the preparation of 
 fluorine - containing aromatic compounds ( arf ) 
 has been a long - standing challenge in organic synthesis . while these compounds are highly prized in the 
 pharmaceutical and agrochemical industries , methods to access aryl fluorides selectively , 
 under mild and general reaction conditions , remain elusive . since 
 the advent of the balz schiemann reaction and the halex process , significant 
 advances have been made toward this end , especially with regard to transition metal - catalyzed methods . in analogy to the practicality , simplicity , and 
 generality of pd(0)/pd(ii)-catalyzed aryl carbon  heteroatom 
 bond - forming processes , the coupling of aryl ( pseudo)halides with 
 simple metal fluoride salts (  f  ) 
 ( figure 1a ) would be 
 ideal . however , several challenges associated with developing such 
 a process have been revealed both experimentally and theoretically . among these 
 difficulties are the formation of stable [ lpd(ii)f]2 dimers 
 and competitive p  f and p  c bond formation , which suggests 
 a high barrier for c  f reductive elimination ( figure 1a ) . to circumvent the difficult 
 reductive elimination from pd(ii ) complexes , electrophilic fluorine 
 sources (  f  ) have been employed to oxidize 
 the metal center to pd(iii ) or pd(iv ) intermediates from which reductive 
 elimination is more facile . f reductive elimination from [ lpdar(f ) ] is 
 unique to biaryl monophosphine - ligated complexes , and has been observed 
 stoichiometrically , albeit at high temperatures 
 and with substrates that contain activated aryl groups . subsequently , it was discovered that incorporating 
 a substituent at the c3 position of the biaryl monophosphine 
 ligand , for example , as in hgphos ( ( l2 ) , figure 1b ) , gives rise to a more active 
 catalyst system . the 
 interaction between ligand - bound pd(ii ) and c1 is shown by 
 a dashed line . ( c ) biaryl monophosphine ligand ( alphos , l1 ) . while these discoveries have shown 
 that pd(ii)-catalyzed fluorination 
 is indeed viable , several problems remain . most importantly , the generation 
 of regioisomeric byproducts ( presumably 
 through a pd  benzyne intermediate ) lowers the yield of the 
 desired product and renders purification difficult or even impossible . additionally , the use of elevated reaction temperatures is required 
 to achieve full conversion of the starting materials . to address these 
 issues , which we ascribe to the difficult c  f reductive elimination 
 from pd(ii ) complexes , we sought to design a ligand to improve this 
 elementary step as well as the overall efficiency of the catalytic 
 transformation . as shown in figure 1b , biaryl monophosphine ligands coordinate to the pd(ii ) 
 metal center in a bidentate fashion , making contacts through both 
 the phosphine and the c1 carbon of the adjacent aromatic ring . because reductive elimination from pd(ii ) complexes 
 is typically favored from a three - coordinate intermediate , we hypothesized that modification at c3 
 with an electron - withdrawing group would diminish the donation of 
 electron density from c1 to the pd(ii ) metal center , providing 
 an intermediate with more three - coordinate character and thereby generating 
 a more active catalyst . to test our 
 hypothesis , we designed and synthesized a ligand that 
 was less electron - rich than the previously reported l2 . this was accomplished by removing the methoxy group adjacent to 
 the dialkylphosphino group on the  upper  aromatic ring 
 and replacing the hydrogen atoms of the pendant 4-(n - bu)ph group at c3 with fluorines ( figure 1c ) . lithium  halogen exchange of 2,4,6-triisopropylbromobenzene 
 with n - buli followed by nucleophilic addition into 
 hexafluorobenzene provides perfluoro biaryl l1a . to improve 
 solubility of the final ligand and prevent subsequent nucleophilic 
 additions into the activated perfluoro aromatic , n - buli was added at 78 c to give the alkylated product 
 via snar , which was then halogenated using n - iodosuccinimide and h2so4 to yield l1b . terphenyl l1c was prepared by nucleophilic addition 
 of l1b into a benzyne intermediate , generated from 3-fluoroanisole , 
 followed by quenching the resulting aryl anion with bromine at 30 
 c . treatment of l1c with t - buli 
 at 78 c followed by the addition of cucl and ad2pcl and then heating to 140 c overnight furnished l1 in 82% yield ( 25% yield over five steps ) . the synthesis 
 was amenable to scale up as more than 10 g of l1 was 
 prepared in a single batch . reagents and conditions : 
 ( a ) 
 thf , 78 c , n - buli , 1 h ; added to c6f6 in thf , 0 c to rt , 2 h , 87% . ( b ) thf , 
 78 c , n - buli , 30 min , 99% . ( c ) acoh , 
 etoac , h2so4 , n - iodosuccinimide , 
 50 c , 17 h , 80% . ( d ) thf , 78 c , t - buli , 1 h ; added to 3-fluoroanisole and n - buli 
 in thf , 78 to 25 c , 44% . ( e ) thf , 78 
 c , t - buli , 1 h ; cucl 78 c to 
 rt ; ad2pcl , toluene , 140 c , 18 h , 82% . ( f ) [ codpd(ch2tms)2 ] , pentane , rt , 48 h , 78% . the highly active pd(0 ) precatalyst [ ( l1pd)2cod ] ( 1 ) was prepared in 78% yield by treating l1 with an equivalent of [ codpd(ch2tms)2 ] in pentane , which could be easily isolated and stored under 
 an inert atmosphere ( scheme 1 ) . because of the electron - rich 
 nature and high reactivity of biaryl monophosphine - ligated pd(0 ) complexes , 
 there exist only a few structurally characterized examples . we have previously described several pd(0 ) precatalysts , 
 of which indirect evidence was obtained suggesting an empirical formula 
 of [ ( lpd)ncod ] ( n = 12 ) ; however , the insolubility of these complexes 
 precluded structural characterization by single - crystal x - ray diffraction . single crystals of 1 suitable for x - ray diffraction 
 were obtained providing the first structural evidence for this class 
 of precatalyst ( figure 2 ) . complex 1 crystallizes in the triclinic centrosymmetric 
 space group p1 with half a molecule of 1 and three molecules of benzene per asymmetric unit . the full molecule is a binuclear complex in which 
 each pd atom is chelated by one l1 ligand . located between 
 the two palladium centers is a cyclooctadiene molecule ( cod ) , which 
 coordinates through its two double bonds to the metal atoms in a side - on 
 fashion that can be described as 2 . this results 
 in a distorted trigonal planar coordination environment for the palladium 
 atoms with the following angles : p  pd c1 , 88 ; 
 p  pd  cod , 135 ; and c1pd  cod , 
 137. crystal structure of [ ( l1pd)2cod ] 
 ( 1 ) . thermal ellipsoids are shown at 50% probability ; 
 hydrogen atoms and residual benzene molecules are omitted for clarity . the reactivity of l1 and l2 was compared 
 by preparing analogous [ lpdar(f ) ] complexes and examining the formation 
 of the arf resulting from the stoichiometric c  f reductive 
 elimination from the pd(ii ) intermediates at room temperature ( scheme 2 ) . these reactions 
 were performed in the presence and absence of added aryl bromide , 
 which serves as a trapping agent for the resulting pd(0 ) that is formed 
 after reductive elimination . after a period of 
 12 h , the l1-supported complex provides approximately 
 twice the amount of the desired product than that bearing l2 . both l1- and l2-ligated complexes provided 
 the arf product and are the first examples of room - temperature c  f 
 reductive elimination from isolated [ lpd(ar)f ] complexes . the 
 enhanced reactivity in the stoichiometric process exhibited 
 by the l1-supported pd(ar)f complex was successfully 
 extended to the catalytic reaction . by using 1 , a variety 
 of activated ( hetero)aromatic triflates ( table 1 ) were transformed to the fluoride derivatives 
 at room temperature . a range of functional 
 groups were tolerated in this transformation , including nitro ( 2 ) , formyl ( 3 ) , methyl ketone ( 4 ) , redox active anthraquinone ( 5 ) , and sulfonamide / tertiary 
 amine ( 6 ) . heteroaryl triflates were also competent substrates 
 as flavone 7 , quinolines 8 and 9 , and quinazoline 10 derivatives were prepared in high 
 yields . notably , xav939 , a tankyrase 
 inhibitor and potential cancer therapeutic , could be fluorinated to 
 give 11 , demonstrating the applicability of this method 
 to fluorinate medicinally relevant compounds . additionally , aryl triflates 
 can be selectively transformed in the presence of aryl chlorides , 
 leaving a reactive handle for downstream modifications ( 1214 ) . while the long reaction times at room temperature 
 speak to the stability of the catalyst , the transformation can be 
 completed in 24 h by increasing the temperature even while lowering 
 the catalyst loading ( table 1 , 7 and 9 ) . reaction conditions unless otherwise noted : 
 aryl triflate ( 1 mmol ) , csf ( 3 mmol ) , tol or 2-methf ( 10 ml ) . aryl bromide ( 0.5 mmol ) , kf ( 0.25 
 mmol ) , agf ( 1.0 mmol ) , tol ( 5 ml ) . tol = toluene , 2-methf = 2-methyl 
 tetrahydrofuran . with our 
 previously described catalyst systems , mixtures of regioisomeric aryl fluorides 
 are sometimes formed during the pd - catalyzed nucleophilic fluorination 
 reaction . in general , substrates with para electron - donating groups or meta substitution 
 are plagued by this undesired reaction pathway . previously , by using 
 cyclohexane as the solvent , the amount of regioisomer formation could 
 be reduced . in some instances , however , the quantity of undesired 
 regioisomer formed was still significant . to probe the effectiveness 
 of catalysts derived from 1 to further suppress the formation 
 of regioisomeric byproducts , we 
 examined 4-(n - bu)photf ( x = otf ) and 4-(n - bu)phbr ( x = br ) as model substrates ( table 2 ) . with either aryl electrophile , the l2-supported precatalyst provides substantial amounts of undesired 
 isomer b ( entry 1 ) . the enhanced reactivity of 1 , however , allows for the use of lower reaction temperatures 
 than were previously possible ( entry 2 , x = otf ) , revealing a temperature 
 dependence on the formation of b ( entries 35 , 
 x = otf ) . the same temperature dependence is not observed for aryl 
 bromides , although using 1 diminishes the amount of b formed . the reaction time 
 was 48 h. the success of 1 in suppressing the formation of b with 4-(n - bu)phenyl triflate or bromide 
 prompted us to study the reaction of a number of substrates that are 
 prone to give regioisomeric mixtures of arf products . as shown in table 3 , a variety of aryl 
 triflates and bromides converted to the corresponding aryl fluorides 
 in high yield with > 100:1 selectivity for the desired regioisomer 
 ( 1521 , 2325 ) . previously , substrates with strongly electron - donating 
 groups in the para position , such as ome , 
 have been the most challenging substrates for this methodology . for 
 example , 4-methoxyphenyl triflate and 
 4-bromoanisole have previously been 
 shown to form the undesired meta isomer as the major 
 product . using 1 , the observed selectivity is reversed 
 and the desired product dominates ( 22 ) . several fluorinated 
 analogues of biologically active compounds were also prepared to give 
 ( )-naproxen 23 , diethylstilbesterol 24 , and tyrosine 25 derivatives with exceptional selectivity . no loss in stereochemical integrity was observed with 25 under the reaction conditions , and reduction ( arh ) was only observed 
 for 16 ( 0.75% ) , 19 ( 0.64% ) , and 22 ( 0.52% ) ( see the supporting information ) . reaction conditions unless otherwise noted : 
 aryl triflate ( 1 mmol ) , csf ( 3 mmol ) , cy ( 10 ml ) . aryl bromide ( 1 mmol ) , kf ( 0.5 mmol ) , 
 agf ( 2.0 mmol ) , cy ( 10 ml ) . , we prepared the [ lpd(ar)br ] 
 complexes , from the reaction of 4-(n - bu)phbr and 
 codpd(ch2tms)2 using l1 and l2 as supporting ligands ( figure 3 ) ( see the supporting 
 information ) . the respective complexes were characterized 
 in the solid state using single - crystal x - ray diffraction . the initial 
 hypothesis from which the design of l1 derived predicts 
 that significant lengthening of the c1pd bond would 
 be observed with the more electron - deficient supporting ligand ( l1 ) . in fact , only a slight increase in this bond length in d was apparent , as compared to that seen with c ( see the supporting information ) . by overlaying the crystal structures of c and d , a more subtle difference was , however , revealed ( figure 3c ) . with c , the pendant 4-(n - bu)ph group of the ligand is 
 shifted toward the pd - bound bromide to form an aromatic chbr 
 contact of 3.874(3 )  ( measured from c to br ) , which is in agreement 
 with typical aromatic chbr interaction distances 
 found in the solid state ( 3.74.2  ; measured from c to 
 br ) . the perfluorinated aryl group of d lacks the required hydrogen atom to achieve the same attractive 
 interaction , giving a cbr distance of 4.370(2 )  . the analogous [ lpd(ar)f ] complexes were synthesized ( e and f ) , and single - crystal x - ray analysis of e shows that this behavior is conserved , with e exhibiting an aromatic chf interaction distance 
 of 3.387(3 )  ( measured from c to f ) ( figure 3d ) . typical aromatic chf 
 interaction distances found in the solid state range from 3.3 to 3.7 
  ( measured from c to f ) . unfortunately , 
 all attempts to obtain single crystals of f suitable 
 for x - ray diffraction yielded decomposition and/or pseudocrystalline 
 material . ( a ) schematic of [ l2pd(ar)x ] complexes c and e where l2 is highlighted in red . ( b ) schematic of [ l1pd(ar)x ] complexes d and f. ( c ) crystal structure overlay of c and d. c is shown in red . hydrogen atoms 
 and an isopropyl group hydrogen atoms and the n - butyl group on 
 the pd - bound aryl omitted for clarity . short chf 
 contacts are frequently observed in 
 structurally characterized pd  f complexes . they serve to stabilize 
 the pd  f bond by alleviating electronic repulsions between 
 the lone pairs on the fluoride atom and the filled d - orbitals of pd . as shown in the solid state , e achieves 
 this pd f bond stabilization intramolecularly while f can not . the lack of an intramolecular chf interaction 
 in f results in ground - state destabilization relative 
 to e , which may account for the observed enhancement 
 in reactivity . density functional theory ( dft ) calculations 
 were carried out to 
 compare complexes e and f and gain further 
 insight into the stabilizing chf interaction that 
 was observed in the solid - state structure of e. to reduce 
 conformational complexity , the pd - bound 4-(n - bu)ph 
 of complexes e and f was replaced with a 
 phenyl group in our computational study , giving complexes e and f , respectively . the calculated 
 ground - state structure of e is in good agreement 
 with the crystallographic data of e , exhibiting an attractive 
 chf contact ( 3.24  , measured from c to f ) 
 ( figure 4a ) . furthermore , 
 npa ( natural population analysis ) charge calculations of complex e showed that the pd  bound fluorine atom bears 
 a partial negative charge of 0.700 and the hydrogen atom at 
 the 2 position of the pendant 4-(n - bu)ph group carries 
 a partial positive charge of + 0.251 . taken together , these analyses 
 clearly indicate the presence of an intramoleuclar stabilizing interaction . as anticipated , this interaction is absent in complex f , which lacks the necessary hydrogen atom required for this 
 attractive interaction ( figure 4b ) . in addition , npa charge analysis of complex f reveals that both the pd - bound fluorine atom and the fluorine 
 atom at the 2 position of the pendant 4-(n - bu)ph 
 group carry a partial negative charge ( 0.690 and 0.318 , 
 respectively ) , further demonstrating the lack of an attractive interaction 
 in complex f. computed ground - state structures of complexes e 
 and f. geometries were optimized at the b3lyp/6 - 31g(d)-sdd(pd ) 
 level of theory . ( a ) the chf 
 interaction of complex e is 3.24  , measured 
 from c to f. ( b ) complex f showing the lack of 
 an intermolecular stabilizing interaction . additionally , we performed dft calculations of the c  f 
 bond - forming 
 reductive elimination step for complexes e and f ( figure 5 ) . this process involves a three - membered transition state 
 where the c  f bond is being formed while the pd  f and 
 the pd the 
 calculations showed that the c  f reductive elimination of complex f ( figure 5b ) has an activation barrier ( g ) 0.7 kcal / mol lower than that of complex e ( figure 5a ) , which is in agreement with the experimentally observed enhanced 
 reactivity of the l1-based catalyst . energies were computed 
 at the m06/6 - 311+g(d , p)-sdd(pd)/smd(toluene ) 
 level of theory with geometries optimized at the b3lyp/6 - 31g(d)-sdd(pd ) 
 level . ( a ) transition state 
 minimization of complex e. ( b ) transition state 
 minimization of complex f. a new ligand ( l1 ) that allows for 
 room - temperature 
 c  f reductive elimination from [ lpd(ar)f ] has been developed . the enhanced reactivity was exploited to provide aryl fluorides from 
 aryl triflates and bromides with greater than 100:1 selectivity for 
 the desired regioisomer . crystallographic analysis of several pd complexes 
 revealed that l2 provides a stabilizing intramolecular 
 aromatic chf interaction , which is not accessible 
 with l1 , giving rise to a more active catalyst system . finally , dft calculations were performed comparing complexes e and f corroborating the observations 
 made in the solid state . this study provides insights into ligand 
 structure , which should aid in the discovery and design of more effective 
 catalysts for c  f bond formation .
a new 
 biaryl monophosphine ligand ( alphos , l1 ) allows 
 for the room - temperature pd - catalyzed fluorination of a variety of 
 activated ( hetero)aryl triflates . 
 furthermore , aryl triflates and 
 bromides that are prone to give mixtures of regioisomeric aryl fluorides 
 with pd - catalysis can now be converted to the desired aryl fluorides 
 with high regioselectivity . 
 analysis of the solid - state structures 
 of several pd(ii ) complexes , as well as density functional theory 
 ( dft ) calculations , shed light on the origin of the enhanced reactivity 
 observed with l1 .