Exploring the Chemistry of the Mechanical Bond: Synthesis of a [2]Rotaxane through Multicomponent Reactions.

The synthesis of a [2]rotaxane through three- or five-component coupling reactions has been adapted to an organic chemistry experiment for upper-division students. The experimental procedure addresses the search for the most favorable reaction conditions for the synthesis of the interlocked compound, which is obtained in a yield of up to 71%. Moreover, the interlocked nature of the rotaxane is proven by NMR spectroscopy. The content of the sessions has been designed on the basis of a proactive methodology whereby upper-division undergraduate students have a dynamic role. The laboratory experience not only introduces students to the chemistry of the mechanical bond but also reinforces their previous knowledge of basic organic laboratory procedures and their skills with structural elucidation techniques such as NMR and FT-IR spectroscopies. The experiment has been designed in such a customizable way that both experimental procedures and laboratory material can be adapted to a wide range of undergraduate course curricula.

Intramolecular Cyclization of Azido-Isocyanides Triggered by the Azide Anion: An Experimental and Computational Study.

This work describes the unprecedented intramolecular cyclization occurring in a set of α-azido-ω-isocyanides in the presence of catalytic amounts of sodium azide. These species yield the tricyclic cyanamides [1,2,3]triazolo[1,5-a]quinoxaline-5(4H)-carbonitriles, whereas in the presence of an excess of the same reagent, the azido-isocyanides convert into the respective C-substituted tetrazoles through a [3 + 2] cycloaddition between the cyano group of the intermediate cyanamides and the azide anion. The formation of tricyclic cyanamides has been examined by experimental and computational means. The computational study discloses the intermediacy of a long-lived N-cyanoamide anion, detected by NMR monitoring of the experiments, subsequently converting into the final cyanamide in the rate-determining step. The chemical behavior of these azido-isocyanides endowed with an aryl-triazolyl linker has been compared with that of a structurally identical azido-cyanide isomer, experiencing a conventional intramolecular [3 + 2] cycloaddition between its azido and cyanide functionalities. The synthetic procedures described herein constitute metal-free approaches to novel complex heterocyclic systems, such as [1,2,3]triazolo[1,5-a]quinoxalines and 9H-benzo[f]tetrazolo[1,5-d][1,2,3]triazolo[1,5-a][1,4]diazepines.

Ring-to-Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams.

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

Reduced nicotinamide mononucleotide is a new and potent NAD+ precursor in mammalian cells and mice.

Nicotinamide adenine dinucleotide (NAD+ ) homeostasis is constantly compromised due to degradation by NAD+ -dependent enzymes. NAD+ replenishment by supplementation with the NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD+ pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD+ precursor for the first time. We show that NMNH increases NAD+ levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD+ surge in whole blood, which is accompanied by increased NAD+ levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD+ precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD+ precursors and establish NMNH as a member of the new family of reduced NAD+ precursors.

Exploring the Conversion of Macrocyclic 2,2'-Biaryl Bis(thioureas) into Cyclic Monothioureas: An Experimental and Computational Investigation.

Macrocyclic bis(thioureas) derived from 2,2'-biphenyl and binaphthyl skeletons have been synthesized by reaction of 2,2'-diaminobiaryl and 2,2'-bis(isothiocyanato)biaryl derivatives. The splitting of these bis(thioureas) into two units of the respective cyclic monothioureas has been monitored by NMR, shedding some light on the factors that control these processes. Additionally, a computational study revealed up to three mechanistic paths for the conversion of the 2,2'-biphenyl-derived bis(thiourea) into the corresponding monothiourea. The proposed mechanisms account for the participation of a molecule of water as an efficient proton-switch as well as for different classes of putative intermediates. The computational study also supports the ability of the thiourea group to participate in a plethora of processes, such as prototropic equilibria, sigmatropic shifts, heteroene and retro-heteroene reactions, and cis ⇆ trans isomerizations.

Stereocontrolled Synthesis of ß-Lactams within [2]Rotaxanes: Showcasing the Chemical Consequences of the Mechanical Bond.

The intramolecular cyclization of N-benzylfumaramide [2]rotaxanes is described. The mechanical bond of these substrates activates this transformation to proceed in high yields and in a regio- and diastereoselective manner, giving interlocked 3,4-disubstituted trans-azetidin-2-ones. This activation effect markedly differs from the more common shielding protection of threaded functions by the macrocycle, in this case promoting an unusual and disfavored 4-exo-trig ring closure. Kinetic and synthetic studies allowed us to delineate an advantageous approach toward ß-lactams based on a two-step, one-pot protocol: an intramolecular ring closure followed by a thermally induced dethreading step. The advantages of carrying out this cyclization in the confined space of a benzylic amide macrocycle are attributed to its anchimeric assistance.

Palladium complexes derived from N,N-bidentate NH-iminophosphorane ligands: synthesis and use as catalysts in the Sonogashira reaction.

The addition of primary amines to the C=C bond of diphenylalkenyl iminophosphoranes yielded a new subtype of N,N-bidentate ligands bearing N=P(V)-C-C-NH backbones. These donor ligands reacted with PdCl(2)(COD) to give the corresponding σN,σN-palladium complexes containing secondary amino groups, bearing an intrinsically chiral nitrogen atom, and iminophosphorane units. These new complexes have been fully characterized by the use of spectroscopic techniques and X-ray crystallography. The comparison of the data extracted from their solution NMR spectra with their solid state structures demonstrated the conformational stability of their six-membered chelate ring and also the configurational stability of the chiral nitrogen atom, thus ruling out an arm-off racemization process. The addition of the chiral, racemic α-methylbenzylamine to the prochiral P-alkenyl iminophosphoranes yielded mixtures of the two expected diasteroisomeric ligands in low diastereoisomeric ratios. One of these mixtures was resolved into their components, each one in turn giving rise to a pair of diasteromeric palladium complexes epimeric at the amino nitrogen atom. One selected example of the new complexes efficiently catalyzes the copper- and amine-free Sonogashira reaction of aryl halides with acetylenes.

Insertion of benzynes into the P═N Bond of P-alkenyl(alkynyl)-λ5-phosphazenes.

Benzynes, generated from 2-(trimethylsilyl)phenyl triflates, have been found to react with P-Alkenyl-λ(5)-phosphazenes via a formal π-insertion into the P═N bond. A subsequent retro [2 + 2] cycloaddition/6π electrocyclization/protonation cascade explains the formation of the resulting 1,4-benzazaphosphorinium triflates. P-Alkynyl λ(5)-phosphazenes and phosphane sulfides undergo similar transformations.

Synthesis and molecular structure of beta-phosphinoyl carboxamides: an unexpected case of chiral discrimination of hydrogen-bonded dimers in the solid state.

A series of N,P,P-trisubstituted aminophosphanes react with diphenylcyclopropenone to afford an easily separable mixture of two diastereomeric alpha,beta-diphenyl-beta-phosphinoyl carboxamides in good yields. X-ray crystal structures reveal that these compounds associate into dimers, formed from two enantiomeric units linked by two bifurcated hydrogen bonds, whereby the oxygen atom of the phosphoryl group acts as a dual acceptor for the vicinal NH and CH of a carbonyl group of a neighbouring molecule. Studies on the interconversion between diastereomeric phosphinoyl carboxamides in basic solution show that the thermodynamically most stable isomer depends on the nature of the substituent at the nitrogen atom. Simple computational calculations explain this phenomenon.

Component exchange as a synthetically advantageous strategy for the preparation of bicyclic cage compounds.

Macrobicyclic triphosphazides are able to reversibly exchange one of their tripodal components by means of a dynamic disassembly-reassembly process; surprisingly this strategy provides better yields of cage compounds than a direct tripod-tripod coupling.

Helical chirality transmission through a p-phenylene fragment in a hexa-lambda5-phosphazene.

The helical chirality of a conformationally stable macrobicyclic tri-lambda5-phosphazene is propagated through to its C3 symmetry axis and causes a measurable stereoinduction in the formation process of a second macrobicyclic tri-lambda5-phosphazene unit connected to the former one by a p-phenylene linker.

On the mechanism of phthalimidine formation via o-phthalaldehyde monoimines. New [1,5]-H sigmatropic rearrangements in molecules with the 5-aza-2,4-pentadienal skeleton.

[reactions: see text] Condensation reaction of o-phthalaldehyde with primary amines is a classical method for the synthesis of phthalimidines. Although the intermediacy of the corresponding monoimines has been occasionally proposed, the mechanism of their transformation into phthalimidines remains to be elucidated. We present here theoretical evidence supporting a three-step mechanistic pathway for that transformation involving the [1,5]-H sigmatropic rearrangement of the aldehydic proton leading to an intermediate (aminovinyl)ketene as the key step. Other alternative routes have been calculated to be energetically less favorable. Similar transformations of related imino aldehydes enclosing a 5-aza-2,4-pentadienal skeleton via [1,5]-H shifts are also studied.

(3h)J((15)N-(31)P) spin-spin coupling constants across N[bond]H....O[bond]P hydrogen bonds.

Equation-of-motion coupled cluster singles and doubles (EOM-CCSD) calculations have been performed to evaluate three-bond (15)N-(31)P coupling constants ((3h)J(N[bond]P)) across N[bond]H....O[bond]P hydrogen bonds in model cationic and anionic complexes including NH(4)(+):OPH, NH(4)(+):OPH(3), NH(3):(-)O(2)PH(2), NFH(2):(-)O(2)PH(2), and NF(2)H:(-)O(2)PH(2). Three-bond coupling constants can be appreciable when the phosphorus is P(V), but are negligible with P(III). (3h)J(N[bond]P) values in complexes with cyclic or open structures are less than 1 Hz, a consequence of the nonlinear arrangement of N, H, O, and P atoms. For complexes with these structures, (3h)J(N[bond]P) may not be experimentally measurable. In contrast, complexes in which the N, H, O, and P atoms are collinear or nearly collinear have larger values of (3h)J(N[bond]P), even though the N[bond]P distances are longer than N[bond]P distances in cyclic and open structures. In linear complexes, (3h)J(N[bond]P) is dominated by the Fermi-contact term, which is distance dependent. Therefore, N[bond]P (and hydrogen-bonding N[bond]O) distances in these complexes can be determined from experimentally measured (15)N-(31)P coupling constants.