Fluorinated click-derived tripodal ligands drive spin crossover in both iron(II) and cobalt(II) complexes.

Control of the spin state of metal complexes is important because it leads to a precise control over the physical properties and the chemical reactivity of the metal complexes. Currently, controlling the spin state in metal complexes is challenging because a precise control of the properties of the secondary coordination sphere is often difficult. It has been shown that non-covalent interactions in the secondary coordination sphere of transition metal complexes can enable spin state control. Here we exploit this strategy for fluorinated triazole ligands and present mononuclear CoII and FeII complexes with "click"-derived tripodal ligands that contain mono-fluorinated benzyl substituents on the backbone. Structural characterization of 1 and 2 at 100 K revealed Co-N bond lengths that are typical of high spin (HS) CoII complexes. In contrast, the Fe-N bond lengths for 3 are characteristic of a low spin (LS) FeII state. All complexes show an intramolecular face-to-face non-covalent interaction between two arms of the ligand. The influence of the substituents and of their geometric structure on the spin state of the metal center was investigated through SQUID magnetometry, which revealed spin crossover occurring in compounds 1 and 3. EPR spectroscopy sheds further light on the electronic structures of 1 and 2 in their low- and high-spin states. Quantum-chemical calculations of the fluorobenzene molecule were performed to obtain insight into the influence of fluorine-specific interactions. Interestingly, this work shows that the same fluorinated tripodal ligands induce SCO behavior in both FeII and CoII complexes.

Synthesis of Intramolecular P/Al-Based Frustrated Lewis Pairs via Aluminum-Tin-Exchange and their Reactivity toward CO2.

Frustrated Lewis pairs (FLPs) composed of acidic alane and basic phosphane functions, separated by a xanthene linker, can be prepared through the corresponding Me3 Sn derivative and methyl aluminum compounds with elimination of Me4 Sn. This way MeClAl-, Cl2 Al- and (C6 F5 )2 Al- moieties could be introduced and the resulting FLPs are stabilized by a further equivalent of the alane precursors. In contact with the FLPs CO2 is bound via the C atom at the phosphane functions and the two O atoms at the Al centers. The residues at the latter determine the binding strength. Hence, in case of MeClAl CO2 capture occurs at higher pressure and under ambient conditions CO2 is released again, while for Cl2 Al and (C6 F5 )2 Al CO2 binding becomes irreversible. The results of DFT calculations rationalize these findings by the high thermodynamic stabilization in case of more electronegative residues, which concomitantly lead to higher barriers, and in case of (C6 F5 )2 Al further stabilization is achieved through a low reorganization energy.

Spin-state control of cobalt(II) and iron(II) complexes with click-derived tripodal ligands through non-covalent and fluorine-specific interactions.

The fine-tuning of intermolecular or intramolecular non-covalent interactions (NCIs) and thus the precise synthesis of metal complexes in which the spin states can be controlled by NCIs remains challenging, even though several such complexes have been intensively studied. In this regard, we present mononuclear cobalt(II) and iron(II) complexes with "click"-derived tripodal ligands that contain fluorinated benzyl substituents in the secondary coordination sphere. The complexes were co-crystallized with different solvent molecules to decipher the effect of the crystallized solvents on NCIs, and on the spin state of the metal ion. Additionally, the fluorine-specific interactions in the secondary coordination sphere were examined. We present a first structure-property correlation between the nature of interaction of the (per)fluorinated aromatic substituents on the ligand periphery, and the spin state of the metal complexes. In particular, the TF5TA containing ligand show interesting stacking motifs depending on the used solvent, and these interactions have an influence on the spin state of the cobalt(II) complexes. Furthermore, the iron(II) complex thereof, Fe(TF5TA)2(BF4)2·2EtOH displays spin crossover (SCO).

MVO-10: A Gas-Phase Oxide Benchmark for Localization/Delocalization in Mixed-Valence Systems.

Ten simple gas-phase, main-group as well as transition-metal, mixed-valence (MV) oxo complexes are suggested for the screening of electronic-structure methods for the computational study of localization vs delocalization of charge and spin density in MV systems, without the usual added complication of environmental effects. Benchmark coupled-cluster energies up to CCSDT(Q)/CBS (for Al2O4-, Si2O4+, Si2O4-, ScO2, TiO2+) and CCSD(T)/CBS (for Ti2O4-, Ti2O4-, V2O4+, Cr2O6-) quality are provided as a basis for screening a variety of density-functional methods, ranging from a generalized gradient approximation via global and range-separated to local hybrid functionals. Additionally, experimental evidence for a delocalized D2d structure of the somewhat larger V4O10- is used. None of the functionals is fully satisfactory when tasked with describing simultaneously the most extreme cases, the localized Al2O4- and the delocalized V4O10-. While relatively large exact-exchange admixtures are required for the former, and for related localized cases, lower ones are preferable for the latter, as well for other delocalized d1d0 systems. The overall best combined performance is provided by a Lh-SVWN (g(r) = 0.670 τW/τ) local hybrid, the MN15 global hybrid, and the ωB97X-D range-separated hybrid. We also provide vibrational data for comparison with experiment.

Reactivity of the Sterically Demanding Siloxanediol Mes2 Si(OH)(µ-O)Si(OH)Mes2 Towards Water and Ether Molecules.

A series of isotopologues of the siloxanediol Mes2 Si(OH)(µ-O)Si(OH)Mes2 (3 a) (Mes=2,4,6-trimethylphenyl) were synthesized by reactions of the corresponding disiloxane precursors Mes2 Si(µ-O)2 SiMes2 (2 a), Mes2 Si(µ-17 O)2 SiMes2 (2 b) or Mes2 Si(µ-18 O)2 SiMes2 (2 c) with an excess of H2 O, H217 O or H218 O. NMR and IR signal assignments for the siloxanediols in benzene are supported by quantum-chemical calculations, which indicate small energy differences between trans and cis conformers, the latter of which exhibits an intramolecular hydrogen bond. 1 H NMR as well as IR data suggest the presence of a mixture of both conformers in C6 D6 . Hydrogen-bonded adducts of Mes2 Si(OH)(µ-O)Si(OH)Mes2 with ethers such as diethylether, dimethoxyethane or dioxane were observed in the solid state, where they form polymeric chain-like structures. The latter appear to be stable only in the crystal. 17 O{1 H} NMR and IR data in THF solution suggest an interaction of 3 a with at least one THF molecule, whereas diethylether appears not to interact. Water adducts form neither in solution nor in the solid state as indicated by NMR and ATR IR data. 17 O{1 H} NMR and ESI-MS experiments illustrate the remarkably high stability of the siloxanediols towards water and show no evidence for intra- or intermolecular oxygen-exchange reactions. In marked contrast, a stepwise exchange of all three oxygen atoms-including the one in the Si-O-Si bridge-occurred in the gas phase, when [Mes2 Si(18 OH)(µ-18 O)Si(18 O)Mes2 ]- was treated with H2 O in the hexapole of an ESI FT-ICR mass spectrometer. The scrambling between the bridging and the other oxygen atoms likely proceeds through cyclic Si2 O2 intermediates.

Metal-Dependent Strengthening and Weakening of M-H and M-C Bonds by an Oxo Ligand: Thermal Gas-Phase Activation of Methane by [OMH]+ and [MH]+ (M=Mo, Ti).

The thermal gas-phase reactions of methane with [OMoH]+ and [MoH]+ were investigated by using electrospray-ionization mass spectrometry (ESI-MS) complemented by quantum-chemical calculations. In contrast to the inertness of [MoH]+ towards methane, [OMoH]+ activates the C-H bond to form the ionic product [OMo(CH3 )]+ concomitantly with the liberation of H2 . The origin of the varying reactivities is traced back to a different influence of the oxo ligand on the Mo-C and Mo-H bonds. While the presence of this ligand weakens both the Ti-H and the Ti-CH3 bonds, both the Mo-H and Mo-CH3 bonds are strengthened. The more pronounced strengthening of the Mo-CH3 bond compared to the Mo-H bond favors the exothermicity of the reaction of [OMoH]+ with CH4 .

Internal Dynamics of the 3-Pyrroline-N-Oxide Ring in Spin-Labeled Proteins.

Site-directed spin labeling is a versatile tool to study structure as well as dynamics of proteins using EPR spectroscopy. Methanethiosulfonate (MTS) spin labels tethered through a disulfide linkage to an engineered cysteine residue were used in a large number of studies to extract structural as well as dynamic information on the protein from the rotational dynamics of the nitroxide moiety. The ring itself was always considered to be a rigid body. In this contribution, we present a combination of high-resolution X-ray crystallography and EPR spectroscopy of spin-labeled protein single crystals demonstrating that the nitroxide ring inverts fast at ambient temperature while exhibiting nonplanar conformations at low temperature. We have used quantum chemical calculations to explore the potential energy that determines the ring dynamics as well as the impact of the geometry on the magnetic parameters probed by EPR spectroscopy.

[Al2O4](-), a Benchmark Gas-Phase Class II Mixed-Valence Radical Anion for the Evaluation of Quantum-Chemical Methods.

The radical anion [Al2O4](-) has been identified as a rare example of a small gas-phase mixed-valence system with partially localized, weakly coupled class II character in the Robin/Day classification. It exhibits a low-lying C2v minimum with one terminal oxyl radical ligand and a high-lying D2h minimum at about 70 kJ/mol relative energy with predominantly bridge-localized-hole character. Two identical C2v minima and the D2h minimum are connected by two C2v-symmetrical transition states, which are only ca. 6-10 kJ/mol above the D2h local minimum. The small size of the system and the absence of environmental effects has for the first time enabled the computation of accurate ab initio benchmark energies, at the CCSDT(Q)/CBS level using W3-F12 theory, for a class-II mixed-valence system. These energies have been used to evaluate wave function-based methods [CCSD(T), CCSD, SCS-MP2, MP2, UHF] and density functionals ranging from semilocal (e.g., BLYP, PBE, M06L, M11L, N12) via global hybrids (B3LYP, PBE0, BLYP35, BMK, M06, M062X, M06HF, PW6B95) and range-separated hybrids (CAM-B3LYP, ωB97, ωB97X-D, LC-BLYP, LC-ωPBE, M11, N12SX), the B2PLYP double hybrid, and some local hybrid functionals. Global hybrids with about 35-43% exact-exchange (EXX) admixture (e.g., BLYP35, BMK), several range hybrids (CAM-B3LYP, ωB97X-D, ω-B97), and a local hybrid provide good to excellent agreement with benchmark energetics. In contrast, too low EXX admixture leads to an incorrect delocalized class III picture, while too large EXX overlocalizes and gives too large energy differences. These results provide support for previous method choices for mixed-valence systems in solution and for the treatment of oxyl defect sites in alumosilicates and SiO2. Vibrational gas-phase spectra at various computational levels have been compared directly to experiment and to CCSD(T)/aug-cc-pV(T+d)Z data.

On the Activation of Methane and Carbon Dioxide by [HTaO](+) and [TaOH](+) in the Gas Phase: A Mechanistic Study.

The thermal reactions of [Ta,O,H](+) with methane and carbon dioxide have been investigated experimentally and theoretically by using electrospray ionization mass spectrometry (ESI MS) and density functional theory calculations. Although the activation of methane proceeds by liberation of H2 , the activation of CO2 gives rise to the formation of [OTa(OH)](+) under the elimination of CO. Computational studies of the reactions of methane and carbon dioxide with the two isomers of [Ta,O,H](+) , namely, [HTaO](+) and [Ta(OH)](+) , have been performed to elucidate mechanistic aspects and to explain characteristic reaction patterns.

Completing the Heterocubane Family [Cp*AlE]4 (E = O, S, Se, and Te) by Selective Oxygenation and Sulfuration of [Cp*Al]4: Density Functional Theory Calculations of [Cp*AlE]4 and Reactivity of [Cp*AlO]4 toward Hydrolysis.

The subvalent aluminum compound [Cp*Al]4 (1) reacts with dioxygen, N2O, or sulfur to yield the heterocubane complexes [Cp*AlX]4 [X = O (2) and S (3)]. Treatment of [Cp*AlO]4 (2) with (tBuO)3SiOH gave [(tBuO)3SiOAlO]4 (6) and Cp*H. The structures and spectroscopic data of the Al clusters are supported by density functional theory (DFT) calculations, which also demonstrate the importance of noncovalent interactions (NCI) in oligomeric Al(I) complexes as well as in [Cp*AlS]4 and the heavier homologues of Se and Te. The computed (27)Al NMR shifts indicate a deshielding at the Al centers with increasing electronegativity of the chalcogen atom as well as significant spin-orbit shielding effects within the heavier heterocubane [Al4E4] cores. Further hydrolysis of 6 with an additional amount of silanol in the presence of water resulted in the formation of [Al4(OH)6(OH2)2(OSiOtBu3)6] (7), which shows a structural motif found in boehmite and diaspore.

Controlled ligand distortion and its consequences for structure, symmetry, conformation and spin-state preferences of iron(II) complexes.

The ligand-field strength in metal complexes of polydentate ligands depends critically on how the ligand backbone places the donor atoms in three-dimensional space. Distortions from regular coordination geometries are often observed. In this work, we study the isolated effect of ligand-sphere distortion by means of two structurally related pentadentate ligands of identical donor set, in the solid state (X-ray diffraction, (57)Fe-Mössbauer spectroscopy), in solution (NMR spectroscopy, UV/Vis spectroscopy, conductometry), and with quantum-chemical methods. Crystal structures of hexacoordinate iron(II) and nickel(II) complexes derived from the cyclic ligand L(1) (6-methyl-6-(pyridin-2-yl)-1,4-bis(pyridin-2-ylmethyl)-1,4-diazepane) and its open-chain congener L(2) (N(1),N(3),2-trimethyl-2-(pyridine-2-yl)-N(1),N(3)-bis(pyridine-2-ylmethyl) propane-1,3-diamine) reveal distinctly different donor set distortions reflecting the differences in ligand topology. Distortion from regular octahedral geometry is minor for complexes of ligand L(2), but becomes significant in the complexes of the cyclic ligand L(1), where trans elongation of Fe-N bonds cannot be compensated by the rigid ligand backbone. This provokes trigonal twisting of the ligand field. This distortion causes the metal ion in complexes of L(1) to experience a significantly weaker ligand field than in the complexes of L(2), which are more regular. The reduced ligand-field strength in complexes of L(1) translates into a marked preference for the electronic high-spin state, the emergence of conformational isomers, and massively enhanced lability with respect to ligand exchange and oxidation of the central ion. Accordingly, oxoiron(IV) species derived from L(1) and L(2) differ in their spectroscopic properties and their chemical reactivity.

Biomimetic [2Fe-2S] clusters with extensively delocalized mixed-valence iron centers.

A complete series of biomimetic [2Fe-2S] clusters, [(L(Dep) Fe)2 (µ-S)2 ] (3, L(Dep) =CH[CMeN(2,6-Et2 C6 H3 )]2 ), [(L(Dep) Fe)2 (µ-S)2 K] (4), [(L(Dep) Fe)2 (µ-S)2 ][Bu4 N] (5, Bu=n-butyl), and [(L(Dep) Fe)2 (µ-S)2 K2 ] (6), could be synthesized and characterized. The all-ferric [2Fe-2S] cluster 3 is readily accessible through the reaction of [(L(Dep) Fe)2 (µ-H)2 ] (2) with elemental sulfur. The chemical reduction of 3 with one molar equivalent of elemental potassium affords the contact ion pair K(+) [2Fe-2S](-) (4) as a one-dimensional coordination polymer, which in turn reacts with [Bu4 N]Cl to afford the separate ion pair [Bu4 N](+) [2Fe-2S](-) (5). Further reduction of 4 with potassium furnishes the super-reduced all-ferrous [2Fe-2S] cluster 6. Remarkably, complexes 4 and 5 are [2Fe-2S] clusters with extensively delocalized Fe(2+) Fe(3+) pairs as evidenced by (57) Fe Mössbauer, X-ray absorption and emission spectroscopy (XAS, XES) and in accordance with DFT calculations.

Synthesis and vibrational spectroscopy of (57)Fe-labeled models of [NiFe] hydrogenase: first direct observation of a nickel-iron interaction.

A new route to iron carbonyls has enabled synthesis of (57)Fe-labeled [NiFe] hydrogenase mimic (OC)3(57)Fe(pdt)Ni(dppe). Its study by nuclear resonance vibrational spectroscopy revealed Ni-(57)Fe vibrations, as confirmed by calculations. The modes are absent for [(OC)3(57)Fe(pdt)Ni(dppe)](+), which lacks Ni-(57)Fe bonding, underscoring the utility of the analyses in identifying metal-metal interactions.

Reversible [4Fe-3S] cluster morphing in an O(2)-tolerant [NiFe] hydrogenase.

Hydrogenases catalyze the reversible oxidation of H(2) into protons and electrons and are usually readily inactivated by O(2). However, a subgroup of the [NiFe] hydrogenases, including the membrane-bound [NiFe] hydrogenase from Ralstonia eutropha, has evolved remarkable tolerance toward O(2) that enables their host organisms to utilize H(2) as an energy source at high O(2). This feature is crucially based on a unique six cysteine-coordinated [4Fe-3S] cluster located close to the catalytic center, whose properties were investigated in this study using a multidisciplinary approach. The [4Fe-3S] cluster undergoes redox-dependent reversible transformations, namely iron swapping between a sulfide and a peptide amide N. Moreover, our investigations unraveled the redox-dependent and reversible occurence of an oxygen ligand located at a different iron. This ligand is hydrogen bonded to a conserved histidine that is essential for H(2) oxidation at high O(2). We propose that these transformations, reminiscent of those of the P-cluster of nitrogenase, enable the consecutive transfer of two electrons within a physiological potential range.

From bis(silylene) and bis(germylene) pincer-type nickel(II) complexes to isolable intermediates of the nickel-catalyzed Sonogashira cross-coupling reaction.

The first [ECE]Ni(II) pincer complexes with E = Si(II) and E = Ge(II) metallylene donor arms were synthesized via C-X (X = H, Br) oxidative addition, starting from the corresponding [EC(X)E] ligands. These novel complexes were fully characterized (NMR, MS, and XRD) and used as catalyst for Ni-catalyzed Sonogashira reactions. These catalysts allowed detailed information on the elementary steps of this catalytic reaction (transmetalation → oxidative addition → reductive elimination), resulting in the isolation and characterization of an unexpected intermediate in the transmetalation step. This complex, {[ECE]Ni acetylide → CuBr} contains both nickel and copper, with the copper bound to the alkyne π-system. Consistent with these unusual structural features, DFT calculations of the {[ECE]Ni acetylide → CuBr} intermediates revealed an unusual E-Cu-Ni three-center-two-electron bonding scheme. The results reveal a general reaction mechanism for the Ni-based Sonogashira coupling and broaden the application of metallylenes as strong σ-donor ligands for catalytic transformations.

Redox-dependent structural transformations of the [4Fe-3S] proximal cluster in O2-tolerant membrane-bound [NiFe]-hydrogenase: a DFT study.

Broken-symmetry density functional theory (BS-DFT) has been used to address the redox-dependent structural changes of the proximal [4Fe-3S] cluster, implicated in the O2-tolerance of membrane-bound [NiFe]-hydrogenase (MBH). The recently determined structures of the [4Fe-3S] cluster together with its protein ligands were studied at the reduced [4Fe-3S](3+), oxidized [4Fe-3S](4+), and superoxidized [4Fe-3S](5+) levels in context of their relative energies and protonation states. The observed proximal cluster conformational switch, concomitant with the proton transfer from the cysteine Cys20 backbone amide to the nearby glutamate Glu76 carboxylate, is found to be a single-step process requiring ~12-17 kcal/mol activation energy at the superoxidized [4Fe-3S](5+) level. At the more reduced [4Fe-3S](4+/3+) oxidation levels, this rearrangement has at least 5 kcal/mol higher activation barriers and prohibitively unfavorable product energies. The reverse transformation of the proximal cluster is a fast unidirectional process with ~8 kcal/mol activation energy, triggered by one-electron reduction of the superoxidized species. A previously discussed ambiguity of the Glu76 carboxylate and 'special' Fe4 iron positions in the superoxidized cluster is now rationalized as a superposition of two local minima, where Glu76-Fe4 coordination is either present or absent. The calculated 12.3-17.9 MHz (14)N hyperfine coupling (HFC) for the Fe4-bound Cys20 backbone nitrogen is in good agreement with the large 13.0/14.6 MHz (14)N couplings from the latest HYSCORE/ENDOR studies.

Synthesis, structure, and bonding of novel homodinuclear cobalt and nickel borylene complexes.

Herein we report for the first time full details on the synthesis and structural characterization of novel homodinuclear bridging cobalt and nickel borylene complexes containing bridging carbonyl ligands, an unusual coordination motif rarely before observed for homodinuclear borylene complexes. Furthermore, the homodinuclear nickel complex represents the first instance of a nickel borylene complex. Quantum chemical analyses of charge-density topology, electron localization function (ELF) and natural charges indicate the absence of direct metal-metal bonds in both the cobalt and nickel systems, in contradiction with electron counting. The topology of the Laplacian of the electron density and of the ELF around the bridging boron atom is consistent with a bis-metallo-substituted borane situation for the dicobalt system, but with a three-center-bonding borylene for the dinickel complex.

Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology.

C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila-SR11237) and 5 b, respectively. Chemistry and biology of the C/Si pairs are reported.SR11237 (BMS649, 4 a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4 b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5 a and 5 b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4 a/4 b and 5 a/5 b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5 a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5 b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5 a and 5 b, respectively, with the ligand-binding domain of hRXRalpha and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5 b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design.

Structure of the nucleotide radical formed during reaction of CDP/TTP with the E441Q-alpha2beta2 of E. coli ribonucleotide reductase.

The Escherichia coli ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates to deoxynucleotides and requires a diferric-tyrosyl radical cofactor for catalysis. RNR is composed of a 1:1 complex of two homodimeric subunits: alpha and beta. Incubation of the E441Q-alpha mutant RNR with substrate CDP and allosteric effector TTP results in loss of the tyrosyl radical and formation of two new radicals on the 200 ms to min time scale. The first radical was previously established by stopped flow UV/vis spectroscopy and pulsed high field EPR spectroscopy to be a disulfide radical anion. The second radical was proposed to be a 4'-radical of a 3'-keto-2'-deoxycytidine 5'-diphosphate. To identify the structure of the nucleotide radical [1'-(2)H], [2'-(2)H], [4'-(2)H], [5'-(2)H], [U-(13)C, (15)N], [U-(15)N], and [5,6 -(2)H] CDP and [beta-(2)H] cysteine-alpha were synthesized and incubated with E441Q-alpha2beta2 and TTP. The nucleotide radical was examined by 9 GHz and 140 GHz pulsed EPR spectroscopy and 35 GHz ENDOR spectroscopy. Substitution of (2)H at C4' and C1' altered the observed hyperfine interactions of the nucleotide radical and established that the observed structure was not that predicted. DFT calculations (B3LYP/IGLO-III/B3LYP/TZVP) were carried out in an effort to recapitulate the spectroscopic observations and lead to a new structure consistent with all of the experimental data. The results indicate, unexpectedly, that the radical is a semidione nucleotide radical of cytidine 5'-diphosphate. The relationship of this radical to the disulfide radical anion is discussed.

Density functional study of EPR parameters and spin-density distribution of azurin and other blue copper proteins.

Modern density functional methods have been used to study spin-density distribution, g tensors, as well as Cu and ligand hyperfine tensors for azurin models, for two more blue copper proteins plastocyanin and stellacyanin, and for small model complexes. The aim was to establish a consistent computational protocol that provides a realistic description of the EPR parameters as probes of the spin-density distribution between metal and coordinated ligands in copper proteins. In agreement with earlier conclusions for plastocyanin, hybrid functionals with appreciable exact-exchange admixtures, roughly around 50%, provide the best overall agreement with all parameters. Then the bulk of the spin density is almost equally shared by the copper atom and the sulfur atom of the equatorial cysteine ligand, and the best values are obtained for copper, histidine nitrogen, and cysteine beta-proton hyperfine couplings, as well as for g(parallel). Spin-orbit effects on the EPR parameters may be appreciable and have to be treated carefully to obtain agreement with experiment. Most notably, spin-orbit effects on the (65)Cu hyperfine coupling tensors in blue copper sites are unusually large compared to more regularly coordinated Cu(II) complexes with similar spin density on copper. In addition to the often emphasized high covalency of the Cu-S(Cys) bond, the characteristically small A(parallel) component of blue copper proteins is shown to derive to a large part from a near-cancellation between negative first-order (Fermi contact and dipolar) and unusually large positive second-order (spin-orbital) contributions. The large spin-orbit effects relate to the distorted tetrahedral structures. Square planar dithiolene complexes with similar spin density on copper exhibit much more negative A(parallel) values, as the cancellation between nonrelativistic and spin-orbit contributions is less complete. Calculations on a selenocysteine-substituted variant of azurin have provided further insight into the relations between bonding and EPR parameters.