
IT
N
S
S
Pd
Pd
8
5
m/z 399
m/z 585
-CH3
-2S
N
N
N
N
N
N
-S
N
N
N
N
N
S
N
S
S
Pd
Pd
Pd
6
4
7
m/z 572
m/z 604
m/z 555
Scheme 2. The formation mechanism and fission mechanism of bis(thiourea) Pd pincer under the (C)ESI-MS condition.
to the middle aryl ring through the newly formed Pd–C bond.
Whereas, the preparartion of the Pd0 complex was synthesized by
the addition of the Pd(dba)2 (0.1 mmol) to a solution of bis (thiourea)
ligand 2 (0.1 mmol) in DCM (2 ml) at room temperature and stirred
overnight, then the solvent was removed under vacuum and the
precipitates washed by toluene to give black powder (50 mg, 78%).
The synthetic routes of Pd0 complex and Pd2C pincer was depicted
in Scheme 3. To validate the above assumption, the ESI tandem mass
experiment of the real bis(thiourea)–Pd pincer was done and this
mahogany powder produced the same fragment ions as those of Pd0
complex 1.
Figure 4. The X-ray structure of bis(thiourea)–Pd pincer.
Copyright  2007 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 542–546
DOI: 10.1002/jms

JMS letters 545
O
O
O
2HCl
NH2
i
N
H
N
H
NH
OH
H2N
HN
NH
Ar
Ar
Ar =mesityl
ii, iii
N
N
N
N
Ar
Ar
iv
v
S
S
Pd
Pd0 complex (black powder)
1
N
N
N
N
S
S
N
N
Ar
Ar
N
N
2
Ar
Ar
S
S
Pd
Cl
9
Pd2+ Pincer (mahogany powder)
Condition: (i) EDCI, HOBt, NEt3, DCM. 85-90%; (ii) BH3-SMe2; (iii) thiophosgene,
Na2CO3, THF. 41-45% for two steps; (iv) Pd(dba)2, DCM. 78% (v) PdCl2(CH3CN)2,
DCM. 62%.
Scheme 3. Synthetic routes of Pd0 complex and Pd pincer.
Table 1. Comparison of Suzuki coupling reaction catalyzed by bis(thiourea)–Pd pincer and
bis(thiourea)–Pd0 complexa
Pd catalyst
Ar-Ar1
1
ArX + Ar B(OH)2
base, H2O
Pd
(mol%)
Entry
1
ArBr
Ar1B(OH)2
PhB(OH)2
Yieldb,d
99
Yieldb,e
99
O2N
0.1
Br
Br
Br
O2N
O2N
2
3
PhB(OH)2
0.001
0.1
81
94
75
93
F3C
B(OH)2
H3Cs
OHC
Br
4
0.1
0.1
0.1
85
82
82
57
89
63
B(OH)2
H CO
3
Br
5
PhB(OH)2
H3CO
Br
c6
PhB(OH)2
H3CO
H3CO
Br
Br
F3C
B(OH)2
7
0.1
0.1
54
64
61
70
B(OH)2
8
a
1
°
ArX/Ar B(OH)2/base, 1.0 : 1.2 : 2.0 in pure H2O in 100 C, base, K2CO3, reaction time 2.5 h.
b Isolated yield.
c base, NaOH.
d Pd pincer 9 as catalyst.
e Pd0 complex 1 as catalyst.
Copyright  2007 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 542–546
DOI: 10.1002/jms

546
JMS letters
The Pd-catalyzed Suzuki cross-coupling reaction of aryl halides
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with aryl boronic acids is a general and efficient synthetic route to
biaryl compounds and has found wide spread application in many
areas of organic synthesis. As a new bis(thiourea) pincer, the catalytic
activity was compared with its counterpart, bis(thiourea)–Pd0
complex 1. As shown in Table 1, the bis(thiourea)–Pd pincer
illustrates higher catalytic activity than Pd0 complex 1, especially in
entry 4 (Table 1 entries 1–4) due to the activated bromides, K2CO3
as base. But for the deactivated p-bromoanisole, their catalystic
activity can be affected by the base added. If the base is K2CO3, the
bis(thiourea)–Pd0 complex shows slightly higher catalystic activity
than Pd pincer. Meanwhile for entry 5 and 6, if the base was changed
to NaOH, the catalystic activity of Pd pincer was not affected and
the activity of Pd0 complex was decreased obviously.
In summary, we have observed a new bis(thiourea)–Pd pincer
in ESI-MS experiments and a series of hybrid (thiourea and carbene)
Pd pincers and bis(carbene)–Pd pincer in ESI-MS/MS experiments.
Guided by the above information, the new bis(thiourea)–Pd pincer
was synthesized and its catalytic activity in the Suzuki reaction was
compared with the bis(thiourea)–Pd0 complex. In the future work, a
series of synthesized hybrid Pd pincers suggested by ESI-IT-MS/MS
experiments will be done.
Yours,
LI RUI,1 CHEN WEI,2 SHI JIANYOU,1 CHEN LIJUAN,1Ł CHEN
YINGCHUN,2 DING LISHENG3 and WEI YUQUAN1
State Key Laboratory of Biotherapy, West China Hospital, Sichuan Univer-
sity, Chengdu 610041, China
Key Laboratory of Drug-Targeting of Education Ministry and Department
of Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu
610041, China
1
2
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Copyright  2007 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 542–546
DOI: 10.1002/jms