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

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

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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Come for the colour changing crystals, stay for the science

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.

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 (λmax = 574 nm and 540 nm, respectively), those containing acetonitrile are red (λmax = 624 nm), and crystals trapping acetone, ether and pentane are yellow (λmax = 588), orange (λmax = 598 nm) and red/brown (λmax = 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 δxy 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 δxy), 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

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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Ruthenium Currency for a Hydrogen Fuel Economy

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

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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Synthesis of Maleimide Dyes with Colourful Fluorescent Emissions

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 aminohalomaleimides and alkoxyhalomaleimides

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 aminomaleimides (2a-c) in increasingly non-polar solvents.

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

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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Synthesis of Oxazolines with a Triple Activation Twist

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 catalysed by a multicatalytic system of silver and a dihydroquinine squaramide organocatalyst

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

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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An Industrial Revolution on the Nanoscale

“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

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 transcis 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

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

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

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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Gold Rocks the Casbah

Researchers at the University of Texas have developed an inventive method to deliver molecules into the cell’s nucleus. Advances in gene therapy and the development of drugs that target DNA, the transcription machinery and other regulatory systems all rely on effective transport of molecules into the nucleus. Furthermore, achieving selective delivery of drugs reduces toxicity to non-target organs while maintaining the therapeutic effect.

Towards this aim, the authors delivered liposomes coated with clusters of gold nanoparticles into the cytoplasm. Laser irradiation of the cells heats the nanoparticles to high temperatures resulting in vapourisation of the water-based cytosol, and the transient formation of nanobubbles. The effect of this is an increase in the porosity of the nuclear envelope, enabling the transfer of various macromolecules from the cytoplasm into the nucleus. The authors describe this technique as ‘nanomechanical transduction’ because it is hypothesised that the mechanical effects brought on by the rapid growth and collapse (20 – 50 ns lifetimes) of the bubbles is responsible for the observed increase in porosity.

Local heating of gold nanoparticles and the subsequent formation of nanobubbles occurs due to ‘plasmon resonance’, whereby an electromagnetic field interacts with gold on the surface of the liposome and drives free-electron oscillation in resonance with the incident laser.

A diagram showing nanomechanical transduction. A gold-coated nanoparticle liposome enters the cell and, upon activation by a laser pulse, creates nanobubbles which causes mechanical disruptions in the cell and increased permeability of the nuclear membrane so molecules such as plasmids can enter.

A diagram showing nanomechanical transduction. A gold-coated liposome enters the cell and, upon activation by a laser pulse, creates nanobubbles and mechanical disruption within the cell, resulting in increased permeability of the nuclear membrane.

As a proof-of-concept the authors investigated whether nanomechanical transduction can improve the nuclear localisation of two different types of macromolecule: a dextran polymer labelled with a fluorescent dye, and a plasmid encoding the green fluorescent protein. In the first experiment, cells containing the dextran polymer were incubated with plasmonic liposomes and subjected to a near-infrared laser pulse. Up to 70% fluorescence intensity was observed in the nucleus compared to the cytoplasm, far exceeding the result from control experiments using electroporation to increase cell membrane permeability. In a similar way, nanomechanical transduction resulted in a 2.7 fold increase in the expression of the green-fluorescent protein compared to using electroporation, demonstrating efficient delivery of the plasmid into the nucleus.

The authors entitle their paper ‘rock the nucleus’ and, unintentional reference or not, I think a Casbah (one meaning is the central keep, or citadel, of a walled city) is a rather fitting analogy for the nucleus: the command post of the cell, and safeguard of genetic information. The authors of this work offer a sophisticated yet general method for molecules to breach the walls.

To find out more please read:

Rock the nucleus: significantly enhanced nuclear membrane permeability and gene transfection by plasmonic nanobubble induced nanomechanical transduction

Xiuying Li, Peiyuan Kang, Zhuo Chen, Sneha Lal, Li Zhang, Jeremiah J. Gassensmith and Zhenpeng Qin.
Chem. Commun., 2008, Advance Article
DOI: 10.1039/c7cc09613e

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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Hiding Carbon Dioxide in Oxazolidinones

Sometimes it feels as though the pinnacle of synthetic achievement is represented by 20 step total syntheses (with 10 contiguous stereocentres and 5 fused rings…). The level of chemical complexity that can be fashioned from simple building blocks is undoubtedly impressive, but amid such feats it is important not to lose sight of the elegance and worth of simple chemistry, especially when it aims to play a part in resolving profound challenges. One such challenge, which will increasingly confront future generations, is how to reduce the load of carbon dioxide in the atmosphere. One solution is to ‘fix’ carbon dioxide by integrating it into chemical building blocks of added complexity in a sustainable way.

The porosity and high surface area of metal organic frameworks (MOFs), a class of three-dimensional coordination networks, proffers them as ideal materials for capture and storage of carbon dioxide. A team of researchers have designed a MOF which consumes carbon dioxide in a different way: by transformation into value-added chemicals. The group have developed a catalytic MOF embedded with lewis-acidic copper centres capable of converting aziridines to oxazolidinones by the addition of carbon dioxide. Oxazolidinones are used as auxiliaries in chiral synthesis, and are structural components of some antibiotics.

The MOF, termed MMPF-10, is a metal-metalloporphyrin framework constructed from a copper-bound porphyrin ring chemically modified to incorporate 8 benzoic acid moieties, generating an octatopic ligand. These carboxylic acids groups form a second complex with copper in situ, termed a ‘paddlewheel’ for its appearance, with the formula [Cu2(CO2)4]. The resulting network contains hexagonal channels measuring 25.6 x 15.6 Å flanked by four of each of the two copper complexes. With 0.625 % of the catalyst at room temperature, 1 bar CO2 pressure, and in a solvent free environment, MMPF-10 catalyses the transformation of 1-methyl-2-phenylaziridine to yield 63% of the product.

metal-metalloporphyrin MOF catalyses catalyzes carbon dioxide fixation aziridines to oxazolidinones

Topology of MMPF-10 showing hexagonal channels in a) and c), and pentagonal cavities in b). Turquoise: copper, red: oxygen, grey: carbon, blue: nitrogen.

This work, a simple reaction to prepare oxazolidinones, shows that carbon dioxide can be fixed in specialised synthetic building blocks in a sustainable way. This is the way the first paragraph ended, ‘in a sustainable way’, because the challenge of developing such a reaction is two-fold: it must use carbon dioxide, and the reaction conditions must be sustainable. There will be no beneficial offset if the reaction uses a lot of energy, requires many resources, or generates larges quantities of waste. In this reaction the researchers have remained mindful of developing a mild, solvent-free reaction with low catalyst loading employing an earth abundant metal, reflecting an earnest aim to develop practical and sustainable chemistry.

To find out more please read:

A metal-metalloporphyrin framework based on an octatopic porphyrin ligand for chemical fixation of CO2 with aziridines

Xun Wang, Wen-Yang Gao, Zheng Niu, Lukasz Wojtas, Jason A. Perman, Yu-Sheng Chen, Zhong Li, Briana Aguila and Shengqian Ma
Chem. Commun., 2018, Advance Article
DOI: 10.1039/c7cc08844b

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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Shoot the Messenger: Circular DNA-Graphene Oxide Material Targets mRNA in Living Cells

Schematic of the circular DNA cDNA/GO graphene oxide platform fabrication for intracellular mRNA messenger RNA imaging and gene therapy.

Scheme showing how cDNA/GO enters the cell and interacts with mRNA

Did you know that the combined length of DNA in your body’s cells is a number so large that the only references I could find use cosmic distances as a reference? Try twice the diameter of the solar system, or the distance to the moon and back 1500 times. Despite the complexity and infinite detail encountered when studying science, it is often something so simple as size that gives us pause. How can DNA be both uncomprehendingly huge and tiny at the same time?

The major function of DNA is to encode proteins, a process which begins with the transcription of genes into single-stranded messenger RNA (mRNA) molecules. It is mRNA that is directly translated into the strands of amino acids which fold to form proteins.

A team of researchers at Fuzhou University in China have developed a graphene oxide and circularised single-stranded DNA (cDNA/GO) hybrid material capable of penetrating living cells and binding mRNA. The material’s utility is shown in two practical applications: mRNA imaging and nucleotide therapeutics. The authors chose the mRNA of survivin and c-raf kinase as targets, because the enzymes are involved in carcinogenesis, and the mRNA are overexpressed in cancer cells and can be used as biomarkers.

cDNA was chosen for its increased stability over linear single-stranded DNA, which is rapidly degraded in vivo by exonucleases. For mRNA imaging the material is designed with a fluorescent dye coupled to the cDNA. GO was chosen as a hydrophilic delivery scaffold capable of adsorbing cDNA and quenching the dye. When cDNA/GO was incubated with HeLa cells (a cancer cell strain) a time-dependent increase in fluorescence was observed in the cytoplasm. Fluorescence is restored when cDNA encounters the target and desorbs from the GO to form a duplex with the mRNA.

CLSM images acquired for HeLa cells treated with both survivin and c-raf targeted cDNA/GO for duplexed intracellular mRNA imaging

The mRNA of both survivin and c-raf kinase can be imaged in living cells with cDNA/GO.

The researchers also probed whether the material might serve as a therapeutic agent: if formation of the cDNA-mRNA duplex blocks translation it may reduce the load of c-raf kinase and survivin in the cell and influence cancer cell growth. Accordingly, the researchers found that when the HeLa cells were incubated with cDNA/GO, cell proliferation was inhibited in a dose-dependent manner.

This research contributes a robust design which can be applied to diverse mRNA targets because optimisable properties such as stability, bioavailability and selectivity are largely independent of the sequence of nucleotides.

To find out more please read:

Circular DNA: a stable probe for highly efficient mRNA imaging and gene therapy in living cells

Jingying Li, Jie Zhou, Tong Liu, Shan Chen, Juan Li and Huanghao Yang
Chem. Commun., 2018, Advance Article
DOI: 10.1039/C7CC08906F

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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