electrochemical synthesis of organophosphorus compounds through nucleophilic aromatic substitution:...

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DOI: 10.1002/ejoc.201101357

Electrochemical Synthesis of Organophosphorus Compounds throughNucleophilic Aromatic Substitution:

Mechanistic Investigations and Synthetic Scope

Hugo Cruz,[a] Iluminada Gallardo,*[a] and Gonzalo Guirado*[a]

Keywords: Nucleophilic substitution / Phosphorus nucleophiles / Electrochemistry / Nitroaromatic compounds /Zwitterions

Advantages of the electrochemical approach in the nucleo-philic aromatic substitution reaction, such as (a) low cost andready availability of reagents, (b) atom economy, and (c) highyields (approaching 100%), are applied to rationalize the(polar or radical) mechanism and to develop new greenersynthetic routes for the synthesis of substituted nitroaromaticorganophosphorus compounds. The nucleophiles used tostudy the feasibility and viability of the reaction are the clas-sical tervalent phosphorus nucleophiles: trimethylphos-

IntroductionThe nucleophilic aromatic substitution reaction is one of

the most thoroughly studied reactions, because of its indus-trial and academic importance.[1] There are numerous syn-theses of novel compounds and natural products for phar-maceutical or medical applications, polymers, and analyti-cal standards for environmental studies based on this classi-cal reaction.[2] However, the main drawbacks related to thenucleophilic aromatic substitution reaction are the lack ofgenerality, the low yield, and the use of external chemicaloxidants, which are hazardous in most cases.[3] Most of thestudies devoted to the selection of the best conditions (sol-vent, nucleophiles and reactants) and procedures for envi-ronmental amelioration require mechanistic investigationsto establish the factors that affect the choice of mechanisticpath as well as the regioselectivity of the reaction.[3] It hasbeen well established by using common spectroscopic tech-niques such as UV/Vis, IR, and NMR spectroscopy[4] thatwhen the aromatic ring is substituted with two or more ni-tro (NO2) groups, the nucleophilic aromatic substitution re-action involves σ complexes (or Meisenheimer complexes).The most common mechanism, the SNAr addition-elimi-nation mechanism, involves two steps. In the first step, thereis a nucleophilic attack on the aromatic ring. In the secondstep, the Ar–X bond breaks, whereby the aromaticity of thenitroarene is recovered.

[a] Departament de Química, Universitat Autònoma de Barcelona,08193 Bellaterra, Barcelona, SpainFax: +34-935812920E-mail: [email protected]

[email protected]

© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 7378–73897378

phane, triethylphosphane, triphenylphosphane, diphenyl-phosphane, trimethyl phosphite, triethyl phosphite, dimethylphosphonate, diethyl phosphonate, oxo(diphenyl)phos-phorane, with two nitroaromatic compounds 1,3,5-trinitro-benzene and 1-chloro-2,4,6-trinitrobenzene in a DMF solu-tion containing 0.1 M tetrabutylammonium tetrafluoroborate.In all cases, in order to establish the feasibility or benefits ofthe electrochemical approach relative to the chemical ap-proach, blank reactions were also performed.

In order to develop a general and environmentallyfriendly route based on the SNAr reaction, we have focusedour attention on the nucleophilic aromatic substitution re-action of either hydrogen (NASH process) or a heteroatom(NASX process) by using electrochemical methods(Scheme 1).[5–14] In previous studies, we described electro-chemical cyanation, amination, formation of ketones, andthe synthesis of alkylnitroaromatic compounds. Therefore,

Scheme 1.

Electrochemical Synthesis of Organophosphorus Compounds through SNAr

the electrochemical approach to SNAr seems to be a highlyattractive approach from a mechanistic and synthetic pointof view. However, the nucleophilic aromatic substitution re-action of hydrogen (NASH process) or heteroatom (NASXprocess) with nucleophiles containing phosphorus, eitherchemically or electrochemically, is, as far as we are aware,limited to a very small number of mechanistic kinetic[15,18]

and synthetic studies.[19–22]

In this regard, in order to obtain esters of substitutedphosphonic acids, which are used in many chemical andmedical applications (for instance, as an agent in the treat-ment of osteoporosis),[19] the vicarious nucleophilic aro-matic substitution approach is used (Scheme 2).[20–21] Inthese NASH reactions, a C–C bond is created instead ofa C–P one when dialkylbenzyl phosphonates are used asnucleophiles in the presence of external bases and at lowtemperatures. The σH complex, formed by addition of thecarbanion of the benzyl phosphonates to nitroarene, canevolve into the final product with use of a second equivalentof base to promote the β-elimination of HX (vicarious nu-cleophilic substitution, VNS, Scheme 2A)[21] or by usingchemical oxidants, such as potassium permanganate (oxi-dative nucleophilic substitution of hydrogen, ONSH,Scheme 2B).[22]

Scheme 2.

Scheme 3.

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When neutral nucleophiles (e.g. amines) are used as nu-cleophiles, an additional step (prior to the formation of σcomplexes or Meisenheimer complex) occurs, and a new in-termediate is formed.[1–4] These intermediates are com-monly known as zwitterionic complexes (ZW) (Scheme 3).In most cases, this type of intermediate has been tentativelycharacterized by spectroscopic techniques.[1–4] The same in-termediates are also proposed when imines[23] and phos-phanes[15] are used. However, it is only possible to fullycharacterize these complexes when they are stable in theirsolid form.[23]

When phosphane acts as a nucleophile, the low stabilityof the intermediates formed, the low extent of the nucleo-philic attack, and the production of undesired products de-rived from secondary reactions are the main drawbacks as-sociated to the use of the SNAr reaction to obtain organo-phosphorus compounds by direct conversion of nitro com-pounds in nitro compounds containing phosphorus(Scheme 4A). In the study of the reaction of P(OAlk)3 with1,3,5-trinitrobenzene in DMSO, the authors proposed theformation of picryl phosphonate NASH products, althoughthey did not consider the mechanism of transforma-tion.[15,18] When 1-fluoro-2,4,6-trinitrobenzene andP(OMe)3 were used, the products obtained were picrylphosphonate, 2,4,6-trinitrotoluene, and 1-fluoro-2,4,6-trini-trobenzene. The formation of the picryl phosphonate deriv-ative as well as MeF can be rationalized in terms of anSNAr reaction through an Arbuzov rearrangement(Scheme 4B).[15,18] There are also some studies based on thereaction between 1,3,5-trinitrobenzene and dialkyl phos-phonates, (AlkO)2P(O)H. This reaction is promoted in thepresence of base and undergoes conversion to picryl phos-phonate compounds in DMSO (Scheme 4C).[15,18] The na-ture of the products formed after either NASH or NASXshown in Scheme 4 as well as the oxidizing character of thenucleophile seem to indicate that the SNAr reaction mayinvolve some radical mechanism running at the same timeas the classic polar mechanism. In this regard, the use ofelectrochemical techniques may be an alternative methodor approach for obtaining nitroaromatic organophosphoruscompounds.

Furthermore, the electrochemical anodic oxidation ofphosphorus nucleophiles leads to the formation of radicalcations as a result of the removal of an electron from theunshared electron pair of the phosphorus atom. After that,the radical cation can abstract a hydrogen atom from the

H. Cruz, I. Gallardo, G. GuiradoFULL PAPER

Scheme 4.

Scheme 5.

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solvent and finally evolve to the formation of the corre-sponding oxidized derivative (Scheme 5).[24]

So, the aim of this study is to develop a synthetic electro-chemical route to obtain organophosphorus compoundsthrough the NASH or NASX process following either polaror radical mechanisms. The presentation of the interestingpossibilities of the SNAr reaction would require a previouselectrochemical study of the reactants (phosphane com-pounds used as nucleophiles) and nitroaromatic com-pounds (electron-deficient aromatic compounds), interme-diates (σH complexes and zwitterionic intermediates), andNASH and NASX products (nitroaromatic organophos-phorus compounds). The mechanistic details and the syn-thetic scope of the electrochemical method are studied fora wide series of phosphorus nucleophiles 1–9: trimeth-ylphosphane (1), triethylphosphane (2), triphenylphos-phane (3), diphenylphosphane (4), trimethyl phosphite (5),triethyl phosphite (6), dimethyl phosphonate (7), diethylphosphonate (8) and oxo(diphenyl)phosphorane (9) withtwo nitroaromatic compounds, 1,3,5-trinitrobenzene (10)and1-chloro-2,4,6-trinitrobenzene (11), in a DMF solutioncontaining 0.1 m tetrabutylammonium tetrafluoroborate(TBABF4). In all cases, in order to establish the feasibilityor benefits of the electrochemical approach relative to thechemical approach, blank reactions were also performed.

Results and Discussion

In the current study, cyclic voltammetry was used in afirst stage as an analytical tool, in such a way as to revealthe concentration of the different species present in the re-action mixture (reactants: nitroaromatic compounds andnucleophiles), σH complexes, and zwitterionic intermedi-ates. For this purpose, it is mandatory to previously studythe electrochemical features of the reactants, products, andintermediates.

Electrochemical Behavior of Phosphorus Nucleophiles 1–9

The same general trend is observed when cyclic voltam-mograms of trialkylphosphanes and phosphites (1–6) arerecorded in DMF at low scan rates. No reduction waves areobserved in the first cathodic scan (until –1.00 V), whereasan irreversible one-electron oxidation wave appears in theanodic scan (Table 1). There is a shift in the anodic peakpotential value, Epa, (Table 1) from phosphane 1 to 2. Tri-ethylphosphane 2 is easier to oxidize, by 150 mV, than 1,which indicates that the methylene group (–CH2–) causesan inductive effect that is responsible for the stabilizationof the phosphane cation radical.[25]

Figure 1a shows the electrochemical behavior of tri-phenylphosphane (3), an irreversible monoelectronic oxi-dation wave is detected at approximately 1.28 V vs. SCE. Inthe case of compound 4, where a phenyl group is replacedwith hydrogen, there is a shift to more positive values. Thesame general trend is also observed for trialkyl phosphites,trimethyl phosphite (5) being more difficult to oxidize than


Table 1. Anodic peak potential, cathodic peak potential, standardpotential, ΔEp, and number of electrons involved in each electrontransfer of phosphorus compounds and nitroaromatic compoundsin DMF and 0.1 m TBABF4 at 20 °C (scan rate 1.0 Vs–1).

Compound 1 2 3 4 5 6

Epa (V) vs. SCE 1.15 1.00 1.28 1.36 1.41 1.26

Compound 10 11 12 13

1st 1st 1st and 2nd 1st and 2ndwave wave waves waves

Epc (V) vs. SCE –0.56 –0.59E° (V) vs. SCE[a] –0.37 –0.88 –0.41 –0.93

[a] E° = (Epc + Epa)/2.

triethyl phosphite (6). Controlled-potential electrolysis afterthe oxidation peak potential of trialkyl-, triphenyl-, and tri-alkylphosphanes and phosphites increases the acidity of thesolvent and leads to the corresponding oxides after thechemical treatment of the electrolyzed sample, as previouslymentioned in the Introduction section (Scheme 5). In thosecases, for nucleophiles 1–6, the oxidation potential valuesobtained for each phosphane, which are depicted in Table 1,would help to determine the excess nucleophile present inthe reaction mixtures.

Figure 1. Cyclic voltammograms of 3 (a) showing the oxidation, 11(b) showing the reduction and 12 (c) showing the reduction inDMF and 0.1 m TBABF4 on a glassy carbon disk (0.5 mm dia-meter); scan rate 0.50 Vs–1.

H. Cruz, I. Gallardo, G. GuiradoFULL PAPERHowever, it is remarkable that the electrochemical study

in terms of the cyclic voltammetry of dimethyl phosphonate(7), diethyl phosphonate (8), and oxo(diphenyl)phos-phorane (9) enables us to conclude that there is no elec-troactive group up to 1.5 V vs. SCE, since no oxidationwaves are detected in this scan range.

Electrochemical Behavior of Nitroaromatic Reactants andProducts

The electrochemical behavior of 1,3,5-trinitrobenzene(10) has been previously published.[26] An irreversible one-electron wave appears at –0.56 V vs. SCE (Table 1). The oxi-dation wave observed in the anodic scan at 0.26 V vs. SCEcorresponds to the oxidation of a biradical bis(1,3,5-trini-trobenzene) dianion. This biradical was characterized as aπ-dimer, which was obtained by the dimerization of twotrinitrobenzene radical anion units. In the case of 1-chloro-2,4,6-trinitrobenzene (11), an irreversible one-electron waveis also obtained at –0.59 V vs. SCE (Figure 1b, Table 1).However, the oxidation wave observed for 11 correspondsto the oxidation of the chlorine ion.[13] It is important toremark that for compounds 10 and 11, no oxidation waveis detected when the cyclic voltammetry begins after an an-odic scan.

Compound 12, diethyl(2,4,6-trinitrophenyl) phos-phonate, is chosen as a model compound to characterizethe electrochemical behavior of phosphorylated nitroaro-matic derivatives. This organophosphorus compound showstwo successive reversible one-electron waves at –0.37 and–0.88 V vs. SCE (Figure 1c, Table 1). The fact that the re-duction potential of the expected substitution product isconsiderably lower than that of the nitroaromatic reactantas well as the reversibility of the wave would make it pos-sible to easily distinguish whether the nucleophilic aromaticsubstitution reaction has been completed or not. It is alsoimportant to highlight that no oxidation waves are observedfor any of the phosphorylated nitroaromatic derivatives 12,13, and 14 in an initial anodic scan. Therefore, none of thenitroaromatic reagents (10–11) and products (12–14) are ox-idizing at this potential range.

Having established the electrochemical oxidation featuresof the phosphorus nucleophiles and the electrochemical re-duction and oxidation behavior of nitroarenes, we nowstudy the electrochemical features of the different interme-

Scheme 6.


diates that will be involved in the nucleophilic aromatic sub-stitution reaction: σH complexes and zwitterionic com-plexes.

Electrochemical Behavior of Phosphorus σH Complexes

The phosphorus σH complex depicted in Table 2, Entry1 is carefully prepared by adding two equivalents of potas-sium tert-butoxide to a mixture of DMF and 0.1 m

TBABF4 solution that contains two equivalents of phos-phorus nucleophile 7 and one equivalent of nitroaromaticcompound 10, under an argon atmosphere. Analysis of thecyclic voltammogram of the mixture enabled us to deter-mine the percentage of 10 remaining in solution, that is, theextent of the nucleophilic attack (by determining the cur-rent value of the cathodic peak of 10 when an initial cath-odic scan is recorded), the type(s) of substitution prod-uct(s), that is, trinitrocyclohexadienyl σH complexes or σX

complexes, for which Epa is expected to be between 0.5 and1.7 V,[5,10] and the type(s) of product(s) obtained after theoxidation of the complex [NASH or NASX product (whichin this case would be reactant 10) can be identified by grow-ing a reduction wave in a second cycle after the oxidationof the σH complex or after thorough controlled-potentialelectrolysis of the sample]. Figure 2 shows the absence ofelectroactive species 10 in the first cathodic cycle, whichmeans that the percentage of the nucleophilic attack is100%. Moreover, in the corresponding anodic counterscan,there are two oxidation peaks; an irreversible two-electron

Figure 2. Cyclic voltammograms of a mixture of 10 (1 equiv.), 7(2 equiv.), potassium tert-butoxide (2 equiv.) in DMF, and 0.1 mTBABF4 on a glassy carbon disk (0.5 mm diameter). Scan rate1.0 Vs–1. Scan range 0.0/–1.0/0.5/0.0 V (2 cycles).


oxidation peak at 0.88 V vs. SCE and a small oxidation pre-peak at 0.65 V vs. SCE. The cyclic voltammogram recordedin a second cycle indicates the formation of a double-substi-tution product, since there are three reduction waves. The

Table 2. Products and yields after exhaustive electrolysis of SNAr intermediates.


first reversible reduction wave and the third wave at –0.42and –0.88 V vs. SCE, respectively, could be assigned to thephosphorus NASH product 13, whereas the secondirreversible reduction peak at –0.56 V vs. SCE should corre-

H. Cruz, I. Gallardo, G. GuiradoFULL PAPERTable 2. (Continued)

[a] The σ complexes were carefully prepared by addition of the nucleophile to nitroarenes, the mixture was dissolved in DMF/0.1 mTBABF4 under an inert atmosphere at 10 °C. [b] The main electroactive intermediates present in the mixture. [c] The oxidation productswere analyzed by cyclic voltammetry, gas chromatography (GC), 1H and 31P NMR spectroscopy and compared with pure samplesavailable in the laboratory. [d] Shift of the equilibrium to the right. [e] Blank reactions (without oxidation of the mixture) led to depictedyields of substitution products. All the potentials are given vs. the SCE reference electrode.



spond to 10 (Figure 2, second cycle and Table 1). Analysisof the electrolyzed sample at 1.00 V vs. SCE after the pass-age of 2F and chemical treatment of the sample (see Experi-mental Section) reveals that two products are obtained: 13(80%, NASH product) and 10 (Scheme 6). The fact that thenucleophilic attack is 100% and there is a 20% yield of 10may be due to the formation of an undesired σ complex.The oxidation of this complex, which leads to compound10, may be related with the substitution product formedafter the oxidation of the first anodic peak at 0.65 V vs.SCE. When the number of equivalents of base is reducedfrom 2 to 1, the percentage of nucleophilic attack decreasesto 80%, the yield of the electrochemically promoted NASHreaction being 70% (Table 2, Entry 2).

Electrochemically Promoted Nucleophilic AromaticSubstitution of Hydrogen (NASH Processes) from σH

Complexes and Zwitterionic Complexes with PhosphorusNucleophiles in the Presence or Absence of an ExternalBase – Synthetic Scope

This section reports for the first time in terms of cyclicvoltammetry and preparative electrolysis on the scope andlimitations of electrochemical NASH with phosphorus nu-cleophiles.

Electrochemical Synthesis of Diethyl(2,4,6-trinitrophenyl)Phosphonate Oxide (12) and Diphenyl(2,4,6-trinitrophenyl)phosphane Oxide (14)

The electrosynthesis of diethyl(2,4,6-trinitrophenyl)phosphonate (12) (in DMF containing 0.1 m TBABF4 withuse of 10 as a nitroarene, 8 as a nucleophile, and potassiumtert-butoxide as a base at a ratio of 1:2:2) is performed byfollowing the procedure described in the previous sectionfor obtaining compound 13. The cyclic voltammogram ofthe mixture reveals that the percentage of nucleophilic at-tack is 81 % and there are of two oxidation peaks at approx-imately 0.66 and 0.87 V. This second oxidation peak shouldcorrespond to the phosphorus σH complex (Table 2, Entry3). After the cyclic voltammetry analysis, the sample is fullyoxidized by thorough controlled-potential electrolysis at1.00 V vs. SCE. Finally, after chemical treatment and analy-sis of the sample by cyclic voltammetry, 1H and 31P NMRspectroscopy enabled confirmation of the synthesis of 12 in33 % yield. It is therefore possible to conclude from the re-action yields of Entries 1–3 that the yield of a NASH reac-tion is lower when a diethyl phosphonate is used instead ofa dimethyl phosphonate, probably due to steric effects.

In order not only to assess the importance of the stericeffects but also to extend the methodology to diarylphos-phane oxide derivatives, we decided to evaluate the use ofoxo(diphenyl)phosphorane (9) as a nucleophile instead ofdialkyl phosphonates 7 and 8. In this case, the cyclic vol-tammogram of the mixture (a DMF solution containing0.1 m of TBABF4, 10 as a nitroarene, 9 as a nucleophile,and potassium tert-butoxide as a base at a ratio of 1:2:2)reveals that, although the percentage of nucleophilic attackis 80%, only 10 % of the NASH product 14 is obtained


after controlled-potential electrolysis of the same reactants(Table 2, Entry 4). It is remarkable that, despite the lowyield of NASH product obtained, this procedure is thecleanest reaction described in the literature for the synthesisof 14, since reactant 10 is recovered at the end of the pro-cess. It can therefore be concluded that the use of bulkyarylphosphanes reduces the percentage of nucleophilic at-tack from the phosphorus center as well as the yield ofphosphorylated nitroaromatic derivatives, mainly becauseof steric effects.

Electrochemical Behavior of Zwitterionic Compounds withTrialkyl-, Triaryl- and Diarylphosphanes as Nucleophiles

The zwitterionic compounds are carefully prepared “insitu” by adding different amounts of trialkylphosphanes (1and 2) to 10. Figure 3 (solid line) shows the cyclic voltam-mogram of a 1:1 mixture of 1 and 10 in DMF. From thecathodic scan it can be deduced that the nucleophilic attackis nonquantitative (55%), since the reduction peak –0.56 Vcorresponds to the reduction of 10. The first oxidation peakobserved in the anodic counterscan at 0.26 V is also relatedwith the electrochemical reactivity of the anion radical of10 [oxidation of biradical bis(1,3,5-trinitrobenzene) di-anion]. The second oxidation wave at 1.15 V vs. SCE corre-sponds to the concentration of 1, which remains “free” insolution. Thus, the oxidation peak at approximately 1.4 Vas well as the reduction peak at –0.8 V correspond to theoxidation and reduction peak potential values of the zwit-terionic compound (Scheme 7).[23] The addition of onemore equivalent of 1 increases the nucleophilic attack to90% as well as the concentration of zwitterionic compound(Figure 3, dotted line).

Figure 3. Cyclic voltammograms of a mixture of 10 (1 equiv.) and1 (1 equiv.) in DMF and 0.1 m TBABF4 on a glassy carbon disk(0.5 mm diameter); scan rate 1.0 Vs–1. Solid line: 0.0/–0.7/1.5/0.0 V.Dotted line: after the addition of one more equivalent of 1; scanrange 0.0/–0.7/1.5/0.0 V.

An exhaustive controlled-potential electrolysis at approx-imately 1.50 V leads to the reactant, 10, in 100 % yield.Then, the number of equivalents of 1 is increased to 10, 20,30, and 40 equiv. so as to shift the equilibrium from thezwitterionic complex to the σ complexes. However, in nocase is the substitution product obtained. It is important toremark that the exhaustive oxidation of the sample corre-sponds to the oxidation of the zwitterionic intermediate andto the excess of nucleophile, so reactant 10 is fully recoveredat the end of the process and the solvent becomes moreacidic. This increase in acidity could be explained by the


Scheme 7.

oxidation of phosphane leading to the corresponding oxideand a proton (Scheme 5). The same results were obtainedwhen the trialkylphosphanes were replaced with 3 and 4and ratios of nitroaromatic 10 to phosphanes from 10 to 40were used. In all cases, compound 10 is recovered in 100%yield and no substitution product is detected (Table 2, En-tries 5–8).

After disclosing that the electrochemical oxidation of theσ complexes yields the substitution product by formally re-placing a hydride (H–) following a NASH mechanism andthat the electrochemical oxidation of the zwitterionic com-pounds leads to the initial nitroaromatic compound, the ev-ident extension of this work is to check whether it is pos-sible to obtain substituted products by means of electro-chemical oxidation methods, in SNAr reactions with trialkylphosphite nucleophiles.

Electrochemical Synthesis of Dialkyl(2,4,6-trinitrophenyl)Phosphonates 12 and 13

Figure 4a shows the cyclic voltammetry of a reactionmixture of 10 (10 mm) in DMF containing 0.1 m ofTBABF4 after the addition of 6 (0.25 equiv.) and prior tothe electrochemical oxidation of the solution. In a first cath-odic scan, the excess unreacted nitroaromatic compound 10is observed (reduction peak at –0.56 V). Moreover, the for-mation of the zwitterionic complex can be deduced fromthe peak current value of the oxidation wave at 0.88 V vs.SCE. The fact that the oxidation potential value is higherthan that associated to the σH complex, as well as previous1H NMR and UV/Vis spectroscopic studies performed inaprotic solvents, led us to conclude that, in this case, theintermediate complex detected is a zwitterionic complexrather than a σH complex.[15] The oxidation peak at 0.26 Vvs. SCE is associated to the electrochemical oxidation ofthe π-dimer dianion, as previously mentioned. In a secondcathodic scan, the new first reduction wave, presumably cor-responding to the substitution product 13, is observed atapproximately –0.47 V vs. SCE. Finally, controlled-poten-tial electrolysis at 1.00 V vs. SCE/1F, after the zwitterionicintermediate oxidation wave, and analysis of the sample (af-ter a chemical treatment) makes it possible to obtain substi-tution product 13 in low yield (20 %, Table 2, Entry 12). Inorder to increase the reaction yield, excess nucleophile isadded to the DMF solution of 10. The addition of 25 equiv.of 6 increases the NASH product yield up to 35% (Table 2,Entry 10), whereas the addition of 200 equiv. leads to a68% yield (Table 2, Entry 11).


Figure 4. Cyclic voltammograms of a mixture of 10 (1 equiv.) and6 (0.25 equiv.) in DMF and 0.1 m TBABF4 on a glassy carbon disk(0.5 mm diameter); scan rate 1.0 Vs–1, scan range 0.0/–1.0/0.5/0.00 V (2 cycles).

Compound 12 was also synthesized by using the samemethodology as described previously for the synthesis of13. The reaction yield was 20% when 50 equiv. of 5 wereused (Table 2, Entry 12). The analysis by cyclic voltamme-try before performing the electrolysis enabled us to calculatethe extent of the nucleophilic attack, to characterize the σH

complex and the NASH product 12. Moreover, the cyclicvoltammogram recorded after the passage of 1F confirmsthe oxidation of the zwitterionic complex, the formation ofthe NASH product 12 and the recovery of unreacted 10.Blank experiments were also performed to test whetherthere is any NASH process in the absence of the electro-chemical oxidation, in no case is the yield of 13 or 12 higherthan 3% (Table 2, Entries 13, 14, and 15).

The proposed oxidation mechanism to electrochemicallysynthesize dialkyl(2,4,6-trinitrophenyl) phosphonates in-volves an initial nucleophilic attack of the phosphorus nu-cleophile. Since there is no detection of the more easily oxi-dizable corresponding complex by cyclic voltammetry whenan excess of nucleophile is used, it is reasonable to considerthat there is 100% zwitterionic complex. Finally, the elec-trochemical oxidation mechanism, which leads to theNASH products, should lead to a radical intermediate afterremoval of an electron and loss of a proton. The displace-ment of a methoxy radical from the phosphorus atom of aphosphoranyl radical can easily occur by an α-scission ofthe MeO–P bond. The fragmentation is a regiospecific pro-cess[27] and will finally evolve into the corresponding NASHproducts 12 and 13 (Scheme 8) following further oxidationprocesses and a similar mechanism to that previously de-scribed for the phosphane cations (Scheme 5).


Scheme 8.

Electrochemically Promoted Nucleophilic AromaticSubstitution of Heteroatom (NASX Processes) fromZwitterionic Compounds with Phosphorus Nucleophiles –Mechanistic Investigations and Synthetic Scope

The electrochemical NASX reaction can be a good alter-native for surpassing the yields obtained when the electro-chemical NASH approach is used, although this approachis less attractive in terms of designing an environmentallyfriendly route, since the leaving group is different from hy-drogen. This situation will be illustrated by synthesizingcompounds 12, 13, and 14.

Electrochemical Synthesis of Dialkyl(2,4,6-trinitrophenyl)Phosphonates 12 and 13 and Diphenyl-(2,4,6-trinitrophenyl)phosphane Oxide (14)

By using trialkyl phosphites (5 and 6) as nucleophilesand 1-chloro-2,4,6-trinitrobenzenes (11) as nitroaromaticstarting materials, it is possible to obtain the NASX substi-tution products (12 and 13), by either a chemical or an elec-trochemical route. The chemical reaction of 11 with50 equiv. of 5 yields 85% 13 and 15% 10 in DMF contain-ing 0.1 m TBABF4, following an SNAr reaction through anArbuzov rearrangement (Table 2, Entry 15). However, theelectrochemical approach makes it possible to reach quanti-tative yield of compound 13 and even reduce the numbersof equivalents of 5 (Table 2, Entry 16). Figure 5 shows acyclic voltammogram of a mixture containing compound11 and 5 equiv. of 5. Starting from a cathodic scan, thepresence of two reversible reduction peaks can be distin-guished at –0.48 and –0.95 V vs. SCE, which correspondto the formation of the radical anion and dianion of thesubstitution product 13, respectively. Moreover, it is alsopossible to detect a peak at –0.55 V vs. SCE, which is attrib-uted to the unreacted starting material, 11. In the corre-sponding anodic scan it is possible to distinguish two oxi-dation peaks at approximately 0.85 and 1.30 V vs. SCE.These peaks can be assigned to the oxidation of the zwitter-ionic compound and to the oxidation of the excess 5,respectively. When triethyl phosphite (6) is used as a nucleo-phile instead of 5, the same general trends are observed.Substitution products 12 and 10 are obtained in 85 % and15% yield through a chemical process (Table 2, Entry 17),whereas the yield increases to 100% when electrochemicaloxidation techniques are used (Table 2, Entry 18). The cy-clic voltammetry of a mixture containing 1 equiv. of 11 and


5 equiv. of 6 is the same as described previously for Fig-ure 5. The presence of substitution product 13, unreactedstarting material 11, excess nucleophile 6, and the zwitter-ionic complex formed can be distinguished.

Figure 5. Cyclic voltammograms of a mixture of 11 (1 equiv.) and5 (5 equiv.) in DMF and 0.1 m TBABF4 on a glassy carbon disk(0.5 mm diameter); scan rate 1.0 Vs–1, scan range 0.0/–1.0/1.5/0.0 V.Solid line: before electrolysis, dotted line: after electrolysis at 1.50 Vvs. SCE.

It is important to remark that the cyclic voltammetryexperiments support the hypothesis that substitution prod-ucts 12 and 13 can be obtained through an Arbuzov re-arrangement. Since the products obtained are the corre-sponding dialkyl(2,4,6-trinitrophenyl) phosphonates, PV

compounds, and the electrochemical experiments are per-formed in the absence of oxygen (argon atmosphere), theformation of the P=O bond under such experimental condi-tions confirms that the oxygen comes from the O-alkylgroup. The electrochemical oxidation mechanism should in-volve the generation of the radical cation of the zwitterioniccompound, which would evolve through an anionic oxi-dation radical NASX Arbuzov-type rearrangement, yield-ing the corresponding substitution product after either achemical (by the excess trialkyl phosphite) or electrochemi-cal (at the electrode) (Scheme 9) oxidation step.[28] The ver-satility of alkyl phosphites and their tolerance to a free radi-cal methodology makes it possible to achieve homolytic re-action for synthetic chemistry purposes.

Conclusions

We have established the electrochemical oxidationmechanism of nine phosphorus nucleophiles as well as theelectrochemical reduction mechanism of four nitroaromaticcompounds. We have also disclosed the electrochemical oxi-dation mechanism of phosphorus σH complexes as well as


Scheme 9.

zwitterionic intermediates by means of cyclic voltammetryand controlled-potential electrolysis. It has been shown thatthe electrochemical oxidation of σH complexes, formed byaddition of dialkyl phosphonates to basic media, as phos-phorus nucleophiles, makes it possible to obtain the NASHproducts through a two-electron mechanism, which corre-sponds to the formal elimination of hydride anion (nucleo-philic aromatic substitution of hydrogen mechanism). In thecase of zwitterionic complexes, the alkyl phosphites haveattacked a substitution position. Those complexes evolvefollowing a promoted anodic oxidation following nucleo-philic aromatic substitution of heteroatom, NASX, throughan Arbuzov rearrangement. Finally, a nucleophilic aromaticsubstitution of hydrogen mechanism is the operatingmechanism for a zwitterionic complex where the nucleo-phile has been attached to a non-substitution position.Hence, the present study not only shows a significant im-provement in the electrochemical preparation of phosphor-ylated aromatic substituted compounds but also helpsunderstand and predict the usefulness or uselessness ofusing the nucleophilic aromatic substitution route to obtainthe organophosphorus compound desired. Finally, the cur-rent approach presents an extension of the electrochemicalmethodology for the synthesis of different chemicals thatcan be used in several fields, such as pharmacy, medicine,or material science.


Experimental SectionGeneral Remarks

Materials: Anhydrous dimethylformamide (DMF, “Pour synthesespeptidiques”) and acetonitrile (ACN, “Anhydre pour analyses”)were purchased from SDS and stored in an inert atmosphere withmolecular sieves. Tetrabutylammonium tetrafluoroborate(TBABF4) was purchased from Fluka (puris.). These reagents wereused without further purification. 1,3,5-Trinitrobenzene was fromSupelco. Phosphorus nucleophiles (1–9) were purchased from Ald-rich. All commercially available reactants (1–9, 10) and products(12–13) were of high purity and were used without further purifica-tion. We synthesized 1-chloro-2,4,6-trinitrobenzene (11) by follow-ing the method reported in ref.[12]

Chemical Reactions: The nitroarene (23.5�10–5 mol) was added tothe phosphorus nucleophile (5 equiv.) in acetonitrile (ACN),purged with nitrogen, and left to react for 2 h in an inert atmo-sphere whilst stirring. After this time, the nitrogen flow wasstopped, and the reaction was left for 8 more hours to promote theoxidation of the product formed. Then the reaction was stopped,and the mixture was subsequently partitioned between water anddichloromethane. The organic layer was dried with anhydrous so-dium sulfate, the solvents were evaporated at low pressure, and theresidue was analyzed by 1H NMR and 31P NMR spectroscopy.This residue was then purified by thin layer chromatography.

Electrochemical Measurements

A conical electrochemical cell equipped with a methanol jacket,which provides a fixed temperature of 20 °C throughout the experi-


ment by means of a thermostat, was used to set up the three-elec-trode system for cyclic voltammetry. For cyclic voltammetry experi-ments, the working electrode was a glassy carbon disk of 0.5 mmdiameter. It was polished by using a 1 μm diamond paste. The co-unterelectrode was a Pt disk of 1 mm diameter. All of the potentialsare measured relative to an aqueous saturated calomel electrode(SCE) isolated from the working electrode compartment by a saltbridge. The salt solution of the reference calomel electrode wasseparated from the electrochemical solution by a salt-bridge endingwith a frit, made of a ceramic material, which permits ionic con-ductivity between the two solutions and thus avoids appreciablecontamination. The electrolyte solution present in the bridge (or-ganic solvent and 0.1 m supporting electrolyte) is the same as thatused for the electrochemical solution so as to minimize junctionpotentials. Solutions were prepared in N,N-dimethylformamide(DMF) as solvent and were purged with nitrogen (or argon) beforeeach measurement, and nitrogen (or argon) was allowed to flowover the solution during the measurements.

Electrosynthesis was carried out in the same cell with a PAR 273Apotentiostat. A graphite rod was used as a working electrode andPt as a counter electrode, isolated from the solution by a salt bridgewith electrolyte solution, and the SCE was used as a reference elec-trode, which was also separated from the solution by a salt bridge.

Procedure for the Electrochemical Synthesis of Phosphorus Substitu-tion Products: A solution of nitroarene (5�10–5 mol) in DMF,which contained TBABF4 (0.1 m) used as a supporting electrolyte,was prepared under nitrogen (or argon). The corresponding σH

complex was prepared by careful addition of the correspondingnucleophile (and potassium tert-butoxide in the indicated cases), atthe desired ratio, to the solution of nitroarene under nitrogen (orargon). The oxidation peaks of the σH complex or zwitterionic in-termediates were measured by the cyclic voltammetry technique.Electrosynthesis of oxidation was then carried out at potentials thatwere more positively shifted, by approximately 100 mV, than thevalue measured for each σ complex or zwitterionic complex. Afterthorough electrolysis of the sample, the mixture was subsequentlypartitioned between water and toluene. The organic layer was driedwith anhydrous sodium sulfate, the solvents were evaporated at lowpressure, and the residue was analyzed by CV, GC, 1H and 31PNMR spectroscopy and compared with pure samples of substitu-tion products. This residue was finally purified by thin layerchromatography and the nitroorganophosphorus compounds wereobtained at high purity. The σH complexes and zwitterionic inter-mediates of NASH processes are stable for more than one hour,whereas the stability of zwitterionic intermediates of NASX is con-siderably lower (less than 30 min).

Diethyl(2,4,6-trinitrophenyl) Phosphonate (12): 1H NMR(250 MHz, CDCl3): δ = 8.66 (d, J = 3.35 Hz, 2 H), 4.33 (m, J =7.025 Hz, J = 3.025 Hz, 4 H), 1.42 (m, J = 7.025 Hz, J = 8.025 Hz,6 H) ppm. 31P NMR (250 MHz, CDCl3): δ = –1.80 ppm.

Dimethyl(2,4,6-trinitrophenyl) Phosphonate (13): 1H NMR(250 MHz, CDCl3): δ = 8.68 (d, J = 3.325 Hz, 2 H), 3.95 (d, J =11.725 Hz, 6 H). 31P NMR (250 MHz, CDCl3): δ = 1.17 ppm. MS:m/z(%) = 290 (15)[M – OCH3]+, 275(3), 244(4), 231(100), 199(11),153 (6), 109 (28).


Diphenyl(2,4,6-trinitrophenyl)phosphane Oxide (14): 1H NMR(250 MHz, CDCl3): δ = 9.00 (s, 2 H), 7.97 (s, 5 H), 7.76 (s, 5 H)ppm. 31P NMR (250 MHz, CDCl3): δ = 17.7 ppm.

Acknowledgments

We gratefully acknowledge the financial support of the Ministeriode Educación y Ciencia of Spain through projects CTQ2006-01040and CTQ 2009-07469.

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1996, 37, 1625Received: September 16, 2011

Published Online: October 25, 2011

electrochemical synthesis of organophosphorus compounds through nucleophilic aromatic substitution:...

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