Volume 92, Issue 1 - Papers from the 24th IUPAC International Conference on Physical Organic Chemistry (1–6 July 2018, Faro, Portugal)

The primary intermediates resulting from the interaction of cisplatin, cis -(PtCl 2 (NH 3 ) 2 ], most widespread antitumor drug, with biomolecular targets are characterized. Electrospray ionization is used to deliver ions formed in solution into the gas phase where they are structurally interrogated by vibrational “action” spectroscopy in conjunction with quantum chemical calculations. The aquation products, cis -[PtX(NH 3 ) 2 (H 2 O)] + (X = Cl, OH), lying along the path responsible for biological activity, are shown to display distinctive features responding to ligation pattern and optimized geometry. The IR spectra of trans -[PtX(NH 3 ) 2 (H 2 O)] + are different, testifying that cis and trans complexes are stable, non interconverting species both in solution and in the gas phase. Ligand substitution by simple nucleophiles (L = pyridine, 4(5)-methylimidazole, thioanisole, trimethylphosphate, acetamide, dimethylacetamide, urea and thiourea) yields cis -[PtCl(NH 3 ) 2 (L)] + complexes displaying remarkable regioselectivity whenever L presents multiple candidate platination sites. The incipient formation of cisplatin-derived complexes with the recognized biological amino acid targets L-histidine (His) and L-methionine (Met) has been investigated revealing the primary platination event to be mainly directed at the N π atom of the imidazole side chain of His and to the thiomethyl sulfur of Met. The isomer and conformer population of the ensuing cis -[PtCl(NH 3 ) 2 (Met/His)] + complexes, sampled in the gas phase, can be ascertained by photofragmentation kinetics on isomer/conformer specific resonances.

The unique ability of the bioorthogonal pairs to withstand and unaffect biological processes while maintaining high selectivity towards each other sparked the interest in better probing and controlling biological functions. In early years, trans- cyclooctene (TCO)/tetrazine ligation readily standed out by encompassing most of the bioorthogonal criteria such as its excellent biocompatibility, selectivity and efficiency, and as a result of high HOMO-LUMO gap. Modifications on the TCO scaffold such as cyclopropanation render bicyclononene-based TCOs with high enhancement of its reactivity, whereas other modifications focused on improving the solubility, stability, or enabling the scaffold to act as click -to-release drug delivery system. The implementation of facile methods to enhance its versatility is essential for potentiating drug-delivery strategies and expanding the dynamic range of bioorthogonal on/off control. Considering the remarkable properties of bicyclononene-based TCOs we envisioned that the incorporation of an additional vector for functionalization at the cyclopropane moiety could allow access to more complex and double-functionalized TCO probes. Herein we report the synthesis and study of a double-functionalizable strained trans- cyclooctenes for tetrazine bioorthogonal reactions.

Sulfonatocalixarenes, like other ionic receptors, possess counterions that can affect the molecular recognition process. In the present review it is shown that the competitive effect of the alkaline cations frequently used as counterions determines not only the magnitude of the external guest association constant, but also the stoichiometry of the complexes. Experimental evidences are shown about the interaction of the counterions with sulfonatocalixarene, allowing to quantify its association equilibrium constants. The counterions recognition will be a competitive process that must be taken into account when investigating the interaction of calixarenes with an external guests. When the external guest is a neutral molecule it will be possible to form ternary complexes where the counterion shows a competitive and cooperative effect. By increasing the size of the receptor, sulfonatocalix[6] and sulfonatocalix[8]arene, the complexity of the system is increased due to the formation of counterion complexes with stoichiometries 1:1 and 1:2. In the presence of an external guest, the formation of heteroternary complexes with 1:1:1 stoichiometries including a counterion and an organic cation will be possible.

Anthracene can be used as a scaffold for intramolecular S N 2 degenerate reactions of the “bell clapper” type, where a central boron atom or its isoelectronic carbocation bonds alternatively towards one or the other lateral Lewis bases at the first and eight anthracene positions. This ping-pong bond-switching reaction possesses a symmetrical double-well potential with low activation barrier and relatively narrow barrier width. Herein we show by computational means the active role played by heavy atom quantum tunneling in this degenerate rearrangement reaction at cryogenic temperatures. At these conditions the thermal “over the barrier” reaction is forbidden, whereas the tunneling effect enhances the rate of reaction up to an experimentally measurable half-life. Kinetic isotope effects and cryogenic NMR spectroscopy can, in principle, experimentally demonstrate the tunneling mechanism.

The properties and applications of 2-methyl-(2 H )-tetrazole-5-amino-saccharinate ( 2MTS ) in catalysis and chelant-based chemotherapy stimulated investigations on its photostability. The photochemistry of monomeric 2MTS in solid argon (15 K) was compared with those of 2-methyl-(2 H )-tetrazole-5-amine ( 2MT ) and 1-methyl-(2 H )-tetrazole-5-amine ( 1MT ). Compounds were subjected to in situ narrowband UV-irradiation at different wavelengths. Reactions were followed by infrared spectroscopy, supported by B3LYP/6-311++G(d,p) calculations. Photochemical pathways for 2MT and 2MTS proved similar but photodegradation of 2MTS was 20× slower, unraveling the photostabilizing effect of the saccharyl moiety that extends into the nitrilimine formed from 2MTS and its antiaromatic 1 H -diazirene isomer, which proved photostable at 290 nm, unlike the 1 H -diazirene formed from 2MT . Analysis of the photochemistries of 2MTS / 2MT (250 nm) and 1MT (222 nm), including energy trends calculated for the isomeric C 2 H 5 N 3 species postulated/observed from photolysis and EPR results, enabled a deeper insight into the photodegradation mechanisms of 1,5-substituted and 2,5-substituted tetrazoles. We postulate a pivotal singlet state imidoylnitrene species, s N1 , as common intermediate, which undergoes a Wolff-type isomerization to a stable carbodiimide. Photo-extrusion of N 2 from 1,5-substituted tetrazoles generates s N1 directly but from 2,5-substituted tetrazoles it originates a nitrilimine, then a diazirene, which finally leads to s N1 . Selective formation of cyanamide from 1MT requires photoisomerization between s N1 and s N2 , accessible at 222 nm. EPR studies enabled the detection of methyl nitrene, arising from photolysis of 1 H -diazirene intermediate.

In the new millennium the well-established paradigms of organic photochemistry have come alive as the basis for a wide range of synthetic methodologies that take advantage of the enhanced redox properties of excited states. While many strategies have been developed using rare, expensive and non-reusable catalysts, the road forward should include catalysts based on more abundant elements and reusable materials. This green road leads to the exploration of heterogeneous systems that can be eventually adapted for flow photocatalysis, and also adopted for the solution of environmental problems such as water treatment and fuel generation using solar radiation. If heterogeneous photocatalysis can play a role in supplying solutions to drug synthesis, energy and potable water supplies, then photochemistry will have an unprecedented societal impact.

DFT calculations for the equilibrium isotope effect for deuterium substitution at the anomeric centre C α in 2-( p -nitrophenoxy)tetrahydropyran with continuum solvation show significant variation in the range of relative permittivity 2 ≤ ε ≤ 10. One-dimensional scans of potential energy (with implicit solvation by water) or of free energy (from QM/MM potentials of mean force with explicit aqueous solvation with a hybrid AM1/OPLS method) for heterolysis of the bond between C α and the nucleofuge do not show a transition state. A two-dimensional free-energy surface that considers also the distance between C α and a nucleophilic water indicates a pre-association D N *A Nint ‡ mechanism with a transition state involving nucleophilic attack upon an ion-pair intermediate, and this is supported by good agreement between the mean values of the calculated and experimental α-D KIEs. However, the magnitudes of the standard deviations about the mean values for the making and breaking C–O bonds suggest that the transition state is rather plastic, with C α –O nu ≈2 ± 0.4 Å and C α –O lg ≈3 ± 0.5 Å. Not only is nucleophilic solvent assistance necessary, but there is also evidence for electrophilic assistance through specific hydrogen bonding to the nucleofuge.

The effect of coordination of a series of tridentate ligands (TDLs) on various features of SmI 2 was determined. The TDLs used in this study were diethylene glycol (OOO), diethanolamine (ONO), 2-(2-Aminoethoxy) ethanol (OON), N-(2-Hydroxyethyl) ethylene diamine (ONN) and glycerol (GLY). Of special interest is the effect of these additives on the reduction potential of SmI 2 . The cyclic voltammograms of the TDLs with nitrogen at the binding sites display simultaneously several peaks, each corresponding to a different coordination level of SmI 2 , enabling determination of three equilibrium constants. The results are in concert with electronic spectra of SmI 2 complexes with these ligands. The second and third equilibrium constants were found to be larger than the first, demonstrating the cooperativity effect. Moreover, the incremental effect of each moiety on the reduction potential of SmI 2 was determined. Regarding reactivity of SmI 2 , excessive coordination of some ligands is shown to have an adverse effect.

A series of amino-acid based ionic liquids (Bmim[AA]s) have been synthesized and evaluated as catalysts, in aqueous solution. The results of a kinetic study of the thiol-Michael reaction of L-Cysteine with trans -β-nitrostyrene demonstrated the advantages of using (Bmim[AA]s) as organocatalysts. The benefits include high rate constants; mild reaction conditions; and, a reusable catalyst, which leads to a simple and efficient method for these important kinds of reactions.

The iridium (III) complex of pentamethylcyclopentadiene and ( S , S ) or ( R , R )-1,2-diphenyl- N ′-tosylethane-1,2-diamine is an effective catalyst for the asymmetric transfer hydrogenation of imines under acidic conditions. However, the enantiomeric excess ( ee ) of the product amines from the reduction of 1-methyl-3,4-dihydroisoquinolines in either acetonitrile or dichloromethane, decreases exponentially. The dominant cause of the enantioselectivity is the difference in kinetic order of the formation of the two enantiomers with the S -enantiomer being formed in a first-order process whereas that for the R -enantiomer follows zero-order kinetics when ( R , R )-TsDPEN is employed, due to different rate-limiting steps for the two processes. A series of 1-fluorinated methyl-3,4-dihydroisoquinolines were synthesised to change the rate-limiting dissociation of the ( R ) amine product from Ir (III) so that both enantiomers are formed with the same kinetic order. This results in almost complete removal of the enantioselectivity of the reduction. It has been suggested that reduction of imines using transition metal complexes occurs through the neutral imine rather than the more reactive iminium-ion. α-Substituted imines with electron-withdrawing groups make protonation more difficult but enhance the electrophilicity of the imine carbon facilitating nucleophilic attack. The p K a of the iminium ions of 1-fluorinated methyl-3,4-dihydroisoquinolines were determined. Using the relative rates of the cyclopentadienyl iridium (III) complex catalysed reduction of these 1-fluorinated methyl-3,4-dihydroisoquinoline in acetonitrile and, under the acidic conditions of a 5:2 ratio of formic acid:triethylamine, showed that the iminium ion is the reactive species.

Oxidative sulfamidation is a promising approach to the synthesis of numerous organic compounds, including N -heterocycles or unsaturated species having the sulfonamide group, which is a key structural motif of synthetic antimicrobial drugs. The formed products can undergo further reactions leading to a wide variety of functionalized sulfonamides. This review summarizes the current state of knowledge on the oxidative reactions of sulfonamides and their derivatives with unsaturated and CH-active compounds with an emphasis on dienes as substrates. This produces a diverse range of compounds possessing sulfonamide function and capable of further functionalization.

A new (tetrazole-saccharin)nickel complex is shown to be a valuable catalyst for the hydrosilative reduction of aldehydes under microwave radiation at low temperatures. With typical 1 mol% content of the catalyst (microwave power range of 5–15 W) most reactions are complete within 30 min. The Ni(II)-catalyzed reduction of aldehydes, with a useful scope, was established for the first time by using this catalyst, and is competitive with the most effective transition-metal catalysts known for such transformation. The catalyst reveals tolerance to different functional groups, is air and moisture stable, and is readily prepared in straightforward synthetic steps. Supported by experimental data and DFT calculations, a plausible reaction mechanism involving the new catalytic system is outlined.

The mechanism of the platinum-catalysed dihydroalkoxylation of allenes to give acetals has been studied experimentally and by computational methods. Our findings further explain divergent reactivity encountered for platinum- and gold-vinyl intermediates after the first nucleophilic attack onto the coordinated allene, as well as provide new details on the catalytic cycle with platinum, uncovering enol ethers as resting states of the catalytic cycle, a S E Ox process via Pt(IV)–H as the final protodemetallation step after the second nucleophilic attack when neutral platinum complexes are used, and a fast acid promoted addition of methanol to enol ethers when cationic platinum complexes are employed.

While according to the thermodynamic hypothesis, protein folding reproducibility is ensured by the assumption that the native state corresponds to the minimum of the free energy in normal cellular conditions, here, the VES kinetic mechanism for folding in vivo is described according to which the nascent chain of all proteins is helical and the first and structure defining step in the folding pathway is the bending of that initial helix around a particular amino acid site. Molecular dynamics simulations are presented which indicate both the viability of this mechanism for folding and its limitations in the presence of a Markovian thermal bath. An analysis of a set of protein structures formed only of helices and loops suggests that bending sites are correlated with regions bounded, on the N-side, by positively charged amino acids like Lysine and Histidine and on the C-side by negatively charged amino acids like Aspartic acid.

Lactic acid enantiomers and cyclic lactic acid dimers, the latter referred to as lactides, are sources of degradable aliphatic polymers that are composed of chiral constitutional repeating units. The different synthesis routes and the various combinations of chiral units result in a multitude of chiral structures and of corresponding properties. Distinctive structural identification is often crucial, especially for applications as degradable polymers. This document provides recommendations for the nomenclature, abbreviations, and terminology related to lactic acid-based polymers in order to allow consistent comparison between polymers of different origins and between data collected within different disciplines.