Monofluorophos-Metal Complexes: Ripe for Future Discoveries in Homogeneous Catalysis.

The discovery that cyclic (ArO)2PF can support Rh-catalysts for hydroformylation with significant advantages in tuning regioselectivity transformed the study of metal complexes of monofluorophos ligands from one of primarily academic interest to one with potentially important applications in catalysis. In this review, the syntheses of monofluorophosphites, (RO)2PF, and monofluorophosphines, R2PF, are discussed and the factors that control the kinetic stability of these ligands to hydrolysis and disproportionation are set out. A survey of the coordination chemistry of these two classes of monofluorophos ligands with d-block metals is presented, emphasising the bonding of the fluorophos to d-block metals, predominantly in low oxidation states. The application of monofluorophos ligands in homogeneous catalysis (especially hydroformylation and hydrocyanation) is discussed, and it is argued that there is great potential for monofluorophos complexes in future catalytic applications.

Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules.

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, 99mTc, and the therapeutic radionuclide, 188Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type Ph2PCH2CH2P(CH2CH2-Glc)2 (L, where Glc = a glucose moiety) using the readily accessible Ph2PCH2CH2PH2 and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media. Furthermore, the resulting glucose-chelator conjugates can be radiolabeled with either 99mTc(V) or 188Re(V) in high radiochemical yields (>95%), to furnish separable mixtures of cis- and trans-[M(O)2L2]+ (M = Tc, Re). Single photon emission computed tomography (SPECT) imaging and ex vivo biodistribution in healthy mice show that each isomer possesses favorable pharmacokinetic properties, with rapid clearance from blood circulation via a renal pathway. Both cis-[99mTc(O)2L2]+ and trans-[99mTc(O)2L2]+ exhibit high stability in serum. This new class of functionalized diphosphine chelators has the potential to provide access to receptor-targeted dual diagnostic/therapeutic pairs of radiopharmaceutical agents, for molecular 99mTc SPECT imaging and 188Re systemic radiotherapy.

Versatile Diphosphine Chelators for Radiolabeling Peptides with 99mTc and 64Cu.

We have developed a diphosphine (DP) platform for radiolabeling peptides with 99mTc and 64Cu for molecular SPECT and PET imaging, respectively. Two diphosphines, 2,3-bis(diphenylphosphino)maleic anhydride (DPPh) and 2,3-bis(di-p-tolylphosphino)maleic anhydride (DPTol), were each reacted with a Prostate Specific Membrane Antigen-targeted dipeptide (PSMAt) to yield the bioconjugates DPPh-PSMAt and DPTol-PSMAt, as well as an integrin-targeted cyclic peptide, RGD, to yield the bioconjugates DPPh-RGD and DPTol-RGD. Each of these DP-PSMAt conjugates formed geometric cis/trans-[MO2(DPX-PSMAt)2]+ (M = 99mTc, 99gTc, natRe; X = Ph, Tol) complexes when reacted with [MO2]+ motifs. Furthermore, both DPPh-PSMAt and DPTol-PSMAt could be formulated into kits containing reducing agent and buffer components, enabling preparation of the new radiotracers cis/trans-[99mTcO2(DPPh-PSMAt)2]+ and cis/trans-[99mTcO2(DPTol-PSMAt)2]+ from aqueous 99mTcO4- in 81% and 88% radiochemical yield (RCY), respectively, in 5 min at 100 °C. The consistently higher RCYs observed for cis/trans-[99mTcO2(DPTol-PSMAt)2]+ are attributed to the increased reactivity of DPTol-PSMAt over DPPh-PSMAt. Both cis/trans-[99mTcO2(DPPh-PSMAt)2]+ and cis/trans-[99mTcO2(DPTol-PSMAt)2]+ exhibited high metabolic stability, and in vivo SPECT imaging in healthy mice revealed that both new radiotracers cleared rapidly from circulation, via a renal pathway. These new diphosphine bioconjugates also furnished [64Cu(DPX-PSMAt)2]+ (X = Ph, Tol) complexes rapidly, in a high RCY (>95%), under mild conditions. In summary, the new DP platform is versatile: it enables straightforward functionalization of targeting peptides with a diphosphine chelator, and the resulting bioconjugates can be simply radiolabeled with both the SPECT and PET radionuclides, 99mTc and 64Cu, in high RCYs. Furthermore, the DP platform is amenable to derivatization to either increase the chelator reactivity with metallic radioisotopes or, alternatively, modify the radiotracer hydrophilicity. Functionalized diphosphine chelators thus have the potential to provide access to new molecular radiotracers for receptor-targeted imaging.

Multi-nuclear, high-pressure, operando FlowNMR spectroscopic study of Rh/PPh3 - catalysed hydroformylation of 1-hexene.

The hydroformylation of 1-hexene with 12 bar of 1 : 1 H2/CO in the presence of the catalytic system [Rh(acac)(CO)2]/PPh3 was successfully studied by real-time multinuclear high-resolution FlowNMR spectroscopy at 50 °C. Quantitative reaction progress curves that yield rates as well as chemo- and regioselectivities have been obtained with varying P/Rh loadings. Dissolved H2 can be monitored in solution to ensure true operando conditions without gas limitation. 31P{1H} and selective excitation 1H pulse sequences have been periodically interleaved with 1H FlowNMR measurements to detect Rh-phosphine intermediates during the catalysis. Stopped-flow experiments in combination with diffusion measurements and 2D heteronuclear correlation experiments showed the known tris-phosphine complex [RhH(CO)(PPh3)3] to generate rapidly exchanging isomers of the bis-phosphine complex [Rh(CO)2(PPh3)2] under CO pressure that directly enter the catalytic cycle. A new mono-phosphine acyl complex has been identified as an in-cycle reaction intermediate.

Palladium-catalysed alkyne alkoxycarbonylation with P,N-chelating ligands revisited: a density functional theory study.

A revised in situ base mechanism of alkyne alkoxycarbonylation via a Pd catalyst with hemilabile P,N-ligands (PyPPh2, Py = 2-pyridyl) has been fully characterised at the B3PW91-D3/PCM level of density functional theory. Key intermediates on this route are acryloyl and η3-propen-1-oyl complexes that readily undergo methanolysis. With two hemilabile P,N-ligands and one or both of them protonated, the overall computed barrier is 16.8 kcal mol-1. This new mechanism is consistent with all of the experimental data relating to substituent effects on relative reaction rates and branched/linear selectivities, including new results on the methoxycarbonylation of phenylacetylene using (4-Me2N-Py)PPh2 and (6-Cl-Py)PPh2 ligands. This ligand is found to decrease catalytic activity over PyPPh2, thus invalidating a formerly characterised in situ base mechanism.

Pyrrolidines and Piperidines by Ligand-Enabled Aza-Heck Cyclizations and Cascades of N-(Pentafluorobenzoyloxy)carbamates.

Ligand-enabled aza-Heck cyclizations and cascades of N-(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non-biased 6-exo aza-Heck cyclizations. The methodology provides direct and flexible access to carbamate protected pyrrolidines and piperidines.

Inorganic Triphenylphosphine.

A completely inorganic version of one of the most famous organophosphorus compounds, triphenylphosphine, has been prepared. A comparison of the crystal structures of inorganic triphenylphosphine, PBaz3 (where Baz=B3 H2 N3 H3 ) and PPh3 shows that they have superficial similarities and furthermore, the Lewis basicities of the two compounds are remarkably similar. However, their oxygenation and hydrolysis reactions are starkly different. PBaz3 reacts quantitatively with water to give PH3 and with the oxidizing agent ONMe3 to give the triply-O-inserted product P(OBaz)3 , an inorganic version of triphenyl phosphite; a corresponding transformation with PPh3 is inconceivable. Thermodynamically, what drives these striking differences in the chemistry of PBaz3 and PPh3 is the great strength of the B-O bond.

Spin Changes Accompany Ultrafast Structural Interconversion in the Ground State of a Cobalt Nitrosyl Complex.

Ultrafast, reversible intersystem crossing (ISC) is reported under ambient conditions for the electronic ground state of the pentacoordinate cobalt nitrosyl complexes, [CoX2 (NO)(PMePh2 )2 ] (X=Cl, Br), in solution. ISCs on such short timescales are more typically observed in electronically excited states reached by absorption of ultraviolet or visible light. Singlet and triplet electron spin states of the complex, corresponding to two different isomers, are populated at room temperature, and the two isomers exchange on a timescale of a few picoseconds. Ultrafast two-dimensional infrared spectroscopy observes the change in wavenumber of the NO ligand band accompanying the isomerization and associated ISC on the (spin) adiabatic ground potential energy surface. Comparison of the dynamics of the chloro- and bromo-complexes shows that inertial effects of the ligand motion have a greater effect than spin-orbit coupling on determining the forward and reverse isomerization and ISC rates.

Single oxygen-atom insertion into P-B bonds: on- and off-metal transformation of a borylphosphine into a borylphosphinite.

An oxygen atom is selectively inserted into the P-B bond of a borylphosphine (L1) by reaction with Me3 NO to afford the corresponding borylphosphinite (L2). This transformation can also be effected when L1 is coordinated to rhodium. The ν(CO) values for trans-[RhCl(CO)(L)2] reveal very different electronic properties for coordinated L1 and L2 which translate into the strikingly different performances of the complexes [RhCl(L)(cod)] (L= L1 or L2, cod=1,5-cyclooctadiene) in hydrosilylation and hydroboration catalysis.

Cooperative Lewis pairs based on late transition metals: activation of small molecules by platinum(0) and B(C6 F5 )3.

A Lewis basic platinum(0)-CO complex supported by a diphosphine ligand and B(C6 F5 )3 act cooperatively, in a manner reminiscent of a frustrated Lewis pair, to activate small molecules such as hydrogen, CO2 , and ethene. This cooperative Lewis pair facilitates the coupling of CO and ethene in a new way.

Mono-, di-, and triborylphosphine analogues of triarylphosphines.

Diazaborinylphosphines based on the 1,8-diaminonaphthylboronamide heterocycle are prepared by a chlorosilane-elimination reaction, and their structural and bonding properties are compared to those of PPh3. The precursor chloroborane ClB{1,8-(NH)2C10H6} (I) is fully characterized including its crystal structure, which features intermolecular π-π stacking, B···N interactions, and N-H···Cl hydrogen bonding. Treatment of I with Ph3-nP(SiMe3)n gave the corresponding Ph3-nP(B{1,8-(NH)2C10H6})n, {L1 (n = 1), L2 (n = 2), and L3 (n = 3)}. The crystal structures of L1-3 reveal an increase in the planarity at P as a function of n, and the steric bulk of the diazaborinyl substituent B{1,8-(NH)2C10H6} is similar to that of a phenyl. Nucleus-independent chemical shift calculations were carried out that suggest that the 14 π-electron diazaborinyl substituent can be described as aromatic overall, though the BN2-containing ring is slightly antiaromatic. The complexes cis-[Mo(L1-3)2(CO)4] (1-3) are prepared from [Mo(nbd)(CO)4] (nbd = norbornadiene) and L1-3. From the position of the ν(CO) (A1) band in the IR spectra of 1-3, it is deduced that the diazaborinyl substituent has a donating capacity similar to an alkyl group.

Computational kinetics of cobalt-catalyzed alkene hydroformylation.

Density functional theory, coupled-cluster theory, and transition state theory are used to build a computational model of the kinetics of phosphine-free cobalt-catalyzed hydroformylation and hydrogenation of alkenes. The model provides very good agreement with experiment, and enables the factors that determine the selectivity and rate of catalysis to be determined. The turnover rate is mainly determined by the alkene coordination step.

A Resorcin[4]arene-Based Phosphite-Phosphine Ligand for the Branched-Selective Hydroformylation of Alkyl Alkenes.

Synthesis of a chelating phosphite-phosphine ligand from a tris(quinoxaline) extended resorcin[4]arene and its application in the rhodium-catalyzed hydroformylation of terminal alkyl alkenes are reported. Rhodium complexes are formed within the cavity of the macrocycle and branched-selective hydroformylation of 1-octene with a b/l ratio of 5.9 has been achieved at 60 °C under 1:1 H2/CO (20 bar).

Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of 99mTc and 188Re Theranostic Agents for Prostate Cancer.

Benchtop 99Mo/99mTc and 188W/188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [99mTc]Tc, [188Re]Re). All 99mTc/188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18-30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.

Reply to the 'Comment on "In Defence of Oxidation States"' by J. C. Green, Dalton Transactions, 2022, 51, DOI: 10.1039/D1DT02930D.

We reiterate and reinforce some of the points concerning oxidation states and the Covalent Bond Classification method we made in the Perspective article entitled 'In Defence of Oxidation States' including a brief discussion of the relative merits of the terms 'metathesis' and 'redox' when considering addition across a metal-metal bond.

In defence of oxidation states.

In this Perspective, some of the criticisms which have been made concerning the use of oxidation states are addressed, particularly in the context of the teaching of inorganic chemistry. The Oxidation State method and the Covalent Bond Classification method are compared and contrasted, and it is concluded that while each method has its strengths and weaknesses, both are important in teaching and it should be recognized that no single model or method is appropriate in all circumstances.

Heterometathesis of diphosphanes (R2P-PR2) with dichalcogenides (R'E-ER', E = O, S, Se, Te).

The reactions of R2P-PR2 with R'E-ER', (where E = Se, S, O, Te) to give R2P-ER' have been explored experimentally and computationally. The reaction of Ph2P-PPh2 with PhSe-SePh gives Ph2P-SePh (1) rapidly and quantitatively. The P-P/Se-Se reaction is inhibited by the addition of the radical scavenger TEMPO which is consistent with a radical mechanism for the heterometathesis reaction. Compound 1 has been fully characterised, including by X-ray crystallography. A range of other Ar2P-SeR (R = Ph, nBu or CH2CH2CO2H) have also been prepared and characterised. The reaction of 1 with [Mo(CO)4(nbd)] (nbd = norbornadiene) gives two products which, from their characteristic 31P NMR data, have been identified as cis-[Mo(CO)4(Ph2PSePh-P)2] (8) and the mixed-donor complex cis-[Mo(CO)4(Ph2P-SePh-P)(Ph2P-SePh-Se)] (9). It is deduced that the P and Se atoms in ligand 1 have comparable capacity to coordinate to Mo(0). The reaction of Ph2P-PPh2 with PhS-SPh gives Ph2P-SPh (2) quantitatively but no reaction was observed between Ph2P-PPh2 and PhTe-TePh. Heterometathesis between Ph2P-PPh2 and tBuO-OtBu does not occur thermally but has been observed under UV irradiation to give Ph2P-OtBu along with P(V) oxidation by-products. DFT calculations have been carried out to illuminate why heterometatheses with dichalcogenides R'E-ER' occur readily when E = S and Se but not when E = O and Te. The calculations show that heterometathesis is predicted to be thermodynamically favourable for E = O, S and Se and unfavourable for E = Te. The fact that a metathesis reaction between Ph2P-PPh2 with tBuO-OtBu is not observed in the absence of UV radiation, is therefore due to kinetics.

Radical-initiated P,P-metathesis reactions of diphosphanes: evidence from experimental and computational studies.

By combining the diphosphanes Ar2P-PAr2, where Ar = C6H5, 4-C6H4Me, 4-C6H4OMe, 3,5-C6H3(CF3)2, it has been shown that P,P-metathesis generally occurs rapidly under ambient conditions. DFT calculations have shown that the stability of unsymmetrical diphosphanes Z2P-PZ'2 is a function of the difference between the Z and Z' substituents in terms of size and electronegativity. Of the mechanisms that were calculated for the P,P-metathesis, the most likely was considered to be one involving Ar2P˙ radicals. The observations that photolysis increases the rate of the P,P-metatheses and TEMPO inhibits it, are consistent with a radical chain process. The P,P-metathesis reactions that involve (o-Tol)2P-P(o-Tol)2 are anomalously slow and, in the absence of photolysis, were only observed to take place in CHCl3 and CH2Cl2. The role of the chlorinated solvent is ascribed to the formation of Ar2PCl which catalyses the P,P-metathesis. The slow kinetics observed with (o-Tol)2P-P(o-Tol)2 is tentatively attributed to the o-CH3 groups quenching the (o-Tol)2P˙ radicals or inhibiting the metathesis reaction sterically.

Rhenium Complexes Bearing Tridentate and Bidentate Phosphinoamine Ligands in the Production of Biofuel Alcohols via the Guerbet Reaction.

We report a variety of rhenium complexes supported by bidentate and tridentate phosphinoamine ligands and their use in the formation of the advanced biofuel isobutanol from methanol and ethanol. Rhenium pincer complexes 1-3 are effective catalysts for this process, with 2 giving isobutanol in 35% yields, with 97% selectivity in the liquid fraction, over 16 h with catalyst loadings as low as 0.07 mol %. However, these catalysts show poorer overall selectivity, with the formation of a significant amount of carboxylate salt solid byproduct also being observed. Production of the active catalyst 1d has been followed by 31P NMR spectroscopy, and the importance of the presence of base and elevated temperatures to catalyst activation has been established. Complexes supported by diphosphine ligands are inactive for Guerbet chemistry; however, complexes supported by bidentate phosphinoamine ligands show greater selectivity for isobutanol formation over carboxylate salts. The novel complex 7 was able to produce isobutanol in 28% yield over 17 h. The importance of the N-H moiety to the catalytic performance has also been established, giving further weight to the hypothesis that these catalysts operate via a cooperative mechanism.

One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for 99mTc radiolabelling of peptides.

Radiotracers labelled with technetium-99m (99mTc) enable accessible diagnostic imaging of disease, provided that radiotracer preparation is simple. Whilst 99mTc radiopharmaceuticals for imaging perfusion are routinely prepared from kits, and regularly used in healthcare, there are no 99mTc-labelled receptor-targeted radiopharmaceuticals in widespread clinical use. This is in part due to the multistep radiosyntheses required for the latter. We demonstrate that the diphosphine, 2,3-bis(diphenylphosphino)maleic anhydride (BMA), is an excellent platform for preparation of kit-based, receptor-targeted 99mTc-labelled radiotracers: its conjugates are simple to prepare and can be easily labelled with 99mTc using one-step, kit-based protocols. Here, reaction of BMA with the αvß3-integrin receptor targeted cyclic peptide, Arg-Gly-Asp-DPhe-Lys (RGD), provided the first diphosphine-peptide conjugate, DP-RGD. DP-RGD was incorporated into a "kit", and addition of a saline solution containing 99mTcO4- to this kit, followed by heating, furnished the radiotracer [99mTcO2(DP-RGD)2]+ in consistently high radiochemical yields (>90%). The analogous [ReO2(DP-RGD)2]+ compound was prepared and characterised, revealing that both [99mTcO2(DP-RGD)2]+ and [ReO2(DP-RGD)2]+ consist of a mixture of cis and trans geometric isomers. Finally, [99mTcO2(DP-RGD)2]+ exhibited high metabolic stability, and selectively targeted αvß3-integrin receptors, enabling in vivo SPECT imaging of αvß3-integrin receptor expression in mice.