Ligand field theory, Pauli shields and ultra-covalency in organometallic chemistry.

This paper explores the ligand field picture applied to organometallic compounds. Given the dearth of experimental data, the high-level ab initio ligand field theory (aiLFT) method is deployed as a surrogate for experiment and the necessary d orbital sequences and relative energies are obtained computationally. These are fitted to local cellular ligand field (CLF) σ, π and δ bonding parameters. Results are reported for planar [Cu(CR3)4]-, (R = F, H), octahedral M(CO)6n (M = Fe, Mn, Cr, V, Ti; n = +2, +1, 0, -1, -2), and the sandwich compounds M(Cp)2 (Cp = cyclopentadienyl, M = Fe, Ni, V), [Ni(Cp)2]2+ and Cr(C6H6)2. With respect to the aiLFT framework, these organometallic systems behave just like coordination complexes and most maintain the integrity of their formal dn configurations. Both [Cu(CR3)4]- compounds are formulated as low-spin d8 CuIII species and have normal ligand fields consistent with their planar geometries. The metal carbonyls reveal a new way of counting valence electrons which only requires the CLF d orbital energy level diagram to rationalise the 18-electron rule as well as its many exceptions. The bonding in sandwich compounds shows a remarkable variation. In ferrocene, Cp- behaves as a strong field ligand, comparable to [CN]- in [Fe(CN)6]4-. Fe(Cp)2 is low spin as is Cr(C6H6)2. Cp- in Fe(Cp)2 is a weak σ donor, strong π donor and weak δ acceptor while benzene in Cr(C6H6)2 is also a weak σ and strong π donor but is a much better δ acceptor. In contrast, Cp- is weak field in high spin, 20-electron Ni(Cp)2 but 'ultra-covalent' in [Ni(Cp)2]2+. The formal IV oxidation state is too high for the ligand set and the integrity of the d6 configuration is lost. Similarly, [V(CO)6]- and [Ti(CO)6]2- are ultra-covalent except now the formal metal oxidation states are too negative. Both mechanisms relate to the breaching of the metal's 3s23p6 'Pauli shield' and these ultra-covalent systems lie outside the ab initio ligand field regime. However, within the ligand field regime, the bonding in 'coordination complexes' and 'organometallic compounds' has the same conceptual footing and the nature of the local σ, π and δ interactions can be extracted from analysing the ligand field d orbitals.

Quantum Bio-Inorganic Chemistry (QBIC) Society Special Collection.

This Editorial by Guest Editors L. Rulísek, M. Gruden, M. Orio and QBIC Society President R. J. Deeth summarizes the Chemistry Europe Special Collection on quantum bioinorganic chemistry, published in collaboration with the Quantum Bioinorganic Chemistry (QBIC) Society. The Collection, which recognizes of the strides made in this area of research, spans several of our portfolio journals Chemistry-A European Journal, the European Journal of Inorganic Chemistry, ChemPlusChem, ChemBioChem, ChemPhysChem, and ChemistryOpen, includes outstanding work in the field by authors across the world and we hope you enjoy reading them!

Revisiting the Fundamental Nature of Metal-Ligand Bonding: An Impartial and Automated Fitting Procedure for Angular Overlap Model Parameters.

The properties and reactivities of transition metal complexes are often discussed in terms of Ligand Field Theory (LFT), and with ab initio LFT a direct connection to quantum chemical wavefunctions was recently established. The Angular Overlap Model (AOM) is a widely used, ligand-specific parameterization scheme of the ligand field splitting that has, however, been restricted by the availability and resolution of experimental data. Using ab initio LFT, we present here a generalised, symmetry-independent and automated fitting procedure for AOM parameters that is even applicable to formally underdetermined or experimentally inaccessible systems. This method allows quantitative evaluations of assumptions commonly made in AOM applications, for example, transferability or the relative magnitudes of AOM parameters, and the response of the ligand field to structural or electronic changes. A two-dimensional spectrochemical series of tetrahedral halido metalates ([MII X4 ]2- , M=Mn-Cu) served as a case study. A previously unknown linear relationship between the halide ligands' chemical hardness and their AOM parameters was found. The impartial and automated procedure for identifying AOM parameters introduced here can be used to systematically improve our understanding of ligand-metal interactions in coordination complexes.

d-orbital energy levels in planar [MIIF4]2-, [MII(NH3)4]2+ and [MII(CN)4]2- complexes: the nature of M-L π bonding and the implications for ligand field theory.

Qualitative MO theory predicts degenerate dπ orbitals for planar coordination complexes with formally σ-only ligands and the splitting energy, ΔEπ = E(dxy) - E(dxz,dyz), should be zero. For π-donor ligands, ΔEπ should be positive (dxy > dxz,yz) while for π-acceptors, ΔEπ should be negative (dxy < dxz,yz). However, experimental d-d spectra, ab initio ligand field theory (AI LFT) and crystal field theory for σ-only [M(NH3)4]2+ complexes give pronounced dπ splittings with ΔEπ around +2500 cm-1 for first-row, divalent metal ions. AI LFT further suggests ΔEπ values around +4500 cm-1 for [MF4]2- and +1000 cm-1 for [M(CN)4]2- species. The origins of these dπ orbital splittings can be traced to the effects of the ligand field potential surrounding the metal centre which includes not only the intrinsic metal-ligand π bonding but also substantial contributions from the 'void' regions above and below the molecular plane. The π component of the 'void cell' potentials increases ΔEπ which, if not explicitly taken into account, artificially enhances the apparent π-donor strength of the ligands. With the inclusion of void cell π interactions, even though the AI LFT d orbital sequence always places dxz,yz below dxy, the ligand field analysis provides a chemically-reasonable description of the M-L π interactions with cyanide being a weak π acceptor, ammonia being π-neutral and fluoride being a strong π donor. In the case of [Ni(CN)4]2-, ligand field calculations further show that, contrary to the recent claims of Oppenheim et al. (Inorg. Chem., 2019, 58, 15202) the sequence of the many-electron excited states is not a definitive guide to the underlying order of one-electron d orbital energies and that the observed sequence of nA2g > nEg > nB1g, n = 1 or 3, does not guarantee a d-orbital sequence of dxy < dxz,yz < dz2.

Molecular dynamics simulations of copper binding to amyloid-ß Glu22 mutants.

We report microsecond timescale ligand field molecular dynamics simulations of the copper complexes of three known mutants of the amyloid-ß peptide, E22G, E22Q and E22K, alongside the naturally occurring sequence. We find that all three mutants lead to formation of less compact structures than the wild-type: E22Q is the most similar to the native peptide, while E22G and especially E22K are markedly different in size, shape and stability. Turn and coil structures dominate all structures studied but subtle differences in helical and ß-sheet distribution are noted, especially in the C-terminal region. The origin of these changes is traced to disruption of key salt bridges: in particular, the Asp23-Lys28 bridge that is prevalent in the wild-type is absent in E22G and E22K, while Lys22 in the latter mutant forms a strong association with Asp23. We surmise that the drastically different pattern of salt bridges in the mutants lead to adoption of a different structural ensemble of the peptide backbone, and speculate that this might affect the ability of the mutant peptides to aggregate in the same manner as known for the wild-type.

A Computational Analysis of the Intrinsic Plasticity of Five-Coordinate Cu(II) Complexes and the Factors Leading to the Breakdown of the Orbital Directing Effect in Paddlewheel Secondary Building Units.

Quantum chemical calculations on model copper paddlewheel (CPW) complexes of general formula [Cu2 (µ2 -O2 CR)4 L2 ] establish two local coordination geometries at the metal centers depending on the balance between equatorial and axial ligand fields. When the equatorial field is stronger than the axial field (large ligand field asymmetry), d x 2 - y 2 dominates the stereochemical activity of the d9 shell resulting in a relatively rigid, "orbitally directed" planar or square pyramidal structure. However, if the axial field is significantly increased, or the equatorial field moderately weakened, a small ligand field asymmetry results and both d x 2 - y 2 and d z 2 are involved in the stereochemical activity. This results in a "plastic," distorted trigonal bipyramidal geometry where the former axial ligand moves into one of the original four equatorial positions. Linkers already used to synthesize zinc-dabco MOFs (dabco = 1,4-diazabicyclo[2.2.2]octane) are shown to generate plastic CPW secondary building unit analogs with potential implications for conferring breathing behavior for MOFs which would currently be assumed to be rigid. © 2019 Wiley Periodicals, Inc.

Metal Binding to Amyloid-ß1-42: A Ligand Field Molecular Dynamics Study.

Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-ß1-42 peptide monomer. Molecular dynamics over several microseconds for both metalated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems as well as between free and metal-bound peptide. Both metals stabilize the formation of helices in the peptide as well as reducing the content of ß secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing ß-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergo noteworthy change, with the free peptide exhibiting globular-like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered; in particular, the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals.

Ligand field molecular dynamics simulation of Pt(II)-phenanthroline binding to N-terminal fragment of amyloid-ß peptide.

We report microsecond timescale molecular dynamics simulation of the complex formed between Pt(II)-phenanthroline and the 16 N-terminal residues of the Aß peptide that is implicated in the onset of Alzheimer's disease, along with equivalent simulations of the metal-free peptide. Simulations from a variety of starting points reach equilibrium within 100 ns, as judged by root mean square deviation and radius of gyration. Platinum-bound peptides deviate rather more from starting points, and adopt structures with larger radius of gyration, than their metal-free counterparts. Residues bound directly to Pt show smaller fluctuation, but others actually move more in the Pt-bound peptide. Hydrogen bonding within the peptide is disrupted by binding of Pt, whereas the presence of salt-bridges are enhanced.

Spin Crossover in a Hexaamineiron(II) Complex: Experimental Confirmation of a Computational Prediction.

Single crystal structural analysis of [FeII (tame)2 ]Cl2 ⋅MeOH (tame=1,1,1-tris(aminomethyl)ethane) as a function of temperature reveals a smooth crossover between a high temperature high-spin octahedral d6 state and a low temperature low-spin ground state without change of the symmetry of the crystal structure. The temperature at which the high and low spin states are present in equal proportions is T1/2 =140 K. Single crystal, variable-temperature optical spectroscopy of [FeII (tame)2 ]Cl2 ⋅MeOH is consistent with this change in electronic ground state. These experimental results confirm the spin activity predicted for [FeII (tame)2 ]2+ during its de novo artificial evolution design as a spin-crossover complex [Chem. Inf. MODEL: 2015, 55, 1844], offering the first experimental validation of a functional transition-metal complex predicted by such in silico molecular design methods. Additional quantum chemical calculations offer, together with the crystal structure analysis, insight into the role of spin-passive structural components. A thermodynamic analysis based on an Ising-like mean field model (Slichter-Drickammer approximation) provides estimates of the enthalpy, entropy and cooperativity of the crossover between the high and low spin states.

Benchmarking of copper(II) LFMM parameters for studying amyloid-ß peptides.

Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-ß1-16 peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 Å and 5°. Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-ß1-16 peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 Å over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand.

Ab Initio Ligand Field Molecular Mechanics and the Nature of Metal-Ligand π-Bonding in Fe(II) 2,6-di(pyrazol-1-yl)pyridine Spin Crossover Complexes.

A ligand field molecular mechanics (LFMM) force field has been constructed for the spin states of [Fe(bpp)2 ]2+ (bpp=2,6-di(pyrazol-1-yl)pyridine) and related complexes. A new charge scheme is employed which interpolates between partial charges for neutral bpp and protonated [H3 bpp]3+ to achieve a target metal charge. The LFMM angular overlap model (AOM) parameters are fitted to fully ab initio d orbital energies. However, several AOM parameter sets are possible. The ambiguity is resolved by calculating the Jahn-Teller distortion mode for high spin, which indicates that in [Fe(bpp)2 ]2+ pyridine is a π-acceptor and pyrazole a weak π-donor. The alternative fit, assumed previously, where both ligands act as π-donors leads to an inconsistent distortion. LFMM optimisations in the presence of [BF4 ]- or [PF6 ]- anions are in good agreement with experiment and the model also correctly predicts the spin state energetics for 3-pyrazolyl substituents where the interactions are mainly steric. However, for 4-pyridyl or 4-pyrazolyl substituents, LFMM only treats the electrostatic contribution which, for the pyridyl substituents, generates a fair correlation with the spin crossover transition temperatures, T1/2 , but in the reverse sense to the dominant electronic effect. Thus, LFMM generates its smallest spin state energy difference for the substituent with the highest T1/2 . One parameter set for all substituted bpp ligands is insufficient and further LFMM development will be required.

Prediction of ligand effects in platinum-amyloid-ß coordination.

Ligand field molecular mechanics (LFMM) and semi-empirical Parametric Model 7 (PM7) methods are applied to a series of six PtII-Ligand systems binding to the N-terminal domain of the amyloid-ß (Aß) peptide. Molecular dynamics using a combined LFMM/Assisted Model Building with Energy Refinement (AMBER) approach is used to explore the conformational freedom of the peptide fragment, and identifies favourable platinum binding modes and peptide conformations for each ligand investigated. Platinum coordination is found to depend on the nature of the ligand, providing evidence that binding mode may be controlled by suitable ligand design. Boltzmann populations at 310K indicate that each Pt-Aß complex has a small number of thermodynamically accessible states. Ramachandran maps are constructed for the sampled Pt-Aß conformations and secondary structural analysis of the obtained complex structures is performed and contrasted with the free peptide; coordination of these platinum complexes disrupts existing secondary structure in the Aß peptide and promotes formation of ligand-specific turn-type secondary structure.

DFT Analysis of Spin Crossover in Mn(III) Complexes: Is a Two-Electron S = 2 to S = 0 Spin Transition Feasible?

Six-coordinate, rigorously octahedral d4 Mn(III) spin crossover (SCO) complexes are limited by symmetry to an S = 1 (intermediate spin, IS) to S = 2 (high spin, HS) transition. In order to realize the potential S = 0 to S = 2 transition, a lower symmetry and/or change in coordination number is needed, which we explore here computationally. First, a number of complexes are analyzed to develop a reliable and relatively fast DFT protocol for reproducing known Mn(III) spin state energetics. The hybrid meta-GGA functional TPSSh with a modest split valence plus polarization basis set and an empirical dispersion correction is found to predict correctly the ground spin state of Mn(III) complexes, including true low-spin (LS) S = 0 systems, with a range of donor sets including the hexadentate [N4O2] Schiff base ligands. The electronic structure design criteria necessary for realizing a ΔS = 2 SCO transition are described, and a number of model complexes are screened for potential SCO behavior. Five-coordinate trigonal-bipyramidal symmetry fails to yield any suitable systems. Seven-coordinate, approximately pentagonal bipyramidal symmetry is more favorable, and when a known pentadentate macrocyclic donor is combined with π-acceptor axial ligands, a novel Mn(III) complex, [Mn(PABODP)(PF3)2]3+ (PABODP = 2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),2,12,14,16-pentaene), is predicted to have the right spin state energetics for an S = 0 to S = 2 transition. Successful synthesis of such a complex could provide the first example of a ΔS = 2 SCO transition for d4 Mn(III). However, the combination of a rigid macrocycle and a high coordination number dilutes the stereochemical activity of the d electrons, leading to relatively small structural changes between HS and LS systems. It may therefore remain a challenge to realize strong cooperative effects in Mn(III) systems.

Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes.

Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(iii) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [C43H43N6O2Ir1·PF6]˙ (Ir-TEMPO1) and two TEMPO spin labels [C52H58N8O4Ir1·PF6]˙ (Ir-TEMPO2). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in Ir-TEMPO2. Both Ir-TEMPO1 and Ir-TEMPO2 showed bright luminescence with long lifetimes (ca. 35-160 ns); while Ir-TEMPO1 displayed monoexponential decay kinetics, the biexponential decays measured for Ir-TEMPO2 indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of Ir-TEMPO2 towards a range of cancer cells was much greater than that of Ir-TEMPO1, and also the antioxidant activity of Ir-TEMPO2 is much higher against A2780 ovarian cancer cells when compared with Ir-TEMPO1. Most notably Ir-TEMPO2 was particularly potent towards PC3 human prostate cancer cells (IC50 = 0.53 µM), being ca. 8× more active than the clinical drug cisplatin, and ca. 15× more selective towards cancer cells versus normal cells. Confocal microscopy showed that both Ir-TEMPO1 and Ir-TEMPO2 localise in the mitochondria of cancer cells.

"Head-to-head" double-hamburger-like structure of di-ruthenated d(GpG) adducts of mono-functional Ru-arene anticancer complexes.

Guanine bases in DNA are targets for some Ru-arene anticancer complexes. We have investigated the structure of the novel di-ruthenated d(GpG) adduct Ru2-GpG (where Ru = {(η6-biphenyl)-Ru(en)}2+ (1')) in aqueous solution. 2D NMR results indicate that there are two conformers, supported by modeling studies. The major conformer I is a novel double-hamburger-like structure with a "head-to-head" (HH) base arrangement involving hydrophobic interactions between neighboring arene rings, the first example of a HH d(GpG) adduct constructed by weak interactions. Hence there are significant differences compared to Pt-d(GpG) adducts formed by cisplatin. There is no obviously rigid bending for the major conformer I. The minor conformer II of Ru2-GpG has a back-to-back structure, with two ruthenated guanine bases flipped away from each other. 19-23 base-pair oligodeoxyribonucleotides containing central TGGT sequences di-ruthenated by 1 show no directional bending, only slightly distorted di-ruthenated duplexes, consistent with the NMR data for conformer I. The structural differences and similarities of d(GpG) residues which are di-ruthenated or cross-linked by platination are discussed in the context of the biological activity of these metal complexes.

Molecular modeling of zinc paddlewheel molecular complexes and the pores of a flexible metal organic framework.

A new all-atom first-principles force field (FF) is constructed for the bimetallic, four-bladed zinc paddlewheel (ZPW) motif. Zinc-ligand interactions are described via Morse functions and the angular geometry at the metal centers is modeled with a pure ligand-ligand repulsion term. The ZPW-FF is principally based on 15 DFT-optimized model systems of general formula ZnPR.nL, where ZnP is the base Zn2(O2CR)4 unit, R = H, CH3 or CF3, L = NH3 or pyridine, and n = 0, 1 or 2. It correctly generates the distorted tetrahedral coordination of the uncapped [Zn2(O2CR)4] species in their ground states as well as giving reasonable structures and energies for the higher symmetry D4h transition state conformations. The zinc-ligand Morse function reference distance, r 0 , is further refined against 30 complexes located in the Cambridge Structural Database and this FF is applied to pore models of the flexible metal-organic framework (MOF) [Zn(bdc)2(dabco)]n (bdc = 1,4-benzendicarboxylate; dabco = 1,4-diazabicyclo(2.2.2)octane). A single pore model reproduces the unit cell of the evacuated MOF system while a 3×3 grid model is necessary to provide good agreement with the observed pronounced structural changes upon adsorption of either dimethylformamide or benzene.

A Unified Treatment of the Relationship Between Ligand Substituents and Spin State in a Family of Iron(II) Complexes.

The influence of ligands on the spin state of a metal ion is of central importance for bioinorganic chemistry, and the production of base-metal catalysts for synthesis applications. Complexes derived from [Fe(bpp)2 ](2+) (bpp=2,6-di{pyrazol-1-yl}pyridine) can be high-spin, low-spin, or spin-crossover (SCO) active depending on the ligand substituents. Plots of the SCO midpoint temperature (T1/2 ) in solution vs. the relevant Hammett parameter show that the low-spin state of the complex is stabilized by electron-withdrawing pyridyl ("X") substituents, but also by electron-donating pyrazolyl ("Y") substituents. Moreover, when a subset of complexes with halogeno X or Y substituents is considered, the two sets of compounds instead show identical trends of a small reduction in T1/2 for increasing substituent electronegativity. DFT calculations reproduce these disparate trends, which arise from competing influences of pyridyl and pyrazolyl ligand substituents on Fe-L σ and π bonding.

Modeling of Platinum-Aryl Interaction with Amyloid-ß Peptide.

Ligand field molecular mechanics (LFMM), density functional theory (DFT), and semiempirical PM7 methods are used to study the binding of two Pt(II)-L systems to an N-terminal fragment of the amyloid-ß peptide, where L = 2,2-bipyridyl or 1,10-phenanthroline. Molecular dynamics simulations are used to explore the conformational freedom of the peptide using LFMM combined with AMBER molecular mechanics parameters. We establish a modeling protocol, allowing for identification and analysis of favorable platinum-binding modes and peptide conformations. Preferred binding modes are identified for each ligand investigated; metal coordination occurs via Nε in His residues for both ligands--His6ε-His13ε and His6ε-His14ε for the bipyridyl and phenanthroline ligands, respectively. The observed change in binding mode for the different ligands suggests that the binding mode of these platinum-based structures can be controlled by the choice of ligand. In the bipy systems, Boltzmann population at 310 K is dominated by a single conformer, while in the phenanthroline case, three conformations make significant contributions to the ensemble. The relative stability of these conformations is due to the inherent stability of binding platinum via Nε in addition to subtle H-bonding effects.

Osmium Atoms and Os2 Molecules Move Faster on Selenium-Doped Compared to Sulfur-Doped Boronic Graphenic Surfaces.

We deposited Os atoms on S- and Se-doped boronic graphenic surfaces by electron bombardment of micelles containing 16e complexes [Os(p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-diselenate/dithiolate)] encapsulated in a triblock copolymer. The surfaces were characterized by energy-dispersive X-ray (EDX) analysis and electron energy loss spectroscopy of energy filtered TEM (EFTEM). Os atoms moved ca. 26× faster on the B/Se surface compared to the B/S surface (233 ± 34 pm·s(-1) versus 8.9 ± 1.9 pm·s(-1)). Os atoms formed dimers with an average Os-Os distance of 0.284 ± 0.077 nm on the B/Se surface and 0.243 ± 0.059 nm on B/S, close to that in metallic Os. The Os2 molecules moved 0.83× and 0.65× more slowly than single Os atoms on B/S and B/Se surfaces, respectively, and again markedly faster (ca. 20×) on the B/Se surface (151 ± 45 pm·s(-1) versus 7.4 ± 2.8 pm·s(-1)). Os atom motion did not follow Brownian motion and appears to involve anchoring sites, probably S and Se atoms. The ability to control the atomic motion of metal atoms and molecules on surfaces has potential for exploitation in nanodevices of the future.

Ring Closure To Form Metal Chelates in 3D Fragment-Based de Novo Design.

We describe a method for the design of multicyclic compounds from three-dimensional (3D) molecular fragments. The 3D building blocks are assembled in a controlled fashion, and closable chains of such fragments are identified. Next, the ring-closing conformations of such formally closable chains are identified, and the 3D model of a cyclic or multicyclic molecule is built. Embedding this method in an evolutionary algorithm results in a de novo design tool capable of altering the number and nature of cycles in species such as transition metal compounds with multidentate ligands in terms of, for example, ligand denticity, type and length of bridges, identity of bridgehead terms, and substitution pattern. An application of the method to the design of multidentate nitrogen-based ligands for Fe(II) spin-crossover (SCO) compounds is presented. The best candidates display multidentate skeletons new to the field of Fe(II) SCO yet resembling ligands deployed in other fields of chemistry, demonstrating the capability of the approach to explore structural variation and to suggest unexpected and realistic molecules, including structures with cycles not found in the building blocks.