1,8,10-Trisubstituted anthracenyl hydrocarbons: Towards versatile scaffolds for multiple-H-bonded recognition arrays

In this work, we describe the synthesis of 1,8,10-trisubstituted anthracenyl scaffolds that, bearing boronic acid functionalities, can act as multiple H-bonding donor systems. The trisubstituted anthracenyl de-rivatives are synthesized following two main synthetic pathways. Whereas in the fi rst approach trisubstituted anthracenyl derivatives are prepared through the regioselective addition of the relevant organomagnesium nucleophile to 1,8-dichloroanthraquinone, in the second avenue a tri fl ate-bearing anthracene is prepared by reduction of the anthraquinone into the anthrone precursor and functional-ized through metal-catalysed cross-coupling reactions. Complementary studies of the Na2S2O 4-mediated reduction of 1,8-dichloroanthraquinone allowed to shed further light on the possible mechanism of formation of the anthrone precursor, suggesting the presence of a cis-diol intermediate undergoing antiperiplanar elimination. Solid-state X-ray diffraction investigations of the bisboronic acids show that the molecules self-assemble into dimers through the formation of four H-bonds established between the anti-syn conformers of the boronic acid moieties. 1H-NMR titrations between bisboronic acids and tetra H-bond acceptor, diisoquinolino-naphthyridine, showed a signi fi cant shift of the -B(OH)2 proton reso-nances, suggesting the presence of H-bonding interactions between both molecules.


Introduction
Organoboronic acids are one of the most important functional groups used in organic chemistry [1].They are commonly used as organometallic species in Pdcatalysed Suzuki cross-coupling re-actions [2e5], in sensing [6e9], and in dynamic covalent chemistry to form boronate esters [10e13].In the recent years, organoboronic acids have also been proposed as versatile H-bonding donors [14e19].Depending on the type of conformation adopted by the boronic acid functionality, i.e. syn-syn, syn-anti and anti-anti, they can form different non-covalent H-bonded arrays both in solution and in the solid state [20].For instance, in the solid state phenyl-boronic acid undergoes formation of doubly-H-bonded dimers (DA-AD-type), in which the boronic acid moieties adopt a syn-anti conformation.The dimers are organised in tapes through the with 5,6,11,12-tetraazanaphthacene [31].However, to the best of our knowledge no examples of multiple H-bonded arrays involving boronic acids have been reported so far both in solution and in the solid state.
Due to their high directionality, selectivity, and reversibility, multiple Hbonding arrays are one of the most exploited non-covalent interactions for the preparation of self-assembled func-tional organic architectures.In particular, linear H-bonded arrays have been extensively used to self-assemble and selforganise functional molecules into well-defined supramolecular architec-tures [35e40].Through the demonstration with key examples in the field [32e34], it has been shown that increasing the number of H-bonds in D-type arrays, the strength of association is dramati-cally enhanced (Fig. 1) [32e34].It is with this idea in mind that in this paper we describe our efforts to prepare suitable molecular structures that, bearing two boronic acid functionalities, could act as versatile scaffolds for preparing multiple H-bonded complexes.In particular, we have envisioned the preparation of peri-substituted anthracenyl derivatives that, bearing two frontal boronic acids at positions 1 and 8, could undergo formation of quadruple H-bonding interactions in the presence of a suitable acceptor (Fig. 1).

Design of the H-bonding systems: theoretical calculations
We began our investigation with the design of the boronic acid derivatives as H-bonding donors.Capitalizing on the DFT calcula-tion, we modelled a substituted anthracenyl structure bearing boronic acids at peri-positions 1 and 8. Geometry optimization of the anthracenyl scaffolds was performed using DFT calculations at the B3LYP/6-311G** level of theory.In the optimized structure both boronic acid functionalities adopt a syn-syn conformation, arran-ging the acidic protons in a DDDD-type array.Notably, the non-acidic anthracenyl CH moiety in position 9 likely hampers the acid functionalities to be fully co-planar with the aromatic core (Fig. 2a).When contacted to diisoquinolino-naphthyridine H-bond acceptor (AAAA), single point energy calculation showed that a highly stabilized quadrupole Hbonded complex (DDDD-AAAA) is formed with a predicted DH of 32.63 kcal/mol (Fig. 2b).It is noteworthy to indicate that this value is superior to that reported for the formation of doubly H-bonded dimers of phenylboronic acid with naphthyridine of 20.41 kcal/mol [31].Encouraged by these predictive theoretical results, we planned the synthesis of the anthracenyl derivatives shown in Fig. 2c.As we have anticipated limited solubility of bisboronic acids in common organic solvents, anthracenyl cores bearing different substituents at position 10 have been prepared.The synthesis of Hbonding acceptor compound 1 (AAAA) was accomplished following a protocol reported in the literature (see also SI) [34].

Synthesis of three-substituted peri-functionalized anthracenyl scaffolds bearing H-bonding boronic acids
Our investigations began with the synthesis of the H-bonding donor anthracenyl derivatives 2 Me , 2

TEG
, and 3 each featuring a different solubilising group at position 10.Starting with compound 2 Me (Scheme 1), bromo-derivative 4 was first reacted with Mg in THF to form its Grignard derivative that reacting with anthraqui-none 5 at position 10, yielded hydroxyl-bearing intermediate 6 in 67% yield.The structure of the addition product could be unam-biguously determined by X-ray diffraction of single crystals ob-tained through evaporation of a solution of 6 in CHCl 3 (Fig. 3a).Me for X-ray diffraction analysis were obtained from slow evaporation of a solution of CHCl 3 (Fig. 3b).Pleasingly, the X-ray structure of com-pound 8 Me shows that the two boronate ester moieties are funda-mentally coplanar (dihedral angles O 1 eB 1 eC 1 eC 6 ¼ 17.6(5) and O 2 eB 1 eC 1 eC 2 ¼ 16.7( 5) ) with the anthracenyl scaffold.On the other hand, the aryl substituent is perpendicular to the polycyclic aromatic core (dihedral angle C 5 eC 8 eC 9 eC 10 ¼ 88.5( 4) ).
To improve the solubility of diboronic acid 2 Me in organic sol-vents, molecular analogue 2 TEG bearing two triethylene glycol tails was also prepared (Scheme 1).In this case, demethylation of in-termediate 7 Me in the presence of BBr 3 in CH 2 Cl 2 followed by alkylation with TEG-OTs under basic conditions led to compound 7 TEG in 55% yield.Following the protocols (i.e., Miyaura borylation and transesterification reactions followed by hydrolysis) described previously for installing the boronic acid moieties in molecule 2

Me
, we prepared target molecule 2 TEG in 37% yield over the two steps.Although the preparative route described so far led to the forma-tion of the desired target molecules, this synthetic strategy is limited by the preparation of a suitable organometallic nucleophile.A more versatile synthetic approach would be one that allows the insertion of any substituents at position 10 through a metal-catalysed cross-coupling reaction.Indulging this line of thought, we turned our attention on anthracene derivative 9 (Scheme 2) as the key intermediate for the new route.
The first synthetic step of this route involves the reduction of   that, under basic conditions, Na 2 S 2 O 4 is an effective reagent for the reduction of al-dehydes and ketones [42].They suggested a two-step mechanism, in which an a-hydroxy sulfinate intermediate is formed followed by its reductive transformation with loss of SO 2 .A similar mechanism was also proposed the year after by Saito and co-workers [43].In 1996, Müller and co-workers reported the regioselective reduction of peri-substituted anthraquinones into the relevant anthrones [44].They hypothesised that the reduction undergoes formation of a diol intermediate that, in the presence of an acid, eliminates to give the relevant anthrone derivative.In a previous report, Cristol reported the rate of H 2 O elimination from cis-and trans-9,10-anthraquinone diols.The author showed that the syn elimination, given by trans diols, is faster than that occurring with the cis-diols, with both diols being able to yield the relevant anthrone [45].To commence, we prepared and isolated those reactive intermediates that, we think, are possibly lying on the reaction path to the anthrone product.In a first attempt, peri-substituted anthraquinone 5 was reacted with Na 2 S 2 O 4 at room temperature for 5 h (Scheme 3).Interestingly, under these reaction conditions intermediate 9hydroxy-10-anthrone 13 was quantitatively ob-tained (structure confirmed by X-Ray diffraction analysis of crystals obtained through vapor diffusion of cyclohexane into a CH 2 Cl 2 so-lution, Fig. 5a).
Successive reaction of 13 with Na 2 S 2 O 4 at 90 C led to anthrone 10 in 94% yield, the structure of which could also be confirmed by X-ray diffraction (Fig. 5b).These observations suggested that the Na 2 S 2 O 4mediated reduction could occur stepwise, with the for-mation of 9-hydroxy-10-anthrone in the first place, and of a diol anthraquinone in the later stage.To confirm this hypothesis, both cis-and trans-diols of 1,8dichloroanthraquinone were also syn-thesized (Scheme 3).trans-Diol 14 was obtained by reaction of 10 in the presence of NaBH 4 in MeOH at 0 C for 3 h, whereas cis-diol analogue 15 could be prepared in 89% yield using DIBALH in THF.
The conformational properties of both 1,8-dichloroanthraquinone diols were confirmed by single-crystal X-Ray diffraction analyses.The structures of both diols were deter-mined from crystals obtained by slow evaporation of acetone so-lutions (Fig. 6a).Interestingly, molecules of trans-diol 14 arrange in a tape-like network through H-bonding interactions, connecting four neighbouring molecules (O 1 ‧‧‧O 2 ¼ 2.867(4) Å and O 1 ‧‧‧ O 2 ¼ 2.926(4) Å).In this isomer, the two hydroxyl groups are in equatorial and axial positions, respectively.On the other hand, the X-ray structure of cisdiol 15 shows the presence of the two  As the first experiment, the thermal elimination in DMF/H 2 O at 90 C for 5 h was attempted with trans-and cis-diols 14 and 15 (Table 1, entries 1&2).In both cases, no conversion was observed, which clearly suggests that heat alone is not sufficient for the re-action to occur.Therefore, we reacted independently trans-and cis-diols 14 and 15 in the presence of Na 2 S 2 O 4 at 90 C for 5 h following the protocol conditions used to transform 1,8-dichloroanthraquinone 5 into anthrone 10.Whereas trans-diol 14 did not yield any product, the reaction with cis-diol 15 led to the formation of anthrone 10 in 64% yield (Table 1, entries 3&4).This observation suggests that cis-diol 15 is likely the intermediate that, formed in the Na 2 S 2 O 4 -mediated reduction, allows the trans-formation of quinone 5 into anthrone 10.When the diols are reacted independently in the presence of HCl at 90 C for 5 h, both led to desired anthrone 10 quantitatively (Table 1, entries 5&6), as previously suggested by Cristol [45].
Taken all together, these observations suggest that the Na 2 S 2 O 4 -mediated reaction to anthrone 10 follows an antiperiplanar elimi-nation pathway as only the cis isomer reacts under these reductive conditions (Scheme 4).Indeed, only cis-diol 15 can adopt a conformation suitable for an antiperiplanar elimination, i.e. hydrogen atom and hydroxyl group in axial positions.The elimi-nation can occur through two different routes (Scheme 5).In route 1, a HSO 3 anion, generated from thermal decomposition of  Me , the boronic acid moieties and the anthracenyl core adopt a non-planar conformation in dimer 3 3.

Heteromolecular H-bonding recognition in solution
At last, we attempted to study the formation of H-bonded heteromolecular complexes in solution using boronic acids de-rivatives (2 equivalents) did not lead to any significant changes of the absorption envelope of acceptor 1.If one considers that shifts in energy are frequently observed for the strongest absorption bands when a chromophore engages in H-bonding interactions in solution, we concluded that if a non-covalent complex is formed, this crashes out of solution (some precipitate was observed in the cuvette).H-bonding donor 3 dis-played a similar behaviour to that of 2 Me , whereas no spectral changes were observed when 2 TEG was used.Despite the numerous attempts, we could not grow suitable crystals for X-ray diffraction analysis of the H-bonded complexes (2 Me 1 and 3 1).
Given the good solubility of H-bonding donor 2 TEG in organic solvents, we studied the binding of 2 TEG with 1 by means of 1 H-NMR titration.As peaks fingerprinting the boronic acid protons are generally not visible in CDCl 3 [31], a 1:1 mixture of C 6 D 6 and THF-d 8 was first employed, but extensive precipitation occurred upon addition of both components to the solution.Instead, reduced precipitation was noticed with a 95:5 mixture of C 6 D 6 and DMSO-d 6 .Titration experiments were thus performed in the latter solvent mixture using H-bonding donor 2 TEG and acceptor 1 as host and acceptor, respectively.Although some precipitation and peak broadening were observed during the titration experiments (Fig. 9  downfield shifts (Dd ¼ 0.49 ppm) upon addition of 1, confirming the presence of interactions involving the frontal boronic acid moieties.Unfortunately, the slight precipitation observed during the titration experiments together with the significant peak broadening (Fig. 9) hampered any further attempts to produce meaningful thermo-dynamic data in solution.

Conclusion
In summary, herein we developed two synthetic pathways to prepare 1,8,10-trisubstituted anthracenes that, bearing two boronic acid functionalities, can act as multiple H-bonding donors.Whereas in the first approach the peri-substituted anthracenyl derivatives are synthesized through the addition of a Grignard nucleophile to 1,8-dichloroanthraquinone, in the second avenue a triflate-bearing 1,8,10-trisubstituted anthracene is prepared

4.
Experimental part 400).Chemical shifts were reported in ppm according to tetramethylsilane using the solvent residual signal as an internal reference 4.1.
General methods (CDCl : Fluorochem, TCI, Carbosynth, and ABCR, and were used as received.in Hz.Resonance multiplicity was described as s (singlet), Deuterated solvents were purchased from Eurisotop.General sol-d (doublet), t (triplet), q (quartet).Carbon spectra were acquired vents were distilled in vacuo.Anhydrous solvents such as Et 2 O and with a complete decoupling for the proton.All spectra were THF were distilled from Na/benzophenone; CH 2 Cl 2 from phosrecorded at 25 C. Infrared spectra (IR) were recorded on a Perkiphorus pentoxide.Anhydrous DMF, 1,4-dioxane and MeOH were nElmer Spectrum II FT-IR System UATR, mounted with a diamond purchased and used without further purification.Anhydrous con-crystal.Selected absorption bands are reported in wavenumber ditions were achieved by drying Schlenk lines, 2-neck flasks or 3-(cm 1 ).Mass spectrometry was generally performed by the neck flasks by flaming with a heat gun under vacuum and purg-Federation de Recherche ICOA/CBM (FR2708) platform of Orleans in ing with argon.The inert atmosphere was maintained using argon-France.High-resolution ESI mass spectra (HRMS) were performed filled balloons equipped with a syringe and needle that was used to on a Bruker maXis Q-TOF in the positive ion mode.The analytes were penetrate the silicon stoppers used to close the flasks' necks.The dissolved in a suitable solvent at a concentration of 1 mg/mL and addition of liquid reagents was done by means of dried plastic sy-diluted 200 times in methanol (z5 ng/mL).The diluted solutions ringes or by cannulation.Column chromatography was carried (1 mL) were delivered to the ESI source by a Dionex Ultimate 3000 out using Grace silica gel 60 (particle size 40e63 mm).Melting  recorded at 1 Hz in the range of 50e3000 m/z.Calibration was performed with ESI-TOF Tuning mix from Agilent and corrected using lock masses at m/z 299.294457 (methyl stearate) and 1221.990638(HP-1221).Data were processed using Bruker Data-Analysis 4.1 software.MALDI-MS were performed by the Centre de spectrometrie de masse at the Universite de Mons and recorded using a Waters QToF Premier mass spectrometer equipped with a nitrogen laser, operating at 337 nm with a maximum output of 500 mW delivered to the sample in 4 ns pulses at 20 Hz repeating rate.Time-of-flight mass analyses were performed in the reflectron mode at a resolution of about 10,000.The matrix solution (1 mL) was applied to a stainless-steel target and air dried.Analyte samples were dis-solved in a suitable solvent to obtain 1 mg/mL solutions.1 mL ali-quots of those solutions were applied onto the target area already bearing the matrix crystals, and air dried.For the recording of the single-stage MS spectra, the quadrupole (rf-only mode) was set to pass ions from 100 to 1000 Th, and all ions were transmitted into the pusher region of the time-of-flight analyser where they were analyzed with 1 s integration time.

10-(3,5-dimethoxyphenyl)anthracene-1,8-diyl)diboronic acid 2Me
To a suspension of compound  In a dry 2 neck flask, 1-bromo-3,5-dimethoxybenzene 4 (108.5 mg, 0.5 mmol) was dissolved in dry THF (2 mL).0.5 mL of the resulting solution were added to a second dry two neck flask containing Mg (14 mg, 0.575 mmol) and a crystal of I 2 .The sus-pension was heated up (around 60 C) until reaching a point in which a transparent suspension was obtained (the iodine disjunc-tion).As soon as no suspension was observed, the rest of the so-lution containing 4 was added to the solution.The mixture was stirred for 1 h at room temperature.The resulting Grignard sus-pension was added to a dry two neck flask containing an ice-cold solution of compound 5 (138.5 mg, 0.5 mmol) dissolved in dry THF (3 mL).The reaction was let to reach room temperature stirring overnight.The solvent was removed in vacuo and compound 6 was purified by silica gel column chromatography (Cyclohexane/EtOAc 75:25) as a white solid (139 mg, 67%    In a dry Schlenk, compound 11 (556 mg, 1.300 mmol), bis(-neopentyl glycolato)diboron (725 mg, 3.211 mmol), XPhos (50 mg, 0.104 mmol) and NaOAc (1.345 g, 16.400 mmol) were added in dry 1,4-dioxane (4.5 mL).The resulting suspension was degassed through 3 freeze-pump-thaw cycles and [Pd 2 (dba) 3 ] (14 mg, 0.016 mmol) added to the mixture.The reaction was stirred at 90 C for 1 h.The solvent was removed in vacuo.The catalyst was precipitated upon addition of toluene and removed through filtration on celite.The filtrate was concentrated in vacuo.A white powder was precipitated upon addition of n-hexane and removed through filtration on celite.The solvent was removed in vacuo, yielding the desired compound 12 (151 mg, 20%) as a pale-yellow powder.M.p. 97e100 C. FTIR (ATR) n (cm  To a solution of 1,8-dichloroanthracene-9,10-dione 5 (277 mg, 1 mmol) in dry THF (30 mL) was added dropwise DIBAH (3 mL, 3 mmol, 1 M in hexane).The reaction mixture was stirred for 5 h, followed by the addition of saturated aqueous Rochelle's salt so-lution (25 mL).The resulting mixture was stirred at room tem-perature overnight.The mixture was extracted with EtOAc (3 25 mL), the organic layers were combined, dried over MgSO 4 , filtered and evaporated.Compound 15 was purified through silica gel column chromatography (Cyclohexane/EtOAc 8:2) and isolated as a white powder (252 mg, 89%

Fig. 2 .
Fig. 2. a) Chemical structure and B3LYP optimized geometry of the donor backbone, b) B3LYP optimized geometry of the 4 H-bonded complex and c) structure of the target molecules.
Building on a literature protocol developed by Tanaka, Wada and coworkers [41], Miyaura borylation of anthracene 7 Me using bis(neopentylglycolato)diboron in the presence of NaOAc, [Pd 2 (dba) 3 ] and XPhos in 1,4-dioxane at 90 C led to the formation of di-boronate ester 8 Me in 57% yield.Transesterification with dieth-anolamine, followed by hydrolysis with HCl, led to diboronic acid 2 Me in 98% yield.Notably, molecule 2 Me proved to be soluble only in DMSO.In addition to classical 1 H-and 13 C-NMR characterizations, the structures of the boronic acid derivative was confirmed by X-ray diffraction analysis of single crystals (for molecule 2 Me see section 2.5).Suitable transparent crystals of diboronate 8

Fig. 5 .
Fig. 5. a) Crystal structure of compound 13; space group: P21/c.b) Crystal structure of compound 10; space group: P-21.H atoms are omitted except for OH and Csp2H.Atom colours: green Cl, red O, grey C, white H.

Fig. 6 .
Fig. 6. a) Crystal structure of compound 14; space group: P21.b) Crystal structure of compound 15; space group: P-1.H atoms are omitted except for OH and Csp2H.Atom colours: green Cl, red O, grey C, white H.

and 3 ) 1 in CH 2 2 Me.
as the H-bonding DDDD partners and molecule 1 as the complementary AAAA-type acceptor.Due to the poor solubility of boronic acids 2 Me and 3 in non-competitive organic solvents, any attempts to study their H-bonding recognition prop-erties by 1 H-NMR titration failed.Thus we turned out attention to UVevis absorption spectroscopy, and monitored any changes in the absorption profile of H-bonding acceptor 1 (c ¼ 10 6 mol L Cl 2 ) upon increasing amount of H-bonding donor 2 Me (Fig. 8).As one can clearly notice in the absorption profiles shown in Fig. 8, only a decrease in the intensity of the absorption bands charac-teristic of acceptor 1 (420e470 nm) was observed upon increasing addition (up to 0.5 equivalents) of donor No energy shifts were observed for any of the electronic transitions.Further increases of the concentration of 2 Me (up to 3 ), addition of increasing amount of 1 to a 5 mM solution of 2 TEG led to noticeable downfield shift (Dd ¼ 1.31 ppm) of the -B(OH) 2 proton resonances, suggesting the presence of H-bonding interactions.Together with the-B(OH) 2 resonances, also the peaks of the proton resonance of the aromatic peri-proton CH in position 9 revealed significant

by
Na 2 S 2 O 4 reduction of the anthraquinone into the anthrone precursor and functional-ized through a metal-catalysed cross-coupling reaction.Complementary studies of the Na 2 S 2 O 4 -mediated of 1,8-dichloroanthraquinone allowed to shed further light on the mechanism leading to the anthrone intermediate, suggesting that the reaction possibly involves the formation of a cis-diol derivative that can undergo antiperiplanar elimination.X-ray diffraction in-vestigations of the 1,8,10-trisubstituted anthracenyl boronic acids in the solid-state show that the molecules selfassemble into di-mers through the formation of frontal H-bonds established be-tween the anti-syn conformers of the boronic acid moieties.The binding properties of the boronic acids (DDDD) were also studied in solution in the presence of a suitable multiple H-bonding acceptor (AAAA), not lead to any conclusive observations, 1 H-NMR titration experiments showed a significant downfield shift of the -B(OH) 2 proton resonances, suggesting the presence of H-bonding interactions.However, the poor solubility of the H-bonded complexes hampered precise determination of the stoichiometry of the complexes and of any thermodynamic parameters.
RSLC chain used in FIA (Flow Injection Analysis) mode at a flow rate points (m.p.) were measured on a Büchi Melting Point B-545.All of of 200 mL/min with a mixture of CH 3 CN/H 2 O þ 0.1% of HCO 2 H (65/ the melting points have been measured in open capillary tubes and 35).ESI conditions were as follows: capillary voltage was set at have not been corrected.Nuclear magnetic resonance (NMR) 1 H 4.5 kV; dry nitrogen was used as nebulizing gas at 0.6 bars and as and 13 C spectra were obtained on a 400 MHz NMR (Jeol JNM EXdrying gas set at 200 C and 7.0 L/min.ESI-MS spectra were
Scheme 4. Possible conformations of a) cis-diol 15 and b) trans-diol 14.The red squares indicate the only conformation able to give antiperiplanar elimination.Scheme 5. Possible antiperiplanar elimination routes.Na 2 S 2 O 4 , may deprotonate the axial hydrogen triggering an E 1cb -type elimination reaction (top, Scheme 5).In route 2, an anti-periplanar E 2 -like elimination is proposed (down, Scheme 5).In both mechanistic propositions, a sulfinate moiety is evoked as leaving group (possibly formed in the presence of Na 2 S 2 O 4 under refluxing conditions).