Click Chemistry for Pyrrole Synthesis

The Pyrrole heterocycle is an important chemical motif, found widely in pharmaceuticals, natural products, agrochemicals and advanced materials. The introduction of new methods or further the work on technical improvements in order to overcome the limitations (such as low efficiency and selectivity) found in pyrrole synthesis is still a pressing experimental challenge. 

The concept of “Click Chemistry” is gaining rapidly due to its high efficiency, selectivity, and yield under mild reaction conditions with a wide variety of readily available starting materials. The copper-catalyzed azide–alkyne cycloaddition (CuAAC) has emerged as the premier example of click chemistry and plays a significant role in organic synthesis. 

Prof. Aiwen Lei and coworkers, Wuhan University, Hubei, have developed a silver catalyst “click reaction” for the synthesis of pyrrole, by cycloaddition. This system benefits from readily-available starting materials, low catalyst loading (0.1 eq), short reaction times (2 h) and excellent chemo-selectivity. And, works for both internal and alkyl substituted terminal alkynes in the presence of many functional groups. The extremely mild conditions used, makes this reaction synthetically attractive. 

This mechanism involves the formation of silver–acetylide complex and silver–isocyanide complex. Subsequently, the cyclo-addition between complexes would afford the key intermediate complex to be followed by protonation and tautomerization of the intermediate complex to form the desired product. 

The catalytic synthesis protocol tolerates a large variety of functional groups, which includes methylthio, methylsulfonyl, and ethynyl groups. Moreover, alkyl substituted terminal alkynes were also found to be suitable reaction partners. Interestingly, both Cu(II) and Cu(I)  turned out to be ineffective.

Useful chemicals and fuel from Carbon dioxide

Carbon dioxide is abundant, non-toxic, inexpensive, and a renewable source of carbon. This makes CO₂ the most coveted compound by Green Chemistry enthusiasts. Industries are always on the lookout for ways that will enable effective use of CO₂ to act as synthetic building blocks for producing fuels like Methane, Di-methyl-ether and Mthanol and fine-chemicals. Furthermore, CO₂ conversion could also help reduce atmospheric CO₂ levels, popularly known as “Green House Gas”, and thus, protect climate.

Nature has been highly successful in using CO₂ as synthetic building blocks in photosynthesis. For decades, scientists have been trying to understand this phenomenon at a molecular level. Such studies have proved useful in developing biomimetic catalysts for CO2 conversion. Chlorophyll (Porphyrin molecules) in green plants helps convert incident sunlight and atmospheric CO2 into sugars (energy). So, this makes them promising target for testing activation catalysts for CO2 adsorption. Effective CO2 adsorption using man-made catalysts is indeed our end-goal. Lot of research is being conducted in this area to further the economic viability of the processes that utilize CO2. Several companies are pursuing the idea / concept of thermochemical and electrochemical conversion of CO2 into chemical feedstock or polymers. Research and development are currently focused on increasing the catalyst life and bringing down the temperature of conversion.

Future research must emphasize on the rational design of highly active catalyst, in order to satisfy the economic development of CO₂ conversion. But, the development of such efficient catalysts requires a complete understanding of CO₂ and CO₂-catalyst interactions.

In order to develop such a catalyst, following points should be considered,

1. CO₂ has strong affinity towards nucleophiles and electron-donating reagents, due to the electron deficiency of its carbonyl-carbon,  If the designed catalyst has nitrogen or base-functionalty (basic), it will have an increased affinity towards CO₂ (eg, Porphyrin, Grignard reagents). Such catalysts lead to the synthesis of acid-derivatives.
2. With low-valent metals and alkene, CO₂ undergoes “oxidative cycloaddition”
3. New CO₂ soluble catalysts may increase efficiency.
4.  Homogeneous catalysis in compressed CO₂, may increase selectivity.
5. Catalyst in supercritical CO₂ may also increase stability. It is essential to make use of CO₂, based on the unique physical properties as that of the supercritical fluid, either as a solvent, or as an anti-solvent, or reactant, or a combination of all.
6. Photoelectrochemistry, the study of using solar energy to split CO₂, is an emerging method for clean production of chemicals. It is also important to develop catalysts (Semiconducting materials) for the electrochemical conversion of CO₂.
7.  Use of high-energy starting materials may ease the catalyst role.
8. The catalyst will be more efficient if it has both CO₂ adsorption and activation functionality. Eg, designer MOF that contains Lewis-base sitewill donate electron to CO2, in contrast to the Lewis-acids sites in traditional MOFs for adsorbing CO₂.
9.  Computational tool such as Density Function Theory (DFT) may help improve the catalytic activity, or, find a new catalyst.
10. Chemical reactions can also benefit from using CO₂ as a mild oxidant, or as a selective source of O₂ atoms because dissociation of CO₂ on a catalyst-surface could produce active O₂ species.

 The trend towards conversion of CO₂ to useful chemicals and fuels will probably intensify in the near future. This could in turn lead to effective management to tackle climate change and energy crisis.

As George Whitesides emphasizes, managing CO₂ and conversion into useful chemicals and energy will be the reinvention of chemistry, and it is also chemistry/ molecular solution to the important problem facing the society.  He says

 “Some of the most interesting problems in science, and many of the most important facing society, need chemistry for their solution. Examples include: understanding life as a network of chemical reactions; interpreting the molecular basis of disease; global stewardship; the production, storage, and conservation of energy and water; and the management of carbon dioxide."

Issues pertaining to CO₂ is truly global, and a major opportunity for the development of sustainable energy options and environmental preservation. So, use of CO₂ for the synthesis of useful chemicals & fuels will mark a new field in chemistry. It is important to establish university-industry-collaboration to search for new-reactions & new-catalysts in this field.

To Readers: If you have experience with CO₂ conversion reaction or specific catalyst, please feel free to comment.

Hope for Drug to Reduce Old-Age-Related Muscle Wasting

Guest Post – Lily Bryant

The results of a study carried out by researchers at the Center of Regenerative Medicine at Massachusetts General Hospital in Boston, USA, and the Department of Craniofacial Development and Stem Cell Biology at King’s College London, England, indicate that a cure for muscle weakening caused by old age might be on the horizon. Muscle wasting is an inevitable symptom of growing older. It can be slowed down by regularly exercising but there is no known way of reversing it at the moment. This looks set to change though, as the researchers have treated old mice with a drug that has significantly improved the ability of their aged muscle tissue to self-repair. 

Fibroblast Growth Factor 2 

Strenuous activity, such as doing press-ups or lifting weights, results in a small level of damage to the muscles. Stem cells are triggered to repair them by dividing and developing into new muscle fibres. This results in big arms and rippling torsos. However weakening of the muscles due to old age means that bulging biceps can soon become puny and weak. This occurs because as people grow older, their muscle loses its ability to regenerate. A study conducted by the University of Potsdam in Germany indicates that people lose just under a third of their muscle strength between the ages of fifty and seventy. The researchers at Massachusetts General Hospital and King’s College London deduced that this is due to the fact that the number of dormant stem cells in muscles decreases with age. They concluded that in mice, this was caused by excessively high levels of a protein that stimulates cells to divide, known as fibroblast growth factor 2 (FGF2). 

Preventing Muscle Stem Cell Decline 

In ageing muscle, fibroblast growth factor 2 was found to be continuously awakening dormant stem cells for no reason. The stem cell supply was observed to deplete over time, meaning that an insufficient number were available when they were really needed. As a result of this, muscle regeneration ability was impaired. The researchers discovered that using a drug called SU5402 that inhibits fibroblast growth factor 2 can prevent muscle stem cell decline in aging mice. Treating the elderly rodents with this drug increased their ability to repair muscle tissue. 

Reducing the Impact of Old Age 

Dr Albert Basson, who is a senior researcher at King’s College London, has stated that the findings mean that treatments that could make old muscles young again could one day be developed, thus reducing the impact of old age. He says that if such a treatment came into existence, people would be able to live more independent, mobile lives as they grew older. Senior author Dr Andrew Brack of Massachusetts General Hospital says that just as it is important for athletes to schedule recovery into the time that is taken for training, stem cells require time in which to recuperate but elderly cells recuperate less often. Scientists are yet to figure out why it is that levels of fibroblast growth factor 2 increase causing excessive stem cell activation as people get older. Research team member Kieran Jones of King’s College London says that the next step is to conduct an analysis of old muscle in humans in order to see whether or not the same mechanism is responsible for the depletion of stem cells in human muscle fibres leading to wasting and loss of mass. 

The Implications of the Research 

Once it has been confirmed that stem cells in human muscle fibres are negatively affected by fibroblast growth factor 2, work can start on introducing a drug to the market that will stop the process from taking place and consequently reduce the extent to which elderly people are immobilised and prevented from doing what they want to do by the effects of age-related muscle weakening. The average life expectancy in India has increased by over four and a half years since 1998. Now that people are living longer than they used to live for, a drug that reduces the amount to which becoming elderly negatively impacts upon the quality people’s lives would be extremely beneficial. It would mean that individuals who have reached the later stages of their lives could enjoy the time that they have left without having their independence limited by their muscles becoming increasingly weak and feeble.

About Lily Bryant

Lily Bryant is a writer working with one of only two licensed online pharmacies in the US. She is strongly interested in promoting and creating content aimed at relevant readers as part of her role in ethical healthcare business. She believes that it is important that we play a strong role in leading society towards a healthier lifestyle through the promotion of exercise and healthy diet rather than an early adoption of drug treatment.

Artificial Photosynthesis using graphite Carbon Nitride

Fine chemicals and hydrogen production from water, carbon dioxide and solar energy is an ideal future chemical and energy source, independent of fossil reserves. The development of new functional molecular materials (catalyst) for the application in fine chemical and clean energy production using water and solar energy is fascinating and quite challenging, because the catalyst must be sufficiently efficient, stable, inexpensive and capable of harvesting light. 

Polymeric graphite carbon nitride (C₃N₄) materials are commonly available simple semiconductor photo catalyst. Being non-volatile up to 600⁰C even in the air with no detectable solubility or reactivity in conventional solvents, including water, alcohols, DMF, THF, diethyl ether, and toluene. Carbon nitride is considered to be extremely stable and basic in nature. It can be used as the multifunctional heterogeneous catalyst for fine chemical and pharmaceutical synthesis as well as a good organic semiconductor due to its right band gap (2.7 eV corresponding to an optical wavelength of 460 nm). 

Prof. Markus Antonietti and his team at Max Planck Institute of Colloids and Interfaces in Germany, have successfully split CO2 or photochemically turn water into hydrogen and oxygen using graphite carbon nitride. However, only four micromoles of hydrogen per hour produced out of the re-searchers' reaction vessel (quantum efficiency of the Pt modified CN is approximately 0.1% with irradiation of 420-460 nm). This opens the door to artificial photosynthesis and produce chemicals and energy from green house gas /solar energy. It will contribute to the prevention of global climate change. 

Harmless Viruses Might be a Potential Treatment for Acne

Guest Post – Lily Bryant

According to a report published in the Indian Journal of Dermatology, Venereology and Leprology, there are thought to be between two million and three million acne sufferers in India. Acne can lead to low self-esteem and image problems and is the scourge of teenage boys all over the country. Fortunately towards the end of 2012, researchers at the University of California, Los Angeles, and the University of Pittsburgh in the United States discovered that phages living on our skin possess the ability to kill propionibacterium acnes, which is the virus that causes it. This could be good news for those whose skin is tarnished by this condition and mean that an end is in sight.

There has been a rapid increase in the promotion of drugs aimed at enhancing individuals’ physical appearances in recent years. The weight loss industry has grown at a yearly rate of over twenty-five percent, with more people than ever purchasing diet pills and fat burners, the hair loss treatment industry has been growing by one percent per year and the acne treatment industry has also seen significant growth. People’s daily lives are affected in a major way by how they look so a cure for acne could be both highly profitable for the pharmaceutical company that is responsible for it and highly beneficial to sufferers.

Immune Resistance Unlikely to Develop

In order to arrive at their discovery, the researchers at the two universities analysed phages and deduced that they make endolysin, which breaks down propionibacterium acnes before killing it. They also discovered that the phages shared eighty-five percent of their DNA. This is unusual for viruses and means that when used as a treatment, it would be unlikely that immune resistance would develop.

Advantages Over Other Forms of Treatment

Accutane

Unlike antibiotics, which kill many different types of bacteria including ones that live in the gut and can have positive effects, phages are programmed to only target specific bacteria. According to director of the University of California, Los Angeles, Clinic for Acne, Rosacea and Aesthetics Dr Jenny Kim, who was one of the researchers, many acne strains are now resistant to antibiotics such as tetracycline, as they are so widely used. Drugs like Accutane are still effective but can have risky side effects, which limits their use. The researchers at the two universities have stated that phages could offer a tailored therapy that has less adverse side effects. Therefore phages could be the new form of acne medication that those inflicted with the condition have been looking for.

Development of New Drugs and Treatments 

Study co-author Graham Hatfull, who is a biotechnology professor at the University of Pittsburgh, has stated that there are two ways in which this research could be used with regards to the development of new drugs and treatments. He says that phages could either be used directly as therapy for acne or phage-based components could be utilised. Professor Hatfull also says that the work that the University of California, Los Angeles, and the University of Pittsburgh have carried out has provided the world with useful information about phages and paved the way for the thinking up of potential applications for them. He points out that whilst acne is a condition that a significant percentage of the population is likely to suffer from at some point in their lives, there are still currently few effective methods for curing it. Hatfull says that harnessing a virus that naturally preys upon the bacteria that causes spots looks to be a promising means of reducing both the physical and the mental scars that acne can inflict upon individuals.

Implications of the Research

It appears that being forced to endure pimples and spots could soon bee a thing of the past. The results of a study published in the Journal of Cosmetic Dermatology in 2010 demonstrate that acne can severely negatively impact upon the self-esteem of sufferers and increase the risk of them developing psychological disorders. It can make them two to three times more likely to become clinically depressed. Therefore it is high time that there was a means of treating it and phages could provide the answer. Now it is just a matter of deciding what the best way of using them to gain the optimum results in acne reduction is.

About Lily Bryant

Lily Bryant is a writer working with one of only two licensed online pharmacies in the US. She is strongly interested in promoting and creating content aimed at relevant readers as part of her role in ethical healthcare business. She believes that it is important that we play a strong role in leading society towards a healthier lifestyle through the promotion of exercise and healthy diet rather than an early adoption of drug treatment.

Modulators of Protein–Protein Interactions

Protein-protein interactions (PPI) play a key role in most biological processes. This nature of PPI has put forward itself as a prospective candidate for therapeutic intervention. Traditional small molecule target classes such as Enzymes, GPCRs, Kinases etc have a deep pocket (often used to bind an endogenous substrate), where small molecule tend to bind. PPIs on the other hand, appear to be too large and featureless for small molecules to bind against. Hence, due to this lack of well defined binding pockets, they were considered unsuitable/ extremely hard for targeting small molecules. 

Attempts at generating small molecule modulators of PPIs have been largely unsuccessful by adopting existing chemical techniques. This leads us to believe that we need to identify novel chemical space that can leverage the flat and expansive surfaces of PPI, which would in turn provide effective binding for small molecules. However, pharmaceutical companies are rather unwilling to add compounds containing multiple rings, multiple stereocenters that are highly complex, into their corporate collection as it does not align with their immediate short term business goals.

Heterocyclic compounds (aromatic, largely flat and hydrophobic)

+

Natural products (rich in sp2 bonds)

=

Natural Product Inspired   (New Chemical toolbox)

A new chemical toolbox enriched with both Heterocyclic Compounds and Natural Products to tackle such issues is being developed by Dr. Prabhat Arya from Dr.Reddy’s Institute of Life Sciences (Org. Lett., Article ASAP, DOI: 10.1021/ol3032126). This approach could create large 3D surface area, numerous binding interactions, rich stereochemical diversity, which would in turn solve the poor cell permeability of natural products, not to mention the added advantage over crowded IP Space.

The field of small-molecule-PP interactions appears to be highly promising, and in the near future, we can hope to see several strategies and techniques that will pave way towards discovering novel agents in this regard.

Useful Concepts for Medicinal Chemist

Useful Numbers, Concepts and Formulae for Medicinal Chemist

Picture of Olympicene

Back in 2009, at the IBM Research lab scientists imaged, for the first time, the chemical structure of an individual molecule (pentacene) with unprecedented resolution, using technique they developed called noncontact atomic force microscopy. The same IBM team, has once again come up with an interesting image. This time they've imaged a new organic molecule, Olympicene.

Olympicene, gets its name because its five linked rings resemble the Olympic symbol. The compound is a powder, that is very sensitive to light. In fact, even with brief exposure it changes color. It is only 1.2 nanometers wide, or 100,000 times thinner than a human hair. This AFM technique could become a real structure-determination tool for organic chemist.

PhD student fellowships

The International Max Planck Research School (IMPRS) "The Exploration of Ecological Interactions with Molecular and Chemical Techniques" in Jena, Germany, invites applications for 6 PhD fellowships beginning in January 2013.

Application deadline is June 29, 2012.

For detailed information about the IMPRS, Projects offered and application requirements, @http://imprs.ice.mpg.de/.

Molecule vending machine

 Nano-catalysis is a fast-growing field of chemistry, which involves the use of nanomaterials as catalysts for a variety of selective organic transformations. Nano-catalysis can be considered as a bridge between homogeneous and heterogeneous catalysis. Because of high surface area of nano materials, the contact between reactants and catalyst increases dramatically and they can operate in the same manner as homogeneous catalysts (homogeneous catalysis), at the same time, due to their insolubility in the reaction solvent, they can be separated out easily from the reaction mixture (heterogeneous). Only the molecules of certain sizes and chemical properties are selected and guided to the reaction centers where they are efficiently transformed to the desired products.

 Solid supports have the potential to house more than one metal and, hence, catalyze multiple types of bond constructions. Such “multifunctional” catalysts attained much attention due to several advantages over mono metal catalyst. The high selectivity of the nano catalyst may help reduce the energy consumption required for product separation and waste disposal processes in chemical industries.