5 Simple Organic Chemistry Reactions that “Saved My Life”.

ORGANIC CHEMISTRYGet ready for a tips-that-saved-my-life type of post for this one. Not with the idea to disappoint you, but this post will not help you to lose weight, improve your relationship with your boss or save your marriage. Rather than all that I have selected a “Top 5” of very simple organic chemistry reactions that at some point were crucial to the progress of my research projects.

Mitsunobu Reaction. Discovered by Oyo Mitsunobu. This reaction can be a very useful and straightforward alternative to nucleophilic substitutions and as in the case of SN2 it proceeds with inversion of configuration.

mitsunobu

The Mitsunobu reaction allows the direct reaction of primary and secondary alcohols with acidic nucleophiles to afford products such as esters, ethers and amines among others. One of the reagents employed in the reaction, DEAD, (diethylazodicarboxylate) can be substituted by its cousin DIAD (diisopropylazodicarboxylate) if you are superstitious.

Sonogashira Coupling. In my opinion every single synthetic chemist must have cross-coupling reactions in their “synthesis toolbox”. Palladium catalysed cross-coupling reactions are unarguably of most relevance as reflected by the 2010 awarded chemistry nobel prize.

sonogashira

Discovered by Kenkichi Sonogashira, Sonogashira reaction allows the coupling of terminal alkynes with aryl or vinyl halides with a palladium catalyst, a copper(I) cocatalyst, and an amine as base.

Wittig reaction. Discovered by Georg Wittig, for which he was awarded the nobel prize in chemistry in 1979. The Wittig Reaction is probably the preferred method for synthetic chemists for making alkenes. The reaction allows the preparation of alkenes by the reaction of an aldehyde or ketone with the ylide generated from a phosphonium salt.

wittig

Triphenylphosphine oxide is generated in the process as a byproduct and sometimes it can be difficult to separate from the desired products. If you are sick of seeing that annoying triphenylphosphine oxide in your Wittig reactions you might want to take a look to the alternative proposed by O’Brien and co-workers from the University of Texas.

Selenoxide elimination. Another useful method for the synthesis of alkenes. Selenoxides decompose to the corresponding alkenes at mild temperatures and can be readily prepared from nucleophilic carbonyl derivatives by reaction with selenylating reagents such as PhSeCl in the presence of a base.

selenoxide

It is for this reason that selenoxide elimination has grown into a general method for the preparation of α,β-unsaturated carbonyl compounds.

Electrophilic aromatic halogenation. Electrophilic aromatic substitution is a general type of reactions you find in the first chapters of all organic chemistry books and you learn during the first semester of organic chemistry. Rule of thumb, electron-donor groups promote substitution at the ortho and para positions while electron-withdrawing groups promote the meta position.

halogenating

In particular electrophilic halogenation is a very useful method to introduce diversity in the molecules as the aromatic halides generated can be easily modified for example with the use of cross-coupling reactions. Electrophilic aromatic halogenation can be performed in the presence of strong halogenating reagents in some cases although the use of Lewis acids is typically required.

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What to Do with All That CO2 Stuff?

CO2_carpetThe Scripps Institution of Oceanography at UC–San Diego reported the past April 2014 a terrifying new milestone of 400 ppm of CO2 in the atmosphere. The accumulation of CO2 into the atmosphere is causing a growing reinforcement of the natural green house effect and is thus “extremely likely” causing the increase of average temperature in our planet. In other words, if we continue denying the evidence of a strong relationship between CO2 emissions and climate change we may reach a “no-return point”.

Let’s not be apocalyptic YET. There is a real concern about CO2 in the scientific community, research institutions and funding agencies are promoting a change of mentality towards bigger efforts on CO2 research. And here it comes the question, What to do with all the CO2? It is a tricky question with no easy answer as unfortunately there are many international conflicts of interests in terms of CO2 emission and climate change. From a scientific perspective there are a few strategies that can be followed to reduce, avoid and make a smart use of CO2.

-Smarter use of energy: an indirect way to reduce CO2 emissions. Invest and research in more efficient use of energy, insulation of buildings, fuel-efficient vehicles. For a higher effectiveness, all this must come along with educating people about a more conscious personal attitude toward energy use.

-Fuel shift from coal to gas: another way to reduce CO2 emissions. As simple as the amount of CO2 produced by burning gas is sensibly lower than by burning coal.

-Renewable sources of energy: such as sun, wind or geothermal. A field in continuous growing and development with the major drawback of reliability of supply as renewable energy often relies on weather and geographical location.

-Carbon  capture and storage: This technology with the focus of capturing and storing CO2 in huge amounts attracted the attention and enthusiasm of many. But there are also certain doubts as it can be seen as sweeping the CO2 under the carpet due to the uncertainty about the time permanence of stored CO2 and the possible impact on natural systems.

-And last but not least, Transform CO2 into chemicals. This is, no doubt, my favourite strategy, what did you expect? I’m a chemist. Transforming CO2 into chemicals is an indirect way to trap CO2 in a productive way and thus reducing the carbon footprint. CO2 has its most important application in the synthesis of urea for the industry of fertilizers and urea-formaldehyde resins, it is used in the synthesis of salicylic acid (the precursor of aspirin), the production of carbonates through direct reaction with epoxides and has many prospective applications in the area of polycarbonates and fuel production.

uses CO2

Production of chemicals with CO2 will pay off if two main objectives are accomplished. The first is that the amount of CO2 produced burning fuels for energy for a process must be lower than the CO2 transformed into a chemical. And the second is that the time CO2 stays as a chemical must be long enough to have an impact on the accumulation of CO2 into the atmosphere.

Do you want to know more? Here you are a couple of interesting reviews:

– Martina Peter, Burkhard Köhler1, Wilhelm Kuckshinrichs, Walter Leitner, Peter Markewitz, Thomas E. Müller. Chemical Technologies for Exploiting and Recycling Carbon Dioxide into the Value Chain. Chem. Sus. Chem. 2011, 9, 1216–1240.

– Michele Aresta, Angela Dibenedetto, Antonella Angelini. Catalysis for the Valorization of Exhaust Carbon: from CO2 to Chemicals, Materials, and Fuels. Technological Use of CO2. Chem. Rev., 2014, 114, 1709–1742.

An Unusual Lewis Acid Hydrocarbon.

I would like to highlight the definition of hydrocarbon, a very basic concept in organic chemistry but of relevance for this post. According to the IUPAC, hydrocarbons are compounds consisting of carbon and hydrogen only. It doesn’t seem obvious to imagine an organic compound composed only by carbon and hydrogen with Lewis acidity not being a charged species such as a carbocation. Back in 2010 the group of Manuel Alcarazo at Max Planck Institute of Coal Research published a  very creative paper describing the properties of a bisfuorenylallene as a Lewis acid. The natural tendency of the fluorene moites to accept a pair of electrons to gain aromatization gives the central carbon of the allene a carbocationic character and thus the ability to behave as a Lewis acid.

Unsual hydrocarbon lewis acid

A clear experimental evidence of the behaviour of the bisfluorenylallene as a Lewis acid is the formation of classical Lewis acid-Lewis base adducts in the presence of small Lewis bases. In another stroke of genius, Acarazo and co-workers apply the Lewis acid ability of the fluorenyl based allene to the field of Frustrated Lewis Pairs (a field dominated by borane-based Lewis acids) towards the activation of sufur-sulfur bonds.

Do you want to know more? Check this paper out.

Blanca Ins, Sigrid Holle, Richard Goddard, and Manuel Alcarazo. Heterolytic S-S Bond Cleavage by a Purely Carbogenic Frustrated Lewis Pair. Angew. Chem. Int. Ed. 2010, 49, 8389 –8391.

Frustration to a Good End.

Frustration: “The feeling of being upset or annoyed as a result of being unable to change or achieve something”. It sounds like a very negative feeling that every researcher has felt at some point at their careers. It is not the case for the topic of Frustrated Lewis Pairs, where frustration is actually a good thing. But, what is a Frustrated Lewis Pair (usually abbreviated as FLP)?, well not that fast, let’s start for the beginning.

frustration

One of the basics of chemistry reactivity is that the combination of a Lewis acid and a Lewis base leads to the formation of a classical Lewis adduct as exemplified by the combination of borane with ammonia to form the ammonia-borane adduct NH3.BH3. But, what happens if we introduce steric impediments in both the Lewis acid and the Lewis base? Then, it comes “the frustration” of the adduct. Do not mistake this with the actual frustration of a chemist attempting a reaction that does not work. In this situation, the steric demands preclude formation of simple Lewis acid-base adducts and then is when we have a Frustrated Lewis Pair.

pubications in FLP

In this very particular scenario where both acidity and basicity remain unquenched, FLPs have an extraordinary reactivity towards the cleavage and activation of small molecules such as hydrogen, alkenes, alkynes or CO2 among others. Unarguably the most important and more developed applications are within the fields of activation of hydrogen and catalytic hydrogenations. The number of publications and citations in Frustrated Lewis Pairs chemistry has been increasing since the first  publication in 2006 by Douglas Stephan, one of the “fathers” and most active researchers of the topic.

hydrogenacion

In my opinion there is still a long way to walk and we’ll see in the next years new developments in catalytic asymmetric hydrogenation along with applications in areas such as hydrogen storage, CO2 capture and fuel cells.

If you want to know more there are many good articles and reviews on the topic, these could be a starting point:

Seminal work by Douglas Stephan’s group

Gregory C. Welch, Ronan R. San Juan, Jason D. Masuda, Douglas W. Stephan. Reversible, Metal-Free Hydrogen Activation. Science, 2006, 314, 1124-1126.

A couple of reviews for newcomers to the topic

Stephan, Douglas W. “Frustrated Lewis pairs”: a concept for new reactivity and catalysis Organic & Biomolecular Chemistry (2008), 6(9), 1535-1539.

Stephan, Douglas W.; Erker, Gerhard. Frustrated Lewis Pairs: Metal-​free Hydrogen Activation and More. Angewandte Chemie, International Edition (2010), 49(1), 46-76.

A Trace-less Directing Group for Meta-Selective Arylation of Phenols.

The methodology developed by Larrosa and co-workers towards the meta-selective arylation of phenols is a  great example of combination of knowledge and creativity. Ortho-carboxylation of phenols with CO2  (Kolbe-Schmitt reaction) is a well known process that is used to synthesise salycilic acid, the precursor of aspirin. In addition, CO2 is a smart choice as directing group as it is abundant, inexpensive, non-toxic and non-flammable.

Traceless directing group

The direct meta-functionalization of phenols is quite a challenge due to the ortho/para directing ability of the hydroxyl group. Previous methodologies to achieve meta-functionalization require the use of protection-deprotection strategies with the consequent additional synthetic and purification steps.

Larrosa an co-workers approach the problem by in-situ introducing an ortho carboxyl group through direct reaction of phenol with CO2. The carboxyl function acts as a transient ortho-directing group that facilitates a palladium mediated metha-selective (to the hydroxyl group) cross coupling before being removed. An important drawback of the methodology is the requirement of high temperatures which could be a limitation for its scope in synthesis.

Do you want to know more? Go directly to the source:

Junfei Luo , Sara Preciado , and Igor Larrosa. Overriding Ortho–Para Selectivity via a Traceless Directing Group Relay Strategy: The Meta-Selective Arylation of Phenols. J. Am. Chem. Soc., 2014, 136, 4109–4112.      

X-Ray Snapshots. Mechanism Study on Pd-mediated Aromatic Bromination.

The study of the mechanism of a reaction is always a complicated task that usually starts with a draft on paper. You apply your knowledge in chemistry to make a hypothesis that you then need to prove with experimental facts. Even when the analyses performed in the lab strongly support your proposals you will never have complete certainty if you don’t have “the photo” of your “intermediate suspects”. A common strategy for the study of reaction mechanisms involving organometallic species is the synthesis of the proposed intermediates (your suspects) and then try to capture “the photo” with the use of X-Ray crystallography techniques. I mean, you have to pray for your compounds to crystallise…

reaction photosnap

Because I have suffered all these problems in the lab is why I consider so remarkable the mechanistic study of a Palladium-mediated aromatic bromination published by Fujita and co-workers in 2014 in JACS. The strategy carried out by the authors consists of the use of a crystalline flask of ZnI2 and tris(4-pyridyl)triazine in which the Palladium complex object of the study is embedded. The reaction is performed in the crystalline flask and the intermediates captured in-situ by time dependent X-Ray diffraction. The authors literally take “photos” of the catalytic cycle of the reaction and show in-situ cristallography as a great tool for the elucidation of reaction mechanisms.

Do you want to know more? Then go directly to the source.

Ikemoto, Y. Inokuma, K. Rissanen and M. Fujita. X‑ray Snapshot Observation of Palladium-Mediated Aromatic Bromination in a Porous Complex. J. Am. Chem. Soc. 2014, 136, 6982-6985

You Know Nothing Jon Snow.

Jon snowI think that Socrates with his “One thing only I know, and that is that I know nothing” and Ygritte from the popular Game of Thrones with her “You know nothing Jon snow” were both right. This of course needs further explanation, recently it was brought to my attention an article published in Journal of Cell Science in 2008 with the catching title “The importance of stupidity in scientific research“. The main conclusion I extract from the article is the good of stupidity, understood as ignorance by choice, for the progress of science. In other words, if you don’t feel “stupid”, meaning that you don’t have questions to answer related to your research project, either the problem you are trying to solve is just trivial or you are not  trying hard enough. In the article it is also discussed the fact that teaching  at universities may not be effective enough as students are not aware of how difficult research is and do not learn how to use their so-called “stupidity” in a productive way.

There is something else I would like to discuss in this post. I enjoyed the concept of “productive stupidity”. But, what if there were no more questions what if you reach the point when you solve the riddle, not just the one but all, I rather die. There is one more important point I do agree with in the article, we (scientists) start loving what we do at first because we are good at science then it comes more (at least that happened to me), we need the knowledge, to solve the puzzle and there is never enough. Knowledge has been my driving force since I remember, to the point that when I master a topic I need to refresh and search for more challenging things. So I hope I can always feel “stupid” and know nothing and have always someone around me able to tell: you know nothing.

 

Nanoputians: Nanoscale Human Figures.

Although this is not new material,  I would like to open  Nanoputianmy section of “Impossible molecules” with a great example of creativity and tons of good sense of humour in organic chemistry: The Nanoputians. Back in 2003, James Tour and colleagues published a paper in Journal of Organic Chemistry where they describe the synthesis of an array of human-shaped organic molecules they called Nanoputians as a reference to the well known small characters, the Lilliputians, from the classic Gulliver’s travels . A very educational paper, ideal for undergrads and organic chemistry newcomers. It is very enjoyable the way they describe the synthesis of their Nanoputians using body-part-like descriptions and the originality of the names given to the molecules for a nano-universe with Nanokids, Nanobakers, Nanoballetdancers and more.  I could not say how many  organic chemistry papers I have read in my life so far, but there is no doubt that I will always remember Nanoputians and I am completely sure I will not be the only one.

Do you want to know more? Read the original papers.

Chanteau, S. H.; Tour, J. M. “Synthesis of Anthropomorphic Molecules:  The NanoPutians”. The Journal of Organic Chemistry 2003, 68, 8750–8766.

Chanteau, S. H.; Ruths, T.; Tour, J. M. “Arts and Sciences Reunite in Nanoput: Communicating Synthesis and the Nanoscale to the Layperson”. Journal of Chemical Education 2003, 80, 395.

“I love it when a plan comes together” didn’t work for me.

I-love-it-when-a-plan-comes-together

If you were a kid in the 80’s (as I was) you have probably recognised the quote in the title “I love it when a plan comes together” from the leader of The A team Hannibal Smith. And now you are picturing Hannibal (I am) saying his quote while lighting a big cigar. Well, I have to say that things didn’t work for me that way but I’m not less happy because of that.

I guess that many people, scientists (yes, scientists are people after all) or more specifically chemists like me make a lot of plans with lots of time in advance imaging how their careers in science will be. I decided I wanted to be a chemist at the age of 16. So, there I was collecting all type of information on “how to become a chemist” and I started to write my own script , my own pathway to become a chemist.  Study hard, get good marks, go to university, study hard, get good marks, get a Ph.D. fellowship, publish a lot in good journals, go abroad for a couple of years as post-doc, work hard, publish a lot, get permanent position and live happily ever after doing chemistry stuff. It wasn’t that difficult, was it?

First year at the university studying chemistry, everything goes as planned, I am happy there are no surprises so far, I am on my way to become a chemist so I only have to stick to the plan. Time goes by, I fall in love with organic chemistry and I get my degree, and now what? Let me check the script, yes of course now is time for a Ph.D. Perfect then, bullet point under the section “start my  Ph.D.”

-Go to see supervisor to discuss about the best options to get funding for my Ph.D.

That was the exact moment my script started to have major failures, my supervisor changed everything when he recognised to me that I would have more opportunities in a better chemistry group. He knew how much I wanted to do a Ph.D. and took the liberty to contact one of his colleagues from probably one of the best groups in organic chemistry at that time in Spain. This is what it was going on, my supervisor was “plotting against me” he was making plans behind my back, he dared to change my script, the script  I had been writing for years. The morning I went to my supervisor’s office with the idea to talk about fellowships he had set me up with a phone interview for a Ph.D. position. Guess what, I got a Ph.D. position in an interview I had not included in my career plans. That moment definitely changed my life and my career.

That was only the beginning, as I was writing the post I realised it was going to be too long and that I should write a bit more on “plan changes” in my next posts.   Life has made many plans on my behalf and I had to re-write my script many times.

Thanks Javier I will never be able to thank you enough.

 

 

Chemistry for NO-MADs

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