“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⁻

Correction: Graph neural network based coarse-grained mapping prediction

Correction for ‘Graph neural network based coarse-grained mapping prediction’ by Zhiheng Li et al., Chem. Sci., 2020, 11, 9524–9531, DOI: 10.1039/D0SC02458A.

The authors regret that eqn (5) was missing the adjacency matrix term. The correct form of eqn (5) is shown below:5where σ is the bandwidth and is set to σ = 1 in the experiment. denotes the adjacency matrix (Ẽ_ij = 1 if atom i and atom j are bonded, otherwise Ẽ_ij = 0).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Benzannulation of isobenzopyryliums with electron-rich alkynes: a modular access to β-functionalized naphthalenes

Described here is a modular strategy for the rapid synthesis of β-functionalized electron-rich naphthalenes, a family of valuable molecules lacking general access previously. Our approach employs an intermolecular benzannulation of in situ generated isobenzopyrylium ions with various electron-rich alkynes, which were not well utilized for this type of reaction before. These reactions not only feature a broad scope, complete regioselectivity, and mild conditions, but also exhibit unusual product divergence depending on the substrate substitution pattern. This divergence allows further expansion of the product diversity. Control experiments provided preliminary insights into the reaction mechanism.

A substituent-controlled divergent benzannulation provides rapid access to various β-functionalized naphthalenes from electron-rich alkynes.

Functionalized naphthalenes are important structural motifs widely present in bioactive natural products, pharmaceuticals and functional materials.^1,2 They also serve as valuable intermediates in organic synthesis.³ Among them, naphthalenes bearing an electron-donating group (EDG) at the β-position (e.g., β-naphthols, β-naphthylamines, and β-naphthyl thioethers) are particularly versatile (Fig. 1).^2,3 For example, BINOL, which is derived from β-naphthol, is an extensively utilized synthetic precursor toward a wide range of privileged chiral ligands and catalysts.³ While various approaches have been developed for the synthesis of naphthalenes, efficient and selective de novo strategies toward these β-functionalized ones still remain in high demand. Moreover, to the best of our knowledge, a general and modular approach for rapid access to all these electron-rich β-functionalized naphthalenes remains unknown.⁴Open in a separate windowFig. 1Useful β-naphthol, β-naphthylamine, and β-naphthyl thioether units.Isobenzopyrylium ions are readily accessible and versatile intermediates in organic synthesis (Scheme 1).⁵ They are known to participate in cycloaddition reactions with diverse carbon–carbon double bonds or triple bonds for the synthesis of naphthalenes.^5,6 While extensive progress has been achieved in this topic, challenges still remain to be addressed. For example, the majority of these benzannulations with alkynes have to be executed at high temperature, except those intramolecular cases or with stoichiometric activators. Moreover, electron-rich alkynes have not been well explored as reaction partners for the benzannulations with isobenzopyrylium ions. Nevertheless, such reactions would provide expedient access to the valuable β-naphthol and β-napthylamine derivatives with diverse substitution patterns (Scheme 1). In this context, here we report our effort in achieving a general and modular strategy toward these electron-rich naphthalenes with high efficiency and regioselectivity under mild conditions. We also observed interesting selectivity divergence controlled by the substituent of the isobenzopyrylium substrates, giving rise to different types of naphthalene products (e.g., 2-hydroxy-1-naphthaldehydes, Scheme 1).Open in a separate windowScheme 1Benzannulation of isobenzopyryliums with electron-rich alkynes.We began our study with isochromene 1a as the isobenzopyrylium precursor. Siloxy alkyne 2a was first employed as the model electron-rich alkyne in view of the extraordinary versatility of this type of alkyne in various cyclization reactions, including benzannulation.^7–9 Various Brønsted and Lewis acids were evaluated as catalysts for this reaction. Unfortunately, most of them did not show obvious catalytic activity toward the formation of a naphthalene product (Table 1). These reactions either had little conversion or resulted in a mixture of undesired products. Nevertheless, further screening led to the identification of AgOTf and BF₃·OEt₂ as capable catalysts (entries 5–6), with the latter being superior, leading to the formation of naphthalene 3a as the major product (75% yield, entry 6). Increasing the catalyst loading to 20 mol% further improved the product yield to 85% (with an isolated yield of 81%, entry 7). Further increasing the catalyst loading proved to be not beneficial (entry 8). Notably, the use of substrate 1a′ bearing an ethoxy leaving group also provided an equally good result. Other solvents, such as toluene and MeCN, were also evaluated, but all gave lower product yields. Finally, it is worth noting that the mild conditions used here are in sharp contrast to the typical high temperature required for the previously known catalytic intermolecular benzannulations involving isobenzopyryliums and alkynes.^5dEvaluation of reaction conditions

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

Nitric oxide monooxygenation (NOM) reaction of cobalt-nitrosyl {Co(NO)}8 to CoII-nitrito {CoII(NO2−)}: base induced hydrogen gas (H2) evolution

Here, we report the nitric oxide monooxygenation (NOM) reactions of a Co^III-nitrosyl complex (1, {Co-NO}⁸) in the presence of mono-oxygen reactive species, i.e., a base (OH⁻, tetrabutylammonium hydroxide (TBAOH) or NaOH/15-crown-5), an oxide (O²⁻ or Na₂O/15-crown-5) and water (H₂O). The reaction of 1 with OH⁻ produces a Co^II-nitrito complex {3, (Co^II-NO₂⁻)} and hydrogen gas (H₂), via the formation of a putative N-bound Co-nitrous acid intermediate (2, {Co-NOOH}⁺). The homolytic cleavage of the O–H bond of proposed [Co-NOOH]⁺ releases H₂via a presumed Co^III-H intermediate. In another reaction, 1 generates Co^II-NO₂⁻ when reacted with O²⁻via an expected Co^I-nitro (4) intermediate. However, complex 1 is found to be unreactive towards H₂O. Mechanistic investigations using ¹⁵N-labeled-¹⁵NO and ²H-labeled-NaO²H (NaOD) evidently revealed that the N-atom in Co^II-NO₂⁻ and the H-atom in H₂ gas are derived from the nitrosyl ligand and OH⁻ moiety, respectively.

Base-induced hydrogen (H₂) gas evolution in the nitric oxide monoxygenation reaction.

As a radical species, nitric oxide (NO) has attracted great interest from the scientific community due to its major role in various physiological processes such as neurotransmission, vascular regulation, platelet disaggregation and immune responses to multiple infections.¹ Nitric oxide synthase (NOS),² and nitrite reductase (NiR)³ enzymes are involved in the biosynthesis of NO. NOSs produce NO by the oxidation of the guanidine nitrogen in l-arginine.⁴ However, in mammals and bacteria, NO₂⁻ is reduced to NO by NiRs in the presence of protons, i.e., NO₂⁻ + e⁻ + 2H⁺ → NO + H₂O.⁵ Biological dysfunctions may cause overproduction of NO, and being radical it leads to the generation of reactive nitrogen species (RNS), i.e., peroxynitrite (PN, OONO⁻)⁶ and nitrogen dioxide (˙NO₂),⁷ upon reaction with reactive oxygen species (ROS) such as superoxide (O₂˙⁻),⁸ peroxide (H₂O₂),⁹ and dioxygen (O₂).¹⁰ Hence, it is essential to maintain an optimal level of NO. In this regard, nitric oxide dioxygenases (NODs)¹¹ are available in bio-systems to convert excess NO to biologically benign nitrate (NO₃⁻).¹²NO₂⁻ + Fe^II + H⁺ ↔ NO + Fe^III + OH⁻1[M–NO]ⁿ + 2OH⁻ → [M–NO₂]⁽ⁿ⁻²⁾ + H₂O2NOD enzymes generate NO₃⁻ from NO;^11b,12−13 however, the formation of NO₂⁻ from NO is still under investigation. Clarkson and Bosolo reported NO₂⁻ formation in the reaction of Co^III-NO and O₂.¹⁴ Nam and co-workers showed the generation of Co^II-NO₂⁻ from Co^III-NO upon reaction with O₂˙⁻.¹⁵ Recently, Mondal and co-workers reported NO₂⁻ formation in the reaction of Co^II-NO with O₂.¹⁶ Apart from cobalt, the formation of Cu^II-NO₂⁻ was also observed in the reaction of Cu^I-NO and O₂.¹⁷ For metal-dioxygen adducts, i.e., Cr^III-O₂˙⁻ and Mn^IV-O₂²⁻, NOD reactions led to the generation of Cr^III-NO₂⁻ (ref. 18) and Mn^V O + NO₂⁻,¹⁹ respectively. However, the NOD reaction of Fe^III-O₂˙⁻ and Fe^III-O₂²⁻ with NO and NO⁺, respectively, generated Fe^III-NO₃⁻via Fe^IV O and ˙NO₂.²⁰ Ford suggested that the reaction of ferric-heme nitrosyl with hydroxide leads to the formation of NO₂⁻ and H⁺.¹² Lehnert and co-workers reported heme-based Fe-nitrosyl complexes²¹ showing different chemistries due to the Fe^II-NO⁺ type electronic structures. On the other hand, Bryan proposed that the one-electron reduction of NO₂⁻ to NO in ferrous heme protein is reversible (eqn (1)).²² Also, it is proposed that excess NO in biological systems is converted to NO₂⁻ and produces one equivalent of H⁺ upon reaction with ˙OH.²³ Previously reported reactivity of M–NOs of Fe²⁴ with OH⁻ suggested the formation of NO₂⁻ and one equivalent of H⁺, where H⁺ further reacts with one equivalent of OH⁻ and produces H₂O (eqn (2)).²⁵Here in this report, we explore the mechanistic aspects of nitric oxide monooxygenation (NOM) reactions of the Co^III-nitrosyl complex, [(12TMC)Co^III(NO⁻)]²⁺/{Co(NO)}⁸ (1),^15,26 bearing the 12TMC ligand (12TMC = 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane) with mono-oxygen reactive species (O²⁻, OH⁻ and H₂O) (Scheme 1). Complex 1 reacts with the base (OH⁻, tetrabutylammonium hydroxide (TBAOH)/or NaOH in the presence of 15-crown-5 as the OH⁻ source) and generates the corresponding Co^II-nitrito complex, [(12TMC)Co^II(NO₂⁻)]⁺ (3), with the evolution of hydrogen gas (H₂) via the formation of a plausible N-bound Co-nitrous acid intermediate ([Co-NOOH]⁺, 2) in CH₃CN at 273 K (Scheme 1, reaction (I)). Also, when 1 reacts with the oxide (O²⁻ or Na₂O in the presence of 15-crown-5), it generates the Co^II-nitrito complex (3) via a probable Co^I-nitro, [(12TMC)Co^I(NO₂⁻)] (4), intermediate (Scheme 1, reaction (II)); however, 1 does not react with water (Scheme 1, reaction (III)). Mechanistic investigations using ¹⁵N-labeled-¹⁵NO, D-labeled-NaOD and ¹⁸O-labelled-¹⁸OH⁻ demonstrated, unambiguously, that the N and O-atoms in the NO₂⁻ ligand of 3 resulted from NO and OH⁻ moieties; however, the H-atoms of H₂ are derived from OH⁻. To the extent of our knowledge, the present work reports the very first systematic study of Co^III-nitrosyl complex reactions with H₂O, OH⁻ and O²⁻. This new finding presents an alternative route for NO₂⁻ generation in biosystems, and also illustrates a new pathway of H₂ evolution, in addition to the reported literature.^12,27Open in a separate windowScheme 1Nitric oxide monooxygenation (NOM) reactions of cobalt-nitrosyl complex (1) in the presence of a base (OH⁻), sodium oxide (Na₂O) and water (H₂O).To further explore the chemistry of [(12TMC)Co^III(NO⁻)]²⁺ (1),^15,26 and the mechanistic insights of NOM reactions, we have reacted it with a base (OH⁻), an oxide (O²⁻), and water (H₂O). When complex 1 was reacted with TBAOH in CH₃CN, the color of complex 1 changed to light pink from dark pink. In this reaction, the characteristic absorption band of 1 (370 nm) disappears within 2 minutes (Fig. 1a; ESI, Experimental section (ES) and Fig. S1a^†), producing a Co^II-nitrito complex, [(12TMC)Co^II(NO₂⁻)]⁺ (3), with H₂ (Scheme 1, reaction (Ib)), in contrast to the previous reports on base induced NOM reactions (eqn (2)).^12,25,28 The spectral titration data confirmed that the ratio-metric equivalent of OH⁻ to 1 was 1 : 1 (ESI, Fig. S1b^†). 3 was determined to be [(12TMC)Co^II(NO₂⁻)](BF₄) based on various spectroscopic and structural characterization experiments (vide infra).^15,26bOpen in a separate windowFig. 1(a) UV-vis spectral changes of 1 (0.50 mM, black line) upon addition of OH⁻ (1 equiv.) in CH₃CN under Ar at 273 K. Black line (1) changed to red line (3) upon addition of OH⁻. Inset: IR spectra of 3-¹⁴NO₂⁻ (blue line) and 3-¹⁵NO₂⁻ (red line) in KBr. (b) ESI-MS spectra of 3. The peak at 333.2 is assigned to [(12TMC)Co^II(NO₂)]⁺ (calcd m/z 333.1). Inset: isotopic distribution pattern for 3-¹⁴NO₂⁻ (red line) and 3-¹⁵NO₂⁻ (blue line).The FT-IR spectrum of 3 showed a characteristic peak for nitrite stretching at 1271 cm⁻¹ (Co^II-14NO₂⁻) and shifted to 1245 cm⁻¹ (Co^II-15NO₂⁻) when 3 was prepared by reacting ¹⁵N-labeled NO (Co^III-15NO) with OH⁻ (Inset, Fig. 1a and Fig. S2^†). The shifting of NO₂⁻ stretching (Δ = 30 cm⁻¹) indicates that the N-atom in the NO₂⁻ ligand is derived from Co^III-15NO. The ESI-MS spectrum of 3 showed a prominent peak at m/z 333.2, [(12TMC)Co^II(¹⁴NO₂⁻)]⁺ (calcd m/z 333.2), which shifted to 334.2, [(12TMC)Co^II(¹⁵NO₂⁻)]⁺ (calcd m/z 334.2), when the reaction was performed with Co^III-15NO (Inset, Fig. 1b; ESI, Fig. S3a^†); indicating clearly that NO₂⁻ in 3 was derived from the NO moiety of 1. In addition, we have reacted 1 with Na¹⁸OH (ES and ESI^†), in order to follow the source of the second O-atom in 3-NO₂⁻. The ESI-MS spectrum of the reaction mixture, obtained by reacting 1 with Na¹⁸OH, showed a prominent peak at m/z 335.2, [(12TMC)Co^II(¹⁸ONO⁻)]⁺ (calcd m/z 335.2), (SI, Fig. S3b^†) indicating clearly that NO₂⁻ in 3 was derived from ¹⁸OH⁻. The ¹H NMR spectrum of 3 did not show any signal for aliphatic protons of the 12TMC ligand, suggesting a bivalent cobalt center (Fig. S4^†).^26b Furthermore, we have determined the magnetic moment of 3, using Evans'' method, and it was found to be 4.62 BM, suggesting a high spin Co(ii) metal center with three unpaired electrons (ESI^† and ES).²⁹ The exact conformation of 3 was provided by single-crystal X-ray crystallographic analysis (Fig. 2b, ESI, ES, Fig. S5, and Tables T1 and T2^†) and similar to that of previously reported Co^II-NO₂⁻/M^II-NO₂⁻.^15,26b Also, we have quantified the amount of nitrite (90 ± 5%), formed in the above reaction, using the Griess reagent (ESI, ES, and Fig. S6^†).Open in a separate windowFig. 2Displacement ellipsoid plot (20% probability) of 3 at 100 K. Disordered C-atoms of the TMC ring, anion and H-atoms have been removed for clarity.As is known from the literature, a metal-nitrous acid intermediate may form either by the reaction of a metal-nitrosyl with a base²⁷ or by the metal-nitrite reaction with an acid (nitrite reduction chemistry);^26b however, the products of both the reactions are different. Here, for the first time, we have explored the reaction of Co^III-nitrosyl (1) with a base. In this reaction, it is clear that the formation of Co^II-nitrito would be accomplished by the release of H₂ gas via the generation of a transient N-bound [Co-(NOOH)]⁺ intermediate (Scheme 2, reaction (II)). The formation of Co^II-NO₂⁻ (3) from the [Co-(NOOH)]⁺ intermediate is likely to proceed by either (i) homolytic cleavage of the O–H bond and release of H₂via the proposed Co^III-H transient species (Co^III-H = Co^II + 1/2H₂)³⁰ (Scheme 2, reaction (III)), as reported in previous literature where the reduced cobalt, in a number of different ligand environments, is a good H⁺ reduction catalyst and generates H₂ gas via a Co^III-H intermediate³¹ or (ii) heterolytic cleavage of the O–H bond and the formation of Co^I-NO₂⁻ + H⁺.²⁷ In the present study, we observed the formation of 3 and H₂via the plausible homolytic cleavage of the NOO–H moiety of 2 as shown in Scheme 2, in contrast to the previous reports on base-induced reactions on metal-nitrosyls (eqn (3)).²⁷ Taking together both possibilities, (i) is the most reasonable pathway for the NOM reaction of complex 1 in the presence of a base (as shown in Scheme 2, reaction (III)). And the reaction is believed to go through a Co^III-H intermediate as reported previously in Co^I-induced H⁺ reduction in different ligand frameworks and based on literature precedence, we believe that complex 1 acts in a similar manner.³¹Open in a separate windowScheme 2NOM reaction of complex 1 in the presence of OH⁻, showing the generation of Co^II-nitrito (3) and H₂via a Co(iii)-hydrido intermediate.In contrast to an O-bound Co^II-ONOH intermediate, where N–O bond homolysis of the ON-OH moiety generates H₂O₂ (Scheme 2, reaction (IV)),^26b the N-bound [Co-(NOOH)]⁺ intermediate decomposes to form NO₂⁻ and a Co(iii)-H transient species, arising from β-hydrogen transfer from the NOO–H moiety to the cobalt-center (Scheme 2, reaction (II)).^30a,c,32 The Co(iii)-hydrido species may generate H₂ gas either (a) by its transformation to the Co(ii)-nitrito complex (2) and H₂ gas as observed in the case of Co^III-H intermediate chemistry^30a,c,e−g as proposed in the chemistry of the Co^I complex with H⁺ reduction³¹ and other metal-hydrido intermediates³² and also explained in O₂ formation in PN chemistry^17,33 or (b) by the reacting with another [Co-(NOOH)]⁺ intermediate (Scheme 2, reaction (III)).Furthermore, we have confirmed the H₂ formation in the NOM reaction of 1 with OH⁻ by headspace gas mass spectrometry (Fig. 3a). Also, carrying out the reaction of 1 with NaOD leads to the formation of the [Co-(NOOD)]⁺ intermediate, which then transforms to a Co^III-D transient species. Further, as described above, the Co^III-D species releases D₂ gas, detected by headspace gas mass spectrometry (Fig. 3b), which evidently established that H₂ gas formed in the reaction of 1 with OH⁻. In this regard, we have proposed that in the first step of this reaction, the nucleophilic addition of OH⁻ to {Co-NO}⁸ generates a transient N-bound [Co-(NOOH)]⁺ intermediate that is generated by an internal electron transfer to Co^III (Scheme 2, reaction (I)). By following the mechanism proposed in the case of Co^III-H,^30a−c O₂,¹⁵ and H₂O₂(ref. 26b) formation, we have proposed the sequences of the NOM reaction of 1, which leads to the generation of Co^II-nitrito and H₂ (Scheme 2, reaction (I)–(III) and Scheme 3). In the second step, O–H bond homolytic cleavage generates a Co^III-H transient species + NO₂⁻via a β-hydrogen elimination reaction of the [Co-(NOOH)]⁺ intermediate.³² The Co^III-H intermediate may undergo the following reactions to generate H₂ gas and Co^II-nitrito either (a) by the natural decomposition of the Co^III-H transient species to generate H₂,^30a,c,e−g or (b) by the H-atom abstraction from another [Co-(NOOH)]⁺ intermediate (Scheme 3). Also, to validate our assumption that the reaction goes through a plausible N-bound [Co-(NOOH)]⁺ intermediate followed by its transformation to the Co^III-H species (vide supra), we have performed the reaction of 1 with NaOH/NaOD (in 1 : 1 ratio). In this reaction, we have observed the formation of a mixture of H₂, D₂, and HD gases, which indicates clearly that the reaction goes through the formation of Co^III-H and Co^III-D transient species via the aforementioned mechanism (Fig. 3c). This is the only example where tracking of the H atoms has confirmed the H₂ generation from an N-bound NOO–H moiety as proposed for H₂ formation from Co^III-H.³⁰Open in a separate windowFig. 3Mass spectra of formation of (a) H₂ in the reaction of 1 (5.0 mM) with NaOH (5.0 mM), (b) D₂ in the reaction of 1 (5.0 mM) with NaOD (5.0 mM), (c) D₂, HD, and H₂ in the reaction of 1 (5.0 mM) with NaOD/NaOH (1 : 1), and (d) H₂ in the reaction of 1 (5.0 mM) with NaOH in the presence of 2,4 DTBP (50 mM).Open in a separate windowScheme 3NOM reaction of complex 1 in the presence of OH⁻, showing the different steps of the reaction.While, we do not have direct spectral evidence to support the formation of the transient N-bound [Co-(NOOH)]⁺ intermediate and its decomposition to the Co^III-H transient species via β-hydrogen transfer from the NOOH moiety to the cobalt center, support for its formation comes from our finding that the reactive hydrogen species can be trapped by using 2,4-di-tert-butyl-phenol (2,4-DTBP).³⁴ In this reaction, we observed the formation of 2,4-DTBP-dimer (2,4-DTBP-D, ∼67%) as a single product (ESI, ES, and Fig. S7^†). This result can readily be explained by the H-atom abstraction reaction of 2,4-DTBP either by [Co-(NOOH)]⁺ or Co^III-H, hence generating a phenoxyl-radical and 3 with H₂ (Fig. 3d and Scheme 2, reaction (a)). Also, we have detected H₂ gas formation in this reaction (ESI,^† ES, and Fig. 3d). In the next step, two phenoxyl radicals dimerized to give 2,4-DTBP-dimer (Scheme 2c, reaction (II)). Thus, the observation of 2,4-DTBP-dimer in good yield supports the proposed reaction mechanism (Scheme 2, reaction (a) and (b)). Further, the formation of 2,4 DTBP as a single product also rules out the formation of the hydroxyl radical as observed in the case of an O-bound nitrous acid intermediate.^26bFurthermore, we have explored the NOM reactivity of 1 with Na₂O/15-crown-5 (as the O²⁻ source) and observed the formation of the Co^II-nitrito complex (3) via a plausible Co^I-nitro (4) intermediate (Scheme 1, reaction (IIa); also see the ESI^† and ES); however, 1 was found to be inert towards H₂O (Scheme 1, reaction (III); also see the ESI, ES and Fig. S8^†). The product obtained in the reaction of 1 with O²⁻ was characterized by various spectroscopic measurements.^15,26b The UV-vis absorption band of 1 (λ_max = 370 nm) disappears upon the addition of 1 equiv. of Na₂O and a new band (λ_max = 535 nm) forms, which corresponds to 3 (ESI, Fig. S9^†). The FT-IR spectrum of the isolated product of the above reaction shows a characteristic peak for Co^II-bound nitrite at 1271 cm⁻¹, which shifts to 1245 cm⁻¹ when exchanged with ¹⁵N-labeled-NO (¹⁵N¹⁶O) (ESI, ES, and Fig. S10^†), clearly indicating the generation of nitrite from the NO ligand of complex 1.^26b The ESI-MS spectrum recorded for the isolated product (vide supra) shows a prominent ion peak at m/z 333.1, and its mass and isotope distribution pattern matches with [(12-TMC)Co^II(NO₂)]⁺ (calc. m/z 333.1) (ESI, Fig. S11^†). Also, we quantified the amount of 3 (85 ± 5%) by quantifying the amount of nitrite (85 ± 5%) using the Griess reagent test (ESI, ES, and Fig. S6^†).In summary, we have demonstrated the reaction of Co^III-nitrosyl, [(12-TMC)Co^III(NO⁻)]²⁺/{CoNO}⁸ (1), with mono-oxygen reactive species (O²⁻, OH⁻ and H₂O) (Scheme 1). For the first time, we have established the clear formation of a Co^II-nitrito complex, [(12TMC)Co^II(NO₂⁻)]⁺ (3), and H₂ in the reaction of 1 with one equivalent of OH⁻via a transient N-bound [Co-(NOOH)]⁺ (2) intermediate. This [Co-(NOOH)]⁺ intermediate undergoes the O–H bond homolytic cleavage and generates a Co^III-H transient species with NO₂⁻, via a β-hydrogen elimination reaction of the [Co-(NOOH)]⁺ intermediate, which upon decomposition produces H₂ gas. This is in contrast to our previous report, where acid-induced nitrite reduction of 3 generated 1 and H₂O₂via an O-bound Co^II-ONOH intermediate.^26b Complex 1 was found to be inert towards H₂O; however, we have observed the formation of 3 when reacted with O²⁻. It is important to note that H₂ formation involves a distinctive pathway of O–H bond homolytic cleavage in the [Co-(NOOH)]⁺ intermediate, followed by the generation of the proposed Co^III-H transient species (Co^II + 1/2H₂)³⁰ prior to H₂ evolution as described in Co^I chemistry with H⁺ in many different ligand frameworks.³¹ The present study is the first-ever report where the base induced NOM reaction of Co^III-nitrosyl (1) leads to Co^II-nitrito (3) with H₂ evolution via an N-bound [Co-(NOOH)]⁺ intermediate, in contrast to the chemistry of O-bound Co^II-ONOH^26b, hence adding an entirely new mechanistic insight of base induced H₂ gas evolution and an additional pathway for NOM reactions.     

Correction: Crystal structure and metallization mechanism of the π-radical metal TED

Radical electrons tend to localize on individual molecules, resulting in an insulating (Mott–Hubbard) bandgap in the solid state. Herein, we report the crystal structure and intrinsic electronic properties of the first single crystal of a π-radical metal, tetrathiafulvalene-extended dicarboxylate (TED). The electrical conductivity is up to 30 000 S cm⁻¹ at 2 K and 2300 S cm⁻¹ at room temperature. Temperature dependence of resistivity obeys a T³ power-law above T > 100 K, indicating a new type of metal. X-ray crystallographic analysis clarifies the planar TED molecule, with a symmetric intramolecular hydrogen bond, is stacked along longitudinal (the a-axis) and transverse (the b-axis) directions. The π-orbitals are distributed to avoid strong local interactions. First-principles electronic calculations reveal the origin of the metallization giving rise to a wide bandwidth exceeding 1 eV near the Fermi level. TED demonstrates the effect of two-dimensional stacking of π-orbitals on electron delocalization, where a high carrier mobility of 31.6 cm² V⁻¹ s⁻¹ (113 K) is achieved.

The molecular arrangement that enables metallic conduction in a single-component pure organic crystal is revealed by single-crystal X-ray diffraction.

Organic molecular solids are typically insulating due to their paired electrons in spatially localized s- and p-orbitals. The concept of charge-transfer (CT) between donor and acceptor¹ enabled the development of conducting molecular complexes (salts) including semiconducting perylene-bromine,² metallic tetrathiafulvalene (TTF)-tetracyano-p-quinodimethane (TCNQ),³ and polyacethylene doped with halogen molecules.⁴ A different strategy was proposed in the 1970s based on organic radicals with an open-shell electronic structure.⁵ π-Radicals such as neutral-,⁶ fully-conjugated⁷ and zwitterionic (betainic)⁸ molecules, with an unpaired electron in their singly occupied molecular orbital (SOMO), offered potential candidates. However, all these π-radicals were insulators or semiconductors with a finite bandgap, which is due to the SOMO being localized on an individual molecule. In the Mott–Hubbard model,⁹ the case of the π-radical solids can be described by the on-site Coulomb repulsion U being larger than the electronic bandwidth W (U/W > 1), in contrast to U/W < 1 in molecular metals like CT metal systems (Fig. 1a).Open in a separate windowFig. 1(a) Schematic representation of the electronic band structure of Mott–Hubbard insulators (left) and possible molecular metals (right), respectively. Solids formed from typical π-radicals possess large on-site Coulomb repulsion U compared with the electronic bandwidth W, resulting a finite bandgap (left). This requires a new mechanism to expand W and overcome U to achieve a metallic state at ambient pressure in π-radical crystals. (b) Molecular structure of the zwitterionic radical, tetrathiafulvalene-extended dicarboxylate (TED) with a symmetric intramolecular hydrogen bond.A straightforward approach to realize high conductivity in π-radical systems is to enhance the intermolecular interaction by applying high pressure.¹⁰ Bisdithiazolyl radical crystal achieved W ∼ 1 eV near the Fermi level and the room temperature conductivity σ_RT = 2 S cm⁻¹ under 11 GPa pressure.^10c An alternative route is to decrease the interatomic spacing by incorporating a metal ion. Introduction of a semimetal Se and intermolecular hydrogen bonding in a donor-type radical succeeded to improve a conductivity to σ_RT = 19 S cm⁻¹ but still required high pressure over 1 GPa for breaking its insulating character.^10d An organometallic compound with a transition metal, [Ni(tmdt)₂], by contrast, is known to form a three-dimensional (3D) Fermi surface with W = 0.48 eV and metallic conduction with σ_RT = 400 S cm⁻¹ at ambient pressure.¹¹ A breakthrough concept for expanding W at ambient pressure is desired for achieving metallization in pure organic π-radicals.Tetrathiafulvalene-extended dicarboxylate (TED) is an organic air-stable zwitterionic radical (Fig. 1b),¹² which was designed based on carrier generation induced by a stably-introduced protonic defect (–H⁺) in hydrogen-bonding molecules without adopting CT between multiple molecules.¹³ A polycrystalline film of TED exhibited metallic conduction at ambient pressure, but the mechanism has not been clarified yet due to lack of single crystal information.¹² Herein, we report the first crystal structure and intrinsic electronic properties of the recently grown single crystal TED. Structural analysis and quantum chemical simulations based on the single crystal reveal the origin of its metallic behavior.     

Development of an active site titration reagent for α-amylases

α-Amylases are among the most widely used classes of enzymes in industry and considerable effort has gone into optimising their activities. Efforts to find better amylase mutants, such as through high-throughput screening, would be greatly aided by access to precise and robust active site titrating agents for quantitation of active mutants in crude cell lysates. While active site titration reagents designed for retaining β-glycosidases quantify these enzymes down to nanomolar levels, convenient titrants for α-glycosidases are not available. We designed such a reagent by incorporating a highly reactive fluorogenic leaving group onto unsaturated cyclitol ethers, which have been recently shown to act as slow substrates for retaining glycosidases that operate via a covalent ‘glycosyl’-enzyme intermediate. By appending this warhead onto the appropriate oligosaccharide, we developed efficient active site titration reagents for α-amylases that effect quantitation down to low nanomolar levels.

α-Amylases are among the most widely used classes of enzymes in industry and considerable effort has gone into optimising their activities.

Amylases are among the most common classes of enzymes employed in industrial settings, being used in detergents, bread, beer, biofuel, and many other sectors. Accordingly, α-amylases account for 25% of the world''s multi-billion dollar enzyme market.^1,2 α-Amylases are endo-acting enzymes that cleave starch into malto-oligosaccharides, which are further degraded by exo-acting α-glucosidases, glucoamylases, β-amylases and α-glucan phosphorylases and lyases. They are found in CAZy GH families 13, 57, 119 and 126, with the vast majority in the large GH13 family.³ GH13 enzymes adopt a (β/α)₈ fold with three highly conserved active site carboxylic acids.^4–6 They employ a classical double-displacement mechanism⁷ in which one of the glutamic acids provides acid catalytic assistance to the leaving group departure while an aspartate attacks the anomeric centre, forming a covalent glycosyl enzyme intermediate. In a second step, water attacks the anomeric centre with base assistance from the glutamate residue (Fig. 1A and B).Open in a separate windowFig. 1Koshland mechanism of retaining β- and α-glycosidases (A & B). The same mechanism has been observed for the hydrolysis of “β”-valienols (C), and for “α”-valienols (D).Given their industrial importance, a huge amount of attention has been given to the discovery and improvement of α-amylases to attain optimal performance for particular applications. These approaches typically require high-throughput analysis of large numbers of gene products or mutants thereof.^8–10 Identification of the best candidates then ideally requires high-throughput assay coupled with a method for determining the enzyme concentration in each sample. This can be a challenging task in the absence of purification, as would be the case for truly high-throughput approaches. The “gold standard” method to quantify active enzyme concentration is active site titration.¹¹ Active site titrants react stoichiometrically with their target enzymes and release one equivalent of a quantifiable agent, which is typically either a chromophore or fluorophore. For enzymes that operate via a covalent intermediate, such as retaining glycosidases, the active site titrants are usually chromogenic or fluorogenic substrates that form this intermediate with a rate constant (k_on) that is much greater than that for its hydrolysis (k_off) – ideally with k_off approaching zero.Our lab has previously developed active site titration reagents for several retaining β-glycosidases^12,13 and neuraminidases.^14,15 By replacing the substituent on the position adjacent to the anomeric centre of the sugar (the hydroxyl at C-2 for many monosaccharides) with a fluorine atom, both the formation and the hydrolysis of the glycosyl-enzyme intermediate are slowed, largely through inductive destabilisation of the transition state. Further incorporation of a reactive fluorogenic leaving group generates a reagent that, upon covalently inactivating the glycosidase, releases a stoichiometric and quantifiable amount of fluorophore. The fluorogenic response is then measured to determine the amount of active glycosidase that is present in solution.Unfortunately, this same strategy does not work for retaining α-glycosidases. In those cases, k_off remains greater than k_on, likely due to the inherently greater reactivity of the β-glycosyl-enzyme intermediate,^16,17 and the compounds are simply substrates with low turnover numbers. By use of 2,2-dihalosugars with yet more reactive leaving groups, this problem could be solved in some cases, but their synthesis is challenging, and inactivation rates were low, or non-existent in some cases.^18,19 Alternative approaches were called for.Recently, a new class of glycosidase substrates was reported in which the sugar moiety is replaced by an equivalently hydroxylated cyclohexene.^20–23 Hydrolysis of these enol ethers likely occurs via an allylic cation of almost identical reactivity to that of the equivalent oxocarbenium ion. Glycosidases cleave these substrates via the classical Koshland mechanism⁷ (Fig. 1C and D), but considerably more slowly than their natural substrates. However, incorporation of a good leaving group will accelerate, relatively, the first step such that, in some cases, they act as mechanism-based inactivators making them candidates for development of an active site titrant for α-amylases.Since α-amylases are endo-acting enzymes that do not usually cleave monosaccharide glycosides, an ‘extended” oligosaccharide version containing a total of 2 or 3 sugar/pseudosugar moieties would be needed. Substrates longer than this would be prone to internal glycoside cleavage. Since 2-chloro-4-nitrophenyl maltotrioside (CNP-G3) functions as a substrate for most amylases, we focused on addition of a maltosyl unit to a valienol moiety containing a 6,8-difluorocoumarin (F₂MU) leaving group at its “anomeric centre”. The low pK_a of this coumarin, 4.7,¹⁴ results in a greater reactivity of the reagent and also ensures the coumarin will be deprotonated and thus fluorescent, upon release at neutral pH.Synthesis of partially protected alcohol 2 from gluconolactone 1via literature methods²⁴ was followed by attachment of F₂MU via a Mitsunobu reaction and subsequent removal of the protecting groups under acidic conditions, generating known pseudo-glycoside 3.²³ To check this concept before we synthesized the longer version, we tested compound 3 as a titrant of a simple α-glucosidase and found that it did indeed titrate the enzyme (Fig. S5^†). Since elongation of this pseudosugar via classical organic synthesis would require substantial protecting group chemistry, we elected instead to employ an enzymatic coupling strategy using the GH13 cyclodextrin transglycosidase, CGTase. This enzyme can use glycosyl fluorides, such as α-maltosyl fluoride, to effect glycosyl transfer onto suitable acceptors. However, a significant competing reaction would involve self-condensation of glycosyl fluorides ultimately forming cyclodextrins. To avoid this problem, we employed a maltosyl fluoride donor (4), in which the 4′-hydroxyl had been capped with a methyl group.^25,26 Incorporation of 4′-methoxy groups does not alter the reaction with α-amylases, as this site in the normal substrate is occupied by additional sugar residues. Thus CGTase-catalysed glycosylation between known glycosyl fluoride 4 and pseudo-glycoside 3, gave the pseudo-trisaccharide 5 in 64% isolated yield (Scheme 1).Open in a separate windowScheme 1Synthesis of titration reagent 5.With this reagent in hand, we proceeded to screen its ability to inactivate a small panel of α-amylases. As shown in Fig. 2, time-dependent inactivation was observed for all enzymes tested, with the most industrially relevant enzymes, Effusibacillus pohliae amylase (EPA) and Aspergillus oryzae amylase (AOA), being inactivated the fastest.Open in a separate windowFig. 2Time-dependent inactivation of a small panel of amylases, showing remaining % activity versus time. Red box with X: AOA (91 nM); blue square: EPA (66.7 nM); purple cross: PPA (500 nM); green triangle: HPA (125 nM). AOA = A. oryzae amylase; EPA = E. pohliae amylase; HPA = human pancreatic amylase; PPA = porcine pancreatic amylase.Kinetic parameters for inactivation were then determined by directly monitoring the release of F₂MU by UV-Vis (Table 1). To determine k_on and k_off (Scheme 2), we monitored chromophore (F₂MU) release by absorbance at 370 or 380 nm (dependent on the concentration of 5 in the measurements of each enzyme). After mixing 5 with each enzyme individually, a burst phase followed by a steady-state phase was observed. For each enzyme, this was then repeated with varying concentrations of 5. Initial rates of F₂MU release versus concentration of 5 were fit to a Michaelis–Menten equation to provide k_on. The rate constant of cyclitol release, k_off, was determined by measuring rates of the steady-state region at a saturating concentration (5× K_i). We found that several amylases: Effusibacillus pohliae amylase (EPA), Aspergillus oryzae amylase (AOA), Rhizomucor pusillus amylase (RPA) and porcine pancreatic amylase (PPA), inactivated quickly (highest k_on, lowest k_off, and greatest k_on/K_i), and are therefore ideal candidates for titration with compound 5. Human pancreatic amylase (HPA), on the other hand, while inactivating rapidly, binds the reagent relatively poorly.Open in a separate windowScheme 2Kinetic parameters for the hydrolysis of 5 by several amylases (at 25 °C for EPA, AOA, and RPA and 30 °C for human pancreatic amylase [HPA] and porcine pancreatic amylase [PPA])

Rational design of an “all-in-one” phototheranostic

We report here porphodilactol derivatives and their corresponding metal complexes. These systems show promise as “all-in-one” phototheranostics and are predicated on a design strategy that involves controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation. The requisite balance was achieved by tuning the aromaticity of these porphyrinoid derivatives and forming complexes with one of two lanthanide cations, namely Gd³⁺ and Lu³⁺. The net result led to a metalloporphodilactol system, Gd-trans-2, with seemingly optimal ISC efficiency, photothermal conversion efficiency and fluorescence properties, as well as good chemical stability. Encapsulation of Gd-trans-2 within mesoporous silica nanoparticles (MSN) allowed its evaluation for tumour diagnosis and therapy. It was found to be effective as an “all-in-one” phototheranostic that allowed for NIR fluorescence/photoacoustic dual-modal imaging while providing an excellent combined PTT/PDT therapeutic efficacy in vitro and in vivo in 4T1-tumour-bearing mice.

We report here porphodilactol derivatives and their corresponding metal complexes as “all-in-one” phototheranostics by controlling the relationship between intersystem crossing (ISC) and photothermal conversion efficiency following photoexcitation.     

Two helices from one chiral centre – self organization of disc shaped chiral nanoparticles

Gold nanoparticles (AuNPs) have been prepared and surface-functionalized with a mixture of 1-hexanethiol co-ligands and chiral discogen ligands separated from a disulfide function via a flexible spacer. Polarized optical microscopy together with differential scanning calorimetry showed that the organic corona of the nanocomposite forms a stable chiral discotic nematic phase with a wide thermal range. Synchrotron X-ray diffraction showed that gold NPs form a superlattice with p2 plane symmetry. Analysis indicated that the organic corona takes up the shape of a flexible macrodisk. Synchrotron radiation-based circular dichroism signals of thin films are significantly enhanced on the isotropic-LC transition, in line with the formation of a chiral nematic phase of the organic corona. At lower temperatures the appearance of CD signals at longer wavelengths is associated with the chiral organisation of the NPs and is indicative of the formation of a second helical structure. The decreased volume required and the chiral environment of the disc ligands drives the nanoparticles into columns that arrange helically, parallel to the shortest axis of the two dimensional lattice.

Gold nanoparticles (NPs) were surface functionalized with hexanethiol groups and chiral nematic discogen ligands. A superlattice, liquid crystal behaviour and helix formation of the discs and a second helical organisation of the NPs were detected.

The exploration of chiral nanomaterials is a rapidly evolving fascinating field with uses ranging from catalysis, chiral molecular sensing, stereoselective separations to super-resolution imaging.^1–3 Bottom-up approach design strategies for nanoparticles (NPs) or nanorods (NRs) as composites in liquid crystal (LC) matrices have been developed, making use of progress in synthesis strategies and characterization techniques.^4–6 For optical applications symmetry breaking by introducing chirality into the systems at the nanoscale is critical.⁷ So far, efforts to obtain chiroptical NP-LC systems have relied mainly on NPs doped in LC hosts: either chiral nematic templates disperse NPs into chiral assemblies⁸ or the NPs functionalized with chiral ligands are included in achiral nematic LCs;⁹ both strategies aim to transfer and amplify chiral effects.^10,11 Beyond the scientific challenge of generating nanocomposites where the interplay of bottom-up structuring enables plasmonic interactions of the NPs, leading to novel, so called metamaterials properties, there are new uses ranging from novel display devices,¹² to more advanced optical communications using spin information between LEDs¹³ and in quantum teleportation for optical computing.¹⁴Precise size control of NPs in LC matrices in combined systems has been found critical to avoid phase separation or precipitation of NPs.¹⁵ For intrinsic liquid crystalline NP-LC systems, targeting of the LC phase range to be close to ambient is of utmost importance, as delamination of ligands occurs at elevated temperatures, even for very stable thiol functions. Degradation tends to occur above 100 °C.¹⁶ Inclusion of chiral groups in the organic corona can lead to chiral LC phase behavior, but there is little evidence that the NPs experience a chiral distortion in their packing; experimental evidence indicates that the nanocomposites minimize energy by packing in non-chiral superlattices and chirality is confined to the corona.¹⁷Here we show that a combination of small NPs with a carefully designed chiral organic coating results in chiral assembly behaviour of both the NPs and the organic corona. Our approach is strictly modular. The surface of the gold NPs is covered and passivated by hexylthiol groups and chiral lipoic acid derivates bearing via a spacer the mesogenic groups. We note that lipoic acid, a naturally occurring chiral antioxidant explored elsewhere for the treatment of several diseases, is bound with a dithiolate bridge via two atoms to the Au surface (see Chart 1).¹⁸ This places the chiral moiety rigidly in position onto the NPs, making thus a chiral surface.¹⁹ A pentaalkynylbenzene (PA) derivative was selected as mesogenic group, as this structural motif is known to promote reliably discotic nematic phase (N_D) behaviour.²⁰ The much larger volume of the PA group, when compared to typical rod shaped mesogens, whilst also delivering LC behaviour close to ambient, is anticipated to impact more strongly on the spatial organization of neighbouring NPs when compared to calamitic functionalized NP systems.¹⁷ The formation of helically ordered superstructures is studied by a combination of dedicated thin film optical polarizing microscopy, X-ray diffraction and synchrotron radiation-based circular dichroism (SRCD). A structural model is proposed based on a chiral nematic phase made up of AuNPs coated with chiral shells forming flexible macrodisks which in turn assemble in a superlattice.^21–23Open in a separate windowChart 1Sketch of the functionalized gold nanoparticle system AuDLC*.The design, synthesis and chemical characterization of the chiral discogen is described in the ESI.^† The precursor disk-like mesogen which forms exclusively a N_D phase above 100 °C consists of six aromatic rings flanked by flexible pentyloxy chains and an undecyloxy chain bearing a terminal hydroxy group (Fig. S1^†). The attachment of the flexible (R)-(+)-1,2-dithiolane-3-pentanoic tail was predicted to promote the desired phase. The new target discogen was obtained in a high yield (93.1%) reaction. For the synthesis and purification of LC-functionalized AuNPs, denoted as AuDLC*, a synthetic pathway was developed involving first the preparing and purifying of the alkylthiol coated NPs to which LC groups are linked, using an exchange reaction (for details see the Scheme 1 in ESI^†).^24,25The thermal behaviour of the chiral discogen was examined by differential scanning calorimetry (DSC) and polarized optical microscopy (POM). The target discogen shows clearly a chiral nematic phase with the characteristic bundles of oily streaks (Fig. S2^†). On heating (Fig. S3^†), phase formation was observed at 49.0 °C from the crystalline state, with the material turning into an isotropic liquid at 95.7 °C (ΔH = 0.20 J g⁻¹ or 0.28 kJ mol⁻¹). Formation of the mesophase from the isotropic state on cooling started from 94.5 °C with an enthalpy change of 0.12 J g⁻¹ (0.17 kJ mol⁻¹), followed by a slow crystallisation occurring at 5.1 °C. In brief, the chiral phase behaviour of the target ligand is exclusively chiral nematic, enantiotropic and with a wide thermal range of up to 89.4 °C.The ¹H-NMR spectra of the investigated AuDLC* nanocomposite and the comparison with the spectra of the monomer ligand (Fig. S4^†) indicate that the chiral discogen with the disulfide group are chemically attached onto the surface of AuNPs with high efficiency. A typical feature for such NPs are the broadened ¹H-NMR spectra caused by the reduced mobility of alkyl chains of the ligands when anchored to NPs and additionally the sharp peaks present in the free ligand have disappeared, typical for such systems.²⁶ The absence of mobile free discogen using thin layer chromatography (silica, with dichloromethane as mobile phase) confirms this result. The amount of chiral discogen bounded onto the gold surface relative to the number of 1-hexanethiol groups was determined from the ¹H-NMR spectra of AuDLC*. The ratio of hydrocarbons to discogens was found to be 2 : 3. Transmission Electron Microscopy (TEM) investigations confirm that this sequential synthesis affords nanoparticles of low polydispersity (Fig. 1a); the average particle size is ∼2.5 ± 0.5 nm. Thermo-gravimetric analysis (TGA) was performed (Fig. S6^†) and gives the weight fraction of gold in AuDLC* to be 47.8% (wt/wt). The mesogen density per Au NP was calculated (ESI^† Part 7) by combining the ¹H-NMR results (Fig. S4^†) with the model developed by Gelbart et al.²⁷ On the basis of these data, we obtain that there are on average 211 Au atoms per particle, and a total number of 53 ligands per particle, of which 32 are chiral discogens and 21 are hexylthiol groups (Table S1^†). This is in accord with a ligand density of up to ∼6.3 ligands per nm².²⁸ Additionally, the characteristic peaks in the UV-vis spectra of AuDLC* arise from the combination of gold (∼500 nm) and LC ligands (absorption maxima at 238, 261 and 351 nm with two shoulder peaks at 378 and 421 nm) (Fig. S7^†).Open in a separate windowFig. 1(a) TEM image of 2.5 nm AuDLC* nanocomposite (inset: the size distribution of AuDLC*). POM micrographs of AuDLC* (b) 86.5 °C (90° crossed polarizer) (×100 μm). (c) 37.8 °C (90° crossed polarizer) (×100 μm). (d) DSC of AuDLC* at heating and cooling rate of 10.0 °C min⁻¹ (e) SAXS diffractograms of AuDLC* on heating from 30 °C to 140 °C. (f) SRCD spectra of sheared AuDLC*. Recorded in 5 °C steps on cooling from 100 °C to 30 °C. The enlarged plots in dotted regions A–C are shown in Fig. S12b–d.^† The CD intensities at a selected wavelengths in each region (A, B and C) are plotted as a function of temperature in Fig. S13^† and these plots clearly show the difference in the formation process between the two helical structures.The mesophase behaviour of the AuDLC* nanocomposite was first characterized by POM observation. As shown in Fig. 1b and c, upon cooling from the isotropic liquid, the colour in the POM texture changes from light green to yellow and we associate this with the helical pitch in AuDLC* increasing with decreasing temperature. In some regions of the POM slides, a chiral nematic phase with the typical Grandjean texture (Fig. S8a and b^†) is found. The LC textures in AuDLC* do recover after gently pressing the microscope coverslip indicating that the LC-decorated NPs form a stable phase and birefringent textures remain stable at ambient (Fig. S9^†). DSC investigations (Fig. 1d) confirm that the AuDLC* nanocomposite shows a thermodynamically stable (enantiotropic) mesophase. In DSC experiments on cooling a small peak associated with the isotropic to phase transition (92.2 °C) can be detected, and at a low temperature (3.8 °C), the glass transition occurs. The transition peak for the transition is wider than in the pure chiral discogen, typical for such systems.⁴ This is associated with the reduced mobility of the LC groups attached to the NPs. The thermal transitions determined by DSC for the pure chiral discogen and AuDLC* are collected in Table 1, showing the low values typical for transitions.²⁰ In contrast to the free chiral ligand, the NPs coated with the chiral ligand and hexylthiol groups show a small decrease in transition temperatures. This could be attributed to both the plastifying effects of the hexylthiol co-ligands and packing constraints of the LC groups due to the attachment to the NPs. This view is supported by the DSC data for the transition at 0.043 J g⁻¹ (0.12 kJ mol⁻¹, considering the evaluated 32 chiral discogen ligands per particle).Transition temperatures (°C) of free chiral discogen and AuDLC*, as determined by DSC (second cooling at rate of 10.0 °C min⁻¹)^a

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.     

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

Correction: Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy

Correction for ‘Rational design of a “dual lock-and-key” supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy’ by Kun-Xu Teng et al., Chem. Sci., 2020, 11, 9703–9711, DOI: 10.1039/D0SC01122C.

The authors regret an error in Fig. 1f. The correct image is shown below.Open in a separate windowFig. 1(f) Fluorescence decay curves of BSG and BIBSG, and the detection wavelength is 600 nm in DMSO.Additionally, there was a minor error in Fig. 4a. The correct image is shown below.Open in a separate windowFig. 4(a) Evaluation of ¹O₂ generation in HepG2 cells with DCFH-DA and SOSG. The scale bar represents 20 μm.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloaddition reactions of donor–acceptor cyclobutenes,cyclopropenes and siloxyalkynes induced by Brønsted acid catalysis

Brønsted acid catalyzed formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloadditions of donor–acceptor cyclobutenes, cyclopropenes, and siloxyalkynes with benzopyrylium ions are reported. [4 + 2]-cyclization/deMayo-type ring-extension cascade processes produce highly functionalized benzocyclooctatrienes, benzocycloheptatrienes, and 2-naphthols in good to excellent yields and selectivities. Moreover, the optical purity of reactant donor–acceptor cyclobutenes is fully retained during the cascade. The 1,3-dicarbonyl product framework of the reaction products provides opportunities for salen-type ligand syntheses and the construction of fused pyrazoles and isoxazoles that reveal a novel rotamer-diastereoisomerism.

Brønsted acid catalysis realizes formal [4 + 4]-, [4 + 3]-, and [4 + 2]-cycloadditions of donor–acceptor cyclobutenes, cyclopropanes, and siloxyalkynes with benzopyrylium ions.

Medium-sized rings are the core skeletons of many natural products and bioactive molecules,¹ and a growing number of strategies have been developed for their synthesis.² Because of their enthalpic and entropic advantages, ring expansion is a highly efficient methodology for these constructions.^3–6 For example, Sun and co-workers have developed acid promoted ring extensions of oxetenium and azetidinium species formed from siloxyalkynes with cyclic acetals and hemiaminals (Scheme 1a).⁴ Takasu and co-workers have reported an elegant ring expansion with a palladium(ii) catalyzed 4π-electrocyclic ring-opening/Heck arylation cascade with fused cyclobutenes (Scheme 1b).⁵ Each transformation is initiated by the formation of fused bicyclic units followed by ring expansion or rearrangement to give medium-sized rings.Open in a separate windowScheme 1Cycloaddition/ring expansion background and this work.Strategies for the formation of fused bicyclic compounds rely on cycloaddition of dienes or dipoles with unsaturated cyclic compounds⁷ and, if the reactant cyclic compound is strained and chiral, the resulting bicyclic compound is activated toward ring opening that results in retention of chirality. We have recently reported access to donor–acceptor cycloalkenes by [3 + n] cycloaddition that have the prerequisites of unsaturated cyclic compounds suitable for cycloaddition.⁸ Donor–acceptor (D–A) cyclopropenes⁹ and cyclobutenes¹⁰ have sufficient strain in the resulting bicyclic compounds to undergo ring opening. We envision that the selection of a diene or dipolar reactant and suitable reaction conditions could realize cycloaddition and subsequent ring expansion. Benzopyrylium species,^11,12 which are generated by metal or acid catalysis, have attracted our attention. We anticipated that their high reactivity would overcome the conventional unfavorable kinetic and/or thermodynamic factors that typically impede medium-sized ring formation. From a mechanistic perspective, benzopyrylium species are often formed by transition metal catalyzed reactions with 2-alkynylbenzaldehydes.¹¹ Recently, the reaction between 1H-isochromene acetal and Brønsted acid catalyst forms the 2-benzopyrylium salts that could react with functional alkenes to give same cycloaddition products.¹² Consequently, we believed that the [4 + 2]-cyclization between benzopyrylium species and donor–acceptor cyclobutenes, cyclopropenes, or siloxyalkynes would give bridged oxetenium intermediates, which contain high strain energy that should provide the driving force for ring expansion. The “push and pull” electronic effect of donor–acceptor functional groups facilitates deMayo-type ring-opening of the cyclobutane or cyclopropane skeletons (Scheme 1c).¹³Here we report bis(trifluoromethanesulfonyl)imide (HNTf₂) catalyzed formal [4 + 4]-, [4 + 3]- and [4 + 2]-cycloaddition reactions of D–A cyclobutenes, cyclopropenes, and siloxyalkynes with benzopyrylium salts. Polysubstituted benzo-cyclooctatrienes, benzocycloheptatrienes and 2-naphthols, are produced in good to excellent yields and selectivities. Complete retention of configuration occurs using chiral cyclobutenes, and opportunities for further functionalization are built into these constructions.Initially, we conducted transition metal catalyzed reactions with 2-alkynylbenzaldehyde intending to produce the corresponding benzopyrylium ion and explore the possibility of cycloaddition/ring opening with donor–acceptor cyclobutene 2a. Use of Ph₃PAuCl/AgSbF₆, Pd(OAc)₂ and Cu(OTf)₂, which were efficient catalysts in previous transformations,¹¹ gave only a trace amount of cycloaddition product (Fig. 1). Spectral analysis showed that mostly starting material remained (Fig. 1-i and ii). Increasing the reaction temperature led only to decomposition of 2-alkynylbenzaldehyde (Fig. 1-iv) or donor–acceptor cyclobutene 2a (Fig. 1-iv).Open in a separate windowFig. 1Reaction of 2-alkynylbenzaldehyde with donor–acceptor cyclobutene 2a.From these disappointments we turned our attention to 1H-isochromene acetal 1a as the benzopyrylium ion precursor. Various Lewis acid catalysts were employed with limited success, but we were pleased to observe the formation of the desired formal [4 + 4]-cycloaddition benzocyclooctatriene product 3aa, albeit in low yields (Table 1, entries 1–6). Selection of the Brønsted super acid HNTf₂ (ref. 14) proved to be the most promising, producing 3aa in 40% yield (Table 1, entry 7). Increasing the amount of D–A cyclobutene 2a by 30% gave a much higher yield of 3aa (Table 1, entry 8 vs. 7). Optimization of the stoichiometric reaction between 1a and 2a by increasing the reaction temperature from rt to 35 °C led to the formation of the desired product in 76% isolated yield (Table 1, entry 9 vs. 8). However, a further increase in the reaction temperature (Table 1, entry 10) or reducing the catalyst loading to 5 mol% did not improve the yield of 3aa (Table 1, entry 11).Optimization of reaction conditions^a

Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution

β-Difluoroalkylborons, featuring functionally important CF₂ moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.

Organofluorine compounds have been widely applied in medicinal chemistry and materials science.^1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.^2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,^3a,b photoredox difluorination,⁴ radical difluorination,⁵ and cross-coupling reactions with suitable CF₂ carriers^6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.^7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).^7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.^7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.^7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.⁷ⁱOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates^8a–c as starting materials.^9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.^9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).¹⁰ While extending the scope of our previous work,^9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.^11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,¹⁰ could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.^12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et₃N·HF in association with PhI(OAc)₂ (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions

Catalytic asymmetric hydrogenation of (Z)-α-dehydroamido boronate esters: direct route to alkyl-substituted α-amidoboronic esters

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized. Using this approach, a class of therapeutically relevant alkyl-substituted α-amidoboronic esters was easily synthesized in high yields with generally excellent enantioselectivities (up to 99% yield and 99% ee). The utility of the products has been demonstrated by transformation to their corresponding boronic acid derivatives by a Pd-catalyzed borylation reaction and an efficient synthesis of a potential intermediate of bortezomib. The clean, atom-economic and environment friendly nature of this catalytic asymmetric hydrogenation process would make this approach a new alternative for the production of alkyl-substituted α-amidoboronic esters of great potential in the area of organic synthesis and medicinal chemistry.

The direct catalytic asymmetric hydrogenation of (Z)-α-dehydroamino boronate esters was realized.

Since FDA approval of bortezomib¹ for the treatment of multiple myeloma, chiral α-aminoboronic acids have been recognized as key pharmacophores for the design of proteasome inhibitors.² The incorporation of chiral α-aminoboronic acid motifs at the C-terminal position of a peptide³ to develop potential clinical drug candidates has drawn increasing interest⁴ (Fig. 1). Meanwhile, chiral α-amidoboronic acids and their derivatives are useful synthetic building blocks for the stereospecific construction of chiral amine compounds.⁵ The biological and synthetic value of α-amidoboronates has led to considerable efforts for the development of efficient synthetic methods. However, up to now, limited transition-metal-catalyzed asymmetric approaches have been reported. The widely used strategies to synthesize these compounds are stepwise Matteson homologation/N-nucleophilic replacement,⁶ borylation of imines,⁷ and alkene functionalization.⁸ Recently, two other elegant approaches, Ni-catalyzed decarboxylative borylation of α-amino acid derivatives⁹ and enantiospecific borylation of lithiated α-N-Boc species,¹⁰ were reported by the Baran and Negishi groups, respectively. To the best of our knowledge, the majority of the methods relied on either stoichiometric amounts of chiral auxiliaries^6,7a,b or substrate-control strategies⁹ and most of these methods enable the construction of aryl-substituted α-aminoboronates. Enantioselective methods to access unfunctionalized alkyl-substituted α-aminoboronic esters are still rarely developed and so far only two examples have been realized by the Miura^8a and Scheidt^7f groups, respectively. Considering that most therapeutically relevant α-amidoboronic acid fragments contain an alkyl subunit and the fact that the options for the synthesis of alkyl-substituted α-amidoboronic esters in an enantioselective manner are still rare, the development of other distinct approaches would be highly desirable. Herein, we report a new alternative to access these compounds by catalytic asymmetric hydrogenation of (Z)-α-dehydroamidoboronate esters. With this approach, the desired chiral alkyl-substituted α-amidoboronic esters could be obtained in high yields and generally excellent enantioselectivities (up to 99% yield and 99% ee) with simple purification.Open in a separate windowFig. 1Selected inhibitors containing chiral alkyl-substituted α-amidoboronic acids.Catalytic asymmetric hydrogenation of olefins is an atom-economic, environmentally friendly and clean process for the synthesis of valuable pharmaceuticals, agricultural compounds and feedstock chemicals.¹¹ Recently, hydrogenation of vinylboronic compounds has emerged for the preparation of chiral boronic compounds in a regiodefined manner.^12,13 However, surprisingly α-dehydroamido boronate esters and their derivatives, as elegant precursors to access alkyl-substituted α-amidoboronic compounds, have never been used as substrates in asymmetric hydrogenation and remain a challenging project. To our knowledge, only one efficient hydrogenation approach to (1-halo-1-alkenyl) boronic esters was reported for indirect synthesis of alkyl-substituted α-aminoboronic esters but it was accompanied by inevitable de-halogenated by-products¹⁴ (Scheme 1). Given the catalytic efficiency and atom economy of the hydrogenation method, the development of a new direct hydrogenation approach to construct these important chiral alkyl-substituted α-amidoboronic esters would be very appealing.Open in a separate windowScheme 1Approaches towards the synthesis of chiral alkyl-substituted α-aminoboronic esters.The inspiration for our approach to the hydrogenation of α-dehydroamido boronates came from the molecular structures of relevant biologically active inhibitors containing alkyl-substituted α-amidoboronic acid fragments. Due to the limited stability of free α-aminoboronic acids, an electron-withdrawing carboxylic N-substituent is often required.¹⁵ Thus, we envisaged that N-carboxyl protected α-dehydroamido boronate esters could serve as a potential precursor for the synthesis of alkyl-substituted α-amidoboronates through Rh-catalyzed asymmetric hydrogenation of the C C bond¹⁶ (Fig. 1), a strategically distinct approach to the construction of unfunctionalized alkyl-substituted α-amidoboronic esters. However, challenges still remain, including: (1) how to synthesize α-dehydroamido boronates; (2) the facile transmetalation process of the starting materials leading to deboronated by-products in the hydrogenation process;¹⁷ (3) the unknown stability of α-amidoboronic compounds in the presence of a transition-metal catalyst and hydrogen molecules. As part of our continuous efforts to develop efficient hydrogenation approaches to construct valuable motifs,¹⁸ here we present the results of the investigation to address the aforementioned challenges.The desired aryl-substituted (Z)-α-dehydroamido boronates could be obtained by Cu-catalyzed regioselective hydroborylation of ynamide according to a previous report.¹⁹ However, different α/β-regioselectivity was observed for the preparation of alkyl-substituted (Z)-α-dehydroamido boronate esters and a new synthetic route was developed (Scheme 2, see the ESI^† for details). Of note, (Z)-α-dehydroamido boronate esters should be purified with deactivated silica gel,^7c or else protodeborylation would occur readily with flash chromatography.Open in a separate windowScheme 2Synthetic route to (Z)-α-dehydroamino boronates.In order to check the feasibility of our hypothesis, three substrates were prepared with Rh(NBD)₂BF₄ and examined and our group prepared (Rc,Sp)-DuanPhos under 50 atm hydrogen pressure (Table 1). Gratifyingly, substrate 1b reacted smoothly to provide the desired product 2b in high yield and enantioselectivity (>99% conv., 98% ee, entry 2) whilst the reaction with substrate 1a yielded a mixture of deborylation products and 1c did not work at all (entries 1 and 3). Of note, we did not observe deborylation products with 1b under the current reaction conditions and we did not select (Z)-α-dehydroamido boronic acid 1a as the model substrate because of its poor solubility in most solvents. Then, a variety of chiral diphosphine ligands were investigated along with Rh(NBD)₂BF₄ and the results are shown in Table 1. In most cases, the reaction proceeded smoothly to furnish the desired products and the best results were obtained when (Rc,Sp)-DuanPhos was used as the ligand (entries 2 and 4–12). Poor results were obtained with axially bidentate phosphine ligands (entries 5, 6 and 9). (R,R)-QuinoxP* and (R,R)-Ph-BPE also gave good conversion with a slightly decreased ee whilst (R,R)-ⁱPr-DuPhos exhibited poor results (entries 4, 7 and 10). Subsequent solvent screening revealed that the desired products could be obtained in most of the solvents and 1,2-DCE was the best solvent. (Entry 13, see the ESI^†).Condition optimization for catalytic asymmetric hydrogenation of 1^a

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