This is a full account of our studies into the generation of highly functionalised 2-aryl-1,2-dihydropyridines and 2-methylene-3-aryl-1,2,3,4-tetrahydropyridines via intermolecular aryne ene reactions of Hantzsch esters. Furthermore, exposure to excess aryne revealed unusual 3′-aryl-spiro[benzocyclobutene-1,1′-(3′,4′-dihydropyridines)]. Mechanistic insights are provided by deuterium-labelling studies and DFT calculations, whilst preliminary cytotoxicity investigations reveal that the spirocycles are selective against colon carcinomas over ovarian cancer cell lines and that all the compounds have high selectivity indices with regards to non-cancer cells.
First day in the labs with our 1st year students. Today we will be doing acid-base titrations to determine the amount of citric acid in a sample of a powdered fruit drink. Students will use a standard solution of NaOH as a titrating agent and Phenolphthalein as indicator.
It is September again and as usual, we start the semester with the advanced practicals in chemistry with our Master students. It seems that after the summer break our students are in a very good mood and organic synthesis under nitrogen atmosphere becomes a balloon party!!!
The reaction of arynes with 1,4-dihydropyridines affords 2-aryl-1,2-dihydropyridines or 2-methylene-3-aryl-1,2,3,4-tetrahydropyridines via a regioselective C-2 or C-3 arylation. These compounds are the first series of isolable and bench-stable covalent ene adducts formed between dihydropyridines and unsaturated substrates. Experimental studies and DFT calculations provide mechanistic support for a concerted intermolecular aryne ene process, which may have implications for NAD(P)H model 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.
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. 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.
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.
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).
It is again this time of the year, the semester has been very long. One more week of practicals and we are all ready for the Christmas break!!!
This year to honour the tradition we have our ChemisTree in the teaching labs. In this post I’m unveiling the secrets behind the colours of our 2016 ChemisTree.
Blue: A pinch of Copper (II) sulfate pentahydrate in water
Red: a few drops of Ferroin indicator in water
Green: A pinch of Nickel(II) nitrate hexahydrate in water
Deep purple: A pinch of potassium Permanganate in water
Violet: Literally 1 mg of Crystal Violet per Liter of water. Crystal Violet is a very strong dye.
Pink: A few drops of Phenolphthalein in a slightly basidified solution of NaOH in water. The colour fades away after a few minutes, long enough for a nice picture.
Many thanks to Indigo and Fosca for their help and creativity.
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”.The 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.
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.Do 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.
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.
-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.