From rock-stable to reactive phosphorus

The main use of phosphate minerals is as fertilizer, but phosphorus is used in herbicides, flame retardants, drugs, battery electrolytes, and other materials. To date, the key feedstock for these materials is elemental phosphorus, particularly white phosphorus (P4). Reduction of phosphate to P4 is energy intensive, and it must be converted into other intermediates, such as PCl3, through reaction with chlorine gas (all of which are highly reactive and toxic). On page 1383 of this issue, Geeson and Cummins ([ 1 ][1]) report a set of simple transformations that afford a less energy-intensive strategy for converting phosphate into the bis(trichlorosilyl)phosphide anion 1 . Anion 1 serves as a P4 surrogate useful for the synthesis of a number of important organophosphorus compounds, including an organophosphorus-based drug. Phosphorus is too reactive to be found in nature in its elemental state. In particular, white phosphorus is reactive with oxygen, and phosphorus is most commonly found in its highest formal oxidation state (+5), as in phosphate (PO43−) salts or in organophosphorus compounds. Phosphate is concentrated in phosphate-containing rock and the mineral apatite ([ 2 ][2]). In the 17th century, Brand, in his pursuit of the philosopher's stone, isolated this element as an eerie glowing substance from human urine ([ 3 ][3]). The awareness that supplies of readily collected phosphate are limited has led to greater interest in its recovery and avoiding its environmental discharge ([ 4 ][4]). The industrial reduction of phosphate requires high temperatures (1400° to 1600°C) and addition of other materials, such as silica and coke (a carbon source), to create strong new element-oxygen bonds that offset the energy costs associated with removing P–O bonds ([ 5 ][5]). Geeson and Cummins's approach begins with phosphoric acid, which is widely available from phosphate rock and used in fertilizer manufacture. Phosphoric acid can be readily transformed into trimetaphosphate in the form of a tetrabutylammonium salt. Remarkably, the reaction of trimetaphosphate with excess trichlorosilane (HSiCl3) under mild heating (110°C) provides a previously unknown anion, 1 , in 65% yield. Anion 1 was unambiguously characterized by a series of spectroscopic techniques and single-crystal x-ray diffraction studies. This transformation of phosphorus in phosphate that was “rock stable” and in its highest oxidation state has three remarkable features. It cleanly reduced phosphorus to a lower formal oxidation state that is better suited for chemical elaboration. It also created a phosphorus center with a formal negative charge that is better able to participate in nucleophilic reactions (i.e., make new phosphorus-element bonds). Further, phosphorus was functionalized with two trichlorosilyl units that serve as additional sites for possible differential reactivity. The use of the reagent HSiCl3 (available in quantity because it is a key precursor to pure silicon for the electronics industry) is important, because the reaction that removes oxygen atoms from phosphorus is facilitated by formation of strong Si–O bonds. ![Figure][6] From rock to drugs Geeson and Cummins harvested phosphorus from unreactive phosphate sources (such as phosphoric acid produced from apatite rock) by reduction with trichlorosilane. Anion 1 can be used to synthesize many compounds, including the drug fosinopril. CREDITS: (GRAPHIC) ADAPTED BY N. CARY/ SCIENCE ; (PHOTO) JOHN PROTASIEWICZ, SAMPLE COURTESY OF THE CLEVELAND MUSEUM OF NATURAL HISTORY AND D. SAJA Anion 1 thus represents a versatile synthon for a variety of interesting materials (see the figure). Consistent with the anionic phosphorus center and oxophilic silicon centers, addition of water protonates the phosphorus center and exchanges the silyl groups for hydrogen atoms to form the phosphorus analog of ammonia, phosphine (PH3). Oxidative fluorination of 1 with xenon difluoride removes the silyl groups to afford the hexafluorophosphate anion [PF6]−, which is an anionic component critical to the function of most lithium-ion batteries. The nucleophilic character of the phosphorus atom in 1 allows direct alkylation (formation of P–C bonds). Addition of excess (4-chlorobutyl)benzene (an alkyl halide) to anion 1 produced the dialkylated phosphine (a secondary phosphine) of the form R2PH (R = CH2CH2CH2CH2Ph). Even more interesting was the discovery that anion 1 need not be isolated to create useful organophosphorus compounds from inorganic phosphate. Specifically, starting with the trimetaphosphate anion, addition of both (4-chlorobutyl)benzene and HSiCl3 followed by heating led to the direct formation of the intermediate secondary phosphine RP(SiCl3)H, which reacts with water to afford the primary phosphine RPH2. Secondary and primary phosphines are important ligands, as well as precursors to ligands, for binding to transition metals and forming catalysts that carry out many important industrial processes. Geeson and Cummins also demonstrated successful transformation of RPH2 to fosinopril, a drug used to treat hypertension and to ward off stroke and heart attacks ([ 6 ][7]), highlighting that their process can afford fine organophosphorus chemicals and avoid use of P4 as a phosphorus source. 1. [↵][8]1. M. B. Geeson, 2. C. C. Cummins , Science 359, 1383 (2018). [OpenUrl][9][Abstract/FREE Full Text][10] 2. [↵][11] 3. [↵][12]1. J. Emsley , The Shocking History of Phosphorus: A Biography of the Devil's Element (Macmillan, 2001). 4. [↵][13] 5. [↵][14]1. J. R. Brummer, 2. J. A. Keely, 3. T. F. Munday , Phosphorus. Kirk-Othmer Encyclopedia of Chemical Technology; . 6. [↵][15][www.webmd.com/drugs/2/drug-6036/fosinopril-oral/details][16] [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: pending:yes [7]: #ref-6 [8]: #xref-ref-1-1 "View reference 1 in text" [9]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DGeeson%26rft.auinit1%253DM.%2BB.%26rft.volume%253D359%26rft.issue%253D6382%26rft.spage%253D1383%26rft.epage%253D1385%26rft.atitle%253DPhosphoric%2Bacid%2Bas%2Ba%2Bprecursor%2Bto%2Bchemicals%2Btraditionally%2Bsynthesized%2Bfrom%2Bwhite%2Bphosphorus%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aar6620%26rft_id%253Dinfo%253Apmid%252F29439027%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [10]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIzNTkvNjM4Mi8xMzgzIjtzOjQ6ImF0b20iO3M6MjM6Ii9zY2kvMzU5LzYzODIvMTMzMy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [11]: #xref-ref-2-1 "View reference 2 in text" [12]: #xref-ref-3-1 "View reference 3 in text" [13]: #xref-ref-4-1 "View reference 4 in text" [14]: #xref-ref-5-1 "View reference 5 in text" [15]: #xref-ref-6-1 "View reference 6 in text" [16]: http://www.webmd.com/drugs/2/drug-6036/fosinopril-oral/details