Sparsely substituted chlorins as core constructs in chlorophyll analogue chemistry. III. Spectral and structural properties

The availability of stable chlorins bearing few or no substituents has enabled a variety of fundamental studies. The studies described herein report absorption spectra of diverse chlorins, comparative NMR features of chlorins bearing 0-3 meso-aryl substituents, and X-ray structures of the fully unsubstituted chlorin and the oxochlorin.     

Sparsely substituted chlorins as core constructs in chlorophyll analogue chemistry. I. Synthesis

Five routes to stable chlorins bearing 0 or 1 meso substituents have been investigated, among which reaction of a 9-bromo-1-formyldipyrromethane and 2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin proved most effective. Application of this route afforded metallochlorins [Cu(II), Zn(II), and Pd(II)] including the chlorin lacking any β-pyrrole and meso substituents.     

Effects of substituents on synthetic analogs of chlorophylls. Part 1: Synthesis, vibrational properties and excited-state decay characteristics

Understanding the effects of substituents on the spectra of chlorins is essential for a wide variety of applications. Recent developments in synthetic methodology have made possible systematic studies of the properties of the chlorin macrocycle as a function of diverse types and patterns of substituents. In this paper, the spectral, vibrational and excited-state decay characteristics are examined for a set of synthetic chlorins. The chlorins bear substituents at the 5,10,15 (meso) positions or the 3,13 (beta) positions (plus 10-mesityl in a series of compounds) and include 24 zinc chlorins, 18 free base (Fb) analogs and one Fb or zinc oxophorbine. The oxophorbine contains the keto-bearing isocyclic ring present in the natural photosynthetic pigments (e.g. chlorophyll a). The substituents cause no significant perturbation to the structure of the chlorin macrocycle, as evidenced by the vibrational properties investigated using resonance Raman spectroscopy. In contrast, the fluorescence properties are significantly altered due to the electronic effects of substituents. For example, the fluorescence wavelength maximum, quantum yield and lifetime for a zinc chlorin bearing 3,13-diacetyl and 10-mesityl groups (662 nm, 0.28, 6.0 ns) differ substantially from those of the parent unsubstituted chlorin (602 nm, 0.062, 1.7 ns). Each of these properties of the lowest singlet excited state can be progressively stepped between these two extremes by incorporating different substituents. These perturbations are associated with significant changes in the rate constants of the decay pathways of the lowest excited singlet state. In this regard, the zinc chlorins with the red-most fluorescence also have the greatest radiative decay rate constant and are expected to have the fastest nonradiative internal conversion to the ground state. Nonetheless, these complexes have the longest singlet excited-state lifetime. The Fb chlorins bearing the same substituents exhibit similar fluorescence properties. Such combinations of factors render the chlorins suitable for a range of applications that require tunable coverage of the solar spectrum, long-lived excited states and red-region fluorescence.     

Rational synthesis of beta-substituted chlorin building blocks

Chlorins bearing synthetic handles at specific sites about the perimeter of the macrocycle constitute valuable building blocks. We previously developed methodology for preparing meso-substituted chlorin building blocks and now present methodology for preparing several complementary beta-substituted chlorin building blocks. The chlorins bear one or two beta substituents, one meso substituent, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. New routes have been developed to two beta-substituted bromo-dipyrromethane monocarbinols (Eastern halves). A new beta-substituted Western half was prepared following the method for preparing an unsubstituted Western half (3,3-dimethyl-2,3-dihydrodipyrrin). Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. beta-Substituted chlorins have been prepared in 18-24% yield bearing a 4-iodophenyl group at the 8-position, a 4-iodophenyl group or a 4-[2-(trimethylsilyl)ethynyl]phenyl group at the 12-position, and a 4-iodophenyl group and a 4-[2-(trimethylsilyl)ethynyl]phenyl group at diametrically opposed beta-positions (2, 12). The latter building block makes possible the stepwise construction of linear multi-chlorin architectures. The chlorins exhibit typical absorption and fluorescence spectra. A systematic shift in the absorption maximum (637-655 nm for the free base chlorins, 606-628 nm for the zinc chlorins) and intensity of the chlorin Q(y)() band (epsilon up to 79 000 M(-)(1) cm(-)(1)) is observed depending on the location of the substituents. The characteristic spectral features and location of substituents in defined positions make these chlorins well suited for a variety of applications in biomimetic and materials chemistry.     

Synthetic chlorins bearing auxochromes at the 3- and 13-positions

Synthetic chlorins bearing diverse auxochromes at the 3- and 13-positions of the macrocycle are valuable targets given their resemblance to chlorophylls a and b, which bear 3-vinyl and 13-keto groups. A de novo route has been exploited to construct nine zinc chlorins bearing substituents at the 3- and 13-positions and two benchmark zinc chlorins lacking such substituents. The chlorins are sterically uncongested and bear (1) a geminal dimethyl group in the reduced pyrroline ring, (2) a H, an acetyl, a triisopropylsilylethynyl (TIPS-ethynyl), or a vinyl at the 3-position, (3) a H, an acetyl, or TIPS-ethynyl at the 13-position, and (4) a H or a mesityl at the 10-position. The synthesis of the 13-substituted chlorins relied on p-TsOH x H2O-catalyzed condensation of an 8,9-dibromo-1-formyldipyrromethane (eastern half) and 2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin (western half), followed by metal-mediated oxidative cyclization, affording the 13-bromochlorin. Similar use of a bromo- or TIPS-ethynyl-substituted western half provided access to 3-substituted chlorins. A 3-bromo, 13-bromo, or 3,13-dibromochlorin was further transformed by Pd-coupling to introduce the vinyl group (via tributylvinyltin), TIPS-ethynyl group (via TIPS-acetylene), or acetyl group (via tributyl(1-ethoxyvinyl)tin, followed by acidic hydrolysis). In the 10-mesityl-substituted zinc chlorins, the series of substituents, 3-vinyl, 13-TIPS-ethynyl, 3-TIPS-ethynyl, 13-acetyl, 3,13-bis(TIPS-ethynyl), 3-TIPS-ethynyl-13-acetyl, or 3,13-diacetyl, progressively causes (1) a redshift in the absorption maximum of the B band (405-436 nm) and the Q(y) band (606-662 nm), (2) a relative increase in the intensity of the Q(y) band (I(B)/I(Q) = 4.2-1.5), and (3) an increase in the fluorescence quantum yield phi(f) (0.059-0.29). The zinc chlorins bearing a 3-TIPS-ethynyl-13-acetyl or a 3,13-diacetyl group exhibit a number of spectral properties resembling those of chlorophyll a or its zinc analogue. Taken together, this study provides access to finely tuned chlorins for spectroscopic studies and diverse applications.     

REGIOSELECTIVE PHOTOREDUCTION OF ZINC(II) PORPHYRINS TO GIVE CHLORINS

The ascorbic acid/organic base photoreduction of zinc(II) porphyrins was investigated. It was established that certain substituents can direct the photoreduction to the site of the macrocycle to which they are attached. For example, zinc(II) vinylporphyrins (8, 12, 16, 20) are photoreduced with cis stereochemistry on the ring bearing the vinyl group to give the corresponding chlorins. Zinc(II) acetylporphyrins (22, 24) were likewise reduced to chlorins such that cis-hydrogenation took place on the ring bearing the acetyl group. Zinc(II) formylporphyrins 33 also appear to reduce at the ring bearing the formyl group. When the zinc(II) acrylic porphyrin 28 was photoreduced, reduction did take place at the ring bearing the acrylic side chain, but migration of the acrylate double bond was very rapid, and the product isolated was the corresponding porphyrin propionate 30. Reduction of a zinc(II) porphyrin 35 bearing both a vinyl group and a nuclear carboxylic ester took place at the ring bearing the carboxylic ester. The reaction provides a general method for regioselective synthesis of chlorins from zinc(II) porphyrins without any evidence of formation of over-reduction products characteristic of many other procedures for formation of chlorins from porphyrin precursors.     

Beyond green with synthetic chlorophylls – Connecting structural features with spectral properties

The distinct features of chlorophylls in photosynthesis have led to the formation of numerous derivatives for applications encompassing solar energy conversion, molecular photonics, photodynamic therapy, and molecular imaging. Synthetic chlorins created de novo and bearing a geminal dimethyl group in the reduced ring have proved invaluable for fundamental studies. Four decades of research have led to accumulation of tabulated spectra for > 400 such synthetic chlorins with distinct structural frameworks (17-oxochlorins, 13¹-oxophorbines, chlorinimides) and substituents (alkyl, aryl, ethynyl, phenylethynyl, acetyl, formyl) located at specific (meso, β) positions. In this review, spectral traces (324 absorption, 247 fluorescence) are assembled along with photophysical data including the molar absorption coefficient (ε), fluorescence quantum yield (Φ_f) and singlet excited-state lifetime (τ_s). The review uses the accumulated spectral data derived from chlorins all containing a uniform molecular scaffold to (1) highlight the effects of molecular structure on spectral features, and (2) identify trends including how ε, Φ_f and τ_s vary with wavelength and other features. Use of a common geminal-dimethyl-substituted chlorin scaffold – beginning with no substituents, to one substituent at designated sites, and to 2 or more substituents – provides a systematic Aufbau approach for understanding the absorption spectra of chlorins on a path to and beyond the native chlorophylls. The review provides insights concerning the rational design of potent analogues of Nature’s preeminent red-region absorbers for potential utilization in diverse applications and is aimed at multiple audiences: those interested in spectral properties, tetrapyrrole photophysics, and the molecular design of new chromophores.     

Rational synthesis of meso-substituted chlorin building blocks

Chlorins provide the basis for plant photosynthesis, but synthetic model systems have generally employed porphyrins as surrogates due to the unavailability of suitable chlorin building blocks. We have adapted a route pioneered by Battersby to gain access to chlorins that bear two meso substituents, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. A 3,3-dimethyl-2,3-dihydrodipyrrin (Western half) was synthesized in four steps from pyrrole-2-carboxaldehyde. A bromodipyrromethane carbinol (Eastern half) was prepared by sequential acylation and bromination of a 5-substituted dipyrromethane followed by reduction. Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. The latter reaction has heretofore been performed with copper templates. Investigation of conditions for this multistep process led to copper-free conditions (zinc acetate, AgIO(3), and piperidine in toluene at 80 degrees C for 2 h). The zinc chlorin was obtained in yields of approximately 10% and could be easily demetalated to give the corresponding free base chlorin. The synthetic process is compatible with a range of meso substituents (p-tolyl, mesityl, pentafluorophenyl, 4-[2-(trimethylsilyl)ethynyl]phenyl, 4-iodophenyl). Altogether four free base and four zinc chlorins have been prepared. The chlorins exhibit typical absorption spectra, fluorescence spectra, and fluorescence quantum yields. The ease of synthetic access, presence of appropriate substituents, and characteristic spectral features make these types of chlorins well suited for incorporation in synthetic model systems.     

Porphyrins. 39. Synthesis and Chemical Transformations of Porphyrins and Chlorins with 2-Acetyl-1-methyl-3-oxobutyl Substituents

Porphyrins and chlorins containing acetylacetone residues in the peripheral substituents [-CH(Me)CHAc₂] are converted under alkaline conditions into the corresponding deacetylated compounds with [-CH(Me)CH₂Ac] residues. Reduction of the latter as acids using sodium borohydride gives the corresponding alcohols and, after esterification, their acetates with branched peripheral [-CH(Me)CH₂CH(OAc)Me] substituents. Porphyrins and chlorins with such substituents in water-soluble form may hold interest as new photosensitizers in photodynamic cancer therapy.     

Rational routes to formyl-substituted chlorins

Two distinct approaches have been developed for the synthesis of chlorins bearing formyl groups: (1) reaction of an acetal-substituted 1-acyldipyrromethane with 2,3,5,6-tetrahydro-1,3,3-trimethyldipyrrin to give upon hydrolysis a 5-formylchlorin and (2) Pd-mediated coupling of a bromochlorin with a one-carbon synthon (hydroxymethyl tributyltin or CO) to give a 13-, 15-, or 3,13-formylchlorin. The zinc chlorins exhibit long-wavelength peak absorption maxima ranging from 626 to 667 nm, indicating the wavelength tunability afforded by formyl substitution.     

Effects of substituents on synthetic analogs of chlorophylls. Part 2: Redox properties, optical spectra and electronic structure

The optical absorption spectra and redox properties are presented for 24 synthetic zinc chlorins and 18 free base analogs bearing a variety of 3,13 (beta) and 5,10,15 (meso) substituents. Results are also given for a zinc and free base oxophorbine, which contain the keto-bearing isocyclic ring present in the natural photosynthetic pigments such as chlorophyll a. Density functional theory calculations were carried out to probe the effects of the types and positions of substituents on the characteristics (energies, electron distributions) of the frontier molecular orbitals. A general finding is that the 3,13 positions are more sensitive to the effects of auxochromes than the 5,10,15 positions. The auxochromes investigated (acetyl>ethynyl>vinyl>aryl) cause a significant redshift and intensification of the Qy band upon placement at the 3,13 positions, whereas groups at the 5,10,15 positions result in much smaller redshifts that are accompanied by a decrease in relative Qy intensity. In addition, the substituent-induced shifts in first oxidation and reduction potentials faithfully track the energies of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), respectively. The calculations show that the LUMO is shifted more by substituents than the HOMO, which derives from the differences in the electron densities of the two orbitals at the substituent sites. The trends in the substituent-induced effects on the wavelengths and relative intensities of the major features (By, Bx, Qx, Qy) in the near-UV to near-IR absorption bands are well accounted for using Gouterman's four-orbital model, which incorporates the effects of the substituents on the HOMO-1 and LUMO+1 in addition to the HOMO and LUMO. Collectively, the results and analysis presented herein and in the companion paper provide insights into the effects of substituents on the optical absorption, redox and other photophysical properties of the chlorins. These insights form a framework that underpins the rational design of chlorins for applications encompassing photomedicine and solar-energy conversion.     

Studies in chlorin chemistry. 3. A practical synthesis of c,d-ring symmetric chlorins of potential utility in photodynamic therapy

[reaction: see text] C,D-ring symmetric chlorins 8 were prepared in 47-85% yield, on scales up to several hundred milligrams, by condensation of appropriately substituted bis-formyldihydrodipyrrins 6 and dipyrromethane bis-carboxylic acids 7 in 5% TFA/CH2Cl2 (25 examples). Target chlorins were chosen to systematically probe the effect of lipophilic and hydrophilic substituents on tissue partitioning and cellular membrane penetration in photodynamic therapy (PDT).     

Two complementary routes to 7-substituted chlorins. Partial mimics of chlorophyll B

Chlorophyll a and chlorophyll b exhibit distinct spectra yet differ only in the nature of a single substituent (7-methyl versus 7-formyl, respectively). Two complementary approaches have been developed for the synthesis of 7-substituted chlorins. The first approach is a de novo route wherein 2,9-dibromo-5-p-tolyldipyrromethane (Eastern half) and 9-formyl-2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin (Western half) undergo acid-catalyzed condensation followed by metal-mediated oxidative cyclization. The resulting zinc chlorin is sterically uncongested and bears (1) a geminal dimethyl group in the reduced, pyrroline ring, (2) a bromo substituent at the 7-position, and (3) a p-tolyl group at the 10-position. The second approach entails regioselective 7-bromination of a 10,15-diarylchlorin that lacks a substituent at the 5-position. In an extension of this latter approach, a 5,15-diarylchlorin that lacks a substituent at the 10-position undergoes regioselective bromination at the 8-position. The introduction of a TIPS-ethynyl, acetyl, or formyl group at the 7-position was achieved using Pd-catalyzed reactions with the corresponding 7-bromochlorin. In the 10-p-tolyl-substituted zinc chlorins, the series of substituents (7-TIPS-ethynyl, 7-acetyl, 7-formyl) progressively causes (1) a bathochromic shift in the absorption maximum of the B band (405 to 426 nm) and (2) a hypsochromic shift in the position of the Qy band (605 to 598 nm). The trends mirror those for chlorophyll b versus chlorophyll a but are of lesser magnitude. Taken together, the facile access to chlorins that bear auxochromes at the 7-position enables wavelength tunability and provides the foundation for fundamental spectroscopic studies.     

The synthesis of chlorophyll-a skeleton homologs bearing linear six-carbon chain from methyl pheophorbide-a

The synthesis of chlorins bearing 6C-straight chain was accomplished from methyl pheophorbide-a. A series of chemical modifications were employed for the construction of active functional groups, such as bromine atom or aldehyde group, on the periphery of chlorins. These functionalized chlorins further reacted with the reagent containing straight carbon-chain by common chemical reactions to produce target compounds. The structures of all new chlorins were characterized by elemental analysis, IR, UV-Vis and ¹H NMR spectra.     

13C NMR studies of reduced porphyrin compounds. Aromatic delocalization pathways

¹³C NMR spectra of ms-tetraphenylchlorins, new aminoalkyl- and hydroxy-pyrroline substituted ms-tetra-phenylchlorins, and ms-tetraphenylisobacteriochlorins are presented and discussed. Significant changes in the chemical shifts of the α-pyrrole, α-pyrroline and meso skeletal carbons are found in chlorins and isobacteriochlorins in comparison to porphyrins. In contrast, the chemical shifts of the β-pyrrole carbons are almost unaffected by the structural modifications in chlorin and isobacteriochlorin. The chemical shifts of the α-pyrrole carbons in the various chlorins and isobacteriochlorins are strongly affected by the substitutents of the pyrroline ring, or by the introduction of an additional pyrroline ring in isobacteriochlorins. The results show that most of the electron density is concentrated in the unreduced part of the molecule, i.e. in the pyrrole rings and, especially, on the α-pyrrole carbons and is transferred or removed through the aromatic pathway by substituents on the pyrroline ring. These observations are supporting evidence that the α-pyrrole, α-pyrroline and meso-carbons are in the aromatic pathway and favour the proposal of a 16 atom dianion as the preferred delocalization pathway in chlorins and isobacteriochlorins.     

Synthesis of New Derivatives of Protoporphyrin IX and Chlorophyll <Emphasis Type="Italic">a</Emphasis>

The vinyl groups in protoporphyrin IX and chlorophyll a derivatives were selectively transformed into hydroxymethyl and acetoxymethyl substituents. The reactivities of β-hydroxymethyl and β-acetoxymethyl groups in porphyrins and chlorins toward nucleophilic reagents were compared for the first time using the reaction with acetylacetone as an example. Peripheral acetylacetone moieties in porphyrins and chlorins were shown to be promising as building blocks for generation of exo heterocyclic structures.     

Synthesis of meso-substituted chlorins via tetrahydrobilene-a intermediates.

Chlorin building blocks incorporating a geminal dimethyl group in the reduced ring and synthetic handles in specific patterns at the perimeter of the macrocycle are expected to have utility in biomimetic and materials chemistry. A prior route employed condensation of a dihydrodipyrrin (Western half) and a bromodipyrromethane-monocarbinol (Eastern half), followed by oxidative cyclization of the putative dihydrobilene-a to form the meso-substituted zinc chlorin in yields of approximately 10%. The limited stability of the dihydrodipyrrin precluded study of the chlorin-forming process. We now have refined this methodology. A tetrahydrodipyrrin Western half (2,3,4,5-tetrahydro-1,3,3-trimethyldipyrrin) has been synthesized and found to be quite stable. The condensation of the Western half and an Eastern half (100 mM each) proceeded smoothly in CH(3)CN containing 100 mM TFA at room temperature for 30 min. The resulting linear tetrapyrrole, a 2,3,4,5-tetrahydrobilene-a, also is quite stable, enabling study of the conversion to chlorin. Refined conditions for the oxidative cyclization were found to include the following: the tetrahydrobilene-a (10 mM), AgTf (3-5 molar equiv), Zn(OAc)(2) (15 molar equiv), and 2,2,6,6-tetramethylpiperidine (15 molar equiv) in CH(3)CN at reflux exposed to air for 4-6 h, affording the zinc chlorin. The chlorin-forming process could be implemented in either a two-flask process or a one-flask process. The two-flask process was applied to form six zinc chlorins bearing substituents such as pentafluorophenyl, 3,5-di-tert-butylphenyl, TMS-ethyl benzoate, iodophenyl, or ethynylphenyl (deprotection of the TMS-ethynyl group occurred during the oxidative cyclization process). The stepwise yields (isolated) for the condensation and oxidative cyclization processes forming the tetrahydrobilene and zinc chlorin were 32-72% and 27-62%, respectively, giving overall yields of zinc chlorin from the Eastern and Western halves of 12-45%. Taken together, the refinements introduced enable 100-mg quantities of chlorin building blocks to be prepared in a facile and rational manner.     

Chelation-controlled nucleophilic additions. 2. A highly effective system for asymmetric induction in the reaction of organometallics with β-alkoxyaldehydes.

Organocuprates have been found to be highly stereoselective reagents for the addition of carbanionic nucleophiles to α-asymmetric aldehydes bearing β-oxygen substituents. The major products are those predicted by a chelation-controlled transition state and have diastereomeric purities ranging from -15-30:1.     

Liquid-crystalline quinoline derivatives

A number of novel liquid crystals have been synthesized. 2-Phenylquinolines with alkyl or alkoxyl substituents in positions 6 and 4' show a texture typical of nematic mesophases and are characterized by a greater thermal stability than Schiff bases bearing the same substituents. The possibility of lowering the melting temperatures by means of eutectic mixtures is discussed.     

Synthesis and optical properties of bacteriochlorophyll-a derivatives having various C3 substituents on the bacteriochlorin pi-system

Methyl bacteriopyropheophorbide-a derivatives having a series of substituents at the C3 position were prepared and their optical properties were compared with the corresponding chlorin analogues. Two kinds of oxidation reaction (C3-vinyl --> formyl --> carboxy group) were found to be applicable with a little alteration of the free-base bacteriochlorin macrocycles. The Qx and Qy electronic absorption peak positions of synthetic bacteriochlorins in CH2Cl2 were affected by the C3 substituents and found to be more sensitive than those of the chlorins. The observed Qx/Qy peaks in their monomeric states were shifted to a longer wavelength in the order of 1-hydroxyethyl < hydroxymethyl < acetoxymethyl < vinyl < acetyl < carboxy < formyl < 2,2-dicyanoethynyl group. Zinc complex with the C3-hydroxymethyl group formed self-aggregates in a nonpolar organic solvent, which showed the largest red-shift of the Qy band (2380 cm(-1), 726 nm in THF to 878 nm in 1% THF-cyclohexane) among those of the synthetic self-aggregative (bacterio)chlorins examined.