Triphenylphosphine

Ph3P

[603-35-0]  · C18H15P  · Triphenylphosphine  · (MW 262.30)

(deoxygenation of ozonides, peroxides, epoxides, and N-oxides; reduction of azides; reduction of organosulfur compounds; dehalogenations)

Physical Data: mp 79-81 °C; bp 377 °C; d (solid) 1.18 g cm-3; n20D 1.59.

Solubility: insol H2O; sol alcohol, benzene, chloroform; v sol ether.

Form Supplied in: white crystalline solid, widely available; polymer supported, ca. 3 mmol P per gram of resin is also available.

Purification: crystallize from hexane, methanol, or 95% ethanol; dry at 65 °C/<1 mmHg over CaSO4 or P2O5.1

Handling, Storage, and Precautions: classified as an irritant upon acute exposure and a neurological hazard upon chronic exposure.2 It is incompatible with strong oxidizing agents. Arylphosphines are less reactive toward molecular oxygen than benzyl- or alkylphosphines, but air oxidation of triphenylphosphine nonetheless occurs to an appreciable extent, particularly in solution, to give triphenylphosphine oxide.3 Triphenylphosphine has low fire and explosion hazards, but, when heated to decomposition, it emits highly toxic fumes of phosphine and POx.4 Use in a fume hood.

Introduction.

Triphenylphosphine is a fairly general reducing agent as the following examples indicate. The chemistry in which triphenylphosphine participates is, in most cases, driven by the formation of triphenylphosphine oxide, a thermodynamically favored reaction. The enthalpies of formation of triphenylphosphine and triphenylphosphine oxide are DfH°m = (207.02 ± 3.52) kJ mol-1 and DfH°m = -(116.41 ± 3.42) kJ mol-1, respectively.5 Triphenylphosphine oxide, however, is a highly crystalline nonvolatile material which often requires chromatography to effect its removal from desired reaction products. While less relevant to its chemistry, it is noteworthy that triphenylphosphine is a considerably weaker base than trialkylphosphines; its pKa is 2.73 compared to, for instance, tributylphosphine with a pKa of 8.43.6

Deoxygenations.

Triphenylphosphine has found widespread use in the reduction of compounds containing the hydroperoxide or endoperoxide functionality to form, depending upon the substrate, alcohols, carbonyl compounds, or epoxides. The primary driving force behind this class of reactions is the formation of the strong P=O bond at the expense of the relatively weak (45-50 kcal mol-1) O-O bond.7 For example, triphenylphosphine constitutes a mild, selective method for the reductive decomposition of ozonides to ketones and aldehydes. Compared to triphenylphosphine, Dimethyl Sulfide has enjoyed more popularity for this purpose,8 probably because of its comparable mildness and the relative ease in removing the byproduct dimethyl sulfoxide compared to triphenylphosphine oxide. Nevertheless, the convenience of handling of triphenylphosphine and its lack of unpleasant odor render it an attractive alternative, as its use in the following examples illustrates (eqs 1 and 2).9,10

Treatment of hydroperoxides with triphenylphosphine affords the corresponding alcohols in high yields under mild conditions and with retention of configuration at the carbon bearing the peroxide (eqs 3 and 4).11,12 The reaction of endoperoxides, on the other hand, affords epoxides with inversion of configuration at one of the two carbon atoms (eq 5).13 Vinylogous endoperoxides react with triphenylphosphine to afford the allylic epoxides (eq 6).14 These examples should not imply that reaction of endoperoxides with triphenylphosphine is necessarily facile, since certain endoperoxides have been shown to be inert to PPh3.15 Nevertheless, the transformation of the a-methylene-b-peroxy lactone to afford the b-lactone (eq 7)16 illustrates the wide scope of the peroxide deoxygenation capability of triphenylphosphine.

The deoxygenation of epoxides affords the corresponding alkenes and results in an inversion in the stereochemistry of substitutents attached to the double bond.17 While the reaction has been known since the mid 1950s,18 it has not found widespread use. Triphenylphosphine has found utility as a reducing agent of N-oxides. While several alternative reagents and conditions are available, these often require fairly strong reducing conditions which are incompatible with a wide range of functionality.19 In fact, triphenylphosphine-mediated reductions of N-oxides require much more vigorous conditions than do the corresponding reductions of peroxides. For example, reduction of trimethylamine oxide with trialkylphosphines requires refluxing in glacial acetic acid,20 and the reduction of pyridine N-oxide derivatives is best carried out at temperatures above 200 °C in the absence of solvent.21 However, it has been found that aromatic amine oxides are reduced in high yield with triphenylphosphine at room temperature with irradiation (eq 8).22 While not general, under special conditions triphenylphosphine is also capable of reducing aromatic nitroso23 and nitro groups (eq 9).24

Reduction of Azides (Staudinger Reaction).

In 1919, Staudinger and Meyer25 reported that the addition of triphenylphosphine to organic azides produced iminophosphoranes. This reaction proceeds by attack on nitrogen by phosphorus to produce an unstable phosphazide which extrudes dinitrogen to give the iminophosphorane (eq 10). This is known as the Staudinger reaction.26

The iminophosphorane is a useful functional group for synthesis and can be isolated, although it is usually generated and used in situ. Iminophosphoranes can be hydrolyzed to amines. This forms the basis for the conversion of azides to amines using triphenylphosphine in the presence of water (eqs 11-13).27 This mild and chemoselective reduction is an attractive alternative to other known methods (Lithium Aluminum Hydride, Diborane, catalytic hydrogenation) that effect this transformation.28 The reduction shown in eq 14 attests to the chemoselectivity of triphenylphosphine for this transformation. This reaction is sensitive to steric effects, but even tertiary azides can be reduced. Reduction of azides at a chiral center produce amines with the same configuration.

Reactions of Iminophosphoranes.

Iminophosphoranes are reactive nucleophilic ylides; electrophiles react with the nitrogen.29 Aldehydes and ketones are particularly favored reaction partners with iminophosphoranes, producing imines and triphenylphosphine oxide.30,31 This reaction is analogous to the Wittig reaction and is known as the aza-Wittig reaction. Again, the driving force for this reaction is the formation of triphenylphosphine oxide (eq 15). Two intramolecular examples are shown in eqs 16 and 17.32,33

Two other examples of reactions proceeding through the intermediacy of an iminophosphorane are shown in eqs 18 and 19.34,35 Both reactions result in aziridine formation, and the driving force is the production of triphenylphosphine oxide.

Reduction of an azide with triphenylphosphine in the presence of phthalic anhydride results in the formation of a phthalimide, a common protecting group for an amine (eq 20).36 This reaction is facilitated by the addition of 0.1 equiv of tetrabutylammonium cyanide. If the reduction is performed in the presence of a carboxylic acid, an amide is formed (eq 21).37 This reaction works with either aromatic or aliphatic (primary, secondary) azides and either aromatic or aliphatic carboxylic acids.

Reduction of Organosulfur Compounds.

Triphenylphosphine converts episulfides to alkenes38 smoothly at room temperature (eq 22). In contrast to the reaction of triphenylphosphine with epoxides, the reduction is stereospecifically syn.39 This syn elimination can also be promoted with alkyllithiums,40 lithium aluminum hydride,41 and excess Iodomethane,40 and by exposure to carbenes.42 This sulfur extrusion reaction plays a crucial role in Barton's method of alkene formation from carbonyl compounds.43 This process (eq 23) is particularly effective for the formation of tetrasubstituted and highly hindered alkenes, where a paucity of methods exist for effective formation of these compounds. For example, cyclohexanone is easily converted to the azosulfide (1) in two steps, which, upon heating to 100 °C in the presence of triphenylphosphine, gives bicyclohexylidene via the episulfide (2) in good overall yield.

Aryl disulfides can also be reduced to aryl thiols with triphenylphosphine in aqueous dioxane (eq 24).44 The resulting aryl thiols are easily removed from the triphenylphosphine oxide byproduct by extraction with aqueous base. The rate of reaction is faster for arenes with electron-withdrawing groups and is susceptible to catalysis by either acid or base. This reaction can also be accomplished with LiAlH4, Sodium Borohydride, and Zinc and dilute acid,45 or by heating with alkali.46

In addition, arenesulfonic acids, their sodium salts, and alkyl arenesulfonates can be reduced to the corresponding aryl thiols by triphenylphosphine and a catalytic amount of Iodine (eq 25).47 Since no reaction occurs in the absence of iodine or triphenylphosphine, the initial reduction is presumably mediated by iodotriphenylphosphonium iodide. The reaction can be greatly accelerated by the addition of a tertiary amine such as Tri-n-butylamine. Use of bromine in place of iodine results in a considerably lower yield of thiol.

Triphenylphosphine has also been used to convert a-aryl-a-chloro sulfides to stilbenes.48 The reaction (eq 26) requires addition of PPh3 to the a-chloro sulfide prior to base addition; reversing the order of addition leads to negligible stilbene formation. The mechanism is not clear, but studies have shown that the phosphonium salt is not an intermediate in the process.

Eschenmoser49 has used triphenylphosphine in an alkylation-sulfide contraction sequence useful in preparing secondary vinylogous amides and enolizable b-dicarbonyl compounds (eq 27). Although the precise mechanism is not known, an episulfide intermediate has been postulated. Addition of 0.1-0.2 equiv of a base such as Potassium t-Butoxide is necessary in some cases to promote enolization of the starting material.

Dehalogenation.

Triphenylphosphine has been used to reduce bromine or iodine atoms in the ortho or para positions of phenols (eq 28).50 The procedure consists of heating the phenol and 1 equiv of triphenylphosphine in benzene at 100-150 °C for 1-5 h followed by alkaline hydrolysis. The corresponding aryl chlorides do not undergo this reaction. In the case of 2,4-dibromophenol, the ortho bromine atom is reduced preferentially.

Secondary and tertiary a-bromo ketones react with triphenylphosphine in refluxing benzene-methanol to afford the debrominated ketone in 60-70% yields (eq 29).51 No quaternary phosphonium salts resulting from nucleophilic displacement of bromide are observed. The intermediacy of enol phosphonium salts has been proposed. Under conditions similar to those employed for bromo ketones, 2-chlorohexanone is dechlorinated to only a slight extent and direct quaternization is not detected.

Triphenylphosphine debrominates ethyl methacrylate dibromide and methyl acrylate dibromide to the unsaturated esters (eq 30).52 Dehydrobromination or displacement of bromide is not observed. Triphenylphosphine also debrominates a-bromodiphenylacetyl bromide at room temperature to generate Diphenylketene (eq 31).53 The mildness of this method avoids problems of other approaches such as the use of unstable intermediates such as phenylbenzoyldiazomethane and polymerization of the ketene.

Finally, triphenylphosphine has been utilized in the preparation of alkyl-substituted thiirene dioxides via a 1,3-elimination of bromine from bis(a,a-dibromoalkyl) sulfones (eq 32).54 The tetrabromo sulfones are synthesized from Dimethyl Sulfone in two steps.55

Miscellaneous.

Trost56 has reported that triphenylphosphine catalyzes the isomerization of ynones, ynoates, and ynamides to their corresponding diene-carbonyl compounds (eq 33). Conjugation of the alkyne with an electron-withdrawing group is necessary for the reaction to occur, and the reactivity order with respect to the electron-withdrawing group is ketone > ester > amide. Esters and amides require the addition of a weak protic acid such as Acetic Acid to facilitate the isomerization. Several examples of selectivity with polyfunctional alkynes have been reported (eq 34). The mildness and selectivity of this method over transition metal-catalyzed alkene redox reactions57 allows for greater functional group compatibility.

Treatment of arylbromonitromethanes with an equimolar amount of triphenylphosphine in an inert solvent such as benzene leads to formation of Benzonitrile Oxide,58 which can be isolated as diphenylfuroxan; use of methyl acrylate as the solvent leads to isoxazolines via a [3 + 2] cycloaddition of the benzonitrile oxide generated in the reaction with Methyl Acrylate (eq 35). However, reaction of 2 equiv of triphenylphosphine with alkyl-1-bromo-1-nitromethanes leads to formation of the corresponding nitriles,59 presumably via reduction of an intermediate nitrile oxides by the second equivalent of triphenylphosphine (eq 36). The putative alkyl nitrile oxide intermediate cannot be isolated or trapped by conducting the reaction in a solvent such as stilbene.

Triphenylphosphine in refluxing acetonitrile has also been used in the dequaternization of pyridinium salts (eq 37).60 Placement of an electron-withdrawing group on the pyridine ring facilitates the dequaternization reaction.

Triphenylphosphine has found wide application as a coreagent with a variety of other compounds including diethyl azodicarboxylate and carbon tetrachloride. These reagent combinations are covered in subsequent articles.

Related Reagents.

Molybdenum(V) Chloride-Triphenylphosphine; Triphenylphosphine-N-Bromosuccinimide; Triphenylphosphine-Carbon Tetrabromide; Triphenylphosphine-Carbon Tetrabromide-Lithium Azide; Triphenylphosphine-Carbon Tetrachloride; Triphenylphosphine-Diethyl Azodicarboxylate; Triphenylphosphine-Hexachloroacetone; Triphenylphosphine-Iodine; Triphenylphosphine-Iodoform-Imidazole; Triphenylphosphine-2,4,5-Triiodoimidazole.


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Jeff E. Cobb, Cynthia M. Cribbs, Brad R. Henke, & David E. Uehling

Glaxo Research Institute, Research Triangle Park, NC, USA



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