Unprecedented side reactions in Stille coupling: Desired ones for Stille polycondensation

Article abstract of DOI:10.1039/c5cc05404d

Two types of unprecedented side reactions were identified in the Stille coupling reaction, including the direct C-H stannylation of the α-hydrogen of thiophene and the stannylation of arylbromides with trialkylstannane bromide. These results reveal the major source of enhancements for Stille polycondensation efficiency.

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Communication
The Unprecedented Side Reactions of Stille Coupling: Desired Ones for
Stille Polycondensation
Hongyan Huang,a,b Guangyuan Jiao,a,b Shuli Liu,a,b Quan Li,a,b Xin Shi,a,b Nina Fu,a,b Lianhui Wang,*a,b
Baomin Zhao,*a,b and Wei Huang*a,c
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
been synthesized with molecular weights as high as 100 kd in
50 good yields using BDT-tin monomers.6a,10 Yet, even the reported
reactions were run under the similar conditions as their polymeric
counterparts, when considering the synthesis of BDT-bearing
small molecules, the yields are always low.11 It is very important
to identify this paradoxical fact that the low yield Stille coupling
55 for small molecules is very efficient as polycondensation method
for high molecular weight polymers. Since the reaction yields of
the Stille cross-coupling reactions can vary in very large ranges,
we assume there must be other side reactions which affect the
yields but have not been noted.
Two kinds of unprecedented side reactions were identified in
the Stille coupling reactions, including the direct C-H
stannylation on α-hydrogen of thiophene units and the
10 stannylation of arylbromides with trialkylstanne bromide.
These results reveal the major source which enhances the
Stille polycondensation efficiency.
The Stille coupling has become an appealing synthetic
methodology and has been widely applied to the syntheses of
15 numerous organic compounds.1,2 The impact of this methodology
has been spread to organic semiconducting material areas,3 which
are important for the development of next-generation
optoelectronic devices.4,5
A survey of the literatures on
conjugated materials will advance the idea that Stille coupling
20 reaction has emerged as the most significant synthetic method
towards the thiophene-bearing materials, especially thiophene-
bearing polymers used in OFETs and OPVs.6 Taking advantage
of the pairing of highly electron-rich thiophene monomers with
electron-deficient halide and triflate monomers, the Stille
25 polycondensation method typically gives excellent yields,
provides a facile route to high molecular weight, narrowly
dispersed polymers under mild conditions, while tolerating a
wide variety of functional groups.6
60
Scheme 1 Organotin and organo-halides tested in this work
With the motivation to explicitly confirm the possible side
reactions which happened in the Stille reaction, a series of model
experiments were systematically designed by combining the
65 reactants and the reaction conditions. As starting materials, we
synthesized 4,7-dibromoquinoxaline (BrQBr)12 as ideal dibromo
compound in that the proton NMR chemical shifts of BrQBr
were clearly separated from each other and the two long alkyl
chains on BrQBr could improve the solubility of the target
70 products(see Scheme 1). In order to obtain a universal conclusion
on the side-reaction issue, two catalyst systems, both Pd(PPh3)4
and Pd2(dba)3/P(o-tol)3 in toluene were tested.
Mechanistically, the Stille cross-coupling reaction involves a
30 repeating oxidative addition, transmetalation and reductive
elimination sequence, which yields the products and regenerates
the catalyst.7 (see ESI†, Fig. S1.) Including the organostannyls
and organohalides, all parameters of ligands, solvents, and
additives have played major roles in the outcome of Stille
35 coupling. Elucidation of the mechanism through the interplay of
these variables has been investigated by many researchers.
Except the homocoupling of organotin compounds and the
decomposition of organotin under palladium catalyst,8 few
systematic investigations on the side reactions of Stille coupling
40 have been rarely conducted. Especially, to the best of our
knowledge, there are no published works on the study of Bu3SnX,
which is generated during the Stille coupling reaction by
stoichiometric quantity.
The reactions of Equation 1 and 2 were conducted to confirm
the Stille coupling conditions in our hands (see Scheme 2). The
75 typical conditions with Pd(PPh3)4/toluene or Pd2(dba)3/P(o-
tol)3/toluene under argon atmosphere were tested. For Equation
o
1, after being heated at 110 C for 16 hr, it could give the target
product 7 with an excellent yield of around 95%. When Equation
1 was scaled up to 3.0 grams level, the yield was slightly reduced
80 by 2.5%. These results indicated that the two reaction conditions
were very efficient in the present work. All of the following
designed reactions will be tested with both of these two
conditions. But for Equation 2, even the mole ratio of 1 to
Our current research focuses on synthesis of novel thiophene-
45 based molecules for organic photovoltaics and organic field-
effect transistors.9 We found the Stille coupling methodology was
by no means problem-free. For example, numerous conjugated
polymers based on benzo[1,2-b:4,5-b’]dithiophene (BDT) have
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DOI: 10.1039/C5CC05404D
DSnTT was 2.4/1.0, the yield of 8 was around 84%. Due to the
1Q2T, 2Q3T and 3Q4T had been generated and for 75 min,
decomposition of DSnTT under Pd-catalyst, mono-coupling 50 4Q5T was also appeared whenc checking the reaction mixture
product of 2-(5-hexylthiophenyl)- thieno[3,2-b]thiophene was
observed by GC-MS measurement. The proton NMR
measurements of all products generated with Equation 1 and 2
indicated that our starting materials designation was reasonable
since all proton signals could be conclusively assigned.
with MALDI-TOF-MS. In addition, 1Q2TSn and 2Q3TSn were
both clearly observed with relatively strong peaks on their
MALDI-TOF-MS spectra after Equation 3 was run for more
than 75 min. (see ESI Fig. S26 and S27) With these results, it
55 could be assumed there may be a C-H direct stannylation
intermediate generated after 1Q2T was generated in the reaction
mixture, i.e. 1Q2TSn (see Equation 5). Thus, this C-H
stannylated intermediate reacted with BrQT to give 2Q3T, then
further to generate 3Q4T with the intermediate of 2Q3TSn. And
60 the tributylstannyl bromide worked as the organotin source. Via
the similar procedure, the side-products of 9 would be generated
5
o
in 3.b. When 3.a was run at a higher temperature of 145 C with
microwave irradiation for 1 hour,13 the direct stannylation side
reaction on the α-hydrogen was improved. When all reaction
65 conditions were fixed for reactions of 3.a and 3.b, it was found
that the yields of 1Q2T and 9 with Pd(PPh3)4 as catalyst were
slightly higher than those with Pd2(dba)3/P(o-tol)3 as catalyst.
These results indicate that the catalyst of Pd2(dba)3/P(o-tol)3 is
more efficient than Pd(PPh3)4 for the C-H direct stannylation and
70 the direct stannylation reaction will be improved by increasing
the reaction temperature.
Scheme 2 Confirmation of the Stille reaction conditions
10
As shown in Scheme 3, another two Stille reactions of 3.a and
3.b were tested by replacing both 2 and 1 with 4 and 3,
respectively. Interestingly, the yields of major products for these
two reactions decreased dramatically with low yields of 62% (for
1Q2T, 4 entries average) and 54% (for 9, 3 entries average).
15 When we moved to the catalyst of Pd(PPh3)4, the yields were still
very low. By carefully checking the reaction mixture by thin
layer chromatography, there were still more polar side products
observed for both Equation 3 and Equation 4.
Firstly, the reaction residue of Equation 3 was carefully
20 separated with silica column chromatography. At least, three
cross-coupling side products of 2Q3T, 3Q4T and 4Q5T were
collected with the preparation yields of 21%, 8% and 3%,
respectively. All of these products were conclusively confirmed
with 1H NMR and matrix-assisted laser desorption ionization
25 time-of-flight (MALDI-TOF) mass spectrometry. As shown in
Figure 1, the end group of thiophene units for all three products
exhibits clear and feature multiple peaks with chemical shifts at
7.18, 7.50 and 7.82 ppm. The thiophene units in the centre part of
the two side products show peaks with chemical shifts at 7.77
30 ppm (for 3Q4T) and and 7.75 ppm (for 4Q5T). Due to the
structural symmetry, there are two kinds of quinoxaline units in
3Q4T, which exhibit two adjacent peaks at 8.11 and 8.16 ppm.
The integration of all peaks for each compound and the mass
spectra are also clearly coincident with their structures. (see ESI†)
35 Although the side-products generated from Equation 4 were not
fully isolated with silica gel chromatography after many attempts
due to their poor solubility and low polar properties, their
structures were unambiguously identified by MALDI-TOF mass
spectrometry. Alternating oligomers composed of 3-
40 hexylthiophene units and thieno-thiophene units were clearly
observed according to their mass spectra (see ESI†). After
collecting all of these side products with chloroform as eluent,
they account for 33% of total yields by calculating their weights.
Obviously, the first side reaction we observed in Equation 3
45 and 4 happened when there were α-hydrogens on the thiophene
units, by comparing the reactions shown in Scheme 2 and 3. The
driving force to selectively generate this side reaction is still
unclear. Interestingly, after Equation 3 was run for 25 min,
Scheme 3 C-H transformation based side reactions: a) Pd2(dba)3, P(o-
tol)3, toluene, 110 oC, 16 hr; 3.c) Possible mechanism towards 2Q3T and
75 3Q4T.
We tried two model reactions to further interrogate the
assumption that Bu3SnBr could play a crucial role in Stille
coupling reaction with aromatic halides (see in Scheme 4). With
2
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Pd2(dba)3/P(o-tol)3 as the catalyst, BrQQH was synthesized with
a yield of about 83% (3 entries average) by mixing BrQBr with
1.1 equivalent of Bu3SnCl in toluene. And with Bu3SnBr as
reagent for Equation 6, the yield was almost the same. With 5 as
starting materials, 10 was also obtained with a yield of 91%.
When we tested Equation 6 and 7, by using 0.6 equivalent of
Bu3SnCl, we obtained both BrQQH and 10 with relatively lower
yields. Meanwhile, in both cases, the starting materials
conversion ratio reached 97%. But, if no Bu3SnBr or Bu3SnCl
chromatography, BrQQSn was decomposed as BrQQH, due to
the organotin decomposition induced by silica gel. Accordingly,
the second possible side reaction of Bu3SnX mediated aryl-aryl
coupling was identified.
5
C8H17
O
OC8H17
C8H17O
OC8H17
Equation 6
BrQBr
Bu
Bu
Bu
N
N
N
N
Cl
Br
SnHBu2
Br
Br
a)
N
N
N
N
10 was added to the reaction mixture, there was no BrQQH and 10
generated. These results show that under Stille coupling
conditions, the aryl bromides undergo an unusual coupling
reaction with the mediation of Bu3SnCl (or Bu3SnBr). Usually,
this kind of reaction is conducted by combining aryl bromides
15 with hexabutyldistannane.14 By monitoring Equation 6 and 7
with MALDI-TOF-MS and GC-MS after they were run for 2 hr,
there were at least two kinds of stannylated intermediates
observed. (see ESI Fig. S28 & S29) And these intermediates
show similarly structural characters. Therefore, we propose the
20 mechanism as follows. Firstly, when Bu3SnBr was heated in
toluene, it gave rise to Bu2HSnSnHBu2 and other organo-stannes.
(see ESI Fig. S30) Then, BrQBr was stannylated with these
distannyl compounds. After this, Stille coupling took place to
give BrQQBr. Later, BrQQBr was further stannylated as
25 BrQQSn. When running the purification by silica column
OC8H17
BrQQSn
C8H17
O
OC8H17
C8H17
O
BrQQBr
OC8H17
C8H17
O
N
N
decompose
on silica gel
Br
N
N
OC8H17
83%
C8H17
O
BrQQH
Equation 7
H3CO
Bu
Bu
Bu
Cl
Br
H3CO
OCH3
a)
10, 91%
30
Scheme 4 C-C bond formation mediated by trialkyl chloride/bromide: a)
Pd2(dba)3/P(o-tol)3, toluene, 110 oC, 16 hr
Fig. 1 1H NMR assignment of 1Q2T, 2Q3T and 3Q4T
35
Since no quinoxaline-quinoxaline directly linked side products
Bu3SnBr (or Me3SnBr) is always generated during the
polymerization. And the decomposition of thiophene-based
organotin monomers is inevitable, which will generate building
blocks with α-hydrogen and make the dibromo monomer
in reaction Equation 3 are isolated, it seems that two kinds of
side reactions do not equally take place. The direct stannylation
side reaction on α-hydrogen of thiophene is more competitive
than arylbromide stannylation side reaction in the same reaction 45 excessive. It can be expected that these side reactions involved
40 system. In case of Stille polycondensations, a quantitative of
with trialkyl bromides can improve the polymerization degree
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DOI: 10.1039/C5CC05404D
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70
75
80
85
90
95
In conclusion, we have identified two unprecedented side
10 reactions in the standard Stille coupling reaction by carefully
designing the starting materials. One is the direct stannylation on
thiophene units when there is α-hydrogen on them; the other is
the stannylation of aryl bromides. Both of these two side
reactions are based on the trialkylstanne bromide generated
15 during the Stille coupling reaction. These two side reactions will
be promoted by increasing the reaction temperature. Both of these
two side reactions will improve the efficiency of the Stille
polycondensation for high molecular weight polymers, but are
detrimental to the synthesis of small molecules. The results
20 presented here represent an interesting and important recognition
on the mechanism of Stille coupling. Further investigation of the
mechanism is still under way.
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This work was financially supported by the National Basic
Research Program of China (2012CB933301), the National
25 Natural Science Foundation of China (51103074, 51203077,
21204038, 81273409, 51173081), Natural Science Foundation of
Jiangsu Province (BK2012438, BM2012010), the National
Synergistic Innovation Center for Advanced Materials (SICAM),
the Sci-tech Support Plan of Jiangsu Province (BE2014719), the
30 Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD).
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Notes and references
a Key Laboratory for Organic Electronics and Information Displays &
Institute of Advanced Materials, bNational Jiangsu Synergetic Innovation
35 Center for Advanced Materials (SICAM), Nanjing University of Posts &
Telecommunications, 9 Wenyuan Road, Nanjing 210023, China
Fax: (+86) 6779 1691 E-mail: iambmzhao@njupt.edu.cn
c Key Laboratory of Flexible Electronics (KLOFE) & Institue of
Advanced Materials (IAM), National Jiangsu Synergetic Innovation
40 Center for Advanced Materials (SICAM), Nanjing Tech University
(NanjingTech), 30 South Puzhu Road, Nanjing 211816, China.
Fax: (+34) 952 132000 E-mail: iamwhuang@njtech.edu.cn
† Electronic Supplementary Information (ESI) available: Synthesis and
characterization data and additional materials. See DOI:
45 10.1039/b000000x/
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