Tag Archives: Organic chemistry

Superbases in FLP chemistry

A new post for the series I am crazy about Frustrated Lewis Pairs (FLPs). If you are new to this exciting field I recommend you to read first one of my previous posts: “Frustration to a Good End”.superbases2The extraordinary reactivity of FLPs allows the stoichiometric and catalytic activation of small molecules being the most important application the heterolytic cleavage of hydrogen. The spectrum of Lewis bases used in FLP chemistry is wider compared to the Lewis acid partners. Phosphines, amines, N-heterocyclic carbenes or carbodiphosphoranes have been used, with a few exceptions, combined with boranes such as B(C6F5)3 and derivatives.

strategy

The activation of the strong H-H bond has been commonly achieved using a type of the Lewis bases mentioned above in the presence of strong Lewis acidic boranes. Krempner and co-workers have recently showed that the use of strong Lewis acids is not strictly necessary for the activation of hydrogen. In this new approach denominated as “Inverse” Frustrated Lewis Pairs, organic superbases combined with rather moderate and weak Lewis acids are capable to reversibly cleavage hydrogen. Organic superbases have an enormous proton affinity and are very strong due to the great stability of their conjugated acids once they are protonated. In their recent work Krempner and co-workers activate hydrogen using phosphazene based superbases with BPh3, HBMes2 or 9-BBN and extend the concept of Inverse Frustrated Lewis Pairs to the catalytic hydrogenation of organic molecules using N-Benzylidenaniline as model substrate.catalysisDo you want to know more? Read the original paper

Suresh Mummadi, Daniel K. Unruh Jiyang Zhao, Shuhua Li and Clemens Krempner. “Inverse” Frustrated Lewis Pairs – Activation of Dihydrogen with Organosuperbases and Moderate to Weak Lewis Acids. J. Am. Chem. Soc., 2016, 138 (10), pp 3286–3289.

Are you a newcomer to the topic? Take a look to this papers

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.

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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.

Two-step Sequence Strategy for the Synthesis of ortho-OCF3 Anilines.

The chemistry of molecules containing fluorine atoms has grown in interest and in consequence a great increase of the number of papers on synthetic strategies to introduce fluorine atoms in molecules has been observed during the last years. Fluor is known to improve the biological activity of drugs by enhancing properties such as the solubility, stability and lipophilicity of molecules. The OCF3 moiety in particular presents one of the highest lipophilicity values favouring  in vivo uptake and transport in biological systems.

orto OCF3 migration

Ngai and co-workers describe a useful procedure for the synthesis of ortho-trifluoromethoxylated anilines through a two-step sequence of O-trifluoromethylation of alkyl hydroxylamines followed by OCF3 migration. The methodology allows the formation o a wide range of ortho-OCF3 aniline derivatives with high regioselectivity and can be performed one-pot. One of the drawbacks is that the migration step requires higher temperatures than the initial trifluoromethylation making  almost unavoidable the removal of solvent and further re-dissolution to achieve the whole sequence.

Do you want to know more? You can find here the paper:

Katarzyna N. Hojczyk, Dr. Pengju Feng, Chengbo Zhan andProf. Ming-Yu Ngai. Trifluoromethoxylation of Arenes: Synthesis of ortho-Trifluoromethoxylated Aniline Derivatives by OCF3 Migration. Angew, Chem. Int. Ed. 2014, 53, 14559-14563.

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.

Frustrating Fuel Cells.

This is not the first time and probably will not be the last time I post about Frustrated Lewis Pairs (FLPs). Due to the unquenched acidity and basicity of FLPs, these systems present an extraordinary reactivity to the cleavage and activation of small molecules. Unarguably, the most important application is the activation of hydrogen, FLPs are capable to heterolitically cleavage the strong bond of the molecule of dihydrogen resulting in a hydride adduct of the Lewis acid and a protonated Lewis base at room temperature. From the point of view of a synthetic chemist, the activation of hydrogen with FLPs opens the door to a new class of metal-free hydrogenation reactions. However, creativity in the area of FLPs seems to be endless as shown in the great contributions by Andrew Ashley and Gregory G. Wildgoose groups from the Imperial College of London and the University of East Anglia towards the oxidation of hydrogen.

FLP Fuel Cell

In the search for alternatives to fossil fuels, hydrogen has raised as a promising and a clean source for the production of electricity from chemical energy with the use of fuel cell technology. In the absence of a catalyst, the necessary process of oxidation of hydrogen is slow and require large overpotentials. Here is where the FLPs play their role as they considerably reduce the voltage required for the hydrogen oxidation due to the generation of hydride intermediates that are easier to oxidise to protons. Ashley, Wildgoose and co-workers were able to stoichiometrically oxidise hydrogen using one of the most basic FLP system B(C6F5)3/P(tBu)3 but unfortunately the system is not robust enough to complete more than one catalytic cycle. Some improvements were made recently replacing B(C6F5)3 for a borenium cation as a Lewis acid although the system is still lacking enough stability to properly catalyse the oxidation. As a proof of principle, it is indeed possible to oxidise hydrogen with an electrochemical/FLP approach. FLP systems have the advantage of their inherent “tuneability”  and there is still plenty of room for improvement in the way to develop a FLP based fuel technology.

Do you want to know more? Here you are the original papers:

Elliot J. Lawrence, Vasily S. Oganesyan, David L. Hughes, Andrew E. Ashley, and Gregory G. Wildgoose. An Electrochemical Study of Frustrated Lewis Pairs: A Metal-Free Route to Hydrogen Oxidation. J. Am. Chem. Soc., 2014, 136 , 6031–6036.

Elliot J. Lawrence, Thomas J. Herrington, Andrew E. Ashley, Gregory G. Wildgoose. Metal-Free Dihydrogen Oxidation by a Borenium Cation: A Combined Electrochemical/Frustrated Lewis Pair Approach. Angew. Chem. Int. Ed. 2014, 53, 9922 –9925.

A Catalytic Wittig Reaction.

The Wittig reaction was discovered by Georg Wittig and co-workers in 1953 and for which Wittig was awarded the chemistry Nobel Prize in 1979.  Since its discovery, the Wittig reaction has probably been the preferred choice of synthetic chemists towards the synthesis of alkenes. The formation of the alkene proceeds through the reaction of an aldehyde or ketone with a phosphonium ylide. The success of the reaction is due first to its regioselectivity, as the double bond of the alkenes is formed only between the reacting carbon of the ylide and the carbonylic partner, and second to its stereoselectivity to the formation of one of the two possible geometric isomers. The major drawback of the reaction is the generation of stoichiometric amounts of undesired triphenylphosphine oxide, a byproduct that frequently complicates the purification of the desired product.

wittig

In a very smart approach to overcome the problem of generating such a big amount of phosphine oxide waste, O’Brien and co-workers from the University of Texas designed a catalytic version of the Wittig reaction. The challenges: to generate in situ the reactive ylide and to reduce the phosphine oxide without reducing the carbonyl compounds involved in the reaction. The solution: the utilization of a cyclic phosphine that is reduced by Ph2SiH2, a reducing agent mild enough to leave the carbonyl  coupling partners intact. The catalytic version has proved effective with a series of aldehydes and stabilised or semi-stabilised ylides. The reaction represents an important first step to a general catalytic Wittig reaction and more research will be needed to achieve the same degree of effectiveness as the stoichiometric variant in terms of the scope of substrates and regioselectivity.

Do you want to know more? Take a look to the original paper:

Christopher J. OBrien, Jennifer L. Tellez, Zachary S. Nixon, Lauren J. Kang, Andra L. Carter, Stephen R. Kunkel, Katherine C. Przeworski, and Gregory A. Chass. Recycling the Waste: The Development of a Catalytic Wittig Reaction. Angew. Chem. Int. Ed. 2009, 48, 6836 –6839.

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.

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.