Isolation and Characterization of Crystalline, Neutral Diborane(4) Radicals.

Diaryldihalodiboranes(4) were reacted with bis(amidinato)- and bis(guanidinato)silylenes to generate the first neutral diborane-centered radicals. These formally non-aromatic 5π electron systems are stable in the solid state as well as in solution and were characterized by solid-state structure determination, high-resolution mass spectrometry, and EPR spectroscopy. The reactivity of one of these radicals with the oxidant 1,4-benzoquinone led to ring-opening and B-O bond formation.

Bis(amidinato)- and bis(guanidinato)silylenes and silylenes with one sterically demanding amidinato or guanidinato ligand: synthesis and reactivity.

This article deals with the synthesis and reactivity of the bis(amidinato)silylene [iPrNC(Ph)NiPr]2Si (5), the bis(guanidinato)silylene [iPrNC(NiPr2)NiPr]2Si (6), the mono(amidinato)silylene [DippNC(Ph)NDipp]SiNMe2 (Dipp = 2,6-diisopropylphenyl) (8) and the mono(guanidinato)silylene [DippNC(NMe2)NDipp]SiN(SiMe3)2 (9). The reactions studied include (i) nucleophilic substitutions, (ii) Lewis acid/base reactions, (iii) Brønsted acid/base reactions, (iv) oxidative additions (bond activations, small-molecule activations), (v) cycloaddition reactions with unsaturated organic substrates, (vi) reductions and (vii) radical formation by muonium addition. Silylenes 5, 6, 8 and 9 have been demonstrated to display unique reactivity profiles and to be versatile precursors for the synthesis of novel four- or five-coordinate silicon(ii) and four-, five- or six-coordinate silicon(iv) complexes with unprecedented structural motifs. This article also deals with the structural characterisation of all the new silicon(ii) and silicon(iv) compounds synthesised. Crystal structure analyses and 29Si NMR spectroscopic studies in the solid state and in solution were used to characterise the silicon coordination polyhedra of these compounds.

Neutral six-coordinate bis(dithiocarbamato)silicon(iv) complexes with an SiCl2S4 skeleton.

Treatment of SiCl4 with lithium dithiocarbamates of the formula type Li[R2NCS2] (R = Ph, iPr) in a molar ratio of 1 : 2 afforded the respective six-coordinate silicon(iv) complexes [Ph2NCS2]2SiCl2 (3) and [iPr2NCS2]2SiCl2 (4), which were isolated as the solvates 3·MeCN and 4·MeCN. Compounds 3·MeCN and 4·MeCN were structurally characterised by single-crystal X-ray diffraction and multinuclear NMR spectroscopic studies in the solid state and in solution. In this study, dithiocarbamato ligands were implemented in silicon coordination chemistry for the first time. Compounds 3 and 4 represent the first six-coordinate silicon(iv) complexes with an SiCl2S4 skeleton.

Iron(II), Cobalt(II), Nickel(II), and Zinc(II) Silylene Complexes: Reaction of the Silylene [iPrNC(NiPr2 )NiPr]2 Si with FeBr2 , CoBr2 , NiBr2 ⋠MeOCH2 CH2 OMe, ZnCl2 , and ZnBr2.

Reaction of the donor-stabilized silylene [iPrNC(NiPr2 )NiPr]2 Si (1) with FeBr2 , CoBr2 , NiBr2 ⋅MeOCH2 CH2 OMe, ZnCl2 , and ZnBr2 afforded the respective transition-metal silylene complexes 4-8, the formation of which can be described in terms of a Lewis acid/base reaction (4, 5, 7, 8) or a nucleophilic substitution reaction (6). However, the reactivity profile of silylene 1 is not only based on its strong Lewis base character; the different coordination modes of the two guanidinato ligands (4-6 vs. 7 and 8) add an additional reactivity facet. The paramagnetic compounds 4 and 5 and the diamagnetic compounds 6⋅THF, 7, and 8⋅0.5 Et2 O were structurally characterized by single-crystal X-ray diffraction. In addition, compound 6⋅THF was studied by 15 N and 29 Si solid-state NMR spectroscopy, and 7 and 8 were characterized by NMR spectroscopic studies in the solid state (15 N, 29 Si) and in solution (1 H, 13 C, 29 Si). Compounds 4-8 represent very rare examples of FeII , CoII , NiII , and ZnII silylene complexes. Four-coordinate silicon(II) compounds with an SiN3 M skeleton (M=Fe, Co, Ni) and M in the formal oxidation state +2 (4-6) have not yet been reported, and five-coordinate silicon(II) compounds with an SiN4 Zn skeleton (7, 8) are also unprecedented.

Cationic Five-Coordinate Bis(guanidinato)silicon(IV) Complexes with SiN4 El Skeletons (El=S, Se): "Heterolytic Activation" of S-S and Se-Se Bonds.

The donor-stabilized silylene [iPrNC(NiPr2 )NiPr]2 Si (2) reacts with PhEl-ElPh (El=S, Se) to form the respective cationic five-coordinate bis(guanidinato)silicon(IV) complexes {[iPrNC(NiPr2 )NiPr]2 SiSPh}(+) PhS(-) (4) and {[iPrNC (NiPr2 )NiPr]2 SiSePh}(+) PhSe(-) (5). Compounds 4 and 5 were characterized by crystal structure analyses and NMR spectroscopic studies in the solid state.

Reactivity of the Donor-Stabilized Silylenes [iPrNC(Ph)NiPr]2 Si and [iPrNC(NiPr2 )NiPr]2 Si: Activation of CO2 and CS2.

Activation of CO2 by the bis(amidinato)silylene 1 and the analogous bis(guanidinato)silylene 2 leads to the structurally analogous six-coordinate silicon(IV) complexes 4 (previous work) and 8, respectively, the first silicon compounds with a chelating carbonato ligand. Likewise, CS2 activation by silylene 1 affords the analogous six-coordinate silicon(IV) complex 10, the first silicon compound with a chelating trithiocarbonato ligand. CS2 activation by silylene 2, however, yields the five-coordinate silicon(IV) complex 13 with a carbon-bound CS2 (2-) ligand, which also represents an unprecedented coordination mode in silicon coordination chemistry. Treatment of the dinuclear silicon(IV) complexes 5 and 6 with CO2 also affords the six-coordinate carbonatosilicon(IV) complexes 4 and 8, respectively.

Synthesis and Pharmacological Properties of Silicon-Containing GPR81 and GPR109A Agonists.

The GPR81 and GPR109A receptors mediate antilipolytic effects and are potential drug targets for the treatment of metabolic disorders such as dyslipidemia and type 2 diabetes. There is still a need to identify potent GPR81 agonists as pharmacological tools. A high-throughput screen identified an acylurea-based GPR81 agonist lead series, with activities at the GPR109A receptor as well. To expand the chemical scope and to explore the pharmacological and pharmacokinetic consequences, a series of structurally related organosilicon compounds with a 6-sila-4,5,6,7-tetrahydrobenzo[d]thiazole skeleton was synthesized and studied for their physicochemical properties [octanol/water distribution coefficient (pH 7.4), solubility in HBSS buffer (pH 7.4)], agonistic potency at rat GPR81 and GPR109A receptors, and intrinsic clearance in human liver microsomes and rat hepatocytes. The straightforward synthesis of these organosilicon compounds offered a valuable expansion of the chemical scope in the above-mentioned GPR81 agonist lead series, provided potency and efficacy SAR, and yielded compounds with sub-micromolar GPR81 potency. This work supports the value of including silicon chemistry into the toolbox of medicinal chemistry.

Stable Four-Coordinate Guanidinatosilicon(IV) Complexes with SiN3El Skeletons (El = S, Se, Te) and Si=El Double Bonds.

To get information about the reactivity profile of the donor-stabilized guanidinatosilicon(II) complexes 2 and 3, a series of oxidative addition reactions was studied. Treatment of 2 and 3 with S8, Se, or Te afforded the respective four-coordinate silicon(IV) complexes 8-10 and 12-14, which contain an SiN3 El skeleton (El = S, Se, Te) with an Si=El double bond. Treatment of 2 with N2O yielded the dinuclear four-coordinate silicon(IV) complex 11 with an SiN3O skeleton and a central four-membered Si2O2 ring. Compounds 8-14 exist both in the solid state and in solution. They were characterized by elemental analyses, NMR spectroscopic studies in the solid state and in solution, and crystal structure analyses. The reactivity profile of 2 was compared with that of the structurally related bis[N,N'-diisopropylbenzamidinato(-)]silicon(II) (1), which is three-coordinate in the solid state and four-coordinate in solution (1'). In contrast, as shown by state-of-the-art relativistic DFT analyses and experimental studies, silylene 2 is three-coordinate both in the solid state and solution. The three-coordinate species 2 is 9.3 kcal mol(-1) more stable in benzene than the four-coordinate isomer 2'. The reason for this was studied by bonding analyses of 2 and 2', which were compared with those of 1 and 1'. The gas-phase proton affinities of the relevant species in solution (1' and 2) amount to 288.8 and 273.8 kcal mol(-1), respectively.

Synthesis, structure and reactivity of a donor-stabilised silylene with a bulky bidentate benzamidinato ligand.

The novel donor-stabilised silylene was prepared in a four-step synthesis, starting from bis(2,6-diisopropylphenyl)carbodiimide (Dipp-N[double bond, length as m-dash]C[double bond, length as m-dash]N-Dipp), and its reactivity was studied in a series of oxidative addition reactions and a nucleophilic substitution reaction. The three-coordinate silicon(ii) complex contains the bulky bidentate amidinato ligand Dipp-NC(Ph)N-Dipp(-) and a dimethylamido ligand. Treatment of with N2O afforded the dinuclear five-coordinate silicon(iv) complex (SiO2N3 skeletons), and the reaction with S8 yielded the dinuclear four-coordinate silicon(iv) complex (SiS2N2 skeletons). Treatment of with Se and Te afforded the respective four-coordinate silicon(iv) complexes (SiSeN3 skeleton) and (SiTeN3 skeleton), which contain an Si[double bond, length as m-dash]Se and Si[double bond, length as m-dash]Te double bond, respectively. The reaction of with the silyl azide Me3SiN3 yielded the four-coordinate silicon(iv) complex (SiN4 skeleton) with an Si[double bond, length as m-dash]N double bond, whereas the reaction with the alkyl azide PhSCH2N3 gave the four-coordinate silicon(iv) complex (SiSN3 skeleton), the first silicon(iv) complex with an unsubstituted methyleneamido ligand. The reaction of with [Fe(CO)5] afforded the four-coordinate silicon(ii) complex (SiFeN3 skeleton) with an Si-Fe bond. Compounds (and the precursors and (five-coordinate silicon(iv) complexes with an SiCl3N2 and SiCl2N3 skeleton, respectively) in the synthesis of ) were characterised by elemental analyses, crystal structure analyses and multinuclear NMR spectroscopic studies in the solid state and in solution.

Invariom based electron density studies on the C/Si analogues haloperidol/sila-haloperidol and venlafaxine/sila-venlafaxine.

The subjects of this study are the structures and electron densities of the carbon/silicon analogues haloperidol/sila-haloperidol (1a/1b) and venlafaxine/sila-venlafaxine (2a/2b). The parent carbon compounds 1a (an antipsychotic agent) and 2a (an antidepressant) are both in clinical use. For haloperidol/sila-haloperidol, three published structures were studied in more detail: the structures of haloperidol hydrochloride (1a·HCl), haloperidol hydropicrate (1a·HPic) and sila-haloperidol hydrochloride (1b·HCl). For venlafaxine/sila-venlafaxine, the published structures of venlafaxine (2a), venlafaxine hydrochloride (2a·HCl; as orthorhombic (2a·HCl-ortho) and monoclinic polymorph (2a·HCl-mono)) and sila-venlafaxine hydrochloride (2b·HCl) were investigated. Based on these structures, the molecular electron densities were reconstructed by using the invariom formalism. They were further analysed in terms of Bader's quantum theory of atoms in molecules, electrostatic potentials mapped onto electron density isosurfaces and Hirshfeld surfaces. These studies were performed with a special emphasis on the comparison of the corresponding carbon/silicon analogues.

Si- and C-Functional Organosilicon Building Blocks for Synthesis Based on 4-Silacyclohexan-1-ones Containing the Silicon Protecting Groups MOP (4-Methoxyphenyl), DMOP (2,6-Dimethoxyphenyl), or TMOP (2,4,6-Trimethoxyphenyl).

4-Silacyclohexan-1-ones 1a-1c, 4-silacyclohexan-1-one oximes 2a-2c, 1,4-azasilepan-7-ones 3a-3c, 1,4-azasilepanes 4a-4c, and 2-bromo-4-silacyclohexan-1-ones 5a and 5b were prepared in multistep syntheses, starting from trimethoxypropylsilane. All of these compounds represent C-functional (R2C═O, R2C═N-OH, R-NH(C═O)-R, R2NH, or R3C-Br) silicon-containing heterocycles that contain Si-MOP, Si-DMOP, or Si-TMOP moieties (MOP = 4-methoxyphenyl; DMOP = 2,6-dimethoxyphenyl; TMOP = 2,4,6-trimethoxyphenyl), which can be cleaved under mild conditions by protodesilylation. As a proof of principle, compounds 3a-3c were transformed quantitatively and selectively into the chlorosilane 6 (treatment with hydrogen chloride in dichloromethane). Thus, the C- and Si-functional compounds 1a-1c, 2a-2c, 3a-3c, 4a-4c, 5a, and 5b represent versatile building blocks for synthesis.

Can silicon make an excellent drug even better? An in vitro and in vivo head-to-head comparison between loperamide and its silicon analogue sila-loperamide.

Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3 COH→R3 SiOH) leads to sila-loperamide (1b). Sila-loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4-methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila-loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila-loperamide exhibits high unbound clearance (CLu ), leading to a significant decrease in unbound concentration (Cu ) and unbound area under the curve (AUCu ) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.

Synthesis and olfactory characterization of silicon-containing derivatives of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal.

5-Methyl-4-methylidene-6-(trimethylsilyl)hexanal (1b), a sila analog of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal (1a), and the Si-containing derivatives 2-6 were prepared in multistep syntheses, starting from Cl3 SiH and Cl2 SiMe2 , respectively. Compounds 1b, 2-6, and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies ((1) H, (13) C, (15) N, and (29) Si). To gain more information about the structureodor correlation in the family of lily-of-the-valley or 'muguet' odorants, C/Si analogs 1a/1b and derivatives 2-6 were evaluated for their olfactory properties.

Reactions of the donor-stabilized silylene bis[N,N'-diisopropyl-benzamidinato(-)]silicon(II) with Brønsted acids.

Reaction of the donor-stabilized silylene 1 (which is three-coordinate in the solid state and four-coordinate in solution) with [HMCp(CO)3 ] (M=Mo, W; Cp=cyclopentadienyl) leads to the cationic five-coordinate silicon(IV) complexes 2 and 3, respectively, and reaction of 1 with CH3 COOH yields the neutral six-coordinate silicon(IV) complex 4. Compounds 2-4 were structurally characterized by crystal structure analyses and multinuclear NMR spectroscopic studies in the solid state and in solution. The formation of 2-4 can be formally described in terms of a Brønsted acid/base reaction, coupled with a redox process (Si(II) →Si(IV) , H(+) →H(-) ).

Bis[N,N'-diisopropylbenzamidinato(-)]silicon(II): Lewis acid/base reactions with triorganylboranes.

Reaction of the donor-stabilized silylene 1 (which is three-coordinate in the solid state and four-coordinate in solution) with BEt3 and BPh3 leads to the formation of the Lewis acid/base complexes 2 and 3, respectively, which are the first five-coordinate silicon compounds with an SiB bond. These compounds were structurally characterized by crystal structure analyses and by multinuclear NMR spectroscopic studies in the solid state and in solution. Additionally, the bonding situation in 2 and 3 was analyzed by quantum chemical studies.

Activation of sulfur dioxide by bis[N,N'-diisopropylbenzamidinato(-)]silicon(II): synthesis of neutral six-coordinate silicon(IV) complexes with chelating O,O'-Sulfito or O,O'-dithionito ligands.

The neutral six-coordinate silicon(IV) complexes 2 and 3 (mixture of cis-3 and trans-3) were synthesized by reaction of the donor-stabilized silylene bis[N,N'-diisopropylbenzamidinato(-)]silicon(II) (1) with SO2 . Compounds 2 and 3 are the first silicon(IV) complexes with chelating sulfito or dithionito ligands, and 3 is even the first molecular compound with a chelating dithionito ligand. Compounds 2 and 3 were structurally characterized by crystal structure analyses and multinuclear NMR spectroscopic studies in the solid state and in solution.

Novel transition-metal (M=Cr, Mo, W, Fe) carbonyl complexes with bis(guanidinato)silicon(II) ligands.

The donor-stabilized silylene 2 (the first bis(guanidinato)silicon(II) complex) reacts with the transition-metal carbonyl complexes [M(CO)6 ] (M=Cr, Mo, W) to form the respective silylene complexes 7-10. In the reactions with [M(CO)6 ] (M=Cr, Mo, W), the bis(guanidinato)silicon(II) complex 2 behaves totally different compared with the analogous bis(amidinato)silicon(II) complex 1, which reacts with [M(CO)6 ] as a nucleophile to replace only one of the six carbonyl groups. In contrast, the reaction of 2 leads to the novel spirocyclic compounds 7-9 that contain a four-membered SiN2 C ring and a five-membered MSiN2 C ring with a MSi and MN bond (nucleophilic substitution of two carbonyl groups). Compounds 7-10 were characterized by elemental analyses (C, H, N), crystal structure analyses, and NMR spectroscopic studies in the solid state and in solution.

The donor-stabilized silylene bis[N,N'-diisopropylbenzamidinato(-)]silicon(II): synthesis, electronic structure, and reactivity.

A convenient and robust synthesis of bis[N,N'-diisopropylbenzamidinato(-)]silicon(II) (1), a donor-stabilized silylene, has been developed (35 g scale). To get further information about the reactivity profile of 1, a series of oxidative addition reactions were studied. Treatment of 1 with PhSe-SePh (Se-Se bond activation), C6F6 (C-F activation), and CO2 (C=O activation/cycloaddition) yielded the neutral six-coordinate silicon(IV) complexes 10, 11, and 13, respectively. Treatment of 1 with N2O resulted in the formation of the dinuclear five-coordinate silicon(IV) complex 12 (oxidative addition/dimerization), which contains a four-membered Si2O2 ring. Compounds 10-13 were characterized by NMR spectroscopic studies in the solid state and in solution and by crystal structure analyses. Silylene 1 is three-coordinate in the solid state (from crystal structure analysis) and exists as the four-coordinate isomer 1' in benzene solution (from computational studies). Based on state-of-the-art relativistic DFT analyses, the four-coordinate species 1' was demonstrated to be the thermodynamically favored isomer in benzene solution (favored by ΔG = 6.6 kcal mol(-1) over the three-coordinate species 1). The reason for this was studied by bonding analyses of 1 and 1'. Furthermore, the (29)Si NMR chemical shifts of 1 and 1' were computed, and in the case of 1' it was analyzed how this NMR spectroscopic parameter is affected by solvation. These studies further supported the assumption that the silylene is four-coordinate in solution.

Five-coordinate silicon(II) compounds with Si-M bonds (M = Cr, Mo, W, Fe): Bis[N,N'-diisopropylbenzamidinato(-)]silicon(II) as a ligand in transition-metal complexes.

Reaction of the donor-stabilized silylene 1 with [Cr(CO)6], [Mo(CO)6], [W(CO)6], or [Fe(CO)5] leads to the formation of the transition-metal silylene complexes 2-5, which contain five-coordinate silicon(II) moieties with Si-M bonds (M = Cr, Mo, W, Fe). These compounds were characterized by NMR spectroscopic studies in the solid state and in solution and by crystal structure analyses. These experimental investigations were complemented by computational studies to gain insight into the bonding situation of 2-5. The nature of the Si-M bonds is best described as a single bond.

Neutral six-coordinate and cationic five-coordinate silicon(IV) complexes with two bidentate monoanionic N,S-pyridine-2-thiolato(-) ligands.

A series of neutral six-coordinate silicon(IV) complexes (4-11) with two bidentate monoanionic N,S-pyridine-2-thiolato ligands and two monodentate ligands R(1) and R(2) was synthesized (4, R(1) = R(2) = Cl; 5, R(1) = Ph, R(2) = Cl; 6, R(1) = Ph, R(2) = F; 7, R(1) = Ph, R(2) = Br; 8, R(1) = Ph, R(2) = N3; 9, R(1) = Ph, R(2) = NCO; 10, R(1) = Ph, R(2) = NCS; 11, R(1) = Me, R(2) = Cl). In addition, the related ionic compound 12 was synthesized, which contains a cationic five-coordinate silicon(IV) complex with two bidentate monoanionic N,S-pyridine-2-thiolato ligands and one phenyl group (counterion: I(-)). Compounds 4-12 were characterized by elemental analyses, NMR spectroscopic studies in the solid state and in solution, and crystal structure analyses (except 7). These structural investigations were performed with a special emphasis on the sophisticated stereochemistry of these compounds. These experimental investigations were complemented by computational studies, including bonding analyses based on relativistic density functional theory.