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  • Synthesis of


    For the chemist who would engage in synthesis

    or study theory, the organic chemistry

    of phosphorus is a fertile area

    DR. MARTIN GRAYSON, American Cyanamid Co., Stamford, Conn.

    Organophosphorus chemistry is a field which has experi-enced a sharp upsurge of interest during the past decade. Contributions to our knowledge of organophosphorus com-pounds have come from many sources, and both academic and industrial laboratories have been prominent in making those contributions. Much activity has been concerned with new methods for preparing the compoundsin some cases for the sake of their unique physical and chemical properties, and in others for theoretical studies related to a variety of new reactions.

    Since the field is so broad, we must necessarily limit our discussion. Therefore, my intention is to offer a brief out-line of methods for forming the carbon-phosphorus bond, with emphasis on those reactions where the phosphorus atom functions as a nucleophilic reagent.

    It is probably no coincidence that a renaissance in this field began some 12 years ago, at about the same time that the encyclopedic compendium, "Organophosphorus Com-pounds," by Prof. Gennedy M. Kosolapoff, appeared. Cer-tainly, no discussion of synthetic organophosphorus chem-istry should proceed before at least mentioning this and acknowledging our indebtedness to the book for its role in sparking current interest.

    Much of this interest is due to some very special proper-

    ties of phosphorus which contrast sharply with those of related organonitrogen compounds. Phosphorus forms stronger bonds than nitrogen does with oxygen, carbon, and halogens, but forms a weaker bond with hydrogen. The phosphorus-carbon bond is as strong as the carbon-carbon bond. The phosphorus-oxygen single bond is stronger than the carbon-oxygen single bond by some 10 kcal., and the phosphorus-oxygen "double bond" is some 55 kcal. stronger still, with a dissociation energy of about 135 to 140 kcal. This affinity for oxygen provides much of the driving force for many of the reactions of phosphorus compounds, such as the Wittig olefin synthesis in which a new P = 0 group is formed:

    R3P=CHR'+ R"CHO>R3P = 0 + R'CH=CHR"

    The bond dissociation energies in phosphine, ammonia, and methane increase in the order given (76, 84, and 91 kcal.), and this in part accounts for the ability of phosphines to participate in free radical and ionic additions to multiple bond systems. Furthermore, phosphorus is a larger atom than nitrogen, with more readily lost or polarized non-bonded electrons. This, coupled with nearly equal basicity in analogous compounds, produces greater nucleophilicity greater reactivity toward centers of electron deficiency.

    90 C&EN DEC. 3, 1962

  • chemical science series

    A point of major difference, compared to the first row elements, which phosphorus has in common with a number of other second-row metalloids, is its ability to accommodate up to 10, and sometimes 12, rather than only eight, valence electrons. This outer shell expansion results from vacant 3d orbitals of low energy, in addition to the s and orbitals to which nitrogen and other first-row elements are limited. This availability of vacant bonding orbitals, coupled with the nucleophilicity of phosphines, permits the formation of strong phosphorus-metal bonds. Trivalent or triply connected phosphorus compounds function as powerful ligands in many inorganic complexes. When we write multiple bonds between phosphorus and metals, carbon, oxygen, or nitrogen, we are actually describing a valence shell expansion with interaction between the vacant d orbitals of phosphorus and the p-electrons of the other atom (-- bonding). This type of interaction is sometimes called back bonding.

    Along these lines, phosphorus also forms stable, five-covalent compounds such as pentaphenylphosphorane (C6H5)5Pin which d, s, and orbitals have rehybridized to give the dsps system, which can be geometrically a bi-pyramid or a square pyramid. Recent x-ray work indicates the square pyramid structure to be correct for (C 6 H 5 ) 5 P, although the geometry for most reactive phosphorane intermediates and transition states remains in doubt. Studies of the stereochemistry and reaction mechanisms involving pentacovalent intermediates are therefore of great theoretical interest. This is the area in which much of the most exciting fundamental work in phosphorus chemistry is being carried out today.

    Many of these characteristics of phosphorus confer unusual and desirable properties on its compounds. Thermal stability and fire resistance are often associated with organophosphorus compounds. They can be used in gasoline to prevent preignition. In mining, they can be used for flotation and extraction of metals, including uranium. A host of other applications could be mentioned, including adhesives, lubricants, chelating agents, textile finishes, plasticizers, and so forth. But all in all, the industrial application of organophosphorus chemistry still seems to be in its earliest stages, with much yet to come.

    It is both convenient and instructive to group methods of forming phosphorus-carbon bonds into those in which the phosphorus atom functions as a nucleophilic, or electron-donating, reagent, those in which it acts as an electrophilic, or electron-accepting, reagent, and those wherein the reactions involve free radicals. Unfortunately, space does not permit a complete discussion of the electrophilic and free radical reactions, and in these areas I shall merely indicate the newer reactions of major, preparative value.

    Nucleophilic Reactions

    This class includes most of the reactions having widest application and the greatest utility for forming a phosphorus-carbon bond. Many of these reactions are catalyzed by bases, or they require formation of a negatively charged phosphide ion or metal salt of a phosphine, phosphine oxide, or dialkyl phosphonate. On the other hand, some of the most useful reactions involve the acid-catalyzed formation of an electron-deficient center, such

    DEC. 3, 1962 C & E N 91


    as a carbonium ion, from an alkyl halide, olefin, or carbonyl compound. This is then attacked by the nonbonded pair of electrons of the nucleophilic phosphorus atom. Base-Catalyzed Nucleophilic Reactions. Compounds containing a phosphorus-hydrogen bond are common starting materials for nucleophilic reactions. *Much of our own early work at the Cyanamid Laboratories made use of phos-phine (PH3) generated from metal phosphides and water. The use of aluminum or magnesium-aluminum phosphides, rather than calcium phosphide, eliminates by-product generation of biphosphine (H 2P-PH 2) , which apparently has been largely responsible for the reported hazards of this gas. Of course, even pure phosphine is toxic and flammable, but handling in conventional equipment presents few difficulties.

    The discovery of the base-catalyzed nucleophilic addition of phosphine to acrylonitrile by I. Hechenbleikner and M. M. Rauhut at Cyanamid made the interesting series of mono-, bis-, and tris-2-cyanoethylphosphines available:

    In this reaction, product distribution can be altered by appropriate changes in reactant ratios, to give high yields of any one of the tNree phosphines. These materials served as useful, easily prepared models for much of our early exploratory work.

    Uncatalyzed addition of acrylonitrile to phenylphosphine, as previously reported in the literature, required temperatures of at least 130 C. Repetition of this reaction with the ION KOH catalyst at 2C C. gave 82% bis(2-cyano-ethyl) phenylphosphine in a t tw hours. This reaction is probably a Michael addition process, involving the nucleophilic phosphide ion:

    The absence of acrylonitrile polymers or hydrolyzed products clearly demonstrates the greater nucleophilicity of the phosphide intermediates, compared to hydroxide ion.

    Similar base-catalyzed addition reactions of dialkyl phos-phonates, probably involving the ion [ ( R O ) 2 P = 0 ] - , were reported by a number of workers in the early 1950's. The enhanced acidity of the phosphonates was probably a major factor in the early recognition of their nucleophilic properties. This highly nucleophilic ion is also the basis for the well-known and useful Michaelis-Becker-Nylen reaction with alkyl halides to give dialkyl alkylphosphonates:

    Secondary phosphine oxides also contain a relatively acidic phosphorus-hydrogen bond, and they readily form the nucleophilic anion with bases. At Cyanamid, for example, the author and Patricia T. Keough found that ethylene carbonate is attacked by secondary phosphine oxides in the presence of bases such as heptamethylbigua-nide (HMBG), producing reactive 2-hydroxyethyl phosphine oxide intermediates. These are comparable to the


    Secondary phosphine oxides, having a relatively acidic phosphorus-hydrogen bond, readily form a nucleophilic anion with bases. They attack ethylene carbonate in the presence of heptamethylbiguanide,

    Interestingly, ethylene carbonate can be used to oxidize secondary phosphines as a starting material in

    centered mechanism, as in the Wittig olefin synthesis from aldehydes and methylene phosphoranes:

    Ethylene carbonate and other cyclic carbonates will also oxidize tertiary phosphines by way of a four-

    92 C & E N DEC. 3f 1962

    the above reactions. Secondary phosphine oxide, then, is rapidly formed concurrently with the olefin:

    for example, to give 2-hydroxyethyl phosphine oxide intermediates. These react, through dehydration and Michael addition of another secondary phosphine ox-ide, to give ethylenebis-disubstitutedphosphine oxides:

  • 2-hydroxyethyl phosphines obtained by others from metal phosphides and ethylene oxide.

    These materials can be isolated in some cases, but they generally react further to give ethylenebis-disubstituted phosphine oxides. This takes place through a dehydration to vinylphosphine oxide, followed by Michael addition of a second mole of starting material. The dehydration and Michael addition processes are quite rapid, and this again emphasizes the phosphinyl anion's great nucleophilicity in adding to activated olefins, as well as in displacement on saturated carbon.

    The ethylene carbonate reaction is an interesting one, since this reagent can also serve as an oxidizing agent and permits the use of secondary phosphines as starting mate-rials in the reaction. The phosphine is rapidly oxidized to the secondary phosphine oxide, with concurrent olefin formation. The mechanism of this oxidation involves a phosphorus-carbon bond cleavage in an intermediate in a way that is quite analogous to the cleavage involved in the Wittig olefin synthesis. With a tertiary phosphine, the oxi-dation reaction can be isolated. The oxidation reaction may have synthesis applications in converting 1,2-glycols to olefins via the cyclic carbonate.

    Nucleophilic addition of phosphinyl anions, derived from secondary phosphine oxides, to active olefins, such as acry-lonitrile, can also be carried out. Such reactions have been reported by R. C. Miller, J. S. Bradley, and L. A. Hamil-ton of Socony-Mobil and Temple University, and also by M. M. Rauhut and H. A. Currier at Cyanamid. In this connection, I should point out that, contrary to earlier reports, secondary phosphine oxides can be prepared in high yield by air oxidation of the phosphines in neutral organic solvents; phosphinic acids are formed only when strong oxidizing agents or alkaline conditions are used. Therefore, secondary phosphine oxides are readily avail-able as starting materials, obtainable from olefins and phos-phine by nucleophilic or free radical addition reactions. Furthermore, work by S. A. Buckler and M. Epstein at Cyanamid has led to the discovery of hitherto unknown primary phosphine oxides, R P ( 0 ) H 2 , and these materials also act as nucleophilic reagents in base-catalyzed addition reactions.

    With the added driving force of ring formation, base catalysis becomes unnecessary. This was shown by R. P. Welcher and Nancy E. Day, of Cyanamid, in their diaddi-tion of primary phosphines to conjugated dienones. The product 4-phosphorinones are six-membered rings, contain-ing carbonyl and tertiary phosphine functions.

    In terms of commercial potential, nucleophilic addition of phosphine to active olefins, such as acrylonitrile, offers perhaps the cheapest route to trivalent organophosphorus compounds containing functional groups. A considerable body of knowledge concerning the reactions of these ma-terials has been developed, but discussion of that chem-istry is beyond the scope of this article. Acid-Catalyzed Nucleophilic Reactions. In general, nucleo-philic attack by phosphorus compounds on unsaturated centers, such as olefins and carbonyl groups, is promoted by acid-catalyzed formation of an electron-deficient center, such as a carbonium ion. Generation of a carbonium ion is essential in reactions involving the weakly nucleophilic phosphorus trihalides. For example, alkyl halides are con-verted to carbonium ions by aluminum chloride in a Friedel-Crafts type of reaction with phosphorus trichloride, giving complex salts containing a new phosphorus-carbon bond:

    Organic phosphorus compounds have valuable flame-retardant properties. Helen C. Gillham, American Cyanamid, compares organophosphorus-treated plas-tic strip with a burning untreated strip (right)

    These salts can be converted to alkyl phosphonic dichlorides [RP(0)C12] or the corresponding acids or esters, depend-ing on work-up procedures. Reducing agents such as metals or other phosphorus compounds, including elemental phosphorus, can also be used to convert the complexes to alkyl phosphonous dichlorides (RPG12).

    In 1951, G. O. Doak and L. D. Freedman, at the Univer-sity of North Carolina, reported an equally general and useful method for preparing aromatic phosphonic or phos-phinic acids. Although not acid-catalyzed, this method is formally a nucleophilic substitution by phosphorus tri-chloride or RPC12 on an aryl cation, formed by copper-catalyzed loss of nitrogen from a diazonium salt. The re-action may well involve radical intermediates, however, as in the related conversion of tertiary phosphines to quater-nary phosphonium compounds by diazonium salts.

    In 1952, H. C. Brown of Purdue, in a patent to Standard Oil ( Ind.) , disclosed a clear-cut case of acid-catalyzed nu-cleophilic addition of phosphine to olefins. This was am-plified by M. C. Hoff and P. Hill of the same company in 1959. Presumably, the olefin is protonated on the least substituted carbon to give a secondary or tertiary car-bonium ion, and carbon-phosphorus bond formation fol-lows. Primary phosphines are the chief products, as the result of salt formation with the acid. Furthermore, at the University of Mainz, L. Horner and H. Hoffmann have shown that stable quaternary phosphonium compounds can be formed by protonat...


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