1,4-Dihydropyrrolo[3,2-b]pyrroles with Two Embedded Heptagons via Alkyne Annulation

Abstract

Drastic changes to the character of the acidic catalyst enable the reversal of the double alkyne benzannulation reaction output. In the presence of a strong Brønsted acid, 1,4-dihydropyrrolopyrroles undergo transformation which results in the formation of two 7-membered rings. Computational studies imply that the thermodynamically unfavored 7-membered ring is forged via the kinetically favored 6-endo-dig attack of a protonated alkyne at the position 3a of pyrrolopyrrole followed by a 1,2-vinyl shift.

Introduction

The incorporation of seven-membered rings into the structure of polycyclic aromatic hydrocarbons and their heterocyclic analogues offers an unprecedented strategy to modify their physicochemical characteristics.¹⁻⁵ In particular, introduction of heptagons leads to nonplanar architectures with bowl shape or negative curvature, which translates to distinct electronic structures and unique intermolecular stacking in the solid state.⁶⁻¹² As a result, electronic, magnetic, and mechanical properties are entirely different from classical alternant systems. As far as purely benzenoid structures are concerned, intramolecular alkyne benzannulation was employed as one of the key reactions used to make new C–C bonds. Although the first case of alkyne benzannulation was reported by Scott et al., who used flash vacuum pyrolysis (FVP),¹³ the method only became popular after the discovery of electrophilic activation of alkyne using Brønsted acid which was reported by Goldfinger and Swager.¹⁴ Over the last 20 years, the reaction has evolved significantly—novel catalysts were introduced such as π-Lewis acids based on either transition metals or main group elements, radical reagents, and non-nucleophilic bases.¹⁵⁻¹⁷ Significant examples involve the 2-fold alkyne annulation utilized to synthesize a bis-chrysene precursor of graphene nanoribbon (GNR),¹⁸ reported by Müllen and co-workers as well as Chalifoux group’s work on multifold cyclization to make narrow and soluble GNRs.¹⁹ The scope of this reaction was also demonstrated on geometrically strained nonplanar nanographenes, namely, tetrasubstituted chiral peropyrenes²⁰ and helicenes.²¹⁻²³ Impressively, this reaction shows tolerance toward sulfur-,²⁴⁻²⁶ oxygen-, and nitrogen-doped^23,27 polycyclic systems as well.

The regioselectivity of alkyne annulation reactions heavily depends on the substrates and catalyst employed (Figure 1a).^15−17,28 In terms of polycyclic aromatic systems, 6-endo-dig-type cyclization is majorly reported, while 5-exo-dig, 6-exo-dig and 7-endo-dig are less common. Formation of nonhexagonal rings induces a warping of the graphenic system, causing a geometrical strain, which can lead to higher activation enthalpies.²⁹⁻³³

Figure 1.

Intramolecular alkyne annulation reactions performed under different conditions leading to the incorporation of one or two new 6- or 7-membered rings.

Tetraarylpyrrolo[3,2-b]pyrroles (TAPPs) have proven to be an excellent platform for the synthesis of aza-doped polycyclic aromatic hydrocarbons.^34,35 Although in most cases dyes comprising exclusively six-membered and five-membered rings were synthesized, a limited number of architectures bearing seven-membered rings were reported as well.^36,37 The presence of highly electron-rich positions 3 and 6 makes TAPPs a potent precursor for intramolecular C–H activation, leading to the introduction of π-extension and curvature. Herein, we report the double intramolecular alkyne annulation via Brønsted acid catalysis toward nonplanar aromatic heterocycle bearing multiple odd rings (Figure 1c).

Results and Discussion

Design and Synthesis

Recently, we reported the synthesis of aza-doped S-shaped nanographenes via a cationic gold-catalyzed alkyne benzannulation reaction (Figure 1b).³⁸ The work capitalized on the modular access to tetraarylpyrrolo[3,2-b]pyrroles (TAPPs) bearing ortho-diphenylethyne moieties at positions 1 and 4, where the triple bonds are placed in close proximity to the electron-rich positions 3 and 6. We envisioned that this design would allow for the formation of two new seven-membered rings leading to a unique (7–5–5–7)-type cyclic system. Interestingly, however, the gold catalyst (IPrAuNTf₂) induced a 6-endo-dig annulation with a subsequent 1,2-aryl shift leading to a 6–5–5–6 ring system. During the additional investigations, we performed the reaction, under the same temperature and using the same solvent on the precursor 4aa, with bistriflimidic acid (HNTf₂)³⁹—the conjugate acid of the gold catalyst’s counteranion employed in our prior work. Both triflic acid and bistriflimidic acid were employed in alkyne benzannulation for various substrates.^40,41 To our surprise, we observed the formation of a new product with a different color and R_f than that of both 1,2-aryl shift product 6aa and starting material 4aa (Scheme 2). However, the reaction mixture showed the presence of additional spots with similar R_f values, which made isolation of the major spot difficult. We anticipate that the formation of multiple byproducts during the reaction is the reason behind the low yield and inability to isolate any of the byproducts made it impossible to characterize them. The initial ¹H NMR analysis showed a significant difference in peak distribution compared to the benzannulated product with the same mass (HRMS-APCI, calculated for C₅₈H₄₉N₄⁺: [M + H]⁺ = 801.3952, found = 801.3956). These results demonstrate the formation of a new cyclic system which can be described as a regio-isomer of 6. The X-ray crystallographic results unambiguously proved the presence of a 2-fold formal 7-endo-dig cyclization at the C3 and C6 positions, resulting in a nonalternant aromatic heterocycle (Figure 2). This distinct arrangement of two adjacent pentagons positioned between two heptagons is recognized as an inverse Stone–Thrower–Wales defect in graphene.

Scheme 2. Synthesis of π-Extended Pyrrolo[3,2-b]pyrroles with Two Embedded Heptagons 5aa via HNTf₂-Mediated Two-fold Alkyne Annulation of Alkyne-Bearing TAPP 4aa.

Figure 2.

Crystal structure (CCDC 2379282) of heptagon-embedded nonalternant aromatic heterocycle 5aa. Solvent molecules and hydrogen atoms were omitted for clarity.

This transformation was quite intriguing as it could only be catalyzed using HNTf₂. Subsequently, we tested a range of catalysts which are commonly utilized for alkyne annulation reactions, including cationic gold catalysts with different ancillary ligands and counteranions compared to the ones we used in our prior work³⁸ (see Table S1 in the Supporting Information for details). However, none of them gave a similar outcome. Alcarazo and co-workers did a comparative study on the hydroarylation of alkynes using Brønsted acid and cationic gold catalysts.²⁵ They showed that the 7-endo-dig-type annulation is induced by acid only when the vinyl carbocation intermediate is stabilized by electron-donating groups on benzene rings attached to it and Au-catalysis toward this product is governed by steric factors around the reaction center. Extensive literature studies focusing on the exo vs endo selectivity of this carbocyclization are limited to gold catalysts.⁴²⁻⁴⁴ Intriguingly, Langer and co-workers found that depending on the choice of Brønsted acid and solvent, alkyne annulation in the case of imidazo[1,2-a]pyridines can be steered toward the formation of either a six-membered ring or seven-membered ring.⁴⁵

Computational Studies—Mechanism

For a better understanding of the dichotomy in reactivity under Brønsted acid and gold catalysts, the annulation of model TAPP Ia (bearing phenyl group at the alkyne terminus) triggered by HNTf₂ was investigated computationally (Scheme 1). The pathway preferred for gold catalysis,³⁸ encompassing 6-endo-dig annulation followed by a 1,2-aryl shift, is also plausible but only when cyclization is triggered by the protonation of the alkyne moiety (TS1a, ΔG^⧧ = 168.8 kJ/mol) to give rise to intermediate IIIa that easily undergoes 1,2-aryl shift (TS3a, ΔG^⧧ = 64.2 kJ/mol). In contrast, despite extensive research on the potential energy surface, we did not locate a transition state associated directly with 7-endo-dig cyclization. However, attack of the protonated alkyne at position 3a of the 1,4-dihydropyrrolo[3,2-b]pyrrole (DHPP) system producing IIa is not only possible (TS2a, ΔG^⧧ = 154.8 kJ/mol) but also kinetically preferred over another 6-endo-dig cyclization proceeding through TS1a. Intermediate IIa is capable of rearranging with ring expansion through a 1,2-vinyl shift (TS4a, ΔG^⧧ = 81.2 kJ/mol) toward IVa, which after deprotonation delivers a thermodynamically less preferred product bearing a 7-membered ring. Similar profiles were found for both cyclization manifolds of annulation of analogues TAPP Ib, bearing p-methoxyphenyl groups at the alkyne. The rate-limiting steps, however, proceeding through TS1b and TS2b were associated with considerably lower activation barriers (ΔG^⧧ = 143.9 and 120.6 kJ/mol, respectively) compared to phenyl-substituted alkynes proceeding through TS1a and TS2a (ΔG^⧧ = 168.8 and 154.8 kJ/mol, respectively).

Scheme 1. Gibbs Free Energy Profile for Benzannulation of Model TAPP I Catalyzed by HNTf₂.

Calculated at the SMD(m-xylene)/M06/def2-TZVPP//B3LYP-D3/def2-SVP level of theory. Structures marked with (a,b) correspond to Ar = Ph and p-MeOPh, respectively.

Scope and Limitations

To showcase the functional group tolerance and synthetic utility of this reaction, we began the synthesis of precursor TAPPs 4 which possessed electronically different substituents at the para-position of the benzene ring attached to the triple bond. These rationally chosen precursors were synthesized by following the method described in our previous work.³⁸ The HNTf₂-catalyzed annulation turned out to be highly selective as it worked only on specific substrates (Scheme 3). It is quite evident that the formal 7-endo-dig cyclization is favored only when the triple bond is activated by electron-donating groups (MeO or Me) present on the benzene ring connected to it. Failed examples of 5cb–ce confirm this hypothesis [Scheme 3(IV)]. Nevertheless, the presence of these groups is not the only requirement. Arene rings on positions 2 and 5 must be electron-deficient (with substituents CN, CO₂Me, or NO₂) to a degree that ensures the stability of the final product. When we changed the electron-withdrawing ability of the substituents from low (Br as in the case of 5ae [Scheme 3(IV)] to high (NO₂ in 5ab), the reaction outcome changed from a complex mixture of byproducts to predominantly yielding the bis-annulated product. We also tested the possibility of performing the reaction on substrates with halogen handles so as to demonstrate the postsynthetic utility of this reaction [Scheme 3(III)]. Alkyne annulation occurred smoothly to obtain 5ac, which then underwent intramolecular direct arylation to form the completely fused nonplanar double helical nanographene 7ac (Figure 3).

Scheme 3. Synthesis of a Non-planar, π-Extended Pyrrolo[3,2-b]pyrroles via HNTf₂-Mediated Two-fold Alkyne Annulation of Alkyne Bearing TAPPs 4. (I) Substrates; (II) Successful Examples; (III) Pd-Catalyzed Intramolecular Arylation of 5ac; (IV) Unsuccessful Examples^,

Compound has been reported previously.³⁸

Reaction kept at 160 °C for 6 h.

Figure 3.

Crystal structure (CCDC 2381915) of multiple heptagon-embedded double helical nanographene 7ac. Solvent molecules and hydrogen atoms were omitted for clarity.

Photophysical Properties

The fused dyes 5 exhibit distinct photophysical properties compared to previously reported π-expanded TAPPs (Table 1 and Section S5.1, Supporting Information).^34,35 In particular, they show a very weak ϕ_fl (typically around 0.01), which indicates low-radiative emission. This is confirmed by theoretical calculations (see below). Their absorption showed a significant vibronic structure with a low energy absorption band ranging from 449 to 515 nm. The substituents at positions 2 and 5 significantly influence the locations of the absorption and emission maxima. Specifically, substituting CN to NO₂ (5aa and 5ab) causes a red shift of ≈65 and 100 nm, respectively. Similar effects are seen in 5ba and 5bb. Compared to their structural isomer S-shaped, π-expanded pyrrolopyrroles,³⁸ these dyes exhibit a bathochromic shift of emission at ≈80 nm. As expected, further extension of the π system (7ac) induces red shifts of absorption and emission, relative to the precursor.

Table 1. Photophysical Properties of the π-Extended Pyrrolopyrroles 5 and 7ac.

	solvent	λabsmax/nm	λemmax/nm	stokes shift/cm–1	ϕfla	ε/M–1 cm–1
5aa	toluene	450	575; 618	4800	0.04	18,000
	THF	449	572; 614	4700	0.05	21,000
5ab	toluene	515	676	4600	0.02	12,000
	THF	515	747	6000	<0.001	12,000
5ac	toluene	462	585; 630	4500	0.01	9000
	THF	465	590; 630	4500	0.01	9000
5ba	toluene	453	573; 613	4600	0.01	18,000
	THF	451	570; 613	4600	0.05	14,000
5bb	toluene	515	641	3800	0.01	11,000
	THF	514	644	3900	<0.001	10,000
5bd	toluene	449	613	5900	0.05	14,000
	THF	449	613	5900	0.04	14,000
7ac	toluene	502	670	5000b	0.01	9000
	THF	503	645	4300b	0.01	12,000

^aStandard: 9,10dDiphenyl anthracene in cyclohexane (ϕ_fl = 0.7).

^bStokes shift calculated from absorption corresponding to lowest energy (λ = 502 and 503 nm).

Computational Studies—Photophysics

To understand the peculiar photophysical properties of these systems, clearly differing from the ones of usual TAPPs, we have performed theoretical calculations (see the Supporting Information for details). Let us first discuss 5bb which is a relevant example; the main conclusions and trends to all systems except 7ac. Given the symmetric chemical substitution in 5bb, we performed ground-state optimizations in both the C₂ and C_i point groups and found that both were stable minima but that the former is significantly favored (by ca. 7 kcal·mol^–1 on the Gibbs energy scale). The electron density difference (EDD) plots obtained for the five lowest transitions of this stable C₂ structure are displayed in Figure 4. As can be seen, the lowest transition of A symmetry is very weakly dipole-allowed. For this transition, the EDD reveals a delocalization on the TAPP core as well as the side seven-membered rings, whereas the contribution of the nitrophenyls is limited. Such topology is very original since for the vast majority of TAPPs developed to date, the lowest transition corresponds to a bright quadrupolar charge-transfer (CT) from the dye core to the side groups located at positions 2 and 5.^38,46−48 This is in fact the topology found for the third transition here, i.e., that of B symmetry (see Figure 4) which is significantly upshifted. The second transition is located at almost the same energy as the first but is bright. It represents intermediate features between the first and third states with a marked CT character, yet with significant contributions to the seven-membered rings. As can be seen from Table S5 in the Supporting Information, the same conclusions (state ordering and dipole strengths) are obtained at both the TD-DFT and CC2 levels of theory, giving confidence in the result.

Figure 4.

EDD plots for the 5 lowest excited states of 5bb. The red and blue lobes are regions of decrease (red) and increase (blue) in density upon absorption. For each state, we provide the symmetry, vertical excitation wavelength, and oscillator strengths computed at a TD-DFT level with the (LR,neq)-PCM(toluene) solvent model. Contour threshold: 0.001 au. See Figures S4 and S5 in the Supporting Information for other compounds.

To give a qualitative comparison with the experiment, one should note that the two first transitions are very close in energy, causing them to form two peaks, which is consistent with the measurements; e.g., the nearly dark lowest transition is likely buried under absorption to the second excited state that should be responsible for the measured λ^max_abs. The presence of such a nearly dark transition is of course detrimental for emission since it is indicative of a very low radiative rate (the oscillator strength obtained on the S₁ minimum is also very small). In other words, dark-state quenching happens in these compounds. Very similar trends are obtained in the full series of compounds 5 and are not further detailed. More quantitative theory/experiment comparisons have also been obtained; see the Supporting Information for details (Table S6). Eventually, 7ac shows some specificities. First, the most stable structure we could obtain belongs to the C_i point group. While this dye still presents two nearly degenerated excited states — the lowest (A_g) being dark and the second (A_u) being bright — it is noteworthy that the CT character of the second transition is much less marked than in 5aa (see EDDs in the SI).

Cyclic Voltammetry

Voltammetric experiments were performed to investigate the electrochemical properties of all of the synthesized compounds (5, 7ac, and their precursors 4) (Table 2). The parent TAPP 4 underwent one reversible oxidation process. While 4ac and 4ba showed one quasireversible reduction event, 4ab exhibited three reduction events, out of which the first two are quasireversible and the third irreversible. Fused compounds 5 displayed two or three oxidation events with a reversible first oxidation. The only exception is 5bd, where all three oxidation events are quasireversible. Considering reduction, these compounds showed one, two, or three quasireversible or nonreversible reduction events. However, molecule 5ac did not show any reduction event. Cyclic voltammetry measurements demonstrated that the fused DHPPs have a lower first oxidation potential than the nonfused parent systems, following the general pattern that as the degree of conjugation increases, the first oxidation potential decreases. A similar trend is visible for the ionization potential as well. However, completely fused molecule 7ac showed higher first oxidation potential than that of the precursor.

Table 2. Redox Potentials of the π-Extended Pyrrolopyrroles 5, 7ac, and Precursors 4.

compounda	event	EOXPA [V]	EOXPC [V]	EOX1/2 [V]	EOXONSET [V]	IPc [eV]	EREDPA [V]	EREDPC [V]	ERED1/2 [V]	EREDONSET [V]	EAd [eV]
4ab	1	1.03	0.94	0.98	0.91	5.2	–0.72	–0.79		–0.68	–3.60
	2						–0.93	–1.17
	3							–1.71
4ac	1	1.10	1.00	1.05	0.99	5.1	–0.66	–0.90		–0.70	–4.22
4bab	1	0.99	0.90	0.94	0.87	5.1	–0.70	–0.90		–0.74	–3.53
4bd	1	0.85	0.75	0.80	0.74	5.0
5aa	1	0.73	0.66	0.69	0.63	4.9	–0.62	–0.89		–0.67	–3.61
	2	1.14
5ab	1	0.76	0.69	0.72	0.65	4.9	–0.67	–0.86		–0.68	–3.60
	2	1.12	1.06				–0.99	–1.09
	3							–1.49
5ac	1	0.76	0.65	0.70	0.65	4.9
	2	1.22	1.12
5ba	1	0.71	0.64	0.67	0.60	4.9	–0.65	–0.92		–0.67	–3.61
	2	0.94						–1.35
	3	1.13
5bb	1	0.73	0.65	0.64	0.62	4.9	–0.68	–0.83		–0.67	–3.61
	2	1.11	1.02	1.06			–0.95	–1.14
	3						–1.29	–1.48
5bd	1	0.63	0.57		0.53	4.8	–0.65	–0.92		–0.69	–3.59
	2	0.91	0.77					–1.37
	3	1.04	0.97
7ac	1	0.88			0.60	4.9	–0.68	–0.92		–0.68	–3.60
	2	1.22						–1.29

^aMeasurement conditions: electrolyte (NBu₄PF₆, c = 0.1 M), dry CH₂Cl₂, potential sweep rate: 100 mV s^–1, working electrode: glassy carbon (GC), auxiliary electrode: Pt wire, reference electrode: Ag/AgCl/NaCl_sat; all measurements were conducted at room temperature.

^bPotential sweep rate: 50 mV s^–1.

^cIonization potential.

^dElectron affinity. Calculated according to the equations: IP(eV) = [E_OX^ONSET – E_1/2(Fc/Fc⁺) + 4.8]; EA(eV) = −[E_RED^ONSET – E_1/2(Fc/Fc⁺) + 4.8]. E_1/2(Fc/Fc⁺) = 0.52 V under the above-mentioned conditions.

Conclusions

In conclusion, the direction of double intramolecular alkyne annulation for dihydropyrrolopyroles can be controlled through the choice of acids. The use of exceptionally strong Brønsted acids induces the formation of a two-seven-membered-ring-containing dye, which possesses an inverse Stone–Thrower–Wales topology. Based on computational studies, we reasoned that the reaction course can be rationalized by the kinetic forces. The presence of conjugated ring systems 7–5–5–7 and 7–7–5–5–7–7 shifts both absorption and emission bathochromically.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c02538.

• Experimental procedures, X-ray crystallography data, mechanistic computational studies, photophysical properties, computational studies, and copies of the NMR spectra of all products (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.