Catalytic artificial nitroalkane oxidases - a way towards organocatalytic umpolung.

Nitroalkane oxidases (NAOs) are flavoenzymes that catalyse the oxidation of nitroalkanes to their corresponding carbonyl compounds while producing nitrite anions. Herein, we present an artificial catalytic system using flavins or ethylene-bridged flavinium salts that works via an NAO-like process. Under conditions optimised in terms of solvent, base, temperature and oxygen pressure, primary nitroalkanes were transformed to aldehydes. In our system, aldehydes immediately reacted with other nitroalkane molecules to form ß-nitroalcohols. The reduced flavin catalyst was re-oxidised by oxygen. An alternative mechanism towards ß-nitroalcohols via 5-(2-nitrobutyl)-1,5-dihydroflavin was suggested through quantum chemical calculations and by trapping and characterising this dihydroflavin intermediate. Interestingly, 5-(2-nitrobutyl)-1,5-dihydroflavin is an analogue of the flavin adenine dinucleotide adduct previously observed in an NAO X-ray structure. In both mechanistic pathways, flavin-5-iminium species is formed by nitroalkanide addition to flavin. This process represents flavin-based umpolung of an original donor to an acceptor.

Regioselective Lithiation of Tetrabromocalix[4]arenes: A Simple Way for the Desymmetrization of the Macrocyclic Skeleton.

Desymmetrization of persubstituted calix[4]arenes represents an interesting way to yield distally disubstituted derivatives. The reaction of tetrabrominated calixarenes in three different conformations (cone, partial cone, and 1,3-alternate) with an excess of n-BuLi surprisingly leads with high selectivity to distally dilithiated derivatives that, by reaction with electrophiles, give substitution patterns which are difficult to obtain by other ways. Using a combination of synthetic and theoretical approaches (DFT), we tried to demonstrate the usefulness of this method and provide a possible explanation for this unexpected selectivity.

Property Map Collective Variable as a Useful Tool for a Force Field Correction.

The accuracy of biomolecular simulations depends on the accuracy of an empirical molecular mechanics potential known as a force field: a set of parameters and expressions to estimate the potential from atomic coordinates. Accurate parametrization of force fields for small organic molecules is a challenge due to their high diversity. One of the possible approaches is to apply a correction to the existing force fields. Here, we propose an approach to estimate the density functional theory (DFT)-derived force field correction which is calculated during the run of molecular dynamics without significantly affecting its speed. Using the formula known as a property map collective variable, we approximate the force field correction by a weighted average of this force field correction calculated only for a small series of reference structures. To validate this method, we used seven AMBER force fields, and we show how it is possible to convert one force field to behave like the other one. We also present the force field correction for the important anticancer drug Imatinib as a use case example. Our method appears to be suitable for adjusting the force field for general drug-like molecules. We provide a pipeline that generates the correction; this pipeline is available at https://pmcvff-correction.cerit-sc.cz/.

Nucleophile-induced transformation of phenoxathiin-based thiacalixarenes.

Oxidized phenoxathiin-based macrocycles, easily accessible thiacalix[4]arene derivatives, consist of a unique set of structural elements representing a key prerequisite for the unexpected reactivity described in this paper. As proposed, the internal strain, imposed by the presence of a heterocyclic moiety, together with a number of electron-withdrawing groups (SO2) opens the way to the cleavage of the macrocyclic skeleton through a cascade of three SNAr reactions triggered by the nucleophilic attack of an SH- anion. The whole transformation, which is unparalleled in classical calixarene chemistry, leads to unique linear sulfinic acid derivatives with a rearranged phenoxathiin moiety that can serve as building blocks for macrocyclic systems of a new type.

Rearrangement of meta-Bridged Calix[4]arenes Promoted by Internal Strain.

The meta-bridged calixarenes possess a rigidified and highly distorted cavity, where the additional single-bond bridge imposes an extreme internal strain on the whole system. As a consequence, these compounds exhibit a reasonably amended reactivity, compared with common calix[4]arene derivatives, which is governed by the release of internal strain. This can be documented by the reaction of the bridged calix[4]arene with P2O5 or Nafion-H, leading (apart from polymers) to a macrocyclic product with a rearranged basic skeleton. The methylene bridge next to the fluorene moiety is intramolecularly shifted from position 2 to position 4 of the phenolic subunit to minimize the tension. As revealed by single-crystal X-ray analysis and by application of the residual dipolar coupling method, the rearrangement occurs without altering the original conformation.

Force-Induced Catastrophes on Energy Landscapes: Mechanochemical Manipulation of Downhill and Uphill Bifurcations Explains the Ring-Opening Selectivity of Cyclopropanes.

The mechanochemistry of ring-opening reactions of cyclopropane derivatives turns out to be unexpectedly rich and puzzling. After showing that a rare so-called uphill bifurcation in the case of trans-gem-difluorocyclopropane turns into a downhill bifurcation upon substitution of fluorine by chlorine, bromine, and iodine in the thermal activation limit, the dichloro derivative is studied systematically in the realm of mechanochemical activation. Detailed exploration of the force-transformed potential energy surface of trans-gem-dichlorocyclopropane in terms of Dijkstra path analysis unveils a hitherto unknown topological catastrophe where the global shape of the energy landscape is fundamentally changed. From thermal activation up to moderately large forces, it is an uphill bifurcation that decides about dis- versus conrotatory ring-opening followed by separate transition states along both pathways. Above a critical force, the two distinct transition states merge to yield a single transition state such that the decision about the dis- versus conrotatory ring-opening process is taken at a newly established downhill bifurcation. The discovery of a force-induced qualitative change of the topology of a reaction network vastly transcends the previous understanding of the ring-opening reaction of this species. It would be astonishing to not discover a wealth of such catastrophes for mechanochemically activated reactions, which will greatly extend the known opportunities to manipulate chemical reaction networks.

An efficient pair natural orbital based configuration interaction scheme for the calculation of open-shell ionization potentials.

A spin adapted configuration interaction scheme is proposed for the evaluation of ionization potentials in α high spin open shell reference functions. There are three different ways to remove an electron from such a reference, including the removal of an alpha or a beta electron from doubly occupied or an alpha electron from singly occupied molecular orbitals. Ionization operators are constructed for each of these cases, and the resulting second quantized expressions are implemented using an automated code generator environment. To achieve greater computational efficiency, the virtual space is reduced using an averaged pair natural orbital machinery developed earlier and applied with great success in the calculation of X-ray absorption spectra [D. Manganas et al., J. Chem. Phys. A 122, 1215 (2018)]. Various approximate integral evaluation schemes including the resolution of identity and seminumerical techniques are also invoked to further enhance the computational efficiency. Although the resulting method is not particularly accurate in terms of predicting absolute energy values, with a simple shift in the ionization potentials, it is still possible to use it for the qualitative characterization of the basic features of X-ray photoionization spectra. While satellite intensities cannot be computed with the current method, the inclusion of vibrational effects using a path integral technique allows for the computation of vibrational transitions corresponding to main peaks.

A toolchain for the automatic generation of computer codes for correlated wavefunction calculations.

In this work, the automated generator environment for ORCA (ORCA-AGE) is described. It is a powerful toolchain for the automatic implementation of wavefunction-based quantum chemical methods. ORCA-AGE consists of three main modules: (1) generation of "raw" equations from a second quantized Ansatz for the wavefunction, (2) factorization and optimization of equations, and (3) generation of actual computer code. We generate code for the ORCA package, making use of the powerful functionality for wavefunction-based correlation calculations that is already present in the code. The equation generation makes use of the most elementary commutation relations and hence is extremely general. Consequently, code can be generated for single reference as well as multireference approaches and spin-independent as well as spin-dependent operators. The performance of the generated code is demonstrated through comparison with efficient hand-optimized code for some well-understood standard configuration interaction and coupled cluster methods. In general, the speed of the generated code is no more than 30% slower than the hand-optimized code, thus allowing for routine application of canonical ab initio methods to molecules with about 500-1000 basis functions. Using the toolchain, complicated methods, especially those surpassing human ability for handling complexity, can be efficiently and reliably implemented in very short times. This enables the developer to shift the attention from debugging code to the physical content of the chosen wavefunction Ansatz. Automatic code generation also has the desirable property that any improvement in the toolchain immediately applies to all generated code. © 2017 Wiley Periodicals, Inc.

Similarity transformed equation of motion coupled-cluster theory based on an unrestricted Hartree-Fock reference for applications to high-spin open-shell systems.

The similarity transformed equation of motion coupled-cluster approach is extended for applications to high-spin open-shell systems, within the unrestricted Hartree-Fock (UHF) formalism. An automatic active space selection scheme has also been implemented such that calculations can be performed in a black-box fashion. It is observed that both the canonical and automatic active space selecting similarity transformed equation of motion (STEOM) approaches perform about as well as the more expensive equation of motion coupled-cluster singles doubles (EOM-CCSD) method for the calculation of the excitation energies of doublet radicals. The automatic active space selecting UHF STEOM approach can therefore be employed as a viable, lower scaling alternative to UHF EOM-CCSD for the calculation of excited states in high-spin open-shell systems.

Unclicking the Click: Metal-Assisted Mechanochemical Cycloreversion of Triazoles Is Possible.

The mechanochemical cycloreversion of 1,2,3-triazole compounds, which serve as unusually stable building blocks in materials and biomolecular chemistry as a result of mild "click chemistry", remains puzzling. We show that the hitherto discussed straight-forward retro-click mechanism of the 1,4-disubstituted isomer, even if CuI catalyzed, can be ruled out in view of more favorable activation free energies of destructive pathways. In stark contrast, the 1,5-regioiomer can undergo cycloreversion under rather mild mechanochemical conditions owing to its favorable response to the external force in conjunction with standard RuII catalysis.

Comparison of fully internally and strongly contracted multireference configuration interaction procedures.

Multireference (MR) methods occupy an important class of approaches in quantum chemistry. In many instances, for example, in studying complex magnetic properties of transition metal complexes, they are actually the only physically satisfactory choice. In traditional MR approaches, single and double excitations are performed with respect to all reference configurations (or configuration state functions, CSFs), which leads to an explosive increase of computational cost for larger reference spaces. This can be avoided by the internal contraction scheme proposed by Meyer and Siegbahn, which effectively reduces the number of wavefunction parameters to their single-reference counterpart. The "fully internally contracted" scheme (FIC) is well known from the popular CASPT2 approach. An even shorter expansion of the wavefunction is possible with the "strong contraction" (SC) scheme proposed by Angeli and Malrieu in their NEVPT2 approach. Promising multireference configuration interaction formulations (MRCI) employing internal contraction and strong contraction have been reported by several authors. In this work, we report on the implementation of the FIC-MRCI and SC-MRCI methodologies, using a computer assisted implementation strategy. The methods are benchmarked against the traditional uncontracted MRCI approach for ground and excited states of small molecules (N2, O2, CO, CO(+), OH, CH, and CN). For ground states, the comparison includes the "partially internally contracted" MRCI based on the Celani-Werner ansatz (PC-MRCI). For the three contraction schemes, the average errors range from 2% to 6% of the uncontracted MRCI correlation energies. Excitation energies are reproduced with ∼0.2 eV accuracy. In most cases, the agreement is better than 0.2 eV, even in cases with very large differential correlation contributions as exemplified for the d-d and ligand-to-metal charge transfer transitions of a Cu[NH3]4 (2+) model complex. The benchmark is supplemented with the investigation of typical potential energy surfaces (i.e., N2, HF, LiF, BeH2, ethane C-C bond stretching, and the ethylene double bond torsion). Our results indicate that the SC-scheme, which is successful in the context of second- and third-order perturbation theory, does not offer computational advantages and at the same time leads to much larger errors than the PC and FIC schemes. We discuss the advantages and disadvantages of the PC and FIC schemes, which are of comparable accuracy and, for the systems tested, also of comparable efficiency.

Force-Induced Reversal of ß-Eliminations: Stressed Disulfide Bonds in Alkaline Solution.

Understanding the impact of tensile forces on disulfide bond cleavage is not only crucial to the breaking of cross-linkers in vulcanized materials such as strained rubber, but also to the regulation of protein activity by disulfide switches. By using ab initio simulations in the condensed phase, we investigated the response of disulfide cleavage by ß-elimination to mechanical stress. We reveal that the rate-determining first step of the thermal reaction, which is the abstraction of the ß-proton, is insensitive to external forces. However, forces larger than about 1 nN were found to reshape the free-energy landscape of the reaction so dramatically that a second channel is created, where the order of the reaction steps is reversed, turning ß-deprotonation into a barrier-free follow-up process to C-S cleavage. This transforms a slow and force-independent process with second-order kinetics into a unimolecular reaction that is greatly accelerated by mechanical forces.

Should the Woodward-Hoffmann Rules be Applied to Mechanochemical Reactions?

Since decades, pericyclic reactions have been well-understood by means of the Woodward-Hoffmann rules and their classification as thermally or photochemically "allowed" or "forbidden". Recently, stunning results on such reactions subject to mechanochemical activation by external forces instead of heat or light have revealed reaction pathways at sufficiently large forces, which are not expected from the Woodward-Hoffmann rules. This led to the much reiterated idea that the "Woodward-Hoffmann rules are broken in mechanochemistry". Here, by studying ring-opening of cyclopropane, we show that the electronic structure underlying the dis- and conrotatory pathways, which are greatly distorted upon applying forces to an extent that eventually the "thermally forbidden" process becomes "mechanochemically allowed", does not change along both pathways. It is rather the mechanical work that lowers the activation barrier of the thermally forbidden conrotatory process relative to the disrotatory one at large forces.

Reactivity of phenoxathiin-based thiacalixarenes towards C-nucleophiles.

A starting thiacalix[4]arene can be easily transformed into oxidized phenoxathiin-based macrocycles 9 and 9', representing an unusual structural motif in calixarene chemistry. The presence of electron-withdrawing groups (SO2, SO) and the considerable internal strain caused by the condensed heterocyclic moiety render these molecules susceptible to nucleophilic attack. The reaction with various organolithium reagents provides a number of different products resulting from the cleavage of either the calixarene skeleton or the phenoxathiin group or both ways simultaneously. This enables the preparation of thiacalixarene analogues with unusual structural features, including systems containing a biphenyl fragment as a part of the macrocyclic skeleton. The above-described transformations, unparalleled in classical calixarene chemistry, clearly demonstrate the synthetic potential of this thiacalixarene subgroup.

Exploring the Reactivity of Flavins with Nucleophiles Using a Theoretical and Experimental Approach.

Covalent adducts of flavin cofactors with nucleophiles play an important role in non-canonical function of flavoenzymes as well as in flavin-based catalysis. Herein, the interaction of flavin derivatives including substituted flavins (isoalloxazines), 1,10-ethylene-bridged flavinium salts, and non-substituted alloxazine and deazaflavin with selected nucleophiles was investigated using an experimental and computational approach. Triphenylphosphine or trimethylphosphine, 1-nitroethan-1-ide, and methoxide were selected as representatives of neutral soft, anionic soft, and hard nucleophiles, respectively. The interactions were investigated using UV/Vis and 1 H NMR spectroscopy as well as by DFT calculations. The position of nucleophilic attack estimated using the calculated Gibbs free energy values was found to correspond with the experimental data, favouring the addition of phosphine and 1-nitroethan-1-ide into position N(5) and methoxide into position C(10a) of 1,10-ethylene-bridged flavinium salts. The calculated Gibbs free energy values were found to correlate with the experimental redox potentials of the flavin derivatives tested. These findings can be utilized as valuable tools for the design of artificial flavin-based catalytic systems or investigating the mechanism of flavoenzymes.

Design of Bis(1,10-phenanthroline) Copper(I)-Based Mechanochromic Indicators.

In the growing field of single-molecule mechanochromism, the potential of transition metal complexes is yet to be examined. In this work, we have synthesized a series of [Cu(phen)2]+ complexes: bis-Cu(I)-phenanthroline, bis-Cu(I)-phenanthroline-2-amine, and bis-Cu(I)-phenanthroline-2-acetamide. After that, we characterized the complexes by UV-vis spectroscopy and employed density functional theory (DFT) calculations to investigate the changes in UV-vis upon mechanical pulling via force calculations. The results of our examination of time-dependent (TD)-DFT-calculated UV-vis suggests that the bis-Cu(I)-phenanthroline-2-acetamide complex is predicted to have an observable shift of the metal-to-ligand charge transfer band upon pulling from 0 to 0.6 nN in the visible region. We have demonstrated the ability to synthesize and characterize bis-Cu(I)-phenanthroline-2-acetamide. In addition, the TD-DFT calculations predict an observable shift in the visible region of the UV-vis spectrum. This indicates that transition metal complexes are feasible candidates as mechanophores and are worthy of further exploration as to their potential role in a new subclass of mechanochromic indicators.

Distribution, biological activities, metabolism, and the conceivable function of cis-zeatin-type cytokinins in plants.

Cytokinins (CKs) are plant hormones affecting numerous developmental processes. Zeatin and its derivatives are the most important group of isoprenoid CKs. Zeatin occurs as two isomers: while trans-zeatin (transZ) was found to be a bioactive substance, cis-zeatin (cisZ) was reported to have a weak biological impact. Even though cisZ derivatives are abundant in various plant materials their biological role is still unknown. The comprehensive screen of land plants presented here suggests that cisZ-type CKs occur ubiquitously in the plant kingdom but their abundance might correlate with a strategy of life rather than with evolutionary complexity. Changing levels of transZ and cisZ during Arabidopsis ontogenesis show that levels of the two zeatin isomers can differ significantly during the life span of the plant, with cisZ-type CKs prevalent in the developmental stages associated with limited growth. A survey of the bioassays employed illustrates mild activity of cisZ and its derivatives. No cis↔trans isomerization, which would account for the effects of cisZ, was observed in tobacco cells and oat leaves. Differences in uptake between the two isomers resulting in distinct bioactivity have not been detected. In contrast, cisZ and transZ have a different metabolic fate in oat and tobacco. Analysis of a CK-degrading enzyme, cytokinin oxidase/dehydrogenase (CKX), reveals that Arabidopsis possesses two isoforms, AtCKX1 expressed in stages of active growth, and AtCKX7, both of which have the highest affinity for the cisZ isomer. Based on the present results, the conceivable function of cisZ-type CKs as delicate regulators of CK responses in plants under growth-limiting conditions is hypothesized.

Amide Bond Formation via Aerobic Photooxidative Coupling of Aldehydes with Amines Catalyzed by a Riboflavin Derivative.

We report an effective, operationally simple, and environmentally friendly system for the synthesis of tertiary amides by the oxidative coupling of aromatic or aliphatic aldehydes with amines mediated by riboflavin tetraacetate (RFTA), an inexpensive organic photocatalyst, and visible light using oxygen as the sole oxidant. The method is based on the oxidative power of an excited flavin catalyst and the relatively low oxidation potential of the hemiaminal formed by amine to aldehyde addition.

Enantioselective interaction of carbamoylated quinine and (S)-3,5-dinitrobenzoyl alanine: theoretical and experimental circular dichroism study.

The interaction between tert-butylcarbamoylquinine selector and (S)-3,5-dinitrobenzoyl alanine selectand was studied experimentally and theoretically by chiroptical methods. Using a combination of experimental and calculated circular dichroism spectra, we present the first work dealing with the interaction of two dissimilar chiral molecules interacting by diverse types of interactions: ion pairing, hydrogen bonding and π-π stacking. Conformational analysis of the free selector, free selectand and the complex of selector with selectand was carried out and the obtained conformers were optimized at the BHandH/6-31+G** and B97d/6-31+G** levels. Consequently, vibrational (VCD) and electronic (ECD) circular dichroism spectra were calculated at the BHandH/6-31+G** and B97d/6-31+G** levels for the VCD and HF/6-31++G** and CAM-B3LYP/6-31++G** levels for the ECD. Spectral patterns of the free selectand and selector together with the complexation-induced spectral changes were compared with experimental data. Despite many simplifications within the theoretical model, the calculated ECD and VCD spectra are in good agreement with experimental data, which proves that the density functional theory (DFT) methods are able to model complicated systems interacting via multiple interactions of different natures.

Hybrid quantum mechanical/molecular mechanical investigation of the beta-1,4-galactosyltransferase-I mechanism.

The enzyme beta-1,4-galactosyltransferase-1 (beta4Gal-T1) catalyzes the transfer of a galactose residue from UDP-Gal to the C4-hydroxyl group of N-acetylglucosamine. The catalytic mechanism of beta4Gal-T1 was investigated using the hybrid quantum mechanical/molecular mechanical (QM/MM) method, with the QM portion containing 253 atoms treated with density functional theory (DFT) at the BP/DZP and BP/TZ2P levels. The remaining parts of the beta4Gal-T1 complex, 4527 atoms in all, were modeled using the AMBER molecular force field. A theoretical model of the Michaelis complex was built using the X-ray structure of beta4Gal-T1 in a complex with the donor or acceptor substrate, respectively. The hybrid QM(DFT)/MM calculations identified an S(N)2-type transition state for the nucleophilic attack of the O4(a) oxygen on the anomeric carbon C1 and the breaking of the C1-O1 glycosidic linkage. The activation barrier found for this process is 15 kcal/mol. In the transition state (TS) model, the sugar donor is partially cleaved from pyrophosphate, while nucleophilic oxygen O4(a) remains protonated with a low barrier hydrogen bond to the catalytic base D318. The structure of TS is characterized by the O4(a)-C1 and C1-O1 distances of 2.703 and 2.092 A, respectively. When the obtained reaction sequence was used, the nature of the captured intermediate resembling the transition state structure (PDB/2FYD) was elucidated. This modeling QM/MM study has provided detailed insight into the mechanism of the Gal transfer catalyzed by beta4Gal-T1 and has supplied further evidence for a concerted S(N)2-type displacement mechanism employed by inverting glycosyltransferases.