Zoë Hearne – Chemical Communications Blog

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Copper A3 Coupling using a Switchable Homogeneous/Heterogeneous Catalyst

06 Nov 2018

A MOC, I learned this week, is a metal-organic cage. I was familiar with MOMs, MOFs and MOBs, but MOCs were a new one. A MOM (metal-organic material) is a coordination-driven assembly constructed from metal nodes linked by organic ligands. MOMs encompass both MOFs (metal-organic frameworks) and MOCs (metal-organic cages). A MOF is an extended network with the potential for inner porosity, and a MOC is a discrete metal-ligand cluster. And that’s just about as far down the nomenclature rabbit hole I’m willing to go. If you’re keeping up you’ll realise that I forgot one! A MOB is a crowd of graduate students competing for free coffee at the public seminar.

Dong and co-workers at Shandong Normal University designed and prepared a MOM catalyst constructed from copper(II) nodes and a tripodal ligand consisting of a phenylic wheel functionalised with diketones. In chloroform these two components arrange into discrete MOC assemblies containing two tripodal ligands and three copper ions. The copper ions in the cluster are each coordinated to two diketone moieties (in a acetylacetonate-like fashion) in a quasi-square planar arrangement.

Synthesis of the tripodal ligand functionalised with diketone coordinating moieties.

An interesting property of the material is that it can switch between the MOC form, soluble in halogenated solvents, and an insoluble MOF that assembles upon addition of 1,4-dioxane. 1,4-Dioxane is both an anti-solvent and a ligand; coordination between copper and 1,4-dioxane binds the discrete MOC cages to each other, arranging them into the extended MOF structure. This behaviour can be exploited to prepare a practical catalyst that combines the benefits of both homogeneous and heterogeneous catalysis, namely that homogeneous catalysts are generally more efficient, selective and easier to study, but heterogeneous catalysis are easier to recover and recycle. What better way to solve this problem than with a catalyst that is homogeneous during the reaction conditions, but heterogeneous when it comes to product separation?

Reversible metal-organic cage MOC(top left)-MOF(top right) metal-organic framework transition mediated by the addition of 1,4-dioxane. Coordination bonds between 1,4-dioxane shown (bottom image).

Reversible MOC(top left)-MOF(top right) transition mediated by the addition of 1,4-dioxane. Coordination bonds between 1,4-dioxane shown (bottom image).

The authors used the A³ coupling reaction to demonstrate this concept in a catalytic reaction. The A³ reaction is a transition metal-catalysed, multi-component coupling reaction between aldehydes, alkynes and amines. The products are propargylamines, practical synthetic intermediates for the synthesis of nitrogen heterocycles. The A³ reaction has been extensively studied and can be effected by a wide range of transition metal catalysts. Its versatility makes it a popular choice as a model catalytic reaction to demonstrate innovative ideas in catalytic design – as the authors have done here.

Coordination-driven assemblies have a unique potential for the synthesis of differentially soluble materials, used by the authors for novel catalytic design. Whether this particular metal-ligand combination can be applied to other copper catalysed reactions remains to be seen, nevertheless the principle offers an innovative approach that augments the range of methods striving to bridge the gap between homogeneous and heterogeneous catalysis.

To find out more please read:

Cu₃L₂ metal-organic cages for A³-coupling reactions: reversible coordination interaction triggered homogeneous catalysis and heterogeneous recovery

Gong-Jun Chen, Chao-Qun Chen, Xue-Tian Li, Hui-Chao Ma and Yu-Bin Dong.
Chem. Commun., 2018, 54, 11550-11553
DOI: 10.1039/c8cc07208f

About the author

Zoë Hearne is a PhD candidate in chemistry at McGill University in Montréal, Canada, under the supervision of Professor Chao-Jun Li. She hails from Canberra, Australia, where she completed her undergraduate degree. Her current research focuses on transition metal catalysis to effect novel transformations, and out of the lab she is an enthusiastic chemistry tutor and science communicator.

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MOFS, ZMOFS and Automobiles

05 Sep 2018

Mohamed Eddaoudi and co-workers at KAUST have synthesised a porous metal organic framework (MOF) constructed from carboxylic acid-functionalised imidazole linkers coordinated to yttrium and potassium cations. The researchers classified this material as a zeolite-like MOF (ZMOF) due to its topological resemblance to the naturally occurring zeolite mineral analcime.

The material’s architecture, with cylindrical channels and a pore aperture measuring 3.8 x 6.2 Å, promised utility as a molecular sieve, and the authors showed the ZMOF could be used to sort small chain alkanes based on their level of branching. Linear and mono-branched pentanes and butanes were adsorbed by the material for different lengths of time (linear isomers were retained longer than their branched counterparts) allowing kinetic separation, while the di-branched alkane 2,2,4-trimethylpentane was excluded entirely. The authors anticipate that this material could have practical applications in crude oil refining, to upgrade petroleum into more energy-efficient fuels with reduced emissions.

ZMOF zeolite-like metal organic framework crystal structure with analcime (ana) topology showing channels and pore aperture.

ZMOF crystal structure with analcime (ana) topology showing channels and pore aperture.

The petroleum used to power internal combustion engines consists of a mixture of low molecular weight, linear and branched alkanes. The research octane number (RON) is a standard measure of petroleum performance, and indicates how much pressure a fuel can withstand before self-igniting (knocking) in the engine. High compression engines, which are more energy efficient and release less emissions than regular engines, require high RON fuels.

The RON increases with the proportion of branched alkanes, so can be improved by supplementing fuels with branched isomers obtained by catalytic isomerisation. This process generates a mixture of linear and branched alkanes, so the desired products must be isolated via fractional distillation, which is energy intensive. This creates a dilemma: high RON fuels are more energy efficient, but their energy-intensive production reduces the net benefit.

The authors envisaged an energy-efficient strategy for increasing the RON of petroleum fuels: A low RON fuel is pumped into the engine, where it encounters a separation chamber consisting of ZMOF-based membranes. The membrane excludes and redirects di-branched alkanes, which have a very high RON, to the internal combustion engine. The low RON fraction, consisting of mono-branched and linear alkanes, passes through the ZMOF pores to undergo further reforming processes downstream. In other words: low RON fuels go in, but high RON fuels are combusted.

Scheme showing how ZMOF materials could be used to upgrade gasoline by separating alkanes based on their level of branching. zeolite-like metal organic framework petroleum reforming

Scheme showing the RON of common small-chain alkanes and the use of ZMOF membranes in upgrading gasoline by separating alkanes based on their level of branching

In this work the authors show the potential of ZMOFs to maximise the energetic potential and reduce emissions of petroleum based fuels, while also offering a glimpse of the more general strategy of energy-efficient separations of chemically-similar molecules using tailored materials.

To find out more please read:

Upgrading gasoline to high octane number using zeolite-like metal organic framework molecular sieve with ana-topology

M. Infas H. Mohideen, Youssef Belmabkhout, Prashant M. Bhatt, Aleksander Shkurenko, Zhijie Chen, Karim Adil, Mohamed Eddaoudi.
Chem. Commun., 2018, 54, 9414-9417
DOI: 10.1039/c8cc04824j

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Marbles, Microreactions and Magic Tricks

03 Aug 2018

The reaction vessel is a fixed variable behind every innovative chemical synthesis, material or catalyst. It may be as simple as a round bottom flask or as complex as a single cell, as large as an industrial batch reactor or as small as a test tube.

Yujun Feng and co-workers, at Sichuan University in China, study a different kind of reaction vessel: water droplets. The droplets are ‘liquid marbles’, composed of microlitre volumes of water with fine hydrophobic particles covering their surface. Liquid marbles can be used as reaction vessels to manipulate small liquid volumes, avoiding the use of specialised microfluidics equipment. In this communication the authors show that carbon dioxide can trigger coalescence of droplets containing multiple reagents, in order to perform microscale chemistry. This research could be useful for developing high-throughput assays for procedures that would benefit from remotely controlled induction such as very fast or hazardous reactions.

The authors synthesised CO₂-responsive particles composed of a mixture of polystyrene and PDEA: a methacrylate polymer bearing tertiary amine ancillary groups. The amine is vital to the properties of the polymer: when deprotonated the powder is hydrophobic, but exposure to carbon dioxide renders the polymer hydrophilic by transforming the amine into an ammonium bicarbonate salt. Liquid marbles were synthesised with a patch of CO₂-responsive polymer powder. The rest of the marble was coated in lycopodium, a moss spore with hydrophobic properties that is not CO₂-responsive (trivia: the high fat content of lycopdoium makes it a great flash powder, used by magicians since the middle ages).

A) Liquid marbles with white hydrophobic/hydrophilic CO2-responsive patches and pink (dyed) lycopodium powder. B) Coalescence of two liquid marbles upon CO2 carbon dioxide exposure within one minute. C) Coalescence schematic

A) Liquid marbles with white CO₂-responsive patches and pink (dyed) lycopodium powder. B) & C) Photos and schematic of coalescence between two liquid marbles upon CO₂ exposure

To realise CO₂-induced chemistry, two liquid marbles containing different chemical reagents are placed side by side with the CO₂-responsive powder positioned at the interface of the two marbles. Upon exposure to CO₂ the responsive powder becomes hydrophilic and disperses into the aqueous solution within the two marbles, causing them to coalesce and the reagents to react within a single vessel. The authors performed several reactions using this method, all with distinct colour changes for rapid analysis: redox (persulfate and iodide, permanganate and persulfate), complexation (starch and iodine), substitution (bromine water and phenol) and chemiluminescence (luminol, peroxide and ferricyanide).

The authors show in this paper that innovations in chemistry needn’t be limited to reactions themselves; the vessel we choose can broaden what is possible on a practical level. On a completely impractical note, remotely controlled microreactions in liquid marbles sounds like a magic trick, resonant with the lycopodium flash powder covering their surface.

To find out more please read:

CO₂-triggered microreactions in liquid marbles

Xinjie Luo, Hongyao Yin, Xian’e Li, Xin Su, Yujun Feng.
Chem. Commun., 2018, Advance Article
DOI: 10.1039/c8cc01786g

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An enzymatic Rube Goldberg machine: a bioluminescent switch for the detection of uracil DNA-glycosylase

06 Jul 2018

A team of researchers from Shandong Normal University in Jinan, China, have developed a highly sensitive and label-free assay for the detection of uracil-DNA glycosylase, a DNA repair enzyme that removes uracil from DNA molecules. Uracil is an RNA base, and when uracil appears in DNA through deamination of cytosine or misincorporation during DNA synthesis, the error can have mutagenic consequences.

Diminished activity of uracil-DNA glycosylase has been linked to a number of disease states including human immunodeficiency and Bloom syndrome, an inherited disorder associated with an increased risk of cancer (among other symptoms). Developing sensitive methods to quantify uracil-DNA glycosylase would enable early diagnosis of such conditions and improve understanding of the DNA-repair machinery. As a proof-of-concept, the researchers showed that this method could quantify the enzyme in the cell lysate of HeLa cancer cells.

Their method reminds me of Rube Goldberg machines, which achieve a task via a series of connected, mechanical steps. Completion of one step triggers the start of another: such as a line of falling dominos hitting a marble that, in turn, rolls down a track. In this work the action of one enzyme returns a product that is the preferred substrate of another enzyme. At the risk of deviating slightly, one of the more spectacular examples of a Rube Goldberg machine is seen in the music video for OK GO’s ‘this too shall pass’, a single-take shoot of a warehouse sized machine, featuring rolling cars, swinging pianos, flowing water and rolling billiard balls, all to perform the task of (spoiler alert) blasting the band members in the face with coloured paint.

The label-free strategy for detecting uracil-DNA glycosylase results in a bioluminescent signal via tricyclic signal amplification

The strategy starts with the action of uracil-DNA glycosylase and ends with a bioluminescent signal via a cascade of enzymatic reactions

The authors’ strategy involves a series of sequential steps employing seven different enzymes and three nucleic acid probes. It begins with a double stranded DNA probe containing one rogue uracil base: the perfect bait for uracil-DNA glycosylase. The action of this enzyme and two others, in a process involving base excision, DNA backbone cleavage and the addition of thymine-rich sequences, produces a large quantity of single-stranded DNA molecules with long thymine-rich tails. These molecules hybridise with adenine-rich RNA probes to generate RNA-DNA duplexes. An enzyme digests the RNA portion, releasing adenosine monophosphate monomers, which are converted to adenosine triphosphate (ATP), a required energy input to activate firefly luciferase. Luciferase catalyses the oxidation of luciferin to form oxyluciferin, accompanied by a large bioluminescent signal. Thus, uracil-DNA glycosylase is detected with 1-2 orders of magnitude more sensitivity than state-of-the-art fluorescent and luminescent assays.

Unlike conventional Rube Goldberg machines, which are characterised by unnecessary complexity, in this ‘enzymatic Rube Goldberg machine’ each step has a specific purpose and serves to amplify the signal of the last. This is dubbed ‘tricyclic cascade signal amplification’ and it enables highly sensitive detection of the enzyme.

To find out more please read:

Label-free and high-throughput bioluminescence detection of uracil-DNA glycosylase in cancer cells through tricyclic cascade signal amplification

Yan Zhang, Qing-nan Li, Chen-chen Li, Chen-yang Zhang.
Chem. Commun., 2018, 54, 6991-6994
DOI: 10.1039/c8cc03769h

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Come for the colour changing crystals, stay for the science

31 May 2018

Synthesis of copper bimetallic complexes from imidazolyl ligands, and the solvatochromic materials formed upon crystallization and solvent guest-exchange. The solvatochromic behaviour was quantified with visible-region diffuse reflectance spectra.

During the first inorganic chemistry course I took during my undergraduate degree, our professor started the class by passing around some mineral samples, promising us that if we pursued the chemistry of metals we could work with beautifully coloured crystals every day. At the time, colour seemed like such a trite detail amongst the complexity of the subject. Why would you choose a field of study based on something so simple? Well, after a PhD dominated by pale yellow oils, I think I get it now.

Nikolayenko and Barbour at the University of Stellenbosch in South Africa bring us colour! The authors synthesised organometallic copper complexes, which crystallise to form porous single crystals that drastically change colour upon absorption of various solvents. The authors investigated the solvatochromic mechanism using X-ray crystallography, EPR, UV-visible spectroscopy and DFT calculations. Solvatochromic materials are not just made to look pretty; they have potential to be used as sensitive, selective and recyclable sensors to detect solvent vapours with useful applications in industrial process risk management, chemical threat detection and environmental monitoring.

The researchers synthesised a series of complexes comprised of a bidentate ligand with 2-methylimidazolyl groups coordinated to copper(II) ions. The complexes stack to form channels in the crystal, capable of trapping solvent molecules to give different coloured crystals: DMSO and THF-containing crystals are green (λ_max = 574 nm and 540 nm, respectively), those containing acetonitrile are red (λ_max = 624 nm), and crystals trapping acetone, ether and pentane are yellow (λ_max = 588), orange (λ_max = 598 nm) and red/brown (λ_max = 592 nm), respectively.

The authors revealed a correlation between the size of the solvent guest, coordination geometry of the copper complex, and the ligand field splitting. Small guests such as acetonitrile minimally perturb the metallocyclic framework, preserving a rhombic ligand field geometry (large δ_xy of g values in the EPR spectrum), small ligand d-orbital splitting and red-shifted optical spectra. Large guests such as THF have the opposite effect, giving ligand field geometries approaching tetragonal (small δ_xy), large ligand field d-orbital splitting and blue-shifted optical spectra.

By delving into the complexity beneath a seemingly simple phenomenon, Nikolayenko, Barbour and their co-workers have shown using a series of single-crystal complexes that there is nothing simple about colour (and nothing trite about detail).

To find out more please read:

Supramolecular solvatochromism: mechanistic insight from crystallography, spectroscopy, and theory

Varvara I. Nikolayenko, Lisa M. van Wyk, Orde Q. Munro, Leonard J. Barbour.
Chem. Commun., 2018, Advance Article
DOI: 10.1039/c8cc02197j

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Ruthenium Currency for a Hydrogen Fuel Economy

02 May 2018

A group of researchers at the Chinese Academy of Sciences and Southwest University want us to kick the fossil fuels habit. Their research comes to us from China, a country using roughly one quarter of the world’s yearly energy consumption, and where the finite nature of fossil fuels is a very real threat to energy supply security. Leading in energy use, China also leads the world in electricity production from renewable sources and investment in clean energy projects.

Hydrogen is considered a viable alternative to fossil fuels as it is energy rich, more so than petrol or ethanol at 39 kWh/kg (petrol: 13 kWh/kg, ethanol: 8.2 kWh/kg), and upon combustion emits only water vapour. However, hydrogen is often obtained from fossil fuels, and it will only be a practical option for the world’s future energy needs if it can be produced from a renewable source.

Preparation of the Ru2P/reduced graphene oxide electrocatalyst for the hydrogen evolution reaction

Preparation of the Ru₂P/reduced graphene oxide catalyst

To this end, water splitting offers a solution. In a water electrolysis cell, hydrogen is produced at the cathode via the hydrogen evolution reaction (HER, 2H⁺ + 2e^– –> H₂), and molecular oxygen is produced at the anode (2H₂O –> O₂ + 4H⁺ + 4e^–). It is ideal in theory, but high energy efficiencies are required to make water splitting viable, and this relies on the development of catalytic electrodes to minimize overpotentials required to drive the reaction. Currently, state of the art HER electrocatalysts use platinum, which is expensive and rare. Furthermore, platinum catalysts are most efficient in an acidic electrolyte and proceed 2-3 times slower in alkaline solutions. On the other hand, the best oxygen evolution catalysts perform better in alkaline environments. Using an alkaline electrolyte has overall advantages as it is less corrosive, thus increasing the stability and lifetime of the electrolytic cell.

The authors have developed a HER catalyst, using ruthenium, with overpotentials and current densities superior to Pt/C in both alkaline and acidic conditions.

DFT calculation to probe the hydrogen adsorption energies on the active catalytic surface of the Ru2P on reduced graphene oxide catalyst.

DFT calculation to probe the hydrogen adsorption energies on the active catalytic surface of the Ru₂P catalyst. a) and b) front and side views of the calculated Ru₂P/reduced graphene oxide surface. c) free energy diagram for the HER with different catalysts.

The electrocatalyst is comprised of small, uniform Ru₂P nanoparticles (~2-4 nm) evenly distributed on reduced graphene oxide sheets. The activity of the prepared catalyst (1.0 mg cm^-2) for the HER was measured in an acidic medium (0.5 M H₂SO₄) and the overpotential to achieve a current density of -10 mA cm^-2 was -22 mV, superior to Pt/C (-27 mV). In an alkaline environment (1.0 M KOH) catalyst performance was enhanced, with an overpotential of -13 mV (29 mV lower than Pt/C). High Faradaic efficiencies of more than 98% were measured in both acidic and alkaline solutions. Additionally, analysis was undertaken to further understand how the structure and composition of the catalyst influences its activity. Double layer capacitance measurements gave clues about the catalyst surface, while theoretical DFT calculations were used to study H-adsorption energies.

There is no way to avoid the reality that ruthenium is also a rare and costly metal, and for this reason may not hold the key to solving our energy woes. However, of real value are the insights gained from probing the structure function relationship of this highly active catalyst, which may guide the synthesis of rationally-designed catalysts using inexpensive and abundant materials.

To find out more please read:

Ultrasmall Ru₂P nanoparticles on graphene: a highly efficient hydrogen evolution reaction electrocatalyst in both acidic and alkaline media

Tingting Liu, Shuo Wang, Qiuju Zhang, Liang Chen, Weihua Hu, Chang Ming Li.
Chem. Commun., 2018, 54, 3343-3346
DOI: 10.1039/c8cc01166d

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Synthesis of Maleimide Dyes with Colourful Fluorescent Emissions

18 Apr 2018

A group of researchers based at universities spanning the UK, China and Spain have synthesised a diverse library of fluorescent maleimide dyes with the aim of developing a structure-function relationship, relating substituent effects to the optical properties of such molecules. This work is not only important to build upon fundamental understanding of the fluorescence mechanism, but to develop knowledge that may be used to guide the synthesis of organic fluorophores which demand particular optical properties.

Organic fluorescent molecules are used as tools in many areas such as forensics, genetic analysis, DNA sequencing and biotechnology. Maleimides are commonly used as fluorescent labels for proteins, as they can couple with the thiol groups of cysteine residues. They are suited to this purpose as they are stable, easily functionalised, give strong emissions and do not perturb the protein structure to a large extent.

Molecules fluoresce upon absorption of UV or visible light, elevating an electron from a ground state orbital to a higher-energy orbital and resulting in a singlet excited state. Relaxation to the ground state occurs rapidly (~ 10 ns) with concomitant emission of a photon – this is what we observe as ‘fluorescence’. The emitted photon almost always has a longer wavelength than the absorbed light, a phenomenon known as the ‘Stokes shift’.

Structures of selected amino-halo-maleimides and alkoxy-halo-maleimides synthesised for the study

With three dihalomaleimide precursers in hand (Cl, Br and I) the researchers assembled a library of amino-halo-maleimides, amino-alkoxy-maleimides, and amino-thio-maleimides. They varied the R groups bound to the N, O and S heteroatoms to include aliphatic, phenyl and benzyl examples.

The optical properties of the amino-halo-maleimides in diethyl ether were examined and the emission wavelengths were measured to be 461-487 nm, giving green-blue fluorescence. The fluorescence quantum yields, a measure of the quantity of emitted photons compared to absorbed photons and an indication of emission brightness, decreased with the electronegativity of the halide (Cl: 37%, Br: 30%, I: 8%). Like many fluorescent molecules in solution the compounds exhibited solvafluorochromism: when the polarity of the solvent alters the optical properties. In protic solvents (methanol and water) the fluorescence quantum yields decreased to below 1% and the emission wavelengths increased by 73-109 nm. On the other hand, in non-polar solvents (cyclohexane) the fluorescence quantum yield increased, up to 56% for the chloro analogue.

a) The UV and emission spectra of fluorescent maleimides bearing amino (2a-c) and alkoxy (3a, 3b) substituents. b) The quantum yields of selected amino and alkoxymaleimides. c) The solvafluorochromism effect for three maleimides (2a-c) in various solvents.

Compared to their amino-substituted counterparts, alkoxy-halo-maleimides have lower quantum yields (reduction of 20-25%), indicating the increased electron-donating capacity of the amine substituent is important for fluorescence intensity. Furthermore, the slight decrease in the emission wavelengths of alkoxy-halo-maleimides (458-465 nm) gives them blue fluorescent emissions. Amino-thio-maleimides, with greater electron-donating capacity than both the amino and alkoxy analogues, have increased emission wavelengths (526-564 nm), thus yellow fluorescent emissions.

This study is a worthwhile read for anyone who uses fluorescent molecules in their work, those wishing to understand a little more about the practical principles of fluorescence and all those curious minds who like to form their own hypotheses.

To find out more please read:

Rational design of substituted maleimide dyes with tunable fluorescence and solvafluorochromism

Yujie Xie, Jonathan T. Husband, Miquel Torrent-Sucarrat, Huan Yang, Weisheng Liu, Rachel K. O’Reilly.
Chem. Commun., 2018, 54, 3339 – 3342
DOI: 10.1039/C8CC00772A

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Synthesis of Oxazolines with a Triple Activation Twist

04 Apr 2018

A group of researchers based in Valencia, Spain, have developed an enantio- and diastereoselective method to synthesize oxazolines, using a combination of silver and an organocatalyst that is only one degree of separation away from a classic British cocktail (to get that one, you might have to keep reading). This method complements the current literature by employing unactivated ketone substrates to prepare products with two adjacent chiral centres, one of which is quaternary.

Oxazolines are a versatile functional group, found in synthetic precursors and functional molecules and materials. They are a common structural feature in many natural products and in medicinal chemistry they are incorporated into synthetic drug candidates as bioisosteres of other functional groups, such as thiazoles and imidazoles. Oxazolines can also be used to prepare poly(2-alkyl/aryl-oxazoline) polymers, which have utility in biomedical fields to prepare hydrogels, nanoparticles for drug delivery and imaging, and polymer-protein conjugates. In an organic synthesis laboratory oxazolines are encountered as ligands in asymmetric catalysis, such as the bis(oxazoline) ‘BOX’ family of compounds.

Synthesis of oxazolines from ketones and isocyanaoacetate esters via a formal [3+2] cycloaddition reaction.

The researchers optimised the reaction with acetophenone and tert-butyl isocyanoacetate, and found that Ag₂O (2.5 mol%) and a dihydroquinine squaramide organocatalyst (5 mol%) promoted the reaction to obtain a quantitative yield of the cis-oxazoline (80:20 cis/trans) in 24 hours with excellent enantiomeric excess (99/93% e.e.). The researchers tested the reaction scope and found that acetophenone derivatives substituted with electron-withdrawing and donating groups (NO₂, Cl, Br, Me) gave the cis-oxazoline products in reliable yields (60 – 99%), fair to good diastereoselectivity (56:44 – 95:5 cis/trans) and excellent enantioselectivities (91 – 99% e.e.). Other examples tested included cyclohexanone, 2-acetylthiophene, deoxybenzoin and acetone as well as aliphatic ketones with a combination of methyl, isopropyl and cyclopropyl groups (63-99% yield, 45:55 – 98:2 cis/trans, 56 – 98% e.e.).

Diagram showing the triple activation of the substrates achieved using a dihydroquinone squaramide organocatalyst combined with a silver lewis acid.

Diagram showing the triple activation of substrates using a dihydroquinine squaramide organocatalyst combined with a silver lewis acid.

The dihydroquinine squaramide organocatalyst used is a composite structure comprising a rigid cyclobutendione ‘squaramide’ and a reduced quinine analogue. The former makes strong hydrogen bonds with carbonyl derivatives while the latter confers chirality on the catalyst and has a Brønsted basic quinuclidine moiety. Quinine is an alkaloid isolated from the cinchona plant, and is the same stuff in anti-malarial tonic that is better washed down with a measure of gin. The reaction proceeds via silver-coordination to the terminal carbon of the isocyanate, accelerating deprotonation of the alpha protons by the quinuclidine base and forming a nucleophilic enoate. The electrophilicity of the ketone is enhanced by the formation of two hydrogen bonds with the N-H bonds of the squaramide, shaping a doubly activated system which rapidly undergoes a formal [3+2] cycloaddition to give the products.

At first glance this seems to be a simple and straightforward transformation, but in reality the authors have succeeded in optimising a reaction for unactivated substrates which has stereocontrol over two chiral centres, one of which is quaternary. Furthermore, the reaction uses a combination of two catalysts reacting via three modes of activation.

To find out more please read:

Enantioselective synthesis of chiral oxazolines from unactivated ketones and isocyanoacetate esters by synergistic silver/organocatalysis

Pablo Martínez-Pardo, Gonzalo Blay, M. Carmen Muñoz, José R. Pedro, Amparo Sanz-Marco and Carlos Vila.
Chem. Commun., 2018, 54, 2862 – 2865
DOI: 10.1039/c8cc00856f

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An Industrial Revolution on the Nanoscale

27 Mar 2018

“What are the possibilities of small but movable machines? They may or may not be useful, but they surely would be fun to make”. In December 1959 Richard Feynman addressed the annual meeting of the American Physical Society at Caltech with a talk entitled ‘There’s Plenty of Room at the Bottom’, imploring the scientific community to start thinking small, like ‘entire 24 volumes of the Encyclopaedia Britannica on the head of a pin’ kind of small. Many quote this lecture as when the notion of nanomachines first entered the scientific sphere – with talk of miniature cars, injectable molecular ‘surgeons’ and machines that place atoms side by side to synthesize any molecule imaginable. The lecture reads like the description of the futuristic setting in ‘Back to the Future’, an exploration of possibilities at a time when we fundamentally lacked the tools to make them a reality.

As in ‘Back to the Future’, which predated yet predicted the emergence of mobile-banking technology, video calling and personal drones, Richard Feynman’s plea for scientists to prepare molecular-scale machines has also become a reality, and for their successes in this field Jean-Pierre Sauvage, Sir Fraser Stoddart and Ben Feringa were jointly awarded the Nobel Prize in Chemistry in 2016.

A group of researchers based in London and Singapore have written a feature article introducing both the foundational work in this field and state-of-the-art examples. Nanomachines are single molecules or molecular assemblies on the nanoscale (this review defines a 1 – 100 nm scope) that have the ability to perform ‘useful work’ upon application of an external energy source. To extract work (often in the form of controlled mechanical movement) molecular machines are designed to operate at a thermodynamically far-from-equilibrium state, maintained by an energy input, with movement occurring as the system relaxes towards equilibrium. At the synthetic level, molecules are designed with components which have restricted translational and rotational movements with respect to each other, and the ability to control these movements is key to obtaining the desired function.

A catalytically active rotaxane synthesised by Nolte and co-workers acts as a tiny epoxidising machine , moving along a polybutadiene polymer

The catalytically active rotaxane synthesised by Nolte and co-workers acts as a tiny epoxidising machine, moving along a polybutadiene polymer

One of the first advances towards the synthesis of nanomachines was by the research group of Jean-Pierre Sauvage, who achieved the templated synthesis of catenanes; structures with two circular molecules that are interlocked like two links in a chain. It was subsequently shown that a catenane motor could be prepared, with one ring rotating with respect to the other in a controlled manner. Fraser Stoddart further contributed to the field with ‘rotaxanes’, composite molecules comprising a ring threaded onto an axle. Nanomachines based on rotaxanes have been developed and include switches, shuttles and ‘molecular elevators’. A state-of-the-art example of a catalytically active rotaxane synthesised by Nolte and co-workers in 2003 demonstrates the potential of nanomachines to revolutionise organic synthesis. The rotaxane is constructed with a magnesium-bound porphyrin, which threads onto a polybutadiene polymer (300 kDa, 98% cis) and catalyses the epoxidation of the double bonds (turnover number: 140, cis/trans ratio of the polyepoxide: 1:4).

Ben Feringa’s electric nano-car, a single molecule with four fluorene ‘wheels’ capable of driving across a copper surface

In 2011 Ben Feringa and co-workers synthesized the worlds tiniest electric car using the same design principles they had used to create a spinning motor in 1999. The car is a single molecule with the ability to propel itself across a crystalline copper surface upon activation by a voltage pulse, with 10 pulses moving the car 6 nm across the surface. The car itself is comprised of a central diyne strut bonded at each end to carbazole ‘axles’. Each axle is bound through alkenes to two fluorene ‘wheels’. The key design elements are the alkenes and two chiral methyl substituents on each axle which forces each wheel to twist out of the plane. For one wheel rotation: an electronic excitation induces trans–cis isomerisation of the alkene causing a quarter turn of the wheel such that it sits adjacent to the methyl group. Next, a vibrational excitation induces helical inversion, allowing the wheel to push past the methyl group another quarter turn. Another isomerisation and helical inversion completes a full rotation. Research achievements like these demonstrate mechanical work on the nanoscale, with the vision of achieving movement on the macroscale via synchronised motion.

These examples represent a small subset of those discussed in the feature article review, which not only spans the current scope of molecular-scale machines, but reviews the design principles guiding their development and the possibilities nanomachines represent in the future of scientific research.

To find out more please read:

Artificial molecular and nanostructures for advanced nanomachinery

Elizabeth Ellis, Suresh Moorthy, Weng-I Katherine Chio and Tung-Chun Lee.
Chem. Commun., 2018, Advance Article
DOI: 10.1039/c7cc09133h

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An Organometallic Toolbox for the Study and Synthesis of Unique N-Heterocyclic Carbenes

05 Mar 2018

N-heterocyclic carbenes (NHCs) are an interesting example of chemical curiosity turned commonplace. NHCs are stable singlet carbenes located within an N-heterocycle, in which the carbon centre bears an sp² hybridised pair of electrons. As early as 1835 chemists were thinking about carbenes, with Dumas’ optimistic (if unsuccessful) attempt to synthesise the methylene carbene by dehydrating methanol. For many years the intentional study of carbenes was considered too demanding because of their instability, and so they remained in relative obscurity. A number of seminal papers changed this preconception; in particular, a report by Wanzlick in 1968 reporting the synthesis of the first NHC-metal complex using mercury and the first synthesis of a stable and isolable NHC by Arduengo in 1991.

Intensification in research and interest in NHCs over the past thirty years may have originated with these seminal reports, but it continues because of the success of NHCs in catalysis: both as strongly σ-donating metal ligands and nucleophilic organocatalysts. One of the most valuable features of NHCs is the ability to tailor their steric and electronic properties by altering the heterocyclic ring and N-bound substituents. Accordingly, the study of NHC reactivity and the development of methods to functionalise NHCs are essential for continued innovation in this field.

Drs Marina Uzelac and Eva Hevia at the University of Strathclyde, Scotland, have written a review article summarising organometallic methods to metallate N-heterocyclic carbenes. The work summarises metallation of all three components of the NHC: the carbenic carbon, the heterocyclic backbone and the N-bound substituents.

The lithiated complex (1), synthesised by treatment of the N-heterocyclic carbene NHC with nBuLi, can be transmetallated at the C4 position by a number of main group elements to give a variety of bimetallic complexes (2). These complexes can be selectively quenched to generate NHC complexes with unconventional regiochemistry (3).

The lithiated complex (1) can be transmetallated at the C4 position by a number of main group elements to give a variety of bimetallic complexes (2). These complexes can be selectively quenched to generate NHC complexes with unconventional regiochemistry (3).

To exemplify the breadth of research discussed; beginning with 2,6-diisopropylphenyl (dipp) substituted imidazole-2-ylidenes, the reactivity of the NHC can be unlocked by initial addition of an alkali metal such as lithium, sodium or potassium (see figure). Metallation at the C4 position occurs by deprotonation of the vinyl protons in the NHC backbone, while a second metal coordinates to the carbene electron pair at the C2 position. From this species (1) it is possible to transmetallate the C4 position with a less-polar metal such as zinc, aluminium, gallium, boron or iron to furnish a bi-metallic NHC (2). Interestingly, addition of an electrophilic methyl or proton source to this species exclusively quenches the C2 position, generating a suite of unconventional complexes (3) with the carbene electron pair positioned on the C4 carbon.

Lithiation of NHC complexes: a) deprotonation of the backbone of NHC-borane complex; b) co-complexation of NHC-zinc complex with alkyllithium affording lithium zincate; c) deprotonation of the abnormal carbene complex.

Reactivity of main-group NHC complexes towards lithiation.

Further studies investigate how different reagents influence the regioselectively and extent of metallation, how metallated NHCs can activate small-molecules such as carbon dioxide, conditions which can lead to the metallation of N-dipp substitutents, as well as products and speciation following treatment of NHCs with a variety of bimetallic reagents.

In addition to expanding the knowledge of NHC reactivity, the work summarised in this review provides a reference and inspiration to researchers seeking to tailor NHCs for unique applications in synthesis and catalysis.

To find out more please read:

Polar organometallic strategies for regioselective C-H metallation of N-heterocyclic carbenes

Marina Uzelac and Eva Hevia.
Chem. Commun., 2018, Advance Article
DOI: 10.1039/c8cc00049b

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