Chemical Science Blog

As a nanocrystal chemist, it pains me to say that sometimes nanoparticles aren’t enough. One strategy for engineering materials with complex functionalities is to embed nanoparticles into a larger host matrix structure. This has been widely studied for polymer-nanoparticle assemblies, but challenges abound for inorganic host matrices. Difficulties stem from problems controlling the microstructure of the host, as nanoparticles tend to accumulate at the borders of individual crystals in polycrystalline materials. Even when higher quality inorganic materials are made in the presence of nanocrystals loadings are below 1 wt%. A possible route to address these issues is by combining inorganic matrices with polymer-functionalized nanoparticles. The polymers can also form into vesicle structures that contain the nanoparticles which are larger and more compatible with characterization techniques.

One of those techniques is cryo-ptychographic X-ray computed tomography (cryo-PXCT), a fascinating and literally cool characterization method to image the internal structure of crystals. This is a variation on imaging techniques used heavily in medicine archeology to non-destructively visualize the interior of humans or artifacts. Cryo-PXCT cools the sample to -180 ^oC and has spatial resolution on the order of 50-70 nm. The researchers synthesized polymer vesicles and worms of approximately 232 nm in diameter and over 1 micron in length, respectively. The nanocomposites were made via an ammonia diffusion method with a solution of calcium chloride containing the polymer nano-structure exposed to gaseous ammonia and carbon dioxide to form CaCO₃ crystals with nano-structure occlusions. The morphology of the nanocomposite crystal altered based on the type of occlusion – the vesicle/calcite combination retained a traditional calcite rhombohedral structure, while the worm/calcite composite crystals featured several rounded sides, an elongated shape, and only three flat faces. These composites possessed 15 – 25 wt% occlusions, significantly higher than prior work with pure nanoparticle incorporation.

Figure 1. SEM images of vessicle/calcite (left) and worm/calcite (right) nanocomposite single crystals.

Once prepared, the researchers examined the crystals by cryo-PXCT to determine the locations of the occlusions within the composites. In the vesicle/calcite composite the vesicles are non-uniformly distributed, with several layers of vesicle density, starting with a vesicle poor core, followed by a vesicle rich region, surrounded by another vesicle poor layer, with a slight vesicle enrichment near the surface. On average the vesicles are 300 nm apart and they maintain their shape, with the larger vesicles preferentially occluding in regions of higher occlusion densities.

Figure 2. Rendering of slice through the vesicle/calcite nanocomposite colored to show both components.

The worm/calcite composite crystals show a very different distribution of occlusions, with an hourglass of low density in the center of the crystal, surrounded by a worm rich zone, and an exterior worm poor layer. These zoning effects are likely determined by the interactions between the polymers and the growing crystal surfaces or the calcium cations in the solution. Cryo-PXCT offers a fascinating way to probe the internal structure of novel multicomponent crystals in three dimensions with nanoscale resolution, providing valuable information to eventually help determine structure-function relationships.

Figure 3. Tomographs of worm/calcite nanocomposites showing the localization of worms in an hourglass shape in the center of the crystal.

To find out more, please read:

Ptychographic X-ray tomography reveals additive zoning in nanocomposite single crystals

Johannes Ihli, Mark A. Levenstein, Yi-Yeoun Kim, Klaus Wakonig, Yin Ning, Aikaterini Tatani, Alexander N. Kulak, David C. Green, Mirko Holler, Steven P. Armes and Fiona C. Meldrum

Chem. Sci., 2020, 11, 355-363.

About the blogger:

Beth Mundy is a PhD candidate in chemistry in the Cossairt lab at the University of Washington in Seattle, Washington. Her research focuses on developing new and better ways to synthesize nanomaterials for energy applications. She is often spotted knitting in seminars or with her nose in a good book. You can find her on Twitter at @BethMundySci.

I feel pretty safe saying that the development of effective antimicrobial drugs (looking at you penicillin!) was one of the most significant pharmacological events of recent history. Unfortunately, the widespread and often indiscriminate use of antibiotics has created an environment where bacteria with evolved drug resistances, colloquially known as “superbugs,” pose a serious threat to global health. While development of new small-molecule antimicrobial drugs is still ongoing, scientists are exploring alternative approaches as well. Of interest are antimicrobial peptides, found in plants and animals as a part of native immune systems. The most common are cationic antimicrobial peptides (CAMPs) comprised of 10-50 amino acids that possess both cationic and hydrophobic subunits and an overall positive charge. This allows them to strongly electrostatically interact with negatively charged bacterial cell membranes without disrupting neutral animal cells. Unfortunately, CAMPs have proved challenging to commercialize with generally unfavorable activities and issues with large-scale manufacture.

Figure 1. General synthetic scheme, structure, and key for components of metallohelices.

Researchers in the UK and Czech Republic recently developed a range of cationic metallohelices (Figure 1) that demonstrate structure-dependent activity against both Gram-positive and -negative bacteria. The diamine ligands form cleanly in the presence of [15]-crown-[5] and upon combination with 2-pyridinecarboxaldehyde and a metal salt self-assemble into the iron or zinc metallohelices. The metallohelices consist of a single enantiomer, as the ligands are optically pure, as determined by NMR and single-crystal X-ray diffraction when possible. Altering the aryl linker unit in the ligand the overall size and shape of the metallohelix in both zinc and iron derivatives. The iron metallohelices are water compatible, with lifetimes exceeding 10 days even in highly acidic conditions, and thus suitable for antimicrobial activity screening.

The researchers used ­in vitro studies to find minimum inhibitory concentrations (MICs), the lowest concentration necessary to see bacterial growth inhibition. While the metallohelices demonstrate the highest activity towards Gram-positive bacteria, some showed lethal effects on Gram-negative E. coli in 20-40 minutes. The 5b helices with a para-benzene bridging group acted most selectively on E. coli with the Λ-5b enantiomer acting as the champion compound and selected for further mechanistic study. The researchers exposed a notorious E. coli strain to inhibitory levels of Λ-5b in an attempt to isolate resistant mutants. The 17 isolates showed only slight tolerance increases rather than true resistance and could be classified into 4 genetic sub-types. Two of the sub-types developed mutations that altered the biophysical properties of their outer membrane, a third lost the ability to produce the vitamin B12 transporter protein, and the fourth lost the pO157 virulence plasmid (which makes this particularly E. coli strain particularly unpleasant). Taken in concert, these 4 sub-types show that tolerance can be derived from disrupting the ability of Λ-5b to interact with and cross the cellular membrane.

Figure 2. Fluorescence images of cells treated with Λ-5b coupled to a fluorescent probe, with arrows pointing to the localization of Λ-5b.

Given data suggesting the ability of Λ-5b to cross the cellular membrane, despite the relatively large of the metallohelices, the researchers used fluorescence microscopy to probe Λ-5b localization by coupling Λ-5b with a fluorescent label. The labeled metallohelix preferentially localized to regions in growing cells that contain anionic phospholipids (Figure 2). This indicates that Λ-5b can cross the cellular membrane and acts internally to the cell rather than simply acting via electrostatic interaction that disrupts the membrane. Overall, this work provides an exciting approach to developing novel anti-microbial drugs that mimic CAMPs with higher stability, activity, and easier synthesis.

To find out more please read:

Metallohelices that kill Gram-negative pathogens using intracellular antimicrobial peptide pathways

Daniel H. Simpson, Alexia Hapeshi, Nicola J. Rogers, Viktor Brabec, Guy J. Clarkson, David J. Fox, Ondrej Hrabina, Gemma L. Kay, Andrew K. King, Jaroslav Malina, Andrew D. Millard, John Moat, David I. Roper, Hualong Song, Nicholas R. Waterfield and Peter Scott

About the blogger:

Beth Mundy is a PhD candidate in chemistry in the Cossairt lab at the University of Washington in Seattle, Washington. Her research focuses on developing new and better ways to synthesize nanomaterials for energy applications. She is often spotted knitting in seminars or with her nose in a good book. You can find her on Twitter at @BethMundySci.

While nanobots are still a thing of science fiction, the development of the fundamental scientific concepts that could lead to highly complex molecular-scale machines has been an active area of research for over 2 decades. Molecular motors rely on isomerization through metastable intermediate states that leads to unidirectional rotation via a rotor portion of the molecule. Initial work utilized molecules that convert high-energy UV-light into this directional motion. However, these systems are limited in their future utility, particularly in biological applications, if they need UV-light for activation. Recent work focuses on driving molecular motors with visible light via a range of approaches, including altering the absorbance profile of the motor molecule itself. Unfortunately, changing the electronics of the molecule has previously substantially decreased the quantum yield while resulting in only slight red shifts.

Researchers in The Netherlands recently developed 2^nd generation molecular motors featuring a mixture of electron-donating and electron-withdrawing groups that exhibit substantial red-shifts. Density functional theory (DFT) calculations predicted that adding cyano- and methoxy- groups to opposite halves of the motor would shift the absorbance past 410 nm. The new molecules were synthesized via a general procedure shown in Figure 1, with yields ranging from 3 – 10%.

Figure 1. General synthetic route to cyano- and methoxy- substituted molecular motors and photoisomerization reaction that results in unidirectional motion.

The addition of the cyano- and methoxy- groups shifted the absorbance maxima corresponding to the HOMO-LUMO transitions to from 422 – 453 nm, an increase of over 60 nm from the parent molecule. When irradiated, the molecules transitioned from their stable ground state to the metastable isomers. These were characterized by UV-Vis spectroscopy, with the emergence of further red-shifted features (Figure 2), and ¹H NMR.  The ¹H NMR spectra were obtained with in-situ irradiation (which sounds like a sweet experimental setup) at various wavelengths and the ratios of several specific protons on the rotor. The derivative 2 with a methoxy- group on the rotor and cyano- groups on the stator demonstrated activity with irradiation at wavelengths up to 530 nm.

Figure 2. UV-Vis absorption spectra of stable (solid) and metastable (dashed) isomers of the molecular motors.

The energy of activation of the rotation for all three derivatives was determined by Eyring analysis and corroborated by DFT calculations. All were around 90 kJ/mol, with 2 requiring the most energy to elongate the central alkene bond and isomerize. The quantum yields of the motors for the forward reaction range from 5.8 – 11.5%, comparable to state-of-the-art UV absorbing motors. The quantum yields for the back reactions were calculated to be significantly lower than those for the forward reaction, which corresponds to the excess of metastable isomers observed under active irradiation. These motors also exhibit high photostability, with no significant change in the ground state absorbance after irradiation and cycling. This is promising for smart materials applications where stability is crucial. This work pushes forward the design of molecular motor systems that utilize visible rather than UV light.

To find out more please read:

Photoefficient 2^nd generation molecular motors responsive to visible light

Lukas Pfeifer, Maximilian Scherübl, Maximilian Fellert, Wojciech Danowski, Jinling Cheng, Jasper Pol and Ben L. Feringa

Chem. Sci., 2019, 10, 8768-8773.

About the blogger:

Beth Mundy is a PhD candidate in chemistry in the Cossairt lab at the University of Washington in Seattle, Washington. Her research focuses on developing new and better ways to synthesize nanomaterials for energy applications. She is often spotted knitting in seminars or with her nose in a good book. You can find her on Twitter at @BethMundySci.

As we transition to an energy future composed primarily of intermittent, renewable technologies, finding ways to store the excess generated charges will be critical. While the general public typically thinks of batteries, another area of massive interest is storing the electrons in a chemical bond. This can be accomplished by creating electrocatalysts that can couple an electric current with chemicals like water and oxygen to generate stable new bonds in molecules for later use as fuels. These renewably generated fuels would then be available whenever needed, like at night. However, finding efficient electrocatalysts composed of earth-abundant materials has proven challenging. Many researchers have turned to nature for inspiration by designing molecules that mimic the active sites of enzymes.

Researchers in the United States used this approach, focusing on creating high-valent iron-oxo species, which others previously identified as the key catalytic intermediates in multiple enzymatic reactions. These types of species have traditionally been synthesized by reacting a reduced iron complex with an oxygen transfer reagent, but the researchers developed a system to generate highly reactive species using electricity as the reaction driving force and water as the oxygen source. The studied catalyst is a commercially available iron(III)-aquo complex with a tetraamido macrocyclic ligand (TAML) as the ancillary ligand (Figure 1B).

Figure 1. A. Cyclic voltammagram of (TAML)Fe in acetonitrile. B. Structure of (TAML)Fe and cyclic voltammagram showing increased current upon the addition of ethylbenzene.

When analyzed by cyclic voltammetry, an electrochemical technique where you cycle the voltage between set points and measure the current output, the (TAML)Fe shows two redox events at around 650 and 1250 mV that the researchers attributed to generating the Fe^IV-OH and Fe^V(O) species (Figure 1). Addition of ethylbenzene, which should react with the Fe^V species, increased the current at voltages of 1250 mV and higher, indicating (TAML)Fe turnover. However, isolating the Fe^v(O) species proved challenging as it reacts rapidly with the (TAML)Fe to form an Fe^IV dimer. This also limits the efficiency of the overall system by decreasing the amount of the most reactive species in solution.

Figure 2. A, B. Products generated by oxidation of various substrates screened with (TAML)Fe for electrocatalysis with isolated yield and calculated conversion in parenthesis. C. Substrates that did not react with the (TAML)Fe complex.

Both the Fe^IV dimer and Fe^V(O) species proved capable of oxidizing C-H bonds in ethylbenzene, but the Fe^V(O) is much more reactive and increases the oxidation rate at high electrochemical potentials. The researchers tested the scope of (TAML)Fe reactivity using a series of compounds with benzylic C-H bonds (Figure 2). They found that the (TAML)Fe performed well with electron-rich and electron-neutral derivatives, with an electron-deficient nitro-substituted derivative showing lower reactivity. Several substrates with non-benzylic C-H bonds showed high selectivity for oxidation at the benzylic C-H bond. (TAML)Fe also showed high electrocatalytic activity for oxidizing alcohols and converted substrates as simple as cyclohexanol and as complex as a steroid to ketones in high yields (up to 97%).

This study of an earth-abundant, stable, and commercially available electrocatalyst acts as a baseline for further studies with other similar metal complexes. Despite the efficiency limits attributed to dimerization, the high stability and selectivity of the (TAML)Fe could lead to its use with a broader range of substrates with varied functional groups.

To find out more please read:

Electrochemical C–H oxygenation and alcohol dehydrogenation involving Fe-oxo species using water as the oxygen source

Amit Das, Jordan E. Nutting and Shannon S. Stahl

Chem. Sci., 2019, 10, 7542-7548

About the blogger:

Beth Mundy is a PhD candidate in chemistry in the Cossairt lab at the University of Washington in Seattle, Washington. Her research focuses on developing new and better ways to synthesize nanomaterials for energy applications. She is often spotted knitting in seminars or with her nose in a good book. You can find her on Twitter at @BethMundySci.

Ever wanted to find a way to replace a carbon-carbon (CC) double bond with another bond that will change the physical and chemical properties of a molecule without significantly altering its sterics? Look no further than a boron-nitrogen bond! BN/CC isosterism involves substituting a CC double bond with a BN bond, which can substantially change the electronic properties of a molecule while keeping it the same size. This isosterism could be a powerful tool in biomedical studies of biologically relevant arene-containing organic molecules, which are plentiful. However, few studies report on the differences in functions cause by substituting a BN bond into an arene. Initial results suggest that the BN compounds can have similar or increased activity and availability when compared to the natural, all carbon molecules.

Figure 1. Image of naturally occuring tryptophan and the BN-tryptophan analogue.

Researchers in the United States synthesized a BN-analogue of tryptophan (Figure 1) for use as an unnatural amino acid (UAA) to study and intentionally alter the properties of proteins. Tryptophan, in addition to making Americans sleepy at Thanksgiving, is relatively rare, but participates in pi system interactions and is the primary source of native protein fluorescence. This makes it an important target for UAA research. The researchers synthesized the sodium salt of BN-tryptophan in a 6-step process, which can be modified to resolve the two enantiomers by chiral HPLC. The BN-tryptophan exhibits noticeably red-shifted absorbance and emission spectra, with the fluorescence maximum shifted by almost 40 nm in the BN compound.

In order to test whether the BN-tryptophan could be incorporated into proteins, researchers incorporated it into media without tryptophan and monitored whether E. coli cells that lacked the ability to produce tryptophan would grow. They found that the cells grew when in the presence of BN-tryptophan, but to a significantly lesser degree than with an equivalent quantity of natural tryptophan. However, cell growth increased when the media contained both BN-tryptophan and natural tryptophan. This suggests that cells will accept BN-tryptophan as a tryptophan analogue, but they don’t tolerate full replacement well.

Figure 2. Representation of the protein sequence, structures of other tryptophan analogues, and fluorescence plot for the studied substrates.

Further studies incorporated BN-tryptophan and three other previously utilized tryptophan analogues into a green fluorescent protein (GFP). For fluorescence to be detected, the analogue must be incorporated into the protein and then accurately read by cells. The BN-tryptophan performs as well or better than the established tryptophan analogues, proving its functionality (Figure 2). The proteins with BN-tryptophan also demonstrate several different properties than those containing natural tryptophan; their fluorescence is red shifted and they are more susceptible to oxidation by hydrogen peroxide. These alterations in activity could prove useful in future studies.

To find out more please read:

Synthesis and characterization of an unnatural boron and nitrogen-containing tryptophan analogue and its incorporation into proteins

Katherine Boknevitz, James S. Italia, Bo Li, Abhishek Chatterjee and Shih-Yuan Liu

Chem. Sci., 2019, 10, 4994–4998.

About the blogger:

Beth Mundy is a PhD candidate in chemistry in the Cossairt lab at the University of Washington in Seattle, Washington. Her research focuses on developing new and better ways to synthesize nanomaterials for energy applications. She is often spotted knitting in seminars or with her nose in a good book. You can find her on Twitter at @BethMundySci.

Metal-organic frameworks, commonly known as MOFs, are one to three-dimensional structures composed of metal ions coordinated to organic linkers. They’ve drawn substantial research interest given their highly porous nature, the extreme tunability of their properties, and, in the early days, relative ease of synthesis. As the field has matured, the syntheses of the organic linkers have increased in complexity. New linkers require substantial expertise in synthetic organic chemistry and can be time and cost intensive to produce. One strategy to avoid the linker-induced bottleneck in MOF development is to create one-pot procedures, generating both the linker and the MOF in a single vessel. While the idea is straightforward, in practice it involves carefully balancing conditions to crystalize the MOF without producing unwanted side reactions.

Figure 1. Reaction motifs utilized for in-situ ligand generation. a) nitro-compound reduction, b) diazo coupling of nitro compounds, c) condensation of boronic acids, and d) imidization of an anhydride and an amine.

Researchers in China recently examined several classes of organic reactions to test the viability of in-situ ligand and MOF synthesis. The basic procedure involves complex ligand generation, formation of small metal clusters, and finally crystallization of the final MOF structure. They chose reduction and diazo coupling of nitro compounds, condensation of boronic acids, and imidization between anhydrides and amines (Figure 1). A rigid, nitro-containing dicarboxylic acid proved the most robust for the reduction studies.  When combined with a hydrated metal salt (copper, zinc, and indium nitrates and manganese chloride), exposed to a protic solvent, and heated, a MOF formed in a single vessel without the addition of a purposeful reductant. This specific ligand didn’t have the proper geometry to produce MOFs via diazo couplings, but a similar motif was used to create a new ligand with greater distance separating the carboxylic acid groups. The researchers dissolved the ligand and various metal salts in DMF, then added proton source, and heated the mixture. The reactions with zirconium, zinc, cadmium, and indium all produced MOFs. The reaction conditions varied from metal to metal, producing different forms of the ligand in-situ that resulted in MOFs of a range of morphologies (Figure 2).

Figure 2. Structures of zirconium, zinc, cadmium, and indium-based MOFs synthesized by ligands generated via diazo coupling.

While these MOFs formed via strong, irreversible reactions, the covalent organic framework literature utilizes the plethora of reversible reactions to expand the scope of possible MOFs. This inspired the researchers to use boronic acid derivatives as a proof of concept. When a ligand with both boronic and carboxylic acid motifs reacted with zirconium or hafnium and formic acid, the researchers isolated a MOF with tetrahedral cages. This approach also proved successful when combining two ligands in a Schiff base synthesis to form a zirconium-based MOF. The reversible reactions required meticulous tuning of the acid source to effectively crystalize and assemble the MOFs. However, the ease of reaction set up allows more rapid screening of conditions than full-scale ligand synthesis.

This relatively simple and efficient strategy for producing new MOFs likely has broader applications than the few reactions currently explored. This will hopefully increase the speed of new MOF discovery with increasingly complex ligands.

To find out more please read:

Constructing new metal-organic frameworks with complicated ligands from “One-Pot” in situ reactions

Xiang-Jing Kong, Tao He, Yong-Zheng Zhang, Xue-Quian Wu, Si-Nan Wang, Ming-Ming Xu, Guang-Rui Si, and Jian-Rong Li

Chem. Sci., 2019, 10, 3949 – 3955.

About the blogger:

Beth Mundy is a PhD candidate in chemistry in the Cossairt lab at the University of Washington in Seattle, Washington. Her research focuses on developing new and better ways to synthesize nanomaterials for energy applications. She is often spotted knitting in seminars or with her nose in a good book. You can find her on Twitter at @BethMundySci.