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New paper in Tetrahedron #CompChem “Why U don’t React?”
Literature in synthetic chemistry is full of reactions that do occur but very little or no attention is payed to those that do not proceed. The question here is what can we learn from reactions that are not taking place even when our chemical intuition tells us they’re feasible? Is there valuable knowledge that can be acquired by studying the ‘anti-driving force’ that inhibits a reaction? This is the focus of a new manuscript recently published by our research group in Tetrahedron (DOI: 10.1016/j.tet.2016.05.058) which was the basis of Guillermo Caballero’s BSc thesis.
It is well known in organic chemistry that if a molecular structure has the possibility to be aromatic it can somehow undergo an aromatization process to achieve this more stable state. During some experimental efforts Guillermo Caballero found two compounds that could be easily regarded as non-aromatic tautomers of a substituted pyridine but which were not transformed into the aromatic compound by any means explored; whether by treatment with strong bases, or through thermal or photochemical reaction conditions.
These results led us to investigate the causes that inhibits these aromatization reactions to occur and here is where computational chemistry took over. As a first approach we proposed two plausible reaction mechanisms for the aromatization process and evaluated them with DFT transition state calculations at the M05-2x/6-31+G(d,p)//B3LYP/6-31+G(d,p) levels of theory. The results showed that despite the aromatic tautomers are indeed more stable than their corresponding non-aromatic ones, a high activation free energy is needed to reach the transition states. Thus, the barrier heights are the first reason why aromatization is being inhibited; there just isn’t enough thermal energy in the environment for the transformation to occur.
But this is only the proximal cause, we went then to search for the distal causes (i.e. the reasons behind the high energy of the barriers). The second part of the work was then the calculation of the delocalization energies and frontier molecular orbitals for the non-aromatic tautomers at the HF/cc-pVQZ level of theory to get insights for the large barrier heights. The energies showed a strong electron delocalization of the nitrogen’s lone pair to the oxygen atom in the carbonyl group. Such delocalization promoted the formation of an electron corridor formed with frontier and close-to-frontier molecular orbitals, resembling an extended push-pull effect. The hydrogen atoms that could promote the aromatization process are shown to be chemically inaccessible.
Further calculations for a series of analogous compounds showed that the dimethyl amino moiety plays a crucial role avoiding the aromatization process to occur. When this group was changed for a nitro group, theoretical calculations yielded a decrease in the barrier high, enough for the reaction to proceed. Electronically, the bonding electron corridor is interrupted due to a pull-pull effect that was assessed through the delocalization energies.
The identity of the compounds under study was assessed through 1H, 13C-NMR and 2D NMR experiments HMBC, HMQC so we had to dive head long into experimental techniques to back our calculations.
Fluorescent Chemosensors for Chloride in Water – Sensors and Actuators B: Chemical
A new publication is now available in which we calculated the binding properties of a fluorescent water-soluble chemosensor for halides which is specially sensitive for chloride. Once again, we were working in collaboration with an experimental group who is currently involved in developing all kinds of sustainable chemosensors.
The electronic structure of the chromophore was calculated at the M06-2X/6-311++G(d,p) level of theory under the SMD solvation model (water) at various pH levels which was achieved simply by changing the protonation and charges upon the ligand. Wiberg bond indexes from the Natural Population Analysis showed strong interactions between the chloride ion and the chromophore. Also, Fukui indexes were calculated in order to find the most probable binding sites. A very interesting feature of this compound is its ability to form a cavity without being a macrocycle! I deem it a cavity because of the intramolecular interactions which prevent the entrance of solvent molecules but that can be reversibly disrupted for the inclusion of an anion. In the figure below you can observe the remarkable quenching effect chloride has on the anion.
A quick look to the Frontier Molecular Orbitals (FMO’s) show that the chloride anion acts as an electron donor to the sensor.
Frontier Molecular Orbitals
If you are interested in more details please check: Bazany-Rodríguez, I. J., Martínez-Otero, D., Barroso-Flores, J., Yatsimirsky, A. K., & Dorazco-González, A. (2015). Sensitive water-soluble fluorescent chemosensor for chloride based on a bisquinolinium pyridine-dicarboxamide compound. Sensors and Actuators B: Chemical, 221, 1348–1355. http://doi.org/10.1016/j.snb.2015.07.031
Thanks to Dr. Alejandro Dorazco from CCIQS for asking me to join him in this project which currently includes some other join ventures in the realm of molecular recognition.
Two more students graduated!
It is with great pleasure that I’d like to announce the thesis defense of Guillermo “Memo” Caballero and Howard Diaz who in past days became the second and third students, respectively, to get their B.Sc. degrees with theses completed at our lab. I want to publicly thank them for their hard work which hasn’t only contributed with a thesis to our library but will soon contribute with research papers to our count.
Guillermo “Memo” Caballero worked on the calculation of a reaction mechanism that cannot happen. He started as a synthetic chemist and when he hit a wall at the lab he thought computational chemistry might help him get synthesis on the right direction. He has proven now that the aromatization process of a substituted glutarimide into the corresponding pyridine can only proceed only if substituents with a very strong electron withdrawing effect are used. For two reaction mechanisms proposed, both of them intramolecular rearrangements and only one of them concerted, the calculated energy barriers to reach for the corresponding transition states (QST2 and QST3 methods used) are higher than a pyrolitic decomposition. Memo found also that the delocalization of the pi electron system and its extent goes a long way into the stabilization of the non-aromatic analogue. At first we wanted to treat this problem as a tautomeric equilibrium but since we cannot observe the aromatic tautomer there is no equilibrium and hence no tautomerism. We are still thinking how to name this correspondence between the two compounds when we submit the corresponding paper. It must be said that Guillermo graduated with the highest honors in a most deserved way.
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- Two reaction mechanisms. Without different substituents the transformation is not possible.
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- A man and his work
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- Memo after his defense
Howard Diaz worked on the design of molecular blockers for the entrance process of the HIV-1 virus into lymphocytes through the GP120 protein. Six known blockers based on phenyl-indoyl-urea were assessed through docking, the binding site of the GP120 protein was described in terms of the interactions formed with each on these compounds and that served as the basis for what in the end came up to be a 36 compound library of blockers, whose structures were first optimized at the B3LYP/6-31G** level of theory. All the 42 blockers were docked in the binding site of the protein and a thorough conformational search was performed. From this set, lead compounds were selected in terms of their binding energies (first calculated heuristically) and further studied at the Density Functional Theory, B97D/cc-pVTZ in order to study the electronic structure of the blocker when interacting with a selection of residues at the binding site. Interaction energies calculated at the quantum level are consistent with the complex formation but since we had to cut the protein to only a few residues little correlation is found with the first calculation; this is fine and still publishable, I just wish we had a more seamless transition between heuristics and quantum chemical calculations. Wiberg indexes were very low, as consistent with a hydrophobic cavity, and delocalization energies calculated with second order perturbation theory analysis on the Natural Bond Orbitals revealed that the two most important interactions are C-H…π and Cl…π, these two were selected as key parameters in our design of new drugs for preventing the HIV-1 virus to bind lymphocytes-T; now we only need to have them synthesized and tested (anyone interested?).
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- Howard after his defense
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- Cavity was explored with 6 known blockers
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- Some of the compounds explored
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- One by one the interactions with the cavity were calculated
Thank you guys for all your hard work, it has truly payed off. I’m completely certain that no matter what you do and where you go you will be very successful in your careers and I wish you nothing but the very best. This lab’s doors will always remain open for you.
Visit to ‘Universidad de la Cañada’ in Oaxaca, Mexico
A couple of weeks ago I was invited to give a talk to a small university in southern Mexico called ‘Universidad de la Cañada‘ in the state of Oaxaca, one of the most underprivileged states in our nation. This institution is a rather small one but the work they are doing over there with as little resources as they have is truly remarkable . UNCA offers degrees in pharmacy, pharmacology, food sciences, clinical chemistry and other topics that aim to supply the needed human resources for the various industries that are settled in the region. There is a true feeling of togetherness at UNCA since they have little pieces of equipment yet they are all fully shared among researchers regardless of who received the finance to acquire them. Last year, two of their students came for a two months stay, after which, Alberto and Eduardo got their names on a publication of our research group. It was nice to see them again and even nicer to learn they are about to finish their studies and that they will come back again to our lab in late July.
Every year at UNCA there is a Pharmacology Day on which the students show the results to their research projects during a poster session and listen to lectures by guest speakers from various universities around Mexico. Most of their projects were aimed to the isolation of natural products from local resources and their usage in several kinds of consumer products. UNCA is in a very small town, village I might say, surrounded by mountains and vegetation; the view was spectacular as you may see from the pictures below. Thank you very much to my good friend Dr. Carmen Hernández-Galindo for inviting me to participate and share our work with their students, I hope we may go back again and keep a fruitful exchange between our groups.
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- UNCA
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- Me, Eduardo, Alberto
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- Some arachnids
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- Dr. Carmen Hernández and I
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- Grasshoppers. A delicacy in Oaxaca
During this talk, I took the opportunity to talk about the aforementioned paper in the context of molecular recognition and their in silico design but I think I should have talked more about the computational strategies that are most employed in the pharmaceutical industry. Never mind. I hope I get the opportunity to right this wrong. Still it was nice to give Alberto and Eduardo the opportunity to brag a little about being published authors.
Kudos to Rola Aburto, Dr. Margarita Bernabé, Dr. Rocío Rosas, and all the academic staff at UNCA for their invaluable dedication to teaching science against all odds, I can testify, through the hard work of their students, hat their effort is paying off.
Taking the Joy of Chemistry into a Children’s Home
On Friday May 30th, my good friend Dr. Josefina Aldeco, my wife and I, visited a children’s home in Querétaro (central Mexico) and brought them a few cool chemistry experiments for a short show. This event was promoted by a non-profit organization called “Anímate a estudiar” (Dare to study), namely by Mrs. Paulina Milanés who is always looking for ways to encourage kids from poor backgrounds to pursue their goals through study; among other things, they provide backpacks with school supplies to orphan kids like the girls we visited.
As a way to inspire them, we handed each girl a balloon drawn in the shape of a brain and asked them to inflate them daily by reading; by doing their homework; by asking questions all the time; by working hard in pursuit of a brighter future for which their brains are the most powerful muscles.
Many reactions took place that Friday; not only inside the flasks and beakers before our little audience but also in their faces and their engagement with us. Little by little these girls got out of their shells and became more excited, up to the point of performing their own chemical reaction themselves by polymerizing some glue with borax in hot water. This was for sure the first time they got in contact with chemistry but the true goal was to set up a spark in their minds that one day may turn into a life opportunity. We are aware that one small chemistry show can’t really have that effect, but if many more scientists reach out to these kids there is a bigger chance of creating a ripple effect that convince disenfranchised children that studying is the way to take the wheel of their own future.
Science is about development; its about spreading knowledge and the love for knowledge. Although we most times sit high on our ivory towers it is paramount to remember that there is also a social component to the scientific activity. Kids are eager to learn, but most school systems do their very best to limit their curiosity and ambition. We hope these girls find in studying a way to a better, happier and safer future. Mexico has a large economic disparity; climbing the social ladder is very hard and even more so for women which makes these girls a very vulnerable social group in the next generation.
It only takes one day. One day and some potassium iodide; some mentos on a diet-coke (sorry, Gina, for the squirt!); some cobalt chloride on paper; some balloons some glue and some borax in hot water. But above all it takes a big commitment.
I hope you readers, computational and experimental chemists alike, take some time out of your busy schedules and share your passion for science with kids, specially those with the lowest opportunities of getting in touch with real scientists. You can also contribute to this noble effort by making a small pay-pal donation to www.animateaestudiar.org or to any other similar organization in your local community.
It only takes one day.
P.S. Thanks to Josefina from Universidad Autónoma de Querétaro for providing material and reagents. Please go and check out her blogs (here and here) and encourage her to write more often! (Did I mention she published in Science a few years ago?)
Elements4D – Exploring Chemistry with Augmented Reality
A bit outside the scope of this blog (maybe), but just too cool to overlook. Augmented reality in chemistry education.
This is a guest post from Samantha Morra of EdTechTeacher.org, an advertiser on FreeTech4Teachers.com.
Augmented Reality (AR) blurs the line between the physical and digital world. Using cues or triggers, apps and websites can “augment” the physical experience with digital content such as audio, video and simulations. There are many benefits to using AR in education such as giving students opportunities to interact with items in ways that spark inquiry, experimentation, and creativity. There are a quite a few apps and sites working on AR and its application in education.
Elements4D, an AR app from Daqri, allows students explore chemical elements in a fun way while learning about real-life chemistry. To get started, download Elements4D and print the cubes.
There are 6 physical paper cubes printed with different symbols from the periodic table. It takes a while to cut out and put together the cubes, but it…
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XIIth Mexican Reunion on Theoretical Physical Chemistry
As every year this month we had the yearly Mexican Reunion on Theoretical Physical Chemistry organized by prominent researchers in the field, such as Dr. Emilio Orgaz (UNAM), Dr. Alberto Vela (CINVESTAV) and many other. Over 150 different works were presented during this edition which took place in Juriquilla, Querétaro at one of the many campuses of the National Autonomous University of Mexico scattered all around the country. Below you can see some pictures from the talks and the first poster session.
This time we contributed with a small poster on a mechanism proposed by Howard Diaz (an undergrad student from UAEM) on the equilibrium transformation of dihydrocinolines into 1-amino-indoles by an intramolecular rearrangement. May this post also serve as the starting point of a -mini-tutorial on how to evaluate a mechanism theoretically using QST3 and IRC in implicitly solvated environments (PCM)
Howard Diaz posing next to his poster
The equilibrium under study and the proposed mechanism by which it occurs, originally proposed by Frontana-Uribe et al. looks a bit like this:
Dihydrocinolines in equilibrium with 1-aminoindole
Mechanistic proposal by Frontana-Uribe et al.
The energy profile, in which all transition states were calculated with the QST3 method, is presented below, calculated at various levels of theory. Also, the Internal Reaction Coordinate (IRC) connecting both states was calculated and is shown further below in the full poster.
Energy Profile
From this results we believe that a new mechanistic proposal is needed since the energy barrier for the first step is quite high (~60 kcal/mol) and hence a bit unlikely to occur through that transition state. Nevertheless this is a first approach to elucidating a mechanism and the more knowledge about it the higher the control will be on this chemical transformation.
A full version of the poster is shown below for your convenience (Spanish). See you all at the next RMFQT in Morelia 2014!
Full Poster
#RealTimeChem – Happy birthday DNA!
What a happy coincidence -if indeed it was- that #RealTimeChem week happened to coincide with the sixtieth anniversary of the three seminal papers published in Nature on this day back in 1953, one of which was co-authored by J. Watson and F. Crick; of course I mean the publication for the first time of the structure of deoxyribose nucleic acid, or DNA, as we now call it.
You can get the original Nature papers from 1953 here at: http://www.nature.com/nature/dna50/archive.html (costs may apply)
Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid 737
J. D. WATSON & F. H. C. CRICK
doi:10.1038/171737a0
Molecular Structure of Nucleic Acids: Molecular Structure of Deoxypentose Nucleic Acids 738
M. H. F. WILKINS, A. R. STOKES & H. R. WILSON
doi:10.1038/171738a0
Molecular Configuration in Sodium Thymonucleate 740
ROSALIND E. FRANKLIN & R. G. GOSLING
doi:10.1038/171740a0
Nature’s podcast released two episodes (called ‘pastcast’) to celebrate DNA’s structure’s birthday, one of them is an interview with Dr. Raymond Gosling who in 1953 worked under Dr. Rosalind Franklin at King’s College London in diffractometry of biological molecules. If you haven’t listened to them you can get them here at nature.com/nature/podcasts. Of course, the history around the discovery of DNA’s structure is not without controversy and it has been long argued that the work of Franklin and Gossling didn’t get all deserved credit from Watson and Crick. In their paper W&C acknowledge the contribution of the general nature of DNA from the unpublished results by Franklin’s laboratory but that is as far as they went, they didn’t even mention photo 51 which Crick saw at Wilkins laboratory, who in turn got it from Gossling at Franklin’s suggestion. Still, no one can deny that the helical structure with which we are now familiar is their work, and more importantly the discovery of the specific pairing, which according to Gossling was a stroke of genious that probably couldn’t have happened in his own group, but without Franklin’s diffraction and Gossling’s crystallization there was little they could do. Details about the process used to crystallize DNA can be heard in the aforementioned podcast, along with an inspiring tale of hard work by Dr. Gossling. Go now and listen to it, its truly inspiring.
For me it was not the story of a helix, that I was familiar with; it was the story of the specific pairing of two hélices
– Dr. Raymond Gosling
The iconic Photo 51 by Dr. Rosalind Franklin and Raymond Gosling (Source: Wikipedia)
Above, the iconic Photo 51 taken by Franklin and Gossling (have you ever noticed how most scientists refer to Franklin just as Rosalind but no one refers to Watson as James? Gender bias has a role in this tale too) To a trained crystallographer, the helical symmetry is evident from the diffraction pattern but going from Photo 51 to the representation below was the subject of hard work too.
Modern DNA representation (Source: Wikipedia)
There are million of pages written during the last 60 years about DNA’s structure and its role in the chemistry of life; the nature of the pairing and the selectivity of base pairs through hydrogen bond interactions, an interaction found ubiquitously in nature; water itself is a liquid due to the intermolecular hydrogen-bonds, which reminds us about the delicate balance of forces in biochemistry making life a delicate matter. But I digress. Millions of pages have been written and I’m no position of adding a meaningful sentence to them; however, it is a fascinating tale that has shaped the course of mankind, just think of the Human Genome Project and all the possibilities both positive and negative! DNA and its discovery tale will continue to amaze us and inspire us, just like in 2011 it inspired the Genetech company to set a Guiness World Record with the largest human DNA helix.
Genetech SF, Cal. USA (Source worldrecordacademy.com)
Happy birthday, DNA!
#RealTimeChem – Day 3
Welcome of the third installment of #RealTimeChem, the diary. As I did yesterday and the day before, I will summarize my day in chemistry throughout the Tweets sent over this event.
Sup. Info finished. Figs & tables will b ready today; on it. Off to a (video)conference by Dr. Marcos Hernandez @iquimicaunam #RealTimeChem
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
(Haha, I found the button to include the feed!)
I finally finished editing that supporting information I’ve been Twitting about all week, now I’m back at the manuscript re-editing a bit. This is a problem I have that I’m sure is shared by most of you: I just can’t let go. If I’m writing a manuscript I’ll read it and change it over and over; if I’m working on a presentation, I will edit and reorder the slides almost ad infinitum if it were not for deadlines. Professor Cea-Olivares, of whom I’ve written before in this blog, used to say that projects are never finished but merely abandoned. In all fairness we are still not on the ‘not letting go’ phase, there are still some sections of the manuscript that need our attention; and when I say we, I mean me and my collaborator Dr. Rodrigo Galindo who is currently working at the University of Utah (BTW go check out his blog and persuade him to pick it up again!)
But in the middle of the day there was a conference at Instituto de Química, in Mexico City, that I wanted to listen to. Dr. Marcos Hernández is a good colleague of mine who deals with asymmetric organocatalysis. I like his work a lot and I hold him in high esteem so I asked for a video transmission of his talk to be sent over to CCIQS at Toluca. In the following two Twits you can get a glimpse of our video conferencing facilities.
Me. At the videoconference hall #CCIQS waiting for @iquimicaunam #RealTimeChem twitter.com/joaquinbarroso…
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
And we are good to go! Live from Mexico City, is Dr Marcos Hernandez conf @iquimicaunam during #realtimechem twitter.com/joaquinbarroso…
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
Not all is work during RealTimeChem week, although perhaps it should be. Still, safety first! that’s our motto! (follow the link in message)
stock pic: important 2 remember: protect eyes & hands when u’re naked in a lab! twitter.yfrog.com/nymcyzp 4 those too excited by #RealTimeChem
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
Today I took some time to have a few interactions with other participants of #RealTimeChem and got to follow very interesting people. Definitely, after this week I will become a more active Twitter user (ouch!). But the research must go on, and today Maru started working on rendering the electrostatic potential surfaces for a rather large set of calix- and thiacalix[n]arenes for our line of research on molecular recognition agents.
#RealTimeChem Electrstatic potential surface of a calix4arene 1 down 119 to go 😉 twitter.com/joaquinbarroso…
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
#RealTimeChem same as before; top view; transparent surface. Which so u like better? Compchem yields nice pics too! twitter.com/joaquinbarroso…
— Joaquin Barroso (@joaquinbarroso) April 24, 2013
#RealTimeChem Another EPS (diff scale as in previous pic) twitter.com/joaquinbarroso…
— Joaquin Barroso (@joaquinbarroso) April 25, 2013
This is pretty much it for today; I’m very tired and I still need to work in other things so I’m off for now but stay tuned for more tomorrow when this blog will celebrate the 60th anniversary of the publication of DNA’s structure in Nature.
Cheerio!
