Iminosugar-dihydroazulenes as Mutant L444P Glucocerebrosidase Enhancers.

A remarkable enhancer of human glucocerebrosidase enzyme (GCase) was identified among a set of dihydroazulene-tagged iminosugars. An unprecedented 3.9-fold increase in GCase activity was detected on fibroblasts bearing the homozygous L444P mutation, which is frequently associated with neuronopathic Gaucher forms, and which commonly results refractory to chaperone-induced refolding.

Multi-redox indenofluorene chromophores incorporating dithiafulvene donor and ene/enediyne acceptor units.

Large donor-acceptor scaffolds derived from polycyclic aromatic hydrocarbons (PAHs) with tunable HOMO and LUMO energies are important for several applications, such as organic photovoltaics. Here, we present a large selection of PAHs based on central indenofluorene (IF) or fluorene cores and containing various dithiafulvene (DTF) donor units that gain aromaticity upon oxidation and a variety of acceptor units, such as vinylic diesters, enediynes, and cross-conjugated radiaannulenes (RAs) that gain aromaticity upon reduction. In some cases, the DTF units are expanded by pyrrolo annelation. The optical and redox properties of these compounds, in some cases carbon-rich, were studied by UV-vis absorption spectroscopy and cyclic voltammetry. Synthetically, the work explores IF diones or fluorenone as central building blocks by subjecting the carbonyl groups to a variety of reactions; that are, phosphite- or Lawesson's reagent-mediated olefination reactions (to introduce DTF motifs), Ramirez/Corey-Fuchs dibromo-olefinations followed by Sonogashira couplings (to introduce enediynes motifs), and Knoevenagel condensations (to introduce the vinylic diester motif). By a subsequent Glaser-Hay coupling reaction, a RA acceptor unit was introduced to provide a DTF-IF-RA donor-acceptor scaffold with a low-energy charge-transfer absorption and multi-redox behavior.

Sensitized Singlet Fission in Rigidly Linked Axial and Peripheral Pentacene-Subphthalocyanine Conjugates.

The goal of harnessing the theoretical potential of singlet fission (SF), a process in which one singlet excited state is split into two triplet excited states, has become a central challenge in solar energy research. Covalently linked dimers provide crucial models for understanding the role of chromophore arrangement and coupling in SF. Sensitizers can be integrated into these systems to expand the absorption bandwidth through which SF can be accessed. Here, we define the role of the sensitizer-chromophore geometry in a sensitized SF model system. To this end, two conjugates have been synthesized consisting of a pentacene dimer (SF motif) connected via a rigid alkynyl bridge to a subphthalocyanine (the sensitizer motif) in either an axial or a peripheral arrangement. Steady-state and time-resolved photophysical measurements are used to confirm that both conjugates operate as per design, displaying near unity energy transfer efficiencies and high triplet quantum yields from SF. Decisively, energy transfer between the subphthalocyanine and pentacene dimer occurs ca. 26 times faster in the peripheral conjugate, even though the two chromophores are ca. 3 Å farther apart than in the axial conjugate. Following a theoretical evaluation of the dipolar coupling, Vdip2, and the orientation factor, κ2, of both the axial (Vdip2 = 140 cm-2; κ2 = 0.08) and the peripheral (Vdip2 = 724 cm-2; κ2 = 1.46) arrangements, we establish that this rate acceleration is due to a more favorable (nearly co-planar) relative orientation of the transition dipole moments of the subphthalocyanine and pentacenes in the peripheral constellation.

Clicking together Alkynes and Tetracyanoethylene.

The [2+2] cycloaddition - retro-electrocyclization (CA-RE) reaction allows ready synthesis of redox-active donor-acceptor chromophores from an electron-rich alkyne and electron-poor olefins like tetracyanoethylene (TCNE). The detailed mechanism of the reaction has been subject of both computational and experimental studies. While several studies point towards a stepwise mechanism via a zwitterionic intermediate for the first step, the cycloaddition, the reaction follows neither simple second-order nor first-order kinetics. Recent studies have shown that the kinetics can be understood if an autocatalytic step is introduced in the mechanism, in which complex formation with the donor-substituted tetracyanobutadiene (TCBD) product possibly facilitates nucleophilic attack of the alkyne onto TCNE, generating the zwitterionic intermediate of the CA step. This Concept highlights the convenient use of the "click-like" CA-RE reaction to obtain elaborate donor-acceptor chromophores and the recent mechanistic results.

Light Driven Ultrafast Bioinspired Molecular Motors: Steering and Accelerating Photoisomerization Dynamics of Retinal.

Photoisomerization of retinal protonated Schiff base in microbial and animal rhodopsins are strikingly ultrafast and highly specific. Both protein environments provide conditions for fine-tuning the photochemistry of their chromophores. Here, by combining time-resolved action absorption spectroscopy and high-level electronic structure theory, we show that similar control can be gained in a synthetically engineered retinal chromophore. By locking the dimethylated retinal Schiff base at the C11═C12 double bond in its trans configuration (L-RSB), the excited-state decay is rendered from a slow picosecond to an ultrafast subpicosecond regime in the gas phase. Steric hindrance and pretwisting of L-RSB are found to be important for a significant reduction in the excited-state energy barriers, where isomerization of the locked chromophore proceeds along C9═C10 rather than the preferred C11═C12 isomerization path. Remarkably, the accelerated excited-state dynamics also becomes steered. We show that L-RSB is capable of unidirectional 360° rotation from all-trans to 9-cis and from 9-cis to all-trans in only two distinct steps induced by consecutive absorption of two 600 nm photons. This opens a way for the rational design of red-light-driven ultrafast molecular rotary motors based on locked retinal chromophores.

Photoswitchable inhibitors of human ß-glucocerebrosidase.

Light-switchable inhibitors of the enzyme ß-glucocerebrosidase (GCase) have been developed by anchoring a specific azasugar to a dihydroazulene or an azobenzene responsive moiety. Their inhibitory effect towards human GCase, before and after irradiation are reported, and the effect on thermal denaturation of recombinant GCase and cytotoxicity were studied on selected candidates.

Photolytic Studies of Norbornadiene Derivatives under High-Intensity Light Conditions.

The photoconversion of a norbornadiene (NBD) derivative was studied under high-intensity mono- and polychromatic light conditions at high concentrations. The photoisomerization quantum yield (ϕNBD→QC), proceeding from NBD to its quadricyclane (QC) isomer, was determined using a tunable OPO laser and a solar simulator light source. The solar simulator was designed to mimic the AM1.5G solar spectrum between 300 and 900 nm. Using the OPO laser, ϕNBD→QC was measured at discrete values between 310 and 350 nm in steps of 10 nm, and a variation between 0.81 and 0.96 was observed. Weighting these values of ϕNBD→QC with the spectral profile of the solar simulator, an averaged value of 0.87 ± 0.03 was obtained. Determination of ϕNBD→QC was also performed directly in the solar simulator providing a value of 0.97 ± 0.14, in good agreement with the weighted values from the OPO. Photoisomerization quantum yields were found to decrease slightly at higher concentrations. At high concentrations, we found that correcting for the presence of QC was important due to similar absorption coefficients of the NBD and QC isomers at the absorption tail. Cyclability of the forward and backward NBD/QC conversion was studied over several cycles. The NBD/QC couple exhibited excellent thermal stability, but a slight photodegradation per cycle was observed, increasing with the concentration of the sample. This result indicates that the molecules undergo some intermolecular reactions.

A Dihydroazulene-Based Photofluorochromic AIE System for Rewritable 4D Information Encryption.

Dynamic patterns based on luminescent materials play an essential role in the digital age. However, it is still challenging to develop highly emissive photofluorochromic materials with dynamic behaviors to store information with multiple characteristics. Here, we report a series of dihydroazulene-based compounds which show typical aggregation-induced emission (AIE) effect. Moreover, the photo-switching ability of the dihydroazulene units, undergoing light-induced ring-opening, enables photofluorochromic properties. The photofluorochromism also shows quantitively described responses to time and temperature via a reverse ring-closing process. Ultimately, a rewritable 4D information system, embedded with a quick response code, dot matrix with microstructures, color matrix of fluorescence, and time/temperature-dependent intensity change, is established with dynamic patterns. This work not only develops a dynamic AIE skeleton with photofluorochromic properties but also provides a new strategy for information encryption and cybernetics.

The 1,3-dithiol-2-ide carbanion.

1,3-Dithiol-2-ide is a fully unsaturated five-membered heterocycle with a carbanion unit between two of the ring sulfur atoms. Derivatives thereof are important intermediates in synthetic protocols for preparing various 1,4-dithiafulvene (DTF) and tetrathiafulvalene (TTF) compounds by Wittig, Horner-Wadsworth-Emmons, or phosphite-mediated olefination reactions. When considering the electronic properties of DTF, one would usually consider this unit as an electron-donating group as it can form a 6π-aromatic 1,3-dithiolium ring by resonance. Yet, in this review, I will move forward a dual character of the DTF by which it can also act as an electron-withdrawing group, involving formation of the 1,3-dithiol-2-ide. In particular, this electronic effect can be used to explain its ability to promote the electrocyclic ring closure of a vinylheptafulvene into a dihydroazulene. This view on the properties of DTF is very much in line with the dual reactivity of ketene dithioacetals that react with both nucleophiles and electrophiles. Moreover, the 1,3-dithiol-2-ide unit was recently generated in the reduction of an extended and quinoid-like TTF where the core became an aromatic carbo-benzene moiety. This aspect is particularly interesting for future design of extended TTFs that can act as both electron donors and acceptors.

ortho-Substituted 2-Phenyldihydroazulene Photoswitches: Enhancing the Lifetime of the Photoisomer by ortho-Aryl Interactions.

Photochromic molecules are systems that undergo a photoisomerization to high-energy isomers and are attractive for the storage of solar energy in a closed-energy cycle, for example, in molecular solar thermal energy storage systems. One challenge is to control the discharge time of the high-energy isomer. Here, we show that different substituents in the ortho position of a phenyl ring at C-2 of dihydroazulene (DHA-Ph) significantly increase the half-life of the metastable vinylheptafulvene (VHF-Ph) photoisomer; thus, the energy-releasing VHF-to-DHA back-reaction rises from minutes to days in comparison to the corresponding para- and meta-substituted systems. Systems with two photochromic DHA-Ph units connected by a diacetylene bridge either at the para, meta and ortho positions and corresponding to a linear or to a cross-conjugated pathway between the two photochromes are also presented. Here, the ortho substitution was found to compromise the switching properties. Thus, irradiation of ortho-bridged DHA-DHA resulted in degradation, probably due to the proximity of the different functional groups that can give rise to side-reactions.

Core carbo-mer of an Extended Tetrathiafulvalene: Redox-Controlled Reversible Conversion to a carbo-Benzenic Dication.

carbo-Benzene is an aromatic molecule devised by inserting C2 units within each C-C bond of the benzene molecule. By integrating the corresponding carbo-quinoid core as bridging unit in a π-extended tetrathiafulvalene (exTTF), it is shown that a carbo-benzene ring can be reversibly formed by electrochemical reduction or oxidation. The so-called carbo-exTTF molecule was thus experimentally prepared and studied by UV-visible absorption spectroscopy and cyclic voltammetry, as well as by X-ray crystallography and by scanning tunneling microscopy (STM) on a surface of highly oriented pyrolytic graphite (HOPG). The molecule and its oxidized and reduced forms were subjected to a computational study at the density functional theory (DFT) level, supporting carbo-aromaticity as a driving force for the formation of the dication, radical cation, and radical anion. By allowing co-planarity of the dithiolylidene rings and carbo-quinoidal core, carbo-exTTFs present a promising new class of redox-active systems.

Toward Redox-Active Indenofluorene-Extended Tetrathiafulvalene Oligomers-Synthesis and Studies of Dimeric Scaffolds.

The promotion of mixed-valence interactions between redox-active, π-conjugated scaffolds is of interest when developing new conducting or electrochromic materials as well as in the construction of redox-controlled supramolecular assemblies. In this work, dimeric structures of the redox-active indenofluorene-extended tetrathiafulvalene (IF-TTF) unit were synthesized in a stepwise protocol. The synthesis relied on the development of a new unsymmetrical IF-TTF building block by a combination of phosphite-mediated and Horner-Wadsworth-Emmons reactions for introduction of the dithiafulvene units. The redox properties were studied by cyclic voltammetry, where it was observed that a first one-electron oxidation, corresponding to a mixed-valence state, occurs at a significantly lower potential when the IF-TTF unit is incorporated into a dimer, compared to a monomer analogue. This result indicates that locking the redox-active IF-TTF units in close proximity promotes intramolecular mixed-valence interactions. A computational study was also conducted, supporting the involvement of intramolecular interactions.

Establishing linear-free-energy relationships for the quadricyclane-to-norbornadiene reaction.

The kinetics of the thermal quadricyclane-to-norbornadiene (QC-to-NBD) isomerization reaction was studied for a large selection of derivatives where the one NBD double bond contains a cyano and aryl substituent of either electron-withdrawing or -donating character. While the kinetics data did not satisfy a linear-free-energy-relationship for all the derivatives based on Hammett σ values, we found individual linear relationships for derivatives containing either electron-withdrawing or electron-donating para substituents on the aryl group; with the most electron-witdrawing substituent in the one series and with the most electron-donating substituent in the other providing the fastest reaction (corresponding to opposite slopes of the Hammett plots). All data were well described, however, by a linear relationship when using Creary radical values; the correlation could be slightly improved by using a combination of σ and values (used in ratio of 0.104 : 1). The results imply a combination of polar and free radical effects for the isomerization reaction of this specific class of derivatives, with the latter playing the most significant role. The NBD derivatives were prepared by Diels-Alder cycloaddition reactions between cyclopentadiene and 3-arylpropiolonitriles, and in the case of bromophenyl derivatives further cyanation and Sonogashira coupling reactions were performed.

Novel synthetic strategy towards subphthalocyanine-functionalized acetylenic scaffolds via various dibromo-enynes.

Boron subphthalocyanine (SubPc) is a strong chromophore with interesting applications in the field of functional materials and can be synthetically modified in both the peripheral and axial positions, allowing tuning of optical and redox properties. Herein we present novel acetylenic scaffolds where SubPc units are bridged via acetylenic moieties at the boron atoms. Specifically, we show that dibromo-functionalized enyne and enediyne units (vinylic dibromides) can be attached to one or two SubPc boron atoms using an AlCl3-mediated alkynylation protocol of trimethylsilyl-protected alkynes, and such compounds can conveniently be employed for further Sonogashira or Glaser-Hay coupling reactions. Thereby, new tetraethynylethene (TEE) - SubPc scaffolds were obtained. The degree of communication between two SubPc units incorporated in dimeric scaffolds was investigated by cyclic voltammetry. When bridged by one TEE unit, the oxidations of the SubPc units occurred sequentially, while the two SubPc units behaved as independent redox centers when separated by two TEE units.

Donor-Acceptor Substituted Benzo-, Naphtho- and Phenanthro-Fused Norbornadienes.

The photochromic norbornadiene/quadricyclane (NBD/QC) couple has found interest as a molecular solar thermal energy (MOST) system for storage of solar energy. To increase the energy difference between the two isomers, we present here the synthesis of a selection of benzo-fused NBD derivatives that contain an aromatic unit, benzene, naphthalene or phenanthrene, fused to one of the NBD double bonds, while the carbon atoms of the other double bond are functionalized with donor and acceptor groups. The synthesis protocols involve functionalization of benzo-fused NBDs with bromo/chloro substituents followed by a subjection of these intermediates to a cyanation reaction (introducing a cyano acceptor group) followed by a Sonogashira coupling (introducing an arylethynyl donor group, -CCC6H4NMe2 or -CCC6H4OMe). While the derivatives have good absorption properties in the visible region (redshifted relative to parent system) in the context of MOST applications, they lack the ability to undergo NBD-to-QC photoisomerization, even in the presence of a photosensitizer. It seems that loss of aromaticity of the fused aromatics is too significant to allow photoisomerization to occur. The concept of destroying aromaticity of a neighboring moiety as a way to enhance the energy density of the NBD/QC couple thus needs further structural modifications, in the quest for optimum MOST systems.

Norbornadiene-dihydroazulene conjugates.

The introduction of various photochromic units into the same molecule is an attractive approach for the development of novel molecular solar thermal (MOST) energy storage systems. Here, we present the synthesis and characterisation of a series of covalently linked norbornadiene/dihydroazulene (NBD/DHA) conjugates, using the Sonogashira coupling as the key synthetic step. Generation of the fully photoisomerized quadricyclane/vinylheptafulvene (QC/VHF) isomer was found to depend strongly on how the two units are connected - by linear conjugation (a para-phenylene bridge) or cross-conjugation (a meta-phenylene bridge) or by linking to the five- or seven-membered ring of DHA - as well as on the electronic character of another substituent group on the NBD unit. When the QC-VHF system could be reached, the QC-to-NBD back-reaction occurred faster than the VHF-to-DHA back-reaction, while the latter could be promoted simply by the addition of Cu(i) ions. The absence or presence of Cu(i) can thus be used to control whether heat releases should occur on different or identical time scales. The experimental findings were rationalized in a computational study by comparing natural transition orbitals (NTOs). Moreover, the calculations revealed an energy storage capacity of 106-110 kJ mol-1 of the QC-VHF isomers, which is higher than the sum of the capacities of the individual, separate units. The major contribution to the energy storage relates to the energetic QC form, while the major contribution to the absorption of visible light originates from the DHA photochrome; some of the NBD-DHA conjugates had absorption onsets at 450 nm or beyond.

Dithiafulvene derivatized donor-acceptor norbornadienes with redshifted absorption.

Photoisomerization of norbornadiene (N) to its metastable isomer quadricyclane (Q) has attracted interest as a strategy for harvesting and storing solar energy. For this strategy to mature the absorption maximum of N has to be moved from the UV to the visible region. Here we show that functionalization of the system with dithiafulvene (DTF) electron donors causes remarkable redshifts of various N derivatives. Thus, some derivatives were found to absorb light with an absorption onset up to 556 nm. The incorporation of DTF units comes, however, with a drawback with regard to achieving reversible N-to-Q and Q-to-N isomerizations. For some derivatives, the photoisomerization was completely quenched. The compounds were subjected to a computational study to shed light on the underlying reason for this reluctance to undergo photoisomerization. The computational study revealed that in these systems, the first excited state (S1) is positioned close to or lower than the transition state for photoconversion, effectively blocking a possible conversion to Q, thus revealing a practical challenge for the future design of N-Q energy storage systems with an improved solar spectrum match.

Norbornadiene-Based Photoswitches with Exceptional Combination of Solar Spectrum Match and Long-Term Energy Storage.

Norbornadiene-quadricyclane (NBD-QC) photoswitches are candidates for applications in solar thermal energy storage. Functionally, they rely on an intramolecular [2+2] cycloaddition reaction, which couples the S0 landscape on the NBD side to the S1 landscape on the QC side of the reaction and vice-versa. This commonly results in an unfavourable correlation between the first absorption maximum and the barrier for thermal back-conversion. This work demonstrates that this correlation can be counteracted by using steric repulsion to hamper the rotational motion of the side groups along the back-conversion path. It is shown that this modification reduces the correlation between the effective back-conversion barrier and the first absorption maximum and also increases the back-conversion entropy. The resulting molecules exhibit exceptionally long half-lives for their metastable forms without significantly affecting other properties, most notably solar spectrum match and storage density.

Synthesis and Properties of Subphthalocyanine-Tetracyanobutadiene-Ferrocene Triads.

A series of boron subphthalocyanine-tetracyanobutadiene-ferrocene (SubPc-TCBD-Fc) triads was synthesized by subjecting SubPcs with a ferrocenylethynyl substituent at either the axial or peripheral position to a [2 + 2] cycloaddition reaction with tetracyanoethylene followed by retroelectrocyclization. The ferrocenylethynyl unit was introduced at the axial position (at the boron atom) by a simple aluminum chloride-mediated alkynylation reaction, while functionalization at the SubPc periphery was accomplished by a Sonogashira coupling reaction. The conversion of one alkyne unit into a TCBD unit in combination with the location of the resulting TCBD-Fc moiety was found to have a strong influence on the optical and redox properties, which is ascribed to very different ground-state interactions between the individual donor/acceptor systems. The first electrochemical oxidation could thus be anodically shifted by as much as 0.4 V from the strongest donor molecule (with most unperturbed ferrocene character) to the poorest donor molecule (with strongly perturbed ferrocene character). Six redox states could be reached reversibly for the SubPc-TCBD-Fc triads, -3, -2, -1, 0, + 1, + 2, and for one compound the formation of a tetraanion persistent at the time scale of slow scan voltammetry was observed.

Heteroaryl-linked norbornadiene dimers with redshifted absorptions.

Development of Molecular Solar Thermal (MOST) systems for harvesting and storing solar energy is based on molecular photoswitches that undergo photoisomerizations to metastable isomers. One challenge is to achieve low-molecular weight molecules that absorb at sufficiently long wavelengths to match the solar spectrum. Here we show that this can be achieved by linking two norbornadiene (NBD) photoswitches to a central heterocycle, thiophene or carbazole, via alkyne appendages. In this approach, the same heteroaryl is used to tune the properties of two photoswitches at the same time, thereby keeping the molecular weight as low as possible. A series of NBD dimers was prepared by Sonogashira coupling reactions, and these compounds showed remarkable redshifted absorptions, with onsets of absorption as high as 468 nm, and thermal half-lives ranging from 44 seconds to 16 hours.