Archive for the ‘synthetic chemistry’ Category:
Slicing and Dicing Molecular Rings
by Kenneth Hanson on Apr 05 2012 (3799 Views)This post is contributed by John Spevacek, an industrial polymer chemist and the author of the blog “It’s the Rheo Thing”
Nature had a report last week of a nice new catalytic procedure for preparation of spiroacetals - bicyclic compounds bridged through a single acetal carbon.
When I read the report, I was surprised that no mention was made of how these compounds could be useful in my field of polymer chemistry. Then again, maybe that shouldn't be so surprising. After all, these researchers had worked quite hard to develop this new method for making these rings, yet the polymer chemist in me wants to do nothing more than take and rip them apart just like I was spatchcocking a chicken.
Ripping molecular rings apart to form polymers has a long history and is properly called ring-opening polymerization (ROP). There are a number of reasons for considering such a polymerization mechanism. Sometimes it is a way to get around a patent. When Carothers discovered nylon (polyamide), he prepared his novel polymers by copolymerizing a diamine with a diacid. Nylons made with this technique are given two numbers in their name, such as nylon 6,6 or nylon 6,10. The first number indicates the number of carbons in the diamine and the second number indicates the number of carbons in the diacid. The patents filed by DuPont claimed just this copolymerization technique. Unfortunately for DuPont, that left the door open for BASF to prepare polyamides by the ring-opening polymerization of lactams. These nylons are identified with a single number such as nylon 6 or nylon 12, which again indicates the number of carbon atoms in the monomer. Read more »
CLT #26: Substituted Benzene Preparation
by azmanam on Mar 06 2012 (11573 Views)Welcome back to CLT!
This is the week my students have their exam on Electrophilic Aromatic Substitution 
via ComicJK
Enjoy!
Neat-o Curved Arrows in Chemdraw
by azmanam on Dec 09 2011 (8909 Views)UPDATE: New Catalytic Cycle video below!
James (of Master Organic Chemistry and the Reagents App/Guide fame) and I had some off-line conversations about curved arrows in ChemDraw. I don't particularly like the suite of arrows ChemDraw gives us in the Arrow Tools menu. Yeah, they give you 4 arc angles, but you have to guess if you need the clockwise or counterclockwise arrow... and I just don't like them. They look, i dunno, amateur or less professional or something. Nothing against people who use the standard arrows, I just don't like them.
So over the years I've become quite adept at using the Edit Curve function in ChemDraw. It allows me to make my arrows look however I want them to. I have a couple of arrow shapes I particularly enjoy, and I use them a lot.
James (@jamesashchem) gave me a hat tip on Twitter for showing him the new arrows, at which point Mark Peczuh (@mwpeczuh) requested a public YouTube video.
So I made one. Here it is. If you already know how to use the Edit Curve function then cool. If not, hope it helps
12/12/11:
Thanks to everyone who left kind comments about the curved arrow video. Stephen Davey (@stephengdavey) asked if the Edit Curve function could make curly q arrows. I'd never tried to make one like that before, so I took a crack at it. Turns out, this arrow doesn't work so well with the Edit Curve function (unless some actual graphic designer knows more about making paths than I do. If so, please let me know!!). I ended up combining an arc, an arrow, and a circle and the effect looked ok. Here are my failed attempts, plus the final output (click for larger):
Later, Bal (@gnak_lab) asked about an easy way to draw catalytic cycles. I think the question was referring to the "circle of arrows" like in this mechanism for the Heck reaction. I've done catalytic cycles before, but was never really pleased with the result either. Then I had an idea. You can add curvature to straight arrows... so I though if I started with a circle as a template, added the arrows, then deleted the circle, that might just work. So without practicing first, I shot a video on me making the catalytic cycle for the Sonogashira reaction (I just recreated the mechanism from that site). The video for that is below. It's not a polished mechanism, I'd go back and tweak a few things, but for a first try, I think it turned out pretty well
(video at 2x speed for brevity)
Cheap Laugh Tuesdays #15: Emeril Chemistry
by azmanam on Dec 06 2011 (8255 Views)Welcome back to CLT!
via Andrew Toos
Enjoy!
Cheap Laugh TuesdaysWednesdays #7: Duct Tape Bonds
by azmanam on Oct 12 2011
(3845 Views)
Welcome back to CLT! Sorry for it being Wednesday...
via Loose Parts
Enjoy!
Product Review: The Reagents App
by azmanam on Oct 03 2011 (5682 Views)James Ashenhurst over at Master Organic Chemistry has developed an awesome new app called Reagents. The app is perfect for students taking undergraduate organic chemistry - but anyone working with organic reagents will benefit from this app. It's available from the iTunes App Store.
via MasterOrganicChemistry.com
The app is a list of all of the most common reagents encountered in undergraduate organic chemistry. Selecting a link takes you to a page which gives you a short narrative overview of the reagent, an image of the structure of the reagent, and several examples of prototypical reactions using the reagent. You can 'save' a reagent to your favorites list so you don't have to scroll through the whole list if you don't want.
This is really a heroic effort. James and his coauthor Richard Apodaca have given organic students everywhere the handy, mobile reagent guide they all should make for themselves... but never do. The interface is clean, readily obvious, operationally simple, and does exactly what it needs to do. It's a slimmed down version of the full Organic Chemistry Reagent Guide James rolled out a while ago (which is also spectacular, btw). I've been playing with it for a little while now, and it's great.
The Reagents app is currently free, but that is a limited time offer and will expire soon. Tell all your organic chemistry professor friends so they can tell their students. It's currently only available for Apple mobile products, but according to the Reddit conversation, there may be an Android version in the works.
And thanks, James, for giving me one more reason to make sure cell phones are safely stowed during my exams.
Blog Carnival: The Diels-Alder Reaction!
by azmanam on Sep 26 2011 (13202 Views)This post was excerpted and featured in a recent edition of C&ENews
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No reaction is more elegant, more heartwarmingly satisfying than the Diels-Alder reaction. No reaction is also more nuanced. It appears deceptively simple and yet has the ability to create immense structural complexity often without additional reagents and sometimes solvent-free. Straightforward enough for an undergraduate organic chemistry class, yet intricate enough to spend several days in a graduate organic chemistry class reading into the engrossing story that is the Diels-Alder reaction. It is by far my favorite reaction and the subject of my Blog Carnival Post. And I am grateful to BRSM for deciding not to blog about the Diels-Alder Reaction.
First reported in 1928 by Otto Diels (1876-1952) and his graduate student Kurt Alder (1902-1958), the chemists at once saw the importance of their work and wanted the exclusive rights to utilize their reaction. They write in their 1928 paper: “[T]he possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps even alkaloids, has been moved to the near prospect … We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.” Fortunately for us, this exclusivity no longer applies. Oh, by the way, the pair won the 1950 Nobel Prize in Chemistry for the reaction.
Striped away from all its layers of complexity, at its core, the Diels-Alder reaction (here's a 3-D animation of the Diels-Alder Reaction) is a reaction of a conjugated diene (4π electrons, in the s-cis conformation) and an alkene (2π electrons, called the dienophile) to form a cyclohexene ring – the reaction is classified as a [4π + 2π] cycloaddition. This is the bare-bones Diels-Alder reaction we all remember from undergraduate organic chemistry classes. Straightforward, right? The Diels-Alder is usually the only cycloaddition reaction to make it into undergraduate organic textbooks. And that may be as deep as most undergraduate texts delve into the Diels-Alder reaction. (Click images for larger throughout. And, like CJ, I also went with the hand-drawn structures.)
The Diels-Alder Reaction
Organic Chemistry Reactions Mind Map
by azmanam on Aug 05 2011 (20363 Views)Well... this oughta cover it.
I was reading comments to my reddit submission of the many oxidation states of carbon, and Aa1979 asked if the functional groups could be arranged logically according to actual chemical transformations. I replied that would be too reaction dependent... alcohols can be turned into a great many things (chlorides, alkenes, ketones, acids, aldehydes...), then aldehydes themselves could be turned into a great many things (alcohols, alkenes, acids, imine/enamine, acetal...). I pointed the commenter to a post by James over at Master Organic Chemistry where he has a picture of a whiteboard-mind map of most of the reactions in a standard undergrad text. Very impressive.
Feeling crazy, and deciding to put of lab work I should be doinghaving nothing to do, I expanded on James' mind map and tried to get as many reactions as I could on one map. It took about a full day's work using Compendium, and here's the result (click for larger):
These are just about all the reactions you'd encounter in your standard, two semester undergraduate organic chemistry course. Sure I probably missed a few, or maybe your institution covers reactions a bit differently, but this is fairly comprehensive. Enjoy.
Casey Anthony and Chloroform: How Does It Work?
by azmanam on Jul 08 2011 (24722 Views)
Much of the country was all caught up in the Casey Anthony trial over the past few weeks as the testimony concluded and the verdict was announced (full disclosure: I was not at all caught up. I didn't even read any articles about the trial until after the verdict was announced). If you want background on the trial, wikipedia's as good as any in this case.
One of the points raised during the trial was whether or not a Google search was performed on How to Make Chloroform. One way to make homemade chloroform is by reacting household bleach with acetone. Whether or not the search was performed or for what reason, and whether or not anyone involved in this case actually tried to prepare homemade chloroform is irrelevant. We're going to talk here about how the process works from a chemical and intellectual perspective (full disclosure: This will NOT be a how-to post on how to prepare and purify chloroform. That information can be found elsewhere).
Safety First: Nearly all the chemicals involved in this process are dangerous and need to be handled with caution and respect. Bleach is a solution of sodium hypochlorite in water, usually containing a small amount of sodium hydroxide (lye) and/or sodium chloride. Sodium hypochlorite is a strong oxidant and will cause severe burns when concentrated (it is generally safe for low level exposure when dilute as in household bleach, but will still discolor skin and clothes). Sodium hydroxide is a strong base and will cause severe burns (think Fight Club). Acetone is generally safe when used as indicated, and it is commonly used as nail polish remover. Careful, though, it can dry out the skin. Chloroform itself is a suspected carcinogen and can cause dizziness and fainting. Also, if this process is done incorrectly, the byproducts can be quite dangerous as well. Bleach mixed with the wrong ingredients (like vinegar - don't mix your bleach with vinegar!) can produce chlorine gas - a highly toxic gas that no one should want to be around. Chloroform will decompose on exposure to oxygen to produce phosgene - a WWI chemical warfare agent. Needless to say, do not try this at home.
General procedure: To make chloroform, acetone is mixed with either sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder). This is a highly exothermic process releasing a lot of heat. The reaction is generally cooled by submersion of the reaction vessel in ice-cold water or by directly adding ice to the reaction mixture. The acetone is oxidized by the hypochlorite to form chloroform, with sodium (or calcium) acetate as a byproduct. The chloroform needs to be purified and stored away from light by processes not discussed here. The general reaction is as follows:
- Net Reaction for Making Chloroform
Three molecules of sodium hypochlorite react with one molecule of acetone to produce one molecule of chloroform, two molecules of sodium hydroxide, and one molecule of sodium acetate.
How it works: The mechanism for this reaction generally follows the mechanism of the haloform reaction: a classical organic chemistry reaction whereby a methyl ketone (acetone is a methyl ketone) reacts with a halogen (Br2, Cl2, or I2) under basic conditions (NaOH) to produce a haloform (bromoform: HCBr3, chloroform: HCCl3, or iodoform, HCI3). Iodoform is a pale yellow solid that is insoluble in water. For this reason, organic chemists have developed what's known as the iodoform test. Aqueous solutions of unknown compounds can be treated with iodine (I2) and sodium hydroxide. If a yellow precipitate forms, this is a positive indication that your unknown has a methyl ketone. This is the general scheme for a haloform reaction involving chlorine (Cl2):
- The classical haloform reaction
The mechanism (below) for the classical haloform reaction is quite clever. We need to break one of the carbon-carbon bonds to liberate chloroform from acetone. As organic chemists, we're always so concerned about how to make carbon-carbon- bonds that we rarely think about breaking them. To begin, in step 1) the base, sodium hydroxide, deprotonates the mildly acidic proton on the CH3 group of acetone, forming a resonance-stabilized enolate intermediate. In step 2) This enolate intermediate becomes monochlorinated by reacting with one molecule of chlorine. By repeating step 1) and step 2) two more times, one side of acetone becomes trichlorinated. This is a favorable process. In step 1), the base was deprotonating a mildly acidic proton. After each addition of chlorine, the acidic proton becomes more and more acidic, making the deprotonation easier and faster each time.
In step 3), the sodium hydroxide acts as a nucleophile and attacks the central carbon atom, causing the carbon-oxygen double bond to break into a single bond resulting in a negative charge on the oxygen atom. Oxygen would rather have a carbon-oxygen double bond than a negative charge, so in step 4), the carbon-oxygen double bond reforms, and the anion Cl3C- is released from the molecule. Typically, carbon is rarely released from a molecule, as a carbon with a negative charge is very, very unstable. Because of the three, electron-withdrawing chlorine atoms attached to carbon, the negative charge is stabilized and the carbon anion can easily be released from the molecule in step 4. As a byproduct of step 4, the carboxylic acid acetic acid (vinegar) is formed.
One more step is needed to finish the mechanism for this reaction, and it is also the final step in forming chloroform. While the carbon anion is somewhat stabilized by the three, electron-withdrawing chlorine atoms, the carbon is still unhappy having a negative charge. All things considered, generally carbon would like to be neutral, not negatively charged. In step 5), the carbon anion acts as a base and deprotonates the acidic proton on acetic acid. This forms chloroform and sodium acetate.
- The Mechanism of the Classical Haloform Reaction
This is not exactly how chloroform is produced when you use bleach, but the process is very similar. There is often a small amount of sodium hydroxide in household bleach to help with the initial deprotonation, and the sodium hypochlorite is the source of chlorine. For the traditional haloform reaction, you must use chlorine gas as one of your starting reagents. Using bleach allows you to work around using the highly hazardous chlorine gas (not that the bleach process is much better). In general, the acetone and bleach react to sequentially place three chlorine atoms on the terminal carbon atom of acetone. That carbon atom then fragments from acetone as the trichlorinated carbon anion, which picks up one hydrogen atom in an acid/base step to form chloroform. I'm not sure exactly what the intermediates look like in the bleach mechanism, but they will be generally similar to the classical haloform mechanism.
A Companion Reagent Table Widget
by azmanam on May 23 2011 (11389 Views)A while ago I introduced my Reagent Table widget (and desktop gadget) I created using the widget builder on Wolfram|Alpha. I've found the widget to be quite handy for quickly accessing physical properties of reagents from my computer. I've embedded the widget on my personal homepage, so it's really quite straightforward to locate key physical properties as I set up a new reaction.
That's all well and good... but finding the data is only half the time-consuming problem. The other time taker is calculating out the rest of the values in the reagent table. If my previous posts haven't made it clear, I really like letting technology help me save valuable time.
So I made a companion widget to augment the capabilities of the first Reagent Table Widget. This one allows you to enter an amount (either in grams, mmol or mL) of a substance and it will calculate out the rest of the values you would normally calculate: grams, mmol and/or mL. Scroll down, and the same basic properties are listed (MW, d, BP, etc), allowing you to fill in the rest of the needed values. Unfortunately, I cannot seem to have the CAS number included in the output. The other widget has your CAS number information.
The coolest addition to this widget is the ability to scale your amount by, oh... say, the number of equivalents you're using. If you've calculated that you're using 2.37 mmol of your starting material, and you need to use 1.5 equivalents of the next reagent, you can type in 1.5 * 2.37, select mmol, type in the molecule, and it will calculate your values based on 3.555 mmol!
The widget is below. Again, feel free to embed it wherever you need it to be - blog, iGoogle, personal home page, wherever . Hover over the plus sign in the bottom right corner and click 'embed this widget.'
I'm unable to create desktop gadget versions of this one. It seems the problems mentioned with the previous desktop widgets are exacerbated when there's more than one input field. The submit functionality is totally broken. I've submitted a bug report and if it gets fixed, I'll post the desktop gadgets.
The Wolfram|Alpha "Reagent Table Widget"
by azmanam on Feb 05 2011 (25127 Views)Update: CAS Number added to output
Update 2: DESKTOP GADGETS are here! See awesome update below!
Update 3: Check out the companion widget which calculates out the rest of the values for your reagent table (g, mmol, mL)!
If you're like me, you don't remember chemicals' physical properties off the top of your head. You're ready to run a reaction, and it's time to fill out your reagent table. This usually means pulling out your calculator or the Aldrich catalog. Sure you can look it up online, but you always wonder if someone had some fun with a Wikipedia page - would you second guess if someone changed one of the digits in a Wikipedia entry? Maybe you used that chemical a few pages back... or was it in the last notebook?
I've really grown to like Wolfram|Alpha. I like the interface and the way they present the data. So I created a small Wolfram|Alpha widgit specifically for filling in reagent tables. Type in the chemical name, and it returns the molecular formula and structure (just to verify you entered the right compound), and tells you the molecular mass, density, boiling point (if you need to distill that liquid first), and a few other physical properties - everything you need to fill in your reagent table. It also recognizes chemical formulas, like TiCl4, and shorthand notation, like EtOH.
So be sure you bookmark this page and use this widgit next time you're ready to run a reaction and can't quite remember the density of that liquid.
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Update 2: A few people, both in the comments and by email, asked if I could make a desktop gadget for the reagent table widget. Ask and you shall receive! Read about their development here.
NOTE: they're not perfect and have some annoying bugs. The PCSmall version opens the results in a new internet explorer window, but works fine otherwise. The PCLarge version remains on the desktop with a flyout for the results, more like a 'real' gadget... but for whatever reason, the X button doesn't work and you can't make the flyout go away, so it stays large with your results open. Also, you must hit the enter button, the Submit button is not clickable. The Mac version's X button works fine, but has scroll bars for the resulting flyout, and you can't click and drag the scroll bars to see results. You must click in the results flyout and use the arrow keys to navigate.
Bad news: they have annoying aesthetic problems. Good news: they work, and you have the reagent table widget on your desktop for your reagent table needs at any time.
Download the Mac version here
Download the PC(Large) version here
Download the PC(Small) version here
Installation instructions: download them and open them. The computer takes care of the rest!
Kudos to the Fagnou Group
by Crystallinity on Jan 21 2011 (9291 Views)I am continuously impressed by the publications that have appeared since Prof. Keith Fagnou's shocking passing a little over a year ago. The chemical community still mourns; it is clear from these post-mortem publications that Fagnou's - and his clearly dedicated and talented graduate students and post-docs - brilliance lives on. (Note - this is the same article that appears on Chemical Crystallinity.)
The chemistry that Fagnou has truly spearheaded, direct C-H functionalization, is a method of forming C-C, C-N, C-B, etc bonds without having to prepare one of the coupling partners, as in traditional transition-metal catalyzed cross-coupling reactions. Palladium, rhodium and ruthenium are commonly used catalysts in direct C-H functionalization reactions. Fagnou has published a great deal on arylation reactions of a wide variety of substrates and even a bit on direct benzylation reactions. Some fairly recent reviews are linked in a previous post at my own blog.
A recent publication in Journal of Organic Chemistry (doi: 10.1021/jo102081a), "Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis," published by David Lapointe and coworkers, explores the development of two approaches to selectively functionalizing multi-ring systems - 1) using site-selective reaction conditions, and 2) a pathway with a particular order of reactivity according to a concerted metalation-deprotonation (CMD) mechanism. It is well-known in the field that a great many (hetero)arenes can be functionalized with (painfully) rigorous fine-tuning of the catalyst, ligand, additives, and other reaction conditions. Some substrates have been more difficult to functionalize than others, and selectivity of particular positions on these rings is always an issue - this publication tackles both issues.
To explore site-selective functionalization, the group used compounds with more than one available C-H bond for direct functionalization, and using multiple protocols specific for specific C-H bonds (Larossa's conditions for C2 arylation of indoles, Gaunt's Cu-catalyzed C3 arylation of indoles which is actually selective for meta to amido groups, and their own protocols for arylation of perfluorobenzenes and aromatic N-oxides) were able to successfully and selectively functionalize targeted C-H bonds in moderate yields. Here is an example with some decent yields, with reaction times ranging from 16 - 24 hours:
The alternative approach relies upon the CMD pathway as the operative mechanism, which favors electron-deficient substrates. Several years ago, Echavarren published support of this mechanism by finding a preference for the most acidic C-H bond and requirement for a carbonate base, and Fagnou established the use of a pivalate additive, which was speculated to play a crucial role via CMD. A recent mechanistic paper with aromatic N-oxides as the substrates strongly supports this mechanism. The metal first inserts into the aryl-X bond, as expected, and in the key transition state, the pivalate coordinated to the metal deprotonates the C-H bond while the palladium forms a bond to the same C. Reductive elimination (not shown) releases the arylated product.
In the current paper DFT calculations were found to agree quite well compared to competition reaction results of a series of heterocycles to elucidate the order of reactivity of the substrates. Those presented in the paper are as follows, in order of reactivity - this is extremely convenient for the synthetic chemist who would like to utilize this chemistry. And it's just plain neat - the kind of thing that will hopefully end up in a textbook someday. (Note: the last two substrates are either switched in the text or switched in the image - they don't agree in the paper and I haven't looked at the supporting information closely.)
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| Reaction conditions: 0.5 eq. of each of two heteroarenes in the competition experiment, 0.125 eq. 4-bromotrifluorobenzene, Pd(OAc)2 5 mol%, PCy3.HBF4 (10 mol%), PivOH (30 mol%), K2CO3 (1.5 eq.), DMA (0.3M), 100ºC. |
And finally, for an example of the method in action - note that the difference between using this method and the previously described is that here, there aren't necessarily general optimized conditions available for each of the substrate classes here. Examples of a few of these are peppered throughout the arylation literature but they aren't like indoles, pyridines, N-oxides, perfluorobenzenes, imidazoles, and pyrazoles and don't have their own special set of conditions (that I'm aware of at the moment). Yields of included substrates range from 65-80%. Instead of optimizing conditions for each, the site of reactivity can be predicted with good specificity - here the indolizine C-H bond over the more electron-rich thiophene's:
Instead of an aryl bromide, benzyl chloride can be used as the coupling partner as well, with published yields from 55-84%.
- Lapointe, D., Markiewicz, T., Whipp, C. J., Toderian, A., Fagnou, K. (2011). Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis Journal of Organic Chemistry : 10.1021/jo102081a
