Annual state of the Research Group


Like everybody else, we are doing a brief recount of the achievements of this lab during 2016 if for no better reason because it helps me map my annual report.

We published seven articles:

  1. A Mixed DFT-MD Methodology for the In Silico Development of Drug Releasing Macrocycles. Calix and Thia-Calix[n]Arenes as Carriers for Bosutinib and Sorafenib Journal of Computational Chemistry 2016, 37, 10, 940–946
  2. In silico design of calixarene-based arsenic acid removal agents J Incl Phenom Macrocycl Chem (2016) 85:169–174
  3. Aromatization of pyridinylidenes into pyridines is inhibited by exocyclic delocalization. A theoretical mechanistic assessment Tetrahedron 72 (2016) 4194-4200
  4. Reactivity of electrophilic chlorine atoms due to σ-holes: a mechanistic assessment of the chemical reduction of a trichloromethyl group by sulfur nucleophiles Phys. Chem. Chem. Phys., 2016, 18, 27300-27307
  5. Ab Initio Modeling Of Friction Reducing Agents Shows Quantum Mechanical Interactions Can Have Macroscopic Manifestation J. Phys. Chem. A, 2016, 120 (46), pp 9244–9248
  6.  Crystal Structure and DFT Studies of 4-Methyl-N-(1-phenylethyl)-N´-(1-phenylethylidene)benzenesulfonohydrazide. Evidence of a carbene insertion in the formation of acetophenone azine fromacetophenone p-toluensulfonyl hydrazone. Canadian Journal of Chemistry 2016 (doi: 10.1139/cjc-2016-0183)
  7. Synthesis and Crystal Structures of Stable 4-Aryl-2-(trichloromethyl)-1,3-diaza-1,3-butadienes Synthesis 2016, 48, 2205–2212

Two students got their degrees:

  1. María Eugenia “Maru” Sandoval got her Masters Degree with a thesis on mechanisms for the excitonic transference in photosynthetic pigments.
  2. Gustavo “Gus” Mondragón got his Bachelor of Sciences Degree also with a thesis on mechanisms for the excitonic transference in photosynthetic pigments.

And even a patent was filed! (more on that next year when appropriate.)

We participated in the annual Mexican Meeting on Theoretical Physical Chemistry with four posters and the internal symposium both at CCIQS and the Institute of Chemistry.

2016 was a great year for us and we hope to have an even better 2017 but just as before it will only be possible thanks to the hard work and dedication of all the members of this lab, -some of which have now left us to pursuit higher ends like Maru Sandoval who leaves for Spain and Guillermo Caballero who is already at Cambridge- and also to my colleagues who keep inviting us to collaborate in exciting projects. We have new members in the lab and also new research interests but the one common denominator throughout the years in the lab is fun; having fun in doing chemistry always.

Thank you to everyone who has ever read this blog and to those who have dropped a line here and there; I know I’ve neglected this space during this year, I want to fix it in 2017. May next year be awesome for everyone; lets make it so!

Finite Element(s) Chemistry


(Ah! Mathematicians, did you see what I did there?)

There are a number of appalling videos on line in which iPhones are destroyed by various means. From a chemist standpoint, the reason why I’m so disgusted with them is the waste of rare elements which go into the making of their components: From Neodymium to Indium, most of these metals come from conflict zones in which they are extracted in the most precarious conditions imaginable, but furthermore, they are so scarce the production of electronics is almost unsustainable. I wont post any links to these infuriating videos so as to not direct traffic to any of them, instead I will direct your attention to a wonderful book titled The Elements of Power: Gadgets, Guns, and the Struggle for a Sustainable Future in the Rare Metal Age by David S. Abraham. (Sheesh! Nobody uses short titles anymore? Can you imagine Nabokov writing Lolita: A little girl with a not so little mind and the professor who picked up on that? I digress.) It is hard not to read this long-titled book and feel a tad guilty; it is in fact a bit blackmailing but above all, realizing what a wasteful society (ugh! I hate that word) we are makes a strong wake up call to the future of sustainability. I would never claim that the solution is renouncing to technology but instead to find a sustainable technology within the framework of current technology. Easier said than done -of course- but stopping waste of such precious resources should be the first step in everyones mind, and don’t even get me started on balloons filled with He! In all fairness, one can also find a lot of scary articles on line from dubious to respectful on how smartphones and other rare-metals-containing gadgets are damaging the Earth.

Last year I enjoyed reading Andy Weir’s novel The Martian (later a major motion picture from Alien’s director Ridley Scott), in which an astronaut is stranded in Mars -left for dead by his crewmates, with nothing but the finite supplies of the station and his knowledge of chemistry, botany and engineering, all of which allows him to survive by extending, but above all reusing, those resources which included not only food but O2, H2O and even hydrazine, H2N2 originally intended for fuel but from where he now gets H2 for synthesizing a larger supply of water by reacting it with the O2 pulled out of the CO2-filled Martian atmosphere. I’m pretty sure Weir didn’t intend this novel to be a metaphor but it definitely works well as one of the limited resources available on Earth and the necessity of optimizing their use, collecting and disposal. Resources on Earth seem infinite, or they at least they did back when the industrial revolution started.

I guess the point is that sustainability goes hand in hand with using the least resources to get new ones as well as with avoiding their waste. I think one must agree that Chemistry, like no other science, has shaped our world for better and worse.

I haven’t rambled on sustainability in a while. Feels bad. Must be the winter.

Mexican Phys.Chem. Meeting XVth edition 


For the fifth year in a row my research group has participated in this traditional meeting on theoretical and computational chemistry, now at the beautiful city of Merida in southeastern Mexico.

Several distinguished international guests included Profs. Jose Luis Mendoza (Florida State University), Adrián Roitberg (University of Florida), Vincent Ortiz (Auburn University) and Paul Ayers (McMaster U. Canada); Their contributions rounded up nicely those of household names like Drs. Alberto Vela, Gabriel Merino (CINVESTAV) (the latter was also the main organizer), Jesus Hernández-Trujillo (UNAM), Jose Luis Gazquez (UAM-I), Óscar Jimenez (Guanajuato), and so many others who were also present.

My students presented four posters summarized below:

1) Maru Sandoval and Gustavo Mondragón on Photosynthesis, particularly the search for exciton transference mechanisms in both natural and theoretical arrangements of photosynthetic pigments. Some very exciting results have been observed; their publication is really near.


2) Raúl Torres and Gustavo Mondragón presented their work on arsenic removing calixarenes, published earlier this year, and the extension of said work to As(III) acids. Graphene oxide is now considered in our simulations as per the experimental work of our colleagues, Prof. Reyes Sierra and Prof. Eddie Lopez-Honorato.


3) Marco Diaz, Guillermo Caballero, Gustavo Mondragón and Raúl Torres had this poster on the calculation of sigma holes as descriptors for predicting pka values in organic acids. Their +1600 calculations project has found the best levels of theory (and ruled out some like B3LYP, of course) with some nice correlations. Yet, much work is still to be done but we’re on the right track.


4) Durbis Castillo presented his work on molecular docking and dynamics of a large library of HIV-1 entry inhibitors for which he uses the suite MAESTRO as a continuation of another project of ours. His enormous library is now in the hundredths of thousands and although we’re facing some technical difficulties, Durbis is thriving in his search. This is our first serious attempt towards a more mature drug discovery project; a manuscript should be ready in the first part of next year.


This guys and the rest of the lab who weren’t present are the ones who make our research flourish and they’ve all earned a day or two at the beach!

Here’s to fifteen more years of RMFQT!

Tribology – New paper in JPC A


Tribology isn’t exactly an area with which us chemists are most familiar, yet chemistry has a great impact on this branch of physics of high industrial importance. Tribology is basically the science which studies the causes and consequences of friction between surfaces. 

The plastic bag industry requires the use of chemical additives to reduce the electrostatic adherence between sheets of plastic. My good old friend Dr. Armando Gama has studied through Dissipative Particle Dynamics (DPD) coarse-grained simulations the friction coefficients of having two slightly different molecules: erukamide and behenamide, which only differ in the presence of a double bond between carbon atoms 12 and 13 (Fig1).

picture1

Fig 1

In order to study the electronic aspects that give rise to different tribological effects in these very similar molecules, four chains of each kind were bounded to a frozen graphene surface (four bonds apart to prevent steric crowding) and were optimized at the B97D/6-31G(d,p) level of theory.

 

 

Double bonds in erukamide pile together through pi-pi stacking interactions (Fig2) which are absent in behenamide which is why these last ones are able to slide better between each other (Fig3). Interaction energies calculated for the inner chains at the same level of theory are 44.21 and 34.46 kcal/mol for erukamide and behenamide, respectively. As per the suggestion of a referee we extended the calculations to a 2D system by placing seven molecules on graphene, which once again was kept at the optimized geometry of its isolated state, at four bonds of separation in order to prevent steric crowding (Fig 4).

picture4

Fig 4

This calculations clearly represent a limit case with a high density covering of the surface, but they nevertheless reflect the observed trend that behenamide works better than erukamide in reducing the static friction coefficient between sheets.

The paper is now available at JPC-A. Thanks to Dr. Gama for this great opportunity to work with his team, I know it wont be the last.

Back in Pécsi Tudomanyegyetem (Hungary)


I’m so glad to be back in Pécs, Hungary, at the lab of my good old friend Prof. Dr. Sándor Kunsági. It has been seven years since I was last here and so many things have happened and yet it feels like yesterday I was walking through these halls.

As part of an agreement between the science councils of both Mexico and Hungary, our research proposal on the development of macrocyclic-based therapeutic agents for capturing micotoxins and other molecules was selected for financing. As before, the theoretical section will be handled by us, namely to some extent by Marco Diaz as part of his BSc thesis, while the experimental part will be handled by the group from Prof. Kunsagi’s lab and Dr. Lemli Beáta‘s. I’m very excited about living for a month here in Pécs but also about having a close friend, to whom I owe so much, working with me in an experimental-theoretical project that will further advance both our researches and careers. It was in fact the work of Profs. Kunsagi here in Pécs and Silaghi in Cluj, Romania, which got me interested in the supramolecular chemistry of calixarenes.

Lets hope we can manage to keep this collaboration between our labs going on for many years to come. For the sake of humor here are some old and new photographs.

New paper in PCCP: CCl3 reduced to CH3 through σ-holes #CompChem


I found it surprising that the trichloromethyl group could be chemically reduced into a methyl group quite rapidly in the presence of thiophenol, but once again a failed reaction in the lab gave us the opportunity to learn some nuances about the chemical reactivity of organic compounds. Even more surprising was the fact that this reduction occured through a mechanism in which chlorine atoms behave as electrophiles and not as nucleophiles.

We proposed the mechanism shown in figure 1 to be consistent with the 1H-NMR kinetic experiment (Figure 2) which shows the presence of the intermediary sulfides and leads to the observed phenyl-disulfide as the only isolable byproduct. The proposed mechanism invokes the presence of σ-holes on chlorine atoms to justify the attack of thiophenolate towards the chlorine atom leaving a carbanion behind during the first step. The NMR spectra were recorded at 195K which implies that the energy barriers had to be very low; the first step has a ~3kcal/mol energy barrier at this temperature.

 

fig1-blog

Figure 1 – Calculated mechanism BMK/6-31G(d,p) sigma holes are observed on Cl atoms

fig2-blog

1H NMR of the chemical reduction of the trichloromethyl group. Sulfide 4 is the only observed byproduct

To calculate these energy barriers we employed the BMK functional as implemented in Gaussian09. This functional came highly recommended to this purpose and I gotta say it delivered! The optimized geometries of all transition states and intermediaries were then taken to an MP2 single point upon which the maximum electrostatic potential on each atom (Vmax) was calculated with MultiWFN. In figure 3 we can observe the position and Vmax value of σ-holes on chlorine atoms as suggested by the mapping of electrostatic potential on the electron density of various compounds.

We later ran the same MP2 calculations on other CCl3 groups and found that the binding to an electron withdrawing group is necessary for a σ-hole to be present. (This fact was already present in the literature, of course, but reproducing it served us to validate our methodology.)

fig3-blog

Figure 3 – Sigma holes found on other CCl3 containing compounds

We are pleased to have this work published in PhysChemChemPhys. Thanks to Dr. Moisés Romero for letting us into his laboratory and to Guillermo Caballero for his hard work both in the lab and behind the computer; Guillermo is now bound to Cambridge to get his PhD, we wish him every success possible in his new job and hope to see him again in a few years, I’m sure he will make a good job at his new laboratory.

Quick note on WFN(X) files and MP2 calculations #G09 #CompChem


A few weeks back we wrote about using WFN(X) files with MultiWFN in order to find σ-holes in halogen atoms by calculating the maximum potential on a given surface. We later found out that using a chk file to generate a wfn(x) file using the guess=(read,only) keyword didn’t retrieve the MP2 wavefunction but rather the HF wavefunction! Luckily we realized this problem very quickly and were able to fix it. We tried to generate the wfn(x) file with the following keywords at the route section

#p guess=(read,only) density=current

but we kept retrieving the HF values, which we noticed by running the corresponding HF calculation and noticing that every value extracted from the WFN file was exactly the same.

So, if you want a WFN(X) file for post processing an MP2 (or any other post-HartreFock calculation for that matter) ask for it from the beginning of your calculation in the same job. I still don’t know how to work around this or but will be happy to report it whenever I do.

PS. A sincere apology to all subscribers for getting a notification to this post when it wasn’t still finished.

A New Graduate Student


With pleasure I announce that last week our very own Gustavo “Gus” Mondragón became the fifth undergraduate student from my lab to defend his BSc thesis and it has to be said that he did it admirably so.

Gus has been working with us for about a year now and during this time he not only worked on his thesis calculating excited states for bacteriochlorophyl pigments but also helped us finishing some series of calculations on calix[n]arene complexes of Arsenic (V) acids, which granted him the possibility to apear as a co-author of the manuscript recently published in JIPH. Back in that study he calculated the interaction energies between a family of calix macrocycles and arsenic acid derivatives in order to develop a suitable extracting agent.

For his BSc thesis, Gus reproduced the UV-Vis absorption spectra of bacteriochlorophyll-a pigments found in the Fenna-Matthews-Olson complex of photosynthetic purple bacteria using Time Dependent Density Functional Theory (TD-DFT) with various levels of theory, with PBEPBE yielding the best results among the tried set. These calculations were performed at the crystallographic conformation and at the optimized structure, also, in vacuo results were compared to those in implicit solvent (SMD, MeOH). He will now move towards his masters where he will further continue our research on photosynthesis.

Thank you, Gustavo, for your hard work and your sense of humor. Congratulations on this step and may many more successes come your way.

 

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.

fig1

 

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.

fig2

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.

fig3

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.

fig4

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.

The “art” of finding Transition States Part 2


Last week we posted some insights on finding Transitions States in Gaussian 09 in order to evaluate a given reaction mechanism. A stepwise methodology is tried to achieve and this time we’ll wrap the post with two flow charts trying to synthesize the information given. It must be stressed that knowledge about the chemistry of the reaction is of paramount importance since G09 cannot guess the structure connecting two minima on its own but rather needs our help from our chemical intuition. So, without further ado here is the remainder of Guillermo’s post.

 

METHOD 3. QST3. For this method, you provide the coordinates of your reagents, products and TS (in that order) and G09 uses the QST3 method to find the first order saddle point. As for QST2 the numbering scheme must match for all the atoms in your three sets of coordinates, again, use the connection editor to verify it. Here is an example of the input file.

link 0
--blank line--
#p b3lyp/6-31G(d,p) opt=(qst3,calcfc) geom=connectivity freq=noraman
--blank line--
Charge Multiplicity
Coordinates of reagents
--blank line—
Charge Multiplicity
Coordinates of products
--blank line--
Charge Multiplicity
Coordinates of TS
--blank line---

As I previously mentioned, it happens that you find a first order saddle point but does not correspond to the TS you want, you find an imaginary vibration that is not the one for the bond you are forming or breaking. For these cases, I suggest you to take that TS structure and manually modify the region that is causing you trouble, then use method 2.

METHOD 4. When the previous methods fail to yield your desired TS, the brute force way is to acquire the potential energy surface (PES) and visually locate your possible TS. The task is to perform a rigid PES scan, for this, the molecular structure must be defined using z-matrix. Here is an example of the input file.

link 0
--blank line--
#p b3lyp/6-31G(d,p) scan test geom=connectivity
--blank line--
Charge Multiplicity
Z-matrix of reagents (or products)
--blank line--

In the Z-matrix section you must specify which variables (B, A or D) you want to modify. First, locate the variables you want to modify (distance B, angle A, or dihedral angle D). Then modify those lines within the Z-matrix, here is an example.

B1       1.41     3          0.05
A1       104.5   2          1.0

What you are specifying with this is that the variable B1 (a distance) is going to be stepped 3 times by 0.05. Then variable A1 (an angle) is going to be stepped 2 times by 1.0. Thus, a total of 12 energy evaluations will be performed. At the end of the calculation open the .log file in gaussview and in Results choose the Scan… option. This will open a 3D surface where you should locate the saddle point, this is an educated guess, so take the structure you think corresponds to your TS and use it for method 2.

I have not fully explored this method so I encourage you to go to Gaussian.com and thoroughly review it.

Once you have found your TS structure and via the imaginary vibration confirmed that is the one you are looking for the next step is to verify that your TS connects both your reagents and products in the potential energy surface. For this, an Intrinsic Reaction Coordinate (IRC) calculation must be performed. Here is an example of the input file for the IRC.

link 0
--blank line--
#p b3lyp/6-31G(d,p) irc=calcfc geom=connectivity
--blank line--
Charge Multiplicity
Coordinates of TS
--blank line--

With this input, you ask for an IRC calculation, the default numbers of steps are 20 for each side of your TS in the PES; you must specify the coordinates of your TS or take them from the .chk file of your optimization. In addition, an initial force constant calculation must be made. It often occurs that the calculation fails in the correction step, thus, for complicated cases I hardly suggest to use irc=calcall, this will consume very long time (even days) but there is a 95% guaranty. If the number of points is insufficient you can put more within the route section, here is such an example for a complicated case.

link 0
--blank line--
#p b3lyp/6-31G(d,p) irc=(calcall,maxpoints=80) geom=connectivity
--blank line--
Charge Multiplicity
Coordinates of TS
--blank line--

With this route section, you are asking to perform an IRC calculation with 80 points on each side of the PES, calculating the force constants at every point. For an even complicated case try adding the scf=qc keyword in the route section, quadratic convergence often works better for IRC calculations.

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