Jeremy N. Harvey

Spin forbidden chemical reactions of transition metal compounds. New ideas and new computational challenges

Many reactions of transition metal compounds involve a change in spin. These reactions may proceed faster, slower--or at the same rate as--otherwise equivalent processes in which spin is conserved. For example, ligand substitution in [CpMo(Cl)2(PR3)2] is faster than expected, whereas addition of dinitrogen to [Cp*Mo(Cl)(PMe3)2] is slow. Spin-forbidden oxidative addition of ethylene to [Cp*Ir(PMe3)] occurs competitively with ligand association. To explain these observations, we discuss the shape of the different potential energy surfaces (PESs) involved, and the energy of the minimum energy crossing points (MECPs) between them. This computational approach is of great help in understanding the mechanisms of spin-forbidden reactions, provided that accurate calculations can be used to predict the relevant PESs. Density functional theory, especially using gradient-corrected and hybrid functionals, performs reasonably well for the difficult problem of predicting the energy splitting between different spin states of transition metal complexes, although careful calibration is needed.

Understanding the reactivity of transition metal complexes involving multiple spin states

Abstract In coordination chemistry, many reactions involve several electronic states, in particular states of different spin. This phenomenon of ‘Multiple-State Reactivity’ has been recognized for some time, both for gas-phase reactions of ‘bare’ metal ions, and for transition metal complexes in solution. Until recently, however, much of the discussion of these systems has remained qualitative, because standard computational methods do not allow the location of the critical points for these processes, the Minimum Energy Crossing Points (MECPs) between states of different spin. Increased computational resources and new algorithms now enable MECPs to be located for large, realistic transition metal containing systems, yielding important new insight into the mechanisms of important reactions such as oxidative addition of CH bonds to metal centers and ligand association/dissociation processes. Several examples will be presented for inorganic, organometallic and bioinorganic reactions.

Taking Ockham's razor to enzyme dynamics and catalysis

The role of protein dynamics in enzyme catalysis is a matter of intense current debate. Enzyme-catalysed reactions that involve significant quantum tunnelling can give rise to experimental kinetic isotope effects with complex temperature dependences, and it has been suggested that standard statistical rate theories, such as transition-state theory, are inadequate for their explanation. Here we introduce aspects of transition-state theory relevant to the study of enzyme reactivity, taking cues from chemical kinetics and dynamics studies of small molecules in the gas phase and in solution--where breakdowns of statistical theories have received significant attention and their origins are relatively better understood. We discuss recent theoretical approaches to understanding enzyme activity and then show how experimental observations for a number of enzymes may be reproduced using a transition-state-theory framework with physically reasonable parameters. Essential to this simple model is the inclusion of multiple conformations with different reactivity.

Does Compound I Vary Significantly between Isoforms of Cytochrome P450

The cytochrome P450 (CYP) enzymes are important in many areas, including pharmaceutical development. Subtle changes in the electronic structure of the active species, Compound I, have been postulated previously to account partly for the experimentally observed differences in reactivity between isoforms. Current predictive models of CYP metabolism typically assume an identical Compound I in all isoforms. Here we present a method to calculate the electronic structure and to estimate the Fe–O bond enthalpy of Compound I, and apply it to several human and bacterial CYP isoforms. Conformational flexibility is accounted for by sampling large numbers of structures from molecular dynamics simulations, which are subsequently optimized with density functional theory (B3LYP) based quantum mechanics/molecular mechanics. The observed differences in Compound I between human isoforms are small: They are generally smaller than the spread of values obtained for the same isoform starting from different initial structures. Hence, it is unlikely that the variation in activity between human isoforms is due to differences in the electronic structure of Compound I. A larger difference in electronic structure is observed between the human isoforms and P450cam and may be explained by the slightly different hydrogen-bonding environment surrounding the cysteinyl sulfur. The presence of substrate in the active site of all isoforms studied appears to cause a slight decrease in the Fe–O bond enthalpy, apparently due to displacement of water out of the active site, suggesting that Compound I is less stable in the presence of substrate.

Accurate modelling of Pd(0) + PhX oxidative addition kinetics

We have used dispersion-corrected DFT (DFT-D) together with solvation to examine possible mechanisms for reaction of PhX (X = Cl, Br, I) with Pd(P(t)Bu(3))(2) and compare our results to recently published kinetic data (F. Barrios-Landeros, B. P. Carrow and J. F. Hartwig, J. Am. Chem. Soc., 2009, 131, 8141-8154). The calculated activation free energies agree near-quantitatively with experimentally observed rate constants.

Aryl Trifluoroborates in Suzuki–Miyaura Coupling: The Roles of Endogenous Aryl Boronic Acid and Fluoride

A wide range of organoboron reagents can be used as alternative reagents to boronic acids in Suzuki–Miyaura (SM) coupling reactions. The readily prepared, convenient to handle potassium trifluoroborates, RBF3K, which have been developed by the groups of Genet and Molander, are often the reagents of choice for these transformations. Although extensive optimization of the base, solvent, and temperature is required for each class of substrate, their utility in SM coupling reactions has led to their widespread commercial availability. Apart from a preliminary study in 2003, their mode of action has not been investigated in detail, and the origin of their efficacy 5a] remains to be elucidated. Herein, we report the SM coupling of aryl trifluoroborate 1 with aryl bromide 2 to generate biaryl 3 (Scheme 1). We show that endogenous aryl boronic acid 4 and fluoride, both arising from 1, play key roles in the coupling reaction, being involved at all stages: from catalyst activation and catalytic turnover, through to the inhibition of side reactions. Collectively, these phenomena result in the exceptional performance of the reagent in the SM coupling. The SM coupling of 1 with 2 was studied in a toluene/ water (3:1) biphasic solution, and in a tetrahydrofuran/ water (10:1) solution, both systems being commonly employed for the SM coupling of trifluoroborates. The reactions in toluene/water, failed to go to completion: turnover ceased after 6 hours, affording 55 % of the basecatalyzed protodeboronation product 6 and 32% of coupling product 3. In aqueous tetrahydrofuran (Scheme 1) the reaction proceeded much more efficiently (5.5 h; > 95% yield of 3), with few side products ( 0.1–2%), even when the reaction was performed in air. In contrast, reaction of the boronic acid (4) under identical conditions, gave 3 in variable yield, and afforded substantially more of side products 9/10 (2–40%), compared to trifluoroborate substrate 1. The performance of aryl boronic acid reagents can be improved by the addition of KF, whereas trifluoroborate reagents require aqueous solvent systems for SM coupling with standard substrates. This observation has led to suggestions that mixed borates, [RBF(3 n)(OH)n] , 13] are the true transmetalating species. 5a, 10,13b] Base titration of 1 in a solely aqueous medium (D2O) was monitored by F and B NMR spectroscopy. Trifluoroborate 1 underwent hydrolysis via boronic acid 4 to give boronate 5 ; the transformation required approximately three equivalents of K2CO3 or Cs2CO3, or six equivalents of KOH to proceed to completion. At ambient temperature, boronate 5 slowly gave rise to fluorobenzene 6 by protodeboronation; the process was substantially faster at 55 8C. Rapid equilibrium between 4 and 5 gave rise to time-averaged F NMR chemical shifts (p-F-Ar nuclei), from which analysis of DdF values versus [base] was used to establish the mol% of boronate 5 (e.g. Figure 1a). When the dibasic nature of M2CO3 was taken into account, there was no significant difference in the curve Scheme 1. SM coupling of trifluoroborate 1 with bromide 2 to generate biaryl 3 together with the three major side products arising from protodeboronation (6), homocoupling (9), and oxidation (10).

Iron(I) in Negishi Cross-Coupling Reactions

Herein we demonstrate both the importance of Fe(I) in Negishi cross-coupling reactions with arylzinc reagents and the isolation of catalytically competent Fe(I) intermediates. These complexes, [FeX(dpbz)(2)] [X = 4-tolyl (7), Cl (8a), Br (8b); dpbz = 1,2-bis(diphenylphosphino)benzene], were characterized by crystallography and tested for activity in representative reactions. The complexes are low-spin with no significant spin density on the ligands. While complex 8b shows performance consistent with an on-cycle intermediate, it seems that 7 is an off-cycle species.

Development and application of a possible mechanism for the generation of cis-pinic acid from the ozonolysis of α- and β-pinene

Abstract Recent experimental studies have identified cis- pinic acid (a C 9 dicarboxylic acid) as a condensed-phase product of the ozonolysis of both α - and β -pinene, and it is currently believed to be the most likely degradation product leading to the prompt formation of new aerosols by nucleation. The observed timescale of aerosol formation appears to require that cis- pinic acid is a first-generation product, and a possible mechanism for its formation has therefore been developed. The key step in the proposed mechanism requires that the isomerisation of a complex C 9 acyl-oxy radical by a 1,7 H atom shift is able to compete with the alternative decomposition to CO 2 and a C 8 organic radical: Thermodynamic and kinetic arguments are presented, on the basis of semi-empirical electronic structure calculations, which support this proposed mechanism, and thereby the competition between the two pathways. The transfer of the labile aldehydic H atom is shown to be especially facile in this case because it occurs though an unstrained transition state; this feature can in turn be attributed to the cis -substitution of the four-membered ring, which enforces the steric proximity of the acyl-oxy and aldehyde groups. The mechanism can explain the formation of cis -pinic acid from both α - and β -pinene, because the acyl-oxy radical is likely to be formed following the decomposition of excited Criegee biradicals formed in both systems. It is also possible that a similar isomerisation reaction of a complex C 10 α -carbonyl oxy radical by a 1,8 H atom shift might explain the very recently observed formation of cis -10-hydroxy-pinonic acid from α -pinene ozonolysis, and this possibility is also explored. An existing detailed scheme describing the degradation of α -pinene (part of the Master Chemical Mechanism, MCM) is updated to include the proposed cis- pinic acid and cis -10-hydroxy-pinonic acid formation mechanisms, and the values of several uncertain parameters are adjusted on the basis of reported yields of a series of organic products from the ozonolysis of α -pinene. The updated degradation scheme is incorporated into a boundary layer box model, and representative ambient concentrations of the organic acids and other oxygenated products are calculated for a range of representative conditions appropriate to the boundary layer over central Europe. The simulated concentrations of the organic acids in general, and cis -pinic acid in particular, are strongly dependent on the level of NO X , and suggest that new aerosol formation from the oxidation of α -pinene is likely to be more favoured at lower NO X levels.

Assembly-line synthesis of organic molecules with tailored shapes

Molecular assembly lines, where molecules undergo iterative processes involving chain elongation and functional group manipulation are hallmarks of many processes found in Nature. We have sought to emulate Nature in the development of our own molecular assembly line through iterative homologations of boronic esters. Here we report a reagent (α-lithioethyl triispopropylbenzoate) which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol. Through repeated iteration we have converted a simple boronic ester into a complex molecule (a carbon chain with ten contiguous methyl groups) with remarkably high precision over its length, its stereochemistry and therefore its shape. Different stereoisomers were targeted and it was found that they adopted different shapes (helical/linear) according to their stereochemistry. This work should now enable scientists to rationally design and create molecules with predictable shape, which could have an impact in all areas of molecular sciences where bespoke molecules are required.Molecular ‘assembly lines’, in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon–boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes—helical or linear—depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

Spin‐forbidden reactions: computational insight into mechanisms and kinetics

Many chemical reactions involve one or more changes in the total electronic spin of the reacting system as part of one or more elementary steps. Computational and theoretical methods that can be used to understand such reaction steps are described, and a number of recent examples are highlighted. A particularly strong focus is given to general rules that govern multistep reactions of this type. The two most important rules are (1) that spin‐state change without change in atom connectivity, or spin crossover, is facile and rapid, at least when it is exothermic; and (2) that reactions involving spin‐state change and changes in atom connectivity tend to prefer stepwise mechanisms in which spin crossover steps alternate with spin‐allowed bond‐making and breaking steps. WIREs Comput Mol Sci 2014, 4:1–14. doi: 10.1002/wcms.1154