For the last few days I have been trying to figure out how I can do a simple Monte Carlo simulation on my computer without much success.
In the last few months I have become convinced that by doing my own computer modeling I could probably avoid making a lot of unnecessary molecules. Indeed, I see no reason why the notion hasn’t struck me in the same way the concept of checking a sample after a reaction for purity why should I check the reaction before I do it to see how well it might work?
Firstly, it’s become pretty obvious that computational chemistry is a giant fucking black box. There are lots of force fields and data sets and letters followed by ** and shit and not a goddamn easy way to deal with ANY of it. Let’s say I want to model a transition state, what do I do? Call a computational chemist? I’m sure they’ve got shit they want to do, too. Not only that, but after a couple decades of ripening, I’d like to think the ability to do simple computational analysis should be in the hands of the average schmuck like me.
So, I want to do a Monte Carlo simulation. This, as I have come to appreciate it, simply means I want to find a global minimum for a structure – i.e. the lowest energy configuration something sits in, but there’s no easy way to figure out how to do this. In so far as I can tell, you can do the following things:
Draw something in chemdraw and either import it into Chem3D if you own a PC or into Avogadro if you own a Mac (which will convert chemdraw .cdx files into 3D coordinate files). Do a minimization using whatever they have. Avogadro is clearly better at this (and it works for PC) and has a number of different choices. The problem with both of those program is that they really don’t find a global minimum. Insofar as I can tell, if you start with a shitty structure, both of them will find a minimum of that shitty structure. True Monte Carlo, as I understand it, means it will rebuild the structure and keep searching.
Then I discovered a program called Tinker… it has a bunch of force fields and shit in it, all prime and ready to use (and it even works on Windows and Mac) but no clear path from Avogadro or Chem3D to a minimization is presented.
I don’t understand why computational chemists don’t want other chemists to do computational chemistry with a graphical user interface and dialog boxes and all those smart things that can be made using Visual Basic or Apple script… It just seems to me that, a lab like Jay Ponder‘s or Dan Gezelter’s could really make a difference by making a user application that would allow the simple importation of a Cartesian coordinate file and allow the user to select a Force Field, Algorithm and a good stopping point to do their own “back of the napkin” calculations before they run off into the lab… If I had the wherewithal to do it, I’d have done it by now.
UPDATE: Re: Collaborate with a computational chemist:
I have done that before, put his name on the paper and everything. The problem is that I’m *JUST* starting out in my little Post-Doc adventure and so I don’t really have systems in mind that I would want to bother someone with. I.E. some of them are likely patently absurd – simply won’t work for reasons I don’t need a computer to tell me… but I have a chemdraw folder full of them and a billion other (more pressing) things to be doing. I also have a pretty ass kickity computer that has no problem crunching numbers all day, both at home and at school.
I also want to obtain some degree of self sufficiency. I feel as though, in this modern era, I don’t need to run to an NMR chemist to take a sample of, what will normaly turn out to be ethyl acetate, so why should I need to run to a computational chemist to do something so very trivial. It’s a waste of her time to do my calculations for me on a compound that has a 1% shot of even being made!
As a function of my new post-doc, I found myself in the need of a refillable fountain pen, which could contain organic solvents. It also needed to be refillable by a plunger or cantilever and, once I was done with the science, I wouldn’t mind converting it to a nice pen for my own use. (You may be wondering, wtf kind of chemistry are you doing where you’d be using a fucking FOUNTAIN PEN? To wit: I am doing awesome chemistry.)
In any regard, I have (as most scientist do) an inexplicable compulsion (it has nothing to do with masturbation, just FYI… I know that’s a common one.) My compulsion happens to be the exclusive use gel pens. I thus figured, if I’m going to get a refillable fountain pen, I might as well inquire into the availability of that gel ink they use in gel pens. (It’s not really available…)
Of course, at the time, I didn’t know what made them so gel-like and why I loved them so… but regardless, now I appreciate that I can feel much safer knowing that the federal government can’t track my ink. (DOI:10.1111/j.1556-4029.2006.00144.x)
As every Republican can tell you The Federal Government has been evil for at least the last 3 months – ever since Glenn Beck started warning you that “they” are coming for your guns and your personal rights and your Fieros and whatever redneck accoutrement that you find so appealing yet have parked out on your lawn. What you may not know is that the feds have been keeping a meticulous database of inks since the 1920′s and at ANY TIME they could take your ink and compare it to their stock samples of ink by… wait for it… TLC! (oh noes! blow up teh fedural buldins!)
Srsly. Co-spotted and everything. The fucking FBI will compare ink composition by how far the little constituent dyes run up a TLC plate:
TLC is one of the most widely used and generally accepted scientific methodologies used to compare and help characterize ink formulations. TLC has been discussed extensively by Witte (21), Brunelle and Pro (22), Brunelle and Reed (23), Brunelle and Crawford (24), Kelly and Cantu (25), and Aginsky (26). TLC analysis begins by removing an ink sample from a document, and subsequently extracting the ink in an appropriate solvent. The extract is then applied to a specially coated TLC plate (e.g., glass or plastic surface coated with silica), and placed in a solvent-equilibrated glass chamber containing a solvent or mixture of solvents. The sample components then migrate up the plate via capillary action. Typically, the colorants (e.g., dye components) that are present in the ink sample will separate into colored bands or spots. As described in the aforementioned study conducted by Roux et al. (20), ‘‘thin layer chromatography had the highest discriminating power for the individual techniques at 0.98 for blue and 0.99 for black.’’
I know, I know… we sent fucking human beings to the moon 40 years ago and we still don’t have one of those fantastic neon lit LC/GC/MS/Magic box from CSI that spits out the type of ink and where it was purchased. But fear not, they can (and will) track your shit down with the almighty TLC plate… unless… you use gel pens. Turns out gel inks are poorly soluble in the highly polar solvents they use for TLC (EtOAc:EtOH:water in a ratio of 70:35:30… not a typo… [these people fucking solve crimes]). While most pens contain inks that are water soluble or organic soluble – gel inks contain both, plus some insoluble pigment shit.
The Gelly Roll, a name which could only be dreamed up by the psychotic lotus eating scientists of Japan at Sakura Color Products Corporation was the first gel pen invented in the mid 80′s and contains water and oil based inks dissolved in an aqueous mixture thickened by xanthan gum and pigments suspended therein. Fountain pens and rollerball pens use water based inks while ballpoint pens use organic derived dyes. Thus, the inherent insoluble nature, as well as the broad range of polarities in the gel pen resulted in EPIC FAILS:
The colorants in 15 of the writing inks did not extract into solvents and/or migrate on the TLC, which indicates that they are pigment based. These inks were not feasible for comparison with the library of standards based on their lack of a colorant profile on a TLC plate; however, this would not preclude additional comparative testing using alternate methods such as Fourier transform-infrared spectrometry (FT-IR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and/or scanning electron microscopy (SEM) coupled with energy-dispersive X-ray analysis (EDXA). It is noted that 14 of the 15 inks that were not extractable were gel inks [...]
I am pleased to know that the feds will be unable to know where I purchased my ink. That’s one more “freedom” I can keep. (I purchased them at Sam’s Club. Great fucking deal. I got, like, 50 of them for $40.)
A good review has recently been published in European Journal of Organic Chemistry (well, five months ago) in which structural elucidation with NMR spectroscopy is discussed. (DOI: 10.1002/ejoc.200700966)
While X-Ray crystallography often provides the “last word” on absolute stereochemistry and atom placement (though one can easily confuse functional groups like amides and esters or, far more rarely, isocyanates and thiocyanates) a far easier method is NMR spectroscopy as sample preparation is infinitely easier and interpretation of data can be done with only a modicum of knowledge. The problem most people have is a rather infantile approach to determining which experiments to run and, even more, what experiments are out there. It is, for instance, completely possible to determine structures as complex as vitamin B12 with NMR and, using total synthesis, confirm your structural hypothesis (and growing a crystal of something isolated in miligram quantities is frustrating if at all possible.)
So, behold, Eugene Kwan and Shaw Huang have written an easily understood microreview to help the student through a structural predicament.
The general procedure is this: skeletal connectivity is deduced by homonuclear and heteronuclear correlation spectroscopy (COSY and then HSQC or HMBC) followed by stereochemical determination by NOE correlations between protons – the provided coupling constants will then guide you to your overall structure.
I have been thinking about producing a series of posts on this review with a more comprehensive description but I’m hesitant for two reasons – firstly, the review is well written and I would just be needlessly reproducing something that could just as easily be read, granted with fewer liberties in curse words. Secondly, I am not an expert at structural elucidation with NMR spectroscopy and wouldn’t do the subject justice, but I’ll tell you what I typically run when I have a “problem” compound.
Firstly, I determine the molecular formula via high-res Mass Spec or, if that fails, elemental analysis. Then, I run -not walk- to the NMR, usually the 600, and drop in a sample. It’s a Varian, so I have to curse it for a few seconds. I then set up seven experiments to be run sequentially. The Varian does this for me, which is the least the piece of shit could do. I come back about 24 hours later and all 7 experiments are pretty much done, assuming the C13 doesn’t take more than two or three hours.
We should be familiar with 1-3. TOCSY is nice because it gives correlations to protons in the same spin system, which help distinguish individual rings or alkyl chains. HSQC and HMBC are HetCorr experiments which provide C-H and C-C-H connectivities respectively. Both of these are very useful if you’re unsure which fragment of your molecule a particular substituent is on OR if you’re unsure if a proton is connected to a carbon at all (in my case, amides give me no indication that they are attached to a heteroatom, though I or anyone in my position could do an exchange experiment with D2O to resolve most of those problems – but that could cause problems too, such as hydrolysis of sensitive compounds and exchange of acidic C-H compounds). Taken together, these 7 experiments should be enough to give at least the skeletal arrangement of even a significantly complex small molecule (as oppose to proteins).
Solving the structure usually starts with an analysis of spectra 1, 2, 6 and 7, which gives me a rough idea of connectivity. After I get a skeleton sketched out, I can use 3, 4 and 5 to give good assignments for the 1D spectra and make conclusions about connectivity. I then celebrate and hope no one proves me wrong with a crystal structure.
Keep in mind that doing these experiments aren’t my normal routine since 99.9% of the time I know what I’m making and I would hope you do too. The spectra of a few compounds, however, are clearly unanticipated or unclear or difficult to assign, so at the very least a second experiment is done so my assignments on my 1D NMR spectra aren’t just guesses based off ChemDraw.
I suggest anyone who seriously is going to publish a spectrum with assigned peaks to do at least one or more of these experiments to make sure your assignments are correct.
Eugene E. Kwan, Shaw G. Huang (2008). Structural Elucidation with NMR Spectroscopy: Practical Strategies for Organic Chemists European Journal of Organic Chemistry, 2008 (16), 2671-2688 DOI: 10.1002/ejoc.200700966
Look at me. I’m cleaning two NMR tubes AT THE SAME TIME for pennies. I learn so much with my blog.
SO, from the comments below. This is about 1000x easier to assemble. Indeed, you’d have to be pretty much a retard to need a diagram. It even allows for multi-tube cleaning just by sticking more needles through the septum! I dunno if that septum is resistant to chloroform and DMSO but the tubes look pretty clean. I grabbed that from a bag of septa we have for 29/40 flasks. It fits perfectly and gives a nice tight vacuum.
We have something in the lab that I like to call the Soviet Eyewash station. It consists of a long needle sticking straight out of a sliced squeeze bottle attached to an aspirator. One of our visiting students made it for us and it was to replace the NMR tube cleaner Aldrich charges a brazillion dollars for (though that 5 NMR tube washing thing is pretty sweet.) Nevertheless, funding was tight and when some clever scholar broke our expensive aldrich NMR tube cleaner so we needed a cheap alternative:
The concept is simple and I think it’s actually on the internet already, but for those of you who aren’t familiar, here is a simple scheme that I made whilst practicing my Adobe Illustrator skills. (Am I the only one that feels like a retard with that Pen tool?) You stick the NMR tube on the long needle and squirt solvent into that ghetto fucking cup there and the suction takes it through the tube and on out. You can pretty much use whatever solvent you want. I like to soak mine in Nitric acid and slurp it out and wash with DI water for that extra sparkle clean. Chloroform followed by acetone also seems to be a good system for most things. I’ve never had the urge to squirt DMSO into there, but I assume it would work.
And there you have it. For some reason the pngs look like shit. But I’m hoping it’s visible. Hope this helps anyone who hasn’t seen it before. *HINT* the best NMR washing solution is nitric acid followed by acetone. (JUST kidding. Please don’t try that. You may blow your face off.)