Four-center Reaction Research Articles

New Full-Dimensional Reactive Potential Energy Surface for the H4 System.

As the most abundant molecule in the universe, collisions involving H2 have important implications in astrochemistry. Collisions between hydrogen molecules also represent a prototype for assessing various dynamic methods for understanding fundamental few-body processes. In this work, we develop a new and highly accurate full-dimensional potential energy surface (PES) covering all reactive channels of the H2 + H2 system, which extends our previously reported H2 + H2 nonreactive PES [J. Chem. Theory Comput., 2021, 17, 6747] by adding 39,538 additional ab initio points calculated at the MRCI/AV5Z level in the reactive channels. The global PES is represented with high fidelity (RMSE = 0.6 meV for a total of 79,000 points) by a permutation invariant polynomial neural network (PIP-NN) and is suitable for studying collision-induced dissociation, single-exchange, as well as four-center exchange reactions. Preliminary quasi-classical trajectory studies on the new PIP-NN PES reveal strong vibrational enhancement of all reaction channels.

One Reaction Served Three Ways: The On-DNA Ugi 4C-3C Reaction for the Formation of Lactams.

Developing new on-DNA reactions is paramount to the development of new encoded libraries in the pursuit of novel pharmaceutical lead compounds. Lactam-containing molecules have been shown to be effective in a wide range of therapeutic areas and therefore represent a promising target for further investigation by DNA-encoded library screening. In pursuit of this motif, we report a novel method for the introduction of lactam-containing structures onto a DNA headpiece through the Ugi four-center three-component reaction (4C-3CR). This novel method is successful in three different approaches to give unique on-DNA lactam structures: on-DNA aldehyde coupled with isonitriles and amino acids; on-DNA isonitrile coupled with aldehydes and amino acids; and on-DNA isonitrile coupled with amines and acid aldehydes.

Theoretical Study of the Thermal Decomposition of Urea Derivatives.

An extensive theoretical study of the thermal decomposition of alkyl- and phenylureas, which are widely used in the pesticides, pharmaceuticals, and materials industries, has been carried out using electronic structure calculations and reaction rate theories. Enthalpies of formation and bond dissociation energies (BDE) of 11 urea derivatives have been calculated using different levels of theory (CBS-QB3, CCSD(T)/CBS//M06-2X/6-311++G(3df,2pd), and CBS-QM062X) according to the size of the system. Potential energy surfaces for the unimolecular decomposition pathways of these urea derivatives were also systematically computed for the first time. Several pericyclic reactions can be envisaged, as a function of the size and the nature of the N substituents, and all of these pathways were explored. Our calculations show that these compounds are solely decomposed by four-center pericyclic reactions, yielding substituted isocyanates and amines, and that initial bond fissions are not competitive. Based on the set of urea derivatives studied, a new reaction rate rule for their thermal decomposition was defined and involves the nature of the transferred H atom (primary or secondary/alkyl or benzyl) and the nature of the N-atom acceptor (primary, secondary, or tertiary). This new reaction rate rule allows us to determine the product branching ratios in the thermal decomposition of a given urea derivative and its total rate of decomposition. Applications on urea derivatives used in the chemical industry are presented and illustrate the usefulness of this new rate rule that allows to predict the previously unknown thermal decomposition kinetics of a large number of these compounds.

Coherent Preparation of Highly Vibrating and Rotating D2 Molecules.

Highly vibrationally and rotationally excited hydrogen molecules are of immense interest for understanding and modeling the physics and chemistry of the cold interstellar medium. Using a sequence of two Stark-induced adiabatic Raman passages, we demonstrate the preparation of rotationally excited D2 molecules in the fourth excited vibrational level within its ground electronic state. The nearly complete population transfer to the target state is confirmed by observing both the threshold behavior as a function of the laser power and the depletion of the intermediate level. The vibrational excitation reported here opens new possibilities in the study of the much debated four-center reaction between a pair of hydrogen molecules. Additionally, these rovibrationally excited molecules could be potentially used to generate the high-intensity D- ion beams considered essential for D-T thermonuclear fusion by enhancing the cross section for dissociative electron attachment by 5 orders of magnitude compared to that of the ground state.

Group-Assisted-Purification Chemistry Strategy for the Efficient Assembly of Cyclic Fused Pyridinones

AbstractA group-assisted-purification (GAP) chemistry strategy-based Ugi four-center three-component reaction (Ugi-4C-3CR) was explored. The reaction proceeded well to deliver the cyclic fused pyridinones selectively. Moreover, the reaction conditions were mild and avoided additional chromatography or recrystallization workup. Also, wide variations in substrates, such as anilines and aliphatic amines as well as amino alcohols and amino acid esters were all tolerated and pyridinones are achieved in good to excellent yields. Importantly, ladder-type cyclic fused pyridinones can be further constructed in excellent yield of 91%.

Shear-Induced Adhesion of Alternating Peptides Prepared by Ugi Four-Center Three-Component Reaction.

The development of new peptide-based glues has been strongly urged from the viewpoints of industrial applications and biomedical engineering. However, the large-scale synthesis of polypeptides with an ordered sequence is highly challenging, which strictly restricts materials resources for the research and development of polypeptides. In this work, the framework of adhesive alternating peptides has been designed to be glycine (Gly)-N-substituted valine (Val) as the dipeptide repeating sequence, considering the peptapeptide repeating sequence of viscoelastic natural elastin as a motif. The alternating peptides are prepared via three-component polymerization exploiting Ugi four-center three-component reaction as the elemental polymerization reaction. The adhesive strength (SAdh ) values of the polymers are evaluated by a shear adhesive test method using two glass plates. Alternating peptides with Gly-N-benzylated Val dipeptide repeating units exhibit the optimal adhesive properties such as much higher SAdh than that of conventional fibrin glue and a unique readhesion capability. It is indicated that the remarkably high SAdh would be attributed to the shear-induced structural change of single polymer chain, the slow relaxation of extended structure, and the weak interchain interactions. Due to the favorable adhesive properties of alternating peptides, these adhesives may be highly suitable for real-world applications.

Decomposition Pathways of Titanium Isopropoxide Ti(OiPr)4: New Insights from UV-Photodissociation Experiments and Quantum Chemical Calculations.

The UV-photodissociation at 266 nm of a widely used TiO2 precursor, titanium tetraisopropoxide (Ti(OiPr)4, TTIP), was studied under molecular-beam conditions. Using the MS-TOF technique, atomic titanium and titanium(II) oxide (TiO) were detected among the most abundant photofragments. Experimental results were rationalized with the aid of quantum chemical calculations (DLPNO-CCSD(T) and DFT). Contrary to the existing data in the literature, the new four-centered acetone-elimination reaction was found to be the primary decomposition process of TTIP. According to computational results, the effective activation barrier of this channel was ∼49 kcal/mol, which was ∼13 kcal/mol lower than that of the competing propylene elimination. The former process, followed by the dissociative loss of an H atom, was a dominating channel of TTIP unimolecular decay. The sequential loss of isopropoxy moieties via these two-step processes was supposed to produce the experimentally observed titanium atoms. In turn, the combination of these reactions with propylene elimination can lead to another detected species, TiO. These results indicate that the existing mechanisms of TTIP thermal and photoinitiated decomposition in the chemical-vapor deposition (CVD) of titanium dioxide should be reconsidered.

One step access to oxindole-based β-lactams through Ugi four-center three-component reaction.

A multicomponent Ugi reaction involving isatin, isocyanide and β-amino acid components has been developed. The reactions proceeded smoothly to give β-lactam-containing 3,3-disubstituted oxindoles in only one step and generally high yields. When chiral, non racemic, β-amino acids were used, products were obtained as enantiomerically pure β-lactams diastereoisomers, whose relative stereochemistry was determined by X-ray analysis. For one compound, a weak antibacterial activity has been preliminarily highlighted.

Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams

We report the synthesis of racetams, a diverse class of small molecule drugs, by means of the Ugi four-center three-component reaction (U4C-3CR). For the first time, γ-aminobutyric acid is employed as bifunctional input in the Ugi reaction. This protocol is simple, general, and allows one-pot access to a range of drugs and bioactive small molecules.

Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct.

Reaction of isonitriles with 3-(arylamino)isobenzofuran-1(3H)-ones in the presence of a catalytic amount of an octahydro (R)-binol-derived chiral phosphoric acid afforded 3-oxo-2-arylisoindoline-1-carboxamides in high yields with good to high enantioselectivities. An enantioselective Ugi four-center three-component reaction of 2-formylbenzoic acids, anilines, and isonitriles was subsequently developed for the synthesis of the same heterocycle. Mechanistic studies indicate that the enantioselectivity results from the dynamic kinetic resolution of the primary Ugi adduct, rather than from the C-C bond-forming process. The resulting heterocycle products are of significant medicinal importance.

Synthesis of novel β-lactams and in vitro evaluation against the human malaria parasite Plasmodium falciparum

The use of three-component four-center Ugi reactions to afford the synthesis of novel β-lactams is described. Three series of compounds have been made using this reaction in combination with the Mannich reaction. All compounds formed are racemic mixtures and were tested against the chloroquine sensitive D10 strain of Plasmodium falciparum in an in vitro assay. All compounds showed low to moderate microMolar range activity with the most active compounds 2.6 and 3.1 showing IC50 values 16 μM and 15 μM respectively

Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold.

A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.

Structures, semisyntheses, and absolute configurations of the antiplasmodial α-substituted β-lactam monamphilectines B and C from the sponge Svenzea flava

Bioassay-guided fractionation of the Caribbean sponge Svenzea flava collected near Mona Island, off the west coast of Puerto Rico, led to the isolation of two isocyanide amphilectane-type diterpenes named monamphilectines B and C (2 and 3). Attached to the backbone of each of these compounds is the first α-substituted monocyclic β-lactam ring to be isolated from a marine organism. The molecular structures of 2 and 3 were established by spectroscopic methods and then confirmed unequivocally by chemical correlation and comparison of physical and chemical data with the natural products. The new β-lactams were successfully synthesized in one step, starting from the known diisocyanide 4, via parallel Ugi four-center three-component reactions (U-4C-3CR) that also established their absolute stereostructures. Interestingly, compounds 2 and 3 exhibited activities in the low nanomolar range against the human malaria parasite Plasmodium falciparum.

Thee-component, one-pot synthesis of hexahydroazepino[3,4-b]indole and tetrahydro-1H-pyrido[3,4-b]indole derivatives and evaluation of their cytotoxicity

A three-component, four-center Ugi reaction has been developed to produce a novel class of 2-aryl-3-oxo-hexahydroazepino[3,4-b]indole and 2-aryl-3-oxo-tetrahydro-1H-pyrido[3,4-b]indole derivatives in good to high yields. A few of them exhibit moderate cytotoxicity against various cancer cell lines such as HeLa (human epithelial cervical cancer), A549 (human lung carcinoma epithelial), DU145 (human prostate carcinoma epithelial) and MCF-7 (human breast adenocarcinoma).

An extensive methodological theoretical study of the kinetics of the benzylperoxy radical isomerization

Theoretical calculations are carried out on benzylperoxy radical four-center isomerization reaction. Geometry optimizations and vibrational frequency calculations are performed using three methods (B3LYP, MPW1K, and MP2) and seven basis sets (6-31G(d,p), 6-31+G(d,p), 6-31++G(d,p), 6-311G(d,p), cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ). Single-point energy calculations are performed with the highly-correlated ab initio coupled cluster method in the space of single, double, and triple (perturbatively) electron excitations (CCSD(T)) using the 6-311G(d,p), 6-311+G(d,p), 6-311++G(d,p), 6-311+G(3df,2p), and cc-pVTZ basis sets, and with the CASPT2/ANO-L-VDZP level of theory. Canonical transition state theory with a Wigner tunneling correction is used to calculate the high-pressure limit rate constant. The rate constants at 773K calculated with the CASPT2/ANO-L-VDZP//B3LYP/cc-pVDZ and CASPT2/ANO-L-VDZP//B3LYP/aug-cc-pVDZ levels of theory are in very good agreement with the literature value from Ellis et al. These levels of theory are then used to compute the temperature dependence of rate constant and leads to the following three-parameter Arrhenius expressions over the range 600–2000K: k (s−1)=1.34×1010T0.79 exp(−133.1kJmol−1/RT) and k (s−1)=1.85×1010T0.78 exp(−133.9kJmol−1/RT) at the CASPT2/ANO-L-VDZP//B3LYP/cc-pVDZ and CASPT2/ANO-L-VDZP//B3LYP/aug-cc-pVDZ levels of theory, respectively. These relations can be used in oxidation thermokinetic models involving toluene and alkylbenzenes.

ChemInform Abstract: Tandem One Pot Synthesis of 1,5‐Benzodiazocine‐2‐one by Isocyanide Based Ugi Multicomponent Reaction.

Abstract We have developed an efficient one-pot, two-step reaction protocol for the synthesis of eight-membered 1,5-benzodiazocine-2-ones by Ugi four-center three-component coupling reaction (U-4C-3CR) and subsequent reductive cyclization using Fe/NH4Cl in protic solvent.

General One-pot, Two-Step Protocol Accessing a Range of Novel Polycyclic Heterocycles with High Skeletal Diversity

An Ugi one-pot three-component four-center reaction was coupled with a subsequent acid mediated cyclodehydration step to furnish a multitude of unique scaffolds having in common an embedded or attached benzimidazole and often a ring system formed through lactamization. Using combinations of tethered Ugi inputs typically via tethered acid-ketone inputs and supporting reagents containing masked internal nucleophiles, such scaffolds were produced in good to excellent yields in an operationally friendly manner.

Tandem one pot synthesis of 1,5-benzodiazocine-2-one by isocyanide based Ugi multicomponent reaction

We have developed an efficient one-pot, two-step reaction protocol for the synthesis of eight-membered 1,5-benzodiazocine-2-ones by Ugi four-center three-component coupling reaction (U-4C-3CR) and subsequent reductive cyclization using Fe/NH4Cl in protic solvent.

Fully converged integral cross sections of collision induced dissociation, four-center, and single exchange reactions, and accuracy of the centrifugal sudden approximation in H2 + D2 reaction

The initial state selected time-dependent wave packet method was employed to calculate the integral cross sections for the H(2) + D(2) reaction with and without the centrifugal sudden (CS) approximation by including all important K (the projection of the total angular momentum on the body-fixed axis) blocks. With a full-dimensional model, the first fully converged coupled-channel (CC) cross sections for different competitive processes from the ground rotational state were obtained: collision induced dissociation (CID), four-center (4C) reaction and single exchange (SE) reaction. The effect of the total angular momentum J on the reaction dynamics of H(2) + D(2) and the accuracy of the CS approximation have also been studied. It was found that the CID and SE processes occur in a wide range of J values while the 4C process can only take place in a narrow window of J values. For this reason, the CC cross section for the 4C channel is merely comparable to the SE channel. A comparison of the integral cross sections from CC and CS calculations showed that the CS approximation works well for the CID process but not for the 4C and SE processes, and the discrepancy between the CC and CS cross sections grows larger as the translational energy and/or the vibrational energy increase(s).

Ugi four-center three-component reaction for the parallel solid-phase synthesis of N-substituted thiomopholinones

Starting with resin-bound bifunctional 2-(2-aminoethylthio)acetic, an efficient synthesis of a variety of N-cycloakyl thiomopholinones is described utilizing the Ugi four-center three-component reaction (U-4C-3CR).