Determination of the glycoprotein specificity of lectins on cell membranes through oxidative proteomics

The cell membrane is composed of a network of glycoconjugates including glycoproteins and glycolipids that presents a dense matrix of carbohydrates playing critical roles in many biological processes. Lectin-based technology has been widely used to characterize glycoconjugates in tissues and cell lines. However, their specificity toward their putative glycan ligand and sensitivity in situ have been technologically difficult to study. Additionally, because they recognize primarily glycans, the underlying glycoprotein targets are generally not known. In this study, we employed lectin proximity oxidative labeling (Lectin PROXL) to identify cell surface glycoproteins that contain glycans that are recognized by lectins. Commonly used lectins were modified with a probe to produce hydroxide radicals in the proximity of the labeled lectins. The underlying polypeptides of the glycoproteins recognized by the lectins are oxidized and identified by the standard proteomic workflow. As a result, approximately 70% of identified glycoproteins were oxidized in situ by all the lectin probes, while only 5% of the total proteins were oxidized. The correlation between the glycosites and oxidation sites demonstrated the effectiveness of the lectin probes. The specificity and sensitivity of each lectin were determined using site-specific glycan information obtained through glycomic and glycoproteomic analyses. Notably, the sialic acid-binding lectins and the fucose-binding lectins had higher specificity and sensitivity compared to other lectins, while those that were specific to high mannose glycans have poor sensitivity and specificity. This method offers an unprecedented view of the interactions of lectins with specific glycoproteins as well as protein networks that are mediated by specific glycan types on cell membranes.

A lectin proximity oxidative labeling (Lectin PROXL) tool was developed to identify cell surface glycoproteins that contain glycans that are recognized by lectins.     

Biomimetic nanochannels for the discrimination of sialylated glycans via a tug-of-war between glycan binding and polymer shrinkage

Sialylated glycans that are attached to cell surface mediate diverse cellular processes such as immune responses, pathogen binding, and cancer progression. Precise determination of sialylated glycans, particularly their linkage isomers that can trigger distinct biological events and are indicative of different cancer types, remains a challenge, due to their complicated composition and limited structural differences. Here, we present a biomimetic nanochannels system integrated with the responsive polymer polyethyleneimine-g-glucopyranoside (Glc-PEI) to solve this problem. By using a dramatic “OFF–ON” change in ion flux, the nanochannels system achieves specific recognition for N-acetylneuraminic acid (Neu5Ac, the predominant form of sialic acid) from various monosaccharides and sialic acid species. Importantly, different “OFF–ON” ratios of the conical nanochannels system allows the precise and sensitive discrimination of sialylated glycan linkage isomers, α2–3 and α2–6 linkage (the corresponding ion conductance increase ratios are 96.2% and 264%, respectively). Analyses revealed an unusual tug-of-war mechanism between polymer-glycan binding and polymer shrinkage. The low binding affinity of Glc-PEI for the α2–6-linked glycan caused considerable shrinkage of Glc-PEI layer, but the high affinity for the α2–3-linked glycan resulted in only a slight shrinkage. This competition mechanism provides a simple and versatile materials design principle for recognition or sensing systems that involve negatively charged target biomolecules. Furthermore, this work broadens the application of nanochannel systems in bioanalysis and biosensing, and opens a new route to glycan analysis that could help to uncover the mysterious and wonderful glycoworld.

A glycan-responsive polymer-modified nanochannels system enables the precise discrimination of sialylated glycan linkage isomers via the different “OFF–ON” changes resulting from a “tug-of-war” between polymer-glycan binding and polymer shrinkage.     

Iron-catalyzed remote functionalization of inert C(sp3)–H bonds of alkenes via 1,n-hydrogen-atom-transfer by C-centered radical relay

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp³ C-centered radical to promote selective cleavage of inert C(sp³)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF₃-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

Remote functionalization of inert C(sp³)–H bonds is described via iron-catalyzed sp³ C-centered radical relay.     

Pressure-and temperature induced phase transitions,piezochromism, NLC behaviour and pressure controlled Jahn–Teller switching in a Cu-based framework

In situ single-crystal diffraction and spectroscopic techniques have been used to study a previously unreported Cu-framework bis[1-(4-pyridyl)butane-1,3-dione]copper(ii) (CuPyr-I). CuPyr-I was found to exhibit high-pressure and low-temperature phase transitions, piezochromism, negative linear compressibility, and a pressure induced Jahn–Teller switch, where the switching pressure was hydrostatic media dependent.

In situ high-pressure single-crystal diffraction and spectroscopic techniques have been used to study a previously unreported Cu-framework bis[1-(4-pyridyl)butane-1,3-dione]copper(ii) (CuPyr-I).

High-pressure crystallographic experiments over the last 25 years or so have proved to be a unique tool in probing the mechanical properties of the organic solid state,¹ metal-complexes, and 2D/3D coordination compounds.² In particular, high-pressure techniques have been used to study an array of mechanical and chemical properties of crystals, such as changes in electrical and thermal conductivity,³ pressure-induced melting,⁴ solubility,⁵ amorphisation,⁶ post-synthetic modification,⁷ and chemical reactions such as polymerisation,⁸ cycloaddition⁹ and nanoparticle formation.¹⁰ Previous high-pressure experiments on porous metal-organic framework (MOF) materials have shown that on loading a diamond anvil cell (DAC) with a single-crystal or polycrystalline powder, the hydrostatic medium that surrounds the sample (to ensure hydrostatic conditions) can be forced inside the pores on increasing pressure, causing the pore and sample volume to increase with applied pressure.¹¹ This technique has also been used to determine the position of CH₄ and CO₂ molecules inside the small pores of a Sc-based MOF at room temperature using a laboratory X-ray diffractometer, and has proved useful in experimentally determining the maximum size of guest molecules that can penetrate into a pore.¹²On direct compression of more dense frameworks, negative linear compressibility (NLC) has also been observed, which results in an expansion of one or more of the unit cell dimensions with an overall contraction in volume. Such changes in the compressibility behaviour of metal-containing framework materials is usually as a result of common structural motifs which rotate or bend in order to accommodate increases in length along particular crystallographic directions.¹³ Changes in coordination environment can also be induced at pressure, as metal–ligand bonds are more susceptible to compression than covalent bonds.^2a In previous high pressure studies on metal complexes or coordination compounds, in which the metal ion has an asymmetric octahedral environment caused by Jahn–Teller (JT) distortions for example (such as those observed in Cu²⁺ and Mn³⁺ complexes), the application of pressure can result in compression of the JT axis, and can even be switched to lie along another bonding direction within the octahedron.¹⁴ Such distortions often result in piezochromism, often observed within a single crystal.¹⁵Here, we present a high-pressure crystallographic study on a novel and unreported Cu-framework bis[1-(4-pyridyl)butane-1,3-dione]copper(ii) (hereafter referred to as CuPyr-I). On application of pressure, CuPyr-I is highly unusual in that it demonstrates several of these phenomena within the same framework, including a single-crystal to single-crystal phase transition, a switching of the JT axis that depends on the hydrostatic medium used to compress the crystal, piezochromism and NLC behaviour. To date, we are unaware of any other material which exhibits all of these phenomena, with the first ever reported hydrostatic media ‘tuneable’ JT-switching.Under ambient temperature and pressure CuPyr-I crystallises in the rhombohedral space group R$\bar{3}$ (a/b = 26.5936(31) Å, c = 7.7475(9) Å). Each Cu-centre is coordinated to four 1-(4-pyridyl)butane-1,3-dione linkers, two of these ligands are bound through the dione O-atoms, with the final two bonding through the N-atom of the pyridine ring to form a 3D polymer. The crystal structure of CuPyr-I is composed of an interpenetration of these 3D polymers to form one-dimensional porous channels (∼2 Å in diameter) that run along the c-axis direction (Fig. 1).Open in a separate windowFig. 1Ball and stick model showing the coordination environment around the Cu²⁺ ion in CuPyr-I, and 3D-pore structure as viewed along the c-axis direction. The yellow sphere represents the available pore-space. Colour scheme is red: oxygen, blue: nitrogen, black: carbon, white: hydrogen and cyan: copper. The Cu²⁺ octahedron is illustrated in green.On increasing pressure from 0.07 GPa to 1.56 GPa using Fluorinert FC-70 (a mixture of large perfluorinated hydrocarbons) as a hydrostatic medium, compression of the framework occurs, resulting in a 9.89% reduction in volume, while the a/b-axes and c-axis are reduced by 4.46% and 1.25% respectively (Fig. 2 (blue triangles) and Table S1^†).Open in a separate windowFig. 2 a/b and c-axes as a function of pressure in a hydrostatic medium of FC-70 (blue triangles) and MeOH (red/black circles). The vertical line indicates the transition from CuPyr-I (red circles) to CuPyr-II (black circles) above 2.15 GPa. Errors in cell-lengths are smaller than the symbols plotted.On increasing pressure to 1.84 GPa, the framework became amorphous, though this is unsurprising as the hydrostatic limit for FC-70 is ∼2 GPa, and compression of frameworks in non-hydrostatic conditions usually results in amorphisation.¹⁶ On increasing pressure to 1.56 GPa, the three-symmetry independent Cu–O/N bond lengths to the ligand were monitored (Fig. 3 and Table S5^†). Under ambient pressure conditions, the two Cu–N1 pyridine bonds are longer than the four Cu–O1/O2 dione bonds, typical for an elongated JT distorted Cu²⁺ complex. However, on increasing pressure the direction of the JT axis gradually changed from Cu–N1 to the Cu–O1 bond (the dione oxygen in the 3-position), becoming equidistant at ∼0.57 GPa. By 1.56 GPa, the lengths of the Cu–N1 and Cu–O1 bonds had steadily reduced and increased by 12.3% and 8.9%, respectively. Throughout this the Cu–O2 bond remained essentially unchanged.Open in a separate windowFig. 3Cu–O1 (orange), Cu–N1 (blue) and Cu–O2 (green) bond lengths on increasing pressure in both FC-70 (triangles and dashed lines) and MeOH (circles and solid lines).Pressure induced JT switching has been observed in other systems, including a Mn₁₂ single-molecule magnet cluster that re-orientates the JT axis on one of the Mn centres at 2.5 GPa.^14a A similar transition was also observed in [CuF₂(H₂O)₂(pyz)] (pyz = pyrazine) and Rb₂CuCl₄(H₂O)₂,¹⁵ where the JT axis was reoriented from the Cu–N bond to the perpendicular Cu–O bond, though this occurs during a crystallographic phase transition at 1.8 GPa.¹⁸ Here, in CuPyr-I, no phase transition takes place, and unusually the JT switching appears to occur progressively on increasing pressure with no phase transition.^14bUsing methanol (MeOH) as the hydrostatic medium, CuPyr-I was compressed in two separate experiments, from 0.52 GPa to 5.28 GPa using synchrotron radiation, and from 0.34 GPa to 2.95 GPa using a laboratory X-ray diffractometer. On increasing pressure to 2.15 GPa, the a/b and c-axes compressed by 6.22% and 0.39% respectively (Fig. 2, Tables S2 and S3^†). On increasing pressure from 2.15 GPa to 2.78 GPa, CuPyr-I underwent a single-crystal to single-crystal isosymmetric phase transition to a previously unobserved phase (hereafter referred to as CuPyr-II).The transition to CuPyr-II resulted in a doubling of the a/b-axes, whilst the c-axis remained essentially unchanged. On increasing the pressure further, the a/b-axes continued to be compressed, whilst the c-axis increased in length, exhibiting negative linear compressibility (NLC) until the sample became amorphous at 5.28 GPa. The diffraction data were of poor quality after the phase transition, and only the connectivity of the CuPyr-II phase could be determined at 3.34 GPa. Above 3.34 GPa, only unit cell dimensions could be extracted. The occurrence of positive linear compressibility (PLC) followed by NLC is unusual in a framework material, and we could find only a few examples in the literature where this occurs.¹⁹During the NLC, the c-axis expanded by 1.46%, to give a compressibility of K_NLC = −5.3 (0.8) TPa⁻¹ (Δp = 2.23–4.90 GPa). K_NLC is calculated using the relationship K = −1/l(∂l/∂p)_T, where l is the length of the axis and (∂l/∂p)_T is the length change in pressure at constant temperature.²⁰ The value of K_NLC here is rather small compared to the massive NLC behaviour observed in the low pressure phase of Ag₃[Co(CN)₆]⁹ (K_NLC = −76(9) TPa⁻¹, Δp = 0–0.19 GPa) or the flexible MOF MIL-53(Al) (K_NLC = −28 TPa⁻¹, Δp = 0–3 GPa) for example,^17b and is much more comparable to the dense Zn formate MOF [NH₄][Zn(HCOO)₃] (−1.8(8) TPa⁻¹ (Δp = 0–0.94 GPa)).²¹ Because of the quality of the data, the exact nature, or reason for the NLC in CuPyr-II is unknown, although we aim to investigate this in the future.On increasing pressure using MeOH, the JT axis was again supressed on compression, with the Cu–N1 bond reducing in length by 0.288 Å (12%) between 0.34 and 2.15 GPa, while the Cu–O1 bond length increased by 0.216 Å (11%). The pressure at which Cu–N1 and Cu–O1 became equidistant was 1.28 GPa, measuring 2.140(5) Å and 2.131(6) Å respectively (Fig. 3 and Table S6^†). Across the entire pressure range, little to no compression or expansion was observed in the Cu–O2 bond in the 1-position of the dione in CuPyr-I, the same trend observed when compressed in FC-70. The JT switching pressure in MeOH however was 0.71 GPa higher than observed by direct compression in FC-70 (0.57 GPa). This, to our knowledge, is the first time that pressure induced JT switching has been observed to be hydrostatic media dependent.Changes to the Cu–N and Cu–O bond lengths were supported by high-pressure Raman spectroscopy of CuPyr-I, using MeOH as the hydrostatic medium (Fig. S10^†). Gradual growth of a shoulder on a band at ∼700 cm⁻¹ during compression is tentatively assigned to the Cu²⁺ coordination environment shifting from elongated to compressed JT distorted geometry. The shouldered peak becomes split above 2 GPa, after which the isosymmetric phase transition occurs.The gradual JT switch is thought to be principally responsible for reversible piezochromism in single crystals of CuPyr-I, which change in colour from green to dark red under applied pressure (Fig. 4b, S1 and S2^†). UV-visible spectroscopy confirms a bariometric blue-shift in the absorption peak at ∼700 nm assigned to d–d electronic transitions, and a red-shift of the tentatively assigned ligand-to-metal charge-transfer (LMCT) edge around 450 nm during the elongated to compressed switch (Fig. 4a and S8^†), accounting for this colour change. The red-shift is observed during compression in both Fluorinert® FC-70 and MeOH hydrostatic media, with a slightly suppressed shift measured in the latter due to filling of the framework pores (Table S2^†). Geometric switching at the metal centre leads to electronic stabilisation of the Cu²⁺ ion, as electrons transfer from higher energy d_x²−y² (Cu–O) orbitals to the lower energy d_z² (Cu–N) state (Fig. S7^†), evidenced by the blue-shift of the d–d intraconfigurational band as the d_z² (Cu–N) is progressively mixing with d_x²−y² (Cu–O) increasing its energy with respect to the lower energy d_xy and d_xz,yz levels becoming the highest energy level at the nearly compressed rhombic geometry. On the other hand, the redshift in the hesitantly assigned O²⁻ to Cu²⁺ LMCT band below 450 nm is ascribed to increase of the Cu–O bond distance and a likely bandwidth broadening with pressure both yielding a pressure redshift of the absorption band gap edge (Fig. 4a).Open in a separate windowFig. 4(a) UV-visible spectroscopy of CuPyr-I during compression in Fluorinert® FC-70 showing a gradual BLUE-shift in the d–d intraconfigurational band (∼700 nm) and a gradual red-shift of the absorption band assigned to LMCT (∼450 nm) with increasing pressure. (b) Gradual pressure-induced Jahn–Teller switch of the Cu²⁺ octahedral coordination environment in CuPyr-1 from tetragonal elongated (left, green) to rhombic compressed (right, red), causing piezochromism. Atom colouring follows previous figures.Compression of the coordination bonds was not the only distortion to take place in CuPyr-I, with the Cu-octahedra also twisting with respect to the 1-(4-pyridyl)butane-1,3-dione linkers on increasing pressure. Twisting of the Cu-octahedra in CuPyr-I with respect to the dione section of the linker could be quantified by measuring both the ∠N1Cu1O2C4 and the ∠N1Cu1O1C2 torsion angles from the X-ray data, which in MeOH gradually decrease and increase by 12.2° and 7.3°, respectively, to 2.15 GPa (Table S8^†). In FC-70, ∠N1Cu1O2C4 and ∠N1Cu1O1C2 decrease and increase by 5.4° and 2.8°, respectively, to 1.56 GPa. On increasing pressure to 1.57 GPa in a hydrostatic medium of MeOH, a difference of ∼5° for both angles was observed compared to FC-70 at 1.56 GPa. Twisting about the octahedra allows compression of the channels to take place in a ‘screw’ like fashion and has been observed in other porous materials with channel structures.²² The overall effect is to reduce the pore volume, and decrease the size of the channels (Tables S2 and S3^†). Using MeOH as a hydrostatic medium therefore appears to reduce this effect by decreasing the compressibility of the framework.It was not possible to determine the pressure dependence in other longer-chain alcohols, including ethanol (EtOH) and isopropanol (IPA), due to cracking of the crystal upon loading into the diamond anvil cell (Fig. S1^†). We believe this is a result of these longer chain alcohols acting as reducing agents, as indicated by the loss in colour of the crystals.To ascertain the origin of the hydrostatic media-induced change in the JT switching pressure and unit cell compressibility, the pore size and content were monitored as a function of pressure. A dried crystal of CuPyr-I was collected at ambient pressure and temperature in order to compare to the high-pressure data and is included in the ESI.^† The pore volume and electron density were estimated and modelled respectively using the SQUEEZE algorithm within PLATON (Tables S1–S3^†).²³ CuPyr-I under ambient pressure conditions has three symmetry equivalent channels per unit cell with a total volume of ∼1152 ų containing diethyl ether (2.5 wt%) trapped in the pores during the synthesis of the framework, confirmed by TGA analysis (Fig. S6^†).On surrounding the crystal with FC-70, direct compression of the framework occurred. The pore content remained almost constant during compression up to 0.88 GPa, inferring no change in the pore contents. On increasing pressure further to 1.56 GPa, an increase in the calculated electron density was observed (23%), though the data here were of depreciating quality and less reliable. During compression of CuPyr-I in MeOH to 0.52 GPa, the pore volume and electron density in the channels increased by 4.5% and 54%, respectively, reflecting ingress of MeOH into the pores. The electron density in the channels continued to increase to a maximum of 0.466e⁻ A⁻³ by 0.96 GPa, although the pore volume began to decrease at this pressure. The uptake of MeOH into the pores therefore results in the marked decrease in compressibility, as noted above.Previous high-pressure experiments on porous MOFs have resulted in similar behaviour on application of pressure, with the uptake of the media significantly decreasing the compressibility of the framework.²⁴ However, using different hydrostatic media to control the JT switch in any material is, to the best of our knowledge, previously unreported. On increasing pressure above 0.96 GPa, the electron density in the pores decreases, and coincides with a steady reduction in volume of the unit cell. Both an initial increase and then subsequent decrease in uptake of hydrostatic media is common in high-pressure studies of MOFs, and has been seen several times, for example in HKUST-1 (ref. 24c) and MOF-5.^24a The ingress of MeOH into the pores on initially increasing pressure to 0.52 GPa is also reflected in a twisting of the octahedra, in-particular the ∠N1Cu1O2C4 angle decreases by 5.8° in MeOH, whereas on compression in FC-70, little to no change is observed in the ∠N1Cu1O2C4 angle to 1.56 GPa. These angles represent a twisting of the dione backbone, which we speculate must interact with the MeOH molecules which penetrate into the framework.Upon compression in n-pentane, the lightest alkane that is a liquid at ambient temperature, we see different behaviour to that in MeOH or FC-70. Poor data quality permitted only the extraction of unit cell parameters but from this it can be seen that CuPyr-I has undergone the transition to CuPyr-II by 0.77 GPa. This is a significantly lower pressure than is required to induce the phase transition in MeOH (ca. 2.15 GPa). We speculate that this difference in pressure is caused by the n-pentane entering the channels at a lower pressure than MeOH due to the hydrophobic nature of the channels. This can be overcome by MeOH but not until substantially higher pressures, as seen in other MOFs that contain hydrophobic pores.²⁵On undergoing the transition to CuPyr-II at 2.78 GPa the unit cell volume quadruples, resulting in three symmetry independent channels (12 per unit cell), with the % pore volume continuing to decrease (Table S4^†). Additionally, the reflections become much broader, significantly depreciating the data quality. Nevertheless, changes in metal–ligand bond lengths and general packing features can be extracted. In particular, the transition to CuPyr-II results in two independent Cu-centres, with six independent Cu–N/O bond distances per Cu. Each exhibits a continuation of the trend seen in CuPyr-I, with the Cu–O bonds (equivalent to the Cu–O1 bond in CuPyr-I) remaining longer than the JT suppressed Cu–N bonds. However, the transition to CuPyr-II results in both an increase and decrease in three of the four Cu–N and Cu–O bonds respectively, compared to CuPyr-I at 2.15 GPa (Table S6^†). The net result is a framework which contains a Cu-centre where the coordination bonds are more equidistant, while the JT axis becomes much more prominent in the other Cu-centre, with the Cu–O dione bond continuing to increase in length. The data for CuPyr-II depreciates rapidly after the phase transition, and more work would be required to study the effect of the anisotropic compression of the JT axis in CuPyr-II on increasing pressure further.It is difficult to determine the mechanism behind the NLC behaviour observed upon compression of CuPyr-II because the phase transition results in a significant reduction in data quality. Further work will be carried out computationally in order to elucidate the structural mechanism that gives rise to the PLC followed by NLC. However, we propose this effect is inherent to this framework and the ingress of MeOH molecules into the channels allows the retention of crystallinity to allow this behaviour to be observed crystallographically.In order to determine whether the JT switch could be induced by decreasing temperature and remove any effect the ingress of hydrostatic media has into the pores on the JT switch, variable temperature X-ray diffraction measurements were undertaken on a powder and single-crystal sample. On cooling below 175 K and 150 K in a powder and single-crystal sample respectively, a phase transition was observed, however, this was to a completely different triclinic phase, hereafter referred to as CuPyr-III. The transition here appears to occur when the disordered diethyl ether becomes ordered in the pores, confirmed by determination of the structure by single-crystal X-ray diffraction, where the diethylether could be modelled inside the pore-channel (see ESI Sections 7 & 8 for details^†).In conclusion, we have presented a compression study on the newly synthesised Cu-based porous framework bis[1-(4-pyridyl)butane-1,3-dione]copper(ii), referred to as CuPyr, compressed in FC-70 to 1.56 GPa and MeOH to 4.90 GPa. In both FC-70 and MeOH hydrostatic media, the JT axis, which extends along the Cu–N pyridyl bond, steadily compresses and then switches to lie along one of the Cu–O dione bonds. Compression in MeOH results in ingress of the medium into the framework pores, which increases the JT switching pressure to 1.47 GPa, compared with 0.64 GPa during compression in Fluorinert® FC-70. Interaction of stored MeOH with the host framework prompts twisting of the ligand backbone, which is not observed in the absence of adsorbed guest. Suppression of the JT axis is accompanied by a piezochromic colour change in the single crystals from green to dark red, as confirmed by crystallographic and spectroscopic measurements. Increasing the applied pressure to at least 2.15 GPa causes the framework to undergo an isosymmetric phase transition to a previously unobserved phase, characterised by a doubling of the a/b axes. Between 2.15 GPa and 4.90 GPa, NLC behaviour is observed.This is to the best of our knowledge the first time a phase transition, NLC, piezochromic and pressure induced JT switching behaviour have been observed within the same material. We have also reported for the first time a pressure induced JT axis switch which is hydrostatic media dependent. In further analysis of this system, we intend to study the magnetic properties under ambient and high pressure.     

Dehydrogenation of iron amido-borane and resaturation of the imino-borane complex

We report on the first isolation and structural characterization of an iron phosphinoimino-borane complex Cp*Fe(η²-H₂B NC₆H₄PPh₂) by dehydrogenation of iron amido-borane precursor Cp*Fe(η¹-H₃B–NHC₆H₄PPh₂). Significantly, regeneration of the amido-borane complex has been realized by protonation of the iron(ii) imino-borane to the amino-borane intermediate [Cp*Fe(η²-H₂B–NHC₆H₄PPh₂)]⁺ followed by hydride transfer. These new iron species are efficient catalysts for 1,2-selective transfer hydrogenation of quinolines with ammonia borane.

Dehydrogenation of an amido-borane iron complex provides an imino-borane complex. Regeneration of the amido-borane precursor was achieved by protonation of the imino-borane followed by hydride transfer to the amino-borane intermediate.

Because of relevance to H₂ storage^1–10 and hydrogenation catalysis,^11–15 metal amine-borane complexes^16–18 and their dehydrogenated forms, such as amino-boranes^20–22 and imino-boranes⁴ are arising as a significant family in organometallic chemistry. In transition metal-catalyzed dehydrocoupling of amine-boranes and related transfer hydrogenations, the interactions between the metal and the borane fragment are essential to dehydrogenation and the consequent transformations.^16–20 Specifically, amino-borane complexes containing a M–H₂B NR₂ moiety are the primary dehydrogenated species and are often identified as a resting point in the catalysis (Scheme 1a).^20–22 Management of reversible dehydrogenation–regeneration reactions on a M–BH₂ NR₂ platform could provide a strategy with which to design efficient catalysts capable of operating sustainable syntheses.Open in a separate windowScheme 1Schematic representation of metal-based amine-borane dehydrogenation.Wider exploration of metal amino-borane chemistry is challenging since M–H₂B NH₂ species are very reactive toward H₂ release. In 2010, Aldridge et al. reported the isolation of [(IMes)₂Rh(H)₂(η²-H₂B NR₂)] and [(IMes)₂Ir(H)₂(η²-H₂B NR₂)] from the metal-catalyzed dehydrogenation of R₂HN·BH₃.^21a At the same time, Alcaraz and Sabo-Etienne reported the preparation of (PCy₃)₂Ru(H)₂(η²-H₂B NH_nMe_2−n) (n = 0–2) complexes^22a by the dehydrogenation of amine-boranes with the corresponding ruthenium precursors. Subsequently, a straightforward synthesis of Ru, Rh, and Ir amino-borane complexes by reaction of H₂B NR₂ (R = iPr or Cy) with the bis(hydrogen) complexes of M(H)₂(η²-H₂)₂(PCy₃)₂ or [CpRu(PR₃)₂]⁺ fragments was developed.^21b,22b Turculet et al. have shown that the ruthenium-alkoxide complex is able to activate H₃B·NHR₂ producing hydrido ruthenium complex.²³ Notably, Weller and Macgregor found that dehydrocoupling of ammonia-borane by [Ph₂P(CH₂)₃PPh₂Rh(η⁶-C₆H₅F)] affords a μ-amino-borane bimetallic Rh complex, in which the simplest H₂B NH₂ moiety is trapped on a rhodium dimer.^20aAlthough iron-catalyzed dehydrocoupling of amine-boranes has attracted great interest,^24–29 iron amine-borane complexes, their dehydrogenated derivatives, and especially the catalysis relevant to organic synthesis are largely unexplored. Recently, Kirchner et al. reported a pincer-type iron complex generated by protonation of the borohydride iron complex (PNP)Fe(H)(η²-BH₄) with ammonium salts.³⁰ Inspired by earlier research on M–H₂B NR₂ chemistry, we intended to establish the reversible conversions of amino-borane complexes and their dehydrogenated forms in a synthetic piano-stool iron system. Herein, we report dehydrogenation of iron amido-borane complex Cp*Fe(η¹-H₃B–NHC₆H₄PPh₂) (2) (Cp* = Me₅C₅⁻) to the imino-borane complex Cp*Fe(η²-H₂B NC₆H₄PPh₂) (3), and resaturation of the imino-borane by stepwise protonation and hydride transfer (Scheme 1b). This new class of iron species is capable of catalyzing 1,2-selective transfer hydrogenation of quinolines with H₃N·BH₃.To synthesize the iron amido-borane complex, a new monomer, the iron tetrahydridoborate precursor Cp*Fe(η²-BH₄)(NCMe) (1), was prepared in situ by the reaction of [Cp*Fe(NCMe)₃]PF₆ with Bu₄NBH₄ in acetonitrile at room temperature for 5 min. Such ferrous borohydrides have been documented only rarely,³¹ since they are prone to form polynuclear iron borate clusters.^32,33 The ¹¹B NMR spectrum of the reaction solution shows a quintet at δ 15.4 (J_BH = 88 Hz) for the BH₄⁻ ligand of 1, and this stands in contrast to the signal at δ −32.0 observed for Bu₄NBH₄. Upon storing the reaction mixture at −30 °C overnight, single crystals suitable for X-ray diffraction were obtained. Crystallographic analysis confirmed the structure of 1 as a piano-stool iron tetrahydridoborate compound (ESI, Fig. S1^†).Addition of phosphinoamine ligand 1,2-Ph₂PC₆H₄NH₂ to a solution of 1 in acetonitrile caused an instantaneous color change from deep blue to dark brown (Scheme 2). ESI-MS studies indicated the production of the iron amido-borane compound (2) with m/z = 481.1793 (calcd m/z = 481.1770), which was isolated in 87% yield. NMR spectra showed a boron resonance at δ −17.5, and a phosphorus resonance at δ 85.9. The ¹H NMR spectrum exhibits a characteristic hydride signal at δ −13.98, which is assigned to the bridging hydride Fe–H–B. Owing to exchange between the hydrogen atoms at the boron,³⁴ the terminal B–H resonances in the ¹H NMR spectrum are very broad and are obscured by the distinct Cp* signals. To assign the B–H hydride signals, the deuterated compound Cp*Fe(D₃B–NHC₆H₄PPh₂) (d-2) was synthesized from Cp*Fe(BD₄)(NCMe). In addition to the Fe–D–B signal at δ −13.98, the ²H NMR spectrum of d-2 displayed discrete peaks at δ 2.23 and 0.19 for the terminal B–D hydrides (Fig. 1).Open in a separate windowFig. 1 ²H NMR spectra for dehydrogenation of d-2 to d-3.Open in a separate windowScheme 2Synthetic route to imino-borane complex.When a C₆H₆ solution of 2 was held at 50 °C for 6 h the dehydrogenated imino-borane compound (3) was produced in 92% yield. The ESI-MS spectrum of 3 has a strong peak at m/z 479.1626 (calcd m/z = 479.1637) which can be compared to the peak at m/z = 481.1793 for 2. The isotopic distributions match well with the calculated values (see Fig. S3^†). GC analysis shows that the reaction produced H₂ nearly quantitatively (see Fig. S4^†). In solution, the ³¹P NMR spectrum of 3 displays a sharp signal at δ 71.9, in contrast to the peak at δ 85.9 for 2. The ¹¹B resonance shifts significantly, from δ −17.5 for 2 to δ 42.7 for 3 (Fig. S16^†), and is particularly diagnostic of a three-coordinate boron atom.^21,35 This result indicates the B N double bond character in the dehydrogenated form of the amido-borane complex. In the ¹H NMR spectrum, the Fe–H–B signal was observed at δ −17.91 with the integral of 2H, and no characteristic signal for a terminal B–H hydride was found. To confirm the formation of an imino-borane compound, the hydrogen decoupling was also carried out with compound d-2 and monitored by ²H NMR spectra. Only a deuterium signal was observed at δ −17.91 for Fe–D–B, indicating the formation of d-3 (Fig. 1). When the dehydrogenation was conducted in a J-Young tube in C₆D₆, a characteristic triplet corresponding to HD appeared at δ 4.43 (J_HD = 45 Hz) in the ¹H NMR spectrum (Fig. S18^†).³⁶The structures of 2 and 3 were verified by X-ray crystallographic analysis (Fig. 2). Consistent with NMR spectroscopic analysis, the BH₃ moiety in 2 is stabilized by one of the B–H bonds binding at the Fe–NH unit to form an Fe–H–B–N four-membered metallacycle. This metal–ligand cooperative binding mode increased the B–H bond length in the bridging B–H(1) bond to 1.362 Å vs. 1.129 Å and 1.121 Å for the two terminal B–H bonds. The B–N bond length of 1.545(3) Å in 2 is slightly shorter than that in H₃B·NH₃ (d_B–N = 1.58(2) Å).³⁷ Crystallographic analysis of 3 confirmed an imino-borane complex with a Cp*Fe(η²-H₂B NC₆H₄PPh₂) framework. After dehydrogenation of 2, striking structural changes were observed. The N atom has been become detached from Fe, while the BH₂ fragment acts as a bis(σ-borane) ligand coordinated to the metal center.^21–23 The B–N bond distance of 1.455(5) Å in 3 is shorter by 0.09 Å than that in 2, and is close to that reported for the cyclic trimer borazine (1.4355(21) Å).³⁸ Combined with the NMR results, the B–N bond length in 3 suggests some double bond character.^21,22 As the imino-borane fragment is tethered in the coordination sphere, the boron center adopts a quasi-tetrahedral geometry, and the B–N bond appears to be partially sp³ hybridized. Dehydrogenation of the amido-borane complex also caused the decrease of the Fe⋯B distances from 2.223(3) Å to 2.026(4) Å which is shorter than the sum of the covalent radii of Fe and B atom (2.16 Å), indicating that the borane and the metal are bonded.Open in a separate windowFig. 2Solid-sate structure (50% probability thermal ellipsoids) of (a) complex 2 and (b) 3. For clarity, hydrogen atoms of Cp* and phenyl rings are omitted.Notably, the amido-borane compound 2 can be regenerated by stepwise protonation of 3 and transfer of a hydride (Scheme 3). Complex 3 reacts readily with H(Et₂O)₂BAr^F₄ in C₆H₅F. The reaction solution was analyzed by ESI-MS spectroscopy, which showed an ionic peak at m/z = 480.1726 (calcd m/z = 480.1715), suggesting the formation of [3H]⁺. Alternatively, the reaction of complex 2 with H(Et₂O)₂BAr^F₄ unambiguously provides [3H]⁺ and produces H₂. X-ray crystallographic analysis reveals that the resulting cationic complex [3H]⁺ exhibits a similar framework to its imino-borane precursor (3). The BH₂ moiety retains a binding mode of the bis(σ-BH₂) fashion (Fig. 3). In contrast, the B–N distance in [3H]⁺ (1.586(6) Å) is extended by 0.13 Å and the [3H]⁺ framework becomes much less compact than that of 3. Probably due to the fluxional structure of the seven-membered Fe–P–C–C–N–B(H) ring, the solution of [3H][BAr^F₄] gives broad ¹H NMR resonances even at −60 °C. The phosphorus resonance arose at δ 72.0 as a singlet when the solution sample was cooled to −40 °C (Fig. S20 and S21^†).Open in a separate windowFig. 3Solid-state structures of (a) complex [3H]⁺ and (b) [3H(PPh₃)]⁺. For clarity, counterion [BAr^F₄]⁻, hydrogen atoms of Cp* and phenyl rings have been omitted.Open in a separate windowScheme 3Conversions of iron imino-borane, amino-borane and amido-borane complexes.In [3H]⁺, the boron is coordinatively unsaturated, as manifested by its interaction with a σ-donor. For instance, treatment of 2 with [HPPh₃][BAr^F₄] (pK^MeCN_a = 7.6)³⁹ provides a Ph₃P-stabilized borane complex, [3H(PPh₃)]⁺ (m/z = 742.2620, calcd m/z = 742.2626). The ¹H NMR spectrum of [3H(PPh₃)]⁺ exhibits an NH resonance at δ 4.68, suggesting that protonation occurred at the N site. The distinctive upfield hydride signal for Fe–H–B is observed at δ −15.58. In the ³¹P NMR spectrum, two phosphorus signals at δ 78.90 and −1.26 correspond to the Fe–P and the B–P resonances, respectively. The ¹¹B signal at δ −13.72 indicates a tetracoordinated boron, which is further confirmed by crystallographic analysis of [3H(PPh₃)]⁺ (Fig. 3). In the solid-sate structure, a Ph₃P molecule is bound to the B center (d_B–P = 1.982(4) Å), leading to the formation of a new Fe–H–B–N four-membered metallacycle. As a amido-borane complex, [3H(PPh₃)]⁺ has a B–N bond length of 1.527(5) Å, somewhat shorter than 1.545(3) Å in 2.After attaching a proton at the N atom, we subsequently explored restoration of the original borane moiety. Treatment of freshly prepared [3H][BAr^F₄] in fluorobenzene with catecholborane-NEt₃ adduct (δ_B = 10.56, J_HB = 142.4 Hz)⁴⁰ results in the regeneration of 2, as evidenced by the NMR spectra (Fig. S29 and S30^†). The ¹H NMR spectrum of the reaction mixture displays a characteristic hydride signal at −13.97 ppm, indicating the recovery of the iron amido-borane complex. On the other side, concomitant formation of the borenium ion (δ_B = 13.86) was also observed in the ¹¹B NMR spectrum, which agrees with the hydride transfer from the organohydride reagent to [3H]⁺. It was interesting that the ion [3H]⁺ is stable towards 5,6-dihydrophenanthridine and Hantszch ester. These results indicate that the hydride-donating ability (ΔG_H⁻) of 2 is in the range of 55–59 kcal mol⁻¹.⁴¹ The reactive nature of the hydride in 2 was demonstrated by the reaction with [HPPh₃][BAr^F₄], which produces [3H(PPh₃)]⁺ and releases H₂ (Scheme 3).1The metal amine-borane complexes and their dehydrogenated derivatives are implicated throughout the catalytic cycle of amine-borane dehydrogenation. We found both the iron complexes 2 and 3 are efficient catalysts for H₃N·BH₃ dehydrogenation at room temperature. In the presence of 1 mol% catalyst, a THF solution of H₃N·BH₃ (1.0 mmol) generates about 2.2 equivalent of H₂ within 6 h based on GC quantification (Fig. S33^†). More importantly, such catalytic dehydrocoupling systems allow for selective transfer hydrogenation of quinolines to dihydroquinolines, which are valuable synthons leading to many bio-active compounds.⁴² For instance, addition of methyl-6-quinolineacetate (4) to the catalytic system containing one equiv. of H₃N·BH₃ and 1 mol% of 3 gave 1,2-dihydro-methyl-6-quinolineacetate (5) in excellent yield within 6 h (eqn (1)). The outcome of this reaction was unaffected by switching the catalyst from 3 to 2, or by use of excess reducing agent or by an increase in the reaction temperature (Table S1^†).     

Regioselective B(3,4)–H arylation of o-carboranes by weak amide coordination at room temperature

Palladium-catalyzed regioselective di- or mono-arylation of o-carboranes was achieved using weakly coordinating amides at room temperature. Therefore, a series of B(3,4)-diarylated and B(3)-monoarylated o-carboranes anchored with valuable functional groups were accessed for the first time. This strategy provided an efficient approach for the selective activation of B(3,4)–H bonds for regioselective functionalizations of o-carboranes.

B–H: site-selective B(3,4)–H arylations were accomplished at room temperature by versatile palladium catalysis enabled by weakly coordinating amides.

o-Carboranes, icosahedral carboranes – three-dimensional arene analogues – represent an important class of carbon–boron molecular clusters.¹ The regioselective functionalization of o-carboranes has attracted growing interest due to its potential applications in supramolecular design,² medicine,³ optoelectronics,⁴ nanomaterials,⁵ boron neutron capture therapy agents⁶ and organometallic/coordination chemistry.⁷ In recent years, transition metal-catalyzed cage B–H activation for the regioselective boron functionalization of o-carboranes has emerged as a powerful tool for molecular syntheses. However, the 10 B–H bonds of o-carboranes are not equal, and the unique structural motif renders their selective functionalization difficult, since the charge differences are very small and the electrophilic reactivity in unfunctionalized o-carboranes reduces in the following order: B(9,12) > B(8,10) > B(4,5,7,11) > B(3,6).⁸ Therefore, efficient and selective boron substitution of o-carboranes continues to be a major challenge.Recently, transition metal-catalyzed carboxylic acid or formyl-directed B(4,5)–H functionalization of o-carboranes has drawn increasing interest, since it provides an efficient approach for direct regioselective boron–carbon and boron–heteroatom bond formations (Scheme 1a),⁹ with major contributions by the groups of Xie,¹⁰ and Yan,¹¹ among others.¹² Likewise, pyridyl-directed B(3,6)–H acyloxylations (Scheme 1b),¹³ and amide-assisted B(4,7,8)–H arylations¹⁴ (Scheme 1c) have been enabled by rhodium or palladium catalysis, respectively.^15,16 Despite indisputable progress, efficient approaches for complementary site-selective functionalizations of o-carboranes are hence in high demand.¹⁷ Hence, metal-catalyzed position-selective B(3,4)–H functionalizations of o-carboranes have thus far not been reported.Open in a separate windowScheme 1Chelation-assisted transition metal-catalyzed cage B–H activation of o-carboranes.Arylated compounds represent key structural motifs in inter alia functional materials, biologically active compounds, and natural products.¹⁸ In recent years, transition metal-catalyzed chelation-assisted arylations have received significant attention as environmentally benign and economically superior alternatives to traditional cross-coupling reactions.¹⁹ Within our program on sustainable C–H activation,²⁰ we have now devised a protocol for unprecedented cage B–H arylations of o-carboranes with weak amide assistance, on which we report herein. Notable features of our findings include (a) transition metal-catalyzed room temperature B–H functionalization, (b) high levels of positional control, delivering B(3,4)-diarylated and B(3)-monoarylated o-carboranes, and (c) mechanistic insights from DFT computation providing strong support for selective B–H arylation (Scheme 1d).We initiated our studies by probing various reaction conditions for the envisioned palladium-catalyzed B–H arylation of o-carborane amide 1a with 1-iodo-4-methylbenzene (2a) at room temperature (Tables 1 and S1^†). We were delighted to observe that the unexpected B(3,4)-di-arylated product 3aa was obtained in 59% yield in the presence of 10 mol% Pd(OAc)₂ and 2 equiv. of AgTFA, when HFIP was employed as the solvent, which proved to be the optimal choice (entries 1–5).²¹ Control experiments confirmed the essential role of the palladium catalyst and silver additive (entries 6–7). Further optimization revealed that AgOAc, Ag₂O, K₂HPO₄, and Na₂CO₃ failed to show any beneficial effect (entries 8–11). Increasing the reaction temperature fell short in improving the performance (entries 12 and 13). The replacement of the amide group in substrate 1a with a carboxylic acid, aldehyde, ketone, or ester group failed to afford the desired arylation product (see the ESI^†). We were pleased to find that the use of 1.0 equiv. of trifluoroacetic acid (TFA) as an additive improved the yield to 71% (entry 14). To our delight, replacing the silver additive with Ag₂CO₃ resulted in the formation of B(3)–H mono-arylation product 4aa as the major product (entries 15–16).Optimization of reaction conditions^a

“Anti-electrostatic” halogen bonding in solution

Halogen-bonded (XB) complexes between halide anions and a cyclopropenylium-based anionic XB donor were characterized in solution for the first time. Spontaneous formation of such complexes confirms that halogen bonding is sufficiently strong to overcome electrostatic repulsion between two anions. The formation constants of such “anti-electrostatic” associations are comparable to those formed by halides with neutral halogenated electrophiles. However, while the latter usually show charge-transfer absorption bands, the UV-Vis spectra of the anion–anion complexes examined herein are determined by the electronic excitations within the XB donor. The identification of XB anion–anion complexes substantially extends the range of the feasible XB systems, and it provides vital information for the discussion of the nature of this interaction.

Spontaneous formation of “anti-electrostatic” complexes in solution demonstrates that halogen bonding can be sufficiently strong to overcome anion–anion repulsion when the latter is attenuated by the polar medium.

Halogen bonding (XB) is an attractive interaction between a Lewis base (LB) and a halogenated compound, exhibiting an electrophilic region on the halogen atom.¹ It is most commonly related to electrostatic interaction between an electron-rich species (XB acceptor) and an area of positive electrostatic potential (σ-holes) on the surface of the halogen substituent in the electrophilic molecule (XB donor).² Provided that mutual polarization of the interacting species is taken into account, the σ-hole model explains geometric features and the variation of stabilities of XB associations, especially in the series of relatively weak complexes.³ Based on the definition of halogen bonding and its electrostatic interpretation, this interaction is expected to involve either cationic or neutral XB donors. Electrostatic interaction of anionic halogenated species with electron-rich XB acceptors, however, seems to be repulsive, especially if the latter are also anionic. Yet, computational analyses predicted that halogen bonding between ions of like charges, called “anti-electrostatic” halogen bonding (AEXB),⁴ can possibly be formed^5–12 and the first examples of AEXB complexes formed by different anions, i.e. halide anions and the anionic iodinated bis(dicyanomethylene)cyclopropanide derivatives 1 (see Scheme 1) or the anionic tetraiodo-p-benzoquinone radical, were characterized recently in the solid state.^13,14 The identification of such complexes substantially extends the range of feasible XB systems, and it provides vital information for the discussion of the nature of this interaction. Computational results, however, significantly depend on the used methods and applied media (gas phase vs. polar environment and solvation models) and the solid state arrangements of the XB species might be affected by crystal forces and/or counterions. Unambiguous confirmation of the stability of the halogen-bonded anion–anion complexes and verification of their thermodynamic characteristics thus requires experimental characterization of the spontaneous formation of such associations in solution. Still, while the solution-phase complexes formed by hydrogen bonding between two anionic species were reported previously,^15–17 there is currently no example of “anti-electrostatic” XB in solution.Open in a separate windowScheme 1Structures of the XB donor 1 and its hydrogen-substituted analogue 2.To examine halogen bonding between two anions in solution, we turn to the interaction between halides and 1,2-bis(dicyanomethylene)-3-iodo-cyclopropanide 1 (Scheme 1).^‡ Even though this compound features a cationic cyclopropenylium core, it is overall anionic, and calculations have demonstrated that its electrostatic potential is universally negative across its entire surface.¹³ The solution of 1 (with tris(dimethylamino)cyclopropenium (TDA) as counterion) in acetonitrile is characterized by an absorption band at 288 nm with ε = 2.3 × 10⁴ M⁻¹ cm⁻¹ (Fig. 1). As LB, we first applied iodide anions taken as a salt with n-tetrabutylammonium counter-ion, Bu₄NI. This salt does not show absorption bands above 290 nm, but its addition to a solution of 1 led to a rise of absorption in the 290–350 nm range (Fig. 1). Subtraction of the absorption of the individual components from that of their mixture produced a differential spectrum which shows a maximum at about 301 nm (insert in Fig. 1). At constant concentration of the XB donor (1) and constant ionic strength, the intensity of the absorption in the range of 280–300 nm (and hence differential absorbance, ΔAbs) rises with increasing iodide concentration (Fig. S1 in the ESI^†). This suggests that the interaction of iodide with 1 results in the formation of the [1, I⁻]-complex which shows a higher absorptivity in this spectral range (eqn (1)):1 + X⁻ ⇌ [1, X⁻]1Open in a separate windowFig. 1Spectra of acetonitrile solutions with constant concentration of 1 (0.60 mM) and various concentrations of Bu₄NI (6.0, 13, 32, 49, 75, 115 and 250 mM, solid lines from the bottom to the top). The dashed lines show spectra of the individual solutions 1 (c = 0.60 mM, red line) and Bu₄NI (c = 250 mM, blue line). The ionic strength was maintained using Bu₄NPF₆. Insert: Differential spectra of the solutions obtained by subtraction of the absorption of the individual components from the spectra of their corresponding mixtures.To clarify the mode of interaction between 1 and iodide in the complex, we also performed analogous measurements with the hydrogen-substituted compound 2 (see Scheme 1). The addition of iodide to a solution of 2 in acetonitrile did not increase the absorption in the 280–300 nm spectral range. Instead, some decrease of the absorption band intensity of 2 with the increase of concentration of I⁻ anions was observed (Fig. S2 in the ESI^†). Such changes are related to a blue shift of this band resulting from the hydrogen bonding between 2 and iodide (formation of hydrogen-bonded [2, I⁻] complex is corroborated by the observation of the small shift of the NMR signal of the proton of 2 to the higher ppm values in the presence of I⁻ anions, see Fig. S3 in the ESI^†).^§ Furthermore, since H-compound 2 should be at least as suitable as XB donor 1 to form anion–π complexes with the halide, this finding (as well as solid-state and computational data^¶) rules out that any increase in absorption in this region observed with the I-compound 1 may be due to this alternative interaction.Likewise, the addition of NBu₄I to a solution of TDA cations taken as a salt with Cl⁻ anions did not result in an increase in the relevant region. Hence, we could also rule out anion–π interactions with the TDA counter-ions as source of the observed changes, which is in line with previous reports on the electron-rich nature of TDA.¹⁸All these observations (supported by the computational analysis, vide infra) indicate that the [1, I⁻] complex (eqn (1)) is formed via halogen bonding of I⁻ with iodine substituents in 1. The changes in the intensities of the differential absorption ΔAbs as a function of the iodide concentration (with constant concentration of XB donor (1) as well as constant ionic strength) are well-modelled by the 1 : 1 binding isotherm (Fig. S1 in the ESI^†). The fit of the absorption data produced a formation constant of K = 15 M⁻¹ for the [1, I⁻] complex (Table 1).^|| The overlap with the absorption of the individual XB donor hindered the accurate evaluation of the position and intensity of the absorption band of the corresponding complex which is formed upon LB-addition to 1. As such, the values of Δλ_max shown in Table 1 represent a wavelength of the largest difference in the absorptivity of the [1, I⁻] complex and individual anion 1, and Δε reflects the difference of their absorptivity at this point (see the ESI^† for the details of calculations).Equilibrium constants and spectral characteristics of the complexes of 1 with halide anions X⁻

N-Directed fluorination of unactivated Csp3–H bonds

Site-selective fluorination of aliphatic C–H bonds remains synthetically challenging. While directed C–H fluorination represents the most promising approach, the limited work conducted to date has enabled just a few functional groups as the arbiters of direction. Leveraging insights gained from both computations and experimentation, we enabled the use of the ubiquitous amine functional group as a handle for the directed C–H fluorination of Csp³–H bonds. By converting primary amines to adamantoyl-based fluoroamides, site-selective C–H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes. Computational studies revealed a unique reaction coordinate for the catalytic process and offer an explanation for the high site selectivity.

By converting primary amines to adamantoyl-based fluoroamides, site-selective C–H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes.

Due to the pervasiveness of fluorine atoms in industrially relevant small molecules, all practicing organic chemists appreciate the importance of this element. As a result of its unusual size and electronegativity, fluorine imparts unique physicochemical properties to pendant organic molecules.¹ For example, the strong C–F bond can prevent biological oxidation pathways, thereby thwarting rapid clearance and potentially improving pharmacokinetics of molecules.² Moreover, the installation of fluorine or trifluoromethyl groups, with their strong inductive effects,² can have a profound effect on the pK_a of nearby hydrogen atoms.³ These attributes, among others, have solidified the importance of fluorinated molecules in the medicinal,^1–4 material,⁵ and agrochemical⁶ industries. Yet, the same unique properties that make fluorine atoms attractive chemical modifiers also make their installation difficult. Consequently, new methods for site-selective fluorine incorporation remain highly desirable.⁷Methods to construct Csp²–F bonds traditionally make use of the Balz–Schiemann fluorodediazonization⁸ and halogen exchange (“Halex” process).⁹ Advances in transition metal-mediated fluorination have broadened access to Csp²–F-containing molecules,¹⁰ but methods to access aliphatic fluorides remain limited. Conventional methods to make Csp³–F bonds—such as nucleophilic displacement of alkyl halides¹¹ and deoxyfluorination¹²—can have limited functional group compatibility and unwanted side reactions. A more efficient route to form aliphatic C–F bonds would target the direct fluorination of Csp³–H bonds (Scheme 1).¹³Open in a separate windowScheme 1(a) Previous work on functional-group directed Csp³–H fluorination; (b) our approach to N-directed fluorination.Recent efforts with palladium catalysis employ conventional C–H-metallation strategies to target Csp³–H bonds for fluorination.¹⁴ Alternatively, radical H-atom abstraction can remove the transition metal from the C–H-cleavage step, thereby offering a promising approach for Csp³–H-bond functionalization.¹⁵ With undirected C–H fluorination,¹⁶ however, selectivity remains a challenge in molecules without strength-differentiated Csp³–H bonds.¹⁷ To overcome this, our group pioneered the directed fluorination of benzylic Csp³–H bonds through an iron-catalyzed process that involves 1,5 hydrogen-atom transfer (HAT) to cleave the desired Csp³–H bond.¹⁸ Since this work, other groups have demonstrated directed Csp³–H fluorination based on radical propagation that proceeds through an interrupted Hofmann–Löffler–Freytag (HLF)¹⁹ reaction (Scheme 1a). These examples employ various radical precursors such as enones,²⁰ ketones,²¹ hydroperoxides,²² and carboxamides²³ to direct fluorination to specific Csp³–H bonds. Since amines are ubiquitous in natural products and drugs, we sought to use amines as the building block of our directing group to achieve fluorination of unactivated Csp³–H bonds (Scheme 1b). By using amines as the starting point, one could use the approach in straightforward synthetic planning for the late-stage functionalization of remote C–H bonds.In the design phase of the project, we needed to devise a synthetically tractable N–F system that would enable 1,5-HAT and allow for fluorine transfer (Scheme 1b). To begin, we decided to examine common amine activating groups that would support 1,5-HAT while avoiding undesired radical reactions. The chosen activating group would provide the ideal steric and electronic properties to enable both N–F synthesis and N–F scission for 1,5-HAT. We first examined common acyl groups (e.g., acetyl-, benzoyl, and tosyl-based amides), but these proved unsatisfactory. For example, fluoroamide synthesis was either not achieved or low yielding, and the desired fluorine transfer proceeded with significant side reactions or returned starting material. We then turned our attention to more sterically hindered amides—which allow for higher yielding fluoroamide synthesis. For fluorine transfer, we hypothesized that the increased steric bulk could slow intermolecular H-atom transfer, thereby leading more efficient intramolecular 1,5-HAT. To that end, we were delighted that pivaloyl-based fluoroamide 1a proceeded in 64% yield to form product 2a (Scheme 2a). Interestingly, 7% of 1a underwent fluorination at the tert-butyl group of the pivaloyl—presumably through a 1,4-HAT reaction (2aa, Scheme 2a).²⁴ The problem is further exacerbated when the pivaloyl group is homologated by one methylene—providing only 7% yield of desired 2b with 32% of the fluorination taking place on the iso-pentyl group (2bb, Scheme 2a). In an attempt to “tie back” the pivaloyl group and prevent the undesired fluorination, we employed a cyclopropylmethyl-based fluoroamide but observed no improvement.Open in a separate windowScheme 2(a) The targeted 1,5-fluorination of unactivated aliphatic C–H bonds results in partial fluorination of the amine activating group; (b) DFT studies (uM06/cc-pVTZ(-f)-LACV3P**//uM06/LACVP** level of theory) identified the competing pathways responsible for alternate fluorination; (c) DFT (uM06/cc-pVTZ(-f)-LACV3P**//uM06/LACVP** level of theory) evaluation of adamantoylamides revealed higher transition state energy for 1,4-HAT due to restricted vibrational scissoring (d) adamantoyl-activated octylamine shows no fluorination of the activating group. ^{a 1}H-NMR yield using 1,3,5-trimethoxybenzene as an internal standard. ^{b 19}F-NMR yield using 4-fluorotoluene as an internal standard.At this point, 1a proved most promising for efficient fluorine transfer, as well as being the most synthetically accessible fluoroamide. The increased steric hindrance minimizes N-sulfonylation during fluorination with NFSI, a problem that plagued the synthesis of our previously targeted fluoroamides.¹⁸ Therefore, to further investigate how to improve fluorine transfer from 1a, we decided to model H-abstraction computationally.We hypothesized that the fluorinated side product 2aa was formed after 1,4-HAT. Since 1,4-HAT is rare,²⁴ we employed DFT (see ESI^† for details) to calculate the 5-membered and 6-memebered transition-states for 1,4- and 1,5-HAT, respectively. Surprisingly, we found that the barrier for 1,4 C–H abstraction in 1a was 18.7 kcal mol⁻¹, which was only 2.6 kcal mol⁻¹ higher in energy than the barrier calculated for 1,5 C–H abstraction in the same system (Scheme 2b). This suggested that both processes were competing at room temperature. We attributed the comparable barriers to the flexibility of the tert-butyl group, which undergoes vibrational scissoring to accommodate the C–H abstraction. The transition state distortion is modest and allows the molecule to maintain bond angles close to the ideal 109.5° (Scheme 2b). Based on this insight, we sought to limit the scissoring of the tert-butyl group and prevent the 1,4-HAT that leads to the undesired side product. After investigating several possible candidates, the underutilized adamantoyl group appeared promising. To evaluate the rigidity of adamantane, we calculated the barriers for 1,4- and 1,5-HAT for the adamantoyl-capped octylamine 1c (Scheme 2c). As expected, the barriers for 1,4- and 1,5-HAT differed significantly—with 1,4 C–H abstraction proceeding with a barrier of 25.1 kcal mol⁻¹ and the 1,5-HAT barely changed at 16.4 kcal mol⁻¹—an 8.7 kcal mol⁻¹ difference. Consequently, we synthesized 1c and subjected it to the reaction conditions. Excitingly, the adamantoyl-capped system produced desired product 2c in 75% yield with no fluorination of the adamantyl group (Scheme 2d).Using the newly devised adamantoyl-based fluoroamides, the reaction conditions were optimized. While a range of metal salts, ligands, and radical initiators were evaluated, Fe(OTf)₂ proved unique in catalyzing fluorine transfer with fluoroamides.¹⁸ Catalyst loading of 10 mol% allowed convenient setup and minor deviations above or below this loading had little effect on yield (see ESI^†). Increasing the temperature to 40 °C produced a slight increase in yield (entry 2, Table 1). Likewise, raising the temperature to 80 °C resulted in full conversion of the starting material in 20 minutes with 81% yield of the desired product (entry 3, Table 1). It should be noted that fluorine transfer occurs efficiently at a variety of temperatures with adjustments in reaction time (see ESI^†). Increasing the reaction concentration or changing the solvent resulted in decreased yield (entries 4 and 5, Table 1). Furthermore, the absence of Fe(OTf)₂ leads to no reaction and quantitative recovery of starting material, attesting to the stability of fluoroamides and the effectiveness of Fe(OTf)₂ (entry 6, Table 1).Optimization of pertinent reaction parameters

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI^†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a

Ruthenium-catalyzed formal sp3 C–H activation of allylsilanes/esters with olefins: efficient access to functionalized 1,3-dienes

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields. Mild reaction conditions, less expensive catalysts, and excellent regio- and diastereoselectivity ensure universality of the reaction. In addition, the unique power of this reaction was illustrated by performing the Diels–Alder reaction, and enantioselective synthesis of highly functionalized cyclohexenone and piperidine and finally synthetic utility was further demonstrated by the efficient synthesis of norpyrenophorin, an antifungal agent.

Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields.

1,3-Dienes not only are widespread structural motifs in biologically pertinent molecules but also feature as a foundation for a broad range of chemical transformations.^1–14 Indeed, these conjugated dienes serve as substrates in many fundamental synthetic methodologies such as cycloaddition, metathesis, ene reactions, oxidoreduction, or reductive aldolization. It is well-understood that the geometry of olefins often influences the stereochemical outcome and the reactivity of reactions involving 1,3-dienes.¹⁵ Hence, a plethora of synthetic methods have been developed for the stereoselective construction of substituted 1,3-dienes.^16–24 The past decade has witnessed a huge advancement in the field of metal-catalyzed C–H activation/functionalization.^25–27 Although, a significant amount of work in the field of C(alkyl)–H and C(aryl)–H activation has been reported; C(alkenyl)–H activation has not been explored conspicuously, probably due to the complications caused by competitive reactivity of the alkene moiety, which can make chemoselectivity a significant challenge. Over the past few years, several different palladium-based protocols have been developed for C(alkenyl)–H functionalization, but the reactions are generally limited to employing conjugated alkenes, such as styrenes,^28–31 acrylates/acrylamides,^32–36 enamides,³⁷ and enol esters/ethers.^38,39 To date, only a few reports have appeared in the literature for expanding this reactivity towards non-conjugated olefins, which can be exemplified by camphene dimerization,⁴⁰ and carboxylate-directed C(alkenyl)–H alkenylation of 1,4-cyclohexadienes.⁴¹ In 2009, Trost et al. reported a ruthenium-catalyzed stereoselective alkene–alkyne coupling method for the synthesis of 1,3-dienes.⁴² The same group also reported alkene–alkyne coupling for the stereoselective synthesis of trisubstituted ene carbamates.⁴³ A palladium catalyzed chelation control method for the synthesis of dienes via alkenyl sp² C–H bond functionalization was described by Loh et al.⁴⁴ Recently, Engle and coworkers reported an elegant approach for synthesis of highly substituted 1,3-dienes from two different alkenes using an 8-aminoquinoline directed, palladium(ii)-mediated C(alkenyl)–H activation strategy.⁴⁵ Allyl and vinyl silanes are known as indispensable nucleophiles in synthetic chemistry.⁴⁶ Alder ene reactions of allyl silanes with alkynes are reported for the synthesis of 1,4-dienes.⁴⁷ Innumerable methods are known for the preparation of both allyl and vinyl silanes^48–52 but limitations are associated with many of the current protocols, which impedes the synthesis of unsaturated organosilanes in an efficient manner. Silicon-functionalized building blocks are used as coupling partners in the Hiyama reaction⁵³ and are easily converted into iodo-functionalized derivatives (precursor for the Suzuki cross-coupling reaction), but there is little attention given for the synthesis of functionalized vinyl silanes. Herein, we report a general approach for the stereoselective synthesis of trisubstituted 1,3-dienes by the Ru-catalyzed C(sp³)–H functionalization reaction of allylsilanes (Scheme 1).Open in a separate windowScheme 1Highly stereoselective construction of 1,3-dienes.In 1993, Trost and coworkers reported an elegant method for highly chemoselective ruthenium-catalyzed redox isomerization of allyl alcohols without affecting the primary and secondary alcohols and isolated double bonds.^54,55 Inspired by the potential of ruthenium for such isomerization of double bonds in allyl alcohols, we sought to identify a ruthenium-based catalytic system that can promote isomerization of olefins in allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes. We initiated our studies by choosing trimethylallylsilane 1a and acrylate 2a by using a commercially available [RuCl₂(p-cymene)]₂ catalyst in the presence of AgSbF₆ as an additive and co-oxidant Cu(OAc)₂ in 1,2-DCE at 100 °C. Interestingly, it resulted into direct formation of (2E,4Z)-1,3-diene 3aa as a single isomer in 55% yield. It is likely that this reaction occurs by C(allyl)–H activation of the π-allyl ruthenium complex followed by oxidative coupling with the acrylate and leaving the silyl group intact (Table 1). π-Allyl ruthenium complex formation may be highly favorable due to the α-silyl effect which stabilizes the carbanion forming in situ in the reaction.⁵⁶ Next, the regioselective C–H insertion of vinyl silanes could be controlled by stabilization of the carbon–metal (C–M) bond in the α-position to silicon. This stability arises due to the overlapping of the filled carbon–metal orbital with the d orbitals on silicon or the antibonding orbitals of the methyl–silicon (Me–Si) bond.⁵⁷ The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 3aa. To quantify the C–H activation mediated coupling efficiency, an extensive optimization study was conducted (allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes). The change of solvents from 1,2-DCE to t-AmOH, DMF, dioxane, THF or MeCN did not give any satisfactory result, rather a very sluggish reaction rate or decomposition of starting materials was observed in each case (entry 2–6).Optimization of reaction conditions^a

Achieving high circularly polarized luminescence with push–pull helicenic systems: from rationalized design to top-emission CP-OLED applications

While the development of chiral molecules displaying circularly polarized luminescence (CPL) has received considerable attention, the corresponding CPL intensity, g_lum, hardly exceeds 10⁻² at the molecular level owing to the difficulty in optimizing the key parameters governing such a luminescence process. To address this challenge, we report here the synthesis and chiroptical properties of a new family of π-helical push–pull systems based on carbo[6]helicene, where the latter acts as either a chiral electron acceptor or a donor unit. This comprehensive experimental and theoretical investigation shows that the magnitude and relative orientation of the electric (μ_e) and magnetic (μ_m) dipole transition moments can be tuned efficiently with regard to the molecular chiroptical properties, which results in high g_lum values, i.e. up to 3–4 × 10⁻². Our investigations revealed that the optimized mutual orientation of the electric and magnetic dipoles in the excited state is a crucial parameter to achieve intense helicene-mediated exciton coupling, which is a major contributor to the obtained strong CPL. Finally, top-emission CP-OLEDs were fabricated through vapor deposition, which afforded a promising g_El of around 8 × 10⁻³. These results bring about further molecular design guidelines to reach high CPL intensity and offer new insights into the development of innovative CP-OLED architectures.

A CPL intensity of up to 3 × 10⁻² is achieved in π-extended 6-helicene derivatives, owing to an intense helicene-mediated exciton coupling. Corresponding top-emission CP-OLEDs afforded a promising g_El of around 8 × 10⁻³.

The design of chiral emitters displaying intense circularly polarized luminescence (CPL) has attracted significant interest, thanks to the potential of CP light in a diverse range of applications going from chiroptoelectronics (organic light-emitting diodes (OLEDs), optical information processing, etc.) to bio-imaging and chiral sensing.¹ Recently, designing OLEDs with CP electroluminescence (CP-OLEDs) has emerged as an interesting approach to improve high-resolution display performance. Namely, using unpolarised OLEDs, up to 50% of the emitted light can be lost due to the use of antiglare polarized filters.² In CP-OLEDs, the electro-generated light can pass these filters with less attenuation owing to its circular polarization and thus lead to an increase of the image brightness with lower power consumption.³ To develop CP-OLED devices, the main approach relies on the doping of the device''s emitting layer by a CPL emitter, which should ensure simultaneously high exciton conversion and a high degree of circular polarization. The harvesting of both singlet and triplet excitons has been successfully addressed using either chiral phosphorescent materials or thermally activated delayed fluorescence (CP-TADF) emitters with device efficiencies of up to 32%.⁴ However, the intensity of circularly polarized electroluminescence (CPEL), evaluated by the corresponding dissymmetry factor g_El, remains inefficient and typically falls within the range of 10⁻³ with limited examples reaching g_El > 10⁻² based on polymeric materials and lanthanide complexes.⁵ For CP-OLEDs using a molecular chiral emissive dopant, g_El, defined as the ratio between the intensity difference of left- and right-CPEL, and the total generated electroluminescence, 2(El_L − El_R)/(El_L + El_R), can be generally related to the luminescence dissymmetry factor g_lum measured in diluted solution.² Accordingly, it is of crucial importance to design luminescent molecules with high g_lum values,^3,28a–d,29 in order to reach strong CP electro-luminescence when going to practical devices. However, structural and electronic factors that govern the CPL of chiral compounds are still poorly understood even if a few studies have recently tried to rationalize and establish molecular guidelines to obtain high g_lum values.⁶Our team has contributed to the research in this area by developing extended π-helical molecular architectures resulting from the association of carbo[6]helicene and achiral dyes,⁷ which afforded enhanced chiroptical properties, with notably a g_lum up to 10⁻², owing to an uncommon chiral exciton coupling process mediated by the chiral helicenic unit.⁸ In addition, we also described an unusual solvent effect on the intensity of CPL of π-helical push–pull helicene–naphthalimide derivatives,^7b which showed a decrease of g_lum from 10⁻² to 10⁻³ upon increasing the polarity of solvent.^7b This solvatochromism effect was shown to be related to a symmetry breaking of the chiral excited state before emission,⁹ which modifies the relative intensity of the magnetic (μ_m) and electric (μ_e) dipole transition moments, and the angle, θ, between them (Fig. 1), ultimately impacting g_lum. The latter is well approximated as 4|m|cos θ/(|μ|) for an electric dipole-allowed transition.¹⁰Open in a separate windowFig. 1Chemical structures of “push–pull” 2,15-diethynylhexahelicene-based emitters with their polarized luminescence characteristics including their calculated electric and magnetic transition dipole moments and the angle between them corresponding to the S₁ → S₀ transition.While these results highlight interesting aspects regarding the key parameters influencing the CPL of organic emitters, this type of “helical push–pull design” remains limited to only one example, which render the systematic rationalization of these findings difficult. Accordingly, we decided to develop a complete family of new chiral push–pull compounds to explore the structural and electronic impact of the grafted substituents on the helical π-conjugated system. In addition, we went a step further and incorporated the designed chiral emitter into proof-of-concept CP-OLEDs using a top-emission architecture,¹¹ which remains scarcely explored for CP-light generation despite its considerable potential for micro-display applications. To the best of our knowledge, only one example of such type of electroluminescent device has been reported, using a CP-TADF emitter, affording a modest g_El of 10⁻³.^11aHerein, we report the synthesis and chiroptical properties of a new family of π-helical push–pull systems based on chiral carbo[6]helicene, functionalized by either electron donor or acceptor units. Interestingly, the chiral π-conjugated system of the helicene may act as either an electron acceptor or a donor, depending on the nature of the attached substituents, thereby impacting the chiroptical properties, notably the resulting CPL. By optimizing the chiral exciton coupling process through the modulation of the magnitude and relative orientation of the electric (μ) and magnetic (m) dipoles, the chiroptical properties of classical carbo[6]helicene-based emitters can be dramatically enhanced and reach high g_lum values at the molecular level, i.e. up to 3–4 × 10⁻². Experimental and theoretical investigations revealed that the mutual orientation of the electric and magnetic dipoles in the excited-state is a crucial parameter and is optimal when the substituents attached to the helicene core possess a rather weak electron withdrawing or donating ability. Finally, proof of concept top-emission CP-OLEDs were fabricated through vapor deposition of π-helical push–pull derivatives and afforded a g_El of around 8 × 10⁻³, which represents a significant improvement for the polarization of electroluminescence emitted using this device architecture.     

Difluorination of α-(bromomethyl)styrenes via I(I)/I(III) catalysis: facile access to electrophilic linchpins for drug discovery

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis.

Structural editing with fluorine enables geometric and electronic variation to be explored in functional small molecules whilst mitigating steric drawbacks.¹ This expansive approach to manipulate structure–function interplay continues to manifest itself in bio-organic and medicinal chemistry.² Of the plenum of fluorinated motifs commonly employed, the geminal difluoromethylene group³ has a venerable history.⁴ This is grounded in the structural as well as electronic ramifications of CH₂ → CF₂ substitution, as is evident from a comparison of propane and 2,2-difluoropropane (Fig. 1, upper). Salient features include localized charge inversion (C–H^δ+ to C–F^δ−) and a widening of the internal angle from 112° to 115.4°.⁵ Consequently, geminal difluoromethylene groups feature prominently in the drug discovery repertoire⁶ to mitigate oxidation and modulate physicochemical parameters. Catalysis-based routes to generate electrophilic linchpins that contain the geminal difluoromethylene unit have thus been intensively pursued, particularly in the realm of main group catalysis.^7–9 Motivated by the potential of this motif in contemporary medicinal chemistry, it was envisaged that an I(I)/I(III) catalysis platform could be leveraged to convert simple α-(bromomethyl)styrenes to gem-difluorinated linchpins: the primary C(sp³)–Br motif would facilitate downstream synthetic manipulations (Fig. 1, lower). To that end, p-TolI would function as a catalyst to generate p-TolIF₂in situ in the presence of an external oxidant¹⁰ and an amine·HF complex. Alkene activation (I) with subsequent bromonium ion formation (II)¹¹ would provide a pre-text for the first C–F bond forming process (III) with regeneration of the catalyst. A subsequent phenonium ion rearrangement¹²/fluorination sequence (III and IV) would furnish the geminal difluoromethylene group and liberate the desired electrophilic building block.Open in a separate windowFig. 1The geminal difluoromethylene group: bioisosterism, and catalysis-based access from α-(bromomethyl)styrenes via I(I)/I(III) catalysis.To validate this conceptual framework, a short process of reaction optimization (1a → 2a) was conducted to assess the influence of solvent, amine·HF ratio (Brønsted acidity)¹³ and catalyst loading (Table 1). Initial reactions were performed with p-TolI (20 mol%), Selectfluor® (1.5 equiv.) as an oxidant, and CHCl₃ as the reaction medium. Variation of the amine : HF ratio was conducted to explore the influence of Brønsted acidity on catalysis efficiency (entries 1–4). An optimal ratio of 1 : 6 was observed enabling the product 2a to be generated in >95% NMR-yield. Although reducing the catalyst loading to 10 and 5 mol% (entries 5 and 6, respectively) led to high levels of efficiency (79% yield with 5 mol%), the remainder of the study was performed with 20 mol% p-TolI. Notably, catalytic vicinal difluorination was not observed at any point during this optimization, in contrast with previous studies from our laboratory.^9d,i A solvent screen revealed the importance of chlorinated solvents (entries 7 and 8): in contrast, performing the reaction in ethyl trifluoroacetate (ETFA) and acetonitrile resulted in a reduction in yield (9 and 10). Finally, a control reaction in the absence of p-TolI confirmed that an I(I)/I(III) manifold was operational (entry 11). An expanded optimization table is provided in the ESI.^†Reaction optimization^a

Visible light driven deuteration of formyl C–H and hydridic C(sp3)–H bonds in feedstock chemicals and pharmaceutical molecules

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D₂O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp³)–H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C–H bonds of aldehydes and other activated hydridic C(sp³)–H bonds can be achieved in a selective manner.

A selective hydrogen deuterium exchange reaction with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds has been achieved by merging tetra-n-butylammonium decatungstate photocatalyst and a thiol catalyst under 390 nm light irradiation.     

Inhibitors of thiol-mediated uptake

Ellman''s reagent has caused substantial confusion and concern as a probe for thiol-mediated uptake because it is the only established inhibitor available but works neither efficiently nor reliably. Here we use fluorescent cyclic oligochalcogenides that enter cells by thiol-mediated uptake to systematically screen for more potent inhibitors, including epidithiodiketopiperazines, benzopolysulfanes, disulfide-bridged γ-turned peptides, heteroaromatic sulfones and cyclic thiosulfonates, thiosulfinates and disulfides. With nanomolar activity, the best inhibitors identified are more than 5000 times better than Ellman''s reagent. Different activities found with different reporters reveal thiol-mediated uptake as a complex multitarget process. Preliminary results on the inhibition of the cellular uptake of pseudo-lentivectors expressing SARS-CoV-2 spike protein do not exclude potential of efficient inhibitors of thiol-mediated uptake for the development of new antivirals.

Thiol-reactive inhibitors for the cellular entry of cyclic oligochalcogenide (COC) transporters and SARS-CoV-2 spike pseudo-lentivirus are reported.

Thiol-mediated uptake^1–10 has been developed to explain surprisingly efficient cellular uptake of substrates attached to thiol-reactive groups, most notably disulfides. The key step of this mechanism is the dynamic covalent thiol-disulfide exchange between disulfides of the substrates and exofacial thiols on cell surfaces (Fig. 1). The covalently bound substrate then enters the cell either by fusion, endocytosis, or direct translocation across the plasma membrane into the cytosol. Thiol-disulfide exchange has been confirmed to play an essential role in the cellular entry of some viruses^1,11–14 and toxins.² Indeed, diphtheria toxin and HIV were among the first to be recognized to enter cells via thiol-mediated uptake.^1,2 The involvement of cell-surface thiols in cellular uptake is most often probed by inhibition with Ellman''s reagent (DTNB). However, this test is not always reliable, in part due to the comparably poor reactivity of DTNB, and the comparably high reactivity of the disulfide obtained as a product. Thus, the importance of thiol-mediated uptake for viral entry and beyond remains, at least in part, unclear.Open in a separate windowFig. 1In thiol-mediated uptake, dynamic covalent exchange with thiols on the cell surface precedes entry through different mechanisms. Inhibition of thiol-mediated uptake by removal of exofacial thiols and disulfides could thus afford new antivirals.We became interested in thiol-mediated uptake^3–5 while studying the cytosolic delivery of substrates such as drugs, probes and also larger objects like proteins or quantum dots with cell-penetrating poly(disulfide)s.⁶ Our recent focus shifted to cyclic oligochalcogenides (COCs) to increase speed and selectivity of dynamic covalent thiol-oligochalcogenide exchange, and, most importantly, to assure reversibility, i.e., mobility during uptake, with a covalently tethered, intramolecular leaving group.⁷ With increasingly unorthodox COC chemistry, from strained disulfides^7,8 and diselenides⁹ to adaptive dynamic covalent networks produced by polysulfanes,¹⁰ uptake activities steadily increased. Their high activities suggested that the same, or complementary, COCs could also function as powerful inhibitors of thiol-mediated uptake that ultimately might perhaps lead to antivirals. In the following, this hypothesis is developed further.Fluorescently labeled COCs 1⁸ and 2¹⁰ were selected as reporters for the screening of thiol-mediated uptake inhibitors because of their high activity, their destination in the cytosol, and their different characteristics (Fig. 2). The COC in 1 is an epidithiodiketopiperazine (ETP). With a CSSC dihedral angle ∼0°, ETPs drive ring tension to the extreme.^15,16 Ring-opening thiol-disulfide exchange is ultrafast, and the released thiols are acidic enough to continue exchanging in neutral water, including ring closure.⁸ This unique exchange chemistry coincides with efficient cellular uptake and poor retention on thiol affinity columns.⁸Open in a separate windowFig. 2Structure of reporters 1 and 2 and inhibitor candidates 3–30 with their concentrations needed to inhibit by ∼15% (MIC) the uptake of 1 (1 h pre-incubation with inhibitors, 30 min incubation with reporter, filled symbols) and 2 (4 h pre-incubation, empty symbols). Red squares: ETPs; orange circles: BPSs; blue upward triangles: heteroaromatic sulfones; purple diamonds: thiosulfonates; magenta downward triangles: di- and polysulfides; brown hexagons: thiosulfinates. Symbols with upward arrows: MIC not reached at the highest concentration tested. Symbols with downward arrows indicate the lowest concentration tested already exceeds the MIC. (a) Similarly active upon co-incubation of reporters and inhibitor; (b–d) similarly (b), less (c), or more (d) active upon co-incubation in the presence of serum (mostly 6 h); (e) pre-incubation for 15 min; (f) isomerizes into cis22; (g) V-shaped DRC (see Fig. 3f); (h) pre-incubation for 30 min, co-incubation with 2; (i) mixture of regioisomers.The COC in 2 is a benzopolysulfane (BPS). Like ETPs, BPSs occur in natural products and have inspired total synthesis.¹⁷ Unlike ETPs, BPSs are not strained but evolve into adaptive networks of extreme sulfur species for cells to select from. Uptake efficiencies and retention on thiol affinity columns exceed other COCs clearly.^10,18With COCs 1 and 2 as cell-penetrating reporters, a fully automated, fluorescent microscopy image-based high-content high-throughput (HCHT)¹⁹ inhibitor screening assay was developed. HeLa cells in multiwell plates are incubated with a reporter at constant and inhibitors at varying concentrations and incubation times. Hindered reporter uptake then causes decrease of fluorescence inside of cells (Fig. 3a). Automated data analysis¹⁹ was established to extract average fluorescence intensity per cell and, at the same time, cell viability from propidium iodide negative nuclei count (Fig. 3 and S3–S6^†). Standard assay conditions consisted of pre-incubation of HeLa cells with inhibitors for different periods of time, followed by the removal of inhibitors and the addition of reporters, thus excluding possible interactions between the two in the extracellular environment. In alternative co-incubation conditions, inhibitors were not removed before the addition of reporters to allow for eventual interactions between the two.Open in a separate windowFig. 3(a) Fluorescence image of HCHT plates (4 images per well) with HeLa cells pre-incubated with 6 (30 min) followed by co-incubation with 1 (left) and 2 (right, 10 μM each) for constant 30 min. (b–f) HCHT data showing relative fluorescence intensity (filled symbols) and cell viability (empty symbols) of HeLa cells after (b) pre-incubation with 4 for 1 h, followed by washing and incubation with 1 (top), or pre-incubation with 4 for 30 min, followed by co-incubation with 4 and 2 (bottom). (c) As in (b) with 18. (d) As in (b) after incubation for 4 h with 16 followed by incubation with 2. (e) As in (b) after pre-incubation with 11 (circles), 14 (crosses), or 21 (diamonds) for 15 min, followed by washing and incubation with 1. (f) As in (b) after pre-incubation with 20 (30 min), followed by washing and incubation with 1.Among the very high number of thiol-reactive probes, compounds 3–30 were selected based on promise, experience, availability and accessibility. Main focus was on COCs offering increasingly extreme sulfur chemistry because dynamic covalent thiol-oligochalcogenide exchange with different intramolecular leaving groups promises access to different exchange cascades for the intramolecular and, perhaps, also intermolecular crosslinking of the target proteins. More hydrophilic, often anionic COCs were preferred to prevent diffusion into cells and thus minimize toxicity. The expectation was that from such a sketchy outline of an immense chemical space, leads could be identified for future, more systematic exploration. Reporters 1 and 2 and candidates 3–30 were prepared by substantial multistep synthesis (Schemes S1–S11 and Fig. S47–S93,^† commercially available: 20, 25, 30). Inhibitors were numbered in the order of efficiency against reporter 1, evaluated by their minimum inhibitory concentrations (MICs), i.e., concentrations that cause a ∼15% reduction of reporter uptake in cells (Fig. 2 and Tables S1–S37^†). We chose to use MICs because half-maximal inhibitions could not always be reached due to the onset of toxicity, formally anticooperative, or even V-shaped dose–response curves (DRCs, e.g., Fig. 3b–f, all DRCs can be found in the ESI, Fig. S7–S43^†). MICs are usually below the half-maximal cell growth inhibition concentration (GI₅₀, Tables S1–S37^†).Among the most potent inhibitors of ETP reporter 1 were ETPs 4 and 5 (Fig. 2, ​,3b).3b). This intriguing self-inhibition was even surpassed by the expanded cyclic tetrasulfide ETP₄3 (MIC < 0.1 μM), which was of interest because they are much poorer transporters.¹⁰ Further formal ring expansion leads to cyclic pentasulfides BPS₅6 as equally outstanding inhibitors (MIC ≈ 0.3 μM). This trend toward the adaptive networks, reminiscent of elemental sulfur chemistry, did not extend toward inorganic polysulfides 13 (MIC ≈ 20 μM). ETPs 4 and 5 were sensitive to modification of the carboxylate, with the cationic 12 being the worst (MIC ≈ 30 μM) and the neutral glucose hemiacetal 7 the most promising (MIC ≈ 0.5 μM).Although this study focuses on increasingly extreme dynamic covalent COC chemistry, the inclusion of one example for covalent C–S bond formation was of interest for comparison. The classical iodoacetamides⁷ and maleimides⁴ were more toxic than active (not shown). However, nucleophilic aromatic substitution of heteroaromatic sulfones,²⁰ just developed for the efficient bioorthogonal conversion of thiols into sulfides, was more promising. Weaker than dynamic covalent COCs, this irreversible inhibition was best with benzoxazole 11 (MIC ≈ 15 μM) and decreased in accordance with reactivity toward free thiols to oxadiazole 14 and benzothiazole 21 (MIC ≈ 300 μM, Fig. 3e).At constant pH, Ellman''s reagent 20 was confirmed to be erratic also in this assay. The DRC showed minor inhibition up to around 2 mM, which disappeared again at higher concentrations (Fig. 3f). Other cyclic disulfides were inactive as well (28–30). Also disappointing were oxidized disulfides, that is thiosulfinates, including allicin 25, the main odorant component of garlic,^21,22 oxidized cystine 26 and oxidized lipoic acid 27. Thiosulfinates were of interest because they should selectively target the vicinal thiols of reduced disulfides bridges, producing two disulfides.²³ The most active trans dithioerythrol (DTE) thiosulfinate 17 isomerized with time into the less active, hydrogen-bonded cis isomer 22 (Fig. S46^†).Reporter 2 was more difficult to inhibit than 1, as expected from high activity with extreme retention on thiol affinity columns.^10,18 For instance, BPS 6 was very efficient against ETP 1 but much less active against BPS 2 (Fig. 3a), although longer pre-incubation could lower the MIC down to 4 μM (Fig. 2, S41^†). The complementary ETP 4 “self-inhibited” ETP 1 but was also unable to inhibit BPS 2 as efficiently (Fig. 3b). Among the best inhibitors of BPS 2 upon co-incubation were disulfide bridged γ-turn²⁴ peptides 18 and 19 (MIC ≈ 5 μM), both less active against 1 (MIC ≈ 300 μM, Fig. 3c). Disulfide-bridged γ-turn CXC peptides consist of an 11-membered ring with significant Prelog strain. They were introduced by Wu and coworkers as transporters for efficient cytosolic delivery.⁵ The cyclic thiosulfonates 15 and 16 showed promising activities against both 1 and 2, and were tolerant toward the presence of serum (Fig. 2d, S33 and S42^†). Contrary to thiosulfinate 27, the oxidation of lipoic acid to pure thiosulfonates was not successful so far. However, weakly detectable activity of the lipoyl-glutamate conjugate oxidized to the thiosulfinate (MIC ≈ 350 μM, not shown) compared to the inactive thiosulfinate 27 implied that lipoic acid oxidized to the thiosulfonate would also be less active than the glutamate conjugate 15.The oxidized DTE 16^25–28 was particularly intriguing because it was more potent against 2 and could achieve nearly complete inhibition (MIC ∼ 20 μM, Fig. 3d). Highly selective for thiols, the cyclic thiosulfonate 16 was stable for weeks at room temperature, without precaution, in all solvents tested. The disulfides and sulfinates obtained from exchange with thiols were stable as well, and the latter can further react with disulfides²⁷ for intramolecular or eventually intermolecular crosslinking of the target proteins.The overall mismatched inhibition profiles found for reporters 1 and 2 supported that thiol-mediated uptake proceeds through a series of at least partially uncoupled parallel multitarget systems instead of a specific single protein or membrane target. From proteomics studies with cysteine-reactive irreversible probes, it is known that different probes generally target different proteins.^29b Proteomics analysis^29a for asparagusic acid derived transporters supports the involvement of many targets beyond the commonly considered protein disulfide isomerases and the confirmed transferrin receptor.^{12–14,26–30} The unusual, formally anti-cooperative (Hill coefficients < 1) DRCs further supported thiol-mediated uptake as complex multitarget systems.Despite the complexity of these systems, results did not much depend on assay conditions. Compared to the standard protocol of pre-incubation with inhibitors followed by inhibitor removal and incubation with reporters 1 or 2 for detection, the co-incubation protocol, in which pre-incubation with inhibitors is followed by co-incubation with reporters 1 or 2 without inhibitor removal, gave reasonably similar results (Fig. 2). Inhibition characteristics naturally depended on pre-incubation time, with weaker activities at shorter and longer times, reflecting incomplete exchange and cellular response or other ways of inhibitor destruction, respectively. The presence of serum also did not affect the activities much (Fig. 2b–d).Preliminary studies on antiviral activity were performed with pseudo-lentivectors³¹ that express the D614G mutant¹¹ of the SARS-CoV-2 spike protein and code for a luciferase reporter gene, which is expressed by the infected cells.¹² A549 human lung alveolar basal epithelium cell line constitutively overexpressing ACE2 and TMPRSS2 was selected to facilitate the entry of the SARS-CoV-2 spike pseudo-lentivirus. The most significant activities were found for DTE thiosulfonate 16 with an IC₅₀ around 50 μM, while toxicity was detected only at 500 μM (Fig. S44^†). The onset of inhibition could be observed for tetrasulfide ETP 3 at 50 μM, but it coincided with the appearance of cytotoxicity. Protease inhibition is less likely to be the mode of action, as similar activity was found with wild type A549 cells transduced with a standard lentivirus expressing vesicular-stomatitis virus G surface protein VSVG (Fig. S45^†).¹³ Short incubation times of cells and inhibitors before the addition of viruses disfavored contributions from changes in gene expression. More detailed studies are ongoing.The lessons learned from this study are that, firstly, thiol-mediated uptake can be inhibited efficiently by thiol-reactive reagents, confirming that thiol-mediated uptake exists and transporters like ETP 1 and BPS 2 do not simply diffuse into cells; the best inhibitors are more than 5000 times better than Ellman''s reagent. Secondly, inhibitor efficiencies vary with the transporters, supporting that thiol-mediated uptake operates as a complex multitarget system. The best inhibitors are COCs that operate with fast dynamic covalent exchange, suggesting that the reversibility provided by COCs is important. The inhibition of thiol-mediated uptake might contribute to activities of thiol-reactive antivirals such as 16, ETPs or ebselen, although they have been shown to bind to zinc fingers or inhibit proteases.^{16,25,32–34} Finally, the inhibitors reported here could also be of interest for delivery applications and might be worth investigation with regard to antiviral activity. We currently plan to focus more systematically on the most promising leads within COCs, particularly cyclic thiosulfonates, and to expand the screening campaign toward new attractive motifs.^33–35     

CsAlB3O6F: a beryllium-free deep-ultraviolet nonlinear optical material with enhanced thermal stability

The design of new beryllium-free deep-ultraviolet nonlinear optical materials is important but challenging. Here, we describe a new strategy to search for such materials based on rational selection of fundamental structural units. By combining asymmetric AlO₃F tetrahedra and π-conjugated B₃O₆ rings, a new aluminum borate fluoride, CsAlB₃O₆F was obtained. It exhibits excellent linear and nonlinear optical properties including a high optical transmittance with a cut-off edge shorter than 190 nm, large second harmonic generation intensities (2.0× KH₂PO₄, KDP), and suitable birefringence for phase-matching under 200 nm. It also has good thermal stability and can be synthesized easily in an open system.

A new potential deep-ultraviolet nonlinear optical material CsAlB₃O₆F was designed by a rational selection of fundamental structural units. This material does not require toxic raw materials and can be grown in an open system.

The exploration of new deep-ultraviolet (DUV) nonlinear optical (NLO) materials is intriguing and of great importance because these materials are crucial for the development of all-solid-state DUV lasers.^1–3 For NLO materials, the main obstacles to DUV application are 3-fold:^4,5 (i) a wide DUV transparency window (wavelength cut-off edge < 200 nm), (ii) high NLO coefficients (>1× commercial KH₂PO₄, KDP), and (iii) sufficient birefringence to satisfy phase matching conditions in the DUV region. Until now, only KBe₂BO₃F₂ (KBBF) can certainly break through these barriers and generate lasers with wavelengths shorter than 200 nm by direct second harmonic generation (SHG).⁶ However, KBBF is limited in practical use because of its adverse layered crystal growth habit and use of the highly toxic beryllium component. To find a KBBF replacement, many new NLO crystals have been developed continuously, but have so far been unable to achieve desired NLO properties.^7–10Recently, it was shown that fluorooxoborates and fluorophosphates with mixed O/F anionic groups might be recognized as new sources for discovering DUV NLO materials. For example, Pan''s group proposed that the [BO_xF_4−x] (x = 1, 2, 3) tetrahedra are good units to balance the multiple criteria of DUV NLO materials.¹¹ Accordingly, monofluorophosphates with non-π-conjugated asymmetric [PO₃F] units were also paid attention, exhibiting superior optical properties.^12,13 Thereafter, numerous fluorooxoborates and fluorophosphates with an unprecedented crystal structure and high performance as potential DUV NLO materials have been reported.^14–17 Nevertheless, because these materials are relatively unstable at high temperature in air, one need to develop a suitable crystal growth method under sealed conditions and/or search for a suitable flux (solvent) system at relatively low temperature.^14,16 Alternatively, it is possible to achieve a beryllium-free, higher stability DUV NLO crystal by combining other anionic groups, such as [AlO₄], [PO₄], [SiO₄], and [ZnO₄].^18–21Enlightened by the successful synthesis of NLO-active fluorooxoborates and fluorophosphates, we proposed that aluminum borate fluorides with [AlO_mF_n] (m + n = 4, 5, 6, AlOF for short) units might be another choice for exploring new NLO materials. Four specific aspects were considered: (I) aluminum borates are preferred because of the chemical and coordination environment similarity between Al³⁺ and Be²⁺ cations.²² (II) similar to fluorooxoborates, the substitution of O²⁻ with larger electronegativity F⁻ can increase the bandgap and optical anisotropy due to the ionicity of the Al–F bond. (III) The rich coordination environment of AlOF groups provides more structural possibilities than those of other mixed-anionic groups (e.g. [BeO₃F], [BO₃F], [BO₂F₂], see Fig. S1^†). Different from the B or Be atom, the Al atom has empty d orbitals, and it can form sp³, sp³d, and sp³d² hybrid orbitals when bonding with O/F atoms. Consequently, diverse AlOF groups without anion-site disorder, such as [AlO₃F] tetrahedra, [AlO₃F₂] or [AlO₄F] trigonal bipyramids, and [AlO₅F], [AlO₄F₂], [AlO₂F₄], or [AlOF₅] octahedra, have been achieved (Fig. S1^†). Replacing oxygen atoms with fluorine in the Al–O polyhedra not only increases the degree of freedom (e.g. cis/trans conformation), but also causes a (local) symmetry breaking and results in increased microscopic susceptibility and optical anisotropy, which are beneficial to build a noncentrosymmetric (NCS) material. (IV) Aluminum borate fluorides without B–F bonds (e.g. BaAlBO₃F₂,²³ Rb₃Al₃B₃O₁₀F,²⁴ and K₃Ba₃Li₂Al₄B₆O₂₀F²⁰) show good thermal stability, and large crystals could be obtained in air.By applying the strategy described above, we tried to design a new DUV NLO material according to the blueprints shown in Fig. 1a. From KBBF to fluorooxoborates (e.g. NH₄B₄O₆F,²⁵ ABF), the nontoxic [BO₃F] units were selected to replace the [BeO₃F] tetrahedra of KBBF while the NLO properties were retained. Meanwhile, benzene-like [B₃O₆] rings (the same as that in β-BaB₂O₄, BBO) with a better conjugated π-orbital system were utilized to replace [BO₃] triangles (the case in CsB₄O₆F,²⁶ CBF), which could contribute to the increase of SHG responses compared to KBBF. In this work, more stable [AlO₃F] units combined with the [B₃O₆] rings were chosen as fundamental building units (FBUs) and a new potential DUV NLO material CsAlB₃O₆F (CABF) has been successfully synthesized. The material can be obtained easily in an open system and it exhibits a short UV cutoff edge below 190 nm with a powder SHG response of 2.0× KDP under 1064 nm incident radiation. The first-principles calculations reveal that CABF possesses moderate SHG coefficients and sufficient birefringence for DUV phase-matching. With the introduction of new AlO₃F units, CABF continues to maintain the excellent structural features of both KBBF and β-BBO, and thus exhibits a great potential to be a Be-free DUV material for nonlinear light–matter interactions.Open in a separate windowFig. 1(a) The structural evolution from KBe₂BO₃F₂ to CsAlB₃O₆F. (b) The 2D [AlB₃O₆F]_∞ layer of CABF. (c) Crystal structure of CABF.Single crystals of CABF were obtained by the conventional flux method in an open system (see the Experimental details in the ESI^†). CABF crystallizes in the NCS orthorhombic polar space group Pna2₁ (Tables S1–S3^†). Its crystal structure is built up from [AlB₃O₆F]_∞ 2D layers and the Cs⁺ cations reside in the interlayer space (Fig. 1b and c). The FBUs of CABF are the [AlB₃O₈F] groups composed of one [B₃O₆] ring and one [AlO₃F] tetrahedron. Three crystallographically independent boron atoms are all three-coordinated to oxygen atoms forming the BO₃ triangles, which further form a B₃O₆ ring by sharing their terminal O atoms. The B–O bond distances and the O–B–O angles are in the range of 1.342(10) to 1.395(11) Å and 117.2(7) to 121.9(8)°, respectively. The Al³⁺ cation is coordinated to three oxygen atoms (Al–O bond lengths: 1.719(6)–1.734(6) Å) and one fluorine atom (Al–F bond length equals 1.675(5) Å) to form a distorted AlO₃F tetrahedron. In the bc-plane, the [AlO₃F] tetrahedra bond with discrete [B₃O₆] rings to create [AlB₃O₆F]_∞ layers that contain 18-membered rings (Fig. 1b). In one layer, the apical F atoms of [AlO₃F] tetrahedra point upward and downward regularly. The Cs⁺ cations are twelve-coordinated, forming the [CsO₁₁F] polyhedra with a Cs–F distance of 3.292(7) Å and Cs–O distances ranging from 3.256(5) to 3.585(6) Å (Fig. S2^†). Because the Cs⁺ cations reside in the tunnels created by the 18-membered rings and adjacent [AlB₃O₆F]_∞ layers, the interlayer distance in CABF is 4.03 Å. Compared to the distance of two adjacent layers in KBBF (6.25 Å), CABF should exhibit stronger interlayer interactions. Theoretical calculation based on the density functional theory (DFT) also confirms that CABF shows a larger interlayer binding energy than KBBF (0.178 vs. 0.0314 eV Å⁻² per layer). These results indicate that CABF might possess a better crystal growth habit without layering. The bond valence sum calculation²⁷ (Table S2^†) and IR spectrum (Fig. S3^†) indicate that all atoms of CABF have the expected oxidation states and coordination environments.Polycrystalline CABF was synthesized by a stoichiometric solid-state reaction of CsF, Al₂O₃ and H₃BO₃ at 500 °C, and the phase purity was confirmed by powder X-ray diffraction (PXRD) Rietveld refinement (Fig. S4^†). To check the stability of CABF, thermal measurements and further PXRD analysis were performed on its polycrystalline samples. Based on the re-crystallization experiment, the CABF sample after melting was almost the same as the original one; however, owing to the loss of volatile fluorines, a small amount of Cs₂Al₂(B₃O₆)₂O²⁸ was obtained (Fig. S6a^†). Thermogravimetric (TG) analysis shows that CABF has nearly no weight loss until 900 °C, and the differential scanning calorimetry (DSC) data show two sharp endothermic peaks around 505 and 702 °C on the heating curve (Fig. 2a). In addition, variable temperature PXRD measurements were performed (Fig. S6b^†), demonstrating a possible phase transition of CABF near 500 °C (consistent with the first peak on the DSC curve). Therefore, an excessive amount of fluorides should be used as the flux for crystal growth of CABF. Different from many fluorooxoborates (e.g. CaB₅O₇F₃ and SrB₅O₇F₃ (ref. 29–31)), CABF can survive at relatively high temperature in an open system after replacing BO₃F with AlO₃F units, which is an important advantage for large crystal growth.Open in a separate windowFig. 2(a) Thermal behaviour of CABF. (b) The diffuse reflectance spectrum of CABF. (c) PSHG measurements at 1064 nm. (d) Calculated type I phase-matching condition of CABF. Dashed lines: refractive-indices of fundamental light. Solid lines: refractive-indices of second-harmonic light. The λ_SH of CABF is estimated by satisfying n_Z(ω) = n_X(2ω). The SHG-weighted electron density maps of the occupied (e) and unoccupied (f) states in the VE process.CABF exhibits a wide transparency window from 300 to 1100 nm, with a short UV cut-off edge below 190 nm (Fig. 2b). Even at 190 nm, the reflectance is nearly 40%. DFT calculations of the band gap using the HSE06 hybrid functional with high accuracy result in 7.49 eV (corresponding to 166 nm), further indicating that CABF could be an excellent candidate for optical materials operating in the DUV region. As described earlier,^26,28 the large band gap of CABF could be attributed to the elimination of dangling bonds in [B₃O₆] units and the introduction of fluorine.Powder SHG (PSHG) measurement using the Kurtz–Perry method³² reveals that CABF has SHG intensities of 2.0× KDP (particle size range: 200–250 μm) under 1064 nm fundamental wave laser radiation. It also suggests that CABF is phase matchable as the SHG intensities continue to rise until it attains the maximum (Fig. 2c). Under 532 nm fundamental wave laser radiation, CABF also shows phase matching behavior and has an SHG response about 1/6 times that of BBO in the particle size range of 200–250 μm (Fig. S7^†). The SHG response of CABF is larger than that of KBBF (∼1.2× KDP) and suitable for DUV NLO applications. Applying Kleinmann symmetry in point group mm2, there are three nonzero and independent SHG coefficients, and our calculated SHG coefficients for CABF are d₁₅ = −0.027 pm V⁻¹, d₂₄ = 0.941 pm V⁻¹, and d₃₃ = −0.955 pm V⁻¹, which are consistent with the PSHG results. The SHG ability of CABF is comparable to those of other DUV NLO materials, including CBF (1.9× KDP),²⁶ ABF (3× KDP),²⁵ MB₅O₇F₃ (M = Ca and Sr, 2.3–2.5× KDP),^29–31 (NH₄)₂PO₃F (1.0× KDP),¹² and NaNH₄PO₃F·H₂O (1.1× KDP).¹⁶ Compared with the CBF archetype, the increased SHG response of CABF can be understood by considering the geometry factor of NLO-active [B₃O₆] units. Structurally, CABF is pretty much like CBF; however, the substitution of [BO₃F] by [AlO₃F] results in structural modulation of the [B₃O₆] groups. As shown in Fig. S8,^† the rotation angle (φ) and deviation angle (θ) of the B₃O₆ groups decrease from 33 and 6.8° in CBF, to 25 and 4.4° in CABF, respectively. The smaller φ and θ angles in CABF result in more “coplanar and aligned” [B₃O₆] units, that is, a favorable arrangement for generating the SHG response according to the anionic group approach.⁶The phase-matching ability is a key factor that should never be ignored for any practical DUV NLO application, which relies on both birefringence (Δn) and its dispersion of the crystal.³³ The calculated Δn of CABF is 0.091 at 1064 nm, large enough to satisfy DUV phase-matching (Fig. S10^†). Based on the dispersion of the refractive indices, the shortest SHG phase-matching wavelength (λ_SH) of CABF can reach 182 nm (Fig. 2d), which is comparable to that of KBBF and other recent reported NLO materials (Table S4^†). To the best of our knowledge, the phase-matching wavelength of CABF is the shortest among the SHG-active aluminum borates and aluminum borate fluorides (Table S4^†).To correlate the observed optical properties and electronic structure of CABF, band structure calculations were performed. The partial density of states (PDOS) projected on the constitutional atoms (see Fig. S9^†) demonstrates that B-2p, Al-3p, O-2p, and F-2p states occupy the frontier orbitals (the top of the valence band and the bottom of the conduction band). The high overlap of these orbitals indicates that both the [B₃O₆] and [AlO₃F] groups determine the SHG response and optical birefringence in CABF, while the Cs⁺ cations show a very small contribution. This observation was also supported by the SHG-weighted electron density analysis.³⁴ The directly perceived images (Fig. 2e, f, and S11^†) indicate that the 2p orbitals of O/F atoms in the occupied states and the anti π-orbitals of the [BO₃] groups in the unoccupied states dominate the SHG contribution. In particular, the O or F atoms in [AlO₃F] groups reveal considerable SHG density values, which further suggests that the [AlO₃F] group could be a promising NLO-active unit.     

Access to P-stereogenic compounds via desymmetrizing enantioselective bromination

A novel and efficient desymmetrizing asymmetric ortho-selective mono-bromination of bisphenol phosphine oxides under chiral squaramide catalysis was reported. Using this asymmetric ortho-bromination strategy, a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates were obtained with good to excellent yields (up to 92%) and enantioselectivities (up to 98.5 : 1.5 e.r.). The reaction could be scaled up, and the synthetic utility of the desired P-stereogenic compounds was proved by transformations and application in an asymmetric reaction.

A highly efficient desymmetrizing asymmetric bromination of bisphenol phosphine oxides was developed, providing a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates with high yields and enantioselectivities.

P-Stereogenic compounds are a class of privileged structures, which have been widely present in natural products, drugs and biologically active molecules (Fig. 1a).^1–4 In addition, they are also important chiral materials for the development of chiral catalysts and ligands (Fig. 1b), because the chirality of the phosphorus atom is closer to the catalytic center which can cause remarkable stereo-induction.^5,6 Thus, the development of efficient methods for the synthesis of P-stereogenic compounds with novel structures and functional groups is very meaningful.^5a Conventional syntheses of P-stereogenic compounds mainly depended on the resolution of diastereomeric mixtures and chiral-auxiliary-based approaches, in which stoichiometric amounts of chiral reagents are usually needed.⁷ By comparison, asymmetric catalytic strategies, including asymmetric desymmetric reactions of dialkynyl, dialkenyl, diaryl and bisphenol phosphine oxides,^8–14 (dynamic) kinetic resolution of tertiary phosphine oxides,¹⁵ and asymmetric reactions of secondary phosphine oxides,¹⁶ can effectively solve the above-mentioned problems and have been considered as the most direct and efficient synthesis methods for constructing P-chiral phosphine oxides (Fig. 1c). Among them, organocatalytic asymmetric desymmetrization methods have been sporadic, in which the reaction sites were mainly limited to the hydroxyl group of bisphenol phosphine oxides that hindered their further transformation.^8–11 It is worth mentioning that asymmetric desymmetrization methods, especially organocatalytic desymmetrization reactions, due to their unique advantages of mild reaction conditions and wide substrate scope, have become an important strategy for asymmetric synthesis. Accordingly, the development of efficient organocatalytic desymmetrization strategy for the synthesis of important functionalized P-stereogenic compounds which contain multiple conversion groups is very meaningful and highly desirable.Open in a separate windowFig. 1(a) Examples of natural products containing P-stereogenic centers. (b) P-Stereogenic compound type ligand and catalyst. (c) Typical P-stereogenic compounds'' synthetic strategies.On the other hand, asymmetric bromination has been demonstrated to be one of the most attractive approaches for chiral compound syntheses.¹⁷ Since the pioneering work on peptide catalyzed asymmetric bromination for the construction of biaryl atropisomers,^18a the reports on constructing axially biaryl atropisomers,¹⁸ C–N axially chiral compounds,¹⁹ atropisomeric benzamides,²⁰ axially chiral isoquinoline N-oxides,²¹ and axially chiral N-aryl quinoids²² by electrophilic aromatic bromination have been well developed (Scheme 1a). In comparison, the desymmetrization of phenol through asymmetric bromination to construct central chirality remains a daunting task. Miller discovered a series of tailor made peptide catalyzed enantioselective desymmetrizations of diarylmethylamide through ortho-bromination (Scheme 1b).²³ Recently, Yeung realized amino-urea catalyzed desymmetrizing asymmetric ortho-selective mono-bromination of phenol derivatives to fix a new class of potent privileged bisphenol catalyst cores with excellent yields and enantioselectivities (Scheme 1b).²⁴ Despite this elegant work, there is no report on the synthesis of P-centered chiral compounds using the desymmetrizing asymmetric bromination strategy.Open in a separate windowScheme 1(a) Constructing axially chiral compounds by asymmetric bromination. (b) Known synthesis of central chiral compounds via asymmetric bromination. (c) This work: access to P-stereogenic compounds via desymmetrizing enantioselective bromination.Taking into account the above-mentioned consideration, we speculated that bisphenol phosphine oxides and bisphenol phosphinates are potential substrate candidates for desymmetrizing asymmetric bromination to construct P-stereogenic centers. The advantages of using bisphenol phosphine oxides and bisphenol phosphinates as substrates are shown in two aspects. First, the ortho-position of electron rich phenol is easy to take place electrophilic bromination reaction. Second, the corresponding bromination product structure contains abundant synthetic conversion groups, including bromine, hydroxyl group, alkoxy group and phosphoryl group. To achieve this goal, two challenges need to be overcome: (i) finding a suitable chiral catalyst for the desymmetrization process to induce enantiomeric control is troublesome, due to the remote distance between the prochiral phosphorus center and the enantiotopic site; (ii) selectively brominating one phenol to inhibit the formation of an achiral by-product is difficult. Herein, we report a chiral squaramide catalyzed asymmetric ortho-bromination strategy to construct a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates with good to excellent yields and enantioselectivities (Scheme 1c). It is worth mentioning that the obtained P-stereogenic compounds can be further transformed at multiple sites.Our initial investigation was carried out with bis(2-hydroxyphenyl)phosphine oxide 1a and N-bromosuccinimide (NBS) 2a as the model substrates, 10 mol% chiral amino-thiourea 4a as the catalyst, and toluene as the solvent, which were stirred at −78 °C for 12 h. As a result, the reaction gave the desired desymmetrization product 3a in 65% yield with 56 : 44 e.r. (Table 1, entry 1). Then, thiourea 4b was tested, in which a little better result was obtained (Table 1, entry 2). To our delight, using the chiral squaramides 4c–4f as the catalysts, the enantiomeric ratios of the desymmetrization products had been significantly improved (Table 1, entries 3–6). Especially, when chiral squaramide catalyst 4c was applied to this reaction, the enantiomeric ratio of 3a was increased to 95 : 5 (Table 1, entry 3). To further improve the yield and enantioselectivity, we next optimized the reaction conditions by varying reaction media and additives. As shown in Table 1, the reaction was affected by the solvent dramatically. Product 3a was obtained with low yield and enantioselectivity in DCM (Table 1, entry 7). Also, when Et₂O was used as the solvent, the yield and e.r. value of product 3a were all decreased (Table 1, entry 8). As a result, the initial used toluene was the optimal solvent. We also inspected the effect of different bromine sources, and found that the initially used NBS was the optimal one (Table 1, entries 3, 11 and 12). Fortunately, by adjusting the amount of bisphenol phosphine oxides to 1.5 equiv., the yield and the enantiomeric ratio of 3a were increased to 80% and 96.5 : 3.5, respectively (Table 1, entries 3, 13 and 14). Further increasing the amount of bisphenol phosphine oxides to 2.0 equiv. resulted in a reduced enantioselectivity (Table 1, entry 15).Optimization of the reaction conditions^a

Diazaphosphinyl radical-catalyzed deoxygenation of α-carboxy ketones: a new protocol for chemo-selective C–O bond scission via mechanism regulation

C–O bond cleavage is often a key process in defunctionalization of organic compounds as well as in degradation of natural polymers. However, it seldom occurs regioselectively for different types of C–O bonds under metal-free mild conditions. Here we report a facile chemo-selective cleavage of the α-C–O bonds in α-carboxy ketones by commercially available pinacolborane under the catalysis of diazaphosphinane based on a mechanism switch strategy. This new reaction features high efficiency, low cost and good group-tolerance, and is also amenable to catalytic deprotection of desyl-protected carboxylic acids and amino acids. Mechanistic studies indicated an electron-transfer-initiated radical process, underlining two crucial steps: (1) the initiator azodiisobutyronitrile switches originally hydridic reduction to kinetically more accessible electron reduction; and (2) the catalytic phosphorus species upconverts weakly reducing pinacolborane into strongly reducing diazaphosphinane.

Diazaphosphinyl radical-catalyzed chemo-selective deoxygenation of α-carboxy ketones with pinacolborane was achieved through the mechanism switch from direct to stepwise hydride transfer of diazaphosphinane.

The importance of reductive deoxygenation can be gauged by the wide use of Barton–McCombie deoxygenation in organic syntheses.¹ Such C–O bond cleavage is also a crucial step in the degradation of natural polymers (e.g., sugars and lignins) to recycle sustainable resources.² Consequently, a great variety of methodologies were explored for activation of these strong C–O bonds.³ Among them, deoxygenation of α-acyloxy ketones^3b,c,4 (represented by benzoin derivatives, stemming from simple aldehydes via benzoin condensation⁵) has attracted considerable attention, because it may provide a facile way for accessing commonly useful building blocks (aryl ketones).⁶ As known, benzoin derivatives bear two types of C–O bonds—the carbonyl π-C O bond and the benzyl σ-C–O bond (Scheme 1). While reduction of the carbonyl π-C O bonds has been well established through transition metal-⁷ or Lewis acid-mediated⁸ hydride transfers, chemo-selective cleavage of the benzyl σ-C–O bonds is challenging and has seldom been achieved.⁹ The later process is occasionally seen, however, in some radical or electron reductions, but toxic tin hydrides^1c or aggressive metal reagents (like Raney nickel,¹⁰ zinc dust,¹¹etc.) are inevitably employed.Open in a separate windowScheme 1Possible reactive sites for benzoin reduction.The recent successful development of super electron donors (SEDs),^4,12 which are defined as ground-state organic electron-donors capable of reducing aryl halides to aryl radicals or aryl anions,¹³ and photocatalytic systems^3b,c may provide alternative protocols for reductive cleavage of the σ-C–O bonds in O-acetylated benzoin. However, these electron transfer-initiated reductions also suffer from some drawbacks, such as, excessive use of SEDs and their tedious synthetic procedures, expensive photoredox catalysts and ligands, and group-tolerance issues. In fact, there have been few reports to date on metal-free systems for efficiently catalytic deoxygenation with commercially available inexpensive reductants.^3h Given the ubiquity of C–O bonds in nature, it is still an unmet need for development of efficient and economical methods for their degradation. N-Heterocyclic phosphines (NHPs)^8c,14 have recently found plentiful applications in hydridic reductions^8b,15 owing to their outstanding hydricity.¹⁶ However, this seems to blind one to search for their other promising reaction patterns, like radical and electron transfer reactivities. Up to now, the catalytic potential of NHPs in radical or electron reductions has never been explored. Given the logical understanding that a deliberately manipulated mechanism variation usually leads to diverse reactivity and selectivity, we anticipate that an intended mechanism switch for NHP-based reactions from the conventional hydride transfer to an alternative electron transfer might provide a chance for originally inaccessible chemo-selectivity in the reduction of the substrates bearing multiple reactive sites. As known from previous studies, NHPs could transfer a hydride ion to carbonyl C O bonds to deliver the corresponding alcohol counterparts (Scheme 2a).^8b This is indeed what we have seen. When NHPs are mixed with O-acetylated benzoins, an exclusive hydridic reduction of the carbonyl π-C O bonds is observed, leaving the benzyl σ-C–O bonds intact. How could we make the propensity of NHP reduction to switch from the original hydridic path to a radical one? Inspired by our recent findings that NHPs are also capable of serving as good hydrogen-atom donors (by P–H bond homolysis) and their corresponding phosphinyl radicals are excellent electron donors¹⁷ (Scheme 2b, bottom), we envisioned that if phosphinyl radicals can be in situ generated, their super electron-donicity may promote the initial electron transfer to benzoin, and trigger the subsequent benzyl σ-C–O bond scission. If this is realizable, chemo-selective deoxygenation of benzoin derivatives with NHPs may be achieved via such a mechanism switch.Open in a separate windowScheme 2Chemical transformations of N-heterocyclic phosphines NHPs in reduction reactions.It is noted that the phosphorus species NHP-OR′ is produced in either the hydride or electron reduction of benzoin derivatives (Scheme 2c). Based on the previous knowledge that NHP-OR′ can be recycled back to NHP through a σ-bond metathesis between its exocyclic P–O bond and the B–H bond of pinacolborane (HBpin),^8b we envisioned that the present deoxygenation may operate in a catalytic fashion with readily available HBpin as the terminal reductant to avoid the use of stoichiometric NHP. To verify this plot, we chose dimethyl 4,4′-(1-acetoxy-2-oxoethane-1,2-diyl)dibenzoate X as the testing substrate, and 1,3-di-tert-butyl-1,3,2-diazaphosphinane 1a as the catalyst based on its compatible reducing capacity (Scheme 3, for structure of 1a, cf.Table 1).^17a It is observed that, under the previously established catalytic conditions for carbonyl reduction (20 mol% of 1a and 1.2 equiv. HBpin),^8b the product X1 of hydridic reduction was obtained in 86% yield and 1 : 0.69 of diastereomer ratio in 12 h. On the other hand, when 10% azodiisobutyronitrile (AIBN) was added as a radical initiator, the σ-C–O bonds were, indeed, selectively cleaved to give the anticipated product X2 in 87% yield. This distinct chemo-selectivity did echo our proposed mechanism switch from the direct hydridic pathway to an electron reduction. In the following, we report this catalytic transformation in a more inclusive fashion. To our best knowledge, this is the first example of catalytic electron reduction mediated by NHPs.Optimization of reaction conditions for C–O bond cleavage