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Early Alzheimer’s diagnosis compound

20 Dec 2012

Alzheimer’s disease is the most common form of dementia and, as there is no cure, early diagnosis is crucial for treatment to be effective. To this end, UK and US scientists have developed a labelled tracer compound that binds to plaques closely associated with Alzheimer’s disease (AD) so that the plaques can be picked up by a medical imaging technique.

The tracer compound is a [¹⁸F]-labelled barbiturate and is used with the imaging technique positron emission tomography (PET). Although other radiolabelled compounds have been used as PET tracers, using [¹⁸F]-labelled barbiturates for molecular imaging in AD has distinct advantages, such as good blood-brain barrier crossing ability, metabolic stability and easy accessibility.

Tree that looks like a face with some leaves blowing away to represent memory loss in Alzheimer's disease As Alzheimer’s disease advances, symptoms can include confusion, irritability and aggression, and long-term memory loss © Shutterstock

Matteo Zanda at the University of Aberdeen and colleagues, in conjunction with Pfizer in the US, developed several fluorinated barbiturate analogues. The key to developing an effective molecular imaging radiotracer is the ability to distinguish between a healthy individual and someone suffering from a neurological disease, such as AD, they say. Barbiturates have a strong capacity for forming structures with biopolymers and are effective metal ion chelators. As such, the team thought that they would bind to AD-related plaques, which consist of the biopolymer β-amyloid and metal cations, such as Zn(II) and Cu(II).

See the Chemistry World story in full or read the Chem Comm article:

18 F-barbiturates are PET tracers with diagnostic potential in Alzheimer’s disease
Elisa Calamai , Sergio Dall’Angelo , David Koss , Juozas Domarkas , Timothy J. McCarthy , Marco Mingarelli , Gernot Riedel , Lutz F. Schweiger , Andy Welch , Bettina Platt and Matteo Zanda
Chem. Commun., 2013,49, 792-794
DOI: 10.1039/C2CC38443D

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Probing assembly of supramolecular architectures with non-linear optics

05 Dec 2012

Molecules containing urea and thiourea groups are well known in supramolecular chemistry to self assemble into chains via hydrogen bonding interactions, which can be broken by interaction with ions or polar molecules.

Pritam Mukhopadhyay’s group in New Delhi have found that, with the right functionalization, this can lead to interesting optical properties in solution.

Molecules such as 1a and 1b were found to have non-linear optical (NLO) behaviour in THF solution. On adding a polar molecule such as methanol, or a strongly coordinating anion such as acetate, the NLO behaviour was reduced. This corresponds to the self-assembled urea chains being disrupted by adding a guest that can compete for hydrogen bonding to the urea NH groups.

With this work, the authors have identified an effective new method to probe the assembly and disassembly of supramolecular architectures.

For more information, you can download the full article (free for a limited time) here.

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Nanoconfinement leads to increased catalytic stability

29 Nov 2012

Steam reforming, where hydrogen gas is produced from hydrocarbon fuels such as natural gas, is an important industrial catalytic process. Nickel is the catalyst of choice due to its low cost and high C-C bond rupture activity, and zirconia (ZrO₂) is widely used as the catalytic support due to its thermal and chemical stability, moderate acidity and surface oxygen mobility. The same supported Ni/ZrO₂ catalyst is a promising candidate for ethanol steam reforming (ESR), but its deactivation caused by sintering and coke deposition remains a problem.

Jinlong Gong and researchers from Tianjin University used a surfactant-assisted method to prepare a nanocomposite Ni@ZrO₂ catalyst made up of nickel nanoparticles distributed evenly throughout a similarly sized zirconia matrix. The new catalyst demonstrated higher activity and selectivity for the conversion of ethanol into CO₂ and H₂. Almost complete conversion of ethanol over a 50 hour period was observed, while the activity of the traditional Ni/ZrO₂ catalyst decreased continually after just six hours.

The even distribution of metal nanoparticles throughout the matrix allows the pore structure of the solid to be maintained while increasing the accessibility of the catalytically active nickel. The larger metal-oxide interface promotes the removal of carbon deposits while the “confinement effect” prevents the nickel metal from sintering. As highlighted in a recent C&EN article, these promising catalytic properties suggest that the synthetic methodology may be useful for the design of metal catalysts for other processes, such as dehydrogenation, that encounter similar problems.

Read this HOT Chem Comm article today (free to access until the 27th December):

A Ni@ZrO₂ nanocomposite for ethanol steam reforming: enhanced stability via a strong metal-oxide interaction
Shuirong Li, Chengxi Zhang, Zhiqi Huang, Gaowei Wu and Jinlong Gong
Chem Commun., 2013, Advance Article
DOI: 10.1039/C2CC37109J

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Cooperative Effects Enhance Biphasic Catalysis

28 Nov 2012

Commodity chemicals are often produced using catalysts. Despite the many advantages of using catalysts (such as faster conversion, improved selectivity) a major difficulty is separating them from the product at the end of the reaction. Such is the significance of this problem, heterogeneous catalysts are often chosen ahead of their homogeneous brothers because they are simpler to remove at the end of the reaction, despite the homogeneous catalysts generally having better performance.

Figure 1 Crystal packing diagram of a POM-phosphazene aggregate.

An alternative solution to the separation problem is to utilise a biphasic solvent system. Partitioning the catalyst and product into different phases provides inherent separation and removes the need for expensive procedures like distillations. Ivan Kozhevnikov and Alexander Steiner at the University of Liverpool have collaborated to join their respective areas of expertise together and create catalytically active polyoxometalate (POM)-phosphazene aggregates (Figure 1) which can operate in a biphasic environment. Their communication reports rapid oxidation of test substrates by enhancing the transfer of the catalytically active POM across the two phases. Furthermore, the chemistry is “green” as it utilises relatively environmentally benign conditions.

The components of the aggregates are independently soluble in the different phases; therefore defining how this catalyst operates will be paramount to understanding and developing the system further. For example, reporting the performance of the POM or the phosphazene independently in the biphasic system would provide essential support to the claim that these aesthetically pleasing aggregates are responsible for the observed catalytic activity and remove some of the alternative potential sources.

Read the ‘HOT’ Chem Comm article today (Free to access until the 27th of December):

Novel polyoxometalate–phosphazene aggregates and their use as catalysts for biphasic oxidations with hydrogen peroxide

Michael Craven, Rana Yahya, Elena Kozhevnikova, Ramamoorthy Boomishankar, Craig M. Robertson, Alexander Steiner and Ivan Kozhevnikov
Chem. Commun., 2012, 48, Advance Article
DOI: 10.1039/c2cc36793a

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Isolating Imine Intermediates

21 Nov 2012

Observing what happens when two substances are mixed together is one of the most important foundations of chemistry. However, to take these observations, understand what they mean and then use that knowledge to manipulate and deliberately influence the outcome of a reaction is where the skill and ingenuity of a chemist truly comes to the fore.

It is with this in mind we can appreciate the work of David Milstein and his co-workers at The Weizmann Institute of Science in Israel. They have shown that nitriles and amines can be coupled using their utilising their versatile “PNN Ru(II) pincer complexes” to produce imines under mild conditions (Scheme 1).

: Scheme 1: Hydrogenative coupling of nitriles with amines catalyzed by complex 1

They can control where the reaction stops, which is remarkable as these types of reactions generally yield a mixture of products. We can see why by looking at the mechanism of the reaction (Scheme 2).

: Scheme 2: Mechanism of the hydrogenation of nitriles to primary, secondary and tertiary amines, via imine intermediates

Scheme 2 shows why the imine would generally be considered as an intermediate; an unstable compound which readily reacts further, yet in this case it is the product. Isolation of intermediates is incredibly challenging because it involves isolating compounds which are, by their very nature, transient.

The paper shows the reaction works well with hydrogen pressures as low as four bar, perhaps the next step might be to examine just how low the pressure can be decreased. This could potentially remove the necessity for specialized pressurized reaction vessels and may make it the method choice for imine synthesis in almost any lab.

Read the ‘HOT’ Chem Comm article today (Free to access until the 17th of December):

Catalytic coupling of nitriles with amines to selectively form imines under mild hydrogen pressure

Dipankar Srimani, Moran Feller, Yehoshoa Ben-David and David Milstein
Chem. Commun., 2012, 48, 11853-11855
DOI: 10.1039/C2CC36639H

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Drug delivery: implications of gold-protein interactions

19 Nov 2012

Researchers in Italy have shown that medicinal gold compounds interact strongly with the proteins of the copper trafficking system, which could have implications for drug delivery.

The copper trafficking system consists of proteins that help the uptake of copper into cells and then promote its transfer and delivery to copper-dependent cellular proteins. One of these ‘chaperones’ is known as Atox-1.

Previous work has shown that platinum-based anticancer drugs strongly interact with copper trafficking system proteins and Messori and co-workers hypothesised that medicinal gold compounds might also do the same, especially in the +1 oxidation state; soft lewis acids, such as gold (I) ions react eagerly with Atox-1.

The interactions of three gold (III) compounds with Atox-1 were analysed through ESI-MS and revealed the formation of metal-protein adducts. The same major adduct was invariantly formed, matching the protein binding of a single gold (I) ion. Formation of this adduct implied that the gold (III) complex had broken down, a loss of ligands and reduction to a gold (I) species. ESI-MS also displayed peaks that corresponded to protein binding with two gold (I) ions. A stability study showed that one of the three gold-protein adducts was stable over 72 hours.

From their findings, the authors conclude that the cytotoxic gold compounds investigated form stable adducts with copper chaperone, Atox-1. These results have implications for medicinal drug design and our little friend, Atox-1 stays in a job.

Read this HOT Chem Comm article today (free to access until the 14th of December 2012):

Medicinal gold compounds form tight adducts with the copper chaperone Atox-1: biological and pharmacological implications
Chiara Gabbiani, Federica Scaletti, Lara Massai, Elena Michelucci, Maria A. Cinellu and Luigi Messori
Chem. Commun., 2012, 48, 11623-11625

Published on behalf of Sarah Brown, Chemical Communications web science writer.

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All Gold – Facile, Air Stable, Regio- and Stereoselective Allylic Etherification

15 Nov 2012

Methods of allylic etherification are usually involved synthetic procedures, due to the need for activation of the starter aliphatic alcohol. By contrast, no such problems exist in analogous reactions to form allylic amines.

Significant steps have been made in this synthetic area, but limitations remain. Iridium catalysis has been successfully employed for this reaction but usually requires the use of a glove box. Derivatisation of starting materials to incorporate suitable leaving groups has also been explored, as has the use of various bases to deprotonate the alcohol nucleophile.

Tertiary butyl alcohol has been extensively investigated for its reactivity also, but it appears that the more conditions you put on this reaction the more limited its scope and applicability become. Add to this the effect of each modification on product regio- and stereoselectivity and you can appreciate the challenge. Each new ‘improvement’ can leave you, figuratively speaking, one step up, and two steps back.

With this situation in mind, the Lee group from Heriot-Watt University report a considerable breakthrough in the catalysis of the allylic etherification of unactivated alcohols, using a gold(I) salt. Well chosen controls and an extensive optimisation of the reaction parameters has yielded a robust strategy, effective for a wide range of substrates and aliphatic alcohols, with very good to excellent regio- (S_N2 vs S_N2′) and stereoselectivity (cis/trans). An inert atmosphere is not even required.

The use of Lewis acidic gold(I) for this reaction seems to provide a reliable activation of the olefin of the allyl group, to nucleophilic attack from the external alcohol nucleophile, all helped along by the possible involvement of a six-membered transition state. It would appear that it is this activation and plausibly reliable mechanism, that has allowed this usually difficult process to be controlled, both chemically and stereochemically.

A large variety of alcohol nucleophiles, (including primary, secondary, tertiary, and functionalised examples) and allyl alcohol electrophiles have been screened. Overall trans- products with S_N2′ regiochemistry are highly favoured. An interesting selection of control reactions were performed, including the use of a hindered proton sponge to prove absolutely the effect of the gold(I) catalyst as well as the sole use of the acidic bis-trifluoromethylsulfonimide (HNTf₂) as catalyst, which resulted in a conversion of less than 5%.

The authors report a breakthrough in the allylic etherification of aliphatic alcohols, the application of which should be substantial, as the team now turns its attention to possible applications in asymmetric synthesis.

Read the ‘HOT’ Chem Comm article today (Free to access until the 14th of December):

Gold(I)-catalysed direct allylic etherification of unactivated alcohols

Paul C. Young , Nina A. Schopf and Ai-Lan Lee
Chem. Commun., 2012, 48, Advance Article
DOI: 10.1039/C2CC36760B

Published on behalf of Kevin Murnaghan, Chemical Communications web science writer.

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Asymmetric Allylic Alkylation for the Introduction of Chiral Fluoroalkyl Groups

14 Nov 2012

Researchers from the University of Geneva have developed a transition-metal-free method for the asymmetric installation of fluoroalkyl groups.

Reaction Scheme

The Alexakis group found that the use of N-heterocyclic carbenes (2) in conjunction with Grignard reagents, enabled the highly selective synthesis of γ-functionalised products (3) from readily accessible starting materials (1). The reaction was initially performed in the presence of copper(l) salts, which afforded the desired products although regioselectivity and ee were suppressed.

A range of alkyl groups (R) could be introduced in moderate yields and very good levels of enantioselectivity (84–95%) from the corresponding Grignard reagent. Similarly, the reaction was tolerant of different aryl substituents (Ar). Exchanging the aryl component with cyclic alkyl groups did not affect the ee, however, the introduction of less bulky aliphatic groups caused enantioselectivity to plummet.

The demonstrated importance of fluoroalkyl groups in medicinal chemistry necessitates the development of new methods for the introduction of this important functional group. Alexander Alexakis and his group have developed the first asymmetric allylic alkylation reaction for the synthesis of quaternary centres containing fluoroalkyl groups; a method that may be of particular benefit to the pharmaceutical industry.

Read this HOT Chem Comm article today (free to access until the 13th of December 2012):

Formation of chiral fluoroalkyl products through copper-free enantioselective allylic alkylation catalyzed by an NHC ligand
David Grassi , Hailing Li and Alexandre Alexakis
Chem. Commun., 2012, 48, 11404-11406

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Metal Free Thiolation Reactions of a Series of Heteroaromatics

12 Nov 2012

Aromatic compounds substituted with a C-S bond are of importance for pharmaceutical and medicinal chemistry, and materials science. A widely employed route to such compounds is a cross coupling reaction, between an aryl halide and a thiol, to yield a thioether. The reaction is usually mediated and catalysed by a metal centre such as palladium, indium or nickel, present as a salt or complex. In this communication, the authors report a high yielding, transition metal free route to aryl thioethers, using just a disulfide and a weak base, in a suitable solvent, under an inert gas.

The authors proved early in their study that a metal salt was not required for reactivity, with better yields being recorded for such reactions, versus a metal salt containing control. A further control reaction was carried out, to disprove the presence or effect of any trace transition metal by using ultrapure caesium carbonate (99.994% purity) and freshly distilled solvent.

The model reaction investigated and optimised was the thiolation of 2-phenyl-1,3,4-oxadiazole with di-p-tolyl disulfide. Reaction conditions which gave the best yields involved the use of 2 equivalents of base and 1,4-dioxane as solvent, under an argon atmosphere, for typically 18-24 h. 5 equivalents of disulfide were found to be the most effective. Using 7 equivalents gave no benefit to the final yield. Coincidently, the excess disulfide proved easily recoverable from the reaction mixture.

Electronic effects proved to be important in the reactivity of the phenyl-oxadiazoles with electron donating groups present on the arene promoting the reaction and electron withdrawing groups having a negative effect. The reaction also shows a good degree of robustness in being effective in thiolating indole and 5-methyl-indole at the 3 positions in excellent yield, as well as other substrates such as caffeine and benzimidazole.

This synthetic methodology represents an important simplification in the preparation of heteroaromatic thioethers, and should prove of interest to synthetic chemists, particularly in the areas of medicinal chemistry, materials science and total synthesis.

Read this HOT Chem Comm article today (free to access until the 7th of December 2012):

Transition metal-free direct C–H bond thiolation of 1,3,4-oxadiazoles and related heteroarenes

Liang-Hua Zou, Jens Reball, Jakob Mottweiler and Carsten Bolm, Chem. Commun., 2012, 48, 11307–11309

Published on behalf of Kevin Murnaghan, Chemical Communications web science writer.

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Unusual Staudinger Reaction Enabled by Frustrated Lewis Pairs

08 Nov 2012

Researchers at the University of Münster have developed an unusual variant of the Staudinger reaction which takes advantage of frustrated Lewis pair (FLP) frameworks to provide internal stabilisation.

The Staudinger reaction represents an important tool for the generation of iminophosphoranes, which can be subsequently utilized in the synthesis of a wide range of functional motifs, including amines, imines, and amides. Additionally, with the variation of the phosphorus compound, the Staudinger reaction can be employed in bio-ligation processes under mild conditions.

Traditionally, the iminophosphorane product (3) is generated from the reaction of an organic azide (1) with a trivalent phosphorus compound. This is thought to proceed via transition state 2, from which elimination of dinitrogen yields the iminophosphorane (3). In the variation developed by the Erker group, such elimination of dinitrogen is avoided, generating products such as 4.

This unusual reactivity was cleverly obtained through the incorporation of the phosphorus moiety in an FLP; specifically, vicinal phosphane–borane FLPs (5). Upon reaction with mesityl azide, these FLPs led to the formation of 5-membered heterocycles (6). Following thermolysis or photolysis, phosphinimines (7) were obtained which benefit from internal stabilisation from borane. The by-product of this formation is indazole 8. While the mechanism of this unusual variation has yet to be confirmed, the authors propose a pathway proceeding via the ion pair 9.

This work contributes to the broadening utility of the Staudinger reaction, and illustrates the potential of FLP chemistry in the development of new reactivity.

Read the ‘HOT’ Chem Comm article today (Free to access until the 7th of December):

Anomalous Staudinger reaction at intramolecular frustrated P–B Lewis pair frameworks

Annika Stute , Lukas Heletta , Roland Fröhlich, Constantin G. Daniliuc, Gerald Kehr and Gerhard Erker
Chem. Commun., 2012, 48, 11739-11741
DOI: 10.1039/C2CC36782C

Published on behalf of Ruth Gilligan, Chemical Communications web science writer.

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