UvA-DARE (Digital Academic Repository) Coordination chemistry of tris(azolyl)phosphines

An overview is given of the chemistry of tris(azolyl)phosphines with focus on their preparation and application in coordination-and organometallic chemistry and catalysis. These systems share with the more abundant tris(pyrazolyl)borates and -methanes the ability to function as tridentate nitrogen ligands with hemilabile character, but the additional phosphine donor site grants them bifunctional potential. Applications of tris(azolyl)phosphine complexes range from enzyme models and medicinal leads to catalysts for organic transformations and polymerization reactions, which demonstrate their versatility.


General introduction
Tris(azolyl)phosphines consist of three azoles linked together by a central phosphorus apex.Several classes with this motive have been reported, mainly as ligands in coordination chemistry.Their topology resembles that of the tris(pyrazolyl)borates, also known as scorpionates [1][2][3][4].These well-known ligands can bind a metal via two or three nitrogens, depending on the nature of the metal and ligands.The tris(azolyl)phosphines can play a similar role by coordinating a metal as either N 2 or N 3 donor, but they offer additional possibilities.The presence of the P-apex serves as a convenient NMR spectroscopic handle and this central phosphorus atom may also function as an alternative or additional coordination site.Moreover, these compounds are neutral instead of anionic like the scorpionates.Our interest in tris(azolyl)phosphines was sparked when working on tris(triazolyl)phosphines [5,6] and grew when uncovering some of the potential of tris(pyrazolyl)phosphines as ligands [6][7][8].A significant number of contributions on tris (azolyl)phosphines have appeared, although the amount of literature reports stands in sharp contrast to the plethora of studies involving scorpionates.This review is intended to create an overview of the chemistry that has been reported on tris(azolyl)phosphines that function or can function as tridentate N ligands.Therefore, the focus is on any phosphorus centered compound with three planar five-membered rings directly connected to the central phosphorus atom, each with a di-substituted nitrogen atom in a beta position relative to the apex (Fig. 1).For each azolyl substituent, the preparation of the tris(azolyl)phosphine is covered first, followed by a short description of reported applications.Publications up to and including 2016 are reviewed.

Preparation of tris(imidazolyl)phosphines
Preparation of imidazolylphosphines (P(Im) 3 ) generally starts with the reaction of PCl 3 with a deprotonated imidazole.The three methods typically used in the literature for deprotonation are (a) reaction with an organometallic base, (b) reaction with an amine, or (c) replacement of the proton with a SiMe 3 group (Scheme 1).The exchange reaction of a halo-imidazole with EtMgBr is sometimes encountered as fourth method to prepare a deprotonated imidazole (Scheme 1).

Application as active site models of Zn enzymes: Zn and Co complexes
Following their introduction of the tris(imidazol-2-yl) phosphines [9], Brown and co-workers applied these compounds as ligands (Fig. 2a) in the study of active site models for Zn containing enzymes, in particular carbonic anhydrase.First, they employed homo-imidazolyl ligands (R 4 ,R 5 = H 2 ; Me 2 ; iPr 2 ) for complexation with Zn and Co [15,16] and found the steric requirements of the ligand to be important.Coordination could only be established unambiguously for R 4 ,R 5 = iPr 2 and its Zn complex [Zn{P(2-Im 4,5-iPr2 ) 3 }](ClO 4 ) 2 was the only one showing moderate catalytic activity in the hydration of CO 2 .A crystal structure of [ZnCl{P(2-Im 4,5-iPr2 ) 3 }]Cl was reported [17].Brown and coworkers extended the range of ligands with R 4 ,R 5 = nPr 2 (25%) [18] and with mixed imidazolyl versions P(2-Im 4,5-iPr2 ) 2 (2-Im 0 ) Fig. 1.General structure of tris(azolyl)phosphine and basic structures of all azolyl substituents considered in this review, including their abbreviations.with Im 0 -R 4 ,R 5 = H 2 (24%) and H,C 2 H 4 OH (21%) [19].These were obtained via reaction of the lithiated imidazoles with PCl 3 , using a two-step sequence for the mixed ligands.Their Co and Zn complexes were explored for catalytic activity in the dehydration of CO 3 H À .In a subsequent study, the rate of hydrolysis of pnitrophenylpicolinate was shown to be moderately enhanced by the Co(II) and Zn(II) complexes of homo-imidazolylphosphines P (2-Im 4,5-R2 ) 3 with R 4 ,R 5 = H 2 , iPr 2 , H,C 2 H 4 OH and those of the mixed imidazolyl ligands P(2-Im 4,5-iPr2 ) 2 (2-Im 0 ) with Im 0 -R 4 ,R 5 = H 2 and H, C 2 H 4 OH [20].The Co(II) complexes of the latter, [CoCl{P(2-Im 4,5-iPr2 ) 2 (2-Im 0 )}]Cl, were also tested as catalysts for the hydrolysis of phosphate esters [21].Subsequently, Brown and co-workers found that Zn(II) can catalyze the decomposition of tris(imidazol-2-yl)phosphines [22].In particular, ZnCl 2 enhanced the decomposition, which was suggested to be a reason for the observed diminishing catalytic activity in their previous studies.In contrast, Kläui et al. reported tris{2-(1-methyl-4-tolylimidazolyl)}phos phine (45%, using nBuLi as a base) and its Zn(NO 3 ) 2 complex as a hydrolytically stable alternative for tris(pyrazolyl)borates [23]; no mention was made of Brown's decomposition study.It is plausible that the introduced 1-Me groups provide moderate shielding for the P-C bonds and prevent decomposition.Such a stability enhancement has been observed on introducing Me groups in the proximity of the P-apex of tris(pyrazolyl)phosphine oxides (see Section 3.2) [7].The group of Brown also studied the Zn(II) and Co(II) complexes [M(ClO 4 ){P(2-Im 4,5-iPr2 ) 3 }](ClO 4 ) in micellar media with the hydrolysis of p-nitrophenyl acetate as a catalytic model reaction, to conclude that the increased rate constant is mainly due to the increased concentration of the substrate inside the micelles [24].
The groups of Kläui and Kunz introduced tris(imidazol-4-yl) phosphine (Fig. 2b) as an alternative ligand for Zn enzyme modeling.Because only one prototropic tautomer functions as N 3 ligand, only one apolar substituent per Im ring is required to ensure a hydrophobic pocket around the metal.The low degree of substitution enhances the solubility of the ligand and its complexes in water.The approach was first demonstrated for [M{P(4-Im 2-iPr ) 3 } X]X with M = Ni (X = NO 3 ), Co (X = Cl, NO 3 ), and Zn (X = Cl) [33].The tris(2-isopropylimidazol-4-yl)phosphine ligand was prepared (35%) from 2-isopropylimidazole by N-protection with a diethoxymethyl group followed by deprotonation with nBuLi and reaction with PCl 3 .Also the phenyl (40%) and tert-butyl (39%) derivatives were synthesized [34].The UV-Vis spectra of the Co(II) complexes indicated that the differently sized substituents on the ligand influence the coordination number of the metal.After converting the Papex to a P@O unit (95%), the oxidized ligand was shown to complex with Zn(NO 3 ) 2 , Co(NO 3 ) 2 , and Cu(SO 4 ) of which the latter two showed the expected j 3 -N 3 coordination [35].Instead, j 2 -N 2 bonding was found for the ZnCl 2 and CoCl 2 complexes and j 2 -N,O coordination, involving the apex P@O, for the NiCl 2 complex (Fig. 3) [36].The NiCl 2 complex of the non-oxidized ligand, [NiCl{P(4-Im 2-iPr ) 3 }]Cl, as well as the related Ni and Co nitrato complexes showed the common j 3 -N 3 coordination [37].While tris(2-isopro pylimidazol-4-yl)phosphine remains bound as a tridentate ligand, the overall coordination number of these complexes is readily effected by temperature, solvent, and by N,O-bidentate ancillary ligands such as amino acids.[Co{2-(OC(O)}Py){P(4-Im 2-iPr ) 3 }] (NO 3 ), featuring an N,O bound picolinato ligand was reported [38].Contrasting the results of Kunz [37], Chavez and co-workers have shown that for [Co{P(2-Im 1-Et,4-iPr ) 3 }X 2 ] the choice of counterion X can dictate the geometry also for the non-oxidized phosphine ligands [39].Whereas weakly coordinating OTf anions led to tridentate coordination of the ligand, more strongly coordinating Cl or Br anions gave tetrahedral complexes with bidentate coordination for the imidazolylphosphine.The geometry of these complexes was determined by X-ray crystallography and their relative stabilities were assessed with DFT calculations.
Fiedler and co-workers showed that also Ph groups in the Im-2 position, as in P(4-Im 2-Ph ) 3 , provide sufficient steric hindrance to obtain mono-ligand complexes.This was illustrated for a series of [Fe(acac X ){P(4-Im 2-Ph ) 3 }](OTf) complexes that were characterized by UV-Vis and NMR spectroscopy, cyclic voltammetry and DFT calculations [48].The complexes have been related to the enzyme acetylacetone dioxygenase (Dke1) which features a trishistidine Fe active center.In contrast to the enzyme, the [Fe(acac X ) {P(4-Im 2-Ph ) 3 }](OTf) complexes were stable for days on exposure to O 2 , while reacting instantaneously with NO, which indicates that reaction with O 2 should be sterically feasible [49].The sharp contrast between the enzyme and the model compounds in O 2 reactivity was taken to suggest that a favorable second step, supported by second-sphere effects, takes place in the enzyme.P(2-Im 1-Me,4,5-Ph2 ) 3 , prepared from the imidazole and PCl 3 with nBuLi as the base (24%), and P(4-Im 2-Ph ) 3 both have been used as suitable scaffolds for Fe enzyme modeling [50].The weaker ligands, like solvent molecules or carboxylates, that complete the coordination sphere in the initially formed precursor complexes are readily replaced upon addition of a b-diketonate or salicylic acid, while the P(Im) 3 remains bound to the Fe center.This contrasts other neutral N 3 ligands and demonstrates the suitability of these complexes as enzyme models.A crystallographic, spectroscopic, and computational comparison of the products of [Fe (NCMe) 3 {P(2-Im 1-Me,4,5-Ph2 ) 3 }](OTf) 2 and [Fe{HB(Pz 3,5-Ph2 ) 3 }{OC(O) Ph}] with an aminophenol showed these complexes to have different electronic structures based upon which different mechanistic pathways were suggested for extradiol catechol dioxygenases (ECDOs) and o-aminophenol dioxygenases [51].A similar comprehensive study was conducted on the reaction of the same starting complexes with 2-(1-methylbenzimidazol-2-yl)hydroquinonate to model another Fe non-heme enzyme [52].Related complexes with either a catechol or diaminophenylene substrate, all characterized by X-ray diffraction, have been studied for their reactivity toward O 2 , showing up to a 10 5 rate difference that contrasts with modeled enzymes, which was ascribed to a lack of control over proton transfer during the oxidation of the models (Scheme 2) [53].

Copper complexes of tris(imidazolyl)phosphines
The study of the Cu complexes of tris(imidazolyl)phosphine has focused mainly on their reactivity toward O 2 and isolation of the oxo-products.The first reported Cu(I) complexes [Cu{P(2-Im 1-Et,4-R ) 3 }]X and [Cu(NCMe){P(2-Im 1-Et,4-iPr ) 3 }]X (X = PF 6 , ClO 4 , OTf, Cl) reacted irreversible with O 2 at ambient temperature via two intermediates to blue bis-ligand Cu(II) complexes [46].At low temperature, the reaction could be stopped at purple O 2 -bridged Cu(I) dimers, which could be reverted to the starting complex for the 4-iPr ligand derivative.
Severin and co-workers reported on P(Im) 3 containing polymers that, when complexed to Cu(II), act as efficient hydrolysis catalysts for phosphoesters [56].The monomer tris(1-vinyl-imidazol-2-yl) phosphine was obtained (29%) via the pyridine/Et 3 N mediated route [13], and could be incorporated into a homopolymer or a co-polymer with ethyleneglycol dimethacrylate.For the latter option, [Mo(g 3 -allyl)(CO) 2 {P(2-Im 1-vinyl ) 3 }], with the Mo atom functioning as template, was also applied.The coordination geometry and the Cu(II) loading differed for the three obtained polymers and their relative activity was dependent on the substrate.

Gold complexes of tris(imidazolyl)phosphines
The P-apex is the primary coordination site in gold complexes of tris(imidazolyl)phosphines.The first such complex was reported in 1998 as analogue of an anti-rheumatoid arthritis drug [57].The P(5-Im 1-Et,2-iPr ) 3 ligand was synthesized by reacting lithiated l-eth yl-2-isopropyl-5-bromoimidazole with PCl 3 .The ethyl groups block the nitrogen atoms beta to the P-apex and thereby inhibit the ligand to act as a tridentate N donor.However, the Au complex of P( 2 AuCl 4 ).Both Au complexes were structurally characterized and shown to display unexpected AuÁ Á ÁH-C interactions with benzylic hydrogens in the solid state (Fig. 5a).
In this study, Kunz et al. showed that the imidazol-2ylphosphine complexes release nearly 2 eq. of CO under UV irradiation and the imidazol-4-yl complex half of that, which was subsequently ascribed to the steric bulk of the ligands [66].The ligand of the used [Mn(CO) 3 {P(4-Im) 3 }] was generated (33%) from the reaction of the Grignard reagent of 4-iodo-1-(methoxymethyl) imidazole with PCl 3 , followed by acidic workup that also removed the N-methoxymethyl protecting group (Scheme 4).
The group of Lammertsma reported a set of tris(pyrazolyl)phosphine oxides with different steric demand [7].All ligands were prepared by reacting PCl 3 with 3 equivalents of the corresponding pyrazole in the presence of a slight excess of base; Et 3 N was used for Pz 3,5-Me2 (90%), Pz 3-Ph (86%) and Pz 3-tBu (93%), while the stronger base KOtBu was required for Pz 3-Ph-5-Me (30%) and Pz 3-tBu-5-Me (53%).The ligands with a single substituent per pyrazolyl group showed immediate decomposition upon exposure to water, but an additional Me group at the 5-position inhibited hydrolysis.Cu (I)(NCMe) complexes could be formed from all ligands and the acetonitrile in the resulting Cu complexes could be exchanged for PPh 3 or CO.The ligands were shown to have stronger electron withdrawing properties than the homologous tris(pyrazolyl)methanes.A computational analysis suggested similar Cu(I) ligating properties for tris(pyrazolyl)phosphine oxide, tris(triazolyl)phosphine oxide (Section 4.2), and their CH centered analogues [6].Lammertsma and co-workers also synthesized the (non-oxidized) tris (pyrazolyl)phosphines P(Pz) 3 (42%) and its 3,5-Me 2 (96%), 3-Ph (52%), and 3-tBu (81%) substituted derivatives by reaction of the corresponding pyrazoles with PCl 3 in the presence of Et 3 N as a base [8].Reaction of the ligands with [Cu(NCMe) 4 ](PF 6 ) gave [Cu(NCMe) {P(Pz X ) 3 }](PF 6 ) complexes, except for unsubstituted P(Pz) 3 .When a 2:1 ratio was used, P(Pz) 3 gave [Cu{P(Pz) 3 } 2 ](PF 6 ) with one P(Pz) 3 acting as a N 3 donor and the other coordinating via its P-apex.With a 1:1 ligand to Cu ratio, a one-dimensional coordination polymer was formed in which each ligand acts as both N 3 donor to one Cu atom and as P donor to the next (Scheme 6).X-ray structures of both complexes were reported.
Contrasting the broad applicability of OP( 1,2,4 Tz) 3 , the reduced form, P( 1,2,4 Tz) 3 , is not as effective in forming phosphate bridges as was illustrated by the reaction with uridine (low temperature, followed by I 2 -oxidation) that gave monomers instead of the desired oligoribonucleosides, supposedly due to the lability of the ligand [88].Finally, penta(1,2,4-triazolyl)phosphine has been explored as P precursor to generate a tricyclic tetra(amino)phosphonium salt, but with disappointing results [120].
The triazolylation also worked in dichloromethane with N-methyl morpholine as base [141].There are several reports on the use of pyridine as solvent and base [142][143][144][145].In one case only a pyridinium salt was isolated, presumed to result from a secondary reaction with pyridine [142].In other instances, the triazolyl-substituted products were successfully used in situ [143,144] or isolated in up to 60% yield [145].

Tris(thiazolyl)phosphines
Moore and Whitesides connected besides imidazoles also thiazoles to phosphorus by reacting PCl 3 with the lithiated heterocycles (47-64%) [11].The parent and the benzannulated derivative, accessible only from (benzothiazol-2-yl)trimethylsilane and PCl 3 (83%), both formed bis-ligand dimethyl platinum complexes, with metal bonding at the P-apex, as derived from NMR spectra (Scheme 14).Reaction of the tris(thiazolyl)phosphines with aryl lithium or heteroaryl lithium reagents resulted in P-substituent exchange, whereas coupling reactions dominated for the benzothiazolyl derivative [146].Abstraction of one benzothiazolyl group from tris(benzothiazolyl)phosphine gave access to the corresponding phosphanide ligand [147].In a study previously mentioned in Section 2.5, AuCl complexes of tris(4,5-R 2 -thiazol-2-yl) phosphines (with R 2 = H,H; Me,H; Me,Me) were studied [58].Crystal structure determinations showed the tris(thiazolyl)phosphines to bind to the metal exclusively via the phosphine apex, while a variety of Au-Au and Au-Cl interactions was found in the solid state.

Concluding remarks
The literature on tris(azolyl)phosphines has been dominated by tris(imidazolyl)phosphines, which have been used mainly to model enzymes with histidine residues at the active site.In recent years, also more non-enzyme inspired metal complexes have been stud-ied.For the other tris(azolyl)phosphines, no biomimetic applications have been reported, while they do display interesting coordination chemistry, with some complexes being applied in catalysis.Tris(1,2,4-triazolyl)phosphine forms an exception as it has almost exclusively been applied as synthon in heterocyclic chemistry.
The tris(imidazolyl)phosphines have their azolyl substituents connected to the phosphorus apex via carbon-phosphorus bonds, making them more stable than most other tris(azolyl)phosphines under diverse conditions.However, they typically suffer from more complex and lower yielding syntheses that often involve functional group protection schemes.
Whereas all tris(azolyl)phosphines have the potential to serve as multi-site ligands, there are very few examples in which both coordination sites are used at the same time, despite their potentially interesting applications.An avenue to explore is to tune the electronic influence on one metal by varying the opposite one, whereas the second binding site might also be used for ligand fixation on a metal surface.