One-stage Synthesis of FcP(O)(OC2H5)2 from Ferrocene and α- Hydroxyethylphosphonate

A new approach is proposed for ferrocene phosphorylation using α-hydroxylalkylphosphonate as a “masked” phosphorylating agent, by electrochemical reduction of a ferrocene and (Me)2C(OH)P(O)(OC2H5)2 mixture at −50 °C. The method makes it possible to obtain the product of diethyl ferrocenyl phosphonate with a high yield (87–89%) and 100% conversion of the initial phosphonate in one stage. It is evidenced with experiments that ferrocene reduction is carried out with preservation of the iron charge in the ferrocene fragment and with the formation of a cyclopentadienyl ligand radical anion at −3.3 V ref. Ag/AgCl (at −50 °C).


Introduction
[3][4][5][6][7][8][9][10][11][12][13][14][15] Ferrocene-bearing ligands proved to be the prospective precursors in design of various complexes and coordination polymers, which possess interesting and practically applicable physical features.7][18][19][20] This is due to the specific geometries that the ferrocenyl moiety can determine as well as to its electronic (redox) properties.Ferrocene can be regarded as a universal modifier for organic compounds and biomolecules.][23][24] Moreover, with its high lipophilicity, ferrocene easily penetrates cell and nuclear membranes and overcomes the blood brain barrier.Ferrocene as a carrier (or, in modern terms, a vector) can be used for the delivery of other molecules through membranes.
It is important that the toxicity of organic compounds decreases upon Fc modification. 24,25Ferrocenyl organophosphorus ligands are usually stable, easy to handle and often isolable as optical stereoisomers.Ferrocenyl phosphine ligands are able to form complexes with transition metals in a variety of coordinative geometries and oxidation states, thus producing efficient catalyst precursors for many chemical transformations. 1,16he first attempts to introduce a phosphorous substituent to a ferrocene by means of (EtO) 2 P(O)H free-radical phosphorylation occurred as early as 1962; 26 however, they were unsuccessful.It was shown that mixing a ferrocene suspension in phosphorous trichloride PCl 3 with aluminum chloride AlCl 3 and a subsequent hydrolysis of the reaction mixture would lead to the formation of ferrocenyl(H-phosphinic) acid and 1,1′-ferrocenyl-bis(Hphosphinic) acid with a low yield of 3-5%. 27The use of 50 (dimethylamine)dichlorophosphine Me 2 NPCl 2 as the phosphorylating reagent somehow made it possible to increase the yield of the acid to 9%. 28Ferrocenyl(phenyl)phosphonic acid was obtained with a high yield of 92% in the course of the reaction of ethyl ether of ferrocenyl(phenyl)phosphonic acid 55 Fc(Ph)P(O)OEt with Me 3 SiBr and subsequent hydrolysis. 29owever, Fc(Ph)P(O)OEt obtaining is based on the use of a hazardous gas Cl 2 , which makes this method much less attractive.][31][32][33] Diethyl ferrocenyl phosphonate FcP(O)(OEt) 2 was obtained with the yield of 33% using a reaction of ferrocene monolithium with diethylchlorophosphate 65 (EtO) 2 P(O)Cl at 0 °C. 27The addition of a base tBuOK facilitated an increase in yield to 79% (at -78 °C in THF, Scheme 1). 32his approach is multi-stage, as it includes the use of t-BuLi (after adding tert-butoxide to ferrocene ) at a very low temperature -78 °С at the first stage, and the use of a chlorinated 70 derivative, i.e., diethyl chlorophosphate, which is toxic, unstable and results in chlorine-containing byproducts, at the second stage. 32It is also disadvantageous to use the explosive solvent THF.For that reason, such a method is expensive and environmentally unacceptable.][36][37] Taking into account the importance of ferrocene derivatives with 5 phosphor-containing substituents, search of new, more convenient, one-stage and selective approaches to their synthesis remains a relevant objective.The purpose of this work is to develop a method for the direct phosphorylation of ferrocene with α-hydroxylethylphosphonate under electrochemical reduction 10 conditions and to identify the intermediate of this reaction.

Electrochemical synthesis
A joint electrolysis of ferrocene and the phosphorylating agent α-hydroxylethylphosphonate (Me) 2 C(OH)P(O)(OC 2 H 5 ) 2 at 15 -50 °C on a platinum electrode led to the formation of monosubstituted 1 (as the basic product) and disubstituted 2 diethyl ferrocenyl phosphonates FcP(O)(OEt) 2 with good yields (Table 1).The electrolysis potential was -3.3 V (ref. to Ag/AgCl), and alkali were used as basic additives to activate the 20 "masked" phosphorylating reagent.The use of Et 4 NOH provides higher yield compared to NaOH, probably because, in the latter case, due to side reactions of sodium reduction and the formation of sparingly soluble sodium salts of phosphorous acids.Alkaline conditions are necessary for 25 a slow transformation of the "masked" phosphorylating agent into H-phosphonate by a known reaction, [38][39][40][41] which we assumed would be quickly captured by the reduced form of ferrocene.In the absence of Et 4 NOH (or NaOH), phosphorylation with (CH 3 ) 2 C(OH)P(O)(OEt 2 ) does not occur.Interestingly, in the proposed low-temperature conditions, phosphorous acid H 3 PO 3 can also serve as a phosphorylating reagent using a lead cathode because it is not reduced in the 40 available range of potentials on Pb at -50 °С (Table 1, line 5, product 3).An alkali activator is not required in this case.It should be noted that the lead cathode at low temperatures and high cathode potentials is gradually degraded, hence its use is limited to (by) only several cycles of synthesis.In this regard, 45 preference was given to a platinum electrode and correspondingly suitable for it phosphorylated substrate, (Me) 2 C(OH)P(O)(OC 2 H 5 ) 2 .After passing of 1F of electricity (not 2F, as shown in Table 1), the yield reduced by ca.10-12%.Further increase (>2F) of the passed current led to a decrease in 50 yield and an unidentified byproducts formation.Ferrocene phosphorylation reaction with the use of dialkyl-H-phosphonate at the lead cathode occurs non-selectively, the yield of target product, determined by 31 P NMR spectra, was 35% (Table 1, line 4).Unidentified phosphorus-containing products were formed 55 and the electrode was partially destroyed.

Voltammetry
Ferrocene and ferrocenyl derivatives are well known due to their ability to undergo a reversible one-electron oxidation, 3,42 and the 60 potential of Fc + /Fc is the internal standard for electrochemical measurement, 43 the values of which have being measured in various aprotic and protonic solvents as well as in ionic liquids.6][47] However, the voltammograms 70 are poorly reproducible, the approximate half-wave potential is -2.9 V (ref.electrode was not specified) at -37 °C43 or -3.0 V at -90 °C in THF (ref.SCE). 45It was assumed that, as a result of the reduction, a relatively unstable Ср 2 Fe -anion would be formed. 48n increase in temperature leads to a two-electron reduction of 75 the ferrocene and its decomposition, thereby forming metal iron on the mercury cathode. 46Attempts were made to reduce the ferrocene in the СО atmosphere, and the formation of [CpFe(CO) 2 ] 2 was observed. 49e have assumed the reversibility of the ferrocene 80 reduction at low temperatures and, accordingly, the relative stability of the reduced form (at least, in the time scale of the voltammetry) could be used to perform the functionalizationphosphorylation with its participation.The choice of partner for the coupling the ferrocene is limited by its reduction potential; 85 that is, its E p should be more negative than that of the ferrocene, or it should be electrochemically inactive in the accessible cathode range of the potentials.The voltammorgams of investigated phosphorylating agents reduction on electrodes with low and high hydrogen overvoltage (Pt and Pd, correspondingly) 90 at 25 °С and -50 °C, respectively, are shown in Fig. 1.Earlier it was known that dialkyl phosphites were reduced on electrodes with low hydrogen overvoltage at room temperature on platinum or glassy-carbon type electrodes in aprotic solvent in the presence of ammonium salts as supporting electrolyte, [50][51] although in the range of high potentials, but still comparable with that for ferrocene.We can clearly see that voltammograms of phosphorus compounds with P-H bonds ((EtO) 2 PHO, H 3 PO 3 ) have no pronounced reduction peaks on platinum, as noted previously 51 , but their electrochemical activity is reflected in the sharp decrease of the limiting potential at which current increases, apparently due to the discharge of phosphoric acids and background electrolyte.The evolution of hydrogen, which can be observed visually, leads to oscillations in the voltammograms.The use of a 10 lead electrode with high hydrogen overvoltage allows to extend the available range of potentials, because no electrode reaction up to -3.4 V is observed (Fig. 1).Consequently, α-hydroxyethylphosphonate, so-called "masked" phosphorylating agent [38][39][40][41] , is a more appropriate phosphorylating agent in our case (Table 1, lines 1-3).    do not undergo further redox or chemical reactions (Table 1).We investigated the electrochemical behavior of diethyl ferrocenyl phosphonate in the electrolysis conditions (Fig. 3, Table 3).It has been found that the CV of this product differs strongly from CV of an unsubstituted ferrocene.So, diethyl ferrocenyl phosphonate 55 is characterized by quasi-reversible oxidation peak at more positive potentials compared to that for ferrocene, ∆E p a-c =0.44 V (Table 3).Importantly, the phosphorylated ferrocene cathodic peak is not observed in the available potential range (Fig. 3).Apparently, heterogeneous rate constants of oxidation and 60 reduction of the phosphorylated ferrocene is much less than those for ferrocene under similar conditions.The observed redox properties explain the success of the ferrocene phosphorylation.

ESR experiments
The key stage in the reaction under investigation is ferrocene reduction.Because up to now the conclusions about 75 this process have been drawn only on the basis of voltammetry, we used modern research methods, namely, combined ESRelectrochemistry in order to clarify the key reduction product (and reagent in phosphorylation process).In the course of the ferrocene reduction in DMF at the temperature of -50 °C and the potential of -3.3 V, a signal was observed, the line width being equal to ∆H peak-peak = 11 Gs and g = 2.000 (Fig. 4).It is known that, in the ground state, the ferrocene Fc 0 is low-spin compound (D 5h symmetry, 3d 6 , S=0). 53It can be expected that, upon its reduction, a paramagnetic form Fc should be formed, which has not previously been registered.However, the ESR spectra of radical anions of substituted ferrocenes were identified. 54,55Their g-factor values range from 2.003 to 2.028; the overall spectrum width varies from some units to tens of Gs; and the intensity of such spectra, as a rule, is not high.The low intensity can be caused by an inner-sphere reorganization of the ferrocene molecule, as assumed in the cited reference. 45In this process, as well as in case of a neutral ferrocene, the spin state of the system probably changes.In all the substituted ferrocenes, the electron transfer to the Cp ligands occurs, and in some cases even splittings on hydrogen nuclei of one of the cyclopentadiene rings are registered. 56Often, as in our case, only a relatively wide single line with no splitting is observed.The lifetime of the paramagnetic product amounts to 1 to 2 minutes in the DMF solution, according to time of the spectrum disappearance after the potential has been removed from the working electrode.This coincides with the data on the lifetime of the ferrocene anion obtained previously. 45The foregoing makes it possible to suppose that the registered spectrum is attributable to the ferrocene radical anion.The g-factor value gives the evidence that, as in the case of substituted ferrocenes, the electron transfer occurs with participation of the orbital of the ligand but not iron.At further increasing negative potential of the electrode, the ESR spectra become more complicated (Fig. 5).It is most likely that they correspond to paramagnetic products of ferrocene molecule decomposition.The simulated signal sim1 with a splitting from two protons refers to a derivative of the free ligand without the ferrocene structure.The simulated signal sim2 most likely refers to a fragment with Fe.ESR signals exist for a long time after the potential has been disconnected, but their intensity did not reduce for at least half an hour at the temperature of -50 °С.

Conclusions
Thus, the ferrocene radical anion ESR spectrum was recorded during Fc electrochemical reduction at the temperature of -50 °C 60 for the first time.We proposed new approach to the synthesis of phosphorylated ferrocene in one stage using αhydroxylethylphosphonate and phosphorous acid as phosphorylating agents with the total yield up to 90%, and 36%, respectively.

Cyclic voltammetry
The BASi Epsilon E2P (USA) electrochemical workstation was used for voltammetric measurements.The device comprises a measuring unit, a Dell Optiplex 320 computer with Epsilon-EC-70 USB-V200 software.As background electrolytes, tetrafluoroborate of tetrabutylammonium (C 4 H 8 ) 4 NBF 4 was used.
The working electrode was a stationary disc glassy-carbon electrode (the surface area of 6 mm 2 ).Ag/AgCl (0.01М) was used as a reference electrode, which was linked to the solution on the cell using a modified Luggin capillary filled with the background electrolyte (0.1 M Bu 4 NBF 4 in DMF).Thus, the assembled electrode had two sections, each of which was completed with an ultra-thin frit glass (Vycor) to divide the AgCl from the analyzed compound.
A platinum wire was used as an auxiliary electrode.The curve recording was performed at the potential linear sweep rate of 100 10 mV/s.The measurements were performed in a temperaturecontrolled electrochemical cell (volume from 1 ml to 5 ml) in an inert gas atmosphere (N 2 ).The cooling of the researched solutions was performed with frozen carbon dioxide.Between measurements or prior to the registration of a voltammetry wave, the solution was actively stirred with a magnetic stirrer in the atmosphere of constant inflow of an inert gas that was run through a dehydrating system, and then through a BI-GAScleaner (manufactured by OOO Modern Laboratory Equipment, Novosibirsk) nickel-based purification system to 20 remove any trace quantity of oxygen.

ESR research
Liquid samples for the ESR spectra registration were freed from oxygen by applying a three-time repeat of the following cycle: freezing in liquid nitrogen, pumping and defrosting.After the last cycle, the electrolysis cell was filled with gaseous helium.The operating electrode was a gold spiral.The experiments were performed in DMF at -50 °C, the background electrolyte was 0.1 M Bu 4 NBF 4 , and the sweep rate E(t) amounted to 0.1 V/s.The measurements were performed with a suite of hardware and 30 software assembled on the basis of the electrochemical analogue with a potentiostat and a PWR-3 programmer, an ELEXSYS E500 X-range ESR spectrometer, an E14-440 ADC and DAC module (L-Card Company), a computer and an original threeelectrode spiral cell. 57The ESR spectra were simulated with the 35 WinSim 0.96 (NIEHS) software.

Preparative electrochemical syntheses
All reactions were obtained in a dry argon atmosphere.The preparative electrolysis was performed using a direct current source B5-49 in a three-electrode cell with 40 ml volume with a 40 separation of the anode and cathode compartments.The potential value of the working electrode was recorded using a directcurrent V7-27 voltmeter in relation to the Ag/AgCl (0.01 M, NaCl) reference electrode that had two sections separated with Vycor, the second of which contained a saturated solution of the background salt in DMF.The surface area of the working platinum (Pt) U-shaped electrode amounted to 48.00 cm 2 .A ceramic plate with the pore rate of 900 nm was used as a membrane.During the preparative synthesis, the electrolyte was continuously stirred using a magnetic stirrer with a continuous 50 inflow of inert gas that was run through a purification system in order to remove any traces of oxygen and other gaseous impurities.NMR spectra were recorded with a Bruker AVANCE-400 multinuclear spectrometer (400.1 MHz ( 1 H), 100.6 MHz ( 13 C) and 55 162.0 MHz ( 31 P)).Chemical shifts are given in parts per million relative to SiMe 4 ( 1 H, internal solvent) and 85% H 3 PO 4 ( 31 P, external).

Reagents and research subjects
Dimethylformamide ("extra pure" by Acrosorganics), was 60 purified by means of double fractionation distillation over melting potash.Diethyl(2-hydroxypropan-2-yl)phosphonate was obtained through the method described in the literature. 58t 4 NBF 4 was obtained by mixing 30-35% water solution of tetraethylammonium hydroxide, Et 4 NOH and HBF 4 acid to a 65 neutral indicator reaction.In the course of the reaction, a white crystal precipitation is deposited, which is filtered and dehydrated.The obtained powder salts were recrystallized from ethyl ester and were dried for 2 to 3 days in a vacuum at 55 °C.Ferrocene (98%) and H 3 PO 3 (extra pure, 98%, Acrosorganics) 70 were used without preliminary purification.Et 4 NOH (20% aqueous solution, Acrosorganics) was subjected to a complete dehydration to a white solid on Schlenk's system prior to the beginning of the experiment.
Diethyl-2-hydroxypropane-2-yl phosphonate was added drop-wise evenly throughout the time of 80 the whole synthesis (2.69•10 -3 mol) in order to obtain monophosphonate.The electrolysis was performed on the Pt electrode in the electrochemical cell with a separation of the anode and the cathode spaces at the temperature of -50 º C in a dry argon atmosphere at the potential of the working electrode of 85 -3.3 V in the galvanostatic mode.The transferred electricity quantity amounted to 2F per mole of phosphonate.Upon completion of the electrolysis, the reaction mixture was washed with a saturated solution of ammonium chloride (50 ml for 3 times) and extracted with benzene (70 ml for 3 times).After 90 separation, the organic layer was dried over magnesium sulfate and the solvent was concentrated.Subsequently, the residue was purified by running through a chromatographic column filled with silica gel (eluent: ethyl acetate-hexane).The spectroscopic data for ferrocenylphosphonic acid matched that reported in the literature. 28

Scheme 1 .
Scheme 1. Multi-stage approach to the synthesis of ferrocene derivatives.

Table 2 .
Ferrocene electrochemical features.Conditions: -50 °С, glassy carbon working electrode, Ag/AgCl ref.electrode, 0.5 mM [Fc], Bu4NBF4 background salt, DMF, 100 mV/s.°C in the available range of potentials.Selectivity of ferrocene phosphorylation, high yield of monophosphorylation product and trace amounts of by-products in the optimal synthesis conditions indicate that the products are stable in electrolysis conditions and 50 45diethylphosphonate at room temperature and at -50