Volume 89, Issue 6

The existence of post-transition state bifurcations on potential energy surfaces for organic and biological reaction mechanisms has been known for decades, but recently, new reports of bifurcations have been occurring at a much higher rate. Beyond simply discovering bifurcations, computational chemists are developing techniques to understand what aspects of molecular structure and vibrations control the product selectivity in systems containing bifurcations. For example, the distribution of products seen in simulations has been found to be extremely sensitive to the local environment of the reacting system (i.e. the presence of a catalyst, enzyme, or explicit solvent molecules). The outlook for the future of this field is discussed, with an eye towards the application of the principles discussed here by experimental chemists to design a reaction setup to efficiently generate desired products.

We have developed the W n X series of quantum chemistry composite protocols for the computation of highly-accurate thermochemical quantities with advanced efficiency and applicability. The W1X-type methods have a general accuracy of ~3–4 kJ mol −1 and they can currently be applied to systems with ~20–30 atoms. Higher-level methods include W2X, W3X and W3X-L, with the most accurate of these being W3X-L. It can be applied to molecules with ~10–20 atoms and is generally accurate to ~1.5 kJ mol −1 . The W n X procedures have opened up new possibilities for computational chemists in pursue of accurate thermochemical values in a highly-productive manner.

The role of metal ions in catalyzing phosphate ester hydrolysis has been the subject of much debate, both in terms of whether they change the transition state structure or mechanistic pathway. Understanding the impact of metal ions on these biologically critical reactions is central to improving our understanding of the role of metal ions in the numerous enzymes that facilitate them. In the present study, we have performed density functional theory studies of the mechanisms of methyl triphosphate and acetyl phosphate hydrolysis in aqueous solution to explore the competition between solvent- and substrate-assisted pathways, and examined the impact of Mg 2+ on the energetics and transition state geometries. In both cases, we observe a clear preference for a more dissociative solvent-assisted transition state, which is not significantly changed by coordination of Mg 2+ . The effect of Mg 2+ on the transition state geometries for the two pathways is minimal. While our calculations cannot rule out a substrate-assisted pathway as a possible solution for biological phosphate hydrolysis, they demonstrate that a significantly higher energy barrier needs to be overcome in the enzymatic reaction for this to be an energetically viable reaction pathway.

Linear free energy relationships, in particular relationships between rate and equilibrium constants, are the basis for our rationalization of organic reactivity. Whereas relationships between the kinetic terms nucleophilicity and nucleofugality and the thermodynamic term basicity have been in the focus of interest for many decades, much less attention has been paid to the relationships between electrophilicity, electrofugality, and Lewis acidity. By using p - and m -substituted benzhydrylium ions (Aryl 2 CH + ) as reference electrophiles, reference electrofuges, and reference Lewis acids of widely varying electron demand and constant steric surroundings of the reaction center, we have developed comprehensive reactivity scales which can be employed for classifying polar organic reactivity and for rationally designing synthetic transformations. It is a general rule that structural variations in electron-surplus species, which increase basicities, also increase nucleophilicities and decrease nucleofugalities, and that structural variations in electron-deficient species, which increase Lewis acidities also increase electrophilicities and decrease electrofugalities. Deviations from this behavior are analyzed, and it is shown that variations in intrinsic barriers are responsible for the counterintuitive observations that structural variation in one of the reactants alters the rates of forward and backward reactions in the same direction. A spectacular example of this phenomenon is found in vinyl cation chemistry: Vinyl cations are not only generated several orders of magnitude more slowly in S N 1 reactions than benzhydrylium ions of the same Lewis acidity, but also react much more slowly with nucleophiles.

Ionic liquids are attractive alternatives to molecular solvents as they have many favourable physical properties and can produce different organic reaction outcomes compared to molecular solvents. Thus far, interactions between the ionic liquid components and specific sites (such as charged centres, lone pairs and π systems) on the reagents and transition state have been identified as affecting reaction outcome; a comprehensive understanding of these interactions is necessary to allow prediction of ionic liquid solvent effects. This manuscript summarises our recent progress in the development of a framework for predicting the effect of an ionic liquid solvent on the outcome of organic processes. There will be a particular focus on the importance of the different interactions between the ionic liquid components and the species along the reaction coordinate that are responsible for the changes in reaction outcome observed in the cases described.

Since 1965, the stereoselectivity in azoalkane denitrogenation has attracted much attention in both synthetic organic chemistry and physical organic chemistry. In this paper, a short review of the recent findings on the mechanism underlying the fascinating stereoselectivity in azoalkane denitrogenation is presented. The two types of singlet diradicals, i.e. the puckered and planar conformations, were found to play important roles in the stereoselectivity in the photochemical denitrogenation of cyclic azoalkanes. The presence of the puckered singlet diradical, which is the third isomer in homolysis, resolves the mechanistic puzzle reported so far for the stereoselectivity in azoalkane denitrogenations.

Recent studies directed to the design of compounds targeting the bc 1 protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc 1 inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol −1 , are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.

The development of iodine(III)-mediated synthetic transformations has received growing interest, in particular to mediate enantioselective processes. In this class, the α-tosyloxylation of ketone derivatives using iodine(III) is a particularly powerful one, as it yields α-tosyloxy ketones – versatile chiral precursors that enable rapid access to numerous α-chiral ketones through nucleophilic displacement. Despite years of research from numerous groups, the enantioselectivities for this transformation have remained modest. Using quantum chemical calculations, we have uncovered a possible rational for the lack of selectivity. With these computational insights, we have developed an alternative experimental strategy and achieved unprecedented levels of selectivities. Applying this newfound knowledge, we have recently developed a new method to access α-halo ketones from non-ketonic precursors.

In this paper we report the outcome of the reduction of NHC stabilized acetylenic dications, [NHC-C n -NHC] 2+ for n=2 and 4. The target compounds were NHC stabilized di- and tetracarbon in the form of NHC-C n -NHC. However, upon chemical reduction, decomposition ensues with release of the free NHC. This effect is also observed in electrochemical studies. This lends credence to Bestman’s hypothesis that two donor ligands cannot stabilize C n for n=even numbers.

Dynamic combinatorial chemistry deals with systems (libraries) of multiple compounds formed by reversible reactions. Interactions of all library components with introduced template molecule are reflected in modification of library composition and are analysed simultaneously. In our studies we investigated a single-substrate dynamic combinatorial library of macrocycles, based on dipicolinic acid diamide, with disulphide bond exchange as the reversible reaction. The library components equipped with hydrogen bond donors interact with anionic guests – carboxylates which act as templates inducing amplification of selected library members. We proved that quantitative analysis of interactions with templates is possible, which led us to a novel method of analysis of association constants of static receptors introduced to the system. With a large set of carboxylates differing in number of anionic groups, size, shape, and flexibility of the linker, we proved that the library is very sensitive to structural parameters of the template. We also showed that with mediation of a photoswitchable azobenzene-based template it is possible to change the library composition by light stimulus. Similarly, with mediation of EDTA the library is sensitive to introduction of metal cations.

Hemispherical polyarenes represent attractive templates from which carbon nanotubes of the same diameter and rim structure (chirality) might be grown by repetitive annulation reactions. The resulting single-index ( n,m ) nanotubes would have one end open and the other end capped by the original template. Efforts in the author’s laboratory to synthesize (5,5) and (6,6) nanotube end-caps are described. Nitroethylene is shown to serve well as a “masked acetylene” for the conversion of polyarene bay regions into new unsubstituted benzene rings by a Diels-Alder cycloaddition/aromatization process. Benzyne reacts similarly, both in solution and in the gas phase. These annulation reactions are proposed as methods for elongating large-diameter templates that have bay regions on their rims into structurally uniform, single-walled carbon nanotubes. Unfortunately, the bay regions on the strongly curved rim of the small-diameter (5,5) nanotube end-cap 3 resist Diels-Alder cycloadditions with both nitroethylene and benzyne. Pentabenzocorannulene ( 14 ) is proposed as a promising candidate for surface-catalyzed cyclodehydrogenation to a surface-bound hemispherical polyarene that could serve as a template for synthesis of pure (5,5) carbon nanotubes.

Rotaxanes, formed by an axis through the cavity of a macrocycle, are promising systems for the construction of molecular machines. A very limited number of experimental techniques are available for mechanistic studies since only mechanical bonds are formed, being NMR one of the most widely used. The major inconvenience derived from NMR use is the time-scale for threading/dethreading processes lasting a few minutes in the case of faster processes. In the present manuscript, we report the application of a new kinetic methodology based on a displacement assay for cyclodextrin-based pseudorotaxane formation. By coupling a very fast (microseconds time-scale) binding/dissociation of nitrophenol to α-CD with a dicationic axle threading/dethreading process, we have been able to study kinetic processes taking place in the millisecond time-scale.

An appealing concept in synthetic chemistry is photo-induced catalysis; where dormant complexes become catalytically active upon activation with light. The ruthenium-based olefin metathesis complexes founded on the original Grubbs catalyst have probably been one of the most widely studied families of catalysts for the past 25 years. Greater stability and versatility of these olefin-metathesis catalysts has been achieved by careful design of the ligand sphere, including latent catalysts which are activated by external stimuli. This article describes our recent developments towards light-induced olefin metathesis reactions based on photoactive sulfur-chelated ruthenium benzylidene catalysts. Alternative chemical reactions, be it photo-induced olefin metathesis or other direct photochemical processes, by using light of different frequencies were studied in chemoselective chromatic orthogonal pathways. The lessons learned during the development of these reactions have given birth to selective photo-deprotection sequences and novel pathways for stereolithographic applications.

Cytochrome P450s belong to a superfamily of enzymes that catalyse a wide variety of oxidative transformations. Hydroxylation is one the most thoroughly investigated of all identified P450-catalysed reactions whilst dehydrogenation has been relatively much less explored to date. P450-catalysed dehydrogenation is often found to occur with hydroxylation and thus, it was initially suspected to be a stepwise process consisting of hydroxylation and subsequent dehydration to yield the final olefin product. This theory has been proven to be invalid and the olefin was shown to be the direct product of a P450-catalysed reaction. This interesting reaction plays a vital role in the metabolism of xenobiotics and the biosynthesis of endogenous compounds, including a number of steroids. A number of well-known examples of P450 mediated dehydrogenation, including those in the metabolism of valproic acid, capsaicin and 3-methylindole and those in the biosynthesis of plant and fungal sterols are discussed in this review.