Stepwise Synthesis of Tetrabenzotriazaporphyrins (TBTAPs) and Their Open 2‐ and 3‐Ring Fragments

ABSTRACT

The intermediate structures between phthalocyanines and porphyrins (so‐called hybrid structures) are intriguing materials that offer the potential to combine features of each parent, and also offer tunability of properties through modification and further functionalization. We report here the stepwise synthesis of tetrabenzotriazaporphyrins(TBTAPs) bearing different core and meso‐aryl substituents. The results are unexpected; our previous results showed that the reaction between aminoisoindoline initiator (“A”) and a phthalonitrile (“B”) led preferentially to 2:2, ABBA hybrids, presumed to be via reaction between 2x “AB” intermediates. Here we report the synthesis of discrete “AB” fragments and their subsequent reaction chemistry. Reaction of the AB intermediates under typical macrocyclization conditions fails to produce more than a trace of the expected ABBA TBTAP hybrid. Rather, the reactions yield the 3:1 ABBB TBTAPs predominantly, alongside an open ABA trimer (a tripyrrin analogue). The protocol provides a useful alternative synthesis of TBTAPs that minimizes the formation of phthalocyanine side‐product. ABA trimer synthesis was separately optimized to produce a short series. The materials show broad absorption across the visible range and assemble into a preferred helical, coiled arrangement as revealed by crystallography.

Unexpected reaction pathways to porphyrin‐phthalocyanine hybrids are uncovered by the synthesis of “half‐macrocycle” fragments and subsequent macrocyclization. Rather than the expected 2:2 “ABBA” product, the 3:1 “ABBB” hybrid is isolated as the only macrocyclic product. Open trimers, isolated as side products, show broad absorption spectra and intriguing, coiled conformations.

1. Introduction

Porphyrinoid macrocycles are ubiquitous in both nature and our everyday lives. The parent structures, porphyrin and phthalocyanine, have been extensively studied and their chemistry and application have been comprehensively reviewed [1, 2]. Linear fragments of porphyrins have separately received significant attention, arguably most notably in relation to the synthetic dipyrromethene compounds and their boron complexes (“BODIPYs”) because of their favorable absorption and emission properties in the visible range, and due to the ability to tune properties by synthetic manipulation [3, 4, 5, 6]. Hybrid structures that share features of both porphyrins (C‐bridges between pyrrolic units) and phthalocyanines (N‐bridges, benzo‐fusion on pyrrolic units) have been known for a century [7]. Such hybrids offer much potential because of the ability to combine properties of both parents (a different approach to tuning) and the inherent additional versatility that is presented in unsymmetrical structures. However, their chemistry is much less well developed than that of the parent macrocycles because synthesis has been challenging and often inefficient. It is worth noting that hybrid structures are also known for the linear fragments, and they also show tunability of properties. The syntheses of these smaller systems are further advanced than for the porphyrinoid hybrids themselves; for example, there are now many examples of aza‐ and benzo‐fused BODIPY analogues (Figure 1) [8].

FIGURE 1.

Core structures of porphyrin, phthalocyanine, DIPY, and BODIPY, plus their hybrids.

Our previous work has expanded the chemistry of the porphyrin–phthalocyanine hybrids, initially through detailed investigation of the use of organometallic nucleophiles reacting with phthalonitrile derivatives [9, 10, 11] (reactions related to the original hybrid syntheses reported in the 1930's [12, 13]). Observations of likely intermediates in these reaction pathways led to the development of a novel synthesis of meso‐aryl‐triazatetrabenzoporphyrins (TBTAPs, e.g., 2) employing aminoisoindoline precursors 1 (Scheme 1) [14, 15]. The related subPhthalocyanine hybrids 3 were prepared when a boron template was employed in place of magnesium [16]. In both cases, the assumed mechanism was one where the aminoisoindoline initiated sequential addition of phthalonitrile units, followed by macrocyclization.

SCHEME 1.

Synthesis of TBTAPs 2 and subTBDAPs 3 from aminoisoindoline precursors 1.

Subsequent extension of the synthesis strategy was investigated in order to demonstrate scope and to produce derivatives that incorporated, in a controlled manner, additional functionality around the core itself. This was achieved in a complementary fashion by modification of the benzo‐fragment of the aminoisoindoline (unit “A”, to incorporate this single substituted benzo fragment next to the meso‐carbon), and/or modification of the phthalonitrile co‐reactant (unit “B”, to be incorporated as the other three benzo‐units around the macrocycle). The expected derivatives were therefore “ABBB” TBTAPs. Remarkably, however, the outcome was a mixture of the expected ABBB systems (minor product, even with slow addition of “A” to excess of “B”) and ABBA TBTAPs (major product) [17]. The reaction outcome implies operation of alternative competing mechanisms, and dominance of the 2:2 ABBA hybrid pointed strongly to a sequence involving condensation between 2 “AB” intermediates. The Ar‐ABBA system presents a potentially very useful architecture, with high symmetry and three distinct regions for tuning electronic and other properties (“A” and “B” regions of the core, and the largely decoupled meso‐aryl unit).

2. Results and Discussion

2.1. Synthesis and Isolation of “AB” Intermediates

The mechanism shown in Scheme 2 was considered the most likely origin of the ABBA TBTAP hybrids. To test the hypothesis and to potentially fully control the formation of a single hybrid, access to the discrete “AB” intermediates was required. Intercepting related intermediates in phthalocyanine chemistry has been attempted with some limited success [18, 19, 20, 21, 22, 23], but it is often challenging to find reaction conditions that initiate oligomer growth without over‐reaction to the stable macrocycle. Phthalonitriles themselves are generally found to have low reactivity—a feature we exploited to produce TBTAP hybrids efficiently [14, 15]. For the current investigation, however, we sought to deliberately activate phthalonitriles such that they would react selectively with aminoisoindolines like 1, and under mild conditions. We focused on the reaction products produced when phthalonitrile derivatives are reacted with (sodium) alkoxides at low or ambient temperatures [24, 25]. Several examples of the resulting cyclic products have been made, characterized, and indeed employed in phthalocyanine chemistry [26, 27]. With simple, unhindered alcohols such as methanol, products from double addition are isolable [24, 25], whereas it is known that more hindered alcohols lead to isolation of the single‐addition adducts [24, 25]. Under solution‐phase reaction conditions, it is expected that the systems are in equilibrium, with the mono‐alkoxy adducts more reactive toward nucleophiles (Scheme 3). We investigated several examples that qualitatively supported this pattern. In particular, we found that spirocyclic adducts (formed from diols) were particularly stable and easy to isolate (see Supporting Information). We found overall that the simple methanol adduct offered the best balance between ease of isolation (driven by solubility, with the adduct easily isolated in pure form, by simple filtration from the reaction mixture) and reactivity. Synthesis of “AB” intermediates initially employed aminoisoindoline 1a. Reaction with the preformed dimethoxy phthalonitrile adduct 6a proceeded smoothly, and again it was convenient to exploit solubility differences to drive the overall equilibration and achieve simple isolation of the AB intermediates, initially by filtration. After further optimization, it was found that in many cases the AB intermediates could be prepared in a single operation by direct reaction between aminoisoindolines and phthalonitrile in methanol with catalytic sodium methoxide, presumably via transient phthalonitrile–methanol adduct 5 (R = Me) (Scheme 3).

SCHEME 2.

Initially proposed mechanistic sequences that lead to ABBB (3:1) and ABBA (2:2) TBTAP hybrids [17].

SCHEME 3.

Sequential and direct synthesis of “AB” intermediates.

AB intermediates 7a–c bear identical (parent) benzo substituents on both A and B units, so would not deliver differentially substituted TBTAP hybrids. Nevertheless, AB intermediates 7a–c were subjected to macrocycle formation conditions in order to ensure that TBTAP formation occurred in accordance with the proposed sequence (Scheme 2, bottom). TBTAP formation occurred smoothly when 7a–c were heated (initially in diglyme at reflux) in the presence of MgBr₂ as a template. In fact, these direct reactions were found to have some advantages over our initially developed protocol that employed aminoisoindoline and phthalonitrile. Yields were comparable (up to ∼40%), but the process is operationally simplified, using just a single reactant plus template. Furthermore, macrocycle formation could be achieved at lower temperatures (refluxing xylene or toluene), and the combination of lower reaction temperatures and no additional phthalonitrile meant that formation of phthalocyanine side product was reduced to just trace quantities, making separation more straightforward (Scheme 4).

SCHEME 4.

Direct synthesis of meso‐aryl TBTAPs 2 from pre‐formed “AB dimers”, plus the observed “ABA trimer” side products 8.

Scheme 4 also shows the formation of an open trimeric product formed from 2 aminoisoindoline units and a central phthalonitrile. We have observed structure 8a as a trace component in the early stages of reactions between aminoisolindoline 1 (R₁ = R₂ = H) and phthalonitrile templated by boron in the synthesis of subPhthalocyanine hybrids [16] (Scheme 1, left), but this is the first observation of their formation in significant quantities. Their optimized synthesis and characterization are described later.

The successful transformation of AB intermediates 7 justified the synthesis of corresponding derivatives bearing different “A” and “B” units in order to interrogate the reaction pathway. A short series of derivatives bearing substituents on either the benzo unit of the aminoisoindoline portion or the phthalonitrile‐derived portion was selected, and in general terms, their synthesis followed the protocols developed for the parent series 7. AB dimer intermediates were prepared by up to three variations on the same general strategy, and the choice of protocol was determined by consideration of solubility (and therefore equilibrium in the synthesis steps and ease of isolation). Substituted aminoisoindoline precursors were prepared as described in our earlier studies [17]. Substituted phthalonitriles were converted to their corresponding dimethoxyisoindolinamine intermediates by treatment with sodium methoxide in the minimum volume of methanol, although the synthesis protocol was refined for these derivatives. Scheme 5 illustrates the sequences for the tetramethyltetralin derivative, and the structures of two further AB dimers that were targeted to investigate TBTAP synthesis.

SCHEME 5.

Synthesis of differentially substituted AB dimers.

Treatment of substituted phthalonitriles like 9 with sodium methoxide/methanol led again to the formation of the required intermediate 10. However, as mentioned previously, the reaction is reversible, and its overall efficiency is controlled by the selective precipitation of the product. In the case of substituted phthalonitriles, this precipitation was less efficient. Moreover, the isolated intermediates like 10 slowly darkened in storage (accelerated in light), and in fact convert readily to phthalocyanine even at moderate temperatures. Intermediate 10 could be used immediately in condensation with an aminoisoindoline, and under the standard protocol (methanol, reflux), the reaction proceeded smoothly but did not precipitate the product. Chromatographic separation was therefore needed, and AB dimer 12 was isolated in modest yield (∼20%) in addition to the ABA trimer product 13. Reasoning that the nucleophilic methanol solvent was responsible for the observed scrambling, the reaction was performed in dichloromethane in the presence of molecular sieves to remove the methanol formed in the reaction. This simple switch improved the yield of AB dimer 12 to ∼60%, and the product separated easily from other reaction products by crystallization. An alternative procedure, designed to eliminate the formation of the ABA trimer product, also proved successful. Dimethoxyisoindolamine intermediate 10 could be smoothly converted to its N‐Boc derivative by treatment with Boc–anhydride in glycerol [28]. Condensation with aminoisoindoline 1a, again using dry DCM and molecular sieves, produced the protected AB dimer 14 (∼60%) and no ABA trimer. Deprotection using NaOtBu/THF/H₂O [29] gave AB dimer 12.

2.2. TBTAP Formation From AB Intermediates

Investigation of hybrid macrocycle formation from differentially substituted AB intermediates started with the tetramethyltetralin derivative 12. ABBA TBTAP 17 was expected from this reaction, and the product has been previously isolated as the dominant product from direct reactions between aminoisoindoline 1a and phthalonitrile 9 (alongside the ABBB TBTAP 18) [17]. Treatment of AB dimer 12 with MgBr₂ in refluxing xylene produced a deep green reaction solution from which a single macrocyclic product was isolated alongside the ABA trimer side product (20%). Remarkably, however, the TBTAP was characterized as the ABBB (3:1) hybrid, produced exclusively in 45% yield (Scheme 6). This outcome was mirrored in reactions of the other AB intermediates 15 and 16, where once again the 3:1 ABBB TBTAP hybrids were the only isolated macrocyclic products. These observations clearly indicate that the proposed AB + AB condensation pathway (Scheme 2) is not operating as a route to ABBA TBTAPs, and they must be formed by another pathway. Dominance of the ABBA (2:2) hybrid in reactions between aminoisoindoline 1a and phthalonitrile 9 was verified again. Its origin is not obvious, but one possible pathway involves condensation between the growing aminoisoindoline–phthalonitrile oligomer and another molecule of aminoisoindoline. At the AB stage (either in the reaction or from pre‐isolated AB—see later), this results in the isolated ABA trimer side product. Condensation with 1a at the ABB stage can result in ABBA intermediate that was thought to originate from AB+AB, and it remains the most likely precursor to the observed 2:2 hybrids. The alternative pathways that dominate in the absence of significant concentrations of 1a lead to open ABBB via ABB, by reaction with either phthalonitrile or any oligomeric intermediate (shown for the AB intermediate 12; natural bond orbital analysis indicates that these two sites and the amine bearing carbon have essentially equivalent partial positive charge and hence electrophilicity, see Supporting Information) and then macrocyclization to give ABBB TBTAPs like 18. Indeed, the potential competition of these pathways was supported by observation of peaks corresponding to ABB and ABBA intermediates in MALDI‐MS analyses of reaction aliquots of reactions performed at lower temperatures. It is clear, therefore, that a complex balance of competing pathways is operating, but it remains remarkable that such a high level of control is possible in the two processes.

SCHEME 6.

Macrocycle formation from preformed AB dimer intermediates unexpectedly yields 3:1 ABBB TBTAPs as the only hybrid product.

2.3. ABA Trimers (Tribenzodiazatripyrrins)

ABA trimers like 8 and 13 were regularly observed as significant side products in the synthesis of AB intermediates and in their subsequent reactions (Scheme 7, top). They are intriguing chromophores in their own right, and their synthesis and spectroscopic properties were separately evaluated in a short study. The ABA trimers could be isolated from high‐temperature syntheses using AB intermediates like 7. However, the mechanism presented in Scheme 7 suggested that a targeted synthesis employing intermediates like 7/22 + additional aminoisoindoline would be efficient, and this proved to be the case. Reactions using 2 equivalents of aminoisoindoline and one equivalent of activated phthalonitrile (like 6) were similarly efficient and follow essentially the same path. Scheme 8 summarizes the routes, and also shows additional derivatives 24 and 25, the latter bearing a π‐extended naphthyl fragment in the central “B” unit. ABA trimers in this short series show broad, relatively featureless electronic absorption spectra that tail to ∼650 nm, therefore covering a significant proportion of the visible range. Scheme 8 shows representative examples alongside spectra for typical AB dimers that also show broad absorption profiles. Absorption spectra are relatively insensitive to variation of substituents, including the introduction of the naphthalene in 25. Neither series shows appreciable emission. Crystals suitable for x‐ray diffraction were obtained for selected examples, and the crystal structure for 25 is also shown in Scheme 8. The observed stereochemistry presents a helical conjugated skeleton, as observed for the symmetrical AA dimers previously reported [30, 31]. At the molecular level, the helical arrangement allows a near‐perfect slipped stacked arrangement of the terminal aryl fragments. The crystal itself is made up of extended stacks of molecules of identical helicity, with neighbouring columns comprised of molecules with the opposite stereochemistry. The stereochemistry and helicity are clearly maintained in solution, evidenced by ¹H NMR spectroscopy that clearly shows peak shifts consistent with overlapping terminal aromatic groups. For example, signals for the terminal methoxyphenyl fragment of AB dimer 7a shift upfield by 0.4 and 0.6 ppm in the corresponding trimer 8b as a result of this overlap (Scheme 8).

SCHEME 7.

Plausible mechanistic pathways that lead to exclusive ABBB TBTAP (from AB dimer intermediates like 12) and dominance of ABBA TBTAP in the aminoisoindoline + phthalonitrile reaction.

SCHEME 8.

Synthetic routes to ABA trimers, crystal structure of trimer 25 (a. top and side view of single molecule; b. crystal packing in columns; c. pair of molecules in neighbouring columns with opposite helicity), and absorption spectra (in dichloromethane) of AB dimers and ABA trimers plus key NMR chemical shift changes as a result of helical architecture being maintained in solution.

3. Conclusion

Condensation between aminoisoindolines and activated phthalonitrile derivatives smoothly yields intermediates that are the expected precursors to “ABBA” tetrabenzotriazaporphyrin (TBTAP) hybrids. Remarkably, when these intermediates are subjected to macrocyclization conditions, the derivative isolated is exclusively the ABBB (3:1) phthalocyanine hybrid, which can only result from selective scrambling. The outcome is surprising, and the synthesis protocol in fact offers general improvements because yields are good, and competing phthalocyanine formation is minimized. The major side‐product in the reactions is the novel ABA trimeric systems (tripyrrin analogues), and their optimized synthesis is separately developed. The ABA trimers present broad absorption spectra up to ∼ 650 nm, and the conjugated core extends from one terminal aryl unit to the second in a helix, allowing near‐perfect overlap of the aromatic termini.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File: chem71357‐sup‐0001‐SuppMat.pdf

The authors have cited additional references within the Supporting Information [32, 33, 34, 35, 36]. Crystal structures have been deposited at the joint CCDC/FIZ Karlsruhe deposition service with the following reference numbers: 8a (2514571), 25 (2521412).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.