© 2015 Joseph Alexander Macor
ON THE COORDINATION CHEMISTRY OF PENTAVALENT (!4, "5) PHOSPHORUS COMPOUNDS
BY
JOSEPH ALEXANDER MACOR
DISSERTATION
Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2015
Urbana, Illinois
Doctoral Committee:
Professor Gregory S. Girolami, Chair Professor Scott E. Denmark Assistant Professor Alison R. Fout Professor Yi Lu
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The work described herein details the synthesis of a variety of pentavalent organophosphorus compounds and their applications as ligands to address important problems in coordination chemistry. This research encompasses two main themes: (1) the asymmetric synthesis of enantiopure !-alkylbenzylphosphonic acids, and the use of these compounds to prepare homochiral vanadium diphosphonate materials that can serve as heterogeneous catalysts for the asymmetric epoxidation of allylic alcohols, and (2) the design and synthesis of novel heterocyclic dithiophosphinic acids and exploration of their coordination chemistry with the f-elements, with the ultimate goal of better understanding the properties that dictate selectivity in Ln/An extractions in the context of nuclear fuel reprocessing.
Enantiopure (R)-BINOLato benzylphosphonate is easily and inexpensively prepared, and is stable to air and moisture. Deprotonation with n-butyllithium followed by addition of a methyl, ethyl, allyl, or benzyl halide electrophile at -78 °C affords (R)-BINOLato (R)-1-alkylbenzylphosphonates in good yields and excellent diastereoselectivities. Removal of the chiral auxiliary is best accomplished in a two step procedure: cesium fluoride promoted transesterification to the dimethyl
! ""! phosphonate ester, followed by acidic hydrolysis to the corresponding phosphonic acid. This sequence affords (R)-1-alkylbenzyl-phosphonic acids in high yield and optical purity.
This technique can be extended to the synthesis of chiral diphosphonic acids containing naphthalene backbones. These ligands, along with their achiral analogues, react with VO2+ to generate vanadyl diphosphonate materials. These products are insoluble in organic solvents and have a layered architecture as judged by powder X-ray diffraction. These compounds are the first examples of homochiral polymers containing diphosphonate linkages, and exhibit exceptional catalytic activity for the heterogeneous chemoselective epoxidation of allylic alcohols when tert-butyl hydroperoxide is employed as a stoichiometric oxidant. With the homochiral catalysts, the enantioselectivity is modest, but apparent (e.r. " 3:2).
Synthetic methodology has also been developed that affords novel heterocyclic 2,2#-biphenylenedithiophosphinic acids, which contain 5-membered dibenzophosphole rings. These new compounds have been fully characterized by conventional techniques, as well as by K-edge X-ray absorption spectroscopy in order to elucidate the electronic consequence of rotational restriction about the P–
Cipso bonds. Liquid/liquid extraction studies show that these compounds exhibit a ca.
10:1 selectivity for the preferential chelation of 241Am over 154Eu. In addition, homoleptic complexes of Eu3+, Nd3+, U4+, and Np4+ with the 2,2#- biphenylenedithiophosphinate ligand have been prepared and characterized by single crystal X-ray diffraction.
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“As the true method of knowledge is experiment, the true faculty of knowing must be the faculty which experiences.”
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A dissertation is an interesting thing. Specifically, it is often difficult to see the human aspects behind the written work: the long nights spent in lab, the heated arguments with reagent bottles, the immense satisfaction of a ‘spot-to-spot’ reaction, or the nervous anticipation while walking to the NMR lab where promises of novel compounds are whispered in multiplets. The final product looks so much cleaner. That being said, it is even harder to imagine its completion without the overwhelming support of various mentors, colleagues, and friends I have had the fortunate consequence of encountering along this journey.
To my advisor Greg Girolami, I am immensely grateful for your guidance, assistance, and the countless scientific conversations that often seemed to completely diverge (in a good way) from what I had originally intended to discuss. I believe you have set me on a path to become precisely the type of scientist I admired when I was younger. I would also like to thank the remainder of my doctoral committee, Scott Denmark, Alison Fout, Yi Lu, and Tom Rauchfuss for all of your advice and constructive criticism.
To the past and present Girolami group members, Andrew Dunbar, Luke
Davis, Jenny Steele, Noel Chang, Justin Mallek, Peter Sempsrott, Brian Trinh,
Tracy Codding, Sumeng Liu, Kaili Zhang, and Chelsea Hadsall, thank you for the beneficial conversations about life and chemistry, and for providing a fantastic work
! 9! environment. I would also like to thank the UIUC SCS staff, namely Marie Keel,
Rudy Laufhutte, Beth Eves, Danielle Gray, Jeff Bertke, Dean Olson, Connie Knight,
Beth Myler, Stacy Dudzinski, Karen Watson, and Theresa Struss. You have all been extremely helpful and are outstanding at what you do. To my other friends and colleagues, Rob Hicklin, Huy Le, Greg Snapper, Dr. Jonathan Eller, and Dr. Scott
Sarfert, I cannot thank you enough for the much needed (and even the occasionally unneeded) distractions from lab. I would wish you all good luck in your future endeavors, but I am certain you will not need it.
To my coworkers at Los Alamos (and otherwise unaffiliated New Mexican friends) particularly Angie Olson, Matthias Loble, Justin Cross, Chantal Stieber, and Ralph Zhender, thank you for the enlightening discussions on actinide chemistry and for generally making my time in the desert an enjoyable one. I would also like to thank Stosh Kozimor– I couldn’t have asked for a better advisor, mentor, and friend.
Lastly, I would also like to thank my family for their continued and unending love and support. To my Ph.D.-holding chemist relatives Uncle Jack, Aunt Kathy, and Uncle Mike, your advice and encouragement through the years has been invaluable. To my parents Cathy and Jim Macor, it has been a true privilege to call myself your offspring. Thank you for everything.
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1. General Overview of the Chemistry of Organophosphorus(V) Compounds ……………………………………… 1 1.1 Nomenclature ...……………………………………………………….. 1 1.2 The Nature of the Phosphoryl Bond ...…………………………. 3 1.3 Synthesis and Reactivity of Pentavalent Organophosphorus Compounds …………………...……………. 4 1.3.1 Synthesis …………………………………………………. 4 1.3.2 Reactivity: Applications in Organic Synthesis …….. 9 1.4 Applications of Pentavalent Phosphorus Compounds in Coordination Chemistry ……………………….. 14 1.4.1 Heterogeneous Systems ……………………..…………. 15 1.4.2 Homogeneous Systems ……………………………….... 17 1.5 References ………………………………………………………….. 20
2. Synthesis of Enantiopure Phosphonic Acids with BINOL as a Chiral Auxiliary ……………………………………………. 28 2.1 Background ………………………………………………………… 28 2.2 BINOL as a Stereocontroller …………………………………..... 31 2.3 Asymmetric Phosphonate Alkylation Using BINOL ………… 34 2.3.1 Attachment of the BINOL Auxiliary ………………… 35 2.3.2 Asymmetric Alkylation ………………………………… 35 2.3.3 Removal of the BINOL Auxiliary……………………… 40 2.4 Conclusions and Future Work …………………………………... 47 2.5 Experimental ………………………………………………………. 47 2.6 References ………………………………………………………….. 60
3. Chiral Vanadium Diphosphonates as Heterogeneous Asymmetric Epoxidation Catalysts ……………………………………… 74
! 9""! 3.1 Background ………………………………………………………… 74 3.2 Prior Art ……………………………………………………………. 78 3.3 Synthesis of Chiral and Achiral Diphosphonic Acid Ligands ……………………………………… 83 3.4 Synthesis of Heterogeneous Vanadium Diphosphonates …… 87 3.5 Catalytic Oxidations with Vanadium Diphosphonates ……… 94 3.6 Conclusions and Future Work …………………………………... 98 3.7 Experimental ………………………………………………………. 98 3.8 References ………………………………………………………….. 119
4. Heterocyclic Dithiophosphinic Acids for the Selective Extraction of Minor Actinides ………………………………… 127 4.1 Background ………………………………………………………… 127 4.2 Prior Art ……………………………………………………………. 134 4.2.1. Dithiophosphinate Extractants ………………………. 134 4.2.2 K-Edge X-ray Absorption Spectroscopy: a Quantitative Probe of Covalency …………………... 135 4.3 Heterocyclic Dithiophosphinate Extractants ………………….. 140 4.3.1 Ligand Synthesis and Characterization …………….. 142 4.3.2 K-Edge X-ray Absorption Spectroscopy ……………… 152 4.3.3 Eu/Am Extraction Experiments ………………………. 154 4.4. Biphenylenedithiophosphinate Complexes of the f-Elements …………………………………………………. 156 4.5 Conclusions and Future Work …………………………………... 169 4.6 Experimental ………………………………………………………. 171 4.7 References ………………………………………………………….. 187
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Although trivalent phosphorus finds many uses in the laboratory, pentavalent phosphorus is far more common (and more important) in the world around us. Its compounds exhibit diverse properties, surpassed only, perhaps, by their potential utility to mankind. This introduction aims to provide general insights into the chemical nature of this class of compounds, and highlights pertinent applications within the context of coordination chemistry.
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The use of valence to describe phosphorus compounds has a long history, but this approach can lead to ambiguities, for example, when applied to compounds with P–P bonds.1 A less subjective way to describe phosphorous compounds is the employment of two parameters: one describing the number of atoms that are directly attached to phosphorus (coordination number, !), and the other describing
! A! the number of electrons that the phosphorus atom uses in bonding (valency, ").2 For example, both phosphines, R3P, as well as diphosphines, R2P-PR2, would be
3 3 5 5 classified as ! " , whereas phosphoranes, R5P, are ! " species. The work described herein will focus on a subset of organophosphorus compounds in which the phosphorus atom is attached to four atoms in a neutral state and uses five electrons for bonding, therefore falling under the !4"5 designation. For convenience, the use of the terms ‘pentavalent’ and ‘phosphorus(V)’ in this work shall be regarded as referring to such !4"5 compounds only.
Pentavalent organophosphorus compounds of stoichiometry PO(R)x(OR)3-x are further classified by the number of carbon atoms directly attached to phosphorus
(Figure 1.1): zero for a phosphate, one for a phosphonate, two for a phosphinate, and three for a phosphine oxide.1
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The phosphoryl (P=O) bond is one of the key features of pentavalent phosphorus compounds. It is thermally robust, (bond energy of 128-139 kcal/mol) and its formation is the thermodynamic driving force behind a variety of synthetic organic transformations.3 The precise nature of the phosphoryl bond has been the topic of debate for some time.1 Earlier theories described it as consisting of one ! bond and one " bond in which electrons from oxygen backbond into a vacant 3d orbital on phosphorus.4 However, recent computational studies have since shown that the phosphorus d orbitals play a negligible role in bonding; a better representation is that there is " donation from the oxygen p orbitals into !*
5 antibonding orbitals of the PR3 fragment through negative hyperconjugation. This
" bond has been calculated to be polarized towards oxygen by more than 90%.6
Regardless, it still remains convention (likely due to convenience) to represent this interaction as ‘P=O’, and it will be referred to as such in this work.
However, it is important to remember that this bond differs greatly from a C=C or
C=O bond, and therefore exhibits unique and characteristic reactivity.
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There are numerous synthetic routes to pentavalent organophosphorus compounds. Outlined below are some commonly employed methodologies.
Direct oxidation from P(III)
Owing to the strength of the phosphoryl bond, the phosphorus lone pair of trivalent phosphines (R3P), phosphinites (R2P(OR)), and phosphonites (RP(OR)2), can often be directly oxidized to afford phosphine oxides, phosphinates, and phosphonates, respectively. This behavior contrasts with that of amines, which can be oxidized only with special reagents, and the resulting amine oxides are easily reduced.1 This oxidation strategy is particularly attractive, because organic functionalities can readily be installed by treatment of PCl3 with an organic nucleophile followed by oxidation to the desired organophosphorus(V) compound.1,7
For example, oxidation of dialkylchlorophosphines followed by alcoholysis provides a convenient route to phosphinate esters, whereas alkyldichlorophosphines yield phosphonate esters.
Depending on the nature of the substituents on the phosphorus(III) starting material, this oxidation can sometimes be accomplished with aerial oxygen, although this strategy can give rise to undesired products in which oxygen inserts
! O! into the P–C bond.8 For more stable substrates and generally higher-yielding reactions, aqueous hydrogen peroxide may used as the oxidizing agent.9 For the formation of thiophosphoryl and selenophosphoryl bonds, elemental sulfur and selenium are often employed.10-11
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The Michaelis-Arbuzov Rearrangement
The Michaelis-Arbuzov rearrangement was developed in the late 1800s by
Michaelis and extensively studied by Arbuzov.1,12-13 To this day it remains one of the most versatile and widely-used methods to synthesize organophosphorus(V) compounds.13 Typically, a trialkyl phosphite is combined with an alkyl halide and heated to effect a formal oxidation of P(III) to P(V), producing a phosphonate. This
! B! approach is amenable to wide variety of primary alkyl halides, and can be modified to afford phosphinates and phosphine oxides.1
The mechanism of this transformation involves nucleophilic attack of the alkyl halide by the lone pair of a trialkyl phosphite to afford a tetrahedral cationic intermediate. An alkyl group of this intermediate is then liberated to form the alkylphosphonate and a new alkyl halide. The driving force behind this reaction is thought to be the formation of the strong phosphoryl bond.13
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Clay-Kinnear-Perren Condensation
The Clay-Kinnear-Perren reaction, developed in the early 1950s, provides a convenient route to alkylphosphonic dichlorides, which are useful intermediates in the generation of phosphonic acids and related esters.14-16 Combination of phosphorus trichloride, aluminum trichloride, and an alkyl halide is believed to generate the complex [RPCl3][AlCl4], which is decomposed to the phosphonic dichloride upon addition of water.15 The ionic nature of the intermediate has been corroborated by its high melting point (~370 °C) and its high electrical conductivity
! R! in nitromethane solutions.14 The order of reagent addition, temperature, and amount of added water all have a profound effect on the outcome of the reaction.14
When propyl or higher or secondary alkyl halides are used, rearrangements are commonplace (akin to Friedel-Crafts alkylation chemistry), which somewhat detracts from the overall utility of this methodology.16
PCl3 + O H O + - 2 AlCl3 [RPCl3] [AlCl4] P R Cl + Cl
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-./01&! 2363! 6*,7 Hirao Cross Coupling In the early 1980s, Hirao and coworkers discovered the palladium-catalyzed cross-coupling of dialkyl phosphites and aryl or vinyl halides.17 This methodology provides a general way to access aryl– and vinylphosphonates that were traditionally unobtainable using Michaelis-Arbuzov technology.18 An extension of the Hirao cross-coupling has been developed to prepare phosphinates as well.19 Recent advances have focused on the replacement of palladium (typical conditions require ~5 mol% for effective catalysis) with less expensive metals such as copper.20-21 ! W! O (RO)2P Ar 0 LnPd Ar X II LnPd X II LnPd X O P(OR) 2 Ar O Et3NHX (RO)2P H Et N 3 -./01&! 2373! S(&! 1,3,*73"1! 171*&! $5! 3(&! ["/,$! 1/$%%! 1$F'*"-=! '/$1&&.%! 3(/$F=(! 3(&! $+".,3"9&! ,.."3"$-!$5!,-!,/7*!(,*".&>!'($%'("3&!&+1(,-=&!H"3(!3(&!,".!$5!,-!,4"-&!;,%&>!,-.!/&.F13"9&! &*"4"-,3"$-!3$!,55$/.!3(&!,/7*'($%'($-,3&E Kabachnik-Fields Reaction The Kabachnik-Fields reaction affords #-aminophosphonates from the combination of a dialkyl phosphite, a carbonyl, and an amine. This transformation, which was discovered independently by both research groups in the early 1950s, likely proceeds by a mechanism similar to the Mannich reaction, in which the dialkylphosphite reacts with the imine intermediate generated in the reaction ! Z! mixture.22-23 Yields for this transformation can be improved by employing water- stable Lewis acid catalysts.22 H R2 R O N 3 O O R1NH2 + + P O R1 P -H O O R2 R3 R5 O H R4 2 O R 5 R 4 -./01&! 2383! S(&! X,;,1(-"Y )*;*2(>.&'$=?=$8C(!770='&$=,/#(=/(@%A&/='(<8/$4.#=#( ( Wittig and Horner-Wadsworth-Emmons Olefinations One of the first (and probably still the best known) uses of pentavalent organophosphorus reagents in organic synthesis is for the production of olefins.?O In the early 1950s, Wittig and coworkers demonstrated the utility of phosphonium ylides for the construction of alkenes from aldehydes or ketones.27 The reaction proceeds by combination of the ylide and the carbonyl to form a betaine, which forms the olefinic product and a phosphine oxide through the intermediacy of an oxaphosphosphetane (Figure 1.7).24 Modification of reactants and reaction conditions can favor the formation of the Z or E alkene.28 ! \! H R'' H R'' O PH2R3 + O PH2R3 R' H H R' betaines R3P CHR' + R''CHO R P O O PR3 O PR3 3 + + R'' R' R'' R' R''CH CHR' oxaohosphetanes -./01&!2393!S(&!]"33"=!/&,//,-=&4&-3!1$4;"-&%!,-!,*.&(7.&!$/!Y&3$-&!H"3(!,!'($%'($/F%!7*".&! 3$!,55$/.!,*Y&-&%E! ! An extension of this methodology, which was developed by Horner in the late 1950s and later modified by Emmons and Wadsworth, employs stabilized phosphonate anions in combination with aldehydes or ketones to produce C=C bonds.26 These reactions typically proceed under very mild conditions and with a great deal of stereocontrol in favor of the E isomer. The analogous Z alkene can be predominantly obtained through the use of electron withdrawing groups on the phosphonate ester linkages along with the aid of crown ethers, as developed by Still and Gennari.29 O 1. NaH EWG (EtO)2P EWG R 2. O R H -./01&! 23:3! S(&! [$/-&/<],.%H$/3(<^44$-%! /&,13"$-! "%! ,-! &55&13"9&! 3$$*! 5$/! 3(&! %7-3(&%"%! $5! !"#$%!$*&5"-%E!^]C!I!&*&13/$-!H"3(./,H"-=!=/$F'E! ! A@! Seyferth-Gilbert Homologation. The Seyferth-Gilbert homologation provides convenient and reliable access to alkynes from aryl ketones and aldehydes.30 In this reaction, dimethyl diazomethylphosphonate is deprotonated with a base, and the resulting anion subsequently attacks the carbonyl substrate to generate an oxaphosphetane intermediate. After elimination of dimethylphosphate, the resulting vinyl diazo species loses N2 to give a vinyl carbene. After a final 1,2-migration, the alkyne is produced.30 The Ohira-Bestmann modification generates the reactive species in situ through acyl cleavage, and requires very mild conditions to facilitate the overall transformation.31 O O O H P(OMe)2 P(OMe)2 N2 N2 RCHO R RCHO t KO Bu, THF K2CO3, MeOH -78 °C 25 °C (a) (b) -./01&!23;3!P,Q!S(&!D&75&/3( Oxygen/Sulfur Exchange Reactions ! Another useful application of phosphorus(V) compounds involves the employment of thiophosphorus(V) compounds to create carbon-sulfur bonds. Probably the best known compound for such transformations is the Lawesson ! AA! reagent, which is a stable and commercially available compound (Figure 1.11).32 The Lawesson reagent is able to transform ketones, esters, amides, hydrazides, epoxides, and nitriles to the corresponding thioketones, thioesters, thioamides, thiohydrazides, thioepoxides, and thioamides, respectively (Figure 1.10).32-34 As before, it is believed that the driving force for these reactions is the strength the newly-formed P–O bond.32 S S R NH2 R1 R2 O RC N R1 R2 O O R R S 1 2 R2 R O S R R R3 R4 1 1 2 LR R2 R3 R4 R1 O O R3 O N R2 R1 N R4 R1 N R2 R3 S R3 S N R2 R1 N R4 R1 N R2 R3 -./01&!232<3!^+,4'*&%!$5!6MD!;$-.!5$/4"-=!/&,13"$-%!F%"-=!3(&!`,H&%%$-!/&,=&-3!P`JQE! ! A?! OMe S S S ! P P P S S S MeO MeO LR ! -./01&!23223!8'$-!(&,3"-=>!3(&!`,H&%%$-!/&,=&-3!P`JQ!;/&,Y%!.$H-!3$!5$/4!3(&!,13"9&!3("$*,3"-=! %'&1"&%>!,!3("$'($%'($/F%!7*".&EN?! Brønsted-Acid Organocatalysis An emerging application of pentavalent phosphorus compounds in organic synthesis is the use of chiral phosphoric acid diesters, particularly (BINOLato)phosphoric acid derivatives (Figure 1.12), for asymmetric organocatalysis. These compounds contain both Lewis basic and Brønsted acid coordination sites in close proximity to the stereogeneic information provided by the BINOL motif. As such, they have found great utility in asymmetric C–C bond forming transformations that include Mannich,35-36 Friedel Crafts,37-38 Diels Alder,39-40 and a variety of other cascade reactions.41 Lewis basic site R R O O Brønsted acid site P O O H ( -./01&! 23243! S(&! %F11&%%! $5! _:KL`<;,%&.! '($%'($/"1! ,1".! 1,3,*7%3%! ,/&! .F&! "-! ',/3! 3$! 3(&! ;"5F-13"$-,*!,1"."1!,-.!;,%"1!%"3&%!"-!1*$%&!'/$+"4"37!3$!3(&!%3&/&$1$-3/$**&/E! ! AN! ( ( )*D( !770='&$=,/#( ,5( 6./$&?&0./$( 64,#74,%1#( B,-7,1/:#( =/( B,,%:=/&$=,/(B4.-=#$%8( Inorganic metal salts of phosphoric acid have been known and used by mankind for centuries.42 In Nature, a large number of minerals contain metal- phosphate interactions and are the result of the ability of the phosphate anion to 43 bind a vast array of different metal ions. The combination of metals and organophosphorus compounds, however, opens the door to a variety of new materials with the potential for interesting, tunable, and novel properties. The structures of metal organophosphorus(V) compounds are often complicated due to the multiple (and often unpredictable) coordination modes such ligands can adopt (Figure 1.13).44 This variability arises in part because (in all cases besides phosphine oxides) multiple heteroatoms are available for binding, and each can coordinate to one, two, or three metal ions depending on a variety of factors including the identity of the heteroatoms, the nature of the organic group, the properties of the metal ion, and the extent of deprotonation. As such, these ligands exhibit rich and diverse coordination chemistry in both heterogeneous and homogeneous systems.44-45 ! AO! -./01&! 23253! ^+,4'*&%! $5! 3(&! ."55&/&-3! 4&3,*! 1$$/."-,3"$-! 4$.&%! ,! '($%'($-,3&! *"=,-.! 1,-! ,.,'3E!S(&![,//"%!-$3,3"$-!(,%!;&&-!F%&.!5$/!.&%1/"'3"$-EOO>OR! ! )*D*)(E.$.%,A./.,1#(<8#$.-#( The best known examples of heterogeneous metal organophosphorus(V) compounds are the polymeric metal phosphonates and phosphate esters.43,45 Such materials can be obtained from a large variety of different metals and metalloids, including the alkali metals, alkali earths, transition metals, and the main group ! AB! elements.43 The synthesis and applications of polymeric metal phosphonates will be covered in greater detail in Chapter 3. One commercial use of dialkyl phosphates and O,O-dialkyl dithiophosphates is as additives in lubricants. Although these compounds have been employed to enhance performance and lifetimes of oils for some time, the precise reasons behind their effectiveness have only recently been studied.47 The success of these compounds is believed to depend on the ability of phosphates to form polymeric metal phosphate compounds. Decomposition of the metal dithiophophate precursor (possibly catalyzed by the metal surfaces and heat within the engine) forms a protective barrier that imparts excellent wear resistance on the internal machinery.47 -./01&!23263!S(&!%F11&%%!$5!a-bD?UPL^3Q?c?!,-3" ! AR! Flame retardants are compounds that, when added to a material (typically a polymer), prevent combustion and delay the spread of fire after ignition.48 Metal phosphinate compounds such as Al[O2PEt2]3 and Zn[O2PEt2]2 are particularly attractive for this use because they do not share the same bioaccumulative and toxic properties of other flame retardants such as polychlorinated biphenyls and organobromides.48-49 Furthermore, they typically exhibit good thermal stability (up to 320 °C) and a low affinity for moisture, which is advantageous for minimalizing 49 hydrolysis to free phosphoric acid during decomposition. Although the exact mechanism has not been elucidated, it is generally thought that organophosphinates decompose on being heating, and condense to form polyphosphoric acid.42,48,50 The latter compound inhibits further combustion by forming a protective barrier that separates the flammable material from oxygen. The organic portion of the organophosphorus species can be synthetically manipulated in order to tailor these properties to better suit a particular application.48 )*D*2(E,-,A./.,1#(<8#$.-#( Despite being overshadowed by their heterogeneous counterparts, there are numerous examples and applications of molecular compounds that contain organophosphorus(V) ligands. In the simplest case, phosphine oxides can function as unidentate ligands bound to the metal center through the phosphoryl oxygen. ! AW! Such M–ligand interactions are typically quite weak, but are sufficient to stabilize reactive species within certain catalytic cycles.51 For phosphonates and phosphinates, the coordination chemistry becomes increasingly more complex and polymeric materials are often formed.45,52 Molecular metal-phosphonates can be synthesized through careful selection of precursors and reaction conditions, although their structures often cannot be predicted in advance.44 A few examples of such homogeneous M-phosphonate complexes are shown in Figure 1.15. !"#$ !%#$ !&#$ -./01&! 23273! ^+,4'*&%! $5! 4$*&1F*,/! 4&3,*<'($%'($-,3&! 1$4'*&+&%E! P,Q! )! 1$''&/! 171*$'&-37*'($%'($-,3&!3/"4&/E!P;Q!)!T"-1!!&"!<;F37*'($%'($-,3&!3/"4&/!P1Q!)!1,.4"F4!."4&/d!J! ' OO ! I!?>N>R< U/N6R[?>!KMK!I!;"'7E ! " " Pentavalent phosphorus compounds have also been used in mixed phosphine- phosphonate ligands.53 In these molecules, the phosphonate diester is linked to a phosphine through an alkyl bridge. Because the phosphonate group is uncharged, it binds to the metal center in a $1 fashion through the phosphoryl oxygen, and is thought to interconvert between a free and bound state in solution.54 This behavior ! AZ! results in coordination complexes having readily available open coordination sites, which is particularly useful for applications in catalysis.54 An example of a rhodium(I) complex bearing such a ligand is shown in Figure 1.16. OR RO OR P P OR O Ph O P Ph Ph Rh I P Ph Rh I L CO L CO " -./01&! 23283! S(&! '($%'($-,3&%! '$/3"$-! $5! 3(&! ;".&-3,3&! *"=,-.! "%! *,;"*&! ,-.! $'&-%! ,! 1$$/."-,3"$-!%"3&E!S(&%&!1$4'*&+&%!(,9&!;&&-!%($H-!3$!;&!&55&13"9&!1,3,*7%3%!5$/!6L!"-%&/3"$-! /&,13"$-%!H"3(!0&:E76! " Another use of organophosphorus(V) ligands is their employment as chelating and extraction agents.55-56 Deprotonated phosphonates and phosphinates bind strongly to “hard” metal ions, and the aqueous or organic solubility of the resulting coordination complex can be very different for different metal ions. The use of dithiophosphinates for Ln/An separations will be discussed in greater detail in Chapter 4. One clinically employed compound, which contains a tetraphosphonate chelated to the radioactive samarium-153 radionuclide, goes by the trade name Quadramet® and is used in the relief of pain from metastatic bone cancer (Figure 1.17).57-58 This isotope, with a short lived half life of ~2 days, is effective in inducing cytotoxicity in malignant cells through potent $-decay processes.59 It is believed that ! A\! the ligand environment is a key factor in targeting the skeletal system, as well as imparting necessary solubility on the complex.58" 5- N N O P 153 PO + 2 Sm 2 5Na O O O O O2P PO2 -./01&! 23293! S(&! .",4"-$3&3/,'($%'($-,3&! *"=,-.! "%! ,-! &55&13"9&! 1(&*,-3! 5$/! 3(&! .&*"9&/7! $5! /,."$-F1*".&%!3$!;$-&%E!S(&!ABND4!1$4'*&+!e,F./$4&3®!"%!,!-$3,;*&!&+,4'*&EBW! )*F(>.5.%./'.#( 1. Quin, L. D. A Guide to Organophosphorus Chemistry. John Wiley & Sons: New York, NY, 2000. 2. Parkin, G. Valence, Oxidation Number, and Formal Charge: Three Related but Fundamentally Different Concepts. J. Chem. Ed. 2006, 83 (5), 791-799. 3. Gilheany, D. G. In The Chemistry of Organophosphorus Compounds, Hartley, F. R., Ed. John Wiley & Sons: New York, NY, 1990; Vol. 2. 4. Kwart, H.; King, K. d-Orbitals in the Chemistry of Silicon, Phosphorus and Sulfur. Springer: Berlin, 1977. 5. Gilheany, D. G. No d Orbitals but Walsh Diagrams and Maybe Banana Bonds: Chemical Bonding in Phosphines, Phosphine Oxides, and Phosphonium Ylides. Chem. Rev. 1994, 94, 1339-1374. ! ?@! 6. Stefan, T.; Janoschek, R. How Relevant are S=O and P=O Double Bonds for the Description of the Acid Molecules H2SO3, H2SO4, and H3PO4, Respectively? J. Mol. Model. 2000, 6, 282-288. 7. Savignac, P.; Iorga, B. Modern Phosphonate Chemistry. CRC Press: Boca Raton, FL, 2003. 8. Barder, T. E.; Buchwald, S. L. Rationale Behind the Resistance of Dialkylbiaryl Phosphines toward Oxidation by Molecular Oxygen. J. Am. Chem. Soc. 2007, 129, 5096-5101. 9. Hilliard, C. R.; Bhuvanesh, N.; Gladysz, J. A.; Blumel, J. Synthesis, purification, and characterization of phosphine oxides and their hydrogen peroxide adducts. Dalton Trans. 2012, 41 (6), 1742-54. 10. Demarcq, M. C. Reactivity of X3P Compounds with Elemental Sulfur, Carbon Disulfide or Both, to Yield X3PS, X3P•CS2 or X3P•Sn•CS2 Adducts. Phosphorus, Sulfur Silicon Relat. Elem. 1998, 134 (1), 307-320. 11. Liu, H.; Owen, J. S.; Alivisatos, A. P. Mechanistic Study of Precursor Evolution in Colloidal Group II–VI Semiconductor Nanocrystal Synthesis. J. Am. Chem. Soc. 2007, 129, 305-312. 12. Michaelis, A.; Kaehne, R. Ueber das Verhalten der Jodalkyle gegen die sogen. Phosphorigsäureester oder O-Phosphine. Chem. Ber. 1898, 31, 1048-1055. 13. Bhattacharya, A. K.; Thyagarajan, G. The Michaelis-Arbuzov Rearrangement. Chem. Rev. 1981, 81, 415-430. ! ?A! 14. Clay, J. P. A New Method for the Preparation of Alkane Phosphonyl Dichlorides. J. Org. Chem. 1951, 16, 892-894. 15. Wang, Z. Clay-Kinnear-Perren Condensation. In Comprehensive Organic Name Reactions and Reagents, John Wiley & Sons: 2010; pp 669-672. 16. Kinnear, A. M.; Perren, E. A. Formation of Organo-phosphorus Compounds by the Reaction of Alkyl Chlorides with Phosphorus Trichloride in the Presence of Aluminium Chloride. J. Chem. Soc. 1952, 3437-3445. 17. Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Stereoselective Synthesis of Vinylphosphonate. Tetrahedron Lett. 1980, (21), 3595-3598. 18. Belbabassi, Y.; Alzghari, S.; Montchamp, J.-L. Revisiting the Hirao cross- coupling: improved synthesis of aryl and heteroaryl phosphonates. J. Organomet. Chem. 2008, 693, 3171-3178. 19. Bravo-Altamirano, K.; Huang, Z.; Montchamp, J.-L. Palladium-catalyzed phosphorus–carbon bond formation: cross-coupling reactions of alkyl phosphinates with aryl, heteroaryl, alkenyl, benzylic, and allylic halides and triflates. Tetrahedron 2005, 61 (26), 6315-6329. 20. Gelman, D.; Jiang, L.; Buchwald, S. L. Copper-Catalyzed C–P Bond Construction via Direct Coupling of Secondary Phosphines and Phosphites with Aryl and Vinyl Halides. Org. Lett. 2003, 5 (13), 2315-2318. 21. Huang, C.; Tang, X.; Fu, H.; Jiang, Y.; Zhao, Y. Proline/Pipecolinic Acid- Promoted Copper-Catalyzed P-Arylation. J. Org. Chem. 2006, 71, 5020-5022. ! ??! 22. Zefirov, N. S.; Matveeva, E. D. Catalytic Kabachnik-Fields reaction: new horizons for old reaction. ARKIVOC 2008, (1), 1-17. 23. Fields, E. K. The Synthesis of Esters of Substituted Amino Phosphonic Acids. J. Am. Chem. Soc. 1952, 74 (6), 1528-1531. 24. Maryanoff, B. E.; Reitzm, A. B. The Wittig Olefination Reaction and Modifications Involving Phosphoryl-Stabilized Carbanions. Stereochemistry, Mechanism, and Selected Synthetic Aspects. Chem. Rev. 1989, 89, 863-927. 25. Wadsworth, W. S.; Emmons, W. D. The Utility of Phosphonate Carbanions in Olefin Synthesis. J. Am. Chem. Soc. 1961, 83 (7), 1733-1738. 26. Bisceglia, J. A.; Orelli, L. R. Recent Applications of the Horner-Wadsworth- Emmons Reaction to the Synthesis of Natural Products. Curr. Org. Chem. 2012, 16, 2206-2230. 27. Wittig, G.; Schollkopf, U. Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien (I. Mitteil.). Chem. Ber. 1954, 87 (9), 1318-1330. 28. Schlosser, M. The Stereochemistry of the Wittig Reaction. Top. Stereochem. 1970, 5, 1-30. 29. Still, W. C.; Gennari, C. Direct synthesis of Z-unsaturated esters. A useful modification of the horner-emmons olefination. Tetrahedron Lett. 1983, 24 (41), 4405-4408. 30. Gilbert, J. C.; Weerasooriya, U. Diazoethenes: Their Attempted Synthesis from Aldehydes and Aromatic Ketones by Way of the Horner-Emmons ! ?N! Modification of the Wittig Reaction. A Facile Synthesis of Alkynes. J. Org. Chem. 1982, 47, 1837-1845. 31. Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes. Synlett. 1996, 521- 522. 32. Ozturk, T.; Ertas, E.; Mert, O. Use of Lawesson's Reagent in Organic Synthesis. Chem. Rev. 2007, 107, 5210-5278. 33. Jones, B. A.; Bradshaw, J. S. Synthesis and reduction of thiocarboxylic O- esters. Chem. Rev. 1984, 84 (1), 17-39. 34. Ozturk, T.; Ertas, E.; Mert, O. A Berzelius Reagent, Phosphorus Decasulfide (P4S10), in Organic Syntheses. Chem. Rev. 2010, 110, 3419-3478. 35. Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Bronsted acid. Angew. Chem. Int. Ed. Engl. 2004, 43 (12), 1566-1568. 36. Uraguchi, D.; Terada, M. Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation. J. Am. Chem. Soc. 2004, 126, 5356- 5357. 37. Uraguchi, D.; Sorimachi, K.; Terada, M. Organocatalytic Asymmetric Aza- Friedel-Crafts Alkylation of Furan. J. Am. Chem. Soc. 2004, 126, 11804- 11805. ! ?O! 38. Kang, Q.; Zhao, Z.-A.; You, S.-L. Highly Enantioselective Friedel-Crafts Reaction of Indoles with Imines by a Chiral Phosphoric Acid. J. Am. Chem. Soc. 2007, 129, 1484-1485. 39. Akiyama, T.; Morita, H.; Fuchibe, K. Chiral Brønsted Acid-Catalyzed Inverse Electron-Demand Aza Diels-Alder Reaction. J. Am. Chem. Soc. 2006, 128, 13070-13071. 40. Liu, H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Enantioselective Direct Aza Hetero-Diels%Alder Reaction Catalyzed by Chiral Brønsted Acids. Org. Lett. 2006, 8 (26), 6023-6026. 41. Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. Chiral BINOL-derived phosphoric acids: privileged Brønsted acid organocatalysts for C–C bond formation reactions. Org. Biomol. Chem. 2010, 8, 5262-5276. 42. Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in Everyday Living. American Chemical Society: Washington, D.C., 1987. 43. Murugavel, R.; Choudury, A.; Walawalker, M. G.; Pothiraja, R.; Rao, C. N. R. Metal Complexes of Organophosphate Esters and Open-Framework Metal Phosphates: Synthesis, Structure, Transformations, and Applications. Chem. Rev. 2008, 108, 3649-3655. 44. Chandrasekhar, V.; Senapati, T.; Dey, A.; Hossain, S. Molecular transition- metal phosphonates. Dalton Trans. 2011, 40, 5394-5418. 45. Shimizu, G. K.; Vaidhyanathan, R.; Taylor, J. M. Phosphonate and sulfonate metal organic frameworks. Chem. Soc. Rev. 2009, 38 (5), 1430-1449. ! ?B! 46. Coxall, R. A.; Harris, S. G.; Henderson, D. K.; Parsons, S.; Tasker, P. A.; Winpenny, E. P. Inter-ligand reactions: in situ formation of new polydentate ligands. Dalton Trans. 2000, 2349-2356. 47. Johnson, D. W.; Hills, J. E. Phosphate Esters, Thiophosphate Esters, and Metal Thiophosphates as Lubricant Additives. Lubricants 2013, 1, 132-148. 48. van der Veen, I.; de Boer, J. Phosphorus flame retardants: Properties, production, environmental occurance, toxicity, and analysis. Chemosphere 2012, 88, 1119-1153. 49. Rakotomalala, M.; Wagner, S.; Doring, M. Recent Developments in Halogen Free Flame Retardants for Epoxy Resins for Electrical and Electronic Applications. Materials 2010, 3, 4300-4327. 50. Schmitt, E. Phosphorus-based flame retardants for thermoplastics. Plast. Addit. Comp. 2007, 9 (3), 26-30. 51. Denmark, S. E.; Smith, R. C.; Tymonko, S. A. Phosphine oxides as stabilizing ligands for the palladium-catalyzed cross-coupling of potassium aryldimethylsilanolates. Tetrahedron 2007, 63, 5730-5738. 52. Clearfield, A. Metal Phosphonate Chemistry. Prog. Inorg. Chem. 1998, 47, 371-510. 53. Grushin, V. V. Catalysis for Catalysis: Synthesis of Mixed Phosphine- Phosphine Oxide Ligands via Highly Selective, Pd-Catalyzed Monooxidation of Bidentate Phosphines. J. Am. Chem. Soc. 1999, 121, 5831-5832. ! ?R! 54. Bischoff, S.; Weigt, A.; Miessner, H.; Lucke, B. Hemilabile Phosphonate– Phosphine–Rh Catalysts for Homogeneous and Heterogeneous Carbonylation. Energy Fuels 1996, 10, 520-523. 55. Preston, J. S. Solvent Extraction of Cobalt and Nickel by Organophosphorus Acids: Comparison of Phosphoric, Phosphonic and Phosphinic Acid Systems. Hydrometallurgy 1982, 9 (2), 115-133. 56. Belova, V. V.; Voshkin, A. A.; Kholkin, A. I.; Payrtman, A. K. Solvent extraction of some lanthanides from chloride and nitrate solutions by binary extractants. Hydrometallurgy 2009, 9 (3). 57. Quadramet. http://www.rxlist.com/quadramet-drug.htm (accessed 22 Mar 2015). 58. Sartor, O. Overview of Samarium 153 Lexidronam in the Treatment of Painful Metastatic Bone Disease. Rev. Urol. 2004, 6, 3-10. 59. Finlay, I. G.; Mason, M. D.; Shelley, M. Radioisotopes for the plliation of metastatic bone cancer: a systematic review. Lancet. Oncol. 2005, 6, 392- 400. ! ! ?W! /012,(3.?. @:$,0(-8-.%9.A$1$,8%2;3(.B0%-20%$8".!"8)-.&8,0. CDE6F.1-.1./0831'.!;G8'813:. . 2*)(9&'GA%,1/:(( Chiral phosphonic acids and their derivatives are important compounds in medicinal and agricultural chemistry.1-4 The biological significance of phosphonic acids garnered the attention of the scientific community in 1959 with the unexpected discovery by Horiguchi and Kandatsu of 2-aminoethylphosphonic acid in the lipids of mixed protozoa found in sheep rumen.5 Before this time, the only organophosphorus compounds thought to exist in Nature were derivatives of phosphoric acid (compounds with P–OR and P–NR2 bonds). Soon thereafter, the isolation of ((2R,3S)-3-methyloxiran-2-yl)phosphonic acid (fosfomycin) from the bacterium Streptomyces fradiae, and the finding that it is an effective (and now clinically employed) antibiotic, further instilled vigor into the rapidly-growing subfield of synthetic organophosphorus chemistry.6 The discovery of fosfomycin established the phosphonate functional group as an unconventional yet promising tool for the development of novel therapeutics.7-10 ! ?Z! ! ! Ph O O O KO HO HO P OPh P HO P Me NH KO HO HO P 2 O F HO SO3K O CO2H (a) (d) (c) (b) ! -./01&! 4323! ^+,4'*&%! $5! 1("/,*! '($%'($-"1! ,1".%! $5! ;"$*$="1,*! /&*&9,-1&E! P,Q! G$%5$4171"->! ,! ;/$,.<%'&13/F4! ,-3";"$3"1EW! P;Q! )-! !<5*F$/$'($%'($-"1! ,1".! 3(,3! &+(";"3%! '/$3&"-! 37/$%"-&! '($%'(,3,%&! PUSUQ! "-(";"3"$-EAA! P1Q! )! 171*$'/$'7*'($%'($-"1! ,1".! 4C*FJ! ,=$-"%3EA?! P.Q! )! '($%'($-,3$%F*5$-,3&!%fF,*&-&!%7-3(,%&!"-(";"3$/EAN! ! ! As might be expected, the biological efficacy of chiral phosphonic acids often relies on their absolute configuration (Figure 2.1). Methodology to produce enantiomerically enriched phosphonic acids in a general and predictable manner thus remains an active area of research to this day.7,11 Several methods to prepare chiral phosphonic acids have been described, including the nucleophilic phosphonylation of aldehydes,14 the hydrophosphonylation of cyclic imines,15-16 the hydrogenation of !,"-unsaturated phosphonates,17-19 the enantioselective reduction of !-ketophosphonates,20 and the alkylation of phosphonate anions.21-28 Of these methodologies, the most versatile involve the use of bidentate chiral auxiliaries directly bound to the phosphorus atom (Figure 2.2). These auxiliaries, such as deprotonated N-alkylamino alcohols21,28-30 or N,N’-dialkyldiamines,25,27,31-33 are generally applicable to a wide variety of transformations and afford highly enantioenriched phosphonic acids.4 The reaction chemistry of lithium-stabilized ! ?\! carbanionic phosphonates bearing these auxiliaries has been extensively studied by Denmark and coworkers.23,29-30,34-36 H R2 OH R1 N R1 NH R3 R1 N OH H NHR1 Hanessian (1984) Denmark (1990) Sisti (1999) Ph Ph OH OH NHR1 NHR1 NHR1 NH Ph Denmark (2000) Moody (2001) Pedrosa (2006) -./01&!4343!6("/,*!,F+"*",/"&%!F%&.!"-!3(&!%7-3(&%"%!$5!$'3"1,**7!'F/&!'($%'($-"1!,1".%E?A?Z>NW ! ! Although these previously reported methods produce chiral phosphonic acids in high yields and stereoselectivities, many of the auxiliaries are expensive, moisture sensitive, and/or require several steps to prepare. Similarly, although the auxiliaries based on natural products such as ephedrine, menthol, and camphor are attractive due to the availability of these compounds in enantiopure form, access to the opposite enantiomer is often limited and requires nontrivial synthesis, which limits their employment as general reagents for reactions of this kind. Another drawback of many of these auxiliaries is a lack of C2 symmetry, which often results in the formation multiple diastereomers upon complexation with a given phosphonic ! N@! acid (Figure 2.3). This feature detracts from the utility of the stereocontroller, because the diastereomers must be separated before carrying out the desired asymmetric transformation. Ph OH Ph Ph Cl P(O)Bn O O O 2 Ph P (a) Me H N P + Me H N Me NH Et N Ph 3 Me O Me Me H H Me Me NHMe H H Cl2P(O)Bn N N O (b) N P Ph N P Et3N Ph NHMe Me O Me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`!&+(";"3!,+",*!1("/,*"37E! ! ! NA! ! 1,1#-Binaphthalene-2,2#-diol (BINOL) is one of the best-known and widely- utilized molecules that exhibits axial chirality (Figure 2.4).41 It was first synthesized as a racemate by von Richter in 1873 through the oxidative homocoupling of 2-naphthol in the presence of ferric chloride.42 Today, BINOL is a ubiquitous tool in asymmetric synthesis. It can be easily synthesized (Figure 2.5)43-44 and resolved45-47 in large quantities (>300 g scale), or can be purchased relatively inexpensively and in resolved form from commercial sources. The 3,3#- and 6,6#-substituted analogues of BINOL are also readily obtained (both commercially or by synthetic manipulation),48-52 thus providing additional opportunities to enhance stereocontrol whenever the unsubstituted parent BINOL yields insufficient selectivities. N Cl 0.5 OH FeCl OH N OH 2 3 (rac) - OH THF OH MeCN OH >99% e.e. N OH HCl (aq) OH OH EtOAc OH Cl H O N >99% e.e. ! -./01&!4373!D7-3(&%"%!$5!/,1&4"1!_:KL`!"%!,11$4'*"%(&.!9",!3(&!$+".,3"9&!($4$1$F'*"-=!$5!?< -,'(3($*EOA>OO>BN! ["=(*7! &55"1"&-3! 1("/,*! /&%$*F3"$-! 1,-! ;&! ,1("&9&.! H"3(! 3(&! ,".! $5! 6"-1($-,! ,*Y,*$".%EOB! ! N?! ( BINOL belongs to a class of compounds that are frequently referred to as “privileged” ligands– a term coined by Jacobsen to describe ligands and catalysts that show exceptional enantioselectivities over a wide range of different reactions.54-55 The barrier to racemization is high (24-26 kcal/mol),41,56-57 due to steric clashing of the hydroxyl groups with the hydrogen atoms at the 8 and 8# positions. Although rotation about the C(1)–C(1#) bond is restricted, there remains enough mobility to enable BINOL to bind in a bidentate fashion to an assortment of atoms of different sizes. In doing so, the remainder of the molecule (defined by an array of planar sp2 carbons) remains conformationally rigid. This rigidity leads to stereochemical predictability in a large variety of synthetic applications. R Li O O O O O O Li Li P Al OH O La O O O O O O R Li (a) (b) (c) -./01&!4383!!^+,4'*&%!$5!$/=,-"1!,-.!$/=,-$4&3,**"1!,%744&3/"1!1,3,*7%3%!3(,3!"-1$/'$/,3&!3(&! _:KL`! 4$3"5E! P,Q! D(";,%,Y"! J,/&<^,/3(<0&3,*<_:KL`! PJ^0_Q! 1,3,*7%3EBZ ! Additionally, the inherent C2 symmetry of ligated BINOL simplifies any given asymmetric transformation by halving the total number of possible ! NN! diastereomeric species present.64 The applications of BINOL as a stereocontroller for highly enantioselective asymmetric reactions, particularly those of a catalytic nature, are legion, and include oxidations, reductions, and a myriad of C–C bond forming transformations (Figure 2.6).41,55,59,61-63,65 2*;(!#8--.$%='(64,#74,/&$.(!0G80&$=,/(J#=/A(9H+@I( In pursuing our goal of employing metal phosphonate materials as heterogeneous asymmetric catalysts (see Chapter 3), we needed access to chiral phosphonic acids.66 We investigated previous alkylation methodologies based on diamine and amino alcohol auxiliaries,4,22,66 but became intrigued by the potential of BINOL as a chiral auxiliary for this transformation, due to its low cost and exceptional utility as a stereocontroller. Furthermore, !,&-unsaturated carbonyls have been known to add stereoselectively to the terminal allylic position of Li[(BINOLato)PO(CH-CH=CH2)] to form Michael addition products in a highly enantioselective manner.67 Hence, we envisioned an extension of this methodology to the asymmetric !-alkylation of Li[(BINOLato)PO(CHPh)], (Li+2.1-), as shown in Figure 2.7. O O 1. n-BuLi O O O O P Ph O P Ph = or O 2. RX O * O O O 2.1 R " -./01&! 4393!!U/$'$%&.! ,%744&3/"1! %7-3(&%"%! $5! h<,*Y7*;&-T7*'($%'($-,3&%! F%"-=! _:KL`! ,%! ,! 1("/,*!,F+"*",/7E! ! NO! 2*;*)(!$$&'4-./$(,5($4.(9H+@I(!1K=0=&%8(( ! Installation of the BINOL auxiliary proceeds readily and without complication, as shown by the previous work of Ellenwood.66 Benzylphosphonic dichloride, which can be prepared from benzylphosphonic acid and oxalyl chloride in DCM, reacts with (R)-BINOL in the presence of Et3N as a proton scavenger to afford chiral (R)-(BINOLato) benzylphosphonate 2.1 in 83% overall yield (over 2 steps) after recrystallization from dry MeCN (Figure 2.8). Compound 2.1 exhibits exceptional hydrolytic stability, and can be stored in air for months without notable degradation of purity. 1. (COCl)2, cat. DMF, DCM O O O 2. (R)-BINOL, TEA, toluene P HO P O HO 2.1 ! -./01&!43:3!!D7-3(&%"%!$5!3(&!1("/,*!P,Q 2*;*2(!#8--.$%='(!0G80&$=,/( With the successful installment of the chiral auxiliary, we envisioned that stereoselective alkylation may be achieved through deprotonation at the ! position followed by quenching with an alkyl halide. Thus, as Ellenwood has previously shown, addition of nBuLi to a THF solution of 2.1 at -78°C is accompanied by an ! NB! instantaneous color change to bright orange as the lithium-stabilized phosphonate anion is generated.66 Subsequent alkylation is complete within a few hours as evidenced by TLC monitoring, with addition of methyl being fastest and ethyl slowest of the electrophiles we investigated (Table 2.1), as expected in accordance with steric parameters involving an electrophilic SN2 attack. During workup, we found it important to first quench the reaction with aqueous HCl. Yields were somewhat reduced when neutral water was used as the initial quenching agent, presumably due to the formation of LiOH and the resulting nucleophilic attack at the phosphorus atom resulting in a unidentate BINOLato group. Diastereomeric ratios of ca. 10:1 were typically observed, as judged by integration of the 31P NMR spectrum of the crude reaction mixtures; in all cases studied, the 31P NMR peak due to the major diastereomer was downfield of that due to the minor diastereomer. The yields and diastereoselectivities vary somewhat with the alkylating agent employed. Subtle differences in the physical properties of the two generated diastereomers could be exploited to achieve effective separation by means of flash column chromatography on silica gel. Hence, this methodology provides access to both the (R,R) and (R,S) diastereomers in enantiomerically pure form. Overall, the yields and diastereoselectivities of this reaction were generally quite high, and competitive with those obtained using previously-reported diamine or amino alcohol chiral auxiliaries.4,22 ! NR! ^-3/7! Ji! U/$.F13,! .E/E! NAU!K0J!%("53;! j"&*.!PkQ1! ! A! 0&:! P,>,Q<434! ZBlAB! OAE?!PO@EZQ! W\! ?! ! _/6[?6[I6[?! P,>,Q<435! \?lZ! N\EO!PNZE\Q! ZO! O! !! _-_/! P,>,Q<436! \NlW! N\EN!PN\EAQ! ZO! B! !! ^3:! P,>,Q<437! ZZlA?! O@ER!PN\E\Q! RZ! m < , ; "#$%&!4323!!DF44,/7!$5!,*Y7*,3"$-!$5!`" bP,Q<2 cE! 0,n$/!.",%3&/$4&/E! 6/F.&!4"+3F/&!"-!626*N>! 0"-$/!.",%3&/&$4&/!"-!',/&-3(&%"%E!1:%$*,3&.!7"&*.!$5!4,n$/!.",%3&/&$4&/>!,9&/,=&!$5!.F'*"1,3&! /F-%E! ! ! -./01&!43;3!NAU!K0J!$5!3(&!1/F.&!.",%3&/&$4&/"1!4"+3F/&!,53&/!,*Y7*,3"$-!$5!432!H"3(!0&:E!_$3(! 3(&!P,>,Q!,-.!P,>-Q!.",%3&/&$4&/%!,/&!$;%&/9&.E!! ! NW! ! O3 C17 C4’ C3’ O1 C6’ C16 C5’ C18 C2’ O2 P1 C1’ C15 C7’ C11 C10’ C12 C8’ C9’ C2 C1 C3 C13 C14 C10 C4 C9 C5 C8 C6 C7 ! -./01&! 432<3! S(&/4,*! &**"'%$".! '*$3! $5! P,>,Q<434! /&9&,*"-=! 3(&! P,>,Q! ,;%$*F3&! 1$-5"=F/,3"$-E! S(&/4,*!&**"'%$".%!,/&!./,H-!,3!NBk!'/$;,;"*"37ERR! ! ! The absolute configuration of (R,R)-2.2, which is the major diastereomer obtained by alkylation of (R)-2.1 with methyl iodide, was determined by X-ray crystallography (Figure 2.10).66 The configuration of the alkyl portion is (R) and the (R)-BINOL retains the stereochemistry originally present in the starting material. From the fact that the optical rotations of all the alkylated products have the same sign, we infer that the absolute configurations of the other products are also (R). ! NZ! The configuration of the isolated product provides some insight into the structure of Li+2.1- in solution and the origin of the enantioselectivity of the alkylation step. Previous studies of the structure of lithium-stabilized benzylidenephosphonate anions with diamine and amino alcohol auxiliaries have shown that the phenyl group is roughly antiperiplanar to the phosphoryl oxygen.23,39-40 If we assume that a similar conformation is adopted by Li+2.1-, asymmetric induction could arise from unfavorable interactions between the hydrogen atoms in the 3 and 3# positions of the BINOL auxiliary and the electrophile. However, approach of the electrophile from the less hindered side in this scenario would afford (R,)-(BINOLato) (S)-P(O)CH(R)Ph, which is the experimentally observed minor diastereomer. This mechanism therefore does not account for the observed asymmetric induction. An alternative possibility is that the steric constraints imposed by the + - BINOL auxiliary favor a rotamer of Li 2.1 in which the phenyl group is closer to synperiplanar with respect to the phosphoryl oxygen. In this configuration, approach of the electrophile from the least hindered side affords the experimentally observed (R)-(BINOLato) (R)-P(O)CH(R)Ph diastereomer. A similar mechanism has previously been proposed to account for the observed stereochemistries of an intramolecular Wittig-type reaction of 1,3-dicarbonyls via a lithiated (BINOLato) benzylidinephosphonate intermediate.68 ! N\! 2*;*;*(>.-,?&0(,5($4.(9H+@I(!1K=0=&%8! Although we had determined that BINOL is an effective chiral auxiliary for the asymmetric alkylation of benzylphosphonic acid, removal of the auxiliary from the chiral product was not as straightforward as originally anticipated. Basic hydrolysis tends to afford only monodeprotected products (i.e., with a unidentate BINOLato group), possibly because the negative charge on the deprotonated phosphonate monoester intermediate disfavors further attack by base.69-71 We have found that the desired transformation can ultimately be induced in this manner, but only when harsh reaction conditions are employed (high heat in a sealed vessel under autogenous pressure). Unfortunately, additional experiments carried out in deuterium oxide revealed the complete incorporation of deuterium at the ! position of the substrate– an indication that such conditions will likely result in racemization of the newly-formed stereocenter when applied to the chiral !-alkylated analogues due to reversible deprotonation at this position. 1. 6M NaOH, reflux O O H2O, dioxane O P HO P (major product) + O 2. H3O O OH ! O ONa O ONa O O P O P O P O O NaO OH H OH doubly deprotonated product ! -./01&! 43223! S7'"1,*>! ;,%"1! 4&3($.$*$=7! 5$/! 3(&! (7./$*7%"%! $5! '($%'($-"1! ."&%3&/%! 5,"*%! 3$! &55&13"9&*7!/&4$9&!3(&!_:KL`!%3&/&$1$-3/$**&/E! ! O@! ! ! ! O O 1. 6M aq. NaOH, 150 °C (only product) O P HO P O 2. aq. HCl HO O O 6M NaOH, 150 °C (only product) O P DO P O D2O DO D D ! -./01&! 43243! _,%"1! [7./$*7%"%! $5! P_:KL`,3$Q! '($%'($-,3&! &%3&/%! 1,-! ;&! ,1("&9&.>! ,*;&"3! $-*7! H(&-!(,/%(!/&,13"$-!1$-."3"$-%!,/&!&4'*$7&.E!2$"-=!%$!"-.F1&%!,!/&9&/%";*&!.&'/$3$-,3"$-!,3! 3(&!h!'$%"3"$-E! ! ! ! ! Typical methods for the acidic hydrolysis of dialkyl phosphonates, either by addition of protic acids72-73 or Lewis acids such as trimethylsilyl bromide74 or boron tribromide75 are also ineffective for BINOL cleavage. Acid-catalyzed hydrolysis of typical dialkyl phosphonates is thought to occur by nucleophilic substitution at the 70,72,76 carbon atom of alkoxide, and the analogous SNAr attack at the 1 and 1# ipso positions of an unactivated aryloxide such as BINOL is unfavorable. Unsurprisingly, our attempts to liberate the BINOL auxiliary by such acidic hydrolysis pathways returned only unreacted starting materials. ! ! OA! Me Me Si Br Me Br TMS OTMS O O MeO MeO P R MeO P R P R + MeBr O O Me Me O ! ! Me Me Si Br Me Br TMS O O X PhO P R PhO P R O O ! -./01&! 43253! )1"."1! 4&3($.$*$=7! 5$/! '($%'($-,3&! &%3&/! (7./$*7%"%! "%! "-&55&13"9&! 5$/! _:KL`! 1*&,9,=&E! ! ! We then explored the possibility of a two-step, transesterification/ hydrolysis pathway to remove the chiral auxiliary. Transesterification of (R)-2.1 with sodium methoxide in methanol rapidly affords the BINOL-free dimethyl phosphonate ester. However, analogous experiments carried out with sodium methoxide in the deuterated solvent CH3OD show that there is significant H/D exchange at the benzylic carbon, which suggests that this position is reversibly deprotonated under these reaction conditions. This finding means that, as before, racemization could occur if this approach is applied to the chiral analogues. ! O?! O (MeO)2P !" Ha Ha O #" (MeO)2P Hb D -./01&! 43263! A[! K0J! $5! 3(&! 3/,-%&%3&/"5"1,3"$-! /&,13"$-! $5! 432! F%"-=! K,L0&! /&9&,*%! %"=-"5"1,-3! P.#+* B@kQ!.&F3&/"F4!"-1$/'$/,3"$-!,3!3(&!;&-T7*"1!1,/;$-E! ! Successful deprotection of the (BINOLato) phosphonate ester without # deprotonation was eventually realized by treatment with cesium fluoride in refluxing methanol.69,71,77 This procedure, which affords the dimethyl ester in high yield, is gentle enough to avoid deprotonation at the ! position,78 as confirmed by experiments carried out in CH3OD. For example, CsF-promoted methanolysis of the 1,2-diphenylethylphosphonate compound (R,R)-2.4, followed by basic workup, affords dimethyl (R)-1,2-diphenylethylphosphonate ((R)-2.6) without erosion of enantiomeric purity. ! ON! O MeO O O P P CsF, ! OH MeO + O MeOH OH -./01&! 43273! S(&! 6%G<'/$4$3&.! 4&3(,-$*7%"%! $5! 3(&! P_:KL`,3$Q! '($%'($-,3&! &%3&/!! P,>,Q<436!/&,."*7!,55$/.%!3(&!.&'/$3&13&.!."4&3(7*!'($%'($-,3&!P,Q<438E! ! ! ! The CsF-promoted methodology is known to effect transesterification of phenyl–, 2,2,2-trichloroethyl–, and 2-cyanoethylphosphonate esters but not alkyl esters, and thus it is particularly suited for BINOL cleavage.77,79 In particular, after methanolysis of the first P–O bond, reformation of the original (BINOLato) phosphonate ester from the monodeprotected intermediate by reverse transesterification (which presumably is favored by the chelate effect) is effectively negated and the dimethyl phosphonate ester is cleanly produced (Figures 2.15 and 2.16). In addition, this methodology facilitates recovery of the cleaved (R)-BINOL auxiliary, which is accomplished in 86% yield upon re-acidification of the basic extracts followed by vacuum filtration. Acidic hydrolysis of the dimethyl 1,2- diphenylethylphosphonate product affords the desired enantiomerically pure phosphonic acid (R)-2.7 in 87% overall yield from (R,R)-2.4. ! OO! !" O (MeO)2P Ha Ha ! A -./01&!43283!S(&! [!K0J!%'&13/F4!$5!3(&!6%G<'/$4$3&.!4&3(,-$*7%"%!/&,13"$-!$5!432!"-!6[NL2! %($H%!-$!.&F3&/"F4!"-1$/'$/,3"$-!,3!3(&!;&-T7*"1!1,/;$-E!! ! The mechanism of the transesterification step likely proceeds through a benzophosphonofluoridate intermediate, which undergoes methanolysis with the solvent. This mechanism has been previously invoked by Ogilvie and coworkers for the CsF-mediated transesterification of bis(2,2,2-trichloroethyl) alkyl phosphate esters. By employing the sterically hindered tBuOH as the transesterification partner, they were able to detect the fluoridate intermediate by gas chromatographic monitoring of the reaction mixture.79 In addition, we have observed that attempts to promote the transesterification of (BINOLato) benzylphosphonate with an excess of CsNO3 in refluxing methanol affords only unreacted starting materials, which supports the hypothesis that the fluoride anion ! OB! is integral for the transesterification. In our system, the proposed benzophosphono- fluoridate intermediate is apparently short lived (it never appears in the 31P NMR spectra taken as the reaction proceeds). Nevertheless, we took care to avoid contact with the reaction solutions owing to the structural similarities of this intermediate with the “G-series” class of chemical nerve agents– compounds known to present extreme hazards to human health.80 ! -./01&3! 43293! 6%G<'/$4$3&.! 4&3(,-$*7%"%! $5! 3(&! P_:KL`,3$Q'($%'($-,3&! P,>,Q<436! 3$! 3(&! ."4&3(7*! '($%'($-,3&! &%3&/! P,Q<438! '/$1&&.%! 1*&,-*7! 3(/$F=(! H(,3! "%! 3($F=(3! 3$! ;&! 3(&! 4$-$.&'/$3&13&.!"-3&/4&.",3&!"-!/&5*F+"-=!4&3(,-$*>!,%!%($H-!;7!NAU!K0J!4$-"3$/"-=E!)3!-$! '$"-3! H,%! &9".&-1&! $5! 3(&! '/$'$%&.! "-3&/4&.",3&! ;&-T7*'($%'($-$5*F$/".,3&%! $;%&/9&.E!! P,Q!;&5$/&!6%G!,.."3"$-!P;Q!N(!P1Q!R(!P.Q!Z(E! ! ! OR! O i Me Sarin (GB): R = Pr R P Soman (GF): R = 3,3-dimethylbutan-2-yl O Cyclosarin (GD): R = Cy F ! -./01&!432:3!D3/F13F/&!3(&!,*Y7*!4&3(7*'($%'($-$5*F$/".,3&!oC<%&/"&%p!-&/9&!,=&-3%E! ! 2*D(B,/'01#=,/#(&/:(L1$1%.(M,%G( We have demonstrated that 1,1#-binaphthalene-2,2#-diol (BINOL) is an effective chiral auxiliary for the asymmetric !-alkylation of benzylphosphonic acid. In addition to producing enantiopure phosphonic acids with excellent yields and diastereoselectivities, this methodology also avoids some of the drawbacks associated with previously reported routes– namely, the use of expensive, water- sensitive, and/or non-C2 symmetric stereocontrollers. Furthermore, because the first deprotection step does not require strongly acidic conditions, it is reasonable that this method should enable the synthesis of chiral dialkyl phosphonate esters with acid-sensitive functionality. These results suggest that the BINOL chiral auxiliary may also be useful for other asymmetric manipulations of phosphonic acids, such as aminations, hydroxylations, fluorinations, epoxidations, and olefinations 2*F(NK7.%=-./$&0( All manipulations were carried out under argon or vacuum unless otherwise specified. Solvents were distilled under nitrogen from calcium hydride ! OW! (dichloromethane), sodium (toluene), sodium/benzophenone (tetrahydrofuran), or magnesium turnings (methanol). 2-naphthol (Baker), oxalyl chloride, n- butyllithium, triisopropyl phosphite, and cesium fluoride (Aldrich) were used as received. 1,1#-Binaphthalene-2,2#-diol (BINOL) was synthesized by the method of Noji et al.,81 as modified by Cai et al.,46,82 and enantiopure BINOL was isolated using the chiral resolution methodology of Hughes.45 Ethyl iodide, methyl iodide, benzyl bromide, allyl bromide (Aldrich) were dried over MgSO4 and distilled under argon before use. Triethylamine (Aldrich) was dried over CaH and distilled under argon before use. High-resolution electrospray ionization mass spectrometry was performed on a Waters Q-Tof Ultima Tandem Quadrupole/Time-of-Flight instrument by the University of Illinois Mass Spectrometry Laboratory. IR spectra were recorded on a Nicolet Impact 410 FT-IR instrument as thin films between KBr plates. NMR spectra were recorded on a Varian Unity-500 spectrometer at 11.74 T. 1 13 NMR chemical shifts are reported in # units relative to TMS ( H, C) or 85% H3PO4 (31P) with positive chemical shifts at higher frequencies. Melting points were measured on a Thomas-Hoover Unimelt apparatus. Flash column chromatography was performed with Merck silica gel (32-63 micron, 230-400 mesh). Analytical TLC was performed with Merck pre-coated silica gel 60 F254 plates (250 µm layer thickness). TLC spots were visualized by irradiation with a Spectroline UV lamp (254 nm). Diastereomeric excesses were determined by integrating 31P NMR resonances. Optical rotation measurements were performed on a Jasco P-2000 spectropolarimeter. ! OZ! . H88-%23%2:'.I($J:'20%-20%$1,(K... " O 5 O O Br P + O P 2 4 O O 1 3 6 7 8 A solution of triisopropyl phosphite (35.0 mL, 0.142 mol) and benzyl bromide (16.0 mL, 0.135 mol) in toluene (40 mL) was brought to reflux for 12 h. Volatile components were removed on a rotary evaporator at 50 °C, and the resulting residue was distilled at 4 Torr and the fraction boiling at 130 °C was collected to 1 afford the desired product as a colorless liquid. Yield: 31.3 g (90%). H NMR (CDCl3, 500 MHz): ' 7.30-7.24 (m, 4H, 3,4-CH), 7.23-7.18 (m, 1H, 5-CH) 4.57 (m, J = 7.8 Hz, J = 6.2, 6.2 Hz, 2H, 6-CH), 3.08 (d, J = 21.6 Hz, 2H, 1-CH2), 1.25 (d, J = 6.2 Hz, 6H, 13 7-CH3), 1.13 (d, J = 6.2 Hz, 6H, 8-CH3). CNMR (CDCl3, 126 MHz): 132.0 (d, JCP = 7.7 Hz), 129.9 (d, JCP = 7.0 Hz), 128.3 (d, JCP = 3.1 Hz), 126.7 (d, JCP = 3.8 Hz), 70.5 (d, JCP = 7.0 Hz), 34.8 (d, JCP = 139.6 Hz), 24.1 (d, JCP = 4.0 Hz), 23.8 (d, JCP = 5.3 31 1 Hz). P{ H} NMR (CDCl3, 202 MHz): ' 25.3 (s). The observed NMR spectra are consistent with literature values.8 ! O\! C($J:'20%-20%$8".1"8)K. O 5 O O P HO P 4 O 2 HO 1 3 ! ! Diisopropyl benzylphosphonate (31.3 g, 0.122 mol) was combined with conc. HCl (300 mL) and the mixture was heated to reflux for 48 h. Removal of solvent by rotary evaporation gave the desired compound as a fluffy white solid, which was further dried under vacuum at 100 °C overnight. Yield: 20.9 g (99%). Mp. 169-171 1 °C. H NMR (CD3OD, 500 MHz): ' 7.33-7.25 (m, 4H, 3,4-CH), 7.24-7.18 (m, 1H, 5- 13 1 CH), 3.11 (d, J = 21.7 Hz, 2H, 1-CH2). C{ H} NMR (CD3OD, 126 MHz): ' 134.3 (d, JCP = 9.2 Hz), 130.9 (d, JCP = 6.5 Hz), 129.4 (d, JCP = 2.7 Hz), 127.6 (d, JCP = 3.7 Hz), 31 1 35.8 (d, JCP = 134.8 Hz). P{ H} NMR (CD3OD, 202 MHz): ' 25.7 (s). The observed melting point and NMR spectra are consistent with literature values.84 H/(#=$1.23(2131,8%$.%9.I($J:'20%-20%$8".)8"0'%38)(.85 O O HO Cl P P HO Cl To a stirred suspension of benzylphosphonic acid (1.51 g, 8.77 mmol) in dichloromethane (55 mL) was added over 1.5 h a solution of oxalyl chloride (1.8 mL, ! B@! 20 mmol) and DMF (3 drops) in dichloromethane (20 mL). As the reaction proceeded, the mixture became clear. Stirring was continued for a total of 10 h. Volatile materials were removed under reduced pressure (1 Torr) to afford the product as a yellow solid. This material was used directly in subsequent reactions without additional purification. The yield was essentially quantitative. <44I>>LMLC($J:')8$120,0%N?O4L:P4QO?QL5RN4OSO?R)8%G120%-20(28$(LML %G8)(O.<>>L?K4K.... 4 5 3 10 15 2 6 O O O 14 Cl 9 1 P 12 P 7 8 11 13 Cl O (R)-2.1 Benzylphosphonic dichloride from the preparation above (8.77 mmol) was dissolved in toluene (30 mL). In a separate flask, a mixture of (R)-1,1#- binaphthalene-2,2#-diol ((R)-BINOL, 2.50 g, 8.73 mmol) and triethylamine (2.57 mL, 18.4 mmol) in toluene (50 mL) was stirred vigorously to dissolve the BINOL. The resulting clear solution was added over 1 h at room temperature to the benzylphosphonic dichloride, during which time a white precipitate was produced. After the mixture had been stirred for 8 h, the white solid was collected by vacuum filtration and dissolved in a mixture of dichloromethane (150 mL) and deionized water (40 mL). The organic layer was washed with deionized water (3 ( 20 mL), dried over anhydrous MgSO4, and taken to dryness on a rotary evaporator to afford ! BA! 3.17 g of crude white solid. Recrystallization from boiling MeCN yielded pure (R)-2.1 as a white solid. Yield: 3.09 g (83% over 2 steps). Mp (MeCN). 285-288 °C. + HRMS (ESI-TOF, m/z): Calcd for C27H20O3P [M + H] , 423.1150; found, 423.1150. 1 O.R.D. (c = 1.0 M, CHCl3): [!]D = -411.2. H NMR (CDCl3, 500 MHz ' 8.05-7.92 (m, 4H, Ar-H), 7.58-7.45 (m, 3H, Ar-H), 7.43-7.25 (m, 10H, Ar-H), 3.41 (d, J = 20.8 Hz, 13 1 2H, 11-CH2). C{ H} NMR (CDCl3, 126 MHz): ' 147.8 (d, JCP = 10.0 Hz), 146.1 (d, JCP = 10.0 Hz), 2132.8 (s), 132.6 (s), 132.1 (s), 131.7 (s), 131.5 (s), 131.3 (s), 130.2 (d, JCP = 7.2 Hz), 129.7 (d, JCP = 8.4 Hz), 129.1 (d, JCP = 2.7 Hz), 128.8 (s), 128.6 (s), 127.7 (d, JCP = 3.5 Hz), 127.5 (s), 127.12 (s), 127.10 (s), 126.9 (s), 126.1 (s), 125.9 (s), 122.1 (d, JCP = 2.8 Hz), 122.0 (d, JCP = 1.7 Hz), 121.4 (d, JCP = 1.9 Hz), 120.5 (d, JCP = 31 1 3.5 Hz), 31.6 (d, JCP = 131.4 Hz). P{ H} NMR (CDCl3, 202 MHz): ' 36.7 (s). IR -1 (film from CH2Cl2, cm ): 1287 (m), 1224 (s), 961 (s). <44I>>LML<<>>L4LB0($:'(,0:'>)8$120,0%N?O4L:P4QO?QL 5RN4OSO?R)8%G120%-20(28$(LML%G8)(O.<>O>>L?K?K... 4 5 3 10 15 2 O O 6 O P O 14 9 1 P 12 7 8 11 13 O O Me 16 (R)-1 (R,R)-2.2 ! B?! A stirred solution of (R)-2.1 (0.431 g, 1.02 mmol) in THF (90 mL) was cooled to –78 °C and treated with n-BuLi (0.665 mL of a 1.54 M solution in hexanes, 1.02 mmol), causing the solution color to become bright orange. After 30 min, iodomethane (70 µL, 1.12 mmol) was added and the resulting mixture was stirred at –78 °C for an additional 1.5 h. At this point the solution was almost colorless and the reaction mixture was quenched with 2M HCl (10 mL), followed by addition of DCM (30 mL) and DI H2O (20 mL) and the mixture allowed to warm to room temperature. The organic layer was separated and washed with 2M HCl (25 mL) and brine (10 mL), dried over anhydrous MgSO4, and taken to dryness on a rotary evaporator to afford a light yellow solid. The 31P{1H} NMR spectrum showed an 85:15 ratio of diastereomers in the crude product. The mixture was then separated by flash column chromatography (2.5:1 hexanes:EtOAc) to yield the major diastereomer (R,R)-2 as a white solid. Yield: 0.353 g (79%). Rf = 0.42 (2:1 hexanes: EtOAc). Mp (Et2O/pentane): 233-236 °C. HRMS (ESI-TOF, m/z): Calcd. for + C28H22O3P [M + H] , 437.1307; found, 437.1303. O.R.D. (c = 1.0 M, CHCl3): [!]D = - 1 338.8°. H NMR (CDCl3, 500 MHz): ' 8.05 (d, J = 8.8 Hz, 1H, Ar-H), 7.99-7.93 (m, 3H, Ar-H), 7.65 (d, J = 8.9 Hz, 1H, Ar-H), 7.56-7.42 (m, 6H, Ar-H), 7.41-7.36 (m, 2H, Ar-H), 7.32 (ddd, J = 8.6, 6.6, 1.1 Hz, 1H, Ar-H), 7.26 (d, J = 3.8 Hz, 2H, Ar-H), 7.07 (d, J = 8.8 Hz, 1H, Ar-H), 3.29 (dq, J = 19.2, 7.3 Hz, 11-CH), 1.72 (dd, J = 19.2, 7.3 13 1 Hz, 3H, 16-CH3). C{ H} NMR (CDCl3, 126 MHz): ' 147.6 (d, JCP = 10.0 Hz), 146.0 (d, JCP = 10.0 Hz), 136.9 (d, JCP = 4.9 Hz), 132.5 (s), 132.4 (s), 131.8 (s), 131.4 (s), 131.2 (s), 130.6 (s), 129.0 (d, JCP = 8.0 Hz), 128.9 (s), 128.5 (s), 128.3 (s), 127.7 (s), ! BN! 127.3 (s), 126.9 (s), 126.7 (s), 126.6 (s), 125.7 (s), 125.6 (s), 121.8 (d, JCP = 2.5 Hz), 121.6 (d, JCP = 1.7 Hz), 121.3 (d, JCP = 1.7 Hz), 120.6 (d, JCP = 3.7 Hz), 36.8 (d, JCP = 31 1 130.4 Hz), 17.7 (d, JCP = 5.2 Hz). P{ H} NMR (CDCl3, 202 MHz): ' 41.2 (s). IR -1 (film from CH2Cl2, cm ): 1281 (m), 1225 (m), 963 (m). <44IT>LML<<>>L4LB0($:'I;,LSL($L4L:'>)8$120,0%N?O4L:P4QO?QL 5RN4OSO?R)8%G120%-20(28$(.LML%G8)(O.<>O>>L?KSK... 4 5 3 10 15 2 O O 6 O P O 14 9 1 P 12 7 8 11 13 O O 16 18 17 (R)-1 (R,R)-2.3 As above for (R,R)-2.2, except that a solution of (R)-2.1 (0.233 g, 0.552 mmol) in THF (50 mL) at -78 °C was treated with n-BuLi (0.40 mL of a 1.51 M solution in hexanes, 0.60 mmol) and alkylated with allyl bromide (50 µL, 0.58 mmol) over 4 h. The 31P{1H} NMR spectrum of the crude product mixture showed a 92:8 ratio of diastereomers. The mixture was separated by flash column chromatography (4:1 hexanes:EtOAc) to yield the major diastereomer (R,R)-3 as a white solid. Yield: 0.215 g (84%). Rf = 0.35 (hexanes: EtOAc = 4:1). HRMS (ESI-TOF, m/z): Calcd. for + C30H24O3P [M + H] , 463.1463; found 463.1462. O.R.D. (c = 1.0 M, CHCl3): [!]D = - 1 285.7°. H NMR (CDCl3, 500 MHz): ' 8.05 (d, J = 8.9 Hz, 1H, Ar-H), 7.98–7.95 (m, ! BO! 3H, Ar-H), 7.64 (dd, J = 8.7, 1.0 Hz, 1H, Ar-H), 7.53-7.42 (m, 6H, Ar-H), 7.41–7.37 (m, 2H, Ar-H), 7.32 (ddd, 1H, J = 8.3, 6.7, 1.2 Hz), 7.27 (d, J = 3.6 Hz, 2H, Ar-H), 6.96 (d, J = 8.8 Hz, 1H, Ar-H), 5.56 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H, 17-CH, 4.96 (dd, J = 17.3, 1.4 Hz, 1H, 18a-CH), 4.91 (d, J = 10.1 Hz, 1H, 18b-CH), 3.16 (ddd, J =18.9, 10.8, 4.2 Hz, 1H, 11-CH, 2.90 (m, 1H, 16a-CH), 2.80 (m, 1H, 16b-CH). 13C{1H} NMR (CDCl3, 126 MHz): ' 147.7 (d, JCP = 10.2 Hz), 146.2 (d, JCP = 10.2 Hz), 135.5 (d, JCP = 4.8 Hz) 134.4 (d, JCP = 16.6 Hz), 132.8 (s), 132.7 (s), 132.1 (s), 131.7 (s), 131.5 (s), 130.9 (s), 130.1 (d, JCP = 8.2 Hz), 129.1 (s), 128.8 (s), 128.6 (s), 128.2 (s), 127.6 (s), 127.2 (s), 127.0 (s), 126.9 (s), 126.0 (s), 125.9 (s), 122.1 (d, JCP = 2.6 Hz), 121.9 (d, JCP = 1.8 Hz), 121.5 (d, JCP = 1.5 Hz), 120.8 (d, JCP = 1.9 Hz), 118.0, 43.0 (d, JCP = 132.2 31 1 -1 Hz), 36.2. P{ H} NMR (CDCl3, 202 MHz): ' 39.4 (s). IR (film from CH2Cl2, cm ): 1281 (m), 1225 (s), 961 (s). <44I>>LML<<>>L4O?LH820($:'(,0:'>)8$120,0%N?O4L:P4QO?QL 5RN4OSO?R)8%G120%-20(28$(LML%G8)(O.<>O>>L?KMK 4 6 3 5 15 2 7 O O O O 14 10 1 P P 12 13 8 9 11 O O 16 17 20 18 (R)-1 (R,R)-2.4 19 ! BB! As above for ((R,R)-2.2, except that a solution of (R)-2.1 (0.985 g, 2.33 mmol) in THF (200 mL) at -78 °C was treated with n-BuLi (1.52 mL of a 1.54 M solution in hexanes, 2.34 mmol) and alkylated with benzyl bromide (305 µL, 2.57 mmol), which was consumed over 3 h. The 31P{1H} NMR spectrum of the crude product mixture showed a 93:7 ratio of diastereomers. The mixture was separated by flash column chromatography (4:1 hexanes:ethyl acetate) to yield the major diastereomer as a white solid. Yield: 0.998 g (84%). Rf = 0.25 (4:1 hexanes:EtOAc). HRMS (ESI-TOF, + m/z): Calcd. for C34H26O3P [M + H] , 513.1620; found, 513.1618. O.R.D. (c = 1.0 M, 1 CHCl3): [!]D = -286.5°. H NMR (CDCl3, 500 MHz): ' 8.07 (d, J = 8.9 Hz, 1H, Ar-H), 7.97 (d, J = 8.2 Hz, 1H, Ar-H), 7.94 (d, J = 8.1 Hz, 1H, Ar-H), 7.91 (d, J = 9.1 Hz, 1H, Ar-H), 7.66 (dd, J = 8.7, 1.0 Hz, 1H, Ar-H), 7.54-7.23 (m, 12H, Ar-H), 7.12 (d, J = 4.0 Hz, 2H, Ar-H), 6.92-6.89 (m, 2H, Ar-H), 6.87 (d, J = 8.8 Hz, 1H, Ar-H), 3.66 (m, 1H, 13 1 11-CH), 3.34 (m, 2H, 16-CH2). C{ H} NMR (CDCl3, 126 MHz): ' 147.7 (d, JCP = 10.2 Hz), 146.2 (d, JCP = 9.9 Hz), 138.1 (d, JCP = 16.2 Hz), 134.4 (d, JCP = 4.8 Hz), 132.8 (s), 132.7 (s), 132.1 (s), 131.7 (s), 131.5 (s), 130.9 (s), 130.2 (d, JCP = 8.9 Hz), 129.4 (s), 129.0 (s), 128.8 (s), 128.6 (s), 128.3 (s), 128.1 (s), 127.6 (s), 127.2 (s), 127.0 (s), 126.9 (s), 126.7 (s), 126.0 (s), 125.9 (s), 122.1 (d, JCP = 2.5 Hz), 121.9 (d, JCP = 1.9 Hz), 121.5 (d, JCP = 1.7 Hz), 120.8 (d, JCP = 3.8 Hz), 45.3 (d, JCP = 128.1 Hz), 38.5 (d, 31 1 - JCP = 3.0 Hz). P{ H} NMR (CDCl3, 202 MHz): ' 39.3 (s). IR (film from CH2Cl2, cm 1): 1279 (m), 1225 (s), 961 (s). ! BR! <44I>>LML<<>>L4LB0($:'23%2:'>)8$120,0%N?O4L:P4QO?QL 5RN4OSO?R)8%G120%-20(28$(LML%G8)(O.<>O>PQUK"" " 4 5 3 10 15 2 O O 6 O P O 14 9 1 P 12 7 8 11 13 O O 16 Me 17 (R)-1 (R,R)-2.5 As above for ((R,R)-2.2, except that a solution of (R)-2.1 (380 mg, 0.90 mmol) in THF (75 mL) at -78 °C was treated with n-BuLi (630 m(630 630 75 mL) at -78 ° C was treated wimmol) and alkylated with ethyl iodide (80 µL, 0.99 mmol) over 5 h. The 31P{1H} NMR spectrum of the crude product mixture showed a 88:12 ratio of diastereomers. The mixture was separated by flash column chromatography (3:2 hexanes:EtOAc) to yield the major diastereomer, (R,R)-5, as a white solid. Yield: 275 mg (68%). Rf = 0.50 (2:1 hexanes: EtOAc). HRMS (ESI-TOF, m/z): Calcd for + C29H24O3P [M + H] , 451.1463; found, 451.1461. O.R.D. (c = 1.0 M, CHCl3): [!]D = - 1 308.4°. H NMR (CDCl3, 500 MHz): ' 8.04 (d, J = 8.8 Hz, 1H, Ar-H), 7.98-7.93 (m, 3H, Ar-H), 7.64 (d, J = 8.7 Hz, 1H, Ar-H), 7.55-7.37 (m, 8H, Ar-H), 7.32 (t, J = 7.7 Hz, 1H, Ar-H), 7.26 (d, J = 3.2 Hz, 2H, Ar-H), 6.96 (d, J = 8.8 Hz, 1H, Ar-H), 2.99 (ddd, J = 19.1, 10.8, 4.2 Hz, 1H, 11-CH), 2.33 (m, 1H, 16a-CH), 2.11 (m, 1H, 16b- ! BW! 13 1 CH), 0.84 (t, J = 7.3 Hz, 3H, 17-CH3). C{ H} NMR (CDCl3, 126 MHz): ' 147.8 (d, JCP = 10.1 Hz), 146.3 (d, J CP = 10.2 Hz), 135.0 (d, JCP = 4.9 Hz), 132.8 (s), 132.7 (s), 132.1 (s), 131.7 (s), 131.5 (s), 130.8 (s), 130.1 (d, JCP = 8.4 Hz), 129.1 (s), 128.8 (s), 128.6 (s), 128.1 (s), 127.6 (s), 127.1 (s), 127.0 (s), 126.8 (s), 126.0 (s), 125.6 (s), 122.1 (d, JCP = 2.7 Hz), 122.0 (d, JCP = 1.9 Hz), 121.5 (d, JCP = 1.2 Hz), 120.9 (d, JCP = 3.7 31 1 Hz), 44.5 (d, JCP = 128.9 Hz), 25.3 (d, JCP = 4.1 Hz), 12.4 (d, JCP = 15.7 Hz). P{ H} -1 NMR (CDCl3, 202.2 MHz): ' 40.4 (s). IR (film from CH2Cl2, cm ): 1277 (m), 1224 (s), 962 (s). H/( #=$1. 23(2131,8%$. %9. +>>LH8+(,0:'. <4O?LH820($:'(,0:'>L20%-20%$1,(O. ?KVK... 12 10 O O MeO O P 1 9 P 7 MeO 8 O 11 2 3 4 6 (R)-2.6 (R,R)-2.4 5 To a solution of (R,R)-2.4 (550 mg, 1.07 mmol) in anhydrous MeOH (40 mL) was added cesium fluoride (975 mg, 6.42 mmol). The resulting mixture was heated to reflux for 8 h. After the mixture was cooled to room temperature, the solvent was removed in vacuum. The resulting gummy, yellow residue was dissolved in dichloromethane (40 mL) and the solution was washed successively with brine (2 ( 25 mL), 2.5 M aqueous NaOH (2 ( 25 mL), and brine (25 mL). The solution was ! BZ! dried over MgSO4 and the solvent was removed in vacuum to afford the crude 1 product as a yellow oil. Yield: 278 mg (89%). H NMR (CDCl3, 500.0 MHz): ' 7.30- 7.25 (m, 4H, Ar-H), 7.24-7.19 (m, 1H, Ar-H), 7.18-7.09 (m, 3H, Ar-H), 7.02-6.99 (m, 2H, Ar-H), 3.71 (d, J = 10.7 Hz, 3H, 11-CH3), 3.18 (d, J = 10.5 Hz, 3H, 12-CH3), 3.46 (m, 1H, 2a-CH), 3.33 (ddd, J = 21.9, 11.0, 3.9 Hz, 1H, 1-CH), 3.20 (m, 1H, 2b-CH). 31 1 P{ H} NMR (CDCl3, 202.2 MHz): ' 31.14 (s). NOTE: acidification of the initial brine washes has the potential to generate HF and should be avoided. Acidification of the NaOH extracts with 4 M HCl results in the precipitation of free (R)-BINOL, which can be collected as a white solid by vacuum filtration and further dried in vacuum. Yield: 264 mg (86% recovery). +>>L<4O?LH820($:'(,0:'>20%-20%$8".1"8).<<>>L?KW>K... . . 10 MeO O HO O 1 P P 7 9 MeO HO 8 2 3 4 6 5 (R)-2.7 To the dimethylphosphonate prepared above (2.6, 278 mg, 0.958 mmol) was added conc. HCl (20 mL) and the resulting mixture was heated to reflux for 18 h. Removal of water in vacuum afforded a white solid, which was further dried in vacuum at 100 ºC for 12 h. Yield: 244 mg (97%) or 87% over two steps from the (BINOLato)phosphonate (R,R)-4). Mp. 150-152 °C. HRMS (ESI-TOF, m/z): Calcd for ! B\! + C14H16O3P [M + H] , 263.0837; found, 263.0834. O.R.D. (c = 0.75, MeOH): [!]D = - 1 105.7°. H NMR (DMSO-d6, 500.0 MHz): ' 7.22-7.14 (m, 4H, Ar-H), 7.13-7.06 (m, 3H, Ar-H), 7.05-6.98 (m, 3H, Ar-H), 3.36 (m, 1H, 2a-CH), 3.22 (ddd, J = 22.0, 12.4, 13 1 2.1 Hz, 1H, 1-CH), 3.07 (td, J = 13.2, 6.0 Hz 1H, 2b-CH). C{ H} NMR (DMSO-d6, 126 MHz): ' 139.8 (d, JCP = 17.4 Hz), 137.5 (d, JCP = 6.4 Hz), 129.4 (d, JCP = 6.1 Hz), 128.6 (s), 128.0 (s), 127.7 (s), 126.1 (s), 125.8 (s), 46.8 (d, JCP = 132.1 Hz), 35.5. 31 1 P{ H} NMR (DMSO-d6, 202.2 MHz): ' 24.6 (s). 2*R(>.5.%./'.#( 1. Gulyukina, N. S.; Dolgina, T. M.; Bondarenko, G. N.; Beletskaya, I. P.; Bondarenko, N. A.; Henry, J. C.; Lavergne, D.; Ratovelomanana-Vidal, V.; Genet, J. P. Synthesis of biologically active 1-arylethylphosphonates. Russ. J. Org. Chem. 2002, 38 (4), 573-587. 2. Kotoris, C. C.; Wen, W.; Lough, A.; Taylor, S. D. Preparation of chiral alpha- monofluoroalkylphosphonic acids and their evaluation as inhibitors of protein tyrosine phosphatase 1B. J. Chem. Soc., Perkin Trans. 2000, 8, 1271-1281. 3. Kolodiazhnyi, O. I. Chiral hydroxy phosphonates: synthesis, configuration, and biological properties. Russ. Chem. Rev. 2006, 75 (3), 227-253. 4. Focken, T.; Hanessian, S. Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules. Beilstein J. Org. Chem. 2014, 10, 1848-1877. ! R@! 5. Horiguchi, M.; Kandatsu, M. Isolation of 2-Aminoethane Phosphonic Acid from Rumen Protozoa. Nature 1959, 184, 901-902. 6. Hendlin, D.; Stapley, E. O.; Jackson, M.; Wallick, H.; Miller, A. K.; Wolf, F. J.; Miller, T. W.; Chaiet, L.; Kahan, F. M.; Foltz, E. L.; Woodruff, H. B.; Mata, J. M.; Hernandez, S.; Mochales, S. Phosphonomycin, a New Antibiotic Produced by Strains of Streptomyces. Science 1969, 122-123. 7. Quin, L. D., A Guide to Organophosphorus Chemistry. John Wiley & Sons: Canada, 2000. 8. Engel, R. Phosphonates as Analogues of Natural Phosphates. Chem. Rev. 1977, 77 (3), 349-367. 9. Wróblewski, A. E.; Ha)ajewska-Wosik, A. An efficient synthesis of an enantiomerically pure phosphonate analogue of l-GABOB. Tetrahedron: Asymmetry 2003, 14 (21), 3359-3363. 10. Naydenova, E. D.; Todorov, P. T.; Troev, K. D. Recent synthesis of aminophosphonic acids as potential biological importance. Amino Acids 2010, 38 (1), 23-30. 11. Kotoris, C. C.; Wen, W.; Lough, A.; Taylor, S. D. Preparation of chiral !- monofluoroalkylphosphonic acids and their evaluation as inhibitors of protein tyrosine phosphatase 1B. J. Chem. Soc., Perkin Trans. 2000, 8, 1271-1281. 12. Marinozzi, M.; Serpi, M.; Amori, L.; Gavilan Diaz, M.; Costantino, G.; Meyer, U.; Flor, P. 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Diastereoselective Alkylation of Chiral Perhydro 1,3,2-Oxazabenzophosphorinane-2-oxides Derived from (-)-8-Amino Menthol. Synthesis 2006, 5, 817-826. 29. Denmark, S. E.; Marlin, J. E.; Rajendra, G. Carbanion-Accelerated Claisen Rearrangements: Asymmetric Induction with Chiral Phosphorus-Stabilized Anions. J. Org. Chem. 2013, 78, 66-82. ! RO! 30. Denmark, S. E.; Dorow, R. L. Stereoselective alkylations of chiral, phosphorus-stabilized benzylic carbanions. J. Org. Chem. 1990, 55 (24), 5926-5928. 31. Blazis, V. J.; Koeller, K. J.; Spilling, C. D. Reactions of Chiral Phosphorus- Acid Diamides - the Asymmetric-Synthesis of Chiral Alpha-Hydroxy Phosphonamides, Phosphonates, and Phosphonic-Acids. J. Org. Chem. 1995, 60 (4), 931-940. 32. Hanessian, S.; Beaudoin, S. Studies in Asymmetric Olefinations - the Synthesis of Enantiomerically Pure Allylidene, Alkylidene, and Benzylidene Cyclohexanes. Tetrahedron Lett. 1992, 33 (50), 7655-7658. 33. Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. 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Soc. 1984, 106 (19), 5754-5756. 38. Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.; Pilati, T.; Sisti, M. Camphor- based oxazaphospholanes as chiral templates for the enantioselective synthesis of !-chlorophosphonic acids. Tetrahedron: Assymetry 1999, 10, 4277-4280. 39. Denmark, S. E.; Kim, J.-H. Diastereoselective alkylations of chiral, phosphorus-stabilized carbanions: N-alkyl substituent effects in P-alkyl- 1,3,2- diazaphosphorinane 2-oxides. Can. J. Chem. 2000, 78, 673-688. 40. Bennani, Y. L.; Hanessian, S. The asymmetric synthesis of alpha-substituted alpha-methyl and alpha-phenyl phosphonic acids: Design, carbanion geometry, reactivity and preparative aspects of chiral alkyl bicyclic phosphonamides. Tetrahedron 1996, 52 (44), 13837-13866. 41. Brunel, J. M. BINOL: A Versatile Chiral Reagent. Chem. Rev. 2005, 105, 857-897. 42. Richter, V. v. Die Chemie auf der vierten ruesischen Naturforscherversammlung in Kasan. Chem. Ber. 1873, 6, 1249-1260. ! RR! 43. Noji, M.; Nakajima, M.; Koga, K. A. New Catalytic-System for Aerobic Oxidative Coupling of 2-Naphthol Derivatives by the Use of Cucl-Amine Complex - a Practical Synthesis of Binaphthol Derivatives. Tetrahedron Lett. 1994, 35 (43), 7983-7984. 44. DeuBen, H. J.; Frederiksen, P.; Bjornholm, T.; Bechgaard, K. A. Facile Large Scale Preparation of Racemic 2,2#-Dihydroxy-1,1#-Binaphthyl. Org. Prep. Proc. Int. 1996, 28 (4), 484-486. 45. Hughes, D. L. Resolution of 1,1'-Bi-2-Naphthol; (R)-(+)- and (S)- (-)-2,2'- Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP). Org. Synth. 2014, 91, 1-11. 46. Cai, D. W.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. Simple and Efficient Resolution of 1,1'-Bi-2-Naphthol. Tetrahedron Lett. 1995, 36 (44), 7991-7994. 47. Toda, F.; Tanaka, K.; Stein, Z.; Goldberg, I. Optical Resolution of Binaphthyl and Biphenanthryl Diols by Inclusion Crystallization with N- Alkylcinchonidium Halides - Structural Characterization of the Resolved Materials. J. Org. Chem. 1994, 59 (19), 5748-5751. 48. Cox, P. J.; Wang, W.; Snieckus, V. Expedient Route to 3-Substituted and 3,3'- Substituted 1,1'-Bi-2-Naphthols by Directed Ortho Metalation and Suzuki Cross Coupling Methods. Tetrahedron Lett. 1992, 33 (17), 2253-2256. 49. Qian, C. T.; Huang, T. S.; Zhu, C. J.; Sun, J. Synthesis of 3,3'-, 6,6'- and 3,3',6,6'-substituted binaphthols and their application in the asymmetric hydrophosphonylation of aldehydes - an obvious effect of substituents of ! RW! BINOL on the enantioselectivity. J. Chem. Soc. Perkin Trans. 1998, 13, 2097-2103. 50. Tsang, W. C. P.; Schrock, R. R.; Hoveyda, A. H. Evaluation of enantiomerically pure binaphthol-based molybdenum catalysts for asymmetric olefin metathesis reactions that contain 3,3'-diphenyl- or 3,3'- dimesityl-substituted binaphtholate ligands. Generation and decomposition of unsubstituted molybdacyclobutane complexes. Organometallics 2001, 20 (26), 5658-5669. 51. Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L. Enantioselective catalytic conjugate addition of dialkylzinc reagents using copper-phosphoramidite complexes; Ligand variation and non-linear effects. Tetrahedron 2000, 56 (18), 2865-2878. 52. Simonsen, K. B.; Gothelf, K. V.; Jorgensen, K. A. A simple synthetic approach to 3,3'-diaryl BINOLs. J. Org. Chem. 1998, 63 (21), 7536-7538. 53. Ding, K.; Wang, Y.; Zhang, L.; Wu, Y., A Novel Two-Phase Oxidative Coupling of 2-Naphthols Suspended in Aqueous Fe3+ Solutions. Tetrahedron 1996, 52 (3), 1005-1010. 54. Yoon, T. P.; Jacobsen, E. N. Privileged chiral catalysts. Science 2003, 299 (5613), 1691-1693. 55. Zhou, Q.-L. Privileged Chiral Ligands and Catalysts. Wiley-VCH: Singapore, 2011. ! RZ! 56. Kyba, E. P.; Gokel, G. W.; De Jong, F.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J. Host–guest Complexation. 7. The Binaphthyl Structural Unit in Host Compounds. J. Org. Chem. 1977, 42, 4173–4184. 57. Meca, L.; Reha, D.; Havlas, Z. Racemization Barriers of 1,1#-Binaphthyl and 1,1#-Binaphthalene-2,2#-diol: A DFT Study. J. Org. Chem. 2003, 68, 5677– 5680. 58. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. Basic Character of Rare Earth Metal Alkoxides. Utilization in Catalytic C-C Bond Forming Reactions and Catalytic Asymmetric Nitroaldol Reactions. J. Am. Chem. Soc. 1992, 114, 4418-4420. 59. Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. Catalytic Asymmetric Nitroaldol Reaction Using Optically Active Rare Earth BINOL Complexes: Investigation of the Catalyst Structure. J. Am. Chem. Soc. 1993, 115, 10372-10373. 60. Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. A New Multifunctional Heterobimetallic Asymmetric Catalyst for Michael Additions and Tandem Michael–Aldol Reactions. Angew. Chem. Int. Ed. Engl. 1996, 35 (1), 104-106. 61. Arai, T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. Catalytic Asymmetric Synthesis of !-Hydroxy Phosphonates Using the Al-Li-BINOL Complex. J. Org. Chem. 1996, 61, 2926-2927. ! R\! 62. Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Chiral BINOL-derived phosphoric acids: privileged Bronsted acid organocatalysts for C-C bond formation reactions. Org. Biomol. Chem. 2010, 8 (23), 5262-76. 63. Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete field guide to asymmetric BINOL-phosphate derived Bronsted acid and metal catalysis: history and classification by mode of activation; Bronsted acidity, hydrogen bonding, ion pairing, and metal phosphates. Chem. Rev. 2014, 114 (18), 9047-9153. 64. Noyori, R. Facts are the enemy of truth-reflections on serendipitous discovery and unforeseen developments in asymmetric catalysis. Angew. Chem. Int. Ed. Engl. 2013, 52 (1), 79-92. 65. Matsunaga, S.; Ohshima, T.; Shibasaki, M. Linked-BINOL: An Approach towards Practical Asymmetric Multifunctional Catalysis. Adv. Synth. Catal. 2002, 344 (1), 3-15. 66. Ellenwood, R. E. Synthesis of Chiral Vanadium Phosphonates and Their Catalytic Activity. Dissertation, University of Illinois at Urbana Champaign, Urbana, IL, 2004. 67. Tanaka, K.; Ohta, Y.; Fuji, K. Asymmetric Michael Addition-Reactions of Chiral Prop-9-enyl-Phosphonate and but-2-enylphosphonate Anions with Cyclic Enones. J. Org. Chem. 1995, 60 (24), 8036-8043. ! W@! 68. Bedekar, A. V.; Watanabe, T.; Tanaka, K.; Fuji, K. Intramolecular asymmetric olefination of binaphthyl phosphonate derivatives of 1,3- diketones. Tetrahedron: Asymmetry 2002, 13, 721-727. 69. Szewczyk, J.; Lejczak, B.; Kafarski, P. Transesterification of Diphenyl Phosphonates using the Potassium Fluoride/Crown Ether/Alcohol System; Part 1. Transesterification of Diphenyl 1-(Benzyloxycarbonylamino)- alkanephosphonates. Synthesis 1982, 5, 409-412. 70. Hudson, R. F.; Keay, L. The Hydrolysis of Phosphonate Esters. J. Chem. Soc. 1956, 2463-2469. 71. Kim, B.-S.; Kim, B.-T.; Hwang, J.-K. A Practical Method to Cleave Diphenyl Phosphonate Esters to Their Corresponding Phosphonic Acids in One Step. Bull. Korean Chem. Soc. 2009, 30 (6), 1391-1393. 72. Keay, L. The Acid-catalyzed Hydrolysis of (–)-2-Octyl Ethyl Methylphosphonate. J. Org. Chem. 1963, 28 (5), 1426-1427. 73. Jansa, P.; Baszczy*ski, O.; Procházková, E.; Dra+ínsk,, M.; Janeba, Z. Microwave-Assisted Hydrolysis of Phosphonates Diesters: An Efficient Protocol for the Preparation of Phosphonic Acids. Green Chem. 2012, 14, 2282-2288. 74. Salomon, C. J.; Breuer, E. Efficient and Selective Dealkylation of Phosphonate Diisopropyl Esters using Me3SiBr. Tetrahedron Lett. 1995, 36 (37), 6759-6760. ! WA! 75. Mortier, J.; Gauvry, N. Dealkylation of Dialkyl Phosphonates with Boron Tribromide. Synthesis 2001, 4, 553-554. 76. Morita, T.; Okamoto, Y.; Sakurai, H. A Convenient Dealkylation of Dialkyl Phosphonates by Chlorotrimethylsilane in the Presence of Sodium Iodide. Tetrahedron Lett. 1978, 28, 2523-2526. 77. Ogilvie, K. K.; Beaucage, S. L. Fluoride ion promoted deprotection and transesterification in nucleotide triesters. Nuc. Acids Res. 1979, 7 (3), 805- 823. 78. Lejczak, B.; Kafarski, P.; Szewczyk, J. Transesterification of Diphenyl Phosphonates using the Potassium Fluoride/Crown Ether/Alcohol System; Part 2. The Use of Diphenyl 1-Aminoalkanephosphonates in Phosphonopeptide Synthesis. Synthesis 1982, 5, 412-414. 79. Ogilvie, K. K.; Beaucage, S. L.; Theriault, N.; Antwistle, D. W. A General Transesterification Method for the Synthesis of Mixed Trialkyl Phosphates. J. Am. Chem. Soc. 1977, 99 (4), 1277-1288. 80. Wiener, S. W. Nerve Agents: A Comprehensive Review. J. Int. Care Med. 2004, 19 (1), 22-37. 81. Noji, M.; Nakajima, M.; Koga, K. A New Catalytic System For Aerobic Oxidative Coupling of 2-Naphthol Derivatives By the Use of CuCl-Amine Complex - a Practical Synthesis of Binaphthol Derivatives. Tetrahedron Lett. 1994, 35 (43), 7983-7984. ! W?! 82. Cai, D. W.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. Resolution of 1,1'-bi- 2-naphthol. Org. Synth. 1999, 76, 1-5. 83. Richardson, R. M.; Barney, R. J.; Wiemer, D. F. Synthesis of dialkyl and diaryl benzylphosphonates through a ZnI2-mediated reaction. Tetrahedron Lett. 2012, 53 (49), 6682-6684. 84. Blackburn, G. M.; Ingleson, D. The Dealkylation of Phosphate and Phosphonate Esters by Iodotrimethylsilane: A Mild and Selective Procedure. J. Chem. Soc., Perkin Trans. 1980, 1150-1153. 85. Kotoris, C. C.; Wen, W.; Lough, A.; Taylor, S. D. Preparation of chiral alpha- monofluoroalkylphosphonic acids and their evaluation as inhibitors of protein tyrosine phosphatase 1B. J. Chem. Soc. Perkin Trans. 2000, (8), 1271-1281. ! ! WN! /012,(3.S. /0831'.=1$1)8;+.H820%-20%$1,(-.1-. X(,(3%*($(%;-.!-:++(,38".A2%G8)1,8%$./1,1':-,-. ;*)(9&'GA%,1/:( ( Metal catalysis is employed in an estimated of 80% of all chemical processes worldwide and directly contributes to approximately 20% of the US gross domestic product.1 Although homogeneous catalysts typically afford greater selectivity and higher reactivity, heterogeneous catalysts are often favored in industry due to their high stability, ease of handling, and facile separation and recovery from the reaction mixture.2 Accordingly, the vast majority of industrial catalytic processes involve heterogeneous catalysis (80%), with the remainder relying on homogeneous catalysts (17%) and biocatalysts (3%).3 ! WO! !"#"$%&# '(($)*"#)+,& !"#$"%& '()*+,-./0"+. 1&%#23&%4#5- 266+."/78(.09-8"8 2,#!:23&%4 ;<+=")/0"+. >*%"#$"%& ?+3(6-*"@/0"+. >+A+$&##:23&%4 '()*+0*-/06-.08 >+#$"%& 5"8B9-*:C*+<8B978(.09-8"8 >D#E.%#23&%4 A-09/.+378(.09-8"8 E-+3"0-7F7B+6<+8"0- '()*+B/*G+.7B*/BH"., ?0#A+*)-."0- 23H-.-79()*+"8+6-*"@/0"+. I&%J#C"%& !%"7/G/0-6-.0 ?)#> '()*+,-./0"+. "#$%&!532!D&*&13&.!&+,4'*&%!$5!(&3&/$=&-&$F%!1,3,*7%3%!F%&.!"-!"-.F%3/7.3 One class of reactions for which heterogeneous catalysts have been greatly overshadowed by their homogeneous counterparts4 is the asymmetric transformation of organic substrates.5 There is, however, increasing interest in the development of novel biphasic catalytic methodology to meet the ever-growing demand for enantiomerically pure compounds on a large scale.4,6 Efforts in this area typically adopt one of two approaches: (1) the immobilization of asymmetric homogeneous catalysts, and (2) the functionalization of surfaces with chiral modifiers.4 A relatively new and promising class of heterogeneous asymmetric catalysts consists of the solids known as metal organic frameworks (MOFs).7 MOFs are porous materials in which metal centers or clusters are linked together by organic bridging ligands into extended networks.8-9 The structures of MOFs are easy to ! WB! modify, which allows for the rapid and facile tuning of the properties of the bulk material.8 MOFs have been proposed for potential use in a myriad of applications including gas storage,10 sensing,11-12 and catalysis.13-16 The tunability of MOFs makes them attractive materials for heterogeneous asymmetric catalysis. They have the potential to combine the activity and selectivity of traditional homogenous catalysts with the ease of handling, separation, and recyclability of heterogeneous catalysts.17 Despite these advantages, the use of MOFs in heterogeneous asymmetric catalysis remains limited, due in part to the thermal and hydrolytic instability of many MOFs and the leaching of the active catalytic species during use.7 Cl Cl N N N N N OH HO N OH HO tBu tBu (a) (b) -./01&! 532! ^+,4'*&%! $5! 1("/,*! *"-Y&/%! F%&.! "-! 3(&! %7-3(&%"%! $5! 0LG%! 5$/! (&3&/$=&-&$F%! ,%744&3/"1! 1,3,*7%"%E! P,Q! 0$."5"&.! _:KL`! *"=,-.! 5$/! 3(&! S"P:VQ! 1,3,*7T&.! a-^3?! ,.."3"$-! 3$! ,/$4,3"1! ,*.&(7.&%EAZ! P;Q! 0$."5"&.! D)`^K! *"=,-.! 5$/! 3(&! 0-P:::Q! 1,3,*7T&.! &'$+".,3"$-! $5! $*&5"-%EA\!:-!3(&%&!,''/$,1(&%>!3(&!4&3,*!1&-3&/!/&%'$-%";*&!5$/!1,3,*7%"%!P;"-."-=!%"3&%!%($H-!"-! =/&&-Q!"%!"-.&'&-.&-3!$5!3(&!4&3,*!1&-3&/%!3(,3!1$-%3/F13!3(&!5/,4&H$/Y!P;"-."-=!%"3&%!%($H-! "-!/&.QE!! ! WR! One strategy to increase the thermal and hydrolytic stability of MOFs is to 2- 20 use phosphonates (RPO3 ) as linkers, since the hydrolytic and thermal robustness of the metal phosphonates are similar to those of metal phosphates. Unlike phosphates, however, phosphonates can be synthetically tuned by varying the organic substituent.21 Phosphonates typically exhibit multiple and often unpredictable coordination modes,20,22,23 although Zubieta and Clearfield have shown that a wide variety of molecular and polymeric metal phosphonates can be obtained through ligand design and careful control of reaction conditions.24-26 Despite this early work, phosphonate-based MOFs have been less studied than carboxylate-based MOFs !"#$ !%#$ !&#$ -./01&! 534! J&'/&%&-3,3"9&! %&13"$-%! $5! %$4&! '$*74&/"1! 4&3,*! ."'($%'($-,3&%E?@! 0>! 17,-d! U>! 4,=&-3,d! 6>! =/&7d! L>! /&.E! P,Q! )! 1$''&/P::Q! 4&3(7*'($%'($-,3&E?W! P;Q! )! -"1Y&*P::Q! 4&3(7*&-&< ."'($%'($-,3&E?Z! P1Q! )! 1$''&/P::Q! '($%'($-,3&! H"3(! A>N>B>W<3&3/,Y"%PO<'(&-7*'($%'($-,3&Q< ,.,4,-3,-&!*"=,-.%E?\! ! WW! MOFs based on chiral phosphonate ligands have the potential to effect stereospecific catalytic transformations. Furthermore, if a single metal center is utilized as both the active catalyst and as a vertex in the metal-phosphonate network, durable materials that are resistant to catalyst leaching should be obtained. Here we describe our efforts to prepare homochiral diphosphonates as linkers, to incorporate them into MOFs, and to employ the latter as heterogeneous asymmetric catalysts. ;*2(6%=,%(!%$( !"#$%&''"()*+,(-.( 5+&,$'"(6.78( /&-&'"0+(( 9.'"8+7$%(( 12$,&3.4*! 9:.*#:.4&-+*( ()! *+! "! &'! #-! (.! /)! ,! #$! %! 0+! &-! -./01&! 5353! V,-,."F4! "%! ,-! ".&,*! 4&3,*! 5$/! 5F/3(&/! %3F.7! ;,%&.! $-! ;$3(! "3%! '&/5$/4,-1&! "-! 1,3,*73"1!$+".,3"$-%!,%!H&**!,%!"3%!,;"*"37!3$!5$/4!'$*74&/"1!'($%'($-,3&%.23,30 Many of the known polymeric diphosphonates are based on the element vanadium, particularly in its tetravalent oxidation state.23,31-34 Vanadium compounds are known to be useful catalysts for a variety of oxidation reactions ! WZ! including the epoxidation of olefins and the sulfoxidation of sulfides.35-38 Although high-valent vanadium(V) species are thought to be the catalytically active species in these reactions, the analogous vanadium(IV) compounds are commonly employed as precatalysts that are oxidized in situ.39-40 For this reason, we chose to focus on vanadium in our studies of the synthesis and catalytic reactivity of chiral metal phosphonates. Previous efforts in our group by Ellenwood focused on the synthesis, characterization, and catalytic potential of chiral vanadium(IV) complexes of the (S)-methylbenzylphosphonate ligand (S)-3.1.41 The composition of the vanadium phosphonate products was heavily influenced by both the identity of the vanadium precursor as well as by the reactions conditions employed.20,22,25 For example, addition of (S)-3.1 to a DCM solution of vanadium oxytrichloride followed by reflux afforded purple crystals of the neutral V6 cage complex (S,S,S,S,S,S,S,S,)-3.2, whereas the reaction of sodium metavanadate, tetraethylammonium bromide, and (S)-3.1 under hydrothermal conditions yielded dark green crystals of the V14 complex anion (S,S,S,S,S,S,S,S,)-3.3. The light blue polymeric compound [(VO)((S)- O3PCHMePh)•H2O]n, (S)-3.4, was obtained by refluxing a mixture of vanadium pentoxide and (S)-3.1 in 95% ethanol in air for 16 d. This compound was the first example of a layered material synthesized from a homochiral phosphonic acid.4 ! W\! O HO P HO Me 6!78!"#) !"#$%& !" *+!"%&),-.*/0) '#() 12"&)!" !2"3&)!" ! 43)5),-"1) ! VOCl , 12 h NaVO Et NBr +) 3 V O !, 16 d3, 4 [(VO)6((S)-O3PCHMePh)8{Cl}] 2 5, [Et4N][(V14O22)(OH)4((S)-O3PCHMePh)8] purple crystalscystals DCM 95 % EtOH!, H2O, 5 d dark green crystals 6!&!&!&!&!&!&!&!&78!"%) 6!&!&!&!&!&!&!&!&78!"!) [(VO)((S)-O3PCHMePh) • H2O]x light blue powder 6!78!"$) !"#$%&' ()*)' $%&'()*+*! ,-! .(+/01! 20&03+45! 6(,*6(,&0')*! 3)/+2)3! -/,5! '()! )&0&'+,64/)! 5,&,6(,*6(,&+.! 0.+3! 7!89()+:!! 0;4)!',!3+--+.41'+)*!+&!,<'0+&+&=!*+&=1)!./%*'01*!,-!7!>!>!>!>!>!>!>!>89(),!*4+'0<1)!-,/!?@;>!'()!A@BCD!61,'!*(,E&!+*!'(0'!,-!'()!0.(+/01! 41 F7GA8H7AIDJ&8"KL1MN>!E(+.(!+*!+*,*'/4.'4/01!',!7!>!>!>!>!>!>!>!>89(),!<0*)3!,&!*+5+10/+'+)*!+&!'()!O@!*6).'/0: ! "#! The ability of the chiral homogeneous heterogeneous vanadium phosphonates (S,S,S,S,S,S,S,S,)-3.2, (S,S,S,S,S,S,S,S,)-3.3, and (S,)-3.4 to catalyze the asymmetric epoxidation of cinnamyl alcohol and geraniol in the presence of tBuOOH was also investigated. These compounds exhibited exceptional catalytic ability with these allylic alcohols as substrates – affording the corresponding 2,3- epoxide products in yields greater than 90% within a few hours at room temperature in DCM. Unfortunately, only racemic product mixtures were obtained in all cases. '!()*!+!,"-"-"-"-"-"-"-"-./+)," )0! '!()*!+!,"-"-"-"-"-"-"-"-./+)+" )0! '!()*!+!,"./+)-! !"! !!#$%%&! !"#$"%" &$'&$"()*)" !"#$%&'()*)'$%&'()*'!&'+!,-.&'+,/0+1!'(2(*+.+(),!3.1!'+&+4(*+.(),!53.31/)2!6'(,6'(.3&+,! 7/&'!&'+!8'/43%!6'(,6'(.3&+!%/*3.1!9!:;()+!7+4+!+<<+8&/5+!83&3%-,&,!<(4!&'+!+6(=/13&/(.!(!.(!/.1/83&/(.!( One possibility for the apparent lack of enantioselectivity may lie in the design of the ligands themselves. The cage-type complex (S,S,S,S,S,S,S,S,)-3.2 can be envisioned as a cube with phosphorus atoms lying at each vertex and vanadyl active sites in the center of each face. A view of this molecule down one of these faces shows that the chirality at the benzylic position of the ligands is projected ! "#! towards the vanadium centers– effectively forming an asymmetric cleft about the active site. P P V V [(VO)6((S)-O3PCHMePh)8{Cl}] = P P = V V P P !!"!"!"!"!"!"!"!"#$!"#%$ V V P P H H Me Me Me H Me H Me H H Me Me H H Me %&'$ %('$ !"#$%&' ()*)' $%&'! ()! *+,-,(&(.+-(/! 0.! ,1(203%+0(.*! &%+%/45,3! 64! 77!8!8!8!8!8!8!8!89:()+8! 7!8!8!8!8!8!8!8!89:()(8'%.3!7!89:(),!;%4!6,!%!-,*%.3!?@A! 6(.3BCD!7%9!E,1-,*,.+%+0(.!()!+=,!&=0-%/!,.F0-(.;,.+!()!+=,!%&+0F,!*0+,!%--%.>,3!0.!%!/,)+:=%.3,3! (-0,.+%+0(.B!769!D#GH!&(<.+,-&/(&'I0*,!-(+%+0(.!%6(<+!+=,!?@A!/0>%.3!6(.3!-,* However, because there is rotational freedom about the P–C bonds, it seems likely that this rotation could result in an erosion of a well-defined asymmetric environment. Two extreme cases of such rotation are exemplified in Figure 3.6, and ! "#! portray active site architectures that would likely afford products of opposite handedness. Although the precise molecular structure was never ascertained, this rationale may also explain the lack of stereocontrol exhibited by the layered heterogeneous vanadium diphosphonate (S)-3.4.41 One way to test this hypothesis is to employ diphosphonates in place of the monophosphonate ligands.41 The additional metal-ligand bonds should lock the !-stereocenters in place by restricting free rotation about the P–C bonds. This chapter reports our exploration of chiral vanadium diphosphonates as asymmetric heterogeneous catalysts.41 !"!#$%&'()*+*#,-#.(+/01#0&2#34(+/01#5+6(,*6(,&+4#34+2#7+80&2*## To use diphosphonates as the linking ligand in vanadium-containing polymers, several criteria need to be met. The target compound should terminate on both ends with a phosphonic acid functionality, and be roughly linear. The linker should also be long enough to result in a material in which the pores are large enough to accommodate a variety of small molecule substrates. Furthermore, the ligands should be rigid enough to maintain a structurally robust and well-defined three-dimensional framework.42 Linear and planar linkers are particularly attractive, because they lack protruding groups that could fill the void spaces and ! "#! interfere with the movement of substrates through the framework.43-44 It was with these points in mind that we selected diphosphonates with naphthalene backbones. In our initial efforts, we thought it prudent to study an achiral diphosphonate in order to benchmark the synthesis of metal-diphosphonate materials and test for general catalytic activity. We chose 2,6-bis(phosphonatomethyl)naphthalene for this purpose. The phosphonic acid form of this species should be easily formed by acidic hydrolysis of the corresponding phosphonate tetraester, which in turn should be accessible by a tandem double Arbuzov reaction of 2,6-bis(dibromomethyl)- naphthalene and two equivalents of a trialkyl phosphite. The corresponding dibromide can be obtained from a variety of possible C–Br forming pathways from readily available starting materials. (HO) P O Br commericially 2 available starting O P(OH)2 Br materials !"#$%&'()*)'$%&'()*+&,%&-.!/0&,10*!&(!&,%!2%)-'%2!+0/,&,03%+%2-/,()/,(+-.!0.-24! Hence, reduction of the commercially available dimethyl 2,6- naphthalenedicarboxylate with BH3•THF in refluxing THF affords the corresponding 2,6-bis(hydroxymethyl)naphthalene 3.5. Treatment with phosphorus tribromide in DCM gives 2,6-bis(bromomethyl)naphthalene 3.6 in 65% yield over two steps. The Arbuzov reaction of 3.6 with excess triethylphosphite in refluxing ! "#! toluene gives the 2,6-bis(phosphonatomethyl)naphthalene tetraester 3.7, and acidic hydrolysis of the latter affords the desired diphosphonic acid 3.8 in essentially quantitative yield. O MeO a. HO b. OMe OH O 3.5 Br c. (EtO)2P O d. Br O P(OEt)2 3.6 3.7 (HO)2P O O P(OH)2 3.8 !"#$%&' ()*)' $%&'()*+*! ,-! ./(+0.1! 2+3(,*3(,&+/! ./+2! 1+&4)0! 5.*)2! ,&! .! &.3('(.1)&)! 5./45,&)6! 7).8)&'*!.&2!/,&2+'+,&*9!:.;!<=>?@=AB!@=AB!CD!EF!:5;!G<0>B!HFIB!JD!EFB!K#L!,M)0!N!*')3*!:/;! G:OP';>B!',1Q)&)B!RRD!EFB!S#L!:2;!R9R!J"L!=<09T/O=B!RND!EFB!RDDL6' For the synthesis of a chiral diphosphonic acid analog, methodology that was recently developed in our laboratory for the asymmetric synthesis of !- alkylphosphonic acids (see Chapter 2) was employed. Starting from the (S)-(BINOLato) benzylphosphonic acid (S)-3.9, deprotonation with nBuLi at -78°C followed by alkylation with a half equivalent of 2,6-bis(bromomethyl)naphthalene 3.6 affords the chiral diphosphonate as a diastereoenriched mixture with a d.r. of ! "#! 82:16:2. Isolation via column chromatography (SiO2, 2:3 EtOAc:hexanes) affords the major diastereomer, (S,S,S,S)-3.10, in 57% yield. The somewhat low yield can be attributed, in part, to the statistical distribution of diastereomers obtained from the installation of two chiral centers simultaneously on the same molecule. The absolute configuration of the major diastereomer was assigned based on our previous studies of the !-alkylation of (BINOLato) benzylphosphonates.41 Cesium fluoride mediated methanolysis followed by hydrolysis via the tetrakis(trimethylsilyl) diphosphonate intermediate45 gives the desired diphosphonic acid (S,S)-3.11 in 87% yield over 3 steps. O O P O O (major) P O (S,S,S,S)-3.10 O + O O O 1. nBuLi/THF, -78 °C O P P 2 2. O O (minor) O Br Br P O (S,R,S,S)-3.10 O 3.9 + O O P O O (minor) P O (S,R,R,S)-3.10 O !"#$%&'()*)'$%&''()*+,!-./&.-)+01!02!)3(!,3+*-.!4(15&.630%6301-)(!(%)(*!7!89()*!:+)3!01(93-.2! (;<+=-.(1)! 02! )3(! >+4*0'+>(! ()+' -220*>%! )3(! 7!?!?!?!8?! 7!?"?!?!8?! -1>! 7!?"?"?!8! >+-%)(*(0'(*%! 02! )3(!,3+*-.!>+630%6301-)(!(),-'+1!-!"@A!B#A!@!*-)+0C! ! "#! O O O P 1. CsF, MeOH HO P O O HO 2. TMSBr OH P O P OH 3. H2O/EtOH O O (S,S,S,S)-3.10 (S,S)-3.11 87% over 3 steps !"#$%&' ()*+)' $%&'()%*+*! (,! -./! 0.'+1)! &+2.(*2.(31-/! /*-/'! -(! -./! 0(''/*2(3&+34! 10+&! 5+1! 6*78 9/&+1-/&!-'13*/*-/'+,+01-+(3!:+-.!9/-.13();!,())(:/&!<%!.%&'()%*+*=!! !"#$%&'()*+,+$-.$/*(*0-1*'*-2+$34'45,26$7,8)-+8)-'4(*+!! Having established suitable synthetic methodology to obtain chiral and achiral diphosphonic acids with naphthalene backbones, we investigated their utility as linkers for the synthesis of polymeric vanadium(IV) compounds. One of the procedures used, which was developed by Johnson et al. and employed by Ellenwood for the synthesis of layered vanadium alkyl– and arylphosphonates, involves the in situ reduction of pentavalent vanadium.41,43,46-47 Our initial studies were carried out on the achiral diphosphonic acid 3.8. This acid and vanadium pentoxide were combined in 95% aqueous EtOH, brought to reflux for 72 h, and then cooled to room temperature. The solids were collected by vacuum filtration and washed with water, acetone, and DCM to afford the new vanadium phosphonate 3.12 as a green-grey powder. The compound is crystalline, but with small domains: the powder X-ray diffraction pattern exhibits an intense but broad peak at a d-spacing of 13.0 Å due to the vanadium diphosphonate product (Figure 3.11). The reaction did not go to completion, however, as shown by the ! "#! presence of peaks due to small amounts of unreacted V2O5. Further characterization of 3.12 was not pursued and instead we investigated how best to obtain pure samples by probing the factors the might have prevented complete conversion. !"#$%&'$(&%)*+,-).'/%&0)) )12)3&45$'""#0%)6789:) !"#$%&'()**)'#$%&'(!)*(+,!&-..(+/0-$1!2+00'(1!$.!()*+',3$00$4!0(+/'5648 ! (HO)2P O 3.12 2 + V2O5 O P(OH)2 95% EtOH green-grey solid 3.8 !"#$%&'()*+)'7,108'9-9!$.!08'!8'0'($:'1'$;9!4+0'(-+ ! In studies of the formation of analogous vanadium phosphonates, Johnson and coworkers have shown that the time required to reach completion can be significantly decreased by the addition of a mineral acid to the reaction mixture.46 ! ""! This finding, which suggests that the reduction from VV to VIV is slow in the absence of an acid, explains why long (> 10 d) reaction times were necessarily employed by Ellenwood and in earlier work by Johnson.47 Notably, acidic conditions are often used to synthesize molecular vanadium(IV) compounds from vanadium(V) starting materials – one example being the synthesis of the widely-utilized compound 49 VO(acac)2. 4H+ + V2O5 + OH 2 VO2+ + O + 3 H2O O 2 VO2+ + 2 2 "(VO)O3PR" + 4H+ P(OH)2 R !"#$%&' ()*()' $%&&'()*! +*,-./'&+! 0%1! 2-*! .,,*)*1.2'/3! *00*,2! %0! .,'4&! %/! 2-*! 1*45,2'%/!! %0!66!2%!6768! Therefore, in order to accelerate the formation of the desired vanadium(IV) species and drive the reaction of V2O5 to completion, the reaction conditions were modified as follows: (1) a catalytic amount of aqueous HCl was added to facilitate the reduction of the vanadium(V) starting materials, and (2) the ethanol solvent was replaced with isopropanol, because the latter solvent is better able to act as a sacrificial reductant (the oxidation from isopropanol to acetone should occur more readily than that from ethanol to acetaldehyde). These changes were effective: the i reaction of V2O5, PrOH, and 1M aqueous HCl affords a deep blue solution 2+ (presumably, of the reduced [VO(H2O)x] species) within 4 h of reflux. Addition of 3.8 and further reflux for 64 h affords a blue precipitate, which was collected by ! "#! vacuum filtration, washed with H2O, acetone, and DCM, and further dried in vacuum at 120 ºC to give 3.13 as a light blue powder. This material is insoluble in a wide variety of common solvents, including neutral H2O, acetone, DMF, DMSO, DCM, toluene, hexane, THF, EtOH, and Et2O. The compound does dissolve in 5 M aqueous NaOH, but this treatment results in the destruction of the compound. (HO) P O 2 2 O P(OH)2 ! 3.8 3.13 V O [VO2+] 2 5 light blue powder iPrOH 1M HCl !"#$%&'()*+)'$%&'()*+*!,-!'()!./(+0.1!()')0,2)&),3*!4.&.5+36!5+7(,*7(,&.')!()*(8! !"#$%&'()*,)'9,:5)0!;<0.%!5+--0./'+,&!*7)/'036!,-!()*(8! ! "#! The powder X-ray diffraction pattern of 3.13 (Figure 3.15) contains peaks out to 40º in 2!. There is an intense low angle peak with a d-spacing of 13.0 Å as calculated from the Bragg relationship.50 The peaks are relatively sharp and well defined in comparison to those observed for 3.12 (see Figure 3.11). These features are similar to those reported for other layered vanadium phosphonates.33,43,46-47 The reaction of VO2+ with monophosphonic acids under similar conditions typically affords layered materials with a 1:1 metal:phosphonate ratio,41,43 and is consistent with the diprotic nature of phosphonic acids. We therefore expected that diphosphonic acids (which are tetraprotic) would afford vanadyl diphosphonates with a metal:ligand ratio of 2:1. However, microanalytical data for 3.13 revealed an empirical formula of C12H16O9P2V, which corresponds to a metal:ligand stoichiometry of 1:1. There are at least two possible structures for this compound, consistent with this stoichiometry (Figure 3.13): (a) Each phosphonic acid group is singly deprotonated and the formula unit contains two molecules of water, or b) Both phosphonic acids are doubly deprotonated, and two hydronium cations balance the negative charges. O P HO (VO) O O • 2H O (a) OH P 2 O x O + P O (b) 2[H3O ] (VO) O O O P O x !"#$%&'()*+)!$%&!'&(()*+,!(-./0-/.,(!1&.!-2,!'&+34,.)0!0&4'&/56!()*(7! ! "#! The same methodology developed for 3.13 also can be used to obtain homochiral vanadium diphosphonates. Thus the reaction of the chiral diphosphonic acid (S,S)-3.11 with V2O5 affords the vanadyl phosphonate. (S,S)-3.14 as a light blue powder. The PXRD data indicates that this material is microcrystalline. (S,S)-3.14 likely has a layered architecture with a d-spacing of 14.8 Å. The 1.8 Å larger d-spacing seen for (S,S)-3.14 vs. 3.13 can be attributed to the two extra methylene groups in the backbone of (S,S)-3.11 relative to 3.8. !"#$%&'()*+)'$%&'()!*+),-!'.//),01.%2!3,11()2!%/!4!5!6+()*,7! ! ! "#! O (HO)2P 2 P(OH)2 ! (S,S)-3.11 O 3.14 V O [VO2+] 2 5 light blue powder iPrOH 1M HCl ! !"#$%&'()*+)'$%&'()*+*!,-!'()!(,.,/(+012!()')0,3)&),4*!51&16+4.!6+7(,*7(,&1')!8!9!:;()*, The samples of (S,S)-3.14 described above were not suitable for analysis by single crystal X-ray diffraction. Large crystals of an insoluble solid are difficult to obtain unless the reaction(s) to assemble the solid are reversible. Some examples of single crystals of metal phosphonates suitable for XRD have been reported; these samples are typically synthesized under solvothermal conditions however, which provide for the necessary reversibility of the assembly process.51-53 Accordingly, we investigated various combinations of conditions, vanadium starting materials, and additives for both solvo– and hydrothermal reactions of our chiral diphosphonates (see Table 3.5 in section 3.7). Additives such as amines and fluoride salts were employed to assist in templating the ordered formation of extended crystalline structures.44,53 Unfortunately, X-ray quality crystals of vanadium diphosphonates using the ligand 3.8 remained elusive despite a large number of attempts. The observed resistance to macrocrystallization may be due to the low aqueous solubility of our diphosphonic acids at the low pH required to generate the reduced vanadium(IV) species, which is due in part to the lipophilicity of the organic portion of the ligand. This result was not entirely unanticipated; it is ! "#! well established that metal-phosphonate compounds tend to precipitate as powders rather than crystallize.20 !"#$%&'&()'*+$,-*.&'*/01$2*'3$4&0&.*56$7*83/183/0&'91$ We next turned to an investigation of the ability of the new vanadium diphosphonates 3.13 and (S,S)-3.14 to serve as heterogeneous catalysts for the epoxidation of olefins. Initial efforts were focused on the achiral compound 3.13 in order to benchmark general reactivity and to optimize the reaction conditions. Addition of a nonane solution of tBuOOH to 3.13 suspended in DCM was accompanied by a rapid color change of the solid powder from light blue to purple, presumably due to the oxidation of VIV to VV. The allylic alchohol substrate was then added and the reaction progress was monitored by TLC. Upon completion of the reaction, the solids were easily separated from the mixture by vacuum filtration. Under these conditions, geraniol is converted to the 2,3-epoxygeraniol in nearly quantitative yield in 4 h with 1.5 equivalents of tBuOOH and 5 mol % (based on V) of 3.13. As previously noted for vanadyl monophosphonates,41 this result illustrates the chemoselectivity of the catalytic transformation, because the epoxidation is selective for the 2,3-ene portion of the allylic alcohol and leaves the 6,7-ene essentially unchanged. Furthermore, simple olefins such as indene, norbornene, and cyclooctene undergo little to no oxidation under these reaction ! "#! conditions. The more electron deficient cinnamyl alcohol and the more sterically hindered linalool both undergo highly efficient allylic epoxidation, although longer reaction times are required for these substrates. In all instances, the final reaction solutions after removal of the catalyst are colorless, and at there is no evidence that phosphonate groups are present in the crude epoxide product as judged by NMR spectroscopy. Furthermore, if the catalyst/tBuOOH mixture is filtered before addition of the geraniol substrate, only trivial amounts (<10 %) of 2,3-epoxygeraniol are observed after 72 h at room temperature. These results suggest that the active polymeric species remains intact under the reaction conditions, and that catalysis effectively proceeds in a heterogeneous fashion. )$%&'( *+,-(./0( !"#$%&'( 1(2#345( 67( 8( 67( 8( 67( 6( 7( 99( :;( 97( :6( 9;( !"#$%& '()(& $%&%'(&)*! +,-.)/%&)-0! 1)&2! #! 3-'! 4! -5! &2+! %*2)6%'! 2+&+6-7+0+-89! :%0%/)83! /),2-9,2-0%&+!'(*'!)9!*2+3-9+'+*&):+!5-6!%''(')*!%'*-2-'9;!<+6*+0&!*-0:+69)-0!1%9!*%'*8'%&+/!=(! )0&+76%&)-0!-5!>?!@AB!6+9-0%0*+9!-6!C$DAE!9)70%'9;!! ! "#! We also investigated the effect of reaction temperatures and the choice of the stoichiometric oxidant and solvent. At 0 ºC instead of room temperature, the rate of catalysis is slowed and the epoxidation reaction is only 80 % complete after 4 h. Conversely, at 70 ºC the rate of catalysis increases so that the epoxidation reaction is complete (>99 % conversion of geraniol to 2,3-epoxygeraniol) after only 3 h in n-hexane, even with a lowered catalyst loading of 2 mol%. Unlike tert-butyl hydroperoxide, the use of hydrogen peroxide–urea adduct as the oxidant affords very little to no oxygen transfer. Aqueous hydrogen peroxide was similarly ineffective, and causes decomposition of the catalyst and dissolution of vanadium species in the aqueous phase. It is also of interest that, unlike with many of the known homogeneous epoxidation catalysts, molecular sieves are not necessary to attain high yields of product.54 However, changing the solvent to a 1:1 acetonitrile:water mixture dramatically inhibits the catalysis. !"#$%&! '('(! $%&'(')*&'+,! -+,.'&'+,/! 0+1! &23! */4((3&1'-! 3%+5'.*&'+,! +0! *6646'-! *6-+2+6/! 7'&2! *-2'1*6!23&31+83,3+9/!:*,*.'9(!.'%2+/%2+,*&3!-*&*64/&!'()';!! ! "#! We then investigated the ability of the homochiral vanadium diphosphonate (S,S)-3.14 to serve as a catalyst for asymmetric epoxidations. As observed previously by Ellenwood41 with the chiral vanadium(IV) monophosphonate (S)-3.4, this material proved capable of catalyzing the chemoselective epoxidation of allylic alcohols under heterogeneous conditions. The extent of asymmetric induction was quantified by chiral stationary phase HPLC, with supercritical CO2 as the mobile phase. The catalysis proceeds with a modest amount of stereocontrol: the epoxidation products of geraniol and cinnamyl alcohol were obtained with e.r.’s of ca. 3:2. The absolute configurations of the epoxide products were assigned from the sign of their optical rotations in comparison with literature values.55-56 R R' O 5 mol % (S,S)-3.14 * * 1.5 tBuOOH, DCM R R' R'' R''' R'' R''' 45678% !"#$%&'(% 9:.5678% ,%-./01% $1:1% O )% (S) 22% )=%;%<>% OH (S) OH O (S) OH OH *+% (S) 23% )2%;%<*% !"#$%&'()(&$%&'()&!*+!),%!-.).(/)0-!%1*203.)0*4!*+!5%6.40*(!.43!-044.7/(!.-*,*(!80),!9!7*(!:!*+! ),%!-,06.(!,%)%6*5%4%*'&!-.).(/&)!;!'(*)?!! ! ! "#! !"#$%&'()*+,&'+$-'.$/*0*12$3&14$ This chapter has described the synthesis of novel chiral and achiral diphosphonic acids with naphthalene backbones, and their use as ligands for the synthesis of polymeric vanadium(IV) phosphonates. These materials, which are insoluble in most common solvents, are active catalysts for the chemoselective epoxidation of allylic alcohols with tBuOOH as the stoichiometric oxidant. The heterogeneous catalyst can readily be separated from the reaction mixture by simple filtration. When constructed from diphosphonic acids bearing !-stereocenters, the vanadium compounds catalyze the asymmetric epoxidation of geraniol and cinnamyl alcohol. Enantioselectivies for this transformation were small (e.r.’s ca. 3:2), which is possibly due to distance between the stereogenic centers in the ligand and the metal active site. Despite the low selectivities, these results provide encouraging evidence that metal-phosphonates constructed from chiral diphosphonate linkers have potential as heterogeneous asymmetric catalysts. !"5$67821,92'0-)$ All manipulations were carried out under argon or vacuum unless otherwise specified. Solvents were distilled under nitrogen from calcium hydride (dichloromethane), sodium (toluene), sodium/benzophenone (tetrahydrofuran), or ! "#! magnesium turnings (methanol). All H2O used during synthetic manipulations was purified to 18.2 M !/cm resistivity using a Thermo-Scientific Barnstead Nanopure or Millipore Nanopure water purification systems. Deuterated solvents were used as received. The (S)-(BINOLato)benzylphosphonic acid (S)-3.9 was obtained by methodology described in Chapter 2 of this dissertation. Triethylamine and pyridine (Aldrich) was dried over CaH and distilled under argon before use. All other reagents were used as received. High-resolution electrospray ionization mass spectrometry was performed on a Waters Q-Tof Ultima Tandem Quadrupole/Time- of-Flight instrument by the University of Illinois Mass Spectrometry Laboratory. High-resolution electron ionization mass spectrometry was performed on a Waters GCT Premier EI/CI/FD/FI spectrometer by the University of Illinois Mass Spectrometry Laboratory. NMR spectra were recorded on a Varian Unity-500 spectrometer at 11.74 T. NMR chemical shifts are reported in ! units relative to 1 13 31 TMS ( H, C) or 85% H3PO4 ( P) with positive chemical shifts being to higher frequency. Melting points were measured on a Thomas-Hoover Unimelt apparatus. Flash column chromatography was performed with Merck silica gel (32-63 micron, 230-400 mesh). Analytical TLC was performed with Merck pre-coated silica gel 60 F254 plates (250 µm layer thickness). TLC spots were visualized using a Spectroline UV lamp (254 nm). Diastereomeric excesses of the ligands were determined by integrating 31P NMR resonances. GC/MS was performed on a Shimadzu GCMS- QP2010 SE Instument. Enantiomeric ratios of the epoxide products obtained from asymmetric catalysis experiments were determined by integrating the HPLC traces ! ""! obtained from analytical supercritical fluid chromatography (CSP-SFC) with spectrophotometric detection (220 nm) using a Daicel Chiralpak OD column, and relative to analytically pure racemic mixtures obtained from epoxidations with t 38 BuOOH and 1 mol % VO(acac)2 according to established literature procedures. Optical rotation measurements were performed on a Jasco P-2000 spectropolarimeter. !"#$%&'()*+,-.*/01)*23456)1)52040"789:9777 7 O 4 5 11' 10 6 OMe 3 OH HO MeO 2 9 7 11 1 8 O A suspension of dimethyl 2,6-naphthalenedicarboxylate (4.40 g, 18.0 mmol) in THF (50 mL) at 0 ºC was treated with a solution of BH3•THF (90 mL of a 1.0M solution in THF, 90 mmol). The mixture stirred at 0 ºC for 30 min, and then was brought to reflux for 16 h. After the mixture was cooled to room temperature, it was quenched with sat. NH4Cl (100 mL) and poured into Et2O (150 mL). The layers were separated and the aqueous layer was extracted with Et2O (2 ! 50 mL). The organic layers were combined, dried over MgSO4, and taken to dryness on a rotary ! "##! evaporator to afford the crude diol as a white solid, which was used in subsequent + transformations without further purification. HRMS m/z (EI ): calcd for C12H12O2 + 1 [M] , 188.0837; found, 188.0837. H NMR (500 MHz, d6-DMSO): ! 7.82 (d, J = 8.4 Hz, 2H, 4,8-CH), 7.77 (s, 2H, 1,5-CH), 7.43 (d, J = 8.3 Hz, 2H, 3,7-CH), 4.64 (s, 4H, 13 1 11,11"-CH2). C{ H} NMR (d6-DMSO, 126 MHz): ! 139.7, 132.1, 127.4, 125.4, 124.2, 63.1. !"#$%&'(%)*+*+,-./01234.-.30,2,"567#!""" 4 5 11' 10 OH 3 6 Br HO Br 2 9 7 11 1 8 To the crude diol 3.5 obtained above was added DCM (80 mL) and the suspension was cooled to 0 ºC. Phosphorus tribromide (2.00 mL, 21.1 mmol) was added dropwise and, after the addition was complete, the mixture was brought to reflux for 12 h. The reaction mixture was cooled to room temperature and quenched with 2M aq. NaOH (100 mL) and the aqueous layer was washed with DCM (3 # 50 mL). The organic fractions were combined and washed with 2M aq. HCl (100 mL), and the aqueous layer was back extracted with DCM (50 mL). The organic fractions were combined and dried over MgSO4. Removal of solvent by rotary evaporation afforded the dibromide as a fluffy, pale yellow solid in pure form. Yield: 3.68 g (65% + + over 2 steps). Mp. 183-186 ºC. HRMS m/z (EI ): calcd for C12H10Br2 [M] , 311.9149; 1 found, 311.9150. H NMR (500 MHz, CDCl3): ! 7.83 (s, 2H, 1,5-CH), 7.82 (d, J = 8.2 ! "#"! Hz, 2H, 4,8-CH), 7.54 (dd, J = 8.4, 1.8 Hz, 2H, 3,7-CH), 4.67 (s, 4H, C(11,11!)H2). 13 1 C{ H} NMR (CDCl3, 126 MHz): " 135.9, 132.8, 128.8, 127.6, 127.4, 33.7. !"#$%&'()&*+,-./,0'/,012+03*+,-.412/,+,2.*1*"5678!""" 4 5 11' 10 O 3 6 Br O P O O Br P 7 O 12 2 9 O 11 1 8 13 To a solution of the dibromide 3.6 (942 mg, 3.00 mmol) in toluene (25 mL) was added triethyl phosphite (2.0 mL, 11.7 mmol) and the resulting mixture was brought to reflux for 36 h. The solvent was removed in vacuum and the volatile byproducts were removed by further drying in vacuum at 90 ºC for 24 h to afford the desired diphosphonate ester as a pale yellow solid. Yield: 1.22 g (95 %). Mp. 149-151 + + 1 ºC. HRMS m/z (ESI ): calcd for C20H31O6P2 [M + H] , 429.1590; found, 429.1589. H NMR (500 MHz, CDCl3): " 7.75 (d, J = 8.4 Hz, 2H, 4,8-CH), 7.72 (s, 2H, 1,5-CH), 7.43 (d, J = 8.4 Hz, 2H, 3,7-CH), 4.07–3.96 (m, 8H, 12a,12b-CH2 # 4), 3.30 (d, J = 31 1 21.5 Hz, 4H, 11,11!-CH2), 1.24 (t, J = 7.1 Hz, 12H, 13-CH3 # 4). P{ H} NMR (202 MHz, CDCl3): " 26.9 (s). !"#$%&'(3*+,-./,0'/,01&9529&)412/,+,2.*1*"567:!""" O 4 5 11' 10 OH 3 6 O P O P O O HO OH P O O P 2 9 7 O HO 11 1 8 ! "#$! The bis(phosphonate) tetraester 3.7 (252 mg, 589 µmol) was combined with a 1:1 mixture of 48% aq. HBr and AcOH (30 mL). The mixture was brought to reflux for 16 h, and then was cooled to room temperature. The solids were separated and washed with H2O (15 mL) and cold DCM (5 mL), and then in vacuum to afford the desired diphosphonic acid as an off-white solid. Yield: 175 mg (94%). Mp. 268-270 ºC - - (dec.). HRMS m/z (ESI ): calcd for C12H13O6P2 [M - H] , 315.0187; found, 315.0184. 1 H NMR (500 MHz, d6-DMSO): ! 7.73 d, J = 8.4 Hz, 2H, 4,8-CH), 7.68 (s, 2H, 1,5- 13 1 CH), 7.39 (d, J = 8.4 Hz, 2H, 3,7-CH), 3.10 (d, J = 21.2 Hz, 4H, 11,11"-CH2). C{ H} NMR (126 MHz, d6-DMSO): ! 131.55 (s), 131.32 (d, JCP = 9.2 Hz), 128.53 (s), 127.49 31 1 (d, JCP = 7.0 Hz), 126.80 (s), 35.55 (d, JCP = 132.1 Hz). P{ H} NMR (202 MHz, d6- DMSO): ! 22.3 (s). !""#!$""#%!&'($(%'!!"!$"%!&')*+,-,*./0/'1$2'345.#46!"'+,/05./-,*0/'1$"' 345.&.!340*+,-,781$"'"9"%$1%'#:8"$;$1:347<*+,76+,/+40/= ('7<43/&$= !!$!$!$!&';>"?!""" " " O O P 2 O 15 14 18 19 24 17 20 1 8 13 O O 9 7 21 O 23 22 P 2 12 16 O 6 P 3 10 11 O 4 5 O ! "#$! To a solution of the chiral benzylphosphonate ester (S)-3.9 (855 mg, 2.02 mmol) in THF (175 mL) at -78 ºC was added dropwise nBuLi (1.30 mL of a 1.6M soln. in hexanes, 2.08 mmol). The resulting bright orange solution was stirred at - 78 ºC for 30 min, and then treated dropwise with a solution of 2,6- bis(bromomethyl)naphthalene 3.6 (314 mg, 1.00 mmol) in THF (20 mL). The solution was stirred at -78 ºC for 3h, quenched with 10% aq. HCl (50 mL), and warmed to room temperature. The mixture was poured into DCM (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (50 mL) and organic fractions were combined and washed with brine (50 mL). The organic solution was dried over MgSO4 and taken to dryness by rotary evaporation to afford a yellow solid. 31P NMR analysis indicated a 89:8:3 mixture of diastereomers. The major diastereomer was isolated by column chromatography on silica gel (2:3 EtOAc:hexanes eluent) as an off-white solid. Yield: 565 mg (57%). 1H NMR (500 MHz, CDCl3): ! 8.02 (d, J = 8.9 Hz, 2H, Ar-H), 7.95 (d, J = 8.2 Hz, 2H, Ar-H), 7.91 (d, J = 8.2 Hz, 2H, Ar-H), 7.85 (d, J = 8.8 Hz, 2H, Ar-H), 7.55 (d, J = 8.8 Hz, 2H, Ar- H), 7.52-7.43 (m, 4H, Ar-H), 7.41-7.20 (m, 22H, Ar-H), 6.86 (d, J = 8.4 Hz, 2H, Ar- H), 6.80 (d, J = 8.8 Hz, 2H, Ar-H), 3.76-3.68 (m, 2H, 12,12"-CH), 3.51-3.23 (m, 4H, 13 1 11,11"-CH2). C{ H} NMR (126 MHz, CDCl3): ! 147.4 (d, JCP = 10.2 Hz), 145.9 (d, JCP = 10.2 Hz), 135.1 (s), 134.9 (s), 134.1 (d, JCP = 4.6 Hz), 132.5 (s), 132.4 (s), 131.9 (s), 131.8 (s), 131.4 (s), 131.2 (s), 130.6 (s), 129.9 (d, JCP = 8.2 Hz), 128.8 (s), 128.5 (s), 128.3 (s), 127.8 (s), 127.4 (s), 127.3 (s), 127.2 (s), 126.9 (s), 126.7 (s), 126.6 (s), 125.7 ! "#$! (s), 125.6 (s), 121.9 (s), 121.6 (s), 121.2 (s), 120.5 (d, JCP = 3.6 Hz), 45.0 (d, JCP = 31 1 128.1 Hz), 38.3 (d, JCP =3.1 Hz). ). P{ H} NMR (202 MHz, CDCl3): ! 39.3 (s). !"#$%&'((!)$!$*+,-./$!$(*+0'*+0-&1231&4),5+./)-3*+5+3/,-,"2(!"!)$6788!""" " O O P O O P O O 15 OH 14 HO 1 8 P 9 7 13 O 2 12 O 3 10 6 P 4 5 11 OH HO The chiral diphosphonate (S,S,S,S)-3.10 (720 mg, 712 µmol) was slurried with dry MeOH (30 mL). Cesium fluoride (1.08 g, 7.12 mmol) was added and the mixture brought to reflux for 18 h. The pale orange solution was cooled to room temperature and the solvent was removed by rotary evaporation. The residue was dissolved in DCM (30 mL) and washed with 2.5 M NaOH (40 mL) and brine (50 mL). The solution was dried over MgSO4 and the solvent removed by rotary evaporation to afford the crude tetramethyl 2,6-bis(phosphonatomethyl)- naphthalene ester as a yellow oil. ! "#$! The crude tetramethyl ester was dissolved in dry DCM (15 mL) and then treated with trimethylsilyl bromide (1.50 mL, 11.4 mmol) by syringe. After the mixture had been stirred at room temperature for 16 h, volatile materials were removed under high vacuum. The resulting solid was dissolved in absolute EtOH (20 mL), and the resulting solution was diluted with H2O (20 mL). Slow evaporation of the solution to approximately 10 mL resulted in the precipitation of an off white solid, which was collected by vacuum filtration and further dried overnight in vacuum. Yield: 308 mg (87% over three steps). HRMS m/z (ESI-): calcd for - 1 C26H25O6P2 [M - H] , 495.1126; found, 495.1121. H NMR (500 MHz, d6-DMSO): ! 7.45 (d, J = 8.5 Hz, 2H, 4,8-CH), 7.37 (s, 1,5-CH), 7.22-7.18 (m, 4H, Ar-H), 7.15-7.10 (m, 4H, Ar-H), 7.10-7.01 (m, 4H, Ar-H), 3.45 (ddd, J = 14.4, 8.5, 1.5 Hz, 2H, 11a,11a"-CH), 3.28 (ddd, J = 21.9, 11.9, 2.4 Hz, 2H, 12,12"-CH), 3.16 (td, J = 13.1, 6.1 13 1 Hz, 2H, 11b,11b"-CH). C{ H} NMR (126 MHz, d6-DMSO): ! 137.6 (d, JCP = 6.3 Hz), 136.8 (d, JCP = 17.3 Hz), 131.4 (s), 129.4 (d, JCP = 6.3 Hz), 127.7 (s), 127.2 (s), 126.9 31 1 (s), 126.4 (s), 126.0 (s), 46.8 (d, JCP = 131.9 Hz), 35.7 (s). P{ H} NMR (202 MHz, d6- DMSO): ! 24.2 (s). !"#$"%&'()*$)+,&"%$-.*$*"/0%1)%!"" Vanadium pentoxide (228 mg, 1.25 mmol) was slurried with iPrOH (20 mL) and 1 M aq. HCl (5 mL) and the mixture was brought to reflux for 2 h. Over this time, the color changed from red-orange to a dark blue, indicative of a reduction to ! "#$! VIV. The diphosphonic acid 3.8 (392 mg, 1.24 mmol) was added and the mixture was heated to reflux for an additional 64 h. After being cooled to room temperature, the light blue precipitate was collected by vacuum filtration and washed with H2O (10 mL), acetone (10 mL), and DCM (10 mL). Drying under high vacuum overnight at 120 ºC afforded of a light blue powder. Yield: 465 mg (89%). Anal. Calcd. for C12H16O9P2V: C, 34.55; H, 3.87; P, 14.85; V, 12.21. Found: C, 34.84; H, 3.35; P, 14.79; V, 12.45. !"#$!%!&'(")*$+$*,&(+(-$+.-(./&+(-+$*,&(&*")(01-(-"%2$!%!&')3.4!"" " A slurry of vanadium pentoxide (74 mg, 407 µmol) in iPrOH (20 mL) and 1M aq. HCl (5 mL) was brought to reflux for 4 h, during which time the color changed from red-orange to dark blue, indicative of a reduction to VIV. The chiral diphosphonic acid (S,S)-3.11 (200 mg, 403 µmol) was added and the mixture was heated to reflux for an additional 64 h. After the mixture was to room temperature, the light blue precipitate was collected by vacuum filtration and washed with H2O (10 mL), acetone (10 mL), and DCM (10 mL). The solid was dried under high vacuum overnight at 120 ºC to afford a light blue powder. Yield: 138 mg (57%). Anal. Calcd. for C26H28O9P2V: C, 52.19; H, 4.88; P, 8.51; V, 10.35. Found: C, 56.17; H, 4.88; P, 11.36; V, 7.80. ! "#$! !"#"$%&'($)*"+,$"'-)$'."/"$)0"#"),1'21344"/$5*'67)85+%/5)#9''' A slurry of the heterogenous catalyst (5 mol % based on V) in DCM (10 mL) was treated with the substrate (typically 0.5 mmol). Addition of 1.5 equivalents of tBuOOH (5.5 M in nonane) caused an instantaneous color change of the solids from light blue to purple. Upon completion of the reaction as judged by TLC (1:1 EtOAc:hexanes) analysis, the mixture was filtered and the precipitate washed with DCM. The washings and the filtrate were combined, washed with 2.5 M NaOH (2 ! 10 mL), brine (1 ! 10 mL), dried over MgSO4, and concentrated by rotary evaporation. The percent conversion and yields were determined by integration of the corresponding 1H NMR resonances or and/or GC/MS signals. ! !"#"$%&' ($)*"+,$"' -)$' /:"' ;)&<)/:"$4%&' ;3#/:"151' )-' =%#%+5,4' >57:)17:)#%/"19''' Pyrex screw-top test tubes (13 ! 100 mm) were charged with an appropriate vanadium precursor, ligand, solvent, and additives, and the mixture was homogenized with the aid of a glass rod and vortex mixer. Unless otherwise noted, the tubes were sealed with Teflon-lined caps and placed in a steel bomb with a Teflon o-ring. The entire apparatus was placed in an oven for a given amount of time at a specified temperature, followed by slow cooling to room temperature over ca. 3 h. Specific conditions for each reaction are shown in Table 3.5. ! "#$! !"#$% &'($)*+$,-$ ./01"2 322/#/4)5,6 7-84)"# 9-"2/#/-",' :$-2+*# ;-#), &'()'*+,'-''''''''''''''''''''''''' (HO) P O 67'8&9:;<'''''''''''''''''''''''''''''''''''''''CDEF0'D=GH=/?'I0=JKL' 20E33H0E'/=/'>1L' < !"#"$ 2 % O P(OH)2 .'/0123'45" &:'(=>?'&@:'AB IDHE'217/E0 EMCEE/'9:'23= 9-"*= :N5'O :N&'O 5'()'5P&P&'''''''''''''''''''' 2FDE'REDD17'D=GH=/?' 67'8&9:;<''''''''''''''''''''''''''''''''''''''' 20E33H0E'/=/'>1L' > !5"9 (HO)2P O % *+,P&O' D=JKLS/F0T'J0EE>' O P(OH) &:'(=>?'&@:'AB EMCEE/'9:'23= 2 4BDP=Q0"4 31D=/3 9-"*= :N:U'O :N:9'O #V'''''''''''''''''''''''''''''''''''''''CD1H/R'D=GH=/?'1D=WE' ? !"#"$ (HO)2P O :N&'()'2R &N9'()'*+, O P(OH)2 U5'K?'5::'AB J0EE>'CKH>T3 9-"*= :N&.'O :N:U'O #V'''''''''''''''''''''''''''''''''''''''D=JKL'IDHE'D=GH=/?' @ !"#"$ (HO)2P O :N&'()'2R &N9'()'45" O P(OH)2 U5'K?'5::'AB I0=JKL'IDHE'CKH>T3 9-"*= :N&.'O :N:U'O &N:'()'*+,'-''''''''''''''''' #V'''''''''''''''''''''''''''''''''''''''2FDE'IDHE'D=GH=/?' 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""#! !"#$% &'($)*+$,-$ ./01"2 322/#/4)5,6 7-84)"# 9-"2/#/-",' :$-2+*# ;-#), 01'''''''''''''''''''''''''''''''''''''''89:;<=>?@@A'BC9DEB':AE' <= !"#$ (EtO)2P O %&'()'*+,-" ".$'/)'-"# 89F@5'/D;?C;?+BG:99DA@' O P(OEt)2 23'45'63&'7* HCIE@? 9-"*> &.&$'J &.&2'J 01''''''''''''''''''''''''''''''''''''''' '*BM ".$'/)'-"# G:A'BC9DEB O P(OH)2 23'45'63&'7* 9-"*> &.66'J &.&2'J 01''''''''''''''''''''''''''''''''''''''';C9C?9@BB'9DNFDE5' 9-"*> 01''''''''''''''''''''''''''''''''''''''';C9C?9@BB'9DNFDE5' << !"#$ (EtO)2P O 2&'()'1OP ".$'/)'-"# O P(OEt)2 L"'45'63&'7* 89F@'BC9DEB 9-"*> 01''''''''''''''''''''''''''''''''''''''';C9C?9@BB'9DNFDE5' <@ !"#$ (EtO)2P O L&'()'*+,-" $.&'/)'-"# O P(OEt)2 L"'45'63&'7* 89F@'BC9DEB 9-"*> ! !"#$%&'()&*+,-.(/(&$%%&'(%)!%*!*+%,-.!)-./0&!123)%,0)!*4!5,.,6-7'!6-(8*)(8*.,%&!1*'(*7.6)!)7-%,+0&!4*2!9:2,3!6-442,1%*'&%23;!<=!>! )*05*%8&2',0;! ! ""#! !"#$% &'($)*+$,-$ ./01"2 322/#/4)5,6 7-84)"# 9-"2/#/-",' :$-2+*# ;-#), 34''''''''''''''''''''''''''''''''''''''';<=>'' <= !"#$ (EtO)2P O %&'()'*%+',-.'/01 *.&'2)'/"# O P(OEt)2 5"'67'8%&'9: B1>>C'DE 9-"*> 34'''''''''''''''''''''''''''''''''''''''G 9-"*> 34'''''''''''''''''''''''''''''''''''''''G 9-"*> 5&.8'2B'F*'>-.H' 8T8T8' D ! ""#! !"#$%&'&(&)*&+! 1. Howard, P.; Morris, G.; Sunley, G. Catalysis in the Chemical Industry. In Metal-catalysis in Industrial Organic Processes, Royal Society of Chemistry: United Kingdom, 2006. 2. George, S. Introduction: Heterogeneous Catalysis. Chem. Rev. 1995 95 (3), 475-476. 3. de Jong, K. P. Synthesis of Solid Catalysts. Wiley-VCH: Darmstadt, Germany, 2009. 4. Heitbaum, M.; Glorius, F.; Escher, I. Asymmetric Heterogeneous Catalysis. Angew. Chem. Int. Ed. 2006, 45, 4732-4762. 5. Pugin, B.; Blaser, H.-U. Catalyst Immobilization: Solid Supports. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. Springer: Germany, 1999; Vol. 3. 6. Wang, Z.; Ding, K.; Uozumi, Y. An Overview of Heterogeneous Asymmetric Catalysis. In Handbook of Asymmetric Heterogeneous Catalysis, Ding, K.; Uozumi, Y., Eds. Wiley-VCH: Weinheim, Germany, 2008. 7. Ma, L.; Abney, C.; Lin, W. Enantioselective catalysis with homochiral metal- organic frameworks. Chem. Soc. Rev. 2009, 38 (5), 1248-1256. 8. Zhoua, H.-C.; Kitagawa, S. Metal–Organic Frameworks (MOFs). Chem. Soc. Rev. 2014, 45, 5415-5418. ! ""#! 9. Ferey, G. Hybrid porous solids: past, present, future. Chem. Soc. Rev. 2008, 37 (1), 191-214. 10. Farha, O. K.; Eryazici, I.; Jeong, N. C.; Hauser, B. G.; Wilmer, C. E.; Sarjeant, A. A.; Snurr, R. Q.; Nguyen, S. T.; Yazaydin, A. O.; Hupp, J. T. Metal-organic framework materials with ultrahigh surface areas: is the sky the limit? J. Am. Chem. Soc. 2012, 134 (36), 15016-15021. 11. Chen, B.; Wang, L.; Zapata, F.; Qian, G.; Lobkovsky, E. B. A Luminescent Microporous Metal-Organic Framework for the Recognition and Sensing of Anions. J. Am. Chem. Soc. 2008, 130, 6718-6719. 12. Xu, H.; Liu, F.; Cui, Y.; Chen, B.; Qian, G. A luminescent nanoscale metal- organic framework for sensing of nitroaromatic explosives. Chem. Commun. 2011, 47 (11), 3153-3155. 13. Lee, J.; Farha, O. K.; Roberts, J.; Scheidt, K. A.; Nguyen, S. T.; Hupp, J. T. Metal-organic framework materials as catalysts. Chem. Soc. Rev. 2009, 38 (5), 1450-1459. 14. Liu, J.; Chen, L.; Cui, H.; Zhang, J.; Zhang, L.; Su, C. Y. Applications of metal-organic frameworks in heterogeneous supramolecular catalysis. Chem. Soc. Rev. 2014, 43 (16), 6011-6061. 15. Leus, K.; Muylaert, I.; Vandichel, M.; Marin, G. B.; Waroquier, M.; Van Speybroeck, V.; Van der Voort, P. The remarkable catalytic activity of the saturated metal organic framework V-MIL-47 in the cyclohexene oxidation. Chem. Commun. 2010, 46 (28), 5085-5087. ! "#$! 16. Farrusseng, D.; Aguado, S.; Pinel, C. Metal-organic frameworks: opportunities for catalysis. Angew. Chem. Int. Ed. Engl. 2009, 48 (41), 7502- 7513. 17. Sherrington, D. C. Polymer-supported metal complex alkene epoxidation catalysts. Catal. Today 2000, 57, 87-104. 18. Wu, C. D.; Lin, W. Heterogeneous asymmetric catalysis with homochiral metal-organic frameworks: network-structure-dependent catalytic activity. Angew. Chem. Int. Ed. Engl. 2007, 46 (7), 1075-1078. 19. Cho, S. H.; Ma, B.; Nguyen, S. T.; Hupp, J. T.; Albrecht-Schmitt, T. E. A metal-organic framework material that functions as an enantioselective catalyst for olefin epoxidation. Chem. Commun. 2006, (24), 2563-2565. 20. Shimizu, G. K.; Vaidhyanathan, R.; Taylor, J. M. Phosphonate and sulfonate metal organic frameworks. Chem. Soc. Rev. 2009, 38 (5), 1430-1449. 21. Demadis, K. D.; Stavgianoudaki, N. Structural Diversity in Metal Phosphonate Frameworks: Impact on Applications. In Metal Phosphonate Chemistry: From Synthesis to Applications, Clearfield, A.; Demadis, K. D., Eds. Royal Society of Chemistry: 2012. 22. Chandrasekhar, V.; Senapati, T.; Dey, A.; Hossain, S. Molecular transition- metal phosphonates. Dalton Trans. 2011, 40, 5394-5418. 23. Clearfield, A. Metal Phosphonate Chemistry. Prog. Inorg. Chem. 1998, 47, 371-510. ! "#"! 24. Clearfield, A. Recent advances in metal phosphonate chemistry. Curr. Opin. Solid State Mater. Sci. 1996, 1, 268-278. 25. Khan, M. I.; Zubieta, J. Oxovanadium and Oxomolybdenum Clusters and Solids Incorporating Oxygen-Donor Ligands. Prog. Inorg. Chem. 1995, 43, 1- 149. 26. Burkholder, E.; Golub, V.; O’Connor, C. J.; Zubieta, J. Solid-State Coordination Chemistry of the Oxomolybdate-Organodiphosphonate/Nickel- Organoimine System: Structural Influences of the Secondary Metal Coordination Cation and Diphosphonate Tether Lengths. Inorg. Chem. 2004, 43, 7014-7029. 27. Bideau, J. L.; Payen, C.; Palvadeau, P.; Bujoli, B. Preparation, Structure, and II Magnetic Properties of Copper(II) Phosphonates. !-Cu (CH3PO3), an Original Three-Dimensional Structure with a Channel-Type Arrangement. Inorg. Chem. 1994, 33, 4885-4890. 28. Gao, Q.; Guillou, N.; Nogues, M.; Cheetham, A. K.; Ferey, G. Structure and Magnetism of VSB-2, -3, and -4 or Ni4(O3P-(CH2)-PO3)2‚(H2O)n (n = 3, 2, 0), the First Ferromagnetic Nickel(II) Diphosphonates: Increase of Dimensionality and Multiple Coordination Changes during a Quasi Topotactic Dehydration. Chem. Mater. 1999, 11, 2937-2947. 29. Taylor, J. M.; Mahmoudkhani, A. H.; Shimizu, G. K. A Tetrahedral Organophosphonate as a Linker for a Microporous Copper Framework. Angew. Chem. Int. Ed. 2007, 46, 795-798. ! "##! 30. Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Advances in Homogeneous and Heterogeneous Catalytic Asymmetric Epoxidation. Chem. Rev. 2005, 105, 1603-1662. 31. Sabbar, E. M.; de Roy, M. E.; Ennaqadi, A.; Gueho, C.; Besse, J. P. Synthesis of Ester-Functionalized Vanadyl Phosphonates. Chem. Mater. 1998, 10, 3856-3861. 32. Ouellette, W.; Yu, M. H.; O'Conner, J.; Zubieta, J. Evolution of the Structural Chemistry of Vanadium Organodiphosphonate Networks and Frameworks: Structural Consequences of Fluoride Incorporation in the Development of Stable Phases with Void Channels. Inorg. Chem. 2006, 45, 7628-7641. 33. Huan, G.; Johnson, J. W.; Jacobson, A. J. Hydrothermal Synthesis and Single-Crystal Structural Characterization of (VO)2[CH2(PO3)2]•4H20. J. Sol. State Chem. 1990, 89, 220-225. 34. Banerjee, A.; Bassil, B. S.; Roschenthaler, G.-V.; Kortz, U. Diphosphates and diphosphonates in polyoxometalate chemistry. Chem. Soc. Rev. 2012, 41, 7590-7604. 35. Bolm, C. Vanadium-catalyzed asymmetric oxidations. Coord. Chem. Rev. 2003, 237 (1-2), 245-256. 36. Mamedov, E. A.; Corberfin, V. C. Oxidative dehydrogenation of lower alkanes on vanadium oxide-based catalysts. The present state of the art and outlooks. App. Cat. A 1995, 127, 1-40. ! "#$! 37. Bolm, C.; Bienewald, F. Asymmetric Sulfide Oxidation with Vanadium Catalysts and H2O2. Angew. Chem. Int. Ed. Engl. 1995, 34 (23), 2640-2642. 38. Sharpless, K. B.; Michaelson, R. C. High Stereo- and Regioselectivities in the Transition Metal Catalyzed Epoxidations of Olefinic Alcohols by tert-Butyl Hydroperoxide. J. Am. Chem. Soc. 1973, 95 (18), 6136-6137. 39. Chong, A. O.; Sharpless, K. B. On the Mechanism of the Molybdenum and Vanadium Catalyzed Epoxidation of Olefins by Alkyl Hydroperoxides. J. Org. Chem. 1977, 42 (9), 1587-1590. 40. Conte, V.; Coletti, A.; Floris, B.; Licini, G.; Zonta, C. Mechanistic aspects of vanadium catalyzed oxidations with peroxides. Coord. Chem. Rev. 2011, 255, 2165-2177. 41. Ellenwood, R. E. Synthesis of Chiral Vanadium Phosphonates and Their Catalytic Activity. Dissertation, University of Illinois at Urbana Champaign, Urbana, IL, 2004. 42. Alherti, G.; Costantino, U.; Marmottini, F.; Vivani, R.; Zappelli, P. Zirconium Phosphite(3,3',5,5'-Tetramethyl-biphenyl)diphosphonate, a Microporous, Layered, Inorganic-Organic Polymer. Angew. Chem. Int. Ed. Engl. 1993, 32 (9), 1357-1359. 43. Johnson, J. W.; Brody, J. F.; Alexander, R. M. Vanadyl Benzylphosphonates and Vanadyl Naphthylphosphonates: Intercalation Reactions with Butanols. Chem. Mater. 1990, 2, 198-201. ! "#$! 44. Ouellette, W.; Wang, G.; Liu, H.; Yee, G. T.; O'Conner, C. J.; Zubieta, J. The Hydrothermal and Structural Chemistry of Oxovanadium–Arylphosphonate Networks and Frameworks. Inorg. Chem. 2009, 48, 953-963. 45. Salomon, C. J.; Breuer, E. Efficient and Selective Dealkylation of Phosphonate Diisopropyl Esters using Me3SiBr. Tetrahedron Lett. 1995, 36 (37), 6759-6760. 46. Johnson, J. W.; Jacobson, A. J.; Butler, W. M.; Rosenthal, S. E.; Brody, J. F.; Lewandowski, J. T. Molecular Recognition of Alcohols by Layered Compounds with Alternating Organic and Inorganic Layers J. Am. Chem. Soc. 1989, 111, 381-383. 47. Johnson, J. W.; Jacobson, A. J.; Brody, J. F.; Lewandowski, J. T. Layered Compounds with Alternating Organic and Inorganic Layers: Vanadyl Organophosphonates. Inorg. Chem. 1984, 23, 3842-3844. 48. Zhou, X.; Wu, G.; Gao, G.; Cui, C.; Yang, H.; Shen, J.; Zhou, B.; Zhang, Z. The synthesis, characterization and electrochemical properties of multi-wall carbon nanotube-induced vanadium oxide nanosheet composite as a novel cathode material for lithium ion batteries. Electrochim. Acta 2012, 74, 32-38. 49. Rowe, R. A.; Jones, M. M. Vanadium(IV) Oxy(acetylacetonoate) [Bis(2,4- pentanediono)oxovanadium(IV)]. Inorg. Synth. 1967, 5, 113-115. 50. Bragg, W. H.; Bragg, W. L. the Reflection of X-rays by Crystals. Proc. R. Soc. Lond. A 1913, 88 (605), 428-438. ! "#$! 51. DeBurgomaster, P.; Liu, H.; O'Conner, C. J.; Zubieta, J. Hydrothermal synthesis and structural characterization of bimetallic organic–inorganic hybrid materials: Copper vanadate–1,4-Carboxy-phenylphosphonate phases. Inorg. Chim. Acta 2010, 363, 330-337. 52. Salta, J.; Zubieta, J. Studies of the oxovanadium–organophosphonate system. The synthesis and crystal structure of (Et3NH)2[(VO)2(acac)2(O3PCH2PO3)]. Inorg. Chim. Acta 1996, 252, 431-434. 53. DeBurgomaster, P.; Ouellette, W.; Liu, H.; O'Conner, C. J.; Zubieta, J. Hydrothermal chemistry of vanadium oxides with aromatic di- and tri- phosphonates in the presence of secondary metal copper(II) cationic complex subunits. Cryst. Eng. Comm. 2010, 12, 446-469. 54. Hanson, R. M.; Sharpless, K. B. Procedure for the Catalytic Asymmetric Epoxidation of Allylic Alcohols in the Presence of Molecular Sieves. J. Org. Chem. 1986, 51, 1922-1925. 55. Balamurugan, R.; Kothapalli, R. B.; Thota, G. K. Gold-Catalysed Activation of Epoxides: Application in the Synthesis of Bicyclic Ketals. Eur. J. Org. Chem. 2011, 1557-1569. 56. Li, X.; Borhan, B. Prompt Determination of Absolute Configuration for Epoxy Alcohols via Exciton Chirality Protocol. J. Am. Chem. Soc. 2008, 130, 16126- 16127. ! "#$! !"#$%&'()( *&%&'+,-,./,(0/%"/+$"+1$"/2/,(3,/41(5+'(%"&( 6&.&,%/7&(89%'#,%/+2(+5(:/2+'(3,%/2/4&1( ( ( !"#$%&'()*+,-.$ Nuclear energy will remain an important alternative to the combustion of fossil fuels until effective renewable-energy technologies can be realized on the large scale.1 Currently in the United States, 20% of electricity is harnessed from sustained fission in nuclear power plants, and this number is only expected to increase in the near future.2 Since the recent disaster at the Fukushima Daiichi nuclear facility, there has been considerable and renewed interest in reducing the quantity of spent nuclear fuel stored indefinitely on-site at nuclear plants. However, there is no general consensus on the appropriate fate of the spent fuel once it has reached the end of its useful lifetime.1,3-4 This global issue is the topic of serious and ongoing political and scientific debate – one that is likely to become increasingly heated in the coming years. ! "#$! ! !"#$%&'()*)'%&'()*!#+,!-.!/0&!&)&1/(212/*!23!/0&!456!27!8(-9:1&9!23!3:1)&'(!(&'1/-(7; ! Under current protocol, spent nuclear fuel rods are cooled in water pools for up to ten years and sealed in concrete containers that are stored at their respective nuclear facilities.6 At the end of 2013, there were 71,780 metric tons of such spent nuclear fuel held on-site at reactors throughout the US, and an additional 2,000- 2,300 tons are being produced annually.7 One proposed long-term management strategy is storage in a federal geological repository where the combined waste would be safely isolated from the environment. The Yucca Mountain site in Nevada has been proposed since the late 1980s for such a purpose.8-9 Ignoring, for a moment, the fact that its construction is currently on an indefinite hold,10 a larger problem remains– the capacity of the Yucca Mountain is limited to 63,000 metric tons, which is already exceeded by the current reserves of spent fuel.11-12 This sobering fact suggests that the use of a geological repository alone is not a long-term solution to the nuclear waste problem. ! "#$! ! "#$%&'!()*)!%&'('!)*!+!,-.*)/'(+01'!+2-3.4!-5!*6'.4!.3,1'+(!53'1!*4-('/!-.7*)4'!4&(-38&-34!4&'!9.)4'/!:4+4'*;""! ! "#$! ! !"#$%&'()*)'%&&'(')*+,-.!-/!012.+!.'&)2*3!/'2)!,0!.-+!-.)4!*!5-(20+,&!,00'26!*!(')+,+'52!-/!&-'.+3,20!7-3)57,52!*32! 82*9,)4!32),*.+!-.!.'&)2*3!2.23:4;< ! "#$! As such, it is important to seek alternative strategies to lessen the burden on geological storage.1,13 In one promising approach, the most radioactive elements (namely, uranium, plutonium, neptunium, americium, and curium) in the spent fuel are separated (partitioned) out, and are converted (transmuted) to short-lived isotopes in fast breeder reactors.14-15 Partitioning and transmutation are enticing because they recycle the spent fuel and allows additional energy to be harnessed from the nuclear transmutation processes.16 Unfortunately, several technical challenges face the implementation of such partitioning and transmutation strategies on an industrial scale.4 Perhaps the most daunting chemical problem is associated with the partitioning of fissionable minor actinides (MA = Am, Cm) from the lanthanide (Ln) fission products. This separation is particularly challenging, because both minor actinides and lanthanides form hard, oxophilic, trivalent ions with similar chemical properties.17-19 These issues are not shared with uranium, neptunium, and plutonium, because their redox chemistries can be exploited to facilitate separation from the spent fuel mixture.20 Although techniques have been developed to remove both Ln and MA components from the spent fuel,21 the large neutron cross sections of the lanthanides make the resulting mixture unsuitable for efficient transmutation.22 ! "#"! !"#$%&' ()()' %&'(&)*+*&,! &-! "! '.+/*0! +&,! &-! )(.,+! ,102.3/! -1.24! 53/.6.3/+7! .2.'.,+)! 3/.! 7*872*87+.9!*,!:21.4!;/3,)1/3,*0!.2.'.,+)!3/.!7*872*87+.9!*,!/.94" VI U O2(NO3)2 xs NaNO V U, Np, Pu Mixture + 2 Np O2(NO3) 6M HNO3 IV 2- [Pu (NO3)6] ! !"#$%&'()*)'=/3,*1'>!,.(+1,*1'>!3,9!(21+&,*1'!03,!:.!/.'&?.9!-/&'!+7.!)(.,+!-1.2!'*@+1/.!:A! -*/)+!.@(2&*+*,8!+7.*/!/.)(.0+*?.!/.9&@!07.'*)+/*.)4! Although the minor actinides constitute a relatively small portion of the spent fuel by weight, effective separation is vital to the success of nuclear fuel reprocessing.14,23-26 Due to the long-lived and high levels of radioactivity (mainly due to the presence of plutonium, neptunium, americium, and curium) it is estimated that it requires 1 ! 105 years for the radiotoxicity of spent nuclear fuel to reach that ! "#$! of natural uranium.14 Effective removal of 99.9% of these elements from the spent fuel mixture would afford a radiotoxic lifetime of hundreds of years – a reduction by a factor of three orders of magnitude.14 Furthermore, removal of the long-lived minor actinides would also considerably reduce the residual heat generated by the remaining waste, consequently affording a significant decrease in the required volume needed to safely store the spent fuel in a geological repository.13,16,27 ! ; 3 45 ! 12 45:! 459! *+,-*.%/*0 C"&D*E! 458! 457! .%&"L! !"#$%&%'$($&) 456! F*GGDGH*EI*+J! F*GGDGH*EI*+JI*K>! 45M! 456! 457! 458! <,"-=*>?,-*!,@%2$/A* B-%@*!,"(&%-! 0"3* 0N3* ! !"#$%&' ()*)' $%%&'&()*! +,! (-*./'*&0)! *('1)0203&(4! 50627! 80*1! 4&3)&%&'/)*29! .(76'(! *1(! :/;! ./7&0*0-&'! 2&%(*&<(! 0%! *1(! .(026<(! .(?6&.(7! &)! 3(0203&'/2! 4*0./3(@"A=BC!! ! ! ! ! "##! !"#$%&'(&$)&*$ !"#"+$,'*-'(.-(/.-'01*2$34*&15*10*/$ Of the separation strategies previously proposed,25,28-36 liquid/liquid extraction tactics that rely on “soft donor” dithiophosphinic acid (HS2PR2) extractants have emerged as a promising solution to the partitioning problem.19,37-44 For example, early studies by Choppin and coworkers discovered that the separation factor (SF) of the phosphinic acid Cyanex 272 is 11.4:1 in favor of Eu over Am, whereas the sulfur-substituted dithiophosphinic acid Cyanex 301 affords a 840:1 selectivity for Am over Eu.44 It has been proposed that the large SFs seen for dithiophosphinic acids reflect an increased covalency in the An–S2PR2 interaction vs. the more ionic Ln–S2PR2 interaction, although the exact reasons for the observed selectivity are not well understood.37,45-46 !" ! !" !"###,-+++' % % #$ !" #$ $ !"#$%&'()(' !"#$%&'*+,' ! ! !"#$%&'()*)'%&'!()*+,-.*/*01!.2,&2*3&*)3&2/24!542.)!45/!6'!7)'.!,*!.2)40282/5,'!6',9''/!,&'! :5/,&5/2.')!5/.!82/*0!54,2/2.')!2/!:2;72.<:2;72.!'=,054,2*/)>$$!! ! ' More recently, the extractant HS2P(o-CF3C6H4)2 (4.1) was found to give the 38 largest Am/Eu separation factor measured to date: SFAm/Eu = 100,000. A puzzle however, was the large discrepancies in the observed SFAm/Eu between the ! "#$! constitutional isomers 4.1, 4.2 and 4.3 (Figure 4.8). These results deviate from 40,47 trends predicted from pKa values or inductive effects. ! ! !"$! !"#! !"%! !" !" !" !"### !" !""#""" % % % #$ # #$ ! #$ ! ! ! !"#$%&' ()*)' %&'()*! +,-./*0! 1.! (,*! 2301(13.! 34! (,*! 0&'0(1(&*.(! 3.! (,*! -56)! 51./0! 34! '107(514)&3538*(,6)2,*.6)9:1(,132,302,1.1+! -+1:0! ,-;*! -! :5-0(1+! 182-+(! 3.! (,*! 0*)*+(1;1(6! 34! <8#=!3;*5!>&#=?@A! ! ! !"#"#$%&'()*$+&,-.$/012,34526$73*84,21823.9$-$:;-6454-45<*$=,20*$2>$ ?2<-@*68.$ $ X-ray absorption spectroscopy (XAS) is a technique that uses high energy X- rays to excite ground-state electrons.48 Specifically, ligand K-edge XAS is used to probe 1s ! np transitions in metal complexes. Because the s ! p transition is dipole allowed, the intensity of the observed transition is directly correlated to the amount of ligand p character in the valence molecular orbital (Figure 4.9 and 4.10).49 Hence, a more intense transition is a result of increased M–ligand orbital ! "#$! mixing. This phenomenon provides a useful metric for the quantitative measure of bond covalency between the metal and ligand.37,49-52 S 4p !* = c*M"M + cL*"L Pre-edge 2.0 1s !* Edge transition 1.5 M nd 1.0 S 3p Pre-edge Edge transitions 0.5 NormalizedIntensity ! = cM"M + cL"L 2468 2472 2476 2480 Energy (eV) S 1s !"#$ !%#$ !"#$%&' ()*)' %&'! ()*+,&-.)! /+0/+1+2-&-.32! 34! -/&21.-.321! .2! &! 15645/! 78+9:+! 10+)-/5,;! +!3>1+/?+9!326@!.4!-*+/+!.1!(!0!3/>.-&6!,.A.2:!=.-*!-*+!6.:&29;!%>'!BA&,06+!(!78 +9:+!CD(!10+)-/5,;EF' !"#$%&'()+,)'G*+!.2-+21.-@!34!&!-/&21.-.32!.1!9./+)-6@!/+6&-+9!-*+!&,352-!34!15645/!08)*&/&)-+/!.2! -*+!3/>.-&6!-3!=*.)*!-*+!"1!+6+)-/32!.1!+A).-+9;EF! ' ! "#$! ! ! ! 1- S2PMe2 exp 1.5 TDDFT 1.0 2b 0.5 a1 1 b2 b1 b2 ("*) b 2 S PPh 1- b (!*) 2 2 1 2a exp 1 1.5 TDDFT Me Normalized Intensity NormalizedIntensity b 1.0 a1 ("*) 1 Me a 0.5 2a1 1 2b1 a1 b b 2 S 1s 1 1- 1- 2470 2472 2474 S2PMe2 S2PPh2 Energy (eV) !"#$ !%#$ ! ! . !"#$%&'()**)'%&'!()*!+,- !&/0123/41/5!678!91:!;10)!0)*!<)*/=>!?!8=80*9!03!@&A8*!8<>1001/5!3B! #$ 0)*8*!3C210&>8D!%2'!E8!&!C*8A>0F!&441013/&>!0C&/81013/8!&C*!328*CG*4!1/!0)*!,!H.*45*!8<*@0CA9!D ! K-edge XAS has been used to provide insight into the anomalous separation 37 factors observed for the (o-CF3)-substituted dithiophosphinic acid 4.1. To determine what electronic effects may be responsible for the extraction properties, - bonding in the simplest dialkyldithiophosphinate, S2PMe2 , was first studied. In this ! "#$! compound, two ! antibonding molecular orbitals (one of a1 symmetry and the other of b2 symmetry) and one " antibonding MO (of b1 symmetry) are expected from the mixing of the valence p-orbitals of the one phosphorus and two sulfur atoms. Experimental results are in agreement with this view: there are two observed peaks in the sulfur K-edge XAS resulting from transitions to these three orbitals, with the higher energy peak consisting of two transitions (Figure 4.11b).37 When the methyl groups are replaced with phenyl rings, additional pre-edge features appear in the XAS spectrum, which have been attributed to the splitting of the a1 and b1 MOs by additional mixing with the phenyl " system. 37 - The K edge XAS spectra of a series of Ar2PS2 compounds shows that, in both the solid state and in solution, the ortho-substituted dithiophoshinate [PPh4][S2P(o-CF3C6H4)2] (4.4) is electronically unique (Figure 4.12). Specifically, 4.4 exhibits unusually intense pre-edge features that are absent in the spectra of the other constitutional isomers [PPh4][S2P(m-CF3C6H4)2] (4.5) and [PPh4][S2P(p-CF3C6H4)2] (4.6). This difference has been attributed to restricted rotation about the P–Cipso bond in 4.4 as a result of unfavorable steric interactions between the ortho CF3 groups. In turn, these geometric constraints lower the symmetry about the phosphorus atom from C2v to C2. The overall result is thought - 37 to be an increased mixing of the phenyl " system and the orbitals of the PS2 core. ! "#$! Solid High Am/ SF 1.5 Eu 1.0 4.4 4.5 0.5 4.6 [PPh4][S2PPh2] Solution Am High /Eu SF 1.5 NormalizedIntensity 1.0 4.4 4.5 0.5 4.6 [PPh4][S2PPh2] 2469 2471 2473 2475 ! ! !"#$%&' ()*+)' %&! '()*! +(,-./! 0&.! +(,1)-(&/2*0+3! +1,415! 6/3.73! 89:! 3;235-<3&)+=! )*3! !"#$!/ +1'+)-)1)3.!()(!3;*-'-)+!1&->13!0&.!-&)3&+3!253/3.73!430)153+?! ! ! ! Additional analyses were performed on other ortho-substituted diaryldithiophosphinic acids. In all instances, the intense pre-edge transition observed with 4.4 is also present. These results suggest that the identity of the substituent (electron withdrawing –CF3 vs. electron donating –CH3 or –OCH3) has relatively little effect on the electronic environment; the important factor is the location of the substituent on the aryl ring. ! "#$! ! o-CF3C6H4 (4.4) m-CF3C6H4 (4.5) 1.5 1.0 0.5 p-CF C H (4.6) R o-MeC6H4 3 6 4 1.5 S [PPh ] P 1.0 4 S 0.5 R NormalizedIntensity o-MeOC6H4 Ph 1.5 1.0 0.5 2470 2472 2474 2470 2472 2474 Energy (eV) ! !"#$%&' ()*+)' %! &'()*(! +,%! )-.-! /0**(/./! .1-.! /.(234! (55(4./! 65! .1(! /07/.3.0(8.! 38! .1(! !"#$!! 96/3.368!385:0(84(!(:(4.26834!/.204.02(;<=!! ! ! ! !"#$%&'&()*+*,-*$.-'/-)0/)10/-23'&$45'(3*'32'1! Conclusions drawn from the previous XAS studies suggest that the extent - and nature of !-mixing between the aryl groups and the PS2 core of diaryldithiophosphinate extractants can be manipulated by the geometric orientation of the aryl rings, with larger separation factors seen when the aryl ! "#$! groups are more nearly coplanar.37 These results suggest that Ln/MA selectivity of dithiophosphinates could be further increased by making the aryl rings precisely coplanar by a synthetic tethering through C–C linkages (Figure 4.14). ! !"#$ !%&%'$ ((($ ! !"#$%&' ()*()' $%&'()*(+! ,-./0! *(1)')234%! 5)&24'*! )'(! 46*('7(+! 89(%! 29(! )':;! '3%<*! 45! +3)':;+32934194*193%)2(*! +(73)2(! 5'4-! )%! 4'294<4%);! 14*3234%! 3%! '(;)234%! 24! 29(! =>?>=! 1;)%(@! A4'&3% ! To obtain additional information about the effect that ring conformation of diaryldithiophosphinates has on minor actinide extraction potential, we wished to develop synthetic methods to access heterocyclic dithiophosphinates. For simplicity, we decided to focus our initial efforts on obtaining ligands based on the 5-membered dibenzophosphole core (Figure 4.15). S SH S SH P P x vs Free Rotation No Rotation !"#$%&' ()*+)' B(29('3%C!"#$!64%+@' ! "#"! !"#"$%&'()*+%,-*./01'1%)*+%2/)3)4.03'5).'6*% ! Commercially available 2,2!-dibromobiphenyl (4.7), is treated with n-butyllithium to generate the known 2,2!-dilithiobiphenyl species 4.8.53 This organolithium reagent has been reported to react with phosphorus trichloride at low (-196 °C) temperature to generate 5-chloro-5H-dibenzophosphole in good yield;53 in our hands however, this reaction affords a mixture of this species with the analogous bromophosphine in a ca. 2:3 ratio. This result, although unanticipated, did not negatively affect subsequent transformations. Similar halogen exchange reactions have been noted in the preparation of some closely related compounds.38 The usual method for converting halophosphines to dithiophosphinic acids involves reduction to the phosphine followed by treatment with elemental sulfur and subsequent addition of either ammonium carbonate or ammonium hydroxide.38,40,54-56 Unfortunately, this method fails for the 5-halo-5H- dibenzophosphole 4.8 – intractable mixtures with low yields (~20% by 31P NMR) of the desired product are formed instead. We find, however, that reaction of the mixture of chloro- and bromophospholes with elemental sulfur followed by addition of sodium hydrosulfide hydrate (NaSH•xH2O) and acidic aqueous workup cleanly provides the desired 2,2!-biphenylenedithiophosphinic acid 4.9. Overall, the desired heterocyclic dithiophosphinic acid is obtained in 54% yield from the starting dibromide 4.7. ! "#$! Br X S SH a,b P c,d,e P Br 4.7 4.8 4.9 ! !"#$%&'()*+)!%&'()*+,+!-.!()*!)*(*/-0&01,0!2,(),-3)-+3),',0!40,2!#565!7*48*'(+!4'2!0-'2,(,-'+9! ! :4;!?@,A!B( This ‘one-pot’ sulfurization method has several advantages over prior art, in that the purification protocol is simple and avoids issues resulting from the instability of dithiophosphinic acids toward hydrolysis or thermolytic conversion 57 (with loss of H2S) to the corresponding anhydrosulfide, and that it circumvents the initial reduction step. Undesired reaction byproducts and unreacted starting materials can be easily removed either by distillation in vacuum, by filtration, or by washing with hexanes. Moreover, the method is atom-efficient, can be carried out in approximately one day, and proceeds in good yields on multi-gram scales. S SH P ! S S 2 P - H S P 2 S 4.9 4.10 !"#$%&' ()*,)' S)*/T41! 2*8/424(,-'! -.! ()-! -00?/+! ()/-?8)! 4! 2,T*/,U4(,-'! 34()V4&! 4(! 433/-W,T4(*1&!HD!EF!,'!+-1?(,-'A!4'2!,+!400-T34',*2!I&!1-++!-.!P<%5! ! "#$! Unfortunately, 4.9 is only slightly soluble in organic solvents such as toluene, MeCN, and DCM, and it was anticipated that this property would likely preclude its use in Eu/Am extraction studies. Consequently, we focused our efforts on the synthesis of a di-tert-butyl derivative of 4.9, because it was expected to exhibit a far greater solubility in organic media. The commercially available hydrocarbon 4,4!-di-tert-butylbiphenyl 4.11 was chosen as a starting material. We first explored the conversion of 4.11 into the corresponding phosphorus- containing heterocycle by Friedel-Crafts methods. It is known that benzene reacts at reflux with phosphorus pentasulfide in the presence of aluminum trichloride to afford primarily diphenyldithiophosphinic acid in what is essentially a one-step procedure after acidic workup.58 With substituted arenes such as toluene or chlorobenzene, however, the Friedel-Crafts reaction gives a mixture of isomers differing in the location of the phosphorus atom with respect to the arene substituent.58 We anticipated that a similar reaction with 4.11 may avoid phosphinylation at the 3 and 5 positions due to the steric blocking of effect of the tBu groups, and should therefore afford the desired 2,2!-bipheneylene- dithiophosphinic acid as the major product. Unfortunately, no phosphorus substitution was observed using a variety of precursors and Lewis acid activators, even under particularly harsh reaction conditions (Figure 4.18). This result probably reflects the steric shielding at the 2 and 2! positions by the neighboring C(1)–C(1!) diaryl bond. ! "##! S ! P SH AlCl3 + P2S5 + C6H6 H3O R S P SH ! AlCl3 + P2S5 + C7H8 or C6H5Cl H3O R R = Me, Cl AlCl3 or No P P2S5, PSCl3, or PCl3 + FeCl3 or incorporation up to 180 °C by 31P NMR InCl3 !"#$%&' ()*+)! %&'! ()*! +,-*.*/01,&2340356*! 6)746)-85/&3-78! 72! 9*8:*8*! 6,7;**.4! 4<773)/5! 37! &227,.!.-6)*85/.-3)-76)746)-8-;!&;-.!=678!>7,?=6@$A!%9'!()*!&8&/7B7=4!,*&;3-78!>-3)!37/=*8*! 7,!;)/7,79*8:*8*!6,7.=;*4!&!<-C3=,*!72!,*B-7-47<*,4@$A!%;'!D-<-/&,!<*3)7.7/7B5!.7*4!873!)&E*! &8!794*,E&9/*!*22*;3!78!#F#G0.-0!"#!09=35/9-6)*85/@! It is known, however, that 4.11 can be deprotonated in situ at the 2 and 2! positions with Schlosser’s base, nBuLi/KOtBu.59 We have found that this doubly- deprotonated species reacts smoothly with phosphorus trichloride to afford 3,7-di- tert-butyl-5-chloro-5H-dibenzo[b,d]phosphole 4.12. Conversion to the desired dithiophosphinic acid 4.13 by treatment with sulfur and sodium hydrosulfide hydrate followed by acidic workup as before proceeds cleanly in 52% overall yield from the 4.11 hydrocarbon starting material. It is also of importance to note that, ! "#$! as anticipated, 4.13 is highly soluble in common solvents such as MeCN, DCM, Et2O, and toluene. Cl P tBu tBu a,b tBu tBu 4.11 4.12 S SH c,d,e P tBu tBu 4.13 !"#$%&'()*+)!%&'()*+,+!-.!/,(),-0)-+0),',1!21,/!()*,3!4*25*'(+!2'/!1-'/,(,-'+6!728!9!*:3!!;<=,>!9! " ! *:3! ?@ ;<>! )*A2'*>! $B! CD3! 7E8! FDGH>! I"J$! CD! K! 9LCD3! 718! "MN! %N>! (-G<*'*>! ""B! CD3! 7/8! 9! *:3! S O2%PQP9@>!R(@PMP9@>!9L!CD3!7*8!PH@ 3! Deprotonation of the heterocyclic dithiophosphinic acids 4.9 and 4.13 with aqueous NH4OH in air, followed by addition of tetraphenylphosphonium or –arsonium chloride, is accompanied by the rapid precipitation of the salts of [Z(C6H5)4][S2P(R2C12H6)], where Z = P (4.14) or As (4.15). These compounds were readily isolated by vacuum filtration of the reaction mixture followed by washing the resulting solid with water and further dried under vacuum. ! "#$! S SH S S P 1. aq NH4OH P [PPh4] 2. PPh4Cl 4.9 4.14 S SH S S P 1. aq NH4OH P t t Bu Bu [AsPh4] tBu tBu 2. AsPh4Cl • H2O 4.13 4.15 !"#$%&'()*+)!%&'(&)*()+*(&,&-!.-&/+!(),'.,/!()-.!.01!01./&23!/1*0)'),.'1/!43!.561)6+!4.+1!.,/! -.,!41!&+)2.'1/!.+!'(1!-)001+*),/&,7!'1'0.*(1,32*,&-'),&68!+.2'+!()-('.,/!()-/9!01+*1-'&:123;! Single crystals of 4.14 and 4.15, grown by slow evaporation of acetone/water solutions, were investigated by X-ray diffractometry. The resulting molecular structures are shown in Figures 4.21, and 4.22, and selected bond distances and angles are summarized in Tables 4.1 and 4.2. In each anion, the S–P bond distances are equal within error, and these distances as well as the S–P–S angles are similar - 54 to those observed previously in other S2PR2 salts (Table 4.2). The solid-state data confirm that the dithiophosphinic acids contain a planar dibenzophosphole unit. The C–C distances between the two aromatic rings are 1.468(4) and 1.476(3) Å in 4.14 and 4.15, respectively, and are consistent with the presence of a C(sp2)–C(sp2) single bond; for comparison, the analogous C(sp2)–C(sp2) single bond length in fluorene is 1.472(3) Å.60 The central phosphorus atoms lie almost exactly in the plane defined by the biphenylene carbon atoms. Neglecting the ! "#$! t - rotameric conformation of the Bu substituents, the S2P(R2C12H6) anions have nearly ideal C2v symmetry. Alkali metal salts of dithiophosphinates typically engage in S–cation–S bridging interactions in the solid state, and this feature complicates the interpretation of the S K-edge X-ray absorption spectra.37,54 The non-coordinating tetraphenylpnictonium salts are advantageous in this respect because they lack such interactions in the solid state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µ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wo aspects of the 31P NMR chemical shifts of the new dithiophosphinic acids are notable. (1) In CDCl3, the two biphenylenedithiophosphinic acids 4.14 and 4.15 both have 31P NMR chemical shifts near ! 46, whereas the untethered 31 HS2P(C6H5)2 analogue has a P NMR chemical shift of ! 56. This comparison suggests that tethering the two aryl rings shields the 31P nucleus by 10 ppm. (2) The change in chemical shift between the free acid HS2PR2 in chloroform and the - conjugate base S2PR2 in CD3CN is 15 ppm for the two biphenylenedithiophosphinic acids, but only 5 to 9 ppm for a series of untethered diaryldithiophosphinic acids54 (Figure 4.23). Both of these differences may reflect changes in the electronic structure that result from making the aryl rings co-planar with each other and with ! "#"! the phosphorus atom. Specifically, the co-planarity enables greater orbital mixing - between the aryl ring and the PS2 core. &" : !"#$%&'()*+%! '!()*!+,-./+!.01!/,2!34$'*$!567!84$'*$9 !;0<=0>67+!-6!?@?A&!567!?@&?(B! 12+=2;/-C2AD%#E! ! !"#"$%&'()*(%+',-.%/012,34526%73(84,21823.% % Phosphorus and sulfur K-edge X-ray absorption experiments were carried out on the unsubstituted 2,2!-bipheneylenedithiophosphinate 4.14. These spectra provide additional insight into the effect that ring tethering has on the electronic structure of these compounds. Figure 4.24 shows the sulfur K-edge XAS spectra of 4.14 and the untethered dithiophosphinate [PPh4][S2PPh2]. Notably, the heterocyclic 4.14 exhibits two additional pre-edge features at approximately 2471 and 2472 eV. These transitions are thought to arise from increased orbital mixing - between the biphenylene ! system and the PS2 core. ! "#$! 2.0 4.14 [PPh4][S2PPh2] 1.5 1.0 0.5 Normalized Intensity NormalizedIntensity 0.0 2470 2472.5 2475 Energy (eV) ! !"#$%&'()*(%!&!'()*+,!-.&!/0,12345!67!()+('89*!:;;<=>:&?;;%! ! The phosphorus K-edge spectra of the analogous tetraphenylarsonium salt of 4.14 and of the ortho, meta, and para isomers of bis(trifluoromethylphenyl)- dithiophosphinate are shown in Figure 4.25. As seen in the sulfur K-edge experiments, the loss of rotational freedom imposed by the biphenylene ring has a profound effect on phosphorus K-edge spectra: there is an unusually intense pre- edge feature at 2147.8 eV in 4.14 that is not observed in the untethered diaryldithiophosphinates. ! "#$! 3.5 - [AsPh4][4.14 ] [AsPh4][S2P(o-CF3C6H4)] 3.0 [AsPh4][S2P(p-CF3C6H4)] [AsPh ][S P(m-CF C H )] 2.5 4 2 3 6 4 2.0 1.5 1.0 Normalized Intensity NormalizedIntensity 0.5 0.0 2144 2146 2148 2150 Energy (eV) ! !"#$%&' ()*+%! &! '()*+,! -./! 01,23456! 78! 39,! 3,34:19,;<=:407;>56! 0:=3! 78! (),(' ?0%! :;:=7+750! @>0A34>8=57476,39<=19,;<=B*>39>7197019>;:3,0%! ! !"#"#$%&'()$%*+,-.+/01$%*23,/)31+4$ ! The extraction capabilities of 4.9 and 4.13 were investigated according to literature methods38 in collaboration with D. R. Peterman and coworkers at Idaho National Laboratory. The procedure involves preparing a 0.1000M solution of the ligand in trifluoromethyl methyl sulfone, and mixing the solution with an equal 241 154 volume of 3.13M aq. HNO3 solution containing tracer amounts of Am and Eu. Final concentrations of each radionuclide in each the organic and aqueous layers ! "#$! were determined by !-ray spectroscopy. Unsurprisingly, we were unable to obtain SFAm/Eu for 4.9 due to its limited solubility in the experimental solvent. A separation factor of ca. 10:1 in favor of americium was determined for the tert-butyl analogue 4.13. S SH S SH P P tBu tBu 4.9 4.13 not obatined– SFAm/Eu = SFAm/Eu = 10:1 solubility issues ! !"#$%&'()*+$!%&'()!*+,-.-/012!3-4/1.*!31.!/5+!67689:0,5+2;<+2+=0/501,51*,5024!-40=*$! ! ! Although 4.13 was less selective for Am over Eu than we had hoped, the result provides some interesting information on the structure/selectivity relationship of dithiophosphinate-based extractants. For example, although overlap - of the arene " system in 4.13 with the b2 PS2 MO is maximized due to the coplanarity of the aryl rings, overlap with the b1 and a1 orbitals is effectively lost. In other words, the constrained C2v symmetry of 4.13 may minimize the total overlap - of the aryl " system with the PS2 antibonding MOs, resulting in a decrease in delocalization/polarizability and loss extraction selectivity. One way to test this hypothesis would be to explore other heterocyclic dithiophosphinates with larger (6- and 7-membered) heterocyclic rings. These ! "##! analogs would still have rotationally constrained aryl rings, but the central ring would be non-planar, and the resulting C2-symmetry may permit greater mixing of - the aryl ! system with all three of the antibonding PS2 MOs of interest. Proposed Extractants Optimized DFT Structures b2 S S– F3C P CF3 b – 1 F C S S CF 3 P 3 – F C S S CF 3 P 3 a1 !"#$ !%#$ ! , !"#$%&' ()*+%! &'(! )*+ ! '-./01-2/-3! 140/.'56! 17! /-.8486.! /-! 2/'4952/.:/1;:16;:/-'.8! 696.8<6%! &0(! )41;1682!8=.4'>.'-.6!?/.:!.8.:8482!'495!341@;6!6/:!28B/'.8!741 ! ! !"!#$%&'()*+()(,%-'%.&'./&'%)0-(#1.2&+(3(/#.4#-'(#456+(2()-/# In addition to determining the Eu/Am extraction ratios, we were also interested in exploring the actinide coordination chemistry of the new 2,2!- biphenylenephosphinate anions. Owing to the relatively poor solubility of the ! "#$! unsubstituted 4.9 in organic solvents, we chose to focus our efforts on the tert-butyl derivative 4.13. To prepare actinide complexes by salt metathesis reactions, 4.13 was first converted to the potassium salt 4.16 by treatment with potassium hexamethyldisilazide in toluene. tBu S SK P S 4 t t + UCl U P Bu Bu 4 THF S 4.16 t Bu 4 4.17 tBu S SK P S 4 t t + NpCl (DME) Np P Bu Bu 4 2 THF S 4.16 t Bu 4 4.18 S SK P 4 t t + [Me4N]2[PuCl6] Reduction to Pu(III) Bu Bu THF 4.16 !"#$%&' ()*+%! &'(')*+,-./! .'(+'0123! 45*! '6,4-1*2! 78*1! (),-! -3! .'(6-1*2! 7-,8! 9:;! '5! <+:;! 34),3%!=-(-)45!5*4.,-'13!7-,8!>0:;!4??'52!784,!-3!6*)-*@*2!,'!6*!4!5*20.,-'1!,'!4!>0A;!3+*.-*3%! ! "#$! The reaction of UCl4 or NpCl4(DME)2 with 4.16 in THF affords the t homoleptic compounds An[S2P( Bu2C12H6)]4 where An = U (4.17) or Np (4.18), in yields of 76% and 49%, respectively (Figure 4.28). Interestingly, analogous reactions with [Me4N]2[PuCl6] did not afford the plutonium(IV) analog. Under these conditions, a color change from yellow to blue-green takes place during the reaction, and a green microcrystalline material is obtained upon workup. These observations are indicative of reduction to Pu3+; this reduction, which has been seen in other Pu(S2PR2)x systems, is consistent with the known redox potentials of Pu relative to U and Np.61-63 t n Green prisms of U[S2P( Bu2C12H6)]4 were grown from toluene/THF/ hexane t and dark red prisms of Np[S2P( Bu2C12H6)]4 were obtained from n toluene/Et2O/ hexane. The molecular structures of 4.17 and 4.18 are shown in Figures 4.30 and 4.31, and selected distances and angles for these compounds are summarized in Tables 4.3 and 4.4. For both of these compounds, the eight sulfur atoms of the four bidentate dithiophosphinate ligands describe a distorted trigonal dodecahedron about the actinide center; the phosphorus atoms are arranged in a flattened tetrahedron (Figure 4.29). ! "#$! !"#$%&' ()*+! %&''! &()! *+,-.! /01/0*0(+&+,2(! 23! (),-! *425,(6! +40! 3,/*+! &()! *0-2()! -22/),(&+,2(! *140/0*! &/27()! +40! -0(+/&'! 81! ,2(! 917/1'0:;! <40! *7'37/! &+2=*! 9>0''25:! )0*-/,?0! &! ),*+2/+0)! +/,62(&'!)2)0-&40)/2(!&()!+40!142*142/7*!&+2=*!92/&(60:!)0*-/,?0!&!3'&++0(0)!+0+/&40)/2(;! ! t The distances and angles in the An[S2P( Bu2C12H6)]4 complexes are very 63 similar to those observed for analogous An[S2P(C6H5)2]4 complexes. For example, the P–S and P–C distances are ~2.01 and ~1.80 Å, and the S–P–S and S–M–S angles are ~109 and ~70º. The An–S distance of 2.85 ± 0.02 for U and 2.83 ± 0.01 for Np are also essentially identical with those seen in their S2P(C6H5)2 analogs. The t major difference between the An[S2P( Bu2C12H6)]4 and An[S2P(C6H5)]x structures is the C–P–C angle: instead of the ~105º value seen for the S2P(C6H5)2 complexes, this t angle is reduced to ~92º in the An[S2P( Bu2C12H6)]4 complexes owing to the 63 constraints of the 5-membered PC4 ring. ! "#$! !"#$%&'()*+!%&'()*'+,!-.,*).*,(!&/!(),-0!12(,3+'!(''45-&46-!-2&7!.2(!8$9!5,&:+:4'4.;!6(<-4.;! -*,/+)(-0!!=;6,&>( ! ! ! "#$! ! ! ! "#$%&'!()*+!$%&'()&*+!,-+)(-)+'!%.!()+,/!01'+2*&!'&&34,%35,!,1%6!-1'!789!4+%:*:3&3-;!5'<,3-;! ,)+.*(',/!!=;5+%>' ! ! ! ! ! "#"! ! ! t t U[S2P( Bu2C12H6)]4 Np[S2P( Bu2C12H6)]4 •toluene, 4.17 •4toluene, 4.18 formula C87H104P4S8U C108H128NpP4S8 formula wt (g mol-1) 1768.09 2043.46 crystal system orthorhombic monoclinic space group P212121 C2/c a (Å) 17.760(3) 22.8029(17) b (Å) 19.279(4) 20.2642(15) c (Å) 25.446(5) 23.9268(17) ! (º) 90 90 " (º) 90 110.020(1) # (º) 90 90 V (Å3) 8713(3) 10388.1(13) Z 4 4 -1 $calcd (g cm ) 1.348 1.307 µ (mm-1) 2.170 1.268 data/restraints/params 18631 / 0 / 926 22227 / 6 / 457 goodness-of-fit on F2 0.831 1.722 2 2 R1 [F >2!(F )] 0.0288 0.0508 wR2 (all data) 0.0482 0.1457 largest diff. peak and hole (e•Å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e were also interested in investigating the coordination chemistry of [4.13]- with the highly radioactive transplutonic element americium, owing to the central role of this element in nuclear waste reprocessing. Few crystal structures of Am compounds have been reported; for example, only 13 Am structures are listed in the Cambridge Structural Database.64-65 Owing to the extreme hazards present to human health and safety when working with americium, it was desirable to develop simple and robust synthetic methodology for a non-radioactive analog of Am. Furthermore, it was important to determine rapid and effective crystallization conditions for the analogue, so as to develop a protocol that would minimize degradation of the crystal lattice by the potent !-decay of Am.66 Europium and neodymium are known to be useful surrogates for Am3+ reaction chemistry: Eu3+ is ! "#$! isoelectronic with Am3+, and the ionic radius of Nd3+ (111 pm) more closely matches that of Am3+ (109 pm) than any other lanthanide.67 ! !"#$%&'()*+)!%&'()*&+!,-.!-/(.0+*&+!1/'/!23(4/-!,4!4&''(5,6/4!7('!,+/'*2*&+!*-!('./'!6(! ./8/9()!'/,26*(-!+/63(.(9(50!,-.!2'046,99*:,6*(-!2(-.*6*(-4;!%9/+/-64!(7!*-6/'/46!1*63!4*+*9,'! 6'*8,9/-6!*(-*2!',.**!,'/!3*539*536/.!*-!<9&/=!*4(/9/26'(-*2!/9/+/-64!,'/!43(1-!*-!'/.;! ! Treatment of europium chloride hydrate with 4.16 and tetraphenyl- phosphonium chloride in refluxing ethanol, followed by removal of solvent, extraction into DCM, and evaporating the extract to dryness affords a brick red solid. The 31P NMR spectrum in the ! 0-200 range shows only one signal from the PPh4 countercation, and no signal for the dithiophosphinate group, as expected due to the paramagnetic nature of the europium ion. Addition of water to the NMR tube causes an immediate change in the color of the solution from bright red to colorless, and an additional resonance at ~60 ppm appeared in the 31P NMR spectrum due to the free dithiophosphinate ligand. Unfortunately, attempts to obtain single crystals of the tetraphenyl- phosphonium salt suitable for X-ray diffractometry were not successful. The tetraethylammonium and triphenylphosphineiminium (PPN) salts were similarly found to be unsuitable. The tetrabutylammonium analogue (4.19) readily forms ! "#$! large, needle-like crystals upon cooling a MeCN/toluene solutions to -20 %C, but the crystals visibly crack upon being warmed to room temperature, probably due to desolvation. Although this result would normally not prevent analysis by single crystal XRD, desolvation would complicate manipulations of the analogous americium complex. Fortunately, we found that by carefully layering a THF solution of 4.19 with toluene affords, over three days at room temperature, large t red blocks of [Bu4N][Eu(S2P Bu2C12H6)4]•toluene•0.5THF. These crystals do not desolvate upon being warmed to room temperature. tBu S SK P + EuCl3•xH2O S 4 t t Bu Bu + Bu NCl [Bu4N] Eu P 4 S 4.16 tBu 4 4.19 tBu S SK P + NdCl3•xH2O S 4 t t Bu Bu + Bu NCl [Bu4N] Nd P 4 S 4.16 tBu 4 4.20 !"#$%&'()**)!&'()*+,-,!./!)0-123+()!32()*2(-4+!5.673+8+,!()+,''2(4!()-.'3-92)+4!:-)*!()+*; ! "#$! To our delight, this methodology was equally effective when applied to neodymium. Hence, combination of neodymium chloride hydrate, 4.16, and tetrabutylammonium bromide in refluxing ethanol, followed by extraction with DCM affords a pale blue solution. Removal of solvent under reduced pressure followed by crystallization from THF/toluene as before yields light blue blocks of t [Bu4N][Nd(S2P Bu2C12H6)4]•toluene•0.5THF (4.20) after 2 days at room temperature. Overall, these procedures appear to be well suited for the synthesis of t [Bu4N][Am(S2P Bu2C12H6)4], which will be attempted in the near future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µ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e have described synthetic methodology for the first examples of 2,2!- t biphenylenedithiophosphinic acids, HS2P(R2C12H6), where R = H or Bu. These new compounds can be prepared in multigram quantities, in moderate yield, and in high purity by what is essentially a ‘one-pot’ procedure. The dithiophosphinic acids can - be readily deprotonated to the corresponding S2P(R2C12H6) anions, which can be isolated as air- and moisture-stable salts with bulky, non-coordinating, organic cations. These anions are chemical relatives of the well-known class of untethered diaryldithiophosphinates, some of which are able to extract actinides highly specifically from lanthanide/actinide mixtures. They differ, however, in that the aryl ! "#$! rings are tied together by means of a C–C single bond to form a 5-membered PC4 ring. We have also prepared the two new tetravalent actinide dithiophosphinate t t complexes U[S2P( Bu2C12H6)]4 and Np[S2P( Bu2C12H6)]4, and the two new trivalent t t lanthanide complexes [Bu4N][Eu(S2P Bu2C12H6)4] and [Bu4N][Nd(S2P Bu2C12H6)4]. These complexes have been characterized by X-ray crystallography. Attempts to obtain the analogous plutonium(IV) compound were not successful, and resulted instead in what we believe to be mixture containing a reduced PuIII species. The crystal structures of the actinide and lanthanide ditihophosphinate complexes suggest that the constraints imposed by the phosphole ring system have few structural consequences, except that the C–P–C angle is smaller than in the M(S2P(C6H5)x analogues. - The unsubstituted dithiophosphinate [S2P(C12H8)] was analyzed by K-edge X-ray absorption spectroscopy. These spectra contain distinctive pre-edge features that can be attributed to geometric constraints imposed by the synthetic tethering t of the aryl rings. When HS2P( Bu2C12H6) was assessed for Ln/MA selectivity with 241Am and 154Eu, a separation factor of approximately 10:1 in favor of americium was obtained. This low selectivity is thought to be a result of diminished mixing of - the aryl ! system with the PS2 core due to the intrinsic C2v symmetry of the compound. Despite the poor selectivity, we are hopeful that these studies will be useful in the design and synthesis of improved extractants relevant to the advanced nuclear fuel cycle. ! "#$! !"#$%&'()*+(,-./$ General Experimental Considerations. The 238U isotope is a low specific-activity (primarily) !-particle emitting radionuclide that decays to !-, "-, and #-emitting isotopes. Its use presents hazards to human health. The 237Np and 239Pu isotopes are high specific activity radionuclides and their use presents extreme hazards to human health. This research was conducted in a radiological facility with appropriate analyses of these hazards and implementation of controls for the safe handling and manipulation of these toxic and radioactive materials. All reactions involving Np were performed inside an MBraun Labmaster 130 glovebox filled with an ultra-high purity helium gas inert atmosphere, and operated at negative pressure relative to the laboratory atmosphere. All other reactions were performed under argon in using standard Schlenk techniques with rigorous exclusion of air and moisture unless explicitly stated otherwise. 68 69 The starting materials [Me4N]2[PuCl6] and NpCl4(DME)2 were prepared in accordance with literature procedures. All other reagents were obtained from Aldrich with the exception of elemental sulfur and tetraphenylarsonium chloride hydrate (Acros), and were used as received. Toluene, diethyl ether, and n-hexane were dried over sodium and benzophenone, vacuum distilled, and degassed by three freeze-pump-thaw cycles before use. All H2O used during synthetic manipulations was purified to 18.2 M$/cm resistivity using a Thermo-Scientific Barnstead Nanopure or Millipore Nanopure water purification systems. Deuterated solvents were used as received. Elemental analyses were carried out by the School of ! "#"! Chemical Sciences Microanalytical Laboratory at the University of Illinois. The infrared spectra were recorded on a Nicolet Magna-IR System 750 spectrometer or a Nicolet IR200 FTIR spectrometer as Nujol mulls on KBr plates. The 1H and 31P NMR data were obtained using a Bruker Avance 300 MHz, Bruker Avance 400 MHz, or a Varian VXR 500 MHz NMR spectrometer at ambient temperature, using 4 mm PTFE tube liners placed inside 5 mm NMR tubes when analyzing radioactive samples. Chemical shifts are reported in ! units (positive shifts to high frequency) 1 31 relative to TMS ( H) or H3PO4 ( P). High resolution mass spectrometry was conducted at the School of Chemical Sciences Mass Spectrometry Laboratory at the University of Illinois. Electronic absorption spectra were recorded on a Varian Cary 6000i UV/vis/NIR spectrophotometer. !"#$%&''()"&*+,-. /0%&,'$1. Single crystals of HS2(R2PC12H6), t [PcPh4][S2P(R2C12H6)], and U[S2P( Bu2C12H6)]4 were mounted in a nylon cryoloop with Paratone-N oil under argon gas flow. Complexes containing transuranic t elements, specifically Np[S2P( Bu2C12H6)]4, were prepared for analyses with three appropriate layers of containment prior to single crystal X-ray diffraction studies by following modifications of the published procedures.68,70-72 Single crystals were coated with epoxy and then mounted inside 0.5 mm capillaries. The capillaries were sealed with additional epoxy, and their external surfaces were coated with a thin film of acrylic dissolved in ethyl acetate (Hard as Nails nail polish). The data were collected on a Bruker D8 diffractometer, with APEX II charge-coupled-device (CCD) ! "#$! detector, and cooled to 120(1) K using an American Cryoindustries low temperature device. The instrument was equipped with graphite monochromatized MoK! X-ray source ("= 0.71073 Å), and a 0.5 mm monocapillary. A hemisphere of data was collected using # scans, with 10-30 second frame exposures and 0.5º frame widths. Data collection and initial indexing and cell refinement were handled using APEX II software.73 Frame integration, including Lorentz-polarization corrections, and final cell parameter calculations were carried out using SAINT+ software.74 The data were corrected for absorption using redundant reflections and the SADABS program.75 Decay of reflection intensity was not observed as monitored via analysis of redundant frames. The structure was solved using direct methods and difference Fourier techniques. All hydrogen atom positions were idealized. The final refinement included anisotropic temperature factors on all non-hydrogen atoms. Structure solution, refinement, graphics, and creation of publication materials were performed using SHELXTL and Mercury.76 ! ! ! "#$%&$! '()! *$+,-.$/$01,2! ! Samples were prepared by grinding with polystyrene beads in a helium-filled glovebox in a Wig-L-Bug grinder for 2 min to obtain a homogeneous mixture. A portion of this mixture was transferred to low- sulfur tape adhered to aluminum sample holders with the aid of a fine paintbrush. Data was collected at the Stanford Synchrotron Radiation Lightsource with operating conditions of 3.0 GeV and 300 mA, with a hutch and chamber setup as described previously.37,49,52 For the sulfur measurements, the energy was calibrated to 2472.02 eV using a Na2S2O3 standard. ! "#$! !"#$%&"!!"'()*+,&-".#/0#&10#&%*.234522 $ Br X P Br x = Br, Cl $ This procedure is a modification of a literature recipe.53 A solution of 2,2!- dibromobiphenyl (2.49 g, 7.98 mmol) in Et2O (50 mL) was cooled to 0 °C and treated dropwise with nBuLi (10.0 mL of a 1.6 M solution in hexanes, 16.0 mmol). The resulting light yellow solution was stirred at 25 °C for 1 h and then cooled to 196 °C with liquid N2. Phosphorus trichloride (5.0 mL, 57.2 mmol) was added dropwise on top of the frozen mixture. The flask was allowed to warm to 25 °C, and vigorous stirring was commenced as soon as possible. A white precipitate formed, and the mixture was stirred at 25 °C for an additional 15 min. Volatile material (including the excess PCl3) was removed under reduced pressure, and the residue was subsequently kept under vacuum at 35 °C for 1 h. The resulting mixture of BrP(C12H8) and ClP(C12H8) was separated from a light yellow solid by extraction into toluene (2 " 15 mL); the extracts were filtered and combined. The resulting mixture of 5-halo-5H-dibenzophospholes in toluene was used in subsequent reactions without further purification. 31P{1H} NMR (162 MHz, toluene): # 68.2 (s, 53 ClPR2), 49.3 (s, BrPR2). Lit: # 69.0 (s, ClPR2). The ratio of BrP(C12H8) to 31 ClP(C12H8) was ca. 2:3 as judged from integration of the P NMR spectrum. ! "#$! !"!#$%&'()*+,)*)-&.(&/'(/0'(&*&1231&-"24562 ! X S SH P P x = Br, Cl ! ! To the above mixture of 5-chloro-5H-dibenzophosphole and 5-bromo-5H- dibenzophosphole (theoretical yield: 7.98 mmol) in toluene (30 mL) was added elemental sulfur (256 mg, 0.998 mmol reckoned as S8). After the mixture had been heated to reflux for 16 h, the light yellow solution was cooled to 25 °C and solvent was removed in vacuum. The flask was opened to air and the yellow solid was suspended in a solution of sodium hydrosulfide hydrate (1.47 g, ca. 15.9 mmol) in water (75 mL). The flask was equipped with a reflux condenser that was vented with a cannula to a 2.5 M aq. NaOH solution (to sequester evolved H2S). The flask was purged with argon, and the mixture was heated to 90 °C for 1 h, during which time most of the solids dissolved. The mixture was allowed to cool to 25 °C and then was filtered using a vacuum filtration apparatus to remove a small amount of tan precipitate. The filtrate was acidified to approximately pH = 1 with 2.4 M aqueous HCl (~10 mL). The resulting solution was extracted with CH2Cl2 (3 ! 25 mL), and the organic extracts were separated from the aqueous solution, combined, and taken to dryness to afford the product as a light beige powder. Crude yield: 1.15 g (58% ! "#$! from 2,2!-dibromobiphenyl). Further purification was carried out by dissolving the HS2P(C12H8) in MeCN (75 mL) and allowing to solution to concentrate to ca. 20 mL. This procedure provided HS2P(C12H8) as pale yellow plates. Crystalline yield: 1.07 g 1 (54% from 2,2!-dibromobiphenyl). H NMR (400 MHz, CDCl3): " 7.98 (dddd, J = 12.2, 7.5, 1.3, 0.7 Hz, 2H, 3,3!-CH), 7.79 (dddd, J = 7.7, 3.6, 1.1, 0.7 Hz, 2H, 6,6!-CH), 7.60 (dddd, J = 7.7, 7.5, 1.9, 1.3 Hz, 2H, 5,5!-CH), 7.51 (dddd, J = 7.5, 7.5, 4.3, 1.1 Hz, 2H, 31 1 + 4,4!-CH). P{ H} NMR (162 MHz, CDCl3): " 46.9 (s). HRMS m/z (EI ). Calcd: 247.9883 [M+]; found: 247.9883. IR (cm-1): 3066 m, 2959 s, 2925 s, 2854 s, 2330 br m, 1592 w, 1470 m, 1439 s, 1377 w, 1269 w, 1157 w, 1128 m, 1066 m, 966 w, 841 w, 756 s, 722 s, 658 s, 617 w, 541 m, 520 w, 483 w, 449 m, 413 m. ! ! !"#$%&'"()*&'+,&'+(-./0121345-&'"()*"("6-#'-+&'+,&'-(%#"2078970 ! S SH S S P P [PPh4] 0 0 ! A solution of HS2P(C12H8) (50.0 mg, 201 µmol) in aqueous NH4OH (10 mL of a 3.6 M solution, 360 µmol) was treated dropwise in air with a solution of tetraphenylphosphonium chloride (120 mg, 320 µmol) in water (5 mL). A white precipitate formed immediately. After the mixture had been stirred at 25 °C for 5 min, the precipitate was collected by vacuum filtration and the solid was washed ! "#$! with H2O (3 ! 5 mL). The solid was dissolved in a 1:1 mixture of acetone (5.0 mL) and H2O (5.0 mL) and the resulting solution was allowed to evaporate slowly to ca. 2 mL open to air. The product was isolated as pale yellow needles. Yield: 48.1 mg (41%). Anal. Calcd. for C36H28P2S2: C, 73.7; H, 4.81; P, 10.56; S, 10.93. Found: C, 1 73.5; H, 4.67; P, 10.46; S, 10.80%. H NMR (500 MHz, d3-MeCN): " 7.94-7.88 (m, 4H, Ar-H), 7.77-7.63 (m, 20H, Ar-H), 7.36 (dddd, J = 7.3, 7.2, 1.6, 1.4 Hz, 2H, 5,5#-CH), 31 1 7.33 (dddd, J = 7.2, 7.2, 3.4, 1.3 Hz, 2H, 4,4#-CH). P{ H} NMR (162 MHz, d3- - + -1 MeCN): " 61.1 (s, S2PR2 ), 24.4 (s, PPh4 ). IR (cm ): 3408 br, 3057 w, 2924 s, 2855 s, 1585 w, 1463 m, 1438 m, 1377 w, 1316 w, 1261 w, 1162 w, 1107 m, 1026 w, 998 w, 759 m, 724 s, 692 m, 656 s. ! !"#$%&$'()'$*+',-$.$/0-1)1$.!$%&*(2314""#56017601-("89:; ! Cl P ! ! ! To 4,4#-di-tert-butylbiphenyl (10.65 g. 40.0 mmol) in hexane (75 mL) was added nBuLi (50 mL of a 1.6 M solution in hexanes, 80.0 mmol). To the mixture was added KOtBu (9.78 g, 80.0 mmol) in one portion against a counterflow of argon. The resulting bright magenta mixture was brought to reflux for 20 h, during which time the solution color became deep purple. The solution was cooled to -196 °C with ! "##! liquid N2, and phosphorus trichloride (20.0 mL, 235 mmol) was added dropwise on top of the frozen mixture. The flask was allowed to warm to 25 °C, and vigorous stirring was commenced as soon as possible. As the mixture warmed, a slight exotherm occurred, the solution color changed from purple to brown and then yellow, and a white precipitate formed. The solution was transferred by filter cannula to a separate flask, and the solid left behind was washed with hexane (2 ! 20 mL). The washings were added to the solution, and the volatile material was removed in vacuum to afford a viscous yellow oil. The oil was dried overnight at 35 °C at 10-3 Torr to a yellow solid, which was used without purification in the next step. 31P{1H} NMR (162 MHz, hexane): " 70.2 (s). ! ! !"!#$%&$'()'$*+',-$.".#$*&/0(1,-(1(%&'0&2/023/0&1&4564&%"5!7897!! ! Cl S SH P P ! ! ! ! To the above solution of 3,7-di-tert-butyl-5-chloro-5H-dibenzophosphole (theoretical yield: 40 mmol) in toluene (50 mL) was added elemental sulfur (1.28 g, 5.0 mmol reckoned as S8) against a counterflow of argon. The mixture was heated to reflux for 8 h. The resulting yellow solution was cooled to 25 °C and filtered to remove a small amount of yellow precipitate. The filtrate was taken to dryness in ! "#$! vacuum to afford a sticky yellow solid, which was triturated with absolute ethanol (60 mL). After the ethanol was removed, the solid was treated with a solution of sodium hydrosulfide hydrate (7.47 g, ca. 80.0 mmol) in H2O:EtOH (1:2 ratio with a total volume of 60 mL). The flask was purged with argon and vented with a cannula to a 2.5 M aq. NaOH solution to sequester evolved H2S. The mixture was stirred at 25 °C for 14 h, during which time the solution color became orange and a gummy white solid precipitated. The solution was separated from the solid by vacuum filtration in air, and the filtrate was washed with hexanes (3 ! 25 mL). The solution was transferred to a 250 Erlenmeyer flask, acidified with 2.4 M aqueous HCl (25 mL), and allowed to stir in air for 30 min. The light yellow precipitate that formed was collected by vacuum filtration and dissolved in CH2Cl2 (xx mL). The resulting solution was dried over MgSO4, and taken to dryness in vacuum to afford the product as a free-flowing, pale yellow powder. Yield: 7.48 g (52% from 4,4"-di- 1 tert-butylbiphenyl). H NMR (400 MHz, CDCl3): # 7.97 (dd, J = 13.4, 1.7 Hz, 2H, 3,3"-CH), 7.67 (dd, J = 8.1, 4.2 Hz, 2H, 6,6"-CH), 7.61 (ddd, J = 8.1, 1.7, 1.7 Hz, 2H, 31 1 5,5"-CH), 1.40 (s, 18H, C(CH3)3). P{ H} NMR (162 MHz, CDCl3): # 46.4 (s). HRMS m/z (ESI+). Calcd: 361.1214 [M + H]+. Found: 361.1209. IR (cm-1): 3047 w, 2924 s br, 2855 s, 2348 m br, 1923 w, 1809 w, 1779 w, 1689 w, 1661 w, 1599 w, 1572 w, 1462 s br, 1405 w, 1378 w, 1363 m, 1300 w, 1272 w, 1255 m, 1156 m, 1110 m, 1084 w, 1061 m, 1084 w, 1061 m, 874 w, 829 s, 794 w, 733 s, 723 s, 671 s, 603 m, 535 s. ! ! ! "#$! !"#$%&'"()*%$+,(-./0121345-4!"#!46.#)*4727346-&'"()*"("5-#'-,4 &',+&'-(%#"20189:80 $ $ S SH S S P P [AsPh4] • 0.5 acetone 0 0 t ! This compound was synthesized by treating a solution of HS2P( Bu2C12H6) (4.13, 100.0 mg, 277 µmol) in aqueous NH4OH (20.0 mL, 3.6 M) (5 mL) with a solution of tetraphenylarsonium chloride hydrate (182 mg, 417 µmol) in H2O (5.0 mL) as described above for [PPh4][S2P(C12H8)]. Purification was affected by slow evaporation of an acetone/H2O solution, which afforded large, pale yellow needles of t [AsPh4][S2P( Bu2C12H6)]•0.5acetone that were suitable for X-ray diffraction. Yield: 95.2 mg (45%). Anal. Calcd. for C45.5H47O0.5AsPS2: C, 70.8; H, 6.14; As, 9.71; P, 4.01; 1 S, 8.31. Found: C, 70.5; H, 6.03; As, 9.99; P, 4.12; S, 8.60%. H NMR (500 MHz, d3- MeCN): ! 7.89 – 7.84 (m, 4H, Ar-H), 7.77-7.66 (m, 18H, Ar-H), 7.63 (dd, J = 8.1, 3.2 Hz, 2H, 6,6"-CH), 7.42 (ddd, J = 8.1, 1.7, 1.7 Hz, 2H, 5,5"-CH), 1.35 (s, 18H, C(CH3)3). 31 1 -1 P{ H} NMR (162 MHz, d3-MeCN): ! 61.8 (s). IR (cm ): 3385 br, 3048 w, 2917 s, 2856 s, 1577 w. 1460 s, 1441 s, 1378 m, 1362 m, 1312 w, 1252 m, 1187 w, 1156 w, 1113 w, 1081 m, 1023 w, 997 m, 823 m, 749 s, 727 s, 789 m, 660 s, 584 m. ! "#$! !"#$%%&'()*+*,-.&-!"#!-/'#01-2+2,-/&345601565.&"34"%34&6$#5+)*7897)) ) $ S SH S SK P P $ $ $ $ To a cold (0 °C) solution of 4,4!-di-tert-butyl-2,2!-biphenylenedithiophosphinic acid (4.13, 2.15 g, 5.96 mmol) in toluene (20 ml) was added a solution of potassium hexamethyldisilazide (1.31 g, 6.57 mmol) in toluene (20 mL). The mixture, which became turbid, was stirred at 25 °C for 30 min. The white solid was collected by filtration, washed with cold (0 °C) toluene (3 " 10 mL) and hexanes (2 " 10 mL), and dried in vacuum to afford the 1 product as a white powder. Yield: 1.94 g (82%)$!! H NMR (400 MHz, d6-acetone): # 7.77 (dd, J = 11.4, 1.8 Hz, 2H, 3,3!"#$), 7.62 (dd, J = 8.0, 3.2 Hz, 2H, 6,6!"#$), 7.38 (ddd, J = 8.0, 1.8, 1.7 31 1 Hz, 2H, 5,5!"#$), 1.35 (s, 18H, C(CH3)3). P{ H} NMR (162 MHz, d6-acetone) #: 61.6. Microanalysis indicated a partial hydrate, with 0.80 molecules of water per formula unit. Anal. calcd. for C20H25.6KO0.8PS2 (%): C, 58.16; H, 6.25; K, 9.47; O, 3.10; P, 7.50; S, 15.53. Found (%): C, 58.36; H, 6.01; K, 9.81; P, 7.48; S, 15.16. IR (cm-1): 3387 br, 2919 s, 2856 s, 1614 w, 1459 s, 1396 w, 1363 m, 1212 m, 1202 w, 1156 m, 1111 m, 1081 w, 1059 w, 823 m, 794 w, 727 s, 647 s, 580 m.$ $ $ $ ! "#"! !"#$%&'()*+*,-.'-!"#!-/0#12-3+3,-/'45"612"6".'#5'7457(45'6%#78- 0$%6'09):;8+<*=>?=<< < S SK P 4 t t S Bu Bu + UCl4 U P S 4 < < To a solution of uranium tetrachloride (12.5 mg, 32.9 µmol) in THF (3 mL) was added a solution of potassium 4,4!-di-tert-butyl-2,2!-dithiophosphinate (52.6 mg, 132 µmol) in THF (5 mL). The mixture, which became turbid, was stirred at 25 °C for 22 h. The solvent was removed under reduced pressure and to the resulting residue was added toluene (2 " 5 mL). The mixture was centrifuged and the yellow solution was filtered away from a white solid. The filtrate was taken to dryness in vacuum to afford the product as a green-yellow solid. Yield: 42.3 mg (76%). Anal. calcd. for C80H96P4S8U (%): C, 57.33; H, 5.77; P, 7.39; S, 15.30; U, 14.20. Found (%): 1 C, 57.83; H, 5.92. H NMR (500 MHz, CDCl3): #:13.1 (s, 8H, 3,3!-CH), 8.49 (d, J = 7.6 31 1 Hz, 8H, 6,6!-CH), 8.26 (d, J = 7.6 Hz, 8H, 5,5!-CH), 2.55 (s, 72H, C(CH3)3). P{ H} -1 NMR (202 MHz, CDCl3): # -603 (br s). IR (cm ): 2955 s, 2924 s br, 1462 m br, 1377 m, 1365 w, 1255 w, 1155 w, 1110 w, 1082 w, 1060 w, 1022 w, 826 w, 794 w, 724 m, 665 w, 654 w, 614 w, 587 m. Crystallization from a mixture of THF (1.5 mL), ! "#$! toluene (1.5 mL), and hexane (0.5 mL) afforded green prisms that were suitable for X-ray diffraction. !"#$%&'()*+*,-.'-!"#!-/0#12-3+3,-/'45"612"6".'#5'7457(45'6%#78- 6"4#06'09):;8+<*=>?=!! ! S SK P 4 t t S Bu Bu + NpCl4(DME)2 Np P S 4 ! ! ! To solid NpCl4(DME)2 (22.6 mg, 40.4 µmol) was added a solution of potassium 4,4!-di-tert-butyl-2,2!-dithiophosphinate (64.8 mg, 162 µmol) in THF (3 mL). The deep red solution was stirred at ambient temperature for 16 h. Volatile materials were removed in vacuum, and the red residue was stirred with toluene (6 mL) at 40 °C for 10 min, causing some of the red product to dissolve although some of the red material remained undissolved. The red solution was filtered while hot through Celite supported on a glass fiber filter circle. The filtrate was concentrated in vacuum to 2.5 mL, layered with Et2O (2.5 mL) and hexanes (13 mL), and stored at –35 °C. After eight ! "#$! days the red microcrystals were collected, washed with hexanes (7 mL), and dried in vacuum. Yield: 6.1 mg (9%). The unextracted red solid was dissolved in THF (4 mL) with heating at 40 °C, and the resulting solution was filtered through Celite supported on a glass fiber filter circle (to remove some undissolved white solid, presumably KCl). The deep red filtrate was layered with hexanes (6 mL) and stored at -35 °C. After three days, the red crystals that had deposited were collected, washed with hexanes (7 mL), and dried in vacuum. Yield: 33.1 mg (49%). The total combined crystalline yield of the 1 two crops was 598%. H NMR (300 MHz, CD2Cl2): ! 8.2 (s, 8H, 3,3!-CH), 7.5 31 1 (d, 8H, 6,6!-CH), 7.4 (d, 8H, 5,5!-CH), 1.4 (s, 72H, C(CH3)3). P{ H) NMR (121 MHz, CD2Cl2): ! -715 (br s). UV/vis/NIR (THF; "max, nm): 480, 693, 714 sh, 745 sh, 773, 788, 814, 852, 893, 919, 971, 1025, 1284, 1322. Solid-state diffuse reflectance UV/vis/NIR ("max, nm): 482, 695, 714 sh, 747 sh, 772, 787, 815, 850, 891, 921, 971, 1016, 1024, 1283, 1323. Single crystals suitable for X-ray diffraction were obtained by adding five drops of THF to a toluene solution of the product, then layering with hexanes (5 mL) followed by storage at -35 °C. After 6 days several large, deep-red, block shaped crystals of t Np[S2P( Bu2C12H6)]4•4toluene had formed. ! "#$! !"#$%&'#()%**+,-'*. !"#$%/-01232456-5!"#!5&'#()573745&-89",()","5 6-#9-+89+089-,%#+:"'$+8-'*1;;;:3.2<=> tBu S SK P + EuCl3•xH2O S 4 t t Bu Bu + Bu NCl [Bu4N] Eu P 4 S tBu 4 ! ! Europium chloride hydrate (13.7 mg, 37.0 µmol) was dissolved in 2 ml anhydrous EtOH. To this was added a solution of potassium 4,4’-di-tert-butyl-2,2’- biphenylenedithiophoshinate (4.16, 59.8 mg, 150 µmol) in 2 mL anhydrous EtOH. The resulting yellow solution was brought to reflux for 30 min followed by addition of a solution of tetrabutylammonium bromide (12.0 mg, 37.2 µmol) in 1 mL anhydrous EtOH. After refluxing for an additional 20 min solvent was removed in vacuo to afford an orange residue, which was extracted with DCM (3 ! 3 mL, filter cannula). Removal of solvent afforded a brick red powder. The product was then taken up in 1 mL THF and 2 mL toluene was carefully layered on top of the t solution. Red blocks of [Bu4N][Eu(S2P Bu2C12H6)]•toluene•0.5THF suitable for XRD were obtained after 3 d at room temperature. Crystalline yield: 51.6 mg (26.3 µmol, 71.1%). Anal. calcd. for C105H144EuNO0.5P4S8 (%): C, 64.32; H, 7.40; N, 0.71; Eu, 7.75; O, 0.41; P, 6.32; S, 13.08. Found (%): C, 63.35; H, 7.28; N, 1.03; Eu, 7.44; P, ! "#$! 1 5.88; S, 12.12. H NMR (300 MHz, CD3CN): ! 8.08 (br s, 8H, 6,6’-CH), 7.95 (br s, 8H, 5,5’-CH), 3.09-3.04 (m, 8H, NCH2Pr), 1.63-1.45 (m, 80H, C(CH3)3, NCH2CH2Et), 1.39-1.31 (m, 8H, NCH2CH2CH2Me), 0.98 (t, J = 7.4 Hz, 12H, NCH2CH2CH2CH3). ! !"#$%&'#()%**+,-'*. !"#$%/-01232456-5#"$#5&'#()573745&-89",()","5 6-#9-+89+089-,%#+:,"+6(*-'*1;;;:3.2<7= tBu S SK P + NdCl3•xH2O S 4 t t Bu Bu + Bu NCl [Bu4N] Nd P 4 S tBu 4 ! Neodymium chloride hydrate (15.4 mg, 42.9 µmol) was dissolved in 2 ml anhydrous EtOH. To this was added a solution of potassium 4,4’-di-tert-butyl-2,2’- biphenylenedithiophoshinate (4.16, 68.4 mg, 171.6 µmol) in 2 mL anhydrous EtOH. The resulting pale blue solution was brought to reflux for 30 min followed by addition of a solution of tetrabutylammonium bromide (13.8 mg, 42.8 µmol) in 1 mL anhydrous EtOH. After refluxing for an additional 20 min, the solvent was removed nder reduced pressure to afford a nearly colorless residue, which was extracted with DCM (3 ! 3 mL, filter cannula). Removal of solvent afforded a pale blue powder. The product was then taken up in 1 mL THF and 2 mL toluene was carefully layered on t top of the solution. Light blue blocks of [Bu4N][Nd(S2P Bu2C12H6)]•toluene•0.5THF suitable for XRD were obtained after 2 d at room temperature. Crystalline yield: ! "#$! 56.8 mg (29.1 µmol, 68.0 %). Anal. calcd. for C105H144NdNO0.5P4S8 (%):C, 64.58; H, 7.43; N, 0.72; Nd, 7.39; O, 0.41; P, 6.34; S, 13.14. Found (%): C, 63.52; H, 7.32; N, 1 1.08; Eu, 7.12; P, 6.48; S, 13.42. H NMR (300 MHz, CD3CN): ! 7.57 (br s, 8H, 3,3’- CH), 7.22 (br s, 8H, 6,6’-CH), 6.50 (br s, 8H, 5,5’-CH), 3.17-3.04 (m, 8H, NCH2Pr), 1.71-1.57 (m, 8H, NCH2CH2Et), 1.43-1.28 (m, 8H, NCH2CH2CH2Me), 1.00 (t, J = 7.4 31 1 Hz, 12H, NCH2CH2CH2CH3), 0.84 (br s, 72H, C(CH3)3). P{ H) NMR (121 MHz, CD3CN): ! -168. !"#$%&'&(&)*&+$ 1. Moratilla Soria, B. Y.; Mas, M. U.; Estadieu, M.; Lejarreta, A. V.; Echevarria- López, D. Recycling versus Long-Term Storage of Nuclear Fuel: Economic Factors. Sci. 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