2.2. Document cleaning#
Since most of the downloaded files include irrelevant sections like bibliography and acknowledgments the next step would be to remove those. In addition, depending on the chosen document parsing techniques there might be additional cleaning steps that are required.
2.2.1. Cleaning text using hand-coded rules#
import matextract # noqa: F401
with open("raw_text.txt", "r") as f:
content = f.read()
2.2.1.1. Removing extraneous line breaks#
print(content)
Linear Amine-Linked Oligo-BODIPYS: Convergent Access via
Sebastian H. Rôttger, [a] Lukas J. Patalag,o) Felix Hasenmaile,a Lukas Milbrandt,o) Burkhard
Buchwald-Hartwig Coupling
Butschke,cl Peter G. Jonesld] and Daniel B. Werz*la)
[a] S.H. Rôttger, Dr. F. Hasenmaile, Prof. Dr. D.B. Werz
Institute of Organic Chemistry
AlbertstraBe 21, 79104 Freiburg (Breisgau), Germany
E-mail: daniel. wer@chemeunltelbupde
[b] Dr. L. J. Patalag, L. Milbrandt
Technische Universitât Braunschweig
Institute of Organic Chemistry
Hagenring 30, 38106 Braunschweig, Germany
[c] Dr. B. Butschke
Abert.ludwgsUnkerstat Freiburg
Institute of Inorganic and Analytical Chemistry
AlbertstraBe 21, 79104 Freiburg (Breisgau), Germany
[d] Prof. Dr. P. G. Jones
Technische Universitât Braunschweig
Institute of Inorganic and. Analytical Chemistry
Hagenring 30, 38106 Braunschweig, Germany
DFG Cluster of Excellence livMats @FIT and Aber.uowgsUnversiat Freiburg
Abstract: A convergent route towards nitrogen-bridged BODIPY
oligomers has been developed. The synthetic key step is a
Buchwald-Hartwig cross-coupling reaction of an a-amino-
synthesis provide control of the oligomer size, but the facile
preparative procedure also enables easy access to this type of
dyes. Furthermore, functionalized examples were accessible via
Various BODIPY oligomer
pocbolag
BODIPY and the
brominated derivatives.
Introduction
halide.
respective
Not only does the selective
- - - EN
cooe
The family of BODIPY dyes, first reported in 1968 by Treibs and
Kreuzer,"l has gained major interest in research in the past
decades because of their fairly simple preparative access, their
flexibility in terms of possible modifications and their useful
properties such as outstanding attenuation coefficients and also
high fluorescence quantum yields.2) Hence, they are already
widely applied for imaging, e.g. as biomarkers for medical
purposes, and have also proven to be applicable in other fields,
for instance as various types of photosensitizers and organic light-
emitting diodes (OLEDs).3) Various types of oligo-BODIPYS have
already shown the capability to enhance such desirable
properties and thus have been the focus of much recent
preparative chemistry. Alkylene bridged or directly connected
BThiswork
symmetric & unsymmetric dimers
and
functionalized examples
BODIPYS have been known for several years (Figure 1A (top).141 Figure 1. A) Various C-C bridged (top) and heteroatom bridged (bottom)
BODIPY oligomers. B) Linearly amine-linked BODIPY oligomers (this work).
Residual substituents of the BODIPY core were omitted for clarity.
1
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These types of connectivity have also been converted to extended ANomenclature
m-systems by oxidative follow-up reactions, allowing a higher level
of conjugation and hence strong bathochromic shifts.5) The
installation of heteroatoms has however been a challenge for
some time. In 2014, Shinokubo et al. presented linearly connect a: Pyrrole substitution pattern
monomers through an azo-bridge at the B-position (Figure 1A Br:
(d).61 Linear connectivity at the a-position using heteroatoms DM (24-Dimethy-yrole): R'= R3= Me,R2= H Ar 4-BuPh:
such as sulfur has been achieved through a similarly iterative EDM GEny*24-dimelhypymol; R' R3 Me, R2=E Et
process by the groups of Hao and Jiao (Figure 1A (e).7
Furthermore, cyclic amine-linked oligo-BODIPYS have already tri: Trimer tet: Tetramer
been synthesized in a one-pot reaction in 2022 by Song et al., DPecurorsynlaess
utilizing Buchwald-Hartwig conditions (Figure 1A (0).181
We present a novel type of BODIPY oligomers, connected
via N-bridges in a linear fashion (Figure 1B). Utilizing both
symmetric and unsymmetric BODIPY monomers as building
blocks has paved the way to selectively synthesize oligomers with
various chain lengths. Both symmetric and unsymmetric dimers
were synthesized starting from unsymmetric mondfunctionalized
monomer units. Additionally, the chain length of these oligo-
BODIPYS was extended using the functionalized monomer Br-Ar-
R3
R2
31
F
a-b-c-d
b(monomers & dimers):
d (monomers only):
Substituent x
R Br, R2 R3= H meso-substitution (R")
T
c: Grade of oligomerization
mono: Monomer di; Dimer
1)n-BuLi, 2,6-dimethyl-
aniline, benzaldehyde 4-iso-butyl
Et0,rt,5h
HN. 2)imidazole, TBSCI
CH2Clz. r, 1h
TFA, 4-iso-butyl-
benzaldehyde CH2Cl.rt,24h
H IN
7: 68%
1)NBS, THF, -78 "C, 1h
2)DDQ, .-78 C thenr rt, 1h
3)PfNEt, BFxOEL2
CH2Cl. rt, 30min
o
NCS o
HN. THF, rt,3-7d HN
2: 529/R"- Ar)
1) M
R2
Me
5; R2=H H
6: R2=Et, POCI3
CH,Clyln-hexane (2:1)
0°Ct thenrt, 16h
2)NEls. BF,-OEl2
0°Ct then rt, 1h
Me
R2.
Me
DM-Me-mono-Ct 49%
DM-Ar-mono-CH EDM-Ar-mono-CH: 83% 91%
Pd(OAc),
(E)-BINAP Cs,CO3
PhMe, 80 "C,3-22h
3:559( (R" Me)
4: 56%(R" Ar)
mono-Br and the dimer Br-Ar-di
Results and Discussion
(Scheme 1).
In contrast to the aforementioned cyclic amine-linked examples, [8]
we have focused on selectively synthesizing open-chained
oligomers and addressing their specific properties. Variation of
the BODIPY core has been shown to have a considerable impact
on the respective reaction times and yields. To dimerize Br-Ar-mono-Br
selectively when forming the nitrogen bridge, monofunctionalized
a-chlorinated BODIPY monomers were used. The key step in
obtaining such unsymmetric BODIPYS (in contrast to the usual
mirror plane through the meso position and boron center) was a
Bischler-Napieralski type reaction of the respective chlorinated
acylpyrrole and alkylpyrrole, following an established procedure
developed by Dehaen and coworkers.9 Converting the a-chloro- C)Oligomerization
BODIPY into the respective amine and performing a Buchwald-
Hartwig coupling of both led to N-bridged BODIPY dimers, in
which alkylpyrroles such as 2,4-dimethylpyrrole (5) and
cryptopyrrole (6) serve as capping units on the BODIPY core.
Terminal a-brominated examples provide an option for further
versatile functionalization. During the investigation of meso
substitution patterns, the 4-iso-buty/phenyl moiety has been
shown to overcome solubility issues, while maintaining
crystallizability (albeit sometimes with disorder problems),
whereas dimer syntheses are made easier by an increasing level
of alkyl-substitution on the pyrrole motif. For a simplified overview
of the BODIPY scope, compounds are labeled according to the
systematic nomenclature shown in Scheme 1A.
The synthetic strategy began with pyrrole (1) for both kinds
of monomers. To obtain monochlorinated BODIPYs, it was first
converted into the respective 2-benzoylpyrrole 2 for the meso aryl
examples.10 TBS protection of the benzyl alcohol by- product in
the crude simplified the purification later on.1) This species and
2-acetylpyrrole were then chlorinated using NCS in THF at room
temperature to obtain a-chlorinated 2- -acylpyrroles 3 and 4.!12]
NH3(7 N in! MeOH)
60-C, 30r min- 7 d
R3 R"
R2. N
R' F B F NH2
DM-Me-mono-NH, 47%
DM-Ar-mono-NH, EDM-Ar-mono-NH, 58% 58%
Br-Ar-mono-NH, quant.
EDM-Ar-
mono-NH2 or
Br-Ar-
mono-NHz
Pd(OAc),
(H)-BINAP
PhMe, Cs,COs 80 *C,1-5h
38%
R"
R3
B. F
R
R1
DM-MelAr-di DM-Me-di: 30% 25%
Br-Ar- DM-Ar-di: EDM-Ar-di: 40% 68%
mono- Br
-Br-Ar-di: 44%
F-B
Ar
F
R3
R'
EDM-tri: Br-tri: 82% 5%
NH
d 0
Ar
8
I E e
R3
Aminated dilutedi in BODIPYS CH2Clz
- -
R
Ar.
Ar
HN
Br-tet: EDM-tet: 1.4% 55%
Scheme 1. A) Nomenclature for BODIPYS. B) Synthetic route towards
monomers. C) Oligomerization to dimers, trimers and tetramers.
2
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We preferred chlorination over the analogous bromination since thus causing one of the peripheral cores to be tilted by as much
the by-products were easier to separate from the desired as 29° with regard to the plane of the residual two units. Moreover,
products. To arrive finally at the monofunctionalized BODIPY one molecule of CH2Cl2 is adjacent to the cavity, indicating
monomers, acylpyrroles 3 and 4 were then converted with the hydrogen bonding to the BF2 units. Furthermore, the C-N-C bond
respective alkylpyrroles 5 and 6 in the presence of POCI3 in angles of the N-bridges range between 123° and 127°, showing
CHaCln-hexane (2:1), followed by the established procedure for deviation from the theoretical value of 120° for sp?-hybridized
BODIPY syntheses from the in situ formed dipyrrin using nitrogen. Within the resulting cavity, the minimum distance
triethylamine and BF3*OEt2, with yields up to 91% over 2 steps. between fluorine and the bridging nitrogen atom amounts to 2.9 A
To obtain higher oligomers, bisfunctionalized monomers had to and 3.4 A for the opposing BF2 units for the dimer. The trimer in
be synthesized prior to amination. For symmetrically comparison shows larger distances of the two closest fluorine
bisfunctionalized monomer Br-Ar-mono-Br, an excess of pyrrole atoms of two different BF2 groups (3.9 A) and as much as 5.2À
(1) was converted into dipyrromethane 7 using 4-iso- for the two peripheral BODIPY units (Figure 2C). For more details
butylbenzaldhyde with catalytic amounts of TFA in CH2Cl2 in 68% see the Supporting Information.
yield.13) Stepwise addition of NBS in small portions to a solution
of 7 in THF at -78 C for selective bromination, followed by A)
oxidation with DDQ, gave the crude dipyrrin, which was used in
the following step after filtration. The actual BODIPY synthesis
was subsequently conducted in a similar manner as for the
unsymmetric monomers. However, Pr2NEt was found to give
higher yields for less substituted dipyrrins. Thus, using this tertiary C)
amine base, in lieu of triethylamine, together with BF3-OEtz gave
Br-Ar-mono-Br in 38% yield over three steps. Bromination was
necessary in this case because the corresponding chlorinated
derivative of an a-amino-BODIPY showed no oligomerization
beyond the dimer under the same conditions. Additionally,
purification was not an obstacle, in contrast to the aforementioned
brominated acylpyrroles. Preparative details of the chlorinated
amino-BODIPY are given in the Supporting Information. The
respective d-amino-BODIPYS were then synthesized by stirring
halogenated BODIPYS in an ammonia solution in MeOH (7 N) in
a sealed tube at 60 oC to furnish the target compounds in up to
58% yieldf for chlorinated derivatives and even in quantitative yield
for the brominated example (Scheme 1B). For Buchwald- Hartwig
coupling of a-chloro- and a-amino-BODIPYS, one equivalent of D)
each was converted with Pd(OAc)2, (+)-BINAP and Cs2CO3 in
PhMe at 80 C.1141 Interestingly, the reaction times and yields
showed a trend of improvement with increasing level of
substitution of the BODIPY core with up to 68% yields. While
these dimer syntheses were straightforward by simply stirring all
of the components together, synthesis of Br-Ar-di required slow
addition of Br-Ar-mono-NH2 to a heated solution of the remaining
starting material was recovered. As for the dimers synthesized via
manner with the respective bromides (Br-Ar-di for EDM-
B)
)
reagents. Such a procedure ensured selectivity by maintaining an Figure 2. Molecular structures of DM-Me-di A) front view, B) top view andl EDM-
excess of Br-Ar-mono-Br to avoid further oligomerization. The tri C) front view and D) top view. Hydrogen atoms were omitted for clarity.
the chlorides, synthesis of trimers and tetramers was achieved in The photophysical behavior of the dimers shows a strong
tet), with a remarkable decrease of the reaction time. Throughout respective monomers (from AA max = 510 nm to 659 nm for the
the reaction of Br-Ar-mono-Br with EDM-Ar-mono-Bir, formation EDM examples) and also significantly increased attenuation
of the respective intermediate dimer was observed within coefficients 6 (Figure 3). An excerpt of the respective data is given
30 minutes, while full conversion took an additional 60 minutes. below (Table 1). The presence of a second absorption region at
It was possible to obtain crystals from the dimers and from approximately 500 nm (S2 state) indicates a Davydov splitting as
EDM-tri. For all dimers, the BODIPY cores are mutually slightly a result of an excitonic coupling process. The unusual double-
twisted (-12°, see Figure 2B). The small twist angle, however, peak shape may suggest some conformational instabilities. In this
implies a certain amount of conjugation through the central context, the absorption profile is expanded to three absorption
nitrogen atom. In contrast, EDM-tri shows a stronger deviation events at the trimer, corresponding to three excitonic states
from planarity, which is probably attributable to steric hindrance, excited at 752 nm (S1), 562 nm (S2), and 470 nm (S3),
reaction yielded 44% of the functionalized dimer, while 45% of the Ellipsoids correspond to 50% probability levels.
bathochromic shift of the main
same
band
absorption
compared to the
respectively. Notably, the S2 state exhibits the highest oscillator
3
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strength, attributed to the significant geometrical deviation from Table 1. Absorption and emission data of EDM- -BODIPYS.al
linearity, gradually leading to a helical superstructure for higher
homologs (Figure 4). This trend is accentuated for the tetramers,
where the absorption signature becomes intricate. However, the
intensified coiling in this case, where the terminal BODIPY units
start overlapping and thus forming a looped superstructure,
results in an exceptionally weak Si+-So excitation at 820 nm. The
remaining states of the exciton manifold are hardly assignable
because of the amount and overlap of absorption bands, yet they mono-NH2
are responsible for the absorptions at 633 nm and 521 nm. The
simulated through TDDFT computations and accurately mirrors
the experimentally observed absorption band intensities for all
oligomer species (Figure 4). The emission strength decreases
gradually along the oligomeric series. While the monomers exhibit
fluorescence quantum yields @F of up to 0.53 in CH2Cl2, these
tetramers, emission is hardly detectable (CPF << 0.01).
Compound AAmax AFmax 4PIcm-1 s[103 M- @
[nm] [nm]
510
534
881
525
539
495
659
cm-"'l
121
59
EDM-Ar-
mono-CI
EDM-Ar-
0.04
0.01
oscillator strength distribution of the exciton manifold was EDM-Ar-di 482, 510, 671
271 47,40, 134 0.01
EDM-tri 562, 757 778 357lb)
EDM-tet 521,633 n.d.Icl
97, 76
111,114
0.01
values decrease to QF < 0.01 for the dimer and trimer. For the [a] Absorption and emission spectra were recorded in solutions of CH2Cl2 at
room temperature. [b] AAmax is not responsible for AFmax. Stokes shift 40 was
calcd. using the respective 2Amax2. [c] Not detecteddetermined. Further
spectroscopic data is given in the Supporting Information.
The frontier orbitals of the oligomeric series integrate the lobe
patterns found for the monomeric building blocks. All BODIPY
units are characterized by an electron-depleted meso position at
the HOMO and also by the cyanine-like relocalization of electron
density to this position during excitation (Figure 4).
Cyclic voltammograms of amine-linked oligomers and the
respective monomers for the EDM-series are shown below
(Figure 5). In general, the larger the molecules, the easier the
oxidation; however, most of them are oxidized irreversibly. The
monomeric primary amine and the trimer show irreversible
oxidation, unlike the respective chloride and the dimer. However,
the chlorinated monomer has only one reversible reduction
potential at -1.28 V, whereas the dimer shows two reduction
150 - Absorption
EDM EDM- -Ar -Ar -mono-NH, mono-cI
EDMr EDM Ar-di
EDM- tet
100
50
Emissien
EDM EDM- -Ar-mono-NH, Ar mono-CI
EDM-Ar-di EDM-tri
450 500 550 600 650 700 750 800 850
Wavelength. AInm]
Figure 3. Absorption and emission spectra of EDM- BODIPYS. Absorption and potentials, at -1.25 V and at -1.64 V.
emission spectra were recorded in solutions of CH2Cl2 at room temperature.
Dimer
&
HOMO (-6.07 ev)
&
CDD S1
Trimer
Tetramer
LUMO (-2.04e evy
HOMO (5.85€ ev)
LUMO
(2.15ev]
HOMO (-5.71ev)
LUMO (2.20ev]
CDD S2
S1: 2.20eV(516nm) /f=1.11 S2: 3.046 ev (407 nm)/f=0.54
CDD_S2
(S1: 2154V57mm/F-02
CDD_ S3
CDD S2
S1:1 1.94eV/(641 inmy/f-0.080
CDD_
S2:2.75ev (451nm)/f=1.45 $3:3.07e ev (403nm)/f-0.34 S2: 2.45eV (508nm)/t-1.12 S3: 2.89eV (430nm)/f-1.55
Figure 4. Frontier orbitals and minimum energy structures of oligomeric series. Geometrical optimizations at the DFT level M052X-D3De2TZVP) in vacuo.
Oscillator strengths (fvalues) obtained from corresponding TDDFT computations (0B97XD/De121ZVP)- The input structures were truncated at the meso phenyl
residues (iso-butyl groups).
4
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Thei trimer shows almost irreversible oxidation potentials at 0.69 V Acknowledgements
and 1.33 V and also reduction at -1.69 V. EDM-tet, however,
shows several oxidation and reduction potentials within the range We thank the Deutsche Forschungsgemeinschat (DFG, German
of t 2.00 V, which are mostly irreversible (Figure 5). Attempts to Research Foundation, WE2932/14-1) and livMats Cluster of
oxidize the obtained oligomers did not provide quinodiimine Excellence under Germany's Excellence Strategy (EXC-2193/1-
analogs as for the cyclic derivates.8)
390951807) for funding. S.H.R. thanks Adrian Bauschke and
Susanne Klein (both TU Braunschweig) for their support and
Boumahdi Benkmil (University of Freiburg) for X-ray diffraction
analysis as well as Dr. Ulrich Papke (TU Braunschweig) for the
HRMS measurements and discussions thereof.
Keywords: BODIPY . dyes amines . oligomers Buchwald-
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-3
-2
-1
0
1
2
3
EDM-tet
EDM-tri
Hartwig coupling
EDM-Ar-
mono- NH,
EDM-Ar-
mono-CI
1
2
3
-3
-2
-1
Potential [VI vs. SCE
5.
Ed.: 2022, 61, e2021168.
D. T.
Sysak,
Figure Cyclic voltammograms. Cyclic voltammetry (IUPAC convention) was
measured of 4 mM solutions in CH2Cl2 with TBAPF6 (0.4 M) in reference to a
saturated calomel electrode (SCE) with a scan rate of 200 mV/s (clockwise,
starting from 0 V) in steps of 1 mV at room temperature.
Conclusion
Ins summary, we have successfully developed a method to access
linearly amine-linked BODIPYS using Buchwald-Hartwig
conditions. Terminal Br substituents allowed elongation of the
chain by two further BODIPY subunits. X-ray structure analyses
revealed conjugation of the various subunits via the linking
nitrogen atom. Absorption spectra show significantly increased
attenuation coefficients for the oligomers in comparison to the
respective monomers, and also strong bathochromic shifts. DFT
calculations provided an insight into the electronic properties and
showed a decreasing HOMO/LUMO gap as well as increasing
oscillator strengths (fvalues) of the excited states with increasing
level of oligomerization. The computed orbital energies are also
closely consistent with cyclovoltammetric investigations,
demonstrating a more facile oxidation and reduction with
22, 7694-7698.
increasing chain length.
Supporting Information
The Supporting
Information
Tang,
is available free of charge and
contains detailed experimental procedures, analytical, X-ray
crystallographic and absorption and emission data, and 'H, 13C,
19F and 11B NMR spectra of all new compounds.
Chem. 2023, 88, 14368-14376.
5
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yuSASN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0
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Linear Amine-Linked Oligo-BODIPYS: Convergent Access via Sebastian H. Rôttger, [a] Lukas J. Patalag,o) Felix Hasenmaile,a Lukas Milbrandt,o) Burkhard Buchwald-Hartwig Coupling Butschke,cl Peter G. Jonesld] and Daniel B. Werz*la) [a] S.H. Rôttger, Dr. F. Hasenmaile, Prof. Dr. D.B. Werz Institute of Organic Chemistry AlbertstraBe 21, 79104 Freiburg (Breisgau), Germany E-mail: daniel. wer@chemeunltelbupde [b] Dr. L. J. Patalag, L. Milbrandt Technische Universitât Braunschweig Institute of Organic Chemistry Hagenring 30, 38106 Braunschweig, Germany [c] Dr. B. Butschke Abert.ludwgsUnkerstat Freiburg Institute of Inorganic and Analytical Chemistry AlbertstraBe 21, 79104 Freiburg (Breisgau), Germany [d] Prof. Dr. P. G. Jones Technische Universitât Braunschweig Institute of Inorganic and. Analytical Chemistry Hagenring 30, 38106 Braunschweig, Germany DFG Cluster of Excellence livMats @FIT and Aber.uowgsUnversiat Freiburg Abstract: A convergent route towards nitrogen-bridged BODIPY oligomers has been developed. The synthetic key step is a Buchwald-Hartwig cross-coupling reaction of an a-amino- synthesis provide control of the oligomer size, but the facile preparative procedure also enables easy access to this type of dyes. Furthermore, functionalized examples were accessible via Various BODIPY oligomer pocbolag BODIPY and the brominated derivatives. Introduction halide. respective Not only does the selective - - - EN cooe The family of BODIPY dyes, first reported in 1968 by Treibs and Kreuzer,"l has gained major interest in research in the past decades because of their fairly simple preparative access, their flexibility in terms of possible modifications and their useful properties such as outstanding attenuation coefficients and also high fluorescence quantum yields.2) Hence, they are already widely applied for imaging, e.g. as biomarkers for medical purposes, and have also proven to be applicable in other fields, for instance as various types of photosensitizers and organic light- emitting diodes (OLEDs).3) Various types of oligo-BODIPYS have already shown the capability to enhance such desirable properties and thus have been the focus of much recent preparative chemistry. Alkylene bridged or directly connected BThiswork symmetric & unsymmetric dimers and functionalized examples BODIPYS have been known for several years (Figure 1A (top).141 Figure 1. A) Various C-C bridged (top) and heteroatom bridged (bottom) BODIPY oligomers. B) Linearly amine-linked BODIPY oligomers (this work). Residual substituents of the BODIPY core were omitted for clarity. 1 yuSASN cyTAN Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4.0
These types of connectivity have also been converted to extended ANomenclature m-systems by oxidative follow-up reactions, allowing a higher level of conjugation and hence strong bathochromic shifts.5) The installation of heteroatoms has however been a challenge for some time. In 2014, Shinokubo et al. presented linearly connect a: Pyrrole substitution pattern monomers through an azo-bridge at the B-position (Figure 1A Br: (d).61 Linear connectivity at the a-position using heteroatoms DM (24-Dimethy-yrole): R'= R3= Me,R2= H Ar 4-BuPh: such as sulfur has been achieved through a similarly iterative EDM GEny*24-dimelhypymol; R' R3 Me, R2=E Et process by the groups of Hao and Jiao (Figure 1A (e).7 Furthermore, cyclic amine-linked oligo-BODIPYS have already tri: Trimer tet: Tetramer been synthesized in a one-pot reaction in 2022 by Song et al., DPecurorsynlaess utilizing Buchwald-Hartwig conditions (Figure 1A (0).181 We present a novel type of BODIPY oligomers, connected via N-bridges in a linear fashion (Figure 1B). Utilizing both symmetric and unsymmetric BODIPY monomers as building blocks has paved the way to selectively synthesize oligomers with various chain lengths. Both symmetric and unsymmetric dimers were synthesized starting from unsymmetric mondfunctionalized monomer units. Additionally, the chain length of these oligo- BODIPYS was extended using the functionalized monomer Br-Ar- R3 R2 31 F a-b-c-d b(monomers & dimers): d (monomers only): Substituent x R Br, R2 R3= H meso-substitution (R") T c: Grade of oligomerization mono: Monomer di; Dimer 1)n-BuLi, 2,6-dimethyl- aniline, benzaldehyde 4-iso-butyl Et0,rt,5h HN. 2)imidazole, TBSCI CH2Clz. r, 1h TFA, 4-iso-butyl- benzaldehyde CH2Cl.rt,24h H IN 7: 68% 1)NBS, THF, -78 "C, 1h 2)DDQ, .-78 C thenr rt, 1h 3)PfNEt, BFxOEL2 CH2Cl. rt, 30min o NCS o HN. THF, rt,3-7d HN 2: 529/R"- Ar) 1) M R2 Me 5; R2=H H 6: R2=Et, POCI3 CH,Clyln-hexane (2:1) 0°Ct thenrt, 16h 2)NEls. BF,-OEl2 0°Ct then rt, 1h Me R2. Me DM-Me-mono-Ct 49% DM-Ar-mono-CH EDM-Ar-mono-CH: 83% 91% Pd(OAc), (E)-BINAP Cs,CO3 PhMe, 80 "C,3-22h 3:559( (R" Me) 4: 56%(R" Ar) mono-Br and the dimer Br-Ar-di Results and Discussion (Scheme 1). In contrast to the aforementioned cyclic amine-linked examples, [8] we have focused on selectively synthesizing open-chained oligomers and addressing their specific properties. Variation of the BODIPY core has been shown to have a considerable impact on the respective reaction times and yields. To dimerize Br-Ar-mono-Br selectively when forming the nitrogen bridge, monofunctionalized a-chlorinated BODIPY monomers were used. The key step in obtaining such unsymmetric BODIPYS (in contrast to the usual mirror plane through the meso position and boron center) was a Bischler-Napieralski type reaction of the respective chlorinated acylpyrrole and alkylpyrrole, following an established procedure developed by Dehaen and coworkers.9 Converting the a-chloro- C)Oligomerization BODIPY into the respective amine and performing a Buchwald- Hartwig coupling of both led to N-bridged BODIPY dimers, in which alkylpyrroles such as 2,4-dimethylpyrrole (5) and cryptopyrrole (6) serve as capping units on the BODIPY core. Terminal a-brominated examples provide an option for further versatile functionalization. During the investigation of meso substitution patterns, the 4-iso-buty/phenyl moiety has been shown to overcome solubility issues, while maintaining crystallizability (albeit sometimes with disorder problems), whereas dimer syntheses are made easier by an increasing level of alkyl-substitution on the pyrrole motif. For a simplified overview of the BODIPY scope, compounds are labeled according to the systematic nomenclature shown in Scheme 1A. The synthetic strategy began with pyrrole (1) for both kinds of monomers. To obtain monochlorinated BODIPYs, it was first converted into the respective 2-benzoylpyrrole 2 for the meso aryl examples.10 TBS protection of the benzyl alcohol by- product in the crude simplified the purification later on.1) This species and 2-acetylpyrrole were then chlorinated using NCS in THF at room temperature to obtain a-chlorinated 2- -acylpyrroles 3 and 4.!12] NH3(7 N in! MeOH) 60-C, 30r min- 7 d R3 R" R2. N R' F B F NH2 DM-Me-mono-NH, 47% DM-Ar-mono-NH, EDM-Ar-mono-NH, 58% 58% Br-Ar-mono-NH, quant. EDM-Ar- mono-NH2 or Br-Ar- mono-NHz Pd(OAc), (H)-BINAP PhMe, Cs,COs 80 *C,1-5h 38% R" R3 B. F R R1 DM-MelAr-di DM-Me-di: 30% 25% Br-Ar- DM-Ar-di: EDM-Ar-di: 40% 68% mono- Br -Br-Ar-di: 44% F-B Ar F R3 R' EDM-tri: Br-tri: 82% 5% NH d 0 Ar 8 I E e R3 Aminated dilutedi in BODIPYS CH2Clz - - R Ar. Ar HN Br-tet: EDM-tet: 1.4% 55% Scheme 1. A) Nomenclature for BODIPYS. B) Synthetic route towards monomers. C) Oligomerization to dimers, trimers and tetramers. 2 yuSASN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0
We preferred chlorination over the analogous bromination since thus causing one of the peripheral cores to be tilted by as much the by-products were easier to separate from the desired as 29° with regard to the plane of the residual two units. Moreover, products. To arrive finally at the monofunctionalized BODIPY one molecule of CH2Cl2 is adjacent to the cavity, indicating monomers, acylpyrroles 3 and 4 were then converted with the hydrogen bonding to the BF2 units. Furthermore, the C-N-C bond respective alkylpyrroles 5 and 6 in the presence of POCI3 in angles of the N-bridges range between 123° and 127°, showing CHaCln-hexane (2:1), followed by the established procedure for deviation from the theoretical value of 120° for sp?-hybridized BODIPY syntheses from the in situ formed dipyrrin using nitrogen. Within the resulting cavity, the minimum distance triethylamine and BF3*OEt2, with yields up to 91% over 2 steps. between fluorine and the bridging nitrogen atom amounts to 2.9 A To obtain higher oligomers, bisfunctionalized monomers had to and 3.4 A for the opposing BF2 units for the dimer. The trimer in be synthesized prior to amination. For symmetrically comparison shows larger distances of the two closest fluorine bisfunctionalized monomer Br-Ar-mono-Br, an excess of pyrrole atoms of two different BF2 groups (3.9 A) and as much as 5.2À (1) was converted into dipyrromethane 7 using 4-iso- for the two peripheral BODIPY units (Figure 2C). For more details butylbenzaldhyde with catalytic amounts of TFA in CH2Cl2 in 68% see the Supporting Information. yield.13) Stepwise addition of NBS in small portions to a solution of 7 in THF at -78 C for selective bromination, followed by A) oxidation with DDQ, gave the crude dipyrrin, which was used in the following step after filtration. The actual BODIPY synthesis was subsequently conducted in a similar manner as for the unsymmetric monomers. However, Pr2NEt was found to give higher yields for less substituted dipyrrins. Thus, using this tertiary C) amine base, in lieu of triethylamine, together with BF3-OEtz gave Br-Ar-mono-Br in 38% yield over three steps. Bromination was necessary in this case because the corresponding chlorinated derivative of an a-amino-BODIPY showed no oligomerization beyond the dimer under the same conditions. Additionally, purification was not an obstacle, in contrast to the aforementioned brominated acylpyrroles. Preparative details of the chlorinated amino-BODIPY are given in the Supporting Information. The respective d-amino-BODIPYS were then synthesized by stirring halogenated BODIPYS in an ammonia solution in MeOH (7 N) in a sealed tube at 60 oC to furnish the target compounds in up to 58% yieldf for chlorinated derivatives and even in quantitative yield for the brominated example (Scheme 1B). For Buchwald- Hartwig coupling of a-chloro- and a-amino-BODIPYS, one equivalent of D) each was converted with Pd(OAc)2, (+)-BINAP and Cs2CO3 in PhMe at 80 C.1141 Interestingly, the reaction times and yields showed a trend of improvement with increasing level of substitution of the BODIPY core with up to 68% yields. While these dimer syntheses were straightforward by simply stirring all of the components together, synthesis of Br-Ar-di required slow addition of Br-Ar-mono-NH2 to a heated solution of the remaining starting material was recovered. As for the dimers synthesized via manner with the respective bromides (Br-Ar-di for EDM- B) ) reagents. Such a procedure ensured selectivity by maintaining an Figure 2. Molecular structures of DM-Me-di A) front view, B) top view andl EDM- excess of Br-Ar-mono-Br to avoid further oligomerization. The tri C) front view and D) top view. Hydrogen atoms were omitted for clarity. the chlorides, synthesis of trimers and tetramers was achieved in The photophysical behavior of the dimers shows a strong tet), with a remarkable decrease of the reaction time. Throughout respective monomers (from AA max = 510 nm to 659 nm for the the reaction of Br-Ar-mono-Br with EDM-Ar-mono-Bir, formation EDM examples) and also significantly increased attenuation of the respective intermediate dimer was observed within coefficients 6 (Figure 3). An excerpt of the respective data is given 30 minutes, while full conversion took an additional 60 minutes. below (Table 1). The presence of a second absorption region at It was possible to obtain crystals from the dimers and from approximately 500 nm (S2 state) indicates a Davydov splitting as EDM-tri. For all dimers, the BODIPY cores are mutually slightly a result of an excitonic coupling process. The unusual double- twisted (-12°, see Figure 2B). The small twist angle, however, peak shape may suggest some conformational instabilities. In this implies a certain amount of conjugation through the central context, the absorption profile is expanded to three absorption nitrogen atom. In contrast, EDM-tri shows a stronger deviation events at the trimer, corresponding to three excitonic states from planarity, which is probably attributable to steric hindrance, excited at 752 nm (S1), 562 nm (S2), and 470 nm (S3), reaction yielded 44% of the functionalized dimer, while 45% of the Ellipsoids correspond to 50% probability levels. bathochromic shift of the main same band absorption compared to the respectively. Notably, the S2 state exhibits the highest oscillator 3 VSeSN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0
strength, attributed to the significant geometrical deviation from Table 1. Absorption and emission data of EDM- -BODIPYS.al linearity, gradually leading to a helical superstructure for higher homologs (Figure 4). This trend is accentuated for the tetramers, where the absorption signature becomes intricate. However, the intensified coiling in this case, where the terminal BODIPY units start overlapping and thus forming a looped superstructure, results in an exceptionally weak Si+-So excitation at 820 nm. The remaining states of the exciton manifold are hardly assignable because of the amount and overlap of absorption bands, yet they mono-NH2 are responsible for the absorptions at 633 nm and 521 nm. The simulated through TDDFT computations and accurately mirrors the experimentally observed absorption band intensities for all oligomer species (Figure 4). The emission strength decreases gradually along the oligomeric series. While the monomers exhibit fluorescence quantum yields @F of up to 0.53 in CH2Cl2, these tetramers, emission is hardly detectable (CPF << 0.01). Compound AAmax AFmax 4PIcm-1 s[103 M- @ [nm] [nm] 510 534 881 525 539 495 659 cm-"'l 121 59 EDM-Ar- mono-CI EDM-Ar- 0.04 0.01 oscillator strength distribution of the exciton manifold was EDM-Ar-di 482, 510, 671 271 47,40, 134 0.01 EDM-tri 562, 757 778 357lb) EDM-tet 521,633 n.d.Icl 97, 76 111,114 0.01 values decrease to QF < 0.01 for the dimer and trimer. For the [a] Absorption and emission spectra were recorded in solutions of CH2Cl2 at room temperature. [b] AAmax is not responsible for AFmax. Stokes shift 40 was calcd. using the respective 2Amax2. [c] Not detecteddetermined. Further spectroscopic data is given in the Supporting Information. The frontier orbitals of the oligomeric series integrate the lobe patterns found for the monomeric building blocks. All BODIPY units are characterized by an electron-depleted meso position at the HOMO and also by the cyanine-like relocalization of electron density to this position during excitation (Figure 4). Cyclic voltammograms of amine-linked oligomers and the respective monomers for the EDM-series are shown below (Figure 5). In general, the larger the molecules, the easier the oxidation; however, most of them are oxidized irreversibly. The monomeric primary amine and the trimer show irreversible oxidation, unlike the respective chloride and the dimer. However, the chlorinated monomer has only one reversible reduction potential at -1.28 V, whereas the dimer shows two reduction 150 - Absorption EDM EDM- -Ar -Ar -mono-NH, mono-cI EDMr EDM Ar-di EDM- tet 100 50 Emissien EDM EDM- -Ar-mono-NH, Ar mono-CI EDM-Ar-di EDM-tri 450 500 550 600 650 700 750 800 850 Wavelength. AInm] Figure 3. Absorption and emission spectra of EDM- BODIPYS. Absorption and potentials, at -1.25 V and at -1.64 V. emission spectra were recorded in solutions of CH2Cl2 at room temperature. Dimer & HOMO (-6.07 ev) & CDD S1 Trimer Tetramer LUMO (-2.04e evy HOMO (5.85€ ev) LUMO (2.15ev] HOMO (-5.71ev) LUMO (2.20ev] CDD S2 S1: 2.20eV(516nm) /f=1.11 S2: 3.046 ev (407 nm)/f=0.54 CDD_S2 (S1: 2154V57mm/F-02 CDD_ S3 CDD S2 S1:1 1.94eV/(641 inmy/f-0.080 CDD_ S2:2.75ev (451nm)/f=1.45 $3:3.07e ev (403nm)/f-0.34 S2: 2.45eV (508nm)/t-1.12 S3: 2.89eV (430nm)/f-1.55 Figure 4. Frontier orbitals and minimum energy structures of oligomeric series. Geometrical optimizations at the DFT level M052X-D3De2TZVP) in vacuo. Oscillator strengths (fvalues) obtained from corresponding TDDFT computations (0B97XD/De121ZVP)- The input structures were truncated at the meso phenyl residues (iso-butyl groups). 4 yuSASN ORCID: panym.pNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4.0
Thei trimer shows almost irreversible oxidation potentials at 0.69 V Acknowledgements and 1.33 V and also reduction at -1.69 V. EDM-tet, however, shows several oxidation and reduction potentials within the range We thank the Deutsche Forschungsgemeinschat (DFG, German of t 2.00 V, which are mostly irreversible (Figure 5). Attempts to Research Foundation, WE2932/14-1) and livMats Cluster of oxidize the obtained oligomers did not provide quinodiimine Excellence under Germany's Excellence Strategy (EXC-2193/1- analogs as for the cyclic derivates.8) 390951807) for funding. S.H.R. thanks Adrian Bauschke and Susanne Klein (both TU Braunschweig) for their support and Boumahdi Benkmil (University of Freiburg) for X-ray diffraction analysis as well as Dr. Ulrich Papke (TU Braunschweig) for the HRMS measurements and discussions thereof. Keywords: BODIPY . dyes amines . oligomers Buchwald- 1] A. Treibs, F.-H. Kreuzer, Justus Liebigs Ann. Chem. 1968, 718, 208. EDM-Ar-di [2] a) A. Loudet, K. 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Pedrosa, L. C. Da Luz, E. S. Moraes, F. S. Rodembusch, J. S. F. Guimarâes, A. G. Oliveira, S. H. Rôttger, D. B. Werz, C. P. Souza, F. Fantuzzi, J. Han, T. B. Marder, H. Braunschweig, E.N. Da Silva Junior, Chem. Eur. J.: 2023, e202303883;h) L.J. Patalag, S. Ahadi, O. Lashchuk, P. G. Jones, S. Ebbinghaus, D. B. Werz, Angew. Chem. Int. Ed. 2021, 60, 8766-8771. [4] a)Y. Hayashi, S. Yamaguchi, W. Y. Cha, D. Kim, H. Shinokubo, Org. Lett. 2011, 13, 2992-2995; b)T. Sakida, S. Yamaguchi, H. Shinokubo, Angew. Chem. Int. Ed. 2011,50, 2280-2283; c)J. Ahrens, B. Cordes, R. Wicht,B B. Wolfram, M. Brôring, Chem. Eur. J. 2016, 22, 10320-10325; d) Q. Wu, Z. Kang, Q. Gong, X. Guo, H. Wang, D. Wang, L. Jiao, E. Hao, Org. Lett. 2020, 22, 7513-7517; e) W. Wu, H. Guo, W. Wu, S.Ji, J. Zhao, J. Org. Chem. 2011, 76, 7056-7064; f) J. Ahrens, B. Haberlag, A. Scheja, M. Tamm, M. Broring, Chem. Eur. J. 2014, 20, 2901-2912; g) L. J. Patalag, L.P. Ho, P. G.Jones, D. B. Werz, J. Am. Chem. 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Lett. 2021, 23, 7661-7665; i) H. F.vonk Kôller, F.J. Geffers, P. Kalvani,A. Foraita, P.-E.J. LoB,B. Butschke, P.G. Jones, D.B. Werz, Chem. Comm. 2023, 59, 14697-14700: C.Yu, Y. Sun,Q. Wu, Y. Shi, L.Jiao,J. Wang, X. Guo, J. Li, J. Li, E. Hao, J. Org. [6] H. Yokoi, S. Hiroto, H. Shinokubo, Org. Lett. 2014, 16, 3004-3007. -3 -2 -1 0 1 2 3 EDM-tet EDM-tri Hartwig coupling EDM-Ar- mono- NH, EDM-Ar- mono-CI 1 2 3 -3 -2 -1 Potential [VI vs. SCE 5. Ed.: 2022, 61, e2021168. D. T. Sysak, Figure Cyclic voltammograms. Cyclic voltammetry (IUPAC convention) was measured of 4 mM solutions in CH2Cl2 with TBAPF6 (0.4 M) in reference to a saturated calomel electrode (SCE) with a scan rate of 200 mV/s (clockwise, starting from 0 V) in steps of 1 mV at room temperature. Conclusion Ins summary, we have successfully developed a method to access linearly amine-linked BODIPYS using Buchwald-Hartwig conditions. Terminal Br substituents allowed elongation of the chain by two further BODIPY subunits. X-ray structure analyses revealed conjugation of the various subunits via the linking nitrogen atom. Absorption spectra show significantly increased attenuation coefficients for the oligomers in comparison to the respective monomers, and also strong bathochromic shifts. DFT calculations provided an insight into the electronic properties and showed a decreasing HOMO/LUMO gap as well as increasing oscillator strengths (fvalues) of the excited states with increasing level of oligomerization. The computed orbital energies are also closely consistent with cyclovoltammetric investigations, demonstrating a more facile oxidation and reduction with 22, 7694-7698. increasing chain length. Supporting Information The Supporting Information Tang, is available free of charge and contains detailed experimental procedures, analytical, X-ray crystallographic and absorption and emission data, and 'H, 13C, 19F and 11B NMR spectra of all new compounds. Chem. 2023, 88, 14368-14376. 5 yuSASN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0
[71 Q. Gong, Q. Wu, X. Guo, W.Li, L. Wang, E. Hao, L. Jiao, Org. Lett. 2021, [8] Y. Rao, L. Xu, M. Zhou, B. Yin, A. Osuka, J. Song, Angew. Chem. Int. Ed. [9] V. Leen, E. Braeken, K. Luckermans, C.. Jackers, M. van der Auweraer, N. Boens, W. Dehaen, Chem. Comm. 2009, 4515-4517. [10] Z. Guo, X. Wei, Y. Hua, J. Chao, D. Liu, Tetrahedron Lett. 2015, 56, 3919- [11] Y.-Z.Ke, R.-J.Ji,T.-C. Wei, S.-L. Lee, S.-L. Huang, M.-J. Huang, C. Chen, T.-Y. Luh, Macromolecules: 2013, 46, 6712-6722. [12] G. Duran-Sampedro, A. R. Agarrabeitia, I. Garcia- Moreno, A. Costela, J. Banuelos, T. Arbeloa, I. L6pez Arbeloa, J. L. Chiara, M. J. Ortiz, Eur. J. Org. Chem. 2012, 2012, 6335-6350. [13] B.J. Littler, M. A. Miller, C.-H. Hung, R. W. Wagner, D.F. O'Shea, P. D. Boyle, J.S S. Lindsey, J. Org. Chem. 1999, 64, 1391-1396. [14] J. Yang, Z. Du, CN106565762A, 2017. 23, 7220-7225. 2022, 134, e202206899. 3922. 6 yuSASN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0
As a next step, we could then remove the parts that we don’t need. In this case, a good approximation might be to remove everything up to the introduction and everything following the introductions.
Regex
Regular expressions (regex) are a powerful tool for pattern matching, allowing for complex searches, substitutions, and data extraction based on specific string patterns. For instance the first regular expression r'\[MISSING_PAGE_FAIL:\d+\] is used to remove any text matching the pattern [MISSING_PAGE_FAIL: followed by one or more digits and a closing bracket.
This page provides a good overview in the context of text-data cleaning.
import re
# Define the pattern to match the text between the introduction and acknowledgments sections
match_text_between_introduction_and_acknowledgment_sections = re.compile(
r"Introduction.*?Acknowledgements", re.DOTALL
)
# Extract the text between the introduction and acknowledgments sections
filtered_text = re.findall(
match_text_between_introduction_and_acknowledgment_sections, content
)[0].replace("Acknowledgements", "")
filtered_text
'Introduction\n\nhalide.\n\nrespective\n\nNot only does the selective\n\n- - - EN\n\ncooe\n\nThe family of BODIPY dyes, first reported in 1968 by Treibs and\nKreuzer,"l has gained major interest in research in the past\ndecades because of their fairly simple preparative access, their\nflexibility in terms of possible modifications and their useful\nproperties such as outstanding attenuation coefficients and also\nhigh fluorescence quantum yields.2) Hence, they are already\nwidely applied for imaging, e.g. as biomarkers for medical\npurposes, and have also proven to be applicable in other fields,\nfor instance as various types of photosensitizers and organic light-\nemitting diodes (OLEDs).3) Various types of oligo-BODIPYS have\nalready shown the capability to enhance such desirable\nproperties and thus have been the focus of much recent\npreparative chemistry. Alkylene bridged or directly connected\n\nBThiswork\n\nsymmetric & unsymmetric dimers\nand\nfunctionalized examples\n\nBODIPYS have been known for several years (Figure 1A (top).141 Figure 1. A) Various C-C bridged (top) and heteroatom bridged (bottom)\n\nBODIPY oligomers. B) Linearly amine-linked BODIPY oligomers (this work).\nResidual substituents of the BODIPY core were omitted for clarity.\n\n1\n\nyuSASN cyTAN Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4.0\n\n\n\nThese types of connectivity have also been converted to extended ANomenclature\nm-systems by oxidative follow-up reactions, allowing a higher level\nof conjugation and hence strong bathochromic shifts.5) The\ninstallation of heteroatoms has however been a challenge for\nsome time. In 2014, Shinokubo et al. presented linearly connect a: Pyrrole substitution pattern\nmonomers through an azo-bridge at the B-position (Figure 1A Br:\n(d).61 Linear connectivity at the a-position using heteroatoms DM (24-Dimethy-yrole): R\'= R3= Me,R2= H Ar 4-BuPh:\nsuch as sulfur has been achieved through a similarly iterative EDM GEny*24-dimelhypymol; R\' R3 Me, R2=E Et\nprocess by the groups of Hao and Jiao (Figure 1A (e).7\nFurthermore, cyclic amine-linked oligo-BODIPYS have already tri: Trimer tet: Tetramer\nbeen synthesized in a one-pot reaction in 2022 by Song et al., DPecurorsynlaess\nutilizing Buchwald-Hartwig conditions (Figure 1A (0).181\nWe present a novel type of BODIPY oligomers, connected\nvia N-bridges in a linear fashion (Figure 1B). Utilizing both\nsymmetric and unsymmetric BODIPY monomers as building\nblocks has paved the way to selectively synthesize oligomers with\nvarious chain lengths. Both symmetric and unsymmetric dimers\nwere synthesized starting from unsymmetric mondfunctionalized\nmonomer units. Additionally, the chain length of these oligo-\nBODIPYS was extended using the functionalized monomer Br-Ar-\n\nR3\nR2\n31\nF\na-b-c-d\n\nb(monomers & dimers):\nd (monomers only):\nSubstituent x\n\nR Br, R2 R3= H meso-substitution (R")\n\nT\n\nc: Grade of oligomerization\nmono: Monomer di; Dimer\n\n1)n-BuLi, 2,6-dimethyl-\naniline, benzaldehyde 4-iso-butyl\nEt0,rt,5h\nHN. 2)imidazole, TBSCI\nCH2Clz. r, 1h\nTFA, 4-iso-butyl-\nbenzaldehyde CH2Cl.rt,24h\n\nH IN\n7: 68%\n1)NBS, THF, -78 "C, 1h\n2)DDQ, .-78 C thenr rt, 1h\n3)PfNEt, BFxOEL2\nCH2Cl. rt, 30min\n\no\nNCS o\nHN. THF, rt,3-7d HN\n2: 529/R"- Ar)\n1) M\nR2\nMe\n5; R2=H H\n6: R2=Et, POCI3\nCH,Clyln-hexane (2:1)\n0°Ct thenrt, 16h\n2)NEls. BF,-OEl2\n0°Ct then rt, 1h\nMe\nR2.\nMe\nDM-Me-mono-Ct 49%\nDM-Ar-mono-CH EDM-Ar-mono-CH: 83% 91%\nPd(OAc),\n(E)-BINAP Cs,CO3\nPhMe, 80 "C,3-22h\n\n3:559( (R" Me)\n4: 56%(R" Ar)\n\nmono-Br and the dimer Br-Ar-di\nResults and Discussion\n\n(Scheme 1).\n\nIn contrast to the aforementioned cyclic amine-linked examples, [8]\nwe have focused on selectively synthesizing open-chained\noligomers and addressing their specific properties. Variation of\nthe BODIPY core has been shown to have a considerable impact\non the respective reaction times and yields. To dimerize Br-Ar-mono-Br\nselectively when forming the nitrogen bridge, monofunctionalized\na-chlorinated BODIPY monomers were used. The key step in\nobtaining such unsymmetric BODIPYS (in contrast to the usual\nmirror plane through the meso position and boron center) was a\nBischler-Napieralski type reaction of the respective chlorinated\nacylpyrrole and alkylpyrrole, following an established procedure\ndeveloped by Dehaen and coworkers.9 Converting the a-chloro- C)Oligomerization\nBODIPY into the respective amine and performing a Buchwald-\nHartwig coupling of both led to N-bridged BODIPY dimers, in\nwhich alkylpyrroles such as 2,4-dimethylpyrrole (5) and\ncryptopyrrole (6) serve as capping units on the BODIPY core.\nTerminal a-brominated examples provide an option for further\nversatile functionalization. During the investigation of meso\nsubstitution patterns, the 4-iso-buty/phenyl moiety has been\nshown to overcome solubility issues, while maintaining\ncrystallizability (albeit sometimes with disorder problems),\nwhereas dimer syntheses are made easier by an increasing level\nof alkyl-substitution on the pyrrole motif. For a simplified overview\nof the BODIPY scope, compounds are labeled according to the\nsystematic nomenclature shown in Scheme 1A.\nThe synthetic strategy began with pyrrole (1) for both kinds\nof monomers. To obtain monochlorinated BODIPYs, it was first\nconverted into the respective 2-benzoylpyrrole 2 for the meso aryl\nexamples.10 TBS protection of the benzyl alcohol by- product in\nthe crude simplified the purification later on.1) This species and\n2-acetylpyrrole were then chlorinated using NCS in THF at room\ntemperature to obtain a-chlorinated 2- -acylpyrroles 3 and 4.!12]\n\nNH3(7 N in! MeOH)\n60-C, 30r min- 7 d\nR3 R"\nR2. N\nR\' F B F NH2\nDM-Me-mono-NH, 47%\nDM-Ar-mono-NH, EDM-Ar-mono-NH, 58% 58%\nBr-Ar-mono-NH, quant.\nEDM-Ar-\nmono-NH2 or\nBr-Ar-\nmono-NHz\nPd(OAc),\n(H)-BINAP\nPhMe, Cs,COs 80 *C,1-5h\n\n38%\n\nR"\nR3\nB. F\nR\nR1\nDM-MelAr-di DM-Me-di: 30% 25%\nBr-Ar- DM-Ar-di: EDM-Ar-di: 40% 68%\nmono- Br\n-Br-Ar-di: 44%\nF-B\nAr\nF\nR3\nR\'\nEDM-tri: Br-tri: 82% 5%\nNH\n d 0\nAr\n8\nI E e\nR3\nAminated dilutedi in BODIPYS CH2Clz\n- -\n\nR\n\nAr.\n\nAr\nHN\n\nBr-tet: EDM-tet: 1.4% 55%\n\nScheme 1. A) Nomenclature for BODIPYS. B) Synthetic route towards\nmonomers. C) Oligomerization to dimers, trimers and tetramers.\n\n2\n\nyuSASN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0\n\n\n\nWe preferred chlorination over the analogous bromination since thus causing one of the peripheral cores to be tilted by as much\nthe by-products were easier to separate from the desired as 29° with regard to the plane of the residual two units. Moreover,\nproducts. To arrive finally at the monofunctionalized BODIPY one molecule of CH2Cl2 is adjacent to the cavity, indicating\nmonomers, acylpyrroles 3 and 4 were then converted with the hydrogen bonding to the BF2 units. Furthermore, the C-N-C bond\nrespective alkylpyrroles 5 and 6 in the presence of POCI3 in angles of the N-bridges range between 123° and 127°, showing\nCHaCln-hexane (2:1), followed by the established procedure for deviation from the theoretical value of 120° for sp?-hybridized\nBODIPY syntheses from the in situ formed dipyrrin using nitrogen. Within the resulting cavity, the minimum distance\ntriethylamine and BF3*OEt2, with yields up to 91% over 2 steps. between fluorine and the bridging nitrogen atom amounts to 2.9 A\nTo obtain higher oligomers, bisfunctionalized monomers had to and 3.4 A for the opposing BF2 units for the dimer. The trimer in\nbe synthesized prior to amination. For symmetrically comparison shows larger distances of the two closest fluorine\nbisfunctionalized monomer Br-Ar-mono-Br, an excess of pyrrole atoms of two different BF2 groups (3.9 A) and as much as 5.2À\n(1) was converted into dipyrromethane 7 using 4-iso- for the two peripheral BODIPY units (Figure 2C). For more details\n\nbutylbenzaldhyde with catalytic amounts of TFA in CH2Cl2 in 68% see the Supporting Information.\n\nyield.13) Stepwise addition of NBS in small portions to a solution\nof 7 in THF at -78 C for selective bromination, followed by A)\noxidation with DDQ, gave the crude dipyrrin, which was used in\nthe following step after filtration. The actual BODIPY synthesis\nwas subsequently conducted in a similar manner as for the\nunsymmetric monomers. However, Pr2NEt was found to give\nhigher yields for less substituted dipyrrins. Thus, using this tertiary C)\namine base, in lieu of triethylamine, together with BF3-OEtz gave\nBr-Ar-mono-Br in 38% yield over three steps. Bromination was\nnecessary in this case because the corresponding chlorinated\nderivative of an a-amino-BODIPY showed no oligomerization\nbeyond the dimer under the same conditions. Additionally,\npurification was not an obstacle, in contrast to the aforementioned\nbrominated acylpyrroles. Preparative details of the chlorinated\namino-BODIPY are given in the Supporting Information. The\nrespective d-amino-BODIPYS were then synthesized by stirring\nhalogenated BODIPYS in an ammonia solution in MeOH (7 N) in\na sealed tube at 60 oC to furnish the target compounds in up to\n58% yieldf for chlorinated derivatives and even in quantitative yield\nfor the brominated example (Scheme 1B). For Buchwald- Hartwig\ncoupling of a-chloro- and a-amino-BODIPYS, one equivalent of D)\neach was converted with Pd(OAc)2, (+)-BINAP and Cs2CO3 in\nPhMe at 80 C.1141 Interestingly, the reaction times and yields\nshowed a trend of improvement with increasing level of\nsubstitution of the BODIPY core with up to 68% yields. While\nthese dimer syntheses were straightforward by simply stirring all\nof the components together, synthesis of Br-Ar-di required slow\naddition of Br-Ar-mono-NH2 to a heated solution of the remaining\nstarting material was recovered. As for the dimers synthesized via\nmanner with the respective bromides (Br-Ar-di for EDM-\n\nB)\n\n)\n\nreagents. Such a procedure ensured selectivity by maintaining an Figure 2. Molecular structures of DM-Me-di A) front view, B) top view andl EDM-\nexcess of Br-Ar-mono-Br to avoid further oligomerization. The tri C) front view and D) top view. Hydrogen atoms were omitted for clarity.\nthe chlorides, synthesis of trimers and tetramers was achieved in The photophysical behavior of the dimers shows a strong\ntet), with a remarkable decrease of the reaction time. Throughout respective monomers (from AA max = 510 nm to 659 nm for the\nthe reaction of Br-Ar-mono-Br with EDM-Ar-mono-Bir, formation EDM examples) and also significantly increased attenuation\nof the respective intermediate dimer was observed within coefficients 6 (Figure 3). An excerpt of the respective data is given\n30 minutes, while full conversion took an additional 60 minutes. below (Table 1). The presence of a second absorption region at\nIt was possible to obtain crystals from the dimers and from approximately 500 nm (S2 state) indicates a Davydov splitting as\nEDM-tri. For all dimers, the BODIPY cores are mutually slightly a result of an excitonic coupling process. The unusual double-\ntwisted (-12°, see Figure 2B). The small twist angle, however, peak shape may suggest some conformational instabilities. In this\nimplies a certain amount of conjugation through the central context, the absorption profile is expanded to three absorption\nnitrogen atom. In contrast, EDM-tri shows a stronger deviation events at the trimer, corresponding to three excitonic states\nfrom planarity, which is probably attributable to steric hindrance, excited at 752 nm (S1), 562 nm (S2), and 470 nm (S3),\n\nreaction yielded 44% of the functionalized dimer, while 45% of the Ellipsoids correspond to 50% probability levels.\n\nbathochromic shift of the main\n\nsame\n\nband\nabsorption\n\ncompared to the\n\nrespectively. Notably, the S2 state exhibits the highest oscillator\n\n3\n\nVSeSN ORCID: parpmpNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4 4.0\n\n\n\nstrength, attributed to the significant geometrical deviation from Table 1. Absorption and emission data of EDM- -BODIPYS.al\n\nlinearity, gradually leading to a helical superstructure for higher\nhomologs (Figure 4). This trend is accentuated for the tetramers,\nwhere the absorption signature becomes intricate. However, the\nintensified coiling in this case, where the terminal BODIPY units\nstart overlapping and thus forming a looped superstructure,\nresults in an exceptionally weak Si+-So excitation at 820 nm. The\nremaining states of the exciton manifold are hardly assignable\nbecause of the amount and overlap of absorption bands, yet they mono-NH2\nare responsible for the absorptions at 633 nm and 521 nm. The\nsimulated through TDDFT computations and accurately mirrors\nthe experimentally observed absorption band intensities for all\noligomer species (Figure 4). The emission strength decreases\ngradually along the oligomeric series. While the monomers exhibit\nfluorescence quantum yields @F of up to 0.53 in CH2Cl2, these\ntetramers, emission is hardly detectable (CPF << 0.01).\n\nCompound AAmax AFmax 4PIcm-1 s[103 M- @\n\n[nm] [nm]\n510\n534\n881\n525\n539\n495\n659\n\ncm-"\'l\n121\n59\n\nEDM-Ar-\nmono-CI\nEDM-Ar-\n\n0.04\n0.01\n\noscillator strength distribution of the exciton manifold was EDM-Ar-di 482, 510, 671\n\n271 47,40, 134 0.01\n\nEDM-tri 562, 757 778 357lb)\nEDM-tet 521,633 n.d.Icl\n\n97, 76\n111,114\n\n0.01\n\nvalues decrease to QF < 0.01 for the dimer and trimer. For the [a] Absorption and emission spectra were recorded in solutions of CH2Cl2 at\n\nroom temperature. [b] AAmax is not responsible for AFmax. Stokes shift 40 was\ncalcd. using the respective 2Amax2. [c] Not detecteddetermined. Further\nspectroscopic data is given in the Supporting Information.\nThe frontier orbitals of the oligomeric series integrate the lobe\npatterns found for the monomeric building blocks. All BODIPY\nunits are characterized by an electron-depleted meso position at\nthe HOMO and also by the cyanine-like relocalization of electron\ndensity to this position during excitation (Figure 4).\nCyclic voltammograms of amine-linked oligomers and the\nrespective monomers for the EDM-series are shown below\n(Figure 5). In general, the larger the molecules, the easier the\noxidation; however, most of them are oxidized irreversibly. The\nmonomeric primary amine and the trimer show irreversible\noxidation, unlike the respective chloride and the dimer. However,\nthe chlorinated monomer has only one reversible reduction\npotential at -1.28 V, whereas the dimer shows two reduction\n\n150 - Absorption\nEDM EDM- -Ar -Ar -mono-NH, mono-cI\nEDMr EDM Ar-di\nEDM- tet\n100\n50\n\nEmissien\nEDM EDM- -Ar-mono-NH, Ar mono-CI\nEDM-Ar-di EDM-tri\n\n450 500 550 600 650 700 750 800 850\n\nWavelength. AInm]\n\nFigure 3. Absorption and emission spectra of EDM- BODIPYS. Absorption and potentials, at -1.25 V and at -1.64 V.\n\nemission spectra were recorded in solutions of CH2Cl2 at room temperature.\n\nDimer\n&\nHOMO (-6.07 ev)\n&\nCDD S1\n\nTrimer\n\nTetramer\n\nLUMO (-2.04e evy\n\nHOMO (5.85€ ev)\n\nLUMO\n(2.15ev]\n\nHOMO (-5.71ev)\n\nLUMO (2.20ev]\n\nCDD S2\n\nS1: 2.20eV(516nm) /f=1.11 S2: 3.046 ev (407 nm)/f=0.54\n\nCDD_S2\n(S1: 2154V57mm/F-02\n\nCDD_ S3\n\nCDD S2\nS1:1 1.94eV/(641 inmy/f-0.080\n\nCDD_\n\nS2:2.75ev (451nm)/f=1.45 $3:3.07e ev (403nm)/f-0.34 S2: 2.45eV (508nm)/t-1.12 S3: 2.89eV (430nm)/f-1.55\n\nFigure 4. Frontier orbitals and minimum energy structures of oligomeric series. Geometrical optimizations at the DFT level M052X-D3De2TZVP) in vacuo.\nOscillator strengths (fvalues) obtained from corresponding TDDFT computations (0B97XD/De121ZVP)- The input structures were truncated at the meso phenyl\n\nresidues (iso-butyl groups).\n\n4\n\nyuSASN ORCID: panym.pNnaR Content notp peer-reviewed by ChemRxiv. License: CCE BY-NC4.0\n\n\n\nThei trimer shows almost irreversible oxidation potentials at 0.69 V '
This now looks already much better as it no longer has the extraneous linebreaks and we also removed a lot of the extraneous text.
2.2.2. Cleaning text using LLMs#
Yet, we still see that there are artifacts where the text has misplaced words or characters. However, those are difficult to remove using hard-coded rules. As alternative, or additional step, one can use LLMs to remove remaining problems.
from litellm import OpenAI
client = OpenAI()
completion = client.chat.completions.create(
model="gpt-4o",
messages=[
{
"role": "user",
"content": "We extracted the following text using OCR from a PDF. Clean up the text, i.e. remove extraneous characters, fix other issues such as words that do not fit in or remove characters that obviously are not part of the text. Return only the cleaned text.",
},
{"role": "user", "content": filtered_text},
],
temperature=0,
)
print(completion.choices[0].message.content)
Introduction
The family of BODIPY dyes, first reported in 1968 by Treibs and Kreuzer, has gained major interest in research in the past decades because of their fairly simple preparative access, their flexibility in terms of possible modifications, and their useful properties such as outstanding attenuation coefficients and high fluorescence quantum yields. Hence, they are already widely applied for imaging, e.g., as biomarkers for medical purposes, and have also proven to be applicable in other fields, for instance, as various types of photosensitizers and organic light-emitting diodes (OLEDs). Various types of oligo-BODIPYs have already shown the capability to enhance such desirable properties and thus have been the focus of much recent preparative chemistry. Alkylene-bridged or directly connected symmetric and unsymmetric dimers and functionalized examples of BODIPYs have been known for several years (Figure 1A, top).
Figure 1. A) Various C-C bridged (top) and heteroatom bridged (bottom) BODIPY oligomers. B) Linearly amine-linked BODIPY oligomers (this work). Residual substituents of the BODIPY core were omitted for clarity.
These types of connectivity have also been converted to extended π-systems by oxidative follow-up reactions, allowing a higher level of conjugation and hence strong bathochromic shifts. The installation of heteroatoms has, however, been a challenge for some time. In 2014, Shinokubo et al. presented linearly connected monomers through an azo-bridge at the β-position (Figure 1A, d). Linear connectivity at the α-position using heteroatoms such as sulfur has been achieved through a similarly iterative process by the groups of Hao and Jiao (Figure 1A, e). Furthermore, cyclic amine-linked oligo-BODIPYs have already been synthesized in a one-pot reaction in 2022 by Song et al., utilizing Buchwald-Hartwig conditions (Figure 1A, f).
We present a novel type of BODIPY oligomers, connected via N-bridges in a linear fashion (Figure 1B). Utilizing both symmetric and unsymmetric BODIPY monomers as building blocks has paved the way to selectively synthesize oligomers with various chain lengths. Both symmetric and unsymmetric dimers were synthesized starting from unsymmetric monofunctionalized monomer units. Additionally, the chain length of these oligo-BODIPYs was extended using the functionalized monomer Br-Ar-mono-Br and the dimer Br-Ar-di (Scheme 1).
Results and Discussion
In contrast to the aforementioned cyclic amine-linked examples, we have focused on selectively synthesizing open-chained oligomers and addressing their specific properties. Variation of the BODIPY core has been shown to have a considerable impact on the respective reaction times and yields. To dimerize Br-Ar-mono-Br selectively when forming the nitrogen bridge, monofunctionalized α-chlorinated BODIPY monomers were used. The key step in obtaining such unsymmetric BODIPYs (in contrast to the usual mirror plane through the meso position and boron center) was a Bischler-Napieralski type reaction of the respective chlorinated acylpyrrole and alkylpyrrole, following an established procedure developed by Dehaen and coworkers. Converting the α-chloro-BODIPY into the respective amine and performing a Buchwald-Hartwig coupling of both led to N-bridged BODIPY dimers, in which alkylpyrroles such as 2,4-dimethylpyrrole (5) and cryptopyrrole (6) serve as capping units on the BODIPY core. Terminal α-brominated examples provide an option for further versatile functionalization. During the investigation of meso substitution patterns, the 4-iso-butylphenyl moiety has been shown to overcome solubility issues while maintaining crystallizability (albeit sometimes with disorder problems), whereas dimer syntheses are made easier by an increasing level of alkyl-substitution on the pyrrole motif. For a simplified overview of the BODIPY scope, compounds are labeled according to the systematic nomenclature shown in Scheme 1A.
The synthetic strategy began with pyrrole (1) for both kinds of monomers. To obtain monochlorinated BODIPYs, it was first converted into the respective 2-benzoylpyrrole 2 for the meso aryl examples. TBS protection of the benzyl alcohol by-product in the crude simplified the purification later on. This species and 2-acetylpyrrole were then chlorinated using NCS in THF at room temperature to obtain α-chlorinated 2-acylpyrroles 3 and 4.
Scheme 1. A) Nomenclature for BODIPYs. B) Synthetic route towards monomers. C) Oligomerization to dimers, trimers, and tetramers.
We preferred chlorination over the analogous bromination since the by-products were easier to separate from the desired products. To arrive finally at the monofunctionalized BODIPY monomers, acylpyrroles 3 and 4 were then converted with the respective alkylpyrroles 5 and 6 in the presence of POCl3 in CH2Cl2-hexane (2:1), followed by the established procedure for BODIPY syntheses from the in situ formed dipyrrin using triethylamine and BF3·OEt2, with yields up to 91% over 2 steps. To obtain higher oligomers, bisfunctionalized monomers had to be synthesized prior to amination. For symmetrically bisfunctionalized monomer Br-Ar-mono-Br, an excess of pyrrole (1) was converted into dipyrromethane 7 using 4-iso-butylbenzaldehyde with catalytic amounts of TFA in CH2Cl2 in 68% yield. Stepwise addition of NBS in small portions to a solution of 7 in THF at -78 °C for selective bromination, followed by oxidation with DDQ, gave the crude dipyrrin, which was used in the following step after filtration. The actual BODIPY synthesis was subsequently conducted in a similar manner as for the unsymmetric monomers. However, iPr2NEt was found to give higher yields for less substituted dipyrrins. Thus, using this tertiary amine base, in lieu of triethylamine, together with BF3·OEt2 gave Br-Ar-mono-Br in 38% yield over three steps. Bromination was necessary in this case because the corresponding chlorinated derivative of an α-amino-BODIPY showed no oligomerization beyond the dimer under the same conditions. Additionally, purification was not an obstacle, in contrast to the aforementioned brominated acylpyrroles. Preparative details of the chlorinated amino-BODIPY are given in the Supporting Information. The respective α-amino-BODIPYs were then synthesized by stirring halogenated BODIPYs in an ammonia solution in MeOH (7 N) in a sealed tube at 60 °C to furnish the target compounds in up to 58% yield for chlorinated derivatives and even in quantitative yield for the brominated example (Scheme 1B). For Buchwald-Hartwig coupling of α-chloro- and α-amino-BODIPYs, one equivalent of each was converted with Pd(OAc)2, (+)-BINAP, and Cs2CO3 in PhMe at 80 °C. Interestingly, the reaction times and yields showed a trend of improvement with increasing level of substitution of the BODIPY core with up to 68% yields. While these dimer syntheses were straightforward by simply stirring all of the components together, synthesis of Br-Ar-di required slow addition of Br-Ar-mono-NH2 to a heated solution of the remaining reagents. Such a procedure ensured selectivity by maintaining an excess of Br-Ar-mono-Br to avoid further oligomerization. The reaction of Br-Ar-mono-Br with EDM-Ar-mono-Br yielded 44% of the functionalized dimer, while 45% of the starting material was recovered. As for the dimers synthesized via the chlorides, synthesis of trimers and tetramers was achieved in the same manner with the respective bromides (Br-Ar-di for EDM-tet), with a remarkable decrease in the reaction time. Throughout the reaction of Br-Ar-mono-Br with EDM-Ar-mono-Br, formation of the respective intermediate dimer was observed within 30 minutes, while full conversion took an additional 60 minutes.
It was possible to obtain crystals from the dimers and from EDM-tri. For all dimers, the BODIPY cores are mutually slightly twisted (~12°, see Figure 2B). The small twist angle, however, implies a certain amount of conjugation through the central nitrogen atom. In contrast, EDM-tri shows a stronger deviation from planarity, which is probably attributable to steric hindrance, thus causing one of the peripheral cores to be tilted by as much as 29° with regard to the plane of the residual two units. Moreover, one molecule of CH2Cl2 is adjacent to the cavity, indicating hydrogen bonding to the BF2 units. Furthermore, the C-N-C bond angles of the N-bridges range between 123° and 127°, showing deviation from the theoretical value of 120° for sp2-hybridized nitrogen. Within the resulting cavity, the minimum distance between fluorine and the bridging nitrogen atom amounts to 2.9 Å and 3.4 Å for the opposing BF2 units for the dimer. The trimer in comparison shows larger distances of the two closest fluorine atoms of two different BF2 groups (3.9 Å) and as much as 5.2 Å for the two peripheral BODIPY units (Figure 2C). For more details see the Supporting Information.
Figure 2. Molecular structures of DM-Me-di A) front view, B) top view and EDM-tri C) front view and D) top view. Hydrogen atoms were omitted for clarity.
The photophysical behavior of the dimers shows a strong bathochromic shift of the main absorption band compared to the respective monomers (from λmax = 510 nm to 659 nm for the EDM examples) and also significantly increased attenuation coefficients (Figure 3). An excerpt of the respective data is given below (Table 1). The presence of a second absorption region at approximately 500 nm (S2 state) indicates a Davydov splitting as a result of an excitonic coupling process. The unusual double-peak shape may suggest some conformational instabilities. In this context, the absorption profile is expanded to three absorption events at the trimer, corresponding to three excitonic states excited at 752 nm (S1), 562 nm (S2), and 470 nm (S3), respectively. Notably, the S2 state exhibits the highest oscillator strength, attributed to the significant geometrical deviation from linearity, gradually leading to a helical superstructure for higher homologs (Figure 4). This trend is accentuated for the tetramers, where the absorption signature becomes intricate. However, the intensified coiling in this case, where the terminal BODIPY units start overlapping and thus forming a looped superstructure, results in an exceptionally weak S1→S0 excitation at 820 nm. The remaining states of the exciton manifold are hardly assignable because of the amount and overlap of absorption bands, yet they are responsible for the absorptions at 633 nm and 521 nm. The oscillator strength distribution of the exciton manifold was simulated through TDDFT computations and accurately mirrors the experimentally observed absorption band intensities for all oligomer species (Figure 4). The emission strength decreases gradually along the oligomeric series. While the monomers exhibit fluorescence quantum yields (ΦF) of up to 0.53 in CH2Cl2, these values decrease to ΦF < 0.01 for the dimer and trimer. For the tetramers, emission is hardly detectable (ΦF << 0.01).
Table 1. Absorption and emission data of EDM-BODIPYs.
| Compound | λmax [nm] | λFmax [nm] | ε [10^3 M^-1 cm^-1] | ΦF |
| --- | --- | --- | --- | --- |
| EDM-Ar-mono-Cl | 510 | 534 | 121 | 0.04 |
| EDM-Ar-mono-NH2 | 525 | 539 | 59 | 0.01 |
| EDM-Ar-di | 482, 510, 671 | 881 | 271, 47, 40, 134 | 0.01 |
| EDM-tri | 562, 757 | 778 | 357 | 0.01 |
| EDM-tet | 521, 633 | n.d. | 97, 76, 111, 114 | 0.01 |
[a] Absorption and emission spectra were recorded in solutions of CH2Cl2 at room temperature. [b] λmax is not responsible for λFmax. Stokes shift was calculated using the respective λmax values. [c] Not detected/determined. Further spectroscopic data is given in the Supporting Information.
The frontier orbitals of the oligomeric series integrate the lobe patterns found for the monomeric building blocks. All BODIPY units are characterized by an electron-depleted meso position at the HOMO and also by the cyanine-like relocalization of electron density to this position during excitation (Figure 4).
Figure 3. Absorption and emission spectra of EDM-BODIPYs. Absorption and emission spectra were recorded in solutions of CH2Cl2 at room temperature.
Figure 4. Frontier orbitals and minimum energy structures of oligomeric series. Geometrical optimizations at the DFT level (M052X-D3/def2-TZVP) in vacuo. Oscillator strengths (f values) obtained from corresponding TDDFT computations (ωB97XD/def2-TZVP). The input structures were truncated at the meso phenyl residues (iso-butyl groups).
Cyclic voltammograms of amine-linked oligomers and the respective monomers for the EDM-series are shown below (Figure 5). In general, the larger the molecules, the easier the oxidation; however, most of them are oxidized irreversibly. The monomeric primary amine and the trimer show irreversible oxidation, unlike the respective chloride and the dimer. However, the chlorinated monomer has only one reversible reduction potential at -1.28 V, whereas the dimer shows two reduction potentials, at -1.25 V and at -1.64 V.
The trimer shows almost irreversible oxidation potentials at 0.69 V.
This LLM-cleaned text already looks much better. However, LLM-based cleaning has the drawback of higher cost and it introduces another possibility for errors to creep in.
2.2.3. Removing sections in Markdown files#
Markdown syntax (as one, e.g., obtains using tools such as nougat) makes document cleaning simpler because sections can be readily identified.
In this example the patterns [MISSING_PAGE_FAIL:x] and the sections ‘Acknowledgments’ and ‘References’ are detected and deleted.
import re
def clean_text(text):
# Delete the pattern [MISSING_PAGE_FAIL:x]
cleaned_text = re.sub(r"\[MISSING_PAGE_FAIL:\d+\]", "", text)
# Delete the acknowledgements section
cleaned_text = re.sub(
r"## Acknowledgements.*?(?=##|$)", "", cleaned_text, flags=re.S
)
# delete the references section
cleaned_text = re.sub(r"## References.*", "", cleaned_text, flags=re.S)
return cleaned_text
input_file = "./markdown_files/10.26434_chemrxiv-2024-1l0sn.mmd"
with open(input_file, "r", encoding="utf-8") as f:
content = f.read()
# clean the text
cleaned_text = clean_text(content)
print(cleaned_text)
These types of connectivity have also been converted to extended \(\pi\)-systems by oxidative follow-up reactions, allowing a higher level of conjugation and hence strong bathochromic shifts.[8] The installation of heteroatoms has however been a challenge for some time. In 2014, Shinokubo et al. presented linearly connect monomers through an azo-bridge at the \(\beta\)-position (Figure 1A (d)).[10] Linear connectivity at the \(\alpha\)-position using heteroatoms such as sulfur has been achieved through a similarly iterative process by the groups of Hao and Jiao (Figure 1A (e)).[7] Furthermore, cyclic amine-linked oligo-BODIPYs have already been synthesized in a one-pot reaction in 2022 by Song et al., utilizing Buchwald-Hartwig conditions (Figure 1A (f)).[10]
We present a novel type of BODIPY oligomers, connected via _N_-bridges in a linear fashion (Figure 1B). Utilizing both symmetric and unsymmetric BODIPY monomers as building blocks has paved the way to selectively synthesize oligomers with various chain lengths. Both symmetric and unsymmetric dimers were synthesized starting from unsymmetric monontunctional monomer units. Additionally, the chain length of these oligopolipYs was extended using the functionalized monomer **Br-Armono-Br** and the dimer **Br-Ar-di** (Scheme 1).
## Results and Discussion
In contrast to the aforementioned cyclic amine-linked examples,[10] we have focused on selectively synthesizing open-chained oligomers and addressing their specific properties. Variation of the BODIPY core has been shown to have a considerable impact on the respective reaction times and yields. To dimerize selectively when forming the nitrogen bridge, monontunctionalized \(\alpha\)-chlorinated BODIPY monomers were used. The key step in obtaining such unsymmetric BODIPYs (in contrast to the usual mirror plane through the _mes_ position and boron center) was a Bischler-Napierals type reaction of the respective chlorinated acylpyrrole and alkylpyrrole, following an established procedure developed by Dehaen and coworkers.[10] Converting the \(\alpha\)-chloropolipPY into the respective amine and performing a Buchwald-Hartwig coupling of both led to _N_-bridged BODIPY dimers, in which alkyl/pyrroles such as 2,4-dimethyl/pyrrole (**5**) and cryptopyrrole (**6**) serve as capping units on the BODIPY core. Terminal \(\alpha\)-brominated examples provide an option for further versatile functionalization. During the investigation of _mes_ substitution patterns, the _4-iso_-butylphenyl moiety has been shown to overcome solubility issues, while maintaining crystallizability (albeit sometimes with disorder problems), whereas dimer syntheses are made easier by an increasing level of alkyl-substitution on the pyrrole motif. For a simplified overview of the BODIPY scope, compounds are labeled according to the systematic nomenclature shown in Scheme 1A.
The synthetic strategy began with pyrrole (1) for both kinds of monomers. To obtain monochlorinated BODIPYs, it was first converted into the respective 2-benzoylpyrrole **2** for the _mes_ and examples.[10] TBS protection of the benzyl alcohol by-product in the crude simplified the purification later on.[11] This species and 2-acetylpyrrole were then chlorinated using NCS in THF at room temperature to obtain \(\alpha\)-chlorinated 2-acyl/pyrroles **3** and **4**.[12]We preferred chlorination over the analogous bromination since the by-products were easier to separate from the desired products. To arrive finally at the monfoundenticalized BODIPY monomers, acy/pyrroles **3** and **4** were then converted with the respective alkyl/pyrroles **5** and **6** in the presence of POCl\({}_{3}\) in CH\({}_{4}\)Cl/n-hexane (2:1), followed by the established procedure for BODIPY syntheses from the _in situ_ formed glytrium using triethylamine and BF\({}_{x}\)-OEL\({}_{x}\), with yields up to 91% over 2 steps. To obtain higher oligomers, bistunctionalized monomers had to be synthesized prior to amination. For symmetrically bistunctionalized monomer **Br-Ar-mono-Br**, an excess of pyrrole (1) was converted into dipryromethane **7** using 4-iso-butylbenzaldehyde with catalytic amounts of TFA in CH\({}_{4}\)Cl\({}_{2}\) in 68% yield.[13] Stepwise addition of NBS in small portions to a solution of **7** in THF at -78 \({}^{\circ}\)C for selective bromination, followed by oxidation with DDQ, gave the crude glytrium, which was used in the following step after filtration. The actual BODIPY synthesis was subsequently conducted in a similar manner as for the unsymmetric monomers. However, \(\text{$\text{$\text{$\text{$\text{$\text{$\text{$\text{$\text{$\text{$ \text{$\text{$\text{$\text{$\text{$\text{$\text{$\text{$}}}$}$}$}$}}}}}$}}$}\)Net was found to give higher yields for less substituted glytrirens. Thus, using this tertiary amine base, in lieu of triethylamine, together with BF\({}_{x}\)-OEL\({}_{x}\) gave **Br-Ar-mono-Br** in 38% yield over three steps. Bromination was necessary in this case because the corresponding chlorinated derivative of an \(\alpha\)-amino-BODIPY showed no oligomerization beyond the dimer under the same conditions. Additionally, purification was not an obstacle, in contrast to the aforementioned brominated acy/pyrroles. Preparative details of the chlorinated amino-BODIPY are given in the Supporting Information. The respective \(\alpha\)-amino-BODIPYs were then synthesized by stirring halogenated BODIPYs in an ammonia solution in MeOH (7 N) in a sealed tube at 60 \({}^{\circ}\)C to furnish the target compounds in up to 58% yield for chlorinated derivatives and even in quantitative yield for the brominated example (Scheme 1B). For Buchwald-Hartwig coupling of \(\alpha\)-chloro- and \(\alpha\)-amino-BODIPYs, one equivalent of each was converted with Pd(OAC\({}_{2}\)), (\(\pm\))-BINAP and Cs\({}_{2}\)CO\({}_{3}\) in PhMe at 80 \({}^{\circ}\)C.[14] Interestingly, the reaction times and yields showed a trend of improvement with increasing level of substitution of the BODIPY core with up to 68% yields. While these dimer syntheses were straight forward by simply stirring all of the components together, synthesis of **Br-Ar-dil** required slow addition of **Br-Ar-mono-MrIz** to a heated solution of the remaining reagents. Such a procedure ensured selectivity by maintaining an excess of **Br-Ar-mono-Br** to avoid further oligomerization. The reaction yielded 44% of the functionalization dimer, while 45% of the starting material was recovered. As for the dimers synthesized via the chlorides, synthesis of trimers and tetramers was achieved in same manner with the respective bromides (**Br-Ar-dil** for **EDM-tet**), with a remarkable decrease of the reaction time. Throughout the reaction of **Br-Ar-mono-Br** with **EDM-Ar-mono-Br**, formation of the respective intermediate dimer was observed within 30 minutes, while full conversion took an additional 60 minutes.
It was possible to obtain crystals from the dimers and from **EDM-tri**. For all dimers, the BODIPY cores are mutually slightly twisted (-12\({}^{\circ}\), see Figure 2B). The small twist angle, however, implies a certain amount of conjugation through the central nitrogen atom. In contrast, **EDM-tri** shows a stronger deviation from planarity, which is probably attributable to steric hindrance, thus causing one of the peripheral cores to be tilted by as much as 29\({}^{\circ}\) with regard to the plane of the residual two units. Moreover, one molecule of CH\({}_{4}\)Cl\({}_{2}\) is adjacent to the cavity, indicating hydrogen bonding to the BF\({}_{2}\) units. Furthermore, the C-N-C bond angles of the _N_-bridges range between 123\({}^{\circ}\) and 127\({}^{\circ}\), showing deviation from the theoretical value of 120\({}^{\circ}\) for sp\({}^{2}\)-hybridized nitrogen. Within the resulting cavity, the minimum distance between fluorine and the bridging nitrogen atom amounts to 2.9 A and 3.4 A for the opposing BF\({}_{2}\) units for the dimer. The trimer in comparison shows larger distances of the two closest fluorine atoms of two different BF\({}_{2}\) groups (3.9 A) and as much as 5.2 A for the two peripheral BODIPY units (Figure 2C). For more details see the Supporting Information.
The photophysical behavior of the dimers shows a strong bathochromic shift of the main absorption band compared to the respective monomers (from \(\hat{A}^{\text{max}}\) = 510 nm to 659 nm for the **EDM** examples) and also significantly increased attenuation coefficients \(\varepsilon\) (Figure 3). An excerpt of the respective data is given below (Table 1). The presence of a second absorption region at approximately 500 nm (S\({}_{2}\) state) indicates a Davydov splitting as a result of an excitonic coupling process. The unusual double-peak shape may suggest some conformational instabilities. In this context, the absorption profile is expanded to three absorption events at the trimer, corresponding to three excitonic states excited at 752 nm (S\({}_{1}\)), 562 nm (S\({}_{2}\)), and 470 nm (S\({}_{3}\)), respectively. Notably, the S\({}_{2}\) state exhibits the highest oscillator
Figure 2: Molecular structures of **DM-Me-di** A) front view, B) top view and **EDM-tri** C) front view and D) top view. Hydrogen atoms were omitted for clarity. Ellipsoids correspond to 50% probability levels.
strength, attributed to the significant geometrical deviation from linearity, gradually leading to a helical superstructure for higher homologs (Figure 4). This trend is accentuated for the tetramers, where the absorption signature becomes intricate. However, the intensified coiling in this case, where the terminal BODIPY units start overlapping and thus forming a looped superstructure, results in an exceptionally weak S\({}_{1}\)-S\({}_{0}\) excitation at 820 nm. The remaining states of the exciton manifold are hardly assignable because of the amount and overlap of absorption bands, yet they are responsible for the absorptions at 633 nm and 521 nm. The oscillator strength distribution of the exciton manifold was simulated through TDDFT computations and accurately mirrors the experimentally observed absorption band intensities for all oligomer species (Figure 4). The emission strength decreases gradually along the oligomeric series. While the monomers exhibit fluorescence quantum yields \(\alpha_{\text{F}}\) of up to 0.53 in CH\({}_{2}\)Cl\({}_{2}\), these values decrease to \(\alpha_{\text{F}}<\) 0.01 for the dimer and trimer. For the tetramers, emission is hardly detectable (\(\alpha_{\text{F}}<\) 0.01).
The frontier orbitals of the oligomeric series integrate the lobe patterns found for the monomeric building blocks. All BODIPY units are characterized by an electron-depleted _meso_ position at the HOMO and also by the cyanine-like relocalization of electron density to this position during excitation (Figure 4).
Cyclic voltammograms of amine-linked oligomers and the respective monomers for the EDM-series are shown below (Figure 5). In general, the larger the molecules, the easier the oxidation; however, most of them are oxidized irreversibly. The monomeric primary amine and the trimer show irreversible oxidation, unlike the respective chloride and the dimer. However, the chlorinated monomer has only one reversible reduction potential at -1.28 V, whereas the dimer shows two reduction potentials, at -1.25 V and at -1.64 V.
Figure 4: Frontier orbitals and minimum energy structures of oligomeric series. Geometrical optimizations at the DFT level (MO52X-D3De6TZ2VP) in vacuu. Oscillator strengths (\(r\) values) obtained from corresponding TDDFT computations (\(\alpha\)B97xDDef2TZVP). The input structures were truncated at the _meso_ phenyl residues (iso-butyl groups).
Figure 3: Absorption and emission spectra of **EDM-BODIPY.** Absorption and emission spectra were recorded in solutions of CH\({}_{2}\) at room temperature.
The trimer shows almost irreversible oxidation potentials at 0.69 V and 1.33 V and also reduction at -1.69 V. **EDM-tet**, however, shows several oxidation and reduction potentials within the range of \(\pm\)2.00 V, which are mostly irreversible (Figure 5). Attempts to oxidize the obtained oligomers did not provide quinodimine analogs as for the cyclic derivates.[11]
## Conclusion
In summary, we have successfully developed a method to access linearly amino-linked BODIPYs using Buchwald-Harwig conditions. Terminal Br substituents allowed elongation of the chain by two further BODIPY subunits. X-ray structure analyses revealed conjugation of the various subunits via the linking nitrogen atom. Absorption spectra show significantly increased attenuation coefficients for the oligomers in comparison to the respective monomers, and also strong bathochromic shifts. DFT calculations provided an insight into the electronic properties and showed a decreasing HOMO/LUMO gap as well as increasing oscillator strengths (_f_ values) of the excited states with increasing level of oligomerization. The computed orbital energies are also closely consistent with cyclovoltammetric investigations, demonstrating a more facile oxidation and reduction with increasing chain length.
## Supporting Information
The Supporting Information is available free of charge and contains detailed experimental procedures, analytical, X-ray crystallographic and absorption and emission data, and \({}^{1}\)H, \({}^{10}\)F and \({}^{11}\)B NMR spectra of all new compounds.
Tip
A more powerful cleaning scripts for Markdown files, e.g., as produced using nougat, was created for the ChemNLP project.
You can find it here.
2.2.4. Harmonizing XML files#
Many APIs return the articles directly in machine-readable XML format. However, the ones of different publishers are quite different, which can make this kind of cleanup tedious. Thus, it is great that there are packages such as Pub2TEI that can help one to streamline this process.
Note
Execute the following lines in bash terminal.
docker run --rm --gpus all --init --ulimit core=0 -p 8060:8060 grobid/pub2tei:0.2
git clone https://github.com/kermitt2/Pub2TEI
cd Pub2TEI/client
pip install requests
This will start the starting the Pub2TEI service with Docker.
import os
import requests
import time
# Define the input directory containing XML files and the output directory for TEI files
input_dir = "./XML_files"
output_dir = "./XML_files_cleaned"
os.makedirs(output_dir, exist_ok=True)
# Define the Pub2TEI server URL
server_url = "http://localhost:8060/service/processXML"
# Function to process a single XML file
def process_xml_file(xml_file, output_dir):
files = {
"input": open(xml_file, "rb"),
"segmentSentences": (
None,
"1",
), # Optional, set to '1' for sentence segmentation
"grobidRefine": (None, "1"), # Optional, set to '1' for refining with Grobid
}
for attempt in range(5): # Retry up to 5 times
try:
response = requests.post(server_url, files=files)
if response.status_code == 200:
with open(output_dir, "wb") as f:
f.write(response.content)
print(f"Processed {xml_file} successfully.")
return output_dir
else:
print(
f"Failed to process {xml_file}. Status code: {response.status_code}"
)
break
except ConnectionError as e:
print(f"Connection error: {e}. Retrying in 5 seconds...")
time.sleep(5)
# Process all XML files in the input directory
for filename in os.listdir(input_dir):
if filename.endswith(".xml"):
input_file = os.path.join(input_dir, filename)
print(input_file)
output_file = os.path.join(output_dir, filename.replace(".xml", ".tei.xml"))
process_xml_file(input_file, output_file)
./XML_files/ao0c01342.xml
Processed ./XML_files/ao0c01342.xml successfully.
with open(output_file, "r", encoding="utf-8") as f:
content = f.read()
print(f"Content of {output_file}:\n")
print(content)
Content of ./XML_files_cleaned/ao0c01342.tei.xml:
<?xml version="1.0" encoding="UTF-8"?>
<TEI xmlns="http://www.tei-c.org/ns/1.0" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:noNamespaceSchemaLocation="https://raw.githubusercontent.com/kermitt2/grobid/master/grobid-home/schemas/xsd/Grobid.xsd">
<teiHeader>
<fileDesc>
<titleStmt>
<title level="a" type="main">Synthesis and Biological Evaluation of Three New Chitosan
Schiff Base Derivatives</title>
</titleStmt>
<publicationStmt>
<publisher>American Chemical Society</publisher>
<availability>
<p>
<s>American Chemical Society</s>
</p>
</availability>
<date type="e-published" when="2020-06-01">2020</date>
<date when="2020-06-16">2020</date>
<date type="Copyright" when="2020">2020</date>
</publicationStmt>
<notesStmt>
<note type="content-type">research-article</note>
<note type="publication-type">journal</note>
</notesStmt>
<sourceDesc>
<biblStruct>
<analytic>
<title level="a" type="main">Synthesis and Biological Evaluation of Three New Chitosan
Schiff Base Derivatives</title>
<author xml:id="author-0000">
<persName>
<surname>Haj</surname>
<forename type="first">Nadia
Q.</forename>
</persName>
<affiliation>
<ref>‡</ref>
<orgName type="institution">Department
of Chemistry, College of Science</orgName>
<orgName type="institution">University
of Kirkuk</orgName>
<settlement>Kirkuk</settlement>
<address>
<country key="IQ">IRAQ</country>
</address>
</affiliation>
</author>
<author role="corresp" xml:id="author-0001">
<persName>
<surname>Mohammed</surname>
<forename type="first">Mohsin O.</forename>
</persName>
<affiliation>
<ref>†</ref>
<orgName type="institution">Department
of Basic Science, College of Agriculture</orgName>
<settlement>Kirkuk</settlement>
<address>
<country key="IQ">IRAQ</country>
</address>
</affiliation>
<email>althker1@uokirkuk.edu.iq</email>
</author>
<author xml:id="author-0002">
<persName>
<surname>Mohammood</surname>
<forename type="first">Luqman E.</forename>
</persName>
<affiliation>
<ref>§</ref>
<orgName type="institution">College
of Pharmacy</orgName>
<orgName type="institution">University of Kirkuk</orgName>
<settlement>Kirkuk</settlement>
<address>
<country key="IQ">IRAQ</country>
</address>
</affiliation>
</author>
<idno type="doi">10.1021/acsomega.0c01342</idno>
</analytic>
<monogr>
<title level="j" type="main">ACS Omega</title>
<title level="j" type="abbrev">ACS
Omega</title>
<idno type="publisher-id">ao</idno>
<idno type="coden">acsodf</idno>
<idno type="ISSN">2470-1343</idno>
<idno type="ISSN">2470-1343</idno>
<imprint>
<publisher>American Chemical Society</publisher>
<date type="e-published" when="2020-06-01">2020</date>
<date when="2020-06-16">2020</date>
<biblScope unit="vol">5</biblScope>
<biblScope unit="issue">23</biblScope>
<biblScope from="13948" unit="page">13948</biblScope>
<biblScope to="13954" unit="page">13954</biblScope>
</imprint>
</monogr>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<abstract>
<p>
<s>Recently, chemical modifications of chitosan (CS) have attracted the attention of scientific researchers due to its wide range of applications.</s>
<s>In this research, chitin (CH) was extracted from the scales of <hi rend="italic">Cyprinus carpio</hi> fish and converted to CS by three chemical steps: (i) demineralization, (ii) deprotonation, and (iii) deacetylation.</s>
<s>The degree (measured as a percentage) of deacetylation (DD %) was calculated utilizing the acid–base titration method.</s>
<s>The structure of CS was characterized by Fourier transform infrared (FT-IR) spectroscopy and thermogravimetric analysis (TGA).</s>
<s>Three new CS Schiff bases (CSSBs) (CS-P1, CS-P2, and CS-P3) were synthesized via coupling of CS with 2-chloroquinoline-3-carbaldehyde, quinazoline-6-carbaldehyde, and oxazole-4-carbaldehyde, respectively.</s>
<s>The newly prepared derivatives were verified, structurally, by nuclear magnetic resonance ( <hi rend="superscript">1</hi> H and <hi rend="superscript">13</hi> C NMR) and FT-IR spectroscopy.</s>
<s>Antimicrobial activity was evaluated for the prepared compounds against both “Gram-negative” and “Gram-positive” bacteria, namely, <name type="genus-species">Escherichia coli</name> , <name type="genus-species">Klebsiella pneumonia</name> , <name type="genus-species">Staphylococcus aureus</name> , and <name type="genus-species">Streptococcus mutans</name> , in addition to two kinds of fungi, <name type="genus-species">Candida albicans</name> and <name type="genus-species">Aspergillus fumigates</name> .</s>
<s>Cytotoxicity of the synthesized CSSBs was evaluated via a MTT screening test.</s>
<s>The results indicated a critical activity increase of the synthesized compound rather than CS generally tested bacteria and fungi and the absence of cytotoxic activity.</s>
<s>These findings suggested that these new CSSBs are novel biomaterial candidates with enhanced antibacterial and nontoxic characteristics for applications in areas of both biology and medicine.</s>
</p>
</abstract>
<abstract>
<p>
<s>
<graphic url="ao0c01342_0004.eps"/>
</s>
</p>
</abstract>
<abstract>
<p>
<s>
<graphic url="ao0c01342_0003.eps"/>
</s>
</p>
</abstract>
<textClass ana="subject">
<keywords scheme="document-type-name">
<term>Article</term>
</keywords>
</textClass>
<textClass ana="keyword">
<keywords>
<term>Amino Polysaccharide</term>
<term>Chitin</term>
<term>Chitosan</term>
<term>Chitosan Schiff base</term>
<term>Antimicrobial polymer</term>
<term>Cytotoxicity
test</term>
</keywords>
</textClass>
</profileDesc>
<revisionDesc>
<change when="2020-03-25">Received</change>
<change when="2020-05-19">Accepted</change>
</revisionDesc>
</teiHeader>
<text>
<body>
<div n="1" xml:id="sec1">
<head>Introduction</head>
<p>
<s>CS has a chemical structure of α(1→4)-2-amino-2-deoxy-β- <hi rend="smallCaps">d</hi> -glucopyranose derived from the N-deacetylation of CH, a typical auxiliary biopolymer found in the exoskeletons of roaches and crustaceans and fungi cell walls ( <ref target="#fig1" type="fig">Figure <ref target="#fig1" type="fig"/>
</ref> ).</s>
<s>The main source of CH and CS is shellfish, for example, crabs, shrimp, and lobsters, and fish scales.</s>
<s>It has a few receptive amino groups, which offer further chemical modifications for the development of an incredible assorted variety of valuable derivatives that are cost-effective.</s>
<s>
<ref target="#ref1" type="bibr"/> CS, deacetylated CH, is an extremely useful, readily available bioactive polymer, which is a renewable, natural, nontoxic, edible, and biodegradable polymer characterized by biocompatibility.</s>
<s>
<name type="bibref-group">
<ref target="#ref2" type="bibr"/>,<ref target="#ref3" type="bibr"/>
</name> CS shows several advantageous biological properties, such as antitumor, antimicrobial, and hemostatic activities, and promotes wound healing.</s>
<s>
<ref target="#ref4" type="bibr"/> It has versatile applications ranging from biomedical designing, pharmaceuticals, drug transport, restorative materials, metal particle chelation, and absorptivity to water treatment and plant security.</s>
<s>
<name type="bibref-group">
<ref target="#ref5" type="bibr"/>−<ref target="#ref6" type="bibr"/>
<ref target="#ref7" type="bibr"/>
</name> CS derivatives, especially those synthesized via a Schiff base reaction, are the most important due to their organic application characteristics.</s>
<s>Recently, the reaction of CS with the rings of aromatic and heterocyclic aldehydes resulted in the efficient production of stable Schiff bases (SBs), which are exceptional compounds in many application areas, particularly in pharmacology and medicine, e.g., as antimicrobial and cancer prevention agents.</s>
<s>
<name type="bibref-group">
<ref target="#ref8" type="bibr"/>,<ref target="#ref9" type="bibr"/>
</name> CSSBs are characteristically prepared by the superficial reaction of CS amine sites with aldehydes or ketones by the elimination of water particles.</s>
<s>
<ref target="#ref10" type="bibr"/>
</s>
</p>
<figure xml:id="fig1">
<head type="label">1</head>
<figDesc>
<div>
<p>
<s>Structure of CH and <hi rend="italic">Cyprinus carpio</hi> fish.</s>
</p>
</div>
</figDesc>
<graphic url="ao0c01342_0001.eps"/>
</figure>
<p>
<s>Furthermore, quinoline and quinazoline compounds are present in several natural products and in manufactured pharmacologically significant heterocyclic materials.</s>
<s>Quinoline and quinazoline derivatives are called antimalarial, <name type="bibref-group">
<ref target="#ref11" type="bibr"/>,<ref target="#ref12" type="bibr"/>
</name> antiviral, <name type="bibref-group">
<ref target="#ref13" type="bibr"/>,<ref target="#ref14" type="bibr"/>
</name> antibacterial, <name type="bibref-group">
<ref target="#ref15" type="bibr"/>,<ref target="#ref16" type="bibr"/>
</name> analgesic, <name type="bibref-group">
<ref target="#ref17" type="bibr"/>,<ref target="#ref18" type="bibr"/>
</name> antihepatoma, <name type="bibref-group">
<ref target="#ref19" type="bibr"/>,<ref target="#ref20" type="bibr"/>
</name> and anti-inflammatory agents.</s>
<s>
<name type="bibref-group">
<ref target="#ref21" type="bibr"/>,<ref target="#ref22" type="bibr"/>
</name> Also oxazole derivatives are known as one of the most essential kinds of heterocyclic compounds, which are very significant for medicinal chemistry.</s>
<s>
<ref target="#ref23" type="bibr"/>
</s>
</p>
<p>
<s>In this study, based on the above facts, first, CH is extracted from the local <hi rend="italic">Cyprinus carpio</hi> fish scales by demineralization and deprotonation followed by deacetylation to produce CS using fresh reagents, thereby reducing the time for the overall procedure to obtain CS with a degree of deacylation (DD) percentage of at least 60.</s>
<s>Second, this study aims to determine the DD % of the products; samples of CS are obtained in different steps of the procedure by the acid–base titration method.</s>
<s>Third, this study also aims to characterize and verify the physicochemical properties of the products employing FT-IR and TGA.</s>
<s>Finally, this study attempts to develop a synthesis method for three new CSSB derivatives CS-P1, CS-P2, and CS-P3 through coupling CS with 2-chloroquinoline-3-carbaldehyde, quinazoline-6-carbaldehyde, and oxazole-4-carbaldehyde, respectively.</s>
<s>The structures of the prepared derivatives were verified via FT-IR and <hi rend="superscript">1</hi> H and <hi rend="superscript">13</hi> C NMR spectroscopy.</s>
<s>The antimicrobial potential of CS and the new derivatives was tested against four kinds of bacteria, <name type="genus-species">E. coli</name> , <name type="genus-species">K. pneumonia</name> , <name type="genus-species">S. aureus</name> , and <name type="genus-species">S. mutans</name> , in addition to two kinds of fungi, <name type="genus-species">C. albicans</name> and <name type="genus-species">A. fumigates</name> .</s>
<s>The cytotoxicity of the newly prepared compounds was evaluated through the MTT assay.</s>
<s>The results were compared with those of CS.</s>
</p>
</div>
<div n="2" xml:id="sec2">
<head>Results and Discussion</head>
<p>
<s>Drug resistance of microorganisms to antibiotics has encouraged researchers to search for new antibiotics to challenge this dangerous phenomenon.</s>
<s>Many CS derivatives were synthesized to improve the antimicrobial effectiveness of CS, for example, SBs, via methylation, amination, etc. <name type="bibref-group">
<ref target="#ref24" type="bibr"/>,<ref target="#ref25" type="bibr"/>
</name> In the present study, CS was extracted and used to prepare three new SBs of CS by reacting CS with 2-chloroquinoline-3-carbaldehyde, quinazoline-6-carbaldehyde, and oxazole-4-carbaldehyde.</s>
<s>The structures of the prepared CSSBs were confirmed using 1H NMR, <hi rend="superscript">13</hi> C NMR, and FT-IR techniques.</s>
</p>
<div n="2.1" xml:id="sec2.1">
<head>CS Extraction Description</head>
<p>
<s>The details of the treatment of C <hi rend="subscript">1</hi> , C <hi rend="subscript">2</hi> , C <hi rend="subscript">3</hi> , and C <hi rend="subscript">4</hi> samples are presented in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Table S1</ref> in the Supporting Information (SI).</s>
</p>
<div n="2.1.1" xml:id="sec2.1.1">
<head>Acid–Base
Titration Method</head>
<p>
<s>The DD % for sample C <hi rend="subscript">4</hi> was determined by the acid–base titration method.</s>
<s>The DD % was calculated using the endpoint of the acid–base titration when the indicator changed into blue-green colors.</s>
<s>The DD % values of the deacetylated products were calculated according to the following equations <name type="bibref-group">
<ref target="#ref26" type="bibr"/>,<ref target="#ref27" type="bibr"/>
</name>
<formula n="1" rend="display" xml:id="eq1"/>
<formula n="2" rend="display" xml:id="eq2"/> where <hi rend="italic">C</hi>
<hi rend="subscript">1</hi> and <hi rend="italic">V</hi>
<hi rend="subscript">1</hi> are the concentration and the volume of HCl used, respectively, <hi rend="italic">C</hi>
<hi rend="subscript">2</hi> and <hi rend="italic">V</hi>
<hi rend="subscript">2</hi> are the concentration and the amount of NaOH used for titration, respectively, <hi rend="italic">W</hi> is the weight of samples used for acid–base titration.</s>
<s>The calculated DD for each sample is tabulated in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Table S2 and Figure S1</ref> in the SI.</s>
</p>
</div>
<div n="2.1.2" xml:id="sec2.1.2">
<head>FT-IR Spectroscopic Study</head>
<p>
<s>FT-IR spectroscopy was used to study the structures of CH and the related derivatives.</s>
<s>The FT-IR spectra of CS, CH, C <hi rend="subscript">3</hi> , and C <hi rend="subscript">4</hi> are shown in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Figures S2–S5</ref> in the SI, respectively.</s>
<s>By comparing the spectra for sample C <hi rend="subscript">3</hi> and CH, and sample C <hi rend="subscript">4</hi> and CS, several bands in the range of 4000–400 cm <hi rend="superscript">–1</hi> were noted in the spectra.</s>
<s>As shown in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Table S3</ref> in the SI, bands of the synthesized CS match with those of CH.</s>
<s>The primary amines showed various bands in the range 3425–2881 cm <hi rend="superscript">–1</hi> correlated with ν(N–H) and ν(NH <hi rend="subscript">2</hi> ) vibrations.</s>
<s>The band at 2921–2879 cm <hi rend="superscript">–1</hi> was observed corresponding to the methyl group in pyranose.</s>
<s>The appearance of a band at 1597 cm <hi rend="superscript">–1</hi> and the disappearance of a band at 1655 cm <hi rend="superscript">–1</hi> indicate the deacetylation of CH.</s>
<s>The doublet form of the amide band is attributed to the existence of intermolecular and intramolecular hydrogen bonds (CO···HN, CO···HOCH <hi rend="subscript">2</hi> ).</s>
<s>
<name type="bibref-group">
<ref target="#ref28" type="bibr"/>−<ref target="#ref29" type="bibr"/>
<ref target="#ref30" type="bibr"/>
</name> The bands at 1264 and 1157 cm <hi rend="superscript">–1</hi> are related to the vibrations of NHCO.</s>
<s>The bands in the range of 1000–1158 cm <hi rend="superscript">–1</hi> were related to the vibrations of C–O–C, C–OH, and C–C ring bonds.</s>
<s>
<ref target="#ref31" type="bibr"/> The characteristic band at 1600–1400 cm <hi rend="superscript">–1</hi> due to the N–H bending of CS was observed, in addition to the bands at 1600.9 and 1647.19 cm <hi rend="superscript">–1</hi> corresponding to the bending of −NH <hi rend="subscript">2</hi> .</s>
<s>
<name type="bibref-group">
<ref target="#ref32" type="bibr"/>,<ref target="#ref33" type="bibr"/>
</name> The existence of CH <hi rend="subscript">3</hi> , CH <hi rend="subscript">2</hi> , and CH groups was confirmed by the appearance of vibration peaks within the 1422–603 cm <hi rend="superscript">–1</hi> range.</s>
</p>
</div>
<div n="2.1.3" xml:id="sec2.1.3">
<head>Thermal Gravimetric Analysis (TGA)</head>
<p>
<s>TGA of CS, CH, C3, and C4 was performed, as shown in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Figures S6–S9</ref> in the SI, respectively.</s>
<s>Physicochemical properties of C3 and C4 were compared with those of CH and CS.</s>
<s>The thermal stability of C3 was similar to that of CH.</s>
</p>
</div>
</div>
<div n="2.2" xml:id="sec2.2">
<head>Preparation of CS Schiff Base Derivatives</head>
<p>
<s>Three CSSBs were prepared, as shown in the schematic diagram in <ref target="#sch1" type="scheme">Scheme <ref target="#sch1" type="scheme"/>
</ref> .</s>
<s>Extracted CS was dissolved in 2.0% aqueous acetic acid, followed by addition of an equimolar amount of the carbonyl compounds dissolved in ethanol to obtain CSSBs.</s>
<s>The resultant compounds obtained from the reaction of CS with 2-chloroquinoline-3-carbaldehyde, quinazoline-6-carbaldehyde, and oxazole-4-carbaldehyde were labeled CS-P1, CS-P2, and CS-P3, respectively.</s>
</p>
<figure xml:id="sch1">
<head type="label">1</head>
<head type="caption-title">Preparation of CSSB Derivatives</head>
<graphic url="ao0c01342_0002.eps"/>
</figure>
<div n="2.2.1" xml:id="sec2.2.1">
<head>Characterization of CSSBs</head>
<div n="2.2.1.1" xml:id="sec2.2.1.1">
<head>FT-IR
Spectroscopy and <hi rend="superscript">1</hi>H NMR
and <hi rend="superscript">13</hi>C NMR Analyses</head>
<p>
<s>The FT-IR spectra of CSSBs (CS-P1, CS-P2, and CS-P3) are shown in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Figures S10–S12</ref> in the SI, respectively.</s>
<s>All spectra of the new derivatives displayed a vibration band at 1633–1655 cm <hi rend="superscript">–1</hi> corresponding to the (−CN) group.</s>
<s>The aromatic ring showed a stretching vibration band ranging from 1400 to 1500 cm <hi rend="superscript">–1</hi> related to the C–C bond, while the absorption band at 1057 cm <hi rend="superscript">–1</hi> corresponded to the aromatic in-plane C–H bending.</s>
<s>
<ref target="#ref34" type="bibr"/> No band was observed in the region 1660–1730 cm <hi rend="superscript">–1</hi> , which proved the absence of the carbonyl group, which in turn indicated that no residue of free aldehydes remained.</s>
<s>The vibration bands at 2921 and 2883 cm <hi rend="superscript">–1</hi> were related to the C–H stretching of methyl and methylene groups, respectively.</s>
<s>
<ref target="#ref34" type="bibr"/> The glycosidic bonds showed bands at 1155 and 900 cm <hi rend="superscript">–1</hi> .</s>
<s>The vibration bands at 1205–975 cm <hi rend="superscript">–1</hi> were related to the C–O, C–C, and C–O–C stretching of glycosidic bonds and the pyranose ring.</s>
<s>
<ref target="#ref35" type="bibr"/>
</s>
</p>
<p>
<s>The structure of the prepared CSSBs was confirmed by <hi rend="superscript">1</hi> H and <hi rend="superscript">13</hi> C NMR.</s>
<s>The <hi rend="superscript">1</hi> H NMR spectra of the synthesized derivatives CS-P1, CS-P2, and CS-P3 are shown in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Figures S13–S15</ref> in the SI, respectively.</s>
<s>The <hi rend="superscript">13</hi> C NMR spectra for CS-P1, CS-P2, and CS-P3 are shown in <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">Figures S16–S18</ref> in the SI, respectively.</s>
<s>The <hi rend="superscript">1</hi> H and <hi rend="superscript">13</hi> C NMR data of all SBs are shown below.</s>
</p>
</div>
<div n="2.2.1.2" xml:id="sec2.2.1.2">
<head>Compound
CS-P1</head>
<p>
<s>δ <hi rend="subscript">H</hi> (500 MHz, <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO) 7.33 (1H, d, <hi rend="italic">J</hi> 0.8), 6.84 (1H, dd, <hi rend="italic">J</hi> 7.5, 1.4), 6.78 (1H, td, <hi rend="italic">J</hi> 7.5, 1.4), 6.38 (1H, td, <hi rend="italic">J</hi> 7.5, 1.4), 6.33 (1H, dd, <hi rend="italic">J</hi> 7.5, 1.5), 6.12 (1H, s), 5.83 (1H, d, <hi rend="italic">J</hi> 2.5), 5.04 (1H, d, <hi rend="italic">J</hi> 0.8), 4.93 (1H, s), 4.25 (1H, s), 3.92 (1H, s), 3.62 (1H, td, <hi rend="italic">J</hi> 7.7, 4.0), 3.46 (1H, dd, <hi rend="italic">J</hi> 12.2, 6.0), 3.35 (1H, ddd, <hi rend="italic">J</hi> 9.4, 5.9, 3.5), 3.21 (1H, dd, <hi rend="italic">J</hi> 12.3, 5.9), 3.00 (1H, dd, <hi rend="italic">J</hi> 4.0, 2.5), 1.80 (1H, ddd, <hi rend="italic">J</hi> 12.3, 7.7, 3.5), 1.31 (1H, ddd, <hi rend="italic">J</hi> 12.3, 7.7, 3.5).</s>
</p>
<p>
<s>δ <hi rend="subscript">C</hi> (125 MHz, <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO)153.38,</s>
<s>143.12, 134.23, 131.24, 129.33, 127.75, 122.07, 120.77, 114.44, 95.68, 74.70, 73.70, 69.45, 66.03, 37.86.</s>
</p>
</div>
<div n="2.2.1.3" xml:id="sec2.2.1.3">
<head>Compound CS-P2</head>
<p>
<s>δ <hi rend="subscript">H</hi> (500 MHz, <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO) 7.84 (1H, s), 7.64 (1H, s), 7.30 (1H, s), 7.25 (1H, dd, J 7.5, 1.5), 6.45 (1H, d, J 7.5), 6.14 (1H, d, J 3.1), 5.67 (1H, s), 5.53 (1H, s), 5.26 (2H, s), 3.88 (1H, td, J 7.8, 5.0), 3.64 (1H, s), 3.37 (1H, dd, J 12.4, 1.3), 3.25 (1H, ddd, J 4.8, 3.4, 1.3), 3.11 (1H, dd, J 12.4, 1.3), 2.89 (1H, dd, J 5.0, 3.1), 1.70 (1H, ddd, J 12.3, 7.8, 3.5), 1.30 (1H, ddd, J 12.3, 7.8, 3.5).</s>
</p>
<p>
<s>δ <hi rend="subscript">C</hi> (125 MHz, <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO) 164.71, 147.34, 147.27, 139.42, 132.73, 125.45, 121.55, 112.39, 96.94, 75.14, 74.96, 70.71, 67.29, 63.16, 39.52, 39.12.</s>
</p>
</div>
<div n="2.2.1.4" xml:id="sec2.2.1.4">
<head>Compound CS-P3</head>
<p>
<s>δ <hi rend="subscript">H</hi> (500 MHz, <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO) 7.36 (1H, d, J 0.8), 6.38 (1H, d, J 2.5), 5.72 (1H, s), 5.26 (1H, s), 4.56 (1H, d, J 0.8), 4.33 (1H, s), 4.18–3.99</s>
<s>(2H, m), 3.89 (1H, s), 3.63 (1H, dd, J 12.4, 1.3), 3.52 (1H, ddd, J 4.9, 3.5, 1.3), 3.38 (1H, dd, J 12.4, 1.3), 3.16 (1H, dd, J 4.4, 2.5), 1.96 (1H, ddd, J 12.3, 7.8, 3.6), 1.54 (1H, ddd, J 12.3, 7.8, 3.6).</s>
</p>
<p>
<s>δ <hi rend="subscript">C</hi> (125 MHz, <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO) 158.92, 152.49, 134.20, 97.34, 86.33, 75.36, 71.11, 67.70, 64.24, 39.52, 34.06.</s>
</p>
<p>
<s>The synthesized new CSSBs presented typical peaks of the Cs and SB parts.</s>
</p>
</div>
<div n="2.2.1.5" xml:id="sec2.2.1.5">
<head>Solubility Study</head>
<p>
<s>Different organic solvents were used to test the solubility of the synthesized compounds.</s>
<s>
<ref target="#tbl1" type="table">Table <ref target="#tbl1" type="table"/>
</ref> shows the results.</s>
<s>The prepared compounds dissolve in dimethyl sulfoxide and mixtures of equal proportions of dimethyl sulfoxide and trifluoroacetic acid.</s>
<s>Partial dissolution or swelling was observed in some solvents such as dilute hydrochloric acid and acetic acid at 70 °C.</s>
<s>In contrast, the products are not soluble in most inorganic solvents.</s>
</p>
<table cols="0" rend="float" rows="0" xml:id="tbl1">
<head type="label">1</head>
<head type="caption-title">Solubility Characteristics of CSSBs
in a Variety of Solvents<ref target="#t1fn1" type="table-fn"/>
</head>
<head> solvents CH3COOH CF3COOH DMSO HCl NaOH H2O KOH DMSO + CF3COOH comp. codes 25 °C 70 °C 25 °C 70 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C</head>
<row>
<cell>CS-P1</cell>
<cell>S+</cell>
<cell>S*</cell>
<cell>S**</cell>
<cell>S**</cell>
<cell>S</cell>
<cell>S*</cell>
<cell>S+</cell>
<cell>S+</cell>
<cell>S**</cell>
<cell>S</cell>
</row>
<row>
<cell>CS-P2</cell>
<cell>S+</cell>
<cell>S*</cell>
<cell>S**</cell>
<cell>S**</cell>
<cell>S</cell>
<cell>S*</cell>
<cell>S+</cell>
<cell>S+</cell>
<cell>S**</cell>
<cell>S</cell>
</row>
<row>
<cell>CS-P3</cell>
<cell>S+</cell>
<cell>S*</cell>
<cell>S**</cell>
<cell>S**</cell>
<cell>S</cell>
<cell>S*</cell>
<cell>S+</cell>
<cell>S+</cell>
<cell>S**</cell>
<cell>S</cell>
</row>
<note type="table-wrap-foot">
<note place="inline" xml:id="t1fn1">
<ref>a</ref>
<p>S = soluble, S+ = insoluble, S*
= partially soluble and swelling, S** = partially soluble.</p>
</note>
</note>
</table>
</div>
</div>
<div n="2.2.2" xml:id="sec2.2.2">
<head>In
Vitro Cytotoxicity Study</head>
<p>
<s>The cytotoxicity assay for the synthesized compounds was carried out based on MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide].</s>
<s>MTT assay is a colorimetric assay used for assessing cell viability and to measure cytotoxicity.</s>
<s>As illustrated in <ref target="#tbl2" type="table">Table <ref target="#tbl2" type="table"/>
</ref> , the results of the tested compounds CS-P1, CS-P2, and CS-P3 show a small variation between samples in comparison with the control.</s>
<s>Several earlier research studies have demonstrated that CS and CSSB derivatives have little cellular toxicity.</s>
<s>Consequently, CS has many applications in the medical field.</s>
<s>
<name type="bibref-group">
<ref target="#ref36" type="bibr"/>−<ref target="#ref37" type="bibr"/>
<ref target="#ref38" type="bibr"/>
</name> The assay revealed that using a higher amount of the sample (200 mg) showed a cell viability of 89, 90, 90.1, and 91% for CS, CS-P1, CS-P2, and CS-P3, respectively.</s>
<s>Conversely, a smaller amount (25 mg) of the tested compound showed a slight cytotoxicity of up to 2.5% compared with high concentrations, which is extremely suitable in medical applications.</s>
<s>According to reported studies, compounds with higher than 75% cell viability are considered noncytotoxic.</s>
<s>
<ref target="#ref39" type="bibr"/> The cell viability assessment proved that the selection of these compound may depend on the antibacterial activity for their use in medical applications.</s>
</p>
<table cols="0" rend="float" rows="0" xml:id="tbl2">
<head type="label">2</head>
<head type="caption-title">Cytotoxicity Test of CS and Their
SB Derivatives on the Viability of Mouse Fibroblast Cell Lines<ref target="#t2fn1" type="table-fn"/>
</head>
<head>comp. conc. (mg) viable
cells in the presence of CS viable cells
in the presence of CS-P1 viable cells
in the presence of CS-P2 viable cells
in the presence of CS-P3</head>
<row>
<cell>25</cell>
<cell>99 ± 0.83</cell>
<cell>99 ± 0.73</cell>
<cell>99 ± 0.60</cell>
<cell>99 ± 0.75</cell>
</row>
<row>
<cell>50</cell>
<cell>97 ± 0.73</cell>
<cell>99 ± 0.91</cell>
<cell>98.1 ± 1.3</cell>
<cell>99 ± 0.89</cell>
</row>
<row>
<cell>100</cell>
<cell>94 ± 0.63</cell>
<cell>98 ± 0.74</cell>
<cell>98 ± 1.2</cell>
<cell>98 ± 0.50</cell>
</row>
<row>
<cell>150</cell>
<cell>93 ± 0.88</cell>
<cell>97 ± 0.65</cell>
<cell>98 ± 0.62</cell>
<cell>96 ± 1.2</cell>
</row>
<row>
<cell>200</cell>
<cell>89 ± 0.53</cell>
<cell>90 ± 0.72</cell>
<cell>90.1 ± 0.74</cell>
<cell>91 ± 1.2</cell>
</row>
<note type="table-wrap-foot">
<note place="inline" xml:id="t2fn1">
<ref>a</ref>
<p>The experiment
was repeated three
times and the mean was calculated.</p>
</note>
</note>
</table>
</div>
<div n="2.2.3" xml:id="sec2.2.3">
<head>Antimicrobial Study</head>
<p>
<s>The inhibition zone technique was used to assess the antibacterial activity of the CSSB derivatives.</s>
<s>The results are shown in <ref target="#tbl3" type="table">Table <ref target="#tbl3" type="table"/>
</ref> .</s>
<s>From the results, all of the CSSBs and CS have a similar impact on strains of both <name type="genus-species">E. coli</name> and <name type="genus-species">K. pneumonia</name> and is similar to that of Cs.</s>
<s>The reported study demonstrated that CS could terminate the cell formation of <name type="genus-species">S. aureus</name> and <name type="genus-species">E. coli</name> .</s>
<s>
<ref target="#ref40" type="bibr"/> CSSBs showed antibacterial action against <name type="genus-species">S. aureus</name> with an inhibition zone of 22 ± 0.3, 20 ± 1.2, and 19 ± 0.62 mm for CS-P1, CS-P2, and CS-P3, respectively.</s>
<s>The results also revealed that CS-P1, CS-P2, and CS-P3 have antibacterial action against <name type="genus-species">S. mutans</name> with an inhibition zone of 15 ± 0.89, 17 ± 0.50, and 18 ± 1.20 mm, respectively.</s>
<s>Antifungal activity tests against two strains of fungi were carried out, and all verified CSSBs presented good results.</s>
<s>The difference in inhibition between the two strains may result from the variances in the cell wall structures.</s>
<s>From the result, it may be confirmed that the antibacterial action is through the breakage of the cell wall rather than the mechanism of interaction of CS derivatives with the DNA in the microorganism.</s>
<s>The reaction of the active group on the CSSBs with the cell wall reduces permeability, which causes a shortage of substances in the cell, for example, amino acids, proteins, electrolytes, and lactate dehydrogenase.</s>
<s>Therefore, the synthesized compounds lead to the inhibition of the metabolism of the bacteria and cause death.</s>
<s>
<ref target="#ref41" type="bibr"/>
</s>
</p>
<table cols="0" rend="float" rows="0" xml:id="tbl3">
<head type="label">3</head>
<head type="caption-title">Antimicrobial
and Antifungal Activity
Results of CS and CSSB Derivatives<ref target="#t3fn1" type="table-fn"/>
</head>
<head> Gram-negative
bacteria Gram-positive
bacteria fungi comp. codes
E. coli
K. pneumonia
S. aureus
S. mutans
C. albicans
A. fumigatus
</head>
<row>
<cell>CS</cell>
<cell>24 ± 0.63</cell>
<cell>26 ± 0.73</cell>
<cell>NA</cell>
<cell>NA</cell>
<cell>26 ± 0.79</cell>
<cell>16 ± 0.83</cell>
</row>
<row>
<cell>CS-P1</cell>
<cell>22 ± 0.73</cell>
<cell>28 ± 0.91</cell>
<cell>22 ± 0.3</cell>
<cell>15 ± 0.89</cell>
<cell>34 ± 0.99</cell>
<cell>26 ± 0.91</cell>
</row>
<row>
<cell>CS-P2</cell>
<cell>27 ± 0.83</cell>
<cell>27 ± 0.72</cell>
<cell>20 ± 1.2</cell>
<cell>17 ± 0.50</cell>
<cell>31 ± 1.29</cell>
<cell>25 ± 0.72</cell>
</row>
<row>
<cell>CS-P3</cell>
<cell>22 ± 0.98</cell>
<cell>26 ± 0.65</cell>
<cell>19 ± 0.62</cell>
<cell>18 ± 1.20</cell>
<cell>26 ± 0.49</cell>
<cell>21 ± 0.65</cell>
</row>
<note type="table-wrap-foot">
<note place="inline" xml:id="t3fn1">
<ref>a</ref>
<p>NA means not detected.</p>
</note>
</note>
</table>
<p>
<s>Based on reported research, <ref target="#ref42" type="bibr"/> many mechanisms are proposed to clarify the action path of CS on microorganisms, which differs depending on the metabolic procedure and the structure of the cell wall.</s>
<s>The first suggestion is the interruption of the cell wall of the organism because of the electrostatic attraction between the positively charged amine groups in CS and the negative residue group in the bacterial cell wall, such as −COO <hi rend="superscript">–</hi> or PO <hi rend="subscript">4</hi>
<hi rend="superscript">3–</hi> .</s>
<s>The second mechanism suggested is the interaction of bacterial DNA with CS, which causes the inhibition of protein synthesis and mRNA by permeation of CS into the bacterial cell and then the nuclei.</s>
<s>Another suggestion is based on the ability of CS to form a complex with metals, for instance, Zn <hi rend="superscript">2+</hi> , Mg <hi rend="superscript">2+</hi> , and Ca <hi rend="superscript">2+</hi> ; these metals are important for bacterial metabolic processes and growth.</s>
</p>
</div>
</div>
</div>
<div n="3" xml:id="sec3">
<head>Conclusions</head>
<p>
<s>The search for new antibiotics has increased parallelly to the increase in the number of antibiotic-resistant microbes known as superbugs.</s>
<s>CS might be a promising material in this field.</s>
<s>CS with DD = 89% was extracted from the scales of <hi rend="italic">Cyprinus carpio</hi> fish obtained from the local market.</s>
<s>The structure of CS was characterized, and the DD % was determined by the acid–base titration method.</s>
<s>Three novel CSSB derivatives with different parts as branches were synthesized, and their configurations were proved by FT-IR and <hi rend="superscript">1</hi> H and <hi rend="superscript">13</hi> C NMR spectroscopy.</s>
<s>The new SB structure showed antibacterial activity against most microorganisms and fungi that were tested.</s>
<s>The prepared CSSBs demonstrated, almost, no cytotoxic effect on mouse fibroblast cell lines.</s>
<s>In light of the above findings, it is safe to say that the prepared CSSBs might be used in different biomedical fields with a high degree of safety and efficacy.</s>
</p>
</div>
<div n="4" xml:id="sec4">
<head>Materials and Methods</head>
<div n="4.1" xml:id="sec4.1">
<head>Materials</head>
<div n="4.1.1" xml:id="sec4.1.1">
<head>Chemicals and Raw Resources</head>
<p>
<s>
<hi rend="italic">Cyprinus carpio</hi> fish scales were collected from the local market in Kirkuk city, Iraq.</s>
<s>Its DD was 89%, which was confirmed via a titration procedure.</s>
<s>
<ref target="#ref43" type="bibr"/> Ethanol (99.7%), hydrochloric acid (37%), 2-chloroquinoline-3-carbaldehyde, methyl orange, quinazoline-6-carbaldehyde, oxazole-4-carbaldehyde, and acetic acid were obtained from Merck (Germany).</s>
<s>Sodium hydroxide pellets, sodium bicarbonate, hexamethylentetramine, magnesium sulfate, aqueous ammonia, sodium borohydride, tetrachloromethane, and trifluoroacetic were purchased from R&M Chemicals Pvt. Ltd., India.</s>
<s>Aniline blue was purchased from Alpha Chemika, India.</s>
<s>All reagents were of analytical grade and directly used without any further purification.</s>
</p>
</div>
<div n="4.1.2" xml:id="sec4.1.2">
<head>Devices</head>
<p>
<s>FT-IR spectra were obtained using a PerkinElmer System 2000 FT-IR spectrometer.</s>
<s>A PerkinElmer TGA 7 thermogravimetric analyzer was applied.</s>
<s>A PerkinElmer 2400 Series II analyzer was used to determine the percentage of N in the samples.</s>
<s>A Bruker AC-400 NMR spectrometer was used to record the <hi rend="superscript">1</hi> H and <hi rend="superscript">13</hi> C NMR spectra.</s>
<s>Deuterated dimethyl sulfoxide ( <hi rend="italic">d</hi>
<hi rend="subscript">6</hi> -DMSO) was used as the solvent.</s>
</p>
</div>
</div>
<div n="4.2" xml:id="sec4.2">
<head>Microorganisms</head>
<p>
<s>Two eukaryote and four bacterial strains were used for assessing the antimicrobial effectiveness of CS and the newly prepared derivatives.</s>
<s>The examined microorganisms included four species of bacteria, <name type="genus-species">E. coli</name> , <name type="genus-species">K. pneumonia</name> , <name type="genus-species">S. aureus</name> , and <name type="genus-species">S. mutans</name> , in addition to two species of fungi, <name type="genus-species">C. albicans</name> and <name type="genus-species">A. fumigates</name> .</s>
<s>These organisms were collected from the biology department of Kirkuk University from patients who had a liver transplant.</s>
<s>Nutrient agar was used as a culture medium.</s>
<s>The strains were refreshed through inoculating Luria-Bertani (LB) culture medium, <name type="bibref-group">
<ref target="#ref44" type="bibr"/>,<ref target="#ref45" type="bibr"/>
</name> 1% peptone, 0.5% yeast extract, and 1% NaCl and kept at 37 °C and pH 7 ±0.2 for 18 h.</s>
<s>The inhibition ability of CS and SB derivatives was assessed.</s>
<s>A 48-well plate was coated with samples, and 250 μL of the organism suspension (100 CFU/mL) was kept at 37 °C with LB culture.</s>
<s>The latter was incubated at 37 °C for 1 day.</s>
<s>Dimethyl sulfoxide (DMSO) was employed as a solvent and served as a control sample.</s>
</p>
</div>
<div n="4.3" xml:id="sec4.3">
<head>Cytotoxicity
Evaluation</head>
<p>
<s>The cytotoxicity evaluation of CS and the new SB derivatives was carried out using MTT assay.</s>
<s>A change in the reagent color to yellow was an indication of cell viability.</s>
<s>
<ref target="#ref40" type="bibr"/> Laminar flow cabinet biosafety class III was used to carry out all tests.</s>
<s>A mouse fibroblast cell line (NIH3T3) was used in the test, which was grown in Dulbecco’s modified Eagle’s medium (DMEM), completed with trypsin/EDTA (100 μg/mL), and enriched with 10% FBS at 37 °C.</s>
<s>Different amounts (25, 50, 100, 150, and 200 mg) of CS and the SB derivatives were used to assess their cytotoxicity.</s>
<s>For the assessment of cytotoxicity of the newly prepared compounds, a microtiter plastic plate with 96 wells was coated with cells at a concentration of 10 × 10 <hi rend="superscript">3</hi> cells per well and incubated overnight.</s>
<s>The cells were incubated for 48 h with a Schiff base sample concentration of 90 μg/mL and alone as a negative control.</s>
<s>At the end of the incubation time MTT (40 μL, 3 μg/mL) was added and kept at 37 °C for another 4 h.</s>
<s>After the formation of crystals, sodium dodecyl sulfate (SDS) in distilled water (15%, 250 μL) was added to end the reaction.</s>
<s>Doxorubicin (100 μg/mL) was used as a positive control under the same conditions.</s>
<s>The absorbance was recorded at 595 and 620 nm as standard wavelengths.</s>
<s>The tests were repeated three times ( <hi rend="italic">n</hi> = 3), and the mean value with mean ± SD was calculated.</s>
<s>The SPSS 11 program was used to calculate the statistical significance between samples and the negative control.</s>
<s>The below equation was used to calculate the percentage of change in cell viability <name type="bibref-group">
<ref target="#ref46" type="bibr"/>,<ref target="#ref47" type="bibr"/>
</name>
<formula n="3" rend="display" xml:id="eq3"/>
</s>
</p>
</div>
<div n="4.4" xml:id="sec4.4">
<head>Extraction of CS from Fish Scales</head>
<p>
<s>Approximately 100 g of fish scales was weighed and then washed and sun-dried for 3 days.</s>
<s>The fish scales were crushed using a high-speed Hamilton beach blender.</s>
<s>The scales were then immersed in hot ethanol (50–60 °C) for an hour to kill the germs and remove the pungent odor.</s>
<s>The resulting sample (designated as C <hi rend="subscript">1</hi> ) was washed with an ample amount of water and subjected to freeze-drying.</s>
<s>C <hi rend="subscript">1</hi> was treated with 5% HCl at 25 °C for 24 h to eliminate the CaCO <hi rend="subscript">3</hi> component through a demineralization process.</s>
<s>Then, 10.0 g of the sample was collected and labeled C <hi rend="subscript">2</hi> .</s>
<s>The remaining sample was processed with a deproteinization step; 10% NaOH was used to remove the protein component at 60 °C.</s>
<s>Then, 10.0 g of the sample was collected and labeled C <hi rend="subscript">3</hi> .</s>
<s>The remaining sample was subjected to a deacetylation process by treating with NaOH (50%) under refluxing conditions to produce CS.</s>
<s>Then, 10.0 g of the sample was collected and labeled C <hi rend="subscript">4</hi> .</s>
<s>
<ref target="#ref48" type="bibr"/>
</s>
</p>
</div>
<div n="4.5" xml:id="sec4.5">
<head>Synthesis of CSSB Derivatives</head>
<p>
<s>The new CSSB derivatives were synthesized according to a reported method.</s>
<s>
<ref target="#ref49" type="bibr"/> A gram of CS in 50 mL of glacial acetic acid (2%) was stirred at 25 °C for 7 h.</s>
<s>A mixture of the aldehyde was dissolved in ethanol (1:1, molar ratio aldehyde to CS) that was added to the mixture gradually.</s>
<s>The mixture was stirred and heated in a water bath at 50 °C for 10 h.</s>
<s>Aqueous sodium hydroxide 6% was added to the reaction mixture until precipitation of the desired compound.</s>
<s>The precipitate was collected and washed several times with distilled water and ethanol to remove any remaining materials.</s>
<s>The products were filtered and dried in a vacuum oven at 60 °C overnight.</s>
<s>The schematic diagram shown in <ref target="#sch1" type="scheme">Scheme <ref target="#sch1" type="scheme"/>
</ref> illustrates the synthesis routes to the new CSSBs.</s>
</p>
</div>
<div n="4.6" xml:id="sec4.6">
<head>Characterization of Extracted CS</head>
<div n="4.6.1" xml:id="sec4.6.1">
<head>Acid–Base Titration</head>
<div n="4.6.1.1" xml:id="sec4.6.1.1">
<head>Preparation
of the Indicators</head>
<p>
<s>A solution of methyl orange and aniline blue (0.10 g of each, 100 mL of distilled water) was added to a beaker, separately.</s>
<s>The mixture was then transferred into a volumetric flask (100 mL).</s>
</p>
</div>
<div n="4.6.1.2" xml:id="sec4.6.1.2">
<head>Titration Methods</head>
<p>
<s>In four clean and dry conical flasks, 0.30 g of each sample, C <hi rend="subscript">3</hi> , C <hi rend="subscript">4</hi> , CH, and CS, was added.</s>
<s>Then, 30 mL of 0.1 M HC was added to each flask.</s>
<s>Equivalent amounts of both methyl orange and aniline blue solutions were added to each set; the mixture was mixed with a glass rod until the color of the mixture became stable.</s>
<s>The titration method was carried out for each sample set against NaOH (0.1 M) until the indicator color changed.</s>
</p>
</div>
</div>
<div n="4.6.2" xml:id="sec4.6.2">
<head>FT-IR
Analysis</head>
<p>
<s>FT-IR spectra of CH, CS, C <hi rend="subscript">3</hi> , and C <hi rend="subscript">4</hi> and the CSSB derivatives (CS-P1, CS-P2, and CS-P3) were recorded via a FT-IR spectroscope (Model 8400, Shimadzu).</s>
<s>KBr was mixed with 2 mg of the sample and pressed to form a homogeneous disc with ≈0.5 mm thickness.</s>
<s>The spectral region between 4000 and 400 cm <hi rend="superscript">–1</hi> was scanned.</s>
</p>
</div>
<div n="4.6.3" xml:id="sec4.6.3">
<head>Thermogravimetric Investigation (TGA)</head>
<p>
<s>The thermal stability of deacetylated CS was evaluated; approximately 5 mg of CS was analyzed using a thermogravimetric analyzer (model 50/50H, Shimadzu).</s>
<s>The heating was done as described from 60 to 750 °C at a rate of of 5 °C/min under 30 mL/min flow rate of nitrogen.</s>
<s>
<ref target="#ref50" type="bibr"/>
</s>
</p>
</div>
</div>
</div>
</body>
<back>
<p>
<s>The Supporting Information is available free of charge at <ref target="https://pubs.acs.org/doi/10.1021/acsomega.0c01342?goto=supporting-info">https://pubs.acs.org/doi/10.1021/acsomega.0c01342</ref> .</s>
<list type="label" xml:id="silist">
<item>
<p>
<s>General procedure and details of the treatment of CS and CH; tables show the results of the acid–base titration method and the characteristic absorption bands in the FT-IR spectra of standard and experimentally prepared CS; figures display the DD % of samples; TG and DTG plots; and <hi rend="superscript">1</hi> H NMR, <hi rend="superscript">13</hi> C NMR, and FT-IR spectra for all prepared compounds ( <ref target="http://pubs.acs.org/doi/suppl/10.1021/acsomega.0c01342/suppl_file/ao0c01342_si_001.pdf">PDF</ref> )</s>
</p>
</item>
</list>
</p>
<p>
<s>All authors contributed to the writing of the manuscript.</s>
<s>All authors have approved the final version of the manuscript.</s>
<s>The photo in <ref target="#fig1" type="fig">Figure <ref target="#fig1" type="fig"/>
</ref> was taken by the authors.</s>
</p>
<p>
<s>The authors declare no competing financial interest.</s>
</p>
<div type="acknowledgements">
<p>
<s>M.O.M. wishes to thank the Ministry of Higher Education and Scientific Research, Iraq, for the award of a grant, and the authors acknowledge the Department of Biology, College of Science, Kirkuk University, Iraq, for their help with carrying out the biological tests.</s>
</p>
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</back>
</text>
</TEI>
One could use this tool to first unify all different downloaded files from different publisher styles and afterwards remove irrelevant section of these articles automatically as shown in the beginning of this section.