Dr. S, Rhodium and the Red Crystal

The new university semester for undergraduates around the world has just started recently. This time, I would like to share some of my fond memories about an inspiring chemistry teacher – Dr. S, and my indirect connection to the Nobel Prize-winning English chemist – Professor Geoffrey Wilkinson. While I will not explicitly state the identity of Dr. S, the smart readers will be able to find out somewhere in this article.

I have taken Chemistry as one of my A-Level subjects when I was studying in London about 10 years ago. One of my chemistry teachers, Dr. S, is someone who has since left a lasting impression on me, and he is probably one of the most admirable teachers I have ever met in school. He is knowledgeable, has a great British sense of humor, and is really committed to help and give advice to his students. I have had a lot of chances to interact with him during my A-Level studies. From all these interactions, I can feel his intense knowledge about the various aspects of chemistry, and furthermore, his wise insights about life. Often, he quite simply dictated the notes onto the whiteboard, without any reference to the textbooks, because, as he has said before, ‘I have taught this course for like 30 years.’ He loves his wife and family, and enjoys a decent glass of red wine. He has always demonstrated a genuine passion for his field. I still vividly remember the excitement he had when he was teaching my class about the various oxidation states of transition metal complexes, and the beautiful range of colors exhibited from those co-ordination compounds. His passion has infected me, too. He has motivated me to learn way beyond the boundary of exam syllabus, digging deep into the concepts of organic chemistry and co-ordination chemistry. These further studies have certainly benefited me in my future university work.

One great aspect regarding Dr. S is that, at the end of each lesson, he would always ask, ‘Does anyone have any questions or comments?’ To me, this is exactly the correct attitude to approach education. After all, the whole process of education should come from both directions, not merely about spoon-feeding some infants not knowing their places. The teacher can just learn as much as the students when the students are willing to provide feedback. The room to allow comments can provide a more liberal atmosphere for everyone, and can lead the students to pose appropriate questions and to generate discussions. This inspiration is something I have always borne in mind since then, and I still ask this to my students whenever I am serving as a teaching assistant in my department.

When I was studying chemistry in my undergraduate years, I had the opportunity to come across the wonderful work of the English chemist, Sir Geoffrey Wilkinson. By accident, I discovered an old research article of which Dr. S was co-authoring with Professor Wilkinson! Soon, I learnt that Dr. S was actually a PhD student from Professor Wilkinson’s research group in the early 1970s. Dr. S has told me on one occasion that he did his PhD in Imperial College, London, yet I have never drawn this connection myself. No wonder Dr. S has always been fascinated with transition metal chemistry! I also feel extremely fortunate that I can have such an indirect connection to Professor Wilkinson, someone I have always admired. Now, let me tell you a bit about Professor Wilkinson’s work, and Dr. S’s contribution to organometallic chemistry.

While Professor Wilkinson’s initial independent research career concentrated on nuclear chemistry, he soon decided to pursue his research in something that has fascinated him since his student years – the chemistry of transition metal complexes. Soon after, he worked in the US through the early 1950s. In Harvard, he and Woodward were instrumental in solving the structure of ferrocene, one of the most famous organometallic compounds in the chemistry world. In mid-1955, he was appointed to a chair professorship of Inorganic Chemistry in Imperial College, UK. He has been there ever since and has placed intense focus in the chemistry of transition metal compounds. He has worked a lot on the chemistry of ruthenium, rhodium and rhenium organometallic compounds, and the developments of many of these complexes have led to advances in the field of homogeneous catalysis. Other than ferrocene he has also led to the development of compounds like Wilkinson's catalyst, hexamethyltungsten and some elimination-stabilized alkyl complexes of transition metals.  His pioneering work in organometallic chemistry has led him to a Nobel Prize in 1973.  

Since last year, I have been working on rhodium-catalyzed hydroboration and hydroformylation reactions in my research, and have also been preparing analogous versions of the Wilkinson’s catalyst. Thus, I can totally appreciate the insightful achievement Professor Wilkinson has contributed to the field of homogeneous catalysis. Without his hard work, the development in organotransition metal chemistry would certainly less likely to be as vibrant as now. Indeed, I am proud of involving and contributing to this wonderful research field!

I am so fortunate to have met such an inspiring chemistry teacher, and more so, we can both stand on the shoulders of a giant, who encourages us to see further in the world of Chemistry. Thank you, Dr. S and Professor Wilkinson!

by Ed Law

4/10/2016

Reference:

1. A. Shortland and  G. Wilkinson

Hexamethyltungsten

J. Chem. Soc., Chem. Commun., 1972, 318.

DOI: 10.1039/C3972000318A

2. A. J. Shortland and G. Wilkinson

Preparation and properties of hexamethyltungsten

J. Chem. Soc., Dalton Trans., 1973, 872.

DOI: 10.1039/DT9730000872

Optoelectronic P DADdy

Figure 1. Synthesis of building block (1).

Speaking of Organic Electronics, I would like to share with you another recent article regarding some interesting organo-phosphorus conjugated compounds. [1]

In the paper, the researchers have developed synthetic routes towards novel phosphorus-containing π-conjugated compounds, by using an interesting phosphorus reagent known as (Tipp)P(SiMe₃)₂ (Figure 1). It was great to observe that the phosphorus compound (1) was not as air-sensitive as one might usually expect. Due to the presence of the two electron-withdrawing carbonyl groups, the yellow-colored compound (1) was stable enough to survive column chromatography.

Figure 2. Building up the conjugated pathway, as in (2).

On the other hand, the DAD (Donor-Acceptor-Donor) type compound (2) was synthesized by a Stille coupling at elevated temperature (Figure 2). It should be noted that the (mono or bis) tributylstannyl-thiophene is often a good candidate in these coupling reactions, especially when the thiophene units are need for organic electronics or functional materials. It is also interesting to note that the presence of the bulky TIPP group is essential for a successful coupling in this case.

X-ray crystallographic structures have been obtained for some of the compounds, and UV/vis spectra and cyclic voltammograms have also been acquired. When these compounds were compared with their corresponding nitrogen analogues, the LUMO energies of the organo-phosphorus compounds were found to be lower. The observations implied σ*-π* electronic couplings in these compounds. These phosphorus compounds were highly stable from TGA studies (likely due to the 2 carbonyl EWGs), which made them potential candidates for uses as organic materials.

Figure 3. Synthesis of the heavily conjugated organic molecule (3).

For the next stage, the compound (2) was used to synthesize the conjugated polymer (3) though sequential Stille coupling reactions (Figure 3). The researchers found that the optical bandgap of (3) was much narrower than its nitrogen counterpart. So, this polymer should be a great contender as a low bandgap conjugated polymer.

I like this paper because the novel organo-phosphorus compound looks interesting and useful to me. In the past, I have read about phospholes, and also some of the zirconium-based methods for their syntheses. A novel strategy has been used in this paper, and this approach is something I am not aware of. As a researcher working a lot with phosphines and phosphorus-based compounds, I find this article a rewarding one to read!

by Ed Law

27/9/2016

Reference:

1. Thieno[3,4-c]phosphole-4,6-dione: A Versatile Building Block for Phosphorus-Containing Functional π-Conjugated Systems 

Youhei Takeda, Kota Hatanaka, Takuya Nishida, and Satoshi Minakata

Chem. Eur. J., 2016

DOI: 10.1002/chem.201602392

Grassy Butterfly Dreams

Figure 1. Structure of the 'Butterfly' Compound.

I have always been interested in the field of Organic Electronics, and it is indeed a research field I would love to be involved in! To me, organic compounds are not merely about biological stuff. It is often the optical and electronic – optoelectronic – properties of the organic compounds that make them useful contenders as novel functional and electronic materials. Too often, it is through an understanding of the chemistry that we can fine-tune the chemical properties of the target compound in question, and lead to better functional materials for the future. I have recently read a paper about an organic material, and it is exactly bearing the above philosophy in mind. [1]

The compound has a potential as novel organic light-emitting diode (OLED) material (Figure 1). The compound can display the property of thermally activated delayed fluorescence (TADF), and for a good candidate in this field, the compound should  (a) have a small energy gap between the lowest singlet and triplet states; (b) a high intrinsic photoluminescence quantum yield (through orbital overlap) and (c) a relatively short delayed lifetime. From the data, the compound seems to do pretty great for all 3 requirements. Thus, this compound has a nice potential to serve as a green fluorescent OLED.

The shape and design of the green-colored compound are interesting. It resembles te shape of a butterfly, because the overall structure is a donor- π system-acceptor- π system-donor type (D-π-A-π-D). The donor group is phenoxazine (PXZ), while the acceptor group is a pyrimidine derivative.  

Figure 2. Buchwald-Hartwig Coupling approach towards the family of target compounds.

The synthesis of the compound was through a double Pd-catalyzed Buchwald-Hartwig amination of the phenoxazine nucelophile to a di-bromophenyl pyrimidine derivative (Figure 2). An X-ray crystal structure could also be obtained, and the molecular structure really resembled a butterfly! It is notable that the twisting angle between the PXZ and the phenyl ring is large, very much due to the steric hindrance provided from the PXZ component. This design is important because by the incorporation of a larger steric demand, it can lead to a spatial separation of the frontier molecular orbitals, lowering the singlet-triplet energy gap as a result (Criterion a).

Cyclic voltammograms have been obtained to probe the HOMO / LUMO energy levels of the butterfly compound. The absorption spectra of the compound provides nice insights into the electronic characters of the compound. An intense band with charge-transfer character signifies the transition from the electron-donating PXZ group to the electron-withdrawing pyrimidine unit. It is also noted that the absorption profiles overlap with that of a commonly used host material, CBP, meaning that in a doping system, effective energy transfer from CBP to this butterfly compound will be possible.

At the pyrimidine unit, there is a substituent at the 2-position, and this substituent can impact the property of the green-colored compound. It is found that the delayed fluorescence (DF) can be reduced by a bulkier 2-substituted group. This can suppress the non-radioactive decay and also other undesirable quenching processes due to triplet excitons, thus improving the performance at high luminance. 

After playing with the chemical aspects, the researchers then tested the novel compounds’ potential as TADFs in OLED devices. All the compounds lead to green light emission in the systems, possess good thermal stability, demonstrate very effective up-conversion (T1 > S1), achieve high intrinsic photoluminescence quantum yield, and perform well at high luminance conditions. The results are promising for the compounds involved.

Impressive work!

by Ed Law

26/9/2016

Reference:

1. Optimizing Optoelectronic Properties of Pyrimidine-Based TADF Emitters by Changing the Substituent for Organic Light-Emitting Diodes with External Quantum Efficiency Close to 25% and Slow Efficiency Roll-Off

Kailong Wu, Tao Zhang, Lisi Zhan, Cheng Zhong, Shaolong Gong, Nan Jiang, Zheng-Hong Lu, and Chuluo Yang, Chem. Eur. J. 2016, 22, 1 – 8.

DOI: 10.1002/chem.201601686

No RHO enSNAREs me

I have read the latest issue (August 2016) of Nature Reviews Molecular Cell Biology, and two of the articles on cell signaling are related to some of the topics I was highly fascinated in when I was doing biochemistry in my undergraduate years. The 2 review articles are about Rho family of GTPases and SNARE complexes. I recommend these articles to those studying in biochemistry or molecular cell biology in university.

The first article is about the regulation of Rho GTPases and the proteins that regulate this particular family of G proteins [1]. Rho proteins are important because it can mediate the changes in the structure of the actin cytoskeleton, when it is subject to a number of upstream signals originated from extercellular stimuli. When it is activated, the Rho protein can bind to a number of proteins that have action on actin, such as ROCK, N-WASP, MRCK, WAVE 2, to name a few examples. That will affect the G-Actin / F-Actin equilibrium, and affect the assembly or disassembly of the actin cytoskeleton. The downstream signaling can lead to effects such as cell migration, endosomal sorting, focal adhesion,  and the formation of cytoskeletal structures such as filopodia and lamellipodia.

I would illustrate with a quick example regarding actin action at the endosome (Figure 1). When Cdc42, a Rho GTPase, is activated, it will in turn activate 2 down stream proteins, N-WASP complex, and CIP4. N-WASP will in turn activate the next down stream protein, Arp2/3 complex. N-WASP, CIP4, Arp2/3 will associate with each other as a multi-protein complex around the internalizing endosome. F-actin will anchor itself at the protein complex, and it will draw the internalization of the endosome, facilitating the endocytosis. 

Figure 1. Example of Rho GTPase signalling.

The review points out that, not only the obvious GDP-GTP recycling can regulate the spatial-temporal action of the GTPase, there are other means that the G Protein can be regulated. The formation of specific protein complexes with the proteins associated with the action of GTPase (GEF, GAP, GDI), and post-translational modification (PTM), which the latter is a hot topic in chemical biology, are also possible means.   

I would like to draw your attention to the fact that, as stressed in the article, a phsophorylation on the Rho GTPase can have various effects on the signaling. It can inactivate the GTPase through a GTP-GDP recycling. It can mark the GTPase as a target for sequestration. It can also direct it towards the action of E3 ligase and lead it to protein degradation via the proteasome. Finally, it can lead to a subcellular localization, and in some case (such as RhoU), the GTPase will be directed towards the endosomal membrane, relevant for endocytic processes.

Figure 2. SNARE-mediated membrane fusion.

The second article is about the SNARE complex (Figure 2), which in most cases mediates intracellular membrane fusions [2]. The basic cycle is as follows. The 2 membranes, which have SNARE proteins on their respective surfaces as ‘contact points’, move towards each other. A docking event takes place and the SNARE proteins associate with each other to lock up the 2 membranes. The pulling action increases the membrane curvature, and ‘breaks’ up the inside by exposing the interior face of membrane. This leads to the contact between the distal sides of the 2 membranes, forming a fusion pore as a result. Finally, hen the curvature is relieved, the 2 membranes are fused together as a new membrane. After that, the SNARE complexes disassemble and can be recycled, via hydrolysis of ATP, to facilitate another round of membrane fusion. Though a basic picture is known, we have to be cautious that some of the detailed points are still controversial and demand further confirmation.

There are already a number of informative review articles regarding the SNARE complex [3], yet this one has a slightly different focus. It is found that, when the assembly of SNARE complex is carried out in vitro, it is far slower in rate than the effective process that takes place in vivo. This obviously suggests there are some missing components in the in vitro conditions that hinder that from being a good model for the real process. Thus, a number of techniques have been used to study and understand the action of the SNARE complex in vivo, and they are reviewed in the article. For example, X-ray crystallography has been used to study the complex formd from SNARE proteins and other accessory proteins (Sec1-Munc18 protein for example), shedding light on the mechanism. A particularly interesting X-ray structure is related to neuronal SNARE complex – its binding to Synaptotagmin 1, the synaptic protein that serves as a Ca²⁺ sensor and is involved in neuronal exocytosis and regulation of release of neurotransmitter. On the other hand, cryo-electron microscopy has also been employed to visualize the disassembly of SNARE complex by NSF and SNAP proteins. Of course, better attempts for the re-constitution of the cell systems in vitro has also led to a more realistic model for the in vivo process.

I have also found a further paper which links up the 2 concepts together, and it should be very useful for us to see how all these mechanisms (and other such as calcium and phosphoinositide signalling) working together in a cellular system [4].

Hope you find all these useful!

by Ed Law

23/8/2016

Reference :

1. Regulating Rho GTPases and their regulators, Richard G. Hodge and Anne J. Ridley,

Nature Reviews Molecular Cell Biology, 2016, 17, 496–510. doi:10.1038/nrm.2016.67

2. Chaperoning SNARE assembly and disassembly, Richard W. Baker and Frederick M. Hughson

Nature Reviews Molecular Cell Biology, 2016, 17, 465–479.

doi:10.1038/nrm.2016.65

3. For example, see: (a) SNAREs — engines for membrane fusion, Reinhard Jahn and Richard H. Scheller, Nature Reviews Molecular Cell Biology, 2006, 7, 631-643; (b) SNARE-mediated membrane fusion, Yu A. Chen and Richard H. Scheller, Nature Reviews Molecular Cell Biology, 2001, 2, 98-106.

4. The role of Rho GTPases and SNAREs in mediator release from granulocytes, Paige Lacy, Pharmacology & Therapeutics, 2005, 107, 358 – 376.

Would the Piano Stools please stand up?

Figure 1. A d6-piano stool complex for Iridium.

I have recently read an article from Chem. Commun. on the chemistry-biology interface [1]. It should be fascinating to both researchers in chemistry and biology alike, as the research is about the application of an artificial metalloenzyme in catalysis.

Modular in nature, the metalloenzyme consists of a host protein and the synthetic metal complex. In order to incorporate the metal catalyst to the protein host, a well-established way, for which the researchers have adopted, is the biotin-streptavidin technology.

The metal complex the researchers were using belonged to the class of d6-piano stool complex, and in this particular case, the metal was iridium (Figure 1). This type of piano-stool complexes seemed to be stable in biological environment, thus providing a benefit for the development of bio-catalysis. In order to make their catalyst more active in a biological environment, they have devised a ‘shielding strategy’, where they coated silicon nanoparticles as a protective layer on the metalloenzyme (Figure 2).

Figure 2. The design of the catalyst architecture.

The synthesis of the iridium complex involved the reaction of a protected TFA salt of the precursor di-amine with [Cp*IrCl₂]₂ in the presence of triethylamine at room temperature, resulting in the iridium catalyst with satisfactory yield (Figure 3).

Figure 3. Synthesis of the iridium complex.

The metalloenzyme, henceforth known as an ATHase, was covalently anchored onto the silicon nanoparticles (Figure 2). After self-assembly and the poly-condensation of silanes, a protective layer could be formed and embedded the ATHase inside the 'silica core'. The nanoparticles were visualized by scanning electron microscopy.

Figure 4. Catalysis of imine reduction by ATHase.

The ATHase was used to catalyze an imine reduction reaction (Figure 4). Depending on the specific mutant employed, it could give rise to a specific enantiomer as the product. In a nutshell, the conversion, enantioselectivity and turnover number of the silica-protected ATHase were impressive. What was notable was that, when the researchers compared the data of the catalysis of the metalloenzyme with or without silica-protection, the results were more or less comparable, signifying that the extra silica protection has not led to a negative impact to the catalysis. The silica-protected catalyst could be recycled and re-used, with almost the same enantiomeric excess in subsequent runs.

In terms of the context of the research aim, the authors would like to explore the applications of their ATHase in biological scenarios. Thus, they used the ATHase to carry out a reaction well known to anyone in biochemistry : the conversion of NAD⁺ to NADH. They have used absorbance spectroscopy (340 nm) – another obvious technique for biochemists – to monitor the conversion. They observed that the silica-protected ATHase had a somewhat better turnover number as compared to the non-protected version.

Another interesting aspect was that the researchers attempted to test their ATHase in vivo, which meant they did the reduction in a cellular ‘soup’. Using cell lysate of E. coli and other cellular media, satisfactory turnover numbers could be achieved, and the results were indeed better than the homogeneous metalloenzyme. They rationalized that, since the homogeneous metalloenzymes did not possess any protective layers, the catalytic activity was lost in the presence of cellular debris in the cellular ‘soup’. Thus, the silica ‘shell’ was able to protect the ATHase in the cellular media, while at the same time allowing the ATHase to carry out its mission. Even an imine reduction in urine (!!) could be achieved (TON= 4500)! 

The methodology has the added advantages that it could be conducted in physiological conditions – room temperature, pH 7, making it a stunning approach for bio-catalysis.

Impressive!

by Ed Law
20/8/2016

Reference:

1. Immobilization of an artificial imine reductase within silica nanoparticles improves its performance

Martina Hestericová, M. Rita Correro, Markus Lenz, Philippe F.-X. Corvini, Patrick Shahgaldian and Thomas R. Ward

Chem. Commun., 2016, asap

DOI: 10.1039/c6cc04604e

Doping the Iron out

The use of recyclable catalysts in chemical reactions seems to be a hot research area! I have looked the a recent issue of Chem. Commun. and have read another nice paper about the immobilization of a ferrocene-containing phosphine onto iron nanoparticles, through the use of dopamine as a linker [1]. The corresponding rhodium and palladium complexes of the magnetic ferrocenyl-phosphine ligands were prepared, and they have been shown to be great and recyclable (hence re-usable) catalysts for hydroformylation (Rh) and Heck coupling reactions (Pd) respectively.

Figure 1. Synthesis of the ligand and preparation of the metal complexes.

Let me show you the design of this modular ligand (Figure 1). First, the ligand was a ferrocenyl phosphine known as BPPFA. This phosphine ligand was first conjugated to dopamine. When the dopamine-linked phosphine was sonicated with Fe₃O₄, the phosphine was thus functionalized with magnetic nanoparticles, and the structure was designated as Fe₃O₄@dop-BPPF. These magnetite nanoparticles were formed as a black precipitate, and it was notable that they could be collected and separated from the reaction mixture through the use of a piece of magnet.

When  Fe₃O₄@dop-BPPF was allowed to react with a slight excess of [Rh(nbd)Cl]₂ or [Pd(C₃H₅)Cl]₂, the resulting rhodium or palladium complexes were afforded respectively.

Why did the researchers use dopamine as a linker? They rationalized that the 2 hydroxyl groups on dopamine, which were arranged in a 1,2 relationship, was great as a bidentate ligand and thus could provide tighter binding to the iron oxide, leading to higher stability for the resulting catalyst.

Before submitting to rounds of catalysis, the chemical and magnetic properties of these compounds were first investigated with a number of techniques. Besides NMR and FTIR spectroscopy, transmission electron microscopy, selected area electron diffraction, and X-ray diffraction studies have also been employed to access the appearances of these ligands and metal complexes.

One aspect I find particularly fascinating is the investigations of the magnetic properties of the nanoparticles. It is related to a phenomenon known as ‘magnetic hysteresis’, and the concept of hysteresis is actually important in the field of Nonlinear Dynamics, something I am also highly fascinated in.

The researchers have found that, the dop-BFFP phosphine’s magnetic properties, namely its coercivity (H_c) and remanence (M_r), were not affected by the functionalization with iron nor complexation to rhodium or palladium. While the saturation magnetization value was decreased slightly upon the iron nanoparticle functionalization and complexation with metals, the bulk magnetization has not been affected, which meant that the magnetic properties were retained even if the iron particles were functionalized with the phosphine and complexed to the metal center, and this would benefit the separation process at the end of a catalytic trial through the use of a magnet. Indeed, if we look at the magnetic hysteresis loops of  Fe₃O₄@dop-BPPF, Fe₃O₄@dop-BPPF-Pd and Fe₃O₄@dop-BPPF-Rh at room temperature were almost overlapping with each other, confirming the above arguments.

Figure 2. Hydroformylation catalysis.

Next, the researchers used their newly-prepared metal complexes to do 2 catalytic reactions – Rh-catalyzed hydroformylation and Pd-catalyzed Heck coupling reaction. Not only they wanted to investigate the conversion and substrate scope, a prime aim was to see whether these nanoparticle catalysts could be recycled and recused efficiently.

For the hydroformylation (Figure 2), they have focused much of their studies on the substrate styrene. They have been able to optimize the reaction conditions and the branch to linear selectivity was reasonably high, with the branched product as the predominant. They have also found that styrene substituted with electron withdrawing groups (such as NO₂ and Br) gave a very high branch to linear selectivity of 99:1. Linear alkenes, such as 1-octene, gave the opposite selectivity, with the normal isomer as the predominant product (b : l = 0 : 100).

The hydroformylation catalyst could be recycled and re-used for 3 further times, and then a gradual loss of reactivity was observed, and the researchers attributed to a higher pressure in the reaction system, leading to catalyst leaching.

Figure 3. Heck coupling catalysis.

The Pd catalyst was subject to Heck coupling reaction, with styrene and iodobenzene as the 2 coupling partners. Reaction temperature, choice of base, and solvent system were optimized. When the less reactive bromobenzene was employed instead of iodobenzene, full conversion could be achieved through a longer reaction time, and this signified the stability of the new catalyst.

With the styrene / iodobenzene system, the Pd catalyst could also be recycled and re-used, by simply using an external magnet to separate the catalyst from the reaction mixture. The clean catalyst could be re-used for at least 9 more times, which was very impressive.

Figure 4. Cobalt-phosphine catalyzed hydroarylation - a potential reaction to explore?

This is great research, and the authors are working on other catalytic reactions to explore the scope of their novel ligands. Since they have been using styrene as a substrate, that fact rings a bell on me as I remember reading an article about a cobalt-catalyzed hydroarylation of styrene from J. Am. Chem. Soc. [2]. That could also be an interesting and potentially useful reaction to try, too!

by Ed Law

19/7/2016

Reference:

1. Magnetic nanoparticle-supported ferrocenylphosphine: a reusable catalyst for hydroformylation of alkene and Mizoroki–Heck olefination

M. Nasiruzzaman Shaikh, Md. Abdul Aziz, Aasif Helal, Mohamed Bououdina, Zain H. Yamani and Tae-Jeong Kim

RSC Adv., 2016, 6, 41687–41695

2. Regioselectivity-Switchable Hydroarylation of Styrenes

Ke Gao and Naohiko Yoshikai

J. Am. Chem. Soc., 2011, 133, 400–402

Fatten up a Few Gear

Ever since my undergraduate years in biochemistry, I have developed an intense fascination with the chemistry and biology of membranes. While most elementary textbooks on biology have often portrayed the cell membrane as a pair of lines (or curves in some cases), this organelle is actually one of the most dynamic components of the cell, and the chemistry and molecular biology behind it serve as the driving force for many wonderful molecular phenomena. 

Now, I am working in the field of bi-phasic catalysis, and it is quite gratifying to see that there are parallels between my field and that of membrane science. If possible in the future, membrane chemical biology is certainly a research field I would love to explore! This week, I have read a great article in Journal of American Chemical Society about lipid membrane and hydrogel formation [1], and I would like to share with you here.

Figure 1. Hydrogel network formation through the catalysis of a lipid membrane.

The paper is about the use of a negative-charged lipid membrane as a catalyst to facilitate the formation of a hydrogel network (Figure 1). A hydrogel is defined as a polymeric, gel-like macromolecular structure, which is made by the cross-linking of polymer chains. Hydrogels have been used in drug delivery, tissue engineering, supramolecular catalysis [2c], and many other fields.  The self-assembly and aggregation of the resulting fibrous hydrogel network has to be designed in a way so that the material properties of the resulting gel fiber can be controlled. On the other hand, the spatial position of hydrogel formation has to be carefully defined, to serve the aim of controlled release or delivery of, for example, drug molecules.

The researchers have found that a negatively-charged lipid membrane can be used as a catalyst to form supramolecular hydrogel networks. The negatively-charged liposomes can be used to catalyze the formation of a gelator molecule 3, and they have been able to achieve spatial control – the gelator molecule 3 is formed near the membrane, so that the resulting hydrogel networks can be formed in this well-defined area. The mechanism involves the generation of a local proton (H⁺) gradient - due to the prevalence of the negative charges. The high proton concentration facilitates the acid-catalyzed formation of hydrazone– the functional group in the gelator molecule 3.

For the chemistry, the first stage to form the hydrogel is a reaction between a hydrazide 1 and an aldehyde 2 to form the hydrazone derivative 3. At neutral pH, this reaction is very slow. Yet, the researchers have established that, when an acid or aniline is added, the reaction rate improves a lot. The structure of the hydrazone enables itself to self-assemble and forms a fiber-like structure, and aggregates towards a cross-linked network, resulting in gelation of the surrounding solvent.

The researchers are interested to see whether a negatively-charged lipid membrane can somehow catalyze the formation of hydrazone 3 and also the formation of the final hydrogel network. Their rationale is that the negative charges on the membrane can induce an increase in the proton concentration, leading to a decrease of pH and renders the chemical environment more acidic. They believe this acidic environment may catalyze the formation of the hydrazone stucture and subsequent hydrogelation.

The reaction is carried out in the following way. The hydrazide 1 and the aldehyde 2 are mixed in a defined ratio in a buffered solution at neutral pH. After that, the negative-charged liposome solution is added, and the reaction is carried out at room condition. As observed, the gelator molecule 3 is formed and eventually gelation of solvent occurs, signifying the complete formation of the hydrogel network.

How did the researchers access whether catalysis occurred from the liposome? They employed a parameter known as minimum gelation concentration (MGC). They have first measured a control value – where no liposome is added to 3 at pH 7. When a liposome from a lipid with negative charges, DPPG (Figure 2), is added to the reaction mixture with 1 and 2, a decrease in MGC is evident. Of course, if an acid or aniline is added to the reaction mixture instead, due to their catalytic effects, the MGC should also decrease. Indeed, the researchers have found that the negatively charged liposomes work even better – they lead to lower MGC as compared to the acid / aniline scenarios. As another control experiment, the addition of a positive charged liposome sample does not lead to a decrease of MGC. With the use of an UV-active hydrazide substrate, the researchers can monitor the formation of hydrazone using absorbance spectroscopy for different reaction conditions. Thus, the logical conclusion from these trials is that a negative charged membrane is essential for catalysis to occur.

Figure 2. Structure of DPPG and DOPG.

Yet, there is one important thing to note before we jump to simple conclusions. The researchers have found that, while negatively charged membrane is likely to catalyze the formation of hydrogelator network, not all negative charged membranes can achieve that. The one missing piece in the puzzle is the melting temperature, T_m, of the liposome. When the researchers added the liposome from the negative charged lipid DOPG (Figure 2, T_m -20^oC, a liquid phase membrane at room temperature), to the reaction mixture, no hydrogelation occurs even at high liposome concentration. Yet, when the researchers increase the rigidity of the DOPG membrane through the addition of cholesterol (this should be familiar to anyone doing biochemistry or membrane biology), the DOPG-cholesterol hybrid membrane can then catalyze hydrogelation, suggesting the T_m of this hybrid liposome has increased.

Thus, the researchers have summarized that, in order for the liposome to catalyze hydrogelation, 2 criteria have to be fulfilled:

(1)   a negatively charged membrane surface

(2)   a solid phase at room temperature

The researchers have also established, from oscillatory rheology, that lipid concentration can control the physical properties of the hydrogel network. They also believe that liposomes are serving as nucleation points for the formation of fibrous network. I can think of a similar analogy in the case of cytoskeleton biology, where accessory proteins can serve as nucleation centers for actin polymerization.

By using confocal microscopy and a fluorescent aldehyde substrate, the researchers can also visualize the formation of the hydrogel network. When no liposomes are present, the resulting structure is very slack and un-connected. In the presence of liposomes, by contrast, the resulting hydrogel network becomes well-organized and dense, and the effect is enhanced when the liposome concentration is increased.

A very interesting aspect of the gel fiber formation occurs from the ‘underdog’, DOPG, which does not meet up to potential at the catalytic tests only until cholesterol comes to help. Rather curiously, because the T_m of DOPG is low, that meant the membrane it forms is more fluid than the membrane from DPPG. If we look at the chemical structure of DOPG and DPPG, it may shed light on this observation, and this concept is also familiar to biochemistry students. DOPG contains carbon-carbon double bonds, while DPPG is totally saturated on the carbon chains. The presence of double bonds will provide kinks and prevent a close-packing of the hydrocarbon chains, which by contrast is facile when only saturated chains are present. Thus, the unsaturated DOPG is more fluid than the saturated DPPG, and this also explains why the T_m of DOPG is lower.

DOPG has a higher affinity for the gel fibers. The affinity of the hydrogel fiber for the lipid membrane is related to the phase behavior of the hydrocarbon chains of the lipids, thus, a more fluid membrane should favor this interaction. Thus, DOPG-derived membrane seems to interact better with the hydrogel fiber than DPPG-type membrane.

What I am particularly impressed is that, by carrying out so many control experiments, the researchers draw together all the clues and provide a coherent explanation for the different performance of the DPPG and DOPG in catalysis. They propose that, because the DPPG membrane has less affinity to the hydrogel fiber, so the fiber is not blocking the way for DPPG to effect catalysis on its surface, therefore an efficient catalysis occurs and it goes on and on. In contrast, DOPG-type membrane, which is fluid and ‘loves’ the hydrogel fiber,  interacts with the gel fiber with such a high affinity that it is literally blocking the way for further rounds of catalysis. The researchers also draw analogy to the product blocking phenomena in heterogeneous catalytic systems, and I find this as an impressive explanation!

At the biological side, the researchers have also generated hydrogel fiber formations on HeLa cell systems.

All in all, this is a wonderful paper on membrane chemical biology. I have learnt a number of new techniques from it, and I am particularly impressed by the mechanistic insights, both in terms of catalytic and material, from all the great experiments they have carried out to arrive at the conclusions. Brilliant!

by Ed Law

13/7/2016

Reference:

1. Negatively Charged Lipid Membranes Catalyze Supramolecular Hydrogel Formation

Frank Versluis, Daphne M. van Elsland, Serhii Mytnyk, Dayinta L. Perrier, Fanny Trausel, Jos M. Poolman, Chandan Maity, Vincent A. A. le Sage, Sander I. van Kasteren, Jan H. van Esch and Rienk Eelkema

J. Am. Chem. Soc., 2016, asap, DOI: 10.1021/jacs.6b03853

2. Originally, I plan to talk about a self-emulsifying system which is used in the hydroformylation of lipid substrates. When I read Ref. [1], I decide to talk about that instead. It is interesting to see there are some connections regarding the two topics. Here are the references:

(a) A self-emulsifying catalytic system for the aqueous biphasic hydroformylation of triglycerides

T. Vanbésien, A. Sayede,   E. Monflier and    F. Hapiot 

Catal. Sci. Technol., 2016,6, 3064-3073

DOI: 10.1039/C5CY01758K

(b) Supramolecular Emulsifiers in Biphasic Catalysis: The Substrate

Drives Its Own Transformation

Théodore Vanbésien, Eric Monflier, and Frédéric Hapiot

ACS Catal. 2015, 5, 4288−4292

DOI: 10.1021/acscatal.5b00861

(c) Thermoresponsive Hydrogels in Catalysis

Frédéric Hapiot, Stéphane Menuel, and Eric Monflier

ACS Catal. 2013, 3, 1006−1010

dx.doi.org/10.1021/cs400118c 

'Rhod' Up the Usual Suspects

Figure 1. The allene molecule.

I have just read an advance article from Angew. Chem. Int. Ed., about an atom-economical, rhodium-catalyzed cyclization reaction [1]. The researchers have found that, with the use of a chiral and modified DIOP ligand, they could carry out asymmetric cyclizations, which resulted in the formation of large-sized cyclic esters known as macrolactones. Certainly, this is a hot research area, yet there are a number of reasons why I am so excited about this article, and I would like to share with you here.

Figure 2. The rhodium-catalyzed asymmetric cyclization.

First, the reaction involves the use of the interesting allene functionality (Figure 1 and 2). This 3-carbon component is not only fascinating in terms of its structure, but it has also found a lot of applications in the areas of transition metal catalysis or phosphine / NHC-type organocatalysis. The allene functionality can form complexes with a number of metals – rhodium, palladium and gold are some examples that immediately come up to my mind. In many cases, the outcome of the catalytic reaction will lead to the generation of an olefin structure. In this paper, it is an exocyclic olefin, and it can be used for further functionalizations. Cross-coupling, metathesis, epoxidation or aziridination followed by organocopper / cuprate coupling or nucleophilic substitutions – all these diverse reactions can be used to build up a side-chain at the cyclic structure, and thus infer interesting chemical or biological properties to the final compound.

Figure 3. Cyclic peptide synthesis.

The target compound class, macrolactone, is an extremely biologically-relevant type of molecules, and they have been intensely studied in the field of natural product chemistry and drug discovery. While the rhodium methodology could provide access to numerous macrolactone targets, what fascinated me even more was the fact that the method could be used in the synthesis of cyclic peptides (Figure 3). Indeed, the researchers have shown their method to be tolerant to a number of sensitive functional groups, and they have also employed their methods in the synthesis of some depsipeptide targets. This novel method should enter the arsenal of methods that can ‘close up’ a peptide chain, such as peptide stapling via metathesis, Pd-catalyzed cycloisomerization, or simply an amide bond formation. In this case, the exocyclic olefin I have mentioned can find further use, because a spacer can be attached through that part, and this should facilitate easy separation if the reaction condition calls for it, for example, if the compound is attached to a solid support for automated synthesis. And, I believe a great research direction is to explore whether this method can be carried out in an aqueous or a more bio-friendly solvent system. This catalytic reaction has the benefit that it can be carried out at room temperature, which is ideal for temperature sensitive bio-molecules. Thus, not only we can make useful cyclic peptides from it, we may even employ this method to generate synthetic protein architectures, which can then be further investigated for biological applications.

All in all, this work is just brilliant and the reaction makes my day!

by Ed Law

7/7/2016

Figure 4. Use of sugar allenes in the synthesis of furanose sugar derivatives. Taken from [2].

P.S. Speaking of the use of allene, I have also read another article from Angew. Chem. Int. Ed. [2], which is about the synthesis of a number of furanose sugars via the use of some ‘sugar allenes’, via a (1) Pd-catalyzed hydroalkoylation, (2) Ru-catalyzed ring closing metathesis, and (3) Os-catalyzed dihydroxylation sequence (Figure 4). Also worth a read.

Reference: 

1. Enantioselective Rhodium-Catalyzed Atom-Economical Macrolactonization

Stephanie Ganss and Bernhard Breit

Angew. Chem. Int. Ed., 2016, asap, DOI: 10.1002/anie.201604301

  

2. De Novo Synthesis of Furanose Sugars: Catalytic Asymmetric Synthesis of Apiose and Apiose Containing Oligosaccharides

Mijin Kim, Soyeong Kang and Young Ho Rhee

Angew. Chem. Int. Ed., 2016, asap, DOI: 10.1002/anie.201604199

Fishing out the Precious

In this recently-published paper, the research team has immobilized a rhodium complex on a solid support, and the resulting catalyst has proved to be an efficient hydroformylation catalyst.

The researchers have designed and synthesized a novel catalyst for hydroformylation, which involved the immobilization of air-stable rhodium nanoparticles on a magnetic support, which was in turn functionalized with intensely branched polymer that contained phosphine groups at the terminal. The researchers have shown that the rhodium phosphine catalyst could be recycled for further runs of catalytic reactions, and the rhodium complex would not be decomposed even if the catalyst recovery process was carried out without using an inert atmosphere, and the leaching of rhodium metal was negligible. These attributes all represent some of the golden standards of a good recyclable catalyst, in particular in biphasic systems.

The catalyst is modular in nature. Because the rhodium metal is incorporated into the system, let me show you the synthesis of the ligand architecture. The iron oxide core and the hyper-branched polymeric section – ‘HYP’ (which contains the key glycine residue), was separated by a long spacer. The phosphorus center is attached onto this architecture through the use of Ph₂PH and paraformaldehyde, resulting in the formation of 2 diphenylphosphine moieties on each glycine residue. The rhodium nanoparticles were then immobilized onto the ligand structure. ICP-OES technique and also transmission electron microscopy have been employed to characterize the resulting phosphine-rhodium complex.

Synthesis of the rhodium hydroformylation catalyst.

The catalyst, designated as Fe₃O₄@SiO₂-HYP-N(CH₂PPh₂)₂Rh (I would abbreviate it as ‘FeRh’ from now on), was tested for hydroformylation reactions. A number of alkene substrates were tested, and some of them were natural-occurring terpenes. Since the compound estragole was the most reactive for the hydroformylation, the researchers chose this as the model compound for their further investigations on catalyst stability and re-usability.

Hydroformylation of estragole as a model reaction.

The researchers have found that, when the new Fe/Rh catalyst was used to perform hydroformylation on estragole, the catalyst loading was lower and the conversion was far higher than their last-generation catalyst, which did not possess the hyperbranched polymeric section (HYP). The researchers proposed that the inclusion of the polymeric structure could open up more active sites for the phosphine-rhodium moieties on the catalyst surface, hence the improvements in the catalyst performance.

The recyclability and re-usability were also investigated. Because the iron nanoparticle could be attracted to a permanent magnet, the Fe/Rh catalyst was thus recovered from the reaction mixture by magnetic separation. The catalyst was re-used for 5 more times, using any compromise in terms of activity, conversion or selectivity, suggesting that the catalyst was not ‘dead’ (or decomposed). ICP-OES data also showed no significant rhodium leaching, and the Fe/Rh catalyst was observed to be stable in air.

They have obtained Raman spectra to show that the diphenylphosphine has been grafted more efficiently on the iron-polymeric backbone of the ligand. Yet, they also cautioned that further investigations were needed because the diphenylphosphine-based ligand, while so far proved air-stable, they could not rule out a likely possibly that partial oxidation could take place on the phosphorus center. Indeed, I feel it makes total sense. Because of the reaction methodology (i.e. HPPh₂ / paraformaldehyde), there would result in the formation of a di-phenylphosphine, and the alkyl CH₂ group could render the phosphine more sensitive to atmospheric oxygen, which is not the case for the indefinitely air-stable triphenylphosphine.

One final thing that fascinates me is the synthesis of rhodium nanoparticles, as I never know how it can be done. The rhodium source is the red-colored rhodium(III) chloride hydrate (RhCl₃.xH₂O), for which I have used before to prepare some [Rh(cod)Cl]₂ for other rhodium complexes. The RhCl₃ and tetraoctylammonium bromide (TOAB) were combined in a 2-phase system, and then NaBH₄ solution was added to the reaction mixture. The organic phase, which was black in color, contained the Rh-TOAB nano-particles.

Wonderful work!

by Ed Law

4/7/2016

  

Reference:

1. Support Functionalization with a Phosphine-Containing Hyperbranched Polymer: A Strategy to Enhance Phosphine Grafting and Metal Loading in a Hydroformylation Catalyst

Marco A. S. Garcia, Rodrigo S. Heyder, Kelley C. B. Oliveira, Jean C. S. Costa,

Paola Corio, Elena V. Gusevskaya, Eduardo N. dos Santos, Reinaldo C. Bazito and

Liane M. Rossi, ChemCatChem,2016, 8, 1951 – 1960.

Helical Silverback

The helicene-NHC-Iridium complex. Notice the twisted nature of the helicene and also the chiral-at-iridium attribute.

I have always been fascinated by the organometallic chemistry of iridium (Ir), and this is a great paper about a new iridium complex from Chem. Comm. [1]. The researchers have reported the first synthesis of a class of helicene- N- heterocyclic carbene-iridium complexes in enantiopure forms. The chirality is due to the helical structure of the helicene (the fused benzene rings) and also the iridium center – so this is what we call a ‘chiral-at-metal’ complex. It is noteworthy that the chiroptical properties of the iridium complex have been investigated by circular dichroism (CD), something very familiar to protein scientists and finding more applications in stereochemistry and supramolecular chemistry in recent years, too.

The complexes were synthesized by a multi-stage approach, for which the last step involved [Cp*IrCl₂]₂, a common starting material for many organoiridium complexes. The complexes were purified by crystallization, because in many cases the undesirable chlorido complexes were also formed.

NMR, molecular rotation, circular dichroism, and X-ray crystallography were among some of the techniques which were used to characterize these novel iridium complexes. X-ray crystal data were particularly informative because that suggested the key cyclometallation occurred at one particular carbon on the helicene (rather than another one) due to steric considerations, meaning that the helical structure was twisted in a particular way.

An important insight gained from all the different experiments was that the formation of the iridium complex led to electronic coupling between the iridium center and the helicenic-NHC ligand. And the researchers believed it was the first example that the properties of the N-heterocyclic carbene have led to impact on the chiroptical properties of the resulting NHC-transition metal complexes.

All in all, this is great research and I love the beautiful architecture of the iridium complex!

by Ed Law

29/6/2016

Reference:

1.  Electronic and chiroptical properties of chiral cycloiridiated complexes bearing helicenic NHC ligands

Nora Hellou,   Claire Jahier-Diallo,   Olivier Baslé,   Monika Srebro-Hooper,   Loïc Toupet,  Thierry Roisnel,   Elsa Caytan,   Christian Roussel,   Nicolas Vanthuyne,   Jochen Autschbach,   Marc Mauduit and Jeanne Crassous
Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6CC04257K

CO2 Medusa

Review on: Matter et. al., 'Rapid carbon mineralization for permanent disposal of anthropogenic carbon dioxide emissions', Science, 2016, 352, 6291, 1312-1314. [1]

This article [1], just published on the 9^th June issue of Science Magazine, has already received a lot of coverage on the web. Of course, having an intense passion in Chemistry and Geology, I am totally excited by this wonderful work!  It represents the two subjects holding hand-in-hand, contributing towards a better future.

The rising level of CO₂ in the atmosphere has been a serious issue, and many means have been devised to counteract this important factor that leads to global warming. A strategy is known as carbon capture and storage (CCS). It is the process of capturing excess anthropogenic CO₂, and to store and then deposit it to a sink, so that the CO₂ will not enter the atmosphere. The deposition site is usually a geological formation under the ground. Of course, deep ocean storage is not yet a feasible approach, because the introduction of CO₂ into ocean will lead to ocean acidification.

So what rock should we shoot the gas into? Most researchers tend to favor a sedimentary rock, sandstone, as the sink, because of the well-established research experience with this type of rock. Yet, a potential pitfall is that the fissures present in the rock layers of sandstone can lead to the leaching of CO₂ back to the atmosphere.

Thus, the researcher direction in the field has changed.  In this collaborative work, the researchers injected CO₂ into the igneous rock – the extrusive volcanic rock known as basalt. This is a great strategy because the minerals present in basalt can react with CO₂, and through a carbonation reaction, that results in the formation of the mineral calcite, a polymorph of CaCO₃. In this way, the excess CO₂ can thus be mopped up. The reaction rate was much faster than the rates modeled by computational methods. Also, the research represented a nice example of using an isotopic labeling technique (¹⁴C in this case) to characterize the formation of carbonate minerals from CO₂.

This is an impressive idea, yet the researchers also noted a possible obstacle to the generalization of this process is cost. Also, when a scaling up of the process is required, the reaction rate has to be acceptable to compromise the long-term cost. It is quite obvious a better understanding of the mechanism is required to fine-tune the carbonation reaction and to shut down other unproductive pathways – like the sandstone scenarios. To me, it seems that catalysis will be able to contribute to an improvement of the CCS process (Once a chemist, always a chemist?!). Indeed, I have found a paper back in 2013 in ‘Catalysis Science & Technology’, where the authors demonstrated the use of nickel nanoparticles as a catalyst for the mineralization reactions from carbon dioxide. [2] So, it seems that the door has already been opened and there are active research projects towards this direction. If the time course of the carbonation / mineralization reaction can be significantly shortened through the application of a low-cost catalyst, the process will become common place and then this can alleviate the problem of excess CO₂ in the long term.

One final chemical point of view is that we should bear in mind that CO₂ is a potential one-carbon building block. In photosynthesis, CO₂ is used to form the six-carbon sugar, catalyzed by the enzyme complex Rubisco. So, similarly, if CO₂ can be stored efficiently, this can be a great starting substrate for the production of other compounds, often employing organometallic catalysis.

All in all, it is a truly brilliant contribution, and it is more so because it has a great potential to lead to a better future.

by Ed Law

11/6/2016

Reference:

1. Rapid carbon mineralization for permanent disposal of anthropogenic carbon dioxide emissions.

J. M. Matter et. al., Science, 2016, 352, 6291, 1312-1314.

Further commentaries on:

http://www.sciencemag.org/news/2016/06/underground-injections-turn-carbon-dioxide-stone

http://science.sciencemag.org/content/352/6291/1262

2.  Nickel nanoparticles catalyse reversible hydration of carbon dioxide for mineralization carbon capture and storage.

G. A. Bhaduri and L. Siller, Catal. Sci. Technol., 2013, 3, 1234.