Synthesis, Spectroscopic Properties, and Metalation of 3-Alkoxybenziporphyrins

A series of 5-alkoxy-1,3-benzenedicarbaldehydes and related dimers were prepared in three steps from dimethyl 5-hydroxyisophthalate. Acid catalyzed condensation of the dialdehydes with a tripyrrane dicarboxylic acid, followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, afforded good yields of 3-alkoxybenziporphyrins, although dimeric tetraaldehydes failed to give isolatable porphyrinoid products. Proton NMR spectroscopy gave no indication of an aromatic ring current, but addition of trifluoroacetic acid resulted in the formation of dications that exhibited weakly diatropic characteristics. Spectroscopic titration with TFA demonstrated that stepwise protonation took place, generating monocationic and dicationic species. 3-Alkoxybenziporphyrins reacted with nickel(II) or palladium(II) acetate to give the related nickel(II) or palladium(II) complexes. These stable organometallic derivatives showed increased diatropic properties that were most pronounced for the palladium(II) complexes. These unique porphyrinoids provide further insights into the properties of benziporphyrins.

In a continuation of our studies in this area, a series of 3-alkoxybenziporphyrins 7 (Scheme 1) were targeted for synthesis.The properties of these substituted benziporphyrins were assessed and metalation studies were performed.In addition, the potential use of this substitution pattern to generate a tether between two porphyrinoid units was considered.In a continuation of our studies in this area, a series of 3-alkoxybenziporphyrins 7 (Scheme 1) were targeted for synthesis.The properties of these substituted benziporphyrins were assessed and metalation studies were performed.In addition, the potential use of this substitution pa ern to generate a tether between two porphyrinoid units was considered.

Results and Discussion
Alkoxybenziporphyrins 7a-c were prepared using the '3 + 1' variant of the MacDonald condensation (Scheme 1) [20,21].The key intermediates were 5-alkoxyisophthalaldehydes 8a-c and tripyrrane dicarboxylic acid 9 [22,23].The dialdehydes were prepared in turn from commercially available dimethyl 5-hydroxyisophthalate 10 (Scheme 2).Alkylation of 10 with methyl or ethyl iodide and potassium carbonate in refluxing acetonitrile gave methoxy and ethoxy derivatives 11a and 11b, respectively.Reduction with lithium aluminum hydride in THF afforded the corresponding dialcohols 12a and 12b, and subsequent treatment with pyridinium chlorochromate (PCC) gave dialdehydes 8a and 8b.Related dialdehyde 8c was prepared by an alternative route.Reduction of 10 with lithium aluminum hydride gave phenolic dicarbinol 13, and subsequent oxidation with PCC afforded dialdehyde 14.Reaction with methyl bromoacetate and potassium carbonate then furnished aryloxyacetate dialdehyde 8c.In a continuation of our studies in this area, a series of 3-alkoxybenziporphyrins 7 (Scheme 1) were targeted for synthesis.The properties of these substituted benziporphyrins were assessed and metalation studies were performed.In addition, the potential use of this substitution pa ern to generate a tether between two porphyrinoid units was considered.
Tripyrrane 9 was treated with trifluoroacetic acid (TFA), the reaction solution diluted with dichloromethane, and the intermediate condensed with dialdehydes 8a-c.Following oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), purification by column chromatography on grade 3 alumina, and recrystallization from chloroform-methanol, 3-alkoxybenziporphyrins 7a-c were isolated as dark-purple crystals in 34-44% yield.Interestingly, no porphyrinoid products could be isolated when phenolic dialdehyde 14 was reacted with tripyrrane 9, possibly due to the instability of hydroxybenziporphyrins.As had been expected, the proton NMR spectra for 7a-c showed no indication of an aromatic ring current.Porphyrins, which exhibit exceptionally powerful diamagnetic ring currents, give strongly deshielded resonances for the external protons, while the internal protons are shifted atypically upfield [24,25].For instance, the bridging methine protons (meso-protons) in porphyrins commonly appear downfield near +10 ppm, while the inner N-H protons are generally observed upfield near −4 ppm.Scheme 2. Synthesis of 5-alkoxyisophthalaldehydes.
Tripyrrane 9 was treated with trifluoroacetic acid (TFA), the reaction solution diluted with dichloromethane, and the intermediate condensed with dialdehydes 8a-c.Following oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), purification by column chromatography on grade 3 alumina, and recrystallization from chloroform-methanol, 3alkoxybenziporphyrins 7a-c were isolated as dark-purple crystals in 34-44% yield.Interestingly, no porphyrinoid products could be isolated when phenolic dialdehyde 14 was reacted with tripyrrane 9, possibly due to the instability of hydroxybenziporphyrins.As had been expected, the proton NMR spectra for 7a-c showed no indication of an aromatic ring current.Porphyrins, which exhibit exceptionally powerful diamagnetic ring currents, give strongly deshielded resonances for the external protons, while the internal protons are shifted atypically upfield [24,25].For instance, the bridging methine protons (mesoprotons) in porphyrins commonly appear downfield near +10 ppm, while the inner N-H protons are generally observed upfield near −4 ppm.
The proton NMR spectrum of 3-ethoxybenziporphyrin 7b (Figure 2) confirmed that the macrocycle possesses a plane of symmetry and demonstrated the absence of overall aromatic character.The meso-protons gave rise to two 2H singlets at 6.5 and 7.1 ppm, values that are consistent with a nonaromatic porphyrinoid.Furthermore, the internal C-H resonance appeared downfield at 7.8 ppm, while the N-H appeared at 8.2 ppm.Benziporphyrins 7a and 7c gave similar results.However, the addition of TFA to the NMR tube resulted in the emergence of weak, but nonetheless significant, aromatic character.In the case of 7b (Figure 2), the meso-protons of the resulting dication 7bH2 2+ (Scheme 3) shifted downfield to give 2H singlets at 7.0 and 7.8 ppm, while the external benzene rings (2,4-H) moved from 7.5 to 8.0 ppm.However, the inner C-H (22-H) shifted upfield by 3 ppm to give a 1H resonance at 4.8 ppm (Figure 2).In the absence of any other changes, protonation would be expected to result in deshielding, so the shift associated with the 22-H resonance is significant.This result can be a ributed to contributions from canonical forms such as 7b′H2 2+ , which possess 18π electron pathways (Scheme 3).Nevertheless, the diatropic character for the dication is relatively weak compared to porphyrins or fully aromatic porphyrinoids such as oxybenziporphyrin 2. Protonation of 7a and 7c gave similar results (Figures S49 and S84).The proton NMR spectrum of 3-ethoxybenziporphyrin 7b (Figure 2) confirmed that the macrocycle possesses a plane of symmetry and demonstrated the absence of overall aromatic character.The meso-protons gave rise to two 2H singlets at 6.5 and 7.1 ppm, values that are consistent with a nonaromatic porphyrinoid.Furthermore, the internal C-H resonance appeared downfield at 7.8 ppm, while the N-H appeared at 8.2 ppm.Benziporphyrins 7a and 7c gave similar results.However, the addition of TFA to the NMR tube resulted in the emergence of weak, but nonetheless significant, aromatic character.In the case of 7b (Figure 2), the meso-protons of the resulting dication 7bH 2 2+ (Scheme 3) shifted downfield to give 2H singlets at 7.0 and 7.8 ppm, while the external benzene rings (2,4-H) moved from 7.5 to 8.0 ppm.However, the inner C-H (22-H) shifted upfield by 3 ppm to give a 1H resonance at 4.8 ppm (Figure 2).In the absence of any other changes, protonation would be expected to result in deshielding, so the shift associated with the 22-H resonance is significant.This result can be attributed to contributions from canonical forms such as 7b ′ H 2 2+ , which possess 18π electron pathways (Scheme 3).Nevertheless, the diatropic character for the dication is relatively weak compared to porphyrins or fully aromatic porphyrinoids such as oxybenziporphyrin 2. Protonation of 7a and 7c gave similar results (Figures S49 and S84).
The UV-vis spectra of 7a-c were also consistent with nonaromatic structures.For instance, benziporphyrin 7b gave two moderate absorptions at 308 and 382 nm and weaker broad absorptions between 500 and 800 nm (Figure 3).Spectroscopic titration with TFA demonstrated that two sequential protonations occurred.The addition of 0.5-3 equivalents of TFA resulted in a bathochromic shift of the band at 382 nm to 391 nm, while long wavelength absorptions emerged at 776 and 858 nm (Figure 3).This was attributed to the formation of monoprotonated cation 7bH + (Scheme 3).At higher concentrations of TFA, further changes were noted, and the long wavelength bands hypsochromically shifted to 760 and 842 nm, while the Soret-like band was reduced in intensity and moved to 400 nm (Figure 3).This was attributed to the formation of dication 7bH 2 2+ (Scheme 3).Similar results were obtained for 7a and 7c (Figures S9-S14 and S17-S18).
Metalation of 3-alkoxybenziporphyrins 7a-c was also investigated (Scheme 4).The palladium complexes were synthesized by refluxing 3-alkoxybenziporphyrins 7a-c in acetonitrile for 30 min in the presence of palladium(II) acetate.Following purification by column chromatography on a grade 3 basic alumina column and recrystallization from chloroform-methanol, organometallic complexes 7Pd were isolated in a 60-73% yield.When benziporphyrins 7a-c were refluxed in N,N-dimethylformamide (DMF) for 30 min in the presence of nickel(II) acetate and purified similarly, the corresponding nickel(II) complexes 7Ni were obtained as dark-green solids in a 55-86% yield.The UV-vis spectra of 7a-c were also consistent with nonaromatic structures.For instance, benziporphyrin 7b gave two moderate absorptions at 308 and 382 nm and weaker broad absorptions between 500 and 800 nm (Figure 3).Spectroscopic titration with TFA demonstrated that two sequential protonations occurred.The addition of 0.5-3 equivalents of TFA resulted in a bathochromic shift of the band at 382 nm to 391 nm, while long wavelength absorptions emerged at 776 and 858 nm (Figure 3).This was a ributed to the formation of monoprotonated cation 7bH + (Scheme 3).At higher concentrations of TFA, further changes were noted, and the long wavelength bands hypsochromically shifted to 760 and 842 nm, while the Soret-like band was reduced in intensity and moved to 400 nm (Figure 3).This was a ributed to the formation of dication 7bH2 2+ (Scheme 3).Similar results were obtained for 7a and 7c (Figures S9-S14 and S17-S18).
Metalation of 3-alkoxybenziporphyrins 7a-c was also investigated (Scheme 4).The palladium complexes were synthesized by refluxing 3-alkoxybenziporphyrins 7a-c in acetonitrile for 30 min in the presence of palladium(II) acetate.Following purification by column chromatography on a grade 3 basic alumina column and recrystallization from chloroform-methanol, organometallic complexes 7Pd were isolated in a 60-73% yield.When benziporphyrins 7a-c were refluxed in N,N-dimethylformamide (DMF) for 30 min The proton NMR spectra for the palladium and nickel complexes demonstrated that metalation induced the emergence of aromatic character in these structures (Figure 4).This was particularly evident for palladium(II) complexes 7Pd. Figure 4 illustrates how the meso-protons are shifted downfield for the 3-methoxybenziporphyrin series 7a, 7aNi, and 7aPd.The meso-protons for free base 7a appeared at 6.48 and 7.14 ppm, but these resonances shifted to 7.08 and 7.35 ppm in 7aNi, and 7.25 and 7.57 ppm in 7aPd.In addition, the 2,4-protons on the arene unit were also shifted downfield from 7.49 to 7.63 to 7.68 ppm, going from 7a to 7aNi to 7aPd.Although the observed global ring currents are weak, the results show significant changes, and these were replicated for the metal complexes of 7b and 7c.The carbon-13 NMR spectra showed the meso-carbon resonances at 95.3 (11,16-CH) and 123.2 ppm (6,21-CH) for 7aNi, while these peaks appeared at 95.5 and 126.6 ppm, respectively, for 7aPd.As was the case for the non-metalated benziporphyrins, the meso-carbons flanking the phenylene unit are ca.30 ppm further downfield than the meso-carbons connecting two pyrrolic moieties.Similar results were obtained for 7bNi, 7cNi, 7bPd, and 7cPd (Figures S69, S74, S88 and S93). in the presence of nickel(II) acetate and purified similarly, the corresponding nickel(II) complexes 7Ni were obtained as dark-green solids in a 55-86% yield.The proton NMR spectra for the palladium and nickel complexes demonstrated that metalation induced the emergence of aromatic character in these structures (Figure 4).This was particularly evident for palladium(II) complexes 7Pd. Figure 4 illustrates how the meso-protons are shifted downfield for the 3-methoxybenziporphyrin series 7a, 7aNi, and 7aPd.The meso-protons for free base 7a appeared at 6.48 and 7.14 ppm, but these resonances shifted to 7.08 and 7.35 ppm in 7aNi, and 7.25 and 7.57 ppm in 7aPd.In addition, the 2,4-protons on the arene unit were also shifted downfield from 7.49 to 7.63 to 7.68 ppm, going from 7a to 7aNi to 7aPd.Although the observed global ring currents are weak, the results show significant changes, and these were replicated for the metal complexes of 7b and 7c.The carbon-13 NMR spectra showed the meso-carbon resonances at 95.3 (11,16-CH) and 123.2 ppm (6,21-CH) for 7aNi, while these peaks appeared at 95.5 and 126.6 ppm, respectively, for 7aPd.As was the case for the non-metalated benziporphyrins, the mesocarbons flanking the phenylene unit are ca.30 ppm further downfield than the meso-carbons connecting two pyrrolic moieties.Similar results were obtained for 7bNi, 7cNi, 7bPd, and 7cPd (Figures S69, S74, S88, and S93). in the presence of nickel(II) acetate and purified similarly, the corresponding nickel(II) complexes 7Ni were obtained as dark-green solids in a 55-86% yield.The proton NMR spectra for the palladium and nickel complexes demonstrated that metalation induced the emergence of aromatic character in these structures (Figure 4).This was particularly evident for palladium(II) complexes 7Pd. Figure 4 illustrates how the meso-protons are shifted downfield for the 3-methoxybenziporphyrin series 7a, 7aNi, and 7aPd.The meso-protons for free base 7a appeared at 6.48 and 7.14 ppm, but these resonances shifted to 7.08 and 7.35 ppm in 7aNi, and 7.25 and 7.57 ppm in 7aPd.In addition, the 2,4-protons on the arene unit were also shifted downfield from 7.49 to 7.63 to 7.68 ppm, going from 7a to 7aNi to 7aPd.Although the observed global ring currents are weak, the results show significant changes, and these were replicated for the metal complexes of 7b and 7c.The carbon-13 NMR spectra showed the meso-carbon resonances at 95.3 (11,16-CH) and 123.2 ppm (6,21-CH) for 7aNi, while these peaks appeared at 95.5 and 126.6 ppm, respectively, for 7aPd.As was the case for the non-metalated benziporphyrins, the mesocarbons flanking the phenylene unit are ca.30 ppm further downfield than the meso-carbons connecting two pyrrolic moieties.Similar results were obtained for 7bNi, 7cNi, 7bPd, and 7cPd (Figures S69, S74, S88, and S93).The UV-Vis spectra of the metalated species also showed characteristic features (Figure 5).Palladium complex 7aPd showed a strong Soret-like absorbance at 407 nm, a shoulder at 391 nm, and a weaker absorbance at band 308 nm.Multiple Q-type absorbances appeared between 407 and 850 nm.However, nickel(II) complex 7aNi gave very different results, showing three moderately strong absorptions at 313, 353, and 405 nm and a broad band centered on 660 nm (Figure 5).Similar spectra were obtained for the nickel(II) and palladium(II) complexes of 7b and 7c (Figures S7, S8, S19 and S20).
The possibility of using this strategy to prepare linked benziporphyrins was also investigated.Alkylation of dimethyl 5-hydroxybenzene-1,3-dicarboxylate 10 with o-, m-, or p-dibromoxylenes 15a-c and potassium carbonate in refluxing acetonitrile gave a series of linked tetraesters 16a-c in a 67-99% yield.Reduction with lithium aluminum hydride afforded the related tetraalcohols 17a-c, and subsequent oxidation with PCC yielded tetraaldehydes 18a-c (Scheme 5).Unfortunately, attempts to prepare benziporphyrin dimers 19a-c by reacting tetraaldehydes 18a-c with two equivalents of tripyrrane 9 only afforded trace amounts of porphyrinoid products.The reactions were attempted using DDQ or FeCl 3 as the oxidant, and at different concentrations of reactants, but none of the conditions investigated produced useful quantities of product, and substantial decomposition was observed.Although this route proved not to be viable, these new tetraaldehydes have potentially valuable architectures that may allow the synthesis of other tethered systems.The UV-Vis spectra of the metalated species also showed characteristic features (Figure 5).Palladium complex 7aPd showed a strong Soret-like absorbance at 407 nm, a shoulder at 391 nm, and a weaker absorbance at band 308 nm.Multiple Q-type absorbances appeared between 407 and 850 nm.However, nickel(II) complex 7aNi gave very different results, showing three moderately strong absorptions at 313, 353, and 405 nm and a broad band centered on 660 nm (Figure 5).Similar spectra were obtained for the nickel(II) and palladium(II) complexes of 7b and 7c (Figures S7, S8, S19, and S20).afforded trace amounts of porphyrinoid products.The reactions were a empted using DDQ or FeCl3 as the oxidant, and at different concentrations of reactants, but none of the conditions investigated produced useful quantities of product, and substantial decomposition was observed.Although this route proved not to be viable, these new tetraaldehydes have potentially valuable architectures that may allow the synthesis of other tethered systems.

Experimental
Melting points are uncorrected.NMR spectra are recorded using a 400 or 500 MHz NMR spectrometer and are run at 302 K unless otherwise indicated. 1H NMR values are reported as chemical shifts δ, relative integral, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak) and coupling constant (J).Chemical shifts are reported in parts per million (ppm) relative to CDCl 3 ( 1 H residual CHCl 3 singlet δ 7.26 ppm, 13 C CDCl 3 triplet δ 77.23 ppm) or DMSO-d 6 ( 1 H residual DMSO-d 5 pentet δ 2.49 ppm, 13 C DMSO-d 6 septet δ 39.7 ppm), and coupling constants are taken directly from the spectra.NMR assignments are made with the aid of 1 H-1 H COSY, HSQC, DEPT-135, and nOe difference proton NMR spectroscopy.Two-dimensional (2D)-NMR experiments are performed using standard software.Mass spectral data are acquired using positivemode electrospray ionization (ESI + ) and a high-resolution time-of-flight mass spectrometer.

Conclusions
A series of nonaromatic 3-alkoxybenziporphyrins were synthesized in 34-44% yield by reacting 5-alkoxyisophthalaldehydes with a tripyrrane dicarboxylic acid.Stepwise protonation of the macrocycles was observed to give mono-and diprotonated species.The proton NMR spectra for the diprotonated dications showed significant upfield shifts to the internal C-H resonances, and this demonstrated that a degree of overall global diatropic character was present.This can be attributed to dipolar resonance contributors that possess 18π-electron delocalization pathways.Metalation of the benziporphyrins with nickel(II) or palladium(II) acetate afforded the corresponding nickel(II) or palladium(II) organometallic complexes in 50-76% isolated yields.These derivatives exhibited enhanced diatropicity compared to the parent free base benziporphyrins, although the nickel(II) complexes showed less diatropic character than their palladium(II) counterparts.This may be due in part to the palladium complexes taking on more planar conformations, as the porphyrinoid macrocycle may be distorted to facilitate coordination to smaller nickel(II) cations.Although the strategy used to prepare 3-alkoxybenziporphyrins was quite successful, attempts to apply the methodology to the synthesis of benziporphyrin dimers did not prove to be fruitful.Nevertheless, this study provides access to structurally novel carbaporphyrinoids and gives insights into the effects that result from the introduction of electron-donating substituents.

Figure 2 .
Figure 2. Partial 500 MHz proton NMR spectra of ethoxybenziporphyrin 7b in CDCl3 (A) and the related diprotonated dication in TFA-CDCl3 (B).Protonation leads to the internal 22-H shifting upfield by ca. 3 ppm while the external protons are significantly deshielded, results that demonstrate the emergence of a global aromatic ring current.

Figure 2 . 17 Scheme 3 . 3 .
Figure 2. Partial 500 MHz proton NMR spectra of ethoxybenziporphyrin 7b in CDCl 3 (A) and the related diprotonated dication in TFA-CDCl 3 (B).Protonation leads to the internal 22-H shifting upfield by ca. 3 ppm while the external protons are significantly deshielded, results that demonstrate the emergence of a global aromatic ring current.Molecules 2024, 29, x FOR PEER REVIEW 4 of 17

Figure 4 .
Figure 4. Partial proton NMR spectra of methoxybenziporphyrin 7a (A) and the related nickel(II) complex 7aNi (B) and palladium(II) complex 7aPd (C) showing a marked increase in diatropicity upon metalation, which was most pronounced for 7aPd.

Figure 4 . 17 Figure 5 .
Figure 4. Partial proton NMR spectra of methoxybenziporphyrin 7a (A) and the related nickel(II) complex 7aNi (B) and palladium(II) complex 7aPd (C) showing a marked increase in diatropicity upon metalation, which was most pronounced for 7aPd.Molecules 2024, 29, x FOR PEER REVIEW 7 of 17