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Mechanical Trapping of the Phlorin Intermediate

2022; Chinese Chemical Society; Volume: 4; Issue: 10 Linguagem: Inglês

10.31635/ccschem.022.202101679

2096-5745

Min Tang, Yimin Liang, Jiali Liu, Lifang Bian, Zhichang Liu,

ATP Synthase and ATPases Research

Open AccessCCS ChemistryCOMMUNICATION3 Oct 2022Mechanical Trapping of the Phlorin Intermediate Min Tang, Yimin Liang, Jiali Liu, Lifang Bian and Zhichang Liu Min Tang Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, and Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024 , Yimin Liang Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, and Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024 , Jiali Liu Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, and Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024 , Lifang Bian Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, and Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024 and Zhichang Liu *Corresponding author: E-mail Address: [email protected] Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science, Westlake University, and Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024 https://doi.org/10.31635/ccschem.022.202101679 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Trapping unstable intermediates for elucidating reaction mechanisms in chemistry presents a formidable challenge. There has long been a lack of direct evidence for key intermediates like the highly reactive phlorin leading to porphyrin. Here, we report a molecular-strain engineering (MSE) strategy that harnesses intramolecular strain to trap the native phlorin during porphyrin synthesis. By mechanically constraining its periphery, a phlorin stable towards oxidation was captured as an isolable intermediate and fully characterized. This strained intermediate was transformed quantitatively into the corresponding bow-shaped porphyrin upon photoirradiation. Theoretical calculations indicate that the constraint imposed on the phlorin enhances the activation energy to reach the transition state of its oxidative aromatization and destabilizes the resulting porphyrin, thus facilitating trapping of this highly reactive intermediate. This proof-of-concept demonstration establishes the potential of MSE to capture native intermediates using mechanical stress as an alternative to adding scavengers and opens up a convenient way for carrying out mechanistic investigations. Download figure Download PowerPoint Introduction Porphyrins, ubiquitous protein cofactors, play crucial roles in biological systems.1,2 The chemical synthesis of porphyrins constitutes a cornerstone for understanding their many-electron redox properties involving multiple intermediates, which endow them with versatile reactivities both in their biological settings and in optoelectronic materials. Common approaches to the synthesis of porphyrins3 involve (Figure 1a) a condensation followed by oxidation starting from pyrroles and aldehydes. The biological, synthetic, and catalytic mechanistic pathways involving porphyrins, however, remain poorly understood because of the lack of direct evidence for proposed key intermediates, whose instability shortens their lifetime and prevents their isolation. In 1960, Woodward and coworkers4 reported a two-electron reduced porphyrin, phlorin—which is readily oxidized by air—as an intermediate during the total synthesis of a class of magnesium porphyrins, that is, chlorophyll. Subsequently, phlorin has been proposed5–10 generally as a key intermediate in proton-coupled electron transfer (PCET) reaction mechanisms in the transformation of porphyrinogen precursors into porphyrins and catalysis by porphyrins. The direct capture of the native intermediate, phlorin, during porphyrin synthesis, however, has still not been achieved because of its propensity to undergo reaction and the high stability of the corresponding oxidation product, porphyrin.1,11–14 Figure 1 | Trapping the phlorin intermediate using a MSE strategy. (a) A one-pot, two-step Lindsey synthesis of porphyrin employing a highly reactive and short-lived phlorin intermediate. (b) A tensioned bow resulting from a bent bow limb with high strain energy. (c) The retrosynthetic analysis of a strained bow-shaped porphyrin macrocycle (PB) which is constructed by connecting two peripheral 5,15-meso-phenyl rings with a short linker. Red wavy lines imply linkers between two 5,15-meso-phenyl rings (bow-limbs). (d) Reaction energy diagrams for the aromatization of phlorin intermediates into porphyrins. Black lines indicate pathway 1 to the unstrained porphyrin from the unconstrained phlorin undergoing an unstrained transition state (TSu), whereas red lines highlight pathway 2 to the strained PB from the constrained phlorin undergoing a strained TS (TSs). In contrast to the relatively small activation energy Δ G u ≠ and small Gibbs free energy Δ G u ° in pathway 1, the strain-engaged pathway 2 exhibits a significantly higher activation energy Δ G s ≠ and a larger Gibbs free energy Δ G s ° . Download figure Download PowerPoint In contrast to the porphyrins, phlorins consist of three sp2-hybridized meso-carbon atoms and one meso-sp3-carbon carrying one hydrogen atom which is sufficient to interrupt the 18π-electron conjugation of the ring in the porphyrin plane. In principle, phlorins can be prepared by two major strategies: (1) starting from porphyrin, which can be attacked by nucleophiles—for example, alkyl lithium reagents or hydride—at its meso-position13–16 and (2) starting from acyclic (oligo)pyrrole building blocks and aldehydes or ketones employing an acid-catalyzed condensation followed by the oxidative dehydrogenation of intermediates.1,17–21 However, native phlorins with unmodified core-structures are highly unstable and readily oxidized,9,19,22,23 making it difficult to isolate them. To stabilize phlorins during their synthesis, chemists have proposed five methods: (1) introducing bulky substituents, for example, mesityl and phenyl, at the meso-sp3-carbon atom to hinder oxidation1,13,18,19,22,24–27 and electron-withdrawing substituents, for example, pentafluorophenyl,1,19,24,27 to enhance the oxidation potential of the phlorin; (2) N-substitution16,28,29 so as to distort its conformation; (3) metalation with metal ions in the core of the phlorin30; (4) replacing pyrrole with thiophene31; and (5) introducing electron-withdrawing groups at the β-position of these pyrroles.4 Most, if not all, of these methods only provide stable phlorins with significantly modified core structures, while no native phlorin has been trapped in situ during porphyrin synthesis or catalysis, making it difficult to establish its role as an intermediate. Theoretically, the process of a chemical reaction is controlled by both kinetics and thermodynamics in which the change in standard Gibbs free energy (ΔG°) defines the driving force while the activation energy (ΔG≠) determines the rate of reaction. Herein, we have employed a strategy we refer to as molecular-strain engineering32 (MSE) to facilitate the trapping of the native phlorin intermediate by modulating the ΔG° and ΔG≠ values for porphyrin synthesis. MSE uses strain to impose intramolecular tension on molecules, which, because of their strained conformations, can exhibit enhanced performance such as the control of reaction pathways. Inspired by the tension of a bow with high strain energy (Figure 1b), the MSE strategy comprises a molecular bow33 (Figure 1c) that consists of a porphyrin unit (bow-limb) with a short flexible chain (bowstring) under tension joining its 5- and 15-meso positions: we call it a porphyrin bow (PB). Because of the geometrical incompatibility between the bow limb and bowstring, the PB-limb is curved under angle strain and stores energy, which raises the Δ G s ° value of porphyrin to a higher level than the Δ G u ° value of the unstrained planar porphyrin, thereby destabilizing it and thus decreasing the driving force for its conversion from phlorin to porphyrin. The retrosynthetic analysis (Figure 1c) of this PB highlights its two-electron reduced precursor, a constrained phlorin intermediate in which the bowstring connects the 5-meso-sp3-carbon with the 15-meso-sp2-carbon atoms to maintain its non-planar conformation. We envision that the mechanically constrained conformation can halt the oxidative aromatization of phlorin to PB on account of the additional energy barrier associated with the strained transition state (TSs) and the lower stability of the resulting strained PB. In contrast to the Δ G u ≠ and Δ G u ° in an unstrained pathway (Figure 1d, pathway 1), the transformation in a strained pathway (Figure 1d, pathway 2) is subjected to higher Δ G s ≠ ( Δ G s ≠ > Δ G u ≠ ) and a lower driving force ( Δ G s ° > Δ G u ° ), thus halting the reaction and stabilizing the constrained phlorin intermediate. Results and Discussion To identify the structure of a PB with appropriate strain energy, we employed molecular modeling and quantum chemistry calculations to screen ( Supporting Information Table S3) bowstrings connecting the 5- and 15-meso positions on the porphyrin unit. When the bowstring was a pyrazine-incorporated flexible chain, the resulting PB 2 exhibits (Figure 2a and Supporting Information Scheme S2b) a strained bow-shaped conformation with a high strain energy of 27.1 kcal mol−1 as confirmed by density functional theory calculations. Figure 2 | Strain-assisted trapping of 1 and its single-crystal X-ray (super)structures. (a) Synthesis and isolation of the stabilized phlorin 1 from the dipyrrolemethane 3 and dialdehyde 4 which does not aromatize in the dark and presence of excess DDQ, to form the strained porphyrin 2. The pyrazine-incorporated linker is highlighted in red. (b) Front and side-on views of single-crystal X-ray structure of 1•TFA in stick representation showing a meso-sp3-carbon atom connecting with a hydrogen atom and three meso-sp2-carbon atoms. (c) A pair of enantiomeric conformations of 1 co-exist in the X-ray superstructure as a result of the two mirror-symmetrical (m) orientations of the pyrazine rings. (d) Stick representation of the superstructure of a racemic 2∶2∶1 adduct (1)2•(TFA)2•DDQH2 between two enantiomeric conformations of 1, TFA, and DDQH2. Magenta dashed lines and brown arrows indicate [N–H⋯O] and [O–H⋯O] hydrogen bonding as well as [π⋯π] interactions, respectively. Except for meso-H, NH, and OH, all hydrogen atoms are omitted for the sake of clarity. C, tan; H, white; O, red; N, blue; Cl, green; F, light green. The carbon atoms of 1 in (c) and (d) are depicted in blue and orange in order to distinguish two enantiomeric conformations. Download figure Download PowerPoint With the designed structure of 2 in hand, we carried out its synthesis (Figure 2a) in order to attempt the capture of the phlorin intermediate 1. We conducted a one-pot, two-step Lindsey synthesis18 (Figure 2a and Supporting Information Scheme S1) starting from dipyrro-4-tert-butylphenylmethane ( 3; Supporting Information Figures S3 and S4) and 2,2′-((pyrazine-2,3-diylbis(methylene))bis(oxy))dibenzaldehyde ( 4; Supporting Information Figures S1 and S2). The first two steps of the synthesis involve a trifluoroacetyl (TFA)-catalyzed condensation, followed by a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation. After adding an excess of DDQ and allowing the reaction mixture to stand for one more hour, thin-layer chromatographic (TLC) analysis revealed the presence of a green spot. In general, the green color of the product porphyrin will change to red after neutralizing with ammonium hydroxide (NH4OH). In this case, however, the green color remained unchanged after this work-up procedure. We isolated ( Supporting Information Figures S5–S8 and S11–S16) the product as a dark green solid following column chromatography. In the dark, the product is stable upon exposure to air and in solution for several months as evidenced ( Supporting Information Figure S21) by 1H NMR spectroscopy. High-resolution mass spectrometric (HRMS) analysis of the product showed ( Supporting Information Figure S23a) a peak at m/z 865.4203 and an isotopic pattern that matched the theoretical m/z 865.4224 [M+H]+ and the simulated pattern for the proposed phlorin 1. X-ray diffraction analysis confirmed the structure of 1. Single crystals, suitable for X-ray crystallography, were obtained by slow liquid-liquid diffusion of cyclohexane into a solution of 1 in toluene for 4 weeks. In the solid-state superstructure (Figure 2b and Supporting Information Figures S27 and S29), 1 exists as its trifluoroacetate salt 1•TFA even though the crude product had been neutralized with NH4OH during the work-up procedure. The structure of 1 features a basket-like conformation, composed of one meso-sp3-carbon (bond angles: 106°–117°) carrying one hydrogen atom, an observation that is typical of phlorins. The meso-sp3-carbon interrupts the 18π conjugation of the macrocycle in 1, a situation which is also confirmed ( Supporting Information Figure S31) by the anisotropy of the induced current density (ACID) and nucleus-independent chemical shifts (NICS(0)) calculations. Theoretical calculations indicate ( Supporting Information Scheme S2a) that the constraint of the pyrazine-incorporated bowstring imposes a strain energy of 9.9 kcal mol−1 upon 1. The two pyrrolic NH groups adjacent to the meso-sp3-carbon form one pair of intramolecular [N–H⋯O] hydrogen bonds (d[H···O] = 2.09 and 2.12 Å) with an oxygen atom on the bowstring, while the other two NH groups form another pair (d[H···O] = 1.77 and 2.03 Å) of intermolecular hydrogen bonds with a TFA anion, an observation which, along with the constrained conformation, rationalizes the strong resistance of 1•TFA toward oxidation and neutralization with base. Despite the pseudo-Cs-symmetry of the phlorin unit, the pyrazine ring is skewed to one side forming a [π⋯π] interaction (3.44 Å) with one of the pyrrole rings, introducing chirality into 1. The resulting enantiomeric conformations of 1 co-exist in the superstructure (Figures 2c and 2d and Supporting Information Table S2) as a compact racemic 2∶2∶1 adduct of ( 1)2•(TFA)2•DDQH2 with TFA and hydrogenated DDQ (DDQH2) by means of four [N–H⋯O] (d[H···O] = 1.77–2.03 Å) and two strong [O–H⋯O] (d[H···O] = 1.70 and 1.80 Å) hydrogen bonds as well as weak [π⋯π] (3.78 and 3.93 Å) interactions. The multiple noncovalent bonding interactions afford 1 an additional stabilization and facilitate the formation of the multi-component supramolecular adduct that survives column chromatography. The 1H NMR spectrum of 1 in CDCl3 at 298 K exhibits sets of broad resonances, presumably because of exchange occurring between the two conformations. We recorded ( Supporting Information Figure S20) the 1H NMR spectra of 1 in CDCl3 over a range of temperatures from 233 to 328 K to gain insight into the exchange process. The 1H NMR spectrum of 1 at 233 K shows ( Supporting Information Figures S5 and S14) well-resolved resonances, enabling us to assign all the protons with the aid of a 1H–1H correlation spectroscopy experiment. The meso-proton appears as a broad singlet at 5.45 ppm,16 while the eight pyrrolic β-protons in 1 exhibit eight heterotopic broad resonances as a result of the chirality imposed by the tilted pyrazine ring. The resonances for two heterotopic CH2 linkers appear as two pairs of doublets centered on 5.10 and 4.94 ppm (Hb1″ and Hb1′) as well as on 4.38 and 4.18 ppm (Hb2″ and Hb2′) below 283 K but merge into two sharp singlets at 5.04 and 4.42 ppm (Hb1 and Hb2) upon increasing the temperature higher than 283 K. This observation confirms that the constraint of the bowstring hinders the exchange between the two enantiomeric conformations of 1. The coalescence temperature is Tc = 283 K. Thus, the energy barrier ΔG≠ for this exchange process is estimated to be 13.4 kcal mol−1 based on the Eyring equation. See Supporting Information. Although 1 is stable in the solid state and in solution in the dark, we discovered (Figure 3b and Supporting Information Figure S26) that the green color characterizing its solution and spots on TLC plates changed to brown upon irradiating with visible light, an observation which suggested we had carried out (Figure 3a and Supporting Information Figures S9, S10, S18, and S19) the photoinduced transformation from phlorin 1 to porphyrin 2. When we performed ( Supporting Information) the photoirradiation of 1 with visible light for 1 week, a purple solid was obtained as the only product, along with the depletion of 1. HRMS analysis of this product exhibited ( Supporting Information Figure S23b) a major peak at m/z 863.4089 that matches the theoretical m/z 863.4068 [M+H]+ for 2, confirming the complete transformation of 1 into 2. Figure 3 | Photoinduced oxidative aromatization of 1 to 2. (a) Transformation of 1 to 2 upon visible light irradiation. (b) Color change from green to brown of a solution (0.18 mM) of 1 in CHCl3 upon irradiating with visible light over a period of 0–18 h. (c) Time-dependent UV–vis spectroscopy of a solution (8.14 × 10−5 M) of 1 in CHCl3 upon irradiating with visible light over a period of 0–120 min exhibiting a significant decrease in band intensity at 703 nm of 1, considerable enhancement of the Soret band at 434 nm and the first Q-band at 534 nm of 2, and two neat isosbestic points at 445 and 601 nm. (d) Time-dependent 1H NMR spectroscopy (600 MHz, CD3SOCD3, 298 K, 1.67 mM) of 1 demonstrating the nearly quantitative transformation of 1 to 2 after irradiating a sample of 1 with visible light for around 73 h. (e) Time-dependent concentration variations of 1 and 2 upon irradiating with visible light. The ratio between integrals of two Hb2 protons on the CH2 linker adjacent to the meso-sp3-carbon in 1 and Hf (phenyl-H) in 2 is used to estimate the molar ratio between 1 and 2. The red square box and black circle indicate the concentrations of 1 (C1) and 2 (C2), respectively. (f) Kinetic analysis for the photopromoted oxidative aromatization of 1 was carried out based on the results derived from (d), and a first-order reaction was confirmed with a rate constant of approximately (3.17 ± 0.03) × 10−6 s−1. Download figure Download PowerPoint The UV–vis spectrum of 1 shows ( Supporting Information Figure S24a) characteristic peaks at 424, 448, and 703 nm, while the spectrum of 2 exhibits ( Supporting Information Figure S24c) a strong Soret band at 434 nm and four Q-bands at 535, 572, 608, and 666 nm—a typical UV–vis spectrum for a freebase porphyrin with a redshift of ∼10 nm compared3 with planar meso-tetraphenylporphyrin (TPP). Next, we conducted (Figure 3c) time-dependent UV–vis spectroscopy to investigate the photoinduced oxidative aromatization of 1 into 2. Upon irradiating a solution (8.14 × 10−5 M) of 1 in CHCl3 with visible light over a period of 0−120 min, the UV–vis spectrum underwent a significant decrease in intensity of the bands at 448 and 703 nm for 1 in concert with considerable enhancement of the Soret band at 434 nm and the first Q-band at 534 nm for 2 in addition to two isosbestic points at 445 and 601 nm, an observation which indicates that the conversion of 1 to 2 is occurring quantitatively. The rate constant and half-life time of the photoinduced transformation of 1 to 2 in CHCl3 was deduced as (3.50 ± 0.17) × 10−4 s−1 and 33 min ( Supporting Information Figure S25), respectively, based on the time-dependent UV–vis spectroscopic data. Time-dependent 1H NMR spectra of 1 upon visible light irradiation also confirmed the transformation of 1 to 2 in quantitative yield. In contrast to that of 1, the 1H NMR spectrum of 2 exhibits ( Supporting Information Figure S9) a relatively simple pattern along with significantly upfield-shifted characteristic resonances for the pyrrolic NH protons at −0.18 ppm and Hf at 9.02 ppm as a result of its curved C2v-symmetrical conformation. Because of the poorly resolved 1H NMR spectrum of 1 in CDCl3 at 298 K, we carried out the time-dependent 1H NMR experiments in CD3SOCD3, leading to well-defined resonances for 1. On increasing the irradiation time with visible light to 73 h, the time-dependent 1H NMR spectrum revealed ( Supporting Information Figure S22) the disappearance of the resonances for 1 in concert with the emergence of those for 2. The rate constant was estimated (Figures 3d–3f) from the time-dependent 1H NMR spectroscopic data to be (3.17 ± 0.03) × 10−6 s−1, a value which corresponds to a half-life time of 61 h. In comparison with the rate observed for the transformation of 1 to 2 in CHCl3, the rate in DMSO-d6 is two-orders of magnitude slower, an observation which might facilitate deeper investigation into this PCET process. Single crystals of 2 suitable for X-ray crystallography were obtained by slow liquid-liquid diffusion of MeOH into a solution of 2 in CHCl3 for 1 week. X-ray diffraction analysis demonstrates (Figures 4a and 4b and Supporting Information Figure S28 and Table S1) that 2 adopts a C2v-symmetrical bow-shaped conformation. In the solid-state structure of 2, the curved porphyrin moiety (bow-limb) with an angle of 137° deviates significantly from the plane and the deformed pyrazine ring (bowstring) confirms the highly strained state of this macrocycle, which agrees with the calculated strain energy of 27.1 kcal mol−1. Figure 4 | Single-crystal X-ray structure of 2. (a) Front view showing the bow-shaped macrocycle wherein the porphyrin moiety is curved, forming an arc with an angle of 137°, which deviates significantly from the angle of 180° of a planar porphyrin, while the 2,3-disubstituted pyrazine ring is deformed from a regular hexagon. (b) Side-on view showing a T-shaped conformation of 2. Download figure Download PowerPoint Quantum chemistry calculations were carried (Figure 5 and Supporting Information Figure S30 and Tables S4–S15) out to gain insight into the mechanism of the MSE strategy for trapping 1 as a stable intermediate during the synthesis of 2 using DDQ as the oxidant. The comparison calculations for the conversion of the unconstrained meso-tetraphenylphlorin (TPPh) to the unstrained TPP under the same conditions provide an activation energy barrier Δ G u ≠ of 12.5 kcal mol−1 and a Gibbs free energy Δ G u ° of −31.4 kcal mol−1. In striking contrast, the transformation from 1 to 2 needs to overcome an energy barrier Δ G s ≠ of 38.1 kcal mol−1 in addition to a much smaller driving force Δ G s ° of −1.6 kcal mol−1. These observations indicate that, as anticipated, the constraint on 1 enhances the activation energy barrier ( Δ G s ≠ > Δ G u ≠ ) to reach the transition state associated with its oxidative aromatization and destabilizes the resulting 2 ( Δ G s ° > Δ G u ° ), thus halting the reaction of 1 to 2. Consequently, 1 was captured as a stable intermediate on account of the cooperative modulation of both kinetics as well as thermodynamics. Figure 5 | Reaction diagram for the transformation from phlorin to porphyrin. Red lines indicate the oxidative aromatization of the constrained phlorin 1 to generate the strained porphyrin 2 with DDQ as an oxidant, while black lines annotate the unconstrained TPPh to planar TPP. TSs and TSu indicate the strained and unstrained transition states, respectively. Download figure Download PowerPoint Conclusion Given the fact that we are able to trap a native intermediate without modifying its core structure using mechanical force instead of adding scavenger species, the MSE strategy demonstrated here offers a convenient way of investigating mechanisms in synthesis and catalysis. The precise control over both kinetics and thermodynamics of reactions by intramolecular strain highlights the real potential of MSE to modulate progress and selectivities of reactions. Supporting Information Supporting Information is available and includes experimental details, characterization, spectra, crystal diffraction data for 1 and 2, and theoretical calculations. Conflict of Interest The authors declare no competing interests. Funding Information This research was made possible as a result of generous grants from the National Natural Science Foundation of China (grant nos. 22171232 and 21971211), the Natural Science Foundation of Zhejiang Province (grant no. 2022XHSJJ007), and the Qiantang River Talent Foundation (grant no. QJD1902029). Acknowledgments We are grateful for financial support from Westlake University. We are very grateful to Sir Fraser Stoddart for his assistance in editing the manuscript. We thank Drs. Xinyu Lu and Xiaohuo Shi, Xiaohe Miao, and Yinjuan Chen for their help in recording NMR spectra, X-Ray collections on diffraction dots, and mass spectrometric data, respectively. We would like also to thank Professor Jing Huang and Jinfeng Chen for their helpful discussion on theoretical calculations. 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Xinyu Lu and Xiaohuo Shi, Xiaohe Miao, and Yinjuan Chen for their help in recording NMR spectra, X-Ray collections on diffraction dots, and mass spectrometric data, respectively. We would like also to thank Professor Jing Huang and Jinfeng Chen for their helpful discussion on theoretical calculations. This research was supported by both the Instrumentation and Service Center for Molecular Science (ISCMS) and the Instrumentation and Service Center for Physical Science (ISCPS) as well as by Westlake University HPC Center. Downloaded 3,338 times PDF downloadLoading ...