Suzuki-Miyaura Micellar One-Pot Synthesis of Symmetrical and Unsymmetrical 4,7-Diaryl-5,6-difluoro-2,1,3-benzothiadiazole Luminescent Derivatives in Water and under Air

Article abstract of DOI:10.1021/acs.joc.8b02204

The Suzuki-Miyaura cross-coupling reaction of 4,7-dibromo-5,6-difluoro-2,1,3-benzothiadiazole with different arylboronic acids can be efficiently carried out in water and under air by means of micellar coupling. The careful tuning of reaction conditions enables preparation of symmetrically and unsymmetrically substituted derivatives. The moderate to good yields obtained, along with the wide variety of available substitution patterns, makes this sustainable methodology very useful for the preparation of building blocks for luminescent optoelectronic materials.

Full text of DOI:10.1021/acs.joc.8b02204

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Article
Suzuki-Miyaura micellar one pot synthesis of symmetrical
and unsymmetrical 4,7-Diaryl-5,6-difluoro-2,1,3-
benzothiadiazole luminescent derivatives in water and under air
Alessandro Sanzone, Adiel Calascibetta, Erika Ghiglietti, Chiara Ceriani,
Giuseppe Mattioli, Sara Mattiello, Mauro Sassi, and Luca Beverina
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02204 • Publication Date (Web): 14 Nov 2018
Downloaded from http://pubs.acs.org on November 17, 2018
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Suzuki-Miyaura micellar one pot synthesis of symmetrical and
unsymmetrical 4,7-Diaryl-5,6-difluoro-2,1,3-benzothiadiazole luminescent
derivatives in water and under air
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Alessandro Sanzone, Adiel Calascibetta, Erika Ghiglietti, Chiara Ceriani, Giuseppe Mattioli, Sara Mattiello,
†
†*
Mauro Sassi, Luca Beverina
†
Department of Materials Science, University of Milano-Bicocca, Via R. Cozzi, 55, Milano, Italy. I-20127
‡
CNR - ISTITUTO DI STRUTTURA DELLA MATERIA, Via Salaria Km 29,300 - C.P. 10 I-00015 - Monterotondo
Scalo (RM)
ABSTRACT: The Suzuki-Miyaura cross coupling reaction of 4,7-dibromo-5,6-difluoro-2,1,3-benzothiadiazole (DBBF) with different arylboronic
acids can be efficiently carried out in water and under air by means of micellar coupling. The careful tuning of reaction conditions enables
preparation of symmetrically and unsymmetrically substituted derivatives. The moderate to good yields obtained, alongside with the wide variety
of available substitution patterns, makes this sustainable methodology very resourceful for the preparation of building blocks for luminescent
optoelectronic materials.
Graphical abstract
INTRODUCTION
Organic (opto)electronics has played a major role in academic and industrial research in the last 30 years. OLEDs
have already evolved into a strong market reality. The other 2 notable members of organic electronics’ “big three”, i.e.
1
photovoltaics (PV) and thin-film field effect transistors (TFTs), are expected to follow in the near future. When moving
from the Lab to the Fab environment, high performance is not enough to ensure successful technology transfer.2
Active materials have to become available at the large scale and through sustainable processes. All hazards have to
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be minimized thus leaving little room for toxic and/or flammable solvents. Current state of the art printable materials
4
are far from optimal in this respect. The processes leading to their synthesis are expensive and do not take into
5
account established sustainability indexes like the E factor (kg of organic waste and byproducts/kg of product). The
class of the 4,7-diaryl-5,6-difluoro-2,1,3-benzothiadiazole derivatives, with 4,7-di(thiophene-2-yl)-5,6-difluoro-2,1,3-
benzothiadiazole (DTBT) as the most prominent member, is a representative example of such situation. DTBT
(Scheme 1) is a commercially available, rather expensive, building block that is gaining a relevant momentum in the
dedicated literature.6–9 In the last 8 years DTBT was reported, directly as it is or as a part of more complex polymer or
molecule, in nearly 300 papers, with a steady increase in the number of hits per year (See Figure S1 of the ESI).
Scheme 1. Literature vs micellar approach for the preparation of DTBT
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As shown in Scheme 1, DTBT can be prepared according to three routes: a) from 4,7-dibromo-5,6-difluoro-2,1,3-
benzothiadiazole (DBBF) and 2-tributylstannyl thiophene with various Stille coupling protocols,10,11 for example in
chlorobenzene and under microwave irradiation8 b) from 4,7-diiodo-5,6-difluoro-2,1,3-benzothiadiazole and 2-
thienylboronic acid pinacol ester via Suzuki-Miyaura (SM) coupling in water/THF mixture in moderate to good yield;12 c)
directly from 5,6-difluoro-2,1,3-benzothiadiazole and 2-bromothiophene via C-H activation, in modest yield.13 None of
such methods can be considered sustainable. The Stille route is efficient but involves both the use of organic solvents
and of tin compounds. The Suzuki coupling is generally inefficient in the case of thiophene containing derivatives as the
poor reactivity of the thienyl-boronic acid is connected with a pronounced tendency to protodeborylation, particularly at
high temperature.14 Finally, the C-H activation is attractive, as it does not require activation of 5,6-difluoro-2,1,3-
benzothiadiazole (DFBT), allowing easy access to several symmetrically and unsymmetrically substituted derivatives.
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However, its generality is limited to substrates having C-H reactivities lower than those of DFBT and the intermediate in
order to retain chemoselectivity and high yields, as testified by literature results with bromothiophene (low product yields
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and olygothiophenes formation) .
Micellar synthesis has demonstrated strong potential to improve sustainability.15–17 Micellar reactions are a well-
established topic in modern organic synthesis.18–23 They enable the use of well-known C−C and C−N bond-forming
strategies in water and frequently at room temperature, with ample recyclability of the reaction medium.24–36 Recently, a
relevant example of a photoredox transformation in micellar environment was also reported.25 The use of such methods
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in the field of organic semiconductors is still limited and only a few examples of relevant conjugated molecular materials
are reported.5,37–40
Here we show that the careful tuning of reaction conditions - in this case particularly referring to the definition of the
micellar environment through a formulation chemistry approach - enables the preparation in quantitative yield of DTBT
in water as the only solvent, at room temperature and under standard laboratory environment by means of the SM
coupling of DBBF and 2-thienylboronic acid. We also show that conditions can be tuned in order to prepare
unsymmetrical derivatives bearing two different aryl residues in a one pot procedure not requiring the isolation of the
monoarylated intermediate.
Results are relevant both as they provide a simple and sustainable access to valuable intermediates and because they
shed some light on the peculiar characteristic of micro-heterogeneous micellar reactions over homogeneous phase
approaches.
RESULTS AND DISCUSSION
Micellar synthesis of DTBT.
We recently prepared the two 4,7-diaryl-2,1,3-benzothiadiazole derivatives shown in Scheme 2a by means of an efficient
room temperature micellar SM reaction, carried out in a 2 wt% water solution of the industrial surfactant Kolliphor EL.40
Whilst the phenyl end-capped derivative 1 can be prepared in quantitative yield using 2 mol% Pd(dppf)Cl
2
as the
catalysts, the synthesis of 2 requires the use of the more efficient Pd(dtbpf)Cl in analogous stoichiometry. No doubt,
2
this is connected with the poor reactivity of 2-thienylboronic acid. However, in both reactions we did not observe the
formation of the monoarylated species. Reactions where selective towards the formation of the diarylated compounds,
even in the case of excess of 4,7-dibromo-2,1,3-benzothiadiazole over the boronic acid employed (Scheme 2a).
The aforementioned syntheses could also be carried out in other popular designer surfactants such as TPGS-750-M
with similar efficiency. However, the use of Kolliphor EL was found to be advantageous as the reaction could be carried
out with identical results irrespective to the atmosphere employed. We routinely carried out reactions in standard test
tubes, under normal laboratory environment. As this feature is advantageous in both speeding up laboratory practices
and improving the overall sustainability of scaled up processes, we decided to further investigate the applicability of
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Kolliphor EL and structurally related commercially available surfactants in the preparation of other relevant molecular
materials and precursors.
Unfortunately, when moving from 4,7-dibromo-2,1,3-benzothiadiazole to the more optoelectronic applications relevant
DBBF, the reaction behaviour changes completely. As it is shown in Scheme 2b, the reaction carried out with Pd(dppf)Cl
2
gives very little conversion, mostly leading to the monoarylated species. The only byproducts we observed by GC-MS
of the reaction mixture were bithiophene (the homocoupling product of the boronic acid) and 4-(thiophene-2-yl)-5,6-
difluoro-2,1,3-benzothiadiazole, both of them in concentration below 0.5%. TLC inspection and NMR analysis confirmed
that the 2-thienylboronic acid was still present, so that protodeborylation can be ruled out as the reason for the reaction
not reaching full conversion.
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When switching to Pd(dtbpf)Cl , the conversion increases substantially yet the reaction does not go to completion.
Further extension of the reaction time does not influence the composition of the reaction mixture. As in the previous
case, the homocoupling and debromination byproducts are barely distinguishable from the background noise in the GC-
MS traces (all traces are reported in the ESI).
Scheme 2. Difference in the mono vs diarylation selectivity in SM reactions carried out on 4,7-dibromo-2,1,3-benzothiadiazole vs DBBF.
B(OH)2
S
a)
N
N
Pd(dppf)Cl2
96%
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N
N(Et)3
Br
Br Kolliphor EL 2%
r.t., 2 h
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7%
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Br
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DTBF
85%
13%
2%
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S
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B(OH)2
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N
Br
Br
N(Et)3
Kolliphor EL 2%
r.t., 24 h
F
F
DBBF
0%
32%
68%
Pd(dtbpf)Cl2
In order to evaluate the generality of the effect, we also tested the coupling of DBBF with two additional boronic acids:
-thienylboronic acid and phenylboronic acid. Reactions were performed in 2 wt% Kolliphor EL under standardized
3
3 2
conditions: 0.5 M DBBF, 1.5 M boronic acid, 3 M N(Et) and 2 mol% with respect to the bromide of Pd(dppf)Cl . Scheme
3 shows the results we obtained.
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Scheme 3. Examples of SM reactions carried out on DBBF and leading to limited conversion.
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None of the reaction gave complete conversion and the monocoupling product was the dominating component. Results
also reflect the different reactivity of the boronic acids employed: the reaction performed with phenylboronic acid was
sizeably more effective. We recently observed a similar behaviour in the SM coupling of both thiophene and phenyl
boronic acid with di-bromides pertaining to the family of the latent pigments. Such species give essentially no conversion
41
with a variety of surfactants (including the popular designer surfactant TPGS-750-M ) and catalysts. The reaction
becomes very efficient in the presence of a small amount of a water immiscible co-solvent of suitable polarity.39 Such
observation hinted at a problem of lack of efficient dispersion of the reactive species within the reaction mixture, thus
requiring evolution from micellar to an emulsion approach. Indeed, micellar reaction have recently been considered
somewhat capricious as sight difference in the experimental conditions can lead to sizeably different outputs.42
The use of a co-solvent is a known and resourceful tool.43,44 Although efficient, it remains unsatisfactory from the stand
point of sustainability and E-factor reduction, as the use of organic solvents should be limited as much as possible.
In the present paper we aim both at finding a satisfactory protocol leading to DTBT in high yield and without the use of
organic solvents and at the elucidation of the factors limiting the conversion in Scheme 2 and 3 reactions. We thus
decided to use the SM coupling of DBBF and 2-thienylboronic acid as a relevant case study and we evaluated the
product distribution as a function of key reaction parameters: the concentration and nature of the surfactant(s), the
concentration of the reagents, and the nature of the catalyst. The computationally aided rationalization of the results was
finally exploited for the identification of conditions preferentially giving mono vs double SM coupling in order to prepare
unsymmetrically substituted derivatives in a one pot procedure.
Influence of the surfactant concentration.
The first parameter we investigated was the concentration of the surfactant. Literature data mostly refer to a 2 wt% as
the best trade-off between efficiency and cost. The latter factor is not that relevant in the case of Kolliphor EL, we thus
examined 2, 5, 10 and 20 wt% solutions. The DLS analysis of the surfactant solution (see figure S2) shows that while
there is little difference between 2, 5 and 10 wt% solutions in terms of the dimensions of the micelles obtained, the 20
wt% one also contains aggregates of larger dimensions. We carried out all reactions under standardized conditions: 0.5
3 2
M DBBF, 1.5 M 2-thienylboronic acid, 3 M N(Et) and 2 mol% with respect to the bromide of Pd(dppf)Cl . Initially, we
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purposefully decided to use Pd(dppf)Cl
the various reaction conditions employed. All reactions were quenched after 12 h stirring at room temperature, extracted
with CH Cl , filtered over a pad of silica gel and submitted to GC-MS characterization. Table 1 shows the product
2 2
over the more reactive Pd(dtbpf)Cl in order to magnify the differences between
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distributions we obtained. All values are corrected for the instrument response factor for the three different analytes,
they thus correspond to the GC-MS yields of the different compounds (See Supporting Information for details).
Table 1. Influence of the Surfactant concentration in the SM coupling reaction between DBBF and 2-thienylboronic acid. Conditions: 0.5
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M DBBF, 1.5 M 2-thienylboronic acid, 3 M N(Et) and 2 mol% with respect to the bromide of Pd(dppf)Cl . Room temperature
Entry Surfactant concentration (wt%) DBBF (mol%) TBF (mol%) DTBT (mol%)
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2
5
85
64
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With the exclusion of the data relative to the 20 wt% solution – where in any case the mixture is out of the micellar regime
as evidenced by the DLS data - the reaction becomes increasingly more efficient at higher surfactant concentration. The
reaction is somewhat selective to the monoarylated product even in the presence of a large excess of boronic acid.
Running the reaction for a longer time and/or under nitrogen atmosphere did not influence the conversion nor changed
in any way the product distribution.
Influence of the reagents formal concentration.
At a fixed surfactant concentration of 2 wt%, we varied the formal concentration of the reagents, while leaving fixed the
3
respective stoichiometry ratio of 1:3:6:0.02 for DBBF:boronic acid:N(Et) :catalyst respectively.
Table 2. Influence of the reagents molarity at 2 wt% Kolliphor concentration in the SM coupling reaction between DBBF and 2-
thienylboronic acid. Reaction carried out at room temperature, 12 h.
Entry DBBF [M] DBBF (mol%) TBF (mol%) DTBT (mol%)
1
2
3
4
0.3
0.5
1.0
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85
77
92
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It should be noted that in a micellar reaction most of the reagents and products are just suspended in water. As such,
the nominal concentration may not be correlated with the stoichiometric ratio within the micelle and/or at the various
interphases between reagents, water and micelles. Table 2 shows the results we obtained.
The reaction shows very little sensitivity to the concentration of the reagents. Within the 0.5-1.0 M nominal concentration
the reaction gives best results. It should be noted that at 1.0 M concentration the reaction mixture is very viscous and
mechanical stirring is recommended.
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Influence of the Surfactant.
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Literature reports a large number of surfactants suitable to carry out SM coupling in high yield and at room temperature
under micellar conditions.16 Some of them are well established industrial surfactants originally developed for the needs
of formulation chemistry.20 Others specifically designed for micellar reactions have been shown to feature superior
performances in terms of yield and/or reduction of the reaction time.32,41,45–47 Despite the seminal value of these
observations, there are no general structure-property relationships clearly correlating performances in micellar reactions
with the surfactant chemical nature. Mostly, the difference in performances are ascribed to the aspect ratio (spherical vs
worm like) and/or dimensions of the micelles obtained in water solution. Recently, a seminal computational investigation
of the association behaviour of micelles was also reported.48
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In the case of underperforming reactions such as the couplings shown in Schemes 2b and 3, the use of specifically
designed surfactants could be of help. Yet, from the standpoint of sustainability, the synthetic effort put in the preparation
of the surfactant should be considered. Some designer surfactants are now commercially available, yet none of them is
comparable, in terms of cost and sustainability, with the large number of industrial surfactants constituting the toolbox of
the formulation chemist.
Moreover, the primary role of the surfactant in a SM micellar coupling is to provide a microenvironment where the reaction
can take place. The task is somewhat similar to the preparation of stable emulsions: organic phase and surfactant
characteristics need to be carefully matched in order to ensure durability. The production of a specific surfactant to suit
the needs of every organics is unpractical and the use of mixtures is a routine practice.
Accordingly, the use of a mixture of existing and readily available surfactants, aimed at tuning the interaction of the
micelles with either the reagents or the products of a given reaction, could be a very resourceful tool for micellar couplings
as well.
Commercial surfactants are complex molecules possessing functional groups of different polarity. In the case of
polyethoxylated species, like Kolliphor EL, they are also intrinsically polydisperse. In order to be able to qualitatively
describe the affinity of a given surfactant with respect to a phase to be dispersed/emulsified, formulation chemists
developed the concept of the Hydrophilic Lipophilic Balance (HLB). This is a completely empirical parameter, not
necessarily linearly correlated for example with the dielectric constant, that gives a qualitative idea of the affinity of a
surfactant for water (HLB>10) or for oil (HLB<10).49 The HLB of Kolliphor EL is 13.5, which identifies it as water soluble
and appropriate for the preparation of oil in water emulsions. Aiming at tuning the interaction of Kolliphor EL with the
components of the reaction mixture, we decided to mix it with two other neutral and polyethoxylated industrial surfactants,
Tween 80 and Span 80, featuring an HLB of 15 and 4.3, respectively. In both cases we mixed the surfactants in a 7:3
ratio Kolliphor/co-surfactant. As it is discussed below, this proportion is dictated by the limited solubility in water of Span
80. The HLB values of the two mixtures can be calculated as the weighted average of the HLB of the pure constituents,
thus the Kolliphor EL/Span 80 mixture has an HLB value of 10.7 and the Kolliphor EL/Tween 80 mixture of 14.0. As we
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
have previously stressed, the HLB cannot be directly related to the dielectric constant or the partition coefficient of the
surfactants, yet it is safe to assume that at higher HLB values more polar derivatives will be preferentially dispersed.
Table 3 shows the results we obtained while running the reaction at a 2 wt% surfactant concentration and at a nominal
concentration of 0.5 M for the bromide. The decision to work at 2 wt% was dictated by the very limited solubility of Span
80 in water.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Influence of the Surfactants nature at 2 wt% concentration in the SM coupling reaction between DBBF and 2-thienylboronic
acid. Conditions: 0.5 M DBBF, 1.5 M 2-thienylboronic acid, 3 M N(Et) and 2 mol% with respect to the bromide of Pd(dppf)Cl
3
2
.
Entry
Surfactant (HLB)
DBBF (mol %) TBF (mol %) DTBT (mol %)
1
2
3
Kolliphor EL (13.5)
85
76
95
13
22
5
2
2
0
70% Kolliphor EL 30% Span 80 (10.7)
70% Kolliphor EL 30% Tween 80 (14.0)
The conversion degree is poor in all three cases, yet sizeably improving when working at low HLB values. In principle,
it could be interesting to explore even lower HLB values, yet this is technically difficult as surfactants approaching an
HLB value of 10 are perfectly balanced between lipophilic and hydrophilic behaviour and are only partially soluble in
water. Span 80 in particular is not water soluble and can be homogeneously dispersed in water only in the employed
7:3 mixture with Kolliphor EL and even then, requiring the use of a high shear mixer. Simple stirring does not provide a
homogeneous formulation.
It should be stressed that even in the case of surfactants mixtures, all reactions were carried out under standard
laboratory environment as no variation whatsoever in the product distribution and/or conversion degree was observed
when working under nitrogen atmosphere.
Influence of the catalyst.
Having assessed that the reaction is favoured by higher surfactant concentration and, at least to some extent by lower
HLB values, we tested under selected formulation conditions the use of the way more reactive catalysts Pd(dtbpf)Cl
instead of Pd(dppf)Cl 50,51. Table 4 shows the results.
2
2
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Table 4. Influence of the catalyst as the function of reaction formulation in the SM coupling reaction between DBBF and 2-thienylboronic
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
acid. Conditions: 0.5 M DBBF, 1.5 M 2-thienylboronic acid, 3 M N(Et)
temperature, 12 h.
3
and 2 mol% with respect to the bromide of the catalyst. Room
Entry
Surfactant
Kolliphor EL
Catalyst
DBBF TBF DTBT
1
2
3
4
5
6
7
8
9
Pd(dppf)Cl
2
85
0
13
32
22
3
2
68
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Kolliphor EL
Pd(dtbpf)Cl
2
70% Kolliphor EL 30% Span 80
70% Kolliphor EL 30% Span 80
Pd(dppf)Cl
2
76
0
Pd(dtbpf)Cl
2
97
0
70% Kolliphor EL 30% Tween 80 Pd(dppf)Cl
70% Kolliphor EL 30% Tween 80 Pd(dtbpf)Cl
70% Kolliphor EL 30% Span 80a Pd(dtbpf)Cl
70% Kolliphor EL 30% Tween 80a Pd(dtbpf)Cl
70% Kolliphor EL 30% Span 80b Pd(dtbpf)Cl
2
95
0
5
2
2
2
2
25
75
83
44
75
25
17
8
0
0
48
a
Reaction conditions: 0.5 M DBBF, 0.75 M 2-thienylboronic acid, 1.5 M N(Et)
3
and 2 mol% with respect to the bromide
of Pd(dtbpf)Cl
2
.b Conditions: 0.5 M DBBF, 1.5 M 2-thienylboronic acid, 3 M N(Et)
3
and 0.05 mol% with respect to the
bromide of the catalyst. Room temperature, 12 h.
2
The use of Pd(dtbpf)Cl greatly improves the conversion under all conditions explored, we however managed to push
reaction to completion, with nearly quantitative formation of the diarylation product, only in the case of the Kolliphor
EL/Span 80 mixture, corresponding to the lowest HLB mixture we explored. The mono Vs diarylation ratio can be
controlled by tuning the stoichiometry of the 2-thienylboronic acid. Entry 8 of Table 4, corresponding to a reaction where
the boronic acid was used in 1.5 to 1 stoichiometric ratio over DBBF instead of the larger excess of 3:1 we employed in
all other trials, shows that is it possible to prepare the monoarylated species at 83% yield without appreciable unreacted
DBBF and in the presence of only 17% of DTBT. As it is discussed below, this result opens the way to the preparation
of unsymmetrical derivatives.
Computational analysis.
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2
3
4
5
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
The datasets described in Table 1-4 demonstrates that the nature of the micro heterogeneous environment where
reactions take place has a strong influence on the product distributions and overall conversion. It remains however an
open question the reason why reactions performed on 4,7-dibromo-2,1,3-benzothiadiazole are selective towards double
SM coupling whilst the opposite is true for DBBF. We carried out a computational analysis of the various aryl halides
and corresponding products of mono- and di-arylation in order to get relevant parameters, mostly the dipole moment, to
be used as a guide in the elucidation of surfactant/molecules interaction within the micelles. A quantitative correlation of
the dipole moment of the chemical species involved and the HLB of the surfactant(s) employed would be an
overstretching of an empirical parameter introduced to describe the stability of industrial formulations. Nonetheless the
comparison of the calculated dipole moments in water and toluene of DBBF, 4,7-dibromo-2,1,3-benzothiadiazole and
the corresponding mono and diarylation products with the various boronic acids we employed (Scheme 4) could offer
relevant trends in the sign and magnitude of the polarity variation of the different species along the pathway going from
reagents to products. In fact, as the capability of the surfactants we used to form stable colloidal dispersions with
lyophobic species is correlated with respective polarities, changes in the dipole moments could offer a rational for
reactions selectively leading to mono over diarylated products.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Calculated dipole moments in toluene for 4,7-dibromo-2,1,3-benzothiadiazole, DBBF and the corresponding mono and
diarylation products with 2-thienylboronic acid, 3-thienylboronic acid and phenylboronic acid. Values are averaged amongst the two
(for monoarylation products) and three (for diarylation products) almost degenerate rotamers available (see ESI for details).
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
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7
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9
0
1
2
3
4
5
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8
9
0
1
2
3
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8
9
0
1
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0
1
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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5
5
5
6
We thus carried out a series of ab initio simulations based on density functional theory (DFT), performed by using the
ORCA suite of programs.52 We report first that all the mono- and diarylated compounds are characterized by the
occurrence of almost degenerate (energy difference never larger than 0.013 eV) stable rotamers. In 2- and 3-thienyl
adducts, the solid angle between the DBBF (4,7-dibromo-2,1,3-benzothiadiazole) and thienyl planes generally
approaches 0° or 180° values, corresponding to two nonequivalent isomers in the case of monoarylated compounds.
Such isomers are characterized by similar molecular dipoles, always higher than that calculated for the unsubstituted
DBBF and 4,7-dibromo-2,1,3-benzothiadiazole. The two equivalent monosubstituted phenyl rotamers (solid angle of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
40°) are also characterized by a similar increase in the molecular dipole. Such increase is due to the strong component
of the dipole moment rotated astray from the C2 symmetry axis of DBBF (4,7-dibromo-2,1,3-benzothiadiazole) in all
monoarylated compounds. The addition of a second aryl group generally leads to the formation of three possible and
again almost-degenerate isomers, and, in turn, to the symmetrisation of the molecule, with the dipole of monoarylated
compounds counterbalanced by the presence of a second thienyl or phenyl group. The resultant dipole vector is far
shorter in diarylated molecules than in monoarylated, and also shorter than that calculated for DBBF, while it is longer
in the case of 4,7-dibromo-2,1,3-benzothiadiazole, having a dipole vector collinear but inverted with respect to DBBF.
Without loss of generality, dipole values reported in Scheme 4 are averaged on rotational isomers; a detailed description
of all the investigated isomers, including relative energies and interconversion barriers, has been reported in the ESI.
Even if the calculated values of the dipole moments in water and toluene are different, the same trend is reproduced in
both datasets. Only derivatives 1 and 2 shows a polarity similar or higher than that of the starting dibromide. In all other
cases, the diarylation product is sizeably less polar than both the starting bromide and the monoarylated intermediate.
The consequences of such findings will be discussed in the next session in the general interpretation of all the data (both
experimental and computational) so far discussed.
Discussion.
Most micellar reactions described in the literature require the use of a 2 to 5 wt% solution of surfactant in the presence
of 0.5 to 1.0 M solutions of the reagents. As it is also quite clear from the various pictures that can be found in the
published papers (as well as in figure S3 of the Supporting Information), reaction vessels contain way more water
insoluble material than the maximum amount that can be incorporated within the micelles at a given time. Actually,
micellar synthesis is not a completely appropriate term as the reaction mixture is a suspension.
For all reactions giving no useful results in water alone (the so called reaction “on water” conditions, documented for SM
couplings but lacking generality and in any case not working at all in the case of DTBT), achievement of complete
conversion requires that a single micelle takes up reagents, localizes them in the same compartment where the catalyst
is also present, assists to their transformation in the product and eventually releases the latter to replace it with a fresh
aliquot of the former. This cycle has to be repeated several times, depending on the concentration of the surfactant. In
the absence of a selective affinity for products vs reagents, within the normal uptake/release equilibria involving all
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micelles, products and reagents will have a probability of being incorporated that will depend on their relative
concentration. The reaction will eventually slow down but go to complete conversion anyway. If, however the aryl halide
and the corresponding arylation product have a sizeably different affinity for the micelle compartment where the reactions
take place, one of the two will be preferentially incorporated. If micelles preferentially take up the halide, the reaction will
be particularly efficient. On the opposite, in the case of preferential uptake of the product, the reaction will be severely
slowed down by saturation of the active sites. The latter effect appears to be affecting the coupling of DBBF and 2-
thienylboronic acid. Indeed, the conversion degree depends linearly upon the amount of surfactant employed. The
dependency of the mono vs diarylation ratio with the surfactant concentration is less pronounced. Within the
experimental error connected with the small amount of DTBT obtained, the ratio can be assumed to be almost
independent from the surfactant concentration. The data suggest that a saturation effect prevents the micelles from
performing the coupling reactions multiple times, opposite to what is happening in the case of, for example, the
preparation of 1 and 2.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To gain further evidence that reactions do not proceed above a certain conversion degree due to selective affinity
towards the products, we carried out Scheme 5 reaction working at 0.5 M nominal concentration of bromide in a 2 wt%
Kolliphor EL solution. We let the formulation equilibrate for 24 h under stirring, prior to add the catalyst and the base.
The formation of the diarylated species was barely detectable. Actually, at least half of the DTBT detected by the GC-
MS after 24 h was already present at the beginning of the reaction as a contaminant of the monoarylated specie, whose
chromatographic purification from DTBT is troublesome.
Scheme 5. SM reaction of TBF and 2-thienylboronic acid in 2 wt% Kolliphor EL demonstrating the micelles saturation effect.
It is accepted that in a micellar protocol, chemical transformations happen preferentially within the apolar core, where
the catalyst is localized (this is in particular demonstrated in the case of Kolliphor EL according to our previous
experience).40 The computational results summarized in Scheme 4 differentiate fluorinated from nonfluorinated
derivatives on the basis of the polarity of both precursors and reagents. In both cases the polarity is increased by the
first coupling and decreased by the second one, essentially due to geometrical reasons. Fluorinated derivatives remain
however in all of the cases less polar than the nonfluorinated ones.
When we carried out reactions in Kolliphor EL, at the relatively high HLB values of 13.5, we privileged the emulsification
of polar over nonpolar substances. In the nonfluorinated series, likewise generally better matched with Kolliphor EL HLB,
dibromide and diarylated derivatives possess similar and relatively high polarity. The micelles do not preferentially
stabilize neither of them and the reaction goes to completion. The most polar species, the monoarylated intermediate,
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
is never observed as it reacts directly prior to leave the micelle. In the fluorinated series the polarity of all involved species
is smaller so that the emulsification of DBBF in the first place is sluggish (indeed even by eye inspection it takes several
minutes to observe the formation of a homogeneous dispersion). Moreover, reaction leads to a further reduction of
polarity on going from DBBF to the diarylated species. At high HLB values the reaction does not perform for lack of
compatibility. At low HLB values the situation improves yet the conversion remains limited by the preferential
accumulation of diarylation product (the less polar species) over reagent within the micelles. Due to the aforementioned
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
1
2
3
4
5
6
7
8
9
0
slow homogenization of the reaction mixture, the saturation effect takes some time to happen. When Pd(dppf)Cl
the reaction is very slow and the micelles saturation effect is dominating over conversion. The opposite is true when
Pd(dtbpf)Cl is used, the reaction is very fast (GC-MS traces after 30 min and 12 h are identical) and proceeds smoothly,
in the low HLB mixture (Table 4 entry 4) and somewhat less performantly at higher HLB factors (Table 4, Entries 2 and
). Interestingly, at catalyst loading of 0.05 mol%, when the reaction is in any case slow, even with Pd(dtbpf)Cl and in
(Table 4,
2
is used
2
6
2
the low HLB surfactant mixture, we obtained results fully comparable with those obtained with Pd(dppf)Cl
2
entry 9).
2
Entry 4 of Table 4 shows that the use of 2 mol% of Pd(dtbpf)Cl in combination with a Kolliphor EL/Span 80 7:3 mixture
gives access, in quantitative yield, at room temperature in the air and without the use of any cosolvent, to DTBT. The
reaction is so efficient that the product can be isolated at analytical purity directly by filtration of the reaction mixture over
a sintered silica filter followed by washing with water and MeOH.
The reaction was scaled up to 20 g of starting DBBF in order to precisely evaluate the E-factor. As the only organic
waste produced was the MeOH employed for the final washing step (performed in a Soxhlet continuous extractor), we
were able to get an E-factor as low as 4.7. The value raises to 10.7 when water and surfactants are included.
Water is not generally included in the calculation of E-factor, nonetheless heavy metal containing water has to be treated
as an hazardous waste. Even thou in a previous communication, we demonstrated that the reaction medium, including
the catalyst, can be recycled multiple times, in the case of DBBF we decided not to do so to privilege the ease of
purification of the product obtained when using a fresh micellar solution. Indeed, recycling of the reaction medium leads
to a crude product of lower purity, thus requiring chromatographic purification. The impact of such protocol on the E-
factor is far greater than the benefit obtained recycling the reaction medium.
Our numbers can be compared with the values spanning from a minimum of 9.1 to a maximum of 48.8, in all of the cases
excluding purifications as no suitable data are available, for all other published routes (In the ESI we give an estimate of
the E-factors including purification, based on standard column chromatography procedures.53 In such case the E-factors
range from 274 to over 1900).
Tuning the reaction stoichiometry enables the control of mono vs diarylation, thus opening the way for the preparation
of unsymmetrically substituted derivatives in a one pot procedure.
One pot synthesis of asymmetrical derivatives.
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Entry 8 of Table 4 shows that when the reaction is carried out with a 1.5 to 1 stoichiometric ratio of 2-thienylboronic acid
over DBBF and in a Kolliphor EL/Tween 80 mixture, the product distribution is 83% monoarylated and 17% diarylated.
In principle this result could open the way for the one pot synthesis of unsymmetrically substituted derivatives. According
to the same Table however, the only way to drive the reaction to completion is to use a Kolliphor EL/Span 80 mixture.
As such, we devised a two-step, but still one pot procedure, as no isolation of the intermediate monoarylation product is
necessary. Firstly, we carried out the reaction according to the conditions reported in Table 4, entry 8. Once verified that
no DBBF was left, we added a second aliquot of another arylboronic acid and as much Span 80 as it is required to reach
the HLB value of 10.7, necessary to drive the reaction to completion, thus giving access to unsymmetrically substituted
derivatives. Scheme 6 shows the general reactions scheme as well as the examples we obtained of original 4,7-diaryl-
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5,6-difluoro-2,1,3-benzothiadiazole derivatives.
Scheme 6. General reaction scheme for the synthesis of asymmetrical 4,7-diaryl-5,6-difluoro-2,1,3-benzothiadiazole derivatives. a
Low yield due to troublesome chromatographic separation. b From the pinacol ester of the corresponding boronic acid.
S
S
N
N
N
N
Br
Br
Ar
S
Step 1:
B(OH)2
S
F
F
F
F
Pd(dtbpf)Cl2,
N(Et)3
(
Kolliphor EL:Tween 80 7:3 wt %) 2 wt % in H2O
3
h, r.t
Step 2: ArB(OH)2, Span 80, 12h h r.t.
S
S
S
N
N
N
N
F
N
N
O
H
F
S
S
S
F
F
F
F
F
F
5
(52 %)
6 (50 %)
7 (54 %)
S
N
S
S
N
N
NH C
N
N
3
CF3
S
S
S
F
F
F
F
CH3
F
F
(33 %)a
10 (54 %)
8
9 (53 %)
S
S
N
N
N
N
S
S
S
S
F
F
F
F
11 (80 %)
12 (40 %)b
3 2
In details, DBBF:2-thienylboronic acid:N(Et) :Pd(dtbpf)Cl are mixed in the 1:1.5:6:0.02 proportion working at 0.5 M
concentration of DBBF. The reaction is stirred at room temperature for 3 h. At this stage the GC-MS analysis of the
reaction mixture only shows traces of unreacted DBBF. 1.5 equivalents of a different boronic acid (or pinacol ester) are
added along with Span 80, and mixture is stirred at r.t. overnight. The final unsymmetrically substituted derivatives are
isolated by chromatographical purification of the reaction mixture.
All reactions proceed till complete conversion of the TBF remained after the first step. We did not observe the formation
of byproducts, other than the DTBT formed in the first step.
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1
1
1
1
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1
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The moderate to good isolated yields shown in Scheme 6 are limited by the sometimes troublesome (particularly in the
case of derivatives 8 and 12) chromatographic purification of the target product from DTBT.
All unsymmetrically substituted derivatives we made are original and could have direct applications as luminescent
compounds in applications the like of Luminescent Solar Collectors, bio-imaging or OLEDs. Indeed, they all share a
good separation between absorption and emission spectra (Stokes Shifts) connected with a moderate to good emission
efficiency. Figure 1 and Table 5 summarize the most relevant features of the absorption and emission spectra for all
new compounds. The magnitude of the Stokes Shift, alongside with moderate to good values of emission quantum yields
make derivatives 5, 7, 10 and 11 particularly interesting for applications like bioimaging, where the use of the
benzothiadiazole core is already well documented54–56. For further details, see the ESI file.
0
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9
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1
2
3
4
5
6
7
8
9
0
2 2
Figure 1. Normalized absorption (solid line) and emission (dotted line) spectra for derivatives 5-12 in CH Cl solution.
Table 5. Optical properties (absorption and emission maxima, Stokes Shift, molar extinction coefficient and emission quantum yield)
for derivatives 7-12 in CH Cl solution.
2
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-1
-1
a
Derivative
abs (eV)/ abs (nm)
em (eV) Stokes Shift (eV)  (M cm )  (%)
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
6
3.16/392
2.47
2.50
2.49
2.49
2.52
2.46
2.37
2.01
0.69
0.69
0.63
0.66
0.69
0.72
0.68
0.62
13400
10100
18000
11400
9700
83
70
99
74
66
39
90
44
3.19/389
7
3.12/396
8
3.15/393
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
3.21/386
10
3.18/390
9100
1
1
2
3.05/406
17550
24300
1
2.63/472
a
Relative to DTBT ( 0.96) as the standard.
Generality of the approach and recyclability of the reaction medium.
In order to further support the suitability of the Kolliphor EL/Span 80 reaction mixture as a superior micellar medium to
carry out reactions leading to an over decrease in the polarity on going from starting materials to the products, we
revisited two reactions we had trouble with in the past using Kolliphor EL alone as the surfactant. The first derivative,
the bithiophene 13, is the starting material for the preparation of another relevant building block for organic photovoltaics
5
we recently introduced: dithienocyclohexanone (DTCH) . In our previous paper we could not prepare 13 by means of a
micellar SM coupling and we reverted to a direct arylation approach in standard organic solvent based conditions. When
we carried out the SM coupling of methyl 2-(2-bromothiophen-3-yl)acetate and 2-thyenylboronic acid using a 2 wt%
Kolliphor EL/Span 80 7:3 mixture under the same conditions optimized for the preparation of DTBT, the reaction gave
complete conversion and an isolated yield of 98% (Scheme 7). Actually, the coupling was so efficient that the reaction
mixture reached 45 °C spontaneously, soon after the addition of the amine.
Scheme 7. SM micellar coupling between methyl 2-(2-bromothiophen-3-yl)acetate and 2-thienylboronic acid in a 2% by weight solution
of Kolliphor EL/Span 80 7:3 mixture.
Even more impressively, we obtained essentially quantitative yield also when working with 9-bromoanthracene: in the
past we obtained good results with this substrate with Kolliphor EL only when working at high formal concentration of
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6
bromide and boronic acid and with a large excess of the latter.40 The use of the Kolliphor EL/Span 80 7:3 mixture not
only enables the preparation of 9-phenylanthracene in quantitative yield in less than 30 minutes, but it also gives an
impressive demonstration of the robustness of such mixture to oxygen deactivation. Indeed, thanks to the highly
crystalline nature of 9-phenylanthracene we could proceed to the work-up of the reaction by simple suction filtration
followed by crystallization of the crude precipitate thus obtained. We thus proceeded to the recycling of the reaction
medium, without addition of any further aliquot of catalyst. In the second run the reaction performed identically, if
not for a little increase of the reaction time that raised to 2 h. The product was again isolated by suction filtration and the
reaction medium recycled. We still observed quantitative conversion and isolated yields exceeding 95% up to the fourth
run. We consistently had to increase the reaction time, no doubt as the multiple filtration of the reaction product gradually
lowered the concentration of the catalyst. Scheme 8 summarizes the results as well as the evolution of the reaction E-
factor as a function of the recycling runs. Even though such kind of very low E-factors upon recycling are documented
in the literature, no such result has ever been obtained without the addition of fresh catalyst after every run.
0
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8
9
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2
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5
6
7
8
9
0
Scheme 8. Study of the recycling of the reaction medium in the SM micellar coupling of phenylboronic acid and 9-bromoanthracene in
a 2% by weight water solution of Kolliphor EL/Span 80 7:3 mixture.
Run* Reaction time (h) Isolated yield (%) E-Factor
1
2
3
4
0.5
2
98
98
97
94
10.84
8.88
8.43
8.31
4
10
*
After each run, reaction mixture was filtered and product crystallized. 9-bromoanthracene, phenylboronic acid and NEt
3
only were added to the filtrate for the subsequent run.
CONCLUSIONS
Micellar reactions are rapidly revolutionising established synthetic methods. In particular, the micellar Suzuki-Miyaura
coupling represents one of the most successful examples of the capability of such techniques to dramatically improve
sustainability while maintaining performances. When not immediately satisfactory, particular reactions might require
tuning of conditions while moving from standard organic solvent to micellar environment. The peculiar characteristic of
micro-heterogeneous micellar reactions requires a specifically devised approach where tuning of common reaction
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parameters (concentration, temperature time, catalyst) has to go hand in hand with the toolbox of the formulation
chemist. In the case of the synthesis of the popular conjugated building block DTBT and of several unsymmetrically
substituted derivatives of the same family, reactions can be driven to completion only when the characteristics of the
employed micellar environment are appropriate. The dedicated literature so far approached the problem of
underperforming reactions by the introduction of new, improved surfactants. We show that the careful selection and
mixing of readily available and fully sustainable commercial surfactants can lead to complete conversion where single
component micellar solutions fail. We particularly focused on Kolliphor EL as the main micellar forming surfactants and
on Tween 80 and Span 80 as hydrophilic and lipophilic co-surfactants respectively.
2
3
4
5
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7
8
9
1
1
1
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8
9
0
We offer an interpretation of the data based on the preferential interaction of reagents vs products with micelles
assembled with one or more surfactants, hampering or speeding up the reaction depending on the micelles dominating
lipophilic over hydrophilic character. In particular we have found an empirical correlation between the surfactant mixture
HLB value and the performance of the reaction in all cases when the polarity of reagents and products is remarkably
different.
Within such optimized micellar environment, it is possible to control the degree of mono vs diarylation to the point of
being able to prepare unsymmetrically substituted derivatives by the sequential reaction of DBBF with two different
arylboronic acids.
The fact that all reactions were performed under standard laboratory conditions with no need for inert gases and any
pre-treatment of water and surfactants offers an additional relevant solicitation for the widespread application of micellar
methods in everyday laboratory practices.
EXPERIMENTAL SECTION
General Information.
Reagents and solvents were bought from TCI, Fluorochem and Sigma-Aldrich and used as received. GC-MS spectra
were collected on a Clarus 560 S PerkinElmer having an Elite-5MS 30.0 m x 250 μm column. Helium was used as carrier
gas. NMR spectra were collected on a Bruker NMR Avance 400 NEO. Absorption spectra of derivatives 5-12 were
collected on a Cary 60 UV-Vis Agilent Spectrophotometer in a 10 mm pathlength quartz cuvette. Photoluminescence
spectra of derivatives 5-12 were collected on a Cary Eclipse Fluorescence Agilent Spectrophotometer in a 10 mm
pathlength quartz cuvette. DLS experiments were performed on a 90Plus Particle Size Analyzer (Brookhaven
Instruments Corporation) with scattering angles of 15° and 90°, equipped with a 35 mW solid state 632,8 nm laser and
a Brookhaven’s TuboCorr correlator with 510 channels.
General synthetic procedure for derivative DTBT.
Reactions were carried in a round bottom vial. Depending on the experiment, the boronic acid (Scheme 3), the
concentration (Table 1), amount (Table 2) and nature (Table 3-4) of surfactant dispersion, and the catalyst (Table 4)
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5
5
5
5
6
vary. DBBF (165 mg, 0.5 mmol) and the boronic acid (1.5 mmol) are weighted in the vial, then 1 mL of surfactant
dispersion in water is added. The mixture is stirred, then N(Et) (303 mg, 3.0 mmol) is added. The mixture is allowed to
homogenize for 5 minutes before addition of the catalyst (0.01 mmol). All reactions were quenched after 12 h stirring at
room temperature, extracted with CH Cl , filtered over a pad of silica gel and submitted to GC-MS characterization.
3
2
2
Scaled synthesis of 4,7-di(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (DTBT) and calculation of E-factor.
0
1
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9
0
DBBF (20.0 g, 60.6 mmol) and 2-thienylboronic acid (23.3 g, 182 mmol) are weighted in a 500 mL roundbottom flask,
then 121 mL of 2% (Kolliphor EL/Span 80 7:3) dispersion in water are added. The mixture is stirred with a mechanical
3 2
stirrer, then N(Et) (36.7 g, 364 mmol) is added. The mixture is allowed to homogenize before addition of Pd(dtbpf)Cl
(1.580 g, 2.42 mmol). After 12 h, the reaction mixture is filtered over a sintered silica filter and washed with deionized
water. The crude solid was finally purified by hot washing with MeOH (40 mL) in a Soxhlet continuous extractor to remove
residual TBF. The product was recovered as a bright yellow solid. (19.8 g, 97% yield). Characterizations are in
agreement with previously published data.57
mass of by - products + mass of solvents
E - factor =
mass of product
36.7
(
푁(퐸푡)
3
)
+ 2.7 (푠푢푟푓.) + 31.68(푀푒푂퐻) + 22.79 (푒푥푐푒푠푠 푏표푟표푛푖푐 푎푛푑 푏표푟표푛 푐표푛푡푎푖푛푔 푏푦푝푟표푑푢푐푡푠)
=
= 4.7
19.8
Including water
mass of by - products + mass of solvents 36.7
(
푁(퐸푡)3
)
+ 31.68 (푀푒푂퐻) + 22.79 (푏표푟표푛.) + 121 (푚푖푐. 푠표푙푢푡푖표푛)
E - factor =
=
= 10.7
mass of product
19.8
1H NMR (CDCl
, 400 MHz): δ 8.30 (dd, J=3.9, 1.1 Hz, 2H), 7.62 (dd, J=5.2, 1.1 Hz, 2H), 7.27 (m, 2H); 13C H NMR
1
3
3
(CDCl , 100 MHz): δ 149.7 (dd, J=260.0, 20.4 Hz), 148.9 (t, J=4.4 Hz), 131.5, 130.9 (t, J=3.9 Hz),128.9 (t, J=3.1 Hz),
127.4, 111.8 (d, J=9.4 Hz).
Synthesis of 4,7-di(thiophen-3-yl)-5,6-difluoro-2,1,3-benzothiadiazole (3).
DBBF (165 mg, 0.5 mmol) and 3-thienylboronic acid (192 mg, 1.5 mmol) are weighted in a Biotage microwave vial, then
1
mL of 2% (Kolliphor EL/Span 80 7:3) dispersion in water is added. The mixture is stirred, then N(Et)
3
(303 mg, 3.0
mmol) is added. The mixture is allowed to homogenize for 5 minutes before addition of Pd(dtbpf)Cl (13.1 mg, 0.02
2
mmol). After 5 h, the reaction is diluted with 10 mL of water and filtered. The crude is crystallized from heptane to afford
1
1
53 mg of the pure product as yellow needles (91% yield). mp 110.9-111.8 °C; H NMR (CDCl
3
, 400 MHz): δ 8.37 (dd,
, 100 MHz): δ 150.5
: C, 49.98; H,
J=3.0, 1.3 Hz, 2H), 7.94 (dq, J=5.1, 1.1 Hz, 2H), 7.51 (dd, J=5.1, 3.0 Hz, 2H); 13C H NMR (CDCl
1
3
(
dd, J=258.6, 20.4 Hz), 150.0, 130.2, 128.9 (t, J=2.9 Hz), 128.2, 125.2, 113.1; anal. calcd for C14
H
6
F
2
N
S
2 3
1.80; N, 8.33; found: C, 49.53; H, 1.52; N, 8.02.
Synthesis of 4,7-diphenyl-5,6-difluoro-2,1,3-benzothiadiazole (4).
DBBF (165 mg, 0.5 mmol) and phenylboronic acid (183 mg, 1.5 mmol) are weighted in a Biotage microwave vial, then
mL of 2% (Kolliphor 10%) dispersion in water is added. The mixture is stirred, then N(Et) (303 mg, 3.0 mmol) is added.
(13.1 mg, 0.02 mmol). After 12 h,
1
3
The mixture is allowed to homogenize for 5 minutes before addition of Pd(dtbpf)Cl
2
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the reaction is diluted with 10 mL of water and filtered. The crude is crystallized from heptane to afford 153 mg of the
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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3
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4
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4
4
5
5
5
5
5
5
5
5
5
5
6
1
pure product as white needles (95% yield). mp 205.0-205.8 °C; H NMR (CDCl
3
, 400 MHz): δ 7.83 (d, J=7.4 Hz, 4H),
1
7
.59 (t,J=7.5 Hz, 4H), 7.52 (t, J=7.4 Hz, 2H); 13C H NMR (CDCl
3
, 100 MHz): δ 151.4 (t, J=3.9 Hz), 151.3 (dd, J=258.6,
2
10 2 2
0.4 Hz), 131.4, 131.1, 130.0, 129.4, 119.7 (dd, J=10.5, 4.4 Hz); anal. calcd for C18H F N
S: C, 66.65; H, 3.11; N, 8.64;
found: C, 66.26; H, 2.76; N, 8.54.
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0
Synthesis of 4-bromo-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (TBF).
DBBF (330 mg, 1.0 mmol) and 3-thienylboronic acid (192 mg, 1.5 mmol) are weighted in a Biotage microwave vial, then
mL of 10% Kolliphor EL dispersion in water is added. The mixture is stirred, then N(Et) (303 mg, 3.0 mmol) is added.
The mixture is allowed to homogenize for 5 minutes before addition of Pd(dtbpf)Cl (13.2 mg, 0.02 mmol). After 12 h,
2
3
2
the reaction is diluted with 10 mL of water and filtered. The crude is purified by column chromatography using
1
heptane:toluene=7:3 as eluent. Isolated product: 187 mg (56% yield), yellow powder. mp 156.5-157.3; H NMR (CDCl
3
,
00 MHz): δ 8.26 (ddd, J=3.9, 1.1, 0.7 Hz, 1H), 7.64 (dd, J=5.2, 1.1 Hz, 1H), 7.27 (ddd, J=5.2, 3.9, 1.4 Hz, 1H); 13C H
1
4
3
NMR (CDCl , 100 MHz): δ 152.4 (dd, J=256.5, 20.3 Hz), 149.1 (dd, J=262.3, 19.0 Hz), 149.9 (d, J=5.1 Hz), 147.9, 131.4
(
d, J=8.7 Hz), 130.8 (dd, J=5.8, 3.6 Hz), 129.5 (d, J=6.6 Hz), 127.5, 113.4 (dd, J=12.3 Hz, 1.4 Hz), 97.1 (dd, J=21.8, 1.4
Hz); anal. calcd for C10 BrF : C, 36.05; H, 0.91; N, 8.41; found: C, 36.03; H, 0.61; N, 8.32.
H
3
2 2 2
N S
General synthetic procedure for asymmetrical derivatives.
Reactions were carried in a Biotage microwave vial. DBBF (330 mg, 1.0 mmol), 2-thienylboronic acid (192 mg, 1.5 mmol)
and Pd(dtbpf)Cl
2
(26.3 mg, 0.04 mmol) are weighted in the vessel, then 2 mL of 2% (Kolliphor/Tween 7:3) dispersion in
(607 mg, 6.0 mmol). The
water are added. The mixture is allowed to homogenize for 5 minutes before addition of N(Et)
3
reaction is stirred for 3 h, then 1.5 mmol of the 2nd boronic acid/ester are added in the vessel. 20 mg of Span 80 are
added as well. The reaction is stirred overnight, and subsequently diluted with 10 mL of water and filtered. The crude
was finally purified by column chromatography or crystallization.
4
-phenyl-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (5). The crude is purified by column chromatography
1
using heptane:DCM=8:2 as eluent. Isolated product: 172 mg (52%), lime green powder. mp 164.7-165.2 °C; H NMR
(
CDCl
3
, 400 MHz): δ 8.31 (d, J = 3.9 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 5.3, 0.9 Hz, 1H), 7.58 (t, J = 7.4, 0.9
Hz, 2H), 7.49-7.52 (m, 1H), 7.29 (m, 1H); 13C H NMR (CDCl
1
, 100 MHz): δ 151.33 (d, 8.6 Hz), 151.32 (dd, J = 255.9,
3
1
9.0 Hz), 150.6 (dd, J = 259.8, 20.0 Hz), 149.9 (d, J = 8.8 Hz), 132.4 (dd, J = 5.4, 3.4 Hz), 131.9 (d, J = 8.3 Hz), 131.4
(d, J = 2.6 Hz), 131.1, 130.0, 129.8 (d, J = 6.4 Hz), 129.4, 128.3, 118.7 (d, J = 14.2 Hz), 113.6 (dd, J = 12.2, 1.2 Hz);
anal. calcd for C16 : C, 58.17; H, 2.44; N, 8.48; found: C, 57.82; H, 2.12; N, 8.45.
-(2,4-difluorophenyl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (6). The crude is purified by column
8 2 2 2
H F N S
4
chromatography using heptane:toluene=7:3 as eluent. Isolated product: 183 mg (50%), orange powder. mp 166.6-167.8
1
°
C; H NMR (CDCl
3
, 400 MHz): δ 8.35 (ddd, J=3.8, 1.2, 0.6 Hz, 1H), 7.62-7.68 (m, 2H), 7.31 (ddd, J=5.2, 3.8, 1.4 Hz,
1
1
H), 7.05-7.15 (m, 2H); 13C H NMR (CDCl
3
, 100 MHz): δ 163.8 (dd, J=252.1, 11.6 Hz), 160.5 (dd, J=253.4, 12.3 Hz),
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1
51.2 (dd, J=260.7, 21.1 Hz), 150.3 (d, J=8.8 Hz), 149.4 (dd, J=265.1, 23.2 Hz), 148.8 (d, J=8.7 Hz), 133.2 (dd, J=9.9,
3.7 Hz), 131.4 (d, J=8.3 Hz), 131.2, 129.3 (d, J=6.5 Hz), 127.5, 114.1 (d, J=16.1), 113.8 (d, J=11.7 Hz), 111.8 (dd,
J=21.7, 3.6 Hz), 111.2 (d, J=16.0 Hz), 104.7 (t, J=25.5 Hz); anal. calcd for C16
found: C, 52.07; H, 1.31; N, 7.59.
6 4 2 2
H F N S : C, 52.45; H, 1.65; N, 7.65;
4-(4-formylphenyl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (7). The crude is purified by column
0
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9
0
chromatography using heptane:DCM=8:2 as eluent. Isolated product: 194 mg (54%), orange powder. mp 171.1-171.4
1
°
C; H NMR (CDCl
3
, 400 MHz): δ 10.17 (s, 1H), 8.38 (ddd, J=3.8, 1.1, 0.7 Hz, 1H), 8.09-8.12 (m, 2H), 8.03-8.06 (m, 2H),
.69 (dd, J=5.1, 1.1 Hz, 1H), 7.33 (ddd, J=5.3, 3.9, 1.4 Hz, 1H); 13C H NMR (CDCl
1
7
3
, 100 MHz): δ 191.7, 150.9 (dd,
J=259.3, 19.6 Hz), 149.9 (d, J=8.0 Hz), 149.4 (dd, J=260.6, 19.6 Hz), 149.0 (d, J=8.7 Hz), 136.3, 136.2 (m), 131.5 (d,
J=8.7 Hz), 131.3 (d, J=2.9 Hz), 131.2, 129.7, 129.5 (d, J=6.5 Hz), 127.5, 116.2 (d, J=13.8 Hz), 113.8 (dd, J=12.5, 2.1
Hz); anal. calcd for C17
8 2 2 2
H F N OS : C, 56.97; H, 2.25; N, 7.82; found: C, 56.64; H, 1.94; N, 7.77.
4-(4-(trifluoromethyl)phenyl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (8). No eluent combination allowed to
separate chromatographically the product from DTBT. Therefore, the crude was refluxed in methanol and hot filtered
twice to remove the symmetrical DTBT derivative. The obtained solid was then crystallized three times from heptane.
1
Isolated product: 131 mg (33%), yellow needles. mp 124.7-125.3 °C; H NMR (CDCl
3
, 400 MHz): δ 8.37 (ddd, J=3.8,
1.0, 0.7 Hz, 1H), 7.97-8.00 (m, 2H), 7.84-7.87 (m, 2H), 7.69 (dd, J=5.1, 1.1 Hz, 1H), 7.33 (ddd, J=5.2, 3.9, 1.4 Hz, 1H);
13
1
3
C H NMR (CDCl , 100 MHz): δ 150.8 (dd, J=257.9, 18.9 Hz), 150.0 (d, J=8.7 Hz), 149.3 (dd, J=260.7, 19.6 Hz),
149.0 (d, J=8.7 Hz), 133.8 (m), 131.4 (d, J=8.7 Hz), 131.3 (m), 131.01 (q, J=32.7 Hz), 130.95 (d, J=2.9 Hz), 129.4 (d,
J=6.5 Hz), 127.5, 125.5 (q, J=3.6 Hz), 124.0 (q, J=272.5 Hz), 116.1 (d, J=13.8 Hz), 113.7 (dd, J=12.3, 2.1 Hz); anal.
7 5 2 2
calcd for C17H F N S : C, 51.25; H, 1.77; N, 7.03; found: C, 50.90; H, 1.42; N, 6.99.
4-(2,5-dimethylphenyl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (9). The crude is purified by column
chromatography using petroleum ether:toluene=8:2 as eluent. Isolated product: 190 mg (53%), yellow powder. mp 96.8-
1
97.3 °C; H NMR (CDCl
3
, 400 MHz): δ 8.33 (ddd, J=3.8, 1.1, 0.6 Hz, 1H), 7.64 (dd, J=5.1, 1.1 Hz, 1H), 7.28-7.32 (m,
H), 7.24-7.26 (m, 1H), 7.20 (br, 1H), 2.41 (s, 3H), 2.15 (s, 3H); 13C H NMR (CDCl
1
2
3
, 100 MHz): δ 150.9 (d, J=8.7 Hz),
150.4 (dd, J=255.0, 18.9 Hz), 149.7 (dd, J=260.9, 19.7 Hz), 148.8 (d, J=8.7 Hz), 135.4, 134.2, 131.5 (dd, J=5.8, 3.6 Hz
Hz), 131.02, 131.00 (d, J=8.7 Hz), 130.5, 130.3, 129.4 (d, J=1.1 Hz), 128.9 (d, J=6.5 Hz), 127.4, 118.2 (d, J=16.4 Hz),
1
12.9 (dd, J=12.4, 1.4 Hz), 21.0, 19.6 (d, J=1.5 Hz); anal. calcd for C18
0.46; H, 3.41; N, 7.56.
12 2 2 2
H F N S : C, 60.32; H, 3.37; N, 7.82; found: C,
6
4-(naphthalen-1-yl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (10). The crude is purified by column
chromatography using heptane:DCM=8:2 as eluent. Isolated product: 207 mg (54%), yellow powder. mp 149.0-149.5
1
°
C; H NMR (CDCl
3
, 400 MHz): δ 8.38 (ddd, J=3.8, 1.1, 0.6 Hz, 1H), 8.05 (dd, J=7.0, 2.4 Hz, 1H), 7.98 (d, J=8.2 Hz,
1H), 7.64-7.69 (m, 3H), 7.54 (ddd, J=8.3, 6.6, 1.4 Hz, 1H), 7.48-7.51 (m, 1H), 7.43 (ddd, J=8.5, 6.6, 1.3 Hz, 1H), 7.32
(ddd, J=5.2, 3.8, 1.3 Hz, 1H); 13C H NMR (CDCl
1
3
, 100 MHz): δ 151.4 (d, J=8.4 Hz), 151.2 (dd, J=256.8, 20.1 Hz),
149.4 (dd, J=262.1, 21.4 Hz), 148.8 (d, J=8.3 Hz), 133.8, 131.6, 131.5 (m), 131.1 (d, J=8.0 Hz), 129.9, 129.0 (m), 128.7,
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27.7 (d, J=2.5 Hz), 127.4, 126.7, 126.2, 125.30, 125.27, 116.8 (d, J=16.7 Hz), 113.4 (d, J=12.0 Hz); anal. calcd for
: C, 63.14; H, 2.65; N, 7.36; found: C, 63.36; H, 2.94; N, 7.02.
-(9H-fluoren-2-yl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (11). The crude is purified by column
chromatography using petroleum ether:toluene=7:3 as eluent. Isolated product: 335 mg (80%), orange powder. mp
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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5
5
5
5
5
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20 10 2 2 2
C H F N S
4
1
3
196.4-197.0 °C; H NMR (CDCl , 400 MHz): δ 8.34 (ddd, J= 3.8, 1.1, 0.6 Hz, 1H), 8.02 (m, 1H), 7.99 (dd, J= 7.9, 0.6 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1H), 7.85-7.90 (m, 2H), 7.66 (dd, J=5.2, 1.1 Hz, 1H), 7.61 (d, J=7.3 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.38 (td, J=7.4, 1.3
Hz), 7.31 (ddd, J=5.2, 3.9, 1.3 Hz, 1H), 4.05 (s, 2H); 13C H NMR (CDCl
1
3
, 100 MHz): δ 150.6 (d, J=8.7 Hz), 150.4 (dd,
J=255.5, 18.9 Hz), 149.8 (dd, J=260.7, 20.3 Hz), 149.0 (d, J=8.7 Hz), 143.8, 143.4, 142.7, 141.1, 131.6 (dd, J=5.8, 3.6
Hz), 131.0 (d, J=8.7 Hz), 129.4 (d, J=2.9 Hz), 128.9 (d, J=6.5 Hz), 128.4, 127.4, 127.3, 127.1 (d, J=2.9 Hz), 126.9, 125.1,
12 2 2 2
120.3, 119.9, 118.2 (d, J=14.1 Hz), 112.5 (dd, J=12.4, 1.4 Hz), 37.1; anal. calcd for C23H F N S : C, 66.01; H, 2.89; N,
6.69; found: C, 65.60; H, 2.67; N, 6.67.
4-(5'-hexyl-[2,2'-bithiophen]-5-yl)-7-(thiophen-2-yl)-5,6-difluoro-2,1,3-benzothiadiazole (12). The crude is purified by
column chromatography using petroleum ether:toluene=6:4 as eluent. Isolated product: 201 mg (40%), red powder. mp
1
125.4-126.5; H NMR (CDCl
3
, 400 MHz): δ 8.28 (dd, J=3.8, 1.1 Hz, 1H), 8.19 (d, J=4.0 Hz, 1H), 7.60 (dd, J=5.2, 1.2 Hz,
1
1
2
H), 7.25-7.27 (m, 1H), 7.22 (d, J=4.1 Hz, 1H), 7.73 (dt, J=3.6, 1.0 Hz, 1H), 2.82 (t, J=7.6 Hz, 2H), 1.71 (m, 2H), 1.31-
.43 (m, 6H), 0.91 (t, J=7.1, 3H); 13C H NMR (CDCl
1
3
, 100 MHz): δ 149.9 (dd, J=260.0, 20.4 Hz), 149.6 (dd, J=259.4,
0.8 Hz), 148.9, 148.7, 146.6, 141.5 (t, J=2.9 Hz), 134.2, 131.9 (dd, J=5.7, 3.6 Hz), 131.7, 130.8 (t, J=3.6 Hz), 129.7 (d,
J=2.2 Hz), 128.8 (t, J=2.9 Hz), 127.4, 125.1, 124.2, 123.2, 111.7 (dd, J=9.5, 3.6 Hz), 111.3 (dd, J=8.9, 5.1 Hz),31.6,
1.5, 30.3, 28.8, 22.6, 14.1; anal. calcd for C24 : C, 57.34; H, 4.01; N, 5.57; found: C, 56.99; H, 3.82; N, 5.40.
Methyl 2-(2-(thiophen-2-yl)thiophen-3-yl)acetate (13). Methyl 2-(2-bromothiophen-3-yl)acetate (0.570 g, 2.42 mmol), 2-
thienylboronic acid (0.450 mg, 3.52 mmol) and Pd(dtbpf)Cl (29 mg, 0.044 mmol) were suspended in 2 mL of 2 wt%
Kolliphor/Span 80 7:3) dispersion and stirred until complete homogenization. NEt (0.608 g, 6.01 mmol) was added,
3
20 2 2 4
H F N S
2
(
3
observing darkening and spontaneous raise in the temperature from 25 °C to 40 °C. After 2 h the GC-MS inspection of
the reaction mixture indicated complete conversion of the bromide. Mixture was diluted with 10 mL of AcOEt and directly
filtered through a pad of silica affording, after evaporation of the solvent, the title compound as a colorless oil (0.560 g,
1
2.35 mmol, 98%). H NMR (CDCl
3
, 400 MHz): δ 7.34 (dd, J=5.2, 1.2 Hz, 1H), 7.24 (d, J=5.2 Hz, 1H), 7.18 (dd, J=3.6,
.2 Hz, 1H), 7.08 (dd, J=5.2, 3.6 Hz, 1H), 7.05 (d, J=5.2 Hz, 1H), 3.77 (s, 2H), 3.72 (s, 3H); 13C H NMR (CDCl
1
, 100
1
3
MHz): δ 171.4, 135.0, 133.3, 130.2, 130.1, 127.7, 126.9, 126.2, 124.5, 52.1, 34.6.
9-phenylanthracene (14). Phenylboronic acid (0.763 g, 6.25 mmol), 9-bromoanthracene (1.289 g, 5.00 mmol) and
Pd(dtbpf)Cl (65.32 mg, 0.100 mmol) are placed in a round bottom flask. A 2 wt% solution of a 7:3 Kolliphor EL/Span 80
mixture is added under stirring (5 mL) and mixture is kept under vigorous stirring till complete homogenization. NEt
1.269 g, 12.5 mmol) is added observing darkening of the emulsion and gradual raise in the temperature from 25 to 55
2
3
(
°C. The reaction is monitored by GC-MS and quenched after 30 min, having observed complete conversion of the
starting bromide. The suspension is filtered through a sintered glass filter to give an off white precipitate and a brown
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filtrate. The precipitate is crystallized from acetic acid to give the pure title compound as a bright white solid (1.246 g,
4.80 mmol, 98%). The filtrate is recycled for the subsequent run, thus fresh aliquots of phenylboronic acid (0.763 g, 6.25
3
mmol), 9-bromoanthracene (1.286 g, 5.00 mmol) and NEt (1.265 g, 12.5 mmol) are added and reaction monitored by
GC-MS. In the second run reaction took 2 h to achieve complete conversion. Work up was performed analogously to
the first run (98% of crystallized product). In the third run, the reaction time was 4 h with 97% of product isolated after
0
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crystallization. In the fourth and final run the reaction took 10 h to give, after standard purification, the product in 94%
1
yield. H NMR (CDCl
3
, 400 MHz): δ 8.50 (s, 1H), 8.05 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.9 Hz, 2H), 7.51-7.60 (m, 3H), 7.43-
1
7
.48 (m, 4H), 7.35 (ddd, J=8.9, 6.5, 1.3 Hz, 2H); 13C H NMR (CDCl
3
, 100 MHz): δ 138.8, 137.0, 131.4, 131.2, 130.2,
1
28.4, 128.3, 127.4, 126.8, 126.5, 125.3, 125.1. See58 for a comparison.
Theoretical details.
All ab initio simulations based on density functional theory (DFT) have been performed by using the ORCA suite of
programs52 in a localized-basis-set framework. In detail, the Kohn–Sham orbitals have been expanded on a def2-TZVPP
Gaussian type basis set.59,60 The corresponding def2/J basis has been also used as an auxiliary basis set for Coulomb
fitting in a resolution-of-identity/chain-of-spheres (RIJCOSX) framework.61 Molecular geometries have been fully
optimized and their properties investigated by using the B3LYP functional.62 In order to simulate molecular properties
inside and outside the micellar environment, the SMD continuum solvation model has been used to solvate the
investigated molecules in toluene and water, respectively.63,64
ASSOCIATED CONTENT
Literature analysis on the relevance of DTBT, GC-MS traces for all reactions described in Table 1-4, UV-Vis and emission
spectra for all new derivatives, copy of the H and 13C spectra for all derivatives, details on the computational analysis,
DLS analysis of surfactant solutions, estimates of the E-factor for the literature and original procedures.
1
AUTHOR INFORMATION
Corresponding Author.
E-mail: luca.beverina@unimib.it
Notes.
There are no conflicts of interest to declare.
ACKNOWLEDGEMENTS
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Financial support from the Italian Ministry of University and Research (MIUR) through grant “Dipartimenti di Eccellenza-
2017 Materials For Energy” is gratefully acknowledged.
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