On the Use of Triarylsilanols as Catalysts for Direct Amidation of Carboxylic Acids.

Triarylsilanols have been reported as the first silicon-centered molecular catalysts for direct amidation of carboxylic acids with amines as identified after a screen of silanols, silanediols, disiloxanediols, and incompletely condensed silsesquioxanes as potential homogeneous catalysts. Subsequent synthesis and testing of various electronically differentiated triarylsilanols have identified tris(p-haloaryl)silanols as more active than the parent triarylsilanol, where the bromide congener is found to be the most active. Catalyst decomposition can be observed by NMR methods, but RPKA methods reveal that product inhibition is operative, where tertiary amides are more inhibitory than secondary amides. Studies using an authentically synthesized triaryl silylester as a putative intermediate in the catalytic system enable a plausible mechanism to be proposed as supported by computationals.

Syntheses and Characterization of Main Group, Transition Metal, Lanthanide, and Actinide Complexes of Bidentate Acylpyrazolone Ligands.

The synthesis of acylpyrazolone salts and their complexes of main group elements, transition metals, lanthanides, and actinides are described and characterized inter alia by means of single-crystal X-ray crystallography, NMR, and IR spectroscopies. The complexes consist of two, three, or four acylprazolone ligands bound to the metal atom, resulting in a structurally diverse set of coordination complexes with (distorted) octahedral, pentagonal-bipyramidal, or antiprismatic arrangements. Several complexes proved to be polymeric in the solid state including heterobimetallic sodium/lanthanide coordination polymers. A selection of the polymeric compounds was analyzed via TG/DTA measurements to establish their stability. The ligands, in turn, were readily synthesized in good yields from commercially available hydrazine hydrochloride salts. These findings demonstrate that acylpyrazolone ligands can form complexes with metals of varying ionic radii, highlighted by their utility in other areas such as analytical and metal organic framework chemistry.

General Synthesis of 3-Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres.

A general approach to 3-azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability of this transformation were studied. The core was incorporated into the structure of the antihistamine drug Rupatidine instead of the pyridine ring, which led to a dramatic improvement in physicochemical properties.

A combined DFT-predictive and experimental exploration of the sensitivity towards nucleofuge variation in zwitterionic intermediates relating to mechanistic models for unimolecular chemical generation and trapping of free C2 and alternative bimolecular pathways involving no free C2.

Following the recent report of the chemical generation and trapping at room temperatures of C2, generated from an alkynyl phenyl iodonium salt, a computational analysis had indicated that both unimolecular fragmentation and bimolecular substitution mechanisms for the process could be envisaged. Here a combined theoretical and experimental analysis explores how the energetics of these mechanisms and resulting experimental products respond to variation in the nucleofuge. When the phenyl iodonium nucleofuge is replaced by pyridinium, trapping products are again obtained, which we conclude favours a bimolecular mechanism involving no free C2. Trapped products in greater yield were also observed using dibenzothiophenium as the nucleofuge in both condensed solution phase and most significantly in a two-flask room temperature experiment in which a volatile species, presumed to be C2, is transferred and trapped in a second flask. The energetics of the unimolecular fragmentation process producing C2 are predicted to be too high to correspond to a facile thermal reaction, which means that an experimental/theoretical dichotomy remains to be explained.

A computational tool to accurately and quickly predict 19F NMR chemical shifts of molecules with fluorine-carbon and fluorine-boron bonds.

We report the evaluation of density-functional-theory (DFT) based procedures for predicting 19F NMR chemical shifts at modest computational cost for a range of molecules with fluorine bonds, to be used as a tool for assisting the characterisation of reaction intermediates and products and as an aid to identifying mechanistic pathways. The results for a balanced learning set of molecules were then checked using two further testing sets, resulting in the recommendation of the ωB97XD/aug-cc-pvdz DFT method and basis set as having the best combination of accuracy and computational time, with a RMS error of 3.57 ppm. Cationic molecules calculated without counter-anion showed normal errors, whilst anionic molecules showed somewhat larger errors. The method was applied to the prediction of the conformationally averaged 19F chemical shifts of 2,2,3,3,4,4,5,5-octafluoropentan-1-ol, in which gauche stereoelectronic effects involving fluorine dominate and to determining the position of coordination equilibria of fluorinated boranes as an aid to verifying the relative energies of intermediate species involved in catalytic amidation reactions involving boron catalysts.

(±)-Polysiphenol and Other Analogues via Symmetrical Intermolecular Dimerizations: A Synthetic, Spectroscopic, Structural, and Computational Study.

We report an improved total synthesis of 4,5-dibromo-9,10-dihydrophenanthrene-2,3,6,7-tetraol, (±)-polysiphenol, via intermolecular McMurray dimerization of 5-bromovanillin and subsequent intramolecular oxidative coupling as the key steps. The synthetic route is applicable to 4,5-dichloro- and 4,5-difluoro-halologues (as well as a 4,5-dialkyl-analogue). Distinctive AA'BB' multiplets in their 1H NMR spectra for the dimethylene bridges of the dibromo and dichloro compounds reveal them to be room-temperature stable atropisomers, while for the difluoro compound they present as a singlet. X-ray crystal structure determinations of their tetramethylated synthetic precursors show atropisomeric twist angles of 48°, 46°, and 32°, respectively, with the former representing the largest yet observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. DFT computational studies reveal an unprecedented two-stage atropisomeric interconversion process involving time-independent asynchronous rotations of the dimethylene bridge and the biaryl axis for halologues containing chlorine or bromine, but a more synchronous rotation for the difluoro analogue.

A data-oriented approach to making new molecules as a student experiment: artificial intelligence-enabling FAIR publication of NMR data for organic esters.

The lack of machine-readable data is a major obstacle in the application of nuclear magnetic resonance (NMR) in artificial intelligence (AI). As a way to overcome this, a procedure for capturing primary NMR spectroscopic instrumental data annotated with rich metadata and publication in a Findable, Accessible, Interoperable and Reusable (FAIR) data repository is described as part of an undergraduate student laboratory experiment in a chemistry department. This couples the techniques of chemical synthesis of a never before made organic ester with illustration of modern data management practices and serves to raise student awareness of how FAIR data might improve research quality and replicability. Searches of the registered metadata are shown, which enable actionable finding and accessing of such data. The potential for re-use of the data in AI applications is discussed.

Understanding the Diastereopreference of Intermediates in Aminocatalysis: Application to the Chiral Resolution of Lactols.

Downstream intermediates are crucial for the reactivity and selectivity of aminocatalytic reactions. We present an analysis of the stereopreference in aminocatalytic downstream intermediates, which reveals an inconspicuous mechanism of chiral recognition between the catalyst and the rest of the molecule. We delineate a stereoelectronic model to rationalize the mode of chiral transmission. We also exploit it for the resolution of chiral lactols relevant in organic synthesis as well as in the flavor and fragrance industry.

Routes involving no free C2 in a DFT-computed mechanistic model for the reported room-temperature chemical synthesis of C2.

Recent lively debates about the nature of the quadruple bonding in the diatomic species C2 have been heightened by recent suggestions of molecules in which carbon may be similarly bonded to other elements. The desirability of having methods for generating such species at ambient temperatures and in solution in order to study their properties may have been realized by a recent report of the first chemical synthesis of free C2 itself under mild conditions. The method involved unimolecular fragmentation of an alkynyl zwitterion 2 as generated from the precursor 1, resulting in production and then trapping of free C2 at ambient temperatures rather than the high temperature gas phase methods normally employed for C2 generation. Here, alternative mechanisms are proposed for this reaction based on DFT calculations involving bimolecular 1,1- or 1,2-iodobenzene displacement reactions from 2 directly by galvinoxyl radical, or hydride transfer from 9,10-dihydroanthracene to 2. These mechanisms result in the same trapped products as observed experimentally, but unlike that involving unimolecular generation of free C2, exhibit calculated free energy barriers commensurate with the reaction times observed at room temperatures. The relative energies of the transition states for 1,1 vs. 1,2 substitution provide a rationalisation for the observed isotopic substitution patterns. The same mechanism also provides an energetically facile path to polymeric synthesis of carbon rich species by extending the carbon chain attached to the iodonium group, eventually resulting in formation of amorphous carbon and discrete molecules such as C60.

Equilibrium Formation of Stable All-Silicon Versions of 1,3-Cyclobutanediyl.

Main group analogues of cyclobutane-1,3-diyls are fascinating due to their unique reactivity and electronic properties. So far only heteronuclear examples have been isolated. Here we report the isolation and characterization of all-silicon 1,3-cyclobutanediyls as stable closed-shell singlet species from the reversible reactions of cyclotrisilene c-Si3 Tip4 (Tip=2,4,6-triisopropylphenyl) with the N-heterocyclic silylenes c-[(CR2 CH2 )(NtBu)2 ]Si: (R=H or methyl) with saturated backbones. At elevated temperatures, tetrasilacyclobutenes are obtained from these equilibrium mixtures. The corresponding reaction with the unsaturated N-heterocyclic silylene c-(CH)2 (NtBu)2 Si: proceeds directly to the corresponding tetrasilacyclobutene without detection of the assumed 1,3-cyclobutanediyl intermediate.

Elevated reaction order of 1,3,5-tri-tert-butylbenzene bromination as evidence of a clustered polybromide transition state: a combined kinetic and computational study.

The kinetics and mechanism of concurrent bromo-de-protonation and bromo-de-tert-butylation of 1,3,5-tri-tert-butylbenzene at different bromine concentrations were studied experimentally and theoretically. Both reactions have high order in bromine (experimental kinetic orders ∼5 and ∼7, respectively). According to quantum chemical DFT calculations, such high reaction orders are caused by participation of clustered polybromide anions Br2n-1- in transition states. Bromo-de-tert-butylation has a higher order due to its bigger reaction center demanding clusters of extended size. A significant primary deuterium kinetic isotope effect (KIE) for bromo-de-protonation is measured indicating proton removal is rate limiting, as confirmed by computed DFT models. The latter predict a larger value for the KIE than measured and possible explanations for this are discussed.

Mono- and Dicoordinate Germanium(0) as a Four-Electron Donor.

We report the synthesis and isolation of molecular iron germanide motifs in the stoichiometry of Fe3 Ge and Fe2 Ge, which are stabilized by the coordination of N-heterocyclic carbene (NHC) and carbon monoxide (CO) ligands. NHCiPr2Me2 ⋅Ge[Fe(CO)4 ][Fe2 (CO)8 ] (NHCiPr2Me2 =1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene), a germanium(0) ligand with just one NHC as an auxiliary ligand, assumes a bridging coordination mode between a mononuclear [Fe(CO)4 ] and a dinuclear [(CO)4 FeFe(CO)4 ] unit with rapid exchange between the two binding modes in solution. The electronic structure of this species is analysed by NBO and ELF calculations with DFT methods, as well as the mechanistic details of its fluxional coordination behaviour. Treatment of NHCiPr2Me2 ⋅Ge[Fe(CO)4 ] [Fe2 (CO)8 ] with the sterically less demanding NHCMe4 (NHCMe4 =1,3,4,5-tetramethylimidazol-2-ylidene) leads to a dinuclear iron complex (NHCMe4 )2 Ge[Fe(CO)4 ]2 that contains a bridging germylone ligand with two stabilizing NHC equivalents.

An Accessible Method for DFT Calculation of 11B NMR Shifts of Organoboron Compounds.

The study of boron-mediated reactions in organic synthesis and reactions of organoboron compounds is greatly facilitated by the use of 11B NMR. However, the identification and characterization of reaction intermediates in often complex systems is far from trivial, as 11B NMR does not provide any detailed structural information. Greater insight into the structures present in such systems can be obtained by using DFT chemical shift calculations to support or exclude proposed reaction intermediates. In this article, we report a rapid and accessible approach to the calculation of 11B NMR shifts that is applicable to a wide range of organoboron compounds.

Tuning Azoheteroarene Photoswitch Performance through Heteroaryl Design.

Photoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one of the aryl rings from the conventional azobenzene class has been replaced with a five-membered heteroaromatic ring. Initial studies have suggested the azoheteroarenes-the arylazopyrazoles in particular-to have excellent photoswitching properties (quantitative switching and long Z isomer half-life). Here we present a systematic computational and experimental study to elucidate the origin of the long thermal half-lives and excellent addressability of the arylazopyrazoles, and apply this understanding to determine important structure-property relationships for a wide array of comparable azoheteroaryl photoswitches. We identify compounds with Z isomer half-lives ranging from seconds to hours, to days and to years, and variable absorption characteristics, all through tuning of the heteraromatic ring. Conformation perhaps plays the largest role in determining such properties: the compounds with the longest isomerization half-lives adopt a T-shaped ground state Z isomer conformation and proceed through a T-shaped isomerization pathway, whereas the most complete photoswitching is achieved for compounds that have a twisted (rather than T-shaped) Z isomer conformation. By balancing these factors, we report a new azopyrazole 3pzH, which can be quantitatively switched to its Z isomer (>98%) with 355 nm irradiation, near-quantitatively (97%) switched back to the E isomer with 532 nm irradiation, and has a very long half-life for thermal isomerization (t1/2 = 74 d at 25 °C). Given the large tunability of their properties, the predictive nature of their performance, and the other functional opportunities afforded by usage of a heteroaromatic system, we believe the azoheteroaryl photoswitches to have huge potential in a wide range of optically addressable applications.

The 'Molecule of the Month' Website-An Extraordinary Chemistry Educational Resource Online for over 20 Years.

The Molecule of the Month website (http://www.chm.bris.ac.uk/motm/motm.htm) is an educational resource that is celebrating its 20th anniversary. Here we reflect on its pioneering role in promoting new technology for visualizing and presenting chemical information on the web, as well as its achievements, as a free educational resource, both as a teaching aid and as a multi-user, multi-author learning platform. We discuss the legal aspects of such sites, as well as issues around how to make the content permanent. Finally, we look forward to how such sites may evolve in the future.

Kinetic Resolution of 2-Substituted Indolines by N-Sulfonylation using an Atropisomeric 4-DMAP-N-oxide Organocatalyst.

The first catalytic kinetic resolution by N-sulfonylation is described. 2-Substituted indolines are resolved (s=2.6-19) using an atropisomeric 4-dimethylaminopyridine-N-oxide (4-DMAP-N-oxide) organocatalyst. Use of 2-isopropyl-4-nitrophenylsulfonyl chloride is critical to the stereodiscrimination and enables facile deprotection of the sulfonamide products with thioglycolic acid. A qualitative model that accounts for the stereodiscrimination is proposed.

Chemoselective Polymerizations from Mixtures of Epoxide, Lactone, Anhydride, and Carbon Dioxide.

Controlling polymer composition starting from mixtures of monomers is an important, but rarely achieved, target. Here a single switchable catalyst for both ring-opening polymerization (ROP) of lactones and ring-opening copolymerization (ROCOP) of epoxides, anhydrides, and CO2 is investigated, using both experimental and theoretical methods. Different combinations of four model monomers-ε-caprolactone, cyclohexene oxide, phthalic anhydride, and carbon dioxide-are investigated using a single dizinc catalyst. The catalyst switches between the distinct polymerization cycles and shows high monomer selectivity, resulting in block sequence control and predictable compositions (esters and carbonates) in the polymer chain. The understanding gained of the orthogonal reactivity of monomers, specifically controlled by the nature of the metal-chain end group, opens the way to engineer polymer block sequences.

Noncatalytic bromination of benzene: A combined computational and experimental study.

The noncatalytic bromination of benzene is shown experimentally to require high 5-14 M concentrations of bromine to proceed at ambient temperatures to form predominantly bromobenzene, along with detectable (<2%) amounts of addition products such as tetra and hexabromocyclohexanes. The kinetic order in bromine at these high concentrations is 4.8 ± 0.06 at 298 K and 5.6 ± 0.11 at 273 K with a small measured inverse deuterium isotope effect using D6 -benzene of 0.97 ± 0.03 at 298 K. These results are rationalized using computed transition states models at the B3LYP+D3/6-311++G(2d,2p) level with an essential continuum solvent field for benzene applied. The model with the lowest predicted activation free energies agrees with the high experimental kinetic order in bromine and involves formation of an ionic, concerted, and asynchronous transition state with a Br8 cluster resembling the structure of the known Br9 (-). This cluster plays three roles; as a Br(+) donor, as a proton base, and as a stabilizing arm forming weak interactions with two adjacent benzene CH hydrogens, these aspects together combining to overcome the lack of reactivity of benzene induced by its aromaticity. The computed inverse kinetic isotope effect of 0.95 agrees with experiment, and arises because C-Br bond formation is essentially complete, whereas C-H cleavage has not yet commenced. The computed free energy barriers for the reaction with 4Br2 and 5Br2 for a standard state of 14.3 M in bromine are reasonable for an ambient temperature reaction, unlike previously reported theoretical models involving only one or two bromines.

How Many Water Molecules Does it Take to Dissociate HCl?

The potential energy surfaces of the HCl(H2O)n (n is the number of water molecules) clusters are systematically explored using density functional theory and high-level ab initio computations. On the basis of electronic energies, the number of water molecules needed for HCl dissociation is four as reported by some experimental groups. However, this number is five owing to the inclusion of entropic factors. Wiberg bond indices are calculated and analyzed, and the results provide a quadratic correlation and classification of clusters according to the nondissociated, partially dissociated, and fully dissociated character of the H-Cl bond. Our computations show that if temperature is not controlled during the experiment, the values obtained for the dipole moment (or for any measurable property) are susceptible to change, providing a different picture of the number of water molecules needed for HCl dissociation in a nanoscopic droplet.