Halogen Bonding in N-Alkyl-bromo-/iodo-pyridinium Salts and its Application in Chromatography.

The alkylation of 3-/4-bromo- and -iodopyridine with methyl triflate smoothly affords the corresponding N-methylpyridinium triflate salts. An anion exchange with NaI or [PPh4]Y (Y = Cl, Br, I) yields the corresponding halide salts. Most of them could be structurally characterized and their strong halogen bonds were investigated. While the halogen atom of 4-halogenopyridinium is susceptible to nucleophilic substitution, 3-halogenopyridinium ions are far more stable against nucleophilic attacks. Due to the comparable interaction strength of halogen bonds and hydrogen bonds, the latter of which is widely used in chromatography, the potential of 3-halogenopyridinium moieties for an application in chromatography is obvious and was successfully employed in affinity chromatography of different proteins.

Chlorodefluorination Induced by Gallium-Based Lewis Acids.

The reaction of [Ga(C2F5)3(FSiMe3)] with chlorotrimethylsilane leads to the selective substitution of the α-fluorine atoms by chlorine atoms and thus to the formation of [Ga(CCl2CF3)3(FSiMe3)]. The corresponding chlorogallate ion, [Ga(CCl2CF3)3Cl]-, could be isolated and structurally characterized as its tetraphenylphosphonium salt. The catalytic potential of [Ga(CCl2CF3)3(FSiMe3)] was demonstrated via the chlorodefluorination of Me3SiCF3, 2,2-difluoropropane and [PPh4][Ga(C2F5)4].

Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation.

Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2-hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X-ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug-resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur-containing derivatives. X-ray crystallographic analysis of a tubulin-bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D.

Adducts of Lewis acidic stibanes with phosphane chalcogenides.

Starting from ClSbRF2 (RF = C2F5, 3,5-(CF3)2C6H3) and H(E)P(tBu)2 (E = O, S), we prepared the oxy- and sulphanediyl-bridged adducts RF2Sb(Cl)-E-(H)P(tBu)2, which are stable against the elimination of HCl. The different electron-withdrawing substituents and chalcogen bridging units influence the size of the Sb-E-P angle. ClSb(C2F5)2 and nBu3SnH react to give HSb(C2F5)2, which seems to interact weakly with H(O)P(tBu)2 in solution as observed via NMR. All products were characterised by NMR spectroscopy and all the stable ones were additionally characterised by X-ray diffraction and elemental analyses.

Chemical constituents of Coccoloba peltata Schott leaves and their cytotoxic activities.

Chromatographic fractionation of CH2Cl2:MeOH (1:1) extract of Coccoloba peltata Schott cultivated in Egypt afforded four compounds, lupeol acetate (1), ent-13-epi-manoyl oxide (2), 5-methoxymethyl-7,8-dimethyltocol (3), and α-tocopherol quinone (4). The planar structures of the isolated compounds were concluded based on HRESIMS and NMR spectroscopy. X-ray crystallography of 2 is reported herein for the first time and its unambiguous absolute configuration was deduced from anomalous dispersion. To the best of our knowledge, this is the first known report on the isolation of compounds 1-4 from this species. Among the isolated compounds, only compound 4 showed a moderate level of cytotoxic activity against six cancer cell lines out of seven cell lines tested.

A geminal antimony(iii)/phosphorus(iii) frustrated Lewis pair.

The geminal Lewis pair (F5C2)2SbCH2P(tBu)2 (1) was prepared by reacting (F5C2)2SbCl with LiCH2P(tBu)2. Despite its extremely electronegative pentafluoroethyl substituents, the neutral 1 exhibits a relatively soft acidic antimony function according to the HSAB concept (hard-soft acid-base). These properties lead to a reversibility in the binding of CS2 to 1, as observed by VT-NMR spectroscopy, while no reaction with CO2 is observed. The reaction behaviour towards heterocumulenes and the specific interaction situation in the CS2 adduct were analysed by quantum chemical calculations. The FLP-type reactivity of 1 has also been demonstrated by reaction with a variety of small molecules (SO2, PhNCO, PhNCS, (MePh2P)AuCl). The reactions of 1 with PhNCO and PhNCS led to different types of cyclic addition products: PhNCO adds with its N[double bond, length as m-dash]C bond and PhNCS adds preferentially with its C[double bond, length as m-dash]S bond. The reaction of 1 with (MePh2P)AuCl gave an adduct {[(F5C2)2SbCH2(tBu)2P]2Au}+ with a clamp-like structure binding a chloride anion by its two antimony atoms in chelate mode. Compound 1 and its adducts have been characterised by X-ray diffraction experiments, multinuclear NMR spectroscopy, elemental analyses and computational calculations (DFT, QTAIM, IQA).

Non-Kekulé meta-Quinodimethane Singlet Diradicals Based on Classical N-Heterocyclic Carbenes.

Diradicals based on a meta-quinodimethane (m-QDM) scaffold generally have a triplet ground state and are rather scarce. Herein, m-QDM-based non-Kekulé diradicals [3,3'-(NHC)2BP] (3-NHC) (NHC = SIPr = C{N(Dipp)CH2}2; IPr = C{N(Dipp)CH}2, Me-IPr = C{N(Dipp)CMe}2; Dipp = 2,6-iPr2C6H3; BP = 1,1'-C6H3C6H3) featuring N-heterocyclic carbene (NHC) pendants are reported as crystalline solids. The EPR spectra of 3-NHC show both allowed (Dms = 1) and forbidden (Dms = 2; 'half-field') transitions characteristic for triplet diradicals. Variable temperature EPR studies however reveal a singlet ground state for 3-SIPr. Consistent with the EPR spectra, calculations predict a remarkably small (open-shell) singlet-triplet energy gap (ΔEST ≤ 0.26 kcal/mol) for the 3-NHC compounds. The calculated singlet diradical character for the ground states of the 3-NHC compounds amounts to ~99%.

First Main-Group Element Lewis Acid Thionyl Chloride Adduct and its Chemistry.

Although the adduct of aluminum trichloride with thionyl chloride has been reported, no thionyl chloride adduct of a main group element Lewis acid or organometallic compound has been structurally characterized. In this communication we present the synthesis and reactivity of the structurally ascertained adduct of thionyl chloride with tris(pentafluoroethyl)gallane as a representative of a main group element Lewis acid. Gallium and indium compounds with electron withdrawing groups, e.g. the pentafluoroethyl ligand, display versatile properties. While gallates and indates, [MR4]-, behave as weakly coordinating anions, neutral gallanes and indanes, MR3, are strong Lewis acids. Salts with the tetrakis(pentafluoroethyl)gallate and -indate, [M(C2F5)4]- (M=Ga, In), have recently been studied in detail. In contrast to this, work on the syntheses of the free Lewis superacids M(C2F5)3 (M=Ga, In) is scarce and underdeveloped. The hydrates [M(C2F5)3(OH2)2] proved to be suitable starting materials, particularly due to their thermal stability. Herein we report on synthesis and characterization of reactive adducts, [M(C2F5)3D], with the weak donor molecules (D) SOCl2 and Me3SiF. The effective Lewis acidities of Ga(C2F5)3 and In(C2F5)3 were experimentally determined by the (modified) Gutmann-Beckett method and their catalytic potential is showcased.

Host-guest chemistry of tridentate Lewis acids based on tribenzotriquinacene.

Flexible poly-Lewis acids (PLA) based on the tribenzotriquinacene (TBTQ) scaffold have been synthesised. Hydrosilylation of 4b,8b,12b-triallyltribenzotriquinacene and subsequent exchange of the chlorine substituents with weaker coordinating triflate groups afforded a novel triple silyl-functionalised PLA. By regioselective hydroboration of triallyl-TBTQ with various organoboranes, PLAs with different Lewis acidities were obtained. The synthesised PLAs were combined with neutral bases in host-guest experiments. DOSY NMR spectroscopy was performed to elucidate the complexation process in solution. These experiments revealed a highly dynamic interaction between the boron-functionalised PLA and triazine. However, the addition of one equivalent of tris(dimethylphosphino(methyl))phenylsilane led to the formation of a 1 : 1 adduct, which was confirmed by diffusion experiments.

Polydentate chalcogen bonding: anion trapping with a water-stable host compound carrying Se-CF3 functions.

Bidentate and tetradentate chalcogen bonding host systems with SeCF3 functions as σ-hole donors in close proximity at the alkyne functions of 1,8-diethynylanthracene and its syn-dimer were prepared in quantitative yield by tin-selenium exchange reactions of the corresponding trimethylstannyl precursors with ClSeCF3. The bidentate system shows chalcogen bonding interactions with THF, but does not bind halide ions. The tetradentate system cooperatively chelates chloride, bromide and iodide ions with its four CC-SeCF3 units by rotating the four σ-holes towards the halide ion. The structures of these halide ion adducts were determined by X-ray diffraction. The hydrobromide and -iodide salts of the ethyl derivative of Schwesinger's phosphazene superbase served as halide salts with very weakly coordinating cations.

Oxidation-dependent Lewis acidity in chalcogen adducts of Sb/P frustrated Lewis pairs.

The reactions of the frustrated Lewis pair (F5C2)2SbCH2P(tBu)2 with oxygen, sulphur, selenium and tellurium led to the mono-oxidation products (F5C2)2SbCH2P(E)(tBu)2 (E = O, S, Se, Te). Further oxidation of these chalcogen adducts with tetrachloro-ortho-benzoquinone (o-chloranil) gave (F5C2)2Sb(CH2)(µ-E)P(tBu)2·CatCl (CatCl = o-O2C6Cl4) with a central four-membered ring heterocycle for E = O, S, and Se. For E = Te the elimination of elemental tellurium led to an oxidation product with two equivalents of o-chloranil, (F5C2)2SbCH2P(tBu)2·2CatCl, which is also accessible by reaction of (F5C2)2SbCH2P(tBu)2 with o-chloranil. The synthesised compounds were characterised by NMR spectroscopy and X-ray structure analyses, and the structural properties were analysed in the light of the altered Lewis acidity due to the oxidation of the antimony atoms.

Tridentate Lewis Acids Based on Tribenzotriquinacene Chalices.

Chalice-shaped tridentate poly-Lewis acids (PLA) based on the tribenzotriquinacene (TBTQ) scaffold have been synthesised. Stannylation of the alkyne units, attached via phenyl-spacers to the benzhydrylic positions to the TBTQ scaffold, with Me2NSnMe3 afforded the trimethyltin substituted TBTQ derivative. Replacement of these tin functions with other elements resulted in rigid boron- and aluminium-functionalised PLAs. More flexible PLAs were obtained by hydrometallation reactions of the terminal alkyne groups of 4b,8b,12b-tris((ethynyl)phenyl)tribenzotriquinacene. The resulting poly-Lewis acids were tested for their acceptor abilities in host-guest experiments with suitable bases. Preliminary tests with pyridine led to the synthesis of a large tridentate base with three pyridyl groups attached to a TBTQ backbone. Complexation of this Lewis base with the PLAs resulted in the formation of aggregates, which were studied in solution in more detail by 1H DOSY NMR experiments regarding their size. Further experiments were performed with the tridentate bases 1,4,7-trimethyl-1,4,7-triazacyclononane and tris((dimethylphosphino)methyl)phenylsilane.

Bidentate boron Lewis acids: synthesis by tin boron exchange reaction and host-guest complex formation.

Four bidentate boron Lewis acids based on the 1,8-diethynylanthracene backbone have been synthesized by a tin-boron exchange reaction with various chloroboranes, yielding the products in good to excellent yields. Complexation experiments of the host compounds with pyridine, pyrimidine and TMEDA demonstrated striking differences in terms of formation and solubility of the supramolecular adducts. The host-guest complexes were investigated by multinuclear NMR spectroscopy and structurally characterized by X-ray diffraction experiments, illustrating the adaptation of the host system upon adduct formation with different neutral guest molecules.

Structure and photochemistry of di-tert-butyldiphosphatetrahedrane.

Di-tert-butyldiphosphatetrahedrane (tBuCP)2 (1) is a mixed carbon- and phosphorus-based tetrahedral molecule, isolobal to white phosphorus (P4). However, despite the fundamental significance and well-explored reactivity of the latter molecule, the precise structure of the free (tBuCP)2 molecule (1) and a detailed analysis of its electronic properties have remained elusive. Here, single-crystal X-ray structure determination of 1 at low temperature confirms the tetrahedral structure. Furthermore, quantum chemical calculations confirm that 1 is isolobal to P4 and shows a strong largely isotropic diamagnetic response in the magnetic field and thus pronounced spherical aromaticity. A spectroscopic and computational study on the photochemical reactivity reveals that diphosphatetrahedrane 1 readily dimerises to the ladderane-type phosphaalkyne tetramer (tBuCP)4 (2) under irradiation with UV light. With sufficient thermal activation energy, the dimerisation proceeds also in the dark. In both cases, an isomerisation to a 1,2-diphosphacyclobutadiene 1' is the first step. This intermediate subsequently undergoes a [2 + 2] cycloaddition with a second 1,2-diphosphacyclobutadiene molecule to form 2. The 1,2-diphosphacyclobutadiene intermediate 1' can be trapped chemically by N-methylmaleimide as an alternative [2 + 2] cycloaddition partner.

N-Heterocyclic Carbene Analogues of Wittig Hydrocarbon.

N-Heterocyclic carbene (NHC) analogues of Wittig hydrocarbon, [(NHC)(Stil)(NHC)] (3a-c) (NHC = SIPr (1a) = C[N(Dipp)CH2]2, Dipp = 2,6-iPr2C6H3; IPr (1b) = C[N(Dipp)CH]2; Me-IPr (1c) = C[N(Dipp)CMe]2 and Stil = C6H4CHCHC6H4) have been reported as crystalline solids. 3a-c are prepared by two-electron reductions of the corresponding bis-1,3-imidazoli(ni)um bromides [(NHC)(Stil)NHC)](Br)2 (2a-c) with KC8 in >94 % yields. 2a-c are accessible by the nickel catalyzed direct C-C coupling of NHCs (1a-c) with (E)-4,4'-dibromostilbene. One-electron oxidation of 3a,b yields the corresponding radical cations [(NHC)(Stil)NHC)]B(C6F5)4 4a,b. All compounds have been characterized by UV-Vis/NMR/EPR spectroscopy as well as 2a, 3a, and 3b by single crystal X-ray diffraction. The electronic structures of representative systems have been analyzed by quantum chemical calculations.

Hexadentate poly-Lewis acids based on the bowl-shaped tribenzotriquinacene.

Hexadentate poly-Lewis acids (PLA) based on the bowl-shaped tribenzotriquinacene (TBTQ) have been synthesised. The introduction of three n-propyl groups into the benzhydrylic positions of the TBTQ backbone has significantly increased the solubility of the subsequently derived compounds. Semi-flexible PLAs containing boron and aluminium were obtained by hydrometallation of the corresponding 2,3,6,7,10,11-hexaalkynyl-TBTQ. Other rigid hexadentate PLAs were synthesised by stannylation of the corresponding alkyne units with Me3SnNMe2 followed by tin-element exchange reactions. The Lewis acidity of these PLAs was investigated in host-guest experiments with pyridine. Further experiments with bidentate bases showed correlations between their flexibility, their Lewis basicity and the complexation behaviour towards the synthesised PLAs. Addition of bis((dimethylphosphino)methyl)dimethylsilane (BisPhos) to solutions of the rigid alkynyl PLAs led to the formation of 3 : 1 adducts. Single crystal X-ray diffraction was used to further elucidate the host-guest connectivtiy. In addition, a sixfold pnictogen-bonding donor was synthesised by tin-antimony exchange.

Access to a peri-Annulated Aluminium Compound via C-H Bond Activation by a Cyclic Bis-Aluminylene.

Carbocyclic aluminium halides [(ADC)AlX2]2 (2-X) (X=F, Cl, and I) based on an anionic dicarbene (ADC=PhC{N(Dipp)C}2, Dipp = 2,6-iPr2C6H3) framework are prepared as crystalline solids by dehydrohalogenations of the alane [(ADC)AlH2]2 (1). KC8 reduction of 2-I affords the peri-annulated Al(III) compound [(ADCH)AlH]2 (4) (ADCH=PhC{N(Dipp)C2(DippH)N}, DippH=2-iPr,6-(Me2C)C6H3)) as a colorless crystalline solid in 76 % yield. The formation of 4 suggests intramolecular insertion of the putative bis-aluminylene species [(ADC)Al]2 (3) into the methine C-H bond of HCMe2 group. Calculations predict singlet ground state for 3, while the conversion of 3 into 4 is thermodynamically favored by 61 kcal/mol. Compounds 2-F, 2-Cl, 2-I, and 4 have been characterized by NMR spectroscopy and their solid-state molecular structures have been established by single crystal X-ray diffraction.

Selectivity in Adduct Formation of a Bidentate Boron Lewis Acid.

A bidentate boron Lewis acid based on 1,8-diethynylanthracene has been studied in detail with respect to its adduct formation with diamines and diphosphanes of different linker lengths between the donor functions. A clear correlation between the linker length of the bifunctional base and the formation of 1 : 1 adducts, 1 : 2 adducts or oligomers was found. The adducts were characterized in solution by NMR titration experiments and structurally by X-ray diffraction. In addition, adduct formation and competition experiments of the host system with ZR3 (Z=N, P; R=H, Me) demonstrated the generally higher stability of alkylphosphane adducts compared to alkylamine adducts with boron functions. The results provide a general insight into the adduct formation of bidentate Lewis acids with guests of different sizes as well as the differences in stability between borane-amine and borane-phosphane adducts.

Boosting the π-Acceptor Property of Mesoionic Carbenes by Carbonylation with Carbon Monoxide.

We report the room temperature dimerization of carbon monoxide mediated by C4/C5-vicinal anionic dicarbenes Li(ADC) (ADC = ArC{(Dipp)NC}2 ; Dipp = 2,6-iPr2 C6 H3 ; Ar = Ph, DMP (4-Me2 NC6 H4 ), Bp (4-PhC6 H4 )) to yield (E)-ethene-1,2-bis(olate) (i.e. - O-C=C-O- = COen ) bridged mesoionic carbene (iMIC) lithium compounds COen -[(iMIC)Li]2 (COen -[iMIC]2 = [ArC{(Dipp)NC}2 (CO)]2 ) in quantitative yields. COen -[(iMIC)Li]2 are highly colored stable solids, exhibit a strikingly small HOMO-LUMO energy gap, and readily undergo 2e-oxidations with selenium, CuCl (or CuCl2 ), and AgCl to afford the dinuclear compounds COon -[(iMIC)E]2 (E = Se, CuCl, AgCl) featuring a 1,2-dione bridged neutral bis-iMIC (i.e. COon -[iMIC]2 = [ArC{(Dipp)NC}2 (C=O)]2 ). COen -[(iMIC)Li]2 undergo redox-neutral salt metathesis reactions with LiAlH4 and (Et2 O)2 BeBr2 and afford COen -[(iMIC)AlH2 ]2 and COen -[(iMIC)BeBr]2 , in which the dianionic COen -moiety remains intact. All compounds have been characterized by NMR spectroscopy, mass spectrometry, and X-ray diffraction. Stereoelectronic properties of COon -[iMIC]2 are quantified by experimental and theoretical methods.

Divergent Reactivity of a Cyclic Bis-Hydridostannylene: A Masked Sn(I) Diradicaloid.

Herein, reactivity studies of a cyclic bis-hydridostannylene [(ADC)SnH]2 (1-H2) (ADC=PhC{(NDipp)C}2; Dipp=2,6-iPr2C6H3) with various unsaturated organic substrates are reported. Reactions of terminal alkynes (RC≡CH) with 1-H2 afford mixed acetylide-vinyl-functionalized bis-stannylenes via dehydrogenation and hydrostannylation. Treatment of 1-H2 with PhC≡CCH3 gives a unique distannabarrelene via dehydrogenative C(sp3)-H stannylation and hydrostannylation of the C≡CCH3 moiety. 1-H2 undergoes dehydrogenative [2+2]-cycloaddition reactions with diphenylacetylene, azobenzene, acetone, benzophenone, and benzaldehyde to form the 1,4-distannabarrelene derivatives. The elimination of H2 in these reactions suggests the masked-diradical property of 1-H2. In fact, these [2+2]-cycloaddition products are also accessible on treatments of the Sn(I) diradicaloid [(ADC)Sn]2 (1) with appropriate reagents. All compounds have been characterized by multinuclear NMR spectroscopy and single crystal X-ray diffraction. Moreover, the catalytic activity of 1-H2 has been shown for the hydroboration of unsaturated substrates.