Expeditious, mechanochemical synthesis of BODIPY dyes

Article abstract of DOI:10.3762/bjoc.9.89

BODIPY dyes have been synthesized under solvent-free or essentially solvent-free conditions, within about 5 minutes in an opento- air setup by using a pestle and mortar, with yields that are comparable to those obtained via traditional routes that typical

Full text of DOI:10.3762/bjoc.9.89

Expeditious, mechanochemical synthesis
of BODIPY dyes
Laramie P. Jameson and Sergei V. Dzyuba*§
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 786–790.
Department of Chemistry, Texas Christian University, Fort Worth, TX
76129, USA
doi:10.3762/bjoc.9.89
Received: 08 February 2013
Accepted: 29 March 2013
Published: 23 April 2013
Email:
Sergei V. Dzyuba* - s.dzyuba@tcu.edu
* Corresponding author
Associate Editor: T. P. Yoon
§ Tel.: +1-817-257-6218; fax: +1-817-257-5851
© 2013 Jameson and Dzyuba; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
BODIPY; condensation; fluorescent dye; mechanochemistry;
solvent-free
Abstract
BODIPY dyes have been synthesized under solvent-free or essentially solvent-free conditions, within about 5 minutes in an open-
to-air setup by using a pestle and mortar, with yields that are comparable to those obtained via traditional routes that typically
require reaction times of several hours to days.
Introduction
BODIPY dyes are fluorescent organic molecules, which have between a 2-substituted pyrrole and an aldehyde, followed by
received a lot of attention in recent years due to their favorable oxidation with DDQ or p-chloranil, and subsequent treatment
chemical and physical characteristics, including high quantum with base (Et3N or Hunig’s base are typically used) and
yields and tunable fluorescent properties as well as high thermal BF3·OEt2; (b) pyrrole condensation with an acid chloride and
and chemical stabilities [1-3]. As such, BODIPY and their subsequent treatment with base (also usually Et3N or Hunig’s
derivatives have found widespread utility in a variety of base as in procedure a) followed by treatment with BF3·OEt2.
different applications including biological [4-7] and light-
harvesting systems [8-11].
While the synthesis of BODIPY dyes from the corresponding
acid chloride (Scheme 1b) is frequently reported to give some-
Despite wide applicability, the synthetic access to BODIPY what better yields (albeit reaction times of several days are
dyes is neither facile nor efficient nor expeditious. The syn- often encountered), the structural diversity of commercially
thesis of BODIPY dyes is typically achieved by one of two available acid chlorides is limited, and they must be prepared
different one-pot procedures (Scheme 1) [1,2]: (a) Lewis acid from the corresponding acid. Furthermore, the sensitivity of
(usually trifluoroacetic acid, TFA) catalyzed condensation acid chlorides to moisture imposes additional constrains.
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Beilstein J. Org. Chem. 2013, 9, 786–790.
Scheme 2: Expeditious synthesis of dye 1.
In view of this positive result (Table 1, entry 1), we attempted
to optimize this procedure (Table 1). Specifically, several
oxidizing agents were tried, including the typically used DDQ
as well as Ce(NH4)2(NO3)6. However, p-chloranil afforded the
highest isolated yield (Table 1, entries 1–3). We also found that
Scheme 1: Literature preparations of symmetric, meso-substituted
BODIPY dyes.
Accordingly, the condensation of pyrroles with aldehydes adding small amounts of CH2Cl2 (1–2 mL) prior to the addition
(Scheme 1a) is the more commonly utilized synthetic approach of p-chloranil allowed for a more efficient grinding to take
[1,2]. Notably, both approaches are carried out under an inert place.
atmosphere. Overall, based on literature accounts, BODIPY
synthesis requires long reaction times (several hours to several
Table 1: Optimization of reaction conditions for the synthesis of dye 1.
days) and isolation of the dyes is performed by chromatog-
Entry Oxidant
Base
Yield, %a
raphy, with poor to moderate (10–50%) yields.
1
2
3
4
5
6
7
p-chloranil
Et3N
29
7
In this light, a more expedient synthesis of the BODIPY dyes is
desired. Toward this end, we reasoned that the condensation
step between the 2-substituted pyrroles and aldehydes (or acid
chlorides) should be more facile at higher concentrations and
probably most efficient under neat conditions. All the subse-
quent steps should also, in principle, benefit from high concen-
trations.
DDQ
Et3N
Ce(NH4)2(NO3)6
Ce(NH4)2(NO3)6
p-chloranil
Et3N
0
DBU
8
DBU
24b
0
p-chloranil
K2CO3
NaOH
p-chloranil
0
aIsolated yield, after column chromatography; byields varied from 8 to
24%.
Results and Discussion
As a trial reaction, we attempted a mechanochemical synthesis
of BODIPY dye 1 [12] with commonly used reagents. The con- Next, we examined several different bases for the deprotona-
densation of 2,4-dimethylpyrrole and 4-nitrobenzaldehyde was tion of the dipyrrolium species. Organic bases such as Et3N and
performed with grinding by using a simple mortar and pestle, DBU (Table 1, entries 1 and 5), proved to be most effective.
followed by the addition of a few drops of TFA (complete Although DBU gave comparable results to Et3N, variations in
consumption of the aldehyde was confirmed by TLC) and oxi- yields were observed, likely due to the air-sensitive nature of
dation with p-chloranil. The reaction mixture was subsequently DBU (Table 1, entry 5). Et3N, however, appeared to give repro-
treated with Et3N and BF3·OEt2 to afford BODIPY dye 1 ducible results. In contrast, inorganic bases added as solids
(Scheme 2). All reagents were added sequentially with grinding (K2CO3 and NaOH, Table 1, entries 6 and 7, respectively)
in ca. 5 minutes. Each step was accompanied by a color change. failed to give the desired product. Overall, this essentially
The desired product was isolated in 29% yield, which was solvent-free, 5-minute procedure can be performed using the
comparable to those reported in literature protocols, 24–40% same reagents as the solution synthesis.
(Supporting Information File 1, Table S1), but in a substan-
tially shorter reaction time. The reported reaction times for the Finally, we also experimented with isolation procedures of the
synthesis of dye 1 range from 5 hours to ca. 12 hours (or crude reaction mixture and found that diluting the mixture with
overnight).
CH2Cl2 and subsequently washing the organic layer with satu-
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Beilstein J. Org. Chem. 2013, 9, 786–790.
rated Na2CO3 solution (to remove the hydroquinone produced dyes 8 and 9 in relatively low yields of 21% and 10%,
byproduct), then brine, followed by column chromatography on respectively. It should be pointed out that in the case of dye 9
silica gel gave satisfactory results. It is worth pointing out that (and unlike the synthesis of 8), the condensation step between
isolation and purification of BODIPY dyes appeared to be prob- 2,4-dimethylpyrrole and benzoyl chloride appeared to be slug-
lematic regardless of the synthetic procedure, i.e., under solu- gish. Specifically, with dye 8, after 1 minute of grinding the
tion (literature accounts) or mechanochemical (current work) pyrrole was consumed as judged by TLC. However, with dye 9,
conditions. Vigorous shaking should be avoided during the a considerable amount of pyrrole remained (extending the
extraction steps as it led to the formation of stable emulsions, grinding time to 5 minutes did not improve the efficiency of this
which significantly lengthened the isolation process, and also step, as noted by TLC), which could have been the reason for
decreased the overall efficiency of the reaction. However, we the low yield of the dye 9. Low yields might have been
found that avoiding the extraction step altogether resulted in expected due to the significantly more moisture-sensitive nature
lower isolated yields of the BODIPY dyes. Also, CHCl3 was of the acid chlorides as compared to the aldehydes. Conven-
found to be a superior solvent for column chromatography as tional procedures, which utilize solvents and are performed
compared to CH2Cl2.
under inert atmosphere for extended periods of time, afford
BODIPY dyes in 30–50% yields [13,14]. Similar to the alde-
With the optimized conditions at hand, we prepared several hyde-based synthesis of BODIPY dyes (Table 2), substituting
BODIPY dyes by using commercially available aldehydes and Et3N with DBU led to inferior results: yields of 7% and 5% for
either 2,4-dimethylpyrrole or 3-ethyl-2,4-dimethylpyrrole dyes 8 and 9, respectively, were obtained.
(Table 2) [13]. The reaction appeared to be insensitive to the
electronic effects of the aldehyde, as both electron-donating and
electron-withdrawing groups were equally tolerated. The yields
were found to be reasonably comparable to those reported in
literature (Supporting Information File 1, Table S1). Yet, the
reaction times are drastically reduced from hours and several
days (the latter holds true, for example, for dyes 4, 6, 7) to just
5 minutes.
Table 2: 5-minute synthesis of BODIPY dyes.
Scheme 3: 5-minute synthesis of dyes 8 and 9.
In addition, we explored the synthesis of BODIPY dye 10,
which does not have a substituent at the meso-position
Dye
R1
R2
Yield, %a
(Scheme 4), using triethyl orthoformate as the aldehyde compo-
nent. Similar to all other cases, the literature synthesis of this
BODIPY dye was performed in solution and required several
hours [15]. The synthesis could be accomplished under solvent-
free conditions within 5 minutes, using the same reagents, in
1
2
3
4
5
6
7
4-NO2
H
29
15
13
32
10b
22
15
4-OCH3
4-CN
H
H
4-ethynyl
3-OH
H
Et
Et
Et
4-CF3
C6H4R1 = 4-pyridyl
aIsolated yield, after column chromatography; b23% yield when DBU
was used as a base.
Furthermore, we examined whether acid chlorides would be
suitable substrates for this procedure (Scheme 3). It appeared
that the condensation between pyrroles and acid chlorides
Scheme 4: 5-minute synthesis of dye 10.
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Beilstein J. Org. Chem. 2013, 9, 786–790.
29% yield. An equimolar amount to TFA was used, in order to Further experimental details (including those for the synthesis
cleave the acetal to produce the aldehyde, which was condensed of dye 10) and spectroscopic characterization of all BODIPY
with the pyrrole.
dyes are given in Supporting Information File 1.
Conclusion
Supporting Information
In conclusion, the developed procedure provides a rapid access
to BODIPY dyes with reaction times being reduced from
several hours or even days to only 5 minutes, while also elimi-
nating large volumes of solvents. The syntheses of BODIPY
dyes that used aldehydes as starting materials appeared to be
superior to the approach that used acid chlorides. In addition,
the unsubstituted BODIPY dye in the meso-position was also
prepared via an acid-catalyzed triethyl orthoformate conden-
sation with a pyrrole. Studies on improving the overall effi-
ciency of this process, especially the isolation and purification
of the BODIPY dyes, are in progress in our laboratory.
Supporting Information File 1
Experimental procedures and characterization data of
prepared BODIPY dyes.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-89-S1.pdf]
Acknowledgements
We would like to thank the National Institute On Aging (Award
Number R15AG038977) for financial support of this work. The
content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institute
On Aging or the National Institutes of Health.
Experimental
All reagents and solvents were from commercial sources
(Sigma-Aldrich or Acros) and were used as received.
Column chromatography was performed using silica gel
(230–400 mesh) or basic alumina (Brockman I). Fraction
collection was monitored by TLC (silica gel 60 F254) and the
spots were visualized by UV. 1H NMR spectra were recorded
on a Varian (300 MHz) spectrometer.
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