Supramolecular dimeric structures of pyrazole-containing meso-oxo carbaphlorin analogues

Abstract Synthesis and properties of a novel meso-oxo carbaphlorin analogue embedded with an N-free pyrazole moiety are described. The N-benzyl precursor was prepared by a [3 + 1]-MacDonald condensation of N-benzyl pyrazole dialdehyde and β-alkyl-substituted tripyrrane dicarboxylic acid and subsequent oxidation by ferric chloride. Upon deprotection of the benzyl group, the resulting N-free oxophlorin analogue formed a unique supramolecular dimer through mutual hydrogen bonding interactions between the pyrazole NH and meso-carbonyl group. The assembled behaviour was characterised by various spectroscopies, X-ray crystallographic analysis and vapour pressure osmometry. Under the similar reaction conditions, the condensation of meso-phenyl-substituted tripyrrane derivative afforded an unprecedented tetrapyrrolic macrocycle fused with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone unit at their α-pyrrolic positions. The X-ray crystallographic analysis of the macrocycle revealed a twisted core structure, and nonaromatic nature was elucidated.


Introduction
Self-assembled structures based on porphyrins (1) and their relatives have attracted interests as biomimetic motifs of the photosynthetic reaction centre naturally occurring in the light-harvesting antenna systems ( Figure 1) (1)(2)(3)(4)(5)(6)(7). From the point of view that the orientation of bacteriochlorophylls is associated with strong electronic coupling, the well-organised porphyrin antenna systems with sophisticated three-dimensional structures play central roles to ensure the coverage of solar energy wavelength. In this respect, supramolecular self-assembly is ideally suited for creating well-defined nanostructures as a result of their high specificity and directionality (8)(9)(10)(11). Since the properties of the components largely dominate the function of assembled structures in general, the self-assembled architectures of newly designed porphyrins would constitute a great importance for applications in optical switches, energy conversion devices and nonlinear optical materials (12)(13)(14)(15)(16)(17)(18)(19)(20).
N-confused porphyrins (NCPs, e.g. 2) are a class of porphyrin isomers wherein one of the pyrrole rings is connected to meso-carbons at α and β′ positions. Since its discovery, we have been focusing on the confused porphyrinoids chemistry (21)(22)(23)(24)(25). Particularly, the outward nitrogen atom of the confused pyrrole ring is fascinating in terms of the supramolecular assemblies, affording self-assembled metal complexes through their exterior binding modes (26). For example, treatment of 2 with Zn(II) salts leads to an N-confused porphyrin trimer where three core units are mutually coordinated by the peripheral nitrogen atom and Zn(II) ion (27)(28)(29). Similar coordination modes were seen in the other transition metal complexes of meso-aryl-substituted N-confused porphyrins (23). In addition, due to the oxidative reactivity of the α-CH of the confused pyrrole ring, the resulting 3-oxo-N-confused porphyrin (3) forms a self-assembled dimer ( [3] 2 ) via complementary hydrogen bonding interactions arising from the peripheral amide units (Figure 2(a)) (30).
Inspired by the supramolecular assembly of N-confused porphyrins, we envisioned that the replacement of the confused pyrrole ring with pyrazole, a nitrogen-rich heterocycle, could alternate the construct of the nanometric multiporphyrin complexes through the distinct hydrogen bonding networks. The adjacent (1,2-positions) nitrogen atoms can play a role in the amphiprotic behaviour with a pyrrole-like σ-donor as well as a pyridine-like π-acceptor characters (31,32). The shape-dependent assembled cyclic structures (i.e. dimer, trimer, etc.) could be in turn realised upon substitution on the periphery. The acylated pyrazole (and confused pyrrole) derivatives form specific dimers with an alternate orientation (33,34).
Previously, lash et al. have reported an efficient synthesis of pyrazole-embedded carbaporphyrins (4) using a [3 + 1] variant on the MacDonald condensation of a pyrazoledicarboxylate and β-alkyl substituted tripyrrane (35,36). Meso-oxo carbaphlorin analogues (5) were also prepared by silver(I) oxidation of the corresponding phlorin precursor. From the viewpoint of supramolecular chemistry, we have prepared novel N-unprotected pyrazole-containing meso-oxo carbaphlorin analogues (6) in this study. The N-free pyrazole species is allowed to form a distinct dimeric structure ([6] 2 ), via intermolecular hydrogen bonding between the meso-oxo group and pyrazole NH site in both the solid and solution phase. The structure of dimer [6] 2 was revealed by the various spectroscopic means as well as X-ray crystallographic analysis ( Figure  2(b)). Meanwhile, upon our synthetic attempt of meso-aryl-substituted pyrazole-porphyrin analogue, formation of a unique 2,3-dichloro-5,6-dicyano-1,4-benzoquinone-fused tetrapyrrolic macrocycle (13) was elucidated. The resulting macrocycle is nonaromatic based on the experimental and theoretical assessment.

Computational methods
DFT calculations were performed with a Gaussian 09 program package without symmetry assumption (41). Initial structures are based on the X-ray structures of the related compounds. The geometries were fully optimised at the Becke's three-parameter hybrid functional combined with the lee-yang-Parr correlation functional abbreviated as the B3lyP level of density functional theory with 6-31G(d,p) basis set for all the calculations (42,43).

X-ray crystallography
X-ray analysis was performed on a Brucker SMarT aPeX equipped with CCD detector using MoKα (graphite, monochromated, λ = 0.71069 Å) radiation. The structures were solved by the direct method of SHelXS-97 and refined using the SHelXl-2013 program (44). The positional parameters and thermal parameters of non-hydrogen atoms were refined anisotropically on F 2 by the full-matrix least squares method. Hydrogen atoms were placed at calculated positions and refined riding on their corresponding carbon atoms. a specific crystal structure of 5 reveals the larger anisotropic thermal factors due to the poor quality of crystals used in this measurement. However, the crystallographic refinement has been correctly completed and the final R value has reached an acceptable level for structural assignment. Crystallographic data are given in the Table S1 and have been deposited at the CCDC, and copies of the data can be obtained on request, free of charge, by quoting the publication citation and the deposition numbers CCDC-1,408,461 for 5 1,408,459 for 6 and 1,408,460 for 13 via www.ccdc.cam.ac.uk/conts/retrieving. html (or from the Cambridge Crystallographic Data Centre, 12 Union road, Cambridge CB2 1eZ, UK; fax: +44-1223-336-033 or e-mail: deposit@ccdc.cam.ac.uk).

Results and discussion
an N-alkyl or phenyl substituted pyrazole-embedded porphyrin analogues were synthesised previously by lash et al. (35,36). In our experiments, the acid-catalysed condensation of pyrazole dialdehyde (7) and tripyrrane dicarboxylic acid (8) and subsequent treatment with excess amounts of ferric chloride afforded meso-oxo derivative (5) in a one-pot reaction through the porphyrin analogue (4) transiently generated in situ (1). The product 5 was isolated by silica gel column chromatography and analysed by the spectroscopic methods (cf. supporting information). The 1 H NMr spectrum revealed the characteristic inner NH and CH resonances at 9.36 and 5.73 ppm, respectively, and the peripheral meso-proton signals at 6.84 (C-10), 6.63 (C-15) and 6.04 (C-20) ppm in the upfield region, which indicates the absence of overall diatropic character in the macrocycle ( Figure S1). This spectral feature is fully consistent with those of the reported N-ethyl pyrazole-oxophlorin derivative (5: N-ethyl) (36).
The position of regiospecific meso-oxygenation of 5 was unambiguously confirmed by X-ray crystallographic analysis in this work (Figure 3(a)). The meso-oxo group of 5 is present at C5-position and the pyrazole ring unit was tilted approximately 25° relative to the core plane due to the steric hindrance between the inner NHs and pyrazole CH. The bond length of the carbonyl group at meso position is estimated to be approximately 1.24 Å, which corresponds to a typical C-o double bond (45). The dominant meso-oxo carbaphlorin resonance structure of 5 was further supported by the carbonyl stretching at 1622 cm −1 obtained from attenuated Total reflection (aTr)-FTIr spectroscopy, though the canonical resonance contribution from meso-hydroxy porphyrin structure can be considered via keto-enol tautomerism ( Figure S2). The carbonyl stretching band present in the N-Ph pyrazole oxophlorin was determined at 1625 cm −1 (36). on this basis, the UVvis absorption spectrum of 5 gave the relatively intense band at 384 nm and featureless band in the far red region, The reaction mixture was cooled in an ice bath and neutralised with triethylamine (4.45 ml) with stirring for 1 h. after the addition of 0.1% aqueous FeCl 3 , the reaction mixture was stirred for further 1 h. The organic solution was washed with H 2 o until the aqueous layer appeared colourless. The organic layer was separated, dried over Na 2 So 4 and evaporated in vacuo. The residue was purified with silica gel column chromatography (elute: CH 2 Cl 2 ) to afford pure 5.

Deprotection of N-benzyl pyrazole meso-oxo carbaphlorin (6)
a benzene solution (10 ml) of the N-protected pyrazol meso-oxo carbaphlorin (5, 10 mg, 0.017 mmol) was added dropwise to a stirred suspension of alCl 3 (27 mg, 0.2 mmol) in the same solvent (10 ml). The mixture was then stirred at 80 °C for 1 h. after cooling, the resulting solution was poured into 50 ml of water and the product was extracted with CH 2 Cl 2 . The organic layer was dried over Na 2 So 4 , and evaporated. The purification was conducted by column crystallography as well as spectroscopic analyses. The solid state structure of 13 exhibited twist-conformation of the core macrocycle (i.e. Porphyrin(6.1.1.1)) with annulation of DDQ building block at the α-pyrrolic positions of the tetrapyrrole (Figure 4). Due to the preferable double bond character of the carbonyl bridges in the annulated moiety (the bond lengths of C=o moieties are determined to be 1.224 and 1.240 Å, respectively), the whole macrocycle is unlikely fully conjugated. although the absorption spectrum of 13 showed porphyrin-like spectral features such as the Soret band (527 nm) and Q-bands, the 1 H NMr spectrum of 13 revealed two broad NH signals at 11.22 and 10.58 ppm, and the peripheral β-pyrrolic protons in which supports the absence of porphyrin-like electronic transition patterns ( Figure S3).
Meanwhile, in an effort to elucidate the substituent effect on the framework, the synthesis of meso-aryl type analogues with a pyrazole unit was attempted ( Figure 4). Surprisingly, the condensation reaction of N-benzyl pyrazole diol (or dicarbaldehyde) derivatives 9 and meso-aryl tripyrromethane 10 and subsequent oxidation produced no desired porphyrin analogues (i.e. pyrazole-embedded 11), but afforded a triphenylcorrole (12) and an unprecedented DDQ-conjugated tetrapyrrolic macrocycle (13). This new macrocycle was isolated from the tarry reaction mixture and unambiguously characterised by X-ray  in the high-field region (i.e. 5.5-6.5 ppm). In contrast, the pyrazole NH and inner pyrrolic NHs signals are observed at 11.3 and 9.14 ppm, respectively. The characteristic carbonyl-carbon resonance was seen at 169.23 ppm in the 13 C NMr spectrum of 6 ( Figure S7). These NMr data suggest that the macrocycle 6 is nonaromatic due to the dominant keto-type macrocyclic conjugated resonance contributor as shown in the compound 5 ( Figure S9). This conclusion was further supported by DFT (B3lyP/6-31G(d,p))-based energy estimations ( Figure 5). The structure 6 depicted in the Figure 5 is more stable than the conjugated enol species 6" by 12.44 kcal mol −1 . likewise, the isomer of 6' is not favourable, which could be attributed by the intrinsic electronic effect of the conjugated circuit of the oxophlorin. The adjacent amino proton could be attracted close to the electron withdrawing carbonyl moiety.
The unique structure of 6 in the solid state was elucidated by single-crystal X-ray diffraction analysis ( Figure  3(b)). Similar to that of 5, a coplanar structure was revealed with the standard deviation value of 0.031 Å (defined with the 24 core atoms). The double bond character of meso-oxo moiety (i.e. bond length of 1.240 Å) was clearly seen in 6.
Notably, a head-to-head hydrogen bonded dimeric structure was demonstrated in the crystal packing ( Figure 6). The pyrazole NH moiety and meso-oxo one are non-covalently interacted with an intercalated molecular orientation. In fact, there is an intermolecular interaction between the hydrogen donor NH group and the acceptor oxo group of 6 with the N-o distance of 2.788 Å in the dimeric structure. the typical alkene region, which indicates the absence of aromatic conjugated circuit (Figures S4 and S5). The preference of this canonical form was also supported by the fact that the corresponding resonant 22 π conjugated model 13' is +46.94 kcal/mol unstable than that of the actual model with an aid of theoretical assessment ( Figure S6). regarding the formation mechanism of the compound 13, the bridged tetrapyrrole skeleton was likely constructed by the pericyclic reaction with DDQ at the α-pyrrolic positions of the tetrapyrrin core, since the reaction with meso-phenyl substituted corrole with DDQ did not afford the corresponding macrocycle in the separated experiment (46). Due to the steric hindrance of the macrocycle, the specific carbon-carbon bond between the atoms appended with cyano groups could be cleaved during the reaction (Scheme S1) (47,48).
accordingly, deprotection of the N-benzyl group in 5 was subjected to obtain the corresponding N-free pyrazole-oxopholorin 6 (Scheme 1). Treatment of 5 with lewis acid (e.g. alCl 3 ) in refluxing benzene solution afforded the N-free derivative 6 in 67% yield. The typical deprotection conditions, such as treatments of hydrogen over Pd/C, aerobic potassium tert-butoxide, BF 3 ·et 2 o and TiCl 4 were not effective to yield the product 6. The high-resolution mass spectrum of 6 displayed the consistent parent ion signal at m/z = 467.2673; [M] + = 467.2685 calcd. for C 29 H 33 N 5 o 1 , and the 1 H and 13 C NMr spectra support the proposed structure with nonaromatic nature. The signals of series of meso-Hs and an inner CH of pyrazole subunit appeared Scheme 1. Synthesis of pyrazole-containing oxophlorins 6 and its benzyl-protected derivative 5.
concentration of the sample solution (e.g. 0.5 to 50 mM) ( Figure S8). The variation of Δδ max = −0.068 ppm is significant for the internal pyrazole C 21 -H compared to the other signal changes of meso-protons: Δδ max = −0.012 (C 15 H), 0.013 (C 10 H) and 0.005 (C 20 H) ppm, respectively. This could be attributed from that the deshielding inner CH present in the pyrazole ring is directly correlated to the electronically perturbed NH moiety via hydrogen bondings (30). The dimerisation constant K associated with this presumed dimerisation was estimated to be 93 ± 13 M −1 (in CDCl 3 ) by nonlinear curve fitting analysis. The value is relatively larger compared to those of the homo-dimers each dimer is aligned in parallel with the interplane distance of 3.622 Å (Figure 6(b) and (c)). The aTr-Ir spectrum of 6 exhibited the diagnostic carbonyl peak at ν Co = 1601 cm −1 , which is negatively shifted in comparison with that of the N-benzyl protected one (ν Co = 1622 cm −1 ) and the stretching band of NH at ν NH = 3193 cm −1 ( Figure S2). The weakened carbonyl and NH stretching bands could be explained by the intramolecular hydrogen bonding interactions.
The supramolecular interactions of [6] 2 in solution were also examined using 1 H NMr and optical spectroscopies and VPo. The chemical shift of the inner pyrazole CH signal in the 1 H NMr spectrum was shifted upon increasing the

Conclusion
In summary, we have synthesised novel N-free form of a pyrazole-containing meso-oxo carbaphlorin 6 and investigated the supramolecular dimeric structure of [6] 2 formed via hydrogen bonding interactions (i.e. Co⋯HN) by the X-ray crystallographic analysis and spectroscopic means. The meso-keto type canonical structure is found to be dominant in 6, showing distinct nonaromaticity. The structural feature of both outward-pointing meso-carbonyl and pyrazolyl amino moieties contributed to the formation of head-to-head dimers in the solid and solutions. DFT calculations also revealed the energetic favourability of this type of interactions compared to the well-known hydrogen bonding fashion occurring in NH⋯N pyrazole moieties. In the future prospect, the analogue 6 can serve as synthons for the self-assembled supramolecular networks through metal coordination abilities of the pyrazole unit. Furthermore, during the synthetic attempt for the meso-aryl substituted analogues 11 containing a pyrazole unit, we found the unique tetrapyrrolic macrocycle 13 annulated with DDQ fragment. although the yield of this macrocycle is low under the present conditions, introduction of DDQ units into the intrinsic porphyrinoid skeleton renders the landscape for developing near Ir optical donor-acceptor materials (50).

Supplementary material
Please see eSI for additional information on spectroscopic and theoretical results here: http://dx.doi.org/10.1080/10610278.20 16.1158408 formed with an 3-oxo N-confused porphyrin or N-confused calix [4]phyrin bearing an identical 3-oxo moiety at the confused ring (K = 26 and 14 M −1 , respectively) (30,49). This NMr spectral behaviour of the CHCl 3 solution 6 was also seen upon lowering the temperature ( Figure S9). In an effort to explore further the spontaneous organisation of 6 in solution, VPo analysis was carried out. The average molecular weight (M n ) of 649 g mol −1 was obtained in CHCl 3 ([6] = 1-5 mM; calcd Mw for monomer 6: 467.3, dimer [6] 2 : 934.5), which suggests the presence of the molecular aggregates, namely a mixture of monomer and dimer with a ratio of 3:2, respectively, under these conditions. This result thus provides the further support for the intermolecular aggregates in solution at the higher concentration. on the other hand, under the low concentration conditions (~120 μM), the profile of UV-vis spectra of 6 in CH 2 Cl 2 was almost unchanged by increasing the concentration (Figure 7). This result is compatible with the dominant presence of monomer as inferred from the K value in CDCl 3 (i.e. 98% monomer at 120 μM). The optical spectral change of 6 upon lowering the temperature (from 300 to 240 K) exhibited the minor change in the spectral shape ( Figure S10). Therefore, the binding behaviour of 6 is not remarkable in the diluted solution.
The configuration of the dimer [6] 2 was theoretically analysed by B3lyP/6-31G(d,p) level calculation ( Figure S11). The optimised structure of [6] 2 constructed by the proposed hydrogen bonding modes well reproduced the structure observed in the experimental, which is 3.25 kcal mol −1 more stable than that of dimer generated via pyrazole NH⋯N interactions. The findings can be explained by a preference for the head-to-head dimeric structures under the higher concentrations, which cancels alignment of the molecular dipoles (dipole moment: 3.7 D for monomer 6), thereby organising the system for the assembly.