Communications in Science and Technology 10.
29Ae35
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Formation and stability investigation of meso-hydroxy diacyldipyrromethane Mohammad Akbar Ferryansyaha.
Anas Santriab,c.
Naoto Ishikawab.
Dikhi Firmansyaha,* Organic Chemistry Division.
Department of Chemistry.
Faculty of Mathematics and Natural Sciences.
Institut Teknologi Bandung.
Bandung 40132.
Indonesia Department of Chemistry.
Graduate School of Science.
The University of Osaka.
Osaka 560-0043.
Japan Research Center for Chemistry.
National Research and Innovation Agency.
Tangerang Selatan 15314.
Indonesia Article history:
Received: 1 December 2024 / Received in revised form: 5 March 2025 / Accepted: 8 March 2025 Abstract The oxidation of dipyrromethane by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) generally produces dipyrrin, but in the presence of trace water, a meso-hydroxy dipyrromethane can be formed.
To investigate this unusual product, we then studied meso-hydroxy bis.
-anisoy.
-pfluorophenyl dipyrromethane .
obtained from the oxidation of bis.
-anisoy.
-p-fluorophenyl dipyrromethane .
Spectroscopic studies .
HNMR.
UV-Vis, and fluorescenc.
, mass spectrometry, and computational analyses were performed to investigate this mechanism.
Zinc complexation of compound 3 altered the 1H-NMR spectrum and shifted the absorption peak from 325 nm to 567 nm with Auturn-onAy fluorescence.
Thermochemical studies have indicated that the formation of meso-hydroxy requires energy higher than dipyrrin.
This study suggests that the electronic properties of meso-aryl and acyl groups are the key factors for the nucleophilic attack of water on cationic dipyrromethane These results further improve the understanding of dipyrromethane oxidation pathways, which is crucial for the design and synthesis of dipyrrin-chemosensors.
Keywords: Acyl dipyrromethene.
DDQ oxidation.
zinc dipyrrin complex.
computational study Introduction Dipyrromethane (DPM) is widely used as a precursor for calixpyrroles, as well as dipyrrin and its metal-dipyrrin Dipyrrins can be obtained through the dipyrromethane oxidation using an oxidant such as 2,3dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or 2,3,5,6tetrachloro-1,4-benzoquinone .
-chlorani.
These compounds and their derivatives have potential applications in bioimaging, and photodynamic therapy, and act as pigments in dye-sensitized solar cells .
Dipyrromethane has also been used as a catalyst in olefin hydroamination and hydrogen transfer reactions .
Among these, acyl dipyrrin has been reported as a potential chemosensor for zinc (II) ions with chelation-enhanced fluorescence (CHEF) Auturn-onAy process .
Inadvertently, some diacyl dipyrromethanes produced meso-hydroxy DPM through the oxidation of dipyrromethanes using DDQ .
These compounds were proposed to be obtained via the formation of a carbocation intermediate reacting with trace Upon closer inspection, meso-hydroxy diacyl * Corresponding author.
email: dikhfi@itb.
https://doi.
org/10.
21924/cst.
dipyrromethane exhibited slower complexation, then rising a question regarding the stability of this DPM compared to the dipyrrin species.
In this study, we report the formation of a meso-hydroxy acyl dipyrromethane derivative using NMR and MS with a focus on the effects of the meso- and diacyl substituents.
The fluorine and anisoyl groups offer the unique duality of inductive electron-withdrawing and mesomeric electrondonating effects.
UV-vis and fluorescence measurements were performed to observe the optical properties of the zinc(II) We also employed computational methods using density functional theory (DFT) to examine the thermochemical and electronic parameters of all intermediates and products involved in the formation of meso-hydroxy acyl dipyrromethane and compared these results with those of known DPM derivatives.
These findings contribute to a deeper understanding of the formation, stability, and complexation of meso-hydroxy acyl dipyrromethanes and their potential Materials and Methods Chemicals and reagents Commercially available solvents and reagents from Aldrich This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.
0 license Ferryansyah et al.
/ Communications in Science and Technology 10.
29Ae35 were used as received.
The crude product was purified by column chromatography on silica gel 60G .
Ae230 mesh ASTM.
Merc.
and monitored by thin-layer chromatography (TLC) using silica gel 60 F254 (Merc.
Synthesis Fig.
1 depicts the synthetic route to meso-hydroxy bis.
-p-fluorophenyl dipyrromethane .
The structures of p-fluorophenyl dipyrromethane .
and bis.
-anisoy.
-pfluorophenyl dipyrromethane .
were identified by 1H NMR and 13C spectroscopy by means of an Agilent DD2 instrument.
H-NMR spectra recorded with a JEOL ECZS confirmed the structure of compound 3 and the identification of its zinc complex.
Zn-3.
Compound 3 was characterized using MALDIMS in the positive linear mode on a Shimadzu AXIMA Performance instrument with dithranol as the matrix.
Furthermore.
HRMS measurements in positive mode by means of ESI-TOF Waters LCT Premier XE were carried out to verify the presence of compound 3.
Compound 1 was synthesized following a previously reported procedure, and its spectroscopic data were consistent with those reported previously .
H, s.
H-mes.
, 5.
H, s.
H-pyrrol.
, 6.
H-pyrrol.
, 6.
H, d, 3J = 8.
8 Hz.
H-benzoy.
, 7.
t, 3J = 8.
6 Hz.
H-pheny.
, 7.
H, dd, 3J = 8.
4 Hz and 4J 4 Hz.
H-pheny.
, 7.
H, d, 3J = 8.
8 Hz.
H-benzoy.
, and 94 .
H, broad s.
NH).
13CNMR .
MHz.
CDCl.
3 (CH-mes.
, 55.
4 (OCH.
, 111.
0 (CH-pyrrol.
, 113.
3 (CHbenzoy.
, 115.
5 and 115.
, 2J = 21.
3 Hz.
CH-pheny.
, 120.
(CH-pyrrol.
, 130.
, 2J = 8.
8 Hz.
CH-pheny.
, 130.
9 (Cqpyrrol.
, 131.
1 (Cq-benzoy.
, 131.
8 (CH-benzoy.
, 136.
, 4J = 3.
8 Hz.
Cq-pheny.
, 140.
5 (Cq-pyrrol.
, 161.
1 and 163.
J = 245.
0 Hz.
Cq-F-pheny.
, 162.
5 (Cq-O-benzoy.
, and 183.
(C=O).
Synthesis of meso-hydroxy bis.
-anisoy.
-p-fluorophenyl dipyrromethane .
The oxidation of acyl dipyrromethane was conducted following a previously reported procedure .
A solution of compound 2 .
mg, 0.
059 mmol, 1 e.
in 6 mL CH2Cl2 was added to a flask containing DDQ .
mg, 0.
062 mmol, 1.
05 e.
and stirred for 2h.
Once it was complete, the solvent was removed in vacuo.
The residue was purified by column chromatography on silica gel using a dichloromethane:ethyl acetate .
eluent and recrystallized from methanol to yield 5 mg .
%) of a reddish-white solid.
The 1H NMR .
MHz.
CDCl.
revealed signals at .
H, s.
H-methox.
, 91 .
H, dd, 3J = 3.
8 Hz and 4J = 2.
6 Hz.
H-pyrrol.
, 6.
H, broad s.
OH-mes.
, 6.
H, dd, 3J = 3.
8 Hz and 4J = 2.
5 Hz.
H-pyrrol.
, 6.
H, d, 3J = 8.
9 Hz.
H-benzoy.
, 02 .
H, t, 3J = 8.
8 Hz.
H-pheny.
, 7.
H, dd, 3J = 8.
9 Hz and 4J = 5.
3 Hz.
H-pheny.
, 7.
H, d, 3J = 8.
Hz.
H-benzoy.
, and 11.
H, broad s.
NH).
HRMS-ESI
1646, calculated 547.
1645 for [M N.
(C31H25FN2NaO5 ).
Zinc complexation Fig.
Synthesis of meso-hydroxy bis.
-anisoy.
-p-fluorophenyl Synthesis of bis.
-anisoy.
-p-fluorophenyl dipyrromethane .
Compound 2 was prepared in accordance to a modified literature procedure .
It began by adding 72 mg .
54 mmol, 57 e.
of AlCl3 to a solution of p-anisoyl chloride .
mg, 56 mmol, 2.
67 e.
2 mL dichloromethane.
The mixture was then stirred for 30 min under an inert nitrogen atmosphere at room temperature.
Subsequently, a solution of compound 1 .
mg, 0.
21 mmol, 1 e.
3 mL dichloromethane was added slowly, and the reaction continued for 2 h.
Upon completion, 8 mL of distilled water was added, the mixture was extracted, the organic layer was collected, and the solvent was removed under reduced pressure.
The resulted brown solid was purified on silica gel using a dichloromethane: ethyl acetate .
eluent to afford a brown solid product .
9 mg, 30.
8%).
H NMR .
MHz.
CDCl.
H, s.
H-methox.
For the UVAeVis studies, a 10 AAM solution of compound 3 was prepared in methanol (Merck, analytical grad.
Aliquots of 200 AAM acetate standard solutions of Zn2 were added to UVAevis titrations were performed using an EvolutionE 220 UV-Visible Spectrophotometer (Thermo Scientifi.
with a 1 cm quartz cuvette at 20AC, while separate complex formation after 24 h was performed with the help of a UV-vis Perkin Elmer Lambda 25 UV-Vis Spectrophotometer.
The zinc complex .
ee Fig.
was prepared by adding excess Zn(OA.
2A2H2O .
5 mg, 10 e.
to a vial containing 1 mg of compound 3 dissolved in 254.
5 L of methanol to ensure the completion of the complexation.
The mixture was sonicated for 5 min until reaching full dissolution and it was then left at room temperature for 24 h.
After the solvent was removed under reduced pressure, a magenta solid .
5 m.
was obtained.
The dried sample was re-dissolved to a concentration of 10 AAM in methanol, and the UV-vis spectra were measured.
The structure of Zn-3 .
inc comple.
was identified by 1H-NMR spectroscopy (Jeo.
MS was carried out in the linear positive mode using MALDI-TOF (Shimadz.
with dithranol as the Furthermore, the emission spectra of the zinc complexes were measured using a DuettaE fluorescence and absorbance spectrometer (Horib.
Ferryansyah et al.
/ Communications in Science and Technology 10.
29Ae35 Fig.
Complexation of 3 with zinc acetate .
for 24 h Computational method shifts in the pyrrole proton signals, while the NH proton exhibited shielding, shifting from 11.
94 ppm to 11.
08 ppm.
addition, the meso-proton signal, initially observed as a sharp singlet at 5.
67 ppm, shifted to a broad singlet at 6.
07 ppm, indicating the formation of meso-OH (Fig.
HRMS-ESI data further confirmed the formation of 3 [M N.
at m/z 547.
However, the MALDI-TOF MS data revealed high-intensity peaks tentatively identified as DPM .
at m/z 509.
1871, [M H] ) and dipyrrin .
at m/z 506.
1715, [M H] ),
along with a lower intensity peak for compound 3 at m/z 0284 .
1820, [M H] ).
These results indicate that in ionic forms the DPM and dipyrrin are more stable than the meso-hydroxy species.
Molecular structures were modelled using BIOVIA TmoleX 2023 .
and Turbomole version 7.
Pre-optimization was first achieved using the GFN2-xTB method .
, followed by complete geometry optimization using DFT with the B3-LYP functional .
, def2-TZVP basis set .
, and DFT-D4 dispersion correction.
TD-DFT
calculations in Turbomole were used for electronic and excited state analyses, employing the similar functional, basis set, and dispersion correction as in the geometry optimization.
BIOVIA
TmoleX provided the visualization of the molecular orbitals and energy levels.
Thermochemical parameters were further calculated from frequency calculations using Turbomole with parameters analyzed using a BIOVIA TmoleX 2023.
Fig.
Comparison of 1H NMR spectra of .
3 and .
2 Results and Discussion Spectroscopic studies of Zinc complexation Synthesis and characterization The non-conjugated system of compound 3 resulted in a maximum absorption wavelength max at 325 nm (Fig.
shorter than that of dipyrrins .
-500 n.
such as allylvanillin dipyrrin .
Upon complexation with zinc(II), a new absorption peak was observed at 567 nm, expected for the complex with dipyrrin ligand.
The isosbestic point was monitored at 357 nm, indicating complexation with zinc(II) ions.
However, even after the addition of 20 eq.
of zinc(II) ions, the intensity of complex remained lower than that of the ligand.
The para-fluorophenyl substituent at the meso position, along with the anisoyl group, was selected with a consideration to its mesomeric electron donor nature, helping in stabilizing the carbocation intermediate.
Additionally, fluorineAos high electronegativity and small atomic radius allowed it to mimic the behavior of hydrogen and hydroxy group.
Compound 1 was successfully synthesized as a precursor of compound 2 with the yield of 66.
Dipyrromethane 1 was characterized by 1H NMR and identified by meso-proton signal at 5.
48 ppm, pyrrole signal in the range of 5.
90 to 6.
74 ppm, and NH signal 94 ppm.
The disubstituted aromatic pattern exhibited ortho-coupling .
, confirming the expected substitution The Friedel-Craft acylation of 1 using anisoyl chloride yielded acyl dipyrromethane 2 by 30.
The proton NMR spectrum of compound 2 displayed additional signals corresponding to the anisoyl substituent with benzoyl protons appearing at 7.
77 ppm and 6.
90 ppm, and a methoxy signal at 85 ppm.
The N-H pyrrole proton was deshielded after acylation .
94 ppm to 11.
91 pp.
This might be due to the hydrogen bonding between the N-H and oxygen from benzoyl C=O.
Furthermore, the loss of one signal of H-pyrrole in the -position confirmed successful acylation.
Compound 3 was synthesized by the oxidation of 2 using DDQ, followed by purification via silica gel chromatography and recrystallization from methanol, resulting in the yield of The proton NMR characterization revealed minimal Fig.
Complexation of 10 M 3 with 200 M Zn(CH3COO)2 0-20 eq molar in methanol and temperature of 20oC Ferryansyah et al.
/ Communications in Science and Technology 10.
29Ae35 After allowing the mixture to stand for 24 h, the absorption intensity of the zinc(II) complex at 567 nm significantly increased (Fig.
This suggested a slow complexation process between ligand 3 and zinc(II) due to the formation of dipyrrin as the true ligand.
The emission of the zinc complex was also measured and an emission peak was detected at 606 nm (Fig.
Further confirmation of complex formation was provided by MALDI-TOF MS where the peaks at 570.
0067 and 507.
were observed, which closely agreed with [(Zn-.
H] .
and dipyrrin .
H] .
alculated The 1H NMR spectrum of the Zn-3 complex showed indistinct multiplicity and integration patterns.
however, the notable chemical shifts provided valuable insights.
When comparing the spectra of 3 to Zn-3 (Fig.
, the pyrrole protons exhibited a downfield shift, similar to the behavior as observed during the oxidation of dipyrromethanes to dipyrrins.
This shift indicated that a dipyrrin-zinc(II) complex was successfully These NMR results corroborated the UV-vis data, showing the development of a dipyrrin ligand after the complexation of meso-hydroxy dipyrromethane 3 with zinc(II).
Moreover, the disappearance of the meso-OH signal postcomplexation indicated the absence of OH at the meso-C position and the formation of a conjugated structure at this site.
While other signals were not individually identifiable, notable changes in the chemical shift ranges of benzoyl and phenyl were observed.
Specifically, the signal range shifted slightly 9 ppm to 6.
6 ppm in Zn-3, indicating subtle structural modifications upon complexation.
Computational study Fig.
UV-vis spectra of 3 with 20 eq Zn(II) measured spontaneously and 3 with 10 eq Zn(II) measured after 24 h Absorption Emission 567 nm 606 nm 333 nm 3 exp.
Zn-3 exp.
3' calc.
3 calc.
Zn-3 calc.
Abs Normalized Intensity The TD-DFT electronic transition calculations were compared with the experimental UV-vis spectra (Fig.
Before complexation, the absorbance profile of the ligand closely aligned with the calculated profile of structure 3, rather than that of structure 3Ao.
The primary absorbance peak corresponded to the fourth electronic transition, involving a transition from the A system of pyrrole-phenyl-benzoyl (HOMO) to the A* orbital of pyrrole-benzoyl (LUMO .
Fig.
Normalized absorption and emission spectra of Zn-3 lexp .
Fig.
Comparison of calculated oscillator strength data and experimental absorbance data of 3, 3Ao, and Zn-3 Fig.
Comparison of 1H NMR spectra of .
3 and .
Zn-3 in CDCl3 After complexation with zinc(II), the absorbance profile of the complex matched the calculated profile of Zn-3.
The dominant peak arose from the first electronic transition, which corresponded to the A system of the pyrrole-benzoyl (HOMO) transitioning to the A* orbital of the pyrrole (LUMO).
This shift in the absorption pattern suggests that complexation induces a structural conversion of the ligand from structure 3 to structure 3Ao, aligned with the experimental data.
The thermochemical .
hemical potential/molar Gibbs energ.
and electronic parameters (HOMO and LUMO energie.
of 3, 3Ao and Zn-3 were compared to analyze their Ferryansyah et al.
/ Communications in Science and Technology 10.
29Ae35 relative stabilities (Table .
The chemical potential () of meso-hydroxy dipyrromethane 3 was calculated to be 11.
57 eV, higher than that of dipyrrin 3Ao .
90 eV).
This indicated that dipyrrin 3Ao was thermochemically more stable than 3, making the conversion of 3Ao to 3 thermochemically unfavorable.
This stability explained the higher intensity of the dipyrrin signal observed in MALDI-TOF MS analysis.
In contrast.
Zn-3 exhibited a chemical potential () of 10.
eV, lower than that of 3, suggesting that the complexation of 3 with zinc(II) was thermochemically favorable.
However, 3 showed the highest HOMO-LUMO gap .
36 eV) compared to those of 3Ao .
00 eV) and Zn-3 .
54 eV), explaining that it was the most electronically stable structure.
This higher electronic stability may contribute to the slow kinetics observed in the complexation of 3 with zinc(II) despite its thermochemical of H-N in 2Ao (LUMO .
with an energy difference of 1.
24 eV (Fig.
In contrast, the side reaction involves a nucleophilic attack by water.
This occurs through the interaction between the non-bonding orbital of oxygen in H2O (HOMO) and the empty p orbital of 2Ao (LUMO) with a much larger energy difference of 1.
96 eV.
Although the main reaction is more favorable, the relatively low energy barrier for the side reaction suggests its significance, particularly in the presence of water.
Table 1.
Calculated chemical potential.
HOMO, and LUMO energies of the species from DFT calculations Species .
V) Zn-3
DDQ
DDQ-H
DDQ-H2
H2O
H3O
HOMO
V) LUMO .
V) HOMO-LUMO Gap .
V) To further study the formation of compound 3, we examined the proposed mechanism for the oxidation of dipyrromethane and its side reactions, as shown in Fig.
9, following a pathway similar to that of a previously reported .
The first step involved a hydride transfer from dipyrromethane 2 to DDQ, producing the cationic intermediate dipyrromethane 2Ao and DDQ-H.
This intermediate was subsequently deprotonated by DDQ-H, leading to the formation of dipyrrin 3Ao and reduced DDQ (DDQ-H.
Additionally, the C-meso of intermediate 2Ao was susceptible to nucleophilic attack, such as by water, which resulted in the formation of the side product meso-hydroxy dipyrromethane 3 after the deprotonation of the hydroxonium The first step in the oxidation of dipyrromethane involved hydride transfer from dipyrromethane to the oxygen of DDQ, driven by a small chemical potential difference of 0.
12 eV (Fig.
The second step showed that the main reaction involving deprotonation had a lower chemical potential difference .
eV) than the side reaction .
66 eV).
Thus, side reaction produced thermochemically less stable products.
The reactivity of these pathways can be explained by the interaction between filled and empty molecular orbitals.
In the main reaction, the deprotonation of the N-H group in the cationic dipyrromethane intermediate .
by DDQ-H involves an orbital interaction between the non-bonding orbital of oxygen in DDQ-H (HOMO-.
and the anti-bonding E orbital Fig.
Proposed mechanism of dipyrromethane 2 oxidation Fig.
Energy diagram of DPM oxidation To determine the role of p-fluorophenyl and diacyl substituents in the competitiveness of the main (N-H deprotonatio.
and side (H2O attac.
reaction pathways, we performed similar computational calculations with mesosubstituted dipyrromethane derivatives as previously reported .
Across the series of these mesoAasubstituted dipyrromethane cations .
ompounds 2Ao, 4-7.
see Fig.
12 for structure.
, the calculated energy gaps (Table .
indicated that N-H deprotonation overall became the more favorable pathway since the N-H deprotonation gaps (E.
consistently were lower than the corresponding water attack gaps (E.
The DPM cation bearing a meso-pentafluorophenyl (CCIFCI) substituent .
exhibited lower E2 .
72 eV) than the electronrich 4 .
22 eV) and p-fluorophenyl substituent .
Ferryansyah et al.
/ Communications in Science and Technology 10.
29Ae35 9 eV), resulting in more dominant N-H deprotonation.
However, dipyrrin of compound 4 can also be obtained experimentally, rationalized by significantly higher E1 = 23 eV compared to E2 = 1.
22 eV, resulting in higher iE = 01 eV, diminishing the competitiveness of water attack.
pAa Fluorophenyl .
-F) substituent uniquely exhibited dual electronic influence, inductively withdrawing-electron and mesomerically electron-donating effect, leading to intermediate energy gaps (E1 = 1.
74 eV and E2 = 0.
90 eV, iE = 84 eV).
On the other hand, the addition of diacyl groups .
Ao 6 and 7 vs.
increased E2 and decreased iE, resulting in a higher possibility of water attack.
These trends suggest that the electronic properties and diacyl groups play an essential role in meso-hydroxy DPM formation.
Conclusion Meso-hydroxy acyl dipyrromethane 3 was synthesized and characterized to investigate its stability and formation The compound was obtained in the yield of 21% and fully identified by NMR and HRMS analyses.
UV-vis absorption studies demonstrated that the meso-hydroxy group in 3 disrupted the conjugated system, resulting in a max of 325 Upon the addition of zinc(II) ions, a typical zinc(II)dipyrrin complex was formed, exhibiting a bathochromic shift to 567 nm and an emission peak at 606 nm.
Thermochemical stability analyses revealed that dipyrrin 3Ao was more stable than meso-hydroxy dipyrromethane 3.
Although the complexation of 3 with zinc(II) was thermochemically favorable, it occurred more slowly than the complexation of dipyrrin.
Mechanistic studies showed that the main oxidation pathway yielded dipyrrin 3Ao, whereas a concurrent side reaction with water formed meso-hydroxy dipyrromethane 3.
Computational studies revealed that the competitiveness of these reaction pathways was modulated by substituent effects.
The electron rich meso-substituent increased the energy for N-H deprotonation, whereas the diacyl groups lowered the iE (E1 Oe E.
for water attack.
This study highlights the potential of the meso-hydroxy DPM fluorescence ligand for zinc(II) ions and the strategy to obtain the desired oligopyrrole.
Acknowledgements Fig.
Energy diagram of molecular orbital in the oxidation reaction of Table 2.
Electronic energy gap analysis of cationic dipyrromethane species and their interactions with HCCO and DDQ-H
ELUMO
V) EE* N-H .
V) E1 .
V) .
V) OIE = E1 Oe E2 .
V) Oe1.
(LUMO .
Oe1.
Oe6.
(LUMO .
Oe2.
Oe7.
(LUMO .
Oe2.
Oe6.
(LUMO .
Oe1.
Oe6.
(LUMO .
E1: gap energy between unoccupied p orbital (LUMO) of C-meso of The experiments resulting in this report are supported by International Research
ITB
rant 4949/IT1.
B07.
1/TA.
00/2.
under LPPM ITB.
The authors are also grateful to FMIPA.
ITB.
Central Laboratory for NMR data and Physical Chemistry Division for emission Oe6.
cationic dipyrromethane species with HOMO of H2O.
E2: gap energy between E* N-H orbital of C-meso of cationic dipyrromethane species with n O orbital (HOMO-.
of DDQ-H (-3.
06 eV).
Fig.
Structure of meso-substituted dipyrromethane cation derivatives References