Sparsely substituted chlorins as core constructs in chlorophyll analogue chemistry. II. Derivatization

Abstract

Stable chlorins bearing few or no substituents have been subjected to a variety of reactions including demetalation, magnesium insertion, oxochlorin formation, and bromination followed by Suzuki coupling. The kinetics of deuteration also have been determined for two oxochlorins and a series of chlorins bearing 0, 1, 2, or 3 meso-aryl substituents.

1. Introduction

The preceding paper describes the synthesis of chlorins bearing no meso substituents or a single meso substituent at the 5- or 10-position.¹ The chlorins are stable toward adventitious dehydrogenation owing to the presence of a geminal dimethyl moiety in the reduced, pyrroline ring. The availability of stable chlorins bearing few or no meso substituents opens the door to a series of fundamental studies of reactivity as well as spectroscopic characterization. Studies of these sparsely substituted chlorins may serve as benchmarks for the naturally occurring chlorophylls, which bear a full complement of β-substituents. The sparsely substituted chlorins also provide minimalist scaffolds for chemistry aimed at mimicking chlorophylls. The presence of the geminal dimethyl group in the pyrroline ring renders these new synthetic chlorins more synthetically malleable than the existing model synthetic chlorins including meso-tetraphenylchlorin,² octaethylchlorin,³ and chlorin.^4,5

In this paper, we describe the examination of sparsely substituted synthetic chlorins in studies of fundamental reactivity. The studies include measuring the kinetics of deuteration for chlorins that bear 0, 1, 2, or 3 meso substituents and no β-substituents, and assessing the regioselectivity of bromination in a series of chlorins that bear 0 or 1 meso substituents. Selected bromo-chlorins have been subjected to Suzuki coupling reactions. Other reactions carried out include demetalation of zinc chlorins to give free base chlorins, metalation of a free base chlorin to give the magnesium chlorin, and oxochlorin formation. Altogether 14 new chlorins have been prepared. The subsequent paper describes the spectroscopic properties of a number of chlorins prepared herein.⁶

2. Results and discussion

The shorthand nomenclature for the chlorins described herein employs the following abbreviations with superscripts to denote substituents and their positions: B (3,5-di-tert-butylphenyl), P (phenyl), M (mesityl), and T (p-tolyl). The chlorins examined include those bearing no meso substituents (ZnC);^1,7 one meso substituent [(ZnC-B⁵),¹ (ZnC-T⁵),¹ (ZnC-M¹⁰),⁷ and (ZnC-P¹⁰)¹]; two meso substituents (H₂C-T⁵M¹⁰ and ZnC-T⁵M¹⁰);^8,9 and three meso substituents (H₂C-T⁵M¹⁰P¹⁵ and ZnC-T⁵M¹⁰P¹⁵).¹⁰ One oxochlorin (Oxo-H₂C-T⁵M¹⁰) also was examined.¹¹

2.1. Reactivity of chlorins

(1) Stability

All of the synthetic chlorins prepared herein were stable upon routine handling in aerobic environments, including use of procedures such as chromatography, recrystallization, and standing in solution on the open benchtop. The ready synthesis, purification, and stability of the chlorins enabled the studies of reactivity described in the following sections.

(2) Oxochlorin formation

Oxochlorins have more positive oxidation potentials compared with chlorins.^11,12 To gain information regarding spectral properties, the chlorins ZnC-B⁵ and ZnC were converted to their corresponding oxochlorins using an established procedure.¹¹ Accordingly, ZnC-B⁵ or ZnC was heated in the presence of basic alumina followed by oxidation with DDQ, giving Oxo-ZnC-B⁵ or Oxo-ZnC in 47% or 56% yield, respectively (Scheme 1).

Scheme 1.

(3) Demetalation

Free base chlorins are valuable compounds and also serve as precursors to diverse metallochlorins. In this regard, the availability of zinc chlorins from the chlorin synthesis is particularly attractive given the facile demetalation of the zinc chelates in the presence of weak acid. Thus, treatment of each member of a series of zinc chlorins and a zinc oxochlorin (ZnC, ZnC-T⁵, ZnC-M¹⁰, ZnC-P¹⁰, Oxo-ZnC) with TFA in CH₂Cl₂ afforded the corresponding free base species (H₂C, H₂C-T⁵, H₂C-M¹⁰, H₂C-P¹⁰, Oxo-H₂C) in good yield (Scheme 2). By contrast, the direct synthesis of other metallochlorins [e.g., Cu(II), Pd(II) ClIn(III)]¹ is attractive only if these are the ultimate metallochlorin targets, given that such tetrapyrrole coordination complexes require severe conditions for demetalation (e.g., concentrated sulfuric acid).¹³

Scheme 2.

(4) Metalation

The treatment of H₂C to a mild method for magnesium insertion¹⁴ (MgI₂ in CH₂Cl₂ containing N,N-diisopropylethylamine at room temperature) afforded the magnesium chelate MgC, a benchmark compound for comparison with chlorophylls (Scheme 3). MgC underwent partial demetalation upon chromatography on basic alumina, or on standing in CH₂Cl₂ solution, but was stable in toluene. Analysis of the isolated sample of MgC by ¹H NMR spectroscopy showed the presence of H₂O, THF, and MgC in ∼12:1:2 ratio. Magnesium chlorins are often isolated as solids in conjunction with coordinative molecules.¹⁴

Scheme 3.

(5) Deuteration

Woodward first reported that chlorins possessing no meso substituents and a partial or full complement of β-substituents undergo deuteration preferentially at the meso sites (15- and 20-positions) flanking the pyrroline ring.¹⁵ However, conclusions concerning relative reactivity were restricted to the four meso sites owing to the presence of the blocking β-substituents. We recently examined the deuteration of chlorins bearing substituents only at the 5- and 10-positions and found that deuteration occurred preferentially at the 15- and 20-positions, but the presence of substituents at the 5-and 10-positions also limited the conclusions that could be drawn.¹⁰ Here we carried out analogous studies using the free base chlorin H₂C and free base oxochlorin Oxo-H₂C, each of which has 10 sites potentially open to electrophilic aromatic substitution (six β-pyrrole and four meso sites).

Five chlorins (H₂C, H₂C-T⁵, H₂C-M¹⁰, H₂C-T⁵M¹⁰, and H₂C-T⁵M¹⁰P¹⁵) and two oxochlorins (Oxo-H₂C and Oxo-H₂C-T⁵M¹⁰) were exposed to neat TFA-d at 50 °C, and the exchange progress was measured by ¹H NMR spectroscopy (Scheme 4). For example, dissolution of H₂C in neat TFA-d at 50 °C resulted in a steady decrease over a few hours in the intensity of the resonances from H¹⁵ (9.26 ppm) and H²⁰ (9.19 ppm) (Figure 1). By contrast, the resonances from the 5, 10-, and all β-protons remained intact over the duration of the experiment (up to 24 h). No deuteration other than at the 15- or 20-positions was observed with the chlorin samples examined herein. Note that upon addition of TFA-d at room temperature, the pyrrolic NH protons of H₂C were immediately exchanged to form D₂C (observed by ¹H NMR spectroscopy), and the imino nitrogens also were deuterated (as observed by the absorption spectrum of the chlorin dication⁶).

Scheme 4.

Figure 1.

¹H NMR spectra over time showing the deuteration of the 15- and 20-positions of chlorin H₂C in TFA-d at 50 °C.

The data obtained obeyed first-order rate expressions quite closely; thus, rate constants (k) and half-lives (t_1/2) were calculated. First-order rate plots of deuterium exchange of chlorins (H₂C, H₂CM¹⁰, and H₂C-T⁵M¹⁰P¹⁵) and oxochlorins (Oxo-H₂C and Oxo-H₂C-T⁵M¹⁰) are illustrated in Figure 2. The deuterium exchange of each proton was monitored to at least 50% conversion (except for H¹⁵ of Oxo-H₂C or Oxo-H₂C-T⁵M¹⁰, which was deuterated up to 40% conversion). These data were used to determine the correlation coefficient R (≥ 0.998 in each case).

Figure 2.

First-order rate plots for deuterium exchange. The rate constants and half-lives are listed in Table 1.

Although the rate constants at the 15- and 20-positions for H₂C-T⁵ and H₂C-T⁵M¹⁰ could not be calculated due to the overlapping resonances of H¹⁵ and H²⁰, the reactivity of H₂C-T⁵ and H₂C-T⁵M¹⁰ could be compared with other chlorins by plotting the sum of the deuteration at both of 15- and 20-positions versus time (Figure 3). The order of overall reactivity toward deuteration was H₂C-T⁵M¹⁰P¹⁵ > H₂C-T⁵M¹⁰ > H₂C ∼ H₂C-T⁵ ∼ H₂C-M¹⁰.

Figure 3.

Comparison of the deuteration of chlorins (H₂C, H₂C-T⁵, H₂C-M¹⁰, H₂C-T⁵M¹⁰, and H₂C-T⁵M¹⁰P¹⁵). The sum of the deuteration at both the 15- and 20- positions is plotted as a function of time (sec).

The pseudo first-order rate constants for deuterium exchange at the 15- and 20-positions of chlorins and oxochlorins are summarized in Table 1. The rate constants for H₂C-T⁵ and H₂C-T⁵M¹⁰ could not be calculated directly; accordingly, the range of minimum and maximum values for the rate constants was estimated from the time of 50% and 75% total conversion (both for the 15- and 20- positions) as described in the following procedure:

1. When the overall exchange for the sum of the 15- and 20- positions reached 50%, at least 50% of the faster exchanging species (in this case H¹⁵) should be already deuterated; thus, the maximum t_1/2 of H¹⁵ is obtained. The maximum value of t_1/2 gives the minimum value of the rate constant. For example, 50% of the sum of the 15- and 20- positions was deuterated at 138 min in H₂C-T⁵, giving a maximum t_1/2 of 138 min for H¹⁵; in turn, the rate constant for H¹⁵ should be ≥ 8.4 × 10⁻⁵ s⁻¹.

2. When the exchange reached 75% for the sum of the 15- and 20-positions, at least 50% of the slower exchanging species (in this case H²⁰) should already be deuterated; thus, the maximum value for t_1/2 and the minimum value of the rate constant for H²⁰ are obtained. For example, 75% of the sum of 15- and 20- positions was deuterated at 286 min in H₂C-T⁵, giving a maximum t_1/2 of 286 min for H²⁰; in turn, the rate constant for H²⁰ should be ≥ 4.0 × 10⁻⁵ s⁻¹.

3. The maximum value of the rate constant for H¹⁵ can be calculated by considering the minimum contribution of H²⁰ at 75% of the overall exchange.

4. The maximum value of the rate constant for H²⁰ can be calculated by considering the minimum contribution of H¹⁵ at 50% of the overall exchange.

Table 1.

Pseudo-first-order rate constants for deuterium exchange of chlorin meso protons.^a

	Rate constants k (× 105) in s−1 and (t1/2 in min)
Compound	15-position	20-position
Chlorins
H2OECb	5.7 (200)c	5.7 (200)c
H2C	13 (91)	4.7 (250)
H2C-T5	10∼12d	5.6∼6.5d
H2C-M10	15 (74)	4.8 (240)
H2C-T5M10	55∼53d	9.7∼10d
H2C-T5M10P15	n.a.	47 (23)
Oxochlorins
Oxo-H2OECe	1.5 (780)f	4.8 (240)f
Oxo-H2C	0.50 (2300)	2.1 (520)
Oxo-H2C-T5M10g	3.2 (350)	9.3 (120)

^aIn TFA-d at 50 °C.

^bThe stereochemistry of H₂OEC (2,3,7,8,12,13,17,18-octaethylchlorin) is not clear.

^cRef ¹⁶.

^dDue to the overlap of the resonances from H¹⁵ and H²⁰ in TFA-d, the rate constants could not be calculated directly (see text).

^e2,3,7,8,12,13,17,17-octaethyl-18-oxochlorin.

^fRef ¹⁷.

^gSee Ref. 10 for previous data.

Iteration of the process described above enabled the range of maximum and minimum rate constant values to be narrowed. For example, the rate constants of H₂C-T⁵ are close to those of H₂C and H₂C-M¹⁰ (as seen in Figure 3); thus, k for the 15-position should be close to 12 × 10⁻⁵ s⁻¹, and k for the 20-position should be close to 5.6 × 10⁻⁵ s⁻¹ (see Table 1).

The major findings from the kinetic study of deuteration are as follows.

1. 15- versus 20-positions: The 15-position was ∼3 times more reactive than the 20-position toward deuterium exchange in chlorins, versus the equivalent reactivity of the 15- and 20-positions in the symmetric H₂OEC (2,3,7,8,12,13,17,18-octaethylchlorin).^16,17 This difference stems from the steric effect of the geminal dimethyl group at the 18-position. On the other hand, the 15-position was ∼3-times less reactive than the 20-position toward deuterium exchange in oxochlorins (Oxo-H₂OEC, Oxo-H₂OEC, and Oxo-H₂C-T⁵M¹⁰). In the case of the oxochlorins, steric and electronic effects of the oxo group at the 17-position should be considered together with the steric effects of geminal dimethyl group at the 18-position. The lesser reactivity of the 15-position in oxochlorins shows that the electron-withdrawing effect of the carbonyl group outweighs the steric effects of the 18-geminal dimethyl group. In summary, the order of reactivity toward deuterium exchange in the benchmark chlorin H₂C is 15 > 20 >> all other meso and β-positions, and the order for the benchmark oxochlorin Oxo-H₂C is 20 > 15 >> all other meso and β-positions.

2. Chlorin versus oxochlorin: The comparisons were made where rate constants could be obtained (H₂C versus Oxo-H₂C, H₂C-T⁵M¹⁰ versus Oxo-H₂C-T⁵M¹⁰). Introduction of the oxo group at the 17-position of H₂C to give Oxo-H₂C rendered the 15-position ∼20 times less reactive. Similar results were obtained from the comparison of H₂C-T⁵M¹⁰ versus Oxo-H₂C-T⁵M¹⁰, where the 15-position was ∼20 times less reactive in the latter versus the former.¹⁰ The presence of the 17-oxo group suppresses reaction at the adjacent 15-position via steric factors and also electronically deactivates the chlorin macrocycle toward deuteration.

3. Effects of meso-aryl substituents: The rate of the exchange of 15- and 20-positions depends largely on the number of meso-aryl substituents. The rate constants for H₂C, H₂C-T⁵, and H₂C-M¹⁰ show almost identical values; thus, introduction of one aryl substituent has almost no effect regardless of steric bulk. The values of the rate constants increase ∼5-fold (15-position) and ∼2-fold (20-position) upon introduction of two aryl groups in chlorins (H₂C-T⁵M¹⁰ versus H₂C). Similar effects are observed for oxochlorins, where the rate constants increase in value 6.4-fold (15-position) and 4.4-fold (20-position) upon introduction of two aryl groups (Oxo-H₂C-T⁵M¹⁰ versus Oxo-H₂C). Introduction of three meso-aryl groups (H₂C-T⁵M¹⁰P¹⁵) causes the value of the rate constant to increase 10-fold (20-position).

Understanding the origin of the increased rate of deuteration with increasing number of mesoaryl groups requires consideration of multiple factors. Relevant factors include the equilibrium between neutral chlorin and chlorin dication (obtained by dideuteration in the core of the macrocycle), ion pairing of deuterated chlorin species and the conjugate base of the acid, the conformational flexibility of the macrocycle, the energy of the initial reactant, and the energy of the transition state. While the charge state of the species undergoing deuteration is not known, in neat TFA-d the chlorin dication is expected to be present in nearly quantitative amount, and hence is the likely precursor. The relevant electronic feature of the initial chlorin reactant is given by the chlorin HOMO, which shows larger lobes at the α-positions (which cannot be deuterated) and the β-pyrrolic positions versus the meso positions.^18-20 On the other hand, an intermediate near the transition state during the course of deuteration of a chlorin would be polyenic in character as illustrated in Scheme 5. A tentative interpretation for the increased rate of reaction owing to the meso-aryl groups is that the transition state is stabilized (by inductive and/or resonance effects) more so than the chlorin HOMO is destabilized. High-level calculations are required to gain insight into the origin of the regiospecificity of deuteration and the role of meso-aryl groups in accelerating the rate of deuteration.

Scheme 5.

(6) Halogenation

Prior studies have shown that chlorins undergo electrophilic halogenation at the meso sites flanking the pyrroline ring.¹⁰ Electrophilic bromination of ZnC was carried out using NBS in THF at room temperature (Scheme 6). The 15-bromochlorin ZnC-Br¹⁵ was obtained accompanied by a small amount of dibromochlorins, as indicated by LD-MS analysis of the crude mixture. Substitution at the 15-position was confirmed upon ¹H NMR spectroscopy by (1) the disappearance of the resonance upon bromo substitution, and (2) the downfield shift of the resonance of the hydrogen positioned adjacent to the bromo atom (H¹³, ca. 0.3 ppm).⁶ Trace amounts of dibrominated products in the purified fraction were observed by LD-MS and ¹H NMR spectroscopy.

Scheme 6.

The purification of ZnC-Br¹⁵ proved to be difficult; therefore, we treated the crude reaction mixture to conditions for demetalation (TFA/CH₂Cl₂). Chromatographic separation of the free-base chlorin species proved easier than the corresponding zinc complexes. In this manner, H₂C-Br¹⁵ was obtained in 56% yield, together with unreacted starting material (∼5%) and one isolated (unidentified) dibromochlorin (∼1%). Similar bromination of ZnC-P¹⁰ provided ZnC-P¹⁰Br¹⁵ together with an unidentified (non-bromo) chlorin. Complete purification again was not achieved, and LD-MS analysis of the isolated sample of ZnC-P¹⁰Br¹⁵ (95% purity, 51% yield) revealed the presence of traces of dibromochlorins. The chromatographic retention of otherwise hydrophobic zinc chlorins is dominated by the polar apical site of the zinc chelated macrocycle. Accordingly, we turned to the bromination of free base chlorins.

Bromination of H₂C under the same conditions employed for ZnC provided H₂C-Br¹⁵ in 51% yield (with recovery of 27% of starting material) without detectable formation of any dibrominated chlorin (Scheme 7). Bromination of H₂C-M¹⁰ provided the corresponding 15-bromochlorin H₂C-M¹⁰Br¹⁵ in 55% yield, together with traces of an unidentified dibromochlorin (∼5%).

Scheme 7.

(7) Suzuki coupling

The availability of regioselective bromination has been exploited in the synthesis of a variety of substituted chlorins.¹⁰ Here, 15-bromination opens the door for further derivatization of sparsely substituted chlorins. Thus, Suzuki coupling of ZnC-P¹⁰Br¹⁵ afforded the corresponding 10,15-diphenylchlorin ZnC-P¹⁰P¹⁵; however, ¹H NMR spectroscopy of the fraction containing the product revealed the presence of a significant amount of aromatic impurities. Demetalation of the partially purified ZnC-P¹⁰P¹⁵ followed by column chromatography afforded the pure H₂C-P¹⁰P¹⁵ in 20% yield. On the other hand, Suzuki coupling of H₂C-Br¹⁵ with 2-phenyl-1,3-dioxoborolane in the presence of Pd(PPh₃)₄ afforded H₂C-P¹⁵ in 83% yield (Scheme 8). In both cases the respective starting bromo-chlorin was quantitatively consumed, but the free base chlorin product was more easily purified.

Scheme 8.

3. Conclusions

Reactivity studies of the unsubstituted chlorin H₂C showed that the positions flanking the pyrroline ring (15- and 20-position) are most reactive (among four meso sites and six β-pyrrolic sites) toward deuteration in acidic media, with the 15-position reacting ∼3-times faster than the 20-position. A single aryl group at the 5- or 10-position has little effect on the rate of deuteration, whereas the presence of two aryl groups (5- and 10-positions) increases the rate by ∼5.5 fold. The 15-position of free base or zinc chlorins also was the most reactive site in the macrocycle toward electrophilic bromination. The sequence of bromination and palladium-mediated coupling provided access to chlorins with substituents at the 15- or 10,15-positions. Compared with prior minimalist or benchmark chlorins, the unsubstituted chlorin H₂C prepared herein and its metal chelates are more accessible, more stable, and therefore more amenable for diverse fundamental studies. The chlorins prepared herein also have been examined spectroscopically as described in the next paper in this series.⁶

4. Experimental section

4.1. General methods

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were collected at room temperature in CDCl₃ unless noted otherwise. Chlorins and oxochlorins were analyzed by laser desorption mass spectrometry without a matrix (LD-MS).^9,21 Fast atom bombardment mass spectrometry (FAB-MS) or electrospray ionization mass spectrometry (ESI-MS) data are reported for the molecule ion or protonated molecule ion. Chromatography was performed with flash silica (80-200 mesh). NBS was recrystallized (H₂O). Absorption and fluorescence spectra were obtained in toluene at room temperature.

4.2. Solvents

THF was distilled over sodium metal and benzophenone as required. Toluene for coupling reactions was distilled from Na. DMF and CH₂Cl₂ were used as anhydrous grade. Toluene used in absorption and fluorescence studies was spectroscopic grade. All other solvents were used as received.

4.3. Deuterium exchange studies

The resonances of the meso- and β-protons of the chlorins exhibit significant shifts in CDCl₃ versus TFA-d. Prior to the deuteration study, the resonances from the four meso-protons and the six β-protons of H₂C were assigned by NOESY and HH COSY spectra (in CDCl₃ or in TFA-d at 25 °C). Note that no significant exchange occurred in TFA-d under these conditions during the course of these preliminary spectral measurements). Deuteration of chlorins and oxochlorins was examined using neat TFA-d in sealed NMR tubes at 50 °C (relaxation time = 3 seconds).

An exemplary procedure is as follows: A sample of H₂C (3.4 mg, 10 μmol, 17 mM) was dissolved in TFA-d (600 μL, 780 equiv). The ¹H NMR spectrum was recorded at 50 °C over time, and the resonances of the aromatic region were integrated. The deuterium exchange processes were followed relative to the non-exchanging protons (H⁷ and H⁸ at 9.42 ppm). Pseudo-first order rate constants were obtained by nonweighted least-squares fitting of the log of the intensity of the resonance versus the elapsed time.

4.4. Oxochlorin formation

4.4.1. Zn(II)-17,18-Dihydro-18,18-dimethyl-17-oxoporphyrin (Oxo-ZnC)

Following a general procedure,¹¹ a mixture of ZnC (39 mg, 0.097 mmol) and basic alumina (activity I, 3.58 g) in toluene (4.5 mL) was stirred for 7 h at 50 °C exposed to air. After standard workup, the residue was dissolved in toluene (44 mL). DDQ (44 mg, 0.19 mmol) was added. Standard workup and chromatography [silica, CH₂Cl₂ → CH₂Cl₂/MeOH (19:1)] gave a bluish-green solid (25 mg, 56%): ¹H NMR δ 2.04 (s, 6H), 8.65–8.68 (m, 2H), 8.83–8.86 (m, 2H) 8.98–8.99 (m, 2H), 9.05–9.07 (m, 1H), 9.30 (s, 1H), 9.36 (s, 1H), 9.44 (s, 1H); ¹³C NMR δ 23.3, 49.4, 94.5, 96.0, 106.9, 109.4, 129.0, 129.6, 129.9,130.7, 132.2, 132.9, 142.7, 147.1, 147.4, 148.7, 149.1, 150.8, 153.5, 163.9, 208.7; LD-MS obsd 415.5; FAB-MS obsd 416.0605, calcd 416.0616 (C₂₂H₁₆N₄OZn); λ_abs 412 (log ε = 5.19), 602 (4.65) nm; λ_em 605 nm.

4.4.2. Zn(II)-5-(3,5-Di-tert-butylphenyl)-17,18-dihydro-18,18-dimethyl-17-oxoporphyrin (Oxo-ZnC-B⁵)

Following a general procedure,¹¹ a mixture of ZnC-B⁵ (32.0 mg, 0.0540 mmol) and basic alumina (activity I, 2.0 g) in 2.5 mL of toluene was stirred for 16 h at 60 °C exposed to air. After standard workup, the residue was dissolved in toluene (25 mL). DDQ (24.5 mg, 0.108 mmol) was added. Standard workup and chromatography [silica, CH₂Cl₂/ethyl acetate (5:1)] gave a bluish-purple solid (15.3 mg, 47%): ¹H NMR δ 1.54 (s, 18H), 2.03 (s, 6H), 7.79–7.81 (m, 1H), 7.99–8.01 (m, 2H), 8.75–8.78 (m, 1H), 8.93–8.95 (m, 2H), 8.97–8.99 (m, 1H), 9.01 (s, 1H), 9.03–9.05 (m, 1H), 9.05–9.07 (m, 1H), 9.47 (s, 1H), 9.77 (s, 1H); LD-MS obsd 603.86; FAB-MS obsd 604.2200, calcd 604.2181 (C₃₆H₃₆N4OZn); λ_abs 419 (log ε = 5.39), 606 (4.77) nm; λ_em 608 nm.

4.5. Demetalation

4.5.1. 17,18-Dihydro-18,18-dimethylporphyrin (H₂C)

Following a general procedure,^8,10 a solution of ZnC (15.0 mg, 0.0371 mmol) in anhydrous CH₂Cl₂ (13 mL) was treated with TFA (284 μL, 3.68 mmol). The mixture was stirred for 30 min at room temperature. The reaction mixture was quenched by addition of 10% aqueous NaHCO3 (50 mL) and extracted with CH₂Cl₂. The organic extract was washed with water, dried (Na₂SO₄), and filtered. The filtrate was concentrated. Purification on a short column [silica, CH₂Cl₂] afforded a green solid (8.5 mg, 67%): ¹H NMR δ −2.60 to −2.44 (br, 2H), 2.07 (s, 6H), 4.66 (s, 2H), 8.94 (d, J = 4.4 Hz, 1H), 8.98 (s, 1H), 8.99 (d, J = 4.4 Hz, 1H), 9.06–9.10 (m, 2H), 9.08 (s, 1H), 9.24 (d, J = 4.4 Hz, 1H), 9.26 (d, J = 4.4 Hz, 1H), 9.86 (s, 1H), 9.89 (s, 1H); ¹³C NMR δ 31.5, 46.8, 52.2, 94.7, 96.7, 106.5, 106.9, 123.66, 123.72, 128.12, 128.20, 132.6, 132.8, 134.7, 135.0, 139.7, 140.5, 151.6, 151.9, 163.3, 174.9; LD-MS obsd 339.7; FAB-MS obsd 340.1692, calcd 340.1688 (C₂₂H₂₀N₄); λ_abs 389 (log ε = 5.20), 634 (4.82) nm; λ_em 636 nm.

4.5.2. 17,18-Dihydro-18,18-dimethyl-5-(4-methylphenyl)porphyrin (H₂C-T⁵)

Following a general procedure,^8,10 a solution of ZnC-T⁵ (98.7 mg, 0.200 mmol) in CH₂Cl₂ (100 mL) was treated with TFA (770 μL, 10.0 mmol). The mixture was stirred for 1 h at room temperature. The reaction mixture was washed with saturated aqueous NaHCO₃ (100 mL), dried (Na₂SO₄), filtered, and concentrated to dryness under reduced pressure. Chromatography [silica, hexanes/CH₂Cl₂ (2:1)] afforded a greenish purple solid (63.6 mg, 74%): ¹H NMR δ −2.34 to −2.24 (br, 1H), −2.00 to −1.90 (br, 1H), 2.05 (s, 6H), 2.68 (s, 3H), 4.61 (s, 2H), 7.53 (d, J = 7.8 Hz, 2H), 8.04 (d, J = 7.8 Hz, 2H), 8.67 (d, J = 4.4 Hz, 1H), 8.84 (d, J = 4.4 Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.91 (s, 1H), 8.95 (d, J = 4.4 Hz, 1H), 8.98 (s, 1H), 9.21 (d, J = 4.4 Hz, 1H), 9.82 (s, 1H); ¹³C NMR δ 21.8, 31.5, 46.8, 52.0, 95.1, 96.4, 107.1, 122.3, 123.4, 123.6, 127.8, 128.55, 128.57, 132.4, 132.6, 134.3, 134.6, 135.4, 137.5, 139.1, 140.43, 140.46, 151.3, 152.8, 163.9, 174.5; LD-MS obsd 429.9; FAB-MS obsd 430.2174, calcd 430.2157 (C₂₉H₂₆N₄); λ_abs 403, 637 nm; λ_em 639 nm.

4.5.3. 17,18-Dihydro-18,18-dimethyl-10-phenylporphyrin (H₂C-P¹⁰)

A solution of ZnC-P¹⁰ (10 mg, 0.021 mmol) in CH₂Cl₂ (7 mL) was treated with TFA (0.159 mL, 2.06 mml) and stirred at room temperature for 1 h. The reaction mixture was neutralized with excess triethylamine (1 mL), and then concentrated. Chromatography [silica, hexanes/CH₂Cl₂ (1:2)] afforded a green solid (6.5 mg, 74%): ¹H NMR δ −2.35 to −2.28 (br, 1H), −1.99 to −1.88 (br, 1H), 2.08 (s, 6H), 4.66 (s, 2H), 7.73–7.76 (m, 3H), 8.16–8.18 (m, 2H), 8.66 (d, J = 4.4 Hz, 1H), 8.82–8.85 (m, 2H), 8.93 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.99 (d, J = 4.4 Hz, 1H), 9.05 (s, 1H), 9.25 (d, J = 4.4 Hz, 1H), 9.88 (s, 1H); ¹³C NMR δ 31.4, 46.7, 52.2, 94.4, 97.1, 107.4, 121.7, 123.4, 123.7, 127.0, 127.8, 128.51, 128.52, 132.3, 132.5, 134.33, 134.37, 135.5, 139.7, 141.1, 141.9, 151.1, 152.8, 163.0, 175.5; LD-MS obsd 416.0; FAB-MS obsd 416.2018, calcd 416.2001 (C₂₈H₂₄N₄); λ_abs 403, 637 nm.

4.5.4. 17,18-Dihydro-10-mesityl-18,18-dimethylporphyrin (H₂C-M¹⁰)

As described for H₂C, a solution of ZnC-M¹⁰ (39.0 mg, 0.0747 mmol) in anhydrous CH₂Cl₂ (26 mL) was demetalated by treatment with TFA (288 μL, 3.74 mmol). Standard workup including chromatography [silica, hexanes/CH₂Cl₂ 9:1 → 3:1 → 1:1)] afforded a green solid (21.0 mg, 62%): ¹H NMR δ −2.28 to −2.18 (br, 1H), −1.96 to −1.82 (br, 1H), 1.85 (s, 6H), 2.06 (s, 6H), 2.61 (s, 3H), 4.63 (s, 2H), 7.25 (s, 2H, overlapped to CHCl₃), 8.47 (d, J = 4.4 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H), 8.77 (d, J = 4.4 Hz, 1H), 8.89 (s, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.93 (d, J = 4.4 Hz, 1H), 8.99 (s, 1H), 9.21 (d, J = 4.4 Hz, 1H), 9.81 (s, 1H); ¹³C NMR δ 21.61, 21.71, 31.5, 46.7, 52.2, 94.4, 96.8, 107.2, 120.1, 123.4, 123.4, 123.9 127.4, 128.0, 128.3, 131.3, 133.0, 134.4, 134.9, 137.7, 138.1, 139.4, 139.8, 141.1, 151.3, 152.8, 163.0, 175.3; LD-MS obsd 459.1; FAB-MS obsd 458.2449, calcd 458.2470 (C₃₁H₃₀N₄); λabs 395, 638 nm.

4.5.5. 17,18-Dihydro-18,18-dimethyl-17-oxoporphyrin (Oxo-H₂C)

Following a general procedure,^8,10 a solution of Oxo-ZnC (34.0 mg, 0.0814 mmol) in CH₂Cl₂ (28 mL) was treated with TFA (316 μL, 4.10 mmol). Standard workup including chromatography [silica, hexanes/CH₂Cl₂ (1:1) → CH₂Cl₂] afforded a blue solid (19 mg, 66%): ¹H NMR δ −3.12 to −3.02 (br, 1H), −2.98 to −2.88 (br, 1H), 2.12 (s, 6H), 9.18 (d, J = 4.4 Hz, 1H), 9.23 (d, J = 4.4 Hz, 1H), 9.26 (d, J = 4.4 Hz, 1H), 9.31 (d, J = 4.4 Hz, 1H), 9.34 (d, J = 4.4 Hz, 1H), 9.37–9.42 (m, 2H), 9.98 (s, 1H), 10.03 (s, 1H), 10.11 (s, 1H); 13C NMR δ 24.1, 50.4, 95.7, 96.3, 105.8, 107.8, 126.3, 126.7, 127.9, 129.0, 134.0, 134.9, 135.8, 137.0, 137.6, 140.0, 146.7, 153.1, 154.4, 168.1, 210.6; LD-MS obsd 353.9; FAB-MS obsd 354.1494, calcd 354.1481 (C₂₂H₁₈N₄O); λ_abs 401, 634 nm.

4.6. Magnesium insertion

4.6.1. Mg(II)-17,18-Dihydro-18,18-dimethylporphyrin (MgC)

Following a general procedure,¹⁴ a sample of H₂C (22.0 mg, 0.0646 mmol) in anhydrous CH₂Cl₂ (6.0 mL) was treated with diisopropylethylamine (0.440 mL, 2.53 mmol) and anhydrous MgI₂ (0.358 g, 1.29 mmol). The mixture was stirred at room temperature. After 1 h, the mixture was washed (water and brine), dried (K₂CO₃) and concentrated. The ¹H NMR spectrum (in C₆D₆) showed the presence of water and THF (12:1:2 ratio of water:THF:MgC), which could not be removed under high vacuum. The title compound was obtained as a greenish-blue solid (18 mg). The following NMR data omit the signals from water and THF: ¹H NMR (THF-d₈) δ 2.05 (s, 6H), 4.59 (s, 2H), 8.57 (s, 1H), 8.61 (s, 1H), 8.63 (d, J = 4.0 Hz, 1H), 8.67 (d, J = 4.0 Hz, 1H), 8.85–8.87 (m, 2H), 8.97–8.99 (m, 2H), 8.56 (d, J = 4.0 Hz, 2H); FAB-MS obsd 362.1393, calcd 362.1382 (C₂₂H₁₈N₄Mg); λ_abs 402 (log ε = 5.35), 607 (4.65) nm; λ_em 611 nm.

4.7. Bromination

4.7.1. Zn(II)-15-Bromo-17,18-dihydro-18,18-dimethylporphyrin (ZnC-Br¹⁵)

Following a general procedure,¹⁰ a solution of ZnC (9.00 mg, 0.0223 mmol) in dry THF (11 mL) under argon was treated with NBS (3.97 mg, 0.0223 mmol). The mixture was stirred at room temperature for 30 min. CH₂Cl₂ (20 mL) was added. The mixture was washed with aqueous NaHCO₃. The organic extract was dried (Na₂SO₄) and filtered. The filtrate was concentrated. Purification on a short column [silica, hexanes/CH₂Cl₂ (1:1)] afforded a green solid (8.4 mg) that was ∼85% pure: ¹H NMR (THF-d₈) δ 2.05 (s, 6H), 4.64 (s, 2H), 8.62 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.93 (d, J = 4.4 Hz, 1H), 9.02–9.06 (m, 2H), 9.10 (d, J = 4.4 Hz, 1H), 9.57 (s, 1H), 9.63 (s, 1H); LD-MS obsd 479.9; ESI-MS obsd 479.9913, calcd 479.9928 (C₂₂H₁₇BrN₄Zn); λ_abs 406, 607 nm.

4.7.2. 15-Bromo-17,18-dihydro-18,18-dimethylporphyrin (H₂C-Br¹⁵) by a bromination-demetalation procedure

Following a general procedure,¹⁰ a solution of ZnC (81 mg, 0.20 mmol) in dry THF (100 mL) under argon was treated at room temperature with NBS (35 mg, 0.20 mmol). The resulting mixture was stirred for 45 min. Saturated aqueous NaHCO₃ solution was added (∼50 mL). The resulting mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried (Na₂SO₄) and concentrated. The resulting green-violet solid was dissolved in CH₂Cl₂ (70 mL) and treated with TFA (1.53 mL, 19.8 mmol). The resulting green solution was stirred at room temperature for 1.5 h, neutralized with excess triethylamine (2 mL), and concentrated. TLC analysis [silica, hexanes/CH₂Cl₂ (1:1)] revealed the presence of one large green spot and several minor spots. Column chromatography [silica, hexanes/CH₂Cl₂ (1:1)] provided an unidentified dibromochlorin (first fraction, violet, 1.3 mg), H₂C-Br¹⁵ (second fraction, green, 47 mg, 56%), a discarded third fraction, and starting material (fourth fraction, green, 4.2 mg). Data for H₂C-Br¹⁵: 1H NMR δ −2.61 (s, 1H), −2.43 (s, 1H), 2.02 (s, 6H), 4.64 (s, 2H), 8.86 (s, 1H), 8.92 (d, J = 4.4 Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.98 (d, J = 4.4 Hz, 1H), 9.12 (d, J = 4.4 Hz, 1H), 9.14 (d, J = 4.4 Hz, 1H), 9.22 (d, J = 4.4 Hz, 1H), 9.70 (s, 1H), 9.75 (s, 1H); ¹³C NMR δ 31.8, 46.6, 55.00, 95.2, 96.0, 106.2, 108.6, 124.2, 125.1, 128.2, 128.5, 132.5, 133.6, 134.3, 136.2, 138.3, 140.6, 151.2, 153.3, 162.4, 176.1; LD-MS obsd 417.9; FAB-MS obsd 418.0797, calcd 418.0793 (C₂₂H₁₉BrN₄); λ_abs 396, 639 nm.

4.7.3. 15-Bromo-17,18-dihydro-18,18-dimethylporphyrin (H₂C-Br¹⁵) by bromination of H₂C

Following a general procedure,¹⁰ a solution of H₂C (26 mg, 0.076 mmol) in dry THF (38 mL) was treated under argon at room temperature with NBS (13 mg, 0.076 mmol). The resulting mixture was stirred for 30 min. Saturated aqueous NaHCO₃ solution was added. The resulting mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried (Na₂SO₄) and concentrated. Column chromatography [silica, hexanes/CH₂Cl₂ (1:1)] afforded traces of an unidentified chlorin (first fraction, green, << 1 mg), H₂C-Br¹⁵ (second fraction, green, 16 mg, 51%), and unreacted starting material (third fraction, green, 7 mg). The characterization data (¹H NMR, LD-MS, FAB-MS, UV-vis) were consistent with those described previously.

4.7.4. Zn(II)-15-Bromo-17,18-dihydro-18,18-dimethyl-10-phenylporphyrin (ZnC-P¹⁰Br¹⁵)

Following a general procedure,¹⁰ a solution of ZnC-P¹⁰ (48 mg, 0.10 mmol) in dry THF (50 mL) was treated under argon at room temperature with NBS (18 mg, 0.10 mmol). The resulting mixture was stirred for 30 min. Saturated aqueous NaHCO₃ solution was added. The resulting mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried (Na₂SO₄), and concentrated. Column chromatography [silica, hexanes/CH₂Cl₂ (1:2)] afforded ZnC-P¹⁰Br¹⁵ (first fraction, green, 28 mg, 51%). Further elution (CH₂Cl₂) afforded an unidentified chlorin (green, 4.2 mg). Data for ZnCP¹⁰-Br¹⁵: ¹H NMR (THF-d₈) δ 2.53 (s, 6H), 4.63 (s, 2H), 7.66–7.72 (m, 3H), 8.04–8.07 (m, 2H), 8.39 (d, J = 4.4Hz, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.59 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.77 (d, J = 4.4 Hz, 1H), 9.01–903 (m, 2H), 9.52 (s, 1H); ¹³C NMR 31.9, 45.8, 55.2, 95.0, 97.1, 109.4, 126.4, 127.4, 127.7, 128.3, 128.8, 129.1, 130.5, 133.4, 134.1, 134.7, 144.2, 146.8, 147.8, 148.5, 148.9, 152.8, 155.8, 158.1, 173.1; LD-MS obsd 555.9; FAB-MS obsd 556.0225, calcd 556.0241 (C₂₈H₂₁BrN₄Zn); λ_abs 411, 610 nm.

4.7.5. 15-Bromo-17,18-dihydro-18,18-dimethyl-10-mesitylporphyrin (H₂C-M¹⁰Br¹⁵)

Following a general procedure,¹⁰ a solution of H₂C-M¹⁰ (23 mg, 0.050 mmol) in dry THF (25 mL) was treated under argon at room temperature with NBS (9 mg, 0.05 mmol). The resulting mixture was stirred for 30 min. Saturated aqueous NaHCO₃ solution was added. The resulting mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried (Na₂SO₄), and concentrated. Column chromatography [silica, hexanes/CH₂Cl₂ (1:1)] afforded a dibrominated chlorin (first fraction, green, 1.5 mg) and H₂C-M¹⁰Br¹⁵ (second fraction, green, 16 mg, 55%). Data for H₂C-M¹⁰Br¹⁵: ¹H NMR δ −2.01 (s, 1H), −1.93 (s, 1H), 1.83 (s, 6H), 1.98 (s, 6H), 2.60 (s, 3H). 4.66 (s, 2H), 7.24 (s, 2H), 8.43 (d, J = 4.4 Hz, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.80-8.82 (m, 2H), 8.89 (d, J = 4.4 Hz, 1H), 9.14 (d, J = 4.4 Hz, 2H), 9.68 (s, 1H); ¹³C NMR δ 21.5, 21.7, 31.7, 46.5, 55.2, 95.0, 96.4, 106.6, 122.4, 124.4, 124.8, 127.5, 127.9, 128.8, 132.4, 132.8, 134.6, 136.0, 137.9, 138.2, 138.3, 139.2, 141.2, 152.3, 153.0, 162.3, 176.7; LD-MS obsd 536.1; FAB-MS obsd 536.1587, calcd 536.1576 (C₃₁H₂₉BrN₄); λ_abs 403, 643 nm.

4.8. Suzuki reactions

4.8.1. 17,18-Dihydro-18,18-dimethyl-10,15-diphenylporphyrin (H₂C-P¹⁵)

Following a general procedure,¹⁰ samples of H₂C-Br¹⁵ (42 mg, 0.10 mmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxoborolane (207 mg, 1.00 mmol), Pd(PPh₃)₄ (35 mg, 0.030 mmol), and K₂CO₃ (111 mg, 0.800 mmol) were weighed in a Schlenk flask. The flask was pump-purged with argon three times. A degassed mixture of toluene/DMF (3:1, 10 mL) was added. The resulting mixture was stirred at 90-95 °C for 20 h. The reaction mixture was diluted with CH₂Cl₂ and filtered. The filtrate was concentrated. Column chromatography [silica, hexanes/CH₂Cl₂ (1:3)] afforded a trace amount of putative PdC-P¹⁵ (first fraction, violet, < 1 mg) and the title compound (second fraction, green, 35 mg, 83%). Data for H₂C-P¹⁵: ¹H NMR δ −2.48 to −2.38 (br, 1H), −2.36 to −2.24 (br, 1H), 1.99 (s, 6H), 4.25 (s, 2H), 7.67–7.76 (m, 2H), 7.90–7.95 (m, 2H), 8.42 (d, J = 4.4 Hz, 1H), 8.99 (s, 1H), 9.00 (d, J = 4.4 Hz, 1H), 9.06–9.09 (m, 2H), 9.13 (d, J = 4.4 Hz, 1H), 9.24 (d, J = 4.4 Hz, 1H), 9.84 (s, 1H), 9.89 (s, 1H); 13C NMR δ 31.6, 46.4, 52.3, 94.9, 106.2, 107.4, 112.2, 123.6, 124.2, 127.70, 127.83, 128.2 (two peaks are overlapped), 132.5, 132.7, 133.0, 134.5, 135.4, 140.2, 140.4, 143.0, 151.4, 152.3, 162.6, 174.7; LD-MS obsd 415.9; FAB-MS obsd 416.1985, calcd 416.2001 (C₂₈H₂₄N₄); λ_abs 395, 638 nm.

4.8.2. 17,18-Dihydro-18,18-dimethyl-10,15-diphenylporphyrin (H₂C-P¹⁰P¹⁵)

Following a general procedure,¹⁰ samples of ZnC-P¹⁰Br¹⁵ (24 mg, 0.043 mmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxoborolane (87 mg, 0.43 mmol), Pd(PPh₃)₄ (15 mg, 0.013 mmol), and K₂CO₃ (47 mg, 34 mmol) were weighed in a Schlenk flask. The flask was pump-purged with argon three times. A degassed mixture of toluene/DMF (3:1, 4.3 mL) was added. The resulting mixture was stirred at 90-95 °C for 20 h. The reaction mixture was diluted with CH₂Cl₂ and filtered. The filtrate was concentrated. The crude mixture was chromatographed [silica, hexanes/CH₂Cl₂ (1:2)] to obtain a green solid, which was chromatographed further [silica, hexanes/CH₂Cl₂ (2:3)] to obtain a green solid (11 mg). The resulting crude ZnC-P¹⁰P¹⁵ (contaminated with some aromatic impurities as shown by ¹H NMR spectroscopy) was dissolved in CH₂Cl₂ (15 mL). The solution was treated with TFA (0.57 mL, 7.4 mmol) and stirred at room temperature for 30 min. The reaction mixture was neutralized with excess triethylamine (1 mL) and concentrated. Chromatography [silica, hexanes/CH₂Cl₂ (1:1)] afforded a green solid (5 mg, 20%): ¹H NMR δ −2.20 to −2.12 (br, 1H), −2.05 to −1.90 (br, 1H), 1.98 (s, 6H), 4.20 (s, 2H), 7.68–7.72 (m, 6H), 7.89–7.91 (m, 2H), 8.11–8.14 (m, 2H), 8.25 (d, J = 4.4 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.64 (d, J = 4.4 Hz, 1H), 8.92 (s, 1H), 8.95 (d, J = 4.4 Hz, 1H), 8.96 (d, J = 4.4 Hz, 1H), 9.23 (d, J = 4.4 Hz, 1H), 9.81 (s, 1H); LD-MS obsd 491.8; FAB-MS obsd 492.2300, calcd 492.2314 (C₃₄H₂₈N₄); λ_abs 408, 641 nm.