Regioselective Oxidative Ring Cleavage of a Phlorin Analogue: An

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Regioselective Oxidative Ring Cleavage of a Phlorin Analogue: An Approach for Synthesizing Linear Tetrapyrroles Jiewei Shao,† Chengjie Li,*,† Jiahui Kong,† Haoran Jiang,‡ Shuangliang Zhao,‡ Minzhi Li,§ Xu Liang,§ Weihua Zhu,§ and Yongshu Xie*,† †

Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China ‡ State Key Laboratory of Chemical Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai 200237, China § School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, China S Supporting Information *

ABSTRACT: Oxidation of neo-N-confused phlorin 1 with excessive FeCl3 leads to regioselective ring opening, generating three linear tetrapyrroles, i.e., (10Z,15Z)-biladienone 2, (10Z,15E)-biladienone 3, and 19-methoxy (10Z,15E)-biladiene 4 with an overall yield of 88%. The coordination of these compounds with Zn(II) is affected by the inverted terminal pyrrolic unit, and the presence of the electron-withdrawing keto moiety. The structural identities were also clearly elucidated by the crystal structures of 3 and 4-Zn and were rationalized by DFT calculations.

O

Scheme 1. Ring-Cleavage Sites and Corresponding Yields for Typical Porphyrin Analogues and Their Complexes

xidative ring opening of porphyrin macrocycles has attracted considerable attention as a model to understand the degradation of naturally occurring porphyrinoids, such as heme and chlorophyll.1−5 For example, coupled oxidation of Fe−porphyrin is a significant pathway to mimic the degradation of heme,1a,b and photo-oxidation of Cd−pheophorbide a methyl ester regioselectively opens the chlorophyll macrocycle and mimics the chlorophyll breakdown in the laboratory (Scheme 1).1c Ring-cleavage reactions of some artificial unsymmetrical tetrapyrrolic macrocycles have also been investigated with the purpose of understanding the structural effects on the products and synthesizing novel linear tetrapyrroles applicable in the areas of supramolecular chemistry and coordination chemistry.2 In this respect, 5,10,15-triphenylcorrole was decomposed to two linear tetrapyrroles with yields of 11% and 21%, respectively, as a consequence of attack by dioxygen under light at different mesopositions, showing no specific selectivity.3a Photo-oxidation of a typical phlorin afforded two isomeric biladienones with an overall yield of 38%, which can be used as N3O ligands for synthesizing metal complexes.3c The decomposition of an Nconfused porphyrin upon refluxing with Cu(OAc)2 in air resulted in loss of its N-confused pyrrole to afford a tripyrrolic Cu(II) complex.4a In these cases, the cleavage reactions of unsymmetrical tetrapyrroles usually give products with relatively low yields and/or poor regioselectivity. Despite the relatively intensive investigations on ring opening of various porphyrin analogues, the ring opening behavior of our previously reported neo-N-confused phlorin (neo-NCphlorin, © XXXX American Chemical Society

1)5a remains unknown. Considering the high reactivity of Nconfused (α, β-linked) pyrrole rings,6,7 it is anticipated that novel linear tetrapyrroles may be effectively developed through regioselective ring opening of 1. Received: February 9, 2018

A

DOI: 10.1021/acs.orglett.8b00478 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Herein, we report the regioselective oxidation of 1 with 21 equiv of anhydrous FeCl3. Thus, three linear tetrapyrroles, i.e., (10Z,15Z)-biladienone 2, (10Z,15E)-biladienone 3, and 19methoxy (10Z,15E)-biladiene 4 (Scheme 2), were isolated with Scheme 2. Syntheses of 2−4 and Their Coordination Behavior (Ar = C6F5)a

Figure 1. (a) 1H,1H-NOESY spectrum of 2 in DMSO-d6. (b) Calculated relative energies of the several possible tautomers of 2.

Reaction conditions: (i) FeCl3, CH2Cl2, and CH3OH; (ii) Zn(OAc)2· 2H2O and DMSO; (iii) Zn(acac)2, CH2Cl2, and CH3OH. a

NMR data of 3 are similar to that of 2, except those of H17, H18, and H24 from pyrrole ring D (Table S1). The signal of H17 at 7.56 ppm couples with that of H22 at ring B and the ophenyl protons in the 1H,1H-NOESY spectrum of 3 (Figure S9), consistent with the inversion of pyrrolic ring D. Thus, biladienone 3 features the E-configuration at the C15C16 bond instead of the Z-configuration observed in 2 (Scheme 2). For compound 4, its HR-ESI mass spectrum exhibits a pseudomolecular ion peak at m/z = 1039.1771, indicating a formula of C52H25F15N4O3, consistent with the presence of a methoxy group attached to ring D. Consistently, the two singlets at 3.56 and 3.42 ppm can be assigned to the ester group at ring A and the methoxy group at ring D, respectively. Similar to that observed for 3, the correlation between the signal of H18 at 6.51 ppm and that of the phenyl protons (Figure S15) indicates the E-configuration of the C15C16 bond, which is in agreement with the similar absorption spectra observed for 3 and 4 (vide infra). With the purpose of further elucidating the structural identity of the compounds, the single crystals of 3 were successfully obtained by slow evaporation of its acetonitrile/water solution. Crystal analyses revealed that 3 is a linear tetrapyrrole with three conjugated pyrroles, confirming that the ring cleavage occurs between the original N-confused pyrrole ring A and ring D (Figures 2a and S32a). The methoxycarbonyl group is attached to the C2 position of ring A. Meanwhile, ring D has been oxidized to the corresponding pyrrinone with an oxygen atom attached at the C19 position. The C6F5 group migrates from the meso-position to C1 of ring A. Tetrapyrrole 3 adopts a severely distorted conformation, probably resulting from the steric hindrance between ring D and the diphenyl groups. The central pyrrolic rings B and C are essentially coplanar, and terminal rings A and D are titled from the mean plane of B and C with dihedral angles of 78.9° and 33.1°, respectively. N3 is intramolecularly hydrogen bonded to H2 and H17 with the N3···N2 and N3···C17 distances of 2.653(6) and 2.948(7) Å, respectively. In addition, intermolecular hydrogen bonds are also observed between the lactam-like moieties of two neighboring molecules, affording hydrogen-bonded dimers (Figure 2b).

an overall yield of 88%. Investigations on the coordination behavior of 2−4 with Zn(II) indicated that the coordination may be affected by the inverted terminal pyrrolic unit as well as the presence of the electron-withdrawing terminal keto moiety. When 15a was treated with 21 equiv of FeCl3 in CH2Cl2/ CH3OH for 17.5 h, it was degraded into three more polar compounds, and thus, compounds 2−4 were isolated in yields of 59%, 14%, and 15%, respectively (Scheme 2). Consistent with the proposed structure of 2 (Scheme 2) with a formula of C51H23F15N4O3, its HR-ESI mass spectrum exhibits a pseudomolecular ion peak of [M + H]+ at m/z = 1025.1604. In the 1H NMR spectrum of 2, signals for three NH, seven pyrrolic β-CH, and 10 phenyl protons are observed in the low-field region of 6.16−11.94 ppm, and the signal for the methoxy group appears at 3.58 ppm as a singlet. Detailed analyses of the 2D NMR spectra (1H,1H-COSY, 1H,1HNOESY, 1H,13C-HSQC, and 1H,13C-HMBC) allow the assignments of all of the signals and well establish the molecular structure (Figure 1a and Figures S3−S5). To be more specific, the signal of the CH3 protons from the ester group at 3.58 ppm correlates with the signal at 163.4 ppm for the carbonyl carbon atom of the group (Figure S5). In the 1H,1H-COSY NMR spectrum of 2, H3 is coupled with the signal at 11.94 ppm assignable to the NH at ring A, while the NH signals at 11.58 and 10.48 ppm were assigned to H22 and H24 from their correlation with H7 and H18, respectively (Figure S3). In fact, all the pyrrolic β-protons could be unambiguously assigned in this way (Figure S3). The NOESY spectrum assists in confirming the configurations of the CC double bonds involving the meso-carbon atoms (Figure 1a). Thus, the pyrrolic proton signals from ring C show no coupling with signals of other protons, and the signal of H24 at 10.48 ppm is coupled with the those for H22 at 11.59 ppm and the ortho-proton of the phenyl group at 7.09 ppm. These observations are indicative of the Z-configurations of both C10C11 and C15C16 bonds (Figure 1a). The HR-ESI mass spectrum of 3 shows a pseudomolecular ion peak at m/z = 1025.1625, consistent with a formula identical to that of 2, indicating that 3 is an isomer of 2. The 1H B

DOI: 10.1021/acs.orglett.8b00478 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Hence, their Zn2+ coordination behavior was investigated. By mixing 2 with Zn(OAc)2·2H2O, a green zinc complex of 2 could be obtained which exhibits a pesudomolecular ion peak at m/z = 1087.0753 in the HR-ESI mass spectrum, indicative of a formula of C51H21F15N4O3Zn. However, 2-Zn tends to decompose during the purification, and it was thus characterized by NMR spectroscopy in situ (Figures S18−S23). By treating 4 with excess zinc acetylacetonate in CH2Cl2/ CH3OH, zinc complex 4-Zn was obtained in a yield of 77% (Scheme 2), showing a pesudomolecular ion peak of [M + Na]+ at m/z = 1123.0708 in the HR-ESI mass spectrum (Figure S31). The disappearance of the peaks for H21 and H23 at 11.99 and 12.12 ppm in the 1H NMR spectrum indicates the deprotonation of the NH moieties accompanied by the coordination of Zn(II) (Figure S24). The crystal structure of 4-Zn reveals that the Zn(II) ion is coordinated to four pyrrolic N atoms, with Zn(II)−N distances varying in the range of 1.989(1) − 2.043(1) Å (Figure 4a and Figure S32b). In the complex molecule, pyrrolic rings B−D are essentially coplanar, with ring A tilted from the plane showing a dihedral angle of 51.9°.

Figure 2. Crystal structure of compound 3. (a) Molecular structure; (b) hydrogen-bonded dimer. The hydrogen atoms attached to carbons are omitted for clarity.

On the basis of the aforementioned structural characterization, the absorption spectra were investigated. Compared with the absorption spectrum of 1, the obtained products 2−4 show blue-shifted spectra typical for linear conjugated tripyrroles (Figure 3). The violet-colored solution of

Figure 3. UV−vis spectra of 1−4 in CH2Cl2. The inset shows the photographs of the corresponding CH2Cl2 solutions.

biladienone 2 in CH2Cl2 exhibits two absorption peaks at 350 and 581 nm. Solutions of 3 and 4 in CH2Cl2 exhibit pink colors and rather similar absorption spectra, consistent with the fact that they have similar conjugation frameworks and identical configurations. The absorption peaks around 535 nm for 3 and 4 are blue-shifted as compared to the corresponding peak of 2 at 581 nm. To further understand the electronic properties of the compounds, DFT calculations were performed.8 The HOMO− LUMO energy gaps of 2−4 were calculated to be 2.33, 2.46, and 2.52 eV, respectively (Tables S2 and S3). This sequence agrees well with those obtained from the absorption spectra and the electrochemical data (Figure 3, Figure S34, and Table S4). Theoretically, each of compounds 2−4 has several potential tautomers (Figure 1b and Figure S33). However, in the NMR spectra of 2−4 and the crystal structure of 3, only one predominant isomer can be observed for each compound. Hence, DFT calculations were used to rationalize the results by evaluating the relative energies of all the possible tautomers.8 Take 2 for example, the tautomer of 2 observed in the NMR spectra has the lowest energy among all three isomers, and the potential tautomers 2′ and 2″ show higher energies of 14.54 and 43.95 kJ/mol, respectively, relative to 2 (Figure 1b). Hence, only 2 could be observed in the NMR spectra. Similar results were obtained for 3 and 4 (Figure S33). Featured with three conjugated pyrrolic units, compounds 2−4 may be used as ligands to chelate transition metal ions.

Figure 4. Crystal structure of complex 4-Zn. (a) Hydrogens attached to carbons are omitted for clarity. Time courses of absorption spectra changes of 2 (b) and 4 (c) (10 μM in CH2Cl2) upon addition of 5 equiv of zinc acetate in CH2Cl2.

To further understand the coordination behavior, the coordination processes were monitored by recording the absorption spectra changes (Figures 4b,c and Figure S35). For both 2 and 4, clear isosbestic points were observed, indicative of generating distinct coordination species (Figures 4b,c). The coordination reaction rate of 2 was estimated to be 3.7 × 10−3 s−1, about 10 times larger than that of 3.4 × 10−4 s−1 obtained for 4 (Figure S36). The dramatically different reaction rates may result from the difficulty of flipping of pyrrole ring D for 4 to achieve the four-coordinated structure. In contrast to 2 and 4, the absorption spectrum of 3 remains almost unchanged within 12 h after addition of Zn(II), implying that the coordination of 3 is much more difficult than 2 and 4, which may be related to the coexistence of inverted terminal pyrrolic unit and the electron-withdrawing keto moiety. In summary, regioselective ring opening of our previously reported neo-NCphlorin was achieved in a high yield of 88% by using 21 equiv of FeCl3 in which the bond between the Nconfused pyrrole ring A and pyrrole ring D was cleaved to C

DOI: 10.1021/acs.orglett.8b00478 Org. Lett. XXXX, XXX, XXX−XXX

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afford three linear tetrapyrroles 2−4. Each of them exhibits only one predominant tautomer in both the NMR spectra of 2−4 and the crystal structure of 3. This observation is well rationalized by DFT calculations, which indicate that all other possible tautomers have much higher energy, compared with the observed ones. Tetrapyrroles 2−4 feature with three conjugated pyrroles over rings B to D, which can be used for metal chelation, and coordination of 2 with Zn(II) was found to be about 10 times faster than 4, and it is rather difficult for 3 to coordinate with Zn(II) due to the presence of the electronwithdrawing keto moiety, and difficulty in flipping of ring D. These results provide successful examples of synthesizing novel linear tetrapyrroles by highly regioselective ring opening of unsymmetrical porphyrin analogues.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00478. Complete experimental details; spectroscopic and analytical data; details on DFT calculations (PDF) Accession Codes

CCDC 1814387−1814388 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected]. ORCID

Jiewei Shao: 0000-0002-5666-5074 Shuangliang Zhao: 0000-0002-9547-4860 Yongshu Xie: 0000-0001-8230-7599 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by NSFC (21472047, 21772041, 21702062), the Program for Professor of Special Appointment (Eastern Scholar, GZ2016006) at Shanghai Institutions of Higher Learning, Shanghai Pujiang Program (17PJ1401700), and the Fundamental Research Funds for the Central Universities (WK1616004, 222201717003, 222201714013).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00478 Org. Lett. XXXX, XXX, XXX−XXX