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We present a convenient three-step synthesis of amino substituted phosphazenyl phosphines of the general formula (R2N)3P=N–P(NR2)2 [NR2 = N(CH2)4, N(CH2)5, N(CH2)6]. These easily accessible mixed valent compounds display a surprisingly high proton affinity and basicity in the same range as the corresponding Schwesinger diphosphazene (Me2N)3P=N–P=NEt(NMe2)2 (Et-P2) and Verkade’s proazaphosphatrane superbases. Within the central [PIII–N=PV] scaffold, the phosphine PIII and not the phosphazene NIII atom is the center of highest proton affinity, basicity and donor strength. As P-bases, the title compounds display calculated proton affinities between 265.8 (NR2 = NMe2) and 274.7 kcal·mol–1 [NR2 = N(CH2)4] and pKBH+ values between 26.4 (NR2 = NMe2) and 31.5 [NR2 = N(CH2)4] on the acetonitrile scale. As P- nucleophiles, they are key intermediates in the synthesis of hyperbasic bis(diphosphazene) proton sponges, chiral bis(diphosphazene) proton pincers, bisphosphazides, and superbasic P2- bisylides. Their Staudinger reactions as nucleophile towards 1, 8-diazidonaphthalene leading to 1, 8-naphthalene-bisphosphazides is described in detail. The donor strength of the title compounds towards fragments [Se] and [Ni(CO)3] is in the same range as that of N-heterocyclic carbenes.

During biodiesel production a large amount of glycerol is created as a byproduct [1, 2]. Dehydration of glycerol to a more valuable product could be obtained by eco-friendly methods utilizing B12-dependent dehydratases which turn glycerol into 3-hydroxypropanal [3-5]. However, the unusual property of glycerol is that it is both the supstrate and the irreversible inhibitor of B12-dependent dehydratases [6]. The proposed mechanism of inactivation is based on the crystal structure of B12-dependant diol dehydratase (DDH, PDB code: 3AUJ) [7]. This mechanism relies on the position of the hydroxyl group at C(3) atom of glycerol being oriented towards the serine residue (Ser301) in the active site. However, incompleteness of the enzyme in crystal structure (missing adenosyl group), poor resolution (2.1 Å) and small electron densityaroud C(3) call for further research. Herein we compare geometrical parameters of the active site of DDH obtained by molecular dynamic simulations (MD) and quantum chemical calculations (DFT) with the crystal structure, and investigate various patterns ofglycerol binding in the active site.

Računalne simulacije molekulske dinamike, QM i QM/MM računi upućuju da je inaktivacija djelomično posljedica velike pokretljivosti kofaktora unutar enzima. Upravo iz tog razloga kofaktor može započeti kemijsku pretvorbu substrata glicerola na dva kemijski ekvivalentna kraja. Kemijska pretvorba na jednom kraju glicerola vodi u katalizu, kemijska pretvorba na drugom kraju vodi u inaktivaciju.

Microbial conversion of crude glycerol, the waste from biofuel production, into compounds of greater industrial value could solve technical difficulties encountered by the conventional means of chemical conversion [1]. During the particular type of microbial conversion, in the first step glycerol undergoes dehydration by enzymes dehydratases into 3‐hydroxylpropionaldehyde (3HPA) [2, 3]. Two classes of dehydratases can catalyze dehydration of glycerol, B12‐independent and B12‐dependent dehydratases, from which B12‐ dependent class is more often used due to its tolerance to aerobic conditions [4]. However, a peculiar property of B12‐dependent dehydratases is that glycerol, which is their substrate, also acts as an irreversible inhibitor [5]. Based on the B12‐dependent diol dehydratase (B12‐dDDH) crystal structure with glycerol (PDB code: 3AUJ), K. Yoshizawa et al. concluded that the geometry of such bound glycerol enables radical reorganization thus causing inhibition. [6] However, in the recent study on similar enzyme B12‐dependent glycerol dehydratase we observed glycerol in a different geometry [7]. Here we present a detailed computational study of glycerol binding within the active site of B12‐dDDH and find a binding geometry similar to one observed in Ref. 7 (Figure 1). We consider larger implications of our findings for the mechanism of substrate induced inactivation.

Palladium complexes have been extensively used for the construction of various self-assembled structures. However, in many cases, the square planar geometry of the palladium atom is coupled with cis-directing bidentate ligands, whereas trans configuration is rarely encountered along with the use of monodentate phosphine ligands. Hydrogen bonding and metal coordination are often combined as orthogonal driving forces for the supramolecular assembly, where complementary interactions are mostly pre-designed rather than emerged from the recognition process. In addition, chiral peptide-palladium systems have not been sufficiently explored in supramolecular assembly, most probably due to the non-specific nature of the amino acid interactions. Recently, we have published our research on supramolecular chirality inversion of small chiral metal-ligand system. The alanylaminopyridine ligand already exhibiting hydrogen-bonded self-assembly in solution can invert its supramolecular chirality upon complexation to zinc ions. Herein, we present an unprecedented dichloropalladium-monodentate phosphine system incorporating different amino acids, which unexpectedly forms non-covalent dimers in chloroform through eight hydrogen bonded amides indicated by NMR and IR measurements. Phosphorous NMR measurements showed different palladium isomers in solution: trans-, cis-, or a mixture thereof, in chloroform, acetonitrile, or methanol, respectively. DOSY measurements confirmed the formation of dimeric species in chloroform. The phenylalanine derivative shows strong exciton-coupled Cotton-effect in chloroform or dichloromethane, in the visible region, assuming two metal centres in close proximity. In 20% acetonitrile/chloroform solution, slow trans-cis isomerisation of the complex is accompanied by the gradual disappearance of Cotton-effect (1 h), indicating the importance of trans-configured palladium for the self-assembly process. The solution structure of the dimeric specie was elucidated by NOESY and computational methods. To the best of our knowledge, monodentate phosphine complexes of trans-dichloropalladium(II) that form discrete hydrogen-bonded dimers in solution have not been reported in the literature.

Some bacteria use alcohol as a source of carbon and energy in order to grow in anaerobic conditions via fermentation. The fermentation of alcohol starts with the dehydration (Figure 1). This reaction is catalyzed by two enzymes: glycerol dehydratase (GDH) and diol dehydratase (DDH), which use coenzyme B12 as an essential cofactor.[1] As with most B12-dependent reactions, the reaction mechanism of these two enzymes involves a formation of radical intermediates. It is known that both GDH and DDH undergo substrate-induced inactivation by glycerol, the rate of which is higher for DDH than for the GDH.[2] Possible inactivation mechanism is recently reported by Yoshizawa et al. It states that glycerol C1 radical can abstract hydrogen from C3 hydroxyl group forming unstable O-centered radical which undergoes homolytic cleavage to form formaldehyde and glycol radical.[3, 4] In this work we propose and explore another mechanism of inactivation for GDH and DDH that does not require energetically expensive intramolecular hydrogen transfer from hydroxyl group to C1 radical. The energy profiles of the proposed inactivation mechanism for both enzymes yielded activation energies that are more consistent with the experimental data providing better explanation to underlying mechanism for the unusual “suicidal” inactivation of GDH and DDH

Human dipeptidyl-peptidase III (h.DPP III) is a zinc-exopeptidase that hydrolysis dipeptides from the N-terminus of its substrates. Our study presents the first insight into the reaction mechanism of h.DPP III ; determined on the model and real systems. The Glu451-assisted water addition on amide carbon followed by nitrogen inversion are shown to be the rate- determine steps with the activation energies in a good agreement with the experimental results for the Leu-enkephalin hydrolysis. We found that precisely defined geometry of the enzyme binding site puts an additional restrains on the tetrahedral intermediate and stimulates the forward reaction towards final hydrolytic product. Namely, differently from the model, the N-inversion is in concerted fashion followed by favourable hydrogen bonding with Glu451 that immediately “locks” the system into the configuration where reversion to the enzyme-substrate complex is hardly achievable. Therefore we propose that the functional significance of DPP III is dual: to lower the energy barrier of the peptide hydrolysis and to suppress the reverse reaction. Based on the determined mechanism and protein dynamics we were able to rationalize the experimentally determined activity of several h.DPP III mutants detected in human cancers.

The basicity of cyclopropenimines (CPIs) and cyclopropenimino-based proton sponges is investigated by means of density functional theory (DFT) calculations and for the first time directly compared with the basicity of phosphazenes. It is found that CPIs are more basic than the corresponding phosphazenes in the gas phase. Proton sponges based on CPI as pincer ligands also possess higher or at least the same gas-phase proton affinity as proton sponges based on phosphazenes. However, in comparison with phosphazenes, CPI-based pincer ligands possess greater conformational flexibility, which enables almost complete avoidance of nitrogen lone pairs. This leads to the substantially smaller destabilization of neutral base in CPI proton sponges. Utilizing homodesmotic reactions, we have shown that significant contribution to the proton affinity of CPI proton sponges is an electron-donating effect of the second CPI substituent, whereas only a smaller portion of the stabilization energy should be attributed to intramolecular hydrogen bond. Further, it was shown that tetrasubstituted CPI naphthalenes possess very low ionization potential, which qualifies them as very strong electron donors. Finally, utilizing cyclopropenimino substituents, it was found that theoretical gas basicity limit of 370 kcal mol−1 recently calculated by Leito and coworkers could be extended beyond 370 kcal mol−1 in a case of cyclopropenimino phosphorus carbenes and cylopropenimino phosphorus ylides.

The prerequisite for creation of the first living organisms on Earth was the existence of a "molecules of life" such as nucleic acids, amino acids and sugars. Model studies of prebiotic chemistry have revealed persuasive routes for the formation of the building blocks of proteins and RNA, but not DNA. Nowadays, the deoxyribonucleotides required for the construction of DNA are formed in reduction of ribonucleotides catalyzed by radical enzymes ribonucleotide reductases. This work considers potential non-enzymatic routes via intermediate radicals for the ancient formation of deoxynucleotides. We will present several computationally modeled mechanisms of ribonucleotide reduction without the presence of enzymes.

Phosphazene bases are extremely strong uncharged bases, built on a unit where a nitrogen basic center is double bonded to pentavalent phosphorus. One of the the most basic representatives, tBu-P4, with an acetonitrile pKa of the conjugate acid of 42.7, was synthesized and characterized by R. Schwesinger. On the other side, Alder discovered the phenomenon of proton sponges in 1968, noticing the unexpectedly high basicity of 1, 8-bis(dimethylamino) naphthalene (DMAN). Such strong nonionic organic bases possess two basic nitrogen centers able to act as a chelate ligand for a proton which commonly is ligated in an asymmetric hydrogen bond N−H•••N. In this work we show that Schwesinger’s phosphazene base concept and Alder’s concept of proton chelation can be combined in a design of highly basic nonionic superbases. Some of them are synthesized and their basicities are theoretically rationalized. Moreover, newly designed substituents that enable a construction of proton sponges with acetonitrile basicity several orders of magnitude more basic than tBu-P4 are proposed. Finally, some organophosphorus compound where intramolecular hydrogen bonds play a crucial role in their superbasic properties will be presented too.

New type of Proton Sponges based on organophosphorus compounds have been investigated. It appears that their basicity in acetonitrile is very close to P4-tBu Schwesinger Base.

New organophopshorus superbases have been designed using the concept of multiple intramolecular hydrogen bonds. Substituents containing PO and PN group that are capable to form strong intramolecular H-bonds were selected based on the energy of stabilization that occurs upon the formation of a complex between N, N’, N’’-trimethylguanidine and small model organophosporus molecules.

Some bacteria are able to grow in anaerobic conditions, using alcohols as source of carbon. First step of fermentation is dehydration of alcohol. This reaction is catalysed by two enzymes, glycerol dehydratase (GDH) and diol dehydratase (DDH). Both of these enzymes use coenzyme B12 as an essential cofactor., As with most B12-dependent reactions, the mechanism of action of these two enzymes involves the formation of radical intermediates. It is known that both enzymes undergo mechanism based inactivation by their substrate glycerol, the rate of which being higher for DDH than for the GDH. The results of computational study of glycerol dehydration catalysed by GDH and DDH are reported. We present and discuss energy profiles of mechanism of action and inactivation, and explain the mechanism of this unusual suicidal inactivation.

Coenzyme B12-dependent diol dehydratase (EC 4.2.1.28) and glycerol dehydratase (EC 4.2.1.30) catalyse the dehydration of 1, 2-diols and glycerol. The dehydration occurs as the first step of the anaerobic fermentation of alcohols in some bacteria. The mechanism of action of these isofunctional and structurally similar enzymes involves the formation of radical intermediates, thanks to the essential cofactor 5’-deoxyadenosylcobalamin (coenzyme B12). Homolytic cleavage of unique cobalt-carbon covalent bond present in coenzyme B12 is responsible for the radical mechanism of catalysis. Both enzymes undergo mechanism based inactivation by their substrate glycerol, the rate of which is higher for diol dehydratase (DDH) than for the glycerol dehydratase (GDH).2 The rate of this suicidal inactivation also depends on the enantiomeric configuration of enzyme-substrate complex. We report the results of a QM/MM study of reactions between glycerol and the B12-dependent dehydratases, DDH and GDH. Energy profiles of enantiomerically different enzyme-substrate complexes are presented and discussed in the context of the mechanism of action and suicidal inactivation.

Glycerol dehydratase (GDH) and diol dehydratase (DDH) are coenzyme B12-dependent enzymes that catalyze the conversion of glycerol and 1, 2-diols into the corresponding aldehydes and water. As with most B12-dependent reactions, the mechanism of action of these two enzymes involves the formation of radical intermediates. It is well known that both of these enzymes undergo mechanism-based inactivation by their physiological substrate glycerol. The rate of this suicidal inactivation is higher for DDH than for GDH, and also depends on the enantiomeric configuration of enzyme substrate complex. We report the results of a QM/MM study of reactions between glycerol and the B12-dependent dehydratases, DDH and GDH. Energy profiles of enantiomerically different enzyme-glycerol complexes are presented and discussed in the context of the mechanism of action and suicidal inactivation.

The first part of the paper outlines the normative and legal framework within which criminal law provides protection of motor vehicles and lists the problems encountered by the judiciary in the practical implementation of legal provisions. The central part of the paper focuses on the modus operandi of organized criminal groups engaged in the perpetration of such criminal acts, particularly in the organization and deployment of various electronic tools used to overcome electronic protection of modern vehicle makes. Finally, the authors emphasize the fact that investigative activities aimed at tracking down organized criminal groups and identifying the roles of their members call for an approach that differs from that used for detecting other criminal acts and point out to the main guidelines for police activities aimed at dealing with such cases. U prvom delu rada autori ukazuju na normativno-pravni okvir kojim se obezbeđuje krivično-pravna zaštita motornih vozila i na probleme koji se pojavljuju u njegovoj praktičnoj primeni od strane policije i pravosuđa. Centralni deo rada tretira modus operandi organizovanih kriminalnih grupa vezan za ovu vrstu krivičnih dela, a u prvom redu organizaciju kriminalne aktivnosti i primenu različitih elektronskih alata u cilju savlađivanja elektronske zaštite prisutne na novijim tipovima vozila. Na kraju, autori ukazuju na činjenicu da kriminalistička delatnost razotkrivanja organizovanih kriminalnih grupa oformljenih za vršenje krivičnih dela krađa vozila, njihove strukture i uloge pojedinih članova, zahteva drugačiji pristup u odnosu na druga krivična dela, te ukazuju na osnovne pravce policijske delatnosti koja se preduzima u tom cilju.

The first part of the paper outlines the normative and legal framework within which criminal law provides protection of motor vehicles and lists the problems encountered by the judiciary in the practical implementation of legal provisions. The central part of the paper focuses on the modus operandi of organized criminal groups engaged in the perpetration of such criminal acts, particularly in the organization and deployment of various electronic tools used to overcome electronic protection of modern vehicle makes. Finally, the authors emphasize the fact that investigative activities aimed at tracking down organized criminal groups and identifying the roles of their members call for an approach that differs from that used for detecting other criminal acts and point out to the main guidelines for police activities aimed at dealing with such cases.

The microbial dehydration of 1, 2-diols is important for several reasons. On one hand, this process enables certain types of bacteria to utilize these chemicals for metabolic purposes. On the other hand, chemical industry has found a novel way to use this process to generate 1, 3-propanediol, for environmentally friendly textile production. In both contexts, a better understanding of the mechanism is desirable. This contribution will outline recent computational investigations aimed at understanding both the fundamental mechanism of action as well as the inactivation of the enzymatic dehydration systems. Our approach combines modern quantum chemical tools, to accurately model the chemical transformations, with a classical molecular mechanical description of the surrounding protein. The calculations have revealed several subtle differences between closely related enzymes that have important consequences on the final outcomes of the reactions.