Two π‐Electrons Make the Difference: From BODIPY to BODIIM Switchable Fluorescent Dyes

Abstract (aza‐)BODIPY dyes (boron dipyrromethene dyes) are well‐established fluorophores due to their large quantum yields, stability, and diversity, which led to promising applications including imaging techniques, sensors, organic (opto)electronic materials, or biomedical applications. Although the control of the optical properties in (aza‐)BODIPY dyes by peripheral functional groups is well studied, we herein present a novel approach to modify the 12 π‐electron core of the dipyrromethene scaffold. The replacement of two carbon atoms in the β‐position of a BODIPY dye by two nitrogen atoms afforded a 14 π‐electron system, which was termed BODIIM (boron diimidazolylmethene) in systematic analogy to the BODIPY dyes. Remarkably, the BODIIM dye was obtained with a BH2‐rigidifying entity, which is currently elusive and highly sought after for the BODIPY dye class. DFT‐Calculations confirm the [12+2] π‐electron relationship between BODIPY and BODIIM and reveal a strong shape correlation between LUMO in the BODIPY and the HOMO of the BODIIM. The modification of the π‐system leads to a dramatic shift of the optical properties, of which the fluorescent emission is most noteworthy and occurs at much larger Stokes shift, that is, ≈500 cm−1 in BODIPY versus >4170 cm−1 in BODIIM system in all solvents investigated. Nucleophilic reactivity was found at the meso‐carbon atom in the formation of stable borane adducts with a significant shift of the fluorescent emission, and this behavior contrasts the reactivity of conventional BODIPY systems. In addition, the reverse decomplexation of the borane adducts was demonstrated in reactions with a representative N‐heterocyclic carbene to retain the strongly fluorescent BODIIM compound, which suggests applications as fully reversible fluorescent switch.


Introduction
BODIPY dyes (boron dipyrromethenes) constitute an important class of fluorophores, which can be considered as boron chelates with ad ipyrrin entity [1] and have attracted broad interest as photoresponsive compounds, in particular as efficient fluorescentd yes (Scheme 1). The success of BODIPYsi sd ue to their excellent opticalk ey properties, whichi nclude strong absorbance andn arrow-band fluorescencea th igh quantum yields combined with excellent photostability in most organic solvents. The Stokess hifts of BODIPYsa re low( typically about 500 cm À1 ), and absorbance and emission maximaare commonly observed between 500-550nm. The extraordinarily rich chemistry of BODIPY fluorophores allows for high functionalgroup tolerance and procedures of post modification, [2] which plays ac rucial role in the development of materials for imaging techniques, [3] sensors, [4] organic (opto)electronic applications, [5] biomedical applications, [6] photodynamic therapy, [7] and sensitizers. [8] Although the parentB ODIPY 1 containing aB H 2complexed dipyrrin entity is currently unknown, the unsubstituted BF 2 -functionalized analogue 2 was obtained with considerable effort. [9] In contrast, derivativeso f2 were readily synthesized as early as 1968 by Treibs and Kreuzer, [10] and various modifications have been achieveda tt he meso-, a-, and b-positions. [11] In addition, the BF 2 entity in derivatives of 2 is subject to facile post functionalization with ab road scope of hydrocarbyl groups. [12] The optical properties of organic p-systems can systematically be tuned by incorporation of hetero atoms into the scaffold. Successful application of this methodology hasb een demonstrated with the development of aza-BODIPY dyes 3,i nw hich the meso-CH unit is replaced by an itrogen atom.I nc ontrast to BODIPY dyes 2,a bsorbance and fluorescence emission in 3 are now significantly redshifted to at least 650 nm (visible red or near-IRr egion), which suggests the application of these systems in bio-imaging procedures. [13] Despite the intriguing results achieved with aza-BODIPY dyes 3,t he furtherh eteroatom incorporation was attempted but remained unachieved.I np articular,c ompounds 4 and 5 were proposed as an extension of the concept but synthetic approaches to afford the key structures were reported to fail. [14] Exploitingt he concept of heteroatom incorporation into the p-system of aB ODIPY dye, compound 6 is presented as ar ecent result from our laboratories. The p-system can be viewed as being formed by the formal replacemento ft wo methyne entitiesf rom the b-position in the unknown parentB ODIPY 1 by NÀCH 3 groups. Due to the systematica nalogy of compound 6 to BODIPY dyes we herein introducet he term boron diimidazolylmethene( BODIIM) for this type of novel compounds.

Results and Discussion
The synthetic access towards compound 6 was performed employing trimethyl imidazole 7 (Scheme 2). [15] Given that BODIPY compounds are commonly synthesized from pre-formed ligand scaffolds (dipyrromethene precursors) by the complexation to the boron reagent being the last step of the synthetic protocol, we attempted such strategy for compound 6.T hus, the lithiation of 7 at low temperature and subsequentr eaction with benzoyl chloride afforded bisimidazole compound 8,t he complexation of which was attempted with variousb oron reagents including BX 3 ,B HX 2 ·SMe 2 or BH 2 X·SMe 2 (X = Cl, Br).
However,i na ll cases unselective reactions were observed giving rise to severals ignals in the 11 BNMR spectra.T his behavior may be rationalized by the presenceo ft he hydroxyl group in 8,w hich prevents selectiver eactions duet ot he oxophilic nature of the boronr eagents employed. Therefore, boron was introduced in the first step of the synthetic se-quence. The reactiono ft rimethyl imidazole 7 with BH 2 Cl·SMe 2 afforded the bisimidazol-functionalized boronium compound 9 in high yield, in which the carbon bridge was readily introduced by lithiation of 9 at the C2-positionsa nd the subsequent reactionw ith methyl benzoate. The resulting alcohol 10 was converted to the respective methyl ether 11 by deprotonation of the hydroxyl group followed by addition of methyl iodide.T he reduction of ether 11 with potassium graphite KC 8 afforded the novel BODIIMcompound 6 as ay ellowish, fluorescent solid. All compounds were fully characterized including multinuclear NMR spectroscopy,e lemental analysis and in the case of 6, 8,a nd 10 by X-ray crystallography;f or 6 and 10 see Figure 1, for 8 see the Supporting Information.
The reduction of ether 11 significantly changes the geometry of the carbon bridge C1 from af ourfold-coordinate carbon atom (in 10 and 11)t ot hreefold coordination (in 6). The bonds C1ÀC2 and C1ÀC8 undergo significant contraction upon reduction with an averageb ond length C1ÀC2/C8 (1.513(3)i n 10 vs. 1.415(1) in 6). This behavior is in line with an increase of the double-bondc haracter at the central carbon C1. In the molecular structures of 6 and 10 the scaffold atoms N1-C2-C1-C8-N3 were found to span ap lane with only minor deviations from the idealized geometry.A lthough in precursor 10 the BH 2 -entityi sw ell aligned within the plane with as light inclination of only 1.56(2)8 the distortion fromt he planarity of the BH 2 -entityi nc ompound 6 is much higher with an angle of 17.76 (2)8,see the Supporting Information.
Ac omparison of BODIPYs ystems 2 with the novel BODIIM compound 6 reveals remarkable differences. Although com-Scheme2.Key conditionsand reagents. i) 1equiv. nBuLi, THF, À30 8C, 30 min, then 0.45 equiv.b enzoyl chloride, 0 8Ctor t, 1h,6 5%.i i) 0.5 equiv. BH 2 Cl·SMe 2 ,DCM, 0 8Ctor t, 15 min, then THF,1 5min, then hexanes, 95 %. iii)2.05 equiv. nBuLi, THF, À78 8Ct ort, overnight, then 1.05 equiv.m ethyl benzoate, rt, 1h,a queous work-upw ith brine,9 5%.i v) 1.05 equiv. Na[N(-SiMe 3 ) 2 ], THF, À78 8Ctor t, 3h,then 3equiv.M eI, rt, 12 h, aqueousworkup with brine, 96 %. v) 4equiv.KC 8 ,THF,08C, 15 min, 95 %. Chem. Eur.J.2020, 26,1422-1428 www.chemeurj.org 2019 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim pound 6 is readily obtained in the parent form with aB H 2 entity,s uch type of BODIPY compounds is currently elusive to the best of our knowledge,and the BODIPY dye class is usually prepared as BF 2 derivatives. Previous attempts by Piers et al. to produce the parent BH 2 -BODIPYc ore from reactions of dipyrrin and BH 3 ·SMe 2 provide hints of the suggested speciesa st he kinetic product in ac rude mixture but its isolation as ac lean materialc ould not be demonstrated. Instead, the thermal treatment of the crude product afforded an onfluorescent dipyrromethano borane derivative formed by hydride migration from the BH 2 entity to the meso-carbona tom. [16] With 12 pelectrons in the organic framework of aB ODIPY system,t he formal replacement of carbon atoms for two NÀCH 3 moieties leads to aB ODIIM system with an increase to 14 p-electrons. For further insight DFT calculations (for computational details, see the Supporting Information) were performed for BODIPY type compounds A (BH 2 ,hypothetical system) and B (BF 2 ,reference system) [17] as wella sf or the novel BODIIM type compounds C (BH 2 ,r epresenting compound 6)a nd D (BF 2 ,h ypotheticala nalogueo f6;F igure 2). Optimizeds tructures of B and 6 closely mimic the experimental metrics (bond length deviations < 1pm) and render the proposed structures of hypothetic A and D highly reliable (see Ta ble S1, Supporting Information). With these systemse ffects of boron substitution (BF 2 versus BH 2 )a nd varied p-electron count (12 p in BODIPYs A, B versus 14 p in BODIIMs 6, D)c an be studied in isolation.I nspection of the frontier orbitals of A-D provest he substitution at boron to be insignificant. In contrast,the strikingly diverging properties of BODIPYa nd BODIIM,b oth in the ground and in the excited state (see below), can be traced to altered frontier orbitalcharacter by virtue of the p-electron count.
Although in BODIPY derivatives A and B both HOMO and LUMO are extendedo ver the dipyrromethene backbone,t his only holds for the HOMO in BODIIM compounds C and D.I n contrast,t he degenerate LUMO and LUMO+ +1a re essentially centeredo nt he phenyle ntity.Acouple of equally phenyl-centered MOs feature at much higher energies as LUMO+ +1a nd LUMO+ +2i nA and B.M ost strikingly,t he LUMO in BODIPYs ystems andt he HOMO in the BODIIM system appear to be relat-ed to each other and display ap ronouncedr esemblance with as trong contribution of the carbon p-orbital at the meso-position. We conclude that the replacement of two methyne CÀ CH 3 entities (A, B)f or two NÀCH 3 moieties (C, D)d oes not simply obey a[ 12+ +2] p-electron-count formalism but can rather be considered as targeted structural tuning. The substitution of two carbon atomsb yt wo nitrogen atoms within the p-conjugated system leads to an increase of the p-electrons by two. Thus, in as implistic view,o ne would expect that the HOMO of the nitrogen-containing compound should display strong similarities with the LUMO in the carbonderivative.
Given that HOMO-LUMOt ransitions often characterize or even determine absorption and fluorescence properties, BODIIM dyes must be expected to deviatef rom the established BODIPY dyes. Time-dependent( TD)-DFT studies of compound B associatea bsorption and emission within the planar BODIPY core withouta ny contribution of the tolyl moiety at the meso-position. Given that the HOMO and the LUMO display significant spatialo verlap, strong absorption and intense fluorescencea re predicted by theory,i nf ull agreement with the experiment (both ca. 530 nm). The emissioni sreported with high quantum yield at al ow Stokes shift (424 cm À1 )i nt oluene solution (Figure 3). [17] In contrast, in the same solventt he absorption of BODIIM 6 is found at 360, 400 nm with an intense greenish fluorescencea t5 20 nm resulting in ar emarkable Stokes shift of 5800 cm À1 .T his behaviorc an be traced back to the modifiedo rbital situation in the BODIIM system 6, in which the transition occurs from the HOMO located in the heterocycle part into LUMO and LUMO+ +1l ocated on the  phenyle ntity with preferred orthogonal orientation. Accordingly,T D-DFT modeling of the optical absorption spectra reveals two moderately intense close-lying transitions located in the near-UV region, which both carry heterocycle!arene charge-transfer character.I nclusion of medium effectsw ithin the polarizable continuum model (PCM) accounts for the solvent-dependent relative intensities (see insertF igure4). In view of this aspect the photophysics of BODIIM 6 is clearly completely different from BODIPY B and BODIPY dyes in general because the aryl entity is essential by serving as the accepting unit in the absorption process. Although aryl entities in the meso-position of BODIPY dyes are also known to give fluorescence-diminished compounds at, however,o nly somewhat increased Stokes shift, the photophysical mechanism is described as an interaction of the aryl based HOMO or LUMO with the BODIPY core-centered S 1 excited state leading to ac-ceptingo rd onating photoelectron transfer processes (PeT) with the arene unit, that is, a-PeTord -PeT mechanisms. [18] The experimental fluorescences pectra of 6 show single bands at 480 nm (n-hexane) or 530 nm (THF), which are in excellent and good agreement with the calculated spectra,a nd give rise to significant Stokes shifts of > 4,170 cm À1 in all studied solvents ( Figure 5). The Stokes shiftt ends to increasew ith solventp olarity: n-hexane (4170cm À1 ) < toluene( 5800 cm À1 ) < THF (6100 cm À1 ), corroborating the charge-transfer (CT)-like natureo ft he emissive excited state which was derived from TD-DFTc alculations. Accordingly,afurther diminished Stokes shift of only 2000 cm À1 is predicted to prevail for gas-phase conditions. AS tokes shift of such large extent again points out distinctive qualitative differences between the BODIIM and BODIPYc hromophores. Given that the latter chromophore undergoes only mild structural evolution upon excitation, energies of excitation and emission are close to degenerate.
Accordingly, significant structurale volution is active in 6 which is revealed through inspection of the metrics of the optimizede xcited-state structure of 6 (see Ta ble S1, Supporting Information). In addition to ah eterocycle-borne CÀNb ond contraction and 1,4-quinoidal distortion in the arene that are natural reportersofthe chargeshift upon excitation, the CT-excited state of 6 undergoes as ubstantial contraction of the CÀC single bond between the 14 p-backbone and the arene;t he difference in bond lengths between ground state (GS) and exited state (ES) amounts to less than 4pm. We believe that this uniquef eature of al arge Stokess hift in 6 will be attractive to the photophysical community,althoughabroader investigation of the photostability remains to be addressed. Compound 6 was found to suffer from photodecomposition in solvents of high polarity.A lthough in CH 2 Cl 2 reproducible measurements were prevented by as light extent of photodecomposition,t he solvents n-hexane and THF gave reproducible results.
In addition to the uniquea spects of photophysics the HOMO in BODIIM 6 can be used as ar epresentative map of Figure 3. Comparison of the optical properties of BODIPYr eference compound B (data reported in Ref. [17],recorded in toluene) and BODIIM 6 (recorded in toluene). i) Solution of compound 6 in toluene at ambient light. ii) Solutionofc ompound 6 in toluenewith UV-lamp excitation(l % 366 nm). l abs,max :wavelengthat the maximum of absorbance, l em,max :w avelength at the maximume mission intensity, F F :f luorescencequantumyield.  the LUMO in BODIPY dyes. In particular,t he strong p z -contribution (24.6 %) of the meso-carbon atom in the HOMO of compound 6 suggests as ignificant contribution to the LUMO in BODIPY B (23.1 %), whereas the HOMO of B essentially lacks the meso-carbon contribution (0.0 %). This qualitative difference suggests the reactivity of BODIIM 6 as ac arbon nucleophile at this distinct position; ab ehavior unparalleled by BODIPY dyes. Indeed, the addition of BH 3 (introduced in the form of the adduct BH 3 ·SMe 2 )a sarepresentative Lewis acid afforded borane adduct 12 with attack at the meso-position, which demonstrates the reactivity of 6 as ac arbon nucleophile (Scheme 3). The reversibility of the adduct formation was probedw ith strong Lewis bases.A lthough phosphines, such as PPh 3 and PMe 3 ,p roved to be inefficient, the N-heterocyclic carbene (NHC) IMe Me (1,3,4,5-tetramethyl-imidazol-2-ylidene) was found to produce 6 from 12 in approximately 5% NMR spectroscopic yield. Thep oor reversibility was attributed to the strong donating ability of 6 at the meso-carbon atom and can be estimated to be comparable to N-heterocyclic carbenes. In view of ab etter reversibility for the donor-acceptor reaction, we reasoned that ab ulkier borane would be boundw eaker to the meso-carbon atom in 6.T his hypothesis was studied with the sterically congested aryl borane MesBH 2 (Mes = 2,4,6-Me 3 C 6 H 2 ), the reaction of which with compound 6 gave the borane adduct 14.I nt his case the treatmento f14 with IMe Me led to ar eversible, quantitative formation of 6.

Conclusions
(aza-)BODIPY dyes(boron dipyrromethene dyes) are well-established fluorophores due to their excellent quantum yields, stability and diversity.A lthought he control of the opticalp roperties in (aza-) BODIPY dyes by peripheral functional groups is well studied, we herein presented an ovel approacht om odify the 12 p-electron system of the BODIPY scaffold. We presented af irst prototype of af luorescentd ye termedB ODIIM (6,b oron diimidazolylmethene), which was obtained by the formal replacemento fC Hg roups in the b-positionb yn itrogen atoms in the organic p-system of aB ODIPY.T he resulting1 4p-electron system in the BODIIM dye can be considered as an extension of the 12 p-electron system in aB ODIPY dye. DFT-Calculations confirm the [12+ +2] p-electron relationship between BODIPY and BODIIMc ores andr eveal as trong shape correlation between LUMO in the BODIPY and the HOMO of the BODIIM.T he BODIIM prototype 6 proved to be less stable than BODIPY dyes:S olid samples weref ound to be bench-stable for ap eriod of 2weeks but solutions of 6 in [D 8 ]THF exposed to air showedd ecomposition to an extent of 1-2 %w ithin 24 ha s assessedb yN MR monitoring. Although reproducible fluorescence spectra were obtained in n-hexane and THF solutions of 6 in CH 2 Cl 2 showeds igns of photo-decomposition.H owever,i n view of the fact that compound 6 is the first prototype of BODIIM these problemsc an be addressed by careful structural design in future work. Remarkably,t he BODIIM prototype compound 6 offers severalf eatures whicha re unprecedentedf or the BODIPY dye class:( i) Even though compound 6 was obtained with aB H 2 rigidifying entity,t his structuralm otive was suggested but not proven for the BODIPY dye class. [16] (ii)The modification of the p-systeml eads to ad ramatic shift of the opticalp roperties, of which the fluorescent emission is most noteworthy and occurs at much higher Stokes shift, that is, % 500 cm À1 in BODIPY versus at least 4170 cm À1 in BODIIM systems in all solvents investigated. (iii)Nucleophilic reactivity was found at the meso-carbon atom in the formationo fs table borane adducts with BH 3 (12)a nd MesBH 2 (14)d isplaying a significant shift of the fluorescent emission. Additionally,t he reversed ecomplexation of the borane adducts was demonstrated in reactions with ar epresentativeN -heterocyclic carbene to retain the strongly fluorescent BODIIM 6.T his reactivity is in contrastt oB ODIPY systems, which lack such nucleophilic behavior.W es uggest our system as af ully reversiblef luorescents witch to probe Lewis acidsa nd bases, in particular for systems of academic interest, for example, frustrated Lewis pairs (FLP). The fluorescencel ifetime is not reported but will be published within al ibrary of modified derivatives to allow for ac onsistent comparison. In addition to the improvement of the stability of the prototype compound 6,f uture work also will focuso nt he influence of the torsiona ngle of the phenyl moiety.I np reliminary computational studies this torsion angle was systematicallyt ilted from the preferred orthogonal orientation and as trong increase of the transition moments for both absorption and fluorescence emission with aconcomitant hypsochromic shift was found (see Ta ble S2, S3 and Figure S48, Supporting Information).