Category Archives: Organic Chemistry

Organic Chemistry

How A-level chemistry solved the 200-year-old problem with the haloform reaction – Chemistry World

The 200-year-old haloform reaction has been given a modern makeover. Using rigorous mechanistic studies to inform their strategy, researchers at the University of Bristol drove this reaction to accept secondary alcohols in stochiometric quantities, something never attempted in the reactions history.

First discovered in 1822, the haloform reaction converts methyl ketones into carboxylic acids or esters, forming an insoluble haloform as a byproduct. The methyl protons are acidified by virtue of being next to the carbonyl which essentially means that the methyl group CH3 can be converted into CX3, the trihalomethyl, which is a leaving group, explains Liam Ball, a physical organic chemist at the University of Nottingham who wasnt involved with the new work. This CX3 group can then be substituted by either water or alcohol at the carbonyl to make a new COH or COR bond. Both mild and reliable, the reaction became an industrial staple for the synthesis of carboxylic acids and methyl esters, but the requirement for solvent quantities of alcohol limited its application in the synthesis of more complex products.

We were very surprised to discover that no one had actually used more complex alcohols in this reaction, says study author Alastair Lennox. So we set out to discover why that was and whether we could use that knowledge to expand the scope of this reaction. The original reaction uses a combination of aqueous bases to generate the trihalogenated leaving group, but subsequent competition of hydroxide ions from this mixture with the intended nucleophile means a vast excess of alcohol is required to favour formation of the ester over the carboxylic acid.

Seeking to eliminate this competing reaction, Lennoxs team began exploring alternative non-aqueous reagents for the initial iodination step, finally settling on the organic base DBU. With these dry conditions, the team could reduce the amount of alcohol to just one equivalent, facilitating the reaction with a range of non-solvent primary alcohols for the first time.

However, the corresponding reactions with secondary alcohols failed to reach completion under these conditions so the team commenced detailed mechanistic studies to identify the problem step. The headline from those studies is that the iodination steps are reversible. Previously that had not been documented, says Lennox.

Kinetic experiments revealed the formation of the trihalo leaving group occurs in three reversible steps. The equilibrium favours the product in the first two stages but the final step, which forms the trihalogenated compound from the dihalo intermediate, is not favoured, with a competing side product dominating the equilibrium. The reason that is important is because with the primary alcohol the substitution is very rapid so you dont observe this reversibility. Whereas, with the secondary alcohols, because the substitution is significantly slower, we see that equilibrium at play, explains Lennox.

This deep mechanistic insight was the crucial missing piece which enabled the team to incorporate a diverse panel of secondary alcohols into the reaction. In the end, the solution was very simple. We just added more DBU and iodine and that pushed the equilibrium via Le Chateliers principle towards the triiodo compound, Lennox explains. At a higher concentration, the secondary alcohol could now react with it in more meaningful rates.

The teams thorough approach particularly impressed Ball. This could be really beneficial to complex molecule synthesis, both in academia and industry, by enabling the use of more valuable alcohols in this reaction, he says. I think the next step has to be extending this to tertiary alcohols too.

Lennox is eager to exploit the possibilities suggested by these mechanistic insights and the team intend to investigate different nucleophiles as a method to generate other complex molecules from methyl ketones. I think this could really open up new avenues in the formation of different complex products, he says.

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How A-level chemistry solved the 200-year-old problem with the haloform reaction - Chemistry World

Organic Chemistry

Porous organic ‘cage of cages’ crystalline structure predicted by computational modelling – Chemistry World

Organic cages have been used as precursors to synthesise higher-order porous structures, adding to their functionality while the ability to solution process them is retained.

The team from the UK and China used ether-bridged cage molecules as a building block its chlorine atoms are essential for forming ether bridges with fluorine-enriched tetrafluorohydroquinone (TFHQ) as the linear bridge. The fluorine atoms offer structural integrity by limiting bond rotation and can improve the solubility of the resulting cagecage molecules.

Models were constructed using molecular dynamics and density functional theory to predict the reaction products of these blocks. Several topologies and their relative energies were predicted, not considering solvent effects, and the results indicated a strong preference for a [4[2+3]+6] cage product. The team, guided by these simulations, conducted two-step assembly experiments to screen optimum conditions.

The results showed good agreement between the predicted structure for the [4[2+3]+6] cage molecule and the observed crystal structure four trigonal cages assembled into a larger tetrahedral cage. The product demonstrated both good sorption capacity and hydrolytic stability important properties for gas separation and water remediation technologies.

This new cage of cages structure could be used as a building block for even more complex structures. This study highlights the use of computational methods to assess the most likely reaction products as well as non-intuitive new materials in supramolecular synthesis.

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Porous organic 'cage of cages' crystalline structure predicted by computational modelling - Chemistry World

Organic Chemistry

Complex Organic Chemistry In Sulfuric Acid And Life On Venus – Hackaday

Finding extraterrestrial life in any form would be truly one of the largest discoveries in humankinds history, yet after decades of scouring the surface of Mars and investigating other bodies like asteroids, we still have found no evidence. While we generally assume that were looking for carbon-based lifeforms in a water-rich environment like Jupiters moon Europa, what if complex organic chemistry would be just as happy with sulfuric acid (H2SO4) as solvent rather than dihydrogen monoxide (H2O)? This is the premise behind a range of recent studies, with a newly published research article in Astrobiology by [Maxwell D. Seager] and colleagues lending credence to this idea.

Previous studies have shown that organic chemistry in concentrated sulfuric acid is possible, and that nucleic acid bases including adenosine, cytosine, guanine, thymine and uracil which form DNA are also stable in this environment, which is similar to that of the Venusian clouds at an altitude where air pressure is roughly one atmosphere. In this new article, twenty amino acids were exposed to the concentrations of sulfuric acid usually found on Venus, at 98% and 81%, with the rest being water. Of these, 11 were unchanged after 4 weeks, 9 were reactive on their side chains, much like they would have been in pure water. Only tryptophan ended up being unstable, but as the researchers note, not all amino acids are stable in water either.

The limitations of this research is of course that it was performed in a laboratory environment, with uncontaminated concentrated sulfuric acid, rather than the Venusian clouds with their trace elements of other gases such as CO2 and the constant bombardment with meteors that have been shown to often be laced with such amino acids. Future research will take these variables into account, even as scientists cannot wait to get data from upcoming Venus missions, with better sensors that may just catch a glimpse of such organic chemistry in action.

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Complex Organic Chemistry In Sulfuric Acid And Life On Venus - Hackaday

Organic Chemistry

Advancing Chemistry with AI: New Model for Simulating Diverse Organic Reactions – Lab Manager Magazine

Key Takeaways:

Researchers from Carnegie Mellon University and Los Alamos National Laboratory have used machine learning to create a model that can simulate reactive processes in a diverse set of organic materials and conditions.

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"It's a tool that can be used to investigate more reactions in this field," said Shuhao Zhang, a graduate student in Carnegie Mellon University'sDepartment of Chemistry. "We can offer a full simulation of the reaction mechanisms."

Zhang is the first author on the paper that explains the creation and results of this new machine learning model, "Exploring the Frontiers of Chemistry with a General Reactive Machine Learning Potential," which was published in Nature Chemistry on March 7.

Though researchers have simulated reactions before, previous methods had multiple problems. Reactive force field models are relatively common, but they usually require training for specific reaction types. Traditional models that use quantum mechanics, where chemical reactions are simulated based on underlying physics, can be applied to any materials and molecules, but these models require supercomputers to be used.

This new general machine learning interatomic potential (ANI-1xnr) can perform simulations for arbitrary materials containing the elements carbon, hydrogen, nitrogen, and oxygen and requires significantly less computing power and time than traditional quantum mechanics models. According to Olexandr Isayev, associate professor of chemistry at Carnegie Mellon and head of the lab where the model was developed, this breakthrough is due to developments in machine learning.

"Machine learning is emerging as a powerful approach to construct various forms of transferable atomistic potentials utilizing regression algorithms. The overall goal of this project is to develop a machine learning method capable of predicting reaction energetics and rates for chemical processes with high accuracy, but with a very low computational cost," Isayev said. "We have shown that those machine learning models can be trained at high levels of quantum mechanics theory and can successfully predict energies and forces with quantum mechanics accuracy and an increase in speed of as much as 6-7 orders of magnitude. This is a new paradigm in reactive simulations."

Researchers tested ANI-1xnr on different chemical problems, including comparing biofuel additives and tracking methane combustion. They even recreated the Miller experiment, a famous chemical experiment meant to demonstrate how life originated on Earth. Using this experiment, they found that the ANI-1xnr model produced accurate results in condensed-phase systems.

Zhang said that the model could potentially be used for other areas in chemistry with further training.

"We found out it can be potentially used to simulate biochemical processes like enzymatic reactions," Zhang said. "We didn't design it to be used in such a way, but after modification it may be used for that purpose.

In the future, the team plans to refine ANI-1xnr and allow it to work with more elements and in more chemical areas, and they will try to increase the scale of the reactions it can process. This could allow it to be used in multiple fields where designing new chemical reactions could be relevant, such as drug discovery.

- This press release was originally published on the Carnegie Mellon University website

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Advancing Chemistry with AI: New Model for Simulating Diverse Organic Reactions - Lab Manager Magazine