Photoswitching neutral homoaromatic hydrocarbons
The identification and characterization of homoaromatic compounds bearing an interrupted system are fundamental challenges for the understanding of electronic interactions in organic molecules. This is further hampered by the fact that no stable neutral homoaromatic hydrocarbon is known. We present the preparation of a new class of neutral homoaromatic compounds, which are supported by experimental evidence (ring current observed by NMR spectroscopy, equalization of bond lengths through X-ray structure analysis) as well as computational analysis (NICS and ACID). Furthermore, we show that one homoaromatic hydrocarbon is a photoswitch through a reversible photochemical [1,11] sigmatropic rearrangement. We provide evidence that the local 6 homoaromatic state vanishes upon photoswitching to produce a purely global 10 homoaromatic state. These results of stable and accessible homoaromatic neutral hydrocarbons and their photoswitching behaviour provide new insights for the understanding and study of homoconjugative interactions in organic molecules, and for the design of new responsive molecular materials.
Introduction<!>Fig. 1 | Examples of potentially neutral homoaromatic compounds/Rational approach to neutral homoaromatics.<!>Results and Discussion<!>Conclusion
<p>Homoaromatic molecules display characteristics of aromatic stabilization yet possess an interrupted cyclic conjugated -system 1 . The concept of homoaromaticity, resting upon through-bond or through-space homoconjugation 2,3 (the interaction between disconnected -systems, usually interrupted by one or more sp 3 -hybridized carbon atoms 1,4 ) has been highly controversial in the past 1 . The difficulty to identify clear criteria for the assignment of molecules as homoaromatic at first 1,5 as well as the small number of known homoaromatic molecules further spurred the discussion in this field.</p><p>The generally accepted criteria 1,4 include (I) one or more homoconjugative interactions (through-space or through-bond); (II) electron delocalization due to effective overlap of orbitals; (III) delocalization of (4n + 2) -electrons in a partially cyclic structure; (IV) bond length equalization of single and/or double bonds; (V) magnetic characteristics associated with "normal aromaticity" and (VI) resonance stabilization energy.</p><p>Several ionic homoaromatic compounds have been disclosed [6][7][8] ; however, examples for neutral homoaromatic molecules (especially purely organic ones) remain extremely rare [9][10][11][12][13][14][15] . In fact, besides a few heteroatom-containing molecules [9][10][11]15 , no undisputed neutral homoaromatic hydrocarbon has been synthesized or isolated to date [12][13][14] , spurring the comment in the leading review that "there remains a dearth of neutral homoaromatics" 1 .</p><p>The simplest homoaromatic analogue of benzene with a potential through-space homoconjugation, cycloheptatriene 1, has been discussed as prototypical homoaromatic (Fig. 1, top) 1,3,[16][17][18] . Calculations indicate a homoaromatic character; however, no experimental data exist to support this claim 19 . For the prototypical through-bond homoaromatic norcaradiene 2, calculations show no indication for homoaromaticity 19 .</p><p>Topic of a long-standing debate about homoaromaticity in neutral molecules was elassovalene 3 20,21 , which represents a potentially neutral 10-electron homoaromatic. However, after independent preparation of 3 by the groups of Paquette and Vogel, evaluation of spectral data, magnetic criteria, and finally comparison to related aromatic annulenes, it was concluded that elassovalene 3 is not a neutral homoaromatic hydrocarbon 20,[22][23][24][25][26] . Therefore, the quest for a neutral homoaromatic hydrocarbon still remains. The group of Quast came close to this goal when they found that for barbaralane-derivative 4 the homoaromatic transition state was markedly stabilized in selected polar solvents [27][28][29][30] , however, in the crystal structure of 4, only limited bond length equalization was observed (see below, Fig. 4) rendering this molecule the closest candidate for a neutral homoaromatic hydrocarbon so far. An isolable, truly homoaromatic hydrocarbon thus far has remained elusive.</p><!><p>The abovementioned examples underscore the required combined computational and experimental evidence for the assignment of a homoaromatic electronic structure. However, structural information is difficult to access, since neutral homoaromatics are often transient species 1,13,14,29 and not crystalline, hampering the identification of bond length equalization as one of the key criteria for homoaromaticity. We herein present the synthesis of a neutral class of homoaromatic hydrocarbons, homoannulenes 6, and discuss its homoaromaticity, supported by experimental data (chemical shifts from NMR spectroscopy and bond length comparison from X-ray structure elucidation) and calculations. We further show that compounds 6 act as a structurally novel photochemical switch through an unprecedented reversible photo-induced [1,11] sigmatropic rearrangement forming a novel neutral 10 homoaromatic.</p><!><p>Our working hypothesis to design stable and isolable neutral homoaromatics emanated from elassovalene 3 (Fig. 1, bottom). Extending the bridging unit from a semibullvalene to a barbaralane core as in 5, we anticipated that an additional carbon atom in the bridge would allow for more structural flexibility and thus would facilitate the interaction of both ends of the -system through-space to allow for homoconjugative interaction 31 . At the same time, the target molecule would in principle bear both a potential 6 as well as a 10 homoaromatic system, allowing to probe larger homoaromatic interactions.</p><p>We targeted the synthesis of a potentially 6-or 10-electron homoaromatic homoannulene 6 with a barbaralone-derived framework (Fig. 2, bottom). For the related bridged aromatic annulenes [32][33][34] , semibullvalenes 20,34 and elassovalene 20 3 (Fig. 2, top), Vogel had emanated from tetrahydronaphthalenes 7 or hexahydroanthracenes, respectively, employing the central alkene(s) of hydrogenated polyaromatic compounds such as tetrahydronaphthalene as synthetic linchpin for a key cyclopropanation (Fig. 2a, inside → outside). We envisioned an orthogonal approach (outside → inside), utilizing first the outer disubstituted alkene of the related dihydronaphthalene 8, leaving the benzene ring untouched.</p><p>In this manner, we could circumvent the inherent higher reactivity of the central tetrasubstituted alkene for the key cyclopropanation, and exploited a challenging intramolecular dearomative Buchner reaction as central methodology in the synthesis 25 .</p><p>In this vein, we first reduced naphthalene 9 to 1,4-dihydronaphthalene 8, making the outer double bond accessible for the subsequent rhodium(II) catalyzed cyclopropanation 35 , giving cyclopropane 10 as a diastereomeric mixture of trans-10 and cis-10 (2:1). Separation of the two isomers trans-10 and cis-10 was achieved by iterative temperature-dependent saponification with KOH exploiting the innate reactivity difference of the diastereomeric cyclopropyl esters trans-10 and cis-10: a first saponification with KOH at room temperature selectively transformed trans-10 to the trans-11 acid and thus facilitated removal of unwanted trans isomer. Raising the temperature from room temperature to reflux afforded the all-ciscarboxylic acid cis-11 through subsequent saponification under elevated temperature. In allcis-11, the carboxylic acid is aligned suitably towards the benzene ring, a key necessity for the downstream intramolecular Buchner reaction. It should be noted that this particular Buchner reaction is further impeded by the fact that acetoacetate-derived diazo compounds generally display significantly lower reactivity in cyclopropanation reactions 25 . We continued by activation of all-cis-11 and chain elongation by Claisen condensation to form acetoacetate 12.</p><p>Subsequent diazo transfer reaction led to the corresponding diazo compound 13. The following intramolecular Buchner reaction, vital for our outside → inside strategy, required excessive catalyst optimization: After investigation of a variety of Rh(II) and Cu(II) complexes, we identified Cu(hFacac)2 as suitable catalyst for the desired Buchner dearomatization to give triasterane 14 (for optimization see Supporting Information). Remarkably, only few of the catalysts employed gave the desired product 14 at all, whereas the Buchner reaction catalyzed by Cu(hFacac)2 did not show any traces of otherwise competing C-H-insertions. Finally, dehydrogenative oxidation using DDQ gave homoannulene ester 15. To support the connectivity and stereochemistry of the desired products, crystal structures were obtained for 11, 12b-14b and 15 36 . Gratifyingly, this allowed for analysis of bond lengths with foresight to potential homoaromaticity (see below).</p><p>When exploring the general chemical reactivity of 15, we found that saponification conditions unexpectedly led to the formation of the rearranged homoannulene carboxylic acid 16 (for a proposed mechanism, see the Supplementary Figure 3). This turned out to be a fortunate discovery, as 16 not only represents yet another neutral homoaromatic compound, but with the X-ray crystal structure of 16 available, it also serves as key reference compound for the following investigation of the magnetic properties of the neutral homoaromatics 15 and 16. Homoannulene ester 15 and the rearranged homoannulene carboxylic acid 16 turned out to be ideal probes for the investigation of magnetic properties (induced ring current) indicative for a homoaromatic interaction 1 . Magnetic anisotropy and susceptibility of homoaromatic compounds is verifiable by NMR spectroscopy through marked chemical shifts 1,[37][38][39][40] . Comparing the 1 H NMR spectra of 14a, 15 and 16 (Fig. 3), we observed that 15 and 16 display a significant down-field shift of hydrogen atoms 5 and 6 of ~1.00 ppm as compared to 14a, giving a first indication of the presence of a ring current in the former two.</p><p>Furthermore, the -carbonyl methine group of homoannulene ester 15, facing away from the potential homoaromatic system, displays an expected chemical shift of  = 3.81 ppm (Fig. 3, top). In stark contrast, the -carbonyl methine 1 H NMR resonance of homoannulene carboxylic acid 16, placed directly above the homoaromatic system, is significantly shifted up-field to  = 0.89 ppm, although being placed directly adjacent an electron-withdrawing ketone (Fig. 3, bottom). Even taking the anisotropic effect of the double bonds into account 16 , this unusually high up-field shift of  = 2.92 ppm unambiguously indicates the presence of a diamagnetic ring current 39,41 , which shields the methine hydrogen of 16 16,32 . Both key spectral properties (downfield shift of hydrogen atoms 5 and 6 and shift of bridgehead methine hydrogen) are missing in elassovalene (3) 20,23 , whose analogous methine hydrogen appears at  = 1.77 ppm (and Csp2-H appear at 6.30 and 6.64 ppm, respectively). Homoannulene ester 15 as well as homoannulene carboxylic acid 16 possess an interrupted cyclic  system. The observation of a strong ring current therefore indicates the existence of through-space interaction of the  system leading to a delocalization of -electrons 2 . Therefore, the fused barbaralone framework prepared in this study seems to structurally enable an efficient homoconjugation by an elongated bridge that facilitates the through-space interaction of carbon atoms C(4)⋅⋅⋅C (9)   through steric congestion. Combined, these findings serve as important indication that homoannulene ester 15 and homoannulene carboxylic acid 16 are neutral homoaromatic compounds. One of the paramount characteristics for homoaromatic compounds is bond length equalization of the single and double bonds involved 1,2 . With the X-ray structures of 14, 15 and 16 available for detailed analysis, we observed significant shortening of the single bonds and elongation of the double bonds (Fig. 4). As limits, bond lengths of isolated C-C-single (1.54 Å) and C=C-double bonds (1.34 Å) as well as the "ideal" bond length equalization of benzene (1.39 Å) are considered for comparison 42 . These values are compared to the longest C-Csingle bond and the shortest C=C-double bond, respectively, of the respective neutral homoaromatic molecules 14a, 15 and 16 (see the Supplementary Figure 2 for detailed analysis of all bond lengths).</p><p>For homoannulene ester 15, a homoaromatic cycloheptatrienyl fragment seems to be present as indicated by the bond length equalization (shortest double bond is 1.364 Å (Fig. 4, red arrows) and the longest single bond is 1.420 Å long (Fig. 4, blue arrows)). The formal vinyl substituents in the barbaralone substructure show alternating (single and double) bond lengths (ca. 1.45 and ca. 1.34 Å, respectively), indicating a 6 homoaromatic compound with two vinyl substituents. Also, for homoannulene carboxylic acid 16, equalized bond lengths are observed (1.428 and 1.360 Å for longest C-C-single and shortest C=C-double bond in the cycloheptatriene moiety). In contrast, non-oxidized triasterane 14a displays the expected bond length alternation for a 1,3-diene and lacks any indication for homoconjugation. We compared our observations to Quast's barbaralane 4 [28][29][30] (Fig. 4), which to our knowledge shows the most neutral homoaromatic properties reported so far 1 (1.459 and 1.347 Å for longest C-C-single and shortest C=C-double bond). Homoannulene ester 15 and carboxylic acid 16 show significantly higher bond length equalization than barbaralane 4. Indeed, the bond length equalization observed for 15 and 16 is rather comparable to Vogel's methano [10]annulene 17 32 (1.372-1.419 Å 43 ), which is considered aromatic 32,44   and longest single bond (blue arrows) of the (homo)aromatic part of methano [10]annulene (17) 32,43 , barbaralane 4 by Quast [28][29][30] , triasterane 14a, homoannulene ester 15 and homoannulene carboxylic acid 16.</p><p>Extended conjugated -systemsespecially aromatic onesexpress particular reactivity and show the ability to absorb energy in the UV/vis range. To further elucidate the homoaromatic character of 15 we investigated its behavior upon irradiation with light, as has been done for several other homoaromatic compounds 20,27,28,45 . We found that homoannulene ester 15 undergoes a photoinduced rearrangement of the barbaralone framework forming ester 18 (305 nm LED irradiation for 80 sec of a dilute cyclohexane or MeCN solution of 15, Fig. 5a). The thermal stability of photoproduct 18 was verified by heating the photostationary state (PSS) mixture obtained at 305 nm in MeCN for 9.25 h at 55 °C without any noticeable change in composition (see Supplementary Figures 13 and 14). Therefore, compounds 15 and 18 could be separated using preparative HPLC chromatography. Full characterization of 18 using NMR spectroscopy and HR-MS analysis allowed the unambiguous determination of its structure.</p><p>The formation of 18 can be rationalized by an unprecedented [1,11] sigmatropic rearrangement from 15 to 18, which is suprafacially allowed under photochemical conditions in accordance with the Woodward-Hoffman rules 46 . UV/vis spectroscopy indicates a clean rearrangement, supported by the HPLC traces and the isosbestic points observed (Fig. 5b and c). Integration of the peak areas of the UV/vis-HPLC traces revealed a ratio 15/18 of 30:70 at the PSS (see Supplementary Fig. 10). This photochemical reaction was found to be independent of solvent polarity and could not only be observed in cyclohexane but equally rapid in MeCN, supportive of a non-polar transition state typically observed for pericyclic reactions (see Supplementary Fig. 7).</p><p>Photochromic systems are of special interest in the development of functional materials 47 . Prediction and rational design of new photochromic motifs that can be reversibly switched from one state into another by light has proven challenging. Attempting the backreaction of 18 to 15, we found that the photochemical [1,11] sigmatropic rearrangement is reversible upon irradiation with a 455 nm LED light source. This renders homoannulene ester 15 a structurally novel photochemical switch [48][49][50] . The photochromic system can be classified as a p-type photoswitch (backreaction photochemically activated).</p><p>We performed multiple cycles of irradiation alternating between a 305 nm and 455 nm LED (Fig. 5b). Although the irradiation repeatedly led to the formation of 18 in the PSS and backformation of 15, analysis of the UV/vis absorption maxima at 390 nm over several cycles indicated a moderate switching fatigue caused by the formation of trace side products in the photoswitching process (see Supplementary Fig. 11). We hypothesize that the formation of rearranged 18 is driven by a homoaromatic stabilization effect and thus turned our attention to the computational electronic and magnetic structure analysis of 15 and 18. Fig. 5 | Photoswitchable [1,11] sigmatropic rearrangement 46 . a) Homoannulene ester 15 undergoes reversible [1,11] sigmatropic rearrangement 46 at  = 305 nm to ester 18 (only one possible enantiomer displayed) and back-reaction to 15 at  = 455 nm; b) Cycling experiments of the photoreaction. Absorbance at 390 nm shown under alternating irradiation between 305 nm (blue shaded) and 455 nm (red shaded); c) UV/vis absorption of 15 (cyan) in cyclohexane (c(15) = 5.5×10 -5 mol L -1 ) upon irradiation with a 305 nm LED (grey, every 5 s, 80 s total) and till the PSS305 nm is reached (green); d) back-irradiation into 15 using a 455 nm LED (grey, spectra recorded every 60 s, 11 min total). Insets show HPLC chromatograms at the start and end of the irradiation.</p><p>The induced ring currents of (homo)aromatic systems by an external magnetic field were probed computationally as a measure for the homoaromaticity of 15 and 18. In conjunction with (indirect) experimentally determined diatropicity via 1 H NMR spectroscopy for the adjacent hydrogen atoms, magnetic indices can be used to theoretically correlating the degree of aromaticity. Two such magnetic indices that are widely used are nucleus independent chemical shifts (NICS) [51][52][53][54] and the anisotropy of the induced ring current density (ACID) 55,56 , which were calculated for 15 and 18 (Fig. 6 and Supplementary Discussion Section 1.7).</p><p>To simplify the calculations, the methyl ester groups in 15 and 18 were replaced by methyl groups (now: Me-15, Me-18). Due to the non-planar  ring geometry we calculated NICSzz values at various distances greater than 1.7 Å below the ring centroids to avoid contaminations of -bond-induced ring currents 53,54 . These one-and two-dimensional NICSzz scans of Me-15 (Fig. 6a, c) reveal a pronounced diatropic ring current of the C(4) to C(9) fragment of Me-15 with NICS(1.8)zz values reaching down to -18.6 ppm. In contrast, the adjacent ring current in the C(2-4)⋅⋅⋅C (9-11) fragment is only moderately diatropic with less negative NICS(1.8)zz values of -12.5 ppm. In contrast, upon [1,11] sigmatropic rearrangement to 18, the diatropic ring currents are equalized over the 10 system of Me-18 with similar NICS(1.8)zz values of -11.3 ppm and -15.2 ppm for the six-and seven-membered fragments, respectively. Finally, the plotted ACID underscores the conjugation paths of the ring currents unambiguously (Fig. 6e, f) 55,56 . A significant homoaromatic through-space interaction for Me-15 can be observed between atoms C(2) and C(11) at a critical isosurface value (CIV) of 0.034 supporting a global 10π homoaromatic character in agreement with the NICS analysis of 15 (in comparison, the CIV for non-planar cycloheptatriene 1 is 0.027 at the same level of theory 55,56 ). A second through-space interaction between C(4) and C( 9) is observed at a CIV of 0.026 indicating a local 6π homoaromatic ring current in 15.</p><p>For 18 the situation is changed again, where a through-space interaction is observed between C(1) and C(10) at a CIV of 0.040, indicating an enhanced global 10 homoaromaticity. On the contrary, no through-space interaction can be observed for the local 6-system between C(4) and C(9) even at an CIV as low as 0.01 (see Supplementary Fig. 26). We conclude that both 15 and 18 are globally 10 homoaromatic with an enhanced local homoaromaticity in the 6system of 15 and a nearly equalized 10 homoaromatic state in 18. The latter is due to geometric constraints originating from the rearranged scaffold in 18, allowing for efficient homoconjugation between C(1) and C(10) that facilitates a 10 electron ring current.</p><!><p>Assigning molecules as homoaromatic has been a long-standing problem since molecules with sufficient stability and lifetime were elusive. We herein describe the synthesis of homoannulene ester 15 and the related acid 16, the first isolated neutral homoaromatic hydrocarbons. Their homoaromatic state was evidenced by 1 H NMR spectroscopic data indicating a significant ring current in addition to a high degree of bond length equalization in the X-ray crystal structures. A detailed computational analysis by means of NICS scans and ACID isosurface plots revealed the ring currents and conjugation pathways. The local 6 homoaromatic state of homoannulene ester 15 can be photoswitched at 300 nm to a purely global 10 homoaromatic state by an unprecedented photochemical [1,11]</p>