Synthesis and stability of the [45Ti]Ti-DOTA complex: en route towards aza-macrocyclic 45Ti-based radiopharmaceuticals.

We report the use of DOTA as a chelator for titanium. The resulting complex is fully characterised and in vitro stability studies reveal its high kinetic inertness against transmetallation and transchelation. The radiolabeling of DOTA with 45Ti, via a guaiacol-based liquid-liquid extraction method, leads to a high radiochemical conversion up to 98%.

Automated de Novo Design of Olefin Metathesis Catalysts: Computational and Experimental Analysis of a Simple Thermodynamic Design Criterion.

Methods for computational de novo design of inorganic molecules have paved the way for automated design of homogeneous catalysts. Such studies have so far relied on correlation-based prediction models as fitness functions (figures of merit), but the soundness of these approaches has yet to be tested by experimental verification of de novo-designed catalysts. Here, a previously developed criterion for the optimization of dative ligands L in ruthenium-based olefin metathesis catalysts RuCl2(L)(L')(═CHAr), where Ar is an aryl group and L' is a phosphine ligand dissociating to activate the catalyst, was used in de novo design experiments. These experiments predicted catalysts bearing an N-heterocyclic carbene (L = 9) substituted by two N-bound mesityls and two tert-butyl groups at the imidazolidin-2-ylidene backbone to be promising. Whereas the phosphine-stabilized precursor assumed by the prediction model could not be made, a pyridine-stabilized ruthenium alkylidene complex (17) bearing carbene 9 was less active than a known leading pyridine-stabilized Grubbs-type catalyst (18, L = H2IMes). A density functional theory-based analysis showed that the unsubstituted metallacyclobutane (MCB) intermediate generated in the presence of ethylene is the likely resting state of both 17 and 18. Whereas the design criterion via its correlation between the stability of the MCB and the rate-determining barrier indeed seeks to stabilize the MCB, it relies on RuCl2(L)(L')(═CH2) adducts as resting states. The change in resting state explains the discrepancy between the prediction and the actual performance of catalyst 17. To avoid such discrepancies and better address the multifaceted challenges of predicting catalytic performance, future de novo catalyst design studies should explore and test design criteria incorporating information from more than a single relative energy or intermediate.

The Janus face of high trans-effect carbenes in olefin metathesis: gateway to both productivity and decomposition.

Ruthenium-cyclic(alkyl)(amino)carbene (CAAC) catalysts, used at ppm levels, can enable dramatically higher productivities in olefin metathesis than their N-heterocyclic carbene (NHC) predecessors. A key reason is the reduced susceptibility of the metallacyclobutane (MCB) intermediate to decomposition via ß-H elimination. The factors responsible for promoting or inhibiting ß-H elimination are explored via density functional theory (DFT) calculations, in metathesis of ethylene or styrene (a representative 1-olefin) by Ru-CAAC and Ru-NHC catalysts. Natural bond orbital analysis of the frontier orbitals confirms the greater strength of the orbital interactions for the CAAC species, and the consequent increase in the carbene trans influence and trans effect. The higher trans effect of the CAAC ligands inhibits ß-H elimination by destabilizing the transition state (TS) for decomposition, in which an agostic MCB Cß-H bond is positioned trans to the carbene. Unproductive cycling with ethylene is also curbed, because ethylene is trans to the carbene ligand in the square pyramidal TS for ethylene metathesis. In contrast, metathesis of styrene proceeds via a 'late' TS with approximately trigonal bipyramidal geometry, in which carbene trans effects are reduced. Importantly, however, the positive impact of a strong trans-effect ligand in limiting ß-H elimination is offset by its potent accelerating effect on bimolecular coupling, a major competing means of catalyst decomposition. These two decomposition pathways, known for decades to limit productivity in olefin metathesis, are revealed as distinct, antinomic, responses to a single underlying phenomenon. Reconciling these opposing effects emerges as a clear priority for design of robust, high-performing catalysts.

Bimolecular Coupling in Olefin Metathesis: Correlating Structure and Decomposition for Leading and Emerging Ruthenium-Carbene Catalysts.

Bimolecular catalyst decomposition is a fundamental, long-standing challenge in olefin metathesis. Emerging ruthenium-cyclic(alkyl)(amino)carbene (CAAC) catalysts, which enable breakthrough advances in productivity and general robustness, are now known to be extraordinarily susceptible to this pathway. The details of the process, however, have hitherto been obscure. The present study provides the first detailed mechanistic insights into the steric and electronic factors that govern bimolecular decomposition. Described is a combined experimental and theoretical study that probes decomposition of the key active species, RuCl2(L)(py)(═CH2) 1 (in which L is the N-heterocyclic carbene (NHC) H2IMes, or a CAAC ligand: the latter vary in the NAr group (NMes, N-2,6-Et2C6H3, or N-2-Me,6-iPrC6H3) and the substituents on the quaternary site flanking the carbene carbon (i.e., CMe2 or CMePh)). The transiently stabilized pyridine adducts 1 were isolated by cryogenic synthesis of the metallacyclobutanes, addition of pyridine, and precipitation. All are shown to decompose via second-order kinetics at -10 °C. The most vulnerable CAAC species, however, decompose more than 1000-fold faster than the H2IMes analogue. Computational studies reveal that the key factor underlying accelerated decomposition of the CAAC derivatives is their stronger trans influence, which weakens the Ru-py bond and increases the transient concentration of the 14-electron methylidene species, RuCl2(L)(═CH2) 2. Fast catalyst initiation, a major design goal in olefin metathesis, thus has the negative consequence of accelerating decomposition. Inhibiting bimolecular decomposition offers major opportunities to transform catalyst productivity and utility, and to realize the outstanding promise of olefin metathesis.

Challenging Metathesis Catalysts with Nucleophiles and Brønsted Base: Examining the Stability of State-of-the-Art Ruthenium Carbene Catalysts to Attack by Amines.

Critical to advancing the uptake of olefin metathesis in leading contexts, including pharmaceutical manufacturing, is identification of highly active catalysts that resist decomposition. Amines constitute an aggressive challenge to ruthenium metathesis catalysts. Examined here is the impact of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), morpholine, n-butylamine, and triethylamine on Ru metathesis catalysts that represent the current state of the art, including cyclic alkyl amino carbene (CAAC) and N-heterocyclic carbene (NHC) complexes. Accordingly, the amine-tolerance of the nitro-Grela catalyst RuCl2(H2IMes)(=CHAr) (nG; Ar = C6H4-2-O i Pr-5-NO2) is compared with that of its CAAC analogues nGC1 and nGC2, and the Hoveyda-class catalyst RuCl2(C2)(=CHAr') HC2 (Ar' = C6H4-2-O i Pr). In C1, the carbene carbon is flanked by an N-2,6-Et2C6H3 group and a CMePh quaternary carbon; in C2, by an N-2- i Pr-6-MeC6H3 group and a CMe2 quaternary carbon. The impact of 1 equiv amine per Ru on turnover numbers (TONs) in ring-closing metathesis of diethyl diallylmalonate was assessed at 9 ppm Ru, at RT and 70 °C. The deleterious impact of amines followed the trend NEt3 ∼ NH2 n Bu ≪ DBU ∼ morpholine. Morpholine is shown to decompose nGC1 by nucleophilic abstraction of the methylidene ligand; DBU, by proton abstraction from the metallacyclobutane. Decomposition was minimized at 70 °C, at which nGC1 enabled TONs of ca. 60 000 even in the presence of morpholine or DBU, vs ca. 80 000 in the absence of base. Unexpectedly, H2IMes catalyst nG delivered 70-90% of the performance of nGC1 at high temperatures, and underwent decomposition by Brønsted base at a similar rate. Density functional theory (DFT) analysis shows that this similarity is due to comparable net electron donation by the H2IMes and C1 ligands. Catalysts bearing the smaller C2 ligand were comparatively insensitive to amines, owing to rapid, preferential bimolecular decomposition.

DENOPTIM: Software for Computational de Novo Design of Organic and Inorganic Molecules.

A general-purpose software package, termed DE Novo OPTimization of In/organic Molecules (DENOPTIM), for de novo design and virtual screening of functional molecules is described. Molecules of any element and kind, including metastable species and transition states, are handled as chemical objects that go beyond valence-rules representations. Synthetic accessibility of the generated molecules is ensured via detailed control of the kinds of bonds that are allowed to form in the automated molecular building process. DENOPTIM contains a combinatorial explorer for screening and a genetic algorithm for global optimization of user-defined properties. Estimates of these properties may be obtained to form the fitness function (figure of merit or scoring function) from external molecular modeling programs via shell scripts. Examples of a range of different fitness functions and DENOPTIM applications, including an easy-to-do test case, are described. DENOPTIM is available as Open Source from https://github.com/denoptim-project/DENOPTIM .

Bimolecular Coupling as a Vector for Decomposition of Fast-Initiating Olefin Metathesis Catalysts.

The correlation between rapid initiation and rapid decomposition in olefin metathesis is probed for a series of fast-initiating, phosphine-free Ru catalysts: the Hoveyda catalyst HII, RuCl2(L)(═CHC6H4- o-O iPr); the Grela catalyst nG (a derivative of HII with a nitro group para to O iPr); the Piers catalyst PII, [RuCl2(L)(═CHPCy3)]OTf; the third-generation Grubbs catalyst GIII, RuCl2(L)(py)2(═CHPh); and dianiline catalyst DA, RuCl2(L)( o-dianiline)(═CHPh), in all of which L = H2IMes = N,N'-bis(mesityl)imidazolin-2-ylidene. Prior studies of ethylene metathesis have established that various Ru metathesis catalysts can decompose by ß-elimination of propene from the metallacyclobutane intermediate RuCl2(H2IMes)(κ2-C3H6), Ru-2. The present work demonstrates that in metathesis of terminal olefins, ß-elimination yields only ca. 25-40% propenes for HII, nG, PII, or DA, and none for GIII. The discrepancy is attributed to competing decomposition via bimolecular coupling of methylidene intermediate RuCl2(H2IMes)(═CH2), Ru-1. Direct evidence for methylidene coupling is presented, via the controlled decomposition of transiently stabilized adducts of Ru-1, RuCl2(H2IMes)Ln(═CH2) (Ln = py n'; n' = 1, 2, or o-dianiline). These adducts were synthesized by treating in situ-generated metallacyclobutane Ru-2 with pyridine or o-dianiline, and were isolated by precipitating at low temperature (-116 or -78 °C, respectively). On warming, both undergo methylidene coupling, liberating ethylene and forming RuCl2(H2IMes)Ln. A mechanism is proposed based on kinetic studies and molecular-level computational analysis. Bimolecular coupling emerges as an important contributor to the instability of Ru-1, and a potentially major pathway for decomposition of fast-initiating, phosphine-free metathesis catalysts.

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.

Decomposition of Olefin Metathesis Catalysts by Brønsted Base: Metallacyclobutane Deprotonation as a Primary Deactivating Event.

Brønsted bases of widely varying strength are shown to decompose the metathesis-active Ru intermediates formed by the second-generation Hoveyda and Grubbs catalysts. Major products, in addition to propenes, are base·HCl and olefin-bound, cyclometalated dimers [RuCl(κ2-H2IMes-H)(H2C═CHR)]2 Ru-3. These are generated in ca. 90% yield on metathesis of methyl acrylate, styrene, or ethylene in the presence of either DBU, or enolates formed by nucleophilic attack of PCy3 on methyl acrylate. They also form, in lower proportions, on metathesis in the presence of the weaker base NEt3. Labeling studies reveal that the initial site of catalyst deprotonation is not the H2IMes ligand, as the cyclometalated structure of Ru-3 might suggest, but the metallacyclobutane (MCB) ring. Computational analysis supports the unexpected acidity of the MCB protons, even for the unsubstituted ring, and by implication, its overlooked role in decomposition of Ru metathesis catalysts.

Loss and Reformation of Ruthenium Alkylidene: Connecting Olefin Metathesis, Catalyst Deactivation, Regeneration, and Isomerization.

Ruthenium-based olefin metathesis catalysts are used in laboratory-scale organic synthesis across chemistry, largely thanks to their ease of handling and functional group tolerance. In spite of this robustness, these catalysts readily decompose, via little-understood pathways, to species that promote double-bond migration (isomerization) in both the 1-alkene reagents and the internal-alkene products. We have studied, using density functional theory (DFT), the reactivity of the Hoveyda-Grubbs second-generation catalyst 2 with allylbenzene, and discovered a facile new decomposition pathway. In this pathway, the alkylidene ligand is lost, via ring expansion of the metallacyclobutane intermediate, leading to the spin-triplet 12-electron complex (SIMes)RuCl2 (3R21, SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene). DFT calculations predict 3R21 to be a very active alkene isomerization initiator, either operating as a catalyst itself, via a η3-allyl mechanism, or, after spin inversion to give R21 and formation of a cyclometalated Ru-hydride complex, via a hydride mechanism. The calculations also suggest that the alkylidene-free ruthenium complexes may regenerate alkylidene via dinuclear ruthenium activation of alkene. The predicted capacity to initiate isomerization is confirmed in catalytic tests using p-cymene-stabilized R21 (5), which promotes isomerization in particular under conditions favoring dissociation of p-cymene and disfavoring formation of aggregates of 5. The same qualitative trends in the relative metathesis and isomerization selectivities are observed in identical tests of 2, indicating that 5 and 2 share the same catalytic cycles for both metathesis and isomerization, consistent with the calculated reaction network covering metathesis, alkylidene loss, isomerization, and alkylidene regeneration.

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.

Integration of Ligand Field Molecular Mechanics in Tinker.

The ligand field molecular mechanics (LFMM) method for transition-metal complexes has been integrated in Tinker, an easily available and popular molecular modeling software package. The capability to calculate LFMM potentials has been provided by extending the functional forms of the Tinker package as well as by integrating routines for calculating the ligand field stabilization energy (LFSE), which is central to LFMM. The capabilities of the implementation are illustrated by both static calculations on the two spin states of [Fe(NH3)6](2+) and on [Cu(NH3)m](2+) (m = 4, 5, 6) and dynamic (LFMD) simulations of an FeN6-type spin-crossover compound. In addition to showing that results obtained with the Tinker-LFMM implementation are consistent with those of experiment and other computational methods and programs, we note that whereas LFMM is able to handle the conventional tetragonal Jahn-Teller distortion of the bond distances in [Cu(NH3)6](2+), the LFSE term is also necessary in order to obtain even qualitatively correct coordination geometries for the two lower-coordinate copper complexes.

BioGPS descriptors for rational engineering of enzyme promiscuity and structure based bioinformatic analysis.

A new bioinformatic methodology was developed founded on the Unsupervised Pattern Cognition Analysis of GRID-based BioGPS descriptors (Global Positioning System in Biological Space). The procedure relies entirely on three-dimensional structure analysis of enzymes and does not stem from sequence or structure alignment. The BioGPS descriptors account for chemical, geometrical and physical-chemical features of enzymes and are able to describe comprehensively the active site of enzymes in terms of "pre-organized environment" able to stabilize the transition state of a given reaction. The efficiency of this new bioinformatic strategy was demonstrated by the consistent clustering of four different Ser hydrolases classes, which are characterized by the same active site organization but able to catalyze different reactions. The method was validated by considering, as a case study, the engineering of amidase activity into the scaffold of a lipase. The BioGPS tool predicted correctly the properties of lipase variants, as demonstrated by the projection of mutants inside the BioGPS "roadmap".

Automated building of organometallic complexes from 3D fragments.

A method for the automated construction of three-dimensional (3D) molecular models of organometallic species in design studies is described. Molecular structure fragments derived from crystallographic structures and accurate molecular-level calculations are used as 3D building blocks in the construction of multiple molecular models of analogous compounds. The method allows for precise control of stereochemistry and geometrical features that may otherwise be very challenging, or even impossible, to achieve with commonly available generators of 3D chemical structures. The new method was tested in the construction of three sets of active or metastable organometallic species of catalytic reactions in the homogeneous phase. The performance of the method was compared with those of commonly available methods for automated generation of 3D models, demonstrating higher accuracy of the prepared 3D models in general, and, in particular, a much wider range with respect to the kind of chemical structures that can be built automatically, with capabilities far beyond standard organic and main-group chemistry.

Automated design of realistic organometallic molecules from fragments.

A method for the automated generation of realistic, synthetically accessible transition metal and organometallic complexes is described. Computational tools were designed to generate molecular fragments, preferably harvested from libraries of existing, stable compounds, to be used as building blocks for the construction of new molecules. These fragments are enriched with information about the number and type of possible connections to other fragments and are stored in library files. When connecting fragments in the subsequent building process, compatibility matrices, which define the connection rules between fragments, are used to delineate organometallic fragment spaces from which molecules can be generated in an automated fashion. The approach is flexible and allows ample structural variation at the same time as the combination of known fragments is easily restrained to avoid generation of exotic and unrealistic substructures and molecules. The method was tested in the generation of ruthenium complexes, with a given coordination environment, which can serve as candidates in catalyst development. The results demonstrate that molecules generated with the described method do not contain exotic arrangements of atoms and are by far more realistic than those obtained by the application of valence rules alone.