Synthesis and metalation of expanded porphyrins and their building blocks

Presented by Hadiqa Zafar

In partial fulfillment of the requirements for graduation with the Dean’s Scholars Honors Degree in the Department of Chemistry.

. . Jonathan L. Sessler (Supervising Professor) Date

I grant the Dean’s Scholars Program permission to post a copy of my thesis on the Texas ScholarWorks.

Synthesis and metalation of expanded porphyrins and their building blocks.

Department: Chemistry

.

. Hadiqa Zafar Date

.

. Jonathan L. Sessler Date

Table of Contents Page 1: Abstract Page 2-6: Porphyrin Chemistry Background Page 7-10: Amethyrin56

Page 11-15: Oligoheterocycles146

Page 16-17: Terpyrrole121

Page 18: Conclusion Pages 19-26: Bibliography

Abstract Porphyrin and related tetrapyrrolic macrocycles, collectively porphyrinoids, are versatile ligands that allow access to a multitude of coordination modes. Judicious modification of the porphyrin core, as well as the pendant substituents, have extended the coordination chemistry of porphyrinoids to include systems that are able to stabilize f-block element complexes with concomitant access to new structures with possible utility. Here our group’s efforts to prepare porphyrinoid ligands and their building blocks, that can serve as tools to study and apply f-element metal coordination chemistry are described, including the background of the topic, selected syntheses, and application of these species in the chemical and medical sciences. My thesis research spans three projects, including the synthesis and characterization of an amethyrin-uranyl complex displaying aromatic character, the iterative synthesis of tuneable α,α’-linked oligoheterocycles displaying fluorescent properties, and the gram-scale synthesis of a bench-stable 5,5”-unsubsituted terpyrrole.

The reaction between amethyrin and non-aqueous uranyl silylamide (UO2[N(SiMe3)2]2) under anaerobic conditions affords a bench-stable uranyl complex. UV-Vis spectroscopy, cyclic voltammetry, as well as proton NMR spectroscopic analyses provide support for the conclusion that all six pyrrole subunits participate in coordination of the uranyl dication and that, upon complexation, the amethyrin-core undergoes a 2-electron oxidation to yield a formal 22 π-electron aromatic species. The controlled synthesis of oligoaromatics can provide materials of utility across a wide range of the chemical sciences. Here, we describe the preparation of higher order oligoheterocycles via a tandem Suzuki cross-coupling protocol. This has allowed for the iterative construction of fluorescent α,α’-linked penta- and septaheterocyclic systems. Modification of the terminal moiety allowed for fine-tuning of the emission features. The controlled preparation of higher order oligopyrrolic species holds broad utility across the chemical and material sciences. Here, we describe the gram-scale synthesis of a bench-stable terpyrrole in excellent yield from commercially available and easily prepared precursors via a tandem Suzuki cross-coupling with in situ deprotection. The solution and solid state stability as well as UV-vis, fluorescence, and x-ray crystallographic analysis of the new 5,5”-unsubstituted terpyrrole are also detailed.

1 Background The f-block elements have played a starring role in chemistry in spite of occupying a less-than- prominent position within the periodic table.1 Initial interest in these elements was driven by academic curiosity and a desire to complete the periodic table.2 Subsequently, industrial applications and wartime efforts spurred further research.3 Early academic programs sought to expand potential applications by elucidating fundamental reactivity patterns, molecular structure, and coordination chemistry.4-9 The resultant studies revealed marked differences between the f- block elements and transition metal or main group species, allowing for useful applications across the chemical,10-15 medical,16-18 and material science fields.19-21 Recent advances, driven by the preparation of new diverse ligand sets, have continued to drive progress in f-element chemistry and revealed unique new utilities.22-24 Tetrapyrrolic ligands, notably the porphyrins and corroles, as well as the ostensibly related phthalocyanines, support remarkable coordination chemistry (Figure 1).25-27 Transition metal and main group complexes have proven invaluable as metalloprotein cofactor models,28 new materials,29 supramolecular constructs,30 pharmaceuticals,31 and catalysts.32 The inherent ability of these ligands to yield stable metal complexes stimulated f-element porphyrin research. Not surprisingly, a diverse array of -containing systems found practical use as NMR shift reagents, luminescent heme protein models, optical materials, and therapeutics, among other applications.33 However, complexes based on porphyrins and other relatively small porphyrinoids remain scarce, with only a limited set of (IV) and (IV) out-of-plane and double or triple-decker sandwich structures being known.34-39 Attempts at transuranic complexes have been limited to neptunium40 and phthalocyanine41 sandwich complexes.42

Figure 1. Tetrapyrrolic porphyrin and related congeners.

A recent research focus in porphyrin chemistry has involved modification of the core via heterocycle replacement, addition of pendant substituents, and variations in the cavity size and shape.43-47 Expanded porphyrins, systems containing larger cavities, have received considerable attention in the context of this general paradigm.48-50 Judicious incorporation of appropriate chelating moieties and size complementarity has allowed for the stabilization of a number of f- element complexes. This new chemistry has yielded structures and functions inaccessible using smaller congeners, such as the porphyrins or related ligand species. Efforts toward the synthesis and use of porphyrinoid species are reviewed to provide context for this seminal work. In providing this summary, particular focus will be placed on reviewing the relevant background, outlining

2 synthetic developments, and, when applicable, discussing potential applications for amethyrin species. The synthesis of new porphyrinoid building blocks has proven instrumental in accessing previously unexplored expanded porphyrin scaffolds. Initial porphyrinoid constructs often relied upon simple pyrrole and bipyrrole frameworks. Improved synthetic methods soon allowed ready access to larger motifs, such as terpyrrole.51-53 For instance, by exploiting a Paal-Knorr cyclization with subsequent functional group manipulation and cyclization, Sessler, Weghorn, and Hiseada provided a scalable route to terpyrrole (36) and terpyrrole-based expanded porphyrins, such as amethyrin (39) (Scheme 1).54 The results of initial metalation experiments were included in this first report. Included among them was a description of a putative uranyl-amethyrin complex, as inferred from UV-vis spectroscopic and high resolution mass spectrometric studies.

Scheme 1. Synthesis of terpyrrole (36) and amethyrin (39).

Additional work on the actinyl coordination chemistry carried out by Sessler, Gorden, Seidel, Hannah, and Lynch, as well as Gordon, Donohoe, Tait, and Keogh from LANL, provided support for the formation of a putative neptunyl(V) complex 41 (Scheme 2).55 The resultant microcrystalline material was characterized by UV-vis, NMR, and Raman vibrational spectroscopy. The presence of an NH resonance in the 1H NMR spectrum led the authors to conclude that metalation had occurred within the cavity such that only part of the internal lacuna was occupied by this metal cation. No XRD was obtained that would have provided definitive proof of structure. In an attempt to revisit this chemistry, Brewster, Aguilar, Sessler and co-workers 2+ prepared an amethyrin-uranyl complex (42) using a non-aqueous uranyl silylamide as the UO2 source (Scheme 2).56 The resultant complex was postulated to have all six pyrrole nitrogen atoms coordinated to the metal center, as determined by NMR spectroscopy. This species was characterized by UV-vis, high-resolution mass spectrometry, NMR, and cyclic voltammetry. Again, however, no supporting single crystal X-ray diffraction structural data could be obtained.

3

Scheme 2. Synthesis and proposed structures of amethyrin-neptunyl (41) and -uranyl (42) complexes.

The preliminary data obtained using amethyrin established precedence for the coordination of actinyls within such expanded systems. Sessler, Seidel, Vivian (Gorden), and Lynch, in collaboration with Scott and Keogh from LANL, would continue these efforts. They reported the synthesis and characterization of isoamethyrin (43), obtained via the oxidative cyclization of the open chain intermediate 44, as well as the corresponding uranyl (45) and neptunyl (46) complexes (Scheme 3).57 The uranyl complex was prepared using uranyl acetate dihydrate in a methanol: dichloromethane mixture containing triethylamine. The neptunyl(V) complex was prepared by adding Np(VI)O2Cl2 in 1 M HCl to a solution of isoamethyrin in methanol in the presence of triethylamine. Over the course of the reaction, either from triethylamine, a known sacrificial reductant, or methanol, the Np(VI) was found to undergo reduction to the corresponding Np(V) form. Single crystal X-ray diffraction data provided definitive proof of structure for the U(VI)O2 and Np(V)O2-isoamethyrin complexes, 45 and 46. This remains the only neptunyl-expanded porphyrin characterized by single crystal XRD to date.

Scheme 3. Synthesis of isoamethyrin (43), as well as the corresponding uranyl (45) and neptunyl (46) complexes. 4 The coordination chemistry with isoamethyrin was further explored by Sessler, Gorden, Seidel, Hannah, and Lynch, as well as Gordon, Donohoe, Tait, and Keogh from LANL, with studies involving plutonyl cations.55 A putative plutonyl complex was characterized by UV-vis spectroscopic analysis. No single crystal XRD structure was reported. Anguera, Brewster, Sessler, and co-workers would later report a structural derivative, naphthoisoamethyrin, as an efficient ligand for the complexation of the uranyl dication.58 An inherent characteristic of many porphyrinoid ligands is the easy-to-visualize color change that occurs upon metal complex formation. Melfi (Pantos), Sessler, and co-workers demonstrated the potential utility of isoamethyrin [hexaphyrin(1.0.1.0.0.0)] as a colorimetric actinyl sensor.59,60 The detection of uranyl acetate was easily observed in a MeOH: CH2Cl2 (95:5, v/v) solution via a change from the initial yellow-orange color of the ligand to the pink-red of the uranyl complex (Figure 2).

Figure 2. Representative color change of hexaphyrin-based systems upon uranyl complexation. The photograph shows the free amethyrin ligand (left) and purified amethyrin-uranyl (42) complex (right) in a 54 CH2Cl2 solution.

A series of control experiments demonstrated that isoamethyrin displays some selectivity towards the uranyl cation over lanthanide and other transition metals. Of the tested metal ions, evidence for complexation was seen only in the case of Cd(II), Mn(II), and Pb(IV), with it being inferred that Cu(II) and Cr(VI) might also form complexes. When dissolved in methanol: dichloromethane (1:1, v/v) with excess triethylamine a detection limit of approximately 5.8 ppm by naked eye monitoring and < 28 ppb by UV-vis spectroscopy was found. Melfi (Pantos), Sessler, Camiolo, McDevitt, and co-workers would continue with these efforts by immobilizing isoamethyrin onto a tentagel-amino resin.156 Partial coverage with isoamethyrin (5-20% amine coverage) allowed for an easy-to-visualize color change from golden yellow to pink-red. Optimized detection conditions were found by extracting red, green, and blue color intensities using a CCD video chip. The red channel displayed the largest change in intensity. Interested in the amethyrin class of macrocycles and the influence of pyridine within macrocyclic constructs, Brewster, Sessler, and co-workers reported the preparation of dipyriamethyrin (47) and its uranyl complex (48) (Scheme 4).61 This work marked the first entry into the metalation chemistry of dipyriamethyrin. A competition experiment employing La(OAc)3, Gd(OAc)3, Nd(OAc)3, Tb(OAc)3, and UO2(OAc)2 yielded only the uranyl complex, albeit in low yield. The ligand also displayed some selectivity for the uranyl cation over other transition metal and lanthanide cation salts when screened individually. In analogy to what was seen for other hexaphyrin systems, an easy-to-visualize color change from orange-red to purple was observed upon uranyl complexation in THF.

5

N N NH N N O N UO [N(SiMe ) ] R R 2 3 2 2 R U R THF N HN N O N N N

R = H or C6F5 47 48 Scheme 4. Synthesis of dipyriamethyrin-uranyl complex 48. Also shown are photographs of the pure free ligand and metalated species in CH2Cl2 solution.

6 Results & Discussion Amethyrin The hexaphyrin class of expanded porphyrins continues to play a key role in terms of exploring the determinants of aromaticity, as well as being central to understanding the coordination chemistry of larger porphyrinoid species.62 Indeed, considerable effort has been devoted to the synthesis and study of classical amethyrin (1)63-67, its structural isomers isoamethyrin (2)68,69 and naphthoisoamethyrin70 , as well as hybrid dipyriamethyrin (3)71 , dithiaamethyrin72 , and dibenziamethyrin73 , among other hexaphyrin congeners74-76 (Figure 3).

Figure 3. Representative hexaphyrin expanded porphyrins.

Figure 4. Potential coordination modes and π-conjugation (bolded) pathways of amethyrin. Previous studies on the coordination chemistry of amethyrin (1) have yielded a number of metal complexes with attendant exploration into the ligand redox chemistry.63-66 These species in particular served to demonstrate the ability of expanded porphyrins to rearrange π-conjugation as well as deviate from planarity to allow for the formation of complexes with large cations and coordination of multiple metal ions (Figure 4). In the context of this prior work we explored

7 whether amethyrin would stabilize a 1:1 complex with a high valent actinide cation. However, initial efforts to prepare such a complex failed to yield a well-characterized product, leading to the 2+ +/2+ +/2+ proposal that, if coordinated at all the actinyl cation (e.g., UO2 , NpO2 or PuO2 ) would not be bound to all six nitrogen donor atoms. On the other hand, it was found that treatment of iso- or 67-69 77 2+ +/2+ naphthoisoamethyrin and cyclo[6]pyrrole with UO2 , and in some instances NpO2 and +/2+ PuO2 , furnished the corresponding actinyl coordination complex where all six nitrogen donor atoms were involved in metal cation complexation. An attendant redox switch accompanies metal complexation to yield aromatic and antiaromatic species in the case of isoamethyrin and cyclo[6]pyrrole, respectively. We thus sought to revisit the coordination chemistry of amethyrin 2+ and determine whether conditions could be found where insertion of the uranyl dication (UO2 ) could be accomplished and whether attendant changes in the electronic structure of the ligand would occur. Here, we report the synthesis and characterization of a bench-stable amethyrin-uranyl complex. In contrast to previously reported coordination modes for amethyrin63.67, the resultant complex is characterized by hexadentate metal cation chelation with the ligand undergoing a 2- electron oxidation to yield a 22 π-electron aromatic amethyrin-core. Support for these conclusions came from proton NMR and UV-vis spectroscopic analyses, as well as cyclic voltammetry. Treatment of the free base methyl-substituted amethyrin 4 with a non-aqueous uranyl 78 precursor, namely uranyl silylamide [UO2(N(SiMe3)2] , in anhydrous THF under anaerobic conditions yielded the corresponding uranyl complex (5) as a dark red solid with green metallic luster in 83% yield, after removal of solvent and purification by flash chromatography over basic aluminum oxide (2% acetone in CH2Cl2, eluent) under normal laboratory conditions (Scheme 5). The product obtained in this way proved bench stable, with no evidence of degradation being observed over the course of several weeks.

Scheme 5. Synthesis of amethyrin-uranyl complex (5). Proton NMR spectroscopic studies of complex 5 revealed a downfield shift (ca. 4.17 ppm) in the signals ascribed to the meso-CH protons (i.e., from 5.73 ppm (a) to 9.90 ppm (a’); Figure 5). Downfield shifts were also observed in the peripheral methyl CH3 protons from 1.85 (b), 1.83 (c), and 1.63 ppm (d) to 3.85 (b’), 3.62 (c’), and 3.42 ppm (d’). No signals attributed to the pyrrole NH protons were observed. Previous studies on related systems in which the uranyl was thought to be complexed without the attendant redox chemistry were characterized by only minute downfield shifts (ca. 0.5 ppm), which were rationalized in terms of loss in electron density arising

8 from metal complexation71,79. In analogy to what was seen upon uranyl cation complexation to iso-67,68 and naphthoisoamethyrin70, wherein a switch from a formally antiaromatic to aromatic species occurs, the significant downfield shifts observed in the context of complex 5 provide support for the presence of a diatropic ring current. The 2-electron oxidation needed to produce an aromatic form of 4 provides a ligand with two pyrrolic NH protons. Their removal provides a 2+ formal dianionic ligand capable of balancing the charge of the UO2 cation. Considered in concert, the absence of NH protons, the dianionic nature of the oxidized ligand, and the observed chemical shift changes, serve to support the notion all six nitrogen atoms participate in coordination and that a redox switch to produce a stable uranyl complex with aromatic character occurs under the above metal insertion conditions.

1 Figure 5. Partial H NMR spectra of (top) uranyl complex 5 and (bottom) neutral macrocycle 4 in CDCl3. Labels shown correspond to those of Scheme 1. An asterisk designates residual protic solvents.

As prepared, the freebase ligand 4 displays a UV-vis spectrum reminiscent of related hexaphyrin systems. Notably, a strong Soret-type band at 490 nm ( = 28,400 M-1 cm-1) and a smaller absorbance peak at 595 nm ( = 3,900 M-1cm-1) are observed (Figure 6). Upon metalation, an easy-to-visualize color change from orange to red takes place. These visual changes are accompanied by a significant bathochromic shift in the Soret-like band to 520 nm, an increase in molar absorptivity () to 89,200 M-1 cm-1, as well as the appearance of a red-shifted Q-band at 826 nm ( = 29,400 M-1 cm-1) in the corresponding absorption spectrum (Figure 6). These changes mirror what are seen in other related systems that undergo a 2-electron oxidative switch to yield 22 π-electron aromatic forms 62,68,70.

9

Figure 6. UV-vis spectrum of ligand 4 (—) and uranyl complex 5 (- - -) recorded in CH2Cl2. Cyclic voltammetry studies of the free-base amethyrin 4 (1 mM) were performed in dry CH2Cl2 in the presence of 0.1 M [(n-Bu4N)(PF6)] in an inert glove box at room temperature. All potentials are referenced to the ferrocene/ ferrocenium (Fc/Fc+) couple (Figure 7). Two quasi- reversible single electron oxidation waves are seen near 0 V vs. Fc0/+ and are attributed to the oxidation of the 24 π-electron antiaromatic ligand to the corresponding 22 π-electron aromatic species; these features are seen at 0.0 V and 0.20 V at a scan rate of 0.1 V s-1. A third quasi- reversible oxidation is also observed at 0.52 V. Cyclic voltammetry studies on the uranyl complex 5 under similar conditions revealed two predominant higher potential reduction features at – 0.84 V and – 1.19 V and two oxidation events at 0.57 V and 0.80 V, respectively (Figure 7). The reduction features are ascribed to reduction of the ligand from a 22 -electron aromatic form to give a metalated 24 -electron antiaromatic species electronically analogous to ligand 4 70.

Figure 7. Cyclic voltammogram of ligand 4 and uranyl complex 5 as measured in CH2Cl2. To conclude this section, a bench-stable amethyrin-uranyl complex has been prepared and characterized by NMR and UV-Vis spectroscopy, as well as cyclic voltammetry. In analogy to what has been seen in the case of several related hexaphyrin congeners, ligand 4 supports the formation of a uranyl complex obtained in 83% yield by reaction with uranyl silylamide under anaerobic conditions. The present findings thus lead us to propose that, in contrast to earlier inferences, amethyrin can indeed serve as a hexadentate ligand for high valent actinyl cations and 2+ that, upon complexation of UO2 , the as-prepared macrocycle undergoes a 2-electron oxidation to produce a 22 π-electron aromatic system.

10 Oligoheterocycles Multiple aromatic heterocyclic systems bridged via biaryl linkages represent important building blocks across a broad range of the chemical and material sciences80,81. Within this arena, α,α’-linked heteroaromatics have emerged as important functional π-conjugated materials82-94 as well as key structural motifs in supramolecular95-97 and coordination chemistry97-102. Due to their broad utility, extensive efforts have been focused on developing improved preparations of homogeneous and heterogeneous oligoheterocycles86-92, 103-109. Typically, two generalized approaches have been pursued involving, respectively, 1) the synthesis of appropriate building blocks followed by oligomerization or 2) the preparation of smaller subunits that are then elaborated in an iterative approach through functionalization to produce higher order oligomers. Nevertheless and in spite of the progress made to date, there is still a need for generalizable procedures that permit the preparation of α,α’-linked heteroaromatics in an economically efficient and scalable manner. Currently, a number of routes leading to bi- and tetraheteroaromatic species are known88, 104-108. However, methodologies allowing for the controlled synthesis of odd numbered ter-, penta-, and septaheterocyclic, especially non-thiophene, oligoaromatic systems remain limited110- 116. We have, therefore, devoted efforts towards the preparation of higher order heterogeneous oligoheterocycles using α,α’-dibromo terheterocycles as precursors for the expedient synthesis of such systems. Here, we present the use of dibromo dipyrrolyl furan (1) as a model building block in a tandem Suzuki cross-coupling protocol to yield a series of mixed penta- and septaheterocycles from easily prepared starting material and commercially available coupling partners. The iterative approach described here allows for the expedient synthesis of larger oligoheterocyclic constructs whose structural diversity provides control over key optical properties, including the UV-vis absorption spectra and fluorescence emission features. The net result are color and fluoescence differences that are easy to differentiate by the naked eye.

Initial synthetic efforts were devoted to developing conditions that would allow the tandem Suzuki coupling between dibromo dipyrrolyl furan (1) [38] with N-boc-2-pyrroleboronic acid (2) to be optimized. Toward this end, various Pd-salts (entries 1-4), bases (entries 4-6), concentrations of the aryl boronic acid (entry 7), and the palladium catalyst (entry 8) were tested (Table 1).§ Gratifyingly, optimized conditions were obtained upon heating 1 in N,N-dimethylformamide-H2O (5:1, v/v) with Pd(PPh3)Cl2 (20 mol%), K2CO3 (5.5 equiv), and N-boc-pyrrole-2-boronic acid (4 equiv) at reflux. This gave 2,5-di-bipyrrolyl furan (3) in 98% yield.

11 Table 1. Reaction development.

Entry Pd cat. Base Yield (%)b c 1 Pd(OAc)2, Ph3 K2CO3 74

2 Pd(dppf)Cl2 K2CO3 63

3 Pd(dba)2 K2CO3 45

4 Pd(PPh3)2Cl2 K2CO3 84

5 Pd(PPh3)2Cl2 KOtBu 62

6 Pd(PPh3)2Cl2 K3PO4 43 d f 7 Pd(PPh3)2Cl2 K2CO3 99 (98) e 8 Pd(PPh3)2Cl2 K2CO3 60 aReactions performed on 0.05 mmol scale with standard conditions consisting of Pd-catalyst (20 mol%),

b base (5.5 equiv), and aryl boronic acid (2.4 equiv) in 2 mL of DMF: H2O (5:1, v/v). Yield determined by

1 c H NMR spectral analysis in CD2Cl2 using an internal standard (1,2-dichloroethane). 40 mol% of PPh3 was used. d4 Equivalents of N-boc-pyrrole-2-boronic acid were used. e10 mol% of the Pd-catalyst was used. fIsolated yield for a reaction run on a 0.1 mmol scale.

Using this protocol we then examined the construction of various mixed oligo- heteroaromatics derived from the dipyrrolyl furan scaffold and various heteroaromatic pinacol boranes (Scheme 6). Under these conditions good-to-excellent yields were obtained for a series of penta- (4-7) and septaheterocycles (8). For instance, commercially available indole-, furan, and thiophene-2-boronic acid pinacol esters were readily coupled to give the corresponding pentaheterocycles 4, 5, and 6 in 93%, 85%, and 86% yield, respectively. Although mixed oligoheterocyclic species analogous to 4, 5, and 6 have previously been reported, these prior protocols typically required greater step counts and proceded in lower overall yields118. 2,2’- Bithiophene-5-boronic acid pinacol ester, a common precursor in oligothiophene synthesis119, was coupled to give 7 in 92% yield. This method was also amenable to pyridine-based substrates, as demonstrated by the reaction between 2 and pyridine-4-boronic acid pinacol ester to give 8 in 95% yield.

12

CO2Et CO2Et CO2Et CO2Et

EtO 2C CO2Et EtO2C CO2Et O O NH HN NH HN

NH HN O O

4, 93% 5, 85%

CO2Et CO2Et CO2Et CO2Et

EtO2C CO2Et EtO2C CO2Et O O NH HN NH HN S S S S

S S 6, 86% 7, 92%

CO2Et CO2Et

EtO2C CO2Et O NH HN

N N

8, 95%b (86%)c Scheme 6. Synthesis of penta- and septa- oligoheterocycles. aReactions performed on 0.1 mmol scale. bReaction performed on 0.2 mmol scale. c2.4 equiv of pyridine-2-boronic acid pinacol ester was used. Crystal structures are shown as ORTEP plots with thermal ellipsoids set at the 50% probability. Hydrogen atoms are removed for clarity.

To demonstrate the influence of the terminal heterocycle on the absorbance and fluorescence properties, the UV-vis and emission profile of compounds 3-8 were measured (Figure 8). Torsion angles of synthesized compounds as well as the shorter terpyrrole and mixed tetrafuran-thiophene (TFFT & FTTF) are shown in Table 2. UV-vis spectral studies carried out in acetonitrile revealed molar absorptivities that varied as well as changes in the maximum absorption (max). Specifically, -1 -1 -1 -1 for compound 3 max = 349 nm (24,500 M cm ) and 2 = 303 nm (20,700 M cm ); for 4 the -1 -1 -1 -1 corresponding values were max = 298 nm (17,600 M cm ), 2 = 334 nm (16,250 M cm ); in the -1 -1 -1 -1 case of 5 max = 389 nm (15,400 M cm ), whereas max = 393 nm (13,500 M cm ) for 6; finally, -1 -1 - the corresponding max values for 7 and 8 were 368 nm (36,150 M cm ) and 366 nm (24,900 M 1cm-1), respectively. The observed spectra lead us to suggest that a complex interplay between conjugation, electron density of the pendant heterocycle, and the electronic absorption features are at play in determining the predominant electronic transition119 (Figure 8).

13

CO2Et CO2Et

(a) (b) EtO2C CO2Et O NH HN

H H N N O

3 4 5

S S

N S

6 7 8

Fig. 8. (a) UV-vis and (b) emission spectra of penta- and septaheterocycles 3-8 in acetonitrile ([c] = 15 μM).

Table 2. Terminal heterocycle torsion angles based upon x-ray crystallography. Compound Terminal Heterocycle Torsion Angles

3 N1 – N2, 178.86°; N3 – N4, 179.78°

5 O1 – N1, 177.60°; N2 – O3, 4.96°

6 T1 – N1, 170.66°; N2 – T2, 173.27° 121 terpyrrole N1 – N2, 164.75°; N2 – N3 , 154.83° 107b TFFT S1– O1, -2.89°; O1 – O2, -180°; O2 – S2, 2.89° 107b FTTF O1 – T1, 175.08°; T1 – T2, 180°; T2 – O2, -175.08°

The emission spectra of pentaheterocycles 3, 4, 5, 6, and 8 recorded in acetonitrile were found to scale in accord with the electron density of the terminal heterocycle120, with 3 giving an emission maximum (Emmax) at 490 nm, 4 at 498 nm, 5 at 481 nm, 6 at 485 nm, and 8 at 460 nm (Figure 8). A bathochromic shift in the emission profile was also observed upon extending the conjugation, as demonstrated by bithiophene-capped septaheterocycle 7 that yielded an Emmax at 511 nm. These spectral differences are readily apparent to the naked eye when acetonitrile solutions of compounds 3-8 were illuminated with a hand held UV-vis lamp, as can be seen from inspection of Figure 9. Absorption and emission maxima as well as Stokes shift of synthesized compounds, terpyrrole, tetrafuran (4F), mixed tetrafuran-thiophene (TFFT & FTTF), and tetrathiophene (4T) are compared in Table 3.

14 Table 3. Absorbance maxima, emission maxima, and Stokes shifts of synthesized and related compounds. Abs Stokes Shift max Em (nm) Compound (nm) max (cm-1) 3 386 490 9.61E5 4 307 481 5.75E4 5 393 485 1.09E5 6 334 498 6.10E4 7 366 460 1.06E5 8 368 511 6.99E4 327 433 9.43E4 terpyrrole121 4F 107b 364 413 2.04E5 TFFT 107b 378 440 1.61E5 FTTF 107b 393 467 1.35E5 4T 107b 392 479 1.15E5

Fig. 9. Visual (top) and fluorescence (bottom) profiles of penta- and septaheterocycles 3-8 in acetonitrile ([c] = 15 μM).

To summarize this project, we have developed a facile synthesis of higher order α,α’-linked heterocycles using a tandem Suzuki cross coupling. This method utilizes easily prepared starting material as well as commercially available coupling partners to yield penta- and septaheterocycles in good to excellent yield while simultaneously allowing for fine-tuning of the photophysical properties. New routes towards the controlled synthesis of homo- and heterogeneous α,α’-linked aromatics in an iterative fashion, such as the one described, are expected to allow for the divergent preparation of previously unexplored constructs with potentially interesting and useful properties.

15 Terpyrrole General procedures for the economic preparation of α,α’-linked pyrroles in an efficient and scalable manner continues to remain desirable122-126. Indeed, numerous routes towards α- functionalized and relatively stable bipyrrole127 and quaterpyrrole128,129 have been procured. However, synthetic methods for the preparation of terpyrrole remain limited (Figure 10). The first procedure of such species was detailed by Rapaport and co-workers by way of acid catalyzed trimerization of pyrrole followed by Pd/C-catalyzed dehydrogenation.128 Following this, LeGeoff and co-workers,129 Meijer and co-workers,130 as well as Sessler and co-workers131 subjected 1,4- diketo precursors to Paal-Knorr conditions preparing the central pyrrole of terpyrrole. More recently, Carretero and co-workers have implemented a 1,3-dipolar cycloaddition for the iterative construction of pyrrole subunits off a central heterocycle.127 Though elegant in nature these and other routes132 suffer from poor to moderate overall yields, often require a pyrrole nitrogen protecting group or capping of the terminal α-position, long step count, and instability of the resultant product. We have therefore directed effort towards the development of new methodologies readily accessing stable terpyrrole derivatives en route to larger α,α’-linked pyrrole systems. Here, we present the gram-scale synthesis of a 5,5”-unsubstituted terpyrrole via a tandem Suzuki-coupling protocol with in situ deprotection utilizing commercially available and easily prepared precursors.

Figure 10. Synthetic routes for the preparation of terpyrrole.

The ability of carbalkoxy substituents to attenuate the reactivity of pyrrole is well appreciated in building complex pyrrole structures.133-137 We thus postulated incorporating β-ethyl ester functionalities into the central pyrrole would allow for improved stability of terpyrrole. Gratifyingly, the tandem Suzuki cross-coupling of easily prepared dibromo pyrrole (2)138 with commercially available N-Boc-pyrrole-2-boronic acid (2.4 equiv) using PdCl2(PPh3)2 (20 mol%) and K2CO3 (5 equiv) in a N,N-dimethylformamide: H2O mixture (5:1, v/v) heated to 120 °C for 5 h furnished terpyrrole 1 in 92% yield on a greater than 5-gram scale after purification (Scheme 7).139

16

Scheme 7. Synthesis of terpyrrole (1) using a tandem Suzuki cross-coupling with in situ deprotection protocol. The bench-stability of the new 5,5”-unsusbtituted terpyrrole species allowed for x-ray crystallographic analysis.140 Analogous to previously reported terpyrrole x-ray crystals and calculations123,141-145, compound 1 adopts an alternating planar-antiperiplanar-antiperiplanar conformation (Figure 11). Interestingly, the β-carbethoxy groups display hydrogen-bonding interactions with the pyrrole NHs. As a result, the terminal pyrrole subunits maintain a twist wherein each pyrrole is directed towards the carbonyl oxygen.

Figure 11. ORTEP plot (thermal ellipsoids set at 50% probability) of the single crystal X-ray diffraction structure of the terpyrrole (1) viewed from the (a) top and (b) side. Hydrogen atoms are removed for clarity.

UV-vis spectrophotometric analysis of terpyrrole 1 displayed a strong absorbance with λmax = 327 nm (ε = 17,000 M-1 cm-1) (Figure 12a). The fluorescence profile was also determined with an emission maximum at 433 nm (Intensity = 201,000 counts/s; [1] = 15 μM) when excited at 327 nm in acetonitrile (Figure 12b).

Figure 12. (a) UV-vis and (b) emission spectra of terpyrrole (1) recorded in acetonitrile. 1H NMR studies were carried out to probe the stability of the new terpyrrole. Compound 1 was found to remain stable in CDCl3 being exposed to laboratory conditions over 72 hours with 47% recovery after purification by silica gel column chromatography. Solid-state stability, without protection from light or air, was measured using 1H NMR with >99% remaining after 1 week. We have described a facile synthesis of a new, bench-stable terpyrrole amenable to preparation on gram-scale using commercially available and easily prepared precursors. The chemistry of bipyrrole and tetrapyrrole precursors have dominated expanded porphyrin and oligopyrrole polymer chemistry. However, new routes providing access to more stable terpyrrole building blocks should thus facilitate the use of such species in accessing new porphyrinoid and polymeric constructs.

17 Conclusion In conclusion, expanded porphyrins display remarkable coordination chemistry complementing and extending that seen in the case of porphyrins, corroles, and phthalocyanines. With knowledge of early examples of lanthanide and actinide cation complexation with pyrrolic ligands from the Sessler group and key collaborators, as well as recent results inspired by these initial efforts, we have been able to expand chemistry for synthesizing the molecules and building blocks that achieve these goals. The synthesis and characterization of an amethyrin- uranyl complex displaying aromatic character56, the iterative synthesis of tuneable α,α’-linked oligoheterocycles displaying fluorescent properties146, and the gram-scale synthesis of a bench- stable 5,5”-unsubsituted terpyrrole121 are three examples of these independent projects. Ongoing work involving expanded porphyrins appears poised to make new contributions to f- element coordination chemistry. We predict that as synthetic methods leading to porphyrinoid-like macrocycles improve even more refined systems will be produced with enhanced utility in f- element coordination chemistry. These systems, we suggest, could have a role to play in addressing key questions in f-element chemistry, including issues of covalency, electronic structure, and biomedical utility, to name just a few areas of potential utility.

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