Room temperature cupric halides mediated olefin alkoxylation of BODIPYs with methanol: Mechanisms and scope

Article abstract of DOI:10.1039/c9ob02590a

We disclose an efficient methodology for olefin alkoxylation of fluorescent BODIPYs (boron-dipyrromethene) at the 3,5-styryl group with methanol by cupric halide (chloride or bromide) at room temperature. Mechanistic studies provide evidence for the alkoxylation reaction firstly initiated by a radical cation, that is, halide promotes the oxidizing ability of the Cu(II) center to an extent that the single electron transfer (SET) from BODIPYs to the cupric ion and results in the production of a BODIPYs radical cation and Cu(I), then the BODIPYs radical cation subsequently reacts with methanol to afford the alkoxylated product. As the dialkoxylated product complexes with cuprous halide and further decreases its reducing ability, which is supported by DFT calculations, only strongly oxidative cupric bromide can mediate tetraalkoxylation and give rise to the tetraalkoxylated product. In addition, the expanded scope studies suggest that this method is also well suited for the alkoxylation of electron-rich conjugated olefins. The active benzyl bromide derivative may be another intermediate in the presence of cupric bromide. Therefore, the reaction is highly dependent on the anions of cupric salts; Cu(OAc)2, CuSO4 and Cu(NO3)2 containing weakly nucleophilic anions show no activity in alkoxylation. This journal is

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DOI: 10.1039/C9OB02590A
ARTICLE
Room temperature cupric halide mediated olefin alkoxylation of
BODIPYs with methanol: mechanisms and scope
Ying Yang,a Xiangrong Wei,a Yuexing Zhang,d Xin Chi,d Dejian Huang,c Fu wang,b Haixia Wu*a,c and
Received 00th January 20xx,
Accepted 00th January 20xx
Jialin Ming*a
DOI: 10.1039/x0xx00000x
We disclose an efficient methodology for olefin alkoxylation of fluorescent BODIPYs (boron-dipyrromethene) at 3,5-styryl
group with methanol by cupric halide (chloride or bromide) at room temperature. Mechanistic stuides provide evidence for
alkoxylation reaction firstly initiated by radical cation, that is, halide promots the oxidizing ability of Cu(II) center to an extend
the single electron transfer (SET) from BODIPYs to cupric ion, results in produce BODIPYs radical cation and Cu(I), the
BODIPYs radical cation subsequently reacts with methanol to afford alkoxylated product. As the dialkoxylated product
complexs with cuprous halide and further decreased its reducing ability, which was supported by DFT calculations, only
strong oxidative cupric bromide can mediate tetraalkoxylation and give rise to tetraalkoxylated product. In addition, the
expanded scope studies suggest that this method also is well suit for alkoxylation of electron rich conjugated olefins. The
active benzyl bromide derivative may be another intermediate in the presence of cupric bromide. Therefore, the reaction is
highly dependent on anion of coupric salts, Cu(OAc)2, CuSO4 and Cu(NO3)2 containing weaker nucleophilicity anions show no
activity in alkoxylation.
equiv cupric chloride, molecular oxygen and 3A molecular
sieves. However, this reaction only worked for styrene
derivatives containing an o-phenol.11,12 To the best of our
Introduction
Olefins difunctionalization is a powerful method for synthesis of
complicated compounds containing carbon-oxygen-bonds,
which are ubiquitous in biological systems.1-5 Olefin
dihydroxylation reaction has been extensively studied, while
olefin dialkoxylation is much less documented. One such rare
example was reported by Tokumaru and co-workers, who
applied mercury lamp to irradiate styrene derivatives in the
presence of copper(II) perchlorate in methanol under nitrogen
stream for 40 hours to yield dimethoxylated products.6 Styrene
derivatives could also undergo dimethoxylation catalyzed by
diaryl ditelluride and sulfuric acid in the presence of various
oxidizing reagents (molecular oxygen, peroxides and peracids)
in refluxing methanol.7,8 Dimethoxylation of cyclic alkene was
achieved by cerium(IV) sulfate9 and a complex mixture of silver
perchlorate sym-collidine and iodine, respectively.10 Recently,
Sigman and co-workers discovered dialkoxylation of styrenes
using palladium(II) complexes as catalyst in the presence of 0.4
knowledge, previous reports on olefin dialkoxylation were
mostly based on simple aromatic compounds, such as styrene
derivatives and 1-phenylcycloalkenes under harsh and tough to
operation conditions. In addition to, cupric halides are widely
used as catalysts or reagents in halogenation of aromatic and
heteroaromatic compounds13-15 and some olefins,16-18 but the
alkoxylation of olefins by the oxidation of cupric halides has not
been reported yet. Furthermore, near infrared region (NIR)
fluorescent BODIPYs are famous fluorescent dyes for synthesis
of various fluorescent probes and targeted fluorescent markers
in vivo,19-21 it is very meaningful to synthesize functional
fluorescent BODIPYs materials by mild and easy to operation
method. Therefore, we disclose here facile method for olefinic
bonds alkoxylation of NIR fluorescent BODIPYs mediated by
cupric halides at room temperature, and the reaction scope and
mechanism of methoxylation were fully investigated and
proposed. In addition, the distinct color change and emission
spectra of NIR BODIPYs caused by alkoxylation has very
potential to design ratiometric fluorescent probe for detection
of alcohol.
a. Department of Chemistry, College of Chemistry and Chemical Engineering, Inner
Mongolia University, Hohhot, China 010021. E-mail: chmwuhx@imu.edu.cn,
mingjialin@imu.edu.cn.
b. School of Environmental Science and Engineering, Shanghai Jiao Tong University,
Shanghai, China 200240.
Results and discussion
Cupric halides mediated alkoxylation of NIR BODIPY dyes
c. Department of Food Science and Technology, National University of Singapore, 3
Science Drive 3, Singapore 117543.
d. Ministry of Education Key Laboratory for the Synthesis and Application of Organic
Functional Molecules. College of Chemistry and Chemical Engineering, Hubei
University, Wuhan, China 430062.
In our previous work, we isolated a dimethoxylated product in
surprise in an attempt to synthesize NIR active BODIPYs
containing Cu complexe19 by using CuCl2. To examine the
Electronic Supplementary Information (ESI) available: Procedures, synthesis, NMR
spectra, spectroscopic data and computational results. See DOI:
10.1039/x0xx00000x
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reaction scope and mechanism, we expanded to other BODIPYs for the maximal emission peaks in the fluorescent spectra of
View Article Online
DOI: 10.1039/C9OB02590A
as shown in Scheme 1, the BODIPYs 1, 2 and 2a were prepared these compounds (Fig. 1B), specifically, 77 and 221 nm of blue
according to our previously reported work.19 Addition of 10 shifts are ascribed to the dimethoxylation and
equiv CuCl2 in MeOH to BODIPYs and in CH2Cl2 gave rise to tetramethoxylation of , respectively. The blue shifts of
dialkoxylated products 1a and 2a19 respectively in quantitative maximal wavelength are resulted from the decreasing size of
conversion. Remarkably, when CuBr2 was used as the cupric salt conjugated system of methoxylated 2a and 2b The
1
2
2
.
under similar conditions, tetraalkoxylated BODIPYs products 1b methoxylation also reduces the ability of dimethylamino as an
and 2b were obtained, and these results suggest that the meso- internal charge transfer electron-donor group, which can
substituent group of BODIPYs has no effect on the alkoxylation partially contribute to the blue shift of spectra.22 It is worth
at 3,5-styryl group no matter it is electron donating group or noting that the distinct spectroscopic characteristics of
electron withdrawing group. Moreover, chose BODIPYs as dimethoxylation and tetramethoxylation products can be
representative substrate, ethanol also worked equally well and employed for monitoring the reaction process.
a corresponding diethoxylated product was obtained under
2,
2
3
CuCl2. The alkoxylation products were characterized with high
resolution mass spectra (Table 1) and NMR spectra (The spectra
were provided as Fig. S1). It is remarkable that the alkoxylation
reaction is independent of molecular oxygen and light.
Scheme 1 Alkoxylation of BODIPYs mediated by cupric halides under mild conditions.
Table 1 HRESI-MS results of alkoxylation products of BODIPY dyes with methanol and
ethanol.
Products a
ROH
Calcd.
Found
1a
1b
2a19
2b
3
Methanol
Methanol
Methanol
Methanol
Ethanol
694.3377
778.3565
664.3636
748.3823
714.3768
694.3392
778.3585
664.3665
748.3857
714.3774
Fig. 1 UV-Vis spectra (A) and fluorescence emission spectra (B) of 2 and corresponding
methoxylated products in CH2Cl2. The inset shows the photograph of their solutions.
Kinetics of yield study: Cupric Chloride vs Cupric Bromide
1 equiv CuCl2 only led dimethoxylation of 2 to around 50% yield
even if the reaction time was extended for 24 h. But increasing
the amount of CuCl2 to 2 equiv, 100% yield of dimethoxylation
was completed and gave to 2a in 2.5 hours (Fig. S2A). When the
dimethoxylation was carried out in the presence of 2 equiv
a Products 1a, 2a Calcd. and Found for [M+H]+, the others for [M+Na]+; Substrate
of dialkoxylated product 3 was BODIPYs 2 mediated by CuCl2.
Absorbance and emission spectra study
-
CuCl3 (mixed equal amount of CuCl2 and tetrabutylamonium
chloride (n-Bu4NCl)), a similar reaction time was needed to
complete dimethoxylation, which indicated that excess chloride
BODIPYs 2 is chosen as the model compound for this study. Fig.
1A shows the maximal absorption wavelengths of
dimethoxylated product 2a and tetramethoxylated product 2b
are at 619 and 522 nm respectively, which are blue shifted by
ions could not accelerate the dimethoxylation rate of
Furthermore, 10 equiv CuCl2 could not convert into
tetramethoxylated product 2b even if reacting for 24 h, but the
dimethoxylation of was accelerated when increased the
2.
2
87 and 184 nm compared to that of
the absorption spectra led to distinct colour changes of their
solutions, which are green for , blue for 2a, and pink for 2b
2. Such large blue shifts in
2
amount of CuCl2, (Fig.S2B). Compared to 2 equiv CuCl2, same
amount of CuBr2 shortened the dimethoxylated reaction time
2
,
respectively (Fig. 1A, inset). Similar blue shifts are also observed
of
2
to around 1 h, but no tetramethoxylation occurred within
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24 h. However, 4 equiv CuBr2 could quickly convert
ARTICLE
2
to which is very similar to the transient spectrum atVhieawlfArmticlienOuntleinse
dimethoxylated product, and finally led to 100% yield of shown in Fig. 2, this indicate that complDeOxIA: 10c.o10u3l9d/Cb9eOaB0s2h5o9r0tA-
tetramethoxylated product after reacting for around 48 h (Fig. life intermediate formed by CuCl2 react with
2
before reacting
2C), 10 equiv CuBr2 would further short the reaction time with alcohol. The solution
around Ih (Fig. S2D). 4 equiv CuBr3 (mixed equal amount of factor of 2.0026 at room temperature (Fig. 3), which indicates
A shows a sharp ESR peak with a g
-
CuBr2 and cetrimonium bromide), could also accelerate the that the intermediate is a radical cation of 2, according to
tetramethoxylation. Therefore, these observations reveal that relevant reports.23-25 Furthermore, the lack of obvious hyperfine
CuBr2 is more reactive than CuCl2 and the reaction structure in the ESR spectrum implies that the unpaired
stoichiometry is one olefinic bond of BODIPYs to two cupric electron can be delocalized on a large conjugated molecular
halides. Moreover, appropriate amount of cupric ion was system of complex A 26
essential for alkoxylation of BODIPYs.
Reaction dynamics
.
The ESI mass spectrum of solution
shows a molecular ion peak at m/z = 601.4 is consistent with the
simulated isotope distribution of the ionized
[M]+ (Fig. S4A).
The generation of radical cation of was further supported by
the following control experiments. First, a solution of in CH2Cl2
A
2
2
In order to detect possible intermediates, the mixture of
2 in
2
CH2Cl2 and 4 equiv CuCl2 in MeOH (the final volume ratio of
CH2Cl2 to MeOH was 10:1) was examined by using of UV-Vis
absorption spectra over time (Fig. 2). It can be seen that the
was titrated with a diluted solution of oxidizing reagent
ferrocenium hexafluorophosphate (Cp2FePF6) and the process
was monitored by UV-Vis spectrum (Fig. S5A). Clearly, with the
addition of Cp2FePF6 into the solution of
at 460 and 558 nm gradually increased to maximum along with
the complete disappearance of the peaks at 706 nm of
Meanwhile, the colour of the solution changed from green to
pink. The pink solution could finally change to blue (colour of 2a
absorption bands of
2 at 706, 440, 340 nm quickly disappears
2, two peaks centred
upon addition of CuCl2 and a different absorption spectrum with
three new absorption at 818, 558 and 460 nm forms
simultaneously at half minutes. The change of absorption
spectrum led to very distinct colour change of the solution from
green to dark pink. As the reaction time increases, the above
three new bands gradually decreased and a new band at 619
nm (belong to 2a) appears and increases. The solution of
reaction mixture finally became blue (colour of 2a).
Furthermore, the spectral kinetics also produces three featured
isosbestic points at 405, 582 and 710 nm, indicating there are
potential intermediates during alkoxylation.
2
.
)
upon addition of small amount of MeOH. The molecular species
in the pink was examined by ESI mass spectra, the results show
that the dominant specie in the pink solution is the radical
cation of
2
identical to complex
A (Fig. S4B). Moreover, the
generation of radical cation of
2
by Cp2FePF6 was also evidenced
by ESR measurement result (Fig. S5B). Therefore, the
alkoxylation of BODIPYs was firstly initiated by oxidation of
cupric halides and generation of radical cation and Cu(I). And
the cuprous ion was confirmed by Cu(I) indicator neocuproine.
Fig. 2 UV-Vis absorbance kinetics of dimethoxylation of 2 (green dotted line) mediated
by 4 equiv CuCl2. The inset shows the photograph of colour change of the reaction
solution over time.
Potential intermediate: Free radical BODIPY.+
Fig. 3 ESR spectra of intermediate complex A and Cu(II)Cl3- in CH2Cl2.
To probe the nature of intermediates in the absence of alcohol,
-
2
was mixed with 4 equiv. CuCl3 in CH2Cl2, the mixture was then
Redox potential study
kept for 2 hours and yielded dark green precipitates, which
were centrifuged and washed several times with CH2Cl2 to
remove excess copper salt, the resulting precipitates were
The different reactivity between CuBr2 and CuCl2 could be
attributed to their different redox potentials. To further
evaluate the possibility of a SET between BODIPYs and oxidants,
the oxidation potential values (vs. SCE) of 2, 2a and cupric
halides (chloride and bromide) with ferrocene as an external
standard in deoxygenated anhydrous acetonitrile were
named complex
formed dark purple solution
solution has two obvious bands at 460 and 558 nm (Fig. S3),
A, then dissolved some complex
A in CH2Cl2 and
A. The absorption spectrum of
A
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measured. As shown in Table 2, oxidation potentials of both the active benzyl bromide derivative, which can eaVsiielwy Aorcticclue Or ntlhinee
DOI: 10.1039/C9OB02590A
2, therefore, nucleophilic substitution of methoxy group and give rise to
cupric halides are more positive than that of
thermodynamically, can be oxidized by cupric halides to yield methoxylated product.
2
radical cation and further reacts with alcohols to give
dimethoxylation product 2a. However, the introduction of two
methoxyl groups onto one olefinic bond of
2 increased the
oxidation potential of 2a. Moreover, the DFT calculations
showed the complex intermediate could form through cuprous
halides with atom F and O of 2a (Fig. 4), which would further
decrease the reducing ability of 2a. However, the oxidation
potential (0.52 V) and electronic affinity of CuBr2 (5.33 eV) are
still high enough to further oxide 2a to yield tetramethoxylated
product 2b, less oxidative CuCl2 and ferrocenium were unable
to mediate further dimethoxylation of 2a. Therefore, CuBr2 is
quite reactivity in such system.
Scheme 2. The structures of tested olefins and dimethoxylated products. The reaction
was carried out in the mixture solution of CH2Cl2 and MeOH (v/v=10:1) with CuBr2 (10
equiv) at r.t for 1.5 h.
Fig. 4 The optimized complex intermediate formed by 2a with cuprous halides.
Table 2 Compounds oxidizability
Compounds
2
Oxidation potential (V)a
IP [EA] (eV)b
4.36
0.36
0.48
0.40
0.44
0.52
Scheme 3. Addition reaction of olefin 16 and 18.
2a
4.70
---
[4.60]
[5.33]
Cp2Fe(+)
CuCl2
CuBr2
The role of anion in cupric salt
10 equiv CuSO4, Cu(OAc)2 or Cu(NO3)2 in MeOH was added into
the solution of
colour and the UV-Vis spectrum of the mixture of Cu(OAc)2 did
not show apparent change compared to that of indicating
2 in CH2Cl2. After mixing for 4 h, the solution
a
Values obtained in deoxygenated anhydrous acetonitrile with 0.1 M tetra-n-
butylammonium phosphate (TBAP) as the supporting electrolyte and Fc/Fc+ as
external standard at room temperature. b IP and EA were calculated in CH2Cl2 using
the B3LYP hybrid exchange-correlation (XC) functional along with the SDD basis set.
2
there is no interaction between them. However, the solution
turned dark green and dark blue for CuSO4 and Cu(NO3)2,
respectively. The UV-Vis spectra of them clearly exhibit two
small absorption bands at 558 and 948 nm, which can be
Scope of Reaction.
To explore the scope of this reaction, we expanded to examine
other olefins 6-13 as shown in Scheme 2. In the presence of 10
assigned to the radical cation of
2 and copper salts, but no
typical band belongs to dimethoxylated product 2a generated
(Fig.5). Then the mixtures were washed twice with deionized
water, the absorption band at 558 nm would be disappeared
equiv cupric bromide, only 12 and 13 occurred dimethoxylation
and gave good yield of products 1427 and 15 at room
temperature, respectively. The others all had no reaction even
if the reaction time was extended to 24 h under the same
conditions. Comparing the structures of tested olefins and
BODIPYs, in such mild reaction conditions, it seems that
dialkoxylation reaction prefer to occur in electron rich
conjugated olefins. In order to confirm this deduction, we did
comparative reaction by using of olefins 16 and 18. However,
only mono-substituted-methoxy bromo products 17 and 19
were obtained even if increasing the reaction time and reaction
temperature (Scheme 3). According to literatures,28,29 we infer
that another intermediate during alkoxylation progress may be
and the absorption spectra of
2 recovered (Fig. S7). Taken
together, these observations suggest that the alkoxylation
reaction of BODIPYs is highly dependent on the cupric anion.
And halide ions indeed play an important role as active species
during reaction progress and have highly reactive with BODIPYs
compared to other anions of cupric salts. To verify this
conclusion, we carried out the methoxylation reaction of
the presence of a mixture of CuSO4 with CTAB or n-Bu4NCl. The
identical methoxylated products to those of cupric halides were
2 in
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also obtained quickly, which were confirmed by UV-Vis and ESI for oxygen activation of dialkoxylated product, thVeierwefAortricele,Oonnlinlye
spectra.
high oxidative CuBr2 could further DoOxIi:d1i0z.e103d9/iaCl9kOoBx0y2la59te0dA
It is known that Cu(II) is a poor π-donor and there is not known BODIPYs and give rise to tetralkoxylated product. Furthermore,
complexes between Cu(II) and π-acidic ligand such as olefin and we deduce that alcohols are more easily electrochemically
carbonyls. However the halides are good π-donor ligands in oxidized with their nucleophilicity increasing and the
CuX3-,30 which may increase the π-donor ability of Cu(II) through corresponding alkoxylated products can be prepared in such
push-pull interactions and facilitate electron transfer between mild method.32
BODIPYs and Cu(II) to give the burst amount of BODIPY radical
cation intermediate compared to other cupric salts. This impact
of halides in cupric mediated oxidation reaction was noted
before. Moreover, the nucleophilic substitution of bromide not
only stable the radical cation not be easily quenched, but also
produce the active benzyl bromide derivative intermediate,
which can easily occur the nucleophilic substitution reaction
with methanol and give rise to methoxylated product.
Therefore, the cupric bromide exhibits the strongest activity
among all cupric salts.
Scheme 4 Alkoxylation mechanism of olefin with methanol mediated by cupric bromide.
Conclusions
Overall, the 3,5-styryl group of fluorescent BODIPYs underwent
an attractive alkoxylation mediated by cupric halides in good
yield under mild and easy to operate reaction conditions, which
will provide a convenient pathway for synthesis of functional
Fig. 5 UV-Vis absorption spectra of 2 mixing with different kinds of 10 equiv copper salts
for 4 hours in mixture solution of CH2Cl2 and MeOH (v/v=10:1). The inset shows the
photograph of mixture solutions. From left to right, they are 2, 2+CuSO4, 2+Cu(OAc)2 and
2+Cu(NO3)2, respectively.
fluorescent BODIPYs, for example, organelle specific tags
triphenylphosphonium
(Ph3P+)
group
for
targeting
mitochondria and polyoxyethylene (OTEG) group for enhancing
hydrophilic of fluorescent dyes. Moreover, the distinct color
change of solution and blue-shift emission peak of BODIPYs
caused by alkoxylation can be used for design of ratiometric
fluorescent probe for detection of alcohol, which is on-going in
our lab now. Furthermore, this efficient methodology for
dialkoxylation of olefinic bonds also work well in electron rich
conjugated olefins at room temperature.
Reaction mechanism
On the basis of these experimental results and DFT calculations,
we proposed the methoxylation mechanism of electron rich
olefin mediated by cupric bromide as presented in Scheme 4.
The alkoxylation reaction is firstly initiated by the oxidation of
cupric bromide and promotes the SET from olefin to cupric ion,
this process produces the burst amount of radical cation
intermediate, which subsequently undergo nucleophilic
substitution of bromide to produce active benzyl bromide
derivative intermediate and quickly reacted with methanol to
give dialkoxylation products. Berreau and co-worker reported
that the presence of a catalytic amount of chloride ion can
accelerate the reaction rates of C-C bond oxidative cleavage
reaction by molecular oxygen. It suggest that the oxygen
activation step involved the formation of a Cu−Cl species, which
facilitates monodentate diketonate formation and lowers the
barrier for oxygen activation.31 But in BODIPYs case, the
intermediate product Cu-X (X= Cl, Br) would complex with
dialkoxylation of BODIPYs and led to increase a little the barrier
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are thankful for financial support from the Natural
Science Foundation of Inner Mongolia Autonomous Region
(2019BS02004), the National Natural Science Foundation of
China (21901132), the National Key Research and Development
Program of China (2017YFC0110202), the National Science
Foundation (NSF) of Hubei Province innovation group project
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32 D. Wang, J. Liu, Z. Wu, J. Zhang, Y. Su, Z.Liu and C. Xu, Int. J.
(2017CFA006) from Science and Technology Research Project of
Hubei, and the Province Department of Education (D20191001)
from the NSF of Hubei University.
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Electrochem. Sci., 2009, 4, 1672-1678.DOI: 10.1039/C9OB02590A
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