Category Archives: Opinion

On the road to the full control of the stereochemistry of dihalogenation reactions

The dihalogenation reactions of alkenes proceed with almost exclusive anti-diastereoselectivity and opposed to other well-known text book reactions, an enantioselective version seems quite elusive. In the last few years, I have been fascinated by two great advances towards the full control of the stereochemistry in reactions of dihalogenation of alkenes. First the discovery of enantioselective dihalogenation reactions and second the discovery of a catalytic syn-dichlorination of alkenes.

anti mechanism
The development of enantioselective versions is very elusive because racemization can easily occur via olefin-to-olefin halenium transfer and non-regioselective nucleophilic opening of the halonium intermediates. The first successful approach to this problem was done by the group of Scott Snyder who developed a stoichiometric dichlorination reaction using a chiral borane auxiliary that forms an in-situ complex with the substrate[1]. The chlorinated olefin was obtained with 87% e.e. and that was a tremendous success due to the difficulty of the reaction. A catalytic version adds the nonenantioselective background reaction to the existing problems. Later discoveries of catalytic enantioselective dichorinaton, dibromination and heterodihalogenation reactions of olefins by the groups of Nicolau, Burns and more recently Borhan are simply spectacular [2–5]. Nicolau and Borhan approach the problem using Sharpless dihydroxylation catalyst (DHQD)2PHAL while Burns uses a combination of a Titanium salt with a chiral promoter. But all these approaches have in common a wise election of substrates (allyl alcohols and amides) that can serve as an anchor to the catalysts to overcome the regioselectivity problem.

dihalogenation of olefins
The almost set-in-stone mechanism of the dihalogenation of alkenes involves the formation of a cyclic halonium ion followed by a backside nucleophilic opening that leads to the formation of the well stablished anti-product. Overturning the anti-diastereospecificity of this process is a major challenge. The group of Scott Denmark was able to develop the first syn-dichlorination of alkenes with a strategy based on a first step of anti-addition of an in-situ generated PhSeCl3 to an alkene followed by a nucleophilic displacement with a chloride ion source leading to a syn-dichlorination product overall.6
The process is made catalytic by adding an oxidant to the Ph-Se-Se-Ph precatalyst.
All these discoveries are impressive and I cannot help finding certain parallelism with the already Nobel Prize awarded hydrogenation and dihydroxylation reactions by Noyori, Knowles and Sharpless. I am very much looking forward to seeing further advances.

nobel prize2

References:
1. Snyder, S. A., Tang, Z.-Y. & Gupta, R. Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin. J. Am. Chem. Soc. 131, 5744–5745 (2009).
2. Nicolaou, K. C., Simmons, N. L., Ying, Y., Heretsch, P. M. & Chen, J. S. Enantioselective Dichlorination of Allylic Alcohols. J. Am. Chem. Soc. 133, 8134–8137 (2011).
3. Hu, D. X., Shibuya, G. M. & Burns, N. Z. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc. 135, 12960–12963 (2013).
4. Hu, D. X., Seidl, F. J., Bucher, C. & Burns, N. Z. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc. 137, 3795–3798 (2015).
5. Soltanzadeh, B. et al. Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides. J. Am. Chem. Soc. 139, 2132–2135 (2017).
6. Cresswell, A. J., T.-C., E. & Denmark, S. E. Catalytic, stereospecific syn-dichlorination of alkenes. Nat Chem 7, 146–152 (2015).

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An alternative to Brady’s test?

In one of our practicals at the chemistry teaching labs of Queen Mary University of London our students are provided with a mixture of 2 unknown organic compounds that they have to separate and identify with the use of spectroscopic methods and analytical qualitative tests. One of the most common tests during the practical is the Brady’s test for the identification of aldehydes and ketones. In this test a solution of 2,4-Dinitrophenylhydrazine (2,4-DNP) is reacted with the unknown mixture and if there is an aldehyde or a ketone, a yellow to deep red precipitate is observed as a consequence of the formation of the corresponding 2,4-dinitrophenylhydrazone.

Here is a nice video from FranklyChemistry showing examples of how a positive Brady’s test looks like:

For the practical this year I realised we had run out of 2,4-DNP and we needed to buy some more. I tried to buy 2,4-DNP from usual providers such as Sigma Aldrich, Alfa Aesar and VWR among others just to find that the chemical has been discontinued because is explosive.

I thought of alternative tests like Tollen’s and Fehling’s but unfortunately they are not general for carbonyl compounds and they only work for aldehydes easy to oxidise. My next move was to consult with colleagues in the department and in the internet community. Networks like researchgate and projects like #realtimechem on twitter are incredibly useful to connect and exchange knowledge with chemists around the world.

This time, very interesting suggestions as alternatives to 2,4-DNP came from Researchgate, (credit to: Joe Olechno, Matthew Mcgrath and Americo Lemos):

-4-Hydrazino-7-nitro-benzofurazan has been used to make fluorescent derivatives of aliphatic aldehydes including reducing sugars.

-4-Amino-3-hydrazino-5-mercapto-1,2,4-triazole (also known as purpald): Used for the determination of formaldehyde, gives a purple colour with aldehydes and also reacts with ketones but the product is not coloured.

-2,4-dichlorophenylhydrazine as a non-explosive alternative.

I still have to test this alternatives and if successful I hope I can write a post explaining the experience.

Ironically, I have recently found that a suitable alternative to 2,4-DNP is actually 2,4-DNP but as a solution in phosphoric acid. The 2,4-DNP solution in phosphoric acid can be purchased from Sigma Aldrich and it is advertised as an alternative to the explosive 2,4-DNP.

Video games to Promote Science

If this is not an amazing way to promote science I don’t know what it is. The Brazilian science magazine Superinteressante is developing a fighting video game using prominent scientists as the characters. Their abilities and fight skills are based in their scientific discoveries. You can take a look to the description of the characters in the website of his creator Diego Sanches. Imagine a fight between Tesla and and Stephen Hawking, I’m still in shock.

Take a look to this youtube demo:

 

Must Read Papers 2015. Part 2.

help 2At the end of 2015 I wrote a post (Must read papers 2015) including my favourite paper of the year and recommendations of a few nice reviews/highlights to read during Christmas. During 2015 I selected several papers I wanted to write about in the blog but unfortunately I have less time than I would like and I couldn’t write a line about many of them. Now 2015 is gone and I already have a few nice papers selected this year to comment in the blog. So all these nice papers are piling up and haunt me in my dreams because I don’t have enough time (or maybe because I’m just lazy).

To make a long story short I have decided to write a follow-up post of the Must read papers 2015 to comment a little bit on the best papers I selected during 2015 that for one reason or the other attracted my attention (click on the pictures if you want to go to the paper’s websites).

The first two papers of the post fit perfectly in the section Cool Synthesis under the topic Impossible Molecules. The Impossible Molecules topic is dedicated to molecules with exotic structures, elusive molecules and synthetically challenging molecules in general.  The first paper describes the first example of an amazing corannulene derivative bearing an internal heteroatom. The second paper describes a creative strategy to stabilise long cumulenes with a phenanthroline-based macrocycle.

1_ACIE_Benzene=Fused Azacorann

2_Cumulene rotaxanes

If you have ever read this blog before, you already know I’m a bit (just a bit) obsessed with halogenating reactions so you will find several posts on the topic. There are 2 papers I couldn’t write about during 2015 that I want to highlight. The first one describes a one-pot vicinal fluorination-iodination of arynes using the diphenyliodonium salt as a catalyst and CsF as a fluorine source. The second paper describes the synthesis of the molecules Halomon, Plocamenone and Isoplocamenone using a dihalogenating reaction I wrote about in a previous post.

3_iodofluorination

3_sintesis total dihalogenacion

Another of my obsessions is the chemistry of Frustrated Lewis Pairs (FLP), and just as I said in one of my previous posts “This is not the first time and probably will not be the last time I post about Frustrated Lewis Pairs”. One of the papers I didn’t have time to write about is this nice contribution by Stephan’s group on the catalytic hydrogenation and reductive deoxygenation of ketones and aldehydes.

4_FLP reduction

The next paper is another creative contribution by Alcarazo and coworkers. The paper describes an interesting alternative to hipervalent iodine species, Dihalo(imidazolium)sulfuranes that are versatile electrophilic group-transfers reagents.

6_paper alcarazo

The last paper I want to mention in this post caught my attention because of the interesting fact that the selectivity of the two products obtained in a copper-catalysed arylation is controlled by the choice of the reaction vessel.

7_reaction vessel

 

A research project true story

INTRO FARGO_4

LUVERNE, MINNESOTA, JULY 1986

Lorne Malvo, a young and ambitious postdoc, joins the lab of rising star Dr. Lou Solverson at the University of Luverne in Minnesota. Within Dr Solverson’s group, Lorne starts an industrially funded project on the Haber-Bosch process toward the artificial nitrogen fixation for the production of ammonia. The Haber-Bosch process is typically conducted at 150–250 bar and between 400–500 °C but recently in 1985 it was published a patent using a new family of iron catalysts that, according to the patent, were capable to substantially reduce the ranges of pressure and temperature with no loss of efficiency. The sponsors of the project wanted Dr Solverson and Lorne to investigate the validity of the results published in the patent and further investigate new catalysts to improve the Haber-Bosh process.

The results published in the patent lacked lots of information related to the synthesis and characterization of the catalysts used, experimental procedures and catalysis conditions were poorly described. So the initial step of reproducing published results turned into a big challenge.

LUVERNE, MINNESOTA, SEPTEMBER 1987

After more than one year of tests and catalyst screening Lorne and Dr. Solverson were not capable to reproduce the results published in the patent and started to question its veracity. Still all this work was very useful to learn about all the difficulties of the process itself and produced enough relevant data for a publication. Solverson and Malvo were aware of the difficulty of publishing a paper based on someone else’s results but also assumed the responsibility of sharing with the catalysis community their results which questioned an accepted patent. Under the title “Reinvestigation of new iron catalysts for the Haber-Bosch process” Solverson and Malvo submitted a paper to the journal Catalysis & Chemistry (from the Editorial Fargo) with an impact factor of 5.04.

LUVERNE, MINNESOTA, OCTOBER 1987

Solverson and Malvo received comments from the referees:

-Referee one considered the paper could be published in Catalysis & Chemistry because of the interest to the catalysis community and wanted to include a few more references (probably this referee’s work)

-Referee two did not accept the paper arguing that Malvo and Solverson’s contribution was only a reproduction of the work published in the patent.

Referee two was what Malvo and Solverson were most afraid of, someone that did not understand the aim of the paper which was a warning to the community about a patent that at first seemed promising. After a few unsuccessful attempts to convince referee two, Malvo and Solverson decided to submit their work to the journal Chemistry of Catalysis (Bo Munk Editorial) with an impact factor of 4.7.

LUVERNE, MINNESOTA, DECEMBER 1987

Malvo and Solverson’s paper was accepted with minor revisions in Chemistry of Catalysis. A few days before the paper was in press Malvo realised that impact factors had changed and now Chemistry of Catalysis had an impact factor of 5.426 (Previously 4.7) and Catalysis & Chemistry had an impact factor of 4.556 (Previously 5.04).

SOME YEARS AFTER THAT…

Dr Solverson was awarded with a prestigious grant and was promoted to Full Professor, he continues producing high quality research but the events occurred during 1987 made him very sceptical about the peer-review system.

Lorne Malvo could not take it anymore and lost all faith in the peer-review system, he quitted science and currently survives as soldier of fortune. If you have a problem, if no one else can help, and if you can find him, maybe you can hire him.

A couple of interesting papers on the Haber-Bosh process:

Lessons learned and lessons to be learned for developing homogeneous transition metal complexes catalyzed reduction of N2 to ammonia. Chinnappan Sivasankar, Sambath Baskaran, Masilamani Tamizmani, Kankanala Ramakrishna. Journal of Organometallic Chemistry, Volume 752, 2014, Pages 44–58.

Exploring the limits: A low-pressure, low-temperature Haber–Bosch process. Aleksandra Vojvodica, Andrew James Medfordb, Felix Studta, Frank Abild-Pedersena, Tuhin Suvra Khana, T. Bligaarda, J.K. Nørskov. Chemical Physics Letters, Volume 598, 2014, Pages 108–112.

To understand better this post you may want to take a look to these links:

Fargo_(TV_series)

Fargo (film)

 

 

 

 

 

 

Must read papers 2015

Now that 2015 is ending I remember a nice tradition we used to have in the research centre where I did my first postdoc. At the end of December we had a “Reaction of the year” seminar in which everyone of us had to present a paper we thought it was the most important contribution of the year.

I would like to use a similar idea in this post to open a discussion in which everyone can say their #favouritepaperof2015 and why. So I am going first…

Yeah, the main reason I liked so much this paper is that I may have a bit of an obsession with halogenation reactions in general. Anyway it is a must read paper in this year 2015, I’ve recently wrote a post about it if you are interested.

Besides my favourite paper of the year, for those who want to read a bit of chemistry during the Christmas break I would like to recommend you a couple of reviews and highlights on topics I really like and I hope you also enjoy (click on the pictures to go to the links).

Conia

FLP

ammonia

asymmetric chlor

Quick guide to get your synthetic methodology in a top journal

Nowadays thousands of “gurus” share their expertise to offer guidance in topics ranging from beauty and health to how to succeed in life. Chemistry of course is not an exception, we have our own gurus to seek for a piece of advice on many chemistry-related topics. Well, I am not a guru but still for my post today I would like to write a few lines on how I think you can improve your chances to get your synthetic methodology published in a good journal. I have also included one beautiful Yes-No flow diagram so my post is taken more seriously.

get published

Even in the case you have developed a new methodology to solve a very challenging synthetic problem, you may not get your results published in the top journals if you don’t include all the relevant information. For example, sometimes including a mechanism proposal is as important as getting excellent yields. I have considered two main scenarios:

Your synthetic methodology is new: The best scenario possible. You are the first one that solved the puzzle, but make sure the problem you are working in has relevance. And make sure that you are the first, so you did a good and meticulous literature research. Let’s say your method is good and your research is relevant, now is time to be creative. Select challenging and varied substrates and explore functional groups tolerance. If you are using a catalyst or a reagent developed by you it has to be fully characterized, an X-Ray structure can make the difference to get to the top journals. A new methodology might mean new reaction pathways or mechanisms. In my opinion at least a mechanism proposal should be always included. More and more often publications in synthetic methodology include now theoretical calculations to support mechanistic proposals.

Your methodology is not new but is way better than the others: Now is time to show your muscles. Besides being creative with substrates, having a full characterization or good mechanistic studies, now more than ever you have to include “extra toppings” to strengthen your chemistry. Stablish clear comparisons between your methodology and current methods using tables, explore recyclability or robustness of your catalyst, reagent or conditions. In other words try to highlight all your methodology’s strengths. Show off, put some efforts trying to scale-up to multi-gram levels “I synthesised 500 g at once, why? Because I can”. Apply your methodology to the synthesis of products of interests.

To conclude this post what could be better than showing a very good example of how to get your synthetic methodology in a good journal? This great work by Snyder and co-workers (click the link) speaks for itself: Et2SBr⋅SbCl5Br: An Effective Reagent for Direct Bromonium-Induced Polyene Cyclizations (Angew.Chem.Int.Ed.2009,48, 7899 –7903). In their paper, Snyder and co-workers describe a new reagent for well known reactions of bromocyclization. They describe the synthesis of their reagent with a full characterization including an X-Ray structure and more importantly they don’t hesitate to show muscle. They compare their reagent with the existing methods at that time to clearly show their reagent is in general better than the others, they also explore the scaleability of their methodology and apply it to the synthesis of natural products.

Celebrities, Pharaohs and Chemists.

“When kids look up to great scientists the way they do to great musicians and actors, civilization will jump to the next level”                                                                                                                                                                   –Brian Greene-

fameThe recent release of Stephen Hawking’s biopic “The theory of everything” along with others like Alan Turing’s “The Imitation game” have helped to revive debates in social media about celebrity scientists. By the way, both are great movies. It turns out that nowadays science is sexy, wasn’t it always? And no doubt that the TV show “The Big Bang theory” had a great deal in catalysing these events. Recently it was brought to my attention a post called Who’s the world’s greatest living chemist? And I started to think if maybe any of my contemporary fellow chemists could be in that list in 30-40 years. People whose work I read every day in the journals or people that work in the same department. This is somewhat exciting and scary at the same time, some of the guys I know are brilliant but won’t make it to their 50s drinking so much beer.

I have always been a great fan of the Authors Profile section of the Journal Angewante Chemie International Edition. ACIE grants chemists, who have recently published their 10th, 25th, 50th or 100th, with a profile consisting on a series of question about themselves. The questions are not always the same but many of them are repeated in several profiles. You can find a lot of interesting, surprising and sometimes odd details about your “chemistry idols”. I learnt about the profiles section during my last year of PhD when I was thinking of sending applications for prospective postdoctoral stays.

Everyone knows about the topics in chemistry they like the most, but if you are moving to another research centre for a couple of years and that is likely to be in a different country you better like both the chemistry and the people you are working with/for. I was very interested about the reasons why my chemistry idols and other big names in chemistry decided to be chemists. I found answers that were not new to me and at the same time were comforting, the kind of: “I was motivated by a teacher”, “it is fun”, “everything around us is chemistry”, “I love working in the lab”, “I like creative challenges”. And I say comforting when other may say boring because I found others answers like “God directed me this way” and  “the registered mail with my application to study biology never arrived at central admissions” you can take your own conclusions on those last ones. It would take many hours to analyse all the profiles published so far. I might do it sometime, but if someone else out there has the time and the dedication I am not claiming the rights for the idea. Just one additional comment/thought about one of the answers given to “if I could be anyone for a day, I would be…” that intrigued me the most, I saw in a few profiles answering that they would be Pharaoh Cheops and a my follow up question to them would be: Is it because you want your legacy to be comparable to the pyramids or because the number of postdoc-slaves you want?

Top Drugs Academy Awards.

redcarpet awardBig Pharma companies invest billions of dollars every year for a very low rate of success and still all these efforts must pay off. Only a few drugs are accepted every year as they have to pass through innumerable tests in order to guarantee, for the most obvious reasons, the safety of patients-customers.

Last September C&EN released a supplement on The Top 50 Drugs of 2014. Something I see like the academy awards of drugs, a very interesting catalogue in which you can see the ultimate tendencies in drugs research and also the direction pharma companies are taking in terms of where to invest their money. The supplement analyses the top 50 drugs according to 3 different categories: The top 10 emerging blockbusters (drugs recently approved with $1 billion plus potential),  the top 10 drugs in development (most promising drugs still in the pipeline) and the 30 top-selling drugs on the market.

Apart from my curiosity as a chemist I wanted to know what are the diseases object of research for pharma companies. When you take a closer look to the diseases treated by the top selling drugs you see that the first and second are for the treatment of rheumatoid arthritis and the third top selling  drug is for asthma and chronic obstructive pulmonary disease. A bit unexpected I have to recognise, if I had to place a bet without all that information I would have said cancer, no doubt, is top 3. You see treatment for leukemia, a type of cancer, in the fourth position. Fifth position for the treatment of diabetes and at last cancer (used as a general term) appears in the sixth position. Then when you continue going down the list you see mainly cancer, HIV, respiratory problems and pain treatments. And it is quite clear that the treatment of pain has a big part in the whole business.

Concerning the top 10 emerging blockbusters and the top 10 drugs in development the tendency is similar. Predominantly cancer with a special mention to breast cancer, HIV, diabetes and in the top positions hepatitis C.

From a more synthetic point of view, there were a few things that caught my attention. First of all, where are all the super-big molecules from the literature in total synthesis? where are all these molecules isolated from plants and algae with medicinal properties? Instead of those, the vast majority of the drugs are small to medium size molecules. Molecules dominated by nitrogenated heterocyclic structures and in a great number of cases bearing fluor atoms or fluorinated functional groups. All these facts highlight the relevance of the development of the chemistry of heterocycles which are ubiquitous in nature. And also the increasing number of papers on fluorination methodologies in the literature as it is known that fluorine atoms often enhance the pharmacological properties of organic molecules.

And with all said, it only rests to congratulate the 2014 awardees. Nevertheless, my advice to all is try to keep yourselves healthy.

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.