Pentacoordinate Phosphorane Research Articles

Photoredox Catalysis-Enabled C-H Difluoromethylation of Heteroarenes with Pentacoordinate Phosphorane as the Reagent.

Difluoromethylated heterocyclic compounds have found broad applications in numerous bioactive molecules. Herein, we report photoredox catalysis-induced direct C-H difluoromethylation of heterocycles by using bis(difluoromethyl) pentacoordinate phosphorane (PPh3(CF2H)2, 1) as the reagent. A variety of heterocycles, such as quinoxalin-2(1H)-one, thiophene, indole, and coumarin, are readily tailored with a difluoromethyl group. The method is featured as transition-metal-free by using an organic compound Erythrosin B as the catalyst and O2 as the oxidant.

Pentacoordinate Phosphoranes as Versatile Reagents in Fluoroalkylation Reactions

Pentacoordinate Phosphoranes as Versatile Reagents in Fluoroalkylation Reactions

Synthesis and characterization of a pair of O-fac/O-mer 12-P-6 alkyloxaphosphates with a P–O–C–C four-membered ring

Structurally characterized hexacoordinate organophosphorus compounds remain rare due to their highly reactive nature and thermal instability. Herein we report the first synthesis of a pair of O-facial and O-meridional hexacoordinate oxaphosphates (5B and 5D) obtained from the O-apical and O-equatorial β-hydroxyalkylphosphoranes 3 and 4. This was achieved by using the bulky C2F5-groups on the ortho-substituted aryl backbone. Calculations of the relative energies of possible isomers indicate 5B and 5D are thermodynamic products. Although the mechanisms of their formation and the determining factor of stereo-selectivity are still unclear, their isolation and structure conformation contributes to a formulation of a viable strategy for diastereoselective synthesis of heteroleptic hexacoordinate organophosphates.

Stereochemistry of electrophilic and nucleophilic substitutions at phosphorus

Abstract Nucleophilic and electrophilic substitutions are the most often applied reactions in organophosphorus chemistry. They are closely interrelated, because in a reacting pair always one reagent is an electrophile, and another nucleophile. The reactions of electrophilic and nucleophilic substitutions at the phosphorus center proceed via the formation of a pentacoordinated intermediate. The mechanism of nucleophilic substitution involves the exchange of ligands in the pentacoordinate phosphorane intermediate, leading to the more stable stereomer under the thermodynamic control. Electrophilic substitution proceeds with retention of absolute configuration, whereas nucleophilic substitution with inversion of configuration at the phosphorus center.

Theoretical investigation of the neutral hydrolysis of diethyl 4-nitrophenyl phosphate (paraoxon) in aqueous solution.

In this work the neutral or spontaneous hydrolysis of paraoxon, one of the most popular organophosphate pesticides, in aqueous solution was investigated at the DFT and MP2 levels of theory, using a combination of local solvation of the phosphoryl group with explicit water molecules, and treating the long range solvent effects using continuum solvation model. In contrast to the alkaline hydrolysis, the neutral hydrolysis takes place in two steps, through an AN + DN mechanism, with formation of a pentacoordinate phosphorane intermediate. The reaction has activation free energies of 31.8 and 1.9kcal mol-1 for the first and second steps, respectively, and has an overall reaction free energy of -9.3kcal mol-1, computed at the MP2/6-311++G(2d,2p)//B3LYP/6-31+G(d) level of theory. The reaction proceeds through a sequence of proton transfer processes from the attacking water molecule and ends with the protonation of the nitrophenolate leaving group. Explicit description of the local solvating water molecules is essential to describe the proton transfer processes along the reaction coordinate and to stabilize the pentacoordinate intermediate formed. The neutral hydrolysis is very slow and has an overall rate constant of 3.05 × 10-11s-1, computed at the MP2/6-311++G(2d,2p)//B3LYP/6-31+G(d) level of theory. This result, in conjunction with the sensitivity of the rate constant to the experimental conditions, indicates that the hydrolysis of paraoxon in aqueous solution can be even slower than predicted experimentally.

Quantum mechanical/effective fragment potential (QM/EFP) study of phosphate diester cleavage in aqueous solution

We report a study of the P–O bond cleavage of the anion of 2,4-dinitrophenyl ethyl phosphate (2,4-DNPEP), promoted by methylamine. The aminolysis reaction was investigated in the gas phase and an aqueous environment using the hybrid quantum mechanical/effective fragment potential (QM/EFP) approach. According to the B3LYP/6-31++G(d,p) results, in the gas phase the cleavage of the P–O bond of 2,4-DNPEP proceeds in one step through a concerted mechanism, with an activation free energy of 39 kcal/mol. Including solvent effects at the B3LYP/6-31++G(d,p)/EFP level changes the reaction to a two-step associative mechanism. The first step corresponds to the formation of the P–NHMe bond and the second step to concerted proton transfer and P–O(2,4-dinitrophenolate) cleavage. In the absence of any assistance of water molecules to promote the proton transfer, the second step is rate determining with an activation free energy for the breakdown of the intermediate of 21.8 kcal/mol at the MP2/cc-pVTZ level and a free energy of activation of 32.3 kcal/mol for the overall reaction. However, the proton transfer with the assistance of a water molecule may occur without significant energy barrier. The results show how solvent can play an important role in favoring an associative mechanism for the aminolysis of phosphate diesters, through the formation and stabilization of a pentacoordinate phosphorane intermediate.

Intermolecular N–H Oxidative Addition of Ammonia, Alkylamines, and Arylamines to a Planar σ3-Phosphorus Compound via an Entropy-Controlled Electrophilic Mechanism

Ammonia, alkyl amines, and aryl amines are found to undergo rapid intermolecular N-H oxidative addition to a planar mononuclear σ(3)-phosphorus compound (1). The pentacoordinate phosphorane products (1·[H][NHR]) are structurally robust, permitting full characterization by multinuclear NMR spectroscopy and single-crystal X-ray diffraction. Isothermal titration calorimetry was employed to quantify the enthalpy of the N-H oxidative addition of n-propylamine to 1 ((n)PrNH2 + 1 → 1·[H][NH(n)Pr], ΔHrxn(298) = -10.6 kcal/mol). The kinetics of n-propylamine N-H oxidative addition were monitored by in situ UV absorption spectroscopy and determination of the rate law showed an unusually large molecularity (ν = k[1][(n)PrNH2](3)). Kinetic experiments conducted over the temperature range of 10-70 °C revealed that the reaction rate decreased with increasing temperature. Activation parameters extracted from an Eyring analysis (ΔH(⧧) = -0.8 ± 0.4 kcal/mol, ΔS(⧧) = -72 ± 2 cal/(mol·K)) indicate that the cleavage of strong N-H bonds by 1 is entropy controlled due to a highly ordered, high molecularity transition state. Density functional calculations indicate that a concerted oxidative addition via a classical three-center transition structure is energetically inaccessible. Rather, a stepwise heterolytic pathway is preferred, proceeding by initial amine-assisted N-H heterolysis upon complexation to the electrophilic phosphorus center followed by rate-controlling N → P proton transfer.

Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: Implications for the Pro‐Tide approach

Cyclic acyl phosphoramidates (CAPAs) are important components in several fundamental biological reactions such as protein synthesis and phosphorylation. These structures are particularly interesting in the nucleotide pro-drug approach, Pro-Tide, since they are putative intermediates in one of the hydrolysis steps required for activation. The central role played by the amino acid carboxylate function suggests first the formation of a cyclic mixed phosphorus anhydride, rapidly followed by water attack. To investigate such speculations, we performed quantum mechanical calculations using the B3LYP/6-311+G** level of theory for the plausible mechanisms of action considered. In the five-membered ring case, transition state theory demonstrated how the overall, gas-phase, mechanism of action could be split into two in-line addition-elimination (A-E) steps separated by a penta-coordinate phosphorane intermediate. The difference between five-membered and six-membered ring first A-E was also explored, revealing a single step, unimolecular reaction for the six-membered ring A-E profile. Implicit solvent contribution further confirmed the importance of CAPAs as reactive intermediates in such kind of reactions. Lastly, the second A-E pathway was analyzed to understand the complete pathway of the reaction. This analysis is the first attempt to clarify the putative mechanism of action involved in the activation of Pro-Tides and casts light also on the possible mechanism of action involved in primordial protein syntheses, strengthening the hypothesis of a common cyclic mixed phosphorus anhydride species as a common intermediate.

Fragmentation of pentacoordinate spirobicyclic aminoacyl‐phosphoranes (P‐AAs) by electrospray ionization tandem mass spectrometry concerning P–O and P–N bond cleavage

The fragmentation pathways of both protonated and sodiated pentacoordinate spirobicyclic aminoacylphosphoranes (P-AAs) have been studied by electrospray ionization multi-stage mass spectrometry (ESI-MS(n)) in positive mode. The possible pathways and their mechanisms are elucidated through the combination of ESI-MS/MS, isotope ((15)N and (2)H) labeling and high-resolution Fourier transform ion cyclotron resonance (FTICR)-MS/MS. The relative Gibbs free energies (ΔG) of the product ions and possible fragmentation pathways are estimated at the B3LYP/6-31 G(d) level of theory. The theoretical calculations show that both protonated and sodiated P-AAs would quickly fragment before Berry pseudorotation. For protonated P-AAs, they have different tendencies to P-O or P-N bond cleavage. For sodiated P-AAs, the P-N bond is easier to cleave and produces the tetracoordinated phosphorus ion H. These results to some extent may give a clue to the chemistry of the active sites of phosphoryl transfer enzymes and will enrich the gas-phase ESI-MS ion chemistry of pentacoordinate phosphoranes.

NMR data do not implicate a phosphorane in the T4 DNA ligase reaction

The interesting article by Cherepanov et al. (1) presents 31P NMR data as evidence for a pentacoordinate phosphorane intermediate in the T4 DNA ligase reaction. Although some sort of intermediate apparently forms under the low-temperature, solid-state conditions that were used, the data are not consistent with a phosphorane.

Synthesis, structure and isomerization of arylphosphoranes with anti-apicophilic bonding modes using a novel bidentate ligand with two C2F5 groups

A series of anti-apicophilic pentacoordinate phosphoranes (with one chelating substituent in an O-equatorial, C-apical bonding mode at pentacoordinated phosphorus atom) bearing a para-substituted aryl group (-C(6)H(4)(p-X); X = H, CF(3), F, OMe) or a mesityl (2,4,6-trimethylphenyl) group were isolated using a novel bulky bidentate ligand with two C(2)F(5) groups. These phosphoranes were stable to isomerization at room temperature, and quantitatively converted into the corresponding more stable isomers (O-apical) at elevated temperatures in solution. On the basis of a kinetic study, the free energy of activation (DeltaG(double dagger)) of the stereomutation of the O-equatorial mesitylphosphorane to its O-apical isomer was higher than that of the CF(3) derivative by 2.6 kcal mol(-1), giving rise to a further example of the steric effect of the C(2)F(5) group to freeze the isomerization of the pentacoordinate phosphorus compounds. Kinetic measurements of the isomerization of the O-equatorial ortho-unsubstituted derivatives (-C(6)H(4)(p-X)) to the corresponding O-apical isomers suggested that the O-equatorial isomers were stabilized by the pi --> sigma*(P-O) interaction in the ground state.

The first structural study on a cyclic tricoordinate phosphorochloridite and a pentacoordinate phosphorane based on 1,2,3,5-protected myo-inositol—a new conformation of 1,3,2-dioxaphosphorinane ring

Treatment of the phosphoramidite [myo-C(6)H(6)-2-[OC(O)Ph]-1,3,5-(O(3)CH)-4,6-(O(2)P-NH-i-Pr)] with o-chloranil affords the first example of inositol-based pentacoordinate phosphorane [myo-C(6)H(6)-2-[OC(O)Ph]-1,3,5-(O(3)CH)-4,6-(O(2)P-NH-i-Pr)(1,2-O(2)C(6)Cl(4))] (9) (X-ray structure) with a trigonal bipyramidal geometry at phosphorus. The six-membered 1,3,2-dioxaphosphorinane ring with the inositol residue has an unusual boat conformation in 9 which is quite different from that found in unrestrained rings investigated before, but is similar to that of its P(III) chloro precursor [myo-C(6)H(6)-2-[OC(O)Ph]-1,3,5-(O(3)CH)-4,6-(O(2)PCl)] (X-ray structure). Also, a convenient and chromatography-free procedure for the protected myo-inositol derivative [myo-C(6)H(6)-2-[OC(O)Ph]-1,3,5-(O(3)CH)-4,6-(OH)(2)] is reported.

A Trojan horse transition state analogue generated by MgF 3 − formation in an enzyme active site

Identifying how enzymes stabilize high-energy species along the reaction pathway is central to explaining their enormous rate acceleration. beta-Phosphoglucomutase catalyses the isomerization of beta-glucose-1-phosphate to beta-glucose-6-phosphate and appeared to be unique in its ability to stabilize a high-energy pentacoordinate phosphorane intermediate sufficiently to be directly observable in the enzyme active site. Using (19)F-NMR and kinetic analysis, we report that the complex that forms is not the postulated high-energy reaction intermediate, but a deceptively similar transition state analogue in which MgF(3)(-) mimics the transferring PO(3)(-) moiety. Here we present a detailed characterization of the metal ion-fluoride complex bound to the enzyme active site in solution, which reveals the molecular mechanism for fluoride inhibition of beta-phosphoglucomutase. This NMR methodology has a general application in identifying specific interactions between fluoride complexes and proteins and resolving structural assignments that are indistinguishable by x-ray crystallography.

Mechanistic Plasticity of DNA Topoisomerase IB: Phosphate Electrostatics Dictate the Need for a Catalytic Arginine

Four conserved amino acids of type IB topoisomerases (Arg130, Lys167, Arg223, and His265 in vaccinia topoisomerase) catalyze the attack by tyrosine on the scissile phosphodiester to form a DNA-(3'-phosphotyrosyl)-enzyme intermediate. The mechanism entails general acid catalysis (by Lys167 and Arg130) and transition-state stabilization (via contact of His265 with the pro-Sp oxygen). Here we query the function of Arg223, which accelerates transesterification by a factor of 10(5). The requirement for Arg223 is alleviated by a neutral Sp methylphosphonate (MeP) linkage at the cleavage site. Arg223 is not required for the 30,000-fold activation of the latent endonuclease activity of topoisomerase by the Sp MeP. The rate of autohydrolysis by the DNA-(3'-MeP)-topoisomerase intermediate approaches 10% of the rate of religation to a 5'-OH DNA strand. These findings underscore the importance of transition-state electrostatics in determining the composition of the active site and dictating the balance between strand transferase and hydrolase functions.

Characteristic reactions and properties of C-apical O-equatorial (O-cis) spirophosphoranes: effect of the sigma(P)(-)(O) orbital in the equatorial plane and isolation of a hexacoordinate oxaphosphetane as an intermediate of the Wittig type reaction of 10-P-5 phosphoranes.

Novel spirophosphoranes (O-cis) that exhibit reversed apicophilicity having an apical carbon-equatorial oxygen array in a five-membered ring showed enhanced reactivity toward nucleophiles such as n-Bu(4)N(+)F(-) or MeLi in comparison with the corresponding stable isomeric spirophosphoranes (O-trans) having an apical oxygen-equatorial carbon configuration. The enhanced reactivity of the O-cis isomer could be explained by the presence of a lower-lying sigma(P)(-)(O(equatorial)) orbital as the reacting orbital in the equatorial plane, whereas the corresponding orbital is a higher-lying sigma(P)(-)(C(equatorial)) in the O-trans isomer. Density functional theory (DFT) calculation on the actual compounds provided theoretical support for this assumption. In addition, we found that the benzylic anion alpha to the phosphorus atom in O-cis benzyl phosphorane is much more stable than that generated from the corresponding O-trans compounds. The experimental results were considered to be due to the n(C) --> sigma(P)(-)(O) interaction in the O-cis anion, and this was confirmed by DFT calculations. Furthermore, the hexacoordinate anionic species derived from the reaction of the benzylic anion from O-cis benzylphosphorane with an aldehyde was also found to be stabilized as compared with analogous species from the corresponding O-trans isomer. The first X-ray structural characterization of a hexacoordinate phosphate intermediate in the Wittig type reaction using pentacoordinate phosphoranes is reported.

Pentacoordinate phosphoranes with reversed apicophilicity as stable intermediates in a mitsunobu-type reaction.

Diisopropyl azodicarboxylate (DIAD) undergoes a cycloaddition reaction with the cyclic phosphites CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2)PX (1) [X = NCS (a), N(3) (b), Cl (c), NHMe (d) and Ph (e)] to afford the novel pentacoordinate phosphoranes 2a-e as crystalline solids. This result is different from the reaction of PPh(3) with DIAD used in the well-known Mitsunobu reaction. X-ray crystallography of 2a, 2b, and 2d reveals that the nitrogen, rather than the oxygen, occupies an apical position of the trigonal bipyramidal phosphorus. This is in violation of the commonly accepted preferences for substituents in trigonal bipyramidal phosphorus. In 2e, although the oxygen of the five-membered ring occupies the expected apical position, the phenyl group also occupies (the other) apical position, forcing the more electronegative oxygen atoms of the eight-membered ring to span equatorial-equatorial positions. In contrast to the above, the isocyanato compound CH(2)(6-t-Bu-4-Me-C(6)H(2)O)(2)PNCO (1f), upon treatment with DIAD, affords compound 3 to which a tetracoordinate structure is assigned.

Cocrystallization of Two Different Pseudorotamers of Monocyclic Phosphorane Bearing Two Martin Ligands

Solution and crystal structures of monocyclic pentacoordinate phosphoranes bearing two Martin ligands and two carbon substituents are described. When the two carbon substituents are different, relative apicophilicity of the two monodentate carbon substituents could be determined based on the equilibrium ratio of the pseudorotamers. In some cases, x-ray structural analysis could be carried out and the crystallized structure from CH 3 CN is consistent with the major pseudorotamer in solution (CD 3 CN). Furthermore, when the equilibrium ratio of pseudorotamers is almost unity, novel cocrystallization of two pseudorotamers in a single crystal was observed.

Conserved Residues in Domain Ia Are Required for the Reaction of Escherichia coli DNA Ligase with NAD+

NAD(+)-dependent DNA ligases are present in all bacteria and are essential for growth. Their unique substrate specificity compared with ATP-dependent human DNA ligases recommends the NAD(+) ligases as targets for the development of new broad-spectrum antibiotics. A plausible strategy for drug discovery is to identify the structural components of bacterial DNA ligase that interact with NAD(+) and then to isolate small molecules that recognize these components and thereby block the binding of NAD(+) to the ligase. The limitation to this strategy is that the structural determinants of NAD(+) specificity are not known. Here we show that reactivity of Escherichia coli DNA ligase (LigA) with NAD(+) requires N-terminal domain Ia, which is unique to, and conserved among, NAD(+) ligases but absent from ATP-dependent ligases. Deletion of domain Ia abolished the sealing of 3'-OH/5'-PO(4) nicks and the reaction with NAD(+) to form ligase-adenylate but had no effect on phosphodiester formation at a preadenylated nick. Alanine substitutions at conserved residues within domain Ia either reduced (His-23, Tyr-35) or abolished (Tyr-22, Asp-32, Asp-36) sealing of a 5'-PO(4) nick and adenylyl transfer from NAD(+) without affecting ligation of pre-formed DNA-adenylate. We suggest that these five side chains comprise a binding site for the nicotinamide mononucleotide moiety of NAD(+). Structure-activity relationships were clarified by conservative substitutions.

The coordination number–photophysical properties relationship of trianthrylphosphorus compounds: doubly locked fluorescence of anthryl groups

A series of tri(9-anthryl)phosphorus compounds including tri(9-anthryl)methylphosphonium iodide ( 2b ), tri(9-anthryl)phophine oxide ( 2c ), and tri(9-anthryl)difluorophosphorane ( 2d ) have been newly synthesized from the already reported tri(9-anthryl)phosphine ( 2a ) and their photophysical properties including UV–vis absorption and fluorescence spectra have been determined in order to elucidate their coordination number–properties relationships. It has been found that their characteristic fluorescence properties are highly dependent on the coordination number of the central phosphorus atom. Thus, while the tri-coordinate phosphine 2a and the tetra-coordinate phosphonium salt 2b and phosphine oxide 2c show no and weak ( Φ f <0.01) fluorescence, respectively, the penta-coordinate phosphorane 2d exhibits intense fluorescence ( Φ f =0.28) which is comparable to that of the parent anthracene. A series of tri(9-anthryl)phosphorus compounds including the corresponding methylphosphonium iodide, phophine oxide, and difluorophosphorane have been newly synthesized from the already known tri(9-anthryl)phosphine. Their fluorescence properties are highly dependent on the coordination number of the central phosphorus atom. In particular, the penta-coordintate phosphorane shows intense fluorescence with a high quantum yield.

Mechanism of the Chemoselective and Stereoselective Ring Opening of Oxathiaphospholanes: An Ab Initio Study

Ab initio investigations of the reaction profiles for the base-catalyzed methanolysis of amino-2-thiono-1,3,2-oxathiaphospholane suggested that ring opening with a retention of configuration at phosphorus would be energetically favorable, which provides a reasonable interpretation for the chemo- and stereoselectivity that have been determined experimentally for the reaction of diastereomerically pure 2-[(1-(α-naphthyl)ethyl)amino]-2-thiono-1,3,2-oxathiaphospholane. Nucleophilic attack at phosphorus will lead to a trigonal bipyramidal (TBP) pentacoordinate phosphorane intermediate, and pseudorotation will then occur concomitantly with collapse of the TBP intermediate. Thus, pseudorotation is strongly coupled with the reaction coordinate for the substitution pathway. This finding suggests that substitution with a retention of configuration can occur even though a TBP species resulting from pseudorotation fails to exist as an intermediate.